Benzoamide piperidine containing compounds and related compounds

专利摘要:
The present invention relates to certain benzoamidopiperidine containing compounds and related compounds that exhibit activity as NK-1 receptor antagonists (e. G., Steroid P receptor antagonists), pharmaceutical compositions containing them, and methods of treatment of central nervous system disorders, Ophthalmic diseases, gastrointestinal diseases, diseases caused by Helicobacter pylori, immune system diseases, urinary incontinence, pain, migraine, vomiting, angiogenesis and other diseases.
公开号:KR20020087134A
申请号:KR1020027013582
申请日:2001-04-06
公开日:2002-11-21
发明作者:에릭 플랫 아놀드；토마스 알렌 채피；지안후아 휴앙；존 마이클 험프리；아써 아담 나겔；브라이언 토마스 오네일；수잔 베쓰 소볼로프-제이네스；로렌스 앨버트 빈센트
申请人:화이자 프로덕츠 인크.；
IPC主号:

专利说明:

BENZOAMIDE PIPERIDINE CONTAINING COMPOUNDS AND RELATED COMPOUNDS [0001]
[1] The present invention relates to certain benzoamidopiperidine containing compounds and related compounds which exhibit activity as NK-1 receptor antagonists (e. G., Substance P receptor antagonists), pharmaceutical compositions containing them and methods for treating central nervous system diseases, inflammatory diseases, And to their use in the treatment and prevention of cardiovascular diseases, ocular diseases, gastrointestinal diseases, diseases caused by helicobacter pylori , immune system diseases, urinary incontinence, pain, migraine, vomiting, angiogenesis and other diseases.
[2] Absorbance P is a natural one undecapeptide belonging to the tachykinin peptide family, and the tachykinin peptide family has been so named because of their rapid stimulating action on smooth muscle tissue. More specifically, Constance P is a pharmaceutical active neuropeptide produced in mammals (originally isolated from the digestive tract) and has the characteristic amino acid sequence as described in D. F. Veber et al., U.S. Patent No. 4,680,283. In the pathology of numerous diseases, extensive association of sterols P and other tachycinins has been well established in the art.
[3] For substituted benzolactams and cyclic thioamide compounds that exhibit activity as an inhibitory P receptor antagonist, see International Patent Application No. WO 97/03066 (published January 30, 1997) and US Patent Application No. 08/98004 (published in 1996 Filed on May 9). For other putrescent P receptor antagonists containing fused bicyclic residues, see U.S. Patent Application Serial No. 09 / 011,271, filed June 10, 1996; U.S. Provisional Application No. 60 / 132,858 (filed May 6, 1999); U.S. Patent Application Serial No. 09 / 402,630 (Oct. 26, 1998); And International Patent Application No. WO 99/13663 (published Jun. 23, 1994).
[4] These patent applications are incorporated herein by reference in their entirety.
[5] SUMMARY OF THE INVENTION [
[6] The present invention relates to compounds of formula I and their pharmaceutically acceptable salts.
[7]
[8] In this formula,
[9] Q is _{C = NH, C = CH 2} , C = S, C = O, SO or SO _2, and;
[10] A is in the case of a _{CH, CH 2, C (C} 1 -C 6) alkyl, CH (C ₁ -C ₆₎ alkyl, C (CF ₃₎ or CH (CF _3), with the proviso, B exists, A must be a _{CH, C (C 1 -C 6} ) alkyl or C (CF _3), and;
[11] B is absent or methylene or ethylene;
[12] Y and Z are each N or CH, provided that Y and Z can not both be N;
[13] G is NH (CH ₂ ) _q , S (CH ₂ ) _q or O (CH ₂ ) _q, wherein q is 0 or 1;
[14] Provided that when q is 0, G is NH ₂ , SH or OH;
[15] W is a 1 carbon bridging group (i.e., methylene) or a saturated or unsaturated 2 or 3 carbon bridging group, wherein each W group is optionally substituted with 1 substituent R ⁷ or 2 substituents R ⁷ and R ⁶ Or W is a 1 carbon bridging group which together with the 2,3, 4 or 5 carbon chains forms a 3, 4, 5 or 6 membered spiro ring, respectively; or
[16] W is a saturated 2 carbon chain bridging group which forms a fused 3, 4 or 5 membered ring with separate 1,2 or 3 carbon chains; or
[17] W is a saturated 2 carbon chain bridging group in which one of the two carbons forms a 3, 4, 5 or 6 membered spiro ring with a separate 2,3 or 4 carbon chain, respectively;
[18] p is 0, 1 or 2;
[19] R ³ is selected from hydrogen, COR ⁹ , CO ₂ R ⁹ , optionally substituted phenyl, optionally substituted heterocyclic ring and optionally substituted (C ₁ -C ₈ ) alkyl, wherein said (C ₁ -C ₈₎ one of the alkyl CH ₂ lifter may be substituted with a sulfur, oxygen or a carbonyl group, the (C ₁ -C ₈₎ alkyl, hydroxy, oxo, phenyl, - (C ₁ -C ₃₎ alkoxy, phenyl, cyano NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ , CO ₂ R ⁹ , NR ⁹ R ¹⁰ , and 1 to 7 fluorine atoms, optionally substituted heterocyclic rings, NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , Optionally substituted with one to three substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
[20] R ³ in the heterocyclic ring, and 3- to 7-membered saturated or unsaturated monocyclic ring, and one to four ring heteroatoms which heterocyclic ring substituents on the alkyl groups of R ³ contain from 1 to 4 ring heteroatoms And wherein the heteroatom is independently selected from oxygen, nitrogen and sulfur, with the proviso that the monocyclic or bicyclic heterocyclic ring , There can not be two adjacent ring oxygen atoms or two adjacent ring sulfur atoms and the heterocyclic ring formed from NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ must contain at least one nitrogen atom;
[21] R ³ heterocyclic heterocyclic on the alkyl group of the cyclic ring, and R ³ of the ring substituent is ^{_{(CH 2) m NR 9 R}} 10, NR 9 COR 10, oxo, hydroxy, thioxo, halo, cyano, phenyl, ( CH ₂ ) _m OR ⁹ , wherein m is 0, 1 or 2, and optionally substituted with one or more substituents independently selected from halo, CF ₃ , methoxy and phenyl, preferably 0 to 2 substituents Optionally substituted with one or more substituents, preferably 0, 1 or 2, substituents independently selected from (C ₁ -C ₆ ) alkyl;
[22] Phenyl substituent on the alkyl group of R ³ groups and R ³ are optionally substituted with halo, cyano, _{nitro, CF 3, (CH 2)} m NR 9 R 10 ( at this time, m is 0, 1 or 2), NR ⁹ COR ^{10 _{, NR 9 CO 2 R 10,}} CONR 9 R 10, CO 2 NR 9 R 10, COR 9, CO 2 R 9, 1 to 7 fluorine atoms, preferably with 0-3 fluorine atoms an optionally substituted (C ₁ C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine the reactor is optionally substituted (C ₂ -C ₆₎ one or more substituents independently selected from alkenyl, preferably, may be optionally substituted with 0-2 substituents;
[23] Each R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ is hydrogen and at least one substituent independently selected from hydroxy, oxo, (C ₁ -C ₆ ) alkoxy and cyano, preferably 0, (C ₁ -C ₆ ) alkyl optionally substituted with one or two substituents; or
[24] R ¹ and R ² together with the carbon atoms to which they are attached or R ² and R ³ together with the carbon and nitrogen to which they are attached contain 5 or 5 heteroatoms independently selected from nitrogen, Or a six membered saturated heterocyclic ring with the proviso that the ring may not contain two adjacent oxygen atoms or two adjacent sulfur atoms; Or R ¹ and R ² form a 5 or 6 membered saturated or unsaturated carbocyclic ring together with the carbon to which they are attached, and at this time, the heterocyclic group formed from R ¹ and R ² or R ² and R ^3, and carbocyclic ring optionally substituted with halo, oxo, NR ⁹ R ^10, one to seven fluorine atoms, preferably from zero to three fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkyl, and one to seven fluorine atoms, Preferably one or more substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted by 0 to 3 fluorine atoms, preferably 0 or 1 substituent; or
[25] R ¹² and R ¹³ , together with the carbon atoms to which they are attached, form a 5 or 6 membered saturated heterocyclic ring containing one or two heteroatoms independently selected from nitrogen, oxygen and sulfur provided that the ring has 2 Or two adjacent sulfur atoms, or R ¹² and R ¹³ together with the carbon to which they are attached form a 5 or 6 membered saturated or unsaturated carbocyclic ring, wherein R ¹² and the heterocyclic group formed from the R ¹³ and the carbocyclic ring is NR ⁹ R ^10, halo, phenyl, -S-, -SO- phenyl, phenyl -SO ₂ -, oxo, one to seven fluorine atoms, preferably 0 to 3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ each of which is independently selected from alkyl One or more substituents, preferably 0, or it can be optionally substituted with 1 substituent;
[26] With the proviso that only one of R ¹ and R ² , R ² and R ³ , and R ¹² and R ¹³ may form a ring;
[27] R ⁴ is selected from phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, and pyrimidyl wherein R ⁴ is halo, 1-7 fluorine atoms, preferably 0 (C ₁ -C ₆ ) alkyl optionally substituted by one to three fluorine atoms, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 Optionally substituted with one or more substituents independently selected from fluorine atoms, preferably (C ₂ -C ₆ ) alkenyl optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
[28] R ⁵ and R ⁸ are hydrogen, -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl - (C ₁ -C ₂₎ alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) ₆₎ alkoxy, phenyl - (C ₁ -C ₃₎ alkoxy, phenyl, cyano, chloro, bromo, ^{iodo, NR 9 R 10, NR 9} COR 10, NR 9 CO 2 R 10, CONR 9 R 10, (C ₁ -C ₆ ) alkyl optionally substituted with one or more substituents independently selected from COR ⁹ and CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
[29] R ⁶ and R ⁷ is -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl- (C ₁ -C ₂ ) alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) (C ₁ -C ₃ ) alkoxy, phenyl, cyano, chloro, bromo, iodo, NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ And (C ₁ -C ₆ ) alkyl substituted with one or more substituents independently selected from CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
[30] Each R ⁹ and each R ¹⁰ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, phenyl and CF ₃ ; or
[31] When R ³ is NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ , R ⁹ and R ¹⁰ together with the nitrogen to which they are attached may form an optionally substituted heterocyclic ring containing at least one nitrogen atom;
[32] R ^5, R ^6, R ⁷ and R ⁸ in the definition of a phenyl group and R ^5, R ^6, the definition of R ⁷ and R ⁸ -phenyl (C ₁ -C ₂₎ alkyl in the phenyl moiety is optionally substituted by halo, hydroxy, 1 to the seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ - C ₆ ) alkyl, preferably with 0 to 2 substituents independently selected from alkyl;
[33] (A) R ⁸ is not methyl substituted with halo, hydroxy, cyano, aryloxy, heteroaryloxy, substituted or unsubstituted (C ₁ -C ₆ ) alkoxy, or with 1 to 3 fluorine atoms ; (b) methylene in which Q is C = O or C = S, Y and Z are both carbon and W is optionally substituted by (C ₁ -C ₆ ) alkyl or fluoro substituted (C ₁ -C ₆ ) , Ethylene or propylene group and R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ are both hydrogen and R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen, halo, optionally substituted with 1 to 7 fluorine atoms (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted by 1 to 7 fluorine atoms, R ³ can not be hydrogen.
[34] Examples of the optionally substituted heterocyclic ring when the substituent on R ^3, form a heterocyclic ring, and R ³ is a substituted alkyl group of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxo-dibenz isopropyl sulfonyl najol Thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolyl, furyl, pyridyl, isothiazolyl, oxazolyl , Triazolyl, tetrazolyl, quinolyl, thiazolyl and thienyl, and groups of the formula:
[35]
[36] Wherein B ² and D are selected from carbon, oxygen and nitrogen, and at least one of B ² and D is not carbon; E is carbon or nitrogen; q is an integer from 1 to 5; _One of the carbon atoms of (CH ₂ ) _q and (CH ₂ ) _{q + 1} may be optionally substituted with (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) spiroalkyl; A pair of carbon atoms of (CH ₂ ) _q and (CH ₂ ) _{q + 1} may be bridged by linkage to one or two carbon atom bridges, or the (CH ₂ ) _q and (CH ₂ ) _{q +} one pairs of adjacent carbon atoms of ₁ can form a cyclic ring (C ₃ -C ₅₎ fused see carboxylic carbonyl with 1 to 3 carbon atoms containing a non-member of the ring.
[37] The compounds of formula I may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of formula (I) as racemic mixtures and as individual enantiomers and diastereomers, and mixtures thereof, and to all pharmaceutical compositions and therapeutic methods as defined above which contain or use, respectively .
[38] As the compound of formula I of the present invention has two or more asymmetric centers, it can exist in various stereoisomeric forms or structures. That is, the compounds may exist in separate (+) - and (-) - optically active forms as well as mixtures thereof. The present invention includes all such forms within its scope. The individual isomers may be obtained by known methods such as optical resolution, optical selective reaction, or chromatographic separation in the final product or in the preparation of an intermediate thereof.
[39] When the compound of formula (I) of the present invention is a basic compound, all of them can form a wide variety of salts with various inorganic and organic acids. These salts should be pharmaceutically acceptable upon administration to the animal, but in practice, the base compound is firstly isolated as a pharmaceutically unacceptable salt from the reaction mixture and then converted to the free base compound by treatment with an alkylating reagent, followed by the free base Is converted to a pharmaceutically acceptable acid addition salt. The acid addition salt of the base compound of the present invention is easily prepared by treating the base compound with an approximately the same amount of a mineral acid or an organic acid in an aqueous solvent or a suitable organic solvent such as methanol or ethanol. After carefully evaporating the solvent, the desired solids salt is readily obtained. The acid used to prepare the pharmaceutically acceptable acid addition salts of the above base compounds of the present invention is a non-toxic acid addition salt, i.e., a salt containing a pharmaceutically acceptable anion such as a hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate Or salts of organic acids such as hydrochlorides, hydrobromides, hydroiodides, or organic acids such as hydrochlorides, hydrobromides, phosphates or phosphates or phosphates or phosphates, acetates, lactates, citrates or citrates, tartrates or tartrates, succinates, maleates, fumarates, , An acid which forms a methanesulfonate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate and a palmomate (ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) .
[40] The individual enantiomers of the compounds of formula I may be advantageous in the treatment of various diseases or conditions as compared to racemic mixtures of these compounds. For example, compounds prepared from 2S-phenyl-piperidin-3S-ylamino templates are preferred.
[41] The present invention also includes isotopically labeled compounds, which are the same as those recited in formula I, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be introduced into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as isotopes of ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing isotopes of said isotopes and / or other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C have been introduced, are useful in drug and / or substrate tissue distribution assays. Tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detection. In addition, heavier isotopes such as double hydrogen (i.e., ² H) may provide certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life or reduced dosage requirements, can do. Isotopically labeled compounds of formula (I) or prodrugs thereof of the present invention can be prepared by reacting an isotopically labeled reagent with an isotopically labeled reagent which is readily available in the following reaction scheme and / Can be prepared by performing the disclosed procedures.
[42] The term " alkyl ", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic residues or combinations thereof. Examples of " alkyl " groups include methyl, ethyl, propyl, isopropyl, butyl, iso-sec- and tert- butyl, pentyl, hexyl, heptyl, 3- ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, Cycloheptyl, norbornyl, and the like, but are not limited thereto.
[43] The term " alkoxy ", as used herein, unless otherwise stated, means " alkyl-O- ", where " alkyl " Examples of " alkoxy " groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.
[44] The term " alkenyl ", as used herein, unless otherwise indicated, includes unsaturated hydrocarbon radicals having one or two double bonds connecting two carbon atoms, wherein the hydrocarbon radicals are straight, branched or cyclic And combinations of these. Examples of " alkenyl " groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and dimethyl pentyl, including E and Z forms where possible.
[45] By the term "aryl" as used herein, unless otherwise stated, haloalkyl, one to three fluorine atoms, optionally substituted (C ₁ -C ₄₎ alkyl, and from one to three fluorine atoms, optionally substituted (C ₁ -C ₄ ) Alkoxy, which may be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, halogen, cyano, nitro, cyano, nitro, cyano,
[46] The term " aryloxy ", as used herein, unless otherwise indicated, means " aryl-O- ", wherein " aryl "
[47] The term " heteroaryl ", as used herein, unless otherwise indicated, includes 5 or 6 ring members, of which 1 to 4 may be heteroatoms independently selected from N, S and O, (C ₁ -C ₄ ) alkyl optionally substituted with one to three fluorine atoms and (C ₁ -C ₄ ) alkoxy optionally substituted with one to three fluorine atoms, or an aromatic heterocycle optionally monosubstituted or disubstituted or optionally substituted with .
[48] The term " heteroaryloxy ", as used herein, unless otherwise indicated, means " heteroaryl-O ", wherein the heteroaryl is as defined above.
[49] The term " one or more substituents ", as used herein, unless otherwise indicated, refers to the number of substituents that are up to the maximum number of possible substituents based on the number of sites that can be joined from one.
[50] The terms " halo " and " halogen ", as used herein, unless otherwise indicated, include fluoro, chloro, bromo and iodo.
[51] As used herein, the term " treating " refers to preventing or reversing, alleviating, inhibiting, or preventing one or more symptoms of the disease or condition to which the term applies. The term " treatment " as used herein refers to the action of treating, as previously defined for " treating ".
[52] The term "methylene" as used herein is -CH ₂ -; means.
[53] The term " ethylene " as used herein means -CH ₂ CH ₂ -.
[54] As used herein, the term "propylene" refers to -CH ₂ CH ₂ CH ₂ -.
[55] A more specific embodiment of the present invention includes compounds of formula I wherein B is absent and A is CH ₂ .
[56] Other more specific embodiments of the present invention include compounds of formula I wherein Q is a carbonyl group.
[57] Other more specific embodiments of the present invention include compounds of formula I wherein Y and Z are both CH.
[58] A specific embodiment B is an ethylene than another of the present invention, wherein A is CH, and G is NHCH ₂ include compounds of formula I.
[59] Other more specific embodiments of the present invention include those compounds of formula I wherein B is ethylene, A is CH and G is SCH ₂ .
[60] Other more specific embodiments of the present invention include those compounds of formula I wherein R < ³ > is hydrogen.
[61] A specific embodiment B is an ethylene than another of the present invention, wherein A is CH, and G is NHCH ₂ include compounds of formula I.
[62] Specific embodiments other than of this invention include the compounds of formula I R ³ is CO ₂ R ^9.
[63] Other more specific embodiments of the present invention include compounds of formula I wherein B is absent, G is NH and A is CH ₂ .
[64] Other more specific embodiments of the present invention include compounds of formula I wherein W is ethylene.
[65] Other more specific embodiments of the present invention include those compounds of formula I wherein R < ⁴ > is phenyl.
[66] Other more specific embodiments of the present invention include those compounds of formula I wherein R < ⁴ > is phenyl and R < ⁸ > is hydrogen.
[67] Other more specific embodiments of the present invention include those compounds of formula I wherein R < ⁴ > is phenyl and R < ⁸ > is methyl.
[68] Other more specific embodiments of the present invention include compounds of formula I wherein p is 1.
[69] Specific embodiments other than of this invention include the compounds of formula I R ² is (C ₁ -C ₆₎ alkyl.
[70] Other more specific embodiments of the present invention include compounds of formula I wherein R ² is (C ₁ -C ₆ ) alkyl, wherein the stereochemistry of the chiral carbon to which R ² is attached is "S".
[71] Other more specific embodiments of the present invention include compounds of formula I wherein R < ⁴ > is 2-, 3- or 4-pyridyl.
[72] Other more specific embodiments of the present invention include compounds of formula I wherein R ² and R ¹² are independently selected from hydrogen, methyl, ethyl and propyl.
[73] Other more specific embodiments of the present invention include compounds of formula I wherein R < ² > and R < ¹² > are not both hydrogen.
[74] Other more specific embodiments of the present invention include compounds of formula I wherein Y is CH.
[75] Other more specific embodiments of the present invention include those compounds of formula I wherein Y is CH and Z is CH.
[76] Other more specific embodiments of the present invention include compounds of formula I wherein Y is CH and Z is nitrogen.
[77] Other more specific embodiments of the present invention include those compounds of formula I wherein Q is C = O and W is methylene optionally substituted with one or two substituents independently selected from (C ₁ -C ₆ ) alkyl and CF ₃ do.
[78] Other more specific embodiments of the present invention include compounds of formula I wherein Q is C = O and W is ethylene optionally substituted with one or two substituents independently selected from (C ₁ -C ₆ ) alkyl and CF ₃ do.
[79] Other more specific embodiments of the present invention include compounds of formula I wherein Q is SO.
[80] Other more specific embodiments of the present invention include compounds of formula I wherein Q is SO ₂ .
[81] Other more specific embodiments of the present invention include compounds of formula I wherein Y is nitrogen and Z is CH.
[82] Other more specific embodiments of the present invention include compounds of formula I wherein Q is C = S.
[83] Other more specific embodiments of the present invention include compounds of formula I wherein R < ⁸ > is hydrogen.
[84] Other more specific embodiments of the present invention include those compounds of formula I wherein R < ⁸ > is methyl.
[85] Other more specific embodiments of the present invention include compounds of formula I wherein R < ³ > is a heterocyclic ring.
[86] Other more specific embodiments of the present invention include compounds of formula I wherein R < ³ > is an alkyl group substituted with a heterocyclic ring.
[87] Other more specific embodiments of the present invention are compounds of formula I, wherein R < ³ > is selected from the group consisting of imidazolyl, 5-oxo-4,5-dihydro-1H- [1,2,4] triazol- And 5-oxo-pyrrolidin-2-yl. ≪ / RTI >
[88] Other more specific embodiments of the present invention include compounds of formula I wherein R < ⁸ > is a cycloalkyl group.
[89] Other more specific embodiments of the present invention include compounds of formula I wherein R < ⁸ > is a cyclopropyl group.
[90] Preferred compounds of the invention are those of formula I wherein R < ⁴ > is optionally substituted pyridyl.
[91] Another preferred compound of the invention is a compound of formula I wherein R ² and R ¹² are selected from (C ₁ -C ₃ ) alkyl.
[92] Examples of preferred compounds of the invention are the following compounds selected from isomers and mixtures of isomers of the following compounds having stereochemistry of the structure < RTI ID = 0.0 > (I) < / RTI &
[93] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one ;
[94] 3-ylamino] -methyl} -3,4-dihydro-1 H- (pyridin-2-yl-acetyl) -piperidin- -Quinolin-2-one;
[95] 3-ylamino] -methyl} -3,4-dihydro-1 H- (pyridin-3-yl-acetyl) -piperidin- -Quinolin-2-one;
[96] 3-ylamino] -methyl} -3,4-dihydro-1 H- (4-fluoro-phenyl) -Quinolin-2-one;
[97] 6-Cyclopropoxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[98] (5-Chloro-2-methoxy-benzyl) - (2-phenyl-octahydro-cyclopenta [b] pyrrol-3-yl) -amine;
[99] 3-ylamino) -methyl] -3, 6-dimethoxy-l- 4-dihydro-1H-quinolin-2-one;
[100] Methyl-6-methoxy-1-methyl-3, 4-dihydro- LH-quinolin-2-one;
[101] 1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyridin-2-yl-ethanone;
[102] 1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyridin-3-yl-ethanone;
[103] 1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyridin-4-yl-ethanone;
[104] 2-Imidazol-1-yl-1- [3- (2-methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-l-yl] -ethanone;
[105] 2-Dimethylamino-l- [3- (2-methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-l-yl] -ethanone;
[106] 3- (2-Benzyloxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane;
[107] 1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyrrolidin-1-yl-ethanone;
[108] (2-methoxy-5-trifluoromethoxy-benzyl) - (1- [1,2,4] oxadiazol-3-ylmethyl-2-phenyl-piperidin-3-yl) -amine;
[109] Methyl} -6-methoxy-l-methyl-3,4-dihydro-lH-quinolin-2- On;
[110] [1- (2-Imidazol-1-yl-ethyl) -2-phenyl-piperidin-3-yl] - (2-methoxy-5-trifluoromethoxy-benzyl) -amine;
[111] Methyl] -6-methoxy-1-methyl-3, 4-dihydro-lH- Quinolin-2-one;
[112] (5-Chloro-2-ethoxy-pyridin-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[113] (5-Chloro-2-methoxy-pyridin-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[114] Dibenzofuran-2-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
[115] [3- (Indan-2-yloxy) -4-methoxy-benzyl] - (2-phenyl-piperidin-3-yl) -amine;
[116] 6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -chroman-4-one;
[117] (5-Methyl-benzo [b] thiophen-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[118] (2,2-dimethyl-chroman-6-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[119] (LH-benzoimidazol-5-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[120] 1- {2 - [(2-Phenyl-piperidin-3-ylamino) -methyl] -phenyl} -pyrrolidin-2-one;
[121] (2-Phenyl-piperidin-3-yl) - [3- (pyridin-2-yloxy) -benzyl] -amine;
[122] [3- (4-Methoxy-phenoxy) -benzyl] - (2-phenyl-piperidin-3-yl) -amine;
[123] (4-phenoxy-benzyl) - (2-phenyl-piperidin-3-yl) -amine;
[124] (2-phenyl-piperidin-3-yl) -thiophen-2-ylmethyl-amine;
[125] Furan-2-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
[126] (5-methyl-furan-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[127] (3-methyl-thiophen-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[128] (2-phenyl-piperidin-3-yl) -thiophen-3-ylmethyl-amine;
[129] (3-Methyl-benzo [b] thiophen-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[130] Benzofuran-2-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
[131] (5-ethyl-furan-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[132] (5-Chloro-3-methyl-l-phenyl-lH-pyrazol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[133] 3-ylamino] -methyl} -l-methyl-3, 4-dihydro-lH- Quinolin-2-one;
[134] (5-Methyl-3-phenyl-isoxazol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[135] (3-phenoxy-benzyl) - (2-phenyl-piperidin-3-yl) -amine;
[136] Furan-3-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
[137] (3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[138] (5,7-dimethoxy-lH-indol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[139] (5-methoxy-lH-indol-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[140] (4-oxy-quinoxalin-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
[141] (2-phenyl-piperidin-3-yl) -quinoxalin-2-ylmethyl-amine;
[142] Propyl) -2-phenyl-piperidin-3-ylamino] -methyl} -6-methoxy-1-methyl-3,4-dihydro -1H-quinolin-2-one;
[143] (2-methoxy-5-trifluoromethoxy-benzyl) - [2-phenyl-l- (2-pyrrolidin-l-yl-ethyl) -piperidin-3-yl] -amine;
[144] 6-Ethoxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[145] [1- (2-Dimethylamino-ethyl) -2-phenyl-piperidin-3-yl] - (2-methoxy-5-trifluoromethoxy-benzyl) -amine;
[146] 3- (2-Cyclopropoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane;
[147] [1- (2-Methoxy-ethyl) -2-phenyl-piperidin-3-yl] - (2-methoxy-5-trifluoromethoxy-benzyl) -amine;
[148] 6-Hydroxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[149] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -3,4-dihydro-1 H-quinolin-2-one To a solution of 6-methoxy- ;
[150] 7 - {[2- (4-Fluoro-phenyl) -piperidin-3-ylamino] -methyl} -6-methoxy-3,4-dihydro-1H-quinolin-2-one;
[151] 6-Methoxy-1-methyl-7- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;
[152] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -1,3-dihydro-indol-2-one To a solution of 6-methoxy-1,3,3-trimethyl- -On;
[153] [3-Chloro-2- (4-fluoro-phenoxy) -pyridin-4-ylmethyl] - (2-phenyl-piperidin-3-yl) -amine;
[154] 6-Ethoxy-1,3,3-trimethyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[155] Methyl-l, 3-dihydro-indol-2 < RTI ID = -On;
[156] 6-Isopropoxy-l, 3,3-trimethyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[157] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -l, 3-dihydro-indol- 2-one;
[158] Methyl-l, 3-dihydro-indol-2 < RTI ID = -On;
[159] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -l, 3-dihydro-indol- 2-one;
[160] 7-Isopropoxy-l-methyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[161] 6-Methoxy-1-methyl-7 - [(6-methyl-2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[162] 6-Methoxy-1,3,3-trimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[163] 6-Methoxy-1,3-dimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[164] 6-Methoxy-1,3-dimethyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[165] 6-Methoxy-1-methyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[166] Methyl-6-methoxy-l, 3,3-trimethyl-l, 3-dihydro-indol-2- On;
[167] 6-Methoxy-1-methyl-7 - [(2-phenyl-1-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[168] 3-ylamino] -methyl} - 3 - {[1- (5-methyl-3H-imidazol- 4-dihydro-1H-quinolin-2-one;
[169] 3-ylamino] -methyl} -6-methoxy-1-methyl-3, 4-dihydro- < / RTI >-1H-quinolin-2-one;
[170] 7 - [(l-isopropyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-l-methyl-3,4-dihydro-lH-quinolin-2-one;
[171] Methyl-3, 4-dihydro-1 H-quinolin-2-one < / RTI >;
[172] Methyl-6-methoxy-l, 3,3-trimethyl-l, 3-dihydro-indol-2- On;
[173] Methyl-7 - {[1- (5-oxo-2,5-dihydro-1H- [1,2,4] triazol- Pyridin-3-ylamino] -methyl} -3,4-dihydro-1H-quinolin-2-one;
[174] 6-Methoxy-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[175] 1-Ethyl-6-methoxy-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[176] 1-Methanesulfonyl-6-methoxy-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[177] 6-Methoxy-1,4,4-trimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl) -3,4-dihydro-1H-quinolin-2-one;
[178] 6-methoxy-1,4,4-trimethyl-7 - [(2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro- 2-one;
[179] 6-Methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[180] 6-Methoxy-1,4-dimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[181] 6-Methoxy-2-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-2H-isoquinolin-1-one;
[182] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a ] Naphthalen-2-one;
[183] 6-Methoxy-1-methyl-3,3-cyclopropyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[184] 5-Methoxy-1-methyl-3,3-cyclopropyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[185] 6-Methoxy-l-methyl- (6-phenyl-l, 7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-lH-quinolin-2-one;
[186] 6-Methoxy-1-methyl-7-phenyl-1,7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;
[187] 3-methyl-5 - [(1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) -methyl] -1,1a, 3,7b-tetrahydro- 3-aza-cyclopropa [a] naphthalen-2-one;
[188] Methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thiobenzo [c] [1,2] thiazin- (2-phenyl-piperidin-3-yl) -amine;
[189] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
[190] 6-Methoxy-1-methyl-7- (6-phenyl-1, 7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;
[191] 2,3-b] pyridin-2-ylmethyl] -1,3-dihydro-pyrrolo [2,3- b] Pyridin-2-one;
[192] 3-dihydro-pyrrolo [3,2-b] pyridin-2-ylmethyl] Pyridin-2-one;
[193] Methyl-7- [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridin- ;
[194] 7 - [(6-Ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
[195] Methyl-6-methoxy-l, 3,3-trimethyl-l, 3-dihydro-indol-2-one ;
[196] 2,3-b] pyridin-2-ylmethyl] -1,3-dihydro-pyrrolo [2,3- b] Pyridin-2-one;
[197] 3-dihydro-pyrrolo [3,2-b] pyridin-2-ylmethyl] Pyridin-2-one;
[198] Methyl-7- [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridin- ;
[199] Methyl-7 - [(6-methyl-2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridine Gt;
[200] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H- [1,5] naphthyridine Gt;
[201] Methyl-7- [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridine Gt;
[202] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one; And
[203] 6-Methoxy-1-methyl-7- (6-phenyl-1, 7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one.
[204] Other examples of preferred compounds of the present invention are those compounds of formula < RTI ID = 0.0 > (I) < / RTI &
[205] Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one;
[206] (1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[207] (1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[208] (1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[209] (1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[210] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
[211] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[212] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[213] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[214] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[215] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one;
[216] 6-Methoxy-1-methyl-7 - [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[217] 7 - [(6-Ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
[218] 6-Methoxy-1-methyl-7 - [(6-methyl-2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[219] 3-ylamino) -methyl] -6-methoxy-1-methyl-3, 4-dihydro-isoquinolin- LH-quinolin-2-one;
[220] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one ;
[221] 3-ylamino) -methyl] -6-methoxy-1-methyl-3, 4-dihydro-isoquinolin- LH- [1,5] naphthyridin-2-one;
[222] Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one;
[223] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
[224] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one;
[225] ^{(6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2. 6-benzo} [c] [1,2] thiazine-7-ylmethyl) - ( 2-phenyl-piperidin-3-yl) -amine;
[226] Methyl-1,3-dihydro-indol-2-one < RTI ID = 0.0 >;
[227] Methyl-3,3-spirocyclopropyl-6 - [(2-phenyl-piperidin-3- ylamino) -methyl] -1,3-dihydro-indol- ;
[228] 5-Methoxy-1-methyl-3,3-cyclobutyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[229] 6-Methoxy-1-methyl-3,3-cyclopentyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[230] 6-Methoxy-1-methyl-3,3-cyclohexyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[231] (1S, 2S, 5R) - (1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) - Methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[232] (1R, 1S, 5S) - (1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) - Methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[233] (2-methoxy-5-trifluoromethoxy-benzyl) - ((lS, 2S, 5R) -1-phenyl-8-azabicyclo [3.2.1] oct-2-yl) -amine;
[234] (2-methoxy-5-trifluoromethoxy-benzyl) - ((1R, 2R, 5S) -1-phenyl-8-azabicyclo [3.2.1] oct-2-yl) -amine;
[235] (1S, 2S, 5R) - (1-phenyl-8-azabicyclo [3.2.1] oct- 2- yl) -amine) -Methyl] -l, 3-dihydro-indol-2-one; And
[236] ^{(6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2. 6-benzo} [c] [1,2] thiazine-7-ylmethyl) - ( 2-phenyl-piperidin-3-yl) -amine.
[237] Other examples of preferred compounds of the invention are the following compounds:
[238] Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one monohydrochloride;
[239] (1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[240] (1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[241] (1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[242] (1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[243] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one monohydrochloride;
[244] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[245] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[246] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[247] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
[248] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one monohydrochloride;
[249] Methyl-7 - [(2-phenyl-6-propyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- Chloride;
[250] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one monohydro- Chloride;
[251] Methyl-7 - [(6-methyl-2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- Chloride;
[252] Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one monohydrochloride;
[253] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one monohydrochloride; And
[254] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one monohydrochloride.
[255] Other examples of preferred compounds of the invention are the following compounds:
[256] Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one mono- (D) -lactate;
[257] (1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[258] (1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[259] (1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[260] (1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[261] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one mono- (D) -lactate;
[262] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[263] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[264] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[265] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
[266] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one mono- (D) -lactate;
[267] Methyl-7-isopropyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin- (D) -lactate;
[268] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2- (D) -lactate;
[269] 6-Methoxy-l-methyl-7 - [(6-methyl-2-phenyl-piperidin- (D) -lactate;
[270] Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one mono- (D) -lactate;
[271] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one mono- (D) -lactate; And
[272] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one mono- (D) -lactate.
[273] Other examples of preferred compounds of the invention are the following compounds:
[274] Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalene-2-one mono- (L) -lactate;
[275] (1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[276] (1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[277] (1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[278] (1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[279] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalene-2-one mono- (L) -lactate;
[280] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[281] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3R, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[282] (1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[283] (1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
[284] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalene-2-one mono- (L) -lactate;
[285] Methyl-7-isopropyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin- (L) -lactate;
[286] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2- (L) -lactate;
[287] 6-Methoxy-l-methyl-7 - [(6-methyl-2-phenyl-piperidin- (L) -lactate;
[288] Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalene-2-one mono- (L) -lactate;
[289] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalene-2-one mono- (L) -lactate; And
[290] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalene-2-one mono- (L) -lactate.
[291] Other examples of preferred compounds of the invention are the following compounds and their pharmaceutically acceptable salts:
[292] 6-Methoxy-1-methyl-7 - [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[293] 7 - [(6-isopropyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
[294] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one ;
[295] 7 - [(6-isobutyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
[296] 7 - [(1,2,3,4,5,6-hexahydro- [2,3 '] bipyridinyl-3-ylamino) -methyl] -6-methoxy- - dihydro-1H-quinolin-2-one;
[297] 7 - [(1,2,3,4,5,6-hexahydro- [2,4 '] bipyridinyl-3-ylamino) -methyl] -6-methoxy- - dihydro-1H-quinolin-2-one;
[298] (6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thiobenzo [c] [1,2] thiazin- 2-phenyl-piperidin-3-yl) -amine;
[299] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
[300] Methyl-3,3-cyclopropyl-5 - [(6-methyl-2-phenyl-piperidin- 2-one;
[301] Aza-bicyclo [3.2.1] oct-2-ylamino) -methyl] -1,3-dimethyl-3,3-cyclopropyl- Dihydro-indol-2-one;
[302] 6-Methoxy-1-methyl-3,3-cyclohexane-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[303] 6-Methoxy-1-methyl-3,3-cyclopentyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[304] Methyl-3,3-cyclopropyl-5 - [(2- (4- fluorophenyl) -piperidin-3- ylamino) -methyl] -1,3-dihydro -Indol-2-one;
[305] 6-Methoxy-1-methyl-3,3-cyclobutyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[306] 5-Methoxy-1-methyl-3,3-cyclobutyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
[307] Methyl-3,3-cyclopropyl-6 - [(6-methyl-2-phenyl-piperidin- 2-one;
[308] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclopropane < / RTI > [a] naphthalen-2-one;
[309] 7 - [(1,2,3,4,5,6-hexahydro- [2,2 '] bipyridinyl-3-ylamino) -methyl] -6-methoxy- - dihydro-1H-quinolin-2-one; And
[310] 6 - [(6-Ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -5-methoxy-1,1-dimethyl- indan-2-one.
[311] The compounds of formula I of the present invention have valuable pharmaceutical and medical properties. The compounds of formula I of the present invention exhibit a significant inhibitory P receptor binding activity and are therefore useful in the treatment of a wide range of clinical symptoms characterized by the presence of excessive tachykinin activity, particularly the inhibitory P activity. Thus, for example, excessive tachykinin activity, particularly inhibitory P activity, is associated with a variety of central nervous system diseases. Such diseases include, but are not limited to, those listed in the paragraphs below.
[312] The invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a mood disorder such as depression and more particularly a depressive disorder, (Including anorexia, weight loss, insomnia, premature ejaculation and psychomotor retardation), atypical depression (or reactive depression) (increased appetite, anorexia nervosa, Hypersomnia, psychomotor retardation or irritability, seasonal affective disorder, and pediatric depression); Or bipolar disorder or bipolar disorder, for example Type I bipolar disorder, Type II bipolar disorder and cyclic mood disorder; Impaired conduct and disruptive behavior; Anxiety disorders such as panic disorder with or without plaque panic, plaque without panic disorder history, specific phobia such as certain animal phobia, social anxiety, social phobia, compulsive personality disorder, stress disorder (posttraumatic stress disorder and acute stress Disorders), and generalized anxiety disorder; Borderline personality disorder; Schizophrenia and other psychotic disorders such as schizophreniform disorders, schizoaffective affective disorders, delusional disorders, short term psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic anxiety episodes, psychotic disorders Anxiety, psychotic mood disorders such as severe major depressive disorder; Mood disorders associated with psychotic disorders, such as depression associated with acute mania and bipolar disorder, mood disorders associated with schizophrenia; Mental retardation related behavioral disorders, autism disorders, and behavioral disorders.
[313] The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of delerium, dementia, Degenerative disorders such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's dementia, memory disorders, vascular dementia and other dementias such as HIV disease, head trauma, Parkinson's disease, Huntington's disease , Peak disease, dementia due to Creutzfeldt-Jakob disease, or multiple causes of dementia; (Including familial paroxysmal ataxia, ankylosing spondylitis, Tourette's syndrome, Scott's syndrome, PALSYS, and anorexic-spasticity syndrome); Such as neuroleptic-induced parkinsonism, neuroinflammatory syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute insufficiency, neuroleptic-induced delayed-movement disorder, and drug-induced disorders Satellite advance; The use of alcohol, amphetamine (or amphetamine-like substance), caffeine, hemp, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioid agents, phenylglycidine derivatives, sedatives, Diseases (drug related illnesses include dependency and abuse, addiction, withdrawal, addictive delerium and pessimistic delerium); Addictive behavior, such as gambling; epilepsy; Down syndrome; Acute pain, chronic pain and migraine; Dehydrating diseases such as multiple sclerosis (MS) and amylolateral sclerosis (ALS), peripheral neuropathy such as diabetic and chemotherapy-induced neuropathy and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia , And cerebrovascular diseases due to acute or chronic cerebrovascular injury, such as cerebral infarction, subarachnoid hemorrhage, or cerebral angioedema.
[314] Examples of types of pain that can be treated with the compounds of formula I and their pharmaceutically acceptable salts of the invention include soft tissue and peripheral injuries such as pain due to acute trauma, osteoarthritis and rheumatoid arthritis related pain, musculoskeletal pain, ache; Spinal pain, tooth pain, myofascial pain syndrome, vulvectomy pain, and burn-induced pain; Deep vein and visceral pain such as heart pain, muscular pain, aches and pains, for example toothache, abdominal pain, gynecological disorders such as dysmenorrhea, labor and endometriosis related pain; Related neuropathic pain, such as peripheral neuropathic pain, such as nerve entrapment and brachial plexus excision, amputation, peripheral neuropathy, painful teak, atypical facial pain, neuromuscular pain, trigeminal neuralgia, Neuropathic pain associated with cancer, diabetic neuropathic pain, and diarrhea; Carcinoma-related neuropathy and non-neuropathic pain (often referred to as cancer pain); Pain due to central nervous system pain such as spinal cord or brainstem damage; Lower back pain; Sciatica; Ventilators, headache (including migraine and other vascular headaches, acute or chronic tension headaches, cluster headache), temporomandibular pain and maxillary sinus pain; Ankylosing spondylitis and pain due to gout; Pain due to increased bladder contraction; Postoperative pain; Scar pain; And chronic neuropathic pain such as fibromyalgia, HIV, rheumatoid arthritis and osteoarthritis pain, trauma related pain such as joint pain and muscle pain, sprains, tension, and fracture; And post-surgical pain.
[315] The present invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a mammal, including a human, in the treatment of respiratory diseases, particularly respiratory diseases of the respiratory tract, such as chronic obstructive airways diseases , Bronchopneumonia, chronic bronchitis, cystic fibrosis, adult respiratory distress syndrome, and bronchospasm; Inflammatory diseases such as inflammatory bowel disease, psoriasis, Reiter's syndrome, Raynaud's syndrome, arthropathies, fibromyalgia, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, pruritus and sunburn; Human immunodeficiency virus (HIV) infection; Allergies such as eczema and rhinitis, and other allergies; Hypersensitivity diseases such as lacquer sensitization; Eye diseases such as conjunctivitis, spring conjunctivitis and the like; Cell proliferative ocular symptoms such as proliferative vitreoretinopathy; Skin diseases, such as contact dermatitis, atopic dermatitis, urticaria, and other eczema dermatitis.
[316] The present invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a mammal, including a human, in the manufacture of a medicament for treating a mammalian tumor, a gastric cancer cell, a gastric lymphoma, a ganglion blastoma and a small cell carcinoma, Neoplasms including lung cancer, and the like.
[317] The present invention also relates to a method of treating a gastrointestinal (GI) disease, including inflammatory gastrointestinal disease, such as Helicobacter pylori, in a mammal, including a human, comprising administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Inflammatory bowel disease, and gastrointestinal diseases such as gastritis, gastroduodenal ulcer, visceral neurological disorders associated with visceral, ulcerative colitis, Crohn's disease, irritable bowel syndrome and vomiting (postoperative nausea and postoperative nausea, and acute, ≪ / RTI > vomiting, and vomiting).
[318] The vomiting described above includes, but is not limited to, chemotherapy, radiation, toxin, viral or bacterial infection, pregnancy, vestibulopathy such as exercise, dizziness, dizziness and Meniere's disease, surgery, migraine, , Addiction to food or drinking, acidic stomach, heartburn or reflux, chest pain, such as vomiting induced by paroxysmal, nighttime or food induced chest pain, and indigestion.
[319] The present invention also relates to a method of treating a disorder or condition selected from the group consisting of: stress-related disorders, such as, in a mammal, including humans, comprising administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; Reflex sympathetic dystrophy, such as shoulder / hand syndrome; Immunological adverse reaction reactions such as transplant rejection and immune enhancement or inhibition related diseases such as systemic lupus erythematosus; Plasma leakage due to cytokine chemotherapy; Bladder dysfunctions such as cystitis, bladder detrusor overactivity, urinary tract inflammation and urinary incontinence (including equine urinary incontinence, overactive bladder, stress urinary incontinence and mixed urinary incontinence); Fibrosis and collagen diseases such as scleroderma and eosinophilic fasiolosis; Blood flow disorders due to vasodilation and vasoconstrictive diseases such as angina and Raynaud's disease; Angiogenesis; Cardiovascular disease; Dietary diseases such as anorexia nervosa and neurogenic bulimia; Attention deficit hyperactivity disorder; Chronic fatigue syndrome; Sexual dysfunction including premature ejaculation and male erectile dysfunction; Premenstrual syndrome and premenstrual dysphoric disorder; Fibromyalgia; And a method for treating a disease or condition selected from the group consisting of rheumatic diseases such as fibromyalgia.
[320] The compounds of formula I are also useful in the treatment of combinations of the above symptoms, in particular in combination with postoperative pain and postoperative nausea and nausea.
[321] The compounds of formula I are particularly useful in the treatment of vomiting, including acute, delayed or prophylactic vomiting, wherein the vomiting factors or conditions are selected from the group consisting of chemotherapy, radiation, toxins, pregnancy, vestibular disorders, Pressure change, or any other vomiting factor or condition. More particularly, the compounds of formula (I) are useful for the treatment of vomiting induced by anti-neoplastic agents (cytotoxic agents), including those commonly used in cancer chemotherapy, and other pharmacologic agents, It is used for treatment. Examples of such chemotherapeutic agents include, but are not limited to, alkylating agents such as nitrogen mustards, ethyleneimine compounds, alkylsulfonates, and other compounds having alkylating action, such as nitroso urea, cisplatin and Dakarbazine; Antimetabolites, such as folic acid, purine or pyrimidine antagonists; Fission inhibitors such as vinca alkaloids and grape philatoxin derivatives; And cytotoxic antibiotics. Specific examples of chemotherapeutic agents are described, for example, in D. J. Stewart, Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al., CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include but are not limited to cisplatin, Dacarbazine (DTIC), darkinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carbustine (BCNU) But are not limited to, doxorubicin (adriamycin), daunorubicin, procavagin, mitomycin, cystarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil RJ Gralla et al., Cancer Treatment Reports (1984) 68 (1), 163-172). The compounds of formula I may also be used for the treatment of radiation induced radiation, including radiation therapy, such as in cancer therapy, or radiation, And post-operative nausea and nausea. It will be appreciated that the compounds of formula I may be used in combination with another therapeutic agent as a combined agent to be used simultaneously, separately or sequentially for alleviation of vomiting. Such a combined preparation may be, for example, in the form of a twin pack.
[322] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[323] The present invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment of mood disorders such as depression, more particularly depressive disorders, (Including anorexia, weight loss, insomnia, premature ejaculation and psychomotor retardation), atypical depression (or reactive depression) (increased appetite, increased sleep, mental impairment, depressed mood, depressed mood, depressed mood and depressed mood) Motility irritability or irritation hypersensitivity, seasonal affective disorder, and pediatric depression); Or bipolar disorder or bipolar disorder, for example Type I bipolar disorder, Type II bipolar disorder and cyclic mood disorder; Impaired conduct and disruptive behavior; Anxiety disorders such as panic disorder with or without plaque panic, plaque without panic disorder history, specific phobia such as certain animal phobia, social anxiety, social phobia, compulsive personality disorder, stress disorder (posttraumatic stress disorder and acute stress Disorders), and generalized anxiety disorder; Borderline personality disorder; Schizophrenia and other psychotic disorders such as schizophreniform disorders, schizoaffective affective disorders, delusional disorders, short term psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic anxiety episodes, psychotic disorders Anxiety, psychotic mood disorders such as severe major depressive disorder; Mood disorders associated with psychotic disorders, such as depression associated with acute mania and bipolar disorder, mood disorders associated with schizophrenia; Mental retardation related behavioral disorder, autistic disorder, and behavioral disorders. .
[324] The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the treatment of delerium, dementia and other cognitive or neurodegenerative disorders such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's dementia, memory impairment, vascular dementia and other dementias such as HIV disease, head trauma, Parkinson's disease, Huntington's disease, - dementia due to Jakob disease, or multiple causes of dementia; (Including familial paroxysmal ataxia, ankylosing spondylitis, Tourette's syndrome, Scott's syndrome, PALSYS, and anorexic-spasticity syndrome); Such as neuroleptic-induced parkinsonism, neuroinflammatory syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute insufficiency, neuroleptic-induced delayed-movement disorder, and drug-induced disorders Satellite advance; The use of alcohol, amphetamine (or amphetamine-like substance), caffeine, hemp, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioid agents, phenylglycidine derivatives, sedatives, Diseases (drug related illnesses include dependency and abuse, addiction, withdrawal, addictive delerium and pessimistic delerium); Addictive behavior, such as gambling; epilepsy; Down syndrome; Acute pain, chronic pain and migraine; Dehydrating diseases such as multiple sclerosis (MS) and amylolateral sclerosis (ALS), peripheral neuropathy such as diabetic and chemotherapy-induced neuropathy and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia , And cerebrovascular diseases due to acute or chronic cerebrovascular injury such as cerebral infarction, subarachnoid hemorrhage, or cerebrovascular edema.
[325] The present invention also relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment or prophylaxis of respiratory diseases, in particular hypermucosal-related respiratory diseases such as chronic obstructive airways diseases, bronchopneumonia, Chronic bronchitis, cystic fibrosis, adult respiratory distress syndrome, and bronchospasm; Inflammatory diseases such as inflammatory bowel disease, psoriasis, Reiter's syndrome, Raynaud's syndrome, arthropathies, fibromyalgia, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, pruritus and sunburn; Human immunodeficiency virus (HIV) infection; Allergies such as eczema and rhinitis, and other allergies; Hypersensitivity diseases such as lacquer sensitization; Eye diseases such as conjunctivitis, spring conjunctivitis and the like; Cell proliferative ocular symptoms such as proliferative vitreoretinopathy; Skin diseases, such as contact dermatitis, atopic dermatitis, urticaria, and other eczematous dermatitis.
[326] The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neoplasms, gastric cancer, gastric lymphoma, glioblastoma and small cell carcinoma, such as small cell lung cancer, ≪ RTI ID = 0.0 > a < / RTI > biological tumor.
[327] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment or prevention of gastrointestinal (GI) diseases including inflammatory gastrointestinal disorders such as Helicobacter pylori. Inflammatory bowel disease, and a pharmaceutical composition for treating a disease or condition selected from the group consisting of GI tract diseases such as gastritis, gastroduodenal ulcer, visceral neural control diseases, ulcerative colitis, Crohn's disease, irritable bowel syndrome and vomiting will be.
[328] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Reflex sympathetic dystrophy, such as shoulder / hand syndrome; Immunological adverse reaction reactions such as transplant rejection and immune enhancement or inhibition related diseases such as systemic lupus erythematosus; Plasma leakage due to cytokine chemotherapy; Bladder dysfunctions such as cystitis, bladder detrusor overactivity, urinary tract inflammation and urinary incontinence (including equine urinary incontinence, overactive bladder, stress urinary incontinence and mixed urinary incontinence); Fibrosis and collagen diseases such as scleroderma and eosinophilic fasiolosis; Blood flow disorders due to vasodilation and vasoconstrictive diseases such as angina and Raynaud's disease; Angiogenesis; Cardiovascular disease; Dietary diseases such as anorexia nervosa and neurogenic bulimia; Attention deficit hyperactivity disorder; Chronic fatigue syndrome; Sexual dysfunction including premature ejaculation and male erectile dysfunction; Premenstrual syndrome and premenstrual dysphoric disorder; Fibromyalgia; And a pharmaceutical composition for the treatment of a disease or condition selected from the group consisting of rheumatic diseases such as fibromyalgia.
[329] The present invention also relates to compounds of formula < RTI ID = 0.0 > (II) < / RTI >
[330]
[331] In this formula,
[332] Q is _{C = NH, C = CH 2} , C = S, C = O, SO or SO _2, and;
[333] Y and Z are each N or CH, provided that Y and Z can not both be N;
[334] W is a 1 carbon bridging group (i.e., methylene) or a saturated or unsaturated 2 or 3 carbon bridging group, wherein each W group is optionally substituted with 1 substituent R ⁷ or 2 substituents R ⁷ and R ⁶ Or W is a 1 carbon bridging group which together with the 2,3, 4 or 5 carbon chains forms a 3, 4, 5 or 6 membered spiro ring, respectively; or
[335] W is a saturated 2 carbon chain bridging group which forms a fused 3, 4 or 5 membered ring with separate 1,2 or 3 carbon chains; or
[336] W is a saturated 2 carbon chain bridging group in which one of the two carbons forms a 3, 4, 5 or 6 membered spiro ring with a separate 2,3 or 4 carbon chain, respectively;
[337] R ⁵ and R ⁸ are hydrogen, -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl - (C ₁ -C ₂₎ alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) ₆₎ alkoxy, phenyl - (C ₁ -C ₃₎ alkoxy, phenyl, cyano, chloro, bromo, ^{iodo, NR 9 R 10, NR 9} COR 10, NR 9 CO 2 R 10, CONR 9 R 10, (C ₁ -C ₆ ) alkyl optionally substituted with one or more substituents independently selected from COR ⁹ and CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
[338] R ⁶ and R ⁷ is -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl- (C ₁ -C ₂ ) alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) (C ₁ -C ₃ ) alkoxy, phenyl, cyano, chloro, bromo, iodo, NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ And (C ₁ -C ₆ ) alkyl substituted with one or more substituents independently selected from CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
[339] Each R ⁹ and each R ¹⁰ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, phenyl and CF ₃ ;
[340] R ^5, R ^6, R ⁷ and R ⁸ in the definition of a phenyl group and R ^5, R ^6, the definition of R ⁷ and R ⁸ -phenyl (C ₁ -C ₂₎ alkyl in the phenyl moiety is optionally substituted by halo, hydroxy, 1 to the seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ - C ₆ ) alkyl, preferably with 0 to 2 substituents independently selected from alkyl;
[341] R ¹⁴ is hydrogen, (C ₁ -C ₆ ) alkyl or CF ₃ ;
[342] (A) R ⁸ can not be halo, hydroxy, cyano, aryloxy, heteroaryloxy, substituted or unsubstituted (C ₁ -C ₆ ) alkoxy, or methyl substituted with 1 to 3 fluorine atoms .
[343] Compounds of formula (II) are useful as intermediates in the preparation of compounds of formula (I).
[344] Compounds of formula (II) may contain a chiral center and thus may exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of compounds of formula (II) as racemic mixtures and as individual enantiomers and diastereomers, and mixtures thereof.
[345] Other examples of preferred compounds of the invention are compounds of formula II: < EMI ID =
[346] 5-Dimethoxymethyl-6-methoxy-3-methyl-l, lla, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[347] (1S, 1aR) -5-Dimethoxymethyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[348] (1R, 1aS) -5-Dimethoxymethyl-6-methoxy-3-methyl-l, lla, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
[349] 6-Methoxy-3-methyl-2-oxo-l, 2,3,7b-tetrahydro-lH-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde;
[350] (1S, 1aR) -6-methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde;
[351] (1R, 1aS) -6-methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde;
[352] 5-Methoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo [3,2-b] pyridine-6-carbaldehyde;
[353] 6-methoxy-l, 3,3-trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo [2,3-b] pyridine-5-carbaldehyde;
[354] 3-Methoxy-8-methyl-7-oxo-5,6,7,8-tetrahydro- [1,8] naphthyridine-2-carbaldehyde; And
[355] 2-Methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro- [1,5] naphthyridine-3-carbaldehyde.
[356] The invention also relates to compounds and pharmaceutically acceptable salts of compounds of formula T-NH _2.
[357]
[358] In this formula,
[359] p is 0, 1 or 2;
[360] R ³ is selected from hydrogen, COR ⁹ , CO ₂ R ⁹ , optionally substituted phenyl, optionally substituted heterocyclic ring and optionally substituted (C ₁ -C ₈ ) alkyl, wherein said (C ₁ -C ₈₎ one of the alkyl CH ₂ lifter may be substituted with a sulfur, oxygen or a carbonyl group, the (C ₁ -C ₈₎ alkyl, hydroxy, oxo, phenyl, - (C ₁ -C ₃₎ alkoxy, phenyl, cyano NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ , CO ₂ R ⁹ , NR ⁹ R ¹⁰ , and 1 to 7 fluorine atoms, optionally substituted heterocyclic rings, NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , Optionally substituted with one to three substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
[361] R ³ in the heterocyclic ring, and 3- to 7-membered saturated or unsaturated monocyclic ring, and one to four ring heteroatoms which heterocyclic ring substituents on the alkyl groups of R ³ contain from 1 to 4 ring heteroatoms And wherein the heteroatom is independently selected from oxygen, nitrogen and sulfur, with the proviso that the monocyclic or bicyclic heterocyclic ring , There can not be two adjacent ring oxygen atoms or two adjacent ring sulfur atoms and the heterocyclic ring formed from NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ must contain at least one nitrogen atom;
[362] R ³ heterocyclic heterocyclic on the alkyl group of the cyclic ring, and R ³ of the ring substituent is ^{_{(CH 2) m NR 9 R}} 10, NR 9 COR 10, oxo, hydroxy, thioxo, halo, cyano, phenyl, ( CH ₂ ) _m OR ⁹ , wherein m is 0, 1 or 2, and optionally substituted with one or more substituents independently selected from halo, CF ₃ , methoxy and phenyl, preferably 0 to 2 substituents Optionally substituted with one or more substituents, preferably 0, 1 or 2, substituents independently selected from (C ₁ -C ₆ ) alkyl;
[363] Phenyl substituent on the alkyl group of R ³ groups and R ³ are optionally substituted with halo, cyano, _{nitro, CF 3, (CH 2)} m NR 9 R 10 ( at this time, m is 0, 1 or 2), NR ⁹ COR ^{10 _{, NR 9 CO 2 R 10,}} CONR 9 R 10, CO 2 NR 9 R 10, COR 9, CO 2 R 9, 1 to 7 fluorine atoms, preferably with 0-3 fluorine atoms an optionally substituted (C ₁ C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine the reactor is optionally substituted (C ₂ -C ₆₎ one or more substituents independently selected from alkenyl, preferably, may be optionally substituted with 0-2 substituents;
[364] Each R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ is hydrogen and at least one substituent independently selected from hydroxy, oxo, (C ₁ -C ₆ ) alkoxy and cyano, preferably 0, (C ₁ -C ₆ ) alkyl optionally substituted with one or two substituents; or
[365] R ¹ and R ² together with the carbon atoms to which they are attached or R ² and R ³ together with the carbon and nitrogen to which they are attached contain 5 or 5 heteroatoms independently selected from nitrogen, Or a six membered saturated heterocyclic ring with the proviso that the ring may not contain two adjacent oxygen atoms or two adjacent sulfur atoms; Or R ¹ and R ² form a 5 or 6 membered saturated or unsaturated carbocyclic ring together with the carbon to which they are attached, and at this time, the heterocyclic group formed from R ¹ and R ² or R ² and R ^3, and carbocyclic ring optionally substituted with halo, oxo, NR ⁹ R ^10, one to seven fluorine atoms, preferably from zero to three fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkyl, and one to seven fluorine atoms, Preferably one or more substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted by 0 to 3 fluorine atoms, preferably 0 or 1 substituent; or
[366] R ¹² and R ¹³ , together with the carbon atoms to which they are attached, form a 5 or 6 membered saturated heterocyclic ring containing one or two heteroatoms independently selected from nitrogen, oxygen and sulfur provided that the ring has 2 Or two adjacent sulfur atoms, or R ¹² and R ¹³ together with the carbon to which they are attached form a 5 or 6 membered saturated or unsaturated carbocyclic ring, wherein R ¹² and the heterocyclic group formed from the R ¹³ and the carbocyclic ring is NR ⁹ R ^10, halo, phenyl, -S-, -SO- phenyl, phenyl -SO ₂ -, oxo, one to seven fluorine atoms, preferably 0 to 3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ each of which is independently selected from alkyl One or more substituents, preferably 0 or 1 substituent;
[367] Provided that only one of R ¹ and R ² , R ² and R ³ , and R ¹² and R ¹³ may form a ring;
[368] R ⁴ is selected from phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, and pyrimidyl wherein R ⁴ is halo, 1-7 fluorine atoms, preferably 0 (C ₁ -C ₆ ) alkyl optionally substituted by one to three fluorine atoms, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 Optionally substituted with one or more substituents independently selected from fluorine atoms, preferably (C ₂ -C ₆ ) alkenyl optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
[369] Each R ⁹ and each R ¹⁰ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, phenyl and CF ₃ ; or
[370] When R ³ is NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ , R ⁹ and R ¹⁰ together with the nitrogen to which they are attached may form an optionally substituted heterocyclic ring containing one or more nitrogen atoms.
[371] The compound of formula T-NH ₂ as defined are useful as intermediates in the preparation of compounds of formula I.
[372] The compounds of formula T-NH ₂ may contain a center of chirality, and thus, may exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of compounds of the formula T-NH ₂ as defined above as racemic mixtures and as individual enantiomers and diastereomers and as mixtures thereof.
[373] Other examples of preferred compounds of the present invention is a compound and pharmaceutically acceptable salt thereof of the formula T-NH _2:
[374] 6-Methyl-2-phenyl-piperidin-3-ylamine;
[375] (2S, 3S, 6S) -6-methyl-2-phenyl-piperidin-3-ylamine;
[376] (2R, 3R, 6R) -6-methyl-2-phenyl-piperidin-3-ylamine;
[377] 6-ethyl-2-phenyl-piperidin-3-ylamine;
[378] (2S, 3S, 6S) -6-ethyl-2-phenyl-piperidin-3-ylamine;
[379] (2R, 3R, 6R) -6-Ethyl-2-phenyl-piperidin-3-ylamine;
[380] 5-Methyl-2-phenyl-piperidin-3-ylamine;
[381] 5-ethyl-2-phenyl-piperidin-3-ylamine;
[382] 5-Propyl-2-phenyl-piperidin-3-ylamine;
[383] 5,5-diethyl-2-phenyl-piperidin-3-ylamine;
[384] 5,5-dimethyl-2-phenyl-piperidin-3-ylamine;
[385] 6,6-dimethyl-2-phenyl-piperidin-3-ylamine;
[386] 8-Benzyl-1-phenyl-8-aza-bicyclo [3.2.1] oct-2-ylamine; And
[387] (LS, 2S, 5R) or (lR, 2R, 5S) l-phenyl- 8-aza- bicyclo [3.2.1] oct- 2- ylamine.
[388] In a further aspect of the invention there is provided a pharmaceutical composition comprising a 5-HT ₃ antagonist such as, for example, ondansetron, granisetron or tropisetron, or other antiepileptic such as a dopamine antagonist such as metoclopramide or domperidone, or GABA- ≪ / RTI > in combination with an agonist such as baclofen. In addition, compounds of formula (I), alone or in combination with one or more other antidiarrhoeal agents, can be used in combination with an anti-inflammatory corticosteroid such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, fluneysolid, budesonide or U.S. Patent No. 2,789,118, 3,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, all of which are incorporated herein by reference. The compound of formula I may also be administered with a chemotherapeutic agent such as an alkylating agent, an antimetabolite, a fission inhibitor or a cytotoxic antibiotic as described above. In general, the compound of formula (I) For such a combination, the dosage form of the currently known known therapeutic agent will be suitable. [0064] The cisplatin-induced (5-hydroxypyridyl) cysteine derivative described in FD Tattersall et al. Eur. J. Pharmacol., (1993) 250, R5- When tested in a ferret model of vomiting, the compounds of the present invention were found to alleviate the discomfort and nausea induced by cisplatin.
[389] For the treatment of certain conditions, it may be desirable to use the compounds according to the invention with another pharmacologically active agent. For example, for the treatment of respiratory diseases, such as asthma, the compounds of formula I may be used in combination with a bronchodilator, such as an ₂ -adrenergic receptor agonist or a tachykinin antagonist acting at the NK-2 receptor. The compounds of formula I and the bronchodilator can be administered to a patient simultaneously, sequentially or in combination. Likewise, the compounds according to the present invention can be used in combination with leukotriene antagonists such as leukotriene D4 antagonists such as those selected from those disclosed in European Patent Applications 0 480 717 and 0 604 114, and U.S. Patents 4,859,692 and 5,210,324 Can be used with. Such combinations are particularly useful for the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
[390] Thus, the present invention provides a method for the treatment of respiratory diseases, such as asthma, comprising administering to a patient in need thereof an effective amount of a compound of formula I and an effective amount of a bronchodilator. The present invention also provides a pharmaceutical composition comprising a compound of formula I, a bronchodilator, and a pharmaceutically acceptable carrier.
[391] It will be appreciated that the compounds of the present invention may be used for the treatment or prevention of migraine with other anti-migraine agents such as ergotamine or 5-HT ₁ agonists, especially suramatriptan, narutriptan, zolmatriptan or lisetriptan. Similarly, for the treatment of hyperalgesia, the compounds of the invention may be used in combination with antagonists of N-methyl D-aspartate (NMDA), such as dinosylphinyl.
[392] For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, the compounds of the present invention may be used in conjunction with anti-inflammatory agents, such as bradykinin receptor antagonists. Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxycam and sulindac.
[393] It will be appreciated that the compounds of the present invention may be used in combination with other analgesics such as acetaminophen (paracetamol), aspirin and other NSAIDs, especially opioid analgesics, especially morpholine, for the treatment or prevention of pain or infiltration. Suitable opioid analgesics that may be used with the compounds of the invention include analgesics such as morphine, codeine, dihydrocodeine, diacetylmorphine, videcodone, hydromorphone, levorphanol, oxymorphone, alfentanil, Butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene, and pentazocine, or a pharmaceutically acceptable salt thereof. Preferred salts of these analgesic analgesic agents include morphine sulfate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulfate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone bitartrate, But are not limited to, hydrochloride, levorupnanol tartrate, oxymorphone hydrochloride, alpethanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride , Propoxyphene hydrochloride, propoxyphenylsulfate (2-naphthalenesulfonic acid (1: 1) monohydrate), and pentazocine hydrochloride.
[394] Thus, in a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention and an analgesic together with one or more pharmaceutically acceptable carriers or excipients. In a further or alternative aspect of the invention there is provided an article of manufacture comprising a compound of the invention and an analgesic agent as a combined agent for simultaneous, separate or sequential use for the treatment of pain or infiltration.
[395] It will be appreciated that for the treatment of depression or anxiety, the compounds of the present invention may be used in conjunction with other antidepressants or anxiolytics. Suitable classes of antidepressants include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), monoamine oxidase reversible inhibitors (RIMAs), serotonin and noradrenaline reuptake inhibitors ), Corticotropin releasing factor (CRF) antagonists, -Adrenoceptor antagonists and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include amitriptyline, clomipramine, poison semipin, imipramine, and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include amoxapine, desipramine, mefrotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof. Suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof. Suitable monoamine oxidase inhibitors include isocarboxazide, phenelzine, tranylcypromine, and selegiline, and their pharmaceutically acceptable salts. Suitable reversible inhibitors of monoamine oxydase include moclobemide, and pharmaceutically acceptable salts thereof. Suitable serotonin and noradrenaline reuptake inhibitors for use in the present invention include venlafaxine, and pharmaceutically acceptable salts thereof. Suitable CRF antagonists include those described in International Patent Publication Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677 . Suitable atypical antidepressants include bupropion, lithium, napadocin, trazodone, and biloxel, and pharmaceutically acceptable salts thereof. Suitable classes of anxiolytics include benzodiazepines and 5-HT _IA agonists or antagonists, especially 5-HT _IA partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazepines include alprazolam, chlorodiaxanthide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam and plazepam, and their pharmaceutically acceptable salts. Suitable 5-HT _1A receptor agonists or antagonists include, in particular, the 5-HT _IA receptor partial agonists buspirone, flushnoic acid, gepirone and incident pyrone, and pharmaceutically acceptable salts thereof.
[396] Thus, in a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention and an antidepressant or an anxiolytic, together with at least one pharmaceutically acceptable carrier or excipient. In a further or alternative aspect of the present invention there is provided a product comprising a compound of the present invention and an antidepressant or an anxiolytic agent as a combined agent for simultaneous, separate or sequential use for the treatment or prevention of depression and / or anxiety .
[397] It will be appreciated that the compounds of the present invention may be used in combination with other anorectic agents for the treatment or prevention of dietary diseases including obesity, neurogenic bulimia and compulsive eating disorders. Thus, the present invention provides the use of compounds of formula I and an anorectic agent in the manufacture of a medicament for the treatment or prevention of dietary disorders. The present invention also provides a method for the treatment or prevention of a dietary disorder, comprising administering to a patient in need thereof a relief effective amount of a compound of formula I and a relief effective amount of an anorectic agent. In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I and an anorectic agent together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the compounds of formula I and the anorectic agent may be present as combined agents for simultaneous, separate or sequential use for the treatment or prevention of dietary disorders. Such a combined preparation may be, for example, in the form of a twin pack. Thus, as a further or alternative aspect of the present invention, there is provided an article of manufacture comprising a compound of formula I and an appetite-suppressing agent as combined agents for simultaneous, separate or sequential use for the treatment or prevention of dietary disorders.
[398] In a further aspect of the present invention there is provided the use of a compound of formula I and an appetite suppressant in the manufacture of a medicament for the treatment or prevention of obesity. The present invention also provides a method of treating or preventing obesity comprising administering to a patient in need thereof a relief effective amount of a compound of formula I and a relief effective amount of an anorectic agent.
[399] In an alternative embodiment of the present invention, there is provided the use of a compound of formula I and an anorectic agent in the manufacture of a medicament for the treatment or prevention of neurogenic bulimia. The present invention also provides a method of treating or preventing neurogenic bulimia comprising administering to a patient in need thereof a relief effective amount of a compound of formula I and a relief effective amount of an anorectic agent.
[400] In a further aspect of the present invention there is provided the use of a compound of formula I and an anorectic agent in the manufacture of a medicament for the treatment or prevention of an obsessive-compulsive disorder. The present invention also provides a method for the treatment or prevention of an obsessive-compulsive disorder comprising administering a relief effective amount of a compound of formula I and a relief effective amount of an anorectic agent to a subject in need thereof.
[401] In an alternative embodiment of the invention, there is provided the use of a compound of formula I and an anorectic agent in the manufacture of a medicament for reducing total body fat mass in an obese mammal, a particular human. The present invention also provides a method for reducing total body fat mass in an obesity mammal, a specific human, comprising administering a relief effective amount of a compound of formula I and a palliative effective amount of an anorectic agent to a patient in need of such treatment.
[402] Suitable anorectic agents that may be used in combination with the compounds of the present invention include, but are not limited to, aminorex, amphechlor, amphetamine, benzphetamine, chlorfentermin, clobenzorex, clofforex, clominorex, chloresterin, cycloplex, Dextrofenamine, dextroamphetamine, diethylpropionion, dipeptethoxidine, N-ethylamphetamine, penbutrazate, fenfluramine, penisolex, fenfluorescein, fludorex, fluminorex, furfurylmethylamphetamine , Pemetrexene, pentamerine, phenylpropanolamine, picilorex, pemetrexene, pemetrexene, pemetrexene, pemetrexene, And sibutramine, and pharmaceutically acceptable salts thereof. Particularly preferred anorectic agents include amphetamine and its derivatives such as amphetamine, benzphetamine, chlorfentermin, clobenzorex, clofrex, clteremin, dexfenfluramine, dextroamphetamine, diethylpropionine, N- ethylamphetamine , Fenfluramine, fenfluramine, furfurylmethylamphetamine, rhamnutetamin, mefenolex, methamppramone, methamphetamine, northern water ephedrine, pentrex, fendimetrazine, penmetrazine, penttermine, phenylpropanolamine, Picilorex and sibutramine, and pharmaceutically acceptable salts thereof. Particularly suitable classes of anorectic agents include halogenated amphetamine derivatives such as chlorfentermin, clofforex, chloresterin, dexfenfluramine, fenfluramine, picilorex and sibutramine, and pharmaceutically acceptable salts thereof. Particularly preferred halogenated amphetamine derivatives for use with the compounds of the present invention include fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
[403] It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with selective serotonin reuptake inhibitors (SSRIs). Accordingly, the present invention provides the use of a compound of formula I and an SSRI in the manufacture of a medicament for the treatment or prevention of obesity. The present invention also provides a method for the treatment or prevention of obesity comprising administering to a patient in need thereof a relief effective amount of a compound of formula I and a relief effective amount of SSRI. In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I and an SSRI together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the compounds of formula I and the SSRIs may exist as combined agents for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such a combined preparation may be, for example, in the form of a twin pack. Thus, in a further or alternative aspect of the invention, there is provided an article of manufacture comprising a compound of formula I and an SSRI as a combined agent for simultaneous, separate or sequential use for the treatment or prevention of obesity.
[404] In an alternative embodiment of the invention, there is provided the use of a compound of formula I and an SSRI in the manufacture of a medicament for reducing total body fat mass in an obese mammal, a particular human. The present invention also provides a method of reducing total body fat mass in an obesity mammal, a specific human, comprising administering to the mammal a relief effective amount of a compound of formula I and a relief effective amount of SSRI. In a further aspect of the invention there is provided a pharmaceutical composition for reducing total body fat mass in an obesity mammal, a particular human, comprising a compound of formula I and an SSRI together with one or more pharmaceutically acceptable carriers or excipients. Suitable selective serotonin reuptake inhibitors that may be used with the compounds of the present invention include fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
[405] As used herein, "obesity" refers to a condition in which a mammal has a body weight index (BMI) of 25.9 or greater (calculated as weight / (height) ² (kg / m 2)). Typically, individuals with normal weight have a BMI of less than 19.9 to less than 25.9. Obesity may be due to any cause, whether genetic or environmental. Examples of obesity-causing or obesity-related diseases include, but are not limited to, overeating and bulimia, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Pradolin syndrome, type II diabetes, GH deficiency, Syndrome, and other pathological conditions indicative of decreased energy expenditure in the resting state, such as a reduction in metabolic activity as a percentage of total fat-free weight, such as in children with acute lymphoblastic leukemia. &Quot; Treating " of obesity indicates that the BMI in mammals is lowered to less than about 25.9 and the body weight is maintained for about six months. As a result of this treatment, the food or caloric intake by the mammal is suitably reduced. &Quot; Prevention " (of obesity) indicates prevention of the occurrence of obesity when administered before the onset of obesity symptoms. In addition, in the case of treating an obese subject, obesity after-effects such as atherosclerosis, type II diabetes, polycystic ovarian disease, cardiovascular disease, osteoarthritis, dermatological disease, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, Or to prevent its progression. Thus, in one aspect, the present invention provides a method of inhibiting the production of fat in obese mammals, one of the main characteristics of human and animal obesity, i.e., inhibiting and / or completely inhibiting excessive accumulation of lipids in adipocytes, . In another aspect, the present invention provides a method of preventing polycystic ovary disease or preventing its progression, increasing insulin sensitivity, and preventing or preventing polycystic ovarian disease in a patient suffering from diabetes such as adult-onset diabetes or type II diabetes Alleviating the symptoms of the disease, such as reducing or eliminating the need or use of insulin.
[406] In a further embodiment of the present invention, there is provided a use of a compound of formula I and a nicotinic receptor partial agonist in the treatment of chronic pain, neuropathic pain and migraine. A nicotine receptor partial agonist which can be used in embodiments of the present invention (Published on May 7, 1998), WO 99/55680 (published on November 4, 1999) and WO 99/35131 (published on July 7, 1998), International Patent Publication No. WO 98/18798 Filed April 29, 1998, and U.S. Provisional Application No. 60 / 083,556, filed April 29, 1998, all of which are incorporated herein by reference.
[407] DETAILED DESCRIPTION OF THE INVENTION [
[408] The compounds of formula (I) of the present invention may be prepared as described in the following scheme. R ¹ to R ¹³ , Q, Z, G, B, B ² , A, W, E, D and Y are as defined above.
[409]
[410] Scheme AI shows that compounds of formula II wherein R ¹⁴ is hydrogen, (C ₁ -C ₆ ) alkyl or CF ₃ and T-NH ₂ Of the formula where A is CH _2, by reductive amination of a compound of T-NH _2, is a B is absent, G is showing a method of manufacturing the NH compounds of formula I.
[411] The reaction may be carried out in a vessel without isolation of the imine intermediate or may be carried out in an inert solvent such as methylene chloride, dichloroethane, toluene or benzene at room temperature or at the reflux temperature of the solvent, NH ₂ and Compound II can be combined to form an imine, which can then be reduced. This reduction reaction can be carried out by catalytic hydrogenation or using various hydride reagents in a reaction inert solvent. The catalytic hydrogenation reaction can be carried out in the presence of a metal catalyst, such as palladium or Raney nickel. Suitable hydride reagents include borohydrides such as sodium borohydride (NaBH ₂ ), sodium cyanoborohydride (NaBH ₃ CN) and sodium triacetoxyborohydride (NaB (OAc) ₃ H), borane, aluminum Based reagents and trialkylsilanes. Suitable solvents include polar solvents such as methanol, ethanol, methylene chloride, dichloroethane, tetrahydrofuran (THF), dioxane, toluene, benzene, and ethyl acetate. This reaction is typically carried out at a temperature of from about -78 째 C to the reflux temperature of the solvent, preferably from about 0 째 C to about 25 째 C, for about 5 minutes to about 48 hours, preferably 0.5 to 16 hours.
[412] Alternatively, compounds of formula I of the present invention may be prepared as shown in the following Schemes A-II.
[413]
[414] Wherein LG is a leaving group such as halo, or sulfonate including tosylate, triflate or mesylate,
[415] Referring to Scheme A-II, B is absent, wherein G is NH The compounds of formula (I) compound with a compound of formula T-NH ₂ of the formula III (In this case, T-NH ₂ are as defined above), the Followed by reaction. The compound of formula III is reacted with a compound of formula III in the presence of a base such as K ₂ CO ₃ or Na ₂ CO ₃ in a polar solvent such as methanol, ethanol, isopropyl alcohol, THF, dioxane, dimethylformamide (DMF) in (DMSO)) it is treated with T-NH _2. This reaction is typically carried out at a temperature of from about -78 째 C to the reflux temperature of the solvent, preferably from about 0 째 C to about 25 째 C, for about 5 minutes to about 48 hours, preferably 0.5 to 16 hours.
[416] The compound of formula (III) may be prepared by reducing the aldehyde of formula (II) and then converting the hydroxy group of the resulting compound to a leaving group LG (e.g., halo, ). The reduction of the aldehyde of formula (II) can be carried out using a variety of reducing agents in a reaction inert solvent. Suitable reducing agent / solvent systems include sodium tetrahydroborate (NaBH ₄ ) in methanol or ethanol; Lithium tetrahydroborate (LiBH ₄ ) in THF or diethyl ether; (LiAlH ₄ ), lithium triethoxyhydroaluminum (LiAl (OEt) ₃ H), lithium tert-buthihydroaluminum (LiAl (OBut) ₃ H) or aluminum trihydrate Reed (AlH ₃ ); And iso-butylaluminum hydride (i-BuAlH ₂ ) or diisopropyl aluminum hydride (DIBAL-H) in dichloromethane, THF or n-hexane. The reaction is generally carried out at a temperature of from about-20 C to about 25 C for about 5 minutes to about 12 hours. The hydroxy group of the resulting compound is then converted to the leaving group LG using methods known to those skilled in the art. For example, when LG is a sulfonate such as a tosylate or mesylate, the hydroxy compound is reacted with sulfonyl chloride in the presence of pyridine or triethylamine in dichloromethane. When LG is halo, such as chloro or bromo, the hydroxy compound can be treated with SOX ₂ , where X is Cl or Br in the presence of pyridine.
[417] Compounds of formula (II) may be prepared as shown in Scheme B below.
[418]
[419] Compounds of formula (II) may be prepared by formylation of a compound of formula (IV) directly or indirectly. Any formylation method known to those skilled in the art can be used to introduce the formyl group into the benzene ring. For example, direct formylation can be carried out by contacting the compound of formula (IV) with a suitable formylating agent in the presence of a suitable catalyst. Suitable formylation / catalyst systems include dichloromethyl methyl ether / titanium chloride (IV) (Cl ₂ CHOCH ₃ / TiCl ₄ ), dichloromethyl methyl ether / aluminum chloride (Cl ₂ CHOCH ₃ / AlCl ₃ ), dichloromethyl methyl ether / (C1 ₂ CHOCH ₃ / SnCl ₄ ), dichloromethyl methyl ether / boron trifluoride etherate (Cl ₂ CHOCH ₃ / BF ₃ -OEt), trifluoroacetic acid (CF ₃ CO ₂ H) / hexa Methylene tetramine (modified Duff conditions) and phosphoryl trichloride (POCl ₃ ) / DMF (Vilsmeier conditions). Indirect formylation can be accomplished by halogenating the compound of formula (IV), replacing the introduced halogen atom with a cyano group, and then reducing the resulting cyano substituted compound. Alternatively, the halogen can be exchanged with butyllithium via halogen metal exchange. The lithium intermediate is then treated with dimethylformamide to give the compound of formula II. Halogenations used herein are described by GA Olah et al. Org Chem, 58, 3194 (1993)]. The replacement of a halogen atom with a cyano group is described in DM Tschaem et al., Synth Commun, 24, 887 (1994) and K. Takagi et al., 64 Bull Chem. Soc. Jpn. 64, 1118 (1991). The reduction can be carried out in the presence of diisopropylaluminum hydride (DIBAL-H) in dichloromethane or in the presence of Raney nickel in formic acid.
[420] Compounds of formula (II) wherein W is vinylene may also be prepared by hydrogenolysis of a similar compound of formula (II) wherein W is ethylene in a suitable solvent such as dioxane.
[421] The starting materials of the formula (IV) are commercially available known compounds or can be prepared by known methods. For example, a compound of formula (IV) wherein R < ¹ > is alkyl may be prepared by reacting a corresponding compound of formula (IV) wherein R < ^{1 >} is hydrogen with a compound of formula (IV) in the presence of a base such as NaH or KH in a suitable solvent - < / RTI > R ² or R ³ a compound of formula IV is different from hydrogen can also be prepared using a similar technique to that described above from a compound of formula (IV) corresponding to the R ² or R ³ are each hydrogen. Compounds of formula IV are also described in EP 385662 and C. Crestini et al. Synth. Commun. 24 2853 (1994)] and GW Reewcastle et al. [J. Med Chem, 37, 2033 (1994). Compounds of formula (IV) wherein Q is S can be prepared by the subsequent vulcanization of the corresponding compound of formula (IV) wherein Q is O. Suitable vulcanization agents are Lawesson's reagent (Tetrahedron, 41, 5061 (1985)) and P ₄ S ₁₀ (Chem. Pharm. Bull., 10, 647 (1962)).
[422] Alternatively, compounds of formula (I) wherein B is absent, G is NH and A is CH ₂ can be prepared as shown in the following Schemes A-III.
[423]
[424] Scheme A-III illustrates the preparation of a compound of formula Ia, which is a compound of formula I wherein T is 2-phenylpiperidinyl.
[425] Referring to Scheme A-III, (t-BuOCO) in the presence of the compound (Ar is phenyl deungim) of formula V base, such as sodium bicarbonate (NaHCO ₃₎ or triethylamine _{(Et 3 N) 2 O (} Boc 2 O) to yield a compound of formula (VI). (Via reaction with FMOC-Cl), benzyl (via reaction with benzyl chloride), trifluoroacetyl (via reaction with trifluoroacetic anhydride), and other nitrogen protecting groups well known to those skilled in the art, such as, for example, Benzoyl (via reaction with benzoyl chloride) can also be used. A discussion of these protecting groups and their attachment and removal methods is found in Greene, Theodora W. and Wiuts, Peter GM, Protective Groups In Organic Synthesis, Second Edition, John Wiley & Sons, Inc., New York, 1991). Hydrolysis of the compound of formula (VI) gives the compound of formula (VII). Can be treated in the presence of an alternative to this, the base of the N- protected compound of formula V, for example sodium bicarbonate (NaHC0 ₃₎ or triethylamine (Et ₃ N) to carbonyloxy benzamide oxychloride (Cbz-Cl). Hydrogenolysis can be performed by treatment with H ₂ or ammonium formate (HCO ₂ NH ₄ ) in the presence of a metal catalyst, such as palladium on charcoal (eg, 20% palladium on charcoal) in a suitable solvent. The compound of formula (VII) is then reductively aminated as described in Scheme AI to give the corresponding compound of formula (VIII), which is then reacted with an acid catalyst such as hydrochloride (HCl) in methanol, concentrated HCl in ethyl acetate, Tanjung treated with CF ₃ CO ₂ H can be converted to the compound of formula Ia.
[426] The compounds of formula (I), and the intermediates shown in the above schemes, can be isolated and purified by conventional methods, such as recrystallization or chromatographic separation.
[427] Selected intermediates shown as compounds IV in Scheme B can be prepared by the transformation methods shown in Schemes C and D.
[428]
[429] Acylation of aniline of formula (IX) with an acylating agent such as acetic anhydride, acetyl bromide, acetyl chloride, acetylsulfonate, acetylphosphonate, or acetic acid with a mixed anhydride of phenyl or alkyl chloroformate gives the compound of formula (XIII) . Typically, this conversion method is carried out in the presence of a base, such as a bicarbonate or carbonate, in an inert solvent such as methylene chloride, dichloroethane, toluene, ether, benzene, THF, dioxane, water or a mixture of solvents such as water or chloroform, In the presence of triethylamine, at a temperature of about-50 C to the reflux temperature of the solvent, for about 15 minutes to about 24 hours. Preferably, the compound of formula (XIII) is formed by reaction with acetic anhydride at about 0 < 0 > C for about 2 hours using triethylamine as base in methylene chloride.
[430] Compounds of formula (XIII) wherein R < ⁸ > = H may be alkylated with suitable electrophiles selected from methyl iodide, dimethyl sulfate and methyl triflate. This reaction is carried out in the presence of a base such as sodium or potassium t-butoxide, or sodium hydride or potassium hydride. Suitable inert solvents such as THF, ether or dimethoxyethane can be used. Conveniently, the reaction is carried out at a temperature of from about-50 C to about ambient temperature. Preferred conditions involve the use of dimethylsulfate in THF in the presence of potassium t-butoxide for 16 hours at 0 < 0 > C to ambient temperature.
[431] Alternatively, when R < ⁸ > is hydrogen, the compound of formula (XIII) may be reacted with a suitable base such as sodium hydride or potassium hydride, sodium carbonate or potassium carbonate in a solvent such as DMF, THF, N-methylpyrrolidinyl, dichloroethane or dichloromethane , Or sodium or potassium t-butoxide) followed by treatment with a sulfonyl or sulfinyl halide or an anhydride (e.g., methanesulfonyl chloride or bromide or anhydride, trifluoromethanesulfonyl anhydride, phenylsulfonyl chloride, Or anhydride, or tosyl chloride or anhydride). Preferably, the reaction is carried out using methanesulfonyl chloride as a reactant, DMF as a solvent, and sodium hydride as a base.
[432] Compounds of formula XIV may be prepared from the corresponding compounds of formula XIII in a solvent such as THF or dimethoxyethane at a temperature of about -100 ° C to about -25 ° C for about 15 minutes to about 5 hours with a suitable base such as lithium diisopropyl Amide, sodium, lithium or potassium hexamethyldisilazane or potassium t-butoxide to form the enolate. Suitable electrophiles include acetone, acetaldehyde, benzaldehyde, formaldehyde, cyclopentanone, and cyclohexanone. A preferred condition for this conversion method involves the use of lithium diisopropylamide in THF for about 2 hours with acetone or acetaldehyde as the electrophile at a temperature of about -78 < 0 > C.
[433] Formation of the compound of formula XII from the corresponding compound of formula XIV can be carried out in the presence of a suitable acid or base in the presence of an acid such as sulfuric acid, phosphoric acid, triflic acid, hydrofluoric acid or polyphosphoric acid, At a temperature of about 5 minutes to about 2 hours. Preferred conditions involve heating the compound of formula XIV at about 100 DEG C for about 15 minutes in pure polyphosphoric acid.
[434] Compounds of formula X may be formed by acylating anilines of formula IX with an acylating agent such as 3-chloropropionyl chloride or chloroacetyl chloride. Typically, this conversion method is carried out in the presence of a base, such as a bicarbonate, carbonate, or a mixture, in an inert solvent or mixture of solvents such as methylene chloride, dichloroethane, toluene, ether, benzene, THF, dioxane, water or chloroform, In the presence of triethylamine, at a temperature from about-50 C to the reflux temperature of the solvent for about 15 minutes to about 24 hours. Preferably, the compound of formula X is formed by reacting 3-chloropropionyl chloride with sodium bicarbonate as a base in methylene chloride / water at ambient temperature for about 16 hours. The compound of formula XI is reacted with a corresponding compound of formula X in the presence of a solvent or an inert solvent such as methylene chloride, dichloroethane, chloroform, benzene or toluene at a temperature from about ambient temperature to about 300 < , Such as aluminum chloride, tin (II) chloride, tin (I) chloride or titanium chloride. Preferably, the compound of formula (XI) is formed by reacting the corresponding compound of formula (X) with aluminum chloride for about 10 minutes at about 210 < 0 > C without a solvent.
[435] R ⁵ is hydroxy, and (or) R ⁸ Compound of formula (XI) is hydrogen is by a suitable electrophile and the reaction is selected from methyl iodide, dimethyl sulfate and methyl triflate R ⁵ or R ⁸ are each alkoxy, or an alkyl group Can be converted to the corresponding compound. This reaction is carried out in the presence of a base such as sodium or potassium t-butoxide or sodium hydride or potassium hydride. Suitable inert solvents such as THF, ether or dimethoxyethane may be used. Conveniently, the reaction is carried out at a temperature of from about-50 C to about ambient temperature. Preferred conditions involve the use of methyl iodide in THF in the presence of potassium t-butoxide at about 0 < 0 > C to about ambient temperature for about 16 hours.
[436]
[437] Compounds XVI and XVIII can be prepared as shown in Scheme D using the conditions described in Bernard et al. [CAN 67: 120195]. This reaction is carried out using a base such as sodium hydride or potassium hydride, butyl or hexyl lithium in a solvent such as DMSO, THF, DME, ether or DMF, using trimethylsulfonium iodide, chloride or bromide, Lt; 0 > C to about 200 < 0 > C for about 1 hour to about 2 days. Preferred conditions involve the use of trimethylsulfonium chloride in DMSO at about 100 < 0 > C for about a week in the presence of sodium hydride. More preferred conditions involve the use of trimethylsulfonium iodide in THF in the presence of hexyl lithium at a temperature of about 0 ° C to about the reflux temperature of the solvent for 1.5 hours. Compounds XVI and XVIII can then be converted as described above to compounds of formula II (see scheme B) and further converted into compounds of formula I (see schemes A-I and A-III).
[438]
[439] The compound of formula XVIII is preferably prepared directly from the corresponding compound of XIX in an inert solvent using a suitable base and an alkylating agent. Suitable bases include sodium hydride, potassium hydride or lithium hydride, and lithium dialkyl amides such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide, It is not limited thereto. Suitable alkylating agents include dibromoethane, iodobromoethane, ethylene glycol dimesylate or ditosylate, iodochloroethane, and the like. Suitable inert solvents include THF, ether, dimethoxyethane and DMF. The reaction may be carried out at a temperature of about 0 ° C to about the reflux temperature of the solvent. The most preferred conditions involve using sodium hydride as the base and dibromoethane as the alkylating agent and using the substrate XIX in DMF at about room temperature for about 4 hours.
[440]
[441]
[442] The spirocyclic compounds shown in Scheme F can be prepared using the following general reaction sequence. The starting aldehyde of formula (II) (a) is dissolved in a nonpolar solvent, preferably ethyl acetate, at about -50 ° C to about 50 ° C, preferably at about room temperature, and to this solution is added aqueous sodium hydrogen sulphite followed by aqueous sodium cyanide ) Is added. The mixture is stirred for about 1 to about 24 hours, preferably about 4 hours, the second portion of aqueous NaCN is added and stirring is continued for about 18 hours. The resulting cyanohydrin of formula XX is isolated and dissolved in methanol saturated with hydrogen chloride (HCl) gas. The resulting solution is then refluxed for about 3 hours. From this solution, the target hydroxy-ester of formula XX can be isolated.
[443] The hydroxy-ester of formula XXI can be oxidized to the corresponding keto-ester in an aprotic solvent, preferably acetone, using various oxidizing agents (preferably CrO ₃ / H ₂ SO ₄ ; Jones reagent) have. The ketone-acid is then reacted with methyl-triphenylphosphonium bromide using standard Wittig conditions (n-BuLi / THF; about-20 C to about ambient temperature) to give the unsaturated ester derivative of formula (XXII) Next, the unsaturated ester derivative of formula (XXII) is mixed with a compound of formula (XXIII) in a nonpolar solvent, preferably tetrahydrofuran (THF), and a nonaqueous base, preferably 1,8-diazabicyclo [5.4. 0] undec-7-ene (DBU). The reaction is then heated to reflux for about 4 to about 36 hours, preferably about 18 hours. The resulting ester adduct of formula XXIV can then be reduced using a variety of reducing agents, preferably LiBH ₄ , in an aprotic ether solvent, preferably ethyl ether, to yield the nitroalcohol derivative of formula XXV.
[444] Reduction of the nitro group can be carried out by hydrogenation in ethanol using a standard method, preferably a Raney nickel catalyst, and the cyclization of the spirocycles is preferably carried out using methanesulfonyl chloride in methylene chloride to about-20 Lt; 0 > C to about 40 < 0 > C, preferably about 5 < 0 > C. Isolation of the resulting enantiomers by chiral chromatography is a standard procedure known to those skilled in the art. The final product of formula I (b) is obtained by final removal of the nitrogen protecting group using standard conditions, preferably dioxane / HCl.
[445] Compounds of formula (I) wherein B is CH ₂ , A is CH and G is OCH ₂ can be prepared using the method shown in Scheme G. Compounds of formula QQ may be prepared by replacing compounds of formula IV as defined in Scheme B above with compounds of formula I having the desired definitions of Q, W, Y, Z, R ⁵ , R ⁶ , R ⁷ and R ⁸ .
[446]
[447]
[448] Reaction Scheme H is a substituent _{Het-CH 2 -C (= O} ) as R ³ - group (Het gateuna is as defined for the heterocyclic substituent on the above-defined R ^3, However, Het can also be contains a secondary amine ) To a similar compound of formula I wherein R < ³ > is hydrogen. With Het-H in the presence of a tertiary amine hydrochloride base catalyst, such as diethylbenzylamine, pyridinium hydrochloride, or diisopropylethylamine hydrochloride, at a temperature of about 0 < 0 > C to about ambient temperature with methoxybromoacetate or ethoxy Condensate with bromoacetate. The ester is hydrolyzed in aqueous potassium hydroxide solution at a temperature of about 0 째 C to about reflux temperature for about 16 hours to about 48 hours using a slurry of potassium carbonate. The substituted acetic acid and the piperidine I (d) are reacted with any standard peptide coupling agent such as Bop (benzotriazol-1-yloxytris (dimethylamino) ) Phosphonium hexafluorophosphate), Py-Brop (bromo-tris-pyrrolidinophosphonium hexafluorophosphate) or T3P (1-propanephosphonic acid cyclic anhydride) to yield the final product.
[449]
[450] Scheme J illustrates the synthesis of certain compounds of formula I wherein R < ² > is alkyl.
[451] The starting material (compound of formula XXXII) used in this scheme can be prepared by reacting a compound of formula XXXII in the presence of a suitable base such as sodium or potassium alkoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, or sodium carbonate and potassium carbonate, Reaction with nitromethane in a solvent such as methanol, ethanol, propanol, isopropanol, tert-butanol, methylene chloride, chloroform, toluene, THF, DMF, DMSO, ether or ethyl acetate at a temperature of about -78 ° C. to about 100 ° C. (J. Am. Chem. Soc., 74, 3664-3668 (1952)). Preferably, the reaction is carried out using sodium methoxide as the base and methyl vinyl ketone as the electrophile and using nitromethane in methanol at about -30 ° C to about 0 ° C. Alternatively, the reaction is described in the literature, for example in Tetrahedron Lett. 1929-1932 (1982). ≪ / RTI >
[452] Compounds of formula XXXIII may be prepared using a modified Henry reaction which condenses to a substituted cyclic imine. First, the ketone is reacted in an alcoholic solvent such as methanol, ethanol, propanol or ethylene glycol in the presence of a water scavenger such as trimethylorthoformate, triethylorthoformate, magnesium sulfate or molecular sieves, Is protected as a ketal using mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, or catalytic organic acids such as camphorsulfonic acid or toluenesulfonic acid at about 75 < 0 > C. The nitroacetal is then condensed in situ at a temperature of about 0 캜 to about 75 캜 using one of the amines, such as, for example, ammonium acetate, ammonium chloride or imine formed with ammonium formate, and aldehydes such as variously substituted aromatic aldehydes . Subsequently, a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid is added in water at a temperature of about 0 ° C to about 75 ° C to convert the acetal to a ketone, through which cyclization occurs to give compound XXXIII. Preferably, the nitro ketone is dissolved in methanol at room temperature with catalytic amounts of camphorsulfonic acid and trimethylorthoformate. Next, ammonium formate is added followed by benzaldehyde. Aqueous sulfuric acid is added and stirred to give the cyclic imine XXXIII.
[453] The resulting compound of formula XXXIII is dissolved in an alcoholic solvent such as methanol, ethanol, propanol, isopropanol or t-butanol and its lithium, sodium or potassium base, and a water scavenger such as trimethyl orthoformate, Is added to a solution of a mineral acid, such as hydrochloric acid, sulfuric acid or nitric acid, at a temperature of about -30 캜 to 75 캜, in the presence of triethyl orthoformate, magnesium sulfate or molecular sieves. This reaction gives the corresponding compound of formula XXXIV. Preferably, the nitroimine is dissolved in sodium methoxide in methanol and added to a 0 ° C solution of sulfuric acid and trimethylorthoformate in methanol.
[454] The corresponding compound of formula XXXV-a is formed by stereoselective reduction of an imine of formula XXXIV. This imine is reduced using a Lewis acid such as trimethylaluminum, triethylaluminum and trichloroaluminum, and a hydride source such as lithium aluminum hydride or diisobutyl aluminum hydride. Typically, the reaction is carried out in an organic solvent such as THF, ether or glyme at a temperature of from about 0 째 C to about -78 째 C. Preferably, the imine is reduced with triethylaluminum and lithium aluminum hydride in THF at about -78 < 0 > C.
[455] Conversion of acetal to oxime followed by reduction affords the amine to convert the compound of formula XXXV-a to the corresponding compound of formula XXXVI-a. The acetal is stirred with water and an organic solvent, such as THF, with a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid, hydroxylamine, and a buffer such as ammonium acetate or ammonium chloride at a temperature of about 0 캜 to about 100 캜. Oxime is reduced in an organic solvent such as methanol, ethanol, ethyl acetate or acetic acid using a catalyst such as Raney nickel, platinum or palladium under a hydrogen atmosphere of about 1 to about 50 psi at a temperature from about room temperature to about 60 & . Preferably, the compound of formula XXXV-a and the hydroxylamine hydrochloride are dissolved in water, THF and concentrated hydrochloric acid, and then ammonium acetate is added at about room temperature. Oxime is then reduced by Raney nickel in ethanol at about room temperature under 40 psi of hydrogen.
[456] The final product of formula XXXVII-a can be reacted with an appropriate aldehyde, an acid such as acetic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid or toluenesulfonic acid, and a hydride source such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride Is prepared by reductive amination of the corresponding compound of formula XXXVI-a in an organic solvent such as methanol, ethanol or THF at about 0 < 0 > C to about 75 & Preferably, the compound of formula XXXVI-a, the appropriate aromatic aldehyde, acetic acid and sodium cyanoborohydride are stirred at about room temperature in methanol to give the desired product of formula XXXVII-a.
[457] The starting material of the formula XXXVII-a type having the opposite stereochemistry at the R ² site with the compound of the formula XXXVII-a can be prepared in a similar reaction sequence by slightly changing the set of conditions used for the imine reduction. For example, by replacing triethylaluminum / LiAlH ₄ with NaBH ₃ CN / MeOH, compound XXXV-b is obtained. Several different reduction methods can be used for this transformation method, and these methods are well known to those skilled in the art. Preferred conditions include reduction with NaBH ₄ in an alcoholic or ethereal solvent or reduction with a chlorinating solvent such as CH ₂ Cl ₂ or CHCl ₃ or another inert solvent such as benzene, toluene, ether, THF Or reduction with NaBHOAc ₃ in glyme. LiAl ₄ in ether, THF or glime may be used in the absence of triethylaluminum. Generally, such reduction is carried out at a temperature from about -78 ° C to about 100 ° C, preferably from about 0 ° C to about 60 ° C. The subsequent reaction sequence to obtain the compound of formula XXXVII-b can be carried out under the same conditions as the reaction sequence to obtain the compound of formula XXXVII-a.
[458]
[459] Scheme K illustrates the synthesis of certain compounds of formula I wherein Q is SO ₂ and W is ethylene.
[460] The starting material (Compound XXXVIII) used in this scheme is reacted with a suitable base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate in an organic solvent (Or bromide) or methanesulfonic anhydride with commercially available 4-methoxy-2-methylaniline in the presence of a base such as methylene chloride, dichloroethane, toluene, ether, ethyl acetate, carbon tetrachloride or chloroform can do. Preferably, the reaction is carried out using methanesulfonyl chloride in the presence of pyridine in methylene chloride. The resulting sulfonamide is treated with a suitable base such as sodium hydride or potassium hydride, or sodium or potassium tert-butoxide in a solvent such as DMF, N-methylpyrrolidinone, dimethylacetamide, THF or DMSO. The resulting salt is reacted with methyl iodide or dimethyl sulfate to give the compound of formula XXXVIII. Preferably, the reaction is carried out using methyl iodide with sodium hydride as the base at ambient temperature in DMF. The reaction of the compound of formula (XXXVIII) with the compound of formula (XXXVIII) in carbon tetrachloride or dichloroethane at almost the reflux temperature of the solvent in the presence or absence of a light emitter with the reaction of N-bromosuccinimide or dibromodymethylhydantoin, dibromodiphenylhydantoin or bromine To yield the bromide of formula XXXIX. Preferably, the reaction is carried out in the presence of high intensity visible light under reflux using N-bromosuccinimide in carbon tetrachloride.
[461] Next, the bromide of formula XXXIX is cyclized to form a sultam of formula XL as follows. The formation of an anion using a base such as sodium hydride or potassium hydride, or sodium or potassium tert-butoxide in a solvent such as DMF, N-methylpyrrolidinone, dimethylacetamide, THF or DMSO, The same intermediate sultam as the structure of compound XL is obtained except for the replacement. The compound of formula XL is obtained via direct or indirect formylation of such intermediate sultam. Any of a variety of formylation methods known to those skilled in the art may be used to introduce the formyl group into the benzene ring. For example, direct formylation can be carried out by contacting the compound with a suitable formylation agent in the presence of a suitable catalyst. Suitable formylation / catalyst systems include dichloromethyl methyl ether / titanium chloride (IV) (Cl ₂ CHOCH ₃ / TiCl ₄ ), dichloromethyl methyl ether / aluminum chloride (Cl ₂ CHOCH ₃ / AlCl ₃ ), dichloromethyl methyl ether / (Cl ₂ CHOCH ₃ / SnCl ₄ ), dichloromethyl methyl ether / boron trifluoride etherate (Cl ₂ CHOCH ₃ / BF ₃ -OEt), trifluoroacetic acid (CF ₃ CO ₂ H) / Hexamethylenetetramine (modified dough conditions) and phosphoryl trichloride (POCl ₃ ) / DMF (Bussumier conditions).
[462] Indirect formylation can be accomplished by halogenating the intermediate sultam described above, replacing the halogen atom with a cyano group, and then reducing the resulting cyano-substituted compound. Alternatively, the halogen can be exchanged with butyllithium via halogen metal exchange. The lithium intermediate is then treated with dimethylformamide to give the compound of formula II. The halogenation used herein can be carried out according to the procedure described in GA Olah et al., J. Org Chem, 58, 3194 (1993). The replacement of a halogen atom with a cyano group is described in DM Tschaem et al., Synth Commun, 24, 887 (1994) and K. Takagi et al., 64 Bull Chem. Soc. Jpn. 64, 1118 (1991). The reduction can be carried out in the presence of diisopropylaluminum hydride (DIBAL-H) in dichloromethane or in the presence of Raney nickel in formic acid. Next, the ring and the appropriate compound of formula T-NH ₂ and coupling as defined above in Scheme AI, except that in Scheme AI to the aldehyde of formula XL R ³ is BOC, as described in A-III.
[463]
[464] Scheme L illustrates a process for preparing compounds of formula I wherein R ³ is benzyl and R ¹² and R ¹³ together with the carbon atoms to which they are attached form a ring.
[465] The starting material of Scheme L can be prepared from 2-bromo-3-hydroxypyridine or from 2-iodo-3-hydroxypyridine in a similar manner. This reaction can be carried out in the presence of one of these starting materials and a nucleophile such as phenyl (or substituted phenyl), boronic acid or another aryl substituted boronic ester or phenylalkylboran and / or aryl (or substituted aryl) For example, phenyltri-n-butylstannane or phenyltrimethylstannane. Usually, a palladium catalyst is used. Palladium catalysts include palladium (0) sources with a variety of phosphine ligands, such as, but not limited to, palladium tetrakis [triphenylphosphine], or a non-phosphine source such as palladium dibenzylidene acetone (dba) ) ≪ / RTI > atoms such as palladium acetate or palladium dichloride bistriphenylphosphine. The reaction may be carried out in a variety of solvents or mixtures of solvents such as ethyl acetate, methylene chloride, dichloroethane, toluene, benzene, ether, THF or DMF and water at a temperature from about ambient to about the reflux temperature of the solvent, Potassium, sodium bicarbonate or potassium bicarbonate. Preferably, 2-bromo-3-hydroxypyridine and phenylboronic acid are used in a mixture of benzene, water and sodium carbonate in the presence of palladium tetrakis triphenylphosphine as catalyst.
[466] The product of this step (the compound of formula XLII) is reacted with benzyl bromide, chloride, mesylate, triflate or iodide in a variety of solvents, such as acetonitrile, ethanol, methanol or water, , ≪ / RTI > or substituted benzyl bromide. The product of this reaction is the pyridine salt (salt of formula XLIII). The most preferred conditions involve the formation of pyridinium bromide with acetonitrile in the presence of benzyl bromide under reflux. The resulting salt of formula XLIII can be converted into betaine as a separate step using a suitable base or in situ via the following reaction. Typically, the pyridium salt is treated with amberlite (TM) or another type of basic ion exchange resin or triethylamine, diisopropylethylamine, sodium hydroxide, sodium carbonate or sodium bicarbonate at about ambient temperature. The most preferred conditions involve the use of a strongly basic ion exchange resin, Ambe, as a light. The betaine is then reacted with a vinylsulfone such as phenylvinylsulfone or substituted phenylvinylsulfone in an inert solvent such as ethyl acetate, methylene chloride, dichloroethane, toluene, benzene, ether, THF or DMF at the reflux temperature of the weak solvent. Typically, a radical inhibitor, such as hydroquinone or a related inhibitor, is added to prevent radical polymerization of the vinylsulfone. Most preferably, phenylvinylsulfone is used in the presence of hydroquinone in refluxing toluene.
[467] The resulting product enone (compound of formula XLIV) contains a carbon-carbon double bond, which is reacted with a suitable catalyst such as palladium on carbon, palladium hydroxide, platinum oxide or platinum on carbon under hydrogen pressure of 1-110 psi Can be reduced. The reaction may be carried out in a solvent such as methanol, ethanol or water at a temperature of from about ambient to about the reflux temperature of the solvent. Alternatively, the reaction may be carried out using ammonium formate or another formate salt as a source of hydrogen. It is preferred to use ammonium formate in methanol with Pd (OH) ₂ / C while refluxing. Hydroxylamine methyl ether or alternatively the ketone produced using ethyl or benzyl ether as well as hydroxylamine itself is converted to oxime ether or oxime. The reaction is carried out in a solvent or mixture of solvents selected from ethyl acetate, methylene chloride, dichloroethane, toluene, benzene, ether, THF, DMF, methanol, ethanol and water, or mixtures thereof at a temperature from about ambient to about the reflux temperature of the solvent Using a suitable buffer, such as sodium or potassium acetate. The most preferred conditions involve the use of a refluxing mixture of methylene chloride, methanol and water in the presence of hydroxylamine methyl ether and sodium acetate. The resulting oxime methyl ether (compound of formula XLV) can be selectively reduced using an appropriate reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride or triethylsilane in a solvent under acidic conditions. Suitable solvents include acetic acid, formic acid and trifluoroacetic acid. This reaction is usually carried out at about ambient temperature. Most preferably, the compound of formula I (g) is obtained using sodium cyanoborohydride in acetic acid.
[468] The phenylsulfone functional group can be removed together with reduction of the hydroxylamine ether. Typically, the reducing agent is sodium, lithium or potassium metal, or sodium amalgam, aluminum amalgam or samarium diiodide. The reaction may be carried out in a solvent or mixture of solvents selected from liquid ammonia, ethanol, methanol, toluene, THF, t-butanol and similar solvents. Usually this reaction is carried out at a temperature of from about -33 [deg.] C to about ambient or about the reflux temperature of the solvent. The most preferred conditions involve the use of a sodium metal in liquid ammonia / THF with reflux to yield a compound of formula XLVI. Removal of the N-benzyl protecting group may be carried out under a hydrogen pressure of 1-110 psi using a suitable catalyst, such as palladium on carbon or palladium hydroxide. The reaction may be carried out in a solvent such as methanol, ethanol or water at a temperature of from about ambient to about the reflux temperature of the solvent. Alternatively, the reaction may be carried out using ammonium formate or another formate salt as a source of hydrogen. Preferably, ammonium formate in methanol is used in the presence of palladium hydroxide on carbon as catalyst, and the reaction is carried out at the reflux temperature of the solvent. In the final step, the aldehyde of formula XLVII is coupled with diazabicyclo [3.2.1] octane of formula XLVI, wherein Bn, the N-benzyl protecting group is removed, under the conditions described above in Schemes A-I to A-III.
[469]
[470]
[471]
[472] Referring to Scheme M, 7-azaindole (Formula XLVII) (Aldrich) is treated with about 1.4 equivalents of m-chloroperbenzoic acid in dichloro at about ambient temperature for about 4 hours. The product is isolated from the reaction and dissolved in THF and treated with one equivalent of hexamethyldisilane and two equivalents of methyl chloroformate for about 16 hours at about ambient temperature. This reaction gives the chlorinated compound of formula XLVIII. 6-Chloro-7-azaindole (XLIX) is obtained via sodium hydroxide hydrolysis in methanol / water at about ambient temperature for about 2 hours. This intermediate was subsequently treated with pyridinium bromide perbromide in t-butanol (t-BuOH) at about ambient temperature for about 16 hours and then treated with Zn in acetic acid (HOAc) at about ambient temperature for about 20 minutes to give 6 -Chloro-7-azaoxindol-2-one (compound LI). Next, the compound of formula LI is permethylated with methyl iodide / potassium t-butoxide at about ambient temperature for about 16 hours and then reacted with sodium methoxide (NaOMe) and Is converted to a 6-methoxy derivative of the formula LII using a copper (I) iodide (CuI) catalyst. Then, by reacting the compound with titanium tetrachloride (TiCl ₄₎ / α, α- dichloromethyl ether of formula LII for about 16 hours at ambient temperature, it is possible to obtain the aldehyde of formula LIII. Via the standard reductive amination conditions for the coupling of the compound with the appropriate compound of formula T-NH ₂ of the formula LIII will give the desired end product of formula I (h).
[473]
[474] Referring to Scheme N, 4-aza-5-methoxy-oxindole intermediate (LX) can be prepared according to literature (Robinson et al., J. Het. Chem., 1996, 33, 287-293 ] Reference). It is permethylated using methyl iodide / potassium t-butoxide for about 16 hours at about ambient temperature and then brominated using liquid bromine (Br ₂ ) and acetic acid at about 60 ° C for about 1 hour. The vinylation of the compound of formula LXII is carried out using tri-butyl-vinyl tin, hexamethylphosphoramide (HMPA) and (Ph ₃ P) ₂ PdCl ₂ catalyst for about 14 hours at about 65 ° C. The aldehyde derivative of formula LXIV is obtained through the ozonolysis of the vinyl group in methylene chloride for about 5 minutes. Scheme AI to using the standard reductive amination conditions A-III using the appropriate compound of formula T-NH ₂ as described above to form the final desired product of formula I (j).
[475]
[476]
[477] Referring to Scheme O, 2-methoxy-5-nitropyridine (Formula LXV) is reacted with potassium t-butoxide in DMF at about ambient temperature for about 16 hours to convert to the phenylsulfone derivative of Formula LXVII. Next, the alkylation and the derivative from the DMF using about 2 hours ethyl bromoacetate while at about 45 ℃ in the presence of potassium carbonate (K ₂ CO _3). The cyclization product of formula LXX is obtained via hydrogenation for about 18 hours (using about 40 psi of hydrogen gas, a palladium catalyst on carbon and an ethanol solvent). The compound of formula LXX is then reacted with methyl iodide in DMF at about 0 ° C for about 1-4 hours in the presence of an organic base, preferably potassium t-butoxide. After mixing the reactants at about 0 < 0 > C, the reaction mixture is allowed to warm to ambient temperature. Bromination of the resulting intermediate with liquid bromine and acetic acid at about 60 < 0 > C for about 1 hour gives the compound of formula LXXI. The vinylation for preparing the compound of formula LXXII can be carried out using tri-n-butyl-vinyl tin, HMPA and (Ph ₃ P) ₂ PdCl ₂ catalyst at about 65 ° C for about 14 hours. Aldehyde derivatives of the formula LXXIII are obtained via the ozonolysis of the vinyl group in methylene chloride for about 5 minutes. Scheme AI to using the standard reductive amination conditions A-III using the appropriate compound of formula T-NH ₂ as described above to give the final desired product of formula I (k).
[478]
[479] Referring to Scheme P, 4-nitrobutyric acid methyl ester is converted to the nitropyridyl derivative of formula LXXIV by reaction with pyridine-3-carboxaldehyde in the presence of an ammonia source such as ammonium acetate, ammonium chloride or ammonium formate. The reaction may be carried out in an alcoholic solvent such as methanol or ethanol at a temperature of about -78 째 C to about reflux (preferably at a reflux temperature). The nitro group is converted to dimethylacetal using the Nef reaction conditions described above. Reduction of the amide group gives the piperidine compound. This reduction can be accomplished by a number of conditions known to those skilled in the art. Preferred conditions include LiAlH ₄ or borane-dimethylsulfide reduction in an inert solvent such as ether or THF. N-Boc protection is then performed via the standard protocol described above to yield the compound of formula LXXV. The reaction of converting an acetal of formula LXXV to an oxime can be carried out under acidic conditions catalysed by mineral acids such as HCl, HBr HNO ₃ or H ₂ SO ₄ , or organic acids such as carboxylic acids or sulfonic acids at temperatures of about -78 ° C. to about 100 ° C. Lt; / RTI > Suitable solvents include water or a mixture of water and various organic solvents such as THF, ether, toluene, DMF, ethanol and methanol. Preferred conditions are to perform HCl-catalyzed hydrolysis in water / THF or water / alcohol at about room temperature. The ketone formed first is converted to an oxime by treatment with hydroxylamine hydrochloride and ammonium acetate at about room temperature. This oxime is reduced by catalytic hydrogenation as described above. The preferred conditions for oxime reduction are treatment with Raney nickel in methanol or ethanol under a hydrogen pressure of 52 psi. The resulting amine of formula LXXVI is converted to a benzylamine derivative by amination under standard conditions described above. The N-Boc group is cleaved under the standard conditions described above to give the compound of formula LXXVII.
[480]
[481] In Scheme R, 3-benzylamino-3-methyl-butyric acid is reduced to the corresponding N-Boc amino alcohol under standard conditions known to those skilled in the art. Preferably, the continuous reaction is achieved by reducing the carboxylic acid with THF or a borane or borane-dimethyl sulfide complex in ether. The N-benzyl group is then hydrolyzed by ethanol or palladium on carbon catalyst in methanol under hydrogen atmosphere at about room temperature. Other sources of hydrogen include ammonium formate or cyclohexene. The Boc group is added under standard conditions using di-tert-butyl dicarbonate in THF / water or dioxane / water in the presence of carbonate bases such as NaHCO ₃ or K ₂ CO ₃ . Alternatively, the Boc group may be added in the presence of triethylamine or other amine bases in CH ₂ Cl ₂ , CHCl ₃ , THF, ether, toluene or related solvents. Oxidation of alcohols to aldehydes is accomplished under standard conditions using Dess-Martin ferrodiene, Swern oxidation or MnO ₂ oxidation. These methods are well known to those skilled in the art. The Henry reaction sequence to obtain the nitroalkene of formula LXXXII is achieved by treating the aldehyde with nitromethane and a suitable base. Typical conditions include alcoholic solvents such as methanol or ethanol and alkoxide bases such as sodium methoxide or sodium ethoxide. Other conditions include amine bases such as CH ₂ Cl ₂ , CHCl ₃ , THF or ether solvents and triethylamine. These conditions provide intermediate nitro alcohols that can be converted to nitroalkenes by activating the alcohol in the presence of a base. Such dehydration reactions are commonly known to those skilled in the art. A preferred method for this transformation involves activating the alcohol with methanesulfonyl chloride or toluenesulfonyl chloride in the presence of triethylamine. The resulting nitroalkene is reduced to the nitroalkane under standard conditions. The preferred conditions for the transformation involves the treatment with NaBH ₄ or LiBH ₄ in alcoholic solvents such as methanol or ethanol. THF can also be used. The reaction may be conducted at a temperature of about -78 째 C to about 88 째 C, but preferably at about 0 째 C to about ambient temperature. Cyclization with a 2,3-trans piperidine ring is accomplished by condensation with an aryl aldehyde such as benzaldehyde in the presence of a catalyst such as ammonium acetate or ammonium chloride. A preferred solvent for the transformation is an alcoholic solvent such as methanol or ethanol, and a typical temperature for the conversion is about -20 캜 to about 100 캜. Alternatively, the conversion may be accomplished in the presence or absence of an acid or base catalyst in a solvent such as CH ₂ Cl ₂ , CHCl ₃ , THF, ether, toluene, ethyl acetate or related solvents. The 2,3-cispiperidine ring is obtained by treating the trans-piperidine with a base followed by quenching by adding the nitronate solution to the excess acid in solution in a dynamic manner. Exemplary bases include amine bases such as triethylamine or Hunig's base in an organic solvent such as CH ₂ Cl ₂ , CHCl ₃ , THF, ether, toluene or ethyl acetate from a metal alkoxide or hydroxide in an alcoholic solution There are LHMDS, KHMDS, and NaHMDS. Other bases include THF or butyllithium in an ether solution. The temperature for the conversion may range from about -78 < 0 > C to about 100 < 0 > C. Nitropiperidine is converted to the aminopiperidine by reduction according to various possible methods known to those skilled in the art. Preferred methods include zinc / HCl, zinc / acetic acid or iron / HCl reduction in a suitable solvent comprising water, THF / water or a water / alcohol mixture. Suitable temperatures range from about -20 캜 to about 118 캜. Reduction can also be achieved by Raney nickel reduction in an alcoholic solvent of a water / alcohol mixture under a hydrogen atmosphere. Typical reaction temperatures range from about 0 캜 to about 100 캜. The resulting amine is treated with reductive amination conditions as described above to provide the compound of interest.
[482]
[483] A mixture of cis and transnitroimine of formula LXXXV-a / LXXXV-b (compound of formula XXXIII prepared in scheme J) can be converted to the single diastereoisomer LXXXV-a by base-induced epimerization. Various bases may be used for this method, including but not limited to 18-crown-6 or 15 crown-5, 12-crown-4, lithium sec-butylborohydride (L- Such as THF, ether or dimethoxyethane, at a temperature of from about 0 C to about -25 C, for a period of from about 15 minutes to about 5 hours, sodium, lithium or potassium hexamethyldisilazane or potassium t- (DBU), tetramethylguanidine, triethylamine, diisopropylethylamine, sodium or potassium, or lithium carbonate, in the presence of a base such as sodium hydroxide, potassium hydroxide, or potassium hydroxide, But are not limited thereto. The reaction mixture is quenched with a suitable acid reagent suspended or dissolved in an inert solvent to give the desired diastereoisomer LXXXV-a. Suitable quenching agents include, but are not limited to, silica gel, alumina, sodium hydrosulfate, pyridinium sulfonate pyridinium salt (PPTS), boric acid, hydrogen chloride, aqueous hydrogen chloride or aqueous sulfuric acid, nafion resin, . Preferred conditions are quenched with a suspension of silica gel in THF after using lithium hexamethyldisilazane in about -78 < 0 > C THF.
[484] Reduction of an imine of the formula LXXXV-a to obtain a mixture in which diastereomers of the formula LXXXV-c / LXXXV-d are preferred can be accomplished using a reducing agent and optionally a Lewis acid activator. Therefore, the imine can be reduced by lithium aluminum hydride with or without triethyl or trimethyl aluminum. Other aluminum reagents such as diethylaluminum chloride or ethylaluminum dichloride may be used. Other reducing agents include, without limitation, boron trifluoride etherate, lithium sec-butyl borohydride (L-select lead), and / or lithium borohydride in the presence of boron trifluoride etherate. ; Or Red (Red) -Al or diisobutyl aluminum hydride and also sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Suitable inert solvents are used during the transformation and may be selected from THF, ether, dimethoxyethane, toluene, hexane, methylene chloride or other suitable solvents. The reaction is generally carried out at room temperature below about -78 < 0 > C to about 0 < 0 > C. The most preferred conditions are to use lithium aluminum hydride in THF at about -78 < 0 > C with triethyl aluminum.
[485] The resulting imine of the formula LXXXV-c or LXXXV-d or a mixture of the compounds of the formula LXXXV-c / LXXXV-d can be prepared by reacting a compound of the formula LXXXVI-a or a compound of the formula LXXXVI-b or a compound of the formula LXXXVI-a / LXXXVI -b < / RTI > The reagent capable of reducing the compound of formula LXXXV-c / LXXXV-d is suitably selected from the group consisting of hydrochloric acid (aq), water, methanol, ethanol, isopropanol, ethyl acetate or a similar inert solvent in the presence or absence of a hydrogen pressure of 1 to 1000 psi But are not limited to, zinc, tin, tin chloride, zinc amalgam, palladium on carbon, palladium hydroxide, platinum oxide, platinum on carbon and Raney nickel in the solvent. Most preferred conditions include zinc metal in aqueous hydrochloric acid at a temperature from about room temperature to about the reflux temperature of the solvent.
[486]
[487] Alternatively, according to Scheme T, compounds of formula LXXXVI-a may also be prepared from compounds of formula LXXXV-a / LXXXV-b in a direct manner. The prepared imines of formula LXXXV-a / LXXXV-b can be prepared by reacting carbobenzyloxychloroformate (cBz-Cl) benzoyl chloride, 9-fluorenylmethyl chloroformate (FMOC-Cl ), t-butoxychloroformate, phenyl chloroformate, nitro and dinitrophenyl chloroformate, methyl, ethyl and isopropyl chloroformate, LXXXVII-a / LXXXVII-b. ≪ / RTI > Suitable solvents include methylene chloride, chloroform, dichloroethane, benzene, toluene, water, ethyl acetate, dioxane and other suitable organic solvents. Typical bases include aqueous sodium, lithium and potassium carbonate or bicarbonate solutions, pyridine, triethylamine, diisopropylethylamine, lutidine, collidine and other suitable bases. The reaction may be carried out at a temperature from about room temperature to about the reflux temperature of the solvent. Most preferred conditions involve reacting a compound of formula LXXXV-a / LXXXV-b with cBz-Cl in aqueous methylene chloride and sodium bicarbonate at about the reflux temperature of the solvent mixture.
[488] The objective cis isomer of formula LXXXVII-a can be obtained directly from the reaction by directly crystallizing the crude product from a suitable solvent such as diethyl ether or diisopropyl ether. Alternatively, a mixture of the cis and trans isomers of the formula LXXXVII-a / LXXXVII-b can be prepared by reacting lithium or sodium bis (trimethylsilyl) amide, lithium diisopropyl (trimethylsilyl) amide in a suitable solvent such as THF or DME at about- Amide, DBU, sodium carbonate or potassium carbonate, followed by quenching with a suitable aqueous acid, such as dilute aqueous hydrochloric acid or dilute acetic acid, into the cis isomer of formula LXXXVII-a. The most preferred conditions involve reacting the compound of formula LXXXVII-a / LXXXVII-b with lithium bis (trimethylsilyl) amide in THF at about -78 < 0 > C followed by quenching with 1N aqueous HCI.
[489] Reduction of the compound of formula LXXXVII-a to form a compound of formula CVI can be accomplished in a variety of ways. The reduction may be carried out in an inert solvent under acidic or neutral conditions at a temperature of about -78 째 C to about room temperature. Suitable reducing agents include 1 to 1000 psi hydrogen gas, ammonium formate, sodium cyanoborohydride, sodium triacetoxyborohydride, tetrabutylammonium triacetoxyborohydride, triethylsilane, polyhydroxysilane, and sodium And lithium borohydride. If the reaction requires a suitable acid, acetic acid or trifluoroacetic acid may be added. In addition, hydrogen chloride triflic acid or sulfuric acid may be used. Typical solvents include methylene chloride, dichloroethane, chloroform, methanol, ethanol, toluene, dioxane and water. The most preferred conditions involve reacting the compound of formula LXXXVII-a with sodium cyanoborohydride in methylene chloride containing trifluoroacetic acid at about -40 < 0 > C. Particularly preferred is a condition involving reacting the compound of formula LXXXVII-a with triethylsilane in methylene chloride containing trifluoroacetic acid at about -40 < 0 > C.
[490] The deprotection of the acyl group and reduction of the nitro to an amine, such as the compound of formula LXXXVI-a, can be done in sequence. For example, reduction of the nitro group can be carried out in the presence or absence of a hydrogen pressure of 1 to 1000 psi in a suitable solvent such as hydrochloric acid (aq), water, methanol, ethanol, isopropanol, ethyl acetate or similar inert solvents, , Zinc amalgam, palladium on carbon, palladium hydroxide, platinum oxide, platinum on carbon, or Raney nickel. Most preferred conditions include zinc metal in aqueous hydrochloric acid at a temperature from about room temperature to about the reflux temperature of the solvent. Removal of the acyl groups can be done in a variety of ways. When the acyl group is cBz-, the catalytic hydrogenation is successful and may or may not occur with the reduction of the nitro group. Typical conditions include hydrogenation with 1 to 1000 psi hydrogen in palladium on carbon or in palladium hydroxide or palladium oxide in methanol or ethanol. Hydrogenolysis can alternatively be carried out in a catalyst such as palladium on carbon or palladium hydroxide or palladium oxide in methanol or ethanol under reflux with ammonium formate or cyclohexene. Another method for cBz cleavage is treatment with HBr in acetic acid or propionic acid solution. For other acyl groups such as t-butoxy- (t-BOC) it is sufficient to simply treat with strong acid, while for the other acyl groups it is essential to treat with an aqueous solution of sodium hydroxide at ambient temperature to about the reflux temperature of the solvent. Alternatively, the cBz or t-Boc group may be removed by treatment with HBr / acetic acid.
[491]
[492] Alternatively, a compound of formula LXLI can be prepared by the reaction sequence shown in Scheme U. The 4-nitrobutyric acid methyl ester or the 4-nitrobutyric acid ethyl ester may be reduced to the aldehyde, and the aldehyde may be protected with the nitroacetal of formula LXXXVIII. Reduction of the 4-nitrobutyric acid methyl ester can be accomplished in one step via reaction with diisobutylaluminum hydride in toluene, hexane or methylene chloride at about -78 < 0 > C. Alternatively, the reduction may be performed in two steps by reducing 4-nitrobutyric acid methyl ester in THF or ether at about 0 < 0 > C to about ambient temperature using lithium aluminum hydride, lithium borohydride or borane in THF. The resulting nitro alcohol may then be oxidized to aldehyde via a Scheren oxidation in methylene chloride or a Death-Martin oxidation. Said aldehyde can be converted to an aldehyde by reaction with a mineral acid such as hydrochloric acid, sulfuric acid and nitric acid or with a catalytic organic acid such as camphorsulfonic acid or toluenesulfonic acid in the presence of a water scavenger such as trimethylorthoformate, triethylorthoformate, magnesium sulphate or molecular sieves Protected with a nitroacetal of formula LXXXVIII in an alcoholic solvent such as methanol, ethanol, propanol or ethylene glycol at a temperature of from about 0 캜 to about 75 캜.
[493] Compounds of formula LXL can be prepared using a modified Henry reaction to give condensed substituted cyclic imines. Nitroacetals of formula LXXXVIII can be prepared by reacting an in situ imine with an imine, such as ammonium acetate, ammonium chloride or ammonium formate, and an aldehyde, such as an optionally substituted aromatic aldehyde, at a temperature of about 0 <Lt; / RTI > The acetal of formula LXXXIX is then converted to the nitroaldehyde by the addition of a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid in water at a temperature between about 0 < 0 > C and about 75 [deg.] C, which causes cyclization to yield a compound of formula LXL . Preferably, the nitroaldehyde is dissolved in methanol together with a catalytic amount of camphorsulfonic acid and trimethylorthoformate at about room temperature. After the addition of ammonium formate, benzaldehyde is added. Aqueous hydrochloric acid is added and stirred to form the cyclic imine of formula LXL.
[494] The imine of formula LXL can be converted to a compound of formula LXLI using an organometallic reagent. For example, other cuffrate reagents such as ethyllithium, ethylmagnesium bromide, diethylmagnesium, diethylzinc, ethylzinc chloride, diethylcouprate, or higher caffeate at a temperature of about -78 ° C to about 0 ° C THF or a solvent such as ether, toluene or dimethoxyethane. Alternatively, a two-step process may be used to add THF or a solvent such as ether, toluene or dimethoxyethane at a temperature from about -78 [deg.] C to about 0 [deg.] C to a solution of vinyl lithium, vinyl magnesium bromide, divinyl magnesium, divinyl zinc, vinyl zinc chloride, Other kuprate reagents such as divinylcouprate, or higher carboperate can be added. When the addition is complete, the resulting product is hydrogenated under 1 to 1000 psi hydrogen pressure on palladium on carbon, palladium hydroxide, platinum oxide, platinum on carbon or Raney nickel. Alternatively, acetylenic lithium may be added under similar conditions as listed above for vinyl in another two step process. Following this step, hydrogenation is also carried out. Optionally, Lewis acid may be included in the addition to the immigration. Typical Lewis acids include boron trifluoride etherate, zinc chloride and trimethyl or triethyl aluminum.
[495] The resulting amine of formula LXLI can be reduced to a compound of formula LXXXVI-a (Scheme T) by a suitable reducing agent. Reagents capable of reducing LXLI include, but are not limited to, hydrochloric acid (aq), water, methanol, ethanol, isopropanol, ethyl acetate or similar inert solvents, in the presence or absence of hydrogen pressures of 1 to 1000 psi, But are not limited to, zinc amalgam, palladium on carbon, palladium hydroxide, platinum oxide, platinum on carbon and Raney nickel. Most preferred conditions include zinc metal in aqueous hydrochloric acid at a temperature from about room temperature to about the reflux temperature of the solvent.
[496]
[497] Alternatively, compounds of formula LXXXVI-a may be prepared by the reaction sequence shown in Scheme V. [ The resulting 1-nitrohex-4-one (compound of the formula LXLII) is reacted and purified by molecular sieve or by refluxing with optional removal of water using a Dean Stark water separator in the presence of benzene, toluene, dichloroethane, methanol Or by reacting phenylglycinol with an array in a suitable solvent such as ethanol to form the hemiacetal of formula LXLIII. Compounds of formula LXLIV may be prepared using a modified Henry reaction, which is then condensed to produce a substituted cyclic acetal of formula LXLV. The cyclic acetals of the formula LXLV can be prepared by reacting an imine produced by an ammine source such as ammonium acetate, ammonium chloride or ammonium formate at a temperature from about 0 C to about 75 < 0 > C in situ, and a base such as benzaldehyde or variously substituted aromatic aldehydes Condensation with aldehyde. In most cases, the compound of formula LXLIV is not isolated but is directly cyclized to a compound of formula LXLV.
[498] Reduction of a compound of formula LXLV to form a compound of formula LXLVI can be accomplished in a variety of ways. The reduction can be carried out in an inert solvent at a temperature from about -78 < 0 > C to about room temperature under acidic or neutral conditions. Suitable reducing agents include 1 to 1000 psi hydrogen gas, ammonium formate, sodium cyanoborohydride, sodium triacetoxyborohydride, tetrabutylammonium triacetoxyborohydride, triethylsilane, polyhydroxysilane, and sodium And lithium borohydride. If the reaction requires a suitable acid, acetic acid or trifluoroacetic acid and boron trifluoride etherate or trimethylaluminum may be added. In addition, hydrochloric acid triflic acid or sulfuric acid may be used. Typical solvents include methylene chloride, dichloroethane, chloroform, methanol, ethanol, toluene, dioxane and water.
[499] Compounds of formula LXLVI can be deprotected via hydrolysis. Typically, the nitro group is also reduced to the amine of formula LXXXVI-a during the process. Typical conditions include hydrogenation with palladium on carbon or palladium hydroxide or palladium oxide in methanol or ethanol with 1-1000 psi hydrogen. Alternatively, hydrogenolysis can be done with ammonium formate or cyclohexene under reflux in methanol or ethanol in a catalyst such as palladium on carbon or palladium hydroxide or palladium oxide. When the nitro group is removed prior to hydrolysis, suitable reaction conditions include the following: The nitro functionality may be removed from a suitable solvent, such as hydrochloric acid (aq), water, methanol, ethanol, isopropanol, ethyl acetate or similar inert solvents, in the presence or absence of a hydrogen pressure of 1 to 1000 psi, Such as, but not limited to, palladium, palladium hydroxide, platinum oxide, platinum on carbon and Raney nickel. Most preferred conditions include zinc metal in aqueous hydrochloric acid at a temperature from about room temperature to about the reflux temperature of the solvent.
[500]
[501] 2-Bromo-3-methoxy-5-nitropyridine (J. Lombardino, J. Med. Chem. 1981, 24, 39-42) is converted to a 2-aldehyde derivative of formula LXLIX using a two step procedure . The compound of formula LXLVII is reacted with a catalytic amount of bis (triphenylphosphine) -palladium (II) chloride in an aprotic solvent (preferably toluene) at about room temperature to about 150 & N-butyl-vinyltin over a period of about 1 hour to about 24 hours (preferably 2 hours). The reaction mixture is chromatographed to give the vinyl compound of formula LXLVIII. The vinyl compound of formula LXLVIII is treated with ozone in methylene chloride at about -100 ° C to about 0 ° C (preferably at -78 ° C) and then quenched with dimethyl sulfide to obtain the aldehyde of formula LXLIX. The aldehyde of formula LXLIX is protected using methods known to those skilled in the art, for example, by reaction with ethylene glycol in benzene in the presence of a catalytic amount of an acid (preferably p-toluenesulfonic acid) to give the acetal of formula C. The pyridine derivative of formula (C) is reacted with benzylsulfonyl chloride using a strong base (preferably potassium t-butoxide) in an aprotic solvent (preferably a mixture of THF and DMF) to give a sulfone derivative of formula CI. The methylene group of the sulfone of formula CI can be alkylated with ethyl bromoacetate in a protic solvent (preferably ethanol) using a strong base (preferably potassium t-butoxide). Among these reaction conditions, benzene sulfinic acid is removed to form the ester of formula CII. The ester of formula CII is hydrogenated in a protic solvent (preferably ethanol) using a metal catalyst (preferably 10% palladium-on-carbon) at about atmospheric pressure to about 50 PSI (preferably 50 PSI). During this reaction the nitro group is reduced to an amine, the double bond is reduced and the cyclization to the 6-amide is accomplished to yield the amide of formula CIII. Alkylation of an amide of formula CIII is accomplished with methyl iodide using a strong base (preferably potassium-t-butoxide) in an aprotic solvent (preferably THF) to give an amide of formula CIV. The aldehyde in the amide of formula CIV is deprotected using an acid (preferably p-toluenesulfonic acid) in an aprotic solvent (preferably acetone) to give the aldehyde of formula CV. The product of formula I (m) is obtained by reductive amination using aminopiperidine T-NH ₂ as shown in Scheme A-1.
[502] The preparation of other compounds of formula I not specifically described in the experimental section can be accomplished using a combination of the reactions described above, which will be apparent to those skilled in the art.
[503] In each of the reactions discussed or exemplified above, the pressure is not critical unless otherwise stated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally permissible, and in terms of convenience, ambient pressure, i.e., about 1 atmosphere, is preferred.
[504] The compounds of formula I and the intermediates shown in the above schemes can be isolated and purified by conventional methods such as recrystallization or chromatographic separation.
[505] The compounds of formula I and their pharmaceutically acceptable salts can be administered to mammals via oral, parenteral (e.g. subcutaneous, intravenous, intramuscular, intrasternal or infusion techniques), rectal, intranasal or topical routes . In general, these compounds are most preferably administered in single or divided doses ranging from about 0.01 to about 1500 mg per day (i.e., from 1 to 4 doses daily), but will vary depending upon the species, weight and condition of the subject to be treated, It may be necessary to vary according to the particular route of administration. However, it is most preferred to use a dosage level ranging from about 0.5 mg to about 500 mg per kg body weight per day. It will nevertheless be possible to vary depending on the species of animal to be treated and the individual response to the medicament, as well as the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some cases, dosage levels lower than the lower limit of the above range may be more suitable, but in other cases more doses may be administered divided into smaller doses over the course of a day and used without any harmful side effects.
[506] The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the routes mentioned above and may be administered in single or multiple doses. More particularly, the novel therapeutic agents of the present invention may be advantageously administered in a variety of different dosage forms. That is, the novel therapeutic agent of the present invention may be in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, In combination with various pharmaceutically acceptable inert carriers in the form of suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, the oral pharmaceutical composition may suitably contain sweetening and / or flavoring agents. In general, the therapeutically effective compounds of the present invention may be present in such dosage forms at a concentration level ranging from about 5.0 to about 70% by weight.
[507] For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be mixed with starches (preferably corn starch, potato starch or tapioca starch), alginic acid and certain silicate complexes Such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. ≪ RTI ID = 0.0 > In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting. Solid compositions of a similar type may also be used as fillers in gelatin capsules, and preferred materials associated therewith also include high molecular weight polyethylene glycols as well as lactose or lactose. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, coloring matter or dyes, and if necessary emulsifying and / or suspending agents, and water, ethanol, propylene glycol, glycerin and / Can be combined with a diluent such as various mixtures thereof.
[508] For parenteral administration, solutions of the compounds of the present invention in sesame oil or peanut oil or aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably above pH 8) if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
[509] In addition, when treating inflammatory conditions of the skin, the compound of the present invention may be administered locally, and this may be carried out by a cream, a jelly, a gel, a paste, a patch, an ointment or the like according to standard pharmaceutical practice.
[510] The activity of the compounds of the present invention as an inhibitory P antagonist is determined by the ability of the compound to inhibit the binding of the inhibitory P at the receptor site of the immunoreactive P of IM-9 cells using a radioactive ligand. The inhibitory P antagonist activity of the compounds described herein is assessed using standard assays as described in DG Payan et al., The Journal of Immunology, 133, 3260 (1984). The method comprises determining the concentration of each compound required to reduce the amount of radiolabeled P-ligand at the receptor site of the isolated bovine tissue or IM-9 cell, thereby obtaining the IC ₅₀ value of each test compound . More specifically, the inhibition of [ ³ H] SP binding to human IM-9 cells by the compound was assayed in assay buffer (50 mM Tris-HCl (pH 7.4), 1 mM MnCl ₂ , 0.02% bovine serum albumin, (40 μg / ml), leupeptin (4 μg / ml), chymostatin (2 μg / ml) and phosphoramidon (30 μg / ml)). The reaction is initiated by adding cells to assay buffer containing 0.56 nM [ ³ H] SP and various concentrations of compound (total volume 0.5 ml) and incubated at 4 ° C for 120 minutes. Incubation is terminated by filtration through a GF / B filter (pre-soaked in 0.1% polyethyleneamine for 2 hours). Non-specific binding is defined as residual radioactivity in the presence of 1 [mu] M SP. The filter is placed in a tube and counted using a liquid scintillation counter.
[511] All of the title compounds of the examples were tested and one or more stereoisomers of each of the compounds showed binding affinities measured with a K _i of 600 nM or greater.
[512] The activity of the compounds of the present invention against anxiety disorders can be determined by inhibition of the GR73632-induced tapping test in gerbils. More specifically, gervilus rats are anesthetized with ether and exposed to the skull surface. GR73632 or vehicle (PBS, 5 μl) is administered directly to the lateral ventricle (pre-treated with antagonist, 0.1 to 32.0 mg / kg, subcutaneous or oral) via a 25 gauge needle inserted at a crown of 4.5 mm or less. After the injection, the gerbils are placed in a 1 L beaker and monitored for repetitive hindpaw tapping. Some compounds prepared in the following examples were tested according to these test methods. As a result, the compounds of the present invention have excellent antagonist activity, particularly with reduced side effects, against interference P, as well as excellent activity against CNS disorders.
[513] The present invention is illustrated by the following examples. However, the present invention should not be construed as being limited to the specific details of these embodiments. The melting point was not corrected. Proton nuclear magnetic resonance spectra ( ¹ H NMR) and ¹³ C nuclear magnetic resonance spectra were measured for solutions in deuterated chloroform (CDCl ₃ ) or CD ₃ OD or CD ₃ SOCD ₃ and the peak positions were determined from tetramethylsilane (TMS) And a low percentage of downfield (ppm). The peak shapes are: s, single; d, double; t, triplet; q, quadrature; m, multiple; b, broad.
[514] Experimental Method
[515] Production Example 1
[516] 6-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinoline
[517] P-Aminophenol [0.5 gm (4.58 mmol)] was dissolved in 30 ml each of methylene chloride and saturated aqueous bicarbonate solution, which was stirred at ambient temperature for 5 minutes. 3-Chloropropionyl chloride [0.49 ml (5.04 mmol)] was added over 10 minutes, and the reaction mixture was stirred at ambient temperature for 4 hours. A large amount of sediment was observed. The solid was filtered and dried to give 0.82 gm (90%) of an off-white solid. MS APCI m / e 200 (p + 1) < RTI ID = 0.0 >
[518] 0.82 gm (4.1 mmol) of the compound and 1.6 gm (12.3 mmol) of aluminum chloride were combined as a mixture of solids. The mixture was then heated in a 210 DEG C oil bath for 10 minutes or until gas evolution ceased. The reaction mixture was then cooled to ambient temperature and then quenched in an ice / water mixture. The aqueous phase was extracted with ethyl acetate, which was separated, dried over sodium sulfate and evaporated in vacuo to afford 0.58 gm (87%) of light brown solid. MS APCI m / e 164 (p + l)
[519] Production Example 2
[520] 6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline
[521] A solution of 0.58 gm (3.56 mmol) 6-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinoline was prepared in 10 mL acetone followed by the addition of 1.46 gm (10.58 mmol) potassium carbonate, 0.51 mL (5.36 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated in vacuo. The residue was partitioned between saturated aqueous bicarbonate solution and methylene chloride. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with 96/4 methylene chloride / methanol to give 0.53 gm (85%) of the desired product as a white solid. MS APCI m / e 178 (p + 1)
[522] Production Example 3
[523] 6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde
[524] After preparing a mixture of methylene chloride and 5 ㎖ of aluminum chloride 0.29 gm (2.19 mmol) under nitrogen gas N ₂ and stirred for 15 minutes and cooled to 0 ℃. The mixture was treated with 0.2 gm (1.13 mmol) of 6-methoxy-3,4-dihydro-1H-quinolin-2-one in 5 ml of methylene chloride. The reaction mixture was stirred at this temperature for 10 minutes and then cooled to -5 < 0 > C. 0.28 ml (3.07 mmol) of alpha, alpha -dichloromethyl methyl ether was added over 5 minutes. The green reaction mixture was slowly warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with 2N HCl and extracted with methylene chloride (4 x 10 mL). The combined organics were dried with sodium sulfate, filtered and concentrated to give an off-white solid. The crude product was purified by chromatography on silica gel, eluting with 7/3 ethyl acetate / hexane. 125 mg (54%) of an off-white solid was obtained. MS APCI m / e 206 (p + l)
[525] Example 1
[526] 6-methoxy-7- [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-
[527] (2S, 3S) -3-amino, 2-phenylpiperidine 66 mg (0.37 mmol) in 15 ml toluene containing a 3 A molecular sieve in a dry nitrogen-air flame dried round bottom flask equipped with a Dean- and 77 mg (0.37 mmole) of 6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde. The reaction mixture was heated at reflux for 6 hours and monitored by mass spectrometry for the presence of imine intermediate. The reaction mixture was cooled to ambient temperature and then evaporated in vacuo. The residue was dissolved in about 15 ml of dichloroethane, treated with 102 mg (0.48 mmol) of sodium triacetoxyborohydride and then stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was then washed with a saturated aqueous sodium bicarbonate solution, washed with brine, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 95/5 CHCl ₃ / MeOH containing 3 drops of concentrated NH ₄ OH solution. 100 mg of the free base (75%) was obtained, which was converted as the hydrochloride with the named product in the following manner. A solution of methanolic hydrochloric acid (HCl) was obtained by treating with methanol containing 3 equivalents of acetyl chloride (53 L, 0.82 mmol), which was stirred for 10 minutes. The free base was added to methanol and the mixture was stirred again for 10 minutes and then evaporated in vacuo. The residue was dissolved in a minimal amount of methanol and treated with ether until a cloudy precipitate formed. To give di-HCl salt as a 46% overall yield (75 mg). Mp 233-235 C MS, APCI m / e 366 (p + 1).
[528] Production Example 4
[529] 1-Ethyl-6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde
[530] 60 mg (0.293 mmol) of 6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (Preparation Example 3) was dissolved in 5 ml of anhydrous THF, Lt; 0 > C. The reaction mixture was treated with 33 mg (0.293 mmol) of potassium t-butoxide and turned yellow. After stirring for 30 minutes, the mixture was treated with 23 l (0.293 mmol) of ethyl iodide and slowly warmed to room temperature with stirring for 16 hours. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to an oil. The residue was chromatographed on silica gel, eluting with 6/4 ethyl acetate / hexanes to give 34 mg (40%) as a white solid. MS APCI m / e 234 (p + 1)
[531] Production Example 5
[532] Methyl-6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde
[533] 30 mg (0.146 mmol) of 6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde was dissolved in 5 ml of anhydrous THF and the solution was cooled to 0 <0> C. The reaction mixture was treated with 16 mg (0.146 mmol) of potassium t-butoxide and turned yellow. After stirring for 30 minutes, the mixture was treated with 14 [mu] l (0.146 mmol) dimethylsulfate and slowly warmed to room temperature with stirring for 16 hours. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to an oil. The residue was chromatographed on silica gel, eluting with 6/4 ethyl acetate / hexanes to give 16 mg (50%) as a white solid. MS APCI m / e 220 (p + 1)
[534] Example 2
[535] Methyl-3, 4-dihydro-1 H-quinolin-2-one &lt; / RTI &
[536] (2S, 3S) -3-amino, 2-phenylpiperidine in 10 ml toluene containing 3A molecular sieves was added to a 50 ml round bottom flask equipped with a Dean-Stark water separator, a condenser and a nitrogen cap, and 0.033 gm (0.151 mmole) of 1-ethyl-6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (Preparation Example 5). The reaction mixture was heated at reflux for 18 hours. The solution was then cooled to room temperature and then evaporated in vacuo. The residue was dissolved in 25 mL of dichloroethane, treated with 0.048 gm (0.229 mmol) of sodium triacetoxyborohydride, and the solution was stirred at ambient temperature for 16 hours. The reaction was then partitioned between saturated aqueous bicarbonate solution and dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulfate and evaporated in vacuo. The crude product 95 CHCl _3, 4 MeOH, 1 NH ₄ OH and was eluted with silica gel chromatography. The resulting oil was dissolved in pre-treated methanol with 17.5 [mu] l of acetyl chloride. The solution was evaporated in vacuo and recrystallized from methanol-ether to give 33 mg (47%) of the dihydrochloride salt of the desired product. Mp 253-255 C; MS, APCI m / e 394 (p + 1).
[537] Production Example 6
[538] Methanesulfonyl-6-methoxy-3,4-dihydro-1H-quinolin-2-
[539] A flame dried round bottom flask equipped with a nitrogen cap was charged with 87 mg (2.17 mmol) of 60% sodium hydride in mineral oil and 15 ml of dimethylformamide (DMF). The mixture was cooled to 0 C and treated with 350 mg (1.97 mmol) of 6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline (Preparation 2) in a minimum amount of DMF. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 0.5 h and then treated with mesyl chloride 226 mg (1.97 mmol). The mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched by addition of 30 mL of a saturated aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 1/1 ethyl acetate / hexanes to give a light yellow oil in 35% yield (177 mg). Mass spectrum APCI m / e 256 (p + 1).
[540] Production Example 7
[541] Methanesulfonyl-6-methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde
[542] To a flame dried round bottom flask equipped with a nitrogen cap was added 180 mg (1.35 mmol) of aluminum chloride and 10 ml of methylene chloride. The mixture was stirred at ambient temperature for 0.25 h, then cooled to 0 &lt; 0 &gt; C and 177 mg (0.69 mmol) of 1-methanesulfonyl-6-methoxy-3,4-dihydro- Was added. The reaction mixture was stirred at this temperature for 10 minutes, then treated with 171 [mu] l (1.89 mmol) of [alpha], [alpha] -dichloromethyl methyl ether and the reaction was slowly warmed to room temperature over 16 hours. The reaction mixture was quenched with 30 mL 2 M HCl and extracted with ethyl acetate (3 x 30 mL). The combined organics were then washed with saturated aqueous bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified on silica gel eluting with 95/5 methylene chloride / methanol to give an off-white solid in 66% yield (130 mg). Mass spectrum APCI m / e 284 (p + 1).
[543] Example 3
[544] Methanesulfonyl-6-methoxy-7 - [(2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin-
[545] (2S, 3S) -3-amino, 2-phenylpiperidine 81 mg (0.46 mmole) and 1-methanesulfonyl-6-methoxy-2-oxo -1,2,3,4-tetrahydro-quinoline-7-carbaldehyde 130 mg (0.46 mmole) was converted to the above 6% overall yield (12.5 mg) as the hydrochloride salt. Mp 237-241 C MS, APCI m / e 444 (p + 1).
[546] Production Example 8
[547] Methoxy-N-methylacetanilide
[548] To a flame dried round bottom flask equipped with a nitrogen cap was added 1.0 gm (6.05 mmol) of 4-methoxyacetanilide and 20 ml of THF. The solution was cooled to 0 C and treated with a 1 M solution of potassium t-butoxide (K-O-t-Bu) 680 mg (6.05 mmol) in tetrahydrofuran (THF) and stirred for 30 minutes. The reaction mixture was treated dropwise with 570 [mu] l (6.05 mmol) dimethyl sulphate and slowly warmed to ambient temperature over 16 hours. At this time, the transparent reaction mixture became a hazy mixture. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with chloroform (3 x 30 mL). The combined extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with petroleum ether and the resulting solid was removed, which was measured as unreacted starting material. The mother liquor was concentrated to 780 mg (72%) of oil to give the named product. Mass spectrum APCI m / e 180 (p + 1).
[549] Production Example 9
[550] 3-Hydroxy-N- (4-methoxy-phenyl) -3, N-dimethyl-butyramide
[551] After adding 10 mL of anhydrous THF to a flame dried round bottom flask equipped with a nitrogen cap, 390 ㎕ (2.79 mmol) of diisopropylamine was added. The solution was cooled to -78 [deg.] C and then 1.1 M (2.57 mmol) of 2.5 M n-butyllithium in hexane was added dropwise. The reaction mixture was stirred at this temperature for 0.5 h, then temporarily warmed to -50 &lt; 0 &gt; C and then cooled again to -78 &lt; 0 &gt; C. A solution of 0.5 gm (2.79 mmol) of 4-methoxy-N-methylacetanilide in 5 ml of anhydrous THF was added to a solution of the base and the reaction mixture was stirred at -78 &lt; 0 &gt; C for 1 h. Then acetone (205 L (2.79 mmol)) was added dropwise and the reaction mixture slowly warmed to ambient temperature over 1 hour. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform (CHCl3) ( ₃ x 30 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was eluted with 1/1 ethyl acetate / hexane and purified on silica gel to give 375 mg (57%) of the desired product. Mass spectrum APCI m / e 238 (p + 1).
[552] Production Example 10
[553] 6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-
[554] To 0.2 gm (0.84 mmol) of 3-hydroxy-N- (4-methoxyphenyl) -3, N-dimethyl-butyramide about 5 ml polyphosphoric acid was added and the mixture was heated Respectively. The reaction mixture was then poured into ice / water, stirred for 15 minutes and then extracted with chloroform (2 x 20 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was weighed to 158 mg (85%) and identified as the desired product. Mass spectrum APCI m / e 220 (p + 1).
[555] Production Example 11
[556] 6-Methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one -7-carboxaldehyde
[557] The aluminum chloride 89 mg (66 mmol) and methylene chloride (CHCl ₂₎ 5 ㎖ was added to bottom flask equipped with a nitrogen cap flame dried round. The mixture was stirred at ambient temperature for 0.25 h and then cooled to 0 &lt; 0 &gt; C and then 75 mg (0.34 mmol, 6 mmol) of 6-methoxy-1,4,4-trimethyl-3,4-dihydro- ). The reaction mixture was stirred at this temperature for 10 minutes, then treated with 84 [mu] l (0.93 mmol) of [alpha], [alpha] -dichloromethyl methyl ether and the reaction was slowly warmed to room temperature over 16 hours. The reaction mixture was quenched with 30 mL 2 M HCl and extracted with ethyl acetate (3 x 30 mL). The combined organics were then washed with saturated aqueous bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel elution with 1: 1 ethyl acetate / hexane to give two products. A more polar material was identified as the desired product: mass spectrum APCI m / e 248 (p + 1). The less polar product was identified as 7-dichloromethyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (mass spectrum APCI m / e 302 (p + This was temporarily stirred in pH 7 phosphate buffer, and the desired product was isolated therefrom. Total yield 56 mg (66%).
[558] Production Example 12
[559] 6-Methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one -7-carboxaldehyde
[560] A flame dried round bottom flask equipped with a nitrogen cap was charged with 83 mg (0.38 mmol) of 6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin- And 53 mg (0.38 mmol) of hexamethylenetetramine were added. The mixture was stirred at reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched with 30 mL of a saturated aqueous bicarbonate solution and extracted with ethyl acetate (3 x 30 mL). The combined organics were then washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue (64 mg; 68%) was used directly in the next step. Mass spectrum APCI m / e 248 (p + 1).
[561] Example 4
[562] 6-methoxy-1,4,4-trimethyl-7 - [(2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin-
[563] (2S, 3S) -3-amino, 2-phenylpiperidine 86 mg (0.49 mmole) and 6-methoxy-1,4,4-trimethyl- (0.49 mmole) of 4-dihydro-1H-quinolin-2-one-7-carboxaldehyde were converted to the above-named product as hydrochloric acid in 29% overall yield (68 mg). Mp > 280 [deg.] C MS, APCI m / e 408 (p + 1).
[564] Production Example 13
[565] 2-Fluoro-4-methoxy-N-methylacetanilide
[566] To a flame dried round bottom flask equipped with a nitrogen cap was added 4 gm (24.46 mmol) of 2-fluoro-4-hydroxyaniline and 200 ml of methylene chloride. The solution was treated with 10.25 mL (73.39 mmol) of triethylamine and 4.62 mL (48.92 mmol) of acetic anhydride and stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (3 x 30 mL). The combined extracts were washed with brine, dried over sodium sulfate (Na ₂ SO ₄ ) and evaporated in vacuo to give an off-white solid (4.82 gm) (93%). Mass spectrum APCI m / e 212 (p + 1) 2-fluoro-4-acetoxyacetanilide (which is used directly in the following preparations).
[567] 1.75 gm (8.29 mmol) of the above product and 100 ml of methanol were added to a flame dried round bottom flask equipped with a nitrogen cap. The solution was treated with 1.1 gm (8.29 mmol) of potassium carbonate and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered and concentrated in vacuo to give a sticky solid 1.4 gm (100%) which was used directly in the next step.
[568] To a flame dried round bottom flask equipped with a nitrogen cap was added 663 mg (16.57 mmol) of 60% sodium hydride in mineral oil and 10 mL of DMF. The mixture was treated with 1.4 gm (8.28 mmol) of 2-fluoro-4-hydroxyacetanilide in a minimal amount of DMF and stirred at ambient temperature for 1 hour. The mixture was treated with 1.03 ml (16.57 mmol) of methyl iodide and stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with chloroform (3 x 30 mL). The combined extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel elution with a gradient of ethyl acetate / hexane 3/7 to ethyl acetate / hexane 1/1 to give 510 mg (32%) of desired product. Mass spectrum APCI m / e 198 (p + 1).
[569] Production Example 14
[570] 3-Hydroxy-N- (2-fluoro-4-methoxy-phenyl) -3, N-dimethyl-butyramide
[571] After adding 10 mL of anhydrous THF to a flame dried round bottom flask equipped with a nitrogen cap, 360 [mu] l (2.58 mmol) of diisopropylamine was added. The solution was cooled to -78 &lt; 0 &gt; C and 1.03 ml (2.58 mmol) of 2.5 M n-butyllithium in hexane was added dropwise. The reaction mixture was stirred at this temperature for 0.5 h, then temporarily warmed to -50 &lt; 0 &gt; C and then cooled again to -78 &lt; 0 &gt; C. A solution of 0.51 gm (2.58 mmol) of 2-fluoro-4-methoxy-N-methylacetanilide in 5 ml of anhydrous THF was added to the solution of the base and the reaction mixture was stirred at -78 <0> C for 1.5 h. Then acetone (200 L (2.58 mmol)) was added dropwise and the reaction mixture was slowly warmed to ambient temperature over 1 hour. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel elution with 3/7 ethyl acetate / hexane to give 315 mg (48%) of desired product. Mass spectrum APCI m / e 255 (p + 1).
[572] Production Example 15
[573] 8-fluoro-6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-
[574] About 5 ml of polyphosphoric acid was added to 0.11 gm (0.43 mmol) of 3-hydroxy-N- (2-fluoro-4-methoxyphenyl) -3, N-dimethylbutyramide, And heated to 110 ° C. The reaction mixture was then poured into ice / water, stirred for 15 minutes and then extracted with chloroform (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was weighed to 93 mg. The crude product was purified by silica gel elution with 2/8 ethyl acetate / hexane to give 84 mg (82%) of the desired product. Mass spectrum APCI m / e 238 (p + 1).
[575] Production Example 16
[576] 8-fluoro-6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one -7-carboxaldehyde
[577] 74 mg (0.312 mmol) of 8-fluoro-6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one was added to a flame dried round bottom flask equipped with a nitrogen cap, 3 ml of trifluoroacetic acid and 53 mg (0.38 mmol) of hexamethylenetetramine were added. The mixture was stirred at reflux for 16 hours and then cooled to ambient temperature. The reaction mixture was first quenched with water, quenched with 30 mL of saturated aqueous bicarbonate solution, and extracted with ethyl acetate (3 x 30 mL). The combined organics were then washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude product was purified by silica gel elution with ethyl acetate to give 43 mg (52%) of desired product. Mass spectrum APCI m / e 266 (p + 1).
[578] Example 5
[579] 6-methoxy-1,4,4-trimethyl-7 - [(2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro- 2-on
[580] (2S, 3S) -3-amino, 2-phenylpiperidine 27 mg (0.151 mmole) and 8-fluoro-6-methoxy- 40 mg (0.151 mmole) of 4-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde was obtained as a hydrochloric acid with 46% overall yield (35 mg) Respectively. Mp > 270 [deg.] C MS, APCI m / e 426 (p + 1).
[581] Example 6
[582] 3-ylamino) -methyl] -3,4-dihydro-1 H-quinolin-2- &lt; On
[583] (2R, 3R) -3-amino, 2-phenylpiperidine 355 mg (2.02 mmole) and 6-methoxy-1-methyl- 420 mg (1.92 mmole) of 2,3,4-tetrahydro-quinoline-7-carbaldehyde was converted to the overall yield of 24% (210 mg) as dihydrochloride by the named product. Mp > 270 [deg.] C MS, APCI m / e 380 (p + 1).
[584] Production Example 17
[585] 3-Hydroxy-N- (4-methoxy-phenyl) -N-methyl-butyramide
[586] After adding 5 mL of anhydrous THF to a flame dried round bottom flask equipped with a nitrogen cap, 230 μL (1.68 mmol) of diisopropylamine was added. The solution was cooled to -78 C and then 0.67 mL (1.68 mmol) of 2.5M n-butyllithium (nBuLi) in hexane was added dropwise. The reaction mixture was stirred at this temperature for 0.5 h, then temporarily warmed to -50 &lt; 0 &gt; C and then cooled again to -78 &lt; 0 &gt; C. A solution of 0.3 gm (1.68 mmol) of 4-methoxy-N-methylacetanilide in 5 ml of anhydrous THF was added to the solution of the base and the reaction mixture was stirred for 1 h at -78 <0> C. Thereafter, acetaldehyde (94 [mu] l (1.68 mmol)) was added dropwise and the reaction mixture was slowly warmed to ambient temperature over 16 hours. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was eluted with 1/1 ethyl acetate / hexane and purified on silica gel to give 201 mg (54%) of the desired product. Mass spectrum APCI m / e 223 (p + 1).
[587] Production Example 18
[588] 6-methoxy-1,4-dimethyl-3,4-dihydro-1H-quinolin-
[589] To 0.201 gm (0.91 mmol) of 3-hydroxy-N- (4-methoxy-phenyl) -N-methyl-butyramide was added approximately 5 mL polyphosphoric acid and the mixture was heated to 110 <0> C for 1 hour. The reaction mixture was then poured into ice / water, stirred for 15 minutes and then extracted with chloroform (2 x 20 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was weighed to 110 mg (60%) and identified as the desired product. Mass spectrum APCI m / e 206 (p + 1).
[590] Production Example 19
[591] 6-Methoxy-1,4-dimethyl-3,4-dihydro-1H-quinolin-2-one -7-carboxaldehyde
[592] A flame dried round bottom flask equipped with a nitrogen cap was charged with 110 mg (0.54 mmol) of 6-methoxy-1,4-dimethyl-3,4-dihydro-1H- 90 mg (0.64 mmol) of hexamethylenetetramine was added. The mixture was stirred at reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was first quenched with water, quenched with 30 ml of a saturated aqueous bicarbonate solution and extracted with chloroform (3 x 30 ml). The combined organics were then washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue (72 mg) was purified by silica gel column chromatography eluting with 4/6 ethyl acetate / hexane to give 50 mg (40%) of a yellow solid which was used directly in the next step. Mass spectrum APCI m / e 234 (p + 1). The enantiomeric separation was complete on a Chiralpak AD column eluting with 9/1 hexane / ethanol (EtOH) containing 1% diethylamine. Retention times were 12 min and 13.8 min, respectively.
[593] Example 7
[594] 6-methoxy-1,4-dimethyl-7- [(2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin-
[595] (2S, 3S) -3-amino, 2-phenylpiperidine 30 mg (0.172 mmole) and 6-methoxy-1,4-dimethyl-3,4 40 mg (0.172 mmole) of dihydro-1H-quinolin-2-one-7-carboxaldehyde was converted to 31% overall yield (21 mg) with the named product. MS, APCI m / e 394 (p + 1). The diastereomeric separation was complete on a chiralcel OD column eluting with 9/1 Hex / EtOH containing 1% diethylamine. Retention times were 14.7 minutes and 16.2 minutes, respectively.
[596] Example 8
[597] Methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-2H-isoquinolin-
[598] (2S, 3S) -3-amino, 2-phenylpiperidine 80 mg (0.456 mmole) and 6-methoxy-2-methyl- , 2,3,4-tetrahydro-isoquinoline-7-carbaldehyde 100 mg (0.456 mmole) was converted to the 6% overall yield (12.5 mg) with the above named product. MS, APCI m / e 379 (p + 1).
[599] Production example 20
[600] 6-Methoxy-1-methyl-1H-quinolin-2-
[601] A solution of 10 gm (63 mmol) 6-methoxyquinoline in 150 mL acetone was treated with 4.4 mL (70 mmol) methyl iodide, heated at reflux for 4.5 hours, and then stirred at ambient temperature for 16 hours. The solution was filtered to give the desired product [14 gm (74%)]. This material was suspended in 360 mL of water and cooled to 5 &lt; 0 &gt; C. The mixture was treated by adding 90 gm (0.273 mol) of potassium ferricyanide in portions over 1 hour. The mixture was maintained at 5 占 폚 for 30 minutes and then treated with a solution of 31 gm (0.56 mol) of KOH in 65 ml of water which had been pre-cooled in the ice bath for 30 minutes. The mixture was very thickened. 250 ml of toluene was added and the mixture was heated to 40 캜 for 30 minutes in a water bath. The organic layer was separated, and the aqueous phase was extracted twice more by the same method. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo to give 8.2 gm of the desired product. Mass spectrum APCI m / e 190 (p + 1).
[602] Production Example 20A
[603] 6-Methoxy-1-methyl-1H-quinolin-2-
[604] A solution of 50 gm (314.1 mmol) of 6-methoxyquinoline in 650 ml acetone was treated with 21.5 ml (345.5 mmol) methyl iodide, heated at reflux for 6 hours and then stirred at ambient temperature for 16 hours. The solution was filtered to give the desired product [81.4 gm (91%)]. This material (285.4 mmol) was suspended in 2000 mL of water and cooled to 5 &lt; 0 &gt; C. The mixture was treated by adding 552.6 gm (1.68 mol) of potassium ferricyanide in portions over 1 hour. The mixture was held at 5 캜 for 30 minutes and then treated with a solution of 191.8 gm (3.43 mol) of KOH in 400 ml of water which had been pre-cooled in the ice bath for 30 minutes. The mixture was very thickened. 250 ml of toluene was added, and the mixture was heated in a water bath at 45 캜 for 45 minutes. The reaction mixture was treated with 100 mL of a saturated aqueous sodium thiosulfate solution. The organic layer was separated and the aqueous phase was extracted twice more with ethyl acetate in the same manner. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo to give 48.9 gm (91%) of desired product. Mass spectrum APCI m / e 190 (p + 1).
[605] Production Example 21
[606] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-
[607] A suspension of 7.0 gm (42.0 mmol) potassium iodide and 4.89 gm (38.0 mmol) trimethylsulfoxonium chloride in 30 ml DMSO was treated with 1.69 gm (42.0 mmol) of 60% sodium hydride in mineral oil under nitrogen. The mixture was stirred for 1 hour and then treated with 2.0 gm (11.0 mmol) of 6-methoxy-1-methyl-1H-quinolin-2-one followed by stirring at ambient temperature for 0.5 hour, Lt; / RTI &gt; The reaction mixture was cooled to ambient temperature and then quenched with ice and then extracted with ether. The ether layer was washed with brine, dried over sodium sulfate and evaporated. The residue was partitioned between acetonitrile and pentane. The acetonitrile layer was concentrated. The residue was partitioned between 1: 1 hexane / ethyl acetate and 50% saturated (sat'd) brine solution. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated in vacuo to give 1.6 gm of a mixture of the desired product and starting material. The residue was purified by silica gel chromatography eluting with 7/3 hexane / ethyl acetate to give 972 mg (44%). Mass spectrum APCI m / e 204 (p + 1).
[608] Production Example 21A
[609] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-
[610] A suspension of 3.35 gm (15.1 mmol) of trimethylsulfoxonium iodide in 10 ml of THF was treated with 5.8 ml (14.6 mmol) of 2.5 M n-hexyl lithium in heptane under nitrogen at 0 &lt; 0 &gt; C over 30 min. The mixture was stirred for 30 min at 0 &lt; 0 &gt; C and then treated with 1.0 gm (5.02 mmol) of 6-methoxy-l-methyl-lH-quinolin-2-one and heated under reflux for 1.5 h. The reaction mixture was cooled to ambient temperature, quenched with 35 ml of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give 1.1 gm of the desired product. Mass spectrum APCI m / e 204 (p + 1).
[611] Production Example 22
[612] Methyl-2-oxo-l, 2,3,7b-tetrahydro-lH-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde
[613] A flame dried round bottom flask equipped with a nitrogen cap was charged with 972 mg (4.8 mmol) of 6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza- mmol), 40 ml of trifluoroacetic acid and 806 mg (5.7 mmol) of hexamethylenetetramine. The mixture was stirred at reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched with 200 mL of ice and then treated with solid sodium bicarbonate until pH 9 was reached. The aqueous phase was extracted with chloroform (3 x 30 mL). The combined organics were then washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was dissolved in ethyl acetate and crystals formed at that time. The yields were 4 in total, 373 mg. The mother liquor was purified by silica gel column chromatography eluting with 1/1 ethyl acetate / hexane to give 98 mg (42% overall yield) of additional white solid which was used directly in the next step. Mass spectrum APCI m / e 232 (p + 1).
[614] Production Example 22A
[615] 6-methoxy-3-methyl-2-oxo-l, 2,3,7b-tetrahydro-lH-3-aza-cyclopropa [a] naphthalene-5carbaldehyde
[616] A flame dried round bottom flask equipped with a nitrogen cap was charged with 935 mg (4.6 mmol) of 6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza- mmol) and 40 ml of methylene chloride were added. The solution was cooled to 0 C and 46.1 mL (46.1 mmol) of 1.0 M titanium tetrachloride was added. Dichloromethyl methyl ether (2.09 mL (23.05 mmol)) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with 100 mL ice / 1 N HCI. The aqueous phase was extracted with chloroform (3 x 30 mL). The combined organics were then washed with saturated bicarbonate solution, then with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was dissolved in ethyl acetate and crystals formed at that time. Four yields were obtained with a total of 902 mg. Mass spectrum APCI m / e 232 (p + 1).
[617] Production Example 22B
[618] Separation of the enantiomers: 6-Methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde
[619] A flame dried round bottom flask was charged with 6-methoxy-3-methyl-2-oxo-l, 2,3,7b-tetrahydro-lH-3-aza-cyclopropa [a] naphthalene- 7.5 gm (32.5 mmol) of the aldehyde and 150 ml of methanol were introduced. The solution was treated with catalytic amounts of toluenesulfonic acid and trimethylorthoformate 4.26 ml (38.9 mmol). The reaction was stirred for 1.5 hours and then treated with a small amount of solid sodium bicarbonate. The reaction mixture was diluted with chloroform, which was passed through a plug of neutral or basic alumina and filtered to make the solution clear. The filtrate was concentrated in vacuo to give 8.0 gm. The acetal was eluted with 60:40 / heptane: ethanol at a flow rate of 200 ml / min and separated by chiral HPLC chromatography on a Chiralpak AS 10 cm X 50 cm column. The retention time of the desired isomer (4.13 gm) was 4.5 min and was approximately 100% ee. This material was dissolved in 100 chloroform and 1N HCl 5 vol. The mixture was stirred at room temperature for 16 hours and then dried with sodium sulfate. The solvent was removed in vacuo to give 3.6 gm of aldehyde as a single enantiomer.
[620] Example 9
[621] Methyl] -1,1a, 3,7b-tetrahydro-3-azacyclopropa [a] pyridin-2- Naphthalen-2-one
[622] (2S, 3S) -3-amino, 2-phenylpiperidine and 331 mg (1.88 mmole) of 6-methoxy-3-methyl- (1.92 mmoles) of 2,3,7b-tetrahydro-1H-3-aza-cyclopropane [a] naphthalene-5-carbaldehyde were combined in 100 ml of toluene and the mixture was stirred for 4 hours in a Dean- And heated under reflux. The crude imine (MS APCI m / e = 390 p + 1) solution was evaporated in vacuo and redissolved in 100 mL dichloroethane. The solution was treated with 528 mg (2.49 mmol) of sodium triacetoxyborohydride and stirred at room temperature for 16 hours. The reaction mixture was washed with a saturated aqueous bicarbonate solution, washed with brine, and dried over sodium sulfate. The product (MS, APCI m / e 392 (p + 1)) dissolved in dichloroethane was treated with 392 μL (2.8 mmol) of triethylamine and 541 mg (2.48 mmol) of t-boc carbonate, Stir at ambient temperature for 24 hours. The reaction mixture was washed with a saturated aqueous bicarbonate solution, washed with brine, and dried over sodium sulfate. After evaporation the crude residue was 98/2/1 methylene chloride, methanol, (CH ₃ OH), ammonium hydroxide (NH ₄ OH) is t- unit N-1 nitrogen by silica gel chromatography eluting with a butoxycarbonyl group ( 780 mg of the desired product protected by t-BOC) was obtained in 84% yield. MS, APCI m / e 492 (p + 1). The diastereomeric separation eluted with 8/2 hex / IPA and completed on a Chiralpak AD column. Retention times were 7.0 min and 10.8 min, respectively. Removal of the t-BOC protecting group was achieved by exposing each substrate to 10 molar equivalents of trifluoroacetic acid in dichloroethane at 65 &lt; 0 &gt; C for 5 hours, followed by washing with saturated carbonate solution and brine. Chromatography on silica gel, eluting with 95: 5 methylene chloride: methanol containing ammonium hydroxide, gave the title product in 62% and 86% yield. MS, APCI m / e 392 (p + 1).
[623] Example 9A
[624] Methyl] -1,1a, 3,7b-tetrahydro-3-azacyclopropa [a] pyridin-2- Naphthalen-2-one
[625] (2S, 3S) -3-amino, 2-phenylpiperidine 331 mg (1.88 mmole) and enantiomerically pure 6-methoxy-3-methyl- A] naphthalene-5-carbaldehyde (443 mg, 1.92 mmole) were combined in 100 ml of toluene, and the mixture was refluxed for 4 hours Lt; RTI ID = 0.0 &gt; Dean-Stark trap. The crude imine (MS APCI m / e = 390 p + 1) solution was evaporated in vacuo and redissolved in 100 mL of dichloroethane. The solution was treated with 528 mg (2.49 mmol) of sodium triacetoxyborohydride and stirred at room temperature for 16 hours. The reaction mixture was washed with a saturated aqueous bicarbonate solution, washed with brine, and dried over sodium sulfate. Chromatography on silica gel, eluting with 95: 5 methylene chloride: methanol containing ammonium hydroxide, gave the title product (550 mg) in 75% yield. MS, APCI m / e 392 (p + 1).
[626] Example 10
[627] (2S, 3S) - (2-phenyl-1-trifluoroacetyl-piperidin-3- ylamino) -methyl] -3,4-dihydro- 1H-quinolin-2-one
[628] Of CH ₂ Cl ₂ 6- methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-yl-amino) -methyl] -3,4-dihydro -1H- quinolin-2-one 208 mg (0.99 mmol) of trifluoroacetic anhydride was rapidly added dropwise to 313 mg (0.825 mmol) at room temperature. After 5 minutes, the mixture was partitioned between water (5 ㎖) and CHCl ₃ (5 ㎖). The organic layer was washed with a saturated aqueous sodium bicarbonate 5 ㎖ (NaH _3), filtered and dried through a cotton plug and concentrated. Chromatograph the residue (10:90 EtOAc / hexane) to give 250 mg (89%) of the title compound as a free amine as a colorless oil.
[629]
[630] The residue was dissolved in methanol (4 mL) and treated with 3.3 mL of a 0.5 M solution of HCl in methanol. Concentration in vacuo yielded the hydrochloride salt as a white powder (mp 222-224 [deg.] C decomposition); Mass spectrum m / e calcd. M + H = 476.2. Found 476.4.
[631] Production Example 23
[632] 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-
[633] To a stirred ice-cooled suspension of sodium hydride (60% in mineral oil, 3.9 g, 98.1 mmol) in dry DMF was added solid 6-methoxy-1,3-dihydro-indol-2-one (4.00 g, 24.5 mmol) Was added portionwise over 10 minutes. MeI (2.68 g, 98.1 mmol) was added dropwise to the resulting gray mixture. The mixture was allowed to warm to room temperature, stirred for 45 minutes, then cooled to 0 &lt; 0 &gt; C and quenched with 90 ml of water. A mixture of ethyl acetate (EtOAc) / toluene mixture (2: 1) and extracted with, The extract was dried over magnesium sulfate (MgSO _4), treated with activated charcoal, and filtered and concentrated to give a red syrup. Silica gel chromatography (1:10 EtOAc / hexane) gave 4.16 g (83%) of the title compound as a white solid (mp 67-69 [deg.] C). Mass spectrum m / e calcd. M + H = 234.1. Found 234.2.
[634] Production Example 24
[635] Methoxy-l, 3,3-trimethyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[636] TiCl ₄ (4.80 ㎖ a stirred ice-cooled solution of indole-2-one (1.0 g, 4.87 mmol) - CH 2 Cl 2 30 ㎖ of 6-methoxy -1,3,3- trimethyl-1,3-dihydro , 43.8 mmol) was added followed by alpha, alpha -dichloromethyl methyl ether (1.98 mL, 21.9 mmol). The reaction was stirred overnight at room temperature and then quenched with 20 ml of water. The aqueous layer was extracted with CH ₂ Cl ₂ ( ₂ x 20 mL) and the combined organic fractions were washed sequentially with saturated NaHCO ₃ , brine and water, dried over Na ₂ SO ₄ and concentrated. The crude product was recrystallized from isopropanol / isopropyl ether to give 680 mg (60%) of a white solid (mp 192-194 [deg.] C). An additional yield of 213 mg was obtained with a total yield of 78%.
[637] Production Example 24A
[638] (2S, 3S) -6-methoxy-1,3,3-trimethyl-5 - [(2- phenyl- piperidin- 3- ylamino) -methyl] -1,3-dihydro- -On
[639] To a solution of (2S, 3S) -7-methoxy-2,3-dihydro-1H- indole- Phenyl-piperidin-3-ylamine (1.0 g, 4.0 mmol) and 3 ml of methanol were added. The solution was heated to reflux temperature for 48 hours with azeotropic water removal. The solution was then concentrated and the residue was dissolved in CH ₂ Cl ₂ . Sodium triacetoxyborohydride (1.0 g, 4.7 mmol) was added and the mixture was stirred overnight. The mixture was then quenched with saturated NaHCO ₃ and the layers were separated. The aqueous portion was extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic fractions were washed sequentially with brine and water and concentrated. Silica gel chromatography (10: 1 EtOAc / MeOH) afforded 1.27 g (81%) of the title compound as an orange oil. The oil was treated with etheric HCl to give 1.44 g of the dihydrochloride salt as an off-white solid.
[640] Production example 25
[641] 6-methoxy-1,3,3-trimethyl-3,4-dihydro-1H-quinolin-
[642] KHMDS (0.5 M in toluene; 22.0 mL, 10.9 mmol) was added to 6-methoxy-l -methyl-3,4-dihydro- lH-quinolin-2-one (1.00 g, 5.23 mmol) Lt; / RTI &gt; After 15 min, methyl iodide (1.55 g, 10.9 mmol) was added and the reaction was stirred overnight. KHMDS / MeI was added repeatedly in the morning and the mixture was stirred for several hours, then quenched with water and extracted twice with ethyl acetate. The extracts were washed sequentially with water and brine, dried with sodium sulfate and concentrated. Silica gel chromatography (3: 1 hexanes / EtOAc) afforded 356 mg (31%) of the title compound as yellow oil.
[643] Production Example 26
[644] 6-Methoxy-1,3,3-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde
[645] CH ₂ Cl ₂ 20 ㎖ of 6-methoxy -1,3,3- trimethyl-3,4-dihydro -1H- quinolin-2-one (350 mg, 1.50 mmol) in TiCl ₄ (CH ₂ Cl ₂ of 1.0 M; 15 mL, 15 mmol) and , - dichloromethyl methyl ether (862 mg, 7.5 mmol). After stirring at room temperature overnight, the reaction was quenched with water and extracted with CH ₂ Cl ₂ . The combined organic extracts were washed sequentially with saturated NaHCO ₃ , water and brine, dried over Na ₂ SO ₄ and concentrated. Silica gel chromatography (1: 1 hexane / EtOAc) provided 162 mg (43%) of a colorless oil.
[646] [Example 11 Erase]
[647] Example 12
[648] (2S, 3S) -6-methoxy-1,3,3-trimethyl-7 - [(2-phenyl- piperidin-3- ylamino) -methyl] -3,4- dihydro- -2-one
[649] 6-methoxy-1,3,3-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (150 mg, 0.6 mmol) in 15 mL of toluene and 2 mL of MeOH, Was added triethylamine (134 mg, 1.32 mmol) and (2S, 3S) -3-amino-2-phenylpiperidine dihydrochloride (150 mg, 0.60 mmol). After heating at reflux temperature for 24 h and concentration, the residue was dissolved in CH ₂ Cl ₂ and treated with sodium triacetoxyborohydride (200 mg). Stir the reaction overnight at room temperature and quenched with saturated NaHCO _3. The aqueous fraction was extracted with CH ₂ Cl ₂ and the combined organic phases were washed with water and brine, dried with NaHCO ₃ and concentrated. Silica gel chromatography (90: 9: 1 EtOAc / MeOH / NH 4 OH) to give a colorless oil 52 mg (23%). Treatment with excess ethereal HCI and concentration afforded 67 mg of dihydrochloride salt as a white solid.
[650] Example 13
[651] 5 - [{(2S, 3S) -l-isopropyl-2-phenyl-piperidin-3- ylamino} -methyl] -6-methoxy-1,3,3-trimethyl- Hydro-indol-2-one
[652] ₃ -ylmethyl) -methyl] -1,3-dihydro-2H-pyran-2-one To a solution of 6-methoxy- To the dihydro-indol-2-one (102 mg, 0.260 mmol) was added triethylamine (108 mg, 1.04 mmol) and isopropyl isodide (87 mg, 0.52 mmol). After heating the mixture to 60 ℃ overnight, diluted with CH ₂ Cl ₂ and washed with saturated NaHCO _3. The organic fraction was dried over MgSO ₄ , concentrated and chromatographed (5:95 MeOH / EtOAc) to give a pale yellow oil. Mass spectrum m / e calcd. M + H = 436.3. Found 436.3. Concentration from HCl in excess ether gave the dihydrochloride salt as a white solid.
[653] Example 14
[654] Methyl-2-phenyl-piperidin-3-ylamino} -methyl] -6-methoxy-1,3,3-trimethyl-1,3-dihydro- -Indol-2-one
[655] To a solution of 6-methoxy-1,3,3-trimethyl-5 - [{(2S, 3S) -2-phenyl-piperidin- Methyl iodide was added to hydro-indol-2-one (102 mg, 0.26 mmol) and triethylamine (150 mg, 1.04 mmol). The solution was stirred for 48 h, then partitioned between saturated NaHCO ₃ and CH ₂ Cl ₂ . The organic fraction was washed with brine, dried over Na ₂ SO ₄ and concentrated. Chromatography (5:95 MeOH / EtOAc) gave the title compound as a pale yellow oil. Mass spectrum m / e calcd. M + H = 408.2. Found 408.2. The solid dihydrochloride salt was treated with excess HCl in ether and then concentrated under vacuum [mp > 250 [deg.] C (decomposition)].
[656] Example 15
[657] (2S, 3S) -6-methoxy-l-methyl-5 - [(2- phenyl- piperidin- 3- ylamino) -methyl] -1,3-dihydro-
[658] CH ₂ Cl ₂ 15 ㎖ the (2S, 3S) addition of 2-phenyl-piperidin-3-ylamine di-malonate (1.26 g, 2.6 mmol) and 6-methoxy-1-methyl-2-oxo -2,3-dihydro-lH-indole-5-carbaldehyde, sodium triacetoxyborohydride (1.01 g, 4.8 mmol) was added in one portion. After 30 minutes, the mixture was diluted with 10 mL of water and basified to pH about 11 with 3N NaOH. The layers were separated and the aqueous fraction was extracted once with CH ₂ Cl ₂ . Then the combined organics were washed 1N NaOH and water in order, dried over Na ₂ SO ₄ and concentrated. Silica gel chromatography (90: 9: 1 EtOAc / MeOH / NH 4 OH) to give the title compound 127 mg (14%) as a white solid. Mass spectrum m / e calcd M + H = 366.2. Found 366.0. The solid dihydrochloride salt was obtained by treatment with excess HCl in ether and then concentrated in vacuo.
[659] [Example 16: Erase]
[660] Example 17
[661] (3S) - and (3R) -6-methoxy-1,3-dimethyl-5 - {[(2S, 3S) -2- phenyl- piperidin- Dihydro-indol-2-one
[662] (Mixture of two diastereomers) To a solution of (+/-) - 6-methoxy-l, 3-dimethyl-2-oxo-2,3-dihydro- lH- (249 mg, 1.0 mmol) was added triethylamine (222 mg, 1.0 mmol) and (2S, 3S) -2-phenyl-piperidin-3-ylamine dihydrochloride , 2.2 mmol). The solution was heated to reflux temperature for 72 hours by azeotropic removal. The resulting mixture was concentrated, and the residue was suspended in 10 mL of CH ₂ Cl ₂ . Sodium triacetoxyborohydride (1.8 mmol, 1.8 mL of a IM solution in CH ₂ Cl ₂ ) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was then quenched with saturated NaHCO ₃ and extracted twice with CH ₂ Cl ₂ . Wash the combined organics with brine, dried over NaHCO ₃ and concentrated. Silica gel chromatography (90: 9: 1 EtOAc / MeOH / NH 4 OH) 1 of the title compound: 1 mixture to give the 109 mg (29%) as a pale yellow oil. The solid dihydrochloride salt was obtained by treatment with excess HCl in ether and then concentrated in vacuo.
[663] Example 18
[664] Methoxy-1,3,3-trimethyl-5 - {[(2S, 3S) -1- (5-oxo-4,5-dihydro- Ylmethyl) -2-phenyl-piperidin-3-ylamino] -methyl} -1,3-dihydro-indol-
[665] To a solution of (2S, 3S) -5-methoxy-1,3,3-trimethyl-6 - [(2- phenyl- piperidin- 3- ylamino) -methyl] 2-one and N '- (2-chloro-1-imino-ethyl) -hydrazinecarboxylic acid methyl ester was added K ₂ CO ₃ (280 mg, 2.0 mmol). The mixture was heated to 70 DEG C for 18 hours and then the temperature was increased to 140 DEG C to achieve ring closure. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with additional fractions of EtOAc and washed the combined organic layers with brine and dried over Na ₂ SO ₄ and concentrated. Silica gel chromatography (EtOAc / MeOH) afforded 27 mg (9%) of an off-white solid [mp> 250 <0> C (decomposition)]. Mass spectrum m / e calcd M + H = 491.5. Found 491.5.
[666] Example 19
[667] Methyl-7 - {[1- (5-oxo-2,5-dihydro-1H- [1,2,4] triazol- Pyridin-3-ylamino] -methyl} -3,4-dihydro-1H-quinolin-2-
[668] .
[669]
[670] Production Example 27
[671] (+/-) - 3- (3-Bromo-butyl) -l- (tert-butyl-dimethyl-silanyl) -4-phenyl-azetidin-
[672] To diethylamine (4.32 g, 59.0 mmol) in 22 mL of THF was added nBuLi (2.5 M in hexane; 50.6 mmol, 20.2 mL) at 0 &lt; 0 &gt; C. After 15 min, the solution was added via cannula to a -50 C solution of l- (tert-butyl-dimethyl-silanyl) -4-phenyl-azetidin-2-one (11.0 g, 42.2 mmol) Respectively. After stirring for 20 minutes, 1,3-dibromobutane was added and the solution was stirred for 1 hour. Addition of saturated aqueous NH ₄ Cl, and the mixture was allowed to warm to room temperature and extracted once with ether. The extract was dried with MgSO ₄ , concentrated and chromatographed (9: 1 hexanes / EtOAc) to yield 11.4 g (68%) of the title compound as a pale yellow oil.
[673]
[674] Production Example 28
[675] (2S, 5S) -2- (amino-phenyl-methyl) -5-bromo-hexanoic acid methyl ester (2R, 5R)
[676] (Tert -butyl-dimethyl-silanyl) -4-phenyl-azetidin-2-one was reacted with 5 eq of a mixture of two diastereomers and their enantiomers And refluxed in 75 ml of sulfuric acid for 24 hours. The acid was neutralized with solid NaHCO ₃ and the mixture was concentrated in vacuo to give 2.6 g of the title compound as a pale yellow oil which was used in the next step without purification.
[677] Production Example 29
[678] (2S, 3S, 6S), and (2R, 3R, 6R) -6-methyl-2-phenyl-piperidine-3-carboxylate ester
[679] (Mixture of two diastereomers and their enantiomers) NaI and NaHCO ₃ were added to 2- (amino-phenyl-methyl) -5-bromo-hexanoic acid methyl ester in DMF. The resulting mixture was stirred in DMF at 100 &lt; 0 &gt; C for 1 hour, then cooled to room temperature and partitioned into ether and water. The organic layer was washed with brine, dried over MgSO ₄ sulphate, filtered and concentrated. Silica gel chromatography _{(97: 3 CHCl 3 / MeOH} ) to give the product 1.63 g (90%) as two separated non mixture of diastereomers.
[680]
[681] Production Example 30
[682] (2S, 3S, 6S), (2S, 3S, 6S), (2R, 3R, 6R) -6-methyl-2-phenyl-piperidine- Lt; / RTI &gt; acid 1-benzyl ester 3-methyl ester
[683] (Mixture of two diastereomers and their enantiomers) To a solution of 6-methyl-2-phenylpiperidine-3-carboxylic acid methyl ester (1.63 g, 7.0 mmol) in 20 mL of 10% aqueous NaHCO _{3 was} added benzylchloroform Mate (1.25 g, 7.35 mmol) at O &lt; 0 &gt; C. The mixture was stirred at 0 &lt; 0 &gt; C for 45 min, then warmed to room temperature and stirred for a further 30 min. The mixture was partitioned into ether and the organic phase, dried over MgSO ₄ and concentrated. Silica gel chromatography (9: 1 hexanes / EtOAc) gave 1.62 g (63%) of the title compound as colorless oil.
[684]
[685] Production Example 31
[686] (2S, 3R, 6R) -3-carbamoyl-6-methyl-2-phenyl-piperidine (2S, 3S, 6R) -1-carboxylic acid benzyl ester
[687] (22.1 mmol, 11.0 mL of a 2.0 M solution in toluene) was added at O &lt; 0 &gt; C to a solution of ammonium chloride (1.18 g, 22.1 mmol) in 20 mL benzene. The resulting mixture was stirred at 0 &lt; 0 &gt; C for 30 min and warmed to room temperature for an additional 30 min. The mixture was then added to a mixture of 6-methyl-2-phenyl-piperidine-l, 3-dicarboxylic acid 1-benzyl ester 3-methyl ester as a solution in benzene 20 ml, And heated to reflux temperature. The reaction was then cooled to 0 &lt; 0 &gt; C and quenched with 10 ml of 1M HCl cautiously. The mixture is stirred for 30 minutes, filtered through celite, and the filter pad is rinsed with CH ₂ Cl ₂ . The filtrate was concentrated and the residue was dissolved in EtOAc, washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated. Silica gel chromatography (eluting the nonpolar material with CHCl ₃ followed by elution of the product with 95: 5 CHCl ₃ / MeOH) gave 560 mg (36%) of the title compound as a white foam.
[688]
[689] Production example 32
[690] (2S, 3S, 6S), (2R, 3R, 6R) -3-Amino-6-methyl-2-phenyl-piperidin- -Carboxylic acid benzyl ester
[691] (525 mg, 1.49 mmol) and lead acetate (IV) (mixture of two diastereomers and their enantiomers) 3-carbamoyl-6-methyl-2-phenyl-piperidine- ) (2.18 g, 4.92 mmol) were refluxed in t-butyl alcohol for 19 hours. The reaction mixture was poured into a mixture of ice-cold 1 M HCl and EtOAc and stirred for 45 min. The mixture was then filtered through celite and the organic layer was washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated to give 598 mg of a yellow solid. After dissolving the solid in CHCl ₃ and 2M HCl in ether, it stirred for 2 hours. The mixture was concentrated, and the residue was partitioned in CHCl ₃ and saturated NaHCO _3. The organic phase was dried over MgSO ₄ sulphate, filtered and concentrated. Silica gel chromatography (3: 1 EtOAc / hexanes) afforded 169 mg (35%) of the title compound as a colorless oil.
[692]
[693] Production Example 33
[694] 3 - [(6-methoxy-l-methyl-2-oxo-l, 2,3,4-tetrahydro-quinolin-7- ylmethyl) -amino] -6- -1-carboxylic acid benzyl ester
[695] Methyl-2-phenyl-piperidine-l-carboxylic acid benzyl ester and 6-methoxy-l-methyl-2-oxo-l, 2,3,4-tetra tetrahydro-quinoline-7-carbaldehyde of NaBH ₃ CN (3.13 mmol, THF solution of 1.0M 3.13 ㎖), and acetic acid was added to 250 ㎕. The mixture was heated to 50 &lt; 0 &gt; C for 3 days. The mixture was diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated. Silica gel chromatography (1: 1 hexanes / EtOAc) afforded 315 mg of the title compound as a white solid, which was a non-separable mixture of the reduced aldehyde. The mixture was used in the next step without further purification.
[696] Examples 20 to 23
[697] 6-methoxy-1-methyl-7 - [(2R, 3R, 6R) Methyl-3 - ((2S, 3S, 6S) - (6-methyl-2-phenyl-piperidin- (6-methyl-2-phenyl-piperidin-3-yl) -pyridin- Amino] -methyl] -3,4-dihydro-1H-quinolin-2-one and 6-methoxy-1-methyl-7 - [(2R, 3R, 6S) - Piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-
[698] To a solution of 3 - [(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- Was added ammonium formate (164 mg, 2.60 mmol) to the title compound (275 mg, 0.52 mmol) and 10% Pd-C (25 mg). The mixture was refluxed for 2 hours, then cooled to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by chromatography (9: 1: 0.05 EtOAc / MeOH / NH ₄ OH saturated) 2,5-cis isomer 48 mg (23%) and 2,5-trans isomers of the title compound 88 mg ( 43%) as a racemate. Each sample was chirally decomposed by HPLC (chiralcel OD 2.1 cm x 25 cm column, 90: 10: 0.025 hexane / isopropanol / diethylamine) to give 4.3 g of (2S, 3S, 6R) (2R, 3R, 6R) -isomer and 25 mg of (2R, 3R, 6S) -isomer were obtained.
[699]
[700] Example 24 (Method A)
[701] (2S, 3S) -6-methoxy-l-methyl-7 - {[1- -Methyl} -3,4-dihydro-1H-quinolin-2-one
[702] (2S, 3S) - (2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinoline 2-one (100 mg, 0.26 mmol), 4-methyl-5-imidazolecarboxaldehyde (116 mg, 1.06 mmol) and acetic acid (5 drops) were added 1.58 ml (1.58 mmol) of 1.0 M sodium cyanoborohydride in THF, Was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then at 50 &lt; 0 &gt; C for 3 days. The reaction was then diluted with methylene chloride, washed once with saturated NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated. Silica gel chromatography (9: 1 ethyl acetate / methanol) gave 83 mg (66%) of the title compound as a white foam. Rf = 0.05 (9: 1 ethyl acetate / methanol).
[703]
[704] 2M HCl in ether was added to a solution of the product in ethyl acetate to produce the dihydrochloride salt. And concentrated to give a white solid (Mp = 225-229 [deg.] C).
[705] Example 25
[706] 3-ylamino] -methyl} -6-methoxy-l-methyl-isoquinolin-2- 3,4-dihydro-1H-quinolin-2-
[707] This compound was prepared according to Method A using 4 (5) -imidazolecarboxaldehyde instead of 4-methyl-5-imidazolecarboxaldehyde. Silica gel chromatography (9: 1 ethyl acetate / methanol) gave the title compound 65 mg (54%) as a white foam. Rf = 0.10 (9: 1 ethyl acetate / methanol).
[708]
[709] 2M HCl in ether was added to a solution of the product in ethyl acetate to produce the dihydrochloride salt. Concentration afforded a white solid.
[710] Production example 34
[711] 3,5-Dimethyl-3H-imidazole-4-carbaldehyde and 1,5-dimethyl-1H-imidazole-4-carbaldehyde
[712] DBU (6.91 g, 45.4 mmol) and MeI (6.45 g, 45.4 mmol) were added to 5-methyl-3H-imidazole-4-carbaldehyde (5.00 g, 45.4 mmol) in 50 mL of THF. The solution was stirred overnight, then partitioned between 100 mL EtOAc and 100 mL water. The aqueous fraction was extracted with 2-butanol (3 x 100 ㎖), and the combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. Chromatography _{(1:99 MeOH / CHCl 3) 44015-106-1} (Rf = 0.58, 12:78 MeOH / CH 2 Cl 2) 1.03 g (23%) and 44015-106-2 (Rf = 0.5, 12 : 78 MeOH / CH ₂ Cl ₂ ) (1.26 g, 18%).
[713] Example 26
[714] 3-ylamino] -methyl} -6-me thiomorpholin-4-ylmethyl) - &lt; / RTI &gt; Methyl-3,4-dihydro-1H-quinolin-2-one
[715] This compound was prepared according to Method A using l, 5-dimethyl-lH-imidazole-4-carbaldehyde (synthesis described above) in place of 4-methyl-5-imidazolecarboxaldehyde. Silica gel chromatography (9: 1 ethyl acetate / methanol) gave 90 mg (70%) of the title compound as a white foam. Rf = 0.09 (9: 1 ethyl acetate / methanol).
[716]
[717] 2M HCl in ether was added to a solution of the product in ethyl acetate to produce the dihydrochloride salt. Concentration afforded a white solid.
[718] Example 27
[719] (2S, 3S) - (2-phenyl-1-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinoline -2-one
[720] 2-Imidazolidine thione (10 g, 97.89 mmol) and methyl iodide (6.70 mL, 107.67 mmol) were stirred in anhydrous ethanol (20 mL) at reflux temperature for 2 hours. The reaction was cooled and an equal volume of diethyl ether was added. The suspension was filtered to give 22.9 g (96%) of 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrogen iodide as an off-white solid which was used in the next reaction. Methyl-3, 4-dihydro-1 H-quinolin-2-one &lt; / RTI &gt; (500 mg, 1.32 mmol) and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrogen iodide (402 mg, 1.65 mmol) were stirred in 5 ml of n-propanol at reflux temperature for 2 days Respectively. The reaction was diluted with ethyl acetate, washed once with saturated K ₂ CO ₃ , dried over MgSO ₄ , filtered and concentrated. (95: 5 ethyl acetate / methanol) to give 123 mg (21%) of the title compound as a pale yellow oil. Rf = 0.12 (9: 1 ethyl acetate / methanol).
[721]
[722] 2M HCl in ether was added to a solution of the product in ethyl acetate to produce the dihydrochloride salt. Concentration afforded a white solid.
[723] Example 28
[724] Methyl-6-methoxy-1-methyl-3,4-di (tert-butyldimethylsilyl) Hydro-1H-quinolin-2-
[725] Methyl-3, 4-dihydro-1 H-quinolin-2-one &lt; / RTI &gt; 2-chlorobenzoxazole (126 mg, 0.11 mmol) was added to catalyst KI in dihydrochloride (50 mg, 0.11 mmol), freshly crushed potassium carbonate (61 mg, 0.44 mmol) and 3 ml of 1,4- Respectively. After heating at reflux for 5 days, the reaction was cooled and partitioned between ethyl acetate and water. Separating the organic fraction, dried with MgSO _4, and filtered and concentrated. Silica gel chromatography (99: 1 chloroform / methanol followed by 3: 1 ethyl acetate / hexanes) afforded 31 mg (56%) of the title compound as a light brown oil. MS (M + H) &lt; ⁺ & gt ^; = 497.2;
[726]
[727] 2M HCl in ether was added to a solution of the product in ethyl acetate to produce the dihydrochloride salt. Concentration afforded a white solid (Mp = 181-183 [deg.] C).
[728] Example 29
[729] (2S, 3S) -2-Phenyl-piperidin-3-ylmethoxy) - &lt; / RTI &gt; Ylamino] -methyl} -3,4-dihydro-1H-quinolin-2-one
[730] To a solution of (S) - (+) - 5- (hydroxymethyl) -2-pyrrolidinone (1.0 g, 8.69 mmol) and triethylamine (1.21 ml, 8.69 mmol) in 50 ml of methylene chloride was added p-toluenesulfonyl chloride 1.66 g (8.69 mmol) was added. The resulting solution was stirred at room temperature for 3 days. The organic solution washed once with water, dried with MgSO _4, filtered and concentrated. Silica gel chromatography (95: 5 ethyl acetate / methanol) provided 1.65 g (71%) of toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as a white powder which was used in the next step Respectively. Rf = 0.29 (95: 5 ethyl acetate / methanol).
[731]
[732] To a solution of 6-methoxy-l-methyl-7- [(2S, 3S) - (2- phenyl- piperidin- 3- ylamino) -methyl] -3,4-dihydro-lH-quinoline 5-oxo-pyrrolidin-2-ylmethyl ester (107 mg, 0.40 mmol) was added to 150 mg (0.40 mmol) potassium carbonate (55 mg, 0.40 mmol) . The suspension was heated to &lt; RTI ID = 0.0 &gt; 60 C &lt; / RTI &gt; The reaction was diluted with methylene chloride, 3 times with water, washed twice with brine, dried over MgSO _4, filtered and concentrated. Silica gel chromatography (85: 15 ethyl acetate / methanol) gave 19 mg (10%) of the title compound as a white foam. Rf = 0.10 (85: 15 ethyl acetate / methanol).
[733]
[734] To a solution of the product in ethyl acetate was added 2M HCl in ether to produce the dihydrochloride salt. Concentration afforded a white solid (Mp = 203-207 [deg.] C).
[735] Example 30
[736] (2S, 3S) -2-phenyl-piperidin-3-ylmethyl) - &lt; / RTI & Ylamino] -methyl} -3,4-dihydro-1H-quinolin-2-one
[737] (8.69 mmol) of (R) - (-) - 5- (hydroxymethyl) -2-pyrrolidinone and 2.42 mL (17.37 mmol) of triethylamine in 80 mL of methylene chloride were added methanesulfonyl chloride 1.01 ml (13.03 mmol) was added at 0 &lt; 0 &gt; C. The resulting solution was stirred at 0 &lt; 0 &gt; C for 1 hour. The solvent was removed. 1.54 g (92%) of methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as an off-white solid was obtained by silica gel chromatography (10: 1 ethyl acetate / methanol) which was used in the next step. Rf = 0.21 (10: 1 ethyl acetate / methanol).
[738]
[739] To a solution of 6-methoxy-l-methyl-7- [(2S, 3S) - (2- phenyl- piperidin- 3- ylamino) -methyl] -3,4-dihydro- lH- quinoline Methoxy-pyrrolidin-2-ylmethyl ester (92 mg, 0.47 mmol) was added to 150 mg (0.40 mmol) potassium carbonate (55 mg, 0.40 mmol) and catalyst KI. The suspension was heated to 70 &lt; 0 &gt; C for 16 hours. The reaction was diluted with methylene chloride, 3 times with water, washed twice with brine, dried over MgSO _4, filtered and concentrated. Silica gel chromatography (9: 1 ethyl acetate / methanol) gave 30 mg (16%) of the title compound as a white foam. Rf = 0.20 (9: 1 ethyl acetate / methanol).
[740]
[741] To a solution of the product in ethyl acetate was added 2M HCl in ether to produce the dihydrochloride salt. Concentration afforded a white solid.
[742] Example 31
[743] Methyl-6-methoxy-1-methyl-3, 4-dihydro-1 H- (2S, 3S) Quinolin-2-one
[744] Methyl-3, 4-dihydro-1 H-quinolin-2-one &lt; / RTI &gt; (100 mg, 0.26 mmol) and 2-iodopropane (0.058 mL, 0.58 mmol) were stirred in acetonitrile at 60 &lt; 0 &gt; C for 2 days. The reaction was diluted with methylene chloride, washed once with saturated NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated. Silica gel chromatography (9: 1 ethyl acetate / methanol) gave 38 mg (34%) of the title compound as yellow oil. Rf = 0.08 (9: 1 ethyl acetate / methanol).
[745]
[746] To a solution of the product in ethyl acetate was added 2M HCl in ether to produce the dihydrochloride salt. Concentration afforded a white solid.
[747] Examples 32 and 33
[748] (3R) - and (3S) -6-methoxy-l, 3-dimethyl-7- (3S) -6-methoxy-1, 3-dimethyl-7 - [(2S, 3S) -6-methoxy-1, 3- dihydro- lH- quinolin- ) - (2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-lH-quinolin-2-one (mixture of diastereomers)
[749] Methyl-7- [(2S, 3S) - (2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinoline 2-one (250 mg, 0.66 mmol) was added KHMDS (0.726 mmol, 1.45 mL of a 0.5 M solution in toluene) at 0 ° C and the resulting solution was stirred for 10 minutes. Thereafter, methyl iodide (0.045 mL, 0.726 mmol) was added and stirred for 10 min, then a further portion of KHMDS solution (0.726 mmol, 1.45 mL) and methyl iodide (0.045 mL, 0.726 mmol) The above process was repeated. The resulting solution was stirred at 0 &lt; 0 &gt; C for 10 min and at room temperature for 1 h. The solution was diluted with water and extracted with ethyl acetate. The organic fractions were washed once with water, dried with MgSO _4, filtered and concentrated. Silica gel chromatography (9: 1 ethyl acetate / methanol) gave the title compound mixture X (two inseparable diastereomers, 36 mg, 13% yield) and Y (two inseparable diastereoisomers, 60 mg, ).
[750]
[751] To the solution of the product in ethyl acetate was added 2M HCl in ether to prepare the dihydrochloride salt of each compound. Each was concentrated to give a white solid.
[752] Example 34
[753] Yl) - (2S, 3S) -2-phenyl-piperidin-3-ylamino] -methyl} -6-me thiazol- Methyl-3,4-dihydro-1H-quinolin-2-one
[754] Step 1: 6-Methoxy-l-methyl-7- [(2S, 3S) - (2- phenyl- piperidin- 3- ylamino) -methyl] -3,4-dihydro-lH-quinoline- 2-one (750 mg, 1.98 mmol) and N-BOC-2-isothiocyanatoethylamine (400 mg, 1.98 mmol) were stirred in 20 ml of benzene at room temperature for 16 hours. The reaction was diluted with diethyl ether, washed once with water, dried over MgSO _4, filtered and concentrated. Silica gel chromatography (6: 1 ethyl acetate / hexane) gave [2 - ({3 - [(6-methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- -Amino) -ethyl] -carbamic acid tert-butyl ester (yield: 70%). Rf = 0.11 (6: 1 ethyl acetate / hexanes).
[755] Step 2: [2 - ({3 - [(6-Methoxy- 1 -methyl-2-oxo- 1,2,3,4-tetrahydro-quinolin- -Carbamic acid tert-butyl ester (800 mg, 1.38 mmol) was dissolved in a mixture of 30 mL of methylene chloride and 10 mL of trifluoroacetic acid At room temperature for 4 hours. The solvent was removed and the residue was partitioned between ethyl acetate and saturated K ₂ CO ₃ . The organics were separated, dried over MgSO ₄ , filtered and concentrated to give 3 - [(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- ) -Amino] -2-phenyl-piperidine-l-carbothioic acid (2-amino-ethyl) -amide. Rf = 0.18 (90: 10: 1 methylene chloride / methanol / saturated aqueous NH ₄ OH).
[756] Step 3: Preparation of 3 - [(6-methoxy-l-methyl-2-oxo-l, 2,3,4-tetrahydro-quinolin- (660 mg, 1.38 mmol) and mercury (II) oxide (600 mg, 2.75 mmol) were dissolved in 30 ml of ethanol at reflux temperature for 4 hours Lt; / RTI &gt; The black reaction was filtered through celite and the filtrate was concentrated. Silica gel chromatography (9: 1 chloroform / methanol) afforded 225 mg (37% yield) of the title compound as yellow oil. Rf = 0.06 (9: 1 chloroform / methanol).
[757]
[758] To a solution of the product in ethyl acetate was added 2M HCl in ether to produce the dihydrochloride salt. Concentration afforded a white solid.
[759] Example 35
[760] Methyl-7 - {[1- ((2S) -1-methyl-5-oxo-pyrrolidin-2- ylmethyl) - (2S, 3S) -2- phenylpiperidine -3-ylamino] -methyl} -3,4-dihydro-1H-quinolin-2-
[761] To a solution of 6-methoxy-l-methyl-7- {[l- (5-oxo-pyrrolidin-2- ylmethyl) - (2S, 3S) -2- phenyl- 18 mg (0.448 mmol) of sodium hydride suspended in 60% mineral oil was added at room temperature to 20 mg (0.408 mmol) of 20 &lt; RTI ID = 0.0 &gt;Lt; / RTI &gt; Methyl iodide (0.028 mL, 0.448 mmol) was then added, stirred for 1 hour, and 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil was added and stirred overnight. A small amount of water was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed twice with water, dried over MgSO _4, filtered and concentrated. Silica gel chromatography (95: 5 ethyl acetate / methanol as eluent) afforded 25 mg (13%) of the title compound as a pale yellow oil. Rf = 0.07 (9: 1 ethyl acetate / methanol).
[762]
[763] To a solution of the product in ethyl acetate was added 2M HCl in ether to produce the dihydrochloride salt. Concentration afforded a white solid.
[764] Example 36
[765] (R) (5 (S) -6 (R) -phenyl-1,7-diaza-spiro [4,5] dec-3-yl) -3,4- Preparation of dihydro-1H-quinolin-2-one
[766] Step 1
[767] Hydroxy- (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) acetic acid methyl ester
[768] To a suspension of 2.0 g (0.0091 m) of 6-methoxy-1-methyl-2-oxo-l, 2,3,4-tetrahydro-quinoline-7-carbaldehyde in 200 ml of ethyl acetate was added 1N 15 ml (0.015 m) of the solution was added. A two-phase solution was formed. To this mixture was added a solution of 0.6 g (0.012 m) of sodium cyanide in 10 ml of water. The reaction was stirred at room temperature for 4 h, at which time 0.2 g (0.004 m) of sodium cyanide dissolved in 10 ml of water was added and the mixture was stirred at room temperature for 18 h. The organic layer was extracted from the water layer, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to give crude cyanohydrin (87% purity by NMR) as a tan solid. The cyanogenohydrin was stirred in methanol 100 ml and HCl gas was passed through the mixture until a solution was formed. The mixture was heated at reflux temperature for 3 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was polished with 25 mL water and stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated. The residue was chromatographed over silica using 3/1 methylene chloride / ethyl acetate as eluent. The appropriate fractions were combined and evaporated to give 1.2 g (48%) of hydroxy- (6-methoxy- l -methyl-2-oxo-l, 2,3,4-tetrahydro-quinolin- As a white amorphous solid.
[769]
[770] Step 2 (6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -oxo-acetic acid methyl ester
[771] 1.2 g (0.0043 m) of hydroxy- (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) acetic acid methyl ester dissolved in 40 ml of acetone To the solution was added dropwise 1.6 ml of a 2.67 m solution of chromic acid in sulfuric acid / H ₂ O (Jones reagent). The mixture was stirred at room temperature for 90 minutes. Acetone was tilted from the green precipitate and evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate solution was dried over sodium sulfate and evaporated to give 1.0 g (84%) of (6-methoxy- l -methyl-2-oxo-l, 2,3,4-tetrahydro-quinolin- As a yellow amorphous solid.
[772]
[773] Step 3
[774] 2- (6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)
[775] A suspension of 3.1 g (0.0087 m) of methyl-triphenylphosphonium bromide in 100 ml of tetrahydrofuran was cooled to -20 &lt; 0 &gt; C. To the suspension was added dropwise 3.5 mL (0.0087 m) of a 2.5 M solution of n-butyllithium in tetrahydrofuran. The mixture was slowly warmed to + 5 &lt; 0 &gt; C, whereupon a yellow solution formed. The mixture was cooled to-20 C and a solution of 2.2 g (0.0079 m) of (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- ). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was filtered and the filtrate was evaporated to give a brown oily residue. This material was chromatographed on 75 g of silica using chloroform as eluent. The appropriate fractions were combined and evaporated to give 1.8 g (83%) of 2- (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- As a solid.
[776]
[777] Step 4
[778] Trans-3-nitro-2-phenyl-piperidine-l-carboxylic acid tert-butyl ester
[779] A mixture of 3.7 g (0.018 m) of trans-3-nitro-2-phenyl-piperidine and 7.8 g (0.036 m) of N-tert-butyloxycarbonyl anhydride was dissolved in 50 ml of methylene chloride. 2.5 ml (0.018 m) of triethylamine was added to the solution, and the mixture was stirred at room temperature for 20 hours. After the reaction, the mixture was extracted with 20 ml of water and 20 ml of 2N HCl. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on 100 g of silica using 5/1 hexane / methylene chloride as eluent. The appropriate fractions were combined to give 2.8 g (51%) of trans-3-nitro-2-phenyl-piperidine-l-carboxylic acid tert-butyl ester as a yellow oil.
[780]
[781] Step 5
[782] Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -ethyl] -cis-3 -Nitro-2-phenyl-piperidine-l-carboxylic acid tert-butyl ester
[783] 2.2 g (0.0072 m) of trans-3-nitro-2-phenyl-piperidine-1 -carboxylic acid tert- butyl ester and 2- (6-methoxy- Tetrahydro-quinolin-7-yl) acrylic acid methyl ester (1.8 g, 0.0065 m) were combined in 20 ml of tetrahydrofuran. To this was added 0.2 ml (0.0014 m) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in 40 mL of ethyl acetate and washed with 20 mL of 1N hydrochloric acid. The ethyl acetate solution was dried with sodium sulfate and evaporated. The residue was chromatographed on silica gel (50 g) using chloroform as eluent. The appropriate fractions were combined to give 3- [2-methoxycarbonyl-2- (6-methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- -Cis-3-nitro-2-phenyl-piperidine-l-carboxylic acid tert-butyl ester as a diastereomeric mixture of amorphous solid (2.9 g, 77%). TLC (3/1 methyl chloride / ethyl acetate) Rf = 0.45. Mass spectrum m / e = 582 (p + 1), 526 (p-56), 482 (p-100).
[784] Step 6
[785] Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -propyl-3 (R) -nitro-2 (S) -phenylpiperidine-l-carboxylic acid tert-butyl ester and 3- [3 (R, -2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -propyl-3 (S) -nitro-2 (R) -phenylpiperidine- ester
[786] Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -ethyl- To a solution of 2.9 g (0.005 m) of cis-3-nitro-2-phenyl-piperidine-l-carboxylic acid tertbutyl ester was added 0.26 g (0.012 m) of lithium borohydride. A white solid precipitate formed. The mixture was stirred at room temperature for 18 hours. Additional 0.26 g (0.012 m) of lithium borohydride was added and the mixture was stirred for an additional 24 hours. The solvent was evaporated and the residue was dissolved in 100 ml of a 50/50 ethyl acetate / water mixture and stirred for 0.5 hour. The ethyl acetate layer was then separated from the water layer, dried over sodium sulfate and evaporated. The residue was chromatographed on 80 g silica using 2/1 methylene chloride / ethyl acetate as eluent. Two pure products were isolated as amorphous solids. The first product (TLC Rf = 0.41; 1/1 chloroform / ethyl acetate) was converted to 3- [3 (R, S) hydroxy- 2- (6-methoxy- Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -propyl-3 (R) -nitro-2 (S) phenyl- piperidine- 1 -carboxylic acid tert- Butyl ester as a mixture of diastereoisomers.
[787]
[788] The second product (TLC Rf = 0.32) was synthesized from 3- [3 (R, S) -hydroxy-2- (6-methoxy- (S) -nitro-2 (R) -phenylpiperidine-1-carboxylic acid tert-butyl ester as a diastereomeric mixture of appear.
[789]
[790] Step 7
[791] Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -Propyl] -2 (R) -phenyl-piperidine-l-carboxylic acid tert-butyl ester
[792] To a solution of 3- [3 (R, S) -hydroxy-2- (6-methoxy- l -methyl-2-oxo-l, 2,3,4-tetrahydro-quinolin- To a solution of 0.5 g (0.0009 m) of propyl-3 (S) -nitro-2 (R) -phenyl- piperidine- 1 -carboxylic acid tert- Hydrogen was added at 50 PSI (room temperature) for 18 hours. The mixture was filtered and the solvent was evaporated. The residue was dissolved in 20 mL water / ethyl acetate (50/50) and the pH was adjusted to 2.0 with 1 N HCl. The ethyl acetate extract was dried and evaporated to give 0.23 g of the starting nitro alcohol. The pH of the water layer was adjusted to 8.5 with 1N NaOH and the water was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and evaporated to give 3 (S) -amino [3 (R, S) -hydroxy- 2- (6-methoxy- 7-yl) -propyl] -2 (R) -phenyl-piperidine-1-carboxylic acid tert-butyl ester (0.22 g) as an amorphous solid.
[793]
[794] Step 7A
[795] 3 (R) -amino [3- (R, S) -hydroxy-2- (6-methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- ) -Propyl] -2 (S) -phenyl-piperidine-l-carboxylic acid tert-butyl ester
[796]
[797] Step 8
[798] 5 (S) -6 (R) -phenyl-1,7-dihydro-quinolin- Diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester
[799] To a solution of 3 (S) -amino [3 (R, S) -hydroxy-2- (6-methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinoline -7-yl) -propyl] -2 (R) -phenyl-piperidine-1 -carboxylic acid tert-butyl ester in 5 ml of tetrahydrofuran was cooled to 5 &lt; 0 &gt; C. 0.08 ml (0.0006 m) of triethylamine and 0.032 ml (0.00042 m) of methanesulfonyl chloride were added to the solution, and the reaction mixture was stirred for 15 minutes. The reaction mixture was washed with dilute sodium bicarbonate, and the methylene chloride extract was dried over anhydrous sodium sulfate and evaporated to give 3 (R, S) - (1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline- Yl) -5 (S) -6 (R) -phenyl-1,7-diaza-spiro [4.5] decane-7-carboxylic acid tert- butyl ester as a diastereomeric mixture . Mass spectrum: m / e = 506.1 (p + 1).
[800] Step 8A
[801] (R) -6 (S) -phenyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -1,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester
[802] Mass spectrum: m / e = 506.1 (p + 1).
[803] -5 (S) -6 (R) -phenyl-1 (S) - (6-methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- , 7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester and 3 (R) - (6-methoxy- (S) -6 (R) -phenyl-1,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester
[804] 200 mg of a sample of the diastereomer mixture prepared in Step 8 was chromatographed on a Chiralpak AD (5 cm x 25 cm) column using a 90/10 mixture of hexane / isopropyl alcohol containing 0.1% diethylamine as eluent Respectively. Fraction 1 (90 mg) was eluted at 13.7 min and 3 (R) - (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin- (S) -6 (R) -phenyl-1,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester.
[805]
[806] Fraction 2 (90 mg) was eluted at 21.3 min and 3 (S) - (6-methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- 5 (S) -6 (R) -phenyl-1,7-diaza-spiro [4.5] decane-7-carboxylic acid tert-butyl ester.
[807]
[808] Step 9
[809] (R) - (5 (S) -6 (R) -phenyl-1,7-diaza-spiro- [4.5] dec- Dihydro-1H-quinolin-2-one hydrochloride
[810] (R) - (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- - phenyl-1, 7-diaza-spiro- [4.5] decane-7-carboxylic acid tert-butyl ester (100 mg, 0.0002 m) was saturated with hydrochloric acid gas. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was triturated with methanol / isopropyl ether to give 6-methoxy-1-methyl-7 (R) - (5 (S) -6 (R) -phenyl- M / e = 406.0 (p + 1). [0253] The above-mentioned hydrosilane was obtained in the same manner as in [ 10 mg of the chloride salt was dissolved in a small amount of ethyl acetate / water and the pH was adjusted to 9.5. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to give 6-methoxy-1-methyl- ) -6 (R) -phenyl-1,7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one as a free base.
[811]
[812] Example 37
[813] (S) - (5 (S) -6 (R) -phenyl-1, 7-diaza-spiro [4.5] dec- Dihydro-1H-quinolin-2-one hydrochloride
[814]
[815] Example 38
[816] (R, S) - (5 (R) -6 (S) -phenyl-1,7-diaza-spiro [4.5] dec- -Dihydro-lH-quinolin-2-one &lt; / RTI &gt; hydrochloride
[817]
[818] Production example 34
[819] 6-hydroxy-1-methyl-3,4-dihydro-1H-quinolin-
[820] 5.74 ml of a 1.0 M BBr ₃ / CH ₂ Cl ₂ solution was added to a dry CH ₂ Cl ₂ solution of 6-methoxy-1-methyl-3,4-dihydro-1H-quinolin- &Lt; / RTI &gt; under nitrogen. The reaction mixture was stirred for 2 h, poured into ice water and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with brine, dried (MgSO _4), was obtained and the solvent evaporated under reduced pressure to give the title compound as a pink solid (392 mg, 84%).
[821]
[822] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hypersil 5 uM, 125 x 4 mm column), 2.51 min.
[823] Production example 35
[824] Methyl-6- (1-phenylsulfanyl-cyclopropoxy) -3,4-dihydro-1H-quinolin-
[825] Hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 1.36 mmol) was added to a dry toluene solution of [1-iodo-cyclopropylsulfanyl] mg, 1.13 mmol) and carbonic acid (312 mg, 1.13 mmol) were added under nitrogen and the reaction mixture was heated to 55 &lt; 0 &gt; C. Reagents were added more than 3 times to complete the reaction. The reaction was cooled to room temperature, filtered to remove the silver iodide and concentrated in vacuo to afford the crude material. Flash chromatography using 30% ethyl acetate / hexanes gave the title compound as a viscous oil (64 mg, 17% yield).
[826]
[827] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperyl 5 [mu] M, 125 x 4 mm column), 6.59 min.
[828] Production Example 36
[829] 6-cyclopropoxy-l-methyl-3,4-dihydro-lH-quinolin-2-
[830] Naphthalene (1.0 g, 7.85 mmol) was dissolved in THF (7.5 mL) under nitrogen and freshly cut lithium metal (54 mg, 7.85 mmol) was added. The mixture was stirred at room temperature until a dark green solution of lithium naphthalene was obtained. The solution was cooled to -78 ° C and a solution of 1-methyl-6- (1-phenylsulfanyl-cyclopropoxy) -3,4-dihydro-1H-quinolin- mmol) was added over 1 min. The reaction was stirred for 17 minutes and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate / hexane to give the title compound (42 mg, 36% yield).
[831]
[832] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.713 min.
[833] Production example 37
[834] 6-cyclopropoxy-l-methyl-2-oxo-l, 2,3,4-tetrahydro-quinoline-7-carbaldehyde
[835] A solution of hexamethylenetetramine (58 mg, 0.42 mmol) in TFA (1.38 ml) was heated to 70 &lt; 0 &gt; C for 1 hour under nitrogen. An additional TFA (0.69 ml) solution of 6-cyclopropoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.138 mmol) The reaction mixture was heated to 65 &lt; 0 &gt; C overnight. It was then cooled to room temperature, quenched with water and extracted with ethyl acetate (30 mL). The combined fractions were dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was chromatographed using 40% ethyl acetate / hexanes to give the title compound as a solid (13 mg, 37% yield).
[836]
[837] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.454 min.
[838] Example 39
[839] Synthesis of 6-cyclopropoxy-l-methyl-7- [(2S-phenyl-piperidin-3S-ylamino) -methyl] -3,4- dihydro- lH- quinolin- 2-one dihydrochloride
[840] Methyl-2-oxo-1,2,3,4-tetrahydro-7-carbaldehyde (12.5 mg, 0.051 mmol) and 2 (S) -phenyl-piperidin- (S) -ylamine (13.5 mg, 0.077 mmol) in dry toluene (0.5 mL) was heated at reflux temperature for 3 hours. The reaction mixture was then cooled to room temperature and sodium triacetoxyborohydride (32.4 mg, 0.153 mmol) was added and stirred overnight at room temperature. The reaction was concentrated and the residue was chromatographed using 5% methanol / methylene chloride to give the free base of the title compound (9 mg, 44% yield). 1. Dihydrochloride salt was prepared using OM HCl / Et ₂ O (45 μl) to give the title compound.
[841]
[842] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.701 min.
[843] Example 40
[844] Methyl] -6-methoxy-1-methyl-3, 4-dihydro-lH-pyrrolo [2,3-d] pyrimidin- Quinolin-2-one
[845] (150 mg, 0.687 mmol) and 2R, S- (4-fluoro-phenyl) -2-oxo-1,2,3,4-tetrahydroquinoline- -Piperidine-3R, S-ylamine (200 mg, 1.03 mmol) in dry toluene (5 mL) was heated at reflux temperature for 2 hours and then cooled to room temperature. Sodium triacetoxyborohydride (437 mg, 2.06 mmol) was added and the reaction mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was chromatographed using 2-10% methanol / methylene chloride to give the title compound (218 mg, 80% yield).
[846]
[847] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperyl 5 [mu] M, 125 x 4 mm column), 3.978 min. A dihydrochloride salt was prepared using 1.0 M HCl / Et ₂ O and obtained as a solid.
[848] Example 41
[849] 6-methoxy-1-methyl-3,4-dihydro-1H-quinoline) -7-ylmethyl-2- (4- Fluoro-phenyl) -piperidin-3-ylamino] methyl-3,4-dihydro-lH-quinolin-
[850] Methyl] -6-methoxy-1-methyl-3, 4-dihydro-lH-pyrrolo [2,3-d] pyrimidin- Quinolin-2-one, the title compound was also obtained (82 mg, 19% yield). m / z (APCI &lt; ⁺ & gt ^; ) 601 (M + 1). HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 5.436 min.
[851] Example 42
[852] Ylamino] -methyl} -6-methoxy-l-methyl-3,4-dihydro-lH-quinolin-2- &lt; On
[853] Methyl] -6-methoxy-1-methyl-3, 4-dihydro-lH-pyrrolo [2,3-d] pyrimidin- Quinolin-2-one (200 mg) was obtained the title compound (72 mg) by chiral separation of the title compound.
[854]
[855] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.221 min.
[856] Production Example 38
[857] 6-Ethoxy-1-methyl-3,4-dihydro-1H-quinolin-
[858] 1.0 M Potassium t-butoxide / THF (5.65 mL, 5.65 mmol) was added to 6-hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 1.13 mmol) , Followed by the addition of ethyl iodide (452 [mu] L, 5.65 mmol). The reaction mixture was stirred at room temperature for 2 hours and heated to 45 &lt; 0 &gt; C overnight. The salt was filtered off, rinsed with ethyl acetate and the combined filtrate was concentrated to a residue. This was chromatographed using 1: 1 ethyl acetate / hexanes to give the title compound as a white solid (76 mg, 33% yield).
[859]
[860] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.453 min.
[861] Production example 39
[862] 6-Ethoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde
[863] Methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde, the title compound was prepared as a yellow solid.
[864]
[865] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.167 min.
[866] Example 43
[867] Methyl-7 - [(2S-phenyl-piperidin-3S-ylamino) -methyl] -3,4-dihydro-1 H- quinolin-2-one dihydrochloride
[868] Methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (90 mg, 0.386 mmol) and 2S-phenyl-piperidin- (102 mg, 0.579 mmol) in dry toluene (3.86 mL) was heated at reflux temperature for 2 hours and cooled to room temperature. Sodium triacetoxyborohydride (245 mg, 1.158 mmol) was then added and the reaction mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was chromatographed using 5-10% methanol / methylene chloride to give the free base of the title compound as a viscous gum (122 mg, 81% yield). Using _{1.0M HCl / Et 2 O (620} ㎕) and the precipitate was filtered to give the title compound.
[869]
[870] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.436 min.
[871] Example 44
[872] Methyl-7 - [(2S-phenyl-piperidin-3S-ylamino) -methyl] -3,4-dihydro-1 H- quinolin-2-one dihydrochloride
[873] Methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (200 mg, 0.976 mmol) and 2S-phenyl-piperidin- (258 mg, 1.46 mmol) in dry toluene (9.OmL) was heated at reflux temperature for 2 hours and cooled to room temperature. Sodium triacetoxyborohydride (620 mg, 2.93 mmol) was then added and the reaction mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was redissolved in ethyl acetate and washed once with dilute sodium bicarbonate. The organic layer was dried (MgSO ₄₎ and concentrated to an oil under reduced pressure. 1.95 mL of 1.0 M HCl / Et ₂ O was added to give a dark solid which was recrystallized from isopropanol / isopropyl ether to give the title compound as yellow crystals (270 mg, 63% yield).
[874]
[875] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 3.006 min.
[876] Example 45
[877] Methyl-6-methoxy-3,4-dihydro-1H-quinolin-2- &lt; RTI ID = 0.0 & Ondihydrochloride
[878] (115 mg, 0.561 mmol) and 2R, S- (4-fluoro-phenyl) -piperidine-4- carboxylic acid (163 mg, 0.841 mmol) in dry toluene (5 mL) was heated at reflux temperature for 2 hours and then cooled to room temperature. Sodium triacetoxyborohydride (357 mg, 1.68 mmol) was added and the reaction mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was chromatographed using 5-15% methanol / methylene chloride to give the free base of the title compound (120 mg, 56% yield). Using 1.0M HCl / Et ₂ 0 to give the title compound as an off-white solid.
[879]
[880] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 3.592 min.
[881] Production example 40
[882] 7-iodo-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-
[883] Trifluoroacetate (2.32 g, 10.48 mmol) was added to a solution of 6-methoxy- l -methyl-3,4-dihydro- lH- quinolin-2-one (1.0 g, 5.24 mmol) in dry methylene chloride ) Solution, a solution of iodine (1.33 g, 10.48 mmol) in methylene chloride (100 mL) was added dropwise over 15 minutes. The reaction mixture was stirred overnight and the precipitated silver iodide salt was filtered off. The filtrate was concentrated and the residue was chromatographed using 50% ethyl acetate / hexanes to give the title compound (795 mg, 48% yield).
[884]
[885] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.959 min.
[886] Production example 41
[887] Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) -6-phenyl- 1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane
[888] Spiro [4.5] dec-3-ene-7-carboxylic acid tert-butyl ester (1.0 g, 0.35 mmol) in dimethylformamide (40 mL) , 3.17 mmol), 7-iodo-6-methoxy-1 -methyl-3,4-dihydro-1H-quinolin-2-one (2.51 g, 7.93 mmol), tetra-n-butylammonium chloride g, 3.17 mmol), lithium chloride (14 mg, 0.032 mmol) and potassium formate (0.81 g, 9.61 mmol) were degassed and kept under nitrogen. Palladium acetate (80 mg, 0.32 mmol) was added and the mixture was degassed and stirred at 60 &lt; 0 &gt; C for 15 h before 7-iodo-6-methoxy- 2-one (0.5 g, 1.58 mmol), potassium formate (0.4 g, 4.8 mmol) and palladium acetate (40 mg, 0.16 mmol). The mixture was stirred at 60 &lt; 0 &gt; C overnight, cooled and filtered. The solvent was evaporated under reduced pressure, water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). Wash the combined organic fractions with brine, dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 35% ethyl acetate / hexanes to give the title compound as a white solid (580 mg, 36% yield).
[889]
[890] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hosporil 5 [mu] M, 125 x 4 mm column), 7.414 min.
[891] Example 46
[892] (3R, S-6S-5R, S) 3- (6-Methoxy- 1 -methyl-2-oxo-1,2,3,4-tetrahydro-quinolin- -Oxa-7-aza-spiro [4.5] decane hydrochloride
[893] Trifluoroacetic acid (0.230 ml) was added to a solution of (3R, S-5R, S-6S) -3- (6-methoxy- To a stirred solution of 4-tetrahydro-quinolin-7-yl) -6-phenyl-1-oxa-7- (tert-butoxycarbonyl) aza-spiro [4.5] decane (45 mg, 0.89 mmol) The mixture was stirred overnight at room temperature. The mixture was poured into water (10 mL), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with dichloromethane (3x25 mL). Drying of the combined organic fractions were (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was redissolved in ethyl acetate and treated with 1.0 M HCl / ether (0.09 mL). It was resuspended in isopropanol and filtered to give the title compound as a solid (19 mg, 49% yield).
[894]
[895] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS HEPOSIL 5 [mu] M, 125 x 4 mm column), 4.170 min.
[896] Example 47
[897] S, S-7 - [(1 -Dimethylaminoacetyl-2-phenyl-piperidin-3- ylamino) -methyl] -6-methoxy- 1 -methyl-3,4-dihydro- One dihydrochloride
[898] Under nitrogen, CH ₂ Cl ₂ 670 ㎕ of S, S-6- methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-yl) -methyl] -3,4-dihydro- 1H-quinolin-2-one (95 mg, 0.25 mmol) was combined with 26 mg (0.25 mmol) of N, N-dimethylaminoacetic acid. After 139 [mu] l (1.00 mmol) of triethylamine was added, 59 mg (0.25 mmol) of bis- (2-oxo-3-oxazolidinyl) phosphine chloride was added. The yellow solution was stirred overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and partitioned into H ₂ O. The aqueous layer was extracted once with CH ₂ Cl ₂ . Drying of the combined organic fractions were (MgSO _4), and the solvent was evaporated under reduced pressure. The yellow residue was first eluted with 9: 1 CH ₂ Cl ₂ / CH ₃ OH and chromatographed on a Biotage Flash 12 followed by gradient of 95: 5 to 85:15 CH ₂ Cl ₂ / CH ₃ OH And purified by flash chromatography on 230-400 mesh silica gel to give 64 mg (55%) of the title compound.
[899]
[900] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperyl 5 [mu] M, 125 x 4 mm column) 3.080.
[901] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ 0 and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[902] Example 48
[903] S, S-6-methoxy-1-methyl-7 - {[2-phenyl- 1- (pyridin- 2- yl-acetyl) -piperidin- Dihydro-1H-quinolin-2-one dihydrochloride
[904] CH ₂ Cl ₂ 670 ㎕ of S, S-6- methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-yl) -methyl] -3,4-dihydro -1H- Quinolin-2-one 95 mg (0.25 mmol) were combined with 43 mg (0.25 mmol) of 2-pyridylacetic acid. After 139 [mu] l (1.00 mmol) of triethylamine was added, 59 mg (0.25 mmol) of bis- (2-oxo-3-oxazolidinyl) phosphine chloride was added. The yellow solution was shaken overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and partitioned with saturated NaHCO ₃ . The aqueous layer was extracted twice with CH ₂ Cl ₂ . Drying of the combined organic fractions were (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was eluted with 95: 5 CH ₂ Cl ₂ / CH ₃ OH and purified by flash chromatography on 230-400 mesh silica gel to give 50 mg (40%) of the title compound.
[905]
[906] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hospityl 5 [mu] M, 125 x 4 mm column) 4.008.
[907] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ 0 and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[908] Example 49
[909] S, S-6-methoxy-1-methyl-7 - {[2-phenyl- 1- (pyridin- Dihydro-1H-quinolin-2-one dihydrochloride
[910] CH ₂ Cl ₂ 670 ㎕ of S, S-6- methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-yl) -methyl] -3,4-dihydro -1H- Quinolin-2-one 95 mg (0.25 mmol) were combined with 43 mg (0.25 mmol) of 3-pyridylacetic acid. After 139 [mu] l (1.00 mmol) of triethylamine was added, 59 mg (0.25 mmol) of bis- (2-oxo-3-oxazolidinyl) phosphine chloride was added. The yellow solution was shaken overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and partitioned with saturated NaHCO ₃ . The aqueous layer was extracted twice with CH ₂ Cl ₂ . Drying of the combined organic fractions were (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 95: 5 CH ₂ Cl ₂ / CH ₃ OH to give 66 mg (53%) of the title compound.
[911]
[912] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS HEPOSIL 5 [mu] M, 125 x 4 mm column) 3.690.
[913] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[914] Example 50
[915] S, S-6-methoxy-1-methyl-7 - {[2-phenyl- 1- (pyridin- Dihydro-1H-quinolin-2-one dihydrochloride
[916] CH ₂ Cl ₂ 670 ㎕ of S, S-6- methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-yl) -methyl] -3,4-dihydro -1H- Quinolin-2-one 95 mg (0.25 mmol) were combined with 43 mg (0.25 mmol) of 4-pyridylacetic acid. After 139 [mu] l (1.00 mmol) of triethylamine was added, 59 mg (0.25 mmol) of bis- (2-oxo-3-oxazolidinyl) phosphine chloride was added. The yellow solution was shaken overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and partitioned with saturated NaHCO ₃ . The aqueous layer was extracted twice with CH ₂ Cl ₂ . Drying of the combined organic fractions were (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was eluted with 95: 5 CH ₂ Cl ₂ / CH ₃ OH and purified by flash chromatography on 230-400 mesh silica gel to give 51 mg (41%) of the title compound.
[917]
[918] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 3.589.
[919] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[920] Example 51
[921] S, S-7 - {[1- (Imidazol-1-yl-acetyl) -2- phenyl- piperidin-3- ylamino] -methyl} -6-methoxy- Dihydro-lH-quinolin-2-one &lt; / RTI &gt; dihydrochloride
[922] CH ₂ Cl ₂ 670 ㎕ of S, S-6- methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-yl) -methyl] -3,4-dihydro -lH- Quinolin-2-one (95 mg, 0.25 mmol) was combined with imidazol-1-yl-acetic acid (31 mg, 0.25 mmol). 139 μl (1.00 mmol) of triethylamine (NEt ₃ ) was added followed by 59 mg (0.25 mmol) of bis (2-oxo-3-oxazolidinyl) phosphine chloride. The yellow solution was shaken overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and partitioned twice with saturated NaHCO ₃ . The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was eluted with 95: 5 CH ₂ Cl ₂ / CH ₃ OH and purified by flash chromatography on 230-400 mesh silica gel to give 85 mg (70%) of product.
[923]
[924] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 2.896.
[925] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[926] Imidazol-1-yl-acetic acid methyl ester
[927] 1.0 g (14.7 mmol) of imidazole in 40 mL of CH ₂ Cl ₂ under nitrogen was combined with 824 mg (14.7 mmol) of potassium hydroxide, 2.0 g (14.7 mmol) of potassium carbonate and 82 mg (7.34 mmol) of benzyltriethylammonium chloride . 695 [mu] l of methyl bromoacetate was added. The reaction was stirred at room temperature for 3 hours. The solid was filtered, rinsed with CH ₂ Cl ₂ , and the filtrate was evaporated under reduced pressure to give a colorless oil. The product was purified by flash chromatography on BioTag Flash 40 (eluent: 95: 5 CH ₂ Cl ₂ / CH ₃ OH) to give 300 mg (27%) of a white solid.
[928]
[929] Imidazol-1-yl-acetic acid
[930] 300 mg of imidazol-1-yl-acetic acid methyl ester in 12 ml of H ₂ O was refluxed under nitrogen for 6 hours. Evaporation in vacuo followed by cooling afforded 240 mg (97%) of a white solid.
[931]
[932] Example 52
[933] S, S-6-methoxy-1-methyl-7 - [(1- [1,2,4] oxadiazol-3-ylmethyl-2-phenyl-piperidin- ] -3,4-dihydro-1H-quinolin-2-one dihydrochloride
[934] S, S-6-Methoxy-1-methyl-7 - [(2-phenyl- piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- (0.25 mmol) were combined with 30 mg (0.25 mmol) of 3- (chloromethyl) [1,2,4] oxadiazole, 105 μl of diisopropylamine and 2 ml of acetonitrile, and the mixture was shaken overnight. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ twice. The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The yellow gum was eluted with 95: 5 CH ₂ Cl ₂ / CH ₃ OH and purified by flash chromatography on 230-400 mesh silica gel to give 73 mg (63%) of product.
[935]
[936] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hospityl 5 [mu] M, 125 x 4 mm column) 4.461.
[937] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[938] Example 53
[939] S, 6-methoxy-7 - {[1- (2-methoxy-ethyl) -2-phenyl-piperidin- Hydro-1H-quinolin-2-one dihydrochloride
[940] 23.5 [mu] l (0.25 mmol) of 2-bromoethyl methyl ether was dissolved in 2 ml of acetonitrile. S, S-6-Methoxy-1-methyl-7 - [(2-phenyl- piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- (0.25 mmol) and 105 [mu] l of diisopropylamine were added. The reaction was shaken for 2 days. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ twice. The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was first eluted with 9: 1, 1% CH ₂ Cl ₂ / CH ₃ OH / triethylamine and flash chromatographed on 230-400 Å mesh silica gel, eluting with 9: 1, 0.1% CH ₂ Cl ₂ / CH ₃ OH / triethylamine elution with 230-400 Å mesh was obtained by flash chromatography gave the product 26 mg (24%) on silica gel to the amine.
[941]
[942] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperyl 5 [mu] M, 125 x 4 mm column) 4.720.
[943] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[944] Example 54
[945] S, S-7 - {[1- (2,3-dihydroxy-propyl) -2-phenyl-piperidin-3- ylamino] -methyl} -6- 4-dihydro-1H-quinolin-2-one dihydrochloride
[946] 21.9 占 퐇 (0.25 mmol) of 3-bromo-1,2-propanediol was dissolved in 2 ml of acetonitrile. S, S-6-Methoxy-1-methyl-7 - [(2-phenyl- piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- (2-phenyl-piperidin-3-ylamino) -methyl] -3, 4-dihydro-1H &lt; / RTI &gt; -Quinolin-2-one (95 mg, 0.25 mmol) and diisopropylamine (105 μl) were added. The reaction was shaken for 2 days. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ twice. The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was first eluted with 9: 1, 0.1% CH ₂ Cl ₂ / CH ₃ OH / triethylamine and flash chromatographed on 230-400 Å mesh silica gel, eluting with 98: 2, 0.05% CH ₂ Cl ₂ / Eluting with CH ₃ OH / triethylamine and purification by flash chromatography on 230-400 mesh silica gel, yielding 19 mg (17%) of product.
[947]
[948] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS HEPOSIL 5 [mu] M, 125 x 4 mm column) 3.608.
[949] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[950] Example 55
[951] S, S-7 - {[1- (2-Dimethylamino-ethyl) -2-phenyl-piperidin-3- ylamino] -methyl} -6-methoxy- Hydro-1H-quinolin-2-one dihydrochloride
[952] 36 mg (0.25 mmol) of 2- (N, N-dimethylamino) ethyl chloride in 2 ml of acetonitrile was added to a solution of S, S-6-methoxy- -Ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one 95 mg (0.25 mmol) and diisopropylamine 105 μl. The reaction was shaken for 2 days. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ twice. The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on 230-400 mesh silica gel eluting with a gradient of 9: 1 CH ₂ Cl ₂ / CH ₃ OH to 8: 2 CH ₃ OH / triethylamine to yield 24 mg (21 %).
[953]
[954] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 3.346.
[955] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[956] Example 56
[957] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -3,4-dihydro-1 H-quinolin-2-one To a solution of 6-methoxy- Dihydrochloride
[958] Amino] -2-phenyl-hexahydro-cyclopenta [b- (2, 3-dimethoxy- ] Pyrrole-1-carboxylic acid benzyl ester (441 mg, 0.82 mmol) was dissolved in 40 mL of EtOH. 55 mg of 10% palladium on carbon was added and placed under 45 l of hydrogen for 4.25 h in a Parr shaker. Filtered through celite, the catalyst was rinsed several times with EtOH, and the filtrate was evaporated under reduced pressure. The residue was purified with BioTag Flash 40 eluting with 96: 4 CH ₂ Cl ₂ / CH ₃ OH to give 222 mg (69%) of the racemic product.
[959]
[960] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 4.200.
[961] The enantiomers were separated by chiral purification HPLC (80/20/0.025% hexane / EtOH / diethylamine, 75 mL / min, Chiralpak AD, 5 cm x 50 cm) to give the S, S- enantiomer with retention time 6.512 Min, and the R, R-enantiomer was obtained at a residence time of 12.078 min.
[962] The product was dissolved in CH ₃ OH, 1 M HCl in Et ₂ O was added and evaporated under reduced pressure to give the dihydrochloride salt.
[963] Production example 42
[964] Amino] -2-phenyl-hexahydro-cyclopenta [b- (2, 3-dimethoxy- ] Pyrrole-1-carboxylic acid benzyl ester
[965] 606 mg (1.80 mmol) of 3-amino-2-phenyl-hexahydrocyclopenta [b] pyrrole-1-carboxylic acid benzyl ester in 10 ml of CH ₂ Cl ₂ under nitrogen was treated with 6-methoxy- Oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (395 mg, 1.80 mmol) were combined and stirred for 15 minutes. 1.15 g (5.40 mmol) of sodium triacetoxyborohydride was added and stirred overnight. The reaction mixture was washed three times with saturated NaHCO ₃ . The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was first purified by flash chromatography on BioTag Flash 40 eluting with 1: 1 EtOAc / hexanes then EtOAc to give 323 mg (33%) of product. Another lot (241 mg, 25%) was isolated and subjected to a second chromatography. M / z (APCI &lt; ⁺ & gt ^; ) 539.9 (M + 1). HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 6.367.
[966] Example 57
[967] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -1,3-dihydro-indol-2-one To a solution of 6-methoxy-1,3,3-trimethyl- -One dihydrochloride
[968] 3-Trimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) -amino] -2-phenyl-hexahydro- cyclopenta [b] pyrrole-1-carboxylic acid phenyl ester (326 mg, 0.59 mmol) was dissolved in 32 mL of EtOH. 32 mg of 10% palladium on carbon was added and placed under 39 pounds of hydrogen in a Parr shaker for 4.5 hours. Filtered through celite, the catalyst was rinsed several times with EtOH, and the filtrate was evaporated under reduced pressure. The residue was purified on a BioTag flash 40 eluting with 95: 5 CH ₂ Cl ₂ / CH ₃ OH followed by CH ₃ OH to give 150 mg (61%) of the racemic product.
[969]
[970] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS HEPOSIL 5 [mu] M, 125 x 4 mm column) 4.522.
[971] The enantiomers were separated by chiral purification HPLC (85/15 / 0.025% hexane / isopropanol / diethylamine, 80 mL / min, Chiralpak AD, 5 cm x 50 cm) to give the S, S- enantiomer, Min, and the R, R-enantiomer was obtained at a residence time of 13.946 min.
[972] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[973] Production Example 43
[974] 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-
[975] In a nitrogen flame dry flask, 490 mg (12.26 mmol) of 60% sodium hydride was slurried three times with hexane and hexane was injected. After addition of 6.25 ml of N, N-dimethylformamide, 500 mg (3.06 mmol) of 6-methoxy-1,3-dihydro-indol-2-one was added and the mixture was stirred at room temperature for 5 minutes. It was chilled in an ice bath and 763 l (12.26 mmol) of methyl iodide was added dropwise. After 10 minutes, it was warmed to room temperature and stirred for 1.5 hours. It was chilled in an ice bath and 20 mL of H ₂ O was added dropwise. And extracted three times with 2: 1 EtOAc / toluene. The combined organics were washed with sodium thiosulfate, H ₂ O and brine, dried (MgSO ₄ ) and the solvent removed in vacuo to give a crude red oil. Eluting with 4: 1 hexanes / EtOAc and purification on BioTag Flash 40 to yield 285 mg (45%) of a white solid.
[976]
[977] Production example 44
[978] Methoxy-l, 3,3-trimethyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[979] 282 mg (1.37 mmol) of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one was combined with 10 mL of CH ₂ Cl _{2 under} nitrogen and chilled in an ice bath. 4.1 mL of 1.0 M titanium tetrachloride in CH ₂ Cl ₂ (4.1 mmol) was added dropwise. It was cooled and stirred for 1.5 hours. 186 [mu] l (2.06 mmol) of [alpha], [alpha] -dichloromethyl methyl ether was added, stirred for 15 minutes while cooling, and then stirred overnight at room temperature. Poured into ice water and extracted three times with CH ₂ Cl ₂ . The combined organics were extracted with brine, saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and the solvent evaporated in vacuo to give 289 mg (91%) of a green solid.
[980]
[981] Production example 45
[982] 3-Trimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) -amino] -2-phenyl-hexahydro- cyclopenta [b] pyrrole-1-carboxylic acid phenyl ester
[983] 288 mg (0.86 mmol) of 3-amino-2-phenyl-hexahydro-cyclopenta [b] pyrrole-1-carboxylic acid benzyl ester in 5 ml of CH ₂ Cl ₂ under nitrogen was treated with 6-methoxy- 3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde (200 mg, 0.86 mmol) and stirred for 10 minutes. 545 mg (2.57 mmol) of sodium triacetoxyborohydride were added and stirred overnight. The reaction mixture was extracted twice with saturated NaHCO ₃ . The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was eluted with 1: 1 EtOAc / hexane and purified by flash chromatography on BioTag Flash 40 to give 336 mg (71%) of product. M / z (APCI &lt; ⁺ & gt ^; ) 554.2 (M + 1). HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 6.531.
[984] Example 58
[985] S, S-6-ethoxy-1,3,3-trimethyl-5 - [(2-phenyl-piperidin- Dihydrochloride
[986] 50 mg (0.20 mmol) of S, S-2-phenyl-piperidin-3-ylamine was dissolved in 1.5 mL of CH ₂ Cl ₂ and 0.5 mL of DMF under nitrogen. 49 mg (0.20 mmol) of 6-ethoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde was added and stirred for 45 minutes. 127 mg (0.60 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred for 40 hours. Diluted with CH ₂ Cl ₂ , extracted with saturated NaHCO ₃ , dried (MgSO ₄ ) and the solvent removed under reduced pressure. 95: 5 CH ₂ Cl ₂ / CH ₃ OH then eluted with 85:15 CH ₂ Cl ₂ / CH ₃ OH and purified by chromatography on BioTag Flash 40 to yield 40 mg (49%) of product.
[987]
[988] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 4.514.
[989] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[990] Example 59
[991] Methyl-l, 3-dihydro-indol-2 &lt; RTI ID = -One dihydrochloride
[992] 3 - [(6-ethoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-6-ylmethyl) -amino] -2- phenyl-hexahydro- cyclopenta [b] pyrrole-1-carboxylic acid phenyl ester 279 mg (0.49 mmol) was dissolved in 28 ml of EtOH. 28 mg of 10% palladium on carbon were added and placed in a Parr shaker under 52 lbs of hydrogen overnight. Filtered through celite, the catalyst was rinsed several times with EtOH, and the filtrate was evaporated under reduced pressure. The residue was purified with BioTag Flash 40 eluting with 95: 5 CH ₂ Cl ₂ / CH ₃ OH then 90:10 CH ₂ Cl ₂ / CH ₃ OH to give 92 mg (43%) of the racemic product.
[993]
[994] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 5.172.
[995] The enantiomers were separated by chiral purification HPLC (90/10/0.025% hexane / isopropanol / diethylamine, 45 mL / min, Chiralpak AD, 5 cm x 50 cm) to give the S, S- enantiomer, Min, and the R, R-enantiomer was obtained at a retention time of 15.159 min.
[996] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[997] Production example 46
[998] 6-hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-
[999] 2.05 g (10.0 mmol) of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one under nitrogen was combined with 28 mL of CH ₂ Cl ₂ . 22 mL of 1.0 M boron tribromide in CH ₂ Cl ₂ was added dropwise over 10 minutes. And the mixture was stirred at room temperature for 3.5 hours. Poured into ice water and filtered to give 2.32 g of a beige solid.
[1000]
[1001] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 3.262.
[1002] Production example 47
[1003] 6-Ethoxy-1,3,3-trimethyl-1,3-dihydro-indol-
[1004] Under nitrogen, 1.16 g (5.0 mmol) of 6-hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one was combined with 10 mL of THF. 2.8 g (25.0 mmol) of potassium t-butoxide was added and stirred for 45 minutes. 2.0 ml (25.0 mmol) of ethyl iodide was added, and the mixture was stirred overnight. The reaction mixture was diluted with EtOAc, extracted three times with H ₂ O, the combined organics were dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to give 864 mg (78%) of a yellow solid.
[1005]
[1006] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 ml / min, Hewlett Packard ODS Hiperysil 5 [mu] M, 125 x 4 mm column) 5.220.
[1007] Production Example 48
[1008] 6-Ethoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[1009] 3.5 ml of trifluoroacetic acid under nitrogen was added to 859 mg (6.13 mmol) of hexamethylenetetramine and heated in an oil bath at 70 &lt; 0 &gt; C for 1 hour. 6-ethoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (448 mg) was dissolved in 1.0 ml of trifluoroacetic acid. After heating at 70 占 폚 for 4 hours, heating at 50 占 폚 for 18 hours. Lt; / RTI &gt; 4.0 mL of H ₂ O was added and extracted three times with EtOAc. The combined organics were dried (MgSO _4), evaporated in vacuo, 2: 1 was purified by flash chromatography on Bio-tag 40 by eluting with hexane / EtOAc to give a green solid 335 mg (66%).
[1010]
[1011] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 4.815.
[1012] Production Example 49
[1013] 3 - [(6-ethoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-indol-6-ylmethyl) -amino] -2- phenyl-hexahydro- cyclopenta [b] pyrrole-1-carboxylic acid phenyl ester
[1014] 202 mg (0.60 mmol) of 3-amino-2-phenyl-hexahydro-cyclopenta [b] pyrrole-1-carboxylic acid benzyl ester in 5 ml of CH ₂ Cl ₂ under nitrogen was treated with 6-ethoxy- 3-Trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde 148 mg (0.60 mmol) were combined and stirred for 45 minutes. 381 mg (1.80 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred for 40 hours. The reaction mixture was extracted with saturated NaHCO ₃ . The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was eluted with 1: 2 EtOAc / hexane and purified by flash chromatography on BioTag Flash 40 to give 279 mg (82%) of product. M / z (APCI ⁺ ) 568.3 (M + 1). HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 7.058.
[1015] Example 60
[1016] S, S-6-isopropoxy-1,3,3-trimethyl-5 - [(2-phenyl-piperidin- Ondihydrochloride
[1017] 50 mg (0.20 mmol) of S, S-2-phenyl-piperidin-3-ylamine was dissolved in 1.5 mL of CH ₂ Cl ₂ and 0.5 mL of DMF under nitrogen. 52 mg (0.20 mmol) of 6-isopropoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde was added and stirred for 1 hour. 127 mg (0.60 mmol) of sodium triacetoxyborohydride was added and slurried overnight. Diluted with CH ₂ Cl ₂ , extracted with saturated NaHCO ₃ , dried (MgSO ₄ ) and the solvent removed under reduced pressure. 9: 1 CH ₂ Cl ₂ / CH ₃ OH followed by 8: 2 CH ₂ Cl ₂ / CH ₃ OH Finally eluted with 1: 1 CH ₂ Cl ₂ / CH ₃ OH and purified by chromatography on a BioTag Flash 40 40 mg (48%) of the product was obtained.
[1018]
[1019] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS HEPOSIL 5 [mu] M, 125 x 4 mm column) 5.053.
[1020] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[1021] Example 61
[1022] Cyclopenta [b] pyrrol-3-ylamino) -methyl] -l, 3-dihydro-indol- 2-one dihydrochloride
[1023] 2-oxo-2,3-dihydro-1H-indol-6-ylmethyl) -amino] -2-phenyl-hexahydro- cyclo Penta-1-carboxylic acid phenyl ester (307 mg, 0.53 mmol) were dissolved in 30 mL of EtOH. 30 mg of 10% palladium on carbon was added and placed in a Parr shaker under 42 pounds of hydrogen overnight. Filtered through celite, the catalyst was rinsed several times with EtOH, and the filtrate was evaporated under reduced pressure. The residue was purified with BioTag Flash 40 eluting with 95: 5 CH ₂ Cl ₂ / CH ₃ OH followed by 1: 1 CH ₂ Cl ₂ / CH ₃ OH to yield 148 mg (63%) of the racemic product.
[1024]
[1025] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 5.426.
[1026] The enantiomers were separated by chiral purification HPLC (90/10/0.05% hexane / isopropanol / diethylamine, 100 mL / min, Chiralpak AD, 5 cm x 50 cm) to give the S, S- enantiomer with a retention time of 8.832 Min, and the R, R-enantiomer was obtained at a residence time of 12.563 min.
[1027] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[1028] Production Example 50
[1029] 6-isopropoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-
[1030] Under nitrogen, 1.16 g (5.0 mmol) of 6-hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one was combined with 10 mL of THF. 2.8 g (25.0 mmol) of potassium t-butoxide was added and stirred for 45 minutes. 2.5 ml (25.0 mmol) of 2-iodopropane was added, and the mixture was stirred overnight. The reaction mixture was diluted with EtOAc, extracted with H ₂ O, the combined organics were dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure. Eluting with 3: 1 hexanes / EtOAc and purification by flash chromatography on BioTag Flash 40 to yield 490 mg (42%) of a yellow solid.
[1031]
[1032] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 5.648.
[1033] Production example 51
[1034] 6-isopropoxy-l, 3,3-trimethyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[1035] 3.5 ml of trifluoroacetic acid under nitrogen was added to 880 mg (6.30 mmol) of hexamethylenetetramine and heated at 70 [deg.] C for 1 hour in a sand bath. Was added 490 mg of 6-isopropoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one dissolved in 1.5 ml of trifluoroacetic acid. After heating at 70 占 폚 for 1 hour, heating was carried out at 50 占 폚 for 18 hours. Lt; / RTI &gt; Was added to 4.5 mL of H ₂ O and extracted three times with EtOAc. The combined organics were dried (MgSO _4), evaporated in vacuo, 2: 1 was purified by flash chromatography on Bio-tag 40 by eluting with hexane / EtOAc to give a green solid 241 mg (49%).
[1036]
[1037] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 5.050.
[1038] Production example 52
[1039] 2-oxo-2,3-dihydro-1H-indol-6-ylmethyl) -amino] -2-phenyl-hexahydro- cyclo Penta [b] pyrrole-1-carboxylic acid phenyl ester
[1040] 202 mg (0.60 mmol) of 3-amino-2-phenyl-hexahydrocyclopenta [b] pyrrole-1-carboxylic acid benzyl ester in 5 ml of CH ₂ Cl ₂ under nitrogen was treated with 6-isopropoxy- 3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde 157 mg (0.60 mmol) were combined and stirred for 1 hour. 381 mg (1.80 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred for one week. CH ₂ Cl ₂ and saturated NaHCO ₃ . The organic layer was dried (MgSO _4), and the solvent was evaporated under reduced pressure. The residue was eluted with 975/25 CH ₂ Cl ₂ / CH ₃ OH and purified by flash chromatography on a BioTag Flash 40 to yield 312 mg (89%) of product. HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS HEPOSIL 5 [mu] M, 125 x 4 mm column) 7.476.
[1041] Example 62
[1042] S, S-7-isopropoxy-l-methyl-6 - [(2- phenyl-piperidin- 3- ylamino) -methyl] -3,4-dihydro-lH- quinolin- Hydrochloride
[1043] 50 mg (0.20 mmol) of S, S-2-phenyl-piperidin-3-ylamine in 1.5 mL of CH ₂ Cl ₂ and 0.5 mL of DMF under nitrogen was added dropwise to a solution of 7-isopropoxy- And 49 mg (0.20 mmol) of 1,2,3,4-tetrahydro-quinoline-6-carbaldehyde were combined and stirred at room temperature for 15 minutes. 127 mg (0.60 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred overnight. The reaction was diluted with CH ₂ Cl ₂ , extracted twice with saturated NaHCO ₃ , dried (MgSO ₄ ) and evaporated under reduced pressure. The residue was eluted with 9: 1 CH ₂ Cl ₂ / CH ₃ OH and purified on BioTag Flash 40 to yield 39 mg (48%) of product.
[1044]
[1045] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 4.147.
[1046] The product was dissolved in CH ₃ OH was added a 1.0M HCl 1 ㎖ of Et ₂ O and evaporated under reduced pressure to prepare a di-hydrochloride salt.
[1047] Production Example 53
[1048] 3-Chloro-N- (3-methoxy-phenyl) -propionamide
[1049] 4.5 mL (0.04 mol) of m-anisidine under nitrogen was added to a vigorously stirred mixture of 25 mL of CH ₂ Cl _{2 and} 25 mL of saturated NaHCO ₃ . 3.82 ml of 3-chloropropionyl chloride was added dropwise over 15 minutes to prevent reflux. The mixture was stirred for 15 minutes, the layers were separated, the aqueous layer was extracted with CH ₂ Cl ₂ , the combined organics were dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to give 7.93 g (93%) of a tan solid .
[1050]
[1051] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 4.131.
[1052] Production example 54
[1053] Hydroxy-3,4-dihydro-1H-quinolin-2-one
[1054] To the exit behind the hood was added 12.37 g (0.093 mol) of aluminum chloride powder under nitrogen to 7.93 g (0.037 mol) of 3-chloro-N- (3-methoxy-phenyl) -propionamide. Placed in a preheated sand bath at 160 DEG C, heated for 4 hours, and the bath temperature was raised to 200 DEG C until no HCl was observed. Cooled to room temperature, refrigerated in an ice bath, and ice water added a little bit. Extracted three times with EtOAc, dried (MgSO _4), it evaporated under reduced pressure. Elution with 1: 1 EtOAc / hexanes and purification by flash chromatography on 230-400 mesh silica gel gave 3.3 g (55%) of a beige solid.
[1055]
[1056] Production example 55
[1057] Methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-
[1058] 3.2 g (0.0196 mol) of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one were combined with 25 ml of THF under nitrogen. 5.1 g (0.0451 mol) of potassium t-butoxide was added and stirred for 1.25 hours. After the addition of 4.3 ml (0.0451 mol) of dimethyl sulfate, 10 ml of THF was added and the mixture was stirred overnight. The reaction mixture was diluted with EtOAc, extracted three times with H ₂ O, dried (MgSO ₄ ) and evaporated under reduced pressure. Eluting with 3: 1 hexanes / EtOAc and purification by chromatography on BioTag Flash 40 to give 1.7 g (45%) of a white solid.
[1059]
[1060] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hospityl 5 [mu] M, 125 x 4 mm column) 4.068.
[1061] Production example 56
[1062] 7-hydroxy-1-methyl-3,4-dihydro-1H-quinolin-
[1063] 1.3 g (6.8 mmol) of 7-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one under nitrogen was combined with 18 ml of CH ₂ Cl ₂ . 15 mL of 1.0 M boron tribromide in CH ₂ Cl ₂ (15.0 mmol) was added dropwise over 3 minutes. The reaction was stirred for 5 h, poured into ice water, slurried for 15 min, and filtered to give 818 mg (68%) of an off-white solid.
[1064]
[1065] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 2.826.
[1066] Production Example 57
[1067] 7-isopropoxy-l-methyl-3,4-dihydro-lH-quinolin-2-
[1068] 818 mg (4.62 mmol) of 7-hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one was added to 7 ml of THF under nitrogen. 2.59 g (23.1 mmol) of potassium t-butoxide was added and the thickening suspension was stirred for 1 hour. 2.3 ml (23.1 mmol) of 2-iodopropane was added and stirred for 9 days. The reaction mixture was diluted with EtOAc, extracted three times with H ₂ O, dried (MgSO ₄ ) and evaporated under reduced pressure. The residue was purified by chromatography on BioTag Flash 40 eluting with 3: 1 hexanes / EtOAc to give 408 mg (41%) of a colorless oil.
[1069]
[1070] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperysil 5 [mu] M, 125 x 4 mm column) 5.044.
[1071] Production Example 58
[1072] 7-isopropoxy-l-methyl-2-oxo-l, 2,3,4-tetrahydro-quinoline-6-carbaldehyde
[1073] 3.0 ml of trifluoroacetic acid under nitrogen was added to 771 mg (5.50 mmol) of hexamethylenetetramine and heated in a sand bath at 70 占 폚 for 1 hour. Was added 402 mg of 7-isopropoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one dissolved in 1.0 ml of trifluoroacetic acid. After heating at 70 占 폚 for 5 hours, the mixture was heated at 50 占 폚 overnight. It was cooled to room temperature and added to H ₂ O 3.6 ㎖. Distribution three times with EtOAc, dried (MgSO _4), evaporated under reduced pressure. The residue was eluted with 1: 1 EtOAc / hexane and purified by flash chromatography on BioTag Flash 40 to yield 169 mg (37%) of a white solid.
[1074]
[1075] HPLC (aqueous 200 mM ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column) 4.802.
[1076] Production example 59
[1077] 6-Methoxy-1-methyl-3, 3-spirocyclopropyl-1,3-dihydroindol-
[1078] Sodium hydride (60% in mineral oil, 117 mg, 2.92 mmol) was added to a stirred, ice-cooled solution of 6-methoxyoxyne (433 mg, 2.6 mmol) in 12 mL dry DMF and the suspension was stirred for 10 min. Methyl iodide (414 mg, 2.92 mmol) was added dropwise to the resulting gray mixture, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0 &lt; 0 &gt; C and quenched with 25 ml of water. Adjusting the pH of the solution with saturated aqueous bicarbonate, and the mixture was extracted with EtOAc, washed with brine, followed by drying the extract with Na ₂ SO _4. The mixture was filtered and concentrated to a syrup. Silica gel chromatography (1: 3 EtOAc / hexanes) afforded 202 mg (51%) of the title compound. Mass spectrum m / e M + H = 178.
[1079] Production Example 59A
[1080] 6-Methoxy-1-methyl-3, 3-spirocyclopropyl-1,3-dihydroindol-
[1081] Sodium hydride (60% in mineral oil, 0.97 g, 24.4 mmol) was added to a stirred, ice-cooled solution of 6-methoxy-1-methyloxynol (1.97 g, 12.1 mmol) in 60 mL dry DMF. The suspension was stirred for 10 minutes. To the resulting gray mixture was added dropwise 1,2-dibromoethane (3.34 g, 17.7 mmol) and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0 C and treated with 25 ml of water Quenched. Adjusting the pH of the solution with saturated aqueous bicarbonate, and the mixture was extracted with EtOAc, washed with brine, followed by drying the extract with Na ₂ SO _4. The mixture was filtered and concentrated to a syrup. Silica gel chromatography (1: 3 EtOAc / hexane) gave 1.5 g (68%) of the title compound. Mass spectrum m / e M + H = 204.
[1082] Production example 60
[1083] Methyl-3,3-spirocyclopropyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[1084] To a stirred, ice-cooled solution of 6-methoxy-1-methyl-3,3-spirocyclopropyl-1,3-dihydroindol-2-one (0.41 g, 2.0 mmol) in 60 mL of CH ₂ Cl ₂ was added TiCl ₄ (20 mL of 1M solution in CH ₂ Cl ₂ , 20 mmol) was added followed by the addition of alpha, alpha -dichloromethyl methyl ether (0.91 mL, 10.1 mmol). The reaction was stirred overnight at room temperature and then quenched with 20 ml of water. The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 20 mL) and the combined organic fractions were washed sequentially with saturated NaHCO ₃ , brine and water, dried over Na ₂ SO ₄ and concentrated. The crude product was chromatographed on silica gel, eluting with 50% ethyl acetate in hexanes to give 450 mg (98%) of the desired product as a yellow solid. Mass spectrum m / z 232 p + 1.
[1085] Example 63
[1086] Methyl-3,3-cyclopropyl-5 - [(2-phenyl-piperidin-3- ylamino) -methyl] -1,3-dihydro-indol-
[1087] (2S, 3S) -3-amino, 2-phenylpiperidine 352 mg (2.00 mmole) and 6-methoxy-1-methyl-3,3-spiro 455 mg (1.97 mmole) of cyclopropyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde was converted to 33% overall yield (302 mg) as the hydrochloride with the named product. Mp 244-246 C MS, APCI m / e 392 (p + 1).
[1088] Production example 61
[1089] Methyl-3,3-spirocyclopropyl-2-oxo-2,3-dihydro-lH-indole-6-carbaldehyde
[1090] By a method analogous to Preparation 59, 59a and 60 starting with 5-methoxyoxynol, 66 mg of the desired product are obtained. Mass spectrum m / z 232 p + 1.
[1091] Example 64
[1092] Methyl-3,3-spirocyclopropyl-6 - [(2-phenyl-piperidin-3- ylamino) -methyl] -1,3-dihydro-indol-
[1093] (2S, 3S) -3-amino, 2-phenylpiperidine 389 mg (2.21 mmole) and 5-methoxy-1-methyl-3,3 485 mg (2.1 mmole) of the spirocyclopropyl-2-oxo-2,3-dihydro-lH-indole-6-carbaldehyde was converted to the above named product as the hydrochloride in 67% overall yield . Mp 240 deg. C decomposition. MS, APCI m / e 392 (p + 1).
[1094] Production example 62
[1095] Methyl-3,3-spirocyclobutane-2-oxo-2,3-dihydro-lH-indole-6-carbaldehyde
[1096] By a method similar to Preparation 59, 59A and 60 starting from 5-methoxyoxyne and 1,3-dibromopropane, 570 mg of the title compound were obtained. Mass spectrum m / z 246 p + 1.
[1097] Example 65
[1098] Methyl-1,3-dihydro-indol-2-one &lt; RTI ID = 0.0 &gt;
[1099] 144 mg (0.82 mmole) of cis- (2S, 3S) -3-amino, 2-phenylpiperidine and 5-methoxy- 183 mg (0.75 mmole) of spirocyclobutyl-2-oxo-2,3-dihydro-1H-indole-6-carbaldehyde was converted as the hydrochloride (143 mg) to the named product. Mp 285-288 [deg.] C decomposition. MS, APCI m / e 406 (p + 1).
[1100] Production Example 63
[1101] Methyl-3,3-spirocyclopentyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[1102] Starting from 5-methoxyoxyne and 1,4-dibromobutane, by a method analogous to Preparation 59, 59A and 60, 215 mg of the desired product are obtained. Mass spectrum m / z 260 p + 1.
[1103] Example 66
[1104] Methyl-3,3-cyclopentyl-5 - [(2-phenyl-piperidin-3- ylamino) -methyl] -1,3-dihydro-indol-
[1105] 74 mg (0.42 mmole) of cis- (2S, 3S) -3-amino, 2-phenylpiperidine and 6-methoxy- 109 mg (0.42 mmole) of spirocyclopentyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde was converted to 65% overall yield (133 mg) as hydrochloric acid with the named product . Mp > 300 [deg.] C MS, APCI m / e 420 (p + 1).
[1106] Production example 64
[1107] Methyl-3,3-spirocyclohexyl-2-oxo-2,3-dihydro-lH-indole-5-carbaldehyde
[1108] Starting from 5-methoxyoxyne and 1,5-dibromopentane by a method similar to Preparation 59, 59A and 60, 260 mg of the desired product was obtained. Mass spectrum m / z 274 p + 1.
[1109] Example 67
[1110] Methyl-3,3-cyclohexyl-5 - [(2-phenyl-piperidin-3- ylamino) -methyl] -1,3-dihydro-indol-
[1111] 79 mg (0.45 mmole) of cis- (2S, 3S) -3-amino, 2-phenylpiperidine and 6-methoxy- 125 mg (0.42 mmole) of spirocyclohexyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde was converted to 65% overall yield (147 mg) as the hydrochloride with the named product . Mp > 300 [deg.] C MS, APCI m / e 434 (p + 1).
[1112] Production example 65
[1113] 2-phenyl-3-hydroxypyridine
[1114] 25 gm (143.68 mmol) of 2-bromo-3-hydroxypyridine, 19.27 gm (156 mmol) of phenylboric acid, tetrakistriphenylphosphinepalladium (0) 5 gm (4.31 mmol). The contents were dissolved in 300 ml of benzene and 100 ml of a 2M aqueous sodium bicarbonate solution. The reaction mixture was heated at reflux for 18 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (4 x 100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in chloroform and then treated with ether to obtain a solid precipitate. Filtration gave 10.4 gm (42%) of 2-phenyl-3-hydroxypyridine.
[1115]
[1116] Production example 66
[1117] 1-Benzyl-3-hydroxy-2-phenyl-pyridinium bromide
[1118] 1.3 gm (7.59 mmol) of 2-phenyl-3-hydroxypyridine and 2.26 ml (18.96 mmol) of benzyl bromide were introduced into a flame dried round bottom flask equipped with a nitrogen inlet and a condenser. The contents were dissolved in 30 ml of acetonitrile and the reaction mixture was heated under reflux for 18 hours. The mixture was cooled to room temperature and evaporated in vacuo. The residue was dissolved in chloroform and then treated with ether to obtain a solid precipitate. Filtration gave 2.09 gm (81%) of 1-phenylmethyl-2-phenyl-3-hydroxypyridinium bromide.
[1119]
[1120] Production example 67
[1121] Benzenesulfonyl-8-benzyl-l-phenyl-8-aza-bicyclo [3.2.1] oct-
[1122] To 7.35 gm (21.5 mmol) of 1-phenylmethyl-2-phenyl-3-hydroxypyridinium bromide in 20 ml of methanol was added 8.69 gm of Amberlyst AG1-X8 resin ^- OH form 20-40 mesh. The mixture was stirred briefly, then filtered, and the resin was washed with methanol. The solvent was removed in vacuo. The solid residue was dissolved in toluene (150 mL), treated with 50 mg of hydroquinone and 6.84 gm (37.1 mmol) of phenylvinylsulfone. The reaction mixture was heated under reflux for 18 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with 8: 2 / hexane: ethyl acetate to give 5.87 gm (64%) as a light yellow solid.
[1123]
[1124] Production example 68
[1125] Benzenesulfonyl-8-benzyl-1-phenyl-8-aza-bicyclo [3.2.1] octan-
[1126] Benzenesulfonyl-8-benzyl-1-phenyl-8-aza-bicyclo [3.2.1] oct-3-en-2-one To a 500 ml round bottom flask equipped with a stirrer, a nitrogen inlet and a condenser was added 5.87 gm 13.68 mmol) was placed with 150 mL methanol, 17.25 gm (273.66 mmol) ammonium formate and 1.95 gm palladium hydroxide. The reaction mixture was heated under reflux for 1.5 hours and then cooled to room temperature. The suspension was filtered through a Celite bath and washed with methanol. The combined organics were evaporated in vacuo and the residue was dissolved in chloroform and partitioned into a saturated aqueous bicarbonate solution. The organics were washed with saturated brine solution and dried with sodium sulfate solution. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel, eluting with 8: 2 / hexane: ethyl acetate to give 4.04 gm (68%) as an off-white solid.
[1127]
[1128] Production Example 69
[1129] 6-Benzenesulfonyl-8-benzyl-1-phenyl-8-aza-bicyclo [3.2.1] octan-
[1130]
[1131] To a solution of the ketone (4.04 gm; 9.37 mmol) in 300 mL of 1: 1 methylene chloride methanol was added a second solution of 2.94 gm (35.24 mmol) methoxyamine hydrochloride and 1.86 gm (22.68 mmol) sodium acetate in 30 mL water Respectively. The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled and then diluted with 100 ml of water. The aqueous phase was extracted with methylene chloride and the combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with 8: 2 / hexane: ethyl acetate to give 3.45 gm (80%) of a white solid.
[1132]
[1133] Production example 70
[1134] Aza-bicyclo [3.2.1] oct-2-yl) -O-methyl-hydroxylamine
[1135]
[1136] A solution of oxime (3.45 gm; 7.5 mmol) in 80 mL acetic acid was treated with 0.71 gm (11.25 mmol) sodium cyanoborohydride and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 50 ml of ice / water and stirred. The pH of the aqueous mixture was basified to 10 by addition of aqueous sodium hydroxide. A precipitate formed and after filtration, the resulting white solid was dissolved in methylene chloride and dried over sodium sulfate. The organic phase was evaporated in vacuo to give 3.01 gm (87%) of a white solid.
[1137]
[1138] Production example 71
[1139] 8-Benzyl-l-phenyl-8-aza-bicyclo [3.2.1] oct-
[1140] A flame dried 3 / N round bottom flask equipped with NH ₃ (9) inlet, dry ice condenser and magnetic stir bar was cooled to -78 ° C and ammonia gas was introduced. To a solution of 464 mg (1.0) of N- (6-benzenesulfonyl-8-benzyl-1-phenyl-8-aza- bicyclo [3.2.1] oct- mmol) was added followed by the dropwise addition of 323 mg (14.05 mmol) of sodium metal. A deep blue color appeared and the reaction mixture was stirred at -78 &lt; 0 &gt; C for 30 minutes. The reaction was quenched by the addition of solid ammonium chloride and the ammonia was evaporated. The residue was dissolved in water and methylene chloride. The aqueous phase was washed once again with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. 203 mg (68%) of a clear oil was obtained. Eluting with 93/7 hexane / ethanol containing 0.025% diethylamine at 25 ml / min to complete the enantiomeric separation on a 5 cm x 50 cm chiralpak AS column. Retention times were 4.6 min and 6.6 min, respectively.
[1141]
[1142] Production Example 72
[1143] (LS, 2S, 5R) or (lR, 2R, 5S) l-phenyl-8-aza- bicyclo [3.2.1] oct-
[1144] To a 25 mL round bottom flask equipped with a nitrogen inlet and a condenser was added (1S, 2S, 5R) (or (1R, 2R, 5S)) 8- benzyl- 1 -phenyl-8-aza- bicyclo [3.2.1] 2-ylamine (37 mg, 0.127 mmol) was placed in a mixture of methanol (10 mL), ammonium formate (80 mg, 1.27 mmol) and palladium hydroxide (12 mg). The reaction mixture was treated with 21 [mu] l of concentrated aqueous HCl, then heated under reflux for 40 minutes and then cooled to room temperature. The suspension was filtered through a Celite bath and washed with methanol. The combined organics were evaporated in vacuo and the residue was dissolved in chloroform and partitioned into a saturated aqueous bicarbonate solution. The organics were washed with saturated brine solution and dried with sodium sulfate solution. The mixture was filtered, and the filtrate was evaporated under vacuum to obtain 20 mg of objective (1S, 2S, 5R) (or (1R, 2R, 5S)) diamine.
[1145]
[1146] Example 68
[1147] (1S, 2S, 5R) - (1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) - Methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one or (1R, 1aS) -6- Aza-bicyclo [3.2.1] oct-2-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza- Par [a] naphthalen-2-one
[1148] (1R, 2S, 5S)) 1-phenyl-8-aza-bicyclo [3.2.1] oct-2-ylamine 20 (0.099 mmole) and (1S, 1aR) (or (1R, 1aS)) - 6-methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetrahydro- 23 mg (0.099 mmole) of propa [a] naphthalene-5-carbaldehyde were combined in 20 ml of toluene and heated in a Dean-Stark trap for 18 hours under reflux. The crude solution (MS APCI m / e = 390 p + 1) was evaporated in vacuo and redissolved in 20 mL of dichloroethane. The solution was treated with sodium triacetoxyborohydride (32 mg, 0.148 mmol) and stirred at room temperature for 16 hours. The reaction mixture was washed with a saturated aqueous bicarbonate solution, washed with brine, and dried over sodium sulfate. After evaporation, the crude residue was chromatographed on silica gel, eluting with 96/4/1 methylene chloride, methanol, ammonium hydroxide (NH ₄ OH) to give 20 mg of the desired product. Mass spectrum APCI m / z 418 (p + 1).
[1149] Example 69
[1150] (1S, 2S, 5R) - (1-phenyl-8-azabicyclo [3.2.1] oct-2-yl) amine) - Methyl] -1,3-dihydro-indol-2-one
[1151] The above-named product was obtained by a method analogous to Example 68 above. Mass spectrum APCI m / z 418 (p + 1).
[1152] Production example 73
[1153] N- (4-methoxy-2-methyl-phenyl) -methanesulfonamide
[1154] To a solution of 6.85 gm (50 mmol) of 4-methoxy-2-methylaniline in 70 ml of methylene chloride was added 8.5 gm (mmol) of pyridine and then 6.87 gm (60 mmol) of methanesulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 1N HCl and then with saturated aqueous brine. The organics were dried over sodium sulphate and evaporated in vacuo. The residue was triturated with diethyl ether to give 7.5 gm (79%) of a light purple solid. Mass spectrum APCI (m / z) 216 (p + 1).
[1155] Production example 74
[1156] N- (4-methoxy-2-methyl-phenyl) -N-methyl-methanesulfonamide
[1157] To a solution of 860 mg (4.0 mmol) of N- (4-methoxy-2-methyl-phenyl) -methanesulfonamide in 15 ml of DMF was added 192 mg (48 mmol) of 60% sodium hydride dispersion at ambient temperature, Was treated with methyl iodide (1.14 gm, 0.5 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, 0.5 ml of methyl iodide was introduced, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1N HCl and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate and evaporated in vacuo to yield 293 mg (X%) as a light purple solid. Mass spectrum APCI (m / z) 230 (p + 1).
[1158] Production Example 75
[1159] N- (2-bromomethyl-4-methoxy-phenyl) -N-methyl-methanesulfonamide
[1160] A solution of 532 mg (2.33 mmol) of N- (4-methoxy-2-methyl-phenyl) -N-methyl-methanesulfonamide in 20 ml of carbon tetrachloride was added to a solution of N- And treated with a catalytic amount of azaobisisobutyronitrile. The reaction mixture was heated to reflux temperature for 16 hours in a light bulb. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo. The residue was chromatographed on silica with 70:30 / hexane: ethyl acetate to give 231 mg of the desired bromide. Mass spectrum APCI (m / z) 308, 310 (p + 1).
[1161] Production Example 76
[1162] 6-Methoxy-1-methyl-3,4-dihydro-1H-benzo [c] [1,2] thiazine 2,2-
[1163] (6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2 ⁶ -benzo [c] [1,2] thiazine)
[1164] A solution of 291 mg (0.95 mmol) of N- (2-bromomethyl-4-methoxy-phenyl) -N-methyl-methanesulfonamide in 15 ml DMF was treated with 45 mg (1.14 mmol) The reaction mixture was stirred at 75 &lt; 0 &gt; C for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was eluted with 25% ethyl acetate in hexanes and passed through a short plug of silica gel. 123 mg (57%) of the desired product was obtained. Mass spectrum APCI (m / z) 228 (p + 1).
[1165] Production Example 77
[1166] 6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2 ⁶ -benzo [c] [1,2] thiazine-
[1167] A solution of sultam (11 mg; 0.04 mmol) in 3 mL of methylene chloride was treated with 0.4 mL (0.4 mmol) of titanium tetrachloride at ambient temperature and the solution was stirred for 15 minutes. Dichloromethyl methyl ether (23 mg, 0.2 mmol) was added dropwise to the reaction mixture at ambient temperature and stirred for 16 hours. The reaction mixture was diluted with 1N HCl and extracted with methylene chloride. The organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica with 50: 50 / hexane: ethyl acetate to give 6 mg of aldehyde. Mass spectrum APCI (m / z) 256 (p + 1).
[1168] Example 70
[1169] (6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2 ⁶ -benzo [c] [1,2] thiazin- 2-phenyl-piperidin-3-yl) -amine
[1170] 65 mg (0.37 mmole) of 2-phenyl-3-aminopiperidine and 92 mg (0.36 mmole) of sultam-7-carbaldehyde were combined in 20 ml of toluene by a method analogous to Examples 1 and 2 above, And heated in a Dean-Stark trap for 18 hours. The crude solution (MS APCI m / e = 414 p + 1) was evaporated in vacuo and redissolved in 20 mL of dichloroethane. The solution was treated with sodium triacetoxyborohydride (154 mg, 0.72 mmol) and stirred at room temperature for 16 hours. The reaction mixture was washed with a saturated aqueous bicarbonate solution, washed with brine, and dried over sodium sulfate. After evaporation, the crude residue was chromatographed on silica gel, eluting with 94/5/1 methylene chloride, methanol, ammonium hydroxide (NH ₄ OH) to yield 95 mg of the desired product. Mass spectrum APCI (m / z) 416 (p + 1).
[1171] Example 71
[1172] (S) -phenyl-piperidin-3 (S) -ylamino) -methyl] -1,3-dihydro-pyrrolo [ 3,2-b] pyridin-2-one
[1173] Step 1
[1174] Methoxy-l, 3,3-trimethyl-l, 3-dihydro-pyrrolo [3,2- b] pyridin-
[1175] 3-dihydro-pyrrolo [3,2-b] pyridin-2-one (J. Het. Chem. 1996, 33, 287-93) in a flame dried round bottom flask under a nitrogen atmosphere. A solution of 0.2 g (1.22 mmol) in 10 mL DMF was cooled to 0 &lt; 0 &gt; C. To this solution was added 4.02 mL (4.02 mmol) of a 1 M solution of potassium t-butoxide in THF and the solution was stirred for 10 min. To this solution was added 0.3 ml (4.88 mmol) MeI and the reaction was stirred at 0 &lt; 0 &gt; C for 15 min. The reaction was quenched with water and extracted with ethyl acetate. Dry the ethyl acetate extracts were (Na ₂ SO ₄₎ and evaporated. The residue was chromatographed over 6 g of silica using 3: 1 hexane / ethyl acetate as eluent. The appropriate fractions were combined and evaporated to obtain 0.14 g of 5-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo [3,2-b] pyridin-
[1176]
[1177] Step 2
[1178] 3-dihydro-pyrrolo [3,2-b] pyridin-2-one
[1179] To a solution of 0.14 g (0.853 mmol) 5-methoxy-l, 3,3-trimethyl-l, 3- dihydro- pyrrolo [3,2- b] pyridin- 0.136 g (0.0853 mmol) was added. The solution was heated to 60 &lt; 0 &gt; C for 1 hour. The reaction was cooled to room temperature and quenched with 5 ml of water. The pH was adjusted to 7.5 and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica using chloroform as eluent. The appropriate fractions were combined and evaporated to give 138 mg of 5-methoxy-6-bromo-1,3,3-trimethyl-1,3-dihydro-pyrrolo [3,2- b] pyridin- . Mass spectrum: m / e = 285,287.
[1180] Step 3
[1181] Methoxy-1,3,3-trimethyl-6-vinyl-1,3-dihydro-pyrrolo [3,2- b] pyridin-
[1182] 138 mg (0.048 mmol) of 5-methoxy-6-bromo-1,3,3-trimethyl-1,3-dihydro- pyrrolo [3,2- b] pyridin- A mixture of 138 mg (0.48 mmol) of tri-n-butyl-vinyltin and 15 mg of bis (triphenylphosphine-palladium (II) chloride) was heated under nitrogen for 14 hours at 65 DEG C. The reaction mixture was cooled to room temperature was diluted with water and ethyl acetate. the ethyl acetate solution was washed with water several times. the ethyl added saturated KF 1 ㎖ the acetate solution, and the mixture was filtered. dry the filtrate was (Na ₂ SO _4), evaporated and the residue The water was chromatographed over silica using 1: 1 ethyl acetate / hexanes as eluent. The appropriate fractions were combined and evaporated to give 5-methoxy-1,3,3-trimethyl-6-vinyl- Pyrrolo [3,2-b] pyridin-2-one.
[1183]
[1184] Step 4
[1185] Oxo-2,3-dihydro-lH-pyrrolo [3,2-b] pyridine-6-carbaldehyde
[1186] 65 mg of 5-methoxy-l, 3,3-trimethyl-6-vinyl-l, 3-dihydro- pyrrolo [3,2- b] pyridin-2-one in 16 ml of methylene chloride and 4 ml of methanol (0.28 mmol) in dichloromethane was cooled to -70 &lt; 0 &gt; C. Ozone was bubbled through the ozone generator (through the ozone generator) until blue appeared. The reaction mixture was stirred at -70 &lt; 0 &gt; C for 30 minutes and warmed to room temperature. About 0.5 ml of dimethyl sulfide was added and the reaction was evaporated. This residue (0.6 g) was used directly in the next step.
[1187]
[1188] Step 5
[1189] (S) -phenyl-piperidin-3 (S) -ylamino) -methyl] -1,3-dihydro-pyrrolo [ 3,2-b] pyridin-2-one
[1190] Methoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo [3,2- b] pyridine-6-carbaldehyde (0.6 g ; 0.15 mmol) was dissolved in 5 mL of dichloroethane. 0.05 g (0.2 mmol) of 2- (S) -phenyl-piperidine-3 (S) -ylamine and 0.06 ml (0.4 mmol) of triethylamine were added and the mixture was stirred at room temperature for 60 minutes Respectively. 0.1 g (0.5 mmol) of sodium triacetoxyborohydride was added to the mixture, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 2 by 1 N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.0 with sodium bicarbonate and extracted with ethyl acetate. pH = 7 ethyl acetate extracts were combined, dried (Na ₂ SO4), and evaporated, to give a yellow amorphous solid 50 mg.
[1191]
[1192] Example 72
[1193] Methyl-l, 3-dihydro-pyrrolo [2,3-c] 2,3-b] pyridin-2-one
[1194] Step 1
[1195] Chloro-l, 3,3-trimethyl-l, 3-dihydro-pyrrolo [2,3-b] pyridin-
[1196] A solution of 0.25 g (1.5 mmol) 6-chloro-l, 3-dihydro- pyrrolo [2,3- b] pyridin- 2-one (W09910349 Al) in 5 mL DMF was cooled to 5 & . To this solution was added 4.5 mL (4.5 mmol) of potassium t-butoxide (1M solution in THF) followed by 0.37 mL (6.0 mmol) of methyl iodide. The reaction mixture was stirred for 1 hour at 5 C. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate. Dry the ethyl acetate extracts were (Na ₂ SO _4), evaporated, 6-chloro--1,3,3- trimethyl-1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one 0.25 g as a dark amorphous solid. TLC; Rf = 0.8 (1: 1 hexane / ethyl acetate).
[1197]
[1198] Step 2
[1199] 6-Methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo [2,3-b] pyridin-
[1200] To a solution of 0.3 g (1.4 mmol) 6-chloro-l, 3,3-trimethyl-l, 3-dihydro- pyrrolo [2,3- b] pyridin- 4.6M) and 1.2 mg of Cul were heated to 145 &lt; 0 &gt; C for 18 hours. The reaction mixture was cooled to room temperature and added to 25 mL of water. The mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with saturated sodium bisulfite 25 ㎖, dried (Na ₂ SO _4), and evaporated. The residue was polished twice with hot hexane and the hexane was decanted off. The residue, 6-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one (0.25 g) was used without purification. TLC: Rf = 0.7 (5: 1 hexane / ethyl acetate).
[1201]
[1202] Step 3
[1203] Oxo-2,3-dihydro-lH-pyrrolo [2,3-b] pyridine-5-carbaldehyde
[1204] A solution of 0.16 g (0.8 mmol) of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo [2,3- b] pyridin- Lt; / RTI &gt; To this solution was added 3.2 mL (3.2 mmol) of titanium tetrachloride (1 M solution in methylene chloride). The reaction was stirred at 5 &lt; 0 &gt; C for 90 minutes. 0.11 ml (1.2 mmol) of 1,1-dichloromethyl methyl ether was added to the mixture, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was then quenched with ice and stirred for 30 minutes. The organic layer was dried (Na ₂ SO _4), and evaporated to give an amorphous white solid, 0.16 g. Mass spectrum and NMR showed that the solid was a mixture of the desired 6-methoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro- lH-pyrrolo [2,3- b] pyridine- And starting 6-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one.
[1205]
[1206] Step 4
[1207] Methyl-l, 3-dihydro-pyrrolo [2,3-c] 2,3-b] pyridin-2-one
[1208] 2,3-b] pyridine-lH-pyrrolo [2,3-b] pyridine prepared in Step 3 (0.16 g; 5-carbaldehyde was dissolved in 5 ml of dichloroethane. 0.1 g (0.4 mmol) of 2- (S) -phenyl-piperidin-3 (S) -ylamine and 0.11 ml (0.8 mmol) of triethylamine were added and the mixture was stirred at room temperature for 60 minutes . To this mixture was added 0.2 g (1.0 mmol) of sodium triacetoxyborohydride and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 2 by 1 N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.0 with sodium bicarbonate and extracted with ethyl acetate. pH = 7 ethyl acetate extracts were combined, dried (Na ₂ SO _4), and evaporated to give an amorphous solid.
[1209]
[1210] The amorphous solid was dissolved in isopropyl alcohol and 0.2 ml of conc. HCl was added to this solution. The mixture was stirred for 10 minutes and the solvent was evaporated to give a brown solid. This solid was polished with isopropyl ether and then recrystallized from isopropyl alcohol / methanol to give 75 mg of a white solid. TLC: Rf = 0.3 (10: 1 chloroform / methanol). Mass spectrum: m / e = 395.3 (p + 1).
[1211] Example 73
[1212] (S) -phenyl-piperidin-3 (S) -ylamino) -methyl] -3,4-dihydro-1H- [1,8] Naphthyridin-2-one
[1213] Step 1
[1214] 3-Methoxy-6-nitro-2-vinyl-pyridine
[1215] To a solution of 1.0 g (4.3 mmol) of 2-bromo-3-methoxy-6-nitropyridine (J. Lombardino, J. Med. Chem. 1981, 24, 39-42) in 25 ml of toluene was added tri- (Triphenylphosphine-palladium (II) chloride) was added and the reaction was refluxed under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and the solvent evaporated The appropriate fractions were combined to give 0.63 g of 3-methoxy-6-nitro-2-vinyl-pyridine as an oil TLC: Rf = 0.5 (5: 1 hexane / ethyl acetate).
[1216]
[1217] Step 2
[1218] 3-Methoxy-6-nitro-pyridine-2-carbaldehyde
[1219] A solution of 0.63 g (3.5 mmol) of 3-methoxy-6-nitro-2-vinyl-pyridine in 50 mL of CH ₂ Cl ₂ and 10 mL of methanol was cooled to -70 ° C. Ozone was bubbled through the solution until continuing to blue. The mixture was stirred at -70 &lt; 0 &gt; C for 60 minutes and then quenched with excess dimethylsulfide. The reaction was allowed to warm to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and water. The pH of the solution was adjusted to 2.0 with 1N HCl and the mixture was stirred for 30 minutes. The pH of the solution was then adjusted to 8.0 with 1 N NaOH. The mixture was extracted with excess ethyl acetate. The ethyl acetate extracts were combined, dried (Na ₂ SO ₄ ) and evaporated to give 0.6 g of 3-methoxy-6-nitro-pyridine-2-carbaldehyde as a tan solid. TLC: Rf = 0.2 (1: 1 ethyl acetate / hexanes).
[1220]
[1221] Step 3
[1222] 2- [1,3] Dioxolan-2-yl-3-methoxy-6-nitro-pyridine
[1223] A mixture of 0.55 g (0.3 mmol) of 3-methoxy-6-nitro-pyridine-2-carbaldehyde, 0.8 ml (15 mmol) of ethylene glycol and 10 mg (catalytic amount) of p- toluenesulfonic acid, The water was trapped by reflux using a Stark trap. After 90 minutes, the reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was chromatographed on silica using 5: 1 (chloroform / ethyl acetate) as eluent. The appropriate fractions were combined and evaporated to give 0.6 g of 2- [1,3] dioxolan-2-yl-3-methoxy-6-nitro-pyridine as an oil. TLC: Rf = 0.9 (1: 1 chloroform / ethyl acetate).
[1224]
[1225] Step 4
[1226] 3-benzenesulfonylmethyl-6- [1,3] dioxolan-2-yl-5-methoxy-2-nitro-pyridine
[1227] (2.6 mmol) of 2- [1,3] dioxolan-2-yl-3-methoxy-6-nitro-pyridine, 0.55 g (2.9 mmol) of chloromethylphenylsulfone, and potassium t-butoxide (2.9 mmol) in THF (1 M solution in THF) was combined at 5 &lt; 0 &gt; C and stirred at ambient temperature for 18 h. The reaction mixture was quenched with 25 mL of water and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica using 5: 1 chloroform / ethyl acetate as eluent. The appropriate fractions were combined and evaporated to give 0.28 g of 3-benzenesulfonylmethyl-6- [1,3] dioxolan-2-yl-5-methoxy-2-nitro-pyridine as an oil. TLC: Rf = 0.4 (1: 1 chloroform / ethyl acetate).
[1228]
[1229] Step 5
[1230] Methoxy-2-nitro-pyridin-3-yl) -acrylic acid ethyl ester
[1231] A mixture of 0.28 g (0.73 mmol) of 3-benzenesulfonylmethyl-6- [1,3] dioxolan-2-yl-5-methoxy-2-nitro-pyridine and 0.8 ml (0.73 mmol) of ethyl bromoacetate Was dissolved in 10 ml of ethanol. To this solution was added 0.5 ml of potassium t-butoxide (1M in t-butyl alcohol) and the reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and the residue was added to 5 ml of water. The suspension was extracted with ethyl acetate. The ethyl acetate extract was dried (Na ₂ SO ₄ ) and evaporated to give about 0.3 g of an oil. Mass spectrum: m / e = 325.1 (p + 1). This material was used directly in Step 6.
[1232] Step 6
[1233] 7- [1,3] dioxolan-2-yl-6-methoxy-3,4-dihydro-1H- [1,8] naphthyridin-
[1234] The oil isolated in step 5 was dissolved in 30 ml of ethanol and hydrogenated at 50 PSI for 90 min using 10% Pd / C as catalyst. The reaction mixture was filtered and evaporated to give the intermediate 3- (2-amino-6- [1,3] dioxolan-2-yl-5-methoxy-pyridin-3- yl) propionic acid ethyl ester as a dark oil. Mass spectrum: m / e = 297.1 (p + 1). This material was dissolved in 10 ml of toluene and heated at reflux temperature for 4 hours. The solution was cooled to room temperature and evaporated to yield 0.1 g of 7- [1,3] dioxolan-2-yl-6-methoxy-3,4-dihydro-1H- [1,8] naphthyridin- Obtained as a dark oil.
[1235]
[1236] This material was used in step 7 without further purification.
[1237] Step 7
[1238] 3-Methoxy-8-methyl-7-oxo-5,6,7,8-tetrahydro- [l, 8] naphthyridine-2-carbaldehyde
[1239] To a solution of 0.1 g of 7- [1,3] dioxolan-2-yl-6-methoxy-3,4-dihydro-1H- [1,8] naphthyridin- (0.4 mmol) in THF (5 mL) was added 0.5 mL (0.5 mmol) of potassium t-butoxide (1M solution in THF). The reaction mixture was stirred for 30 minutes. 0.06 ml (1 mmol) of methyl iodide was added to the mixture, and the reaction was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate. Dry the ethyl acetate extracts were (Na ₂ SO _4), Evaporation of the intermediate 7- [1,3] dioxolan-2-yl-6-methoxy-1-methyl-3,4-dihydro -1H- [1 , 8] naphthyridine 2-one as a dark oil. Mass spectrum: m / e = 205.1 (p + 1). This material was dissolved in 5 ml of acetone containing 0.1 g of para-toluenesulfonic acid and refluxed for 2 hours. The reaction mixture was evaporated and the grinding of the residue with saturated NaHCO _3. The mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (Na ₂ SO ₄ ) and evaporated, and the residue was chromatographed over silica using 3: 1 chloroform / ethyl acetate as eluent. The appropriate fractions were combined to give 12 mg of 3-methoxy-8-methyl-7-oxo-5,6,7,8-tetrahydro- [l, 8] naphthyridine-2-carbaldehyde as an oil.
[1240]
[1241] Step 8
[1242] (S) -phenyl-piperidin-3 (S) -ylamino) -methyl] -3,4-dihydro-1H- [1,8] Naphthyridin-2-one.
[1243] Oxo-5,6,7,8-tetrahydro- [l, 8] naphthyridine-2-carbaldehyde (12 mg, 0.05 mmol) prepared in Step 7 was added to a solution of 3-methoxy- And dissolved in 3 ml of dichloroethane. To this was added 25 mg (0.1 mmol) of 2- (S) -phenyl-piperidin-3 (S) -ylamine and 0.014 mL (0.1 mmol) of triethylamine and the mixture was stirred at room temperature for 60 minutes . To this mixture was added 32 mg (0.15 mmol) of sodium triacetoxyborohydride and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 2 by 1 N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.0 with sodium bicarbonate and extracted with ethyl acetate. pH = 7 ethyl acetate extracts were combined, dried (Na ₂ SO _4), and evaporated, to give a yellow amorphous solid 7 mg.
[1244]
[1245] Example 74
[1246] (S) -phenyl-piperidin-3 (S) -ylamino) -methyl] -3,4-dihydro-1H- [1,5] Naphthyridin-2-one
[1247] Step 1
[1248] 6-methoxy-3,4-dihydro-1H- [1,5] naphthyridin-2-
[1249] (M. Makosza, A. Tryula Synthesis, 1987, 1142-7) in 50 ml of ethanol containing a catalytic amount of 10% Pd / C. 1144) was hydrogenated at 50 PSI for 2 hours. The reaction was filtered and the solvent was evaporated to give crude intermediate 3- (3-amino-6-methoxy-pyridin-2-yl) -propionic acid ethyl ester. This material was dissolved in 5 mL acetic acid and heated in a steam bath for 30 min. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in 25 ㎖ ethyl acetate and washed with saturated NaHCO _3. The ethyl acetate solution was dried (Na ₂ SO ₄ ) and evaporated to give a brown solid residue. This material was chromatographed over silica using 5: 1 chloroform / ethyl acetate as eluent. The appropriate fractions were combined and evaporated to give 1.2 g of 6-methoxy-3,4-dihydro-1H- [1,5] naphthyridin-2-one.
[1250]
[1251] Step 2
[1252] Methoxy-1-methyl-3,4-dihydro-1H- [1,5] naphthyridin-2-
[1253] A solution of 1.2 g (6.7 mmol) of 6-methoxy-3,4-dihydro-1H- [1,5] naphthyridin-2-one in 15 ml of DMF was cooled to 5 & 6.7 ml (6.7 mmol) of butoxide (1 M solution in THF) was slowly added. The mixture was stirred for 10 minutes and then 0.46 mL (7.4 mmol) of methyl iodide was added. After the addition was complete, the reaction mixture was stirred at 5 &lt; 0 &gt; C for 1 hour. The reaction mixture was poured into saturated NaCl. The mixture was extracted with ethyl acetate. Dry the ethyl acetate extracts were (Na ₂ SO _4), and evaporated. The residue was chromatographed over silica using 5: 1 chloroform / ethyl acetate as eluent. The appropriate fractions were combined and evaporated to give 0.83 g of 6-methoxy-1-methyl-3,4-dihydro-1H- [1,5] naphthyridin-2-one. TLC Rf = 0.6 (1:10 ethyl acetate / chloroform).
[1254]
[1255] Step 3
[1256] 7-Bromo-6-methoxy-l-methyl-3,4-dihydro-lH- [1,5] naphthyridin-
[1257] To a solution of 0.6 g (3.1 mmol) 6-methoxy-1-methyl-3,4-dihydro-lH- [1,5] naphthyridin-2-one in 8 mL acetic acid was added 8 mL water. To this mixture was added 0.32 mL (6.2 mmol) of bromine. The reaction mixture was heated to 60 &lt; 0 &gt; C for 1 hour. The reaction mixture was cooled to room temperature and poured into 50 ml of water. The suspension was extracted with ethyl acetate. Dry the ethyl acetate extracts were (Na ₂ SO _4), and evaporated. The residue was chromatographed on silica using chloroform as eluent. The appropriate fractions were combined and evaporated to give 0.69 g of 7-bromo-6-methoxy-1-methyl-3,4-dihydro-1H- [1,5] naphthyridin- TLC Rf = 0.8 (10: 1 ethyl acetate / chloroform).
[1258]
[1259] Step 4
[1260] 6-methoxy-1-methyl-7-vinyl-3,4-dihydro-1H- [1,5] naphthyridin-
[1261] 690 mg (2.5 mmol) of 7-bromo-6-methoxy-1-methyl-3,4-dihydro-1H- [1,5] naphthyridin- A mixture of 0.8 ml (2.7 mmol) of butyl-vinyl tin and 100 mg of bis (triphenylphosphine-palladium (II) chloride) was heated under nitrogen for 6 hours at 100 C. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate The ethyl acetate solution was washed several times with water. To this ethyl acetate solution was added 1 ml of saturated KF and the mixture was filtered. The filtrate was dried, evaporated and the residue was purified by chromatography on silica gel eluting with 1: 5 ethyl acetate / The appropriate fractions were combined and evaporated to give 6-methoxy-1-methyl-7-vinyl-3,4-dihydro-1H- [1,5] 200 mg was obtained.
[1262]
[1263] Step 5
[1264] Methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro- [1,5] naphthyridine-3- carbaldehyde
[1265] 1.1 g (5.0 mmol) solution of 6-methoxy-1-methyl-7-vinyl-3,4-dihydro-1H- [1,5] naphthyridin- Was cooled to -70 &lt; 0 &gt; C. Ozone was bubbled through the ozone generator (through the ozone generator) until blue appeared. The reaction mixture was stirred at -70 &lt; 0 &gt; C for 30 min and quenched with 4.0 ml of dimethyl sulphide. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 50 ml of water. The organic layer was dried (Na ₂ SO _4), and evaporated. The residue was chromatographed over silica using 10: 1 chloroform / ethyl acetate as eluent. The appropriate fractions were combined to give 0.52 g of 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro- [1,5] naphthyridine-3-carbaldehyde. TLC Rf = 0.4 (1: 1 ethyl acetate: hexane).
[1266]
[1267] Step 6
[1268] (S) -phenyl-piperidin-3 (S) -ylamino) -methyl] -3,4-dihydro-1H- [1,5] Naphthyridin-2-one
[1269] Methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro- [1,5] naphthyridine-3-carbaldehyde prepared in step 5 (0.35 g; And dissolved in 20 ml of dichloroethane. To this was added 250 mg (1.1 mmol) of 2- (S) -phenyl-piperidin-3 (S) -ylamine and 0.4 ml (2.8 mmol) of triethylamine and the mixture was stirred at room temperature for 60 minutes . To this mixture was added 0.7 g (3.3 mmol) of sodium triacetoxyborohydride and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The mixture was adjusted to pH of 8.5 by Na ₂ CO _3. The organic layer was separated from the water layer. An additional 20 mL of water was added to the organic layer. The pH of the mixture was adjusted to 2 by 1 N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.5 with sodium bicarbonate and extracted with ethyl acetate. The pH = 7.5 ethyl acetate extracts were combined, dried (Na ₂ SO _4), evaporated to give 6-methoxy-1-methyl -7 - [(2 (S) -phenyl-piperidin--3 (S) - ylamino ) -Methyl] -3,4-dihydro-1H- [1,5] naphthyridin-2-one 300 mg.
[1270]
[1271] Example 75
[1272] (S) -methyl-3, &lt; / RTI &gt; 4-dihydro- 1H- [1,5] naphthyridin-2-one
[1273] (S) -methyl-2 (S) -phenyl-piperidin-3 (S) -ylamine (Scheme J) and 2-methoxy- Starting from oxo-5,6,7,8-tetrahydro [1,5] naphthyridine-3-carbaldehyde (example 74, step 5), the coupling procedure (example 74, step 6) (S) -methyl-3, &lt; RTI ID = 0.0 &gt; 4-trifluoromethyl- Dihydro-1H- [1,5] naphthyridin-2-one.
[1274]
[1275] Example 76
[1276] Methyl-6-methoxy-1-methyl-3, 4-dihydro-pyrazol- 1H- [1,5] naphthyridin-2-one
[1277] (Scheme J) and 2-methoxy-5-methyl-6-oxo-5,6, 7-dihydro- Starting from 7,8-tetrahydro [1,5] naphthyridine-3-carbaldehyde (example 74, step 5) and using the coupling procedure (example 74, step 6) (6-ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy- 1 -methyl-3, 4-dihydro- I got warm. (6 (S) -ethyl-2 (S) -quinolinecarboxylic acid was prepared using a 95: 5 heptane / ethanol mobile phase (flow rate = 275 ml / min) containing Chiralpak AD (10 X 50 cm) and 0.025% diethylamine. ) -Phenyl-piperidin-3 (S) -ylamino) -methyl] -6-methoxy- 1 -methyl-3,4- dihydro- IH- [1,5] naphthyridin- Retention time 13.545 min) was isolated as pure enantiomer.
[1278]
[1279] The corresponding 7 - [(6R) -ethyl-2 (R) -phenyl-piperidin-3 (R) -ylamino) -methyl] -6-methoxy- Hydro-1H- [1,5] naphthyridin-2-one enantiomer (retention time 14.539 min) was also isolated. NMR and mass spectra were the same as above.
[1280] Example 77
[1281] Methyl-7- [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridine -2-one
[1282] (Scheme J) and 2-methoxy-5-methyl-6-oxo-pyrrolidine-4-carboxylic acid in a similar manner to that of Example 74, Starting with 5,6,7,8-tetrahydro- [1,5] naphthyridine-3-carbaldehyde (example 74, step 5) and using the coupling procedure (example 74, step 6) Methyl-6-methoxy-l-methyl-3,4-dihydro-lH- [l, 5] benzodiazepin- Naphthyridin-2-one. Methyl-7 - [((2-methoxy-1-methyl-1 H -benzoylamino) -2-pyridyl] 2 (S) -phenyl-6 (S) -propyl- piperidine-3 (S) -ylamino) -methyl] -3,4- dihydro- IH- [1,5] naphthyridin- (Retention time 11.479 min) was isolated as pure enantiomer.
[1283]
[1284] The corresponding enantiomer of 6-methoxy-1-methyl-7 - [(2 (R) -phenyl-6 (R) -propyl- piperidin- - dihydro-lH- [1,5] naphthyridin-2-one (retention time 11.592 min) was also isolated. NMR and mass spectra were the same as above.
[1285] Example 78
[1286] (2R, S- (4-fluoro-phenyl) -piperidine-3R, S-ylamino) -methyl] - 1 - methyl-3,3-spirocyclopropyl- , 3-dihydro-indol-2-one
[1287] Methylene chloride To a stirred solution of 2R, S- (4-fluoro-phenyl) -piperidine-3R, S-ylamine (169 mg, 0.63 mmol) in 2 mL of 6-methoxy- 3-spirocyclopropyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde (146 mg, 0.63 mmol) (prepared by the method described in Preparation 60) . After 5 min, sodium triacetoxyborohydride (401 mg, 1.9 mmol) was added and stirred overnight at room temperature. The reaction was diluted with methylene chloride, it extracted three times with saturated NaHC0 _3. The organics were dried over anhydrous MgS0 ₄ and concentrated and the residue was chromatographed using 0.1% triethylamine, 5% methanol / methylene chloride Photography, to give the title compound (88 mg, 34% yield).
[1288]
[1289] HPLC (aqueous 200Mm ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.241.
[1290] Example 79
[1291] Methyl] -3-spirocyclopropyl-5 - [(2R- (4-fluoro-phenyl) -piperidin- Hydro-indol-2-one
[1292] (2R, S- (4-fluoro-phenyl) -piperidine-3R, S-ylamino) -methyl] - 1 - methyl-3,3-spirocyclopropyl- 2-one (by Chiralpak AD column, 5 cm x 50 cm, eluent: 85/15 hexanes / isopropanol, 0.025% diethylamine, 50 mL / min) The title compound (41 mg) was obtained.
[1293] Example 80
[1294] Methyl] -3-spirocyclopropyl-5 - [(2S- (4-fluoro-phenyl) -piperidin- Hydro-indol-2-one
[1295] (2R, S- (4-fluoro-phenyl) -piperidine-3R, S-ylamino) -methyl] - 1 - methyl-3,3-spirocyclopropyl- The title compound was prepared according to the procedure described in Example 1 by purification HPLC chiral separation (Chiralpak AD column, 5 cm x 50 cm, eluent: 85/15 hexane / isopropanol, 0.025% diethylamine, 50 mL / min) of 3-dihydro- (43 mg).
[1296] Example 81
[1297] Methyl] -3,3-spirocyclopropyl-6 - [(2S- (4-fluoro-phenyl) -piperidin- Hydro-indol-2-one
[1298] To a stirred solution of 2S- (4-fluoro-phenyl) -piperidin-3S-ylamine (39 mg, 0.20 mmol) in 1 mL methylene chloride was added 5-methoxy- 2-oxo-2,3-dihydro-lH-indole-6-carbaldehyde (46 mg, 0.20 mmol) (prepared by the method described in Preparation 61) was added. After 5 min, sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added and stirred overnight at room temperature. After the reaction was diluted with methylene chloride and quenched with saturated NaHC0 _3. The resulting product was subjected to pH-treatment to obtain the title compound (16 mg).
[1299]
[1300] HPLC (aqueous 200Mm ammonium acetate buffer / acetonitrile gradient, 3.0ml / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4mm column), 4.235.
[1301] Example 82
[1302] Methyl] -3-spirocyclopropyl-6 - [(2R- (4-fluoro- phenyl) -piperidin- Hydro-indol-2-one
[1303] To a stirred solution of 2R- (4-fluoro-phenyl) -piperidin-3R-ylamine (39 mg, 0.20 mmol) in 1 mL methylene chloride was added 5-methoxy- 2-oxo-2,3-dihydro-lH-indole-6-carbaldehyde (46 mg, 0.20 mmol) (prepared by the method described in Preparation 61) was added. After 5 min, sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added and stirred overnight at room temperature. After the reaction was diluted with methylene chloride and quenched with saturated NaHCO _3. The pH-after-treatment afforded the title compound (21 mg).
[1304]
[1305] HPLC (aqueous 200Mm ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.314.
[1306] Example 83
[1307] Methyl} -6-methoxy-3-methyl-l, l, 3a, 7b-tetrahydro-3- &lt; / RTI &gt; Aza-cyclopropa [a] naphthalen-2-one
[1308] To a stirred solution of 2S- (4-fluoro-phenyl) -piperidin-3S-ylamine (39 mg, 0.20 mmol) in 1 mL methylene chloride was added 6-methoxy- A] naphthalene-5-carbaldehyde (46 mg, 0.20 mmol) (Preparation 22 and / or 22A and ) 22B) was added. After 45 min, sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added and stirred overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and then quenched with H ₂ 0. The pH-after-treatment afforded the title compound (69 mg). The HCl salt and concentrated hydrochloric acid prepared in isopropanol were azeotropically removed with H ₂ O and recrystallized from methanol / isopropanol.
[1309]
[1310] HPLC (aqueous 200 Mm ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.210.
[1311] Example 84
[1312] Methyl} -6-methoxy-3-methyl-l, l, 3a, 7b-tetrahydro-3- &lt; / RTI &gt; Aza-cyclopropa [a] naphthalen-2-one
[1313] To a stirred solution of 2S- (4-fluoro-phenyl) -piperidin-3S-ylamine (39 mg, 0.20 mmol) in 1 mL methylene chloride was added 6-methoxy- A] naphthalene-5-carbaldehyde (46 mg, 0.20 mmol) (Preparation 22 and / or 22A and ) 22B) was added. After 45 min, sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added and stirred overnight at room temperature. The reaction was diluted with CH ₂ Cl ₂ and then quenched with H ₂ 0. The pH-after-treatment afforded the title compound (69 mg). The HCl salt and concentrated hydrochloric acid prepared in isopropanol were azeotropically removed with H ₂ O and recrystallized from methanol / isopropanol.
[1314]
[1315] HPLC (aqueous 200 Mm ammonium acetate buffer / acetonitrile gradient, 3.0 mL / min, Hewlett Packard ODS Hiperxyl 5 [mu] M, 125 x 4 mm column), 4.214.
[1316] Production Example 78a
[1317] 1-nitroheptan-4-one
[1318] To 53.4 g (544 mmol) of 1-hexen-3-one in 250 mL of methanol and 294 mL (5440 mmol) of nitromethane was added 30 mL (136 mmol) of 25% NaOMe in methanol as a slow static stream. The resulting yellow solution was warmed to -5 &lt; 0 &gt; C over 1 hour and kept at -5 [deg.] C to -10 [deg.] C for 3 hours. After heating for 1 h the solution to 0 ℃, quenched with saturated NH ₄ Cl 250 ㎖. The mixture was diluted with 200 mL of brine to help layer separation and extracted with ether (2 x 250 mL). The combined ether extracts washed with brine, dried over MgS0 ₄ and, filtered and concentrated to give a yellow liquid 75.7 g (88%). The presence of about 10% 7-nitro-trideca-4,10-dione produced by combining 1 mole equivalent of nitromethane and 2 mole equivalents of 1-hexen-3-one by ¹ H NMR was found. The product was not separable by silica gel chromatography (EtOAc / hexanes), and the material was generally used in the next step without purification. Title compound: mass spectrum m / e = 144 (M-1).
[1319] Production Example 79a-1
[1320] 1-nitrohexan-4-one
[1321] To a solution of ethyl vinyl ketone (90.1 g, 1285 mmol) in 550 mL of methanol and 556 mL (10282 mmol) of nitromethane was added 84 mL (about 386 mmol) of 25% methanolic NaOMe at -40 ° C as a static stream. The resulting light yellow slurry was allowed to warm to room temperature over 5 hours and was stirred overnight. The mixture was quenched with 300 mL of saturated NH ₄ Cl followed by 250 mL of water and 250 mL of brine. The mixture was then extracted with CH ₂ Cl ₂ (250 mL x 4). The extract was treated with MgSO ₄ and decolorizing carbon, filtered and concentrated to give 154 g (92%) of a pale yellow liquid.
[1322]
[1323] Production Example 79a-2
[1324] 1-nitrohexan-4-one
[1325] Sodium methoxide (about 123 mmol; 27 mL, 25% solution in MeOH) was added to ethyl vinyl ketone (41.4 g, 493 mmol) in MeOH (150 mL) and nitromethane (160 mL). The mixture was allowed to warm to-10 C over 30 min. At -10 ℃ 1.5 hours, quenched with saturated and the mixture NH ₄ Cl (250 ㎖) and water (250 ㎖). The mixture was poured into a separatory funnel and the lower organic layer was removed. The aqueous fraction was extracted with CH ₂ Cl ₂ (2 x 250 mL) and the combined organic fractions were dried over MgSO ₄ and concentrated. The resulting liquid was reconcentrated from toluene (2 x 250 mL) followed by methanol (1 x 250 mL) to give the desired material.
[1326] Production Example 80a
[1327] 1-nitropentan-4-one
[1328] Prepared by a procedure analogous to Preparation 79a-1. Mass spectrum m / e = 130 (M-1).
[1329] Production Example 81a
[1330] 6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine
[1331] The crude product (1-nitrohexan-4-one) was then dissolved in MeOH (90 mL) and trimethylorthoformate (90 mL) and treated with camphorsulfonic acid (5.7 g, 24.7 mmol). After 30 minutes, benzaldehyde (110 g, 1035 mmol) was added followed by ammonium acetate (75.9 g, 986 mmol) and MeOH (200 mL). The solution was stirred for 7 hours and then seeded to induce crystallization. The resulting slurry was stirred overnight and then the crystals were collected and lyophilized with 300 ml of cold methanol to give 100 g (53%) of benzylidene- (5,5-dimethoxy-2-nitro- ) As a white powder. The material was dissolved in EtOAc (300 mL) and p-toluenesulfonic acid (54.3 g, 286 mmol) in 300 mL warm EtOAc was added to the stirred solution. The mixture was stirred overnight and the resulting crystals were isolated and rinsed with 250 mL of EtOAc followed by ether EtOAc to give 92 g (48%) of the title compound as a white powder, approximately 1: 1 cis / trans mixture. Mass spectrum Calc. C ₁₃ H ₁₆ N ₂ O ₂ (M-pTsO ^- ) 233. Found 233.
[1332] Production Example 82a
[1333] 6-methyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine
[1334] Was prepared by a procedure similar to that of Preparation 81a. Mass spectrum m / e = 219 (M + l).
[1335] Production Example 83a
[1336] 2-phenyl-2,3,4,5-tetrahydro-pyridine
[1337] Was prepared by a procedure similar to that of Preparation 81a. Mass spectrum m / e = 247 (M + 1).
[1338] Production Example 84a
[1339] 6-ethyl-3,3-dimethoxy-2-phenyl-2,3,4,5-tetrahydro-pyridine camphorsulfonate
[1340] A solution of 25% NaOMe / MeOH (180 mL, ca. 864 mmol) was added to 6-methyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro- pyridine (50.0 g, Was added. The solution was stirred at room temperature for 25 minutes, then 2 M methanolic H ₂ SO ₄ (1080 mL, 2160 mmol) was added dropwise at 0 ° C over 1 hour. The mixture was allowed to warm to room temperature and stirred for 3.5 hours. Thereafter, the watch and the mixture was poured carefully to a solution of 2 L of water, _{NaHC0 3 362 g (4320 mmol)} . The mixture was then diluted with 2 L of ether and 1 L of water and stirred well for 5 minutes. The layers were separated and the aqueous fraction extracted with ether (1 x 2 L). The ether portion was extracted with 5% HOAc (aq) (3 x 750 mL). The HOAc extract was basified with 500 mL of saturated Na ₂ CO ₃ and extracted with CH ₂ Cl ₂ (2 x 700 mL). The extract was dried (MgSO ₄ ) and concentrated to give 33.2 g of a viscous red oil. The oil was dissolved in EtOAC (100 mL) and a solution of (+/-) - camphorsulfonic acid (31.3 g, 13.5 mmol) in 50 mL warm THF was added with vigorous stirring. A precipitate formed within 30 minutes. The resulting thick slurry was diluted with EtOAc (100 mL) and cooled on ice. After 1 h, the precipitate was collected via filtration and rinsed with EtOAc (200 mL) followed by ether (200 mL) to give 48.0 g (47%) of off-white powder.
[1341]
[1342] Production Example 85a
[1343] 6-methyl-3,3-dimethoxy-2-phenyl-2,3,4,5-tetrahydro-pyridine camphorsulfonate
[1344] Was prepared by a procedure analogous to Preparation 84a.
[1345] Production example 86a
[1346] 6-propyl-3,3-dimethoxy-2-phenyl-2,3,4,5-tetrahydro-pyridine camphorsulfonate
[1347] Was prepared by a procedure analogous to Preparation 84a.
[1348] Production Example 87a
[1349] Trans-6-ethyl-3,3-dimethoxy-2-phenyl-piperidine
[1350] Imine salt 6-Ethyl-3,3-dimethoxy-2-phenyl-2,3,4,5-tetrahydro-pyridin-camphor sulfonate a saturated NaHC0 ₃ (1 x 100 ㎖) and ether (2 x 100 ㎖) Lt; / RTI &gt; The extract was washed with brine, dried over MgS0 ₄ and concentrated. The resulting oil was dissolved in 40 mL of THF and cooled to -78 &lt; 0 &gt; C. Triethylaluminum (35 mL, 35 mmol, 1 M solution in heptane) was added and the solution was stirred for 10 min. The precooled LiAlH ₄ (39 mL, 39 mmol, 0.5 M solution in THF) was then rapidly added via a jacketed addition funnel at -78 ° C. After stirring for 1 h, the mixture was carefully quenched by dropwise addition of a 2 M Rochelle salt solution. When the strong bubbling was stopped, the mixture was diluted with 100 m &lt; 2 &gt; of an additional 2 M solution of the sodium chloride solution and stirred overnight. The mixture was then diluted and extracted once with ether. The extract was washed with brine, dried over MgS0 ₄ and concentrated to obtain the title compound as an oil 8.9 g (99%) colorless.
[1351]
[1352] Production Example 88a
[1353] Trans-6-methyl-3, 3-dimethoxy-2-phenyl-piperidine
[1354] Prepared by a similar procedure to Preparation 87a. Mass spectrum m / e = 236 _{(base) [C 15 H 23 NO 2} (M + 1) Calcd 236], 204.
[1355] Production Example 89a
[1356] Trans-6-propyl-3, 3-dimethoxy-2-phenyl-piperidine
[1357] Prepared by a similar procedure to Preparation 87a. Mass spectrum m / e = 264 (base) [C ₁₅ H ₂₃ NO ₂ (M + 1) theory 264], 232.
[1358] Production Example 90a
[1359] 3,3-Dimethoxy-1,2,3,4,5,6-hexahydro- [2,3 '] bipyridinyl
[1360] Prepared by a similar procedure to Preparation 87a. Mass spectrum m / e = 223 (M + 1, base), 191.
[1361] Production example 91a
[1362] 6-Ethyl-2-phenyl-piperidin-3-one oxime
[1363] To a mixture of trans-6-ethyl-3,3-dimethoxy-2-phenyl-piperidine (6.3 g, 25.3 mmol) and 17.5 g (253 mmol) of hydroxylamine hydrochloride in 250 ml of 50% aqueous acetonitrile 9.7 ml (126 mmol) of trifluoroacetic acid were added. The resulting solution was heated to &lt; RTI ID = 0.0 &gt; 60 C &lt; / RTI &gt; The reaction mixture was cooled to 5 &lt; 0 &gt; C and the pH was adjusted to 7.0 with saturated sodium bicarbonate. The mixture was extracted with methylene chloride. The methylene chloride extract was dried (Na ₂ SO ₄ ) and evaporated to give 5.1 g of a dark oil. The oil was dissolved in 70 ml of ethyl acetate and 30 ml of water and the pH was adjusted to 3.4 by 1 N HCl. The aqueous layer was extracted with ethyl acetate. The aqueous layer was then diluted with an equal volume of ethyl acetate and the pH was adjusted to 7.5 with saturated sodium bicarbonate. The ethyl acetate layer was dried (Na ₂ SO _4), the product was evaporated to 3.67 g (66%) of the cis-oxime was obtained as a mixture of isomers and trans.
[1364]
[1365] Production Example 92a
[1366] (+/-) - 6-methyl-2-phenyl-piperidin-3-one oxime
[1367] Prepared by similar procedure to Preparation 91a. Mass spectrum 205 (M + 1, base), 187.
[1368] Production Example 93a
[1369] 6-Propyl-2-phenyl-piperidin-3-one oxime
[1370] Prepared by similar procedure to Preparation 91a. Mass spectrum 233 (M + 1, base), 215. &lt; RTI ID = 0.0 &gt;
[1371] Production Example 94a
[1372] 1,4,5,6-tetrahydro-2H- [2,3 '] bipyridinyl-3-one oxime
[1373] Prepared by similar procedure to Preparation 91a. Mass spectrum 191 (M + 1, base), 173.
[1374] Production Example 95a
[1375] 6-Ethyl-2-phenyl-piperidin-3-ylamine
[1376] 6-Ethyl-2-phenyl-piperidin-3-one oxime was dissolved in EtOH (20 mL) and hydrogenated at 52 p.s.i. via a freshly prepared Raney nickel catalyst (wet slurry 6.0 g) for 20 h. The mixture was carefully filtered through celite and concentrated. The ditosylate salt was prepared by treatment of p-toluenesulfonic acid (12.3 g, 65 mmol) in MeOH / EtOAc to give 7.2 g (40%) of off-white crystals. Recrystallization from 2-propanol gave 3.80 g (21%) of a white powder. Mass spectrum 205 (base), 188.
[1377] Production Example 96a
[1378] 6-Methyl-2-phenyl-piperidin-3-ylamine
[1379] Lt; / RTI &gt; was prepared by a procedure analogous to Preparation 95a. Mass spectrum (M + l) = 191 (base), 174.
[1380] Production Example 97a
[1381] 6-Propyl-2-phenyl-piperidin-3-ylamine
[1382] Lt; / RTI &gt; was prepared by a procedure analogous to Preparation 95a. Mass spectrum (M + l) = 219 (base), 202.
[1383] Production Example 98a
[1384] 1,2,3,4,5,6-hexahydro- [2,3 '] bipyridinyl-3-ylamine
[1385] Lt; / RTI &gt; was prepared by a procedure analogous to Preparation 95a. Mass spectrum (M + 1) = 176.
[1386] Production Example 99a
[1387] (+/-) - 6-ethyl-2-phenyl-piperidin-3-ylamine
[1388] (2S, 3S, 6S) -6-ethyl-2-phenyl-piperidin-3- ylamine dibenzoyl-L-tartrate
[1389] (102 mg, 0.50 mmol) and (-) - dibenzoyltartaric acid were heated in 5 mL of 2-propanol and 1 mL of water to give (+/-) - 6-ethyl-2-phenyl-piperidin- . The resulting solid (26 mg, 25%) was determined to be 94% of the (2S, 3S, 6S) -enantiomer.
[1390] Preparation 78b
[1391] 6-ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine.
[1392] Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine as a mixture of cis and trans isomers under nitrogen and 5 ml (TLC rf. = Trans 0.6; cis 0.4; eluting with solvent hexane: ethyl acetate / 50: 50). The reaction mixture was cooled to -78 ° C and 1.07 mL (1.07 mmol) of a 1N lithium bis (trimethylsilyl) amide solution in THF was introduced. The reaction mixture was stirred for 20 minutes and then directly quenched into a well stirred solution of 2 gm Baker silica gel (40 uM flash chromatography packing). The solid was filtered and the filtrate was concentrated in vacuo to afford 0.23 gm (92%) of orange red oil to the desired cis isomer cis-6-ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine (TLC rf. = 0.4, hexane: ethyl acetate / 50: 50). Mass spectrum APCI (m / z) 233 (p + 1).
[1393] Production example 79b
[1394] (2S, 3S, 6S) -6-ethyl-2-phenyl-piperidin-
[1395] To a solution of the above prepared cis-6-ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine (322 mg; 1.39 mmol) in 5 mL of THF at -78 < M triethyl aluminum solution (1.39 mL, 1.39 mmol). The reaction mixture was stirred for 5 minutes, then 1.39 mL (1.39 mmol) of 1 M lithium aluminum hydride in THF was added and stirred again for 5 minutes. The reaction mixture was treated directly with 5 mL of 6 N HCl solution at -78 &lt; 0 &gt; C and warmed to room temperature. The mixture was treated with zinc dust 1.81 gm (27.7 mmol) and heated at reflux for 30 minutes. The mixture was cooled and then treated with 20% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, washed with saturated brine solution, dried over sodium sulfate and evaporated to dryness in vacuo to give a clear oil. This oil was dissolved in ethyl acetate (25 mg / ml), treated with 176 mg (0.757 mmol) of camphorsulfonic acid and stirred overnight at room temperature. The resulting solid was filtered to obtain 70 mg of the main product (2S, 3S, 6S) -6-ethyl-2-phenyl-piperidin-3-ylamine as camphorsulfonate. Mass spectrum APCI (m / z) 204 (p + 1).
[1396] Production Example 78c
[1397] Methyl-2-phenyl-1,2,3,4, -tetrahydro-2H-pyridine-1-carboxylic acid benzyl ester
[1398] A solution of cis-6-ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydro-pyridine (12 gm; 29.7 mmol) in a saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (100 mL) The solution was treated with 5.08 mL (35.6 mmol) benzyl chloroformate. The mixture was stirred rapidly and heated to 45 &lt; 0 &gt; C for 3 h and then cooled to ambient temperature. The layers were separated and the aqueous layer was washed once with additional methylene chloride. The combined organic layers were concentrated and the residue was treated with isopropyl ether (80 mL). In this case, a solid precipitated. However, when no precipitate was formed, the mixture was cooled to -78 占 폚 for 2 hours. A solid of 4.92 gm (45%) was collected as the first product. The second product, 1.18 gm (11%), was obtained from the filtrate. By TLC and NMR, it was confirmed that this material was the cis isomer cis-6-ethyl-3-nitro-2-phenyl-1,2,3,4-tetrahydro-2H-pyridine-1-carboxylic acid benzyl ester .
[1399]
[1400] Production example 79c
[1401] (2S, 3S, 6S) -6-ethyl-3-nitro-2-phenyl-piperidine- 1 -carboxylic acid benzyl ester
[1402] A three-necked flask equipped with a nitrogen inlet, addition funnel and magnetic stirring bar was charged with 81 mL (1.05 mol) of trifluoroacetic acid (TFA) and 80 mL of methylene chloride. The solution was cooled to-15 C, whereupon TFA was often precipitated as a white solid. The addition funnel was added to a solution of cesium-6-ethyl-3-nitro-2-phenyl-1,2,3,4, -tetrahydro-2-H-pyridine- 1 -carboxylic acid benzyl ester (38.75 gm 105.8 mmol) and triethylsilane (46.4 mL, 291.0 mmol). The contents of the addition funnel were slowly added to the reaction flask over 20 minutes and stirred for 15 minutes. The reaction was confirmed to be complete by TLC and then evaporated in vacuo to give a thick red oil. This material was used directly for the next transformation.
[1403]
[1404] Production Example 80c
[1405] (2S, 3S, 6S) -6-ethyl-3-nitro-2-phenyl-piperidine
[1406] (40 gm; 108 mmol) was dissolved in 80 mL of 30% HBr in propionic acid at room temperature, and a solution of (2S, 3S, 6S) -6-ethyl- . The gas was released rapidly, and the desired product precipitated after 3-5 minutes. The mixture was stirred at room temperature for 16 hours. The tan solid was collected, washed with ether and dried in vacuo to give 29 gm of (2S, 3S, 6S) -6-ethyl-3-nitro-2-phenyl-piperidine HBr salt.
[1407]
[1408] Production example 81c
[1409] (2S, 3S, 6S) -6-ethyl-2-phenyl-piperidin-
[1410] 250 ml Parr bottle was charged with 1 gm (3.18 mmol) of the above prepared (2S, 3S, 6S) -6-ethyl-3-nitro-2-phenyl-piperidine HBr salt in 60 ml methanol. An excess of commercially available Raney nickel was added to the resulting solution, which was strongly washed with deionized water until the pH of the supernatant was 7.00. The reaction mixture was placed in a Parr hydrogen generator under 50 p.s.i and shaken for 4 hours. The reaction mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was partitioned between methylene chloride and 1 N NaOH. The combined organics were washed with brine, then dried and evaporated to give 0.47 gm (72%) of crude racemic 6-ethyl-2-phenylpiperidin-3-ylamine. The racemic mixture was partitioned by forming salts with (-) - O, O'-dibenzoyl-L-tartaric acid in isopropanol water.
[1411]
[1412] Example 85
[1413] Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one
[1414] Ethyl-2-phenyl-piperidin-3-ylamine [or (2S, 3S, 6S) -6- (2R, 3R, 6R) -6-ethyl-2-phenyl-piperidin-3-ylamine] and 6-methoxy- -Tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde [or (1S, 1aR) -6- (A) naphthalene-5-carbaldehyde or (1R, 1aS) -6-methoxy-3-methyl- 7b-tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde].
[1415]
[1416] Mass spectrum APCI (m / z) 420 (p + 1).
[1417] Example 86
[1418] Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one
[1419] Phenyl-piperidin-3-ylamine [or (2S, 3S, 6S) -6-methyl-2-phenyl-piperidin- (2R, 3R, 6R) -6-methyl-2-phenyl-piperidin-3-ylamine] and 6-methoxy- (A) naphthalene-5-carbaldehyde [or (9S, 1aR) -6-methoxy- (A) naphthalene-5-carbaldehyde or (1R, 1aS) -6-methoxy-3-methyl- Tetrahydro-1H-3-azacyclopropa [a] naphthalene-5-carbaldehyde]. Mass spectrum APCI (m / z) 406 (p + 1).
[1420] Example 87
[1421] 3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one
[1422] In a similar manner to that described in Examples 9 and 9A, 6-propyl-2-phenyl-piperidin-3-ylamine [or (2S, 3S, 6S) (2R, 3R, 6R) -6-propyl-2-phenyl-piperidin-3-ylamine] and 6-methoxy- -1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde [or (1S, 1aR) -6- (1R, 1aS) -6-methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetra Hydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde]. Mass spectrum APCI (m / z) 434 (p + 1).
[1423] Example 88
[1424] Methyl-7- [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-
[1425] In a similar manner to Examples 9 and 9A above, the title compound was prepared from 6-propyl-2-phenyl-piperidin-3-ylamine [or (2S, 3S, 6S) -6- (2R, 3R, 6R) -6-propyl-2-phenyl-piperidin-3-ylamine] and 6-methoxy- Tetrahydro-quinoline-7-carbaldehyde. &Lt; / RTI &gt; Mass spectrum APCI (m / z) 422 (p + 1).
[1426] Example 89
[1427] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one
[1428] Ethyl-2-phenyl-piperidin-3-ylamine [or (2S, 3S, 6S) -6- (2R, 3R, 6R) -6-ethyl-2-phenyl-piperidin-3-ylamine] and 6-methoxy- -Tetrahydro-quinoline-7-carbaldehyde. &Lt; / RTI &gt; Mass spectrum APCI (m / z) 408 (p + 1).
[1429] Example 90
[1430] Methyl-7 - [(6-methyl-2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin-
[1431] Phenyl-piperidin-3-ylamine [or (2S, 3S, 6S) -6-methyl-2-phenyl-piperidin- (2R, 3R, 6R) -6-methyl-2-phenyl-piperidin-3-ylamine] and 6-methoxy- -Tetrahydro-quinoline-7-carbaldehyde. &Lt; / RTI &gt; Mass spectrum APCI (m / z) 394 (p + 1).
[1432] Example 91
[1433] 3-ylamino) -methyl] -6-methoxy-1-methyl-3, 4-dihydro-isoquinolin- 1H-quinolin-2-one hydrochloride
[1434] 2-phenyl-piperidin-3-ylamine with 6-methoxy-l-methyl-2-oxo-l, 2,3,4- Tetrahydro-quinoline-7-carbaldehyde. &Lt; / RTI &gt; Mass Spectrum Calc. C ₂₆ H ₃₆ N ₃ O ₂ (M + 1) 423; Found 423.
[1435] Example 92
[1436] 3-ylamino) -methyl] -6-methoxy-1-methyl-3, 4-dihydro-isoquinolin- 1H- [1,5] naphthyridin-2-one
[1437] 2-phenyl-piperidin-3-ylamine with 2-methoxy-5-methyl-6-oxo-5,6,7,8- Tetrahydro- [l, 5] naphthyridine-3-carbaldehyde. Mass Spectrum Calc. C ₂₅ H ₃₄ N ₄ O ₂ (M + 1) 423; Found 423.
[1438] Production example 100
[1439] 3-Benzylamino-3-methyl-butan-l-ol
[1440] To the slurry of 3-benzylamino-3-methyl-butyric acid (1.00 g, 4.83 mmol) in THF was added borane (9.7 mmol, 9.7 mL, 1.0 M solution in THF). After stirring for 1 hour, the mixture was poured into a mixture of 1 M HCl and crushed ice and quenched. The mixture was neutralized with K ₂ CO ₃ and extracted once with CHCl ₃ . The material was passed through cotton balls, dried and concentrated to give 441 mg (47%) of the title compound. _{Rf 0.40 (12:88 MeOH / CHCl 3} ).
[1441] Production example 101
[1442] (3-hydroxy-1,1-dimethyl-propyl) -carbamic acid tert-butyl ester
[1443] Followed by di -tert- butyl dicarbonate to butane-1-ol (3.75 g, 36.0 mmol) NaHC0 3 (4.0 g, 47.6 mmol) in (- 30 ㎖ of THF and water 76 ㎖ 3- benzyl-3-methyl 7.8 g, 36 mmol). After stirring overnight, the mixture was washed with 2 M NaHSO ₄ (3 x 30 mL) followed by brine. Concentration gave 5.13 g (70%) of the title compound as colorless oil. Mass spectrum (M-100) = 103.
[1444] Production Example 102
[1445] (L, l-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester
[1446] Butyl ester (6.0 g, 30 mmol) was dissolved in CH ₂ Cl ₂ (50 mL), and de-martin periostinan (20.0 g, , 44 mmol). After stirring overnight, the NaHCO ₃ and Na ₂ S ₂ 0 ₃ was added followed by water 50 ㎖. The resulting mixture was stirred vigorously for 30 min and then extracted with CH ₂ Cl ₂ (3 x 50 mL). The extract was dried with MgSO ₄ and concentrated to give 3.26 g (54%) of an orange oil. This material was used in the next step without purification.
[1447] Production example 103
[1448] (3-hydroxy-1,1-dimethyl-4-nitro-butyl) -carbamic acid tert-butyl ester
[1449] Butyl ester (3.20 g, 16 mmol) was dissolved in EtOH (10 mL). Nitromethane (976 mg, 16 mmol) was added dropwise followed by NaOH solution (640 mg in 1.6 mL water). The pH of the solution was reduced to about 6.0 by HOAc and the mixture was extracted with EtOAc (3 x 20 mL). The extract was washed with brine, dried over MgS0 ₄ and concentrated. Chromatography (9: 1 hexanes / EtOAc) gave 2.17 g (52%) of a pale yellow oil. Mass spectrum 144.
[1450] Production example 104
[1451] (1,1-dimethyl-4-nitro-but-3-enyl) -carbamic acid tert-butyl ester
[1452] Butyl ester (2.00 g, 7.6 mmol) and triethylamine (2.73 g, 27.0 mmol) in 50 mL of CH ₂ Cl _{2 was} added dropwise a solution of (3-hydroxy-1,1- Methanesulfonyl chloride was added dropwise over 5 minutes at -10 &lt; 0 &gt; C. The mixture was allowed to warm to room temperature for 1 h, then diluted with water and extracted with CH ₂ Cl ₂ (3 x 30 mL). The extract was washed successively with 1% HCl, water and brine, dried over MgS0 ₄ and concentrated. Silica gel chromatography (10: 1 hexanes / EtOAc) gave 1.07 g (60%) of a colorless oil.
[1453]
[1454] Production example 105
[1455] (L, l-dimethyl-4-nitro-butyl) -carbamic acid tert-butyl ester
[1456] NaBH ₄ (500 mg, 13.5 mmol) was added to (1,1-dimethyl-4-nitro-but-3-enyl) -carbamic acid tert- butyl ester (2.0 g, 8.2 mmol) in 20 mL EtOH. The mixture was stirred for 1 h and then quenched with saturated NH ₄ Cl (40 mL). The solution was extracted with EtOAc (2 x 25 ㎖), and the extract was washed with brine, dried over MgS0 ₄ and concentrated. Silica gel chromatography (10: 1 hexanes / EtOAc) gave 1.57 g (78%) of a colorless oil. Mass spectrum m / e = 147 (M-100).
[1457] Production Example 106
[1458] 1,1-dimethyl-4-nitro-butylamine trifluoroacetate
[1459] To (1,1-dimethyl-4-nitro-butyl) -carbamic acid tert-butyl ester (1.0 g, 4.0 mmol) in 25 mL of CH ₂ Cl ₂ was added 2.5 mL of TFA at -10 ° C. The mixture was allowed to warm to room temperature and monitored by TLC. When complete by TLC analysis, the mixture was concentrated to give 518 mg (88%) of the title compound as an orange oil. Mass spectrum m / e = 147 (M + 1).
[1460] Production example 107
[1461] Trans-2,2-dimethyl-5-nitro-6-phenyl-piperidine
[1462] NH ₄ OAc (53 mg, 0.69 mmol) and benzaldehyde (69 mg, 0.688 mmol) were added to 1,1-dimethyl-4-nitro-butylamine (0 mg, 0.344 mmol) in 1 mL MeOH. Mixture was stirred overnight at room temperature, diluted with water and extracted with CHCl _3. The extract was dried by filtration through cotton and concentrated. Chromatography (20: 1 hexanes / EtOAc) gave 17 mg (21%) of a white solid. Mass spectrum m / e = 235 (M + 1).
[1463] Production Example 108
[1464] Cis-2,2-dimethyl-5-nitro-6-phenyl-piperidine
[1465] Transnitropiperidine (500 mg, 2.45 mmol) was dissolved in 10 mL methanol and treated with 4 mL 25% NaOMe / MeOH solution. After stirring for 30 min, the reaction was added dropwise to a slurry of 5 g of silica gel in EtOAc. The silica gel was removed by filtration and the filtrate was concentrated. Silica gel chromatography (1: 9 EtOAc / hexanes) gave 155 g (32%) of the title compound and 227 mg of the trans-starting material. Title compound: mass spectrum m / e 205 (M + 1).
[1466] Production Example 109
[1467] 6,6-Dimethyl-2-phenyl-piperidin-3-ylamine
[1468] 0.2 M HCl 6M and 100 mg (1.5 mmol) of zinc powder were added to 2,2-dimethyl-5-nitro-6-phenyl-piperidine in 0.4 ml THF. The mixture was stirred at room temperature until completion by TLC analysis. The mixture is filtered through celite and rinsed with 5 ml of water. The aqueous solution was washed with Et ₂ O (3 x 5 mL) and basified to pH = 12 with 1 N NaOH. The mixture was extracted with CHCl ₃ and the extract was dried by filtration through cotton plug and concentrated to give 6 mg (69%) of the title compound as colorless oil. Mass spectrum m / e = 205 (M + l).
[1469] Example 93
[1470] Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one
[1471] In a similar manner to that described in Examples 9 and 9A above, 6,6-dimethyl-2-phenyl-piperidin-3-ylamine and 6-methoxy- -Tetrahydro-quinoline-7-carbaldehyde. &Lt; / RTI &gt; Mass Spectrum Calc. C ₂₅ H ₃₄ N ₃ O ₂ (M + 1) 408; Found 408.
[1472] Production Example 110
[1473] 3-nitro-2,3,4,5-tetrahydro-1H- [2,2 '] bipyridinyl-6-one
[1474] To a solution of 4-nitro-butyric acid methyl ester (29.4 g, 200 mmol) in 350 mL EtOH was added pyridine-3-carboxaldehyde (21.4 g, 200 mmol). The mixture was refluxed overnight and cooled to ice bath temperature. The solid was collected by filtration and rinsed with cold EtOH followed by ether to give 36.8 g (83%) of a pale yellow solid. Mass spectrum m / e = 221 (M + 1).
[1475] Production Example 111
[1476] 3,3-Dimethoxy-2,3,4,5-tetrahydro-1H- [2,3 '] bipyridinyl-6-one
[1477] Lactam 3-nitro-2,3,4,5-tetrahydro-lH- [2,3 '] bipyridinyl-6-one was dissolved in 2.6 M methanolic sodium methoxide (160 mL) The solution was then added dropwise to 4M methanolic sulfuric acid (300 mL) at -10 &lt; 0 &gt; C. The resulting green solution was warmed to room temperature and stirred for 2 hours. The methanol volume was removed in vacuo and the remaining viscous liquid was diluted with 300 mL of CH ₂ Cl ₂ . While stirring, the mixture was carefully watch was diluted with saturated NaHCO ₃ 1 L. The resulting mixture was extracted with CH ₂ Cl ₂ (6 x 500 mL) and the extract was dried over cotton and concentrated. The residue was re-concentrated from 250 mL of EtOAc to give almost the dried product. The resulting precipitate was collected by filtration, bingon of 1: 1 followed by Et ₂ 0 / EtOAc and washed with Et ₂ O, to give a white solid 13.2 g (41%). Mass spectrum m / e = 237 (M + 1), 205.
[1478] Production Example 112
[1479] 3,3-Dimethoxy-1,2,3,4,5,6-hexahydro- [2,3 '] bipyridinyl
[1480] To a solution of 3,3-dimethoxy-2,3,4,5-tetrahydro-1H- [2,3 '] bipyridinyl-6-one (1.0 g, 421 mmol) in 3 mL of THF was added borane- Complex (3.0 mL, 6.0 mmol, 2 M solution in THF) at 0 &lt; 0 &gt; C. The solution was stirred at room temperature overnight, then quenched with methanol and heated at reflux temperature for 2 hours. The methanol was removed in vacuo and the residue was partitioned between water and chloroform. The mixture was acidified to pH = 3 and washed with _{CHCl 3 (3 x 10 ㎖)} . The aqueous was then acidified with solid NaHCO ₃ to pH = 8 and then extracted with CHCl ₃ (3 x 15 mL). The extract was dried with MgSO ₄ and concentrated to give 812 mg (86%) of a pale yellow oil. Mass spectrum m / e = 223.

权利要求:
Claims (79)
[1" claim-type="Currently amended] A compound of formula I or a pharmaceutically acceptable salt thereof.
(I)

In this formula,
Q is _{C = NH, C = CH 2} , C = S, C = O, SO or SO _2, and;
A is in the case of a _{CH, CH 2, C (C} 1 -C 6) alkyl, CH (C ₁ -C ₆₎ alkyl, C (CF ₃₎ or CH (CF _3), with the proviso, B exists, A must be a _{CH, C (C 1 -C 6} ) alkyl or C (CF _3), and;
B is absent or methylene or ethylene;
Y and Z are each N or CH, provided that Y and Z can not both be N;
G is NH (CH ₂ ) _q , S (CH ₂ ) _q or O (CH ₂ ) _q, wherein q is 0 or 1;
Provided that when q is 0, G is NH ₂ , SH or OH;
W is a 1 carbon bridging group (i.e., methylene) or a saturated or unsaturated 2 or 3 carbon bridging group, wherein each W group is optionally substituted with 1 substituent R ⁷ or 2 substituents R ⁷ and R ⁶ Or W is a 1 carbon bridging group which together with the 2,3, 4 or 5 carbon chains forms a 3, 4, 5 or 6 membered spiro ring, respectively; or
W is a saturated 2 carbon chain bridging group which forms a fused 3, 4 or 5 membered ring with separate 1,2 or 3 carbon chains; or
W is a saturated 2 carbon chain bridging group in which one of the two carbons forms a 3, 4, 5 or 6 membered spiro ring with a separate 2,3 or 4 carbon chain, respectively;
p is 0, 1 or 2;
R ³ is selected from hydrogen, COR ⁹ , CO ₂ R ⁹ , optionally substituted phenyl, optionally substituted heterocyclic ring and optionally substituted (C ₁ -C ₈ ) alkyl, wherein said (C ₁ -C ₈₎ one of the alkyl CH ₂ lifter may be substituted with a sulfur, oxygen or a carbonyl group, the (C ₁ -C ₈₎ alkyl, hydroxy, oxo, phenyl, - (C ₁ -C ₃₎ alkoxy, phenyl, cyano NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ , CO ₂ R ⁹ , NR ⁹ R ¹⁰ , and 1 to 7 fluorine atoms, optionally substituted heterocyclic rings, NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , Optionally substituted with one to three substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
R ³ in the heterocyclic ring, and 3- to 7-membered saturated or unsaturated monocyclic ring, and one to four ring heteroatoms which heterocyclic ring substituents on the alkyl groups of R ³ contain from 1 to 4 ring heteroatoms And wherein the heteroatom is independently selected from oxygen, nitrogen and sulfur, with the proviso that the monocyclic or bicyclic heterocyclic ring , There can not be two adjacent ring oxygen atoms or two adjacent ring sulfur atoms and the heterocyclic ring formed from NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ must contain at least one nitrogen atom;
R ³ heterocyclic heterocyclic on the alkyl group of the cyclic ring, and R ³ of the ring substituent is ^{_{(CH 2) m NR 9 R}} 10, NR 9 COR 10, oxo, hydroxy, thioxo, halo, cyano, phenyl, ( CH ₂ ) _m OR ⁹ , wherein m is 0, 1 or 2, and optionally substituted with one or more substituents independently selected from halo, CF ₃ , methoxy and phenyl, preferably 0 to 2 substituents Optionally substituted with one or more substituents, preferably 0, 1 or 2, substituents independently selected from (C ₁ -C ₆ ) alkyl;
Phenyl substituent on the alkyl group of R ³ groups and R ³ are optionally substituted with halo, cyano, _{nitro, CF 3, (CH 2)} m NR 9 R 10 ( at this time, m is 0, 1 or 2), NR ⁹ COR ^{10 _{, NR 9 CO 2 R 10,}} CONR 9 R 10, CO 2 NR 9 R 10, COR 9, CO 2 R 9, 1 to 7 fluorine atoms, preferably with 0-3 fluorine atoms an optionally substituted (C ₁ C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine the reactor is optionally substituted (C ₂ -C ₆₎ one or more substituents independently selected from alkenyl, preferably, may be optionally substituted with 0-2 substituents;
Each R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ is hydrogen and at least one substituent independently selected from hydroxy, oxo, (C ₁ -C ₆ ) alkoxy and cyano, preferably 0, (C ₁ -C ₆ ) alkyl optionally substituted with one or two substituents; or
R ¹ and R ² together with the carbon atoms to which they are attached or R ² and R ³ together with the carbon and nitrogen to which they are attached contain 5 or 5 heteroatoms independently selected from nitrogen, Or a six membered saturated heterocyclic ring with the proviso that the ring may not contain two adjacent oxygen atoms or two adjacent sulfur atoms; Or R ¹ and R ² form a 5 or 6 membered saturated or unsaturated carbocyclic ring together with the carbon to which they are attached, and at this time, the heterocyclic group formed from R ¹ and R ² or R ² and R ^3, and carbocyclic ring optionally substituted with halo, oxo, NR ⁹ R ^10, one to seven fluorine atoms, preferably from zero to three fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkyl, and one to seven fluorine atoms, Preferably one or more substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted by 0 to 3 fluorine atoms, preferably 0 or 1 substituent; or
R ¹² and R ¹³ , together with the carbon atoms to which they are attached, form a 5 or 6 membered saturated heterocyclic ring containing one or two heteroatoms independently selected from nitrogen, oxygen and sulfur provided that the ring has 2 Or two adjacent sulfur atoms, or R ¹² and R ¹³ together with the carbon to which they are attached form a 5 or 6 membered saturated or unsaturated carbocyclic ring, wherein R ¹² and the heterocyclic group formed from the R ¹³ and the carbocyclic ring is NR ⁹ R ^10, halo, phenyl, -S-, -SO- phenyl, phenyl -SO ₂ -, oxo, one to seven fluorine atoms, preferably 0 to 3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ each of which is independently selected from alkyl One or more substituents, preferably 0, or it can be optionally substituted with 1 substituent;
With the proviso that only one of R ¹ and R ² , R ² and R ³ , and R ¹² and R ¹³ may form a ring;
R ⁴ is selected from phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, and pyrimidyl wherein R ⁴ is halo, 1-7 fluorine atoms, preferably 0 (C ₁ -C ₆ ) alkyl optionally substituted by one to three fluorine atoms, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 Optionally substituted with one or more substituents independently selected from fluorine atoms, preferably (C ₂ -C ₆ ) alkenyl optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
R ⁵ and R ⁸ are hydrogen, -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl - (C ₁ -C ₂₎ alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) ₆₎ alkoxy, phenyl - (C ₁ -C ₃₎ alkoxy, phenyl, cyano, chloro, bromo, ^{iodo, NR 9 R 10, NR 9} COR 10, NR 9 CO 2 R 10, CONR 9 R 10, (C ₁ -C ₆ ) alkyl optionally substituted with one or more substituents independently selected from COR ⁹ and CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
R ⁶ and R ⁷ is -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl- (C ₁ -C ₂ ) alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) (C ₁ -C ₃ ) alkoxy, phenyl, cyano, chloro, bromo, iodo, NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ And (C ₁ -C ₆ ) alkyl substituted with one or more substituents independently selected from CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
Each R ⁹ and each R ¹⁰ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, phenyl and CF ₃ ; or
When R ³ is NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ , R ⁹ and R ¹⁰ together with the nitrogen to which they are attached may form an optionally substituted heterocyclic ring containing at least one nitrogen atom;
R ^5, R ^6, R ⁷ and R ⁸ in the definition of a phenyl group and R ^5, R ^6, the definition of R ⁷ and R ⁸ -phenyl (C ₁ -C ₂₎ alkyl in the phenyl moiety is optionally substituted by halo, hydroxy, 1 to the seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ - C ₆ ) alkyl, preferably with 0 to 2 substituents independently selected from alkyl;
(A) R ⁸ is not methyl substituted with halo, hydroxy, cyano, aryloxy, heteroaryloxy, substituted or unsubstituted (C ₁ -C ₆ ) alkoxy, or with 1 to 3 fluorine atoms ; (b) methylene in which Q is C = O or C = S, Y and Z are both carbon and W is optionally substituted by (C ₁ -C ₆ ) alkyl or fluoro substituted (C ₁ -C ₆ ) , Ethylene or propylene group and R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ are both hydrogen and R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen, halo, optionally substituted with 1 to 7 fluorine atoms (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted by 1 to 7 fluorine atoms, R ³ can not be hydrogen.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ³ is an optionally substituted heterocyclic ring or an optionally substituted heterocyclic ring alkyl group, wherein said heterocyclic ring is selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3 Thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolyl, isoindolyl, isoquinolyl, A thiazolyl, a thienyl, and a group of the formula: &lt; EMI ID = 14.1 &gt;

Wherein B ² and D are selected from carbon, oxygen and nitrogen, and at least one of B ² and D is not carbon; E is carbon or nitrogen; q is an integer from 1 to 5; _One of the carbon atoms of (CH ₂ ) _q and (CH ₂ ) _{q + 1} may be optionally substituted with (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) spiroalkyl; A pair of carbon atoms of (CH ₂ ) _q and (CH ₂ ) _{q + 1} may be bridged by linkage to one or two carbon atom bridges, or the (CH ₂ ) _q and (CH ₂ ) _{q +} one pairs of adjacent carbon atoms of ₁ can form a cyclic ring (C ₃ -C ₅₎ fused see carboxylic carbonyl with 1 to 3 carbon atoms containing a non-member of the ring.
[3" claim-type="Currently amended] The compound according to claim 1, wherein B is absent and A is CH ₂ .
[4" claim-type="Currently amended] 2. The compound according to claim 1, wherein Q is a carbonyl group.
[5" claim-type="Currently amended] 2. The compound according to claim 1, wherein Y and Z are both CH.
[6" claim-type="Currently amended] The method of claim 1 wherein B is ethylene, A is CH, G is NHCH ₂ compounds.
[7" claim-type="Currently amended] The method of claim 1 wherein B is ethylene, A is CH, the compound G is SCH _2.
[8" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ³ &gt; is hydrogen.
[9" claim-type="Currently amended] The compound according to claim 1, wherein R ³ is CO ₂ R ⁹ .
[10" claim-type="Currently amended] The compound according to claim 1, wherein B is absent, G is NH and A is CH ₂ .
[11" claim-type="Currently amended] 2. The compound according to claim 1, wherein W is ethylene.
[12" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ⁴ &gt; is phenyl.
[13" claim-type="Currently amended] 3. The compound of claim 1 wherein R &lt; ⁴ &gt; is phenyl and R &lt; ⁸ &gt; is hydrogen.
[14" claim-type="Currently amended] The compound according to claim 1, wherein p is 1.
[15" claim-type="Currently amended] The compound according to claim 1, wherein R ² is (C ₁ -C ₆ ) alkyl.
[16" claim-type="Currently amended] The compound of claim 1, wherein R ² is (C ₁ -C ₆ ) alkyl, wherein the stereochemistry of the chiral carbon to which R ² is attached is "S".
[17" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ⁴ &gt; is 2-, 3- or 4-pyridyl.
[18" claim-type="Currently amended] 3. A compound according to claim 1 wherein R &lt; ² &gt; and R &lt; ¹² &gt; are independently selected from methyl and ethyl.
[19" claim-type="Currently amended] 2. The compound according to claim 1, wherein Y is CH.
[20" claim-type="Currently amended] 4. The compound according to claim 3, wherein Q is a carbonyl group.
[21" claim-type="Currently amended] 2. The compound according to claim 1, wherein Y is CH and Z is nitrogen.
[22" claim-type="Currently amended] 3. The compound according to claim 2, wherein Q is a carbonyl group.
[23" claim-type="Currently amended] 3. The compound according to claim 2, wherein Y is CH and Z is CH.
[24" claim-type="Currently amended] The method of claim 1 wherein Q is C = O, W is (C ₁ -C ₆₎ a methylene compound of optionally substituted with one or two substituents independently selected from alkyl and CF _3.
[25" claim-type="Currently amended] The compound according to claim 1, wherein Q is C = O and W is ethylene optionally substituted with one or two substituents independently selected from (C ₁ -C ₆ ) alkyl and CF ₃ .
[26" claim-type="Currently amended] The compound according to claim 1, wherein Q is SO.
[27" claim-type="Currently amended] 3. Compounds according to claim 1, wherein Q is SO _2.
[28" claim-type="Currently amended] 2. The compound according to claim 1, wherein Y is nitrogen and Z is CH.
[29" claim-type="Currently amended] 2. The compound of claim 1, wherein Q is C = S.
[30" claim-type="Currently amended] 4. The compound according to claim 3, wherein R &lt; ⁸ &gt; is hydrogen.
[31" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ³ &gt; is a heterocyclic ring.
[32" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ³ &gt; is an alkyl group substituted by a heterocyclic ring.
[33" claim-type="Currently amended] ^3. The compound of claim 1 wherein R &lt; ³ &gt; is selected from the group consisting of imidazolyl, 5-oxo-4,5-dihydro-lH- [1,2,4] triazol-3-yl, benzoxazol- Oxo-pyrrolidin-2-yl. &Lt; / RTI &gt;
[34" claim-type="Currently amended] 3. The compound of claim 1 wherein R &lt; ⁴ &gt; is optionally substituted pyridyl.
[35" claim-type="Currently amended] The compound according to claim 1, wherein R ² and R ¹² are selected from (C ₁ -C ₃ ) alkyl.
[36" claim-type="Currently amended] 33. The compound of claim 32, wherein Q is a carbonyl group.
[37" claim-type="Currently amended] 3. The method of claim 2, wherein B is ethylene, A is CH, G is NHCH ₂ compounds.
[38" claim-type="Currently amended] 3. The method of claim 2, wherein B is ethylene, A is CH, the compound G is SCH _2.
[39" claim-type="Currently amended] 4. The compound according to claim 3, wherein R &lt; ³ &gt; is hydrogen.
[40" claim-type="Currently amended] 4. The method of claim 3, wherein B is ethylene, A is CH, G is NHCH ₂ compounds.
[41" claim-type="Currently amended] The compound according to claim 3, wherein R ³ is CO ₂ R ⁹ .
[42" claim-type="Currently amended] The compound according to claim 3, wherein G is NH.
[43" claim-type="Currently amended] The compound according to claim 3, wherein W is ethylene.
[44" claim-type="Currently amended] 4. A compound according to claim 3 wherein R &lt; ⁴ &gt; is phenyl.
[45" claim-type="Currently amended] 4. A compound according to claim 3 wherein R &lt; ³ &gt; is phenyl and R &lt; ⁸ &gt; is hydrogen.
[46" claim-type="Currently amended] The compound according to claim 3, wherein p is 1.
[47" claim-type="Currently amended] The method of claim 3, wherein, R ² is (C ₁ -C ₆₎ alkyl.
[48" claim-type="Currently amended] The compound according to claim 3, wherein R ² is (C ₁ -C ₆ ) alkyl, wherein the stereochemistry of the chiral carbon to which R ² is attached is "S".
[49" claim-type="Currently amended] 4. The compound according to claim 3, wherein R &lt; ⁴ &gt; is 2-, 3- or 4-pyridyl.
[50" claim-type="Currently amended] 4. A compound according to claim 3 wherein R &lt; ² &gt; and R &lt; ¹² &gt; are independently selected from hydrogen, methyl, ethyl and propyl.
[51" claim-type="Currently amended] The compound according to claim 3, wherein R ² and R ¹² are both not hydrogen.
[52" claim-type="Currently amended] 4. The compound according to claim 3, wherein Y is CH.
[53" claim-type="Currently amended] 4. The compound according to claim 3, wherein Y is CH and Z is CH.
[54" claim-type="Currently amended] 3. The compound according to claim 2, wherein Y is CH and Z is nitrogen.
[55" claim-type="Currently amended] The method of claim 3 wherein Q is C = O, W is (C ₁ -C ₆₎ alkyl and CF ₃ with a compound of methylene optionally substituted with one or two substituents independently selected from.
[56" claim-type="Currently amended] The compound of claim 3, wherein Q is C = O and W is ethylene optionally substituted with one or two substituents independently selected from (C ₁ -C ₆ ) alkyl and CF ₃ .
[57" claim-type="Currently amended] The compound according to claim 3, wherein Q is SO.
[58" claim-type="Currently amended] Compounds selected from mixtures of isomers and isomers of the following compounds having stereochemistry of the structure &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one ;
3-ylamino] -methyl} -3,4-dihydro-1 H- (pyridin-2-yl-acetyl) -piperidin- -Quinolin-2-one;
3-ylamino] -methyl} -3,4-dihydro-1 H- (pyridin-3-yl-acetyl) -piperidin- -Quinolin-2-one;
3-ylamino] -methyl} -3,4-dihydro-1 H- (4-fluoro-phenyl) -Quinolin-2-one;
6-Cyclopropoxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
(5-Chloro-2-methoxy-benzyl) - (2-phenyl-octahydro-cyclopenta [b] pyrrol-3-yl) -amine;
3-ylamino) -methyl] -3, 6-dimethoxy-l- 4-dihydro-1H-quinolin-2-one;
Methyl-6-methoxy-1-methyl-3, 4-dihydro- LH-quinolin-2-one;
1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyridin-2-yl-ethanone;
1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyridin-3-yl-ethanone;
1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyridin-4-yl-ethanone;
2-Imidazol-1-yl-1- [3- (2-methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-l-yl] -ethanone;
2-Dimethylamino-l- [3- (2-methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-l-yl] -ethanone;
3- (2-Benzyloxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane;
1- [3- (2-Methoxy-5-trifluoromethoxy-benzylamino) -2-phenyl-piperidin-1-yl] -2-pyrrolidin-1-yl-ethanone;
(2-methoxy-5-trifluoromethoxy-benzyl) - (1- [1,2,4] oxadiazol-3-ylmethyl-2-phenyl-piperidin-3-yl) -amine;
Methyl} -6-methoxy-l-methyl-3,4-dihydro-lH-quinolin-2- On;
[1- (2-Imidazol-1-yl-ethyl) -2-phenyl-piperidin-3-yl] - (2-methoxy-5-trifluoromethoxy-benzyl) -amine;
Methyl] -6-methoxy-1-methyl-3, 4-dihydro-lH- Quinolin-2-one;
(5-Chloro-2-ethoxy-pyridin-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(5-Chloro-2-methoxy-pyridin-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
Dibenzofuran-2-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
[3- (Indan-2-yloxy) -4-methoxy-benzyl] - (2-phenyl-piperidin-3-yl) -amine;
6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -chroman-4-one;
(5-Methyl-benzo [b] thiophen-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(2,2-dimethyl-chroman-6-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(LH-benzoimidazol-5-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
1- {2 - [(2-Phenyl-piperidin-3-ylamino) -methyl] -phenyl} -pyrrolidin-2-one;
(2-Phenyl-piperidin-3-yl) - [3- (pyridin-2-yloxy) -benzyl] -amine;
[3- (4-Methoxy-phenoxy) -benzyl] - (2-phenyl-piperidin-3-yl) -amine;
(4-phenoxy-benzyl) - (2-phenyl-piperidin-3-yl) -amine;
(2-phenyl-piperidin-3-yl) -thiophen-2-ylmethyl-amine;
Furan-2-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
(5-methyl-furan-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(3-methyl-thiophen-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(2-phenyl-piperidin-3-yl) -thiophen-3-ylmethyl-amine;
(3-Methyl-benzo [b] thiophen-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
Benzofuran-2-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
(5-ethyl-furan-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(5-Chloro-3-methyl-l-phenyl-lH-pyrazol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
3-ylamino] -methyl} -l-methyl-3, 4-dihydro-lH- Quinolin-2-one;
(5-Methyl-3-phenyl-isoxazol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(3-phenoxy-benzyl) - (2-phenyl-piperidin-3-yl) -amine;
Furan-3-ylmethyl- (2-phenyl-piperidin-3-yl) -amine;
(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(5,7-dimethoxy-lH-indol-4-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(5-methoxy-lH-indol-3-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(4-oxy-quinoxalin-2-ylmethyl) - (2-phenyl-piperidin-3-yl) -amine;
(2-phenyl-piperidin-3-yl) -quinoxalin-2-ylmethyl-amine;
Propyl) -2-phenyl-piperidin-3-ylamino] -methyl} -6-methoxy-1-methyl-3,4-dihydro -1H-quinolin-2-one;
(2-methoxy-5-trifluoromethoxy-benzyl) - [2-phenyl-l- (2-pyrrolidin-l-yl-ethyl) -piperidin-3-yl] -amine;
6-Ethoxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
[1- (2-Dimethylamino-ethyl) -2-phenyl-piperidin-3-yl] - (2-methoxy-5-trifluoromethoxy-benzyl) -amine;
3- (2-Cyclopropoxy-5-trifluoromethoxy-phenyl) -6-phenyl-1-oxa-7-aza-spiro [4.5] decane;
[1- (2-Methoxy-ethyl) -2-phenyl-piperidin-3-yl] - (2-methoxy-5-trifluoromethoxy-benzyl) -amine;
6-Hydroxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
Cyclopenta [b] pyrrol-3-ylamino) -methyl] -3,4-dihydro-1 H-quinolin-2-one To a solution of 6-methoxy- ;
7 - {[2- (4-Fluoro-phenyl) -piperidin-3-ylamino] -methyl} -6-methoxy-3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1-methyl-7- (6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;
Cyclopenta [b] pyrrol-3-ylamino) -methyl] -1,3-dihydro-indol-2-one To a solution of 6-methoxy-1,3,3-trimethyl- -On;
[3-Chloro-2- (4-fluoro-phenoxy) -pyridin-4-ylmethyl] - (2-phenyl-piperidin-3-yl) -amine;
6-Ethoxy-1,3,3-trimethyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
Methyl-l, 3-dihydro-indol-2 &lt; RTI ID = -On;
6-Isopropoxy-l, 3,3-trimethyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
Cyclopenta [b] pyrrol-3-ylamino) -methyl] -l, 3-dihydro-indol- 2-one;
Methyl-l, 3-dihydro-indol-2 &lt; RTI ID = -On;
Cyclopenta [b] pyrrol-3-ylamino) -methyl] -l, 3-dihydro-indol- 2-one;
7-Isopropoxy-l-methyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1-methyl-7 - [(6-methyl-2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1,3,3-trimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1,3-dimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1,3-dimethyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
6-Methoxy-1-methyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
Methyl-6-methoxy-l, 3,3-trimethyl-l, 3-dihydro-indol-2- On;
6-Methoxy-1-methyl-7 - [(2-phenyl-1-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
3-ylamino] -methyl} - 3 - {[1- (5-methyl-3H-imidazol- 4-dihydro-1H-quinolin-2-one;
3-ylamino] -methyl} -6-methoxy-1-methyl-3, 4-dihydro- &lt; / RTI &gt;-1H-quinolin-2-one;
7 - [(l-isopropyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-l-methyl-3,4-dihydro-lH-quinolin-2-one;
Methyl-3, 4-dihydro-1 H-quinolin-2-one &lt; / RTI &gt;;
Methyl-6-methoxy-l, 3,3-trimethyl-l, 3-dihydro-indol-2- On;
Methyl-7 - {[1- (5-oxo-2,5-dihydro-1H- [1,2,4] triazol- Pyridin-3-ylamino] -methyl} -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
1-Ethyl-6-methoxy-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
1-Methanesulfonyl-6-methoxy-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1,4,4-trimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl) -3,4-dihydro-1H-quinolin-2-one;
6-methoxy-1,4,4-trimethyl-7 - [(2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro- 2-one;
6-Methoxy-1-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1,4-dimethyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-2-methyl-7 - [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-2H-isoquinolin-1-one;
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a ] Naphthalen-2-one;
6-Methoxy-1-methyl-3,3-cyclopropyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
5-Methoxy-1-methyl-3,3-cyclopropyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
6-Methoxy-l-methyl- (6-phenyl-l, 7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-lH-quinolin-2-one;
6-Methoxy-1-methyl-7-phenyl-1,7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;
3-methyl-5 - [(1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) -methyl] -1,1a, 3,7b-tetrahydro- 3-aza-cyclopropa [a] naphthalen-2-one;
Methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thiobenzo [c] [1,2] thiazin- (2-phenyl-piperidin-3-yl) -amine;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
6-Methoxy-1-methyl-7- (6-phenyl-1, 7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;
2,3-b] pyridin-2-ylmethyl] -1,3-dihydro-pyrrolo [2,3- b] Pyridin-2-one;
3-dihydro-pyrrolo [3,2-b] pyridin-2-ylmethyl] Pyridin-2-one;
Methyl-7- [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridin- ;
7 - [(6-Ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
Methyl-6-methoxy-l, 3,3-trimethyl-l, 3-dihydro-indol-2-one ;
2,3-b] pyridin-2-ylmethyl] -1,3-dihydro-pyrrolo [2,3- b] Pyridin-2-one;
3-dihydro-pyrrolo [3,2-b] pyridin-2-ylmethyl] Pyridin-2-one;
Methyl-7- [(2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridin- ;
Methyl-7 - [(6-methyl-2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridine Gt;
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H- [1,5] naphthyridine Gt;
Methyl-7- [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H- [1,5] naphthyridine Gt;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one; And
6-Methoxy-1-methyl-7- (6-phenyl-1, 7-diaza-spiro [4.5] dec-3-yl) -3,4-dihydro-1H-quinolin-2-one.
[59" claim-type="Currently amended] 2. A compound according to claim 1 selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:
Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one;
(1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one;
6-Methoxy-1-methyl-7 - [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
7 - [(6-Ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
6-Methoxy-1-methyl-7 - [(6-methyl-2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
3-ylamino) -methyl] -6-methoxy-1-methyl-3, 4-dihydro-isoquinolin- LH-quinolin-2-one;
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one ;
3-ylamino) -methyl] -6-methoxy-1-methyl-3, 4-dihydro-isoquinolin- LH- [1,5] naphthyridin-2-one;
Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one;
^{(6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2. 6-benzo} [c] [1,2] thiazine-7-ylmethyl) - ( 2-phenyl-piperidin-3-yl) -amine;
Methyl-1,3-dihydro-indol-2-one &lt; RTI ID = 0.0 &gt;;
Methyl-3,3-spirocyclopropyl-6 - [(2-phenyl-piperidin-3- ylamino) -methyl] -1,3-dihydro-indol- ;
5-Methoxy-1-methyl-3,3-cyclobutyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
6-Methoxy-1-methyl-3,3-cyclopentyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
6-Methoxy-1-methyl-3,3-cyclohexyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
(1S, 2S, 5R) - (1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) - Methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1R, 1S, 5S) - (1-phenyl-8-aza- bicyclo [3.2.1] oct- 2- ylamino) - Methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(2-methoxy-5-trifluoromethoxy-benzyl) - ((lS, 2S, 5R) -1-phenyl-8-azabicyclo [3.2.1] oct-2-yl) -amine;
(2-methoxy-5-trifluoromethoxy-benzyl) - ((1R, 2R, 5S) -1-phenyl-8-azabicyclo [3.2.1] oct-2-yl) -amine;
(1S, 2S, 5R) - (1-phenyl-8-azabicyclo [3.2.1] oct- 2- yl) -amine) -Methyl] -l, 3-dihydro-indol-2-one; And
^{(6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2. 6-benzo} [c] [1,2] thiazine-7-ylmethyl) - ( 2-phenyl-piperidin-3-yl) -amine.
[60" claim-type="Currently amended] 60. The compound according to claim 59 selected from the group consisting of:
Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one monohydrochloride;
(1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
(1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
(1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
(1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one monohydrochloride;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one monohydrochloride;
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one monohydrochloride;
Methyl-7 - [(2-phenyl-6-propyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- Chloride;
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one monohydro- Chloride;
Methyl-7 - [(6-methyl-2-phenyl-piperidin-3- ylamino) -methyl] -3,4-dihydro-1H-quinolin- Chloride;
Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one monohydrochloride;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one monohydrochloride; And
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one monohydrochloride.
[61" claim-type="Currently amended] 60. The compound according to claim 59 selected from the group consisting of:
Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one mono- (D) -lactate;
(1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
(1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
(1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
(1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one mono- (D) -lactate;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) La, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (D) -lactate;
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one mono- (D) -lactate;
Methyl-7-isopropyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin- (D) -lactate;
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2- (D) -lactate;
6-Methoxy-l-methyl-7 - [(6-methyl-2-phenyl-piperidin- (D) -lactate;
Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalen-2-one mono- (D) -lactate;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one mono- (D) -lactate; And
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalen-2-one mono- (D) -lactate.
[62" claim-type="Currently amended] 60. The compound of claim 59, selected from the group consisting of: &lt; RTI ID = 0.0 &gt;
Methyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalene-2-one mono- (L) -lactate;
(1S, 1aR) -5- [(2S, 3S, 6S) - (6-ethyl- 2- phenyl- piperidin- 3- ylamino) -methyl] -6- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
(1R, 1aS) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
(1R, 1aS) -5- [(2S, 3S, 6S) - (6-ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
(1S, 1aR) -5- [(2R, 3R, 6R) - (6-Ethyl- 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalene-2-one mono- (L) -lactate;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3R, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
(1R, 1aS) -6-methoxy-3-methyl-5 - [(2S, 3S, 6S) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
(1S, 1aR) -6-methoxy-3-methyl-5 - [(2R, 3R, 6R) 1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalene-2-one mono- (L) -lactate;
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalene-2-one mono- (L) -lactate;
Methyl-7-isopropyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin- (L) -lactate;
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2- (L) -lactate;
6-Methoxy-l-methyl-7 - [(6-methyl-2-phenyl-piperidin- (L) -lactate;
Methyl-6-methoxy-3-methyl-l, l, 3,7b-tetrahydro-3-aza-cyclohexyl- Propa [a] naphthalene-2-one mono- (L) -lactate;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalene-2-one mono- (L) -lactate; And
3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclohexylcarbamate Propa [a] naphthalene-2-one mono- (L) -lactate.
[63" claim-type="Currently amended] Compounds selected from mixtures of isomers and isomers of the following compounds having stereochemistry of the structure &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &
6-Methoxy-1-methyl-7 - [(2-phenyl-6-propyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one;
7 - [(6-isopropyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
Methyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one ;
7 - [(6-isobutyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;
7 - [(1,2,3,4,5,6-hexahydro- [2,3 '] bipyridinyl-3-ylamino) -methyl] -6-methoxy- - dihydro-1H-quinolin-2-one;
7 - [(1,2,3,4,5,6-hexahydro- [2,4 '] bipyridinyl-3-ylamino) -methyl] -6-methoxy- - dihydro-1H-quinolin-2-one;
(6-methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thiobenzo [c] [1,2] thiazin- 2-phenyl-piperidin-3-yl) -amine;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclohexane-2-carboxylic acid Propa [a] naphthalen-2-one;
Methyl-3,3-cyclopropyl-5 - [(6-methyl-2-phenyl-piperidin- 2-one;
Aza-bicyclo [3.2.1] oct-2-ylamino) -methyl] -1,3-dimethyl-3,3-cyclopropyl- Dihydro-indol-2-one;
6-Methoxy-1-methyl-3,3-cyclohexane-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
6-Methoxy-1-methyl-3,3-cyclopentyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
Methyl-3,3-cyclopropyl-5 - [(2- (4- fluorophenyl) -piperidin-3- ylamino) -methyl] -1,3-dihydro -Indol-2-one;
6-Methoxy-1-methyl-3,3-cyclobutyl-5 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
5-Methoxy-1-methyl-3,3-cyclobutyl-6 - [(2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indol-2-one;
Methyl-3,3-cyclopropyl-6 - [(6-methyl-2-phenyl-piperidin- 2-one;
Methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclopropane &lt; / RTI &gt; [a] naphthalen-2-one;
7 - [(1,2,3,4,5,6-hexahydro- [2,2 '] bipyridinyl-3-ylamino) -methyl] -6-methoxy- - dihydro-1H-quinolin-2-one; And
6 - [(6-Ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -5-methoxy-1,1-dimethyl- indan-2-one.
[64" claim-type="Currently amended] In a mammal, including a human, comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1, there is provided a method of treating mood disorders such as depression, more particularly depressive disorders, (Including anorexia, weight loss, insomnia, premature ejaculation and mental retardation), atypical depression (or reactive depression) (increased appetite, excessive sleep, psychomotor retardation or irritation hypersensitivity), depressive disorder, depressive and neurotic depression, melancholic depression , Seasonal affective disorder and pediatric depression); Or bipolar disorder or bipolar disorder, for example Type I bipolar disorder, Type II bipolar disorder and cyclic mood disorder; Impaired conduct and disruptive behavior; Anxiety disorders such as panic disorder with or without plaque panic, plaque without panic disorder history, specific phobia such as certain animal phobia, social anxiety, social phobia, compulsive personality disorder, stress disorder (posttraumatic stress disorder and acute stress Disorders), and generalized anxiety disorder; Borderline personality disorder; Schizophrenia and other psychotic disorders such as schizophreniform disorders, schizoaffective affective disorders, delusional disorders, short term psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic anxiety episodes, psychotic disorders Anxiety, psychotic mood disorders such as severe major depressive disorder; Mood disorders associated with psychotic disorders, such as depression associated with acute mania and bipolar disorder, mood disorders associated with schizophrenia; Mental retardation related behavioral disorder, autism disorder, and conduct disorder.
[65" claim-type="Currently amended] Dementia, dementia, and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), in mammals, including humans, comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1. & , Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorders, vascular dementia and other dementias such as HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease and Creutzfeldt- Dementia due to multiple causes, or multiple causes; (Including familial paroxysmal ataxia, ankylosing spondylitis, Tourette's syndrome, Scott's syndrome, PALSYS, and anorexic-spasticity syndrome); Such as neuroleptic-induced parkinsonism, neuroinflammatory syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute insufficiency, neuroleptic-induced delayed-movement disorder, and drug-induced disorders Satellite advance; The use of alcohol, amphetamine (or amphetamine-like substance), caffeine, hemp, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioid agents, phenylglycidine derivatives, sedatives, Diseases (drug related illnesses include dependency and abuse, addiction, withdrawal, addictive delerium and pessimistic delerium); Addictive behavior, such as gambling; epilepsy; Down syndrome; Acute pain, chronic pain and migraine; Dehydrating diseases such as multiple sclerosis (MS) and amylolateral sclerosis (ALS), peripheral neuropathy such as diabetic and chemotherapy-induced neuropathy and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia , And cerebrovascular diseases resulting from acute or chronic cerebrovascular injury, such as cerebral infarction, subarachnoid hemorrhage, or cerebral angioedema.
[66" claim-type="Currently amended] In particular, the present invention relates to a method for the treatment of respiratory diseases, particularly respiratory diseases associated with excessive mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis , Adult respiratory distress syndrome, and bronchospasm; Inflammatory diseases such as inflammatory bowel disease, psoriasis, Reiter's syndrome, Raynaud's syndrome, arthropathies, fibromyalgia, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, pruritus and sunburn; Human immunodeficiency virus (HIV) infections; allergies such as eczema and rhinitis, and other allergies; Hypersensitivity diseases such as lacquer sensitization; Eye diseases such as conjunctivitis, spring conjunctivitis and the like; Cell proliferative ocular symptoms such as proliferative vitreoretinopathy; A skin disease, such as contact dermatitis, atopic dermatitis, urticaria, and other eczema dermatitis.
[67" claim-type="Currently amended] A mammal comprising a therapeutically effective amount of a compound according to claim 1 in a mammal, including a mammal, comprising a neoplastic tumor comprising a mammary tumor, a gastric cancer type, a gastric lymphoma, a ganglion blastoma and a small cell carcinoma, &Lt; / RTI &gt;
[68" claim-type="Currently amended] Inflammatory bowel disease caused by gastrointestinal (GI) diseases such as inflammatory gastrointestinal diseases such as Helicobacter pylori in a mammal, including a human, comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 , And a method of treating a disease or condition selected from the group consisting of GI tract diseases such as gastritis, gastroduodenal ulcer, neurological disorders related to visceral organs, ulcerative colitis, Crohn's disease, irritable bowel syndrome and vomiting.
[69" claim-type="Currently amended] In a mammal, including a human, comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1; Reflex sympathetic dystrophy, such as shoulder / hand syndrome; Immunological adverse reaction reactions such as transplant rejection and immune enhancement or inhibition related diseases such as systemic lupus erythematosus; Plasma leakage due to cytokine chemotherapy; Bladder dysfunctions such as cystitis, bladder detrusor overactivity, urinary tract inflammation and urinary incontinence (including equine urinary incontinence, overactive bladder, stress urinary incontinence and mixed urinary incontinence); Fibrosis and collagen diseases such as scleroderma and eosinophilic fasiolosis; Blood flow disorders due to vasodilation and vasoconstrictive diseases such as angina and Raynaud's disease; Angiogenesis; Cardiovascular disease; Dietary diseases such as anorexia nervosa and neurogenic bulimia; Attention deficit hyperactivity disorder; Chronic fatigue syndrome; Sexual dysfunction including premature ejaculation and male erectile dysfunction; Premenstrual syndrome and premenstrual dysphoric disorder; Fibromyalgia; And a rheumatic disease, such as fibrous tissue inflammation.
[70" claim-type="Currently amended] In a mammal, including a human, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of mood disorders such as depression, more particularly depressive disorders such as monoplegic or recurrent major depressive disorder, (Including anorexia, weight loss, insomnia, premature ejaculation and mental retardation), atypical depression (or reactive depression) (increased appetite, excessive sleep, psychomotor retardation or irritation), depressed mood, depressive and neurotic depression, melancholic depression Hypersensitivity, seasonal affective disorder, and pediatric depression); Or bipolar disorder or bipolar disorder, for example Type I bipolar disorder, Type II bipolar disorder and cyclic mood disorder; Impaired conduct and disruptive behavior; Anxiety disorders such as panic disorder with or without plaque panic, plaque without panic disorder history, specific phobia such as certain animal phobia, social anxiety, social phobia, compulsive personality disorder, stress disorder (posttraumatic stress disorder and acute stress Disorders), and generalized anxiety disorder; Borderline personality disorder; Schizophrenia and other psychotic disorders such as schizophreniform disorders, schizoaffective affective disorders, delusional disorders, short term psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic anxiety episodes, psychotic disorders Anxiety, psychotic mood disorders such as severe major depressive disorder; Mood disorders associated with psychotic disorders, such as depression associated with acute mania and bipolar disorder, mood disorders associated with schizophrenia; Mental retardation related behavioral disorder, autism disorder, and conduct disorder.
[71" claim-type="Currently amended] Dementia and other cognitive or neurodegenerative disorders such as Parkinson's disease (PD), Hunting &lt; RTI ID = 0.0 &gt; (PD), &lt; / RTI &gt; in a mammal, including a human, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. Alzheimer's disease, Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory impairment, vascular dementia, and other dementias such as HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease and Creutzfeld- , Or multiple causes of dementia; (Including familial paroxysmal ataxia, ankylosing spondylitis, Tourette's syndrome, Scott's syndrome, PALSYS, and anorexic-spasticity syndrome); Such as neuroleptic-induced parkinsonism, neuroinflammatory syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute insufficiency, neuroleptic-induced delayed-movement disorder, and drug-induced disorders Satellite advance; The use of alcohol, amphetamine (or amphetamine-like substance), caffeine, hemp, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioid agents, phenylglycidine derivatives, sedatives, Diseases (drug related illnesses include dependency and abuse, addiction, withdrawal, addictive delerium and pessimistic delerium); Addictive behavior, such as gambling; epilepsy; Down syndrome; Acute pain, chronic pain and migraine; Dehydrating diseases such as multiple sclerosis (MS) and amylolateral sclerosis (ALS), peripheral neuropathy such as diabetic and chemotherapy-induced neuropathy and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia , And a cerebrovascular disease caused by acute or chronic cerebrovascular injury such as cerebral infarction, subarachnoid hemorrhage or cerebral angioedema.
[72" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier in a mammal, including a human, for use in the manufacture of a medicament for the treatment of respiratory diseases, particularly respiratory diseases associated with hyperglycemia, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, Fibrosis, adult respiratory distress syndrome, and bronchospasm; Inflammatory diseases such as inflammatory bowel disease, psoriasis, Reiter's syndrome, Raynaud's syndrome, arthropathies, fibromyalgia, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, pruritus and sunburn; Human immunodeficiency virus (HIV) infection; Allergies such as eczema and rhinitis, and other allergies; Hypersensitivity diseases such as lacquer sensitization; Eye diseases such as conjunctivitis, spring conjunctivitis and the like; Cell proliferative ocular symptoms such as proliferative vitreoretinopathy; A pharmaceutical composition for the treatment of a disease or condition selected from the group consisting of skin diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczema dermatitis.
[73" claim-type="Currently amended] Comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier in a mammal, including a human, comprising a neoplastic tumor comprising a breast tumor, a gastric carcinoma, a gastric lymphoma, a ganglion blastoma and a small cell carcinoma, Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt;
[74" claim-type="Currently amended] (GI) disease, including inflammatory gastrointestinal disease, such as inflammatory bowel disease caused by helicobacter pylori , in a mammal, including a human, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. , And a pharmaceutical composition for treating a disease or condition selected from the group consisting of GI tract diseases such as gastritis, gastroduodenal ulcer, visceral neural control diseases, ulcerative colitis, Crohn's disease, irritable bowel syndrome and vomiting.
[75" claim-type="Currently amended] In a mammal, including a human, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier; Reflex sympathetic dystrophy, such as shoulder / hand syndrome; Immunological adverse reaction reactions such as transplant rejection and immune enhancement or inhibition related diseases such as systemic lupus erythematosus; Plasma leakage due to cytokine chemotherapy; Bladder dysfunctions such as cystitis, bladder detrusor overactivity, urinary tract inflammation and urinary incontinence (including equine urinary incontinence, overactive bladder, stress urinary incontinence and mixed urinary incontinence); Fibrosis and collagen diseases such as scleroderma and eosinophilic fasiolosis; Blood flow disorders due to vasodilation and vasoconstrictive diseases such as angina and Raynaud's disease; Angiogenesis; Cardiovascular disease; Dietary diseases such as anorexia nervosa and neurogenic bulimia; Attention deficit hyperactivity disorder; Chronic fatigue syndrome; Sexual dysfunction including premature ejaculation and male erectile dysfunction; Premenstrual syndrome and premenstrual dysphoric disorder; Fibromyalgia; And rheumatoid diseases, such as fibrotic tissue inflammation.
[76" claim-type="Currently amended] A compound of formula (II) or a pharmaceutically acceptable salt thereof.
&Lt;

In this formula,
Q is _{C = NH, C = CH 2} , C = S, C = O, SO or SO _2, and;
Y and Z are each N or CH, provided that Y and Z can not both be N;
W is a 1 carbon bridging group (i.e., methylene) or a saturated or unsaturated 2 or 3 carbon bridging group, wherein each W group is optionally substituted with 1 substituent R ⁷ or 2 substituents R ⁷ and R ⁶ Or W is a 1 carbon bridging group which together with the 2,3, 4 or 5 carbon chains forms a 3, 4, 5 or 6 membered spiro ring, respectively; or
W is a saturated 2 carbon chain bridging group which forms a fused 3, 4 or 5 membered ring with separate 1,2 or 3 carbon chains; or
W is a saturated 2 carbon chain bridging group in which one of the two carbons forms a 3, 4, 5 or 6 membered spiro ring with a separate 2,3 or 4 carbon chain, respectively;
R ⁵ and R ⁸ are hydrogen, -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl - (C ₁ -C ₂₎ alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) ₆₎ alkoxy, phenyl - (C ₁ -C ₃₎ alkoxy, phenyl, cyano, chloro, bromo, ^{iodo, NR 9 R 10, NR 9} COR 10, NR 9 CO 2 R 10, CONR 9 R 10, (C ₁ -C ₆ ) alkyl optionally substituted with one or more substituents independently selected from COR ⁹ and CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
R ⁶ and R ⁷ is -SO (C ₁ -C _{6) alkyl, -SO 2 - (C 1 -C} 6) alkyl, aryl -SO-, -S0 ₂ - aryl, CF _3, halo, phenyl, phenyl- (C ₁ -C ₂ ) alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, optionally substituted with 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 7 fluorine atoms, preferably 0 to 3 fluorine atoms, and hydroxy, oxo, (C ₁ -C ₆ ) (C ₁ -C ₃ ) alkoxy, phenyl, cyano, chloro, bromo, iodo, NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ And (C ₁ -C ₆ ) alkyl substituted with one or more substituents independently selected from CO ₂ R ⁹ , preferably with from 0 to 2 substituents;
Each R ⁹ and each R ¹⁰ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, phenyl and CF ₃ ;
R ^5, R ^6, R ⁷ and R ⁸ in the definition of a phenyl group and R ^5, R ^6, the definition of R ⁷ and R ⁸ -phenyl (C ₁ -C ₂₎ alkyl in the phenyl moiety is optionally substituted by halo, hydroxy, 1 to the seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ - C ₆ ) alkyl, preferably with 0 to 2 substituents independently selected from alkyl;
R ¹⁴ is hydrogen, (C ₁ -C ₆ ) alkyl or CF ₃ ;
(A) R ⁸ can not be halo, hydroxy, cyano, aryloxy, heteroaryloxy, substituted or unsubstituted (C ₁ -C ₆ ) alkoxy, or methyl substituted with 1 to 3 fluorine atoms .
[77" claim-type="Currently amended] 78. The compound of claim 76, selected from the group consisting of: &lt; RTI ID = 0.0 &gt;
5-Dimethoxymethyl-6-methoxy-3-methyl-l, lla, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1S, 1aR) -5-Dimethoxymethyl-6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
(1R, 1aS) -5-Dimethoxymethyl-6-methoxy-3-methyl-l, lla, 3,7b-tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;
6-Methoxy-3-methyl-2-oxo-l, 2,3,7b-tetrahydro-lH-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde;
(1S, 1aR) -6-methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde;
(1R, 1aS) -6-methoxy-3-methyl-2-oxo-1a, 2,3,7b-tetrahydro-1H-3-aza-cyclopropa [a] naphthalene-5-carbaldehyde;
5-Methoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo [3,2-b] pyridine-6-carbaldehyde;
6-methoxy-l, 3,3-trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo [2,3-b] pyridine-5-carbaldehyde;
3-Methoxy-8-methyl-7-oxo-5,6,7,8-tetrahydro- [1,8] naphthyridine-2-carbaldehyde; And
2-Methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro- [1,5] naphthyridine-3-carbaldehyde.
[78" claim-type="Currently amended] A compound or a pharmaceutically acceptable salt thereof of the formula T-NH _2.

In this formula,
p is 0, 1 or 2;
R ³ is selected from hydrogen, COR ⁹ , CO ₂ R ⁹ , optionally substituted phenyl, optionally substituted heterocyclic ring and optionally substituted (C ₁ -C ₈ ) alkyl, wherein said (C ₁ -C ₈₎ one of the alkyl CH ₂ lifter may be substituted with a sulfur, oxygen or a carbonyl group, the (C ₁ -C ₈₎ alkyl, hydroxy, oxo, phenyl, - (C ₁ -C ₃₎ alkoxy, phenyl, cyano NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ , CO ₂ R ⁹ , NR ⁹ R ¹⁰ , and 1 to 7 fluorine atoms, optionally substituted heterocyclic rings, NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , Optionally substituted with one to three substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
R ³ in the heterocyclic ring, and 3- to 7-membered saturated or unsaturated monocyclic ring, and one to four ring heteroatoms which heterocyclic ring substituents on the alkyl groups of R ³ contain from 1 to 4 ring heteroatoms And wherein the heteroatom is independently selected from oxygen, nitrogen and sulfur, with the proviso that the monocyclic or bicyclic heterocyclic ring , There can not be two adjacent ring oxygen atoms or two adjacent ring sulfur atoms and the heterocyclic ring formed from NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ must contain at least one nitrogen atom;
R ³ heterocyclic heterocyclic on the alkyl group of the cyclic ring, and R ³ of the ring substituent is ^{_{(CH 2) m NR 9 R}} 10, NR 9 COR 10, oxo, hydroxy, thioxo, halo, cyano, phenyl, ( CH ₂ ) _m OR ⁹ , wherein m is 0, 1 or 2, and optionally substituted with one or more substituents independently selected from halo, CF ₃ , methoxy and phenyl, preferably 0 to 2 substituents Optionally substituted with one or more substituents independently selected from (C ₁ -C ₆ ) alkyl, preferably 0 to 2 substituents;
Phenyl substituent on the alkyl group of R ³ groups and R ³ are optionally substituted with halo, cyano, _{nitro, CF 3, (CH 2)} m NR 9 R 10 ( at this time, m is 0, 1 or 2), NR ⁹ COR ^{10 _{, NR 9 CO 2 R 10,}} CONR 9 R 10, CO 2 NR 9 R 10, COR 9, CO 2 R 9, 1 to 7 fluorine atoms, preferably with 0-3 fluorine atoms an optionally substituted (C ₁ C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine the reactor is optionally substituted (C ₂ -C ₆₎ one or more substituents independently selected from alkenyl, preferably, may be optionally substituted with 0-2 substituents;
Each R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ is hydrogen and at least one substituent independently selected from hydroxy, oxo, (C ₁ -C ₆ ) alkoxy and cyano, preferably 0, (C ₁ -C ₆ ) alkyl optionally substituted with one or two substituents; or
R ¹ and R ² together with the carbon atoms to which they are attached or R ² and R ³ together with the carbon and nitrogen to which they are attached contain 5 or 5 heteroatoms independently selected from nitrogen, Or a six membered saturated heterocyclic ring with the proviso that the ring may not contain two adjacent oxygen atoms or two adjacent sulfur atoms; Or R ¹ and R ² form a 5 or 6 membered saturated or unsaturated carbocyclic ring together with the carbon to which they are attached, and at this time, the heterocyclic group formed from R ¹ and R ² or R ² and R ^3, and carbocyclic ring optionally substituted with halo, oxo, NR ⁹ R ^10, one to seven fluorine atoms, preferably from zero to three fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkyl, and one to seven fluorine atoms, Preferably one or more substituents independently selected from (C ₁ -C ₆ ) alkoxy optionally substituted by 0 to 3 fluorine atoms, preferably 0 or 1 substituent; or
R ¹² and R ¹³ , together with the carbon atoms to which they are attached, form a 5 or 6 membered saturated heterocyclic ring containing one or two heteroatoms independently selected from nitrogen, oxygen and sulfur provided that the ring has 2 Or two adjacent sulfur atoms, or R ¹² and R ¹³ together with the carbon to which they are attached form a 5 or 6 membered saturated or unsaturated carbocyclic ring, wherein R ¹² and the heterocyclic group formed from the R ¹³ and the carbocyclic ring is NR ⁹ R ^10, halo, phenyl, -S-, -SO- phenyl, phenyl -SO ₂ -, oxo, one to seven fluorine atoms, preferably 0 to 3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkoxy, and one to seven fluorine atoms, preferably with 0-3 fluorine atoms, optionally substituted (C ₁ -C ₆₎ each of which is independently selected from alkyl One or more substituents, preferably 0, or it can be optionally substituted with 1 substituent;
With the proviso that only one of R ¹ and R ² , R ² and R ³ , and R ¹² and R ¹³ may form a ring;
R ⁴ is selected from phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, and pyrimidyl wherein R ⁴ is halo, 1-7 fluorine atoms, preferably 0 (C ₁ -C ₆ ) alkyl optionally substituted by one to three fluorine atoms, (C ₁ -C ₆ ) alkoxy optionally substituted by from 1 to 7 fluorine atoms, preferably from 0 to 3 fluorine atoms, and from 1 to 7 Optionally substituted with one or more substituents independently selected from fluorine atoms, preferably (C ₂ -C ₆ ) alkenyl optionally substituted with 0 to 3 fluorine atoms, preferably 0 or 1 substituent;
Each R ⁹ and each R ¹⁰ is independently selected from hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, phenyl and CF ₃ ; or
When R ³ is NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ , R ⁹ and R ¹⁰ together with the nitrogen to which they are attached may form an optionally substituted heterocyclic ring containing one or more nitrogen atoms.
[79" claim-type="Currently amended] 78. The compound of claim 78, selected from the group consisting of &lt; RTI ID = 0.0 &gt;
6-Methyl-2-phenyl-piperidin-3-ylamine;
(2S, 3S, 6S) -6-methyl-2-phenyl-piperidin-3-ylamine;
(2R, 3R, 6R) -6-methyl-2-phenyl-piperidin-3-ylamine;
6-ethyl-2-phenyl-piperidin-3-ylamine;
(2S, 3S, 6S) -6-ethyl-2-phenyl-piperidin-3-ylamine;
(2R, 3R, 6R) -6-Ethyl-2-phenyl-piperidin-3-ylamine;
5-Methyl-2-phenyl-piperidin-3-ylamine;
5-ethyl-2-phenyl-piperidin-3-ylamine;
5-Propyl-2-phenyl-piperidin-3-ylamine;
5,5-diethyl-2-phenyl-piperidin-3-ylamine;
5,5-dimethyl-2-phenyl-piperidin-3-ylamine;
6,6-dimethyl-2-phenyl-piperidin-3-ylamine;
8-Benzyl-1-phenyl-8-aza-bicyclo [3.2.1] oct-2-ylamine; And
(LS, 2S, 5R) or (lR, 2R, 5S) l-phenyl- 8-aza- bicyclo [3.2.1] oct- 2- ylamine.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-04-10|Priority to US19592200P

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2000-04-10|Priority to US60/195,922

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2000-06-20|Priority to US21292200P

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2000-06-20|Priority to US60/212,922

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2001-04-06|Application filed by 화이자 프로덕츠 인크.

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2001-04-06|Priority to PCT/IB2001/000629

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2002-11-21|Publication of KR20020087134A

优先权:

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申请号 | 申请日 | 专利标题

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US19592200P| true| 2000-04-10|2000-04-10|

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US60/195,922|2000-04-10|

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US21292200P| true| 2000-06-20|2000-06-20|

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US60/212,922|2000-06-20|

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PCT/IB2001/000629|WO2001077100A2|2000-04-10|2001-04-06|Benzoamide piperidine compounds as substance p antagonists|