Substituted 1-aminoalkyl-lactams and their use as muscarinic receptor antagonists

专利摘要:
The present invention relates to a compound represented by the following formula (I), which is an M2 / M3 muscarinic receptor antagonist: Formula I Where One of X, Y or Z is independently —S—, —O—, —CH 2 — or> NR 6 , and the other is —CH 2 —; m is an integer from 0 to 3; n is an integer from 1 to 6; R 4 is (C 1-6 ) -alkyl; R 5 is independently at each occurrence (C 1-6 ) -alkyl, (C 1-6 ) -alkenyl, (C 1-6 ) -alkynyl or cycloalkyl; R 1 , R 2 and R 3 are hydrogen or certain substituents. These compounds are effective in treating diseases associated with smooth muscle disorders.
公开号:KR20030003763A
申请号:KR1020027015885
申请日:2001-05-16
公开日:2003-01-10
发明作者:드보락찰스알로이스；피셔로렌스에머슨；그린키나린；해리스랄프뉴3세；매그한스；프린스앤쏘니；렙케데이비드브루스；스테블러러셀스티븐
申请人:에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

SUBSTITUTED 1-AMINOALKYL-LACTAMS AND THEIR USE AS MUSCARINIC RECEPTOR ANTAGONISTS} as substituted 1-aminoalkyl-lactams and muscarinic receptor antagonists
[13] Surprisingly, it has been found that the compound of formula I is an M2 / M3 selective muscarinic receptor antagonist.
[14] Acetylcholine (Ach) is a major transporter of the parasympathetic nervous system. The physiological action of Ach is mediated by the activity of nicotinic or muscarinic receptors. All of these receptor classes are heterogeneous. For example, the muscarinic receptor class consists of five subtypes (M ₁ , M ₂ , M ₃ , M ₄ and M ₅ ) each encoded by a unique gene and having unique pharmacological and distribution properties.
[15] Almost all smooth muscle tissue contains both muscarinic M2 and M3 receptors, all of which play a functional role. The number of M2 receptors prevails at a rate of approximately 4 to 1 over the M3 receptors. In general, the M3 receptor mediates the direct contractile effect of acetylcholine in most extensive smooth muscle tissues. M2 receptors, on the other hand, indirectly cause smooth muscle contraction by sympathetically inhibiting (β-adrenergic receptor) -mediated relaxation.
[16] Compounds that act as antagonists of muscarinic receptors have been used to treat some disease states associated with inadequate smooth muscle function. Until recently, most of these compounds were nonselective for a variety of muscarinic receptor subtypes, resulting in unpleasant anticholinergic side effects such as oral dryness, constipation, unclear vision or tachycardia. Most of these side effects are oral dryness resulting from obstruction of muscarinic receptors in the salivary glands. Recently developed M2 or M3 specific antagonists have been suggested to reduce side effects. This implicitly demonstrates that simultaneous occlusion of M2 and M3 receptors can be therapeutically effective in the treatment of disease states associated with smooth muscle disorders.
[17] Very few M2 / M3 selective antagonists have been developed. The present invention satisfies this conventional need by providing these types of antagonists useful for the treatment of disease states associated with inadequate smooth muscle function.
[18] More information about muscarinic receptor subtypes and their antagonists can be obtained from the following references. Specific subtypes of muscarinic receptors in smooth muscle are described in Ehlert et al., Life Sciences 1997 , 61, 1729-1740. Hedge et al., Life Sciences 1999 , 64, 419-428, refer to muscarinic receptor subtypes that regulate smooth muscle contractility in the bladder. Eglen et al ., Trends. Pharmacol. Sci. 1994 , 15, 114-119 and Eglen et al ., Pharmacol. Rev. 1996 , 48, 531-565, mention certain muscarinic receptor subtypes and smooth muscle function. Clinical studies of selective muscarinic antagonists are described in Nielvebrant et al., Life Sciences 1997 , 60, 1129-1136; Alabaster, Life Sciences 1997 , 60, 1053-1060; Osayu et al ., Drug Res. 1994 , 44, 1242-1249 and Homma et al., Neurourology and Urodynamics 1997 , 345-346. Selective modulation of muscarinic receptor subtypes has been reported in Emerging Drugs 1998 , 3, 67-79. Eglen et al ., Curr. Opin. Chem. Biol. 1999 , 3, 426-432, mention muscarinic receptor ligands and their therapeutic potential. Specific classification of muscarinic acetylcholine receptors is described in Caulfield et al., Pharmacological Reviews 1998 , 50 (2), 279-290.
[19] The following documents describe compounds associated with compounds of Formula (I). U. S. Patent No. 5,693, 630, assigned to Astra Aktebolag, mentions certain phenylethyl- and phenylpropylamines for treating mental disorders. U.S. Pat.Nos. 5,382,595, 5,177,089, 5,047,417 and 5,607,953, assigned to Eisai Co., Ltd., refer to certain butenoic and propenoic acid derivatives. US Pat. No. 3,354,178, assigned to Sterling Drug Inc., certain N- (4-amino-2-butynyl) -N-alkyl-carboxamides useful as anxiety stimulants of the central nervous system. And 4,065,471. U.S. Patent Nos. 4,087,541 and 4,038,407, assigned to Boehringer Ingelheim GmbH, mention certain 2- (aralkylaminoalkyl) phthalimidines useful for lowering heart rate. U. S. Patent No. 4,490, 369, assigned to Dr. Karl Thomae GmbH, mentions certain benzazine derivatives and their use as bradycardiac. U. S. Patent No. 3,054, 794, assigned to US Vitamin & Pharmaceutical Co., refers to a process for preparing 3- (aminoalkyl) -oxazolidine-2,4-dione. Certain benzene derivatives for treating ischemic disease are described in US Pat. No. 5,998,452, assigned to Chugai Seiyaku Kabushiki Kaisha. Benzothiazepine vasodilators with aralkyl substituents are disclosed in US Pat. No. 4,729,994 assigned to McNeilab Inc. Franco Patent No. 2,302,733 assigned to Dr. Carl Thomas to Geembeha mentions certain arylalcoylamines, and European Patent No. 259,793 assigned to Dr. Carlo Thomas to Geembeha refers to certain naphthyl derivatives. F. WO 9943657, assigned to F. Hoffmann-La Roche AG, refers to certain 2-arylethyl- (piperidin-4-ylmethyl) amine derivatives as muscarinic receptor antagonists. Certain 1-ethyl-3- (2-dialkylaminoethyl) -hexahydro-pyrimidin-2-ones are described in Singh et al. Indian Journal of Chemistry 1976 , 14, 528-531. . Glozman et al., Khim.-Farm.Zh. 1996 , 30 (4), 11-14, refers to certain substituted 1- (dialkylaminoalkyl) -4-phenylpyrrolidin-2-ones.
[20] All patent publications, patent documents, and patent applications cited herein are hereby incorporated by reference in their entirety.
[21] An object of the present invention is a heterocyclylalkylamine derivative of formula (I), a prodrug thereof, a racemic or non-racemic mixture of individual isomers or isomers, or a pharmaceutically acceptable salt or solvate. The present invention also contains one or more compounds of formula (I), their prodrugs, individual racemates or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates in admixture with one or more suitable carriers in a therapeutically effective amount. It relates to a pharmaceutical composition. In a more preferred embodiment, the pharmaceutical composition is suitable for administration to a subject having a disease state that is alleviated by treatment with a muscarinic M2 / M3 receptor antagonist.
[22] In another aspect, the invention relates to the use of said compound in treating a subject having a disease state that is alleviated by treatment with a muscarinic M2 / M3 receptor antagonist. In a preferred embodiment, the subject has a smooth muscle disorder, preferably a genitourinary disorder, a respiratory tract disorder, a gastrointestinal disorder; More preferably urogenital disorders such as hyperactive bladder or bladder muscle hyperactivity, and their symptoms such as urgency, frequent, reduced bladder dose, incontinence episodes, and the like; Urodynamic symptoms such as bladder dose, urination threshold, unstable bladder contraction, sphincter spasm, etc .; And conditions usually manifested as idiopathic hyperreflection (neuropathic bladder) in detrusor conditions, such as detrusor obstruction, pelvic hypersensitivity, and the like, or detrusor instability. In another preferred embodiment, the disease includes respiratory tract disorders such as allergy and asthma. In another preferred embodiment, the disease state comprises a gastrointestinal disorder.
[23] In another aspect, the present invention
[24] a) reacting a compound of formula II with a compound of formula III to yield a compound of formula I;
[25] b) (i) reacting an aryl metal compound of formula IV with a compound of formula V to yield a compound of formula VI, (ii) reducing the compound of formula VI and then cyclizing, wherein R ⁵ L, wherein L Is a leaving group) to obtain a compound of formula VII, (iii) reducing the compound of formula VII and treating with a compound of formula II to obtain a compound of formula I; or
[26] c) (i) reducing the compound of formula VI, followed by cyclization, (ii) treating the compound of formula VI with a compound of formula VIII, (iii) reducing the product to give a compound of formula IX, and (iv A process for the preparation of a compound according to claim 1 comprising alkylating a compound of formula IX with a suitable aldehyde or a compound of formula R ⁵ L wherein L is a leaving group to obtain a compound of formula I :
[27] Formula I
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37] Where
[38] R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, n, X, Y and Z are as defined above,
[39] M is a metal or magnesium halide,
[40] R is alkyl, aryl or arylalkyl,
[41] R ^a and R ^b are alkyl or alkoxy or together with the nitrogen to which they are attached form a ring,
[42] L is a leaving group.
[43] Unless otherwise indicated, the following terms used in the specification and claims have the meanings given below. As used in the specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.
[44] "Lower alkyl" means a monovalent linear or branched saturated hydrocarbon radical having 1 to 6 carbon atoms unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl, secondary-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.
[45] "Substituted lower alkyl" is lower alkyl as defined herein comprising one to three, preferably one, substituents such as hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro, thiol, and the like. Means. The substituents may be attached to any carbon atom of the lower alkyl moiety. Examples of substituted lower alkyl radicals include 2-methoxyethyl, 2-hydroxy-ethyl, dimethyl-aminocarbonylmethyl, 4-hydroxy-2,2-dimethyl-butyl, trifluoromethyl, trifluorobutyl And the like, and the like.
[46] "Alkylene" means a divalent linear or branched saturated hydrocarbon radical having 1 to 6 carbon atoms unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
[47] "Alkenyl" means a monovalent linear or branched unsaturated hydrocarbon radical containing 2 to 6 carbon atoms unless otherwise indicated. Examples of alkenyl radicals include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-butenyl, and the like.
[48] "Alkynyl" means a monovalent linear or branched unsaturated hydrocarbon radical containing 2 to 6 carbon atoms and unless otherwise indicated. Examples of alkynyl radicals include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, propargyl, and the like.
[49] "Alkoxy" means a radical of the formula -O-R wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy and the like.
[50] "Aryl", unless otherwise indicated, consists of one individual ring, or of one or more fused rings in which one or more rings are aromatic in nature, optionally hydroxy, cyano, lower alkyl, lower alkoxy, lower halogen Alkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsul Monovalent aromatic carbocyclic radicals, which may be substituted with one or more, preferably one or two substituents selected from, such as phenylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino and the like it means. Alternatively, two adjacent atoms of the aryl ring may be substituted with methylenedioxy or ethylenedioxy groups. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, tert-butyl-phenyl, 1,3-benzodioxolyl, and the like.
[51] "Arylalkyl" (or "aralkyl") means a radical of the formula R'R ", wherein R 'is an aryl radical as defined herein and R" is an alkyl radical as defined herein. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl, and the like.
[52] "Cycloalkyl", unless otherwise indicated, consists of one or more rings, preferably one or two rings, having from 3 to 8 carbon atoms per ring, optionally hydroxy, cyano, lower alkyl, lower alkoxy, lower Halogenalkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, aryl Monovalent saturated carbocyclic, which may be substituted with one or more, preferably one or two substituents selected from sulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino and the like. Means radicals. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cycloheptyl, and the like.
[53] "Cycloalkylalkyl" means a radical of the formula R'R "-, wherein R 'is a cycloalkyl radical as defined herein and R" is an alkyl radical as defined herein. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.
[54] "Heteroaryl" means one or more rings incorporating one or more, preferably one or two, heteroatoms (selected from nitrogen, oxygen, or sulfur) in the ring and 4 to 8 atoms per ring, unless otherwise indicated, Preferably having 1 to 3 rings, optionally hydroxy, cyano, lower alkyl, lower alkoxy, lower halogenalkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkyl Amino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, etc. It means a monovalent aromatic cyclic radical, which may be substituted with one or more, preferably one or two substituents selected from. Examples of heteroaryl radicals include imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benz Imidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzenesulfonyl-thiophenyl, and the like. It is not limited.
[55] "Heteroarylalkyl" (or "heteroaralkyl") means a radical of the formula R'R "where R 'is a heteroaryl radical as defined herein and R" is an alkylene radical as defined herein. do. Examples of heteroarylalkyl radicals include, but are not limited to, 2-imidazolylmethyl, 3-pyrrolylethyl, and the like.
[56] "Heterocyclyl" means one or more rings, preferably 3 to 8 atoms per ring, in which one or more ring heteroatoms (selected from N, O or S (O) _0-2 ) are incorporated unless otherwise indicated Consists of 1 or 2 rings, optionally hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower halogenalkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, Alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino By monovalent saturated cyclic radicals, which may be substituted with one or more, preferably one or two substituents selected from the like and the like. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and the like.
[57] A "heterocycloalkyl" (or "heterocyclylalkyl") is a radical of the formula R'R "where R 'is a heterocyclic radical as defined herein and R" is an alkylene radical as defined herein. Means. Examples of heterocycloalkyl radicals include, but are not limited to, 1-piperazinylmethyl, 2-morpholinomethyl, and the like.
[58] "Halogen" means radical fluoro, bromo, chloro and / or iodo.
[59] "Halogenalkyl" means a lower alkyl radical as defined herein substituted at any position with one or more halogen atoms as defined herein. Examples of halogenalkyl radicals include 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Without limitation.
[60] "Hydroxyalkyl" means a lower alkyl radical as defined herein substituted with one or more hydroxy groups. Examples of hydroxyalkyl radicals include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3 -Dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxy-ethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxy Oxypropyl, and the like.
[61] "Alkylthio" means a radical of the formula -SR wherein R is a lower alkyl radical as defined herein. Examples of alkylthio radicals include, but are not limited to, methylthio, butylthio, and the like.
[62] "Alkylamino" means a radical of the formula -NR'R "wherein R 'is a heterocyclic radical as defined herein and R" is hydrogen or lower alkyl as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, (1-methylpropyl) amino, dimethylamino, methylethylamino, diethylamino, hydroxyethyl-ethylamino, methoxyethyl-ethylamino, and the like.
[63] "Acyloxy" means a radical of the formula -OC (O) R wherein R is a lower alkyl radical as defined herein. Examples of acyloxy radicals include, but are not limited to, acetoxy, propionyloxy and the like.
[64] "Alkoxycarbonyl" or "alkyl ester" means a radical of the formula -C (O) -0-R, wherein R is a lower alkyl radical as defined herein. Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, secondary-butoxycarbonyl, isopropyloxycarbonyl, and the like.
[65] "Aryloxycarbonyl" or "aryl ester" means a radical of the formula -C (O) -O-R, wherein R is an aryl radical as defined herein. Examples of aryloxycarbonyl radicals include, but are not limited to, phenyl esters, naphthyl esters, and the like.
[66] "Arylalkoxycarbonyl" or "arylalkyl ester" means a radical of the formula -C (O) -O-RR 'wherein R is a lower alkyl radical and R' is an aryl radical as defined herein. . Examples of aryloxycarbonyl radicals include, but are not limited to, benzyl esters, phenyl ethyl esters, and the like.
[67] "Alkylcarbonyl" (or "acyl") means a radical of the formula R-C (O)-, wherein R is a lower alkyl radical as defined herein. Examples of alkylcarbonyl radicals include, but are not limited to, acetyl, propionyl, n-butyryl, secondary-butyryl, t-butyryl, iso-propionyl, and the like.
[68] "Arylcarbonyl" means a radical of the formula R-C (O)-, wherein R is an aryl radical as defined herein. Examples of arylcarbonyl radicals include, but are not limited to, benzoyl, naphthoyl, and the like.
[69] "Arylalkylcarbonyl" (or "aralkylcarbonyl") means a radical of the formula R-C (O)-, where R is an arylalkyl radical as defined herein. Examples of arylalkylcarbonyl radicals include, but are not limited to, phenylacetyl and the like.
[70] "Heteroarylcarbonyl" means a radical of the formula R-C (O)-, wherein R is a heteroaryl radical as defined herein. Examples of heteroarylcarbonyl radicals include, but are not limited to, pyridinoyl, 3-methylisoxazoloyl, isoxazoloyl, thienoyl, furoyl, and the like.
[71] "Heterocyclylcarbonyl" (or "heterocyclocarbonyl") means a radical of the formula R-C (O)-, wherein R is a heterocyclyl radical as defined herein. Examples of heterocyclylcarbonyl radicals include, but are not limited to, piperazinoyl, morpholinoyl, pyrrolidinoyl, and the like.
[72] "Cycloalkylcarbonyl" means a radical of the formula R-C (O)-, wherein R is a cycloalkyl radical as defined herein. Examples of cycloalkylcarbonyl radicals include, but are not limited to, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, and the like.
[73] "Alkylaminocarbonyl" means a radical of the formula -C (O) NR'R "wherein R 'is lower alkyl as defined herein and R" is hydrogen or lower alkyl as defined herein. Examples of alkylaminocarbonyl include, but are not limited to, methylaminocarbonyl, dimethylaminocarbonyl, t-butylaminocarbonyl, n-butylaminocarbonyl, iso-propylaminocarbonyl, and the like.
[74] "Arylaminocarbonyl" means a radical of the formula -C (O) NR'R "where R 'is aryl as defined herein and R" is hydrogen or aryl as defined herein. Examples of arylaminocarbonyl include, but are not limited to, phenylaminocarbonyl, methoxyphenylaminocarbonyl, diphenylaminocarbonyl, dimethoxyphenylaminocarbonyl, and the like.
[75] "Heteroarylaminocarbonyl" means a radical of the formula -C (O) NR'R "where R 'is heteroaryl as defined herein and R" is hydrogen or heteroaryl as defined herein. . Examples of heteroarylaminocarbonyl include, but are not limited to, pyridinylaminocarbonyl, thienylaminocarbonyl, furanylaminocarbonyl, and the like.
[76] "Alkylcarbonylamino" means a radical of the formula -NC (O) R 'wherein R' is lower alkyl as defined herein. Examples of alkylcarbonylamino include, but are not limited to, methylcarbonylamino, iso-propylcarbonylamino, t-butylcarbonylamino, and the like.
[77] "Arylcarbonylamino" means a radical of the formula -NC (O) R 'wherein R' is aryl as defined herein. Examples of arylcarbonylamino include, but are not limited to, phenylcarbonylamino, tosylcarbonylamino, and the like.
[78] "Alkylcarbamoyl" means a radical of the formula -OC (O) NR'R "where R 'is lower alkyl as defined herein and R" is hydrogen or lower alkyl as defined herein. Examples of alkyl carbamoyl include, but are not limited to, methyl carbamoyl, ethyl carbamoyl, and the like.
[79] "Arylcarbamoyl" means a radical of the formula -OC (O) NR'R "where R 'is lower aryl as defined herein and R" is hydrogen or aryl as defined herein. Examples of arylcarbamoyl include, but are not limited to, phenylcarbamoyl, naphthylcarbamoyl, and the like.
[80] "Arylalkylcarbamoyl" means a radical of the formula -OC (O) NHR'R ", wherein R 'is lower alkyl as defined herein and R" is aryl as defined herein. Examples of arylalkylcarbamoyl include but are not limited to benzylcarbamoyl, phenylethylcarbamoyl and the like.
[81] "Alkylaminosulfonyl" means a radical of the formula -S (O) ₂ NR'R "wherein R 'is lower alkyl as defined herein and R" is hydrogen or lower alkyl as defined herein. . Examples of alkylaminosulfonyl include, but are not limited to, methylaminosulfonyl, dimethylaminosulfonyl, and the like.
[82] "Arylaminosulfonyl" means a radical of the formula -S (O) ₂ NR'R "wherein R 'is aryl as defined herein and R" is hydrogen or aryl as defined herein. Examples of arylaminosulfonyl include, but are not limited to, phenylaminosulfonyl, methoxyphenylaminosulfonyl, and the like.
[83] "Heteroarylaminosulfonyl" means a radical of the formula -S (O) ₂ NR'R "where R 'is heteroaryl as defined herein and R" is hydrogen or heteroaryl as defined herein. do. Examples of heteroarylaminosulfonyl include but are not limited to thienylaminosulfonyl, piperidinylaminosulfonyl, furanylaminosulfonyl, imidazolylaminosulfonyl, and the like.
[84] "Alkylsulfonylamino" means a radical of the formula -NS (O) ₂ R 'wherein R' is lower alkyl as defined herein. Examples of alkylsulfonylamino include, but are not limited to, methylsulfonylamino, propylsulfonylamino, and the like.
[85] "Arylsulfonylamino" refers to a radical of the formula -NS (O) ₂ R 'wherein R' is lower alkyl as defined herein. Examples of arylsulfonylamino include, but are not limited to, phenylsulfonylamino, naphthylsulfonylamino, and the like.
[86] "Alkylsulfonyl" means a radical of the formula -S (O) ₂ R, wherein R is lower alkyl or substituted lower alkyl as defined herein. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, trifluoromethylsulfonyl, propylsulfonyl, and the like.
[87] "Arylsulfonyl" means a radical of the formula -S (O) ₂ R, wherein R is aryl as defined herein. Examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, nitrophenylsulfonyl, methoxyphenylsulfonyl, 3,4,5-trimethoxyphenylsulfonyl, and the like.
[88] "Heteroarylsulfonyl" means a radical of the formula -S (O) ₂ R, wherein R is heteroaryl as defined herein. Examples of heteroarylsulfonyl include but are not limited to thienylsulfonyl, furanylsulfonyl, imidazolylsulfonyl, N-methylimidazolylsulfonyl, and the like.
[89] "Heterocyclylsulfonyl" means a radical of the formula -S (O) ₂ R, wherein R is heterocyclyl as defined herein. Examples of heterocyclylsulfonyl include, but are not limited to, piperidinylsulfonyl, piperazinylsulfonyl, and the like.
[90] "Alkylsulfonyloxy" means a radical of the formula -OS (O) ₂ R, wherein R is lower alkyl or substituted lower alkyl as defined herein. Examples of alkylsulfonyloxy include, but are not limited to, methylsulfonyloxy, trifluoromethylsulfonyloxy, propylsulfonyloxy, and the like.
[91] "Optional" or "optionally" means that an event or environment described subsequently may, but does not necessarily need to occur, including both cases where and when such an event or environment does and does not occur. For example, "selective bond" means that a bond may or may not be present and includes single, double or triple bonds.
[92] "Leaving group" means a group having the meaning commonly used in synthetic organic chemistry, i.e., an atom or group which may be substituted under alkylation conditions. Examples of leaving groups include halogen, alkane- or alkylsulfonyloxy, for example methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy and thienyloxy, dihalogenphosphinoyloxy Optionally substituted benzyloxy, isopropyloxy, acyloxy and the like.
[93] "Protective group" or "protecting group" as used in synthetic chemistry means a group that selectively blocks one reaction site in a multifunctional compound so that the chemical reaction can be selectively carried out at another unprotected reaction site. Particular methods of the invention rely on protecting groups to block reactive oxygen atoms present in the reactants. Acceptable protecting groups for alcoholic or phenolic hydroxyl groups that can be removed successively and selectively include groups protected with acetates, halogenalkyl carbonates, benzyl ethers, alkylsilyl ethers, heterocyclyl ethers and methyl or alkyl ethers, and the like. Include. The protecting or blocking group for the carbonyl group is similar to the group described for the hydroxyl group and is preferably tert-butyl, benzyl or methyl ester. Examples of protecting groups include TW Greene et al., Protective Groups in Organic Chemistry , (J. Wiley, 2 ^nd ed. 1991 ), and Harrison et al., Compendium of Synthetic Organic Methods , Vols. 1-8 (J. Wiley and Sons 1971-1996 ).
[94] "Amino-protecting group" refers to a protecting group that refers to an organic group for protecting nitrogen atoms against undesirable reactions during the synthesis process, such as benzyl, benzyloxycarbonyl (carbenzyloxy, CBZ), p-methoxybenzyl Oxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. Preference is given to using BOC or CBZ as amino-protecting groups, as they are relatively easy to remove by weak acids such as trifluoroacetic acid or hydrochloric acid in ethyl acetate for BOC or by catalytic hydrogenation for CBZ.
[95] "Hydroxy-protecting group" means a protecting group that preserves hydroxy groups that are also modified by certain chemical reactions. Suitable hydroxy-protecting groups include ether-forming groups, benzyl or trityl groups optionally substituted with a phenyl ring, after all other reaction steps have been completed. Other suitable hydroxy-protecting groups include alkyl ether groups, tetrahydropyranyl, silyl, trialkylsilyl, ether groups and allyl groups.
[96] "Deprotection" or "deprotection" means a process in which a protecting group is removed after the selective reaction is completed. Certain protecting groups may be preferred over others because of the convenience or ease of removal. Deprotection reagents for protected hydroxyl or carboxyl groups include potassium carbonate or sodium carbonate, lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalysts or boron tribromide and the like.
[97] "Isomer" means a compound that has the same molecular formula but differs in nature, differs in the order of atomic bonding or differs in the arrangement of atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers", and stereoisomers that are non-overlapping mirror images are called "enantiomers" or sometimes optical isomers. Carbon atoms bonded to four nonidentical substituents are referred to as "chiral centers".
[98] "Cyral isomer" means a compound having one chiral center. Chiral isomers have two enantiomeric forms of opposite chirality, and can exist as individual enantiomers or as a mixture of enantiomers. A mixture containing the same amount of the opposing chiral individual enantiomeric forms is referred to as a "racemic mixture". Compounds having at least one chiral center have 2 ^n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds having one or more chiral centers may exist as individual diastereomers or as mixtures of diastereomers, referred to as "diastereomeric mixtures". If one chiral center is present, the stereoisomer may be characterized by the absolute arrangement of the chiral centers (R or S). Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Substituents attached to the chiral center under consideration are graded according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit . 1966 , 5, 385; errata 511; Cannes et al. Angew. Chem. 1966 , 78, 413; Cann and Ingold) J. Chem. Soc. 1951 (London), 612; Cannes et al. , Experientia 1956 , 12, 81; Cannes, J. Chem. Educ. 1964 , 41, 116).
[99] "Geoisomeric" means diastereomers which exist because of hindered rotation relative to a double bond. These arrangements are by cis or trans or Z and E used as prefixes indicating that the group is on the same or opposite side of the intramolecular double bond according to the Cahn-Ingold-Prelog law. Distinguished by name.
[100] "Atropic isomer" means isomers that exist because of the limited rotation caused by the rotational disturbance of large groups relative to the central bond.
[101] "Substantially pure" means that the desired enantiomer or stereoisomer is present at least about 80 mole percent, more preferably at least about 90 mole percent, most preferably at least about 95 mole percent.
[102] "Pharmaceutically acceptable" means that it is generally useful for preparing safe, nontoxic, biologically or otherwise desirable pharmaceutical compositions, and includes acceptable for pharmaceutical use in humans as well as animals.
[103] "Pharmaceutically acceptable salt" of a compound means salts that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound as defined herein. Such salts include the following compounds:
[104] (1) acid addition salts formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Or acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic Acids, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, etc. Acid addition salts formed using organic acids; or
[105] (2) Salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions, or in combination with an organic base or an inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
[106] Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid and phosphoric acid.
[107] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms (solvents) or crystalline forms (polymorphs) of the same acid addition salt as defined herein.
[108] By "crystal form" (or polymorph) is meant a crystal structure in which compounds can be crystallized in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically differ in X-ray diffraction pattern, infrared spectroscopy, melting point, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can predominate one crystal form.
[109] "Solvent compound" means a solvent addition form containing a stoichiometric or non stoichiometric amount of solvent. Some compounds have a tendency to form a solvate by catching a fixed molar ratio of solvent molecules in the crystalline solid state. The solvent compound formed when the solvent is water is a hydrate, and the solvent compound formed when the solvent is alcohol is an alcoholate. Hydrates are formed by combining one or more water molecules with one substance, where water remains in the molecular state as H ₂ O, and the combination may form one or more hydrates.
[110] "Prodrug" refers to a pharmacologically active form of a compound, which is administered to the metabolism to produce the desired pharmacological effect, followed by metabolism in vivo, such as by biological fluids or enzymes. do. Prodrugs can be metabolized before, during, after, or at specific sites. Metabolism occurs primarily for many compounds in the liver, but almost all other tissues and organs, especially the lungs, can change the degree of metabolism. Using the prodrug forms of the compounds, for example, to improve bioavailability, to improve target tolerance, such as to hide or reduce unpleasant properties such as bitter taste or gastrointestinal irritation, to change the solubility and extend for intravenous use. Or sustained release or delivery, improve the ease of formulation or provide site-specific delivery of the compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action , by Richard B. Silverman, Academic Press, San Diego, 1992 , Chapter 8: "Prodrugs and Drug delivery Systems" pp. 352-401, Design of Prodrugs , edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985 , Design of Biopharmaceutical Properties through Prodrugs and Analogs , ed. by EBRoche, American Pharmaceutical Association, Washington, 1977 and Drug Delivery Systems , ed. by RL Juliano, Oxford Univ. Press, Oxford, 1980 .
[111] "Subject" means mammals and non-mammals. Mammals include humans, non-human primates such as chimpanzees and other apes and monkey species; Farm animals such as cattle, horses, sheep, goats, and swine; Domestic animals such as rabbits, dogs, and cats; Means a member of a mammal including, but not limited to, laboratory animals including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds.
[112] A "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to have an effect on treatment for the disease state. A "therapeutically effective amount" depends on the compound, the disease state being treated, the disease or gastric neutrality being treated, the age and relative health state of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.
[113] As used herein, “pharmacological effect” includes effects occurring in a subject achieving the intended therapeutic purpose. In one preferred embodiment, the pharmacological effect means that the main signs of the subject being treated are prevented, alleviated or lowered. For example, a pharmacological effect is an effect that results in the prevention, alleviation or the reduction of major signs in the subject being treated. In another preferred embodiment, the pharmacological effect means that the disorder or symptom of the main sign of the subject being treated is prevented, alleviated or diminished. For example, a pharmacological effect is an effect that results in the prevention or degradation of major signs in the subject being treated.
[114] "Disease condition" means any disease, condition, symptom or sign.
[115] "Treatment" of a disease state includes:
[116] (1) preventing the disease state, i.e. not developing clinical symptoms of the disease state in a subject exposed to or susceptible to the disease state but not experiencing or exhibiting the symptoms of the disease state,
[117] (2) inhibiting the disease state, ie, arresting the development of the disease state or clinical symptoms thereof; or
[118] (3) alleviation of a disease state, ie, temporary or permanent degeneration of the disease state or its clinical symptoms.
[119] An “antagonist” means a molecule, such as a compound, drug, enzyme inhibitor or hormone, that reduces or prevents the action of another molecule or receptor site.
[120] "Urinary tract disorder" or "uropathy" as used interchangeably with "symptoms of the urinary tract" means a pathological change in the urinary tract. Symptoms of the urinary tract include overactive bladder (also known as bladder muscle hyperactivity), ventilator blockage, ventilator defects, and pelvic hypersensitivity.
[121] “Overactive bladder” or “bladder muscle hyperactivity” includes changes such as urgency, frequent, reduced bladder capacity, incontinence, and the like; Urethral changes such as bladder capacity, urination threshold, unstable bladder contraction, sphincter spasm, etc .; And conditions usually manifested as detrusor overreflection (neuropathic bladder) in idiopathic conditions such as ventilator blockage, ventilator defects, pelvic hypersensitivity, or detrusor instability.
[122] "Exhaust obstruction" includes but is not limited to benign prostatic hyperplasia (BPH), urethral stenosis, tumors, and the like. It usually manifests as symptoms such as obstructive (low flow rate, difficulty in initiating urination, etc.) or irritant (urgent, pain in the pubic bone).
[123] “Drainage defects” include, but are not limited to, urethral hypermotility, intrinsic sphincter deficiency, or mixed incontinence. This is usually a symptom of stress incontinence.
[124] "Pelvic hypersensitivity" includes, but is not limited to, pelvic pain, epileptic (cell) cystitis, prostadynia, prostatitis, vulvadynia, urethritis, testicular pain, and the like. It is manifested as pain, inflammation or discomfort associated with the pelvic area and usually includes overactive bladder symptoms.
[125] Nomenclature : Naming and numbering of the compounds of the present invention are illustrated below.
[126]
[127] In general, the nomenclature used herein is based on AUTOTONOM, a Beilstein Institute computerized system for the generation of IUPAC system nomenclature. For example, R ¹ is ethanesulfonyl, R ² and R ³ are H, R ⁴ is methyl, R ⁵ is ethyl, n is 3, m is 2, and X, Y and Z are CH The compound of general formula (I) which is _{2 is} named 1- (4-{[2- (4-ethanesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -azepan-2-one.
[128] Similarly, R ¹ is chloro, R ² and R ³ are H, R ⁴ is methyl, R ⁵ is propyl, n is 2, m is 1, X is N, Y and Z are CH The compound of general formula (I) which is _{2 is} named 1- [3-{[2- (4-chlorophenyl) -1-methylethyl] propylamino} propyl] -pyrimidin-2-one.
[129] Similarly, R ¹ is methanesulfonyl, R ² and R ³ are H, R ⁴ is methyl, R ⁵ is ethyl, n is 3, m is 2, X and Z are CH ₂ , Compound of formula (I), wherein Y is N-methanesulfonyl, is 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl] -4-methane-sulfonyl -[1,4] diazepan-2-one.
[130] Among the compounds of the present invention set forth in the Summary of the Invention, certain compounds of formula (I), or their prodrugs, individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates are preferred.
[131] R ¹ , R ² and R ³ are independently at each occurrence preferably hydrogen, halogen, (C _1-6 ) -alkyl, alkoxy, alkylsulfonyl or alkylsulfonyloxy, more preferably hydrogen, methoxy, methyl Sulfonyl or methylsulfonyloxy.
[132] Another preferred group is a 5 or 6 member, if R ¹ and R ² are adjacent to each other, optionally containing 0, 1 or 2 ring heteroatoms independently selected from nitrogen, oxygen or sulfur together with the ring to which they are attached; It is also possible to form monocyclic saturated or unsaturated rings, or more preferably, if R ¹ and R ² are adjacent to each other, together with the ring to which they are attached, naphthalene, indole, 2,3-dihydrobenzofuran, 2,3 -Dihydrobenzo [1,4] -dioxin, chromman, benzo [1,3] dioxol, benzo [1,3] oxathiolyl, benzo [1,3] oxathiol dioxide, even more preferably 2 Included are compounds that form, 3-dihydrobenzo [1,4] -dioxin.
[133] R ⁴ in each occurrence is independently preferably (C _1-6 ) -alkyl, more preferably methyl.
[134] R ⁵ is independently at each occurrence preferably (C _1-6 ) -alkyl, lower alkenyl or lower alkynyl, more preferably ethyl, propyl, iso-propyl, allyl or propargyl, even more preferably ethyl or Profile.
[135] m is preferably 0 to 3, more preferably 1 to 2, even more preferably 2, and n is preferably 1 to 6, more preferably 1 to 3, even more preferably 3.
[136] One of X, Y or Z is independently at each occurrence preferably -S-, -O-, -CH ₂ -or> NR ⁶ , more preferably -CH ₂ -or> NR ⁶ , even more preferably> NH.
[137] Particular preference is given to compounds of the formula I in which R ⁴ is methyl. In a more preferred embodiment, R ⁴ is methyl and m is 0.
[138] In another preferred embodiment R ⁴ is methyl and m is 1. An example of such a compound is 1- (2- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one. In a more preferred embodiment, R ⁴ is methyl, m is 1 and Y is> NR ⁶ .
[139] Examples of such compounds are as follows:
[140] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -piperazin-2-one,
[141] 1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] propyl-amino} -butyl) -4-methyl-piperazin-2-one, and
[142] N-Methyl-4-((S) -2-{[4- (2-oxo-piperazin-1-yl) -butyl] -propyl-amino} -propyl) -benzenesulfonamide.
[143] In another preferred embodiment R ⁴ is methyl, m is 2, more preferably R ⁴ is methyl, m is 2 and n is 3.
[144] Examples of such compounds are as follows:
[145] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one,
[146] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} -butyl)-[1,4] oxazepan-3-one, and
[147] 1,1,1-trifluoromethanesulfonic acid 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] -amino} propyl) -phenyl ester.
[148] Particular preference is given to compounds of the formula I in which R ⁴ is methyl, m is 2, one of X, Y or Z is> NR ⁶ and the other is -CH _2- . Even more preferred are compounds of formula I, wherein R ⁴ is methyl, m is 2 and X is> NR ⁶ . In another preferred embodiment, R ⁴ is methyl, m is 2, Y is> NR ⁶ , and in another preferred embodiment, R ⁴ is methyl, m is 2 and Z is> NR ⁶ .
[149] Even more preferred are compounds of formula I, wherein R ⁴ is methyl, m is 2, and Y is> NR ⁶ .
[150] Examples of such compounds are as follows:
[151] 1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-2-one,
[152] 1- (4- {ethyl-[(S) -1-methyl-2- (4-trifluoromethyl-phenyl) -ethyl] amino} -butyl)-[1,4] diazepan-2-one, And
[153] 1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] propyl-amino} -butyl) -4-methyl- [1,4] diazepane-2 -On.
[154] Particular preference is given to compounds of the formula I in which R ⁴ is methyl, m is 2 and Z is> NR ⁶ .
[155] Examples of such compounds are as follows:
[156] 4- (4- {allyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one,
[157] 4- (4-{[2- (4-tert-butylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one,
[158] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid ethyl ester,
[159] 4- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methyl-ethyl] propylamino} butyl)-[1,4] diazepan-5-one,
[160] Propane-2-sulfonic acid 4-((S) -2-{[4- (7-oxo- [1,4] -diazepin-1-yl) -butyl] -propyl-amino} -propyl) -phenyl Esters, and
[161] 4- (4-{[(S) -2- (2,3-dihydro-1,4-benzodioxin-6-yl) -1-methyl-ethyl] propyl-amino} -butyl)-[1 , 4] -diazephan-5-one.
[162] In another preferred embodiment, R ⁴ is methyl, m is 2 and one of X, Y or Z is —O— or —S—.
[163] Other preferred compounds of the present invention include pharmaceutically acceptable salts of the compounds of the present invention, wherein the pharmaceutically acceptable salts are hydrochloric acid, 2,2,2-trifluoroacetic acid, dibenzoyl-L-tartaric acid , Sodium or phosphoric acid, more preferably the salt is formed from hydrochloric acid, 2,2,2-trifluoroacetic acid or phosphoric acid. Even more preferably the salt is formed from hydrochloric acid.
[164] Compounds of the present invention can be prepared by the methods described in the exemplary synthetic schemes presented and described below.
[165] Starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or are described in Fieser and Fieser ( 1991 ), Reagents for Organic Synthesis ; Wiley & Sons: New York, Volumes 1-15, Rodd ( 1989 ), Chemistry of Carbon Compounds , Elsevier Science Publishers, Volumes 1-5 and Supplementals, and ( 1991 ) Organic Reactions , Wiley & Sons, New York, Volumes 1-40] are prepared by methods known to those skilled in the art according to the process set forth. The following synthetic schemes merely describe some of the ways in which the compounds of the present invention can be synthesized, and these synthetic schemes can be varied in a variety and can be modified by those skilled in the art with respect to the disclosure contained herein. It will be suggested that various modifications can be made.
[166] The starting materials and intermediates of the synthetic schemes can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like, if desired. Such materials can be characterized using conventional means, including physical constants and spectral data.
[167] Unless otherwise indicated, the reactions described herein are temperatures of about -78 to about 150 ° C, more preferably about 0 to about 125 ° C and most preferably near room temperature (or room temperature), such as about 20 ° C, under atmospheric pressure. Happens in
[168] In general, the compounds of formula (I) can be prepared by the processes described in the following schemes.
[169] Scheme A
[170] In general, Scheme A describes a process for the preparation of compounds of formula I, wherein X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as previously defined herein.
[171]
[172] Compounds of formula (I) can generally be prepared by coupling carboxaldehyde (1) and phenylalkylamine (2) under reductive amination conditions. Suitable reducing conditions include sodium triacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxide and sodium cyanoborohydride, hydrogen and metal catalysts, and hydrogen transfer agents such as cyclohexene, Treatment with formic acid and its salts, zinc and hydrochloric acid, formic acid, or borane dimethylsulfide, followed by formic acid. Suitable inert organic solvents for the reaction include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, alcohols or ethyl acetate, etc. Preferably, the reaction is sodium triacetoxybo in 1,2-dichloro-ethane. It is carried out under basic conditions using a low hydride.
[173] Reductive amination processes are described in the chemical literature. See, eg, J. Org. Chem. 1996 , 61, 3849 and Tetrahedron Letters 1996 , 37, 3977 describe the use of sodium triacetoxyborohydride as a reagent for reductive amination of aldehydes using a wide variety of amines. See, eg, J. Am. Chem. Soc. 1971 , 93, 2897 and in Org. Synth. Coll. 1988 , 6, 499 describe the use of sodium cyanoborohydride as a reagent for reductive amination of carbonyl compounds.
[174] Conventional starting materials of Scheme A are commercially available, known to those skilled in the art, or can be readily synthesized by those skilled in the art. For example, the starting material carboxaldehyde 1 can be readily synthesized as shown in Schemes 1, 2 and 3 below.
[175]
[176] Carboxaldehyde (1) wherein X, Y, Z, m and n are as defined above, the amido group of compound (a) under basic conditions is represented by the formula L (CH ₂ ) _n CH = CH ₂ , wherein L is By reacting with an alkylating agent of a leaving group such as halogen or methanesulfonyloxy, preferably chloro) to afford compound (b). After the alkylation reaction, the terminal alkene group of compound (b) is oxidized / divided into an aldehyde group to give carboxaldehyde (1). Various oxidants used for the oxidation / disruption of aldehydes of alkenes are described in the chemical literature. See, eg, J. Org. Chem. 1956 , 21, 478 describe methods using osmium tetraoxide and sodium (meth) periodate; Syn. Comm. 1982 , 12, 1063 describe methods using potassium permanganate and sodium (meth) periodate; J. Org. Chem. 1987 , 52, 3698 describe methods using potassium permanganate and silica gel; Chem. Rev. 1958 , 58, 925 describe methods using ozone; J. Org. Chem. 1986 , 51, 3213 describe methods using only potassium permanganate; J. Org. Chem. 1987 , 52, 2875 describe methods using sodium (meth) periodate and catalytic ruthenium. Preferably, the reaction is carried out using osmium tetraoxide and sodium (meth) periodate or ozone.
[177]
[178] Alternatively, the carboxaldehyde (1), wherein X, Y, Z, m and n are as defined above, is a compound of formula (a) where the free amine group is represented by the formula L (CH ₂ ) _n C (OR) ₂ , Can be prepared by reaction with an alkylating agent of a (C _1-6 ) -alkyl and L is a leaving group such as halogen, preferably bromo). After the alkylation reaction, the acetal group of compound (c) is hydrolyzed under acidic conditions to give carboxaldehyde (1).
[179]
[180] Alternatively, carboxaldehyde (1), wherein X, Y, Z, m and n are as defined above, represents aminoacetal (d) wherein R is (C _1-6 ) -alkyl with the formula L (CH ₂ ) _n COL ', L (CH _{2) n} OCOL', or L (CH _{2) n} n = C = O treated with a suitable acylating agent such as acylating agents of (wherein, L 'is a leaving group such as halogen, preferably chloro) Can be prepared by obtaining compound (e). After the acylation reaction, internal N-alkylation of the compound (e) is carried out, and subsequently, the acetal group (f) is hydrolyzed to obtain the carboxaldehyde (1).
[181] For example, the starting material phenylalkylamine (2) can be synthesized as shown in Schemes 4, 5 and 6.
[182]
[183] Phenylalkylamines (2), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, benzaldehyde (g) is reacted with nitroalkanes under noebenagel or Henry reaction conditions. After the reaction to obtain compound (h), the nitro group is reduced to an amino group and the alkene bond of compound (h) is reduced to give compound (i). Phenylalkylamine (2) reacts the free amine group of compound (i) with an aldehyde of formula RCHO under reducing amination conditions, or with an acylating agent of formula RCOL, followed by reduction, or an alkylating agent of formula R ⁵ L Obtained by reaction with (wherein R is (C _1-6 ) -alkyl, CH ₂ R is R ⁵ and L is a leaving group such as halogen).
[184]
[185] Phenylalkylamines (2), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in the Summary of the Invention, react the bromobenzene (j) with magnesium metal and alkenyl halides After k) is obtained, it is prepared by ozonolysis of compound (k) to obtain compound (1). Phenylalkylamine (2) can be prepared by subsequently treating compound (l) with a primary amine of the formula R ⁵ NH ₂ under reductive amination conditions. Various methods of synthesizing phenylalkylamines (2) are described in the chemical literature, such as in J. Med. Chem . 1973 , 23, 480-483; J. Med. Chem. 1986 , 29, 2009-2015; And in J. Med. Chem. 1991 , 34, 1662-1669.
[186]
[187] Alternatively, phenylalkylamine (2), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as previously defined herein, is of the formula n wherein R is alkyl, aryl or alkylaryl, more preferably Is benzyl, and R ^a and R ^b are alkyl or alkoxy or form a ring with the nitrogen to which they are attached, more preferably R ^a and R ^b form a morpholine ring) , More preferably by reacting with an aryl Grignard reagent of formula m to obtain a carbamic acid ester of formula o, wherein R is alkyl, aryl or alkylaryl, more preferably benzyl. Reduced with a weak reducing agent such as sodium or lithium borohydride or borane, preferably sodium borohydride, and then treated with a base such as potassium hydroxide or potassium tert-butoxide to form oxazolidin-2-one ( p) is obtained. The oxazolidinone (p) can be alkylated with an alkyl substituted with leaving group, preferably an alkyl halide, to give N-alkyloxazolidinone (q). Using a formate salt, preferably ammonium formate and palladium on carbon, cleavage of the oxazolidinone ring of compound (p) or compound (q) by hydrolysis to yield the corresponding chiral amphetamine of formula 2 or Can be obtained.
[188] Scheme B
[189] Scheme B is particularly a process for the preparation of compounds of formula I wherein X, Y and Z are each -CH ₂ -and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as previously defined herein. Describe.
[190]
[191] Compounds of formula IA can be prepared by proceeding as described in Scheme B. Preferably, the compound of formula IA can be prepared by reacting carboxaldehyde (1) with phenylalkylamine (2) under reducing amination conditions as described in Scheme B.
[192] An example of preparation of the compound of formula IA is shown in Example 1.
[193] Scheme C
[194] Scheme C is particularly wherein X is> NR ⁶ , -O- or -S-, Y and Z are each -CH ₂ -and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n have been Described are methods for the preparation of compounds of formula (I) as defined herein.
[195]
[196] Compounds of formula IB can be prepared by proceeding as described in Scheme C. Preferably, the compound of formula IB can be prepared by reacting carboxaldehyde (1b) with phenylalkylamine (2) under reducing amination conditions as described in Scheme C.
[197] An example of preparation of the compound of formula IB is shown in Example 2.
[198] Scheme D
[199] Scheme D in particular has X and Z each being -CH _2- , Y being> NR ⁶ , -O- or -S-, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , m and n describes a process for the preparation of a compound of formula (I) as previously defined herein.
[200]
[201] Compounds of formula ICa, ICb or ICc can be prepared by proceeding as described in Scheme D.
[202] Preferably, compounds of formula ICa wherein Y is —O— or —S— may be prepared by reacting carboxaldehyde (1c) with phenylalkylamine (2) under reductive amination conditions as shown in Scheme D. .
[203] Alternatively, a compound of formula ICc wherein Y is> NR ⁶ also couples the nitrogen protected carboxaldehyde (1d), wherein P is a suitable nitrogen-protecting group, with phenylalkylamine (2) under the conditions as described in Scheme A. Can be prepared by After this reaction, the nitrogen-protecting group of compound (3) is removed under acidic conditions to give a compound of formula ICb wherein Y is> NH. The compound of formula ICb can then be reacted with a suitable alkylating agent, acylating agent or sulfonylating agent by processes known to those skilled in the art to obtain a compound of formula ICc wherein R ⁶ is other than H.
[204] Examples of the preparation of compounds of formula ICa, ICb or ICc are shown in Examples 3, 4 and 5.
[205] Scheme E
[206] Scheme E in particular has X and Y each being -CH _2- , Z being> NR ⁶ , -O- or -S-, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , m and n describes a process for the preparation of a compound of formula (I) as previously defined herein.
[207]
[208] Compounds of formula IDa, IDb or IDc can be prepared by carrying out as shown in Scheme E.
[209] Preferably, compounds of formula IDa wherein Z is -O- or -S- can be prepared by reacting carboxaldehyde (1e) under the conditions as shown in Scheme E.
[210] Alternatively, a compound of formula IDc wherein Z is> NR ⁶ can be prepared by coupling an aminoprotected carboxaldehyde (1f) in which P is a suitable nitrogen-protecting group with phenylalkylamine (2) as described in Scheme E. Can be. Alternatively, compound (4) can be prepared by coupling with phenylalkylamine (2a) from amino-protected carboxaldehyde (1f), followed by reductive alkylation.
[211] The nitrogen-protecting group of compound (4) can be removed under acidic conditions to give a compound of formula IDb wherein Z is> NH. The compound of formula IDb can then be optionally reacted with a suitable alkylating agent, acylating agent or sulfonylating agent by processes known to those skilled in the art to obtain a compound of formula IDc wherein R ⁶ is other than H.
[212] Examples of the preparation of compounds of formula IDa, IDb or IDc are shown in Examples 6, 7 and 8.
[213] Scheme F
[214] Scheme F describes in particular the process for the preparation of compounds of formula (I), wherein X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as previously defined herein.
[215]
[216] Compounds of formula I can be prepared by proceeding as shown in Scheme F. Alternatively, the compound of formula (I) is N-alkylated oxazolidinone (5) by alkylating a suitably substituted oxazolidinone (p) with a compound of the formula r, wherein L is a leaving group, preferably a halide. It can be prepared by obtaining. If X, Y or Z is N, the secondary amino groups of compound r will be protected by processes known to those skilled in the art as previously described. After this reaction, the oxazolidinone ring is cleaved using the formate salt under hydrolysis conditions, such as in the presence of palladium hydroxide, to obtain the intermediate amine 6. The secondary amines of formula 6 are alkylated with the appropriate aldehydes under reductive amination conditions or alkylated with the appropriate alkyl halides as described in Scheme F to afford the desired compounds of formula (I). When X, Y or Z is N, the nitrogen protecting group can be removed under acidic conditions.
[217] Examples of the preparation of compounds of formula I by the method of Scheme F are described in Example 9.
[218] Compounds of the invention are muscarinic receptor antagonists. Compounds that act as antagonists of muscarinic receptors have been used to treat various disease states associated with inadequate smooth muscle function. Until recently, these compounds were mostly nonselective for various muscarinic receptor subtypes, causing unpleasant anticholinergic side effects such as dry mouth, constipation, unclear vision or tachycardia, the most common of which are muscarins in the salivary glands. Oral dryness resulting from sex receptor blockade. Recently developed M2 or M3 specific antagonists have been shown to reduce side effects. This mechanically demonstrates that simultaneous blocking of M2 and M3 receptors on M5 receptors can be therapeutically effective in the treatment of disease states associated with smooth muscle disorders such as urogenital disorders, airway disorders, gastrointestinal disorders and smooth muscle disorders.
[219] Urogenital disorders treatable with the compounds of the present invention include, in particular, changes in the symptoms of hyperactive bladder or bladder muscle hyperactivity, and symptoms thereof such as urgency, frequent, reduced bladder dose, incontinence experience, and the like; Urethral changes such as bladder capacity, urination threshold, unstable bladder contraction, sphincter spasm, etc .; And conditions usually manifested as idiopathic hyperreflection (neuropathy bladder) in detrusor conditions, such as detrusor obstruction, pelvic hypersensitivity, or detrusor instability.
[220] Gastrointestinal disorders treatable with the compounds of the present invention include, in particular, irritable bowel syndrome, divergent disease, inability to relax, gastrointestinal hypermotility and diarrhea. Airway disorders treatable with the compounds of the present invention specifically include chronic obstructive pulmonary disease, asthma and pulmonary fibrosis.
[221] Such or other therapeutic uses are described, for example, by Goodman & Gilman ( 1996 ) The Pharmacological Basis of Therapeutic , ninth edition, McGraw-Hill, New York, Chapter 26, 601-616 and Coleman, RA ( 1994 ) Pharmacological Reviews , 46, 205-229.
[222] Muscarinic receptor affinity of test compounds can be determined by in vitro receptor binding assays using cell membranes prepared from ovarian cells of Chinese hamsters expressing recombinant human muscarinic receptors (M ₁ -M ₅ ). This is described in more detail in Example 17.
[223] The muscarinic antagonist properties of the test compounds can be confirmed by an in vivo assay that determines the inhibitory activity on muscarinic receptor mediated saliva secretion in anesthetized rats, which is the oxotremorin / phylocarpine- of Example 18. It is described in more detail in the model Oxotremorine / Pilocarpine-induced salivation (OIS / PIS).
[224] The muscarinic antagonist properties of the test compounds can be confirmed by an in vivo assay that determines the inhibitory activity against muscarinic receptor mediated bladder contraction in anesthetized rats, which was determined in the volume induced contraction inhibition assay of Example 19. It is described in more detail.
[225] The muscarinic antagonist properties of the test compounds can be confirmed by in vivo assays that determine the inhibitory activity against muscarinic receptor mediated bladder contraction and saliva secretion in anesthetized dogs, which is described in more detail in Example 20.
[226] The present invention provides one or more pharmaceutically acceptable carriers and optionally together with one or more compounds of the invention, or prodrugs thereof, individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates Pharmaceutical compositions comprising other therapeutic and / or prophylactic ingredients.
[227] In general, the compounds of the present invention will be administered in a therapeutically effective amount by any mode of administration that is acceptable for agents that provide similar utility. Suitable dosage ranges depend on a number of factors, such as the neutrality of the disease being treated, the age and relative health of the subject, the efficacy of the compound used, the route and form of administration, the instructions for administration, and the preferences and experience of the physician. Thus, it is 1 to 500 mg, preferably 1 to 100 mg and most preferably 1 to 30 mg per day. One of ordinary skill in the art of treating such a disease will be able to ascertain the therapeutically effective amount of a compound of the invention for a particular disease in accordance with the knowledge of the individual and the disclosure herein without the need for inappropriate experimentation. In general, compounds of the invention include oral (including buccal and sublingual administration), rectal, intranasal, topical, pulmonary, intravaginal or parenteral (intramuscular, intraarterial, intradural, subcutaneous and intravenous administrations). Will be administered as a pharmaceutical formulation including a form suitable for administration, or a form suitable for administration by inhalation or infusion. A preferred mode of administration is oral administration using a suitable daily dosage regimen that can be adjusted according to the extent of pain.
[228] The compounds of the present invention in combination with one or more conventional adjuvants, carriers or diluents may be administered in pharmaceutical compositions and unit dosage forms. The pharmaceutical compositions and unit dosage forms may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage form may be comprised of any of the active ingredients similar to the intended daily dosage range used. It may contain a suitable effective amount. The pharmaceutical compositions of the present invention can be used as solids, semisolids, powders, sustained release formulations, such as tablets or filled capsules for oral administration, or liquids such as solutions, suspensions, emulsions or elixirs; Used in the form of suppositories for rectal or vaginal administration; Or in the form of sterile injectable solutions for parenteral use. Accordingly, formulations containing about 1 mg of active ingredient or more broadly about 0.01 to about 100 mg of active ingredient per tablet are suitable representative unit dosage forms.
[229] The compounds of the present invention can be formulated in a variety of oral dosage forms. The pharmaceutical compositions and dosage forms of the invention may comprise the compound (s) of the invention or a pharmaceutically acceptable salt thereof as the active ingredient. Pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid carriers may be one or more substances that may act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is generally a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain about 1 to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. It doesn't work. “Formulation” includes formulations of the active compound with the encapsulating material as a carrier, in the presence or absence of a carrier, providing a capsule in which the active ingredient is surrounded by a carrier associated with the encapsulating material. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be suitable for oral administration in solid form.
[230] Other suitable forms for oral administration include liquid formulations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid preparations that are converted to liquid formulations just prior to use. Emulsions may be prepared in solution in aqueous propylene glycol solution or may contain emulsifiers such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.
[231] Compounds of the invention are formulated for parenteral administration (eg, by injection, such as bolus injection or continuous infusion), and ampoules, pre-filled syringes, small infusions or multiple doses with added preservatives It may be provided in unit dosage form in a container. The composition may take the form of a suspension, a solution, or an emulsion in an oily or aqueous vehicle, such as a solution in an aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, and preservatives, wetting agents, emulsifiers, suspending agents. And formulating agents such as stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of sterile solids, consisting of a suitable vehicle such as sterile water free of pyrogen before use, or in powder form obtained by lyophilization from solution. have.
[232] The compounds of the present invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will generally contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents. Formulations suitable for topical administration to the oral cavity include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; And water-containing agents comprising the active ingredient in a suitable liquid carrier.
[233] The compounds of the present invention may be formulated for administration as suppositories. Low melt waxes such as mixtures of fatty acid glycerides or cocoa butter are first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a mold of the appropriate size and cooled to solidify.
[234] The compounds of the present invention may be formulated for nasal administration. The solution or suspension is administered directly to the nasal cavity by conventional means such as a dropper, pipette or spray. The formulations may be provided in a single dosage form or in multiple dosage forms. Dropping or multiple dosage forms of pipettes can be achieved by administering to a subject a suitable predetermined volume of solution or suspension. Multiple dosage forms of the spray can be achieved using, for example, a spray spray pump for weighing.
[235] The compounds of the present invention can be formulated for administration as an aerosol, particularly to the airways, including intranasal administration. The compound will generally have a small particle size, for example up to about 5 μm. Such particle diameters can be obtained by means known in the art, such as by miniaturization. The active ingredient is provided in a pressurized pack with a suitable propellant such as chlorofluorocarbons (CFCs) (e.g. dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), carbon dioxide or other suitable gas. do. Aerosols may also suitably contain surfactants such as lecithin. The dose of drug may be controlled by a weighed valve. Alternatively, the active ingredient is provided in the form of a powder mixture of compounds in suitable powder bases such as dry powders such as lactose, starch, starch derivatives (e.g. hydroxypropylmethyl cellulose) and polyvinylpyrrolidine (PVP). Can be. The powder carrier will form a gel in the nasal cavity. The powder composition may be provided in unit dosage form, such as a capsule or cartridge of a gelatin or blister pack into which the powder may be administered via an inhaler.
[236] The compounds of the present invention may be formulated in a transdermal or subcutaneous drug delivery device. Such delivery systems are useful when the sustained release of the compound is necessary and difficult for the subject according to the treatment regimen. In the transdermal delivery system, compounds are often attached to skin-adhesive solid supports. Compounds of interest may also be combined with penetration enhancers, such as azone (1-dodecylazacycloheptan-2-one). Sustained release systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subcutaneous implants encapsulate the compound with a fat soluble membrane (such as silicone rubber) or a biodegradable polymer (such as polylactic acid).
[237] The pharmaceutical preparations of the invention are preferably in unit dosage form. In this form, the formulation is divided into unit doses containing an appropriate amount of active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation such as packeted tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, casein or lozenge alone, or may be in a packaged form containing an appropriate number thereof.
[238] Other suitable pharmaceutical carriers and their formulations are described in Remington, The Science and Practice of Pharmacy , 1995 , edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative examples of pharmaceutical formulations containing a compound of the present invention are described in Examples 10-16.
[239] The following Preparation Examples and Examples can be presented to those skilled in the art to more clearly understand and to practice the present invention. Those skilled in the art should not be construed as limiting the scope of the present invention only as illustrative and representative of the present invention.
[1] The present invention relates to compounds of formula (I), or prodrugs thereof, individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts thereof:
[2]
[3] Where
[4] R ¹ , R ² and R ³ are independently at each occurrence hydrogen, halogen, (C _1-6 ) -alkyl, -OR ', -SR', -NR'R ", -SOR ', -SO ₂ R', -COOR ', -OCOR', -OCONR'R ", -OSO ₂ R ', -OSO ₂ NR'R";-NR'SO ₂ R ", -NR'COR", -SO ₂ NR'R ", -SO ₂ (CH ₂ ) _1-3 CONR'R ", CONR'R", cyano, halogenalkyl or nitro, or
[5] R ¹ and R ² , if adjacent to each other, optionally incorporate one or two ring heteroatoms selected from N, S (O) _0-2 or O together with the carbon to which they are attached and (C _1-6 ) -alkyl Can also form 5-7 membered aromatic saturated or unsaturated rings, optionally substituted with halogen, cyano or lower alkoxy;
[6] R 'and R "are each independently hydrogen, (C _1-6 ) -alkyl, substituted (C _1-6 ) -alkyl, (C _0-3 ) -alkyl-alkoxy, aryl, heterocyclyl, hetero Aryl, aryl- (C _1-3 ) -alkyl, heteroaryl (C _1-3 ) -alkyl, heterocyclyl- (C _1-3 ) -alkyl, cycloalkylalkyl, cycloalkyl, or nitrogen to which they are attached Together, it may also form a 5 to 7 membered ring, optionally incorporating one additional ring heteroatom selected from N, O or S (O) _0-2 ;
[7] R ⁴ in each occurrence is independently (C _1-6 ) -alkyl;
[8] R ⁵ is independently at each occurrence (C _1-6 ) -alkyl, (C _1-6 ) -alkenyl, (C _1-6 ) -alkynyl or cycloalkyl;
[9] One of X, Y or Z is independently —S—, —O—, —CH ₂ — or> NR ⁶ , and the other is —CH ₂ —;
[10] R ⁶ is hydrogen, (C _1-6 ) -alkyl, halogenalkyl, aryl- (C _1-6 ) -alkyl, heteroaryl- (C _1-6 ) -alkyl,-(C _1-6 ) -CR ′ R'R ', -COOR', -SO ₂ R ', -C (O) R', -SO _2- (CH ₂ ) _0-3 -NR'R ", -CONR'R", -C (O ) OCH ₂ OC (O) R ', -C (O) O-CH ₂ -SC (O) R' or -PO (OR ') ₂ , wherein R' and R "are as defined above;
[11] m is an integer from 0 to 3;
[12] n is an integer of 1-6.
[240] Preparation Example 1 (Preparation Example of Compound of Formula 1)
[241] 4- (2-oxo-azokane-1-yl) -butyraldehyde
[242] To a stirred solution of sodium hydride (0.9 g, 37.5 mmol) in dimethylformamide (50 mL) was added azocan-2-one (3.83 g, 30 mmol). The mixture was stirred for 15 minutes at room temperature, then 5-bromo-1-pentene (5.03 g, 33.7 mmol) was added slowly. The reaction mixture was stirred for 30 minutes at room temperature and then for 16 hours at 80 ° C. The solvent was removed under reduced pressure and water was added to the residue. The mixture was extracted with ethyl ether, the organic phase was washed with water, dried (with magnesium sulfate) and concentrated to give 1-pent-4-enyl-azonocan-2-one (5.53 g) as an oil.
[243] Osmium tetroxide (17 mg, 0.07 mmol) 1-pent-4-enyl-azokane-2-one (5.52) in a mixture of tetrahydrofuran (100 mL) and water (50 mL) under normal water bath cooling g, 28.3 mmol). The mixture was stirred for 5 minutes and solid sodium periodate (15.11 g, 70.65 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred for 3 hours and filtered. The filtrate was concentrated, saturated with solid sodium chloride and extracted with methylene chloride. The organic phase was dried (with magnesium sulfate) and concentrated. Purification by silica gel chromatography eluting with chloroform gave 4- (2-oxo-azokane-1-yl) -butyraldehyde (4.72 g).
[244] Similarly, follow the procedure as described above, optionally replacing azocan-2-one with another suitable compound of formula a and optionally 5-bromo-1-pentene with another suitable formula L (CH ₂ ) _n Substituting an alkylating agent of CH═CH ₂ , wherein L is a leaving group such as halogen, and following a modified procedure known to those skilled in the art, a compound of formula 1 was further prepared: 4- (5 -Oxo- [1,4] oxazepin-4-yl) -butyraldehyde; And 5-oxo-4- (4-oxobutyl)-[1,4] diazepan-1-carboxylic acid tert-butyl ester.
[245] Preparation Example 2 (Other Preparation Example of Compound of Formula 1)
[246] 5-oxo-4- (4-oxobutyl)-[1,4] diazepan-1-carboxylic acid tert-butyl ester
[247] To a suspension of 60% sodium hydride (0.2 g, 5 mmol) in mineral oil in N, N-dimethylformamide (6 mL) 5-oxo- [1,4] diazepane-1-carboxylic acid tert-butyl ester (1.0 g, 4.67 mmol) was added. The reaction mixture was allowed to warm at 50 ° C. for 5 minutes and then at room temperature for 15 minutes. To the resulting solution was added 4-bromobutyraldehyde dimethyl acetal (0.99 g, 5 mmol). The reaction mixture was stirred at rt for 16 h, then the solvent was removed and the residue partitioned between water and ethyl acetate. The organic phase was washed with water, dried (with magnesium sulfate) and concentrated. The residue was dissolved in diethyl ether, the suspension was filtered and the filtrate was concentrated. Purification by silica gel chromatography eluting with 2% methanol in chloroform to give 4- (4,4-dimethoxybutyl) -5-oxo- [1,4] diazephan-1-carboxylic acid tertiary- as a heavy syrup. Butyl ester (0.8 g) was obtained. NMR: (chloroform-d) δ (ppm) 1.49, s, (9H); 2.64, m, 3 H; 3.3.2, s (3H); 4.37, m, (1 H).
[248] 4- (4,4-dimethoxybutyl) -5-oxo- [1,4] diazepane-1-carboxylic acid tert-butyl ester (3 g, 9.08 mmol) in glacial acetic acid (10 mL) containing 0.5 mL of water ) Solution was stirred for 24 h at room temperature. The solution was concentrated under reduced pressure at 35 ° C. and the residue was partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The organic phase is dried (with magnesium sulfate), concentrated and the residue is recrystallized from diethyl ether / hexane to give 5-oxo-4- (4-oxobutyl)-[1,4] diazephan having a melting point of 86 to 87 ° C. -1-carboxylic acid tert-butyl ester (0.85 g) was obtained.
[249] Preparation Example 3 (Other Preparation Example of Compound of Formula 1)
[250] (2-oxo-piperidin-1-yl) -acetaldehyde
[251] To a stirred mixture of aminoacetaldehyde dimethylacetal (0.74 g, 7 mmol) and 2M sodium carbonate (20 mL) in ethyl acetate (20 mL) was added 5-chlorovaleryl chloride (1.55 g, 10 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phases were washed with 1% hydrochloric acid and water, dried (with magnesium sulfate) and concentrated. The oil residue was dissolved in tetrahydrofuran and sodium hydride (60% in oil) was added. The reaction mixture was heated at reflux for 1.5 hours and filtered. The filtrate was concentrated to give 1- (2,2-dimethoxyethyl) -piperidin-2-one (1.06 g) as pale yellow oil.
[252] A mixture of 1- (2,2-dimethoxyethyl) -piperidin-2-one (1.06 g, 5.67 mmol) in 5% aqueous tetrahydrofuran (20 mL) was heated at reflux for 1 hour. The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated to give (2-oxo-piperidin-1-yl) -acetaldehyde (0.69 g) as a pale yellow oil.
[253] 4- (2-oxo- [1,3] oxazocan-3-yl) -butyraldehyde
[254] To an ice-cold solution of 1.93 M phosgene in toluene (31 mL, 60 mmol), 5-chloro-1-pentanol (4.9 g, 40 mmol) in toluene (40 mL) and N, N-diethylaniline (5.97 g, 40 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered, and the solution was ice-cold of 4-aminobutyraldehyde diethylacetal (7.09 g, 44 mmol) and triethylamine (4.45 g, 44 mmol) in ethyl acetate (60 mL). It was added dropwise to the solution. The reaction mixture was stirred for 15 hours at room temperature, filtered and concentrated. Purification by silica gel chromatography eluting with 10% ethyl acetate in hexanes gave (4,4-diethoxybutyl) carbamic acid 5-chloro-pentyl ester (11.4 g) as an oil.
[255] Sodium hydride (1.01 g) without oil in a solution of (4,4-diethoxybutyl) carbamic acid 5-chloro-pentyl ester (11.4 g, 44 mmol) dissolved in N, N-dimethylformamide (100 mL) 42.3 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours and then at 70 ° C. for 3 hours. The mixture was diluted with water, saturated aqueous sodium chloride was added and extracted with ethyl ether. The organic phase was washed with water, dried (with magnesium sulfate) and concentrated. Recrystallization by silica gel chromatography gave 3- (4,4-diethoxybutyl)-[1,3] oxazocan-2-one (2.03 g) as a viscous oil.
[256] 3- (4,4-diethoxybutyl)-[1,3] oxazocan-2-one (2 g, 7.3 mmol) in 3% aqueous tetrahydrofuran (30 mL) and Dowex 50W2-200 ion exchange resin 1.5 The mixture of g was heated at reflux for 24 hours. The mixture was filtered, the filtrate was concentrated and dissolved in dichloromethane. The solution was dried over magnesium sulfate and concentrated to afford 4- (2-oxo- [1,3] oxazokan-3-yl) -butyraldehyde (1.45 g) solidified as viscous oil.
[257] 3- (2-oxo-tetrahydropyrimidin-1-yl) -propionaldehyde
[258] To a stirred ice cold solution of 3-aminopropionaldehyde diethylacetal (5.88 g, 40 mmol) in diethyl ether (35 mL) was added dropwise 3-chloropropyl isocyanate (4.78 g, 40 mmol). The reaction mixture was stirred for 4 hours at room temperature. The mixture was concentrated and dissolved in N, N-dimethylformamide (40 mL). To this solution was added oil-free sodium hydride (0.96 g, 40 mmol). The reaction mixture was stirred for 18 h at 70 ° C., concentrated, dissolved in diethyl ether (40 mL) and filtered. The filtrate was concentrated and re-purified by silica gel chromatography eluting with hexane-ethyl acetate-methanol (10: 9.7: 0.3) to give 1- (3,3-diethoxypropyl) -tetrahydro-pyrimidine- as an oil. 2-one (9.05 g) was obtained.
[259] 1- (3,3-diethoxypropyl) -tetrahydro-pyrimidin-2-one (1 g, 4.35 mmol) and 3 g of Dowex 50W2-200 ion exchange resin in 3% aqueous tetrahydrofuran (30 mL) The mixture was heated at reflux for 24 h. The mixture is filtered, the filtrate is concentrated and the residue is dissolved in dichloromethane (30 mL), dried over magnesium sulfate and concentrated to 3- (2-oxo-tetrahydropyrimidin-1-yl) -propionaldehyde (0.46 g) was obtained.
[260] Preparation Example 4 (Preparation Example of Compound of Formula 2)
[261] (R ¹ and R ³ = H, R ² = tert-butyl, R ⁴ = methyl, R ⁵ = ethyl)
[262] (S) -2- (4-tert-butylphenyl) -1-methylethyl-ethylamine
[263] Step 1:
[264] (S) -2- (4-tert-butylphenyl) -1-methyl-2-oxoethyl-carbamic acid benzyl ester (o)
[265] To a solution of 0.85 g (34.6 mmol) of magnesium turning in 25 mL of tetrahydrofuran, add 5 mL of a solution of 5 g (28.8 mmol) of 1-bromo-4-tert-butylbenzene in 25 mL of tetrahydrofuran It was. One iodine crystal and 1,2-dibromoethane (0.3 mL) were added and the mixture was heated to reflux to initiate the reaction. Then, the remaining 1-bromo-4-tert-butylbenzene solution was added dropwise and the reaction mixture was stirred for 1 hour at room temperature. The remaining magnesium was precipitated and the supernatant was washed with 8 g (27.4 mmol) of ((S) -1-methyl-2-morpholin-4-yl-2-oxoethyl) -carbamic acid benzyl ester (n) in 30 ml of tetrahydrofuran. ) And 30 mL (60 mmol) of 2M isopropylmagnesium chloride in diethyl ether were added dropwise to the pre-cooled mixture. The reaction mixture was stirred for 16 hours at room temperature. The mixture was then added to a well stirred mixture of 100 ml of 5% hydrochloric acid and crushed ice. The mixture was extracted with 50 ml of two ethyl acetate portions. The organic phase was washed with 25 mL saturated sodium chloride, dried (with magnesium sulfate) and concentrated under reduced pressure. 9.2 g of (S) -2- (4-tert-butylphenyl) -1-methyl-2-oxoethyl-carbamic acid benzyl ester (o) was isolated as a solid having a melting point of 156 to 158 ° C.
[266] Step 2:
[267] (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-oxazolidin-2-one (p)
[268] 9 g (26.5 mmol) of (S) -2- (4-tert-butylphenyl) -1-methyl-2-oxoethyl-carbamic acid benzyl ester (o) in 40 ml of toluene and 10 ml of 2-propanol A solution of 0.7 g (18.42 mmol) of 2 mL water sodium deuterium containing 1 drop of 50% sodium hydroxide was added dropwise. The reaction mixture was stirred for 15 hours at room temperature. The layers were separated and the organic phase was washed with 25 mL 10% sodium hydroxide. 2-propanol was removed under reduced pressure and the residual toluene solution was heated at reflux for 1 hour. The solvent was removed under reduced pressure. The residue was recrystallized from diethyl ether / hexane to give (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-oxazolidin-2-one (p) 3 at a melting point of 199 to 200 ° C. g was obtained.
[269] Similarly, following the procedure described above, the following compounds were prepared:
[270] (S) -5- (4-benzyloxyphenyl) -4-methyl-oxazolidin-2-one. Melting point 138 to 139 ° C;
[271] (S) -4-methyl-5- (4-trifluoromethylphenyl) -oxazolidin-2-one. Melting point 158-159 ° C., diethyl ether / hexane;
[272] (S) -5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -4-methyloxazolidin-2-one. M + H = 235; And
[273] (S) -4-methyl-5- (4-methylsulfanylphenyl) -oxazolidin-2-one. Melting point 112 to 114 ° C.
[274] Step 3:
[275] (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-3-ethyl-oxazolidin-2-one (q)
[276] A solution of 1 g (4.3 mmol) of (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-oxazolidin-2-one (p) in 10 ml of N, N-dimethylformamide To this was added 5.2 mL (5.2 mmol) of 1M potassium tert-butoxide in tetrahydrofuran. To the resulting gel was added 4 mL (4.7 mmol) of iodoethane. The reaction mixture was heated at 70 ° C. for 1 hour. Cold water (25 mL) was added and the mixture was extracted with 30 mL ethyl acetate. The organic phase was washed with two 10 ml portions of water, dried (with magnesium sulfate) and concentrated under reduced pressure. 1.06 g (M + H) (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-3-ethyl-oxazolidin-2-one (q) from ethyl acetate / hexane as crystalline solid = 261).
[277] Similarly, following the procedure described above, the following compounds were prepared:
[278] (S) -5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -4-methyl-3-propyl-oxazolidin-2-one. M + H = 277.
[279] Step 4:
[280] (S) -2- (4-tert-butylphenyl) -1-methylethyl-ethylamine
[281] 1 g (3.83 mmol) of (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-3-ethyl-oxazolidin-2-one in 20 ml of methanol, 2 g of ammonium formate ( 31.74 mmol) and 0.1 g of 10% palladium on carbon were heated at reflux for 2 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned between 10 ml of saturated sodium carbonate and 40 ml of ethyl acetate. The organic phase was dried (with magnesium sulfate) and concentrated under reduced pressure. 0.93 g of (S) -2- (4-tert-butylphenyl) -1-methylethyl-ethylamine having a melting point of 169.4 to 171.0 ° C. was isolated from the diethyl ether as a hydrochloride salt.
[282] Preparation Example 5 (Preparation Example of Compound of Formula 2)
[283] (R ¹ , R ³ and R ⁵ = H, R ⁴ = methyl, R ² = tert-butyl)
[284] (S) -2- (4-tert-butylphenyl) -1-methylethylamine
[285] 1 g (4.3 mmol) of (4S, 5S) -5- (4-tert-butylphenyl) -4-methyl-oxazolidin-2-one (p) in 25 ml of methanol (see step 2 of Preparation Example 4) ), A mixture of 2 g (31.74 mmol) of ammonium formate and 0.1 g of 10% palladium on carbon were heated at reflux for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between 10 ml of 10% saturated sodium carbonate and 25 ml of ethyl acetate. The organic phase was dried (with magnesium sulfate) and concentrated under reduced pressure. 0.93 g (95%) of the title compound as a hydrochloride salt having a melting point of 259.5 to 261.3 ° C. was isolated from diethyl ether.
[286] Example 1
[287] Preparation of Compounds of Formula (IA) Described in Scheme B)
[288] 1- (2- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} -ethyl) -azpan-2-one
[289]
[290] [2- (4-methoxyphenyl) -1-methylethyl] ethylamine (0.53 g, 2.75 mmol) in 1,2-dichloroethane (15 mL), (2-oxo-azpan-1-yl) acet A mixture of aldehyde (0.5 g, 3.2 mmol), and sodium triacetoxyborohydride (0.88 g, 4.1 mmol) was stirred at room temperature for 60 hours. The mixture was concentrated and the residue was partitioned in diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The organic solution was extracted with 5% hydrochloride (20 mL) and the acidic aqueous phase was washed with diethyl ether and the pH was adjusted to 12 with 25% sodium hydroxide. The mixture was extracted with dichloromethane, the organic phase was dried (sodium sulfate) and concentrated to give 1- (2- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] -amino} ethyl as a viscous oil. ) -Azepan-2-one 11 (0.84 g) was obtained, which was converted to the dibenzoyl-L-tartrate salt. Analysis: Calcd for C ₃₈ H ₄₆ N ₂ O ₁₀ : C, 66.07; H, 6.71; N, 4.06%; Found: C, 64.69; H, 6. 45; N, 3.90%.
[291] Similarly, following the procedure described in Example 1 above, optionally replacing (2-oxo-azepane-l-yl) acetaldehyde with another suitable compound of formula 1a and optionally [2- (4-meth) Further compounds of formula I were prepared by replacing oxyphenyl) -1-methylethyl] -ethylamine with other suitable compounds of formula 2 and utilizing modified methods known to those skilled in the art, wherein X , Y, and Z are each -CH ₂ ):
[292] 1- (2- {ethyl- [2- (4-methoxy-phenyl) -1-methylethyl] amino} ethyl) -pyrrolidin-2-one, dibenzoyl-L-tartrate salt, 12 , analysis : Calcd for C ₃₈ H ₄₆ N ₂ 0 ₁₀ : C, 65.24; H, 6.39; N, 4.23%; Found: C, 64.75; H, 6.08; N, 3.97%;
[293] 1- (4-{[2- (4-Bromo-2,5-dimethoxyphenyl) -1-methylethyl] ethylamino} butyl) -piperidin-2-one, dibenzoyl-L-tartrate Salt, 13 , melting point 97-98 ° C., M + H = 455;
[294] 1- (2- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 14 , analysis: Calcd for C ₃₇ H ₄₄ N ₂ 0 ₁₀ : C, 65.67; H, 6.55; N, 4.14%; Found: C, 64.86; H, 6. 23; N, 3.92%;
[295] 1- (3- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} propyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 15 , assay: Calcd for C ₃₈ H ₄₆ N ₂ 0 ₁₀ .0.5H ₂ O: C, 65.22; H, 6. 77; N, 4.00%; Found: C, 65.37; H, 6. 48; N, 3.94%;
[296] 1- (2-{[2- (4-methoxyphenyl) -1-methylethyl] propylamino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 16 , Assay: C Calcd for ₃₈ H ₄₆ N ₂ 0 ₁₀ : C, 66.07; H, 6.71; N, 4.06%; Found: C, 65.10; H, 6. 29; N, 3.71%;
[297] 1- (2- {ethyl- [2- (4-fluorophenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 17 , melting point 95 To 96 ° C., M + H = 307;
[298] l- (2-{[2- (4-chlorophenyl) -l-methylethyl] ethylamino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 18 , M + H = 323;
[299] 1- (2- {ethyl- [2- (4-trifluoromethoxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 19 , Anal: calcd for C ₃₇ H ₄₁ F ₃ N ₂ O ₁₀ : C, 60.82; H, 5. 66; N, 3.83%; Found: C, 60.70; H, 5. 46; N, 3.56%;
[300] 1- (4- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} butyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 20 , assay: Calcd for C ₃₉ H ₄₈ N ₂ 0 ₁₀ : C, 66.46; H, 6. 84; N, 3.97%; Found: C, 66.29; H, 6. 69; N, 4.04%;
[301] 1- (2- {ethyl- [2- (4-isobutoxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 21 , analysis: Calcd for C ₄₀ H ₅₀ N ₂ 0 ₁₀ : C, 66.84; H, 7.01; N, 3.90%; Found: C, 66.03; H, 6.76; N, 3.74%;
[302] 1- (2-{[2- (3-phenoxyphenyl) -1-methylethyl] propylamino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 22 , Assay: C Calcd for ₄₃ H ₄₈ N ₂ 0 ₁₀ : C, 68.60; H, 6. 43; N, 3.72%; Found: C, 67.56; H, 6. 23; N, 3.48%;
[303] 1- (2- {isobutyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 23 , M + H = 347;
[304] 1- {2- [2-naphthalen-2-yl) -1-methylethyl] propylamino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 24 , Assay: C ₄₁ H Calcd for ₄₆ N ₂ 0 ₉ : C, 69.28; H, 6.52; N, 3.94%; Found: C, 67.58; H, 6. 16; N, 3.48%;
[305] 1- (2-{[2- (6-methoxynaphthalen-2-yl) -1-methylethyl] propylamino} ethyl) -piperidin-2-one, hydrochloride salt, 25 , Assay: C ₂₄ H ₃₅ N ₂ 0 ₉ .Calculated for 0.4H ₂ O: C, 67.63; H, 8. 47; N, 6.69%; Found: C, 67.42; H, 8. 30; N, 6.63%;
[306] 1- (2-{[2- (4-chlorophenyl) -1-methylethyl] propylamino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 26 , M + H = 377;
[307] 1- (4-{[2- (4-chlorophenyl) -l-methylethyl] propylamino} butyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 27 , M + H = 365;
[308] Diethylcarbamic acid 4- (2- {ethyl- [2- (2-oxo-piperidin-1-yl) ethyl] amino} propyl) -phenyl ester, dibenzoyl-L-tartrate salt, 28 , M + H = 404;
[309] Dimethylcarbamic acid 4- (2- {ethyl- [2- (2-oxo-piperidin-1-yl) ethyl] amino} -propyl) -phenyl ester, dibenzoyl-L-tartrate salt, 29 , M + H = 321;
[310] Propane-2-sulfonic acid 4- (2- {ethyl- [2- (2-oxo-piperidin-1-yl) ethyl] amino} ethyl) -phenyl ester, dibenzoyl-L-tartrate salt, 30 , M + H = 411;
[311] 1- (2- {ethyl- [2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 31 , M + H = 305;
[312] Isopropylcarbamic acid 4- (2- {ethyl- [2- (2-oxo-piperidin-1-yl) ethyl] amino} -propyl) -phenyl ester, dibenzoyl-L-tartrate salt, 32 , M + H = 390;
[313] 1- (4-{[2- (3-trifluoromethylphenyl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 33 , M + H = 399;
[314] 1- (6- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} hexyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 34 , M + H = 375;
[315] 1- (4-{[2- (3-chlorophenyl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 35 , Assay: C ₃₉ H ₄₇ CIN ₂ O ₉ calcd for 0.8 H ₂ O: C, 63.35; H, 6.65; N, 3.79%; Found: C, 63.64; H, 6.65; N, 3.79%;
[316] 1- (4-{[2- (3-fluorophenyl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 36 , M + H = 349;
[317] 1- (4-{[2- (4-bromophenyl) -1-methylethyl] ethylamino} butyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 37 , M + H = 395;
[318] 1- (5- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} pentyl) -piperidin-2-one, hydrochloride salt, 38 , M + H = 361;
[319] 1- {4- [2-naphthalen-2yl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 39 , Assay: C ₂₅ H ₃₇ ClN ₂ O.0.8 Calcd for H ₂ O: C, 69.60; H, 9.02; N, 6.49%; Found: C, 69.69; H, 8. 80; N, 6.70%;
[320] 1- (4-{[2- (4-tert-butylphenyl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 40 , M + H = 387;
[321] 1- (4-{[2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydro Chloride salt, 41 , M + H = 389;
[322] 1- (4- {isopropyl- [2- (3-trifluoromethylphenyl) -1-methylethyl] amino} butyl) -piperidin-2-one, hydrochloride salt, 42 , M + H = 377 ;
[323] 1- (4-{[2- (2,3-Dihydrobenzofuran-5-yl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 43 , M + H = 373;
[324] 1- (4-{[1- (4-chlorobenzyl) propyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 44 , M + H = 379;
[325] 1- (4-{[1- (3-methoxy-4-methylbenzyl) propyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 45 , M + H = 389;
[326] N- [3- (2-{[4- (2-oxo-piperidin-1-yl) butyl] propylamino} propyl) phenyl] -methanesulfonamide, hydrochloride salt, 46 , M + H = 424 ;
[327] 1- {4-[(2-1-benzopyran-6-yl-1-methylethyl) propylamino] butyl} -piperidin-2-one, hydrochloride salt, 47 , M + H = 387;
[328] 1- {4-[(2-benzo [1,3] dioxol-5-yl-l-methylethyl) ethylamino] butyl} -piperidin-2-one, hydrochloride salt, 48 , M + H = 361;
[329] 1- (4-{[2- (3-chloro-4-fluorophenyl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 49 , M + H = 383;
[330] 1- (4-{[2- (4-methylsulfanylphenyl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 50 , M + H = 377;
[331] 1- (4- {isopropyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -piperidin-2-one, hydrochloride salt, 51 , M + H = 409 ;
[332] 1- (4-{[2- (lH-Indol-5-yl) -l-methylethyl] isopropylamino} butyl) -piperidin-2-one, hydrochloride salt, 52 , M + H = 370 ;
[333] 1- (4-{[2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -1-methylethyl] isopropylamino} butyl) -piperidin-2-one, Hydrochloride salt, 53 , M + H = 389;
[334] 1- (4-{[2- (3,3-dimethyl-2,3-dihydrobenzofuran-6-yl) -l-methylethyl] propyl-amino} butyl) piperidin-2-one, hydro Chloride salt, 54 , Anal .: Calcd for C ₂₅ H ₄₁ ClN ₂ O ₂ : C, 68.70; H, 9. 45; N, 6.41%; Found: C, 63.93; H, 9. 16; N, 6.34%;
[335] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -piperidin-2-one hydrochloride salt, 55 , Anal: C ₂₂ H ₃₇ ClN ₂ Calcd for 0 ₃ S.1.5H ₂ 0: C, 55.97; H, 8.54; N, 5.93%; Found: C, 55.83; H, 8.21; N, 6.70%;
[336] 1- (4- {ethyl- [2- (4-trifluoromethylsulfonylphenyl) -1-methylethyl] amino} butyl) -piperidine-2-one, 2,2,2-trifluoro Acetate salt, 56 , M + H = 449;
[337] 1- (4-{[2- (4-tert-Butylphenyl) -1-methylethyl] ethylamino} butyl) -piperidin-2-one, hydrochloride salt, 57 , Anal: C ₂₄ H ₄₁ Calcd for ClN ₂ 0.0.65H ₂ 0: C, 68.51; H, 10.13; N, 6.66%; Found: C, 68.48; H, 9.92; N, 6.85%;
[338] Propane-2-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} -propyl) -phenyl ester, phosphate salt, 58 , assay: C ₂₅ H ₄₅ Calcd for N ₂ 0 ₈ PS.1.75H ₂ 0: C, 47.05; H, 7. 46; N, 4.39%; Found: C, 46.96; H, 7. 35; N, 4.40%;
[339] 4-Methanesulfonyl-benzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoro Acetate salt, 59 , M + H = 579;
[340] Benzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoroacetate salt, 60 , M + H = 510;
[341] 5-benzenesulfonyl-thiophene-2-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] -propylamino} propyl) -phenyl ester, 2,2, 2-trifluoroacetate salt, 61 , M + H = 647;
[342] Butane-1-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} -propyl) -phenyl ester, 2,2,2-trifluoroacetate salt , 62 , M + H = 481;
[343] 4-chlorobenzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propyl-amino} propyl) phenyl ester, 2,2,2-trifluoroacetate salt, 63 , M + H = 535;
[344] 3,4-dimethoxybenzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propyl-amino} propyl) -phenyl ester, 2,2,2-trifluoro Roacetate salt, 64 , M + H = 561;
[345] Ethanesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoroacetate salt, 65 , M + H = 453;
[346] Dimethylsulfonic acid 4- (2-{[4- (2-oxo-azpan-l-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoroacetate salt, 66 , M + H = 468;
[347] Methanesulfonic acid 4- (2-{[2- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoroacetate salt, 67 , M + H = 439;
[348] 4-methoxybenzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propyl-amino} propyl) phenyl ester, 2,2,2-trifluoroacetate salt , 68 , M + H = 531;
[349] Naphthalene-1-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propyl-amino} propyl) phenyl ester, 2,2,2-trifluoroacetate salt, 69 , M + H = 551;
[350] Naphthalene-2-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propyl-amino} propyl) phenyl ester, 2,2,2-trifluoroacetate salt, 70 , M + H = 551;
[351] 4-nitrobenzenesulfonic acid 4- (2-{[2- (2-oxo-azpan-l-yl) butyl] propyl-amino} propyl) phenyl ester, 2,2,2-trifluoroacetate salt, 71 , M + H = 546;
[352] Propane-1-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} -propyl) -phenyl ester, 2,2,2-trifluoroacetate salt , 72 , M + H = 467;
[353] Thiophen-1-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} -propyl) -phenyl ester, 2,2,2-trifluoroacetate Salt, 73 , M + H = 507;
[354] Phenylmethanesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} -propyl)-phenyl ester, 2,2,2-trifluoroacetate salt, 74 , M + H = 515;
[355] 4-trifluoromethoxybenzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoro Acetate salt, 75 , M + H = 585;
[356] 4-Cyanobenzenesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} -propyl) -phenyl ester, 2,2,2-trifluoroacetate Salt, 76 , M + H = 526;
[357] 1,1,1-trifluoromethanesulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) butyl] propyl-amino} propyl) -phenyl ester, 2,2,2 -Trifluoroacetate salt, 77 , M + H = 493;
[358] Propane-2-sulfonic acid 4- (2-{[4- (2-oxo-azpan-1-yl) ethyl] propylamino} -propyl) -phenyl ester, phosphate salt, 78 , Assay: C ₂₃ H ₄₁ Calcd for N ₂ 0 ₈ PS: C, 51.48; H, 7. 70; N, 5.22%; Found: C, 45.23; H, 7. 12; N, 9.45%;
[359] 4-methanesulfonyl-N- [3- (2-{[2- (2-oxo-azpan-1-yl) ethyl] propylamino} propyl) -phenyl] -benzamide, hydrochloride salt, 79 , Anal: calcd for C ₂₈ H ₄₀ ClN ₃ O ₄ S.0.7H ₂ O: C, 59.76; H, 7.41; N, 7.47%; Found: C, 59.71; H, 7. 20; N, 7.44%;
[360] 4-Methyl-N- [3- (2-{[2- (2-oxo-azpan-1-yl) ethyl] propylamino} propyl) -phenyl] -benzamide, hydrochloride salt, 80 , Assay: Calcd for C ₂₈ H ₄₀ ClN ₃ 0 ₂ .0.7H ₂ 0: C, 67.44; H, 8. 37; N, 8.43%; Found: C, 67.32; H, 8. 18; N, 8.43%;
[361] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 81 , melting point 78-79 ° C., M + H = 409;
[362] 1- (4-{[2- (4-ethanesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -azpan-2-one, hydrochloride salt, 82 , M + H = 423;
[363] 1- (4- {ethyl- [2- (4-isopropanesulfonylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 83 , M + H = 437;
[364] 4-tert-butyl-N- [3- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl] -benzamide, 84 , Assay: C Calcd for ₃₃ H ₄₉ N ₃ 0 ₂ : C, 76.26; H, 9. 50; N, 8.08%; Found: C, 76.32; H, 9.39; N, 8.19%;
[365] 1- (4-{[2- (3-benzenesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -azpan-2-one, hydrochloride salt, 85 , M + H = 471;
[366] 1- (4-{[2- (3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1-benzo [b] thiophen-5-yl) -1-methylethyl ] Isopropylamino} butyl) -azepan- ₂ -one, hydrochloride salt, 86 , Anal. Calcd for C ₂₆ H ₃₇ ClN ₂ O ₃ S: C, 62.56; H, 8.68; N, 5.61%; Found: C, 58.09; H, 8. 16; N, 5.26%;
[367] 1- (4-{[2- (4-benzenesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -azpan-2-one, hydrochloride salt, 87 , M + H = 471;
[368] 1- (4- {ethyl- [2- (4- (2-methylpropane-1-sulfonyl) phenyl) -1-methylethyl] amino} -butyl)-azepan-2-one, hydrochloride salt, 88 , M + H = 451;
[369] Benzo [1,3] dioxol-5-carboxylic acid [2-methanesulfonyl-5- (2-{[4- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) phenyl] -Amide, hydrochloride salt, 89 , Anal .: Calcd for C ₃₁ H ₄₄ ClN ₃ O ₆ S.9H ₂ O: C, 56.72; H, 7. 34; N, 6.40%; Found: C, 56.79; H, 6.98; N, 6.40%;
[370] 1- (4-{[2- (3,3-dioxo-2,3-dihydrobenzo [1,3] oxathiol-5-yl) -l-methylethyl] -ethylamino} butyl) -ase Pan-2-one, hydrochloride salt, 90 , M + H = 423;
[371] 1- (4-{[2- (2,3-dihydrobenzo [1,3] oxathiol-5-yl) -1-methylethyl] isopropylamino} -butyl) -azpan-2-one, Hydrochloride salt, 91 , M + H = 405;
[372] 1- (4- {ethyl- [2- (3-methanesulfonylphenyl) -l-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 92 , M + H = 4 09;
[373] 1- (4-{[2- (3,3-dioxo-2,3-dihydrobenzo [1,3] oxathiol-5-yl) -1-methylethyl] -isopropylamino} butyl)- Azepan-2-one, hydrochloride salt, 93 , M + H = 437;
[374] 1- (4- {isopropyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 94 , M + H = 423;
[375] 1- (4-{(1-ethylpropyl)-[2- (4-methanesulfonylphenyl) -1-methylethyl] amino} -butyl) -azpan-2-one, hydrochloride salt, 95 , M + H = 451;
[376] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -azpan-2-one, hydrochloride salt, 96 , M + H = 423;
[377] 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) -N, N-dimethyl- benzenesulfonamide, hydrochloride salt, 97 , M + H = 438;
[378] 1- (3-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} propyl) -azpan-2-one, hydrochloride salt, 98 , M + H = 409;
[379] 1- [4- (ethyl- {2- [4- (4-methylpiperazin-1-sulfonyl) phenyl] -1-methylethyl} -amino) butyl] azepan-2-one, dihydrochloride salt , 99 , M + H = 493;
[380] 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) -N-methyl-benzenesulfonamide, hydrochloride salt, 100 , M + H = 424;
[381] 1- {4- [ethyl- (1-methyl-2-phenylethyl) amino] -butyl} -azpan-2-one, hydrochloride salt, 101 , M + H = 331;
[382] 1- (4-{[2- (3-chloro-4-methanesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -azpan-2-one, hydrochloride salt, 102 , Anal: C ₂₂ Calcd for H ₃₆ Cl ₂ N ₂ 0 ₃ S.1.4H ₂ 0: C, 52.35; H, 7.75; N, 5.55%; Found: C, 52.34; H, 7. 36; N, 5.65%;
[383] 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) -benzenesulfonamide, hydrochloride salt, 103 , M + H = 410;
[384] N-dimethylethyl-4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) benzenesulfonamide, 104 , M + H = 466;
[385] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] -amino} butyl) -azpan-2-one, hydrochloride salt, 105 , M + H = 463;
[386] 1- (4- {ethyl- [2- (4-trifluoromethylsulfanylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 106 , M + H = 431;
[387] 1- (4- {ethyl- [2- (4-nitrophenyl) -1-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 107 , Assay: C ₂₁ H ₃₄ ClN ₃ O ₃ calcd for 0.7H ₂ O: C, 59.41; H, 8. 40; N, 9.90%; Found: C, 59.48; H, 8.21; N, 9.92%;
[388] 1,1,1-trifluoromethanesulfonic acid 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) -phenyl ester, hydrochloride salt, 108 , M + H = 479;
[389] N- [4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) phenyl] -1, l, l-trifluoromethanesulfonamide, sodium salt , 109 , Anal .: Calcd for C ₂₂ H ₃₄ F ₃ N ₃ NaO ₃ S: C, 55.33; H, 7. 18; N, 8.80%; Found: C, 51.96; H, 6.73; N, 8.62%;
[390] 1- (3- {ethyl- [2- (4-trifluoromethylsulfonylphenyl) -1-methylethyl] amino} propyl) -azpan-2-one, 2,2,2-trifluoroacetate Salt, 110 , M + H = 449;
[391] 1- (2- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} ethyl) -azpan-2-one, 2,2,2-trifluoroacetate Salt, 111 , M + H = 435;
[392] 1- [4- (ethyl- {2- [4- (thiazol-2-sulfonyl) phenyl] -1-methylethyl} amino) butyl] -azpan-2-one, hydrochloride salt, 112 , analysis : Calcd for C ₂₄ H ₃₆ ClN ₃ O ₃ S ₂ .1H ₂ O: C, 54.17; H, 7. 20; N, 7.90%; Found: C, 54.09; H, 6.91; N, 7.86%;
[393] 4- (2- {ethyl- [4- (2-oxo-azpan-l-yl) butyl] amino} propyl) -N-isopropylbenzenesulfonamide, 2,2,2-trifluoroacetate salt, 113 , M + H = 452;
[394] 4- (2- {ethyl- [4- (2-oxo-azpan-l-yl) butyl] amino} propyl) -N- (2-hydroxyethyl) -benzenesulfonamide, 2,2,2- Trifluoroacetate salt, 114, M + H = 454;
[395] 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) -N- (2-methoxyethyl) -benzenesulfonamide, 2,2,2- Trifluoroacetate salt, 115 , M + H = 468;
[396] 1- [4- (ethyl- {2- [4- (morpholin-4-sulfonyl) phenyl] -1-methylethyl} amino) butyl] azepan-2-one, 2,2,2-tri Fluoroacetate salt, 116 , M + H = 480;
[397] 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] amino} propyl) -N- (2,2,2-trifluoroethyl) -benzenesulfonamide, 2 , 2,2-trifluoroacetate salt, 117 , M + H = 492;
[398] 1- (4- {ethyl- [2- (4-tert-butylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one, hydrochloride salt, 118 , Assay: C ₂₅ H ₄₃ Calcd for ClN ₂ 0 ₃ .0.45H ₂ 0: C, 69.64; H, 8.53; N, 5.55%; Found: C, 57.12; H, 8.41; N, 5.61%; or
[399] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -l-methylethyl] amino} butyl) -azonocan-2-one, hydrochloride salt, 119 , assay: C ₂₃ H ₃₉ ClN Calcd for ₂ 0 ₃ S.2H ₂ 0: C, 55.75; H, 8.14; N, 5.65%; Found: C, 55.67; H, 8.52; N, 5.43%.
[400] Example 2
[401] Preparation of Compounds of Formula IB Described in Scheme C
[402] 3- (4- {ethyl-[(S) -2- (4-methanesulfonylphenyl) -l-methyl-ethyl] amino} butyl)-[1,3] oxazinan-2-one
[403]
[404] Tri-suspended in suspension of ethyl-[(S) -2- (4-methylsulfanylphenyl) -1-methylethyl] -amine hydrochloride (0.25 g, 1 mmol) in 1,2-dichloroethane (10 mL). Ethylamine (0.2 mL, 1.5 mmol) was added. To the mixture was added 4- (2-oxo- [1,3] oxazinan-3-yl) -butyraldehyde (0.18 g, 1.05 mmol) and sodium triacetoxyborohydride (0.32 g, 1.5 mmol). Added. The reaction mixture was stirred at rt for 15 h, concentrated and the residue was partitioned in 5% sodium hydroxide (5 mL) and diethyl ether (20 mL). The organic phase was dried (magnesium sulfate) and concentrated to give 3- (4- {ethyl-[(S) -2- (4-methylsulfanyl-phenyl) -1-methylethyl] amino} butyl)-[as a viscous oil. 1,3] oxazinan-2-one (0.33 g) was obtained.
[405] 3- (4- {ethyl-[(S) -2- (4-methylsulfanylphenyl) -1-methylethyl] amino} butyl)-[l, 3] oxazinan-2- in methanol (10 mL) To a cold (0.33 g, 0.9 mmol) ice cold solution was added a solution of potassium peroxymonosulfate (Oxone) (1.22 g, 1.98 mmol) in water (10 mL). The reaction mixture was stirred at rt for 5 h. Then 1.5 M sodium carbonate solution (10 mL) was added and the mixture was extracted with diethyl ether (20 mL). The organic phase was dried (magnesium sulfate) and concentrated. Purify the residue by silica gel chromatography with 10% ethyl acetate in chloroform to give 3- (4- {ethyl-[(S) -2- (4-methanesulfonylphenyl) -1 -methylethyl] as colorless oil. Amino} -butyl)-[1,3] oxazinan-2-one, 122 , (0.17 g) was obtained. Anal: calcd for C ₂₀ H ₃₃ ClN ₂ O ₄ S: C, 55.48; H, 7.68; N, 6.47%; Found: C, 52.32; H, 7. 42; N, 5.97%.
[406] Similarly, following the procedure described in Example 2 above, optionally replacing 4- (2-oxo- [1,3] oxazinan-3-yl) butyraldehyde with another suitable compound of Formula 1b and optionally Modified ethyl-[(S) -2- (4-methylsulfanyl-phenyl) -1-methylethyl] -amine hydrochloride with other suitable compounds of formula 2 and modified to those known to those skilled in the art Was used to prepare additional compounds of Formula I, wherein X is -O- or -S-.
[407] 3- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,3] oxazepan-2-one, hydrochloride salt, 123 , assay: Calcd for C ₂₁ H ₃₅ ClN ₂ O ₄ S: C, 60.78; H, 8.50; N, 6.75%; Found: C, 52.82; H, 7. 82; N, 5.84%;
[408] 3- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl)-[1,3] oxazepan-2-one, hydrochloride salt, 124 , Assay: C ₂₂ H ₃₇ ClN calculated on _{2 O 4 S · 0.85H 2 O} : C, 55.47; H, 8. 19; N, 5.88%; Found: C, 55.42; H, 7.94; N, 5.72%;
[409] 3- (4- {isopropyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,3] oxazepan-2-one, hydrochloride salt, 125 , analysis : C ₂₂ H ₃₇ ClN calculated on _{2 O 4 S · 1.5H 2 O} : C, 54.14; H, 8. 26; N, 5.74%; Found: C, 54.12; H, 7.94; N, 5.64%;
[410] 3- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,3] oxazepan-2-one, 2,2,2 -Trifluoroacetate salt, 126 , M + H = 465;
[411] 3- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,3] oxazinan-2-one, 2,2,2 -Trifluoroacetate salt, 127 , M + H = 451;
[412] 3- [4- (ethyl- {2- [4- (propane-2-sulfonylmethyl) phenyl] -1-methylethyl} amino) -butyl]-[1,3] oxazepan-2-one, hydro Chloride salt, 128 , Anal .: Calcd for C ₂₄ H ₄₁ ClN ₂ O ₄ S.0.85H ₂ O: C, 57.15; H, 8.53; N, 5.55%; Found: C, 57.12; H, 8.41; N, 5.61%;
[413] 3- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,3] oxazocan-2-one, hydrochloride salt, 129 , Assay: Calcd for C ₂₂ H ₃₇ ClN ₂ 0 ₄ S .0.95H ₂ 0: C, 55.26; H, 8. 20; N, 5.86%; Found: C, 55.26; H, 7.92; N, 5.99%;
[414] 3- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) [1,3] oxazocan-2-one, 2,2,2- Trifluoroacetate salt, 130 , M + H = 479; or
[415] 3- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,3] thiazinan-2-one, hydrochloride salt, 131 , M + H = 413.
[416] Similarly, following the procedure described in Example 2 above, optionally replacing 4- (2-oxo- [1,3] oxazinan-3-yl) butyraldehyde with another suitable compound of Formula 1b and optionally By replacing ethyl-[(S) -2- (4-methylsulfanyl-phenyl) -l-methylethyl] -amine hydrochloride with another suitable compound of formula (2) and using a modified method known to those skilled in the art. Utilization, additional compounds of formula IB were prepared (where X is> NR ⁶ ):
[417] 1- [4- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino) butyl] -tetrahydro-pyrimidin-2-one, dibenzoyl-L-tartrate salt, 134 , Analysis: Calcd for C ₃₈ H ₄₇ N ₃ O ₁₀ : C, 64.67; H, 6.71; N, 5.95%; Found: C, 62.96; H, 6. 28; N, 5.76%;
[418] 1- [4- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino) butyl] -3-methyl-tetrahydropyrimidin-2-one, dibenzoyl-L-tartrate salt , 135 , Anal .: C ₃₉ H ₄₉ N ₃ O ₁₀ .calculated for 0.9H ₂ O: C, 63.64; H, 6.96; N, 5.71%; Found: C, 63.66; H, 6. 61; N, 5.62%;
[419] 3- [4-{[2- (3-trifluoromethylphenyl) -l-methylethyl] propylamino) butyl] -methyl-tetrahydropyrimidin-2-one, dibenzoyl-L-tartrate salt , 136 , Anal .: Calcd for C ₄₀ H ₄₈ F ₃ N ₃ O ₉ : C, 62.25; H, 6. 27; N, 5.44%; Found: C, 60.64; H, 6.05; N, 4.81%;
[420] 1- [4-{[2- (3-trifluoromethylphenyl) -l-methylethyl] propylamino) butyl] -tetrahydropyrimidin-2-one, hydrochloride salt, 137 , Anal: C ₂₁ H ₃₃ Calcd for ClF ₃ N ₃ 0 ₉ .0.8H ₂ 0: C, 56.00; H, 7. 74; N, 9.33%; Found: C, 56.00; H, 7. 45; N, 9.11%;
[421] 3- [4-{[2-naphthalen-2-yl-1-methylethyl] propylamino) butyl] -1-methyl-tetrahydropyrimidin-2-one, hydrochloride salt, 138 , Assay: C ₂₅ H Calcd for ₃₈ ClN ₃ O.1.4H ₂ O: C, 65.67; H, 8.99; N, 9.19%; Found: C, 65.64; H, 8.99; N, 9.19%;
[422] 1- [3-{[2- (4-chlorophenyl) -l-methylethyl] propylamino) propyl] -tetrahydropyrimidin-2-one, hydrochloride salt, 139 , assay: C ₁₉ H ₃₁ Cl ₂ Calcd. For N ₃ O.1.15H ₂ O: C, 55.78; H, 8. 20; N, 10.27%; Found: C, 55.81; H, 7.93; N, 10.25%;
[423] 1- (4- {ethyl-[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -tetrahydropyrimidin-2-one, hydrochloride salt, 140 , M + H = 396;
[424] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methyl-ethyl] amino} butyl) -3-methyl- [1,3] diazepan-2-one, hydrochloride salt , 141 , M + H = 424;
[425] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methyl-ethyl] propylamino} butyl)-[1,3] diazepan-2-one, hydrochloride salt, 142 , M + H = 424;
[426] 1- [4-({2- [4- (thiazol-2-sulfonyl) phenyl] -1-methylethyl} propylamino) butyl] -tetrahydropyrimidin-2-one, hydrochloride salt, 143 , Anal: calcd for C ₂₃ H ₃₅ ClN ₄ O ₃ S ₂ : C, 53.63; H, 6. 85; N, 10.88%; Found: C, 48.86; H, 6. 42; N, 9.84%; or
[427] 1- [4- (ethyl- {2- [4- (thiazole-2-sulfonyl) phenyl] -1-methylethyl} amino) butyl] -tetrahydropyrimidin-2-one, hydrochloride salt, 144 , Analysis: Calcd for C ₂₂ H ₃₃ ClN ₄ O ₃ S ₂ : C, 52.73; H, 6. 64; N, 11.18%; Found: C, 48.74; H, 6. 31; N, 10.33%.
[428] Example 3
[429] (Example of Preparation of Compound of Formula ICa Described in Scheme D)
[430] 4- [4- (ethyl-{(S) -2- [4- (thiazole-2-sulfonyl) phenyl] -1-methylethyl} amino) butyl]-[1,4] oxazepan-3- On
[431]
[432] Ethyl-{(S) -1-methyl-2- [4- (thiazole-2-sulfonyl) phenyl] ethyl} -amine (0.326 g, 1.02 mmol) in 1,2-dichloroethane (10 mL), A mixture of 4- (3-oxo- [1,4] oxazepan-4-yl) -butyraldehyde (0.22 g, 1.2 mmol), and sodium triacetoxyborohydride (0.3 g, 1.4 mmol) Stir at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was partitioned in 5% hydrochloric acid and diethyl ether. The aqueous phase was adjusted to pH 12 with 25% sodium hydroxide and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and concentrated to give 4- (4- {ethyl- [2- (4-thiazole-2-sulfonylphenyl) -1-methylethyl] amino} butyl)-[1, 4] oxapanane-3-one, 145 , was obtained. Analyzes: Calcd for C ₂₃ H ₃₄ ClN ₃ O ₄ S ₂ .1H ₂ O: C, 51.72; H, 6.79; N, 7.87%; Found: C, 51.71; H, 6. 49; N, 7.82%.
[433] Similarly, following the procedure described in Example 3 above, optionally replacing 4- (3-oxo- [1,4] oxazepan-4-yl) -butyraldehyde with another suitable compound of formula 1c and optionally By replacing ethyl-{(S) -1-methyl-2- [4- (thiazole-2-sulfonyl) phenyl] ethyl} -amine with another suitable compound of formula 2 and known to those skilled in the art. Using a modified method, additional compounds of compound ICa are prepared, wherein Y is -O- or -S-.
[434] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] oxazepan-3-one, hydrochloride salt, 146 , analysis: C ₂₂ H ₃₇ ClN calculated on _{2 O 4 S · 1.5H 2 O} : C, 54.14; H, 8. 26; N, 5.74%; Found: C, 54.19; H, 8. 26; N, 5.85%; or
[435] 4- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] oxazepan-3-one, 2,2,2 -Trifluoroacetate salt, 147 , M + H = 465.
[436] Example 4
[437] (Example of Preparation of Compound of Formula ICb Described in Scheme D)
[438] 1- (4-{[(S) -2-(-4-methanesulfonylphenyl) -1-methylethyl] -propylamino} butyl)-[1,4] diazepan-2-one
[439]
[440] Propyl-[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -amine hydrochloride (0.50 g, 1.7 mmol), 3-oxo- in 1,2-dichloroethane (20 mL) 4- (4-oxobutyl)-[l, 4] diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 1.76 mmol), triethylamine (0.24 mL, 1.7 mmol), and sodium triacetoxy A mixture of hydride (0.54 g, 2.6 mmol) was stirred at rt for 17 h. Solvent was removed and the residue was partitioned in ethyl acetate (30 mL) and 5% sodium carbonate (20 mL). The organic phase was dried (magnesium sulfate) and concentrated to give 4- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -3-oxo as a syrup. -[1,4] diazepan-1-carboxylic acid tert-butyl ester (0.89 g) was obtained. NMR (chloroform-d) δ (ppm): 0.82, t, 3H; 0.94, d, 3 H; 1.46, s, 9 H; 3.05, s, 3 H; 7.36, d, 2 H; 7.83, d, 2 H.
[441] 4- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propyl-amino} butyl) -3-oxo- [1,4] diazepane-1-carboxy A mixture of acid tert-butyl ester (0.9 g, 1.75 mmol) and 3 N hydrochloric acid (4 mL) was heated to 50 ° C. The reaction mixture was stirred at rt for 30 min and the pH was adjusted to 10 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (30 mL) and the organic phase was dried (magnesium sulfate) and concentrated. The residue was added 1 M hydrogen chloride in diethyl ether (10 mL) and diethyl ether (2 mL). The precipitate was collected, washed with diethyl ether and hexanes and dried in vacuo to give 1- (4-{[(S) -2-(-4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -1,4] diazepan-2-one, dihydrochloride salt (0.49 g) was obtained ( 149 , M + H = 424).
[442] Similarly, following the procedure described in Example 4 above, optionally, 3-oxo-4- (4-oxobutyl)-[l, 4] diazepane-1-carboxylic acid tert-butyl ester Replace with another suitable compound, optionally replace propyl-[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] amine hydrochloride with another suitable compound of formula 2 and Other suitable compounds of formula ICb were prepared using a modified method known to those wherein Y is> NH.
[443] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-2-one, hydrochloride salt, 150 , M + H = 464;
[444] 1- (4- {ethyl- [2- (4-thiazol-2-sulfonylphenyl) -l-methylethyl] amino} butyl)-[1,4] diazepan-2-one, hydrochloride salt, 151 , Anal .: Calcd for C ₂₃ H ₃₅ ClN ₄ O ₃ S ₂ .1.25H ₂ O: C, 48.12; H, 6.76; N, 9.76%; Found: C, 48.10; H, 6.52; N, 9.81%;
[445] 1- (4- {ethyl- [2- [4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -piperazin-2-one, hydrochloride salt, 152 , M + H = 450;
[446] N-methyl-4- (2-{[4- (2-oxo-piperazin-1-yl) butyl] propylamino} propyl) -benzenesulfonamide, hydrochloride salt, 153 , M + H = 425;
[447] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -piperazin-2-one, hydrochloride salt, 154 , M + H = 410;
[448] 1- (4-{[2- (4-thiazole-2-sulfonylphenyl) -1-methylethyl] propylamino} butyl) -piperazin-2-one, hydrochloride salt, 155 , Assay: C ₂₅ Calcd for H ₃₅ ClN ₄ 0 ₃ S ₂ .1.5H ₂ 0: C, 48.81; H, 6. 66; N, 9.49%; Found: C, 48.69; H, 6. 54; N, 9.64%;
[449] 1- (4-{[2- (4-thiazole-2-sulfonylphenyl) -l-methylethyl] propylamino} butyl)-[1,4] diazepan-2-one, hydrochloride salt, 156 Anal: calcd for C ₂₄ H ₃₆ ClN ₄ O ₃ S ₂ .0.75H ₂ O: C, 49.78; H, 6.88; N, 9.67%; Found: C, 49.74; H, 6.75; N, 9.69%;
[450] N-methyl-4- (2-{[4- (2-oxo- [1,4] diazepane-l-yl) butyl] propylamino} propyl) -benzenesulfonamide, dihydrochloride salt, 157 , M + H = 439;
[451] 1- [4- (ethyl- {2- [4- (4-methoxybenzenesulfonyl) phenyl] -1-methylethyl} amino) butyl]-[1,4] diazepan-2-one, 158 , M + H = 502;
[452] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -butyl]-[1,4] diazepane- 2-on, 159 , M + H = 530;
[453] l- (4- {ethyl- [2- (4-trifluoromethylphenyl) -l-methylethyl] amino} butyl)-[1,4] -diazepan-2-one, dihydrochloride hemihydrate salt, 160 , Anal .: Calcd for C ₂₁ H ₃₃ ClF ₃ N ₃ O: C, 52.39; H, 7. 33; N, 8.73%; Found: C, 52.44; H, 7. 32; N, 8.58%; or
[454] 1- (4-{[2- (4-tert-Butylphenyl) -1-methylethyl] propylamino} butyl) -piperazin-2-one, hydrochloride salt, 161 , M + H = 374.
[455] Example 5
[456] (Example of Preparation of Compound of Formula ICc Described in Scheme D)
[457] 1- (4-{[(S) -2-(-4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -4-methyl- [1,41 diazepan-2-one
[458]
[459] 1- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propylamino} butyl-1,4-diazepine-2 in tetrahydrofuran (10 mL) Triethylamine (3 drops) was added to the -on (0.08 g, 0.19 mmol) solution, followed by sodium triacetoxyborohydride (0.06 g, 0.3 mmol) and 37% formaldehyde (0.1 mL, 1.2 mmol). The reaction mixture was stirred for 16 h at rt The reaction mixture was concentrated and the residue was partitioned in 5% sodium carbonate and chloroform The organic phase was dried (magnesium sulfate) and concentrated to 1- (4-{[ (S) -2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -4-methyl- [1,4] diazepan-2-one was obtained, which diethyl ether (With hygroscopicity) was separated as dihydrochloride salt ((0.07 g), 166 , M + H = 438).
[460] Similarly, follow the procedure described in Example 5 above, optionally with 1- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propylamino} butyl-1 Modified method known to those skilled in the art, wherein, 4-diazepin-2-one is replaced with another free amine compound of formula ICb, and optionally formaldehyde is replaced with another suitable acylating agent, alkylating agent, or sulfonating agent Was utilized to prepare additional compounds of formula ICc, wherein Y is> NR ⁶ .
[461] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -l-methylethyl] amino} butyl) -3-oxo-piperazine-1-carboxylic acid tert-butyl ester, 167 , M + H = 496;
[462] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4-methanesulfonylpiperazin-2-one, hydrochloride salt, 168 , M + H = 474;
[463] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (morpholin-4-carbonyl) -piperazin-2-one, hydro Chloride salt, 169 , M + H = 509;
[464] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4-methanesulfonyl- [1,4] diazepan-2-one, hydrochloride Salt, 170 , M + H = 488;
[465] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4-methanesulfonyl-4-ethyl- [1,4] diazepan-2- On, 2,2,2-trifluoroacetate salt, 171 , M + H = 438;
[466] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-acetyl-
[467] [1,4] diazepan-2-one, 172 , M + H = 466;
[468] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-propionyl- [1,4] diazepan-2-one, 173 , M + H = 480;
[469] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-pentanoyl- [1,4] diazepan-2-one, 174 , M + H = 508;
[470] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (3-cyclopentylpropanoyl- [1,4] diazepane-2- On, 175 , M + H = 548;
[471] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -4- (thiophene-2-carbonyl)-[1,4] diazepane-2 -On, 176 , M + H = 534;
[472] 4- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -3-oxo- [1,4] diazepane-1-carboxylic acid methyl ester, 177 , M + H = 482;
[473] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-benzene-sulfonyl- [1,4] diazepan-2-one, 178 , M + H = 564;
[474] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (thiophene-2-sulfonyl)-[1,4] diazepan-2 -On, 179 , M + H = 570;
[475] 4- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -3-oxo- [1,4] diazepane-1-carboxylic acid isopropylamide, 180 , M + H = 509;
[476] 4- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -3-oxo- [1,4] diazepane-1-carboxylic acid butylamide, 181 , M + H = 523;
[477] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -4-benzoyl- [1,4] diazepan-2-one, 2,2,2 -Trifluoroacetate salt, 182 , M + H = 528;
[478] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-phenylacetyl- [1,4] diazepan-2-one, 2,2, 2-trifluoroacetate salt, 183 , M + H = 542;
[479] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -4- (3-phenyl-propionyl)-[1,4] diazepane-2- On, 2,2,2-trifluoroacetate salt, 184 , M + H = 556;
[480] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (pyridine-3-carbonyl)-[1,4] diazepan-2- On, 2,2,2-trifluoroacetate salt, 185 , M + H = 529;
[481] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -4- (isoxazole-5-carbonyl)-[1,4] diazepan-2 -One, 2,2,2-trifluoroacetate salt, 186 , M + H = 519;
[482] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (furan-2-carbonyl)-[1,4] diazepan-2- On, 2,2,2-trifluoroacetate salt, 187 , M + H = 518;
[483] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (propane-1- sulfonyl)-[1,4] diazepan-2- On, 2,2,2-trifluoroacetate salt, 188 , M + H = 530;
[484] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -4- (l-methyl-1H-imidazole-4-sulfonyl)-[1, 4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 189 , M + H = 568;
[485] 4- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -3-oxo- [1,4] diazepane-1-carboxylic acid methylamide, 2, 2,2-trifluoroacetate salt, 190 , M + H = 481;
[486] 4- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -3-oxo- [1,4] diazepane-1-carboxylic acid ethylamide, 2, 2,2-trifluoroacetate salt, 191 , M + H = 495;
[487] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -3-oxo- [1,4] diazepane-l-carboxylic acid phenylamide, 2, 2,2-trifluoroacetate salt, 192 , M + H = 543;
[488] l- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-methane-sulfonyl- [1,4] diazepan-2-one, 2, 2,2-trifluoroacetate salt, 193 , M + H = 502;
[489] 1- (4-{[2- (4-thiazole-2-sulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-methylpiperazin-2-one, hydrochloride salt, 194 , analysis : Calcd for C ₂₅ H ₃₇ ClN ₄ O ₃ S ₂ .1.8H ₂ O: C, 48.20; H, 7.01; N, 9.37%; Found: C, 48.25; H, 6. 64; N, 9.41%;
[490] 1- (4- {ethyl- [2- (4-thiazole-2-sulfonylphenyl) -1-methylethyl] amino} butyl) -4- (pyridine-3-sulfonyl) -piperazine-2- On, hydrochloride salt, 195 , Anal .: Calcd for C ₂₇ H ₃₆ ClN ₅ O ₅ S ₃ .1.25H ₂ O: C, 46.25; H, 5.68; N, 9.99%; Found: C, 46.26; H, 5.68; N, 9.99%;
[491] 1- (4- {ethyl- [2- (4-thiazole-2-sulfonylphenyl) -1-methylethyl] amino} butyl) -4- (pyridine-3-sulfonyl)-[1,4] Diazepan-2-one, hydrochloride salt, 196 , Anal .: Calcd for C ₂₈ H ₃₈ ClN ₅ O ₅ S ₂ .1.05H ₂ O: C, 47.26; H, 5. 82; N, 9.84%; Found: C, 47.26; H, 5.65; N, 9.81%;
[492] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (pyridine-3-sulfonyl) piperazin-2-one, Hydrochloride monohydrate salt, 197 , M + H = 511;
[493] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- methylpiperazin-2-one, hydrochloride salt, 198 , M + H = 464;
[494] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (pyridine-3-sulfonyl)-[1,4] diazepane-2 -One , hydrochloride salt, 199 , M + H = 551;
[495] 1- (4- {ethyl- [2- (4-methanesulfonyl) -1-methylethyl] amino} butyl) -4- (pyridine-3-sulfonyl) piperazin-2-one, hydrochloride monohydrate Salt, 200 , M + H = 537;
[496] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4
[497] (Pyridine-3-sulfonyl)-[1,4] diazepan-2-one, hydrochloride salt, 201 , M + H = 605;
[498] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4-trifluoromethanesulfonyl- [1,4] diazepan-2-one , Hydrochloride salt, 202 , Analytical: calcd for C ₂₂ H ₃₅ ClF ₃ N ₄ O ₅ S.0.75H ₂ O: C, 44.66; H, 6. 22; N, 7.10%; Found: C, 44.66; H, 6.08; N, 6.96%;
[499] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -l-methylethyl] amino} butyl) -4-thiazol-2-ylmethyl- [l, 4] diazepan-2- On, hydrochloride salt, 203 , Anal .: Calcd for C ₂₅ H ₃₉ ClN ₄ O ₃ S ₂ .0.85H ₂ O: C, 47.56; H, 6. 82; N, 8.87%; Found: C, 47.58; H, 6. 77; N, 9. 12%;
[500] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4-thiazol-2-ylmethyl- [1,4] diazepan -2-one, hydrochloride salt, 204 , M + H = 561;
[501] 1- (4- {ethyl- [2- (3-trifluoromethylphenyl) -1-methylethyl] amino} butyl) -4- (pyridin-3-sulfonyl) -piperazin-2-one, hydrochloride Salt, 205 , M + H = 527;
[502] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (1-methyl-lH-imidazole-4-sulfonyl) -Piperazin-2-one, hydrochloride salt, 206 , M + H = 594;
[503] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2,2,2-trifluoroacetyl)-[1,4] Diazepan- ₂ -one, hydrochloride salt, 207 , Anal .: Calcd for C ₂₃ H ₃₇ ClF ₃ N ₃ O ₄ S.1.05H ₂ O: C, 49.25; H, 6.67; N, 7.49%; Found: C, 48.90; H, 6. 27; N, 7.47%;
[504] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (1-methyl-lH-imidazole-4-sulfonyl) -[1,4] diazepan-2-one, hydrochloride salt, 208 , M + H = 608;
[505] 1- (4- {ethyl- [2- (3-trifluoromethylphenyl) -1-methylethyl] amino} butyl) -4- (1-methyl-1H-imidazole-4-sulfonyl) -piperazine -2-one, dihydrochloride salt, 209 , M + H = 530;
[506] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2,2,2-trifluoroethyl)-[1,4] Diazepan- ₂ -one, dihydrochloride salt, 210 , Anal .: Calcd for C ₂₃ H ₃₈ Cl ₂ F ₃ N ₃ O ₃ S · 1.20H ₂ O: C, 47.13; H, 6. 95; N, 7.17%; Found: C, 47.17; H, 6.59; N, 7.22%;
[507] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (2-dimethylaminoethanesulfonyl)-[1,4] diazepan-2 -One , dihydrochloride salt, 211 , M + H = 559;
[508] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (1H-imidazol-4-ylmethyl)-[1, 4] diazepan-2-one, hydrochloride salt, 212 , M + H = 544;
[509] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4-methyl-piperazin-2-one, hydrochloride salt, 213 , M + H = 424;
[510] 1- (4-{[2- (4-tert-butylphenyl) -l-methylethyl] ethylamino} butyl) -4- (1-methyl-1H-imidazole-4-sulfonyl)-[1 , 4] diazepan-2-one, hydrochloride salt, 214 , M + H = 532;
[511] 1- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-methyl-1H-imidazole-4-sulfonyl) -[1,4] diazepan-2-one, hydrochloride salt, 215 , M + H = 608;
[512] 1- (4-{[2- (4-tert-butylphenyl) -1-methylethyl] ethylamino} butyl) -4- (2-methyl-1H-imidazole-4-sulfonyl)-[1 , 4] diazepan-2-one, hydrochloride salt, 216 , M + H = 532;
[513] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -4- (2-imidazol-1-ylethanesulfonyl)-[1,4] Diazepan-2-one, hydrochloride salt, 217 , M + H = 582;
[514] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (3-methoxybenzoyl )-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 218 , M + H = 664;
[515] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] -propylamino} -butyl) -4- (furan-2- Carbonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 219 , M + H = 624;
[516] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (thiophene-2- Carbonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 220 , M + H = 640;
[517] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (3-nitrobenzoyl) -[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 221 , M + H = 679;
[518] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (pyridine-3-carbo Nil)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 222 , M + H = 635;
[519] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (pyridine-4-carbo Nil)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 223 , M + H = 635;
[520] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (isoxazole-5- Carbonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 224 , M + H = 625;
[521] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4-benzoyl- [1,4 ] Diazepan-2-one, 2,2,2-trifluoroacetate salt, 225 , M + H = 634;
[522] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (4-methoxybenzoyl )-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 226 , M + H = 664;
[523] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (2-chloropyridine- 4-carbonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 227 , M + H = 670;
[524] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (3,4-dimeth Oxybenzoyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 228 , M + H = 694;
[525] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (5-methylisoxo Sazol-3-carbonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 229 , M + H = 639;
[526] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (thiophen-2- Sulfonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 230 , M + H = 676;
[527] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -butyl] -3-oxo- [1,4 ] Diazepan-1-sulfonic acid dimethylamide, 2,2,2-trifluoroacetate salt, 231 , M + H = 637;
[528] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4-benzenesulfonyl- [1 , 4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 232 , M + H = 670;
[529] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4-methanesulfonyl- [1 , 4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 233 , M + H = 608;
[530] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (3-nitrobenzenesul Phonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 234 , M + H = 715;
[531] 1- (4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl] propylamino} -butyl) -4- (1-methyl-1H -Imidazole-4-sulfonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 235 , M + H = 674;
[532] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -butyl] -3-oxo- [1,4 ] Diazepan-1-carboxylic acid (2-methoxyphenyl) -amide, 2,2,2-trifluoroacetate salt, 236 , M + H = 679;
[533] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -butyl] -3-oxo- [1,4 ] Diazepan-1-carboxylic acid (3-methoxyphenyl) -amide, 2,2,2-trifluoroacetate salt, 237 , M + H = 679;
[534] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -part
[535] Methyl] -3-oxo- [1,4] diazepane-1-carboxylic acid (4-methoxyphenyl) -amide, 2,2,2-trifluoroacetate salt, 238 , M + H = 679;
[536] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -part
[537] Methyl] -3-oxo- [1,4] diazepane-1-carboxylic acid methylamide, 2,2,2-trifluoroacetate salt, 239 , M + H = 587;
[538] 4- [4-({2- [3- (benzo [1,3] dioxol-5-sulfonyl) phenyl] -1-methylethyl} propylamino) -part
[539] Tyl] -3-oxo- [1,4] diazepane-1-carboxylic acid (3,4,5-trimethoxyphenyl) -amide, 2,2,2-trifluoroacetate salt, 240 , M + H = 739;
[540] 1- [4- (ethyl- {2- [4- (4-methoxybenzenesulfonyl) phenyl] -1-methylethyl} amino) -butyl] -4- (pyridine-3-carbonyl)-[1 , 4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 241 , M + H = 607;
[541] 1- [4- (ethyl- {2- [4- (4-methoxybenzenesulfonyl) phenyl] -1-methylethyl} amino) -butyl] -4-benzoyl- [1,4] diazepane-2 -One, 2,2,2-trifluoroacetate salt, 242 , M + H = 606;
[542] 1- [4- (ethyl- {2- [4- (4-methoxybenzenesulfonyl) phenyl] -1-methylethyl} amino) -butyl] -4- (1-methyl-1H-imidazole-4 -Sulfonyl)-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 243 , M + H = 646;
[543] 1- (4- {ethyl- [2- (4-trifluoromethylphenyl) -1-methylethyl] amino} butyl-4- (2-methyl-1H-imidazole-4-sulfonyl)-[1, 4] -diazepan-2-one, dihydrochloride salt, 244 , Anal .: Calcd for C ₂₅ H ₃₇ ClF ₃ N ₅ O ₃ S.1.0H ₂ O: C, 47.32; H, 6.35; N, 11.04 % Measured: C, 47.24; H, 6.11; N, 11.21%;
[544] 1- (4-{[2- (4-chlorophenyl) -1-methylethyl] ethylamino} butyl-4- (1-methyl-1H-imidazole-4-sulfonyl)-[1,4]- Diazepan-2-one, hydrochloride salt, 245 , M + H = 510;
[545] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methyl-ethyl] propylamino} butyl) -4-chloro-methanesulfonyl- [1,4] diazepan-2-one, Hydrochloride salt, 246 , M + H = 536;
[546] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -4- (2-dimethylamino-ethanesulfonyl)-[1,4] diazepan- 2-one, 2,2,2-trifluoroacetate salt, 247 , M + H = 545;
[547] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-pyrrolidin-1-yl-ethanesulfonyl)-[l , 4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 248 , M + H = 571;
[548] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -l-methylethyl] amino} butyl) -4- (2-pyrrole-1-yl-ethanesulfonyl)-[1,4 ] Diazepan-2-one, 2,2,2-trifluoroacetate salt, 249 , M + H = 567;
[549] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-piperazin-1-yl-ethanesulfonyl)-[1, 4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 250 , M + H = 586;
[550] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- [2- (4-methylpiperazin-1-yl) -ethanesulfonyl ]-[1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 251 , M + H = 600;
[551] 1- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] ethylamino} butyl) -4- (2-methylamino-ethanesulfonyl)-[1,4] diazepan- 2-one, 2,2,2-trifluoroacetate salt, 252 , M + H = 531;
[552] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -4- (2-diethylamino-ethanesulfonyl)-[1,4] diazepan -2-one, 2,2,2-trifluoroacetate salt, 253 , M + H = 573;
[553] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] ethylamino} butyl) -4- (2-isopropyl-amino-ethanesulfonyl)-[1,4] dia Empan-2-one, 2,2,2-trifluoroacetate salt, 254 , M + H = 559;
[554] 1- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] ethylamino} butyl) -4- (2-benzyl-amino-ethanesulfonyl)-[1,4] dia Empan-2-one, 2,2,2-trifluoroacetate salt, 255 , M + H = 607;
[555] 1- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] ethylamino} butyl) -4- (2-benzyl-methylamino-ethanesulfonyl)-[1,4] Diazepan-2-one, 2,2,2-trifluoroacetate salt, 256 , M + H = 621;
[556] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- [2- (2-methoxy-ethylamino) -ethanesulfonyl]- [1,4] diazepan-2-one, 2,2,2-trifluoroacetate salt, 257 , M + H = 575;
[557] {2- [4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -l-methylethyl] amino} -butyl) -3-oxo- [1,4] diazepane-1-sul Ponyl] ethylamino} -acetic acid methyl ester, 2,2,2-trifluoroacetate salt, 258 , M + H = 589;
[558] 1- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] ethylamino} butyl) -4- (2-amino-ethanesulfonyl)-[1,4] diazepan- 2-one, 2,2,2-trifluoroacetate salt, 259 , M + H = 517;
[559] 1- (4- {ethyl- [2- (4-methanesulfonyl-phenyl) -1-methylethyl] amino} butyl) -4- (2-dimethylamino-ethanesulfonyl) -piperazin-2-one , 2,2,2-trifluoroacetate salt, 260 , M + H = 531;
[560] 1- (4- {ethyl- [2- (4-methanesulfonyl-phenyl) -1-methylethyl] amino} butyl) -4- (2-diethyl-amino-ethanesulfonyl) -piperazine-2 -One, 2,2,2-trifluoroacetate salt, 261 , M + H = 559;
[561] 1- (4- {ethyl- [2- (4-methanesulfonyl-phenyl) -1-methylethyl] amino} butyl) -4- (2-isopropyl-amino-ethanesulfonyl) -piperazine-2 -One, 2,2,2-trifluoroacetate salt, 262 , M + H = 545;
[562] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-pyrrolidin-1-yl-ethanesulfonyl) -piperazine 2-one, 2,2,2-trifluoroacetate salt, 263 , M + H = 557;
[563] 1- (4- {ethyl- [2- (4-methanesulfonyl-phenyl) -1-methylethyl] amino} butyl) -4- (2-benzyl-amino-ethanesulfonyl) -piperazine-2- On, 2,2,2-trifluoroacetate salt, 264 , M + H = 593;
[564] 1- (4- {ethyl- [2- (4-methane-sulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-benzyl-methylamino-ethanesulfonyl) -piperazine-2 -One, 2,2,2-trifluoroacetate salt, 265 , M + H = 607;
[565] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- [2- (2-hydroxy-ethylamino) -ethanesulfonyl]- Piperazine-2-one, 2,2,2-trifluoroacetate salt, 266 , M + H = 547;
[566] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- [2- (2-methoxy-ethylamino) -ethanesulfonyl]- Piperazin-2-one, 2,2,2-trifluoroacetate salt, 267 , M + H = 561;
[567] {2- [4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -3-oxo-piperazine-1-sulfonyl] ethylamino}- Acetic acid methyl ester, 2,2,2-trifluoroacetate salt, 268 , M + H = 575;
[568] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-piperazin-1-yl-ethanesulfonyl) -piperazin- 2-one, 2,2,2-trifluoroacetate salt, 269 , M + H = 572;
[569] 1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -4- [2- (4-methyl-piperazin-1-yl) -ethanesulfur Ponyl] -piperazin-2-one, 2,2,2-trifluoroacetate salt, 270 , M + H = 586; or
[570] 1- (4- {ethyl- [2- (4-methane-sulfonylphenyl) -1-methylethyl] amino} butyl) -4- (2-amino-ethanesulfonyl) -piperazin-2-one, 2,2,2-trifluoroacetate salt, 271 , M + H = 503.
[571] Example 6
[572] (Example of Preparation of Compound of Formula IDa Described in Scheme E)
[573] 4- (4-{[(S)-(4-Methanesulfonylphenyl) -1-methylethyl] -propylamino} butyl)-[1,4] oxazepan-5-one
[574]
[575] [(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propylamine (0.2 g, 0.78 mmol) and 4- (5-oxo-) in 1,2-dichloroethane (8 mL) To a mixture of [1,4] oxazapan-4-yl) -butyraldehyde (0.22 g, 1.2 mmol) sodium triacetoxyborohydride (0.25 g, 1.17 mmol) was added. The reaction mixture was stirred at rt for 15 h. The mixture was diluted with dichloromethane and washed with 5% sodium hydroxide. The organic phase was dried (magnesium sulfate) and concentrated to afford 4- (4-{[(S)-(4-methane-sulfonylphenyl) -1-methylethyl] -propylamino} butyl)-[1,4] oxazepan -5-one was obtained which was separated as a hygroscopic hydrochloride salt in diethyl ether (0.23 g), 273 ; Anal: calcd for C ₂₅ H ₃₇ ClN ₂ O ₄ S.1.4H ₂ O: C, 54.34; H, 8. 25; N, 5.76%; Found: C, 54.32; H, 8.03; N, 5.98%;
[576] Similarly, following the procedure described in Example 6 above, optionally replacing 4- (5-oxo- [1,4] oxazepan-4-yl) -butyraldehyde with another suitable compound of formula 1e, Optionally replace [(S) -2- (4-methane-sulfonylphenyl) -1-methylethyl] -propylamine with another suitable compound of Formula 2 and utilize modified methods known to those skilled in the art To prepare further compounds of formula IDa, wherein Z is -O- or -S-:
[577] 4-tert-butyl-N- [3- (2-{(4- (S-oxo- [1,4] oxapanane-4-yl) -butyl] propylamino} propyl) -phenyl] -bentamide , 274 , Analysis: Calcd for C ₃₂ H ₄₇ N ₃ O ₃ : C, 73.67; H, 9.08; N, 8.05%; Found: C, 73.74; H, 8.99; N, 8.23%; or
[578] 4- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] oxazepan-5-one, 2,2,2 -Trifluoroacetate salt, 275 , M + H = 465.
[579] Example 7
[580] (Example of Preparation of Compound of Formula IDb Described in Scheme E)
[581] 4- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methylethyll-propylamino} butyl)-[1,4] diazepan-5-one
[582]
[583] [(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propylamine hydrochloride (2.05 g, 7.03 mmol) in 1,2-dichloroethane (40 mL), triethylamine (0.98 ML, 7 mmol), 5-oxo-4- (4-oxobutyl)-[1,4] diazepane-1-carboxylic acid tert-butyl ester (2.0 g, 7.03 mmol), and sodium triacetoxybo A mixture of lohydrides (2.23 g, 10.5 mmol) was stirred at rt for 15 h. The mixture was concentrated and the residue was partitioned in diethyl ether and saturated sodium carbonate. The organic phase was dried (magnesium sulfate) and concentrated to a thick syrup as 4- (4-{[(S) -2- (4-methane-sulfonylphenyl) -1-methylethyl] propyl-amino} butyl) -5- Oxo- [1,4] diazepane-1-carboxylic acid tert-butyl ester (3.6 g) was obtained. M + H = 524. The hydrochloride salt was recrystallized from acetone / diethyl ether (melting point 156-158 ° C.).
[584] 4- (4-{[(S) -2- (4-Methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid 3 To N-butyl ester (3.7 g, 7.06 mmol) was added 6 N hydrochloric acid (7 mL). The reaction mixture was heated to 50 ° C. and then stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 10 with saturated sodium carbonate and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated to 4- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methyl from diethyl ether to dihydrochloride salt (with hygroscopicity) -Ethyl] propylamino} butyl)-[1,4] diazepan-5-one was obtained ((2.86 g), 277 , M + H = 424).
[585] Similarly, following the procedure described in Example 7, above, optionally, 5-oxo-4- (4-oxobutyl)-[1,4] diazepane-l-carboxylic acid tert-butyl ester Replace with another suitable compound, optionally replace [(S) -2- (4-methane-sulfonylphenyl) -1-methylethyl] -propylamine hydrochloride with another suitable compound of formula 2 and Using a modified method known to the skilled person, further compounds of formula IDb were prepared (where Z is> NH):
[586] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 278 , M + H = 410;
[587] 4- (4- {ethyl- [2- (4-trifluoromethanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 279 , M + H = 464;
[588] 4- (4-{[2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -1-methylethyl] ethylamino} butyl)-[1,4] diazepan-5 -One, 2,2,2-trifluoroacetate salt, 280 , M + H = 390;
[589] 4- (4-{[2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -1-methylethyl] propylamino} butyl)-[1,4] diazepane-5 -One, 2,2,2-trifluoroacetate salt, 281 , M + H = 404;
[590] 4- (4-{[2- (4-tert-Butylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepane-5-one, hydrochloride salt, 282 , M + H = 402;
[591] 4- (4-{[2- (3-trifluoromethylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 283 , M + H = 414;
[592] 4- (4-{[2- (4-methoxyphenyl) -l-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 284 , M + H = 376;
[593] 4- (4-{[2- (4-tert-Butylphenyl) -1-methylethyl] ethylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 285 , M < + > H = 388;
[594] 4- (4-{[2- (4-tert-butylphenyl) -1-methylethyl] isopropylamino} butyl)-[1,4] diazepane-5-one, hydrochloride salt, 286 , M + H = 402;
[595] 4- (4-{[2- (4-propanesulfonylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 287 , Assay: C Calcd for ₂₄ H ₄₂ ClN ₄ 0 ₃ S.0.75H ₂ 0: C, 53.57; H, 8.34; N, 7.81%; Found: C, 53.55; H, 8. 19; N, 7.91%;
[596] 4- [4-({2- [4- (propane-2-sulfonyl) phenyl] -1-methylethylpropylamino) butyl]-[1,4] diazepan-5-one, hydrochloride salt, 288 , Analysis: Calcd for C ₂₅ H ₄₄ ClN ₃ O ₃ S ₂ .0.95H ₂ O: C, 54.03; H, 8.51; N, 7.56%; Found: C, 54.05; H, 8. 36; N, 7.55%;
[597] 4- (4-{[2- (4-ethanesulfonylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 289 , Assay: C Calcd for ₂₃ H ₄₀ ClN ₃ O ₃ S: C, 54.11; H, 8.09; N, 8.23%; Found: C, 50.88; H, 7. 85; N, 7.67%;
[598] 4- (4-{[2- (4-naphthalen-2-yl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 290 , M + H = 396;
[599] 4- (4-{[2- (4-thiazole-2-sulfonylphenyl) -l-methylethyl] propylamino} butyl)-[1,4] diazepane-5-one, hydrochloride salt, 291 Anal: calcd for C ₂₅ H ₃₇ ClN ₄ O ₃ S ₂ .35 H ₂ O: C, 48.86; H, 6. 77; N, 9.91%; Found: C, 48.89; H, 6.71; N, 9.40%;
[600] 4- (4- {allyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 292 , Assay: Calcd for C ₂₂ H ₃₇ ClN ₃ 0 ₃ S ₂ 0.8H ₂ 0: C, 51.92; H, 7.65; N, 8.26%; Found: C, 51.82; H, 7. 48; N, 8.27%;
[601] 4- (4-{[2- (4-isobutoxyphenyl) -l-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 293 , M + H = 418;
[602] 4- [4-({2- [4- (2-methylpropane-2-sulfonyl) phenyl] -1-methylethyl} propylamino) -butyl]-[1,4] diazepan-5-one, Hydrochloride salt, 294 , M + H = 452;
[603] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 295 , M + H = 410;
[604] 4- (4-{[2- (4-aminophenyl) -l-methylethyl] ethylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 296 , M + H = 347 ;
[605] 4- (4- {ethyl- [2- (4-nitrophenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one, hydrochloride salt, 297 , M + H = 377;
[606] 4- (4-{[2- (4-hydroxyphenyl) -l-methylethyl] propylamino} butyl)-[l, 4] diazepan-5-one, hydrochloride salt, 298 , M + H = 362;
[607] 4- [4- (ethyl- {2- [4- (thiazol-2-sulfonyl) phenyl] -1-methylethyl} amino) butyl]-[1,4] diazepan-5-one, hydrochloride Salt, 299 , Anal .: Calcd for C ₂₅ H ₃₅ ClN ₄ O ₃ S ₂ .80 H ₂ O: C, 47.30; H, 6.83; N, 9.59%; Found: C, 47.31; H, 6. 43; N, 9.45%;
[608] 4- (2- {ethyl- [4- (7-oxo- [1,4] diazepane-1-yl) -butyl] amino} propyl) -benzoic acid methyl ester, hydrochloride salt, 300 , assay: C ₂₂ H ₃₆ ClN ₃ O ₃ .calculated for 0.80H ₂ O: C, 55.41; H, 8. 16; N, 8.81%; Found: C, 55.38; H, 8.04; N, 8.87%;
[609] N- [4- (2- {ethyl- [4- (7-oxo- [1,4] diazepane-1-yl) butyl] amino} propyl) phenyl] -methanesulfonamide, hydrochloride salt, 301 , M + H = 425;
[610] N-ethyl-4-2- {ethyl- [4- (7-oxo- [1,4] oxazepan-1-yl) butyl] amino} propyl) -benzamide, 302 , assay: C ₂₃ H ₃₉ ClN Calcd for ₄ 0 ₂ : C, 58.10; H, 8. 48; N, 11.78%; Found: C, 52.73; H, 8. 10; N, 10.80%;
[611] 4- [4- (ethyl- {2- [4- (pyrrolidin-1-carbonyl) phenyl] -1-methylethyl} amino) butyl]-[1,4] diazepan-5-one, hydro Chloride salt, 303 , Anal. Calcd for C ₂₅ H ₄₁ ClN ₄ O: C, 59.87; H, 8.44; N, 11.17%; Found: C, 50.76; H, 7.95; N, 9.52%;
[612] 4- [4- (ethyl- {2- [4- (2-oxo-piperidin-1-yl) phenyl] -1-methylethyl} amino) butyl]-[1,4] diazepan-5- On, hydrochloride salt, 304 , M + H = 429;
[613] 4- [4-({2- [4- (lH-imidazol-2-sulfonyl) phenyl] -1-methylethyl} amino) butyl]-[1,4] diazepan-5-one, hydrochloride Salt, 305 , Anal .: Calcd for C ₂₅ H ₄₀ ClN ₅ O ₃ S.0.3H ₂ O: C, 49.68; H, 7. 10; N, 11.59%; Found: C, 49.63; H, 7.00; N, 11.62%;
[614] N, N-dimethyl-2- [4-2-{[4- (7-oxo- [1,4] diazepan-l-yl) butyl] propylamino} propyl) benzenesulfonyl] acetamide, 306 , Anal: calcd for C ₂₅ H ₄₃ ClN ₄ O ₄ S: C, 52.90; H, 7.81; N, 9.87%; Found: C, 50.43; H, 7.56; N, 9.38%;
[615] 4- [4-({2- [4- (thiazol-2-yloxy) phenyl] -1-methylethyl} propylamino) butyl]-[1,4] diazepan-5-one, hydrochloride salt , 307 , M + H = 445;
[616] Propane-2-sulfonic acid 4- (2-{[4- (7-oxo- [1,4] diazepane-l-yl) butyl] propyl-amino} propyl) phenyl ester, hydrochloride salt, 308 , M + H = 468;
[617] 4- [4-({2- [4- (1,1-dioxo-isothiazolidin-2-yl) phenyl] -1-methylethyl} ethylamino) -butyl]-[1,4] dia Emulation-5-one, hydrochloride salt, 309 , M + H = 451; or
[618] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] -prop-2-ynylamino} butyl)-[1,4] diazepan-5-one, hydrochloride salt , 310 , Analysis: Calcd for C ₂₂ H ₃₄ ClN ₃ O ₃ S: C, 53.65; H, 7. 16; N, 8.53%; Found: C, 49.57; H, 6.83; N, 7.84%.
[619] Example 8
[620] Preparation of Compounds of Formula IDc Described in Scheme E
[621] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] -amino} butyl) -1- (isoxazole-5-carbonyl)-[l, 4] diazepan -5-on
[622]
[623] 4- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propyl-amino} butyl)-[1,4] diazepan-5 in toluene (5 mL) To a mixture of -one dihydrochloride (0.15 g, .3 mmol) and sodium carbonate (2 mL), isoxazole-5-carbonyl chloride (0.04 g, 0.31 mmol) was added. The reaction mixture was stirred at rt for 4 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate) and concentrated to 4- (4- {ethyl- [2- (4-methanesulfonyl-phenyl)-as a hygroscopic hydrochloride salt in ethyl acetate / diethyl ether. 1-methylethyl] amino} butyl) -1- (isoxazole-5-carbonyl)-[1,4] diazepan-5-one (0.14 g) was obtained ( 316 , M + H = 505).
[624] Similarly, follow the procedure described in Example 8 above, optionally with 4- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methylethyl] -propylamino} butyl)- [1,4] diazepan-5-one dihydrochloride is replaced with another free amine compound of formula IDb, optionally isoxazolezol-5-carbonyl chloride is replaced with other suitable acylating agents, alkylating agents, sulfonating agents, Additional compounds of formula I have been prepared utilizing modified methods known to those skilled in the art, where Z is> NR ⁶ .
[625] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-benzyll- [1,4] diazepan-5-one, hydrochloride salt , 317 , M + H = 500;
[626] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -l-methanesulfonyl- [1,4] diazepan-5-one, hydrochloride Salt, 318 , M + H = 488;
[627] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid amide, hydrochloride Salt, 319 , M + H = 453;
[628] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid dimethylamide, 2 , 2,2-trifluoroacetate salt, 320 ,
[629] M + H = 481;
[630] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid ethyl ester, 2 , 2,2-trifluoroacetate salt, 321 , M + H = 482;
[631] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1- (2-methoxy-acetyl)-[1,4] diazepan-5 -One, 2,2,2-trifluoroacetate salt, 322 , M + H = 482;
[632] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-propionyl-
[633] [1,4] diazepan-5-one, 2,2,2-trifluoroacetate salt, 323 , M + H = 466;
[634] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1- (furan-2-carbonyl)-[1,4] diazepan-5 -One, 2,2,2-trifluoroacetate salt, 324 , M + H = 504;
[635] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-iso-butyryl- [1,4] diazepan-5-one, 2 , 2,2-trifluoroacetate salt, 325 , M + H = 480;
[636] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-benzoyl- [1,4] diazepan-5-one, 2,2, 2-trifluoroacetate salt, 326 , M + H = 514;
[637] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-cyclobutan-carbonyl- [1,4] diazepan-5-one, 2,2,2-trifluoroacetate salt, 327 , M + H = 492;
[638] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1- (morpholine-4-carbonyl)-[1,4] diazepan- 5-one, 2,2,2-trifluoroacetate salt, 328 , M + H = 523;
[639] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1- (pyridine-3-carbonyl)-[1,4] diazepan-5 -One, 2,2,2-trifluoroacetate salt, 329, M + H = 515;
[640] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-cyclohexane-carbonyl- [1,4] diazepan-5-one, 2,2,2-trifluoroacetate salt, 330 , M + H = 520;
[641] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-sulfonic acid dimethylamide, 2 , 2,2-trifluoroacetate salt, 331 , M + H = 526;
[642] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid tert-butyl Amide, 2,2,2-trifluoroacetate salt, 332 , M + H = 509;
[643] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid phenylamide, 2 , 2,2-trifluoroacetate salt, 333 , M + H = 529;
[644] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid (2-meth Methoxyphenyl) amide, 2,2,2-trifluoroacetate salt, 334 , M + H = 559;
[645] 4- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -1-ethyl- [1,4] diazepan-5-one, 2,2, 2-trifluoroacetate salt, 335 , M + H = 438;
[646] 1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -4- (isoxazole-5-carbonyl)-[1,4] diazepane-5 -One , hydrochloride salt, 336 , M + H = 519;
[647] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -1-methyl- [1,4] diazepan-5-one, hydrochloride salt, 337 , M + H = 438;
[648] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methyl-ethyl] propylamino} butyl) -1- (2-amino-3-methylbutyryl)-[1,4] dia Emulation-5-one, hydrochloride salt, 338 , M + H = 523;
[649] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methyl-ethyl] propylamino} butyl) -1- (2-dimethylaminoethanesulfonyl)-[1,4] diazepan- 5-one, hydrochloride salt, 339 , M + H = 559;
[650] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid phenyl ester, hydrochloride Salt, 340 , Anal. Calcd for C ₂₉ H ₄₂ ClN ₃ O ₅ S: C, 60.04; H, 7. 30; N, 7.24%; Found: C, 58.80; H, 7. 84; N, 6.57%;
[651] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid tert-butyl ester , Hydrochloride salt, 341 , melting point 156 to 158 ° C .;
[652] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino] butyl} -5-oxo- [1,4] diazepane-1-yl) -phosphonic acid diethyl Ester, hydrochloride salt, 342 , M + H = 560;
[653] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid ethyl ester, hydrochloride Salt, 343 , melting point 135-137 ° C .;
[654] Acetic acid 2- [4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propyl-amino} butyl) -5-oxo- [1,4] diazepane-1-carbo Nil] -phenyl ester, hydrochloride salt, 344 , M + H = 586;
[655] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methyl-ethyl] propylamino} butyl) -1- (2-hydroxybenzoyl)-[1,4] diazepan-5- On, hydrochloride salt, 345 , M + H = 465;
[656] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo [1,4] diazepane-1-carboxylic acid propyl ester, hydrochloride salt , 346 , melting point 152 to 154 ° C .;
[657] 4- (4-{[2- (4-methanesulfonylphenyl) -l-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid isobutyl ester, hydro Chloride salt, 347 , Anal .: Calcd for C ₂₇ H ₄₆ ClN ₃ O ₅ S · 1.80H ₂ O: C, 57.89; H, 8. 28; N, 7.50%; Found: C, 57.59; H, 8. 20; N, 7.39%;
[658] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo [1,4] diazepane-1-carboxylic acid 2,2-dimethylpropyl Ester, hydrochloride salt, 348 , M + H = 538;
[659] 4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo [1,4] diazepane-1-carboxylic acid butyl ester, hydrochloride salt , 349 , M + H = 524;
[660] 4- (4-{[2- (4-methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-l-carboaldehyde , Hydrochloride salt, 350 , M + H = 452;
[661] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid Isopropyl ester, hydrochloride salt, 351 , melting point 142 to 143 ° C .;
[662] 1-acetyl-4- (4-{[2- (4-methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl)-[1,4] diazepan-5-one, Hydrochloride salt, 352 , M + H = 466;
[663] Acetic acid 2- [4- (4-{[2- (4-methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane- 1-carbonyl] -benzyl ester, hydrochloride salt, 353 , M + H = 600;
[664] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -1- (4-trifluoromethyl-benzyl)-[1, 4] diazepan-5-one, hydrochloride salt, 354 , M + H = 582;
[665] Acetic acid 4- [4- (4-{[2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane- 1-ylmethyl] -phenyl ester, hydrochloride salt, 355 , M + H = 572;
[666] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -1- [2- (3-trifluoromethyl-phenyl)- Ethyl]-[1,4] diazepan-5-one, hydrochloride salt, 356 , M + H = 596;
[667] 1- [2- (4-Chloro-phenyl) -ethyl] -4- (4-1 [2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl)- [1,4] diazepan-5-one, hydrochloride salt, 357 , M + H = 562;
[668] 4- (4-{[2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-aminol-butyl) -l- (2-methoxy-acetyl)-[1,4] Diazepan-5-one, 358 , M + H = 496;
[669] 1- (2-Isopropoxy-acetyl) -4- (4-{[2- (4-methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl)-[1,4 ] Diazepan-5-one, 359 , M + H = 524;
[670] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid Benzoylsulfanylmethyl ester, 360 , M + H = 618;
[671] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid Acetoxymethyl ester, 361 , melting point 143 to 144 ° C;
[672] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester, 362 , melting point 129 to 130 ° C;
[673] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -l-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-l-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester, 363 , M + H = 580;
[674] 4- (4-{[2- (4-Methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid Acetylsulfanylmethyl ester, 364 , melting point 142 to 144 ° C.
[675] Example 9
[676] (Other Preparations of Compounds of Formula I Described in Scheme F)
[677] 4- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -l-methyl-ethyl1-propyl-amino} -butyl) -5-oxo- [1,4] diazepane- 1-carboxylic acid tert-butyl ester
[678]
[679] Step 1:
[680] 4- {4- [5- (4-Methanesulfonyl-phenyl) -4-methyl-2-oxo-oxazolidin-3-yl] -propyl} -5-oxo- [1,4] diazepane- 1-carboxylic acid tert-butyl ester
[681] 5 g of 25% potassium- in toluene solution in a low temperature mixture of 2.5 g 5- (4-methanesulfonyl-phenyl) -4-methyl-oxazolidin-2-one and 7.5 ml N-methylpyrrolidone Tert-amylate was added slowly. After the mixture was stirred, it was cooled and 4.5 g of 4- (4-iodobutyl) -5-oxo- [1,4] diazepane-l-carboxylic acid tert-butyl ester was added. The mixture was stirred under room temperature for 6 hours. Add water and stir. The precipitated product was collected and dried to yield about 3.5 g of 4- {4- [5- (4-methanesulfonyl-phenyl) -4-methyl-2-oxo-oxazolidin-3-yl] -propyl}- 5-oxo- [1,4] diazephan-l-carboxylic acid tert-butyl ester was obtained.
[682] Step 2:
[683] 4- {4- [2- (4-Methanesulfonyl-phenyl) -1-methyl-ethylamino] -butyl} -5-oxo- [1,4] diazepane-1-carboxylic acid tert-butyl ester
[684] 10 g of 4- {4- [5- (4-methanesulfonyl-phenyl) -4-methyl-2-oxo-oxazolidin-3-yl] -butyl} -5-oxo- [1,4 ] A mixture of diazepan-1-carboxylic acid tert-butyl ester, 1 g of 20% palladium hydroxide on carbon, 10 ml of water, and 90 ml of isopropanol was stirred and heated to 50-60 ° C. 3.5 g of potassium formate in 5 ml of water was added slowly. The mixture was stirred for 3 hours, then cooled and filtered. The filtrate was removed to yield approximately 9 g of 4- {4- [2- (4-methanesulfonyl-phenyl) -1-methyl-ethylamino] -butyl} -5-oxo- [1,4] diazepane-1 -Carboxylic acid tert-butyl ester was obtained.
[685] Step 3:
[686] 4- (4-{[(S) -2- (4-Methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -5-oxo [1,4] diazepane-1 Carboxylic acid tert-butyl ester
[687] A mixture of sodium borohydride (0.55 g) and tetrahydrofuran (40 mL) was stirred and a mixture of acetic acid (2.62 g) and tetrahydrofuran (10 mL) was added slowly and cooled to maintain a temperature below room temperature. The mixture was stirred for several hours. 4- {4- [2- (4-Methanesulfonyl-phenyl) -1-methyl-ethylamino] -butyl} -5-oxo- [1,4] diazepan-1 in tetrahydrofuran (25 mL) A mixture of carboxylic acid tert-butyl ester (7.0 g) and propionaldehyde (0.85 g) was prepared. The solution was slowly added to the borohydro mixture with stirring. After the mixture was stirred for several hours, 25% sodium hydroxide (14 g) was added slowly. The upper organic layer was evaporated in vacuo. The residue was dissolved in toluene and washed with water. The organic layer was evaporated in vacuo to give 7.5 g of 4- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] -propyl-amino} -butyl) -5 as an oil. -Oxo- [1,4] diazepan-1-carboxylic acid tert-butyl ester was obtained.
[688] Example 10
[689] Compositions for Oral Administration
[690] ingredient% (Weight / weight) Active ingredient20.0% Lactose79.5% Magnesium stearate0.5%
[691] The ingredients are mixed and formulated into capsules containing about 100 mg each; One capsule is close to the total daily dose.
[692] Example 11
[693] Compositions for Oral Administration
[694] ingredient% (Weight / weight) Active ingredient20.0% Magnesium stearate0.5% Croscarmellose sodium2.0% Lactose76.5% PVP (polyvinylpyrrolidine)1.0%
[695] The components are combined and granulated using a solvent such as methanol. The formulation is then dried and formulated into tablets (which contain about 20 mg of active compound) with a suitable tablet making machine.
[696] Example 12
[697] Compositions for Oral Administration
[698] ingredientamount Active compound1.0 g Fumaric acid0.5 g Sodium chloride2.0 g Methyl paraben0.15 g Profile paraben0.05 g Granular sugar25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavor0.035 ml coloring agent0.5 mg Distilled waterProper amount to 100 ml
[699] The components are mixed and prepared in suspension for oral administration.
[700] Example 13
[701] Preparations for Parenteral Administration (Ⅳ)
[702] ingredient% (Weight / weight) Active ingredient0.25 g Sodium chlorideAppropriate amount to be in appearance Water for injection100 ml
[703] The active ingredient is dissolved in a portion of the water for injection. Sufficient sodium chloride is then added and stirred to form an isotonic solution. The solution is made up to the weight of the residue of the water for injection, filtered through 0.2 micron membrane filter paper and packaged under aseptic conditions.
[704] Example 14
[705] Suppository
[706] ingredient% (Weight / weight) Active ingredient1.0% Polyethylene Glycol 100074.5% Polyethylene Glycol 400024.5%
[707] The components are dissolved and mixed together in a steam bath and then poured into a mold containing a total weight of 2.5 g.
[708] Example 15
[709] Topical preparation
[710] ingredientg Active compound0.2 to 2 Span 602 Tween 602 Mineral oil5 Vaseline10 Methyl paraben0.15 Profile paraben0.05 Butylated Hydroxy Anisole (BHA)0.01 waterAppropriate amount to be 100
[711] All of the above components except water are combined and stirred and heated to about 60 ° C. A sufficient amount of water at 60 ° C. is then added and vigorously stirred to emulsify the components, then water is added to about 100 g.
[712] Example 16
[713] Nasal injection
[714] Several aqueous suspensions containing about 0.025 to 0.5% of active compound are prepared as nasal spray preparations. The agent optionally contains an inert component such as microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and the like. Hydrochloric acid is added to adjust pH. Nasal injection preparations may typically be injected via a nasal injector equipped with a metered pump to deliver about 50-100 μl of preparation at a time. A typical dosing regimen is 2-4 sprays every 4-12 hours.
[715] Example 17
[716] Study on Radioligand Binding
[717] In vivo inhibitory effects of the compounds of the invention are described in Hedge et al ., Br. J. Pharmacol. 1997 , 120, 1409-1418, using the modification method described.
[718] Cell membranes expressing human muscarinic receptors (m ₁ to m ₅ ) recombinant from ovarian cells of Chinese hamsters were used. Validation was performed with the radioligand [ ³ H] N-methyl scopolamine (0.4 nM, specific action 84 Cimmolmol- ¹ ) in Tris-Krebs buffer with a final volume of 0.25 ml. Nonspecific binding was characterized by 1 μM atropine. Verification was performed using the flash approximation verification technique. Competition-substitution curves were made using 10 concentrations of assay compound and analyzed by repetition curves fitting four parameter logics. pIC ₅₀ values (ie, -log values of IC ₅₀ ) were converted to pKi values using the Cheng-Prusoff equation.
[719] The muscarinic inhibitory action (which is expressed in pKi values) of some exemplary compounds of the invention is as follows:
[720] compoundm2m3m5m2 / m3m2 / m5m2 / m5 1- (2- {ethyl- [2- (4-methoxy-phenyl) -1-methylethyl] amino} ethyl) -pyrrolidin-2-one, dibenzoyl-L-tartrate salt, 12 7.326.955.362.3919 1- (2- {ethyl- [2- (4-methoxyphenyl) -1-methylethyl] amino} ethyl) -piperidin-2-one, dibenzoyl-L-tartrate salt, 14 7.156.485.14.711224 1- {4- [2-naphthalen-2yl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydrochloride salt, 39 7.757.475.691.911560 1- (4-{[2- (3,3-dimethyl-2,3-dihydrobenzofuran-6-yl) -1-methylethyl] propylamino} butyl) -piperidin-2-one, hydro Chloride salt, 54 8.518.446.241.2186151 4-nitrobenzenesulfonic acid 4- (2-{[2- (2-oxo-azpan-1-yl) butyl] propylamino} propyl) -phenyl ester, 2,2,2-trifluoroacetate salt, 71 8.197.996.631.63623 1- (3-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} propyl) -azpan-2-one, hydrochloride salt, 98 8.928.627.261.994623 1- (4 {ethyl- [2- (4-methanesulfonyl-phenyl) -1-methylethyl] amino} butyl) -azokan-2-one, hydrochloride salt, 119 8.708.386.862.086833 3- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl)-[1,3] oxazepan-2-one, hydrochloride salt, 124 8.448.096.272.2314866 1- (4- {ethyl- [2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] amino} butyl) -3-methyl- [1,3] diazepan-2-one, hydrochloride Salt, 141 7.527.506.161.032322 1- [4- (ethyl- {2- [4- (thiazole-2-sulfonyl) phenyl] -1-methylethyl} amino) butyl] -tetrahydropyrimidin-2-one, hydrochloride salt, 144 7.697.925.430.58182309 4- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl)-[1,4] oxazepan-3-one, hydrochloride salt, 146 8.018.046.030.9394101 1- (4-{[(S) -2-(-4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-2-one, dihydrochloride Salt, 149 8.268.365.870.79245309 N-methyl-4- (2-{[4- (2-oxo-piperazin-1-yl) butyl] propylamino} propyl) -benzenesulfonamide, hydrochloride salt, 153 7.718.325.930.2460245 1- (4- {ethyl- [2- (4-trifluoromethyl-phenyl) -1-methylethyl] amino} butyl)-[1,4] -diazepan-2-one, dihydro-chloride half Hydrate Salts, 160 8.548.466.7One6958
[721] compoundm2m3m5m2 / m3m2 / m5m2 / m5 1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methylethyl] propyl-amino} butyl) -4-methyl- [1,4] diazepan-2-one , Dihydrochloride salt, 166 8.297.945.772.23330148 1- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -4- (furan-2-carbonyl)-[1,4] diazepan-2 -One, 2,2,2-trifluoroacetate salt, 187 7.597.595.881.005151 1- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -4-methyl-piperazin-2-one, hydrochloride salt, 213 7.826.965.54719126 4- (4-{[(S)-(4-Methanesulfonyl-phenyl) -1-methylethyl] -propylamino} butyl)-[1,4] oxazepan-5-one, hydrochloride salt, 273 7.827.615.91.638150 4- (4-{[2- (2,3-Dihydrobenzo- [1,4] dioxin-6-yl) -1-methylethyl] propylamino} butyl)-[1,4] diazepane- 5-one, 2,2,2-trifluoroacetate salt, 281 8.057.585.922.9713545 4- (4-{[2- (4-tert-butylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepane-5-one, hydrochloride salt, 282 8.558.366.651.548052 4- (4- {allyl- [2- (4-methanesulfonyl-phenyl) -l-methylethyl] amino} butyl)-[1,4] diazepane-5-one, hydrochloride salt, 292 8.297.596.325.059419 Propane-2-sulfonic acid 4- (2-{[4- (7-oxo- [1,4] diazepan-1-yl) butyl] propylamino} propyl) -phenyl ester, hydrochloride salt, 308 7.837.526.042.046230 4- (4-{[2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid ethyl ester, hydro Chloride salt, 343 8.187.696.633.093511
[722] Example 18
[723] Oxotremorin / Pyrocarpin-induced Saliva Secretion (OIS / PIS) Model in Anesthetized Rats
[724] Female Spraque-Dawley rats (Charles-River, 200-300 g) were anesthetized with urethane (1.5 g / kg) and tracheostomy. A cannula for drug administration was inserted into one femoral vein. After an hour stabilization period, rats were pretreated with methoktramine (only for OIS) to antagonize the bradycardia mediated M ₂ receptor. Each animal was administered in a single dose of carrier or reference compound by intravenous injection. After 10 minutes, the previously weighed cotton pads were placed in the oral cavity of the animals, followed by administration of carrier or oxotremoline (0.1 mg / kg, iv) / pirocarpine (1 mg / kg, iv). Fresh cotton pads were placed 5 minutes after administration of oxotremoline / pyrocarpin and saliva was collected for an additional 5 minutes. The cotton pads (5 and 10 minute periods) were then reweighed to determine the amount of saliva secreted for 10 minutes.
[725] All groups treated with oxotremoline / pyrocarpin were compared using one-way batch analysis. Corresponding comparisons were made using Dunnett's test. The actual levels of data ranked by nonparametric techniques or data of parametric techniques are applied to analyzes that depend on the results of Bartlett's test, which tests for homogeneity of variance. The carrier / oxotremorin group and carrier / pyrocarpine were compared to the carrier / carrier group using the Wilcox on rank-sum test. The determination of ID ₅₀ for each compound was made in terms of the total weight secreted for 10 minutes for each animal. The sigmoidal model is of the form:
[726]
[727] Where ID ₅₀ is the dose when half of the maximum response is reached, N is the curvature parameter, and max is the maximum response to the dose response curve. The minimum response (min) was fixed at zero in this model.
[728] Compounds of the invention were active in this validation.
[729] Example 19
[730] Inhibition of Volume-Induced Contraction in Rats
[731] In vivo muscarinic receptor inhibition of a compound of the present invention is described in the modified method described in Hesd, SS et al., Proceedings of the 26th Annual Meeting of the international Continence Society 1996 (August 27th-30th), Abstract 126. Was defined using
[732] Female Spracu-Dawley rats were anesthetized with urethane and equipped with instruments for intravenous administration of the drug, and in some cases, instruments for measuring arterial pressure, heart rate and bladder internal pressure. The effect of assay compounds on volume-induced bladder contractions was defined in separate groups of animals. Volume-induced reflex bladder contractions were induced by filling the bladder with saline. Assay compounds were administered by intravenous infusion every 10 minutes. Atropine (0.3 mg / kg, iv) was administered at the end of this study as a positive control.
[733] Compounds of the invention were active in this validation.
[734] Example 20
[735] Anti-muscarinic action in anesthetized dogs
[736] In vivo muscarinic receptor inhibitory action of the compounds of the invention is described in Newgreen, DT et al ., J. Urol. 1996 , 155 ( suppl . 5), 1156].
[737] Female beagles (Marshall Farms, Knowles Rose, NY) were fasted for 18 hours prior to the experiment; Water was allowed to drink freely. On the day of the experiment, dogs were anesthetized and maintained at pentobarbital (36 mg / kg, iv immediate, then 5-10 mg / kg, iv sustained). Intravenous injections were also administered to dogs for the remainder of the experiment. The dog was ventilated through an endotracheal tube with a Harvard respirator (Model 163). Cannula was inserted into both femoral vein and femoral artery for drug administration and blood pressure measurement, respectively. Blood pressure was measured with a Gould transducer (model P23XL) and recorded with a Gould recorder (model 3400). The sublingual tongue was excised to expose the left lower jaw conduit, which inserted the cannula into a pre-weighed vial for subsequent saliva collection. The left salivary gland was exposed through the submandibular incision site. The chordal-lingual nerves were separated and a bipolar electrode placed on them for stimulation. The assay response of the chord-lingual nerves was obtained to confirm proper electrode placement.
[738] After surgery completion, physostigmine (180 μg / kg / hr, iv) (cholinesterase inhibitor) was filled for the remainder of the experiment. After the 1 hour stabilization period, two control chord-lingual nerve stimuli were performed at 20 hertz (Hz), 10 volts (V), and 0.5 ms periods (Grass S48). Chord-lingual nerves were stimulated for 20 seconds and 2 minutes, respectively, at least 10 minutes apart between each set of stimuli. After obtaining two compatible control reactions, the carrier or reference compound was administered in a cumulative manner 3 minutes before stimulating each chord-lingual nerve. The assay was not included in experiments in which a compatible saliva response could not be obtained. Atropine (1.0 mg / kg, iv) was administered at the end of this study as a positive control.
[739] Mean arterial blood pressure was calculated as dilatation arterial pressure + (constriction arterial pressure-dilation arterial pressure) / 3. Heart rate was derived from pressure pulse. Saliva was collected in pre-weighed vials and after each collection, the weight was measured to determine the volume of secreted saliva. Inhibitors of salivary gland response were expressed as a percentage of the atropine (1 mg / kg, iv) effect.
[740] ED ₅₀Measure
[741] For maximal inhibitory saliva, parameter measurements were performed using a nonlinear mixed model. The method was initially implemented using PROC NLIN and repeatedly using PROC MIXED. This procedure assumes the following sigmoidal dose-response model:
[742]
[743] Where the response is the maximum inhibition bladder contraction% of the peak, x is the log10 value of the therapeutic dose and the 4 parameters are as follows: log ₁₀ ED ₅₀ (μ), maximum and minimum response values (Max and Min), and curvature (σ). The minimum value was assumed to be 0%. The method assumes that the compound is symmetric to the covariance structure. An iterative curve-fit procedure could account for the dependencies between multiple measures from the same animal, and by adjusting the error calculation, predicted the desired parameters and their confidence limits and explained them within the range of main correlations.
[744] Baseline comparison
[745] In order to compare the respective doses to the baseline control for each variable, a binary ANOVA with the main effect of the subject and treatment was performed, followed by paired t-tests for each dose level. -test). If the overall therapeutic effect was not significant in Anova (p value> 0.05), Bonferroni adjustment to p value used the p value of the paired t-test for each dose.
[746] Compounds of the invention were active in this validation.
[747] While the invention has been described in connection with specific embodiments thereof, those skilled in the art will understand that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of the subject, process, process step or steps, to the purposes, spirit, and scope of the invention. All such modifications are considered to be within the scope of the claims appended hereto.

权利要求:
Claims (25)
[1" claim-type="Currently amended] A compound of formula (I), or a prodrug thereof, an individual isomer or a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt thereof:
Formula I

Where
R ¹ , R ² and R ³ are independently at each occurrence hydrogen, halogen, (C _1-6 ) -alkyl, -OR ', -SR', -NR'R ", -SOR ', -SO ₂ R', -COOR ', -OCOR', -OCONR'R ", -OSO ₂ R ', -OSO ₂ NR'R";-NR'SO ₂ R ", -NR'COR", -SO ₂ NR'R ", -SO ₂ (CH ₂ ) _1-3 CONR'R ", CONR'R", cyano, halogenalkyl or nitro, or
R ¹ and R ² , if adjacent to each other, optionally incorporate one or two ring heteroatoms selected from N, S (O) _0-2 or O together with the carbon to which they are attached and (C _1-6 ) -alkyl Can also form 5-7 membered aromatic saturated or unsaturated rings, optionally substituted with halogen, cyano or lower alkoxy;
R 'and R "are each independently hydrogen, (C _1-6 ) -alkyl, substituted (C _1-6 ) -alkyl, (C _0-3 ) -alkyl-alkoxy, aryl, heterocyclyl, hetero Aryl, aryl- (C _1-3 ) -alkyl, heteroaryl (C _1-3 ) -alkyl, heterocyclyl- (C _1-3 ) -alkyl, cycloalkylalkyl, cycloalkyl, or nitrogen to which they are attached Together, it may also form a 5 to 7 membered ring, optionally incorporating one additional ring heteroatom selected from N, O or S (O) _0-2 ;
R ⁴ in each occurrence is independently (C _1-6 ) -alkyl;
R ⁵ is independently at each occurrence (C _1-6 ) -alkyl, (C _1-6 ) -alkenyl, (C _1-6 ) -alkynyl or cycloalkyl;
One of X, Y or Z is independently —S—, —O—, —CH ₂ — or> NR ⁶ , and the other is —CH ₂ —;
R ⁶ is hydrogen, (C _1-6 ) -alkyl, halogenalkyl, aryl- (C _1-6 ) -alkyl, heteroaryl- (C _1-6 ) -alkyl,-(C _1-6 ) -CR ′ R'R ', -COOR', -SO ₂ R ', -C (O) R', -SO _2- (CH ₂ ) _0-3 -NR'R ", -CONR'R", -C (O ) OCH ₂ OC (O) R ', -C (O) O-CH ₂ -SC (O) R' or -PO (OR ') ₂ , wherein R' and R "are as defined above;
m is an integer from 0 to 3;
n is an integer of 1-6.
[2" claim-type="Currently amended] The method of claim 1,
R ¹ , R ² and R ³ are each independently hydrogen, halogen, (C _1-6 ) -alkyl, -OR ', -SR', -NR'R ", -SOR ', -SO ₂ R', -COOR ', -OCOR', -OCONR'R ", -OSO ₂ R ', -OSO ₂ NR'R";-NR'SO ₂ R ", -NR'COR", -SO ₂ NR'R ", -SO ₂ (CH ₂ ) _1-3 CONR'R ", CONR'R", cyano, halogenalkyl or nitro, or
If R ¹ and R ² are adjacent to each other, they optionally incorporate one or two ring heteroatoms selected from N, S (O) _0-2 or O together with the carbon to which they are attached and (C _1-6 ) -alkyl Can also form 5-7 membered aromatic saturated or unsaturated rings, optionally substituted with halogen, cyano or lower alkoxy;
R 'and R "are each independently hydrogen, (C _1-6 ) -alkyl, substituted (C _1-6 ) -alkyl, aryl, heterocyclyl, heteroaryl, aryl- (C _1-3 )- Alkyl, heteroaryl (C _1-3 ) -alkyl, heterocyclyl- (C _1-3 ) -alkyl, cycloalkylalkyl, cycloalkyl, or together with the nitrogen to which they are attached, N, O or S (O) Can also form 5-7 membered rings, optionally incorporating one additional ring heteroatom selected from _0-2 ;
R ⁴ in each occurrence is independently (C _1-6 ) -alkyl;
R ⁵ in each occurrence is independently (C _1-6 ) -alkyl, (C _1-6 ) -alkenyl, (C _1-6 ) -alkynyl or cycloalkyl;
One of X, Y or Z is independently —S—, —O—, —CH ₂ — or> NR ⁶ , and the other is —CH ₂ —;
R ⁶ is hydrogen, (C _1-6 ) -alkyl, halogenalkyl, aryl- (C _1-6 ) -alkyl, heteroaryl- (C _1-6 ) -alkyl,-(C _1-6 ) -CR ′ R'R ', -COOR', -SO ₂ R ', -C (O) R', -SO _2- (CH ₂ ) _0-3 -NR'R ", -CONR'R" or -PO (OR ') ₂ , wherein R' and R "are as defined above;
m is an integer from 0 to 3;
n is an integer from 1 to 6
compound.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
n is 3;
[4" claim-type="Currently amended] The method according to claim 1 or 2,
R ⁴ is methyl.
[5" claim-type="Currently amended] The method of claim 4, wherein
m is 0.
[6" claim-type="Currently amended] The method of claim 4, wherein
m is 1;
[7" claim-type="Currently amended] The method of claim 6,
Y is> NR ⁶ .
[8" claim-type="Currently amended] The method of claim 7, wherein
1- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -piperazin-2-one,
1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] propyl-amino} -butyl) -4-methyl-piperazin-2-one, and
N-methyl-4-((S) -2-{[4- (2-oxo-piperazin-1-yl) -butyl] -propyl-amino} -propyl) -benzenesulfonamide .
[9" claim-type="Currently amended] The method according to claim 3 or 4,
m is 2.
[10" claim-type="Currently amended] The method of claim 9,
1- (4- {ethyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl) -azpan-2-one,
4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} -butyl)-[1,4] oxazepan-3-one, and
1,1,1-trifluoromethanesulfonic acid 4- (2- {ethyl- [4- (2-oxo-azpan-1-yl) butyl] -amino} propyl) -phenyl ester selected from the group consisting of compound.
[11" claim-type="Currently amended] The method of claim 9,
One of X, Y or Z is> NR ⁶ and the other is -CH _2- .
[12" claim-type="Currently amended] The method of claim 11,
X is> NR ⁶ .
[13" claim-type="Currently amended] The method of claim 11,
Y is> NR ⁶ .
[14" claim-type="Currently amended] The method of claim 13,
1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-2-one,
1- (4- {ethyl-[(S) -1-methyl-2- (4-trifluoromethyl-phenyl) -ethyl] amino} -butyl)-[1,4] diazepan-2-one, And
1- (4-{[(S) -2- (4-methanesulfonyl-phenyl) -1-methyl-ethyl] propyl-amino} -butyl) -4-methyl- [1,4] diazepane-2 A compound selected from the group consisting of
[15" claim-type="Currently amended] The method of claim 11,
Z is> NR ⁶ .
[16" claim-type="Currently amended] The method of claim 15,
4- (4- {allyl- [2- (4-methanesulfonylphenyl) -1-methylethyl] amino} butyl)-[1,4] diazepan-5-one,
4- (4-{[2- (4-tert-butylphenyl) -1-methylethyl] propylamino} butyl)-[1,4] diazepan-5-one,
4- (4-{[2- (4-methanesulfonylphenyl) -1-methylethyl] propylamino} butyl) -5-oxo- [1,4] diazepane-1-carboxylic acid ethyl ester,
4- (4-{[(S) -2- (4-methanesulfonylphenyl) -1-methyl-ethyl] propylamino} butyl)-[1,4] diazepan-5-one,
Propane-2-sulfonic acid 4-((S) -2-{[4- (7-oxo- [1,4] -diazepin-1-yl) -butyl] -propyl-amino} -propyl) -phenyl Esters, and
4- (4-{[(S) -2- (2,3-dihydro-1,4-benzodioxin-6-yl) -1-methyl-ethyl] propyl-amino} -butyl)-[1 , 4] -diazepan-5-one.
[17" claim-type="Currently amended] The method according to claim 3 or 4,
One of X, Y or Z is -O- or -S-, and the other is -CH _2- .
[18" claim-type="Currently amended] A pharmaceutical composition containing a therapeutically effective amount of at least one compound according to any one of claims 1 to 17 together with a pharmaceutically acceptable carrier.
[19" claim-type="Currently amended] The method of claim 18,
A pharmaceutical composition suitable for administration to a subject with a disease state that the compound is alleviated by treatment with a M2 / M3 muscarinic receptor antagonist.
[20" claim-type="Currently amended] a) reacting a compound of formula II with a compound of formula III to yield a compound of formula I;
b) (i) reacting an aryl metal compound of formula IV with a compound of formula V to yield a compound of formula VI, (ii) reducing the compound of formula VI and then cyclizing, wherein R ⁵ L, wherein L Is a leaving group) to obtain a compound of formula VII, (iii) reducing the compound of formula VII and treating with a compound of formula II to obtain a compound of formula I; or
c) (i) reducing the compound of formula VI, followed by cyclization, (ii) treating the compound of formula VI with a compound of formula VIII, (iii) reducing the product to give a compound of formula IX, and (iv A process for the preparation of a compound according to claim 1 comprising alkylating a compound of formula IX with a suitable aldehyde or a compound of formula R ⁵ L, wherein L is a leaving group
Formula I

Formula II

Formula III

Formula IV

Formula V

Formula VI

Formula VII

Formula VIII

Formula IX

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, n, X, Y and Z are as defined in claim 1,
M is a metal or magnesium halide,
R is alkyl, aryl or arylalkyl,
R ^a and R ^b are alkyl or alkoxy or together with the nitrogen to which they are attached form a ring,
L is a leaving group.
[21" claim-type="Currently amended] The method according to any one of claims 1 to 17,
A compound prepared by the method of claim 20 or an equivalent method.
[22" claim-type="Currently amended] Use of at least one compound according to any one of claims 1 to 17 for the treatment or prevention of a disease.
[23" claim-type="Currently amended] Use of at least one compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment or prophylaxis of a disease state that is alleviated by treatment with a M2 / M3 muscarinic antagonist.
[24" claim-type="Currently amended] Use wherein the disease state is associated with a smooth muscle disorder comprising a genitourinary or gastrointestinal disorder, or a respiratory disease.
[25" claim-type="Currently amended] Inventions described herein.

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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:
2000-05-25|Priority to US20748300P

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2000-05-25|Priority to US60/207,483

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2001-02-09|Priority to US26757901P

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2001-02-09|Priority to US60/267,579

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2001-05-16|Application filed by 에프. 호프만-라 로슈 아게

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2001-05-16|Priority to PCT/EP2001/005584

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2003-01-10|Publication of KR20030003763A

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2006-01-20|Application granted

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2006-01-20|Publication of KR100544000B1

优先权:

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申请号 | 申请日 | 专利标题

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US20748300P| true| 2000-05-25|2000-05-25|

---

US60/207,483|2000-05-25|

---

US26757901P| true| 2001-02-09|2001-02-09|

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US60/267,579|2001-02-09|

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PCT/EP2001/005584|WO2001090081A1|2000-05-25|2001-05-16|Substituted 1-aminoalkyl-lactams and their use as muscarinic receptor antagonists|