Piperidine ccr-3 receptor antagonists

专利摘要:
The present invention relates to piperidine quaternary salts of the formula (I) which are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods of using them and methods of preparing these compounds: Formula I
公开号:KR20010081034A
申请号:KR1020017006393
申请日:1999-11-08
公开日:2001-08-25
发明作者:허쉬펠드도날드로이；케르테즈데니스존；스미스데이비드버나드
申请人:프리돌린 클라우스너, 롤란드 비. 보레르；에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Piperidine CCR-3 RECEPTOR ANTAGONISTS < RTI ID = 0.0 >
[2] Tissue eosinophilia is a hallmark of a number of pathological conditions such as asthma, rhinitis, eczema, and congenital infection (Bousquet, J. et al ., N Eng. J. Med . 323 : 1033-1039 (1990) and Kay, AB and Corrigan, CJ, Br. Med. Bull . In asthma, eosinophil accumulation and activation are associated with damage to the bronchial epithelium and hypersensitivity to the sphincter mediator, such as RANTES, eotaxin, and MCP-3. Chemokine is known to activate eosinophils (Baggiolini, M. and Dahinden, CA, Immunol. Today . 15: 127-133 (1994), Rot, AM et al ., J. Exp. Med . 176, 1489-1495 (1992), and Ponath (PD) et al., J. Clin. Invest. , Vol. 97, # 3, 604-612 (1996)]. However, unlike RANTES and MCP-3, which also induce the migration of other types of leukocyte cells, eotaxin is selectively chemotactic for eosinophils - Griffith-Johnson, DA et al., Biochem. Biophy. Res. Commun . 197: 1167 (1993), and Jose, PJ et al., Biochem. Biophy. Res. Commun . Specific eosinophil accumulation was found regardless of endothelial or intraperitoneal injection or inhalation of aerosols at the site of injection of eotaxin [Creepitz-Johnson et al., Biochem. Biophy. Res. Commun . 197: 1167 (1993); Jos et al ., J. Exp. Med . 179, 881-887 (1994); Rothenberg, ME, et al ., J. Exp. Med . 181, 1211 (1995) " and Fonas et al., J. Clin. Invest. , Vol. 97, # 3, 604-612 (1996)).
[3] Glucocorticoids such as dexamethasone, metoprednisolone and hydrocortisone have been used to treat a number of eosinophil-related disorders, including bronchial asthma [RP Schleimer et al . , Am. Rev. Respir. Dis. , 141 , ≪ / RTI > 559 (1990)). Glucocorticoids are thought to inhibit the survival of IL-5, IL-3 mediated eosinophils in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis, and delayed patient growth (Hanania NA et al. , J. Allergy and Clin. Immunol. , Vol. 96, 571- 579 (1995) and Saha MT et al., Acta Paediatrica , Vol. 86, # 2, 138-142 (1997)). Accordingly, there is a need to find other means of treating eosinophil-related diseases without causing such undesirable side effects.
[4] Recently, the CCR-3 receptor has been identified as a major chemokine receptor using eosinophils because of the response to eotaxin, RANTES and MCP-3. CCR-3 binds to eotaxin, RANTES and MCP-3, and the chemotactic response to these cells is transferred to Eotaxin, RANTES and MCP-3 when cells are infected into the murine pre-beta rimforma line J. Exp. Med . 183, 2437-2448 (1996)). The CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin.
[5] Studies have shown that pre-treatment of eosinophils with anti-CCR-3 mAbs completely inhibits eosinophil chemotaxis against eotaxin, RANTES and MCP-3 (Heath H. et al., J. Clin. Invest ., Vol. 99, # 2, 178-184 (1997)). WO 98/04554 discloses piperidine analogs that are CCR-3 receptor antagonists.
[6] For the treatment of eosinophil-mediated inflammatory diseases, the ability of the CCR-3 receptor to bind RANTES, MCP-3 and eotaxin is blocked, thereby blocking eosinophil replenishment.
[7] Accordingly, the present invention relates to novel piperidine quaternary salts that can inhibit the binding of eotaxin to the CCR-3 receptor and thereby provide a means of treating eosinophil-induced diseases such as asthma.
[1] The present invention relates to a specific piperidine quaternary salt which is a CCR-3 receptor antagonist, a pharmaceutical composition containing the same, a method of using the same, and a method for producing these compounds.
[8] In a first aspect, the present invention relates to a compound selected from the group of compounds represented by formula (I), or a prodrug thereof, an individual isomer, a mixture of isomers and a pharmaceutically acceptable salt thereof:
[9]
[10] In this formula,
[11] One of T and U is -N ⁺ R ⁵ - provided that, where R ⁵ is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl alkyl, amido alkyl, sulfonylamino alkyl Or aralkyl and the remainder is -CH-;
[12] X ^- is a pharmaceutically acceptable counter ion;
[13] R ¹ and R ² are independently of each other hydrogen or alkyl;
[14] m is an integer being 0 to 3, with the proviso that T is -N ⁺ R ⁵ - If, m is 1 or more and;
[15] Ar and Ar < ¹ > are independently of each other aryl or heteroaryl;
[16] F is alkylene, alkenylene or a bond;
[17] R is hydrogen or alkyl, or taken together with R < ³ > or R < ⁴ >, and the atoms to which they are attached, form a carbocycle or heterocycle;
[18] R ³ and R ⁴ are independently from each other hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, Z is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, Aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy);
[19] E is ^{-C (O) N (R 6} ) -, -SO 2 N (R 6) -, -N (R 7) C (O) N (R 6) -, -N (R 7) SO 2 N ^{(R 6) -, -N (} R 7) C (S) N (R 6) -, -N (R 7) C (O) - or -N (R ⁷⁾ SO ₂ - provided that, where R ⁶ and R ⁷ is independently hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkyl, alkenyl each other, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or - (alkylene) (O) -Z wherein Z is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, Aryl, heteroaryloxy or heteroaralkyloxy;
[20] Q is -CO-, or ^{-C (O) -, -NR 8} -, -O-, S (O) 0-2 -, -C (O) N (R 8) -, -N (R 8) C (O) -, -N ( R 8) SO 2 -, -SO 2 N (R 8) -, -N (R 9) C (O) N (R 10) -, -N (R 9) SO ₂ N (R ¹⁰⁾ - or ^{-N (R 9) C (S} ) N (R 10) - being optionally substituted alkylene swaeyi intervention by wherein R ^8, R ⁹ and R ¹⁰ are each independently hydrogen, Heteroaryl, heterocyclylalkyl, heteroalkyl or - (alkylene) -C (O) -Z (alkyl), acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, Z is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or hetero Aralkyloxy.
[21] In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[22] In a third aspect, the present invention relates to a method of treating a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. will be. Such diseases include respiratory diseases such as asthma.
[23] In a fourth aspect, the invention relates to a process for the preparation of a compound of formula (I).
[24] Unless otherwise indicated, the following terms used in the specification and claims have the meanings given below: < RTI ID = 0.0 >
[25] "Alkyl" means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms, examples of which are methyl, ethyl, propyl, 2-propyl, pentyl and the like.
[26] &Quot; Alkenyl " means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms containing at least one double bond, such as ethenyl, propenyl, and the like.
[27] "Alkylene" means a linear saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms, examples of which include methylene, ethylene, propylene, 2-methylpropylene, pentylene,
[28] &Quot; Alkenylene " means a linear bivalent hydrocarbon radical having 2 to 6 carbon atoms, or a branched bivalent hydrocarbon radical having 3 to 6 carbon atoms containing at least one double bond, examples of which include ethenylene, 2,4-pentadienylene .
[29] "Acyl" refers to a radical -C (O) R where R is alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, Benzoyl, < / RTI >
[30] "Acyloxy" refers to the radical -OC (O) R, wherein R is hydrogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, or optionally substituted phenyl, examples of which include acetoxy, benzoyloxy, and the like .
[31] &Quot; Acylamino " means a radical -NRC (O) R ', where R is hydrogen or alkyl and R' is alkyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, Acetylamino, trifluoroacetylamino, benzoylamino, methyl acetylamino, and the like.
[32] &Quot; Halo " means fluoro, chloro, bromo and iodo, preferably fluoro and chloro.
[33] "Haloalkyl" means alkyl substituted by one or more same or different halo atoms, examples of which are -CH ₂ Cl-, -CF ₃ -, -CF ₂ CF ₃ , -CH ₂ CCl _3, and the like.
[34] &Quot; Cycloalkyl " means a saturated monovalent cyclic hydrocarbon radical having from 3 to 6 carbon atoms, examples of which are cyclopropyl, cyclohexyl, and the like.
[35] "Carbocycle" means a saturated cyclic group of 3 to 6 ring atoms in which all the ring atoms are carbon, examples of which are cyclopentyl, cyclohexyl, and the like.
[36] &Quot; Mono-substituted amino " means a radical -NHR, wherein R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, ) Amino, phenylamino, and the like.
[37] &Quot; Disubstituted amino " is a radical -NRR ', wherein R and R' are independently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl. Representative examples thereof include, but are not limited to, dimethylamino, methylethylamino, di (1-methylethyl) amino, and the like.
[38] &Quot; Aryl " means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical having 6 to 10 ring atoms; Optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted heteroaryl, Substituted or unsubstituted amino, acylamino, hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, -OR where R is hydrogen, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl , optionally substituted phenyl, heteroaryl or a _{heteroaralkyl], -S (O) n R} [ where, n is an integer from 0 to 2, R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl , Optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, mono-substituted amino or disubstituted amino], -NRSO ₂ R 'wherein R is hydrogen or alkyl and R' is alkyl, Substituted amino Wherein R is hydrogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, or optionally substituted phenyl, -COOR where R is hydrogen, alkyl Heteroaryl or heteroaralkyl, - (alkylene) COOR where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl, methylenedioxy, R 'and R " are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl, Heteroaryl, or heteroaralkyl. ≪ Desc / Clms Page number 6 >< RTI ID = 0.0 > More specifically, aryl Includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
[39] &Quot; optionally substituted phenyl " is optionally substituted alkyl, haloalkyl, halo, nitro, cyano, -OR where R is hydrogen or alkyl, -NRR 'wherein R and R' Or alkyl, -COOR where R is hydrogen or alkyl, or -CONR'R ", wherein R 'and R " are independently hydrogen or alkyl. Means a substituted phenyl group.
[40] &Quot; Heteroaryl " means a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms containing one to three ring heteroatoms selected from N, O or S (wherein the remaining ring atoms are C). Aromatic radicals include, but are not limited to, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted phenyl, amino, monosubstituted amino, disubstituted amino, acylamino, Wherein R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, - (CH2) n -, - S (O) _n R [where, n is an integer from 0 to 2, R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, be a substituted amino, or disubstituted amino , -COOR where R is hydrogen, alkyl or optionally substituted phenyl, - C (O) R wherein R is hydrogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, - (alkylene) CO < RTI ID = 0.0 > OR, wherein R is hydrogen, alkyl or optionally substituted phenyl, methylenedioxy, 1,2-ethylenedioxy, -CONR'R "or - (alkylene) -CONR'R" And R " are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl or optionally substituted phenyl. In particular, the term heteroaryl is meant to include pyridyl, pyrrolyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzo Triazolyl, benzisoxazolyl, furunyl, quinolinyl, benzopyranyl, and derivatives thereof.
[41] &Quot; Heterocycle " or " heterocyclyl " refers to a monocyclic or bicyclic heterocyclic ring containing 3 to 8 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O, or S (O) _n wherein n is an integer from 0 to 2, Quot; means a saturated or unsaturated cyclic radical. The heterocyclo ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, acylamino, , -COOR where R is hydrogen or alkyl, -XR where X is O or S (O) _n , n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cycloalkyl R ' and R " are independently selected from hydrogen or alkyl), or - CONR ' R & . Representative examples include, but are not limited to, tetrahydropyranyl, piperidino, 1- (4-chlorophenyl) piperidino, and the like.
[42] &Quot; Heteroalkyl " means an alkyl, cycloalkyl or cycloalkylalkyl having a substituent containing a heteroatom selected from N, O or S (O) _n , wherein n is an integer from 0 to 2, do. Representative substituents include -NR ^a R ^b , -OR ^a or -S (O) _n R ^c where n is an integer from 0 to 2 and R ^a is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl , Optionally substituted phenyl, pyridyl, -COR where R is alkyl or alkoxy, or aminoalkyl, and R ^b is hydrogen, alkyl, -SO ₂ R where R is alkyl or hydroxyalkyl, , -SO ₂ NRR '(wherein, R and R' are independently hydrogen or alkyl from each other), or -CONR'R "(where, R 'and R" are independently selected from hydrogen or alkyl), and, R ^c Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, mono-substituted amino, or disubstituted amino. Representative examples include, but are not limited to, 2-methoxyethyl, benzyloxymethyl, and the like.
[43] &Quot; Hydroxyalkyl " is a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, with the proviso that at least two hydroxy groups are the same carbon It can not exist at the same time on an atom. Representative examples thereof include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, Dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) Hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- (hydroxymethyl) -2-hydroxyethyl, preferably 2-hydroxyethyl, -Hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and 4-hydroxybutyl.
[44] &Quot; Aminoalkyl " means an alkyl radical having one or two amino groups as described above, examples of which include 2-aminoethyl, 2-aminopropyl, 3- aminopropyl, 1- -Methylpropyl and the like.
[45] &Quot; Amidoalkyl " means an alkyl radical having the group -NRCOR ^a (where R is hydrogen or alkyl and R ^a is alkyl as described above) as described above, examples of which include (CH ₂ ) ₂ NHCOCH ₃ , - (CH ₂ ) ₃ NHCOCH _3, and the like.
[46] &Quot; Sulfonylaminoalkyl " means an alkyl radical having ^a -NRSO ₂ R ^a group as described above, examples of which include - (CH ₂ ) ₂ NHSO ₂ CH ₃ , - (CH ₂ ) ₃ NHSO ₂ CH ₃ , - (CH ₂ ) ₂ NHSO ₂ C ₂ H _5, and the like.
[47] &Quot; Carboxyalkyl " means an alkyl radical having a carboxy group as described above, examples of which include carboxymethyl, 2- carboxyethyl, 2- carboxypropyl, 3- carboxypropyl, 1- (carboxymethyl) -2- Methyl-propyl and the like.
[48] &Quot; Alkoxycarbonylalkyl " means an alkyl radical having a COOR group (where R is an alkyl group as defined above) as described above, examples of which include 2-methoxycarbonylethyl, ethoxycarbonyl Methyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, and the like.
[49] &Quot; Alkoxyalkyl " means an alkyl radical having an alkoxy group as described above, examples of which include methoxymethyl, 2- methoxyethyl, 2- methoxypropyl, 3- methoxypropyl, 1- (methoxy Methyl) -2-methylpropyl and the like.
[50] &Quot; Cyanoalkyl " means an alkyl radical having a cyano group as described above, examples of which include 2-cyanoethyl, 2-cyanopropyl, 3- cyanopropyl, 1- (cyanomethyl) Methylpropyl and the like.
[51] &Quot; Cycloalkylalkyl " means ^a radical -R ^a R ^b where R ^a is an alkylene group and R ^b is a cycloalkyl group, as described above, examples of which include cyclopropylmethyl, cyclohexylpropyl, 3- Cyclohexyl-2-methylpropyl and the like.
[52] &Quot; Aralkyl " is ^a radical -R ^a R ^b where R ^a is an alkylene group and R ^b is an aryl group, as described above, and examples thereof include benzyl, phenylethyl, 3- (3- ) -2-methylpentyl and the like.
[53] &Quot; Heteroaralkyl " means ^a radical -R ^a R ^b , wherein R ^a is an alkylene group and R ^b is a heteroaryl group, as described above, examples of which include pyridin- 2-yl) propyl and the like.
[54] &Quot; Heterocyclylalkyl " means ^a radical-R ^a R ^b where R ^a is an alkylene group and R ^b is a heterocyclo group, as described above, examples of which include tetrahydrofuran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, and the like.
[55] The term " alkoxy ", " haloalkyloxy ", " aryloxy ", " heteroaryloxy ", " aralkyloxy " or " heteroaralkyloxy " Alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl), examples of which are methoxy, phenoxy, pyridin-2- yloxy, benzyloxy and the like.
[56] &Quot; Optional " or " optionally " means a subsequently described event or circumstance that may or may not occur, and includes instances where an event or circumstance occurs and instances in which it does not . For example, "a heterocyclo group optionally mono- or disubstituted with an alkyl group" may or may not be present, and it is not necessary that the heterocyclo group be mono- or di-substituted with an alkyl group and the case where the heterocyclo group is alkyl Quot; is meant to include a situation in which the group is not substituted.
[57] &Quot; Amino-protecting group " refers to an organic group that is intended to protect a nitrogen atom against undesired reactions during synthetic procedures, such as benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC) Fluoroacetyl and the like.
[58] &Quot; Isomers " refer to compounds that have the same molecular structure but differ in the nature or sequence of bonding of their atoms, or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are referred to as " stereoisomers ". Stereoisomers that are not mirror images of one another are referred to as " diastereomers ", and stereoisomers that are non-superimposable mirror images are referred to as " enantiomers ". When a compound has an asymmetric center, for example when a carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers may characterize the complete form of their asymmetric center and may be described by Cahn and Prelog in the R- or S-Sequencing Rules, or by the way the molecule rotates the polarizer And are referred to as dextrorotatory or levorotatory (i.e., as (+) - or (-) - isomers, respectively). The chiral compound may be present as an individual enantiomer or as a mixture thereof. A mixture containing the same proportions of enantiomers is referred to as a " racemic mixture ".
[59] Since the compounds of the present invention may have one or more asymmetric centers, such compounds may be prepared as individual ( R ) - or ( S ) -stereoisomers or mixtures thereof. For example, if the R < ³ > and R < ⁴ > substituents in the compounds of formula I are different, the carbon to which they are attached is an asymmetric center and the compound of formula I may exist as an ( R ) - or ( S ) -stereoisomer. Unless otherwise indicated, the description or designation of specific compounds within the specification and claims is intended to include individual enantiomers and mixtures, racemates, and the like. Methods of measuring photochemistry and methods of separating optical isomers are well known in the art (see J. March, Advanced Organic Chemistry, 1992, New York, NY, published by John Wiley and Sons, , ≪ / RTI > 4th edition ").
[60] &Quot; Pharmaceutically acceptable excipient " means an excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically unacceptable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. &Quot; Pharmaceutically acceptable excipient " as used in the specification and claims includes one or more of the above excipients.
[61] &Quot; Pharmaceutically acceptable counter ion " refers to an ion having a charge opposite to the relevant substance and is pharmaceutically acceptable. Examples thereof include chloride, bromide, iodide, methanesulfonate, p-tolylsulfonate , Trifluoroacetate, acetate, and the like.
[62] &Quot; Pharmaceutically acceptable salt " of a compound means a pharmaceutically acceptable salt having the desired pharmacological activity of the parent compound. Such salts include the following.
[63] (1) using an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; Examples of the organic acid include organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy- 1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert -butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Acid addition salts;
[64] (2) when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion); A salt that coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.).
[65] &Quot; leaving group " is typically associated with an atom or group that can be replaced by a nucleophilic compound, such as halo, alkanesulfonyloxy, arenesulfonyloxy, ester or amino, in synthetic organic chemistry, Bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N, O-dimethyl-hydroxyl-amino and the like.
[66] &Quot; Prenatal drug " means any compound that releases an active parent drug according to formula I in vivo when such a pioneering agent is administered to a mammalian subject. The precursor drugs of the compounds of formula I are prepared by modifying the functional groups present in the compounds of formula I in such a way that the modified substance can be cleaved in vivo to release the parent compound. The precursor agent is a compound of formula I wherein any of the hydroxy, sulfhydryl or amino groups in the compounds of formula I can be cleaved in vivo to regenerate the free hydroxyl, amino or sulfhydryl groups, Lt; / RTI > Examples of precursor agents include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives), carbamates of hydroxy functionalities (e.g., N, N-dimethylaminocarbonyl) .
[67] The term " treating or treating " of a disease is intended to include: (1) preventing the disease from occurring in a subject that has been exposed to the disease or is susceptible to the disease but has not yet suffered from the disease, Or; (2) inhibiting the disease, i. E. Inhibiting the progression of the disease or its clinical symptoms; Or (3) relieving the disease, i. E., Alleviating the disease or its clinical symptoms.
[68] &Quot; Therapeutically effective amount " means an amount of a compound that, when administered to a mammal for treating a disease, exhibits a sufficient effect in treating the disease. The " therapeutically effective amount " will vary with the compound, the disease and its gastric neutering and the age, weight, etc. of the mammal being treated.
[69] The nomenclature used herein is generally based on IUPAC recommendations.
[70] For example, in a compound of formula I, T is -N ⁺ R ⁵ -, and U is carbon, m is 1, and R, R ^1, R ² and R ³ are hydrogen, R ⁴ is 1-methyl is ethyl, R ⁵ is ethyl, X is iodide, E is -NHC (O) NH-, F is a bond, Q is -CH ₂ - and, Ar is 3,4,5-trimethoxy ethoxy-phenyl, and Ar ¹ is 3, 4-chlorophenyl, when R ³ and R ⁴ is attached to the carbon is R, 4- (3,4-dichlorobenzyl) -1-ethyl-1-stereochemistry at the [ Methyl-2 ( R ) - [3- (3,4,5-trimethoxyphenyl) ureido] butyl] -piperidinium iodide.
[71] In the compounds of formula I, T is -N ⁺ R ⁵ -, and U is carbon, and m is 1, R, R ^1, R ² and R ³ is hydrogen, R ⁴ is 1-methylethyl, R and ⁵ is methyl, X is chloride, E is -C (O) NH-, F is a bond, Q is -CH ₂ -, and Ar is 4- (2-aminoethyl) phenyl, Ar ¹ is and 3, 4-chlorophenyl, R ³ and R ⁴ if the carbon is attached to R, in the stereochemistry of 1- [2- (R) - [ 4- (2- aminoethyl) -benzoylamino] -3 Methylbutyl] -4- (3,4-dichlorobenzyl) -1-methyl-piperidinium chloride.
[72] Representative compounds of the invention are:
[73] I. T is -N ⁺ R ⁵ -, and U is carbon, m is 1, and R, R ^1, R ² and R ³ is hydrogen, F is bonded, Q is -CH ₂ -, and E Is -C (O) NH- and the other groups are defined as in Table 1 below, representative compounds of Formula I are compounds of structural formula in Table 1 below.
[74] CPD # Stereochemistry Ar R ⁴ R ⁵ X ^- Ar ¹ Mass spectrum (m / e) One ( R ) 4-methylphenyl 1-methylethyl methyl Cl 3,4-dichlorophenyl 461 2 ( R ) 4-methylphenyl 1-methylethyl methyl TFA 3,4-dichlorophenyl 461 3 ( R ) 4- [2- (tert-Butoxy-carbonylamino) -ethyl)] phenyl 1-methylethyl ethyl I 3,4-dichlorophenyl 604 4 ( R ) 4- (2-aminoethyl) phenyl 1-methylethyl methyl Cl 3,4-Dichlorophenyl-HCl 490 5 ( S ) 4-methylphenyl 1-methylethyl methyl Cl 3,4-dichlorophenyl 461 6 ( R ) 4- (2-aminoethyl) phenyl 1-methylethyl ethyl Cl 3,4-Dichlorophenyl-HCl 504 7 ( S ) 4- [2- (tert-Butoxy-carbonylamino) -ethyl)] phenyl 1-methylethyl ethyl I 3,4-dichlorophenyl 604 8 ( S ) 4- (2-aminoethyl) phenyl 1-methylethyl ethyl Cl 3,4-Dichlorophenyl-HCl 504 9 ( S ) 4- (2-aminoethyl) phenyl 1-methylethyl ethyl Cl 3,4-Dichlorophenyl-HCl 490
[75] II. And T are carbon, U is -N ⁺ R ⁵ -, and m is 0, and R, R ^1, R ^2, R ³ and R ⁴ is hydrogen, F is bonded, Q is -CH ₂ -, and When E is -C (O) NH- and the other groups are defined as shown in Table 2 below, representative compounds of Formula I are compounds of structural formula shown in Table 2 below.
[76] CPD # Stereochemistry Ar R ⁵ X ^- Ar ¹ Mass spectrum (m / e) One ( RS ) 4-Amino-5-chloro-2-methoxyphenyl methyl I 3,4-dichlorophenyl 470
[77] III. T is -N ⁺ R ⁵ -, and U is carbon, m is 1, and R, R ^1, R ² and R ³ is hydrogen, F is bonded, Q is -CH ₂ -, and E is - NHC (O) NH- and the other groups are defined as shown in Table 3 below, the representative compounds of formula (I) are compounds of the structural formula shown in Table 3 below.
[78]
[79] While the broadest definition of the present invention has been provided above, certain compounds of formula (I) as described below are preferred.
[80] (I) The compounds of the preferred group, T is -N ⁺ R ⁵ - provided that, R ⁵ is alkyl, hydroxyalkyl, alkoxycarbonyl-alkyl, preferably methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl , Methoxycarbonylmethyl, ethoxycarbonylmethyl, most preferably methyl, ethyl or 2-hydroxyethyl, m is 1, R, R ¹ , R ² and R ³ are hydrogen and F is a bond And Q is an alkylene chain, more preferably methylene or ethylene, most preferably methylene.
[81] In said group (I), a more preferred group of compounds is:
[82] (A) E is -C (O) NH-, and, R ⁴ is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1- Hydroxyethyl or 2-hydroxyethyl, more preferably 1-methylethyl or 1,1-dimethylethyl.
[83] In said preferred group or more preferred group, a still more preferred group of compounds is:
[84] When the carbon to which R < ³ > and R < ⁴ > are attached is ( R )
[85] Ar is heteroaryl or aryl ring; Preferably alkyl, heteroalkyl, alkoxy, -COR (where, R is an alkyl), -SO ₂ R (where, R is alkyl, amino, one is a substituted amino or disubstituted amino), methylenedioxy, hydroxy - (alkylene) -CONR'R " wherein R 'and R " are hydrogen or alkyl, - COOR, - (alkylene) -COOR (where, R is hydrogen or alkyl) or -NRSO ₂ R '(wherein, R is hydrogen or alkyl, R' is alkyl, amino, substituted amino, or disubstituted amino days Pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring or a phenyl ring which is optionally substituted with 1 to 3 substituents selected from methyl, methoxy, fluoro, chloro, dimethylamino, acetyl, hydroxy, amino, methylenedioxy, -SO ₂ Me, 2- acetylamino-ethyl, 2 - [(R) - O Methylbutyryl-amino] ethyl, 2-aminoethyl, aminomethyl, hydroxymethyl, aminocarbonyl, dimethylaminocarbonyl, -COOH, carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethyl, A phenyl ring optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, , 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, 4 - [(2-acetylamino) ethyl] phenyl, 4- [2 - [( R ) -amino-3-methylbutyl (2-aminoethyl) phenyl, 4- (aminoethyl) phenyl, 4- (hydroxymethyl) Dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-aminocarbonylmethylphenyl, 4-acetylaminomethylphenyl, 4-methylsulfonyl- Aminophenyl, 4-methylsulfonylamino-methylphenyl or 4-aminophenyl;
[86] Ar ¹ is heteroaryl or aryl ring; Acetylindol-3-yl, optionally substituted with 1 to 3 substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, mono-substituted amino or di- Methylbenzothiophen-2-yl, 5-nitrothiophen-3-yl or phenyl ring; More preferably a phenyl ring optionally substituted with one or two substituents selected from methyl, methoxy, chloro, fluoro, trifluoromethyl or nitro; Most preferably 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 4-fluorophenyl or 3,4-dichlorophenyl.
[87] In this group (I), a further group of other compounds is as follows:
[88] (B) E is -NHC (O) NH-, and, R ⁴ is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1- Hydroxyethyl or 2-hydroxyethyl, more preferably 1-methylethyl or 1,1-dimethylethyl.
[89] In said preferred group or more preferred group, a still more preferred group of compounds is:
[90] When the carbon to which R < ³ > and R < ⁴ > are attached is ( R )
[91] Ar is heteroaryl or aryl ring; Preferably alkyl, heteroalkyl, alkoxy, -COR (where, R is an alkyl), -SO ₂ R (where, R is alkyl, amino, one is a substituted amino or disubstituted amino), methylenedioxy, hydroxy - (alkylene) -CONR'R " wherein R 'and R " are hydrogen or alkyl, - COOR, - (alkylene) -COOR (where, R is hydrogen or alkyl) or -NRSO ₂ R '(wherein, R is hydrogen or alkyl, R' is alkyl, amino, substituted amino, or disubstituted amino days Pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring or a phenyl ring which is optionally substituted with 1 to 3 substituents selected from Methyl, methoxy, fluoro, chloro, dimethylamino, acetyl, acetylamino, hydroxy, amino, methylenedioxy, -SO ₂ Me, Ethyl, 2 - [( R ) -amino-3-methylbutyrylamino] ethyl, 2-aminoethyl, aminomethyl, hydroxymethyl, aminocarbonyl, dimethylaminocarbonyl, -COOH, carboxymethyl, methoxycarbo Which is optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isobutyl, sec-butyl, 3-acetylaminophenyl, 3-acetylphenyl, 3- [2-acetylamino) ethyl] - 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3 -Aminocarbonylmethylphenyl, 3-dimethylaminocarbonylphenyl, 3-acetylaminomethylphenyl, 3-carboxymethylphenyl, 3- Aminophenyl, 3-methylsulfonylaminomethylphenyl or 3-aminophenyl;
[92] Ar ¹ is heteroaryl or aryl ring; Acetylindol-3-yl, optionally substituted with 1 to 3 substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, mono-substituted amino or di- Methylbenzothiophen-2-yl, 5-nitrothiophen-3-yl or phenyl ring; More preferably a phenyl ring optionally substituted with one or two substituents selected from methyl, methoxy, chloro, fluoro, trifluoromethyl or nitro; Most preferably 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 4-fluorophenyl or 3,4-dichlorophenyl.
[93] (II) the other group preferred compounds R ⁴ is alkyl or heteroalkyl, preferably a is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2 -Hydroxyethyl, more preferably 1-methylethyl or 1,1-dimethylethyl.
[94] (III) In a preferred compound of the other group, E is ^{-C (O) N (R 6} ) - or ^{-N (R 7) C (O} ) N (R 6) -, preferably -C (O) NH - or -NHC (O) NH-.
[95] Yet another more preferred compound is the compound of formula I wherein T is -N ⁺ R ⁵ , R ⁵ is alkyl, F is a bond, and R, R ¹ , R ² and R ³ are hydrogen.
[96] 1. Compound (C) wherein m is 1, R ⁵ is methyl or ethyl, and Q is a methylene chain.
[97] 2. E is ^{-C (O) N (R 6} ) -, -SO 2 N (R 6) -, -N (R 7) C (O) N (R 6) - or -N (R ⁷⁾ C (O) -, wherein R < ⁶ > and R < ⁷ > are hydrogen.
[98] 3 and E is -C (O) NH-, a compound (2) R ⁴ is alkyl or heteroalkyl.
[99] 4. A compound (3) wherein Ar and Ar < ^{1 >} are an optionally substituted aryl ring.
[100] 5. Ar is alkyl, heteroalkyl, alkoxy, -COR (where, R is alkyl), -SO ₂ R (where, R is alkyl, amino, one is a substituted amino or disubstituted amino), methylenedioxy, - (alkylene) -CONR'R " wherein R 'and R " are hydrogen or alkyl, and R is hydrogen, halo, acylamino, amino, monosubstituted amino, disubstituted amino, -COOR, - (alkylene) -COOR where R is hydrogen or alkyl, or -NRSO ₂ R 'where R is hydrogen or alkyl and R' is alkyl, amino, mono-substituted amino or di- Amino); < / RTI >
[101] Ar ¹ is a phenyl ring optionally substituted with alkyl, heteroalkyl, alkoxy, halo, methyl, nitro, from 1 to 3 substituents selected from a substituted amino, or disubstituted amino trifluoromethyl compound (4).
[102] 6. A compound according to claim 1, wherein R ⁴ is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ar ¹ is 4-nitrophenyl, Fluorophenyl, 3-chloro-4-fluorophenyl or 3,4-difluorophenyl, 3-chlorophenyl, (5) < / RTI >
[103] 7. A compound according to claim 1, wherein Ar is selected from the group consisting of phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-acetylaminophenyl, 4-dimethylaminocarbonylphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4- [ 2 - [(R) - amino-3-methyl-butyrylamino] ethyl] phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) phenyl, 4- (hydroxymethyl) phenyl, 2,5 Dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-amino-carbonylmethylphenyl, 4-acetylaminomethylphenyl, 4- (6), wherein R < 1 >
[104] 8 and E is -NHC (O) NH-, R ⁴ is alkyl or heteroalkyl of compound (2).
[105] 9. A compound (8) wherein Ar and Ar < ^{1 >} are an optionally substituted aryl ring.
[106] 10. Ar is alkyl, heteroalkyl, alkoxy, -COR (where, R is alkyl), -SO ₂ R (where, R is alkyl, amino, one is a substituted amino or disubstituted amino), methylenedioxy, - (alkylene) -CONR'R " wherein R 'and R " are hydrogen or alkyl, and R is hydrogen, halo, acylamino, amino, monosubstituted amino, disubstituted amino, -COOR, - (alkylene) -COOR where R is hydrogen or alkyl, or -NRSO ₂ R 'where R is hydrogen or alkyl and R' is alkyl, amino, mono-substituted amino or di- Amino); < / RTI >
[107] The compound Ar ¹ is a phenyl ring optionally substituted with alkyl, heteroalkyl, alkoxy, halo, methyl, nitro, from 1 to 3 substituents selected from a substituted amino, or disubstituted amino trifluoromethyl 9.
[108] 11. R ⁴ is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, and 1-hydroxyethyl or 2-hydroxyethyl, Ar ¹ is 4-nitrophenyl, 4 Fluorophenyl, 3-chloro-4-fluorophenyl or 3,4-difluorophenyl, 3-chlorophenyl, Dichlorophenyl. ≪ / RTI >
[109] 12. A compound according to claim 1, wherein Ar is selected from the group consisting of phenyl, 3-methoxyphenyl, 3-methylsulfonylphenyl, 3- dimethylaminophenyl, 3- acetylaminophenyl, 3- acetylphenyl, 3- dimethylaminocarbonylphenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-tri (11) wherein R < 3 > is methoxyphenyl, 3-aminocarbonylmethylphenyl, 3-acetylaminomethylphenyl, 3-carboxymethylphenyl, 3-methylsulfonylaminophenyl, 3-methylsulfonylaminomethylphenyl or 3-aminophenyl.
[110] 13. A compound of formula I, wherein Ar ¹ is 3,4,5-trimethoxyphenyl, Ar ² is 3,4-dichlorophenyl, R ⁴ is 1-methylethyl, R ⁵ is methyl and X ^- is iodide Compound (12), i.e., 4- (3,4-dichlorobenzyl) -1-methyl-1- [3-methyl- 2- ( R ) - [3- (3,4,5-trimethoxyphenyl) Ureido] butyl] piperidinium iodide.
[111] And provided that a, R ⁵ is alkyl, and F is bonded, R, R ^1, R ² and R ³ the compounds of formula (I) is a hydrogen (D) - Another preferred compound is T is -N ⁺ R ^5.
[112] 1. Compound (D) wherein m is 1, R ⁵ is methyl or ethyl, and Q is a methylene chain.
[113] Another preferred compound is T is -N ⁺ R ⁵ - provided that, R ⁵ is alkoxycarbonyl, and carbonyl-alkyl, F is a bond, R, R ^1, R ² and R ³ is the compound (E) of formula (I), wherein hydrogen .
[114] 1. A compound (E) wherein m is 1, R ⁵ is methyl or ethyl, and Q is a methylene chain.
[115] The compounds of the present invention can be prepared by a number of methods known to those skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described below.
[116] The starting materials and reagents used to prepare these compounds are commercially available from Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, CA), Emka Chemie), or Sigma (St. Louis, Missouri), or can be obtained from reference suppliers such as Fieser and Fieser's Reagents for Organic Synthesis , Volumes 1-15 (John Wiley and Sons Organic Reactions , Volumes 1-40 (John Wiley and Sons, 1991) ","March's Advanced Organic Chemistry ", Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Rodd's Chemistry of Carbon Compounds , (John Wiley and Sons, 1992) and Larock ' s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These summaries illustrate only some of the ways in which the compounds of the present invention can be synthesized, and these summaries can be variously modified and will be suggested to those skilled in the art with reference to this disclosure.
[117] The starting materials and intermediates of the reaction can be isolated and purified using conventional methods, including, but not limited to, filtration, distillation, crystallization, chromatography and the like, if necessary. Such materials may be characterized using conventional means including physical constants and spectral data.
[118] Synthesis of compounds of formula (I)
[119] Typically, after conversion of the amino alkyl derivatives) and (IIc and carboxyalkyl derivative of Formula IId of general formula IIa) and (IIb with a compound of formula Ia, by converting the quaternary salt of formula I, m, R, R ^1, R ² , R ³ , R ⁴ , R ⁵ , Q, Ar and Ar ¹ are as broad as described above.
[120]
[121] The synthesis of the compounds of formulas (IIa) to (IId) and their conversion to the compounds of formulas (Ia) and (I) are described in detail in the following Schemes A to J.
[122] Synthesis of Compounds of Formulas (IIa) to (IId)
[123] Preparation Example of Compound of Formula (IIa)
[124] Compounds of formula (IIa) wherein T is nitrogen, m is 1 or greater, and R, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , Q and Ar ¹ are as broadly described above, Lt; / RTI >
[125]
[126] Generally, as described in detail below, the compound of formula (IIa) can be prepared in two steps, i.e., first converting the compound of formula (1) into an N-protected aminoalkyl derivative of formula (2) ≪ / RTI >
[127] Formula 2 N- protected aminoalkyl derivative of [wherein, PG is an amino protecting group: - A (for example, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), benzyl, etc.), R ⁶ is hydrogen; Is prepared by reacting a compound of formula (1) with a compound of formula (3): < EMI ID =
[128] ^{PG-N (R 6) CR} 3 R 4 (CHR) m-1 X
[129] In this formula,
[130] X is an aldehyde, a ketone (X = -C (O) R, where R is alkyl), carboxy or a reactive carboxy derivative such as an acid halide.
[131] The reaction conditions used in the preparation of the compound of formula (2) depend on the nature of the X group. If X is a halide or ketone group, the reaction is carried out under reductive amination conditions, such as a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and organic acids such as glacial acetic acid, Trifluoroacetic acid and the like). Suitable solvents for this reaction are halogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform, etc.). When X is a carboxy group, the reaction is carried out in the presence of a suitable coupling agent such as N, N-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide and the like) to obtain an amide intermediate. The amide intermediate is reduced with an appropriate reducing agent (e.g., diborane, lithium ammonium hydride, etc.) in an ether organic solvent (such as ether or tetrahydrofuran) to give the compound of formula (2). If X is an acid derivative such as an acid chloride, the reaction is carried out in the presence of a suitable base such as triethylamine, pyridine in an organic solvent such as methylene chloride, dichloroethane, N, N-dimethylformamide, After obtaining an intermediate, it is reduced to the compound (2) as described above.
[132] In general, the compounds of formula (III) are commercially available or can be prepared by methods well known to those skilled in the art of organic chemistry. Examples of such procedures are shown and described in detail below:
[133]
[134] (i) first converting an alpha -amino acid to the corresponding ester and then reducing the ester group to an aldehyde group using a suitable reducing agent (e.g., DIBAL-H (R) And m-1 is 0) is prepared from the corresponding natural or unnatural a-amino acid of formula (3), wherein X is a carboxy group and m-1 is zero. The aldehyde of formula (3), wherein m-1 is 1 or 2, is reacted with an aldehyde or ketone of formula (3) where m-1 is 0, where X is -COR, Alkyl). ≪ / RTI > For example, an aldehyde (3), wherein m-1 is 1 and R is hydrogen or alkyl, is reacted with the corresponding aldehyde or ketone of formula (3) wherein m-1 is 0 from chloromethyl methyl ether Followed by condensation with an induced Wittig reagent, followed by acid hydrolysis of the resulting enol ether intermediate. (3), wherein m-1 is 2 and R is hydrogen or alkyl, is reacted with the corresponding aldehyde or ketone (3), wherein m-1 is 0, with bromoacetate or 2- Is condensed with a Wittig reagent derived from a corresponding compound of formula (I), respectively, and then the double bond and the ester group in the produced , - unsaturated ester are produced by successive reduction. (3) is converted to a Weinreb amide and then treated with a Grignard reagent of the formula RMgBr wherein R is an alkyl group, wherein the ketone of formula 3, wherein m-1 is 0, ≪ / RTI > Alternatively, the aldehyde can be prepared by oxidation of the hydroxy group in -Aminoalcohols, such as 2-amino-1-propanol, and the like.
[135] In general, natural and unnatural amino acids and their corresponding esters are commercially available from vendors (e.g., Aldrich and Bachem). Examples of unnatural amino acids include homoserine, homocysteine, N-α-methyl arginine, norleucine, N-methylisoleucine, phenylglycine, hydroxyproline, pyroglutamine, ornithine, 2-aminoisobutyric acid, 2- (2-naphthyl) alanine, citrulline, piperolinic acid, piperazic acid, 4-chlorophenylalanine, 4-fluorophenylalanine, sarcosine, Serine ethyl ester and alanine methyl ester, which are commercially available.
[136] (ii) a compound of formula (3) wherein X is a carboxy group and m-1 is greater than 0, can be prepared by oxidation of an aldehyde group with a suitable oxidizing agent such as, for example, potassium manganese potassium, as described in (i) Can be prepared from the corresponding aldehyde of formula (3), wherein X is -CHO. Alternatively, they can be prepared from the , -Unsaturated ester formed in the Wittig reaction by reducing the double bond as referred to in (i) above and then hydrolyzing the ester group by methods known in the art .
[137] (iii) a compound of formula 3, wherein X is -C (O) R where R is alkyl and m-1 is 0 to 2, is reacted with the corresponding aldehyde of formula 3, CHO) with a Grignard reagent, followed by oxidation of the resulting alcohol with a suitable oxidizing agent (e.g., light potassium potassium, etc.). Alternatively, they may be prepared from an acid of formula (3) as described in (i) above.
[138] (iv) a compound of formula 3 wherein X is an acid derivative such as an acid chloride is reacted with a suitable chlorinating agent such as oxalyl chloride, thionyl chloride, etc., in a suitable organic solvent such as methylene chloride, (Wherein X is -COOH) by chlorination with a suitable base such as < RTI ID = 0.0 > (iii). ≪ / RTI >
[139] Alternatively, the compound of formula 2 is also prepared by reacting a compound of formula 1 with a compound of formula 4:
[140] ^{PG-N (R 6) CR} 3 R 4 (CHR) m Y
[141] In this formula,
[142] Y is a leaving group under alkylation conditions such as halo (e.g. chloro, bromo or iodo) or sulfonyloxy group (e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy or trifluoromethylsulfonyloxy) .
[143] The reaction is carried out in the presence of a base (for example, sodium carbonate, sodium hydride, triethylamine, etc.). Suitable solvents are aprotic organic solvents such as tetrahydrofuran, N, N-dimethylformamide and the like.
[144] In general, the compound of formula 4, wherein Y is a halo or sulfonyloxy group, may be prepared by converting an aldehyde, ketone or carboxy group to an alcohol followed by reaction with a suitable halogenating agent such as thionyl chloride, thionyl bromide, triphenyl (E.g., carbon tetrabromide in the presence of a phosphine), or a sulfonylating agent (e.g., methylsulfonyl chloride, para-toluenesulfonyl chloride and triflic anhydride) have. Suitable reducing agents for the aldehyde, ketone or carboxy group include lithium aluminum hydride, borane and the like.
[145] For example, a compound of formula (IIa) can be prepared by reacting a compound of formula (I) with a conjugated nitro-olefin under Michael addition reaction conditions, followed by reduction of the nitro group under standard hydrogenation conditions. The conjugated nitro-olefins are commercially available or can be prepared by known procedures in literature such as those described in Corey, EJ et al. , J. Am. Chem. Soc , 100 (19), 8294-5, ≪ / RTI >
[146] The N-protected aminoalkyl derivative (2) is converted to a compound of formula (IIa) by removing the amino protecting group. The conditions used depend on the nature of the protecting group. For example, if the protecting group is a tert-butoxycarbonyl group, it is removed under acidic hydrolysis conditions, but if the protecting group is a benzyl group, it is removed under catalytic hydrogenation conditions.
[147] Compounds of formula IIa wherein R ⁶ is other than hydrogen can be prepared by reacting a corresponding compound of formula IIa where R ⁶ is hydrogen under alkylation conditions using the reaction conditions described above with an alkylating agent R ⁶ Y, , And Y is a leaving group.
[148] Compounds of formula (I) may be prepared from suitable N-protected piperidinones by known procedures. Some examples of such procedures are described below:
[149] (i) compounds of formula (1) (wherein, Q is -C (O) -) or alkylene chain TIG reagent above the non-4-piperidinyl a suitable N- protecting _{^{Br - (Ph) 3 P +}} - alkyl Lt; RTI ID = 0.0 > Ar- ¹ < / RTI > After treating the alkylene polymer with borane, the resulting alkylborane is reacted with an oxidizing agent (e . G. , & Lt ; RTI ID = 0.0 > Chromic acid) and the N-protecting group is removed to give a compound of formula (I) wherein Q is -CO-. Reduction of the olefinic bond in the alkylidene intermediate is followed by removal of the N-protecting group to yield a compound of formula 1 wherein Q is an alkylene chain. A detailed description of the synthesis of the piperidine of formula (1) wherein Q is an alkylene chain is provided in Example 1 by the above method.
[150] (ii) a compound of formula I (where, Q is -O- alkylene -Ar is ¹⁾ 4-hydroxypiperidine alkylating agent of the formula Ar ¹ -QY under alkylation reaction conditions, as the above piperidine (wherein, Y Lt; / RTI > is a leaving group).
[151] (iii) compounds of the formula (wherein, Q is -NH- alkylene -Ar is ¹⁾ is N- protected 4-piperidine the reductive amination under the conditions of the reaction formula NH ₂ as described above-alkylene Lt; / RTI > with an amine of formula -Ar &^lt; ¹ >.
[152] 4-Hydroxypiperidine and 4-piperidinone are commercially available.
[153] Preparation of the compound of formula (IIb)
[154] Compounds of formula IIb wherein U is nitrogen, m is 1 and R, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , Q and Ar ¹ are as broadly described above, Lt; RTI ID = 0.0 > (5) < / RTI >
[155]
[156] The compound of formula IIb, wherein m is 1, can be prepared by reacting the compound of formula 5 as shown in method (a) under the Wittig reaction conditions, i.e. the presence of a strong non-nucleophilic base such as sodium hydride, sodium amide, etc. With a phosphonate ylide of formula (VI) in a suitable aprotic organic solvent such as tetrahydrofuran to give an alpha, beta -unsaturated ester of formula (7). The alpha, beta -unsaturated ester (7) can be obtained by first converting compound (7) to an aldehyde and then treating with an organometallic reagent (such as Grignard reagent or organolithium reagent of formula R ⁴ MgBr or R ⁴ Li) Is converted to an alcohol derivative 8a (m = 1). The double bond is reduced under hydrogenation reaction conditions and the ester group is reduced to the aldehyde group using a suitable reducing agent (e.g., DIBAL-H (R)). The alcohol (8a) is then converted to a compound of formula (IIb) by oxidation of the alcohol group to the ketone group and subsequent treatment with an amine of formula NH (R < ⁶ >) under reductive amination conditions. The oxidation reaction is carried out using an appropriate oxidizing agent (eg pyridinium dichromate) in an aprotic solvent such as dimethylformamide.
[157] A compound of formula IIb wherein m is 0 can be prepared by reducing an ester group to an aldehyde as shown in process (b) to convert compound (9) to the corresponding alcohol derivative (8b) Lt; RTI ID = 0.0 > (9). ≪ / RTI > Compound (8b) is then converted to a compound of formula (IIb), wherein m is 0, by carrying out an oxidation step and a reductive amination step and using reaction conditions as described above. The compound of formula IIb, wherein m is 0, can also be prepared by the procedure described in WO 92/12128.
[158] Compounds of formula 5 or formula 9 can be prepared by N-alkylating 4-piperidone or ethyl isonipecotate with alkylation conditions Ar ¹ -QY, where Y is a leaving group, under alkylation conditions as described in Scheme A above .
[159] Preparation of the compound of formula (IIc)
[160] Carboxyalkyl derivatives of formula (IIc) wherein T is nitrogen and m, R ¹ , R ² , R ³ , R ⁴ , Q and Ar ¹ are as broad as described above can be prepared by reacting a compound of formula (1) ≪ / RTI >
[161]
[162] A carboxy derivative of formula (IIc) is prepared by reacting a compound of formula (I) with an alkylating agent of formula (10), wherein Y is a halo or sulfonyloxy group, as shown above, followed by hydrolysis of the ester group. The alkylation reaction is carried out under the reaction conditions described above (see Scheme A). The hydrolysis of the ester group is carried out in the presence of an aqueous base (for example, sodium hydroxide, lithium hydroxide, etc.) in an alcohol organic solvent (e.g., methanol, ethanol, etc.). The reaction proceeds at ambient temperature or with heating.
[163] Alternatively, a carboxyethyl derivative of formula IIc, wherein R ³ is hydrogen, can be prepared by reacting a compound of formula 1 under Michael addition reaction conditions, that is, in a suitable base such as methoxide and in a protic organic solvent such as methanol, Ethanol or the like) with an , - unsaturated ester of formula (11) to obtain a 3-propionate derivative of formula (12). Hydrolysis of the ester group in compound (12) yields the corresponding carboxyethyl derivative of formula (IIc), wherein R < ³ > is hydrogen.
[164] The compound of formula (1) is prepared as described above in scheme A. The compounds of formulas (10) and (11) are either commercially available or can be prepared by methods known in the art. For example, a halocarboxylic acid and an alpha, beta -unsaturated ester (e.g., methyl 2-bromo-2-methylpropionate, methyl 2-bromophosphonate, methyl 3-bromo-2-methylpropionate , Methyl [alpha] -bromophenylacetate, methyl methacrylate) are commercially available.
[165] Preparation of the compound of formula (IId)
[166] Carboxyalkyl derivatives of formula IId wherein U is nitrogen and m, R ¹ , R ² , R ³ , R ⁴ , Q and Ar ¹ are as broadly described above can be prepared by reacting a compound of formula Can be prepared from the compound of formula (13).
[167]
[168] The carboxyalkyl derivative of formula (IId) can be prepared by reacting a compound of formula (5) or formula (13) with a Wittig reagent (m = 1) of formula Br (Ph ₃ P) (CHR) _m CR ³ R ⁴ CO ₂ Et, And hydrolyzing the ester group to an acid in the resulting unsaturated ester (14a) or (14b) as described above.
[169] Synthesis of compounds of formula (Ia) from compounds of formulas (IIa) to
[170] Compounds of formula Ia wherein E is C (O) N (R < ⁶ >) - are prepared as described in Scheme E below.
[171]
[172] Compounds of formula (IIa) wherein E is an amide group can be prepared as follows:
[173] (i) reacting a compound of formula (IIa) and (IIb) with an acylating agent Ar-FC (O) L where L is a leaving group under acylation conditions such as halo (especially Cl or Br) or imidazolide Lt; / RTI > Solvents suitable for the reaction include aprotic polar solvents such as dichloromethane, THF, dioxane, and the like. When the acyl halide is used as an acylating agent, the reaction is carried out in the presence of a non-nucleophilic organic base such as triethylamine or pyridine, preferably pyridine.
[174] (ii) heating the compound of formula (IIa) and (IIb) with an acid anhydride. Suitable solvents for the reaction include tetrahydrofuran, dioxane, and the like.
[175] E is ^{N (R 7) C (O} ) N (R 6) - or ^{-N (R 7) C (S} ) N (R 6) - , a compound of formula (Ia) are prepared as described in Scheme F .
[176]
[177] Compounds of formula Ia, wherein E is a urea / thiourea group, can be prepared as follows:
[178] (i) reacting a compound of formula (IIa) and (IIb) with an activating agent such as carbonyl diimidazole / thiocarbonyldiimidazole and then nucleophilic substitution of the imidazole group with a primary or secondary amine step. The reaction is carried out at ambient temperature. Suitable solvents include polar organic solvents such as tetrahydrofuran, dioxane, and the like.
[179] (ii) reacting a compound of formula (IIa) and (IIb) with a carbamoyl / thiocarbamoyl halide. The reaction is carried out in the presence of a non-nucleophilic organic base. Suitable solvents for the reaction include dichloromethane, 1,2-dichloroethane, tetrahydrofuran or pyridine.
[180] (iii) reacting the compound of formula (IIa) and (IIb) with an isocyanate / isothiocyanate in an aprotic organic solvent such as benzene, tetrahydrofuran, dimethylformamide and the like.
[181] A detailed description of the conversion of a compound of formula (IIa) to a compound of formula (Ia), wherein E is -NHC (O) NH-, is set forth in Example 1.
[182] Compounds of formula (Ia) wherein E is SO ₂ N (R ⁶ ) - are prepared as described in Scheme G below.
[183]
[184] Compounds of formula Ia wherein E is a sulfonamido group can be prepared by reacting a compound of formula (IIa) and (IIb) with a sulfonyl halide using the reaction conditions described in method (i) of Scheme E. The sulfonyl halide is either commercially available or can be prepared according to (1) Langer, RF, Can. J. Chem ., 61, 1583-1592, (1983); (2) Aveta, R. et al., " Gazetta Chimica Italiana , 116, 649-652, (1986)"; (3) King, J. F. and Hillhouse, JH Can. J. Chem., 54, 498, (1976) and (4) Szymonifka, Can be prepared by the method as described in Heck, JV, Tet. Lett. , 30, 2869-2872, (1989).
[185] E is _{^{-N (R 7) SO 2 N}} (R 6) - , a compound of formula (Ia) are prepared as described in Scheme H:
[186]
[187] Compounds of formula (Ia) wherein E is a sulfamide group can be prepared by reacting a compound of formula (IIa) and (IIb) with a sulfamoyl halide using the reaction conditions described in method (i) of Scheme E above. The sulfamoyl halide is either commercially available or can be prepared according to the method described in Graf, R. German Patent, 931225 (1952) and Catt, JD and Matler, WL, J. Org. Chem. , ≪ / RTI > 39, 566-568, (1974).
[188] E is ^{-N (R 7) C (O} ) - , a compound of formula (Ia) are prepared as described in Scheme I:
[189]
[190] Compounds of formula (Ia) wherein E is an inverse amide may be prepared by reacting a compound of formula (IIc) and (IId) with a suitable coupling agent such as N, N-dimethylformamide in a suitable organic solvent such as methylene chloride, tetrahydrofuran, dimethylformamide, Dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and the like).
[191] Synthesis from compounds of formula (Ia) to compounds of formula (I)
[192] Compounds of formula (I) wherein T or U is -N ⁺ R ⁵ - may be prepared from compounds of formula (Ia) as described in Scheme J:
[193]
[194] The compounds of formula (Ia) are compounds of the formula I - in the alkylating agent (here, T or U is -N ⁺ R ⁵ is a) the formula R ⁵ X (wherein, R ⁵ are as defined in the Summary of the Invention, X is halo (Bromide or iodide, preferably iodide), tosylate, mesylate, and the like). Alkylating agents such as methyl iodide, ethyl iodide, ethyl toluene sulfonate, 2-hydroxyethyl iodide and the like are commercially available.
[195] Compounds of formula (I) wherein X ^- is iodine can be converted to the corresponding compounds of formula (I) wherein X ^- is chloride using a suitable ion exchange resin such as Dowex 1 x 8-50.
[196] Detailed descriptions of the conversion of compounds of formula (Ia) to compounds of formula (I) wherein E is -NHC (O) NH- are set forth in examples 1-3.
[197] Since the compounds of the present invention are CCR-3 receptor antagonists, they inhibit eosinophils, T-cells, basophils and mast cell accumulation by chemokines such as RANTES, eotaxin and MCP-3. The quaternary salts of the present invention are generally more potent than the corresponding quaternized piperidine homologues. Thus, the compounds of the present invention and compositions containing them are useful for the treatment of eosinophil-induced diseases such as asthma, rhinitis, eczema, and arthritic infections in mammals, especially humans.
[198] The CCR-3 antagonistic activity of the compounds of the present invention can be measured by in vitro assays such as ligand binding and chemotaxis assays described in more detail in Examples 5, 6 and 7. In vivo activity can be assayed in an Ovalbumin induced asthma of the Balb / c Mice Model described in more detail in Example 8. [
[199] In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration of the reagents which serve similar purposes. The actual amount of a compound of the present invention, i.e., an active ingredient, will depend on a number of factors such as gastric neutrality of the disease to be treated, age and relative health of the patient, efficacy of the compound employed, route and form of administration, .
[200] A therapeutically effective amount of the compound of formula I will range from about 0.005 to 20 mg per day per kg body weight of the recipient, preferably from about 0.01 to 10 mg / kg per day. Thus, for administration to a 70 kg man, the dosage range would most preferably be about 0.7 mg to 0.7 g per day.
[201] In general, a compound of the invention will be administered as a pharmaceutical composition by any one of the following routes: oral administration, systemic administration (e.g., transdermal, nasal, or suppository) or parenteral (e.g., Intramuscular, intravenous, or subcutaneous administration). A preferred method of administration is oral administration using a convenient daily dosage regimen which can be controlled according to the degree of pain. The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or other suitable compositions.
[202] The choice of formulation depends on a variety of factors such as the manner of administration of the drug (for example, for oral administration, formulations in the form of tablets, pills and capsules are preferred) and the bioavailability of the drug.
[203] Drugs and lipids are dissolved in a suitable organic solvent such as tert-butanol, cyclohexane (1% ethanol) for liposomal formulation of the drug for parenteral or oral delivery. The solution is lipidated to suspend the lipid mixture in an aqueous buffer solution to form a liposome. If necessary, liposomal size can be reduced by sonification (Frank Szoka, Jr. and Demetrios Papahadjopoulos, Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes) &Quot; Ann. Rev. Biophys. Bioeng ., 9: 467-508 (1980) and DD Lasic, " Novel Applications of Liposomes ", Trends in Biotech. , 16: 467-608 (1998)).
[204] Recently, pharmaceutical formulations have been developed specifically for drugs that exhibit poor bioavailability based on the principle that they can be increased by increasing the surface area, i. E., By reducing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles having a size of 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the preparation of pharmaceutical formulations wherein the drug substance is pulverized into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to exhibit very high bioavailability.
[205] The composition generally comprises a compound of formula I in admixture with one or more pharmaceutically acceptable excipients. Acceptable excipients are non-toxic and aid administration, but do not adversely affect the therapeutic benefit of the compounds of formula (I). Such excipients may be any solids, liquid, semi-solids, or, in some cases, aerosol compositions, gaseous excipients, which are generally available to those skilled in the art.
[206] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, powder, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, (skim milk) and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils such as petroleum, animal oils, or vegetable or synthetic oils such as peanut oil, soybean oil, mineral oil, Particularly preferred liquid carriers for injectable solutions include water, saline, aqueous dextrose and glycols.
[207] Compressed gases may be used to disperse the compounds of the present invention in the form of aerosols. Suitable inert gases for this purpose are nitrogen, carbon dioxide, and the like.
[208] Other suitable pharmaceutical excipients and their formulations are described in the " Remington " Pharmaceutical Sciences , edited by EW Martin (Mack Publishing Company, 18th ed., 1990).
[209] The concentration of the compound in the formulation may vary within the full range of uses used by those skilled in the art. Typically, the formulation will contain from about 0.01 to 99.99% by weight of the compound of Formula I, based on total formulation, and the remainder will contain one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of from about 1 to 80% by weight. Representative pharmaceutical formulations containing a compound of formula (I) are described in Example 4.
[210] Example 1
[211] Methyl-2- [3- (3,4,5-trimethoxyphenyl) -ureido] butyl] piperidinium iodide Id (Table 3, Cpd. 1)
[212]
[213] Step 1
[214] n-Butyl lithium (43.2 mL, 2 M in pentane, 108 mmol) was added to a solution of 3,4-dichlorobenzyl bromide and triphenylphosphine in anhydrous THF in dry THF (500 mL) Was slowly added to an ice-cooled suspension (54 g, 108 mmol) of 3,4-dichlorobenzyltriphenylphosphonium bromide (prepared by stirring at -78 [deg.] C). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred for another 2 hours. 1-3-tert-butoxycarbonyl-4-piperidone (21.42 g, 108 mmol) was added and stirring was continued overnight. Hexane (2 L) was added and the reaction stirred and filtered. The filtrate was concentrated in vacuo to give 41.8 g of an orange gum. After subjecting to 0.5 kg of flash grade silica column chromatography (eluting with a gradient of 70% methylene chloride / hexane to 100% methylene chloride), 1% methanol / methylene chloride to 5% methanol / methylene chloride To give 1- (tert-butoxycarbonyl) -4- (3,4-dichloro-benzylidene) piperidine (29 g) as a light yellowish brown oil.
[215] Step 2
[216] Platinum oxide (0.3 g) was added to a solution of l- (tert-butoxycarbonyl) -4- (3,4-dichloro-benzylidene) piperidine (29 g, 84.7 mmol) in ethyl acetate (500 mL) And the reaction mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated to give 1- (tert-butoxycarbonyl) -4- (3,4-dichlorobenzyl) piperidine (30 g) as a tan oil.
[217] Step 3
[218] Trifluoroacetic acid (50 mL) was added to a solution of l- (tert-butoxycarbonyl) -4- (3,4-dichlorobenzyl) piperidine (24 g, 69.7 mmol) in methylene chloride (150 mL) And the reaction mixture was stirred for 1 hour. After removal of the solvent under reduced pressure, ethyl acetate (200 mL) was added and the resulting mixture was basified with 1 N aqueous sodium hydroxide. The organic layer was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 4- (3,4-dichlorobenzyl) piperidine (17.1 g) as a light brown solid.
[219] Step 4
[220] (1.3 g, 5.98 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (1.15 g, 5.98 mmol) were added to a solution of 4- (3, 4-dichlorobenzyl) piperidine (1.12 g, 4.57 mmol) in dichloromethane and the reaction mixture was stirred at room temperature under an argon atmosphere. After 3 hours, the solvent was removed in vacuo and water (10 mL) and ethyl acetate (25 mL) were added. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography with 15-20% ethyl acetate / hexanes as eluant gave 1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin- 1 -ylcarbonyl] -N- (tert-butoxy-carbonyl) -2-methylpropylamine (1.89 g).
[221] Step 5
[222] To a solution of 1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin-1 -ylcarbonyl] -N- (tert- butoxy- carbonyl) -2- To a solution of methylpropylamine (5.9 g, 13.2 mmol) at room temperature was added trifluoroacetic acid (30 mL). After 4 h, the reaction mixture was concentrated and the residue was stirred with ethyl acetate (200 mL) and water (100 mL) while adjusting the pH to 8 with 15% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate, filtered and concentrated in vacuo to give 1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin- 1 -ylcarbonyl] -2- Methylpropylamine (4.53 g) was obtained.
[223] Step 6
[224] To a solution of 1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin- 1 -ylcarbonyl] -2-methylpropylamine (4.53 g, 13.3 mmol) in anhydrous tetrahydrofuran (100 mL) To the solution was added diborane (92.4 mL, 92.4 mmol, 1 M in THF) and the reaction mixture was added under argon at 65 < 0 > C. After 3 h, the reaction mixture was cooled in an ice bath and aqueous hydrochloric acid (60 mL, 6 N) was slowly added with stirring. The reaction mixture was concentrated in vacuo and the aqueous solution was stirred at 100 < 0 > C. After 1 hour, the reaction mixture was cooled to 0 < 0 > C and calcium hydroxide pellets were slowly added until the pH was 8. The solution was extracted twice with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated in vacuo. The colorless liquid (3.84 g) was chromatographed eluting with 2.5-10% MeOH / CH ₂ Cl ₂ containing 1% NH ₄ OH. The free amine was dissolved in anhydrous ether and ether HCl was added to give 1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin- 1 -ylmethyl] -2- .
[225] Step 7
[226] 3,4,5-trimethoxyphenyl isocyanate (1.9 g, 9.11 mmol) was added to a solution of 1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin- Ylmethyl] -2-methylpropylamine (2.5 g, 7.59 mmol) in dichloromethane (5 mL). The solution was stirred at room temperature for 45 minutes and then at 38 DEG C for 30 minutes. The reaction mixture was concentrated in vacuo. The crude product was chromatographed on silica gel column with 1.5-2.5% MeOH / CH ₂ Cl ₂ containing 1% NH ₄ OH to give 1- [1- ( R ) - [4- (3, Ylmethyl] -2-methylpropyl] -3- (3,4,5-trimethoxyphenyl) urea (3.7 g) was obtained.
[227] Step 8
[228] A solution of 1- [1- ( R ) - [4- (3,4-dichlorobenzyl) piperidin- 1 -ylmethyl] -2-methylpropyl] -3- (3,4 , 5-trimethoxyphenyl) urea (0.19 g, 0.353 mmol) in dichloromethane (10 ml) was stirred overnight at 68 <0> C under argon. The yellow mixture was concentrated in vacuo and the crude product was flash chromatographed eluting with 3-4% methanol / methylene chloride to give 4- (3,4-dichlorobenzyl) -1 -Ethyl-1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] butyl] piperidinium iodide (0.18 g).
[229] Was carried out as described in Example 1 above but replacing ethyl iodide in step 8 with a solution of methyl iodide (0.5 mL) in methylene chloride (20 mL) and the reaction mixture was stirred at room temperature overnight Methyl-1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] -7- Butyl] piperidinium iodide (Table 3, Cpd. 14).
[230] The reaction was carried out as described in Example 1, but replacing the ethyl iodide in step 8 with a solution of ethyl iodoacetate (5 ml), and the reaction mixture was stirred for 5 h at room temperature overnight, (3,4-dichlorobenzyl) -1-ethoxycarbonylmethyl) -1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido ] Butyl] piperidinium iodide (Table 3, Cpd. 17).
[231] Ethyl iodide was replaced with benzyl bromide (0.5 mL) in 10 mL of dichloromethane at room temperature as described in Example 1 to give 4- (3,4-dichlorobenzyl ) -1-benzyl-1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] butyl] piperidinium bromide (Table 3, Cpd.18) .
[232] In step 4, D-Boc-valine was replaced with Boc-glycerine, and in step 8, ethyl iodide was replaced with a solution of methyl iodide (0.5 mL) in methylene chloride (20 mL) 1 and the reaction mixture was stirred at room temperature overnight to give 4- (3,4-dichlorobenzyl) -1-methyl-1- [2 - [(3,4, 5-trimethoxyphenyl) ureido] ethyl] piperidinium iodide (Table 3, Cpd. 19).
[233] Example 2
[234] Methyl-2- [3- (3,4,5-trimethoxyphenyl) -ureido] butyl] piperidinium chloride (prepared by reacting 4- (3,4-dichlorobenzyl) Table 3, Cpd. 20)
[235]
[236] To a solution of 4- (3,4-dichlorobenzyl) -1-ethyl-1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) -ureido] butyl ] Piperidinium iodide (0.2 g) was slowly passed through a column of Dowex 1 x 8-50 ion exchange resin (3 g). The eluted product was concentrated under vacuum to give 4- (3,4-dichlorobenzyl) -1-ethyl-1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ] Butyl] piperidinium chloride. &Lt; / RTI &gt;
[237] Methyl-2- [3- (3,4,5-trimethoxyphenyl) -ureido] butyl] piperidinium iodide (4-methyl-2- [3- (3,4,5-trimethoxyphenyl) -ureido] butyl] piperidinium Methyl-l- [3-methyl-2- (3-methyl-lH-imidazol-4- [3- (3,4,5-trimethoxyphenyl) ureido] butyl] piperidinium chloride (Table 3, Cpd. 21).
[238] Example 3
[239] Methyl-2- [3- (3,4,5-trimethoxyphenyl) -ureido] butyl (2-hydroxyethyl) ] Piperidinium chloride (Table 3, Cpd. 16)
[240]
[241] 1- [1- (R) - [ 4- (3,4- dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropyl] -3- (3,4,5-trimethoxyphenyl) Urea (0.21 g) was dissolved in 2-chloroethanol (5 mL) and the solution was heated in an oil bath at 90 &lt; 0 &gt; C. After stirring for one day under nitrogen, the reaction mixture was cooled and then poured directly onto a pad of silica gel. Elution with 6% methanol in methylene chloride followed by elution with 11% methanol in methylene chloride followed by removal of the solvent from the appropriate fractions gave 4- (3,4-dichlorobenzyl) -1- (2 -Hydroxyethyl) -1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] butyl] piperidinium chloride (41.6 g).
[242] Example 4
[243] (Table 1, Cpd. 5): &lt; RTI ID = 0.0 &gt; 1- [2- (4-methylbenzoylamino)
[244]
[245] A solution of N- [1- ( S ) - [4- (3, 5-dihydroxy-phenyl) Ylmethyl] -2-methylpropyl] -4-methylbenzamide (0.104 g, 0.232 mmol) in dichloromethane was added at room temperature to iodomethane (1 ml) At room temperature. The solvent was removed and the residue was flash chromatographed on flash silica gel with a gradient of 2-3% methanol / methylene chloride (containing 1% ammonia). 1- [2- (4-methylbenzoylamino) -3-methylbutyl] -4- (3,4-dichlorobenzyl) -1-methyl-piperidinium iodide as a solid (12 mg). This was dissolved in methanol and passed through a glass column (25 mm id) containing 2-inch Dowex 1 x 8-50 ion exchange resin previously washed with methanol. After passing methanol through the column, no product was detected by TLC. The solvent was removed to give 1- [2- (4-methylbenzoylamino) -3-methylbutyl] -4- (3,4-dichlorobenzyl) -1-methyl-piperidinium chloride (8 mg).
[246] Example 5
[247] (3,4-dichlorobenzyl) -1- (2-carboxyethyl) -1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] Peridin (Table 3, Cpd. 22)
[248]
[249] (3,4-dichlorobenzyl) -1- (2-hydroxyethyl) -1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] butyl] A mixture of piperidinium iodide (0.27 g, 364 mmol, obtained from example 5 above), methanol (5 mL), water (5 mL) and lithium hydroxide monohydrate (30.6 mg, 0.728 mmol) Lt; RTI ID = 0.0 &gt; 50 C &lt; / RTI &gt; After removal of the solvent, water (10 mL) and ethyl acetate (20 mL) were added to the crude residue and the pH was adjusted to 7 with dilute aqueous HCl. The organic layer was separated and the aqueous layer was washed with more ETOAc. The combined organic portions were dried (anhydrous magnesium sulfate) and removed. The crude residue is chromatographed on flash silica gel with 7% methanol / methylene chloride (containing 1% ammonia) to give 4- (3,4-dichlorobenzyl) -1 - (2-carboxyethyl) -1- [3-methyl-2- [3- (3,4,5-trimethoxyphenyl) ureido] butyl] piperidine (90 mg).
[250] Example 6
[251] Formulation Example
[252] The following are representative pharmaceutical formulations containing a compound of formula (I).
[253] Tablet formulation
[254] The following ingredients are mixed well and compressed into a single dose tablet.
[255] ingredientThe amount of refined sugar (mg) The compound of the present invention400 Corn starch50 Croscarmellose sodium25 Laktos120 Magnesium stearate5
[256] Capsule formulation
[257] The following ingredients are mixed well and loaded into hard-shell gelatin capsules.
[258] ingredientAmount per capsule (mg) The compound of the present invention200 Spray dried Lactose148 Magnesium stearate2
[259] Suspension formulation
[260] The following ingredients are mixed to form a suspension for oral administration.
[261] ingredientamount The compound of the present invention1.0 g Fumaric acid0.5 g Sodium chloride2.0 g Methyl paraben0.15 g Propylparaben0.05 g Granulated sugar25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanerbilt Co.)1.0 g Flavor0.035 ml coloring agent0.5 mg Distilled waterThe titration volume to 100 ml
[262] Injectable formulation
[263] The following ingredients are mixed to form the injectable formulation.
[264] ingredientamount The compound of the present invention0.2 g 0.4 M sodium acetate buffer solution2.0 ml HCl (1N) or NaOH (1N)Appropriate amount to suitable pH Distilled water, sterilized waterA volume of 20 ml or less
[265] Liposome formulation
[266] The following ingredients were mixed to form a liposome formulation.
[267] ingredientamount The compound of the present invention10 mg L-α-phosphatidylcholine150 mg Tert-Butanol4 ml
[268] Samples were freeze-dried and frozen overnight. The sample was reconstituted with 1 ml 0.9% brine. Liposome size can be reduced by sonication.
[269] Formulation for local application
[270] A topical formulation was prepared using the following ingredients.
[271] ingredientAmount (g) The compound of the present invention10 Span 602 TWIN (registered trademark, TWEEN) 602 Mineral oil5 Vaseline10 Methyl paraben0.15 Propylparaben0.05 BHA (butylated hydroxyanisole)0.01 waterAmount to 100
[272] All of the above ingredients (except water) were mixed and heated to 60-70 C with stirring. Subsequently, a sufficient amount of water was added at 60 DEG C with vigorous stirring to emulsify the components, and then water was added in an appropriate amount up to 100 g.
[273] Suppository formulations
[274] The compounds of the present invention were mixed with Witepsol H-15 (triglyceride of saturated plant fatty acids, Riches-Nelson, Inc., New York) g &lt; / RTI &gt; and has the following composition.
[275] The compound of the present invention500 mg Witepsol (R) H-15Remainder
[276] CCR-13 antagonistic active binding assay - in vitro
[277] The CCR-3 antagonistic activity of the compounds of the present invention was measured by their ability to inhibit the binding of CCR-3 L1.2 cell infected cells prepared from ¹²⁵ I eotaxin and LeukoSite (Cambridge, Mass.) (See, for example, Pohnase et al., J. Exp. Med., Vol. 183, 2437-2448, (1996)).
[278] The assay is performed in a Costar 96-well polypropylene round bottom plate. After dissolving the test compound in DMSO binding buffer a final DMSO concentration of 2% (in 50 mM HEPES, 1 mM of CaCl _2, 5 mM of MgCl _2, 0.5% of bovine serum albumin, 0.02% sodium azide , pH 7.24). 25 μl of the test solution or only the buffer solution (control sample) was added to each well and 25 μl of ¹²⁵ I eotaxin (100 pmol) (NEX314, New Cleveland, Boston, MA) and 25 μl of binding buffer Lt; ⁵ &gt; cells infected with CCR-3 L1.2 cells. The final reaction volume was 75..
[279] The reaction mixture was incubated at room temperature for 1 hour and then the reaction mixture was filtered through a Packard Unifilter GF / C filter plate (Packard Chicago II.) Treated with polyethyleneimine to remove the reaction Terminated. The filter was washed four times with ice-cold wash buffer containing 10 mM HEPES and 0.5 M sodium chloride (pH 7.2) and dried at 65 DEG C for about 10 minutes. 25 μl / well of Microscint-20 (trademark, Microscint-20) scintillation fluid (available from Packard) was added and the radioactivity contained on the filters was measured using a Packed TopCount (trade name, Packard TopCount).
[280] The IC ₅₀ values for the representative compounds of the invention (the concentration of test compound required to reduce binding of ¹²⁵ I-eotaxin to CCR-3 L1.2 cell infected cells by 50%) are as follows:
[281] Cpd #IC ₅₀ ([mu] M)Cpd #IC ₅₀ ([mu] M) One0.21120.198 74.37141.32
[282] Example 8
[283] Inhibition of eotaxin-mediated chemotaxis on CCR-3 L1.2 cell infected cells - In vitro assay
[284] The CCR-3 antagonistic activity of the compounds of the present invention can be determined using the CCR-3 &lt; RTI ID = 0.0 &gt; L1.2 &lt; / RTI &gt; By measuring the inhibition of eotaxin-mediated chemotaxis on cell-infected cells. The assays were performed in a 24-well Kotocet six-plate (Collaborative Biomedical Products). CCR-2 L1.2 cells infected cells (referred to as 10E6 search) are RPMI 1640, 10% of high-clones (trade name, Hyclone), fetal bovine serum, 5.5% × 10 ^-5 2- mercaptoethanol and G 418 (0.8 &Lt; / RTI &gt; mg / ml). Cell-infected cells were treated with n-butyric acid to a final concentration of 5 mM / lxlO ⁶ cells / ml, 18-24 h before assay, isolated, and homogenous RPMI 1640 with 0.5% fetal bovine serum and M 199 at a density of 1 x 10 &lt; ⁷ &gt; cells / ml.
[285] Human Eotaxin suspended in PBS (Gibco # 14190-029) at 1 mg / ml was added to the bottom chamber to a final concentration of 100 nm. (Biocoat) Transwell culture insert (Costa Corporation, Cambridge, Mass., USA) with a 3 micron pore size was inserted into each well and L1.2 cells (1 x 10 &lt; ⁶ & Was added to the top chamber to a volume of 10 [mu] l. The test compounds in DMSO were added to the upper and lower chamber to a final DMSO volume of 0.5%. Assays for two control sets were performed. In the positive control, the upper chamber contained no test compound and the lower chamber contained cells with only eotaxin. In the negative control, cells in the upper chamber contained no test compound and no cells in the lower chamber, either Eotaxin or test compound. Plates were incubated at 37 &lt; 0 &gt; C. After 4 hours, the insert was removed from the chamber and transferred to the lower chamber by transferring 500 μl of the cell suspension from the lower chamber to the 1.2 ml cluster tube (Costa) by pipetting and counting them on FACS for 30 seconds The number of cells that have been cultured is calculated.
[286] Example 9
[287] Inhibition of eotaxin-mediated chemotaxis of human eosinophils - In vitro assays
[288] The ability of the compounds of the invention to inhibit eotaxin-mediated chemotaxis on human eosinophils is reviewed in Carr, M. W. et al.Proc. Natl. Acad. Sci.USA, 91: 3652-3656 (1994). "The experiment was carried out using 24-well chemotaxis plates (Correlative Biomedical Products), PCT Eosinophils were isolated from blood using the method described in WO 96/22371. The endothelial cells used were selected from the European Collection of Animal Cell Cultures (Salisbury, Endothelial cells were cultured on a 6.5 mm diameter biocotte transwell tissue culture insert with a pore size of 3.0 [mu] M (Costa Corporation, Cambridge, Mass.). Culture for ECV 304 cells The medium consisted of M199, 10% fetal bovine serum, L-glutamine and antibiotics. The assay medium contained the same volume of 0.5% BSA RPIM 1640 and M199. Twenty-four hours before the test, 2 x 10⁵ECV 304 cells were plated on each insert of a 24-well kerosene six-plate and incubated at 37 ° C. 20 nM of eotaxin diluted in the black medium was added to the lower chamber. The final volume of the lower chamber was 600 [mu] l. Endothelial coated tissue culture inserts were inserted into each well. 10 &lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;⁶doggy Eosinophils were added to the upper chamber. Test compounds dissolved in DMSO were added to the upper and lower chambers so that the DMSO final volume in each well was 0.5%. The assays were performed on two control sets. In the positive control group, the upper chamber contained cells and the lower chamber contained eotaxin. In the negative control, the upper chamber contains cells and the lower chamber contains only the assay buffer solution. The plates were washed with 5% CO₂/ 95% air for 1 to 1.5 hours at &lt; RTI ID = 0.0 &gt; 37 C. &lt; / RTI &gt;
[289] The flow cytometry is used to count the number of cells transferred to the lower chamber. 500 μl of the cell suspension from the lower chamber is placed in the tube and the relative number of cells is counted by capturing for a set time of 30 seconds.
[290] Example 10
[291] Inhibition of eosinophil chemotaxis by CCR-3 antagonists in ovalbumin sensitized balb / c mice - In vitro assay
[292] The CCR-3 antagonistic potency of the compounds of the present invention was determined by measuring the inhibition of eosinophil accumulation of Ovalbumin (OA) -sensitive balb / c mice into BAL fluid after aerosol administration of the antigen. Briefly, male balb / c mice weighing 20-25 g were sensitized to OA (10 μg in 0.2 ml aluminum hydroxide solution) administered intraperitoneally on days 1 and 14. One week later, mice were divided into 10 groups. The test compound or vehicle (positive control) was administered. One hour later, the mice were placed in a Plexiglass box and exposed to OA aerosols generated by a PARISTAR nebulizer for 20 minutes. Supernatants not sensitized or administered are included in the negative control. After 24 or 72 hours, the mice were anesthetized (urethane, approximately 1 g / kg, i.p.), the tracheal cannula (PE 60 tubing) was inserted and the lungs were washed 4 times with 0.3 ml PBS. The BAL fluid was transferred to a plate tube and stored on ice. Total leukocytes in 20 [mu] l aliquots of BAL fluid were measured by hemocytometer / Coulter Counter (trade name, Coulter Counter). A differential leucocyte counter is performed by optical microscopy using a standard format reference on a modified light dye (Wright's stain) (Cytospin preparation colored with Diff-Quick (trade name, Diff-Quick) .

权利要求:
Claims (26)
[1" claim-type="Currently amended] A compound selected from compounds of formula (I), or a prodrug thereof, a mixture of individual isomers, a mixture of isomers or a pharmaceutically acceptable salt thereof:
Formula I

In this formula,
One of T and U is -N ⁺ R ⁵ - provided that, where R ⁵ is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl alkyl, amido alkyl, sulfonylamino alkyl Or aralkyl and the remainder is -CH-;
X ^- is a pharmaceutically acceptable counter ion;
R ¹ and R ² are independently of each other hydrogen or alkyl;
m is an integer being 0 to 3, with the proviso that T is -N ⁺ R ⁵ - If, m is 1 or more and;
Ar and Ar &lt; ¹ &gt; are independently of each other aryl or heteroaryl;
F is alkylene, alkenylene or a bond;
R is hydrogen or alkyl, or taken together with R &lt; ³ &gt; or R &lt; ⁴ &gt;, and the atoms to which they are attached, form a carbocycle or heterocycle;
R ³ and R ⁴ are independently from each other hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, Z is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, Aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy);
E is ^{-C (O) N (R 6} ) -, -SO 2 N (R 6) -, -N (R 7) C (O) N (R 6) -, -N (R 7) SO 2 N ^{(R 6) -, -N (} R 7) C (S) N (R 6) -, -N (R 7) C (O) - or -N (R ⁷⁾ SO ₂ - provided that, where R ⁶ and R ⁷ is independently hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkyl, alkenyl each other, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or - (alkylene) (O) -Z wherein Z is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, Aryl, heteroaryloxy or heteroaralkyloxy;
Q is -CO-, or ^{-C (O) -, -NR 8} -, -O-, S (O) 0-2 -, -C (O) N (R 8) -, -N (R 8) C (O) -, -N ( R 8) SO 2 -, -SO 2 N (R 8) -, -N (R 9) C (O) N (R 10) -, -N (R 9) SO ₂ N (R ¹⁰⁾ - or ^{-N (R 9) C (S} ) N (R 10) - being optionally substituted alkylene swaeyi intervention by wherein R ^8, R ⁹ and R ¹⁰ are each independently hydrogen, Heteroaryl, heterocyclylalkyl, heteroalkyl or - (alkylene) -C (O) -Z (alkyl), acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, Z is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or hetero Aralkyloxy.
[2" claim-type="Currently amended] The method according to claim 1,
T is -N ⁺ R ⁵ -, and provided that, R ⁵ is alkyl, and F is bonded, R, R ^1, R ² and R ³ is a hydrogen.
[3" claim-type="Currently amended] 3. The method of claim 2,
m is 1, R &lt; ⁵ &gt; is methyl or ethyl, and Q is a methylene chain.
[4" claim-type="Currently amended] The method of claim 3,
E is ^{-C (O) N (R 6} ) -, -SO 2 N (R 6) -, -N (R 7) C (O) N (R 6) - or -N (R ⁷⁾ C (O ) -, wherein R &lt; ⁶ &gt; and R &lt; ⁷ &gt; are hydrogen.
[5" claim-type="Currently amended] 5. The method of claim 4,
And E is -C (O) NH-, R ⁴ is alkyl or heterocyclic alkyl.
[6" claim-type="Currently amended] 6. The method of claim 5,
Ar and Ar &lt; ^{1 &gt;} are optionally substituted aryl rings.
[7" claim-type="Currently amended] The method according to claim 6,
Ar is alkyl, heteroalkyl, alkoxy, -COR (where, R is alkyl), -SO ₂ R (where, R is alkyl, amino, one is a substituted amino or disubstituted amino), methylenedioxy, hydroxy , - (alkylene) -CONR'R " wherein R 'and R " are hydrogen or alkyl, -COOR , - (alkylene) -COOR where R is hydrogen or alkyl, or -NRSO ₂ R 'where R is hydrogen or alkyl and R' is alkyl, amino, mono-substituted amino or di- &Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
The compound Ar ¹ is a phenyl ring optionally substituted with alkyl, heteroalkyl, alkoxy, halo, methyl, nitro, from 1 to 3 substituents selected from a substituted amino, or disubstituted amino trifluoroacetate.
[8" claim-type="Currently amended] 8. The method of claim 7,
R ⁴ is selected from the group consisting of 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1 -hydroxyethyl or 2-
Wherein Ar ¹ is selected from the group consisting of 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, Fluoro-phenyl or 3,4-dichlorophenyl.
[9" claim-type="Currently amended] 9. The method of claim 8,
Ar is selected from the group consisting of phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, 4-aminocarbonylphenyl, Phenyl, 4-acetylaminophenyl, 4-dimethylaminocarbonylphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4- [(R) - amino-3-methyl-butyrylamino] ethyl] phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) phenyl, 4- (hydroxymethyl) phenyl, 2,5-dimethoxy Dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-amino-carbonylmethylphenyl, 4-acetylaminomethylphenyl, 4-methylsulfonylamino Phenyl, 4-methylsulfonylaminomethylphenyl or 4-aminophenyl.
[10" claim-type="Currently amended] 5. The method of claim 4,
And E is -NHC (O) NH-, R ⁴ is alkyl or heterocyclic alkyl.
[11" claim-type="Currently amended] 11. The method of claim 10,
Ar and Ar &lt; ^{1 &gt;} are optionally substituted aryl rings.
[12" claim-type="Currently amended] 12. The method of claim 11,
Ar is alkyl, heteroalkyl, alkoxy, -COR (where, R is alkyl), -SO ₂ R (where, R is alkyl, amino, one is a substituted amino or disubstituted amino), methylenedioxy, hydroxy , - (alkylene) -CONR'R " wherein R 'and R " are hydrogen or alkyl, -COOR , - (alkylene) -COOR where R is hydrogen or alkyl, or -NRSO ₂ R 'where R is hydrogen or alkyl and R' is alkyl, amino, mono-substituted amino or di- &Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
The compound Ar ¹ is a phenyl ring optionally substituted with alkyl, heteroalkyl, alkoxy, halo, methyl, nitro, from 1 to 3 substituents selected from a substituted amino, or disubstituted amino trifluoroacetate.
[13" claim-type="Currently amended] 13. The method of claim 12,
R ⁴ is selected from the group consisting of 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1 -hydroxyethyl or 2-
Wherein Ar ¹ is selected from the group consisting of 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, - &lt; / RTI &gt; fluorophenyl or 3,4-dichlorophenyl.
[14" claim-type="Currently amended] 14. The method of claim 13,
Wherein Ar is phenyl, 3-methoxyphenyl, 3-methylsulfonylphenyl, 3-dimethylaminophenyl, 3-acetylaminophenyl, 3- acetylphenyl, 3- dimethylaminocarbonylphenyl, 3- [ Ethyl] -phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxy Phenyl, 3-aminocarbonylmethylphenyl, 3-acetylaminomethylphenyl, 3-carboxymethylphenyl, 3-methylsulfonylaminophenyl, 3-methylsulfonylaminomethylphenyl or 3-aminophenyl.
[15" claim-type="Currently amended] 15. The method of claim 14,
Wherein Ar ¹ is 3,4,5-trimethoxyphenyl, Ar ² is 3,4-dichlorophenyl, R ⁴ is 1-methylethyl, R ⁵ is methyl and X ^- is iodide Methyl-1- [3-methyl-2- ( R ) - [3- (3,4,5-trimethoxyphenyl) ureido] butyl] Piperidinium iodide) compound.
[16" claim-type="Currently amended] The method according to claim 1,
T is -N ⁺ R ⁵ -, and provided that, R ⁵ is alkyl, and F is bonded, R, R ^1, R ² and R ³ is a hydrogen.
[17" claim-type="Currently amended] 17. The method of claim 16,
m is 1, R &lt; ⁵ &gt; is methyl or ethyl, and Q is a methylene chain.
[18" claim-type="Currently amended] The method according to claim 1,
T is -N ⁺ R ⁵ - provided that, R ⁵ is alkoxy-carbonyl-alkyl, F is a bond, R, R ^1, R ² and R ³ is a hydrogen.
[19" claim-type="Currently amended] 19. The method of claim 18,
m is 1, R &lt; ⁵ &gt; is methyl or ethyl, and Q is a methylene chain.
[20" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
[21" claim-type="Currently amended] (1) reacting a compound of formula (Ia) with an alkylating agent of formula R ⁵ X, wherein R ⁵ is as defined in claim 1, and X is a leaving group, under alkylating conditions;
(2) optionally substituting one counterion of the compound of formula (I) prepared in step (1) with another counterion; And
(3) optionally converting the compound of formula (I) prepared in step (1) or step (2) to the corresponding acid addition salt by treatment with an acid.
19. A process for the preparation of a compound according to any one of claims 1 to 19,

In this formula,
T or U is nitrogen,
R, R ¹ , R ² , R ³ , R ⁴ , Ar, Ar ¹ , E, F and Q are as defined in claim 1.
[22" claim-type="Currently amended] 20. The method according to any one of claims 1 to 19,
22. A compound produced by the method of claim 21.
[23" claim-type="Currently amended] 20. The method according to any one of claims 1 to 19,
Compounds which are therapeutic agents.
[24" claim-type="Currently amended] 19. A method for the treatment of diseases of mammals, especially asthma, which can be treated by administration of a CCR-3 antagonist, comprising administering to the mammal an effective amount of a compound according to any one of claims 1 to 19.
[25" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for the treatment of diseases which can be treated by the administration of a CCR-3 antagonist comprising a compound according to any one of claims 1 to 19 as an active ingredient, The use of a compound according to any one of claims 1-6.
[26" claim-type="Currently amended] The invention as hereinbefore described.

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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:
1998-11-20|Priority to US10929398P

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1998-11-20|Priority to US60/109,293

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1999-11-08|Application filed by 프리돌린 클라우스너, 롤란드 비. 보레르, 에프. 호프만-라 로슈 아게

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1999-11-08|Priority to PCT/EP1999/008554

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2001-08-25|Publication of KR20010081034A

优先权:

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申请号 | 申请日 | 专利标题

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US10929398P| true| 1998-11-20|1998-11-20|

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US60/109,293|1998-11-20|

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PCT/EP1999/008554|WO2000031033A1|1998-11-20|1999-11-08|Piperidine ccr-3 receptor antagonists|