Thienopyrimidine and thienopyridine derivatives substituted with cyclic amino group

Abstract

An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain, etc. A thienopyrimidine or thienopyridine derivative substituted with a cyclic amino group represented by the following formula [I]: has a high affinity for CRF receptors and is effective against diseases in which CRF is considered to be involved.

1 . A thienopyridine compound substituted with the cyclic amino group represented by the following formula [IV]: 
     
       
         
         
             
             
         
       
     
     (wherein the cyclic amino group is represented by the following formula [II]: 
     
       
         
         
             
             
         
       
       in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C 1-5 alkylene or C 1-4 alkylene-O—C 1-4 alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR 1 R 2 ) m —(CHR 3 ) n —X, R 4  and R 5  independently on the same or different carbon atoms of the cyclic amine; 
     
     wherein
 X is cyano, hydroxy, —CO 2 R 8  or —CONR 9 R 10 ; 
 R 1  is hydrogen, hydroxy, C 1-5 alkyl, C 1-5 alkoxy-C 1-5 alkyl or hydroxy-C 1-5 alkyl; 
 R 2  is hydrogen or C 1-5 alkyl; 
 R 3  is hydrogen, cyano, C 1-5 alkyl, C 1-5 alkoxy-C 1-5 alkyl or hydroxy-C 1-5 alkyl; 
 m is an integer selected from 0, 1, 2, 3, 4 and 5; 
 n is 0 or 1; 
 R 4  is hydrogen, hydroxy, hydroxy-C 1-5 alkyl, cyano, cyano-C 1-5 alkyl or C 1-5 alkyl; 
 R 5  is hydrogen or C 1-5 alkyl; 
 R 6  is hydrogen, C 1-5 alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-5 alkyl, hydroxy, C 1-5 alkoxy, C 3-8  cycloalkyloxy, halogen, C 1-5 alkylthio or —N(R 12 )R 13 ; 
 R 7  is hydrogen, halogen, C 1-5 alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-5 alkyl, hydroxy, C 1-5  alkoxy, C 3-8  cycloalkyloxy, —N(R 14 )R 15 , —CO 2 R 16 , —CON(R 17 )R 18 , cyano, nitro, C 1-5 alkylthio, trifluoromethyl or trifluoromethoxy; 
 Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C 1-5 alkyl, C 3-8  cycloalkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, C 1-5 alkylthio, C 1-5  alkylsulfinyl, C 1-5 alkylsulfonyl, cyano, nitro, hydroxy, —CO 2 R 19 , —C(═O)R 20 , —CONR 21 R 22 , —OC(═O)R 23 , —NR 24 CO 2 R 25 , —S(═O) r NR 26 R 27 , trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R 28 )R 29 ; 
 R 8  is hydrogen, C 1-10  alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-5 alkyl, aryl or aryl-C 1-5  alkyl; 
 R 9  and R 10  are the same or different, and independently are hydrogen, C 1-5 alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-5 alkyl, aryl or aryl-C 1-5 alkyl; or R 9  and R 10  form a ring selected from saturated 3 to 8 membered ring with the attached nitrogen atom, wherein one of the carbon atoms of such saturated 3 to 8 membered ring is optionally replaced by an oxygen or sulfur atom or by N-Z wherein Z is hydrogen, benzyl or C 1-5 alkyl; 
 R 11  is hydrogen, halogen or C 1-5 alkyl; 
 R 12 , R 13 , R 14  and R 15  are the same or different, and independently are hydrogen or C 1-5  alkyl; 
 R 16 , R 19  and R 25  are the same or different, and independently are hydrogen or C 1-5 alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-5 alkyl, aryl or aryl-C 1-5 alkyl; 
 R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 26 , R 27 , R 28  and R 29  are the same or different, and independently are hydrogen, C 1-5 alkyl or C 3-8  cycloalkyl; 
 r is 1 or 2), 
 
     individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, pharmaceutically acceptable prodrugs thereof or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       2 . The thienopyridine compound substituted with the cyclic amino group according to  claim 1  represented by formula [IV], wherein X is cyano; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; n is 0; m is an integer selected from 1, 2 and 3; R 1 , R 2 , R 4  and R 5  are hydrogen; R 6  is C 1-5 alkyl; R 7  is hydrogen or C 1-5 alkyl; R 11  is hydrogen or C 1-5 alkyl; and Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, trifluoromethyl, trifluoromethoxy and —N(R 28 )R 29  (wherein R 28  and R 29  are the same or different, and independently are hydrogen or C 1-3  alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       3 . The thienopyridine compound substituted with the cyclic amino group according to  claim 2  represented by formula [IV], wherein X is cyano; the cyclic amino group is a 6-membered saturated cyclic amine; n is 0; m is 0 or 1; R 1 , R 2,  R 4  and R 5  are hydrogen; R 6  is C 1-5 alkyl; R 7  is hydrogen or C 1-5 alkyl; R 11  is hydrogen; and Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen and C 1-3  alkyl, individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       4 . The thienopyridine compound substituted with the cyclic amino group according to  claim 1  represented by formula [IV], wherein X is hydroxy; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; n is 0; m is an integer selected from 1, 2 and 3; R 1 , R 2 , R 4  and R 5  are hydrogen; R 6  is C 1-5 alkyl; R 7  is hydrogen or C 1-5 alkyl; R 11  is hydrogen or C 1-5 alkyl; and Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, trifluoromethyl, trifluoromethoxy and —N(R 28 )R 29  (wherein R 28  and R 29  are the same or different, and independently are hydrogen or C 1-3  alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       5 . The thienopyridine compound substituted with the cyclic amino group according to  claim 1  represented by formula [IV], wherein X is hydroxy; the cyclic amino group is a 6-membered saturated cyclic amine; n is 0; m is an integer selected from 1, 2 and 3; R 1 , R 2 , R 4  and R 5  are hydrogen; R 6  is C 1-5 alkyl; R 7  is hydrogen or C 1-5 alkyl; R 11  is hydrogen; and Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen and C 1-3  alkyl, individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       6 . The thienopyridine compound substituted with the cyclic amino group according to  claim 1  represented by formula [IV], wherein X is —CO 2 R 8  or —CONR 9 R 10 ; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; n is 0; m is an integer selected from 0, 1, 2 and 3; R 1 , R 2 , R 4  and R 5  are hydrogen; R 6  is C 1-5 alkyl; R 7  is hydrogen or C 1-5 alkyl; R 8  is hydrogen or C 1-10  alkyl; R 9  and R 10  are the same or different, and independently are hydrogen or C 1-5 alkyl; R 11  is hydrogen or C 1-5 alkyl; and Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, trifluoromethyl, trifluoromethoxy and —N(R 28 )R 29  (wherein R 28  and R 29  are the same or different, and independently are hydrogen or C 1-3  alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       7 . The thienopyridine compound substituted with the cyclic amino group according to  claim 1  represented by formula [IV], wherein X is —CO 2 R 8  or —CONR 9 R 10 ; the cyclic amino group is a 6-membered saturated cyclic amine; n is 0; m is an integer selected from 0, 1, 2 and 3; R 1 , R 2 , R 4  and R 5  are hydrogen; R 6  is C 1-5 alkyl; R 7  is hydrogen or C 1-5 alkyl; R 8  is hydrogen or C 1-10  alkyl; R 9  and R 10  are the same or different, and independently are hydrogen or C 1-5 alkyl; R 11  is hydrogen; and Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen and C 1-3  alkyl, individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. 
   
   
       8 . Compounds represented by formula [IV] according to  claim 1 , which compounds are selected from the group consisting of
 {1-[3-(2,4-dichloro-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-methanol,   {1-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-methanol,   {1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-methanol,   {1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-methanol,   {1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-methanol,   {1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-methanol,   2-{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-ethanol,   2-{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-ethanol,   2-{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-ethanol,   2-{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-ethanol,   1-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidine-3-carbonitrile,   {1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-acetonitrile,   {1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-acetonitrile,   {1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-acetonitrile   and {1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperidin-4-yl}-acetonitrile.   
   
   
       9 . A composition comprising a thienopyrimidine compound substituted with a cyclic amino group, a pharmaceutically acceptable salt thereof or its hydrate according to  claim 1 , and a pharmaceutically acceptable carrier. 
   
   
       11 . Use of a thienopyrimidine compound substituted with a cyclic amino group, a pharmaceutically acceptable salt thereof or its hydrate according to  claim 1 , for the manufacture of a therapeutic agent as an antagonist for CRF receptors.