1H-Pyrimido[4,5-b]indole Derivatives, Their Preparation and Therapeutic Use

Abstract

The disclosure concerns compounds of general formula (I): wherein n, X, Y, R 1 and R 2 are as defined herein. The disclosure also concerns a method for preparing the compounds and their therapeutic use.

1 . A compound of formula (III): 
     
       
         
         
             
             
         
       
     
     in which
 X represents a hydrogen or halogen atom; 
 R 1  represents a hydrogen atom or a (C 1 -C 6 )alkyl group; and 
 R 4  and R 5  each represent, independently of one another, a hydrogen atom or a (C 1 -C 6 )alkyl group, or else R 4  and R 5  form, with the nitrogen atom that they bear, an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, optionally subtituted by a (C 1 -C 6 )alkyl, phenyl or heterocycle. 
 
   
   
       2 . A method for the treatment of a disease in a patient, said disease selected from the group consisting of traumatic or ischemic neuropathy, spinal amyotrophy, amyotrophic lateral sclerosis, cerebrovascular accident, cranial and medular trauma, multiple sclerosis, Alzheimer's disease, Parkinson's disease, anxiety, epilepsy and sleep disorder, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     in which:
 n represents the number 0 or 1; 
 X represents a hydrogen or halogen atom; 
 Y represents an OR 3  group or an NR 4 R 5  group; 
 R 1  represents a hydrogen atom or a (C 1 -C 6 )alkyl group; 
 R 2  represents a (C 1 -C 6 )alkyl group, a phenyl or a monocyclic or bicyclic heterocycle, said phenyl or heterocycle groups optionally bearing one or more groups independently selected from halogen atoms, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl and (C 1 -C 6 )dialkylamino(C 1 -C 6 )alkyl groups; 
 R 3  represents a hydrogen atom, a (C 1 -C 6 )alkyl group or a benzyl; and 
 R 4  and R 5  each represent, independently of one another, a hydrogen atom or a (C 1 -C 6 )alkyl group, or else R 4  and R 5  form, with the nitrogen atom that they bear, an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, optionally substituted by a (C 1 -C 6 )alkyl, phenyl or heterocycle. 
 
   
   
       3 . The method according to  claim 2 , wherein:
 n represents the number 0 or 1;   X represents a hydrogen or halogen atom;   Y represents an OR 3  group or an NR 4 R 5  group;   R 1  represents a hydrogen atom or a (C 1 -C 6 )alkyl group;   R 2  represents a phenyl or a heterocycle chosen from pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, the phenyl or heterocycle optionally bearing one or more groups independently selected from halogen atoms, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxyl groups;   R 3  represents a hydrogen atom, a (C 1 -C 6 )alkyl or a benzyl; and   R 4  and R 5  each represent, independently of one another, a hydrogen atom or a (C 1 -C 6 )alkyl group, or else R 4  and R 5  form, with the nitrogen atom that they bear, an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group, optionally substituted by a (C 1 -C 6 )alkyl, phenyl or azetidinyl.   
   
   
       4 . The method according to  claim 2 , wherein:
 n represents the number 0 or 1;   X represents a hydrogen or fluorine or chlorine atom;   Y represents a hydroxy, OCH 3 , O(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , pyrrolidinyl, piperidinyl, morpholinyl, (N-azetidinyl)piperidinyl or N-methylpiperazinyl group;   R 1  represents a hydrogen atom, a methyl or isobutyl group; and   R 2  represents a phenyl, a methyl, isopropyl or cyclopropyl group or a heterocycle chosen from pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, tetrahydroquinolinyl or tetrahydropyranyl, the phenyl and heterocycle groups optionally being substituted by one or more groups independently selected from halogen groups, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )dialkylamino and (C 1 -C 6 )dialkyl-amino (C 1 -C 6 )alkyl groups.   
   
   
       5 . The method according to  claim 2 , wherein the compound is selected from the group consisting of: 
     N,N,9-trimethyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-fluoro-N,N-9-trimethyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     6-chloro-N,N-9-trimethyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N-dimethyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N-diethyl-9-methyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-9-methyl-2-phenyl-4-(pyrrolidin-1-ylcarbonyl)-9H-pyrimido[4,5-b]indole; 
     7-chloro-9-methyl-2-phenyl-4-(piperidin-1-ylcarbonyl)-9H-pyrimido[4,5-b]indole; 
     7-chloro-9-methyl-4-(morpholin-4-ylcarbonyl)-2-phenyl-9H-pyrimido[4,5-b]indole; 
     4-[(4-azetidin-1-yl)piperidin-1-ylcarbonyl]-7-chloro-9-methyl-2-phenyl-9H-pyrimido-[4,5-b]indole; 
     7-chloro-9-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]-2-phenyl-9H-pyrimido[4,5-b]indole; 
     6-chloro-N,N-9-trimethyl-2-pyridin-4-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-fluoro-N,N,9-trimethyl-2-pyridin-4-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-9-methyl-2-pyridin-4-yl-4-(pyrrolidin-1-ylcarbonyl)-9H-pyrimido-[4,5-b]indole; 
     7-chloro-N,N,9-trimethyl-2-pyridin-4-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-pyridin-3-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N-9-trimethyl-2-pyridin-2-yl-9H-pyrimido[4,5-b]indole-4-carboxamide 
     7-chloro-N,N-9-trimethyl-2-pyrazin-2-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     2-(7-chloro-9-methyl-2-phenyl-9H-pyrimido[4,5-b]indol-4-yl)-N,N-dimethylacetamide; 
     2-(6-chloro-9-methyl-2-phenyl-9H-pyrimido]4,5-b]indol-4-yl)-N,N-dimethylacetamide; 
     2-(7-chloro-9-methyl-2-pyridin-4-yl-9H-pyrimido[4,5-b]indol-4-yl)-N,N-dimethylacetamide; 
     2-(7-chloro-9-methyl-2-pyridin-3-yl-9H-pyrimido[4,5-b]indol-4-yl)-N,N-dimethylacetamide; 
     N,N-dimethyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     ethyl 7-chloro-9-methyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxylate; 
     methyl 7-chloro-9-methyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxylate; 
     7-chloro-9-methyl-2-phenyl-9H-pyrimido[4,5-b]indole-4-carboxylic acid; 
     7-chloro-N,N-9-trimethyl-2-(6-methylpyridin-3-yl)-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(6-methoxypyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N-9-trimethyl-2-(2-methylpyridin-4-yl)-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(2-methoxypyridin-4-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-9-isobutyl-N,N-dimethyl-2-pyridin-4-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-cyclopropyl-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,2,9-tetramethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-isopropyl-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-(tetrahydro-2H-pyran-4-yl)-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-{4-[(dimethylamino)methyl]phenyl}-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(6-chloropyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-[6-(trifluoromethyl)pyridin-3-yl]-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(6-ethoxypyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(6-ethylpyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(5-ethylpyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-(5-methylpyridin-3-yl)-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-pyrimidin-5-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(5-methoxypyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-[6-(methoxymethyl)pyridin-3-yl]-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-(2-methyl-1,3-thiazol-4-yl)-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-{6-[(dimethylamino)methyl]pyridin-3-yl}-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-2-(5,6-dimethylpyridin-3-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     7-chloro-N,N,9-trimethyl-2-(5,6,7,8-tetrahydroquinolin-3-yl)9H-pyrimido[4,5-b]indole-4-carboxamide; and 
     7-chloro-2-(2,6-dimethylpyridin-4-yl)-N,N,9-trimethyl-9H-pyrimido[4,5-b]indole-4-carboxamide; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The method according to  claim 2 , wherein the disease is selected from traumatic or ischemic neuropathy, spinal amyotrophy and amyotrophic lateral sclerosis. 
   
   
       7 . The method according to  claim 5 , wherein the disease is selected from traumatic or ischemic neuropathy, spinal amyotrophy and amyotrophic lateral sclerosis. 
   
   
       8 . The method according to  claim 2 , wherein the disease is cerebrovascular accident. 
   
   
       9 . The method according to  claim 5 , wherein the disease is cerebrovascular accident. 
   
   
       10 . The method according to  claim 2 , wherein the disease is cranial and medular trauma. 
   
   
       11 . The method according to  claim 5 , wherein the disease is cranial and medular trauma. 
   
   
       12 . The method according to  claim 2 , wherein the disease is multiple sclerosis. 
   
   
       13 . The method according to  claim 5 , wherein the disease is multiple sclerosis. 
   
   
       14 . The method according to  claim 2 , wherein the disease is chosen from Alzheimer's disease or Parkinson's disease. 
   
   
       15 . The method according to  claim 5 , wherein the disease is chosen from Alzheimer's disease or Parkinson's disease. 
   
   
       16 . The method according to  claim 2 , wherein the disease is anxiety. 
   
   
       17 . The method according to  claim 5 , wherein the disease is anxiety. 
   
   
       18 . The method according to  claim 2 , wherein the disease is chosen from epilepsy or sleep disorder. 
   
   
       19 . The method according to  claim 5 , wherein the disease is chosen from epilepsy or sleep disorder.