Arylindenopyridines and arylindenopyrimidines and related therapeutic and prophylactic methods

Abstract

This invention provides novel arylindenopyridines and arylindenopyrimidines of the formula: wherein R 1 , R 2 , R 3 , R 4 , and X are as defined above, and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing adenosine A2a receptors. This invention also provides therapeutic and prophylactic methods using the instant compounds and pharmaceutical compositions.

What is claimed is:  
     
         1 . A compound having the structure of Formula 1 or 11 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein  
         (a) R 1  is selected from the group consisting of 
 (i)-COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; 
 wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 7 R 8  wherein R 7  and R 8  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 7 R 8  taken together form a heterocycle or heteroaryl;  
 
 (ii) COOR 5 , wherein R 5  is as defined above;  
 (iv) cyano;  
 (v) —CONR 9 R 10  wherein R 9  and R 10  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, amino, alkoxy or arylalkyl, or R 9  and R 10  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
 (v) optionally substituted C 1-8  straight or branched chain alkyl; 
 wherein the substituents on the alkyl, group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, carboxyl, aryl, heterocyclyl, heteroaryl, sulfonyl, thiol, alkylthio, or NR 7 R 8  wherein R 7  and R 8  are as defined above;  
 
 
         (b) R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C 3-7  cycloalkyl, C 1-8  alkoxy, aryloxy, C 1-8  alkylsulfonyl, arylsulfonyl, arylthio, C 1-8  alkylthio, or —NR 24 R 25  
 wherein R 24  and R 25  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 24  and R 25  taken together with the nitrogen form a heteroaryl or heterocyclyl group,  
 
         (c) R 3  is from one to four groups independently selected from the group consisting of: 
 hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl, —NR 11 R 12 , 
 wherein R 1 , and R 12  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group,  
 
 —NR 13 COR 14 , 
 wherein R 13  is selected from hydrogen or alkyl and R 14  is selected from hydrogen, alkyl, substituted alkyl, C 1-3  alkoxyl, carboxyalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, R 15 R 16 N(CH 2 ) p —, or R 15 R 16 NCO(CH 2 ) p —, wherein R 15  and R 16  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R 13  and R 14  taken together with the carbonyl form a carbonyl containing heterocyclyl group;  
 
 
         (d) R 4  is selected from the group consisting of hydrogen, C 1-6  straight or branched chain alkyl, benzyl 
 wherein the alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 17 R 18 , aryl and heteroaryl,  
 —OR 17 , and —NR 17 R 18 , 
 wherein R 17  and R 18  are independently selected from hydrogen, and optionally substituted C 1-6  alkyl or aryl; and  
 
 
         (e) X is selected from C═S, C═O; CH 2 , CHOH, CHOR 19 ; or  
         CHNR 20 R 21  where R 1  g, R 20 , and R 2 , are selected from optionally substituted C 1-8  straight of branched chain alkyl, wherein the substituents on the alkyl group are selected from C 1-8  alkoxy, hydroxy, halogen, amino, cyano, or NR 22 R 23  wherein R 22  and R 23  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, heteroaryl, or NR 22 R 23  taken together from a heterocycle or heteroaryl;  
         with the proviso that in a compound of Formula II when R 1  is a cyano, then R 2  is not phenyl.  
       
     
     
         2 . The compound of  claim 1 , formula 1, wherein R 4  is amino.  
     
     
         3 . The compound of  claim 1 , formula 1, wherein R 2  is aryl or heteroaryl.  
     
     
         4 . The compound of  claim 1 , formula II, wherein R 2  is aryl or heteroaryl.  
     
     
         5 . The compound of  claim 4 , wherein R 2  is furyl or substituted furyl.  
     
     
         6 . The compound of  claim 4 , wherein R 1  is COOR 5 , wherein R 5  is selected from optionally substituted C 1-8  straight or branched chain alkyl.  
     
     
         7 . The compound of  claim 1 , which is 2-amino-4-furan-2-yl-indeno[1,2-d]pyrimidin-5-one.  
     
     
         8 . The compound of  claim 1 , which is 2-amino-4-phenyl-indeno[1,2-d]pyrimidin-5-one.  
     
     
         9 . The compound of  claim 1 , which is 2-amino-4-thiophen-2-yl-indeno[1,2-d]pyrimidin-5-one.  
     
     
         10 . The compound of  claim 1 , which is 2-amino-4-(5-methyl-furan-2-yl)-indeno[1,2-d]pyrimidin-5-one.  
     
     
         11 . The compound of  claim 1 , which is 2,6-diamino-4-furan-2-yl-indeno[1,2-d]pyrimidin-5-one.  
     
     
         12 . The compounds of  claim 1 , which is 9H-indeno[2,1-c]pyridine-4-carbonitrile, 3-amino-1-furan-2-yl-9-oxo-.  
     
     
         13 . The compound of  claim 1 , which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 2-dimethylamino-ethyl ester.  
     
     
         14 . The compound of  claim 1 , which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-phenyl-9-oxo-, 2-dimethylamino-ethyl ester.  
     
     
         15 . The compound of  claim 1 , which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino]-furan-2-yl-9-oxo-, (2-dimethylamino-1-methyl-ethyl)-amide.  
     
     
         16 . The compound of  claim 1 , which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-ethyl)-methyl-amide.  
     
     
         17 . The compound of  claim 1 , which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 1-methyl-pyrrolidin-2-ylmethyl ester.  
     
     
         18 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         19 . A method of treating a subject having a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, which comprises administering to the subject a therapeutically effective dose of the compound of  claim 1 .  
     
     
         20 . A method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, comprising administering to the subject a prophylactically effective dose of the compound of  claim 1  either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.  
     
     
         21 . The method of  claim 19  comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of  claim 18 .  
     
     
         22 . The method of  claim 20  comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of  claim 18 .  
     
     
         23 . The method of  claim 19 , wherein the disorder is a neurodegenerative disorder or a movement disorder.  
     
     
         24 . The method of  claim 19 , wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.  
     
     
         25 . The method of  claim 20 , wherein the disorder is a neurodegenerative disorder or a movement disorder.  
     
     
         26 . The method of  claim 20 , wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.  
     
     
         20 . A method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, comprising administering to the subject a prophylactically effective dose of the compound of  claim 1  either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.  
     
     
         21 . The method of  claim 19  comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of  claim 18 .  
     
     
         22 . The method of  claim 20  comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of  claim 18 .  
     
     
         23 . The method of  claim 19 , wherein the disorder is a neurodegenerative disorder or a movement disorder.  
     
     
         24 . The method of  claim 19 , wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.  
     
     
         25 . The method of  claim 20 , wherein the disorder is a neurodegenerative disorder or a movement disorder.  
     
     
         26 . The method of  claim 20 , wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.