Arylindenopyridines and related therapeutic and prophylactic methods

Abstract

This invention provides novel arylindenopyridines of the formula: and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing Adensine A2a receptors or reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

1 . A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure  
     
       
         
         
             
             
         
       
       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 20 R 21  wherein R 20  and R 21  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 20 R 21  taken together form a heterocycle or heteroaryl;  
 
 (ii) COOR 6 , wherein R 6  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 20 R 21  wherein R 20  and R 21 , 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 20 R 21  taken together form a heterocycle or heteroaryl;  
 (iii) cyano;  
 (iv) a lactone or lactam formed with R 4 ;  
 (v) —CONR 7 R 8  wherein R 7  and R 8  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, alkoxy or arylalkyl,  
 
  or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 (vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups  
 
       (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) R 3  is from one to four groups independently selected from the group consisting of: 
 (i) 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;  
 (ii) —NR 10 R 11  wherein R 10  and R 11  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;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 1-3  is selected from hydrogen, alkyl, substituted alkyl, C 13 alkoxyl, carboxyalkyl, R 30 R 31 N (CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl;  
        wherein the C 1-3 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 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       with the proviso that when R 4  is isopropyl, then R 3  is not halogen, and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
     
   
   
       2 . A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure:  
     
       
         
         
             
             
         
       
       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 20 R 21  wherein R 20  and R 21  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 20 R 21  taken together form a heterocycle or heteroaryl;  
 
 (ii) COOR 6 , wherein R 6  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 20 R 21  wherein R 20  and R 21  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 20 R 21  taken together form a heterocycle or heteroaryl;  
 
 (i) cyano;  
 (ii) a lactone or lactam formed with R 4 ;  
 (iii) —CONR 7 R 8  wherein R 7  and R 8  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, alkoxy or arylalkyl,  
 
  or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 (vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups  
 
       (b) R 2  is —NR 15 R 16  wherein R 15  and R 16  are independently selected from hydrogen, optionally substituted C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, aryl, heteroaryl, and heterocyclyl or R 15  and R 16  taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2  is NHR 16 , R 1  is not —COOR 6  where R 6  is ethyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (i) 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;  
 (ii) —NR 10 R 11  wherein R 10 and R 11  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;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N (CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31 , 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;  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl;  
        wherein the C 1-3 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 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
     
   
   
       3 . A method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject, in need of such treatment, a prophylactically effective dose of a compound as defined in  claim 1  or  claim 2  either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.  
   
   
       4 . The method of  claim 3  comprising administering to the subject a therapeutically or prophylactically effective dose of a pharmaceutical composition comprising a compound as defined in  claim 1  or  claim 2  and a pharmaceutically acceptable carrier.  
   
   
       5 . The method of  claim 3  comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition comprising a compound as defined in  claim 1  or  claim 2  and a pharmaceutically acceptable carrier.  
   
   
       6 . A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of a compound as defined in  claim 1  or  claim 2 .  
   
   
       7 . The method of  claim 1  or  claim 2 , wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.  
   
   
       8 . The method of  claim 3 , wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.  
   
   
       9 . The method of  claim 6 , wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.  
   
   
       10 . The method of  claim 1  or  claim 2 , wherein the disorder is selected from the group consisting of hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.  
   
   
       11 . A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound as defined in  claim 1  or  claim 2 .  
   
   
       12 . The method of  claim 11  wherein the animal is a mammal.  
   
   
       13 . The method of  claim 12  wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.  
   
   
       14 . A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure of Formula I wherein R 4  is C 1-8  straight or branched chain alkyl and X is O.  
   
   
       15 . 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 a compound as defined in  claim 1  or  claim 2 .  
   
   
       16 . 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 a compound as defined in  claim 1  or  claim 2 , either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.  
   
   
       17 . The method of  claim 15  comprising administering to the subject a therapeutically or prophylactically effective dose of a pharmaceutical composition comprising the compound as defined in  claim 1  or  claim 2  and a pharmaceutically acceptable carrier.  
   
   
       18 . The method of  claim 16  comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition comprising a compound as defined in  claim 1  or  claim 2  and a pharmaceutically acceptable carrier.  
   
   
       19 . The method of  claim 15  or  claim 17 , wherein the disorder is a neurodegenerative disorder or a movement disorder.  
   
   
       20 . 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.  
   
   
       21 . The method of  claim 16 , wherein the disorder is a neurodegenerative disorder or a movement disorder.  
   
   
       22 . The method of  claim 21 , 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.