Cyanoamidine P2X7 Antagonists for the Treatment of Pain

Abstract

Novel cyanoamidines compounds of formula (I) and (II) and their derivatives wherein R 1 -R 12 are as defined in the specification act as antagonists of the P2X 7 receptor. These compounds are particularly useful in the treatment of pain, inflammation and neurodegeneration states.

1 . A method of a disorder selected from the group consisting of pain, inflammation, arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke, neurodegeneration, and varicose veins in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1  is a bond or a chain selected from the group consisting of alkyl, alkenyl, and alkynyl,  
 R 2  is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be independently substituted with 0, 1, 2, or 3 alkenyl, alkyl, alkynyl, halo, haloalkyl, nitro, —C(O)—N—RaRb, —C(O)O—Ra, —C(O)—Ra, —N—RaRb, alkyl-N—RaRb, —O—Ra, —OC(O)—Ra, alkyl-O—Ra, —N—(Ra)—C(O)O—Rb, —N—(Ra)—C(O)N—RaRb, S—Ra, —S(O)—Ra, —S(O) 2 —Ra, S(O) 2 —RaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl;  
 R 3  is selected from the group consisting of alkyl and haloalkyl,  
 R 4  is alkyl, and  
 R 5  is selected from the group consisting of halogen, aryl, and heteroaryl, wherein aryl, and heteroaryl can be independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from alkenyl, alkyl, alkynyl, cyano, halo, haloalkyl, nitro, ethylenedioxy, methylenedioxy, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —NRaRb, alkylNRaRb, —ORa, —OC(O)Ra, alkylORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NRaRb, SRa, —S(O)Ra, —S(O) 2 Ra, S(O) 2 RaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl; and  
 R 6  and R 7  are independently selected from the group consisting of hydrogen and alkyl.  
 
   
   
       2 . The method of  claim 1 , wherein the disorder is pain.  
   
   
       3 . A compound of formula (II)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 10  is a carbon chain selected from the group consisting of alkyl, alkenyl, and alkynyl,  
 R 11  is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from alkenyl, alkyl, alkynyl, halo, haloalkyl, nitro, —C(O)—N—RaRb, —C(O)O—Ra, —C(O)—Ra, —N—RaRb, alkyl-N—RaRb, —O—Ra, —OC(O)—Ra, alkyl-O—Ra, —N—(Ra)—C(O)O—Rb, —N—(Ra)—C(O)N—RaRb, S—Ra, —S(O)—Ra, —S(O) 2 —Ra, S(O) 2 —RaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl;  
 R 8  is a bond or a carbon chain selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein the carbon chain can be substituted with 0, 1, or 2 substituents selected from the group consisting of —NH 2 , —N(H)alkyl, —N(alkyl) 2 , and heterocycle;  
 R 9  is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from alkenyl, alkyl, alkynyl, cyano, halo, haloalkyl, nitro, heterocycle, —C(O)NRaRb, —C(O)ORa, —C(O)Ra, —NRaRb, alkylNRaRb, —ORa, —OC(O)Ra, alkylORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NRaRb, SRa, —S(O)Ra, —S(O) 2 Ra, S(O) 2 RaRb, wherein Ra and Rb are independently selected form the group consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl;  
 R 12  is selected from the group consisting of hydrogen and alkyl; alternatively, R 12  and R 8  together with the nitrogen to which they are attached form a 4, 5, or 6 membered heterocycle ring, or when R 9  is aryl, R 12  along with any available carbon atom of R 9  form a 5 or 6 membered heterocycle ring, with the proviso that when R 11  is unsubstituted aryl or aryl substituted with 0, 1, 2, 3 or 4 halogen, and R 12  is selected from the group consisting hydrogen and alkyl, then R 9  is not substituted pyridinyl.  
 
   
   
       4 . The compound of  claim 3 , wherein 
 R 10  is alkyl,    R 11  is aryl wherein aryl is phenyl substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, alkyl, and haloalkyl. R 8  is selected from the group consisting of a bond and a carbon chain selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein the carbon chain can be substituted with 0, 1, or 2 —NH 2 , —N(H)alkyl, —N(alkyl) 2 , or heterocycle,    and    R 9  is aryl.    
   
   
       5 . The compound of  claim 3 , wherein 
 R 8  is a carbon chain selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein the carbon chain can be substituted with 0, 1, or 2 —NH 2 , —N(H)alkyl, —N(alkyl) 2 , or morpholinyl,    R 9  is phenyl substituted with 0, 1, 2, 3, or 4, substituents independently selected from the group of alkyl, halo and haloalkyl, and,    R 11  is phenyl substituted with 0, 1, 2, 3, or 4, substituents independently selected from the group of alkyl, halo and haloalkyl.    
   
   
       6 . The compound of  claim 5 , wherein the compound is selected from the group consisting of 
 N′-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylethyl]ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-(1-methyl-1-phenylethyl)ethanimidamide,    N′-cyano-N-[(1R)-1-(4-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylpropyl]ethanimidamide,    N′-cyano-N-[(1R)-1-(2-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-N-[1-(3-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-N-[3-(4-methoxyphenyl)-1-methylpropyl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylpropyl]ethanimidamide,    N-[2-(2-chlorophenyl)-2-(dimethylamino)ethyl]-N′-cyano-2-(2-methylphenyl)ethanimidamide,    N′-cyano-N-[1-(4-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,    N-[2-(2-chlorophenyl)ethyl]-N′-cyano-2-(2-methylphenyl)ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-(2-morpholin-4-yl-1-phenylethyl)ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-[1-(2-morpholin-4-ylphenyl)ethyl]ethanimidamide,    N′-cyano-N-(2-methylbenzyl)-3-phenylbutanimidamide, and    N′-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-[2-(trifluoromethyl)phenyl]ethanimidamide.    
   
   
       7 . The compound of  claim 3 , wherein 
 R 11  is aryl and,    R 9  is heteroaryl.    
   
   
       8 . The compound of  claim 7 , wherein R 9  is selected from the group consisting of thienyl and pyridinyl.  
   
   
       9 . The compound of  claim 8 , wherein the compound is selected from the group consisting of 
 N′-cyano-2-(2-methylphenyl)-N-[(1R)-1-thien-2-ylethyl]ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-(1-pyridin-4-ylpentyl)ethanimidamide, and    N′-cyano-2-(2-methylphenyl)-N-(1-pyridin-4-ylpropyl)ethanimidamide.    
   
   
       10 . The compound of  claim 3 , wherein 
 R 11  is aryl,    R 8  is a bond and,    R 9  is aryl.    
   
   
       11 . The compound of  claim 10  wherein R 11  is phenyl substituted with one alkyl group and R 9  is selected from the group consisting of 2,3-dihydro-indenyl, 1,2,3,4-tetrahydronaphthalenyl and 1,2,3,4-tetrahydro-1,4-methanonaphthalenyl.  
   
   
       12 . The compound of  claim 11  wherein the compound is selected from the group consisting of 
 N′-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]ethanimidamide,    N′-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(2-methylphenyl)ethanimidamide,    N′-cyano-N-(1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-methylphenyl)ethanimidamide,    N-(4-chloro-2,3-dihydro-1H-inden-1-yl)-N′-cyano-2-(2-methylphenyl)ethanimidamide,    N′-cyano-2-(2-methylphenyl)-N-[(1R,2R,4R)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-2-yl]ethanimidamide,    N′-cyano-N-[(1S,2S,4S)-6,7-dimethoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-2-yl]-2-(2-methylphenyl)ethanimidamide,    N′-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-fluorophenyl)ethanimidamide, and    2-(2-chlorophenyl)-N′-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)ethanimidamide    
   
   
       13 . The compound of  claim 11 , wherein 1,2,3,4-tetrahydronaphthalenyl can be substituted with 0, 1 or 2 substituents selected from the group consisting of alkyl and alkoxy.  
   
   
       14 . The compound of  claim 3 , wherein 
 R 11  is heteroaryl, and    R 9  is aryl.    
   
   
       15 . The compound of  claim 14 , wherein 
 R 11  is pyridinyl and    R 9  is phenyl    
   
   
       16 . The compound of  claim 15 , wherein the compound is selected from the group consisting of 
 N′-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylethyl]ethanimidamide,    N-[2-(2-chlorophenyl)ethyl]-N′-cyano-2-(2-methylpyridin-3-yl)ethanimidamide,    N′-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylpropyl]ethanimidamide,    N′-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-(2-methylpyridin-3-yl)ethanimidamide, and    N′-cyano-N-[1-(3-fluorophenyl)ethyl]-2-(2-methylpyridin-3-yl)ethanimidamide.    
   
   
       17 . The compound of  claim 3 , wherein 
 R 11  is heteroaryl, wherein heteroaryl is pyridinyl, and    R 9  is aryl wherein aryl is selected from the group consisting of 2,3-dihydro-indenyl and 1,2,3,4-tetrahydronaphthalenyl.    
   
   
       18 . The compound of  claim 17  wherein the compound is selected from the group consisting of 
 N′-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-methylpyridin-3-yl)ethanimidamide,    N′-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)ethanimidamide, and    N′-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]ethanimidamide.    
   
   
       19 . The compound of  claim 3 , wherein 
 R 11  is heteroaryl wherein heteroaryl is quinolinyl, and    R 9  is aryl, wherein aryl is selected from the group consisting of 2,3-dihydro-indenyl and 1,2,3,4-tetrahydronaphthalenyl.    
   
   
       20 . The compound of  claim 19  wherein the compound is selected from the group consisting of 
 N′-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimidamide and    N′-cyano-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimidamide.    
   
   
       21 . A method of treating a disorder selected from the group consisting of pain, inflammation, rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke, neurodegeneration and varicose veins in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or prodrug thereof.  
   
   
       22 . The method of  claim 21  wherein the disorder is pain.  
   
   
       23 . The method of  claim 21  wherein the disorder is inflammation.  
   
   
       24 . The method of  claim 21  wherein the disorder is neurodegeneration