Pyridine non-classical cannabinoid compounds and related methods of use

Abstract

Disclosed are compounds of the formula I: wherein R 1 , R 2 , V, W, X, Y and Z can be as defined herein. The compounds can be used in the treatment of disorders mediated by the cannabinoid receptors.

1 . A method of treating a disorder mediated by a cannabinoid receptor comprising contacting said receptor with a compound in an amount to treat said cannabinoid receptor/mediated disorder, wherein the compound is of the formula 
       
         
           
           
               
               
           
         
         wherein 
         one of W and V is N and the other is C; 
         X is selected from the group consisting of
 cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein the ring portion of each is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, nitro, alkylamino, dialkylamino, thiol, alkylthiol, haloalkyl, carboxy and alkylcarboxy; 
 
         Y is selected from the group consisting of S, O, CH 2 , CH(CH 3 ), CH(OH), C(CH 3 )(OH), C(CH 3 ) 2 , C(—U(CH 2 ) n U—), C(O), S(O), and S(O) 2 ; 
         n is an integer from 1 to 3; 
         U is selected from the group consisting of CH 2 , S, and O; 
         Z is selected from the group consisting of H,
 alkyl optionally substituted with a substituent selected from the group consisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, thiol, alkylthiol, haloalkyl, carboxy, alkylcarboxy and carbamoyl; 
 cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein the ring portion of each is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, thiol, alkylthiol, haloalkyl, carboxy, alkylcarboxy and carbamoyl; and 
 
         R 1  and R 2  are independently selected from the group consisting of H and alkyl. 
       
     
     
         2 . A method according to  claim 1  wherein the cannabinoid receptor is selected from CB-1 and CB-2. 
     
     
         3 . A method according to  claim 3  wherein the disorder is selected from lung cancer, prostate cancer, colorectal cancer, pancreatic cancer, CNS cancer, brain cancer and human glaucoma. 
     
     
         4 . A method according to  claim 1  wherein
 X is selected from the group consisting of_alkyl,
 phenyl, benzyl, thiophene and pyridinyl, the ring portion of each is optionally substituted with one to five groups independently selected from the group consisting of halo, alkyl and alkoxy; 
 
 Y is selected from the group consisting of_carbonyl, dimethylmethylene and hydroxymethylene; and 
 Z is selected from the group consisting of alkyl, cycloalkyl, phenyl, and thiophene, each of which is optionally substituted with a substituent selected from the group consisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, thiol, alkylthiol, haloalkyl, carboxy, alkylcarboxy and carbamoyl. 
 
     
     
         5 . A method according to  claim 4  wherein X is alkyl, or benzyl or phenyl wherein the ring portion is optionally substituted with one, two or three groups independently selected from the group consisting of chloro, methyl and methoxy. 
     
     
         6 . A method according to  claim 5  wherein X is hexyl, benzyl, 3-methoxyphenyl, 3-methylphenyl or 3,5-dichlorophenyl. 
     
     
         7 . A compound according to  claim 5  wherein Y is dimethylmethylene. 
     
     
         8 . A compound according to  claim 5  wherein Z is alkyl, phenyl or cycloalkyl. 
     
     
         9 . A method according to  claim 1  wherein the compound is selected from the group consisting of
 6-(2-(Thiophen-2-yl)propan-2-yl)-3-m-tolylpyridine-2,4-diol; 
 6-(2-Cyclohexylpropan-2-yl)-3-(3,5-dichlorophenyl)pyridine-2,4-diol; 
 3-(3,5-Dichlorophenyl)-6-(2-phenylpropan-2-yl)pyridine-2,4-diol; 
 3-(3,5-Dichlorophenyl)-6-(2-(thiophen-2-yl)propan-2-yl)pyridine-2,4-diol 
 3-(3,5-dichlorophenyl)-6-(2-methyloctan-2-yl)pyridine-2,4-diol; 
 6-(2-Cyclohexylpropan-2-yl)-3-m-tolylpyridine-2,4-diol; 
 6-(2-Phenylpropan-2-yl)-3-m-tolylpyridine-2,4-diol; 
 2-(2-Methyloctan-2-yl)-5-m-tolylpyrimidine-4,6-diol; 
 6-(2-Methyloctan-2-yl)-3-phenylpyridine-2,4-diol; 
 3-Cyclohexyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol; 
 6′-(2-Methyloctan-2-yl)-2,3′-bipyridine-2′,4′-diol; 
 3-(3-Methoxyphenyl)-6-(2-methyloctan-2-yl)pyridine-2,4-diol; and 
 3-Benzyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol.