Modulator

Abstract

The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is selected from OH, NHCH 2 CH 2 F, NHCH(Me)CH 2 OH and NHCH 2 CH 2 OH; X is an alkylene, alkenylene, or alkynylene group, each of which may be optionally substituted by one or more substituents selected from alkyl, COOH, CO 2 -alkyl, alkenyl, CN, NH 2 , hydroxy, halo, alkoxy, CF 3 and nitro; Y is a polar functional group selected from OH, NO 2 , CN, COR 3 , COOR 3 , NR 3 R 4 , CONR 3 R 4 , SO 3 H, SO 2 —R 3 , SO 2 NR 3 R 4 and CF 3 , where each of R 3 and R 4 is independently H or a hydrocarbyl group; A is phenyl or pyridyl; and B is (CH 2 ) n where n is 0; with the proviso that: (i) when A is phenyl, and Z is OH, X—Y is other than C≡C—(CH 2 ) 2 CO 2 H, C≡C—(CH 2 ) 2 CO 2 Me, (CH 2 ) 4 CO 2 H. Uses of such compounds as medicaments for the treatment of a muscular disorder, a gastrointestinal disorder, or for controlling spasticity or tremors are provided.

We claim: 
     
         1 . A compound of formula I, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         Z is OR 1  or NR 1 R 2  wherein each of R 1  and R 2  is independently H, or a hydrocarbyl group; 
         X is an alkylene, alkenylene, or alkynylene group, each of which may be optionally substituted by one or more substituents selected from alkyl, COOH, CO 2 -alkyl, alkenyl, CN, NH 2 , hydroxy, halo, alkoxy, CF 3 , and nitro; 
         Y is a polar functional group selected from OH, NO 2 , CN, COR. 3 , COOR 3 , NR 3 R 4 , 
         CONR 3 R 4 , SO 3 H, SO 2 —R 3 , SO 2 NR 3 R 4  and CF 3 , where each of R 3  and R 4  is independently H or a hydrocarbyl group; 
         A is phenyl or pyridyl; and 
         B is (CH 2 ) n  where n is 0; 
         with the proviso that: 
         (i) when A is phenyl, and Z is OH, X—Y is other than C≡C—(CH 2 ) 2 OH, C≡C—(CH 2 ) 2 OH, C≡C—(CH 2 ) 2 CO 2 Me, (CH 2 ) 4 CO 2 H; and 
         (ii) when A is phenyl, and Z is OMe, X—Y is other than C≡C—(CH 2 ) 4 OH; —(CH 2 ) 4 —CHO, cis-CH═CH—(CH 2 ) 3 OH, trans-CH═CH—(CH 2 ) 3 OH; 
         and wherein the compound is other than 1-(N-octylcarbamoyl)methyl-3-carboxmidopyridinuim chloride, 3-methylcarbamoyl-1-dodecyloxycarbonylmethyl-pyridinium or 6-aminomethylpyridine-2-carboxylic acid ethyl ester. 
       
     
     
         2 . A compound according to  claim 1  wherein Y is selected from CN, OH, COOR 3 , SO 2 NR 3 R 4 , CONR 3 R 4 , where each of R 3  and R 4  is independently H or a hydrocarbyl group. 
     
     
         3 . A compound according to  claim 1  wherein each of R 1 , R 2 , R 3  and R 4  is independently H, an alkyl group, an aryl group, or a cycloalkyl group, each of which may be optionally substituted. 
     
     
         4 . A compound according to  claim 1  wherein Y is selected from OH, CN, COOR 3 , CONR 3 R 4 , where each of R 3  and R 4  is independently H or an optionally substituted alkyl group. 
     
     
         5 . A compound according to  claim 1  wherein Y is selected from OH, CN, COOMe, COOH, CONH 2 , CONHMe and CONMe 2 . 
     
     
         6 . A compound according to  claim 1  wherein X—Y is selected from
 —C≡C—(CH 2 ) p —Y 
 —C(R 5 )═C(R 6 )—(CH 2 ) q —Y; and 
 —C(R5)(R6)C(R8)-(CH2)r-Y; 
 wherein each of R 5 , R 6 , R 7 , and R 8  is independently H or alkyl, and each of p, q and r is independently 2, 3, or 4. 
 
     
     
         7 . A compound according to  claim 1  wherein X—Y is selected from
 —C≡C—(CH 2 ) p —Y; and 
 —CH═CH—(CH 2 ) q —Y; 
 wherein each of p and q is independently 2, 3 or 4. 
 
     
     
         8 . A compound according to  claim 6  wherein X—Y is
 cis-C(R 5 )═C(R 6 )—(CH 2 ) q —Y and q is 2, 3 or 4. 
 
     
     
         9 . A compound according to  claim 1  wherein X—Y is —C(Me) 2 -CH 2 —(CH 2 ) r —Y and r is 2, 3 or 4. 
     
     
         10 . A compound according to  claim 1  wherein A is phenyl. 
     
     
         11 . A compound according to  claim 1  wherein Z is OR 1  or NR 1 R 2  and each of R 1  and R 2  is independently H, an alkyl or a cycloalkyl group, each of which may be optionally substituted by one or more OH or halogen groups. 
     
     
         12 . A compound according to  claim 1  wherein Z is selected from OH, OEt, NHCH 2 CH 2 F, NH-cyclopropyl, NHCH(Me)CH 2 OH and NHCH 2 CH 2 OH 
     
     
         13 . A compound according to  claim 1  which is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 13  which is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 14  which is in the form of a racemic mixture. 
     
     
         16 . A method of treating at least one of a muscular disorder, a gastrointestinal disorder, a disorder associated with the modulation of peripheral cannabinoid receptors or tremors, comprising administering to a person in need of said treatment a compound of  claim 1 . 
     
     
         17 . The method of  claim 16  wherein the muscular disorder is a neuromuscular disorder, or the gastrointestinal disorder is a gastric ulcer, or the gastrointestinal disorder is Crohn's disease, or the gastrointestinal disorder is secretory diarroehea, or the gastrointestinal disorder is paralytic ileus. 
     
     
         18 . A method of treating a disorder associated with the modulation of peripheral cannabinoid receptors, said method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         19 . A method according to  claim 18  wherein said disorder is associated with peripheral cannabinoid receptor deactivation. 
     
     
         20 . A method according to  claim 18  wherein the compound binds substantially agonise central cannabinoid receptors.