Novel analgesic and immunomodulatory cannabinoids

Abstract

Disclosed are novel compounds represented by the following structural formula: R—X—Y; and physiologically acceptable salts thereof. R is a tricyclic core of a cannabinoid or substituted cannabinoid. X is a covalent bond, —CH2— or —CHR 1 —, wherein R 1 a C1 to C3 substituted or unsubstituted alkyl group. Y is a heterocyclic ring, a substituted heterocyclic ring, a carbocyclic ring, a substituted carbocyclic ring, a fused bicyclic ring system, a substituted fused bicyclic ring system, a bridged bicyclic ring system, a substituted bridged bicyclic ring system, a bridged tricyclic ring system or a substituted bridged tricyclic ring system. Also disclosed is a method of stimulating a CB1 and/or CB2 receptor in a subject. The method comprises administering to the subject a therapeutically effective amount of R—X—Y.

What is claimed is:  
     
         1 . A compound represented by the following structural formula:  
       R—X—Y;  and physiologically acceptable salts thereof, wherein:    R is a tricyclic core of a cannabinoid or substituted cannabinoid;    X is a covalent bond, —CH— or —CHR 1 —, wherein R 1  a C1 to C3 substituted or unsubstituted alkyl group; and    Y is a heterocyclic ring, a substituted heterocyclic ring, a carbocyclic ring, a substituted carbocyclic ring, a fused bicyclic ring system, a substituted fused bicyclic ring system, a bridged bicyclic ring system, a substituted bridged bicyclic ring system, a bridged tricyclic ring system or a substituted bridged tricyclic ring system.    
     
     
         2 . The compound of    claim 1    wherein R is represented by the following structural formula:  
                 

 wherein Ring A has zero to three endocyclic double bonds; 
 Z is >C(CH 3 ) 2  or —C=O; and  
 R 2  is —H, —OH, —OCH 3 , —OCH 2 CH 3 , halogen, —CN, —NO 2 , —CH 3 , —C(halogen) 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 (halogen), —CH 2 CN, —CH 2 NO 2 , —CH 2 CH 3  or —CH 2 C(halogen) 3 , —CH 2 NH 2 , —CH 2 NHCH 3  or —CH 2 N(CH 3 ) 2 .  
 
 
     
     
         3 . The compound of    claim 2    wherein R is represented by the following structural formula:  
                 

 wherein R 2  is —CH 3  or —CH 2 OH.  
 
     
     
         4 . The compound of    claim 3    wherein the compound is represented by the following structural formula: 
 wherein X is a covalent bond and Y is a C5-C7 carbocyclic ring, a substituted C5-C7 carbocyclic ring, a C5-C7 heterocyclic ring or a C5-C7 substituted heterocyclic ring.  
 
     
     
         5 . The compound of    claim 4    wherein X is represented by the following structural formula:  
                 

 wherein:  
 R 3  is —H or —CH 3 ;  
 R 4  and R 5  are independently —H or a C1 to C8 substituted or unsubstituted straight chained alkyl group and wherein at least one of R 4  and R 5  is —H.  
 
     
     
         6 . The compound of    claim 4    wherein X is a covalent bond and Y is represented by a structural formula selected from:  
                 

 wherein:  
 Z′ and Z″ are independently —S—, —O— or —N(R 7 )—;  
 R 6  is a substituted or unsubstituted C1 to about C12 straight chained alkyl group; and  
 R 7  is —H or —CH 3 .  
 
     
     
         7 . The compound of    claim 6    wherein Z′ and Z″ are each —O— or —S— and R 6  is a C4 to C10 alkyl group.  
     
     
         8 . The compound of    claim 4    wherein X is a covalent bond and Y is represented by the following structural formula:  
                 

 wherein:  
 R 8  is —H or —CH 3 ; and  
 R 9  is —H, a substituted or unsubstituted C1-C4 alkyl group.  
 
     
     
         9 . The compound of    claim 3    wherein X is a covalent bond and Y is a bridged bicyclic ring system, a substituted bridged bicyclic ring system, a bridged tricyclic ring system or a substituted bridged tricyclic ring system.  
     
     
         10 . The compound of    claim 9    wherein Y is a substituted or unsubstituted 0,1,1,1,1,1-tricyclic nine-membered ring system, 1,3,3-bicyclic nine-membered ring system, 1,2,3-bicyclic eight-membered ring system, 1,1,1,1,1,1-tricyclic ten-membered ring system, 1,1,3-bicyclic nine-membered ring system or 1,3-bicyclic six-membered ring system.  
     
     
         11 . The compound of    claim 3    wherein the X is a covalent bond and Y is a substituted or unsubstituted norbornyl ring system.  
     
     
         12 . The compound of    claim 11    wherein the norbornyl ring system is represented by the following structural formula:  
                 

 wherein R 10 -R 12  are independently —H, C1-C3 alkyl group or C1-C3 substituted alkyl group.  
 
     
     
         13 . The compound of    claim 12    wherein R 10 -R 12  are independently —H or —CH 3 .  
     
     
         14 . The compound of    claim 3    wherein X is a covalent bond and Y is a substituted or unsubstituted adamantyl ring system which contains zero, one or two heteroatoms.  
     
     
         15 . The compound of    claim 14    wherein Y is represented by the structural formula:  
                 

 wherein:  
 R 13 , R 14 , R 15  and R 16  are independently —H, C1-C3 alkyl group or C1 to C3 substituted alkyl group; and  
 X 1  and X 2  independently are >N— or >CH—.  
 
     
     
         16 . The compound of    claim 15    wherein R 14 -R 16  are each —H, R 13  is —CH 3  and X 1  and X 2  are >CH—.  
     
     
         17 . A method of stimulating a CB1 or CB2 receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:  
       R—X—Y;  and physiologically acceptable salts thereof; wherein:    R is a tricyclic core of a cannabinoid or substituted cannabinoid;    X is a covalent bond, —CH 2 — or —CHR 1 —, wherein R 1  a C1 to C3 substituted or unsubstituted lower alkyl group; and    Y is a heterocyclic ring, a substituted heterocyclic ring, a carbocyclic ring, a substituted carbocyclic ring, a fused bicyclic ring system, a substituted fused bicyclic ring system, a bridged bicyclic ring system, a substituted bridged bicyclic ring system, a bridged tricyclic ring system or a substituted bridged tricyclic ring system.    
     
     
         18 . The method of    claim 17    wherein R is represented by the following structural formula:  
                 

 wherein Ring A has zero to three endocyclic double bonds;  
 Z is >C(CH 3 ) 2  or —C=O; and  
 R 2  is —H, —OH, —OCH 3 , —OCH 2 CH 3 , halogen, —CN, —NO 2 , —CH 3 , —C(halogen) 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 (halogen), —CH 2 CN, —CH 2 NO 2 , —CH 2 CH 3 , CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N (CH 3 ) 2  or —CH 2 C(halogen) 3 .  
 
     
     
         19 . The method of    claim 17    wherein R is represented by the following structural formula:  
                 

 wherein R 2  is —CH 3  or -CH 2 OH.  
 
     
     
         20 . The method of    claim 19    wherein X is a covalent bond and Y is a substituted or unsubstituted norbornyl ring system.  
     
     
         21 . The method of    claim 20    wherein the norbornyl ring system is represented by the following structural formula:  
                 

 wherein R 10 -R 12  are independently —H, C1-C3 alkyl or C1-C3 substituted alkyl.  
 
     
     
         22 . The method of    claim 21    wherein R 10 -R 12  are independently —H or —CH 3 .  
     
     
         23 . A substituted or unsubstituted cannabinoid having substituted at C-3 with a heterocyclic ring, a substituted heterocyclic ring, a carbocyclic ring, a substituted carbocyclic ring, a fused bicyclic ring, a substituted fused bicyclic ring, a bridged bicyclic ring, a substituted bridged bicyclic ring, a bridged tricyclic ring or a substituted bridged tricyclic ring, and physiologically acceptable salts thereof.