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, —CH 2 — 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.

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 2 — or —CHR 1 —, wherein R 1  is 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;    with the provisos that:    a) if the tricyclic core has an A ring with a double bond in a tricyclic core 8.9 position, a (CH 3 ) 2  group in a tricyclic core 6 position, and if X is a covalent bond in a tricyclic core 3 position, then Y cannot be:                          wherein R 6  is H, a C4 to about C6 alkyl group or a dialkyl group; and    b) if the tricyclic core has an A ring with three endocyclic double bonds, a ring O in a tricyclic core 5 position, a ═O group in a tricyclic core 6 position and if X is a covalent bond in a tricyclic core 3 position, then Y cannot be the following structural formulas:                          where Z′ and Z″ are each independently selected from C, O, S and NH and n is an integer from 3-5; or                          where Q is H, (CH 2 ) n CH 3 , and n is a maximum of 7.    
   
   
       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 , —H 2 CH 3 , —CH 2 C(halogan) 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 one of the following structural formulas:  
     
       
         
         
             
             
         
       
     
   
   
       4 . (canceled)  
   
   
       5 . The compound of  claim 2  wherein Y 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.  
 
   
   
       6 . The compound of  claim 2  wherein Y is represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Z′ and Z″ are each independently selected from —S—, —O—, or —N(R 7 )—; 
 R 7  is —H or —CH 3 ;  
 
 R 6  is selected from a substituted or unsubstituted C1 to about C12 straight chained alkyl group, a substituted or unsubstituted C1 to C8 branched alkyl group, —H, —OH, —OCH 3 , —OCH 2 CH 3 , halogen, —CN, N3, —NCO, —NCS, —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 C(halogen) 3 , —CH 2 NH 2 , —CH 2 NHCH 3  or —CH 2 N(CH 3 ) 2 .  
 
   
   
       7 . (canceled)  
   
   
       8 . The compound of  claim 2  wherein Y is represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     wherein R 8  is H or CH 3 ; and 
 R 9  is H or a substituted or unsubstituted C1-C4 alkyl group.  
 
   
   
       9 .- 11 . (canceled)  
   
   
       12 . The compound of  claim 2  Y is represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     wherein R 10 , R 11  and R 12  are each independently selected from H, a C1 to C3 alkyl group or a C1 to C3 substituted alkyl group.  
   
   
       13 . (canceled)  
   
   
       14 . The compound of  claim 2  wherein Y is a substituted or unsubstituted adamantyl ring system which contains zero, one or two heteroatoms.  
   
   
       15 .- 16 . (canceled)  
   
   
       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  is 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 systems;    with the provisos that:    a) if the tricyclic core has an A ring with a double bond in a tricyclic core 8,9 position, a (CH 3 ) 2  group in a tricyclic core 6 position, and if X is a covalent bond in a tricyclic core 3 position, then Y cannot be:                          wherein R 6  is H, a C4 to about C6 alkyl group, and    b) if the tricyclic core has an A ring with three endocyclic double bonds, a ring O in a tricyclic core 5 position, a ═O group in a tricyclic core 6 position and if X is a covalent bond in a tricyclic core 3 position, then Y cannot be the following structural formulas:                          where Z′ and Z″ are each independently selected from C, O, S and NH and n is an integer from 3-5; or                          where Q is H, (CH 2 ) n CH 3 , and n is a maximum of 7.    
   
   
       18 . The method of  claim 17  wherein the compound 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 18  wherein R is represented by one of the following structural formulas:  
     
       
         
         
             
             
         
       
     
   
   
       20 .- 23 . (canceled)  
   
   
       24 . The compound of  claim 1  wherein Y is a heterocyclic ring having 5 to 7 ring atoms, a substituted heterocyclic ring having 5 to 7 ring atoms, a 5 ring atom non-dithiolane heterocyclic ring, a substituted 5 ring atom non-dithiolane heterocyclic 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.  
   
   
       25 . the compound of  claim 1  wherein R is represented by one of the following structural formulas:  
     
       
         
         
             
             
         
       
     
   
   
       26 . The compound of  claim 2  wherein Y is represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 13 , R 14 , R 15  and R 16  are each independently selected from H, a C1 to C3 alkyl group or a C1 to C 3  substituted alkyl group;  
 X 1 , X 2  and X 3  are each independently selected from >N—, >CH— or >S; and  
 Y 1 , Y 2 , Y 3  and Y 4  are each independently selected from >CH 2 , >NH or >O.  
 
   
   
       27 . The compound of  claim 2  wherein Y is represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 13 , R 14 , R 15  and R 16  are each independently selected from H, a C1 to C3 alkyl group or a C1 to C3 substituted alkyl group;  
 X 1  and X 2  are each independently selected from >N— or >CH—;  
 X3 is >CH—; and  
 Y 1 , Y 2 , Y 3  and Y 4  are each >CH 2 .  
 
   
   
       28 . The compound of  claim 2  represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     and physiologically acceptable salts thereof, wherein: 
 Y is represented by a structural formula selected from:  
                     
 wherein:  
 Z′ and Z″ are each independently selected from —S—, —O—, or —N(R 7 )—; 
 R 7  is —H or —CH 3 ; and  
 
 R 6  is selected from a substituted or unsubstituted C1 to about C12 strait chained alkyl group, a substituted or unsubstituted C1 to C8 branched alkyl group, —H, —OH, —OCH 3 , —OCH 2 CH 3 , halogen, —CN, N3, —NCO, —NCS, —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 C(halogen) 3 , —CH 2 NH 2 , —CH 2 NHCH 3  or —CH 2 N(CH 3 ) 2 .  
 
   
   
       29 . The method of  claim 18  wherein Y is represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Z′ and Z″ are each independently selected from —S—, —O—, or —N(R 7 )—; 
 R 7  is —H or —CH 3 ; and  
 
 R 6  is selected from a substituted or unsubstituted C1 to about C12 straight chained alkyl group, a substituted or unsubstituted C1 to C8 branched alkyl group, —H, —OH, —OCH 3 , —OCH 2 CH 3 , halogen, —CN, N3, —NCO, —NCS, —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 C(halogen) 3 , —CH 2 NH 2 , —CH 2 NHCH 3  or —CH 2 N(CH 3 ) 2 .  
 
   
   
       30 . The method of  claim 18  wherein Y is represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
     
     wherein R 10 , R 11  and R 12  are each independently selected from H, a C1 to C3 alkyl group or a C1 to C3 substituted alkyl group.  
   
   
       31 . The method of  claim 18  wherein Y is represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 13 , R 14 , R 15  and R 16  are each independently selected from H, a C1 to C3 alkyl group or a C1 to C3 substituted alkyl group;  
 X 1 , X 2  and X 3  are each independently selected from >N—, >CH— or >S; and  
 Y 1 , Y 2 , Y 3  and Y 4  are each independently selected from >CH 2 , >NH or >O.  
 
   
   
       32 . The method of  claim 18  wherein the compound is represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     and physiologically acceptable salts thereof; 
 Y is represented by a structural formula selected from:  
                     
 wherein:  
 Z′ and Z″ are each independently selected from —S—, —O—, or —N(R 7 )—; 
 R 7  is —H or —CH 3 ; and  
 
 R 6  is selected from a substituted or unsubstituted C1 to about C12 strait chained alkyl group, a substituted or unsubstituted C1 to C8 branched alkyl group, —H, —OH, —OCH 3 , —OCH 2 CH 3 , halogen, —CN, N3, —NCO, —NCS, —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 C(halogen) 3 , —CH 2 NH 2 , —CH 2 NHCH 3  or —CH 2 N(CH 3 ) 2 .