Cannabimimetic indole derivatives

Abstract

Novel cannabimimetic indole derivatives are presented which have preferentially high affinities for one of the cannabinoid CB1 or CB2 receptors. The improved receptor affinity makes these analogs therapeutically useful as medications in individuals and animals for treatment of pain, glaucoma, epilepsy, nausea associated with chemotherapy.

1 . A method of stimulating a CB1 or CB2 cannabinoid receptor in an individual or animal comprising administering to the individual or animal a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
       
       including any optical isomers and physiologically acceptable salts thereof, wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from the group consisting of hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy and lower alkyl;  
 X is selected from the group consisting of halogen, hydrogen, hydroxy, lower alkanoate, formyl, amino, cyano, and isothiocyano, and if Z is not hydroxy, methoxy or lower alkyl then X may also be selected from the group consisting of OTs and azido;  
 R 1  is selected from the group consisting of saturated or unsaturated straight carbon chains with a maximum length of seven carbon atoms, saturated or unsaturated branched carbon chains with a maximum length of seven carbon atoms; a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, and if Z is not hydroxy, methoxy or lower alkyl then R 1  may also be selected from a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;  
 R 2  is selected from the group consisting of H and lower alkyl;  
 Y is selected from the group consisting of carbonyl and CH═CH (cis or trans); and  
 R 3  is selected from the group consisting of phenyl, naphthyl, 9-anthracenyl, adamantyl, pyrenyl, phenyl with no more than two substituents selected from the group consisting of halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano, naphthyl with no more than two substituents selected from the group consisting of halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano, and 9-anthracenyl with no more than two substituents selected from the group consisting of halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano.  
 
     
     
         2 . The method of  claim 1 , wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from halogen, hydroxy, methoxy, or lower alkyl;    X is selected from halogen, hydrogen, hydroxy, lower alkanoate, formyl, amino, cyano or isothiocyano;    R 1  is selected from cyclic aliphatic rings interconnected to the indole-1 position with one or two carbon atoms or bicyclic aliphatic rings interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans); and    R 3  is selected from phenyl, naphthyl, 9-anthracenyl, phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano, naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano, or 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         3 . The method of  claim 1 , wherein: 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano and phenyl;    X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs and azido;    R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, and a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H and lower alkyl;    Y is selected from carbonyl and CH═CH (cis or trans); and    R 3  is selected from phenyl, naphthyl, 9-anthracenyl, adamantyl, pyrenyl, phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano, naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano.    
     
     
         4 . The method of  claim 1 , wherein: 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano or phenyl;    X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs or azido;    R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms or a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans); and    R 3  is selected from phenyl with two substituents independently selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         5 . The method of  claim 1 , wherein: 
 Z is selected from hydrogen in the 6 position or halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl in the 4-, 5-, 6- or 7-position;    R 1  is a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans);    X is OTs; and    R 3  is selected from phenyl, naphthyl or 9-anthracenyl substituted with a first substituent selected from halogen, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido or isothiocyano and a second substituent selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido and isothiocyano; or    R 3  is selected from phenyl, naphthyl or 9-anthracenyl substituted with one to four substituents groups independently selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido and isothiocyano; or    R 3  is selected from adamantyl or pyrenyl either unsubstituted or substituted with no more than two substituents selected from halogen, nitro, nitroso, amino, hydroxy, azido, cyano and isothiocyano; and    X is OTs.    
     
     
         6 . The method of  claim 1 , wherein: 
 Z is H in the 6 position;    R 2  is hydrogen;    Y is C═O; and    R 3  is phenyl substituted with I and a second substituent selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         7 . The method of  claim 1 , wherein one of the CB1 or CB2 cannabinoid receptors is preferentially stimulated to a greater extent than the other of the CB1 or CB2 cannabinoid receptors.  
     
     
         8 . A pharmaceutical preparation comprising a) at least one member selected from an excipient, a vehicle, an adjuvant, a flavoring, a colorant, or a preservative and b) a therapeutically effective amount of at least one compound of the formula below, including any optical isomers, and physiologically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl;  
 X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano or isothiocyano, and if Z is not hydroxy, methoxy or lower alkyl then X may also be OTs or azido;  
 R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, and if Z is not hydroxy, methoxy or lower alkyl then R 1  may also be a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;  
 R 2  is selected from H or lower alkyl;  
 Y is selected from carbonyl or CH═CH (cis or trans); and  
 R 3  is selected from phenyl; naphthyl; 9-anthracenyl; adamantyl; pyrenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; or 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.  
 
     
     
         9 . The pharmaceutical preparation of  claim 8 , wherein: 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano or phenyl;    X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs or azido;    R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms or a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans); and    R 3  is selected from phenyl with two substituents independently selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         10 . The pharmaceutical preparation of  claim 8 , wherein: 
 Z is selected from hydrogen in the 6 position or halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl in the 4-, 5-, 6- or 7-position;    R 1  is a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans);    X is OTs; and    R 3  is selected from phenyl, naphthyl or 9-anthracenyl substituted with a first substituent selected from halogen, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido or isothiocyano and a second substituent selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido or isothiocyano; or    R 3  is selected from phenyl, naphthyl or 9-anthracenyl substituted with one to four substituents groups independently selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido or isothiocyano; or    R 3  is selected from adamantyl or pyrenyl either unsubstituted or substituted with no more than two substituents selected from halogen, nitro, nitroso, amino, hydroxy, azido, cyano or isothiocyano.    
     
     
         11 . The pharmaceutical preparation of  claim 8 , wherein: 
 Z is H in the 6 position;    R 2  is hydrogen;    Y is C═O; and    R 3  is phenyl substituted with I and a second substituent selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         12 . The pharmaceutical preparation of  claim 8 , wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from halogen, hydroxy, methoxy, or lower alkyl;    X is selected from halogen, hydrogen, hydroxy, lower alkanoate, formyl, cyano or isothiocyano;    R 1  is selected from cyclic aliphatic rings interconnected to the indole-1 position with one or two carbon atoms or bicyclic aliphatic rings interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans); and    R 3  is selected from phenyl, naphthyl, 9-anthracenyl, phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano, naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano, and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         13 . The pharmaceutical preparation of  claim 8 , wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano and phenyl;    X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs and azido;    R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, and a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H and lower alkyl;    Y is selected from carbonyl and CH═CH (cis or trans); and    R 3  is selected from phenyl, naphthyl, 9-anthracenyl, adamantyl, pyrenyl, phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano, naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano.    
     
     
         14 . The pharmaceutical preparation of  claim 8 , wherein the compound is in isolated and substantially purified form.  
     
     
         15 . A method of treating a condition susceptible to stimulation of a cannabinoid receptor in an individual or animal having the condition comprising administering to the individual or animal a pharmaceutical preparation comprising a) at least one member selected from an excipient, a vehicle, an adjuvant, a flavoring, a colorant, or a preservative and b) a therapeutically effective amount of at least one compound of the formula below, including any optical isomers, and physiologically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl;  
 X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano or isothiocyano, and if Z is not hydroxy, methoxy or lower alkyl then X may also be OTs or azido;  
 R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, and if Z is not hydroxy, methoxy or lower alkyl then R 1  may also be a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;  
 R 2  is selected from H or lower alkyl;  
 Y is selected from carbonyl or CH═CH (cis or trans); and  
 R 3  is selected from phenyl; naphthyl; 9-anthracenyl; adamantyl; pyrenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; or 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.  
 
     
     
         16 . The method of  claim 15 , wherein: 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano or phenyl;    X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs or azido;    R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms or a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans); and    R 3  is selected from phenyl with two substituents independently selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         17 . The method of  claim 15 , wherein: 
 Z is selected from hydrogen in the 6 position or halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl in the 4-, 5-, 6- or 7-position;    R 1  is a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans);    X is OTs; and    R 3  is selected from phenyl, naphthyl or 9-anthracenyl substituted with a first substituent selected from halogen, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido or isothiocyano and a second substituent selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido or isothiocyano; or    R 3  is selected from phenyl, naphthyl or 9-anthracenyl substituted with one to four substituents groups independently selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido or isothiocyano; or    R 3  is selected from adamantyl or pyrenyl either unsubstituted or substituted with no more than two substituents selected from halogen, nitro, nitroso, amino, hydroxy, azido, cyano or isothiocyano.    
     
     
         18 . The method of  claim 15 , wherein: 
 Z is H in the 6 position;    R 2  is hydrogen;    Y is C═O; and    R 3  is phenyl substituted with I and a second substituent selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         19 . The method of  claim 15 , wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from halogen, hydroxy, methoxy, or lower alkyl;    X is selected from halogen, hydrogen, hydroxy, lower alkanoate, formyl, cyano or isothiocyano;    R 1  is selected from cyclic aliphatic rings interconnected to the indole-1 position with one or two carbon atoms or bicyclic aliphatic rings interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H or lower alkyl;    Y is selected from carbonyl or CH═CH (cis or trans); and    R 3  is selected from phenyl, naphthyl, 9-anthracenyl, phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano, naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano, and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.    
     
     
         20 . The method of  claim 15 , wherein, 
 Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano and phenyl;    X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs and azido;    R 1  is selected from a cyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, a bicyclic aliphatic ring interconnected to the indole-1 position with one or two carbon atoms, and a heterocyclic ring interconnected to the indole-1 position with one or two carbon atoms;    R 2  is selected from H and lower alkyl;    Y is selected from carbonyl and CH═CH (cis or trans); and    R 3  is selected from phenyl, naphthyl, 9-anthracenyl, adamantyl, pyrenyl, phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano, naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano.    
     
     
         21 . The method of  claim 15 , wherein the compound is in isolated and substantially purified form.  
     
     
         22 . The method of  claim 15 , wherein the condition is selected from pain, peripheral pain, glaucoma, epilepsy, nausea, AIDS Wasting Syndrome, cancer, neurodegenerative diseases, Multiple Sclerosis, Parkinson's Disease, Huntington's Chorea, Alzheimer's Disease, mental disorder, schizophrenia, depression; endotoxic shock, hypotensive shock; appetite modulation, fertility reduction, Tourette's syndrome, and inflammation.  
     
     
         23 . The method of  claim 15 , wherein the condition is selected from pain, peripheral pain and inflammation.