Novel cannabinoid receptor 2 (cb2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases

Abstract

Cannabinoid receptor-2 inverse antagonists include compounds represented by Formula IV, or a pharmaceutically acceptable salt thereof: wherein: R 1 and R 2 are independently H, alkyl, or alkenyl; R 3 is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; R 4 and R 5 are independently a bond, alkylenyl, or alkenylenyl; each R 6 and R 7 is independently selected from the group consisting of OH, F, Cl, Br, I, (C 1 -C 6 )alkyl, alkoxy, amino, COOH, CONH 2 , SO 3 H, PO 3 H 2 , CN, SH, NO 2 and CF 3 ; and p and q are independently 0, 1, 2, 3, 4, or 5. Such compounds may be used to treat osteoporosis or multiple myeloma.

1 . A compound according to Formula I 
       
         
           
           
               
               
           
         
         wherein: 
         D and D′ are independently —H, —OH, —OR a , (C 1 -C 6 )alkyl or 
       
       
         
           
           
               
               
           
         
         R a  is H, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, or (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
         A, B and Q are each independently (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene or (C 2 -C 6 )alkynylene; 
         e, f and g independently are integers between 0 and 6 inclusive; and 
         V, W, X, Y, and Z are each independently a bond, —C(R′″) 2 —, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, or —S—; 
         wherein: 
         no two adjacent members of V, W, X, Y, and Z are simultaneously —O—, —S—, or —NR′″—; 
         R′″ is H, —OH, —OR a , halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —CN, (C 3 -C 8 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 8 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 8 )aryl(C 1 -C 6 )alkenylene-, or (C 1 -C 6 )alkyl-(C 3 -C 8 )arylene; 
         l, m, n, p and q independently are integers between 0 and 2 inclusive, wherein at least one of l, m, n, or p is not 0; 
            represents the option of having one or more double bonds; 
         wherein any alkyl, alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, or (C 3 -C 8 )aryloxy; and 
         wherein R d  and R e  are each independently H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )aryl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, and H 2 N(C 1 -C 6 )alkylene-, 
         or a pharmaceutically acceptable salt thereof; 
         with the proviso that when each 
       
       
         
           
           
               
               
           
         
       
       is independently a phenyl, B f  and Q g  are both methylene and e is 0, D is not 4-dimethylaminophenyl. 
     
     
         2 . The compound according to  claim 1 , wherein when D is 
       
         
           
           
               
               
           
         
         each of V, W, X, Y and Z is C(R′″) and   represents alternating double bonds. 
       
     
     
         3 . The compound according to  claim 2 , wherein R′″ is (C 3 -C 8 )heterocycloalkyl. 
     
     
         4 . The compound according to  claim 3 , wherein R′″ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, 1,3-dioxanyl, oxazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl-1-oxide, tetrahydrothiopyranyl-1,1-dioxide, pyrrolidinonyl, piperidinonyl, azepinonyl, piperazidinonyl, oxazidilinonyl, azetidinonyl, or morpholinonyl. 
     
     
         5 . The compound according to  claim 1 , selected from the following table: 
       
         
           
                 
               
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . (canceled) 
     
     
         7 . A compound according to Formula I′ 
       
         
           
           
               
               
           
         
         wherein: 
         D and D′ are independently —H, —OH, —OR a , (C 1 -C 6 )alkyl or 
       
       
         
           
           
               
               
           
         
         R a′ , R a″ , and R a′″  are independently selected from the group consisting of H, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 5 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, or (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
         A, B and Q are each independently (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene or (C 2 -C 6 )alkynylene; 
         e, f and g independently are integers between 0 and 6 inclusive; 
         V, W, X, Y, and Z are each independently a bond, —C(R′″) 2 —, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, or —S—; 
         wherein: 
         no two adjacent members of V, W, X, Y, and Z are simultaneously —O—, —S—, or —NR′″—; 
         R′″ is H, —OH, —OR a , halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —CN, (C 3 -C 8 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 8 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 8 )aryl(C 1 -C 6 )alkenylene-, or (C 1 -C 6 )alkyl-(C 3 -C 8 )arylene; 
         l, m, n, p and q independently are integers between 0 and 2 inclusive, wherein at least one of l, m, n, or p is not 0; and 
            represents the option of having one or more double bonds; 
         wherein any alkyl, alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, or (C 3 -C 8 )aryloxy; and 
         wherein R d  and R e  are each independently H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )aryl, optionally substituted (C 3 -C 4 )aryl(C 1 -C 6 )alkylene-, and H 2 N(C 1 -C 6 )alkylene-, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound according to  claim 7 , wherein:
 D is H;   D′ is phenyl;   B and Q are independently (C 1 -C 6 )alkylene;   e is 0 and each of f and g is 1; and   each of R a′ , R a′″ , and R a′″  is independently selected from the group consisting of H, straight chain (C 1 -C 6 )alkyl, and branched chain (C 1 -C 6 )alkyl.   
     
     
         9 . The compound according to  claim 7  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to Formula II 
       
         
           
           
               
               
           
         
         wherein: 
         A, B′ and E are each independently a bond, —C(R′″) 2 —, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, or —S—; wherein no two adjacent members of A, B′ and E are simultaneously —O—, —S—, or —NR′″—; 
         h, j and k independently are integers between 0 and 2 inclusive, wherein at least one of h, j or k is not 0; 
            represents the option of having one or more double bonds; 
         D and D″ are each independently —C(O), —CH 2 C(O)—, (C 1 -C 6 )alkylene, —C(O)NH—, or —NHC(O)—; 
            represents the option of having a C 5 -C 6  fused ring optionally having one or more double bonds; 
         R and R 1  are each independently OH, —OR a , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 8 )heteroaryl-(C 1 -C 6 )alkylene-, or (C 3 -C 8 )aryl(C 1 -C 6 )alkylene-; and 
         R a  is H, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, or (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
         wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more of halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , (C 1 -C 6 )alkoxy, or (C 3 -C 8 )aryloxy; and 
         wherein R d  and R e  are each independently H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, and H 2 N(C 1 -C 6 )alkylene-, 
         or a pharmaceutically acceptable salt thereof; 
         or a compound according to Formula IV or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently H, alkyl, or alkenyl; 
         R 3  is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; 
         R 4  and R 5  are independently a bond, alkylenyl, or alkenylenyl; 
         each R 6  and R 7  are independently OH, F, Cl, Br, I, (C 1 -C 6 )alkyl, alkoxy, amino, COOH, CONH 2 , SO 3 H, PO 3 H 2 , CN, SH, NO 2  or CF 3 ; and 
         p and q are independently 0, 1, 2, 3, 4, or 5; 
         with the proviso that where R 1  and R 2  are both H, R 4  and R 5  are both methylene, p and q are 0, R 3  is not 4-dimethylaminophenyl. 
       
     
     
         11 . The compound according to  claim 10 , wherein the compound is a compound of Formula II and   is phenyl and subscripts h, j and k are each 1. 
     
     
         12 . The compound according to  claim 10 , wherein the compound is a compound of Formula II and subscripts h and k independently are 0 and subscript j is 1. 
     
     
         13 . The compound according to  claim 10 , that is 
       
         
           
           
               
               
           
         
       
     
     
         14 - 22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         24 - 28 . (canceled) 
     
     
         29 . A method for modulating the activity of a cannabinoid receptor-2 (CB2) in a subject, comprising contacting the CB-2 receptor with a compound of  claim 1 ,
 or a pharmaceutically acceptable salt thereof.   
     
     
         30 - 37 . (canceled) 
     
     
         38 . The compound according to  claim 10 , selected from the following table: 
       
         
           
                 
               
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         39 . (canceled) 
     
     
         40 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV according to  claim 10  and a pharmaceutically acceptable carrier. 
     
     
         41 . A method for treating multiple myeloma or osteoporosis in a subject by modulating the activity of a cannabinoid receptor-2 (CB2), comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula IV according to  claim 10 . 
     
     
         42 - 47 . (canceled)