Peripherally-acting cannabinoid receptor agonists for chronic pain

Abstract

Peripherally acting cannabinoid agonist compounds, pharmaceutical compositions, and methods of using them are presented.

1 . A compound having the structure 
       
         
           
           
               
               
           
         
         wherein 
         Ar 1  is optionally substituted biphenyl, optionally substituted bicyclic aromatic or heteroaromatic other than 1-naphthyl, optionally substituted tricyclic aromatic or heteroaromatic, or optionally substituted tetracyclic aromatic or heteroaromatic; wherein the optional substituents are halo, alkyl, or alkoxy, provided that if Ar 1  is naphthyl, then the optional substituents are alkyl; 
         m 1  is 1, 2, 3, or 4; 
         R 1  is morpholin-4-yl; and 
         G 1  is one, two, three, or four substituents, each independently selected from hydrogen, halogen, fluorine, hydroxyl, alkoxy, and methylenedioxy; and 
         each R 8  independently is H or alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein m 1  is 1 or 2. 
     
     
         3 . The compound of  claim 1 , wherein G 1  is one fluorine substituent. 
     
     
         4 . The compound of  claim 1 , wherein Ar 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein R 6  is H, alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide; 
         Y is O, S, S(O), S(O) 2 , NR 10 , or CH 2 ; and 
         R 10  is H or alkyl. 
       
     
     
         5 . The compound of  claim 1 , wherein Ar 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         where R 6  is alkyl, or alkoxy. 
       
     
     
         6 . The compound of  claim 1 , wherein R 8  is hydrogen. 
     
     
         7 . The compound of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A compound having the structure 
       
         
           
           
               
               
           
         
         wherein 
         Ar 2  is optionally substituted biphenyl, optionally substituted bicyclic aromatic or heteroaromatic, optionally substituted tricyclic aromatic or heteroaromatic, or optionally substituted tetracyclic aromatic or heteroaromatic; wherein the optional substituents are halo, alkyl, —O-alkyl, —CO-alkyl, —COOR 4 , or —CON(R 4 ) 2 , provided that if R 8  is methyl, then Ar 2  is not 4-halonaphth-1-yl; 
         m 2  is 2, 3, 4, 5, or 6; 
         R 2  is —CH 3 , —CO 2 R 3 , —CON(R 4 ) 2 , F, Cl, I, hydroxyl, nitro, amino, monoalkylamino, or morpholin-4-yl; 
         R 3  is H or alkyl; 
         R 4  is, independently, hydrogen or alkyl; 
         G 2  is one, two, three, or four substituents, each independently selected from hydrogen, halogen, fluorine, hydroxyl, alkoxy, and methylenedioxy; and 
         R 9  is H or alkyl. 
       
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         10 . A method for treating a disease or disorder in a subject comprising administering to a subject a compound according to  claim 1 , wherein the disease or disorder may be treated by activating or blocking a peripheral cannabinoid receptor. 
     
     
         11 . The method of  claim 10 , wherein the compound has less than 10% permeability across the blood brain barrier, as measured using the Madin-Darby canine kidney cell line assay. 
     
     
         12 . The method of  claim 10 , wherein the disorder is pain. 
     
     
         13 . The method of  claim 12 , wherein the pain is chronic, inflammatory, or neuropathic. 
     
     
         14 . The method of  claim 10 , wherein said disease or disorder is hyperalgesia or allodynia. 
     
     
         15 . The method of  claim 15 , wherein said disease or disorder is rheumatoid arthritis, inflammatory bowel disorders, soft tissue pain, bone cancer pain, chemotherapy-induced neuropathy, pain caused by thermal injury, pain caused by nerve injury, migraine headache, and pain caused by cancer. 
     
     
         16 . The method of  claim 10 , wherein said disease or disorder is intraocular pressure. 
     
     
         17 . The method of  claim 10 , wherein said treatment is anti-emetic, or anti-nausea treatment. 
     
     
         18 . The method of  claim 10 , wherein said disease or disorder is a tumor. 
     
     
         19 . The method of  claim 10 , wherein said disease or disorder is a bone disease associated with accelerated bone resorption. 
     
     
         20 . The method of  claim 19 , wherein the bone disorder is osteoporosis, rheumatoid arthritis, or bone metastasis.