Ultrapure tetrahydrocannabinol-11-oic acids

Abstract

This application is in the field of medicinal chemistry and relates to ultrapure ajulemic acid, its synthesis, pharmaceutical compositions and methods of use thereof for the treatment and/or prevention of inflammation, pain, and fibrotic diseases including scleroderma, systemic sclerosis, scleroderma-like disorders, sine scleroderma, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren's contracture, keloids, chronic kidney disease, chronic graft rejection, and other scarring-wound healing abnormalities, post-operative adhesions, and reactive fibrosis.

1 . A pharmaceutical composition comprising an enterically coated tablet containing (i) (6aR,10aR)-3-(1′,1′-dimethylheptyl)-Δ8-tetrahydro-cannabinol-9-carboxylic acid, or a pharmaceutically acceptable salt thereof, (ii) an opiate, and (iii) a pharmaceutically acceptable excipient. 
     
     
         2 . A method of treating post-operative adhesions in a subject in need thereof, said method comprising topically administering to the subject a solution comprising (i) (6aR,10aR)-3-(1′,1′-dimethylheptyl)-Δ8-tetrahydro-cannabinol-9-carboxylic acid, or a pharmaceutically acceptable salt thereof, (ii) an anti-inflammatory agent, and (iii) a carrier comprising mineral oil. 
     
     
         3 . A method of treating a human subject having a fibrotic disease, the method comprising administering once daily, twice daily, or three times daily to the subject an effective amount of a pharmaceutical composition comprising a preparation of ajulemic acid and a pharmaceutically acceptable excipient, wherein the preparation of ajulemic acid comprises at least 98% (w/w) ajulemic acid or a pharmaceutically acceptable salt thereof, wherein the preparation of ajulemic acid has a Ki for the CB1 receptor (Ki CB1) ranging from 10 times to 40 times greater than its Ki for the CB2 receptor (Ki CB2), and wherein the Ki CB1 and the Ki CB2 are each determined according to a competitive radioligand binding assay with [ 3 H]-CP55940 as the radioligand. 
     
     
         4 . The method of  claim 3 , wherein the fibrotic disease is selected from the group consisting of scleroderma, systemic sclerosis, sine scleroderma, a scleroderma-like disorder, liver cirrhosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, Dupuytren's contracture, keloids, cystic fibrosis, chronic kidney disease, chronic graft rejection, scarring or would healing abnormalities, post-operative adhesions, reactive fibrosis, dermal fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, and heart fibrosis. 
     
     
         5 . The method of  claim 4 , wherein the fibrotic disease is selected from the group consisting of dermal fibrosis, scleroderma, cystic fibrosis, and idiopathic pulmonary fibrosis. 
     
     
         6 . The method of  claim 3 , wherein the preparation of ajulemic acid has Ki CB1 ranging from 10 times to 20 times greater than its Ki CB2. 
     
     
         7 . The method of  claim 3 , wherein the preparation of ajulemic acid comprises at least 99% (w/w) ajulemic acid. 
     
     
         8 . The method of  claim 3 , wherein the preparation of ajulemic acid comprises less than 0.5% (w/w) of 11-hydroxy-(6aR,10aR)-3-(1′,1′-dimethylheptyl)-Δ8-tetrahydrocannabinol (HU-210). 
     
     
         9 . The method of  claim 8 , wherein the preparation of ajulemic acid comprises less than 0.1% (w/w) of 11-hydroxy-(6aR,10aR)-3-(1′,1′-dimethylheptyl)-Δ8-tetrahydrocannabinol (HU-210). 
     
     
         10 . The method of  claim 3 , wherein the pharmaceutical composition is administered orally, intravenously, topically, interstitially, by inhalation, via an implant, via a patch, or by ophthalmic administration. 
     
     
         11 . The method of  claim 3 , wherein the pharmaceutical composition is in the form of a capsule. 
     
     
         12 . The method of  claim 11 , wherein the tablet or the capsule comprises from 5 mg to 180 mg of the preparation of ajulemic acid or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method of treating a human subject having an inflammatory disease, the method comprising administering once daily, twice daily, or three times daily to the subject an effective amount of a pharmaceutical composition comprising a preparation of ajulemic acid and a pharmaceutically acceptable excipient, wherein the preparation of ajulemic acid comprises at least 98% (w/w) ajulemic acid or a pharmaceutically acceptable salt thereof, wherein the preparation of ajulemic acid has a Ki for the CB1 receptor (Ki CB1) ranging from 10 times to 40 times greater than its Ki for the CB2 receptor (Ki CB2), and wherein the Ki CB1 and the Ki CB2 are each determined according to a competitive radioligand binding assay with [ 3 H]-CP55940 as the radioligand. 
     
     
         14 . The method of  claim 13 , wherein the inflammatory disease is selected from the group consisting of systemic lupus erythematosus, AIDs, multiple sclerosis, rheumatoid arthritis, psoriasis, diabetes, cancer, asthma, atopic, dermatitis, an autoimmune thyroid disorder, ulcerative colitis, Crohn's disease, stroke, ischemia, and a neurodegenerative disease. 
     
     
         15 . The method of  claim 14 , wherein the inflammatory disease is systemic lupus erythematosus. 
     
     
         16 . The method of  claim 13 , wherein the preparation of ajulemic acid has Ki CB1 ranging from 10 times to 20 times greater than its Ki CB2. 
     
     
         17 . The method of  claim 13 , wherein the preparation of ajulemic acid comprises at least 99% (w/w) ajulemic acid. 
     
     
         18 . The method of  claim 13 , wherein the preparation of ajulemic acid comprises less than 0.5% (w/w) of 11-hydroxy-(6aR,10aR)-3-(1′,1′-dimethylheptyl)-Δ8-tetrahydrocannabinol (HU-210). 
     
     
         19 . The method of  claim 18 , wherein the preparation of ajulemic acid comprises less than 0.1% (w/w) of 11-hydroxy-(6aR,10aR)-3-(1′,1′-dimethylheptyl)-Δ8-tetrahydrocannabinol (HU-210). 
     
     
         20 . The method of  claim 13 , wherein the pharmaceutical composition is administered orally, intravenously, topically, interstitially, by inhalation, via an implant, via a patch, or by ophthalmic administration. 
     
     
         21 . The method of  claim 13 , wherein the pharmaceutical composition is in the form of a capsule. 
     
     
         22 . The method of  claim 21 , wherein the tablet or the capsule comprises from 5 mg to 180 mg of the preparation of ajulemic acid or a pharmaceutically acceptable salt thereof.