Novel Interleukin-1 and Tumor Necrosis Factor-Alpha Modulators, Syntheses of Said Modulators and Their Enantiomers and Methods of Using Said Modulators

Abstract

Disclosed herein are novel tricyclic diterpene compounds. These compounds, including their prodrug esters and acid-addition salts, are useful as Interleukin-1 and Tumor Necrosis Factor-alpha modulators, and thus useful in the treatment of various diseases. Pharmaceutical compositions comprising, and uses of, theapeautically effective amounts of the above compounds and their prodrug esters, and pharmaceutically acceptable carrier, are also disclosed, and are useful as, for example, anti-inflamatory analgestics, treatments for immune disorders, anti-cancer and anti-tumor agents, and in the treatment of cardiovascular disease, skin redness, and viral infection, for example. Completley synthetic and semi-synthetic methods of making these compounds and their analogs are disclosed.

1 . A method of treating a disease condition selected from the group consisting of inflammation, tuberculous pleurisy, rheumatoid pleurisy, cancer, the reduction of fatigue associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis and viral infection, septic shock, transplantation, graft-vs-host disease, ischemia/reperfusion injury, Graves' opthalmopathy, Hashimoto's thyroiditis, thryoid-associated opthalmopathy, nodular goiter, herpetic stromal keratitis, microbial keratitis, peripheral ulcerative keratitis, Behcet's disease, uveitis, vitreoretinal proliferative disease, rabies virus ocular disease, Vogt-Koyanagi-Harada's disease, retinopathy, retinal laser photocoagulation, acute retinal necrosis syndrome, systemic vasculitis, recurrent aphthous stomatitis, neovascular glaucoma, eye infections, ocular allergic diseases, retinal detachment, optic neuritis, multiple sclerosis, systemic sclerosis, hereditary retinal degeneration, trachoma, autoimmune diseases, and chemotherapy related mucosal injury comprising:
 contacting a compound to living tissue of said animal, wherein the compound has the following chemical structure:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of hydrogen, a halogen, COOH, C 1 -C 12  carboxylic acids, C 1 -C 12  acyl halides, C 1 -C 12  acyl residues, C 1 -C 12  esters, C 1 -C 12  secondary amides, (C 1 -C 12 )(C 1 -C 12 ) tertiary amides, C 1 -C 12  cyclic amides, C 1 -C 12  amines, C 1 -C 12  alcohols, (C 1 -C 12 )(C 1 -C 12 ) ethers, C 1 -C 12  alkyls, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyls, C 2 -C 12  substituted alkenyls, and C 5 -C 12  aryls; 
         R 2  and R 9  are each separately selected from hydrogen, a halogen, C 1 -C 12  alkyl, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyl, C 2 -C 12  substituted alkenyl, C 2 -C 12  alkynyl, C 1 -C 12  alcohol, C 1 -C 12  acyl, and C 5 -C 12  aryl; 
         R 3 -R 5 , R 7 , R 8 , and R 11 -R 13  are each separately selected from hydrogen, a halogen, C 1 -C 12  alkyl, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyl, C 2 -C 12  substituted alkenyl, C 2 -C 12  alkynyl, and C 5 -C 12  aryl; 
         R 6  is selected from hydrogen, a halogen, C 1 -C 12  alkyl, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyl, C 2 -C 12  substituted alkenyl, and C 2 -C 12  alkynyl; 
         R 10  is selected from hydrogen, a halogen, CH 2 , C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 1 -C 12  alcohol, and C 5 -C 12  aryl; and 
         R 14  and R 15  are separately selected from hydrogen, a halogen, CH 2 , C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 1 -C 6  alcohol, and C 5 -C 6  aryl;
 wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof. 
 
       
     
     
         2 . The method of  claim 1 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of hydrogen, a halogen, COOH, C 1 -C 12  carboxylic acids, C 1 -C 12  acyl halides, C 1 -C 12  acyl residues, C 1 -C 12  esters, C 1 -C 12  secondary amides, (C 1 -C 12 )(C 1 -C 12 ) tertiary amides, C 1 -C 12  cyclic amides, C 1 -C 12  amines, C 1 -C 12  alcohols, (C 1 -C 12 )(C 1 -C 12 ) ethers, C 1 -C 12  alkyls, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyls, C 2 -C 12  substituted alkenyls, and C 5 -C 12  aryls; 
         R 2  and R 9  are each separately selected from hydrogen, a halogen, C 1 -C 12  alkyl, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyl, C 2 -C 12  substituted alkenyl, C 2 -C 12  alkynyl, C 1 -C 12  alcohol, C 1 -C 12  acyl, and C 5 -C 12  aryl; 
         R 3 -R 5 , R 7 , R 8 , and R 11 -R 13  are each separately selected from hydrogen, a halogen, C 1 -C 12  alkyl, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyl, C 2 -C 12  substituted alkenyl, C 2 -C 12  alkynyl, and C 5 -C 12  aryl; 
         R 6  is selected from hydrogen, a halogen, C 1 -C 12  alkyl, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyl, C 2 -C 12  substituted alkenyl, and C 2 -C 12  alkynyl; 
         R 10  is selected from hydrogen, a halogen, CH 2 , C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 1 -C 12  alcohol, and C 5 -C 12  aryl; and 
         R 14  and R 15  are separately selected from hydrogen, a halogen, CH 2 , C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 1 -C 6  alcohol, and C 5 -C 6  aryl; wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof, and wherein, 
         R 14  and R 15  are not simultaneously methyl. 
       
     
     
         3 . The method of  claim 1  wherein R 1  is selected from hydrogen, a halogen, and C 1 -C 12  carboxylic acids, C 1 -C 12  acyl halides, C 1 -C 12  acyl residues, C 2 -C 12  esters, C 2 -C 12  secondary amides, (C 1 -C 12 )(C 1 -C 12 ) tertiary amides, C 2 -C 12  alcohols, (C 1 -C 12 )(C 1 -C 12 ) ethers, C 2 -C 12  alkyls, C 1 -C 12  substituted alkyls, C 2 -C 12  alkenyls, C 2 -C 12  substituted alkenyls, and C 5 -C 12  aryls.