Interleukin-1 and tumor necrosis factor-alpha modulators; syntheses of such modulators and methods of using such modulators

Abstract

Described herein are chemical compounds and pharmaceutical compositions, including novel chemical compounds and pharmaceutical compositions thereof, useful in the treatment of various diseases and disease states. Also described are methods of synthesizing natural products and novel, structurally-related chemical compounds. More particularly, disclosed are new analogs of and processes for the preparation of compounds and pharmaceutical compositions thereof useful in the treatment of, for example, inflammation, cancer, multiple myeloma, cachexia, cardiovascular disease, anti-infectious, diabetes, otitis media, sinusitis and transplant rejection.

1 . A method of treating a disease condition in an animal selected from the group consisting of inflammation, tuberculous pleurisy, rheumatoid pleurisy, fatigue associated with cancer or its treatment, cardiovascular disease, skin redness, diabetes, transplant rejection, otitis media (inner ear infection), sinusitis, viral infection, septic shock, transplantation, graft-vs-host disease, ischemia/reperfusion injury, Graves' ophthalmopathy, Hashimoto's thyroiditis, thryoid-associated ophthalmopathy, 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 having the following chemical structure to living tissue of said animal   
       
         
           
           
               
               
           
         
         
           wherein: 
           R 2  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 17  is selected from C 5 -C 12  cyclic alkyls; C 5 -C 12  cyclic alkenyls; C 5 -C 12  substituted cyclic alkyls; C 5 -C 12  substituted cyclic alkenyls; phenyl and C 5 -C 12  aryls; 
           R 9  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, 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; 
           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; and 
           R 16  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; 
           wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof. 
         
       
     
     
         2 . The method of  claim 1 , wherein R 16  is hydrogen. 
     
     
         3 . The method of  claim 1 , wherein R 17  is cyclohexane; R 16  is hydrogen; and R 3 -R 5 , R 7 , R 8 , R 11 -R 15  is each hydrogen. 
     
     
         4 . The method of  claim 1 , wherein R 16  and R 17  form a 3 to 12 membered ring. 
     
     
         5 . The method of  claim 1  wherein the compound is 
       
         
           
           
               
               
           
         
         and prodrug esters and acid-addition salts thereof. 
       
     
     
         6 . The method of  claim 1 , wherein the disease condition is an inflammatory condition. 
     
     
         7 . The method of  claim 6  wherein the inflammatory condition is selected from the group consisting of:
 tuberculous pleurisy, rheumatoid pleurisy, 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' ophthalmopathy, Hashimoto's thyroiditis, thryoid-associated ophthalmopathy, 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. 
 
     
     
         8 . The method of  claim 6  wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         and prodrug esters and the acid-addition salts thereof. 
       
     
     
         9 . A compound having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  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 9  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, 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; 
         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; and 
         R 16  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 2 )(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 17  is selected from C 5 -C 12  cyclic alkyls; C 5 -C 12  cyclic alkenyls; C 5 -C 12  substituted cyclic alkyls; C 5 -C 12  substituted cyclic alkenyls; phenyl and C 5 -C 12  aryls; 
         wherein the compound includes the prodrug esters of the above compounds, and the acid-addition salts thereof. 
       
     
     
         10 . The compound of  claim 9  wherein R 16  is hydrogen. 
     
     
         11 . The compound of  claim 9  wherein R 17  is cyclohexane; R 16  is hydrogen; and
 R 3 -R 5 , R 7 , R 8 , R 11 -R 15  is each hydrogen. 
 
     
     
         12 . The compound of  claim 9 , wherein R 16  and R 17  form a 3 to 12 membered ring 
     
     
         13 . The compound of  claim 9 , wherein the compound is 
       
         
           
           
               
               
           
         
         and prodrug esters and acid-addition salts thereof. 
       
     
     
         14 . A method of treating a disease condition of an animal 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' ophthalmopathy, Hashimoto's thyroiditis, thryoid-associated ophthalmopathy, 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 of  claim 10  to living tissue of said animal.   
     
     
         15 . The method of  claim 14  wherein the compound is 
       
         
           
           
               
               
           
         
         and prodrug esters and acid-addition salts thereof. 
       
     
     
         16 . The method of  claim 14  wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         and prodrug esters and the acid-addition salts thereof. 
       
     
     
         17 . A compound of having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein the compound includes the prodrug esters of the above compound, and the acid-addition salts thereof. 
       
     
     
         18 . A method of treating an inflammatory disease or a neoplatic disease in an animal comprising: 
       contacting a compound to living tissue of said animal, wherein the compound has the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 18 , wherein the inflammatory disease is selected from the group consisting of:
 tuberculous pleurisy, rheumatoid pleurisy, 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' ophthalmopathy, Hashimoto's thyroiditis, thryoid-associated ophthalmopathy, 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.   
     
     
         20 . The method of  claim 18 , wherein the neoplastic disease is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer.