Methods of treating disease states using antiangiogenic agents

Abstract

Compositions and methods for treating mammalian disease characterized by undesirable angiogenesis by administering compounds of the general formula: wherein the variables are defined in the specification.

1 . (canceled)  
   
   
       2 . A method of inhibiting angiogenesis in a human or animal comprising administering to the human or animal a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein, R a  is selected from —OCH 3 ; —OCH 2 CH 3 ; or —CCCH 3 ; Z′ is selected from >C—F, >C—NH 2 , >CCONH 2 , >C—NHCOH, >C—OSO 2 NH 2 , or >C—CHCH 2 , and Z″ is selected from >C(H 2 ), >C(H)—CH 3 , >C═CH 2 , >C═CHCH 3 , or >C═O; provided that when Z′ is >C—OSO 2 NH 2  and Z″ is >C(H 2 ) or >C═O, R a  is neither —OCH 3  nor —OCH 2 CH 3 .  
   
   
       3 . The method of  claim 2 , wherein the administration of the compound is in a daily dose, a daily sub-dose, or any appropriate fraction thereof to the human or animal.  
   
   
       4 . The method of  claim 2 , wherein the amount of the compound administered is approximately 0.1 to approximately 300 mg/kg/day.  
   
   
       5 . The method of  claim 2 , wherein the amount of the compound administered is approximately 0.5 to approximately 50 mg/kg/day.  
   
   
       6 . The method of  claim 2 , wherein the amount of the compound administered is approximately 1 to approximately 10 mg/kg/day.  
   
   
       7 . The method of  claim 2 , wherein the administration of the compound is oral, parenteral, transdermal, topical, intravenous, subcutaneous, intramuscular, intradermal, ophthalmic, epidural, intratracheal, sublingual, buccal, rectal, vaginal, nasal or inhalation.  
   
   
       8 . The method of  claim 2 , wherein the compound is administered in a composition comprising an additive selected from an anti-oxidant, a buffer, a bacteriostat, a liquid carrier, a solute, a suspending agent, a thickening agent, a flavoring agent, a gelatin, glycerin, a binder, a lubricant, an inert diluent, a preservative, a surface active agent, a dispersing agent, a biodegradable polymer, or any combination thereof.  
   
   
       9 . The method of  claim 2 , wherein the compound is administered in the form of a tablet, a capsule, a lozenge, a cachet, a solution, a suspension, an emulsion, a powder, an aerosol, a suppository, a spray, a pastille, an ointment, a cream, a paste, a foam, a gel, a tampon, a pessary, a granule, a bolus, a mouthwash, or a transdermal patch.  
   
   
       10 . The method of  claim 2 , wherein the angiogenesis is associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, Sjögren's syndrome, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, trauma, arthritis, rheumatoid arthritis, polyarteritis, systemic lupus, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, macular degeneration, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme's disease, Eales' disease, Behcet's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, post-laser complications, abnormal proliferation of fibrovascular or fibrous tissue, hemangiomas, Osler-Weber-Rendu disease, solid tumors, blood-borne tumors, acquired immune deficiency syndrome, ocular neovascular disease, age-related macular degeneration, osteoarthritis, diseases caused by chronic inflammation, Crohn's disease, ulcerative colitis, tumors of rhabdomyosarcoma, tumors of retinoblastoma, Ewing's sarcoma, neuroblastoma, tumors of osteosarcoma, leukemia, psoriasis, atherosclerosis, pemphigoid, infections causing retinitis, infections causing choroiditis, presumed ocular histoplasmosis, Best's disease, proliferative vitreoretinopathy, Bartonellosis, acoustic neuromas, neurofibroma, trachoma, or pyogenic granulomas.  
   
   
       11 - 95 . (canceled)  
   
   
       96 . A method of treating an eye condition in a human or an animal comprising administering to the human or animal a compound having the formula  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       97 . The method of  claim 96 , wherein the eye condition is ocular neovascular disease, diabetic retinopathy, retinopathy of prematurity, macular degeneration, age related macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, epidemic keratoconjunctivitis, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, myopia, chronic retinal detachment, optic pits, Terrien's marginal degeneration, hyperviscosity syndromes, chronic uveitis, chronic vitritis, presumed ocular histoplasmosis, retinitis, choroiditis, proliferative vitreoretinopathy, scleritis, Eales' disease, Best's disease, trachoma, pars planitis, due to chronic inflammation, due to post-laser complications, or due to radial keratotomy.  
   
   
       98 - 124 . (canceled)  
   
   
       125 . A method of treating an inflammatory or immune mediated disease in a human or an animal comprising administering to the human or animal a compound selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       126 . The method of  claim 125 , wherein the inflammatory or immune mediated disease is rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, Mooren's ulcer, arthritis, sarcoidosis, inflammatory bowel diseases, immune mediated bowel disease, systemic lupus, pars planitis, Wegener's syndrome, Stevens-Johnson disease, Behcet's disease, pemphigoid, Lyme's disease, or acquired immune deficiency syndrome.  
   
   
       127 - 138 . (canceled)  
   
   
       139 . A method of treating an infectious disease in a human or an animal comprising administering to the human or animal a compound selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       140 . The method of  claim 139 , wherein the infectious disease is syphilis, a bacterial infection, a mycobacterial infection, a bacterial ulcer, a fungal ulcer, a Herpes simplex infection, a Herpes zoster infection, a protozoan infection, a Bartonellosis infection, or toxoplasmosis.  
   
   
       141 - 149 . (canceled)  
   
   
       150 . A method of treating a cancerous disease in a human or an animal comprising administering to the human or animal a compound selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       151 . The method of  claim 150 , wherein the cancerous disease is rhabdomyosarcoma, retinoblastoma, Ewing sarcoma, neuroblastoma, acoustic neuroma, osteosarcoma, neurofibroma, hemangioma, breast cancer, prostrate cancer, renal cell cancer, a brain tumor, ovarian cancer, colon cancer, liver cancer, lung cancer, bladder cancer, cutaneous melanoma, Kaposi's sarcoma, or leukemia.  
   
   
       152 - 166 . (canceled)  
   
   
       167 . A method of treating a blood or blood vessel disease in a human or an animal comprising administering to the human or animal a compound selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       168 . The method of  claim 167 , wherein the blood or blood vessel disease is vein occlusion, artery occlusion, carotid obstructive disease, polyarteritis, atherosclerosis, Osler-Weber-Rendu disease, sickle cell anemia, leukemia, an acute neoplastic disease of the bone marrow, a chronic neoplastic disease of the bone marrow, a hemangioma, a hereditary hemorrhagic telangiectasia, a disease of the bone marrow, anemia, impaired blood clotting, enlargement of the lymph nodes, enlargement of the liver, or enlargement of the spleen.  
   
   
       169 - 175 . (canceled)  
   
   
       176 . The method of  claim 168 , wherein the acute or chronic neoplastic disease of the bone marrow is multiple myeloma.  
   
   
       177 . The method of  claim 168 , wherein the acute or chronic neoplastic disease of the bone marrow is myelo dysplastic syndrome.  
   
   
       178 - 183 . (canceled)  
   
   
       184 . A method of treating a skin condition in a human or an animal comprising administering to the human or animal a compound selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       185 . The method of  claim 184 , wherein the skin condition is abnormal wound healing, acne rosacea, due to chemical burns, or psoriasis.  
   
   
       186 - 188 . (canceled)  
   
   
       189 . A method of treating a tumor in a human or an animal comprising administering to the human or animal a compound having the formula  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       190 . The method of  claim 189 , wherein the tumor is a blood borne tumor, a cancerous blood borne tumor, a solid tumor, a benign tumor, or a cancerous tumor.  
   
   
       191 - 194 . (canceled)  
   
   
       195 . A method of inhibiting abnormal cell mitosis in a human or animal comprising administering to the human or animal a compound selected from  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       196 - 197 . (canceled)