Methods and compositions for inhibition of angiogenesis

Abstract

The present invention is directed to a group of compounds that effectively inhibit angiogenesis. Furthermore, the present invention provides a method of treating angiogenesis and diseases, including, but not limited to, eye diseases, inflammatory or immune mediated diseases, infectious diseases, cancerous diseases, blood or blood vessel diseases, and skin diseases.

What is claimed is:  
     
         1 . A method of inhibiting angiogenesis in a human or animal comprising administering to the human or animal an angiogenesis-inhibiting amount of a teratogenic compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from —H; —OH; ═O; straight chained and branched chain alkanes, alkenes, alkynes; cyclic alkanes, alkenes, and alkynes; combinations of cyclic and acyclic alkanes, alkenes, and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; —XO n  or —O—XO n , (where X=N and n=2; X=S and n=2 or 3; or X=P and n=1-3); and halogens and wherein R 5 , R 6 , and R 7  are each independently selected from:  
       
         
           
           
               
               
           
         
       
       or —O— where Y is optional and is the same as defined above for R 1 , and where R 10  is the same as defined above for R 1 , or (where Y is absent) R 10  is ═O; and where R 8  is independently selected from  
       
         
           
           
               
               
           
         
       
       and wherein R 9  is a moiety having formula D), E), F), G) or H):  
       
         
           
           
               
               
           
         
       
       where R 12 -R 17  is independently the same as defined above for R 5  and where R 11  is independently the same as defined above for R 8 , and where R 18 , R 19  and R 20  are independently selected from  
       
         
           
           
               
               
           
         
       
       and n=1 to 4, and wherein the teratogenic compound is not thalidomide.  
     
     
         2 . The method of  claim 1 , wherein the administration of the angiogenesis-inhibiting amount of the compound is in a daily dose, a daily sub-dose, or any appropriate fraction thereof to the human or animal to inhibit the effects of angiogenesis.  
     
     
         3 . The method of  claim 1 , wherein the amount of the compound administered is approximately 0.1 to approximately 300 mg/kg/day.  
     
     
         4 . The method of  claim 1 , wherein the amount of the compound administered is approximately 0.5 to approximately 50 mg/kg/day.  
     
     
         5 . The method of  claim 1 , wherein the amount of the compound administered is approximately 1 to approximately 10 mg/kg/day.  
     
     
         6 . The method of  claim 1 , wherein the administration of the compound is oral, parenteral, transdermal, topical, intravenous, subcutaneous, intramuscular, intradermal, ophthalmic, epidural, intratracheal, sublingual, buccal, rectal, vaginal, or nasal.  
     
     
         7 . The method of  claim 1 , 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.  
     
     
         8 . The method of  claim 1 , 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 tamport, a pessary, a granule, a bolus, a mouthwash, or a transdermal patch.  
     
     
         9 . A method of inhibiting angiogenesis in a human or animal comprising administering to the human or animal an angiogenesis-inhibiting amount of a teratogenic compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from —H; —OH; ═O; straight chained and branched chain alkanes, alkenes, alkynes; cyclic alkanes, alkenes, and alkynes; combinations of cyclic and acyclic alkanes, alkenes, and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; —XO n  or —O—XO n , (where X=N and n=2; X=S and n=2 or 3; or X=P and n=1-3); and halogens and wherein R 5 , R 6 , and R 7  are each independently selected from:  
       
         
           
           
               
               
           
         
       
       or —O— where Y is optional and is the same as defined above for R 1 , and where R 10  is the same as defined above for R 1 , or (where Y is absent) R 10  is ═O; and where R 8  is independently selected from  
       
         
           
           
               
               
           
         
       
       and wherein R 9  is a moiety having formula D), E), F), G) or H):  
       
         
           
           
               
               
           
         
       
       where R 12 -R 17  is independently the same as defined above for R 5  and where R 11  is independently the same as defined above for R 8 , and where R 18 , R 19  and R 20  are independently selected from  
       
         
           
           
               
               
           
         
       
       and n−1 to 4, and wherein the teratogenic compound is not thalidomide.  
     
     
         10 . The method of  claim 9 , wherein: 
 R 1 , R 2 , R 3 , and R 4  are independently selected from —H, —OH, amino and —XO n , where X=N and n=2;    R 5  is                          where R 10  is ═O and Y is absent;    R 6  is                          where R 10  is O and Y is absent or R 10  is —H and Y is —H;    R 8  is                          R 9  is                          where R 11  is                          and Y is —H; R 12  and R 13  are                          and R 10  is —H and Y is —H; R 14  and R 16  are                          and R 10  is ═O and Y is absent; and R 15  is                          where Y is —H.    
     
     
         11 . The method of  claim 9 , wherein the administration of the angiogenesis-inhibiting amount of the compound is in a daily dose, a daily sub-dose, or any appropriate fraction thereof to the human or animal to inhibit the effects of angiogenesis.  
     
     
         12 . The method of  claim 9 , wherein the amount of the compound administered is approximately 0.1 to approximately 300 mg/kg/day.  
     
     
         13 . The method of  claim 9 , wherein the amount of the compound administered is approximately 0.5 to approximately 50 mg/kg/day.  
     
     
         14 . The method of  claim 9 , wherein the amount of the compound administered is approximately 1 to approximately 10 mg/kg/day.  
     
     
         15 . The method of  claim 9 , wherein the administration of the compound is oral, parenteral, transdermal, topical, intravenous, subcutaneous, intramuscular, intradermal, ophthalmic, epidural, intratracheal, sublingual, buccal, rectal, vaginal, or nasal.  
     
     
         16 . The method of  claim 9 , 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.  
     
     
         17 . The method of  claim 9 , 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 tamport, a pessary, a granule, a bolus, a mouthwash, or a transdermal patch.  
     
     
         18 . A method of inhibiting angiogenesis in a human or animal comprising administering to the human or animal an angiogenesis-inhibiting amount of a teratogenic compound having the formula:  
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , R 3 , and R 4  are independently selected from —H, —OH, amino and —XO n , where X=N and n=2; Z is CH 2  or C═O, and R″ is H, —CH 2 CH 3 , —C 6 H 5 , —CH 2 C 6 H 5 , or —CH 2 CH═CH 2 , and wherein the teratogenic compound is not thalidomide.  
     
     
         19 . The method of  claim 18 , wherein the administration of the angiogenesis-inhibiting amount of the compound is in a daily dose, a daily sub-dose, or any appropriate fraction thereof to the human or animal to inhibit the effects of angiogenesis.  
     
     
         20 . The method of  claim 18 , wherein the amount of the compound administered is approximately 0.1 to approximately 300 mg/kg/day.  
     
     
         21 . The method of  claim 18 , wherein the amount of the compound administered is approximately 0.5 to approximately 50 mg/kg/day.  
     
     
         22 . The method of  claim 18 , wherein the amount of the compound administered is approximately 1 to approximately 10 mg/kg/day.  
     
     
         23 . The method of  claim 18 , wherein the administration of the compound is oral, parenteral, transdermal, topical, intravenous, subcutaneous, intramuscular, intradermal, ophthalmic, epidural, intratracheal, sublingual, buccal, rectal, vaginal, or nasal.  
     
     
         24 . The method of  claim 18 , 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.  
     
     
         25 . The method of  claim 18 , 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 tamport, a pessary, a granule, a bolus, a mouthwash, or a transdermal patch.  
     
     
         26 . (New) A method of treating undesired angiogenesis in a human or animal comprising administering to the human or animal with undesired angiogenesis an effective amount of a teratogenic compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from —H; —OH; ═O; straight chained and branched chain alkanes, alkenes, alkynes; cyclic alkanes, alkenes, and alkynes; combinations of cyclic and acyclic alkanes, alkenes, and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; —XO n  or —O—XO n , (where X=N and n=2; X=S and n=2 or 3; or X=P and n=1-3); and halogens and wherein R 5 , R 6 , and R 7  are each independently selected from:  
       
         
           
           
               
               
           
         
       
       or —O— where Y is optional and is the same as defined above for R 1 , and where R 10  is the same as defined above for R 1 , or (where Y is absent) R 10  is ═O; and where R 8  is independently selected from  
       
         
           
           
               
               
           
         
       
       and wherein R 9  is a moiety having formula D), E), F), G) or H):  
       
         
           
           
               
               
           
         
       
       where R 12 -R 17  is independently the same as defined above for R 5  and where R 11  is independently the same as defined above for R 8 , and where R 18 , R 19  and R 20  are independently selected from  
       
         
           
           
               
               
           
         
       
       and n=1 to 4, and wherein the teratogenic compound is not thalidomide.  
     
     
         27 . The method of  claim 26 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 27 , wherein: 
 R 1 , R 2 , R 3 , and R 4  are independently selected from —H, —OH, amino and —XO n , where X=N and n=2;    R 5  is                          where R 10  is ═O and Y is absent;    R 6  is                          where R 10  is O and Y is absent or R 10  is —H and Y is —H;    R 8  is                          R 9  is                          where R 11  is                          and Y is —H; R 12  and R 13  are                          and R 10  is —H and Y is —H; R 14  and R 16  are                          and R 10  is ═O and Y is absent; and R 15  is                          where Y is —H.    
     
     
         29 . The method of  claim 26 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , R 3 , and R 4  are independently selected from —H, —OH, amino and —XO n , where X=N and n=2; Z is CH 2  or C═O, and R″ is —H, —CH 2 CH 3 , —C 6 H 5 , —CH 2 C 6 H 5 , or —CH 2 CH═CH 2 .  
     
     
         30 . The method of  claim 26 , 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 to reduce the effects of the undesired angiogenesis.  
     
     
         31 . The method of  claim 26 , wherein the amount of the compound administered is approximately 0.1 to approximately 300 mg/kg/day.  
     
     
         32 . The method of  claim 26 , wherein the amount of the compound administered is approximately 0.5 to approximately 50 mg/kg/day.  
     
     
         33 . The method of  claim 26 , wherein the amount of the compound administered is approximately 1 to approximately 10 mg/kg/day.  
     
     
         34 . The method of  claim 26 , wherein the administration of the compound is oral, parenteral, transdermal, topical, intravenous, subcutaneous, intramuscular, intradermal, ophthalmic, epidural, intratracheal, sublingual, buccal, rectal, vaginal, or nasal.  
     
     
         35 . The method of  claim 26 , wherein the undesired angiogenesis is associated with an eye condition, an inflammatory disease, an immune mediated disease, an infectious disease, a cancerous disease, a blood disease, a blood vessel disease, a skin condition, or a tumor.  
     
     
         36 . The method of  claim 26 , wherein the undesired angiogenesis is associated with ocular neovascular disease, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, 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, post-laser complications, Vitamin A deficiency, Sjögren's syndrome, phylectenulosis, lipid degeneration, Kaposi sarcoma, marginal keratolysis, trauma, radial keratotomy, pseudoxanthoma elasticum, Paget's disease, erythematosis, Stargarts disease, pars planitis, rubeosis, or corneal neovascularization.  
     
     
         37 . The method of  claim 26 , wherein the undesired angiogenesis is associated with rheumatoid arthritis, osterarthritis, ulcerative colitis, Crohn's disease, Mooren's ulcer, arthritis, sarcoidosis, systemic lupus, Wegener's syndrome, Stevens-Johnson disease, Behcet's disease, pemphigoid, Lyme's disease, or acquired immune deficiency syndrome.  
     
     
         38 . The method of  claim 26 , wherein the undesired angiogenesis is associated with syphilis, a bacterial infection, a bacterial ulcer, a fungal ulcer, a Herpes simplex infection, a Herpes zoster infection, a protozoan infection, a Bartonellosis infection, or toxoplasmosis.  
     
     
         39 . The method of  claim 26 , wherein the undesired angiogenesis is associated with rhabdomyosarcoma, retinoblastoma, Ewing sarcoma, neuroblastoma, osteosarcoma, acoustic neuroma, neurofibroma, hemangioma, a blood borne tumor, or a blood borne cancerous disease.  
     
     
         40 . The method of  claim 26 , wherein the undesired angiogenesis is associated with vein occlusion, artery occlusion, carotid obstructive disease, polyarteritis, atherosclerosis, Osler-Weber-Rendu disease, sickle cell anemia, leukemia, hemangioma, hereditary hemorrhagic telangiectasia, a disease of the bone marrow, anemia, impaired blood clotting, enlargement of a lymph node, enlargement of a liver, enlargement of a spleen, an acute neoplastic disease of bone marrow, or chronic neoplastic disease of bone marrow.  
     
     
         41 . The method of  claim 26 , wherein the undesired angiogenesis is associated with abnormal wound healing, acne rosacea, chemical bums, or psoriasis.  
     
     
         42 . The method of  claim 27 , wherein the undesired angiogenesis is associated with a cancerous blood borne tumor, a benign solid tumor, or a cancerous solid tumor.