Methods and compositions for inhibition of angiogenesis

Abstract

The present invention comprises a group of compounds that effectively inhibit angiogenesis. More specifically, thalidomide and various related compounds such as thalidomide precursors, analogs, metabolites and hydrolysis products have been shown to inhibit angiogenesis and to treat disease states resulting from angiogenesis. Additionally, antiinflammatory drugs, such as steroids and NSAIDs can inhibit angiogenesis dependent diseases either alone or in combination with thalidomide and related compounds. Importantly, these compounds can be administered orally.

We claim:  
     
         1 . An angiogenesis inhibitory composition comprising an angiogenesis inhibiting compound and an antiinflammatory drug.  
     
     
         2 . The angiogenesis inhibitory composition of  claim 1  wherein the antiinflammatory drug is a steroid.  
     
     
         3 . The angiogenesis inhibitory composition of  claim 2  wherein the steroid is selected from the group consisting of cortisol, corticosterone, hydrocortisone, hydrocortisol, cortisone, prednisone, prednisolone, dexamethasone, beclomethasone, betamethasone, mometasone, mometasone furoate, budesonide, triamcinolone acetonide, and fluticasone.  
     
     
         4 . The angiogenesis inhibitory composition of  claim 1  wherein the antiinflammatory drug is a nonsteroidal, antiinflammatory drug (NSAID).  
     
     
         5 . The angiogenesis inhibitory composition of  claim 4  wherein the NSAID is selected from group consisting of aspirin, acetominophen, ibuprofen, esculetin, phenidone, quercetin, ketoprofen, nordihydroguiaretic acid (NDGA), sulindac, sulindac sulfone, sulindac sulfide, indomethacin, NS-398 (a cyclooxygenase-2 inhibitor), cyclooxygenase-1 inhibitors, methylheptyl imidazole, furegrelate sodium, SKF525AHCL, thromboxane inhibitors, toradol, ecasa, salsalate, diflunisal, mefenamic acid, naproxen, naproxen sodium, floctafenine, meclofenamate, phenylbutazone, oxyphenbutazone, diclofenac, etodolac, fenoprofen, flufenamic acid, flurbiprofen, pirprofen, tolmetin, apazone, fenbufen, nabumetone, oxaprozin, piroxicam, salicylate, and tenoxicam.  
     
     
         6 . The angiogenesis inhibitory composition of  claim 5  wherein the NSAID is selected from indomethacin and sulindac.  
     
     
         7 . The angiogenesis inhibitory composition of  claim 1  wherein the angiogenesis inhibiting compound is selected from the group consisting of 
 (1) a compound selected from the formula  
                     
 wherein  
 R 1 -R 4  are each independently selected from H; OH; ═O; straight or branched chain alkanes, alkenes, and 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;  
 R 5 -R 8  are each independently selected from  
                     
 or —O—, where Y is absent and R 10  is ═O or Y and R 10  are each independently the same as R 1 ;  
 and R 9  is a moiety selected from the group consisting of  
                     
 wherein each of R 11 -R 17  is independently the same as R 5 , and  
 wherein R 18 , R 19  and R 20  are each independently selected from  
                     
 and n=1 through 4;  
 (2) a compound selected from the formula  
                     
 where R 22  and R 23  are each independently H, F, Cl, Br, I, CH 3 , or —CH 2 —CH 3 ;  
 and R 24  is H, CH 3 , or —CH 2 —CH 3 ;  
 and  
 (3) a compound selected from the formula  
                     
 where X is R 6  as defined in (1) above.  
 
     
     
         8 . The angiogenesis inhibitory composition of  claim 7  wherein the angiogenesis inhibiting compound has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 4  are as defined in  claim 8;  
 R 5  and R 6  are independently selected from the group consisting of  
                     
 and R 9  is selected from F) or H) wherein R 14  and R 16  are each independently selected from the group consisting of  
                     
 and R 15  is  
                     
 where R 21  is H, CH 3 , or OH.  
 
     
     
         9 . The angiogenesis inhibitory composition of  claim 7  wherein the angiogenesis inhibiting compound is selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The angiogenesis inhibitory composition of  claim 7  wherein the angiogenesis inhibiting compound is selected from the group consisting of thalidomide, metabolites of thalidomide, thalidomide analogs, epoxides of thalidomide, hydolysis products thereof, EM-12, metabolites of EM-12, epoxides of EM-12, hydolysis products thereof, EM-138, metabolites of EM-138, epoxides of EM-138, hydolysis products thereof, N-phthaloyl-DL-glutamic acid (PGA), N-phthaloyl-DL-glutamine anhydride, and mixture thereof.  
     
     
         11 . The angiogenesis inhibitory composition of  claim 10  wherein the inhibiting compound is selected from  
       
         
           
           
               
               
           
         
       
       wherein 
 R is selected from the group consisting of H, (C 1 -C 6 )alkyl, phenyl, and benzyl; and  
 R′ is selected from the group consisting of phthalimido and succinimido;  
 wherein  
 X is CH 2  or C═O; and  
 R″ is H, —CH 2 CH 3 , —C 6 H 5 , —CH 2 C 6 H 5 , —CH 2 CH=CH 2 , or  
                     
 and  
 (III) hydrolysis products of (II) wherein R″ is H and the piperidino ring or both the piperidino and the imido ring are hydrolyzed.  
 
     
     
         12 . The angiogenesis inhibitory composition of  claim 10  wherein the angiogenesis inhibiting compound is selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A method for inhibiting angiogenesis in a human or animal comprising administering to the human or animal a composition comprising a nonsteroidal, antiinflammatory drug (NSAID).  
     
     
         14 . The method of  claim 13  wherein the composition further comprises an angiogenesis inhibiting compound.  
     
     
         15 . A method for inhibiting angiogenesis in a human or animal comprising administering to the human or animal a composition comprising an angiogenesis inhibiting compound and an antiinflammatory compound.  
     
     
         16 . A method for treating an angiogenesis dependent disease in a human or animal having such a disease comprising administering to the human or animal a composition comprising a nonsteroidal, antiinflammatory drug (NSAID).  
     
     
         17 . The method of  claim 16  wherein the composition further comprises an angiogenesis inhibiting compound.  
     
     
         18 . The method of  claim 16  wherein the angiogenesis dependent disease is selected from the group consisting of macular degeneration, diabetic retinopathy, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, solid tumors, blood-borne tumors, leukemia, hemangioma, psoriasis, Kaposi's sarcoma, Crohn's disease, ulcerative colitis, cancer, retinopathy of prematurity, corneal graft rejection, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration chemical burns, bacterial ulcers, fungal ulcers,  Herpes simplex  infections,  Herpes zoster  infections, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, trauma, rheumatoid arthritis, systemic lupus, polyarteritis, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, corneal graft rejection, sickle cell anemia, pseudoxanthoma elasticum, pemphigoid, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme's disease, systemic lupus erythematosis, Eales' disease, Behcet's disease, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, post-laser complications, and rubeosis.  
     
     
         19 . A method for treating an angiogenesis dependent disease in a human or animal having such a disease comprising administering to the human or animal a composition comprising an angiogenesis inhibiting compound and an antiinflammatory compound.  
     
     
         20 . The method of  claim 19  wherein the angiogenesis dependent disease is selected from the group consisting of macular degeneration, diabetic retinopathy, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, solid tumors, blood-borne tumors, leukemia, hemangioma, psoriasis, Kaposi's sarcoma, Crohn's disease, ulcerative colitis, cancer, retinopathy of prematurity, corneal graft rejection, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers,  Herpes simplex  infections,  Herpes zoster  infections, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, trauma, rheumatoid arthritis, systemic lupus, polyarteritis, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, corneal graft rejection, sickle cell anemia, pseudoxanthoma elasticum, pemphigoid, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme's disease, systemic lupus erythematosis, Eales' disease, Behcet's disease, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, post-laser complications, and rubeosis.