Methods and compositions for inhibition of angiogenesis with phthaloyl glutamic acid derivatives

Abstract

The present invention comprises a group of compounds that effectively inhibit angiogenesis. More specifically, thalidomide and various related compounds such as EM-12 and its derivatives have been shown to inhibit angiogenesis and to treat disease states resulting from angiogenesis. Importantly, these compounds can be administered orally.

1 . A compound comprising the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from —H; —OH; ═O; straight chained and branched 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; —NO 2 , —ONO 2 , —SO 2  or —O—SO 3 , PO 3 , OPO 2 , OPO 3 ; and halogens; R 9  is a moiety selected from one of the following formulas:  
       
         
           
           
               
               
           
         
         where R 11 -R 16  are each independently selected from:  
         
           
             
             
                 
                 
             
           
         
         or —O— where Y is optional and is the same as defined above for R 1 ; and R 10  is the same as defined above for R 1 , or R 10  is ═O.  
       
     
     
         2 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         3 . A compound according to  claim 1  comprising the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from: —H; —OH; ═O; straight chained and branched alkanes; aza; amino; —NO 2 , —ONO 2 , —SO 2  or —O—SO 3 , PO 3 , OPO 2 , OPO 3 ; and halogens; R 11 -R 16  are each independently selected from:  
       
         
           
           
               
               
           
         
       
       Y is optional and is the same as defined above for R 1 ; and R 10  is the same as defined above for R 1 , or R 10  is ═O.  
     
     
         4 . A composition comprising a compound of  claim 3  and a pharmaceutically acceptable carrier.  
     
     
         5 . A compound according to  claim 3  comprising the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from: —H; —OH; ═O; CH 3 ; aza; amino; —NO 2 ; and halogens; R 12 -R 16  are each independently selected from: 
 —C—R 10  and —N—R 10 ;  
 wherein R 10  is H, OH, or ═O.  
 
     
     
         6 . A composition comprising a compound of  claim 5  and a pharmaceutically acceptable carrier.  
     
     
         7 . A compound according to  claim 5  having the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         8 . A composition comprising a compound of  claim 7  and a pharmaceutically acceptable carrier.  
     
     
         9 . A method of treating undesired angiogenesis in a human or animal comprising administering to the human or animal with undesired angiogenesis a composition comprising an effective amount of a compound comprising the following formula  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from —H; —OH; ═O; straight chained and branched 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; —NO 2 , —ONO 2 , —SO 2  or —O—SO 3 , PO 3 , OPO 2 , OPO 3 ; and halogens; R 9  is a moiety selected from one of the following formulas:  
       
         
           
           
               
               
           
         
       
       where R 11 -R 16  are each independently selected from:  
       
         
           
           
               
               
           
         
       
       or —O— where Y is optional and is the same as defined above for R 1 ; and R 10  is the same as defined above for R 1 , or R 10  is ═O.  
     
     
         10 . The method of  claim 9  wherein the compound comprises the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from: —H; —OH; ═O; straight chained and branched alkanes; aza; amino; —NO 2 , —ONO 2 , —SO 2  or —O—SO 3 , PO 3 , OPO 2 , OPO 3 ; and halogens; R 11 -R 16  are each independently selected from:  
       
         
           
           
               
               
           
         
       
       Y is optional and is the same as defined above for R 1 ; and R 10  is the same as defined above for R 1 , or R 10  is ═O.  
     
     
         11 . The method of  claim 10  wherein the compound comprises the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , and R 4  are independently selected from: —H; —OH; ═O; CH 3 ; aza; amino; —NO 2 ; and halogens; R 12 -R 16  are each independently selected from: 
 —C—R 10  and —N—R 11 ,  
 wherein R 10  is H, OH, or ═O.  
 
     
     
         12 . The method of  claim 11  wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 9  wherein the amount administered is between approximately 0.1 and approximately 300 mg/kg/day.  
     
     
         14 . The method of  claim 13  wherein the amount administered is between approximately 0.5 and approximately 50 mg/kg/day.  
     
     
         15 . The method of  claim 14  wherein the amount administered is between approximately 1 and approximately 10 mg/kg/day.  
     
     
         16 . The method of  claim 9  wherein the compound is administered in the form of a tablet or capsule.  
     
     
         17 . The method of  claim 9  wherein the compound is administered in the form of 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, or a pessary.  
     
     
         18 . The method of  claim 9  wherein the administration is oral, parenteral, transdermal, or topical.  
     
     
         19  The method of  claim 9  wherein the administration is sublingual, buccal, rectal, vaginal, or nasal.  
     
     
         20 . The method of  claim 9  wherein the undesired angiogenesis is associated with cancer.  
     
     
         21 . The method of  claim 20  wherein the cancer is selected from the group consisting of Kaposi's sarcoma, hemangiomas, solid tumors, blood borne tumors, acoustic neuroma, neurofibroma, tumors of rhabdomyosarcoma, tumors of retinoblastoma, tumors of Ewing's sarcoma, tumors of neuroblastoma, tumors of osteosarcoma, acoustic neuroma, and leukemia.  
     
     
         22 . The method of  claim 9  wherein the undesired angiogenesis is associate with an eye condition.  
     
     
         23 . The method of  claim 22  wherein the eye condition is selected from the group consisting of diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, myopia, Terrien's marginal degeneration, mariginal keratolysis, radial keratotomy, macular degeneration, post-laser complications, chronic retinal detachment; optic pits, hyperviscosity syndromes, chronic uveitis, chronic vitritis, ocular neovascular disease, age-related macular degeneration, presumed ocular histoplasmosis, infections causing retinitis or choroiditis, proliferative vitreoretinopathy, scleritis, Eales' disease, Best's disease, and trachoma.  
     
     
         24 . The method of  claim 9  wherein the undesired angiogenesis is associated with non-tumor blood conditions.  
     
     
         25 . The method of  claim 24  wherein the blood condition is selected from the group consisting of vein occlusion, artery occlusion, carotid obstructive disease, polyarteritis, atherosclerosis, Osler-Weber-Rendu disease, and sickle cell anemia.  
     
     
         26 . The method of  claim 9  wherein the undesired angiogenesis is associated with an ulcerative disease.  
     
     
         27 . The method of  claim 26  wherein the ulcerative disease is selected from the group consisting of bacterial ulcers, fungal ulcers, Mooren's ulcer, Wegener's sarcoidosis, Stevens-Johnson disease, Behcet's disease, pemphigoid, and ulceritive colitis.  
     
     
         28 . The method of  claim 9  wherein the undesired angiogenesis is associated with a skin condition.  
     
     
         29 . The method of  claim 28  wherein the skin condition is selected from the group consisting of acne, rosacea, chemical burns, and psoriasis.  
     
     
         30 . The method of  claim 9  wherein the undesired angiogenesis is associated with an immune disease.  
     
     
         31 . The method of  claim 30  wherein the immune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus, acquired immune deficiency syndrome, and osteoarthritis.  
     
     
         32 . The method of  claim 9  wherein the undesired angiogenesis is associated with an infection.  
     
     
         33 . The method of  claim 32  wherein the infection is selected from the group consisting of Herpes simplex infections, Herpes zoster infections, Mycobacteria infections, protozoan infections, toxoplasmosis, syphilis, and Bartonellosis.  
     
     
         34 . The method of  claim 9  wherein the undesired angiogenesis is associated with a condition selected from the group consisting of trauma, sjogren's syndrome, phylectenulosis, sarcoid, pseudoxanthoma elasticum, Stargardt's disease, Paget's disease, Lyme's disease, par planitis, pyogenic granulomas, and lipid degeneration.  
     
     
         35 . The method of  claim 9  wherein the undesired angiogenesis is associated with a condition selected from the group consisting of Crohn's disease and chronic inflammation.  
     
     
         36 . The method of  claim 9  wherein the undesired angiogenesis is associated with abnormal proliferation of fibrovascular or fibrous tissue.