Compositions and methods to treat disease characterized by cellular proliferation and angiogenesis

Abstract

Described herein are compositions and methods for preventing and/or treating diseases involving aberrant angiogenesis employing one or more benzo[c]chromen-6-one derivatives.

1 . A composition comprising a compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein, 
         R1 is H or alkyl; 
         R2 is H, OH, O-alkyl, amino, O-heterocyc, O-aryl, O-Ac, O-PO 3 , OSO3, OSO2NH2 or O-substituted alkyl wherein said substitution is halo, aryl, or heteroaryl; 
         R3 is H, OH, O-alkyl, O-CH2Aryl, O-CH2heteroaryl, O-alkylaryl, O-acyl, or nitro; 
         R4 is H, Alkyl, CH2Aryl, substituted alkyl, OH, O-alkyl, O-aryl, OCH2Aryl, OCH2Heteroaryl, O-Acyl, OPO3, OSO3, or OSO2NH2; 
         R5 is H, Oxo, aryl, hydroxyl, alkyl, or O-alkyl; 
         R6 is H; 
         R7 is H, Acyl, alkyl, O-alkyl, substituted alkyl wherein said substitution is hydroxyl or sulfamoyl, or O-substituted alkyl wherein said substitution is O-PO3 or OSO3; 
         R8 is H; and 
         X is O, N, or S. 
       
     
     
         2 - 4 . (canceled) 
     
     
         5 . The composition of  claim 1 , wherein said composition is one or more compositions selected from the group consisting of Table I. 
     
     
         6 . The composition of  claim 5 , wherein said Table I comprises benzo(c)chromen-6-one derivatives SG00272, SG00273, SG00373, SG00477, SG00519, SG00526, SG00527, SG00528, SG00529, SG00530, SG00531, SG00532, SG00533, SG00535, SG00536, SG00537, SG00538, SG00539, SG00540, SG00541, SG00542, SG00543, SG00544, SG00545, SG00546, SG00547, SG00548, SG00549, SG00550, SG00551, SG00552, SG00553, SG00554, SG00555, SG00556, SG00557, SG00558, SG00559, SG00560, SG00561, SG00562, SG00563, SG00564, SG00565, SG00566, SG00567, SG00568, SG00569, SG00570, SG00571, SG00572, SG00573, SG00574, SG00575, SG00576, SG00577, SG00579, SG00580, SG00581, SG00582, SG00583, SG00584, SG00585, SG00586, SG00587, SG00588, SG00589, SG00590, SG00591, SG00592, SG00593, SG00594, SG00595, SG00596, SG00597, SG00598, SG00599, SG00600, SG00601, SG00602, SG00603, SG00604, SG00605, SG00606, SG00607, SG00608, SG00609, SG00610, SG00611, SG00612, SG00613, SG00614, SG00615, SG00616, SG00617, SG00618, SG00619, SG00620 and SG00629. 
     
     
         7 . A composition for preventing or treating a disease characterized by unwanted angiogenesis comprising a compound selected from the group consisting of Formula I, Formula II, Formula III and Formula IV. 
     
     
         8 . The composition of  claim 7 , wherein said disease is further characterized by unwanted cellular proliferation. 
     
     
         9 . The composition of  claim 8 , wherein said composition exhibits anti-angiogenic activity or anti-proliferation activity. 
     
     
         10 . The composition of  claim 8 , wherein said composition exhibits anti-angiogenic activity and anti-proliferation activity. 
     
     
         11 . The composition of  claim 8 , wherein said composition exhibits apoptotic activity. 
     
     
         12 . The composition of  claim 1 , wherein said composition is formulated in a biodegradable or non-biodegradable format for sustained release. 
     
     
         13 . The composition of  claim 1 , wherein said composition is conjugated to a prodrug. 
     
     
         14 . The composition of  claim 13 , wherein said prodrug is selected from the group consisting of a peptide, antibody, antibody fragment, hydrolysable ester amides, and carbamates. 
     
     
         15 . The composition of  claim 13 , wherein said prodrug is selected from the group consisting of glycolic acid, lactic acid, 2-hydroxyoctanoic acid, hydroxylauric glycolic acid, and combinations thereof. 
     
     
         16 . A method of preventing or treating a disease characterized by unwanted angiogenesis, comprising administering to a subject a therapeutic amount of one or more compositions selected from the group consisting of Formula I, Formula II, Formula III and Formula IV. 
     
     
         17 . The method of  claim 16 , wherein said composition further comprises an acceptable delivery vehicle. 
     
     
         18 . The method of  claim 16 , wherein said subject has or is predisposed toward a cancer. 
     
     
         19 . The method of  claim 18 , wherein said cancer is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, hemangioma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinomas, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, osteosarcoma, meningioma, melanoma, neuroblastoma, retinoblastoma, acousticneuroma, neurofibromas, trachoma and pyogenic granulomas, acute lymphocytic leukemia and acute myelocytic leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroblobulinemia, and heavy chain disease. 
     
     
         20 . The method of  claim 16 , wherein said subject has or is predisposed toward a disease selected from the group consisting of hereditary hemorrhagic telangiectasia, solid or blood born tumors, acquired immune deficiency syndrome, post-menopausal symptoms, osteoporosis, cardiovascular disease, Alzheimer's disease, strokes, vascular malformations, abnormal wound healing, inflammatory and immune disorders, gout, macular degeneration, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, multifocal choroiditis, Best's disease, Stargardt's disease, cb1C-type cobalamin deficiency, hyperviscosity syndrome, Sorsby's fundus dystrophy, pseudoxanthoma elasticum, rubeosis iridis, Osler Weber syndrome, Osler-Weber-Rendu disease, keratoconjunctivitis, Vitamin A deficiency, phylectenulosis, bacterial infection, viral infection, parasitic infection, fungal infection, atopic and superior limbic dermatitis, chronic uveitis, chronic vitritis, Eales' disease, radial keratotomy, uncharacteristic proliferation of fibrovascular or fibrous tissue, proliferative vitreoretinopathy, chronic retinal detachment, trauma (including but not limited to abrasion, previous surgery with complications such as corneal allograft rejection, alkaline burns, acid burns or hydrocarbon burns, mechanical or thermal damage to Bruch's membrane), pterygium, arthritis (rheumatoid and osteoarthritis), psoriasis, atopic dermatitis, dermal photodamage), Sjögren's syndrome, systemic lupus, polyarteritis, pemphigoid, sickle cell anemia, Paget's disease, vein or artery occlusion, carotid obstructive disease, Lyme disease, Behcet's disease, bartonelosis, arteriosclerosis, induction of amenorrhea to block ovulation or to prevent implantation by the blastula, surgical adhesions, chronic inflammation, ulcerative colitis and Crohn's disease. 
     
     
         21 . The method of  claim 16  further comprising the co-administration to said subject said one or more compositions selected from the group consisting of Formula I, Formula II, Formula III and Formula IV and a therapeutic agent directed toward the treatment or prevention of said disease. 
     
     
         22 . The method of  claim 21 , wherein said therapeutic agent is selected from the group consisting of an oncolytic agent, an anti-cancer agent, an anti-nausea agent and an anti-emesis agent. 
     
     
         23 . The method of  claim 16 , wherein said administration includes topical, oral, nasal, rectal, and parenteral administration of said one or more compositions. 
     
     
         24 . The method of  claim 16 , wherein said one or more compositions is associated with an implant. 
     
     
         25 . The method of  claim 16 , wherein said one or more compositions is associated with a device. 
     
     
         26 . The method of  claim 25 , wherein said device is a vascular stent.