Method of using biothionol and biothionol-like compounds as anti-angiogenic agents

Abstract

The present disclosure relates generally to treating or preventing diseases associated with angiogenesis by administering to a patient certain compounds found to inhibit or substantially reduce angiogenesis. Compounds employed according to the present disclosure exhibit good anti-angiogenic activity as well as demonstrate a prophylactic effect for preventing and substantially reducing angiogenesis. Examples of such compounds include Ritanserin, Amiodarone, Terfenadinc, Perphenazine, Bithionol, and Clomipramine.

What is claimed is: 
     
         1 . A method of inhibiting or reducing angiogenesis in a patient in need thereof comprising administering to said patient an anti-angiogenically effective amount of a compound of Formula (III) 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of hydrogen or hydroxy; 
         R 1  is hydrogen; or 
         R and R 1  taken together form a second bond between the carbon atoms bearing R and R 1 ; 
         n is an integer from 1 to 3; and 
         Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino. 
       
     
     
         2 . The method of  claim 1  comprising administering to said patient an anti-angiogenically effective amount of a compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of hydrogen or hydroxy; 
         R 1  is hydrogen; or 
         R and R 1  taken together form a second bond between the carbon atoms bearing R and R 1 ; 
         n is an integer from 1 to 3; and 
         Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
       
     
     
         3 . The method of  claim 1  wherein the compound of Formula (III) is terfenadine. 
     
     
         4 . A method of inhibiting the growth or metastasis of an angiogenesis-dependent tumor in a patient in need thereof comprising administering to said patient an effective amount of a compound of Formula (III) 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of hydrogen or hydroxy; 
         R 1  is hydrogen; or 
         R and R 1  taken together form a second bond between the carbon atoms bearing R and R 1 ; 
         n is an integer from 1 to 3; and 
         Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino. 
       
     
     
         5 . The method of  claim 4  comprising administering to said patient an effective amount of a compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of hydrogen or hydroxy; 
         R 1  is hydrogen; or 
         R and R 1  taken together form a second bond between the carbon atoms bearing R and R 1 ; 
         n is an integer from 1 to 3; and 
         Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
       
     
     
         6 . The method of  claim 4  wherein the compound of Formula (III) is terfenadine. 
     
     
         7 . A method for treating a disease or disorder associated with angiogenesis in a patient in need thereof, said disease or disorder being selected from the group consisting of neoplastic diseases, restenosis, rheumatoid arthritis, Crohn's disease, diabetic retinopathy, psoriasis, endometriosis, macular degeneration, neovascular glaucoma, and adiposity, comprising administering to said patient an effective amount of an anti-angiogenic compound of Formula (III) 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of hydrogen or hydroxy; 
         R 1  is hydrogen; or 
         R and R 1  taken together form a second bond between the carbon atoms bearing R and R 1 ; 
         n is an integer from 1 to 3; and 
         Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino. 
       
     
     
         8 . The method of  claim 7  comprising administering to said patient an effective amount of an anti-angiogenic compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of hydrogen or hydroxy; 
         R 1  is hydrogen; or 
         R and R 1  taken together form a second bond between the carbon atoms bearing R and R 1 ; 
         n is an integer from 1 to 3; and 
         Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
       
     
     
         9 . The method of  claim 7  wherein the compound of Formula (III) is terfenadine.