Anti-angiogenic agents and methods of use

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, Terfenadine, Perphenazine, Bithionol, and Clomipramine.

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 (I) 
     
       
         
         
             
             
         
       
       wherein: 
       R is hydrogen, hydroxy or lower alkyloxy; 
       R 1  is a member selected from the group consisting of hydrogen and lower alkyl; 
       Alk is a lower alkanediyl radical; 
       X is a member selected from the group consisting of —S—, —CH 2 — and —C(R 2 )═C(R 3 )—, said R 2  and R 3  being each independently hydrogen or lower alkyl; 
       A is a bivalent radical having the formula —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or 
     
     
       
         
         
             
             
         
       
       wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, amino and lower alkyl; and 
     
     Ar 1  and Ar 2  are each independently selected from the group consisting of pyridinyl, thienyl and phenyl, being optionally substituted with halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl; 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is an alkyl group containing 1 to 6 carbon atoms; 
       R 2  is selected from the group consisting of hydrogen and methyl; 
       NR 3  is a radical selected from the group consisting of a dimethylamino, diethylamino, dipropylamino, piperidino, piperazino, pyrrolidino, morpholino, and N-substituted hetero aryl; and 
       Y and Y 1  are independently selected from the group consisting of hydrogen, fluorine, bromine, chlorine, and iodine; 
     
     
       
         
         
             
             
         
       
       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; 
     
       
         
         
             
             
         
       
       wherein 
       X at each occurrence independently represents hydrogen, chlorine or bromine; 
       A represents OH, OR, NR 1 R 2 , OC(O)R, OC(O)OR, C(O)OH, C(O)OR, C(O)NR 1 R 2 , OC(O)N R 1 R 2 , NHC(O)N R 1 R 2  or NHC(NH)N R 1 R 2 ; 
       R represents alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, or heterocyclalkyl; 
       R 1  and R 2  each independently represent hydrogen, alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl, or R 1  and R 2  can together form a 3 to 8 membered heterocyclic ring which may be further optionally substituted with one to four (CH 2 ) n A substituents; 
       n is a number between 0 and 5 inclusive; 
       or 
     
     
       
         
         
             
             
         
       
       wherein 
       X represents a member selected from the group consisting of the ethylene radical —CH2-CH2- and the vinylene radical —CH═CH—; 
       R represents a member selected from the group consisting of the methyl radical, the ethyl radical, the propyl radical, chlorine and bromine, 
       Y represents an alkylene radical with 2-3 carbon atoms, and 
       Am represents a member selected from the group consisting of a lower dialkylamino group, the pyrrolidinio, piperidino, piperazino, morpholino and N-methyl-piperidyl(2)-group; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
     
   
   
       2 . The method of  claim 1  comprising administering to said patient an anti-angiogenically effective amount of a compound of Formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
       R is hydrogen, hydroxy or lower alkyloxy; 
       R 1  is a member selected from the group consisting of hydrogen and lower alkyl; 
       Alk is a lower alkanediyl radical; 
       X is a member selected from the group consisting of —S—, —CH 2 — and —C(R 2 )═C(R 3 )—, said R 2  and R 3  being each independently hydrogen or lower alkyl; 
       A is a bivalent radical having the formula —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or 
     
     
       
         
         
             
             
         
       
       wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, amino and lower alkyl; and 
     
     Ar 1  and Ar 2  are each independently selected from the group consisting of pyridinyl, thienyl and phenyl, being optionally substituted with halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
   
   
       3 . The method of  claim 2  wherein Alk is an 1,2-ethanediyl radical. 
   
   
       4 . The method of  claim 2  wherein the compound of Formula (I) is Ritanserin. 
   
   
       5 . The method of  claim 1  comprising administering to said patient an anti-angiogenically effective amount of a compound of Formula (II): 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is an alkyl group containing 1 to 6 carbon atoms; 
       R 2  is selected from the group consisting of hydrogen and methyl; 
       NR 3  is a radical selected from the group consisting of a dimethylamino, diethylamino, dipropylamino, piperidino, piperazino, pyrrolidino, morpholino, and N-substituted heteroaryl; and 
       Y and Y 1  are interpedently selected from the group consisting of hydrogen, fluorine, bromine, chlorine, and iodine; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
     
   
   
       6 . The method of  claim 5  wherein the compound of Formula (II) is Amiodarone. 
   
   
       7 . 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. 
     
   
   
       8 . The method of  claim 7  wherein the compound of Formula (III) is Terfenadine. 
   
   
       9 . The method of  claim 1  comprising administering to said patient an anti-angiogenically effective amount of a compound of Formula (IV): 
     
       
         
         
             
             
         
       
       wherein 
       X at each occurrence independently represents hydrogen, chlorine or bromine; 
       A represents OH, OR, NR 1 R 2 , OC(O)R, OC(O)OR, C(O)OH, C(O)OR, C(O)NR 1 R 2 , OC(O)N R 1 R 2 , NHC(O)N R 1 R 2  or NHC(NH)N R 1 R 2 ; 
       R represents alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, or heterocyclalkyl; 
       R 1  and R 2  each independently represent hydrogen, alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl, or R 1  and R 2  can together form a 3 to 8 membered heterocyclic ring which may be further optionally substituted with one to four (CH 2 ) n A substituents; 
       n is a number between 0 and 5 inclusive; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
     
   
   
       10 . The method of  claim 9  wherein the compound of Formula (IV) is Perphenazine. 
   
   
       11 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . The method of  claim 1  comprising administering to said patient an anti-angiogenically effective amount of a compound of Formula (VI): 
     
       
         
         
             
             
         
       
       wherein 
       X represents a member selected from the group consisting of the ethylene radical —CH2-CH2- and the vinylene radical —CH═CH—; 
       R represents a member selected from the group consisting of the methyl radical, the ethyl radical, the propyl radical, chlorine and bromine, 
       Y represents an alkylene radical with 2-3 carbon atoms, and 
       Am represents a member selected from the group consisting of a lower dialkylamino group, the pyrrolidinio, piperidino, piperazino, morpholino and N-methyl-piperidyl(2)-group; 
       and salts, solvates, and prodrugs thereof. 
     
   
   
       14 . The method of  claim 13  wherein the compound of Formula (VI) is Clomipramine. 
   
   
       15 . 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 (I) 
     
       
         
         
             
             
         
       
       wherein: 
       R is hydrogen, hydroxy or lower alkyloxy; 
       R 1  is a member selected from the group consisting of hydrogen and lower alkyl; 
       Alk is a lower alkanediyl radical; 
       X is a member selected from the group consisting of —S—, —CH 2 — and —C(R 2 )═C(R 3 )—, said R 2  and R 3  being each independently hydrogen or lower alkyl; 
       A is a bivalent radical having the formula —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or 
     
     
       
         
         
             
             
         
       
       wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, amino and lower alkyl; and 
     
     Ar 1  and Ar 2  are each independently selected from the group consisting of pyridinyl, thienyl and phenyl, being optionally substituted with halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl; 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is an alkyl group containing 1 to 6 carbon atoms; 
       R 2  is selected from the group consisting of hydrogen and methyl; 
       NR 3  is a radical selected from the group consisting of a dimethylamino, diethylamino, dipropylamino, piperidino, piperazino, pyrrolidino, morpholino, and N-substituted heteroaryl; and 
       Y and Y 1  are independently selected from the group consisting of hydrogen, fluorine, bromine, chlorine, and iodine; 
     
     
       
         
         
             
             
         
       
       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; 
     
     
       
         
         
             
             
         
       
       wherein 
       X at each occurrence independently represents hydrogen, chlorine or bromine; 
       A represents OH, OR, NR 1 R 2 , OC(O)R, OC(O)OR, C(O)OH, C(O)OR, C(O)NR 1 R 2 , OC(O)N R 1 R 2 , NHC(O)N R 1 R 2  or NHC(NH)N R 1 R 2 ; 
       R represents alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, or heterocyclalkyl; 
       R 1  and R 2  each independently represent hydrogen, alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl, or R 1  and R 2  can together form a 3 to 8 membered heterocyclic ring which may be further optionally substituted with one to four (CH 2 ) n A substituents; 
     
     n is a number between 0 and 5 inclusive; 
     
       
         
         
             
             
         
       
       wherein 
       X represents a member selected from the group consisting of the ethylene radical —CH2-CH2- and the vinylene radical —CH═CH—; 
       R represents a member selected from the group consisting of the methyl radical, the ethyl radical, the propyl radical, chlorine and bromine, 
       Y represents an alkylene radical with 2-3 carbon atoms, and 
       Am represents a member selected from the group consisting of a lower dialkylamino group, the pyrrolidinio, piperidino, piperazino, morpholino and N-methyl-piperidyl(2)-group; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
     
   
   
       16 . The method of  claim 15  comprising administering to said patient an effective amount of a compound of Formula (I) 
     
       
         
         
             
             
         
       
       wherein: 
       R is hydrogen, hydroxy or lower alkyloxy; 
       R 1  is a member selected from the group consisting of hydrogen and lower alkyl; 
       Alk is a lower alkanediyl radical; 
       X is a member selected from the group consisting of —S—, —CH 2 — and —C(R 2 )═C(R 3 )—, said R 2  and R 3  being each independently hydrogen or lower alkyl; 
       A is a bivalent radical having the formula —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or 
     
     
       
         
         
             
             
         
       
       wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, amino and lower alkyl; and 
     
     Ar 1  and Ar 2  are each independently selected from the group consisting of pyridinyl, thienyl and phenyl, being optionally substituted with halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
   
   
       17 . The method of  claim 16  wherein Alk is an 1,2-ethanediyl radical. 
   
   
       18 . The method of  claim 16  wherein the compound of Formula (I) is Ritanserin. 
   
   
       19 . The method of  claim 15  comprising administering to said patient an effective amount of a compound of Formula (II): 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is an alkyl group containing 1 to 6 carbon atoms; 
       R 2  is selected from the group consisting of hydrogen and methyl; 
       NR 3  is a radical selected from the group consisting of a dimethylamino, diethylamino, dipropylamino, piperidino, piperazino, pyrrolidino, morpholino, and N-substituted heteroaryl; and 
       Y and Y 1  are independently selected from the group consisting of hydrogen, fluorine, bromine, chlorine, and iodine; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
     
   
   
       20 . The method of  claim 19  wherein the compound of Formula (II) is Amiodarone. 
   
   
       21 . The method of  claim 15  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. 
     
   
   
       22 . The method of  claim 21  wherein the compound of Formula (III) is Terfenadine. 
   
   
       23 . The method of  claim 15  comprising administering to said patient an effective amount of a compound of Formula (IV): 
     
       
         
         
             
             
         
       
       wherein 
       X at each occurrence independently represents hydrogen, chlorine or bromine; 
       A represents OH, OR, NR 1 R 2 , OC(O)R, OC(O)OR, C(O)OH, C(O)OR, C(O)NR 1 R 2 , OC(O)N R 1 R 2 , NHC(O)N R 1 R 2  or NHC(NH)N R 1 R 2 ; 
       R represents alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, or heterocyclalkyl; 
       R 1  and R 2  each independently represent hydrogen, alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl, or R 1  and R 2  can together form a 3 to 8 membered heterocyclic ring which may be further optionally substituted with one to four (CH 2 ) n A substituents; 
       n is a number between 0 and 5 inclusive; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
     
   
   
       24 . The method of  claim 23  wherein the compound of Formula (IV) is Perphenazine. 
   
   
       25 . (canceled) 
   
   
       26 . (canceled) 
   
   
       27 . The method of  claim 15  comprising administering to said patient an effective amount of a compound of Formula (VI): 
     
       
         
         
             
             
         
       
       wherein 
       X represents a member selected from the group consisting of the ethylene radical —CH 2 CH 2 — and the vinylene radical —CH═CH—; 
       R represents a member selected from the group consisting of the methyl radical, the ethyl radical, the propyl radical, chlorine and bromine, 
       Y represents an alkylene radical with 2-3 carbon atoms, and 
       Am represents a member selected from the group consisting of a lower dialkylamino group, the pyrrolidinio, piperidino, piperazino, morpholino and N-methyl-piperidyl(2)-group; and salts, solvates, and prodrugs thereof. 
     
   
   
       28 . The method of  claim 27  wherein the compound of Formula (VI) is Clomipramine. 
   
   
       29 - 44 . (canceled) 
   
   
       45 . The method of  claim 1  where the patient is in need of treatment for a disease or disorder selected from the group consisting of neoplastic diseases, restenosis, rheumatoid arthritis, Crohn's disease, diabetic retinopathy, psoriasis, endometriosis, macular degeneration, neovascular glaucoma, and adiposity.