Carboline derivatives useful in the inhibition of angiogenesis

Abstract

In accordance with the present invention, compounds that inhibit the expression of VEGF post-transcriptionally have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the inhibition of VEGF production, in the treatment of solid tumor cancer, and in reducing plasma and/or tumor VEGF levels, are provided. In another aspect of the invention, methods are provided for the inhibition of VEGF production, the treatment of cancer, and the reduction of plasma and/or tumor VEGF levels, using the compounds of the invention.

1 . A method for treating a solid tumor cancer comprising administering a therapeutically effective amount of a compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, racemate or stereoisomer of said compound, to a subject having a solid tumor cancer; wherein:
 X is hydrogen; a C 1  to C 6  alkyl, optionally substituted with one or more halogens; a hydroxyl group; a halogen; a C 1  to C 5  alkoxy, optionally substituted with a C 6  to C 10  aryl group; 
 A is CH or N; 
 B is CH or N, with the proviso that at least one of A or B is N, and that when A is N, B is CH; 
 R 1  is a hydroxyl group; a C 1  to C 8  alkyl group, optionally substituted with an alkylthio group, a 5 to 10 membered heteroaryl, a C 6  to C 10  aryl group optionally substituted with at least one independently selected R o , group; a C 2  to C 8  alkenyl group; a C 2  to C 8  alkynyl group; a 3 to 12 membered heterocycle group, wherein the heterocycle group is optionally substituted with at least one independently selected halogen, oxo, amino, alkylamino, acetamino, thio, or alkylthio group; a 5 to 12 membered heteroaryl group, wherein the heteroaryl group is optionally substituted with at least one independently selected halogen, oxo, amino, alkylamino, acetamino, thio, or alkylthio group; or a C 6  to C 10  aryl group, optionally substituted with at least one independently selected R o , group; 
 R 1  is a halogen; a cyano; a nitro; a sulfonyl, wherein the sulfonyl is optionally substituted with a C 1  to C 6  alkyl or a 3 to 10 membered heterocycle; an amino group, wherein the amino group is optionally substituted with a C 1  to C 6  alkyl, —C(O)—R b , —C(O)O—R b , a sulfonyl, an alkylsulfonyl, a 3 to 10 membered heterocycle group optionally substituted with a —C(O)O—R n ; —C(O)—NH—R b ; a 5 to 6 membered heterocycle; a 5 to 6 membered heteroaryl; a C 1  to C 6  alkyl group, wherein the alkyl group is optionally substituted with at least one independently selected hydroxyl, halogen, amino, or 3 to 12 membered heterocycle group, wherein the amino group and heterocycle group are optionally substituted with at least one independently selected C 1  to C 4  alkyl group, which C 1  to C 4  alkyl group is optionally substituted with at least one independently selected C 1  to C 4  alkoxy group, amino group, alkylamino group, or 5 to 10 membered heterocycle group; a —C(O)—R n  group; or an —OR a  group; 
 R a  is hydrogen; C 2  to C 8  alkylene; a —C(O)O—R b  group; a —C(O)—NH—R b ; a C 1  to C 8  alkyl, wherein the alkyl group is optionally substituted with at least one independently selected hydroxyl, halogen, C 1  to C 4  alkoxy, amino, alkylamino, acetamide, —C(O)—R b , —C(O)O—R b , C 6  to C 10  aryl, 3 to 12 membered heterocycle, or 5 to 12 heteroaryl group, further wherein the alkylamino is optionally substituted with a hydroxyl, a C 1  to C 4  alkoxy, or a 5 to 12 membered heteroaryl optionally substituted with a C 1  to C 4  alkyl, further wherein the acetamide is optionally substituted with a C 1  to C 4  alkoxy, sulfonyl, or alkylsulfonyl, further wherein and the heterocycle group is optionally substituted with a C 1  to C 4  alkyl optionally substituted with a hydroxyl group, —C(O)—R a , —C(O)O—R n , or an oxo group; 
 R b  is hydroxyl; an amino; an alkylamino, wherein the alkylamino is optionally substituted with a hydroxyl, an amino, an alkylamino, a C 1  to C 4  alkoxy, a 3 to 12 membered heterocycle optionally substituted with at least one independently selected C 1  to C 6  alkyl, oxo, —C(O)O—R a , or a 5 to 12 membered heteroaryl optionally substituted with a C 1  to C 4  alkyl; a C 1  to C 4  alkoxy; a C 2  to C 8  alkenyl; a C 2  to C 8  alkynyl; a C 6  to C 10  aryl, wherein the aryl is optionally substituted with at least one independently selected halogen or C 1  to C 4  alkoxy; a 5 to 12 membered heteroaryl; 3 to 12 membered heterocycle group, wherein the heterocycle is optionally substituted with at least one independently selected acetamide, —C(O)O—R n , 5 to 6 membered heterocycle, or C 1  to C 6  alkyl optionally substituted with a hydroxyl, C 1  to C 4  alkoxy, amino group, or alkylamino group; or a C 1  to C 8  alkyl, wherein the alkyl is optionally substituted with at least one independently selected C 1  to C 4  alkoxy, C 6  to C 10  aryl, amino, or 3 to 12 membered heterocycle group, wherein the amino and heterocycle groups are optionally substituted with at least one independently selected C 1  to C 6  alkyl, oxo, or —C(O)O—R n  group; 
 R 2  is a hydrogen; a hydroxyl; a 5 to 10 membered heteroaryl group; a C 1  to C 8  alkyl group, wherein the alkyl group is optionally substituted with a hydroxyl, a C 1  to C 4  alkoxy, a 3 to 10 membered heterocycle, a 5 to 10 membered heteroaryl, or C 6  to C 10  aryl group; a —C(O)—R c  group; a —C(O)O—R d  group; a —C(O)—N(R d R d ) group; a —C(S)—N(R d R d ) group; a —C(S)—O—R e  group; a —S(O 2 )—R e  group; a —C(NR e )—S—R e  group; or a —C(S)—S—R f  group; 
 R c  is hydrogen; an amino, wherein the amino is optionally substituted with at least one independently selected C 1  to C 6  alkyl or C 6  to C 10  aryl group; a C 6  to C 10  aryl, wherein the aryl is optionally substituted with at least one independently selected halogen, haloalkyl, hydroxyl, C 1  to C 4  alkoxy, or C 1  to C 6  alkyl group; —C(O)—R n ; a 5 to 6 membered heterocycle, wherein the heterocycle is optionally substituted with a —C(O)—R n  group; a 5 to 6 membered heteroaryl; a thiazoleamino group; a C 1  to C 8  alkyl group, wherein the alkyl group is optionally substituted with at least one independently selected halogen, a C 1  to C 4  alkoxy, a phenyloxy, a C 6  to C 10  aryl, —C(O)—R n , —O—C(O)—R n , hydroxyl, or amino group, optionally substituted with a —C(O)O—R n  group; 
 R d  is independently hydrogen; a C 2  to C 8  alkenyl group; a C 2  to C 8  alkynyl group; a C 6  to C 10  aryl group, wherein the aryl is optionally substituted with at least one independently selected halogen, nitro, C 1  to C 6  alkyl, —C(O)O—R e , or —OR e ; or a C 1  to C 8  alkyl group, wherein the alkyl group is optionally substituted with at least one independently selected halogen, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, phenyloxy, C 6  to C 10  aryl, 5 to 6 membered heteroaryl, —C(O)—R n , —O—C(O)—R n , or hydroxyl group, wherein the C 6  to C 10  aryl group is optionally substituted with at least one independently selected halogen or haloalkyl group; 
 R e  is a hydrogen; a C 1  to C 6  alkyl group, wherein the alkyl group is optionally substituted with at least one independently selected halogen or alkoxy group; or a C 6  to C 10  aryl group, wherein the aryl group is optionally substituted with at least one independently selected halogen or alkoxy group; 
 R f  is a C 1  to C 6  alkyl group, optionally substituted with at least one independently selected halogen, hydroxyl, C 1  to C 4  alkoxy, cyano, C 6  to C 10  aryl, or —C(O)—R n  group, wherein the alkoxy group may be optionally substituted with at least one C 1  to C 4  alkoxy group and the aryl group may be optionally substituted with at least one independently selected halogen, hydroxyl, C 1  to C 4  alkoxy, cyano, or C 1  to C 6  alkyl group; 
 R n  is a hydroxyl, C 1  to C 4  alkoxy, amino, or C 1  to C 6  alkyl group; 
 R 3  is hydrogen or —C(O)—R g ; and 
 R g  is a hydroxyl group; an amino group, wherein the amino is optionally substituted with a C 6  to C 10  cycloalkyl group or a 5 to 10 membered heteroaryl group; or a 5 to 10 membered heterocycle group, wherein the heterocycle group is optionally substituted with a-C(O)—R n  group; 
 with the proviso that the compound is other than a compound wherein R 1  is phenyl, A is N, B is CH, R 3  is hydrogen and R 2  is —C(O)O-phenyl; and 
 wherein the compound inhibits VEGF production in a HT1080 solid tumor grown in a nude mouse, inhibits HT1080 solid tumor growth in a nude mouse or inhibits angiogenesis in a HT1080 solid tumor grown in a nude mouse. 
 
     
     
         2 . A method for treating a solid tumor cancer comprising administering a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, racemate or stereoisomer of said compound, to a subject having a solid tumor cancer,
 wherein the compound inhibits VEGF production in a HT1080 solid tumor grown in a nude mouse, inhibits HT1080 solid tumor growth in a nude mouse or inhibits angiogenesis in a HT1080 solid tumor grown in a nude mouse. 
 
     
     
         3 . The method of  claim 1 , where said compound has a chiral carbon at the point of attachment of R 1  and said compound is an (5) isomer at said chiral carbon. 
     
     
         4 . The method of  claim 2 , wherein said compound has a carboline scaffold and at a chiral carbon of said scaffold, said compound is an (5) enantiomer. 
     
     
         5 . The method of  claim 1 , wherein said compound is administered simultaneously or sequentially with one or more additional agents useful in the treatment of cancer. 
     
     
         6 . The method of  claim 5 , wherein said one or more additional agents useful in the treatment of cancer is selected from the group consisting of paclitaxel, fluorouracil, irinotecan, thalidomide, gemcitabine, squalamine, endostatin, angiostatin, neovastat, lenalidomide, vitaxin, 2-methoxyestradiol, carboxyamidotriazole, combretastatin A4 phosphate, 5-[1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid, sunitinib malate, rebimastat, metastat, cilengitide, ramucirumab, vatalanib, enzastaurin, aflibercept, vandetanib, halofuginone, hydrobromide, celecoxib, interferon alpha, interleukin-12, and bevacizumab. 
     
     
         7 . The method of  claim 6 , wherein said one or more additional agents are selected from bevacizumab, paclitaxel and fluorouracil. 
     
     
         8 . The method of  claim 2 , wherein said compound is administered simultaneously or sequentially with one or more additional agents useful in the treatment of cancer. 
     
     
         9 . The method of  claim 8 , wherein said one or more additional agents useful in the treatment of cancer is selected from the group consisting of paclitaxel, fluorouracil, irinotecan, thalidomide, gemcitabine, squalamine, endostatin, angiostatin, neovastat, lenalidomide, vitaxin, 2-methoxyestradiol, carboxyamidotriazole, combretastatin A4 phosphate, 5-[1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid, sunitinib malate, rebimastat, metastat, cilengitide, ramucirumab, vatalanib, enzastaurin, aflibercept, vandetanib, halofuginone, hydrobromide, celecoxib, interferon alpha, interleukin-12, and bevacizumab. 
     
     
         10 . The method of  claim 9 , wherein said one or more additional agents are selected from bevacizumab, paclitaxel and fluorouracil. 
     
     
         11 . The method of  claim 3 , wherein said compound is administered simultaneously or sequentially with one or more additional agents useful in the treatment of cancer. 
     
     
         12 . The method of  claim 11 , wherein said one or more additional agents useful in the treatment of cancer is selected from the group consisting of paclitaxel, fluorouracil, irinotecan, thalidomide, gemcitabine, squalamine, endostatin, angiostatin, neovastat, lenalidomide, vitaxin, 2-methoxyestradiol, carboxyamidotriazole, combretastatin A4 phosphate, 5-[1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid, sunitinib malate, rebimastat, metastat, cilengitide, ramucirumab, vatalanib, enzastaurin, aflibercept, vandetanib, halofuginone, hydrobromide, celecoxib, interferon alpha, interleukin-12, and bevacizumab. 
     
     
         13 . The method of  claim 12 , wherein said one or more additional agents are selected from bevacizumab, paclitaxel and fluorouracil. 
     
     
         14 . The method of  claim 4 , wherein said compound is administered simultaneously or sequentially with one or more additional agents useful in the treatment of cancer. 
     
     
         15 . The method of  claim 14 , wherein said one or more additional agents useful in the treatment of cancer is selected from the group consisting of paclitaxel, fluorouracil, irinotecan, thalidomide, gemcitabine, squalamine, endostatin, angiostatin, neovastat, lenalidomide, vitaxin, 2-methoxyestradiol, carboxyamidotriazole, combretastatin A4 phosphate, 5-[1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid, sunitinib malate, rebimastat, metastat, cilengitide, ramucirumab, vatalanib, enzastaurin, aflibercept, vandetanib, halofuginone, hydrobromide, celecoxib, interferon alpha, interleukin-12, and bevacizumab. 
     
     
         16 . The method of  claim 15 , wherein said one or more additional agents are selected from bevacizumab, paclitaxel and fluorouracil. 
     
     
         17 . The method of  claim 1 , wherein the solid tumor cancer is selected from a group consisting of a solid tumor carcinoma, a pediatric solid tumor, a Wilms tumor, a neuroblastoma, a carcinoma of the epidermis, a malignant melanoma, a cervical carcinoma, a cervical cancer, a colon carcinoma, a colon cancer, a lung carcinoma, a lung cancer, a renal carcinoma, and a solid tumor sarcoma. 
     
     
         18 . The method of  claim 2 , wherein the solid tumor cancer is selected from a group consisting of a solid tumor carcinoma, a pediatric solid tumor, a Wilms tumor, a neuroblastoma, a carcinoma of the epidermis, a malignant melanoma, a cervical carcinoma, a cervical cancer, a colon carcinoma, a colon cancer, a lung carcinoma, a lung cancer, a renal carcinoma, and a solid tumor sarcoma. 
     
     
         19 . The method of  claim 3 , wherein the solid tumor cancer is selected from a group consisting of a solid tumor carcinoma, a pediatric solid tumor, a Wilms tumor, a neuroblastoma, a carcinoma of the epidermis, a malignant melanoma, a cervical carcinoma, a cervical cancer, a colon carcinoma, a colon cancer, a lung carcinoma, a lung cancer, a renal carcinoma, and a solid tumor sarcoma. 
     
     
         20 . The method of  claim 4 , wherein the solid tumor cancer is selected from a group consisting of a solid tumor carcinoma, a pediatric solid tumor, a Wilms tumor, a neuroblastoma, a carcinoma of the epidermis, a malignant melanoma, a cervical carcinoma, a cervical cancer, a colon carcinoma, a colon cancer, a lung carcinoma, a lung cancer, a renal carcinoma, and a solid tumor sarcoma. 
     
     
         21 . The method of  claim 1 , wherein the compound has an EC 50  of less than 50 μM for inhibiting hypoxia-induced VEGF expression in cultured HeLa cells. 
     
     
         22 . The method of  claim 2 , wherein the compound has an EC 50  of less than 50 μM for inhibiting hypoxia-induced VEGF expression in cultured HeLa cells. 
     
     
         23 . The method of  claim 3 , wherein the compound has an EC 50  of less than 50 μM for inhibiting hypoxia-induced VEGF expression in cultured HeLa cells. 
     
     
         24 . The method of  claim 4 , wherein the compound has an EC 50  of less than 50 μM for inhibiting hypoxia-induced VEGF expression in cultured HeLa cells.