Aryloxy phenoxy acrylic compound having hif-1 inhibition activity, method for preparing same, and pharmaceutical composition containing same as an active ingredient

Abstract

The present invention relates to a compound inhibiting HF-1 activity, a preparation method of the same, and a pharmaceutical composition comprising the same as an active ingredient. The compound of the present invention demonstrates anticancer activity not by non-selective cytotoxicity but by inhibiting the activity of HIF-1, the transcription factor playing an important role in cancer cell growth and metastasis. Accordingly, the compound or the pharmaceutically acceptable salt thereof according to the present invention inhibits HIF-1 activity, and therefore can be used as a therapeutic agent for solid tumors such as colon cancer, liver cancer, stomach cancer and breast cancer. In addition, the compound or the pharmaceutically acceptable salt thereof according to the present invention can be used as an active ingredient for a therapeutic agent for diabetic retinopathy or arthritis which may become worse when hypoxia-induced VEGF expression by HIF-1 increases.

What is claimed is: 
     
         1 . A method for treating a disease by inhibiting HIF-1 activity comprising, administering a composition comprising a therapeutically effective dose of the compound represented by Formula 1 or the pharmaceutically acceptable salt thereof to a patient in need thereof, 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is C 1-10  straight or branched alkyl, or C 8-12  bicyclic ring; 
 R 2  is —H, COOR 5 , COOR 5 R 6 , —SO 2 NH 2 , —SO 2 —(C 1-4  straight or branched alkyl), or —CONHR 7 ;
 wherein, 
 R 5  is —H, C 1-4  straight or branched alkyl, or C 1-4  alkoxy; 
 R 6  is —NH 2 , or 5-6 membered heterocycle containing one or more N or O; and 
 R 7  is —H, or —(CH 2 ) n —R 8 , 
 R 3  is —H, —OH, or —COO—(C 1-4  straight or branched alkyl); 
 
 R 4  is —H, or C 1-4  straight or branched alkyl; 
 R 8  is —H, 5-6 membered heteroaryl containing one or more N or O, or 5-6 membered heterocycle containing one or more N or O; and 
 n is an integer of 0-4. 
 
     
     
         2 . The method of  claim 1 , wherein the disease is selected from the group consisting of cancer, angiogenesis, diabetic retinopathy, rheumatoid arthritis, migration of cancer, and metastasis of cancer. 
     
     
         3 . The method of  claim 2 , wherein the cancer is selected from the group consisting of solid cancers generally caused by the accumulation of HIF-1α such as colorectal cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small bowel neoplasm, anal cancer, colon cancer, carcinoma of the fallopian tubes, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulva carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, kidney pelvic carcinoma, and CNS tumors. 
     
     
         3 . The method of  claim 3 , wherein the cancer is selected from rectal cancer, kidney cancer, melanoma, or colorectal cancer. 
     
     
         4 . The method of  claim 1 , wherein
 R 1  is C 1-10  straight or branched alkyl, or   
       
         
           
           
               
               
           
         
         R 2  is —H, COOR 5 , COOR 5 R 6 , —SO 2 NH 2 , —SO 2 CH 3 , or —CONHR 7 ; 
         R 3  is —H, —OH, or COOCH 3 ; 
         R 4  is —H, or methyl; 
         R 5  is —H, methyl, ethyl, methoxy, or ethoxy; 
         R 6  is —NH 2 , or 5-6 membered heterocycle containing one or more N or O; 
         R 7  is —H, or —(CH 2 ) n —R 8 ; 
         R 8  is —H, 5-6 membered heteroaryl containing one or more N or O, or 6 membered heterocycle containing one or more N or O; and 
         n is an integer of 0-3. 
       
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the R 2  is 
     
     
         6 . The method of  claim 1 , wherein the R 2  is —H, —COOH, —COOCH 3 , —COOCH 2 CH 3 , —COOCH 2 CH 2 OCH 3 , —CONH 2 , —SO 2 NH 2 , —SO 2 CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein the compound represented by formula 1 is selected from the group consisting of
 (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid methylester,   (E)-3-(3-(4-t-butylphenoxy)acrylamido)benzoic acid methylester,   (E)-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoic acid methylester,   (E)-3-(3-(4-adamantan-1-yl-2-methylphenoxy)acrylamido)benzoic acid methylester,   (E)-4-(3-(4-adamantan-1-yl-phenoxy)acrylamido)benzoic acid methylester,   (E)-3-(4-adamantan-1-yl-phenoxy)-N-(3-sulfamoylphenyl) acrylamide,   (E)-3-(4-adamantan-1-ylphenoxy)-N-(3-(methylsulfonyl)phenyl)acrylamide,   (E)-5-[3-(4-adamantan-1-yl-phenoxy)-acryloamino]-2-hydroxy-benzoic acid methylester,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid,   (E)-3-(3-(4-adamantan-1-yl-phenoxy)acrylamido) benzoic acid ethylester,   (E)-3-(3-(4-adamantan-1-ylphenoxy)acrylamido)benzoic acid2-methoxyethylester,   (E)-3-(3-(4-adamantan-1-yl-phenoxy)acrylamido)benzoic acid 2-(dimethylamino)ethylester,   (E) -3-(3-(4-adamantan-1-yl-phenoxy)acrylamido)benzoic acid 2-pyrrolidine-1-yl)ethylester,   (E)-3-(3-(4-adamantan-1-yl-phenoxy)acrylamido)benzoic acid morpholinoethylester,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-benzamide,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-N-isopropyl-benzamide,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-N-furan-2-ylmethyl-benzamide,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-N-(2-morpholine-4-yl-ethyl)-benzamide,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-N-(2-pyridine-4-yl-ethyl)-benzamide,   (E)-3-[3-(4-adamantan-1-yl-phenoxy)-acryloylamino]-N-(3-imidazole-1-yl-propyl)-benzamide,   (E)-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoic acid,   (E)-2-methoxyethyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate, and   (E)-2-morpholinoethyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate.