Biguanide compounds and use thereof

Abstract

The present invention relates to biguanide compounds and use thereof, more particularly, to biguanide derivatives exhibiting excellent effects for inhibition of cancer cell proliferation and inhibition of cancer metastasis and recurrence, a method for preparing the same, a pharmaceutical composition containing the same as an active ingredient, and a method of prevention or treatment of cancer comprising the step of administering an effective amount of the composition to a subject in need thereof.

What is claimed is: 
     
         1 . A compound selected from the group consisting of Chemical Formula 1 to Chemical Formula 7 or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         Wherein, 
         R 1  is hydrogen, a hydroxy group, or a linear or branched C 1-6  alkyl which can be substituted by hydrogen or a hydroxy group, 
         R 2  has Chemical Formula 11 or Chemical Formula 12, or is phenoxyphenyl, biphenyl, benzodioxol, or naphthalene, 
       
       
         
           
           
               
               
           
         
         In the Chemical Formula 11, R 3  is a linear or branched C 1 -C 6  alkyl, 
         R 4  and R 5  of the Chemical Formula 11 and Chemical Formula 12, phenoxyphenyl, biphenyl, benzodioxol and naphthalene may be substituted by at least one substituent selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, amine, C 1 -C 6  alkylamine and amide, and, 
         m and n are independently an integer of 1 to 3, 
         a compound of the following Chemical Formula 2 or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         In the Chemical Formula 2, 
         R 6  is hydrogen, hydroxyl, or a linear or branched C 1 -C 6  alkyl, 
         R 7  is independently hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, C 1 -C 6  aminoalkyl, or phenoxy unsubstituted or substituted by halogen, and 
         p and q are an integer of 1 or 2, 
         a compound having Chemical Formula 3 or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         R 8  is hydrogen, or C 1 -C 6  alkyl, 
         R 9  is phenyl or benzyl, which is independently substituted by at least one selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, and C 1 -C 6  aminoalkyl, 
         a compound having Chemical Formula 4 or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         Wherein, R 10  is a substituent derived from phenyl, phenoxyphenyl, piperidine, pyridine, dihydropyridine, pyrazine, pyrrolidine, piperidine, cyclopentane, or furane, which may be substituted by at least one substituent selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, and sulfonyl, 
         R 11  is independently a phenyl, a biphenyl, or a benzyl group, which may be substituted by at least one substituent selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, and C 1 -C 6  alkoxy unsubstituted or substituted by halogen, 
         a compound having Chemical Formula 5 or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         Wherein, X is a compound of Chemical Formula 15 or Chemical Formula 16: 
       
       
         
           
           
               
               
           
         
         R 12  is pyrrolidine, piperidine, or dihydropyridine, which is independently substituted by at least one selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, and C 1 -C 6  aminoalkyl, 
         a compound having Chemical Formula 6 and a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         Wherein, R 13  is at least one selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl which may be unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, and C 1 -C 6  aminoalkyl, and 
         a compound having Chemical Formula 7 or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         Wherein, R 14  is independently selected from hydrogen, halogen, C 1 -C 6  alkyl unsubstituted or substituted by halogen, C 1 -C 6  alkoxy unsubstituted or substituted by halogen, C 1 -C 6  thioalkyl unsubstituted or substituted by halogen, and C 1 -C 6  aminoalkyl, and 
         r is an integer of 1 to 3. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of:
 N1-pyrrolidine-N5-(benzo[1,3]dioxol-5-ylmethyl) biguanide,   N1-pyrrolidine-N5-(4-methoxy)phenyl biguanide,   N1-pyrrolidine-N5-(3-chloro-4-methoxy)phenyl biguanide,   N1-pyrrolidine-N5-(2,6-difluorophenyl)-N-methyl)phenyl biguanide,   N1-pyrrolidine-N5-(4-dimethylamino)phenyl biguanide,   N1-pyrrolidine-N5-(4-isopropyl)phenyl biguanide,   N1-pyrrolidine-N5-(3-phenoxy)phenyl biguanide,   N1-pyrrolidine-N5-(N-biphenyl-3-yl) biguanide,   N1-pyrrolidine-N5-(N-biphenyl-4-yl) biguanide,   N1-pyrrolidine-N5-(4′-fluorobiphenyl-3-yl) biguanide,   N1-pyrrolidine-N5-(3′-fluorobiphenyl-4-yl) biguanide,   N1-pyrrolidine-N5-(4-fluoro)phenethyl biguanide,   N1-pyrrolidine-N5-(2-phenylpropane-2-yl) biguanide,   N1-pyrrolidine-N5-(5,6,7,8-tetrahydronaphthalene-2-yl) biguanide,   N1-pyrrolidine-N5-((1,2,3,4-tetrahydronaphthalene-1-yl) biguanide,   N1-(S)-2-methyl pyrrolidine-N5-(4-(trifluoromethoxy)phenyl biguanide,   N1-(S)-3-hydroxy pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-(R)-3-hydroxy pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-3-hydroxy methyl pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-pyrrolidine-N5-4-benzamide biguanide,   N1-pyrrolidine-N5-4-methyl-N-ethyl benzamide biguanide,   N1-pyrrolidine-N5-4-(2-oxo-2-(piperidine-1-yl)ethyl thio)phenyl, and   N1-(S)-2-hydroxy pyrrolidine-N5-4-(2-oxo-2-(piperidine-1-yl)ethyl thio)phenyl biguanide.   
     
     
         3 . The compound according to  claim 1 , wherein the compound of Chemical Formula 2 is selected from the group consisting of:
 N1-4-hydroxy piperidine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-4-hydroxy piperidine-N5-(4-phenoxyphenyl)phenyl biguanide,   N1-4-hydroxy piperidine-N5-(3-phenoxyphenyl)phenyl biguanide,   N1-(2R,6S)-2,6-dimethylpiperidin-2-ylmethyl-N5-(4-(2-aminoethyl)phenyl biguanide,   N1-2-methyl piperidine-N5-(4-(2-aminoethyl)phenyl biguanide,   N1-3,5-dimethyl piperidine-N5-(4-(2-aminoethyl)phenyl biguanide, and   N1-3-methyl piperidine-N5-(4-(2-aminoethyl)phenyl biguanide.   
     
     
         4 . The compound according to  claim 1 , wherein the compound of Chemical Formula 3 is selected from the group consisting of:
 N1-4-methyl piperazine-N5-(4-bromo)phenyl biguanide,   N1-4-methyl piperazine-N5-(3-bromo)phenyl biguanide,   N1-4-methyl piperazine-N5-(2-bromo)phenyl biguanide,   N1-4-methyl piperazine-N5-(3-bromo)benzyl biguanide,   N1-4-methyl piperazine-N5-(4-fluoro-3-trifluoromethyl)phenyl biguanide,   N1-4-methyl piperazine-N5-(3-chloro-4-trifluoromethoxy)phenyl biguanide,   N1-4-methyl piperazine-N5-(3-chloro-4-trifluoromethoxy)phenyl biguanide,   N1-4-methyl piperazine-N5-(4-chloro-3-trifluoromethyl)phenyl biguanide,   N1-4-methyl piperazine-N5-(4-chloro-3-trifluoromethoxy)phenyl biguanide,   N1-4-methyl piperazine-N5-(4-fluoro-3-trifluoromethoxy)phenyl biguanide,   N1-4-methyl piperazine-N5-(4-fluoro-3-trifluoromethyl)benzyl biguanide,   N1-4-methyl piperazine-N5-(3-fluoro-4-trifluoromethyl)benzyl biguanide,   N1-4-methyl piperazine-N5-(3-fluoro-4-trifluoromethoxy)benzyl biguanide,   N1-4-methyl piperazine-N5-(3-fluoro-4-trifluoromethyl)phenyl biguanide, and   N1-4-ethyl piperazine-N5-(4-trifluoromethoxy)phenyl biguanide.   
     
     
         5 . The compound according to  claim 1 , wherein the compound of Chemical Formula 4 is selected from the group consisting of:
 N1-3-pyridine-N5-(4-trifluoromethyl)phenyl biguanide,   N1-3-pyridine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-3-pyridine-N5-(4-trifluoromethyl)benzyl biguanide,   N1-3-pyridine-N5-(4-fluoro-3-trifluoromethyl)phenyl biguanide,   N1-2-pyrazine-N5-(4-trifluoromethoxy)phenyl biguanide   N1-2-pyrazine-N5-(4-trifluoromethyl)phenyl biguanide,   N1-cyclopentyl-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-cyclopentyl-N5-(4-fluoro)phenyl biguanide,   N1-furane-2-ylmethyl-N5-(4-chloro)phenyl biguanide,   N1-furane-2-ylmethyl-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-furane-2-ylmethyl-N5-(4-trifluoromethyl)phenyl biguanide,   N1-dihydropyridine-N5-(4-(2-aminoethyl)phenyl biguanide,   N1-phenyl-N5-(3-trifluoromethyl)benzyl biguanide,   N1-4-trifluoromethoxy phenyl-N5-(N-biphenyl-4-yl) biguanide,   N1-3,3-difluoro pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-3,3-difluoro piperidine-N5-(4-trifluoromethoxy)phenyl biguanide,   N1-4-(methylsulfonyl) piperidine-N5-(4-trifluoromethoxy)phenyl biguanide, and   N1-3-phenoxyphenyl-N5-(4-trifluoromethoxy)phenyl biguanide.   
     
     
         6 . The compound according to  claim 1 , wherein the compound of Chemical Formula 5 is selected from the group consisting of:
 N-(4-(3-(imino(pyrrolidine-1-yl)methyl)guanidino)phenethyl)-5-(2-oxohexahydro-1H-thieno[2,3-d]imidazol-5-yl)pentanamide,   N-(4-(3-(imino(2-methylpiperidin-1-yl)methyl)guanidino)phenethyl)-5-(2-oxohexahydro-1H-thieno[2,3-d]imidazol-5-yl)pentanamide,   N-(4-(3-((3,5-dimethylpiperidin-1-yl)(imino)methyl)guanidino)phenethyl)-5-(2-oxohexahydro-1H-thieno[2,3-d]imidazol-5-yl)pentanamide,   N-(4-(3-((5,6-dihydropyridin-1 (2H)-yl)(imino)methyl)guanidino) phenethyl)-5-(2-oxohexahydro-1H-thieno[2,3-d]imidazol-5-yl)pentanamide,   N-(4-(3-(((2R,6S)-2,6-dimethylpiperidin-1-yl)(imino)methyl) guanidino)phenethyl)-5-(2-oxohexahydro-1H-thieno[2,3-d]imidazol-5-yl) pentanamide,   N-(4-(3-(imino(pyrrolidin-1-yl)methyl)guanidino)phenyl)-5-(2-oxohexahydro-1H-thieno[2,3-d]imidazol-5-yl)pentanamide,   2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-(3-(imino(pyrrolidin-1-yl)methyl)guanidino)benzyl)benzamide,   N-(4-(3-(((2R,6S)-2,6-dimethylpiperidin-1-yl)(imino)methyl) guanidino)benzyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzamide,   N-(4-(3-((3,5-dimethylpiperidin-1-yl)(imino)methyl)guanidino)benzyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzamide, and   2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-(3-(imino(3-methylpiperidin-1-yl)methyl)guanidino)benzyl)benzamide.   
     
     
         7 . The compound according to  claim 1 , wherein the compound of the Chemical Formula 6 is selected from the group consisting of:
 N-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)pyrrolidine-carboximidamide,   N-(5-fluoro-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboximidamide,   N-(5-methyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboximidamide,   N-(5-methoxy-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboximidamide, and   N-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboximidamide.   
     
     
         8 . The compound according to  claim 1 , wherein the compound of Chemical Formula 6 is selected from the group consisting of:
 N5-(2,4-(dichloro)phenyl biguanide   N5-4-fluorophenyl biguanide   N5-(3,4-(dichloro)phenyl biguanide   N5-(2-chloro-5-trifluoromethyl)phenyl biguanide   N5-(3-chloro-4-fluoro)phenyl biguanide   N5-(2-chloro-3-chloro)phenyl biguanide   N5-(4-trifluoromethylthio)phenyl biguanide, and   N1,N1-dimethyl-N5-4-(2-oxo-2-(piperidin-1-yl)ethylthio)phenyl biguanide.   
     
     
         9 . A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:
 N1-pyrrolidine-N5-4-(3-oxo-3-(piperidin-1-yl)propenyl) biguanide,   N1-pyrrolidine-N5-4-(piperidin-1-carbonyl)benzyl biguanide,   N1-pyrrolidine-N5-4-(3-oxo-3-(piperidin-1-yl)propyl)phenyl,   N—(N-(4-(trifluoromethoxy)phenyl)carbamimidoyl)-3,4-dihydroisoquinolin-2(1H)-carboximidamide,   N—(N-(4-(trifluoromethoxy)phenyl)carbamimidoyl)indoline-1-carboximidamide,   N-(imino(pyrrolidin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-carboximidamide,   N—(N-(4-phenoxyphenyl)carbamimidoyl)indoline-1-carboximidamide, and   N—(N-(3-phenoxyphenyl)carbamimidoyl)indoline-1-carboximidamide.   
     
     
         10 . The compound according to  claim 1  or  9 , wherein the pharmaceutically acceptable salt is a salt of acid selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, triflouroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid. 
     
     
         11 . A pharmaceutical composition comprising the compound according to  claim 1  or  9  or a pharmaceutical salt thereof as an active ingredient. 
     
     
         12 . A method of prevention or treatment of cancer comprising the step of administering an effective amount of the compound according to  claim 1  or  9  or a pharmaceutically acceptable salt thereof to a subject in need thereof. 
     
     
         13 . The method according to  claim 12 , wherein the cancer is selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer and liver cancer 
     
     
         14 . The method according to  claim 12 , wherein the compound or a pharmaceutically acceptable salt thereof is formulated in the form of tablets, capsules, pills, granule, powder, injections or liquid.