Novel bis-amide derivative and use thereof

Patent metadata

Field	Value
Publication number	US-2016297751-A1
Application number	US-201415021001-A
Country	US
Kind code	A1
Filing date	Sep 5, 2014
Priority date	Sep 10, 2013
Publication date	Oct 13, 2016
Grant date	—

Abstract

The present invention relates to a novel bis-amide derivative compound or a pharmaceutically acceptable salt thereof; a method of preparation thereof; and a pharmaceutical composition for preventing or treating diseases caused by hepatitis C virus infection and health functional food for preventing or ameliorating diseases caused by hepatitis C virus infection, containing the bis-amide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The novel bis-amide derivative compound of the present invention, particularly WJCPA-126, specifically binds to the catalytic site of CypA to effectively inhibit the activity of an isomerase, and the duration of the inhibitory effect can be increased because WJCPA-126 binds to CypA with high binding affinity exhibiting a low dissociation rate (K off ). Accordingly, WJCPA-126 has nontoxic and non-immunosuppressive characteristics and can effectively inhibit HCV replication in vitro and in vivo model systems. Additionally, WJCPA-126 reactivates the host interferon response through an increase in the expression of IFN-stimulated genes (ISGs) and the inhibition of interleukin-8 (IL-8) secretion. Therefore, a series of the bis-amide derivatives including WJCPA-126 can be useful as a novel type CypA inhibitor exhibiting antiviral effect.

First claim

1 . A bis-amide derivative compound of the following Formula 1 or a pharmaceutically acceptable salt thereof:

wherein:
R 1 is C 1 -C 6 linear or branched alkyl, unsubstituted or substituted cyclohexyl, or unsubstituted or substituted benzyl;
R 2 is unsubstituted or substituted aryl, in which the substituent is in multiple number and each substituent is independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, carboxy, nitro, halogen, or a 5-membered ring comprising a heteroatom formed by an interconnection between two adjacent substituents;
R 3 is unsubstituted or substituted C 1 -C 6 linear or branched alkyl, cyclohexyl, unsubstituted or substituted phenyl-C 1 -C 4 alkyl, or unsubstituted or substituted aryl, in which the substituent is in multiple number and each substituent is independently C 1 -C 4 alkoxy or halogen; and
R 4 is unsubstituted or substituted C 1 -C 6 linear or branched alkyl, unsubstituted or substituted arylalkyl with or without heteroatom(s), or unsubstituted or substituted aryl with or without heteroatom(s), in which the substituent is in multiple number and each substituent is independently C 1 -C 4 alkoxy, C 1 -C 4 alkoxybenzyl, nitro, or halogen,
wherein the substituted functional group of R 1 and R 3 includes one or more substituent(s) selected from the group consisting halogen, CN, CF 3 , hydroxy, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.

2 . The bis-amide derivative compound or a pharmaceutically acceptable salt thereof of claim 1 ,
wherein: R 1 is C 1 -C 6 linear or branched alkyl, cyclohexyl, or benzyl; R 2 is unsubstituted or substituted phenyl or naphthyl, in which the number of substituents is in the range of from 1 to 3 and each substituent is independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, carboxy, nitro, halogen, or a 5-membered ring comprising two oxygen atoms formed by an interconnection between two adjacent substituents; R 3 is unsubstituted or substituted C 1 -C 6 linear or branched alkyl, cyclohexyl, unsubstituted or substituted phenyl-C 1 -C 4 alkyl, or unsubstituted or substituted aryl, in which the number of substituents is 1 or 2 and each substituent is independently C 1 -C 4 alkoxy or halogen; and R 4 is unsubstituted or substituted C 1 -C 6 linear or branched alkyl, unsubstituted or substituted phenyl, indolyl, or nicotinyl, or unsubstituted or substituted phenylalkyl or indolylalkyl, in which the substituent is in multiple number and each substituent is independently C 1 -C 4 alkoxy, C 1 -C 4 alkoxybenzyl, nitro, or halogen.

3 . The bis-amide derivative compound or a pharmaceutically acceptable salt thereof of claim 1 ,
wherein: R 1 is n-pentyl, tert-butyl, cyclohexyl, or benzyl; R 2 is phenyl, naphthyl, 4-ethylphenyl, 6-hydroxyphenyl, 4-carboxyphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-methoxy-4-hydroxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, or benzo[1,3]dioxol-5-yl; R 3 is n-butyl, 2,2-dimethoxyethyl, cyclohexyl, phenyl, naphthyl, 4-bromophenyl, 4-fluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-isopropylphenyl, 4-methoxybenzyl, 3-methoxyphenylethyl, or 3,4-dimethoxyphenylethyl; and R 4 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, tert-butyl, chloromethyl, 1-bromopentyl, phenyl, 2-methylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2-methyl-5-nitrophenyl, 2-nitro-5-methoxy, 2-nitro-4-chlorophenyl, 6-chloronicotinyl, indol-2-yl, indol-3-ylmethyl, 1-(4-methoxybenzyl)-indol-3-yl, 3-methoxyphenylethyl, or 4-methoxyphenylethyl.

4 . The bis-amide derivative compound or a pharmaceutically acceptable salt thereof of claim 3 ,
wherein the compound of Formula 1 is selected from the group consisting of: 1) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-phenyl-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 2) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-phenyl-amino]-2-phenyl-acetamide, 3) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(4-methoxy-phenyl)-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 4) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(2-methoxy-phenyl)-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 5) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-naphthalen-1-yl-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 6) 2-[butyl-(2-1H-indol-3-yl-acetyl)-amino]-N-cyclohexyl-2-(3,4,5-trimethoxy-phenyl)-acetamide, 7) N-cyclohexyl-2-[[2-(3,4-dimethoxy-phenyl)-ethyl]-(2-1H-indol-3-yl-acetyl)-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 8) N-[cyclohexylcarbamoyl-(3,4,5-trimethoxy-phenyl)-methyl]-N-(4-isopropyl-phenyl)-benzamide, 9) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 10) 2-[(4-bromo-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-N-cyclohexyl-2-(2,3,4-trimethoxy-phenyl)-acetamide, 11) N-cyclohexyl-2-[(3,4-dimethoxy-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 12) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(4-isopropyl-phenyl)-amino]-2-(3,4,5-trimethoxy-phenyl)-acetamide, 13) N-[cyclohexylcarbamoyl-(2,3,4-trimethoxy-phenyl)-methyl]-N-(4-isopropyl-phenyl)-benzamide, 14) N-cyclohexyl-2-(3,4-dimethoxy-phenyl)-2-[(2-1H-indol-3-yl-acetyl)-(4-isopropyl-phenyl)-amino]-acetamide, 15) N-cyclohexyl-2-(3,4-dimethoxy-phenyl)-2-[3,4-dimethoxy-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-acetamide, 16) N-cyclohexyl-2-[cyclohexyl-(2-1H-indol-3-yl-acetyl)-amino]-2-(3,4-dimethoxy-phenyl)-acetamide, 17) N-cyclohexyl-2-[(2,2-dimethoxy-ethyl)-(2-1H-indol-3-yl-acetyl)-amino]-2-(3,4-dimethoxy-phenyl)-acetamide, 18) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-phenyl-amino]-2-(4-nitro-phenyl)-acetamide, 19) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(4-methoxy-benzyl)-amino]-2-(4-nitro-phenyl)-acetamide, 20) N-cyclohexyl-2-[(3,4-dimethoxy-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-2-(4-nitro-phenyl)-acetamide, 21) 2-[(4-bromo-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-N-cyclohexyl-2-(4-nitro-phenyl)-acetamide, 22) N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(4-isopropyl-phenyl)-amino]-2-(4-nitro-phenyl)-acetamide, 23) N-[cyclohexylcarbamoyl-(4-hydroxy-3-methoxy-phenyl)-methyl]-N-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-propionamide, 24) N-cyclohexyl-2-[(3,4-dimethoxy-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-2-(4-hydroxy-phenyl)-acetamide, 25) 2-bromo-hexanoic acid [cyclohexylcarbamoyl-(4-hydroxy-phenyl)-methyl]-(3,4-dimethoxy-phenyl)-amide, 26) N-[cyclohexylcarbamoyl-(4-hydroxy-phenyl)-methyl]-N-(3,4-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-propionamide, 27) 2-(4-chloro-phenyl)-N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-phenyl-amino]-acetamide, 28) N-[(4-chloro-phenyl)-cyclohexylcarbamoyl-methyl]-N-(4-isopropyl-phenyl)-benzamide, 29) N-[(4-chloro-phenyl)-cyclohexylcarbamoyl-methyl]-N-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-propionamide, 30) N-[(4-chloro-phenyl)-cyclohexylcarbamoyl-methyl]-N-(4-isopropyl-phenyl)-2,5-dimethyl-benzamide, 31) 2-[(4-bromo-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-2-(4-chloro-phenyl)-N-cyclohexyl-acetamide, 32) 2-(4-chloro-phenyl)-N-cyclohexyl-2-[(3,4-dimethoxy-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-acetamide, 33) 2-(4-chloro-phenyl)-N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(4-isopropyl-phenyl)-amino]-acetamide, 34) 2-(4-chloro-phenyl)-N-cyclohexyl-2-[(2-1H-indol-3-yl-acetyl)-(4-methoxy-phenyl)-amino]-acetamide, 35) N-[(4-chloro-phenyl)-cyclohexylcarbamoyl-methyl]-N-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propionamide, 36) 2-benzo[1,3]dioxol-5-yl-2-[butyl-(2-1H-indol-3-yl-acetyl)-amino]-N-cyclohexyl-acetamide, 37) N-cyclohexyl-2-(4-ethyl-phenyl)-2-[(2-1H-indol-3-yl-acetyl)-phenyl-amino]-acetamide, 38) 2-[(4-bromo-phenyl)-(2-1H-indol-3-yl-acetyl)-amino]-N-tert-butyl-2-(4-nitro-phenyl)-acetamide, 39) N-(4-bromo-phenyl)-N-[ter

Assignees

• Univ-Industry Coop Group Of Kyung Hee Univ

Inventors

• Kim Sung Soo
• Cho Won Jea

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D209/42

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title