Oxazolidinone derivatives and composition for preventing or treating hepatitis C containing the same

Patent metadata

Field	Value
Publication number	US-9422274-B2
Application number	US-201414539472-A
Country	US
Kind code	B2
Filing date	Nov 12, 2014
Priority date	Nov 15, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The present invention relates to oxazolidinone compounds represented by Chemical Formula 1, pharmaceutically acceptable salts thereof or hydrates, a method of preparing the same, and a pharmaceutical composition for preventing or treating Hepatitis C infection:

Wherein R 1 , R 7 and X are defined in the detailed description.

First claim

What is claimed is:

1. An oxazolidinone compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate:

wherein, in Formula 1,
R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
R 3 is C 1 -C 6 alkyl or C 6 -C 10 aryl,
R 4 is C 1 -C 6 alkyl,
R 7 is

R 2 is H, (CH 2 ) n WR 5 or C 6 -C 10 aryl,
n is an integer of 0, 1, 2, 3 or 4,
R 5 is H, C 1 -C 6 alkyl, benzyl, or C 1 -C 6 alkyl carbonyl,
R 6 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
W is oxygen or —NH, and
X is H or F.

2. The oxazolidinone compound, a pharmaceutically acceptable salt thereof, or a hydrate according to claim 1 , wherein the oxazolidinone compound is represented by Formula 2:

wherein, in Formula 2,
R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
R 2 is H, (CH 2 ) n WR 5 or C 6 -C 10 aryl,
n is an integer 0, 1, 2, 3, or 4,
R 3 is C 1 -C 6 alkyl or C 6 -C 10 aryl,
R 4 is C 1 -C 6 alkyl,
R 5 is H, C 1 -C 6 alkyl, benzyl, or C 1 -C 6 alkyl carbonyl,
W is oxygen or —NH, and
X is H or F.

3. The oxazolidinone compound, a pharmaceutically acceptable salt thereof, or a hydrate according to claim 2 , wherein, in Formula 2,
R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
R 2 is H, (CH 2 ) n WR 5 or phenyl,
n is an integer of 1 to 3,
R 3 is isopropyl or phenyl,
R 5 is H, C 1 -C 6 alkyl, benzyl, or C 1 -C 6 alkyl carbonyl,
W is oxygen or —NH, and
X is H or F.

4. The oxazolidinone compound, a pharmaceutically acceptable salt thereof, or a hydrate according to claim 1 , wherein the oxazolidinone compound is represented by Formula 3:

wherein in Formula 3,
R 1 and R 6 are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
R 3 is C 1 -C 6 alkyl or C 6 -C 10 aryl,
R 4 is C 1 -C 6 alkyl, and
X is H or F.

5. The oxazolidinone compound, a pharmaceutically acceptable salt thereof, or a hydrate according to claim 4 , wherein, in Formula 3,
R 1 and R 6 are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
R 3 is isopropyl or phenyl,
R 4 is C 1 -C 6 alkyl, and
X is H or F.

6. The oxazolidinone compound, a pharmaceutically acceptable salt thereof, or a hydrate according to claim 1 , wherein the oxazolidinone compound is selected from the group consisting of:
tert-butyl (S)-2-(5-(4′-((R)-5-((1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-carboxylate;
(R)-5-((1H-1,2,3-triazole-1-yl)methyl)-3-(4′-(2-((S)-1-acetylpyrrolidine-2-yl)-1H-imidazole-5-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)oxazolidine-2-one;
methyl ((S)-1-((S)-2-(5-(4′-((R)-5-((1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
methyl ((S)-2-((S)-2-(5-(4′-((R)-5-((1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-2-oxo-1-phenylethyl)carbamate;
methyl ((S)-1-((S)-2-(5-(2′-fluoro-4′-((R)-5-((4-(hydroxymethyl)-1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
methyl ((S)-1-((S)-2-(5-(2′-fluoro-4′-((R)-5-((4-(2-hydroxyethyl)-1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
methyl ((S)-1-((S)-2-(5-(2′-fluoro-4′-((R)-5-((4-(methoxymethyl)-1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
(1-(((R)-3-(2-fluoro-4′-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidine-2-yl)-1H-imidazole-5-yl)-[1,1′-biphenyl]-4-yl)-2-oxooxazolidine-5-yl)methyl)-H-1,2,3-triazole-4-yl)methyl acetate;
methyl((S)-1-((S)-2-(5-(4′-((R)-5-((4-((benzyloxy)methyl)-1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
methyl((S)-1-((S)-2-(5-(4′-((R)-5-((4-(acetamidomethyl)-1H-1,2,3-triazole-1-yl)methyl)-2-oxoxazolidin-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
methyl((S)-1-((S)-2-(5-(2′-fluoro-4′-((R)-2-oxo-5-((4-phenyl-H-1,2,3-triazole-1-yl)methyl)oxazolidine-3-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
methyl((S)-1-((S)-2-(5-(4′-((S)-5-(acetamidomethyl)-2-oxazolidine-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate;
tert-butyl(S)-2-(5-(4′-((S)-5-(acetamidomethyl)-2-oxoxazolidin-3-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-carboxylate;
N—(((S)-3-(4′-(2-((S)-1-acetylpyrrolidine-2-yl)-1H-imidazole-5-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)-2-oxooxazolidine-5-yl)methyl)acetamide;
methyl ((S)-1-((((S)-3-(2-fluoro-4′-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidine-2-yl)-1H-imidazole-5-yl)-[1,1′-biphenyl]-4-yl)-2-oxooxazolidine-5-yl)methyl)amino)-3-methyl-1-oxobutane-2-yl)carbamate;
tert-butyl (S)-2-(5-(2′-fluoro-4′-((S)-5-(((S)-2-((methoxycarbonyl)amino)-3-methylbutanamido)methyl)-2-oxoxazolidin-3-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazole-2-yl)pyrrolidine-1-carboxylate; and
methyl((S)-1-((((S)-3-(4′-(2-((S)-1-acetylpyrrolidine-2-yl)-1H-imidazole-5-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)-2-oxooxazolidine-5-yl)methyl)amino)-3-methyl-1-oxobutane-2-yl)carbamate.

7. The oxazolidinone compound, a pharmaceutically acceptable salt thereof, or a hydrate according to claim 1 , wherein the pharmaceutically acceptable salt is a salt of organic acid or inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, a phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, a mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzene sulfonic acid and toluene sulfonic acid.

8. A method of preparing an oxazolidinone compound represented by Formula 2, or a pharmaceutically acceptable salt thereof, comprising a step of reacting the compound of Formula 4 and the compound of Formula 5:

wherein, in Formula 2,
R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —CH(R 3 )NHCO 2 R 4 ,
R 2 is H, (CH 2 ) n WR 5 or C 6 -C 10 aryl,
n is an integer 0, 1, 2, 3 or 4,
R 3 is C 1 -C 6 alkyl or C 6 -C 10 aryl,
R 4 is C 1 -C 6 alkyl,
R 5 is H, C 1 -C 6 alkyl, benzyl, or C 1 -C 6 alkyl carbonyl,
W is oxygen or —NH, and
X is H or F,

wherein Formula 4,
R 1 is C

Assignees

• Jang Sung Key
• Keum Gyo Chang
• Kim Eunice Eun-Kyeong
• Kang Soon Bang
• Yeom Suyeon
• Lee Juhyeon
• Lee SeungGi
• Kim Hee Sun
• Korea Inst Sci & Tech

Inventors

• Jang Sung Key
• Keum Gyo Chang
• Kim Eunice Eun-Kyeong
• Kang Soon Bang
• Yeom Suyeon
• Lee Juhyeon
• Lee SeungGi
• Kim Hee Sun

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/421

  1,3-Oxazoles, e.g. pemoline, trimethadione · CPC title