Benzidine derivative, method for preparing same, and pharmaceutical composition containing benzidine derivative for treating liver disease caused by hepatitis C virus

Patent metadata

Field	Value
Publication number	US-9598362-B2
Application number	US-201514884356-A
Country	US
Kind code	B2
Filing date	Oct 15, 2015
Priority date	Apr 26, 2013
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The disclosed compounds have antiviral activity against C-type virus, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating liver disease caused by hepatitis C virus. The benzidine derivative according to the present invention has excellent antiviral activity against hepatitis C virus and exhibits excellent medicinal activity in the living body, and thus the pharmaceutical composition containing the same as an active ingredient can be useful as a pharmaceutical composition for preventing or treating liver disease, such as acute hepatitis C, chronic hepatitis C, cirrhosis, or hepatocellular carcinoma, caused by C-type virus.

First claim

What is claimed is:

1. A compound represented by the following formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

wherein, R 1 and R 2 are independently —H, —OH, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, unsubstituted or substituted C 6-10 aryl, —NR 12 R 13 , or —NHC(═O)R 14 , wherein the said substituted C 6-10 aryl is substituted with one or more substituents selected from the group consisting of C 1-5 straight or branched alkyl, C 1-5 straight or branched alkoxy, and halogen, or R 1 and R 2 form a C 5-10 heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O and S along with carbon atoms which are conjugated to the same;
R 12 and R 13 are —H, or C 1-5 straight or branched alkyl;
R 14 is —H, or C 1-5 straight or branched alkoxy;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently —H, halogen, or unsubstituted or substituted C 1-5 straight or branched alkyl in which one or more halogens are substituted,
wherein, R 4 and R 7 , or R 6 and R 9 can form a C 5-6 ring along with carbon atoms which are conjugated to the same, and the C 5-6 ring can contain one or more substituents selected from the group consisting of halogen, C 1-5 straight or branched alkyl, and ═O;
X is —O—, —S—, or —CH 2 —;
R 11 is —H, —OH, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkyl alkoxy, or ═O;
is single bond or double bond; and
a is an integer of 0-3.

2. The compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 1 and R 2 are independently —H, —OH, halogen, C 1-5 straight or branched alkyl, C 1-5 straight or branched alkoxy, unsubstituted or substituted C 6-8 aryl, —NR 12 R 13 , or —NHC(═O)R 14 , wherein the said substituted C 6-8 aryl is substituted with one or more substituents selected from the group consisting of C 1-5 straight or branched alkyl, C 1-5 straight or branched alkoxy, and halogen, or R 1 and R 2 form a C 5-8 heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O and S along with carbon atoms which are conjugated to the same;
R 12 and R 13 are —H, or C 1-3 straight or branched alkyl;
R 14 is —H, or C 1-3 straight or branched alkoxy;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently —H, halogen, or unsubstituted or substituted C 1-5 straight or branched alkyl in which one or more halogens are substituted,
wherein, R 4 and R 7 , or R 6 and R 9 can form a C 5-6 ring along with carbon atoms which are conjugated to the same, and the C 5-6 ring can contain one or more substituents selected from the group consisting of halogen, C 1-5 straight or branched alkyl, and ═O;
X is —S—, or —CH 2 —;
R 11 is —H, —OH, C 1-5 straight or branched alkyl, C 1-5 straight or branched alkyl alkoxy, or ═O;
is single bond or double bond;
a is an integer of 0-2.

3. The compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 1 and R 2 are independently methyl, isopropyl, tert-butyl, phenyl, dimethylamino, diethylamino, or methoxycarbonylamino, or R 1 and R 2 form tetrahydrofuran along with carbon atoms which are conjugated to the same;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently —H, —F, —Cl, —Br, —CF 3 , or methyl,
wherein, R 4 and R 7 , or R 6 and R 9 can form C 5 ring along with carbon atoms which are conjugated to the same, and the C 5 ring can contain one or more substituents selected from the group consisting of —F, ═O, and methyl;
X is —S—, or —CH 2 —;
R 11 is —H, or ═O;
is single bond or double bond; and
a is an integer of 0-1.

4. The compound represented by formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound represented by formula 1 is selected from the group consisting of the below compounds:
(1) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((3,3′-dimethyl-[1,1′-biphenyl]-4,4′-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(2) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-4,4′-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(3) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((2,2′-dimethyl-[1,1′-biphenyl]-4,4′-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(4) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((9H-fluorene-2,7-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(5) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((2,2′-difluoro-[1,1′-biphenyl]-4,4′-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(6) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((2,2′-dichloro-[1,1′-biphenyl]-4,4′-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(7) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((2,2′-dibromo-[1,1′-biphenyl]-4,4′-diyl)bis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(8) dimethyl ((1R,1′R)-((2R,2′R)-2,2′-(([1,1′-biphenyl]-4,4′-diylbis(azandiyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(9) dimethyl ((1R,1′R)-((5S,5'S)-5,5′-(([1,1′-biphenyl]-4,4′-diylbis(azandiyl))bis(carbonyl))bis(3-oxopyrrolidine-5,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(10) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(([1,1′-biphenyl]-4,4′-diylbis(azandiyl))bis(carbonyl))bis(piperidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(11) dimethyl ((1R,1′R)-((2R,2′R)-2,2′-(([1,1′-biphenyl]-4,4′-diylbis(azandiyl))bis(carbonyl))bis(piperidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(12) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(([1,1′-biphenyl]-4,4′-diylbis(azandiyl))bis(carbonyl))bis(2-methylpyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate;
(13) dimethyl (2R,2′R)-1,1′-((2S, 2′S)-2,2′-(biphenyl-4,4′-diylbis(azandiyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate;
(14) (S,2S,2′S)—N,N′-(biphenyl-4,4′-diyl)bis(1-((S)-2-(dimethylamino)-2-phenylacetyl)pyrrolidine-2-carboxamide);
(15) (S,2S,2′S)—N,N′-(biphenyl-4,4′-diyl)bis(1-((S)-2-(diethylamino)-2-phenylacetyl)pyrrolidine-2-carboxamide);
(16) dimethyl (1S,1'S)-2,2′-((2S, 2S′)-2,2′-(biphenyl-4,4′-diylbis(azandiyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate;
(17) (R,2S,2′S)—N,N′-(biphenyl-4,4′-diyl)bis(1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide;
(18) dimethyl (2S, 2′S)-1,1′-((2S,2R′)-2,2′-(biphenyl-4,4′-diylbis(azandiyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(1-oxopropane-2,1-diyl)dicarbamate;
(19) dimethyl (2S,2S′)-1,1′-((2S,2R′)-2,2′-(biphenyl-4,4′-diylbis(azandiyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate;
(20) dimethyl (2S,2′S)-1,1′-((2S, 2′R)-2,2′-(biphenyl-4,4′-diylbis(azandiyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate;
(21) dimethyl (1S,1S′)-2,2′-((4R,4′R)-4,4′-(biphenyl-4,4′-diylbis(azandiyl))bis(oxomethylene)bis(thiazolidine-4,3-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)bicarbamate;
(22) dimethyl ((1R,1′R)-((2S,2′S)-2,2′-(((9,9-difluoro-9H-fluorene-2,7-diyl)bis(azandiyl))bis(carb

Assignees

• Univ Seoul Nat R & Db Found
• Postech Academy-Industry Found

Inventors

• Jang Sung Key
• Kim Byeong Moon
• Bae Il Hak
• Choi Jin Kyu
• Keum Sun Ju
• Lee Seung Gi
• Kim Hee Sun

Classifications

• C07D277/06

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

• C07D207/16 Primary

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

• C07D211/60

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

• C07D207/24

  Oxygen or sulfur atoms · CPC title

• A23L33/10

  using additives (addition of substantially indigestible substances A23L33/21) · CPC title