2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivatives and use thereof

Patent metadata

Field	Value
Publication number	US-9932355-B2
Application number	US-201514698073-A
Country	US
Kind code	B2
Filing date	Apr 28, 2015
Priority date	Apr 29, 2014
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

Provided are a pharmaceutical composition containing a 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative represented by Formula 1 as an active ingredient and a use thereof effective on a vascular inflammation-related infectious disease triggered by activity of HMGB1 protein.
As investigating an anti-sepsis effect through a CLP-induced sepsis animal test that a sepsis survival rate is increased, it is identified that the pharmaceutical composition contains the 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative or a pharmaceutically available salt thereof as an active ingredient to be used as a therapeutic agent for a vascular inflammatory disease and infectious disease including sepsis triggered by activity of HMGB1 protein.

First claim

What is claimed is:

1. A method of inhibiting activity of HMGB1 protein, comprising:
contacting HMGB1 protein with a 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative represented by Formula 1 or a pharmaceutically available salt thereof,

where R 1 is a five to seven-membered substituted or unsubstituted aromatic group to which carbon, oxygen, nitrogen or sulfur is added, in which the aromatic group is a heteroaryl group, a phenyl group or a substituted phenyl group, here, the substituent is one to four substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 10 linear or branched alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, C 1 -C 10 alkylthio, C 1 -C 10 alkyl carbonyl and a C 1 -C 10 alkoxy carbonyl group,
R 2 and R 3 are hydrogen, a C 1 -C 10 linear, branched or cyclic alkyl group, a cyclic C 1 -C 10 alkyl group including a heteroelement (—S— or —O—) or heteroalkyl group, or a C 1 -C 10 linear or branched carbonyl group, which are independently or identically substituted,
R 4 is an amino group substituted by one or at least two C 1 -C 10 linear, branched or cyclic alkyl groups, C 5 -C 10 aryl groups, C 5 -C 10 heteroaryl groups or substituted heteroaryl groups, C 5 -C 10 arylalkyl groups, a benzyl group, a substituted benzyl group or C 5 -C 10 heteroarylalkyl groups, or a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a C 1 -C 10 linear, branched or cyclic alkyl group, or an amine group having a piperazine

substituted by phenyl or a heteroarylamide group, or C 3 -C 10 cyclic amine groups, or C 3 -C 10 cyclic amine groups containing at least one heteroatom selected from the group consisting of N, O, and S, here, the substituent is one to three substituents selected from the group consisting of a halogen atom, a nitro group, a C 1 -C 10 alkyl group, a C 1 -C 10 alkoxy group, a C 1 -C 10 haloalkyl group and a C 1 -C 10 haloalkoxy group.

2. A method of inhibiting activity of HMGB1 protein, comprising:
contacting HMGB1 protein with a 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative represented by Formula 1 or a pharmaceutically available salt thereof,

wherein, in Formula 1, R 1 is a five to seven-membered substituted or unsubstituted aromatic group to which carbon, oxygen, nitrogen or sulfur is added, in which the aromatic group is a furanyl group, a thiophenyl group, a phenyl group, a thiazole group, an indole group, an isoindole group, a pyridinyl group, a piperazinyl group, a pyridazinyl group, a naphthyl group, a quinolinyl group, or an isoquinolinyl group, here, the substituent includes one to three substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6 linear or branched alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkyl carbonyl and a C 1 -C 6 alkoxy carbonyl group,
R 2 and R 3 are hydrogen, a C 1 -C 6 linear, branched or cyclic alkyl group, a cyclic C 1 -C 6 alkyl group including a heteroelement (—NH—, —S—, —O—) or heteroalkyl group, or a C 1 -C 6 linear or branched carbonyl group, which are independently or identically substituted, and
R 4 is an amino group substituted by one or at least two C 1 -C 6 linear, branched or cyclic alkyl groups, C 5 -C 6 aryl groups, C 5 -C 6 heteroaryl groups or substituted heteroaryl groups, C 5 -C 6 arylalkyl groups, a benzyl group, a substituted benzyl group or C 5 -C 6 heteroarylalkyl groups, or a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a C 1 -C 6 linear, branched or cyclic alkyl group, or an amine group having a piperazine

substituted by phenyl or a heteroarylamide group, or a C 3 -C 6 cyclic amine group, or a C 3 -C 6 cyclic amine groups containing at least one heteroatom selected from the group consisting of N, O, and S, here, the substituent is one to three substituents selected from the group consisting of a halogen atom, a nitro group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 haloalkyl group and a C 1 -C 6 haloalkoxy group.

3. The method according to claim 2 , wherein, in Formula 1, R 1 is a phenyl group, a substituted phenyl group, an aryl group, or a substituted aryl group, in which the aryl group is a furanyl group, a thiophenyl group, a thiazole group, an indole group, an isoindole group, a pyridinyl group, a piperazinyl group, a pyridazinyl group, a naphthyl group, a quinolinyl group, an isoquinolinyl group, here, the substituent includes one to three substituents selected from the group consisting of hydrogen, chloro, fluoro, a hydroxyl group, a cyano group, a nitro group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a t-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a thiomethoxy group, a thioethoxy group, a thio n-propoxy group, a thio isopropoxy group, a trifluoromethoxy group, a trifluoromethyl group, a methylester group, and an ethylester group,
R 2 and R 3 are independently hydrogen, methyl, ethyl, n-propyl, butyl, an isopropyl group, or identically cyclopentyl, cyclohexyl, cycloheptyl, cyclopentanone, cyclohexanone, cycloheptanone, tetrahydropyran, tetrahydrothiopyran or piperidine, and
R 4 is an amino group substituted by one or at least two C 1 -C 6 linear, branched or cyclic alkyl groups, C 5 -C 6 aryl groups, C 5 -C 6 heteroaryl groups or substituted heteroaryl groups, C 5 -C 6 arylalkyl groups, a benzyl group or C 5 -C 6 heteroarylalkyl groups, or a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a C 1 -C 10 linear, branched or cyclic alkyl group, or a C 3 -C 6 cyclic amine group, or a C 3 -C 6 cyclic amine groups containing at least one heteroatom selected from the group consisting of N, O, and S, here, the substituent is one to three substituents selected from the group consisting of a halogen atom, a nitro group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 3 haloalkyl group and a C 1 -C 3 haloalkoxy group.

Assignees

• Kyungpook Nat Univ Ind Academic Coop Found

Inventors

• Lee Taeho
• Bae Jong-Sup
• Song Kyung-Sik
• Lee Sangkyu
• Liu Kwang-Hyeon
• Lee Wonhwa
• Lee Doohyun

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/429

  condensed with heterocyclic ring systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title