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4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors

A kind of technology of oxoquinoline, compound

Active Publication Date: 2005-11-02
JAPAN TOBACCO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, no effective integrase inhibitors have been found so far

Method used

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  • 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors
  • 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors
  • 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors

Examples

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specific example

[0372] Specific examples thereof include 2-fluoroethyl, 2-chloroethyl, 2-bromomethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl, trifluoromethyl , 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl, 2,2,2-trifluoro-1- Trifluoromethyl-ethyl etc.

[0373] as R 31 , R 4 , R 5 , R 6 , R 6′ , R 6″ , R 6 And group A, preferably trifluoromethyl.

[0374] "C 1-4 Alkoxy" is "C" in which the alkyl moiety is defined above 1-4 The alkoxy group of "alkyl", its specific examples are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

[0375] for R 31 , preferably methoxy.

[0376] "C 1-4 Alkylthio" is "C" in which the alkyl moiety is defined above 1-4 An alkylthio group of "alkyl". Specific examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio and the like.

[0377] for R 31 , preferably methylthio.

[0378] "Halo C 1-4 Alkoxy" i...

reference example 1

[0594] Preparation of 2,3-Dichlorobenzylzinc Chloride in THF

[0595]

[0596] To a suspension of zinc powder (55.1 g, 843 mmol) in tetrahydrofuran (THF; 56 ml) was added 1,2-dibromoethane (2.9 ml, 33.8 mmol) under argon flow and the mixture was heated to reflux for 5 minutes. Then, trimethylsilyl chloride (8.6ml, 67.5mmol) was added at 0°C, and the mixture was stirred at 0°C for 5 minutes, after which 2,3-dichlorobenzyl chloride was added dropwise under ice-cooling (82.4g, 421.7mmol) in THF (330ml). After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 1 hour to obtain a THF solution of 2,3-dichlorobenzylzinc chloride.

Embodiment 1-1

[0597] Example 1-1 Synthesis of 6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid

[0598] step 1 Synthesis of 1,2-dichloro-3-(4-nitrobenzyl)benzene

[0599]

[0600] Bis(dibenzylideneacetone)palladium(0) (3.2 g, 5.6 mmol) and tris(2-furyl)phosphine (2.6 g, 11.2 mmol) were dissolved in THF (310 ml) under argon flow. To this solution, a THF solution of 2,3-dichlorobenzylzinc chloride (421.7 mmol) obtained in Reference Example 1 was added dropwise under ice cooling by cannula, followed by 4-iodonitrobenzene (70.0 g, 281 mmol) in THF (700 ml). After stirring at room temperature for 2 hours, to the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After fil...

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Abstract

An anti-HIV agent containing, as an active ingredient, a 4-oxoquinoline compound represented by the following formula, wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. The compound of the present invention has HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compound can become a more effective anti-HIV agent. Since the compound has high inhibitory activity specific for integrases, it can provide a safe pharmaceutical agent with a fewer side effects for human.

Description

technical field [0001] The present invention relates to novel 4-oxoquinoline compounds and pharmaceutically acceptable salts thereof as anti-HIV agents. The present invention also relates to the novel use of certain 4-oxoquinoline compounds and pharmaceutically acceptable salts thereof as anti-HIV agents. More specifically, the present invention relates to an anti-HIV agent comprising a 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof, which particularly exhibits an anti-HIV effect based on integrase inhibitory activity. Background technique [0002] HIV (Human Immunodeficiency Virus (Type I)), which belongs to retroviruses, is a virus that causes AIDS (Acquired Immunodeficiency Syndrome, AIDS). [0003] HIV targets CD4-positive cell populations such as helper T cells, macrophages, and dendritic cells, etc., and destroys these immunocompetent cells, resulting in immunodeficiency. [0004] Therefore, agents that eradicate HIV in the body or inhibit its ...

Claims

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Application Information

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IPC IPC(8): A61KA61K31/47A61PA61P31/12C07DC07D215/56
Inventor 佐藤元秀川上浩伊藤佳治新海久本村隆尚荒卷久晃松崎裕児渡辺渡和卷修一
Owner JAPAN TOBACCO INC
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