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8a,9-dihydro-4ah-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents

A compound, solvate technology, applied in the field of 8A,9-dihydro-4A-H-isothiazo[5,4-B]quinoline-3,4-dione and related compounds used as anti-infective agent , which can solve problems such as unsatisfactory results

Inactive Publication Date: 2008-02-06
ACHILLION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Attempts to improve antimicrobials are ongoing, with mostly disappointing results

Method used

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  • 8a,9-dihydro-4ah-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents
  • 8a,9-dihydro-4ah-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents
  • 8a,9-dihydro-4ah-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Prepare 7-[(4Z)-3-aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6-fluoro-9H-isothiazole [5 ,4-b]quinoline-3,4-dione (12).

[0203] Using the procedure described by CHU (J. Heterocyclic Chem., (1990) 27:839), 9-cyclopropyl-6,7-difluoro-9H-isothiazole was prepared from 2,4,5-trifluorobenzoic acid [ 5,4-b] Quinoline-3,4-dione. LCMS(API)m / z C 13 H 8 F 2 N 2 O 2 S calculated value 294 ((M + ]); Measured value 295([M+H] + ). 1 H NMR (300MHz, DMSO-d6): δ 1.25 (m, 2H), 1.36 (m, 2H), 3.56 (m, 1H), 8.04 (dd, J H-F6 =11Hz, J H-F7 =8.8Hz, 1H), 8.10(dd, J H-F7 =11.6Hz, J H-F6 =5.8Hz, 1H). 19 F NMR (DMSO-d6): δ143.30 (d, J=27 Hz), 130.12 (d, J=27 Hz).

[0204] Stir at room temperature containing glycine ethyl ester hydrochloride (25.0g, 179mmol) and K 2 CO 3(55.0 g, fine powder, 362 mmol) a mixture of DMF (300 ml), 30 min. Slowly add ethyl acrylate (19.7 g, 197 mmol) (about 30 min), and then stir the reaction mixture at 80° C. for 8 hr. DMF was removed in vacuo, and the resi...

Embodiment 2

[0215] The compounds in Table I below can be obtained according to the method described in Example 1. Those skilled in the art should recognize that the starting materials and reaction conditions can be different, and the compounds in Table I can also be prepared using other steps.

[0216] Unless specified, R 7 The three-dimensional configuration of the group oxime double bond can be Z-type or E-type, and the three-dimensional configuration of other chiral carbon atoms in the group can be racemic, R or S-type.

Embodiment 3

[0217] The antimicrobial activity of the compounds of the present invention can be evaluated according to many methods including the following minimum inhibitory concentration (MIC) test. This test determines the minimum concentration of a compound required to inhibit bacterial growth.

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Abstract

The invention provides compounds and salts of Formula I and Formula II which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula I and Formula II. The variables n, m, p, RA, RB, A1, R2, R3, R5, R6, R7, A8 and R9 are defined herein. Certain compounds of Formula I and Formula II disclosed herein are potent and / or selective inhibitors of bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula I or Formula II and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula I or Formula II as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in eukaryotes.

Description

[0001] Cross-references to related applications [0001] This application claims the priority of the U.S. Provisional Patent Application No. 60 / 626,961 filed on November 11, 2004, the entire content of which is incorporated herein by reference. Technical field [0002] The present invention provides a 8A,9-dihydro-4a-H-isothiazole [5,4-b]quinoline-3,4-dione with antibacterial activity (many of which contain oxime substitution at the 7th position) Heterocycloalkyl substituents) and related compounds. Certain compounds given herein have potent antibacterial, antiprotozoal or antifungal activity. In particular, some compounds can also potently and / or selectively inhibit the DNA synthesis and reproduction of prokaryotes. The present invention provides antimicrobial compositions, including pharmaceutical compositions, and also one or more carriers, diluents or excipients. The pharmaceutical composition provided by the present invention either only contains the active agent 8A, 9-dihydro-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61K31/437A61P31/04A61P33/02
CPCC07D513/04C07D513/14A61P31/04A61P31/10A61P33/00A61P33/02A61K31/437
Inventor B·J·布拉德伯里M·德士潘德M·J·普斯王秋萍J·A·威尔斯宋永胜桥本明广E·卢西恩
Owner ACHILLION PHARMA INC