3-aminoquinazolin-2,4-dione antibacterial agents

a technology of aminoquinazolin and antibacterial agent, which is applied in the field of 3 aminoquinazolin2, 4diones, and can solve problems such as cross-resistantness

Inactive Publication Date: 2006-08-17
ZOETIS WLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] The present invention provides 3-aminoquinazolin-2,4-diones having antibacterial activity. The compounds inhibit DNA gyrase, but are not cross-resistant with quinolone mutants that are no longer sensitive to agents such as ciprofloxacin.

Problems solved by technology

The compounds inhibit DNA gyrase, but are not cross-resistant with quinolone mutants that are no longer sensitive to agents such as ciprofloxacin.

Method used

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  • 3-aminoquinazolin-2,4-dione antibacterial agents
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  • 3-aminoquinazolin-2,4-dione antibacterial agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Benzoates

(a) 2,3,4,5-Tetrafluorobenzoic acid ethyl ester

[0531]

[0532] A solution of 2,3,4,5-tetrafluorobenzoic acid (4.68 g, 24.1 mmol) in dichloromethane (50 mL) at 0° C. is treated with oxalyl chloride (11.5. mL, 132 mmol) followed by N,N-dimethylformamide (4 drops). The mixture is stirred at 0° C. for 5 minutes and then at room temperature for 1.5 hours. The mixture is concentrated to dryness and subsequently co-evaporated from benzene. The resulting acid chloride is diluted with dichloromethane (50 mL), cooled to 0° C., and anhydrous ethanol (15.0 mL, 256 mmol) is added dropwise. The resulting solution is stirred at room temperature for 4.5 hours, then poured into saturated NaHCO3 and extracted with chloroform. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (5.37 g). 1H NMR (CDCl3): δ 7.67-7.55 (m, 1H), 4.42 (q, 2H), 1.41 (t, 3H).

(b) 2,3,4,6-Tetrafluorobenzoic acid ethyl ...

example 2

Synthesis of 4-Heterocyclic Benzoates

General Procedure

[0552] A mixture of 4-fluoro substituted benzoic acid ester (1 eq.), substituted pyrrolidine (1.3-2.5 eq.), and triethylamine (2-10 eq.) in N,N-dimethylacetamide or acetonitrile is heated to 50° C.-100° C. for 15 to 60 hours. The solution is then concentrated to near dryness, poured into saturated NaHCO3 solution, and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by column chromatography (ethyl acetate / hexanes) to afford 4-pyrrolidinyl substituted benzoic acid esters.

(a) 4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2,3,5-trifluorobenzoic acid ethyl ester

[0553]

[0554] A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3 -ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L., Priebe S. R., Sesnie J. ...

example 3

Synthesis of 2-Substituted-Amino Benzoates

General Procedure

[0579] A solution of 4-(pyrrolidin-1-yl)-2-fluorobenzoic acid ethyl esters (Example 2) and cyclopropylamine (10-15 eq.) in dimethyl sulfoxide and triethylamine (2-5 eq.) is heated in a sealed glass tube for 3 days at 140° C. Compressed air is blown into the mixture to remove excess cyclopropylamine. The resulting solution is concentrated under vacuum and purified by column chromatography (ethyl acetate / hexanes) to afford 4-(substituted pyrrolidin-1-yl)-2-cyclopropylamino-benzoic acid esters.

(a) 4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoic acid ethyl ester

[0580]

[0581] A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5-trifluorobenzoic acid ethyl ester (Example 2a, 1.95 g, 5.01 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in dimethyl sulfoxide (5 mL) is heated in a sealed glass tube for 44.5 hours at 100° C. Compressed air is blown into the black solution ...

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Abstract

Antibacterial 3-aminoquinazolin-2,4-diones have formula (I) wherein: R1 and R3 include alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl; R5, R6, and R8 include H, alkyl, alkoxy, halo, NO2, CN, NH2, alkyl and dialkylamino; R7 includes hydrogen, alkyl, cycloalkyl, heterocyclic, fused heterocyclic, aryl and fused aryl; J and K are C or N; and pharmaceutically acceptable salts thereof.

Description

FIELD OF THE INVENTION [0001] This invention relates to 3-aminoquinazolin-2,4-diones that have potent in vitro and in vivo antibacterial activity. In addition, this invention relates to a method of inhibiting both wild-type and quinolone resistant mutants of DNA gyrase. This invention further relates to a method of treating patients having antibiotic resistance and in need of treatment for bacterial infections. BACKGROUND OF THE INVENTION [0002] Antibiotic resistance is a worldwide problem with catastrophic potential. The American Society of Microbiology Task Force recently issued a report defining the resistance problem and calling for new antibacterial agents with novel structures or mechanisms to offer alternatives to existing therapeutic choices (Southern Med. J., 1995;88:797). [0003] The quinolones are a class of antibacterials that are widely used throughout the world. The quinolones are potent inhibitors of gram positive and gram negative bacteria, and may be administered ora...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/517C07D403/02C07D239/96A61K31/505C07D239/92A61K31/519A61K31/5383A61P31/04A61P31/14C07D401/04C07D403/04C07D403/14C07D409/04C07D413/04C07D417/04C07D471/04C07D471/06C07D471/16C07D487/04C07D487/10C07D498/06C07D498/16C07D519/00
CPCC07D239/96C07D401/04C07D403/04C07D487/10C07D471/04C07D487/04C07D403/14A61P31/04A61P31/14
Inventor BIRD, PAULELLSWORTH, EDMUNDNGUYEN, DAISANCHEZ, JOSEPHSHOWALTER, HOWARDSINGH, RAJESHWARSTIER, MICHAELTRAN, TUANWATSON, BRIANYIP, JUDY
Owner ZOETIS WLC
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