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Tricyclic derivatives of azetidine and pyrrole with antibacterial activity

A cycloalkyl and alkyl technology, applied in the field of tricyclic derivatives of azetidine and pyrrole with antibacterial activity, can solve problems such as poor antibacterial drugs

Inactive Publication Date: 2008-04-30
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite potent activity against DNA gyrase, cyclothialidine is a poor antimicrobial, shown to be active only against certain eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656 -2661)

Method used

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  • Tricyclic derivatives of azetidine and pyrrole with antibacterial activity
  • Tricyclic derivatives of azetidine and pyrrole with antibacterial activity
  • Tricyclic derivatives of azetidine and pyrrole with antibacterial activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 9

[0345] The MIC of the compound of Example 9 against Streptococcus pneumoniae (Streptococcus pneumoniae) was 2 μg / ml. Other examples are listed in the table below.

[0346] Example number

MIC SPN548

MIC SAU516

MIC HIN446

4

5

8

9

4

0.5

1

2

32

4

8

2

2

0.5

8

4

[0347] The present inventors have found that the compounds of the present invention inhibit bacterial DNA gyrase, so that they have antibacterial effects of interest.

[0348] According to another feature of the invention, there is provided a method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, such as a human, the method comprising administering to said animal an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0349] According to another feature of the present invention, there is provid...

Embodiment 1

[0406] 2-(3-{[3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}azetidine-1- base)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester

[0407] N-azetidin-3-yl-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide trifluoroacetate (Intermediate 2; 724 mg, 2.0 mmol), DMF (4ml), a solution of ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (500mg, 2.0mmol) and triethylamine (0.538ml, 4mmol) were combined and heated at 60°C Stir overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate / water. Organic phase with 1N HCl, saturated NaHCO 3 solution and brine. The organic layer was dried and concentrated under reduced pressure to give the product (0.50 g) as a light brown solid. Analytical pure samples were purified by reverse phase HPLC. to C 16 h 18 Cl 2 N 4 o 3 MS (ES) for S: 417 (M+H). NMR: 1.24(t, 3H); 2.18(s, 3H); 2.45(s, 3H); 4.10(m, 2H); 4.17(q, 2H); 4.36(t, 2H); 4.93(m, 1H) ;8.11(d, 1H); 12.01(s, 1H).

Embodiment 2-3

[0409] By the method of Example 1, the following compounds were prepared from the given starting materials (SM).

[0410] Ex

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PUM

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Abstract

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.

Description

Background of the invention [0001] The present invention relates to compounds with proven antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as active ingredients, their use as medicaments and their use in the preparation of medicaments for the treatment of bacterial infections in warm-blooded animals such as humans use. In particular, the present invention relates to compounds useful in the treatment of bacterial infections in warm-blooded animals such as humans, and more particularly to the use of these compounds in the manufacture of medicaments for the treatment of bacterial infections in warm-blooded animals such as humans. [0002] The international microbiology community continues to express serious concern about the evolution of antibiotic resistance, which can produce strains against which existing antimicrobials are ineffective. In general, bacterial pathogens can be classified as Gram-positive or Gram-negative patho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D403/12A61K31/506A61K31/427A61K31/4025A61P31/00
CPCC07D417/14C07D403/12A61P31/00A61P31/04A61P43/00
Inventor S·比斯特S·I·豪克K·G·赫尔
Owner ASTRAZENECA AB