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Pyrrole derivatives as DNA gyrase and topoisomerase inhibitors

An alkyl, selected technology, applied in the field of pyrrole derivatives as DNA gyrase and topoisomerase inhibitors, can solve the problem of 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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  • Pyrrole derivatives as DNA gyrase and topoisomerase inhibitors
  • Pyrrole derivatives as DNA gyrase and topoisomerase inhibitors
  • Pyrrole derivatives as DNA gyrase and topoisomerase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 30

[0396] The MIC of the compound of Example 30 against Streptococcus pneumoniae was 1 μg / ml. Other examples are listed in the table below.

[0397] Example number

MIC SPN548

MIC SAU516

MIC HIN446

23

25

26

27

36

0.13

1

1

0.13

0.25

4

2

32

2

2

2

4

8

2

1

[0398] The present inventors have found that the compounds of the present invention inhibit bacterial DNA gyrase, so that they have antibacterial effects of interest.

[0399] 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.

[0400] According to another feature of the present invent...

Embodiment 1

[0460] [4-(4-{{(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}phenyl)-1H-1,2,3-tri Azol-1-yl] ethyl acetate

[0461] Make 3,4-dichloro-N-(4-ethynylphenyl)-5-methyl-1H-pyrrole-2-carboxamide (intermediate 11; 1g, 3.4mmol), CuI (1.3g, 6.8mmol , 2 eq) and ethyl azidoacetate (880 mg, 6.8 mmol, 2 eq) were mixed and dissolved in DIEA (1.3 g, 10.1 mmol, 3 eq) and 1,4-dioxane (20 ml). The resulting slurry was heated to 100 °C for 6 h. The reaction was monitored by LC / MS. The solid was filtered and the mother liquor was concentrated to a foam. MS(ES)(M+H) + =422,424; NMR: 1.22(t,3H), 2.24(s,3H), 4.18(q,2H), 5.54(s,2H), 7.74(dd,4H), 8.51(s,1H), 9.54 (s, 1H), 12.2 (s, 1H).

Embodiment 2

[0463] [4-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}phenyl)-1H-1,2,3-tri Azol-1-yl]acetic acid

[0464] [4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}phenyl)-1H-1,2,3-triazole-1 -yl]ethyl acetate (Example 1; 1.4 g, 3.4 mmol) was dissolved in a 1:1 mixture of EtOH (10 mL) and 2N KOH (10 mL). The reaction mixture was stirred at room temperature for 3 days. The solution was cooled to 0°C and acidified to pH 7 with 2N HCl. The mixture was concentrated to dryness and purified by HPLC (15-95% acetonitrile / 0.1% TFA for 35 min). The product fractions were collected, the acetonitrile was removed by rotary evaporation, the water was frozen and lyophilized. After isolation, 60 mg of the title compound were obtained. M / z 393, 395; NMR: 2.17(s, 3H), 5.25(s, 2H), 7.67(dd, 4H), 8.42(s, 1H), 9.46(s, 1H), 12.1(s, 1H), 13.4 (broads, 1H).

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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): C07D403/12C07D401/12C07D417/12C07D405/12C07D413/12C07D471/04A61K31/4192A61P31/04
CPCC07D401/12C07D403/12C07D405/12C07D471/04C07D417/12C07D413/12A61P31/04A61P43/00
Inventor G·S·巴萨拉布M·B·格拉弗斯托克S·I·豪克
Owner ASTRAZENECA AB
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