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Peptide-deformylase inhibitors

A formyl hydroxylamine group, methyl group technology, applied in the field of peptide deformylase inhibitors, can solve the problems of high sequence polymorphism and low consistency

Inactive Publication Date: 2004-06-16
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sequence polymorphism among PDF homologues is very high and identity between distantly related sequences is as low as 20%

Method used

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  • Peptide-deformylase inhibitors
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  • Peptide-deformylase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

no. 2 approach

[0088] As the second embodiment of the present invention, the compound of X=O in the formula (1) is disclosed, namely racemic compound (34) and chiral compounds (36) and (38). These compounds preferably have R1=H.

[0089]

[0090] Preferred compounds for use in the present invention are selected from the following group of compounds:

[0091] N-Butyl-N-(tert-butoxycarbonyl)-N'-{(2R)-[(formylhydroxylamino)methyl]-heptanoyl}hydrazine;

[0092] N-butyl-N-phenoxycarbonyl-N'-{(2R)-[(formylhydroxylamino)methyl]-heptanoyl}-hydrazine;

[0093] N-isobutyl-N-(tert-butoxycarbonyl)-N'-{(2R)-[(formylhydroxylamino)methyl]heptanoyl}-hydrazine;

[0094] N-isobutyl-N-phenoxycarbonyl-N'-{(2R)-[(formylhydroxylamino)methyl]heptanoyl}-hydrazine;

[0095] N-phenethyl-N-(tert-butoxycarbonyl)-N'-{2-[(formylhydroxylamino)methyl]heptanoyl}-hydrazine;

[0096] N-cyclohexylmethyl-N-(tert-butoxycarbonyl)-N'-{2-[(formylhydroxylamino)methyl]heptanoyl}-hydrazine;

[0097] N-Benzyl-N-(tert-butoxycarb...

Embodiment 1

[0210] N-Butyl-N-(tert-butoxycarbonyl)-N'-{(2R)-[(formylhydroxylamino)methyl]heptanoyl}-hydrazine

[0211] 10% Pd / C (60 mg) was added to tert-butyl N'-{(R)-2-[(benzyloxycarboxamido)methyl]heptanoyl}-N-butylhydrazinecarboxylate (195 mg, 0.421 mmol) in ethanol (15 ml) solution. The reaction solution was hydrogenated overnight at room temperature. After the reaction was completed, the reaction solution was filtered through a pad of Celite and washed with ethanol (10 mL×2). The solvent was removed to obtain the crude product, and the crude product was purified by high performance liquid phase to obtain 52 mg (33%) of the target compound

[0212] 1 HNMR (400MHz, CDCl 3 ): δ9.94(s, 1H), 9.39(s, 1H), 8.32(s, 1H), 4.10(dd, J=14.1, 4.0Hz, 1H), 3.62(m, 1H), 3.35(m, 2H), 2.55(m, 1H), 1.72(m, 1H), 1.56(m, 1H), 1.50(s, 9H), 1.30(m, 10H), 0.90(m, 6H).

[0213] MH+374.

[0214] Preparation 12

[0215] Phenyl N-butylhydrazine carboxylate

[0216]Phenyl chloroformate (0.53 mL, 4.20 mm...

Embodiment 2

[0220] N-Butyl-N-phenoxycarbonyl-N'-{(2R)-[(formylhydroxylamine and)methyl]heptanoyl}-hydrazine

[0221] Purification by preparative HPLC yielded 49 mg (41%) of the title product.

[0222] 1 HNMR (400MHz, CDCl 3 ): δ9.78(s, 1H), 9.39(s, 1H), 8.27(s, 1H), 7.40-7.10(m, 5H), 4.20-3.30(m, 4H), 2.70(m, 1H), 1.80-1.20(m, 10H), 0.90(m, 6H).

[0223] MH+394.

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PUM

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Abstract

Nobel PDF inhibitors and novel methods for their use are provided.

Description

field of invention [0001] The present invention relates to the use of novel antibacterial compounds, and pharmaceutical compositions of these compounds as peptide deformylase inhibitors. Background of the invention [0002] Bacterial promoter methionyl tRNA is modified by methionyl tRNA formyltransferase (FMT) to generate formylmethionyl tRNA. Formylmethionine (f-met) then binds to the N-terminus of the newly generated polypeptide. Subsequently, the primary translation product is deformylated by polypeptide deformylase (PDF or Def) to generate N-methionyl polypeptide. Most intracellular proteins are further processed by methionine aminopeptidase (MAP) to generate mature peptides and free methionine, and this process goes on again and again. Both PDF and MAP are essential factors for bacterial growth. In addition, PDF is also a necessary condition for MAP activity. This series of reactions refers to the following methionine cycle (Figure 1). [0003] [0004] Fig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/99A61K31/165A61K31/166A61K31/167A61K31/175A61K31/27A61K31/341A61K31/343A61K31/351A61K31/357A61K31/36A61K31/401A61K31/4015A61K31/4025A61K31/404A61K31/4045A61K31/405A61K31/415A61K31/4164A61K31/4166A61K31/4178A61K31/4184A61K31/4192A61K31/42A61K31/421A61K31/4355A61K31/4375A61K31/44A61K31/4402A61K31/4406A61K31/4439A61K31/445A61K31/4465A61K31/453A61K31/47A61K31/472A61K31/4745A61K31/495A61K31/496A61K31/4965A61K31/498A61K31/505A61K31/5375A61K31/5377A61P31/04A61P43/00C07C243/32C07C243/38C07C259/06C07C281/02C07C281/06C07D207/16C07D207/28C07D209/14C07D209/42C07D211/62C07D211/78C07D213/42C07D213/56C07D213/82C07D215/48C07D215/50C07D217/26C07D231/06C07D233/64C07D233/78C07D235/16C07D239/42C07D239/52C07D241/08C07D241/44C07D249/18C07D261/14C07D263/34C07D265/30C07D295/12C07D295/13C07D295/14C07D295/18C07D295/192C07D295/20C07D295/215C07D307/24C07D307/85C07D309/14C07D317/68C07D321/10C07D321/12C07D401/04C07D413/02C07D471/04C07D471/06C07D491/048
CPCC07D295/215C07C243/32C07C2101/08C07C2101/14C07D295/13C07C281/06C07C281/02C07C243/38C07D295/192C07C2601/08C07C2601/14A61P31/04A61P43/00C07C243/34
Inventor 向家宁西格弗里德·B·克里斯坦森李镇华丹尼尔·J·默瑟
Owner SMITHKLINE BECKMAN CORP
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