Peptide deformylase inhibitors

A compound, C1-C3 technology, applied in the field of {2--3-[2-hydrazino]-3-oxopropyl}hydroxyformamide compound, can solve the problem of no effect

Inactive Publication Date: 2012-11-14
GLAXO SMITHKLINE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, PDF inhibitors active against human PDF enzymes in vitro had no effect on the growth of normal human cell

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0556] ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-2-methyl-6-(1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-3 -Oxopropyl)hydroxyformamide

[0557]

[0558] Part A:

[0559] 5-Fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine

[0560] 4,6-Dichloro-5-fluoro-2-methylpyrimidine (100 mg, 0.55 mmol) was dissolved in 2 mL of DMSO and stirred at room temperature. Pyrrolidine (50 μL, 0.61 mmol) was added followed by DIPEA (210 μL, 1.21 mmol). The resulting reaction mixture was stirred for 2 hours, and then hydrazine (1.0 mL) was added and the contents heated at 80 °C for 1 hour. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to give 5-fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine (69 mg, 59%).

[0561] Part B:

[0562] ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-2-methyl-6-(1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-3 -Oxopropyl)[(phenylmethyl)oxy]formamide

[0563] 5-Fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine (69 ...

Embodiment 2

[0569] [(2R)-3-{2-[6-(1-Azetidinyl)-2-ethyl-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl )-3-oxopropyl]hydroxyformamide

[0570]

[0571] Part A:

[0572] 6-azetidinyl-2-ethyl-5-fluoro-4-hydrazinopyrimidine

[0573] 4,6-Dichloro-2-ethyl-5-fluoropyrimidine (195 mg, 1.0 mmol) was dissolved in 3 mL of MeOH and stirred at room temperature. Azetidine (74 μL, 1.1 mmol) was added followed by DIPEA (383 μL, 2.2 mmol). The resulting reaction mixture was stirred at room temperature until the azetidine replaced one chlorine as monitored by LCMS. Then, MeOH was removed in vacuo, and the remaining residue was dissolved in a mixture of 2 mL DMSO and 1 mL hydrazine. The resulting solution was heated at 40 °C for 1 hour until the reaction was deemed complete by LCMS. The crude reaction mixture was purified by RP-HPLC to give 4-(1-azetidinyl)-2-ethyl-5-fluoro-6-hydrazinopyrimidine (136 mg, 64%). LCMS: (M+H) + : 212.1.

[0574] Part B:

[0575] [(2R)-3-{2-[6-(1-Azetidi...

Embodiment 3

[0582] [(2R)-3-{2-[6-(1-Azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentyl methyl)-3-oxopropyl]hydroxyformamide

[0583]

[0584] Part A:

[0585] [(2R)-3-{2-[6-(1-Azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentyl Methyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide

[0586] Add [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl )-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.100g, 0.204mmol), azetidine hydrochloride (19.1mg, 0.204mmol), DIPEA (71.2 μL, 0.408 mmol) and DMSO (2 mL). The tube was sealed and heated to 65-70°C with stirring for 3 days. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to give [(2R)-3-{2-[6-(1-azetidinyl)-5-fluoro-2-(methylthio )-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (68mg, 65% ). LCMS: (M+H) + : 511.2.

[0587] Part B:

[0588] [(2R)-3-{...

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Abstract

The present invention is directed to certain {2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}hydroxyformamide derivatives, compositions containing them, the use of such compounds in the inhibition of bacterial peptide deformylase (PDF) activity, and in the treatment of bacterial infections. Specifically, the invention is directed to compounds of formula (I), wherein R1, R2 and R3 are defined herein and to pharmaceutically acceptable salts thereof. The compounds of this invention are bacterial peptide deformylase inhibitors and can be useful in the treatment of bacterial infections.

Description

field of invention [0001] The present invention relates to certain {2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}hydroxycarboxamide compounds, compositions comprising them, The use of the compound in inhibiting the activity of peptide deformylase (PDF) in bacteria, and the use in treating bacterial infection. Background of the invention [0002] Bacterial protein synthesis begins with N-formyl-methionyl-tRNA (f-Met-tRNAi), therefore, all newly synthesized polypeptides contain N-formyl-methionine termini (f-Met-pp)( Scheme I). Peptide deformylase (PDF) is a metalloenzyme that removes the N-formyl group of a polypeptide as it is produced from the ribosome during elongation [Adams, J.M. (1968) J.Mol.Biol.33 , 571-589; Livingston, D.M. and Leder, P. (1969) Biochemistry 8, 435-443; Ball, L.A. and Kaesberg, P. (1973) J. Mol. Biol. 79, 531-537]. Depending on the nature of their second amino acid, polypeptides are further treated with methionine aminopeptidase (M...

Claims

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Application Information

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IPC IPC(8): A61K31/16A61K31/195C07D239/42
CPCC07D487/08C07D471/04C07D491/18C07D417/04C07D239/42C07D403/04C07D405/12C07D409/12C07D403/14C07D498/04C07D401/14C07D401/12C07D413/04C07D239/48C07D417/12C07D487/04C07D401/04A61P11/00A61P11/02A61P13/00A61P17/00A61P27/16A61P31/00A61P31/04A61P9/00
Inventor 秦东辉贝丝·诺顿廖湘民安德鲁·N·诺克斯方育红李镇华贾森·C·德雷比特西格弗里德·B·克里斯滕森四世安德鲁·B·贝诺维茨凯利·M·奥巴特
Owner GLAXO SMITHKLINE LLC
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