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Nitroimidazole compounds

A technology of compounds and groups, applied in the fields of organic chemistry, antibacterial drugs, organic active ingredients, etc., can solve the problems of complex tablet formulations, expensive synthetic routes, low solubility, etc.

Inactive Publication Date: 2009-01-07
NOVARTIS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, PA-824 has an expensive synthetic route, complex tablet formulation (due to its low solubility), and requires further enhancement of potency

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0303] (S)-1-(tert-butyldimethylsilyloxy)-3-(2-chloro-4-nitro-imidazol-1-yl)-propan-2-ol (3)

[0304]

[0305] Dissolve 2-chloro-4-nitro-imidazole (20.0 g, 0.14 mol, 100 mol%) in anhydrous EtOH (200 mL), add anhydrous K 2 CO 3 (2.82g, 0.020mol, 15mol%), followed by tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (22.2mL, 0.11mol, 0.78mol%) . The reaction mixture was heated to 70 °C for 6-10 h. The solvent was then removed in vacuo and the reaction mixture was dissolved in ethyl acetate. The organic layer was washed several times with water, 0.5 N HCI, water, brine, and the solvent was removed in vacuo to give crude alcohol as a yellowish solid. The solid was suspended in ether and filtered to give the final product as a colorless powder. The remaining filtrate was concentrated and the process of settling the product with diethyl ether was repeated twice.

[0306] MS: M + 336.3.

[0307] Melting point: 116-118°C.

[0308] [α] 21 D =-29.43 (C=0.003, MeOH).

Embodiment 2

[0310] 1-[(S)-3-(tert-butyl-dimethyl-silyloxy)-2-(tetrahydro-pyran-2-yloxy)-propyl]-2- Chloro-4-nitro-1H-imidazole (4)

[0311]

[0312] (S)-1-(tert-butyl-dimethyl-silyloxy)-3-(2-chloro-4-nitro-imidazol-1-yl)-propan-2-ol (3.0g, 8.9mmol, 100mol%) was dissolved in dichloromethane (100mL), and freshly distilled 3,4-dihydro-2H-pyran (1.5g, 17.8mmol, 200mol%) was added to the solution, followed by p-toluene Pyridinium sulfonate (3.4 g, 13.4 mmol, 150 mol%). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous portion was extracted with dichloromethane. The combined organic layers were washed with water, brine, and washed with MgSO 4 After drying, the solvent was removed in vacuo to give 1-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-2-(tetrahydro-pyran-2-yl as a colorless oil Oxy)-propyl]-2-chloro-4-nitro-1H-imidazole.

[0313] MS: M + 420....

Embodiment 3

[0315] (S)-2-nitro-6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-imidazo[2,1-b]-[1,3]- evil Zinc (5)

[0316]

[0317] 1-[(S)-3-(tert-butyl-dimethyl-silyloxy)-2-(tetrahydro-pyran-2-yloxy)-propyl]-2-chloro-4 -Nitro-1H-imidazole (0.74g, 1.76mmol, 100mol%) was dissolved in anhydrous THF (180mL), and TBAF (1M THF solution, 1.76mL, 100mol%) was added to the above solution. The reaction tube was sealed and exposed to microwaves at 140 °C for 7 min. The solvent was removed under vacuum and the residue was purified on silica gel to give (S)-2-nitro-6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro as a yellowish oil -5H-imidazo[2,1-b]-[1,3]oxazine.

[0318] (S)-3-(2-Chloro-4-nitro-imidazol-1-yl)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (0.053g, 0.172 mmol, 100 mol%) was dissolved in anhydrous tetrahydrofuran (17 mL), and TBAF (1M THF solution, 0.17 mL, 100 mol%) was added to the solution. The reaction tube was sealed and exposed to microwaves at 140 °C for 7 min. The solvent was rem...

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Abstract

The present invention relates to certain nitroimidazole compounds, which have interesting pharmaceutical properties. In particular, the compounds are useful in the treatment and / or prevention of infections such as those caused by Mycobacterium tuberculosis, Trypanosoma cruzi or Leishmania donovani. The invention also relates to pharmaceutical compositions containing the compounds, as well as processes for their preparation.

Description

technical field [0001] The present invention relates to nitroimidazole compounds, processes for their preparation, their use as medicines and pharmaceutical compositions containing them. Background technique [0002] Tuberculosis (TB), one of the oldest diseases known to man, is caused by the bacterium Mycobacterium tuberculosis (MTB). The disease is contagious and, like common flu, spreads easily through the air through coughing and sneezing. At present, MTB has infected one-third of the world's population. After AIDS, it is the second leading cause of death for adults due to infectious diseases. Every 15 seconds, a tuberculosis patient dies. The last two decades have seen a resurgence of TB disease, especially in regions like Southeast Asia and sub-Saharan Africa. [0003] The first effective anti-TB drug, streptomycin, was discovered in 1946. However, monotherapy quickly becomes ineffective due to the development of bacterial resistance. As more antimycobacterial drug...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D498/04A61K31/519A61P31/06
CPCY02A50/30
Inventor J·基里塞克S·帕特尔T·H·凯勒C·E·巴里三世C·S·多德
Owner NOVARTIS AG
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