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Nitroimidazooxazine and nitroimidazooxazole analogues and their uses

A kind of imidazo, nitro technology, is applied in the analog of nitroimidazoxazine and nitroimidazoxazole and the use field thereof, can solve the problems such as drug resistance increase

Active Publication Date: 2012-10-17
GLOBAL ALLIANCE FOR TB DRUG DEV (US)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Their administration at low doses over long periods of time resulted in increased resistance, so they can no longer be used in India (Cavalli et al., 2009)

Method used

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  • Nitroimidazooxazine and nitroimidazooxazole analogues and their uses
  • Nitroimidazooxazine and nitroimidazooxazole analogues and their uses
  • Nitroimidazooxazine and nitroimidazooxazole analogues and their uses

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Experimental program
Comparison scheme
Effect test

Embodiment 1 1

[0166] Example 1. General Synthetic Scheme

[0167] It can be achieved through the listed in Scheme 1-15, Figure 3-17 Compounds are prepared according to the general methods shown or any other suitable method. In the descriptions of Scenarios 1-15 below, refer to Table 1 below and the attached figure 2 and 18 Representative compounds shown in -21.

[0168] Table 1: Representative Compounds

[0169]

[0170]

[0171]

[0172] In Scenario 1, such as image 3 As shown, the reagents and conditions are (i) RPhOH, K 2 CO 3 , acetone, reflux, 36~52 hours; (ii) 77, 78 or 79, DIPEA, 105 ℃, 6.5~12 hours; (iii) NaH, DMF, 0 ℃, 45 minutes; (iv) NaH, DMF, 0 ℃, 80 minutes, then 17℃, 60 minutes; (v) ArB(OH) 2 , 2M Na 2 CO 3 , toluene, EtOH, DMF, N 2 Lower Pd(dppf)Cl 2 , 88-90°C, 50-90 minutes. 2-bromo-4(5)-nitroimidazole (80) or 2-chloro-4(5)-nitroimidazole (81) and epoxy 77~79 [by using 2-(bromomethyl) epoxy Prepared by alkylation of the appropriate 4-substituted phe...

Embodiment 2

[0187] Embodiment 2: preparation method

[0188] A. Synthesis of 6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][ 1,3] Oxazole (Compound 1 of Table 1).

[0189]

[0190] Stir 4-trifluoromethoxyphenol (0.152 mL, 1.17 mmol), K 2 CO 3 (260 mg, 1.17 mmol) and 2-(bromomethyl)oxirane (76) (0.30 mL, 3.51 mmol) in anhydrous acetone (3 mL) for 36 hours. The resulting mixture was filtered with CH 2 Cl 2 After washing, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel. With 0~15%CH 2 Cl 2 / pentane elution to obtain the first eluate, and then use 20-25% CH 2 Cl 2 2-{[4-(trifluoromethoxy)phenoxy]methyl}oxirane (77) as an oil (compared to Cao et al., WO 2008112483A2 using epichlorohydrin preparation similar) (260mg, 95%);

[0191] 1 HNMR (CDCl 3 )δ7.14 (br dd, J=9.0, 0.6Hz, 2H), 6.91 (dt, J=9.1, 3.0Hz, 2H), 4.23 (dd, J=11.1, 3.1Hz, 1H), 3.94 (dd, J=11.1, 5.7Hz, 1H), 3.34(m, 1H), 2.91(dd, J=4.8, 4.2Hz, 1H), 2.75(...

Embodiment 3

[0616] Example 3. Biological Activity and Stability

[0617] The biological activity of the compounds of the present invention was evaluated as follows. The results are shown in Table 2 below.

[0618] (a) Minimum inhibitory concentration (MIC). Activity of compounds against M. tuberculosis replication was assessed using Alamar blue reagent (added on day 7) to measure growth (MABA) in an 8-day microplate-based assay (Collins et al., 1997; Falzari et al., 2005) . The lowest compound concentration that achieved >90% inhibition was considered the MIC. Compounds were screened for activity against bacteria in a non-replicating state (mimicking clinical persistence) using an 11-day high-throughput, luminescence-based low-oxygen-recovery assay (LORA), in which prolonged culture M. tuberculosis, which contains a plasmid with an acetamidase promoter driving the bacterial luciferase gene, was first adapted to hypoxic conditions (Cho et al., 2007).

[0619] (b) Maximum cytotoxici...

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Abstract

The current invention pertains to nitroimidazooxazine and nitroimidazooxazole analogues, their methods of preparation, and uses of the compounds as treatment for Mycobacterium tuberculosis, for use as anti-tubercular drugs, for use as anti-protozoal agents with unexpectedly high potency against Trypanosoma cruzi or Leishmania donovani, and for the treatment of other microbial infections.

Description

Background technique [0001] This application claims priority to US Provisional Patent Application Serial No. 61 / 230,422, filed July 31, 2009, entitled "Nitroimidazooxazine and Nitroimidazooxazole Analogues and Their Uses," the entire contents of which are incorporated herein by reference. [0002] The present invention relates to nitroimidazoxazines and analogues of nitroimidazoxazoles, their preparation and their use alone or in combination with other treatments as drugs effective against Mycobacterium tuberculosis and as antiprotozoa Use of medicines. [0003] Tuberculosis remains the leading cause of death from infection worldwide (mortality estimated at 1.3 million in 2008), with recent resurgence due to increased susceptibility of HIV patients, increased incidence of multidrug-resistant strains, and emergence of extensively drug-resistant strains . Current drug therapy for tuberculosis is long-term and complex, involving daily administration of multiple drug combination...

Claims

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Application Information

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IPC IPC(8): C07D498/04A61K31/424A61K31/4439A61K31/506A61K31/497A61K31/5365A61P31/06
CPCC07D498/04A61P31/00A61P31/04A61P31/06Y02A50/30A01N43/90A61K31/5365A61K31/5383
Inventor 安德鲁·M·托姆普松威廉·亚历山大·丹尼亚德里恩·布拉泽马振坤
Owner GLOBAL ALLIANCE FOR TB DRUG DEV (US)
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