6,7-Dihydroimidazo[2,1-b][1,3]oxazine fungicide

A technology of oxazine and dihydro, applied in antibacterial drugs, organic active ingredients, organic chemistry, etc., can solve problems such as death and difficult treatment of atypical mycobacterial disease

Active Publication Date: 2016-11-16
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, the treatment of atypical mycobacteriosis requires long-term drug administration compared to the treatment of conventional bacterial infections, and in some cases, it has been reported that atypical mycobacterial disease has become refractory to treatment, likely resulting in death

Method used

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  • 6,7-Dihydroimidazo[2,1-b][1,3]oxazine fungicide
  • 6,7-Dihydroimidazo[2,1-b][1,3]oxazine fungicide
  • 6,7-Dihydroimidazo[2,1-b][1,3]oxazine fungicide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 202

[1421] Preparation of 4-{4-[3-(4-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenol

[1422] The title compound was prepared in the same manner as in Reference Example 191 using appropriate starting materials.

[1423] brown solid

[1424] Reference Example 203

[1425] Preparation of 4-[2-(4-chlorophenoxymethyl)oxazol-4-yl]phenol

[1426] 2-Bromo-1-(4-hydroxyphenyl)ethanone (2.90g) and 2-(4-chlorophenoxy)acetamide (5.0g) were added to N-methylpyrrolidone (5ml), and The mixture was stirred at 100°C under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the layers were separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. A solution of sodium acetate (11.1 g) in DMF (20 ml) was added to the residue and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, ...

Embodiment 212

[1464] Preparation of 4-{(3R,5S)-3,5-Dimethyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenol

[1465] The title compound was prepared in the same manner as in Reference Example 191 using appropriate starting materials.

[1466] brown amorphous

[1467] MS(m / z):486[M] +

Embodiment 213

[1469] Preparation of 4'-[4-(4-trifluoromethoxyphenoxy)piperidin-1-ylmethyl]-biphenyl-4-ol

[1470] To a solution of 4'-hydroxybiphenyl-4-carbaldehyde (1.13g) and 4-(4-trifluoromethoxyphenoxy)piperidine (1.78g) in 1,2-dichloroethane (11ml) Sodium triacetoxyborohydride (1.69 g) was added to and stirred overnight at room temperature. Aqueous potassium carbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→0:10) to obtain the title compound (1.73 g) as a yellow powder.

[1471] MS(m / z):443[M] +

[1472] Reference Example 214

[1473] Preparation of 4-{3,5-Dimethyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenol

[1474] The title compound was prepared in the same manner as in Reference Example 187 using appropriate starting...

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Abstract

The present invention provides a 6,7-dihydroimidazo[2,1-b][1,3]oxazine compound, which has excellent bactericidal properties against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis and atypical acid-fast bacilli effect. Specifically, the present invention provides a compound represented by formula (1) or a salt thereof, wherein R 1 Represents tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydrobenzazepanyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolinyl, naphthyl, quinolyl Linyl, phenyl, biphenyl or pyridyl, these groups are optionally substituted, by R 1 Represented phenyl, biphenyl and pyridyl are each substituted directly or via a linker with at least one group selected from the group consisting of: tetrahydropyridyl, diazepanyl, diazabicyclo Heptyl, tetrahydrotriazolopyrazinyl, tetrahydroimidazopyrazinyl, azabicyclooctyl, oxazolyl, piperazinyl, piperidinyl, thiazolyl, etc., each of these groups one is optionally substituted; and R 2 represents hydrogen or lower alkyl. The present invention also provides pharmaceutical compositions comprising the above compounds.

Description

technical field [0001] The present invention relates to 6,7-dihydroimidazo[2,1-b][1,3]oxazine compounds. Background technique [0002] Mycobacterium tuberculosis is a well-known acid-fast bacillus that is said to infect one third of the population. In addition to M. tuberculosis, M. africanum and M. bovis are also known to be classified in the Mycobacterium tuberculosis complex, known as mycobacteria, which are highly pathogenic to humans. [0003] These are treated with three agents, rifampicin, isoniazid, and ethambutol (or streptomycin), or four agents, the three above plus pyrazinamide, which are first-line drugs. [0004] However, the treatment of tuberculosis requires extremely long-term drug administration, which leads to poor compliance, often leading to treatment failure. [0005] In addition, the above agents have been reported to cause side effects such as the following: rifampicin causes liver disease, flu symptoms, and drug allergy, and combined use with other...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04A61K31/5365A61P31/04A61P31/06
CPCC07D498/04C07D519/00A61P31/04A61P31/06
Inventor 川野芳和原口佳和佐佐木博文植松幸崇壶内英继矢田裕美清水洋小桥一穗系谷元宏田井国宪竹村勋林美佳世桥诘博之松叶未贵中村出陈修浩松本真
Owner OTSUKA PHARM CO LTD
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