CN109836395A - A kind of o-trifluoromethyl phenoxy acetamide base thiazole sulfonamide MptpB inhibitor - Google Patents
A kind of o-trifluoromethyl phenoxy acetamide base thiazole sulfonamide MptpB inhibitor Download PDFInfo
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- CN109836395A CN109836395A CN201811165280.6A CN201811165280A CN109836395A CN 109836395 A CN109836395 A CN 109836395A CN 201811165280 A CN201811165280 A CN 201811165280A CN 109836395 A CN109836395 A CN 109836395A
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- antituberculotic
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Abstract
The present invention relates to a kind of o-trifluoromethyl phenoxy acetamide base thiazole sulfonamide MptpB inhibitor, and in particular to a kind of compound of formula I or its pharmaceutically acceptable salt, Formulas I structure are as follows:
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of o-trifluoromethyl phenoxy acetamide base thiazole sulfonamide
MptpB inhibitor.
Background technique
Tuberculosis is the chronic infectious disease as caused by mycobacterium tuberculosis infection, is that the incidental one kind of young people is chronic gentle
The infectious disease of hair, incubation period 4~8 weeks, wherein 80% occurs in lung.The tyrosine phosphatase secreted by mycobacterium tuberculosis
(MptpB) it is the important virulence factor for combining mycobacteria, is to cause phthisical major reason.MptpB is considered as resistive connection
The novel targets of nuclear pharmaceuticals.Novel MptpB inhibitor is developed, becomes and captures effective way lungy.
Summary of the invention
The present invention provides a kind of compound of formula I or its pharmaceutically acceptable salt, it is characterised in that Formulas I structure is as follows:
Another embodiment of the present invention provides the preparation method of above-mentioned compound of formula I, it is characterised in that including walking as follows
It is rapid:
In organic solvent, Formula II compound reacts under alkaline condition with formula III compound generates compound of formula I.
The alkaline condition is provided by one or more of potassium carbonate, sodium carbonate, cesium carbonate；Formula II compound and formula
The molar ratio of III compound is 1.0~1.5:1；Organic solvent is in methylene chloride, chloroform, ether, acetone, THF, DMF
It is one or more of.
Another embodiment of the present invention provides above-mentioned compound of formula I or its pharmaceutically acceptable salt is preparing treating tuberculosis
Application in drug.The antituberculotic is MptpB inhibitor.
A kind of antituberculotic, it is characterised in that its using compound of formula I or its pharmaceutically acceptable salt as effectively at
Point.The antituberculotic also optionally includes other antituberculotics and/or pharmaceutically acceptable auxiliary material.
Term " pharmaceutically acceptable salt " refers to the addition of atoxic inorganic or organic acid and/or alkali in the present invention
Salt.It can be found in " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for better understanding invention, reality of the invention
The mode of applying is not limited to the following contents.
Embodiment 1
It weighs Formula II compound (1.0mmol) to be dissolved in chloroform (5mL), at room temperature, is added sodium carbonate (2.0mmol), stirs
It mixes after five minutes, is added formula III compound (1.0mmol), reaction is stirred at room temperature overnight, is concentrated under reduced pressure, ethyl acetate is added to dilute
(25mL) is successively washed with water, saturation NaCl, and organic layer is dry with anhydrous sodium sulfate, filters, after concentration, through silica gel column chromatography
(ethyl acetate/petroleum ether=1/5-1/10) obtains compound of formula I (319mg, 83.5%),1H NMR(600MHz,CDCl3):δ
9.84(s,1H,-NH),7.82-7.75(m,2H,Ph-H),7.58-7.50(m,2H,Ph-H),7.18(s,2H,-NH2),4.65
(s,2H,CH2)；19F NMR(564MHz,CDCl3):δ-65.0；ESI-MS(m/z):404.99[M+Na]+。
Embodiment 2
It weighs Formula II compound (1.5mmol) to be dissolved in THF (5mL), at room temperature, be added cesium carbonate (1.5mmol), stirring
After five minutes, formula III compound (1.0mmol) is added, reaction is stirred at room temperature overnight, is concentrated under reduced pressure, ethyl acetate is added to dilute
(25mL) is successively washed with water, saturation NaCl, and organic layer is dry with anhydrous sodium sulfate, filters, after concentration, through silica gel column chromatography
(ethyl acetate/petroleum ether=1/5-1/10) obtains compound of formula I (309mg, 80.8%),1H NMR、19F NMR and ESI-MS
(m/z) data and embodiment 1 are consistent.
Embodiment 3
It weighs phenol (1.0mmol) to be dissolved in acetone (5mL), at room temperature, is added potassium carbonate (1.2mmol), stirs 5 minutes
Afterwards, formula III compound (1.0mmol) is added, reaction is stirred at room temperature overnight, is concentrated under reduced pressure, ethyl acetate is added to dilute (25mL), according to
It is secondary wash with water, saturation NaCl, organic layer is dry with anhydrous sodium sulfate, filtering, be concentrated after, through silica gel column chromatography (ethyl acetate/
Petroleum ether=1/5-1/10), it obtains -3 compound of Formulas I (251.5mg, 80%), ESI-MS (m/z): 337.00 [M+Na]+。
Embodiment 4 mycobacterium tuberculosis tyrosine phosphatase (MptpB) Inhibition test
According to Chinese invention patent (application number: mycobacterium tuberculosis tyrosine phosphatase disclosed in 201510660475.8)
(MptpB) Inhibition test method tests the MptpB inhibitory activity of formula I, I-3 and naphthazarin, as a result
It is as follows:
| Compound | IC50(μM) |
| I | 4.3±0.6 |
| I-3 | >100 |
| naphthazarin | 93.6±13.5 |
Claims (8)
1. a kind of compound of formula I or its pharmaceutically acceptable salt, it is characterised in that Formulas I structure is as follows:
2. the preparation method of compound of formula I described in claim 1, it is characterised in that include the following steps:
In organic solvent, Formula II compound reacts under alkaline condition with formula III compound generates compound of formula I.
3. preparation method as claimed in claim 2, it is characterised in that the alkaline condition is by potassium carbonate, sodium carbonate, cesium carbonate
One or more of provide.
4. the described in any item preparation methods of claim 2-3, it is characterised in that mole of Formula II compound and formula III compound
Than for 1.0~1.5:1；Organic solvent is selected from one or more of methylene chloride, chloroform, ether, acetone, THF, DMF.
5. compound of formula I described in claim 1 or its pharmaceutically acceptable salt are preparing the application in antituberculotic.
6. application described in claim 5, it is characterised in that the antituberculotic is MptpB inhibitor.
7. a kind of antituberculotic, it is characterised in that it is with compound of formula I described in claim 1 or its is pharmaceutically acceptable
Salt is as effective component.
8. antituberculotic as claimed in claim 7, it is characterised in that the antituberculotic also optionally includes other anti-tubercular drugs
Object and/or pharmaceutically acceptable auxiliary material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711235080 | 2017-11-29 | ||
| CN2017112350809 | 2017-11-29 |
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| CN109836395A true CN109836395A (en) | 2019-06-04 |
| CN109836395B CN109836395B (en) | 2020-08-04 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102732474A (en) * | 2012-05-21 | 2012-10-17 | 中山大学 | Compound for inhibiting mycobacterium tuberculosis, screening method and uses thereof |
| CN103694209A (en) * | 2013-06-07 | 2014-04-02 | 中山大学 | Marine fungus-derived acetophenone compounds and preparation method and application thereof |
| CN105193775A (en) * | 2015-10-14 | 2015-12-30 | 华南师范大学 | Application of naphthazarin derivatives in preparation of mycobacterium tuberculosis tyrosine phosphatase inhibitor and anti-tuberculosis drugs |
| CN105687187A (en) * | 2016-03-11 | 2016-06-22 | 中山大学 | Application of compounds Pyrrocidines in preparation of anti-tuberculosis drug |
| CN107286120A (en) * | 2016-04-11 | 2017-10-24 | 中国海洋大学 | A kind of application of butyrolactone compound in antituberculotic is prepared |
-
2018
- 2018-09-30 CN CN201811165280.6A patent/CN109836395B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102732474A (en) * | 2012-05-21 | 2012-10-17 | 中山大学 | Compound for inhibiting mycobacterium tuberculosis, screening method and uses thereof |
| CN103694209A (en) * | 2013-06-07 | 2014-04-02 | 中山大学 | Marine fungus-derived acetophenone compounds and preparation method and application thereof |
| CN105193775A (en) * | 2015-10-14 | 2015-12-30 | 华南师范大学 | Application of naphthazarin derivatives in preparation of mycobacterium tuberculosis tyrosine phosphatase inhibitor and anti-tuberculosis drugs |
| CN105687187A (en) * | 2016-03-11 | 2016-06-22 | 中山大学 | Application of compounds Pyrrocidines in preparation of anti-tuberculosis drug |
| CN107286120A (en) * | 2016-04-11 | 2017-10-24 | 中国海洋大学 | A kind of application of butyrolactone compound in antituberculotic is prepared |
Non-Patent Citations (2)
| Title |
|---|
| 汪静；张惠斌；周金培；李清: "抗结核新靶点及相关药物的研究进展", 《中国药科大学学报》 * |
| 王艳；周成合: "三唑类药物研究新进展", 《中国科学:化学》 * |
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