CN109836396B - Novel thiazole sulfonamide compound and application thereof as antituberculosis drug - Google Patents
Novel thiazole sulfonamide compound and application thereof as antituberculosis drug Download PDFInfo
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- CN109836396B CN109836396B CN201811165620.5A CN201811165620A CN109836396B CN 109836396 B CN109836396 B CN 109836396B CN 201811165620 A CN201811165620 A CN 201811165620A CN 109836396 B CN109836396 B CN 109836396B
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Abstract
The invention relates to a novel thiazole sulfonamide compound and application thereof as an antituberculosis drug, in particular to a novel thiazole sulfonamide compound with a structure shown in a formula I or pharmaceutically acceptable salt thereof, wherein the structure shown in the formula I is as follows:
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel thiazole sulfonamide compound and application thereof as an anti-tuberculosis drug.
Background
Tuberculosis is a chronic infectious disease caused by tubercle bacillus infection, is a chronic and slow infectious disease which is easy to occur in young people, and has a latent period of 4-8 weeks, wherein 80% of tuberculosis occurs in lungs. Tyrosine phosphatase (MptpB) secreted by mycobacterium tuberculosis is an important virulence factor for binding to mycobacteria, and is an important cause of tuberculosis. MptpB is considered to be a new target for antitubercular drugs. The development of a novel MptpB inhibitor becomes an effective way for overcoming tuberculosis.
Disclosure of Invention
The invention provides a novel thiazole sulfonamide compound with a structure shown in a formula I or a pharmaceutically acceptable salt thereof, which is characterized in that the structure shown in the formula I is as follows:
another embodiment of the present invention provides a process for the preparation of a compound of formula I as described above, characterized by the steps of:
in an organic solvent, the compound of the formula II and the compound of the formula III react under the alkaline condition to generate the compound of the formula I.
The alkaline condition is provided by one or more of potassium carbonate, sodium carbonate and cesium carbonate; the molar ratio of the compound of the formula II to the compound of the formula III is 1.0-1.5: 1; the organic solvent is one or more selected from dichloromethane, chloroform, diethyl ether, acetone, THF, and DMF.
In another embodiment of the present invention, there is provided the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of an anti-tuberculosis medicament. The antituberculous drug is an MptpB inhibitor.
An antituberculous drug characterized by comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The anti-tuberculosis drug also optionally comprises other anti-tuberculosis drugs and/or pharmaceutically acceptable auxiliary materials.
The term "pharmaceutically acceptable salts" according to the present invention refers to non-toxic inorganic or organic acid and/or base addition salts. See, e.g., "Salt selection for basic drugs", int.J. pharm. (1986),33, 201-.
Detailed Description
In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
Weighing the compound of formula II (1.0mmol) dissolved in acetone (5m L), adding potassium carbonate (1.2mmol) at room temperature, stirring for 5 min, adding the compound of formula III (1.0mmol), stirring at room temperature overnight, concentrating under reduced pressure, diluting with ethyl acetate (25m L), sequentially adding water and saturated NaWashed with Cl, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether: 1/5-1/10) to give a compound of formula I (269mg, 82%),1H NMR(600MHz,CDCl3):9.82(s,1H,-NH),7.65-7.59(m,1H,Ph-H),7.53-7.45(m,3H,Ph-H),7.16(s,2H,-NH2),4.62(s,2H,CH2),2.28(s,3H,CH3)；ESI-MS(m/z):351.02[M+Na]+。
example 2
Weighing the compound of formula II (1.5mmol), dissolving in THF (5m L), adding cesium carbonate (1.5mmol) at room temperature, stirring for 5 minutes, adding the compound of formula III (1.0mmol), stirring at room temperature overnight, concentrating under reduced pressure, diluting with ethyl acetate (25m L), washing with water and saturated NaCl in turn, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, performing silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/5-1/10) to obtain the compound of formula I (283mg, 86.2%),1the H NMR and ESI-MS (m/z) data were in accordance with example 1.
Example 3
Weighing phenol (1.0mmol), dissolving in acetone (5M L), adding potassium carbonate (1.2mmol) at room temperature, stirring for 5 min, adding compound of formula III (1.0mmol), stirring at room temperature overnight, concentrating under reduced pressure, diluting with ethyl acetate (25M L), washing with water and saturated NaCl, drying organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/5-1/10) to obtain compound of formula I-3 (251.5mg, 80%), ESI-MS (M/z):337.00[ M + Na ])]+。
Example 5 Mycobacterium tuberculosis tyrosine phosphatase (MptpB) inhibition assay
The MptpB inhibitory activities of the formula I, I-3 and naphthazarin of the present invention were tested according to the experimental method for inhibiting Mycobacterium tuberculosis tyrosine phosphatase (MptpB) disclosed in the Chinese patent application No. 201510660475.8, and the results were as follows:
| compound (I) | IC50(μM) |
| I | 10.5±1.8 |
| I-3 | >100 |
| naphthazarin | 93.6±13.5 |
Claims (8)
1. A thiazole sulfonamide compound with a structure shown in a formula I or a pharmaceutically acceptable salt thereof, wherein the structure shown in the formula I is as follows:
2. a process for the preparation of a compound of formula I according to claim 1, characterized in that it comprises the following steps:
in an organic solvent, the compound of the formula II and the compound of the formula III react under the alkaline condition to generate the compound of the formula I.
3. The method of claim 2, wherein the alkaline conditions are provided by one or more of potassium carbonate, sodium carbonate, and cesium carbonate.
4. The process according to any one of claims 2 to 3, wherein the molar ratio of the compound of formula II to the compound of formula III is from 1.0 to 1.5: 1; the organic solvent is one or more selected from dichloromethane, chloroform, diethyl ether, acetone, THF, and DMF.
5. The use of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-tubercular agent.
6. The use according to claim 5, characterized in that the antitubercular drug is an MptpB inhibitor.
7. An antituberculous drug characterized by comprising a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The anti-tubercular drug according to claim 7, further comprising pharmaceutically acceptable excipients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017112350796 | 2017-11-29 | ||
| CN201711235079 | 2017-11-29 |
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| Publication Number | Publication Date |
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| CN109836396A CN109836396A (en) | 2019-06-04 |
| CN109836396B true CN109836396B (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 |
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2018
- 2018-09-30 CN CN201811165620.5A patent/CN109836396B/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 |
|---|
| 三唑类药物研究新进展;王艳；周成合;《中国科学:化学》;20111231;第41卷(第9期);1429-1456 * |
| 抗结核新靶点及相关药物的研究进展;汪静；张惠斌；周金培；李清;《中国药科大学学报》;20121231;第43卷(第1期);第1-8页 * |
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