CN109836395B - O-trifluoromethyl phenoxyacetamido thiazole sulfonamide MptpB inhibitor - Google Patents
O-trifluoromethyl phenoxyacetamido thiazole sulfonamide MptpB inhibitor Download PDFInfo
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- CN109836395B CN109836395B CN201811165280.6A CN201811165280A CN109836395B CN 109836395 B CN109836395 B CN 109836395B CN 201811165280 A CN201811165280 A CN 201811165280A CN 109836395 B CN109836395 B CN 109836395B
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- acceptable salt
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000000814 tuberculostatic agent Substances 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229940124976 antitubercular drug Drugs 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 abstract description 3
- -1 o-trifluoromethyl phenoxyacetamido thiazole sulfonamide Chemical class 0.000 abstract description 2
- 229940124530 sulfonamide Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- RQNVIKXOOKXAJQ-UHFFFAOYSA-N naphthazarin Chemical compound O=C1C=CC(=O)C2=C1C(O)=CC=C2O RQNVIKXOOKXAJQ-UHFFFAOYSA-N 0.000 description 4
- 201000008827 tuberculosis Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 206010060976 Bacillus infection Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an o-trifluoromethyl phenoxyacetamido thiazole sulfonamide MptpB inhibitor, in particular to a compound shown in a formula I or a pharmaceutically acceptable salt thereof, wherein the structure of the formula I is as follows:
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an o-trifluoromethyl phenoxyacetamido thiazole sulfonamide MptpB inhibitor.
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 compound of formula I or a pharmaceutically acceptable salt thereof, which is characterized in that the structure of 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) and dissolving in chloroform (5m L), adding sodium carbonate (2.0mmol) 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), washing with water and saturated NaCl, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (acetic acid) to obtain the final productEthyl ester/petroleum ether 1/5-1/10) to give a compound of formula I (319mg, 83.5%),1H NMR(600MHz,CDCl3):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):-65.0；ESI-MS(m/z):404.99[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 over 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 (309mg, 80.8%),1H NMR、19f 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 4 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 | 4.3±0.6 |
| I-3 | >100 |
| naphthazarin | 93.6±13.5 |
Claims (8)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized by the structure of formula I 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 |
|---|---|---|---|
| CN2017112350809 | 2017-11-29 | ||
| CN201711235080 | 2017-11-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109836395A CN109836395A (en) | 2019-06-04 |
| CN109836395B true CN109836395B (en) | 2020-08-04 |
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| CN201811165280.6A Expired - Fee Related CN109836395B (en) | 2017-11-29 | 2018-09-30 | O-trifluoromethyl phenoxyacetamido thiazole sulfonamide MptpB inhibitor |
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| Country | Link |
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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 not_active Expired - Fee Related
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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| CN109836395A (en) | 2019-06-04 |
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Granted publication date: 20200804 |