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Benzenesulfonamide compound containing five-membered heterocycle and preparation method and application thereof

A technology of benzenesulfonamide and five-membered heterocyclic ring, which is applied in the field of pharmacy and can solve problems such as poor water solubility, limited application, and obvious side effects of acetazolamide

Active Publication Date: 2020-06-05
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, acetazolamide has obvious side effects, such as numbness of limbs, general discomfort, temporary myopia, gastrointestinal symptoms, etc., which limits its application in long-term treatment.
Currently marketed drugs include acetazolamide, formazolamide, diclofenamide, ethozolamide, dorzolamide, and brinzolamide, but they have problems such as poor water solubility, eye irritation, and short duration of action (Pang Xin et al. Research progress on optic nerve protection therapy for glaucoma, Shenzhen Journal of Integrated Traditional Chinese and Western Medicine, 2018, 28(24):196-198; Song Chunze, Research progress on sulfonamide carbonic anhydrase inhibitors, China New Drugs 2007, 16(18 ): 1438-1444)

Method used

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  • Benzenesulfonamide compound containing five-membered heterocycle and preparation method and application thereof
  • Benzenesulfonamide compound containing five-membered heterocycle and preparation method and application thereof
  • Benzenesulfonamide compound containing five-membered heterocycle and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0142] Example 1: Ethyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylate

[0143]

[0144] 4-carboxybenzenesulfonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol) and 1-hydroxybenzotriazole ( HOBT, 12.0 mmol) was added to DMF (10 ml) and stirred at room temperature for 30 minutes. Then 2-amino-4-ethoxycarbonylthiazole (12.0 mmol) and DMAP (3.0 mmol) were added. React at 45°C until the reaction is complete as detected by TLC. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The starting product was purified by column chromatography (DCM / MT60:1-30:1) to obtain a white solid compound with a yield of 69%. 1H NMR (DMSO-d6) δppm: 13.30 (s, 1H, CONH), 8.27 (d, J = 8.0Hz, 2H, Ar-H), 8.18 (s, 1H, S-CH), 7.98 (d, J =8.0Hz,2H,Ar-H),7.60(s,2H,SO 2 NH 2 ),4.32(q,2H,OCH 2 )...

Embodiment 2

[0145] Example 2: Ethyl 5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxylate

[0146]

[0147] Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1, a white solid, and the yield was 73%. 1 H NMR (DMSO-d6) δppm: 13.77 (s, 1H, CONH), 8.29 (d, J = 8.0Hz, 2H, Ar-H), 8.00 (d, J = 8.0Hz, 2H, Ar-H), 7.61(s,2H,SO 2 NH 2 ),4.43(q,2H,OCH 2 ), 1.37(t,3H,CH 3 ); 13 CNMR(DMSO-d6)δppm: 165.42, 163.26, 159.50, 154.57, 148.38, 134.52, 129.93, 126.41, 63.02, 14.53; ESI-MS: 357.01[M+H] + .

Embodiment 3

[0148] Example 3: N-cyclopropyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

[0149]

[0150] The first step: the preparation of 2-(4-sulfamoylbenzamido)thiazole-4-carboxylic acid

[0151]

[0152] Ethyl 2-(4-sulfamoylbenzamido)thiazole-4-carboxylate (3.56 mmol) was dissolved in tetrahydrofuran (THF, 15 ml). Lithium hydroxide (10.68 mmol) was then added, and the reaction was stirred at room temperature. TLC detected that the reaction was complete, and the pH value of the mixture was adjusted to 5-6 with 10% aqueous hydrochloric acid. After filtering and washing the filter cake with methanol, a white solid compound was obtained with a yield of 91%. 1 H NMR (DMSO-d6) δppm: 13.20-13.00 (m, 2H, CONH, COOH), 8.27 (d, J = 8.0H Z ,2H,Ar-H),8.10(s,1H,CH),7.98(d,J=8.0H Z ,2H,Ar-H),7.59(s,2H,SO 2 NH 2 ); ESI-MS: 328.00[M+H] + .

[0153] The second step: the preparation of N-cyclopropyl-2-(4-sulfamoylbenzamido)thiazole-4-carboxamide

[0154]

[0155] 2-(4-Su...

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Abstract

The invention relates to a benzenesulfonamide compound containing five-membered heterocycle shown as a formula I, enantiomer, diastereoisomer, racemate and mixture thereof, pharmaceutically acceptablesalts, crystalline hydrates and solvates thereof, an application of the compounds in preparation of CA inhibitors, and a pharmaceutical composition containing the compound. The compound is used as acarbonic anhydrase inhibitor. Compared with a clinically common carbonic anhydrase (CA) inhibitor aceturamide, the compound provided by the invention has stronger inhibitory activity on CAI, shows very strong inhibitory ability on CAI and CAII, has IC50 of nanomole level, and is expected to avoid in-vivo drug effect loss caused by imbalance of aceturamide.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a five-membered heterocycle-containing benzenesulfonamide compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and its preparation for treatment Glaucoma, plateau hypoxia, epilepsy, cancer, leukemia, obesity, arthritis and other drugs. Background technique [0002] Human carbonic anhydrase (Carbonic Anhydrases, CA S ) is a zinc-containing protein receptor that catalyzes the reversible hydration of carbon dioxide to form protons and bicarbonate, a reaction involved in many physiological and pathological processes. Includes respiration and transport of carbon dioxide, bicarbonate transport between metabolic tissues and lungs; pH and CO 2 Homeostasis; electrolyte secretion in different tissues and organs; therefore closely related to diseases including human edema, glaucoma, obesity, cancer, ...

Claims

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Application Information

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IPC IPC(8): C07D277/56C07D285/135C07D417/12A61K31/426A61K31/433A61K31/496A61K31/5377A61P27/06A61P9/10A61P25/08A61P35/02A61P3/04A61P19/02
CPCA61P3/04A61P9/10A61P19/02A61P25/08A61P27/06A61P35/02C07D277/56C07D285/135C07D417/12
Inventor 何新华周涛杨朝福李爱玲陈亮李涛韩秋影王静
Owner ACADEMY OF MILITARY MEDICAL SCI
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