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A kind of thienopyrimidinone acylsulfonamide derivatives and preparation method and application thereof

A technology for pyrimidinone acyl sulfonamides and derivatives, which is applied in the field of thienopyrimidinone acyl sulfonamide derivatives and their preparation, and can solve the problems of poor curative effect, toxic and side effects, etc.

Active Publication Date: 2022-06-24
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The marketed drugs of this class of inhibitors include Probenecid, Sulfinpyrazone, Benzbromarone and Lesinurad, etc., but these drugs have poor or severe curative effects. Toxic and side effects greatly limit the clinical use

Method used

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  • A kind of thienopyrimidinone acylsulfonamide derivatives and preparation method and application thereof
  • A kind of thienopyrimidinone acylsulfonamide derivatives and preparation method and application thereof
  • A kind of thienopyrimidinone acylsulfonamide derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1. Intermediate 2-((3-(4-Cyclopropylnaphthalen-1-yl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl ) Preparation of thio) acetic acid (I-5)

[0035] Preparation of intermediate 4-cyclopropyl-1-naphthylamine (I-1):

[0036] 4-Bromo-1-naphthylamine (3.0 g, 13.51 mmol), cyclopropylboronic acid (1.5 g, 17.44 mmol), K 3 PO 4 (10.2g, 48.05mmol), tetrakis (triphenylphosphine) palladium (1.5g, 1.3mmol) were successively added to a 250mL double-neck flask, 50mL of toluene and 4mL of distilled water were added as solvents, mixed well, N 2 Under the protection, the reaction was heated and refluxed at 100 °C for 12 h; after monitoring the completion of the reaction by TLC, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was evaporated to dryness, the residue was dissolved in ethyl acetate, and washed with saturated NaCl solution (50 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and filtere...

Embodiment 2

[0045] Example 2. Preparation of Compound I1

[0046] Intermediate I-5 (0.2 g, 0.49 mmol) was dissolved in 5 mL of dry dichloromethane, stirred in an ice bath for 10 min, added DMAP (0.09 g, 0.74 mmol), continued to stir in an ice bath for 10 min, and then added EDCI (0.14 g) , 0.74 mmol), and finally, after stirring in an ice bath for 30 min, benzenesulfonamide (0.085 g, 0.54 mmol) was added, slowly raised to room temperature, and stirred for 15 h; monitored by TLC, after the reaction was completed, the solvent was evaporated under reduced pressure, and acetic acid was added to the residue. Ethyl ester 20mL, successively with saturated NaHCO 3 , 1 mol / L dilute hydrochloric acid, washed with saturated NaCl solution (20 mL × 2 times), combined the organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated by column chromatography (methanol: dichloromethane: glacial acetic acid = 1: 30:1.5%). White solid, yield 48.5%, melting po...

Embodiment 3

[0048] Example 3. Preparation of compound I2

[0049] The operation is the same as that in Example 2, except that the sulfonamide used is 4-nitrobenzenesulfonamide, white solid, yield 41.4%, melting point: 176-180°C.

[0050] Compound I2 spectral data: 1 H NMR (400MHz, DMSO-d 6 )δ12.70(s, 1H), 8.53(d, J=8.5Hz, 1H), 8.18(d, J=8.7Hz, 2H), 7.90(d, J=8.5Hz, 2H), 7.66(t, J=7.7Hz, 1H), 7.53 (dd, J=14.8, 6.8Hz, 3H), 7.41 (dd, J=8.0, 5.3Hz, 2H), 7.35 (d, J=5.8Hz, 1H), 3.75– 3.65 (m, 2H), 2.58–2.54 (m, 1H), 1.15 (dd, J=8.7, 4.2Hz, 2H), 0.93–0.81 (m, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ171.31,164.05,162.79,160.38,157.99,151.90,148.56,142.31,134.14,131.02,129.71,128.57,128.19,127.88,127.09,125.43,123.54,123.39,122.91,122.76,122.44,120.64,36.26,13.43,7.72 ,7.39.ESI-MS:m / z 591.06[M-H] - ,C 27 H 20 N 4 O 6 S 3 [592.05].

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Abstract

The invention relates to a thienopyrimidinone acyl sulfonamide derivative and its preparation method and application. The compound has the structure shown in formula I. The present invention also relates to a preparation method and a pharmaceutical composition containing the compound of general formula I. The present invention also provides the application of the above compound in the preparation of anti-gout medicine.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and in particular relates to a thienopyrimidinone acyl sulfonamide derivative and a preparation method and application thereof. Background technique [0002] Gout is a metabolic disease caused by the increased production or decreased excretion of uric acid caused by the disorder of purine metabolism, resulting in the deposition of monosodium urate crystals in joint tissues. Its clinical manifestations are mainly hyperuricemia. In recent years, with the improvement of people's living standards and dietary structure, the number of patients with gout and hyperuricemia has been increasing and tending to be younger, bringing a heavy burden to patients and society. In my country, the incidence of gout is 1.1%, and the incidence of hyperuricemia is 13.3%. Gout has become the second largest metabolic disease after diabetes. The "fourth highest" after blood sugar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61K31/519A61P19/06
CPCC07D495/04A61P19/06
Inventor 刘新泳董悦展鹏赵彤庞建新吴婷孙卓森艾炜
Owner SHANDONG UNIV
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