CN-116874406-B - Indolyl sulfonamide compound and preparation method and application thereof

Abstract

The invention relates to an indolyl sulfonamide compound, a preparation method and application thereof. The compound has a structure shown in a formula I. The invention also relates to a preparation method of the compound containing the structure shown in the formula I and a pharmaceutical composition. The invention also provides application of the compound in preparing uric acid reducing medicines.

Inventors

• ZHANG ZHIJIAO
• ZHAN PENG
• LIU XINYONG
• WANG ZHENQIAN
• SHI XIAOYU
• Qi Danhui
• ZHAO TONG
• ZHANG JIAN

Assignees

• 山东大学

Dates

Publication Date

20260505

Application Date

20230625

Claims (5)

1. 1. The indolyl sulfonamide compound or the pharmaceutically acceptable salt thereof has a structure shown in the following general formula I: Wherein R 1 is cyclopropyl or bromine, R 2 is selected from C1-C5 alkyl or cyclopropyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle, the aromatic heterocycle is selected from furyl or thienyl, and the substituent is selected from halogen, hydroxy, nitro, trifluoromethyl and C1-C5 alkyl.
2. 2. The indolyl sulfonamide compound is characterized by being one of the following compounds:
3. 3. the method for preparing the indolyl sulfonamide compound according to claim 2, which is one of the following methods: (1) Synthesis of Compounds 1 to 24: Firstly, taking 1-bromo-4-methylnaphthalene as A starting material, reacting with N-bromosuccinimide in normal hexane under the catalysis of dibenzoyl peroxide to generate ZS-A, namely 1-bromo-4- (bromomethyl) naphthalene, reacting an intermediate ZS-A with 1H-indole-2-methyl formate under the catalysis of cesium carbonate in acetonitrile to generate an intermediate ZS-B, namely 1- (4-bromonaphthalene-1-yl) methyl-1H-indole-2-methyl formate, hydrolyzing the intermediate ZS-B in A mixed solution of tetrahydrofuran and methanol by using lithium hydroxide to obtain A compound ZS-C, namely 1- (4-bromonaphthalene-1-yl) methyl-1H-indole-2-formic acid, and condensing the ZS-C with different types of sulfonamides under the catalysis of 4-Dimethylaminopyridine (DMAP) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) to obtain target products 1-24; Route one: Reagents and conditions of (i) N-bromosuccinimide, dibenzoyl peroxide, N-hexane, 70 ℃, (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70 ℃, (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature, (iv) sulfonamide, in DMAP, EDCI, dichloromethane, 0 ℃ -room temperature; wherein R 2 is as defined in claim 1, and the structure of the compounds 1 to 24 is as shown in claim 2; (2) Synthesis of Compounds 25 to 47 The synthesis of a compound ZS-B, namely 1- (4-bromonaphthalene-1-yl) methyl-1H-indole-2-methyl formate, is consistent with the synthesis of the compounds 1-24, except that ZS-B reacts with cyclopropylboric acid in toluene under the action of tricyclohexylphosphine, potassium phosphate and palladium acetate to generate an intermediate SZ-B, namely 1- (4-cyclopropyl-1-yl) methyl-1H-indole-2-methyl formate, the intermediate SZ-B is hydrolyzed by lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain SZ-C, namely 1- (4-cyclopropyl-1-yl) methyl-1H-indole-2-formic acid, and the SZ-C is condensed with different types of sulfonamides under the catalysis of DMAP and EDCI to obtain target products 25-47; route two: Reagents and conditions of (i) N-bromosuccinimide, dibenzoyl peroxide, N-hexane, 70 ℃, (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70 ℃, (iii) tricyclohexylphosphine, cyclopropylboric acid, palladium acetate, potassium phosphate, toluene, 100 ℃ and nitrogen, (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature, (v) sulfonamide, in DMAP, EDCI, dichloromethane, 0 ℃ to room temperature; Wherein R 2 is as defined in claim 1, and the structure of the compound 25-47 is as shown in claim 2; The room temperature is 20-30 ℃.
4. 4. Use of an indolyl sulfonamide compound according to any of claims 1-2 for the manufacture of a medicament for reducing uric acid.
5. 5. A uric acid lowering pharmaceutical composition comprising an indolyl sulfonamide compound of any one of claims 1-2 and one or more pharmaceutically acceptable carriers or excipients.

Description

Indolyl sulfonamide compound and preparation method and application thereof Technical Field The invention belongs to the technical field of synthesis and medical application of organic compounds. In particular to an indolyl sulfonamide compound, a preparation method thereof or a pharmaceutical composition containing the same and application thereof in medicine. Background Hyperuricemia (HUA) refers to fasting blood uric acid levels of >420 μmol/L twice a day under normal purine dietary conditions. Gout refers to a concentration of blood uric acid exceeding 6.8mg/dL, a crystal-related arthropathy caused by the deposition of monosodium urate (MSU), and is directly related to hyperuricemia caused by purine metabolic disorder or uric acid excretion reduction, in particular to acute characteristic arthritis and chronic tophus diseases. Gout and hyperuricemia are both associated with uric acid levels in humans. Normal adults produce approximately 750mg of uric acid daily, 1/3 of which is catabolized by the intestinal tract and 2/3 of which is excreted by the kidneys, thus maintaining stable uric acid levels in the body. At present, the medicines for treating gout mainly have two types, namely a xanthine oxidase inhibitor for inhibiting uric acid generation and a URAT1 inhibitor for promoting uric acid excretion. Uric acid transporter 1 (URAT 1) is located on the brush border of human kidney proximal tubular epithelial cells, and mainly mediates uric acid reabsorption in the kidney, and increased URAT1 activity or increased gene expression due to gene mutation is one of the important pathogenesis of hyperuricemia. Lesinurad is a URAT1 inhibitor for treating hyperuricemia and gout, and has large therapeutic dosage and serious toxic and side effects. Therefore, the novel uric acid reducing drug with better activity and safety and independent intellectual property is hopeful to be obtained by further structural modification. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a preparation method of an indolyl acyl sulfonamide compound, and also provides an activity screening result of the compound serving as a uric acid reducing drug and application thereof. The technical scheme of the invention is as follows: 1. indolyl sulfonyl sulfonic acid amide compounds The indolyl sulfonamide compound or the pharmaceutically acceptable salt thereof has a structure shown in the following general formula I: Wherein R 1 is cyclopropyl or bromine, R 2 is selected from C1-C5 alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle, the aromatic heterocycle is selected from naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl, and the substituent is selected from halogen, hydroxy, amino, nitro, hydroxy, cyano, trifluoromethyl, C1-C5 alkyl or cycloalkyl. According to a preferred embodiment of the invention, the indolyl sulfonamide compound is one of the following: TABLE 1 structural formulas of Compounds 1-47 2. Preparation method of indolyl sulfonamide compound The preparation method of the indolyl acyl sulfonamide compound comprises one of the following steps: (1) Synthesis of Compounds 1 to 24: Firstly, reacting 1-bromo-4-methylnaphthalene serving as A starting material with N-bromosuccinimide in normal hexane under the catalysis of dibenzoyl peroxide to generate ZS-A, namely 1-bromo-4- (bromomethyl) naphthalene, reacting an intermediate ZS-A with 1H-indole-2-methyl formate in acetonitrile under the catalysis of cesium carbonate to generate an intermediate ZS-B, namely 1- (4-bromonaphthalene-1-yl) methyl-1H-indole-2-methyl formate, and hydrolyzing the intermediate ZS-B with lithium hydroxide in A mixed solution of tetrahydrofuran and methanol to obtain A compound ZS-C, namely 1- (4-bromonaphthalene-1-yl) methyl-1H-indole-2-formic acid, and condensing the ZS-C with different types of sulfonamides under the catalysis of 4-Dimethylaminopyridine (DMAP) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) to obtain target products 1-24. Route one: Reagents and conditions of (i) N-bromosuccinimide, dibenzoyl peroxide, N-hexane, 70 ℃, (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70 ℃, (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature, (iv) sulfonamide, DMAP, EDCI, dichloromethane, 0 ℃ -room temperature; Wherein R 2 is the same as the general formula I, and the structures of the compounds 1-24 are shown as 1-24 in table 1; (2) Synthesis of Compounds 25 to 47 The synthesis of a compound ZS-B, namely 1- (4-bromonaphthalene-1-yl) methyl-1H-indole-2-methyl formate, is consistent with the synthesis of the compounds 1-24, except that ZS-B reacts with cyclopropylboric acid in toluene under the action of tricyclohexylphosphine, potassium phosphate and palladium acetate to generate an intermediate SZ-B, namely 1- (4-cyclopropyl-1-yl) methyl-1H-indole-