Sulfonamide compound for treating gout or hyperuricemia and preparation method thereof

A technology for hyperuricemia and compounds, applied in the field of sulfonamide compounds and their preparation, in the field of treating gout or hyperuricemia, can solve the problems of poor curative effect and increasing the response rate of gout patients, etc.

Active Publication Date: 2021-04-02
HINOVA PHARM INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, Lesinurad, a selective uric acid reabsorption inhibitor developed by AstraZeneca, can reduce the secretion of uric acid and reduce the level of uric acid in the serum by inhibiting the URAT1 transporter in the kidney. The drug was approved by the FDA in December 2015. The treatment associated with high levels of uric acid in the blood (hyperuricemia) and gout was approved by the European Medicines Agency (EMA) on February 18, 2016. It is combined with drugs that reduce uric acid production (such as allopurinol and febuxo) Tan) combined use can increase the response rate of gout patients who originally did not respond well to the above drugs, but its single use still has kidney-related risks and poor curative effect. How to maximize the efficacy of URAT1 inhibitors and overcome its side effects as much as possible , has become a research hotspot

Method used

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  • Sulfonamide compound for treating gout or hyperuricemia and preparation method thereof
  • Sulfonamide compound for treating gout or hyperuricemia and preparation method thereof
  • Sulfonamide compound for treating gout or hyperuricemia and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The synthesis of embodiment 1,4-(4-aminopyridin-3-yl)-1-naphthalene nitrile (Int 2)

[0054] 1) Synthesis of 4-(pinacol borate-3-yl)-1-naphthonitrile (Int1)

[0055]

[0056] Add 4-bromo-1-naphthonitrile (232mg, 1mmol), potassium acetate (196mg, 2mmol), bipinacol borate (380mg, 1.5mmol), Pd(dppf)Cl to a 100mL reaction flask 2 (73mg, 0.1mmol), DMSO (5mL), nitrogen replacement three times, heated to 80°C and stirred for 6 hours. Then the reaction solution was poured into water (30mL), extracted three times with ethyl acetate (3×15ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and passed through the column after rotary evaporation to obtain intermediate 1 (176mg ), yield 63%. 1 H NMR (400MHz, Chloroform-d) δ8.88–8.72(m,1H),8.30–8.18(m,1H),8.08(d,J=7.1Hz,1H),7.88(d,J=7.2Hz, 1H),7.72–7.56(m,2H),1.43(s,12H).

[0057] 2) Synthesis of 4-(4-aminopyridin-3-yl)-1-naphthonitrile (Int 2)

[0058]

[0059]...

Embodiment 2

[0061] Embodiment 2, the synthesis of N-(3-(4-cyanonaphthalene-1-yl)pyridin-4-yl)cyclobutylsulfonamide (4)

[0062]

[0063] Add Intermediate 2 (245mg, 1mmol), dichloromethane (8mL), triethylamine (303mg, 3mmol) to a 100mL reaction flask, and add cyclobutylsulfonyl chloride (185mg, 1.2mmol) in batches under ice-water bath conditions ), naturally slowly return to room temperature and react for 3 hours. After the reaction was completed, the reaction solution was poured into water (30mL), extracted three times with dichloromethane (3×15ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and passed through the column after rotary evaporation to obtain compound 4 (72 mg), yield 20%. Mass Spectrum: 364.1(M+H + ).

[0064] 1 H NMR (400MHz, Chloroform-d) δ8.74–8.66 (m, 1H), 8.49 (d, J = 5.1Hz, 1H), 8.41 (dd, J = 8.4, 5.2Hz, 1H), 8.23 ​​(dd, J=6.9,5.4Hz,1H),8.11(dd,J=7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.6...

Embodiment 3

[0065] Example 3, N-(3-(4-cyanonaphthalene-1-yl)pyridin-4-yl)cyclopropylsulfonamide (1)

[0066]

[0067] Replace the raw material cyclobutylsulfonyl chloride for the preparation of compound 4 with cyclopropylsulfonyl chloride, and follow the same preparation method as compound 4 to obtain compound 1, mass spectrum: 350.1 (M+H + ).

[0068] 1H NMR (400MHz, Chloroform-d) δ8.74–8.66 (m, 1H), 8.49 (d, J = 5.1Hz, 1H), 8.41 (dd, J = 8.4, 5.2Hz, 1H), 8.23 ​​(dd, J=6.9,5.4Hz,1H),8.11(dd,J=7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J=7.4, 5.3Hz, 1H), 7.58(dd, J=8.5, 5.2Hz, 1H), 7.37(s, 1H), 2.74–2.81(m, 1H), 1.39–1.13(m, 4H).

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Abstract

A compound as represented by formula (I), and optical isomers, solvates, pharmaceutically-acceptable salts, or prodrugs thereof. The present invention has urate transporter 1 (URAT1) inhibitory activity, can be used for treatment of gout and hyperuricemia, and can also be used for treatment of diseases related to abnormal URAT1 activity, such as recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, coronary heart disease, Lesch-Nyhan syndrome, Kearns-Sayre syndrome, kidney diseases, kidney stones, kidney failure, joint inflammations, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, or hypoxanthine-guanine phosphoribosyltransferase deficiency. (I)

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to sulfonamide compounds, a preparation method thereof, and an application thereof for treating gout or hyperuricemia. Background technique [0002] Gout is an inflammatory disease characterized by pain and swelling caused by the deposition of monosodium urate (MSU) in joints and subcutaneous parts. It is one of the oldest diseases that plague humans. The premise of MSU deposition instrument gout is hyperuricemia, that is, a pathological state in which the level of serum uric acid (sUA) is higher than the solubility of uric acid in the blood. Hyperuricemia is usually caused by excessive uric acid production and / or decreased uric acid excretion, with the latter accounting for about 90% of patients with hyperuricemia. [0003] At present, the treatment drugs for hyperuricemia and gout mainly include: ① Anti-inflammatory and analgesic drugs used to control symptoms such as jo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/76C07D405/12C07D401/12C07D417/12C07D409/12C07D413/12A61K31/4418A61K31/4439A61K31/4427A61K31/443A61K31/4545A61K31/4433A61K31/55A61K31/444A61K31/506A61K31/497A61K31/501A61K31/4436A61P19/06A61P19/02A61P9/12A61P9/00A61P9/10A61P13/12A61P13/04A61P39/02A61P17/06A61P5/20
CPCA61P5/20A61P9/00A61P9/10A61P9/12A61P13/04A61P13/12A61P17/06A61P19/02A61P19/06A61P39/02C07D213/76C07D401/12C07D405/12C07D409/12C07D413/12C07D417/12A61K31/44A61K31/4418A61K31/4427A61K31/443A61K31/4433A61K31/4436A61K31/4439A61K31/444A61K31/4545A61K31/497A61K31/501A61K31/506A61K31/55A61P5/18A61P25/00C07D213/75
Inventor 樊磊胥珂馨陈锞张少华杜武李兴海陈元伟
Owner HINOVA PHARM INC
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