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2-[5-bromo-4-(4-fluorocyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio]acetic acid compound and its application

A technology of cyclopropyl naphthalene and compounds, applied in metabolic diseases, drug combinations, organic chemistry, etc., can solve the problems of large side effects of drugs, and achieve the effect of enhanced inhibitory activity

Active Publication Date: 2020-12-01
GUANGDONG SCI FINDER PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although uricosuric drugs such as benzbromarone and probenecid can inhibit URAT1, they are all non-selective inhibitors and act on multiple targets in the body, resulting in serious side effects.

Method used

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  • 2-[5-bromo-4-(4-fluorocyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio]acetic acid compound and its application
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  • 2-[5-bromo-4-(4-fluorocyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio]acetic acid compound and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Synthesis of 1-(2,2-Difluorocyclopropyl)naphthalene (Compound 2)

[0035] 1.54g (10mmol) 1-vinylnaphthyl ester (compound 1) was dissolved in 22ml of 50% aqueous sodium hydroxide solution, and slowly added dropwise under ice bath to contain 2.53g (13.2mmol) bromodifluoromethane and 0.1g ( 0.04mmol) benzyltriethylammonium chloride in 20ml dichloromethane. After the dropwise addition was completed, the temperature was raised to room temperature. Stir at room temperature for 72 hours. After the reaction was completed, 20 g of ice was added to quench the reaction. The organic phase was separated, the aqueous phase was extracted three times with dichloromethane, and dried over anhydrous magnesium sulfate. After separation by column chromatography, 1.10 g of a colorless oil was obtained, with a yield of 54%.

[0036] ESI / MS[M+H]: 205.

Embodiment 2

[0037] Example 2 Synthesis of 1-(2,2-difluorocyclopropyl)-4-nitronaphthalene (compound 3)

[0038] 2.04g (10mmol) of compound 2 was placed in the reaction flask, and stirred in an ice bath for 10 minutes. Slowly drop 10ml of sodium nitrite into the reaction flask under ice cooling (at least 1 hour). The reaction was carried out under ice bath for 1.5 hours. Add 100 ml of ice water, extract three times with ethyl acetate, and dry over anhydrous magnesium sulfate. After separation by column chromatography, 1.79 g of compound 3 was obtained, with a yield of 72%.

[0039] 1 H-NMR (CDCl 3 300MHz): 0.92-1.17(m, 2H), 2.04-2.36(m, 1H), 7.25-7.39(d, 1H), 7.90-8.04(m, 2H), 8.25-8.31(d, 1H), 8.51- 8.57(d, 1H), 8.87-8.93(d, 1H).

[0040] ESI / MS[M+H]: 250.

Embodiment 3

[0041] Example 3 Synthesis of 1-(2,2-difluorocyclopropyl)-4-aminonaphthalene (Compound 4)

[0042] 2.49g (10mmol) of compound 3 was dissolved in 200ml of ethanol, 10% 0.9g of palladium carbon was added, hydrogen was introduced, and stirred at room temperature overnight. Filtered through celite, concentrated under reduced pressure, and separated by column chromatography to obtain 1.84 g of compound 4 with a yield of 84%.

[0043] ESI / MS [M-H]: 218.

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Abstract

The invention discloses a 2-[5-bro-4-(4-fluorocyclopropyl-naphthalene-1-base)-4H-1,2,4-triazole-3-sulfenyl] acetate compound with a structure of formula (I), and an acceptable salt on pharmacy, an optical isomer or a prodrug thereof, wherein R1, R2, R3 and R4 respectively independently represents H or F, and R1, R2, R3 and R4 are not all H. By introducing F atoms onto cyclopropyl of lesinurad Sodium, the inhibition activity for urate transporter 1 is greatly improved, no serious side effect presents, and the 2-[5-bro-4-(4-fluorocyclopropyl-naphthalene-1-base)-4H-1,2,4-triazole-3-sulfenyl] acetate compound is particularly suitable for preparing a drug for preventing or treating hyperuricemia.

Description

technical field [0001] The present invention relates to the field of medicine, more specifically, to a kind of 2-[5-bromo-4-(4-fluorocyclopropylnaphthalen-1-yl)-4H-1 used as urate transporter 1 inhibitor , 2,4-triazol-3-ylthio]acetic acid compound and use thereof. Background technique [0002] Uric acid is the end product of human purine metabolism, which is produced by hypoxanthine and xanthine under the action of xanthine oxidase (XO). In most mammals, uric acid can be oxidized to water-soluble allantoin by urate oxidase and excreted. In the human body, due to gene silencing of urate oxidase, uric acid cannot be re-oxidized to form allantoin, resulting in elevated blood uric acid and easily forming hyperuricemia. [0003] Hyperuricemia is a common metabolic syndrome, and the prevalence rate of hyperuricemia in western countries is 15%-20%. It is estimated that there are about 120 million patients with hyperuricemia in my country [Society of Endocrinology, Chinese Medical...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/12A61K31/4196A61P19/06A61P3/10A61P9/12A61P3/06
CPCC07D249/12
Inventor 冯文周冯鑫黄志鹏郭庆磊
Owner GUANGDONG SCI FINDER PHARMA TECH CO LTD
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