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Lesinurad analog and preparation method and medical application thereof

A technology of analogs and medicinal salts, applied in the field of medicinal chemistry, can solve the problems of slow development, difficulty in developing therapeutically effective compounds, and no great progress, and achieve low toxic and side effects, significant curative effect, and high safety Effect

Active Publication Date: 2015-08-05
ANHUI HEALSTAR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the development of therapeutic drugs for this disease is very slow, and it is difficult to develop compounds that improve therapeutic effectiveness, and there is no great progress

Method used

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  • Lesinurad analog and preparation method and medical application thereof
  • Lesinurad analog and preparation method and medical application thereof
  • Lesinurad analog and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: 2-(1-(4-cyclopropylnaphthalene-1-yl)-1H-tetrazolium-5-sulfur)acetic acid (compound I 1 ) preparation

[0047] Preparation process:

[0048]

[0049] 1) Preparation of 1-cyclopropylnaphthalene

[0050] To a dry 5 L round bottom flask, add 1-bromonaphthalene (414.0 g, 2 mol), [1,3-bis(diphenylphosphino)propane]nickel chloride (165 g, 0.4 mol) and 1500 mL of dry 3000 mL of THF solution of 1.0 mol / L cyclopropylmagnesium bromide was slowly added dropwise to the system with a constant pressure dropping funnel. After the dropwise addition, the reaction compound was stirred at room temperature for 8 h under nitrogen protection, then heated to reflux, and reacted for 36 h. After the reaction was complete, the reaction mixture was cooled to room temperature, then carefully poured into 10 L of stirred ice water, stirred, and adjusted to pH 2 with concentrated hydrochloric acid, CH 2 Cl 2(4000 mL×3) extraction. Combine the organic phases, wash with 3000 mL of...

Embodiment 2

[0068] Embodiment 2: 2-(1-(4-cyclopropyl naphthalene-1-yl)-1H-tetrazolium-5-sulfur) sodium acetate (compound I 1 ) Preparation of sodium salt

[0069] In a dry reaction kettle of 5L, add compound I 1 (162g, 0.49mol) and 2500mL methanol, stirred at room temperature, added 300mL of NaOH (19.6g, 0.49mol) aqueous solution, stirred at room temperature for 20min, then evaporated to dryness in a rotary evaporator, and the residue was vacuum-dried to obtain a light yellow amorphous solid , the above solid was recrystallized with 95% ethanol to obtain white solid compound I 1 Sodium salt 138g, yield 81%, HPLC content 99.6%.

Embodiment 3

[0070] Embodiment 3: Compound I 2 preparation of

[0071] The target compound was synthesized in the same manner as in Example 1, substituting isopropylmagnesium bromide for cyclopropylmagnesium bromide.

[0072]

[0073] 1 H—NMR (500MHz, CDCl 3 / TMS,ppm):

[0074] 12.91 (1H, bs, CO 2 H), 8.50 (1H, d, J = 9.7 Hz, Ar-H), 7.55 ~ 7.66 (4H, m, Ar-H), 7.43 (d, 1H, J = 9.7 Hz, Ar-H), 7.15 ( 1H, d, J=11.6Hz, Ar-H), 3.99 (s, 2H, SCH 2 ), 2.47~2.52 (m, 1H, isopropyl-CH), 1.42 (s, 6H, isopropyl-CH 3 ).

[0075] MS: m / z (M + ) 328 (100%).

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Abstract

The invention relates to a lesinurad analog as shown in the general formula (I), its preparation method, a pharmaceutical composition containing the derivative and an application of the pharmaceutical composition used as a therapeutic agent, especially as a medicine for treating hyperuricemia and gout, wherein definition of each substituent group in the general formula (I) is as the same as definition in the specification.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a lesinurad analogue represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially for hyperuricemia and use in gout medicine. Background technique [0002] Gout is a disease characterized by joint inflammation and pain caused by the deposition of monosodium uric acid (MSU) in joints and other parts. It is also one of the oldest diseases that plague humans. The premise of gout is hyperuricemia, which is generally caused by excessive uric acid production and / or abnormal uric acid metabolism. Gout has gradually developed into the fourth metabolic disease after hypertension, hyperlipidemia and hyperglycemia, and its incidence is increasing rapidly. Uric acid transporter 1 (URAT1) is a new target discovered in recent years that can be used for the treatment of hyperuricemi...

Claims

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Application Information

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IPC IPC(8): C07D257/04A61K31/41A61P19/06
CPCC07D257/04
Inventor 徐奎刘经星
Owner ANHUI HEALSTAR PHARM CO LTD
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