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Deuterium-substituted 2-phenylthiazole compound, and pharmaceutical composition thereof

A compound, thiazole technology, is used as a xanthine oxidase inhibitor to treat gout and hyperuricemia, and can solve problems such as adverse reactions

Inactive Publication Date: 2014-06-11
镇江新元素医药科技有限公司(中外合资)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in allopurinol therapy, repeated high-dose administration is required to maintain high drug levels
This also brings serious and even fatal adverse reactions due to drug accumulation.

Method used

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  • Deuterium-substituted 2-phenylthiazole compound, and pharmaceutical composition thereof
  • Deuterium-substituted 2-phenylthiazole compound, and pharmaceutical composition thereof
  • Deuterium-substituted 2-phenylthiazole compound, and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] 2-[3-cyano-4-(2′,3′,4′,5′,6′-pentadeuteriophenyl)-phenyl]-4-methyl-thiazole-5-carboxylic acid (8) Synthesis

[0086]

[0087] Step A: Add thioacetamide (17.0g, 226.7mmol) and p-hydroxybenzonitrile (18.0g, 151.1mmol) into concentrated hydrochloric acid (470mL), heat up to 50°C, stir for 3 hours, TLC analysis shows that the reaction is complete . The reaction solution was cooled to 0°C, filtered, the filter cake was washed with a small amount of water, and dried in vacuo to obtain a crude product of p-hydroxythiobenzamide (2) (26.0g) as a yellow powder, which was directly used in the next step without purification . MS (EI, m / z): 154.1 [M+H] + .

[0088] Step B: The crude compound 2 (25.0g, 163.2mmol) and ethyl 2-chloroacetoacetate (26.5g, 161.0mmol) were added to absolute ethanol (75mL), and the resulting mixture was stirred at reflux for 3 hours and analyzed by TLC Indicates the end of the reaction. The reaction solution was cooled to 0°C, continued to stir for...

Embodiment 2

[0096] Synthesis of 2-(3-cyano-4-phenyl-5-deuterophenyl)-4-methyl-thiazole-5-carboxylic acid (14)

[0097]

[0098] Step A: NBS (4.2g, 23.6mmol) was added in batches to a mixture containing compound 5 (6.2g, 21.5mmol), methanol (150mL) and triethylamine (6mL) in an ice-water bath, and the addition was completed. Stirring was continued for 30 minutes, and TLC analysis showed that the reaction was complete. The solvent was evaporated under reduced pressure, water (60mL) was added, extracted with ethyl acetate (40mL×3), the combined organic phase was washed with 2M hydrochloric acid (30mL), the product was precipitated in ethyl acetate, filtered, and the filter cake was dried in vacuo Ethyl 2-(3-cyano-4-hydroxy-5-bromophenyl)-4-methyl-thiazole-5-carboxylate (9) (5.6 g) was obtained as a milky white solid. Yield: 82.3%.

[0099] 1 HNMR (DMSO-d 6 , 400MHz) δ8.34(d, J=2.4Hz, 1H), 8.22(d, J=2.0Hz, 1H), 4.29(q, J=7.2Hz, 2H), 2.65(s, 3H), 1.30( d, J=6.8Hz, 3H). MS (EI, m / z): 3...

Embodiment 3

[0108] Synthesis of 2-[3-cyano-4-(4-methylphenyl)-5-deuterophenyl]-4-methyl-thiazole-5-carboxylic acid (16)

[0109]

[0110] For the experimental operation, see Step E and Step F in Example 2.

[0111] 1 HNMR (DMSO-d 6 , 400MHz) δ8.46(s, 1H), 8.31(s, 1H), 7.55(d, J=8.0Hz, 2H), 7.38(d, J=8.0Hz, 2H), 2.70(s, 3H), 2.41(s, 3H). MS (EI, m / z): 335.2 [M-H] - .

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Abstract

The invention discloses a deuterium-substituted 2-phenylthiazole compound and a pharmaceutical composition thereof, and specifically relates to a deuterium-substituted 2-phenylthiazole compound with a general formula represented by formula (I), and a pharmaceutically acceptable salt thereof. At least one of R<3>, R<4>, and R<5> are used for representing deuterium or a substituent group containing deuterium. The deuterium-substituted 2-phenylthiazole compound is capable of inhibiting activity of xanthine oxidase. The deuterium-substituted 2-phenylthiazole compound or the pharmaceutically acceptable salt of the deuterium-substituted 2-phenylthiazole compound can be used for preparation of medicines used for preventing or treating hyperuricemia, gout, diabetic nephropathy, inflammatory diseases, and nervous system diseases.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to different deuterated compounds of a class of 2-phenylthiazole series compounds, their preparation methods, pharmaceutical compositions containing these compounds and their medical applications, especially as xanthine oxidase inhibitors Use for treating gout and hyperuricemia. Background technique [0002] Gout is a kind of crystalline arthritis caused by purine metabolism disorder and / or decreased uric acid excretion. , Chronic arthritis. In addition to depositing tophi in joints, tendons and their surroundings, tophi can also deposit in the kidneys, and urate nephropathy, uric acid urinary stones, etc. can occur, and renal insufficiency can occur in severe cases. Gout is often accompanied by obesity, hyperlipidemia, diabetes, hypertension, and cardiovascular and cerebrovascular diseases. According to available data, the prevalence of hyperuricemia in Europe and Amer...

Claims

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Application Information

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IPC IPC(8): C07D277/56A61K31/426A61P19/06A61P13/12A61P3/10A61P29/00A61P25/00
CPCC07D277/56
Inventor 史东方傅长金王荣超刘俊
Owner 镇江新元素医药科技有限公司(中外合资)
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