Triazole malonic acid compounds as well as preparation method and application thereof

A compound and general formula technology, applied in the field of uric acid transporter 1 inhibitors, can solve the problems of allopurinol liver and bone marrow toxicity, fulminant hepatitis, allergy, etc.

Inactive Publication Date: 2015-02-11
张远强
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs have different degrees of toxic and side effects, such as benzbromarone has the risk of causing fulminant hepatitis, allopurinol has adverse reactions such as liver and bone marrow toxicity and allergic reactions, etc.

Method used

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  • Triazole malonic acid compounds as well as preparation method and application thereof
  • Triazole malonic acid compounds as well as preparation method and application thereof
  • Triazole malonic acid compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1 compound I-1

[0022]

[0023] A. Synthesis of Compound IV-1

[0024] 5.65g (20mmol) of compound II-1 and 4.22g (20mmol) of compound III were dissolved in 100mL of dry DMF, stirred at room temperature, and 8.29g (60mmol) of solid K was added 2 CO 3 , and then the reaction mixture was stirred at room temperature until TLC tracking found that the reaction was complete (generally within 12 h). The reaction mixture was poured into 400 mL of ice water, stirred, using 100 mL × 3 CH 2 Cl 2 After extraction, the extract phases were combined, washed with 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV-1, a white solid, ESI-MS, m / z=435 ([M+Na] + ).

[0025] B. Synthesis of Compound V-1

[0026] 5.23g (12mmol) compound IV-1 was dissol...

Embodiment 2-6

[0030] Referring to the operation steps of Example 1, the compounds listed in the following table were synthesized.

[0031]

[0032]

Embodiment 7

[0034] The compounds of the present invention and related compounds inhibit IC of URAT1 50 The values ​​are determined in a similar manner as described in the literature (Example 12 in US2014 / 0005136).

[0035] Construction of a cell line stably expressing the humanized URAT1 transporter: The humanized URAT1 gene (SLC22A112) was subcloned from the plasmid pCMV6-XL-5 (Origene) into the eukaryotic expression plasmid pCMV6 / neo (Origene). Gene sequencing confirmed that the humanized URAT1 was consistent with the information recorded in the gene bank (NM_144585.2). HEK293 human embryonic kidney cells (ATCC#CRL-1573) were cultured in EMEM tissue culture medium under 5% CO 2 And cultured in 95% air atmosphere. pCMV6 / Neo / URAT1 was transfected onto HEK293 cells using L2000 type transfection reagent (Invitrogene). After 24 hours, the transfected cells were divided into tissue culture dishes with a diameter of 10 cm, continued to grow for one day, and then the medium was replaced with...

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PUM

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Abstract

The invention relates to the field of medicines related to hyperuricemia and gout and in particular relates to urate transporter I (URAT1) inhibitors containing triazole malonic acid structures, a preparation method thereof, a medicine composition containing the URAT1 inhibitors and an application of the URAT1 inhibitors and the medicine composition to preparation of diabetes medicines. In a general formula in the specification, R is selected from H, C1-C8 alkyl and C3-C6 cycloalkyl.

Description

technical field [0001] The invention relates to the field of drugs related to the treatment of hyperuricemia and gout. Specifically, the present invention relates to a class of uric acid transporter 1 (urate transporter 1, URAT1) inhibitors containing a triazole-malonic acid structure that has a therapeutic effect on hyperuricemia and gout, a preparation method, and a drug containing them Composition and use in medicine. Background technique [0002] Gout is a chronic metabolic disease characterized by hyperuricemia and pain caused by deposition of monosodium uric acid (MSU) in joints and other parts. The main reason is purine metabolism disorder and / or uric acid excretion disorder. It is estimated that there are more than 20 million gout patients worldwide. Drugs currently used to treat gout include anti-inflammatory drugs for pain relief (such as colchicine, etc.), drugs that inhibit uric acid production (xanthine oxidase inhibitors represented by allopurinol and febuxos...

Claims

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Application Information

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IPC IPC(8): C07D249/12A61P19/06
CPCC07D249/12
Inventor 不公告发明人
Owner 张远强
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