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Nitro-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof

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

Inactive Publication Date: 2015-02-11
深圳市莱宝生物科技有限公司
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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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  • Nitro-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof
  • Nitro-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof
  • Nitro-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1 Synthesis of Compound I

[0015]

[0016] A. Synthesis of compound IV

[0017] 5.74g (20mmol) of compound II 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 (usually within 12h). The reaction mixture was poured into 400mL ice water and stirred, using 100mL×3 CH 2 Cl 2 After extraction, the extracts 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, a white solid, ESI-MS, m / z=440([M+Na] + ).

[0018] B. Synthesis of compound V

[0019] 5.00g (12mmol) of compound IV was dissolved in 30mL of bromoform, stirred at room temper...

Embodiment 2

[0024] Example 2 Preparation of Comparative Compound I-2

[0025] In order to fully compare the beneficial effects of the compounds of the present invention, the present invention prepares an undisclosed brand new compound discovered by the applicant as a comparison. The specific structure is as follows:

[0026]

[0027] The preparation method is as follows:

[0028]

[0029] A. Synthesis of compound IV-2

[0030] 4.84g (20mmol) of compound II-2 and 4.22g (20mmol) of compound III-2 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 (usually within 12h). The reaction mixture was poured into 400mL ice water and stirred, using 100mL×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 fil...

Embodiment 3

[0038] The compounds of the present invention and related compounds inhibit the IC of URAT1 50 The value was determined according to a similar method described in the literature (Example 12 in US2014 / 0005136).

[0039] 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) to the eukaryotic expression plasmid pCMV6 / neo (Origene). Gene sequencing confirmed that the humanized URAT1 is consistent with the information recorded in the gene bank (NM_144585.2). HEK293 human embryonic kidney cells (ATCC#CRL-1573) in EMEM tissue culture medium in 5% CO 2 And cultivate in 95% air atmosphere. PCMV6 / Neo / URAT1 was transfected into HEK293 cells using L2000 transfection reagent (Invitrogene). After 24 hours, the transfected cells were divided into tissue culture dishes with a diameter of 10 cm and continued to grow for one day, and then the medium was changed to fresh medium contain...

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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 nitro-substituted triazolesulfonylmalonic 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. A structure of the URAT1 inhibitors is shown in the specification.

Description

Technical field [0001] The invention relates to the field of medicines related to the treatment of hyperuricemia and gout. Specifically, the present invention relates to a nitro-substituted triazole sulfonylmalonic acid structure urate transporter 1 (urate transporter 1, URAT1) inhibitor, and a preparation method for treating hyperuricemia and gout , The pharmaceutical composition containing it and its use in medicine. Background technique [0002] Gout is a chronic metabolic disease characterized by pain caused by hyperuricemia and monosodium uric acid (MSU) deposited on joints and other parts, mainly due to disorders of purine metabolism and / or uric acid excretion disorders. It is estimated that there are more than 20 million gout patients worldwide. The 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 febuxostat), a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12A61P19/06
CPCC07D249/12
Inventor 不公告发明人
Owner 深圳市莱宝生物科技有限公司
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