A nitro-substituted triazole sulfinyl malonate compound, its preparation method and use

A technology of dimethyl bromomalonate and compounds, applied in the field of uric acid transporter 1 inhibitors, can solve problems such as fulminant hepatitis, allopurinol liver and bone marrow toxicity, and allergic reactions

Active Publication Date: 2016-08-17
山东产研中科高端化工产业技术研究院有限公司
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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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  • A nitro-substituted triazole sulfinyl malonate compound, its preparation method and use
  • A nitro-substituted triazole sulfinyl malonate compound, its preparation method and use
  • A nitro-substituted triazole sulfinyl malonate compound, its preparation method and use

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] The synthesis of embodiment 1 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 (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, a white solid, ESI-MS, m / z=440 ([M+Na] + ).

[0018] B. Synthesis of Compound V

[0019] 5.00g (12mmol) compound IV was dissolved in 30mL ...

Embodiment 2

[0024] Embodiment 2 Preparation of comparative compound 1-2

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

[0026] Comparative compound I-2

[0027] Its 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 (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 anhy...

Embodiment 3

[0038] 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).

[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) 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 agent (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 f...

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Abstract

The invention relates to the field of medicaments associated with hyperuricemia and gout. Specifically, the invention relates to a urate transporter 1 inhibitor with a nitro-substituted triazole sulfinyl malonate structure, a preparation method of the urate transporter 1 inhibitor, a pharmaceutical composition containing the urate transporter 1 inhibitor and application of the urate transporter 1 inhibitor in preparation of diabetic medicaments. The structure is shown in the specification.

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 uric acid transporter 1 (urate transporter 1, URAT1) inhibitor with a nitro-substituted triazole sulfinyl malonate structure that has a therapeutic effect on hyperuricemia and gout, and a preparation Methods, pharmaceutical compositions containing it and uses 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 allopur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/12A61K31/4196A61P19/06
CPCC07D249/12
Inventor 不公告发明人
Owner 山东产研中科高端化工产业技术研究院有限公司
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