Nitro containing and halogen benzene substituted 1H-tetrazole-1-acetic acid structure, and preparation method and use thereof

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

Active Publication Date: 2015-01-07
浙江西塘实业有限公司
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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 containing and halogen benzene substituted 1H-tetrazole-1-acetic acid structure, and preparation method and use thereof
  • Nitro containing and halogen benzene substituted 1H-tetrazole-1-acetic acid structure, and preparation method and use thereof
  • Nitro containing and halogen benzene substituted 1H-tetrazole-1-acetic acid structure, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The synthesis of embodiment 1 compound I-1

[0026]

[0027] A. Synthesis of Compound IV-1

[0028] 3.76g (20mmol) of compound II-1 and 2.96g (20mmol) of compound III-1 were dissolved in 40mL of dry DMF, stirred, added 3.32g (20mmol) of potassium iodide and 6.91g (50mmol) of potassium carbonate, in a nitrogen atmosphere 100 React at °C until the reaction is complete (TLC tracking, generally 5h). After the reaction mixture was cooled, it was poured into 300 mL of ice water, stirred, and 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=278 ([M+Na] + ).

[0029] B. Synthesis of Compound VI-1

[0030] 3.06g (12mmol) of compound IV-1 and 1.76g (12m...

Embodiment 2-10

[0036] Referring to the operation steps of Example 1, the compounds listed in the following table were prepared.

[0037]

[0038]

[0039]

Embodiment 11

[0041] 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).

[0042] 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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PUM

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Abstract

The invention relates to the field of medicines relative to hyperuricemia and gout, particularly to an inhibitor for a urate transporter 1 in a nitro containing and halogen benzene substituted 1H-tetrazole-1-acetic acid structure, a preparation method of the urate transporter 1, a medicine composition containing the inhibitor, and the application of the inhibitor in preparing diabetes medicines. The general formula (refer to the Specification) of the compound is disclosed by the invention, wherein X is selected from halogen substituent.

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 transporter1, URAT1) inhibitors containing nitro- and halobenzene-substituted tetrazoleacetic acid structures that have a therapeutic effect on hyperuricemia and gout, a preparation method, Pharmaceutical compositions containing them and their 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 inhib...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04A61P19/06
CPCC07D257/04
Inventor 不公告发明人
Owner 浙江西塘实业有限公司
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