Nitronaphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives

A technology of alkyl 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 allergies

Active Publication Date: 2015-01-28
茅婷婷
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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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  • Nitronaphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives
  • Nitronaphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives
  • Nitronaphthalene-ring-containing butanedioic acid amide derivatives, preparing method thereof and uses of the derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] .

[0030] A. Compounds IV-1 Synthesis

[0031] 3.76g (20 mmol) compound II-1 and 2.64 g (20 mmol) of compound III Dissolve in 50 mL of dry THF, stir under ice-water bath cooling, add 4.13 g (20 mmol) of dicyclohexylcarbodiimide (DCC) and 0.61 g (5 mmol) of 4-dimethylaminopyridine (DMAP), and then Stir at room temperature until the reaction is complete (within 12 h) as detected by TLC. The reaction mixture was poured into 300 mL of ice water, stirred, using 100 mL × 3 CH 2 Cl 2 Extract, combine the extract phases, successively wash with 100 mL of 1% dilute hydrochloric acid and 100 mL of 5% brine, and dry 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 , white solid, ESI-MS, m / z = 325([M+Na] + ).

[0032] B. Compounds V-1 Synthesis

[0033] compound IV-1 Dissolve 4.53 ...

Embodiment 2-13

[0038] With reference to the operating steps of Example 1, the compounds listed in the following table were prepared:

[0039]

Embodiment 9

[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). The results are listed below.

[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 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 10 cm diameter tissue culture dishes and grown for another day, after which the medium was replac...

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PUM

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Abstract

The invention relates to the field of medicines related to hyperuricemia and gout, and particularly relates to urate transporter 1 inhibitors having structures of nitronaphthalene-ring-containing butanedioic acid amides, a preparing method thereof, pharmaceutical compositions containing the inhibitors and applications of the inhibitors in preparation of medicines for diabetes. A formula (I) is shown in the specification, wherein R1 is selected from -NO2 and -CN, and R2 is selected from H, C1-C5 alkyl and C3-C6 cycloalkyl.

Description

Technical field [0001] The invention involves the treatment of drugs related to hyperuricemia and gout.Specifically, the present invention involves a type of uric acid transshipment 1 (Urate Transporter 1, URAT1) inhibitor and preparation method for hyperuric acid alpinemia and gout., Contain their pharmaceutical compositions and use in medicine. Background technique [0002] Gout is a chronic metabolic disease that is characterized by pain caused by hyperuricemia and sodium salt (MSU) deposited in joints and other parts. The main reason is purine metabolism disorders and / or uric acid excretion disorders.It is estimated that there are currently more than 20 million gout patients.Drugs currently used to treat gout include anti -inflammatory drugs (such as falling water pylogen) for relieving pain, inhibiting uric acid generic drugs (eblotic oxidase inhibitors represented by natives and non -pesotan)Expeditional drugs (represented by propylcuscopus, phenylsulzolone, benzinemon and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/15C07C253/30C07C255/60A61K31/167A61K31/277A61P19/06
Inventor 不公告发明人
Owner 茅婷婷
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