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

A halogen and compound technology, 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

Inactive Publication Date: 2015-01-28
天津华祥医药科技有限公司
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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 fulmina

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] .

[0035] A. Compounds IV-1 Synthesis

[0036] 3.54g (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 = 314([M+Na] + ).

[0037] B. Compounds V-1 Synthesis

[0038] compound IV-1 Dissolve 4.36 ...

Embodiment 2-13

[0043] Referring to the operation steps of Example 1, the compounds listed in the following table were prepared.

[0044]

Embodiment 14

[0046] 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.

[0047] 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 repla...

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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 halonaphthalene-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 substituents are 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 class of uric acid transporter 1 (urate transporter 1, URAT1) inhibitors, preparation methods, 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 inhibitors represented by allopurinol and febuxostat), crude uric acid Excretion drugs (uric acid excretion drugs represented by probenecid...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/15A61K31/167A61P19/06
Inventor 不公告发明人
Owner 天津华祥医药科技有限公司
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