Nitrophenyl substituted naphthalene cyclosuccinic acid amide derivatives, preparation method and use thereof

A technology of succinic acid and substituents, applied in the preparation of carboxylic acid amides, preparation of organic compounds, chemical instruments and methods, etc., can solve problems such as allopurinol liver and bone marrow toxicity, fulminant hepatitis, and allergic reactions

Active Publication Date: 2016-01-20
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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  • Nitrophenyl substituted naphthalene cyclosuccinic acid amide derivatives, preparation method and use thereof
  • Nitrophenyl substituted naphthalene cyclosuccinic acid amide derivatives, preparation method and use thereof
  • Nitrophenyl substituted naphthalene cyclosuccinic acid amide derivatives, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] .

[0031] A. Compound IV-1 Synthesis

[0032] 3.76g (20mmol) compound II-1 and 2.64g (20mmol) of compound III Dissolve in 50mL of dry THF, stir under ice-water bath cooling, add 4.13g (20mmol) of dicyclohexylcarbodiimide (DCC) and 0.61g (5mmol) of 4-dimethylaminopyridine (DMAP), and then stir at room temperature , until the TLC detection reaction was complete (within 12h). 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 100mL of 1% dilute hydrochloric acid and 100mL 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] + ).

[0033] B. Compound V-1 Synthesis

[0034] compound IV-1 Dissolve 4.53g (15mmol) in 30mL ...

Embodiment 2-9

[0039] Referring to the operation steps of Example 1, the compounds listed in the following table were prepared.

[0040]

Embodiment 10

[0042] 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.

[0043]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 tissue culture dishes with a diameter of 10 cm, continued to grow for one day, and then the medium...

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PUM

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Abstract

The invention relates to the field of medicines related to hyperuricemia and gout. Specifically, the present invention relates to a class of uric acid transporter 1 inhibitors of nitrophenyl substituted naphthalene cyclosuccinic acid amide structures, their preparation methods, pharmaceutical compositions containing them, and their application in the preparation of diabetes drugs . (I ) Wherein, R1 is selected from H and halogen substituents.

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 (uratetransporter1, URAT1) inhibitors containing nitrophenyl-substituted naphthalene cyclosuccinic acid amide derivatives that have therapeutic effects on hyperuricemia and gout, and 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 oxid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/15C07C231/14A61K31/165A61P19/06
Inventor 不公告发明人
Owner 茅婷婷
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