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URAT1 inhibitor, preparation method and application thereof

The technology of a condensing agent and C1-C4 is applied in the field of medicines related to the treatment of hyperuricemia and gout, and can solve the problems of easily causing liver damage, large side effects, not many, etc. Excellent effect of lowering serum uric acid concentration

Inactive Publication Date: 2018-11-02
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are very limited drugs for the treatment of gout: 1. Emergency medicine: colchicine tablets, non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids for pain relief; 2. Inhibition of uric acid production: allopurinol, side effects Large; febuxostat, ineffective in some patients
3. Drugs that promote uric acid excretion: benzbromarone, etc., which are prone to liver damage and are not suitable for patients with renal insufficiency
Currently published URAT1 inhibitor patents include WO2006057460, WO2008153129, WO2009145456, WO2010044403, WO2011046800, WO2011159839, WO20121022405, WO2013057722, WO2014183555, WO20147728, but many of them are not actually entered into the clinic.

Method used

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  • URAT1 inhibitor, preparation method and application thereof
  • URAT1 inhibitor, preparation method and application thereof
  • URAT1 inhibitor, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0048] When M is a carboxylic acid, the compound of the formula I is a compound of the formula I', wherein the preparation method of the compound of the formula I' comprises:

[0049] The compound of formula II and the compound of formula III are heated and reacted under the action of a base to obtain the compound of formula IV, wherein the base is an organic base or an inorganic base, and the organic base is preferably selected from pyridine, 4-dimethylaminopyridine, triethylamine, Tributylamine or 1,8-diazabicycloundec-7-ene, the inorganic base is preferably selected from sodium hydride, lithium hydride, potassium carbonate, lithium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate;

[0050] The compound of formula IV is condensed with the compound of formula V under the action of a base or a condensing agent to obtain a compound of formula VI, wherein, when X in the compound of formula V is a halogen, OMs, OTs or OTf leaving group, the compound of form...

Embodiment 1

[0060] The synthesis of embodiment 1 compound 1

[0061]

[0062] Synthesis of Intermediate Compound A

[0063] 3-Mercaptophenol (12.6g, 100mmol), ethyl bromoacetate (16.7g, 100mmol) were added to 100mL of anhydrous DMF, and NaHCO 3 (8.4g, 100mmol), and heated to 60°C for 4 hours. Cooled to room temperature and poured into ice water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound A , (18 g, 85% yield).

[0064] Synthesis of Intermediate Compound B

[0065] Compound A (4.2 g, 20 mmol) was dissolved in 30 mL of anhydrous DMF, and cooled to 0° C. in an ice-water bath. Add sodium hydrogen (800mg, 60% content, 20mmol) under stirring and keep stirring at 0°C for 15min, add 2,5-dichlorobenzyl bromide (5.3g, 22mmol), and naturally warm to room temperature after the addition, and stir overnight. Th...

Embodiment 2-16

[0069] Select suitable raw materials and reagents, prepare compound 2-16 according to the method of Example 1:

[0070] Compound 2:

[0071]

[0072] MS m / z(ESI):357[M+1]; HNMR(400MHz d-DMSO) 12.74(s,1H),7.67(d,J=2.4Hz1H),7.57(d,J=8.4Hz,1H) ,7.47(dd,J=8.4Hz,J=2.8Hz 1H),7.12(d,J=7.6Hz,1H),7.07(s,1H),6.90(d,J=7.6Hz,1H),5.14( s,2H),3.78(s,2H),2.15(s,3H).

[0073] Compound 3:

[0074]

[0075] MS m / z (ESI): 393[M+Na]; HNMR (400MHz d-DMSO) 12.74(s, 1H), 7.68(d, J=2.4Hz1H), 7.56(d, J=8.4Hz 1H), 7.48(dd, J=2.4Hz, J=8.8Hz, 1H), 7.32(t, J=8.Hz, 1H), 7.06-7.12(m, 3H), 5.15(s, 2H), 1.38(s, 6H).

[0076] Compound 4:

[0077]

[0078] MS m / z (ESI): 385[M+1]; HNMR (400MHz CDCl 3 )7.54(d, J=2.0Hz 1H), 7.30(d, J=8.4Hz 1H), 7.23(dd, J=8.4Hz, J=2.0Hz, 1H), 7.12(d, J=7.6Hz, 1H ),7.05(d,J=8Hz,1H),7.01(s,1H),5.05(s,2H),2.3(s,3H),1.44(s,6H).

[0079] Compound 5:

[0080]

[0081]MS m / z(ESI):385[M+1]; HNMR(400MHz d-DMSO) 12.65(s,1H),7.58(d,J=8.4Hz2H),7.47(dd,J=8.8Hz,J= 7.2Hz 1...

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Abstract

The invention relates to the field of drugs related to hyperuricemia and gout, in particular to a compound as shown in a formula I and a preparation method thereof, and application of the compound serving as a novel URAT1 inhibitor, particularly application of the compound serving as a therapeutic agent for diseases related to abnormal level of uric acid, wherein the definitions of M, R1, R2, R3,R4, R5, R6, R7 and n formula I are as described in the description.

Description

technical field [0001] The invention relates to the field of drugs related to the treatment of hyperuricemia and gout. In particular, it relates to a novel URAT1 inhibitor and its use as a therapeutic agent for conditions associated with abnormal levels of uric acid. 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. Currently, there are very limited drugs for the treatment of gout: 1. Emergency medicine: colchicine tablets, non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids for pain relief; 2. Inhibition of uric acid production: allopurinol, side effects Large; febuxostat, some patients are invalid. 3. Drugs that promote uric acid excretion: benzbromarone, etc., which...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/52C07C323/53C07C319/20C07D257/04A61K31/192A61K31/277A61K31/41A61P19/06A61P19/02A61P9/12A61P9/10A61P9/00A61P13/12A61P29/00A61P13/04A61P39/02A61P5/16A61P17/06
CPCC07C323/52C07C323/53C07D257/04
Inventor 王亚平郑国君刘礼飞刘永榜石磊周结波丁芳姬凯歌
Owner ZHEJIANG HISUN PHARMA CO LTD
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