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URAT1 inhibitor as well as preparation method and application thereof

A compound and a selected technology are applied in the field of hyperuricemia and gout treatment to achieve good inhibitory effect and low uric acid toxicity.

Pending Publication Date: 2022-04-12
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In summary, the non-negligible adverse reactions of existing drugs gradually outweigh the benefits of existing treatments. In order to meet future clinical needs, it is urgent to develop new high-efficiency and low-toxicity URAT1 inhibitors

Method used

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  • URAT1 inhibitor as well as preparation method and application thereof
  • URAT1 inhibitor as well as preparation method and application thereof
  • URAT1 inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of Intermediate A1

[0044]

[0045] Add 4-chloro-3-iodopyridine (500mg, 2.09mmol), sodium sulfide (195.46mg, 2.50mmol), DMF (3mL) into a 50mL reaction flask, and stir the reaction solution at 80°C for 4h. After the reaction is complete, add 20mL of water and use 1mol·L -1 dilute hydrochloric acid to adjust the pH to 5-6, and a pale yellow solid was precipitated, which was filtered by suction to obtain intermediate A1 (405 mg), with a yield of 82%.

[0046] Synthesis of Intermediate B1

[0047]

[0048] Add Intermediate A (400mg, 1.69mmol), ethyl 2-bromoisobutyrate (337.62mg, 2.03mmol), cesium carbonate (1.66g, 5.08mmol), DMF (5mL), reaction solution to a 50mL reaction flask Stir at 60 °C for 4 h. After the reaction was completed, 20 mL of water was added, extracted three times with ethyl acetate (3×50 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and passed through a column after ro...

Embodiment 2

[0059] 2-((3-(2-Methyl-pyridin-4-ylethynyl)pyridin-4-yl)mercapto)-2-methylpropionic acid (compound 2) synthesis, 4-bromo-2-methyl Pyridine (344.06 mg, 2.00 mmol) was substituted for 4-bromopyridine in Example 1, and the other steps were exactly the same as in Example 1 to obtain Compound 2 (72 mg), with a total yield of 14%. The structure of Compound 2 is as follows:

[0060]

[0061] The characterization results are as follows: 1 H NMR (500MHz, DMSO-d 6 )δ8.60(s,1H),8.53(d,J=5.1Hz,1H),8.40(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),7.42(s, 1H), 7.34(dd, J=5.1, 1.6Hz, 1H), 1.58(s, 9H).MS: 312.82(M + ).

Embodiment 3

[0063] 2-((3-(2-Methoxy-pyridin-4-ylethynyl)pyridin-4-yl)mercapto)-2-methylpropionic acid (compound 3) was synthesized, 4-bromo-2-methyl Oxypyridine (376.04 mg, 2.00 mmol) was substituted for 4-bromopyridine in Example 1, and the other steps were exactly the same as in Example 1 to obtain Compound 3 (79 mg), with a total yield of 15%. The structure of Compound 3 is as follows:

[0064]

[0065] The characterization results are as follows: 1 H NMR (500MHz, DMSO-d 6 )δ8.67(s,1H),8.47(d,J=5.5Hz,1H),8.29-8.20(m,1H),7.41(d,J=5.5Hz,1H),7.13(dd,J=5.3 ,1.3Hz,1H),6.98(t,J=1.1Hz,1H),3.89(s,3H),1.61(s,6H).MS:328.83(M + ).

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Abstract

The invention discloses a URAT1 inhibitor, a preparation method thereof and an application of the URAT1 inhibitor in preparation of a medicine for inhibiting URAT1, the structural formula of the URAT1 inhibitor is shown as a formula I. The invention provides a compound shown as the formula I or a tautomer, a mesomer, a raceme, an enantiomer, a diastereoisomer and a mixture form of the compound, and pharmaceutically acceptable salts of the compound or the tautomer, the mesomer, the raceme, the enantiomer, the diastereoisomer and the mixture form. The compound disclosed by the invention is a selective uric acid reuptake inhibitor, can treat hyperuricemia and gout by promoting excretion of uric acid from a body and reducing serum uric acid, has a very good inhibition effect on urate transporter 1, and shows the effects of efficiently reducing uric acid and being low in toxicity in animal bodies.

Description

technical field [0001] The invention specifically relates to a class of URAT1 inhibitors, a preparation method thereof and an application in the treatment of hyperuricemia and gout. Background technique [0002] Uric acid is the end product of endogenous and dietary purine metabolism. Uric acid exists in the blood as an antioxidant. Due to the lack of uricase that degrades uric acid in the human body, uric acid is mainly excreted through the kidneys and intestines, and the kidney is the main route of uric acid excretion. , and the rest are excreted in feces. Excessive production of uric acid, insufficient excretion, or the coexistence of both will lead to hyperuricemia. Hyperuricemia refers to a state of the body where the concentration of uric acid in the blood exceeds the normal range. Generally, it exceeds 417 μmol / L for men and 357 μmol / L for women. L, studies have shown that 90% is due to the reduction of uric acid excretion. In recent years, with the improvement of p...

Claims

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Application Information

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IPC IPC(8): C07D213/70C07D401/06A61P19/06A61K31/44A61K31/444A61K31/4709
Inventor 靳浩吴沣俞哲健叶凯周玉宝徐仲军
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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