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Heterocyclic compound and its preparation method

A compound and drug technology, applied in the field of heterocyclic compounds and its preparation, can solve problems such as poor curative effect and increase the response rate of gout patients

Active Publication Date: 2020-03-31
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, Lesinurad, a selective uric acid reabsorption inhibitor developed by AstraZeneca, can reduce the secretion of uric acid and reduce the level of uric acid in the serum by inhibiting the URAT1 transporter in the kidney. The drug was approved by the FDA in December 2015. The treatment associated with high levels of uric acid in the blood (hyperuricemia) and gout was approved by the European Medicines Agency (EMA) on February 18, 2016. It is combined with drugs that reduce uric acid production (such as allopurinol and febuxo) Tan) combined use can increase the response rate of gout patients who originally did not respond well to the above drugs, but its single use still has kidney-related risks and poor curative effect. How to maximize the efficacy of URAT1 inhibitors and overcome its side effects as much as possible , has become a research hotspot

Method used

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  • Heterocyclic compound and its preparation method
  • Heterocyclic compound and its preparation method
  • Heterocyclic compound and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Embodiment 1, the synthesis of compound of the present invention

[0100] The general reaction formula is as follows:

[0101]

[0102] R 1 One selected from a hydrogen atom, a chlorine atom, a bromine atom, a methyl group, a phenyl group, and an amido group.

[0103] R 2 One selected from a hydrogen atom, a chlorine atom, a bromine atom, and a cyano group.

[0104] R 3 , R 4 One selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group. It can be the same group or different groups; or the combination of R3 and R4 is cyclobutyl.

specific example

[0105] Specific example: the synthesis of product 1

[0106]

[0107] 1) Synthesis of ethyl 2-(thiophene[3,2-b]pyridine-7-mercapto)-2-methylpropionate (Int 1.2)

[0108]

[0109] Add 7-chlorothieno[3,2-b]pyridine (1.69g, 10mmol), sodium sulfide (1.17g, 15mmol), N-methylpyrrolidone (30mL) into a 100mL reaction flask, heat to 80°C and stir the reaction After 3 hours, cesium carbonate (6.52g, 20mmol) and ethyl 2-bromoisobutyrate (2.15g, 11mmol) were added to the reaction flask, and the reaction was continued at 100°C for 2 hours. After the reaction was completed, water ( 150 mL), extracted three times with ethyl acetate (3×100 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and passed through the column after rotary evaporation to obtain Intermediate 2 (1.72 g), with a yield of 61%. MS:282.1(M+H + ).

[0110] 2) Synthesis of 2-(thiophene[3,2-b]pyridine-7-mercapto)-2-methylpropionic acid (1)

[0111]

...

Embodiment 2

[0256] Embodiment 2, the synthesis of compound of the present invention

[0257] The general reaction formula is as follows:

[0258]

[0259] R 1 One selected from a hydrogen atom and a bromine atom.

[0260] R 2 One selected from hydrogen atom, bromine atom, methyl group, pyridine, 3-chloropyridine and p-cyanophenyl group.

[0261] R 3 , R 4 One selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group. can be the same group or different groups; or R 3 and R 4 The combination is cyclobutyl.

[0262] Specific examples:

[0263]

[0264] 1) Synthesis of ethyl 2-(thiophene[2,3-b]pyridine-3-methyl-4-mercapto)-2-cyclobutylacetate (Int 17.2)

[0265]

[0266] Add 3-methyl-4-chlorothiophene [2,3-b] pyridine (1.83g, 10mmol) in the reaction flask of 100mL, sodium sulfide (1.17g, 15mmol), N-methylpyrrolidone (30mL), heat Stir the reaction at 80°C for 3 hours, then add cesium carbonate (6.52g, 20mmol) and ethyl 2-bromo-2-c...

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Abstract

Disclosed in the present invention is a compound as represented by formula (A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The new compound as represented by formula (A) disclosed in the present invention exhibits good URAT1 inhibitory activities, providing a new medicinal possibility for the clinical treatment of diseases associated with abnormal URAT1 activities.

Description

technical field [0001] The present invention relates to heterocyclic compounds and methods for their preparation. Background technique [0002] Heterocyclic compounds are organic compounds containing heterocyclic structures in their molecules. The atoms constituting the ring contain at least one heteroatom in addition to carbon atoms. Is the largest number of a class of organic compounds. The most common heteroatoms are nitrogen, sulfur, and oxygen atoms. It can be divided into two categories: aliphatic heterocycle and aromatic heterocycle. Heterocyclic compounds generally exist in the structure of drug molecules. [0003] Gout is an inflammatory disease characterized by pain and swelling caused by the deposition of monosodium urate (MSU) in joints and subcutaneous parts. It is one of the oldest diseases that plague humans. The premise of MSU deposition instrument gout is hyperuricemia, that is, a pathological state in which the level of serum uric acid (sUA) is higher ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04C07D471/04C07D487/04A61K31/4365A61K31/444A61K31/506A61K31/519A61P19/06A61P19/02A61P9/12A61P9/00A61P9/10A61P13/12A61P13/04A61P39/02A61P5/20A61P17/06
CPCA61P5/20A61P9/00A61P9/10A61P9/12A61P13/04A61P13/12A61P17/06A61P19/02A61P19/06A61P39/02C07D471/04C07D487/04C07D495/04A61K31/4353A61K31/4365A61K31/444A61K31/506A61K31/519
Inventor 樊磊杜武胥珂馨陈锞王飞吴孝全罗童川张少华李兴海陈元伟
Owner HINOVA PHARM INC