Indoxazine derivatives and their application in medicine

A kind of technology of indolazine, compound, be used in its preparation and its application in medicine, the field of indolizine derivatives

Active Publication Date: 2021-03-02
KIND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, to date, no hypoxia-inducible factor-related proline hydroxylase inhibitor drugs have been approved for marketing

Method used

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  • Indoxazine derivatives and their application in medicine
  • Indoxazine derivatives and their application in medicine
  • Indoxazine derivatives and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0190] (6'-Hydroxy-8'-oxo-8'H-spiro[cyclopropane-1,5'-indolezine]-7'-carbonyl)glycine ( 1 )

[0191]

[0192] first step

[0193] 1-(1H-pyrrol-1-yl)cyclopropane-1-carboxylic acid ( 1a )

[0194]

[0195] Add 1 ml of concentrated hydrochloric acid to a mixture of 2,5-dimethoxytetrahydrofuran (3.16 g, 24 mmol) and 20 ml of water and stir at room temperature for 1 hour; then add solid sodium acetate (3.28 g, 40 ml mol) and 1-aminocyclopropane-1-carboxylic acid (2.02 g, 20 mmol). The mixture was stirred overnight at room temperature; then diluted with water, neutralized to about pH 4 by adding 1M hydrochloric acid; then extracted with ethyl acetate; the ethyl acetate layer was separated, then washed twice with dilute aqueous sodium chloride; The solid was dried in ethyl acetate; the desiccant was removed by filtration, and the filtrate was spin-dried on a rotary evaporator; the residue was purified by column chromatography to obtain 1.8 g of product 1a . 1 H NMR (500MH...

Embodiment 2

[0210] (6'-Hydroxy-8'-oxo-8'H-spiro[cyclopropane-1,5'-indolezine]-7'-carbonyl)-L-alanine ( 2 )

[0211]

[0212] first step

[0213] (6'-Hydroxy-8'-oxo-8'H-spiro[cyclopropane-1,5'-indolezine]-7'-carbonyl)-L-alanine ( 2 )

[0214]

[0215] compound 1c (124 mg), L-alanine (250 mg) and 0.5M sodium methoxide methanol solution (5 ml); spin dry; then add n-propanol (4 ml), reflux until the reaction is complete. Cool, dilute the reaction solution with water, carefully add 1M dilute hydrochloric acid aqueous solution to acidify to about pH 4; precipitate the solid; collect the solid by filtration, then wash the solid with water; then dry to obtain 98 mg of the product 2 . 1 H NMR (500MHz, dmso-d6) δ (ppm): 17.99 (1H, s), 13.14 (1H, s), 10.14 (1H, d), 7.36 (1H, s), 6.98 (1H, s), 6.46 (1H, s), 4.53-4.46 (1H, m), 1.89 (2H, s), 1.79 (2H, s), 1.44 (3H, d). LCMS ESI(+):291(M+1) + .

Embodiment 3

[0217] (6'-Hydroxy-8'-oxo-8'H-spiro[cyclopropane-1,5'-indolezine]-7'-carbonyl)-D-alanine ( 3 )

[0218]

[0219] first step

[0220] (6'-Hydroxy-8'-oxo-8'H-spiro[cyclopropane-1,5'-indolezine]-7'-carbonyl)-D-alanine ( 3 )

[0221]

[0222] compound 1c (90 mg), D-alanine (192 mg) and 0.5M sodium methoxide methanol solution (3.6 ml); spin dry; then add n-propanol (4 ml), reflux until the reaction is complete. Cool, dilute the reaction solution with water, carefully add 1M dilute hydrochloric acid aqueous solution to acidify to about pH 4; precipitate the solid; collect the solid by filtration, then wash the solid with water; then dry to obtain 98 mg of the product 3 . 1H NMR (500MHz, dmso-d6) δ (ppm): 17.99 (1H, s), 13.16 (1H, s), 10.14 (1H, d), 7.35 (1H, s), 6.98 (1H, s), 6.45 (1H,s), 4.51-4.45(1H,m), 1.88(2H,s), 1.78(2H,s), 1.43-1.42(3H,d). LCMS ESI(+):291(M+1) + .

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Abstract

The present invention relates to indoxazine derivatives and their application in medicine. Specifically, the present invention discloses novel substituted indoxazine derivatives of general formula I, or isotope-labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof, or Its pharmaceutically acceptable salt, or its prodrug. The invention also relates to the use of these compounds in medicine.

Description

[0001] This application claims the priority of the Chinese invention patent application No. 201710322377.2 submitted on May 9, 2017. technical field [0002] The invention belongs to the field of medicine and relates to indoxazine derivatives, their preparation and their application in medicine. In particular, the present invention relates to the treatment of diseases related to proline hydroxylase (such as anemia, etc.). Background technique [0003] Anemia is a disease caused by a decrease in the number of red blood cells in the body's blood or a decrease in the hemoglobin content of red blood cells. Because the main function of hemoglobin is to carry oxygen to various organs for utilization, low levels of hemoglobin directly lead to insufficient oxygen supply to various organs of the body. Since the normal physiological activities of the body depend on the full utilization of oxygen, different degrees of anemia will cause various clinical symptoms. Common anemia seconda...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D491/20A61K31/437A61K31/444A61P7/06A61P9/00A61P9/10A61P9/12A61P25/00A61P31/18A61P29/00A61P19/02A61P35/00A61P27/06A61P27/02A61P25/28A61P13/12A61P25/16A61P1/16A61P3/10A61P15/10A61P11/00
CPCA61P1/16A61P3/10A61P7/06A61P9/00A61P9/10A61P9/12A61P11/00A61P13/12A61P15/10A61P19/02A61P25/00A61P25/16A61P25/28A61P27/02A61P27/06A61P29/00A61P31/18A61P35/00C07D471/04C07D491/20A61K31/437A61K31/438A61K31/444C07D471/10A61P7/00
Inventor 刘栋陈冬冬邓彪涂相云方子楠吴浩浩顾丹燕刘静
Owner KIND PHARMA
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