Indolizine derivatives and application thereof in medicines

A compound, isomer mixture technology, used in the field of medicine

Inactive Publication Date: 2018-02-27
KIND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, to date, no hypoxia-inducible factor-related proline hydroxylase inhibitor drugs have been approved for marketing

Method used

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  • Indolizine derivatives and application thereof in medicines
  • Indolizine derivatives and application thereof in medicines
  • Indolizine derivatives and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] (7'-Hydroxy-5'-oxo-1'-phenyl-5'H-spiro[cyclopentane-1,8'-indolezine]-6'-carbonyl)glycine ( 1 )

[0184]

[0185] first step

[0186] 5-(1,3-dioxolan-2-yl)-3-oxo-4-phenylpentanoic acid ethyl ester ( 1b )

[0187]

[0188] Ethyl 3-oxo-4-phenylbutyrate (1.03 g, prepared according to the method described in the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334]) was dissolved in anhydrous tetrahydrofuran (20 ml), and ice Cool in a water bath, slowly add 60% pure mineral oil and sodium hydride mixed solids (200 mg) in small portions under nitrogen flow, and stir for 0.5 hours; then add hexamethylphosphoramide (2.7 g) and 1.6M A solution of n-butyllithium in hexane (3.13 mL); then 2-bromomethyl-1,3-dioxolane (840 mg) was added. The reaction was stirred overnight at room temperature. The reaction solution was carefully poured into saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate; the ethyl acetate layer was...

Embodiment 2

[0212] (1'-(4-fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-indolezine]-6'-carbonyl) Glycine ( 2 )

[0213]

[0214] first step

[0215] 5-(1,3-dioxolan-2-yl)-4-(4-fluorophenyl)-3-oxopentanoic acid ethyl ester ( 2b )

[0216]

[0217] compound 2b According to the first step of embodiment 1 1b The synthetic method preparation, wherein raw material 2a : Ethyl 4-(4-fluorophenyl)-3-oxobutanoate was prepared according to the method described in the literature [European Journal of Medicinal Chemistry, 2014, vol 84, 312-334]. LCMS ESI(+):311(M+1) + .

[0218] second step

[0219] 1-(3-(1,3-dioxolan-2-yl)-2-(4-fluorophenyl)propionyl)cyclopentane-1-carboxylic acid ethyl ester ( 2c )

[0220]

[0221] compound 2c According to the second step of Example 1 1c Synthetic method from the compound 2b preparation. LCMS ESI(+):365(M+1) + .

[0222] third step

[0223] 1-(3-(4-fluorophenyl)-1H-pyrrol 0-2-yl)cyclopentane-1-carboxylic acid ethyl ester ( 2d...

Embodiment 3

[0239] (1'-(4-fluorophenyl)-7'-hydroxy-5'-oxo-5'H-spiro[cyclopentane-1,8'-indolezine]-6'-carbonyl) Ethyl glycinate ( 3 )

[0240]

[0241] compound 2 (1 equivalent) was suspended in ethanol (5 volumes), and thionyl chloride (4 equivalents) was carefully added dropwise; then refluxed until the reaction was complete. Naturally cooled to room temperature and then cooled in an ice-water bath, the solid was collected by filtration and washed with cold ethanol to obtain the compound 3 . LCMS ESI(+):427(M+1) + .

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PUM

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Abstract

The invention relates to an indolizine derivative and application thereof in medicines. Specifically, the invention discloses a novel substituted indolizine derivative as shown in a general formula I,or an isotope marked compound thereof, or an optical isomer, geometric isomer, tautomeride or isomer mixture thereof, or a medicinal salt thereof, or a prodrug thereof. The invention further relatesto application of the compounds in medical science. The general formula I is shown in the description.

Description

technical field [0001] 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 [0002] 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 secondary diseases include cardiovascular system diseases (heart failure, atrial fibrillation, angina pectoris, etc.), urinary system diseases...

Claims

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Application Information

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IPC IPC(8): C07D471/10A61K31/438A61P35/00A61P7/06A61P9/00A61P9/10A61P9/12A61P25/00A61P31/18A61P19/02A61P13/12A61P27/02A61P3/10A61P25/16A61P25/28A61P15/00A61P27/06
CPCC07D471/10
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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