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Compound and crystals thereof

A technology of compounds and crystals, applied in the field of pharmacy, can solve the problems of low biological activity, inconsistent with drug characteristics, and high toxicity

Active Publication Date: 2013-08-21
HUTCHISON MEDIPHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in further research, it was found that in a series of compounds disclosed by it, there are some defects, or problems such as small biological activity, high toxicity, or pharmacokinetics, which do not meet the characteristics as drugs, so it is necessary to Explore more effective KDR inhibitors with better pharmaceutical properties

Method used

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  • Compound and crystals thereof
  • Compound and crystals thereof
  • Compound and crystals thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0062] The compound can be prepared by the attached figure 1 route is realized.

[0063] The first step: the synthesis of 5-(2-chloropyrim-5-oxo)-2-methyl-1H-indole (compound 3)

[0064] Under low temperature and alkaline conditions, in an appropriate solvent, the hydroxyl group of 5-hydroxyl-2-methylindole (compound 1) selectively attacks the 4-position of 2,4-dichloropyrimidine (compound 2), Form intermediate 5-(2-chloropyrim-5-oxo)-2-methyl-1H-indole (compound 3); wherein, the base used can be an inorganic base, such as NaHCO 3 , KOH, NaOH, K 2 CO 3 , KHCO 3 , or organic bases, such as diisopropylethylamine, pyridine, triethylamine, trimethylamine, etc.; the reaction solvent can be acetonitrile, N, N-dimethylformamide, dioxane, tetrahydrofuran, etc.; the reaction temperature It is suitable to be controlled within the range of 0~60 degrees;

[0065] The second step: N-[2-(dimethylamino)ethyl]-[3-[4-(2-methyl-1H-indole-5-oxyl)pyrimidine-2-amino]phenyl]methanol Synthesi...

Embodiment 1

[0168] Synthesis of N-[2-(dimethylamino)ethyl]-[3-[4-(2-methyl-1H-indole-5-oxyl)pyrimidine-2-amino]phenyl]methanesulfonamide

[0169] Preparation of compound 5-(2-chloropyrim-5-oxo)-2-methyl-1H-indole (compound 3)

[0170] Add 3kg of 5-hydroxy-2-methylindole (compound 1), 9L of acetonitrile, and 4.2Kg of potassium carbonate into a 50L reaction flask, stir and cool down to 0-5°C under nitrogen protection; slowly add 2,4-dichloro Pyrimidine (compound 2) 3.05kg of acetonitrile solution; after dripping, the temperature was raised to 5-10°C, and the reaction was stirred for 4-8 hours; under stirring, the reaction solution was transferred to a 100L treatment tank with 54L of pure water, and the solid was precipitated. Stir at room temperature for 1 hour. Filter, wash the filter cake with pure water, and dry to obtain 5.1 kg of the product, with a purity of 98.6% and a yield of 96%.

[0171] Synthesis of N-[2-(dimethylamino)ethyl]-[3-[4-(2-methyl-1H-indole-5-oxyl)pyrimidine-2-amin...

Embodiment 2

[0175] Determination of the inhibitory effect of compound A on KDR activity using Z’-lyte detection kit

[0176] Experimental materials and experimental methods: using Z′-LYTE TM Tyr1 substrate peptide kit (Invitrogen, Cat. PV3190) was used to detect the inhibitory effect of compound A on KDR kinase activity in vitro. The detection reaction contained 300 ng / mL recombinant human KDR kinase catalytic region (Invitrogen, Cat. PV3660), 10 μM ATP, 1 μM fluorescent double-labeled substrate peptide and different concentrations of compound A obtained in Example 1. Reactions were performed in black 384-well plates (Thermolabsystems, Cat. 7805). According to the method recommended by the manufacturer, the enzyme catalyzes the reaction at room temperature for 1 hour, then adds a fluorescence accelerator, continues to react at room temperature for 1 hour, and then adds a terminator to terminate the reaction. The inhibition rate of the compound on the enzyme reaction was calculated acco...

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Abstract

Compound of Formula A and pharmaceutically acceptable salts thereof and crystalline Forms I and II of Compound of Formula A! Also, methods for the preparation of such compounds, pharmaceutical compositions comprising such compounds, and methods for their uses.

Description

technical field [0001] The invention belongs to the field of pharmacy and provides a pyrimidine compound N-[2-(dimethylamino)ethyl]-[3-[4-(2-methyl-1H-indole-5-oxyl)pyrimidine- 2-Amino]phenyl]methanesulfonamide and its medicinal use and crystal form, in particular to a kinase-inserted-region receptor (KDR) inhibitor for treating diseases related to angiogenesis. Background technique [0002] Angiogenesis is the physical process of growing new blood vessels from pre-existing blood vessels. It often occurs when a healthy body uses it to heal a wound, such as restoring blood flow to injured tissue in the hand. [0003] Excessive vascular proliferation can be initiated by some specific pathological conditions, such as tumors, age-related macular degeneration (Age-related Macular Degeneration, AMD), rheumatoid arthritis, psoriasis and so on. Therefore, under these conditions, new blood vessels often nourish pathological tissues and destroy normal tissues. For example, in tumors,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12A61K31/513A61P35/00A61P27/02A61P29/00A61P35/02
CPCC07D403/12A61P27/02A61P29/00A61P35/00A61P35/02A61P43/00A61P9/00A61K31/506
Inventor 苏慰国张维汉贾红崔玉敏任永欣赛杨吴振平李文姬邵江勇
Owner HUTCHISON MEDIPHARMA LTD
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