3-cyanoquinoline compound as well as pharmaceutical composition and application thereof

A compound and solvate technology, applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve problems such as inability to form network-like branches, immature blood vessels, etc.

Inactive Publication Date: 2013-09-18
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies in knockout mice have found that in Tie2-deficient mice, the number of endothelial cells is normal and integrated into the lumen, but due to the lack of peripheral endothelial cells, the blood vessels are immature and scattered, unable to form network-like branches

Method used

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  • 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof
  • 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof
  • 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0125] The preparation method of the compound represented by the general formula (I) of the present invention and its pharmaceutically acceptable salt, or prodrug, solvate, polymorph, stereoisomer, or tautomer, etc., comprises the following Preparation:

[0126] Method 1: The reaction raw material IA is reacted with aromatic amines, phenols or thiophenols under acid catalysis (such as hydrochloric acid, pyridine hydrochloride, sulfuric acid, etc.) or base catalysis (such as potassium carbonate, sodium bicarbonate, triethylamine, etc.) reaction to generate intermediate IB; intermediate IB is then subjected to substitution reaction with halogenated hydrocarbon (or sulfonate of alcohol, etc.), or Mitsunobu reaction with alcohol to obtain intermediate IC; intermediate IC and various amines (ring A) A substitution reaction was carried out to obtain the target compound ID. Wherein n is an integer such as 1, 2, 3; LG is a leaving group such as halogen, sulfonate, acetate; A, Ar and ...

Embodiment 1

[0137] 4-(2,4-Dichloro-5-methoxy-anilino)-6-methoxy-7-[3-(2-oxa-7-aza-spiro[3.5]nonan-7- Base)-propoxyl]-quinoline-3-methyl cyanide

[0138]

[0139] Synthesis line:

[0140]

[0141] The first step: 4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-cyanide

[0142] Anhydrous potassium carbonate (10.6g, 6eq) was added to a DMF solution (30mL) of 4-chloro-7-hydroxyl-6-methoxyquinoline-3-cyanide (3g, 12.7mmol) under ice-cooling, and stirred for half After 1 hour, 1-chloro-3-iodopropane (13 g, 63.9 mmol) was added to the above suspension and stirred overnight at room temperature. The reaction solution was diluted with water (500mL), extracted with dichloromethane (250mLX2), the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4-chloro- 7-(3-Chloro-propoxy)-6-methoxy-quinoline-3-cyanide (yellow solid, 3.1g), yi...

Embodiment 2

[0154] 4-(2,4-dichloro-5-methoxy-aniline)-7-[3-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-propoxy ]-6-methoxy-quinoline-3-cyanocyanide

[0155]

[0156] Using the intermediate in the second step of Example 1 and 8-aza-bicyclo[3.2.1]octan-3-ol as raw materials, the target compound 4-(2,4- Dichloro-5-methoxy-aniline)-7-[3-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-propoxy]-6-methoxy -Quinoline-3-cyanocyanide (gray solid, 21 mg).

[0157] 1 H NMR(300MHz,DMSO-d6):δ9.71(s,1H),8.41(s,1H),7.87(s,1H),7.74(s,1H),7.33(s,2H),4.22(m ,2H),4.00(m,1H),3.95(s,3H),3.85(s,3H),3.41(m,2H),3.03(m,2H),2.10(m,2H),1.82(m, 2H),1.55(m,2H).

[0158] MS m / z(ESI):531.2[M+H].

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Abstract

The invention relates to a compound as shown in a formula I or a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, a tautomer, a polymorphic substance or metabolite, a pharmaceutical composition and medicinal usage of the compound. The compound as shown in the formula I or the pharmaceutically acceptable salt, the solvate, the prodrug, the stereoisomer, the tautomer, the polymorphic substance or metabolite and the pharmaceutical composition of the compound can be used as protein kinase inhibitors and particularly used for treating or preventing tumors.

Description

technical field [0001] The present invention belongs to the field of chemical medicine, and specifically relates to a compound having the structural characteristics shown in the general structural formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph substances or metabolites. The present invention also relates to a pharmaceutical composition containing this type of compound, and the application of these compounds or composition in the preparation of drugs for treating or preventing tumors or protein kinase inhibitor drugs. Background technique [0002] In recent years, the incidence of tumor diseases in the world has been on the rise. According to the statistics of the World Health Organization, in 2007, the number of newly diagnosed tumor patients has reached more than 12 million. Malignant tumors (cancer) have become the main cause of human death. one of the diseases. It is estimated that by 2020, there will be 15 million n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107C07D471/08C07D471/04C07D471/10C07D487/04C07D487/10C07D401/12C07D519/00A61K31/4709A61P35/00A61P35/02
Inventor 万惠新李春丽韩雅男张永白蕊刘海燕马晨
Owner SHANGAI PHARMA GRP CO LTD
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