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Quinoline and cinnoline compound and application thereof

一种化合物、水合物的技术，应用在含有所述化合物的药物组合物,制备治疗和/或预防癌症的药物领域，能够解决减少生物活性等问题，达到强抑制作用、抑制c-Met激酶活性的效果

Inactive Publication Date: 2012-08-22
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reduced biological activity correlates well with the assay's reduced binding of c-Met to its own corresponding HGFβ mutant, eliminating the dominant α-chain binding effect

Method used

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  • Quinoline and cinnoline compound and application thereof
  • Quinoline and cinnoline compound and application thereof
  • Quinoline and cinnoline compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0198] Example 1: N -[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidinyl)propoxy)quinoline-4-oxyl)phenyl-1-(2-trifluoromethyl phenyl)-4-oxo-1,4-dihydrocinnoline-3-carboxamide dihydrochloride

[0199] Step A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (Ⅱ)

[0200] Add 3-methoxy-4-hydroxyacetophenone (600g, 3.61moL) and anhydrous potassium carbonate (698g, 5.055moL) into DMF (5v / w, 2500mL), and stir well at 25°C for 30min , and then 1,3-bromochloropropane (795.9g, 1.4moL) was slowly added dropwise, and after the dropwise addition was completed, the reaction was stirred at 25°C for 10h. After the reaction, filter with suction, wash the filter cake with a small amount of DMF, collect the filtrate, slowly pour the filtrate into ice water and stir vigorously, a solid is precipitated, filter with suction, and dry the filter cake to obtain 827.2 g of a solid, with a yield of 93.8%.

[0201] Step B 1-(4-(3-chloropropoxy)-5-methoxy-2-nitro)acetophenone (Ⅲ)

[0202] the intermediate ...

Embodiment 2

[0233] Example 2: N -[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propoxy]quinoline-4-oxyl]phenyl]-1-(2-chlorobenzene Base)-4-oxo-1,4-dihydrocinnoline-3-carboxamide dihydrochloride

[0234] ESI-MS [M+H] (m / z): 741.7; 1 H NMR (300 MHz, DMSO) δ 11.84 (s, 1H), 8.83 (d, J = 6.5 Hz, 1H), 8.40 (d, J =7.2 Hz, 1H), 8.13 (dd, J =12.8, 2.1 Hz, 1H), 7.97-7.86 (m, 3H), 7.85-7.78 (m, 3H), 7.78-7.70 (m, 3H), 7.65 (t, J =8.8 Hz, 1H), 7.10 (d, J =8.6 Hz, 1H), 7.02 (d, J = 6.4 Hz, 1H), 4.37 (t, J = 5.8 Hz, 2H), 4.07 (s, 3H), 3.50 (d, J =11.6 Hz, 4H), 2.92 (d, J = 9.6 Hz, 2H), 2.38 (d, J = 6.5 Hz, 2H), 1.81 (m, 6H).

Embodiment 3

[0235] Example 3: N -[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propoxy]quinoline-4-oxyl]phenyl]-1-(4-bromobenzene base)-4-oxo-1,4-dihydrocinnoline-3-carboxamide

[0236] ESI-MS [M+H] (m / z): 752.6; 1 H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 8.55 (s, 1H), 8.51-8.38 (m, 2H), 8.00 (d, J =12.1 Hz, 1H), 7.87–7.22 (m, 10H), 6.51 (s, 1H), 4.24 (s, 2H), 3.96 (s, 3H), 3.06 (s, 6H), 2.27 (s, 2H) , 1.76 (s, 4H), 1.52 (s, 2H).

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PUM

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Abstract

The invention relates to a quinoline shown in the formula I, a cinnoline derivant, and pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof, wherein substituent groups Ar, R1, R2, R3, X, Y, P, Z and n have the meanings given in the specification. The invention also relates to a compound shown in the formula I, which plays a strong role of restraining c-Met kinase, and the usages of the compound and the pharmaceutically acceptable salt and hydrate thereof in preparing drugs for treating diseases caused by c-Met kinase overexpression, particularly in preparing drugs for treating and / or preventing cancer.

Description

technical field [0001] The present invention relates to novel quinoline and cinnoline compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, their preparation methods and pharmaceutical compositions containing the compounds. The present invention also relates to the strong inhibitory effect of quinolines and cinnolines on c-Met kinase, and also relates to the use of such compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of therapeutic The use in medicine for diseases caused by abnormally high expression of c-Met kinase, especially in the preparation of medicines for treating and / or preventing cancer. Background technique [0002] Malignant tumor is a disease that seriously endangers human life and health. With the change of external factors such as environmental pollution, the number of cancer cases in the world is increasing year by year. According to the statistics of the World Health Or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/12A61K31/502A61K31/496A61K31/5377A61P35/00
CPCA61P35/00A61P43/00C07D401/12C07D401/14C07D403/12C07D403/14A61K31/496A61K31/502A61K31/506A61K31/5377
Inventor 宫平赵燕芳刘亚婧翟鑫
Owner SHENYANG PHARMA UNIVERSITY
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