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Quinoline or quinazoline derivatives with apoptosis inducing activity on cells

A technology of quinazoline and derivatives, applied in the field of novel quinoline or quinazoline derivatives, can solve the problems of low cell permeability, insurmountable and the like

Active Publication Date: 2013-08-07
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The key sequence (AVPI or AVPF) exhibits pharmacological activity of 120-500 nM in in vitro assays, but cannot overcome its low cell permeability

Method used

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  • Quinoline or quinazoline derivatives with apoptosis inducing activity on cells
  • Quinoline or quinazoline derivatives with apoptosis inducing activity on cells
  • Quinoline or quinazoline derivatives with apoptosis inducing activity on cells

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 2

[0223] Preparation Example 2: Preparation of (S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propionamido)-3,3-dimethylbutanoic acid

[0224] Preparation of (S)-benzyl 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid

[0225] Boc-Tle-OH (4.8 g, 22.3 mmol) was dissolved in dichloromethane (50 mL), and EDCI (4.3 g, 44.6 mmol), DMAP (0.6 g, 4.46 mmol), DIPEA (16 mL, 89.2 mmol) and benzyl alcohol (5 mL, 44.6 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with 5% aqueous citric acid. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure to give the title compound (6.7 g, 99%) as a yellow oil.

[0226] MS (ESI + , m / z): 322[M+H] +

[0227] Preparation of (S)-benzyl 2-amino-3,3-dimethylbutyrate hydrochloride

[0228] The compound (6.7 g, 22.3 mmol) obtained in was dissolved in 4M HCl / dioxane (17 mL) solution, and the mixture was stirred at room temperature for 1 hr. The...

Embodiment 1

[0236] Example 1: Preparation of (S)-N-(4-(3-chloro-2,4-difluoroanilino)-7-methoxyquinazolin-6-yl)-1-((S)- 3,3-Dimethyl-2-((S)-2-(methylamino)propionamido)butyryl)pyrrolidine-2-carboxamide hydrochloride

[0237] Preparation of 7-fluoro-3H-quinazolin-4-one

[0238] 2-Amino-4-fluorobenzoic acid (100 g, 0.64 mol) and formamide (154 mL, 3.87 mol) were mixed with a catalytic amount (1 mL) of N,N-dimethylformamide. The mixture was heated to 180°C and stirred for a further 14 hours. The mixture was cooled to room temperature, and distilled water (1000 mL) was added thereto. The mixture was stirred for 30 minutes and filtered to give the title compound (86 g, 81.3%).

[0239] 1 H NMR (300MHz, CDCl 3 ): δ12.34(s, 1H), 8.19-8.12(m, 2H), 7.46-7.34(m, 2H)

[0240] MS (ESI + , m / z): 165[M+H] +

[0241] Preparation of 7-fluoro-6-nitro-3H-quinazolin-4-one

[0242] The compound (25 g, 152 mmol) obtained in was added dropwise to a solution of sulfuric acid (50 mL) and nitric a...

Embodiment 2

[0269] Example 2: Preparation of (S)-N-(4-(3-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)quinazolin-6-yl)-1-( (S)-3,3-Dimethyl-2-((S)-2-(methylamino)propionylamido)butanoyl)pyrrolidine-2-carboxamide hydrochloride

[0270] Repeat except that 2-fluoro-4-chloro-aniline was used instead of 3-chloro-2,4-difluoro-aniline in and 2-methoxyethanol was used instead of NaOMe in The method of Example 1 was used to obtain the title compound (300mg, 9%).

[0271] 1 H NMR (300MHz, DMSO-d6): δ9.76(s, 1H), 9.32(m, 1H), 8.89(s, 1H), 8.78(m, 2H), 8.60(d, 1H), 7.63(t , 1H), 7.52(m, 2H), 7.35(m, 1H), 4.80(m, 1H), 4.43(m, 1H), 4.41(m, 2H), 3.99(m, 2H), 3.88(s, 3H), 3.80(m, 4H), 1.99(m, 6H), 1.35(d, 3H), 1.01(s, 9H)

[0272] MS (ESI + , m / z): 658[M+H] +

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Abstract

Provided is a pharmaceutical composition comprising, as an active ingredient, a quinoline or quinazoline derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate, and a solvate thereof, which is effective in the prevention and treatment of a cancer, inflammation, autoimmune diseases or neurodegenerative disorders which are induced by the overexpression of inhibitor of apoptosis proteins (IAPs).

Description

technical field [0001] The present invention relates to novel quinoline or quinazoline derivatives for effectively preventing or treating cancer, inflammation, autoimmune disease or neurodegenerative disease induced by overexpression of apoptosis inhibitor protein (inhibitor of apoptosis protein, IAP); and comprising pharmaceutical composition. Background of the invention [0002] Apoptosis, or programmed cell death, plays an important role in the homeostasis of multicellular organisms. This apoptosis maintains the organism by regulating cell growth and death, however, if it is inhibited by several factors, it can lead to a variety of pathologies including cancer, autoimmune diseases, neurodegenerative diseases, etc. [cf. Thompson, C.B. Science, 267 , 1456-1462 (1995); Hanahan, D. & Weinberg, R.A., Cell, 100, 57-70 (2000)]. [0003] During the stage of tumorigenesis, this regulatory step of apoptosis allows the intracellular accumulation of IAP (Inhibitor of Apoptosis Prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D239/94A61K31/517A61P35/00
CPCC07K5/02C07K5/0812C07D403/12A61K31/4709C07K5/0806C07D215/42A61K31/495C07D239/94A61P29/00A61P35/00A61P37/00A61K31/517
Inventor 裴仁焕边恩映朱惠景宋芝英丁承贤田承妸金镐硕郑煐熹沈美娟安永吉金孟燮
Owner HANMI SCI CO LTD
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