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Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor and medicinal composition containing the same

A kind of technology of compound and solvate, applied in the field of quinoline derivatives and quinazoline derivatives

Inactive Publication Date: 2004-12-08
KIRIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, there are no reports on low-molecular-weight compounds having met autophosphorylation inhibitory effects, or low-toxicity substances having antitumor effects by oral administration

Method used

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  • Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor and medicinal composition containing the same
  • Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor and medicinal composition containing the same
  • Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor and medicinal composition containing the same

Examples

Experimental program
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preparation example Construction

[0464] Compound preparation

[0465] Compounds of the invention can be prepared, for example, according to Schemes 1-9. The raw materials necessary for the synthesis of the compounds of the present invention are commercially available or can be easily prepared by conventional methods. Program R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 18 , R 19 and X are the same as defined above. PG stands for protecting group, R 3’ O represents an alkoxy group that may be substituted, Hal represents a halogen atom, R 51 and R 52 Can be the same or different, denote C that can be substituted 1-6 Alkyl, or R 51 and R 52 A saturated or unsaturated 3-8 membered heterocyclic ring can be formed together with the nitrogen atom connected to it, and n represents an integer of 1-6.

[0466] Scheme 1: Preparation of 4-(aminophenoxy) quinoline derivatives and corresponding quinazoline derivatives prepare

[0467]

[0468] 4-Chloroquinoline derivat...

Embodiment

[0515] The invention is illustrated by the following examples, but the invention is not limited to these examples.

[0516] The raw materials required for the synthesis can be prepared according to the records of WO97 / 17329, WO98 / 47873, WO00 / 43366 and JP-A-9-328782. Raw materials not described in these publications were prepared as shown in the following Preparation Examples.

[0517] Scheme 10: Preparation of starting materials 1-10

[0518]

[0519] Scheme 11: Preparation of starting materials 11 and 12

[0520]

preparation example 1

[0521] Preparation example 1 (raw material 1)

[0522] Add 7-(benzyloxy)-4-chloro-6-methoxyquinoline (29g), 3-fluoro-4-nitrophenol (20g), N,N-diisopropylethylamine (33ml) , Chlorobenzene (14ml), heated and stirred at 140°C for 15 hours. After completion of the reaction, 2N aqueous sodium hydroxide solution (30 ml) was added, followed by stirring at room temperature for 3 hours. Water was added to the reaction liquid, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 40 g of the target compound in a yield of 50%.

[0523] 1 H-NMR (CDCl 3 , 400MHz): δ8.58(d, J=5.1Hz, 1H), 8.48-8.44(m, 1H), 8.21-8.19(m, 1H), 7.64-7.35(m, 8H), 6.79(d, J =5.1Hz, 1H), 5.33(s, 2H), 3.94(s, 3H)

[0524] Mass spectral analysis value (m / z): 421[M+H] +

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Abstract

An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein X=CH or N; Z=O or S; L=O or S; M=CR10R11, wherein R10 and R11 =H, alkyl, or alkoxy, NR12 wherein R12=H or alkyl; R1, R2, and R3=H or optionally substituted alkoxy; R4=H; R5-R8=H, halogen, alkoxy or the like; and R9=alkyl optionally substituted by -R14, -T-R15, or -NR16R17 wherein T=O, S, or NH; R14 =an optionally substituted carbocyclic or heterocyclic ring; and R15-R17=alkyl or an optionally substituted carbocyclic or heterocyclic ring, or -NR18R19 wherein R18 and R19 =H, optionally substituted alkyl, or an optionally substituted carbocylic or heterocyclic ring, or optionally substituted carbocyclic or heterocyclic ring.

Description

technical field [0001] The present invention relates to quinoline derivatives and quinazoline derivatives with anti-tumor effect, more specifically, to the effect of inhibiting the autophosphorylation of hepatocyte growth factor receptor, and the inhibitory effect on abnormal cell proliferation or cell movement quinoline derivatives and quinazoline derivatives. Background technique [0002] Growth factors such as epithelial growth factor, platelet-derived growth factor, insulin-like growth factor, and hepatocyte growth factor (Hepatocyte Growth Factor, hereinafter referred to as "HGF") play an important role in cell proliferation. Among them, HGF is known as Liver regeneration factor and kidney regeneration factor are related to the regeneration of injured liver and kidney (Oncogenesis, 3, 27 (1992)). [0003] However, overexpression of HGF or its receptor (hereinafter referred to as "met") in various tumors such as brain tumors, lung cancer, gastric cancer, pancreatic can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61K31/4709A61K31/496A61K31/517A61K31/5377A61P35/00C07D215/22C07D215/233C07D215/40C07D239/88C07D401/12C07D405/12C07D409/12C07D413/12
CPCC07D401/12C07D239/88A61K31/47A61K31/4709C07D405/12A61K31/496C07D409/12A61K31/5377C07D413/12C07D215/40C07D215/233A61K31/517A61P35/00A61P43/00
Inventor 藤原康成千贺照文西鸟羽刚大泽立志三轮笃史中村一英
Owner KIRIN PHARMA
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