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Substituted amino quinazoline compound and pharmaceutical composition and application thereof

A technology of compounds and compositions, applied in the field of medicine, can solve the problems of limited application scope, cost of side effects treatment, poor patient compliance, etc.

Active Publication Date: 2019-07-26
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Poor absorption, distribution, metabolism and / or excretion (ADME) properties are known to be a major reason for failure of many drug candidates in clinical trials
Many currently marketed drugs also limit their application range due to poor ADME properties
The rapid metabolism of drugs will cause many drugs that can treat diseases with high efficiency to be eliminated from the body too quickly, making it difficult to become a drug
Although frequent or high-dose medication may solve the problem of rapid drug clearance, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and increased treatment costs
In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites
[0007] Although Poziotinib as a broad-spectrum ErbB inhibitor can effectively treat cancers mediated by ErbB family tyrosine kinase receptors, there is still a serious clinical unmet need in this field, and it has been found that there are therapeutic effects caused by EGFR (ErbB-1), Her2 / Novel compounds that mediate disease with c-neu(ErbB-2), Her3(ErbB-3), and Her4(ErbB-4) wild-type and mutant kinases with good oral bioavailability and druggability remain challenging sex work

Method used

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  • Substituted amino quinazoline compound and pharmaceutical composition and application thereof
  • Substituted amino quinazoline compound and pharmaceutical composition and application thereof
  • Substituted amino quinazoline compound and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0106] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found in, eg, Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0107] The reaction can be monitored according to any suitable method known in the art. For example, spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectroscopy (MS)) or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) Product formation was monitored.

[0108] The following general preparation r...

Embodiment 1

[0162] Example 1 tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate-3,3,5,5-d 4 Preparation of (Intermediate A-1) prepare.

[0163]

[0164] Synthesize using the following route:

[0165]

[0166] Synthesis of Step 1 Compound 2

[0167] TBU was added to compound 1 (10 g, 50.2 mmol) in deuterated chloroform (100 mL), and the reaction solution was stirred at room temperature for 24 hrs. The reaction solution was neutralized with 1M dilute hydrochloric acid, then extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.02 g of a yellow solid, which was directly used in the next step.

[0168] Step 2 Synthesis of Compound 3

[0169] Under ice-cooling, sodium borohydride (200 mg) was added in batches to compound 2 (2.0 g) in anhydrous methanol (10 mL), and the mixture was reacted at room temperature for 4 hrs. The reaction was quenched...

Embodiment 2

[0172] Example 2 Preparation of tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate-4-d (Intermediate A-2).

[0173]

[0174] Synthesize using the following route:

[0175]

[0176] Step 1 Synthesis of Compound 4

[0177] Under ice-cooling, deuterated sodium borohydride (300 mg) was added in batches to compound 1 (2.0 g) in deuterated methanol (15 mL), and the reaction was carried out at room temperature for 4 hrs. The reaction was quenched by adding saturated ammonium chloride solution, and the deuterated methanol was removed under reduced pressure. Extracted with ethyl acetate (50 mL x 3), combined the organic layers, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain an oil that was directly used in the next reaction.

[0178] Step 2 Synthesis of intermediate compound A-2

[0179] Under ice-cooling, TsCl was added to the above compound 4, DMAP (75mg) and T...

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Abstract

The invention provides a substituted amino quinazoline compound and a pharmaceutical composition and application thereof. The substituted amino quinazoline compound refers to a compound shown as a formula (I), or a pharmaceutically acceptable salt of the compound, a prodrug, a hydrate or a solvate, a crystal form, a stereoisomer or an isotope variant. The compound and the composition can be used for treatment and / or prevention of ErbB family tyrosine kinase mediated diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted aminoquinazoline compound, a pharmaceutical composition containing the compound and its application. More specifically, the present invention relates to certain deuterium-substituted 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazoline-6 -yl)oxy)piperidin-1-yl)prop-2-en-1-one, these deuterium-substituted compounds and compositions thereof can be used for the treatment and / or prevention of ErbB family tyrosine kinases (such as EGFR (ErbB -1), Her2 / c-neu (ErbB-2), Her3 (ErbB-3) and Her4 (ErbB-4) kinases) mediated related diseases, and these deuterium-substituted compounds have better pharmacokinetics nature. Background technique [0002] Protein kinases represent a large class of proteins that play an important role in maintaining control of cellular functions and in the regulation of various cellular pathologies. Protein tyrosine kinases...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/506A61K45/06A61P35/00A61P35/02A61P37/06A61P27/02A61P3/10A61P27/06A61P1/04A61P9/10A61P11/00
CPCA61P1/04A61P3/10A61P9/10A61P11/00A61P27/02A61P27/06A61P35/00A61P35/02A61P37/06C07D401/12A61K31/506A61K31/517A61K45/06C07D403/12
Inventor 王义汉任兴业
Owner SHENZHEN TARGETRX INC
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