Substituted aminoquinazoline compounds, pharmaceutical compositions and uses thereof

A compound and composition technology, applied in the field of medicine, can solve problems such as poor patient compliance, poor absorption, distribution, metabolism and/or excretion, and limited application range

Active Publication Date: 2020-11-27
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 aminoquinazoline compounds, pharmaceutical compositions and uses thereof
  • Substituted aminoquinazoline compounds, pharmaceutical compositions and uses thereof
  • Substituted aminoquinazoline compounds, pharmaceutical compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0106] The preparation of the compounds of the invention can involve protection and removal protection of different chemical groups. Those skilled in the art can readily determine whether to protect and remove protection and appropriate protecting groups are required. The chemical properties of the protecting base can be found, for example, WUTS and GREENE, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference.

[0107] The reaction can be monitored in accordance with any suitable method known in the art. For example, a spectral means (such as nuclear magnetic resonance (NMR) spectroscopy (eg, 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (eg, UV- visible light), mass spectrometry (MS)) or by chromatography (such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC)) Monitor product formation.

[0108] The universal preparation route below can be used to synt...

Embodiment 1

[0162] Example 1 4- (Toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester-3, 3, 5, 5-D 4 (Intermediate A-1) Preparation.

[0163]

[0164] Synthesized using the following scheme:

[0165]

[0166] Step 2 Synthesis of Compound 1

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

[0168] Step 2 Synthesis of Compound 3

[0169] Under ice-cooling, sodium borohydride (200 mg of) was added portionwise to the compound 2 (2.0g) in anhydrous methanol (10mL), the reaction was warmed to room temperature at 4hrs. Saturated ammonium chloride solution was added to q...

Embodiment 2

[0172] Example 2 4- (For toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester-4-D (intermediate A-2) was prepared.

[0173]

[0174] Synthesized using the following scheme:

[0175]

[0176] Synthesis of Compound 1 Step 4

[0177] Under ice-cooling, deuterated sodium borohydride (300mg) was added to Compound 1 (2.0g) deuterated methanol (15mL), the reaction was warmed to room temperature at 4hrs. Saturated ammonium chloride solution was added to quench the reaction, deuterated methanol was removed under reduced pressure. (50mL x 3) and extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under reduced pressure to give an oil which was used directly in the next reaction.

[0178] Step 2 Synthesis of Intermediate Compound A-2 is

[0179] In an ice bath was added to the above compound TsCl 4, DMAP (75mg) and TEA (3.75mL) in dry dichloromethane (45...

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PUM

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Abstract

The present invention relates to a substituted aminoquinazoline compound, and a pharmaceutical composition and a use thereof. The aminoquinazoline compound is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, a prodrug, a hydrate or a solvent compound, a crystal form, a stereoisomer or an isotope variant. The compound and the composition can be used for treating and / or preventing ErbB family tyrosine kinase mediated diseases.

Description

Technical field [0001] The present invention belongs to the field of medical technology, and more particularly to a substituted aminoquinazoline compound and a pharmaceutical composition comprising the compound and its use. More specifically, the present invention relates to 1- (4- ((4- (4- (4-dichloro-2-fluorophenyl) amino) -7-methoxy quinzoline-6-7-methoxy quinzoline-6 - Base) oxygen - 1-ketone, these deuterium-substituted compounds and their compositions can be used in the treatment and / or prevention of Erbb family tyrosine kinases (eg EGFR (Erbb) -1), HER2 / C-NEU (Erbb-2), Her3 (ErbB-3) and HER4 kinase-mediated related diseases, and these deuteri-substituted compounds have more excellent pharmacokinetics nature. Background technique [0002] Protein kinase represents a major protein that plays an important role in the regulation of cellular functional control and various cellopathy. Protein tyrosine kinases can be classified in growth factor receptors such as VEGFR, EGFR, ...

Claims

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Application Information

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Patent Type & Authority Patents(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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