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Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines

A technology of thiazole amides and compounds, which is applied in the field of preparation of anti-malignant tumor drugs, can solve the problems of increasing side effects, low water solubility, affecting bioavailability, etc., and achieves the effects of easy preparation, high bioavailability, and improved effective bioavailability

Inactive Publication Date: 2011-01-19
苏州得普医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the compound represented by formula (I), that is, dasatinib, has a very obvious first-pass effect after oral administration, and its bioavailability is only about 14-34%. Therefore, its dosage is generally large, and to a certain extent Increased side effects and aggravated treatment costs for patients
In addition, the water solubility of dasatinib is very low, only 0.008mg / ml, which largely affects the formulation preparation and bioavailability of dasatinib

Method used

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  • Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines
  • Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines
  • Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Formula Ia compound, its chemical name is: N-(2-chloro-6-methylphenyl)-2-[[6-[4-tert-butoxycarbonyl-2,2,3,3,5,5, 6,6-Octadeutero-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

[0039]

[0040] The compound of formula Ia can be obtained by the following synthetic route:

[0041]

[0042] (1), preparation of 1-tert-butoxycarbonyl-deuterated piperazine: at room temperature, slowly add an aqueous solution of sodium hydroxide (0.78g, 19.5mmol) 1ml to deuterated piperazine hydrochloride while stirring (3.25g, 19.4mmol), reacted for about 5 minutes, then added dropwise 250ml of methanol, stirred for 30 minutes, reacted in an ice-salt bath at -20°C for 30 minutes, and slowly added di-tert-butyl dicarbonate dropwise About 50ml of methanol solution (4.25g, 19.5mmol), put it at room temperature and react for 1 hour, concentrate, add water and stir for 15 minutes, then filter, the filtrate is extracted with dichloromethane, and the organic phase is drie...

Embodiment 2

[0049] Compound of formula Ib: N-(2-chloro-6-methylphenyl)-2-[[6-[4-ethoxycarbonyl-2,2,3,3,5,5,6,6-octadeuterium -1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

[0050]

[0051] The compound can be obtained by making N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide with 1- Ethoxycarbonyl-deuterated piperazine is obtained through a substitution reaction, and the specific preparation process can be found in Example 1.

Embodiment 3

[0053] Compound of formula Ic: N-(2-chloro-6-methylphenyl)-2-[[6-[4-tert-butylcarbonyl-2,2,3,3,5,5,6,6-octadeuterium -1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, the structural formula is as follows:

[0054]

[0055] The compound can be obtained by making N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5thiazolecarboxamide with 1-tert Butylcarbonyl-deuterated piperazine is obtained through a substitution reaction, and the specific preparation process can be found in Example 1.

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Abstract

The invention relates to a thiazoleamide compound and a use thereof for the preparation of anti-malignant tumor medicines. As an ideal Bcr-Abl and Src protein tyrosine kinase inhibitor, the thiazoleamide compound according to the invention shows outstanding effect when being used for chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myeloproliferative syndrome, lung cancer, ovarian cancer, prostatic cancer, soft tissue sarcoma, malignant glioma and other malignant tumors, and simultaneously has the advantages of small dose and side effect.

Description

technical field [0001] The invention relates to thiazole amide compounds and their application in the preparation of anti-malignant tumor drugs. Background technique [0002] Protein tyrosine kinase (PTK) activates downstream signaling proteins through phosphorylation, thereby regulating cellular responses. When signaling proteins are overactive, they cause abnormal cell growth and differentiation. Therefore, abnormal regulation of tyrosine kinases is closely related to the invasion and poor prognosis of many tumors, and is an important feature of malignant tumors. [0003] Known, the compound represented by formula (I), N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]- 2-Methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (also known as dasatinib or BMS-354825) is a protein tyrosine kinase inhibitor, such as a Src kinase inhibitor, and can be used in For the treatment of immune and tumor diseases. The compounds represented by formula (I) are also BCR / A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/506A61P35/00A61P35/02
Inventor 殷建明朱惠霖
Owner 苏州得普医药科技有限公司
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