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5-thiazole amides and their biological applications

A technology of thiazolamide and compound, which is applied in the application field of preparing antitumor drugs, can solve the problems of decreased radiotherapy sensitivity and the like, and achieve the effect of strong proliferation inhibition effect

Inactive Publication Date: 2016-08-03
SUN YAT SEN UNIV CANCER CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, after the plasmid carrying the AKT active fragment was transfected in MCF-7 breast cancer cells, the sensitivity of MCF-7 cells to radiotherapy decreased significantly.

Method used

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  • 5-thiazole amides and their biological applications
  • 5-thiazole amides and their biological applications
  • 5-thiazole amides and their biological applications

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0075] (S)-N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5- Carbonic acid amide

[0076] (S)-N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-2-(2-(methylamino)primidin-4-yl)thiazole-5-carboxamide

[0077]

[0078] 2-Acetyl-5-thiazole methyl ester (1b)

[0079] methyl-2-acetylthiazole-5-carboxylate

[0080]

[0081] Under ice bath at 0°C, 5-thiazole methyl ester 1a (2.86g, 20mmol) was dissolved in 10ml of 4M sulfuric acid solution (2.0eq), and FeSO 4 7H 2 O (33.4g, 6.0eq), 40% acetaldehyde solution (13.22g, 6.0eq), N 2 Under protection, 70% t-BuOOH (12ml, 6.0eq) was slowly added dropwise through a constant pressure funnel, and the dropwise addition was completed in 15 minutes, then transferred to room temperature for 2 hours, extracted with EA (60mlx3), saturated with FeSO 4 solution washed twice with water, saturated NaHCO 3 solution, washed once with saturated saline, anhydrous Na 2 SO 4 After drying, the solvent was evapo...

example 2

[0119] (S)-N-(1-amino-3-phenyl)propan-2-yl)-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5-carbonic acid amide

[0120] (S)-N-(1-amino-3-phenylpropan-2-yl)-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5-carboxamide

[0121]

[0122] MS(ESI)m / z369.1[M+H] + . 1 HNMR (400Hz, MeOH-d 4 )δ8.41(d, J=4.8Hz, 1H), 8.37(s, 1H), 7.30(t, J=4.36, 5.6Hz, 5H), 7.20-7.24(m, 1H), 4.57(m, 1H ),3.24(dd,q,J=13.08,3.44Hz,1H),3.15(dd,q,J=12.84,10.28Hz,1H),2.99(m,2H),2.96(s,3H).

[0123] (S)-N-Boc--2-Amino-3-phenyl-1-propanol (2a)

[0124] (S)-tert-butyl1-hydroxy-3-phenylpropan-2-ylcarbamate

[0125]

[0126]1M solution of Boc-Phe-OH (5.32g, 20mmol) in THF, N 2 Cool to 0°C under protection, followed by TEA (3.34ml, 1.2eq), ClCO 2 Me (1.85ml, 1.2eq), continue to stir for 25min, filter with suction, transfer the filtrate to 0°C, add 4M NaBH4 solution (7.5ml, 1.5eq) dropwise, continue to stir for 30min, transfer to room temperature, stir for 2h, 2M HCl Adjust the pH to 2, extract with EA (60mlx3...

example 3

[0129] (S)-N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-4-methyl-2-(2-(methylamino)pyrimidin-4-yl ) Thiazole-5-carbonic acid amide

[0130] (S)-N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-4-methyl-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5-carboxamide

[0131]

[0132] 2-Amino-4-methyl-5-thiazole ethyl carbonate (3a)

[0133] ethyl2-amino-4-methylthiazole-5-carboxylate

[0134]

[0135] In 200ml of absolute ethanol, add ethyl 2-chloroacetoacetate (25g, 150mmol), thiourea (22.8g, 2.0eq), reflux overnight, cool to room temperature, spin off the solvent under reduced pressure, add 500ml of water, 2N NaOH The pH of the solution was adjusted to 10, and a white solid precipitated out. The stirring was continued for 10 min, filtered by suction, and dried in vacuo to obtain 3a (27.37 g, 98%). MS(ESI)m / z187.1[M+H] + . 1 HNMR (400Hz, CDCl 3 )δ5.55(br,s,2H),4.29(d,J=7.2Hz,2H),2.52(s,3H),1.34(t,J=7.2Hz,3H).

[0136] 4-Methyl-5-thiazole ethyl carbonate (3b)

[0137] ethyl...

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Abstract

The present invention relates to a kind of 5-thiazole amides compound and biological application, its structural formula is The present invention provides 5-thiazole amide compounds represented by general formula (I) targeting AKT / PKB kinase (ATP binding site). Experiments have proved that the thiazole amide AKT inhibitor involved in the present invention can significantly inhibit the activity of AKT kinase in vitro, and has a strong proliferation inhibitory effect on various tumor cell lines with high AKT activity, indicating that thiazole amide compounds can be used for Preparation of antitumor drugs.

Description

technical field [0001] The present invention belongs to the field of chemical medicine, 5-thiazole amide compounds with structural characteristics of formula (I) or pharmaceutically acceptable stereoisomers thereof, or prodrug molecules thereof, pharmaceutical compositions containing such compounds and these compounds or Application of the composition in the preparation of antitumor drugs. Background technique [0002] Chemotherapy is one of the important methods to treat tumors, but the anticancer drugs commonly used in clinical practice mainly affect the synthesis of DNA or its precursors, which have poor selectivity, high toxicity, and are prone to drug resistance, thus limiting their use. Over the past 20 years, a large number of new antineoplastic drugs targeting tumor-specific molecular changes have entered the clinic. In this class of drugs, inhibitors targeting tyrosine kinase signal transduction pathways have been most successfully developed, such as Gleevec, Suten...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D471/04A61K31/506A61K31/427A61K31/437A61P35/00
Inventor 朱孝峰邓蓉丁克常少华李迎君
Owner SUN YAT SEN UNIV CANCER CENT
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