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A kind of 2-acylaminothiazole derivative and its preparation method and application

A group, alkyl technology, applied in the field of novel 2-amidothiazole derivatives, can solve the problems of limited application, liver toxicity, side effects, serious and other problems

Active Publication Date: 2021-07-09
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although eltrombopag is well tolerated in humans, it has severe hepatotoxic side effects, which greatly limit its clinical application

Method used

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  • A kind of 2-acylaminothiazole derivative and its preparation method and application
  • A kind of 2-acylaminothiazole derivative and its preparation method and application
  • A kind of 2-acylaminothiazole derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] Example 1: 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5 (1H)-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (K1)

[0170]

[0171] Step 1: 5-[2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylic acid tert Synthesis of Butyl Ester

[0172] 5-Bromo-4-(4-chlorothien-2-yl)-2-amino-thiazole (1.4g, 4.7mmol), hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylic acid Tert-butyl ester (1.1g, 4.7mmol) was dissolved in N,N-dimethylformamide (30mL), anhydrous potassium carbonate (820mg, 5.6mmol) was added, and reacted at about 70°C for about 1h. The solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 1.7 g of the title compound.

[0173] ESI-MS(m / z):427.2[M+H] +

[0174] Step 2: 5-[4-(4-chlorothien-2-yl)-2-(5,6-dichloro-pyridine-3-amido)-thiazol-5-yl]-hexahydropyrrolo[3 ,4-b]Synthesis of tert-butyl ...

Embodiment 2

[0190] Example 2: 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-cyclobutyl-hexahydropyrrolo[3,4-b]-pyrrole -5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid (K2)

[0191]

[0192] Using a method similar to that of Example 1, but replacing the paraformaldehyde in the fifth step of Example 1 with cyclobutanone, 28 mg of the trifluoroacetate salt of the title compound was obtained.

[0193] 1 H NMR (400MHz, DMSO-d 6 )δ12.66(s,1H),12.32(s,1H),9.92(s,1H),8.83(d,J=2.0Hz,1H),8.39(d,J=2.0Hz,1H),7.58( d,J=1.4Hz,1H),7.50(d,J=1.4Hz,1H),4.14(s,1H),3.99(s,1H),3.96(s,1H),3.94-3.92(m,1H ),3.63(s,1H),3.53-3.50(m,1H),3.34-3.31(m,1H),3.22-3.14(m,3H),3.03(t,J=2.4Hz,2H),2.91( t,J=8.5Hz,1H),2.52(s,1H),2.39(s,1H),2.27-2.22(m,4H),1.96-1.92(m,3H),1.78-1.63(m,4H)

[0194] ESI-MS(m / z):647.2[M+H] +

Embodiment 3

[0195] Example 3: 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-cyclopentyl-hexahydropyrrolo[3,4-b]pyrrole- 5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid (K3)

[0196]

[0197] Using a method similar to that of Example 1, but replacing the paraformaldehyde in the fifth step of Example 1 with cyclopentanone, 27 mg of the trifluoroacetate salt of the title compound was obtained.

[0198] 1 H NMR (400MHz, DMSO-d 6 )δ12.67(s,1H),12.33(s,1H),9.82(s,1H),8.83(d,J=2.1Hz,1H),8.39(d,J=2.1Hz,1H),7.58( d,J=1.4Hz,1H),7.51(d,J=1.4Hz,1H),4.33-4.28(m,1H),3.99(s,1H),3.96(s,1H),3.77-3.72(m ,1H),3.67-3.61(m,1H),3.56(d,J=10.5Hz,1H),3.41-3.37(m,1H),3.29-3.20(m,2H),3.18-3.14(m,1H ), 3.03(t, J=11.5Hz, 2H), 2.87(dd, J=9.6Hz, 6.8Hz, 1H), 2.57-2.52(m, 1H), 2.42-2.33(m, 1H), 2.07-2.00 (m,2H),1.96-1.92(m,2H),1.90-1.85(m,1H),1.75-1.66(m,6H),1.63-1.50(m,2H)

[0199] ESI-MS(m / z):661.2[M+H] +

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Abstract

The present invention relates to a kind of 2-amidothiazole derivatives. The present invention also relates to the preparation methods of these 2-acylaminothiazole derivatives and their intermediates and the pharmaceutical compositions containing these compounds. In addition, the present invention also relates to the use of these 2-acylaminothiazole derivatives and pharmaceutical compositions containing them in the treatment and / or prevention of diseases mediated by thrombopoietin receptors.

Description

technical field [0001] The present invention relates to a novel 2-acylaminothiazole derivative. The present invention also relates to the preparation methods of these novel 2-acylaminothiazole derivatives and their intermediates and pharmaceutical compositions containing these compounds. In addition, the present invention also relates to the use of these novel 2-amidothiazole derivatives and pharmaceutical compositions containing them in the treatment and / or prevention of diseases mediated by thrombopoietin receptor agonists. Background technique [0002] Thrombopoietin (TPO) receptor is a member of the thrombopoietin growth factor receptor family. This family of receptors is characterized by a common extracellular structure comprising similar N-terminal portions of C residues and a WSXWS characteristic structure near the transmembrane region (Bazan, Proc. Natl. Acad. Sci. USA, 87, 6934-6938 (1990)). Thrombopoietin (TPO) receptor expression is restricted to mouse spleen, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D471/04C07D487/10C07D487/08C07D471/08A61K31/4545A61P7/02
CPCA61P7/04C07D471/04C07D471/08C07D487/04C07D487/08C07D487/10A61P7/02C07D513/04
Inventor 蔡家强郁楠曾宏宋宏梅卿燕宋帅邓汉文唐祖建段小凡黄海涛叶红刘钢王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD