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2-amidothiazole derivatives and its preparation method and use

A drug and propyl-based technology, applied in the treatment of diseases mediated by thrombopoietin, can solve serious, limited application, liver toxicity and side effects, etc., achieve excellent metabolic stability, excellent effect of promoting platelet production, and promote platelet production and the effect of megakaryocyte production

Active Publication Date: 2021-06-15
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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  • 2-amidothiazole derivatives and its preparation method and use
  • 2-amidothiazole derivatives and its preparation method and use
  • 2-amidothiazole derivatives and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] Example 1 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-cyclohexyl-1,2,3,6-tetrahydropyridin-4-yl )thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (compound L1)

[0222]

[0223] Step 1: Synthesis of 4-[2-amino-4-(4-chlorothiophen-2-yl)thiazol-5-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0224] 5-Bromo-4-(4-chlorothiophen-2-yl)-2-amino-thiazole (900mg, 3.1mmol), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4 - pinacol borate (960mg, 3.1mmol), anhydrous sodium carbonate (920mg, 7.3mmol) and tetrakistriphenylphosphine palladium (180mg, 0.2mmol), dissolved in a mixed solvent of ethylene glycol dimethyl ether and water Medium (45mL, V:V=2:1). Reacted at 70°C for 1.5h under the protection of nitrogen. Cool down to room temperature, filter, and concentrate the filtrate to obtain a crude product, which is purified by silica gel column chromatography to obtain 1.1 g of the title compound.

[0225] ESI-MS(m / z): 398.2[M+H] +

[02...

Embodiment 2

[0242] Example 2 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl )thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (compound L2)

[0243]

[0244] Using a method similar to Example 1, but in the first step, replace N- Starting from tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (960 mg, 3.1 mmol), the title was prepared by substituting paraformaldehyde for cyclohexanone in the fifth step Trifluoroacetate salt of compound, 32 mg.

[0245] 1 H NMR (400MHz, DMSO-d 6 )δ12.73(s, 1H), 12.31(s, 1H), 9.26(s, 1H), 8.84(d, J=2.1Hz, 1H), 8.40(d, J=2.1Hz, 1H), 7.62( d, J=1.5Hz, 1H), 7.52(d, J=1.5Hz, 1H), 6.29(s, 1H), 4.00-3.97(d, J=13.1Hz, 2H), 3.68(s, 1H), 3.60-3.52(m, 1H), 3.46(d, J=11.6Hz, 2H), 3.07-3.01(m, 2H), 2.93(d, J=12.1Hz, 2H), 2.82(d, J=3.9Hz , 3H), 2.56-2.54 (m, 1H), 1.95 (d, J=10.5Hz, 2H), 1.72-1.63 (m, 2H), 1.38 (s, 3H), 1.31-1.18 (m, 2H).

[0246] ESI-MS(m / z): 578.2[M+H] + .

Embodiment 3

[0247] Example 3 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-cyclohexyl-1,2,5,6-tetrahydropyridin-3-yl )thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (compound L3)

[0248]

[0249] Using a method similar to Example 1, but in the first step, replace N- 32 mg of the trifluoroacetic acid salt of the title compound were prepared from tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (960 mg, 3.1 mmol).

[0250] 1 H NMR (400MHz, DMSO-d 6 )δ12.89(s, 1H), 12.26(s, 1H), 9.80(s, 1H), 8.85(d, J=2.1Hz, 1H), 8.42(d, J=2.1Hz, 1H), 7.63( s, 1H), 7.42(s, 1H), 6.30(s, 1H), 4.00-3.97(m, 3H), 3.82(d, J=15.4Hz, 1H), 3.62(s, 1H), 3.29-3.24 (m, 1H), 3.07-3.01(t, J=11.9Hz, 2H), 2.93(d, J=12.1Hz, 2H), 2.69-2.53(m, 2H), 2.09-1.93(m, 4H), 1.82 (d, J=10.4Hz, 2H), 1.71-1.59 (m, 3H), 1.48-1.39 (m, 2H), 1.32-1.23 (s, 3H), 1.14-1.05 (m, 2H).

[0251] ESI-MS(m / z): 646.2[M+H] + .

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Abstract

The present invention provides a kind of 2-acylaminothiazole derivatives, or their pharmaceutically acceptable salts, esters, solvates, hydrates, isomers, or any crystal forms or racemates thereof, or their metabolites The drug forms, or their mixtures, are used for therapeutic purposes in the medical field, especially for promoting thrombopoiesis and megakaryocytogenesis, thereby treating or preventing diseases mediated by thrombopoietin.

Description

technical field [0001] The present invention relates to 2-amidothiazole derivatives, more specifically, to 2-amidothiazole derivatives useful as thrombopoietin receptor agonists. The present invention also relates to the preparation method, pharmaceutical composition and application of the 2-amidothiazole derivatives in the treatment of diseases mediated by thrombopoietin. Background technique [0002] Thromboietin (TPO) receptor is a member of the thrombopoietin growth factor receptor family. This family of receptors is characterized by a common extracellular structure, including an N-terminal portion of similar C residues and a characteristic WSXWS structure near the transmembrane region. Expression of TPO receptors is restricted to mouse spleen, bone marrow, fetal liver and human megakaryocytes, platelets, and CD34+ cells. These lines of evidence suggest that TPO receptors play a role in hematopoiesis. [0003] Platelets are very important in physiological hemostasis a...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D417/04A61K31/444A61K31/4439A61P7/04
CPCA61K31/4439A61K31/444A61P7/04C07D417/04C07D417/14
Inventor 蔡家强刘钢郁楠曾宏宋宏梅卿燕宋帅邓汉文唐祖建段小凡黄海涛王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD