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4-Aminopyrimidine compound, and preparation method and medicinal use thereof

A technology of aminopyrimidines and compounds, which can be used in pharmaceutical formulations, antipyretics, drug combinations, etc., and can solve the problem of few types of BTK inhibitors

Active Publication Date: 2017-08-15
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still few types of BTK inhibitors with good druggability, and Ibrutinib has been resistant to clinical applications, so it is of great significance to develop new BTK inhibitors

Method used

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  • 4-Aminopyrimidine compound, and preparation method and medicinal use thereof
  • 4-Aminopyrimidine compound, and preparation method and medicinal use thereof
  • 4-Aminopyrimidine compound, and preparation method and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Preparation of 4,6-dichloro-5-pyrimidinecarbaldehyde (1)

[0087] DMF (5.50mL, 71.34mmol) was slowly dropped into POCl under ice bath 3 (17.00mL, 185.71mmol), stirred for 1h, removed the ice bath, added 4,6-dihydroxypyrimidine (4.00g, 35.68mmol), heated and refluxed for 3h, cooled to room temperature, poured into ice water, extracted with dichloromethane, Concentrate under reduced pressure, and recrystallize from petroleum ether-ethyl acetate (P:E=4:1(V:V)) to obtain 4.74 g of yellow solid, yield 75.4%, mp 68-70°C. ESI-MS:177[M+H] + ; 1 H NMR (300MHz, CDCl 3 ): δ (ppm): 8.89 (s, 1H), 10.43 (s, 1H).

[0088] Preparation of 4,6-dichloro-5-pyrimidinecarboxylic acid (2)

[0089] 1 (4.00g, 22.72mmol) and NaH 2 PO 4 (9.55g, 79.58mmol) was dissolved in a mixed solvent of 60mL tert-butanol and 10mL water, and NaClO was added under ice-cooling 2 (7.66g, 84.69mmol), reacted for 1h, distilled off tert-butanol under reduced pressure, poured into water, adjusted pH to 5 with...

Embodiment 2

[0100] Preparation of (R)-3-[[6-amino-5-(4-phenoxybenzoyl)pyrimidin-4-yl]aminomethyl]piperidine-1-carboxylic acid tert-butyl ester (5b)

[0101] Referring to the preparation method of 5a, a pale yellow solid was obtained from the reaction of 4 and (R)-1-Boc-3-aminomethylpiperidine with a yield of 56.2%. ESI-MS:504[M+H] + .

[0102] (R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propene-1 - Preparation of ketone (A-2)

[0103]

[0104] Referring to the preparation method of A-1, a yellow solid was obtained by reacting 5b with acryloyl chloride after removing the Boc protecting group, with a yield of 17.2%. ESI-MS:458[M+H] + ; 1 H NMR (300MHz, DMSO-d 6 ):δ(ppm):7.97(s,1H),7.65(d,J=8.2Hz,2H),7.39(d,J=8.7Hz,2H),7.19(s,1H),7.09-6.94(m ,4H),6.64(s,3H),5.99(d,J=16.7Hz,1H),5.57(s,1H),4.20-3.62(m,3H),3.18(s,2H),2.98(s, 1H), 2.74(s, 1H), 1.57(s, 3H), 1.16(d, J=24.2Hz, 2H).

Embodiment 3

[0106] Preparation of [4-amino-6-[(piperidine-2-methyl)amino]pyrimidin-5-yl](4-phenoxyphenyl)methanone (5c)

[0107] Referring to the preparation method of 5a, a pale yellow solid was obtained from the reaction of 4 and 2-aminomethylpiperidine with a yield of 45.8%. ESI-MS:404[M+H] + .

[0108] 1-[2-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]aminomethyl]piperidin-1-yl]-2-propen-1-one (A -3) Preparation

[0109]

[0110] 5c (0.23g, 0.57mmol) was dissolved in 18mL tetrahydrofuran-water (THF:H 2 O=5:1(V:V)) mixed system, add NaHCO 3 (0.14g, 1.71mmol), acryloyl chloride (0.06mL, 0.68mmol) was added dropwise under ice bath conditions, reacted at room temperature overnight, THF was distilled off under reduced pressure, an appropriate amount of water was added to the remaining reaction solution, CH 2 Cl 2 Extracted, dried over anhydrous magnesium sulfate, and purified by column chromatography [ethyl acetate (EA)] to obtain 0.04 g of a yellow solid with a yield of 16.0%. E...

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Abstract

The invention belongs to the field of medicines, and concretely relates to a 4-aminopyrimidine compound having a structural represented by formula (I), or pharmaceutically acceptable salts thereof, a preparation method of the compound, and a use of the compound and the salts as a Bruton tyrosine kinase (BTK) inhibitor. A result of experiments shows that the compound has a significant inhibition effect on the BTK, and can be used for treating thromboembolism, inflammatory disorders, autoimmune diseases, Waldenstrom macroglobulinemia, B cell lymphomas and other diseases.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and their use as Bruton's tyrosine kinase inhibitors. [0002] technical background [0003] Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine protein kinases. It consists of 659 amino acids and contains multiple domains, such as Pleckstrin homology (PH) domain, Tec homology (TH ) domain, Src homology 3 (SH3) domain, SH2 and SH1 domains (Future Med Chem, 2014, 6(6):675-695). Studies have shown that BTK, as an important part of the B cell receptor (BCR) signal transduction pathway, plays an extremely important role in many physiological processes such as the development, maturation, differentiation and proliferation of B cells (Nature, 1993, 361 (6409 ):226-233). [0004] Precise regulation of BTK is crucial to maintain the normal physi...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D403/12A61K31/506A61P7/02A61P9/10A61P29/00A61P37/00A61P37/02A61P11/06A61P19/02A61P7/00A61P17/06A61P35/00A61P35/02
CPCC07D401/12C07D403/12Y02P20/55
Inventor 赖宜生章颖溢肖建虎金双龙李月珍张奕华
Owner CHINA PHARM UNIV
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