Pyrimidotriazole compounds, preparation method and application thereof

A compound, triazole technology, applied in the field of medicine, can solve problems such as low selectivity and large side effects

Active Publication Date: 2019-03-26
天津药物研究院药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing JAK inhibitors have some problems such as low selectivity and large side effects. It is necessary to study new specific JAK kinase inhibitors to improve the status quo

Method used

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  • Pyrimidotriazole compounds, preparation method and application thereof
  • Pyrimidotriazole compounds, preparation method and application thereof
  • Pyrimidotriazole compounds, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0073]

[0074] Referring to the synthesis method of Reference Example 1, the key intermediate III-2 was synthesized by replacing cyclopentylamine with benzylamine.

[0075] 1 H NMR (400MHz, CDCl 3 )δ: 0.97(t, J=7.6Hz, 3H), 1.64-1.73(m, 2H), 3.01(t, J=7.2Hz, 2H), 3.14-3.19(m, 3H), 4.67(d, J =4.0Hz, 2H), 5.92(s, 1H), 7.27-7.33(m, 5H).

Embodiment 3

[0077]

[0078] Referring to the synthesis method of Reference Example 1, the key intermediate III-3 was synthesized by replacing cyclopentylamine with methylamine hydrochloride.

[0079] 1 H NMR (400MHz, CDCl 3 )δ: 1.02(t, J=7.2Hz, 3H), 1.69-1.79(m, 2H), 3.02-3.08(m, 5H), 3.21(s, 2H), 5.38(s, 1H).

[0080] Reference Example 4:

[0081]

[0082] Add 28.6g of compound III-1 and 200ml of acetonitrile into the reaction flask, add 24.02g of acetic acid at 5-10°C and stir, dropwise add 8.30g of NaNO 2 80ml of the aqueous solution, dropwise, add 20ml of ethyl acetate, continue to stir for 1h, then pour the reaction solution into 300ml of distilled water, extract with ethyl acetate, dry the organic phase with anhydrous magnesium sulfate, concentrate under reduced pressure, and the residue with n-hexane - Refined with ethyl acetate to obtain 26.15 g of brown needle-like solid IV-1. 1 H NMR (400MHz, CDCl 3)δ: 1.08(t, J=7.2Hz, 3H), 1.77-1.86(m, 4H), 2.00-2.09(m, 2H), 2.27-2...

Embodiment 1

[0090] (R)-N-(1-(3-cyclopentyl-5-(propylthio)-3H-[1,2,3]triazol[4,5-d]pyrimidin-7-yl) Preparation of piperidinyl-3-yl)-3-cyanoacetamide (compound Ⅰa-1)

[0091]

[0092] Add 1g (R)-3-tert-butoxycarbonylaminopiperidine, 1.5g compound IV-1, 0.8K 2 CO 3 React with 50ml of DMF at 60°C for 8h, TLC controls the completion of the reaction, pour the reaction solution into 150ml of cold water, extract with ethyl acetate (100ml×3), dry the organic phase with anhydrous magnesium sulfate, filter, evaporate the organic solvent under reduced pressure, Compound V-1 was obtained by column chromatography.

[0093] Add 50mLCH to a reaction flask equipped with a thermometer and stirring device 2 Cl 2 and 20ml of trifluoroacetic acid, stir evenly, add 2.3g of intermediate Ⅴ-1 to the mixture, react at 30°C for 3h, TLC controls the reaction to be complete, concentrate under reduced pressure, add 1.5g of DBU, 1.15g of ethyl cyanoacetate to the residue Ester and 50ml of n-butanol, stirred, re...

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Abstract

The invention belongs to the technical field of medicines and in particular relates to pyrimidotriazole compounds with structures as shown in a formula I or pharmaceutically acceptable salt, a preparation method thereof, a pharmaceutical composition comprising the same and an application thereof in preparing medicines for treating autoimmune diseases, for example, rheumatoid arthritis, psoriasis,organ rejection reaction and the like. The formula I is as shown in the description.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and more specifically, relates to a class of pyrimidotriazole compounds and a preparation method thereof, a pharmaceutical composition containing the compound as an active ingredient and its use in preparing medicines for treating autoimmune diseases . Background technique [0002] Janus kinase is a cytoplasmic non-transmembrane non-receptor tyrosine kinase, which contains 4 subtypes: JAK1, JAK2, JAK3, and TYK2, of which JAK3 is only expressed in bone marrow and lymphoid tissues, and the other three are widely present. in the whole body tissue. The JAK / STAT signal transduction pathway is widely involved in cell proliferation, differentiation, apoptosis and immune regulation, and is closely related to various systemic diseases [Aringer M, et al, (1999), Life Science, 64(24):2173- 2186], such as rheumatoid arthritis, psoriasis, chronic colitis, organ transplant rejection and other immune...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P19/02A61P29/00A61P17/06A61P37/06A61P35/02A61P35/00
CPCC07D487/04
Inventor 刘冰妮刘登科支爽商倩
Owner 天津药物研究院药业有限责任公司
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