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Macrocyclic derivative serving as protein kinase inhibitor and preparation method and usage of macrocyclic derivative

A technology of drugs and compounds, applied in the field of biomedicine, can solve the problems of high incidence of adverse reactions, low bioavailability, and large dosage, and achieve broad anti-cancer and malignant tumor, broad application prospects, good clinical application and Effects of medicinal use

Active Publication Date: 2019-10-22
WUHAN YUXIANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to overcome the deficiencies of existing drugs and prior art, thereby providing a macrocyclic derivative as a protein kinase inhibitor. As an ALK inhibitor, this compound can effectively solve the problem of prior art Problems of large dosage, low bioavailability, and high incidence of adverse reactions

Method used

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  • Macrocyclic derivative serving as protein kinase inhibitor and preparation method and usage of macrocyclic derivative
  • Macrocyclic derivative serving as protein kinase inhibitor and preparation method and usage of macrocyclic derivative
  • Macrocyclic derivative serving as protein kinase inhibitor and preparation method and usage of macrocyclic derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: compound shown in synthetic formula I-1

[0058] synthetic route:

[0059]

[0060] Preparation:

[0061] Step 1: Synthesis of Compound 1B

[0062] In the first reaction vessel, to a solution of cooled (0 °C) water (3.5 mL) was added SOC1 2 (0.642 mL, 1.64 g / mL, 8.84 mmol) and allowed to warm to room temperature and stir for 1 hour. Then cuprous chloride (19mg, 0.20mmol) was added, and the solution was cooled to -5°C to obtain the first mixed solution. In a second reaction vessel, dissolve in HCl (1.97 mL, 37% in H 2 O, 1.18g / mL, 23.6mmol) solution was added compound 1A (500mg, 2.5mmol) (synthetic reference patent WO2015050989A1), and cooled to -5 ° C, then sodium nitrite (149mg, 2.16mmol) in water ( 1 mL) solution was added thereto to obtain a second mixed solution. Then the second mixed solution was added dropwise to the first mixed solution, and kept at -5°C by cooling. After the dropwise addition was completed, the third mixed solution was ob...

Embodiment 2

[0083] Embodiment 2: compound shown in synthetic formula I-2

[0084]

[0085] The compound of Example 2 was synthesized with reference to the operation steps of Example 1, but methylamine hydrochloride was replaced with ethylamine hydrochloride in the second step.

[0086] MS m / z(ESI):471[M+1]

[0087] 1 H NMR (400MHz, CDCl 3 )δ7.84(d, 1H, J=2.0Hz), 7.32(dd, 1H, J=9.6, 2.4Hz), 7.23(dd, 1H, J=8.0, 5.2Hz), 7.01(dt, 1H, J =8.4,2.4Hz),6.86(d,1H,J=1.6Hz),5.71-5.75(m,1H),4.85(s,2H),4.08(s,3H),3.24(m,2H),1.78 (d, 3H, J=6.4Hz), 1.19 (t, 3H, J=6.90Hz).

Embodiment 3

[0088] Embodiment 3: compound shown in synthetic formula I-3

[0089]

[0090] The compound of Example 3 was synthesized with reference to the operation steps of Example 1, but in the first step, it was replaced with 3-amino-4-bromo-1-ethyl-1H-pyrazole-5-carbonitrile (synthetic reference patent WO2015050989A1) 3-Amino-4-bromo-1-methyl-1H-pyrazole-5-carbonitrile was dropped.

[0091] MS m / z(ESI):471[M+1]

[0092] 1 H NMR (400MHz, CDCl 3 )δ7.85 (d, 1H, J = 2.0Hz), 7.31 (dd, 1H, J = 9.6, 2.4Hz), 7.22 (dd, 1H, J = 8.4, 5.6Hz), 6.98 (dt, 1H, J =8.0,2.8Hz),6.87(d,1H,J=1.2Hz),5.71-5.75(m,1H),4.85(s,2H),4.12(q,2H,J=7.2Hz),3.24(s , 3H), 1.78 (d, 3H, J=6.0Hz), 1.28 (t, 3H, J=7.1Hz).

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PUM

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Abstract

The invention discloses a macrocyclic derivative serving as a protein kinase inhibitor and a preparation method and usage of the macrocyclic derivative. A compound shown as a formula I, or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof is provided, wherein R1-R4 is defined by the specification. The compound shown in the formula I can be used for preparing a drug for adjusting activity of protein kinase and for preventing and / or treating diseases related to the protein kinase.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to a macrocyclic derivative as a protein kinase inhibitor, a preparation method and application thereof. Specifically, the present invention relates to macrocyclic derivatives as protein kinase inhibitors, their preparation methods, and their use in the preparation of drugs for the prevention and / or treatment of ALK-related diseases. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. It is characterized by abnormal proliferation of cells or mutant cells. The proliferation, apoptosis, and metastasis of tumor cells are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside the cells. In these signaling pathways, an important class of molecules is protein kinases. The abnormality of protein kinases is closely related to the occurrence, developme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D515/18A61K31/439A61P35/00
CPCA61P35/00C07B2200/07C07D515/18
Inventor 方华祥余斌李芳芳张晓林车鹏许勇
Owner WUHAN YUXIANG PHARM TECH CO LTD