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5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor

A technology of aminoisoxazole and derivatives, applied in the field of 5-aminoisoxazole derivatives and its application in the preparation of multi-kinase inhibitors, which can solve the problems of reduced absorption, unstable action, low water solubility, etc.

Inactive Publication Date: 2021-08-31
ANRUI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, sorafenib suffers from high lipophilicity and low water solubility due to the high hydrophobicity and high lattice properties of the phenylurea skeleton.
Low water solubility is a serious problem, especially in the clinical development of orally administered drugs, as this property can easily lead to problems such as reduced absorption, unstable action due to interpatient pharmacokinetic variation, and tendency to accumulate (PharmaZeutische Indus trie 2002 , 64(9), 985-991)

Method used

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  • 5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor
  • 5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor
  • 5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1: 2-(4-(5-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)-N-(isoxazol-5-yl) ) Synthesis of Acetamide (I-1)

[0106] Using intermediate 8a and N-Boc pyrazole borate derivative (10c) to react to obtain the target product. Product Characterization Results:

[0107] MS: m / z: 385.1 (M+H)+.

Embodiment 2

[0108] Example 2: 2-(4-(5-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)-N-(3-methylisoxazole Synthesis of -5-yl)acetamide (I-2)

[0109] The desired product was obtained using intermediate 8b and the N-Boc pyrazole borate derivative (10c).

[0110] MS: m / z: 399.2 (M+H)+.

Embodiment 3

[0111] Example 3: N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzene Synthesis of [d]imidazol-1-yl)phenyl)acetamide (I-3)

[0112] The desired product was prepared using intermediate 8c and N-methylpyrazoleboronic acid (9b).

[0113] MS:m / z:455.2(M+H) + ; 1 H NMR(DMS:O-d6,400MHz):δ=11.87(s,1H),8.53(s,1H),8.17(s,1H),7.97(s,1H),7.92(s,1H),7.68 -7.65(m,2H),7.59-7.56(m,4H),6.23(s,1H),3.88(s,3H),3.83(s,2H),1.25(s,9H); 13 C NMR (DMS: O, 100MHz): δ=172.9, 167.9, 161.4, 145.0, 144.0, 136.5, 135.2, 134.9, 132.1, 131.3, 128.1, 127.9, 123.8, 122.8, 121.8, 116.3, 111.4, 81.4, 42. 32.4, 29.4.

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Abstract

The invention relates to a 5-aminoisoxazole derivative and an application thereof in preparation of a multi-kinase inhibitor. The invention provides a 5-aminoisoxazole derivative shown in a formula I, and an isotope form, a stereoisomeric form, a tautomeric form, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, a prodrug and a polymorphic form thereof. The invention relates to a preparation method of the compound in the formula I, wherein A, B, R1, R2, W1, W2, W3, W4, W5, W6, W7, W8 and Y are as described in the description. The compound and the pharmaceutical composition thereof are multi-kinase inhibitors and can be used for treating cancer and immune related diseases.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a 5-aminoisoxazole derivative and its application in the preparation of multikinase inhibitors. Background technique [0002] Protein phosphorylation regulates various aspects of cellular function such as cell division, metabolism, motility, survival and apoptosis. Disruption of any phosphorylation alters cellular function and can lead to many diseases, including cancer, inflammatory, cardiovascular, neurodegenerative and metabolic diseases. Phosphorylation is catalyzed by kinases. Protein kinases transfer a γ-phosphate group from ATP to various amino acid residues. Upon activation, kinases phosphorylate tyrosine hydroxyls (tyrosine kinases) or serine or threonine hydroxyls (serine / threonine kinases). Protein kinases play crucial roles in processes such as signal transduction, cell differentiation, cell proliferation, and cell cycle progression. Protein tyrosine kin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D413/12C07D417/14C07D403/14C07D401/14C07D487/04C07D471/04C07D473/00C07D487/10A61K31/422A61K31/4439A61K31/437A61K31/52A61K31/497A61K31/427A61K31/5355A61K31/496A61K31/454A61K31/541A61K31/553A61K31/4184A61P35/00A61P37/00
CPCC07D413/14C07D413/12C07D417/14C07D403/14C07D401/14C07D487/04C07D471/04C07D473/00C07D487/10A61P35/00A61P37/00
Inventor 王景炳谢玲芝乔丹丹D·达斯
Owner ANRUI PHARMA CO LTD