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Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia

A technology of tyrosine kinase and chronic granulocytes, applied in the field of Bcr/Abl tyrosine kinase inhibitors, can solve problems such as ineffectiveness, and achieve good inhibitory effect, drug safety, and convenient clinical drug use

Inactive Publication Date: 2013-05-22
WUXI ALLNATURE BIOLOGICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In response to these mutations, people are constantly designing new drug molecules to inhibit the Bcr / Abl tyrosine kinase after these mutations, so as to achieve the treatment of chronic myeloid leukemia, but these inhibitors have no effect on the mutation T315I

Method used

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  • Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia
  • Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia
  • Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 (E)-N2-(cyclopropylmethyl)-N4-((1-methyl-tetrahydropyrrolyl)-3-methyl)-N6-(4-(2-(2-naphthaleneethylene base)-2-pyrimidinyl-2,4,6-triaminopyrimidine (VIax1)

[0040]1. Add 2,4-dichloropyrimidine (14.5g, 97.5mmol), dichlorobis(triphenylphosphine) palladium (II) complex (1.3g, 2.6mmol) into a 500ml round bottom flask, iodide Cuprous (25mg, 0.13mmol), tetrahydrofuran (250ml), triethylamine (34ml, 263mmol). After the mixture was heated to 50°C, a solution of naphthaleneacetylene (97.5 mmol) in tetrahydrofuran (100 ml) was added. After 5 hours, the reaction solution was cooled and diluted with dichloromethane. The organic phase was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The concentrated crude product was purified by column chromatography to obtain 18.5 g of product intermediate IIa (R1=2-naphthyl).

[0041] 2. Add IIa (16.0g) and saturated ammonia ethanol solution (200ml) into a tube. The system was heated w...

Embodiment 2

[0048] Example 2 (E)-N2-(cyclopropylmethyl)-N4-((1-phenyl-tetrahydropyrrolyl)-3-methyl)-N6-(4-(2-(2-naphthaleneethylene base)-2-pyrimidinyl-2,4,6-triaminopyrimidine (VIax2)

[0049] In a 10ml round bottom flask, add the intermediate Vax (100mg), solvent (3ml) and (1-phenyl-tetrahydropyrrolyl)methylamine (3 equivalents) prepared by the method in Example 1, and the reaction mixture is heated and stirred for 18 Hours, after cooling, add water to dilute and precipitate out. After filtration and purification, 59.85 mg of the final product compound VIax2 (R1=2-naphthyl, R3=cyclopropylmethyl, R2=phenyl, n=1) was obtained. Its structural formula is as follows.

[0050]

[0051] The obtained compound spectral data is:

[0052] LCMS m / z=569 (M+H); 1H-NMR (DMSO-d6, 400MHz): δ8.30 (d, 1H), 7.30-8.15 (m, 7H), 6.80-7.30 (d, 7H).

Embodiment 3

[0053] Example 3 (E)-N2-(cyclopropylmethyl)-N4-tetrahydropyrrolyl-3-methyl)-N6-(4-(2-(2-naphthylvinyl)-2-pyrimidinyl- Preparation of 2,4,6-triaminopyrimidine (VIax3)

[0054] In a 10ml round bottom flask, add the intermediate Vax (100mg) prepared by the method in Example 1, solvent (3ml), (1-Boc-tetrahydropyrrolyl)methylamine (3 equivalents), and the reaction mixture was heated and stirred for 18 hours After cooling, add water to dilute and precipitate out. After filtration and drying, the product was dissolved in 25% TFA in dichloromethane solution, concentrated after 4 hours of reaction, and the crude product was purified to obtain the final product compound VIax3 (R1=2-naphthyl, R3=cyclopropylmethyl, R2=H, n=1) 32.55 mg. Its structural formula is as follows

[0055] .

[0056] The obtained compound spectral data is:

[0057] LCMS m / z=493(M+H); 1H-NMR(DMSO-d6,400MHz):δ8.30(d,1H),7.30-8.05(m,7H),7.10(d,1H),7.01( d,1H),6.85(d,1H).

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Abstract

The invention discloses a Bcr / Abl tyrosine kinase inhibitor capable of treating chronic granulocytic leukemia and a preparation method thereof. The Bcr / Abl tyrosine kinase inhibitor capable of treating chronic granulocytic leukemia obtained by a large number of experimental screenings not only can effectively inhibit Bcr / Abl tyrosine kinase, and still has a good inhibitory effect to mutated Bcr / Abl tyrosine kinase, so that the Bcr / Abl tyrosine kinase inhibitor is a novel Bcr / Abl tyrosine kinase inhibitor for effectively treating chronic granulocytic leukemia.

Description

technical field [0001] The invention relates to the field of biomedical research, in particular to a Bcr / Abl tyrosine kinase inhibitor capable of treating chronic myeloid leukemia, as well as its preparation method and application. Background technique [0002] Chronic myelogenous leukemia (CML) is a common type of blood cancer, characterized by abnormal proliferation of white blood cells in the blood causing cancer. Chronic myeloid leukemia (CML for short) is mainly produced by chromosomal mutations. The proportion of patients in the world is one to two out of 100,000 people, and the number of CML patients in China is about 20,000. [0003] Imatinib, a drug for the treatment of chronic myeloid leukemia, is developed and marketed by Novartis. It acts on the target Bcr-Abl kinase to cause apoptosis of cancer cells to achieve the purpose of controlling or treating chronic myeloid leukemia (Quitas-Cardama , A.; Cortes, J. Blood 2009, 113, 1619-1630; Druker, B.J., et al Nature...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D401/14A61K31/506A61P35/02
Inventor 吴俊军
Owner WUXI ALLNATURE BIOLOGICAL SCI & TECH CO LTD
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