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Bruton's tyrosine kinase inhibitor

An amino and solvate technology, applied in the field of medicine, can solve the problems of no significant prolongation of the overall survival of patients, high toxicity, and frequent occurrence of adverse reactions

Inactive Publication Date: 2017-06-13
NANJING GENTAI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The current first-line treatment for CLL is the FCR regimen, which is a combination of fludarabine (F), cyclophosphamide (C) and rituximab (R), which has a certain effect but no disease The progression survival rate is 38%, and grade 3 or 4 adverse reactions occur from time to time (Xia Yi et al., Chinese Journal of Blood 2013 34(2):182-183)
MCL often chooses anthracyclines or drugs containing high-dose cytarabine, but most of them are not sensitive to conventional chemotherapy drugs. Although many drugs have been used for treatment, the overall survival of patients has not been significantly prolonged (Chandran et al., Leuk Lymphoma 201253(8):1488-1493); although drugs and monoclonal antibodies combined with chemotherapy are also used to treat MCL, the toxicity is relatively high, the incidence of infection is about 14%, and the incidence of grade 3-4 adverse reactions is as high as 87% (Zhu Jun et al., Chinese Journal of Clinical Oncology 201138(18):1067-1069)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0166] Synthetic route of compound 16-1

[0167]

[0168] N-((3-chloropyrazin-2-yl)methyl)-(7-benzyloxycarbonyl-7-aza-bicyclo[2.2.1]heptane-1)-carboxamide 10

[0169]

[0170] To a solution of compound 9 (3g, 10.9mmol) and (3-chloropyrazin-2-yl)methanamine hydrochloride (1.96g, 10.9mmol) in dichloromethane (50ml) was added DIEA (5.62g, 43.6mmol) ). It was stirred at this temperature for 15 minutes, HATU (4.35 g, 11.44 mmol) was added and stirred at 0 °C for a further 1 hour. It was then stirred overnight at room temperature. Pour into water (100ml) and separate the organic phase. The aqueous phase was extracted with dichloromethane (2 x 30ml). The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate / petroleum ether=1:5 to obtain 3.12 g of compound 10, yield: 71%.

[0171] 1H NMR (400MHz, CDCl3): δ1.50-1.60(m,2H); 1.85-2.10(m,4H); 2.15-2.25(m,2H); 2.40-2.60(m,...

Embodiment 2

[0197] 4-(8-Amino-3-(7-but-2-ynoyl-7-aza-bicyclo[2.2.1]heptane-1-yl)imidazo[1,5-a]pyrazine-1 -yl)-N-(4-fluoropyridin-2-yl)benzamide 16-2

[0198]

[0199] Synthesis of Compound 16-2 Using intermediate 13 and B-2 as raw materials, it was synthesized using Synthesis Method 1 of 16-1. After purification, 7 mg of compound 16-2 was obtained. LC-MS m / z=510.2[M+1] + .

Embodiment 3

[0201] 4-(8-Amino-3-(7-but-2-ynoyl-7-aza-bicyclo[2.2.1]heptane-1-yl)imidazo[1,5-a]pyrazine-1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide 16-3

[0202]

[0203]Synthesis of Compound 16-3 Using intermediate 13 and B-3 as raw materials, it was synthesized using Synthesis Method 1 of 16-1. After purification, 11 mg of compound 16-3 was obtained. LC-MS m / z=560.2[M+1] + .

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Abstract

The invention relates to a compound with a formula I and a pharmaceutically acceptable salt, a solvent compound, an active metabolite, a polycrystalline compound, an ester, an isomer or a prodrug thereof, a pharmaceutical composition containing the compound in the formula I, and application using the same as a selective Bruton's tyrosine kinase inhibitor to prepare a medicine for preventing or treating heterologous immunity diseases and self immunity diseases or cancers. The formula is shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a Bruton's tyrosine kinase inhibitor, its pharmaceutical composition, its preparation method and its application in the preparation of medicines. Background technique [0002] B cell receptor (B-cell receptor, BCR) signaling pathway plays a key role in the maturation, differentiation and development of B cells. Aberrant BCR-mediated signal transduction can lead to misregulated (deregulated) B cell activation and / or formation of pathogenic autoantibodies, leading to a variety of human diseases, including cancer, autoimmune disease and heteroimmune disease, autoimmune Diseases include lupus erythematosus, chronic lymphocytic lymphoma, diffuse large cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia, and heteroimmune diseases include inflammatory diseases, asthma, etc. [0003] Bruton tyrosine kinase (BTK) is a member of the TEC family of non-receptor tyrosine ki...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61K31/501A61K31/506A61P35/00A61P29/00A61P11/06A61P19/04
CPCC07D487/04
Inventor 陈荣耀
Owner NANJING GENTAI PHARMA TECH CO LTD
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