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Bruton tyrosine kinase inhibitor

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

Active Publication Date: 2018-01-19
TRANSTHERA SCIENCES (NANJING) INC
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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 doses of cytarabine, but most of them are not sensitive to conventional chemotherapy drugs. Although more drugs have been used for treatment, the overall survival of patients has not been significantly prolonged (Chandran et al., Leuk Lymphoma 2012 53(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 2011 38(18):1067-1069)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0187] The synthetic route of compound I-1

[0188]

[0189] 4-(8-Amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)cyclohex-3-enylcarbamate Benzyl ester 24-1

[0190]

[0191] Intermediate A-1 (30mg, 0.06mmol), 4-(pyridin-2-ylcarbamoyl)phenylboronic acid B-1 (18mg, 0.074mmol), Pd(PPh 3 ) 4 (7mg, 0.006mmol) and Cs 2 CO 3 (25mg, 0.074mmol) in DME: H 2 The mixture in a mixed solvent of O (2.5ml:0.5ml) was heated to 80°C overnight. It was concentrated and purified by column chromatography, eluting with EA-MeOH / DCM (1:40) to give compound 24-1 (25 mg, 75%).

[0192] LC-MS m / z=560.2[M+1] + .

[0193] 4-(8-Amino-3-(4-aminocyclohex-1-enyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide 25-1

[0194]

[0195] To a solution of compound 24-1 (20 mg, 0.036 mmol) in DCM (5 ml) was added HBr (33% in AcOH) solution (2 drops). The suspension was stirred at room temperature for 2 hours. The solvent was evaporated to give the crude product 25-1 hydrob...

Embodiment 2

[0200] 4-(8-Amino-3-(4-but-2-ynamidocyclohex-1-enyl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-fluoro Pyridin-2-yl)benzamide I-2

[0201]

[0202] Synthesis of Compound I-2 Using intermediates A-1 and B-2 as raw materials, it was synthesized using Synthesis Method 2 of I-1. Compound I-2 was obtained after purification. LC-MS m / z=510.2[M+1] + .

Embodiment 3

[0204] 4-(8-amino-3-(4-but-2-yne amidocyclohex-1-enyl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-( Trifluoromethyl)pyridin-2-yl)benzamide I-3

[0205]

[0206] Synthesis of Compound I-3 Using intermediates A-1 and B-3 as raw materials, it was synthesized using Synthesis Method 2 of I-1. Compound 1-3 was obtained after purification. LC-MS m / z=560.2[M+1] + .

[0207] The synthesis of compound I-3 can be synthesized by synthetic method 3

[0208]

[0209] 4-(8-(2,4-dimethoxybenzylamino)-3-(4-(tert-butoxycarbonylamino)cyclohex-1-enyl)imidazo[1,5-a]pyridine Oxin-1-yl) methyl benzoate 5-3

[0210]

[0211] Methyl 4-(8-(2,4-dimethoxybenzylamino)-3-bromoimidazo[1,5-a]pyrazin-1-yl)benzoate M (721 mg, 1.45 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxa)boran-2-yl)cyclohex-3-enylcarbamate L-3 (562mg, 1.74mmol), Pd[PPh 3 ] 4 (168mg, 0.145mmol) and Cs 2 CO 3 (706 mg, 2.17 mmol) was stirred in dioxane (30 mL) at 90°C for 2.5 hours. Concentrated and dissolved in DCM (100 mL)...

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Abstract

The invention relates to a compound with a structure shown in a formula I or a pharmaceutically acceptable salt, a solvate, an active metabolite, a polymorphic substance, an ester, an optical isomer or a prodrug, a pharmaceutical composition comprising the compound with the structure shown in the formula I, and application of the pharmaceutical composition as a bruton tyrosine kinase inhibitor topreparing a medicine for preventing or treating various immune diseases, autoimmune diseases or cancers.

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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61K31/501A61P35/00A61P35/02A61P37/02A61P37/06A61P29/00A61P11/06
Inventor 陈荣耀
Owner TRANSTHERA SCIENCES (NANJING) INC
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