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Bruton's kinase inhibitor

A C1-C6, selected technology, applied in the field of new derivatives, can solve the problems of easy metabolism and low exposure

Active Publication Date: 2014-12-03
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, we believe that the methyl group on the piperazine ring at the end of the molecule may be easily metabolized, which will lead to a faster clearance of the compound in the body and a low exposure. The reports in the literature have also initially verified our speculation (Xu et al. J .Pharmacol.Exp.Ther.2012341:190)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Embodiment 1: the preparation of compound 1

[0110]

[0111] Preparation of tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazine-1-carboxylate

[0112] Weigh 5-bromo-2-nitropyridine (17.1g, 84.7mmol) and dimethyl sulfoxide (DMSO) (550mL) into a 1L three-necked flask, add N-tert-butoxycarbonylpiperazine (15.8 g, 84.7mmol) and potassium carbonate (K 2 CO 3 ) (35.4g, 254.1mmol), after the addition was completed, the temperature was raised to 65°C to react overnight, cooled to room temperature, and the reaction solution was slowly poured into 2L of ice-water mixture and stirred for 30 minutes. A large amount of solids were precipitated, filtered and dried in vacuo to obtain Yellow product (14g, 53.8%). MS(ESI)m / z:[M+H] + =309.2. 1 H-NMR (CDCl 3 ,400MHz): δ8.18(d,1H),8.13(s,1H),7.16(d,1H),3.64(t,4H),3.45(t,4H),1.49(s,9H)ppm.

[0113] Preparation of tert-butyl 4-(6-amino-3-pyridyl)-1-piperazine-1-carboxylate

[0114]Weigh tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazine-1-c...

Embodiment 2

[0125] Embodiment 2: the preparation of compound 2

[0126]

[0127] Preparation of tert-butyl-6-nitro-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0128] Weigh 5-bromo-2-nitropyridine (250mg, 1.23mmol), N-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (456mg, 1.47mmol), Pd (dppf) 2 Cl 2 ·CH 2 Cl 2 (30mg, 0.37mmol) was placed in a 50mL three-necked flask, replaced with argon three times, added 1,4-dioxane (15mL) and stirred for 5 minutes, then added 2M NaHCO 3 (1.85mL, 3.7mmol) was replaced with argon three times, then heated to 100°C for 2 hours, stopped the reaction and cooled to room temperature, filtered with diatomaceous earth, added water and ethyl acetate (20mL*3) to the filtrate, and then Wash once with saturated NaCl (10mL), and finally wash the ester layer with anhydrous NaCl 2 After drying with SO4, the product was separated by column chromatography (270 mg, 71%), MS (ESI) m / z: [M+H] + =306.2. 1 H-NMR (CDCl 3 , 400MHz):...

Embodiment 3

[0141] Example 3: In vitro biochemical level inhibition of protein kinase (PK) activity experiment

[0142] Materials and methods: BTK kinase, from Invitrogen; HTRF KinEASE; TK kit (Cisbio); 384-well plate (Greiner); ATP (sigma), MgCl 2 (sigma) company; PHERAstar FS multifunctional microplate reader (BMG company); low-speed centrifuge (StaiteXiangyi company); incubator (Binder company). The selected positive drug is RN486, which can be prepared by referring to existing literature reports in this field (WO2010100070), and the structure is as follows:

[0143]

[0144] Compound dissolution and storage: Depending on the solubility, the test compound is prepared into a 0.5-10mmol / L mother solution with DMSO, and stored at -20°C after aliquoting;

[0145] Preparation of compound working solution: Before testing, take out the aliquoted compound from the refrigerator, dilute it to 50× required concentration with pure DMSO; then dilute the compound to 4× required concentration wit...

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Abstract

Provided are a 2-phenyl-isoquinoline-1-ketone derivative having a structure of formula (I), and uses thereof. The compound has good inhibitory effect on Bruton's tyrosine kinase activity, and the median inhibition concentration of the compound is generally below 10-7 mol.L-1. The compound having the structure of formula (I) and prepared in an embodiment of the present invention has clear anti-inflammatory activity on different animal models.

Description

technical field [0001] The present invention relates to novel derivatives useful for inhibiting Bruton's kinase (Btk) and can be used in the treatment of autoimmune and inflammatory diseases resulting from abnormal B cell activation. The novel derivatives 2-phenyl-isoquinolin 1-one derivatives described herein can be used in the treatment of arthritis. Background technique [0002] Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins (T. Hunter, Ce11198750:823-829). In particular, tyrosine kinases phosphorylate the phenolic moieties of proteins at tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration and differentiation. Aberrant kinase activity has been implicated in many human diseases, including cancer, autoimmune and inflammatory diseases. Since protein kinases are among the key regulators of cellular signaling, they pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D407/14A61K31/4725A61K31/497A61P29/00A61P37/06A61P19/02
CPCC07D401/14C07D405/14A61P19/02A61P29/00A61P37/06C07D407/14
Inventor 金秋黄伟王亚洲赵兴俄蔡建锋杨洁唐锋赵勇祝建平
Owner HAINAN SIMCERE PHARMA CO LTD
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