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Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor

A compound, amino technology, applied in the direction of active ingredients of heterocyclic compounds, anti-inflammatory agents, digestive system, etc.

Active Publication Date: 2014-06-18
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] At present, there is no selective Btk inhibitor on the market. The fastest-developing drug is CC-292 (structure as follows), which entered clinical phase II research at the end of October 2013. It serves as an irreversible selective inhibitor of Btk for the treatment of rheumatoid joints inflammation

Method used

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  • Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
  • Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
  • Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0270] Example 14-(4-(8-(3-acrylamidophenyl)-6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine -2-base Preparation of amino)phenoxy)-N-methylpyridine-2-carboxamide (compound 1)

[0271]

[0272] (1) Preparation of 5-(methylamino)pyrimidine-2,4(1H,3H)-dione

[0273]

[0274] 5-Bromouracil (10g, 52.4mmol) was added to 50mL of 27% methanol solution, and the reaction was refluxed for 16h after addition. The system was cooled and suction filtered to obtain 4.7 g of a light yellow solid with a yield of 63.5%.

[0275] (2) Preparation of 2,4-dichloro-N-methylpyrimidin-5-amine

[0276]

[0277] Add 5-(methylamino)pyrimidine-2,4(1H,3H)-dione (4.7 g, 33.3 mmol) to 50 mL POCl 3 Add 2mL of N,N-dimethylaniline dropwise, and react at 110°C for 24h after the addition. Cooling, concentrating the system under reduced pressure, adding 20mL toluene and spinning the system again, the obtained oil was poured into ice water, and washed with Na 2 CO 3 Neutralized to neutr...

Embodiment 2

[0295] Example 24-(4-(7-(3-acrylamidophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenoxy)-N-methyl Preparation of pyridine-2-carboxamide (compound 2)

[0296]

[0297] (1) Preparation of 2-chloro-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0298]

[0299] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.54 g, 10.0 mmol) and 3-nitrophenylboronic acid (2.51 g, 15.0 mmol) were dissolved in dry dichloromethane (60 mL) . Add anhydrous copper acetate (3.64g, 20.0mmol) and pyridine (1.58g, 20.0mmol) to it, react at room temperature for 24 hours, filter, wash the solid with dichloromethane several times, concentrate the filtrate and perform silica gel column chromatography (Petroleum ether: ethyl acetate = 5:1), 1.42 g of white solid was obtained with a yield of 51.7%.

[0300] (2) Preparation of 3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)aniline

[0301]

[0302] Dissolve 2-chloro-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.42g, 5.17mmol) in a mixed solution of tetr...

Embodiment 3

[0311] Example 3N-(3-(2-(4-(2-methoxyethoxy)anilino)-7-methyl-8-oxo-7H-purin-9(8H)-yl)phenyl ) C Preparation of Enamide (Compound 3)

[0312]

[0313] (1) Preparation of 4-(2-methoxyethoxy)aniline

[0314]

[0315] Add 1-(2-methoxyethoxy)-4-nitrobenzene (1.97g, 10mmol) to 50mL of methanol solution, add 10% Pd / C197mg, add Biton H 2 Reaction at room temperature for 16h. The solid was removed by suction filtration, and the filtrate was concentrated to obtain 1.6 g of a light red oil, with a yield of 95.7%.

[0316] (2) Preparation of tert-butyl 3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylamino)pyrimidin-4-ylamino)phenylcarbamate

[0317]

[0318] Dissolve 4-(2-methoxyethoxy)aniline (668mg, 4.0mmol) in 6mL of ethanol, then add 3-(2-chloro-5-(methylamino)pyrimidin-4-ylamino)benzene tert-butyl carbamate (1.4g, 4.0mmol) was added and microwaved at 100°C for 3h. After cooling, the system was spin-dried, and column chromatography (DCM:MeOH=100:1—4:1) obtained 900 mg of...

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Abstract

The invention belongs to the technical field of medicine, particularly relates to a heterocyclic nitrogen compound which acts as a tyrosine kinase inhibitor and is represented by a general formula (I) as well as a deuterated material, pharmaceutically acceptable salt or stereisomer thereof. In the general formula (I), X, W, R1, R2, R3, L1, L2, a, b, c, d, e, p, q, a ring A and a ring B are defined in specification. The invention further relates to a preparation method of the compounds, a pharmaceutic preparation containing the compounds, and important actions of the compounds in treatment of leukemia (such as B cell chronic lymphocytic carcinoma and non-hodgkin lymphoma) related to B cell, and autoimmune diseases (such as rheumatoid arthritis and systemic lupus erythematosus).

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a nitrogen-containing acyclic compound as a tyrosine kinase inhibitor, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer, and the preparation method of the compound comprises The pharmaceutical preparation of the compound, and the compound is used in the preparation and treatment of blood cancers related to B cells (such as B cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), and autoimmune diseases (such as rheumatoid arthritis, systemic Lupus erythematosus, etc.) plays an important role. 2. Background technology [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, Cell 198 750:823-829). In particular, tyrosine kinases phosphorylate the phenolic moieties of proteins at tyrosine residues. The tyr...

Claims

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Application Information

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IPC IPC(8): C07D473/32C07D487/04C07D473/28C07D473/36A61K31/522A61K31/519A61K31/5377A61K31/52A61P35/02A61P29/00A61P19/02A61P37/02A61P17/06A61P37/08A61P1/00A61P37/06A61P11/06A61P21/00A61P9/10A61P25/16A61P25/28A61P3/10A61P21/04
CPCC07D473/28C07D473/32C07D473/36C07D487/04
Inventor 张倩张艳
Owner KBP BIOSCIENCES CO LTD
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