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Adenine derivatives as protein kinase inhibitors

A technology for kinase inhibitors, compounds, used in medicinal chemistry and pharmaceuticals to address the problems of decline in compliance, limited efficacy, emergence of tolerance, etc.

Active Publication Date: 2019-02-05
BCI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] There is a need for protein kinase inhibitors that can overcome the shortcomings of current protein kinase therapies, such as side effects, limited efficacy, development of tolerance, and decline in compliance

Method used

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  • Adenine derivatives as protein kinase inhibitors
  • Adenine derivatives as protein kinase inhibitors
  • Adenine derivatives as protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0288] Example 1: General method for the synthesis of carbamate acyclic purine nucleoside analogs

[0289] The following procedures illustrate the preparation of several carbamate acyclic purine nucleoside analogs, and the synthetic routes are outlined below. The synthesis begins with an appropriate haloalkyl acetate at the N of the adenine ring in step (1). 9 Alkylation of the purine is performed in position and the carboethoxy group is removed in step (2). In step (3) (the final step), the carbamate acyclic nucleoside (3) is prepared by activation of the corresponding alcohol with carbonyldiimidazole (CDI), followed by reaction with an appropriate amine. The synthesis of various amine intermediates, such as that used in step (3), is shown in Example 6 below. Examples of final compound structures can be found in Table 1 below.

[0290]

[0291] Step (1): To a stirred mixture of the appropriate purine (1 eq) and cesium carbonate (1.2 eq) in anhydrous DMF (1.5 mL / mmol) wa...

Embodiment 2A

[0309] Example 2A: General method for the preparation of 2-substituted alkyl or aryl purine acyclic nucleoside analogs

[0310]

[0311] To a stirred solution of 4-(6-amino-2-chloro-purin-9-yl)butyl-carbamate derivative (0.2 mmol, 1 equiv) in dioxane (2 mL) was added (hetero ) aryl or alkyl boronic acid (R-B(OH) 2 ) or pinacol ester (R-Bpin) (0.3mmol, 1.5eq) and aqueous cesium carbonate (1M, 0.6mmol, 3eq). The reaction mixture was purged three times with nitrogen, then Pd(PPh 3 ) 4 (23mg, 0.02mmol, 0.1 equiv). The reaction mixture was warmed to 100°C overnight. The solvent was evaporated under reduced pressure and the crude mixture was purified by flash column chromatography (0-10% MeOH in DCM) to give the expected compound.

[0312] The following compounds are exemplified to illustrate the method:

[0313] Prepared from 4-(6-amino-2-chloro-purin-9-yl)butyl N-(1,3-benzobisoxazol-5-ylmethyl)carbamate 4-[6-Amino-2-(3-furyl)purin-9-yl]butyl N-(1,3-benzobisoxazol-5-ylmeth...

Embodiment 2B

[0319] Example 2B: General method for the preparation of 2-alcoholate purine acyclic nucleoside analogs

[0320]

[0321] Step 1: Add the appropriate alcohol (30 eq) and sodium tert-butoxide (3 eq) to 4-(6-amino-2-chloro-purin-9-yl)butan prepared in step 2 of Example 1 -1-ol (1 equivalent). NOTE: In the case of methoxy, sodium methoxide (7.5 eq.) was used. The reaction mixture was heated in microwave to 100-150°C until completion (10-90 min). The solvent was then evaporated under reduced pressure and the residue was purified by flash column chromatography (0-10% MeOH in DCM) to give the expected compound.

[0322] The following compounds are exemplified to illustrate step 1:

[0323] Prepared from 4-(6-amino-2-chloro-purin-9-yl)butan-1-ol (241 mg, 1.0 mmol) after microwave irradiation at 100 °C for 10 min 4-(6-Amino-2-methoxy-purin-9-yl)butan-1-ol . Yield: 172 mg (73%) of the title compound as a white powder. ESI-MS: 238.3 (M+H) + .

[0324] Prepared from 4-(6-amin...

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Abstract

The present invention relates to a compound suitable for use as a kinase inhibitor according to general formula (I) [compound (C), herein after], or the N- oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, formula (I) wherein A, R1, R2, R3, R3', R4, R4', X, Y, Z, T are as defined in the claims. The invention further relates to an in vitro methodof inhibiting protein kinase activity which comprises contacting a protein kinase with a compound of formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof. The invention further relates to the compounds of formula (I) per se, as well as to their use as a medicament, and for use or in a method of treatment of a disease mediatedby a protein kinase selected from cancer, inflammatory disorders, cardiovascular diseases, viral induced diseases, circulatory diseases, fibro-proliferative diseases and pain sensitization disorders.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacy. Background technique [0002] Cells process environmental signals through signaling and transcriptional networks (also known as signal transduction pathways), resulting in the appropriate regulation of output genes. [0003] Protein kinases play key roles in almost all signal transduction pathways. The pivotal role of kinases is highlighted by the fact that the human genome encodes 518 protein kinases, representing one of the largest protein families. A kinase is an enzyme that transfers a phosphate group from a high-energy donor molecule, such as adenosine triphosphate (ATP), to a specific substrate, a process called phosphorylation. The phosphorylation state of a substrate (whether protein, fat or carbohydrate) can affect its activity, reactivity and ability to bind other molecules. Thus, kinases are critical in metabolism, cell signaling, protein regulation, cellular traffick...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34A61K31/52A61P35/00
CPCC07D473/34A61P29/00A61P31/12A61P35/00A61P43/00A61P9/00A61K31/52
Inventor 多米尼克·苏拉劳克斯克莱尔·阿米娅布尔瑞米·圭尔龙
Owner BCI PHARMA
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