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Inhibitors of protein kinases

A compound, alkyl technology, applied in the field of treating diseases characterized by unwanted thrombosis, preparing the compounds described in this article, can solve the problems of Src kinase inactivity and the like

Inactive Publication Date: 2011-05-18
PORTOLA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interestingly, this ATP-competitive inhibitor of Syk is also active against Flt3, cKit and JAK kinases, but not against Src kinase (Braselmann, Taylor et al., 2006)

Method used

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  • Inhibitors of protein kinases
  • Inhibitors of protein kinases
  • Inhibitors of protein kinases

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0335] a. Compound

[0336]In one group of embodiments, the present invention provides a compound having formula (I), a tautomer or a pharmaceutically acceptable salt thereof:

[0337]

[0338] in:

[0339] Y 1a selected from N, CH and C;

[0340] Z 1a selected from the bond, -N(C 1-4 Alkyl)-, -SO 2 -, -CO-, -NR 4d SO 2 -, heterocyclyl, heterocyclic carbonyl and heterocyclic sulfonyl;

[0341] R 1a selected from:

[0342] (a) hydrogen;

[0343] (b)C 1-8 Alkyl, optionally 1-3 selected from amino, hydroxyl, C 1-8 Alkoxy, heterocyclyl, aminocarbonyl, amino C 1-8 Substitution of alkoxy, aryl and heteroaryl groups;

[0344] (c)C 3-8 Cycloalkyl, optionally substituted by 1-3 amino substituents;

[0345] (d) aryl, optionally selected from 1-3 C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylcarbonylamino, aminocarbonyl C 1-8 Alkoxy, aminosulfonyl, aminocarbonyl, amino C 1-8 Alkylenecarbonyl C 1-8 Alkoxy and halogen substituent substitution;

[0346] ...

Embodiment 1

[0802] N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0803]

[0804] To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 10.6 mmol) in DCM (32 mL) was added NIS (2.4 g, 10.6 mmol) at room temperature . After stirring for 1 hour, the obtained precipitate was collected by filtration to obtain 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.8 g).

[0805] To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.80 g, 5.73 mmol) in DCM (20 mL) was added TsCl (1.09 g, 5.73 mmol) and TEA (1.60 mL, 11.46 mmol), followed by DMAP (70 mg, 0.573 mmol). After stirring at room temperature for 1 h, the solution was concentrated and the residue was dissolved in EtOAc and H 2 Partition between O, separate the organic phase with 1N HCl, 5% NaHCO 3 Washing, drying and concentration gave 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g).

[0806]To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,...

Embodiment 2

[0811] 1-(4-(4-(4-(methylamino)-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) phenyl)piperazin-1-yl)ethanone

[0812]

[0813] To 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.044g, 0.11mmol) To a mixture of nBuOH (0.6 mL) was added 1-(4-4-aminophenyl)piperazin-1-yl)ethanone (0.047 g, 0.22 mmol) and TMSCl (0.043 mL, 0.33 mmol). After heating at 115 °C for 48 h, the mixture was purified by preparative HPLC to obtain 1-(4-(4-(4-(methylamino-5-(pyridin-4-yl)-7H-pyrrolo[2,3- d] pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (0.015 g), MS (MH 443.3), λ = 259.4, 302.1.

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Abstract

The present invention is directed to compounds of formula (I)-(II) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and / or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and / or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and / or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Application No. 61 / 047077, filed April 22, 2008, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to pyrimidines, pyrrolopyrimidines and purines useful as spleen tyrosine kinase (syk) and / or JAK kinase inhibitors. The invention also relates to pharmaceutical compositions containing pyrimidine compounds, and methods of using the compounds or compositions to treat disorders characterized by undesired thrombosis. The present invention also relates to methods of preparing the compounds described herein. Background technique [0004] Protein kinases constitute a large family of structurally related enzymes that are responsible for the regulation of a variety of signal transduction processes in cells (see for example Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, S...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D401/04C07D401/14C07D403/04C07D471/04C07D473/16A61K31/506A61K31/52A61P9/00A61P29/00A61P35/00
CPCC07D401/14C07D473/16C07D403/04C07D239/48C07D471/04C07D401/04C07D403/14A61P1/04A61P11/06A61P13/12A61P17/02A61P17/06A61P19/02A61P25/00A61P29/00A61P35/00A61P35/02A61P3/06A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/02A61P7/04A61P7/06A61P9/00A61P9/04A61P9/10A61P9/14
Inventor 宋永红徐亲S·M·鲍尔Z·J·贾M·梅赫罗特拉A·潘迪
Owner PORTOLA PHARMA INC
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