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Selective Kinase Inhibitors

a kinase inhibitor and selective technology, applied in the field of selective kinase inhibitors, can solve the problems of difficult design of compounds with acceptable selectivity, inhibiting other members of the family with detrimental long-term consequences, etc., and achieve the effect of suppressing the immune system of a subj

Inactive Publication Date: 2008-08-28
YM BIOSCI AUSTRALIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0038]In a yet further aspect, the present invention provides for a method of suppressing the immune system of a subject, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.

Problems solved by technology

However, the boundaries of the JAK homology domains are arbitrary, and may or may not define functional domains.
In particular, the high degree of sequence identity held in common by members of the JAK family of kinases raises the possibility that a compound which inhibits Jak3 would also inhibit other members of the family with detrimental long term consequences.
Since the concentration of ATP in a cell is normally very high (millimolar), compounds that are competitive with ATP many lack in vivo activity since it is unlikely that said compounds can reach the concentrations within the cell that are necessary to displace the ATP from its binding site.
The high homology between members of the JAK family of kinases makes the design of compounds with acceptable selectivity highly challenging.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

6-Chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine

[0135]

[0136]A solution of R-α-methylbenzylamine (0.57 g, 4.7 mmol) and 2,6-dichloropyrazine (0.6388 g, 4.29 mmol) in dioxane (2.5 mL) was heated at reflux under N2 for 48 hours. The solvent was removed and the product crystallised from toluene-hexane (0.82 g, 82%).

[0137]1H-n.m.r. (CDCl3) δ 1.58 (d, J=6.6 HZ, 3H, CH3), 4.88 (m, 1H, CH), 5.07 (d, 1H, NH), 7.24-7.36 (m, 5H, Ar-H), 7.61 (s, 1H, pyraz-H), 7.79 (s, 1H, pyraz-H).

example 2

N-(tert-butyl)-6-chloropyrazin-2-amine

[0138]

[0139]A mixture of tert-butylamine (14.9 g, 20 mmol), 2,6-dichloropyrazine (6.0 g, 40 mmol), Hünig's base (10 mL) and ethoxyethanol (6 mL) was heated at 130° C. in a sealed tube for 18 hours. The solvent was removed in vacuo and the residue taken up in CHzCl2 (100 mL) and filtered. The filtrate was washed with H2O (2×20 mL), brine (20 mL) and dried (Na2SO4). Chromatography eluting with CH2Cl2 separated the product as a white solid (5.4 g, 72%).

[0140]1H-n.m.r. (CDCl3) δ 1.44 (s, 9H, CH3), 4.68 (br s, 1H, NH), 7.71 (s, 1H, pyraz-H), 7.72 (s, 1H, pyraz-H).

example 3

6-Chloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]pyrazin-2-amine

[0141]

[0142]In a procedure analogous to Example 1, reaction of R-α-methylbenzylamine (1.0 g, 6.6 mmol) and 2,6-dichloropyrazine (0.440 g, 2.95 mmol) furnished the product (517 mg, 67%).

[0143]1H-n.m.r. (CDCl3) δ 1.59 (d, J=6.9 Hz, 3H, CH3), 3.81 (s, 3H, OCH3), 4.87 (m, 1H, CH), 5.47 (br s, 1H, NH), 6.79-7.30 (m, 4H, Ar-H), 7.66 (s, 1H, pyraz-H), 7.79 (s, 1H, pyraz-H).

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Abstract

A compound of the general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein A represents a variety of six membered nitrogen containing heterocyclic rings, Q is a bond, halogen, C1-4 alkyl, O, S, SO2, CO or CS and X1, X2, X3 and X4 are optionally substituted by 9 specific substituents or one can be nitrogen. Compositions comprising a carrier and at least one compound of formula (I) are also provided. Further provided are methods of treating tyrosine kinase-associated disease states by administering a compound of formula (I) and methods of suppressing the immune system of a subject by administering a compound of formula (I).

Description

FIELD OF THE INVENTION[0001]The present invention relates to the field of inhibitors of protein tyrosine kinases in particular the JAK family of protein tyrosine kinases.BACKGROUND OF THE INVENTION[0002]Protein kinases are a family of enzymes that catalyse the phosphorylation of specific residues in proteins. In general protein kinases fall into several groups; those which preferentially phosphorylate serine and / or threonine residues, those which preferentially phosphorylate tyrosine residues and those which phosphorylate both tyrosine and Ser / Thr residues. Protein kinases are therefore key elements in signal transduction pathways responsible for transducing extracellular signals, including the action of cytokines on their receptors, to the nuclei, triggering various biological events. The many roles of protein kinases in normal cell physiology include cell cycle control and cell growth, differentiation, apoptosis, cell mobility and mitogenesis.[0003]Protein kinases include, for exa...

Claims

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Application Information

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IPC IPC(8): A61K31/5377C07D403/04C07D403/14C07D401/04C07D407/14C07D409/14C07D413/14A61P37/06C07D401/14C07D235/04A61K31/497A61K31/4439A61K31/506A61K31/4184C07D235/30C07D241/20C07D401/12C07D405/12
CPCC07D235/30C07D241/20C07D405/12C07D401/14C07D403/04C07D401/12A61P1/00A61P1/04A61P1/16A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P25/00A61P25/28A61P27/02A61P29/00A61P3/10A61P35/00A61P35/02A61P37/00A61P37/06A61P43/00A61P5/14A61P9/10A61K31/4439A61K31/497A61K31/506C07D401/04C07D403/14C07D407/14C07D409/14C07D413/14C07D405/14
Inventor STYLES, MICHELLE LEANNEZENG, JUNTREUTLEIN, HERBERT RUDOLFWILKS, ANDREW FREDERICKKLING, MARCEL ROBERTBURNS, CHRISTOPHER JOHNBU, XIANYONG
Owner YM BIOSCI AUSTRALIA
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