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Inhibitor of casein kinase 1[delta] and casein kinase 1[epsilon]

A technology of oxazolone and its derivatives, which can be applied in the direction of medical preparations containing active ingredients, drug combinations, cardiovascular system diseases, etc., can solve the problem that the drug treatment of pancreatic cancer has not been completed, and achieve high safety and high selectivity. Effect

Active Publication Date: 2013-05-08
NB HEALTH LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Drugs that are anticancer agents based on the inhibition of casein kinase 1ε or casein kinase 1δ have not been known in the prior art. In addition, especially in the prior art, for refractory pancreatic cancer based on this mechanism Cancer drug treatment is also not complete

Method used

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  • Inhibitor of casein kinase 1[delta] and casein kinase 1[epsilon]
  • Inhibitor of casein kinase 1[delta] and casein kinase 1[epsilon]
  • Inhibitor of casein kinase 1[delta] and casein kinase 1[epsilon]

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] [Example 1] 4-((6-methoxy-3-pyridyl)methylene)-2-(5-fluoro-2-thienyl)-5(4H)- Zazolone

[0095]

[0096] In general, it is very difficult to introduce a fluorine group into a thiophene ring, so the formula ( 2) As a result of the synthesis of the compounds shown, they were successfully prepared. It should be noted that the synthesis method of the compound represented by the formula (2) is not limited to the steps shown in Scheme 1.

[0097] plan 1

[0098]

[0099] Add 3.0g of 5-nitro-2-thiophenecarbonitrile (compound 3, 19.5mmol), 5.66g of potassium fluoride (9.75mmol), tetraphenyl bromide 0.82g (1.95mmol), sulfolane 70ml, phthaloyl chloride 2.81ml (19.5mmol), heated and stirred at an internal temperature of 180°C for 2 hours. Cool to room temperature after the reaction, add 300ml of water, and extract 3 times with 200ml of diethyl ether. Collect the organic layer, wash twice with 200ml of 1N sodium hydroxide, wash with 200ml of water and 100ml of saturated ...

Embodiment 2

[0117] [Example 2] 4-((6-methoxy-3-pyridyl)methylene)-2-(5-chloro-2-thienyl)-5(4H)- Zazolone

[0118]

[0119] Along with the fluorine group-introduced compound represented by formula (2), a chlorine group-introduced compound represented by formula (11) was also produced. It should be noted that the synthesis method of the chlorine group-introduced compound represented by the formula (11) is not limited to the steps shown in Scheme 3.

[0120] Option 3

[0121]

[0122] 1.00 g (6.15 mmol) of 5-chlorothiophenecarboxylic acid, 1 ml (13.8 mmol) of thionyl chloride, and 10 ml of benzene were added to a three-necked flask, and heated and stirred at a bath temperature of 105° C. for 2 hours. After cooling to room temperature, thionyl chloride was distilled off, and then azeotroped with benzene and carbon tetrachloride to obtain a brown oil.

[0123] 323.2 mg (4.31 mmol) of glycine and 15 ml of 0.5N sodium hydroxide were added to a separately prepared three-necked flask, a...

Embodiment 3

[0128] [Example 3] 4-((6-methoxy-3-pyridyl)methylene)-2-(5-bromo-2-thienyl)-5(4H)- Zazolone

[0129]

[0130] Along with the fluorine group-introduced compound represented by formula (2), a bromo group-introduced compound represented by formula (14) was also produced. It should be noted that the synthesis method of the bromo group-introduced compound represented by the formula (14) is not limited to the steps shown in Scheme 4.

[0131] Option 4

[0132]

[0133] 1.00 g (4.83 mmol) of 5-bromothiophene carboxylic acid, 5 ml (68.9 mmol) of thionyl chloride, and 4 ml of benzene were added to a three-necked flask, and heated and stirred at a bath temperature of 105° C. for 2 hours. After cooling to room temperature, thionyl chloride was distilled off, and then azeotroped with benzene and carbon tetrachloride to obtain a brown oil.

[0134] In a separately prepared three-necked flask, 412.9 mg (5.80 mmol) of glycine and 5 ml of 6N sodium hydroxide were added and stirred,...

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Abstract

Provided is a novel oxazolone derivative having an inhibitory activity on casein kinase 1[delta] and casein kinase 1[epsilon]. The inhibitor can inhibit casein kinase 1[delta] and casein kinase 1[epsilon], and therefore can provide a medicinal agent useful for the treatment and / or prevention of diseases of which the disease condition are associated with the mechanism of activation of casein kinase 1[delta] or casein kinase 1[epsilon]. Particularly, the inhibitor can provide a medicinal agent useful for the treatment of circadian rhythm disorders (including sleep disorder), central nervous system degenerative diseases and cancer. An inhibitor of casein kinase 1[delta] and casein kinase 1[epsilon], which comprises an oxazolone derivative represented by general formula (1), a salt of the derivative, or a solvate or hydrate of the derivative or the salt as an active ingredient. [In formula (1), X represents a halogen atom (which may be any one of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom).]

Description

technical field [0001] The present invention involves containing A casein kinase 1δ and casein kinase 1ε inhibitor comprising an azolone derivative or a salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient. The present invention relates to medicaments for the treatment of diseases in which activation of the enzyme casein kinase 1 delta or casein kinase 1 epsilon is associated with its disease state. The present invention relates to diseases in which the enzyme activation of casein kinase 1δ or casein kinase 1ε is associated with its disease state, especially for the treatment and / or prevention of circadian rhythm cycle disorders (including sleep disorders), central nervous degenerative diseases, cancer Useful medicines for casein kinase 1 delta and casein kinase 1 epsilon inhibitors. Background technique [0002] Casein kinase 1 is a serine / threonine kinase (and in some cases also phosphorylates tyrosine residues), known as α, β, γ1, γ2 as its iso...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/4439A61P9/10A61P25/16A61P25/20A61P25/24A61P25/28A61P35/00A61P43/00
CPCC07D413/14A61K31/4439A61P25/00A61P25/16A61P25/20A61P25/24A61P25/28A61P35/00A61P43/00A61P9/10A61K31/4436
Inventor 冈本雅子高山喜好
Owner NB HEALTH LAB
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