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Thienopyridine derivatives and use thereof as hsp90 modulators

A technology of derivatives and compounds, applied in the field of new compounds, can solve problems such as incorrectly regulated molecular and physiological functions, loss of wild-type functions, etc.

Inactive Publication Date: 2008-02-27
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Improper protein folding can also lead to loss of wild-type function, which can have consequences for incorrectly regulated molecular and physiological functions

Method used

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  • Thienopyridine derivatives and use thereof as hsp90 modulators
  • Thienopyridine derivatives and use thereof as hsp90 modulators
  • Thienopyridine derivatives and use thereof as hsp90 modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0364] Preparation of 2-aminocarbonyl-3,6-diamino-5-cyano-4-(3,4-dimethoxyphenyl)thieno[2,3-b]pyridine ("A1"):

[0365] 1.1 Add 12.1 g of cyanothioacetamide to 10 g of 3,4-dimethoxybenzaldehyde in 100 mL of ethanol solution. Then 10 mL of 4-methylmorpholine were added dropwise and the mixture was stirred at room temperature for a further 16 hours. The mixture was then refluxed for 4 hours. The mixture was adjusted to pH 5.0 with 10% HCl and stirred at room temperature for an additional 16 hours. The precipitated material was separated, washed with ethanol and n-heptane and dried to give 9.2 g of 6-amino-3,5-dicyano-4-(3,4-dimethoxyphenyl)-2-thio-1 , 2-dihydropyridine ("1")

[0366]

[0367] 1.2 Add 255 μL of 47% KOH aqueous solution to 1 g of “1” in 5 mL of DMF. Then 300 mg of 2-chloroacetamide were added and the mixture was stirred for a further 1 hour at room temperature. Another 255 μL of 47% aqueous KOH was added and the mixture was stirred at room temperature for ...

Embodiment 2

[0388] 2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(5-ethoxycarbonylpentyloxy)-4-methoxyphenyl]thieno[2,3-b Preparation of ]pyridine ("A4"):

[0389]

[0390] 2.1 A mixture of 100 mg "A3", 60 μL ethyl bromohexanoate, 100 mg potassium carbonate and 1 mL DMF was stirred at 50° C. for 4 hours. The whole mixture was added to 20 mL of water, the precipitated material was separated and dried to give 129 mg of "A4", R f 1.569, MW 498.6.

[0391] The following compounds were obtained in a similar manner:

[0392] 2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(4-ethoxycarbonylbutoxy)-4-methoxyphenyl]thieno[2,3-b ]pyridine ("A7"), R f 1.450, MW 484.5.

[0393] Ester hydrolysis of "A7" in NaOH / methanol affords compound

[0394] 2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(4-carboxybutoxy)-4-methoxyphenyl]thieno[2,3-b]pyridine ( "A7a"), R f 1.531, MW 456.5.

[0395] Ester hydrolysis of "A4" in NaOH / methanol affords compound

[0396] 2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(5-carboxy...

Embodiment 3

[0402] Similar to Example 1, "1" was reacted with methyl chloroacetate to obtain the compound 2-methoxycarbonyl-3,6-diamino-5-cyano-4-(3,4-dimethoxybenzene base) thieno[2,3-b]pyridine ("A8bis").

[0403] The following compounds were obtained in a similar manner:

[0404] 2-ethoxycarbonyl-3,6-diamino-5-cyano-4-(3,4-dimethoxyphenyl)thieno[2,3-b]pyridine (“A9”),

[0405] 2-methoxycarbonyl-3,6-diamino-5-cyano-4-(3-hydroxy-4-methoxyphenyl)thieno[2,3-b]pyridine (“A8d”),

[0406] 2-methoxycarbonyl-3,6-diamino-5-cyano-4-(3-hydroxyphenyl)thieno[2,3-b]pyridine (“A8e”),

[0407] 2-methoxycarbonyl-3,6-diamino-5-cyano-4-(3-hydroxy-4-trifluoromethoxyphenyl)thieno[2,3-b]pyridine (“A8f” ),

[0408] 2-methoxycarbonyl-3,6-diamino-5-cyano-4-(3-hydroxy-4-methylsulfanylphenyl)thieno[2,3-b]pyridine (“A8g” ).

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Abstract

The invention relates to novel thienopyridine derivatives of formula (I), where R<1>, R<2>, R<3> and Y have the meanings given in claim 1, which are HSP90 inhibitors and can be used for the production of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of HSP90 play a role.

Description

Background of the invention [0001] The present invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds in which the inhibition, regulation and / or regulation of HSP90 plays a role, to pharmaceutical compositions comprising these compounds and to the use of said compounds in the treatment of diseases in which HSP90 plays a role. [0003] The correct folding and conformation of proteins in cells is ensured by molecular chaperones and is critical for the regulation of the balance between protein synthesis and degradation. These chaperones are important for many important functions of cells such as the regulation of cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith et al., 1998; Smith, 2001). [0004] heat shock protein (HSP) [0005] Cells of tissues respond to external stresses such as heat, hypoxia, oxidat...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365
CPCC07D495/04A61P1/04A61P1/16A61P3/10A61P9/00A61P9/10A61P11/00A61P11/06A61P13/12A61P15/00A61P17/06A61P21/00A61P25/00A61P25/14A61P25/28A61P27/02A61P29/00A61P29/02A61P31/04A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/06A61P43/00A61K31/4365
Inventor H-M·埃根韦莱M·沃尔夫
Owner MERCK PATENT GMBH
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