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Thienopyridines

A technology of compounds and mixtures, applied in the field of treating diseases where HSP90 works, treating HSP90-induced diseases, and compounds that can be used as drugs, can solve the problems of wild-type loss of function, misregulation of molecular functions and physiological functions, etc.

Inactive Publication Date: 2008-04-16
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Misfolded proteins also lead to wild-type loss of function, which can have consequences for misregulating molecular and physiological functions

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0330] Prepare R 2 A general reaction scheme for compounds of formula I referring to acylated amino groups:

[0331]

[0332] Preparation of 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-trifluoromethylbenzoylamino)phenyl]thieno[2,3 -b] pyridine ("A1")

[0333] 1.1 10.9g of cyanothioacetamide and 9ml of 4-methylmorpholine were added to a solution of 10g of 4-methoxy-3-nitrobenzaldehyde in 100ml of ethanol, and the mixture was stirred at room temperature for 48 hours. 10% HCl was added until the pH was 5, and the mixture was stirred for a further 16 hours. The precipitated material was separated, washed with ethanol and n-heptane, and dried to obtain 9.6 g of 6-amino-3,5-dicyano-4-(4-methoxy-3-nitrophenyl)-2-sulfur Substituent-1,2-dihydropyridine ("1").

[0334]

[0335] 1.2 Add 1 equivalent of KOH dissolved in water to 30.7g of "1" in 100ml of DMF solution. Then 8.8 g of 2-chloroacetamide were added and the mixture was stirred for a further 1 hour. An addit...

Embodiment 2

[0357] Under standard conditions,

[0358] Ester hydrolysis of "A4a" gave the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybutyrylamino)phenyl]thieno [2,3-b]pyridine ("A4"), M+H + 469.49;

[0359] Ester hydrolysis of "A6a" affords the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybenzoylamino)phenyl]thiophene And[2,3-b]pyridine ("A6"), M+H + 503.51;

[0360] Ester hydrolysis of "A7a" affords the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxymethoxyacetamido)phenyl] Thieno[2,3-b]pyridine ("A7"), M+H + 471.46;

Embodiment 3

[0362] Add 82 mg of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (DAPECI) and 47 μl of 4-methylmorpholine to 55 mg of BOC-glycine (BOC-Gly-OH) and 48 mg of 1-hydroxybenzotriazole hydrate was dissolved in 1 ml of DMF, and the mixture was stirred at room temperature for 1 hour. 100 mg of "3" was added and the mixture was stirred for a further 16 hours. The mixture was stirred and added to 10 ml of water, the precipitate was separated and washed with water to give

[0363] 2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butoxycarbonyl)amino]acetamido}phenyl)thieno[2 , 3-b] pyridine ("A10"),

[0364]

[0365] Similarly, "3" is reacted with the following compound, which is

[0366] BOC-β-Ala-OH (BOC-β-alanine),

[0367] BOC-GABA-OH (BOC-γ-aminobutyric acid),

[0368] 1H-indole-7-carboxylic acid,

[0369] BOC-His-OH (BOC-Histidine),

[0370] BOC-Asn-OH (BOC-Asn-OH),

[0371] N-(2-carbamoylacetyl)glycine,

[0372] 1H-indazole-7-carboxylic acid,...

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PUM

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Abstract

The invention relates to novel thienopyridine derivatives of formula (I), wherein R1, R2, R3, R4 and Y have the meaning cited in claim 1, are HSP90-inhibitors and can be used for producing a medicament for treating illnesses, wherein the inhibition, regulation and / or modulation of HSP90 plays a roll.

Description

Background technique [0001] The object of the present invention is to find new and valuable new compounds, especially compounds which can be used as medicines. [0002] The present invention relates to compounds which play a role in the inhibition, regulation and / or regulation of HSP90, furthermore to pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of diseases in which HSP90 plays a role. [0003] Correct folding and conformation of proteins in cells are ensured by molecular chaperones and are important for the regulation of protein synthesis and degradation balance. Molecular chaperones are important for the regulation of many important functions of cells, such as cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith et al., 1998; Smith, 2001). [0004] heat shock proteins (HSPs) [0005] Tissue cells respond to external stress such as heat, hypoxia, oxidative stress or toxic substances such as heavy metals ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61K31/4365A61P35/00
CPCC07D495/04A61P1/00A61P1/16A61P11/06A61P19/02A61P19/04A61P25/00A61P25/28A61P29/00A61P3/10A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P35/04A61P37/06A61P9/00A61P9/10A61K31/4365
Inventor H-M·埃根韦莱M·沃尔夫
Owner MERCK PATENT GMBH
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