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2-amino-4-phenylquinazoline derivates and their use as HSP90 modulators

A use, phenyl technology, applied in the field of treating diseases in which HSP90 plays a role, treating HSP90-induced diseases, and preparing drugs, can solve problems such as loss of wild-type function

Inactive Publication Date: 2011-05-04
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 abnormally regulated molecular and physiological functions

Method used

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  • 2-amino-4-phenylquinazoline derivates and their use as HSP90 modulators
  • 2-amino-4-phenylquinazoline derivates and their use as HSP90 modulators
  • 2-amino-4-phenylquinazoline derivates and their use as HSP90 modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0326] Preparation of 2-amino-6-chloro-4-[3-(3-methoxycarbonylpropionylamino)-phenyl]quinazoline ("A1"):

[0327] 1.1 Reaction method similar to Okabe, Masami; Sun, Ruen-Chu; Tetrahedron (1995), 51(7), 1861-6

[0328] To a solution of 2.0 kg of methyl 2-aminobenzoate in 15 liters of dichloromethane was added 1 liter of glacial acetic acid and 10 liters of ice water. Under vigorous stirring, 1.9 kg of calcium hypochlorite was added thereto at 10°C, during which time its temperature should not be higher than 15°C. The mixture was stirred for another 6 hours and allowed to stand for 16 hours. The dichloromethane was separated, the aqueous phase was washed with dichloromethane and the combined organic phase was washed with 10% Na 2 SO 3 solution (warm!) for washing. The combined dichloromethane phases are stirred with 2 kg of silica gel, 200 g of activated carbon and 2 kg of sodium sulfate. The phases were separated, dichloromethane was removed, 10 liters of n-hexane was adde...

Embodiment 2

[0381] In 2ml of ammonia / THF solution (0.5M in 1,4-di 48 mg of "A1" in alkanes) was irradiated under microwaves. Removal of the solvent afforded 2-amino-6-chloro-4-[3-(3-aminocarbonylpropionylamino)phenyl]quinazoline ("A3").

Embodiment 3

[0383] To a solution of 73.6 mg 1H-indole-7-carboxylic acid and 67.9 mg 1-hydroxybenzotriazole hydrate (HOBt) in 1 ml DMF was added 106.2 mg N-(3-dimethylaminopropyl)-N' - Ethylcarbodiimide hydrochloride (DAPECI) and 56 mg N-methylmorpholine. The mixture was stirred at room temperature for 1 hour. Then, 100 mg of "6" was added thereto, and the mixture was stirred for 16 hours. The mixture was added to 10 ml of water with stirring, and the precipitated material was separated and washed with water. The residue was boiled once with 10 ml of acetonitrile / water and dried to give 132 mg of 2-amino-6-chloro 4-[3-(indol-7-ylcarbonylamino)phenyl]quinazoline ("A11" ).

[0384] Similarly react "6" with:

[0385] BOC-β-Ala-OH (BOC-β-alanine),

[0386] BOC-GABA-OH (BOC-γ-aminobutyric acid),

[0387] BOC-Ala-OH (BOC-(S)-alanine),

[0388] BOC-(R)-Ala-OH (BOC-(R)-alanine),

[0389] BOC-Ser(O-tert-butyl)-OH(BOC-(S)-serine tert-butyl ether),

[0390] BOC-(R)-Ser(O-tert-butyl)-OH(BOC-(...

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Abstract

Novel phenylquinazoline derivatives of the formula (I), in which R<1>, R<2>, R<3>, R<4 >and R<5 > have the meanings indicated in Claim 1, are HSP90 inhibitors and can be used for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of HSP90 plays a role.

Description

Background technique [0001] The object of the present invention was to discover novel compounds of value, especially those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds that act in the inhibition, modulation and / or regulation of HSP90, and also to pharmaceutical compositions comprising these compounds and the use of said compounds for the treatment of diseases in which HSP90 acts. [0003] The correct folding and conformation of proteins in cells is ensured by molecular chaperones and are critical for the regulation of the balance between protein synthesis and degradation. These chaperones are important for many important functions of the cell, 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, oxidative stress or toxic substances such a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/84C07D401/12C07D403/12A61K31/517
CPCA61P1/00A61P1/04A61P1/16A61P3/00A61P3/10A61P9/00A61P9/10A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/02A61P17/06A61P19/02A61P21/00A61P25/00A61P25/14A61P25/28A61P27/02A61P29/00A61P31/00A61P31/12A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P35/04A61P37/06A61P39/00A61P43/00C07D239/84C07D401/12C07D403/12A61K31/517
Inventor H-M·埃根韦莱M·沃尔夫H-P·布赫施塔勒
Owner MERCK PATENT GMBH