Quinazoline derivatives

A technology of compounds and mixtures, applied in the treatment of diseases in which HSP90 plays a role, those compounds for the preparation of drugs, and the treatment of HSP90-induced diseases can solve problems such as misregulation of molecular functions and physiological functions, loss of wild-type functions, etc.

Active Publication Date: 2012-08-22
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • Quinazoline derivatives
  • Quinazoline derivatives
  • Quinazoline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0335] Preparation of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate ("A1") and 2-[2-amino-4-(isodihydro Indoline-2-carbonyl)quinazolin-6-yl]acetic acid ("A2")

[0336] step 1: Ethyl 2-[4-[[(2Z / E)-2-hydroxyiminoacetyl]amino]phenylacetate

[0337]

[0338] Dissolve 18g of chloral hydrate in 100ml of water, add 27g of Na 2 SO 4 , and the mixture was stirred at 23° C. for 10 minutes. A solution of 20 g of ethyl 4-aminophenylacetate hydrochloride in 100 ml of water was added to the solution. A solution of 19 g of hydroxylamine hydrochloride in 50 ml of water was added to the resulting suspension, and the mixture was stirred at 60° C. for 90 minutes. The mixture was then cooled, during which a precipitate settled. It was filtered off, washed with water and dried under vacuum at 40°C. The resulting mixture was used in subsequent reactions without further purification.

[0339] Yield: 11.2 g (2-[4-[[(2Z / E)-2-hydroxyiminoacetyl]amino]phenylacetate ethyl...

Embodiment 2

[0370] Preparation of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetamide ("A3")

[0371]

[0372] 100 mg of "A1" was dissolved in 40 ml of methanol, and 135 mg of magnesium nitride was added. The mixture was stirred at 80°C for 12 hours, cooled, diluted with 10 ml of water and adjusted to pH 2 with 25% hydrochloric acid. The resulting precipitate was filtered off and purified by column chromatography. Yield: 18mg (20%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetamide; LC-MS retention time: 0.74min;

[0373] 1 H NMR (500MHz, DMSO-d 6 / TFA -d 1 ):δ[ppm]7.98(dd,J=8.7,1.8,1H),7.93(d,J=1.4,1H),7.73(d,J=8.5,1H),7.48(d,J=7.3,1H ), 7.34 (dt, J=17.9, 6.9, 2H), 7.25 (d, J=7.3, 1H), 5.05 (s, 2H), 4.80 (s, 2H), 3.58 (s, 2H).

[0374] The compound 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanamide ("A4") was obtained analogously

[0375]

[0376] Yield: 15mg (16%); LC-MS retention time: 1.64min;

[0377] 1 H NMR (500MHz, ...

Embodiment 3

[0383] Preparation of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylacetamide ("A6")

[0384]

[0385] Dissolve 50 mg of "A2" in 2 ml ethylamine and microwave at a maximum of 120 °C (CEM )60 minutes. The mixture was evaporated to dryness in vacuo, the residue was dissolved in DMSO and purified by column chromatography. Yield: 8 mg (16%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-N-ethylacetamide;

[0386] LC-MS retention time: 1.53min;

[0387] 1 H NMR (500MHz, DMSO-d 6 / TFA -d 1 ):δ[ppm]7.99(dd,J=8.6,1.8,1H),7.95(d,J=1.2,1H),7.75(d,J=8.5,1H),7.48(d,J=7.2,1H ),7.34(dt,J=18.6,6.9,2H),7.25(d,J=7.3,1H),5.07(s,2H),4.81(s,2H),3.59(s,2H),3.07(q ,J=7.2,2H),0.99(t,J=7.2,3H)

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Abstract

Novel quinazoline amide derivatives of the formula (I), in which R1 - R4 and X have the meanings specified in claim 1, are HSP90 inhibitors and can be used for preparing a pharmaceutical for treating diseases, in which the inhibition, regulation and / or modulation of HSP90 plays a part.

Description

Background of the invention [0001] The object of the present invention was to find novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds that play a role in the inhibition, regulation and / or regulation of HSP90, and also to pharmaceutical compositions comprising these compounds, and 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 are guaranteed by molecular chaperones, and the correct folding and conformation of proteins are very important for regulating the balance of protein synthesis and degradation. Molecular 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 proteins (HSPs) [0005] The cells of a tissue ...

Claims

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Application Information

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IPC IPC(8): C07D209/44C07D239/84C07D403/06C07D403/14C07D405/14A61K31/517A61P35/00
CPCC07D209/44C07D239/84C07D403/06C07D403/14C07D405/14A61P25/00A61P25/28A61P29/00A61P31/00A61P31/12A61P35/00A61P35/04A61P37/06A61P39/02A61P9/10
Inventor H-M·埃根韦莱C·西伦贝格H-P·布赫施塔勒
Owner MERCK PATENT GMBH
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