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Novel HSP90 Inhibitor

a technology of hsp90 inhibitor and triazole, which is applied in the direction of organic chemistry, organic active ingredients, drug compositions, etc., to achieve the effect of superior hsp90 inhibitory activity

Inactive Publication Date: 2013-05-09
NIPPON KAYAKU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a drug made of a compound that can inhibit the activity of HSP90, which is involved in the growth of cancer cells. This compound can be used as a treatment for cancer.

Problems solved by technology

Among the HSP90 antagonists, 17-AAG is subjected to ongoing Phase I / II clinical trials, and investigations on RD derivatives are also being conducted (non-patent document 4), but any one of these has problems for use as a pharmaceutical product in physical properties such as molecular weight, stability, and water solubility.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1-1

Preparation of 4-isopropyl-6-{5-mercapto-4-[4-(morpholin-4-yl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SH-a01) and trifluoroacetate thereof (SH-a01-TF)

[0130]

The First Step: Preparation of 4-bromo-6-isopropyl-benzene-1,3-diol (IM1-a)

[0131]4-isopropyl-benzene-1,3-diol (IMO-a: 9.13 g, 60 mmol) and benzyltrimethyl ammoniumtribromide (24.6 g, 63 mmol) and methylene chloride 250 mL were placed in a 500 mL three-neck flask and were stirred at room temperature for 4 hours. After the reaction was finished, the reaction mixture was washed twice with saturated ammonium chloride and once with saturated sodium chloride, and then dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column chromatography to obtain the title compound (IM1-a: 10.5 g, 76%).

[0132]LC / MS (Method 3): m / z (ESI, POS): 229, 231 [M+H]+;

[0133]retention time: 5.68 minutes.

[0134]1H-NMR (200 MHz, CDCl3, TMS) ppm: 7.21 (1H, s), 6.48 (1H, s), 5.33 (1H, s), 4.87 (1H...

example 1-2

Preparation of 4-isopropyl-6-{5-mercapto-4-[4-(morpholin-4-ylmethyl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SH-a02)

[0153]

The First Step: Preparation of 4-[4-(morpholin-4-ylmethyl)-phenyl]-1-(5-isopropyl-2,4-bismethoxymethoxy-benzoyl)thiosemicarbazide (IM5-S-a02)

[0154]5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid hydrazide (IM4-a: 1.99 g, 6.67 mmol), 4-(4-isothiocyanate-benzyl)-morpholine (1.72 g, 7.34 mmol) and ethanol (30 mL) were placed in a 100 mL eggplant shaped flask and heated under reflux for 2 hours. After completing the reaction, the reaction mixture was concentrated under reduced pressure to obtain 4-[4-(morpholin-4-ylmethyl)-phenyl]-1-(5-isopropyl-2,4-bismethoxymethoxy-benzoyl)thiosemicarbazide (IM5-S-a02). This crude product was subjected to the next reaction without purification in particular.

[0155]LC / MS (Method 3): m / z (ESI, POS): 533 [M+H]+; retention time: 3.72 minutes.

The Second Step: Preparation of 5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-[4-(mo...

example 1-3

Preparation of 4-[4-(4-bromo-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yl]-6-isopropyl-benzene-1,3-diol (SH-a03)

[0161]The title compound (SH-a03) was synthesized in a similar manner as described in Example 1-1.

[0162]LC / MS (Method 5): m / z (ESI, POS): 406, 408 [M+H]+;

[0163]retention time: 4.38 minutes.

[0164]1H-NMR (200 MHz, CDCl3, TMS) ppm: 9.25 (1H, s), 7.75 (2H, d, J=8.7 Hz), 7.26 (2H, d, J=8.7 Hz), 6.43 (1H, s), 6.42 (1H, s), 2.91 (1H, sept, J=6.9 Hz), 0.81 (6H, d, J=6.9 Hz).

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Abstract

Disclosed is a triazole derivative(s) represented by the general formula (1) below or a pharmacologically acceptable salt(s) thereof. Also disclosed are a prodrug(s) of such a triazole derivative(s) and an HSP90 inhibitor(s) containing any one of them as an active constituent. (1) (In the formula, X represents a halogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group or the like; Y represents a mercapto group, a hydroxyl group, an optionally substituted sulfonyl group, an optionally substituted amino group or the like; and R represents an optionally substituted aryl or alkyl group or the like.)

Description

[0001]This application is a continuation of U.S. Ser. No. 11 / 885,575, filed Sep. 4, 2007, which is a §371 of PCT / JP2006 / 304496 filed Mar. 8, 2006, the disclosures of which are hereby incorporated by reference.TECHNICAL FIELD[0002]The present invention relates to a novel triazole derivative and an HSP90 inhibitor containing the triazole derivative as an active ingredient. The triazole derivative of the present invention inhibits the function of HSP90 by binding to its ATP binding site, blocks the binding of HSP90 and its client protein and finally suppresses cellular growth.BACKGROUND ART[0003]Molecular chaperones are a general term for proteins that form a complex temporally with client proteins to promote the formation of the conformation of the client proteins. These proteins, the activity of which is to help folding and association of protein and to prevent aggregation, are broadly defined as molecular chaperones and classified into several families according to their molecular w...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D249/12C07D401/06C07D249/14C07D403/04C07D403/06C07D401/04C07D405/06
CPCC07D249/12C07D401/04C07D401/06C07D405/06C07D403/04C07D403/06C07D249/14A61P35/00A61P43/00C07D401/12C07D405/12A61K31/4196C07D413/10
Inventor NAKAMURA, MASAHARUKASUGA, YOUSUKESATO, YOSHITAKANIITSUMA, SETSUKO
Owner NIPPON KAYAKU CO LTD
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