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5-phenyl-isoxazole-3-carboxamides modulating HSP90 with antitumoral activities

A technology of isoxazole and formyl ethylamine, which can be used in antineoplastic drugs, organic active ingredients, and resistance to vector-borne diseases, etc., and can solve the safety and stability problems of Hsp90 inhibitors.

Inactive Publication Date: 2011-06-01
SIGMA TAU RES SWITZERLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, so far there is no Hsp90 inhibitor that can fully meet the prerequisites for safety and stability

Method used

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  • 5-phenyl-isoxazole-3-carboxamides modulating HSP90 with antitumoral activities
  • 5-phenyl-isoxazole-3-carboxamides modulating HSP90 with antitumoral activities
  • 5-phenyl-isoxazole-3-carboxamides modulating HSP90 with antitumoral activities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] 4-Acetamido-5-(5-chloro-2,4-dihydroxy-phenyl)isoxazole-3-formylethylamine SST0072AA1

[0136] Step i: 1-(5-Chloro-2,4-dihydroxyphenyl)-ethanone

[0137] Acetic acid (17.5ml) was added dropwise to 4-chlorobenzene-1,3-diol (20g, 0.138mol) in BF under nitrogen atmosphere 3 .OEt 2 (100ml). The reaction mixture was stirred at 90°C for 3.5 hours and then cooled to room temperature, allowing a solid to precipitate. This mixture was poured into 10% w / v aqueous sodium acetate (350ml). The mixture was then stirred vigorously for 2.5 hours to afford a light brown solid which was filtered, washed with water, and air dried overnight to afford the title compound 1-(5-chloro-2,4-dihydroxyphenyl)-ethanone ( 11.3 g, 44%).

[0138] 1 H NMR (200MHz CDCl 3 ), δ: 2.56 (s, 3H), 6.11 (s, 1H), 6.59 (s, 1H), 7.70 (s, 1H), 12.48 (s, 1H).

[0139] Step ii: 1-[2,4-bis(benzyloxy)-5-chlorophenyl]ethanone

[0140] Benzyl bromide (17.5ml, 0.147mol) was added to 1-(5-chloro-2,4-dihydroxyphenyl...

Embodiment 2

[0170] 5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-methoxy-benzoylamino)-isoxazole-3-formylethylamine SST0081AA1

[0171] Step viii: 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-methoxy-benzoylamino)-isoxazole-3-formylethyl amine

[0172] 1 H NMR (200MHz CDCl 3 ), δ: 1.28(t, J=7.2Hz, 3H), 3.45-3.54(m, 2H), 3.84(s, 3H), 4.85(s, 2H), 5.11(s, 2H), 6.57(s, 1H), 6.83(d, J=9.0Hz, 2H), 6.95(br, 1H), 7.08-7.13(m, 2H), 7.21-7.29(m, 2H), 7.35-7.43(m, 6H), 7.55 (d, J = 9.0 Hz, 2H), 7.75 (s, 1H), 9.47 (s, 1H).

[0173] [M+H] + 612.1 / 613.3

[0174] Step ix: 5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-methoxy-benzoylamino)-isoxazole-3-formylethylamine

[0175] 1 H NMR (400MHz DMSO), δ: 1.06(t, J=6.8Hz, 3H), 3.19-3.24(m, 3H), 3.82(s, 3H), 6.64(s, 1H), 7.04(d, J= 8.8Hz, 2H), 7.43(s, 1H), 7.87(d, Hz, 2H), 8.71(t, J=5.6Hz, 1H), 9.62(s, 1H), 10.48(br, 1H), 10.68( s, 1H).

[0176] 13C NMR (100 MHz DMSO), δ: 14.4, 33.5, 55.3, 103.8, 106.2, 110.4, 113.6, 125.7, 129.4, 155.3, 155.5, 155.7, 158.5, 16...

Embodiment 3

[0178] 5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(3,4-dimethoxy-benzoylamino)-isoxazole-3-formylethylamine SST0100AA1

[0179] Step viii: 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(3,4-dimethoxy-benzoylamino)-isoxazole-3-carba Acylethylamine

[0180] 1 H NMR (200MHz CDCl 3 ), δ: 1.27(t, J=7.2Hz, 3H), 3.46-3.54(m, 2H), 3.84(s, 3H), 3.92(s, 3H), 4.85(s, 2H), 5.10(s, 2H), 6.57(s, 1H), 6.74(d, J=8.6Hz, 1H), 6.94(br, 1H), 7.05-7.12(m, 2H), 7.22-7.25(m, 2H), 7.32-7.40 (m, 8H), 7.75 (s, 1H), 9.56 (s 1H).

[0181] Step ix: 5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(3,4-dimethoxy-benzoylamino)-isoxazole-3-formylethylamine

[0182] 1 H NMR (400MHz DMSO), δ: 1.06(t, J=6.8Hz, 3H), 3.18-3.22(m, 3H), 3.79(s, 3H), 3.81(s, 3H), 6.63(s, 1H) , 7.05(d, J=8.8Hz, 1H), 7.41(s, 1H), 7.43(d, J=1.6Hz, 1H), 7.52(dd, J=8.8, J=1.6Hz, 1H), 8.69( t, J = 6.0 Hz, 1H), 9.59 (s, 1H), 10.44 (br, 1H), 10.66 (s, 1H).

[0183] 13 C NMR (100 MHz DMSO), δ: 14.4, 33.5, 55.5, 55.6, 103.8, 106.2, 110.7, 110.9, 113.6, 120.9...

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Abstract

The present invention relates to formula I compounds having antitumoural activities through, as one possible biological target, the molecular chaperone heat shock protein 90 (Hsp90) inhibition. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of Hsp90 is responsive, and the pharmaceutical compositions containing such compounds.

Description

technical field [0001] The present invention relates to arylisoxazole derivatives having antitumor activity by inhibiting molecular chaperone heat shock protein 90 (Hsp90) as a possible biological target. The invention includes the use of these compounds in medicine related to cancer and other diseases responsive to Hsp90 inhibition, and pharmaceutical compositions comprising these compounds. Background technique [0002] Heat shock proteins (Hsp's) play a key role in cellular protection against different cellular stressors (i.e., toxic xenobiotics, chemotherapy, radiation), which acts as a countermeasure against the necessity involved in maintaining cellular functionality Protective factors for protein misfolding. Hsp90 proteins, members of these molecular chaperones, are proteins that play a key role in the so-called "client" protein structure maturation, stability and function, many of which belong to the oncogenic protein family, such as Bcr-Abl, p53, Raf-1, Akt / , ErbB...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/18C07D413/12C07D498/04A61K31/42A61K31/422A61K31/5025A61P35/00A61P25/00A61P23/00
CPCC07D498/04C07D413/12C07D413/06C07D261/18A61P21/00A61P21/02A61P23/00A61P25/00A61P25/14A61P25/16A61P25/28A61P29/00A61P33/06A61P35/00A61P35/04A61P37/00A61P37/02A61P37/06A61P43/00A61P9/10Y02A50/30C07D261/14A61K31/42
Inventor G·简尼尼W·卡布里D·西蒙尼R·巴鲁克谢罗P·卡米纳蒂C·皮萨诺
Owner SIGMA TAU RES SWITZERLAND
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