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Cinnamic, phenylpropiolic and phenylpropanoic acid derivatives useful as anti-tumour agents

一种化合物、芳基的技术，应用在肉桂酸和苯丙炔酸和苯丙酸衍生物领域，能够解决抗肿瘤治疗无效等问题

Inactive Publication Date: 2008-06-04
SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Regardless of the cause of resistance, antineoplastic therapy is ineffective when used long-term

Method used

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  • Cinnamic, phenylpropiolic and phenylpropanoic acid derivatives useful as anti-tumour agents
  • Cinnamic, phenylpropiolic and phenylpropanoic acid derivatives useful as anti-tumour agents
  • Cinnamic, phenylpropiolic and phenylpropanoic acid derivatives useful as anti-tumour agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] Preparation of (2E)-N-hydroxy-3-(4-{[(allyloxy)imino]methyl}phenyl)acrylamide (ST2984)

[0174] Step 1: Warm trans-4-formyl-cinnamic acid A (Y=CH=CH, R 1 = H, R 3 =H, 0.346 g, 1.96 mmol.) and B O-allylhydroxylamine hydrochloride (0.258 g, 2.37 mmol.) were dissolved in 2 mL of DMF and stirred for 5 h. Then, the solution was diluted with AcOEt and washed with water. in Na 2 SO 4 The organic layer was dried and then concentrated under reduced pressure to give 0.421 g of intermediate C(2E)-3-(4-{[(benzyloxy)imino]methyl}phenyl)acrylic acid (93% yield) .

[0175] MS (ESI) m / z: [M-1] - =230.3

[0176] Step 2: Intermediate C from Step 1 (0.123 g, 0.53 mmol) was dissolved in 1.5 mL DMF along with HATU (0.222 g, 0.58 mmol) and DIEA (185 μL, 1.06 mmol) in a flask. After 0.5 h, a solution of hydroxylamine hydrochloride (0.055 g, 0.80 mmol) and DIEA (139 μL, 0.80 mmol) in 1.5 mL DMF was added. The mixture was stirred at room temperature for 24 h, then diluted with HCl solu...

Embodiment 2

[0182] Preparation of (2E)-N-hydroxy-3-{4-[(phenoxyimino)methyl]phenyl}acrylamide (ST2985)

[0183] Step 1: Starting from trans 4-formyl-cinnamic acid A (0.342 g, 1.94 mmol) and B 0-phenylhydroxylamine hydrochloride (0.339 g, 2.33 mmol) as described in Example 1, Step 1, gave Intermediate C(2E)-3-{4-[(phenoxyimino)methyl]phenyl}acrylic acid used in the synthesis of ST2985 (0.520 g, 99% yield).

[0184] MS (ESI) m / z: [M-1] - =266.4

[0185] Step 2: Compound ST2985 (0.100 g, 48% yield) was obtained starting from Intermediate C (0.201 g, 0.75 mmol) as described in Example 1, Step 2.

[0186] MS(ESI)m / z: [M-1] - =281.1

[0187] [M+23] + =305.0

[0188] 1 H-NMR (200MHz, DMSO-d6) δ (ppm): 6.5-6.7 (d, J = 15.7Hz, 1H, CH), 7.0-7.1 (t, J = 6.9Hz, 1H, CH ar ), 7.2-7.3 (d, J=8.0Hz, 2H, 2×CH ar ), 7.3-7.4 (t, J=7.3Hz, 2H, 2×CH ar ), 7.4-7.6 (d, J=16.1Hz, 1H, CH), 7.6-7.7 (d, J=7.7Hz, 2H, 2×CH ar ), 7.8-7.9 (d, J=7.7Hz, 2H, 2×CH ar ), 8.7 (s, 1H, CH), 9.1 (...

Embodiment 3

[0191] Preparation of (2E)-N-hydroxy-3-[4-({[(4-nitrobenzyl)oxy]imino}-methyl)phenyl]acrylamide (ST2987)

[0192] Step 1: As described in step 1 of Example 1, from trans-4-formyl-cinnamic acid A (0.348g, 1.97mmol) and B 0-(4-nitrobenzyl) hydroxylamine hydrochloride (0.485g, 2.37 mmol) to give intermediate C(2E)-3-[4-({[(4-nitrobenzyl)oxy]imino}-methyl)phenyl]acrylic acid (ST3075) for the synthesis of ST2987 (0.610 g, 94% yield).

[0193] MS(ESI)m / z: [M-1] - =325.3

[0194] 1 H-NMR (200MHz, DMSO-d6) δ (ppm): 5.34 (s, 2H, CH 2 ), 6.5-6.7 (d, J=15.7Hz, 1H, CH), 7.5-7.8 (m, 7H, 6×CH ar , CH), 8.2-8.3 (d, J=8.4Hz, 2H, 2×CH ar ), 8.41(s, 1H, CH), 12.4(bs, 1H, OH).

[0195] 13 C-NMR (50MHz, DMSO-d6, δ): 75.0, 121.0, 124.3, 128.1, 129.4, 129.5, 133.8, 136.7, 143.7, 146.5, 147.7, 150.3, 168.2.

[0196] Step 2: Compound ST2987 (0.120 g, 44% yield) was obtained starting from Intermediate C (0.262 g, 0.80 mmol) as described in Example 1, Step 2.

[0197] MS(ESI)m / z: [M-1] - =34...

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Abstract

Cinnamic and phenylpropiolic acid derivatives of Formula (I) having antitumour and chemosensitizing activity are described. Also described are pharmaceutical compositions containing the above-mentioned compounds, for the treatment of tumours.

Description

field of invention [0001] The present invention relates to cinnamic acid and phenylpropiolic acid and phenylpropionic acid derivatives having antitumor activity. Background of the invention [0002] Currently, tumor treatment is achieved through surgical intervention, radiation therapy, and chemotherapy. The latter disadvantage is mainly due to the toxicity of cytotoxic drugs (which is usually not restricted to cancer cells) and the acquired resistance of cancer cells to some of the most widely used drugs (which reduces the long-term efficacy of the treatment). [0003] Surgical elimination of the primary tumor is not always possible and in no case prevents the most metastatic tumors, such as breast cancer or melanoma, from invading other target organs. [0004] Treatment of metastatic tumors has proven unlikely to completely cure patients; therefore, cytotoxic drug therapy is now considered palliative and life-prolonging rather than curative. Chronic treatment with drugs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/48C07C251/80C07D209/08A61P35/00A61K31/165A61K31/195A61K31/405
CPCC07C251/40C07C251/52C07C313/28C07C251/60C07D295/088C07D209/08C07C381/00C07C251/48C07C251/86C07C251/36A61P35/00A61P35/02A61P35/04A61P43/00A61K31/165A61K31/195A61K45/06A61K2300/00
Inventor C·皮萨诺G·巴蒂斯图齐M·迪马尔佐G·詹尼尼M·马尔齐L·韦希F·祖尼诺R·佩齐
Owner SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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