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Substituted acylhydroxamic acids and method of reducing TNF-alpha levels

A technology of acyl hydroxamic acid and amido, which is applied in the field of pharmaceutical compositions containing the derivatives, and can solve problems such as treatment, unavailable tumors, and unavailable tumor diseases

Inactive Publication Date: 2003-04-23
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although surgery is sometimes effective in removing tumors located in some areas (such as in the chest, colon, and skin), surgery cannot be used to treat tumors in other areas (such as the spine) or spread Treatment of sexual neoplastic conditions (such as leukocytosis)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] (3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionylamino)propionate

[0096] A 3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propane hydroxamic acid (5.8 g, 15 mmol) and propionic anhydride (3.93 g, 30.2 mmol), a solution in anhydrous acetonitrile (170 mL) was stirred overnight at room temperature under nitrogen. The solvent was removed in vacuo to form an oil which was then stirred in diethyl ether (25 mL) and the resulting suspension was filtered and washed with diethyl ether to give a white solid (3-(1,3-dioxoisoindoline-2 -yl)-3-(3-ethoxy-4-methoxyphenyl)propionylamino)propionate (2.8 g, 42%): melting point, 181.0-183.5°C; 1 HNMR (DMSO-d6) δ1.01 (t, J=7.5Hz, 3H, CH 2 CH 3 ), 1.31(t, J=6.9Hz, 3H, OCH 2 CH 3 ), 2.39 (q, J=7.4Hz, 2H, CH 2 ), 3.12-3.35 (m, 2H, CH 2 ), 3.97 (q, J=7.4Hz, 2H, CH 2 ), 5.67(t, J=7.7Hz, 1H, CH), 6.90(s, 2H, Ar), 7.02(s, 1H, Ar), 7.83-7.86(m, 4H, Ar), 11.87(brs, 1H , NH); 13 C NMR (DMSO-d6) δ8.2, 14.1, 23.7...

Embodiment 2

[0098] (3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionylamino)acetate

[0099] From 3-(1,3-dioxoisoindoline-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propane hydroxamic acid (0.5 g , 1.3 mmol) and propionic anhydride (0.27 g, 2.6 mmol), in anhydrous acetonitrile (20 ml) to prepare (3-(1,3-dioxoisoindolin-2-yl)-3-( 3-ethoxy-4-methoxyphenyl)propionylamino)acetate. The product obtained is a white solid (0.25 g, 45%): melting point, 180.0-182.0 °C; 1 H NMR (DMSO-d6) δ1.31 (t, J=6.7Hz, 3H, CH 3 ), 2.07 (s, 3H, CH 3 ), 3.10-3.26 (m, 2H, CH 2 ), 3.72 (s, 3H, OCH 3 ), 4.00 (q, J=6.4Hz, 2H, OCH 2 ), 5.67(t, J=7.7Hz, 1H, CH), 6.89(s, 2H, Ar), 7.02(s, 1H, Ar), 7.82-7.85(m, 4H, Ar), 11.86(brs, 1H , NH); 13 C NMR (DMSO-d6) δ8.2, 14.6, 17.9, 33.9, 49.8, 55.4, 63.7, 111.8, 112.1, 119.4, 123.1, 130.9, 131.2, 134.5, 147.7, 148.5, 166.5, 167.6, 168.1; 22 h 22 N 2 o 7 Analytical calculations: C, 61.97; H, 5.20; N, 6.57, found: C, 62.01; H, 5.26; N, 6.43.

Embodiment 3

[0101] (3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionylamino)pentanoate

[0102] From 3-(1,3-dioxoisoindoline-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propane hydroxamic acid ( 1.0 g, 2.6 mmol) and valeric anhydride (0.97 g, 5.2 mmol) in anhydrous acetonitrile (30 ml) prepared (3-(1,3-dioxoisoindolin-2-yl)-3 -(3-Ethoxy-4-methoxyphenyl)propionylamino)pentanoate. The product obtained is a white solid (0.45 g, 37%): melting point, 200.0-201.5°C; 1 H NMR (DMSO-d6) δ0.83 (t, J=7.3Hz, 3H, CH 3 ), 1.25-1.33 (m, 2H, CH 2 ), 1.31(t, J=6.8Hz, 3H, CH 3 ), 1.33-1.48 (m, 2H, CH 2 ), 2.36(t, J=7.2Hz, 2H, CH 3 ), 3.10-3.20 (m, 2H, CH 2 ), 3.72 (s, 3H, CH 3 ), 4.02 (q, J=6.4Hz, 2H, OCH 2 ), 5.67(t, J=7.6Hz, 1H, CH), 6.89-7.01(m, 3H, Ar), 7.85(s, 4H, Ar), 11.86(s, 1H, NH); 13 C NMR (DMSO-d6) δ13.4, 14.6, 21.3, 26.3, 30.4, 49.7, 55.4, 63.7, 111.8, 112.2, 119.4, 123.1, 130.9, 131.2, 134.5, 147.7, 148.5, 166.6, 167.6, 170.8; C 25 h 28 N 2 o 7 Anal. Calculated: C, 64.09...

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Abstract

Imido and amido substituted acylhydroxamic acids which reduce the levels of TNF alpha and inhibit phosphodiesterase in a mammal. A typical embodiment is (3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoylamino)propanoate.

Description

technical field [0001] The present invention relates to imido- and amido-substituted acylhydroxamic acids, methods of reducing the level or activity of cytokines (such as tumor necrosis factor alpha) in mammals by administering such compounds, and derivatives containing the same pharmaceutical composition. Background technique [0002] Tumor necrosis factor-α (TNFα) is a cytokine that is released primarily by cells of the autoimmune system in response to certain autoimmune stimuli. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, cachexia, and acute reactions similar to those seen during acute infection, inflammatory disease, and sudden illness. Excessive or unregulated TNFα production has been found to be associated with a number of disease states including endotoxemia and / or complications of toxic shock [Tracey et al., Nature (Nature) 330, 662-664 (1987) and Yin Xiao et al. (Hinshaw, et al.,) Circ.Sho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4035A61K31/4439A61P1/00A61P1/02A61P11/00A61P11/06A61P17/00A61P17/06A61P19/02A61P29/00A61P31/18A61P35/00A61P37/06A61P37/08A61P43/00C07D209/46C07D209/48C07D209/66C07D401/12
CPCC07D401/12C07D209/46C07D209/48A61P1/00A61P1/02A61P11/00A61P11/06A61P17/00A61P17/06A61P19/02A61P29/00A61P31/18A61P35/00A61P37/06A61P37/08A61P43/00A61K31/404A61K31/4015A61K9/0019A61K9/08A61K9/20A61K9/48
Inventor 鸿瓦·曼乔治·穆勒雪艾·Y·黄
Owner CELGENE CORP
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