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MIF inhibitors

A technology selected from, alkyl, applied in the field of treatment of MIF cytokines or biologically active diseases or diseases, inflammatory or cancerous diseases or diseases, and can solve the problem of incomplete effectiveness of glucocorticoids

Inactive Publication Date: 2009-04-15
CORTICAL PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Furthermore, glucocorticoids are not fully effective in the management of many diseases, leading to the concept of "steroid-resistant" diseases

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0480]

[0481] Preparation of methyl 3-((2-oxo-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl)thio)propionate (1)

[0482] (i) 5-Bromoacetyloxindole (US 5849710)

[0483] To a stirred suspension of anhydrous aluminum chloride (11.4 g, 85 mmol) in 1,2-dichloroethane (25 ml) at 0°C was added bromoacetyl bromide (5.9 ml, 68 mmol) dropwise. After 1 h, a suspension of oxindole (4.52 g, 34 mmol) in 1,2-dichloroethane (25 ml) was added and stirring was continued at 0 °C for 2 h, then at 50 °C for 3 h. The reaction mixture was cooled, poured onto ice / water (500ml) and filtered to give 5-bromoacetyloxindole (7.1g, 82%) as a beige solid which was used without further purification .

[0484] (ii) Methyl 3-((2-oxo-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl)thio)propanoate (1)

[0485] To a suspension of 5-bromoacetyloxindole (4.15g, 16.3mmol) in N,N-dimethylformamide (20ml) was added methyl 3-mercaptopropionate (2.14ml, 19.6mmol) and diiso Propylethylamine (6.1 mL, 35 mmol), resulting in ...

Embodiment 2

[0489]

[0490] Preparation of 3-((2-oxo-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl)thio)propionic acid (2)

[0491] A solution of the methyl ester (1) (3.0 g, 10.2 mmol) in concentrated hydrochloric acid (30 ml) was heated to reflux for 5 minutes and then cooled to room temperature to give a yellow precipitate. The solid was filtered, washed with water and recrystallized in methanol to give acid (2) (1.50 g, 52%) as a pale yellow solid, mp. 182-184°C (TLC: R F = 0.31 in SiO 2 above, 9:1 chloroform / methanol).

[0492] 1 H nmr (300MHz, d 6 -dmso) δ2.5, shielded, CH 2 ;2.65, t(7.1Hz), CH 2 ;3.54,s,H3;3.94,s,SCH 2 CO; 6.89, d(8.1Hz), H7; 7.82, s, H4; 7.87, d(8.4Hz), H6; 10.74, br s, NH; 12.21, br s, COOH.

[0493] ESI(+ve) m / z 280(M+H, 100%).ESI(-ve)m / z 278(M-H, 100%).

Embodiment 3

[0495]

[0496] Preparation of methyl 3-((2-oxo-2-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)ethyl)thio)propionate (3)

[0497] (i) 5-(Chloroacetyl)-1,3-dihydro-2H-benzimidazol-2-one (WO 92 / 50070)

[0498] Under nitrogen, anhydrous aluminum chloride (7.5 g, 60 mmol) was powdered and then suspended in 1,2-dichloroethane (10 ml). The suspension was cooled to 0°C, and chloroacetyl chloride (3.6ml, 45mmol) was added dropwise. After stirring at 0°C for 30 minutes, 2-hydroxybenzimidazole (3.0 g, 22.4 mmol) and further 1,2-dichloroethane (5 ml) were added in portions. The reaction mixture was heated at 50-55 °C under nitrogen with vigorous stirring for 2 hours, during which time the blue-green suspension turned into a dark solution. After stirring at room temperature for 16 hours, the mixture was poured on ice (100 g) and the resulting gray precipitate was filtered. The resulting solid was washed with water, then ethyl acetate and dried under vacuum to give 5-(chloroacetyl)-1,3-di...

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Abstract

The present invention relates to the use of specific benzimidazolone analogues and derivatives to inhibit the cytokine or biological activity of macrophage migration inhibitory factor (MIF), and diseases or conditions wherein MIF cytokine or biological activity is implicated. Novel benzimidazole analogues and derivatives are also provided.

Description

technical field [0001] The invention generally relates to the treatment of diseases or conditions resulting from cellular activation, such as inflammatory or cancerous diseases or conditions. In particular, the present invention relates to the use of certain benzimidazolone analogs and derivatives for inhibiting the biological activity of cytokines or macrophage migration inhibitory factor (MIF) and diseases or conditions in which MIF cytokines or biological activities are involved the use of. Background technique [0002] MIF was the first identified T-cell-derived soluble lymphokine. MIF was originally described as a soluble factor with the ability to alter macrophage migration (1) . In 1989, molecules responsive to the biological effects attributed to MIF were identified and cloned (2) . Originally found to activate macrophages at inflammatory sites, it has been shown to have multiple potential roles in the immune system. MIF has been shown to be expressed in human ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/404A61K31/573A61P1/04A61P3/10A61P9/00A61P17/00A61P25/00A61P29/00A61P37/00A61F2/82C07D209/34
CPCC07D277/68C07D235/26C07D209/34C07D263/58A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P13/12A61P15/08A61P17/00A61P17/02A61P17/06A61P19/02A61P19/08A61P21/00A61P25/00A61P27/02A61P29/00A61P3/10A61P31/04A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/02A61P9/00A61P9/10A61K31/404A61F2/82A61K31/573
Inventor E·F·莫兰德C·E·斯克恩P·M·塔普利X·李T·H·乔泽菲亚克
Owner CORTICAL PTY LTD
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