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Novel Methods for the Treatment of Inflammatory Diseases

a technology for inflammatory diseases and new methods, applied in the field of new methods for the treatment of inflammatory diseases, can solve the problems of limited universal use of glucocorticoids, biochemical molecules are expensive to prepare on a commercial basis, and do not readily lend themselves to formulations, so as to enhance the effect of glucocorticoids

Inactive Publication Date: 2010-12-23
CORTICAL PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The phenyl substituted cyclic derivatives effectively inhibit MIF-induced proliferation and IL-1 induced COX-2 expression, enhancing the effects of glucocorticoids, reducing their required dosage, and providing a "steroid-sparing" therapy for inflammatory and immune diseases, including steroid-resistant cases.

Problems solved by technology

Although antibody antagonism of MIF is one potential way to provide therapeutic treatments, such biological molecules can be expensive to prepare on a commercial basis and further, can be limited in the way they are administered (generally by injection) and do not readily lend themselves to formulations for administration by other means eg oral administration.
Despite their benefits and efficacy; the use of glucocorticoids is limited by universal, predictable, dose-dependent toxicity.
However, currently available combination therapies are non-specific as the other therapeutic agents do not address biological events which inhibit the effectiveness of glucocorticoids.
Such combination therapies are also typically associated with serious side effects.
Furthermore, glucocorticoids are incompletely effective in a number of disease settings, leading to the concept of “steroid-resistant” diseases.

Method used

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  • Novel Methods for the Treatment of Inflammatory Diseases
  • Novel Methods for the Treatment of Inflammatory Diseases
  • Novel Methods for the Treatment of Inflammatory Diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-1,3-dioxolane (Compound 1)

[0242]

[0243]A mixture of 3-methyl-p-hydroxybenzaldehyde (05 g, 3.6 mmol), ethylene glycol (0.34 g, 5.5 mmol) and p-toluenesulfonic acid (0.07 g, 0.36 mmol) in toluene was heated under reflux. After 24 h, the reaction mixture was cooled to room temperature, TLC showed no starting material. The toluene was removed in vacuo and saturated solution of sodium hydrogen carbonate (20 ml) was added to the residue, which was then extracted with ethyl acetate (3×20 ml). The organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was then recrystallised from an ethyl acetate and hexane mixture to give the product as a brown solid in 24% yield.

[0244]1H NMR (CDCl3): 2.21 (s, 3H), 3.62 (t, 2H, J=4.5 Hz), 3.70 (t, 2H, J=4.2 Hz), 3.81 (t, 2H, J=4.7 Hz), 4.42 (t, 2H, J=4.7 Hz), 6.74 (d, 1H, J=8.4 Hz), 7.21 (d, 1H, J=8.4 Hz) and 7.78 (s, 1...

example 2

Preparation of 2-(2-hydroxyethoxy)-2-(4-hydroxyphenyl)-1,3-dioxolane (Compound 2)

[0246]

[0247]To a solution of p-hydroxybenzaldehyde (1 g, 8.18 mmol) in anhydrous toluene (100 mL) was added ethylene glycol (0.68 mL, 12.28 mmol), pyridinium toluene sulphonate (0.2 g, 0.88 mmol) and p-toluene sulphonic acid monohydrate (0.16 g, 0.88 mmol). The solution was refluxed overnight before concentrating the solvent to furnish an amber gum. Saturated sodium bicarbonate (50 mL) was then added to the reaction mixture, and extracted with ethyl acetate (3×50 mL). The organic extracts were dried over magnesium sulphate, filtered, and concentrated to furnish a dark brown gum. The gum was chromatographed on silica (ether / methanol, 9.5:0.5) to furnish the title compound as a dark brown solid (173 mg, 9%).

[0248]1H NMR (CDCl3): 7.88 (d, 2H, 2×ArCH, J 8.7 Hz), 7.49 (bs, 1H, phenolic hydroxyl), 6.82 (d, 2H, 2×ArCH, J 8.7 Hz), 4.46, 3.84 (2×appt, 2×2H, 2× ethoxy CH2, Jvic 4.5 Hz), 3.74 (m, 2H, dioxolan CH2)...

example 3

Preparation of 2-(2-hydroxyethoxy)-2-(3-bromo-4-hydroxy-5-methylphenyl)-1,3-dioxolane (Compound 3)

[0250]

[0251]A mixture of compound 1 (109 mg; 0.4 mmol), N-bromosuccinimide (80 mg; 0.4 mmol) and AIBN (7.3 mg; 0.045 mmol) in dry carbon tetrachloride was refluxed for 5 hrs, TLC did not show any of the starting material. The reaction mixture was cooled to room temperature and then concentrated to dryness. The residue was dissolved in ethyl acetate (2×10 ml). The clear solution was washed with distilled water (5×10 ml), dried over anhydrous Na2SO4 and evaporated to dryness. This gave a 47% yield of compound 3.

[0252]1H NMR (CDCl3): 2.32 (s, 3H), 3.65 (t, 2, J=4.4 Hz), 3.74 (t, 2H, J=4.3 Hz), 3.83 (t, 2, J=4.7 Hz), 4.46 (t, 2H, J=4.8 Hz), 7.80 (s, 1H) and 8.02 (s, 1H).

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Abstract

Methods of inhibiting the cytokine or biological activity of Macrophage Migration Inhibitory Factor (MIF) comprising contacting MIF with a compound of formula (I) are provided. The invention also relates to methods of treating diseases or conditions where MIF cytokine or biological activity is implicated comprising administration of compounds of formula (I), either alone or as a part of combination therapy. Novel compounds of formula (I) are also provided for.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to the treatment of diseases or conditions resulting from cellular activation, such as inflammatory or cancerous diseases or conditions. In particular, the invention relates to the use of phenyl substituted cyclic 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.BACKGROUND TO THE INVENTION[0002]MIF is the first identified T-cell-derived soluble lymphokine. MIF was first described as a soluble factor with the ability to modify the migration of macrophages(1). The molecule responsible for the biological actions ascribed to MIF was identified and cloned in 1989(2). Initially found to activate macrophages at inflammatory sites, it has been shown to possess pluripotential actions in the immune system. MIF has been shown to be expressed in human diseases which include inflammation...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A01N43/56C07D317/34C07D277/04C07D317/30C07D317/20C07D317/16C07D231/12C07D213/69C07D339/06C07D319/06A61K31/357A61K31/426A61K31/4418A61K31/385A61K31/56A61P29/00A61P35/00A61P19/02A61P9/10A61P27/02A61P11/06A61P35/02A61P3/10A61P25/28A61P1/00A61P17/00A61K31/085A61K31/39A61K31/415C07C43/225C07D233/02C07D239/04C07D251/04C07D263/10C07D263/12C07D317/12C07D317/22C07D327/04C07D327/06C07D405/12C07D411/10C07D417/10
CPCC07C43/225C07D417/10C07D231/12C07D233/02C07D239/04C07D251/04C07D263/10C07D263/12C07D277/04C07D317/12C07D317/16C07D317/20C07D317/22C07D317/30C07D317/34C07D319/06C07D327/04C07D327/06C07D339/06C07D405/12C07D411/10C07D213/69A61P1/00A61P1/04A61P1/16A61P3/10A61P5/14A61P7/00A61P9/00A61P9/10A61P11/00A61P11/02A61P11/06A61P11/08A61P13/12A61P15/00A61P17/00A61P17/02A61P17/06A61P19/02A61P19/04A61P19/06A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/04A61P25/28A61P27/02A61P27/12A61P29/00A61P29/02A61P31/04A61P33/06A61P35/00A61P35/02A61P35/04A61P37/06A61P37/08A61P43/00
Inventor MORAND, ERIC FRANCISISKANDER, MAGDY NAGUIBSKENE, COLIN EDWARD
Owner CORTICAL PTY LTD
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