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Therapeutic Molecules and Methods-1

a technology of glucocorticoids and molecules, applied in the field of therapeutic molecules, 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 formulation, so as to enhance the effect of glucocorticoids

Inactive Publication Date: 2010-12-23
MORAND ERIC FRANCIS +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The small molecule inhibitors effectively target MIF activity, potentially reducing glucocorticoid dosages, enhancing their therapeutic effects, and making them more effective in steroid-resistant diseases, while minimizing side effects.

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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  • Therapeutic Molecules and Methods-1
  • Therapeutic Molecules and Methods-1
  • Therapeutic Molecules and Methods-1

Examples

Experimental program
Comparison scheme
Effect test

example 1

5-Methylbenzimidazol-2-one (2)

[0191]

[0192]This was prepared as described by Harvey et al (12).

[0193]A solution of urea (6.00 g, 0.1000 mol) and 3,4-diaminotoluene (1) (12.20 g, 0.0999 mol) in pentan-1-ol (40 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. After 2 hours the heating was discontinued and on cooling to room temperature a pink solid settled out. This was filtered off and recrystallised from boiling ethanol (17.98 g. in 400 mL) to give 2 crops of 5-methylbenzimidazol-2-one (2) as a pink powder. The total mass was recovered was 8.21 g (56% yield);

[0194]Rf: 0.40 (9:1 CHCl3:MeOH),

[0195]mp: 300-302° C., lit.3 mp: 297-300° C.;

[0196]1H NMR (CDCl3 / CD3OD): δ 2.12 (s, 3H, CH3), 6.63-6.70 (m, 3H, ArH);

[0197]LRESI mass spectrum: m / z 149 (100%, MH+).

example 2

Benzimidazol-2-one-5-carboxylic acid (4)

[0198]

[0199]The method described by Harvey et al (12) and used in Example 1 for the preparation of 5-methylbenzimidazol-2-one (2) was used except this preparation started with 3,4-diaminobenzoic acid (3).

[0200]Urea (1.20 g, 0.0200 mol) and 3,4-diaminobenzoic acid (3) (3.04 g, 0.0200 mol) in pentan-1-ol (10 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. The heating was discontinued after 4 hours and on cooling to room temperature, water (30 mL) was added. The pH was adjusted to 1 with conc. HCl. The resultant dark solid was filtered off, washed with further water (2×20 mL) and dried to give 3.00 g (84% yield) of benzimidazol-2-one-5-carboxylic acid (4) as a black powder,

[0201]Rf: 0.09 (9:1 CHCl3:MeOH), 0.20 (4:1 CHCl3:MeOH),

[0202]1H NMR (d6-DMSO): δ 6.98 (d, 1H, J7,6 8.1 Hz, H-7), 7.45 (d, 1H, J4,6 1.2 Hz, H-4), 7.60 (dd, 1H, H-6), 10.78 (bs, 1H, NH), 10.94 (bs, 1H, NH);

[0203]LRESI negative ion mass spectrum: m / z 1...

example 4

5 [2(1-oxy-2-hydroxyethyl)ethyl]benzimidazol-2-one-5-carboxylate (6)

[0212]

[0213]Benzimidazol-2-one-5-carboxylic acid (4) (300 mg, 1.6853 mmol) and Dowex 50W-X8(H+) resin (300 mg) were suspended in diethylene glycol (50 mL) and the mixture heated to reflux for 44 hours. The solid was filtered off and washed with methanol (3×20 mL) and the combined filtrates reduced in volume (approx 2 mL) with vacuum distillation. This residue was column chromatographed (SiO2, isocratically with 4:1 CHCl3:MeOH) to give with evaporated to dryness to give 5 [2(1-oxy-2-hydroxyethyl)ethyl]benzimidazol-2-one-5-carboxylate (6) (310 mg, 43% yield) as an off-white powder,

[0214]Rf: 0.63 (4:1 CHCl3:MeOH),

[0215]mp: 227-228° C.

[0216]1H NMR (CDCl3 / CD3OD): δ 0.88-0.92 (pseudo t, 3H, CH3), 1.33-1.43 (m, 4H, 2×CH2), 1.70-1.79 (m, 2H, CH2), 4.25-4.29 (pseudo t, 2H, CH2), 7.04 (d, 1H, J7,6 8.4 Hz, H-7), 7.44 (bs, 1H, NH), 7.55 (bs, 1H, NH), 7.66 (bs, 1H, H-4), 7.75 (dd, 1H, J6,5 1.5 Hz, H-6);

[0217]LRESI negative ion m...

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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) as defined herein, is 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 part of a combination therapy. Novel heterocyclic compounds 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 heterocyclic 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 OF 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, injury, i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/56A61K31/4184A61K31/506A61K31/343C07D235/26C07D235/28C07D407/12C07D403/12C07D307/83A61P19/02A61P37/02A61P35/00A61P29/00A61P31/04A61P19/04A61P35/04A61P1/04A61P1/16A61P9/10A61P25/00A61P27/02A61P37/08A61P27/12A61P19/08A61P3/10A61P15/08A61P11/06A61P19/06A61P43/00A61P17/02A61P25/28A61P11/00A61P35/02A61K31/57A61K31/585A61K31/7024A61P5/02A61P5/14A61P7/00A61P9/00A61P13/12A61P15/00A61P17/00A61P17/06A61P17/16A61P19/00A61P19/10A61P21/00A61P21/04A61P25/04A61P33/06A61P37/06C07C43/225C07C43/23C07C45/00C07C45/46C07C59/58C07C65/24C07C65/28C07C69/94C07C205/59C07C229/70C07C255/37C07C309/60C07C309/75C07C333/04C07D263/58C07D319/18C07H13/10
CPCA61K31/4184A61K31/585C07H13/10C07D403/12C07D319/18C07C43/225C07C43/23C07C45/004C07C45/46C07C59/58C07C65/24C07C65/28C07C69/94C07C205/59C07C229/70C07C255/37C07C309/60C07C309/75C07C333/04C07D235/26C07D235/28C07D263/58C07D307/83C07C47/575C07C49/84A61P1/04A61P1/16A61P11/00A61P11/06A61P13/12A61P15/00A61P15/08A61P17/00A61P17/02A61P17/06A61P17/16A61P19/00A61P19/02A61P19/04A61P19/06A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/04A61P25/28A61P27/02A61P27/12A61P29/00A61P3/10A61P31/04A61P33/06A61P35/00A61P35/02A61P35/04A61P37/02A61P37/06A61P37/08A61P43/00A61P5/02A61P5/14A61P7/00A61P9/00A61P9/10Y02A50/30
Inventor MORAND, ERIC FRANCISISKANDER, MAGDY NAGUIBDANYLEC, BASIL
Owner MORAND ERIC FRANCIS
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