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

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

US20100323999A1Inactive Publication Date: 2010-12-23MORAND ERIC FRANCIS +2
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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

Patent Timeline
23 Dec 2010
Publication
US20100323999A1
IPC
A61K31/56; A61K31/4184; A61K31/506; A61K31/343; C07D235/26; C07D235/28; C07D407/12; C07D403/12; C07D307/83; A61P19/02; A61P37/02; A61P35/00; A61P29/00; A61P31/04; A61P19/04; A61P35/04; A61P1/04; A61P1/16; A61P9/10; A61P25/00; A61P27/02; A61P37/08; A61P27/12; A61P19/08; A61P3/10; A61P15/08; A61P11/06; A61P19/06; A61P43/00; A61P17/02; A61P25/28; A61P11/00; A61P35/02; A61K31/57; A61K31/585; A61K31/7024; A61P5/02; A61P5/14; A61P7/00; A61P9/00; A61P13/12; A61P15/00; A61P17/00; A61P17/06; A61P17/16; A61P19/00; A61P19/10; A61P21/00; A61P21/04; A61P25/04; A61P33/06; A61P37/06; C07C43/225; C07C43/23; C07C45/00; C07C45/46; C07C59/58; C07C65/24; C07C65/28; C07C69/94; C07C205/59; C07C229/70; C07C255/37; C07C309/60; C07C309/75; C07C333/04; C07D263/58; C07D319/18; C07H13/10
CPC
A61K31/4184; A61K31/585; C07H13/10; C07D403/12; C07D319/18; C07C43/225; C07C43/23; C07C45/004
Inventors
MORAND, ERIC FRANCIS; ISKANDER, MAGDY NAGUIB