Compounds having CRTH2 antagonist activity

A compound, CH2 technology, applied in the direction of organic active ingredients, organic chemistry, medical preparations containing active ingredients, etc., can solve problems such as low efficacy and not optimal pharmacokinetic distribution

Inactive Publication Date: 2009-08-12
OXAGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, we have now found that the pharmacokinetic profiles of certain compounds are not optimal when tested in vivo and that they are not optimal in the whole blood eosinophil deformity test (which gives an indication of the possible in vivo activity of the compound) The potency is often slightly lower than the possible in vivo activity expected from in vitro binding results

Method used

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  • Compounds having CRTH2 antagonist activity
  • Compounds having CRTH2 antagonist activity
  • Compounds having CRTH2 antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Example 1: Preparation of 2-(5-fluoro-2-methyl-3-(2-(benzenesulfonyl)benzyl)-1H-indol-1-yl)acetic acid (compound 1)

[0204] Start with commercially available sodium salt of benzenesulfinate and 2-fluorobenzaldehyde.

[0205] a) Process I.(S N Ar) to produce 2-(phenylsulfonyl)benzaldehyde

[0206] To a solution of 2-fluorobenzaldehyde (5.00ml, 47.6mmol) in dimethylsulfoxide (45ml) was added benzenesulfinic acid sodium salt (8.60g, 52.4mmol), and the resulting mixture was heated to 100°C. Benzene sulfinate is dissolved by heating. The solution was heated at 100°C for 3 days. The reaction solution was cooled to room temperature, and water (50ml) was added. The mixture was extracted with ethyl acetate, the combined organic extracts were washed with saturated brine, washed with MgSO 4 Dry and concentrate in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 25% ethyl acetate:petroleum ether (40-60°C) to 33% ethyl acetate:petroleu...

Embodiment 2

[0213] Example 2: Preparation of 2-(3-(2-(4-chlorobenzenesulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid (compound 2)

[0214] Start with commercially available 2-(4-chlorophenylthio)benzaldehyde.

[0215] a) Process J. (direct oxidation) to produce 2-(4-chlorobenzenesulfonyl)benzaldehyde

[0216] To a solution of 2-(4-chlorophenylthio)benzaldehyde (2.00 g, 8.00 mmol) in dichloromethane (20 mL) was added m-chloroperoxybenzene in portions over 15 minutes at 0°C Formic acid (77% max, 5.40 g, 24.17 mmol) was then warmed to room temperature and stirred for 2 hours. Aqueous sodium metabisulfite solution was added carefully until bubbling ceased. The solution was extracted with dichloromethane, the combined organic extracts were washed with NaOH (1 N), followed by saturated brine, washed with MgSO 4 Drying and concentration in vacuo yielded a white solid (1.05 g, 3.74 mmol, 46%). δ H (300MHz, d 6 -DMSO) 10.69 (1H, s, CHO), 8.25-8.18 (1H, m, Ar), 8.07-8.00 (2H, m, ...

Embodiment 3

[0220] Example 3: Preparation of 2-(5-fluoro-3-(2-(4-fluorobenzenesulfonyl)benzyl)-2-methyl-1H-indol-1-yl)acetic acid (compound 3)

[0221] a) Process A.(S N Ar) to produce 2-(4-fluorophenylthio)benzaldehyde

[0222] in N 2 Next, to 4-fluorobenzenethiol (0.86ml, 8.06mmol) and K 2 CO 3 (2.50g, 18.12mmol) in DMSO suspension (5ml) was added 2-fluorobenzaldehyde (1.00g, 8.06mmol), and the mixture was heated at 100°C for 3 hours. The reaction solution was cooled to room temperature, and water (20ml) was added. The mixture was extracted with ethyl acetate, the combined organic extracts were washed with saturated brine, washed with MgSO 4 Drying and concentration in vacuo yielded a yellow solid (1.20 g, 5.17 mmol, 64%).

[0223] δ H (300MHz, d 6 -DMSO) 10.23 (1H, s, CHO), 7.98 (1H, dd, J 7.3 and 1.7Hz, Ar), 7.63-7.49 (3H, m, Ar), 7.45-7.32 (3H, m, Ar) and 6.88 (1H, doublet, J7.7Hz, Ar).

[0224] b) Process B. (Aldehyde protection) to produce (2-(dimethoxymethyl)phenyl)(4-fl...

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Abstract

Compounds of general formula (I) wherein R is phenyl optionally substituted with one or more halo substituents ; and their pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs are useful in orally administrable compositions for the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

Description

technical field [0001] The present invention relates to compounds for use as medicaments, to processes for the preparation of these compounds, to compositions containing them and to their usefulness in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and by prostaglandin D 2 (PGD 2 ) or other inflammatory diseases mediated by other agonists acting on CRTH2 receptors on cells (including eosinophils, basophils and Th2 lymphocytes). Background technique [0002] PGD 2 It is a kind of eicosanoid, which is a kind of chemical medium synthesized by cells in response to local tissue damage, normal stimulation or hormone stimulation or activation pathway of cells. Eicosanoids bind to specific cell surface receptors in various tissues throughout the body and mediate various effects in these tissues. Known PGD 2 Produced by mast cells, macrophages and Th2 lymphocytes, and high concentrations of PGD were detected in the airway...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10A61K31/405
Inventor R·E·阿默G·M·温P·D·约翰逊C·R·多甘
Owner OXAGEN
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