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6-substituted phenoxychroman carboxylic acid derivatives

A substituent, phenyl technology, applied in the field of novel compounds

Inactive Publication Date: 2013-09-25
ARRAY BIOPHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ramatroban was originally developed as a thromboxane A2 (TP) receptor antagonist but has shown unexpected clinical activity in allergy that cannot be readily explained by its activity against TP

Method used

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  • 6-substituted phenoxychroman carboxylic acid derivatives
  • 6-substituted phenoxychroman carboxylic acid derivatives
  • 6-substituted phenoxychroman carboxylic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0590] DP-2 binding inhibition assay

[0591] The coding sequence for human DP2 was introduced into the human leukemia cell line K562 by electroporation and stable clones expressing DP2 were obtained by limiting dilution followed by staining of the cell surface with a rat monoclonal antibody specific for human DP2. Membranes were prepared from one of these DP2 expressing clones and used to determine the ability of compounds of the invention to inhibit the binding of prostaglandin D2 (PGD2) to its receptor DP2 by the following procedure in the presence of one or more of the following serum protein concentrations: The concentration is 0.1% BSA, 1% HSA or 4% HSA. Cell membranes (1.25 μg / well for 0.1% BSA and 6 μg / well for 1% or 4% HSA) were mixed with vitrified 96-well U-bottom polypropylene plates. 3 H-labeled PGD 2 and various concentrations of test compounds in 150 microliters of binding buffer (50mM Tris-HCl (pH7.4), 40mM MgCl 2 , 0.1% fetal bovine serum albumin, 0.1% NaN...

Embodiment B

[0602] Mouse model of allergic rhinitis

[0603] Allergic rhinitis (AR) is the most common form of atopy, with an estimated prevalence of 5% to 22% (Naclerio, R.M., N. Engl. J. Med. 1991, 325:860-869) , which results in huge associated costs for treatment. Typical symptoms of AR in human patients are well known, mainly sneezing and nasal congestion (Corrado O.J., et al., Br.J.Clin.Pharmacol.1987, 24:283-292; Mygind N and Anggard A.Clin Rev. Allergy, 1984, 2:173-188). The three main causes of nasal congestion are considered to be the direct result of dilation of volume vessels in the nasal septum and turbinates, edematous swelling of the nasal membranes, and secretions (Sherwood J.E., et al.J. Allergy Clin. Immunol., 1993, 92:435- 441; Juliusson S. and Bende M., Clin Allergy 1987, 17: 301-305; Mygind N. et al., Eur J Respir Dis Suppl. 1987, 153: 26-33; Gawin A. Z., et al., J Appl Physiol .1991, 71:2460-2468).

[0604] Nasal reactivity in AR has been demonstrated to occur ...

preparation example 1

[0614] 4 - (6 - chlorine - 4 - (Ethoxycarbonyl)chroman - 7 - oxy)benzoic acid

[0615]

[0616] Step A: Preparation of 3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one: Trifluoromethanesulfonic acid (500 g, 3.33 mol) was charged to 2 L of 4- Neck round bottom flask and cool the contents of the flask to below 10°C. 4-Chlororesorcinol (100 g, 0.69 mol) was added in portions over 20-30 minutes, maintaining the temperature at 4-8 °C. The reaction mixture was stirred at or below 10°C until a clear solution formed (40 minutes). 3-Chloropropionic acid (78.8 g, 0.73 mol) was heated until melted and then added dropwise in liquid form to the bottle over 45 minutes maintaining the temperature at or below 10°C. The reaction mixture was stirred at or below 10°C for an additional 10 minutes, then slowly heated to 50-55°C and maintained at this temperature for 6 hours. The reaction mixture was cooled to ambient temperature and added dropwise to water (1.1 L) contained in a 3...

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Abstract

Provided herein is a method of treating an allergic inflammatory disease selected from asthma, dermatitis, allergic rhinitis, urticaria, anaphylaxis, angioedemea, allergies, contact hypersensitivity, drug hypersensitivity, and allergic conjunctivitis in a mammal, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, to said mammal in need thereof, wherein A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 are as defined herein.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutical compositions comprising the compounds of the invention, processes for the preparation of the compounds of the invention and the use of the compounds of the invention in therapy. More specifically, the present invention relates to certain 6-substituted phenoxychroman carboxylic acid derivatives, which are useful in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and by prostaglandin D 2 (PGD 2 ) mediated other inflammatory diseases. Background technique [0002] DP2 is a G protein-coupled receptor that is selectively expressed on cell types that mediate allergic inflammation and include mast cells, basophils, eosinophils, and Th2 cells and There is increasing evidence that DP2 plays an important role in the pathophysiology of allergy (Hirai et. al., Journal of Experimental Medicine (2001) 193:255-261). Endogenous ligands for DP2 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/04C07D405/12C07D407/12A61K31/353A61P29/00
CPCC07D311/04C07D407/12C07D405/12C07D311/58A61P11/02A61P11/06A61P17/00A61P29/00A61P37/00A61P37/08C07D311/20C07D311/02A61K31/352
Inventor 劳伦斯.E.伯吉斯克里斯托弗.T.克拉克亚当.库克克里斯托弗.P.科雷特罗伯特.K.德莱尔乔治.A.多尔蒂凯文.W.亨特托德.罗莫夫甘吉约克.金
Owner ARRAY BIOPHARMA INC
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