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7-phenoxychroman carboxylic acid derivatives

A technology of phenyl and alkyl, applied in the field of 7-phenoxychroman carboxylic acid derivatives

Inactive Publication Date: 2014-05-14
ARRAY BIOPHARMA
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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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  • 7-phenoxychroman carboxylic acid derivatives
  • 7-phenoxychroman carboxylic acid derivatives
  • 7-phenoxychroman carboxylic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0524] DP-2 binding inhibition assay

[0525] 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: Concentrations were 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 the 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 3 ) mixed in. After 60 min incubation at roo...

Embodiment 1

[0553] 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid

[0554]

[0555] Step A: Preparation of 7-fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile: 7-fluoro-2,3-dihydrochromen-4-one (470 mg, 2.829 mmol) and ZnI 2 (45.15 mg, 0.1414 mmol) was diluted with trimethylsilyl cyanide (1.413 mL, 11.32 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (750 mg, 99.92% yield).

[0556] Step B: Preparation of 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid: 7-fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile (750 mg, 2.83 mmol) and SnCl 2 The dihydrate (2551 mg, 11.3 mmol) was diluted with glacial acetic acid (3 mL) and cone. HCl (3 mL). The reaction mixture was heated at 130 °C overnight in an oil bath....

Embodiment 2

[0564] 7-(4-(5-Chloropyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid

[0565]

[0566] Step A: Preparation of 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid: At ambient temperature, 6-cyano-7-fluoro-3,4-di Hydrogen-2H-chromene-4-carboxylate methyl ester (3.3 g, 14.0 mmol) and LiOH-H 2 O (5.89 g, 140 mmol) was stirred together in THF (25 mL) and water (25 mL) for 1 h. The reaction mixture was diluted with ether and water and filtered to remove undissolved solids. The filtrate was collected and the aqueous layer was washed with additional ether. The aqueous layer was acidified to pH 1-2, and the resulting solid was collected. The solid was then dissolved in ethyl acetate, dried, filtered and concentrated to provide the desired product (2.53 g, 81%) as a pale yellow solid.

[0567] Step B: Preparation of tert-butyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate: Making 6-cyano-7-fluoro-3,4-dihydro -2H-chromene-4-carboxylic acid was diss...

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Abstract

Compounds of Formula I: (I) in which A, A1, R1, R7a, R7b, R8 and R10 have the meanings given in the specification, are DP2 receptor inhibitors useful in the treatment of useful in the treatment and prevention of immunologic diseases, allergic diseases such as asthma, allergic rhinitis and atopic dermatitis, and other inflammatory diseases mediated by prostaglandin D2 (PGD2). The compounds of Formula I may also be useful in treating diseases or medical conditions involving the Th2 T cell via production of IL-4, IL-5 and / or IL-13.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutical compositions comprising the compounds, methods of making the compounds, and uses of the compounds in therapy. More specifically, it relates to certain 7-phenoxychroman carboxylic acid derivatives, which are useful in the treatment and prevention of immune and allergic diseases, such as asthma, allergic rhinitis and atopic dermatitis, and other Prime D 2 (PGD 2 ) mediated inflammatory disease. Compounds of formula I are also useful in the treatment of diseases or medical conditions involving Th2 T cells via the production of IL-4, IL-5 and / or IL-13. 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 Experime...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12C07D405/14C07D413/12C07D417/12A61K31/353A61P29/00
CPCC07D405/14C07D413/12C07D405/12C07D417/12A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/04A61P19/02A61P27/14A61P29/00A61P37/00A61P37/02A61P37/08
Inventor A.库克K.W.亨特R.K.得利斯尔T.罗莫夫C.T.克拉克G.金C.P.科雷特G.A.多尔蒂L.E.伯吉斯
Owner ARRAY BIOPHARMA
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