Quinoline Derivatives as CRTH2 Antagonists

a technology of derivatives and quinolines, applied in the field of quinoline derivatives, can solve the problems of limited use and low efficacy of these agents

Inactive Publication Date: 2007-08-23
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally however, the usefulness of these agents is limited by side effects and low efficacy.

Method used

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  • Quinoline Derivatives as CRTH2 Antagonists
  • Quinoline Derivatives as CRTH2 Antagonists
  • Quinoline Derivatives as CRTH2 Antagonists

Examples

Experimental program
Comparison scheme
Effect test

synthesis examples

[0503] The following examples illustrate, without limiting it, the synthesis of particularly active compounds of formula (I) according to the invention.

[0504]1H-NMR spectra were recorded at 400 MHz. The residual solvent peak, usually chloroform (δH 7.27 ppm) or DMSO (δH 2.5 ppm) was used as internal shift reference. Analytical HPLC was run on a DIONEX Summit equipped with a diode array detector, using a Kromasil C-18 reversed-phase column and eluting with the following general system: acetonitrile with 0.1% v / v of acid formic in water with 0.1% v / v of acid formic (5:95 to 95:5 in a 13 minutes gradient). LC / MS studies were run on a Hewlett-Packard HPLC 1100 coupled to a Micromass mass spectrometer.

[0505] HPLC: the purity was obtained at 214 nm, and expressed as a percentage of areas (are of the considered peak vs total of the peak areas).

Preparation of Intermediates

Intermediate A

Cis-N-(2-Methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-phenyl-acetamide

[0506] Intermediate A correspo...

example 1

Cis-N-[2-Methyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide

[0545] R1: phenyl, R2: CH3, R3: thien-2-yl, R4: CH3, R5: H, R6: H, R7: H, R8: H.

[0546] To a solution of intermediate A (0.1 g), diisopropyl ethyl amine (0.05 g) in dioxane (1 ml), was added 2-thiophencarbonyl chloride (0.057 mg), under stirring, at room temperature for 3 hours. Then dichloromethane (2 ml) and water (2 ml) were added. The organic layer was separated and the solvent was removed under reduce pressure. The crude compound was crystallized in diethyl ether, filtered and dried to give a white solid (0.055 g, 39.6% yield).

[0547]1H NMR [CDCl3]: d 7.4-7.2 (m, 8H), 7.05 (m, 1H), 6.85 (t, 1H), 6.75 (t, 1H), 6.7 (d, 1H), 5.5 (m, 1H), 4.7 (m, 1H), 2.3 (m, 1H), 2.0 (s, 3H), 1.6 (s, 1H), 1.1 (d, 3H).

[0548] HPLC: rT: 10.15, 100% purity

[0549] MS positive ESI: m / z (m+H)+=391

example 2

Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-phenyl-acetamide

[0550] R1: phenyl, R2: CH3, R3: phenyl, R4: CH3, R5: H, R6: H, R7: H, R8: H.

[0551] The titled compound was prepared according to protocol A, using intermediate A and appropriate reactants.

[0552]1H NMR [CDCl3]: d 7.4-7.15 (m, 12H), 6.9 (t, 1H), 6.5 (d, 1H), 5.6 (m, 1H), 4.8 (m, 1H), 2.3 (m, 1H), 2.0 (s, 3H), 1.6 (s, 1H), 1.1 (d, 3H).

[0553] HPLC: rT: 10.15, 100% purity

[0554] MS positive ESI: m / z (m+H)+=385

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Abstract

The invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the description, their use as medicament, pharmaceutical compositions containing them and processes for their preparation.

Description

FIELD OF THE INVENTION [0001] The invention relates to quinoline derivatives, pharmaceutical compositions containing them, processes for their preparation and their use as medicament. BACKGROUND OF THE INVENTION [0002] In 1999, Nagata et al identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), a novel G protein-coupled receptor (GPCR) belonging to the leucocyte chemoattractant receptor family. [0003] The CRTH2 receptor is selectively expressed from a wide variety of tissues including the brain, lung and lymphoid organs in mouse (Abe et al., Gene (1999) 227 (1):71-7). With respect to expression from immune system cells, it is reported that CRTH2 receptor is selectively expressed on Th2 cells, eosinophils and basophils, but not Th1 cells, B cells and NK cells in human (Nagata et al., FEBS Letters (1999) 459 (2): 195-9). [0004] Bauer et al., (see EP 1170594A2) identified Prostaglandine D2 (PGD2) as the endogenous ligand of CRTH2. PGD2 is released from ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/47A61K31/4706A61K31/4709A61P29/00A61P37/00C07D215/42C07D215/44C07D315/00C07D401/06C07D401/10C07D401/14C07D405/06C07D409/06C07D413/06C07D417/06C07D471/04
CPCC07D215/42C07D215/44C07D315/00C07D401/06C07D401/10C07D471/04C07D405/06C07D409/06C07D413/06C07D417/06C07D401/14A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/02A61P17/04A61P17/06A61P19/02A61P29/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/00A61P9/10
Inventor ALI AWAD, MOHAMED M.BAZIN, MARC J.FERU, FREDERICGOLDSTEIN, STEVEN W.KUHN, CYRILLE F.
Owner PFIZER INC
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