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Imidazo 1,2-c pyrimidinylacetic acid derivatives

A technology of pyrimidinyl acetic acid and its derivatives, which is applied in the field of pyrimidinyl acetic acid derivatives and can solve undisclosed problems

Inactive Publication Date: 2007-03-28
ACTIMIS PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, there is no disclosure of imidazo[1,2-c]pyrimidinylacetic acid derivatives having CRTH2 antagonistic activity

Method used

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  • Imidazo 1,2-c pyrimidinylacetic acid derivatives
  • Imidazo 1,2-c pyrimidinylacetic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0265] [Preparation of human CRTH2-transfected L1.2 cell line]

[0266] Human CRTH2 cDNA was amplified from human eosinophil cDNA using gene-specific primers containing restriction sites for cloning into the pEAK (Edge Biosystems) vector. The cDNA of human CRTH2 was cloned into the mammalian expression vector pEAK. Using an electroporator (Gene Pulser II, Biorad) with parameters of 250V / 1,000uF, this expression plasmid (40 micrograms) was transfected into L1.2 cells at a cell density of 1×10 7 cells / 500 μl. One day after transfection, puromycin (lug / ml, sigma) was added to the cell culture dish. Two weeks after transfection, growing cells were picked for further culture.

[0267] [Determination of Ca in human CRTH2 transfected L1.2 cell line 2+ Movement] (Trial 1)

[0268] Ca 2+ The loading buffer was configured as follows: Mix 5 microliters of Fluo-3AM (2mM DMSO solution, final concentration of 1 micromolar, Molecule Probe) and 10 microliters of Pluronic F-127 (Molecule...

Embodiment 1-1

[0295] [7-Chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidin-8-yl]acetic acid

[0296]

[0297] N,N-Diisopropylethylamine (0.127 mL, 0.73 mmol) was added to [7-chloro-5-(4-aminobenzyl)imidazol[1,2-c]pyrimidin-8-yl]acetic acid CH of a mixture of methyl ester (0.081 g, 0.243 mmol), 3,4-dichlorobenzoic acid (0.070 g, 0.365 mmol) and WSCI (0.070 g, 0.365 mmol) 2 Cl 2 (5 mL) solution. After stirring at room temperature for 20 hours, the reaction mixture was concentrated under reduced pressure to give the crude product as a thick oil, which could be purified by silica gel chromatography and washed with 30% EtOAc in CHCl 3 Solution elution, thereby obtaining [7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]-amino}benzyl)imidazol[1,2-c]pyrimidin-8-yl] Methyl acetate as a white solid (0.100 g, 82%).

[0298] Aqueous 6N HCl (0.5 mL) was added to [7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8 -yl] methyl acetate (0.100 g,...

Embodiment 2-1

[0310] [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazol[1,2-c]pyrimidin-8-yl]acetic acid

[0311]

[0312] At room temperature, [5-(4-aminobenzyl)imidazol[1,2-c]pyrimidin-8-yl]acetic acid methyl ester (17 mg, 0.06 mmol), p-trifluoromethylbenzoyl chloride (0.01 mL, 0.07 mmol) and triethylamine (0.016 mL, 0.11 mmol) in dichloromethane (1 mL) was stirred for 1 hour. The reaction was quenched with water and extracted with chloroform. The extract was washed with water and saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, chloroform:methanol, 95 / 5) to give [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazol[1,2 -c] Pyrimidin-8-yl] methyl acetate (21.5 mg, 80%) as pale yellow solid.

[0313] [5-(4-{[4-(Trifluoromethyl)benzoyl]amino}benzyl)imidazol[1,2-c]-pyrimidin-8-yl]acetic acid methyl ester (20 mg, 0.04 mmol) in methanol (1 mL) was added 1M aqueous NaOH (0.2 mL), a...

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Abstract

The present invention relates to an imidazo[1,2-c]pyrimidinylacetic acid derivative and salts thereof which is useful as an active ingredient of pharmaceutical preparations. The imidazo[1,2-c]pyrimidinylacetic acid derivative of the present invention has excellent CRTH2 (G-protein-coupled chemoattractant receptor, expressed on Th2 cells) antagonistic activity and can be used for the prophylaxis and treatment of diseases associated with CRTH2 activity, in particular for the treatment of allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis; eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis; basophil-related diseases, such as basophilic leukemia, chronic urticaria and basophilic leukocytosis in human and other mammals; and inflammatory diseases characterized by T lymphocytes and profuse leukocyte infiltrates such as psoriasis, eczema, inflammatory bowel disease, ulcerative colitis, Crohn's disease, COPD (chronic obstructive pulmonary disorder) and arthritis.

Description

technical field [0001] The present invention relates to pyrimidinylacetic acid derivatives for use as active ingredients of pharmaceutical preparations. The pyrimidyl acetic acid derivatives of the present invention have CRTH2 (G protein-coupled chemoattractant receptor, expressed on Th2 cells) antagonistic activity, and can be used to prevent and treat diseases related to CRTH2 activity, especially for the treatment of allergic reactions Diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis; eosinophil-related diseases such as Churg-Strauss syndrome and sinusitis; basophil-related diseases such as human and others Mammalian basophilic leukemia, chronic rubella, and basophilic leukocytosis; and inflammatory diseases characterized by T lymphocytes and massive leukocyte infiltration, such as psoriasis, eczema, inflammatory bowel disease, ulcerative colitis, gram Rohn's disease, CPOD (chronic obstructive pulmonary disease) and arthritis. Bac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519
CPCC07D487/04A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/04A61P17/06A61P19/02A61P27/02A61P27/14A61P29/00A61P35/00A61P35/02A61P37/08A61P43/00A61K31/519
Inventor 连泰威吉野隆佚武川由纪新谷拓哉杉本宏美凯文·B·培根克劳斯·俄拜斯
Owner ACTIMIS PHARM INC
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