Pyrazole compounds as CRTH2 antagonists

A compound, pyrazole technology, applied in the direction of anti-inflammatory agent, drug combination, organic chemistry, etc., can solve the problem of not promoting inflammatory response and so on

Inactive Publication Date: 2013-01-16
GB007 INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In contrast, the selective DP1 agonist BW245C was unable to promote inflammatory responses such as migration or activation of Th2 lymphocytes, basophils or eosinophils (Yoshimura-Uchiyama et al., Clin Exp Allergy, 2004, 34:1283- 90; Xue et al., Immunol, 2005, 175:6531-6; Gervais et al., J Allergy Clin Immunol, 2001, 108:982-8)

Method used

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  • Pyrazole compounds as CRTH2 antagonists
  • Pyrazole compounds as CRTH2 antagonists
  • Pyrazole compounds as CRTH2 antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11

[0239] {3,5-Dimethyl-1-[4-(4-trifluoromethyl-benzoylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid

[0240]

[0241] Intermediate 1.1.1

[0242] (1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester

[0243] (1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid (1.00 g, 4.1 mmol) was dissolved in 3N methanolic HCl (7.5 mL) and stirred at room temperature for 18 hours . with NaHCO 3 The reaction mixture was neutralized with aqueous solution and extracted with dichloromethane. The organic layer was treated with MgSO 4 X was dried and concentrated under reduced pressure.

[0244] Yield: 963mg

[0245] ESI mass spectrum: [M+H] + =259

[0246] Retention time HPLC: 2.05 minutes (method A)

[0247] Intermediate 1.1.2 (via nitration)

[0248] [3,5-Dimethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid methyl ester

[0249] Under cooling, (1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (intermediate 1.1.1, 3.10 g, 12.0 mmol) was dissolved in concent...

Embodiment 11

[0266] {3,5-Dimethyl-1-[4-(4-trifluoromethyl-benzoylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid

[0267] Coupling: To [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (Intermediate 1.1.3, 85mg, 0.26mmol) To a solution in dimethylformamide (1 mL) was added 4-(trifluoromethyl)benzoic acid (62 mg, 0.32 mmol), diisopropylethylamine (90 μL, 0.53 mmol) and TBTU (94 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 18 hours. with K 2 CO 3 The reaction mixture was treated with aqueous solution (2M, 0.15 mL) and filtered through Alox B, eluting with 10% methanol in dichloromethane. Saponification: The volatiles were removed under reduced pressure and the remaining residue was treated with aqueous NaOH (4M, 0.2 mL). Via preparative reverse phase HPLC (gradient is methanol in water+0.1%NH 3 ) to purify the mixture.

[0268] Yield: 44mg

[0269] ESI mass spectrum: [M+H] + =432

[0270] Retention time HPLC: 1.94 minutes (method A) ...

Embodiment 21

[0280] {3,5-Diethyl-1-[4-(4-trifluoromethyl-benzoylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid

[0281]

[0282] Intermediate 2.1.1

[0283] [3,5-Diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-tert-butyl acetate

[0284] [3,5-Diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester was prepared according to intermediate 1.1.2, after alkylation In the reaction, (3,5-diethyl-1H-pyrazol-4-yl)-tert-butyl acetate (prepared according to WO2007 / 141267) was used instead of (3,5-dimethyl-1H-pyrazole-4 -yl)-methyl acetate.

[0285] Intermediate 2.1.2

[0286] [1-(4-Amino-benzyl)-3,5-diethyl-1H-pyrazol-4-yl]-tert-butyl acetate

[0287] [1-(4-Amino-benzyl)-3,5-diethyl-1H-pyrazol-4-yl]-acetic acid tert-butyl ester was prepared according to intermediate 1.1.3 and used in the hydrogenation reaction Intermediate 2.1.1 replaced Intermediate 1.1.2.

[0288] ESI mass spectrum: [M+H] + =344

[0289] Retention time HPLC: 1.90 minutes (method A)

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Abstract

The present invention relates to pyrazole compounds of formula (I) and pharmaceutically acceptable salts thereof having CRTH2-activity, wherein W, L1, L2, X, L3, Y, R1 and R2 are as defined in the specification and claims, to their use as medicaments and to pharmaceutical formulations, containing said compounds or containing a combination of said compounds with one or more active substances.

Description

[0001] The present invention relates to a pyrazole compound of formula (I) and a pharmaceutically acceptable salt thereof having CRTH2 antagonistic activity, [0002] [0003] where W, L 1 , L 2 , L 3 , Y, R 1 and R 2 has one of the meanings given in the description, and relates to the use of said compound as medicine; to pharmaceutical formulations containing said compound, and to pharmaceutical formulations comprising said compound in combination with one or more active substances. Background of the invention [0004] Prostaglandin D2 (PGD 2 ) is eicosanoid produced by the metabolism of arachidonic acid when inflammatory cells are stimulated by allergens, inflammatory stimulation or tissue damage. PGD 2 It is mainly released by mast cells, of which Th2 cells, dendritic cells and macrophages are secondary sources. PGD 2 is the major arachidonic acid metabolite produced by mast cells when challenged by an allergen (Lewis et al., J. Immunol. 1982, 129:1627-1631) and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12A61K31/415A61P29/00A61P37/00
CPCC07D401/06C07D405/12C07D231/12C07D401/12A61P1/00A61P1/04A61P1/18A61P11/00A61P11/02A61P11/04A61P11/06A61P11/14A61P13/12A61P17/00A61P17/06A61P19/00A61P19/02A61P21/04A61P25/00A61P27/00A61P27/02A61P29/00A61P31/00A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P7/04A61P7/06A61P9/00A61P9/04A61P3/10A61K31/415A61K31/4155A61K45/06A61K2300/00
Inventor T.奥斯特R.安德斯克维茨D.W.哈姆普莱克特C.霍恩克D.马蒂雷斯W.里斯特P.塞瑟
Owner GB007 INC
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