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Azetidine derivatives and their use as prostaglandin E2 antagonists

A prodrug, alkyl technology, applied in the direction of anti-inflammatory agents, medical preparations containing active ingredients, anti-tumor drugs, etc., can solve the problems of efficacy and selective discomfort medical treatment, etc.

Inactive Publication Date: 2010-03-24
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Known EP2 antagonists include AH6809, (Pelletier et al. 2001), but its potency and selectivity are less suitable for medical treatment

Method used

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  • Azetidine derivatives and their use as prostaglandin E2 antagonists
  • Azetidine derivatives and their use as prostaglandin E2 antagonists
  • Azetidine derivatives and their use as prostaglandin E2 antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0384] Example 1: 1-(4-chlorobenzoyl)-3-{[(4′-cyanobiphenyl-4-yl)oxy]methyl}azetidine-3-carboxylic acid

[0385]

[0386] 4'-Hydroxy-4-biphenylcarbonitrile (30.9 mg, 0.15 mmol) and potassium carbonate (109 mg, 0.79 mmol) were added to 1-(4- Into a stirred solution of ethyl chlorobenzoyl)-3-(chloromethyl)azetidine-3-carboxylate (50 mg, 0.15 mmol) (see Preparation 8). The resulting mixture was stirred at 130°C for 0.25 hours. Then, water (1 mL) was added and the resulting mixture was heated at 80 °C for 10 min. It was then allowed to cool before partitioning between aqueous hydrochloric acid (2M, 5 mL) and dichloromethane (5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residual brown oil was purified by HPLC (method a).

[0387] LCMS Rt 3.54 min, ES m / z 446 [M+H] +

[0388] Examples 2 to 13 were prepared according to the method described above for Example 1 from the appropriate halogenated compound of formula (II) an...

Embodiment 14a

[0397] Example 14a: 1-(4-Fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl}azetidine-3-carboxylic acid

[0398]

[0399] 2-Hydroxy-6-methoxynaphthalene (32.3 g, 0.19 mol) and potassium carbonate (51.3 g, 0.37 mol) were added to 1-(4-fluorobenzoyl )-3-(Chloromethyl)azetidine-3-carboxylic acid ethyl ester (37.1 g, 0.12 mol) (see Preparation 5). The resulting mixture was stirred at 120°C for 50 minutes. Water (50 mL) was added and the reaction mixture was heated at 80 °C for 1 h, then allowed to cool before partitioning between aqueous hydrochloric acid (2M, 1.2 L) and ethyl acetate (1.5 L). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residual brown solid was triturated with diethyl ether (1.5 L) and the resulting pink solid was collected by filtration. The pink solid was then purified by silica gel column chromatography eluting with 97.5 / 2.5 / 0.25 dichloromethane / methanol / acetic acid to provide the title compound as a pale...

Embodiment 14b

[0401] Example 14b: 1-(4-Fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl}azetidine-3-carboxylic acid

[0402]

[0403] Ethyl 1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl}azetidine-3-carboxylate (50.0 g, 114 mg mol) (see Preparation 33) was suspended in acetonitrile (500 mL), and sodium trimethylsilanolate (14.1 g, 126 mmol) and water (2.05 mL, 114 mmol) were added. The suspension was stirred at ambient temperature for 4 hours. Then, 10% (v / v) aqueous phosphoric acid solution (100 mL, 171 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour, then at 0 °C for an additional 2 hours. The precipitate was collected and washed twice with water (2x250 mL) and dried under reduced pressure to provide the title compound as a white solid in 85% yield, 39.5 g.

[0404] 1 H NMR (400MHz, CD 3 OD)δ: 3.84(s, 3H), 4.27(d, 1H), 4.42(m, 2H), 4.44(s, 2H), 4.67(d, 1H), 7.07(m, 2H), 7.20(m, 4H), 7.63(m, 2H), 7.72(m, 2H); ES m / z 410[M+H] + ...

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PUM

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Abstract

The present invention relates to a class of EP2 antagonist azetidines of general formula (I) wherein the variables and substituents are as defined herein, and especially to EP2 antagonist compounds, to their use in medicine, particularly in the treatment of endometriosis and / or uterine fibroids (leiomyomata) and to intermediates useful in their synthesis and to compositions containing them.

Description

technical field [0001] The present invention relates to a specific class of azetidine compounds and their pharmaceutically acceptable salts, solvates and prodrugs, their use in medicine, compositions containing them, their preparation methods and their use in this Intermediates in class methods. Such compounds are preferably prostaglandin E 2 (PGE 2 ) receptor-2 (also known as EP2 receptor) antagonists. More preferably, such compounds are compounds that have a relative 4 (PGE 4 ) receptor-4) selective EP2 antagonists. Optimally, such compounds are EP2 antagonists selective for DP1 and EP4. In particular, the present invention relates to a class of azetidines which should be useful in the treatment of EP2-mediated conditions such as endometriosis, uterine fibroids (leiomyomas of the uterus), menstrual bleeding, uterine Adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dyschexia, and chronic pelvic pain), chronic pelvic pain syndrome. B...

Claims

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Application Information

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IPC IPC(8): C07D205/04C07D417/14C07D403/12A61K31/397C07D403/14A61P29/00C07D405/06
CPCC07D405/06C07D417/14C07D403/12C07D205/04C07D403/14A61P11/06A61P15/00A61P15/08A61P19/00A61P29/00A61P35/00A61P43/00A61K31/397
Inventor K·N·达克S·K·耶普S·E·斯凯拉特
Owner PFIZER INC
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