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Pyrrolidines

A compound and hydrate technology, applied in the direction of effective components of heterocyclic compounds, organic chemistry, drug combination, etc., can solve the problems of insufficient efficacy and selectivity in medical treatment, etc.

Inactive Publication Date: 2011-10-05
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Known EP2 antagonists include AH6809 (Pelletier et al., 2001), but neither potency nor selectivity is sufficient to make it suitable for medical treatment

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0366] Example 1: 3-(4'-Cyano-biphenyl-4-yloxymethyl)-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid (enantiomer body 1)

[0367]

[0368] Sodium trimethylsilanolate (72.1 g) and water (7.72 ml, 428.6 mmol) were added to the stirred 3-(4'-cyano-biphenyl-4-yloxymethyl)-1-(4 -Methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 28a) (207.7 g, 428.6 mmol) in acetonitrile (2090 mL). The resulting mixture was stirred at room temperature (RT) for 18 hours. The reaction mixture was filtered and the solid was partitioned between ethyl acetate (2000 mL) and aqueous hydrogen chloride (2000 mL, 2M). The organic layer was washed with water (1000 mL), then concentrated under reduced pressure to give a pale orange foam. Recrystallization twice sequentially from ethyl acetate (700 mL) and isopropanol (700 mL) afforded the title compound (107.2 g, 55%) as a white solid.

[0369] 1H NMR (400MHz, DMSO d-6) δppm 1.89-2.05(m,1H), 2.15-2.19(m,1H), 3.40-3.53(m,3H)...

Embodiment 2

[0372] Example 2: 3-(4'-Cyano-biphenyl-4-yloxymethyl)-1-(4-fluoro-benzoyl)-pyrrolidine-3-carboxylic acid (Enantiomer 1 )

[0373]

[0374] Lithium hydroxide (16 mg, 0.67 mmol) was added to stirred 3-(4'-cyano-biphenyl-4-yloxymethyl)-1-(4-fluoro-benzoyl)-pyrrolidine - Ethyl 3-carboxylate (see Preparation 29, peak 2) (105 mg, 0.22 mmol) in ethanol (1 mL) and water (1 mL). The resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure to remove ethanol and the residue was partitioned between ethyl acetate (5 mL) and 2M aqueous HCl (5 mL). The organic layer was washed with brine (5 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. Recrystallization from isopropanol (2.5 mL) gave the title compound (76 mg, 77%) as a white solid.

[0375] LCMSRt 3.06 min, ES m / z 445 [MH] +

[0376] This method is hereinafter referred to as hydrolysis method B.

Embodiment 3

[0377] Example 3: 3-(4-(5-Cyanopyridin-2-yl)phenyloxymethyl)-1-(2-methoxybenzoyl)-pyrrolidine-3-carboxylic acid (enantio Isomer 1)

[0378]

[0379] Potassium trimethylsilanolate (14 mg, 0.10 mmol) was added to the stirred 3-[4-(5-cyano-pyridin-2-yl)-phenoxymethyl]-1-(2-methoxy yl-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 43, peak 1) (40 mg, 0.08 mmol) in tetrahydrofuran (5 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and the residue was partitioned between ethyl acetate (5 mL) and 2M aqueous HCl (5 mL). The organic layer was washed with brine (5 mL), then concentrated under reduced pressure to give a colorless gum. The residue was purified by silica gel column chromatography, which was successively eluted with ethyl acetate and methanolic ammonia solution to give the title compound (18 mg, 48%) as a white solid.

[0380] LCMSRt 2.79 min, ...

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PUM

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Abstract

This invention relates to a class of pyrrolidine compounds of formula (I), and pharmaceutical ly acceptable derivatives thereof, to their use in med icine, to compositions containing them, and to processes for their preparation. It also relates to intermediates used in the preparation of such compounds and derivatives. In particular the compounds of formula (I) are useful for the treatment of EP2-mediated conditions, such as endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome, polycystic kidney disease and polycystic ovarian syndrome.

Description

technical field [0001] The present invention relates to certain pyrrolidine compounds, as well as their pharmaceutically acceptable derivatives, their application in medicine, compositions containing them and their preparation methods. The present invention also relates to intermediates useful in the preparation of such compounds and derivatives. [0002] The compound is preferably prostaglandin E 2 (PGE 2 ) receptor-2 (also known as EP2 receptor) antagonist. More preferably, the compound is directed against DP1 (prostaglandin D1 receptor) and / or EP4 (prostaglandin E receptor). 4 (PGE 4 ) receptor-4) selective EP2 antagonist. Most preferably, the compound is an EP2 antagonist selective for both DP1 and EP4. In particular, the present invention relates to a class of pyrrolidine compounds useful in the treatment of disease states mediated by EP-2, such as endometriosis, uterine fibroids (leiomyomas), menorrhagia, uterine glands Myopathy, primary and secondary dysmenorrhea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07D401/12C07D403/12A61K31/40A61P43/00
CPCC07D403/12C07D207/16C07D401/12A61P13/12A61P15/00A61P25/00A61P29/00A61P43/00A61P5/24A61K31/40
Inventor 凯文.N.达克詹姆斯.E.J.米尔斯萨拉.E.斯克雷特
Owner PFIZER INC
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