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Pyrrolidine oxadiazole-and thiadiazole oxime derivatives being oxytocin receptor antagonists

a technology of oxytocin receptor and oxime, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of inconvenient agents, respiratory depression and cardiac arrest, and preterm labor

Inactive Publication Date: 2006-10-12
LAB SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the field of obstetrics, one of the most important problems is the management of preterm labor and premature birth as they represent a major cause of perinatal morbidity and mortality.
However, magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg / dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable notably when the renal function is impaired.
Ethanol is effective in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress.
Also, ethanol is assumed to have a negative impact on the fetus.
The principal drawback to the use of peptide antagonists like atosiban is the problem of low oral bioavailability resulting from intestinal degradation.

Method used

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  • Pyrrolidine oxadiazole-and thiadiazole oxime derivatives being oxytocin receptor antagonists
  • Pyrrolidine oxadiazole-and thiadiazole oxime derivatives being oxytocin receptor antagonists
  • Pyrrolidine oxadiazole-and thiadiazole oxime derivatives being oxytocin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

General Procedure for the Solution-Phase Synthesis of Pyrrolidine Oxadiazole Derivatives of General Formula I, With B=IIa (Schemes 1,11): (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime, (3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime and (3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime

[0289]

a) Protocol for the Formation of the Oxadiazole Ring

[0290] Diisopropylcarbodiimide (3.16 g, 25.17 mmol) was added to a solution of (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2, 6.50 g, 25.17 mmol) and acetamidoxime (Intermediate 7, 1.86 g, 25.17 mmol) in DCM (55 ml) and stirred overnight at room temperature (DCM-insoluble amidoximes were pre-dissolved in 15 THF, to which was added a solution of DIC and Intermediate 2 in DCM). After filtering at the pump...

example 2

(3EZ,5S)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime

[0298]

[0299] Following the general methods as outlined in Example 1 (Method B), starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and 2′-chloro [1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the title compound was isolated, after flash-chromatography, as a mixture of E- / Z-isomers as an oil in 31% yield (98.5% purity by HPLC).

[0300] Oil; 1H NMR (300 MHz, CDCl3): 2.41 (s, 3H, CH3), 2.96-3.31 (m, 2H, CH2), 3.87 (s, 3H, NOCH3), 4.31-4.59 (m, 2H, CH2), 6.03 (m, 1H), 7.30 (s, 3H, H arom.), 7.50-7.64 (m, 5H, H arom.); MS(ESI+): 411.2; MS(ESI−): 408.9.

example 3

(3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-pyrrolidinone O-methyloxime

[0301]

[0302] Following the general methods as outlined in Example 1 (Method B), starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and 2′-(trifluoromethyl) [1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the title compound was isolated, after flash-chromatography, as a mixture of E- / Z-isomers as an oil in 44% yield (88.2% purity by HPLC).

[0303] Oil; 1H NMR (300 MHz, CDCl3): 2.40 (s, 3H, CH3), 2.88-3.31 (m, 2H, CH2), 3.87 (s, 3H, NOCH3), 4.27-4.53 (m, 2H, CH2), 6.03 (m, 1H), 7.27-7.70 (m, 7H, H arom.), 7.77 (m, 1H, H arom.); MS(ESI+): 445.4; MS(ESI−): 443.1.

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Abstract

The present invention is related to pyrrolidine oxadiazole and thiadiazole derivatives for use as pharmaceutically active compounds, as well as pharmaceutical formulations containing such pyrrolidine oxadiazole derivatives. Said pyrrolidine derivatives are useful in the treatment and / or prevention of preterm labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and / or prevention of disease states mediated by oxytocin, including preterm labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation. B is a oxadiazole or thiadiazole group.

Description

FIELD OF THE INVENTION [0001] The present invention is related to new pyrrolidine oxadiazole and pyrrolidine thiadiazole derivatives, in particular for use as medicaments, as well as pharmaceutical formulations containing such pyrrolidine derivatives. Said pyrrolidine derivatives are useful in the treatment and / or prevention of preterm labor, premature birth and dysmenorrhea. Preferably, the pyrrolidine derivatives display a modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and / or prevention of disease states mediated by oxytocin, including preterm labor, premature birth and dysmenorrhea. BACKGROUND OF THE INVENTION [0002] In the field of obstetrics, one of the most important problems is the management of preterm labor and premature birth as they represent a major cause of perinatal morbidity and mortality. [0003] For the treatment of preterm labor the use of magnesium sulfate and ethanol has been suggest...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/433A61K31/4245C07D413/14C07D417/14A61K31/401A61K31/4025A61K31/4439A61K31/454A61K31/496A61P5/24A61P15/00A61P15/06A61P43/00C07D207/14C07D413/04
CPCC07D413/14C07D413/04A61P15/00A61P15/06A61P43/00A61P5/24
Inventor SCHWARZ, MATTHIASQUATTROPANI, ANNAPAGE, PATRICKTHOMAS, RUSSELL J.POMEL, VINCENT
Owner LAB SERONO SA
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