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Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor

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

Inactive Publication Date: 2005-09-29
MERCK 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.
For the treatment of preterm labor, several approaches have been considered such as the use of magnesium sulfate, ethanol or therapeutic agents acting as β2 adrenergic agonists or oxytocin antagonists: With the use of magnesium sulfate, it has been observed that 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.
Therefore, there is strong evidence that interfering with the prostaglandin pathway by blocking selectively the contractile FP receptor will delay the progression of labor.

Method used

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  • Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor
  • Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor
  • Thiazolidine carboxamide derivatives as modulators of the prostaglandin f receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

General Protocols for the Solution-Phase Synthesis of 1,3-thiazolidine-2-carboxamide derivatives of general formula (I) e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide, (25)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (2R)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (2S)-3-(1,1′-biphenyl-4-ylsulfonyl)-N-[(R)-phenyl(pyridin-2-yl)methyl]-1,3-thiazolidine-2-carboxamide.

Strategy 1:

[0484] N-methyl morpholine (NMM) (3.240g, 2.5eq, 32.15 mmol) was added to a solution of a compound of general formula (VIII) (Intermediate 8, 4.50 g, 1 eq, 12.86 mmol), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid, in dry THF (100 ml) and the reaction mixture was cooled down to −25° C. To the reaction mixture was then added drop wise, over a period of 5 minutes, isobutyl chloroformate (1.84 g, 1.05eq, 13.50 mmol) in s...

example 2

3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R)-2-hydroxy-1-phenylethyl]-1,3-thiazolidine-2-carboxamide

[0490] Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (2R)-2-amino-2-phenylethanol, the title compound was obtained in 98% purity by RPLC.

[0491]1H NMR (300 MHz, CDCl3); 2.4-2.9 (m, CH2S, 2H), 3.5-3.7 (m, CH2N, 2H), 3.7-3.9 (m, CH2O, 2H), 4.9 (m, CH, 1H), 5.2 (s, CH, 1H), 7.1-7.9 (m, CH(Ar), 14H); M+(ESI+): 469.2; M−(ESI−) 467.1.

example 3

3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(R)-phenyl(2-pyridinyl)methyl]-1,3-thiazolidine-2-carboxamide

[0492] Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and (R)-phenyl(2-pyridinyl)methanamine (Intermediate 1), the title compound was obtained in 96% purity by HPLC.

[0493]1H NMR (300 MHz, CDCl3); 2.5-3.0 (m, CH2S, 2H), 3.6-4.0 (m, CH2N, 2H), 5.41 (s, CH, 0.5H), 5.42 (s, CH, 0.5H), 6.07 (m, CH, 1H), 5.2 (s, CH, 1H), 7.1-7.8 (m, CH(Ar), 16H), 7.8-7.9 (m, CH, 1H), 8.5-8.6 (m, CH, 1H); M+(ESI+): 516.3; M−(ESI−) 514.1.

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Abstract

The present invention is related to thiazolidine carboxamide derivatives of formula (II) for the treatment and / or prophylaxis of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery. G is selected from the group consisting of C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C1-C6 Alkyl cycloalkyl, C1-C6-alkyl heteroaryl, aryl, heteroaryl, C3-C8-cycloalkyl or -heterocycloalkyl, said cycloalkyl or aryl or hetetoaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups. R1 is selected from the group consisting of aryl, heteroaryl, C3-C8-cycloalkyl or -heterocyclo-alkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)cycloalkyl or aryl or heteroaryl groups. R2 is selected from the group consisting of H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, C1-C5-alkyl carboxy, C1-C5-alkyl acyl, C1-C5-alkyl alkoxycarbonyl, C1-C5-alkyl aminocarbonyl, C1-C5-alkyl acyloxy, C1-C5-alkyl acylamino, C1-C5-alkyl ureido, C1-C5alkyl amino, C1-C5-alkyl alkoxy, C1-C5-alkyl sulfanyl, C1-C5-alkyl sulfinyl, C1-C5-alkyl sulfonyl, C1-C5-alkyl sulfonylamino, C1-C5-alkyl sulfonyloxy, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, heterocycloalkyl, C1-C6-alkyl aryl, C2-C6-alkyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, or C2-C6-alkynyl heteroaryl.

Description

FIELD OF THE INVENTION [0001] This present invention is related to thiazolidine carboxamide derivatives of formula (II) for the treatment and / or prophylaxis of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery. Specifically, the present invention is related to substituted thiazolidine carboxamide derivatives for the modulation, notably the inhibition of the activity or function of the prostaglandin receptors, particularly of the prostaglandin F2α receptor. Also, the present invention is related to novel thiazolidine carboxamide derivatives of formulae (I) and (Ia). 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] In recent years, strong evidence has accumulated indicating that the hormone oxytocin plays a major role in initiating labor in mammals, notably in hu...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61K31/427A61K31/4439A61K31/454A61K31/5377A61K31/55A61P15/00A61P15/06A61P43/00C07D277/06C07D417/12C07D417/14
CPCA61K31/426A61K31/427C07D417/14C07D417/12C07D277/06Y02P20/582A61P15/00A61P15/04A61P15/06A61P43/00
Inventor PAGE, PATRICK NAXOSJORAND-LEBRUN, CATHERINEQUATTROPANI, ANNAPOMEL, VINCENTSCHWARZ, MATTHIASHAMELIN, ESTELLE
Owner MERCK SERONO SA