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Trpv4 antagonists

A technology selected from, alkyl, applied in the field of TRPV4 antagonists, can solve problems such as increasing left ventricular end-diastolic pressure and pulmonary artery blood pressure

Active Publication Date: 2019-05-21
GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Decreased ejection fraction and / or dilation of the left ventricle indicates that heart failure results in a decreased ability of the left ventricle to pump blood into the peripheral circulation, which increases the end-diastolic pressure of this left ventricle, resulting in elevated pulmonary artery pressure

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0760] 3-Chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine- 1-yl)sulfonyl)benzonitrile

[0761]

[0762] step 1: (R)-3-((5-Chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylic acid tert-butyl ester

[0763]

[0764] Dissolve (S)-tert-butyl 3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (22.2 g, 80 mmol) in DMF (300 mL) and add 5 -Chloropyridine-2-thiol (11.7g, 80mmol), then add K 2 CO 3 (16.7 g, 120 mmol). The reaction mixture thickened with stirring and was complete after 1 hour at room temperature. The mixture was poured into ice water, and extracted with 400 mL ethyl acetate / hexane (1:1 V / V). The organic extracts were washed with water (2x 400 mL), washed with MgSO 4 Dry, filter, and concentrate to give crude product. Purified by flash column chromatography (SiO 2 ), eluting with a gradient of 0-15% EtOAc / hexanes. The combined product fractions were concentrated to afford the title compound...

Embodiment 2

[0774] 3-Chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl) Sulfonyl)benzonitrile

[0775]

[0776] step 1: (R)-3-((4-Chlorophenyl)sulfanyl)-4-methylenepyrrolidine-1-carboxylic acid tert-butyl ester

[0777]

[0778] To a solution of (S)-tert-butyl 3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (8.85 g, 31.9 mmol) in DMF (177 mL) was added K 2 CO 3 (8.82g, 63.8mmol), then 4-chlorothiophenol (5.54g, 38.3mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with EtOAc (4 times). The combined organic layers were concentrated under reduced pressure, and the crude product was subjected to flash column chromatography (SiO 2 ) was purified, eluting with a gradient of 0-40% MTBE / hexane. The desired fractions were combined, concentrated under reduced pressure and dried under high vacuum to afford the title compound as a white solid (5.14 g, 49% y...

Embodiment 22

[0798] 4-(((3S,4R)-1-((2-bromo-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl) Sulfonyl)benzonitrile

[0799]

[0800] step 1: (R)-3-((4-cyanophenyl)thio)-4-methylenepyrrolidine-1-carboxylic acid tert-butyl ester

[0801]

[0802] To a 3-necked flask equipped with a mechanical stirrer and a thermocouple was added tert-butyl (S)-3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (28.8 g, 104 mmol) in DMF (300 mL). Add 4-mercaptobenzonitrile (16.9g, 125mmol), then add K 2 CO 3 (21.5 g, 156 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Additional DMF (100 mL) was added to facilitate stirring, and two additional portions of 4-mercaptobenzonitrile (4.2 g each, 31 mmoL) were added 30 min apart. H 2 Quenched with O (500 mL) and extracted with hexane / EtOAc (1:1, 2x500 mL). The combined extracts were washed with H 2 O (4x 500mL), brine (1x500mL), washed with Na 2 SO 4 Dry, filter and concentrate under red...

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PUM

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Abstract

The present invention relates to pyrrolidine sulfonamide analogs (I), pharmaceutical compositions containing them and their use as TRPV4 antagonists.

Description

technical field [0001] The present invention relates to pyrrolidinesulfonamide analogues, pharmaceutical compositions containing them and their use as TRPV4 antagonists. Background technique [0002] TRPV4 is a member of the transient receptor potential (TRP) superfamily of cation channels and is activated by heat, exhibiting its spontaneous activity at physiological temperature (Guler et al., 2002. J Neurosci 22:6408-6414). Consistent with the polytypic activation nature of TRPV4, by a mechanism involving phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid production (Vriens et al., 2004. Proc Natl Acad Sci US A 101:396- 401), TRPV4 is also activated by hypotonicity and body cell stress / stress (Strotmann et al., 2000. Nat Cell Biol 2:695-702). Furthermore, tyrosine kinase activity and protein kinases A and C may also regulate TRPV4, among other proposed mechanisms (Wegierski et al., 2009. J Biol Chem. 284:2923-33; Fan et al., 2009. J Biol Chem. Chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/48C07D401/12C07D403/12C07D417/12A61K31/40A61K31/41A61K31/426A61K31/4439A61P1/16A61P9/00A61P11/00A61P11/14A61P13/10
CPCC07D403/12C07D401/12C07D417/12C07D207/48A61P1/04A61P1/10A61P1/14A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/14A61P11/16A61P13/10A61P13/12A61P15/00A61P15/04A61P17/00A61P17/04A61P19/00A61P19/02A61P21/02A61P25/00A61P25/04A61P25/06A61P25/28A61P27/02A61P27/06A61P29/00A61P3/00A61P3/04A61P31/04A61P35/00A61P3/10A61P37/06A61P37/08A61P43/00A61P7/10A61P9/00A61P9/04A61P9/10A61P9/12A61K31/40A61K31/41A61K31/426A61K31/4439A61K31/427A61K31/506A61K31/5386A61K45/06C07D498/10
Inventor E.J.伯纳迪克C.A.布鲁克斯B.G.拉夫霍恩李鹏J.M.马修斯J.J.麦卡蒂M.R.森德L.R.特雷尔J.E.佩罗D.J.贝姆
Owner GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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