TRPV4 antagonist

A compound and pharmaceutical technology, used in anti-inflammatory, anti-bacterial, anti-tumor drugs, etc., can solve problems such as the decline in the ability of the left ventricle to pump blood into the peripheral circulation

Active Publication Date: 2021-12-07
GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Reduced ejection fraction and / or dilation of the left ventricle indicates that heart failure has resulted in a reduced ability of the left ventricle to pump blood into the peripheral circulation

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Preparation: 1-(((5S,7R)-3-(5-cyclopropylpyrazin-2-yl)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5] Decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Compound A)

[0083]

[0084] plan 1

[0085]

[0086] Scenario 2

[0087]

[0088] Option 3

[0089]

[0090] Phase 1: 1,4-dioxaspiro[4.5]decane-7-one

[0091] Cyclohexane-1,3-dione (500g, 4459mmol), A solution of molecular sieves (500 g, 4459 mmol) and p-toluenesulfonic acid (254 g, 1338 mmol) in anhydrous ethylene glycol (2 L) was stirred at room temperature under nitrogen for 4 hours. The reaction mixture was washed with saturated NaHCO 3 The solution (1 L) was diluted to adjust to basic pH, and the basic mixture was extracted with ethyl acetate (3 X 1 L). The combined organic extracts were washed with brine solution (500ml) and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to give the title compound (280 g, 1732 mmol, 38.8% yield) as a yellow liquid. LCMS (m / z) 1...

Embodiment 2

[0114] Example 2 - Capsule Composition

[0115] Oral dosage forms for administration of the present invention are prepared by filling standard two-part hard gelatin capsules with the ingredients and proportions shown in Table 1 below.

[0116] Table 1

[0117]

Embodiment 3

[0118] Example 3 - Injectable Parenteral Compositions

[0119] The injectable form for administration of the present invention is prepared by adding 1.7% by weight of 1-(((5S,7R)-3-(5-cyclopropylpyrazin-2-yl)-7-hydroxy-2-oxy Generation-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (compound A) in 10% by volume of propylene glycol aqueous solution Prepared by stirring.

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Abstract

The present invention relates to novel compounds useful as TRPV4 antagonists, in particular compound 1-(((5S,7R)-3-(5-cyclopropylpyrazine-2-yl)-7-hydroxyl-2-oxo Generation-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile, its pharmaceutically acceptable salts and Pharmaceutical compositions of compounds.

Description

technical field [0001] The present invention relates to novel compounds useful as TRPV4 antagonists, in particular the compound 1-(((5S,7R)-3-(5-cyclopropylpyrazin-2-yl)-7-hydroxyl-2-oxo Generation-1-oxa-3-azaspiro[4.5]decane-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile, its pharmaceutically acceptable salts and the Pharmaceutical compositions of compounds. 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 its polytypic activation nature, TRPV4 also acts through a mechanism involving phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid production (Vriens et al., 2004. Proc Natl Acad SciU S A101:396 -401) are activated by hypotonicity and body cell stress / stress (Strotmann et al., 2000. Nat Cell Biol 2:695-702). Furthermore, t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14A61P9/10A61K31/497
CPCA61P1/00A61P1/04A61P1/10A61P1/12A61P1/18A61P3/00A61P3/04A61P3/10A61P7/00A61P7/10A61P7/12A61P9/00A61P9/04A61P9/10A61P9/12A61P11/00A61P11/02A61P11/06A61P11/14A61P13/10A61P13/12A61P15/00A61P15/06A61P17/00A61P17/04A61P19/00A61P19/02A61P25/00A61P25/02A61P25/04A61P25/06A61P27/02A61P27/06A61P29/00A61P31/04A61P35/00A61P37/06A61P43/00C07D413/14A61K31/497
Inventor C.A.布鲁克斯P.斯托伊G.叶
Owner GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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