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Trpv4 antagonist

A compound and pharmaceutical technology, applied in anti-inflammatory agents, anti-bacterial drugs, anti-tumor drugs, etc., can solve the problem of decreased ability of the left ventricle to pump blood into the peripheral circulation

Active Publication Date: 2019-01-04
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

[0081] 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)

[0082]

[0083] plan 1

[0084]

[0085] Scenario 2

[0086]

[0087] Option 3

[0088]

[0089] Phase 1: 1,4-dioxaspiro[4.5]decane-7-one

[0090] 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

[0113] Example 2 - Capsule Composition

[0114] 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.

[0115] Table 1

[0116]

Embodiment 3

[0117] Example 3 - Injectable Parenteral Compositions

[0118] 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 a novel compound useful as a TRPV4 antagonist, specifically the compound 1-(((5S,7R)-3-(5-cyclopropylpyrazin-2-yl)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compound. The compound of the invention can be useful in the treatmentof a disease state selected from: atherosclerosis, disorders related to vasogenic edema, postsurgical abdominal edema, ocular edema, cerebral edema, local and systemic edema, fluid retention, sepsis,hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude inducedpulmonary edema, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis / rhinitis, asthma, cough; including acute cough, sub-acute cough and chronic cough, pulmonary hypertension, overactive bladder, cystitis, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, stroke, glaucoma, retinopathy, endometriosis, pre-term labor, dermatitis, pruritus, pruritus in liver disease, diabetes, metabolic disorder, obesity, migraine, pancreatitis, tumor suppression, immunosuppression, osteoarthritis, crohn's disease, colitis, diarrhea, intestinal irregularity (hyperreactivity / hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence.

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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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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