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Fused ring azetidinyl triazole derivatives, preparation method and application in medicine

A technology of alkyl and hydroxyl, applied in the field of medicine, can solve problems such as not showing drug effect

Active Publication Date: 2021-05-14
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GSK557296 did not show the corresponding drug effect after oral administration in Phase II clinical trials (Shinghal et.al., J.Sex Med., 10:2506-17, 2013)

Method used

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  • Fused ring azetidinyl triazole derivatives, preparation method and application in medicine
  • Fused ring azetidinyl triazole derivatives, preparation method and application in medicine
  • Fused ring azetidinyl triazole derivatives, preparation method and application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0247] 7-fluoro-4-(1-(5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazole-3-yl ) azetidin-3-yl) quinoline 1

[0248]

[0249] first step

[0250] 3-(7-Fluoroquinolin-4-yl)azetidine-1-carboxylic acid tert-butyl ester 1c

[0251] Zinc (173.54mg, 2.65mmol), iodine (112.28mg, 0.4400mmol) and tert-butyl 3-iodoazetidine-1-carboxylate 1b (250.48mg, 0.88mmol, were prepared by the well-known method "Organic Letters , 2014, 16(23), 6160-6163 "prepared) was dissolved in 30mL N,N-dimethylformamide, added, protected by argon, reacted for 1 hour, then added bis(dimethoxy Benzylacetone) palladium (405.1mg, 0.4400mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (211mg, 0.44mmol), 4-bromo-7-fluoroquine After the addition of morphine 1a (200mg, 0.88mmol, Shaoyuan), the mixture was heated and stirred at 50°C for 3 hours. The reaction solution was cooled to room temperature, distilled under reduced pressure, the organic solvent was removed by spin, and the resulting r...

Embodiment 2

[0271] 5-(3-(3-(6-fluoronaphthalen-1-yl)azetidin-1-yl)-5-(methoxymethyl)-4H-1,2,4-triazole -4-yl)-2-methoxypyridine 2

[0272]

[0273] first step

[0274] tert-butyl 3-(6-fluoro-3,4-dihydronaphthalen-1-yl)azetidine-1-carboxylate 2b

[0275] 1b (1134.58mg, 4.01mmol), iodine (39.12mg, 0.15mmol), zinc (604.65mg, 9.25mmol) were added to the reaction flask, protected by argon, and reacted for 0.5 hours, bis(dibenzylideneacetone) palladium (141.15mg, 0.15mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (73.48mg, 0.15mmol) and 4-bromo-7-fluoro-1,2- Dihydronaphthalene 2a (700mg, 3.08mmol, prepared by the known method "Chemistry-A European Journal, 2015, 21(14), 5561-5583") was added to the above reaction solution, after addition, heated at 50°C The reaction was stirred for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent s...

Embodiment 3

[0299] 1-(1-(4-(Benzo[d][1,3]dioxolan-5-yl)-5-(methoxymethyl)-4H-1,2,4-tri Azol-3-yl)azetidin-3-yl)-3-chloro-5-fluoro-1H-indole 3

[0300]

[0301] first step

[0302] tert-butyl 3-(5-fluoroindolin-1-yl)azetidine-1-carboxylate 3c

[0303] 5-Fluoroindoline 3a (2000mg, 7.44mmol) and 3-carbonylazetidine-1-carboxylate tert-butyl ester 3b (1273.16mg, 7.44mmol) were sequentially prepared using the well-known method "Organic Process Research & Development, 2015 , 19(11), 1548-1553 "prepared) was dissolved in 30mL of dichloromethane, reacted for 1 hour, then added sodium triacetoxyborohydride (3.15g, 14.88mmol) in the reaction solution, and added, React for 12 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in 50 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated ...

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Abstract

The invention relates to a condensed ring-based azetidinyl triazole derivative, a preparation method thereof and an application in medicine. Specifically, the present invention relates to a new fused ring-based azetidinyl triazole derivative represented by general formula (I), its preparation method and its pharmaceutical composition containing the derivative and its therapeutic agent, especially as an oxytocin antagonist and in the preparation of a medicament for the treatment or prevention of a disease or condition for which inhibition of oxytocin is known or can be shown to have a beneficial effect, wherein each of the general formula (I) replaces The base is the same as defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a new condensed ring-based azetidinyl triazole derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an oxytocin antagonist The use of and in the preparation of a medicament for the treatment or prevention of a disease or condition for which oxytocin inhibition is known or can be shown to have a beneficial effect. Background technique [0002] Oxytocin (OT) is a cyclic nonapeptide that is usually synthesized by the paraventricular nucleus of the hypothalamus and released via the posterior pituitary gland. OT has a wide range of physiological functions, including social bonding, sexual reproduction, childbirth, etc. OT plays a physiological role by binding to its specific receptors (oxytocin receptors; OTRs). [0003] In recent years, strong evidence has accumulated that the hormone oxytocin plays ...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/4196A61K31/397A61P15/00
CPCA61P15/00C07D401/14C07D405/14C07D409/14C07D413/14C07D401/12A61K31/4709A61K31/4439A61K31/538
Inventor 李心何威王斌张志高贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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