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Piperazine-2,5-dione derivative, as well as preparation method and application thereof to medicine

A compound and mixture technology, applied in the field of medicine, can solve problems such as low oral bioavailability, toxic side effects, and respiratory arrest

Active Publication Date: 2019-02-05
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, some anti-oxytocin drugs have been used in clinical research. Ritodrine, ritodrine), magnesium sulfate and ethanol, but because these drugs have different degrees of toxic and side effects, such as ritodrine can cause infantile tachycardia, increased renin secretion, hyperglycemia, magnesium sulfate is higher than the treatment When the plasma concentration is in the range of 4-8mg / dL, it will cause the inhibition of cardiac conduction and neuromuscular conduction, respiratory arrest and other problems, which greatly limit the use of these drugs (Thorton, S.etal., Experimental Physiology 2001; 86,297-302 )
Atosiban is a peptide antagonist of OT and, like most peptides, has low oral bioavailability due to intestinal degradation

Method used

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  • Piperazine-2,5-dione derivative, as well as preparation method and application thereof to medicine
  • Piperazine-2,5-dione derivative, as well as preparation method and application thereof to medicine
  • Piperazine-2,5-dione derivative, as well as preparation method and application thereof to medicine

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Experimental program
Comparison scheme
Effect test

Embodiment

[0211] Compound structures were determined by nuclear magnetic resonance (NMR) or / and mass spectroscopy (MS). NMR shift (δ) in 10 -6 (ppm) is given. The mensuration of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethylsilane (TMS).

[0212] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0213] High performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatography.

[0214] Chiral HPLC analysis and determination use column CHIRALPAK IE (150*4.6mm, 5μm (with guard column).

[0215] The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel...

Embodiment 9

[0321] (3R,6R)-6-((S)-sec-butyl)-3-(2,3-dihydro-1H-inden-2-yl)-1-((6,8-dihydro-5H- Imidazo[5,1-c][1,4]oxazin-3-yl)(2-methyloxazol-4-yl)methyl)piperazine-2,5-dione 9

[0322]

[0323]

[0324] first step

[0325] (3R,6R)-6-((S)-sec-butyl)-3-(2,3-dihydro-1H-inden-2-yl)-1-(2-(3-(hydroxymethyl) Morpholine)-1-(2-methyloxazol-4-yl)-2-oxoethyl)piperazine-2,5-dione 9b

[0326] Dissolve compound 1a (380 mg, 0.74 mmol) in 5 mL of 1,4-dioxane, add N, N-carbonyldiimidazole (143.13 mg, 0.88 mmol), react at room temperature for 1 hour, add morpholin-3-yl Methanol 9a (112.03mg, 0.96mmol) was reacted at 85°C for 2 hours. After the reaction, it was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography with developer system A to obtain the title compound 9b (180 mg, 46.6%).

[0327] second step

[0328] 4-(2-((2R,5R)-2-((S)-sec-butyl)-5-(2,3-dihydro-1H-inden-2-yl)-3,6-dioxo Piperazin-1-yl)-2-(2-methyloxazol-4-yl)acetyl)morpholine-3-...

Embodiment 10

[0337] (3R,6R)-6-((S)-sec-butyl)-3-(2,3-dihydro-1H-inden-2-yl)-1-((R)-(6,8-di Hydrogen-5H-imidazo[5,1-c][1,4]oxazin-3-yl)(2-methyloxazol-4-yl)methyl)piperazine-2,5-dione 10

[0338]

[0339] Compound 9 (82 mg, 0.163 mmol) was purified by HPLC (Waters 2767-SQ Detecor2, eluent system: water, acetonitrile, 0.05% trifluoroacetic acid) to obtain the title compound 10 (22 mg).

[0340] MS m / z (ESI): 504.5 [M+1].

[0341] 1 H NMR (400MHz, CDCl 3 )δ7.82(s,1H),7.25-7.19(m,4H),6.87(s,1H),6.26(s,1H),4.91-4.82(m,2H),4.11-3.99(m,5H) ,3.97-3.79(m,2H),3.29-3.07(m,4H),2.80-2.77(m,1H),2.44(s,3H),1.26(s,1H),0.95-0.87(m,4H) ,0.67-0.63(m,3H).

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Abstract

The invention relates to a piperazine-2,5-dione derivative, as well as a preparation method and application thereof to medicine, and particularly relates to a piperazine-2,5-dione derivative shown asa general formula (I) in the description, a preparation method, a medicinal composition containing the derivative thereof, and application thereof to treatment or prevention of known diseases or diseases to which oxytocin has a beneficial effect as a therapeutic agent, particularly an oxytocin antagonist. The definition of each group in the general formula (I) is the same as the definition in thedescription. The formula (I) is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a novel piperazine-2,5-dione derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an oxytocin antagonist , for use in the treatment or prevention of a disease or condition in which inhibition of oxytocin is known or shown to have a beneficial effect. Background technique [0002] Oxytocin (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] Concentrations of OT receptors correlate with spontaneous uterine activity, and human myometrial oxytocin receptor mRNA levels during ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D498/04C07D413/06C07D413/14A61K31/4985A61K31/5383A61K31/496A61K31/5377A61P15/06
CPCA61P15/06C07D413/06C07D413/14C07D487/04C07D498/04Y02P20/55
Inventor 李心张志高谢志超贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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