181227-46-3Relevant articles and documents
Method for preparing D-indanyl glycine
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Paragraph 0116-0117; 0119; 0129, (2018/04/01)
The invention discloses a method for preparing D-indanyl glycine. The method specifically comprises the following steps: dissolving 2-indan aldehyde, R-2-hydroxylamino-2-phenylethanol in a mixed solution of ethanol and water or an organic solvent A, and stirring at the temperature of 10-40 DEG C to be completely reacted so as to obtain a compound I; dissolving the obtained compound I and trimethylsilyl cyanide in an organic solvent B, reacting at the temperature of 0-70 DEG C in the presence of a catalyst A for 1-8 hours so as to obtain a compound II; mixing the obtained compound II and an acid, and carrying out a hydrolysis reaction at the temperature of 30-120 DEG C for 1-10 hours so as to obtain a compound III; and dissolving the obtained compound III in an organic solvent C, adding a catalyst B, carrying out an atmospheric hydrogenation reaction at the temperature of 40-60 DEG C for 4-12 hours, and filtering the obtained product to remove the catalyst B, thereby obtaining the D-indanyl glycine. The method disclosed by the invention has the advantages of mild reaction conditions, easy and convenient operation, high atom utilization rate, environmental friendliness, low production cost and the like, and is a novel method for preparing the D-indanyl glycine.
Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: Synthesis, pharmacokinetics, and in vivo potency
Borthwick, Alan D.,Liddle, John,Davies, Dave E.,Exall, Anne M.,Hamlett, Christopher,Hickey, Deirdre M.,Mason, Andrew M.,Smith, Ian E. D.,Nerozzi, Fabrizio,Peace, Simon,Pollard, Derek,Sollis, Steve L.,Allen, Michael J.,Woollard, Patrick M.,Pullen, Mark A.,Westfall, Timothy D.,Stanislaus, Dinesh J.
experimental part, p. 783 - 796 (2012/03/11)
A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R, 6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pKi > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′- pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pKi = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.
2,5-Diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics
Borthwick, Alan D.,Davies, Dave E.,Exall, Anne M.,Livermore, David G.,Sollis, Steve L.,Nerozzi, Fabrizio,Allen, Michael J.,Perren, Marion,Shabbir, Shalia S.,Woollard, Patrick M.,Wyatt, Paul G.
, p. 6956 - 6969 (2007/10/03)
A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pKi > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2′,4′-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pKi = 8.9) that has > 1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR10 = 0.44 mg/kg iv).
