- Phosphinamide-directed benzylic lithiation. application to the synthesis of peptide building blocks
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N-Benzyldiphenylphosphinamides are deprotonated at the NCα position diastereospecifically upon treatment with f-BuLi in diethyl ether at low temperature. The reaction of the anions with alkyl, acyl, and tin halides, aliphatic and aromatic aldehydes, and Michael acceptors allowed installation of a variety of functional groups into the benzylic arm in excellent yields. Cleavage of the P-N linkage affords 1,2-amino alcohols and α-, β-, and γ-amino acids.
- Burgos, Pascual Ona,Fernandez, Ignacio,Iglesias, Maria Jose,Garcia-Granda, Santiago,Ortiz, Fernando Lopez
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p. 537 - 540
(2008/04/05)
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- Discovery of an orally active non-peptide fibrinogen receptor antagonist based on the hydantoin scaffold
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Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promising new class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist 44 (S 1197). Compound 44 inhibited, in a dose dependent and reversible manner, human and dog platelet aggregation as well as 125I-fibrinogen binding to ADP-activated human gel filtered platelets and isolated GP IIb/IIIa with Ki values of 9 nM and 0.17 nM, respectively. A pharmacophore mapping procedure with QXP and a 3D-QSAR analysis applying the GRID/GOLPE methodology yielded a stable, rather predictive model and revealed structural features which are important for binding. Hydrophobic substitutions both at the hydantoin nucleus and at the C-terminus increase the affinity toward the fibrinogen receptor. The crystalline ethyl ester prodrug 48 (HMR 1794) is an orally active antithrombotic agent which is a promising drug candidate for the treatment of thrombotic diseases in humans.
- Stilz,Guba,Jablonka,Just,Klingler,K?nig,Wehner,Zoller
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p. 1158 - 1176
(2007/10/03)
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- Synthesis of the Alkaloid Homaline in (+/-) and Natural (S,S)-(-) Forms, using Amination and Transamidative Ring Expansion in Liquid Ammonia
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Synthesis of the alkaloid homaline in (+/-) and natural (S,S)-(-) forms is reported.Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes is examined. (+/-)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2'-dithiodipyridine/triphenylphosphine-mediated cyclisation, and then by amination and transamidative ring expansion from N-(3-chloropropyl)-4-phenylazetidin-2-one in liquid ammonia, followed by N-methylation.Coupling through a 1,4-dihalogenobutane of either the N-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in (+/-) and meso forms. (R)-(-)-Phenylglycine was converted via (S)-β-phenyl-β-alanine into an (S)-β-lactam which was then alkylated with 1-bromo-3-chloropropane, and aminated and ring expanded in liquid ammonia.Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, gave (S,S)-(-)-homaline identical with the natural material.
- Crombie, Leslie,Haigh, David,Jones, Raymond C. F.,Mat-Zin, Ab. Rasid
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p. 2047 - 2054
(2007/10/02)
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- Cyclic diones
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A 2-benzoylcyclic-1,3-dione derivative of the formula: STR1 wherein X represents methylene, oxygen, sulphur or --NR4 --, Y represents --C(R5) (R6)-- or oxygen, R1 represents hydrogen or alkyl optionally substitu
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