Die nach unterschiedlichen Methoden zugänglichen Aminobenzylthiophene (I) bzw. (VI) werden zu den Isocyanaten (II) bzw. (VII) umgesetzt, die beim Erhitzen mit PPA zu den Lactamen (III) bzw. (VIII) cyclisieren.
Syntheses of a series of enantiomerically pure, substituted analogues 7b–t of SDZ EAB 515 (7a) were described (Schemes 1 and 2). Affinites for the NMDA receptor were measured ([3H]CGP‐39653 binding assay) and competitive NMDA antagonistic potencies determined in a functional test (rat neocortical slice preparation). Structure‐activity relationships show that attachment of an OH group at position 4 of the chain‐inserted benzene ring of the biphenyl moiety and/or expansion of the angle between the planes of the two benzene rings by ortho‐substituents increase in vitro activities into the low nanomolar range.
An alternative synthesis of enantiomerically pure SDZ 220-881 (la) and SDZ EAB 515 (lb) starting from L-Z-tyrosine is described.Introduction. -Biphenyl analogues of AP7 ((2R)-2-amino-7-phosphonoheptanoic acid) such as SDZ 220-581 (la) and SDZ EAB 515 (lb) are selective competitive NMDA antagonists with high affinities for the NMDA recognition site in vitro [1][2] and with corresponding in vivo activities in various animal models [3]. Recently [I], we published a synthesis of enantiomerically pure SDZ EAB 51 5 (lb) and its substituted analogues by employing the chiral glycine derivative 3 (Scheme 1) [4]. We describe here an alternative synthesis of such compounds by starting from the readily available L-Z-tyrosine.
Syntheses of a series of enantiomerically pure, substituted analogues 7b-t of SDZ EAR 51 5 (7a) were described (Schemes I and 2). Affinities for the NMDA receptor were measured ((3H]CGP-39653 binding assay) and competitive NMDA antagonistic potencies determined in a functional test (rat neocortical slice preparation). Structure-activity relationships show that attachment of an OH group at position 4 of the chain-inserted benzene ring of the biphenyl moiety and/or expansion of the angle between the planes of the two benzene rings by ortho-substituents increase in vifro activities into the low nanomolar range.
An Alternative Synthesis of the Enantiomerically Pure Competitive NMDA Antagonists SDZ 220-581 and SDZ EAB 515.-The title compounds are synthesized starting from tyrosine derivative (I) as alternative to a method starting from a chiral glycine derivative. -(MUELLER, W.; BAENZIGER, M.; KIPFER, P.; Helv. Chim. Acta 81 (1998) 4, 729-733; Novartis Pharma AG, CH-4002 Basel, Switz.; EN)
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