Jacob Szmuszkovicz

Medicinal agents incorporating the 1,2-diamine functionality

The 1,2-diamine (vicinal diamine) functionality is a remarkable template which displays a broad spectrum of biological activity. For the purpose of this review, molecules possessing two nitrogen atoms separated by two carbon atoms, at least one of which being sp3-hydridized, will be considered to be 1,2-diamines. Structural units such as piperazine and imidazolidine will be included as examples of 1,2-diamines. The 1,2-diamine conformation may be found in many important compounds including antiarrhythmics, antihypertensives, antipsychotics, analgesics, antianxiety agents, local anesthetics, anticonvulsants, gastrointestinal agents, anticancer drugs, and antiparasitic agents. The number of compounds falling into the 1,2-diamine category as defined above is considerable. Consequently, this review is intended to be illustrative rather than exhaustive.

Stereocontrolled syntheses of some conformationally restricted analogs of serotonin

Abstract Syntheses of serotonin analogs 2 and 3 are described including a case of retention in the Mitsunobu reaction. An unusual stereoselectivity in a reductive amination sequence is also described. Dopamine and serotonin activity of the eight analogs has been determined.

The synthesis of 9-(1-azetidinyl)-1,2,3,4-tetrahydroacridine

Synthesis of analogue (2) of tacrine is described in which the primary amino group is replaced by the azetidine moiety. The synthesis was accomplished in two steps from the acridinone derivative 10. This involved conversion of 10 to triflate 11, followed by treatment with azetidine to give the target compound 2

U-50,488 and the к receptor: A personalized account covering the period 1973 to 1990

All clinically significant analgesics for severe pain derive from the morphine model. Morphine has provided a fertile area for medicinal chemistry research and received an additional stimulus in the 1970s with the appearance of the Opioid receptors. The background for the birth of U-50,488 is described herein. It occurred before the discovery of the K receptor and, thus, U-50,488 was classified originally as a non-μ compound, and only later as a K agonist. U-50,488 provided a succinct template for structural modifications and they are described for the period up to 1990. A description of the structural classes of K agonists is provided including a summary of K recognition sites based on known agonists.

U-50,488 and the к receptor Part II: 1991–1998

This review, Part 11, follows an earlier article, Part I, published in volume 52 of this series. Part 11 is a discussion of centrally and peripherally acting K agonists which can be considered analogs of U-50,488. Included also are three classes of K agonists which fall outside of the scope of the general structure of U-50,488. These are benzodiazepines, phenothiazines and diazobicyclonanones. The discussion also covers other pertinent topics including labelled ligands and sigma receptor.

Syntheses of 1,2-diamino and 1,2-aminoalcohol derivatives in the piperidine and pyrrolidine series as anti-amnesic agents.

Tacrine, one of the drugs available for Alzheimers disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine has been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research is a continuation of our efforts in the area of 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) (cf. ref9). A serendipitous discovery led us to the biologically active open chain analogue 9, and we proceeded to elaborate on this molecule. Overall, the compounds we prepared were poor inhibitors of acetylcholinesterase as compared to tacrine. The single exception was compound 20 which exhibited an effect comparable to that of tacrine, but only at a dose in the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 9, this compound was found to be an effective antiamnesic agent.

Syntheses of benzoquinolizidine and benzoindolizidine derivatives as anti-amnesic agents.

Tacrine, one of the drugs available for Alzheimers disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine have been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research was undertaken to produce an acetylcholinesterase inhibitor by employing 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) as templates. Thus, we aimed to achieve three goals relative to tacrine: eliminate the pyridine and quinoline moieties and render the molecule less flat. Overall, the compounds we prepared were poorer inhibitors of acetylcholinesterase compared to tacrine. The single exception was compound 6f which exhibited an effect comparable to that of tacrine, but only at a dose of the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 6b, this compound proved to be an effective anti-amnesic agent at 45 mg/kg dose.

An unusual lithium aluminum hydride reduction of an isolated olefin in a 1,2-diamine system

Das ungesattigte N-Formyl-diamin (I) reagiert mit Lithiumalanat uber diskutierte Zwischenstufen zu den beiden Reduktionsprodukten (II) und (III).

Anticonvulsants related to U-54494 prepared from cis-1,2- and cis-2,3- diaminotetralin

Abstract cis-Diaminotetralins 4 and 10 were converted in 4 steps to benzologs of the novel anticonvulsant U-54494. Attempted alkylation of 4 and 10 with 1,4-dibromobutane provided mixtures of the bis-pyrrolidino compounds and starting free bases together with the desired mono- pyrrolidino compounds 5 and 11. Treatment of these mixtures with ethyl chloroformate followed by Chromatographic separation gave the carbamates 7 and 12. Reduction of these carbamates with LiAlH4 provided the N-methylamino compounds 8 and 14. Finally, benzamide formation gave rise to the analogs of U-54494, compounds 9 and 15.

Unusual C-C cleavage during reduction of a β-aminonitroalkene

Abstract An unusual ring cleavage product 3 , a diamine, was observed during LAH reduction of β-aminonitroalkene 1 .