Alicyclic Alkylamines and Alkanolamines

Abstract

Alicyclic structures carrying alkylamine chains have been the subject of a number of pharmacodynamic studies,1-3 especially for their effect on blood pressure. By comparison with their aromatic prototypes, such alicyclic compounds show less activity and higher toxicity.2 Cyclohexenyl, cyclohexyl and cyclopentyl derivatives were of the same general order of lowered activity.Branching of the side chain increased duration of action, in analogy with similar effects of 2-phenylisopropylamines as compared with those of phenethylamines.These observations acquired renewed significance in the wake of Belleau's proposal4 of a working model of an adrenergic receptor site which emphasized the importance of van der Waals bonds in reinforcing the ionic linkage between the amino group and an anionic site. Obviously, a flat benzene ring may be expected to furnish a supporting attachment of 2-3 kcal/mole while a puckered, non-aromatic ring will be of much less value as a source of shortrange bonds. Three factors should influence the magnitude of these forces: (a) the size of the ring; (b) the planarity of the ring; and (c) the angle between the substituent chain and the ring. In the present work, the amino alcohols II-V were tested and compared with phenylethanolamine (I). The pressor activity of these compounds increases in the order V < IV s III < II < I.

Resistance-Modifying Agents. 8. Inhibition of O6-Alkylguanine-DNA Alkyltransferase by O6-Alkenyl-, O6-Cycloalkenyl-, and O6-(2-Oxoalkyl)guanines and Potentiation of Temozolomide Cytotoxicity in Vitro by O6-(1-Cyclopentenylmethyl)guanine

“…The failure of the 2-oxoalkyl substituent to endow the reactivity observed in a simple chemical system serves to illustrate the difficulty of rational design of compounds intended to interact with a complex biological system. With the exception of 36, which exhibited weak activity, the O 6 -(2-oxoalkyl)guanine precursors (34)(35)(36)(37) were all essentially inactive.…”

“…Burger et al . reported a low yield (15%) of 12 , following reduction of methyl 1-cyclobutenecarboxylate ( 8 ) with LiAlH 4 . We have attempted to improve this reaction.…”

“…The structures and properties of the compounds evaluated as AGT inactivators are recorded in Table 1, and their syntheses are outlined in Scheme 1. The required O 6 -alkylguanines were synthesized from 2amino-6-chloropurine, either by direct reaction with the appropriate sodium alkoxide, prepared by treating the corresponding alcohol with sodium (7, 13-21) or sodium hydride in THF (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), 30,31 or following conversion into the more reactive 2-aminotrimethylpurin-6-ylammonium chloride 32 (39)(40)(41)(42)(43). The target O 6 -(2-oxoalkyl)guanines (44)(45)(46)(47) were prepared by acid-catalyzed hydrolysis of the corresponding acetals (34)(35)(36)(37).…”

“…Initial efforts to synthesize 12 by direct LiAlH 4 reduction of the unstable 1-cyclobutenecarboxylic acid (7a), prepared by dehydrobromination of commercially available ethyl 1-bromocyclobutanecarboxylate, 33 were unsuccessful, presumably as a consequence of the poor solubility of the lithium salt of the acid in ether. Burger et al 34 reported a low yield (15%) of 12, following reduction of methyl 1-cyclobutenecarboxylate (8) with LiAlH 4 . We have attempted to improve this reaction.…”

Interaction of non-conjugated olefinic substrate analogues with dopamine β-monooxygenase: catalysis and mechanism-based inhibition

“…The final product was purified as the hydrochloride by recrystallization from ethanol/ether (20 %). {Melting point 140°C (dec.) [literature value 137-138°C (Burger et al, 1961)]; 'H n.m.r. (free amine)(C2HCl3)(8): 3.9 (t, 1H), 5.83 (s, broad, 1H), 1.0-3.06 (m, 12H); 'H n.m.r.…”