87489-99-4Relevant academic research and scientific papers
Acyloxymethyl as a drug protecting group: Part 4. The hydrolysis of tertiary amidomethyl-ester prodrugs of carboxylic acid agents
Iley, Jim,Moreira, Rui,Calheiros, Teresa,Mendes, Eduarda
, p. 1634 - 1639 (2007/10/03)
Purpose. Novel tertiary amidomethyl esters were synthesized and evaluated as potential prodrugs of carboxylic acid agents. Methods. The hydrolyses of the title compounds in buffer solutions and in plasma were studied by UV spectroscopy and HPLC. Results.
Acyloxymethyl as a drug protecting group. Part 3. Tertiary O-amidomethyl esters of penicillin G: Chemical hydrolysis and anti-bacterial activity
Moreira, Rui,Calheiros, Teresa,Cabrita, Jose,Mendes, Eduarda,Pimentel, Madalena,Iley, Jim
, p. 70 - 75 (2007/10/03)
Purpose. O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. Methods. Their hydrolysis in aqueous buffers containing 20% (v/v) of acetonitrile was investigated by HPLC. Results. A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that p-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself. Conclusions. Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted β(1g) value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pK(a) > 4.
Acyloxymethyl as a Drug Protecting Group. Kinetics and Mechanism of the Hydrolysis of N-Acyloxymethylbenzamides
Iley, Jim,Moreira, Rui,Rosa, Eduarda
, p. 563 - 570 (2007/10/02)
Acyloxymethyl derivatives of secondary and tertiary amides undergo hydrolysis via acid-catalysed, base-catalysed and pH-independent processes.The pH-independent pathway involves rate-limiting iminium ion formation and is characterised by the following: a Hammett ρ value for the substituent in the benzamide moiety of ca. -1.2 for both types of substrate; the absence of general-base or nucleophilic catalysis; a common benzoate ion effect; a solvent deuterium isotope effect, kobsH2O/kobsD2O, of ca. 1.6; Σ(excit.) values of -4 and -12 J k-1 mol-1 for secondary and tertiary substrates respectively; and higher reactivity of the tertiary amides over their secondary counterparts.The acid-catalysed process involves protonation of the substrate followed by iminium ion formation, and is characterised by the following: a Hammett ρ value of ca. -1.5 for the substitutent effect of the benzamide moiety; a solvent deuterium isotope effect of ca. 0.4; a monotonic rise in the pseudo-first-order rate constant kobs with increasing ; ΔS(excit.) values > 0 J K-1 mol-1; higher reactivity of the tertiary substrates over their secondary counterparts; and a value of 0.85 for the Bronsted coefficient, βlg, for the carboxylate nucleofuge.The base-catalysed hydrolysis of tertiary substrates involves normal ester hydrolysis via acyl-oxygen bond cleavage, and is characterised by a Hammett ρ value of +0.38, a solvent deuterium isotope effect, kOH-/kOD-, of 0.85, and a ΔS(excit.) balue of -96 J K-1 mol-1.The corressponding base-catalysed process for the secondary substrates involves imine formation via an E2 elimination reaction.The secondary acyloxymethylamides are some 7 * 104 times more reactive than their tertiary counterparts in the base-catalysed region.Hammett ρ values of +1.1 and +0.6 are obtained for the substituents in the base-catalysed region.Hammett ρ values of +1.1 and +0.6 are obtained for the substituents in the ester and amide moieties, respectively.Buffer catalysis is observed, and the value of ca. 0.5 for the Bronsted β coefficient identifies the amide proton as approximately 50percent transferred to the buffer species in the transition state.Heats of formation, ΔHf, calculated using the AM1 SCF MO package reveal that iminium ion formation is thermodynamically equi-energetic for cyclic and acyclic systems.Iminium ion formation from tertiary substrates is favoured by ca. 25 kJ mol-1 over the corresponding secondary analogues.
Electrochemical Models for Cytochrome P-450. N-Demethylation of Tertiary Amides by Anodic Oxidation
Hall, Larry R.,Iwamoto, Reynold T.,Hanzlik, Robert P.
, p. 2446 - 2451 (2007/10/02)
Anodic oxidation of N,N-dimethylamides in acetonitrile/water (95:5) containing NaClO4 gives the corresponding N-methylamides in high yields.N-Methyl-N-(hydroxymethyl)benzamide was isolated as an intermediate in the electrochemical N-demethylation of N,N-d
