Fumio Satoh

Effect of SUN 1165, a new potent antiarrhythmic agent, on the kinetics of rate-dependent block of Na channels and ventricular conduction of extrasystoles

Effects of SUN 1165, disopyramide, lorcainide, and mexiletine were studied either on the kinetics of onset of and recovery from rate-dependent depression of maximum rate of rise of phase 0 action potential (Vmax) in isolated guinea pig papillary muscles using standard microelectrode techniques or on intraventricular conduction time of extrasystoles evoked at varied coupling intervals in anesthetized dogs. SUN 1165 and lorcainide produced a slow-developing rate-dependent block of Vmax with the rate constant of 0.12 AP-1 and 0.09 AP-1, respectively. Mexiletine also produced a rate-dependent block of Vmax, but with very rapid onset so as not to be fitted by a single exponential curve. Disopyramide produced an intermediate rate-dependent block of Vmax with the rate constant of 0.46 AP-1. The time constants for recovery from the rate-dependent block for SUN 1165, lorcainide and disopyramide were 27.3-28.2, 23.2, and 17.0 s, respectively, while that for mexiletine was 0.118 s. SUN 1165, lorcainide, and disopyramide slowed ventricular conduction time of extrasystoles at all coupling intervals of 800-250 ms. On the other hand, mexiletine slowed conduction time at short coupling intervals of 500-250 ms. These findings suggest that, like lorcainide, SUN 1165 belongs to class Ic antiarrhythmic agents, and that SUN 1165 and lorcainide as well as disopyramide with slow and intermediate kinetics and mexiletine with fast kinetics may inhibit ventricular extrasystoles conducted at long and short range of coupling intervals, respectively.

The syntheses of isoquinoline alkaloids and related compounds by biogenetic type reactions

Abstract This contribution describes the biogenetic-type syntheses of some isoquinoline alkaloids and related compounds which, without duplicating our previous review ( 1 ), is based on papers published after 1970.

Studies on the synthesis of heterocyclic compounds. Part 698. An alternative protoberberine synthesis; total synthesis of (±)-xylopinine, (±)-schefferine, (±)-nandinine, (±)-corydaline, and (±)-thalictricavine

9,10-Disubstituted protoberberines were synthesised by photolysis of the corresponding bromo-enamides in high yields. The products were converted into (±)-xylopinine, (±)-schefferine, (±)-nandinine, (±)-corydaline, and (±)-thalictricavine. Xylopinine was also synthesised, together with the corresponding styrene derivative, from the corresponding enamide under benzyne reaction conditions.

Synthesis of 2-Phenyl-2,3,4,5-tetrshydro-1-benzoxepin-5-ones

A series of 2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ones were synthesized by 2 steps from flavones through 3,4-benzo-5-oxo-2-oxabicyclo[4.1.0]heptanes.

A simple route to spiro[indene-2,1′-isoquinoline]s, a spiro[indene-2,1′-β-carboline], and hexadehydroyohimbane

1′,2,2′,3,3′,4′-Hexahydro-5,6,6′,7′-tetramethoxyspiro[indene-2,1′-isoquinolin]-1-one (13) and its 6′-benzyloxyanalogue (14) were synthesised from 3,4-dihydro-1-(1,2-dihydro-4,5-dimethoxybenzocyclobuten-1-yl)isoquinolines [(6) and (7)]. Autoxidation of the 1-(1,2-dihydrobenzocyclobuten-1-yl)-β-carboline (26) gave the spiro[indene-2,1′-β-carbolin]-1-one, which was converted photochemically into the hexadehydroyohimbane (29).

Biosynthesis of porphyrins and related macrocycles. Part 10. Vitamin B12: biochemical derivation of cobyrinic acid from uroporphyrinogen III, studies with the corresponding ring c methyl hepta-carboxylic porphyrinogen, and proof of seven intact methyl transfers

A broken-cell enzyme system is developed from Propionibacterium shermanii which converts porphobilinogen into cobyrinic acid in 7–12% yields. This system is used to demonstrate incorporation of unsymmetrically labelled uroporphyrinogen III (7) into cobyrinic acid (5) and retention of specificity of labelling is proved by degradation of (5). Comparative incorporation experiments with the ring c methyl porphyrinogen (13) show that it is 30–50 times less effective than uroporphyrinogen III as a precursor of cobyrinic acid; this finding is discussed.Double labelling with 2H and 13C is used to prove that all seven methionine-derived methyl groups of vitamin B12 are transferred intact without significant exchange of their protons with the medium; the importance of this result for the C-1 methyl group is explained.

Synthetic approach to rhoeadine-type alkaloids

The reaction of 3,4-dihydropapaveraldine [1-(3,4-dimethoxybenzoyl)-3,4-dihydro-6,7-dimethoxyisoquinoline] methiodide (2) with diazomethane gave 5-(3,4-dimethoxybenzoyl)-2,3-dihydro-7,8-dimethoxy-3-methyl-1H-3-benzazepine (5), which was converted into 5,6,7,7a-tetrahydro-2,3,9,10-tetramethoxy-7-methylindeno-[2,1-a][3]benzazepin-12-ol (3) with hot phosphoryl chloride.

Short and stereoselective construction of a key intermediate for synthesis of unsymmetrical pentacyclic triterpenes

A key intermediate, 10-ethoxy-3-methoxy-6bβ, 12bα, 14aβ-trimethyl-5,6,6aα, 6b,7,8,12b,13,14,14a-decahydropicene (1), for synthesis of pentacyclic triterpenoids has been stereoselectively synthesised; the key stage is an intramolecular cycloaddition of the o-quinodimethane (19) to give the corresponding cyclised compound (4).