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A 58-year-old man was referred to our emergency room with hemodynamically unstable sustained ventricular tachycardia (VT). The morphology of the VT exhibited a left bundle branch block and inferior axis deviation. He had no past history of cardiovascular disease. Echocardiography, cardiac catheterization, cardiac biopsy, gallium scintigram, myocardial scintigram, T1,T2-weighted magnetic resonance imaging (MRI), and gadolinium-enhanced cine MRI did not detect any structural heart disease or abnormal cardiac function. However, delayed-enhancement MRI (DE-MRI) detected a focal intramural scar within the septal ventricular outflow tract. An electrophysiological study revealed a sustained VT with several morphologies and the entrainment phenomenon. Radiofrequency catheter ablation to the site corresponding to the focal scar detected by DE-MRI successfully eliminated the VT.

We studied the effect of intraatrial reentry (IAR) on initiation of orthodromic reentrant tachycardia (ORT) in 150 patients with Wolff-Parkinson-White syndrome using His-bundle recording and the atrial extrastimulus technique. IAR was initiated by premature atrial stimulation in 44 patients (29%), and it was followed by ORT in 16 patients (11%). In 8 patients (5%), IAR promoted the initiation of ORT, whereas in 5 patients (3%), IAR inhibited the initiation of ORT. These findings suggest that ORT is frequently induced following IAR. IAR, which was frequently observed during electrophysiological studies, seems to play an important role in the initiation of ORT.

Bicyclic 5-hydroxy-2-pyrrolidinones (2a - f) were synthesized with high enantioselectivity by the reduction of meso-cyclic-1,2-dicarboximides (1a - f) with lithium aluminum hydride (LiAlH 4 )-methanol (MeOH)-1,1'-bi-2-naphthol complex (BINAL-H). Treatment of 2a - f with triethylsilane (Et 3 SiH) and trifluoroacetic acid(CF 3 CO 2 H) gave optically active 2-pyrrolidinones (3a - f) in quantitative yields. For the absolute configuration correlation, 2a - d were converted into known lactones (4a - d)

A series of 2-aryl-4, 5-dihydro-1H-thieno[3, 2-e]benzimidazoles (1, 2) was prepared by condensation of 5-acylamino-4, 5, 6, 7-tetrahydrobenzo[b]thiophen-4-ones (9, 10) with ammonium acetate under azeotropic reaction conditions. Various congeners, N-methyl and N-phenyl analogues (3-5), 4, 5-dihydro-1H-thieno[2, 3-e]benzimidazoles (6), 4, 5-dihydro-1H-thieno[2, 3-g]benzoxazoles (7), and 4, 5-dihydro-1H-thieno[2, 3-g]benzothiazoles (8), were also prepared. Several compounds in this series were shown to be K+-competitive inhibitors of the gastric (H+/K+)-ATPase and more potent inhibitors than SK&F-96067, 3-butyryl-8-methoxy-4-(2-tolylamino)quinoline, on pentagastrin-stimulated acid secretion in chronic gastric fistula rats after intraduodenal administration.

Purpose: Corpus callosotomy (CC) has recently been recognized as an effective treatment for patients with intractable generalized seizures. Experimental studies also reported the same seizure-suppressive effects. We investigated the effects of sectioning the corpus callosum in models of epilepsy in cats. Methods: Acute and subacute models of epilepsy were made by the topical application of estrogen and cobalt powder, respectively, at the left anterior sigmoid gyrus (ASG). The electrocorticogram (ECoG) and steady potentials (SPs) were recorded from both sides of the anterior sigmoid gyrus and the ventrolateral (VL) nucleus of the thalamus. The spindle-like afterdischarges were elicited by direct stimulation of the cortex or VL nucleus of thalamus. The “surface negative (SN) wave” produced by pyramidal tract stimulation and recorded at the cortical surface has been identified as a reflection of postsynaptic potentials generated through recurrent inhibitory pathways (Humphrey et al. 1968). SN waves were analyzed for the assessment of the cortical inhibitory mechanisms before and after sectioning the corpus callosum. Results: Topical application of estrogen to the left ASG (acute model) induced spike-waves on both sides of the ASG and VL. The SP showed a negative shift on the same side as the estrogen application: however, no change in the SP was seen on the contralateral side. In this (acute) model, a remarkable reduction or disappearance of spike-waves on the side contralateral to estrogen application, was seen just after the sectioning of the corpus callosum. The spindle-like afterdischarges were also difficult to induce on the same side as estrogen application after callosal sectioning. Cobalt powder also induced spike-waves after topical application to the left ASG (subacute model). The spindle-like afterdischarges showed a reduction after the callosal sectioning. The SN waves gradually diminished in amplitude after topical application of cobalt powder on the same side of the ASG as the application. In the contralateral ASG, the SN waves showed a slight reduction in amplitude. These phenomena were presumably due to depression of recurrent postsynaptic inhibition caused by the topical application of the epileptogenic agents. After callosal section, the SN waves recovered in amplitude on both sides. Conclusions: These data suggest that the corpus callosum is maintaining epileptiform activity during the advanced stages of epilepsy. They also suggest that sectioning of the corpus callosum suppress epileptic activity because of recovery of cortical inhibitory mechanisms as represented by the amplitude of the SN wave.

Synthesis of 10-oxa-11-deoxyprostaglandin E1 (2b) and related compounds (2a, 17b, and 20) was successfully accomplished starting from nonanedioic acid (3). Decarboxylation of 3, 3-di-tert-butoxycarbonyl-2-(6-methoxycarbonyl) hexyl-4-butanolide (6) by heating gave predominantly trans-3-carboxy-2-(6-methoxycarbonyl) hexyl-4-butanolide (7a). Conversion of 7a into the hydroxymethyl lactone (13) and the Pfitzner-Moffatt oxidation of 13 provided trans-3-formyl-2-(6-methoxycarbonyl) hexyl-4-butanolide (14) which served as a key intermediate. The Wittig reaction of 14 with dimethyl 2-oxoheptylphosphonate gave enone (15) which was converted to 10-oxa-11-deoxy PGE1 methyl ester (16b) by NaBH4 reduction. Alkaline hydrolysis of 16b and relactonization of the resulting diacid (17b) gave 2b as crystals in a good yield.

1-Sorboyl-2-pyrrolidone was prepared from sorbic acid and 2-ethoxy-1-pyrroline using 1-methyl-2-chloropyridinium iodide as a coupling reagent. Variotin and its analogs were similarly synthesized from lactim ethers and (2E,4E,6E)-8-hydroxy-2,4,6-dodecatrienoic acids without protecting the hydroxyl group at C-8. (2E,4E,6E)-8-Hydroxy-6-methyl-2,4,6-dodecatrienal, a precursor of trienoic acid, was synthesized by the elimination of methanol from (2E,6E)-8-acetoxy-5-methoxy-6-methyl-2,6-dodecadienal prepared from the reaction of 1-trimethylsiloxy-1,3-butadiene with (2E)-4-acetoxy-2-methyl-2-octenal dimethyl acetal.

A new series of N-(1H-tetrazol-5-yl)-6-phenyl-2-pyridinecarboxamides was prepared to determine the effects of substituents on the benzene and pyridine rings on antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) assay after oral administration. One member of this series, N-(1H-tetrazol-5-yl)-4-methyl-6-[4-(methylamino)-phenyl]-2- pyridinecarboxamide (231), has an ED50 value of 0.8 mg/kg po and is 85 times more potent than disodium cromoglycate (DSCG) on intravenous administration. Further evaluation of 231 as a clinically useful antiallergic agent is in progress.

The synthesis of 11-deoxy-8, 10-diazaprostaglandin E1 (1a) starting from methyl 3-benzyloxycarbonyl-2-oxo-4-imidazolidinecarboxylate (3a) is reported. Alkylation of 3a with methyl 7-bromoheptanoate and NaH gave methyl 1-benzyloxycarbonyl-3-(6-methoxycarbonyl) hexyl-2-oxo-4-imidazolidinecarboxylate (9), which was converted into the 4-hydroxymethyl-imidazolidine derivative (10). The Moffatt oxidation of 10, and the Wittig reaction of the resulting aldehyde (11) with dimethyl 2-oxoheptylphosphonate provided an enone (12). Reduction of 12, and hydrolysis of a mixture of C15-epimeric alcohols (15) followed by re-esterification afforded 11-deoxy-8, 10-diazaprostaglandin E1 methyl ester (17a). Alkaline hydrolysis of 17a gave 1a as crystals in a good yield. The 10-methyl derivative (2a) was also synthesized. Methylation of 3a with methyl iodide and K2CO3 gave the 1-methylimidazolidine analog (7a), which was converted into methyl 3-(6-methoxycarbonyl) hexyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (20) after debenzyloxycarbonylation and alkylation with methyl 7-bromoheptanoate. Conversion of 20 into 2a was carried out by a synthetic sequence similar to that used for the elaboration of 1a.

N-Alkylthiocarbonyl tryptophan (Ia-f) and tryptamine (Ig-j) derivatives can be converted into the corresponding 3, 4-dihydro-β-carbolines (3) under mild and non-acidic conditions by use of alkylating reagents.

Various carbonyl compounds undergo the reductive dimerization to produce symmetrical olefins in high yields on treatment with low valent titanium compounds, formed in situ from TiCl4 and LiAlH4, in the presence of a tertiary amine such as 1,8-bis(dimethylamino)-naphthalene or tri-n-butylamine. This method is successfully applied to the direct synthesis of β-carotene (6) from retinal (5).

N-Alkylthiocarbonyltryptophan (2a-i) and tryptamine (2j-m) derivatives can be converted into the corresponding 3, 4-dihydro-β-carbolines (3) under mild conditions by the use of alkylating or acylating agents. The NaBH4 reduction of 1, 3-disubstituted 3, 4-dihydro-β-carbolines (3a-i) gave cis- (5) or trans-1, 2, 3, 4-tetrahydro-β-carbolines (6) with satisfactory stereoselectivity. The synthesis of optically active 3a, b and 5a, b is also described.

The decarboxylation of various 1-substituted-3, 7-dioxabicyclo[3.3.0]octane-2, 8-diones (2b-j) was in vestigated. On treatment with potassium acetate in aqueous pyridine under reflux, all the compounds (2b-j) examined were decarboxylated in high yields to give the corresponding trans-3-hydroxymethyl-4-butanolides (3b-j). The synthesis of 10-oxa-11-deoxyprostaglandin E2 (1a) from the compounds 3i and 3j is also described. The Moffatt oxidation of 3i and the Wittig reaction of the resulting aldehyde (6a) with dimethyl 2-oxoheptylphosphonate gave an enone (7a), which was converted into 10-oxa-11-deoxyprostaglandin E2 methyl ester (8a) and the C15-epimer (9a) by NaBH4 reduction. Hydrolysis and subsequent relactonization of 8a gave 1a in 88% yield. A similar treatment of 9a gave 1b in 87% yield. Using a similar sequence of reactions, 1a and 1b were also prepared from the nitrile analog 3j via 8b and 9b.

Dienoxysilanes (2) react with acetals in the presence of TiCl4 and also in the coexistence of TiCl4 and Ti(OiPr)4 to give δ-alkoxy-α,β-unsaturated aldehydes (3–5) in good yields. In the presence of 1,8-diazabicyclo[5.4.0] undec-7-ene or 1,5-diazabicyclo[4.3.0]non-5-ene and molecular sieves 3A or 4A, the elimination reaction of δ-alkoxyl group of α,β-unsaturated aldehydes (3–5) proceeds smoothly to afford the corresponding polyenals in good yields.

New dilactones (2a-j, 3a, and 3b) having a 3, 7-dioxabicyclo [3.3.0] octane-2, 8-dione system (1f) have been prepared starting from diethyl 2-formyl succinate (5). Treatment of a 2-ethoxycarbonyl-3-hydroxymethyl-4-butanolide derivative (9) with acidic ethanol gave 3, 7-dioxabicyclo [3.3.0] octane-2, 8-dione (2a). Alkylation of 2a with various alkyl halides gave C1-substituted-3, 7-dioxabicyclo [3.3.0] octane-2, 8-diones (2b-g) in moderate yields. The same compounds (2b-g) were also prepared from 9 after alkylation followed by acid treatment. 1-(6-Methoxycarbonyl-2-hexynyl)-3, 7-dioxabicyclo [3.3.0] octane-2, 8-dione (2h) and the 1-(6-cyano-2-hexynyl) analog (2i) were also prepared from 9. Partial hydrogenation of the acetylenic derivatives (2h and 2i) gave the corresponding cis-olefinic compounds (3a and 3b), which are potential synthetic intermediates for 10-oxa-11-deoxyprostaglandin E2 (4).

Several 5-substituted Nb-methoxycarbonyl-L- and -D-tryptophan derivatives were synthesized from proline by a new route involving electrochemical oxidation, as well as by the known procedures. Removal of the Nb-methoxycarbonyl group was accomplished by treatment with Me3SiI in refluxing chloroform, then alkaline hydrolysis of the methyl esters afforded 5-substituted L- and D-tryptophans with high optical purities.