This paper mostly describes our recent studies on the ring transformations of various aromatic and aliphatic cyclic amine N-imides into novel N-heterocyclic ring systems such as diazepines and diazonines by photochemical or thermal rearrangements. Further ring transformations of these new heterocycles thus obtained into other ring systems are also described.
Adsorption of oxalate ion (Ox2-) in aqueous solutions (30°C, pH 7.5-12.0) to hydroxyapatite (HAP) was confimed to be reversible and of Langmuir type. The amount (xOx) of adsorbed Ox2- from Na2Ox was larger than that from K2Ox through the size effect of the counter ion. As the thermodynamic activity (ionic activity product) of adsorbate (Na2Ox or K2Ox) increases with an increase in concentration of the counter ion, xOx increased with an increase in the amount of added NaCl or KCl. But the amount of adsorption, xOx, increased with a decrease in pH because of competitive adsorption with OH-. It was also suggested that Ox2- competes with Cl- for the adsorption sites on HAP. Therefore, the amount of adsorption, xOx, increased apparently by the addition of L-lysine HCl or glycine, but it was concluded that the increase was due to the decrease of pH and these substances do not affect xOx after pH-correction. On the other hand, xOx was decreased by the addition of Na2HPO4, NaHCO3 or sodium L-aspartate even after pH-correction owing to the competitive adsorption between Ox2- and these anions. It was concluded that Ox2- is adsorbed to HAP by electrostatic force and that some portion of adsorbed Ox2- is subjected to the ion-exchange with orthophosphate ion on the HAP surface. Some properties of renal calculus formation was explained on the basis of the results presented here.
Treatment of thiazolo[3, 2-b]pyridazinium perchlorates (I) with hydrazine hydrate afforded 1, 4-bis (2-vinyl-2, 3-dihydro-3-pyridazinylidene)-2-tetrazenes (II), 1-(1, 6-dihydro-6-thioxopyridazin) ylacetaldehyde azines (III), 2-alkylpyridazine-3-thiones (IV), 3, 4-dihydro-2H-pyridazino[6, 1-c] [1, 2, 4]triazines (V), s-triazolo[4, 3-b]pyridazines (VI, VI'), pyridazino[6, 1-c] [1, 2, 4]triazinium salts (VII), imidazo[1, 2-b]pyridazines (VIII), 8-aminothiazolo[3, 2-b]pyridazinium salts (IX) and pyridazine-3-thiones (X), depending upon the substituents of the substrates, reaction time and temperature. Catalytic reduction of the tetrazenes (II) gave V and oxidation with 30% H2O2 in acetic acid yielded 3, 4-dihydro-2H-pyridazino[6, 1-c] [1, 2, 4]triazin-3-ones (XV).
Several factors having an influence on the thrombin activity were investigated, and the following two results were obtained : 1) Inactivation of thrombin activity apparently depended on not only incubation time of solution, but also the amount adsorbed on the glass surface of the test tube. 2) Thrombin (J.P.) solution, being incubated at 4°C, showed the temporary increase of thrombin activity, and this phenomenon might be attributed to the conversion of contained prothrombin to thrombin.
Metabolism of sodium 7β-[(2R, 3S)-2-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-3-hydroxybutanamido]-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate (T-1982), a new β-lactam antibiotic, was studied in vitro and in vivo. When T-1982 was administered intravenously to various animals, the bioautogram of their urine samples showed that T-1982 existed in quantity, but 7β-[(2R, 3S)-2-[3-[2-(N-ethyl-N-oxaloamino)ethyl]ureido]-3-hydroxybutanamido]-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (T-1982A) and 7α-methoxy-7β-[(5-methyl-2-oxooxazolidin-4-yl)carboxamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (T-1982 B) existed slightly. Similarly, T-1982A and T-1982B as metabolites of T-1982 were detected in the urine, bile and feces of various animals by high pressure liquid chromatography (HPLC). After the intravenous administration of 14C-T-1982 to rat and mouse, 14C-radioactivity excreted in the urine, bile and feces was measured with HPLC and radioassay. As a result, 92.2-98.1% of each collected radioactivity was 14C-T-1982, 0.5-2.6% was 14C-T-1982A and 1.1-3.8% was 14C-T-1982B. The degradation rate of T-1982 during the incubation with the homogenates of various rat's organs was similar to that in 0.1 M P.B. (pH 7.0), therefore it seemed that T-1982 was not degraded by enzymes from various organs. 1-Ethyl-2, 3-dioxopiperazine (T-1982C) was assumed to be produced in company with the production of T-1982B. Further T-1982A and T-1982B were administered to rabbits, and 14C-T-1982C was administered to rat. Plasma levels of these compounds disappeared immediately. When T-1982 was administered intravenously to volunteers, T-1982A and T-1982B were detected in their urine as seen in the urine of various animals. It was considered that the metabolism of T-1982 in human was the same as that in these animals.
Effects of various co-administrated drugs and dosing conditions on the bioavailability of diltiazem were studied in dog and human in single oral doses. Bioavailability was assessed from plasma diltiazem levels in dog and urinary diltiazem excretion in human. In dog, absorption of diltiazem delayed on the co-administration of food and antacid, depending on dissolution rate of diltiazem from dosage form. Other bioavailability parameters were not changed by these dosing conditions. Administration of alcohol and dipyridamole, on the other hand, markedly increased the peak level and area under the curve of diltiazem. Biological half-lives were not altered as compared with diltiazem alone on any occasion. In healthy subjects, sleep caused a delay in diltiazem absorption. Results in experiments of dog and human did not parallel except time to reach the peak level. The relationship between number of co-administrated drugs in a clinic and the steady state plasma diltiazem levels was not significant. It is considered that the bioavailability of diltiazem preparation was rather unsusceptible to the dosing conditions.
Drug interaction between diltiazem and propranolol was studied in dog and human from the standpoint of bioavailability. It was found that oral co-administration of diltiazem enhanced the bioavailability of propranolol in dog without affecting the biological half-lives. This effect was proportional to the doses of diltiazem from 5 to 60 mg per head and seemed to be comparable to the effect of food. Similar but lesser effect was also observed when diltiazem was co-administered by non-oral routes. Inter-individual uniformity of plasma propranolol levels as well as dose proportionality of the peak level and area under the curve were improved by the co-administration of diltiazem. In healthy subjects and patients, there was a tendency toward elevation in plasma propranolol levels by the combined administration of diltiazem as in the case of dogs, but the mean blood pressure and heart rates were not different significantly as compared to that of diltiazem or propranolol alone. No change in the plasma diltiazem levels was confirmed on the co-adiministration with propranolol in any species.
The chinese crude drug "Zhu" is said to be effective to edema, reumatic trouble, indigestion, headache and so on. In China, a division has been made between "Changzhu" and "Baizhu". In the Japanese pharmacopoeia it has been classified into "Atractylodes lancea Rhizoma" and "Atractylodes Rhizoma." However, their difference on clinical use has been confused. In order to clear up the pharmacological difference between these two groups, anti-ulcerogenic activities of 50% MeOH extracts of Atractylodes lancea, A. lancea var. chinensis, A. ovata, A. japonica were examined. As a result, both varieties of "Changzhu" ext. significantly decreased the ulcer index in Shay-ulcer, aspirin ulcer in pylorus-ligated rats, histamine-induced ulcer, serotonin-induced ulcer, and stress ulcer. In contrast to the results of this group, "Baizhu" ext. was effective only for stress ulcer. Thus, some striking differences were observed between these two groups.
Effect of 3-(di-2-thienylmethylene)-5-methyl-trans-quinolizidinium bromide (HSR-902), a new antispasmodic agent, on the microcirculation of gastric mucosa in rabbits treated with neostigmine bromide was investigated. Intravenously administrated HSR-902 (25μg/kg) increased the blood flow of gastric mucosa in rabbits treated with neostigmine bromide (50μg/kg, i.v.). The increased microcirculation was recognized in five of eight rabbits after HSR-902 (25μg/kg, i.v.) administration. HSR-902 administered at a dose of 50μg/kg (i.v.) completely restored the decreased blood flow to the control level without exerting significant effects on systemic blood pressure, and inhibited the elevated stomach movement evoked by neostigmine bromide. This effect was durable in almost all rabbits. On the other hand, intravenous administrations of 50μg/kg of butylscopolamine bromide, timepidium bromide and cyclonium iodide failed to restore the decreased microcirculation induced by neostigmine bromide. These results suggest that HSR-902 may be effective in repairing ischemia and oligemia of gastric ulcer which result from decreased microcirculation in the stomach mucosa.
Propiolic acid (β-naphthyl) methyl ester (PNE) was found to have a strong antifungal action, weak skin irritation and acute toxity in mammals. The results of therapeutic tests in guinea-pig revealed that a tincture and hydrophilic ointment containing 1-2% PNE had about 76-82% cure rate on experimental trichophytosis, and that those containing 10% salicylic acid besided 1% PNE, had about 90%. PNE was tested on general pharmacological actions in mice, rats, rabbits and guinea-pigs. The results were as follows : (1) PNE was found to have a temporary fall of blood pressure in rabbits. (2) PNE did not have remarkable effects on the isolated ileum of guinea-pigs, but it showed inhibitory effects on the contraction which was caused by acetylcholine, histamine and barium chloride. (3) PNE showed weak hemolysis effects on the erythrocyte of a rabbit.
Actions of three "saiko-zai, " daisaiko-to, shosaiko-to and saikokeishi-to consist of basic (BASE) and additional (A, B and C, respectively) prescriptions, on the experimental models of inflammation in rats was studied. BASE did not produce any inhibitions on paw edema induced by carrageenin, dextran and burn, but had a potent action on adjuvant arthritis. A and BASE+A (daisaiko-to) inhibited paw edema induced by carrageenin and dextran as much as aspirin did, and also inhibited adjuvant arthritis, in which secondary stage of inflammation was suppressed more strongly than primary stage. C and BASE+C (saikokeishi-to) inhibited dextran-induced paw edema to the same extent as aminopyrine, and BASE+C showed a potent anti-inflammation on adjuvant arthritis. On the other hand, any inhibitory actions on various inflammatory models by B and BASE+B (shosaiko-to) were not observed. None of BASE and additional prescriptions showed a protective action on heat-induced hemolysis of rat erythrocytes. These results suggest that daisaiko-to and saikokeishi-to possess potent inhibitory actions on acute and chronic inflammation in rats.
Ethyl 1, 4-dihydro-1, 4-dioxo-3-methoxy-2-naphthoate (I) is condensed with amidines, 2-aminopyridines and 3-aminopyrazole, to give new tetracyclic quinones (IIIa-c and VI) containing nitrogen atom and hydrogenation of IIIa and IIIb over Pd-C or Raney-Ni afforded 1, 2, 3, 4-tetrahydro (IXa, b) or 1, 2, 3, 4, 7, 8, 9, 10-octahydrobenzo[g]pyrido[2, 1-b]quinazoline (Xa), respectively. Benzo[g]pyrido[2, 1-b]quinazoline derivatives except for Xa showed inhibitory activities to S. aureus and T. interdigitale.
Diphenylacetyl derivatives of glycine (1), L-phenylalanine (2), DL-alanine (3), DL-serine (4), DL-valine (5), DL-leucine (6), L-aspartic acid (7), and L-glutamic acid (8) were synthesized and their effects on tumor cell were investigated using Sarcoma 180, HeLa, and KB cells. Compounds 2, 5, and 6 showed weak growth inhibition and damage of the tumor cells in culture.