The effect of ammonium chloride on urinary excretion of chloroquine (CQ) was examined in the rabbit. Volume, pH and CQ content of the urine were measured every day for 2 weeks. The animals were divided into two groups. One group of animals were given CQ diphosphate, 30 mg/kg/day (s.c.), during the 2 weeks, and one-half of these animals were given NH4Cl (ca. 0.5 g/kg/day, oral) during the second week, when they excreted 2-4 times the amount of CQ excreted by the animals not given NH4Cl throughout. The other group of animals were given CQ during the first week only, and one-half of these animals were given NH4Cl during the second week. During the CQ treatment, the daily urine volume was much more variable and 2-3 times less than that excreted after cessation of CQ treatment. NH4Cl affected neither the urine volume nor the amount of CQ excreted. pH of the urine excreted during NH4Cl treatment (6.29-6.91) was lower than that excreted during the control period (7.25-8.57). These results indicate that NH4Cl facilitates urinary excretion of CQ only when given simultaneously with CQ, and may suggest a possibility that CQ caused a kidney dysfunction.
Reaction of 5-substituted 2-furyl phenyl ketones and phenylhydrazine afforded the corresponding phenylhydrazones (A). Majority of these hydrazones were separated into E-form and Z-form compounds, and their steric configuration was determined from their nuclear magnetic resonance spectra. Treatment of these hydrazones with lead tetraacetate and cyclization with boron trifluoride etherate afforded furo [3, 2-c] pyrazoles when the furan ring possessed a methyl, hydrogen, or a bromine atom in 5-position, while indazoles were produced when the substituent (s) was methoxycarbonyl or nitro group.
In order to improve the facile cleavage of the C2-N bond on N-acetylation of 1, 3-diazines, various conditions for N-acetylation were examined with three kinds of 1, 3-diazines. Three acetylating reagents (acetyl chloride, acetic anhydride, and ethyl acetate) were used. Results were as follows : (1) For the synthesis of 1-acetyl-2-methyl-1, 4, 5, 6-tetrahydropyrimidine, 1, 3-diacetyl-2-methylhexahydropyrimidine, and 1-acetyl-3-methylhexahydropyrimidine, it is most suitable to react the starting compound with acetyl chloride in absolute benzene. (2) Water is required for the synthesis of 1-acetyl-2-hydroxy-2-methylhexahydropyrimidine. (3) Acetic anhydride is the most suitable reagent for synthesis of 1, 3-diacetyl-2-exomethylenehexahydropyrimidine. On N-acetylation of 2-methyl-1, 4, 5, 6-tetrahydropyrimidine, C2-N1 bond of the intermediate is split to N, N'-diacetyltrimethylenediamine, and the mechanism of such a cleavage is discussed.
The interaction of synthetic aminoquinone derivative, 2, 5-diamino-1, 4-naphthoquinone imine (DANQI), with calf thymus deoxyribonucleic acid (DNA) in vitro in a ratio of up to 1 mol to two nucleotide residues with the binding constant of 3.9×103 M-1 was confirmed by spectrometric and melting experiments, and by equilibrium dialysis. The three sites in DNA assumed to take part in this interaction are the adenine base, the 2'-deoxycytidine residue, and possibly the phosphodiester bond. Although the mode of this interaction was somewhat different from those for both 2-amino-1, 4-naphthoquinone imine (ANQI) and 2-hydroxyamino-1, 4-naphthoquinone (HANQ), which interacted with DNA at the adenine and the guanine bases, DANQI inhibited the DNA synthesis, possibly as the primary action, in Ehrlich ascites carcinoma cells in vitro in the same manner as the above two derivatives. The extent of inhibition by DANQI in the carcinoma cells was greater than that by mitomycin C and was also greater than that in E. coli. The difference in the biological activities between the hydroxyamino (HANQ) and the amino (DANQI and ANQI) derivatives was that the former had a therapeutic effect on Ehrlich mouse ascites carcinoma in vivo, while the latter did not.
A new glycoside, clerodendroside (A), C22H20O12·2H2O, mp 208-211°, which shows a hypotensive activity in a rat, was isolated from butanolic fraction of Clerodendron trichotomum Thunb. var. fargessii REHD. (Verbenaceae), and its structure was determined as 5, 6, 7-trihydroxy-4'-methoxyflavone 7-O-glucuronide by chemical degradation and spectral means.
D (-)-α-(4-Substituted 2, 3-dioxo-1-piperazinecarboxamido) benzylpenicillin (I), D (-)-α-(4-substituted 2, 5-dioxo-1-piperazinecarboxamido) benzylpenicillin (II) and D (-)-α-(4-substituted 3, 5-dioxo-1-piperazinecarboxamido) benzylpenicillin (III) were prepared. These compounds showed in vitro antibacterial activity against S. aureus, E. coli, P. aeruginosa, P. vulgaris, K. pneumoniae, and S. marcescens, the activity being in the order of I>II, III. These compounds were found to have a stronger antibacterial activity against gram-negative bacilli than aminobenzylpenicillin or carbenicillin.
Structure-activity relationship of new semisynthetic penicillins, 6-[D (-)-α-(4-alkyl-2, 3-dioxo-1-piperazinecarboxamido) phenylacetamido] penicillanic acid (I) was investigated. In in vitro antibacterial activity against clinically isolated strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis, P. vulgaris, P. morganii, P. rettgeri and Pseudomonas aeruginosa, structure-activity relationship was recognized, except in P. aeruginosa, and antibacterial activity became stronger with the increase in carbon number of the alkyl group in I. Such a tendency was especially marked against K. pneumoniae and S. marcescens. Stability against β-lactamase, blood level, protein binding, acute toxicity and distribution coefficient of I were all related to the number of carbon atoms in the alkyl group of I. In protective effect against experimental infection in mice, T-1220 (I : R=C2H5) was the most effective, and more effective than carbenicillin against P. aeruginosa infection.
Degradation pattern of 6-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) phenylacetamido] penicillanic acid (T-1220) in aqueous solution was investigated. In acidic solution, T-1220B and T-1220D were found, while T-1220A, T-1220B, and T-1220C were identified in alkaline solution. Stability of T-1220 in aqueous solution and body fluid was measured by means of High Pressure Liquid Chromatography. T-1220 was more stable at neutral pH of 5.0-6.0, slightly unstable at acidic pH of 4.0, and markedly unstable at alkaline pH of 9.0. Stability of T-1220 in various body fluids seemed to depend on pH, and its degradation pattern was similar to that in aqueous solution.
Inflammation was induced in rabbits by intracutaneous injection of lysosomal particles prepared from guinea pig leukocytes. As far as the proinflammatory activity of lysosomal particles is concerned, when assessed by leakage of intravenous dye (5% Evans Blue), intact lysosomes were more potent than the broken ones, the activity was optimal 90 min after injection, and 0.04 μg of lysosomal protein can induce the inflammation. The anti-inflammatory potency of betamethasone 17, 21-dipropionate against the inflammation was higher than that of hydrocortisone acetate.
Eighteen kinds of 2-[α-(N-substituted carbamoyl)-β-(5-nitro-2-furyl) vinyl] furans were prepared. 2-[α-Isocyanato-β-(5-nitro-2-furyl) vinyl] furan, 2-[α-amino-β-(5-nitro-2-furyl) vinyl] furan, and 2-[β-(5-nitro-2-furyl) ethynyl] furan were obtained by the thermolysis of 2-[α-azidocarbonyl-β-(5-nitro-2-furyl) vinyl] furan. Fourteen kinds of 2-[α-(N'-substituted ureido)-β-(5-nitro-2-furyl) vinyl] furans were also prepared. 2-[α-(N-Methylcarbamoyl)-β-(5-nitro-2-furyl) vinyl] furan and 2-[α-(N-ω-hydroxyethylcarbamoyl)-β-(5-nitro-2-furyl) vinyl] furan exhibited a prominent antibacterial activity in vitro against gram-positive and gram-negative bacteria.
Dimethylformamide solutions containing copper (II) perchlorate and amines were studied by absorption spectra and by magnetic measurement. Solutions of [butylamine]/[Cu (II)]=2-8 were yellow with a considerable absorption in the 400-nm region. The absorption can be ascribed to the presence of dimeric or oligomeric copper species, which was supported by the results of magnetic measurements. Solutions of the ratio over 10 were blue and their spectra had an absorption peak at 640 nm and no appreciable absorption in the 400-nm region. In these solutions copper was concluded to be present as Cu (amine)42+. Similar results were obtained with benzylamine and ammonia. Solutions containing Cu (II) and aniline had an intense absorption at 384 nm, which disappeared on acidification or on addition of amines with complexing ability. A similar absorption was produced by p-anisidine, p-toluidine, and m-toluidine but not by diphenylamine, ethyl p-aminobenzoate, or 2, 6-dimethylaniline. Magnetic measurement indicated Cu (II) species to be monomeric in the solutions. These results are interpreted in terms of the formation of a weak Cu (II)-aniline complex, possibly Cu (aniline)2+.
Penicillin G added to a human erythrocyte suspension was found to exert the following actions on their plasma membranes : (1) It inhibits acetylcholinesterase activity in concentrations higher than 100 mM and this inhibitory effect increases with time. The lost activity is not restored by washing of the treated cells. (2) Penicillin G added to a hypotonic hemolyzing medium in a concentration over 5 mM increases osmotic resistance of the cells. (3) It promptly induces, in a similar concentration as in (2), the membrane externalization and the resulting echinocyte-spherocyte formation. Upon continuing the incubation, however, these cells change their shape further, showing pictures of a combined type of the membrane externalization and internalization. When these cells are washed with saline, they show a typical picture of the membrane internalization. Penicillin G in the surrounding medium was rapidly taken up by the cells into the intracellular fluid and, therefore, it is possible that it may act on the membrane from both the outer and inner surfaces.
Eighty-four compounds (mainly N-heteroaromatic compounds) were synthesized and their antitumor activity was examined. Four quinoline derivatives were found to have some antitumor effect on the solid type of Ehrlich carcinoma. These compounds were, 3-hydroxy-6-quinolinecarbonitrile (sample No. 7-III), 6-bromoquinaldic acid 1-oxide (No. 7-VIII), 8-(hydroxyimino)-5, 6, 7, 8-tetrahydroquinoline (No. 7-XIX) and 4-(hydroxyimino)-1, 2, 3, 4-tetrahydroacridine (No. 7-XX). No other derivatives were found effective.
Sixty-one indole derivatives containing oxindole, spiro-oxindole, and condensed-ring indole were prepared and their antitumor activity was examined using a solid type of Ehrlich carcinoma. 1-Methyl-3-(1-methylthio-1-morpholinomethylene) oxindole was found to have some antitumor effect, but no other derivatives were found effective.
Eighty-seven compounds of maleimide, five- or six-ring heterocyclic 4H-quinolizines, and ethylene derivatives were prepared and their antitumor activity was examined using a solid type of Ehrlich carcinoma. 1, 3-Dicyano-2-benzylamino-4H-quinolizin-4-one was found to have some antitumor effect, but no other synthesized compounds were found effective.
A facile preparative method for N, N-disubstituted diphenylphosphinamides was developed. Treatment of N-alkyl (or phenyl) diphenylphosphinamides with a slight excess of sodium hydride followed by a reaction with alkyl halides produced the corresponding N, N-disubstituted derivatives in a fair yield. It is suggested that this method of N-alkylation provides a potentially useful means for the conversion of primary amines to secondary amines.