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At least 145 records · Page 8Linked to original sources
PubMed1992

Blockade of 5-HT3 receptor-mediated currents in dissociated frog sensory neurones by benzoxazine derivative, Y-25130.

1. The effect of Y-25130, ((+-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dih ydr o- 2H-1,4-benzoxazine-8-carboxamide hydrochloride), a high affinity 5-hydroxytryptamine3 (5-HT3) receptor ligand, was examined on the 5-HT-induced response in dissociated frog dorsal root ganglion (DRG) neurones by use of the extremely rapid concentration-jump ('concentration-clamp') and the conventional whole-cell patch-clamp techniques. 2. 5-HT induced a rapid transient inward current associated with an increase in membrane conductance at a holding potential of -70 mV. The current amplitude increased sigmoidally as 5-HT concentration increased. The half-maximum value (Ka) and the Hill coefficient estimated from the concentration-response curve were 1.7 x 10(-5) M and 1.7, respectively. 3. The current-voltage (I-V) relationship of 5-HT-induced current (I5-HT) showed inward rectification at potentials more positive than -40 mV. The reversal potential (E5-HT) was -11 mV. The E5-HT value was unaffected by total replacement of intracellular K+ by Cs+, indicating that the 5-HT-gated channels might be large cation channels. 4. Both the activation and inactivation phases of I5-HT were single exponentials. The time constants of activation and inactivation (tau a and tau i) decreased with increasing 5-HT concentration. 5. The 5-HT response was mimicked by a selective 5-HT3 receptor agonist, 2-methyl-5-HT, but the maximum response induced was approximately 25% that of 5-HT. The 5-HT response was reversibly antagonized by the 5-HT3 receptor antagonists, ICS 205-930, metoclopramide and Y-25130, but not by a 5-HTIA receptor antagonist, spiperone, and a 5-HT2 receptor antagonist, ketanserin. The half-inhibition concentrations (IC50) were 4.9 x 10-10 M for Y-25130, 4.8 x 10-10 M for ICS 205-930 and 8.6 x 10-9 M for metoclopramide.6. Y-25130 (5 x 10-10 M) caused a rightward shift of the concentration-response curve for 5-HT while decreasing the maximum response.7. The results suggest that Y-25130 is a potent antagonist of the 5-HT3 receptor-channel complex.

Animals↗
PubMed1990

Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: synthesis and biological activity.

N-Acetic acid derivatives (I) of 2-substituted 1,4-benzoxazines and benzothiazines were designed and synthesized for evaluation as new aldose reductase inhibitors. In general, 3-thioxo derivatives were more potent inhibitors of aldose reductase from human palcenta in vitro than the corresponding 3-oxo derivatives. While many compounds (I) were not very effective in inhibiting sorbitol accumulation in the rat sciatic nerve in vivo, the 3-thioxo compounds bearing an isopropyl group at the 2-position showed highly potent activity in the in vivo assay. Compound 46 (AD-5467) was selected from this series as a candidate for further development.

Aldehyde Reductase↗
PubMed1991

Synthesis and biological activities of new 2-substituted 1,4-benzoxazine derivatives.

A series of new 1,4-benzoxazine derivatives (XI, XII) possessing (4-phenyl-1-piperazinyl)alkyl moieties at the 2-position and related compounds (XIII) were synthesized and tested for calcium antagonistic, calmodulin antagonistic and antihypertensive activities. Various compounds had in vitro calmodulin antagonistic activity superior or comparable to that of trifluoperazine. Among these compounds, tetrahydronaphtho[2,3-b] [1,4]oxazine derivatives such as 51, 53, 54, 58, 59, 60, 73 and 75 showed potent antihypertensive effects in spontaneously hypertensive rats. Optical isomers of 51 were also synthesized and evaluated biologically. No differences in biological activities were seen between the enantiomers.

Animals↗
PubMed1992

Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.

Animals↗
PubMed1994

Pyridonecarboxylic acids as antibacterial agents. IX. Synthesis and structure-activity relationship of 3-substituted 10-(1-aminocyclopropyl)-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]- 1,4-benzoxazine-6-carboxylic acids and their 1-thio and 1-aza analogues.

A series of the title compounds listed in Chart 1 have been synthesized to study the effects of 3-alkyl substituents on the antibacterial potency and in vivo efficacy of 10-(1-aminocyclopropyl)-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3 -de]-1,4-benzoxazine-6-carboxylic acid and its 1-thio and 1-aza variants. Compound (S)-1, which proved most active in vitro against five representative gram-positive and gram-negative organisms, was assayed in vivo using Staphylococcus aureus and Pseudomonas aeruginosa mouse infection models. It exhibited an excellent in vivo efficacy, being superior to ofloxacin and ciprofloxacin, and was then assayed for convulsion-inducing activity, mammalian cell cytotoxicity, and topoisomerase II inhibition. The biological results showed that (S)-1 displayed antibacterial and toxicological advantages over ofloxacin and ciprofloxacin. Compound (S)-1 and its methanesulfonate showed high serum concentrations after oral and intravenous administrations to mice.

Animals↗
PubMed1995

New 5-HT3 (serotonin-3) receptor antagonists. V. Synthesis and structure-activity relationships of pyrrolo[2,1-c][1,4]benzoxazine-6-carboxamides.

This paper describes the discovery of structurally novel heterocyclic carboxamides which are highly potent 5-HT3 (serotonin-3) receptor antagonists. Pyrrolo[2,1-c][1,4]benzoxazine-6-carboxamides (12 and 20) were found to possess potent 5-HT3 receptor antagonist activity on the von Bezold-Jarisch reflex in anesthetized rats. Structure-activity studies showed that compounds with small and lipophilic substituents such as chloro and methyl at the 8-position of the aromatic ring portion retained high potency, whereas those with bulky substituents showed essentially no activity. A dimethyl group at the 4-position slightly decreased the potency. 1-Azabicyclo[2.2.2]octan-3-amine as the amine part afforded the most potent activity. From this series, 20a was found to be the most potent 5-HT3 receptor antagonist, being 40-fold more potent than ondansetron (1).

Animals↗
PubMed1999

Novel potassium channel activators. II. Synthesis and pharmacological evaluation of 3,4-dihydro-2H-1,4-benzoxazine derivatives: modification of the aromatic part.

Three new series of analogues related to 3,4-dihydro-2H-1,4-benzoxazine derivative 1a were synthesized and evaluated for their potassium channel activating activity. In the first series I, where the 6,7-positions were disubstituted, it was found that an electron-withdrawing substituent was preferable at the 6 position, but either an electron-withdrawing or releasing substituent without bulkiness was tolerated at the 7 position. In the second series II, where several heterocycles were introduced into the 6,7-positions, the oxadiazole derivative 6 showed more potent activity than cromakalim. In the third series III, where the benzene ring was replaced by a pyridine ring, borane complex 16 had equivalent activity to cromakalim. Especially, compound 6 showed a potent hypotensive effect with a long duration of action in the spontaneous hypertensive rat and had a lesser increasing effect on intracranial pressure in dogs than 1a and levcromakalim, showing a good profile as an antihypertensive agent.

Animals↗
PubMed2000

Novel potassium channel activators. III. Synthesis and pharmacological evaluation of 3,4-dihydro-2H-1,4-benzoxazine derivatives: modification at the 2 position.

A new series of 3,4-dihydro-2H-1,4-benzoxazine derivatives, where various substituents were introduced into one of the geminal dimethyl groups at the 2 position, were synthesized and their potassium channel-activating activity was evaluated. Introduction of a hydroxyl group, as in compound 5, resulted in good solubility in water and a long duration of action compared with the parent compound 1. Introduction of a nitrato group, as in compound 8, produced typical nitrate activity such as exhibited by nitroglycerine in addition to potassium channel-activating activity. X-ray structural analysis of compound 5 showed that the sum of the bond angles around the N atom at the 4 position was 357.8 degrees, suggesting that the N atom had an approximately sp2-like planar bond configuration.

Animals↗
PubMed1995

[Studies on structure of light degradation products of (-)-(S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihyd ro-7H- pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (T-3761) in aqueous solution and solid state].

The structures of light degradation products of (-)-(S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dih ydr o-7H- pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (T-3761) in aqueous solution and in the solid state were investigated. In aqueous solution, ten products were detected using HPLC and in the solid state, one main product was detected. All these light degradation products were isolated and their structures were elucidated. It was revealed that in almost all light degradation products only the 1-aminocyclopropyl side chain at the 10-position of T-3761 is changed to various structures by light oxidation. Surprisingly we found a unique light degradation product, in which carboxylic acid at the 6-position of T-3761 is changed to the hydroxy moiety.

Anti-Infective Agents↗
PubMed1991

Four-week sub-acute toxicity study of S-(-)-9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl)-7-oxo-7H-pyrido-[1,2,3,-de] [1,4]benzoxazine-6- carboxylic acid hemihydrate (DR-3355) in CD rats and cynomolgus monkeys.

S-(-)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3,-de] [1,4]benzoxazine-6-carboxylic acid hemihydrate, DR-3355, a new quinolone antimicrobial agent, was administered by oral gavage to groups of ten male and ten female CD rats at dosages of 50, 200 or 800 mg/kg/day and to groups of three male and three female cynomolgus monkeys at dosages of 10, 30, or 100 mg/kg/day. Both species were treated for four weeks. The vehicle (0.5% sodium carboxymethyl cellulose)-treated group served as control. Rats at the high dose showed salivation, slight increases in total leucocyte and lymphocyte counts, slight changes in the plasma electrolyte balance, and minor reductions in urea concentration. The articular surfaces of the humerus and femur of rats at the high dose showed minor degenerative changes. Increased caecal weight occurred in rats at all the treatment groups. Monkeys at the high dose showed salivation, diarrhoea and lost weight. There was no microscopic change in the tissues examined. No effect levels under these conditions were established at 200 mg/kg/day in the rat, and 30 mg/kg/day in the monkey.

Animals↗
PubMed1991

Inhibition of chymotrypsin and pancreatic elastase by 4H-3,1-benzoxazin-4-ones.

Eight 3,1-Benzoxazin-4-ones have been used to inactivate chymotrypsin and pancreatic elastase. Whereas 6,7-dimethoxy substitution only slightly decreased the acylation rate constant, the deacylation reaction was nearly unaffected. Bulky alkoxy groups in position 2 of the heterocyclic moiety were shown to increase enormously the acylation rate of chymotrypsin, but not that of elastase.

Acylation↗
PubMed1999

Antimycoplasmal activities of (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10 -[4-(2-pyridyl)-1-piperazinyl]-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine -6-carboxylic acid (YH-6) in comparison with other antibiotics in vitro.

AIM: To determine the susceptibilities of Mycoplasma and Ureaplasma to (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10 -[4-(2-pyridyl)-1-piperazinyl]-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine -6-carboxylic acid (YH-6) and to compare it with those referential quinolones, macrolides, and tetracyclines. METHODS: The minimum inhibitory concentration (MIC) were determined by microdilution method in vitro. RESULTS: The MIC of YH-6 for Ureaplasma urealyticum (Uu: 250 micrograms.L-1), Mycoplasma hominis (Mh: 500 micrograms.L-1), M orale (Mo: 125 micrograms.L-1) and M salivarium (Ms: 125 micrograms.L-1) were closely similar to those of macrolides (erythromycin and leucomycin) and were 2-8 folds greater than those of ofloxacin (Ofl). Uu and Mh easily induced resistance to erythromycin and tetracycline. They did not easily form resistance to quinolone (YH-6, Ofl), josamycin and tylosin. Tetracycline-resistance (Tcr) or erythromycin-resistance (EMr) strains of Uu (or Mh) had cross-resistance to erythromycin or tetracycline. However, they had no cross-resistance to quinolone, josamycin and tylosin. CONCLUSION: YH-6 was a highly active quinolone against Mycoplasma, but could hardly induce resistance to Uu. EMr- or Tcr- strains of Uu (or Mh) had no cross-resistance to YH-6.

Anti-Bacterial Agents↗
PubMed1991

New 2-substituted 2,3,3a,4-tetrahydro-1H-imidazo[5,1-c] [1,4]benzoxazin-1-ones as alpha 2-adrenoceptor antagonists.

The synthesis of new 2-imidazol(in)yl-alkyl derivatives of 2,3,3a,4-tetrahydro-1H-imidazo[5,1-c][1,4]benzoxazin-1-one is reported. Some compounds of the series have shown high affinity for alpha 2 receptors, high alpha 2/alpha 1 selectivity and alpha 2 antagonism in vitro (vas deferens). Owing to their selective alpha 2-antagonism associated to a novel structure, compounds 8 and 20 have been selected for further biological investigation as potential antidepressants.

Adrenergic alpha-Antagonists↗
PubMed1995

Potentially active antimicrobial agents from 2-benzenesulfonyloxyphenyl-3,1-benzoxazine-4-one derivative.

Fourteen of nitrogeneous heterocyclic compounds that accommodate the sulfonate-ester moiety were synthesized through interaction of 2-benzenesulfonylo xyphenyl-3,1-benzoxazine-4-one with some nucleophilic reagents. The assigned structures for the prepared new compounds were confirmed on the basis of elemental and spectral data. Evaluation of the antimicrobial activity of these products, relative to standard antibiotics was tested and discussed.

Anti-Bacterial Agents↗
PubMed1996

LD50 value, phototoxicity and convulsion induction test of the new quinolone antibacterial agent (S)-10-[(S)-(8-amino-6-azaspiro[3,4]octan-6-yl)]-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxyl ic acid hemihydrate in laboratory animals.

(S)-10-[(S)-(8-Amino-6-azaspiro[3,4]octan-6-yl)]-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxyli c acid hemihydrate (CAS 151390-79-3, DV-7751a) a new quinolone antibacterial agent, was examined for LD50 value, phototoxicity and convulsion inducing potential in laboratory animals. A single oral administration of DV-7751a induced soft stool in rats at 1000 and 2000 mg/ kg and in monkeys at 250 mg/kg and vomiting in monkeys at 500 mg/kg or more. A single intravenous administration caused a decrease in locomotor activity, respiratory depression, convulsion, pulmonary edema and death in rats and mice. The LD50 values with oral administration were more than 2000 mg/ kg for rats and mice and more than 250 mg/kg for monkeys, and those with intravenous administration were 164.3 mg/kg for rats of both sexes at an injection rate of 2 ml/min, 118.8 mg/kg for male rats and 104 to 125 mg/kg for female rats at 0.5 ml/min, and 184.7 mg/kg for male mice and 187.4 mg/kg for female mice. DV-7751a showed very weak phototoxicity in mice after single oral administration of 600 mg/kg, followed by UVA irradiation, but no convulsion after oral administration of 200 or 1000 mg/kg in combination with 4-biphenylacetic acid at 400 mg/kg.

Administration, Oral↗
PubMed1996

One-month oral toxicity study of the new quinolone antibacterial agent (S)-10-[(S)-(8-amino-6-azaspiro[3,4]octan-6-yl)-9-fluoro-2,3-dihydro-3- methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hemihydrate in rats and cynomolgus monkeys.

One-month oral toxicity of (S)-10-[(S)-(8-amino-6-azaspiro[3,4] octan-6-yl)]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid hemihydrate (CAS 151390-79-3, DV-7751a) a new quinolone antibacterial agent was investigated in Sprague-Dawley rats at doses of 12.5, 50, 200 and 800 mg/kg/d and in cynomolgus monkeys at 10, 30 and 100 mg/kg/d. Rats receiving 200 mg/ kg showed abnormal urine crystals, enhanced deposition of lipid in hepatocytes and exacerbation of osteochondrotic lesions in the femoral condyle. In addition, dosing at 800 mg/kg induced decrease in body weight gain and increased levels of serum alkaline phosphatase (ALP), cholinesterase, leucine aminopeptidase and total cholesterol. Monkeys receiving 100 mg/kg showed abnormal urine crystals and increases in serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and ALP levels. The non-toxic doses of DV-7751a in rats and monkeys were 50 and 30 mg/kg, respectively, under the present experimental conditions.

Animals↗