Search

Energy transitions and oscillator strengths for the singlet and triplet states of anthranil, benzisoxazole, and benzoxazole have been calculated using self-consistent field molecular orbital methods. Agreement with experimental absorption data is quite good for benzisoxazole and benzoxazole, but less satisfactory for anthranil.

7-Acetyl-3-methyl-2,1-benzisoxazole has been synthesized by reduction of 2,6-diacetylnitrobenzene. While the chemical properties of the compound indicate that it undergoes valency-tautomerism, spectroscopic studies indicate that this is a relatively slow process. Comparisons with other heterocyclic systems having similar properties are noted.

A compound formulated in the literature as 4-hydroxylaminocoumarin is now recognized to be the isomeric 1,2-benzisoxazole-3-acetic acid. Therefore, a preceding paper by the authors describing this acid is proved incorrect due to inexact data in the previous literature on the preparation of 3-methyl-1,2-benzisoxazole.

C~3HTBr2NO2, Mr=369.02 , monoclinic, P2Jn, a = 13.362 (3), b = 23.544 (4), c = 3.8893 (8) A, t= 96.10 (2) ° , V= 1216.59 A 3, z=4, D x = 2.014 Mg m -3, 2(Mo Ka) = 0.71069 A, ~t = 7.05 mm -I, F(000) = 712, T= 298 K, R = 0.062 for 970 independent non-zero reflections. In the isoxazole 2-oxide ring the acyclic N-O bond distance compares well with that of a nitro group while the cyclic one is longer. Both compare very well with the correspon- ding bond distances in furoxans. These features may be used to interpret some aspects of the mass spectra of benzisoxazole N-oxides.

Hydrogenation of 3-sulfamoylmethyl-1, 2-benzisoxazole (1) gave ω-sulfamoyl-2-hydroxyacetophenone (3) and its imide (2). Treatment of 3 with acid afforded a new route to 1, 2-benzoxathiin-4 (3H)-one-2, 2-dioxide (5). The oxime of 3 (4) was recyclized to provide 1, 2-benzisoxazole derivatives by treatment with acid or base. On pyrolysis 4 gave benzoxazole derivatives.

Twelve in vitro oxygenated metabolites of 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436) were produced by incubation of this antiprotozoal agent with the postmitochondrial supernatant (S9) fraction isolated from the livers of rats treated with phenobarbital. Metabolite structure elucidation was achieved using NMR and mass spectrometry. Seven monohydroxy and two dihydroxy metabolites were fully characterized; two other metabolites were partially characterized as dihydroxy derivatives of the drug. The major in vitro metabolite is the 5 axial hydroxy compound, and a minor metabolite is the corresponding ketone. In all cases metabolite formation involved biotransformation on the hexahydrobenzisoxazole ring.

Une isomerisation des ions moleculaires precede la fragmentation du benzoxazole et de l'anthranile (2,1- benzisoxazole) sour l'impact electronique. Molecular ion isomerisation precedes the fragmentation of benzoxazole and anthranil (2,1-benzisoxazole) upon electron-impact.

Zonisamide is a benzisoxazole-based compound first synthesized in the early 1970s by the research laboratories of Dainippon Pharmaceutical Company in Osaka, Japan. Identified as an anticonvulsant during exploratory research, zonisamide has since been characterized as having broad-spectrum antiepilepsy and neuroprotective effects. Early clinical studies in Japan demonstrated that zonisamide has a long elimination half-life and is well tolerated; Phase II and III clinical trials established the drug's efficacy and safety for the treatment of partial and generalized seizures. In 1989, zonisamide was approved and marketed in Japan under the trade name of Excegran ® . Data from postmarketing surveillance studies and clinical observations over 10 years of use have continued to support zonisamide's efficacy and safety, identified its usefulness as monotherapy, and characterized its effectiveness for various seizure types and epilepsy syndromes.

The base catalyzed ring expansion of 2-substituted 2H-1, 2-benzisoxazolin-3-one (3) to 2-substituted 2H-1, 3-benzoxazin-4-one (4) was observed during the alkylation of 3-hydroxy-1, 2-benzisoxazole (1).

N-Phenylsalicylohydroxamic acids, salicylohydroxamic acids, o- hydroxyacetophenone oximes and salicylaldoximes gave the corresponding N-phenyl-1,2-benzisoxazol-3(2H)-ones, 1,2-benzisoxazol-3-ols, 3-methyl- 1,2-benzisoxazoles and 1,2-benzisoxazoles when treated with thionyl chloride in the presence of dry pyridine in anhydrous ether at 0°C.

A gas chromatographic method has been developed that permits the accurate and specific determination of a new psychotropic agent, PF-257, in plasma. PF-257 is extracted with ethyl acetate from alkaline plasma and, after a clean-up procedure, derivatized with heptafluorobutyric anhydride to form 3-[(5-n-heptafluoropropyl-1,2, 4-oxadiazol-3-yl)methyl]-1,2-benzisoxazole (HOMB). The HOMB is assayed on a gas chromatograph equipped with an electron-capture detector. Accurate determinations of PF-257 are possible in the concentration range from 1–40 ng/ml with a relative standard deviation of 6.8%. The minimum detectable concentration in plasma is 0.1 ng/ml. Plasma levels of PF-257 in rats receivingintravenous or oral dosing (10 mg/kg) were determined.

Le PF-257 ou chlorhydrate de benzisoxalzole-1,2 acetamidoxime-3 produit des effets varies sur le systeme nerveux central des animaux. Le profil pharmacologique et l'action fondamentale de cet agent paraissent nouveaux, compares a ceux des psychotropiques actuels.

Treatment of α-mono-substituted 1,2-benzisoxazole-3-acetic acid esters (1) with strong bases caused a ring transformation to afford 2H-azirines (2) or 3-imino-2,3-dihydrobenzofurans (3).

1H-NMR and MS were employed to identify 13 rat urinary metabolites of 14C-labeled cis-3a,4,5,6,7,7a- hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436). The major free (unconjugated) metabolite was cis-3a,4,5,6,7, 7a-hexahydro-3-carboxamido-1,2-benzisoxazole; it was also the second most abundant metabolite released during hydrolysis of the conjugated fraction. All other identified metabolites were hydroxylated analogues substituted at C(4)-C(7a) of the cyclohexane ring. the 4-equatorial,5-axial,7a-triol was the second most abundant metabolite excreted in an unconjugated form. Four monohydroxy (5-axial, 6-axial, 6-equatorial, 7-equatorial) metabolites of the drug were identified; they were found in the conjugated fraction only and were released by hydrolysis. The 5-axial hydroxy compound is the major conjugated metabolite and is overall the most abundant of all the metabolites. Six dihydroxy metabolites were identified: one was found exclusively in the free state, three as conjugates only (including the 7-axial,7a-diol, which is the major dihydroxy species), and two both free and conjugated. A second triol was found both free and conjugated.

Die Cyclisierung von 3-(2-Pyridyl)-2,1-benzisoxazol (I) zu (III) uber die Nitren-Zwischenstufe (II) wird auf ahnliche Verbindungen ubertragen.

A series of substituted 5,6-dihydrofuro[3,2-f]-1,2-benzisoxazoles was prepared and evaluated for their saluretic and uricosuric properties. Pharmacological evaluation of the title compounds was carried out in mice, rats, dogs, and monkeys. The diuretic/saluretic nature of these compounds was observed in all species, whereas the uricosuric activity was best seen in the Cebus monkey. Evaluation of the enantiomers of 8-chloro-3-(o-fluorophenyl)-5,6-dihydrofuro [3,2-f]-1,2-benzisoxazole-6-carboxylic acid (15k) revealed that only the (+) enantiomer (29) displayed diuretic and saluretic activity, whereas both enantiomers possessed uricosuric activity. X-ray analysis showed that the (-) enantiomer (30) possesses the 2R configuration.

Hydrogenation of 3-sulfamoylmethyl-1, 2-benzisoxazole (1) gave ω-sulfamoyl-2-hydroxyacetophenone (3) and its imide (2). Treatment of 3 with acid afforded a new route to 1, 2-benzoxathiin-4 (3H)-one-2, 2-dioxide (5). The oxime of 3 (4) was recyclized to provide 1, 2-benzisoxazole derivatives by treatment with acid or base. On pyrolysis 4 gave benzoxazole derivatives.

The site of the electrophilic substitution of 1, 2-benzisoxazole-3-acetic acid (1) altered depending on species of electrophiles and reaction conditions. In halogenation, only the α-methylene group of 1 was substituted. In the chlorosulfonation, the α-methylene group was substituted at first and then the 5-position of the nucleus was substituted. On the other hand, in the nitration, the 5-position was substituted at first and the α-methylene group was substituted secondly.

Several 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives were synthesized from 3-(bromomethyl)-1,2-benzisoxazole by the reaction with sodium bisulfite followed by chlorination and amination. Some of them displayed marked anticonvulsant activity in mice. The introduction of a halogen atom to the 5 position of the benzisoxazole ring caused increased activity and neurotoxicity; the substitution of a sulfamoyl group caused decreased activity. The activity of monoalkylated compounds might be the result of biotransformation. Among these compounds, 3-(sulfamoylmethyl)-1,2-benzisoxazole (1a) was thought to be the most promising as an anticonvulsant from the ratio of NTD50 and ED50.

C8H8N2O3S, Mr = 212.54, monoclinic, P2(1)/a, a = 7.347 (9), b = 13.237 (4), c = 10.128 (8) A, beta = 108.916 (6) degree, V = 931.9 (1) A3, Z = 4, Dm = 1.52 (4), Dx = 1.514 g cm-3, lambda (Cu K alpha) = 1.54184 A, mu = 28.35 cm-1, F(000) = 440, room temperature, R = 0.040 for 1864 observed reflections. The sulfonamide N forms intermolecular hydrogen bonds with the benzisoxazole ring N and also with the O on the sulfonamide group. Centrosymmetrically related benzisoxazole ring pairs are pi bonded with a high degree of overlap.

1,2-Benzisoxazole 2-oxides are prepared by the oxidative cyclisation of o-acylphenol oximes, using either lead(IV) acetate or sodium hypochlorite. The scope and limitations of the reaction are discussed.

1,2-Benzisoxazole N-oxides are prepared by oxidation of o-hydroxyaryl ketoximes with lead tetraacetate.

The indazole, benzisothiazole, and benzisothiazole 1,1-dioxide analogues of [[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]acetic acid were synthesized and tested for diuretic activity in saline-loaded mice. Each analogue was found to be less active than the parent benzisoxazole: the diuretic activity followed the order O greater than S greater than N = SO2 in regard to the heteroatom in the 1-position of the ring.

6-Methoxy-3-(2′-thienyl)-1,2-benzisoxazole has been prepared simultaneously with 6-methoxy-2-(2′-thienyl)-1,3-benzoxazole. The spectral data of these new compounds have been discussed. Mass spectroscopy has proved to be a valid tool in the structural characterization of these isomers and 13C nmr spectrometry confirmed their structures.

Several 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives were synthesized from 3-(bromomethyl)-1,2-benzisoxazole by the reaction with sodium bisulfite followed by chlorination and amination. Some of them displayed marked anticonvulsant activity in mice. The introduction of a halogen atom to the 5 position of the benzisoxazole ring caused increased activity and neurotoxicity; the substitution of a sulfamoyl group caused decreased activity. The activity of monoalkylated compounds might be the result of biotransformation. Among these compounds, 3-(sulfamoylmethyl)-1,2-benzisoxazole (1a) was thought to be the most promising as an anticonvulsant from the ratio of NTD50 and ED50.

The antiprotozoal drug 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (I), which exhibits activity against trypanosomiasis, is also antibacterial in vivo. Since the urine from a dog dosed with I showed a broader spectrum of antibacterial activity than I itself, metabolites from this urine were isolated and partially characterized. The metabolites were mono- and dihydroxy-substituted species with the hydroxyl groups on carbons 4--7 of the hexahydrobenzisoxazole ring. These observations led to the synthesis of several such hydroxy derivatives of I, and their properties fully supported the proposed positions of metabolic hydroxylation. One synthetic compound, the 6,7-cis-dihydroxy compound, exhibited higher antibacterial activity against Salmonella schottmuelleri in mice and greater trypanocidal activity in vivo against Trypanosoma cruzi (Brazil strain) than I.

Le PF-257 ou chlorhydrate de benzisoxalzole-1,2 acetamidoxime-3 produit des effets varies sur le systeme nerveux central des animaux. Le profil pharmacologique et l'action fondamentale de cet agent paraissent nouveaux, compares a ceux des psychotropiques actuels.

Das (i-Hydroxybenzisoxazol (I) reagiert mit den Dialkylsulfaten (II) bzw. den Alkylhallogeniden (III) zu den Alkoxyderivaten (IVa)-(IVd).

A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.

Three benzisoxazole haptens designed to elicit antibody binding sites with widely differing polarity have been synthesized and used to induce antibodies in mice. Monoclonal antibodies were prepared using hybridoma technology, and screened for catalysis of the ring-opening isomerization and/or decarboxylation of a series of related benzisoxazoles and their 3-carboxy-derivatives. No catalysis of decarboxylation was observed, but 4 of a total of 47 antibodies obtained against the three haptens catalyzed the isomerization process. Of 12 antibodies raised against the 3-acetylbenzisoxazole structure 5 none was catalytically active; but one of 24 raised against a 3-isopropenylbenzisoxazole 6 increased the rate of ring-opening of 6-nitrobenzisoxazole, and 5 of 11 antibodies raised against a benzisoxazole 7 with a 3-amidinium group were moderately active against either 6-nitro or 6-acylaminobenzisoxazoles. Competitive binding studies suggest that at least some of the antibodies induced by the isopropenyl hapten do possess a recognizably hydrophobic binding site.