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At least 19 recordsLinked to original sources
PubMed1991

Synthetic approaches to the guanosine and xanthosine analogues 5-amino-3-beta-D-ribofuranosylpyrazolo[3,4-e][1,3]oxazin-7-one and 3-beta-D-ribofuranosylpyrazolo[3,4-e][1,3]oxazine-5,7-dione and studies of their antitumor potential.

5-Amino-3-beta-D-ribofuranosylpyrazolo[3,4-e][1,3]oxazin-7-o ne has been synthesized via cyclization of the appropriately protected pyrazofurin derivatives and subsequent transformations of the heterocyclic moiety. This guanosine analogue was marginally cytotoxic to L1210 cells in vitro. The xanthosine analogue 3-beta-D-ribofuranosylpyrazolo[3,4-e][1,3]oxazine-5,7-dione was also synthesized, and was found to be highly cytotoxic. It appeared to act as a prodrug of pyrazofurin.

Animals↗
PubMed2003

2-silyloxy-1,2-oxazines, a new type of acetals of conjugated nitroso alkenes.

3-alkyl-substituted 1,2-oxazine N-oxides 2 can be selectively transformed into 2-silyloxy-1,2-oxazines 1 upon treatment with silylating reagents. In the solid state derivatives 1 adopt a chair conformation with the pyramidal nitrogen atom, whereas in solution they exist as an equilibrating mixture of two conformers (DeltaG++ 55-60 kJ/mol). A preliminary study of the reactivity of nitrosals 1 has shown that they react with O- and N-stabilized carbocations to yield 1,2-oxazine N-oxides with a functionalized alkyl substituent at the 3-position. Moreover, compounds 1 can rearrange into silyloxy-1,2-oxazines 5 and react with morpholine to produce 3-morpholinoalkyl-1,2-oxazines 7 existing in a tautameric equilibrium with open-chain oximes 6.

Journal Article↗
PubMed1992

Qualitative analysis of the stability of the oxazine ring of various benzoxazine and pyridooxazine derivatives with proton nuclear magnetic resonance spectroscopy.

A series of 3,4-dihydro-1,3-benzoxazine and 3,4-dihydro-1,3-pyridooxazine derivatives was synthesized, and the hydrolysis of the derivatives was studied with proton nuclear magnetic resonance spectroscopy. The oxazine derivatives underwent various degrees of hydrolysis when H2O was added to dimethyl sulfoxide solutions of the compounds. The rates and extents of decomposition of the oxazine ring systems depended on the electronic effects of substituents within the molecules. Examination of the proton nuclear magnetic resonance spectra that were generated during decomposition of the oxazines and trends in stability of the oxazine derivatives suggest the formation of an intermediate in the hydrolysis mechanism.

Drug Stability↗
PubMed1975

2-Aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazines, a new class of antidepressants.

Some 2-aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazines have been shown to possess marked antidepressant activity. The 1,4-oxazines were synthesized by lithium aluminum hydride reduction of the readily available 6-aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazin-3-ones. High antidepressant activity was associated with ortho substitution of the 2-phenoxymethyl group and with 1,4-oxazines devoid of 4-substituents.

Animals↗
PubMed1986

[Compounds with anti-gastric secretion and antiulcer activity. V. Derivatives of 3,3,4a,6,7,11b-hexahydro-2H,5H-benzo [1,4]cyclohep[1,2-b][1,4]-oxazine and related products].

A series of hexahydrobenzo[3,4]cyclohept[1,2-b][1,4]oxazines, with different substituents at the benzene and oxazine rings and nitrogen atom, was synthetized. The diastereomers and enantiomers of the unsubstituted compound and the related derivatives hexahydrobenzo[5,6] and exahydrobenzo[6,7]cyclohept[1,2-b][1,4]oxazine, hexahydro[1]benzoxepine and hexahydro[1]benzothiepin[5,4-b][1,4]oxazine, octahydrobenzo[3,4]cyclohept[1,2-b][1,4]diazine were also prepared. Some of these compounds inhibited at low doses gastric secretion in pylorus-ligated rats and antagonized ulcers in pylorus-ligated rats plus acetylsalicylic acid and in cold+restraint-stressed rats. When the most active compounds were tested on cats with Heidenhain pouch, they induced unwanted side effects that ruled out further development of these chemical series.

Animals↗
PubMed1976

Synthesis and pharmacological evaluation of some 3-substituted octahydropyrido(2,1-c)(1,4)oxazines.

3-Phenyloctahydropyrido[2,1-c][1,4]oxazine hydrochloride and the 10R and 10S diastereomers have been synthesized from (+/-)-, (+)-, and (-)-2-piperidinemethanol. Treatment of 2-piperidinemethanol with alpha-bromoacetophenone gave 3-hydroxy-3-phenyloctahydropyrido[2,1-c][1,4]oxazine which was readily converted to the 3-phenyl derivative by catalytic hydrogenolysis. These compounds were shown to possess a depressant action on the CNS which was quantitated in terms of reduction of locomotor activity in mice. Qualitative differences were noted in the central effects of the 3-phenyl compound and its hemiketal derivative. Further, qualitative differences in the effects of the diastereomers of the 3-phenyl compound on locomotor activity of mice were also noted. The results of this study suggest that the octahydropyrido[2,1-c]1,4]oxazine system may provide a useful molecular framework for the construction of agents exhibiting pharmacologically useful actions in the CNS.

Animals↗
PubMed1976

Synthesis and biological studies of 3-(beta-D-ribofuranosyl)-2,3,-dihydro-6H-1,3-oxazine-2,6-dione, a new pyrimidine nucleoside analog related to uridine.

Reaction of the trimethylsilyl derivative of 2,3-dihydro-6H-1,3-oxazine-2,6-dione (2, "uracil anhydride") with protected 1-O-acetylribofuranoses in the presence of stannic chloride gave the corresponding block nucleosides. 3-(2,3-5-Tri-O-2',2',2'-trichloroethoxycarbonyl-beta-d-ribofuranosyl)-2,3-dihydro-6H-1,3-oxazine-2,6-dione (4c) thus prepared from the protected sugar 3c, 1-O-acetyl-2,3,5-tri-O-(2,2,2-trichloroethoxycarbonyl)ribofuranose, gave, on removal of the protecting groups with zinc dust,3-(beta-d-ribofuranosyl)-2,3-dihydro-6H-1,3-oxazine-2,6-dione (1). The structure of 1 was confirmed by uv, ir, NMR, and CD spectral data and was shown to be an N nucleoside. Uracil anhydride, 2, and, to a lesser extent, its ribonucleoside 1 exert a moderate growth inhibition of mouse leukemia L5178Y, HeLa, and Novikoff hepatoma cells i- culture. Both compounds produce weak inhibition of vaccinia viral replication in HeLa cells.

Animals↗
PubMed2002

Alternate substrate inhibition of cholesterol esterase by thieno[2,3-d][1,3]oxazin-4-ones.

In a kinetic study, the interaction of bovine pancreatic cholesterol esterase (CEase) with fused 1,3-oxazin-4-ones and 1,3-thiazin-4-ones was investigated, and the compounds were characterized as alternate substrate inhibitors. Inhibition assays were performed in the presence of sodium taurocholate with p-nitrophenyl butyrate as chromogenic substrate. Strong active site-directed inhibition was detected for 2-diethylaminothieno[2,3-d][1,3]oxazin-4-ones with a cycloaliphatic chain at positions 5,6. The most potent inhibitors, compounds 3 and 4, exhibited K(i) values of 0.58 and 1.86 microm, respectively. An exchange of the ring oxygen by sulfur and the removal of the cycloaliphatic moiety as well as the replacement of the thiophene ring by benzene led to a loss of inhibitory potency. CEase has the capability to catalyze the hydrolysis of representatives of fused 1,3-oxazin-4-ones as well as the highly stable 1,3-thiazin-4-ones by using an acylation-deacylation mechanism. Hydrolyses were performed in the presence of a high enzyme concentration, and products were identified spectrophotometrically and by means of high performance liquid chromatography. The kinetic parameters V(max)I and V(max)I/K(m)(I) for the CEase-catalyzed turnover were determined. The compounds whose enzyme-catalyzed hydrolysis followed first-order kinetics (K(m)(I) > 25 microm) failed to inhibit CEase. On the other hand, inhibitors 3 (initial concentration of 25 microm) and 4 (20 microm) were hydrolyzed by CEase under steady-state conditions in the first phase of the reaction. Rate-limiting deacylation was demonstrated in nucleophilic competition experiments with ethanol as acyl acceptor wherein the conversion of compound 3 was accelerated up to an ethanol concentration of 1.5 m. The characterization of these compounds (i.e. 3 and 4) as alternate substrate inhibitors is not only based on the verification of the CEase-catalyzed hydrolysis. It also rests upon the concurrence of corresponding K(i) values obtained in the inhibition assay compared with separately determined K(m)(I) values of their enzyme-catalyzed consumption, as could be predicted from the kinetic model used in this study.

Animals↗
PubMed1997

Design, synthesis and quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine derivatives as potent Na/H exchange inhibitors.

Inhibition of the Na/H exchanger is a promising approach for treating ischemia-reperfusion injury, but no clinical agent is yet available. Recently, we established the structural requirements for potent inhibitors of the Na/H exchanger. In the present work, we designed N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine 3a as a new lead compound for potent inhibitors with good water-solubility, based on the previous information. During the structural optimization, care was taken to keep the hydrophobicity (clogP) in the range of about 1.5-2.0, which is considered optimum for good bioavailability. Various derivatives of 3a were synthesized and the quantitative structure-activity relationship (QSAR) was studied. The QSAR result indicated that the lengths of the substituents at the 2- and the 4-positions of the 2H-benzo[1,4]oxazine ring are parabolically related to activity. The most potent compounds were (R) and/or (S)-N-(2-ethyl-4-isopropyl(or ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidines 3q-t with IC50 values of 0.036-0.073 microM. The water-solubility of the hydrochlorides and methanesulfonates is 3-5 mg/ml, which is sufficient for therapeutic use.

Animals↗
PubMedDate not supplied

Cytochrome P450 modification by a new oxazine derivative with hypolipidemic activity.

Plasma lipoprotein levels, related to atheromatosis, are influenced by liver function. Microsomal enzyme inducers are reported to modify serum lipoproteins and triglycerides. In this study, the effects of subchronic and acute treatment of rats with 3-(4-biphenyl)-3-n-propoxy-octahydro-1,4-pyrido[2,1-c]oxazine, a novel compound with hypolipidemic and antioxidant activities, on rat hepatic microsomal protein and total cytochrome P450, as well as on p-nitrophenol hydroxylase (CYP2E) and erythromycin N-demethylase (CYP3A) activities are examined. The subchronic treatment had no significant effect on liver weight, microsomal protein and total cytochrome P450. The acute administration lowered considerably cytochrome P450 content. The metabolic activities of CYP2E1 and CYP3A1/2 were not altered by the subchronic treatment, but were notably decreased after the single administration of 3-(4-biphenyl)-3-n-propoxy-octahydro-1,4-pyrido[2,1-c]oxazine. The inhibition of drug metabolism by 3-(4-biphenyl)-3-n-propoxy-octahydro-1,4-pyrido[2,1-c]oxazine cannot be completely correlated with the modification of plasma cholesterol, triglycerides and LDL cholesterol, although published data connect microsomal enzyme induction with a decrease of these parameters. This discrepancy could be attributed to the different biochemical events involved in enzyme induction and inhibition.

Animals↗
PubMed2001

Asymmetric mono-oxazine: an inevitable product from Mannich reaction of benzoxazine dimers.

The Mannich reaction is detailed, which was carried out on benzoxazine dimers under various conditions, that is, temperature, reaction time, and solvents. Against our expectation, in any condition, instead of generating a disubstitution oxazine compound, the reaction gives a product with only a single oxazine ring, a mono-oxazine benzoxazine dimer, as characterized by FT-IR, 1H NMR, 13C NMR, 2D-NMR (1H-1H COSY, 1H-13C HMQC, and 1H-13C HMBC), and EA. The asymmetrical reaction is found to be based on the original structure of the benzoxazine dimer which has two phenol rings in a different stability as clarified by X-ray structure analysis of the single crystal. All types of benzoxazine dimers indicate the specific structure with a pair of inter- and intramolecular hydrogen bonds. The bond distance indicates that the intramolecular hydrogen bonding is very strong, while the packing structure emphasizes the high stability of the dimer unit and implies the deactivation of one phenol ring in the benzoxazine dimer. In this contribution, we demonstrate one of the quite rare examples, showing how the stereostructure of the reactant molecule is an important factor to control the reaction and give an asymmetric product which we never expected when considering only the chemical formula.

Journal Article↗
PubMed1976

Optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and related compounds.

The optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine have been prepared and absolute configurations have been assigned. In their action on the central nervous system the S isomers are at least ten times more potent than the R isomers. The intermediate 4-benzyl-2-(p-toluensulfonyloxymethyl)tetrahydro-1,4-oxazine has been resolved. Its isomers provide a convenient starting point for the preparation of optical isomers of viloxazine analogues of known configuration.

Animals↗
PubMed2001

Hetero-Diels-Alder reactions of alpha-aryl-beta-monohalo-alpha-nitrosoethylenes: diastereoselective synthesis of 6-substituted 3-aryl-4-halo-5,6-dihydro-4H-1,2-oxazines.

Treatment of alpha-aryl-beta-bromo(or chloro)-alpha-nitrosoethylene, prepared in situ from alpha-monobromo(or chloro)ketoximes and sodium carbonate in ether at rt, with allytrimethylsilane afforded exclusively trans-(4S,6S)- and trans-(4R,6R)-3-aryl-4-halo-6-[(trimethylsilyl)methyl]-5,6-dihydro-4H-1,2-oxazines 10 albeit in low yields. Similar treatment of beta-halo-alpha-nitrosoethylenes with ethyl vinyl ether, however, gave single stereoisomers, i.e., cis-(4S,6S)- and cis-(4R,6R)-6-ethoxy-4-halo-5,6-dihydro-4H-1,2-oxazines 11, in moderate to good yields. The result is in contrast to the reported predominant formation of trans-11a by a radical reaction. On the other hand, similar reactions with tert-butyl vinyl ether at 30 degrees C gave diastereomeric mixtures of cis-(4S,6S)-, cis-(4R,6R)-, trans-(4S,6R)-, and trans-(4R,6S)-6-(tert-butoxy)-4-halo-5,6-dihydro-4H-1,2-oxazines 12. In contrast to compounds 11, the major isomers have (4S,6R) and (4R,6S) configurations. The tendency of a [4 + 2] cycloaddition reaction is consistent with that observed in the Diels-Alder reaction with inverse-electron demand. The stereochemistries of compounds 10-12 were assigned on the basis of the (1)H NMR coupling constants, which were unambiguously determined by the decoupling experiments. All reactions leading to compounds 10-12 proceed with very high regioselectivity. Diastereoselectivity and high regioselectivity are understood in terms of the frontier orbital method. It has been found that cis-12g is isomerized to a mixture of stereoisomers in favor of the trans-isomer in the presence of HClO(4) (72%) in CHCl(3) at rt.

Journal Article↗