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PubMed1979

Synthesis and biological activity of 5-fluoro- and 5-methyl-1,3-oxazine-2,6(3H)-dione.

5-Fluoro-1,3-oxazine-2,6(3H)-dione (3-oxa-FU) was synthesized by reacting 3-oxauracil with fluoroxytrifluoromethane and decomposing the adduct in the presence of a catalytic amount of Et3N. 5-Methyl-1,3-oxazine-2,6(3H)-dione (3-oxathymine) was prepared by polyphosphoric acid catalyzed ring closure of beta-(N-ethoxycarbonylamino)-2-methacrylic acid and by treatment of citraconimide with sodium hypochlorite. As determined in vitro, 3-oxa-FU was markedly inhibitory to S. faecium (ID50 = 9 X 10(-8) M) and E. coli (ID50 = 1 X 10(-7) M) but was less active against leukemia L-1210 cells (ID50 = 1 X 10(-5) M). At 1 x 10(-4) M, 3-oxathymine was inactive in these cell systems. Inhibition of the growth of S. faecium by 3-oxa-FU was reversed competitively by the natural pyrimidines. The relatively rapid hydrolysis of the compounds in the growth media is a major factor in determining their biological effectiveness.

Animals↗
PubMed1984

Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists.

A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.

Animals↗
PubMed2002

Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines.

A series of phenylcarbamate analogues of geneserine (8, 10, 12, 14) were synthesized from their counterparts, the phenylcarbamate analogues of physostigmine (2-5), by oxidation. The geneserine analogues can undergo tautomerism between N-oxide and 1,2-oxazine structures in a pH- and time-dependent manner. Assessment by (1)H NMR indicated that the N-oxide structure is adopted at neutral pH and that the compound exists in an equilibrium between several epimers. Evaluation of their biological action to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), ex vivo, demonstrated that the N-oxide (7, 9, 11, 13, 15) and 1,2-oxazine (6, 8, 10, 12, 14) structures possessed similar potencies against AChE, but the latter structures were more potent against BChE. With the exception of the BChE selective inhibitor, 12, none of the geneserine analogues were as potent or enzyme subtype selective as their physostigmine analogue counterparts.

Acetylcholinesterase↗
PubMed1998

Novel thieno[2,3-d][1,3]oxazin-4-ones as inhibitors of human leukocyte elastase.

A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with Ki values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.

Enzyme Inhibitors↗
PubMed1997

Antihypertensive effect of some oxazolo[3,2-a]pyridines, thiazolo[3,2-a]pyridines and pyrido[2,1-b]oxazines in conscious spontaneously hypertensive rats.

The antihypertensive activity of eighteen 'oxazolo[3,2-a]pyridine, thiazolo[3,2-a]pyridine and pyrido[2,1-b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference. At a dose of 50 mg kg-1 (i.p.) eleven compounds resulted in a significant reduction in mean arterial blood pressure; four of the eleven were particularly effective, resulting in significant hypotension more than 6 h after administration and an effect that was still apparent after 24 h. The hypotension induced by nifedipine gradually decreased, disappearing 6-8 h after administration. The long-lasting activity shown by these compounds is, in general, not accompanied by reflex tachycardia. Intraperitoneal administration of two oxazolo[3,2-a]pyridine derivatives and two pyrido[2,1-b]oxazine derivatives resulted in potent and long-lasting antihypertensive action in SHRs. Further studies on the mechanism of action of these derivatives might help the determination of better structure-activity correlations and the design, synthesis and evaluation of better antihypertensive agents.

Animals↗
PubMed1996

Synthesis of furonaphth[1,3]oxazine and furo[1,3]oxazinoquinoline derivatives as precursors for an o-quinonemethide structure and potential antitumor agents.

The synthesis of dihydro furonaphth[1,3]oxazine derivatives 3 was performed through a Mannich-type condensation between 2-cyano-5-hydroxy-3-methylnaphtho[1,2]furan 2a, 1.5 eq of a primary amine and 3 eq of formaldehyde. Similarly, 2-cyano-5-hydroxy-3-methylfuro[2,3-f]quinoline 2b gave the dihydro furo[1,3]oxazino-quinoline compounds 4. Heating a mixture of the naphthofuran 2a, tert-butylamine and formaldehyde at toluene reflux led to the furonaphthoxazine 3e, which decomposes to afford an o-quinonemethide intermediate 5. The latter was trapped with 1-morpholinopropene to give a dihydro furonaphthopyran derivative 6. All compounds 2, 3, 4 and 6 were assayed for in vitro cytotoxic activity toward L 1210, MDA-MB 231 and PC tumor cells. Among them, furonaphth[1,3]oxazines 3b, 3c, and furo[1,3]oxazinoquinolines 4c, 4d showed significant activity against L 1210 cells, while furoquinoline 2b was the most cytotoxic compound towards all three cell lines.

Animals↗
PubMed1995

A selective stain for eosinophils using two oxazine dyes applied sequentially.

A methanolic solution of the oxazine textile dye, C.I. basic blue 122, followed by an aqueous alkaline solution of the oxazine dye, C.I. basic blue 141, and a brief rinse in an acetate buffer at pH 3.45 produces intense black staining of eosinophil granules. This staining was selective for eosinophils while other types of peripheral blood leukocytes showed little if any staining under the same conditions. This staining procedure may be useful for detecting eosinophils in samples of blood, bone marrow, or urine when eosinophiluria results from interstitial nephritis.

Eosinophils↗
PubMedDate not supplied

[Toxicity and radioprotective properties of 1,3-oxazine and 1,3-thiazine derivatives].

Toxicity and radioprotective properties of 18 derivatives of oxazine and thiazine with a varying degree of the cycle saturation were studied in experiments on mice. Monotypic regularity in variations of their toxic properties relative to the chemical structure was noted. 4,4,6-Trimethyl-2-dimethylamino-4H-1,3-oxazine exerted a pronounced radioprotective action.

Animals↗
PubMed1993

[Biological effects of substances similar to salicylanilides. 3-aryl-2H, 4H-benz(e)(1,3)oxazine-2, 4-diones and thiosalicylanilides].

The review paper is the first collected communication about the biological activity of 3-aryl-2H,4H-benz(e)(1,3)oxazine-2,4-diones and thiosalicylanilides. The substances of the above mentioned structures show a number of biological activities (antibacterial, antituberculous, antimycotic, anthelmintic, molluscocidal, neuroleptic, analgesic and anti-inflammatory) which can be modelled by structural changes. Only very few of them have been hitherto introduced into practice as anthelmintic agents, or agents with a special purpose (destroying the sea lamprey in Canadian lakes). In the group of 3-aryl-2H,3H-benz(e)(1,3)-oxazine-2,4-diones, i.e. substances developed from salicylanilides by the action of alkyl-chloroformiates, antibacterial activity is reported in refs. 3-12, antituberculous activity in refs. 13, 14, antimycotic activity in refs. 5, 6, 9, 12, 15, 16, anthelmintic activity in refs. 6,917-20, molluscocidal activity in refs. 6, 21, analgesic and anti-inflammatory activity in refs. 22-24, herbicidal activity in refs. 25, 26, allergenic activity in ref. 27. In the group of salicylanilides, antibacterial activity is reported in refs. 28-37, antimycotic activity in refs. 28-36, antiprotozoal activity in ref. 35, anthelmintic activity in refs. 28-40, 49, molluscocidal activity in refs. 7, 28-36. The present paper furthermore sums up the papers concerned with the toxicities of the above-mentioned agents. Though the peak of research of the groups of the above-mentioned structure was in the 1960s and 1970s, papers investigating their biological activity can be encountered also at present.

Analgesics↗
PubMed2004

Ring contraction reactions of 2,3-dihydro-4H-1,3-oxazin-4-ones under electrospray ionization conditions.

The mass spectral behavior of 2,3-dihydro-4H-1,3-oxazin-4-ones has been investigated using electrospray ionization multi-stage mass spectrometry (ESI-MS(n)). All compounds showed a predominant retro-Diels-Alder (RDA) fragmentation pathway, and a novel ring contraction reaction by loss of isocynates was also found. The fragmentation mechanisms proposed for 4H-1,3-oxazin-4-ones are supported by ESI-MS/MS/MS spectra.

Journal Article↗
PubMed2005

Development of 3,4-dihydro-2H-benzo[1,4]oxazine derivatives as dual thromboxane A2 receptor antagonists and prostacyclin receptor agonists.

We discovered a novel series of 3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid derivatives as potent dual-acting agents to block the TXA2 receptor and to activate the PGI2 receptor. We report the synthesis, structure-activity relationship, and in vitro, ex vivo, and in vivo pharmacology of this series of compounds. 4-[2-(1,1-Diphenylethylsulfanyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid N-methyl-D-glucamine salt (7) is a promising candidate for a novel treatment in the anti-thrombotic and the cardiovascular fields avoiding hypotensive side effects.

Animals↗
PubMedDate not supplied

Resin-bound 4H-1,3-oxazine-masked beta-diketones for functionalizing cleavage strategy.

Resin-bound 4H-1,3-oxazines are synthesized by the stepwise condensation of an amide resin, an aldehyde, and an alkyne. Upon DDQ activation, oxazines are converted into oxazinium salts. When treated with hydrazines, these resin-bound beta-diketone equivalents yield pyrazoles through a functionalizing release process. This multicomponent capture strategy, tedious to handle in classical synthesis in solution, is well-suited to solid-supported chemistry. It facilitates the handling of sensitive and unstable intermediates, such as N-alpha-methoxyalkylamides and 1,3-oxazinium salts.

Journal Article↗
PubMed2003

Synthesis of oxazines and N-arylpyrroles by reaction of unfunctionalized dienes with nitroarenes and carbon monoxide, catalyzed by palladium-phenanthroline complexes.

The reaction between an unfunctionalized conjugated diene and a nitroarene under CO pressure and at 100 degrees C, catalyzed by [Pd(Phen)2][BF4]2 (Phen = 1,10-phenanthroline), affords the corresponding hetero-Diels-Alder adduct (oxazine) in up to 91% yields in one pot. If the reaction mixture is then heated to 200 degrees C, the oxazines are converted into the corresponding N-arylpyrroles in good yields. Pressures as low as 5 bar can be employed, and 0.08% catalyst is sufficient to effect the transformation. The reaction can be equally run by employing the nitroarene or the diene as limiting agent and works well for nitroarenes bearing either electron-withdrawing or mildly electron-donating substituents. A moderate steric hindrance on the nitroarene (o-methyl) is well tolerated, but 1,4-disubstituted-1,3-dienes are not suitable substrates.

Journal Article↗
PubMed2005

Energy profiles for ketene cyclizations. Interconversion of 1,3-oxazin-6-ones, mesoionic 1,3-oxazinium olates and acylketenes, imidoylketenes, oxoketenimines, and cyclization products.

The energy surface connecting oxazinium olates 9, several possible conformers of ketenes 10 and 11, and the final cyclization products 12, 13 and 14, as well as the isomeric 1,3-oxazine-6-ones 15, ring opening of the latter to N-acylimidoylketenes 16, and subsequent rearrangement of 16 to oxoketenimines 17, azetinones 18, and the cyclization products 19 and 20 are evaluated computationally at the B3LYP/6-31G and B3LYP/6-311+G//B3LYP/6-31G levels. The cyclizations of ketenes to oxazinium olates 9 and oxazines 15 have the characteristics of pseudopericyclic reactions. Plots of the energy vs internal reaction coordinate for the cyclization of transoid acylketenes such as 10 to 9 (via TS1) and 16 to 15 (via TS7) feature two inflection points and indicate that the part of the energy surface above the lower inflection points describe internal rotation of the acyl function in the ketene moiety, and the part below this point describes the cyclization of the cisoid ketene to the planar mesoionic oxazinium olate 9 or oxazinone 15. The 1,3-shifts of the OR group that interconvert ketenes 16 and ketenimines 17 via four-membered cyclic transition states TS8 behave similarly, the first portion (from the ketenimine side) of the activation barrier being due largely to internal rotation of substituents, and the top part being due to the 1,3-shift proper.

Journal Article↗
PubMed2005

Fast and stable photochromic oxazines.

We have designed and synthesized two photochromic compounds incorporating fused indoline and benzooxazine fragments. Variable-temperature 1H NMR spectroscopy demonstrates that their central [1,3]oxazine ring opens thermally with free energy barriers ranging from 14 to 19 kcal mol(-1). The ring-opened species reverts rapidly to the original isomer and can only be detected after chemical trapping. Specifically, the nucleophilic attack of a hydroxide anion to the indolium cation of the ring-opened species prevents re-isomerization. Laser excitation of both compounds induces the opening of the [1,3]oxazine ring in less than 6 ns with quantum yields up to 0.1. The photoinduced ring opening generates a 4-nitrophenolate chromophore, which absorbs strongly at 440 nm. The photogenerated species reverts to the original form with a lifetime of 22 ns for both compounds. Thus, these transformations can be exploited to interconvert the two isomers of each species with nanosecond switching speeds. Furthermore, thousands of switching cycles can be repeated consecutively without any sign of degradation, even in the presence of molecular oxygen. These processes can be reproduced efficiently in poly(methyl methacrylate) matrixes. Under these conditions, the thermal re-isomerization occurs with biexponential kinetics in submillisecond time scales. In principle, the fast isomerization kinetics and excellent fatigue resistance of both compounds offer the opportunity to modulate rapidly and efficiently a variety of molecular and macroscopic properties. Thus, our molecular design can evolve into the realization of a new family of photochromic compounds and materials with promising photoresponsive character.

Journal Article↗
PubMed2005

Investigation of the Diels-Alder cycloadditions of 2(H)-1,4-oxazin-2-ones.

[Reaction: see text]. A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-positions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-deficient, and electron-neutral dienophiles. These reactions proceed with moderate regio- and stereoselectivity to afford relatively stable and readily isolable bridged bicyclic lactone cycloadducts. Chemical manipulation of these cycloadducts affords highly substituted and functionally rich piperidines. The regio- and stereochemical preferences of the cycloadditions of 5-chloro-2(H)-1,4-oxazin-2-ones are investigated computationally using density functional theory (B3LYP/6-31G).

Journal Article↗
PubMed2006

Substituted 2-methylene-1,3-oxazolidines, -1,3-thiazolidines, -1,3-benzothiazines, -1,3-oxazines, and substituted imidazopyrimidinediones from Cl(CH2)nNCO and Cl(CH2)nNCS and active methylene compounds.

The reaction of omega-chloroalkyl isocyanates Cl(CH2)nNCO (n = 2 (2), 3 (4)) and isothiocyanate Cl(CH2)2NCS (3) with active methylene compounds CH2YY' 1 in the presence of Et3N or Na give 2-YY'-methylene-1,3-oxazolidines, (E,Z)-1,3-thiazolidines, and 1,3-oxazines from 2, 3, and 4, respectively. 2-(Chloromethyl)phenyl isocyanate 8 gives with 1 the corresponding benzo-oxazines. Ethyl 2-isothiocyanatobenzoate 10 gives the corresponding benzothiazolinone, whereas the analogous isocyanate 12 gives noncyclic enols. Ethoxycarbonyl isothiocyanate 14 gives an open-chain thioenol or an enol-thioamide. The cyanoamides CH2(CN)CONHR, R = H, Me, CHPh2, give with Et3N and 2 the bicyclic imidazopyrimidinediones 16, derived from two molecules of 2, but with their preformed Na salt they give the 1,3-oxazolidines. Reaction of cyanoacetamide with 3 in the presence of Na gave a tricyclic triaza(thia)indacene, derived from two molecules of 3. A reaction mechanism involving an initial attack of the anion 1- on the N=C=X (X = O, S) moiety gives an anion 18, which cyclizes intramolecularly and after tautomerization gives the mono-ring heterocycle. With the cyanoamides, the N- site of the ambident ion 18 attacks another molecule of 2 giving the anion 20, which by intramolecular attack on the CN, followed by expulsion of the Cl- gives the bicyclic 16 after tautomerization.

Journal Article↗
PubMed2005

Chirp dependence of wave packet motion in oxazine 1.

The motion of vibrational wave packets in the system oxazine 1 in methanol is investigated by spectrally resolved transient absorption spectroscopy. The spectral properties of the probe pulse from 600 to 700 nm were chosen to cover the overlap region where ground-state bleach and stimulated emission signals are detected. The spectral phase of the pump pulse was manipulated by a liquid crystal display based pulse-shaping setup. Chirped excitation pulses of negative and positive chirp can be used to excite vibrational modes predominantly in the ground or excited state, respectively. To distinguish the observed wave packets in oxazine 1 moving in the ground or excited state, spectrally resolved transient absorption experiments are performed for various values of the linear chirp of the pump pulses. The amplitudes of the wave packet motion show an asymmetric behavior with an optimum signal for a negative chirp of -0.75 +/- 0.2 fs/nm, which indicates that predominantly ground-state wave packets are observed.

Journal Article↗