NL8105883A - SUBSTITUTED TETRAHYDRO-1,2,4-OXADIAZIN-5-ON DERIVATIVES WITH ANTI-COMPULSIVE ACTIVITY, METHOD FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

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Substituted tetrahydro-1,2,4-oxadiazin-5-one derivatives with anticonvulsant activity, process for their preparation and pharmaceutical compositions containing these derivatives »

The invention relates to new tetrahydro-1,2,4-oxadia-5-one derivatives with a CNS activity. More particularly, the invention relates to new substituted tetrahydro-1,2,4-oxadiazin-5-one derivatives of the general formula 1, wherein 5 R.2 is hydrogen, alkylcarbonyl having 1 to 12 carbon atoms in the alkyl moiety optionally substituted with halogen, formyl, benzoyl optionally substituted with methoxy, halogen or trifluoromethyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, optionally substituted on the nitrogen atom is carbamoyl or N-benzyloxycarbonyl-10 glycyl, r 3 alkyl having 1 to 5 carbon atoms of nitrofuryl, optionally substituted is phenyl, naphthyl or thienyl and Rp 'is hydrogen, or R' and r3 'together form a pentamethylene group, R' is hydrogen or acyl, hydrogen is alkyl of 1 to 5 carbon atoms, phenyl or benzyl and r6 'is hydrogen or R 1 and R 6 'each represent a phenyl group, having anticonvulsant activity.

In another aspect, methods of preparing these compounds are provided. Another aspect of the invention is a pharmaceutical composition which contains, as active ingredient, a pharmaceutically effective amount of a compound of formula 1 with at least one pharmaceutically inert carrier or the like diluent.

Substituted derivatives of tetrahydro-1,2,4-oxadiazine have only recently become known in the art. The synthesis of such compounds was first reported by Calcagno et al.

(J. Org. Chem. 39, 162 (1974)). The authors prepare 4-aroyl-tetrahydro-1,2,4-oxadiazine by cyclic addition of a nitron and a corresponding 1-aroyl-aziridine. Recently, F.G. Riddel et al (Heterocycles _9, (1978) 267; Tetrahedron 35, (1979) 1391) a tetrahydro-1,2,4-oxadiazine structure prepared by condensing an N-alkyl-0- (methylamino) -ethylhydroxylamine with formaldehyde .

The biological activity of these compounds was not reported, nor were tetrahydro-1,2,4-oxadiazine derivatives containing 8105883 * 2 an oxo group in the 5-position.

Surprisingly, it has been found that the compounds of formula I, wherein R2, R3, R3 ", R4, R6 and r6" as described above, have valuable pharmacological properties, especially without showing excellent CNS activity.

It was further found that the new tetrahydro-1,2,4-oxadiazin-5-one derivatives of the formula 1 are obtained by a) condensation of an α-aminooxycarboxylic amide of the formula 2, wherein R2 * has the same meaning as R2 as defined above, except hydrogen and R 2 and R 2 T as defined above, with an oxo compound of formula 3, wherein R 3 and R 3 'as defined above, in a protic or aprotic environment, in the presence of an acid, for the preparation of compounds of formula 1, wherein R 2 is other than hydrogen and R 4 is hydrogen, or h) treatment of a compound of formula 1, wherein R 2 is benzyloxy-carbonyl and R 4 is hydrogen, R 3, R 3 ', R 4 and R ^ * as defined above, with catalytically activated hydrogen to provide compounds of formula 1 wherein R2 and R4 are hydrogen, or c) reaction of. a compound of formula 1, wherein R 2 is hydrogen, R 3, R 3r, 'R 4, R 6 and R 2' have the same meaning as defined above, with an acyl halide or carboxylic anhydride of the formula 4, wherein X is halogen or an acyloxy group of the formula R2 "-O— is wherein R2 * 25 is as defined above to obtain compounds of formula 1, wherein R2 is an acyl group as defined in connection with R2" above, or d) conversion of a compound of formula 1, wherein R 2 is hydrogen, R 3, R 3 ', r 6 and R 6 * as defined above, with formic acid in the presence of a condensing agent to obtain compounds of formula 1, wherein R 2 is formyl, or e) reaction of a compound of formula 1, wherein R 4 is hydrogen and R 2, R 3, R 3 *, R 4 and R 3 'as defined above, with acetyl chloride or acetic anhydride under reactive conditions to obtain compounds of formula 1, wherein R 4 is acetyl, or f) response from a compound of formula 1, wherein R 2 is phenoxycarbonyl and E3, R3 *, R4, R ^ and R ^ * as defined above, with ammonia or a primary or secondary amine to obtain 40 compounds of formula 1, wherein R2 is an optional to the nitrogen 8105883 5 1 atom substituted carbamoyl group, or g) reaction of a compound of formula 1, wherein R 1 is hydrogen and R 1, r 3, r 6 and R®f are as defined above, with an alkyl isocyanate of formula 5, wherein 5 is R alkyl of 1 to 6 carbon atoms to obtain compounds of formula 1 wherein R 1 is N-alkyl carbamoyl.

The term "alkyl" alone or in alkyl-containing groups is used herein to refer to straight or branched chain saturated hydrocarbon groups. The alkyl groups R 1 and R 2 contain 1 to 5, preferably 1 to 4, and more preferably 1 or 2 carbon atoms. In the definition of R 1, the alkyl portion of the alkyl carbonyl group contains 1 to 12, preferably 1 to 6, and more preferably 1 to 4 carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

In the definition of R 1, the term "acyl" preferably refers to alkanoyl groups of 1 to 6, preferably 1 to 4 carbon atoms, and preferably is acetyl.

Preferred representatives of compounds of formula 1 are the following: 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one, 2-acetyl-3-phenyl-6-methyl -tetrahydro-1,2,4-oxadiazin-5-one and its optical antipodes, 2,4-diacetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one and 2-acetyl-3- thienyl-tetrahydro-1,2,4-oxadiazin-5-one.

The previously defined process variant a) can be carried out in aprotic or protic solvents. Hydrocarbons, for example benzene or toluene, are preferably used as the aprotic solvent. The solubility of the reagents can be improved by adding a small amount of butyl acetate to the reaction medium. The reaction is catalyzed by a catalytic amount of acids, preferably inorganic acids, for example sulfuric acid, preferably camphor-10-sulfonic acid (camphor-10-sulfonic acid has not previously been proposed for a similar purpose). To eliminate the solvent formed during the reaction, the reaction is preferably conducted at a temperature of about the boiling point of the reaction mixture and water formed is continuously eliminated through a suitable water separator.

For example, a 1: 1 mixture of acetic acid and acetic anhydride can be used as protic solvent in method variant a), if desired in the presence of an inorganic acid and camphor-10-sulfonic acid. In this case, the reaction can be successfully performed even at room temperature.

The reaction is preferably followed by thin layer chromatography. Once the reaction is complete, the solvent is removed in a conventional manner and the residue is recrystallized from a suitable solvent.

The α-aminooxycarboxylic acid amides of the general formula II, which are used as starting compounds in process variant a), are known (see, for example, A. Frank and K. Riedl, Mh. Chem. 92, (1961) 725; Blaser et al Helv Chim Acta 1969, 569; M. Bellando et al. II Farm. Ed. Sci. 1976, 31 (3), 169), which can be prepared according to the methods described in the cited literature or by reaction of acetethyl droxamic acid with a corresponding o-halocarboxylic acid amide.

In process variant b), compounds of formula 1, wherein R 2 is benzyloxycarbonyl and R 2 is hydrogen, prepared according to process variant a) are used as starting products. The benzyloxycarboxylic acid group is cleaved from these compounds by catalytic hydrogenation. The hydrogenation is carried out in a suitable organic solvent or solvent mixture, for example methanol or ethyl acetate, preferably under atmospheric pressure, preferably using palladium on charcoal as a catalyst. In order to avoid the formation of by-products, the progress of the reaction is preferably followed by thin layer chromatography. The reaction is stopped as soon as the reaction is free from starting compounds according to the thin layer chromatogram and at the same time the amount of by-products is negligible. The catalyst is then filtered off, the filtrate is evaporated and the residue is triturated with an inert solvent and / or recrystallized.

According to process variant c), the compounds of formula 1, wherein R 1 is hydrogen (which can be prepared, for example, according to process variant b), are converted into compounds of formula 1, in which R 1 represents an acyl group. The acylation is carried out by means of • compounds of formula 4, which contain the desired acyl part. Compounds of formula 4 are either acyl halides or carboxylic anhydrides. The reaction is effected by conventional N-acylation methods under conventional conditions. Preferably, a solution of the starting compound in a dry organic solvent is added with a cooled solution of the corresponding acyl-40 halide, preferably acyl chloride, in an organic solvent at 8105883 ° C in the presence of an acid binding agent. When a carboxylic anhydride of formula IV is used as an acylating agent, this solvent can also serve as a reaction medium.

The starting compounds of process variant c) may also contain an exchangeable hydrogen atom on the nitrogen atoms in the 2 and 4 position. Under the reaction conditions described above, however, nitrogen in the 2-position is always acylated selectively. However, when the compounds of formula 1 containing hydrogen instead of R2 and are acylated with acetyl chloride or acetic anhydride under severe reaction conditions (in the presence of excess acylating agent under boiling), the corresponding 2,4-diacetyl compound is reacted obtained. Similarly, in the 2-position acylated compounds which contain hydrogen in the 4-position, a further acetyl-15 group can be introduced under the reaction conditions described above.

The elimination of the 2-benzyloxycarbonyl group according to process variant b) and the acylation of the obtained compound according to process variant c) can also be carried out simultaneously, when an acid anhydride corresponding to the 2-position to be introduced acyl group, is used as reaction medium in the catalytic hydrogenation step. In this case, parallel to the cleavage of the 2-benzyloxycarbonyl group, the acylation at the 2 position also takes place.

Compounds of formula 1, which contain a formyl group instead of R2, can be prepared according to process variant d) by a compound of formula 1, wherein R2 is hydrogen, with formic acid in a dry organic solvent, for example dry tetrahydrofuran, in the presence of a condensing agent, for example dicyclohexylcarbo diimide. The reaction is preferably carried out at a temperature between 0 and -10 ° C.

Compounds of formula 1, prepared according to process variant c), which contain a phenoxycarbonyl group instead of R2, can be converted into compounds of formula 1, wherein R2 is an optionally substituted nitrogen atom carbamoyl group according to method of variant f ). The reaction is carried out by reacting compounds of formula 1, wherein R2 is phenoxycarbonyl, with a corresponding organic amine or, when nitrogen-substituted carbamoyl derivatives are to be prepared, with an aqueous solution of ammonium hydroxide, in an inert organic solvent, for example, chloroform or tetrahydrofuran. Accordingly, the 8105883 has * *. - 6 reaction with organic amines takes place in a homogeneous reaction medium, while the reaction with an aqueous ammonium hydroxide solution proceeds in a heterogeneous system. The phenol formed during the reaction can be bound by the excess of the amine reagent or by an organic tertiary amine, for example triethylamine. The reaction may even take place at room temperature for a few days, but at the boiling temperature of the reaction mixture it is completed in a few hours. The reaction product can be separated from the reaction mixture by conventional techniques.

Compounds of formula 1, wherein R 1 is an N-alkylcarbamoyl group, can also be prepared directly by reacting corresponding compounds of formula 1, wherein R 1 is hydrogen, with an alkyl isocyanate of formula 5. This reaction is carried out in a dry organic solvent, eg dry tetrahydrofuran, under conditions commonly used to carry out such acylation reactions carried out and the product can be separated from the reaction mixture by conventional preparative techniques.

In the compounds of formula 1, wherein R ^ is other than hydrogen and r6 * is hydrogen, the 6-position carbon atom is asymmetric and therefore these compounds may be in the form of an optically active antipode or a racemate The invention includes the preparation of optically active and racemic compounds of the formula 1. Optically active compounds of the formula 1 can be prepared starting from corresponding optically active starting materials in the reactions described above, ie from compounds in which R 1 is different then hydrogen and R1 is hydrogen.

The pharmaceutical activity of the new compounds of the invention was tested according to conventional animal experiments. Tests were performed on CFLP (LATI) mice of both sexes weighing 18 to 22 g in groups of 10. Test compounds were suspended in a 5 percent aqueous solution of Tween 80 and the suspension was administered orally through a probe. Doses of 20 mg / kg were used in the study of anticonvulsant activity, while doses of 80 mg / kg were used in the tests on neurotoxic activity. The effect induced was measured one hour after administration by the following method: 1. Test on anticonvulsant activity, a) Maximum electroshock (MES):

According to the method of E.A. Swinyard et al. [J. Pharmacol. 106, 40 (1952) 319], test animals were shock-treated with a corneal electrode (20 mA, 0.2 8105883 V · 7 sec.). When stimulated, 100% of the control animals responded with a tonic stretch muscle spasm of the lower limbs. Absence of this phenomenon was considered to be a treatment protection.

5 b) Inhibition of spasms induced by pentatetrazole (PTT)

According to the method of Cr. N. Everett and R.K. Richards [J.

Pharmacol. Exp. Therap. JU, (1944) 402], 125 mg / kg of pentatetrazole (pentanmethylene tetrazole) were administered subcutaneously to the animals. Animals were observed one hour after administration. Absence of clonic spasm (KI) and tonic lower limb extensor spasm (TE) was considered to be a protection due to the administration of the test compounds.

2. Experiment on the neurotoxic activity.

Muscle coordination (RR) in mice.

Change of the coordinated muscle movement was investigated according to W.J. Kinnard and C.F. Carr [Brit. J. Pharmacol. 121, (1957) 354] on a rotating rod (diameter 20 ram, frequency 12 / min.). Normally trained animals were able to stay on the rotating rod for about 120 seconds. One hour after the administration, it was examined what percentage of the test animals showed no muscle coordination, ie the number of animals that fell from the rotating rod within 120 seconds was determined and expressed as a percentage of the control animals.

3. Acute Toxicity The toxicity of the compounds was investigated by administration of several separate dosages. The evaluation was performed 14 days after the administration. The LD 1 values were calculated based on the number of animals killed in 14 days by probation analysis using a TPA / 101 computer.

Diphenylhydantoin and 3-methyl-5-ethyl-5-phenylhydantoin were used as reference substance in the previous experiments. The results obtained are shown in the following table.

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It can be concluded from the data of the preceding table that the compounds of formula 1 show excellent anticonvulsant activity, that their neurotoxic activity can be neglected, are only lethal in very high dosages and accordingly their therapeutic breadth is considerably wider. than that of compounds with similar activity. The new compounds of formula 1, because of their excellent pharmaceutical properties, can be used effectively for the treatment of epileptic diseases and provide better results in this field than hydantoin derivatives, which are widely used for this purpose.

The compounds of formula 1 can be used in the therapy in the form of pharmaceutical compositions containing an effective amount of these active ingredients in admixture with organic or inorganic carriers or diluents suitable for enteral or parenteral administration. The compositions may be in the form of tablets, injection liquids, dilute or concentrated suspensions or emulsions or other conventional formulations. These formulations are prepared according to conventional techniques of the pharmaceutical industry.

The pharmaceutical compositions of the invention generally contain about 30 to 100 mg of active ingredient per dosage unit. Their administration in the rational therapy includes oral or parenteral administration, preferably in the form of intravenous injections. The actual dosages depend on the disease to be treated, on the condition of the patient, the route of administration and the desired effect. In general, daily doses of between 200 and 600 mg are used.

Further details of the invention are illustrated by the following non-limiting examples. The abbreviations used in the examples are fully in accordance with the IUPAG rules.

The melting points of the compounds described in the examples were determined in an apparatus according to Dr. Tottoli (Büchi). The thin layer chromatograms were prepared on "Silica gel G" (Merck) silica gel plates according to Stahl, which are sensitive to ultraviolet radiation. The following solvent mixtures were used for the preparation of the chromatograms: (A): 1: 1 mixture of benzene and acetone (B): 3: 1 mixture of chloroform and methanol (C): 30: 4: 2: 1 mixture of ethyl acetate , acetic acid, water and pyridine 40 (D): 1: 4: 8 mixture of n-hexane, acetic acid and chloroform 8105883 '10 (E): 63: 4: 2: 1 mixture of ethyl acetate, acetic acid, water and pyridine.

The thin layer chromatograms were developed by one or more of the following methods: 1. U.V. irradiation at 254 nm 5 2. treatment with iodine vapor 3. tolidine / potassium iodide spray liquid after chlorination.

The structure of the prepared compounds was analyzed according to elemental analysis and based on the IR and NMR spectra. The IR spectra were determined on a Perkin-Elmer 257 device and the NMR spectra were recorded on a Varian EM-60 device.

The evaporation of the reaction mixture was carried out on a "Rotavapor R" (Büchi) vacuum evaporator at a temperature of at most 50 ° C.

When the NMR spectra were recorded in a water-immiscible solvent, for example deuterochloroform, the spectra were also recorded after shaking with heavy water, when the signal of the protons disappeared easily from the spectrum with deuteria (these deuteria are asterisk marked) and the multiplicity of the protons bound thereto was simplified. This is also indicated in the text. For example, the sign "d — ► s" shows that a doublet had been converted into a singlet.

Example I

2-Benzyloxycarbonyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (method a) In a flask equipped with a Marcusson water separator, a mixture of 10.1 g (45 mmol) of benzyloxycarbonylamonooxyacetate amide, 5.05 ml (50 mmol) freshly distilled benzaldehyde and 1.0 g dl-campersulfonic acid in 200 ml benzene boiled for 8 to 10 hours. The progress of the reaction is monitored by thin layer chromatography. The reaction mixture is then evaporated to dryness and the residue is crystallized again. from 80 ml of methanol. 10.2 g of 2-benzyloxycarbonyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (76%) are obtained, melting at 130 ° C to 133 ° C; R ^ = 0.7

Analysis for (Molecular Weight: 312.33): 35 Calculated: C 65.38%, H 5.16%, N 8.97%

Found: C 65.11%, H 5.43%, N 8.55%.

IR spectrum (KBr) cm- * *: (3180 (-NH-), 1740 (C = 0, Z), 1685 (C = 0, amide), 1412, 824 (ring), 1583, 748, 698 ( aromatic).

40 MR spectrum (DMSO-Dg + CDCl ^, TMS) ppm: 4.48 AB quadruplet (-C ^ -CgHfi), 6.55 wide, singlet (10H, aromatic), 8105883 11 _ 8.90 wide (-NH -).

Example II

2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (method b)

A mixture of 1.32 g (0.01 mol) acetylaminooxacetamide, 1.1 ml 5 (1.06 g, 0.01 mol) benzaldehyde, 0.2 g camphor-10-sulfonic acid, 10 ml toluene and 10 ml butyl acetate is heated under reflux for one hour. 0.5 ml of benzaldehyde is added to the reaction mixture and boiling is continued for one more hour. The product which precipitates after cooling is filtered off and washed with twice 10 ml of ether. 1.12 g of 10 2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (55%) are obtained

"D

gene, melting at 167 to 168eC; R ^ * 0.7.

Analysis for cnHi2N2 ° 3 (molecular weight: 220.23):

Calculated: G 59.99%, H 5.49%, N 12.72%; 15 Found: G 60.12%, H 5.92%, N 12.73%.

IR spectrum (KBr) cm -1: 3180 (-NH-), 1690, 1668 (C = O, amide), 1412, 790 (ring), 740, 700 (aromatic).

NMR spectrum (DMSO-dg + CDCI3, ®®S) ppm: 2.13 singlet (-CH3) 4.56 A® quadruplet (-0¾-), 6.70 wide, singlet 20 (-GH-), 7, 45 singlet (5H, aromatic), 9.2 wide (-NH-).

Example III

2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (in situ preparation of the starting compound).

34.75 g (0.5 mol) of hydroxylamine hydrochloride are dissolved in 500 ml of methanol and 55 g (0.52 mol) of anhydrous sodium carbonate and 75.5 ml (0.79 mol) of ethyl acetate are added to the solution. The mixture is refluxed for 5 hours and left overnight. 46.7 g (0.5 mol) of chloroacetamide are added to the reaction mixture, which contains the acetalroxamic acid obtained, and the mixture is refluxed with stirring for 5 hours. The reaction mixture is cooled and the solvent is evaporated under reduced pressure. As a residue, impure N-acetylaminooxyacetic acid amide is obtained, which is contaminated with a certain amount of inorganic salts. This crude product can be used in the next reaction step without further purification. However, if desired, the product can be purified by chromatography on an ion-exchange column. The pure product melts at 88 to 90 ° C.

The crude N-acetylaminooxyacetic acid amide obtained above is suspended in a mixture of 500 ml acetic acid and 61.5 ml 40 acetic anhydride. 61.5 g (0.67 mol) of benzaldehyde are added, followed by the addition of 25 ml of concentrated sulfuric acid, whereby 8105883 12 ...

care is taken to ensure that the temperature of the reaction mixture does not rise above 30 ° C. The mixture is stirred at room temperature for one hour. 140 g of crystalline sodium acetate are added, stirred for 10 minutes and the solvent is evaporated under reduced pressure. The residue is dissolved in 1 liter of ethyl acetate. The solution is shaken with 250 ml of water and dried over anhydrous sodium acetate. The solution is evaporated to dryness and the solid residue is recrystallized from 100 ml of ethanol. 28 g of 2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (yield on hydroxylamine: 25.4%) are obtained, melting at 165 to 66 ° C; R® = 0.7.

The IR and NMR spectra of the product are identical to the spectra given in Example II.

Example IV

2- benzyloxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one (method c)

A mixture of 45 g (0.2 mol) a- (benzyloxyearbonylaminooxy) -acetamide, 23 ml (20.2 g, 0.28 mol) butyraldehyde, 200 ml acetic acid, 26 20 ml acetic anhydride and 10 ml concentrated sulfuric acid becomes 24 stored at room temperature for hours. Then another 5 ml of butyraldehyde are added to the reaction mixture, which is then stored at room temperature for 2 more days. 56 g of sodium acetate trihydrate are added and the reaction mixture is decolorized with activated charcoal, filtered and the filtrate is evaporated. The residue is mixed with a mixture of 100 ml of water and 100 ml of diisopropyl ether, the solid is filtered off and washed several times with water and diisopropyl ether alternately. 32 g of 2-benzyloxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one (57%) are obtained, melting at 105 to 106 ° C.

Analysis for Cj ^ H ^ g ^ O ^ (molecular weight: 278.31):

Calculated: C 60.42 X, H 6.52%, N 10.07%

Found: C 60.69 X, H 6.60 X, N 9.83% IR spectrum (KBr) cm -1: 3180 (-NH-), 1730 (OO, Z), 1680 (C = 0, amide) , 1422, 790 (ring), 755, 35 695 (aromatic).

^ -NMR spectrum (CMSO-dg + CDClg, TMS) ppm: 0.8-2.2 multiplet (-C3H7), 4.30 AB quadruplet (-CH2 ~ C = 0), 5.27 singlet (-C ^ -CgH2), 7.44 singlet (5H, aromatic), 8.80 broad (-NH-).

Example v 3-Phenyl-tetrahydro-1,2,4-oxadiazin-5-one (method d) 8105883 13.

To a solution of 6.8 g (21.8 mol) of 2-benzyloxycarbonyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one in a mixture of 100 ml of methanol and 125 ml of ethyl acetate is 1 .0 g of a 5 percent palladium on activated carbon catalyst is added and hydrogen gas is bubbled through the solution. The progress of the reaction is followed by thin layer chromatography. When the reaction is complete, i.e. no further starting compound is present, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from a mixture of 10 ml ethyl acetate and 30 ml 10 n-hexane. 3.0 g (77 Z) of 3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 118 to 119 ° C. 0.35.

Analysis for CqH ^ QN202 (molecular weight: 178.19):

Calculated: C 60.66 Z, H 5.66 Z, N 15.72 Z; 15 Found: C 60.33 Z, H 5.57 Z, N 15.94 Z, IR spectrum (KBr): 3160 (-NH-), 1670 (> OO), 1420, 806 (ring), 700 (aromatic ).

NMR spectrum (DMSO-dg + CDCI3, TMS) ppm: 4.22 singlet (-CH2-), 5.33 d- * S, J = 6.5 Hz (> CH-), 7.02 d *, 20 I = 6.5 Hz (-NH-), 7.47 singlet (5H, aromatic), 8.80 wide * (-NH-).

Example VI

2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (method e) 38.5 g (216 mmol) 3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one in 190 25 ml of acetic anhydride are stirred for one hour. The initial suspension is quickly converted to a solution followed by the precipitation of the product. When the reaction is complete, the solvent is evaporated under reduced pressure and the residue is recrystallized from 150 ml of ethanol. 36.3 g (81 Z) of 2-Acetyl-3-phenyl-tetrahydro-1,2,4-30 oxadiazin-5-one are obtained, melting at 167 to 168 ° C. Rg = 0.7.

Analysis for ¢ 11 ^ 2 ^ 2 ^ 3 (molecular weight: 220.23):

Calculated: C 59.99 Z, H 5.49 Z, N 12.72 Z;

Found: C 60.12 Z, H 5.92 Z, N 12.73 Z.

IR spectrum (KBr) cnT ^: 3180 (-NH-), 1690, 1668 (> C = 0, amide), 1412, 790 (ring), 740, 700 (aromatic), NMR spectrum (DMSO-dg + CDCI3 , TMS): ppm: 2.13 s (-CH3), 4.56 AB quadruplet (-0¾), 6.70 (broad singlet) (> CH-), 7.45 (singlet) (5H, aromatic), 40 9.2 wide * (-NH-).

Example VII

8105883 η 2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (method f) 6.28 g (20 mmol) 2-Benzyloxycarbonyl-3-phenyl-tetrahydro-1,2,4 oxa-diazin-5-one are dissolved in 50 ml of acetic anhydride. 0.5 g of a ». 5% palladium-on-activated carbon catalyst is added and hydrogen is bubbled through the solution. The progress of the reaction is followed by thin layer chromatography. When the reaction is complete, the catalyst is filtered off, the filtrate is evaporated to dryness and the residue is recrystallized from 15 ml of ethanol. 3.55 g (80%) of 2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one '10 are obtained. The physical constants of the resulting compound are identical to those of the product of Example II.

ί

EXAMPLE 8 ^ 2,4-Diacetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one.

1.1 g (5 mmol) of 2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one 15 are dissolved in 10 ml of dry tetrahydrofuran. 1.5 ml of triethylamine are added to the solution, the solution is cooled to 0 ° C and 0.8 ml (11 mol) of acetyl chloride is added. The reaction mixture is then refluxed for 20 hours. After cooling, the triethylamine salt precipitate is filtered off and the filtrate is evaporated to dryness. The residue is passed through a silica gel column using a 1: 1 mixture of benzene and acetone for the elution. Fractions containing the desired product are evaporated and then recrystallized from a mixture of 2 ml ethyl acetate and 6 ml n-hexane.

0.3 g (23%) 2,4-Diacetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one

a

are obtained, melting at 104 to 106 ° C. = 0.8.

Analysis for ¢ 13 ^ 14½¾. (molecular weight: 262.27):

Calculated: C 59.54%, H 5.38%, N 10.68%; Found: C 59.30%, H 5.12%, N 10.84%.

IR spectrum (KBr) cm * *: 1710, 1680, 1648 ° C = 0), 1585, 755, 700 (aromatic).

NMR spectrum (DMS0-d5 + CDCI3 + TMS) ppm: 2.13 singlet (-CH3), 2.56 singlet (-CH3), 4.8 AB quadruplet 35 (-CII2-), 7.36 singlet (5H, aromatic), 7.5 singlet (CHCH-).

Example IX

2-Fenoxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one (method g) 40 11.25 ml (13.9 g, 89 mmol) Fenoxycarbonyl chloride are dissolved in 75 ml of dry tetrahydrofuran, the solution is cooled to a temperature below 0 ° C of 8105883 and at this temperature a solution of 10.8 g (75 mmol) of 3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one in a mixture of 150 ml dry tetrahydrofuran and 11.4 ml dry triethylamine added dropwise. After the addition, the mixture is heated to room temperature and stirred for 3 hours. The triethylamine hydrochloride precipitate is filtered off, the filtrate is evaporated under reduced pressure, the residue is triturated with a mixture of water and ether and filtered.

14.7 g (80 Z) of 2-phenoxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-10 5-one are obtained, melting at 106 to 107 ° C.

Analysis for (Molecular Weight: 264.28):

Calculated: C 59.08 Z, H 6.10 Z, N 10.60 Z;

Found: C 59.31 Z, H 5.70 Z, N 10.70 Z.

IR spectrum (KBr) cm -1: 3180 (-NH-), 1735 (^ OO, Z), 1680 ° C = 0, amide), 1210 (J'C-O-C ^), 1592, 690, 742 (aromatic).

NMR spectrum (DMSO-dg + CDCI3, IMS) ppm: 0.95 (-CH3), 1.44 multiplet (-CH9-CH ^), 2.10 multiplet (> GH-GH9-), 4.5 AB quadruplet Q CH9 -CO-) 5.3 multiplet triplet (CH-), 7.5 multiplet (5H, aromatic), 9.0 doublet * (-NH-). ,

Example X.

2-Carbamoyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one (method h).

7.94 g (30 mmol) 2-Phenoxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxa-25 diazin-5-one in a mixture of 75 ml chloroform and 75 ml concentrated ammonium hydroxide solution are stirred vigorously at room temperature until in a sample taken from the organic phase the starting compound can no longer be detected by thin layer chromatography (about 1 to 2 days). When the reaction is complete, the precipitated product is separated by filtration, washed with water and then with ether and dried.

After the filtrate, the organic phase is separated, dried with anhydrous sodium sulfate and evaporated. The evaporation residue is triturated with ether and filtered. The resulting second yield 35 is combined with the product from the previous step. There are thus obtained 4.6 g of 2-carbamoyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one (82 Z), melting at 189 ° C.

Example XI

2- (n-Butylcarbamoyl) -3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one 40 3.0 g (20.8 mmol) 3-n-Propyl-tetrahydro-1,2 4-oxadiazin-5-one wor 8105883 '. . Dissolved in 40 ml of dry tetrahydrofuran for 16 den. The solution is cooled to a temperature below 5 ° C and at this temperature a solution of 2.5 ml (2.2 g, 22.5 mmol) of n-butyl isocyanate in 20 ml of dry tetrahydrofuran is added dropwise. The mixture is stirred at room temperature for 4 days. When the site corresponding to the starting compound is no longer present on the thin layer chromatogram, the reaction mixture is evaporated to dryness under reduced pressure, the residue is triturated with n-hexane, filtered and from a mixture of ethyl acetate and n-hexane recrystallized. 4.23 g (87 10 Z) of 2- (n-Butylcarbamoyl) -3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 105 to 106 ° C.

Analysis for Ο ^^ - ^ Οβ (molecular weight: 243.31%):

Calculated: C 54.30 Z, H 8.70%, N 17.27%;

Found: C 54.68%, H 8.77 Z, N 17.54%.

IR spectrum (KBr) cm -1: 3320, 3180 (-NH-), 1690 ((C = O, carbamoyl-) 1660 ° C = O, amide), 1441, 820 (ring).

^ H-NMR spectrum (DMSO-dg + CDClg, TMS) ppm: 0.7-1.9 multiplet (14H ", aliphatic), 3.15 quadruplet - * triplet (-NH-CH9-), 4.21 quadruplet (-O-CH9-), 5.30 20 multiplet ^ triplet (CH-), 7.13 doublet *, J = 6 Hz (-NH-), 8.70 doublet J = 3 Hz (-NH-) .

Example XII

2-Formyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one.

5.4 g (30 mmol) of 3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (prepared according to Example I) and 10.5 g (51 mmol) of dicyclohexylcarbodiimide are dissolved in 50 ml of absolute tetrahydrofuran. The solution is cooled to a temperature below -5 ° C and at this temperature 2.3 ml (2.35 g, 51 mmol) formic acid are added dropwise. The mixture is stirred at -5 ° C for 30 minutes, after which the dicyclohexyl carbamide-precipitate is filtered off. The filtrate is evaporated to dryness under reduced pressure, the oily residue is dissolved in warm water, the insoluble compounds are filtered off and the filtrate is evaporated to dryness under reduced pressure. Recrystallization of the residue from ethyl acetate gives 1.52 g (24%) of 2-formyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one, melting at 115 to 116 ° C.

Rf - 0.4.

Analysis for 010 ^ 10 ^ 2 ^ 3 (molecular weight: 206.20):

Calculated: C 58.25%, H 4.89%, N 13.59 Z; 40 Found: C 58.30 Z, H 4.69 Z, N 13.59 Z.

IR spectrum (KBr) cm -1: 3180 (-NH-), 3050, 1700 (-CH0), 1670 (C = 0.8105883, 17 amide), 1585, 755, 702 (aromatic).

^ H-NMR spectrum (DMSO-dg + CDClg, IMS) ppm: 4.5 AB quadruplet (-CH2 “G-0), 6.5 wide, singlet (CH-) 7.3 wide (5H, aromatic, 8 1.5 singlet (-CH0), 9.2 broad * (NH-).

The compounds of the general formula I, which are listed in the following table, can be prepared in an analogous manner. The table also lists the process used to prepare these compounds, their physical constants, the yields and the solvents used for recrystallization. Different reaction media or other differences compared to the detailed examples are noted in the last column as a note.

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Claims (2)

Tetrahydro-1,2,4-oxadiazin-5-one derivatives of the formula 1, wherein R 2 is hydrogen, alkylcarbonyl having 1 to 12 carbon atoms in the alkyl moiety, optionally substituted with halogen, formyl, benzoyl, optionally substituted with methoxy, halogen or trifluoromethyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, optionally substituted on the nitrogen atom is carbamoyl or N-benzyloxycarbonyl-glycyl, r3 alkyl having 1 to 5 carbon atoms, nitrofuryl optionally substituted phenyl, naphthyl or thienyl R 1 'is hydrogen, or R 3 and r 3' together form a pentamethylene group, R 1 'is hydrogen or acyl, R' is hydrogen, alkyl of 1 to 5 carbon atoms, phenyl or benzyl is 15 and R 'T is hydrogen, or R and R4 each represent a phenyl group. 2. 7-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one. 3. 2-Acetyl-3-phenyl-6-methyl-tetrahydro-1,2,4-oxadiazin-5-one and its optical antipodes. 4.2,4-Diacetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one. 5. 2-Acetyl-3-thienyl-tetrahydro-1,2,4-oxadiazin-5-one. 6. Process for the preparation of tetrahydro-1,2,4-oxadiazin-5-on-derivatives, characterized in that compounds of the formula 1 in which R 2, R 3, 3, 3, 4, 4, 6 and g 6i are Claim 1 have the meanings stated, prepared by condensing a) an α-aminooxycarboxylic amide of formula 2, wherein R 2 'has the same meaning as R 2 defined above, except hydrogen and R 2 and R 2 as defined above, with a oxover bond of formula 3, wherein R2 and R2 'are as defined above, in a protic or aprotic environment, in the presence of an acid for the preparation of compounds of formula 1, wherein R2 is other than hydrogen and R1 is hydrogen , or b) a compound of formula 1, wherein R 2 is benzyloxycarbonyl, R 1 is hydrogen and R 2, R 2 ', R 1, and R 2' as defined above, is treated with catalytically activated hydrogen to obtain compounds of formula 1 wherein R2 and R1 are hydrogen, or c) a compound of form ule 1, wherein R 2 is hydrogen and R 2, R 2 ', r', R 'and r 6' have the aforementioned meanings, react 40 with an acyl halide or carboxylic anhydride of formula 4, wherein 8105883