TETRAHYDRO-1,2,4-OXADIAZINE-5-THIONE DERIVATIVES

Abstract: The present invention relates to optically active or racemic tetrahydro-1,2,4-oxadiazine-5-thione derivatives, to methods for their preparation, and pharmaceutical compositions con­ taining the said compounds. Methods for the anticonvulsive treatment of mammals, especially human beings are de­ scribed. The compounds of the formula I have similar activity to diphenyl hydantoin but their toxicity is much lower.

Description: The present invention relates to optically active and racemic tetrahydro-1,2,4-oxadiazine-5-thion derivatives. More particularly it relates to compounds of the formula to processes for preparing them, to pharmaceutical compositions containing them and their use in therapy. In the general formula (I) R¹ represents benzyloxycarbonyl, alkanoyl having 1 to 5 carbon atoms, thioalkanoyl having 1 to 5 carbon atoms, benzoyl optionally substituted with one or more alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, alkylcarbamoyl having 1 to 4 carbon atoms in the alkyl moiety or alkylsulphonyl having 1 to 4 carbon atoms, R² represents phenyl or naphthyl optionally substituted with one or more alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or amino disubstituted with the same or different alkyl groups having 1 to 4 carbon atoms; R³ represents hydrogen, alkyl having 1 to 8 carbon atoms or benzyl, and R⁴ represents hydrogen or alkyl having 1 to 4 carbon atoms. The tetrahydro-1,2,4-oxadiazine-5-thion derivatives have not believed to have been described in the prior art. Analogous oxo-compounds have been disclosed in Hungarian patent specification No. 181,586. The pharmaceutical activity of these compounds is similar to that of the compounds of the invention, but as an undesired side-effect, they posses a neurotoxic effect. The target compounds of the present invention do not show any such undesirable side-effects. The compounds of the formula (I) can be prepared by either, a) reacting an optically active or racemic tetrahydro-1,2,4-oxadiazine-5-one derivative of the formula - wherein R¹, R², R³ and R⁴ are as defined hereinabove - with phosphorous pentasulfide in an aprotic medium, or b) reacting an optically active or racemic alpha-aminooxythiocarboxyclic amide of the formula wherein R¹, R³ and R⁴ are the same as defined hereinabove, with an aldehyde of the formula R²- CHO (IV) wherein R² is as defined hereinabove. The compounds of the formula (II) are known, they can be propared according to the process of Hungarian patent specification No. 191,586. In process variant a) hydrocarbons, especially aromatic hydrocarbons, e.g. benzene, toluene, xylene can preferably be used as protic medium. The reaction is carried out preferably at the boiling point of the solvent and is generally complete within 0.5 to 24 hours. The progress of the reaction can be controlled by thin-layer chromatography. As the reaction is finished, the suspension is filtered off and the solution is evaporated. The residual oil can be purified e.g. by recrystallization or column chromatography. In the process according to process variant b) it is preferred to use a mixture of acetic acid and acetic anhydride supplemented with some mineral acid as reaction medium. The condensation is carried out under similar conditions to those described by Hungarian patent specification No. 181,586. The reaction can be carried cut at room (15 to 22 o C) temperature within 1 to 2 hours. The progress of the reaction is preferably monitored by thin-layer chromatography. When the reaction is finished, the reaction mixture is evaporated, the residue is dissolved in a water non-miscible solvent, washed to neutral with water and evaporated to dryness after drying. The endproduct can be purified in a manner similar to the preceding procedure e.g. by recrystallization or column chromatography. The novel compounds of the formula (III) can be prepared from the alpha-aminooxy carboxylic amides of the formula by analogy with methods known from the prior art [J. Zabicky: "The Chemistry of Amides", Interscience Publishers, a division of Wiley and Sons, London-New-York-Sydney-Toronto (1970) and other publications cited therein] e.g. by preparing a nitrile of the formula wherein R¹, R³, R⁴ are the same as defined hereinabove, from the corresponding acid amide in an aprotic solvent, preferably pyridine in a reaction with phosphorous oxychloride, and obtaining the thioamide of the formula (III) after coupling hydrogen sulfide in an aprotic solvent (pyridine). The alpha-aminooxy-carboxylic amides of the formula (V) are known compounds [Mh. Chem., 92 , 725. (1961); Helv. Chim. Acta., 1969 , 569; II. Farm. Ed. Sci., 31(3), 169 (1976)]. In the compounds of the formula (I) wherein R³ and R⁴ are different, the carbon atom in position 6 is of assimetric configuration These compounds can therefore exist in either optically active or racemic forms. The present invention relates to both the racemic and optically active forms of the compounds of the formula (I) having an assymetric carbon atom in position 6. The optically active compounds of the formula (I) can be prepared e.g. by using the optically active derivative of the compounds of the formula (II) or (III) having an assymetric carbon atom in position 6 as starting material. Preferred compounds within the formula (I) are those having the formulae wherein R¹ is alkanoyl having 1 to 4 carbon atoms, R² is phenyl optionally substituted with alkyl having 1 to 4 carbon atoms or amino disubstituted with alkyl having 1 to 4 carbon atoms, R³ is hydrogen or alkyl having 1 to 4 carbon atoms, R⁴ stands for hydrogen. Particularly preferred compounds of the formula (I) are those wherein R¹ represents acetyl, R² stands for phenyl, tolyl or dimethylamino phenyl, R³ is hydrogen, methyl or ethyl and R⁴ stands for hydrogen. The most preferred compound is 2-acetyl-3-o-tolyl-6-methyl-tetrahydro-1,2,4-oxadiazine-5-thion. The anticonvulsive activity, neurotoxicity as well as the acute toxicity of the compounds of the invention has been examined in animal tests. The compound to be tested was suspended in 2 per cent aqueous Tween 80 (polyoxyethylene sorbitan monolaurate) solution and it was orally administered to the animals through a bougie in a dose of 30 mg/kg when the anticonvulsive activity was tested, and in a dose of 120 mg/kg when the neurotoxic activity was examined. The effect triggered was measured 1 hour after of the administration. Male CFLP (LATI) mice having a weight of 18 to 22 g were used in the tests. 1. Examination of the anticonvulsive activity a) Maximal electroshock (MES): The animals were given a shock with a corneal electrode (20 mA, 0.2 sec.) (H. Schachs Elektronik, Marchs, Augstatten, Germany, "schockreizgerat" typ. 207) according to the method of E. A. Swinyard et al. (J. Pharmacol. Exp. Ther. 106 , 318 (1952)]. 100 % of the control animals responded to the stimulus by the tonic extensoric spasm of the lower limbs. The lack of those occurences was attributed to the protection obtained by the treatment. b) Spasm stimulated by Pentetrazole (PTT) According to the method of G. M. Everett and R. K. Richard [J. Pharmacol. Exp. Ther., 81 , 402 , (1944)] the test animals were treated with 125 mg/kg of Pentetrazole (pentamethylene tetrazole) 1 hour after administration of the compound to be tested. The lack of the clonic spasm (KI) and the tonic extensoric spasm of the lower limbs (TE) was attributed to the protection obtained as a result of the treatment. c) Spasm stimulated by strychnine (STr) According to the method of T. L. Kerley et al. [J. Pharmacol. Exp. Ther. 132 , 360 (1961)] the test animals were i. p. treated with 2.5 mg/kg of strychnine 1 hour after the administration of the active ingredient to be tested. Those animals were considered to be protected which, as a result of the treatment, did not suffer from spasms. 2. Examination of the neurotoxicity (measure of the muscle incoordination) (FR) The change of the coordinated muscle motion was examined on a rotating bar according to the method of C. J. Carr [J. Pharmacol. Exp. Ther., 121 , 354 (1957)] (diameter: 20 mm, number of revolutions: 12/minute). Trained control animals could stay on the bar for 120 seconds. 1 hour after administration of the test compound, the percentage of the animals which fell down from the rotating bar within 120 seconds was determined and this percentage listed in the FR column of Table I. In contrast, the number of animals to fall down in the same test 1 hour after administration of a control compound only was such that an ED₅₀ for each control compound could be determined. Therefore, the ED₅₀ rather than the percentage figure is given for each control compound in the FR column of Table I. 3. Acute toxicity The toxicity of the compounds was examined after the administration of 1000 mg/kg of the test compound in one dose by an observation over 14 days. The LD₅₀ value (50 percentile lethal dose) was calculated by probite analysis on the basis of the percentile ratio of the animals which died within the 14 days. As control compounds diphenyl hydantoin and 2-acetyl-3-phenyl-(tetrahydro-1,2,4-oxadiazine-5-one) (Hungarian patent specification No. 181,568) were used. The results are summarized in Table I. The symbols given in the column of the active ingredient represent the following compounds: It is demonstrated by the data of the above table that the compounds of the formula (I) possess significant anticonvulsive activity, their protection against the tonic extensoric spasms of the lower limbs - caused by maximal electroshock and Pentetrazole - is in the same order as that of diphenyl hydantoin. After administration of the active ingredient in one dose, the effect can be rapidly observed and the action is long-lasting; the ED₅₀ values of the active ingredients measured after 0.5 to 6 hours of the administration are practically the same. Neurotoxic symptoms cannot be observed when a dose of 120 mg/kg is administered, their toxicity is very favourable, therefore they can be much more widely used in therapy than the known compounds with similar action. The quality of their pharmaceutical effect is the same as that of diphenyl hydantoin. They would appear therefore to be preferable for use in accessions of the grand mal type. They appear also to be more preferable for use in therapy than diphenyl hydantoin due to their lower toxicity. The compounds of the present invention can be administered in the form of conventional pharmaceutical formulations. The dosage administered will, of course, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient would be about 5 to 15 mg/kg of body weight, and preferably 5 to 7.5 milligrams per kilogram per day, preferably given in divided doses 2 to 4 times a day or in sustained release form. Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligram to about 500 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5 to 95 % by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions, it can also be administered parenterally, in sterile liquid dosage forms or enterally. The dosage forms comprise one or more pharmaceutically acceptable carriers and/or diluents and/or excipients besides the active ingredient. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field. The invention is illustrated by the following, non-limiting examples. The abbreviations used in the Examples are in accordance with the IUPAC prescriptions. The melting points of the compounds prepared according to the examples were determined in a dr. Tottoli-type (Büchi) equipment. The thin-layer chromatograms were prepared on a "Kieselgel G" (Merck) silica gel layer being sensitive to ultraviolet light prepared according to the method of Stahl. The following solvent mixtures were used for the development of the chromatograms: A = chloroform:methanol = 80 : 1 (by volume) B = chloroform C = benzene : acetone = 1 : 1 (by volume). In most cases the detection of the thin-layer chromatograms was carried out by applying one or more from the following methods: 1. Radiation with ultra violet light having a wave lenght of 254 nm 2. Treatment with iodine vapours 3. Spraying with a mixture of tolidine/ potassium iodide after treating with chlorine gas The structure of the compounds prepared was verified with elemental analysis and on the basis of their infra red (IR) and NMR spectras. The IR spectras were measured in an equipment of "Perkin--Elmer 257" type, while the NMR spectras were measured in an equipment of "Varian EM-60" type. The reaction mixtures were evaporated in vacuo in a "Rotavapor R" (Büchi) evaporator at a temperature below 50 o C. In the course of the measuring of the NMR spectra, if a non-miscible solvent, e.g. deuterochloroform was used, the spectra were also taken after an extraction with heavy water (deuterium oxide) when the signals of the protons being able to be easily exchanged with deuterium disappeared. (This is indicated in the text with the symbol "x"). Example 1 2-Acetyl-3-(2-methylphenyl)-6-methyl-tetrahydro-1,2,4-oxadiazine-5-thion 4.96 g (20 millimoles) of 2-acetyl-3(2-methylphenyl)-6-methyl-tetrahydrol-1,2,4-oxadiazine-5-thion are vigorously stirred with 4.5 g (20 millimoles) of phosphorous pentasulphide in 100 ml of dry benzene under boiling until the starting material cannot be detected by thin-layer chromatographic examination. This is 50 minutes in this case. The hot reaction mixture is clarified with charcoal, filtered and evaporated. The residual oil is dissolved in 45 ml of ethanol, clarified with charcoal and filtered off, The product is crystallized at a temperature of +5 o C. The precipitating crystalls are filtered off, 2.6 g of crystalline product are obtained. Yield: 49 %. Melting point: 167-170 o C. The 2.6 g of thione are purified by chromatography on a column filled with 140 g of Merck Kieselgel 60 (70-230 mesh) using an eluent consisting of a 80:1 mixture of chloroform and methanol. 1.85 g of pure title product are obtained. Elemental analysis (C₁₃H₁₆N₂O₂S) (M: 264.34) C H N S Calculated: 59.06 6.1 10.59 12.12 %; Found: 58.92 6.14 10.38 11.95 %. IR (KBr) cm⁻¹: 3200 (NH) 1645 (C = 0) 1530 (thioamide) 770 (aromatic) ¹H-NMR (CDCl₃) (ppm): 1.72 d (CH- CH ₃) 2.12 s (-CO- CH ₃) 2.64 s (Ar- CH ₃), 4,68 g ( CH -CH₃) 6.8 s ( CH -Ar) 7.3 m (4H, aromatic) 9.2 b x (NH). Examples 2 to 21 The compounds of the formula I listed in Table 2 are prepared according to the method of Example 1. Example 22 2-Acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazine-5-thion I. Alpha-(acetyl-aminooxy)-thioacetamide 19.82 g (150 millimoles) of alpha-(acetyl--aminooxy)-acetamide were dissolved in 100 ml of pyridine under vigorous stirring. A mixture of 24.53 g (160 millimoles) of phosphorous oxychloride and 25 ml of dichloromethane are added dropwise to this solution at a temperature of -5 o C and the solution is stirred at a temperature of 0 o C for 1.5 hours. The dichloromethan solution is dryed over anhydrous sodium sulphate and evaporated. The 15 g of oil thus obtained are dissolved in 15 ml of pyridine, 18.1 ml (131 millimols) of triethyl amine are added and H₂S is led into the solution for 2 hours. The end of the reaction is controlled by thin-layer chromatography. After the disappearance of the starting nitrile, the solution is evaporated, the residual oil is dissolved in 200 ml of ethyl acetate and extracted with 3x100 ml of water. The residue is crystallized from a mixture of ethyl acetate and ether at a temperature of +5 o C. 11 g (49.5 %) of crystalline title product are obtained. Melting point: 136-138 o C. R f = 0.38 (C). Elemental analysis (C₄H₈N₂O₂S) (M = 148.18) C H N S calculated 32.44 5.44 18.9 21.63 %; found: 32.35 5.58 19.06 21.47 %. IR (KBr) cm⁻¹: 1650 (C=O) 1270 (C=S) 3280, 3130 (NH) 1540 (Amide II) II. 2-Acetyl-3-phenyl-tetrahydrol-1,2,4-oxadiazine-5-thion 1.48 g (10 millimoles) of alpha-(acetyl-aminooxy)-thioacetamide are dissolved in a mixture of 10 ml of acetic acid and 1.3 ml of acetic anhydride, thereafter 1.3 ml (13 millimoles) of freshly distilled benzaldehyde and then 0.5 ml of concentrated sulfuric acid are added. The mixture is stirred for 3 hours at room temperature, then 2.8 g of crystalline sodium acetate are added, stirred for 10 minutes, thereafter the solvent is evaporated under vacuum. The residue is dissolved in 30 ml of ethyl acetate, the solution is extracted with 20 ml of water. The organic layer is dried over anhydrous sodium sulfate then evaporated to dryness. The residue is crystallized from ethanol at a temperature of +5 o C. 1.25 g (52.9 %) of crystalline title product are obtained. M.p.: 172-174 o C. R f (A) = 0.43. Elemental analysis (C₁₁H₁₂N₂O₂S) (M = 236.34) C H N S Calculated: 56.15 5.1 11.9 13.63 %; Found: 56.3 5.2 11.9 13.62 %. IR (KBr) cm⁻¹: 3220 (NH) 1655 (C = O) 1525 (thioamide) 1585,740,702 (aromatic) ¹H-NMR(polysol) (ppm): 2.13 s (-CO- CH ₃) 4.83 s (-CH₂₋) 6.61 s ( CH -Ar) 7.36 s (aromatic) 10.6 b x (-NH-) Hungarian patent specification No. 181,586 referred to in the text corresponds to Belgian patent specification No 891,652.

Claims: Claims for the following Contracting States: BE, CH, DE, FR, GB, IT LI NL, SE Optically active and racemic forms of tetrahydro-1,2,4-oxadiazine-5-thion derivatives of the formula wherein R¹ represents benzyloxycarbonyl, alkanoyl having 1 to 5 carbon atoms, thioalkanoyl having 1 to 5 carbon atoms, benzoyl optionally substituted with one or more alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, alkylcarbamoyl having 1 to 4 carbon atoms in the alkyl moiety or alkylsulphonyl having 1 to 4 carbon atoms, R² represents phenyl or napthyl optionally substituted with one or more alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or amino disubstituted with the same or different alkyl groups having 1 to 4 carbon atoms, R³ represents hydrogen, alkyl having 1 to 8 carbon atoms or benzyl, and R⁴ is hydrogen or alkyl having 1 to 4 carbon atoms. A compound of the formula (I) as claimed in claim 1 wherein R¹ is alkanoyl having 1 to 4 carbon atoms, R² is phenyl optionally substituted with alkyl having 1 to 4 carbon atoms or amino disubstituted by the same or different alkyl groups having 1 to 4,carbon atoms, R³ is hydrogen or alkyl having 1 to 4 carbon atoms, R⁴ is hydrogen. A compound Of formula (I) as claimed in claim 1 wherein R¹ is acetyl, R² is phenyl, tolyl or dimethylamino phenyl, R³ is hydrogen, methyl or ethyl and R⁴ is hydrogen. 2-acetyl-3-tolyl-6-methyl-tetrahydro--1,2,4-oxadiazine-5-thione. A process for the preparation of the optically active or racemic tetrahydro-1,2,4-oxadiazino--5-thione derivatives of formula I as defined in claim 1 which comprises a) reacting an optically active or racemic tetrahydro-1,2,4-oxadiazine-5-one derivative of the formula wherein R¹, R², R³ and R⁴ are as defined in claim 1 with phosphorous pentasulfide in an aprotic medium, or b) reacting an optically active or racemic alpha-aminooxy-thiocarboxylic amide of the formula wherein R¹, R³ and R⁴ are as defined in claim 1, with an aldehyde of the formula R² - CHO (IV) wherein R² is as defined in claim 1. A process as claimed in claim 5 a) which comprises using an aromatic hydrocarbon as an aprotic solvent and carrying out the reaction at the boiling point of the reaction mixture. A process as claimed in process variant b) of Claim 5 which comprises carrying out the reaction in a mixture of an organic acid and its anhydride in the presence of an inorganic acid at room temperature A pharmaceutical composition which comprises a racemic or optically active compound of the formula (I) as defined in claim 1 in association with a pharmaceutically acceptable carrier, excipient and/or diluent. A process for the preparation of a pharmaceutical composition which comprises mixing an optically active or racemic tetrahydro-1,2,4-oxadiazine-5-thione derative of the formula (I) as defined in claim 1 with a pharmaceutically acceptable carrier, excipient and/or diluent. Use of a compound of formula (I) as defined in claim 1 for the preparation of a medicament having anti-convulsive activity. Compounds of formula (III) wherein R¹, R³ and R⁴ are as defined in claim 1. Claims for the following Contracting State: AT A process for the preparation of optically active or racemic tetrahydro-1,2,4-oxadiazine-5-thione derivatives of the formula wherein R¹ stands for benzyloxycarbonyl, alkanoyl having 1 to 5 carbon atoms, thioalkanoyl having 1 to 5 carbon atoms, benzoyl optionally substituted with one or more alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, alkylcarbamoyl having 1 to 4 carbon atoms in the alkyl moiety or alkylsulphonyl having 1 to 4 carbon atoms, R² is phenyl or napthyl optionally substituted with one or more alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or amino disubstituted with the same or different alkyl groups having 1 to 4 carbon atoms, R³ is hydrogen, alkyl having 1 to 8 carbon atoms or benzyl, and R⁴ is hydrogen or alkyl having 1 to 4 carbon atoms which comprises a) reacting an optically active or racemic tetrahydro-1,2,4-oxadiazine-5-one derivative of the formula wherein R¹, R², R³ and R⁴ are the same as defined hereinabove, with phosphorous pentasulfide in an aprotic medium, or b) reacting an optically active or racemic alpha-aminooxy-thiocarboxylic amide of the formula wherein R¹, R³ and R⁴ are the same as defined hereinabove, with an aldehyde of the formula R² - CHO (IV) wherein R² is the same as defined hereinabove. A process as claimed in claim 1 a) which comprises using an aromatic hydrocarbon as aprotic solvent. A proces as claimed in claim 2 which comprises using benzene, toluene or xylene as the aromatic hydrocarbon. The process as claimed in any of claims 1 a), 2 and 3 which comprises carrying out the reaction at the boiling point of the reaction mixture. The process as claimed in claim 1 b) which comprises carrying out the reaction in a mixture of an organic acid and its anhydride in the presence of an inorganic acid. A process as claimed in claim 5 which comprises carrying out the reaction in a mixture of acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. A process as claimed in any of claims 1 b), 5 or 6 in process variant which comprises carrying out the reaction at room temeprature. A process for the preparation of a pharmaceutical composition which comprises mixing an optically active or racemic tetrahydro-1,2,4-oxadiazine-5-thione derivative of the formula (I) as defined in claim 1 with a pharmaceutically acceptable carrier, excipient and/or diluent. A process for the preparation of compounds of formula (III) wherein R¹, R³ and R⁴ are as defined in claim 1 which comprises reacting a compound of formula (VI) with hydrogen sulphide in an aprotic solvent.

Inventors: CHOLNOKY, ESZTER, KISFALUDY, LAJOS, OTVOS, LASZLO, PALOSI, EVA, RONAI, SARA, SZPORNY, LASZLO, TEGYEY, ZSUZSANNA, TUDOS, HELGA, UROGDI, LASZLO, VEZERT, CSILLA
Applicants: MAGYAR TUDOMANYOS AKADEMIA KOEZPONTI KEMIAI KUTATO INTEZETE, RICHTER GEDEON VEGYESZETI GYAR R.T.
Application year: 1985
Main classification: C07D273
IPC codes: C07D273, A61K31