Novel triazolyl hydrazide derivatives and process for their preparation

Abstract: This invention relates to novel triazolyl hydrazide derivatives and a process for the preparation thereof. The new triazolyl hydrazide derivatives of the general formula (I), wherein Q represents hydrogen or a heterocyclic group optionally substituted by a C₁₋₄ alkyl group; or a group of the formula SR¹, wherein R¹ stands for C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl), or a group of the formula NR²R³, wherein R² and R³ each represent hydrogen, straight or branched chained C₁₋₆ alkyl or C₂₋₆ alkenyl; Z represents hydrogen or a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶, wherein X stands for oxygen or sulfur, R⁴, R⁵ and R⁶ each stand for hydrogen or C₁₋₄ alkyl; R⁷ denotes hydrogen, C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally substituted by one or more halogen atom(s), R⁸ stands for hydrogen or a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, wherein X, R⁴, R⁵ and R⁶ are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R⁵)-NR⁵R⁶, R⁸ stands for hydrogen, and if Z represents hydrogen, R⁸ stands for a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶, and pharmaceutically acceptable acid addition salts thereof exert valuable antianginal and/or gastric ulcer inhibiting properties and are useful in therapy.

Description: This invention relates to novel triazolyl hydrazide derivatives, a process for the preparation thereof, pharmaceutical compositions comprising the same, to the use of them for the treatment of diseases and also for the preparation of pharmaceutical compositions suitable for the treatment of said diseases. According to an aspect of the present invention there are provided new triazolyl hydrazide derivatives of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein Q represents hydrogen or a heterocyclic group optionally substituted by a C₁₋₄ alkyl group; or a group of the formula SR¹, wherein R¹ stands for C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl), optionally substituted by one or more halogen, C₁₋₄ alkyl or nitro substituents; or a group of the formula NR²R³, wherein R² and R³ each represent hydrogen, straight or branched chained C₁₋₆ alkyl or C₂₋₆ alkenyl; Z represents hydrogen or a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶, wherein X stands for oxygen or sulfur, R⁴, R⁵ and R⁶ each stand for hydrogen or C₁₋₄ alkyl; R⁷ denotes hydrogen, C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally substituted by one or more halogen atom(s) or an amino group that may optionally be substituted by one or more C₁₋₄ alkyl substituents, R⁸ stands for hydrogen or a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, wherein X, R⁴, R⁵ and R⁶ are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, R⁸ stands for hydrogen, and if Z represents hydrogen, R⁸ stands for a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶. The invention encompasses all the isomers or tautomeric forms of the compounds of the general formula (I). The new compounds according to the present invention exhibit excellent biological activity and low toxicity, e.g. they possess antianginal, tranquillant-sedative, cardiovascular, acid secretion inhibiting, gastric ulcer inhibiting and antimicrobial properties and they can be used as starting materials of other pharmaceutically active derivatives as well. The term "heterocyclic group" used throughout the specification relates to 4 to 8 membered heterocyclic groups which can be formed from compounds comprising independently one or more nitrogen and/or oxygen atom(s) or a group which can be obtained by condensing the same compounds with each other or with benzene. Such groups may be aromatic or partially or completely saturated and may carry one or more substituent(s). As examples for such groups e.g. the piperidyl, morpholinyl, piperazinyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyranyl or delta-3-piperidin-1-yl groups are mentioned. The term "alkyl group" relates to straight or branched chained saturated aliphatic hydrocarbon groups comprising 1 to 4 or 1 to 6 carbon atom(s), e.g. methyl, ethyl, i-butyl, t-butyl, n-hexyl, etc. As "C₂₋₆ alkenyl" groups straight or branched chained alkenyl groups are mentioned (e.g. vinyl, allyl, 2-methyl-allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-pentenyl, 2-hexenyl etc.). The term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms. Compounds of the general formula (I), wherein Q represents morpholino, methylthio, dimethylamino or N-methyl-piperazinyl and R⁷ and R⁸ each stand for hydrogen, and pharmaceutically acceptable acid addition salts thereof possess particularly valuable pharmaceutical properties. Particularly preferred representatives of the compounds of the general formula (I) are the following derivatives: 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methylcarbo-thiohydrazide, 1-(5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbothiohydrazide; 1-(5-amino-3-N-methylpiperazinyl-1 H -1,2,4-triazol-1-yl)-carbothiohydrazide, 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N,N′-dimethyl-carbothiohydrazide, and pharmaceutically acceptable acid addition salts thereof. The compounds of the general formula (I) are organic bases, so they can be transformed into acid addition salts. The pharmaceutically acceptable acid addition salts of the compounds of the general formula (I) can be formed with inorganic or organic acids. As examples for the pharmaceutically acceptable acid addition salts the hydrohalides (such as hydrochlorides or hydrobromides), carbonates, sufates, acetates, fumarates, maleates, citrates, ascorbinates and tartrates can be mentioned. According to a further aspect of the present invention there is provided a process for the preparation of compounds of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, with comprises a) reacting a triazolyl ester of the general formula (II), wherein Y represents hydrogen or a group of the formula (C=X)-XR⁹, wherein X is as stated above, R⁹ is C₁₋₄ alkyl or phenyl optionally substituted by one or more halogen atom(s), R⁷ and Q are as defined above, R¹⁰ represents hydrogen or a group of the formula (C=X)-XR⁹, with the proviso that if Y stands for hydrogen, R¹⁰ represents a group of the formula (C=X)-XR⁹, wherein X and R⁹ are as stated above, and if Y stands for a group of the formula (C=X)-XR⁹, R¹⁰ represents hydrogen, with a hydrazine derivative of the general formula (III), wherein R⁴, R⁵ and R⁶ are as stated above, or b) for the preparation of isomeric compounds of the general formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), reacting a triazolyl ester of the general formula (IIa), wherein R⁷, R⁹, X and Q are as stated above, with a hydrazine derivative of the general formula (III), heating the thus-obtained compound of the general formula (Ia), and separating the isomers from each other by methods known per se ; or c) for the preparation of isomeric compounds of the general formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), heating a compound of the general formula (Ia) and separating the isomers from the thus-obtained product by methods known per se ; or d) for the preparation of compounds of the general formula (Ia) representing a subgroup of the compounds of the general formula (I), wherein R⁴, R⁵, R⁶ and R⁷ represent hydrogen and Q stands for a group of the formula SR¹¹, wherein R¹¹ denotes C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally bearing one or more halogen, C₁₋₄ alkyl or nitro substituent (s), reacting a compound of the general formula (IV), wherein X is as stated above, with a compound of the general formula (V), wherein R¹¹ is as stated above; and, if desired, converting the compound of the general formula (I) thus-obtained into a pharmaceutically acceptable acid addition salt thereof or setting free a base of the general formula (I) from an acid addition salt thereof, or converting an acid addition salt of a base of the general formula (I) into another acid addition salt. The reaction of the compounds of the general formulae (II) and (IIa), respectively, with hydrazine derivatives of the general formula (III) is carried out in a solvent inert toward the reactants. For this purpose preferably methanol, 2-propanol, benzene or dimethyl sulfoxid are used. The reaction is performed at a temperature of 0 to 190 °C, preferably between 20 and 110 °C. The reaction is optionally carried out in the presence of a base, preferably an organic base. The isomerisation of the compounds of the general formula (Ia) into compounds of the general formulae (Ib), (Ic) and (Id) can be carried out in melt or by thermic rearrangement in a polar or dipolar aprotic solvent, preferably in acetic acid or dimethylformamide, at a temperature between 50 °C and 250 °C, preferably at a temperature of 100 to 190 °C. During the reaction a mixture of the compounds of the general formulae (Ib), (Ic) and (Id) is produced, which can be separated into the individual isomers by methods known per se , e.g. by chromatography or fractional crystallization. The reaction of the compounds of the general formulae (IV) and (V) can be performed in a polar solvent, preferably in an aqueous methanol solution, dimethylformamide or dimethyl sulfoxide, at a temperature between 0 and 190 °C, preferably at a temperature of 50 to 160 °C. The compounds of the general formula (I) obtained in form of a base can be converted into acid addition salts by methods known per se . For this purpose the free bases are reacted with the corresponding acid in an inert solvent. The triazolyl esters of the general formula (II) used as starting materials are known compounds or can be produced on the analogy of known compounds (US patent specification No. 3,686,301, DD patent specification No. 105,897). The hydrazine derivatives of the general formula (III) are also known compounds (Belsteins Handbuch der Organischen Chemie 4 , 546, Verlag Springer, Berlin, 1922; Ullmann: Encyklopädie der Technischen Chemie 13 , p. 95, Verlag Chemie Weinheim, 1977). The carbohydrazide and thiocarbohydrazide of the general formula (IV) are commercially available products. The compounds of the general formula (V) are also commercial products or can be prepared as described in Hungarian patent specification No. 184,743. The compounds of the general formula (I) are only very slightly toxic and show excellent biological properties. They exert antianginal, tranquillant-sedative, cardiovascular, acid secretion inhibiting, gastric ulcer inhibiting and antimicrobial effects. The activity of the compounds of the general formula (I) has been examined by the following tests. 1. Antianginal effect Method: Nieschulz, E., Popendiker, K. and Hoffmann, I., Arzneimittel-Forschung, 5 , 680 (1955) The test was carried out on rats weighing 180 to 220 g. The animals were narcotised with chloralese-urethane (70 - 700 mg/kg ip.). The ECG was registered with needle electrodes in standard II leading. The experimental coronaria insufficiency was induced with vasopressin (1 NE/kg i.v.). The height of wave T was measured before and after the administration of vasopressin in both the control and treated groups. Test compounds were administered intravenously 2 minutes prior to the treatment with vasopressin The results are summarized in Table I. Antianginal effect Test compound (Example No.) ED₅₀ mg/kg (iv.) 17 0.84 16 0.70 Prenylamine 6.5 2. Motility inhibiting activity Method: Borsy, 3., Csányi, E., Lázár, I.: Arch. Int. Pharmacodyn. 124 , 1-2 (1960) The tests were performed on mice. Groups consisting of 3 mice each were treated perorally with different doses of the compounds to be tested. One hour after the administration the test animals were placed in a Dews equipment. In this equipment the number of interruptions of infrared beam within 30 minutes was counted. The results obtained are shown in Table II. Motility inhibiting effect Compound (Example No.) LD₅₀ mg/kg p.o. Therapeutical index 1 100 >10 17 70 ∿ 5 Meprobamate 270 4.1 3. Acute toxicity on mice Method: Litchfield, J.T., Wilcoxon, F.W.: Pharmacol. Exp. Ther., 96 , 99 (1949) White mice belonging to the CFLP strain (body weight 18 to 22 g, both male and female) were used, 6 animals for each dose. The test compounds were administered orally in a volume of 20 ml/kg. After treatment the animals were observed for a period of 14 days. The mice were kept in a plastic cage at room temperature. The animals get tap water and standard mouse fodder ad libitum. The toxicity data were determined with the aid of the method of Litchfield and Wilcoxon. The results are summarized in Table III. Acute toxicity on mice Example No. LD₅₀ mg/kg p.o. 17 350 16 1000 1 >1000 4 300 9 1000 20 1000 The above data show that certain representatives of the compounds according to the invention are 8 or 10 times as effective on the antianginal test as the reference substance Prenylamine and are superior as motility inhibitors to the reference compound Meprobamate. At the same time they are only very slightly toxic. In addition, the compounds according to the invention possess valuable antimicrobial effect, especially against nonfermenting Gram-negative bacteria strains. So the compound of Example 9 inhibits, determined by agar diffusion method in a concentration of 500 µg/hole, the bacteria strains listed in Table IV. Antimicrobial effect of the compound according to Ex. 9 Microbe strain HNCMB⁺ deposition number Inhibition (%) Salmonella enteritidis 10091 17 Shigella sonnei 20046 19 Acinetobacter calcoaceticus 150001 20 Pseudomonas aeruginosa 170006 14 Pseudomonas stutzeri 173008 25 Alcalingenea faecalis 140001 23 HNCMB⁺ = Hungarian National Collection of Medical Bacteria 4. Stomach-secretion and ulcus tests on mice Method: Shay, H., Komarov, S.A., Fels. S.S., Meranze, D., Gruenstein, M., Siplet, H.: Gastroenterology 5 , 45 (1945); Adami, E., Marazzi-Ubertti, E. Tirba, C.: Arch. Int. Pharmacodyn. 147 , 113 (1964). Starved wistar mice of 150-250 g body weight were used, 4 male and 4 female animals for each dose. On the day of the experiment the pylorus of the animals was ligatured under ether narcosis. The doses of the test compounds were administered per os, 3 hours before the operation. The control groups were treated with the carrier in identical way. 4 hours after the operation the animals were over-narcotized with ether, their stomach was removed, the stomach contents were separated and after centrifugation the volume of the gastric juices was measured, then their free-acid content and total acidity, resp., were determined by titration with 0.1 N NaOH solution. The changes of the gastric mucous membrane were investigated macroscopically and characterized by an ulcus index determined with the aid of the punctuation method of Adami and coworkers. The results obtained are shown in Table V. Gastric-secretion- and ulcus-inhibiting effects on mice Example No. Dose mg/kg po. Inhibition related to the control in % Gastric juice Free acid Total acidity Ulcus index 4 60 41 60 50 67 20 50 36 46 36 39 200 58 91 78 70 Cimetidine 50 22 24 15 18 200 59 91 71 72 The above data unambiguously show that the effect of the compounds according to the invention reach or even surpass that of Cimetidine but their toxicity is slight and due to the differing structures they are exempt from the very unfavourable side-effect of causing impotency of Cimetidine. According to a further aspect of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with suitable inert solid or liquid pharmaceutical carriers. The pharmaceutical compositions of the present invention can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form. The pharmaceutical compositions of the present invention may be suitable for oral (e.g. tablet, pill, coated pill, dragée, solid or soft gelatine capsule, solution, emulsion or suspension), parenteral (e.g. injection solution) or rectal (e.g. suppository) administration. As carrier for the preparation of tablets, coated tablets, dragées and solid gelatine capsules e.g. lactose, corn starch, potatoe starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or the salts thereof, etc. can be used. As carrier for the soft gelatine capsules e.g. vegetable oils, fats, waxes or polyols of suitable consistency can be used. As carriers for the solutions and syrups e.g. water polyols (polyethylene glycol), saccharose or glucose can be used. The injection solutions can comprise e.g. water alcohols, polyols, glycerol or vegetable oils as carrier. The suppositories can be prepared with the aid of e.g. oils, waxes, fats or polyols of suitable consistency. In addition, the pharmaceutical formulations may comprise auxiliaries usually applied in pharmaceutical industry, e.g. wetting, sweetening agents, aroma substances, salts causing the change of osmotic pressure, buffers, etc. The compounds of the general formula (I) can preferably be used in therapy orally in the form of tablets or capsules. Especially preferred are the capsules or tablets comprising 0.5 to 500 mg of active ingredient. The daily dose of the compounds of the general formula (I) can vary within wide ranges depending on several factors, e.g. on the activity of the active ingredient, the patient's condition and age, the severity of the disease, etc. The oral dose is generally 2 to 5000 mg/day, preferably 5 to 1000 mg/day. It has to be stressed that the above dose is only of informative character and the administered dose must always be determined by the physician therapeutist. According to a further aspect of the present invention there is provided the use of the compounds of the general formula (I) or pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions having particularly antianginal and/or gastric ulcer inhibiting effects. According to a still further aspect of the present invention there is provided a method for antianginal and/or gastric ulcer inhibiting treatment, which comprises administering to the patient an effective amount of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof. The invention is further illustrated by the aid of the following Examples of non-limiting character. Example 1 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 25.7 g (0.1 mole) of methyl (5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. Then the separated crystals are filtered off and recrystallized from benzene. Yield: 15.0 g (59 %) M.p.: 144 to 146 °C. Example 2 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N′-methyl-carbothiohydrazide One proceeds as described in Example 1, with the difference that the mother liquor obtained after filtering the reaction mixture is allowed to stand for 2 days. The separated crystals are then filtered off and recrystallized from 2-propanol. Yield: 3.8 g (15 %) M.p.: 125 to 126 °C. Example 3 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 25.7 g (0.1 mole) of methyl (5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 100 ml of dimethyl sulfoxide, in the presence of 5.7 ml (0.11 mole) of methylhydrazine for 8 hours at room temperature. The reaction mixture is poured onto 100 ml of water, the separated crystals are filtered off and recrystallized from benzene. Yield: 8.3 g (38 %) M.p.: 144 to 146 °C. Example 4 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 22.0 g (0.1 mole) of methyl (5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene. Yield: 11.8 g (54 %) M.p.: 164 to 166 °C. Example 5 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 22.0 g (0.1 mole) of methyl (5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 400 ml of 2-propanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 8 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene. Yield: 10.5 g (48 %) M.p.: 164 to 166 °C. Example 6 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 22.0 g (0.1 mole) of methyl (5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 200 ml of benzene, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 8 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene. Yield: 8.9 g (41 %) M.p.: 164 to 166 °C. Example 7 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 22.0 g (0.1 mole) of methyl (5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene. Yield: 11.8 g (54 %) M.p.: 164 to 166°C. Example 8 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 22.0 g (0.1 mole) of methyl (5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbodithioate are boiled in 140 ml of methanol, in the presence of 5.7 ml (0.11 mole) of methylhydrazine for 1 hour. The reaction mixture is then evaporated to 70 ml, the separated crystals are filtered off and recrystallized from benzene. Yield: 8.3 g (38 %) M.p.: 164 to 166 °C. Example 9 1-[5-Amino-3-N-methylpiperazinyl)-1 H -1,2,4-triazol-1-yl]-N-methylcarbothiohydrazide 27.2 g (0.1 mole) of methyl (5-amino-3-N-methylpiperazinyl-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours. The reaction mixture is evaporated to dryness in vacuo . The oily product thus obtained crystallises upon adding of 2-propanol. The separated crystals are filtered off and recrystallized from acetonitrile. Yield: 13 g (48 %) M.p.: 150 to 152 °C. Example 10 1-(5-Amino-3-dimethylamino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 21.7 g (0.1 mole) of methyl (5-amino-3-dimethylamino-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 100 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene. Yield: 12.2 g (51 %) M.p.: 165 to 167 °C. Example 11 1-(5-Amino-3-morpholino-4 H -1,2,4-triazol-4-yl)-N-methyl-carbothiohydrazide 25.5 g (0.1 mole) of 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbodithiohydrazide are boiled in 75 ml of acetic acid for 30 minutes, under stirring. The reaction mixture is cooled, the separated crystals are filtered off and recrystallized from methanol. Yield: 10.5 g (41 %) M.p.: 239 to 240°C. Example 12 1-(5-Amino-3-morpholino-2 H -1,2,4-triazol-2-yl)-N-methyl-carbothiohydrazide On proceeding as described in Example 11 the mother liquor obtained after filtering the reaction mixture is evaporated to dryness and the residue is recrystallized first from an aqueous ethanol solution then from acetonitrile. Yield: 6.12 g (24 %) M.p.: 258 to 259 °C. Example 13 2-Methyl-4-(3-morpholino-1 H -1,2,4-triazol-5-yl) thiosemicarbazide 25.7 g (0.1 mole) of methyl (3-morpholino-2 H -1,2,4-triazol-5-yl)dithiocarbaminate are boiled in 250 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 2 hours, under stirring. The separated crystals are filtered off and recrystallized from methanol. Yield: 17.34 g (68 %) M.p.: 211 to 212 °C. Example 14 1-(5-Benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 34.9 g (0.1 mole) of methyl (5-benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene. Yield: 22.5 g (63 %) M.p.: 133 to 134 °C. Example 15 1-(5-Benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N′-methyl-carbothiohydrazide One proceeds as described in Example 14, with the difference that the mother liquor obtained after filtration is allowed to stand for 2 days. Then the separated crystals are filtered off and recrystallized from a mixture of n-hexane and ether. Yield: 5.6 g (16 %) M.p.: 86 to 87 °C. Example 16 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-1-yl) carbothiohydrazide A mixture of 25.7 g (0.1 mole) of methyl (5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate, 200 ml of methanol and 6 ml (0.12 mole) of a 99 % hydrazine hydrate solution is stirred for 4 hours at room temperature. Then it is filtered and the thus-obtained crystals are recrystallized from a mixture of dimethylformamide and acetonitrile. Yield: 20.9 g (86 %) M.p.: 180 to 182 °C. Example 17 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl) carbothiohydrazide A mixture of 22.0 g (0.1 mole) of methyl (5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbodithioate, 200 ml of methanol and 6 ml (0.12 mole) of a 99 % hydrazine hydrate solution is stirred for 4 hours at room temperature. Then it is filtered and the precipitated crystals are recrystallized from dimethylformamide. Yield: 17.3 g (85 %) M.p.: 185 to 186 °C. Example 18 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl) carbothiohydrazide To a mixture of 10.6 g (0.1 mole) of thiocarbohydrazide and 130 ml of water a solution of 15 g (0.102 mole) of dimethyl (N-cyanocarbonimidodithioate) in 65 ml of methanol is added, and the reaction mixture is boiled for 2 hours. Then it is cooled, the precipitated crystals are filtered off and recrystallized from dimethylformamide. Yield: 17.8 g (86 %) M.p.: 185 to 186 °C. Example 19 1-[5-Amino-3-(N-methylpiperazinyl)-1 H -1,2,4-triazol-1-yl]carbothiohydrazide 27.2 g (0.1 mole) of methyl [5-amino-3-(N-methylpiperazinyl)-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of hydrazine hydrate for 4 hours at room temperature. Then the reaction mixture is cooled and the thus-obtained crystals are recrystallized from dimethylformamide. Yield: 24.5 g (94 %) M.p.: 194 to 196 °C. Preparation of the trihydrochloride salt: 1 g of base obtained as described above is dissolved in 5 ml of hot dimethylformamide, and the solution is acidified to pH=2 with a 15 % (v/v) solution of hydrogen chloride in isopropanol. The separated product is filtered off and washed with isopropanol. Yield: 0.9 g M.p.: 158 to 160 °C. Example 20 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N,N′-dimethyl-carbothiohydrazide 25.7 g (0.1 mole) of methyl (5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate are boiled in 150 ml of methanol, in the presence of 14.6 ml (0.12 mole) of N,N′-dimethylhydrazine dihydrochloride and 46 ml of triethylamine for 16 hours. Then the reaction mixture is evaporated to dryness in vacuo . 400 ml of water are added to the residue and the aqueous phase is extracted three times with 200 ml of chloroform. The organic phase thus obtained is washed two times with 200 ml of water, dried over magnesium sulfate and evaporated in vacuo . The precipitated crystals are suspended in diethyl ether and filtered off. Yield: 11.3 g (43 %) M.p.: 127 to 128 °C. Example 21 1-(5-Amino-3-diallylamino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 4.2 g (0.0156 mole) of methyl (5-amino-3-diallylamino-1 H -1,2,4-triazol-1-yl)carbodithioate and 1.38 ml (0.026 mole) of methylhydrazine are reacted in 20 ml of methanol at room temperature for 8 hours. Upon adding 10 ml of water to the thus-obtained solution 1.2 g (29 %) of pure 1-(5-amino-3-diallylamino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide get separated. M.p. : 86 to 88 °C. When evaporating the mother liquor further 2 g of crystalline product are obtained which melt at 85 to 88 °C. So the total yield amounts to 77 %. Example 22 1-(5-Benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N,N′-dimethyl-carbothiohydrazide 6.98 g (0.02 mole) of methyl (5-benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate are boiled in 50 ml of methanol, in the presence of 2.92 ml (0.024 mole) of N,N′-dimethylhydrazine dihydrochloride and 9.4 ml of triethylamine for 8 hours. Then the reaction mixture is evaporated to dryness in vacuo . 100 ml of water are added to the residue and the aqueous phase is extracted three times with 50 ml of chloroform. The thus-obtained organic phase is washed twice with 50 ml of water, dried over magnesium sulfate and evaporated to dryness in vacuo . The thus-obtained crystals are suspended in diethyl ether and filtered off. Yield: 3.25 g (45 %) M.p.: 66 to 68 °C. Example 23 1-[5-(4-Dimethylaminobenzylamino)-3-morpholino-1 H -1,2,4-triazol-1-yl]carbothiohydrazide 1.96 g (0.005 mole) of methyl [5-(4-dimethylaminobenzylamino)-3-morpholino-1 H -1,2,4-triazol-1-yl]carbodithioate are boiled in 20 ml of methanol, in the presence of 0.3 ml of hydrazine hydrate for 1 hour, under stirring. The reaction mixture is cooled, the separated crystals are filtered off and recrystallized from methanol. Yield: 1.43 g (83 %) M.p.: 127 to 129 °C. Example 24 1-(4-Chlorobenzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 38.2 g (0.1 mole) of methyl /5-(4-chlorobenzylamino)-3-morpholino-1 H -1,2,4-triazol-1-yl/carbodithioate are boiled in 700 ml of methanol, in the presence of 6.4 ml (0.12 mole) of methylhydrazine for 1 hour, under stirring. The reaction mixture is cooled, the precipitated crystals are filtered off and recrystallized from a mixture of benzene and cyclohexane. Yield: 23.2 g (61 %) M.p.: 152 to 154 °C. Example 25 1-/5-(4-chlorobenzylamino)-3-methylthio-1 H -1,2,4-triazol-1-yl/carbothiohydrazide 17.2 g (0.05 mole) of methyl /5-(4-chlorobenzylamino)-3-methylthio-1 H -1,2,4-triazol-1-yl/carbodithioate are boiled in 200 ml of methanol, in the presence of 6 ml of hydrazine hydrate for 0.5 hour, under stirring. The reaction mixture is cooled, the separated crystals are filtered off and recrystallized from methanol. Yield: 13.8 g (84 %) M.p.: 140 to 142 °C. Example 26 1-(5-Benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbothiohydrazide 3.49 g (0.01 mole) of methyl (5-benzylamino-3-morpholino-1 H -1,2,4-triazol-1-yl)carbodithioate are stirred in 50 ml of methanol, in the presence of 0.64 ml (0.013 mole) of hydrazine hydrate for 4 hours, at room temperature. The separated crystals are filtered off and recrystallized from methanol. Yield: 2.84 g (85 %) M.p.: 141 to 143 °C. Example 27 1-/5-(4-Chlorobenzylamino)-3-morpholino-1 H -1,2,4-triazol-1-yl/carbothiohydrazide 1.9 g (0.005 mole) of methyl /5-(4-chlorobenzylamino)-3-morpholino-1 H -1,2,4-triazol-1-yl/carbodithioate are boiled in 40 ml of methanol, in the presence of 0.3 ml (0.0058 mole) of hydrazine hydrate for 1 hour, under stirring. Then the separated crystals are filtered off and recrystallized from methanol. Yield: 2.64 g (71 %) M.p.: 169 to 171 °C. Example 28 1-(3,5-Diamino-1 H -1,2,4-triazol-1-yl)-N-methylcarbothiohydrazide 0.76 g (0.004 mole) of methyl (3,5-diamino-1 H -1,2,4-triazol-1-yl)-N-methyl-carbodithioate is stirred in 75 ml of methanol, in the presence of 0.29 ml of hydrazine hydrate for 1 hour at room temperature. The separated crystals are filtered off and recrystallized from 2-propanol. Yield: 0.68 g (73 %) M.p.: 184 to 186 °C. Example 29 1-(5-Amino-3-diallylamino-1 H -1,2,4-triazol-1-yl) carbothiohydrazide 26.90 g (0.1 mole) of methyl-(5-amino-3-diallylamino-1 H -1,2,4-triazol-1-yl)carbodithioate are boiled in 200 ml of methanol, in the presence of 6 ml of hydrazine hydrate for 1 hour, under stirring. The precipitated crystals are filtered off and recrystallized from benzene. Yield: 20.64 g (82 %) M.p. : 142 to 144 °C. Example 30 1-(5-Amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbothiohydrazide To a mixture of 9 g (0.1 mole) of carbohydrazide and 160 ml of methanol a solution of 14.6 g (0.102 mole) of dimethyl N-cyanocarbonimidodithioate in 100 ml of methanol is added under stirring. The reaction mixture is boiled for 3 hours, then it is cooled, the separated crystals are filtered off and recrystallized from methanol. Yield: 15.6 g (83 %) M.p.: 163 to 164 °C. Example 31 1-(5-Amino-2 H -1,2,4-triazol-2-yl)-N-methylcarbothiohydrazide 0.61 g (0.0035 mole) of 1-(5-amino-2 H -1,2,4-triazol-2-yl)carbodithioate is stirred in 10 ml of methanol, in the presence of 0.184 ml (0.004 mole) of methylhydrazine for 2 hours, at room temperature. The solution is evaporated to dryness in vacuo and the residue is recrystallized from isopropanol. Yield: 0.4 g (66 %) M.p.: 85 to 90 °C. Example 32 Tablets having the following composition are prepared by methods known per se of the pharmaceutical industry: Components Amount, g/tablet 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-l-yl)carbothiohydrazide 5 Lactose 18.5 Potato starch 13.0 Polyvinylpyrrolidone 6.8 Stearic acid 2.7 Talc 4.0 Total weight 50.0 g Example 33 Ointments having the following composition are prepared by methods known per se of the pharmaceutical industry: Components Amount 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-l-yl)-N-methylcarbothiohydrazide 500 mg Unguentum hydrophilicium nonbonicum 10 g The active ingredient is in the outer phase of the ointment, in dissolved state. Example 34 Suppositories having the following composition are prepared by methods known per se of the pharmaceutical industry: Components Amount, mg/suppository 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-l-yl)carbothiohydrazide 100 Lecithin 48 Cera alba 96 Cocoa butter 1870 Distilled water 386 Total weight 2500 mg Example 35 Capsules having the following composition are prepared by methods known per se of the pharmaceutical industry: Components Amount, mg/capsule 1-(5-Amino-3-morpholino-1 H -1,2,4-triazol-l-yl)carbothiohydrazide 50 Lactose 119 Potato starch 10 Magnesium stearate 1 Total weight 180 mg

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, NL, SE Triazolyl hydrazide derivatives of the general formula (I) and pharmaceutically acceptable salts thereof, wherein Q represents hydrogen or a 4 to 8 membered heterocyclic group containing one or more nitrogen and/or oxygen atom(s) and optionally substituted by a C₁₋₄ alkyl group or the condensed product of such a heterocyclic group with another such heterocyclic group or with benzene; or a group of the formula SR¹, wherein R¹ stands for C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl), optionally substituted by one or more halogen, C₁₋₄ alkyl or nitro substituents; or a group of the formula NR²R³, wherein R² and R³ each represent hydrogen, straight or branched chained C₁₋₆ alkyl or C₂₋₆ alkenyl; Z represents hydrogen or a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶, wherein X stands for oxygen or sulfur, R⁴, R⁵ and R⁶ each stand for hydrogen or C₁₋₄ alkyl; R⁷ denotes hydrogen, C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally substituted by one or more halogen atom(s) or an amino group that may optionally be substituted by one or more C₁₋₄ alkyl substituents, R⁸ stands for hydrogen or a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, wherein X, R⁴, R⁵ and R⁶ are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, R⁸ stands for hydrogen, and if Z represents hydrogen, R⁸ stands for a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶. The following compounds of the general formula (I) according to claim 1: 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methylcarbo-thiohydrazide, 1-(5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbothiohydrazide, 1-(5-amino-3-N-methylpiperazinyl-1 H -1,2,4-triazol-1-yl)carbothiohydrazide, 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N,N′-dimethyl-carbothiohydrazide, and pharmaceutically acceptable acid addition salts thereof. A process for the preparation of compounds of the general formula (I), which comprises a) reacting a triazolyl ester of the general formula (II), wherein Y represents hydrogen or a group of the formula (C=X)-XR⁹, wherein X is as stated above, R⁹ is C₁₋₄ alkyl or phenyl optionally substituted by one or more halogen atom(s), R⁷ and Q are as defined above, R¹⁰ represents hydrogen or a group of the formula (C=X)-XR⁹, with the proviso that if Y stands for hydrogen, R¹⁰ represents a group of the formula (C=X)-XR⁹, wherein X and R⁹ are as stated above, and if Y stands for a group of the formula (C=X)-XR⁹, R¹⁰ represents hydrogen, with a hydrazine derivative of the general formula (III), wherein R⁴, R⁵ and R⁶ are as stated above; or b) for the preparation of isomeric compounds of the general formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), reacting a triazolyl ester of the general formula (IIa), wherein R⁷, R⁹, X and Q are as stated above, with a hydrazine derivative of the general formula (III), heating the thus-obtained compound of the general formula (Ia), and separating the isomers from each other by methods known per se ; or c) for the preparation of isomeric compounds of the general formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), heating a compound of the general formula (Ia) and separating the isomers from the thus-obtained product by methods known per se ; or d) for the preparation of compounds of the general formula (Ia) representing a subgroup of the compounds of the general formula (I), wherein R⁴, R⁵, R⁶ and R⁷ represent hydrogen and Q stands for a group of the formula SR¹¹, wherein R¹¹ denotes C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally bearing one or more halogen, C₁₋₄ alkyl or nitro substituent(s), reacting a compound of the general formula (IV), wherein X is as stated above, with a compound of the general formula (V), wherein R¹¹ is as stated above; and, if desired, converting the compound of the general formula (I) thus-obtained into a pharmaceutically acceptable acid addition salt thereof or setting free a base of the general formula (I) from an acid addition salt thereof, or converting an acid addition salt of a base of the general formula (I) into another acid addition salt. A process according to variants a) and b) of claim 3, which comprises carrying out the reaction in melt or in a solvent inert toward the reactants, preferably in methanol, 2-propanol, dimethyl sulfoxide or benzene, optionally in the presence of a base. A process according to claim 4, which comprises carrying out the reaction in the presence of an organic base, preferably triethylamine. A process according to variants b) and c) of claim 3, which comprises heating the compound of the general formula (Ia) in melt or in a solvent, preferably in a protic or dipolar aprotic solvent. A process according to variant d) of claim 3 which comprises carrying out the reaction in a protic or dipolar aprotic solvent, preferably in an aqueous methanol solution or dimethylformamide. Pharmaceutical compositions comprising as active ingredient at least one compound of the general formula (I) or a pharmaceutically acceptable salt thereof in admixture with suitable inert solid or liquid pharmaceutical carriers. Use of compounds of the general formula (I) or pharmaceutically acceptable acid addition salts thereof for the preparation of medicaments for treating angina, cardiovascular conditions, acid secretion or microbial diseases and/or for inhibiting or treating gastric ulcers and/or having a tranquillant/sedative effect. The compounds claimed in claim 1 or claim 2 for use in therapy. Claims for the following Contracting States : ES, GR A process of preparing pharmaceutical compositions which comprises admixing one or more triazolyl hydrazide derivatives of the general formula (I) or pharmaceutically acceptable salts thereof, wherein Q represents hydrogen or a 4 to 8 membered heterocyclic group containing one or more nitrogen and/or oxygen atom(s) and optionally substituted by a C₁₋₄ alkyl group or the condensed product of such a heterocyclic group with another such heterocyclic group or with benzene: or a group of the formula SR¹ wherein R¹ stands for C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl), optionally substituted by one or more halogen, C₁₋₄ alkyl or nitro substituents; or a group of the formula NR²R³, wherein R² and R³ each represent hydrogen, straight or branched chained C₁₋₆ alkyl or C₂₋₆ alkenyl; Z represents hydrogen or a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶, wherein X stands for oxygen or sulfur, R⁴, R⁵ and R⁶ each stand for hydrogen or C₁₋₄ alkyl; R⁷ denotes hydrogen, C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally substituted by one or more halogen atom(s) or an amino group that may optionally be substituted by one or more C₁₋₄ alkyl substituents, R⁸ stands for hydrogen or a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, wherein X, R⁴, R⁵ and R⁶ are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R⁴)-NR⁵R⁶, R⁸ stands for hydrogen, and if Z represents hydrogen, R⁸ stands for a group of the formula (C=X)-(N-R⁴)-NR⁵R⁶, with suitable inert solid or liquid therapeutic carriers. A process as claimed in claim 1, wherein Q represents morpholino, methylthio, dimethylamino or N-methyl-piperazinyl and R⁷ and R⁸ each stand for hydrogen, and pharmaceutically acceptable acid addition salts thereof. A process as claimed in claim 1, wherein the triazol hydrazide derivative is one or more of the following compounds: 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N-methylcarbo-thiohydrazide, 1-(5-amino-3-methylthio-1 H -1,2,4-triazol-1-yl)carbothiohydrazide, 1-(5-amino-3-N-methylpiperazinyl-1 H -1,2,4-triazol-1-yl)carbothiohydrazide, 1-(5-amino-3-morpholino-1 H -1,2,4-triazol-1-yl)-N,N′-dimethyl-carbothiohydrazide, and pharmaceutically acceptable acid addition salts thereof. A process for the preparation of compounds of the general formula (I), which comprises a) reacting a triazolyl ester of the general formula (II), wherein Y represents hydrogen or a group of the formula (C=X)-XR⁹, wherein X is as stated above, R⁹ is C₁₋₄ alkyl or phenyl optionally substituted by one or more halogen atom(s), R⁷ and Q are as defined above, R¹⁰ represents hydrogen or a group of the formula (C=X)-XR⁹, with the proviso that if Y stands for hydrogen, R¹⁰ represents a group of the formula (C=X)-XR⁹, wherein X and R⁹ are as stated above, and if Y stands for a group of the formula (C=X)-XR⁹, R¹⁰ represents hydrogen, with a hydrazine derivative of the general formula (III), wherein R⁴, R⁵ and R⁶ are as stated above; or b) for the preparation of isomeric compounds of the general formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), reacting a triazolyl ester of the general formula (IIa), wherein R⁷, R⁹, X and Q are as stated above, with a hydrazine derivative of the general formula (III), heating the thus-obtained compound of the general formula (Ia), and separating the isomers from each other by methods known per se ; or c) for the preparation of isomeric compounds of the general formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), heating a compound of the general formula (Ia) and separating the isomers from the thus-obtained product by methods known per se ; or d) for the preparation of compounds of the general formula (Ia) representing a subgroup of the compounds of the general formula (I), wherein R⁴, R⁵, R⁶ and R⁷ represent hydrogen and Q stands for a group of the formula SR¹¹, wherein R¹¹ denotes C₁₋₄ alkyl or phenyl-(C₁₋₄ alkyl) optionally bearing one or more halogen, C₁₋₄ alkyl or nitro substituent(s), reacting a compound of the general formula (IV), wherein X is as stated above, with a compound of the general formula (V), wherein R¹¹ is as stated above; and, if desired, converting the compound of the general formula (I) thus-obtained into a pharmaceutically acceptable acid addition salt thereof or setting free a base of the general formula (I) from an acid addition salt thereof, or converting an acid addition salt of a base of the general formula (I) into another acid addition salt. A process according to variants a) and b) of claim 4, which comprises carrying out the reaction in melt or in a solvent inert toward the reactants, preferably in methanol, 2-propanol, dimethyl sulfoxide or benzene, optionally in the presence of a base. A process as claimed in claim 5, which comprises carrying out the reaction at a temperature between 0 °C and 190 °C, preferably between 20 °C and 110 °C. A process according to claim 5 or 6, which comprises carrying out the reaction in the presence of an organic base, preferably triethylamine. A process according to variants b) and c) of claim 4, which comprises heating the compound of the general formula (Ia) in melt or in a solvent, preferably in a protic or dipolar aprotic solvent. A process according to variant d) of claim 4, which comprises carrying out the reaction in a protic or dipolar aprotic solvent, preferably in an aqueous methanol solution or dimethylformamide. Use of compounds of the general formula (I) or pharmaceutically acceptable acid addition salts thereof for the preparation of medicaments for treating angina, cardiovascular conditions, acid secretion or microbial diseases and/or for inhibiting or treating gastric ulcers and/or having a tranquillant/sedative effect.

Inventors: BARKOCZY JOZSEF, FEKETE MARTON, GACSALYI ISTVAN, GOERGENYI FRIGYES, GYERTYAN ISTVAN, PETOECZ LUJZA, PONGO LASZLO, REITER JOZSEF, SZECSEY MARIA, SZIRT ENIKOE, BARKOCZY, JOZSEF, FEKETE, MARTON, GACSALYI, ISTVAN, GOERGENYI, FRIGYES, GYERTYAN, ISTVAN, PETOECZ, LUJZA, PONGO, LASZLO, REITER, JOZSEF, SZECSEY, MARIA, SZIRT, ENIKOE, Barkóczy, József, Fekete, Márton, Gacsályi, István, Görgényi, Frigyes, Gyertyán, István, Petöcz, Lujza, Pongó, László, Reiter, József, Szécsey, Mária, Szirt, Enikö
Applicants: EGYT GYOGYSZERVEGYESZETI GYAR, EGIS GYOGYSZERGYAR
Application year: 1990
Main classification: C07D249
IPC codes: C07D403, A61K31, C07D249, A61P9, C07D413, A61P1