PROCEDURE FOR the PRODUCTION of NEW 1,1-DIARYL-1-OXADIAZOL-ALKYLAMINE AND THEIR NON--TOXIC SALTS

The invention concerns a procedure for the production of new 1,1-Diaryl-l-oxadiazol-alkylaminen the general formula N I O I Z/N - (alkene) - C - RK E Xw X (I) where alkene a geradkettigen or branched alkyl remainder with 2 to 4 carbon atoms, R an alkyl residue with 1 to 7 carbon atoms, X and Xt hydrogen or ha! ogen, to acre the Phenyloder Pyridylrest and Z the hydroxyl group, a low Alkanoyloxyrest with 1 to 7 carbon atoms in the Alkanoylanteil, the group of carboxyls or a down Alkoxycarbenylrest with 1 to 7 carbon atoms in the Alkoxyanteil represent. Examples of alkyl remainders alkene are ethylen, Propylenoder tri triremaindertri remainder. Examples of All0 kylreste are methyl, ethyl, Propyl, wheel Butylrest, and the designation halogen covers fluorine, chlorine, bromine and iodine. An example of a Alkanoyloxyrest is the Acetoxyrest, for a Alkoxycarbonylrest of the Methoxyearbonylund Äthoxycarbonylrest. The amine part can be illustrated by the 4-Phenyl-4-carboxypiperidino, 4 - Phenyl - 4carbäthoxypiperidino, 4-Phenyl - 4 - hydroxypiperidinound 4-Phenyl-4-acetoxypiperidinorest. A preferential execution form of this remainder is the 4-Phenyl-4-hydroxypiperidinorest. Producible the according to invention bases form non-toxic acid addition salts with verscbießenen organic and inorganic acids. Such salts develop with acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, Sulfaminsäure, citric acid, lactic acid, maleic acid, apple acid, succinic acid, tartaric acid, Zimtsäure, acetic acid, Beñzoesäure, Gluconsäure, Aseorbinsäure and such. The connections are manufactured according to invention, by one a Tetrazol of the general formula N, N N IN - H i Z /-- \ N - (alkene) - C - acre/=Q I X' x where alkene, RK, X, X' and Z those managing indicated meaning to possess, with a acylierenden connection of the general formula (R C 0) 20 or O R C-C1 where R an alkyl residue with 1 to 7 carbon atoms represents, convert and, if Z is a low Alkanoyloxyrest, if necessary for the education of the Hydroxy connection afterwards hydrolyzed, the raw material of the formula (II) can be received, by one a connection of the general formula CN Z I \/--\ N - (alkene) - C - acre [...] x (m) where alkene, acre, X, X” and Z those managing indicated meaning possess, following of G. Moersch and D. the Morrow, J. Mod. Chem. one, 10, P. 149 descriptive methods with einemAzidion converts. Producible the according to invention connections are effective means against diarrhea. The effect against diarrhea according to invention the herste! lbaren connections becomes by the example of the activity the 5 [1, 1-Diphenyl-3 (4-hydroxy-4-phenylpiperidino) - propyl] - 2-methyl-1, 3, 4-oxadiazols demonstrates. The effect of the connections against diarrhea is pointed on the basis their ability to the Inhibierung of the gastrointestinal Motilität. Test with a meal from charcoal the used procedure was developed from well-known procedures (power and Barba Gose, and Janssen and Jageneau). Male Charles of Rider mice (weight 20 to 25 g, 6 experimental animals), which 24 h had before been hungry, with the test connection were pre-treated, whereby this was given orally in wässetiger solution or in suspension in 0, 5% methyl cellulose. A constant volume was used of 10 tal/kg. 30 min after administration of the test connection received the animals a only one oral dose at charcoal (0, 2 ml a 10%igen Kohlesuspensien in 1, 0% methyl cellulose per mouse). 3, 5 h after this administration were gesohlaohtet the animals and the blind intestine (Caecum) was examined on Anoder absence by charcoal, whereby the test result read only or no. The middle effective dose (EDs0) was determined for each connection according to the logistisohen method by Berkson. Apart from the anti-diarrhea effect available the according to invention connections possess also strong analgetische effect. The analgetische effect was determined at the mouse with the test with the tail tie-clip. Test with the tail tie-clip a special tie-clip becomes at the tail beginning of the mouse (full-grownly and male, fastened weight 18 to 25 g), then the time, up to which the animal begins to turn and at the CHp bites, is measured. The sensitivity of each mouse is determined 1/2 h before the active substance administration. Only such mice, which try, to bite the tie-clip are used for the attempt. The Test'verbindung is given sodarm intraperitoneal and the reaction to the attachment of the tie-clip is determined 30, 60, 90 and 120 min according to the treatment. A positive reaction is present, if the animal needs than doubly more solang as before the administration, in order to bite after these time intervals at the tie-clip. A test connection is regarded as active, if 50% or more of the animals show a positive reaction. In the following examples quantities refer to the weight, if nothing else is said. Example 1: A mixture aus15 parts of 2, 2-Diphenyl-4-brombuWroni ril, 8.9 Teilen4-Hydroxy-4 - phenylpiperidin and 400 VOL. - One cooks for parts of Äthylenglykolmenomethyläther 18 h under nitrogen at the Rücldluß. Then the solution is cooled down and their volume is decreased with 60°C under pressure by 50%. The concentrated mixture is diluted with 1200 parts water, with sodium hydroxyl basic placed and mi ether extracts the ether solution with diluted hydrochloric acid is extracted. The screen end fern-like solid filters themselves off, one washes with water and then with ether and at air more getrockner. As product one receives the 2,2-Diphenyl-4 (4-hydroxy-4-phenylpiperidino) - butyronitril from the Fp. 221 to 223°C. 8, 0 parts of this nitrile, 2, 0 parts sodium azide, 1, 6 parts ammonium chloride, 0, 03 parts of IAtbiumchlorid and 20 VOL top parts dimethylformamide are combined and 12 h on 1250C are heated up. Then the mixture is cooled down and the solid becomes by dimethylformamide filters off. He with Dimethylformaraid and water is then washed and dried, whereby one the 5 [1,1-Diphenyl-3 (4-hydroxy-4-phenylplperidino) - pr opyl] - LH-tetra zol receives. 3, 16 parts of this 1H-Tetrazols and 7.1 parts acetic anhydride become in 36 VOL. - Parts of Pyridin 1 h at the Rüekfluß cooked. Then the reaction mixture is cooled down and the Pyridin is abgedunstet with decreased pressure. The resulting Rüokstand is taken up to ethers, the ether solution is washed with Natriumbioarbonatlösung. Afterwards the ether is removed and one receives a raw product, that after recrystallizing from pentane 5 - [1, 1 - Diphenyl - the 3 - (4-aeetoxy-4-phenylpiperidino) - propyl] - 2-methyl -1, 3, 4-exadiazol of the Fp. 157, 5 to 160°C supplies. If one repeats essentially the above procedure, however under substitution of the Aeefanhydrids by acetyl chloride, then one receives the same product. If one furthermore above procedure repeat, however under substitution of the 4-Hydroxy-4-phenylpiperidins by 4-Hydroxy-4 (4-ohlorphenyl) - piperidin, then one receives 5 {1,1-Diphenyl-3 [4-acetoxy-4 (4-chlorphenyl) - - piperidino] - propyl} - 2-methyl-1, 3, 4-oxadiazol, which melts with 155 to 15800. B e i s p i e 1 2: A part the 5 - [1,1-Diphenyl-3 (4-acetoxy-4-phenylpiperidino) - propyl] - 2-methyl-l, 3, 4 - - oxadiazols in accordance with example 1 into the 4-Hydroxylverbindung transferred by hydrolysis in 55 parts of MethanoI and 15 parts of 20%iger Natri, mhydroxydlösung. The product is isolated by Abdunsten of methanol with decreased pressure, diluting with water, additive of sodium hydroxide and extraction in dichloromethane. After removing the dichloromethane the Predut from ether is recrystallized, one receives the 5 [1,1-Diphenyl-3 (4-hydroxy-4-phenylpiperidino) - propyl] - 2-methyl-1, 3,4-oxadiazol of the Fp. 160 to 162°C. Example 3: Naeh of the regulation of example 1 becomes using equivalent quantities the 2,2-Biphenyl-4 (4-carbäthoxy-4-phenylpiperidino) - butyreni ril in the 5 [1,1-Diphenyl-3 (4-earbäthoxy-4 - phenylpiperidino) - propyl] - LH-tet-razol transferred. Furthermore naeh example 1, likewise using equivalent IVIengen, is converted this IH-Te razol into 5 [1, l-Diphenyl-3 (4-earbäthoxy-4-phenylpiperidino) - propyl] -2-methyl-1, 3, 4-oxadlazol. The hydrolysis of 1 part of this ester in 50 parts iVIetlmnol, welehes of 15 parts of 20%ige aqueous sodium hydroxide solution contains, and following isolation results in that 5 [i, 1-Diphenyl-3 (4-earboxy-4-phenylpiperidino) - propyl] - 2-methyl-l, 3, 4=oxadiazol. Example 4: According to the regulation of example 1 2, 2-Diphenyl-4 (4-hydroxy-4-phenylpiperidino) becomes - butyronitril in the 5 [1,1-Diphenyl-3 (4-hydroxy-4-phenylpiperidino) - propyl] using equivalent l lengendas - LH-tetrazol transfers. When continuing working after example 1 under substitution of the Aeetanhydrids dureh Propionsäuneanhydrid this lII Tetrazol in the 5 [1, 1-Diphenyl-3 (4-propionyloxy-4 - phenylpiperidino) - propyl] becomes - 2-äthyl-1, 3, 4-oxadiazol transfers. Pa TENTANSPR Üc HE: i. Procedure for the production of new 1, 1-Diaryl-l-oxadiazol-alkylaminen of the general formula Z Y X' I I N JO I “- \/-- \ N - (alkene) - C - acre x R < I) where alkene a geradkettigen or branched alkyl remainder with 2 to 4 carbon atoms, R an alkyl residue with 1 to 7 carbon atoms, acre the P, henyloder Pyridylrest, X and X' hydrogen or I-Ialogen and Z the hydroxyl group, a Alkanoyloxyrest with 1 to 7 carbon atoms in the Alkanoylanteil, those