PROCEDURE FOR the PRODUCTION again 1 (3 (N, NDIMETHYLAMINO) PROPYL) - 3,4-DIPHENYL-1H-PYRAZOL AND ITS SALTS

The invention concerns a procedure for the production again 1 [3 (N, N-Dimethylamino] - propyl 3,4-diphenyl-IH-pyrazol and its salts, which are suitable as antidepressives. Rosenthal, Arch. Internally. Pharmacodynamie, 96, 2Z0-Z3O (1953) describes l (2-Aminoäthyl] - 3,5-diphenyl-lH-pyrazol with lokalanästhetischer effect; Grandberg et al., Zh. Ohsch. Khim. 31, 53700-3705 (1961): C.A. 5. _77, 9839 (1957) describe l (3-Aminopropyl) - 3,5-diphenyl-iH-pyrazol without an indication of use to give; Peat et al., Biol. Aktivn. Soedin, Akad, Nauk CSSR, 1965, 171-174, C.A. 633, 16329d (1965) describe 1 (2-Diäthylaminoäthyl) - 3,5-diphenyl-iH-pyrazol, without indicating a range of application; That et al., J. suppl. chem. one 19, 1428-14S4 (1954) describe different 1 (2-Amino thyl) - 3-phenyl-iH-pyrazele, were examined and as I0 gastrosekretori che Stimulantien and histaminische means to have inactively shown oneself and Büchi the et al., Helv. Chim. Aota, 38, 670-679 (1955) describe l (2-Dimethylaminoäthyl) - 3-phenyl-4-methyl-iHpyrazol, to which a analgetische effectiveness is attributed. So far however no reference to producible the according to invention connection let itself find, which owes a useful anti-depressive effect to its structural characteristics. z5 the invention concerns thus a procedure for the production of the new connection of the formula C0H5. --C “H5 I [CH2) n-N=B (z) where n the meaning of 8 has and: N=B Dimethylamino means. This species is particularly suitable as anti-depressive means. The procedure the according to invention for the production of the new connection of the formula (I) exists in the Reduktien of a mixture of 1 (3-Aminopropyl) - 3,4-diphenyl-lH-pyrazo! and of at least two equivalents formaldehyde, either with formic acid or with hydrogen in presence of a catalyst. The conversion one accomplishes preferably in solvents, for example in a low Alkanol, organic under the Beaktionsbedingungen inert, like ethanol. A preferential method exists in the reduction of the reaction mixture with hydrogen over a catalyst with a hydrogen printing from approximately 350 to approximately 630 kPa; a preferential catalyst is platinum oxide, which used l (3-Aminopropyl) as parent compound - 3,4-1H-pyrazol can be manufactured according to different methods. A method exists in the reduction of - [1 (S, 4-Diphenyl-lH-pyrazolyl)] - per pion amide with the Formei (II) with a Alka imetallaluminiumhydrid: (OH=) =--C' N B = (CH=), - NH = (II) (I) the conversion preferably in an organic solvent one accomplishes, which is inert under the Reaktiensbedingungen, for example to Dioxan, diethylether or tetrahydrofurane, at temperatures of the solvent used from approximately -10°C to the boiling point. The Ausgangsmaterlal of the formula (IT) is manufactured by conversion by 3,4-Diphenylpyrazol with a low alkyl acrylate in presence of a strong base, soaps of the resulting ester, transformation of the resulting acid in the appropriate Säurechlorid and conversion of the latter with ammonia to presence of an acid acceptor, e.g. by Fyridin. A further method for the production of the connections of the necessary parent compound covers the reduction of l (2-Cyanoäthyl) - 3,4-diphenyl-iH-pyrazol [formula (III) with hydrogen übar a Baney nickel catalyst in presence of ammonia; Nr.363075 NI NJ I l (CH=) =-C--N (CH=) A-NH = (nz) (one accomplishes i) the reduction in on the reaction conditions inert organic solvents, for example a low Alkanol, at ambient temperature and with hydrogen printings within the range of approximately 358 to approximately 630 kPa. The raw material of the formula (III) one places by conversion of 3,4-Diphenylpyrazol with Acry! nitrile in presence of a strong base ago. A third procedure for the production of the necessary parent compound exists in the reaction of an l [3 [Tosyloxy) - propyl] - 3,4-diphenyl-iH-pyrazols with the formula (IV) with ammonia, as represented by the following equation. N/ ” N “(CH =) OTs (CH =) - NH = (iv) (1) the conversion one accomplishes by warming up a mixture of the connection of the formula (IV) with ammonia in an organic solvent, which is inert on the reaction conditions, for example acetonitrile, or a low Alkanol, at a temperature from approximately 100 to for instance 150°C. One places the intermediate product of the formula (IV) by condensation of Formyldesoxybenzoin [Russell et al., J. to. Chem. Soc. 76, 5714-5718 (1954)] with a 3-Hydroxypropylhydrazin and following conversion of the resulting 1 (3-Hydroxypropyl) - 3,4-diphenyl-lH-pyrazols with a toluol sulphonyl halide to presence of Pyridin through. A further procedure for the production of the necessary parent compound consists of it, 8,4-Diphenyl-lH-pyrazol with a strong base, for example sodium hydride in an organic solvent, which is inert on the reaction conditions, for example tetrahydrofurane, Dioxan or diethylether converting and converting resulting sodium salt with a Halogenpropylamin in the same solvent system with its Rüekflußtemperatur. The Z5 procedure is represented by the following equation: C6H5-- ] 1 C6 H5: CöHs] I--C “H5 N + x (CH=) a-NH= N n n I I H (CH2) - NH2 (v) where X halogen represents. As managing indicated, becomes the production of the final product of the formula (I) either an alkylation of 3,4-Diphenylpyrazol by me-olAddition of a low alkyl acrylate or of acrylonitrile accomplished [here called method (A)]; the alkylation of 3,4-Diphenylpyrazol with a Halogenpropylamin in presence of an acid acceptor accomplished [here called method (B)]; or a Hydroxypropylgruppe into the 1-Stellung of 3,4-Diphenylpyrazol by condensation of Formyldesoxybenzoin with a 3-Hydroxypropylhydrazin imported [here called method (C)]. The different transformations are represented schematically in the following diagram: (C] C “Hs - I B C i] --. --C H IF IJ (CB2) 3-NH2 + H NNB (CH2) sOH C6 Hs-- --1 Cößs C'H° QI…. IL coH (CH,) 2 - COOR where X those managing indicated meaning exhibits. From the understanding pattern it is evident that to the formation of a mixture of the 3,4-Diphenylund 4,5-Diphenylprodukte leads all three methods. With the methods (A) and (B) result these mixtures from the alkylation of one of the two possible tautomeren forms of the I0 of Diphenylpyrazol raw material. With the method (e) results this mixture from the Beaktionsselektivität lacking of Ketonund Aldehydcarbony! groups of the Formyldssoxybenzoin raw material. Generally seen alkylation with a low Alkylaorylat or with Aerylnitril [method (A)] leads to approximately 85% of the 3,4-Diphenylisomeren; alkylation with a Halogenpropylamin [method (b]] leads mixture that to a 50:50 - isomers; and the method (C) seems to favour the formation of the 3,4-Isomeren. In any case the 3,4und 4,5-Isomeren at any point of the complete synthesis must be separated independently from the applied method. The structural allocation of the 3,4und 4,5-Diphenylisomeren takes place on the basis their Ultraviolettund NMR spectra as well as due to their behavior with the gas chromatography. Thus a steady and unambiguous relationship between the isomers in the ultraviolet spectrum shows itself. A member of each pair of isomers shows absorption maxima with 223 Nm and with 249 + 2 Nm, whereas that shows other absorption maxima with 227-+ 2 and 252-+ 1 Nm in 95 per cent 21thanol. Beyond that the Extinktionskoeffizienten are generally higher for the 227/252 member of the pair. So the ultraviolet spectra can be used for the identification isomers, as soon as a certain structure was assigned to special isomers of the entire Beihe. A such allocation can take place with application of the NMB data. Elguero and Jacquier [J. Chim. Physical 6. _33, 1242 (1966)] it showed that in strongly polar solvents, for example Hexamethylphosphordiamid the proton fell into the 3-Stellung a Beihe of 1,4-disubstituierten Pyrazolen in each case field upward from the proton in 5-Stellung. If one applies this to the available row, then the 3,4-Diphenylsubstituenten of the Beihe with UV maxima can be assigned bsi to 227/252 and the 4,5-Diphenylsubstitution of the row 233/249, since in the NMB spectra the same absorption is regarded feldab by the Preton in 5-Stellung as the 3,4-Diphenyliscmere and field upward the lying absorption of the 3-Stellung is not present. One keeps the same absorption turned around field up from that to paws in 3-Stellung for the 4,5-Diphenylisomere, while feldab the lying absorption of the proton is missing in 5-Stellung. In the NMR spectra a completely regular unvorhersagbare relationship between the members of a pair comes out also from the chemical shifts of the protonproton protons in neighbourhood to the nitrogen atoms in the i-position of the Pyrolringes. The 3,4-Diphenylisomere always is field downward the 4,5-Diphenylisomeren. Finally the retention times that reflect isomers with the gas chromatography the managing division in two parts, which comes out from the spectral data against, whereby the 3,4-isomere exhibits the longer retention time into all I0 cases. Because of the presence reacts to a basic amino group by the formula (I) represented free nose form with organic and inorganic acids under formation of acid addition salts. The acid addition salt forms are made of any organic or inorganic acids. One receives it in usual way, for example either by direct mixing of the base with the acid or, if this is not suitable, by dissolving either the base and the acid, separately into water, or an organic solvent and mixing of the two solutions or by dissolving both the base and the acid together in a solvent. The resulting acid addition salt is isolated by filtering, if it is insoluble in the Beaktionsmedium or by evaporation of the Reaktionsmedinms, whereby the acid addition salt remains as arrears. The acid residues or anions of these Salzformen are even neither new nor critically and can from there any acid anion or each acid-like substance be, which is suitable for the Salzbildung with the base. Examples of acids for the formation of acid addition salts are formic acid, acetic acid, ISO butter acid, A - Meroaptopropionsäure, tri fluorine acetic acid, apple acid, fumaric acid, succinic acid, Succinamidsäure, Gerbsäure, Glutaminsänre, Weinsänre, oxalic acid, Brenzschleimsäure, Citronensäure, lactic acid, Glykolsänre, Gluoonsäure, sugar acid, ascorbic acid, penicillin, benzoic acid, Phthalsäure, Salicylsäure, S, 5-Dinitrobenzoesäure, Anthranilsäure, Cholsäure, 2-Pyridincarbonsäure, Pamoasäure, 3-Hydroxy-2-naphthossäure, Picrinsäure, China acid, Tropasäure, 3-Indolessigsäure, Barbitursäure, Sulfaminsänre, Methansulfonsäur ethane sulfone acid, Isäthionsäure, benzene sulfone acid, p-t luolsulfonsäure, Butylarsonsäure, methane phosphonic acid, sour resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid u.dgl. All acid addition salts are suitable as sources for the free base form by reaction with an inorganic base. It is as evidently that if or several make the Gharakteristika, as solubility, molecular weight, physical manifestation, toxicity CD, dgl, unsuitable a certain base or an acid addition salt of it this form for the respective customs purpose it easily into another more suitable form be converted can. For pharmaceutical purposes naturally acid addition salts are used by relatively atoxischen pharmaceutical useful acids, for example Ghlorwasserstoffsäure, lactic acid, Weinsänre u.dgl. Like managing on shown, the connections of the understanding formula with pharmakologischen standard investigations (I) have themselves, where n has the meaning of 3 and N=B Dimethylamino proved meant as well as their Sänreadditionssalze as useful anti-depressive means. The connection of the formula (I) can first-be enough in the same way like usual antidepressives, i.e. either parenterally or orally in any usual pharmaceutical form, as for example in the form of solutions, suspensions, tablets, caps u.dgl. The favorable characteristics producible of the according to invention connection by pharmakologische Standar D-Testmethoden one demonstrated, which can be accomplished by the Durohschnittsfachmann, so that the respective determination of the numeric biological data without large experimental expenditure can be assigned. The method used for the determination of the anti-depressive effectiveness producible of the according to invention connections becomes as follows beschriehen: Male mice (Swiss Webster von Taconic farm) with a weight from 19 to 24 g were divided in four groups from in each case 9 to mice. To the first three groups test connections were given solved in the respective Desierungen from 64, 18 and/or 4 mg/kg, either in water as water-soluble acid addition salts or as suspension in I% Tragantgummi. The fourth group received only the carrier, to 4 h after the medication became all Kontrollund of test animals with 50 mg/kg (i.p.] Tetrabenazin mediziert and into a photoelectric cell activity cage [described from Harris et al., Psychon. ., 4, 267 (1966}], with a digital counter for the admission of the number of procedures, with those a Liohtstrahl, which fell on a photoelectric cell, while the test period one interrupted, is equipped, brought in. 30 min after the Tetrabenazin administration was activated the photoelectric cell units and the photoelectric cell counting was accomplished during one duration by 50 min. The connections I0 were called either actively or inactively afterwards, whereby the activity was defined as a considerable difference (0.05 level or among them, zweizählig and/or “two tailed”) between the photoelectric cell countings at the groups treated with the means and the control groups after the Kruskal Valais statistic probability test. The structure producible of the according to invention connection was determined according to the synthesis methods, by elementary analysis and by ultraviolet, Infrarotund nuclearmagnetic resonance spectra. The process of the Reaktienen and the Hemogenität of the products were supervised by Dünnschichtchromatographie. The following examples serve the invention for the explanation. The fusion points are, if not differently indicated, does not correct. Production of the intermediate products production I: A solution of 22 g (0, i mol) 3,4-Diphenylpyrazol in 150 ml Dioxan became 10 ml triton B (benzyle tri methyl ammonium hydroxide} added and the solution was shifted afterwards drop by drop with 26,3 ml (0.4 mol) acrylonitrile, whereby the temperature was held with to 45°C. The mixture was agitated further 20 min at ambient temperature and acidified by addition by 3 ml acetic acid and vibrated and filtered in 700 ml ice/water poured, which became mixture afterwards treated with 200 ml ethyl acetate and about 1 Teelöffel sodium chloride, in order to remove the unsolvable precipitation. The organic layer was separated from the filtrate and the aqueous layer twice with ethyl acetate was extracted. The united organic excerpts were treated, filtered washed with satisfied Natriumbicarbonat and afterwards with salt solution, over magnesium sulfate dried, with activated charcoal and evaporated to dry ones, whereby one received a red oil, which crystallized from 60 ml methanol. One received so 13.82 g of a material from the Fp. = 90 to I03°C, which showed the presence of two isomers with the gaechromatographischen analysis in the relationship of 13/87 and from 13% of the 4,5-Diphenylisomeren and 87% of the 3,4-Diphenylisomeren of l (2-Cyanoäthyl) - diphenyl iH pyrazol existed. With another beginning a thin suspension was rapidly agitated by 7,7 g (0.14 mol] potassium hydroxide and 805 g (3.65 mol) 3,4-Diphenylpyrazel in 3,4 l ethanol, whereby with 292 ml (4.4 mol) Aerylnitril during 2 h were course-dripped. With complete addition further 2 h was agitated, whereby in an outside ice bath it was cooled on which the mixture was left untouched 2 days at ambient temperature. The mixture was cooled afterwards on 0°C and the solid was won again and dried, under formation of 723 g of a material of the Fp, = 103 to I08°C. By recrystallizing from ethanol one received 681 g from the Fp. = 108 to III°C (softening with 106°C), which itself by vapor phase chromatography as 92 to 93 of the 3,4-Isomeren and 6 to 7 of the 4,5-Diphenylisomeren of l (2-Cyanoäthyl) - diphenyl iH pyrazol proved. Production 2: To a mixing into a paste with of 18,8 g (0.05 mol) l (2-Cyanoäthyl) - 3,4-diphenyliH-pyrazol, descriptive understanding by production I, in a solution about I00 ml methanol, which water-free ammonia contained, was added a small quantity of Raney nickel Eatalysator and the mixture was reduced in a Parr Schüttelvorrichtuug with a hydrogen pressure by 3,52 bar (50 ₜ). After 3 days the mixture was filtered and the filtrate was brought to dry ones, whereby arrears behind-remained, which were solved in 40 ml isopropanol and 30 ml Isopropylacetat. The solution was shifted with 20 ml 5.7 n hydrogen chloride in ethanol and the solid, which separated, was won, rinsed and dried with further solvent, whereby one 15.2 g1 (3-Aminöpr0pyl) - 3,4-diphenyl-lH-pyzaz0l-dihydr0chl0rid of the Fp. = 177 to 188°C received, which proved in the Gaschromatogramm as to 94% pure of isomer. Production of Endpr0dukt example: A solution of! 1.5 g (0.04 mol) l (3-Aminopropyl) - 3,4-diphenyl-iH-pyrazol and B0 ml 35% wässsrigem Formaldchyd in 125 ml ethanol were reduced in a Parr Schüttslvorrichtung over 500 mg Platlnoxyd with a landing on water EFF printing by 3,52 bar (50). The reduction was interrupted after the admission of 2,04 bar (29), further 500 mg catalyst were course-set and the reduction had been continued, up to further 2.74 bar (39) taken up was. The reduction was interrupted, added again additional formaldehydes and catalyst and continued again the reduction up to a final admission of 2,18 bar (of 81) i0. The mixture became managing in that in example IA. descriptive way regenerated and the product into the Hydrechloridsalz was converted, whereby one two parliamentary groups of altogether 6.6 g i [8 (N, N-Dimethylamino) - propyl] -3,4-diphenyl-iH-pyrazol-dihydrochlorid, 4.0 g from the Fp. = 178 to 191°C and 2.6 g of the Fp. = 185 to 191°C received. Biological Untersuchungser gebnissc with the anti- Tetrabenazin test (TB) with according to invention made the 8,4-Diphenylverbindung of received results is below specified. All dosages are in milligrams per kilogram (mg/kg) indicated. TB: actively /4, 8, 16 inactively /2