PROCEDURE FOR the PRODUCTION of NEW of AMINOSUBSTITUIERTER 4,5,6,7-TETRAHYDRO-1H (OR 2H) - INDAZOLE AND the SAEUREADDITIONSSALZE AS WELL AS OPTICAL ISOMERS OF IT

The subject of the invention is a procedure for the production new aminosubstituierter 4,5,6,7-Tetrahydro-IH (or 2H) - indazole of the formulas H HN (1) (IL) where one of the substituents B or B* for H and the other one stand for 2 for N (R2), how the substituents B2 allyl, Methy! , Ethyl or n-Propyl means, and the pharmaceutical harmless acid addition salts as well as optical isomers hievon, thereby characterized that one Tautomeren of the formulas H I n' (eat) (IIB) where one of the substituents B or R* for H and the other one stand for N (B2) for 2, whereby both substituents B2 mean H in each case, with an aldehyde B4CHO, where R stands for H, Vinyl, h4ethyl or ethyl, in presence of a metal hydride than reducing agents or with an alkyl halide or an anhydride under following reduction convert, if required a in such a way received connection into an acid addition salt transferred and if necessary a in such a way received connection or a in such a way received acid addition salt in its optical isomers split. “The above connections and their salts are suitable as Dopaminagonisten for the treatment of park in on illness and for the inhibition of a Prolaktinabscheidung. The connections of the formulas (I) and (II) are to each other more tautomer. This means that they are present in solution in a dynamic equilibrium, whereby the proportional portion of a certain Tautomeren in the mixture depends both on the environment and on electronic forces. The above formula (I) stands for a iH-Indazol and a formula (IL) for a 2H-Indazol. Many for the production of the connections of the formulas (i) and (II) used intermediate products are likewise Tautomeren. To pharmaceutical harmless acid addition salts of the connections of the general formulas (I) and (II) among other things salts of nichttoxiscner inorganic acids belong, like hydrochloric acid. Nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, salpetriger acid or phosphorous acid, as well as salts of not-toxic organic acids, like aliphatic Monooder dicarbonic acids, phenylsubstituierter alkane carbonic acids, Hydroxyalkancarbonsäuren, Hydroxyalkandicarbonsäuren, aromatic acids, aliphatic sulfone acids or aromatic sulfone acids. Examples of such pharmaceutical harmless salts are from there the appropriate sulfates, Pyrosulfate, Bisulfate, sulfites, Bisulfite, nitrates, phosphates, mono hydraulic gene phosphates, Dihydrogenphosphate, etapbosphate, Pyrophosphate, chloride, Bromi3s de, iodides, fluorides, acetates, Propionate, Decanoate, Caprylate, Aerylate, formates. Isobutyrate, Caprate, Heptanoate, Propiolate, oxalates, Malonate, Succinate, Suberate, Sebacate, Fumarate, Maleate, Mandelate, Butin l, 4-dioate, Hexine l, 6-dioate, Benzoate, Chlorbenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxybenzoate, Methoxybenzoate, Phthalate, Terephthalate, Benzolsulfonate, Toluolsulfonate, Chlorbenzolsulfonate, Xylolsu] fonate, Phenylacetate, Phenylpropionate, PhenylbutyraNr.364827 Te, CIT rate, Lactate, B-Hydroxybutyrate, Glykolate, Malate, Tartrate, Methansulfonate, Propansulfonate, Naphthalin l sulfonate or Naphthalin-2-sulfonate. Examples of connections, which under the general formula (I) fall, are the following: dl-5-Dimethylamino-4,5,6,7-tetrahydro-lH-indazol-methansulfonat dl-5-Diäthyl amino-4,5,6,7-tetrahydro-lH-indazol-maleat dl-6-Diallylamino-4,5,6,7-tetrahydro-I H-indazol-sulfate dl-5-Di (n-propyl) amino-4,5,6,7-tetr ahydro LH indazol hydrochloride. Examples of connections, which under the above general formula (II), are the following fall: I0 N-methyl-N-all yl-D] - 5-amino-4,5,6,7-tetrahydro-2H-indazol-methansulfonat dl-6-Dimethylamino-4,5,6,7-tetrahydroH-indazol-maleat N-Methyl-N-äthyl-dl-amino-4,5,6,7-tetrahydro-2H-indazol-hydrochlorid N-Methy] - N-n-propyl-dl-5-amino-4,5,6,7-tetrahydro-2H-indazol-sulfat N-Allyl-N-n-propyl-dl-5-amino-4,5,6,7-tetrahydro-2H-indazol-t kind advice. Is by the presence of a substituent at the C-5 or at the C-6 in the Indazolring is introduced to this “Ldoleküle an assymmetric center. The connections of of the general formulas (I) and (IL) occur from there in form of two optical Isomerer, which appears to Racemat as DL-few or. According to invention a manufactured lets itself DL-few isolate in well-known way into its optical antipodes. Those connections of the formulas {I) and (II), with which 1 l stands for N (B2) for H and R for, can be manufactured according to the following reaction pattern I. Reaction pattern I 0 I \ l time NH-CO-CHa (CH30) CH-N [CH) A O CH-N (CHs) 2 I (II11 NH-CO-CHs n. //N-- [v) • zHC1 [Va) NaOAc • aHC1 MeOH NH2 NH2 \ R3CHO “. NaBHaCN get to H20 H (VT) I /N (via) R” = H, CH3, C2 Hs (IV) (IVa) N [CH2R) z • 2HG1 N (CH2R) 2 • 2HG1 or CH=CH 2 • NH-CO-CHa NH-CO-CHa in accordance with the above reaction pattern I is converted 4-Acetamidocyclohexanon with Dimethylformamiddimethylacetal. By following conversion hiebei of of the received product, i.e. 4-Acetamido-2-dimethylaminomethylencyclohexanon (III), with hydrazine hydrate in a suitable inert a mutual solvent, like methanol, erhäIL one directly dl-5-Acetamido-4,5,6,7-tetrahydro-iH-indazol (IV) and its 2H-Tautomeres (IVa], which are isolated usually in form of an acid addition salt, like in the form of Methansulfonat odBr hydrochloride, since the free base does not crystallize. By following hydrolysis of the connections (IV) and (IVa) with for example aqueous hydrochloric acid one keeps to dl-5-Amino-4,5,6,7-tetrahydro-IH direct - indazol and its 2H-Tautomeres in form of the Dihydrochloride (V) and (Va), i.e. connections of the formulas (IA) and (ITA), with which R for NH2 and R stand for H. Hiedurch erhalte'nen primary amines become according to invention in connections of the formulas (T) and (IL), with which R for N (l ethyl) 2, N (ethyl) 2, N (n-Propyl) 2 or N (allyl) 2 stands transferred, by with an aldehyde of the formula MACHO, where R stands for H, Vinyl, methyl or ethyl, in a reductive alkylation in presence of Natriumcyanoborhydrid or an other suitable metal hydride as reducing agent it converting it. The connections of the formulas (I) and (IL), with which R* for N (RZh and R for H, I0 stands after something different one, however nevertheless similar procedures is manufactured, which from the following reaction pattern tl comes out. In this reaction pattern IT R2 has the meaning indicated above, during R-S for (c1 - C3) alkyl or benzyle stands. By (C - C3) alkyl hiebei methyl, ethyl, n-Propyl or Isopropyl are understood. Reaction pattern II 0 OR H HOHC N2 ne. Cycles per second of 0 /N------/' tOH NI…/v (vm “/IL (wn] /N I OR s HN _ _ - < II. I J N/acid i (zx). -; NH AC MeOH NaBH3CN (IXa) /N -- N (CH2R ") = R " CHO N” “NaBHaCN (xI) NaOAc MeOH OR5 (VIIIa) H /N---- I H2 N% II, x, IL HN J B (Xa} /N--/ % (Xla) N (CH2 R”) 2 in detail shows the reaction pattern II the conversion of a a-Enoläther-6-hydroxymethylen-2 - cyelohexenons, like 3-Äthoxy-6-hydrexymethylen-2-cyolohexenon, manufactured gom if J.Org.Ohem.27, 2278 (1962), with hydrazine hydrate in a mutual inert solvent, like ethanol, under formation of dl-6-Äthoxy-4,5-dihydro-lH-indazol (VIII) and its 2H-Tautomeren (VIIIa). Hiebei the connections of the formulas (VIII) and (VllIa), received as intermediate products, are likewise new. By hydrolysis of these connections with acid, preferably tri fluorine acetic acid or chlorine landing on water EFF acid, one arrives to a strong hochlonisierten acid, like p-Toluolsulfonsäure, at dl-6-Oxo-4,5,6,7-tetrahydro-lH-indazol (IX) and its 2H-Tautomeren (IXa). The intermediate products of the formulas (IX) and (IXa) are likewise new. By reductive laminating of these Oxoverbindungen with Ammeniumacetat and Natriumcyanoborhydrid or a suitable metal hydride as reducing agents with sufficient reduction strength in presence of of a mutual of an inert solvent one receives the appropriate thing dl-6-Amino-4,5,6,7-tetrahydro-lH-indazol (X) and dl-6-Amino-4,5,6,7-tetrahydro-2H-indazol to an other, i.e. connections of the formulas (IA) and (IIA), where R for H and R stand for NHz. To the production of connections of the formulas IL) and (II), where R for H and RZ stand for z, N (Cz Hs) for N (CH3) 2 or N (n-Propyl) z, one submits the 6-Aminoverbindungen of the formulas (X) and (Xa] a reductive alkylation with an aldehyde in presence of a t etallhydrids as reducing agents, like Natriumcyanoborhydrid, in described the procedure together with the Reakticnsschema the I, whereby one to dl-6-Dialkyl (or Diallyl) amino-4,5,6,7-tetrahydro-iH-indazol (XI) and appropriate 2 [l-Tautomeren (XIa) arrived. Connections, with which the 6-Aminogruppe is asymmetrically substituted, can be manufactured, by one the primary amine (X) and (Xa) with 1 mol of a Säurechlorids or a Säureanhydrids to the appropriate 6-Acylaminoderivat converts, by transferring the acyl group into an alkyl group (for example acetyl in ethyl), by one the appropriate connection with a metal hydride. how LiAIH treats and hiedureh the received secondary amine at the C-6 then with an alkylating agent, which contains another alkyl group (like methyl or n-Propyl with the above example) alkylated. The new intermediate products of the formulas (VIII) and (VIIIa) as well as (IX) and (IXa) in the reaction pattern II can be manufactured, by a Enoläther of cyclohexane l, 3-dion of the general formula O • ORs where R-S for (Cz-C3) alkyl or benzyle standing, at the C-6 after in J. suppl. the Chen. 27, 2278 (1902} descriptive procedures formyliert, whereby one arrives at a connection of the formula (VII). By conversion of a connection of the formula (VII) with hydrazine hydrate one receives the appropriate Tautemeren (VIIl) and (mansion), whose D¢enolisierung with an acid leads then to the Ketoverbindungen (IX) and (IXa). The connections of the formulas (I) and (II) are all as dl-5 (or 6) - Dialkylamino-4,5,6,7 - tetrahydro LH indazole and dl-5 (or 6) - Dialkylamino-4,5,6,7-tetrahydro-2H-indazole designated. The presence of the amino group at the C-5 or C-6 of the Indazolringes forms an assymmetric center, so that the connections of the formulas (I) and result (II) when their production in form of a Racemats or a DL mixture. This Raeemate can be isolated in usual way in their respective dund l-isomers. It is accepted that the effectiveness of these connections as Dopaminagonisten, which on the basis the Racemate of the formulas (I) and (IL} is shown, majority, if not at all whole, is to be assigned to individual stereoisomers. To the invention from there not only DL-Bacemate with an effectiveness belong as Diaminagonisten, but also practically pure stereoisomers, which have an effectiveness as Dopaminagonisten. The invention is continued to describe on the basis the following examples. Example i: dl-5-Dimethylamino-4,5,6,7-tetrahydro-iH-indazol and dl-5-Dimethylamino-4,5,6,7 - tetrahydro-2H-indazol Losan places a reaction mixture ago from 630 mg dl-5-Amino-4,5,6,7-tetrahydro-IH-indazol dirtydrochlorid and to a 2H-Tautomer-dihydrochlorid, 410 g Natriumacetat and 75 ml ethanol. The s received mixture is shifted first with 380 mg Natriumcyanoborhydrid and then with 1 ml 37%igem aqueous Formalin. Then the Beaktionsgemisch about 17 h agitated with ambient temperature, on which one it on a mixture from ice and 1-normaler aqueous CH] orwasserstoffsäure pours. The aqueous layer is extracted with chloroform and the chloroform excerpt is rejected. The aqueous layer is then extracted with 14-normalem aqueous ammonium hydroxide basic placed, on which one the received alka] ische solution several times with a solvent mixture from chloroform and isopropanol. The excerpts are combined, and the united excerpts are washed with satisfied aqueous sodium chloride and dried then. By evaporation of the solvent one arrives to 5-Dimethylamino-4,5,6,7-tetrahydro-IH-indazol and dl-5-Dimethy] amino-4,5,6 at 0.42 g of arrears from the D formed with above reaction] -? - tetrahydro-2HiS - indazol. An appropriate NMR spektreskopische investigation using CDC] ù of the tautomeren mixture results in characteristic maxima in the case of 142 cps (Singlett Aminomethyl) as well as in the case of 432 and 440 cps (broad Singlett C-3H). For the further cleaning of the connections one solves the arrears in 10 ml l-normal hydrochloric acid and dilutes the received mixture with water-free ethanol. The Lüsung is then evaporated under vacuum to dry ones and the received arrears from a solvent mixture from methanol and ether are recrystallized. In this way manufactured dl-5-Dimethylamino-4,5,6,7-tetrahydro-lH-indazol-dihydroch] orid and dl-5Dimethylamino-4,5,6,7-tetrahydro-2H-indazol-dihydrochlorid melts with 230 to 238°C under foams, and the yield amounts to 430 mg. Analysis: 2S C H N computes: 45.39% 7.20% 17.64% found: 45.26% 7.13% 17.46% example 2: dl-5-Di (n-propyl) amino-4,5,6,7-tetrahydro-IH-indazol and dl-5-Di (n-propyl) amino -4,5,6,7-tetrahydro-2H-indazol in procedures, however under substitution of the formaldehyde by Propiona, descriptive in example]] dehyd, one places a mixture from dl-5-Di (n-propyl) to amino-4,5,6,7-tetrahydro-IH-indazol and its 2H-Tautomeren more ber. An appropriate NMR spectroscopic investigation in CDCI of L 4aterials received thereby results in characteristic maxima in the case of 52 cps (triplet Propyl GH3) un “in the case of 432 cps (Singlett-C-3H). In appropriate way the manufactured Dihydrochlorid of the tautomeren mixture received in above 3S way melts with 154 to 160°C under foams. The product yield amounts to 2.97 g (on the basis of 2,15 g raw material). Analysis: C H N computes: 53,064 8.564 14.28% found: 52.83% 8.83% 14.30% example 3: In the procedure described in example 1 one alkylates dl-6-Amino-4,5,6,7 - tetrahydro LH (and 2H) - indazol with Propiona] dehyd and NaBH CN, whereby one to dl-6-Di (n-propyl) - amino-4,5,6,7-tetrahydro-IH (and 2H) - indazol arrives. With this free base it concerns a not-crystalline glasslike mass. In the mass spectrum hiefür a Molekularion (M+) results in the case of 221. The available according to invention connections of the formulas (I) and (II) it is suitable for the treatment of park in on syndrome which expresses itself to the fact that her with appropriate investigations the Drehverha] ten from rats injured using 6-Hydroxydopamin affects. For these investigations neostriatal damaged rats are used, like one them after so in Brain the Res. 24, 485 (1970) descriptive procedures receives. A connection, which works as Dopaminagonist, leads after appropriate injection to that the rats turn in circles against-lateral for the side of the damage. After a latency, which is different from connection to connection, the number of turns is counted over a length of time of 15 min. The connections which can be examined are solved in water, and the received aqueous solution is injected to the respective attempt rats intraperitoneal into different dosages. Hiebei the received results come out from the following table I. In their the respective active substance is indicated in column 1, while made of column 2 the active substance dose comes out, made of column 3 the proportional quantity of the rats with a turning behavior and made of column 4 the middle number of turns. Active substance table I girkstaFfdosls proportional Henke of the rats with a Orehverhalten dl-5-Oi (n-pvopyl) amlno -4,5,6,7-tetrahydro-IH (and 2H) - - indazol dfhydr ““hlorid I ag/kg I00 g/kg 67 33 number of turns b, B 6 dl-5-Dimethylamino-4,5,6,7-tetrahydro-lH (and 2H) - indazol - dlhydrochloeid! mg/kg 33 dl-6-Di (n-propyl) A ino1 mg/kg lDO 98 -4,5,6,7-tetrahydro-lH (and 2H) - 250 g/kg 50 - indazol dihydrocblorid 100 pg/kg 0 the connections of the formulas (I) and (II) are characterised furthermore by a prolaktinhemmende effect, so that they can be used for the treatment of an unwanted Laktation, for example a Postpartum Laktation or a Galaktorrhöe. The suitability of the connections of the formulas (I) and (II) for the treatment of conditions, with which one would like to degrade the Prolaktinspiegel, i.e. to the Prolaktinhemmung, in the following investigation procedure one determines. Adults male Sprague Dawley rats with a weight of approximately 200 g are given to an air-conditioned area with controlled lighting (the light is of 6 o'clock early to 8 o'clock in the evening on) and fed with LaborfutLer and water ad libitum. 18 h before administration of the Indazols which can be examined in each case one injects each rat intraperitoneal 2.0 mg reserpine in aqueous suspension. Purpose of this reserpine injection is it to keep the Prolaktinwerte homogeneously increased. The connections which can be examined are solved in water and injected intraperitoneal in doses from 5 mg/kg to down there up to 50 pg/kg. Each connection is given in each active substance dose of a group from 10 rats, while an control group from z5 likewise receives i0 intact male rats only an equivalent solvent quantity. I h after treatment are killed all rats by cutting the heads off, whereby one examines subsets of 150 in each case pl serum concerning the Prolaktingehaltes. The difference between the Prolaktingehalt of the treated rats and the Prolaktingehalt of the control rats divided by the Prolatingehalt of the control rats results in an appropriate value for the proportional inhibition of the Prolaktinabscheidung, which on the administration of the connections of the formulas (I) and (II) to lead back is. These values for the proportional Prolaktinhemmung come out from the following table IL. In column i for it the respective active substance is indicated, while from the columns 2 to 4 mentioned the proportional Prolaktfnhemmung arising with the active substance doses comes out. Table II proportional Prolaktionshemmung with a given active substance dose active substance dl-5-Di (n-propyl) amino -4,5,6,7-tetrahydro-iH (and 2H) - - indazol dihydrochlorid dl-5-Dimethylamino-4,5,6,7 - tetrahydro iH (and 2H) - indazol - dihydrochlorid dl-6-Di (n-propyl) amino -4,5,6,7-tetrahydro-IH (and 2H) - - indazol dihydrochlorid mg/kg 500 pg/kg 50 pg/kg 94 66 73 31 31 for the employment of the connections of the formulas (1) and (IL) for the inhibition of a Prolaktinabscheidung or for the treatment of park in on syndrome or for achievement other pharmakologischer Birkungen one delivers an appropriate connection of the formula (1) or the Formei (II) or a salt hievon with a pharmaceutical harmless acid an appropriate patient, who suffers from Parklnson illness or with that the Prolaktinsplegel degraded will is, in such mixes that hiedurch a certain relief of the symptoms of the park in on illness or a degradation of a increased Prolaktinspiegels results. An oral administration is preferred hiebei. With application of a parenteral administration the injection preferably takes place subkutan under employment of an appropriate pharmaceutical formulation. Other kinds of administration, like intraperitoneal, intramuskuläre or intravenous administrations, are just as effective. For intravenous or intramuskuläre administrations in particular water-soluble, pharmaceutical harmless salts are used. For an oral delivery one sets the respective connection of the formula (1) or (II) appropriately either in form of the free base or in form of a salt hievon in the mixture with a conventional pharmaceutical Exzipiens in, which is injected either into empty telescope gelatin capsules filled up or to tablets. The oral dose should amount to about 0.01 to l0 mg/kg body weight, while the parenteral dose is appropriately to be appropriate for body weight between approximately 0.0025 and 2.5 mg/kg. The LDs0 - Values for dl-5-Di (n-propyl) amino-4,5,6,7-tetrahydro-IH (and 2H) - indazol - dihydrochlorid lie with intraperitoneal administration at the mouse between i00 and 300 mg/kg. Doses of 10 and 30 mg/kg body weight are not deadly, but lead an active substance dose of 30 mg/kg body weight to some unwanted side effects.