HU184624B - Process for preparing amino-substituted 4,5,6,7-tetrahydro-1h/or 2h/-indazole derivatives - Google Patents

Abstract

Indazol tautomers(I; one of R and R1 is H, and the other is H(R2)2; R2 = H, allyl, Me, Et, n-Pr) were prepd. and they were effective in the treatment of Parkinsonism and in the inhibition of prolactin. Thus, the reaction of 4-acetamidocy-clohexanone with HC(OMe)2NMe2 gave 4-acetamido-2-≮(dimethylamino) methylene≉ cyclohexanone, the latter was treated with N2H4 to give I.

Description

The present invention relates to tetrahydro-1 H (or 2 H) -indazole derivatives I and II wherein one of R ⁶ and R ¹ is hydrogen and the other is -N (R ² ) ₂ and each R ^{2 is} independently methyl, ethyl - or an n-propyl group - and their pharmaceutically acceptable acid addition salts.

These compounds are prepared by reacting tautomers IB and IIB, wherein one of R ⁶ and R ¹ is hydrogen and the other is -N (R ² ) ₂ and both R ^{2 are} hydrogen, in the presence of a metal hydride reducing agent.

These compounds and their salts, being dopamine agonists, can be used to treat Parkinson's disease and to inhibit prolactin secretion.

The closest compounds are described in U.S. Patent 3,520,901. These are differently substituted tetrahydroindazole derivatives in the 2-position.

The novel intermediates of formulas IA and HA are prepared by:

a) a compound of formula III - wherein R ³ is reacted with the above hydrazine hydrate in a solvent inert to both reagents to give compounds of formula IA and IIA, wherein

R ^{1 is} hydrogen and

R-NH-CO-R ^{3 is} then optionally hydrolyzed to provide compounds IA and IIA wherein

R ^{1 is} hydrogen and

RN ^(R2) ₂ formula wherein R ² is hydrogen;

obsession

b) Reductive amination of tautomeric compounds of formulas IX and IXa in a solvent inert to the reagents to give compounds of formulas IA and IIA wherein

R is hydrogen; and j

_N R ¹ (R ²⁾ ₂ of the formula wherein ^R2 is hydrogen.

Compounds of formula I and II are tautomers, i.e., in solution, the two forms are in dynamic equilibrium and the equilibrium ratio of the components depends on environmental factors and the strength of the electron bond. The above formula represents the 1H-indazole and the formula II the 2H-indazole compound. Many of the intermediates for the preparation of compounds of formulas I and II are also tautomers.

Pharmaceutically acceptable acid addition salts of compounds of Formulas I and II include, for example, non-toxic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitric, phosphoric and the like, as well as non-toxic organic acids, dicarboxylic acids, phenyl-substituted aliphatic carboxylic acids, aliphatic hydroxy monocarboxylic and dicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogen sulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, , formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, butyrate, lactate , glycollate, malt, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like.

Representative compounds of Formula I include the following;

dl-5-dimethylamino-4,5,6,7-tetrahydro-1H-indazolmethanesulfonate; dl-5-diethylamino-4,5,6,7-tetrahydro-1H-indazole maleate;

dl-5-di (n-propyl) amino-4,5,6,7-tetrahydro-indazole hydrochloride.

Representative compounds of formula II include, but are not limited to:

dl-6-dimethylamino-4,5,6,7-tetrahydro-2H-indazolmaleát.

The presence of C-5 or C-6 substituents on the indazole ring introduces an asymmetric center into these molecules. Thus, the compounds of Formulas I and II may exist in the form of two optical isomers, as dl pairs or as racemates. The dl pairs of the present invention can be separated into their optical antipodes by known methods.

Compounds of formula I and II wherein

R ^{1 is} hydrogen and

RN (R ²⁾ ₂ radical, can be prepared according to Reaction Scheme 1; in the formulas therein, R ⁴ is H, methyl, ethyl or n-propyl.

In Scheme 1, 4-acetamidocyclohexanone is reacted with dimethylformamide dimethylacetal. The reaction product (H1) of 4-acetamido-2-dimethylaminomethylene-cyclohexanone is directly reacted with hydrazine hydrate in a suitable inert solvent such as methanol to give 1-5-acetamido-4,5,6,7-tetrahydro-1H-indazo [. IV) and its 2H tautomer (IVa), which is usually isolated in the form of an acid addition salt such as methanesulfonate or hydrochloride, since the free base is not crystalline. Hydrolysis of the compounds of formulas IV and IVa, e.g. with aqueous hydrochloric acid, directly produces dl-5-amino-4,5,6,7-tetrahydro-1H-indazole and its 2H tautometry in the form of the dihydrochloride salts (V and Va) of formula IA and IIA. correspond vegyieteknek, RNH ₂ wherein R and ^R1 groups are hydrogen. Conversion of the primary amine to the compounds of formulas I and 11 wherein R is N (methyl) ₂ , N (ethyl) ₂ or N (n-propyl) _{2 is} readily accomplished by reductive alkylation, i.e., R ^{4 is} CHO aldehyde - wherein R ^{4 is} hydrogen, methyl or ethyl - in the presence of a sodium cyanoborohydride or other suitable metal hydride reducing agent.

The I and II compounds wherein R is prepared by ^two different groups such as C-5 acetamide such as compounds of formula IV or IVa by reduction. The resulting N-ethyl derivative (secondary amine) is conventionally alkylated, for example, with an alkyl halide such as methyl iodide to give the N-methyl-N-ethylamine group at C-5. In addition, the secondary amine is acyl-21 with propionic anhydride, for example

184,624 is triturated and the resulting propionamide is reduced with a metal hydride such as lithium aluminum hydride to give the N-ethyl-N-n-propylamine group at the C-5 position. The acylation of indaznitrogen, if at all, is a selectively reversible reaction.

Compounds of formula I and II wherein

R ^{1 is} -N (R ² ) ₂ ;

R is hydrogen, prepared by slightly different synthetic methods. according to the reaction scheme. In this scheme, R ² is as defined above, and R ^{5 is C} 1-3 alkyl or benzyl. C 1-3 alkyl means methyl, ethyl, n-propyl and isopropyl.

II. a 3-enol ether-6-hydroxymethylene-2-cyclohexenone [Wenkert et al., J. Org. Chem. 27, 2278 (1962)] is reacted with hydrazine hydrate in an inert solvent such as ethanol to give dl-6-ethoxy-4,5-dihydro-1H-indazole (VIII) and its 2H tautomer (Villa). . Intermediates VIII and VIII are also novel. Dl-6-oxo-4,5,6,7-tetrahydro-1H-indazole (IX) and its 2H tautomer (IXa) are hydrolyzed with an acid, preferably a strong highly dissociated acid such as p-toluenesulfonic acid, trifluoroacetic acid and the like. ). Intermediates IX and IXa are also novel. The oxo compound is reduced with ammonium acetate and sodium cyanoborohydride or other strong metal hydride reducing agents to the corresponding dl-6-amino4,5,6,7-tetralridro-1H-indazole (X) and dl-6-amino4, 5,6,7-Tetralidro-2H-indazole is obtained which corresponds to the compounds IA and 1IA in which! R is hydrogen and R ¹ is NH ₂ group.

Compounds of formulas 1 and II wherein R is hydrogen and R ^{1 is} -N (CH ₃ ) ₂ <-N (C ₂ H ₅ ) ₂ or -N (n-propyl) ₂ are represented by the formula X and Xa. is prepared by reducing alkylation of an amino compound by reaction with an aldehyde in the presence of a metal hydride reducing agent such as sodium cyanoborohydride in Scheme I; d1 -6-dialkylamino-4,5,6,7-tetrahydro-1H-indazole (XI) and the corresponding 2H tautomer (Xia).

II. The new intermediates of Formulas VIII, VIIIa, and IX and IXa shown in Scheme II are prepared by Wenker formylation of the cyclohexane-1,3-dionenol ether XII wherein R ^{5 is C} 1-3 alkyl or benzyl. et al., supra. Reaction of the starting compound VII with hydrazine hydrate yields tautomers VIII and VIIIa which undergo enol oxo conversion to give the keto compounds IX and IXa.

All compounds of Formulas I and II are dl-5 (or 6) -dialkylamino-4,5,6,7-tetrahydro-1H-indazole and dl-5 (or 6) -dialkylamino-4,5,6,7 We called it -tetrahydro-2H-indazole. The amino group at the C-5 or C-6 position of the indazole ring forms an asymmetric center and thus the compounds of formula I and II exist as racemates or dl mixtures. These racemates can be separated into the corresponding d- and 1-isomers by known methods. It is believed that the dopamine agonist activity of the racemates of Formulas I and II is largely, if not completely, bound to one of the stereoisomers.

The invention is further illustrated by the following examples:

The example

Preparation of 4-Acetamido-2-dimethylammoniethylene-cyclohexalion

To 15.5 g of 4-acetamidocyclohexanone (prepared by Fraser and Swingle, Can. J. Chem. 48, 2065 (1970)), 80 g of dimethylformamide dimethylacetal, 1.5 ml of triethylamine and 500 ml of benzene We are added. Benzene is distilled from the mixture for 1 1/2 hours, during which time the volume is reduced to about half the original volume. Benzene (250 mL) was again added to the reaction mixture, heated just under the boiling point of benzene for about 2 hours, and then distilled again until the volume was reduced to about half the original volume (250 mL). The above procedure was repeated once more, but this time the volume was reduced to 1/3 of the initial volume (167 ml). The reaction mixture was cooled and filtered. The filtered solid consists of 4-acetamido-2-dimethylaminomethylene-cyclohexanone formed in the above reaction; weight 6.45 g. The filtrate is evaporated to dryness and the residue is dissolved in chloroform, chromatographed on 200 g of Florisile using as eluent chloroform (0-5%) containing increasing amounts of methanol. Pure 4-acetamido-2-dimethylaminomethylene-cyclohexanone is obtained; 132-133 ° C (from benzene); yield 5.55 g; total yield 12 g.

Elementary analysis.

C Η N calculated 62.83; 8.63; 13.32%, found 62.07; 8.38; 13.12%.

Example B Preparation of dl -5-Acetamido-4,5,6,7-tetrahydro-1H-indazole and dl -5-acetamido-4,5,6,7-tetrahydro-2H-indazole

1.46 g of 4-acetamido-2-dimethylaminomethylene-cyclohexanone are dissolved in 25 ml of methanol. 0.35 ml of hydrazine hydrate is added and the mixture is stirred at room temperature for about 16 hours. The reaction mixture was evaporated in vacuo and the residual chloroform solution was chromatographed on 30 g Florisile, eluting with chloroform containing increasing methanol (2-5%). The thin layer chromatography (TLC) indicated that the fractions containing the larger non-starting material were pooled and the solvent removed in vacuo. 1.5 g of dl-5-acetamido-4,5,6,7-1H-indazole and its 2H tautomer are obtained. The material was dissolved in anhydrous ethanol and 0.5 mL of methanesulfonic acid was added. The resulting dl-5-acetamido-4,5,6,7-tetrahydro-1H-indazole-indanesulfonate and dl-5-acetamido-4,5,6,7-tetrahydro-2H-indazole methanesulfonate had a melting point of about 190-192 ° C; yield 1.61 g.

Elementary analysis:

C 43 N S calcd 43 62; 6.22; 15.26; 11.65%, found 43.83; 6.37; 15.15; 11.39%.

-3184 624

Example C Preparation of dl -5-amino-4,5,6,7-tetrahydro-1H-indazole and dl -5-amino-4,5,6,7-tetrahydro-2H-indazole d1-5-acetamido4, 950 mg of a mixture of 5,6,7-tetrahydro-1H-indazole methanesulfonate and dl-5-acetamido-4,5,5,8,7-tetrahydro-2H-indazole methanesulfonate were dissolved in 50 mL of 6N aqueous hydrochloric acid and the solution was refluxed under nitrogen. Boil for 1 hour. The reaction mixture was cooled and its volatile components evaporated in vacuo. The residue was dissolved in ethanol and the ethanol solution was evaporated and cooled. The crystallized dl-5-amino-4,5,6,7-tetrahydro-1H-indazole dihydrochloride and dl-5-amino-4,5,6,7-tetrahydro-2H-indazole dihydrochloride were isolated by filtration; mp 260-270 ° C; yield 380 mg.

Elementary analysis

C Η N Cl calculated 40.20; 6.24; 20.00; 33.75%, found 40.29; 5.99; 20.12; 33.63%.

Example D Preparation of dl-6-Ethoxy-4,5-dihydro-1H-indazole and dletoxy-4,5-dihydro-2H-indazole g of 3-ethoxy-6-hydroxymethylene-2-cyclohexenone [prepared by Wenkert and et al., J. Org. Chem. 27, 2278 (1962)] is dissolved in 150 ml of ethanol. 1.9 ml of hydrazine hydrate are added and the mixture is stirred at room temperature under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in chloroform. The chloroform solution was chromatographed on 100 g of Florisil eluting with chloroform containing increasing amounts of ethanol (0-2%). According to TLC, the larger, spot-free fractions were combined and the solvent evaporated in vacuo. The residue was crystallized from ether / hexane. The resulting dl-6-ethoxy-4,5-dihydro-1H-indazole and 2H-automeqe melted at 118-120 ° C in a yield of 3.64 g. Elementary analysis;

C Η N calculated 65.83; 7.37; 17.06%, found 66.03; 7.25; 16.81%.

Example E Preparation of dl -6-oxo-4,5,6,7-tetrahydro-1H-indazole and dl-6-oxo-4,5,6,7-tetrahydro-21I-indazole A mixture of 3.2 g of 4,5-dihydro-1H-lindazole and its 2-acetic acid is stirred in 150 ml of aqueous hydrochloric acid at ambient temperature under nitrogen for 1/4 hour. Thin layer chromatogram shows another larger spot (not starting material)

show up. The infrared spectrum of this material shows a higher spot on absorbance at 1710 cm ^_1, suggesting the formation of a keto group. The reaction mixture was saturated with solid sodium bicarbonate and the aqueous basic reaction mixture was extracted several times with chloroform. The chloroform solutions were combined, washed with saturated sodium chloride solution and dried. After evaporation of the chloroform, the residue was dissolved in chloroform and chromatographed on 30 g of Florisil eluting with 10% chloroform in 2% methanol. The resulting fractions containing d1-6-oxo-4,5,6,7-tetrahydro-1H-indazole and d1-6-oxo-4,5,6,7-tetrahydro-2H-indazole were combined and dissolved in methanol. Methanesulfonic acid (0.7 mL) was added and the mixture was diluted with ether to about 125 mL. The solution 15 is cooled and the volatile constituents evaporated in vacuo. The residue was dissolved in ethanol and the ethanol solution was diluted with ether. On cooling, an oil is formed. The oil was dissolved in ethanol, ether was added until precipitation started, and the mixture was allowed to cool. Crystalline 20 dl-6-oxo-4,5,6,7-tetrahydro-1 H (and 2 H) -indazole methanesulfonate, m.p. 95-105 ° C by recrystallization from ether / ethanol; yield 1.86 g.

Elementary analysis:

CΗΗ N S calculated 41.13; 5.21; 12.06; 13.81%, found 41.57; 5.38; 11.77; 13.53%.

Example F Preparation of dl-6-amino-4,5,6,7-tetrahydro-1H-indazole and dl-6-amino-4,5,6,7-tetrahydro-2H-indazole ³⁵ d 1 -6- 8 g of a mixture of oxo-4,5,6,7-tetrahydro-1H-indazole hydrochloride and 2H-tautomeric hydrochloride (prepared from the methanesulfonate of Example E above) and 30 g of ammonium acetate in 400 ml of methanol40 and 2.9 g of sodium cyanoborohydride are added. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for about 1 day and then poured into an excess of 1N aqueous hydrochloric acid. The aqueous layer was extracted with ether and the ether extract was discarded. The aqueous layer was then basified with dilute aqueous sodium hydroxide solution and extracted several times with chloroform / isopropanol. The organic extracts were combined, washed with brine, and dried. The solvent was evaporated to give a residue of dl-6-amino50 4,5,6,7-tetrahydro-1H-indazole and dl-6-airsino-4,5,6,7-tetrahydro-2H-indazole, which was dissolved in 200 ml of ethanol. The ethanolic solution was added dropwise, with stirring, to 7.7 ml of 12N aqueous hydrochloric acid. The mixture was concentrated in vacuo to give an equilibrium mixture of dl-655 amino-4,5,6,7-tetrahydro-1H-indazole dihydrochloride and dl-6-amino-4,5,6,7-tetrahydro-2H-indazole dihydrochloride. m.p. 275-280 ° C (dec), recrystallized from ethanol. Yield: 4.20 g.

Elementary analysis:

C Η N calculated 40.02; 6.24; 20.00%, found 39.74; 6.02; 19.80%

184,624

end products

Example 1 Preparation of dl-5-dimethylamino-4,5,6,7-tetrahydro-1H-indazole and dI-5- (dimethylamino) -4,5,6,7-tetrahydro-2H-indazole

A reaction mixture containing 630 mg of dl-5-amino-4,5,6,7-tetrahydro-1H-imidazole dihydrochloride and 2H-tautomeric dihydrochloride, 410 g of sodium acetate and 75 ml of ethanol was prepared. To the mixture was added 380 mg of sodium cyanoborohydride followed by 1 ml of 37% aqueous formalin solution. The mixture is stirred at ambient temperature for about 17 hours and then poured into ice / IN aqueous hydrochloric acid. The aqueous layer was extracted with chloroform and the chloroform extract was discarded. The aqueous layer was basified with 14N ammonium hydroxide solution and the basic solution was extracted several times with chloroform-isopropanol. The combined extracts were washed with saturated aqueous sodium chloride solution and dried. The solvent was evaporated to give dl-5- (dimethylamino) -4,5,6,7-tetrahydro-1H-indazole and dl-5- (dimethylamino) -4,5,10,7-tetrahydro-2H-indazole. 0.43 g of a residue is obtained. In tautomeric mixture by nuclear magnetic resonance spectra give characteristic peaks (NMR) at 142 cps (singlet-aminomethyl) 432 and 440 cps at (broad singlet, C-3H), _CDCl3 -as solution. The compounds were further purified by dissolving the residue in 10 mL of IN hydrochloric acid and diluting with anhydrous ethanol. The solution was evaporated to dryness in vacuo and the residue was crystallized from methanol / ether. The resulting dl-5- (dimethylamino) -4,5,6,7-tetrahydro-1H-indazole dihydrochloride and dl-5- (dimethylamino) -4,5,6,7-tetrahydro-2H -indazole dihydrochloride melting at 230-238 ° C with foaming; yield 430 mg.

Elementary analysis:

C Η N calculated 53.06; 8.56; 14.28%, found 52.83; 8.83; 14.30%.

Example 2 dl-5- [Di (n-propyl) amino] -4,5,6,7-tetrahydro-1H-indazole and dl-5- [di (n-propyl) amino] -4,5,6; Preparation of 7-tetrahydro-2H-indazole.

The procedure of Example 1 is repeated, but propionaldehyde is used instead of formaldehyde. In this way, a mixture of d1- [di (n-propyl) -amino] -4,5,6,7-tetrahydro-1H-indazole and 2H-tautomers is obtained.

NMR (COC1 ₃₎ characteristic bands 52 cps (t, propyl CH ₃₎ and 432 cps (s, C-3H). The dihydrochloride of the tautomeric mixture had a melting point of 154-160 ° C (foaming). Yield: 2.97 g (2.15 g of starting material). Elementary analysis:

date; C, 53.06; H8,56; N, 14.28%; Found: C, 52.83; H, 8.83; N, 14.30%.

Example 3

According to the procedure of Example 1, dl-6-amino-4,5,6,7-tetrahydro-ΙΗ (and 2H) -indazole is alkylated with propionaldehyde and sodium cyanoborohydride to give dl-6- [di (n-propyl) amino] 4,5,6,7-tetrahydro-1 H (and 2 H) -indazole is obtained. The free base is non-crystalline glass; mass spectrum: molecular ion (M ⁺ ) at 221.

Examining the utility of the compounds of Formulas I and II for the treatment of Parkinson's disease, they have been found to influence the rotational behavior of rats exposed to 6-hydroxydopamine. Ungerstedt and Arbuthnott [Brain Slit. 24, 485 (1970)] using rat brainstem nuclei of the substantia nigra and neostriatum. When injected with dcpamine agonist compounds, the rats rotate in the opposite direction to the affected side. After a latency period from compound to compound, the number of revolutions is counted for 15 minutes. The compounds are dissolved in water and the aqueous solution is injected intraperitoneally in a series of dose levels. The results of this test are shown in Table 1. In this table, Column 1 shows the name of the compound, Column 2 the dose, Column 3 shows the percentage of animals showing spinning behavior and Column 4 shows the average number of spins.

Table 1

Rotational behavior

Name of compound dose Level rotary behavior indicator rats %-the benzathine many number d 1- 5- [di (n-propyl) amino] -4,5,6,7-tetrahydro-1 H (and 2 H) indazole dihydrochloride 1 mg / kg 67 48 100 meg / kg 33 6 dl-5- [dimethyl-amino] · 4,5,6,7-tetrahydro-1H (and 2H) -indazole dihydrochloride 1 mg / kg 33 5 d 1-6 - [d i (n-propyl) amino] -4.5.6,7-tetrahydro-1H (and 2H) -indazole dihydrochloride 1 mg / kg 100 98 250 meg / kg 50 30 100 meg / kg 0 -

The compounds of formulas 1 and 11 can also be used as prolakinin inhibitors and as such can be used to treat undesirable milk production such as postpartum milk secretion and milk leak. In diseases where a reduction in prolactin levels is desired, the utility of the compounds of Formulas I and II as prolactin inhibitors is demonstrated by the following procedure.

Adult male rats of Sprague-Dawley strain, approximately 200 g, are housed in a controlled light (6 am to 8 pm) air-conditioned room, fed with standard laboratory food and provided with unlimited supply of drinking water. Each rat is administered an aqueous suspension of 2.0 mg reserpine intraperitoneally

-5184 624 injections for 18 hours! prior to administration of indazole.

Reserpine treatment is intended to maintain a consistently high level of prolactin. The test compounds are dissolved in water and injected intraperitoneally at a dose of 5 mg / kg to 50 mcg / kg. Each compound is administered at each dose level to groups of 10 rats and the control group of 10 untreated male animals is treated with the same amount of solvent. One hour after treatment, all animals are sacrificed by decapitation and prolactin concentrations are determined in 150 M aliquots of their serum.

Dividing the difference between the prolactin levels of the treated and control rats by the prolactin level of the control rats gives the% inhibition of prolactin secretion caused by the compounds of formulas I and II. 1% inhibition is shown in Table 2. In this table, column 1 shows the name of the compound and columns 2 through 4. Columns 1 to 4 indicate the% prolactin inhibition at the given dose level.

Table 2>

% Inhibition of prolactin at a given dose level

The name of the compound is 5 mg / kg 500 mcg / kg 50 mcg / kg dl-5- [di (n-propyl) amino] 4,5,6,7-tetrahydro-1H (and 2H) -indazole dihydrochloride 94 66 1 d 1- (5-Dimethylamino) 4,5,6,7-tetrahydro-1 H (and 2 H) -indazole dihydrochloride 73 30 31 dl -6- [di (n-propyl) amino] -4,5,6,7-tetrahydro-1H (and 2H) -indazole dihydrochloride 31

The compounds of formulas I and II are useful in inhibiting prolactin secretion or in treating Parkinson's disease or other pharmacological activity in patients with Parkinson's disease or in need of a prolactin-lowering agent to ameliorate certain symptoms of parkinsonism or to reduce high prolactin levels. an amount of a compound of formula I or II, or a pharmaceutically acceptable acid addition salt thereof. Oral administration is preferred. For parenteral administration, the injection is preferably administered subcutaneously in the form of a suitable pharmaceutical composition. Other modes of parenteral administration, such as intraperitoneal, intramuscular, or intravenous administration, are also effective. In particular, for intravenous and intramuscular use, water-soluble pharmaceutically acceptable salts are used for oral administration. The oral dosage range for mammals is about 0.01 to 10 µg / kg body weight and the parenteral dose range is about 0.0025 to 2.5 mg / kg body weight. The LD ₅₀ value of dl-5- [di (npropyl) amino] -4,5,6,7-tetrahydro-1 H (and 2 H) -indazole dihydrochloride, when administered intraperitoneally, is 100-300 mg / kg. Doses of 10-30 mg / kg are not fatal, but doses of 30 mg / kg cause some undesirable side effects.

Claims (5)

PATENT CLAIMS A process for preparing tautomers of formulas 1 and II wherein One of R and R ¹ is hydrogen and the other is N (R ² ) ₂ , and in the latter Each C ² substituent represents a methyl, ethyl or n-propyl group and a pharmaceutically acceptable acid addition salt thereof, wherein the tautomers of formulas IB and IB are wherein 5 R and R ¹ each represent hydrogen and the other amino group is reacted with the appropriate 'aldehyde of a metal hydride reducing agent and, if desired, the base thus obtained into an acid addition salt. 0 A process for the preparation of a compound according to claim 1, wherein R and R ^{1 are} as defined in claim 1 and R ^2N propilcsoportotjelentés elő5 pharmaceutically acceptable acid addition salts thereof, wherein formula IB and IIB are tautomeric compounds - where R, R 'and R ^{2 are as} defined in FIG. The compound of claim 1 is reacted with propionaldehyde in the presence of a metal hydride reducing agent. 0 3. The process according to claim 1, wherein dl-5-di (n-propyl) amino] -4,5,6,7-tetrahydro-2H-indazole and dl-5-di (n-propylamino) - 4,5,6,7-tetrahydro-1H-indazole for the preparation of tautomers characterized in that dl-5-amino-4,5,6,7-tetrahydro-1H-indazole 5 and dl-5-amino-4,5,6,7-tetrahydro-2H-indazole are reacted with propionaldehyde and sodium cyanoborohydride. 4. The process of claim 1 wherein d1-6- [di- (n-propyl) amino] -4,5,6,7-tetrahydro-1H-indazole and d1-6- [di (n-propyl) are used. -amino] -4,5,6,7-tetrahydro-2H-indazole tautomers characterized in that dl-6-amino-4,5,6,7-tetrahydro-1H-indazole and dl-6- amino-4,5,6,7-tetrahydro-2H-indazole is reacted with propionaldehyde and sodium cyanoborohydride. 5. The process according to claim 1, wherein d1-5- (dimethylamino) -4,5,6,7-tetrahydro-1H-indazole and d1-5- (dimethylamino) -4,5 are used. For the preparation of 6,7-tetrahydro-2H-indazole tautomers, characterized in that d 1-5 -ninno-4,5,6,7-tetrahydro-1H-indol-ol and dl-5-amno-4,5,6,7-tetrahydro-9 2H-inda-4H-formaldehyde isopropylated with sodium cyanoborohydride.