CS227009B2 - Method of preparing octahydropyrazolo (3,4-g)quinoline - Google Patents

Abstract

The title compds. of formula (XIII) were prepd. by reacting compds. of formula (XII) with pyridine hydrochloric acid salts and chromium trioxides. In the formulas, R is C1-3 alkyl, alkyl, or benzyl, and Z' is C1-2 alkyl or phenyl-substd. C1-2 alkyl. C1-3 alkyl includes n- propyl and iso-propyl, and C1-2 alkyl includes methyl and ethyl.

Description

(54) A process for the preparation of octahydropyrazolo [3,4-g] quinolines

The present invention relates to a process for the preparation of octahydropyrazolo [3,4-g] quinolines of the formulas Ia and Ib

(laJ

where

R is alkyl of 1 to 3 carbon atoms or allyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula VIIIa is reacted

(Pound) where

R is as defined above with ihydrazine hydrate, whereupon optionally the compound of formula Ia or Ib is converted to a pharmaceutically acceptable acid salt.

The compounds of formulas Ia and Ib together with their pharmaceutically acceptable salts are useful as dopamine agonists. Pharmaceutically acceptable salts with acids of formulas Ia and Ib include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphoric acid and the like, as well as salts derived from nontoxic acids. organic acids, such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyaillkanic acids and alkanedicarboxylic acids, laromatic acids, aliphatic and aromatic sulfonic acids.

Such pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogensulfates, sulfates, hydrogen sulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyirophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates , iheptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, butin-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, , terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, α-hydroxybutyrates, glycolates, malate, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-1-sulfonates, naphthalene-1-sulfonates.

Compounds of formula (Ia) above are systematically called 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolo [3,4-g] pyridinolines, and compounds of formula (Ib) 4,4a, 5,6,7 , 8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinolines.

These structural formulas represent tautomeric pairs and tautomers represent structures that are in dynamic equilibrium. In addition, the compounds of formulas Ia and Ib above have two chiral centers at the joining of rings 8a and 4a. Thus, the compounds may exist as two iracemates, commonly referred to as trans-dl-racemates and cis-dl-racemates. However, according to the best data from the ¹³ C NMR data, it is believed that the cyanoborothiohydride reduction process, which introduces hydrogen atoms to the quinolone bridge, the step in the synthetic process used to prepare compounds of formulas Ia and Ib provides the trans-linkage of decahydrocihinoline. While the zfókány arguments for the trans configuration based on ¹³ C NMR spectral data, crystallographic analysis of X-rays was carried out in a well-crystalline enamino the decahydroquinoline series (VIIIa: R ^=! CH3).

This X-ray analysis clearly shows that the ring junction in the quinoline portion of the molecule is trans. Further operations in the decahydroquinoline molecule for condensation of the pyrrazole ring do not alter the configuration on the hydrogen atoms on the bridge. Thus, only the trans-racemate is prepared by the synthetic procedure below and the compounds of formulas Ia and Ib * are preferably referred to as trans-d1-stereoisomers. The two trans-stereoisomers of the 2H-tautomer may be depicted in the following formulas IIa and IIb.

(II b) which form a racemic pair. A similar racemic pair can be depicted for the 1H tautomer that corresponds to the general formulas P s and I d

The resolution of these racemates to the optical antipodes can be carried out by a conventional method and the individual trans-d- and trans-1-isomers are included within the scope of the present invention.

The following compounds fall within the scope of formulas Ia and Ib:

trans-dl-5-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolo [3,4-g] quinoline, β

S-tirans-dl-5-methyl-4,4a, 5,6,7,8,8a, 9-octaidro-2H-pyrazolo [eta] < 4 > -g] quinoline sulfate, trans-dl-5-isopropyl-4,4a, 5 , 6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline, trans-dl-5-allyl-4,4a, 5,6,7,8,8a, 9-octahydro-12H -pyrazolo [3,4-g] ohinoline.

For the above compounds, it is understood that each name also includes a second tautomer, since an equilibrium mixture of two tautomers is always present. 2H-tautomer is predominant in some tautomeric mixtures. In addition, the orientation of the substituents or the configuration of the hydrogen atoms at positions 4a and 8a is not given, but it is understood that the hydrogen atoms are trans with each other.

Compounds of formulas Ia and Ib are prepared according to the following procedure outlined in Reaction Scheme I. In the Reaction Scheme, for simplicity, only one stereoisomer of the raoemic pair, i.e., the 4α, 3, 8α and isomer is depicted and it is understood that each decahydroquinoline and each octahydropyrazolo [3,4-g] quinolines are present in the form of the racemate.

Reaction Scheme I

O pyrrolidine. acid catalyst

0-C0-2 acrylamide -------------------->

HCl

Η ₂ εο _φ

(cH ₃ ) ₂ nch (oz \

In the above reaction scheme, the Z-CO group is an acyl protecting group wherein Z is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, alkynyl of 2 to 3 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, phenyl or substituted phenyl, wherein the substituent may be methyl, methoxy, chloro and the like at any position of the phenyl ring. For example, Z-CO may be acetyl, propionyl, butyryl, acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl, m-methoxybenzoyl and the like.

Z 'is alkyl of 1 to 8 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, alkenyl of 3 to 4 carbon atoms, alkynyl of 3 to 4 carbon atoms and the like. According to Reaction Scheme I, 4-acyloxycyclohexanone is prepared according to ERH Jones; F. Sondheimer, J. Cihern. Soc. 615 (1949). 4-Bemzoyloxycyclohexanone is reacted with pyrrolidine in the presence of an acid catalyst to give pyrrolidine enamine. This enamine is then reacted with acrylamide to give a mixture of dl-6-acyloxy-3,4,5,6,7,8-hexahydro-2 (1H) -quinolinone and dl-6-acyloxy-3,4,4a, 5 6,7-hexahydro-2- (1H) -quinolinone of formula III, wherein the dotted line represents alternative double bond positions.

The acidic nitrogen atom (acidic because it is in the alpha position to the carbonyl group) is alkylated with an alkyl halide RX where R is as defined above and X is a halogen atom such as Cl, Br or J in the presence of sodium hydride to give a mixture of dl -1-C 1 -C 3 alkyl or allyl-6-acyloxy-3,4,5, 6,7,8-ihexahydro-2 (1H) -quinoline and its Δ ⁸ isoimer (IV). Reduction of this amide with 11thium aluminum hydride or a conventional suitable organometallic reducing agent yields a mixture of C 1 -C 3 alkyl or C 1 -C 3 allyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and its A of the ^8- isomer.

In this reaction mixture, the conditions are adjusted to also serve for the hydrogenolysis of the acyloxy group to the hydroxyl group at the 6-position. This C 1 -C 3 -alkyl or α-llyl-6-hydroxyoctahydroquinoline is then converted to the ammonium salt by reaction with hydrochloric acid and the ammonium salt are then reduced with sodium cyanoborohydride to form trans-dl-1-C 1 -C 3 alkyl or allyl-6-hydroxydecahydroquinoline (VI). Trans-dl-1-C 1 -C 3 -alkyl or allyl-6-hydroxydecahydroquinoline (VI) is preferably oxidized with chromium trioxide in acetic acid to give the corresponding 6-oxo compound (VII). This 6-oxo compound (VII) is treated with dimethylformamide dimethylacetal to give the 7-dimethylaminomethylene-6-oxo derivative (VIII). Reaction of this derivative with hydrazine hydrate yields a tautomeric mixture of a tricyclic derivative predominantly trans; dl-5- [alkyl (C 1 -C 3) or allyl] -4,4a, 5,6,7,8,8a, 9-octaihydro -2H-pyrazolo [3,4-g] quinoline (Ia) and its 1H tautomer (Ib) in minor amounts.

The compounds of formulas Ia and Ib, wherein R is alkyl of 1 to 3 carbon atoms or allyl, are dopamine agonists.

The present invention is illustrated by the following examples.

Example 1

Preparation of trans-dl-5-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline.

46.5 g isomer mixture containing about 60%

6-Benzoyloxy-3,4,5,6,7,8-hexahydro-1H-chloro-2-Oine and 40% 3,4,4a, 5 ', (6,7-hexahydroisoimer) are dissolved in 400 mL of tetrahydrofuran 80 ml of methyl iodide are added and the resulting mixture is cooled in an ice bath, 9.6 g of sodium hydride (50% suspension in mineral oil) are added in portions. The reaction mixture was then diluted with water and the aqueous mixture was extracted with chloroform, the chloroform extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Drying in vacuo and evaporation consisted of 47.3 g of an orange oil, and crystallization of the residue from ether / hexane gave crystals of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydiro. -2 (1H) -chmel and the corresponding 3,4,4a, 5,6,7-hexahydroisomer.

Analysis:

calculated:

% H, 6.71;% N, 4.91;

• И Я 1 CX7 FROM O *

% C, 71.33;% H, 6.90;% N, 4.67.

A solution of 47.3 g of a mixture of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2 (1H) -quinoline and the corresponding 3,4,4a, 5,6,74-oxahydroSOmBru prepared above, in 800 mL of tetrahydrofuran was cooled to about 0 ° C, 20 g of lithium aluminum hydride were added portionwise and the resulting mixture was heated under nitrogen for 4 hours. The reaction mixture was cooled and the excess lithium aluminum hydride was quenched by addition of ethyl acetate. Then 10% sodium hydroxide was added and the mixture was diluted with water to decompose the organometallic compounds. The aqueous mixture was extracted several times with a solvent mixture of chloroform-isopropanol. The combined organic extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a mixture 'of enamines, l-methyl-6-hydroxy-2,3,4,5,6,7,7-yne and ¹ oklahydrochinol. Methyll6-1-hydroxy <-hydroxy-l, 2,3 The 4,4,4,5,5,6,7-octahydroquinoline formed by the above reaction. (Lithium aluminum hydride reduction serves only to remove the benzoyl group present in C-6 as the benzyl alcohol moiety and leave the free hydroxyl group in this position).

The above residue was dissolved in about 300 ml of ether without further purification and the ether solution was saturated with hydrogen chloride gas to give the enamine hydrochloride mixture. The ether was removed by decantation and the residue dissolved. in a mixture of 200 ml of tetrahydrofuran and 50 ml. of methanol. This solution was cooled in an ice bath and 12 g of sodium cyanoborohydride was added under cooling and stirring. How nice it is to add. The reaction mixture was stirred for a further 60 minutes and then poured onto a mixture of ice and 1N aqueous hydrochloric acid. The acidic aqueous solution was extracted with chloroform and the chloroform extract was discarded. The solution was basified with 14N aqueous. ammonium hydroxide. The trans-dl-1-methyl-6-hydroxydecahydroquinoline formed by the above reaction is insoluble in alkaline medium, separated and extracted several times with a mixture of chloroform-isopropanol solvents. The combined extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave 15 g of trans-dl-1-methyl-β-hydroxy-decahydroquinoline.

g of trans-dl-1-methyl-6-hydroxydecahydroquinoline is dissolved in 250 ml of 6N aqueous sulfuric acid. The solution was cooled in an ice bath. While stirring, 9 g of chromium trioxide in 60 ml of 6N aqueous sulfuric acid are added dropwise over 10 minutes. Remove the cooling bath and stir the reaction mixture at room temperature for a further 60 minutes. Excess oxidizing agent is quenched by adding isopropanol to the reaction mixture. The reaction mixture was then poured onto ice and the acidic aqueous solution was basified with 14N aqueous ammonium hydroxide. The trans-dl-1-methyl-6-oxo decal hydroquinoline thus formed is insoluble in the alkaline phase. It was separated and extracted several times with chloroform. and isopropanol. The extracts were combined and the combined extracts were washed. saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent in vacuo afforded the tans-dimethyl-6-oxodecahydro-quinoline boiling in the range of 105-116 ° C at 0.8 kPa. Yield 7.7 g (45%).

The reaction mixture was prepared from 7.7 g of trans-dl-1-methyl-6-oxodecahydroquinoline, 36 g of dimethylformamide dimethyl acetal and 251 ml of benzene. By distillation at atmospheric pressure under a nitrogen atmosphere, benzene is distilled off until about half of the original volume remains (1.25 hours). Benzene is then added until the original volume is reached and the distillation procedure is repeated (4 times). The residue was dissolved in dimethylformamide dimethyl acetal (100 g) and heated to reflux for 20 hours under nitrogen. (1 to 5%) m-ethanol Fractions containing similar compounds by thin layer chromatography were combined.The third eluted compound was a yellow solid (3 g), which was heated in 100 mL of ether and filtered. By concentrating the filtrate to about 50 ml, 590 mg of trans (methyll610x0 17 -dimethylamino) methylendecahydroquinoline are obtained, m.p. at 107-109 ° C.

Analysis:

calculated:

% C, 70.23;% H, 9.97;% N, 12.60;

found:

% C, 70.17;% H, 9.74;% N, 12.87.

Dissolve 175 mg of trans-dl-1-methyl-6-oxo-7-dimethylaminomethylendecahydrocihinoline in 10 mL of methanol to prepare a solution to which 0.05 mL of ihydrazine hydrate is added. The resulting reaction mixture was stirred at room temperature for 4.5 days. room in a nitrogen atmosphere. The volatiles were removed by evaporation. The chloroform solution of the residue is chromatographed on 25 g of florisil using an increasing amount (2-15%) of methanol. Fractions which, according to thin-layer chromatography, contain compounds moving the start-up light and which are different from the starting material are combined and the combined fractions are evaporated. It is thus obtained in the form of the free base trans. -dl-5-methyl-4,4a, 5,6,7,8,88,9-c-ctahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline, M + molecular ion at 191 .

The resulting residue was dissolved in ethanol and 2 ml of 1N hydrochloric acid was added. The acidic solution is then evaporated to dryness. Crystallization of the residue from ethanol yielded a tautomeric mixture containing trans-dl-5-methyl - 4,4a, 5,6,7,8, ββ, .θ-ο ^ ^ βηνΕίΓΟ-ΙΗ- 2H) -pyrazolo ^[3, 4 g ⁾ quinoline dihydrochlorides melting at 268-270 ° C with decomposition. Yield 140 mg.

Analysis:

calculated:

% C, 50.01%; H 7.25;% N 15.90;

26.84% Cl;

found:

H, 7.08; N, 15.66.

26.80% Cl.

Example 2

Preparation of trans-d - 5-allyl - 4,4a ₁ 5,6,7,8,8a, 9okřa ·! ^ ^ ™ (and 2H) -pyrazolo [3,4-gjcihinolinu.

g of 4-benzoyloxycyclohexanone, 38 ml of pyrrolidine and several crystals of p-toluenesulfonic acid monohydrate are dissolved in 1000 ml of cyclohexane. The resulting mixture was heated to boiling under nitrogen for 30 minutes and a Dean Stark trap was used to remove water. The mixture was then cooled and the solvents evaporated in vacuo. The residue containing pyrrolidine-enamine by 4-benzoyloxycyclohexanone is mixed with 53 g of acrylamide in 1000 ml of dioxane. The reaction mixture is heated to boiling under nitrogen for 1 day and evaporated after evaporation of the volatile component. The resulting residue was diluted with water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was evaporated, washed with water, saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a mixture of 6-benzoyloxyl-4-yl, 4,5,6,7,8-hexahydro-1H-quinolin-2-one and the corresponding 3,4,4a, 5,6,7- hexahydro compounds.

The above mixture was dissolved in 250 ml of tetrahydrofuran and 250 ml of dimethylformamide. 12 g of sodium hydride are added as a 50% suspension in mineral oil, and the mixture is stirred to give complete quinolin-2-one sodium salt. 30 g of allyl bromide are added as a solution of 75 ml of tetrahydrofuran and the mixture is stirred for 24 hours. The temperature of the reaction mixture rises rapidly, and therefore external cooling is introduced. After completion of the reaction, the reaction mixture was diluted with water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was separated, diluted with water, saturated brine and then dried. Evaporation of the solvent gave a mixture of 1-ally-6-benzoyloxy-3,4,5,6,7,8-hexaindro-1H-chlorolin-2-one and the corresponding 3,4,4a, 5,6,7- Compounds of the invention.

The N-allyl derivative thus prepared is dissolved in 750 ml of tetrahydrofuran and the solution is cooled in an ice bath. 20 g of lithium aluminum hydride are then added in portions. After the addition was complete, the resulting mixture was heated to reflux under nitrogen for three hours. The reaction mixture was then cooled in an ice bath and the excess of aluminum hydride was quenched by addition of ethyl acetate. To dissolve the organometallic compounds present in the mixture, a 10% aqueous solution of sodium hydroxide is added and the mixture thus treated is diluted with water. The aqueous mixture was extracted several times with chloroform and the chloroform extracts were combined.

The combined extracts were washed with saturated aqueous sodium chloride solution and dried. Evaporation of the solvent yielded a mixture of 1-allyl-C 1-4 hydroxy-1,7,3,4,5,6,7,8-octahydroquinoline and its 1,2,3,4,5,5,6,7-a-4-oxoquinoline. 31 ^ ηisomer. The residue was dissolved in 750 ml of ether and saturated with anhydrous hydrogen chloride gas. Octanol hydrochloride hydrochloride is insoluble in ether, precipitates and the ether is removed by decantation. Dissolve 4-xyl-1-uride in 100 ml of methanol and 300 ml of tetrahydrofuran. This solution is cooled in an ice bath and 20 g of sodium cyanoborohydride are added in portions with constant cooling. After the addition was complete, the cooling bath was removed. The reaction mixture was stirred at room temperature for one hour and then diluted with saturated sodium bicarbonate solution. · The alkaline phase is extracted several times with chloroform. The chloroform extracts were combined and the combined extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave about 12.8 g of trans-dl-1-ally-6-hydroxydiethylamine.

The trans-d-allyl-6-hydroxy-dehydrohydrateCh12227009 noline prepared as described above was dissolved in 500 ml of methylene chloride, to which 8.2 g of sodium acetate was added. 21.6 g of a mixture of pyridine hydrochloride and chromium trioxide are then added. The reaction mixture was stirred at room temperature under nitrogen for 7.5 hours and then filtered. The filtrate was concentrated in vacuo. Chromatography of the filtrate on 150 g of florisil using chloro-form with increasing (1-5%) methanol yields 3.2 g of trans-dl-1-allyl-6-oxodecahydroquinoline. The 6-oxo compound is dissolved in toluene and 25 ml of dimethyl acetal-dimethylformamide are added. The reaction mixture was heated at room temperature under nitrogen for 24 hours, after which the reaction mixture was cooled and the solvent was evaporated. The resulting residue is chromatographed on 150 grams of florisil using chloroform with increasing (2-20%) methanol. Thin layer fractions containing the desired trans-dl-1-allyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline provided the title compound after evaporation to yield 1.3 g of the desired product.

IC (CHC13)

1535 cm ^-1 > N — C = 'C — C—

I I II o

1.1. dihydrochloride 215 ° C (dec.) - acetone.

This material is dissolved in 75 ml of methanol to which 0.5 ml of hydrazine hydrate is added. The reaction mixture was stirred at room temperature for 20 hours, after which time the volatiles were removed in vacuo. The chloroform solution of the residue is chromatographed on 35 g of florisil using -chloroform containing an increasing amount of (2-4%) methanol. Fractions containing the desired trans-dl-5-allyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g ]chi according to thin layer chromatography. The noline and its 1H tautomer were combined and the solvent removed in vacuo. Mass spectrometry of the residue shows a molecular ion of 217. The 0.55 g residue is dissolved in 75 ml of acetone and the acetone solution is heated to boiling. 0.5 ml of 12N aqueous hydrochloric acid was then added dropwise to the reaction mixture. The reaction mixture was allowed to cool and the trans-dl-5-allyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H (and 1H) -pyrazolo [3,4-g] quinoline thus prepared melts at 215 ° C, with decomposition. Yield ~ 495 mg.

Analysis:

calculated:

% C, 53.80;% H, 7.29;% N, 1.48.

24.43% Cl;

found:

% C, 53.52;% H, 7.13;% N, 1.65.

As evidence of the utility of the compounds of formulas Ia and Ib for the treatment of Parkinson's syndrome, these compounds have been found to affect rotation behavior. In this test, rats prepared according to the procedure of Ungestedt and Arbuthnott Brain Res were used. 24, 485 (1970). Compounds having dopamine agonist activity cause rats to turn in circles against the wound side. After a latency period, which is different for different compounds, the number of revolutions is calculated for 15 minutes.

The results of representative compounds of formulas 1a and Ib in this rat -turn test are shown in Table 1 below. The compounds are dissolved in water and the resulting aqueous solution is injected intraperitoneally into rats at doses of 1 mg / kg and 100-pg per kg. Table 1 shows the compound names, column 2 shows the percentage of test animals exhibiting rotational behavior, and column 3 shows the number of turns observed in the first 15 minutes after the end of the latency period.

Table 1 Compound% of rats exhibiting a rotational behavior of 1 mg / kg 100 µg / kg Mean-number of revolutions per rat mg / kg 100 (zg / kg trans-dl-5-n-propyl-4,4 <, &gt; 7 ', 8', 8e ', 4' - (4 ') - (4') - (4 ') -1H-2H-pyrazolo [3,4-g] quinoline dihydrochloride trans-dl-4 -allylc4,4a, 5,6,7,8,88,9-octahydro-1H-2H-pyrazolo [3,4-gquinoline dihydrochloride

100 75

100 ALIGN!

66

165

2 7 0 0 8

The compounds of formulas (Ia) and (Ib) are also useful as prolactin inhibitors and as such may be used to treat inappropriate lactations such as delivery lactation and galactorrhea. To demonstrate utility in the treatment of diseases in which it is desirable to lower the prolactin level by the compounds of Formulas Ia and Ib, inhibition of prolactin has been demonstrated as follows.

Adult male Sprague-Dawley rats weighing 200 g were placed in a climate-controlled room with controlled lighting (illumination from 6 to 20 hours) and rats were allowed access to laboratory feeding and water ad libitum. Each rat injected intraperitoneally with 2.0 mg of reserpine in an aqueous suspension 18 hours before administration of the test compound. The purpose of reserpine is to maintain the level of prolactin at a uniformly elevated level. Test compounds are dissolved in 10% ethanol and injected intraperitoneally at doses of 50 µg / kg, 0.5 mg / kg and 5 mg / kg. Each compound is administered in each dose to a group of 10 rats and a control group of 10 male is treated with an equivalent amount of 10% ethanol only. One hour after treatment, all rats are killed by shearing off their heads and 150 µg of serum is analyzed for prolactin levels.

The difference between the level of prolactin treated rats and the level of control prolactin divided by the level of control rat prolactin indicates the percent inhibition of prolactin secretion attributable to the compounds of formulas Ia and Ib. These percent inhibition are shown in Table 2 below. The table in column 1 lists the compound names and columns 2, 3 and 4 show the percent inhibition of prolactin at doses of 50 µg / kg, 0.5 mg / kg and 5 mg / kg.

Table 2

Compound.

Percent inhibition of prolactin in doses of µg / kg 0.5 mg / kg 5 mg / kg trans-dl-4-n-propyl-4,4a, 5,6,7,8,88,9-sokahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline hydrochloride tra'ns-dl-5-methyl-4,4a, 5,6,7,8,8a, .9-occahydro-1H (- and 2H) -pyrazolo- [3, 4-g] quinoline dihydrochloride

When using compounds of formulas Ia and Ib for inhibiting prolactin secretion or treating Parkinson's syndrome or other pharmacological effects, a compound of formula Ia or Ib above or a salt thereof with a pharmaceutically acceptable acid is administered to a person with Parkinsonism or in need of reducing prolactin levels in an amount effective for elimination of some syndromes or to reduce prolactin levels. Oral administration is preferred. If parenteral administration is used, injection is preferably carried out subcutaneously using appropriate pharmaceutical compositions. Other methods of parenteral administration, such as intraperitoneal, intramuscular or intravenous administration, are equally effective. Especially for intravenous or intramuscular administration, pharmaceutically acceptable water-soluble salts are used. For oral administration, the compound, either in the form of a free base or in the form of a salt, can be admixed with a standard pharmaceutical ingredient and filled into empty telescopic gelatin capsules or compressed into tablets. The oral dose ranges from 0.01 to 10 mg / kg of mammalian body weight and the parenteral dose ranges from 0.0025 to 2.5 mg / kg. An intraperitoneal dose of 10 to 100 mg / kg of trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-occahydro-1H (and 2H) spyrazolos [3,4-gquinoline dihydrochloride does not cause any death, but doses of 300-mg / kg are lethal; The LD 50 is in the range of 100 to 300 mg / kg.

Example 3

Of trans-dl-5-n-propyl-4,4a, _5,6,7,8) 8a 9sOktas dihydro-2H-pyrazo.lo [3,4-g] chinol'in partition the residue to the dihydrochloride optical antipodes - by dissolving 10 g of compound · 100 ml water. To this solution, 50% aqueous K 2 CO 5 is added dropwise until the solution is basic to. pH paper. The aqueous phase is then extracted with methylene chloride. the organic extracts were combined and dried over sodium sulfate and evaporated in vacuo. The residue is then dissolved in boiling methanol (about 5 ml per 0.5 g of residue). To this solution was added a solution of 1.2 molar equivalent of (-) tartaric acid in hot methanol. The solution was heated at reflux for 5 minutes and then left at room temperature for about 118 hours. The precipitated solid was filtered off, washed with ether and dried in a vacuum desiccator. The filtrates are kept. The solid is crystallized (5 ml of methanol per 0.5 g of salt) until a constant melting point and / or optical rotation. The physical data for the (-) isomer is shown in Table I.

ia

Table I crystallization number melting point ° C [: O] _D ²⁵ [solvent]

3.1

1,8

0.6

0.13

182—185

185—187

199—201

203-204 - 29.75 (CH 3 OH) - 43.48 (CH 3 OH) - 93.24 (H2O) - 94.55 (H2O)

The filtrates were combined, evaporated and the residue crystallized from methanol. 0.08 g (mp 199-200 ° C) of [α] dh _{2 O} ² 5 - 94.550 is obtained.

The filtrates were re-combined, evaporated and dissolved in water. The solution was basified and extracted

Tab for crystallization grams number

11.46

20.70

30,15 as described above. In an analogous manner to that described for the [-] tartrate, the (+) tartrate is formed, and the physical data for the [+ J] isomer is shown in Table II.

melting point ° C [?]? ⁵ HzO

173—177 +32,76

185—188 +58.44

201—202 +93.88

In vivo assays show that the (-J-isomer is active and the (-J-isomer is inactive).

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of octahydropyrazolo [3,4-g] quinolines of formulas Ia and Ib (Ib) wherein: R is alkyl of 1 to 3 carbon atoms or allyl, or a pharmaceutically acceptable acid addition salt thereof, characterized in that a compound of formula VIIIa is reacted where: R is as defined above with hydrazine hydrate, whereupon optionally the compound of formula Ia - or Ib is converted to a pharmaceutically acceptable acid salt. 2. The method of item 1 for the preparation of tautomers of trans-d-5-methyl-4,4a, 5,6,7,8,8a, 9-octaihydro-1H [and 2H] -pyrazolo] 3,4- g) quinoline, characterized by reacting tin-1-N-methyl-5-oxo-7-diinomethyl-aminomethylendecahydroquinoline with hydrazine hydrate. 3. The process of item 1 for preparing the trans-d-5-ally-4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ (and 2H) -pyrazolo [3,4- g) quinoline, characterized by reacting trans-dl-1-allyl6Hxxo7-dimethylaminomethylendecahydroquinoline with hydrazine hydrate.