CS227046B2 - Method of preparing octahydropyrazolo (3,4-g) quinoline - Google Patents

Description

The present invention relates to a process for the preparation of octahydro opyrazolo [3,4-g] quinolines of the formula Ia and Ib by selines, which is characterized by reacting a compound of the formula VIIIa.

where

R is alkyl of 1 to 3 carbon atoms,

R ¹ is CH 2 SCH 3 and pharmaceutically acceptable salts thereof with ky227046

where

R is as defined above,

R ² is CO 2 -alkyl of 1 to 2 carbon atoms in the alkyl, with hydrazine hydrate, the resulting compound is reacted with a metal hydride to form an intermediate wherein R ² is CH ² OH and reacted with a nucleophilic reagent to form an intermediate wherein R ² is CH 2 OSO 2 alkyl having 1 to 3 carbon atoms in the alkyl, followed by reaction with methyl mercaptan and optionally converting a compound of formula Ia or Ib to a pharmaceutically acceptable acid salt.

Pharmaceutically acceptable salts with acids of formulas Ia and 1b 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, hydroxyalkanoic acids and alkanedicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogensulfates, sulfites, hydrogensulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutates, isobutates, isobutates , heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleinates, 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, β-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] quinolines, and compounds of formula (1b) 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 1b above, when R ¹ is a hydrogen atom, have two chiral centers at the interconnection of rings 8a and 4a. Thus, the compounds may exist as two racemates, commonly referred to as trans-dl-racemates and cis-dl-racemates. However, according to the best ¹³ C NMR data, it is believed that the cyanoborohydride reduction process, which introduces hydrogen atoms to the quinoline bridge, a step in the synthetic process used to prepare compounds of formulas Ia and 1b, provides a trans-decahydroquinoline. While arguments for the trans-configuration based on ¹³ C NMR spectral data were obtained, X-ray crystallographic analysis was performed on a well-crystalline enamlnoketone in the decahydroquinoline series (R = CH3) .This X-ray analysis clearly shows that the ring coupling in the quinoline The other operation in the decahydroquinoline molecule for condensation of the pyrazole ring does not change the configuration on the hydrogen atoms on the bridge, so only the trans racemate is prepared by the synthetic procedure below and the compounds of the formulas

Ia and 1b are preferably referred to as trans-d1-stereoisomers. Two trans stereomers of the 2H-tautomer can be depicted in the following formulas IIa and IIb

(Nb) which form a racemic pair. A similar racemic pair can be depicted for the 1H-tautomer. which corresponds to the general formulas of faces and folk

Resolutions of these racemates to the optical antipodes can be carried out in a conventional manner, and the individual trans-d and trans-1-isomers are included within the scope of the present invention.

In addition, there is a third chiral center on carbon 7. However, it is believed that the configuration at the carbon atom 7 is substantially in the β-position to the α-hydrogen atom at the 8a position as shown in Formula IIa. In the mirror image, litho is R ¹ aa relative to position 8a, which is β. Thus, the trans-di-7-substituted octahydropyrazolo [3,4-g] quinolines of formulas 1a and 1b are substantially one racemate or diastereoisomeric pair. An equilibrium mixture of two tautomers is always present and the 2H-tautomer predominates in some tautomeric mixtures. In addition, the orientation of the substituents or the configuration of the hydrogen atoms at the 4a and 8a positions is not indicated, but it is understood that the hydrogen atoms are trans with each other and that Reaction Scheme I substituent at position 7 is "trans" with respect to the hydrogen atom 8a; the hydrogen atom 8a is α, the substituent at position 7 is β, and if the hydrogen atom 8a is β, the substituent at position 7 is oriented in the configuration.

The starting compound of formula VIIIa are prepared according to the following procedure shown in Scheme I. In Scheme is drawn for simplicity only one stereoisomer of the racemic pair, i.e. ₁ 4a S, 8a and isomer and it is understood that each decahydroquinoline is present as a racemate.

kys.

R (Vlia)

I kde

R ² and R ² are as defined above and Z is C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl, C 5 -C 6 cycloalkyl, phenyl optionally substituted with methyl, methoxy , chlorine, and the like

Z 'has the meaning given below.

In accordance with Reaction Scheme I, 4-acyloxycyclohexanone is reacted with a N-halomethylacrylic acid ester such as methyl ester and amine, RNHz, where R is C 1 -C 3 alkyl. The product of this reaction is a mixture of dl-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,4,5,6,7,8-octahydroquinoline and dl-1-substituted-3-ethoxycarbonyl-6-acyloxy -1,2,3,4,4a, 5,6,7-octahydroquinoline of formula X, wherein the dotted line represents alternative positions of double bonds. The hydrochlorides of these isomers are prepared and the resulting mixture is reduced with sodium cyanoborohydride to give trans-dl-1-substituted-3-ethoxycarbonyl-6-acyloxydecahydroquinoline (XIJ. Hydrolysis of this diester affords 6-hydroxy-3-carboxylic acid and subsequent reesterification of the carboxylic acid ethanol or other suitable alcohol in the presence of an acid provides a novel intermediate, trans-dl-1-substituted-3-ethoxycarbonyl-6-hydroxydecahydroquinoline (XII j. Oxidation of the hydroxyl group by Sarett's reagent (pyridine hydrochloride and chromium trioxide) provides the corresponding novel 6-oxo compound (XIII) Reaction of this 6-oxo derivative with dimethylformamide acetal, preferably dimethylformamide dimethyl acetal, by reaction at the C-7 position (adjacent to the keto group yields the starting compound trans-dl-1-substituted-3-ethoxycarbonyl-6-oxo-7- (dimethylaminomethylene) decahydroquinoline (VIIIa).

The dimethylformamide acetals useful in the preparation of compounds of Formula VIII in Reaction Scheme I have the general formula (CH5) 2N-CH- (OZ ') 2 wherein:

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. Preferably one of commercially available dimethylformamide acetals is used, for example dimethyl- , diethyl, diisopropyl, dibutyl, dicyclohexyl, dipropyl, or dineopentylacetal.

As evidence of the utility of the compounds of Formulas Ia and 1b for the treatment of Parkinson's syndrome, it has been found that these compounds affect the rotational behavior. In this test, rats prepared according to the procedure of Ungestedt and Arbuthnott Brain Res were used. 24, 485 (1970). Compounds that have agonist effect cause rats to rotate in circles against the wound side. After a latency period that is different for different compounds, the number of revolutions is counted for 15 minutes.

The results of a representative compound of Formulas Ia and 1b compared to analogous compounds in this rat rotation 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 μ.% Per kg. The table in column 1 lists the compound names, column 2 shows the percentage of test animals showing rotational behavior, and column 3 shows the number of revolutions observed in the first 15 minutes after the end of the latency period.

compound

Table 1% of rats showing a rotational average number of rats per mg / kg 100 µg / kg 1 mg / kg 100 µg / kg trans-dl-5-n-propyl-4,4a, 5,6,7,8, 8a, 9-octahydro-1H- and 2H-pyrazolo (3,4-g) quinoline dihydrochloride 100 trans-dl-5-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9- octahydro-ΙΗ- and 2H-pyrazolo [3,4-g] quinoline dihydrochloride 100

66 trans-dl-5-allyl-4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ- and 2H-pyrazolo [3,4-g] quinoline dihydrochloride

100 ALIGN!

165

67

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 postpartum 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-Da. Ley rats weighing 200 g were placed in an air-conditioned room with controlled lighting (6 to 20 hours illumination) and rats were allowed access to laboratory feeding and water ad libitum. Each rat is injected intraperltoneally 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 prolactin level 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 males is treated with an equivalent amount of 10% ethanol only. One hour after treatment, all rats are killed by shearing their heads and 150 µg of serum is analyzed for prolactin levels.

The difference between the rat-treated prolactin level and the control-rat prolactin level divided by the control-rat prolactin level gives the percent inhibition of prolactin secretion attributable to the compounds of formulas Ia and Ib. These percent inhibition compared to the inhibition of analogous compounds 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.

compound

Table 2 pro inhibition of prolactin at doses of 50 µg / kg 0.5 mg / kg 5 mg / kg trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro- 1 H- (a 2H) -pyrazolo [3,4-g] quinoline dihydrochloride 61 trans-dl-5-methyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- (a 2H) - trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- (and 2H) - pyrazolo [3,4-g] quinoline dihydrochloride pyrazolo [3,4-g] quinoline -

When using compounds of formulas Ia and Ib for inhibiting prolactin secretion or treating Parkinson's syndrome or other pharmacological effects, the compound of formula Ia or Ib above or a pharmaceutically acceptable acid salt thereof is administered to a person with Parkinsonism or in need of reducing prolactin levels in an amount effective to eliminate some syndromes. or to reduce the level of prolactin. 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 immitable, are equally effective. Especially for intravenous or intramuscular administration, water-soluble pharmaceutically acceptable salts are used. For oral administration, the compound, either in free base or salt form, can also be mixed with a standard pharmaceutical excipient and filled into empty telescopic gelatin capsules or compressed into tablets. The oral dose is in

84

73 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. Intraperitoneal dose of 10 to 100 mg / kg trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3, 4-gquinoline dihydrochloride causes no death, but doses of 300 mg / kg are fatal; The LD 50 is in the range of 100 to 300 mg / kg.

The present invention is illustrated by the following examples.

Example 1

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

A mixture of n-propylamine (10 ml) and toluene (400 ml) was cooled in an ice bath. A solution of 16.5 g of .alpha.-bromomethyl) acrylic acid ethyl ester in 50 ml of toluene is then added dropwise. The resulting mixture was stirred under cooling for 25 minutes. A solution of 11 g of 4-benzoyloxycyclohexanone in 75 ml of toluene is then added dropwise. The new mixture was heated to reflux for 23 hours under a nitrogen atmosphere. The reflux condenser was equipped with a Soxlet extractor containing 5A water removal sieves. Then the reaction mixture was cooled and the cooled mixture was filtered. Evaporation of the filtrate gave a residue consisting of a mixture of 1n-propyl-3-ethoxycarbonyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1-n-propyl-3-ethoxycarbonyl-6- benzoyloxy-1,2,3,4,4a, 5,6,7-octahydroquinoline. The residue was dissolved in an ether-chloroform solvent mixture and the resulting solution was saturated with hydrogen chloride gas, maintaining the temperature between 0-5 ° C. The solvent is removed by decantation from the crystalline hydrochloride thus formed. The salts are dissolved in 100 ml of methanol, 300 ml of tetrahydrofuran are added and the solution is cooled in an ice bath. 15 g of sodium cyanoborohydride are added in portions to the stirred reaction mixture. After the addition was complete, the reaction was stirred for an additional 1.25 hours and then diluted with aqueous sodium bicarbonate. The aqueous alkaline mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were combined and the combined extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave trans-dl-1-n-propyl-3-ethoxycarbonyl-6-benzoyloxydecahydroquinoline. The compound was dissolved in a mixture of 400 mL of methanol and 100 mL of 2N aqueous sodium hydroxide. The mixture was stirred at room temperature for 64 hours under nitrogen, then the volatiles were removed by evaporation in vacuo. The resulting residue was suspended in 800 ml of ethanol and 15 ml of 12N aqueous hydrochloric acid. The esterification mixture is heated to boiling and about 300 ml of solvent is then distilled off. An additional 300 mL of ethanol was added and the reaction mixture was heated at reflux for 26 hours in a Soxhler-equipped apparatus containing 3A sieves. The reaction mixture was cooled, diluted with aqueous sodium bicarbonate solution and extracted with chloroform several times. The chloroform extracts were combined and the combined extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of chloroform gave 10.3 g of a residue containing trans-dl-1-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline resulting from the hydrolysis described above, which was purified by ehromatography to 150 g of florisil using chloroform containing increasing amounts (2-10%). o) methanol as eluent.

A solution was prepared from 8.8 g of trans-dl-1-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline in 400 ml of methylene chloride, to which 4.1 g of sodium acetate was added. 10.8 g of a mixture of pyridine hydrochloride and chromium trioxide are then added and the mixture is stirred for 22 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting concentrate was dissolved in chloroform and the chloroform solution was chromatographed on 150 g of florisil using chloroform with increasing (1-2%) methanol. Fractions containing trans-dl-1-n-propyl-3-ethoxycarbonyl-6-oxodecahydroquinoline according to the above reaction were combined according to thin layer chromatography, the solvent was removed from the combined extracts to give 3.48 g of the 6-oxo compound. The 6-oxo compound is dissolved in 100 ml of toluene containing 25 ml of dimethylformamide dimethyl acetal. The resulting mixture was heated under reflux for 44 hours under nitrogen, and allowed to stand at room temperature for 4 days. The volatiles were evaporated in vacuo and the residue containing trans-dl-ln-propyl-3-ethoxycarbonyl-6-oxo-7- (dimethylaminomethylene) decahydroquinoline formed by the above reaction was purified by chromatography of the chloroform solution on florisil using chloroform with increasing amounts Fractions which, according to thin layer chromatography, contained the desired 7-dimethylaminomethylene compound were combined and the solvent was evaporated in vacuo.

A solution was prepared from 2.24 g of trans-dl-l-n-propyl-3-ethoxycarbonyl-6-oxo-7-dimethylaminomethylendecahydroquinoline and 150 ml of ethanol, and 0.45 ml of hydrazine hydrate was added thereto. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated to dryness in vacuo. The residue containing a mixture of trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and trans-dl Dissolve -5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolo [3,4-g] quinoline in chloroform and chromatograph on 35 g of florisil using chloroform with 2% methanol. Fractions containing the desired pyrazoloquinoline according to thin layer chromatography were combined and the solvent was evaporated in vacuo. Crystallization from ether-hexane gave trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and its 1H tautomer, mp 125-127 ^° C.

IR (CHCl3):

1720 cm ^-1 ester> C = O

1540 cm> *> N — C = C — C = O

I I I

NMR (CDCl3) 60 MHz:

246

186

448 eps triplet, eps triplet eps quartet eps singlet> N — CH2CH2CH3 — O — CH2CH3 — O — CH2CH3 - N (CH3) 2 eps / wide singlet> C — C — H

Analysis:

calculated:

% C, 65.95;% H, 8.65;% N, 14.42.

65.75%, 8.42% H, 14.16% N. Example 2 "Preparation of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8, 8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline.

A mixture of trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline dihydrochloride and the dihydrochloride salt corresponding to 1H of the tautomer (3.7 mmoles) was suspended in 200 ml of tetrahydrofuran. 1 g of lithium aluminum hydride is then added portionwise. The resulting reaction mixture was then stirred at room temperature for 16 hours under a nitrogen atmosphere and then cooled. Ethyl acetate and a 10% aqueous sodium hydroxide solution were then added to the reaction to react excess lithium aluminum hydride and decompose any organometallic compounds present. The reaction mixture thus treated is then diluted with water and the aqueous mixture is extracted several times with a mixture of chloroform and isopropanol. The organic phase was separated and combined. The combined phases were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a mixture of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and its 1H tautomer. The residue was dissolved in ethanol and 0.2 ml of 12N aqueous hydrochloric acid was added. Evaporation of the volatiles yielded a residue consisting of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H and 1H-pyrazolo [3,4] dihydrochloride -g] quinoline. The residue was dissolved in a mixture of methanol and acetone to give crystals melting at 270-275 ° C with decomposition. Yield 350 mg.

The above reaction was repeated using 1.55 g of trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo (3,4 -g] quinoline in tetrahydrofuran which has been previously reduced by excess lithium aluminum hydride The reaction product of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H; 2H-pyrazolo [3,4-g] quinoline was crystallized from a mixture of chloroform and ethanol to give a crystalline material melting at 167-169 ° C.

Analysis:

calculated:

% C, 67.43;% H, 9.30;% N, 16.85.

% H, 9.13;% N, 16.62.

Example 3

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

millimole of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H and 2H-pyrazolof 3,4-g] quinoline were prepared by suspension in 100 ml of pyridine . 1 ml of methanesulfonyl chloride (mesyl chloride) was added and the resulting mixture was allowed to stand overnight at room temperature. The mixture was diluted with dilute aqueous ammonium hydroxide solution and the alkaline phase obtained was extracted several times with chloroform and the combined chloroform extracts were washed with aqueous saturated sodium chloride solution. The chloroform solution of the residue is chromatographed on 30 g of florisil using chloroform containing an increasing amount (1-2%) of methanol as the eluent. dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline was combined and the solvent was evaporated After crystallization from ether, trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4- g] quinoline at 15 M.p. 2-154 ° C.

Analysis:

calculated:

H, 6.71; N, 10.36; S, 15.81. Found:

H, 6.71; N, 10.32; S, 15.69.

The second fraction obtained by chromatography is a 2: 1 NMR mixture of trans-dl-5-n-propyl-7-mesyloxymethyl-2-methanesulfonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H- pyrazolo [3,4-g] quinoline and its 1-methanesulfonyl-1H isomer.

g of methyl mercaptan is dissolved in 40 ml of dimethylformamide. The solution was cooled in an ice bath. 1 g of sodium hydride (50% suspension in mineral oil) was added portionwise. Remove the cooling bath and add a solution of 0.4 g of trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H- pyrazolo [3,4-g] quinoline containing some trans-dl-1-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolo [5,4-g] quinoline in 10 ml dimethylformamide. The reaction mixture was stirred at room temperature for 5 hours and then diluted with water. The aqueous mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were separated and combined. The combined extracts were washed with water and saturated

2 7 04 6 with brine and then dried. Evaporation of the solvent gave an oily residue containing trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ and 2H-pyrazolo [3,4-g] quinoline. Yield 0.17 g. The residue was dissolved in ethanol and attempts were made to prepare both hydrochloride and oxalate. Both salts are non-crystalline. The free base is released from the non-crystalline oxalate by dissolving in water, adding the base, and then extracting the mixture with ether. The thus purified trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ and 2H-pyrazolo [3,4-g] quinoline crystallized by evaporation of ether. Melting point 175-177 ° C, yield = 40 mg.

Analysis:

calculated:

% C, 64.47;% H, 9.02;% N, 15.04;

11.47 o / o N, found:

% C, 64.47;% H, 8.96;% N, 15.96.

11.29% S.

The purified free base tautomeric mixture as described above was dissolved in ethanol and excess 12N hydrochloric acid was added. The volatiles were removed by evaporation and the resulting residue containing the corresponding dihydrochlorides crystallized from a mixture of acetone and methanol.

Analysis:

calculated:

% C, 51.13%; H 7.72%; N 11.93%; Cl 20.10%; S 9.10%.

C, 50.89; H, 7.57; N, 12.15.

20.18% Cl, 9.31% S.

Example 4

Trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline dihydrochloride is separated into the optical antipodes by dissolving 10 g of the compound in 100 ml water. To this solution is added dropwise 50% aqueous potassium carbonate until the solution is basic (pH paper). The aqueous phase was then extracted with methylene chloride, the organic extracts were combined, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in boiling methanol (about 5 mL per 0.5 g of residue). To this was added a solution of 1.2 mol equivalents of (-) - tartaric acid in hot methanol. The solution is boiled for 5 minutes and then allowed to stand for about 18 hours at room temperature. The resulting solid was filtered, washed with ether and dried in a vacuum desiccator. The filtrate is retained. The solid is recrystallized (5 ml of methanol per 0.5 g of salt) until a constant melting point and / or constant rotation is achieved. The physical data of the (-) isomer is shown in Table I below.

Table I

crystallization G mp ° C [α] ϋ ²⁵ (solvent) 1 3.1 182 to 185 ⁰ —29.75 ° (CH 3 OH) 2 1,8 185 DEG-187 DEG —43.48 ⁰ (CH3OH) 3 0.6 199 to 201 ⁰ —93.24 ⁰ (H2O) 4 0.13 203 to 204 ⁰ —94.55 ⁰ (H2O)

The filtrates were combined, evaporated and crystallized from methanol. 0.08 g of mp 199 DEG-200 DEG C. [ _.alpha. ] _D @ ²⁵ -94.55 DEG (H2O) is obtained.

The filtrates were re-combined, evaporated and dissolved in water. The solution was basified and extracted as described above. The (+) tartrate obtained is obtained in an analogous manner to that described in the previous paragraph for the preparation of (-) tartrate.

Table II

crystallization number G mp ° C [fli] _D ²⁵ (H 2 O) 1 1.46 173-177 ° + 32.76 ° • 2 0.70 185 to 188 ⁰ + 58.44 ⁰ 3 0.15 201 to 202 ⁰ + 93.88 ⁰

In vivo testing shows that the (- isomer is active and the (+) isomer is inactive).

Claims (2)

SUBJECT A process for the preparation of octahydropyrazolo [3,4-g] quinolines of Formulas Ia and Ib R (1b) wherein R is C 1 -C 3 alkyl and R ¹ is CH 2 SCH 3 and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of general formula VIIIa OF THE INVENTION where R ² is CO 2 -alkyl of 1 to 2 carbon atoms in the alkyl a R is as defined above, reacted with hydrazine hydrate, the resulting compound is reacted with a metal hydride to form an intermediate wherein R ² is CH ² OH and reacted with a nucleophilic reagent to form an intermediate wherein R ² is CF 1 OSC 1-6 alkyl The reaction is carried out with methyl mercaptan and optionally the compound of formula Ia or 1b is converted to a pharmaceutically acceptable acid salt. 2. The method of item 1 for the preparation of trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- (and 2H) -pyrazolo [ta] 3,4-g] quinoline, characterized by reacting trans-dl-ln-propyl-3-ethoxycarbonyl-6-oxo-7-dimethylaminomethylendecahydroquinoline with hydrazine hydrate, then reacting with lithium aluminum hydride to prepare compounds wherein R ² is CH ² OH followed by reaction with methanesulfonyl chloride and then reaction with methyl mercaptan.