CS237331B2 - Processing of octahydropyrazole/3,4-g/chinoline - 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

xylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic acids and alkanedicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, hydrogen sulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, formates, formates caprylates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, butin-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, malate, tartrates, methanesulfonates, propanesulfonates and naphthalene-1-sulfonates-naphthalene-1-naphthalene-1 .

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) 4,4a5,6, 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 have two chiral centers at the joining of rings 8a and 4a. Thus, the compounds can exist as two racemates, commonly referred to as trans-dl-racemates and cis-dl-racemates. However, according to the best data from 1'0 NMR data, it is believed that the cyanoborohydride reduction process, which introduces hydrogen atoms to the quinoline bridge, the step in the synthetic process used to prepare the starting compounds of formulas I‘a and I‘b provides a trans-decahydroquinoline.

While the arguments for the trans-configuration based on the ¹³ C NMR spectral data were obtained, X-ray crystallographic analysis was performed on a well crystalline enaminoketone in the decahydroquinoline series used as an intermediate in the synthesis of the invention. 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 as described below, and the compounds of Formulas Ia and 1b are preferably referred to as the trans-d1-stereoisomers. Two trans-stereoisomers of the 2H-tautomer can be depicted in the following formulas IIa and IIb

H

(Ila-)

that form a racemic pair. A similar racemic pair can be depicted for the 1H tautomer that corresponds to the general formulas IIc and IId

(llo)

Resolutions of these racemates to the optical antipodes can be carried out in a manner known per se 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 1b:

trans-dl-5-ethyl-4,4a, 5,6,7,8,8a, 9-octahydro-b-1H-pyrazolo [3,4-g] quinoline, trans-dl-S-methyl-αS ^; N, N-.alpha.-octahydro-2H-pyrazolo [3,4-g] quinoline sulfate, trans-dl-S-isopropyl, 4a, 5,6,7,8, 9-O-hydro-2H-pyrazolo [ 3,4-] quinoline.

An equilibrium mixture of two tautomers is always present and the 2H-automer predominates in some tautomeric mixtures. In addition, the orientation of the substituents or the configuration of the hydrogen atoms at the 4a and 7a positions is not given, but it is understood that the hydrogen atoms are trans with each other.

The starting compounds used in the process of the invention may be prepared, for example, by reacting trans-dl-6-oxo-7-dimethylaminomethylendecahydroquinoline with hydrazine hydrate or by reacting trans-dl-1-cyano-6-oxo-7-dimethylaminomethylendecahydroquinoline with hydrazine hydrate and subsequent cleavage of the cyano group. with zinc and acetic acid.

The alkylation by the process of the invention is carried out either by reaction with a lower alkyl halide or alternatively using acetaldehyde, acrolein or propionaldehyde by treatment with a metal hydride such as sodium cyanoborohydride. Alkylation using aldehyde and sodium cyanoborohydride is carried out by stirring in an alcoholic solvent under an inert nitrogen atmosphere. For example, the alkylation using a lower alkyl halide is carried out at room temperature in dimethylformamide by stirring with potassium carbonate in an inert nitrogen atmosphere.

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 rotational behavior. This test uses rats prepared according to the Ungestedt and Arbuthnott Brain Rea procedures. 24, 485 (1970). Compounds having dopamine agonist activity cause rats. rotate in circles against the side of the wound.

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 in this rat rotation test are shown in Table 1 below. The compound is dissolved in water and the resulting aqueous solution is injected intraperitoneally into rats at doses of 1 mg / kg and 100 µg per kg.

Column 1 shows the name of the compound, Column 2 shows the percentage of test animals exhibiting rotational behavior, and Column 3 shows the number of revolutions observed in the first 15 minutes after the end of the latency period.

Table 1 Compound% of rats exhibiting rotational behavior mg / kg 100 µg / kg average rat / mg mg / kg 100 µg / kg trans-dl-5-n-propyl-4,4a, 5,6,7,8 88,9-occahydro-1H-2H-pyrazolo [3,4-gquinoline dihydrochloride 100 75

The compounds of formulas Ia and Ib are also useful as prolactin inhibitors and as such may be used for the treatment of inappropriate lactations such as postpartum lactation and galacto. 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 200 g male Sprague-Dawley rats were placed in an air-conditioned room with controlled lighting (6 to 20 hrs illumination) and rats were allowed access to laboratory feeding and water ad libitum · Each · rat was injected intraptritkneally with 2.0 mg of reserpine in an aqueous suspension 18 hours prior to administration of the test compound The purpose of reserpine is to maintain the prolactin level at a uniformly elevated level The test compounds are dissolved in 10% ethanol and injected intraperitoneally at doses of 50 .mu.g / 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 treated only with an equivalent amount of 10% ethanol.After one hour, all rats are killed by shearing a 150 [mu] g sera. prolactin level.

The difference between the treated rat 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 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 Prolactin Inhibition Percentage (g / kg 0.5 mg / kg 5 mg / kg trans-dl-5-n-propyl-4,4?, 5, (?, 7?,?,?) .alpha., 9-occt. @ 1 H @ 1 R @ 1 R @ 1 R @ 1 H (a 2H) -pyrazolo [3,4-g] quinoline dihydrochloride.

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

- 91

84

When using compounds of formulas Ia and 1b to inhibit prolactin secretion or to treat Parkinson's syndrome or other pharmacological effects, the compound of formula Ia or 1b above or a salt thereof with a pharmaceutically acceptable acid is personally administered with Parkinsonism or the need to reduce prolactin levels in an amount effective to eliminate some syndromes or; to reduce prolactin levels. Oral administration is preferred. When parenteral administration is used, the injection is carried out, preferably subcutaneously using the appropriate pharmaceutical compositions. Other methods of parenteral administration, such as intraperitoneal, intramuscular or intravenous administration, are equally effective. Particularly 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 ingredient and filled into empty telescopic gelatin capsules or compressed into tablets. Oral dosages range from 0.01 to 10 mg / kg of mammalian body weight, and parenteral dosages range from 0.0025 to 2.5 mg / kg. Intraperitoneal dose of 10-100 mg / kg trans-dl-5-n-propyl · 4,4a, 5,6,7,8,8a, 9-occahydro-1H (and 2H) -pyrazolo [3,4-g] ] quinolm dihydrochloride causes no death, but doses of 300 mg / kg are fatal; The LD50 is in the range 100-300 mg / kg.

The present invention is illustrated by the following examples.

Example 1

Preparation of trans-dl-5n-propy-4,4a, 5,6,7, a, aa, 9-oc-ahydro-1H- (a 2H) -pyrazolo [3,4-g] quinoline.

Reaction mixture prepared from 6.3 g of a mixture of traIls-dl-5-cyalro-4.4a, 5,6,7, a, aa, 9-olktahydro-2H-pyrazolo [3,4-g] quinoline and its 1H-tautomer 30 g of zinc dust, 375 ml of acetic acid and 75 ml of water are heated at reflux for 16 hours under a nitrogen atmosphere. After this time, it is filtered and the filtrate is poured on ice. The resulting aqueous mixture was basified by the addition of 14 N aqueous ammonium hydroxide, and the alkaline phase was extracted several times with a mixture of chloroform and isopropanol.

The combined organic extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a residue consisting of trans-dl-4,4a, 5,6,7, a, aa, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and its 1H-tautomer. The residue is dissolved in 500 ml of methanol to which 1.9 g of sodium cyanoborohydride are added. 20 ml of propionaldehyde are then added and the mixture is stirred for 28 hours under a nitrogen atmosphere. The reaction mixture was then poured into 1 N aqueous hydrochloric acid. The aqueous phase is extracted with ether and the ethereal extracts are discarded. The aqueous phase was then basified by the addition of an excess of 14 N aqueous ammonium hydroxide, and the resulting alkaline phase 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 yielded a residue containing trans-dl-5-n-propyl-4,4a, 5,6,7,8, α, 2-α-α-methyl-2H-pyrazolo [3,4-g]. quinoline.

Mass Spectrum M + = 219.

The residue was dissolved in boiling acetone (100 ml) to which was added dropwise 12 N hydrochloric acid (5 ml). The resulting mixture was cooled and the trans-dl-5-n-propyl-4,4a, 5,6,7, a, aa, 9-octahydro-1H- and 2H-pyrazolo [3,4-g] quinoline dihydrochlorides thus formed are filtered. Yield = 4.6 g, m.p. = 250-257 ° C.

Analysis: Calculated: C 53.43, H 7.93, N 14.38, Cl 24.26, found:

% C, 53.15;% H, 7.91;% N, 14.47;

Example 2

Preparation of trans-d-5-n-propyl-4,4a, 5,6,7, a, 8a, 9-octathiazol-4-yl-1H- (a 2H) -pyrazrrr [3.4lg] ] quinoline.

Using the procedure. according to Example 1, 1.2 grams of the trans-dl-5-cyano-4,4a, 5,6,7,8, mixture.

8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and mixtures of its ta-tautomer are reacted with zinc dust in acetic acid to give trans-dl-4,4a, 5,6,7,8, 8a, 9-octahydro-2 H -pyrazolo [3,4- g] quinoline and its 1H-tautomer. This mixture was dissolved in 50 ml of DMF and 1.7 g of potassium carbonate was added. 0.6 ml of n-propyl iodide is then added and the mixture is stirred for 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water and the resulting aqueous mixture was extracted several times with ethyl acetate. The ethyl acetate extracts are combined and the combined extracts are washed successively with water and saturated aqueous sodium chloride solution and then dried. Evaporation of ethyl acetate yielded a residue consisting of trans-di-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-1 H -pyrazolo [3,4- g] quinoline and its 1 H-tautomer, which was purified by chromatography on 30 min. g of florisil · using chloroform containing increasing amounts of 2-10% methanol. Fractions which undergo thin layer chromatography include trans-dl-5-n-propyF -4,4a, 5,6,7,8,8a, 9-octahydrof2Hi and 1H-pyrazolo [3,4-g] quinoline The combined extracts were evaporated to dryness. 0.28 g of transid-5-n-propyl-4,4a, 5,6,7,8,8a, 9-ocahydro-2H-pyrazolo [3,4-g] quinoline and its 1H-tautomers are obtained.

The residue was dissolved in ethanol and treated with 0.16 mL of 12 N aqueous hydrochloric acid. Thus, di-hydrochlorides of trans-di-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and its III tautomer are obtained. The reaction mixture was concentrated in vacuo and the concentrate was diluted with ether. The crystallized trans-dl-5-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- and 2H-pyrazolo [3,4-g] quinoline dihydrochloride, m.p. = 276-278 ° C, were separated by filtration.

Example 3

Trans-d 5 -In-p-propyl-4,4a _! 5,6,7,7a, aa, 9,10-octahydro-2H-pyrazolo [3,4-g] quinoline dihydrochloride was separated into the optical antipodes by dissolving 10 g of the compound in 100 ml of water. To this solution is added dropwise 50% aqueous K 2 CO 3 until the solution is basic to pH paper. The aqueous phase is then extracted with methylene chloride, the organic extracts are 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 is added a solution of 1.2 molar equivalent of (-) tartaric acid in hot methanol. The resulting solid was filtered off, washed with ether and dried in a vacuum desiccator.The filtrates were stored and the solid crystallized (5 ml of methanol per 0.5 g of salt) until a constant melting point or The physical data for the · (-) isomer is given in Table I.

Table I

crystallization no. G mp ° C [a] o25 (solvent) 1 3.1 182—185 —29.75 (CH30H) 2 1,8 185—187 —43.48 (CH3OH) 3 0.6 199—201 —93.24 (H2O) 4 0.13 203—204 —94.55 (H2O)

The filtrates were combined, evaporated and the residue crystallized from methanol. 0.08 g of substance (mp 199-200 ° C) (α) _D ² H ² O 5 - 94.55 ° was obtained.

The filtrates were re-combined, evaporated and dissolved in water. The solution was basified and extracted as described above. In an analogous manner to that described with (-) -tartrate, (+) -tartrate is formed. Physical data for · (+ Pisomer is given in Table II).

Table II crystallization No. g

11.46

20.70

30.15

mp ° C

173—177

185—188

201-202 [α] H ₂ O +32.76 ^- +58.44 +93.88

In vitro assays show that the (-) isomer is active and the (+) liSGmer is inactive.

Claims (3)

Subject A process for the preparation of octahydropyrazolo [3,4-g] quinolines of formulas Ia and Ib wherein R is alkyl of 1 to 3 carbon atoms and pharmaceutically acceptable acid addition salts thereof, comprising reacting a compound of formula I'a or I ' b, where the compound of formula Ia 'or Ib is optionally converted into a pharmaceutically acceptable acid salt. 2. A process according to claim 1 wherein the compound of formula (Ia) or (Ib) is alkylated with an alkylhaiogenide. 3. The process of claim 1, wherein the compound of formula Ia or Ib is reductively alkylated with the appropriate aldehyde and metal hydride.