FI68052B - TRANSMISSION OF THERAPEUTIC ANALYTICAL PRODUCTS TRANS-4,4A, 5,6,7,8,8A, 9-OCTAHYDRO-1H (OCH 2H) -PYRAZOLO- (3,4-G) QUINOLINER - Google Patents

Description

1 68052

Process for the preparation of new therapeutically useful trans-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-57] quinolines 5 Partitioned from application 792046

The invention relates to a process for the preparation of trans-4,4a / 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinolines of the novel formulas Ia and Ib and their pharmaceutically for the preparation of acceptable acid addition salts,

H. ? . B

15 Λ i 7 λ 9a 1 7 \ 3 I <=:> h- ^ 3 1

a 4a N 3a · N

• l 20 R Λ

Ia Ib wherein R is C 1-6 alkyl.

The compounds of formulas Ia and Ib and their acid addition salts can be prepared by reacting a compound of formula

H H

30> Λ; Λ

Cl. zr — s -Ό i f

- '.' Ιγ - "W

«H

React with an alkylating agent such as an alkyl halide or aldehyde and a base in the presence of an organic solvent, and if desired, convert the resulting compound into a pharmaceutically acceptable acid addition salt.

The compounds of formulas Ia and Ib and their pharmaceutically acceptable salts are useful as dopamine agonists.

The pharmaceutically acceptable acid addition salts of formulas Ia and Ib include those formed with inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitric acid, phosphoric acid, phosphoric acid such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and alkanoic diacids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts include, for example, sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogen sulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromate, iodide, fluoride, iodide, iodide, iodide, iodide, , caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyn-1,4-dioate, hexin-1 , 6-dioate, benzoate, chloro-30-benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, thienenesulfonate, chlorobenzenesulfonate, xylene, xylene, hydroxybutyrate, glycol 3 68052 plate, malate, tartrate, methanesulphonate, propanesulphonate, naphthalene-1-sulphonate and naphthalene-2-sulfonate.

The compounds of formula Ia are systematically referred to as 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolo [1,4-g] quinolines and the compounds of formula Ib are named 4.4a, 5,6,7 , 8,8a, 9-octahydro-2H-pyrazolo / 3,4 g / quinolin-neiksi. The two structures represent a pair of tautomers and the tautomers represented by the structures are in dynamic equilibrium with each other. The compounds of formulas Ia and Ib further have two chiral centers at carbon atoms 8a and 4a. Thus, the compounds may exist as two racemates, commonly referred to as trans-dl racemate and cis-dl racemate.

However, 13 C NMR spectral values indicate that a cyanoborohydride reduction process in which the hydrogens are attached to the quinoline bridge end, which is a synthetic step, in the preparation of compounds of formulas Ia and Ib, yields trans-fused decahydroquinoline. Although the NMR spectral values of each and are clear evidence of the structure, an X-ray crystallographic study has also been performed using an enamine ketone that readily crystallizes in the decahydroquinoline series (VIII, R = CH 2 Reaction Scheme I). This X-ray analysis clearly shows that the ring junction of the quinoline moiety corresponds to the trans form. Further steps to condense the pyrazole ring on the decahydrocyroline molecule do not alter the configuration of the bridgehead hydrogens. Thus, in the synthetic methods described below, only 30 trans racemates are formed and the compounds of formulas Ia and Ib are shown mainly as trans-dl stereoisomers. The two trans stereoisomers of the 2H-tautomer can be represented as follows: 4 68052

B

• - · # H.

Ji "= · * · N = · X.X ·

HN ^ | and HN ^ | I

c CH - ·? · CH - · «J

5

"'.« R

R

Ib Ib ’

Ib and Ib' correspond to racemic pairs. The 1H-autoromer can be represented as a similar racemic pair.

> / Ψ \

is! I ΐ and ^ Il I I

CH- · · · XH_ «, \ \ / \ /

«H N · U

1 'H' R "

R

Ia ia '20

Ia and Ia 'also correspond to racemic pairs.

The resolution of these racemates into optical delivery systems can be performed by methods known to those skilled in the art, and the individual trans-d and trans-1 isomers are also within the scope of the invention.

For compounds, each designation also includes a second tautomer because an equilibrium mixture of both tautomers is always present. The 2H tautomer is apparently predominant in several tautomer mixtures. Furthermore, the orientation of the substituents is not mentioned, nor is the condensation of the hydrogens 4a and 8a, but it is clear that the hydrogens are in the trans position relative to each other.

Compounds of formulas IIa and Hb are prepared according to the procedure described in Reaction Scheme I below.

35 5 68052

Only one stereoisomer of the racemic pair, the 4a S ', 8a ά isomer, is shown in the reaction scheme, but it should be remembered that each decahydroquinoline and each octahydropyrazolo [3,4-a] quinoline is present as a racemate.

5,68052

Reaction scheme ι 0

II

• / \ T T pyrrolidine χ acrylic anudic acid-cat- / I lyt,, O-CO-Z Z-CO-O-j f • · · 1

V

111 H

--ο} - CH2X MaH

\ / z

C/O

® ft I Q Q

H0_T / 'i | / N | / __ LJ_Aj_H4 0 - \ w N vv \ v 4 · ® iv 4-®

HCl

NaCNBHa H ° f’f, si Vf> V * Y _ My ’VI Υ® VI1 L ·, H / \ - A Y *. H (CHa) uNCH (OZ · Oa <'"i I i" YK * CX' · CHYiY 'rg' Y! X: H I VII (cHaizUCl · / VA | /

I / j \ CN ~ ---- H I

\ l / I ^ ix CN

H UHsNHa * HjP

* ~ ·,, '\. / IT Zn H, l \ „CII ^ COOH ---> TTW alkylation T -5»,., CH = »x J. * x ---> IIa <- Hb ί -------- ---> la i lb VA'V '»» "ii! 68052

In the above reaction scheme, Z-CO is an acyl protecting group wherein Z is C 1-6 alkyl, C 1-4 alkenyl, C 1-2 alkynyl-C 1-8 cycloalkyl, phenyl or substituted phenyl, wherein the substituent group may be methyl, methyl, 5 toxin, chlorine or the like substituent at any position of the phenyl ring. Z-CO can be, for example, acetyl, propionyl, butyryl, propiol, acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl or m-methoxybenzoyl. According to Reaction Scheme I, 4-acyloxycyclohexanone prepared by E.R.H. By the method of Jones and F. Sonderheimer1 in 4-benzoyloxycyclohexanone J. Chem. Soc., 615, (1949), is reacted with pyrrolidine in the presence of an acid catalyst to give pyrrolidineamine. This enamine is in turn reacted with acrylamide 15 to give dl-6-acyloxy-3,4,5,6,7,8-hexahydro-2 (1H) quinoline and dl-6-acyloxy-3,4, 4a, 5,6,7-hexahydro-2 (1H) quinoline, represented by Formula III, with dashed lines indicating alternative sites for the double bond.

Next, in the presence of sodium hydride, the acidic nitrogen (acidic because it is in the β-position relative to the carbonyl group) is benzylated with a benzyl halide (X is, e.g., Cl, Br or J) to give dl-1-benzyl-6-acyloxy-3,4,5,6 , A mixture of 7,8-hexahydro-2 (1H) quinolinone and its β-isomer (iv). Reduction of this amide with lithium aluminum hydride or other suitable organometallic reducing agent gives a mixture of dl-1-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and its N-isomer. This reaction mixture takes into account conditions which also contribute to the hydrogenolysis of the acyloxy group to the hydroxyl group at the C-6 position. Next, this dl-1-benzyl-6-hydroxy-octahydroquinoline is converted to the ammonium salt by treatment with hydrochloric acid, and the ammonium salt is then reduced with sodium cyanoborohydride to give trans-dl-1-benzyl-6-hydroxydecahydroquinoline (VI). The benzyl-35 group of compound (VI) is removed by treatment with cyanogen bromide to give the 1-cyano compound of formula (VII).

___- Il ____ 68052

Next, the trans-dl-1-cyano-6-hydroxydecahydroquinoline (VII) is oxidized, preferably using chromium trioxide in acetic acid, to give the corresponding 6-oxo compound (VIII). This 6-oxo compound (VIII) is reacted with di-5-methylformamide dimethyl acetal to give the 7-dimethylaminomethylene-6-oxo derivative (IX). Reaction of this derivative with hydrazine hydrate gives a tautomeric mixture of a tricyclic derivative, mainly trans-dl-5-cyano-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] -10 quinoline (Xb) and its 1H-tautomer (Xa) to a lesser extent. The cyano group can be cleaved by reduction using zinc and acetic acid to give compounds Ha and Hb.

From the above reaction scheme, considering dl-trans-1-cyano-6-ketodecahydroquinoline (VIII), it appears that the reaction of dimethylformamide-dimethylacetal. could occur with either C-5 or C-7, as both of these carbon atoms are in the ..- position relative to the ketone group and thus available in the reaction. X-ray crystallographic analysis of the enamine (IX) clearly showed that the reaction occurred at C-7 rather than C-5. Thus, the final tricyclic compounds, Xb and Xa, are linear pyrazolo / 3,4-g / quinolines and rather than non-linear tricyclic compounds (which should be designated 4,4a, 5,6,7,8,8a, 9 -oc-tachydro-1H-pyrazolo [* 2,1g] quinolines i.

The dimethylformamide acetals useful in the preparation of the compound of formula IX shown in Reaction Scheme I have the formula (CH 2) «N-CH- (O 2") -, wherein Z "is C 1-4 alkyl, C 3-8 2-10-5 cycloalkyl, -alkenyl or C 1-4 alkynyl. It is preferred to use a commercial dimethylformamide acetal such as dimethyl, diethyl, diisopropyl, dibutyl, dicyclohexyl, dipropyl or dineopentyl acetal.

The compounds of formulas Ia and Ib have been found to affect the conversion behavior of rats injured by 6-hydroxydopamine in a test method for compounds suitable for the treatment of Parkin-35 son disease. Nigroneostriatal injured rats prepared by the method of Ungerstedt and Arbuthnott, Barin Res, 24, 485 (1970) are used in this experiment.

9 68052

A compound having a dopamine agonist effect causes rats to turn in the opposite direction to the injured side of the ring. After a latency period that varies with the compound, the number of turns over 15 minutes is counted.

The results obtained using the compound of formulas Ia and Ib in a reversal test in rats are shown in Table 1 below. The compound was dissolved in water and the aqueous solution was injected intraperitoneally into rats at doses of 1 mg / kg and 100 micrograms / kg. Column 1 of Table 10 shows the name of the compound, column 2 the percentage of experimental animals that showed turning behavior, and column 3 the average number of turns observed during the first 15 minutes after the end of the latency period.

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The compounds of formulas Ia and Ib are also useful as prolactin inhibitors and as such may be used in the treatment of undesirable milk secretion such as postpartum milk secretion and milk leakage. As evidence of their utility under conditions in which they are desired to lower prolactin, the compounds of formulas Ia and Ib have been shown to inhibit prolactin formation using the following method.

10 adult male Sprague-Dawley rats weighing about 200 were placed in an air-conditioned room with controlled lighting (lit between 6.00 and 20.00) and were given free access to laboratory food and water. Each rat received an intraperitoneal injection of 2.0 mg of reserpine as an aqueous suspension 18 hours before study drug administration. The purpose of reserpim was to keep prolactin levels consistently high. The test compound was dissolved in 10% ethanol and injected intraperitoneally at doses of 50 micrograms / kg and 0.5 and 5 mg / kg. The compound was administered in each dose amount to groups of 10 rats, and a control group of 10 untreated males received a corresponding amount of 10% ethanol. One hour after treatment, all rats were sacrificed by decapitation, and 150 ul aliquots of blood were sampled to determine prolactin.

The difference between the prolactin level of the treated rats and the prolactin level of the control rats divided by the prolactin level of the control rats indicates the percentage inhibition of prolactin secretion by the compound of formulas Ia 30 and Ib. These percentages of inhibition are reported in Table 2 below. Column 1 of the table indicates the name of the compound; and in columns 2, 3 and 4, the percentage inhibition of prolactin secretion at doses of 50 micrograms / kg and 0.5 and 5 mg / kg.

12 68052 c

♦ H

i

• S

B cr Ö <

• H rH

g 6 σι m

•B

+ j

-P

§ c

CL CT

• S

I ϊ i

(N W LD

_ <D

5 ° C? 8

rH * H

0 (Jl • B <U (Ö CU | c i • a ύ • H σ

• HO rH

-PH l £> 3

rH S

o

& S

§ I k

• H + J -P

rH M rt δ f g, i O. σ a ro O *> I -H H <0 K d

• H CL 00 CM -H

B I * »-H

• H G CO (Ö rH -H

d I - -n o t)

_ in r 'G -H

G I * I -H H

S 3 "> 3 5 li 1" i P -8

H C (C ΰ Tl · G

When a compound of formula Ia or Ib is used to inhibit prolactin secretion or to treat the symptoms of Parkinson's disease or to produce another pharmacological effect, a compound of formula Ia or 5 Ib above or a salt thereof is used in the manufacture of a pharmaceutically acceptable acid. preferably administered orally. If parenteral administration is used, the injection is preferably administered subcutaneously using a suitable pharmaceutical composition. Other parenteral routes of administration, such as intraperitoneal, intramuscular, or intravenous, are equally effective. In particular, for intravenous or intramuscular administration, a water-soluble pharmaceutically acceptable salt is used. For oral administration, the compound can also be mixed, either as the free base or a salt thereof, with conventional pharmaceutical excipients and filled into empty nested capsules or compressed into tablets. The dose to be administered orally is in the range of about 0.01 to 10 mg per kilogram of mammalian weight, and the parenteral dose range is about 0.0025 to 2.5 mg / kg. Intraperitoneal doses containing 10-100 mg / kg of trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [4 , 4 g / quinoline dihydrochloride, did not cause deaths, but doses of 300 mg / kg were lethal, indicating an LD50 in the range of 100-300 mg / kg. The following examples illustrate the invention.

Example 1

Trans-dl-5-n-prop-yl-4,4a, 5,6,7,8,8a, 9-octa-30-hydro-1H (and 2H) -pyrazolo [3,4-g] quinoline

A reaction mixture was prepared containing 6.3 g of trans-dl-5-cyano-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo-3,4-g-quinoline and a mixture of its 1H tautomer, 30 g of zinc dust, 375 ml of acetic acid and 75 ml of water. The reaction mixture was heated at reflux under nitrogen for 16 hours, then filtered and the filtrate poured onto ice. The resulting aqueous mixture was basified by the addition of 14-norm. aqueous ammonium hydroxide solution and the alkaline layer was extracted several times with a chloroform-5 isopropanol solvent mixture. The organic extracts were combined, the combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a residue containing the trans-dl-10,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] [7-quinoline] formed in the above reaction. its 1H tautomer. The residue was dissolved in 500 lanes of methanol to which 1.9 g of sodium cyanoborohydride had been added. Next, 20 ml of propionaldehyde was added and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 28 hours. The reaction mixture was then poured into 1-norm. aqueous hydrochloric acid. The aqueous layer was extracted with ether and the ether extracts were discarded. The aqueous layer was then basified by the addition of an excess of 14-norm. aqueous ammonium hydroxide solution 20 and the resulting alkaline layer was extracted several times with a chloroform-isopropanol solvent mixture. The organic extracts were combined and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a residue containing the trans-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H and 2H-pyrat-Solo [4,4] formed in the above reaction. -g ^ quinoline. Mass spectrum: M + = 219.

The residue was dissolved in 100 ml of boiling acetone, to which 5 ml of 12-norm was added dropwise. 30 aqueous hydrochloric acid. The mixture was cooled and the trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- and 2H-pyrazolo [5,4-g] quinoline dihydrochlorides thus formed were filtered off; yield 4.6 g; mp. 250-257 ° C. Analysis calculated: C, 53.43; H, 7.93; N, 14.38; Cl, 24.26; 35 Found: C, 53.15; H, 7.91; N, 14.47; Cl, 24.33.

tl 15 68052

Example 2

Trans-dl-5-n-propyl-4,43,5,6,7,8,83,9-octahydro-1H (and 2H) -pyrazolo [4,4-g] quinoline Using the method of Example 1 1,2 g of a mixture of trans-5dl-5-cyano-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-b] quinoline and its 1H tautomer was reacted with zinc dust and with acetic acid to give a mixture of trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-%] quinoline and its 1H-tautomer, which was isolated as a residue . This residue was dissolved in 50 ml of DMF to which 1.7 g of potassium carbonate was added. Next, 0.6 ml of n-propyl iodide was added, and the resulting mixture was stirred at ambient temperature for about 4 hours 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 were combined, and the combined extracts were washed successively with water and saturated aqueous sodium chloride solution, and then dried. Evaporation of ethyl acetate gave a residue containing trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [5,4-g] quinoline and its 1H tautomer, and was chromatographically purified on 30 grams of Florisil using chloroform containing an increasing amount of 25 (2-10%) methanol as the eluent. Fractions shown by TLC to contain trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H and 1H-pyrazolo [4,4-c] quinoline , combined and the combined extracts evaporated to dryness to give 0.28 g of trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-30 octahydro-2H-pyrazolo [3,4 -g ^ quinoline and its 1H tautomers. The residue was dissolved in ethanol, to which was added 0.16 ml of 12-norm. aqueous hydrochloric acid to give trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-q] quinoline and its 1H-tauto-35 16 68052 mers dihydrochlorides. The reaction mixture was concentrated in vacuo and the concentrate was diluted with ether.

A mixture of trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- and 2H-pyrazolo [5,4-g] cinnoline dihydrochloride-5 crystallized and isolated by filtration; mp. 276-278 ° C.

Preparation of starting material

Preparation of trans-dl-5-cyano-4,4a, 5,6,7,8,8a, 9-octahydro-1H- (and 2H) -pyrazolo-Z3,4-g7quinoline.

A reaction mixture was prepared containing 65 g of 4-benzoyl-10-oxycyclohexanone, 38 ml of pyrrolidine, a few crystals of p-toluenesulfonic acid monohydrate and 1000 ml of benzene. The reaction mixture was heated to reflux under a nitrogen atmosphere for one hour in a apparatus equipped with a Dean-Stark water trap. The reaction mixture was then cooled and the volatiles removed by evaporation in vacuo. The residue containing the pyrrolidinienenamine of 4-benzoyloxycyclohexanone formed in the above reaction was dissolved in 1000 ml of dioxane without further purification. 64 g of acrylamide were added. This new reaction mixture was heated at reflux for two days under a nitrogen atmosphere, then cooled and the volatiles removed by evaporation in vacuo. The reaction mixture was diluted with ethyl acetate, and the ethyl acetate layer was separated, washed, first with water and then with saturated aqueous sodium chloride solution. The ethyl acetate layer was dried and the volatiles were removed by evaporation in vacuo. The obtained residue containing 2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and 2-oxo-6-benzo-30-yloxy-3,4,4a formed in the above reaction, A mixture of 5,6,7-hexahydroquinoline was dissolved in chloroform and the chloroform solution was chromatographed on Florisil. Chloroform containing an increasing amount of ethanol (0-2%) was used as the eluent. Fractions found to contain 2-35 oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and its A8 (8a) isomer were combined by thin layer chromatography and the solvent was removed in vacuo. The resulting residue was crystallized by trituration with hexane to give a mixture of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinolin-2-one and the corresponding 3,4,4a, 5, 6,7-hexahydro derivative. The mixture melted between 130-150 ° C after recrystallization from ether-hex-5 cyano-solvent mixture.

Analysis: Calculated C, 70.83; H, 6.32; N, 5.16; Found: C, 71.05; H, 6.19; N, 5.33.

NMR of the product isolated above showed that the mixture contained about 60% 6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinolin-2-one and 40% 3,4,4a, 5,6 , 7-hexahydro-isomer.

A mixture of 2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and its isomer obtained as described above from 65 grams of 4-benzoyloxycyclohexanone was dissolved in the mixture without further purification. with 300 ml of tetrahydrofuran (THF) and 300 ml of dimethylformamide. 14 g of sodium hydride were added to form the sodium salt of quinoline. This mixture was stirred at ambient temperature for about 20 minutes under a nitrogen atmosphere, after which time 55 g of benzyl bromide in 75 ml of THF was added very slowly over 10 minutes. The reaction mixture was stirred for an additional hour at 32-45 ° C, and then diluted with water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was separated, washed with water and saturated aqueous sodium chloride solution, and then dried. Evaporation of ethyl acetate gave 1-benzyl-2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and 1-benzyl-2-oxo-6-benzoyloxy-3,4,4a, A mixture of 5,6,7-30 hexahydroquinoline; yield 106 g.

106 g of the above mixture was dissolved in 1 liter of THF and the solution was cooled in an ice-water bath. 40 g of lithium aluminum hydride was added portionwise. At the end of the addition, the reaction mixture was heated to reflux under a nitrogen-35 atmosphere for about 4 hours. The reaction mixture was then cooled and the excess lithium aluminum hydride was destroyed by the addition of ethyl acetate. To decompose the remaining 18 68052 organometallic compounds in the mixture, 10% aqueous sodium hydroxide solution was added. At this point, the reaction mixture was diluted with water. The resulting aqueous mixture was extracted several times with chloroform. The chloroform extracts were separated and combined. The combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of chloroform gave a residue which was 1-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1-benzyl-6-hydroxy-1,2, A mixture of 3,4,4a, 5,6,7-octahydroquinoline.

10 (Both the 2-oxo group and the 6-benzoyloxy group reacted with lithium aluminum hydride to give octahydroquinoline with the free alcohol at the C-6 position). The mixture of compounds thus obtained was dissolved in ether, the ether solution was cooled, and anhydrous gaseous hydrogen chloride was introduced into the solution, thereby dosing the hydrochloride salts of the quinoline isomers. The quinoline hydrochlorides did not dissolve and were isolated by decanting off the ether. The remaining salts were dissolved in 100 ml of methanol and 400 ml of THF. The solution was cooled and 30 g of sodium cyano-20 borohydride was added portionwise. At the end of the addition, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 1.25 hours, after which time it was poured into a 1-norm mixture. aqueous hydrochloric acid and freeze.

The acidic solution was extracted with ether, and the ether extract was discarded.

The acidic solution was then basified with 10% aqueous sodium trioxide and the alkaline mixture was extracted several times with chloroform-isopropanol solvent mixture. The organic extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave the trans-dl-1-benzyl-6-hydroxydeca-hydroquinoline formed in the above reaction; yield 53.6 g. The total yield obtained in six steps was 73%, calculated on the basis of the 4-benzovyloxycyclohexanone starting material taken from the tea.

53 g of trans-dl-1-benzyl-6-hydroxydecahydroquinoline were dissolved in 1.5 liters of methylene dichloride and the solution was cooled in an ice-water bath. 50 g of cyanobroinide were added and the resulting mixture was stirred at room temperature for 15 hours.

il 19 68052

The reaction mixture was washed successively with 1-norm. with aqueous hydrochloric acid and water, and then dried. Evaporation of the solvent gave a residue containing the trans-dl-1-cyano-6-hydroxy-5 decahydroquinoline formed in the above reaction. The residue was dissolved in chloroform, and the chloroform solution was chromatographed on 300 grams of Florisil using chloroform containing increasing amounts (0-2%) of methanol as the eluent. Fractions shown by TLC to contain the desired cyano compound were combined and the solvent was removed from the combined fractions by evaporation in vacuo. The trans-dl-1-cyano-6-hydroxy-decahydroquinoline thus prepared weighed 22.5 g.

22.5 g of trans-dl-1-cyano-8-hydroxy-decahydroquinoline were dissolved in 1200 ml of methylene dichloride. 33 g of a mixture of pyridine hydrochloride chromium trioxide (Sarett's reagent) were added. The reaction mixture was stirred at room temperature under nitrogen for about 6 hours, and then filtered. The filtrate was concentrated in vacuo and the concentrate was chromatographed on 300 grams of Florisil using 20% chloroform in 1% methanol as eluent. Fractions shown by TLC to contain trans-dl-1-cyano-6-oxodecahydroquinoline formed in the above reaction were combined and the combined fractions were evaporated to dryness in vacuo. The residue obtained by recrystallization from an ether-chloroform solvent mixture gave trans-dl-1-cyano-6-oxodeca-hydroquinoline, melting at 86-88 ° C; yield 18.9 g.

Analysis: Calculated: C, 67.39; H, 7.92; N, 15.72; Found: C, 67.15; H, 7.75; N, 15.46.

17.6 g of trans-dl-1-cyano-6-oxodecahydroquinoline Liu were taken up in 200 ml of benzene to which 100 g of dimethylformamide dimethylacetal had been added. The reaction mixture was heated to reflux under nitrogen for about 20 hours and then cooled. Evaporation of the solvent in vacuo gave a residue containing the trans-dl-1-cyano-6-oxo-7-dimethylaminomethylene decahydroquinoline formed in the above reaction. The compound was purified by chromatography on 300 grams of Florisil using chloroform with an increasing amount (0-2%) of methanol as eluent. 10.2 g of trans-dl-1-cyano-6-oxo-7-dimethylaminomethylene decahydroquinoline were obtained, melting at 159-163 ° C. The compound was crystallized from toluene to give crystals melting at 162-164 ° C.

Analysis calculated: C, 66.92; H, 8.21; N, 18.01; Found: C, 67.14; H, 8.16; N, 18.04.

10.2 g of trans-dl-1-cyano-6-oxo-7-dimethylaminomethylene decahydroquinoline were dissolved in 400 ml of methanol.

2.8 g of 85% hydrazine were added and the resulting reaction mixture was stirred for about a day under a nitrogen atmosphere. The volatiles were then removed by evaporation in vacuo. The residue was dissolved in chloroform, and the chloroform solution was chromatographed on 150 g of Florisil using chloroform with an increasing amount (2-5%) of methanol as the eluent. Fractions shown by TLC to contain the desired octahydropyrazoloquinoline were combined and the fractions evaporated to dryness; yield 6.3 g. Recrystallization of the residue from ethanol gave trans-20dl-5-cyano-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and its 1H- a mixture of tautomers melting at 193-195 ° C.

Analysis calculated: C, 65.32; H, 6.98; N, 27.70; Found: C, 65.48; H, 6.80; N, 27.64.

Claims (2)

68052 A process for the preparation of therapeutically useful trans-4,4a, 5,6,7,8,8a, 9-5 octahydro-1H (and 2H) -pyrazolo [3,4-g] quinolines of the formulas Ia and Ib and their pharmaceutically acceptable derivatives. to prepare acceptable acid addition salts ,. ‘* = * <I? R 15 Ia Ib in which R is C 1-3 alkyl, characterized in that the compound of formula 20 H h. H ali <=> · <γη 25 ÄY «ly H 1Ia Hb is reacted with an alkylating agent such as an alkali halide or with an aldehyde and a base in the presence of an organic solvent, and if desired the compound obtained is extracted into a pharmaceutically acceptable acid addition salt .. 68052 A process according to claim 1 for trans-dl-5-n-propyl-4,43,5,6,7,8,83,9- octahydro-1H (and 2H) -pyrazolo [4,5-g] quinoline as tautomers, characterized in that trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -Pyrazolo [1,4-g] quinoline is reacted with propionaldehyde and sodium cyanoborohydride in methanol A process according to claim 1 for trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a To prepare 9-octahydro-10H (and 2H) -pyrazolo [1,4-g] quinoline as tautomers, characterized in that trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro- 1H (and 2H) -pyrazolo [3,4-g] quinoline is reacted with n-propyl iodide in dimethylformamide. 15 '' N »li 68052 A process for the preparation of therapeutically active compounds trans-4,4a, 5,6,7,3,8a, 9-octahydro-1H (och 2H) -5 pyrazolo [3,4-g] quinoline with the formulation Ta and Jb and far-maceutiskt godtagbara syraadditionssalter därav, HH * '. H <X \! c = ^ <ft \ R 15 * · Ib i vilken formler R är C ^^ - alkyl, kännetecknat därav, att en förening med formeln: 20 * -oTr „- \ | y- v M,! H 'K IIa Hb 30 is an intermediate with an alkylating agent, preferably an alkyl halide, unless an aldehyde and a base is present in the organic solvents, and in its own right, is preferably used in the form of a pharmaceutical formulation. 35 A preferred embodiment of the invention which is trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (och 211) -pyrazolo / 3,4- g / quinoline som tautomer, k -