SU1360586A3 - Method of producing octahydropyrazolo(3,4-g)-quinoline derivatives or their salts - 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

  1360586

The invention relates to new chemical compounds, specifically to the N derivatives of octahydropyrazolo f3,4-rj, quinoline of the general formula

N

HN

 CCA

R

n

N.

.

R

where R is C-C-alkyl or allyl, which are competitors of dopamine-and can be used to treat Parkinson's disease and to inhibit prolactin secretion.

The aim of the invention is a process for the preparation of octahydropyrazolo derivatives of 3,4-g quinoline, with high activity as competitors, dopamine and prolactin secretion inhibitors, which can be used to treat Parkinson's disease and postpartum lactation.

Example. Preparation of trans-Bb-5-methyl-4,4a, 5,6,7,8,8a, 9-octahyde ro-1H and 2H-pyrazolo G3.4-g quinoline.

46.5 g of a mixture of isomers containing 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, dissolved in 400 ml of tetrahydrofuran and added to the resulting solution. 80 ml of methyl iodide, which forms the reaction mixture, is cooled with a mixture of water and ice. 9.6 g of sodium hydride (in the form of a 50% suspension in mineral oil) are added to the reaction mixture}. After the addition of the sodium hydride suspension is completed, the bath with the cooling mixture is removed and the reaction mixture is stirred at room temperature under nitrogen atmosphere in for about 4 hours. Then the reaction mixture is diluted with water, the aqueous mixture is thoroughly extracted with chloroform, the extracts are combined, and i the combined extract is washed with a saturated aqueous solution of sodium chloride and sumat. The chloroform is removed by distillation to dryness in vacuo Ie and get the residue in the form of an orange oil, having a weight of 47.3 g. The residue is crystallized, the current is from ether-hexane to obtain a crystalline 1.-methyl-6-benzoyl-3,4,5,6., 7, 8-hexahydro-2 (1H) -quinoline and the corresponding 3,4,4a, 5,6, 7-hexahydro-isomer.

71.33; H 6.90; C, 71.56; H 6.71;

N

0

five

0

five

thirty

36

40

five

0

five

N

4.91.

A solution of 47.3 g of a mixture of 1-metsh1-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2 (1Hlquinoline and the corresponding 3,4,4a, 5,6,7-hexahydroisomer is dissolved in 800 ml of THF and cool the resulting solution to about. To the solution, add 20 g of lithium aluminum hydride in small portions and heat the resulting reaction mixture at reflux for 4 h under nitrogen atmosphere, then cool the reaction mixture and decompose excess lithium -aluminum hydride by adding ethyl acetate. A 10% solution of sodium hydr is then added to the reaction mixture. and dilute the reaction mixture with water to completely decompose all the organometallic compounds.The aqueous mixture is extracted with several portions of a mixture of chloroform and isopropanol, the organic extracts are combined and washed with a saturated aqueous solution of sodium chloride, and then dried. the residue containing a mixture of enamines: 1-metsh1-6-hydroxy-1,2,3,4,5, 6,7,8-octahydroquinoline and 1-metsh1-6-hydroxy-1,2,3,4, 4a, 5,6,7-octahydroquinoline. The above residue is directly, without further purification, dissolved in 300 ml of ether and the resulting ethereal solution is saturated with hydrogen chloride gas to give the hydrochloric acid salts of the components of the enamine mixture. The ester is removed de. canting and the residue is dissolved in 200 ml of THF and 50 ml of methanol, the resulting solution is cooled with an ice-water mixture and 12 g of sodium cyanoborohydride are added with cooling and stirring. After the completion of the introduction of sodium cyanoborohydride, the reaction mixture is stirred for 60 minutes and poured into a mixture of ice and 1N. aqueous solution of hydrochloric acid. The acidic aqueous solution is extracted with chloroform, the extracts are discarded. The solution is alkalinized 14 n. ammonium hydroxide and alkali-insoluble trans-DL-I-methyl-6-hydroxydecahydroquinoline, which was extracted with chloroform-isopropanol in several portions of the mixture.

ten

saturated sodium chloride solution and dried. After distilling off the solvent, 15 g of TpaHc-DL-l-Me of thyl-6-hydroxydecahydroquinoline are obtained.

15 g of trans-DL-l-methyl-6-hydroxy-decahydroquinoline is dissolved in 250 ml of 6N. aqueous solution of sulfuric acid4. The solution is cooled with a mixture of ice-water and a solution of 9 g of chromium trioxide in 60 ml of 6N is added dropwise to it under stirring over 10 minutes. an aqueous solution of sulfuric acid. The cooling water bath is removed and the reaction mixture is stirred for another 60 minutes at room temperature, after which the excess oxidant is decomposed by the addition of isopropanol to the reaction mixture. Then the reaction mixture is poured into ice and the resulting acidic aqueous solution is alkalinized with 14N. ammonium hydroxide aqueous solution. The resulting trans-Bb-meths1-6-oxodec-25 hydroquinoline is insoluble in alkaline medium, it is separated and extracted with several portions of a mixture of isopropanol and chloroform. The extracts are combined and the combined extract is washed with a saturated aqueous solution of sodium chloride and then dried. After distilling off the solvent in vacuo, trans-Bb-1-methyl-6 is obtained for 150 g of florisil, using methylene dichloride as the eluent, containing gradually increasing amounts (1-5%) of methanol. The fractions containing the same substance according to thin layer chromatography are combined. The third fraction (third substance) eluted from the chromatographic column is a yellow solid weighing 3 g. This solid is heated with 100 ml of ether and the resulting solution is filtered. After concentrating the filtrate, 590 mg of crystalline trans-DL-l-methyl-6-oxo-7-dimethylaminomethylene decacidroquinoline having a melting point of 107-109 C are obtained. Results of the quantitative analysis:

C, 70.17; H 9.74;

20

Found,%: N 12.87.

.

C, 70.23; H 9.97;

Calculated N 12.60.

175 mg of trans-Bb-1-methyl-6-oxo-7-dimethylaminomethylenedecanohydroquinoline is dissolved in IO ml of methanol and 30 is added to it with stirring at room temperature under a nitrogen atmosphere for 4.5 days 0.05 ml of hydrazine hydrate, after which the volatile components of the mixture are removed by distillation. oxodecahydroquinoline, having a temperature - Dissolves the residue in chloroform and boiling range from 105 to chromatograph on 25 g of florisil, 1i6 P at a pressure of 6 Torr, yield 7.7 g (45% of chloroform) as eluent. ). Forms containing gradually increasing amounts (2-15%) of methanol-40. The fractions containing, according to thin layer chromatography, the same substance, propagating closer to the source, and differing from the starting product, are combined and removed from the combined fraction of the solvent. TpaHc-DL-5-methyl-: 4,4a, 5,6,7,8,8a, 9-octahydro-1H- (u2H) - pyrazolo (3,4-g) quinoline is obtained in the form of free base, giving the molecules pny .ioH (M) with a mass number of 191, with a mass spectroscopic study. The resulting base is dissolved in ethanol and 2 ml of 1N is added to the solution. hydrochloric acid is distilled from the resulting acidic solution; the reaction mixture is prepared from 7.7 g of trans-DL-1-methyl-6-oxodecahydroquinoline, 36 g of dimethyl acetalmethylformamide and 250 ml of benzene, after which part of the benzene is distilled off. at atmospheric pressure in a nitrogen atmosphere until the volume of the reaction mixture is reduced to 1/2 of the original (1.25 h). An amount of benzene is then added in order to bring the volume to the reaction. to the initial mixture and repeat the whole process from the beginning (only 4 times). Finally, all benzene is removed by distillation in vacuo, the resulting residue is dissolved in 100 g of dimethyl acetalmethylformamide and the solution is heated under nitrogen at reflux for 20 hours. The reaction mixture is distilled off in vacuo and the residue is dissolved in

ten

25

florisil per 150 g, using methylene dichloride containing gradually increasing amounts (1-5%) of methanol as eluent. The fractions containing the same substance according to thin layer chromatography are combined. The third fraction (third substance) eluted from the chromatographic column is a yellow solid weighing 3 g. This solid is heated with 100 ml of ether and the resulting solution is filtered. After concentrating the filtrate, 590 mg of crystalline trans-DL-l-methyl-6-oxo-7-dimethylaminomethylene decacidroquinoline having a melting point of 107-109 C are obtained. Results of the quantitative analysis:

C, 70.17; H 9.74;

0

Found,%: N 12.87.

.

C, 70.23; H 9.97;

Calculated N 12.60.

175 mg of trans-Bb-1-methyl-6-oxo-7-dimethylaminomethylenedecanohydroquinoline is dissolved in IO ml of methanol and 0 is added to it with stirring at room temperature under a nitrogen atmosphere for 4.5 days 0.05 ml of hydrazine hydrate, after which the volatile components of the mixture are removed by distillation. The residue is dissolved in chloroform and chromatographed on 25 g of florisil using chloroform as an eluant containing gradually increasing amounts (2-15%) of methanol-0L. The fractions containing, according to thin layer chromatography, the same substance, propagating closer to the source, and differing from the starting product, are combined and removed from the combined fraction of the solvent. TpaHc-DL-5-methyl-: 4,4a, 5,6,7,8,8a, 9-octahydro-1H- (u2H) - pyrazolo (3,4-g) quinoline is obtained in the form of free base, giving the molecules pny .ioH (M) with a mass number of 191, with a mass spectroscopic study. The resulting base is dissolved in ethanol and 2 ml of 1N is added to the solution. hydrochloric acid is distilled from the resulting acidic solution

five

tel dry. The residue is crystallized from ethanol to give a tautomeric mixture containing trans-Bb-5-methyl-4.4a, 5,6,7,8,8a-9-Octagidro-1H- (and

51360586b

2H) -pyrazole (3,4-g) quinolines in the form of water and extract the aqueous salt salts thereof (dihydrochloride layer with ethyl acetate, the extract is washed with a don), having a melting point of water and a saturated aqueous solution of 268-270 ° C (with decomposition), the yield of sodium chloride and dried. After about 140 mg of the race, the solvent is obtained;

Found,%: C 49.82; H 7.08; consisting of 1-allyl-6-benzoyloxy- N 15.66; C1 26.80.3,4,5,6,7,8-hexahydro-1H-quinolin C H N3 2HC12-one and the corresponding 3,4,4a, 5,6,

Calculated,%: C 50.01; H 7.25; th 7-hexahydrocompounds. N 15.90; 26.84. . Received N-allyl-derivative

Example 2. Preparation of trans-dissolve in 750 ml of THF and cool B-5-allyl-4,4a, 5,6,7,8,8a, 9-oct. To cool the resulting solution with a mixture of water. with hydro-1H (and 2H) -pyrazolo (3,4-g) quinolode. 15 t of liter 20 g of lithium aluminum hydride are added to the solution;

65 g of 4-b.benzoyl-oxycycly- dissolve this reagent, 38 ml of pyrrolidine and dissolve the mixture at boiling with the reverse of the Cristal monohydrate in a fridge under nitrogen in lolsulfonic acid in 1000 ml. for about 3 hours, then oh- - cyclohexane, the resulting 20 is heated with a mixture of ice-water and the reaction mixture at boiling with an excess of lithium aluminum hydride, with a rat cooler in an azo-addition atmosphere. 1/2 h, using water tat. A 1% Dean-Stark trap is then added to the mixture. Cool the reaction solution with sodium hydroxide mixture and dissolve it to dissolve to decompose all those present in the reaction by distillation in a vacuum. The residue, a mixture of organometallic compounds consisting of 4-benzoylcyclo compounds, is diluted with the treated hexanonpyrrolidinenamia, and the reaction mixture is mixed in this way with 53 g of acrylamide in 1000 ml of dioxane doi. The aqueous mixture is extracted with an unboiled mixture and the reaction mixture is heated at small amounts of chloroform, extracted under reflux into an at-. The ract is combined. The combined exotherm of nitrogen is washed for about a sample with a saturated aqueous day, cooled, and removed by dispersing sodium chloride and chitium. Coy volatile components of the mixture. Formation- After distilling off the solvent, the resulting residue was diluted with water and a residue consisting of a mixture of 1-allyl-extracted the resulting aqueous mixture of 6-hydroxy-1,2,3,4,5,6,7,8-octagonal With ethyl acetate, the extract is washed with vinquinoline and its 1,2,3,4,4a, 5,6,7-octad and with a saturated aqueous solution of hydroisomer. The residue is dissolved in sodium chloride and then dried. 750 ml of ether and saturate. After distilling off the solvent, the solvent is obtained with an ethereal solution with anhydrous mixture gas, containing 6-benzoyloxy-3,4, with hydrogen chloride. Salt-acid-5,6,7,8-hexag: vdro-1H-quinolin-2-one salts of the components of the mixture octahydro and the corresponding 3,4,4a, 5,6,7, -hequinolines, soluble in the ether, the hydro-compounds are precipitated and decanted are separated. The resulting mixture is dissolved in cy from the ether. 250 ml of tetrahydrofuran and 250 ml of di-dissolve in a mixture of 100 ml of methanol and methylformamide, 300 ml of THF are added to the solution and the resulting sodium hydride is cooled in a 50% solution with ice-water. To the plant suspension in the mineral oil and the distillation are added in portions while cooling the mixture is obtained: until the complete completion of the addition of 20 g of sodium cyanoborohydride, after the formation of the quinoline sodium salt after the introduction of this reagent 2-one. Then a cooling bath is added to the reaction mixture. The reaction mixture of 30% allyl bromide was stirred at room temperature in 75 ml of THF and stirred at room temperature for 1 hour, the resulting mixture was diluted for 24 hours gg with saturated bicarbonate water. The temperature of the reaction mixture was rapidly. sodium and sodium is extracted with alkaline increases. As a result, the layer is required in several portions of chloroform. with external. cool; cdenia. After finishing, the extracts are combined and the reaction mixture is washed neither with a mixture of the combined extract with a full water 7.1360586 8

sodium chloride solution, and the total number of 217. The residue having

ten

15

dried After distilling off the solvent, about 12.8 g of TpaHc-DL-1-allyl-6-hydroxydecahydroquinoline is obtained.

The resulting trans-OH-1-allyl-6-hydroxydecahydroquinoline is dissolved in 500 ml of methylene dichloride, to which 8.2 g of sodium acetate is added and 21.6 g of a mixture of hydrochloric acid pyridine-chromium trioxide is introduced into the resulting solution. The reaction mixture is stirred under nitrogen at room temperature for 7.5 hours, filtered, and the filtrate is concentrated in vacuo. After chromatography of the filtrate on I to 50 g of florisil using chloroform as the eluant, containing a gradually increasing amount (1-5%) of methanol, 3.2 g of trans-DL-1-allyl-6-oxo-dehydroquinoline is obtained . The 6-oxo compound is dissolved in toluene and 25 ml of dimethyl acetal dimethyl formamide is added to the solution, the reaction is heated; the mixture was boiled under reflux for 24 hours under a nitrogen atmosphere, and then cooled and the solvent was removed by distillation. The residue is chromatographed on 150 g of florisil using chloroform containing gradually increasing amounts (2-20%) of methanol as eluent. The fractions containing, according to the thin layer chromatography data, the target trans-DL-1-allyl-6-oxo-7-dimethylaminomethylene decahydroquinoline, are combined and obtained after distilling off the solvent 1.3 g of the intended product.

: Weight 0.55 g, dissolved in 75 ml of acetone and heated in acetone

boil under reflux

jK solution is added dropwise 0.5 12N. an aqueous solution of hydrochloric acid and the resulting reaction mixture is cooled. The resulting hydrochloric acid salt (dihydrochloride) trans-B1-5 allyl-4 4a, 5,6,7,8,8a, 9-octahydro-2H (and 1H) - pyrazolo (3,4-g) quinoline has melting point about 215 ° C with decomposition: weight 495 mg.

Found,%: C 53.52; H 7.13; N 1, 65; C1 24.17.

 gNg ZHCl.

Calculated,%: C, 53.80; H 7.29;

N 1.48; C1 24.43.

In the study of the use of compounds that meet the general formulas, it was found that they affect the rotational behavior of rats treated with 6-hydroxydopes with 25 grams according to the test used

for testing compounds that can serve as an agent against Parkinson’s disease. For this test, rats affected by the nigroneostricial method are used according to the method described by Angerstedt and Arbatnoto (1970J. Compounds with dopam activity as competitors, force rats to describe circles in the direction opposite to the affected side. After the latent period, which may vary from compound to compound, count the number of circles for 15 minutes between

thirty

35

This product is dissolved in 75 ml of meta-time. The results obtained for nol, to which 0.5 ml of compounds are added, which meet the general formulas of hydrazine hydrate, stir the reaction mixture at room temperature for 20 hours and then distill off the volatile components of the mixture in vacuo. The residue is dissolved in chloroform -and chromatographed on 35 g of florisil using chloroform containing gradually increasing amounts (2-4%) of methanol as eluent. The fractions containing, according to the data of thin layer chromatography, the target trans-Bb-5-allyl-4,4a, 5,6,7,8,8a-9-octahydro-2H-pyrazolo (3,4-g) quinoline. and its 1H-tautomer is combined and from the combined fraction the solvent is distilled off in vacuo. Mass spectroscopic examination of the residue indicates the presence of molecular ion with a mass test for rotation test for rats, are given in Table 1. Compound. was dissolved in water and the resulting aqueous solution of rat was injected.

when administered intraperitoneally in doses in the order of 1 mg / kg and 100 mg / kg.

Compounds that respond to general formulas can also be useful as prolactin inhibitors and can accordingly be used in the treatment of postpartum lactation and galactorrhea. To illustrate the activity of substances in those conditions when it is necessary to reduce the effects of prolacty 55

on, experiments were conducted according to

following method.

 Adult male rats of Sprague-Dawley breed weighing about 200 g

50

: Weight 0.55 g, dissolved in 75 ml of acetone and heated in acetone

reflux.

jK solution is added dropwise 0.5 ml of 12N. an aqueous solution of hydrochloric acid and cooled the resulting reaction mixture. The resulting hydrochloric salt (dihydrochloride) trans-B1-5 allyl-4, 4a, 5,6,7,8,8a, 9-octahydro-2H (and 1H) - pyrazolo (3,4-g) quinoline has a melting point of about 215 ° C; with decomposition: weight 495 mg.

Found,%: C 53.52; H 7.13; N 1, 65; C1 24.17.

 gNg ZHCl.

Calculated,%: C, 53.80; H 7.29;

N 1.48; C1 24.43.

When studying the use of compounds that meet the general formulas, it was found that they affect the rotational behavior of rats treated with 6-hydroxydopamine according to the test used

for testing compounds that can serve as an agent against Parkinson's disease. For this test, rats affected by the nigroneostrial method were used according to the method described by Angerstedt and Arbatnot (1970J. Compounds that have dopami-C on as competitors, force the rats to describe circles in the direction opposite to the affected side. After a latent period, which may vary from compound to compound, count the number of laps within a 15 min interval

of time. Results obtained for compounds meeting general formulas.

when tested for rotation test for rats, are given in Table 1. Compound. was dissolved in water and an injection of the resulting aqueous solution of rat- was performed.

when administered intraperitoneally in doses of the order of 1 mg / kg and 100 mg / kg.

Compounds that respond to general formulas can also be beneficial as prolactin inhibitors and can accordingly be used in the treatment of postpartum lactation and galactorrhea. To illustrate the activity of substances in those conditions when it is necessary to reduce the effects of prolactin

on, experiments were conducted according to

following method.

Adult male rats of Sprague-Dawley breed weighing about 200 g

They were placed inside an air-conditioned room with a certain illumination (the light came from 6 am to 8 pm) and was supplied with water and food ad libitum.

. Each rat was injected intraperitoneally with 2.0 mg of reserpine c. as an aqueous suspension 18 hours before the introduction of the test product. The purpose of introducing a reserpine was to increase the level of pro-. lactin. Compounds to be tested were dissolved in 10% ethanol and administered intraperitoneally at doses of 50 µg / kg 5 and 0.5 mg / kg. Each of the studied compounds was administered in each dose in groups of 10 rats, the control group of 10 rats were injected. an equivalent amount of 10% ethanol. One hour after this treatment, the rats were killed by decapitation and an aliquot of 150 µl serum was taken from them for testing for prolactin.

The difference in the amount of prolactin in rats that were treated: and the amount of prolactin in counterbreed animals, referred to the amount of prolactin in control animals, was interpreted as the percentage inhibition of Prolactin secretion due to the effect of compounds corresponding to the general formulas. The percentage of inhibition obtained is given in Table 2, in comparison with the known compounds (3-7), which have the same activity.

Toxicity (LDUR) of monohydrochloride (WR,) -4.4 o (5,6,7,8,8o /, 9-okTpaHc-DL-5-n-propyl 4,4a, 5,6,7,8 , 8a, 9-octahydro-1H (and 2H) is pyrazole; o (3,4-g) quinoline dihydrochloride

TpaHC-DL-5-allyl-4,4a, 5,6,7,8,8a, 9-octagrvdro-1H (and 2H) - pyrazole, 3-g quinolindihydrochlo-yrid

Parkinson's Lazy.

tagidro-5-propyl 1H-pyrazole 3,4-g} chi nolin of 98.6% purity is 119 mg / kg for males, 122 for females (88-170; mg / kg).

Thus, the novel compounds have a high activity as inhibitors of prolactin secretion superior to those of known inhibitors of prolactin secretion, and in addition, the proposed compounds compete with dopamine, which makes them useful in the treatment of postpartum lactation, galactorrhea and Parkinson's disease.

Form m a la invention

The method of obtaining octa-eidropyrazolo derivatives of 3,4-g quinoline of total Lormula. . .

  .

NTTj ± HNjrTj

- ..

R

R

thirty

where R C -Se-alksh1 or allyl,

or their salts, different

the fact that the compound of the general formula

ABOUT

n

five

(SNS) 2. KNS

n 1

R

0

where R has the indicated meanings, is reacted with hydrazine: hydrate with the selection of the target product in free and salt form.

100

75

80 66

165 Oh

eleven

TpaHc-DL-5-n-propyl-4.4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo (3,4-g) quinoline dihydrochloride

TpaHc-DL-5-methyl-4,4а, 5,6,7,8,8а, 9-octahydro-1H (and 2H) - pyrazolo (3,4-g) quinoline dihydrochloride

Racemic Methyl Dihydroisolysis P

Fumiclavin B

K-methyldeoxychoac 1

Lisergin Izolyzergin

Editor Y. Sereda

Compiled by G. Zhukov Tehred M.Hodanich Proofreader L, Pa Tay

Order 6166/57 Circulation 372 Subscription

VNIIPI USSR State Committee

for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5

Production and printing company, Uzhgorod, st. Project, 4

1360586

12

table 2

61

91

42

84

20 21

30 14 4

Claims (1)

Claim The method of obtaining derivatives of octa · hydropyrazolo [3,4-g] quinoline of the General Formula Hn R C <-Cz-alkyl of their salts / o t where or by the fact that the compound of the general formula or allyl is liable (CH 165 0 eleven Table 2. Compound The percentage of inhibition at a given dose prolactin fifty μg / kg j 0.5 mg / kg 5 mg / kg TpaHc-DL-5-n-propyl 4.4a, 5.6.7.8.8a, 9 octahydro-1H (and 2H) pyrazolo (3,4-g) quinoline dihydrochloride 61 91 TpaHc-DL-5-methyl 4.4a, 5.6.7.8.8a, 9 octahydro-1H (and 2H) ~ pyrazolo (3,4-g) quinoline dihydrochloride 42 84 Racemic methyl dihydroisolisergate P 20 Fumizlavin B 21 N-methyldeoxychaclavin 1 thirty Lizergin 14 Isolisergin 4