DE1695003B - 1,2,3,4-Tetrahydroquinolines and a process for their preparation - Google Patents

Description

35 The lower alkyl group R ₁ is e.g. B. the methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or isopentyl group, preferably the methyl group.

R ₂ is e.g. B. one of the aforementioned lower alkyl groups, preferably the methyl group.

The following connections are particularly noteworthy:

1 -Methyl ^ methylamino-ö-chloro-1,2,3,4-tetra-

hydroquinoline,
l-methyl ^ methylamino ^ -chlor-l ^^ tetra-

hydroquinoline,
1-methyl-4-methylamino-1,2,3,4-tetrahydroquinoline

and their pharmaceutically acceptable salts with acids, especially the hydrochlorides.

As has been found, surprisingly, the compounds mentioned have valuable pharmaco-logical properties Properties. You antagonize z. B. the depressant effects of neuroleptics without one having a stimulating effect or increasing blood pressure or the effects of catecholamines to reinforce. The pharmacological findings characterize the new compounds of the general formula I as a new type of psychostimulants that differ in terms of their pharmacological Clearly differentiate effect from the previously known preparations. They are indicated for treatment of lack of drive of various origins, without any accompanying hypertension adversely affect. The compounds of general formula I also have an antitussive effect and anorectic effects.

Various compounds according to the invention are compared with known substances.

1. Checked connections

hydrogenated with catalytically excited hydrogen or a complex hydride and optionally then a base of the general formula I obtained with an inorganic or organic one Acid converted into a salt.

40

45

The invention relates to new 1,2,3,4-tetrahydroquinolines of the general formula

R,

NH

55

60

in which R ₁ and R _{2 are} lower alkyl groups and R _{3 is} a hydrogen atom or a fluorine, chlorine or bromine atom in the 6- or 7-position, and their salts with inorganic or organic acids and a process for their preparation.

1 -MethyM-methylamino-o-chloro-l ^^ - tetrahydroquinoline hydrochloride (according to Example Ib); II. 2 -MethyM-methylamino ^ -chlor-l ^^ - tetrahydroquinoline hydrochloride (according to Example 1);

III. 1 - methyl - 4 - methylamino -1,2,3,4 - tetrahydroquinoline hydrochloride (according to Example 1 a);

IV. Α-Phenyl-α-piperidyl- (2) -acetic acid methyl ester - hydrochloride (psychotonicum according to M. N eg wer, organic-chemical drugs, Berlin 1961, p. 254);

V. N - (y - Dimethylamine - propyl) - iminodibenzyl hydrochloride, (Psychoanalepticum according to M. N e g w e r, organic-chemical drugs, Berlin 1961, p. 386).

2. Results of the present test report

The substances I, II and III according to the invention differ from the commercial preparations IV and V in an advantageous way:

The superiority over compound IV consists in the lack of an increase in spontaneous motility (psychomotor arousal), with the other effects (e.g. 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7 - hexahydro - HbH - benzo [a] quinolizine antagonism and dl - α - methylphenethylamine hyperthermia) the compounds IV and V are equal.

Compared to Compound V, the lack of pronounced peripheral effects is advantageous.

This results in a novel spectrum of activity for the test substances.

The toxicity of the substances according to the invention is of the same order of magnitude as that of the comparison substances.

3. Orientation motility

The superiority of the substances according to the invention over the compound IV is shown below provided by demonstrating that it advantageously does not increase compared to compound IV the spontaneous motility (psychomotor excitation) cause what due to the orientation motuity is determined as follows:

Groups of mice, the average weight of which is 18 to 21 g per mouse, are placed in plexiglass cages of 30 × 20 × 9 cm. The interruptions of a beam of light guided through the cages, which are caused by the movement of the mice, are recorded by means of a PhotozeHe and a counter. The animals are placed in the cages 30 minutes after the intraperitoneal injection of the test substance. The motility is recorded for 15 minutes and the dose is sought at which a decrease (DD ₅₀ ) or increase (DS _S0 ) of 50% of the mean value compared to the controls is achieved. The evaluation takes place on the semi-logarithmic paper.

connection Orientation m
Acceptance of DD ₅₀ otility (mg / kg)
Increase in DS ₅₁₁ I. around 24
> 40
23
> 40 6.5 π in IV V

magnesium chloride, 1 g sodium carbonate, 0.05 g primary sodium phosphate and 1 g glucose. The intestine is made to contract with acetylcholine, and then the amount of test substance is determined, which has an antispasmodic effect. The intensity of the spasmolytic effect during acetylcholine contraction is compared with the effect of atropine.
The values in the table give the ratio

ίο more effective doses.

4. Adrenolysis and acetylcholinolysis

The superiority of the substances according to the invention over compound V is shown in the following it has been demonstrated that, compared to compound V, they are advantageously not pronounced have peripheral effects, which is determined on the basis of adrenolysis and acetylcholinolysis as follows will:

Adrenolytic effect

The adrenolytic effect on the isolated organ is tested on the seminal vesicle of guinea pigs. The contractions on this organ, which is in a bath of 50 ml of Tyrode's solution, are triggered by adrenaline.

The adrenolytic effectiveness of the tested substances is determined by the action of 2- [N- (m-hydroxyphenyl) - ρ - toluidinomethyl] - imidazoline compared: The values in the table give the ratio more equally effective Cans on.

Acetylcholine antagonistic activity
(Atropine value)

The experiments were carried out with surviving guinea pig intestines according to Magnus in a Tyrode solution, which was made up of 1 l of water, 8 g of sodium chloride, 0.2 g of potassium chloride, 0.1 g of calcium chloride, 0.1 g of Ma- Tested compound

I ..

II.
III

IV.
V.

Adrenolysis

(2- [N- (m-hydroxy-

phenyl) -p-toluidino-

methyl] irudazoline = 1)

900: 1

> 1000: l

1000: 1

12: 1
5. Toxicity

Acetylcholinolysis (atropine = 1)

6900: 1
1142: 1

869: 1
24: 1

The acute toxicity (DL ₅₀ ) was determined on mice in the usual way. The compounds I to III according to the invention and the comparative compounds IV and V have the following toxicity values:

Tested connection Acute toxicity, mouse
DL ₅₀ (mgAg) ip 35 I.
II
111
IV
40 V 150
150
150
175
150

6. 2-Oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro 1 lbH-benznr _rI ] quinolizine antagonism

Male ten rats weighing 120 to 160 g are first the test substance and 30 minutes later 20 mg / kg 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7 - hexahydro - 1IbH - benzo [a] - quinolizine injected intraperitoneally, and 1 hour later is the intensity of the catatonia assessed (stage III and IV by W i r t h and colleagues, Arch. int. pharmacodyn. 115, 1 [1958]). The animals are then placed individually in running wheels for 30 minutes. The dose is determined at which 50% of the animals show no catatonia.

Tested connection

I ..

II.

⁶⁵ III

IV.
V.

Antagonism to 2-oxo-3-isobutyl-9,10-dimethoxy-

1,2,3,4,6,7-hexahydro-

11 bH-benzo [«] quinolizine

DE ₅₀ (mg / kg) ip

about

16.5
8th
17th
16.5
24

7. dl-a-methylphenethylamine hyperthermia rat

It is the influence of a test substance on the administration of 5 mg / kg i. p. dl-a-methylphenethylamine sulfate generated hyperthermia measured in rats (Morpurgo and Theobald, Europ. Journ. Pharmacol, 2, pp. 287-294 [1967]).

The temperature curve is followed over time and that of the temperature ordinate, time abscissa and Temperature-time curve included area size determined.

Checked connection

Γ ..
II.
HI
IV.
V.

dl-a-methylphenylethylarain-hyper-

thermie (rat) maximum change (planar measurement)

5 mg / kg i.v. p.

+ 3.4 + 3.4

10 mg / kg i.p.

+ 12.53

+ 7.38
+ 9.7

The new 1,2,3,4-tetrahydroquinoline derivatives of the general formula I can be taken orally, rectally or in The form of aqueous solutions of their salts can also be administered parenterally.

The new tetrahydroquinoline derivatives of the general Formula I and its salts with acids are prepared by being known per se Way a compound of the general formula

quinolines. Some ketones of this type are known and others can be produced analogously to the known; their imines are also available in a manner known per se.

The 1,2,3,4-tetrahydroquinoline derivatives obtained by this process of the general formula I are then, if desired, converted into their salts with inorganic and organic acids in the customary manner convicted. For example, you move a

ίο solution of a 1,2,3,4-tetrahydroquinoline derivative of general formula I in an organic solvent with the desired acid or with a Solution of the same. Organic solvents are preferably chosen for the reaction in which the

The resulting salt is sparingly soluble, so that it can be separated off by filtration. Such solvents are e.g. methanol, methanol-ether and ethanol-ether.

For salt formation with the 1,2,3,4-tetrahydroquinoline

derivatives of the general formula I can, for. B. hydrochloric acid. Hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, / 3-hydroxyethanesulfonic acid, acetic acid, Malic acid, tartaric acid, citric acid, lactic acid,

Oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and 4,4'-methylene-bis- (3-hydroxy-2-naphthoic acid) can be used.
The following examples explain the preparation of the new compounds. The temperatures are given in degrees Celsius.

II

35

40

hydrogenated with catalytically excited hydrogen or a complex hydride and optionally then a base of the general formula I obtained with an inorganic or organic acid transferred into a salt.

• As catalysts, for. B. palladium on charcoal or another conventional carrier or Raney nickel and as reaction media z. B. dioxane or another inert, with water at least partially miscible organic solvent to which a little sodium hydroxide solution is added. As reaction conditions room temperature and normal pressure are usually sufficient; if necessary, the hydrogenation is carried out by increasing the pressure and / or the temperature accelerated.

As a complex hydride is z. B. Lithium aluminum hydride or diborane, in an ether or other ethereal organic liquid, or with sodium or potassium borohydride, e.g. B. in a lower alkanol such as methanol at room temperature to moderately high temperatures, e.g. B. the boiling point of the solvent used, applied.

The starting materials of the general formula II are imines of substituted 4-oxo-l, 2,3,4-tetrahydro-

example 1

1 -MethyM-methylamino ^ -chlor-1,2,3,4-tetrahydroquinoline

To a concentrate which crude 1-methyl-4 - methylimino - 7 - chloro -1,2,3,4 - contains tetrahydroquinoline and from 8.5 g of 1-methyl ^ -chloro ^ -oxo-1,2,3,4 - Tetrahydroquinoline, as has been obtained below, is set in portions at 15 ° with stirring 2.6.g sodium borohydride. The mixture is stirred and heated for IV2 hours at room temperature briefly to reflux. The mixture is evaporated under a pressure of 11 torr at 40 °. The residue is dissolved in 100 ml of ether. The ethereal solution is washed over with water Dried sodium sulfate and evaporated under a pressure of 11 torr. The residue is distilled one under high vacuum. 1-Methyl-4-methylamino-7-chloro-1,2,3,4-tetrahydroquinoline boils at 105 to 11070.001 torr; Yield 80% of theory.

To prepare the hydrochloride, 2.1 g of the base are dissolved in 20 ml of methanol and 10 ml of 1N hydrochloric acid. The solution is evaporated under a pressure of 11 torr at 50 ^c. The residue is crystallized from methanol-ether. The hydrochloride melts at 197 to 199 °; Yield 92% of theory.

Analogously the following are obtained:

a) 1 - methyl - 4 - methylamino -1,2,3,4 - tetrahydroquinoline, Bp 79 to 82 ° / 0.33 torr .; Hydrochloride, mp 162-163 °;

b) 1 -Methyl ^ -methylamino-o-chloro-l ^^ - tetrahydroquinoline, Bp 135 to 14070.01 torr .; Hydrochloride, mp 184-186 °;

c) 1 - methyl - 4 - ethylamino - 1,2,3,4 - tetrahydroquinoline hydrochloride, F. 171 to 173 °.

The concentrate of l-methyl ^ -methylimino ^ -chlor-l ^^ - tetrahydroquinoline required as starting material can e.g. B. can be produced by the following reaction sequence:

a) l-MethyM-dimethylamino ^ -chlor-l ^ -dihydroquinoline

IO

To a suspension of 15.5 g of lithium aluminum hydride in 320 ml of anhydrous tetrahydrofuran, a solution of 32.7 g of l-methyl-4-dimethylamino-7-chlorocarbostyril is obtained at 10 ° added dropwise in 320 ml of anhydrous tetrahydrofuran within 30 minutes. The reaction mixture is then refluxed for a further 5 hours and left then stand at room temperature for about 14 hours. The mixture is then cooled to 10 ° and add 16 ml of water, 16 ml of 15% sodium hydroxide solution and 48 ml of water in succession with thorough stirring. The mixture is stirred at room temperature for 30 minutes. Then it is filtered and the filter material is washed with tetrahydrofuran. The filtrate is evaporated under 11 torr at 40 °. The l-methyl-4-dimethylamino - 7 - chlorine -1,2 - dihydroquinoline remains as an orange-colored oil; Yield 97% of the Theory.

1 -Methyl-4-dimethylamino-1,2-dihydroquinoline is obtained in an analogous manner, Bp. 82 to 83 ° / O, 00 Torr, m.p. 30 to 32 ° (crystallized from petroleum ether).

b) 1-methyl-7-chloro-4-oxo-1,2,3,4-tetrahydroquinoline

A solution of 27.5 g of 1-methyl-4-dimethylamino-7-chloro-1,2-dihydroquinoline (orange-colored oil) in 300 ml of ether is added with stirring to a mixture of 150 ml of 2N sulfuric acid and 150 g of ice. Mix well and add another 150 g of ice. Then you put the solution with concentrated Alkaline sodium hydroxide solution (pH 9). The mixture is shaken in the separating funnel. then the ether layer is separated off and the aqueous solution is extracted again with 300 ml of ether. the combined ether solutions are washed twice with water, dried over sodium sulfate and under evaporated at a pressure of 11 torr at 40 °. The residue crystallizes from ether-petroleum ether. The

I - methyl - 7 - chloro - 4 - oxo -1,2,3,4 - tetrahydroquinoline melts at 85 to 87 °; Yield 88% of theory.

L-Methyl-4-oxo-1,2,3,4-tetrahydroquinoline is obtained in an analogous manner, Bp. 95 to 99 ° / 0.01 Torr.

c) 1 -MethyM-methylimino ^ -chlor-1,2,3,4-tetrahydroquinoline

A solution of 8.5 g of 1-methyl-7-chloro-4-oxo-1,2,3,4-tetrahydroquinoline and 21.3 g of anhydrous methylamine in 85 ml of anhydrous methanol is in a steel autoclave for 7 hours at 100 ° under a Maintained pressure of 100 atmospheres of nitrogen. Mar cools the reaction mixture and concentrates it in part

I1 torr to approximately 50 ml. This concentrate wire used as starting material.

209545

Claims (5)

Patent address: 1. 1,2,3,4-Tetrahydroquinolines of the general formula 10 wherein R ₁ and R _{2 are} lower alkyl groups and R _{3 is} a hydrogen atom or a fluorine, chlorine or bromine atom in the 6- or 7-position, and their salts with inorganic or organic acids. 2. 1 -MethyM-methylamino-o-chloro-l ^^ - tetrahydro-quinoline and its hydrochloride. 3. 1 -Methyl - ^ - methylamino ^ -chlor-l ^^ - tetrahydro-quinoline and its hydrochloride. 4. 1 -MethyM-methylamino-l ^^ - ietrahydroquinoline and its hydrochloride. 5. Process for the preparation of the 1,2,3,4-tetrahydroquinolines according to claim 1, characterized in that a compound of the general formula is obtained in a manner known per se