DE1805659C - 10- (3-Diethylaminopropionyl) -3-trifluoromethyl-phenothiazine hydrochloride - Google Patents

Description

The invention relates to IQ- (3-diethylaminenoprapionyl) -3-trißuormethy! -Phenothiuzin-hyarochlorid the formula

C ₂ H ₅

CH ₂ - CH ₂ - N

HCI

C ₂ H ₃

This compound represents a white, crystalline one. Powder that is soluble in water and warm alcohol; M.p. 163 to 165 ^° C; Molecular weight 430.9.

The new substance serves as an active ingredient for psychotropic remedies with antidepressant effects and instructs broad spectrum of pharmacological activity, which in the main features of the effect of the antidepressants tricyclic structure (thymoleptics) is similar.

The basic indication of its use is the existence of depression. The most effective Compound in the treatment of anxiety-depression states within the limits of manic-depressive Psychosis, in organic vascular diseases of the central nervous system, in reactive and neurotic Depression, as in the treatment of periodic schizophrenia with dominant affective ones Disorders and neuroleptic depression.

As an antidepressant and corrector, the preparation can be administered orally and intramuscularly.

The new compound is a remedy with pronounced psychotropic and antidepressant (thymoleptic) Effect and the ability to deal with complications, such as extrapyramidal disorders, which occur in the Cure arising from neuroleptics, eliminate it. Animal studies have shown the following:

Although the new compound is a phenothiazine derivative surprisingly, it is not a neuroleptic. In contrast to the neuroleptics of the phenothiazine series, the agent also has no adrenolytic and hypothermic effects (can but in individual cases increase the effect of catecholamines) and does not suppress the spontaneous one Movement activity of animals.

Due to its mode of action, the new means can be used as antidepressants, namely thymoleptics with a tricyclic structure.

When administered subcutaneously at a dose of 5 to 10 mg / kg daily for a period of 30 days If the new remedy does not show any negative effects on the blood count: it changes the ability of the blood to clot not, the weight of the animals also remains unchanged during the experiment. In the histological one Examination of the internal organs of the test animals, which the new active ingredient in a dose of 5 to No pathological changes were observed when given 10 mg / kg for 30 days. With subcutaneous When the agent is introduced in the form of a 0.1% solution, there is no local irritant effect.

To compare the antidepressant effects of the new active ingredient with three of the best known Antidepressants (thymoanaleptics), namely imipramine, amitriptyline and chloracyzine, served eleven test methods, which are characteristic of the assessment of antidepressants tricyclic structure (compare ζ, B, F. HaTlinger and V. Burck-E ft r d!, "Psychopharmiioological agents", New York, M. Gο r dο η, Aoad. Press, Vol. 1 [1964], pp. 75 bis 101). The three AuDepressants named above with their short names established by the WHO represent the following chemical compounds:

Imipramine:

5- (3-dimethylaminopropyl) -10.11 -dihydro-
_{| 0} 5 H-dibenz [b, f] azepine hydrochloride,

Amitriptyline:

10.1 i-Dihydro-N, N-dimethyl-5 H-dibenzo [a, d] -heptalen- / l ^s , y-propylamine hydrochloride,

Chloracyzine:

, 2-chloro-10- (3-diethy laminopropionyl) -

phenothiazine hydrochloride.

The eleven test methods concerned intraperitoneal applications in mice or rats. For each test method, the respective active ingredients were applied to ίο individual groups of animals (4 to 6 groups of animals each) in different doses (in an increasing series from minimum to maximum effect), with the following calculation (with the exception of methods no.2 and 10) of the For 50% of the animals effective doses (ED ₅₀ ) according to the method of L itchfi .e 1 d and W i 1 c ο χ ο η (J. Pharmacol. Exper. Therap., 96/1949, pp. 99 to 117) . For methods 2 and 10, see below.

To determine the potentiating effect

(Methods No. 1,7 and 8) threshold doses were used

(ED ₅ ) of amphetamine, hexobarbital and barbital,

d. H. Doses which only produce corresponding effects in 5% of the animals.

To determine the antagonistic effect

(Methods No. 3 and 4) were maximum doses

(ED ₉₅ ) of perphenazine and benzquinamide, ie

Doses causing catalepsy in 95% of the animals were used.

The following should be assessed through the individual test methods, the labeling and results of which can be seen _{in ED 50 values in the table:}

No. 1: The number of mice with stereotypical movements was evaluated. The amphetamine

was at a dose of ED ₅ at the same time

with the respective active ingredient intraperitoneally

applied.

No. 2: The increase in the duration of the amphetamine stereotype in rats was determined. Ver

Amphetamine doses were administered which produced a stereotype lasting 60 ± 20 minutes in each rat. The doses of the antidepressant that doubled the duration of the stereotype were calculated ( _{designated ED x} in the table). No. 3/4: The test substances were administered to rats 30 minutes before application of an ED ₉₅ dose of the cataleptogenic agent. The ED ₉₅ was perphenazine 2.5 mg / kg, Pur Benz

quinamide 30 mg / kg.

No. 5: The experiments were carried out on mice with the climbing test according to the method of P. Kneip (Arch, internat. Pharmacodyn., 126 [1960], No: 1/2, pp. 238 to 245)

guided.

No. 6: The reserpine was administered intraperitoneally at a dose of 5 mg / kg to mice. the

Investigations were carried out in a thormo-. ' stable space. The existence of an antagonism for each animal in the test substances was based on the reduction in hypothermia No. 10: by 2.5 ° C in comparison to reserpine (control substance measured,

No. 7/8: The number of mice that fell asleep was evaluated. The antidepressants were administered intraperitoneally 30 minutes before entering an ED _S dose of hexobarbital (50 mg / kg) or barbital (16 mg / kg).

No. 9: The suppression of the conditioned movement disturbance No. 11: defensive reflexes (tone and electrical stimulation) was determined in rats according to the method of Cook and '5' Weidley (»Ann, N, Y. Acad. Sci . ", 66 [1957], p. 740; C ο ο k et al.," J. Pharmacoe. Exper. Therapy ", 113 [1955], p. U),
The active ingredients are administered to mice intraperitoneally 45 minutes before the subcutaneous administration of 25 mg / kg arecoline (N methyl -1,2,5,6-telrahydronicotinic acid methyl ester). The dose for each test substance was calculated, which was the duration of tremor caused by arecoline reduced to half ( _{denoted by ED x} in the table).

The LD ₅₀ was determined in mice at an ambient temperature of 2O ⁰ C; Observation period 24 hours.

Ongoing

Investigation mcthotJe

Inlraperilonale

Dose determined

uls active ingredient)

according to
invention
mg / kg ip

Imipramine
mg / kgi.p.

Amitriptyline
mg / kg ip

Chloracyzin mg / kgi.p.

Potentiation of the d, l-amphetamine

effect

Prolongation of the same effect elimination of perphenazine

catalepsy

Likewise elimination of the

Benzquinamide catalepsy

Disturbance of the orientation reactions antagonism to the hypothermic Reserpine effect

Potentiation of the sleep effect of hexobarbital

Likewise from Barbital

Suppression of conditioned reflexes ... antagonism to the tremor effect

from Arecoline

LD ₅₀

ED ₅₀ ED,

ED,

'50

ED ₅₀ ED ₅₀

ED ₅₀

ED ₅₀ ED ₅₀ ED ₅₀

ED _XX LD ₅₀ 0.17
0.12

2.8

19.3
35.0

38.0

2.0
50.0
11.0

15.9
215.0

2.0
2.3

6.0

18.5
12.5

10.0

15.5
50.0

16.0
160.0

21.0
43.2

41.0

15.4

2.7
18.0
1.85

11.2

1.8
0.35

16.0

20.0
70.0

38.0

35.0
70.0
20.0

15.0
160.0

*) 10-IS-diethylaminopropionylJO-trilluomethyl-phenothiazine hydrochloride.

To prepare the active ingredient according to the invention, the procedure is as follows: 3-Trifluoromethylphenothiazine is dissolved in an organic solvent, then 3-chloropropionyl chloride is added and the reaction mixture is heated to a temperature of 60 to 150 ° C. over the course of 3 to 6 hours - depending on Boiling point of the solvent used. Methanol or ethanol is added to the reaction mixture to destroy the unreacted 2-chloropropionyl chloride and the mixture is heated for 30 minutes to 1 hour, then cooled to room temperature and diethylamine is added to the resulting 10-ß-chloropropionylJ-S-trifluoromethylphenothiazine with stirring. The mixture is heated in the course of 3 to 6 hours to a temperature of 60 to 150 ⁰ C, the base obtained, 10- (3-diethylaminopropionyl) -3-trifluoromethyl-, phenothiazine, treated with dilute hydrochloric acid and then with sodium hydroxide solution obtained product extracted with ethyl ether, benzene, toluene, xylene, chloroform or dichloroethane and treated the ethereal solution of the base with hydrogen chloride. The 10 - (3 - diethyl - aminopropionyl) - 3 - trifluoromethylphenothiazine hydrochloride obtained is recrystallized from anhydrous ethanol. 163 to 165 ° C. Yield 66% of theory.

The preparation of 10- (3-diethylaminopropionyl) -3-irifluoromethyl-phenothiazine hydrochloride can also be done by isolating the intermediate product formed, 10 - (3 - chloropropionyl) - 3 - trifluoromethylphenothiazine, by reacting 3-trifluoromethylphenothiazine with 3-chloropropionic acid chloride and Distilling off the organic solvent take place. After removing the organic Solvent the remaining 10- (3-chloropropionyl) -3-trifluoromethyl-phenothiazine recrystallized from aqueous isopropyl alcohol. F. 82 to 84 ° C.

example

16 g of 3-trifluoromethylphenothiazine in 120 ml of anhydrous toluene are introduced into a three-necked flask equipped with a stirrer and reflux condenser, and 9.9 g of 3-chloropropionic acid chloride are then gradually added. The solution is ^{heated to 110 °} C. for 3 hours and then cooled ^{to 50 ° C.} Then 30 ml of anhydrous toluene and 30 ml of methanol are added. The mixture obtained is heated for 30 minutes at HO ⁰ C, then cooled to room temperature, 9.9 g of diethylamine are added with stirring and the mixture is boiled for 2 hours. The

Diilthylnmin hydrochloride precipitated after cooling is abilltrierl, the toilet solution three times with Washed water and the base, 10- (3-Dililhylaminopropionyl) -3-trifluormethyI-phenothinzin, with 5 to 6% hydrochloric acid until an acid reaction (Congo red, see p as an indicator).

The acidic aqueous extract is treated with activated charcoal at a temperature of 40 to S0 ° C and the Base by adding 40% sodium hydroxide solution until an alkaline reaction is achieved (phenolphthalein as an indicator) eliminated. The precipitated base is extracted with toluene, the toluol solution with anhydrous Magnesium sulfate dried, the dry solution treated with dry hydrogen chloride gas, the resulting Precipitate, 10- (2-Difllhylaminopropionyl) - '5 3 - trifluoromethyl - phenothiazine hydrochloride, filtered off and washed with dry ether.

Yield 20.1g. F. 160 to 161 ^° C. It is then recrystallized from 30 ml of anhydrous ethanol. 16.6 g of hydrochloride are obtained (66% of theory, based on 3-trifluoromethylphenolhiazine). M.p. 163 to 165 ° C.

Calculated ... Cl 8.23, S7.44%; '

found .... Cl 8.22, 8.30, S 7.36, 7.37%.

Claims (2)

Patent claims: 1. 10 - (3 - Dia "thylaminopropionyl) - 3 - trifiuormothylphenothiazine hydrochloride the formula CjH ■ 2 ^ll $ C ₂ H ₅ HCI 2. Pharmaceutical preparation with antidepressant activity, consisting of 10- (3-diethylaminopropionyl) -3 - trifluoromethyl - phenothiazine hydrochloride as an active ingredient in conjunction with usual Auxiliary and carrier materials.