DE1287573B - Process for the preparation of antidepressant 5- (3-methylaminopropyl) -5H-dibenzo [a, d] -cyclohepten - Google Patents

Description

The invention relates to a process for the preparation of 5- (3'-methylaminopropyl) -5 with an antidepressant effect H-dibenzo [a, d] -cydoheplene of the formula

CH

CH ₂ CH ₂ NHCH ₃

which is characterized in that a compound of the formula

20th

H CH,

/ CH ₃

CHXH ₁ N

CH,

with a haloformic acid ester of the formula ROCOX or a haloformic acid thioester of the formula RSCOX, in which R is an alkyl, aryl, aralkyl or alkaryl group and X is a halogen atom means, reacts in a manner known per se and the compound of the formula thus obtained

/ CH,

CH ₂ CH ₂ N

35

40

^X C = O

ZR

in which Z denotes an oxygen or sulfur atom, hydrolyzed in a manner known per se.

In the first stage of the process according to the invention, the dimethylaminopropyl derivative is des 5H.-Dibenzo [a, d] -cycloheptens with a haloformic acid ester or a haloformic acid thioester condensed to a urethane or thiourelhan. For example, the 5- [3 '- (N-dimelhylamino) propyl] -5 H-dibenzo [a, d] -cycloheptene with methyl chloroformate to the urethane 5 - [N - methyl - N - carbomethoxyamino) - propyl] -5H-dibenzo [a, d] -cytiohepten and methyl chloride reacted.

Although the reaction can be carried out without a solvent, it is preferably carried out using one. Suitable solvents are inert solvents such as aromatic hydrocarbons, e.g. B. benzene or toluene, aliphatic hydrocarbons such as heptane or hexane, halogenated hydrocarbons, e.g. B. chloroform or carbon tetrachloride, and ether, / .. B. tetrahydrofuran. The reaction can take place at room temperature, but is preferably carried out at reflux temperature for a sufficient period of time, preferably up to several hours.

After the reaction has ended, the solution is extracted with dilute acid and dried to dryness evaporated to give the desired urethane.

The urethane or thiourethane obtained as an intermediate is then hydrolyzed to give the substituted Carbamyl group of urethane or the thiocarbamyl group of thiourethane into a hydrogen atom to convict. The hydrolysis is preferably carried out under alkaline or acidic conditions. Hydrolysis in an alkaline alcoholic solution at reflux temperature can be advantageous be performed.

The hydrolytic conversion of the thiourethane is preferably carried out by first adding the thiourethane with an oxidizing agent, expediently hydrogen peroxide in acetic acid, or with other oxidizing agents such as perbenzoic acid. Peracetic acid. Chromic acid or potassium permanganate, oxidized and the oxidized intermediate product then with an alkaline solution, such as caustic soda, is treated.

Preferably the urethane is applied under nitrogen in a solution of potassium hydroxide in n-butanol heated to reflux temperature. After the hydrolysis has ended, the solvent is reduced in vacuo evaporated and the residue extracted with suitable solvents to the hydrolysis product isolate.

The compound obtainable according to the invention is for the treatment of the mental health condition useful as it counteracts depression and as a mood enhancer or psychic activator can be used. The compound is preferably in shape administered their physiologically acceptable acid addition salts, and the production of these salts falls also within the scope of the invention.

The therapeutic superiority of the 5- (3'-methylaminopropyl) -5 H-dibenzo [a, d] -eycioheplene hydrochloride (protriptyline) compared to the known 5- (2'-methylaminoethyl) -5 H-dibenzo [a, dj-cycloheptene hydrogen maleate is possible from the following experiment:

Female mice (CF No. 1-S) were used as test animals. The animals received prior to the experiment Nothing to eat for 16 to 20 hours. 10 animals were studied at 3 or more dose levels each. The test solutions were encrypted and according to a statistical schedule 30 minutes before intraperitoneal administration of 32 mg / kg tetrabenazine administered orally. The animals were 30 minutes after receiving the tetrabenazine, on the reduction of the instinct to participate and the presence of eyelid paralysis (plose, i.e. a narrowing of the eyelid gap of 75% or more) was examined. To evaluate the depressed Effect of the tetrabenazine, the animal was placed in the mille of a 20.3 x 30.5 cm (jitter (cap of a mouse cage), and his ability to get to the edge of the (jitter to move, observed. Normal animals reach because of their exploratory !! Action this Aim quickly. A depressive effect (loss of exploration activity) is shown by the fact that the Animal fails two out of three attempts.

Results

Protriptyline, 5 - (3 '- methylaminopropy!) - 5 H - dibenzo [a, dj cyelohepten hydrochloride, is a stronger one Antagonist against the depressive effect of tetrabenazine as L-605 823, 5- (2'-methylaminoethyl) -5H-dibenzo [a, d] -cycioheptene-hydrogen maleate. as can be seen from Table I:

Table I.

Antagonism of the depressive effect;
Dose (mg / kg)

link

Protriptyiin
L-605 823 ..

ED *

0.1 0.7

0.8

4.5

HD ₇ -,

4.8
28.2

link

Protriptyiin
L-605 823 ..

0.1

0.3

EDa.

0.2
0.9

0.4 3.2

Tabel Sp III DL. "
intravenous link DL: ,,
per os 42.0 Protriptyiin 281 26.0 L-605 823 96.5 at iel

11 B

The protrusion according to the invention is a stronger antagonist of the ptotic effect of tetrabenazine than the L-605 823 as shown in Table II. At a near maximum effective dose (ED-.) Protriptyiin was about eight times more effective.

Table II

Antagonism of the ptotic effect;
Dose (mg / kg)

EDtS
30th

The lethal dose in mg / kg body weight, at

of the 50 ¹ Vo of the test animals die (DL-m), is shown in Table III.

40

45

a) 5- [3 '- (N-Methyi-N-carbäthoxyamino) propyl] -

5 H-diber.zo [a, d] -cycloheptene

A solution of 27.7 g (0.1 mol) 5- [3 '- (N-dimeihylamino) propyl] -5H-dibenzo [a, d] -cyclohepten in KX) ml of benzene is converted into a solution of 32.4 g (0.3 mol) of ethyl chloroformate within one hour in KX) ml of benzene added at room temperature / i. The solution is stirred for 20 hours heated to reflux temperature, then cooled to room temperature and three times with 100 ml 2.5 L hydrochloric acid extracted, twice with 50 ml each Washed water, dried over magnesium sulfate and evaporated to dryness. The obtained thick Oil is pure urethane. Yield 29.5g = -88 ", O the theory.

The preparation of the 5- [3 '- (N-dimethylamino) - (>? propyl] -5H-dibenzo [a, d] -cyc! oheptens, the starting material is used is described below:

1.08 g (0.0442 g atom) of magnesium turnings are in a stirrer, dropping funnel and a 200 ml three-necked flask equipped with a drying tube fitted with a reflux condenser. the The entire reaction takes place under dry nitrogen. One sets an iodine crystal and then K) ml dry tetrahydrofuran too. Then 3 m! a solution of 3-dimethylaminopropyl magnesium chloride is added and the mixture is heated to reflux on the steam bath. On that a solution of 5.37 g (0.0442 mol) of 3-dimethyiaminopropyl chloride in 35 ml of dry Tetrahydrofuran is added dropwise, the reflux temperature being maintained, if necessary, by supplying heat. When the addition is complete, the The mixture was heated under reflux for a further 2 hours, whereupon almost all of the magnesium dissolved is. Instead of 3-dimethylaminopropyl magnesium chloride you can also use ethyl bromide in an amount of 0.05 mol to initiate the reaction use per mole of magnesium.

The Grignard's solution is cooled to room temperature, followed by stirring and if necessary External cooling to keep the temperature close to room temperature, a solution of 5.05 g (0.0221 mol) 5-C "chloro-5H-dibenzo [a. D] -cycloheptene (which is derived from the method described in the literature Method has been prepared) is added dropwise in 25 ml of dry tetrahydrofuran. After finished In addition, the mixture is refluxed for 15 minutes heated. Most of the tetrahydrofuran is then distilled off under reduced pressure, the water bath temperature being kept at 50 to 60 ° C. The syrupy residue is dissolved in 75 ml of benzene, and 15 ml of water are added dropwise to the solution with stirring. the Benzene layer is decanted from the gelatinous precipitate and the precipitate three times with extracted each 20 ml of boiling benzene. The combined benzene extracts are washed with water and extracted three times with 15 ml of 3η hydrochloric acid each time. The acidic extract is made alkaline with caustic soda and the yellow oily base which separates out is extracted with hexane. After washing the combined extracts with water, the hexane is distilled off. 4.61 g of a product are obtained yellow oil.

b) 5- [3 '- (N-Methyiainino) propyl] -5 H -dibenzofa. d] -eyclohepten

29.5 g of 5- [3 '- (N-methyl-N-carbäthoxyamino) -propyl] - 511 - dibenzo [a, d] - cyciohepten are 24 hours under nitrogen in a solution of 36.3 g of potassium hydroxide in 378 ml of n-butanol Return temperature heated. After cooling to room temperature, the solvent is im The vacuum is removed and the residue is stirred with 2 (X) ml of water and 300 ml of η-hexane. The layers are separated, the aqueous layer is extracted with 100 ml of n-He \ an, and the combined Hexan layers are made twice with 100 m each! Water and then successively with 100 ml, 80 ml and washed 80 nil 0.5 η-sulfuric acid. The saute Solution is made alkaline and first twice with 150 ml each. Then once with 100 ml of ether extracted, dried over magnesium sulfate and evaporated to dryness. The product is a

practically pure monomethyl base and is then converted into the oxalate (melting point = 181 ° C.). Liberating the free base and converting the latter into the hydrochloric! (Fp. = 169 to 170 C ") cleaned.

Claims (1)

Claim: Method of making antidepressant active 5 - (3'-methylaminopropyl) -5 H -dibenzo [a. d] -cyclohepten of the formula CH
CH ₂ CH ₂ NHCH ₃ d a characterized in that one is a compound of the formula CH ₂ CH ₂ N CH, CH ₃ with a haloformic acid ester of the formula RO (X) X or a haloformic acid thioester the formula RSCOX. wherein R is an alkyl. Aryl. Aralkyl or alkaryl group and X is Halogen atom means reacted in a manner known per se and the compound thus obtained the formula in which Z is an oxygen or sulfur atom, hydrolyzed in a manner known per se.