DE1593918C - Basically substituted phthalans and their pharmacologically non-toxic acid addition salts and processes for their production - Google Patents

Description

CH ₃ / CH ₃ \ /
C. / V \ X- -f Ϊ O W. / c— H .

- CN

in which X has the meaning given, with a compound of the general formula

55

A.

Hal- (CH ₂ ): - N

60

in which R ₁ and R _{2 have} the meanings given and Hal represents a halogen atom, is reacted in the presence of a condensing agent and, if appropriate, the free base obtained according to a) or b) is converted into a non-toxic acid addition salt.

The invention relates to basic substituted phthalanes of the general formula

CH ₃ CH ₃

45 / V

X-f f

Λλ

OR ₁

C- (CH ₂ ) ₃ -N
CN R ₂

in which R ₁ and R ₂ denote a hydrogen atom or a methyl group and X denotes a hydrogen atom or a methoxy group, and their pharmacologically non-toxic acid addition salts.

It has been found that the compounds of the above general formula and their pharmacological Non-toxic acid addition salts have valuable pharmaco-dynamic properties and are very useful Represent psychotherapeutics and are particularly suitable for the treatment of endogenous depression are. These compounds show a very clear potentiating effect in animal experiments Adrenaline and nor-adrenaline and also a very strong antireserpine effect. In addition, own they have relatively weak sedative and anticholinergic effects and low toxicity.

In comparative tests, the effect of the new compounds compared to known compounds checked.

The experiments on thymoleptic properties were carried out with the compounds given in Table I below:

Table I.

example - N
\ X. salt Enamel
Point R ₂ "C 1 -N (CH ₃ ) ₂ H HCl 165-167 2 -NHCH ₃ H HCl 180-182 3 - N (CH ₃ ) ₂ 5-CH ₃ O HCl 157-159 4th -NH ₂ H HCl 212-214

5- (3-Dimethylaminopropyl) -10, ll-dihydro-5H-dibenz (b, f) -azepine hydrochloride
(known comparative compound A),

5- (3-Dimethylaminopropylidene) -10, l 1-dihydro-SH-dibenzoia.dVcycloheptene hydrochloride
(known comparative compound B),

5- (3-N-methylaminopropyI) -5H-dibenzo (a, d) -cycloheptene hydrochloride
(known comparative compound C).

pharmacology

The acute toxicity was determined by intravenous injection of the test compounds into male mice of a strain from Navy Medical Research Industries, USA, which weighed 18 to 22 g and were kept in individual cages ^{at a temperature of approximately 23 ° C.} The LD ₅₀ values, based on 3 to 4 dose levels with 5 mice per group, were determined by the Miller & Tainter method (Proceedings of the Society for experimental Biology and Medicine, 1944, 57, pp. 261 to 264).

Reserpine antagonism

Γ. The anti-reserpine activity was determined by injecting the test compound intraperitoneally at dose levels of 10 and 50 mg / kg on two groups of three male mice each. The animals were then checked for signs of a CNS activity (sedation or stimulation) observed for a period of one hour. then a standard dose of reserpine (5 mg / kg) was administered intravenously to the animals. During the next The occurrence as well as the degree of ptosis as well as the presence or absence of the typical was determined hourly Reserpine Syndrome observed. Two untreated comparison groups are used on each trial tested, one of these groups receiving reserpine after the first hour. The degree of antagonism versus ptosis and immobility is roughly determined on a scale ranging from 0 to + + +. The observer was unaware of the identity of the groups examined until after the experiment had ended not in the clear.

2. Prevention of reserpine-induced ptosis.

Non-fasting male mice (NMRI) weighing between 18 to 25 g were caged in groups of 5 animals each and treated with the test compound. An untreated group served as a comparison. Injections of the test compounds were made by a person who was not the same person as the observer. The latter was not informed of the identity of the groups until after the end of the experiment. After V ₂ hours, all animals were given reserpine (2.0 mg / kg) and returned to their original cages. All injections were made. intraperitoneally, the dose being administered diluted in a volume of 0.1 ml per 10 g of body weight. One hour after the administration of the reserpine dose, the cages were tilted up and down a few times, and three seconds later the animals were examined for the degree of ptosis.

The evaluation system worked out by Rubin et al. (Journal of Pharmacology and Experimental Therapeutics, 1957, 120, pp. 125 to 136) was used: 4 = complete, 3 = ^3/4 > 2 = V2> 1 = ¹ U closure of the eyelids . A normal opening is rated with 0. If different degrees of ptosis were observed in the two animal eyes, the average was taken. The activity of each compound tested was expressed as the dose (mg / kg) capable of reducing _{ptosis to half that of control mice (ED 50).}

Norepinephrine (NA) potentiating effects

This effect is in the rat preparation by Shipley & Tilden (see. "Proceedings of the Society for experimental Biology and Medicine", 1947, 64, pp. 453 to 455, recently described by Miller Nielsen & Neuholdin Acta pharmacologica et toxicologica 1959, 15, pp. 335 to 355) determined. The test was only performed using a few compounds which were found to be active in performing the aforementioned tests. A small submaximal active dose, ie 0.05 µg / kg (NA), causing a 10-20 mm Hg increase in blood pressure by intravenous route, was used as the standard. After intravenous injection of the subject test compound, the increase in NA response was calculated as a percentage of the initial value. If 1 mg / kg of the test compound gave less than 50% potentiation and if the anti-reserpine effect was weak, no further doses were usually tested. The result was reported as> 1000 (weak effect) or »1000 (extremely weak effect). In performing other experiments, at least 3 doses (n = 2) were tested. A dose-response curve was plotted on a semi-logarithmic paper from which the ED _{50 was} read. Some active ingredients were tested at a dose of 8 mg / kg to find out whether a maximum potentiation was still present or whether a reversal had occurred. r

The results obtained in the experiments are summarized in Table II below.

Table II

LD ₅₀ Reserpine antagonism ED ₅₀ , mg / kg NA potentiation example mg / kg 1 ED ₅₀ , mcg / kg 0.25 44 introductory > 8 340 1 59 + + + 7.5 45 2 111 + + + 3 > 1000 3 71 + + 14th > 1000 4th 40 + 0.7 350 Comparison compound A 38 + about 4000 Comparison compound B 49 + (+) 25th Comparison compound C + + +

As can be seen from the tests, the comparison compounds are stronger with one exception (C) toxic and show, again with one exception, a higher initial reserpine antagonism. Taking into account the fact that Comparative Compound C at a dose of 64 mg / kg changes from the thymoleptic to a neuroleptic effect, while this in the case of the invention Compounds at much higher values, if any, are found to be those of the invention Compounds as superior thymoleptics.

The new compounds can also be administered either orally or parenterally, e.g. B. in the form of Tablets, capsules, powders, syrups or injection solutions. The basic substituted phthalanes of the The general formula given above and their pharmacologically non-toxic acid addition salts are produced by being in a known manner

a) a compound of the general formula

CH

(CH ₂ ) ₃ -N

OH

R ₂

in which R ₁ , R ₂ and X are those given above
Have meanings with an alkali metal cyanide
in the presence of a mineral acid or a
organic acid, or that one

b) a compound of the general formula

CHa

30th

35

40

45

in which X has the meaning given,
with a compound of the general formula

Hai- (CH ₂ ) ₃ -N

■ R,

55

in which R ₁ and R _{2 have} the meanings given and Hal represents a halogen atom, is reacted in the presence of a condensing agent and, if appropriate, the free base obtained according to a) or b) is converted into a non-toxic acid addition salt.

Non-toxic acid addition salts are, for example, those with hydrochloric acid, hydrobromic acid, Phosphoric acid, sulfuric acid or acetic acid, tartaric acid, maleic acid, citric acid, methanesulfuric acid.

60 The 3-hydroxyphthalane to be used for method a) can be obtained from a corresponding 1,1-dimethyl-3-oxophthalane by customary Grignardation with a corresponding 3-aminopropylmagnesium halide compound.

Method b) can be carried out in an inert solvent, using as a condensing agent usual means, e.g. B. butyllithium, phenyllithium, sodium amide, potassium amide, sodium hydride suitable.

B e i s ρ i e 1 1

1,1-dimethyl] -3- (3-dimethylaminopropyl) -3-cyanophthalan and its hydrochloride

35 g of sodium cyanide (0.7 mol) became 125 g of 1,1-dimethyl-3 - (3-dimethylaminopropyl) -3 - added hydroxyphthalane (0.5 mol). The mixture was then mixed with 245 g of 40% sulfuric acid added dropwise with stirring at a temperature of about 0 ° C., followed by the reaction mixture Stirred for 2 hours at 0 ° C., then refluxed for 1 hour and finally the excess removed from hydrogen cyanide in vacuo. The reaction mixture was then made alkaline with a concentrated aqueous solution of sodium hydroxide and extracted with ether. The ethereal phase was dried over anhydrous sodium sulfate, filtered, and the ether was removed on a steam bath. The residue was distilled in vacuo, with Kp.! 140 to 142 ° C 107 g of 83% 1,1-dimethyl-3 - (3 - dimethylaminopropyl) - 3 - cyanophthalan were obtained.

26 g of this base was dissolved in hot acetone and the solution was made acidic with dry hydrogen chloride. 3 - - on cooling of the hydrochloride of l, l-dimethyl-3- (3-dimethylaminopropyl) crystallized from 28 g cyanophthalans, melting at 163-165 ⁰ C.

■ B e i s ρ ie I 2

1,1-Dimethyl-3- (3-methylaminopropyl) -3-cyanophthalan and its hydrochloride.

There was 1,1-dimethyl-3- (3-methylbenzylaminopropyl) -phthalan-3-ol (0.5 mol), which had been prepared from 3,3-dimethylphthalide and 3-methylbenzylaminopropylmagnesium chloride and was a yellow oil, according to Example 1 with sodium cyanide (0.7 mol) and sulfuric acid into the hydrochloride of 1,1-dimethyl - 3 - (3 - methylbenzylaminopropyl) - 3 - cyanophthalane (mp 162 to 165 ° C). 20 g of this hydrochloride were dissolved in 250 ml of ethanol and, after addition of 2 g of 5% palladium on carbon, hydrogenated at room temperature and a hydrogen pressure of 50 atm for about 3 hours until the pressure remained constant. The catalyst was filtered off and the ethanol was evaporated in vacuo. The residue was dissolved in 50 ml of acetone and cooled. 13 g of hydrochloride of l l-dimethyl-3- (3-dimethylaminopropyl) -3-cyanophthalans obtained as colorless crystals with a melting point of 167 to 17O ⁰ C.

B e i s ρ i e 1 3

5-methoxyphthalane hydrochloride

According to Example 1, using the equivalent amount of l, l-Dimethy! -3- (3-dimethyl-

aminopropyl) - 3 - hydroxy - 5 - methoxyphthalane instead of 1,1 - dimethyl - 3 - (3 - dimethylaminopropyl) - 3 - hydroxyphthalan 98 g of the hydrochloride of 1,1 - dimethyl - 3 - (3 - dimethylaminopropyl) - 3 - cyano - 5 - methoxyphthalans. Melts after recrystallization from acetone the connection at 157 to 159 ° C.

Example 4

1,1-dimethyl-3- (3-aminopropyl) -3-cyanophthalan
and its hydrochloride

A solution of 8 g, l-dimethyl-S-cyanophthalan was was added dropwise with stirring to a solution of butyllithium in 40 ml of ether, consisting of 8 g of butyl bromide and lithium, at a temperature of - added 20 ^0C. The temperature was allowed to rise to -5 ° C, the mixture for 1 minute kept at this temperature, after which ^0C was cooled again to -2O. Then, the mixture was added dropwise with cooling and stirring at -2O ⁰ C to -1O ⁰ C with a solution of 5.5 g of 3-Aminopropylchlorid in 20 ml of ether. The mixture was then allowed to warm to room temperature and then poured into ice water. The ether phase was separated off, extracted with dilute hydrochloric acid and the base was precipitated from the acid solution by adding aqueous ammonia. The base obtained was taken up again in ether, the ether phase was dried over anhydrous potassium carbonate, then filtered and the ether was drawn off. By adding hydrochloric acid and recrystallizing, 7 g of 1,1-dimethyl - 3 - (3 - aminopropyl) - 3 - cyanophthalan hydrochloride were obtained which, after recrystallization from ethanol, melted at 212 to 214 ° C.

The 1,1-dimethyl-3-cyanophthalane used as starting material was prepared as follows: 16 g of 1-dimethyl-3-hydroxyphthalane were dissolved in 400 ml of glacial acetic acid. With cooling and stirring, 12.5 g of sodium cyanide dissolved in the smallest possible amount of water was added dropwise to the solution at 0 to 5 ° C, and the mixture was stirred at room temperature for 2 hours and then at 50 ° C for 2 hours. The excess of hydrogen cyanide was stripped off in vacuo, whereupon the mixture was poured into ice water. The precipitate was filtered off and recrystallized from benzene. There were 8 gl, l-dimethyl-3-cyanophthalan mp 55 to 58 ⁰ C obtained.

309 614/179

Claims (3)

Patent claims: 1. Basically substituted phthalanes of the general formula CH, CH, 3. Medicinal products containing a basic substituted phthalane or its non-toxic Acid addition salt according to claim 1 in addition to customary inert carriers. / V \ ■ Xf- II · OR ₁ Λλ / / C- (CH ₂ ) ₃ -N
CN R ₂ in which R ₁ and R ₂ denote a hydrogen atom or a methyl group and X denotes a hydrogen atom or a methoxy group, and their pharmacologically non-toxic acid addition salts. 2. Process for the preparation of compounds according to claim 1, characterized in that one in a well-known way a) a compound of the general formula CH C- (CH ₂ ) ₃ -N OH R ₂ in which R ₁ , R ₂ and X have the meaning given in claim 1, with an alkali metal cyanide in the presence of a mineral acid or an organic acid or that one b) a compound of the general formula 35 40