DE1695781C3 - Psychotropic drug - Google Patents

Description

CH ₃ O

NCH.,

(D

HO

The invention relates to a psychotropic drug containing glaziovin or one of its Acid addition salts. The alkaloid is obtained from Ocotea species, in particular from Ocotcaglaziovii.

Both the leaves of the plant and the bark of the plant are suitable for obtaining this alkaloid Plant branches. A method for its isolation is given in J.A.C.S. 88, (1964) p. 694 ff). the Isolation takes place by cutting the leaves and / or the bark after comminuting and triturating subjected to the action of an alcohol until the active one is completely displaced alkaloid substances. The residue of the alcoholic residue obtained by concentration at low temperature Extractions are taken up with dilute acetic acid. You acidic solution becomes viscous Precipitate decanted; the principle itself is successively repeated several times with ever smaller quantities diluted acetic acid added until the complete extraction of the alkaloids is complete. This works by means of Mayer's reagent.

The combined and filtered, acidic extracts are made alkaline to a pH of? · 9 and extracted thoroughly using chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate anhydride and evaporated to a small volume. The concentrated, chloroformic solution is extracted again several times with dilute acetic acid.

The combined, acidic extracts are made alkaline and again several times with chloroform, such as indicated above, undressed. The chloroform extracts are washed with water, over anhydrous Sodium sulfate dried and evaporated to dryness under reduced pressure.

The alkaloid substance obtained in this way is purified by hot washing, whereby it is cleaned holds at boiling point for an hour with anhydrous ether. The ether suspension is cooled and filtered. The ether filter is then removed, while the residue remaining on the filter is dried is crystallized, for which purpose it is dissolved warm in a volume of methanol that is twice its own Corresponds to the weight. This process is carried out under a neutral gas.

When the methanol solution is cooled to 0 ° C., a crystalline alkaloid is obtained, which is another subsequent cleaning is subjected to the alkaloid twice in succession in one Chloroform-acetone mixture in a volume ratio of 1: 2 crystallizes. The resulting crystalline The product consists of pure glaziovine of the formula I, which has a melting point between 234 and 236 ° C (Zer.) Owns. The product is presented in the form of colorless needles, is in chloroform, methylene chloride, warm Soluble in alcohols and has a low solubility in ether, acetone and ethyl acetate.

The ultraviolet absorption spectrum of the substance obtained in this way has a characteristic maximum in alcoholic solution at 288 πιμ (log.ε = 357). The infrared absorption spectrum in a KBr tablet shows main bands at the following wavelengths: 6.0, 6.15,6.65,7.8,11.6 μ. Furthermore, Glaziovin gives a Piorat, which is obtained in a crystalline state from alcohol and which has a melting point of 199 - 203 ° C. It has been found that this has psychotropic properties, which can be demonstrated in test animals using the standardized methods, for example in rats on the basis of doses between 10 pg and 50 mg / kg by oral introduction.

Glaziovin represents the basic substance of a new class of psychotropic compounds with anti-anxiety and has an antidepressant effect and is relatively free of toxic side effects. For therapeutic Use can include the alkaloid in such pharmaceutical compositions are derived from the new, crystallized alkaloid in basic form or in the form of an addition salt with a non-toxic acid and suitable pharmaceutical binders. The on this Wise obtained compositions according to the invention can be used in suitable doses, for. B. to internal Application, are prescribed, in particular in the form of tablets, capsules, solutions or Suspensions.

The binders for such preparations can be used in solid or liquid form.

When using a solid binder, mix the pure, crystalline alkaloid with the binder, the Z. B. from tallow, mannitol, laclose, amidone, magnesium stearate, Polyvinylpyrrolidone can exist. It is granulated in the usual way and obtained in the form of Tablets, compressible powder. The tablets can for their part be enclosed in sugar as coated tablets will. In mixtures with certain of the above-mentioned binders, the alkaloid can alternatively can also be produced in the form of gelatin capsules.

As already mentioned, the free alkaloid base can be in the form of an addition salt with a non-toxic Acid can be used. For example, organic acids such as acetic acid, maleic acid, fumaric acid, Tartaric acid, citric acid, benzoic acid, methanesulfonic acid and the like with the free base and give the corresponding salts. These salts are prepared in a generally known manner.

There are among the organic salts of Glasziovins numerous, which due to their water solubility are suitable for the production of such pharmaceutical agents which can be prescribed parenterally in the form of ampoules. The adequate binder for these preparations in this case z. B. distilled water or a physiological solution.

You can continue to use the solid or liquid

Suitable preserving reagents, for example antioxidants, are also added to binders To obtain a complete preservation of the active substance included in the drug in terms of time. For example, hydroquinone can be used as such an antioxidant.

The pharmaceutical preparations according to the invention with glaziovin and its salts prove As already said above, especially in the treatment of anxiety states and psychoneuroses, especially reactive, depressive neuroses, as useful.

The following examples serve to further illustrate the present invention.

Example ' ⁵

Glaziovin base (P.5g) is mixed with lactose (460 g), amidone (550 g) and hydroquinone 2.5 g) until it is uniform distribution results. Polyvinyl pyrrolidone (87.5 g) and magnesium stearate are then added (25 g) too. Mix again and granulate the powder using the usual technique. That Granulate is pressed with a suitable pressure ram, so that tablets with a weight of 100 mg result in a dose of 10 mg of the active Contained in the substance.

The tablets are then placed in a basin with sugar syrup by applying the usual Technique encased, so that dragees with a weight of 200 mg result.

Extraction of glaziovin

Dry, ground leaves of Octoea glaziovii (78 kg) are extracted with cold alcohol until the Alcohol gives a negative Mayer reaction to the alkaloids.

The combined alcoholic extracts are in vacuo at a maximum temperature of 45 ° C to concentrated to a liquid-syrupy consistency.

The residue (15 l) is diluted with 10% acetic acid solution. The aqueous acidic phase is of the precipitating, gummy precipitate decanted; the latter is diluted with warm alcohol (1 L); then 5% aqueous acetic acid solution (10 l) is added. This operation is repeated - im generally four times - until a negative Mayer reaction occurs.

The combined acidic extracts (about 65 liters) are then made light by the addition of concentrated ammonia made alkaline (pH = 8.5). A precipitate forms, which is separated off by centrifugation. The precipitate is stirred with chloroform (15 L) for one night.

The suspension is centrifuged and the residue is dissolved in warm alcohol (1 l), whereupon it is taken up in chloroform (5 l). The chloroform phase is combined with the main phase, while the chloroform treatment is repeated on the new Precipitat until a negative Mayer reaction occurs (on the residue). The combined chloroform extracts are washed while stirring them twice with water. They are then dried over sodium sulfate anhydride and evaporated to a small volume (3.5 l) ^{in vacuo at a temperature of at most 45 ° C.}

The concentrate becomes more negative several times with a dilute, 10% strength aqueous acetic acid solution Mayer reaction extracted. The combined new, acetic acid extracts are removed by means of aqueous ammonia

20 sodium solution made alkaline; then they are extracted with chloroform (3 χ 1.3 l).

The pooled chloroformic extracts are washed three times with water, over dry Sodium sulfate dried and evaporated dry in vacuo at a temperature of 45 ° C maximum.

The residue consisting of alkaloid material (about 600 g) is then left to boil for one hour under reflux conditions with ether (2.1 l). It is then cooled and filtered. The new residue (about 300 g) is ^{heated to 50 °} C. for a quarter of an hour while stirring with methanol. The operation takes place under nitrogen atmosphere. It is cooled again in the ice and nitrated. In this way, raw galziovine (about 200 g) is obtained, which is further purified for the purpose of increased purity by mixing it twice from a mixture of chloroform with acetone in a ratio of 1: 2 crystallized out Once again, the operation takes place under a nitrogen atmosphere.

The pure glaziovin (approx. 160 g) obtained in this way is in the form of colorless needles with a melting point (dec.) Between approx. 234 and 236 ° C. Chromatography on a thin layer shows the substance to be homogeneous. The analysis shows the following result:
Calculated for Ci ₈ H 14NO3:

C-72.7, H-6.4, N-4.7, OCH ₃ -10.4

Found:

C-72.5, H-6.5, N-4.9, OCH ₃ -10.5.

The ultraviolet spectrum of the glaziovin obtained in ethanol shows a maximum at 288 Γημ (log. ε = 3.57).

The infrared spectrum of glaziovin in chloroform solution shows main bands at the following wavelengths: 6,0,6,15,6,65,7,8,11,6 µ.

Comparison of the pharmacological effectiveness of
Glaziovin with diazepam.

Clinical test

Glaziovin was administered to 70 test subjects who were divided into the following 3 groups according to their symptoms became:

1. Psychoneuroses with dominant

anxious component 30 cases

2. Depressive, phobic and general
- ₍₎ disturbed psychoneuroses

with an anxious component 30 cases

3. Neurasthenic forms, arterioclerotic

Table syndromes with anxiety 10 cases

a total of 70 cases

55 The evaluation of the results was carried out according to an arbitrarily chosen point system from 0 to 3 for the following results. This agreed with the most widely used criterion on the

bo area of this type of experimental study (Cattaneo and KoIl., 1964), so that comparative comparisons with those of others Authors obtained data were possible. For the purpose of statistical evaluation (Beccari and

b ^r ) ia η ch i, 1960) were rated as “none” 0 (no effect) and 1 (weak effect), and “positive”, the results labeled 2 (good effect) and 3 (best effect).

The distribution of points was based solely on the anti-anxiety effect that the drug exerts. Therapeutic modifications for secondary symptoms (malaise, depression, phobic symptoms, etc.) were not taken into account because this, even if one had only rated these symptoms as low, would have resulted in an incorrect overall assessment of the therapeutic result (B e c c a r i, 1961).

The following table summarizes the results obtained together:

Tabel

group Test- positive % Positive negative % Negative cases (2 + 3) (0 + 1) 1 30th 23 77 7th 23 2 30th 18th 60 12th 40 3 10 7th 70 3 30th

total

70 48

68.6%

22nd

31.4%

Toxicity from Glaziovm:

LD50 in rats, oral 530 mg / kg
LD »in rats, intravenously 80 mg / kg

Regarding the effectiveness of diazepam, data on the anxiolytic effect have been published in the literature taken and statistically evaluated so that the following results match those in the table above are comparable.

Total number
of the test subjects

positive
(3 + 2)

% Positive

Negative% Negative (0 + 1)

280

174

106

38

Compared to diazepam, in addition to the 21) increased anxiolytic effect, Glaziovin has the advantage that it does not have any debilitating or hypnogenic effect.

Claims (1)

Claim: Psychotropic drug containing glaziovin or one of its acid addition salts. The invention relates to a psychotropic drug which glaziovin as a therapeutically effective component contains. This alkaloid has, as has since been found, the following formula (I)