DE1940192C3 - Reserpine derivatives, processes for their manufacture and pharmaceutical preparations - Google Patents

Description

transferred or with gaseous ammonia in the presence of Raney nickel in absolute alcohol at a temperature of about 10O ° C below one Pressure of 120 atmospheres hydrogenated to Reserpüvl-propylamine or with absolute ethanol in Presence of gaseous hydrogen chloride and subsequent reaction of the imino ester with Ammonia converted into reserpine-1-piropionamidine.

3. Pharmaceutical preparations consisting of the reserpine derivatives according to claim 1 or their non-toxic salts and common auxiliaries and carriers.

Alkaloids of the indole type are already known, especially from the reserpine series, which have antihypertensive properties. This is Compounds with an amine substituent which can be in different positions of the reserpine nucleus. Take this as an example of such a connection 11-Whore thy laminodeserpidine, which is in the FR-PS 12 38 752 is described, mentioned. Furthermore, derivatives with a dialkylaminoalkyl radical in Position 1 of the yohimbane and yohimbine known in the FR-PS 102 M and the FR-PS 360M are described. The latter compounds are produced quite generally by a condensation obtained, which takes place on the indole nitrogen with the corresponding dialkylaminoalkyl halide.

It has now been found that certain novel derivatives of reserpine, the indole nitrogen one possess certain functional chains, possess remarkable pharmacological properties. Here the particular advantage is that they have the retain beneficial effects of the parent alkaloid, such as B. the antihypertensive effect in the case of the Reserpine, but without secondary side effects, for example sedative or depressive, on the central nervous system exercise. Quite generally leaves say that the compounds according to the invention have a significantly lower toxicity than the starting alkaloid.

The invention therefore relates to Re £ «-jpine derivatives general formula

^CH3 °

OCH ₃

Ο-0C- </ -OCH ₃

OCH ₃ OCH ₃

in the

R for 2-cyanoethyl, S-oximinoO-aminopropyl, 3-aminopropyl or 2-carbamidino-ethyl radical, and their non-toxic salts.

The invention also relates to processes for the preparation of the new compounds.

The first process stage consists of cyanoethylation of the starting alkaloid reserpine, i. H. in a Reaction of this alkaloid with acrylonitrile in the presence of benzyltrimethylammonium hydroxide as a catalyst in an inert organic solvent. Reserpine-1-propionitrile is obtained in this way.

The propionamide oxime compound according to the invention is in a second process stage by action obtained from hydroxylamine to the propionitrile produced in the first stage.

Through a gentle hydrogenation of the propionitrile from comers, in which the alkaloid skeleton is preserved remains, the derivative of 1-propylamine according to the invention is obtained. This hydrogenation is carried out in the Way carried out that gaseous ammonia in the presence of Raney nickel in absolute alcohol in an autoclave at a constant temperature of about 100 ° C and under a pressure of about 120 Atmospheres is brought into action.

ι I

CH, = CH-CN

On the other hand, the propionitrile derivative can also used as starting substance for the preparation of the propionamidine compound according to the invention be done by first reacting with anhydrous ethanol in the presence of gaseous Hydrogen chloride, the imino ester, is formed by reaction with gaseous ammonia Amidine supplies

The following scheme shows the various ίο stages of the aforementioned synthesis, with from Reserpine only the indole nitrogen is shown in position 1:

N CH ₂

C-NH ₂ \ NOH

C ₂ H ₅ OH HCl gaseous

CH ₂ CH ₂ C

CH ₂

CH ₂

CH ₂

NH ₂

HN

CH ₂

CH ₂ C-NH ₂

The following examples are intended to illustrate the process according to the invention.

example 1 Reserpine-1 propionitrile

18.2 g (0.03 mol) of reserpine are suspended in 250 ml of anhydrous benzene, after which 200 ml of acrylonitrile are added. The reaction takes place in a glass container with mechanical stirring and cooling. After the temperature of the reaction medium has risen to 40 ° C., 1.5 ml of a 40% strength methanolic solution of benzyltrimethyl-6 :; ammonium hydroxide added. The reaction begins quickly, resulting in a complete dissolution of the suspension and then a precipitation of a high molOC ₂ H ₅

-molecular product is connected The reaction is continued for 45 minutes at 6O ⁰ C

After the solution has been concentrated to dryness, aas high molecular weight nitrile is separated off by extraction with benzene on a reflux condenser

The crude nitrile is obtained by concentrating the benzene solution.

The nitrile is purified by crystallization from methanol. Melting point - 230 ° C (K o f 1 e r); Yield: 80%.

Analysis for C ₃ SH ₄₃ N ₃ O ₉ ; Molecular weight 661.72:

Calculated: C 6533, H 6.54, N 635, O 21.76%; Found: C 65.51, H 635, N 6.25, O 21.59%.

The infrared spectrum: A characteristic gang of the group

-C = N at 2260 cm- '.

Example 2 Reserpine-1 propionamide oxime

6.6 g (O ₁ Ol mol) of reserpine-1-propionitrile are suspended in 200 ml of ethyl alcohol at 95.degree. This is done in a glass container with mechanical stirring and cooling.

The theoretical amount of hydroxylamine hydrochloride (3.5 g) is added in 5 portions to the suspension of the nitrile; the hydroxylamine is released by adding a _{solution saturated with Na 2} CO _3. The pH of the reaction medium should not exceed 7. The mixture is left to stand at a temperature of <50 ° C. for 15 hours.

By concentrating the reaction solution the amidoxime obtained in the raw state. The mineral salts are removed by extraction that Amidoxime crystallizes from methanol.

Uncolored crystals:

Melting point = 165 ° C (suitcase). Yield: 65%.

Analysis for C ₃₆ H ₁₁₆ N ₄ OiO; Molecular weight 694.75:

Calculated: C 62 ^ 3, H 6.67, N 8.06, O 23.03%; Found: C 62.18, H 6.78, N 7.91, 022.94%.

Infrared spectrum: = N - OH. 3460 cm - '

N-H ... H

-CsN

13360 cm- '

13180 cm- ¹

1660 cm- '

Example 3 Reserpine-1-propylamine

10 g of reserpine-1-propionitrile, 200 ml of absolute alcohol, 2.6 g of gaseous ammonia and 5 g of Raney nickel are brought together in an autoclave. The reduction is carried out at 130 ^° C. under 120 atmospheres for more than 6 hours

After the catalyst has been separated off, the amine formed is used as crystallized dichlorohydride in isopropanol isolated Melting point = 241 ° C (K o f 1 e r); Yield: 95%.

Analysis for C ₃₄ H ₄₉ N ₃ O ₉ · 2 HC>; Molecular weight 738.68:

Calculated:

C 58.53, H 6.68, N 5.69, O 19.49, Cl 9.60%;

found:

C 5837, H 6.75, N 5.51, O 1930, Cl 9.19%.

Example 4 Reserpine-1-propionamidine

a) Manufacture of Reserpine-1 - (imino-ethyl propionate)

About 1/200 moles (33 g) of reserpine-1-propionitrile are placed in a 250 ml flask equipped with a magnetic stirrer, condenser and downwardly directed tube through which gaseous HCl can be introduced , 8OmI of absolute ethanol and 80 ml of anhydrous benzene entered. After dissolution, the mixture is brought to a temperature between 0 and 5 ° C. and gaseous HCl is allowed to pass through for 7Ui hours! Jn. The whole is left to stand on ice for 48 hours.

b) Preparation of reserpine-1-propionamidine

The iminoester obtained is with 60 ml absolute Ethanol added and for 30 minutes at normal temperature in a stream of ammonia. Thereafter, the whole thing is 30 minutes under the Bring the reflux condenser and concentrate to dryness. The amidine hydrochloride is crystallized from isopropanol

Melting point (Kofier): A pasty melting point starts between 245 and 250 ° C.

Analysis for dihydrochloride C ₃₆ H ₄₈ N ₄ O ₉ Cl ₂ ; Molecular weight 751.68:

Calculated:

C 57 _r 52, H 6.44, N 7.45, O 19.16, Cl 9.43%;

found:

C 5737, H 6.58, N 7.57, 019.19, Cl 930%.

, ₀ Pharmacological consideration

The pharmacological properties of the substances according to the invention were tested on the basis of the following investigations. In particular, it was tested the effect of the substances according to the invention on the central nervous system, as well as the antihypertensive and the cardiovascular effect of these substances was investigated. The substances according to Examples 1, 2 and 3 are based

I - Behavioral examinations and approximate determination of the lethal dose-50

The substances according to the invention are each made up of groups of animals consisting of 3 mice either orally or administered intravenously in doses, each in geometric series by a value of 2 or 3 change (5,10,30,60,100 mg / kg body weight).

The results obtained here show that the three After intravenous administration investigated substances according to Examples 1, 2 and 3 less toxic are than reserpine, the DL-50 value of which is about 25 mg / kg when administered intravenously to a mouse Administration of the compounds according to Examples 1 and 2 do not lead to doses of 100 and 60 mg / kg to the death of the mice.

When the substance from Example 3 is intravenously administered to a mouse, the DL-50 value is approximately at 80 mg / kg. With all three substances, administration of high doses (30-60 mg / kg) notice clear symptoms, as with reserpine

so even with doses in the order of magnitude χρπ 2 mg / kg occur, namely ptosis, decrease in spontaneous responsiveness, decreased responsiveness '' Feeling of touch, tremors, passivity, reduced grip, need for sleep, breathing difficulties, '' intestinal

55, emptying, fetal position.

Furthermore, the substance according to Example 1 was also administered orally and then its effect with the des Reserpine compared. The symptoms observed occur only in doses that are at least ten times as high make up the reserpine dose, which is, however, more toxic (DL-50.80 mg / kg orally).

II - experiments /. For general investigation of the central nervous system

The attempt? are without exception to groups of performed 10 male mice each and the injected doses each represent more or less strong fractions of the DL-50 value.

The results are given in percentages, either based on the animals and their response as a function of time, or related to the gain or decrease of a certain Effect, or in some cases also on the basis of another arbitrarily chosen scale.

The following experiments were carried out:

1) The so-called "Kota-rod" test with the rotating axis:

According to Tripod J. and co-workers.

Arch. Int. Pharmacodyn. 112, 319 (1957).

2) Chimney test:

After Bo issicr |. R. and co-workers. Medicina Exp, 3. No. 1.81 (1960).

3) Train csl:

According to C υ U r ν υ i s i e r S. j ..

Clin. Exper. Psychopaihol .. 17.25-37 (1956).

In these three tests nos. 1-3, the following results were obtained:

After the so-called Rota-rod and the chimney test, the substances according to Examples 2 and 3 only effective at very high doses (40 and 30 mg / kg), while at lower doses for the substances according to Examples 1 and 2 no results whatsoever can be obtained. The tensile test was negative for all three substances.

In contrast, the reserpine was after these three Tests very effective even in low doses.

4) Strengthening of barbituric acid anesthesia

The barbituric acid (phenthiobarbital) is 20 minutes injected intraperitoneally at a dose of 40 mg / kg according to the tested substance. It will be the Sleep duration determined, the criterion for sleep being the loss of the return reflex. the Results are given as the percentage of animals asleep over time.

The substance according to Example 3, which is practical at a dose of 15 mg / kg when administered intravenously is ineffective, causes a significant increase in penthiobarbital anesthesia when administered intravenously Dose of 30 mg / kg. The substances according to Examples 1 and 2 show when administered intravenously no effect at doses of 10 or 40 mg / kg.

In contrast, reserpine already has a very strong effect at a dose of 2.5 mg / kg.

5) Reinforcement of the chloral anesthesia

In order to investigate this question, the procedure described by L Buch el and co-workers (TMrapie, XVlI, 1053-1094 [1962]). The chloral hydrate is groups of 10 Mice administered intraperitoneally at a dose of 325 mg / kg 20 minutes after they received the Test substance was administered intravenously.

The chloral anesthesia is administered intravenously by the substances according to Examples 2 and 3 Doses of 40 and 30 mg / kg are significantly increased. The effect of the substance according to Example 1 is at hardly noticeable at a dose of 10 mg / kg.

6) Antagonism in terms of effects
of pentetrazole

20 minutes after administration of the investigated product, pentetrazole is administered intravenously with one dose administered, which is approximately in the range of the DL-100 value (60 mg / kg). Phenomena of tremors, crises and deaths are determined proportionally, None of the three substances examined counteracts the effects of pentetrazole.

7) Activity observation through actography

This procedure consists in drawing

ι ·> is how often an animal faces two perpendicular rays of light len passes through. For this purpose, groups of two mice each are placed in so-called activity cages from Tyr L) EWS (mil into it piiuiOclckiiisCiicn AkiiiTicicr APC

LAB) are used after the examined substances have been administered intravenously.

The activity of the animals is in each case after 5 or after

Measured 20 minutes. The results are given in percentages and relate to the increase or the reduction in activity towards the dei

J-. Activity of comparison animals.

The substances according to Examples 2 and 3 have au]

the activity measured by actography has no effect, while reserpine has already been shown to be a dose of 1 mg / kg administered intraperitoneally

in quite considerably decreases.

8) Enhancing the toxicity of yohimbine

This attempt was made by Q u i η t ο η R. M. in Brit. J

π Pharmacol. 21, 51-66. The toxicity of the Yohimbins is only by the substance according to Example 1 at an orally administered dose of 100 mg / kg increased (40% mortality).

9) Antagonistic effects to strychnine, which occurs by way of slow perfusion
was administered

The substances to be examined were

Given before slow perfusion. the Perfusion itself took place at a rate of 0.1 ml / min with the aid of a BRAUN pump with a 50 ml syringe to which a very fine catheter was attached, at the end of which there was another fine needle that was inserted into the tail tendon of the mouse. The concentration of so through Perfusion administered strychnine was 0.075 mg / mL There were two consecutive time periods established, namely the period of time that was required to reach the tonic crisis arrive, and the rest of the time until the onset of death. Starting from these points in time taking into account body weight each; Tieres those doses in milligrams per kilogram calculated, in which on the one hand the symptoms of intoxication (tonic crisis) and on the other hand death occur. The substance according to Example 3 was administered in two different doses, namely by way of an intraperitoneal administration of 30 or 60 mg / kg 30 minutes before the perfusion. Even with the The strongest dose was compared with the normal reference or comparison animals neither with regard to the the dose that caused the tonic crisis is still looking

borrowed any significant differences in the lethal dose. On the contrary, when 30 mg / kg were administered, a significant difference (for P <0.01) with regard to the lethal dose was noticeable, which is higher in the treated animals than in the untreated comparison animals; from this you could possibly get a certain amount of. slight protective effect against the toxicity of strychnine.

After administration of the substance from Example 2 at a dose of 40 mg / kg 30 minutes before the perfusion was carried out, it was found that the onset of the tonic crisis occurred later, even at a higher dose than in the corresponding predatory animals (essential difference for 0.05 >P> 0.01).

However, no differences were found in those doses at which death occurred.

In summary it can be said, therefore, that when taken into ^r .kh! FINISH of the DL 50 value in intravenous administration of the substances according to the invention are much less toxic than the reserpine, the depressive effect of these substances is less than that of reserpine as far as are the 1-propionitrile and 1-propylamine derivatives, and that it is even very much lower in the case of the 1-propionamidoxime derivative.

III - antihypertensive effect

in rats with increased blood pressure

as a result of abnormal kidney function

In order to induce an increase in blood pressure in rats, the method of Page E. W. et al. Employees (Am. J. Obstetr. Gynecol. 41, 53 [1941]) proceeded in which collodion caused a kidney inflammation caused.

To investigate the antihypertensive effect of the substances to be tested, two different Experimental ways proceeded by

a) either a weaker dose was administered every day for several days and then the changes in arterial pressure were measured over the course of time, or by

b) only a single dose was administered and then the changes in arterial pressure over the course of the period the 24 or 48 hours following the injection.

In the first procedure (a) the investigations were based on the substance according to Example 1, which was administered in the form of a 3% solution in ascorbic acid ir. Physiological solution to 6 rats -, -, with increased blood pressure; the administration was carried out intraperitoneally for a period of 13 days, and a daily dose of 1 mg / kg, and then the treatment was interrupted to the blood pressure rise again to _b o blank.

For comparison, 6 rats with elevated blood pressure were given reserpine under the same conditions administered intraperitoneally at a dose of 1 mg / kg during these 13 days a significant reduction in the arterial blood pressure (-25% at medium pressure and -16.5% at maximum pressure compared to the Comparison animals with high blood pressure) occurred in the group of animals exposed to the substance were treated according to Example 1 with a daily, intraperitoneally administered dose of 1 mg / kg. A less significant reduction was found in the group of animals that were treated with reserpine in was treated with the same dosage (mean pressure: -16.5% on day 11, -11% on day 13; maximum Pressure: - 14% on the 2nd day, - 11.5% on the 13th day).

After discontinuing the treatment, the blood pressure values went up to the 45th day after the start of the experiment

η back to their original values The substance according to Example 1 thus appears to be somewhat more active than reserpine, as far as this is possible lets close these quite intensive experiments.

In the second procedure (b) the

. '(ι antihypertensive effect of the substances according to Examples I ₁ 2 and 3 investigated in such a way that they were each administered intraperitoneally in a dose which is equal to one 20th of the DL-50 value (intraperitoneally) in rats:

Substance according to Example 1 ^ = - »37 mg / kg

Substance according to example 2 ^ = 20 mg / kg

Substance according to example 3

and this administration also after 3 days interrupted.

The results of the tests carried out with the substance according to Example 1 make it clear that in the

3 mg / kg

The active ingredients were either in suspension (substance 1) or in solution (2 and 3) in a 9% physiological saline solution.

The reserpine used as a comparison substance was administered in a dose that was essentially 2.5 mg / kg (= 1/20 of the LD-50 value in rats.), With administration intraperitoneally took place. Changes in blood pressure caused by these substances were compared with those which can occur spontaneously in comparison rats with increased blood pressure, which a 9% Saline was administered intraperitoneally.

The mean (or diastolic) and highest (or systolic) pressures were 1, 3, 5, 24, 30, and 48 hours measured after administration of the substances. The study was carried out on 7 rats for the comparison substance and substance 2 and on 5 rats for substances 1 and 3 and reserpine. Based on what was done on the individual rats of the different groups at the different times Measurements will be the mean or highest blood pressure changes up or down given below in comparison to the initial pressure values which were taken before the administration of the substances had been determined. It then takes an algebraic sum of the changes in the arterial Blood pressure is formed and the mean value calculated for the individual groups over the course of time for the The results obtained with the individual substances are compared with those obtained with reference animals were in those after the srudent test one high blood pressure has been detected.

The general results obtained in this way are shown in Tables I and II below.

12th

Table I.

Antihypertensive effect of reserpine and the substances according to Examples 1, 2 and 3: Changes in the mean blood pressure

Time after
administration Hypertonic
Control series
Jim *) in
cm Hg Reserpine
2.5 mg / kg IP
Jim in DW **)
cm Hg IF. Substance after
example 1
37 mg / kg IP
Jim in DW
cm Hg IF. Substance after
Example 2
20 mg / kg IP
Jim in DW
cm Hg substance
Example 3
3 mg / kg I
Jim in
cm Hg after
IP
DW I hour -0.04 -1.2 / J = 0.05 -1..6 / j = 0.05 -2.1 ρ = 0.05 +0.1 IF. 3 hours -0.3 -2.1 /) = 0.05 -2.1 ρ = 0.02 -3.4 / i = 0.001 -1.1 IF. 5 hours -0.07 -3.1 IF. -3.3 ρ -0.001 -1.8 O.B. -2.4 IF. 24 hours -1.2 -2.2 / J = O ₁ ol -5.9 ρ = 0.01 -3.3 ρ = 0.05 -3.2 P = 0.05 30 hours -0.37 -3.1 IF -4.3 _n = Q QQ J -3.1 / »= 0.05 -2.8 IF. '!?, Hours —0 ^Λ Α _2 -Λ Ο -2 /; = 0.0! -0.6 IF.

*) Jim = mean pressure changes in cm of mercury. **) D.W. = Difference value in comparison with the comparison animals. IF. = Without meaning.

Table II
Antihypertensive effects of the
at maximum pressure -0.08
-0.42 Reserpins and the Substances according to the IF
/ 7 = 0.02 Examples 1, 2 and 3: changes after
I.
[P
DW if
ί
I. Time after hypertonic
Administration of control series
JIM *) in
cm Hg -0.41 Reserpine
2.5 mg / kg IP
JIM in DW ··!
cm Hg Substance after
example 1
37 mg / kg IP
JIM in DW
cm Hg / j = 0.01 Substance after
Example 2
20 mg / kg IP
JIM in DW
cm Hg substance
Example J
3 mg / kg I
JIM in
cm Hg IF
IF j I hour
3 hours -1.1
-0.40 -1.8 OB
-2.4 / 7 = 0.05 -1.4
-2.8 / J-0.01
p = 0.01 -2 OB
-3.6 / J = O ₁ OOl "0.1
-0.7 / j = 0.05 ν. 5 hours -0.45 -3.7 / j = 0.01 -3.8 / J = O ₁ OOl -2.1 O.B. -2.8 C B.
P = 0.05 24 hours
30 hours -2 OB
-4.1 / j = 0.001 -6.4
-4yy -3.5 / J = 0.05
-3.4 / j = 0.01 -3.1
-2.8 IF. % 48 hours -2.6 "= 0.01 -5.5 -2 / j = 0.02 -0.6 I.
%
U *) J1M =
**) DW =
OB = Changes in the maximum pressure in cm of mercury.
Difference value compared to the comparison animals.
Without meaning.

The following is to be said about these results:
1) Speed of action

Of the 4 substances examined, only substance 2 shows a rapid onset the effect, since the drop in mean blood pressure is already a value 1 hour after administration of 2.1 cm Hg (P = 0.05) is achieved. The effects of reserpine and substance 1 are only reproduced The lapse of 3 hours is clearly noticeable. In comparison, substance 3 only becomes 3 after 5 or 24 hours clearly effective.

2) Duration of action

These substances have a relatively long duration of action. The degradation of the medium or maximum pressure is produced even after 48 hours with reserpine and with the Substances ί and 2 noticeable. In contrast, the

-, η duration of action of substance 3 is somewhat shorter because of this nothing can be seen after just 24 hours.

3) Kinetics and intensity of the effect

In terms of the intensity of the effects -, -, substance No. 1 is apparently the most active, since between this substance and the three other administered substances after 24 hours Let differences of effect be determined.

It should also be noted that substance 2

«J has a two-phase effect curve: it comes namely initially to a rapid drop in blood pressure, which, however, rises again after 5 hours, and then after 24 hours hypotension sets in, which is somewhat similar to the first phase, however

_b -, lasts much longer than this (this phenomenon has been found several times, so that a double mechanism of action can undoubtedly be assumed here).

IV - Cardiovascular Action
in an anesthetized dog with normal pressure

Dogs are given intravenous administration of chloral at a dose of 100 mg / kg body weight anesthetized. As soon as the animals show signs of awakening in the course of the state of anesthesia indicated, they were also given an appropriate dose of pentobarbital intravenously, to get her back to sleep

The so-called SANBORN physiograph is used to measure the arterial blood flow through the femoral artery and the kidney volume recorded, with one connected to a pressure gauge in the artery Cannula was inserted. The heart rhythm is determined from the beginning of the recording of the electrocardiogram counted on.

The following reactions in particular are determined:

Injection of adrenaline 5) »/ kg
Injection of serotonin 20 y / kg

These experiments are repeated after an intravenous injection of the substance to be examined performed. In turn, the reactions are determined which led to the administration of the substance can follow.

In this way, the effect of the substance according to Example 2 on the Coronary arteries examined in the dog Ivi repeated administration of the substance according to Example 2 in doses of 5 mg / kg or 10 mg / kg the The following results were obtained: With regard to the rhythm of the heart's activity, none were found to be significant Changes found, neither in thigh throughput and kidney volume. The resulting reactions in relation to the pressure of the eyeballs (oculo-cardiac reflex) Stimulation of the peripheral X and upon injection of

Treatment with the substance according to Example 2 unchanged.

If the injections of this substance were repeated, however, in the course of the Time a clear progressive decrease in arterial pressure can be observed:

Arterial pressure
before the injection

number of
Injections

Arterial pressure
after the injections

Dog No. I:
Dog No. II:
Dog no. Ill:

11.6 cm Hg
15.4 cm Hg
14.4 cm Hg

2X5mg / kg
3X5 mg / kg
x 10 mg / kg

9 cm Hg 1 hour
after the first injection

13.5 cm Hg 2 hours
after the first injection

11 cm Hg 2 hours
after the first injection

These results can be considered quite remarkable, given that it is typically a dog's blood pressure under the test conditions given here, remains very stable over the course of several hours, unless it is is somehow stimulated and given the injections as set out above described test conditions are provided.

The increase in blood pressure caused by a blockage of the carotid artery or by stimulation of the central X. is only very weak or not noticeable at all; from this one would conclude, that the antihypertensive effect of the substance according to Example 2 is caused by a central mechanism is.

The following conclusions can be drawn from the experiments described above:

The three investigated derivatives are clearly less toxic than the reserpine, whereby the substance according to example 2 is the most interesting on this point.

The psychotropic effect is compared to that of reserpine much weaker or ever after the administered doses even NuIL with regard to a decrease in the psychotropic effect can classify the three substances roughly as follows: substance according to example 1> substance according to example 3 > Substance according to example 2.

The antihypertensive effect of the three substances is less intense than that of reserpine and takes apparently in the following order: substance laughs

Example 1> Substance according to Example 3> Substance according to Example 2.

However, there still remains a marked effect at low, non-depressive doses, especially as far as the substance of Example 2 is concerned, which is of particular importance here, as it is with it there is sufficient antihypertensive effect, but no longer any psychotropic effect makes noticeable.

The substance according to Example 2 has a marked hypotensive effect, however, in a anesthetized dog is slow to restore normal blood pressure.

With regard to the mechanism of action of the substances according to the invention, the hypothesis establish that this is due to a blockage in the release of adrenaline in the recipients or Occurs as a result of a ganglion blockage or possibly also due to a central blockage How namely, has already been indicated above, some central reflexes are either weakened or entirely off By this hypothesis, however, the scope of the invention is in no way intended to be in any way be restricted.

V - cardiovascular effect
in anesthetized rats with normal blood pressure

There were male rats from the breed CD Charles River with a mean body weight of 500 g by intraperitoneal administration of urine

than in a dose of 1.25 g / kg body weight anesthetized Then a cannula was inserted into the penile vein to administer the substances to be examined A physiological saline solution mixed with heparin was introduced into the carotid artery filled catheter inserted and one double with the mercury collector of the pressure chain connected to recording RACIA polygraphs. The electrocardiogram was in lead D2 recorded Heparin was administered intravenously to the animals in order to avoid any risk of coagulation Turn off the carotid artery.

In the 40th minute of the experiment, a first injection was made with the substance according to Example 2 performed. The results were found in 9 animals treated with the substance according to Example 2 intravenous administration of a dose of 10 mg / kg.

At the same time, for comparison purposes and under the same conditions, the effect of reserpine was shown intravenous administration of the same at a dose of 2 mg / kg on blood pressure and heart rhythm of 5 rats examined

Results
1 - effect on arterial blood pressure

After the first injection you can see that the Reserpine caused a significant increase in blood pressure over time, which in the 105th minute after the injection accounts for -30%; when the substance according to example 2 is administered, the result achieved with it is achieved Hypotension less noticeable; it reaches -20% in the 30th minute and then increases again slightly

to finally stabilize at a level which is a little below normal

2 - effect on the heart rhythm

Neither the reserpine nor the substance according to the invention have a clearly noticeable effect of the heart rhythm after the first or the second injection.

3 - Modification of the pressure-influencing

Effects of adrenaline (5 y / kg)

and of noradrenaline (5 y / kg) after injection

of the substances

Reserpine increases the effect of adrenaline and noradrenaline, especially with regard to the hypertensive tip.

After injection of the substance according to Example 2, both the peak and the duration of the Adrenaline achieved hypertension increased significantly

The effects of noradrenaline remain after the

first injection is still unchanged and only after the second injection does the hypertensive peak a slight increase is noticeable.

It is thus in the anesthetized rats with normal blood pressure for the compound each Example 2 determine the following:

A definite and long-lasting hypotensive effect.

An intensification of the hypertensive effects of adrenaline, as also observed with reserpine
Slight change in the effect of noradrenaline.

909 616/41

Claims (2)

Claims: 1. Reserpine derivatives of the general formula CH ₃ O O-OC- \ J- OCH ₃ OCH ₃ in the R for 2-cyanoethyl, S-oximino-S-aminopropyl, 3-aminopropyl or 2-carbamidino-ethyl radical, and their non-toxic salts. 2. A process for the preparation of reserpine derivatives according to claim 1, characterized in that reserpine in an inert solvent and in the presence of benzyltrimethylammoni- Umhydroxyd reacts as a catalyst with acrylonitrile and optionally then the resulting Reserpine-1-propionitrile either by treatment with hydroxylamine in reserpine-1-propionamidoxime OCH ₃