DE2733056A1 - VINCAMENIN AND ITS ACID ADDITIONAL SALTS, QUATERNAEREN VINCAMENINIUM SALTS AND MOLECULAR COMPOUNDS, SUCH MEDICINAL PRODUCTS AND METHOD FOR MANUFACTURING THE SAME - Google Patents

Description

Place.STEPHAN G. BESZEDES
PATENT ADVOCATE

uACIiAÜ BtI

PORI FACH I te «

ON HEIOEWEG

TELEPHONE: DACHAU 4371 Postal checking account Munich (BLZ 700 100 SO)

Account No. 1368

Bank account no. 906 370 at the district end city

aparkaas Dachau-Indersdorf (BLZ 700 SIS 40)

(VIA Bayerisch Landesbank

Girozentrale, some)

P 1 007

description

for patent application

JUDGE GEDEON VEGYESZETI GYAR RT.

Budapest, Hungary

concerning

Vincamenia and its acid addition salts, quaternary vincaminium salts and molecular compounds, medicaments containing them and methods of making the same

The invention relates to the new alkaloid vincamenine from Vinenmine type and its acid addition salts, quaternary Vincaraeninium salts and molecular compounds containing them Medicines, especially those with hemodynamic Effect, as well as a method for producing the same.

The invention is based on the object of providing superior pharmacological, especially hemodynamic, effects

709884/1 OB 7

273305b

-T-

comprising new vincamine degradation products, pharmaceuticals containing them and a method for producing the same .

It has now been found, surprisingly, that there are more degradation products of the alkaloid vincamine There are new compounds which have not yet been described in the literature and which have physiologically valuable effects.

The invention relates to vincamenine of the formula

as well as its acid addition salts, quaternary vincameninium salts and molecular compounds.

She. do not occur in nature. Vincamenine of formula I. is rather the optical antipode of the naturally occurring alkaloid Eburnamenin.

The acid addition salts of the vincaraenines according to the invention are, preferably those with inorganic acids, especially hydrogen halides. But you can also use organic ones Acids, such as 1- or polybasic carboxylic acids, noin.

709884 / 1-067

A particularly preferred acid addition compound of vincamenine is viucumenin hydrochloride. Of the fermentation addition salts with Carboxylic acids are preferred with tartaric acid and picric acid.

The vincameninium quaternary salts can, for example those with alkyl halides, in particular lower alkyl iodides with 1 to 6, especially 1 to 4, carbon atoms.

A preferred quaternary vincaminium salt is Vincaraeninium methyl iodide.

A preferred molecular compound of vincamenine is that with picrolonic acid.

Furthermore, pharmaceuticals according to the invention, which 1 or more of the compounds according to the invention as an active ingredient or Active ingredients and optionally known other therapeutically active compounds, expediently together with conventional pharmaceutical carriers and / or other pharmaceutical excipients.

The compounds according to the invention vincamenine and his Guureadditioris salts, quaternary vincameninium salts and As already mentioned, molecular compounds have valuable pharmacological, in particular office dynamic, properties.

The hemodynamic effects of vincamenine hydrochloride as well that of vincamine hydrochloride as a comparison substance was used 8 anesthetized dogs examined. The animals were given 30 mg / kg intravenously administered 5-ethyl-5- (i-methylbutyl) - -barbituric acid [anesthetized pentobarbital; the said Active ingredient according to the invention or the above-mentioned pre-equilibrium substance was then also administered intravenously at doses of 1 rag / kg. The following parameters were examined :

7098RZ, / 1 067

OR. STEPHAN G. BESZEDES PATENT ADVOCATE

3OC0 DACIiAlJ AT

POST BOX MOI

ON HEIDEWEG

TELEPHONE: DACHAU 43Tt PoitKhKkkonto Munich (BU TO0100 Μ »

Account No. 1368 Tl

Bank account No. 90β 370 at dar Krall- and Stat * ·

• parkMM Dadiwlndaradorf (BU 700ItMO)

(VIA BayarladM landasbank

Glrozantral ·. MOnchan)

August 12, 1977 P 27 33 056.9 p 1 007

Arterial blood pressure (MABP),

Pulse rate (HIi),

Internal carotid artery (CBP) blood flow,

Vascular resistance in the internal carotid artery (CVH),

Blood flow in the femoral artery (FBP) and

Vascular resistance in the femoral artery (FVH).

The values of the above parameters were taken before treatment (Baseline) and 3 »5, 10 and 15 minutes after administration of the active ingredient measured; the change in values was expressed as a percentage. In the following table 1 are the average values of 8 tests and the scatter, in each case in relation to the initial value Percentages, as well as the initial values.

9RRW1067

Tabslie

parameter

ns the parameter i scatter in

be ,. sucked on the Aus3 ans sv; e rte ! 5;
after the ¹ 5 iii = ut en 10 Minutes ¹ Ip L'ir.uten, 7-series

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on

Viscaaenlsäyüro-1 Vincamin-

^ Vl ^

j connection)

(Comparative

; r.e. ^ t Yerbir.cu ")

-'2.6 ί 4.5 + 2.4 ± 3.1 i + 5.8 ί 6.1 | +2.9 ± 2.1! 1JS ± 5.7 E = Eg

± 5.9

-3.9 ± 4.3 -10.3 ± 4.2-8.8 ± 4.4 i-9.0 ± 3.8.-6.5 -

-

-1

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7098BA / 1067

From the above Table 1 it is clear that the vincamenine hydrochloride reduces the number of pulses and approximately Has 15 to 21% vasodilator or vasodilator effect on the femoral vascular area, this being the case is better than that of the reference substance.

In the following Table 2 are the toxicity values of vincamenine hydrochloride and the comparative substance Vincamine hydrochloride compiled.

Table 2

link toxicity
Intravenous LDcQ value (confidence
on mice interval)
in
mgAg Vine amenine hydro-
chloride
(according to the invention
Link) 68.5 (63.4 to 74.0) Vine aminhydro chloride
(Comparison substance) 72.3 (65.6 to 79.9)

From Table 2 above, it can be seen that the compound according to the invention is approximately the same in terms of toxicity as the comparative substance, so that due to the superiority of the former in terms of vasodilator or vasodilatory effect on the femoral vascular area, this results in a better therapeutic index

This is followed by pages 8 to 26 of the original description of July 21, 1977

709884/1067

The effective doses of the compounds according to the invention are generally 1 to 5 mg / kg for intravenous or oral administration. This effective dose is calculated for 1 day and can be administered all at once or during the day in several equal divided doses. the In the given case, the most advantageous dosage can be based on the condition of the patient and the experience of the Be determined by the doctor.

The compounds according to the invention can be present as active ingredients together with customary solid or liquid pharmaceutical carriers and / or other pharmaceutical auxiliaries in the form of pharmaceutical preparations for parenteral or enteral administration. Examples of carriers are water, gelatin, milk sugar (lactose), starch, pectins, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil and olive oil, gum arabic, tragacanth, polyalkylene glycols and petrolatum. The pharmaceutical preparations according to the invention can be used in the usual application forms, such as in solid application form, for example as tablets, dragees, capsules, pills and suppositories, or in liquid application form, for example as oily or aqueous solutions or suspensions, emulsions, syrups, soft gelatin capsules and injectable aqueous or oily solutions are present. Such pharmaceutical preparations can also contain various pharmaceutical auxiliary substances, for example preservatives, stabilizers and flavorings.

All other known therapeutically effective compounds,

709884/1067

which, as already mentioned, are combined with the compounds according to the invention in the medicaments according to the invention can be, for example theophylline, phenylethylbarbituric acid, Phenyl barbiturate, acetylsalicylic acid and further Vitamins such as vitamin E and vitamin P, with which significant synergetic effects can be achieved, as well as vitamin C. (Ascorbic acid) and its salts and complexes, which, for example, when administered orally, the absorption of the Accelerate Vincamenines and thereby a faster entry allow the effect in question. The vincamenine according to the invention as an active ingredient can also be used in the embonate or Pamoatform, that is, in the form of a salt present with the emboxylic acid, whereby a more permanent effect can be achieved. By dioctyl sulfosuccinate respectively Lauryl sulfate salts can be used in pharmaceutical preparations according to the invention to be administered orally bitter taste of the active ingredient according to the invention be eliminated. Furthermore, the pharmaceutical preparations according to the invention can inorganic salts, for example monoammonium phosphate or a monoalkali metal phosphate, which when administered orally favor the formation of stable solutions. The active ingredient according to the invention can optionally be used also in the form of an alkyl sulfonate or 2-ketoglutarate are present.

The pharmaceutical preparations according to the invention are advantageously used in those suitable for the intended therapeutic application Dosage units produced. These drug preparations can be done in the usual way, for example by grinding, sieving, mixing, granulating, pressing or dissolving, can be prepared and, if necessary, other treatments customary in the pharmaceutical industry subjected to, for example, sterilized.

The invention also relates to a process for the preparation of the compounds according to the invention, welohes daduroh

- 10 709884/1067

is characterized as a compound of the general formula

A ~ B is a group of the formula

\ l

HO-C C HO-C C

/ V 0 H

- 11 -

709884/1067

-4i ~

ι αν / ι

\ Ι \ Ι

C or C

HO 0 H

H ₂ H ₂

represents

or a mixture of the last two is subjected to a heat treatment, whereupon the obtained Vincamenine of the formula I into an acid addition salt or quaternary vincaminium salt or a molecular compound or the acid addition salt of the vincamenine of the formula I obtained is converted into the free vincamenine base of the formula I and / or into another acid addition salt or via the former into a quaternary vincaminium salt or a molecular compound is transferred.

The heat treatment is preferably carried out at a temperature of 80 to 300 ^° C. for 0.5 to 4 hours. It is particularly preferred to carry it out at a temperature of 100 to 260 ° C. for 1 to 3 hours.

The heat treatment is preferably carried out in an inert gas atmosphere.

Thus, according to an advantageous embodiment of the process according to the invention, the compound of the formula II,

- 12 -709884/1067

in which A ^ B is a group of the formula

" ⁰

C (a), i.e. vincamine-

HO-G C II ^H 2 O

acid, heated ^{to 150 to 30O 0} C for about 0.5 to 4 hours. During this heat treatment, the vincamic acid is dehydrated and decarboxylated; these two reactions can take place simultaneously or one after the other. In this way the vincamic acid is converted into vincamenine. This reaction is advantageously carried out in an inert gas atmosphere, preferably in a nitrogen atmosphere. The reaction product obtained can then be worked up in a manner known per se. For example, the following procedure can be used: The reaction product is dissolved in a water-immiscible organic solvent, such as an ether or hydrocarbon, and the organic solution is washed with a basic aqueous solution to remove any unreacted vincamic acid. Then the organic phase is dried and evaporated. The oil that remains as a residue is vincamenine. The vincamenine obtained in this way in almost quantitative yield is so pure that practically no further purification is necessary.

In another advantageous embodiment of the invention Process becomes the compound of the formula II in which A ~ B is a group of the formula

HO-C represents C (b), that is

709884/1067 - 13 -

Apovincaminic subjected, a 0.5 to 4 Standen continuous heat treatment at 200 to 300 ⁰ C. The apovincaminic acid is decarboxylated and converted into vincamenine. In this case too, it is advantageous to carry out the heat treatment in an inert gas atmosphere, preferably in a nitrogen atmosphere. The work-up of the reaction product can be carried out in the manner described above.

According to a further advantageous embodiment of the invention Process becomes one of the two compounds of the formula II in which A ~ B is a group of the formula

₇ 0 (c) or Q (d)

Hü 'C HC

H ₂ H ₂

represents, or a mixture thereof as starting material heated to 170 to 300 ° C for about 0.5 to 4 hours. While this heat treatment, expediently carried out in an inert gas atmosphere, preferably a nitrogen atmosphere the vincanol and / or epivincanol is or are dehydrated and thus converted into vincamenine. To work up the reaction product, the crude molten reaction product obtained can with an inert organic Solvents are treated, the pure vincamenine crystallizing out of the resulting solution. As a solvent are appropriate organic liquids of the ether type, such as diethyl ether or halogenated hydrocarbons, for Example chloroform or dichloromethane is used. As a starting material In this embodiment of the method according to the invention, epivincanol can also be used instead of pure vincanol containing crude vincanol can be used, since, as already mentioned, during the heat treatment, the epivincanol in

709884/1067

Vincamenine is transferred.

It is, especially in the case of either of the two Compounds of the formula II in which A ^ v B is a group

\ i

of formula C (c) respectively

HO

^H 2

C (d) represents, or a mixture thereof,

H C

that is, vincanol or epivincanol or a mixture thereof is assumed, preferably the heat treatment to be carried out in the presence of a dehydration catalyst, which is a preferred embodiment of the process according to the invention. Aluminum oxide is preferably used as the dehydration catalyst. Becomes beneficial this in large excess, namely in about 2 to 6 times the amount, based on the weight of the vincanole and / or epivincanole used as starting material, used as the aluminum oxide present on the one hand adsorbs the by-products that contaminate the vincamenine that is formed and on the other hand, in the presence of aluminum oxide, the dehydration can be carried out at a temperature which is about 40 to 80 ° C. lower. After the reaction has ended, that can The resulting vincamenine can be separated from the aluminum oxide by extraction with an inert organic solvent.

- 15 -709884/1067

The heat treatment can, especially in the case that starting from Vincanol or Epivincanol or a mixture thereof, advantageously also in a solvent be performed. A dehydrating solvent is preferably used as the solvent. Special it is preferred to use acetic anhydride or 75 to 8% formic acid as the solvent.

Thus, according to a further preferred embodiment of the method according to the invention, the vincanol and / or Epivincanol in 3 to 12 times the amount of acetic anhydride, advantageously 0.5 to 3 hours, heated to boiling under reflux. In this way, the dehydration can be carried out at an even lower temperature. In this case, the solvent used is used to work up the reaction mixture Acetic anhydride partially evaporated, the remaining solution poured into ice water and the aqueous Mixture with a dilute solution of a base, for example with dilute sodium hydroxide solution, made weakly alkaline and with a water-immiscible inert organic solvent, advantageously a halogenated hydrocarbon, for example dichloromethane or chloroform, exhaustively extracted.

In the embodiment of the invention described above Process can be used in place of acetic anhydride also a 75 to 85%, especially 80%, Formic acid can be used. The reaction mixture can be worked up in the same way as after that in acetic anhydride performed dehydration. The oily product obtained after partial evaporation of the solvent However, in addition to the desired vincamenine, it also contains certain contaminating by-products, which is why the oily crude product in an inert organic solvent, advantageously one

- 16 -

709884/1067

Ether, for example diethyl ether, dissolved and insoluble The residue is filtered off and the pure vincamenine is isolated by evaporating the filtrate.

From the vincamenine obtained in the form of an oil you can its acid addition salts obtained by reacting with acids will. The acid addition salts of vincamenine are mostly easily identifiable crystalline substances. The salt formation will preferably carried out in a solvent, in particular an aliphatic alcohol, for example ethanol.

The conversion of the vincamenine into its quaternary Vincameniniumsalze is preferably carried out in such a way that it is in an inert organic solvent, especially an aliphatic ketone, for example acetone, with the quaternizing agent, for example the alkyl halide, is implemented. The quaternary vincameninium salts are mostly easily crystallizable compounds.

The conversion of the vincamenine into molecular compounds can be carried out in a manner known per se with suitable compounds, in particular ficrolonic acid.

The starting materials of the process according to the invention can have been prepared as follows:

That compound of the formula II in which A ~ B represents a group of the formula C (a),

HO-c σ

Il

0
that is, vincamic acid, can be obtained from vincamine by simple

- 17 709884/1067

Saponification have been produced (compare the German Offenlegungsschrift 22 53 750 and the Austrian Patent 322 118).

That compound of formula II in which A ^ B represents a group of the formula C (b),

HO-C

0 H

that is, apovincaminic acid, can be obtained from apovincaminic by saponification (compare the German patent specification 1 958 514- and the Austrian patent specification 291 446).

Those compounds of the formula II in which A ^ -B is a group of the formula

H ₁ HO.

\ l \ l

G (o) or C (d)

HO C HC

H ₂ H ₂

represents, i.e. vincanol and epivincanol, can be prepared from vincamine by reduction with lithium aluminum hydride (compare German patent specification 1 795 146 and Austrian patent specification 279 060).

The invention is explained in more detail by means of the following examples, which are not to be interpreted as limiting *

- 18 709884/1067

example 1

3 ^{g (0.01 mol) of vincamine acid were heated to its melting point (260 °} C.) in a sulfurizing flask in a nitrogen atmosphere on an oil or metal bath and the melt was kept at 240 to 260 ^° C. for 1 to 2 hours. The vincamic acid, which was heated to the melting point, immediately gave off carbon dioxide, but it was kept at the mentioned temperature of 240 to 260 ° C. for the specified period of time to complete the reaction. The formation of the vincamenine or the conversion of the vincaminic acid into vincamenine was followed by thin-layer chromatography (on a silica gel plate, mobile phase: a mixture of 100 parts by volume of chloroform and 14 parts by volume of methanol). When the spot characteristic of vincamine acid had disappeared from the chromatogram, the reaction could be considered to have ended. The residue of the melt was then dissolved in a water-immiscible solvent, for example ether, benzene or dichloroethane, and the organic solution was treated with 10% aqueous sodium hydroxide solution about twice and then once with 10% of distilled water Shaken out to remove any remaining unreacted vincamine acid. The aqueous phases were combined and extracted with half the volume of a water-immiscible organic solvent. The separated organic phase was combined with the first organic solution, dried over anhydrous sodium sulfate and filtered and the filtrate was evaporated in vacuo.

All residue was 2.70 g of vincamenine (almost quantitative Auebeute) in the form of a pale yellow oil. This oily product could only work under high vacuum at very high Temperatures are distilled.

- 19 709884/1067

Boiling point: 208 to 210 ⁰ CZiO " ⁴ mm Hg and [<yJ _D value - 180 ° (o - 1%, in chloroform).

The vincamenine picrate is an easily crystallizable compound .

Melting point: 170 to 172 ⁰ C.

Melting point of the molecular compound formed with picrolonic acid: 218 to 220 ° C.

Analysis:
For C

calculated: C - 82.37%, H - 7.83%, N - 10.07%; found: C - 82.02%, H - 7.80%, N - 9.95%.

Example 2

The procedure was as described in Example 1, but with the difference that the melt of the starting material was maintained for 3 hours at 240 to 25O ⁰ C. 2.50 g (90% of theory) of vincamenine in the form of an oil, the color of which was somewhat darker than that of the product of Example 1, were obtained.

Example 3

3.24 g (0.01 mol) of apovincamic acid were heated to their melting point in a sulfurizing flask in a nitrogen atmosphere in an oil or metal bath and the melt was kept at 250 to 260 ^° C. for 1 to 2 hours.

- 20 709884/1067

The melt obtained was then not in a water-containing state miscible solvents, for example ether, benzene or dichloroethane, dissolved and the organic solution was with 10 cnr each of an aqueous η sodium hydroxide solution about 2 times and then extracted once with 10 cnr distilled water to remove any remaining unreacted apovincamic acid. The aqueous phases were combined and with half the volume of a water-immiscible organic solvent. They severed organic Phase was combined with the first organic solution, dried over anhydrous sodium sulfate and filtered and the filtrate was evaporated in vacuo.

The residue was 2.10 g (75% of theory) of vinoamenine obtained in the form of a pale yellow oil.

Melting point of the vincamenine picrate: 172 ° C.

Example 4

The procedure described in Example 3 was followed, but with the difference that the melt of the starting material was kept at 250 to 260 ° C. for 3 hours became. 2.00 g (71.4% of theory) of vincamenine were obtained in this way.

Example 5

There were 1.48 g (0.005 mol) Vincanol in a nitrogen atmosphere for 1 hour to 220 to 25O ⁰ C heated. The melt obtained was then dissolved in ether and the solution was worked up in the manner described in Example 1. So were 1.98 g (93% of theory) vinoamenin in the form of a

- 21 709884/1067

- a.6 ~

obtained light yellow oil. The corresponding vincamen picrate had identical properties to the properties of the vincamenine picrate obtained according to Example 1.

Example 6

The procedure described in Example 5 was followed, but with the difference that the heat treatment was carried out for 3 hours. So 1.25 g (90% of theory) obtained vincamenine in the form of an oil.

Example 7

It was heated 1.48 g (0.005 mol) of crude Vincanol for 1 hour in a nitrogen atmosphere at 220 to 250 ⁰ C. The melt obtained was then dissolved in chloroform and the solution was worked up in the manner described in Example 1. 1.20 g (86% of theory) of vincamenine were thus obtained in the form of a light yellow oil. The corresponding vincamenine picrate had identical properties to the properties of the vincamenine picrate obtained according to Example 1.

Example 8

The procedure described in Example 7 was repeated, with the difference that the melt of the starting material was kept at 250 to 260 ^° C. for 3 hours. 1.25 g (90% of theory) of vincamenine were obtained in this way.

Example 9 It was made in the manner described in Example 5

- 22 709884/1067

proceeded, but with the difference that instead of the ether, bichloroethane was used as the solvent. So 1.25 g (90% of theory) were vincamenine in the form of a Obtain oil.

Example 10

1.48 g (0.005 mol) of vincanol were mixed with 5 times the amount, that is to say 4.50 g of aluminum oxide, and the mixture was kept at 185 to 200 ^° C. for 1 hour. After cooling, the reaction product was extracted with benzene, the organic solution was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness. 1.20 g (86% of theory) of vincamenine were thus obtained in the form of a light yellow oil. The corresponding vincamenine picrate had identical properties to the properties of the vincamenine picrate obtained according to Example 1.

Example 11

The procedure described in Example 10 was followed, but with the difference that instead of the 4.5 g of aluminum oxide 7.5 g of aluminum oxide were added to the 1.48 g of vincanol used as the starting material. Yield: 1 * 10 g (79 «1% of theory) vincamenine. The quality of the same was the same as that prepared according to Example 10.

Example 12

There were 1.48 g (0.005 mol) of vincanol in 7 »5 cm ^ acetic anhydride Heated to boiling under reflux for 1 hour. Then the excess of the solvent became partial

- 23 709884/1067

evaporated and the remaining solution in Biswasser poured. The pH of the aqueous mixture was adjusted to 8 to 9 with a 20% sodium hydroxide solution and the The alkaline solution thus obtained was extracted 4 times with approximately the same amount of dichlorine than each time. The United Dichloromethane extracts were freed from the remaining sodium hydroxide solution by shaking with a little water dried anhydrous sodium sulfate and evaporated in vacuo. The residue was 1.26 g (91% of theory) of crude Vincamenine obtained in the form of an oil.

Melting point of the vincamenine picrate: 170 to 172 ° C.

Example 15

The procedure described in Example 12 was repeated, with the difference that 14.8 g of acetic anhydride were used and instead of dichloromethane, it was extracted with chloroform. 1.21 g (87% of theory) of vincamenine were thus obtained in the form of an oil.

Example 14

1.48 g (0.005 mol) of vincanol were dissolved in 8 g of an 80% strength formic acid and the solution was refluxed for 1 hour. The excess acid was then evaporated off in vacuo and the residue was poured into ice water. The reaction mixture was then worked up in the manner described in Example 12. Thus 1.25 g of an oily product was obtained. This was not a uniform vincamenine, but also contained a certain amount of vinoan. When dissolving this oil in the 2-fold

- 24 -

709884/1067

Weight amount of acetone and leaving the solution in a refrigerator separated the vast majority of the vincanes in crystalline form from solution.

Example 15

1.48 g (0.005 mol) of vincanol in 80 cnr 80% formic acid for 8 hours under reflux to the Boiling heated. Otherwise, the reaction mixture was worked up in the manner described in Example 14. So were 1.20 g of a crude oily product were obtained which could be purified in the manner described.

Example 16

2.78 g (0.01 mol) of vincamenine in 9 cnr absolute Ethanol dissolved and 1 cm * of a 36.5% ethanol Hydrochloric acid added. The vincamenine hydrochloride was precipitated by dropping about 5 times the amount of ether. It was part initially in an oily form, but crystallized on standing in a refrigerator.

2.70 g (97.1% of theory) of vincamenine hydrochloride were thus obtained obtain.

Melting point: 246 to 247 ⁰ C and

^ ° - -50 ° (c - 1%, in chloroform).

Analysis:
For C ₁₀ H ₂₂ N ₂ HCl (molecular weight: 316.83)

Calculated: C - 72.1556 »H - 7.98%, N - 9.10%, Cl - 10.7%; found: C - 72.02%, H - 7, W, N - 9.83%, Cl - 11.5%.

- 25 709884/1067

Example 17

There were 1.39 g (0.005 mol) of vincamenine in 8 cnr of ethanol dissolved and mixed with the solution of 0.375 S D-tartaric acid in 2 cnr ethanol. The vincamenine tartrate separated into more oily Form out of solution. This oily product was readily soluble in water.

Example 18

0.278 g (0.001 mol) of vincamenine were dissolved in 1.0 cnr acetone and treated at room temperature with 0.5 cur (1.15 g> 0.008 mol) of methyl iodide were added. After standing for a short time, oily drops collected on the surface of the clear solution; after brief stirring, the product began to crystallize. The mixture was left to stand in a refrigerator for 1 day, after which time the crystallization was over. The crystalline product was filtered off and washed with a little acetone and dried. So there was 0.42 g of vincameninium methyl iodide (100% of theory).

Melting point: 275 ^° C

After recrystallization from ethanol, the product had the following optical rotatory power:

d ° - -155 ° (c - 1, in chloroform)

Analysis:
Pure C ₁₉ H ₂₂ N ₂ . CH ₅ J (molecular weight: 420)

calculated: C - 57.38%, H - 5.80%; found: C - 57.20%, H - 5.73%.

- 26 709884/1067

Example 19

For the production of vincamenine hydrochloride as an active ingredient containing tablets, the following ingredients were used:

Vineamenine hydrochloride 5 g gelatin 3 g Magnesium stearate 2 g Talk 5 g Potato starch 40 g Lactose 95 g

Sas vincamenine hydrochloride was mixed with the potato starch amount and with the whole amount of milk sugar and the homogeneous mixture was kneaded with an aqueous solution of gelatin, granulated and dried. The dry granules were mixed with the talc, the remaining part of the potato starch and the magnesium stearate, and 1,000 tablets of 150 mg each were pressed from this mixture. The tablets could be provided with partial notches to facilitate dosing.

Claims 709884/1067

Claims (1)

Claims 1.) Vincamenine of the formula as well as its acid addition salts, quaternary Vincameninium Salts and Molecular Compounds. 2.) Vincamenine hydrochloride. 3.) Medicines, characterized by a content of 1 or more compounds according to claim 1 or 2 as an active ingredient or active ingredients and possibly known other therapeutically effective Compounds, expediently together with customary pharmaceutical carriers and / or other pharmaceutical auxiliaries. 3-.) Process for the preparation of the compounds according to 70988Λ / 1067 ORIGINAL INSPECTED 2733QSb -α- Claim 1 or 2, characterized in that a compound of the general formula a group of the formula \ l HO-G C, HO-C C Il ** Il I 0 OH - 29 - 273306b \ l \ l C or C HO C HC Hp Ho represents or a mixture of the last two is subjected to a heat treatment, whereupon the obtained vincamenine of the formula I in an acid addition salt or quaternary vincaminium salt or transferred a molecular compound or the acid addition salt of the vincamenine obtained Formula I into the free vincamenine base of the formula I and / or into another acid addition salt or above the former into a quaternary vincaminium salt or transferred a molecular compound. 5.) The method according to claim 4 ·, characterized in that the heat treatment is carried out at a temperature of 80 to 300 ⁰ C for 0.5 to 4 hours. 6.) Process according to claim 4 or 5 »characterized in that the heat treatment is carried out at a temperature of 100 to 260 ⁰ C for 1 to 3 hours. 7.) Method according to claim 4 to 6, characterized in that - 30 709884/1067 -χ- that the heat treatment is carried out in an inert gas atmosphere. 8.) Method according to claim 4 to 7, characterized in that that the heat treatment, especially in the case that one of the two compounds of the formula II, in which A ^ B is a group of the formula H, HO \ l \ l C (c) or C (d) HO C HC H ₂ H ₂ represents, or proceeds from a mixture thereof, in the presence of a dehydration catalyst. 9.) Method according to claim 8, characterized in that that aluminum oxide is used as the dehydration catalyst used. 10.) Method according to claim 4 to 9, characterized in that that, especially in the case that one of the two compounds of the formula II, at which A ~ B is a group of the formula H HO, \ i \ l (c) or 0 (d) HO C HC HTT ρ ρ represents, or runs out of a mixture thereof, which carries out the heat treatment in a solvent. - 31 709884/1087 11.) Process according to claim 10, characterized in that the solvent used is a dehydrating agent Solvent used. 12.) Process according to claim 10 or 11, characterized in that the solvent used is acetic anhydride used. 13 ·) Process according to claim 10 or 11, characterized in that the solvent is a
75 to 85% formic acid is used. 709884/1067