DE2733056C2 - Vincamenine and its acid addition salts, medicaments containing them and processes for the preparation of the compounds mentioned - Google Patents

Description

(H)

wherein

A ~ a group of formulas

HO

\ l c

HO-C C

HO-C C

Il I ο η

b HO

HO C HC

H ₂ H ₂

^or

represents

or a mixture of the latter two is ^{heated to a temperature of 80 to 300 0} C, optionally in the presence of a dehydritation catalyst and optionally then the vincamenine obtained of the formula I is converted into an acid addition salt or an acid addition salt obtained from vincamenine is converted into the free base and / or into another Acid addition salt transferred

The invention relates to the subject matter of the claims.
. The compounds according to the invention do not occur in nature. Vincamenine of the formula I is rather the optical antipode of the naturally occurring alkaloid eburnamenine.

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

A particularly preferred acid addition salt of vincamenine is vincamenine hydrochloride. Of the Acid addition salts with carboxylic acids are preferred with tartaric acid and picric acid.

The compounds according to the invention vincamenine and its acid addition salts have valuable pharmacological, especially hemodynamic properties.

The hemodynamic effect of vincamenine hydrochloride as well as that of vincamine hydrochloride as The comparison substance was examined on 8 anesthetized dogs. The animals were given 30 mg / kg intravenously

administered 5-ethyl-5- (l-methylbutyl) barbituric acid [pentobarbital] anesthetized; said invention Active ingredient or the mentioned comparison substance was then also intravenously in Doses of 1 mg / kg administered.The following parameters were examined:

Arterial blood pressure,
Pulse rate,
so blood flow in the internal carotid artery,

Vascular resistance in the internal carotid artery,
Blood flow in the femoral artery and
Vascular resistance in the femoral artery.

The values of the above parameters were before treatment (baseline) as well as 3, 5, 10 and 15 Measured minutes after administration of the active ingredient; the change in values was in percent expressed in the following table 1 are the average values of 8 tests and the scatter, in each case in percentages related to the initial value, as well as the initial values compiled.

Table 1 Change of parameters ± variance Vincamenine in%, based on the Baseline values 15 minutes after Baseline values Vincumin hydrochloride K) parameter 3 minutes after the hydrochloride S minutes after 10 minutes after of administration Vincaminine hydrochloride (Sub-settlement) administration (Comparative of administration of administration from (inventive compound) U)
CO from substance) from from Vincamenine Vincamenine Vincamenine Vincamenine hydrochloride Oi hydrochloride -12.6 ± 4.5 hydrochiorid hydrochloride (inventive CD (invention -10.3 ± 4.2 (invention (invention appropriate appropriate + 3.2 ± LO appropriate appropriate Link) Link) Link) Link) + 2.9 ± 2.1 151 ± 5.9 mm Hg + 1.3 ± 2.5 + 2.4 ± 3.1 + 5.8 ± 6.1 -6.5 ± 3.1 138 ± 5.7 mm Hg 165 ± 17.2 minute " ¹ Artificial blood pressure -8.9 ± 4.3 -10.2 ± 3.1 -8.8 ± 4.4 -9.0 ± 3.8 -4.8 ± 2.5 171 ± 16.4 minute " ¹ 47.6 ± 6.2 cmV minute Pulse rate + 0.3 ± 3.7 -1.7 ± 3.0 -4.8 ± 1.7 60.5 ± 9.1 cmV minute Blood circulation in the Carotid artery + 18.5 ± 9.8 + i, 2 ± 3.0 3.9 ± 0.5 mm Hg internals + 0.7 ± 3.5 + 3.1 ± 3.5 + 4.7 ± 1.7 2.8 ± 0.5 mm Hg per cmV minute Vascular resistance - 21.0 ± 1 1.0 per cmV minute in the artery + 15.1 ± 6.9 48.3 ± 5.9 cmV minute internal carotid + 21.4 ± 10.0 + 18.6 ± 9.4 + 16.4 + 8.5 44.9 ± 5.5 cmV minute Blood circulation in -10.7 ± 5.1 3.8 ± 0.6 mm Hg the femoral artery -13.0 ± 7.1 -12.9 ± 6.2 -7.9 ± 6.3 3.3 ± 0.4 mm Hg per cmV minute Vascular resistance per cmV minute in the artery femoralis

p 'From Table 1 above it is clear that

U the vincamenine hydrochloride reduces the heart rate

and an approximately 15 to 21% vasodilator or vasodilator effect on the femoral vascular area, being about the same

ι " ₄ therapeutic index as the reference substance

The vincamenine hydrochloride has however compared to the comparison substance vincamine hydrochloride the great advantage that, in contrast to the latter, the arterial blood pressure is strong decreased, has no effect on him Since the decrease in blood pressure in addition to the hemodynamic Effect is undesirable, so counteracts the vincamenine hydrochloride according to the invention the comparison substance vincamine hydrochloride represents a major technical advance.

The following table 2 shows the toxicity values of vincamenine hydrochloride and the comparison substance Vincamine hydrochloride compiled

Table 2 link

Toxicity

Intravenous

on mice (confidence

interval)

in mg / kg

be and injectable aqueous or oily solutions. Such drug preparations can also various pharmaceutical excipients, for example preservatives, stabilizers and flavorings, de-cold.

The pharmaceutical preparations according to the invention are advantageously produced in dosage units suitable for the intended therapeutic application , for example, sterilized.
In the process according to the invention, the heating is preferably carried out for 0.5 to 4 hours. It is particularly preferred to run it to a temperature of 100 to 260 ° C. for up to 3 hours.

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

Thus, according to an advantageous embodiment of the method according to the invention, the compound is Formula general II, in which A ~ B is a group of the formula

Vincamenine hydrochloride 68.5 (63.4 to 74.0)

(according to the invention

Link)

Vincamine hydrochloride 72.3 (65.6 to 79.9)

(Comparison substance)

It can be seen from Table 2 above that the compound of the present invention was found to be toxic in terms of toxicity the comparison substance is about the same, so that as a result of the equality of the former with regard to the vasodilator or vasodilator effect on the femoral vascular area and the Superiority of the former in terms of arterial blood pressure gives a better therapeutic index.

The effective doses of the compounds of the invention are intravenous or peroral Administration generally 1 to 5 mg / kg. This effective dose is calculated for 1 day and can be used on be administered once or during the day in several equal divided doses. The in In any given case, the most advantageous dosage may be based on the patient's condition and the The doctor’s experience.

The compounds according to the invention can be used as active ingredients together with customary solid or liquid pharmaceutical carriers and / or other pharmaceutical auxiliaries in the form of pharmaceutical preparations are for parenteral or enteral administration. Examples of carriers are Water, gelatine, 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 petroleum jelly. The invention Medicinal preparations can be used in the usual application forms, such as in solid application form, for example as tablets, coated tablets, capsules, pills and suppositories, or in liquid form, for Example as oily or aqueous solutions or suspensions, emulsions, syrups, soft gelatin caps

HO

\ l c

HO-C C

II H ₂

(a)

^{represents, that is, vincamic acid, heated to 150 to 300 °} 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. The vincamic acid is thus 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 there is practically no further purification

is required

In another advantageous embodiment of the method according to the invention, the compound of the general formula II, in which A ~ B is a group of the formula

HO-C C

(b)

O H

represents, that is, apovincamic acid, a 0.5 to 4

Heat treatment at 200 to 300 ⁰ C for hours. The apovincaminic acid is decarboxyzed 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 method according to the invention, one of the two compounds of the general formula II in which A ~ B is a group of the formula

\ l c

HO

(c) respectively

CH ₂

HO

\ l c

H C

H ₂

represents or a mixture thereof is heated as the starting material about 0.5 to 4 hours at 170 to 30Q ⁰ C during this, advantageously in an inert gas atmosphere, preferably a nitrogen atmosphere, heat treatment performed is respectively the Vincanol and / or Epivincanol be dehydrated and so converted into vincamenine To work up the reaction product, the crude, molten reaction product obtained can be treated with an inert organic solvent, the pure vincamenine crystallizing out of the resulting solution. Solvents are expedient ether type organic liquids such as diethyl ether or halogenated hydrocarbons, for example Chloroform or dichloromethane, used as the starting material of this embodiment of the process according to the invention can be used instead of pure Vincanol, crude Vincanol containing epivincanol can also be used, as already mentioned in the Heat treatment also converts the epivincanol into vincamenine.

It is, especially in the case that of either of the two

Compounds of the general formula II in which A ~ B is a group of the formula

\ l c

HO

CH ₂

(c) respectively

HO

\ l c

H C

H ₂

represents, or a mixture thereof, i.e. vincanol or epivincanol or a mixture thereof, is assumed, it is preferred to carry out the heat treatment in the presence of a dehydration catalyst, which is a preferred embodiment of the method according to the invention. Preferably, aluminum oxide is used as the dehydration catalyst. This is advantageous in large excess, namely in about 2 to 6 times the amount, based on the weight of the vincanoles and / or epi vincanoles used as starting material, because the aluminum oxide present on the one hand adsorbs the by-products contaminating the vincamenine and on the other hand in the presence of aluminum oxide Dehydration can be carried out at about 40 to 80 ^{0 C lower temperature.} After the reaction has ended, the vincamenine formed can be separated from the aluminum oxide by extraction with an inert organic solvent.

The heat treatment can, especially in the case that of cincanol or epivincanol or a mixture the same is assumed, can advantageously also be carried out in a solvent. Preferably will a dehydrating solvent is used as the solvent. It is particularly preferred acetic anhydride or 75 to 85% formic acid should be used 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 So can the Dehydration at an even lower temperature be performed. In this case, the solvent is used to work up the reaction mixture acetic anhydride used was partially evaporated, the remaining solution was 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 treated with a water-immiscible inert organic solvent, advantageously a halogenated hydrocarbon, for example dichloromethane or chloroform, exhaustively extracted

In the embodiment of the method according to the invention described above, instead of the Acetic anhydrides, a 75 to 85%, in particular 80%, formic acid can also be used. The reaction mixture can be worked up in the same way as after the dehydration carried out in acetic anhydride. That after the partial However, the oily product obtained by evaporation of the solvent also contains the desired vincamenine certain contaminating by-products, which is why the oily crude product in an inert organic Solvent, advantageously an ether, for example diethyl ether, dissolved and from the insoluble residue filtered off and the pure vincamenine is isolated by evaporating the filtrate.

The acid addition salts thereof can be converted from the compound obtained in the form of an oil Acids are obtained. The acid addition salts of vincamenine are mostly easily identifiable crystalline Fabrics. The salt formation is preferably carried out in a solvent, in particular an aliphatic alcohol

230232/2) 9

hol, for example ethanol.

The starting materials for the process according to the invention can be prepared as follows.

The vincamic acid can be produced from vincamine by simple saponification (cf. DE-OS 22 53 750 and AT patent specification 3 22 118).

The apovincaminic acid can be prepared from apovincaminic by saponification (cf. DE-PS 19 58 514 and AT-PS 2 91 446).

Vincanol and Epivincanol can be made from Vincamine Reduction can be produced with lithium aluminum hydride (cf. DE-PS 17 95 146 and AT-PS 2 79 060).

The invention is illustrated by the following examples explained in more detail.

example 1

It was heated 3.4 g (0.01 mol) in a Vincaminsäure Sulfurierkolben in a nitrogen atmosphere on an oil or metal to its melting point (260 ⁰ C) and the melt was held for 1 to 2 hours at 240 to 260 ° C . The vincamic acid, heated to the melting point, immediately gave off carbon dioxide, but was kept at the mentioned temperature of 240 to 260 ° C. for the specified period of time to complete the reaction. The formation of vincamenine or the conversion of vincamic 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). 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 mixed with 10 cm ³ of aqueous η-sodium hydroxide solution about twice and then with 10 cm ^{3 of} distilled water Shaken out once to remove any remaining unreacted vincamic 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

The residue was 2.70 g of vincamenine (almost quantitative yield) in the form of a pale-yellow oil Obtaina This oily product could only be distilled under high vacuum at very high temperatures will.

Boiling point: 208 to 210 ^o C / 10- «mmHgund

[<x] o value = 180 ° (c - 1%, in chloroform).

The vincamenine picrate is easy to crystallize Link.

Melting point: 170 to 172 ° C Analysis:

Example 2

The procedure described in Example 1 was repeated, with the difference that the melt of the starting material was kept at 240 to 260 ^° C. for 3 hours. 2.50 g (90% of theory) of vincamenine were thus obtained in the form of an oil, the color of which was somewhat darker than that of the product of Example 1.

Example 3

There were 3.24 g (0.01 mol) of apovincamic acid in a sulfurizing flask in a nitrogen atmosphere heated oil or metal bath to their melting point and the melt was held at 250 to 260 ^° C. for 1 to 2 hours. The melt obtained was then dissolved in a water-immiscible solvent, for example ether, benzene or dichloroethane, and the organic solution was each 10 cm ^{3 of} an aqueous η-sodium hydroxide solution about twice and then ^{extracted once with 10 cm 3 of} distilled water to remove any remaining unreacted apovincamic acid. The aqueous phases were combined and not with half the volume of one with water miscible organic solvent shaken out The separated organic phase was combined with the first organic solution over anhydrous Dried sodium sulfate and filtered and the filtrate was evaporated in vacuo

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

Melting point of the vincamenine picrate: 172 ° C. Example 4

Calculated: found:

C 8237, C 82.02,

H 7.83, H 7.80,

N 10.07%; N 935%.

It was in the manner described in Example 3

proceeded, but with the difference that the

Melt the starting material at 250 for 3 hours

until 260 ⁰ C was held. 2.00 g (71.4% of the

Theory) obtained vincamenine. Example 5

There were 1.48 g (0.005 mol) Vincanol in a nitrogen atmosphere for 1 hour at 220 to 250 ⁰ C.

The resulting melt was then heated in ether dissolved, and the solution was worked up in the manner described in Example 1. Thus 1.29 g (93% of theory) obtained vincamenine in the form of a light yellow oil. Had the corresponding vincamine pilcrat

properties identical to those of the vincamine picrate obtained according to Example 1.

Example 6 It was made in the manner described in Example 5

proceeded, but with the difference that the

Heat treatment was carried out for 3 hours. 1.25 g (90% of theory) of vincamenine in Preserved the form of an oil. Example 7

It was heated 1.48 g (0J005 MoQ crude Vincanol for 1 hour in a Stickstoffatmosphire at 220 to 250 ⁰ C. Then, the resulting melt was dissolved in chloroform and the solution worked up in the manner described in Example 1, there were Thus 1.20 g (86% of theory) Vincamenine was obtained in the form of a pale yellow ocher

20th

obtained vincaminine picrates identical properties.

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

The procedure described in Example 5 was followed, with the difference that instead of of the ether dichloroethane was used as a solvent. Thus 1.25 g (90% of Theroie) were vincamenine obtained in the form of an oil.

Example! 10

1.48 g (0.005 mol) of vincanol were mixed with 3 times the amount, that is to say 4.50 g of aluminum oxide, and the mixture was held at 185-200 ° C for 1 hour. After cooling, the reaction product became extracted with benzene, the organic solution dried over anhydrous sodium sulfate and filtered and the filtrate was evaporated to dryness. 1.20 g of i86% of theory) were vincamenine in the form of a light yellow Obtain oil. Had the corresponding vincamine picrate Properties identical to the properties of the vincamenine picrate obtained according to Example 1.

Example 11

The procedure described in Example 10 was followed, with the difference that instead of the 4.5 g of aluminum oxide, 7.5 g of aluminum oxide, mixed with the 1.48 g of vincanol used as the starting material became. Yield: 1.10 g (79.1% of theory) of vincamenine. The quality of the same was the same as that prepared according to Example 10.

Example 12

1.48 g (0.005 mol) of vincanol in 7.5 cm ^{3 of} acetic anhydride were refluxed for 1 hour. Then the excess of the solvent was partially evaporated and the remaining solution was poured into ice water. The pH of the aqueous mixture was adjusted to 8 to 9 with 20% sodium hydroxide solution, and the alkaline solution thus obtained was shaken out 4 times with approximately the same amount of dichloromethane each time. Dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was 1.26 g (91% of theory) of crude vincamenine in the form of an oil.

JO Thus 1.21 g (87% of theory) of vincamenine were obtained in the form of an oil.

Example 14

1.48 g (0.005 mole) of vincanol was dissolved in 8 g of 80% formic acid and the solution became 1 hour heated to boiling under reflux for a long time. Then the excess acid was evaporated under vacuum and the Poured residue into ice water. Thereafter, the reaction mixture was as described in Example 12 Way worked up. Thus 1.25 g of an oily product was obtained. This was not a uniform one Vincamenine, but also contained a certain amount of vincan. When dissolving this oil in 2 fold Weight amount of acetone and leaving the solution in a refrigerator differed for the most part des Vincanes in crystalline form from solution. The pure vincamenine was made from the latter Evaporation isolated.

Example 15

1.48 g (0.005 mol) of vincanol in 80 cm ^{3 of} 80% formic acid were refluxed for 8 hours. Otherwise, the reaction mixture was worked up in the manner described in Example 14 obtained, which could be purified in the manner described.

J5

40

50

Example 16

2.78 g (0.01 mol) of vincamenine were dissolved in 9 cm ^{3 of} absolute ethanol and 1 cm ³ of 363% ethanolic hydrochloric acid was added. The vincamenine hydrochloride was precipitated by dropping about 5 times the amount of ether 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 "C and

[<x]? - value = -50 ° (c = 1%, in chloroform).

Analysis:

FOrCi ₉ H ₂₂ N ₂ HQ (molecular weight: 316.83)

Calculated: C 72.15, H 7.98, N 9.10, α 10.7%;
Found: C 72.02, H 734, N 933, α

60

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

Example 13

The procedure described in Example 12 was repeated, with the difference that 143 g

»Wttyrfrirl i wnHwi mvl an RtAlIo Ar *

Dknlormethini was extracted with chloroform .

55

Example 17

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

65

Vincamenine hydrochloride 5g gelatin 3g Magneshim stearate 2g Talk 5g Potato starch 40g Milk sugar 95 g

13 14

The vincamenine hydrochloride was mixed with ³ A, the granules were mixed with the talc, the remaining part of the

Potato starch and mixed with the whole amount of the potato starch and the magnesium stearate

Milk sugar mixed, and the homogeneous mixture and from this mixture were 1000 tablets of each

was pressed with an aqueous solution of gelatin 150 mg. The tablets could be used to facilitate

kneaded, granulated and dried. The dry *> tion of the dosage can be provided with partial notches.

Claims (4)

Claims: 1. Vincamenine of the formula as well as its acid addition salts. 2. Vincamenine hydrochloride. 3. Medicaments containing one or more compounds according to claim 1 as active ingredients and customary pharmaceutical carriers and / or other pharmaceutical excipients. 4. Process for the preparation of the compounds according to claim 1, characterized in that one a compound of the general formula in a manner known per se