NO761366L - - Google Patents

Description

Method of manufacture

of alkaloids of the eburnamine type

The present invention relates to a method for the production of new alkaloids of the eburnamine type with the general formula:

where is hydrogen or hydroxy,

R 2 is carboxy or C 2 - 6 alkoxycarbonyl, and

is hydroxy, or

and salts of such compounds.

It is already known that alkaloids of the eburnamine type such as vincamine and its derivatives can be used in therapy as blood pressure-lowering and cerebral vasodilators (L. Szporny, K. Szåsz: Aren. Exp. Path. Pharmacol. 236, 296 (1957 )).

It has now been shown that new alkaloids of the eburnamine type with the general formula (I) and their salts have valuable pharmacological properties.

Among the new compounds produced according to the present invention, 16-carboxy-17-methoxy-eburnane and 17-hydroxy-vincamine have proven particularly useful.

The pharmacological properties of the new process compounds are related to those of vincamine, a compound used in therapy with good results. The relative values are summarized in Table 1. The LD₂Q values were determined in white mice by intravenous administration (Miller L.C, Tainter M.L.: Proe. Soc. Exp. Biol. Med. 57, 26l (1944)). LD ,-Q-v are the ones indicated in table 1, they are in relation to vincamine, i.e. the higher the relative value, the more favorable the toxicity of the compound in question.

When investigating the effects exerted on blood pressure and cerebral flow, intravenous doses of 4 mg/animal, as well as intra-arterial doses of 1 mg/animal of the investigated compounds were used.

The experiments were carried out on dogs. The examination of the effect of the compounds exerted on cerebral circulation, cerebral flow (arteria carotis interna) and the vascular resistance was recorded respectively. calculated. The compounds were administered intravenously and intraarterially.

Among the relative values indicated in Table 1, the largest represent the highest reduction or increase.

From the data in Table 1, it appears that the investigated compounds effectively increase the cerebral current, and moreover their toxicity is very favorable. Thus, e.g. 16-carboxy-17~methoxy-eburnane approx. 3 times less toxic than vincamine.

The new alkaloid derivatives of formula (I) can be prepared by reacting apovincamine with an alkali metal alcoholate or alkali metal permanganate and thus saturate the 16-17 double bond, and possibly isolate the new compounds formed.

A detailed description of the present method is given below.

Apovincamine is dissolved in a solvent, preferably one. alcohol, the solution is heated to boiling, and a solution of alkali metal alcoholate is added dropwise to the reaction mixture. The course of the reaction is followed by thin-layer chromatography. The mixture is boiled until the stain characteristic of apovincamine disappears, then the solution is cooled and neutralized to pH 7.0 with a strong acid, preferably with concentrated hydrochloric acid. The solution is evaporated to dryness, and the dry residue is dissolved in a chlorinated hydrocarbon, preferably in methylene chloride. The solution obtained is filtered, and the filtrate is evaporated to dryness under reduced pressure. The dry residue is dissolved in ethanol and crystallized.

According to another method according to the invention, apovincamine is dissolved in a mixture of formic acid and acetone, the solution is cooled to 0°C, and an aqueous alkali metal permahganate solution is added. The mixture is stirred for 5 minutes, then the reaction is stopped by the addition of a reducing agent, preferably an alkali metal bisulphite. The pH of the solution obtained is adjusted to 8> and the alkaloid base is extracted from the solution with a chlorinated hydrocarbon, preferably with methylene chloride. The methylene chloride solution is dried, evaporated to dryness, and the dry residue is dissolved in a solvent which is an agent suitable for salt formation. Then a pharmaceutically acceptable organic acid or mineral acid, preferably tartaric acid, or a quaternary agent is added to the solution, and the formed acid addition salt or quaternary salt is separated from the mixture by crystallization.

The therapeutically active new compounds produced according to the invention can be used in therapy in the form of pharmaceutical products. Such pharmaceutical products, suitable for enteral, par-enteral or topical application, contain active agents together with organic or mineral, solid or liquid pharmaceutically acceptable carriers. The carriers suitable for the manufacture of pharmaceutical products must not react with the active agents. Such carriers are e.g. water, alcohol, gelatin, propylene glycol, vegetable oils, cholesterol, starch, lactose, talc, gum, magnesium stearate or other known pharmaceutical carriers. The pharmaceutical products can also be sterilized if desired.

The pharmaceutical products may also contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, solubility-increasing compounds or salts or buffers capable of changing the osmotic pressure, further

other pharmaceutically valuable substances, e.g. reserpine, to produce products with combined effects. The pharmaceutical products can be prepared by usual methods. For example, injectable solutions are prepared by dissolving the acid addition salt or quaternary salt of the active agent in pyrogen-free physiological salt solution or in double-distilled water, the solution being sterilized if necessary, and the solution being filled into ampoules under sterile conditions.

The method according to the invention will be further illustrated with the help of the following examples.

Example 1

16-carboxy-17-methoxy-eburnane

0.14 9 (0.006 mol) of metallic sodium is dissolved in 100 ml of anhydrous methanol, and 1 g (0.0029 mol) of apovincamine is dissolved in the methanolic sodium methoxy solution obtained. The reaction mixture is boiled under reflux for 6 hours, and the course of the reaction is followed by layer chromatography. The spot characteristic of apovincamine gradually disappears, and at the same time a new spot appears in the chromatogram. If the transfer is not complete at the end of 6 hours, a sodium methoxy solution prepared from 0.014 g (0.0006 mol) of metallic sodium and 20 ml of anhydrous methanol is added to the mixture and the boiling is continued for an additional 1 hour.

The solution is cooled to 20°C and neutralized to pH 7.0 with concentrated hydrochloric acid. The resulting solution is evaporated to dryness under reduced pressure. The dry residue is dissolved in 50 ml of methylene chloride, and the solution is left at 0-2°C for 4-5 hours.

the separated crystals of sodium chloride are filtered off, the filtrate is evaporated to dryness, and the dry residue is dissolved in 20 ml of anhydrous ethanol. The product crystallizes at 0 - 2°C.

0.78 9 (79%) of 16-carboxy-17-methoxy-eburnane is obtained. on the basis of thin-layer chromatography, a uniform product is formed which melts at 264°C.

Analysis:

Calculated: C = 71.16% R = 7.39% N = 7.90% OCH^=8.78%

Found: C = 71.50%. H = 7.23% N=7.90% 0CH3=8.9.2%

The structure of the product is identified by its infrared spectrum.

Example 2

17-hydroxy-vincamin- tartrate

1 g (0.0029 mol) of apovincamine is dissolved in a mixture of 200 ml of acetone and 1.3 ml of concentrated formic acid. The solution is cooled to 0°C, and a solution of 0.949 (0.004 mol) potassium permanganate in 50 ml of distilled water is added with stirring. The resulting solution is stirred for 5 minutes, then the reaction is interrupted by the addition of 15 ml of 10% aqueous sodium bisulphite solution. The secreted dark brown manganese oxide is removed by filtration and washed with water. The filtrate and the washing water are combined, and the pH of the resulting solution is adjusted to 8.0 with a 5% aqueous sodium hydroxide solution. There alkaline solution is extracted with 5 x 200 ml of dichloromethane. The organic solutions are combined, dried over anhydrous potassium carbonate, and evaporated to dryness under reduced pressure. The dry. residuum is dissolved in 10 ml of methanol, and the pH of the solution is adjusted to 3.0 with a methanol solution of tartaric acid. The solution is stored at 0 2°C..—

0.94 g (94%) of crystalline 17-hydroxy-vincamine tartrate is obtained, m.p. 215°C. On the basis of layer chromatography, a uniform product is formed.

Analysis:

Calculated: C = 57.68% H = 6.19% N=5.38%

Found: C=57.58% H = 6.62% N=5.37%

The structure of this substance is identified by its infrared spectrum.

Example 3'

Tablets containing 16-carboxy-17-methoxy-eburnane as active ingredient.

Composition of 1 tablet:

The active agent is mixed with the starch and lactose, and the homogeneous mixture is granulated with the aqueous solution of gelatin. The wet granules are dried at 30 - 50°C, mixed with talc and magnesium stearate, and the obtained homogeneous mixture is pressed to

pills.

Example 4

Tablets containing 17-hydroxy-vincamine tartrate as active ingredient.

Composition of 1 tablet:

The tablets are prepared as described in example 3-

Claims (2)

1. Procedure for the production of <v> 17-hydroxy-vincamine with the general formula: and salts thereof, characterized in that apovincamine is reacted with an alkali metal permanganate, and, if desired, the compound obtained is separated, and optionally transferred to an acid addition salt or quaternary. salt, and, if desired, the salt is transferred to the free base or to other salts. 2. Method according to claim 1, characterized in that the reaction is carried out in a solvent medium, preferably a mixture of formic acid and acetone, at a temperature below room temperature, using potassium permanganate as reactant.