MXPA97007015A - Procedure to isolate galantam - Google Patents

Abstract

The present invention relates to: The object of the present invention is a method for isolating the alkaloid galantamine (formula I), galantamine produced through the process in question, the use of galantamine thus produced in galenic forms, and the use of galantamine thus produced in the treatment of narrow-angle glaucoma, Alzheimer's disease and alcohol and nicotine dependence

Description

PROCEDURE FOR ISOLATING GALANTAMINE The object of the present invention is a method for isolating the alkaloid galantamine, the galantamine itself prepared by means of said process, the use of the galantamine thus prepared in galenic preparations, as well as the application of the galantamine thus prepared in the treatment of Narrow angle glaucoma, Alzheimer's disease and alcohol and nicotine dependence.

BACKGROUND Galantamine (4a, 5,9, 10,11, 12-hexahydro-3-methoxy-11-methyl-6-H-benzofuro- (3a, 3,2, -ef) - (2) -benzazepin-6- ol) is a tetracyclic alkaloid, which considering its pharmacological properties belongs to the group of reversible inhibitory substances of ester choline and its effects are similar to physostigmine and neostigmine. However, it also possesses specific properties, such as for example strong analgesic effects comparable to morphine. As an inhibitor of ester choline, galantamine has, considering its reduced toxicity compared to physostigmine and neostigmine, a range of therapeutic action three to six times wider. This advantage compensates for a somewhat smaller inhibitory effect of the ester choline based on the application rate. Galantamine is applied in the treatment of polio and various diseases of the nervous system, but mainly in the treatment of narrow-angle glaucoma and as an antidote after curare applications. In experimental form, galantamine is applied in the case of Alzheimer's disease. Recently, the treatment of alcohol dependence and nicotine has also been described (DE-OS 40 10 079, DE-OS 4301 7S2). Both the therapy of Alzheimer's disease, of alcohol and nicotine dependence, as well as of narrow-angle glaucoma, require forms of long-acting drugs suitable for particular conditions. Among these forms is the treatment of narrow-angle glaucoma, an ocular ointment. Due to reasons that are easy to understand, complex treatment regimens and permanent infusions can not be used in the treatment of Alzheimer's disease, alcohol dependence and pcotin. In these diseases, a transdermal therapeutic system (STT) is provided, such as that described, for example, in DE-OS 43 01 783. Both the intact skin and the cornea of the eye do not allow a resorption of the salts of the eye. os active principles. Galantamine hydrochloride or galantamine hydrochloride can not therefore be used in the therapy of narrow angle glacoma, Alzheimer's disease or alcohol or nicotine dependence with ointments or in J? STT. Due to this it is necessary to apply a pure Galantan base.

Due to its complex tetracyclic structure provided with three optically active carbon atoms, an economical synthesis of the galantamine base is not possible. For this reason, galantamine is usually isolated from the amarylidaceous plants, for example the galantusa types, such as the bell or the Leucojum aestivum. These plants have the advantage of containing galantamine in concentrations of up to 0.3%, with low proportions of secondary alkaloids, whereby the extraction procedure described in patent DE-1 1 93 061 can be used. However, both galantusa and Leucojum aestivum are protected species in nature. On the other hand, in the extraction process described in DE 1 1 93 061, chlorinated hydrocarbons are used, which have been discredited due to toxicological reasons. The medical books of the western world demand to maintain the residual content of the chlorinated hydrocarbons at a level < 10 ppm. For this reason, the use of chlorinated hydrocarbons in the preparation of medicines should be avoided. On the other hand, in the known process it is necessary to adsorb the extract in the solvent on aluminum oxide, in order to ensure a preparation of resinous substances and secondary alkaloids. From the solution obtained after filtering the aluminum oxide, the galantamine is then purified, passing through the galantamine hydrobromide, with the corresponding need for the halogen salts. For the application in ointments and in the STT it is still necessary to release the galantamine base from this galantamine hydrobromide salt.

DESCRIPTION OF THE INVENTION The object of the present invention is, therefore, to provide a method for isolating and purifying galantamine, which does not have the disadvantages of the process described in the state of the art. In particular, it seeks to simplify the purification, avoiding the use of chlorinated hydrocarbons and purification through the galantamine salts. This object has been achieved in the present invention by means of a process with the features indicated in the first claim. Those preferred modalities are characterized in the dependent claims. The particular object of the invention is a method for isolating galantamine from biological material, obtained from cultivated amaryllid varieties or those generally known as "weeds" and not subject to natural protection, preferably from bulbs. of these plants. Among these amaryllidaceae there are, for example, daffodils or crinum types. Particularly advantageous is the plant Narcissus pseudonarcissus "Carlton" or the Asian plant thistle called Crinum amabile. Although these plants only contain a tenth of the amount of galantamine of the protected plants of nature and on the other hand contain up to twelve secondary alkaloids, surprisingly it is possible to isolate the galantamine base from them by the method of the invention. with a purity suitable for use in medicines. According to the present invention, the preferably milled galantamine carrier biological material is mixed with powder of an alkaline material, preferably with flakes of sodium hydroxide, soda, soda ash or other similar salts, suitable for releasing the bases from the material biological and to obtain the pharmacological active ingredients, then extracted with toxicologically tolerable organic solvents and galantamine is purified from this extract by means of a liquid / liquid extraction. Of particular importance for the success of the process of the invention is the maintenance of the pH in the first stage of the liquid / liquid extraction. The liquid / liquid extraction is carried out in the first stage at a pH of around 4 and in the second stage at a pH of around 9. To adjust the pH, a solution of soda or another base can also be used outside of ammonia. As a toxicologically tolerable organic solvent, diethyl ether or special benzine is used. Preferentially, special benzine is used since it is thus possible to obtain a certain previous purification. The solvent is removed and the galantamine is recrystallized from a suitable solvent, preferably isopropanol. The galantamine base is obtained with a melting point of 129 to 1 30 ° C. The purity of the galantamine thus obtained is shown in the H PLC chromatogram of Figure 2. This result is all the more surprising because the procedure used up to now by the DE 1 1 91 061 patent for isolating galantamine to from the biological material, which contains little galantamine and up to 12 secondary alkaloids, proved not to be adequate. With the process described in the patent DE 1 1 93 061 a non-unfoldable emulsion is formed, whereby it is not possible to carry out an extraction. A slightly modified procedure delivered an oily residue, which contains according to the H PLC chromatogram at least four additional substances (Figure 1). Therefore it should be considered as clearly surprising that from the biological material, which contains little galantamine out of a high number of secondary alkaloids, it is possible to isolate the free galantamine base in a pure form with a good yield using the procedure according to the invention, without the need for an additional adsorption step on aluminum oxide. The galantamine base prepared according to the invention can be used in the treatment of narrow-angle glaucoma, of Alzheimer's disease or the dependence on alcohol and nicotine. The galantamine base prepared according to the invention can be further employed in forms of galenic preparations, such as, for example, in ophthalmic ointments or in transdermal therapeutic systems, which can similarly be used in the treatment of the diseases mentioned above. Throughout the following examples the invention will be further explained without limiting the scope thereof.

EXAMPLE 1 (Comparative) Analogously to the process described in the DE 1 1 93 061 patent, 10 kg of air-dispersed and air-dried tubers of the Narcissus pseudonarcissus "Carlton" plant were carefully mixed with 2.5 I of an aqueous solution of 8% monia. %. The material swells; all the preparation is adhesive. The incorporation of 23 liters of dichloroethane for the extraction gives an emulsion that can not be split.

EXAMPLE 2 (Comparative) The known method was modified through the state of the art to isolate galantamine (DE 1 1 93 061). Ten kg of tubers of Narcissus pseudonarcuissus "Carlton" subdivided and air-dried with 400 g of sodium carbonate were carefully mixed. Then 23 I dichloroethane was added. The mixture is allowed to stand for 10 hours; then the solvent is separated by pouring. The tubers were again covered with 23 I dichloroethane, which is separated after 2 to 3 hours. The tubers were then treated a third time with 17 I dichloroethane, which was again separated directly. The combined dichloroethane extracts were extracted with 10% sulfuric acid (2 times each time with 600 ml, 2 x each time 300 ml). The acid extracts were combined and, by stirring with diethyl ether, purified from the traces of the contained dichloroethane. Subsequently, about 200 ml of a 25% aqueous solution of ammonia were added under agitation and cooling to 15-20 ° C until an alkaline reaction of Lackmus was obtained. The pH value is around 7 to 8. In a different way to that indicated in the state of the art, the secondary alkaloids do not precipitate. The alkaline solution was saturated with common salt and extracted with diethyl ether. After evaporating the ether, it results, unlike those indicated in the state of the art, a negligibly small residue. Saturation with potash adjusts the pH of the aqueous phase to about 14. The aqueous phase is extracted several times with diethyl ether. The combined ether extracts were evaporated to dryness and the galantamine base carrier residue was dissolved in acetone (50 ml). Unlike what is indicated in the state of the art, a precipitate does not form. 350 ml of acetone are replaced, 200 g of aluminum oxide are added and the mixture is stirred for 45 minutes. The aluminum oxide is separated by means of filtration and washed twice with each time 100 ml of acetone. The combined acetone solutions were evaporated to dryness. 1.3 g of an oily residue is obtained which was analyzed with the aid of H PLC. The chromatogram is shown in Figure 1. The main maximum corresponding to galantamine is characterized. It is clearly seen that galantamine isolated in this manner contains at least four impurities substances.

EXAMPLE 3 The tubers of the subdivided, air-dried Narcissus pseudonarcissus "Carlton" were carefully mixed with 4 kg of sodium carbonate. The mixture was subdivided into three equal portions on each of which 15 I of special benzine 80/110 were poured. It is left to rest for 24 hours. The solvents renewed two voices, met and evaporated in a weak vacuum to dryness. The extracts were taken up in 2% aqueous sulfuric acid and, with the aid of a concentrated aqueous ammoniacal solution, a pH of 4 was adjusted. The mixture was then extracted five times with diethyl ether. The aqueous phase was adjusted with concentrated ammonia to a pH of 9 and extracted five times with diethyl ether. These fractions were combined in ether, dried over sodium sulfate and concentrated by evaporation. 20 g of a weakly yellow oily residue are obtained which was recrystallized from hot isopropanol. 10 g of white galantamine base with a melting point of 129-130 ° C are obtained. Only one maximum is observed in the HPLC chromatogram (Figure 2).

Claims (26)

1. - Process for isolating galantamine, characterized in that the biological material carrying galantamine is extracted with toxicologically tolerable organic solvents and galantamine is purified from this extract by means of liquid / liquid extraction, said liquid / liquid extraction being carried out in the first stage a a pH of around 4.

2 - The process according to claim 1, characterized in that the biological material is subdivided before extraction and mixed with an alkaline powder.

3 - The process according to any of claims 1 or 2, characterized in that the liquid / liquid extraction is carried out in the second stage at a pH of around 9.

4. The process according to any of claims 1 to 3, characterized in that sodium carbonate is used as the alkaline powder.

5. The process according to any of claims 1 to 4, characterized in that as a toxicologically tolerable organic solvent, diethyl ether or special benzine, preferably special benzine, is used.

6. The process according to any of claims 1 to 5, characterized in that the galantamine obtained is recpstahza from a suitable solvent.

7. - The process according to claim 6, characterized in that isopropanol is used as the solvent.

8. The process according to any of claims 1 to 7, characterized in that the parts of the amarylidaceous plant are used as biological material.

9. The process according to claim 8, characterized in that the bulbs are used as plant parts.

10. The process according to any of claims 1 to 9, characterized in that the narcissus species or the crinum species are used as rilidácea ama.

The method according to claim 10, characterized in that Narcissus pseudonarcissus "Carlton" is used as a Narcissus species, or Crinum amabile as Crinum species.

12. - Galantamine in a pharmaceutical grade with a purity of > . 99%, produced according to a method according to any of claims 1 to 11.

13. Galenic administration forms characterized by a content of galantamine according to claim 12.

14. The use of galantamine according to claim 12 for the production of ophthalmic ointments.

15. The use of galantamine according to claim 12 for the production of transdermal therapeutic systems.

16. The use of galantamine according to claim 12 for the production of a drug for the treatment of narrow-angle glaucoma.

17. The use of galantamine according to claim 12 for the production of a drug for the treatment of Alzheimer's disease.

18. The use of galantamine according to claim 12 for the production of a drug for the treatment of alcohol dependence.

19. The use of galantamine according to claim 12 for the production of a drug for the treatment of nicotine dependence.

20 - A pharmaceutical preparation characterized in that it comprises galanthamine according to claim 12, in addition to pharmaceutical auxiliaries known per se.

21 - The pharmaceutical preparation according to claim 20, characterized in that it is for topical application.

22. The pharmaceutical preparation according to claim 20 or 21, characterized in that it is for the treatment of narrow-angle glaucoma.

23. The pharmaceutical preparation according to claim 20 or 21, characterized in that it is for the treatment of Alzheimer's disease.

24 - The pharmaceutical preparation according to claim 20 or 21, characterized in that it is for the treatment of alcohol dependence.

25 - The pharmaceutical preparation according to claim 20 or 21, characterized in that it is for the treatment of nicotine dependence.

26. A procedure for the therapeutic treatment of the human organism, characterized in that galantamine is used according to claim 12 or a pharmaceutical preparation according to any claim 20 or 21.