Alkaloid compounds, method of production thereof, and pharmaceutical composition


(57) Abstract:

This invention relates to new alkaloids from Mappia foetida (polidano 1 and 2 given in the text opisanie), have anticancer and antiviral properties. These alkaloids are soluble in water, are present in all parts of the plant and are precursors camptothecin and 9-methoxyamphetamine, which, as you know, are alkaloids that possess pharmacodynamic properties, but is not soluble in water. It is the ability of new compounds to dissolve in water makes them particularly suitable for parenteral injection in the treatment of patients, which avoids the use of toxic fillers or unacceptable chemical derivatives. Foeticide obtained by extraction of various plant parts Mappia foetida low molecular weight aliphatic alcohols or ketones. 3 s and 5 C.p. f-crystals.

This invention describes the new alkaloids from Mappia foetida, their therapeutic use and containing preparations.

The alkaloids of the present invention have the following formula (I):

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foetidus 1 : R = H, palidin 2 : R = OCH3.

When handling acids or alkalis, or by hydrolytic enzymes feet is about has been widely tested pharmacologically and clinically as such or in the form of derivatives, in cancer and in the treatment of some viral diseases, or 9 - methoxycoumarin, useful for the same indications.

Camptothecin formula II

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was first isolated together with other compounds of Camptoteca acuminata (Nyssaceae) and from other plants, among which Mappia foetida (Olinaceae), although the latter has been studied for a long time, with further chemical screening were unexpectedly discovered new alkaloids that even when processing crude plant extracts gave camptothecin.

Among the compounds of which was dedicated camptothecin, especially important foetidus 1, as it is contained in plants in large quantities. The study of its structure with the help of spectral analysis and chemical degradation have led to the identification of compounds characterized by the presence of link spermidine, double-esterified coumaric acid, which, in turn, etherification open link camptothecin (see formula I). This compound is found in all parts of the plant, but especially in the seeds and roots, in amounts ranging from 0.1 to 0.5%. Its advantage compared to camptothecin is that it is easily soluble in diversified media so were undertaken intensive efforts to eliminate this drawback and to obtain a semi-synthetic drug.

Foetidus 1 obtained by extraction of various plant parts of low molecular weight aliphatic alcohols or ketones, separately or in a mixture with water at room temperature; the extracts were concentrated at a low temperature, preferably below the 25oC in vacuum; the organic solvent was removed and the aqueous concentrate was extracted with chlorinated solvents to extract weakly basic alkaloids, among which camptothecin, 9-methoxyamphetamine and luppicini; thereafter the aqueous phase was extracted with n-butanol or not miscible with water, alcohols, which are then concentrated to dryness at low temperature in a vacuum. Sediment from butanolic extracts was purified on silica gel or similar adsorbents; for elution used a mixture of chlorinated solvents, preferably methylene chloride, aliphatic alcohols, preferably methanol or ethanol. Used mainly a mixture in a ratio of from 4:1 to 1:1. The fractions containing the described in the invention alkaloids, were combined, concentrated to dryness and the residue was further purified with POM with the ratio of methanol/water 1:1, to pure methanol. The fractions containing the alkaloids, was concentrated at a low temperature in a vacuum, the aqueous concentrate was subjected to drying at a temperature below 0oC (freezing). Pure alkaloids were obtained by using the crystallization.

The obtained substances were subjected to biological evaluation on the lines of human tumor cells (ovary, breast, colon, lung, resistant or not resistant to other anticancer compounds, and so on) and some strains of viruses. In fact, it is known that camptothecin, or, rather, some of its derivatives possess cytotoxic activity associated with inhibition of DNA topoisomerase I and II.

For example, cytotoxicity for cell line carcinoma of the rectum is about 25 nm. Antiviral activity of foetida 1, even taking into account the different resistance strains, appears at concentrations ranging from 1 to 100 ng/ml of Foetidum 2 different foetida 1 by the presence of methoxyl in the 9-position, operates in a similar way. It is proved that the herpes virus, cytomegalovirus and HIV sensitive to the alkaloids of the invention.

The compounds of this invention can be incorporated in all kinds of f is compatible with the pH of the blood, without causing precipitation or incompatibility. The drugs can be used in all standard pharmaceutical excipients. The dosage of these new alkaloids can vary from 0.5 to 200 mg per dose and therapeutic cycle. According to preliminary data, the effective dose of about 50 mg/m2.

The following examples further illustrate the invention without limiting its scope.

Example 1. Getting foetida 1 from the seeds of Mappia foetida.

5 kg of finely crushed seeds Mappia foetida was extracted three times with 50 l of acetone with stirring at room temperature; the combined acetone extracts were concentrated in vacuo to 10 l; the concentrate was diluted with 10 l of a 1% solution of citric acid; the insoluble matter was filtered and discarded, while the water-acetone phase prototechno was extracted with methylene chloride to highlight alkaloids (camptothecin, methoxyamphetamine and so on); water-acetone phase was concentrated to the water, and the concentrate was extracted with n-butanol after neutralization to pH 7.5 to remove palidino 1 and 2. N-butanolic the solution was concentrated and the residue was dried to yield about 200 g butanole faction, which was fractionally sleduya first with a mixture of methylene chloride/methanol in the ratio of 4:1, then a mixture of the same solvents in the ratio 7:3. The product contained in the faction, elyuirovaniya a mixture of 7:3 was purified on a column of Li Chroprep RP8 and suirable gradient of methanol/water. The fractions containing foeticide 1 and 2 were combined and concentrated to dryness in vacuo at a temperature below 30oC, the precipitate was led from a mixture of acetone/hexane. Received 5,1 g foetida 1, having the following characteristics: I. pl. 157 - 158oC; []D= -37,9 (c = 0,31, MeOH). 1H-NMR - spectrum / 300 MHz, DMCO-d6/, 8,60 /1H, s, H-7/, 8,19 /1H, t, J = 5,2, H-10/, 8,15 /1H, d, J = 8,6, H-12/, 8,05 /1H, d, J = 8,6, H-9/, 8,04 /1H, t, J = 5,2, H-19/, 7,80 /1H, t, J = 7,8, H-11/, 7,65 /1H, t, J = 7,8, H-10/, 7,35 /2H, d, J = 8,6, H-3 + H-5/, 7,34 /2H, d, J = 8,6, H-24 + H-28/, 7,29 /1H, d, J = 15,8, H-7/, 7,28 /1H, d, J = 15,8, H-22/, 6,76 /4H, d, J = 8,6, H-6 + H-25 + H-27/, 6,36 /1H, d, J = 15,8, H-8/, 6,35 /1H, d, J = -15,8, H-21/, 5,58, 5,41 /2H, AB system, J = 10,6, H-17/, 5,18 /2H, s, H-5/, 3,21 /2H, m, H-11/, 3,13 /2H, m, H-18/, 2,84 /4H, items J = 7,2, H-13 + H-15/, 2,02 /1H, m, H-19A/, 1,96 /3H, s, CH3CO/, 1,90 /1H, m, H-19B/, 1,74 /2H, m, H-12/, 1,55 /2H, m, H-16/, 1,46 /2H, m, H-17/, 0,84 /3H, t, J = 7,2, H-18/.

13C-NMR-spectrum: /78,1 MHz, DMCO-d6/: 175,23 /s, C-21/, 170,81 /s, CH3CO/, 166,27 /C, C-9'/, 165,83 /s, C-20'/, 161,43 /s, C-16a/, 159,40 /s, C-1'/, 159,14 /s, C-15/, 153,50 /s, C-2/, 148,36 /s, C-13/, 143,56 /s, C-3/, 139,37 /d, C-7/, 139,06 /d, C-22'/, 131,74 /d, C-7/, 130,58 /d, C-11/, 130,33 /s, C-6/, 129,63 /s, C-3' + C-5'/, 129,56 /d, C-24' + C-28'/, 129,40 /d, C-12/, 128,83 /d, C-9/, 128,23 /s, C-8/, 127,78 /d, C-10/, 126,23 /d, C-4'/, 126,13 /s, C-26 /t, C-15'/, 38,41 /t, C-18/, 36,36 /t, C-11'/, 33,40 /t, C-19/, 26,99 /t, C-12'/, 26,87 /t, C-17'/, 24,04 /t, C-16'/, 21,22, CH3CO/, 9,29, C-18/.

Foetidus 2 /1,2,/ was obtained from the mother liquor after crystallization of foetida 1 by purification by chromatography with reversed phase using the same eluent.

Foetidus 2 has the following characteristics: I. pl. 172 and 174oC. []d-44,6 (c = 0,35, methanol). NMR - spectrum overlap with the spectrum of foetida 1, with the exception of the signal - OCH3on the aromatic ring at 3.2 million dollars.

Example 2. Cooking dried by freezing vials containing foetidus 1.

5 g of foetida 1 was dissolved in 500 ml of distilled water containing 1.2 g of citric acid, the solution was filtered, sterilized and poured into a sterile room 100 bottles, which were immediately frozen and subjected to drying at below 0oC.

1. Alkaloid compounds of General formula I

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in which R represents hydrogen or methoxy.

2. Connection on p. 1, which represents foetidus 1, in which R represents hydrogen.

3. Connection on p. 1, which represents foetidus 2, in which R is methoxy.

4. The method of obtaining compounds is their nizkomolekulyarnymi alcohols or ketones, individually or in a mixture with water at room temperature;

C) the concentration of the extracts at a temperature below the 25oWith in a vacuum;

C) extraction of the water-acetone concentrate obtained by partial removal of the organic solvent, chlorinated solvents to extract weakly alkaline alkaloids;

d) extraction of the aqueous phase n-butanol;

e) cleaning butanolic extracts obtained by concentration at low temperature in vacuum, using chromatography on silica gel, using mixtures of chlorinated solvents and aliphatic alcohols as solvents;

f) concentration to dryness of fractions containing alkaloids, and purification of the residue using preparative GHUR, elution gradient of methanol/water, since the ratio of methanol/water = 1 : 1 to pure methanol;

g) drying by freezing the resulting aqueous extract and crystallization of pure foetida 1;

h) chromatographic purification of the mother liquor from crystallization with reversed phase using the same eluent as in stage f) obtaining foetida 2.

5. The method according to p. 4, characterized in that in stage e) using methylene chloride and methane is a mixture of from 4 : 1 to 1 : 1.

6. The method according to p. 4, characterized in that in stage (f) use column "LiChroprep RP8".

7. Pharmaceutical composition having antitumor and antiviral activity, containing as active ingredient one of the compounds according to paragraphs.1 to 3 in an effective amount.

8. The compound according to any one of paragraphs.1 to 3, which has antiviral and antitumor activity.


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