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):
< / BR>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
< / BR>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
< / BR>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.
< / BR>where R represents the residue obtained by removal of COOH from C3-C7sugar carboxylic acids, present in the residue of the hydroxyl group can be protected by means of protective groups
FIELD: medicine, phthisiology.
SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.
EFFECT: higher efficiency of differential diagnostics.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.
EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.
26 cl, 2 tbl, 253 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes diazepane derivative of the general formula (I)
or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.
EFFECT: valuable medicinal properties of compound.
5 cl, 5 tbl, 6 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:
wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.
EFFECT: valuable medicinal properties of compound.
13 cl, 1 dwg, 4 tbl, 16 ex
FIELD: organic chemistry, cardiology, pharmacy.
SUBSTANCE: invention describes compounds of the formula (I)
wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.
EFFECT: valuable medicinal properties of compounds.
41 cl, 1 tbl, 8 ex
SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.
EFFECT: higher efficiency of prophylaxis.
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.
EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.
12 cl, 2 dwg, 32 ex
FIELD: organic chemistry, biochemistry, pharmacy.
SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)
showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.
EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.
14 cl, 11 sch, 7 tbl, 13 ex
FIELD: organic chemistry, pharmacy.
SUBSTANCE: invention relates to new pharmaceutical compositions comprising bicyclic compound of the formula (I): wherein A means -COOH or their functional derivative; X1 and X2 mean hydrogen or halogen atom; V1 and V2 mean carbon atoms; W1 and W2 mean groups and wherein R4 and R mean hydrogen atom, hydroxy-group; Z means carbon, oxygen, sulfur or nitrogen atom; R1 means saturated or unsaturated bivalent (C1-C10)-aliphatic hydrocarbon residue; R2 means saturated or unsaturated (C1-C10)-aliphatic hydrocarbon residue; R3 means hydrogen atom and glyceride. Also, invention relates to a method for stabilizing compositions and novel bicyclic compounds. Invention provides enhancing stability of pharmaceutical composition based on its dissolving in glyceride.
EFFECT: improved and valuable properties of compositions, improved stabilization of compositions.
42 cl, 8 tbl, 8 ex
FIELD: medicine, neurology, virology.
SUBSTANCE: invention relates to treatment of neurological diseases caused by herpes virus, such as Bell's paralysis, Hunt's disease, herpetic encephalitis accompanying with damage of cerebral nerves. Invention involves using 1,4-dihydropyridine blockers of calcium channels, such as felodipine, nifedipine, nimodipine, nisodipine being taken preferably in combination with herpes virus antagonist. Invention provides repairing damaged cerebral nerves by topical expanding arteriols and recovery of local microcirculation based on specific competitive interaction of definite groups of calcium blockers of 1,4-dihydropyridine type with vasoconstrictor endothelin.
EFFECT: enhanced effectiveness of treatment.
47 cl, 2 dwg, 1 ex