PL105113B1 - THE METHOD OF MAKING WINKAMEIN - Google Patents

Description

The invention relates to a manufacturing process ingestion of vinamenine, a new type alkaloid vincamine and its salts.

It has been found that in products for the reconstruction of alkaline There are new, undescribed examples of vincamine loid then relationships with valuable properties physiological. So therapeutically active the product is a non-naturally occurring al vincamenine caloid of formula I, which is optical antipode of the naturally occurring al¬ eburnamenine caloid.

According to the invention, vimkamenine of formula loraz its acid addition salts, quaternary salts and molecular compounds are obtained in this a method with a compound of general formula II in which A ~ B is a group of formula (a), (b), (c) or (d), is subjected to thermal treatment and the obtained win- the kamenine is optionally converted into salt ad with acid or quaternary salt relatively in a molecular compound or vinca- menine is freed from salt or carried out in a different salt.

The starting materials used in the process of inoculation The debt of the invention is prepared in the following manner sleigh.

A compound of formula 2, wherein A ~ B represents a group of formula (a), i.e. tartaric acid- m, it is obtained from vinamine by the way saponification (published German patent description See DOS No. 22 53 750, Austrian patent specification no.322,118).

A compound of general formula II wherein A ~ B represents a group of formula (b) i.e. apovin acid rocket, can be obtained from yeast apovincamine saponification (German patent specification No. 1958 514 and Austrian Patent No. 291,446).

Compounds of general formula II in which A ~ B represents groups (c) and (d), that is vinanol relative to not epivinanol, obtained from yeast vinamine saponification (German patent specification No. 1958,514 (German patent specification No. 1,795,146 and Austrian description Patent No. 279,060).

By the method according to the invention, vinkamenine o- is held so that vinaminic acid is of the formula r 2, wherein A ~ B is a group of formula (a), it is heated for about 0.5-4 hours at temperature 150-300 ° C. During this treatment, ter and vinaminic acid is dehydrated and decarboxylation. Both of these reactions can take place chase at the same time or in turn and like this vincaminic acid is converted to vinca menine.

These events are conducted favorably in the atmosphere an inert gas, for example under a nitrogen atmosphere.

The obtained product is then processed in a known manner, for example it dissolves it is not mixed with an organic solvent compatible with water such as ether or carbon hydrogen and an organic solution to remove no 105 113 105 113 3 4 reacted vinaminic acid washed with weighs with an alkaline aqueous solution. Next the organic phase is dried and evaporated. Winkame- nine is obtained as an oily residue.

Thus obtained from an almost quantitative exclusion The yield of vinhamenine is so pure that it is practically no further purification is required.

You can also proceed in such a way that the apinic acid of the formula II, wherein A ~ B is the group of formula (b) is thermally treated preferably in 0.5-4 hours, especially At a temperature of 200-300 ° C. In this case apovincaminic acid is decarboxylated and v thus it becomes winkamenine.

Again, the reactions are carried out preferably under an inert gas atmosphere, preferably dies under nitrogen atmosphere. The product of the reaction can processed as described above.

If in the method according to the invention as a sub starting conditions are vinanol or epi vinanol, i.e. compounds of the general formula 2, w wherein A ~ B is a group of formula (c) or (d), or a mixture of these. Thermal treatment is preferably carried out at a temperature of 170 ° C. 300 ° C for about 0.5-4 hours. During this thermal treatment, preferably carried out at in an inert gas atmosphere, for example in the atmosphere The nitrogen gas, the vinanol and / or the epivinanol undergoes dehydration to give winkamenine.

The reaction product is worked up in this way so that the obtained crude and melted product is re the action is treated with an inert solvent organic. From the obtained solution, lyses pure vinkamenine. As solvents preferably ether-type organic liquids are used such as diethyl ether or halogenated ne hydrocarbons, for example chloroform or dichloromethane.

As starting materials for this variant you can also instead of pure vinegar a table crude vinanol containing epivinanol, because during thermal treatment also epi vinkanol becomes vinkamenine.

Dehydration of vinanol and / or can epivinanol on also preferably lead in the presence of feces talcum dehydration. Egg, catalyst, such a co Alumina is preferably used. Alumina is preferably introduced in large excess, about 2-6 times (based on the mass pro¬ of the output product), because the aluminum oxide with on the side it adsorbs the by-products of the impure looming rising winkamenine, and on the other side In the presence of alumina, dehydration can be performed should be carried out at a temperature of about 40-80 ° C lower than she. After completion of the reaction, the vinegar was obtained nine separates from the alumina by extraction and with an inert organic solvent one.

You can also do so with vinanol relatively the epivinanol is heated under the cooler back with 3-12 times the amount of acid anhydride acetic acid within a few hours, preferably 0.5-3 hours. In this way, dehydration can be carried out today at even lower temperatures.

In this case, the reaction mixture was subjected to they are processed in such a way that they are used as the solvent of the acetic acid anhydride evaporates partially grooved, obtained as a residue the solution is poured into ice water, a water solution the product becomes slightly alkaline (in dilute solution of with a base, for example in a dilute solution sodium hydroxide and the mixture is extracted drawing with the help of water immiscible an inert organic solvent such as like a halogenated hydrocarbon, for example a bicarbonate chloromethane or chloroform.

Instead of acetic acid anhydride you can w the above vinanol dehydration reaction and / or epivinanol also use 80% form acid as a solvent.

The reaction mixture is worked up in the the method described when discussing dehydration in with acetic anhydride. Received after . an oily product is evaporated from the solvent it also contains some pollutants in addition to vincamenine cleaning by-products, in relation to what the oily crude product dissolves into neutral in an organic solvent, preferably in theoretically, for example in diethyl ether, it releases the siphoning route from the insoluble residue, and pure vinkamenine extracts the evaporation route move.

Vinkamenine can be obtained in the form of oily to convert to acid addition salts by reactions with various acids. Addition salts with acids are generally well identifiable fake crystalline substances. Additive salts with acids, for example, with acid themselves with hydrochloric acid, preferably with an acid hydrochloric, with monobasic or polybasic acids carboxylic acid, for example with tartaric acid, and also with picric acid. The salts are made in a solvent environment, preferably in alcohol an aliphatic lobby, for example in ethanol.

Winkamenine can also be carried out in quaternary salts. For this purpose, winkamenine in an inert organic solvent, especially Cha in an aliphatic ketone, for example aceto. no, reacts with an alkyl halide, for example, with methyl iodide. Fourth row vinhamenine salts are generally good substances crystallizing.

You can also make vincaminine molecular compounds with suitable for this purpose relationships. Particularly suitable for this purpose turned out to be picrolonic acid.

The wine obtained by the method according to the invention menin and its salts show a valuable property pharmacological properties.

The haemodynamic action of the hydrochloride of wine kamenins were tested on 8 dogs under anesthesia. Animal they received anesthesia with 30 mg / kg intravenously pen- tobarbital, after which it was also administered intravenously active substance in doses of 1 mg / kg. I'm sorry the following parameters were tested: MABP = arterial blood pressure IjR = pulse CBF = artery carotis interna blood flow CVR = vascular resistance in the artery carotis interna 40 45 51 55 605 105 113 6 FBF = artery femoralis blood flow FVR = vascular resistance in artery femoralis The values of the above parameters were measured before treatment (output values) and after elapse knows 3, 5, 10 and 15 minutes after administration of the active substance on. Value changes are given as a percentage. IN the mean values z are given in table 1 below a range of 8 experiments as a percentage j to the output values.

Table 1 Minutes after administration MABP HR CBF CVR FBF FVR 3 + 1.3 ± 2.5 -8.9 ± 4.3 + 0.3 ± 3.7 + 0.7 ± 3.5 +21.4110.0 -13.0 ± 7.1 + 2.4 ± 3.1 -8.8 ± 4.4 -1.7 ± 3.0 + 3.1 ± 3.5 + 18.6 ± 9.4 -12.9 ± 6.2 + 5.8 ± 6.1 -9.0 ± 3.8 -4.8 ± 1.7 + 4.7 ± 1.7 + 16.4 ± 8.5 -7.9 ± 6.3 \ + 2.9 ± 2.1 -6.5 ± 3.1 -4.8 ± 2.5 + 6.2 ± 3.0 + 15.3 ± 6.9 -10.7 ± 5.1 As shown in Table 1, wimka's hydrochloride menin lowers the number of pulse beats and shows about 15-21% vasodilating effect in the field of femoral vessels.

The effective dose of the active ingredient upon administration intravenously or orally is 1-5 mg / kg.

This dose is a daily dose and may be administered in one portion or several of the same partial doses throughout the day. Profitable the dose is determined in each case on the basis of the constant patient and doctor's experience.

In order to compare the utility effect of new connections with the known connections of Fr. research was carried out in an analogous structure the haemodynamic effect of vincaminic acid it, apovincaminic acid, epivincanol and vinanol.

Hemodynamic action of the above-mentioned known compounds were tested on 6 dogs each relationship. The compounds were administered intravenously in doses 1 mg / kg. The aforementioned parameters of the city 3 minutes after administration of each relationship. The results are presented in Table 2: MABP HR 1 CBF 1 CVR FBF FVR Acid and vinkamine -11.3 ± 2.1 -5.1 ± 1.9 + 2.5 ± 1.6 -7.1 ± 2.1 + 4.3 ± 1.2 -6.1 ± 1.8 Blackboard Acid apovincaminic -7.5 ± 1.9 -3.4 ± 1.6 + 3.8 ± 1.9 -9.7 ± 2.2 + 8.9 ± 1.8 -10.2 + 2.6 and 2 Epivinanol -1.2 + 1.8 + 1.3 ± 1.9 -0.5 + 2.5 + 0.2 ± 1.9 + 1.6 ± 0.6 -1.7 + 0.9 Winkanol -32.4 + 6.2 -M ± 2.8 + 4.6 ± 2.3 -16.2 ± 3.9 + 15.1 ± 6.0 -38.5 + 16.2 From the comparison of the test results obtained for known compounds and for the hydrochloride of win- kamenins can be seen that very relevant in the case vinhamenine has an increasing effect (21.5%) blood flow in the artery femoralis (FBF), especially Cha in the absence of an effect on arterial blood pressure (MABP). In comparison, vinanol shows blood flow in the arteria femoralis (FBF) at strong blood pressure lowering effect blood. Epivinkanol is inactive. Vinca acid Minic acid and apovincaminic acid show barium canine weak action of increasing blood flow in artery femoralis (FBF) while lowering blood pressure (MABP).

The wine obtained by the method according to the invention menine and its salts as active substances in the can to convert into appropriate medications for parenteral or enteral administration mixing route with common solids or liquid pharmaceutical and / or other carriers pharmaceutical auxiliary agents. 50 55 60 65 You can use, for example, water, gelatine, lactose, starches, pectin, stearate magnesium, talc, vegetable oils such as oil from o- groundcakes, olive oil, etc., traganthus, polyethylene glycols, petroleum jelly, etc. Paint preparations pharmaceuticals can be in the usual form sacks such as tablets, dragees, capsules, drinks bumps, suppositories and the like, or in liquid form as an oil liquid or aqueous suspensions, emulsions, syrups, soft gelatine, water or oil capsules injection preparations and the like. Such preparations may also be used do not contain various pharmaceutical substances adjuvants, for example preservatives, solid stabilizers, fragrances, etc., and possibly also possibly further therapeutically active compounds. Pre¬ The paraty is preferably prepared to suit single doses for therapeutic purposes steak. Such pharmaceutical preparations can be produce in a known manner, for example by road grinding, sieving, mixing, granulating, ironing, relatively dissolving, etc., you can them7 105113 8 can also be processed further, if necessary used in the pharmaceutical industry, na sterilization example.

The known compounds are known as further terephthalically active compounds ki that can be combined with the compounds received Other methods of the invention are mentioned for example, theophylline, phenylbarbiturates, ace acid tylsalicylic acid, moreover vitamins, for example wi¬ tamine E or P with which meaning can be obtained ne synergistic actions, and vitamin C. (ascorbic acid) and its salts and derivatives of com plex, which, for example, when serving orally, they accelerate the resorption of vinamenine and therefore they enable faster operation.

Vinkamenine as an active ingredient can be 100 also in the form of pamoate, which is why it is used the prolonged operation becomes effective. By% applied not dioctylsulfosuccinate or laurylsulfate- nu can be used when administering oral preparations eliminate the bitter taste of the active ingredient. Pre¬ parates can also contain some inorganic salts others, for example monoammonium phosphate or alkali metal dihydrogen phosphate, which at when administered orally, they promote the formation of a stable poor solutions. The active substance can be administered also in the form of alkylsulfonate or 2-ke- toglutarate.

EXAMPLE 1 3.4 g (0.01 mol) of tartaric acid The minefield is heated in a sulfonation flask under nitrogen atmosphere in an oil bath or metallic down to the melting point (260 ° C) and the alloy of is kept for 1-2 hours at temperature 240-260 ° C. Heated to melting point vincaminic acid gives off carbon dioxide from at once, but in order to bring the reaction to completion it is kept at a subdued temperature 240-260 ° C. Formation of vincamenine relative to not carrying vincaminic acid in vinamenine is tested by thin chromatography multi-layer (on silica gel plates, using a mixture of 100 as a developing agent parts of chloroform and 14 parts of methanol). When the pla¬ has the characteristic of vinaminic acid disappears from the chiromatogram, reactions can be considered as finished. The remainder of the melt dissolves into a solid stepping in a solvent that does not mix with water, for example in ether, benzene or di- chloroethane and the organic solution are shaken twice with 10 ml of IN aqueous solution sodium hydroxide formation, and then once with ml of distilled water to remove any possible possibly residual unreacted acid vinkamine. The water phases merge and shake with half the volume of an organic solvent immiscible with water. Separated or¬ phase organic is combined with the original organic solution is dried over anhydrous sodium sulfate it is clearing, and the litter evaporates under the lowering low pressure. As a remainder you get 2.70 g of vinamenine (yield near quantitative) in the form of a pale yellow oil. This oily product can only be distilled under high vacuum very high temperatures. Temperature boiling point: 208-210 ° C) 10-4 mm Hg, [a] D = 180 ° (c-1%, in chloroform). Picryan vincamenine is a compound that crystallizes easily mp 170-172 ° C. Relationship molecular with picrolonic acid melts into temperature 218-220 ° C.

Analysis for C19H »2N2: Calculated: C 82.37% H 7.83% N 10.07% Found: C 82.02% H 7.80% N 9.95% Pr z y k l a d II. The example is followed And with the melt of the starting material holding on for 3 hours at a temperature of 240-260 ° C.

2.50 g of vinamenine are obtained (90% of the yield) theoretical value) in the form of a colored oil slightly darker than in example I.

Example III. 3.24 g (0.01 mol) of apo- r of vinamine is heated in a flask to a sulfonate .5 under nitrogen atmosphere in an oil bath or metallic to the melting point and alloy u- kept for 1-2 hours at temperature 250-260 ° C The obtained alloy dissolves in a solvent which is immiscible with water, such as such as ether, benzene or dichloroethane and a solution of or The organic mixture is shaken twice in 10 ml of In water of lower sodium hydroxide solution and then more than once with 10 ml of distilled water to remove possibly remaining unreacted apovincaminic acid. The water phases merge and shakes it out at half the solvent volume organic, immiscible with water. Separate The solid organic phase is combined with the primary solution organic matter, dried over anhydrous sulfur sodium chloride, filter and evaporate the filtrate under reduced pressure. As a remainder it receives 2.10 g (76% of theory) of vinegar nina in the form of pale yellow oil. A picrin of it the product melts at 172 ° C.

Example IV. The example is followed III with the fact that the alloy of the starting substance is maintained at 250-260 ° C for 3 hours.

2.00 g of vincamenine are obtained.

Example 5 1.48 g (0.005 mol) of vinanol heated to 220-250 ° C. under atmosphere nitrogen sphere for 1 hour. The resulting alloy it is then dissolved in ether and the solution is rehydrated gives a treatment as described in example I.

1.98 g (93% of theory) are obtained nej) vincamenine as pale yellow oil.

The picrate of this product is identical properties, such as picrate obtained by app clade I.

Example VI. The example is followed V but the thermal treatment is carried out in within 3 hours. 1.25 g (91% of yield) are obtained theoretical value) of vincamenine oil.

Example VII. 1.48 g (€ .005 mol) raw vinanol is heated at 220-250 ° C under nitrogen atmosphere for 1 hour. Received the alloy then dissolves in chloroform, a the solution is worked up as described in Ex Clade I. 1.20 g (87% yield theoretical) of vincamenine in the form of pale yellow oil. The picrate of this product is identical other properties, such as the picrate obtained in example class I.

Example VIII. It is followed according to the case clade VII with the original u-9 alloy 105113 It is thirteen hours at temperature 250-260 ° C. 1.25 g (91% yield) are obtained theoretical) of vincamenine.

Example IX. I follow the example du V, but instead of ether, roethane as a solvent. 1.25 g are obtained (91% of theory) oily vinegar nina.

Example X. 1.48 g (0.005 mol) of vinanol mixed with three times the amount, that is 4.50 g of oxide of aluminum and the mixture is kept for 1 hour at a temperature of 185-20 ° C. After it cools down the reaction product is extracted with benzene, solution the organic is dried over anhydrous sodium sulfate is choking, and the percolate evaporates to dryness. Received 1.20 g of vinamenine is obtained as pale yellow oil. The picrate of this product is identical physical properties, such as picrate obtained in- long example I.

Example XI. The example is followed X with the fact that instead of 4.5 g is introduced in it in the case of 7.5 g of alumina used as a starting compound in the amount of 1.48 g of vinanol.

1.10 g of identical product are obtained with the product according to example X.

Example XII. 1.48 g (0.005 mol) of vinanol lasts for 1 hour in September a reflux condenser with 7.5 ml of anhydride acetic acid. Then an excess of solvent The solvent is partially evaporated and the remaining solution poured into ice water. Water pH value the mixture is adjusted to 8-9 with 20% sodium hydroxide solution and the obtained al the calcine solution is shaken four times from two chloromethane in amounts approximately such themselves. Combined methane lifts is released by shaking it with a small amount water from residual sodium hydroxide, dry over anhydrous sodium sulfate and evaporated grooves under reduced pressure. As a remainder yield 1.26 g (92% of theoretical yield crude vinaminine in the form of oil.

The picrate of this product melts at temperature 170-172 ° C.

Example XIII. The procedure is as follows: clade XII except that 14.8 g of anhydride are used acetic acid and instead of dichloromethane shakes with chloroform. 1.21 g is obtained an oily product.

Example XIV. 1.47 g (0.005 mol) of vinanol is dissolved in 8 g of an 80% solution of formic acid and the solution is boiled under reflux condenser within 1 hour. Next excess acid is evaporated under reduced pressure pressure, and the remainder poured into water with ice dem. The reaction mixture is then reacted processed as described in example XII. ABOUT- 1.25 g of an oily product is kept. Product this is not a homogeneous vinaminine, but rather a a certain amount of vinane. If this oil is diluted is released in twice the quantity by weight of acetone and the solution is left in the refrigerator, it's a century The majority of the vinane separates from the solution as crystalline.

Example XV. 147 g (0.005 mol) of vinanol boils under the radiator reflux with 80 ml of 80% formic acid solution within 8 hours. Then the mixture of re stock is processed as described in example XIV. 1.20 g of crude are obtained an oily product that cleans itself in a way described above.

Example XVI. 2.78 g (0.01 mole) of vincamine nina (dissolved in 9 ml of absolute ethanol and 1 ml of an ethanolic 36.5% acid solution is added salt. Vinkamenine hydrochloride is lost by dropping about five times the amount of ether.

The hydrochloride initially separates as oily, but crystallizes when left in 13 refrigerated cabinet. 2.70 g of chlorine are obtained Vincamenine dorc with melting point 246-247 ° C, [a] 2D = -50 ° (c = 1% in chloroform).

Analysis for C19HnN2'HCl (molecular weight 316.83): Found: C 72.02% H 7.94%, 9.83% Cl 11.5% Calculated: C 72.15% H 7.98% 9.10% Cl 10.7% Example XVII. 1.39 g (0.005 mole) of wine menin is dissolved in 8 ml of ethanol and inflicted with a solution of 0.375 g of D-tartaric acid in 2 ml of eta nolu. Vincamenine tartrate separates with dilution oily form. This oily product is well soluble in water.

Example XVIII. 0.277 g (0.001 mole) of wine of menin are dissolved in 1.0 ml of acetone and at room temperature, treat 0.5 ml (1.15 g, 0.008 mole) of methyl iodide. After a short standstill, oil is collected on the surface of the clear solution iste drops. After briefly mixing, the product begins to crystallize. The mixture is still left on 1 day in the refrigerator and including time crystallization is complete. Crystalline product it is filtered off, washed with a little acetone and dries. 0.42 g of wine methyl iodide is obtained meninium, m.p. 275 ° C 40 yielding 71% of the theoretical amount. Pre- crystallizing from ethanol, the product shows a optical totality [a] R = -155 ° (c = 1% in chlorine form).

Analysis for CiBH22N2, CH3J (molecular weight «420): Calculated: C 57.38% H 5.80% Found: C 57.20% H 5.73%. 50

Claims (9)

Patent claims 1. Process for the preparation of vincamenine of formula I and its acid addition salts, quaternary salts and molecules, characterized in that a compound of formula II in which A-B is a group of formula (a) is processed temperature at 80-300 ° C for 0.5-4 hours, or in an inert gas atmosphere, and the vinamenine obtained is optionally converted into an acid addition salt or into a quaternary salt or a molecular compound, or into a vinamenine it is freed from salt or converted into another salt. 2. A process for the preparation of vincamenine of formula 1 and its acid addition salts, quaternary salts and molecular compounds, characterized in that a compound of formula 2, wherein A ~ B is the group of formula (b) is subjected to a thermal treatment at a temperature of 80-300 ° C for 0.5-4 hours, optionally in an inert gas atmosphere, and the vinamenine obtained is optionally converted into an acid addition salt or a quaternary salt or a molecular compound, or the winkamenine is released from the salt or converted to a different salt. 3. A process for the preparation of vincamenine of formula I and its acid addition salts, quaternary salts and molecular compounds, characterized by a compound of formula II in which A ~ B is a group of formula (c) or (d) is subjected to a thermal treatment at a temperature of 80-300 ° C for 0.5-4 hours, optionally in an inert gas atmosphere, and the vinamenine obtained is optionally converted into an acid addition salt or a quaternary salt, or The molecule drug or vinamenine is released from the salt or converted to a different salt. 4. The method according to p. The process of claim 3, wherein the thermal treatment is carried out in the presence of a dehydration catalyst. 5. The method according to p. 4. The process of claim 4, wherein alumina is used as the dehydration catalyst. 6. The method according to p. The process of claim 3, wherein the thermal treatment is carried out in a solvent environment. 7. The method according to p. 6. The process of claim 6, wherein the dehydrating solvent is used. 8. The method according to p. The process of claim 7, wherein the solvent is acetic acid anhydride. 9. The method according to p. A process as claimed in claim 7, characterized in that the solvent used is 75-85% formic acid. WZdR 1 HO, HOOC "\ CH ^ WZdR lal HOOC ^ ChT MODEL lbl H HO". CHf PATTERN / c / HO, h "\ h ^ PATTERN Id AND GRAPH. Lz. 1423 copies (95 + 17) copies Price PLN 45