CS196378B2 - Mehtod of producing vincamenine - Google Patents

Abstract

The new alkaloid of the vincamine type of the formula <IMAGE> and addition salts thereof are prepared. The new compound is obtained by subjecting either vincamic acid to dehydration and decarboxylation or by decarboxylating apovincamic acid. The compound obtained is converted into quaternary ammonium salts.

Description

The present invention provides a process for the preparation of a novel alkaloid of the vincamine type and its salts.

It has been found that among the degradation products of the vincamine alkaloid there are other novel compounds not yet described in the literature, having valuable physiological properties. Such a therapeutically effective product is the vinca-menin alkaloid of formula I,

which does not occur in nature and is the optical antipode of eburnamenine alkaloid, occurring in nature.

The novel wolkimenin alkaloid of formula I and its acid addition salt, quaternary salts and molecular compounds are prepared by the process of the invention by producing a compound of formula II wherein:

A-B represents a group of formula (a), (b), (c) or (d),

HOOC '(a.). · *

The HOOC4 -W (b) is subjected to a heat treatment and optionally the obtained vinca-amino is converted into an acid addition salt or a quaternary salt, optionally a molecular compound, or the vinca-amino is released from its salt, optionally converted into another salt.

The starting materials used in the process according to the invention can be prepared as follows:

The compound of formula (II) in which A-B is a group of formula (a), i.e., vincamic acid, is obtained from vincaimine by simple saponification (see German publication DOS 2253 750, Austrian patent 32'2118).

A compound of formula Π wherein A-B

198376

means a group of formula (b), i.e. apovincaminic acid, can be prepared from apovincamine by saponification (see German Patent Specification 1958 514 and Austrian Patent Specification 291446). Compounds of formula (II) wherein A-B is one of groups (c) and (d), i.e., vincanol or eplvincanol, can be obtained from vincamine by reduction of lithium aluminum hydride (cf. German Pat. No. 279,060).

Method according to 'the invention' to produce vínkamenlnu is effected, for example, 'that the acid ^ J ^ ni- ·' vincaminic ^[1 of Formula II, wherein A-B is &apos; (a)] is heated form 0.5 to 4 hours at a temperature between 150 ° C and 300 ° C. During this heat 'treatment', the vincamic acid is dehydrated and decarboxylated; both of these reactions may be carried out simultaneously or sequentially, thereby converting the vincamic acid into the vincamenine. .

This reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen. Get-. . The reaction product is then processed in a known manner; it dissolves', for example, in an organic, water-immiscible solvent, Ether or hydrocarbon, and the resulting organic solution is washed. aqueous alkaline solution to remove nonreactic acid "tartaric acid." · "Pakistan", the organic phase is dried and evaporated; vincamenin remains as an oily product. The vincamenine thus obtained in almost quantitative yield is so pure that practically no further purification is required.

In another variation of the process of the present invention, a heat treatment of 0.5 to 4 hours at a temperature in the range of 200 to 300 ° C is subjected to pancinnamic acid [II] wherein A-B is a group [b). . In this case, apovincaminic acid is decarboxylated 'and thereby converted to vinca-amine,'. . ·. · .. '

In this case too, it is advantageous to carry out the heating in an inert gas atmosphere, preferably nitrogen; further processing of the reaction product may be carried out as described above. . .. ·

In the 'further variation of the process of the invention', the starting material used is vincanol or epivincanol [a compound of formula II, wherever 'A ~ B.' Is a group (c). or '(d)]' or 'these' compounds; The 'warming up' will be done at room temperature. between 170 and 1300 °! .after. a period of about 0.5 to 4 hours. During this'. heat treatment, 'effected' conveniently in an inert gas atmosphere, for example. of nitrogen, vincanol and / or epivlnanol is 'dehydrated' and is thus converted into vincamenine. , .., ·. .

To 'treat the reaction product, the obtained' crude melt 'of the reaction product is treated with an inert organic solvent; '' _THAT. ' of the resulting solution, the system is pure vincamenine. Suitably, organic ether liquids such as diethyl ether or halogenated hydrocarbons such as chloroform or dichloromethane are used as solvents. "What starting materials in this process"is; it is possible to use 'crude' vincanol containing epivincanol instead of 'pure' vincanol, since in the heat treatment also epivincanol is converted into vincamenine.

The dehydration of the vincanol '- / or epi-ethanol' can also be carried out preferably in the presence of a 'dehydration' catalyst. As such. It is expedient to use the alumina which is preferably used. It is used in large excess, about two to six times the amount (based on the weight of the starting material), since the aluminum oxide present on the one hand adsorbs the by-product. pollutant resulting vinkamenin, "secondly in the presence of aluminum oxide · dehydration may be carried out at a temperature of about 40 C ^and 80 .When lower. Upon completion of the reaction, the resulting vincamine is separated from the alumina by extraction with an inert organic solvent.

In another embodiment of this reaction, the vincanol, optionally epivincanol, is heated to reflux in 3 to 12 times the amount of acetic anhydride for several hours, preferably 0.5 to 3 hours. This allows' no 'dehydration to work at an' even 'lower' temperature.

. -To process the reaction mixture, in this case, part of the acid amide. The acetic acid used as the solvent evaporates, the remaining solution is poured into the ice water formed, the mixture is slightly alkalinized with a dilute alkali solution, e.g. a dilute lye. sodium, and 'perfect' extracts with an inert_ non-water-miscible organic solvent, such as a halogenated hydrocarbon, conveniently 'dichloromethane' or chlorofluoride. mem. .. '/

Instead of the acetic acid anhydride, 80% of formic acid can also be used as solvent in the dehydration of vincanol and / or epivincanol described above. The reaction mixture is treated as in dehydration by acetic anhydride. The oily ip-product obtained after evaporation of the solvent contains, in addition to the manufactured tartar, some polluting by-products; therefore, the crude oily product is dissolved in an inert organic solvent, preferably in an ether, for example diethyl ether, by filtration to remove insolubles, and the pure vinamines are isolated by evaporation of the filtrate.

The vinca-amine obtained in the form of an oil can be converted into the appropriate acid addition salts by reaction with various acids, which are mostly easily identifiable crystalline substances. In this way, acid addition salts, for example with hydrohalic acids, preferably hydrochloric acid, monohydric or polybasic carboxylic acids, can be prepared,

198378, for example with tartaric acid, followed by pluric acid. The salt formation reaction is carried out in a solvent, preferably an aliphatic alcohol, for example ethanol.

Vincamenine can also be converted into quaternary salts. For this purpose, the vinca-amine is reacted in an inert organic solvent, preferably an aliphatic ketone, for example acetone, with an alkyl halide, for example methyl iodide. Quaternary salts of vinca-amine are usually well crystallizable compounds. 1 molecular compound can be prepared from vinca-amine using suitable compounds in a known manner; Especially well suited for this purpose is plic acid.

Vlnkamerijň ;. and its sqII, produced by the method according to the invention, have valuable pharmacological properties; .

Memodynamic effect of tartrate hydrochloride. was tested on 8 narcotized dogs; Animals were anesthetized with 30 mg / kg of intravenous Pentobarbital; the drug was also administered intravenously at doses of 1 mg / kg. '

The following parameters were measured: - arterial pressure (MABP), pulse rate (HR), carotid artery flow (CBF), resistance to flow in the carotid artery (CVR), femoral arterial flow (FBF), flow resistance in the femoral artery (FVR).

The values of the above parameters were measured before application of the active substance [baseline] as well as 1, 3, 5, 10 and 15 minutes thereafter; changes in values were expressed as a percentage. In the table below, the mean values of the eight trials and the variation are given as a percentage of the starting value.

Minutes after application 3 '1 5 10 15 Dec MABP + 1,3 ± 2.5 + 2,4 ± ’ 3.11 + 5.8 • ± 6.1 . + 2.9 · ± 2.1 3.1 H.R —8.9 ± 4.3 —8.8 ± • 4.4 —9.0 ± 3.8 • —6.5 ± CBF. + 0.3 ± 3.7 -1.7 ± 3.0 -4.8 ± 1.7 -4.8 + 2.5 CVR. . + 0.7 ± 3.5 + 3,1 ± 3.5. + 4.7 ± 1.7  +6,2 ±. 3.0 FBF + 21.4 ± 10.0 + 18.6 + 9.4 + .16,4 ± 8.5. · + 15.3 -and 6.9 FVR · —13.0 ± 7.1 —12.9 ± 6.2 -7.9 + 6.3. -10., 7. ± 5.1

From the results shown in the table, it appears that vincamenine hydrochloride reduces the number of types and has approximately 15 to 21% vasodilating effect on the femoral vessel area.

The effective dose of such compounds for intravenous' or oral administration are in the range of 1-5 mg / kg ^ This dose is calculated for one day and can be administered in one or more of the same portions during the day: Best .dávka _R is in each case determined depending on the condition of the patient and the experience of the physician. .

The vinca-amine and its salts produced by the process of the invention may be formulated as active ingredients by mixing with conventional solid or liquid pharmaceutical carriers and / or other pharmaceutical excipients into pharmaceutical compositions suitable for parenteral or enteral use. As carriers, for example, water may be used. gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, etc., tragacanth, polyethylene glycols, petrolatum, etc. The pharmaceutical compositions may be formulated in conventional forms, e.g. as tablets, dragees, capsules, pills, suppositories, etc., or in liquid form, such as oily or aqueous suspensions, emulsions, syrups, soft gelatin capsules, injectable aqueous or oily solutions, etc. These compositions may also contain various pharmaceutical auxiliaries, for example preservatives, stabilizers, flavoring agents, etc., and optionally other known therapeutically active compounds. The compositions of the present invention are conveniently manufactured in dosage units suitably adapted to the intended therapeutic use. These compositions may be prepared by conventional methods, for example, by milling, sieving, mixing, granulating, pressing, or dissolving, and may optionally be subjected to other processes customary in the pharmaceutical industry, for example sterilization.

Other known therapeutically active compounds which can be combined with the compounds produced by the process according to the invention are, for example, thiophyllin, phenybarbiturate, acetylsalicylic acid; furthermore ^, vitamins, such as vitamin E or P, which can produce a significant synergistic effect, as well as vitamin C (ascorbic acid) and its salts and complex derivatives, which, for example, when taken orally, accelerate the absorption of vincamenine and thereby achieve faster effects. Vincamenine can be used as active ingredients. use as pamoate for a more lasting effect; by using a dioctyl sulfosuccinate or lauryl sulfate salt, the bitter taste of the active ingredient can be paralyzed in the orally administrable compositions. The compositions may further contain certain inorganic salts, for example monoammonium phosphate or monoalkaliphosphate, which, when administered orally, favorably affect the stability of the solutions. If desired, the active compounds can be used

198378 to be used in the form of an alkyl sulfonate or 2-ketoglutarate.

The method of the invention is. further explained below! but not limiting its scope.

He did

3.4 g) 0.01 mole) of the cyanic acid are heated in a sulfurizing flask under a nitrogen atmosphere in an oil or metal bath to a melting point of 250 DEG C. and the melt formed is maintained at a temperature of 240 DEG C. up to 260¾ for 1 to 2 hours. Vincaminic acid,. heated to the melting point, immediately releases carbon dioxide, but is maintained at said temperature of 240-260 ° for a longer period of time to complete the reaction. The formation of vincamenine, i.e. the conversion of vincaminic acid to vincamenine, is monitored by silica gel thin-plate chromatography (wash system · mixture · 100 parts of chloroform · and 14 parts of methanol). The reaction can be considered to be complete when the spot characteristic of vincamic acid is removed from the chromatogram. The remainder of the melt is then dissolved in. a water-immiscible solvent such as ether, benzene. Or dichloroethane, and the organic solution is washed twice with 10 ml of aq. Sodium hydroxide solution each time, then shaken once with 10 ml of distilled water to remove any unreacted vincamic acid remaining. The aqueous phases are then combined and shaken with half the volume of an organic, water-immiscible solvent. The separated organic phase was combined with the accompanying organic solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. . .

The residue was 2.70 g of vinca-amine (almost quantitative yield) as a pale yellow oil. This oily product can only be distilled under high vacuum at very high temperature. Boiling point: 1.33-10-2 Pa: 208 DEG -210 DEG C., [ _.alpha. ] _D = 180 DEG (c = 1% in chloroform).

Five times vinegar is. well-crystallizable compound having a melting point in the range of WO to 172 ° C. .

The molecular compound with picrolonic acid melts at a high temperature in the range of 218-220 ° C. ·,

Analysis · prp. . C19H22N2:

calculated.

82.37 0/0 · C, 7.83% H, 10.07 PPo N,

Й Й 1.Q 7OT

82.02 ю / o C, 7.80% · H, 9.95% N.

Example · 2

The procedure of Example 1 is followed. Only the melt of the starting material is heated at a temperature

240 to 260 ^o C for three hours. This gives 2.50 g of vinca-amine (9-0% of theory) as an oil whose color is somewhat darker than the color! product ζ example 1..

Example 3,

On an oil or metal bath, 3.24 grams (0.01 mol of apovincaminic acid) are heated to the melting point in a sulfurizing flask under a nitrogen atmosphere, and the resulting melt is heated at 2 ° C to 260 ° C pm for 1 to 2 hours. the melt is dissolved in a water-immiscible solvent such as ether, benzene or dichloroethane, and the organic solution is shaken twice with 10 ml of aqueous sodium hydroxide solution each time and then once with 10 ml of distilled water to remove any residue. unreacted apovincaminic acids · The aqueous phases · combine and shake · half the volume of organic, non-water-borne solvent · The separated organic phase · combine with the original organic solution, dry with anhydrous sodium sulfate, filter and the filtrate was evaporated under reduced pressure.

As a residue, 2.10 · kg of vinca-amine are obtained (76% · theory) as a pale yellow oil. Five times this product melts at 172 ° C.

Ex

The procedure of Example 3 is followed, except that the melt of the starting material is heated at 250 to 260 ° C for 3 hours. 2.0 g of vincamenine are obtained.

Example 5

1.418 · g (0.005 mol) of vincanol are heated at a temperature in the range of 220 to 250 ° for one hour in a nitrogen atmosphere. Acquired melt. The mixture is then dissolved in ether and the solution is treated as described above. in the example

1. Obtained. (988% of theory) as a light yellow oil. Five times this product has identical properties to the picrate prepared according to Example 1.

Example 6

The procedure of Example 5 was followed, except that the heating was carried out for three hours. 1.25 g of oily tartrate oil are obtained. (91 percent ttorit).

Example 7. .

1.418 g (0.005 mol) of crude vincanol was heated at 220-250 ° C for one hour under a nitrogen atmosphere. · The melt is then dissolved in chloroform and • the solution was treated as described in Example ·!., Yielding 1.20 g · 'vinkameninu · (87 · β / ο theory) of ^1' form svěCle · · yellow oil. Twice of this product, it has identical ϊ 9.03 7 8 properties ... with four times the preparation. according to Example 1.

Example 8.

The procedure is as in Example 7, except that the melt of the starting material is heated for 3 hours at a temperature in the range of 2'50 to 260 ° C. 1.215 g of vincamenine (91% of theory) are obtained.

Example 9

As in Example 5, dichloroethane was used as the solvent instead of ether. 1.26 g of oily vincalamine (91% of theory) are obtained.

Example. 1.48 g (0.006 mol) of vincanol are mixed with three times the amount of 4.50 g of alumina and heated at 186 DEG-200 DEG C. for one hour. After cooling, the reaction product is extracted with benzene, and the organic solution is dried over anhydrous. sodium sulfate, filtered and the filtrate evaporated to dryness. 1.20 g of vincamenine are obtained in the form of a pale yellow oil. The filtrate of this product has identical properties to the filtrate prepared according to Example 1.

Example 11

The procedure is as in Example 10, except that 7.5 g of alumina are added in place of 4.5 g to 1.48 g of vincanol used as starting material. Yield 1.10 g. Quality is the same as in Example 10.

Example 1 a d 12

F

1.48 g (0.05 mmol) of vincanol are heated under reflux in 7.5 ml of acetic anhydride for one hour. The excess solvent was then partially evaporated and the remaining solution was poured into ice water. The pH of the aqueous mixture was adjusted to 8-9 by addition of 20% sodium hydroxide solution, and the alkaline solution thus obtained was shaken four times with equal portions of dichloromethane. The combined dichloromethane extracts were then freed from sodium hydroxide by shaking with a small amount of water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. 1.26 g of crude vincamenine (92% of theory) are obtained in the form of an oil. This product melts at 170-172 ° C five times.

Example 1 a · d 13

The procedure is as in Example 12 except that 14.8 g of acetic anhydride is used and the reaction mixture is shaken with chloroform instead of dichloromethane. 1.20 g of an oily product are obtained.

Example 14.

1.47 g (0.005 mol) of vincanol are added. is dissolved in 8 g of 80% formic acid and the resulting solution is refluxed for one hour. Excess acid is then distilled off under reduced pressure and the residue is poured into ice water. The reaction mixture was further worked up as described in Example 12. 1.25 g of an oily product were obtained. This product is not a uniform vinegar product but also contains certain. amount of wavelet. This oil was dissolved in twice the amount of acetone by weight, and if the solution was left in the refrigerator, most of the vincamine was separated from the solution in crystalline form.

Example 15 ^p

1.47 g (0.005 mol) of vincanol are heated to reflux for 8 hours in 80 ml of 80% formic acid. The reaction mixture is then worked up as described in Example 14. 1.20 g of crude oil are obtained which can be purified as described.

Example 16

2.78 g (0.01 mol) of vinca-amine are dissolved in 9 ml of anhydrous ethanol, and 1 ml of an ethainolic, 36.51% hydrochloric acid solution is added to the solution. Vinca-amine hydrochloride is precipitated by dropwise addition of about five times the amount of ether. First, the hydrochloride is excreted as an oil, but crystallizes on standing in the refrigerator.

This gives 2.70 g of vincamenine hydrochloride, m.p. 246 DEG-247 DEG C. [ _.alpha. ] _D @ ²⁰ = -50 DEG. (с = 1%, in chloroform).

Analysis for C 19 H 22 N 2. HC.1 (molecular mass 316.83):

calculated

72.02. % C, H 7.94, N 9.83, Cl 11.5,

% H, 7.98; H, 9.10; Cl, 10.7.

Example 17

Dissolve 1,39 g (0,005 mol) of vincamenine in 8 ml of ethanol and add a solution of 0,375 g of tartaric acid in 2 ml of ethanol. The tartarate tartrate is precipitated from the solution in the oily form. This oily product is well soluble in water.

Example 18

0.277 g (0.001 mol) of vincamenine are dissolved in 1.0 ml of acetone and 0.5 ml (1.15 g, 0.008 mol) of methyl iodide are added at room temperature. After standing for a short time, oily accumulates on the surface of the clear solution

6378 'drops; After brief stirring: the product starts to crystallize. The mixture is left to stand in the refrigerator for one day, after which crystallization is complete; Crystalline product; it is filtered off, washed with a small amount of acetone and dried; - -tím- sé'získá O, ^42-am-i g.vink ENI _Niu-i-m- methyljod chloride. (7% of theory) m.p. 275 DEG. '.

After - -překrystalování '- · - & ethanolu- product appears - optical - -oŤáčiv.ost- [a ^.] = 2P-i »- -155 ° ^(c = - 1% in Lot-chloro ^ Irirmu);

Aiuaiýaa pro C19HMN2. CH 3 - (molecular: 420; 420):. calculated. - - 57.38% Q, - 5.8Q-% - H, found C 57.20, H 5.73

EXAMPLE 19 These are used. Substances · - in <listed - quantities:

vincamenin hydrochloride 5g magnesium stearate 3.g talc. / 5g potato starch. . 40g dairy · 95'g;

The active ingredient is mixed with 3/4 of the amount of potato starch and milk sugar. . The homogeneous mixture is bent with an aqueous solution of gelatin, whereupon it is granulated - and dried. The dry granulate is mixed with the grease, the remaining 1/4 of the potato starch and the magnesium stearate, and the resulting mixture is compressed into 1000 tablets of each weight. 150 mg. Tablets may be provided with a separating score to facilitate dosing.

Tablets containing hydrotreatment. '

Claims (11)

1. Method of production of vipKamenín. of formula (1) (n as well as its acid addition salts, quaternary salts, α-molecular compounds), characterized in that the compound is generally a , - a pattern, c-IJ, wherein A-B 'is one of - groups of formula', a), (b), (c} or - (d), HOOC ^LH from fa.) · AND HOOC ^LH (b); I w ^CH Z. (c) -v. - a molecular compound, or a vincamenine. relaxed -ze - -your? the salts, if any, is converted; other; salt. ' 2. Method - Share, Item 1; characterized in that - wolframic acid is used as starting material. 3. The method of claim 1, wherein the method is as follows. The starting materials used are α-povinkamic acid. ' 4. Method, report claim 1, characterized, in that 'it is. · - starting material - used vinkanhu.-or- eipivi.nk-a.nolu _-. ' 5. A process according to any one of claims 1 to 4, wherein the heat treatment is carried out at a temperature in the range of 80 to 300 ° C after. - up to 4 hours. .. 6. Method; 1 to 4, characterized in that:. se? heat treatment: carried out at a temperature in the range of 1 ° C to; 26070 - for., 1 to - 3 hours ... 7. Method according to points; l ·. to -4, denoting. The heat treatment is carried out in an inert atmosphere. · ’·. ' 8. The method of the invention. 4- characterized. This is because the heat treatment is carried out in the presence. déhýdraíačníh.o. of the catalyst. ' 9. A method according to claim 8, wherein the method is as follows. such as dehydration tin-o- catalysts of pairfire, oxidizer; aluminum. ' IQ. Method according to. 4, characterized in that the heat treatment is carried out. v <dehydration: acting; A solvent. 11. The process of claim 1, wherein the solvent is acetic anhydride. 13. A process according to claim 10, wherein the solvent is 75-75% 85% - acids, - formic. subjected to a heat treatment and to the obtained vinylamine _; - if necessary, is converted. in, editorial, acid ¹ - or, in, or