CH631175A5 - Processes for preparing a novel alkaloid of the vincamine type and salts thereof. - Google Patents

Abstract

The novel alkaloid of the vincamine type of the formula <IMAGE> and acid addition salts thereof are prepared. This compound is obtained by subjecting either vincanol or epivincanol to a heat treatment, resulting in a dehydration. The compound of the formula I is converted into corresponding quaternary ammonium salts. The novel compounds can be used as haemodynamic agents.

Description

The invention relates to processes for the preparation of a new alkaloid of the vincamine type and salts thereof.

It has been found that the degradation products of the alkaloid vincamine include further physiologically valuable effects which have new compounds and have not been described in the literature to date. Such a therapeutically active product is the new alkaloid vincamenin of the formula which does not occur in nature

(II)

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(I)

the optical antipode of the naturally occurring alkaloid eburnamenin.

The new vincamenin of the formula I and its acid addition salts are prepared according to the invention by signifying a compound of the formula

is subjected to a heat treatment and, if appropriate, a compound obtained is converted into the corresponding acid addition salts.

2. The method according to claim 1, characterized in that one carries out the heat treatment at 80 ° C to 300 ° C for 0.5 to 4 hours, preferably at 100 ° C to 260 ° C, for 1 to 3 hours.

3. The method according to claim 1, characterized in that one carries out the heat treatment in an inert gas atmosphere.

4. The method according to claim 1, characterized in that one carries out the heat treatment in the presence of a dehydration catalyst.

5. The method according to claim 4, characterized in that aluminum oxide is used as the dehydration catalyst.

6. The method according to claim 1, characterized in that one carries out the heat treatment in a solvent.

7. The method according to claim 6, characterized in that one uses a dehydrating solvent.

8. The method according to claim 7, characterized in that acetic anhydride is used as the solvent.

9. The method according to claim 7, characterized in that one uses 75 to 85% formic acid as a solvent.

(II)

55

C or

\ /

2

(a)

(b)

60 means

is subjected to a heat treatment and, if appropriate, a compound obtained is converted into the corresponding acid addition salts.

The corresponding quaternary ammonium salts are prepared from the compound of formula I obtained by reaction with an alkyl halide.

The vincamenin can be released from one salt or converted into another salt.

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The starting materials of the process according to the invention can be produced in the following way:

The compounds of the general formula II in which A ~ B represents one of groups (a) and (b), i.e. vincanol or epivincanol, can be obtained from vincamine by reduction with lithium aluminum hydride (cf. DT-PS 1795146; OE-PS 279 060) can be obtained.

The heat treatment according to the invention is advantageously carried out at 170 ° to 300 ° C. for about 0.5 to 4 hours. During this, suitably in an inert gas atmosphere, e.g. The Vincanol and / or Epivincanol are dehydrated in a heat treatment carried out in a nitrogen atmosphere and thus converted into Vincamenin.

To work up the reaction product, the crude molten reaction product obtained can be treated with an inert organic solvent; The pure vincamenin crystallizes out of the solution obtained. Ethereal organic liquids are expediently used as solvents, e.g. Diethyl ether or halogenated hydrocarbons e.g. Chloroform or dichloromethane used.

Instead of pure vincanol, crude vincanol containing epivincanol can also be used as the starting material for this process, since the epivincanol is also converted into vincamenin during the heat treatment.

The dehydration of vincanol and / or epivincanol can advantageously also be carried out in the presence of a dehydration catalyst. Aluminum oxide can expediently be used as such a catalyst; the aluminum oxide is advantageously in large excess,

used in about 2-6 times the amount (calculated on the weight of the starting material), since the aluminum oxide present on the one hand adsorbs the by-products which contaminate the vincamenin formed and, on the other hand, the dehydration can be carried out at around 40-80 ° C lower temperature in the presence of aluminum oxide. After the reaction has ended, the vincamenin formed can be separated from the aluminum oxide by extraction with an inert organic solvent.

According to another preferred embodiment of this reaction, the vincanol or epivincanol is boiled under reflux in 3-12 times the amount of acetic anhydride for a few hours, advantageously 0.5 to 3 hours. In this way, the dehydration can be carried out at an even lower temperature.

In this case, the acetic anhydride used as solvent can be partially evaporated to work up the reaction mixture. The remaining solution is preferably poured into ice water, the aqueous mixture can be mixed with the dilute solution of a base, e.g. with dilute sodium hydroxide solution, made slightly alkaline and with an water-immiscible inert organic solvent, e.g. exhaustively extracted with a halogenated hydrocarbon, suitably with dichloromethane or chloroform.

Instead of acetic anhydride, 80% formic acid can also be used as solvent in the embodiment of the dehydration of vincanol and / or epivincanol described above.

The reaction mixture can be worked up as described after the dehydration carried out in acetic anhydride. The oily product obtained after evaporation of the solvent contains certain contaminating by-products in addition to the desired vincamenin, therefore the oily crude product is usually in an inert organic solvent, advantageously in an ether, e.g. Diethyl ether, dissolved, freed from the insoluble residue by filtration and the pure vincamenin isolated by evaporating the filtrate.

The vincamenin obtained in oily form can be converted into the corresponding acid addition salts by reaction with various acids; the acid addition salts are mostly easily identifiable crystalline substances. In this way e.g. with hydrogen halides, advantageously with hydrochloric acid, with mono- or polybasic carboxylic acids, e.g. with tartaric acid, furthermore with acidic salts formed with picric acid. Salt formation is usually carried out in a solvent, advantageously in an aliphatic alcohol, e.g. performed in ethanol.

The vincamenin is also converted into quaternary salts. For this purpose the vincamenin can be used in an inert organic solvent, suitably in an aliphatic ketone, e.g. in acetone with an alkyl halide, e.g. be reacted with methyl iodide. The quaternary salts of vincamenin are mostly well crystallizable compounds.

With suitable compounds, it is also possible to produce molecular compounds from the vincamenin in a manner known per se; Picrolonic acid is particularly suitable for this purpose.

The vincamenin and its salts which can be produced by the process according to the invention have valuable pharmacological properties.

The hemodynamic effect of vincamenin hydrochloride was investigated in 8 anesthetized dogs. The animals were given 30 mg / kg i.v. pentobarbital administered anesthetized; the active ingredient was then administered IV in doses of 1 mg / kg. The following parameters were examined:

arterial blood pressure (MABP),

Pulse rate (HR),

Blood flow in the internal carotid artery (CBF), vascular resistance in the internal carotid artery (CVR), blood flow in the arteria femoralis (FBF), vascular resistance in the arteria femoralis (FVR).

The values of the above parameters were measured before the treatment (starting value), as well as 3.5, 10 and 15 minutes after the administration of the active compound; the change in values was evaluated in percent. The table below shows the mean values of 8 tests and the scatter, in percentages based on the starting value.

Minutes after administration:

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MABP

+ 1.3 + 2.5

+ 2.4 ± 3.1

+ 5.8 ± 6.1

+ 2.9 ± 2.1

MR

-8.9 ± 4.3

-8.8 ± 4.4

-9.0 ± 3.8

-6.5 ± 3.1

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 ± 6.9

FVR

-13.0 ± 7.1

- 12.9 ± 6.2

-7.9 ± 6.3

- 10.7 ± 5.1

It can be seen from the results summarized in the table that the vincamenine hydrochloride reduces the pulse number and has an approximately 15-21% vasodilator effect on the femoral vascular area.

The effective doses of these agents are between 1 mg / kg and s when administered intravenously or orally

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5 mg / kg. This effective dose is calculated as one day and can be administered at once or during the day in several sub-doses that are the same as one another. The most advantageous dosage in any given case can be determined on the basis of the condition of the patient and the experience of the doctor.

The vincamenin and its salts produced according to the invention can be processed as active ingredients, by mixing with the customary solid or liquid pharmaceutical carriers and / or other pharmaceutical auxiliaries to give the customary pharmaceutical preparations suitable for parenteral or enteral administration. As carriers, e.g. Water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils, such as e.g. Peanut oil, olive oil, etc., tragacanth, polyethylene glycols, petroleum jelly, etc. can be used. The pharmaceutical preparations can be in the usual forms, e.g. as tablets, dragees, capsules, pills, suppositories etc., or in liquid form as oily or aqueous suspensions, emulsions, syrups, soft gelatin capsules, injectable aqueous or oily solutions etc. Such preparations can also contain various pharmaceutical auxiliaries, e.g. Preservatives, stabilizers, flavorings, etc., and optionally also contain other known, therapeutically active compounds. The preparations are advantageously produced in dosage units suitable for the intended therapeutic use. These pharmaceutical preparations can be made according to the usual methods, e.g. by grinding, sieving, mixing, granulating, pressing or dissolving, etc. and can optionally also be subjected to further treatments customary in the pharmaceutical industry, e.g. be sterilized.

Further therapeutically active known compounds which can be combined with the compounds which can be prepared according to the invention include e.g. Theophylline, phenyl barbiturate, acetylsalicylic acid, also vitamins, e.g. Vitamin E or P, with which significant synergetic effects can be achieved, as well as vitamin C (ascorbic acid) and its salts and complex derivatives, which e.g. when administered orally, accelerate the absorption of vin-camenine and thereby enable the effects to occur more quickly. The vincamenin can also be used as an active ingredient in the form of pamoate, whereby a more permanent effect can be achieved; by using the dioctyl sulfosuccinate or lauryl sulfate salt, the bitter taste of the active ingredient can be eliminated in the case of preparations to be administered orally. The preparations can also contain certain inorganic salts, e.g. Contain moncammonium phosphate or a monoalkali phosphate, which promote the formation of stable solutions when administered orally. If necessary, the active ingredient can also be used in the form of an alkyl sulfonate or 2-ketoglutarate.

The process according to the invention is illustrated in more detail by the examples below; however, the invention is in no way limited to the content of these examples.

example 1

1.48 g (0.005 mol) of Vincanol are heated at 220-250 ° C in a nitrogen atmosphere for one hour. The melt obtained is then dissolved in ether and the solution is worked up. 1.98 g of vincamenin (93% of theory) are obtained in the form of a light yellow oil. The picrate of this product is a good crystallizing compound: F 170-172 ° C

Example 2

The procedure is as in Example 1, with the difference that the heat treatment is carried out for three hours. 1.25 g of oil-like vincamenin (91% of theory) are obtained.

Example 3

1.48 g (0.005 mol) of crude vincanol are heated at 220-250 ° C in a nitrogen atmosphere for one hour. The melt obtained is then dissolved in chloroform and the solution is worked up. 1.20 g of vincamenin (87% of theory) are obtained in the form of a light yellow oil. The picrate of this product shows identical properties to the picrate obtained according to Example 1.

Example 4

The procedure is as in Example 3, with the difference that the melt of the starting material is kept at 250-260 ° C. for three hours. In this way, 1.25 g of vincamenin (91% of theory) are obtained.

Example 5

The procedure is as in Example 1, with the difference that dichloroethane is used as the solvent instead of ether. 1.25 g of oil-like vincamenin (91% of theory) are obtained.

Example 6

1.48 g (0.005 mol) of vincanol are mixed with three times the amount, ie with 4.50 g of aluminum oxide, and the mixture is kept at 185-200 ° C. for one hour.

After cooling, the reaction product is extracted with benzene, the organic solution is dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness. 1.20 g of vincamenin are obtained in the form of a light yellow oil. The picrate of this product shows identical properties to the picrate obtained according to Example 1.

Example 7

The procedure is as in Example 6, with the difference that instead of 4.5 g in this case 7.5 g of aluminum oxide are added to the 1.48 g of vincanol used as the starting material. Yield: 1.10; the quality of the product is the same as in example 6.

Example 8

1.48 g (0.005 mol) of Vincanol are boiled under reflux in 7.5 ml of acetic anhydride for one hour. The excess of the solvent is then partially evaporated and the remaining solution is poured into ice water. The pH of the aqueous mixture is adjusted to 8-9 with 20% sodium hydroxide solution and the alkaline solution obtained in this way is shaken four times with approximately equal amounts of dichloromethane. The combined dichloromethane extracts are freed from the remaining sodium hydroxide solution by shaking with a little water, dried with anhydrous sodium sulfate and evaporated in vacuo. 1.26 g of crude vincamenin (92% of theory) are obtained as an oily residue. The picrate of this product melts at 170-172 ° C.

Example 9

The procedure is as in Example 8, with the difference that 14.8 g of acetic anhydride are used and is shaken out with chloroform instead of dichloromethane. The oily product obtained weighs 1.21 g.

Example 10

1.47 g (0.005 mol) of Vincanol are in 8 g of 80% Amei4

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dissolved sensic acid and the solution boiled under reflux for one hour. The excess acid is then evaporated in vacuo and the residue poured into ice water. The reaction mixture is then worked up in the manner described in Example 8. 1.25 g of oily product s are obtained. This product is not a uniform vincamenin, but also contains a certain amount of vincan. If you dissolve this oil in twice the amount of acetone and leave the solution in the refrigerator, the majority of the vincan is separated from the solution in crystalline form.

Example 11

147 g (0.005 mol) of Vincanol are boiled under reflux in 80 ml of 80% formic acid for 8 hours. The reaction mixture is then worked up in the manner described in Example 10. 1.20 g of crude oily product are obtained, which can be purified in the manner described.

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Example 12

2.78 g (0.01 mol) of vincamenin in 9 ml of abs. Dissolved ethanol and mixed with 1 ml of ethanolic, 36.5% hydrochloric acid solution. The hydrochloride of vincamenin is precipitated by the dropwise addition of about five times the amount of ether 25. The hydrochloride initially separates out in an oily form, but crystallizes when standing in the refrigerator.

In this way 2.70 g of vincamenine hydrochloride are obtained; Mp 246-247 ° C; [a] g> = -50 ° (c = 1% in chloroform).

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Analysis for C19H22N2 • HCl (Mol. 316.83):

Calc .: C 72.15%; H 7.98%; 9.10%; Cl 10.7%

Found: C 72.02%; H 7.94%; 9.83%; Cl 11.5%

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Example 13

1.39 g (0.005 mol) of vincamenin are dissolved in 8 ml of ethanol and a solution of 0.375 g of D-tartaric acid in 2 ml of ethanol is added. The vincamenin tartrate divides into

oily form from solution. This oily product is easily soluble in water.

Example 14

0.277 g (0.001 mol) of vincamenin 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 briefly, oily drops collect on the surface of the clear solution; after brief stirring, the product begins to crystallize. The mixture is left in the refrigerator for a day, at which time crystallization is complete. The crystalline product is filtered off, washed with a little acetone and dried. In this way, 0.42 g of vincamenium-methyl-iodide (71% of theory) is obtained; F. 275 ° C.

After recrystallization from ethanol, the product shows an optical rotation [a] ^ 0 = -155 ° (c = 1% in chloroform).

Analysis for C19H22N2 • CH3J (Mol. 420):

Ber. C 57.38%; H 5.80%

Found: C 57.20%; H 5.73%

Application example

Tablets with vincamenin hydrochloride

Vincamenine hydrochloride 5 g

Gelatin 3 g

Magnesium stearate 2 g

Talc 5 g

Potato starch 10 g

Milk sugar 95 g

The active ingredient is kneaded together with 3A part of the potato starch and with the aqueous solution of the gelatin, granulated and dried. The dry granules are mixed with the talc, the remaining 1A portion of the potato starch and the magnesium stearate and pressed into 1000 tablets, each weighing 150 mg. The tablets can be provided with partial notches to facilitate dosing.

B

Claims (2)

6S \ Y15 1 PATENT CLAIMS 1. Process for the preparation of a new compound of the formula (I) as well as acid addition salts thereof, characterized in that a compound of the formula wherein A ~ B is a group of the formulas (a) or (b) Hxl 2 HO (a) \ l , - 'C \ / H CH2 (b) 10. A process for the preparation of quaternary ammonium salts of the compound of the formula I, characterized in that a compound of the formula I is prepared by the process according to claim 1 and then the said compound is reacted with an alkyl halide.