CH629803A5 - Process for preparing a new alkaloid of the vincamine type and salts thereof - Google Patents

Description

629803

2nd

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

(II)

wherein A ~ B is a group of the formulas (a) or (b)

HO

HOOC

-CH2

HOOC

'N / A/

Ca)

(b)

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

It was found that among the degradation products of the alkaloid vincamine there are further physiologically valuable effects which have not yet been described in the literature. Such a the-s therapeutically active product is the new alkaloid vincamenin of the formula which does not occur in nature

10th

(I)

the optical antipode of the naturally occurring 20 alkaloids eburnamenin.

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

25th

30th

(II)

means subjected to heat treatment, with the use of compounds of the formula II in which A ~ B is the grouping (a), dehydration and decar-boxylation takes place and when compounds of the formula II in which A ~ B are the grouping (b ), a decarboxylation takes place 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.

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

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

5. 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 the compound mentioned is reacted with an alkyl halide.

wherein A ~ B is a group of formulas (a) or (b) HO

40

45

HOOC '' CH2 (a)

HOOC

'N /

(b)

means subjected to heat treatment, when using compounds of the formula II in which A ~ B is the grouping (a), dehydration and decarso boxylation takes place and when using compounds of the formula II in which A ~ B is the grouping (b) is, a decarboxylation takes place, and optionally obtained compounds are converted into the corresponding acid addition salts.

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

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

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

The compound of formula II in which A ~ B represents the group of formula (a), i.e. H. vincamic acid, is usually produced from vincamine by simple saponification (see: DOS 22 53 750; OE-PS 322118).

The compound of formula II, in which A ~ B is group (b), ie the apovincaminic acid can be prepared from apovincamine by saponification (cf. DT-PS 1958514;

3rd

629803

OE-PS 291 446).

The inventive method for the production of vincamenin z. B. carried out by heating vincaminic acid - formula II, A ~ B = (a) - for about 0.5 to 4 hours at 150 ° to 300 ° C. During this heat treatment, the vincamic acid is dehydrated and decarboxylated; these two reactions can take place simultaneously or in succession and so the vincamic acid is converted into vincamenin.

This reaction is advantageously carried out in an inert gas atmosphere, e.g. B. carried out in a nitrogen atmosphere. The reaction product obtained can then be worked up in a manner known per se. B. in a water-immiscible organic solvent, e.g. B. dissolved in an ether or hydrocarbon and washed the organic solution to remove the unreacted vincamic acid with a basic aqueous solution. Then the organic phase is dried and evaporated; the vincamenin remains as an oily product. The vincamenin obtained in almost quantitative yield in this way is so pure that practically no further purification is required.

In another embodiment of the process according to the invention, apovincamic acid - formula II, A ~ B = (b) - is advantageously subjected to the heat treatment, which lasts from 0.5 to 4 hours, advantageously at from 200 ° to 300 ° C. In this case the apovincamic acid is decarboxylated and converted into vincamenin.

In this case too, it is advantageous to carry out the heat treatment in an inert gas atmosphere, expediently in a nitrogen atmosphere; work-up of the reaction product can be carried out in the manner described above.

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. B. with hydrogen halides, advantageously with hydrochloric acid, with mono- or polybasic carboxylic acids, for. B. with tartaric acid, further formed with picric acid acid addition salts. Salt formation is usually carried out in a solvent, advantageously in an aliphatic alcohol, e.g. B. in ethanol.

The vincamenin is also converted into quaternary salts. For this purpose, the vincamenin in an inert organic solvent, suitably in an aliphatic ketone, e.g. B. in acetone, with an alkyl halide, e.g. B. 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 femoral artery (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 the 3rd

5

10th

15

Administration:

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 active substances are between 1 mg / kg and 5 mg / kg when administered intravenously or orally. This effective dose is calculated as one day and can be administered at once or during the day in several sub-doses that are identical to one another. The most advantageous dosage in any given case can be determined on the basis of the patient's condition and the experience of the doctor.

The vincamenin and its salts produced according to the invention can be administered as active ingredients, by mixing with the customary solid or liquid pharmaceutical carriers and / or other pharmaceutical adjuvants to give the customary pharmaceutical preparations suitable for parenteral or enteral administration. As carriers such. As water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils, such as. As peanut oil, olive oil etc., tragacanth, polyethylene glycols, petroleum jelly etc. are used. The pharmaceutical preparations can be in the usual forms, e.g. B. 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 be various pharmaceutical excipients, e.g. B. 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 by the usual methods, e.g. B. by grinding, sieving, mixing, granulating, pressing or dissolving, etc. and can optionally also be subjected to other treatments customary in the pharmaceutical industry, for. B. be sterilized.

As further therapeutically active known compounds that can be combined with the compounds that can be prepared according to the invention come, for. B. theophylline, phenyl barbiturate, acetylsalicylic acid, also vitamins, e.g. B. Vitamin E or P, with which significant synergetic effects can be achieved, and vitamin C (ascorbic acid) and its salts and complex derivatives,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

629803

4th

which z. B. accelerate the reserption of vin-camenin with oral administration and thereby enable a faster onset of the effect. The vincamenin can also be used in the form of pamoate as an active ingredient, as a result of which 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 may also contain certain inorganic salts, e.g. B. monoammonium phosphate or a monoalkali phosphate, which favor 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

3.4 g (0.01 mol) of vincamic acid are heated to the melting point (260 ° C.) in a sulfurizing flask, in a nitrogen atmosphere, in an oil or metal bath and the melt is heated to 240-260 ° for 1-2 hours C held. The vincamic acid heated to the melting point immediately releases carbon dioxide; but is still kept at the mentioned temperature of 240-260 ° C to complete the reaction. The formation of vincamenin or the conversion of vincamic acid to vincamenin is followed by thin layer chromatography (on silica gel plate, eluent: the mixture of 100 parts chloroform and 14 parts methanol). If the spot characteristic of vinamic acid already disappears from the chromatogram, the reaction can be regarded as complete. The residue of the melt is then in a water-immiscible solvent, e.g. B. dissolved in ether, benzene or dichloroethane and the organic solution with 10 ml of N aqueous sodium hydroxide solution about two times and then shaken once with 10 ml of distilled water to remove any unreacted vincamic acid. The aqueous phases are combined and extracted with half a volume of an organic, water-immiscible solvent. The separated organic phase is combined with the original organic solution, dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo.

2.70 g of vincamenin (almost quantitative yield) are obtained as a residue in the form of a pale yellow oil. This oil-like product can only be distilled under high vacuum at very high temperatures; Kp. At 10-4mm Hg: 208-210 ° C. [a] D = 180 ° (c = 1%, in chloroform).

The picrate of vincamenin is a well crystallizable compound; M. 170-172 ° C.

The molecular compound formed with picrolonic acid melts at 218-220 ° C.

Analysis for C19H22N2:

Calc .: C 82.37%, H 7.83%, N 10.07%;

Found: C 82.03%, H 7.80%, N 9.95%.

Example 2

The procedure is as in Example 1, with the difference that the melt of the starting material is kept at 240-260 ° C. for three hours. In this way, 2.50 g of vincamenin (90% of theory) are obtained in the form of an oil, the color of which is somewhat darker than that of the product from Example 1.

Example 3

3.24 g (0.01 mol) of apovincamic acid are heated to the melting point in a Sulfier flask, in a nitrogen atmosphere, in an oil or metal bath and the melt is kept at 250-260 ° C. for 1-2 hours. The melt obtained is then in a water-immiscible solvent, e.g. B. dissolved in ether, benzene or dichloroethane and the organic solution with 10 ml of N aqueous sodium hydroxide solution about two times and then shaken once with 10 ml of distilled water to remove any unreacted apovincamic acid. The aqueous phases are combined and shaken out with half a volume of an organic, water-immiscible solvent. The separated organic phase is combined with the original organic solution, dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo.

The residue obtained is 2.10 g of vincamenin (76% of theory) in the form of a pale yellow oil. The picrate of this product melts at 172 ° C.

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 2.00 g of vincamenin are obtained.

Example 5

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. 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] ^ ° = -50 ° (c = 1% in chloroform).

Analysis for C19H22N2.HCI (Mol. Wt. 316.83):

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

Calcd .: C 72.15%, H 7.98%, 9.10%, Cl 10.7%;

Example 6

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

Example 7

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 to stand 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 vincamenin methyl iodide (71% of theory) is obtained; F. 275 ° C.

After recrystallization from ethanol, the product shows an optical rotation [<x] d = —155 ° (c = 1% in chloroform).

Analysis for C19H22N2.CH3J (Mol.Wt. 420):

Calc .: C 57.38%, H 5.80%;

Found: C 57.20%, H 5.73%.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

629 803

Example of use Tablets with vincamenin hydrochloride The following amounts of substance are used:

Vincamenine hydrochloride gelatin

Magnesium stearate talcum potato starch milk sugar

The active ingredient is mixed with V * part of the potato starch and with the milk sugar. The homogeneous mixture is kneaded together with the aqueous solution of the gelatin, granulated and dried. The dry granules of 5 g are mixed with the talc, the remaining 1A portion of the 3 g of potato starch and the magnesium stearate, and 2 g are pressed into 1000 tablets, each weighing 150 mg. The 5 g tablets can be provided with partial 40 g notches to facilitate dosing.

95 g io

B