GB1568417A - Vincamine derivatives - Google Patents

Description

(54) VINCAMINE DERIVATIVES (71) We, RICHTER GEDEON VEGYESZETI GYAR RT., a Body Corporate, organised under the laws of Hungary of 21 Gyomroi ut, Budapest X., Hungary, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to a new alkaloid of the vincamine type and the salts thereof, as well as to a process for the preparation of the said compounds.

It has been found that among the decomposition products of the known alkaloid vincamine there are further compounds having valuable physiological activities, not described in the literature hitherto. One of these new therapeutically active compounds is the vincamenine having the structural formula I

This compound is the optical antipode of the known eburnamenine which is an alkaloid of natural origin. The pharmaceutically acceptable acid addition and quaternary salts and molecular complexes also form part of our invention.

According to another aspect of the present invention, the vincamenine of the formula I and the salts and molecular complexes thereof are prepared by subjecting a compound of the general formula II

wherein A-B represents one of the groups (a), (b), (c) or (d)

to a heat treatment, and isolating the desired product of formula I. Optionally the process includes the step of converting the product so obtained into a pharmaceutically acceptable acid addition or quaternary salt, converting it into another such salt, liberating a free base from a product salt, or converting the product into a molecular addition complex.

The heat treatment may e.g. be performed at a temperature between 80"C and 300"C for 0.5 to 4 hours, more preferably between 100"C and 260"C for 1 to 3 hours.

The starting materials of the process of the invention can be prepared in the following way: The starting compound of the general formula II, wherein A-B is the group (a), i.e. the compound vincaminic acid is prepared from vincamine, by simple saponification, as described in the German Auslegeschrift DT-OS 22 53 750.

The starting compound of the general formula II, wherein A-B is the group (b), i.e. the compound povincaminic acid is prepared from apovincamine by saponification, as described in German Patent Specification No. 1,958,514.

The starting compounds of the general formula II, wherein A-B is the group (c) and/or (d), i.e. the compounds vicanol and/or epivincanol, are prepared from vincamine by reduction with lithium aluminium hydride, as described in German Patent Specification No. 1,795,146.

According to one embodiment of the present invention, the vincamenine of the formula I is prepared by heating the compound of the general formula 11, wherein A-B is the group (a), i.e.

vincaminic acid. The heat-treatment is performed preferably at 1500C to 3000C, for several hours, or preferably for 1/2 to 4 hours. During this heat-treatment, the vincaminic acid is dehydrated and decarboxylated. These reaction steps may take place either simultaneously or one after the other; the end product is in both cases vincamenine.

The reaction is performed preferably in an inert gas atmosphere, e.g. in nitrogen atmosphere.

The reaction product may be isolated by conventional procedures, e.g. by dissolving the product in a waterimmiscible organic solvent, e.g. in an ether or in a hydrocarbon solvent, and the organic solution obtained is extracted with an aqueous solution of a base, to remove the residual unreacted vincaminic acid. After this extraction the organic solution is dried and evaporated. The oil obtained as evaporation residue is the desired vincamenine; this product is obtained in this way in high purity grade, in almost quantitive yield. Further purification steps are not necessary.

According to another embodiment of the invention, the vincamine of the formula I is prepared by heating apovincaminic acid, i.e.

the compound of the general formula II, wherein A-B is the group (b). The heattreatment is carried out preferably at a temperature between 200"C and 3000C, for a time period of several hours, or preferably for 1/2 to 4 hours. During this heattreatment the apovincaminic acid is decarboxylated and vincamenine is obtained. The reaction is carried out preferably in an inert gas atmosphere, e.g. in nitrogen.

The further processing of the reaction mixture may be performed analogously to the reaction using vincaminic acid as starting material.

According to a further embodiment of the invention, the vincamenine of the formula I is prepared by heating vincanol or epivincanol or a mixture thereof, i.e.

compounds of general formula II, wherein A-B is the group (c) and/or (d). In this case, the heat-treatment may be carried out at a temperature between 1700C and 300"C, for a time period of several hours, or preferably of 1/2 to 4 hours. The heat-treatment may be performed preferably in an inert gas atmosphere, preferably in nitrogen. During this heat-treatment, the vincanol and/or epivincanol are dehydrated and vincamenine is formed in this way.

After the heat treatment the product is obtained in the form of a melt, which is then treated with an inert organic solvent, to obtain pure vincamenine. Preferably an organic liquid of the ether-type, e.g. diethyl ether, or a halogenated hydrocarbon, e.g.

chloroform or dichloromethane are used as solvents for this purpose.

Instead of pure vincanol, also a crude vincanol containing substantial amounts of epivincanol may be used as starting material; both are converted in the same way into vincamenine.

The dehydration of compounds of the general formula II, wherein A-B is the group (c) and/or (d), i.e. of vincanol and/or epivincanol by heat-treatment may be carried out also in the presence of a dehydration catalyst. Preferably an excess, e.g. a 2 to 6-fold amount of alumina is used as dehydration catalyst. By the use of such catalysts the end-product is purified from undesired contaminating by-products and the dehydration can be carried out at a temperature lower by 40 to 800C than the reaction temperature of the uncatalyzed reaction.

After the completion of the reaction, the obtained vincamenine can be separated from the alumina catalyst by extraction with an inert organic solvent.

Alternatively, the dehydration of vincanol and/or epivincanol may be performed in the presence of a water binding agent, e.g. by boiling the starting compounds in an excess, preferably in a 3 to 12-fold amount of acetic anhydride for a time period of several hours, preferably of 1/2 to 3 hours. In the case of this method of performance, the dehydration can be performed at still lower temperatures than in the case of the previously described methods. In any of these methods a solvent may be present if desired.

In the further processing of the reaction mixture preferably the solvent is partially evaporated, the residual concentrated solution is poured into ice water, the mixture is made alkaline by adding a dilute solution of a base, e.g. of sodium hydroxide, and the aqueous alkaline solution is exhaustively extracted with a waterimmiscible inert organic solvent, e.g. with a halogenated hydrocarbon, preferably with a chlorinated aliphatic hydrocarbon, e.g. with dichloromethane or chloroform.

The dehydration of vincanol and/or epivincanol can be performed also by boiling the starting compound in 80 per cent. formic acid, instead of acetic anhydride.

The further processing of the reaction mixture can be performed in the same way, as in the case of boiling with acetic anhydride. The product obtained is, however, contaminated by some byproducts especially vincane; in order to obtain pure vincamenine, the crude oily product is dissolved in an inert organic solvent, preferably of the ether type, e.g. in diethyl ether, the precipitate is filtered off and the pure vincamenine is isolated from the filtrate. The preparation of vincane by reductive dehydration of vincanol e.g. with formic acid is disclosed and claimed in our copending Application No. 30287/77 (Serial No. 1,568,418).

The oily vincamenine of the formula I can be converted into various pharmaceutically acceptable acid addition salts by reacting it with the corresponding acids, optionally in the presence of a solvent. These acid addition salts are mostly crystalline substances, which can be easily identified.

Any of the usual inorganic or organic acids may be used for the preparation of such salts, e.g. hydrohalic acids as hydrochloric acid, further picric acid, tartaric acid and the like, provided they are pharmaceutically acceptable in the intended dosage range.

Preferably aliphatic alcohols, e.g.

ethanol, are used as solvent media for the salt-forming reaction.

The vincamenine of the formula I may be converted also into quaternary vincameninium salts. For this purpose, the vincamenine is reacted preferably with an alkyl halide, e.g. with methyl iodide; this reaction may be performed in an inert organic solvent, e.g. in an aliphatic ketone, such as acetone.

The quaternary vincameninium salts are in general well crystallizable products.

The vincamenine of the formula I can form also molecular complexes with appropriate organic compounds, e.g. with picrolonic acid.

The products prepared according to the invention, vincamenine and the salts thereof have valuable therapeutical activity.

The haemodynamic effect of vincamenine hydrochloride was examined on eight dogs narcotized by i.v. doses of 30 mg/kg. of pentobarbital. The substance was administered intravenously, in doses of 1 mg/kg., and the following parameters were registered: arterial blood pressure (MABP), pulse rate (HR), blood flow in the arteria carotis interna and the resistance of this blood vessel (CBF and CVR, respectively), blood flow in the arteria femoralis and the resistance thereof (FBF and FVR, respectively).

The values of the above parameters were measured before the treatment with the drug and then in the third, fifth, tenth and fifteenth minute after the administration thereof. The average values of eight experiments and the percentage deviations therefrom are shown in the following table.

Minute 3 5 10 15 MABP +1.3+2.5 +2.4+3.1 +5.8+6.1 +2.9+2.1 HR -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 -4.8c2.5 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 -10.7t5.1 It can be seen from the above results that the substance decreases slightly the pulse rate and has a marked vasodilatory effect (1521%) in the femoral blood vessel region.

The effective daily dosage of the substances is e.g. between 1 and 5 mg/kg., administered in one dose, or divided in several equal doses. The actual doses are to be determined in each case on the basis of the requirement of the patient and of the experience of the physician, according to the circumstances of the given case. It is to be noted, however, that the dosage range mentioned above is given for guidance only and should not be considered as limitating the invention or the use thereof.

The vincamenine of the formula I prepared according to the invention and the salts or molecular complexes thereof can be used as active principles in the usual pharmaceutical compositions for parenteral or enteral administration. Such pharmaceutical compositions can be prepared in the usual way, by mixing the active substance with the usual inert, nontoxic, solid or liquid pharmaceutical carriers and/or auxiliary materials. For instance water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils, (e.g. arachis oil, olive oil and the like), gum arabic, polyethylene glycol, or petrolatum may be used as carriers. The compositions may be prepared in the usual pharmaceutical forms, e.g. in the form of solid dosage units, as round or angular tablets, dragees, capsules, e.g. hard gelatine capsules, pills, suppositories etc., or in liquid form, as oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc. The amount of the solid carriers in the said dosage units may vary between wide limits. The said compositions may ulso contain usual pharmaceutical adjuvants, e.g.

preservatives, stabilizers, flavouring substances etc. Also further therapeutically valuable compounds may be added to the said compositions. The form of the dosage units can be selected in accordance with the intended route of administration.

The preparation of said pharmaceutical compositions can use conventional methods of pharmacy, e.g. grinding, sieving and mixing of the ingredients, granulating, pressing or dissolving. The products may be subjected also to further conventional pharmaceutical operations, e.g. to sterilization.

The other therapeutically valuable known compounds, which may be included optionally in the pharmaceutical compositions, are e.g. the following: theophylline, phenyl barbiturate, aspirin, vitamins, such as vitamin E, vitamin P, which may exert a remarkable synergistic effect, also vitamin C, i.e. ascorbic acid and the salts and complexes thereof, which promotes absorption e.g. in the case of oral administration and accelerates the effect of the active substance. The pharmaceutical compositions of the invention may contain the active compound also in the form of the pamoate salt, exerting a prolonged action, or in the form of the dioctyl sulfonate or lauryl sulfate salt; the use of the latter in compositions for oral administration eliminates the bitter taste of the product.

The compositions may further contain inorganic salts, e.g. monoammonium phosphate or monoalkali metal phosphates, which promote the formation of stable solutions in the compositions for oral administration. The active compound of the invention may be used also in the form of an alkylsulfonate or 2-ketoglutarate salt in the pharmaceutical compositions.

Further details of the process of the invention are shown by the following examples; it is to be noted, however, that the invention is by no means restricted to the contents of these examples.

Example 1 3.4 g (0.01 mol.) of vincaminic acid are heated to 2600C in a sulfonating flask, in an oil or metal bath, under nitrogen atmosphere, for 1--2 hours. At the melting point, vincaminic acid instantly loses carbon dioxide; the further heating at the said temperature of 240--260"C is performed in order to complete the reaction. The formation of vincamenine, i.e. the conversion of the vincaminic acid into vincamenine is monitored by thin layer chromatography on silica gel, using 100 parts by volume of chloroform and 14 parts by volume of methanol as eluting agent. After the disappearance of the spot of vincaminic acid the reaction is considered as completed. The residue is dissolved in a water-immiscible organic solvent, e.g. in ether, benzene or dichloroethane, and the organic solution is shaken out once or twice with 10 ml. of aqueous N/1 solution of sodium hydroxide and then with 10 ml. of distilled water. This operation removes any residual vincaminic acid. The combined aqueous alkaline phases are then shaken out once or twice with half part by volume of one of the organic solvents mentioned above, the organic phases are combined with the original organic solution, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo. 2.70 g of vincamenine (nearly quantitative yield) are obtained as a pale yellow oily residue. The yield is somewhat lower, if the decarboxylation reaction is carried out in much greater quantities, but in such cases it reaches 85 to 90%. The pale yellow oil obtained can be distilled only in high vacuo and at very high temperatures, its boiling point 208-2100C at 10-4 Torr. Its optical rotation value is []%G=180a (c=1%, chloroform).

The picrate of the vincamenine is a well crystallizable compound, m.p. 170--1720C.

The picrolonate of vincamenine melts at 218--220"C.

Analysis for C19H22N2: Calculated: C 82.02%, H 7.80%, N 9.95%; Found: C 82.37%, H 7.83%, N 10.07%.

Example 2 The process of Example 1 is repeated with the difference that the heating is continued for 3 hours.

2.50 g oily vincamenine are obtained. This oil has a somewhat darker colour than the product of Example 1.

Yield: 90% Example 3 3.24 g (0.01 mol.) of apovincaminic acid are heated in a sulfonating flask, in an oil or metal bath, under nitrogen atmosphere to the melting point of the compound. The melt obtained is kept at 25O2600C for a further hour. The melt is then dissolved in a water-immiscible organic solvent e.g. in ether, benzene or dichloroethane and the solution is shaken out once or twice with 10 ml of aqueous N/I sodium hydroxide solution to remove any residual unreacted apovincaminic acid, as described in Example 1, and the organic solution is then washed with 10 ml. water to remove the residual alkali. The aqueous-alkaline washings are combined and shaken out with half volume of the organic solvent used in the previous step, the combined organic phases are dried with anhydrous sodium sulfate and evaporated in vacuo. 2.10 g vincamenine are obtained as evaporation residue in the form of a pale yellow oil.

Yield: 76%.

The picrate of the obtained product is identical with the vincamenine picrate obtained in Example 1; m.p. 1720C.

Example 4 The process of Example 3 is repeated with the difference that the starting material is heated for 3 hours at 25O-2600C 2.00 g of the same oily product are obtained.

Example 5 1.48 g (0.005 mol) vincanol are heated in nitrogen atmosphere for one hour at 220 250"C. The melt obtained is dissolved in ether. The ether solution is processed further as described in Example 1. 1.98 g of the oily product are obtained; yield: 93%.

The obtained product is converted into the picrate salt which is identical with the vincamenine picrate obtained in Example 1.

Example 6 The process of Example 5 is repeated with the difference that the starting material is heated for three hours. 1.25 g of the same oily product are obtained; yield: 95%.

Example 7 1.48 g (0.005 mol) of crude vincanol are heated for one hour under nitrogen atmosphere at 220-2500 C. The melt obtained is dissolved in chloroform. The chloroform solution is processed further as described in Example 1. 1.20 g of the same oily product are obtained; yield: 87%.

The product obtained is converted into the picrate salt which is identical with the vincamenine picrate obtained in Example 1.

Example 8 The process of Example 7 is repeated with the difference that the starting material is heated for three hours. 1.25 g of the same oily product are obtained; yield: 95%.

Example 9 The process of Example 5 is repeated with the difference that dichloroethane is used as solvent instead of ether. 1.25 g of the same oily product are obtained; yield: 95%.

Example 10 1.48 g (0.005 mol) of vincanol are mixed with a cca. threefold amount of alumina (4.50 g) and the mixture is heated for one hour at 185--200"C. The cooled product is then extracted with benzene, ether, chloroform, dichloroethane or an other water-immiscible organic solvent. The organic extract is dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness. 1.20 g oily product are obtained.

The picrate of the obtained product is identical with the vincamenine picrate obtained in Example 1.

Example 11 The process of Example 10 is repeated with the difference that 7.50 g of alumina is used instead of 4.50 g 1.10 g of the same oily product are obtained.

Example 12 1.48 g (0.005 mol) of vincanol in 7.50 ml.

of acetic acid anhydride is refluxed for one hour. The excess of the solvent is partially evaporated in vacuo and the residual solution is poured into ice cold water. The solution is adjusted with a 20% sodium hydroxide solution to pH=8 to 9, and this basic solution is shaken out four or five times with an equal (or at least half) volume of dichloromethane. The dichloromethane solution is shaken out with a small amount of water to remove the residual alkali, dried with anhydrous sodium sulfate and the solvent is evaporated in vacuo.

1.26 g of crude vincamenine are obtained in oily form; yield: 92%.

The picrate of the above product melts at 170-1720C and is identical with the vincamenine picrate described in Example 1.

Example 13 The process of Example 12 is repeated with the difference that 14.8 g. of acetic acid anhydride are used instead of 7.35 g and the extraction is carried out with chloroform instead of dichloromethane.

1.21 g of the same oily product are obtained.

Example 14 1.47 g (0.005 mol) of vincanol are dissolved in 8 g of 80% formic acid and the solution is refluxed for one hour.

The excess of the acid is evaporated in vacuo and the residue is poured into ice cold water. The reaction mixture is processed further as described in Example 12.

1.25 g of the same oily product are obtained.

The oily product obtained in this reaction is not pure vincamenine, it contains partially also vincane. This crude oily mixture of vincamenine and vincane is dissolved in two parts by weight of acetone and cooled in a refrigerator; a substantial part of the vincane crystallizes from the solution.

Example 15 1.47 g (0.005 mol) of vincanol in 8 g of 80 /n formic acid is refluxed for eight hours.

The reaction mixture is then processed further as described in Example 14.

1.20 g of the same oily product are obtained; the ratio of vincane to vincamenine is approximately the same as in Example 14.

Example 16 2.78 g (0.01 mol) of vincamenine are dissolved in 9 ml of abs. ethanol. An equivalent amount of 36.5% ethanolic solution of hydrochloric acid (1 ml) is added to the solution and approximately a fivefold amount of ether is added dropwise, whereby the vincamenine hydrochloride is precipitated from the solution. The hydrochloride salt precipitates initially in oily form, but crystallizes on standing in a refrigerator.

2.70 g of vincamenine hydrochloride are obtained, m.p.: 246--2470C; optical rotation value: [(Z]2g=50O (1%, in chloroform).

Analysis for C,9H22N2.HCI (mol wt 316.83): Calculated: C 72.15%, H 7.98%, N 9.10%, Cl 10.7%; Found: C 72.02 /, H 7.94%, N 9.83%, Cl 11.5%.

Example 17 1.39 g (0.005 mol) of vincamenine are dissolved in 8 ml of ethanol and the solution of 0.375 g of D-tartaric acid in 2 ml of ethanol is added thereto. The vincamenine tartrate separates from this solution in oily form. This oily product is readily 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 to the solution.

After standing for a short time period oily drops accumulate on the surface of the clear solution; after a short stirring this product begins to crystallize. The mixture is allowed to stand in a refrigerator for one day; the crystallization is finished during this time.

The obtained crystals are separated by filtration, washed with a small amount of acetone and dried.

0.42 g of vincameninium methoiodide are obtained (yield: 71%), m.p.: 2750C.

This product is recrystallized from ethanol. The optical rotation value of the recrystallized product is [ez12g=155 .

Analysis for CrgH22N2CH3I (mol wt 420): Calculated: C 57.38%, H 5.80%; Found: C 57.20%, H 5.73%.

Example 19 Tablets containing vincamenine hydrochloride.

The following ingredients are used to prepare this pharmaceutical composition: vincamenine hydrochloride 5 mg gelatine 3 mg magnesium stearate 2 mg talc 5 mg potato starch 40 mg lactose 95 mg The active material is mixed with 3/4 part of the potato starch and with the lactose.

The resulting homogenous mixture is kneaded together with the aqueous solution of the gelatine, the mass obtained is granulated and dried. The dry granules obtained are mixed with the talc, the residual 1/4 part of the potato starch and with the magnesium stearate, and this mixture is compressed into tablets. If desired, the tablets may be provided with dividing scores to facilitate the dosage.

WHAT WE CLAIM IS: 1. Vincamenine of the formula

and the pharmaceutically acceptable acid addition and quaternary salts and molecular complexes thereof.

2. Vincamenine hydrochloride.

3. Vincamenine tartrate.

4. Vincameninium methyl iodide.

5. The molecular complex of vincamenine with picrolonic acid.

6. A process for the preparation of a compound as defined in claim 1 which comprises subjecting to heat treatment a compound of the formula

wherein A-B represents one of the groups (a), (b), (c) or (d)

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (29)

**WARNING** start of CLMS field may overlap end of DESC **. vincamenine and vincane is dissolved in two parts by weight of acetone and cooled in a refrigerator; a substantial part of the vincane crystallizes from the solution. Example 15 1.47 g (0.005 mol) of vincanol in 8 g of 80 /n formic acid is refluxed for eight hours. The reaction mixture is then processed further as described in Example 14. 1.20 g of the same oily product are obtained; the ratio of vincane to vincamenine is approximately the same as in Example 14. Example 16 2.78 g (0.01 mol) of vincamenine are dissolved in 9 ml of abs. ethanol. An equivalent amount of 36.5% ethanolic solution of hydrochloric acid (1 ml) is added to the solution and approximately a fivefold amount of ether is added dropwise, whereby the vincamenine hydrochloride is precipitated from the solution. The hydrochloride salt precipitates initially in oily form, but crystallizes on standing in a refrigerator. 2.70 g of vincamenine hydrochloride are obtained, m.p.: 246--2470C; optical rotation value: [(Z]2g=50O (1%, in chloroform). Analysis for C,9H22N2.HCI (mol wt 316.83): Calculated: C 72.15%, H 7.98%, N 9.10%, Cl 10.7%; Found: C 72.02 /, H 7.94%, N 9.83%, Cl 11.5%. Example 17 1.39 g (0.005 mol) of vincamenine are dissolved in 8 ml of ethanol and the solution of 0.375 g of D-tartaric acid in 2 ml of ethanol is added thereto. The vincamenine tartrate separates from this solution in oily form. This oily product is readily 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 to the solution. After standing for a short time period oily drops accumulate on the surface of the clear solution; after a short stirring this product begins to crystallize. The mixture is allowed to stand in a refrigerator for one day; the crystallization is finished during this time. The obtained crystals are separated by filtration, washed with a small amount of acetone and dried. 0.42 g of vincameninium methoiodide are obtained (yield: 71%), m.p.: 2750C. This product is recrystallized from ethanol. The optical rotation value of the recrystallized product is [ez12g=155 . Analysis for CrgH22N2CH3I (mol wt 420): Calculated: C 57.38%, H 5.80%; Found: C 57.20%, H 5.73%. Example 19 Tablets containing vincamenine hydrochloride. The following ingredients are used to prepare this pharmaceutical composition: vincamenine hydrochloride 5 mg gelatine 3 mg magnesium stearate 2 mg talc 5 mg potato starch 40 mg lactose 95 mg The active material is mixed with 3/4 part of the potato starch and with the lactose. The resulting homogenous mixture is kneaded together with the aqueous solution of the gelatine, the mass obtained is granulated and dried. The dry granules obtained are mixed with the talc, the residual 1/4 part of the potato starch and with the magnesium stearate, and this mixture is compressed into tablets. If desired, the tablets may be provided with dividing scores to facilitate the dosage. WHAT WE CLAIM IS:

1. Vincamenine of the formula

and the pharmaceutically acceptable acid addition and quaternary salts and molecular complexes thereof.

2. Vincamenine hydrochloride.

3. Vincamenine tartrate.

4. Vincameninium methyl iodide.

5. The molecular complex of vincamenine with picrolonic acid.

6. A process for the preparation of a compound as defined in claim 1 which comprises subjecting to heat treatment a compound of the formula

wherein A-B represents one of the groups (a), (b), (c) or (d)

and isolating a compound as defined in claim 1.

7. A process as claimed in claim 6, wherein vincaminic acid is used as starting material of the formula II.

8. A process as claimed in claim 6, wherein apovincaminic acid is used as starting material of the formula II.

9. A process as claimed in claim 6, wherein vincanol and/or epivincanol are used as starting materials of the formula II.

10. A process as claimed in any of claims 99, wherein the heat treatment is performed at a temperature between 80"C and 3000C for 0.5 to 4 hours.

Il. A process as claimed in claim 10, wherein the heat treatment is performed at a temperature between 100"C and 260"C for 1 to 3 hours.

12. A process as claimed in any of claims 911 wherein the heat treatment is performed in an inert gas atmosphere.

13. A process as claimed in claim 12, wherein nitrogen is used as an inert gas.

14. A process as claimed in claim 9, wherein the heat treatment is performed in the presence of a dehydrating catalyst.

15. A process as claimed in claim 14, wherein alumina is used as dehydrating catalyst.

16. A process as claimed in claim 15, wherein a 2--6 fold weight of alumina is employed based on the starting material.

17. A process as claimed in claim 9, wherein the heat treatment is performed in the presence of a water binding agent.

18. A process as claimed in claim 17, wherein acetic anhydride is used as water binding agent.

19. A process as claimed in any of claims 9 or 1" 18 wherein the heat treatment is performed in a solvent.

20. A process as claimed in claim 19, wherein formic acid is used as solvent.

21. A process as claimed in any of claims 6-20 including the step of converting the product so obtained into a pharmaceutically acceptable acid addition or quaternary salt converting it into another such salt, liberating a free base from a product salt, or converting the product into a molecular addition complex.

22. A process as claimed in claim 6, substantially as hereinbefore described.

23. A process as claimed in claim 6, substantially as hereinbefore described with reference to Examples 1--18.

24. Compounds of claim 1 whenever made by the process of any of claims 6-23.

25. A pharmaceutical composition comprising a compound of any of claims 15 or 24 in admixture with a pharmaceutical carrier and/or auxiliary material.

26. A composition as claimed in claim 25 comprising a pharmacologically effective amount of theophylline, phenyl barbiturate, aspirin, vitamin E or vitamin C.

27. A composition as claimed in claim 25 comprising a pharmacologically effective amount of vitamin P.

28. A composition as claimed in any of claims 25-27 wherein said vincamenine is present as the pamoate, dioctylsulfonate or lauryl sulfate salt thereof.

29. A composition as claimed in claim 25, substantially as illustrated in Example 19.