CH625241A5 - Process for preparing novel salts of vincamine and apovincamine - Google Patents

Abstract

A salt of vincamine and apovincamine is obtained by means of reacting vincamine or apovincamine in the form of a solution or suspension with the acid corresponding to the desired salt. The salts are of the formula I in which R1, R2 and X are as defined in claim 1. The salts have interesting therapeutic properties at the cardiovascular level and on the circulation system in general. <IMAGE>

Description

The present invention relates to a process for the manufacture of new vincamine and apovincamine salts having interesting therapeutic properties at the cardiovascular level and, in general, of the circulatory system.

The vincamina, having formula

5

I

15

20

25

30

35

40

45

50

55

60

65

3

625241

and apovincamine, having formula, are substances already known and used in the therapy of cerebral arteriosclerosis, due to their effective cerebral vasodilator action and also their ability to activate the metabolism of nerve cells.

However, their therapeutic action in the different routes of administration is characterized by a short duration, consequent to their rapid elimination, so that repeated administrations are necessary within 24 hours.

It has now been found that some derivatives of vincamine and apovincamine have the property of having similar therapeutic activity associated with a protracted effect over time, i.e. of the so-called long-acting type, said salts having general formula in which if it represents OH, R2 represents MeOOC, or if Rj represents MeOOC, there is a double bond in position A1 "'17, and X represents a radical of a 15 acid chosen from 2,6-, 2,5- and 3,5-dihydroxybenzoic acids, p -toluensulphonic, clofibric [2- (p-cIorophenoxy) -2-methylpro-pionic], pivalic, 4-acetamido-butyric, 2-furoic, L (+) - 0,0-dibenzoyltartaric, methylsulforic, enanthic, p- chlorophenos-siacetic, theophylline-7-acetic, capronic, caprinic, alginic, 20 tannic, (D, L) -mandelic, indolyl-3-acetic, salicylic, hydrochlorine-none, dihydroxyphenylalanine and pectin. In turn the general procedure for the preparation of the compounds according to the present invention provides for the vincamine or the apovin to react depending on the desired derivative, in 25 form of solution or suspension, with the acid, preferably in the form of a solution, the reaction being carried out in hot conditions under controlled temperature, and under stirring, until the reaction is completed, after of which the reaction product is separated.

30 The following examples illustrate the present invention in more detail. In the formulas of the examples Me is methyl and Et means ethyl.

Example 1

35

l.a Vincamine 2,6-dihydroxybenzoate

MeOOC

COOH

I \ A ^ oh

• w c2sh32n2o7

P.M. = 508.6

A suspension of 7.08 g (2.IO-2 moles) of vincamine in 100 ml of ethyl alcohol is heated to reflux under stirring and is gradually added with a solution consisting of 3.08 g (2.IO-2 moles ) of 2,6-dihydroxybeno-zoic acid in a sufficient amount of ethanol. It is kept at boiling for about 1 hour and at the same time 50 ml of CHCl are added, so as to obtain a homogeneous solution. It is concentrated under stirring reduced to a small volume and the precipitation of the salt is completed by dilution with diethyl ether.

It is filtered on Büchner and dried in a ventilated oven at 50 ° C. 60 10 g of amorphous product, insoluble in water and in alcohol, are obtained. The dosage of vincamine in salt is 74.6%.

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l.b Apovincamine 2,6-dihydroxybenzoate

4

Hi

This salt is obtained according to the methods of Example l.a above starting from 3.37 g (IO-2 moles) of apovincamine and 1.54 g (IO "2 moles) of 2,6-dihydroxybenzoic acid.

4.8 g of product having a melting point of 145%, insoluble in water and slightly soluble in alcohol are obtained. The dosage of apovincamine in salt is 69.6%.

Example 2

2.a Vincamine 2,5-dihydroxybenzoate

15

COOH

OH

or

P.M. = 490.54

COOH

C2 & H & 2N 2O7 P.M. = 508.6

Et

Analogously to Example 1, starting from 7.08 g (2.io * 2 moles) of vincamine and 3.08 g (2. 10 "2 moles) of 2,5-dihydroxybenzoic acid, 10 g of amorphous product, insoluble in water and in alcohol, with a vincamine content of 69%.

2.b Apovincamine 2,5-dihydroxybenzoate

MeOO

40

OOH

^ i; HH.30N ^ O ,;

P.M. = 490.54

Similarly to the previous examples, from 3.37 g (10 ~ 2 55 moles) of apovincamine and from 1.54 g (IO-2 moles) of 2,5-dihydroxybenzoic acid, 4.8 g of product insoluble in water are obtained and in alcohol, with a melting point of 120-130 ° C and a 64% apovincamine content.

5

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Example 3

3.a Vincamine 3,5-dihydroxybenzoate

COOH

P.M. = 508.6

From 7.08 g (2.10 ~ 2 moles) of vincamine and 3.08 g (2.IO-2 moles) of 3,5-dihydroxybenzoic acid, 10 g of salt are obtained in the manner of the previous examples form of amorphous substance, insoluble in water and alcohol.

The dosage of vincamine in salt is equal to 67.4%.

3.b Apovincamine 3,5-dihydroxybenzoate

15

20

COOH

C28H30N2O,}

P.M. = 490.54

Like the previous examples, the product is prepared from 3.37 g of apovincamine and 1.54 g of 3.5-dihydroxybenzoic acid.

4.8 g of salt are obtained with a melting point of 220 ° C, insoluble in water and soluble in alcohol. The dosage of apovincamine is 53%.

Example 4 4.a Vincamine-p-toluenesulfonate

35

40

I have

MeOOcf

7.08 g (2.IO-2 moles) of vincamine are suspended in 100 ml of absolute ethanol. The mixture is heated in a water bath at 60 ° C and a solution of 3.8 g (2.IO-2 moles) of p-toluenesulfonic acid monohydrate is added in 30 ml of ethanol.

Once the addition is complete, a clear solution weakly colored in yellow is obtained. The mixture is left under slow stirring for 60 minutes at 60 ° C and subsequently concentrated to dry residue at normal pressure.

The solid is taken up with a mixture consisting of 5 ml of ethanol and 20 ml of diethyl ether and is left to crystallize in the cold. It is filtered, dried at 60 ° C in a ventilated oven and 9.5 g of crystalline solid product are obtained, soluble in water and in alcohol, with a melting point of 204-212 ° C.

The dosage of vincamine in salt is 67%.

C28H34N 2OfiS P.M. = 526.6

55

60

65

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4.b Apovincamine p-toluenesulfonate

6

H

I ^ MeOOC ^

The product is prepared in the manner of Example 1, using 4.29 g (2.IO "2 moles) of clofibric acid [2- (p - chlorophenoxy) -2-methylpropionic] and 7.08 g (2. I "2 moles) of vincamina.

11 g of salt soluble in alcohol and insoluble in water are obtained, with a melting point of 195 ° C. The dosage of vincamine in salt is approximately 60%.

5.b Apovincamine clofibrated there

CH,

^ 28 ^ 3,2 ^ 2O5S

P.M. = 508.6

Using the methods of Example 4.a the salt is prepared from 3.36 g (IO-2 moles) of apovincamine and from 1.72 g (IO-2 moles) of anhydrous p-toluenesulfonic acid. 4.3 g of alcohol-soluble salt, insoluble in water, with a melting point of 150 ° C and an apovincamine titre equal to 60% are obtained.

Example 5

5.a Vincamine clofibrate [2- (p-chlorophenoxy) -2-methylpropium-born]

15

20

csihgjn 2c106 P.M. = 569

35

40

CH,

COOH

k

C31H315N2C105 P.M. = 551

The procedure of the previous examples is repeated starting from 3.36 g of apovincamine and from 2.14 g of clofibric acid.

The final product (3.5 g) appears as a low melting solid, at 65 ° C, insoluble in water and soluble in alcohol, with an apovincamine titre equal to 61%.

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Example 6 6.a Vincamine pivalate (trimethylacetate)

HC-C-COOH

3,

CH3

C20H, 31ÌN 205 P.M. = 456.56

MeOOC

Analogously to Examples 1 and 4, this salt is prepared from 2.41 g (2. IO-2 moles) of pivalic acid and from 7.08 g (2. IO-2 moles) of vincamine. 9 g of solid substance insoluble in water and alcohol are obtained with a melting point of 235 ° C. The dosage of vincamine in salt is 70%.

15

6.b Apovincamine pivalate

CH3

I J

CH-C-CH

3 I 3 COOH

C2cHmN204

P.M. = 438.6

With the methods of the previous examples 4 g of salt are prepared starting from 1.02 g of pivalic acid and from 3.36 g of apovincamine. The product has a melting point of 110 ° C, is insoluble in water and soluble in alcohol; it has an apovincamine titre of 73.8%.

Example 7

7.a Vincamine 4-acetammidobutyrate M

CH?-Cho-cho-C00H

I & & (L

NHCOCH "

P.M. = 499.6

MeOOC

The salt is prepared from a mixture of alcohol-chloroform as for the salt of Example 1, starting from 2.9 g of 4-acetamide amidebutyric acid (2.IO'2 moles) and from 7.08 g (2.IO " 2 moles) of vincamine 9 g of product insoluble in water and alcohol are obtained with a melting point of 210 ° C. The dosage of vincamine in salt is 70%.

7.b Apovincamine 4-acetammidobutyrate fi

55

• ^ H2-CH2-CH2-C00H

NHCOCH,

MeOOC Et

C27Ha, 5N305 P.M. = 481.6

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8

Using the operating methods of the previous examples, starting from 3.36 g of apovincamine and from 1.45 g of 4-acetamidobutyric acid, 4.4 g of product having a melting point of 128 ° C, insoluble in water and in alcohol. The dosage of apovincamine in salt is 56%.

Example 8

8.a Vincamine furoate (furan-2-carboxylate)

OR

COOH

C2CH 'ON206

P.M. = 466.5

MeOOC

7.08 g of vincamine are hot suspended in 100 ml of ethyl alcohol at 60-70 ° C and, under stirring, a solution of 2.24 g of 2-furoic acid in alcohol is slowly added and is kept refluxing for 1 hour. It is desirable to add 40-50 ml of chloroform in order to obtain a homogeneous solution.

Subsequently it is concentrated to dry residue, the product is ground and dried in a ventilated stove. 9.3 g of substance insoluble in water and in alcohol are obtained, having a titre of vincamine equal to 74.6%.

8.b Apovincamine furoate

/ N

MeOOC

20

25

30

OOH

C2oH2SN205

P.M. = 448.5

Operating as in the previous example, 8.2 g of salt from 6.73 g (2.IO-2 moles) of apovincamine and 2.24 g (2.IO * 2 moles) of furan-2-carboxylic acid are obtained . The product has a melting point of about 120 ° C, is insoluble in water and soluble in alcohol; it has an apovincamine titre of 66%.

Example 9 9.a Vincamine D (+) - camphor sulphonate

Et

5 g (2.IO "2 moles) of D (+) - camphor sulfonic acid monohydrate are dissolved in 15 ml of ethanol and this solution is added to a suspension of 7.08 g (2.IO" 2 moles) of vincamine in 90 ml of ethanol at 70 ° C under stirring.

A homogeneous solution is obtained which is kept at 70 ° C for 10-15 minutes. The mixture is then concentrated to a volume of 20-25 ml and allowed to crystallize in

45

50

2H

C31H «Na07S P.M. = 586.74

ice bath. It is filtered, washed on a filter with very little cold alcohol, and dried in a ventilated oven at 60 ° C. Approximately 11 g of product are obtained with a melting point of 65 228-230 ° C, soluble in water, slightly soluble in alcohol and insoluble in common organic solvents.

The title in vincamina is 61%.

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9.b Apovincamine D (4-) -chalphorsulfonate

MeOOC

From 6.73 g of apovincamine and from 4.64 g of D (+) - camphor sulphonic acid, 10.6 g of salt having a melting point of about 258 ° C are obtained, in the same way as in example 9.a, 15 soluble in water and in alcohol, with an apovincamine titre of 53%.

ch2oso2h

^ 31 ^ 4ON206S

P.M. = 568.7

Example 10 lO.a Vincamine L (+) - 0,0-dibenzoyltarthrate

20

COOH I

CH-O-OC-Ph I

H-O-Ph-OC

THE

COOH

Ce0H06N4O14 P.M. = 1067

3.76 g (2. 10 "2 moles) of L (+) - 0.0-dibenzoyltartaric acid monohydrate are dissolved in 40 ml of ethanol and the resulting solution is added to a suspension of 7.08 g (2. 10 ° "2 moles) of vincamine in 200 ml of alcohol at 70 ° C. The mixture is kept hot under stirring for 20 minutes and the solution is then concentrated up to a final volume of 25-30 ml. The cold precipitation is completed in an ice bath. It is filtered, washed with very little cold alcohol and dried in a ventilated oven at 60 ° C. About 10 g of product are obtained with a melting point of 210 ° C, slightly soluble in water and alcohol, insoluble in common organic solvents. The dosage of vincamine in salt is 60%.

lO.b Apovincamine L (+) - 0,0-dibenzoylarthrate

40

45

50

MeOOC

C00H I

CH-O-OC-Ph I

CH-0-0C-Ph i

COOH

C (joHo2N4012 P.M. - 1031

Similarly to the previous example, 1.8 g of dibenzoyltartaric acid and 3.37 g of apovincamine yield 5.1 g of alcohol-soluble salt with a melting point of 120 ° C and an apovincamine titer equal to 53%.

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Example 11 ll.b Apovincamine nicotinate

the

N!

1

MeOOC ^

A solution of 3.6 g (2.IO-2 moles) of acetylsalicylic acid in 30 ml of ethanol is added to a solution of 7.08 g (2.IO-2 moles) of vincamine in 80 ml of ethanol and 60 mi of CHC13. The mixture is kept under stirring at 70 ° C for 10 minutes and then the mixture is concentrated to 60 ml. The mixture is taken up in ethanol (70 ml) and the solvent is evaporated to a final volume of 15 ml.

The precipitation is completed with 10 ml of ether, cooling in an ice bath, filtered, washed on a filter with ether and dried in an oven at 60 ° C.

10 g of product with an undefined melting point, scarcely soluble in all common solvents, are obtained. The dosage of vincamine is 61%.

12.b Apovincamine acetylsalicylate yXvCOOH

or

P.M. = 459.5

2.46 g (2. IO-2 moles) of nicotinic acid are suspended in 30 ml of ethanol and the mixture is added to a solution containing 6.73 g (2. IO-2 moles) of apovincamine in 80 ml. of ethanol and 60 ml of chloroform.

The mixture was kept at 70 ° C under stirring for 10-15 minutes and then concentrated at 15-20 ml and the cold precipitation was completed. It is filtered and dried in an oven at 60 ° C.

8.7 g of product having a melting point of 135 ° C, insoluble in water and in alcohol, are obtained with an apovincamine titer of 86.5%.

Example 12 12.a Vincamine acetylsalicylate

15

20

25

COOH

aj *

w eocH

P.M. = 534.6

40

45

50

COOH

OCOCH,

or

3 '2 ^ 2O

P.M. = 516.55

Repeating example 12.a above, from 1.8 g of acetylsalicylic acid and from 3.36 g of apovincamine 4.1 g 65 of salt having a melting point of about 120 ° C, soluble in alcohol, very little soluble are obtained in water and with an apovincamine titre of 75.34%.

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Example 13 13.a Vincamine methylsulfate

1 '^ CH- (CH SO ")

c2ßih-12n 207s P.M. = 480.6

MeOOC

7.08 g (2.10-2 moles) of vincamine are dissolved in 900 ml of boiling dry acetone. 1.8 ml of dimethylsulphate are added under stirring and the resulting mixture is kept in boiling for 6 hours. It concentrates at 400 ml and is left to rest for one night. It is filtered, washed on an ether filter and dried in a stove under vacuum at 50 ° C. 7 g of product are obtained with a melting point of 191 ° C, soluble in water and alcohol.

15

20

13.b Apovincamine methylsulfate

/ Ch3 (oh3so4-)

C23H30N 2SOG P.M. = 462.5

.MeOOC

Similarly to the previous example, 7.3 g of salt are prepared, starting from 6.73 g (2. 10 -2 moles) of apovincamine and from about 2 ml of dimethyl sulphate. The final product has a melting point of 280 ° C and is soluble in water but slightly soluble in alcohol.

Example 14 14.a Vincamine enanthate

35

40

. C.H, .COOH \ 6 13

c2sh40o5n2

P.M. = 484.6

MeOOC

The preparation is carried out according to the methods of Example 11, starting from 7.08 g (2. IO-2 moles) of vincamine and from 2.61 g (2.10-2 moles) of enanthic acid. You get around

10 g of semi-solid product, insoluble in common solvents.

The dosage of vincamine is equal to 66.5%.

55

MeOOC

c6h13cooh

C2fiH38N204 P.M. = 466.4

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12

With the methods of the previous example, 8.3 g of salt are obtained starting from 6.73 g of apovincamine and 2.61 g of enanthic acid. The substance is insoluble in water and alcohol and has an apovincamine titre of 73%.

Example 15

15.a Vincamine-p-chlorophenoxyacetate

CsoHgßN 2OtîCl P.M. = 541

och2cooh

Like the previous example, the preparation is carried out from 7.08 g (2. 10 -2 moles) of vincamine and from 3.73 g (2.10 ~ 2 moles) of p-chlorophenoxyacetic acid. 9.6 g of amorphous product, soluble in alcohol and insoluble in water and in common organic solvents are obtained. The vincamine dosage is 64.7%.

25

15.b Apovincamine-p-chlorophenoxyacetate

CI

<Or>

chgcooh

P.M. = 523

MeOOC

According to the methods of Example 15.a 4 g of salt are prepared starting from 3.36 g of apovincamine and from 1.86 g of p-chlorophenoxyacetic acid. The salt has a melting point of about 120 ° C and is insoluble in water; it has an apovincamine titre of 64%. 45

Example 16 16.a Vincamine theophylline-7-acetate

, The II

MeOOC

CH COOH

t ^

CsoHseNgOY

P.M. = 593

Like the previous examples, the salt is prepared from 7.08 g (2.10 ~ 2 moles) of vincamine and from 4.77 g (2.IO-2 65 moles) of theophylline-7-acetic acid. 12 g of crystalline product are obtained with a melting point of 188 ° C, soluble in alcohol, insoluble in water and in common organic solvents.

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16.b Apovincamine theophylline-7-acetate

MeOOC

CH-COOH i 2

G3OH34N0O11

P.M. = 574.6

Using the methods of the previous example, the 3.36 g (IO-2 mol) salt of apovincamine and the 2.38 g (IO-2 mol) of theophylline-7-acetic acid are prepared.

5.4 g of water-soluble amorphous substance with a titre in apovincamine equal to 50% are obtained.

Example 17 17.a Vincamina capronate

.TO,

<xl

15

20

• C6H12 ° 2

C27H3.8N2O.5

P.M. = 452.6

In the same way as in the previous example, 7.08 g (2. 10 mole) of vincamine and 2.32 g (2. 10 mole) of capronic acid are reacted. 8.2 g of oily substance, insoluble in water and common solvents.The vincamine dosage is 67%.

17.b Apovincamine capronate

35

MeOOC

C6H12 # 2

C21HacN204 P.M. = 452.6

As in the previous example, 3.36 g of apovincamine 50 and 1.17 g of capronic acid yield 4.1 g of semi-solid low-melting products, insoluble in water and in alcohol,

with an apovincamine titer of 71%.

Example 18 18.a Vincamine caprinate

55

'C10H20 ° 2

MeOOÒ

qih «n205 P.M. = 526.7

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14

From 7.08 g (2. IO-2 moles) of vincamine and from 3.45 g (2. IO-2 moles) of caprinic acid, in the manner of the previous examples, 10 g of oily, semi-solid, insoluble substance are obtained in water and common organic solvents. The dosage of vincamine is 65.3%.

18.b Apovincamine caprinate

C10H20 ° 2

Q1h44n2o4

P.M. = 508.7

MeOOC

Similarly to the previous examples, 4.5 g of salt are obtained starting from 3.36 g (IO-2 moles) of apovincamine and 1.72 g (l (h2 moles) of caprinic acid. The product is presented as a substance semi-solid low melting, insoluble in water and in alcohol, with apovincamine titre equal to 50%.

Example 19 19.a Vincamine alginate

7.08 g (2. IO "2 moles) of vincamine and 4.75 g (2. IO-2 equivalent) of alginic acid, are brought to react with the methods of the previous examples. For the determination of the acid equivalent number of the alginic acid (polymannurine) dissolves 1.00 g of alginic acid in 50.00 ml of 0.1N NaOH. The excess alkalinity is titrated with 8.00 ml of 0.1N HCl. It is thus obtained that 4.2 x 0.1 = 4.2 meq of alginic acid / g of substance neutralize 1.49 g of vincamine base.

10.5 g of product are obtained with a melting point of 280 ° C, insoluble in water and in common organic solvents. The dosage in vincamine is equal to 56.6%.

19.b Apovincamine alginate

By operating according to the methods of the previous example 20, 4.7 g of adduct are obtained starting from 3.36 g of apovincamine and from 2.37 g of alginic acid. The product decomposes at 198 ° C, is insoluble in water and alcohol and has an apovincamine titre of 48%.

25 Example 20

20.a Vincamina tannate

The compound is prepared from 3.54 g of vincamine base and from 17 g of tannic acid, in the manner described in the previous examples. 19 g of amorphous product 30 soluble in alcohol are obtained. The vincamine dosage is 18.6%.

20.b Apovincamine tannate

From 3.36 g of apovincamine and from 17 g of tannic acid, operating as in the previous example, 18 g of 35 water insoluble adduct are obtained, with an apovincamine dosage equal to 16%.

Example 21

21.a Vincamina (D, L) - melted

40

COOH

CH-0H

AA

MeOOC ^ V = N / Et

HeOOC

A or c2shmn2o6

P.M. = 506.6

This salt is prepared from 7.08 g (2. IO * 2 moles) of vincamine and 3.05 g (2. IO-2 moles) of (D, L) -mandelic acid, in the manner of Example 11 10 g of substance is obtained with a melting point of 210 ° C, soluble in alcohol and insoluble in water and common solvents. The title in vincamina is 55.64%.

21.b Apovincamine (D, L) - melted

H-COOH OH

C2N

P.M. = 488.54

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With the same operating procedures, starting from 3.36 g of apovincamine and 1.52 g of (D, L) -mandelic acid, 4.3 g of salt are obtained with a melting point of 72 ° C, soluble in alcohol and insoluble in water. The dosage of apovincamine in the substance is 69.7%.

Example 22 22.a Vincamine indolyl-3-acetate

• 4XJ

CKLCOOH 2

.vx l

H

CïjH ^ N ^ O-, P.M. = 530

The preparation is carried out on 7.08 g (2.IO-2 moles) 20 of vincamine base and 3.54 g (2. IO-2 moles) of indolyl-3 -acetic acid according to the operating procedures given in the previous examples. .

10.5 g of amorphous product, insoluble in water and in common solvents, are obtained. The title in vincamina is equal to 25 63%.

22.b Apovincamine indolyl-3-acetate

I ^ MeOOC? "

I l

CHaC00H CWW.A

P.M. = 511.6

MeOOC

4.7 g of salt are prepared from 3.36 g of apovincamine and 1.75 g of indolyl-3-acetic acid in the manner of the previous example. The product has a melting point of 132 ° C, is insoluble in water and slightly soluble in alcohol; it has an apovincamine titre of 61%.

Example 23 23.a Vincamine-hydroquinone

The combination is carried out in an equimolar ratio of 7.08 g (2. IO-2 moles) of vincamine and 2.2 g (2. IO "2 moles) of hydroquinone. The product is insoluble in water and in municipalities

H

organic solvents and has a vincamine content of 40 77.3%.

23.b Apovincamine-hydroquinone

The association is made in equimolar ratio from 3.36 g of apovincamine and 1.1 g of hydroquinone. 45 3.4 g of alcohol-soluble and water-insoluble adduct are obtained, with a melting point of 122 ° C and an apovincamine titre of 72.3%.

Example 24

50

24.a Vincamine salicylate

COOH

H

OR

"V

C, Jl "N? Oi; P.M. = 492.55

According to the methods of example 11, the salt is prepared from 2.77 g (2.io "2 moles) of salicylic acid and from 7.08 g 65 (2.io" 2 moles) of vincamine. 9.5 g of product are obtained with a melting point of 120 ° C, soluble in alcohol and insoluble in water and in common organic solvents. The title in vincamina is equal to 53.5%.

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24.b Apovincamine salicylate

16

I HAVE

I HAVE

Et

COOH

CîgHjoNjjQs

P.M. = 474.55

HeOOi

The previous example is repeated starting from 1.39 g of salicylic acid and from 3.36 g of apovincamine, obtaining 3.9 g salt with a melting point of 110 ° C, soluble in alcohol and having an apovincamine title equal to 77.6%.

Example 25 25.a Vincamine-dihydroxyphenylalanine (Dopa)

The product is prepared starting from 7.08 g (2. 10 "2 moles) of vincamine and from 3.91 g (2. 10 2 moles) of dihydroxyphenyl-alanine (Dopa).

10.8 g of substance are obtained with a melting point of 235 ° C, practically insoluble in water and in common organic solvents. The title of the vincamina is 65%.

25.b Apovincamine-dihydroxyphenylalanine

15

20

25

CH2-CHC0CH

CsoH ^ NsOe P.M. = 533.6

With the modalities of the previous example and starting from 6.73 g of apovincamine and from 3.94 of dihydroxyphenylalanine, 9.7 g of amorphous adduct, insoluble, with an apovincamine titre equal to 58.3% are obtained.

Example 26 26.a Vincamine-pectin (Association 1: 1)

The product is obtained by mixing 7.08 g of vincamine and 7.08 g of pectin (methyl polygalacturonate) in an alcohol-chloroform mixture. The resulting solution or partial suspension is concentrated to residue. The residue is ground and dried in a ventilated oven at 60 ° C.

About 14 g of product are obtained with a melting point around 235 ° C, insoluble in water and common organic solvents.

26.b Apovincamine-pectin (Association 1: 1)

From 6.73 g of apovincamine and from 6.73 g of pectin, 12.2 g of adduct with melting point of 163 ° C and slightly soluble in alcohol are obtained. The titre in apovincamine is equal to 50%.

Example 27

27.a Vincamine-pectin (Association 2: 1)

The product is obtained from 7.08 g of vincamine and 3.54 g of pectin, in the manner of example 26.a. 10.5 g of adduct are obtained with a melting point around 228-235 ° C, practically insoluble in water and in common organic solvents.

27.b Apovincamine-pectin (Association 2: 1)

From 6.73 g of apovincamine and from 3.36 g of pectin, 9.4 g of adduct with melting point of 165 ° C, insoluble in water and slightly soluble in alcohol, are obtained with a titre in apovincamine equal to 63% .

The compounds obtained with the process of the present invention have been subjected to pharmacological and pharmacokinetic investigations. In the following table 1 the values of the DL are reported, by intraperitoneal way from which it is clear that the compounds in question have a relatively low toxicity. As far as pharmacodynamic activity is concerned, it was investigated by studying the changes in blood pressure at the femoral of the rabbit and the changes in blood flow recorded at the common carotid always in the rabbit after the administration of the salts. For the pharmacokinetics, investigations were carried out on the Wistar som-55 rat by ministering the salts orally and determining blood concentrations, urinary elimination and intestinal recovery at different times from treatment. The results have shown that not only are the therapeutic properties of vincamine and apovincamine maintained, but also 60 that, to a more or less significant extent, the compounds according to the present invention have a protracted effect over time.

65

17

625241

TABLE 1 TABLE 1 (Continued)

X

E.g.

DL50 x

E.g.

LD50

2,6-dihydroxybenzoate l.a.

5

550 p-chlorophenoxyacetate

15.a

750

»

l.b

750 »

15.b

750

2,5-dihydroxybenzoate

2.a

800 theophylline-7-acetate

16.a

700

»

2.b

750 10 "

16.b

400

3,5-dihydroxybenzoate

3.a

850 capronato

17.a

900

»

3.b

750 »

17.b

1900

p-toluenesulfonate

4.a

1250 15 caprinato

18.a "

2000

»

4.b

900 »

18.b

1900

clofiborato

5th

900 alginate

19.a

550

»

5.b.

800 2nd »

19.b

750

pivalate

6.a

1300 tanned

20.a

700

»

6.b

750 »

20.b

-

4-acetamidobutirrato

7.a

700 25 (D, L) - frozen

21.a

900

»

7.b

- »

21.b

300

furoate

8.a

800 indolyl-3-acetate

22 and had

1000

»

8.b

150 30 "

22.b

750

D (+) canforsoIfonato

9.a

1350 hydroquinone

23.A

500

»

9.b

»

23.b

750

L (+) - 0,0-dibenzoyltarthrate lO.a

950 35 salicylate

24. a

700

»

lO.b

1500

24.b

-

nicotinate ll.b dihydroxyphenylalanine

25.A

1500

acetylsalicylate

12.a

900

40 »

25. b

»

12.b

750

methylsulfate

13.a

150 pectin (1: 1)

26.A

2000

»

13.b

_ "(1: 1)

26b

750

enanthate

14.a

_45 "(2: 1)

27.a

2000

»

14.b

- "(2: 1)

27.b

-

v

Claims (28)

625241 2. Process according to claim 1, characterized in that 2,6-dihydroxybenzoate of vincamine or apovincamine is prepared. 2 CLAIMS 1. Procedure for the preparation of vinca-mine and apovincamine salts having therapeutic activity of these substances associated with a protracted effect over time having structural formula R wherein if R [represents OH, R2 represents CH3OOC, or if Rj represents CH3OOC there is a double bond in position A10,17, and X represents a radical of an acid selected from the acids 2,6-, 2,5-, 3,5-dihydroxybenzoic, p-toluene sulfonic, clofibric, pivalic, 4-acetamidobutyric, 2-furoic, camphorphosulphonic, L (+) - 0,0-dibenzoyltartaric, nicotinic, acetylsalicylic, methylsulforic, enanthic, p-chlorophenos-iscetic, theophylline -7-acetic, capronic, caprinic, alginic, tannic, (D, L) -mandelic, indolyl-3-acetic, salicylic, hydroquinone, dihydroxyphenylalanine and pectin, characterized in that it binds it or Fapovincamine according to the desired salt , in the form of a solution or suspension, it is brought to react, under heat and under stirring, with a solution or suspension of the acid, after which the reaction product is separated. 3. Process according to claim 1, characterized in that the 2,5-dihydroxybenzoate of vincamine or apovincamine is prepared. 4. Process according to claim 1, characterized in that the 3,5-dihydroxybenzoate of vincamine or apovincamine is prepared. 5. Process according to claim 1, characterized in that the vincamine or apovincamine p-toluenesulfonate is prepared. 6. Process according to claim 1, characterized in that the vincamine or apovincamine clofibrate is prepared. 7. Process according to claim 1, characterized in that the vincamine or apovincamine pivalate is prepared. 8. Process according to claim 1, characterized in that the 4-acetamidobutyrate of vincamine or apovincamine is prepared. 9. Process according to claim 1, characterized in that the vincamine or apovincamine furoate is prepared. 10. Process according to claim 1, characterized in that D (+) - vincamine or apovincamine camphorforsulfonate is prepared. 11. Process according to claim 1, characterized in that L (+) - 0,0-dibenzoylarthrate of vincamine or apovincamine is prepared. 12. Process according to claim 1, characterized in that the vincamine or apovincamine nicotinate is prepared. 13. Process according to claim 1, characterized in that the vincamine or apovincamine acetylsalicylate is prepared. 14. Process according to claim 1, characterized in that the vincamine or apovincamine methyl sulfate is prepared. 15. Process according to claim 1, characterized in that the vincamine or apovincamine enanthate is prepared. 16. Process according to claim 1, characterized in that the p-chlorophenoxyacetate of vincamine or apovincamine is prepared. 17. Process according to claim 1, characterized in that theophylline-7-acetamine of vincamine or apovincamine is prepared. 18. Process according to claim 1, characterized in that the vincamine or apovincamine capronate is prepared. 19. Process according to claim 1, characterized in that the vincamine or apovincamine caprinate is prepared. 20. Process according to claim 1, characterized in that the vincamine or apovincamine alginate is prepared. 21. A process according to claim 1, characterized in that the tannate of vincamine or apovincamine is prepared. 22. Process according to claim 1, characterized in that the (D, L) -melamine of vincamine or apovincamine is prepared. 23. Process according to claim 1, characterized in that the indamine di-vincamine or apovincamine is prepared. 24. Process according to claim 1, characterized in that the hydroquinone adduct is prepared with vincamine or apovincamine. 25. A process according to claim 1, characterized in that the vincamine or apovincamine salicylate is prepared. 26. Process according to claim 1, characterized in that the dihydroxyphenylalanine adduct is prepared with vincamine or apovincamine. 27. Process according to claim 1, characterized in that the adduct is prepared in the ratio 1: 1 or 2: 1 of vincamine or apovincamine with pectin. 28. Salts of vincamine and apovincamine obtained by the process according to claim 1.