FR2499571A1 - NEW APOVINCAMINOL DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS - Google Patents

Abstract

The invention relates to novel apovincaminol derivatives of the general formula (I) and pharmaceutically suitable acid addition salts thereof (in which R<1> and R<2> both denote hydrogen, or one of the symbols R<1> and R<2> represents hydrogen and the other represents nitro). The novel compounds according to the invention are prepared by acylating apovincaminol or an acid addition salt thereof with 3, 4, 5-trimethoxybenzoic acid or a reactive acid derivative thereof and if desired nitrating the apovincaminol-3', 4', 5'-trimethoxybenzoate obtained and if desired resolving the isomer mixture obtained into the 9-nitro- and 11-nitro-apovincaminol-3', 4', 5'-trimethoxybenzoate obtained and if desired converting a compound of the general formula (I) thus obtained into a pharmaceutically suitable acid addition salt. The novel compounds of the general formula (I) can be used in therapy for the treatment and prevention of skin diseases associated with a pathological cell proliferation - in particular psoriasis.

Description

The present invention relates to novel apovincaminol derivatives, a process for their preparation and pharmaceutical compositions which contain them.

à savoir l'apovincaminol-3',4',5'-triméthoxy-benzoate de formule (Ia)

le 9-nitro-apovincaminol-3',4 '5 '-triméthoxy-benzoate de formule (Ib)

et le ll-nitro-apovincaminol-3',4',5'-triméthoxy-benzoate de formule (Ic)

et leurs sels d'addition acide.According to one aspect of the invention, there is provided novel apovincaminol derivatives of general formula (I)

namely apovincaminol-3 ', 4', 5'-trimethoxy-benzoate of formula (Ia)

9-nitro-apovincaminol-3 ', 4' 5 '-trimethoxy-benzoate of formula (Ib)

and ll-nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate of formula (Ic)

and their acid addition salts.

In general formula (I), either R and R both represent hydrogen, or one of the symbols R1 and R represents hydrogen and the other a nitro.

The acid addition salts of the compounds of general formula (I) can be formed with inorganic or organic acids. Among the salts formed with inorganic acids, the hydrochlorides, sulfates and phosphates are particularly useful, while among the salts formed with organic acids, the acid tartrates, succinates, citrates and ascorbates are particularly useful.

It is known that apovincaminol and its acetate have an action on the coronary artery (French Patent No. 2,035,784). It is also known that apovincaminol benzoate has general vasodilatory properties (Hungarian Patent No. 166,476; CA). 82, 129 279 v (1975)) and that the esters of apovincaminol formed with an alkane-carboxylic acid in
C3 to C12 exhibit a cerebral vasodilatory effect (Hungarian Patent No. 171,662, corresponding US Patent No. 4,108,996 and Federal German Patent No. 26,320,118).

Thus all the known esters of apovincaminol exhibit vasotropic effects. On the other hand, the new compounds of the invention inhibit the enzymatic activity of phosphodiesterase and can be used firstly in the treatment of skin diseases linked to pathological cell proliferation and in the prophylaxis of recurrence. of these diseases.

Diseases linked to the pathological proliferation of the epidermis are relatively frequent and affect a few hundredths of the population. These diseases can be benign or malignant such as atopic psoriasis dermatitis, primary contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinoma, ichthyosis, pre-malignant hyperkeratosis, keratosis. light-induced acne and seborrheic dermatitis. Some diseases only appear in humans while others appear in humans as well as in animals.

Since some of the skin diseases associated with pathological cell proliferation (such as psoriasis) do not occur in animals, it is not possible to demonstrate in animal experiments the activity of the compounds against psoriasis. only indirectly.

Voorhees et al. (Arch. Derm. 104, 359-365, (1971)) have found that pathological cell proliferation is accompanied by a drop in the level of cyclic adenosine monophosphate (c-AMP). It is known that c-AMP is formed under the effect of adenyl cyclase and decomposed by phospho dissterase. Voorhees has been successful in working on psoriasis with agents that stimulate adenyl cyclase function (such as norepinephrine) or inhibit phosphodiesterase function (eg papaverine).

In planning the present model experimental test, we started from the presumption that the conclusion of
Voorhees also holds true for the opposite. Thus, if it can be shown that a certain compound inhibits the function of phosphodiesterase, this makes it indirectly probable that said compound is suitable for the treatment of skin diseases associated with pathological cell proliferation.

This presumption has been found to be true: compounds showing phosphodiesterase inhibitory activity in in vitro experiments have also been shown to be active in the treatment of psoriasis in clinical experiments.

The present model tests are carried out using phosphodiesterase isolated from animal tissues (rat brain, beef brain, beef heart). The enzyme is isolated according to the method of J. Schröder and H.V. Richenberg (Biochem.

Biophys. Acta 302, 50 (1973)), the isolated phosphodiesterase is purified by the method of JG Hardman and EW Sutherland (J. Biol. Chem. 240, 3704 (1965)) and finally the activity of the purified enzyme is measured according to the radioisotopic method of G. Pdch in the presence of an excess of tritiated c-AMP (10.1 millimoles of c-AMP substrate, from which the 3H-c-AMP is 2.59 K Bq) in a system of incubation first without inhibitor and then in the presence of an apovincaminol-3 ', 4', 5'-trimethoxy-benzoate derivative as inhibitor after an incubation period of 20 minutes (NS Arch. Pharmacol.

268, 272 (1979)). From the experimental compound, a 1 millimolar stock solution is prepared and various amounts are added to the incubated enzyme preparation using said stock solution so that the concentration of the test compound in the incubated sample must correspond to 5. x 107, 1 x 10 6, 5 x 10 6, 1 x 5 x 10 5 and 10 4 mole / liter, respectively. The aqueous solution of the compound used for comparison (papaverine) is added to the enzyme prepared in an analogous manner.

The activity of the control (enzymatic solution containing no inhibitor) is taken as 100%, while the activity of the solutions containing the compounds of general formula (I) such as papaverine is expressed as a percentage of the control. The results measured on the enzyme isolated from rat brain are summarized in the following table.

Experimental compound Concentration of test compound (enzyme inhibitor) rimental, mole / liter 5 x 10 6 1 x 10 5 5 x
(Effect on enzymatic activity
that,% of witness)
Apovincaminol-3 ', 4', 5'trimethoxy-benzoate.HCl 64.5 49.2 47.2 (-) - ll-nitro-apovincami nol-3 ', 4', 5l-trimethoxy-benzoate.HCl 53, 6 44.4 37.3 (-) - 9-nitro-apovincami nol-3 ', 4', 5 '-trimethoxy- benzoate.HCl 62.9 61.6 37.7
Papaverine 91.2 89.7 60.5
The results on the enzyme isolated from the brain and the heart of bovine animals are measured in an analogous manner. Using the results obtained, the curve of the enzyme activity is constructed as a function of the logarithm of the concentration of the enzyme inhibitor (expressed in micromoles).

We read on the curve the concentration of the enzyme inhibitor which decreases the enzyme activity by 50% (I50). The results obtained are summarized in the following table.

Experimental compound I50 in micromoles on the enzyme
phosphodiesterase isolated from
from the heart of beef / from the brain of
rat
Apovincaminol-3 ', 4', 5'trimethoxy-benzoate.HCl 1.5 10 (-) - ll-nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate.HCl 1 8 (-) - 9 -nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate.HCl 1 15
Papaverine.HCl 50 70
It appears from the above table that on the enzyme isolated from bovine heart and rat brain the new compounds of the invention are 33-50 and 4.5-9 times, respectively, more active than papaverine used as a reference compound.

The first clinical trials were made with local compositions containing the active ingredient (ointment, cream, solution, tincture, paste, aerosol). Creams containing 2%, 1%, 0.5%, 0.25 and 0.1% of (-) - 9-nitro or (-) - ll-nitro-apovincaminol-3 ', 4a, 5'- are used. trimethoxy-benzoate, respectively.

We treat patients suffering from psoriasis. Another fundamental criterion of choice is that patients do not simultaneously receive general treatment for their basic disease (eg, immunosuppressive, cytostatic or glucocorticoid therapy.

Groups of 5 patients each are examined by what is called the plaque method. One side of the symmetrical skin lesions is treated with the cream containing the active ingredient while the other side is treated with a placebo. The other surfaces of the patient's skin to be affected are treated by other local methods - inter alia with an ointment generally used for the treatment of psoriasis, containing flumethasone pivalate and salicylic acid, said ointment being used. as a reference substance.

The experiment is started with creams having a high active ingredient content and other patients are treated with a cream having a lower active ingredient content, although still active. The treatment is continued for 2 weeks, twice a day, in an open bandage.

The effect is evaluated by observing 3 different symptoms of inflammation, infultration and desquamation (peeling). The intensity of symptoms is expressed by the following scale ranging from 0 to 3.

O = no symptom 2 = strong symptom 1 = moderate symptom 3 = very strong symptom.

Symptoms are evaluated before treatment (I), after 7 days of treatment (II) and after 14 days of treatment (III). The following table gives the average number of points (total number of points divided by the number of patients.

A cream containing 2% active ingredient is used.

<tb> Compound <SEP> exp- <SEP> Average number <SEP><SEP> of <SEP> points
<tb> rimental <SEP> Infiltration- <SEP> Inflammation <SEP> Desquamation
<tb><SEP> I <SEP> II <SEP> III <SEP> I <SEP> II <SEP> III <SEP> I <SEP> II <SEP> III
<tb> Compound <SEP> of
<tb> formula <SEP> (Ia) <SEP> 1.8 <SEP> 0.6 <SEP> 0.5 <SEP> 1.8 <SEP> 1.3 <SEP> 0.75 <SEP> - 1.2 <SEP> 0.4 <SEP> 0
<tb> Compound <SEP> of
<tb> formula <SEP> (Ib) <SEP> 2.2 <SEP> 1 <SEP> 0.7 <SEP> 2.5 <SEP> 2.5 <SEP> 1.3 <SEP> 1.5 <SEP> 0.5 <SEP> O
<tb> Compound <SEP> of
<tb> formula <SEP> (Ic) <SEP> 2.4 <SEP> 1.8 <SEP> 1.3 <SEP> 2.2 <SEP> 1.3 <SEP> 1.3 <SEP> 1 , 6 <SEP> 1.2 <SEP> 0.8
<tb>

According to another aspect of the invention, there is provided a process for the preparation of novel compounds of general formula (I) (where either R and R both represent hydrogen, or one of the symbols R1 and R2 is a hydrogen and the other is unnitro) and their pharmaceutically acceptable acid addition salts in which apovincaminol or one of its acid addition salts is reacted with 3,4,5-trimethoxy-benzolic acid or a of its reactive derivatives capable of acylation and the compound of formula (la) is isolated or it is converted into one of its pharmaceutically acceptable acid addition salts, or if desired, the compound of formula (la) is nitrated into separating the mixture of compounds of formulas (Ib) and (Ic) thus obtained into the two compounds and, if desired, a compound of general formula (Ib) or (Ic) thus obtained is converted into an addition salt pharmaceutically acceptable acid.

The process of the invention is preferably carried out in the presence of an organic solvent, in particular a chlorinated hydrocarbon or an aliphatic ketone or pyridine, in particular in methylene chloride, chloroform or acetone. If 3,4,5-trimethoxybenzoyl halide is used as the acylating agent, the reaction is carried out in the presence of an equimolar amount or a small excess of an acidic binding agent. For this purpose we can use p. ex.

an alkali carbonate, an alkaline acid carbonate or an organic amine. If 3,4,5-trimethoxy-benzoic acid is used as the acylating agent, the reaction is carried out in the presence of a catalytic amount of an acid (preferably hydrochloric acid or sulfuric acid) or an activator of the carboxylic group and / or a dehydrating agent. The carboxylic group can be activated by a helogenated phenol, preferably pentachlorophenol. As a dehydrating agent, p. ex. N, N'-dicyclohexyl-carbodiimide. The acylation can be carried out at a temperature between -20 ° C and the boiling point of the reaction mixture, preferably at 20-60 ° C.

The compound of formula (Ia) can be isolated from the reaction mixture by extraction and / or evaporation.

The product thus obtained can be converted into a pharmaceutically acceptable acid addition salt. Salification can be carried out using an inorganic or organic acid (e.g. hydrochloric acid, sulfuric acid or phosphoric acid, or tartaric acid, succinic acid, citric acid or acid. ascorbic). The salification is carried out by conventional methods. This can preferably be done by adding a solution of the acid in ethyl ether or acetone to the solution of the base.

Salification is carried out at a pH of 3-6.

The compound of formula (Ia) thus obtained can be nitrated if desired. The nitration can preferably be carried out using concentrated nitric acid. The reaction preferably takes place in glacial acetic acid as a medium.

The nitration is preferably carried out by cooling to a temperature of about 0 C. When the reaction is complete, the excess acid is neutralized and the mixture of compounds of formulas (Ib) and (Ic) is isolated from the reaction mixture as well. obtained by extraction and / or evaporation.

The mixture of isomers thus obtained can be separated into its two components. The separation of the isomers can preferably be carried out by chromatographic methods.

The compounds of formulas (Ib) and (Ic) can be converted into their pharmaceutically acceptable acid addition salts, if desired, by the methods described in connection with the preparation of the acid addition salts of the compound of formula (Ia ).

According to another feature of the invention, pharmaceutical compositions are provided which have a phosphodiesterase inhibiting effect and which are especially useful in the treatment of skin diseases linked to pathological cell proliferation, and in the prophylaxis of recurrence. such diseases, said compositions comprising as active ingredient a compound of general formula (i) or one of its pharmaceutically active salts and optionally other therapeutically active compounds mixed with usual pharmaceutical carriers and / or diluents.

The active ingredient content of the pharmaceutical compositions of the invention is preferably 0.1-8.0%, in particular 0.2-2.0%. The compositions may optionally contain other pharmaceutically active compounds1 such as antibiotics, cytostatic agents, prostaglandins, ditranol, salicylic acid, tar, anti-inflammatory agents, immunosuppressants, glucocorticoids and - in the case of compositions suitable for parenteral administration - local anesthetic agents. As a glucocorticoid, triamcinolone acetonide can preferably be used.

us-lone. The active ingredient can be formulated preferably in the form of compositions for topical use, such as creams, ointments, solutions, jellies, aerosols, aerosol foams, adhesive plasters, etc.

The active ingredient can preferably be used in the form of the base, but acid addition salts can also be employed.
It is preferred to incorporate the active ingredient into a cream, which can be washed off.

Creams are prepared by dissolving the active ingredient in an alcohol type solvent, preferably in propylene glycol or ethylene glycol or a mixture thereof formed with a small amount of water, and mixing the solution thus obtained with a phase oily, easy to spread and compatible with the skin.

Said fatty phase may comprise cetyl alcohol, stearyl alcohol, cetostearyl alcohol, paraffin oil, glycerin monostearate, etc.

The cream may also contain an emulsifying agent, preferably polyoxyethylenesorbitan monooleate or monostearate - and a preservative such as a benzolic acid derivative, preferably methyl-p-hydroxybenzoate.

The creams can preferably contain 0.25 to 2.0% of the active ingredient, 45 to 50% glycol, 23 to 27% paraffin oil, 11 to 15% stearyl alcohol and possibly up to 100% of other auxiliary agents.

The active ingredient can also be formulated as an ointment which cannot be washed off with water by incorporating the active ingredient directly into the fatty phase.

The active ingredient can also be formulated as a solution or tincture which may contain p. ex.

20 to 40% prolymene glycol or dipropylene glycol, 40 to 55% 96% ethanol and up to 100% distilled water.

Aerosol formulations can be prepared by adding a fatty substance to the solution of the active ingredient in propylene glycol - e.g. ex. isopropyl myristate and a propellant (eg, freon).

Injectable solutions suitable for parenteral administration, preferably applicable subcutaneously or intracutaneously, can be prepared by dissolving a salt of the active ingredient in 0.72% aqueous sodium chloride solution and adjusting the pH of the solution to 5.

The pharmaceutical compositions of the invention can be prepared by methods known in the pharmaceutical industry. This can be done by mixing the active ingredient and optionally other therapeutically active compounds with known, non-toxic, inert and suitable pharmaceutical carriers and / or additives having the same properties and formulating a mixture thus obtained in a form suitable for use. medical application.

Further details of the invention can be found in the following examples, the scope of protection not being limited to said examples.

Example 1
Preparation of (-) - apovincaminol-3 ', 4', 5'-trimethoxy-benzoate
3.10 g (10.1 mMoles) of (-) - apovincaminol are dissolved in 60 ml of anhydrous dichloromethane, then 3.10 g of anhydrous sodium carbonate and 2.50 g (10.9 mMoles) of sodium chloride are added. 3,4,5-trimethoxybenzpyl and the reaction mixture is stirred at room temperature for 24 hours.

The reaction mixture is diluted with 100 ml of water, the organic phase is separated and the aqueous layer is extracted twice with 20 ml of dichloromethane each time. The combined dichloromethane phases are dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. In this way 4.50 g of the title compound is obtained, yield 89.1%.

Molecular formula C30H34N205. Molecular weight 502.61. -1
IR spectrum (film): v max 1725 cm (-C = O); 1620 cm (= C = C =)
NMR spectrum (deuterochloroform): 6: 1.01 (t, 3H, CH3CH2-);
6: 3.72 (s, 6H, 2 x -OCH3); 6: 3.85 (s, 3H, -OCH3);
6: 4.25 (s, 1H, denomination); - 6: 5.29 (s, 1H, -CH =);
6: 5.4 (m, 2H, -OCH2); 6: 7.0-7.8 (m, 6H, aromatic).

MS (m / e): 502 (53), 432 (100), 290 (17), 261 (41), 220 (19), 216 (23), 212 (18), 195 (35).

E. 25 = -22.0 (c = 0.7; dichloromethane).

D
Example 2
Preparation of (-) - apovincaminol-3 ', 4', 5'-trimethoxybenzoate acid tartrate
The compound prepared according to Example 1 is dissolved in diethyl ether. To the solution is added a saturated solution of D-tartaric acid in diethyl ether until the precipitation of the acid tartrate salt becomes complete.

The salt is filtered and dried. Pf: 120-121 C. IR spectrum (KBr):
v max 1730 cm 1 (-C = O); 1640-1655 cm 1 (= C = C =).

max 25
La 1D = -8.5 (c = 1, pyridine). Molecular weight 652.7.

Example 3
Preparation of (-) - 9-nitro-apovincaminol-3 ', 4', 5 '-trimethoxy- benzoate and ((-) - 11-nitro-apovincaminol-3', 4 ', 5'-trimethoxy- benzoate
5 g of (-) - apovincaminol-3 ', 4', 5'-trimethoxy benzoate are dissolved in 50 ml of glacial acetic acid. A mixture of 20 ml of glacial acetic acid and 10 ml of concentrated nitric acid (d = 1.52) at 0 C while stirring is added to the solution obtained. The reaction mixture is poured into 350 mg of ice water and the pH is adjusted to 9 by adding a 25% aqueous solution of ammonium hydroxide. The alkaline solution is extracted first with 250 ml and then twice with 200 ml of dichloromethane each time. The combined organic solution is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness in vacuo.

The isomer mixture thus obtained is separated into its two components by chromatographic methods using silica gel 60 as the adsorbent and a 10: 2 mixture of benzene and acetone as the developing agent. Under these conditions, the R f of the 9-nitro compound is greater than that of the ll-nitro derivative. Thus, 1.7 g of the 9-nitro compound and 1.8 g of the 11-nitro derivative are obtained.

The physical constants of (-) - 9-nitro-apovincaminol3 ', 4', 5'-trimethoxybenzoate are as follows:
Mp: 77-78 C. [α] = -78.5 (c = 1; chloroform).

1H-NMR (CDCl3): #: 3.8 (s, 6H, 2 x CH3O-); ; : 3.91 (s, 3H, 1 x CH3O-); #: 7.3 (d, 1H, H12); #: 7.96 (d, 1H, H11)
#: 8.1 (d, 1H, h10).

The physical constants of (-) - ll-nitro-apovincaminol3 ', 4', 5'-trimethoxybenzoate are as follows:
P f: 72-73 C. [&alpha;] D La =
D = 134.30 (c = 1; chloroform).

H-NMR (CHCl3): 6: 3.8 (s, 6H, 2 x CH3O-); 6: 3.9 (s, 3H, 1 x CH3O-); 6: 7.56 (d, 1H, Hg); 6: 8.1 (d, 1H, H10);
6: 8.9 (d, 1H, H12).

Example 4
Preparation of 9-nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate hydrochloride and 11-nitro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate hydrochloride
The 9-nitro- or 11-nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate prepared according to Example 3 is dissolved in methanol and the pH of the solution is adjusted by adding a solution of hydrochloric acid and methanol. The hydrochloric salt formed is precipitated by adding diethyl ether. The salt is filtered, washed and dried. The hydrochloride of the 9-nitro derivative melts at 144-150 ° C, while the hydrochloride of the 11-nitro derivative has a melting point of 141-144 ° C.

Example 5
A cream is prepared having the following composition:
Component Quantity (g) Apovincaminol-3 ', 4', 5'-trimethoxybenzoate 2
Propylene glycol 50
Paraffin oil 26
Polyethylene glycol 5
Stearyl alcohol 15
Glycerol monostearate 2
The active ingredient is dissolved in propylene glycol on a water bath (the bath temperature not exceeding 50 "C). The other components are heated until they melt and then cooled to 40-45" C. constantly stirring.

To the melt is added the solution of the active ingredient while stirring and the cream thus obtained is cooled while stirring.

Similarly, creams containing 0.25%, 0.5%, 1.0% and 1.5% of the ingredient are prepared. active, respectively.

The active ingredient 9-nitro or 11-nitro-apovincaminol-3 ', 4', 5l-trimethoxy-benzoate can also be used.

Example 6
A cream is prepared having the following composition:
Component Quantity (g) 9-nitro-apovincaminol-3 ', 4', 5'-trimer * hoxy-benzoate 2
0.1 triamcinolone acetonide
Glycerol monostearate 3.0
Polyethylene glycol 400 5.0
Stearyl alcohol 13.0
Paraffin oil 24.9
Propylene glycol 53.0
The procedure is analogous to Example 5 except that two active ingredients are dissolved in lepropylene glycol. As active ingredient, it is also possible to use the 11-nitro derivative or apovincaminol-3 ', 4', 5'-trimethoxybenzoate.

Example 7
A dye solution is prepared having the following composition:
Component Quantity (g) 9-nitro-apovincaminol-3 ', 4', 5'-trimethoxy-benzoate 1
Propylene glycol 30
96% methanol 69
The above process can also be carried out using 11-nitro derivatives as an active ingredient.

Example 8
A dye solution is prepared having the following composition:
Component Quantity (%)
Apovincaminol-3 ', 4', 5'trimethoxy-benzoate 1 acid tartrate
Propylene glycol 30
96% ethanol 47
Distilled water 22
Example 9
An aerosol is prepared having the following composition:
Component Quantity (%)
Apovincaminol-3 ', 4', 5'trimethoxy-benzoate acid tartrate 0.5
Propylene glycol 30
Isopropyl myristate 4.5
Freon 65
As active ingredient, it is also possible to use the 9-nitro or 11-nitro derivative.

Example 10
An aerosol foam is prepared having the following composition:
Component Quantity (%)
Apovincaminol-3 ', 4', 5'trimethoxy-benzoate 2 acid tartrate
Cetostearyl alcohol 1
Benzyl alcohol 2
Polyoxyethylene sorbitan monostearate 15
96% ethanol 30
Distilled water 30
Freon 20

Claims (14)

(where either R1 and R2 are both hydrogen, or one of the symbols R1 and R2 is hydrogen and the other is nitro) and their pharmaceutically acceptable acid addition salts.

CLAIMS 1. Compounds of general formula (I) 2. Apovincaminol-3 ', 4', 5'-trimethoxy-benzoate of formula (Ia)

and its pharmaceutically acceptable acid addition salts. 3. 9-nitro-apovincaminol-3l, 4l, 5l-trimethoxy-benzoate of formula (Ib)

and its pharmaceutically acceptable acid addition salts. 4.11-nitro-apovincaminol-3 '1', 5'-trimethoxy-benzoate of formula (Ic)

and its pharmaceutically acceptable acid addition salts. 5. Process for the preparation of new compounds of general formula (I)

(where either R and R both represent hydrogen, or one of the symbols R and R is hydrogen and the other is nitro) and their pharmaceutically acceptable acid addition salts, in which one reacts apovincaminol or one of its acid addition salts with 3,4,5-trimethoxy-benzoic acid or one of its reactive derivatives capable of acylation and the compounds of formula (Ia) are isolated

or they are converted into one of their pharmaceutically acceptable acid addition salts or, if desired, the compound of formula (Ia) is titrated and the mixture of compounds of formulas (Ib) and (Ic) is separated.

thus obtained into the two components and, if desired, the compounds of general formula (Ib) or (Ic) thus obtained are converted into a pharmaceutically acceptable acid addition salt. 6. Process according to Claim 5, in which 3,4,5 (trimethoxy-benzoyl chloride is used as acylating agent. 7. The method of claim 5 or claim 6 wherein the acylation is carried out in the presence of an organic solvent. 8. The method of claim 5 wherein the nitration is carried out in the presence of glacial acetic acid. 9. The method of claim 5 or claim 8 wherein the nitration is carried out at a temperature of about 0 C. 10. Pharmaceutical compositions for the treatment of diseases related to pathological cell proliferation, preferably psoriasis - and the prophylaxis of the recurrence of such diseases. which comprises as active ingredient a compound of general formula (I)

(where R1 and.R2 are as defined in claim 1) or a pharmaceutically acceptable acid addition salt thereof and optionally other therapeutically active compounds in admixture with suitable inert non-toxic pharmaceutical carriers and / or auxiliary agents. 11. A pharmaceutical composition according to claim 10 which comprises from 0.1 to 8.0%, preferably from 0.2 to 2.0% of compound of general formula (I). 12. A pharmaceutical composition according to claim 10 or claim 11 in the form of a cream, ointment, solution, aerosol, aerosol foam or injection suitable for subcutaneous or intracutaneous administration. 13. Process for the preparation of pharmaceutical compositions according to claims 10-12, in which a compound of general formula (I) or one of its pharmaceutically acceptable acid addition salts and optionally one or more other therapeutically active compounds is mixed with carriers and / or suitable inert non-toxic auxiliary agents and the mixture is formulated in a form ready for medical application. 14. A method of treatment and prophylaxis of patients suffering from skin diseases associated with pathological cell proliferation, in particular psoriasis, in which the affected skin surface is treated with a therapeutically active amount of a pharmaceutical composition comprising as active ingredient a compound of general formula (I)

or a pharmaceutically acceptable acid addition salt thereof.