GB2094787A

GB2094787A - New apovincaminol derivatives

Info

Publication number: GB2094787A
Application number: GB8204018A
Authority: GB
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1981-02-11
Filing date: 1982-02-11
Publication date: 1982-09-22
Also published as: SE449863B; GR75857B; ES8307006A1; ES509419A0; DK151023B; GB2094787B; FI70215C; IL64808A0; SU1093249A3; IL64808A; DK151023C; IT1157301B; DE3204509C2; FR2499571B1; FR2499571A1; NL8200490A; AR227574A1; AU544455B2; DD202570A5; AU8033882A

Abstract

New compounds of the general formula (I): <IMAGE> wherein either both R<1> and R<2> stand for hydrogen or one of the symbols R<1> and R<2> is hydrogen and the other is nitro, and pharmaceutically acceptable acid addition salts thereof are prepared by reacting apovincaminol with 3,4,5-trimethoxy- benzoic acid or a reactive derivative thereof capable of acylation and, if desired, nitrating the resulting compound and separating the isomeric mixture of nitro derivatives thus obtained, and, if desired, converting the said compound or nitro derivatives into pharmaceutically acceptable acid addition salts thereof. These compounds can be used in therapy in the treatment of skin diseases associated with pathological cell proliferation and in the prophylaxis of such diseases.

Description

SPECIFICATION New apovincaminol derivatives This invention relates to new apovincaminol derivatives, a process for the preparation thereof and pharmaceutical compositions containing them.

According to one aspect of the present invention, there are provided new apovincaminol derivatives of the general formula (I):

namely apovincaminol-3',4', 5'-trimethoxy-benzoate of the formula (la):

9-nitro-apovincaminol-3',4'-5'-trimethoxy-benzoate of the fomula (Ib):

and 11-nitro-apovincaminol-3'-4'-5'trimethoxy-benzoate of the formula (Ic):

and acid addition salts thereof.

In the general formula (I), either R' and R2 both stand for hydrogen, or one of the symbols R and R2 represents hydrogen and the other represents nitro.

The acid addition salts of the compounds of the general formula (I) may be formed with inorganic or organic acids. Particuarly useful salts formed with inorganic acids include the hydrochlorides, sulphates and phosphates while particularly useful salts formed with organic acids include the hydrogen tartarates, succinates, citrates and ascorbates.

It is known that apovincaminol and its acetate exhibit an effect on the coronary artery (French Patent Specification tlo. 2 035 784). It is also known that aprovincaminol benzoate possesses general vasodilatory properties (Hungarian Patent Specification No. 1 66 476; CA 82, 1 29 279 v (1975)E and the esters of apovincaminol formed with alkane carboxylic acids having 3-1 2 carbon atoms exhibit cerebral vasedilatory effects (Hungarian Patent Specification No. 171 662, the corresponding US Patent Specification No. 4 108 996 and the BR German Federal Republic Patent Specification No. 26 32 118).

Thus, all the known esters of apovincaminol exhibit vasotropic effects. On the other hand, the new compounds of the present invention inhibit the enzyme activity of phosphodiesterase and can be used primarily in the treatment of skin diseases associated with pathological cell proliferation and in the prophylaxis of the recurrence of such diseases.

Diseases associated with pathological proliferation of the epidermis are relatively frequent and involve a few per cent of the population. These diseases can be of both benign and malignant character, and include psoriasis atopias dermatitis, primary contact dermatitis, allergical contact dermatitis, baso- and spinocellular carcinoma, inchthyosis, premalignant hyperceratosis, lightinduced ceratosis, acne and seborrhoeas dermatitis. Some diseases occur only on humans while others occur both in humans and in animals.

Since some e of the skin diseases associated with pathological cell proliferation (e.g. psoriasis) do not occur in animals, the activity of the compounds against psoriasis can be investigated in animal experiments only indirectly.

Voorhees et a. (Arch. Derm. 104, 359-365, (1971)) have found that pathological cell proliferation is accompanied by a decrease 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 phosphodiesterase. Voorhees succeeded in influencing psoriasis by agents which stimulate the function of adenyl cyclase (such as norepinephrine) or inhibit the function of phosphodiesterase (e.g. papaverine).

In placing our model experiments we have started from the assumption that the converse of the statement of Voorhees is also true. Thus, if it can be proven that a certain compound inhibits the function of phosphodiesterase this makes it probable in an indirect way that the said compound is suitable for the treatment of skin diseases associated with pathological cell proliferation.

This assumption turned out to be true: compounds showing phosphodiesterase inhibiting activity in in vitro tests proved to be active in the treatment of psoriasis in clinical experiments as via !.

Our model tests are carried out with the aid of phosphodiesterase isolated from animal body tissues (rat brain, bovine brain and bovine heart). The enzyme is isolated according to the method Qf J. SchrBder and H.V. Richenberg (Biochem. Biophys. Acta 320, 50 (1973)), the isolated phosphodiesterase is purified by the method of J.G. Hardman and E.W. Sutherland (J.

Biol. Chem. 240, 3704 (1965)) and finally the activity of the purified enzyme is measured according to the radioisotope method of G. Pöch in the presence of an excess of tritiated c-AMP (10.1 millimoles of c-AMP substrate, in which the amount of 3"-c-AMP is 2.59 K Bq) in an incubation system, at first without an inhibitor and thereafter in the presence of an apovincaminol-3'-4'-5 '-trimethoxy-benzoate derivative as inhibitor after an incubation period of 20 minutes (N.S. Arch. Pharmacol. 265, 272 (1979)).A 1 millimolar stock solution of the test compound is prepared and to the incubated enzyme preparation various amounts of the said stock solution are added so that the concentration of the test compound in the incubated sample corresponds to 5 X 10-7, 1 X 10-6, 5 X 10-6, 1 > < X 10-5, 5 X 10-5 and 10-4 mole/litre, respec- tively. The aqueous solution of the compound used for comparison (papaverine) is added to the enzyme preparation in a similar manner.

The activity of the control (enzyme solution containing no inhibitor) is taken as 100 %, while the activities of the solutions containing the compounds of the general Formula (I) and of papaverine are expressed as a percentage of the control. The results measured on the enzyme isolated from rate brain are summarised in the following Table.

Test compound Concentration of the test compound, (enzyme inhibitor) mole/litre 5X10-6 1x10-5 5x10-5 (Effect on the enzyme activity, % of the control) Apovincaminol-3', 4', 5'- -trimethyoxy-benzoate . HCl 64.5 49.2 47.2 (-)- 11 nitro-apovin- caminol-3',4',5'-tri- methoxy-benzoate . HCI 53.6 44.4 37.3 (-)-9-nitro-apovincaminol-3',4',5'-trimethoxybenzoate. HCI 62.9 61.6 37.7 Papaverine 91.2 89.7 60.5 The results on enzyme isolated from bovine brain and bovine heart are measured in a similar manner.By using the results obtained, the enzyme activity is plotted against the logarithm of the enyme inhibitor concentration (expressed in,ymoles). The concentration of the enzyme inhibitor which decreases the enzyme activity by 50% (150) is read off the curve. The results obtained are summarised in the following Table.

Test compound i50 values, in /mmoles, on phosphodiesterase enzyme isolated from bovine heart rat brain Apovincaminol-3',4',5' -trimethyoxy-benzoate . HCI 1.5 10 (-)- 11 -nitro-apovinc- aminol-3',4',5'-trimethoxy-benzoate . HCI 1 8 (-)- 9-nitro-apovincaminol-3',4',5'-trimethoxy benzoate HCI 1 1 5 Papaverine . HCI 50 70 It appears from the above Table that, on the enzyme isolated from bovine heart and rat brain, the new compounds of the present invention are, respectively, 33-50 and 4.5-9 times more active than the papaverine used as reference compound.

The first clinical tests were carried out with topical 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 (-)-1 1-nitroapovincaminol-3',4',5'-tri-methoxybenzoate, respectively, were used.

Patients suffering from psoriasis were treated. A further fundamental selection requirement was that the patients did not simultaneously receive a systemic treatment of their basic disease (e.g. immunosuppressive, cytostatic or glucocorticoid treatment).

Groups consisting of five patients each were examined by the soWcalled plaque method. One side of the symmetrical skin lesions was treated with the cream containing the active ingredient while the other side was treated with a placebo. The other affected skin surfaces of the patient were treated by other topical methods, among others with an ointment generally used for the treatment of psoriasis, containing flumethasone pivalate and salicyclic acid, this ointment being used as reference substance.

The test was started with creams having a high active ingredient content and further patients were treated with a cream having the lowest active ingredient content but being still active. The treatment was carried on for two weeks, twice a day, with open dressings.

The effect was evaluated by observing three different symptoms: inflammation, infiltration and desquamation (peeling). The intensity of the symptoms was expressed by the following scale between 0 and 3.

O = no symptoms 2 = strong symptoms 1 = moderate symptoms 3 = very strong symptoms The symptoms were evaluated before treatment (I), after a treatment of seven days (II) and after a treatment of fourteen days (III). In the following Table the average number of points (total number of points divided by the number of patients) is disclosed. A cream containing 2 % active ingredient was used.

Test Compound Average number of points Infiltration Inflammation Desquamation II ill I 11 Ill I ll Ill Compound of the Formula (lea) 1.8 0.6 0.5 1.8 1.3 0.75 1.2 0.4 0 Compound of the Formula (lob) 2.2 1 0.7 2.5 2.5 1.3 1.5 0.5 0 Compound of the Formula (c) 2.4 1.8 1.3 2.2 1.3 1.3 1.6 1.2 0.8 According to a further aspect of th present invention there is provided a process for the proparation of new compounds of the general formula (I), wherein either R and R both stand for hydrogen or one of the symbols R and R is hydrogen and the other is nitro and pharmaceutically acceptable acid addition salts thereof, which process comprises reacting apovincaminol or an acid addition salt thereof with 3 ,4 ,5 -trimethoxy-benzoic acid or a reactive derivative thereof capable of acylation and isolating the compound of the formula (la) or converting the same into a pharmaceutically acceptable acid addition salt thereof, or, if desired, nitrating the compound of the formula (la), separating the mixture of the compounds of the formulae (lb) and Ic) thus obtained into the two components, and, if desired, converting a compound of the general formula (lb) or (Ic) thus obtained into a pharmaceutically acceptable acid addition salt.

The process of th invention is carried out preferably in the presence of an organic solvent, preferably a chlorinated hydrocarbon or an aliphatic ketone or pyridine, particularly in methylene chloride, chloroform or acetone. If a 3 ,4 ,5 -trimethyoxy-benzoyl halide is used as acylating agent the reaction is carried out in the presence of an equimolar amount or a small excess of an acid-binding agent. For this purpose, e.g. an alkali metal carbonate, alkali metal hydrogen carbonate or organie amine may be used. if 3, 4, 5 -trimethyoxy-benzoic acid is used as acylating agent the reaction is carried out in the presence of a catalytic amount of an acid (preferably hydrochloric acid or sulphuric acid) or an activator of the carboxylic group and/or a dehydrating agent. The carboxylic group may be activated by a halogenated phenol, preferably pentachlorn phenol.As dehydrating agent e.g. N,N'-dicyclohexyl carbodiimide may be used. The acylation may 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 the formula (la) may be isolated from the reaction mixture by extraction and/or evaporation.

The product thus obtained may be converted into a pharmaceutically acceptable acid addition salt. Salt fornication may be carried out by using an inorganic or organic acid (e.g. hydrochloric acid, sulphuric acid or phosphoric acid or tartaric acid, succinic acid, citric acid or ascorbic acid).

The salt formation is carried out by methods known per se. One may proceed preferably by adding a solution of the acid in ethyl ether or acetone to the solution of the base. Salt formation is accomplished at a pH value of 3-6.

The compound of the formula (la) thus obtained may be nitrated if desired. Nitration is preferably carried out using concentrated nitric acid. The reaction is preferably accomplished in glacial acetic as reaction medium. Nitration is preferably carried out under cooling at a temperature of about 0 C. After termination of the reaction, the excess of the acid is neutralised and the mixture of the compounds of the formulae (lib) and (Ic) thus obtained is isolated from the reaction mixture by extraction and/or evaporation.

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

The compounds of the formulae (lb) and (Ic) may 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 the formula (la).

According to another feature of the present invention, there are provided pharmaceutical compositions having a phosphodiesterase inhibitory effect and being mainly useful in the treatment of skin diseases associated with pathological cell proliferation and the prophylaxis of the recurrence of such diseases, the said compositions comprising as an active ingredient a compound of the general formula (I) or a pharmaceutically acceptable acid addition sit thereof, and optionally further therapeutically active compounds, in admixture with usual pharmaceutical carriers and/or diluents.

The active ingredient content of the pharmaceutical compositions of the present invention is preferably 0.1-8.0 %, particularly 0.2-2.0 %. The compositions may optionally contain further pharmaceutically therapeutically active compounds, such as antibiotics, cytostatical agents, prostaglandins, ditranol, salicylic acid, tar, antiinflammatory agents, immunosupressants, glucocorticoid and, in the case where the compositions are intended for parenteral administration, local anaesthetic agents. As glucocorticoid triaminolon-acetonide is preferably used. The active ingredient may be provided preferably in the form of compositions for topical use, such as creams, ointments, solutions, gelees, aerosols, aerosol foams, adhesive plasters, etc.

The active ingredient is preferably used in the form of the base but acid addition salts may be applied as well.

It is preferred to incorporate the active ingredient into a cream, which can be washed off.

The cremas may be prepared by dissolving the active ingredient in a solvent of the alcoholic type, preferably in propylene glycol or ethylene glycol or a mixture thereof formed with a small amount of water, and admixing the solution thus obtained with a readily spreadable fatty phase which is skin compatible.

The said fatty phase may comprise cetyl alcohol, stearly alcohol, cetostearyl alcohol, paraffin oil, glycerine monostearate etc.

The cream may also contain an emulsifying agent, preferably polyoxyethylene sorbitan monooleate or monostearate, and a preservative such as benzoic acid derivatives, preferably methyl-p-hydroxy benzoate.

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

The active ingredient can also be formulated in the form of an ointment which cannot be washed off with water by incorporating the active ingredient d,.ectly in the fatty phase.

The active ingredient can also be formulated in the form of a solution or tincture which may contain e.g. 20-40 % of propylene glycol or dipropylene glycol, 40-55 % of 96 % ethanol and distilled water up to 100 %.

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

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

The pharmaceutical compositions of the present invention can be prepared by methods known in the pharmaceutical industry. One may proceed by admixing the active ingredient and optionally further therapeutically active compounds with suitable inert, non-toxic, known pharmaceutical carriers and/or additives and converting the mixture thus obtained to a form suitable for medical use.

The invention is illustrated by the following Examples.

Example 1 Preparation of (-)-apovincaminol-3', 4 '5, '-trimethoxy-benzoate 3.10 g (10.1 millimoles) of (-)-apovincaminol are dissolved in 60 ml of anhydrous dichloromethane, whereupon 3.10 g of anhydrous sodium carbonate and 2.509 (10.9 millimoles) of 3 ,4 ,5 -trimethoxy-benzyl chloride are added 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, each time with 20 ml of dichloromethane. The united dichloromethane phases are dried over magnesium sulphate, filtered and the filtrate is evaporated in vacuo. Thus, 4.50 9 of the title compound are obtained, yield 89.1%.

Brutto formula C30H34N205. Molecular weight 502.61.

IR spectrum (film); v max 1725 cam~' (-C = 0); 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):#: 4.25 (s, 1 H, anellation);S: 5.29 (s, 1 H, -CH = ):#: 5.4 (m, 2H, -OCH2)8: 7.0-7.8 (m, 6H, aromatic).

MS (m/e): 502(53), 432(108, 290(17), 261(41), 220(19), 216(23), 212(18), 195(35).

[α]D25= - 22.0 (c=0.7: dichloromethane).

Example 2 Preparation of (-)-apovincaminol-3',4'5,'-trimethoxy-benzoate hydrogen tartrate The compound prepared according to Example 1 is dissolved in diethyl ether. To the solution a saturated solution of D-tartaric acid in diethyl ether is added until the precipitation of the hydrogen tartarate salt is complete. The salt is filtered off and dried. Mpt.: 120-121 C. IR spectrum (KBr):# max 1730 cm- (-C = O); 1640-1665 cm-(=C=C=). [α]D25=#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,'-trimethoxybenzoate 5 g of (-)-apovincamionol-3',4'5,'-trimethoxy-benzoate are dissolved in 50 ml of glacial acetic acid. To the solution obtained a mixture of 20 ml of glacial acetic acid and 10 ml of concentrated mitric acid (d=1.52) is added at 0 C with stirring. The reaction mixture is poured into 350 mg of ice cold water and the pH is adjusted to g by adding a 25% aqueous ammonium hydroxide solution. The alkaline solutyion is extracted, first with a 250 ml portion and thereafter twice, each time with a 200 ml portion of dichloromethane. The united organic solutions are dried over anhydrous sodium sulphate, filtered and the filtrate is evaporated to dryness in vacuo.

The isomer mixture thus obtained is separated into the two components by chromatograpy using Kieselgel 60 as absorbent and a 10:2 mixture of benzene and acetone as developing agent. Under these conditions the Rf value of the 9-nitro-compound is greater than that of the 1 1-nitro-derivative. Thus, 1.7 g of the 9-nitro-compound and 1.8 9 of the 1 1-nitro-derivative are obtained.

The physical constants of the (-)-9-nitro-apovincaminol-3',4'5,'-trimethoxy-benzoate are as follows: Mp.: 77-78 C. [α]D = # 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 the (-)-11-nitro-apovincaminol-3',4'5,'-trimethoxy-benzoate are as follows: Mp.: 72-73 C. [α]D = - 134.3 (c=1; chloroform).

1H-NMR (CDCl3):#: 3.8 (s, 6H, 2 X CH3O-):#: 3.9 (s, 3H, 1 X CH3O-);#: 7.56 (d, 1H, H9);#: 8.1 (d, 1H, H10):#: 8.9 (d, 1H, H,2).

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

Example 5 A cream having the following composition is prepared: Component: Amount (g): Apovincaminol-3',4'5, '-trimethoxy- benzoate 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 (bath temperature not exceeding 50 "C). The other components are heated until they melt and thereafter cooled to 40-45 "C with constant stirring. The solution of the active ingredient is added with stirring to the melt and the cream thus obtained is cooled with stirring.

In an analogous manner creams containing 0.25 %, 0.5 %, 1.0 % and 1.5 % of the active ingredient, respectively, are prepared.

The active ingredient 9-nitro- or 1 1-nitro-apovincaminol-3',4'5,'-trimethoxy-benzoate may be used as well.

Example 6 A cream having the following composition is prepared: Component: Amount (g): 9-nitro-apovincaminol-3',4' 5, '-trimethoxybenzoate 2 Triamcinolon acetonide 0. 1 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 manner to Example 5 except that two active ingredients are dissolved in propylene glycol. As active ingredient the 1 1-nitro- derivative or apovincaminol3',4'5,'-trimethoxy-benzoate may be used as well.

Example 7 A tincture solution having the following composition is prepared: Component: Amount (g): 9-nitro-apovincamino1-3',4"5, '-trimethoxybenzoate 1 Propylene glycol 30 96 % methanol 69 The above process may also be carried out by using the 11-nitro-derivative as active ingredient.

Example 8 A tincture solution having the following composition is prepared: Component: Amount (%): Apovincaminoi-3 ',4' 5, '-trimethoxy-benzoate hydrogen tartrate 1 Propylene glycol 30 96 % ethanol 47 Distilled water 22 Example 9 An aerosol having the following composition is prepared: Component: Amount (%): Apovincaminol-3',4'5, '-trimethoxy-benzoate hydrogen tartrate 0.5 Propylene glycol 30 Isopropyl myristate 4.5 Freon 65 As active ingredient the 9-nitro- or 11-nitro-derivative may be used as well.

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

Claims

1. A compound of the general formula (I):

wherein either both R1 and R2 are hydrogen or one of the symbols R' and R2 stands for hydrogen and the other for nitro, or a pharmaceutically acceptable acid addition salt thereof.

2. Apovincaminol-3',4'5,'-trimethoxy-benzoate of the formula (la):

and pharmaceutically acceptable acid addition salts thereof.

3. 9-Nitro-apovincaminol-3',4'5,'-trimethoxy-benzoate of the formula (Ib):

and pharmaceutically acceptable acid addition salts thereof.

4. 1 1 -Nitro-apovincaminol-3', 4' 5, '-trimethoxy-benzoate of the formula (Ic):

and pharmaceutically acceptable acid addition salts thereof.

5. A process for the preparation of a compound of the general formula (I) , as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting apovincaminol or an acid addition salt thereof with 3',4'5,'-trimethoxy-benzoic acid or a reactive derivative thereof capable of acylation and isolating~the compound of the formula (la), as defined in claim 2, or converting the same into a pharmaceutically acceptable acid addition salt thereof, or, if desired, nitrating the compound of the formula (la) and separating the mixture of the compounds of the formulae (Ib) and (Ic), as defined respectively in claims 3 and 4, thus obtained into the two components, and, if desired, converting a compound of the general formula (Ib) or (Ic) thus obtained into a pharmaceutically acceptable acid addition salt.

6. A process according to claim 5, which comprises using 3 ,4 ,5 -trimethoxy-benzoyl chloride as acylating agent.

7. A process according to claim 5 or 6, which comprises carrying out acylation in the presence of an organic solvent.

8. A process according to claim 5, which comprises carrying out nitration in the presence of glacial acetic acid.

9. A process according to claim 5 or 8, which comprises carrying out nitration at a temperature of about 0 "C.

1 0. A pharmaceutical composition for the treatment of diseases associated with pathological cell proliferation, preferably psoriasis, and the prophylaxis of the recurrence of such diseases, which comprises as an active ingredient a compound of the general formula (I) as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, and optionally a further therapeutically active compound, in admixture with a suitable inert non-toxic pharmaceutical carrier and/or auxiliary agent.

11. A pharmaceutical composition according to claim 10, which comprises 0.1-8.0 % of the compound of the general formula (I).

1 2. A pharmaceutical composition according to claim 11, which comprises 0.2-2.0 % of the compound of the general formula (I).

1 3. A pharmaceutical composition according to any of claims 10 to 12, in the form of a cream, ointment, solution, aerosol, aerosol foam or an injection suitable for subcutaneous or intracutaneous administration.

14. A process for the preparation of pharmaceutical compositions according to claims 10 to 1 3 which comprises admixing a compound of the general formula (I) or a pharmaceutically acceptable acid additiion salt thereof and optionally one or more further therapeutically active compounds with a suitable inert non-toxic carrier and/or auxiliary agent and converting the mixture to a form ready for medical use.

1 5. A method for the treatment and prophylasis of patients suffering from skin diseases associated with pathological cell proliferation, particularly psoriasis, which comprises treating the affected skin surface with a therapeutically active amount of a pharmaceutical composition comprising as an active ingredient a compound of the general formula (I) as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.

1 6. A compound as claimed in claim 1, substantially as hereinbefore described with reference to any of the Examples.

1 7. A process as claimed in claim 5, substantially as hereinbefore described with reference to any of the Examples.

1 8. A compound when prepared by a process as claimed in any of claims 5 to 9 and 1 7.

1 9. A pharmaceutical composition as claimed in claim 10, substantially as hereinbefore described with reference to any of the Examples.