CA1202028A

CA1202028A - Apovincaminol-3',4',5'-trimethoxy-benzoate compounds

Info

Publication number: CA1202028A
Application number: CA000394857A
Authority: CA
Inventors: Csaba Szantay; Lajos Szabo; Bela Rosdy; Arpad Kiraly; Gyongyver Kiraly; Lilla Forgach; Egon Karpati; Laszlo Szporny; Maria Zajer; Bela Zsadon; Janos Galambos; Gyorgy Fekete; Zsuzsanna Gyulai; Csaba Lorincz; Tibor Keve; Gyorgy Kalaus
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1981-02-11
Filing date: 1982-01-25
Publication date: 1986-03-18
Also published as: GB2094787B; SE8200248L; AT386203B; DK151023C; IT1157301B; GR75857B; ATA26082A; SE449863B; IL64808A0; CH651038A5; DK151023B; FI70215C; AR227574A1; NO820394L; IL64808A; FI70215B; SU1093249A3; DK57782A; FR2499571B1; FR2499571A1

Abstract

ABSTRACT

The invention relates to new compounds of the general Formula /I/

/I/

/wherein either both R1 and R2 stand for hydrogen or one or the symbols R1 and R2 is hydrogen and the other is nitro/ and pharmaceutically acceptable acid addition salts thereof.
The new compounds of the general Formula /I/ can be prepared by reacting apovincaminol with 3,4,5-trimethoxy-benzoic acid or a reactive derivative thereof capable of acylation and if desired, nitrating the com-pound of the Formula /Ia/

/Ia/

thus obtained and separating the isomeric mixture thus obtained into the com-pounds of the Formulae /Ib/ and /Ic/

/Ib/

/Ic/

and if desired, converting a compound of the Formula /Ia/, /Ib/ or /Ic/ thus obtained into a pharmaceutically acceptable acid addition salt thereof.
The new compounds of the present invention can be used in therapy in the treatment of skin diseases attached to pathological cell prolifera-tion and in the prophylaxis of such diseases.

Description

~ 2~ ~
N~/ A~OYINCA~iINO~ DE~IYA'~IVES

Thi~ invention relate~ to new apovincaminol derivati-vee, a prOCe~8 for the preparation thereof and pharmaceutical compo~ition~ cont~i n ~ ng the ~ame.
Accordlng to an a~pect of the present invention there ar~ provlded new apo~incaminol derivative~ of the general For-mula /I/, ~1 ~ N
~l.... J /I/
c~o~&
~3~
o~3 namely the apovincaminol-3',4',5'-trimethoxy-benzoate o~ the Formula /Ia/

C~
O~ -2~5 r~
tH~O ~ /la/

ct~

the 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate of the ~ormula /Ib/

A 2~87-67/Fe ~i~
~f~

~c~l~
o C21ls 3 ~ ICO ' /Ib/
C1130 ~
cH3b and the ll-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate of the Formula /Ic/

o ~CH2 ~ 2H5 C / /Ic/

3 ~ J
C~130 CH.,b and pharmaceutically acceptable acid addition salts thereof.
In the general Formula /I/ either both Rl and R stand for hydrogen, or one of the symbols Rl and R2 represents hydrogen and the other nitro.

The acid addition salts of the compounds of the general Formula /I/ may be formed with inorganic or organic acids. From the salts formed with inorganic acids the hydrochlorides, sulfates and phosphates hile from the salts formed with organic acids the hydrogen tartarates, succinates, citrates and ascorbates are particularly useful.
It is known that the apovincaminol and its acetate exhibit an effect on the coronary artery /French Pa-tent Specification No. 2 035 784/.
It is also kno~m th~t the apovincamino] benzoate possesses general asodilatory properties /llungarian Patent Specification No. 166 476;
CA 82, 129 279 v /1975// and the esters of apovincaminol formed with alkane carboxylic a~id ~ ~3~

having 3-12 carbon atoms exhibit cerebral vasodilatory effect /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 exhlbit vasotropic effects. On the other hand the new compounds of the present invention inhibit the enzyme activity of phosphodiesterase and can be used first of all in the treatment of skin diseases attached to the pathological cell pro-liferation and in the prophylaxis of the recurrence of such diseases.
Diseases attached to the pathological proliferation of the epidermis are relatively frequent and involve a few per cents of the popula-tion. These diseases can be of both benign and malignant character such as psoriasis atopias dermatitis, primary contact dermatitis, allergical contact dermatitis, baso- and spinocellular carcinoma, inchthyosis, premalignant hyperceratosis, light induced ceratosis, acne and seborrhoeas dermatitis.
Some diseases occur only on humans while others both on humans and animals.
Since some of the skin diseases attached ~o pathological cell pro-liferation /e.g. psoriasis/ do not occur on animals, the activity of the com--pounds against psoriasis can be made probable in animal experiments only indirectly.
Voorhees et al. /Arch. Derm. 104, 359-365, /1971// have found that the pathological cell proliferation is accompanied by the decrease of the level of cyclic adenozine monophosphate /c-AMP/. It is known that c-AMP is formed under the effect of adenyl-cyclase and decomposed by phosphodiester-ase. Voorhees succeeded in influencing the psoriasis by agents which stimu-late the function of adenyl cyclase /such as nor-epinephrine/ or inhibit the function of phosphodiesterase /e.g. papaverine/.
By planning our model experiment test we have started from the pre-sumption that the statement of Voorhees is relevant to the contrary as well.

Thus if it can be proven that a certain compound inhibits the function of phosphodiesterase this makes it probable in an indirecc way that the said compound is suitable for the treatment of skin diseases attached to the pathological cell proliferation.
This presumption turned out to be true: compounds showing phos-phodiesterase inhibiting activity in in vitro tests proved to be active in the treatment of psoriasis in clinical experiments as well.
Our model tests are carried out with the aid of phosphodiesterase isolated from animal body tissues /rat brain, bovine brain, bovine heart/.
The enzyme is isolated according to the method of J. Schr-oder and H. V.
Richenberg /Biochem. Biophys. Acta 302, 50 /1973//, the isolated phos-phodiesterase 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. Poch 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 an incubation system at first without an inhibitor and thereafter in the presence of apovincAm;nnl-3',4',5'-trimethoxy-benzoate-derivative as inhibitor after an incubation period of 20 minutes /N. S. Arch. Pharmacol. 268, 272 /1979//. From the test compound a 1 millimolar stock solution is prepared and to the incubated enzyme preparation various amounts are added with the aid of the said stock solution so that the concentration of the test compound in the incubated sample should correspond to 5 x 10 7, 1 x 10 6, 5 x 106, 1 x 10 5, 5 x 10 5 and 10 mole/litre, respectively. The aqueous solution of the compound used for comparison /papaverine/ is added to the enzyme prepared in a similar manner.
The actlvity of the control /enzyme solution containing no inhibitor/ is taken as 100 %, while the activity of the solutions containing the compounds of the general Formula /I/ as papaverine is expressed as the percentage of the control. The results measured on the enzyme isolated from rat brain are summarized in the following Table.

Test compound Concentration of the test compound, /enzyme inhibitor/ mole/litre 5 x 10 6 1 x 10 5 5 x 10 /Effect on the enzyme activity, % of the control/

Apovincaminol-3',4',5'--trimethoxy-benzoate . HCl 64.5 49.2 47.2 /-/-ll-nitro-apovin-caminol-3',4',5'-tri-methoxy-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 enzyme isolated from bovine brain and brovine heart are measured in a similar manner. By using the results obtained, the enzyme activity is plotted against the :Logarithm of the enzyme inhibitor concentra-tion /expressed in ~moles/. The concentration of the enzyme inhibitor which decreases the enzyme activity by 50 % /I50/ is read off the curve. The re-sults obtained are summarized in the following Table.

Test compound I50 values, in ~moles on phosphodiesterase enzyme isolated from bovine heart rat brain Apovin~minnl-3',4',5'--trimethoxy-benzoate . HCl 1.5 10 /-/-ll-nitro-apovin-caminol-3',4',5'-tri-methoxy-benzoate . HCl 1 8 /-/-9-nitro-apovincami-nol-3',4',5'-trimethoxy--benzoate . HCl 1 15 Papaverine . HCl 50 70 It appears from the above Table that on the enzyme isolated from bol~ine heart and rat brain the new compounds of the present invention are 33-50 and 4.5-9 times, respective]a~ more active than the papaverine used as reference compound.
The first clinical tests were carried out with topical composi-tions containing the active ingredient /ointment, cream, solution, trincture, paste, aerosol/. Creams containing 2 %, 1 %, 0.5 %, 0.25 % and 0.1 % of ~ 9-nitro- or /-/-11-nitro-apovincaminol-3',4',5'-trimethoxy-ben~oate, respectively, were used.
Patients suffering from psoriasis were treated. A further funda-mental point of view of the selection was that the patients did not receive simultaneously a systemic treatment of their basic disease /e.g. an immuno suppressive, cytostatical or glucocorticoidal treatment/.
Groups consisting of five patients each were examined by the so called 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 effected skin surfaces of the patient were treated by other topical methods - among others with an ointment gener-ally used for the treatment of psoriasis, containing flumethasone pivalate and salicylic acid, said ointment being used as reference substance.
The test had been started with creams having high active ingredi-ent content and further patients were treated with a cream having the lowestactive ingredient content but being still active. The treatment was carried on for two weeks, twice a day, in open dressing.
The effect was evaluated by observing three different symptoms -inflammation, infiltration and desquamation (peeling). The intensity of the symptoms ~,ras expressed by the following scale between O and 3 O = no symptoms 2 = strong symptom 1 = moderate symptom 3 = very strong symptom The symptoms were evaluated before treatment /I/, after a treat-ment 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 ~1.,'2(:~2V~3 divided by the number of patients/ is disclosed. A cream containing 2 %
active ingredient was used.
Test compound Average number of points Infiltration Inflummation Desquamation I II III I II III I II III
Compound of the Formula /Ia/ 1.8 0.6 0.5 1.8 1.3 0.75 1.2 0.4 0 Compound of the Formula /Ib/ 2.2 1 0.7 2.5 2.5 1.3 1.5 0.5 0 Compound of the Formula /Ic/ 2.4 1.8 1.3 2.2 1.3 1.3 1.6 1.2 0.8 According to a further aspect of the present invention there is provided a process for the preparation of new compounds of the general Formula /I/ /wherein either R and R2 both stand for hydrogen or one of the symbols Rl and R2 is hydrogen and thc other is nitro/ and pharmaceutically acceptable acid addition salts thereof which comprises reacting apovincaminol or an acid addition salt ther~of with, as an acylating agent, 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 /Ia/ or an acid addition salt thereof separating the mixture of the compounds of the Formulae /Ib/ and /Ic/ 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 thereof.
The process of the invention is carried out preferably in the presence of the organic solvent, particularly a chlorinated hydrocarbon or an aliphatic ketone or pyridine, particularly in methylene chloride, chloroform or acetone. If a 3,4,5-trimethoxy-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 carbonate, alkali hydrogen carbonate or organic amine may be used. If 3,4,5-trimethoxy-benzoic acid is used as acalating agent the reaction is carried out in the presence of a catalytic amoun-t of an acid /preferably hydrochloric acid or sulfuric acid/ or an activator of the carboxylic group and/or a dehydrating agent. The carboxylic group may be activated by a halogenated phenol, preferably pentachloro phenol. As dehydrating agen~ e.g. N,N'-dicyclohexyl carbodiimid may be used. The acylation may be carried out at a temperature between -20 C and the boilin~ point of the reaction mixture, preferably at 20-60C.
The compound of the Formula /Ia/ may be isolated from the reaction mixture by extraction and/or evaporation.

~,.

~I'Z~2~

The product thus obtained may be converted into a pharmaceutically acceptable acid addition salt. Salt formation may be carried out by using inorganic or organlc acid /e.g. hydrochloric acid, sulfuric acid or phos-phoric 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 The compound of the Formula /Ia/ thus obtained may be nitrated if desired. Nitration may be preferably carried out with the aid of concen-trated nitric acid. The reaction is preferably accomplished in glacial acetic as medium. Nitriation is preferably carried out under cooling at a temperature of about 0 C. The reaction having been terminated the excess of the acid is neutralised and the mixture of the compounds of the Formulae /Ib/ and /Ic/ thus obtained is isolated from the reaction mixture by extrac-tion and/or evaporation.
The isomer mixture thus obtained may be separated into the two com-ponents. The separation of the isomers may be preferably carried out by chromatographical methods.
The compounds of the Formulae /Ib/ 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 /Ia/.
According to another feature of the present invention there are provided pharmaceutical compositions having phosphodiesterase inhibitory effect and being mainly useful in the treatment of skin diseases attached to pathological cell proliferation and the prophylaxis of the recurrence of such diseases, the said compositions comprising as active ingredient a com-pound of the general Formula /I/ or a pharmaceutically acceptable acid addi-tio}1s salt thereof and optionally further therapeutically active compounds in admi~,ture with usua] 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 %.
rhe compositions may optionally contain further pharmaceutically therapeu-tically active compounds, such as antibiotics, cytostatical agents, pro-staglandines, ditranol, salicylic acid, tar, antiinflammatory agents, immuno-supressants, glucocorticoid and - in the case if compositions suitable for parenteral administration - local anaesthetical agents. As glucocorticoid preferably triaminolon-acetonide may be used. The active ingredient may be finished preferably in the form of compositions for topical use, such as creams, ointments, solutions, gelées, aerosols, aerosol foams, adhesive plasters, etc.
The active ingredient may be 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 creams may be prepared by dissolving the active ingredient in a solvent of the alcoholic type, preferably in propylene glycole or ethylene glycole or a mixture thereof formed with a small amount of water, and admix-ing the solution thus obtained with a readily spreadable fatty phase being skin compatible.
The said fatty phase may comprise cetyl alcohol, stearyl alcohol, cetostearyl alcohol, paraffin oil, glycerine monostearate or etc.
The cream may also contain an emulsifying agent - preferably poly-oxyethylene sorbitan monooleate or monostearate - and a preservative such as benzoic acid derivatives, preferably methyl-p-hydroxy benzoate.
rhe creams may contain preferably 0.25-2.0 % of the active ingredi-ent, 45-50 % of glycole, 23-27 % of paraffin oil, 11-15 % of stearyl alcohol and optionally up to 100 % other auxiliary agents.
rrle active ingredient can also be formulated in the form of an ointmen~ which cannot be ~lashed off with water by incorporating the active ingredient directly in the fatty phase.

3~

~e active ingredient can also be formulated in the form of a 501u-tion or tincture which may contain e.g. 20-40 % of propylene glycole or dipropylene glycole, 40-55 % of 96 % ethanol and up to 100 % distilled water.
The aerosol formations may be prepared by adding to the solution of the active ingredient in propylene glycole a fatty substance - e.g. iso-propyl myristate - and a propellant /e.g. freon/.
Injectable solutions suitable for parenteral administrations, pre-ferably applicable in a subcutanous 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-toxical, known pharmaceutical car-riers and/or additives and finishing a mixture thus obtained in a form suit-able for medical use.
Further details of the present invention can be found in the fol--lowing Examples without limiting the scope of protection to the said Examples.
Example 1 Preparation of /-/-apovincaminol-3',4'5'-trimethoxy-benzoate 3.10 g /10.1 millimoles/ of /-/-apovineAm;T-~l are dissolved in 60 ml of anhydrous dichloromethane, whereupon 3.10 g of anhydrous sodium carbonate and 2.50 g of /lO.9 millimoles/ of 3,4,5-trimethoxy-benzoyl 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 with 20 ml of dichloromethane each. The united dichloromethane phases are dried over rnagnesium suliate, filtered and the filtrate is e~aporated in vacuo.
Thus 4.50 g of the title compound are obtained, yield 89.1 %.

~ ~13~8 Brutto formula C30H34~l2o5. Molecular weight 502.61.
IR spectrum /film/: v 1725 cm /-C=O/; 1620 cm /=C=C=/
~MR spectrum /deuterochloroform/: ~: 1.01 /t, 3H, CH3CH2-/; ~: 3.72 /s, 6H,

2 x -OCH3/; ~: 3.85 /s, 3H, -OCH3/; ~: 4.25 /s, lH, anellation/; ~: 5.29 /s, lH, -CH=/; ~: 5.4 /m, 2H, -OCH2/; ~: 7.0-7.8 /m, 6H, aromatic/.
MS /m/e/: 502/53/, 432/100/, 290/17/, 261/41/, 220/l9/, 216/23/, 212/18/, /~/D5 = -22.0 /c = 0.7; dichloro methan/.
Example 2 Preparation of /-/-apovincaminol-3',4',5'-trimethoxy-benzoate hydrogen tartarate 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 becomes complete. The salt is filtered off and dried. Mpl.: 120-121 C.
IR spectrum /KBr/: vmax 1730 cm /-C=O/; 1640-1665 cm /=C=C=/.
/~/D = -8.5 /c = 1; pyridine/. Molecular weight 652.7.
Example 3 Preparation of /-/-9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate and /-/-ll-nitro-apov; nr~m; nol-3 ~ ~ 4',5'-trimethoxy-benzoate 5 g of /-/-apovi nr~m; nnl-3 ~, 4',5'-trimethoxy-benzoate are dis-solved in 50 ml of glacial acetic acid. To the solution obtained a mixtureof 20 ml glacial acetic acid and 10 ml of concentrated mitric acid /d = 1.52/
is added at O C under stirring. The reaction mixture is poured into 350 mg of icecold water and the pH is adjusted to 9 by adding a 25 % aqueous ammonium hydroxyde solution. The alkaline solution is extracted at first with 250 ml and thereafter twice with 200 ml of dichloro methane each. The united organic solution are dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness in vacuo.

The isomer Mixture thus obtained is separated into the two compon-;, ents by chromatographical methods by using ~ieselgel 60 as adsorbent and a10:2 mixture of benzene and acetone as developing agent. Under these condi-tions the Rf value 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 ll-nitro-derivative are obtained.
The physical constants of the /-/-9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate are as follows:
Mp.: 77-78 C. /~/D = -78.5 /c = 1; chloroform/.
H-N~IR /CDC13/: ~: 3.8 /s, 6H, 2 x CH30-/; ~: 3.91 /s, 3H, 1 x CH30-/;
' ' 12/; ~: 7-96 /d, lH, Hll/; ~: 8.1 /d, lH, H
The physical constants of the /-/-ll-nitro-apovincaminol-3',4',5'-trimethoxy-b~nzoate are as follows:
Mp.: 72-73 C. /~/D = -134.3 /c = 1; chloroform/.
H-NMR /CDC13/: ~: 3.8 /s, 6H, 2 x CH30-/; ~: 3.9 /s, 3H, 1 x CH30-/;
~: 7-56 /d, lH, Hg/; ~: 8.1 /d, lH, Hlo/; ~: 8.9 /d, lH, H12/.
Example 4 Preparation of 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride and ll-nitro-apovincaminol-3',4',5'-trimethoxy~benzoate-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 hydrogen chloride and methanol. The hydrochloride salt formed is precipitated by adding diethyl ether. The salt is rriltered off, washed and dried. The hydrochloride of the 9-nitro-derivative melts at 144-150 C, while the melting point of the hydrochloride of the ll-nitro-derivative amounts to 141-144 C.
Example 5 A cream having the following composition is prepared:

Cornponent: Amount /g/:
Apovincaminol-3',4',5'-trimethoxy-benzoate 2 Propylene glycole 50 Paraffin oil 26 Polyethylene glycole 5 Stearyl alcohol 15 Glycerol monostearate 2 The active ingredient is dissolved in propylene glycole 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 under constant stir-ring. To the melt the solution of the active ingredient is added under stir-ring and the cream thus obtained is cooled under stirring.
In an analogeous 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 11-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-apov;nc~minol-3',4',5'-trimethoxy-benzoate 2 Triamcinolon acetonide O.l Glycerol monostearate 3.0 Polyethylene glycole 400 5.0 Stearyl alcohol 13.0 Paraffin oil 24.9 Propylene glycole 53.0 One proceeds in an analogeous manner to Example 5 except that two active ingredients are dissolved in propylene glycole. As active ingredient the ll-nitro-derivative or apovincaminol-3',4',5'-trimethoxy-benzoate may be used as ~"ell.

. ,/

;7~ 8 Example 7 A tincture solution having the following composition is prepared:
Component: Amount /g/:
9-nitro-apov;n~m;n~1-3',4',5l-trimethoxy-benzoate Propylene glycole 30 9G % methanol 69 The above process may also be carried out by using the ll-nitro-derivatives as active ingredient.
Example 8 A tincture solution having the following composition is prepared:
Component: Amount /%/:
Apovincaminol-3',4',5'-trimethoxy-benzoate hydro~
gen tartarate Propylene glycole 30 96 % ethanol 47 Distilled water 22 Example 9 An aerosol having the following composition is prepared:
Component: Amount /%/:
Apov;nc~m;n~1-3',4',5'-trimethoxy-benzoate hydro-gen tartarate 0 5 Propylene glycole 30 Isoprop~yl myristate ~.5 ~reon 65 As active ingredient the 9-nitro- or ll-nitro-derivative may be used as ~,Jell.
Example 10 An aerosol foam having the following composition is prepared:

, "

2~

Component: Amount ~povincaminol-3',4',5'-trimethoxy-benzoate hydro-gen tartarate 2 Cetostearyl alcohol Benzyl alcohol 2 Polyoxyethylene-sorbitan-monostearate15 96 ~ ethanol 30 Distilled water 30 Freon 20 ~'

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of formula (I) (I) (wherein either R1 and R2 is hydrogen or one of R1 and R2 is hydrogen and the other is nitro) or a pharmaceutically acceptable acid addition salt thereof which comprises reacting apovincaminol, or an acid addition salt thereof, with, as an acylating agent, 3,4,5-trimethoxy-benzoic acid or a reactive derivative thereof capable of acylation, to obtain a com-pound of formula (Ia), (Ia) and where required converting a compound of formula Ia into a pharmaceuti-cally acceptable acid addition salt thereof, or if a compound of formula I
is required in which either R1 or R2 is nitro, or a pharmaceutically acceptable acid addition salt thereof, nitrating a compound of formula (Ia) or an acid addition salt thereof and separating the required compound of formulae (Ib) or (Ic) ([b) (Ic) from the mixture so obtained and where required, converting a compound of formula (Ib) or (Ic) so obtained into a pharmaceutically acceptable acid addition salt thereof.

2. A process according to claim 1 wherein the acylating agent is 3,4,5-trimethoxy-benzoyl chloride.

3. A process according to claim 1 wherein the acylation is effected in admixture with an organic solvent.

4. A process according to claim 2 wherein the acylation is effected in admixture with an organic solvent.

5. A process according to claim 1 wherein the nitration is effected in admixture with glacial acetic acid.

6. A process according to claim 1 wherein the nitration is effected at a temperature of about O °C.

7. A process according to claim 5 wherein the nitration is effected at a temperature of about O °C.

8. A compound of formula (I) as defined in claim 1 or a pharmaceutic-ally acceptable acid addition salt thereof whenever prepared by a process according to claim 1, 2 or 3, or by an obvious chemical equivalent thereof.

9. A compound of formula (I) as defined in claim 1 or a pharmaceutic-ally acceptable acid addition salt thereof whenever prepared by a process according to claim 4 or 5, or by an obvious chemical equivalent thereof.

10. A compound of formula (I) as defined in claim 1 or a pharmaceutic-ally acceptable acid addition salt thereof whenever prepared by a process according to claim 6 or 7, or by an obvious chemical equivalent thereof.

11. A process for preparing apovincaminol-3',4',5'-trimethoxy-benzoate which comprises reacting apovinraminol with 3,4,5-trimethoxy-benzoyl chloride.

12. A process according to claim 11 further comprising the step of reacting the apovincaminol-3',4',5'-trimethoxy-benzoate so obtained with tartaric acid to obtain apovincaminol-3',4',5'-trimethoxy-benzoate hydrogen tartarate.

13. The compound apovincaminol-3',4',5'-trimethoxy-benzoate or apovincaminol-3',4',5'-trimethoxy-benzoate hydrogen tartarate whenever pre-pared by a process according to claim 11 or 12 or by an obvious chemical equivalent thereof.

14. A process according to claim 11 which comprises nitrating the apovincaminol-3',4',5'-trimethoxy-benzoate with nitric acid and collecting the 9-nitro-apovinaminol-3',4',5'-trimethoxy-benzoate so formed.

15. A process according to claim 11 further comprising the step of nitrating the apovincaminol-3',4',5'-trimethoxy-benzoate so obtained with nitric acid and collecting the 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate so formed.

16. A process according to claim 14 further comprising the step of reacting the 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate so formed with hydrogen chloride to obtain 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride.

17. A process according to claim 15 further comprising the step of reacting the 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate so formed with hydrogen chloride to obtain 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride.

18. The compound 9-nitro-apovincamino1-3',4',5'-trimethoxy-benzoate whenever prepared by a process according to claim 14 or 15 or by an obvious chemical equivalent thereof.

19. The compound 9-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride whenever prepared by a process according to claim 16 or 17 or by an obvious chemical equivalent thereof.

20. A process according to claim 11 which comprises nitrating the apov;ncam;nol-3',4',5'-trimethoxy-benzoate with nitric acid and collecting the 11-nitro-apovinrcaminol-3',4',5'-trimethoxy-benzoate so formed.

21. A process according to claim 11 further comprising the step of nitrating the apovincaminol-3',4',5'-trimethoxy-benzoate so obtained with nitric acid and collecting the 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate so formed.

22. A process according to claim 14 further comprising the step of reacting the 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate so formed with hydrogen chloride to obtain 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride.

23. A process according to claim 15 further comprising the step of reacting the 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate so formed with hydrogen chloride to obtain 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride.

24. The compound 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate whenever prepared by a process according to claim 20 or 21, or by an obvious chemical equivalent thereof.

25. The compound 11-nitro-apovincaminol-3',4',5'-trimethoxy-benzoate-hydrochloride whenever prepared by a process according to claim 22 or 23, or by an obvious chemical equivalent thereof.