IE41667B1

IE41667B1 - Substituted phenylpiperazine compounds and pharmaceutical uses thereof

Info

Publication number: IE41667B1
Application number: IE1929/75A
Authority: IE
Original assignee: Boehringer Sohn Ingelheim
Priority date: 1974-09-03
Filing date: 1975-09-03
Publication date: 1980-02-27
Also published as: CS192521B2; SE7509746L; DK137387B; GB1521051A; DE2442158B2; DK137387C; ES440630A1; GB1521052A; GB1514546A; IE43338L; IL48033A0; ZA755602B; ES453932A1; IE43338B1; DE2442158A1; NL7510319A; IL48036A0; NO753020L; ES453933A1; BE833002A

Abstract

1521052 Pharmaceutical compositions BOEHRINGER INGELHEIM GmbH 2 Sept 1975 [3 Sept 1974] 03218/78 Divided out of 1521051 Heading A5B Pharmaceutical compositions in the form of dosage units useful in reducing the blood lipid level and the blood cholesterol level comprise as active ingredient N-[1-(3', 4'- methylenedioxyphenyl) - prop - 2 - yl] - N' - (2- chloro-phenyl)-piperazine or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient, each dosage unit containing greater than 40 mg, but no greater than 60 mg of active ingredient. The compositions may further contain a coronary dilator such as 2, 6- bis-(diethanolamino)-4, 8-dipiperidino pyrimido [5, 4-d] pyrimidine, 3-(#-diethylamino ethyl)- 4-methyl-7-carbethoxymethoxy-2-oxo-2H - chromen, 3, 3'-(N, N'-dimethylethylenediamino)- bis-(propyl 3, 4, 5-trimethoxy benzoate, N-3'- phenylpropyl-(2')-1, 1-diphenyl-(3)-amine, α- isopropyl-α-[N-(methyl-N-homoveratryl)- y - aminopropyl]-3, 4-dimethoxy phenyl-acetonitrile or L-#-(#-hydroxy-α-methyl-phenylethylamino)-3-methoxypropiophenone. The compositions may be administered orally, parenterally or rectally in the form of granules, tablets, coated tablets, capsules, pills, syrups, emulsions, suspensions, powders, drops, suppositories or injection solutions.

Description

The present invention relates to novel substituted N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl-N’-substituted phenylpiperazines, the acid addition salts thereof and processes for their preparation. The novel compounds show interesting physiological properties.

German Offenlegungsschrift No. 1670144, describes compounds of general formula: (II) (wherein Ar represents an aromatic radical comprising two condensed rings of which the ring that is not linked to the remainder of the molecule may be a carbocyclic or heterocyclic saturated ring or an aromatic ring; and and R2» which may be the same or different, each represents a hydrogen or halogen atom a trifluoromethyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms) and the acid addition salts thereof. These compounds have a depressant effect on the central nervous system.

It has now been found that certain compounds of the above-mentioned formula and the acid addition salts there of not specifically described in German Offenlegungs5 schrift No. 1670144 possess, not only a depressant action on the central nervous system but also the property of decreasing the level of lipids and the cholesterol level in the blood. The compounds of the present invention are therefore potentially of interest as active ingredients in pharmaceutical compositions for decreasing the level of lipids in the blood. In particular the compounds of formula I hereinafter defined and the physiologically compatible acid addition salts thereof have been found, in certain tests to be superior 15 to the compounds described in German Offenlegungsschrift 2136929. Moreover the toxicity of the compounds of formula I and the physiologically compatible acid addition salts thereof is low, so that these compounds are suitable for therapeutic use.

Thus according to one feature of the present invention there are provided compounds of the general formula: - 3 20 CH„ Ό CH2 - CH - - / (wherein either both R^ and R^ represent chlorine atoms or R-^ represents a methyl group and R2 represents a methoxy group) and the acid addition salts thereof.

Thus the compounds of the present invention include the following compounds: N- [l- (3,4-methylenedioxyphenyl)prop-2-yfi-N'[(2,4dichlorophenyl)piperazine and the physiologically compatible acid addition salts thereof; and N-[l-(3,4-methylenedioxyphehyl)prop-2-yl]-N,-(2methyl-4-methoxyphenyl)piperazine and the physiologically compatible acid addition salts thereof.

The acid addition salts useful for incorporation in pharmaceutical compositions are physiologically compatible - 4 . acid addition salts. Other acid addition salts may however be useful in the preparation of compounds of formula I and physiologically compatible acid addition salts thereof.

The compounds of formula I according to the present invention as hereinbefore defined contain an asymmetric carbon atom and thus exist not only in racemic form but also in the form of optically active isomers. It will be appreciated that pharmaceutical compositions containing any or all such forms of the compounds of formula I (and physiologically compatible acid addition salts thereof) are within the scope of the present invention.

The compounds of formula I and the acid addition salts thereof may, for example, be produced by one of the following processes (a) to (f) which processes constitute further features of the present invent·!on: (a) the aralkylation of a compound of the formula: H-/ \---—Z -R w>=/ R1 - 5 (rn) (wherein and R2 are as hereinbefore defined) whereby a compound of formula I (as hereinbefore defined) is obtained.

The aralkylation may, for example, be effected by react 5 ing a compound of general formula III with an electrophilic l-(3,4-methylenedioxyphenyl)prop-2-yl compound such as 1-(3,4-raethylenedioxyphenyl)prop-2-yl chloride, -bromide, -mesylate or -tosylate conveniently in the presence of an acid-binding agent. Alternatively, for example, the aralkylation may be effected by reacting a compound of general formula III with l-(3,4-methylenedioxyphenyl)-propan-2-one in the presence of a reducing agent such as catalytically activated hydrogen or a metal hydride such as, for example, lithium aluminium hydride or sodium borohydride). - 6 _ (wherein and R2 are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) whereby a compound of formula I (as hereinbefore defined) is obtained.

A compound of formula IV is preferably used in which Hal represents a chlorine atom. The reduction is preferably effected by the use of catalytically activated hydrogen (c) the reaction of a compound of the formula: q-n(ch2ch2x)2 (wherein Q represents the group: (V) CHI 3 CH2 - CH or -ΛΛ. (wherein R^ and R2 are as hereinbefore defined and X - 7 41667 represents an atom or group removable as an anion) with a compound of the formula: (VI) (wherein is as defined for Q with the proviso that Q 5 and do not both represent the group: ' (wherein and R2 are as hereinbefore defined), a compound of formula V is preferably used in which X represents a halogen atom or an alkyl- or aryl- sulfony10 loxy group. (d) the reaction of a compound of the formula: - 8 _ (wherein and R2 are as hereinbefore defined) with a compound of the formula: X - ch2 - ch2 - X (VIII) (wherein X is as hereinbefore defined) .

It is advantageous to effect processes (b) to (d) in the presence of an acid-binding agent preferably at an elevated temperature, (e) the reduction (wherein R. and R2 as hereinbefore defined and A / represents the group -COCH2> -CO-CO'-.or -CH2-CO-)with a metal hydride effective to reduce the group -CO-CH2-, -CO-CO- or -CH2-CO- to a -CH2-CH2- group whereby a compound of formula I as hereinbefore defined is obtained.

A preferred metal hydride for use in the reduction is . 9 41667 lithium alumimium hydride. (f) the reaction of a compound of the formula HO CH.

HO.

R. ‘2 Ί (X) (wherein R^ and R2 are as hereinbefore defined)with a 5 compound of the formula: X - CH2 - X (xi) (wherein X is as hereinbefore defined).

A compound of formula XI is preferably used in which X represents a chlorine or bromine atom. The reaction may advantageously be effected in the presence of an acidbinding agent and preferably at an elevated temperature. Certain of the starting compounds of processes (a) to (f) are already known. Those compounds that are not known may, for example, be produced according to conventional methods described in the conventional chemical textbooks, -10 41667 such as for example, as described in Houben-Weyl, 1st and 2nd editions.

The compounds of general formula III may, for example, be obtained according to processes described in J.Am.

Chem.Soc. 76, page 1853 (1954) and J. med. Chem. 8, page 332 (1965). The electrophilic 1-(3,4-methylenedioxyphenyl)prop-2-yl derivatives, such as l-(3,4-methylenedioxyphenyl)prop-2-yl chloride, -bromide, -tosylate or -mesylate may, for example, be obtained by esterification of l-(3,4-methylenedioxyphenyl)propan-2-ol (see Example 1), while the 1-(3,4-methylenedioxyphenyl)propan-2-one may, for example., be obtained by a method corresponding to the method described in Org. Synth. Coll, vol IV, page 573.

The compounds of general formula IV may, for example, be obtained by reducing a corresponding N-.[l-(3,4-methylenedioxyphenyl)]-N'-(substituted phenyl)-piperazine according to the process of Japanese Patent No. 23412/64, such compound being obtained from l-(3,4-methylenedioxyphenyl) l-bromopropan-2-one by reaction with an N-(substituted phenyl)-piperazine and by halogenating the - 11 416 67 N- [l- (3,4-methy lenedioxypheny l)-l-hydroxypropyl(2)-N* (substituted phenyl)-piperazine obtained in the conventional way. The halogenation may for example, be effected with SOCI2 according to the process described in German Auslegeschrift 1,212,973 or with PCl^ according to the process described in J. Chem. Soc. (London) 1963, page 1385.

The bis(p-haloethyl)amines of general formula V required as starting products for process (c) may, for example, be obtained by reacting the corresponding amine Q-Nl^ (wherein Q is as hereinbefore defined) with ethylene oxide or with a haloethanol, followed by treatment of the bis(p-hydroxyethyl)amine thus obtained with SOCI2 or PCI5.

The starting compounds of general formulae VI and VII may for example, be obtained ,a<^cc>r,ding t,o methods described in German Auslegeschrift.·'1212973, while certain of the compounds of formulae VIII and XI may, for example, be produced by esterification of the corresponding glycol, other compounds of formula VIII may, for example, be produced by addition of halogen to the corresponding - 12 41667 alkene and the remaining compounds of formulae VIII and XI may for example, be produced by substitution of hydrogen by halogen in the corresponding alkane. The starting compounds of general formula IX may be produced, for example, according to the method described in J. med.

Chem. 7, p. 154-158 (1964) and production of the starting compounds of general formula X may advantageously be effected according to process (a) of the present application, whereby 3,4-dihydroxyphenylprop-2-yl derivatives are reacted with compounds of formula III instead of 3,4-methylenedioxyphenyl derivatives.

The compounds of general formula I have an asymmetric carbon atom on the -CH(CHg) group and therefore occur as optically active isomers and as racemic mixtures.

The optically active isomers can be obtained by using corresponding optically active starting materials already containing the -CH(CHp grouping in processes (a) to (f) or by converting the racemic mixtures prepared according to processes (a) to (f) into the diastereoisomeric salts by means of optically active auxiliary acids, e.g. dibenzoyl-D-tartaric acid or bromo-camphorsulfonic acid and separating the diastereoisomeric salts by fractional precipitation or fractional crystallization.

The compounds of formula I according to the invention may, if desired, be converted into their acid addition e.g. their physiologically compatible acid addition salts in the conventional manner, for example, by reaction with acids appropriate for this purpose. Acids suitable, for salt formation include for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, succinic acid and tartaric acid.

The cholesterol decreasing action of the compounds of formula I and their physiologically compatible acid addition salts was examined in a trial lasting 18 days and involving rats of the FW 49 strain. The compounds were administered perorally, once daily by stomach probe, in emulsion form together with the solubilizer *Tween 80. The controls received physiological common salt solution together with Tween 80.

The serum cholesterol was determined according to the methods of Levine, and J. and B.Zak in Clin. Chem.

Acta 10, pages 381-384 (1964). The doses of Clofibrate, . 14 .

*Tween is a trade mark a preparation at present on the market, were 6 times higher than the doses of all the other substances. The results are presented in the following table:- Compound Day 0 Day 4 Day 8 Day 18 Comparison compounds: Clofibrate 93.3 72.8 (-22%) 65.6 (-30%) 78.1 (-16%) N-[l-(3,4-Methylenedi oxypheny l)-prop-2yl]-N’ -pheny lpiperazine. HCl 89.9 70.8 (-21%) 55.7 (-38%) 51.3 (-43%) Compounds of the present : invention: N-[1-(3,4-Methylenedioxy-pheny])-prop-2-yl]N'-(o-methyl-£-methoxyphenyl)piperazine. HCl 88.2 48.6 (-45%) 19.4 (-78%) 12.7 (-86%) N-[1-(3,4-Methylenedioxy-pheny^-prop-2yl]-N’-(o- ,£-dichlorophenyl )piperazine. HCl ' 69.8 » I 50.0 ' (-28%) 23.2 (-67%) 11.7 (-83%) The total cholesterol content (averaged over 10 animals) in mg per 100 ml of serum and the percentage decrease over the course of the examination is stated in each case together with the final value for each group - 15 41667 (Day Ο = 100 %).

According to a yet still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

The compositions according to the invention may also include, if desired, other physiologically active compounds, such as for example coronary dilators. Thus, for example, for the prophylactic treatment of coronary thrombosis the compounds of formula I and their physiologically compatible acid addition salts may, if desired, be combined with a coronary dilator e.g. dipyridamol [2,61 5 bis-(diethanolamino)-4,8-dipiperidino-[5,4-d]-pyrimidine].

The coronary dilator is preferably administered in a daily dosage of from 50 -ϋ.ύ3L50 rtigi each dosage unit preX i / / ferably containing from 10-t«S‘ L50 mg. of the coronary dilator.

The composition according to the invention may be presented, for example, in a form suitable for oral, -16 _ parenteral or rectal administration.

The compounds according to the invention may be presented in the conventional pharmacological forms of administration, such as granules, tablets, coated tablets, pills, solutions, emulsions, suspensions, powders, capsules, drops or sustained release forms. Conventional pharmaceutical excipients as.well as the usual methods of production may be employed for the preparation of these forms. Tablets may be produced, for example, by mixing the active ingredient or ingredients with known excipients, such as for example with diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as com starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talcum, and/or agents for obtaining sus15 tained release, such.as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinylacetate.

The tablets may if desired consist of several layers. Coated tablets may be produced by coating cores, 20 obtained in a similar manner to the tablets, with agents commonly used for tablet coatings for example polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. In order to obtain sustained release or to avoid incompatibilities, the core may consist of several layers too. The tablet-coat may also consist of several layers in order to obtain sustained release, in which case the excipients mentioned above for tablets may be used. Syrups of the active ingredient according to the invention or combinations of active ingredients may additionally contain a sweetener, such as saccharin, cyclamate, glycerin or sugar, and/or taste improving agents such as flavourings, e.g. vanillin or orange extract. They may also contain suspension agents or thickeners, such as sodium carboxymethyl cellulose, wett ing agents, such as for example· condensation products of fatty alcohols With ethylene oxide, or preservatives, such as £-hydroxybenzoates.

Injection solutions may, for example, be produced in the conventional manner, such as by the addition of preservatives, such as £-hydroxybenzoates, or stabi20 lizers, such as Complexons e.g. ethylenediamine tetraacetic acid. The solutions are then filled into injection vials or ampoules.

Capsules containing one or several active ingredients may be produced for example by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and filling the mixture into gelatin capsules.

Suitable suppositories may, for example be produced by mixing the active ingredient or active ingredient combinations with the conventional carriers envisaged for this purpose, such as neutral fats or polyethylene1° glycol or derivatives thereof.

Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and dmpoiiies ate examples of suitable dosage unit forms. fiach'Soshge unit preferably contains 5 to 75 mg. of the said active ingredient, the dosage unit being administered, for example, 1 to 5 times daily. The daily dose of the said active ingredient is preferably from 25 to 75 mg. especially from 40 to 60 mg. - 19 41667 According to a still further feature of the present invention there is provided a method of treating patients to decrease the blood lipid level and the blood cholesterol level, which method comprises administering to the patient an effective amount of a compound of formula I (as hereinbefore defined) or a physiologically compatible acid addition salt thereof.

The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients:20 41667 Example 1 N-[1-(3,Λ-Methylenedioxyphenyl)prop-2-yl]-N’-(2-methyl-Amethoxyphenyl)piperazine 29.0 g (0.1Λ mol) of 2-methyl-4-methoxyphenylpipera2ine 5 are refluxed together with 41.5 g (0.16 mol) of 1-(3,4methylenedioxyphenyl)-propan-2-ol methanesulfonate (produced by esterification of the propanol with mesyl chloride) and LL g of anhydrous potash in 25Ο ml of xylene for hours and the solvent is distilled off in vacuo. The residue is recrystallized from aqueous-methanolic hydrochloric acid. The hydrochloride of the title compound melts at 256 - 259'C.

Example 2 N-[1-(3, Λ-Methylenedioxypheny1)-prop-2-yl]-N’-(2,Λ-di1 5 chlorophenyl·) piperazine______ 32.5 g (0.1Λ mol) of 2,4-dichlorophenylpiperazine are refluxed with ΛΙ.5 g (0.16 mol) of l-(3,A-methylenedioxyphenyl)-propan-2-ol methanesulfonate and ΛΛ g of anhydrous potash in 25Ο ml of xylene for 7 hours. The reaction mixture is worked up as described in Example 1. Melting point of the hydrochloride of title compound: 259 - 263°C. - 21 1 Pharmaceutical_Composition_Examgles Example A (Tablets) N-[1-(3',4'-methylenedioxypheny1)- prop-2-yl]-N’-(2,4-dichlorophenyl)- . piperazine . HCl 50 mg lactose 50 mg com starch 93 mg sec. calcium phosphate 47 mg soluble starch 3 mg magnesium stearate 3 mg colloidal silicic acid Λ 250 mg Production: The active ingredient is mixed with part of the excipients, thoroughly kneaded with. An aqueous solution of the starch and granulated with,,the aid of a screen 15 in the conventional way. The granulate is mixed with the remaining excipients and pressed into tablets each weighing 250 mg. -22 41667 Example B (Coated Tablets') N-[l-(3',Λ’-methylenedioxyphenyl)prop-2-y1 ]-N'-(2-methy1-4-methoxyphenyl) -piperazine . HCl Λ0 mg 2,6-bis-(diethanolamino)-A,8-di p iperidinopyrimido(5,Δ-d]pyrimidine 70 mg com starch 60 mg sec. calcium phosphate 50 mg magnesium stearate 3 mg soluble starch 3 mg colloidal silicic acid —Lsa 280 mg Production: The active ingredients are mixed with part of the excipients, thoroughly kneaded with aqueous solutions of the soluble starch and then granulated in the conventional manner. The granulate is mixed with the remaining excipients and pressed into tablet cores each weighing 380 mg. The cores are coated with the aid of talcum, sugar and gum arabic in the conventional way.

Example C (Dry-filled Capsules) Gelatin capsules suitable for oral administration, containing the ingredients described below, may be produced in a manner known per se by filling the capsules with the dry powder and subsequently sealing the capsules. Ν—[1—(3*,A.'-methylenedioxyphenyl)prop-2-y11-Ν' -2-methy1-4-methoxyphenylpiperazine . HCl 60 mg inert solid diluent (starch, lactose or kaolin) 2AO mg 300 mg

Claims

1.CLAIMS 1. Compounds of the general formula:- (wherein either both R^ and R 2 represent chlorine atoms ® or R| represents a methyl group and R 2 represents a methoxy group) and the acid addition salts thereof.

2. N-[l-(

3. > 4-methylenedioxyphenyl)prop-2-yl]-N'(2,4-dichlorophenyl)piperazine and the physiologically compatible acid addition salts thereof. 10 3. N-[1-(3,4-methylenedioxyphenyl)prop-2-yl-N'(2-methyl-4-methoxyphenyl)piperazine and the physiologically compatible acid addition salts thereof.

4. Compounds as claimed in any of claims 1 to 3 in the form of optically active isomers. 15

5. Compounds as claimed in any of claims 1 to 3 in racemic form.

6. A protess for the preparation of compounds of compounds of formula I (as defined in claim 1) which - 2 5 41667 comprises aralkylating a compound of the formula: “-0 R 1 (wherein R^ and R2 are as defined in claim l) whereby a compound of formula I (as defined in claim 1) is obtained. 5.

7. A process as claimed in claim 6 wherein the aralkylation is effected by the use of an electrophilic i-(3,4-methylenedioxyphenyl)prop-2-yl compound. 6.

8. A process as claimed in claim 7 wherein the electrophilic 1-(3,4-methylenedioxyphenyl)prop-2-yl IO compound is 1-(3,4-methylenedioxyphenyl) prop-2-yl chloride, bromide, mesylate or tosylate. 7.

9. A process as claimed in any of claims 6 to 8 wherein the aralkylation is effected in the presence of an acid binding agent. 5

10. A process as claimed in claim 6 wherein the compound of formula III is reacted with a 1-(3,4-methylenedioxyphenyl) -propan-2 -one in the presence of a reducing agent. -2641667

11. A process as claimed in claim 10 wherein the reducing agent is catalytically activated hydrogen.

12. A process as claimed in claim 10 wherein the reducing agent is a metal hydride. 5

13. A process as claimed in claim 12 wherein the metal hydride is lithium aluminium hydride or sodium borohydride.

14. A process for the preparation of compounds of formula X (as defined in claim 1) which comprises reducΊθ ing a compound of the formula:- (wherein R^ and R 2 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) whereby a compound of formula I (as defined in claim 1) is obtain15 ed.

15. A process as claimed in claim 14 wherein a compound of formula IV is used in which Hal represents -27 416 6 7 a chlorine atom.

16. A process as claimed in claim 14 or claim I5 wherein the reduction is effected by the use of catalytically activated hydrogen. 5

17. A process for the preparation of compounds of formula I (as defined in claim 1) which comprises reacting a compound of the formula: q-n(ch 2 ch 2 x) 2 (V) (wherein Q represents the group: CH, I J (wherein R^ and R 2 are defined in claim 1 and X represents an atom or group removable as an anion) with a compound of 1 5 the formula: q l -nh 2 · (VI) .28 (wherein is as defined for Q with the proviso that Q and do not both represent the group: •R, or CH, I j CH 2 - CH wherein R^ and R 2 are as defined in claim 1). 5

18. A process as claimed in claim 17 wherein a compound of formula V is used in which X represents a halogen atom or an alkyl- or aryl- sulfonyloxy group.

19. A process for the preparation of compounds of formula I (as defined in claim 1) which comprises reacting a 0 compound of the formula: R, 1 (VII) (wherein R^ and R 2 are as defined in claim 1) with a compound of the formula: X - ch 2 - ch 2 - X (VIII) (wherein X is as defined in claim 17).

20. A process as claimed in any of claims 14 to 19 wherein the reduction or reaction is effected in the presence of an acid binding agent.

21. A process as claimed in any of claims 14 to 20 wherein the reduction or reaction is effected at an elevated temperature.

22. A process for the preparation of compounds of formula I (as defined in claim 1) which comprises reducing a compound of the formula (IX) (wherein and R 2 are as defined in claim 1 and A represents the group -COCH 2> -CO-CO- or -CH 2 -C0) with a metal hydride effective to reduce the group -CO-CH 2 -, -CO-CO- or -CH 2 “CO- to a -CH 2 -CH 2 - group whereby a compound of formula I as defined in claim 1 is obtained.

23. A process as claimed in claim 22 wherein the metal hydride comprises lithium aluminium hydride.

24. A process for the preparation of compounds of formula I (as defined in claim 1) which comprises reacting a compound of the formula (X) (wherein and R 2 are as defined in claim l) with a compound of the formulas IS X - ch 2 - X (XI) (wherein X is as defined in claim 17) .

25. A process as claimed in claim 24 wherein a compound of formula XI is used in which X represents a chlorine or bromine atom.

26. A process as claimed in claim 24 or claim 25 wherein the reaction is effected in the presence of an acid binding agent.

27. A process as claimed in any of claims 24 to 26 wherein the reaction is effected at an elevated temperature - 31 41667

28. A process as claimed in any of claims 6 to 27 wherein the compound of formula I obtained is converted into an acid addition salt thereof.

29. A process for the preparation of compounds as 5 claimed in claim 1 in the form of optically active isomers in which a compound of formula I in the form of a racemic mixture is resolved into its optically active isomers.

30. A process as claimed in any of claims 6 to 29 substantially as herein described. 8. 10

31. A process for the preparation of compounds as defined in claim 1 substantially as herein described in either of Examples 1 and 2.

32. Compounds as claimed in claim 1 when prepared by a process as claimed in any of' claims 6 to 31. .- X 9. 15

33. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as claimed in any of claims 1, 4 and 5 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient. 10. 20

34. Compositions as claimed in claim 33 in a form suitable for oral, parenteral or rectal administration. - 32 41667

35. Compositions as claimed in claim 34 in the form of granules, tablets, coated tablets, capsules, pills, syrups, emulsions, suspensions, powders, drops, suppositories or injection solutions. 10 3b· Compositions as claimed in any of claims 33 to 32 in the form of dosage units. 37. Compositions as claimed in claim 36 wherein each dosage unit contains from 5 to 75 mg of the said active ingredient. 15 38. Compositions as claimed in any of claims 33 to 37 which contain a further physiologically active ingredient. 39. Compositions as claimed in claim 38 wherein the further physiologically active ingredient is a coronary dilator. 20 40. Compositions as claimed in claim 39 wherein the coronary dilator comprises 2,6-bis-(diethanolamino)-4,8dipiperidino-[5,4-d]-pyrimidine. Zil. Compositions as claimed in claim 40 in the form of dosage units wherein each dosage unit contains from 11. 25 10 to I5O mg of the coronary dilator. 42. Compositions as claimed in claim 33 substantially as herein described. .43. Pharmaceutical compositions substantially as herein described in any one of Examples A to C.