IL39620A - Substituted 1-(4-imidazolidinonylphenylalkyl)-4-phenylpiperazines and their salts their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

1391491 Substituted phenylimidazolidinones BOEHRINGER INGELHEIM GmbH 7 June 1972 [7 June 1971] 26623/72 Heading C2C Compounds of the general Formula I wherein R is hydrogen, halogen or C 1 alkyl or alkoxy; R<SP>1</SP> is -CHR 1 QA, -CHR 2 A or in the meta- or para-position to the imidazolidinone ring, where A is XIII or XIV where R 3 and R 4 , which may be the same or different, each are hydrogen, halogen, alkyl or alkoxy or trifluoromethyl or R 3 and R 4 together form a condensed aliphatic or aromatic 5- or 6- membered ring with the benzene ring to which they are attached; Z is an aromatic ring containing one or two heteroatoms, which ring may be condensed with a benzene ring; Q is a straight or branched C 1-4 alkylene; R 1 is hydrogen, hydroxy, alkoxy or -OCOR 5 in which R 5 is alkyl (optionally substituted by halogen, hydroxy or alkoxy), or amino or mono- or dialkyi amino; R 2 is hydrogen or methyl; and R<SP>11</SP> is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyi or dialkylaminoalkyl or an aralkyl group and acid addition salts thereof wherein all alkyl, alkenyl, and alkynyl groups except that in aralkyl have up to four carbon atoms may be prepared by (i) reaction of a compound H-A with a compound III wherein Ra is -CHR 2 -X, -CHR 1 QX or -OCHR 2 CHR 1 QX in the meta- or paraposition to the imidazolidone ring and X is a radical which can combine with H in H-A to be cleaved as HX; (ii) where R<SP>1</SP> is -CHR 1 QA or -OCHR 2 CHR 1 QA in which R 1 is hydrogen, hydroxyl or alkoxy, cyclization of a compound IV (iii) where R<SP>11</SP> is other than hydroxyalkyl, R 1 where present is other than a hydroxyl group and R 5 where present is other than a hydroxyalkyl, amino or monoalkylamino, ring closure of a compound V with an appropriate carbonic acid derivative or metal cyanate; (iv) where R<SP>11</SP>, R 1 and R 5 are as in (iii), ring closure of a compound Va wherein W is an atom or group removable as an anion with a compound R<SP>11</SP>NHCH 2 CH 2 U where U is an atom or group removable as an anion; (v) where R<SP>11</SP>, R 1 and R 5 are as in (iii) , ring closure of a compound Vb with a compound UCH 2 CH 2 U<SP>1</SP> where U<SP>1</SP> is as U in iv and U and U<SP>1</SP> are the same or different; (vi) where A is XIII and when R<SP>1</SP> is CHR 2 A, R 2 is hydrogen, reductive amination of a compound VI wherein Rb is meta- or parato the imidazolidone ring and is -CHO, -CHR 1 C n H 2n-1 O or -OCHR 2 CHR 1 C n H 2n-1 O wherein the C n H 2n-1 O group contains an aldehyde or ketone group and n is an integer of 1 to 4 with an amine H-A; (vii) where R<SP>1</SP> is -CHOHQA, reduction of a compound VII (viii) where R 1 where present is hydrogen and R<SP>11</SP> is the radical R<SP>11</SP> 1 , which is C 1-4 alkyl or an aralkyl group, dehydroxylation of a compound VIII wherein Re is -CR 2 OH-A, -CHOHQA or OCHR 2 CHOHQA; (ix) where R 1 is hydroxy, reaction of a compound IX wherein Rd is a radical XV or XVI wherein R 6 and R 7 are hydrogen or C 1-3 alkyl providing is not more than a C 1-4 alkylene, with an amine HA; (x) where R<SP>11</SP> is other than hydrogen, R 1 where present is hydrogen or -OCOR 5 wherein R 5 is alkyl, alkoxyalkyl or dialkylamino, reaction of a compound X with a compound R<SP>11</SP>X, where X is an atom or group removable as an anion; (xi) where R<SP>1</SP> is -OCHR 2 CH 2 QA, reaction of a compound XI where the phenolic OH group is in the meta- or para-position to the imidazolidone ring with a compound XCHR 2 CH 2 QA in the presence of an acid binding agent ; (xii) where R<SP>1</SP> is -CHR 1 QA or -OCHR 2 CHR 1 QA and R 1 is alkoxy or -OCOR 5 and R<SP>11</SP> is other than hydroxyalkyl, etherification or esterification of a compound XII wherein R e is -CHOHQA or OCHR 2 CHOHQA to introduce the alkoxy or -OCOR 5 group at R 1 . Intermediates of the Formula III may be prepared by chlorinating a hydroxyl group at X. 1 - (4 - Hydroxymethylphenyl)- imidazolidinone- (2) may be prepared by reduction of the corresponding 1-(4-formylphenyl) compound. Intermediates IV in which -CHR 1 Q- is alkylene may be prepared by reacting a pnitrophenyl alkyl halide with an amine HA to form the appropriate 1-(4-nitrophenylalkyl)-4- substituted piperazine which is reduced to the 1 - (4 - aminophenylalkyl) - 4 - substituted piperazine which is reacted with #-chloroethyl isocyanate to form IV in which X is chlorine. Intermediates V may be prepared by reacting a 1 - (4 - aminophenylalkyl) - 4 - substitutedpiperazine with paraformaldehyde and potassium cyanide to yield a 1-(4-cyanomethylaminophenylalkyl)-4-substituted piperazine which is reduced to the required 1-(4-aminoethylaminophenylalkyl)-4-substituted piperazine. 4 - Imidazolidinon - 2 - yl - benzaldehyde, i.e. an intermediate VI, may be prepared by reacting 4-aminobenzaldehyde with #-chloroethylisocyanate" to yield 4-(#-chloroethylurea)benzaldehyde which is cyclized analogously to process (ii) above to yield the required compound. Intermediates VII may be prepared by reacting m- or p-alkylanilino ketone with #-chloroethylisocyanate to form the corresponding #-chloroethylurea substituted phenone which is cyclized with base as in process (ii) to form an alkyl (m- or p-imidazolidon-2-yl)phenyl ketone which is brominated in the alkyl chain and reacted analogously to process (i) to form the intermediates VII. 4:-Methoxy-3-aminoacetophenone may be prepared by reducing 4- methoxy-3-nitroacetophenone. Intermediates XI may be prepared by reacting a 4=benzyloxyaniline with #-chloroethylisocyanate to form the corresponding #-chloroethylurea derivative which is cyclized as in process (ii) to form a 1 - (4.benzyloxyphenyl)imidazolidin.2. one which is debenzylated to give the intermediate XI. 4 - (1 - Imidazolidinon - 2 - yl) - w - bromoacetophenone may be prepared by reacting 4 - aminoacetophenone with #-chloroethylisocyanate and then base as in process (ii) to form 4 - (1 - imidazolidinon - 2 - yl)acetophenone followed by bromination. 2 - (4 - Imidazolidinon - 2 - yl - phenyl)ethyl methylsulphonate may be prepared by reaction of 2 - (4 - imidazolidinon - 2 - yl - phenyl)ethanol with methane sulphonyl chloride. Pharmaceutical compositions of the compounds I are central nervous depressants, neuroleptics, analgesics, anti-phlogistics, spasmolytics and broncholytics and lower blood pressure and cholesterol level when administered orally, parenterally, rectally or bucally with the usual excipients. [GB1391491A]

Description

G.H. BOEHRINGrER SOHN C: 37470 The present invention relates to novel substituted phenylimidozolidinones and their acid addition salts and also to processes for their preparation. The novel compounds show interesting physiological activity.

According to one feature of the present invention there are provided compounds of the general formula:- [wherein R represents a hydrogen atom, or a lower alky1 or alkoxy group; R' represents one of the following groups in the meta-: or parar-position...to .the ijnidazolidinone ring:- - ■ " -CHRj^Q-A -CH2 -A or -0-(¾ -CHR1-Q-A (in which A represents the radical: 39620/2 > - / \ N N-Z \ (wherein and R^, which may be the same or different, each represents a.hydrogen atom, a halogen atom, a lower alkyl or alkoxy group or a trifluoromethyl group; or and. together form a condensed benzene or cyclopentane ring with the adjacent phenyl group; and Z represents pyridyl or quinolyl; Q represents a straight or branched alkylene group with 1 to 4 carbon atoms; R^ represents a hydrogen atom, a hydroxy1 group, a "lower alkoxy group or the group - 0 - CO - R5 - in which R^ represents a lower alkyl group or a monoalkylamino group and acid additipn salts The compounds according to the present invention may contain an asymmetric carbon atom and then- exist not only in racemic form but also i the form of optically active isomers and meso-isomers. Thus, for example, the compounds according to the invention may exist in the form of enantiomeric pairs as well as i the form of diastereo- isomeric pairs. It will be appreciated that all such forms of the compounds of formula I (arid their acid addition salts) are within the scope of the present invention.

Acid addition salts useful for incorporation in pharmaceutical compositions are physiologically compatible 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 terms "alkyl and alkoxy groups" and "lower alkyl and alkoxy groups" as used herein generally refer to alkyl and alkoxy groups with 1 to 4 carbon atoms, such -groups-preferably -containing L.or..2..carbon atoms. . - Preferred halogen atoms include, for example, the chlorine or bromine atom.

The compounds of formula I may, for example, be prepared by one of the following processes (1) to (12), which processes constitute further features of the present invention:- 1) Reaction of a compound of the formula H-A il (wherein A is as hereinbefore defined with a compound of the formula (wherein R is as defined in; formula I and R. represents one of the following groups in the meta- or para- position to the imidazolidinone ring:- -CH2 - X -CHR, - Q - X or - 0 -C¾ - CHR1 - Q - in which X represents a radical which can combine with the hydrogen atom of the compound of formula II to be cleaved as HX).

A compound of formula III in which X represents a halogen atom, or an -0-S02-alkyl or -0-S02~aryl group may, for example be used. The reaction is advantageously effected in the presence, of a compound which is capable of binding HX, such as potassium carbonate, sodium carbonate or an excess .of the compound of formula II. 2) For the preparation of compounds of formula I as hereinbefore defined in which R1 represents the group -CHRj^ Q - A or s -0-C¾. 'CHRj-Q-A (wherein* Q and A are as defined in tormula I and R. represents a hydrogen atom, a hydroxyl group or a lower alkoxy group)] which comprises the cyclisation of a compound of the formula: - (wherein R and R' are as defined in formula I and X is as defined in formula III) .

The cyclisation is preferably effected by heating for example with strong bases such as potassium or sodium hydroxide. 3) For the preparation bf compounds of formula I as hereinbefore defined (wherein R^^ where present is other than a hydroxyl group and Rg where present is other than a monoalkylamino group), the ring closure of a compound of the formula: (wherein R and R' are as defined in formula I with the proviso that R^ where present is other than a hydroxy1 group and R,. where present is other than a monoalkylamino group with an appropriate carbonic acid derivative or. metal cyanate.

Carbonic acid derivatives which may conveniently be used to effect ring closure include for example phosgene, chlorocarbonic acid esters, carbonic acid esters, Ν,Ν'-diimidazo or urea. The ring closure is advantageously effected in the presence of an acid. 4) For the preparation of compounds of formula I as hereinbefore defined . (wherein R^ where present is other than a hydroxy group and R^ where present is other than a monoalkylamino group) the ring closure of a compound of the formula: (wherein R and R' are as defined in \ formula I with the proviso that R^ where present is other than a hydroxyl group and R5 where presen is other than a hydroxy- alkyl, amino or monoalkylamino group and W represents an atom or group removable as an anion) with a compound of the formula :- • v ; ¾CH2-CH2-U A compound of formula Va is preferably used in which W represents a chlorine atom or hydroxyl or alkoxy group or the group -0M where M is a metal e.g. the compound of formula Va represents, a carbamate derivative. 5) For the preparation of compounds of formula I as hereinbefore defined (wherein where present is other than a hydroxyl group and where present is other than a monoalkylamino group) the ring closure■ of the compound (where R' and R' are as defined in j formula .I with the proviso that! . I R^ where present is other than a hydroxyl group and R^ where present is other than a ί monoalkylamino group) with a compound of the formula: u - CH2-CH2 - y (wherein U and U1 , which may be the same or different, each represents an atom or. group removable as an anion).

Thus compounds of formula I may_be prepared starting with an amine of the formula V, or ring closure may be effected using an intermediate product such as for example a carbamate, urea or carbamic acid' chloride. 6.) For the preparation of compounds of formula I as herein before defined [ wherein A represents the radical: (in which R^ and are as hereinbefore defined)] the reductive amination of a compound of the formula: [wherein-; R is as defined in formula I and' represents one of the following groups in the meta— or para- position to 'the imidazolidinone ring:- -CHO -CHR.-C H .0 or 1 n 2n-l -0-CH* -CHR.-C H„ .0 I n 2n-l (in which R. is as defined in formula I and n is an integer from 1 to 4)] with an amine of the - in which R„ and R. are as defined in j formula I: The reduction is. conveniently effected by the use of . hydrogen in the presence of- a hydrogenation catalyst. 7.) For the preparation of compounds of formula l[wherein R' represents the radical -CHOH-Q-A (in which Q and A are as hereinbefore defined) in the meta- or para-position to the imidazolidinone ring], the reduction of a compound. of the formula: (wherein R, Z and A are as hereinbefore defined) .

The reduction is preferably effected by the use of an appropriate hydride such as sodium borohydride, the reduction may also be effected, for example by the use of hydrogen and a hydrogenation catalyst. 8, For the preparation of compounds .of formula I (in which - - [wherein R, is . as defined inj formula I and R^ represents one of the radicals (wherein R^ and R^ , which may be the same of different, each represents a hydrogen atom or an alkyl group - with up to three carbon atoms) in the meta- or para-position to the imidazolidinone ring] with an amine of the formula: H-A (wherein A is as hereinbefore defined). 9) For the preparation of compounds of Formula I [in which R^, where present, represents a hydrogen atom, a lower alkyl group or the group -O-CO-R^ (wherein represents an alkyl, alkoxyalkyl or dialkylamino group), the reaction of a compound 0 [wherein R and R' are as hereinbefore defined with the compound of the formula HX (wherein X represents an. atom or group removable as an anion) . ι The compound of formula X may, for example,, be obtained from the corresponding NH compound by introduction of a metal, e.g. by means of sodium hydride, lithium amide or potassium tert. -butylate. , 10) For the preparation of compounds of formula I [in which R' represents the radical -0-CH2-CH2-Q-A : (wherein Z and A are as hereinbefore defined) in the meta— or- para-position -to the imidazolidinone ring], the reaction of a compound of the formula: 0 II XI -OH group is in the meta- or para-position to the imidazolidinone ring) with a compound of the formula: X - CH2 - CH2 -Q - A _ ■-! ■ (wherein X Q and A are as hereinbefore def ned in the presence of an acid binding agent, such as for example sodium or potassium carbonate. or re Etherification may advantageously be effected by the use of an appropriate alkylating agent such as, for example, an alkyl halide, a dialkyl sulphate or a sulphonic acid ester Alternatively, the compound of formula XII may, if desired, be chlorinated, for example, by the use of a chlorinating agent such as PCl^ or SOC^, whereby the -OH group is replaced by a chlorine atom and the compound thus formed is subsequently reacted with an alkali metal alkoxide whereby a compound of formula I is obtained.

Esterification, i.e. the introduction of the group -COR,., may be conveniently effected by the use of an appropriate acylating agent such as for example an acid chloride, carbamoyl chloride or an. anhydride.

Where. the group represents an alkyl or halo- substituted or alkoxy- substituted alkyl group, the compound of formula XII may .conveniently also be reacted with the corresponding acid advantageously in the presence of a con'V.nsing agent such as for example dicyclohexyl -carbodiimide or carbonyl . diimidazol'e.

For the preparation of compounds of formula I as hereinbefore defined [in which represents the group -0-CO-R (wherein R represents a methyl,, or mono-j-alkylamino group)] according to process II.' the compound of formula XII is advantageously reacted with ketene, Where a compound according to the present invention exists in the form of racemates or diasteroisomeric optically active pairs, these can be separated in the conventional manner into diastereoisomeric racemates or into optically active isomers. Thus the optically active isomers may be prepared for example either by starting from optically active starting compounds or by resolving the racemates obtained into their optical isomers in a conventional manner.

The compounds of general formula I obtained according to the processes of the present invention may, if desired, be converted into their acid addition salts e.g. their physiologically compatible acid addition salts.

Certain of the starting materials for the processes according to the invention have already been described in the literature but the starting may in any case be obtained by conventional methods of synthesis.

The compounds according to the present invention show interesting physiological activities and in particular are potentially useful as central nervous depressants, neuroleptics, analgesics, antiphlogistics, spasmolytics and broncholytics as well as for effecting the lowering of blood pressure and the lowering of the cholesterol level. One of the activities, in general, predomininates according to the nature of the substituents in the compound according to the invention.

Preferred compounds according to the present inventipja-, by virtue of their particularly favourable physiological activities include compounds of formula .. wherein Ι1χ represents a hydrogen atom, ' •or a lower alky1 or alkoxy group; and R' represents one of the following groups, in the meta- or para-position to the imidazolidinone ring:- (:in which Q represents an alkylene group with 1 to A carbon atoms; R'g represents a hydrogen atom or a hydroxyl group; R' j and Rg, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl or alkoxy group or a trifluoromethyl group;- or R' and RD together form a condensed benzene or cyclo Especially preferred compounds according to the present invention, by virtue of their particularly favourable physiological activities, include :- 1- (4-imidazolidinone- (2)-yl-phenethyl)-4- (2-e hylphenyl)-piperazine and acid addition salts thereof; and 1- (4-imidazolidinine- (2)-yl-phenethyl)-4- (2-methylphenyl) -piperazine au · acid addition salts thereof.

According to a 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 may be presented in a forra suitable for oral, nasal, -rectal or parenteral administration, or in forms suitable for use in sprays (e.g. aerosols) and inhalants. Thus, for example, compositions for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, syrups, - m - emulsions, suspensions, sprays, or drops, such compositions comprising carrier or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tabletting excipients include lactose, potato and soluble stitches and magnesium stearate.

For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e.g. arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.

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 ampoules are examples of suitable dosage unit forms. For a 75 kg patient the individual dose is advantageously 2 to 100 mg. , preferably 5 to 50 mg. of active ingredient. Thus each dosage unit preferably contains 2 to 100 mg. , and especially 5 to 50 mg. , of active ingredient.

The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients.

Example 1 l-(4-Imidazolidinon-(2)-ylphenethyl)-4-(3-chlorophenyl)-piperazine (Me 446) 19.6 g (0.1 mol) of N-3-chlorophenylpiperazine and 23.0 g (0.1 mol) of 2-(4-nitrophenyl)-ethylbromide are boiled under reflux in 150 ml of acetonitrile in the presence of 20 g of potassium carbonate for 2 hours. The hot solution is suction filtered, the residue is washed with acetonitrile and the combined solutions are concentrated by evaporation. Treatment of the residue with isopropanol yields 19 g of l-(4-nitrophenethyl)-4-(3-chlorophenyl)-piperazine (m. p. 87°C) and a further 4.5 g are obtained from the mother liquor.

The total yield is 23.5 g (70% of the theory).

The nitro compound is dissolved in 240 ml of methanol and hydrogenated in the presence of 1 g of Pt02 at 20°C and 5 excess atmospheres of hydrogen until the nitro group has been reduced. After separation of the catalyst, 21 g of amine are obtained as distillation residue which is reacted without further purification with 8.5 g of β-chloroethylisocyanate in 150 ml of benzene by heating to 50°C for 3 hours, the following compound being produced: (yield 27 g (96% of theory)), decomposition point above 200°C. 27 g of this substance are dissolved hot in 360 ml of ethanol^ and a. solution of 4.0 g of potassium hydroxide in 40 ml of ethanol is then added¾ The reaction mixture is boiled under reflux for 3 to 5 minutes and suction filtered after cooling, and the residue is then freed from inorganic substance by extraction with water. 17 g of the following compound 0 If are obtained in the form of the base. For conversion into the salt, the base is heated to boiling in 500 ml of ethanol, and an equivalent quantity of methane-sulphonic acid is then added in the form of an ethanolic solution. 20.5 g of methanesulphonate , 239°C (from ethanol) are obtained.

The following compounds are produced in a similar manner to that described in Example 1: Table 1 Compounds of Formula I, R denotes hydrogen a) Acid/m.p. or decomposition point of the salt [°C] . . Name R' b) M.p. of base [°C] Table 1 continued a) Acid/m.p.. or decomposition point of the salt [°C] b) M.p. of base [°C] o. Name R' Table 1 continued a) Acid/m.p. or decomposition point of the salt [°C] No. Name R' b) M.P. of base [°C] Table 1 continued a) Acid/m.p. or decomposition point of the salt [°C] M.p. of base o. Name R' [°C] Table 1 continued a) Acid/m.p. or decomposition point of the salt [°C] b) M.p. of base o. Name R' [°c] / \ 22 Ren 255 -CH2-CH-N N- a) CH3S03H 275-279 23 Ren 266 a) CH3S03H/270 The following compound was also obtained by a method analogous to that of Example 1: In the following examples, Z denotes the radical Example 2 28.4 g (0.1 mol) of 2-(4-imidazolidinon-(2)-yl-phenyl) -ethyl methyl sulphonate obtained from 2- (4-imidazolidinon-(2)-yl-phenyl)-ethanol and methane-sulphochloride in pyridine are reacted with 17.5 g of N-2-methylphenyl-piperazine in 120 ml of acetonitrile in the presence of 21 g of sodium hydroxide solution by boiling under reflux for one hour. Compound A is isolated as the base, melting point 195°C.

The following compounds' are prepared in analogous manner (Formula I, R equal's hydrogen, R' as indicated)  10 g of l-(4-Imidazolidinon-2-yl-phenyl)-2-oxo-propane are hydrogenated with 8.1 g of 2-methyl-phenylpiperazine in 100 ml of methanol in the presence of 1 g of Pt02 at 60°C and 5 excess atmospheres until the calculated quantity of hydrogen has been taken up.

After removal of the catalyst, the methanol is distilled off and the residue is crystallised by the addition of acetonitrile . The hydrochloride of B, which melts at 299-301°C and crystallises as the monohydrate is obtained from the base in a small quantity of methanol by adding concentrated hydrochloric acid.

The following compounds are prepared in analogous manner (Formula I, R equals hydrogen, R' as indicated) : CH 3 Example 4 15.5 g (0.05 mol) of l-[2-(4-aminophenyl)-ethyl] -4-(2-ethylphenyl)-piperazine, 1.6 g of paraformaldehyd and a solution of 4.1 g of potassium cyanide in 7 ml o water are added together in 85 ml of glacial acetic acid at 15 to 20°C and left to react overnight at room temperature. The resulting product, which has the following formula: has a melting point of 137-138°C. It is hydrogenated in methanol, using PtO? as catalyst, to form C2H5 which is treated in benzene with the calculated quantity of Ν,Ν' -carbonyldiimidazole dissolved in tetrahydrofuran. The mixture is left to stand overnight at room temperature and then boiled under reflux for 2 hours and the resulting product C is isolated as the base (m.p. 178-181°C).

The following compounds are prepared in analogous manner: (Formula I, R equals hydrogen, R1 as indicated) CH.

Example 5 4-Methoxy-3-nitroacetophenone is reduced to A- methoxy-3-aminoacetophenone which is reacted with β-chloroethylisocyanate to form CH -Cl X (m.p. 1A9°C) which is converted into the imidazolidinone derivative of the formula (m.p. 186-188°C) by reaction with potassium hydroxide in ethanol. Reaction of this compound with bromine in chloroform yields the following compound which is reacted as the crude product (85 g) with 105 g of N-2-ethyl-phenylpiperazine in 1500 ml of acetonitrile to yield (m.p. 170-172°C). 5 g of NaBH^ is added portionwise to 32 g of this compound in 250 ml of methanol. The reaction mixture is left to stand overnight and then worked up, yielding 32.5 g of compound D in the form of its hydrochloride (m.p. 234°C).

The following compounds are prepared in analogous manner: 35 g of 3-Aminopropiophenone in 250 ml of be are reacted with 27 g of β-chloroethylisocyanate to yield (m.p.: 114°C) which is cyclised with potassium hydroxide to form 3-(imidazolidinon-(2)-yl)-propiophenone . (m.p. 162°C) which is reacted with bromine in chloroform to yield the bromoketone: (m.p. 181°C). 33 g of the bromoketone are boiled with 39 g of 2-methylphenylpiperazine in 660 ml of acetonitrile for 30 minutes and worked up to yield 40 g of the following compound: M.p. 157°C. 6 g of the aminoketone in 60 ml of ethanol are mixed with 1 g of NaBH. and the mixture is heated to 50°C. After cooling, 1 g of NaBH^ is again added. 5 g of the threoform of E (m.p. 204°C) crystallise after about 1 hour. M.p. of the methane sulphonate equals 241°C.

To prepare the erythro form of E, 6 g of amino ketone are dissolved in methanol and hydrogenated with palladium/charcoal at 60°C and 5 excess atmospheres. Working up yields the erythro form of E, m.p. 161°C.

Example 7 5 g of the following compound: are added portionwise to 20 ml of thionyl chloride, the solution turning red after some time. The excess thionyl chloride is distilled off and the residue is brought to crystallisation by the addition of acetonitrile and boiled. 3.3 g of the following compound are thereby obtained, which are hydrogenated in the presence of 1.67 g of dimethylaniline and Raney nickel as catalyst in methanol until the uptake of hydrogen ceases. After removal of dimethylaniline by distillation, compound F is isolated from the residue as the hydrochloride.

M.p. 256-257°C.

The following compounds are prepared in analogous manner: 39.620/2 4-Aminoacetophenone is converted into 4-(imidazoli-dinon-(2)-yl)-acetophenone (m.p. 208°C) by reaction with β-chloroethylisocyanate followed by treatment with potassium hydroxide. The CJ -bromoketone of the following formula is obtained in chloroform by the addition of 1 mol of bromine M.p. 175°C. 2 g of sodium borohydride are slowly added to 14.2 g of the bromoketone in 200 ml of ethanol with ice cooling and the reaction mixture is then stirred for 2 hours at room temperature. Precipitated sodium bromide is removed by suction filtration, 0.5 ml of water and 17.6 g of N-2-methylphenylpiperazine are added to the solution and the mixture is left to stand overnight at room temperature and then boiled under reflux for 2 hours. Compound (G) is then isolated. It has a melting point of 221-223°C.

The following compounds are prepared in analogous manner: s is cyanate to produce the following compound C1-CH -CH -NH-C-NH 0-CH2-C6H5 II 0 (m.p. 176°C) which is converted with potassium hydroxide in ethanol to the imidazolidinone derivative (m.p. 226°C).

Catalytic hydrogenation yields the compound m.p. 180°C. 14.2 g of this substance are reacted in ethanol with 12.6 g of N-3-chloropropyl-N1 -2-methylphenyl-piperazine by boiling in the presence of 3.1 g of potassium hydroxide to yield compound H (m.p. 171°C).

The following are prepared in analogous manner: 43 Example 10 l-(A-Imidazolidinon-(2)-yl-phenylmethyl)-4-phenyl-piperazine (Method 1) l-Phenyl-4-(4-nitrobenzyl)-piperazine is prepared from 4-nitrobenzyl bromide and 1-phenylpiperazine by boiling under reflux in acetonitrile. Reduction of this compound with hydrogen/PtC^ in methanol yields l-phenyl-4-(4-aminobenzyl)-piperazine (m.p. 105°C) which is reacted with β-chloroethyl-isocyanate in benzene to yield the following compound 21 g of this compound are mixed with 2.4 g of NaOH in 160 ml of ethanol and boiled under reflux for 10 minutes. 16 g of the compound indicated in the heading are obtained by isolation from ethanol (m.p. 218°C). The methanesulphonate (m.p. 210°C) is obtained from the base with the calculated quantity of methane sulphonic acid in ethanol.

Example 11 l-(4-Imidazolidinon-(2)-yl-phenylmethyl)-4-phenyl-piperazine (method 2) 4-Aminobenzaldehyde and β-chloroethylisocyanate are reacted together in chloroform to yield the corresponding β-chloroethyl urea derivative. The imidazolidinone ring is then closed by reaction with NaOH in ethanol. The resulting aldehyde is reductively aminated in methanol with 1-phenylpiperazine under the action of hydrogen/Pt02 until the theoretical amount of hydrogen has been taken up. The compound indicated in the heading is obtained from ethanol (melting point 218°C).

Example 12 l-(4-Imidazolidinon-(2)-yl-phenylmethyl)-4-phenyl-piperazine (Method 3) 20 g of l-(4-formylphenyl) -imidazolidinone- (2) prepared according to Example 11 are reduced with sodium borohydride in ethanol to the corresponding "V l-(4-hydroxymethylphenyl) compound. The hydroxyl group is then replaced by chlorine by reacting the compound with thionyl chloride in methylene chloride with the addition of pyridine. The resulting l-(4-chloromethylphenyl)-imidazolidinone-(2) is then reacted with 1-phenylpiperazine in acetonitrile to yield the compound indicated in the heading (m.p. 218°C) (from ethanol).

Example 13 l-(4-Imidazolidinon-(2)-yl-phenylmethyl)-4-phenyl-piperazine (Method 4) 13.35 g of l-Phenyl-4-(4-aminobenzyl)-piperazine , 1.6 g of paraformaldehyde and a solution of 4.1 g of potassium cyanide in 7 ml of water are added together in 85 ml of galcial acetic acid at 15 to 20°C. The cyanomethyl amino compound is formed in the course of several hours' stirring at room temperature and is hydrogenated in methanol over Pti^. The resulting ethylene diamino derivative of the following formula is dissolved in benzene, and the calculated quantity of Ν,Ν' -carbonyldiimidazole dissolved in tetrahydrofuran is added. The reaction mixture is left to stand for several hours at room temperature and then boiled under reflux for 2 hours. The compound indicated in the heading is obtained from ethanol (m.p. 218°C).

The following compounds are prepared in acco with Examples 10 to 13: 0 C 0 Example 14 l-(4-Imidazolldinon-(2)-yl-phenylethyl)-4-(2-quinolyl)-piperazine (Me 482) 9 g of N-(2-quinolyl)-piperazine and 9.7 g of p-nitro-phenethyl bromide are refluxed for 4 hours in the presence of 12 g of sodium hydroxide in 125 ml of acetonitrile. The solution is suction filtered while hot and the residue is washed with acetonitrile. l-(2-quinolyl)-4-(4-nitrophenethyl)-piperazine crystallises from the mother liquor on cooling. The yield after suction filtration and recrystallisation from acetonitrile is 11 g (m.p. 162°C). 20 g of the nitro compound dissolved in 1 litre of methanol are hydrogenated at 20°C and 5 excess atmospheres in the presence of 1 g of PtC^ until the theoretical amount of hydrogen has been taken up. After removal of the catalyst by filtration and concentration of the solvent by evaporation, the crystalline distillation residue is recrystallised from acetonitrile and 18 g of the amino compound are isolated (m.p. 133°C). 10 g of this compound are reacted with 3.8 g of β-chloroethylisocyanate in 200 ml of chloroform by heating for one hour at 50°C to yield the following compound m.p. 233°C. Ring closure is carried out by suspending 11 g of this compound in 165 ml of methanol and then adding a solution of 1.05 g of NaOH in 15 ml of H20 at boiling point. A solution is formed and crystallisation takes place after 2 minutes. After cooling and suction filtration, the crystals are washed with water and acetonitrile. 7 g of the compound indicated in the heating are obtained} m.p. 230°C (from dimethylformamide) . The base is converted into the di-methane sulphonate by reaction with the calculated quantity of methanesulphonic acid in alcohol and recrystallised from methanol. The dimethane sulphonate contains 1 mol of water of crystallisation; m.p. 197°C.

Example 15 l-[l-(4-Imidazolidinon-(2)-yl-phenyl)-l-hydroxyethyl] - 4-(2-pyridyl)-piperazine 14.15 g of 4-(imidazolidinon-(2)-yl)-w-bromo- acetophenone (m.p. 175°C) are refluxed with 16.3 g of a-pyridylpiperazine in 150 ml of acetonitrile for 45 minutes. After separation of the precipitated a-pyridylpiperazine hydrobromide, the compound represented by the following formula 0 is isolated as the base (76% of the theory); m.p. 214°C (from ethanol).

Reduction of the ketone with NaBH, in 90% 4 methanol results in the corresponding hydroxyl compound in a yield of 88.5%; m,p. 218°C (from ethanol) .

Example 16 l-(4-Imidazolidinon-(2)-yl-phenethyl)-4-(2-pyridyl)-piperazine 14.1 g of l-(4-aminophenethyl)-4-(2-pyridyl)-piperazine, 1.6 g of paraformaldehyde and a solution of 4.1 g of potassium cyanide in 7 ml of water are added together in 85 ml of glacial acetic acid at 15 to 20°C and the reaction is completed by leaving the reaction mixture to stand overnight at room temperature. The resulting cyanoethylamino compound is hydrogenated to the corresponding ethylene diamino derivative with hydrogen in methanol, using PtC^ as catalyst. The calculated quantity of Ν,Ν' -carbonyl diimidazole dissolved in tetrahydrofuran is added to this ethylenediamino derivative in benzene. This reaction mixture is left to stand overnight at room temperature and then boiled under reflux for 2 hours to yield the following compound 39620/2 which is isolated as the base; m.p, 200°C 39620/2 Example ..17 1- [l-(4-Imidazolidinon-(2)-yl-phenyl)-l-acetyloxy-^ ethyl] -4-( 2-methylphenyl)-piperazine (Me 474) 7.6 g (0.02 mol) of l-[l-(4-imidazolidinon-(2)-yl-phenyl) -1-hydroxyethyl] -4-( 2-methylphenyl) -piperazine , 2.5 ml of acetic acid anhydride and 76 ml of chloroform are boiled under reflux for 2 hours. After removal of the solvent by distillation, the residue crystallised from ethanol is .dissolved in chloroform and extracted by shaking with potassium carbonate solution and water. . The organic phase is dried with sodium sulphate and the chloroform is distilled off. A residue which can be crystallised from ethanol remains behind. The hydrochloride is obtained from the base by the addition of concentrated hydrochloric acid in hot ethanol.

After recrystallisation from ethanol, the salt has a melting point at 310°C (decomposition).

The yield is 5.5 g.

IS Example 2& l-[l-(4-Imidazolidinon-(2)-yl-phenyl)-l-methylcarbamoyl- oxyethyl] -4-(2-methylphenyl)-piperazine (Me 473) 7.6 g (0.02 mol) of l-[l-(4-imidazolidinon-(2)- yl-phenyl)-l-hydroxyethyl] -4-(2-methylphenyl)- piperazine, 1.1 ml¾ of methylisocyanate and 114 ml of chloroform are shaken in a monte-jus for one hour at 60-70°C. aAfter removal of the chloroform by distillation, a residue which can be crystallised from ethanol is left behind. The base in hot ethanol is converted into the hydrochloride by the addition of ethanolic hydrochloric acid. After recrystallisation from ethanol, the salt has a melting point of 159°C (decomposition). The yield is 7.5 g.

Example 19 l-[l-(4-Imidazolidinon-(2)-yl-phenyl)-l-ethoxyethyl] -4- ( 2-methylphenyl) -piperazine - 5 - . 8.7 g .(0.02 mol) of l-[l-(4-imidazolidinon-(2)-yl-phenyl)-l-chloroethyl] -4-(2-methylphenyl)-piperazine-chloride prepared from the corresponding hydroxyl compound by chlorination with PCl^ in aceto-nitrile are introduced into a solution of 1.84 g (0.08) of sodium in 200 ml of absolute ethanol. After one hour's stirring at 40°C, the . calculated quantity of ethanolic hydrochloric acid is added, the precipita NaCl is removed by suction filtration and ethanol is distilled down to a residue of 20 ml. The base is obtained from the residue. Crystallisation of the base from ethanol with the calculated quantity of methanesulphonic acid yields the methane sulphonate of the compound indicated in the heading.

The following compounds are prepared by methods analogous to those of Examples 17-19: 39620/2 0 H-N-CH(CH3)2 0 c=o H- -C2H5 \ \ II Pharmaceutical Examples Example 20 Tablets (Composition) Active substance according to the invention 30 parts by wt Lactose 70 Maize starch 93 sec. calcium phosphate 47 Soluble starch 3 Magnesium stearate 3 Colloidal silicic acid 4 A granulate is prepared in the usual manner from the active substance and part of the auxiliary substance-. The granulate is then mixed with the remaining constituents and compressed into tablets weighing 250 mg. · Example 3" Pills (composition) Active substance according to the invention 40 parts by wt, Lactose 50 " 1 0 Maize starch 80 parts by wt. sec. calcium phosphate 50 " Magnesium stearate 3 11 Soluble starch 3 " Colloidal silicic acid 4 " Pill centres each weighing 230 mg are prepared from the above constituents in the usual manner.

These centres are then coated with talcum, sugar and gum arabic.

Example 2fr Suppositories Active substance according to the invention 30 parts by wt.

Powdered lactose 45 " Cocoa butter 1625 " The lactose is carefully mixed with the active substance and the mixture is uniformly distributed in melted cocoa butter. The mixture is then formed into suppositories each weighing 1700 mg. 1 1

Claims (50)

1. CLAIMS Compounds of the general formula [wherein R represents a hydrogen atom, or a. lower alky1 or alkoxy group; R' represents one of the following groups in the meta-or para-position to the imidazolidinone ring:- -CH -A or -0-CH'2 -CHR-^-Q-A (in which A represents the radical: or the radical: bv ■N N-Z (wherein R^ and R^,- which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl or alkoxy group or a trifluoromethyl group; or R^ and ^ together form a condensed benzene or cyclopentane ring with the adjacent phenyl group; and Z represents pyridyl or quinolyl; Q represents .a straight or branched alkylene group with 1 to 4 carbon atoms; R. represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or the group - - 0 - CO - R5 - in which R,. represents a lower alkyl group or a monoalkylamino group -; and acid addition salts thereof. ' 2.. .

2. Compounds as claimed in Claim 1 wherein R1 represents the group: -CHR1 - Q - A or - 0 - CH2 - Cffi^ - Q A wherein ^ represents a hydrogen atom or a hydroxyl group and A is as. defined in Claim 1. 39620/3.

3. Compounds of the formula: '."Wherein R^ represents a hydrogen atom, •or a lower alkyl or alkoxy group; and R' represents one of the following groups, in the meta- or para-position to the imidazolidinone ring:- win which Q represents an alkylene group with 1 to 4 carbon atoms; R1 ^ represents a hydrogen atom or a hydroxyl group; R'_ and RQ , which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl ότ alkoxy group or a trifluoromethyl group; or R'^ and Rg together form a condensed benzene or cyclo pentane ring with the adjacent phenyl group; and " " acid addition salts thereof.

4. l-(4-Imidazolidinone-(2)-yl-phenethyl)-4-(2-ethylphenyl)-piperazine and acid addition salts thereof.

5. l-(4-Iraidazolidinone-(2)-yl-phenethyl)-4-(2-methylphenyl)-piperazine and acid addition salts thereof.

6. Compounds as claimed in claim 1 in the form of physiologically compatible acid addition salts.

7. Compounds as claimed in claim 3 in the form of physiologically compatible acid addition salts.

8. Compounds as claimed in claim 1, other than as claimed in claim 4 or claim 5 as herein specifically disclosed.

9. Compounds as claimed in claim 3, other than as claimed in claim 4 or claim 5, as herein specifically disclosed.

10. A process for the preparation of compounds of formula I as defined in claim 1 which comprises reacting a compound of the formula: - H - A II ~ 2& N 39620/2 (wherein A is as defined in claim 1) with a compound of the formula (wherein R is as defined in i Claim 1 and R_ represents one of the following groups in* the meta-or para- position to the imidazolidinone ring:- -CH2 - X -CHR.^ - Q - X or , r in which X represents a radical which can combine with the hydrogen atom of the compound of formula II to be cleaved as HX and R^ ' and Q are as defined in claim 1).

11. A process as claimed in claim 10 wherein a compound of formula III is used in which X represents a halogen atom, or an -0-S02~alkyl or an -0-S02-aryl group.

12. , A process as claimed in claim 10 or claim 11 - J* - wherein the reaction is effected in the presence of a compound capable of binding HX.

13. A process as claimed in claim 12 wherein the compound capable of binding HX comprises potassium or sodium carbonate or an excess of the compound of formula II.

14. A process as claimed in any of claims 10 to 13 for the preparation of compounds of formula la as defined in claim 3 wherein a compound of the formula (wherein- and Rg are as defined in claim 3) is reacted with a compound of the formula [wherein R is as defined in claim 3 and R . repres one of the following groups in the meta- or para- - 39620/2 position to the imidazolidinone ring:- -CHR^ - Q - X -O-CH2 -CHR'6 - Q - X (in which and Q are as defined in claim 3 and X represents a radical which can combine with the hydrogen atom of the compound of formula Ila to be cleaved as HX)].

15. A process for the preparation of compounds of formula I as defined in claim 1 [in which R' represent the group: - -CHR^ Q - A or (wherein Q and A are as defined in claim 1 and R^ -represents a.hydrogen atonij a hydrox 1 group or a lower alkoxy group)] which comprises the cyclisation of a compound of the formula:- - r - (o9. 39620/2 [wherein R, and R' are as defined in claim 1 with the proviso that R1 represents the group: - -CH j^ - Q - A or -0-CH2 -CHR-^ - Q-A (in which Q and A are as defined in claim 1 and R^ represents a hydrogen atom, a hydroxy1 group or a lower alkoxy group) and X is as defined in claim 10],

16. A process as claimed in claim 15 wherein the' cyclisation is effected at an elevated temperature.

17. A process as claimed in claim 15 or claim 16 wherein the cyclisation is effected in the presence o a strong,base.

18. A process as claimed in claim 17 wherein the strong base comprises potassium or sodium hydroxide.

19. A process as claimed in any of claims 15 to 18 for the preparation of compounds of formula la as defined in claim 3 wherein a compound of the formula 0 V 39620/2 (wherein R and R1 are as defined in Glaim 3 and X X X is as defined in Claim 14) is cyclised.

20. A process for the preparation of compounds of formula I as defined in Claim 1 (wherein where present is other than a hydroxyl group and R^ where present is other than a monoalkylamlno group) which comprises the ring closure of a compound of the formula (where R and R* are as defined in Claim 1 with the proviso that R^ where present is other than a hydroxyl group and ^ where present is other than a monoalkylamlno group) with an appropriate carbonic acid derivative or metal cyanate.

21. A process as claimed in Claim 20 wherein the appropriate carbonic acid derivative comprises phosgene, 10 39620/2 I 1 ■ a chlorocarbonic acid ester, a carbonic acid ester, Ν,Ν' -carbonyl-diimidazole or urea.

22. Λ process as claimed in claim 20 or claim 21 wherein the ring closure is effected in the presence of an acid.

23. A process as claimed in any of claims 20 to 22 for the preparation of compounds of formula la as defined in claim 3 (with the proviso that R^ where present, is other thari a hydroxyl group) which compris the ring closure of a compound of the formula: - (wherein R and R' are as defined in claim 3 with x x the proviso that R^ where present is other than a hydroxyl group).

24. A process for the preparation of compounds of. formula I as defined in claim 1 (wherein ■ ·. R^ where present is other than a hydroxyl group and R,. where present is other " ' 7/ 39620/2 than a monoalkylamino group) ' which comprises the ring closure of a ..compound the formula: - (wherein R and R' are as defined in claim 1 with the proviso that R, where present is other than a hydroxyl group and R,. where present is other than a hydroxy— alkyl) amino er monoalkylamino group and W represents an atom or group removable as an anion) with a compound of the formula: - . N¾CH2-CH2-U . (wherein. U represents an atom or group, removable as an anion).

25. A process as claimed in claim 24 wherein a compound of formula Va is used in which W represents a chlorine atom or a hydroxyl or alkoxy group or the group -0 (where M represents an alkali metal). - - 7T- 39620/2

26. A process as claimed in claim 24 or claim 25 for the preparation of compounds of formula la as defined in claim 3 (with the proviso that where present is other than a hydroxyl group) which comprises the ring closure of a compound of the formula: 0 (wherein R and R* are as defined in claim 3 with x x the proviso that R^ where present is other than a hydroxyl group) with a compound of the formula: H2N-CH2-CH2-U (wherein U represents an atom or group removable as an anion).

27. A process for the preparation of compounds of formula I as defined in claim 1 (wherein : R^ where present is other than a hydroxyl group and R^ where present is other ~13 39620/2 than a monoalkylamino group) which comprises the ring cl'osure of a compound of the formula :- 0 (where R, and R' are as defined in claim 1 with the proviso that i R^ where present is other than a hydroxyl group and R^ where present is other than a , monoalkylamino group) with a compound of the formula: U - CH2-CH2 - U1 (wherein U and U' , which may be the same or different each represents an atom or group removable as an anion) .

28. A process as claimed in claim .27 for the preparation of compounds of formula la as defined in claim 3 (with the proviso that R^ where present is other than a hydroxyl group) which comprises the ring 7*f- closure of a compound of the formula : - 0 (wherein R and R' are as defined in claim 3 with x x / the proviso that R^ where present is other than a hydroxyl group) with a compound of the formula : - U - CH2 - CH2 - U (wherein U and U' , which may be the same or different , each represents an atom or group removable as an anion) .

29. A process for the preparation of compounds of formula I as defined in claim 1 [wherein A represents the radical : ( in which R^ and R^ are as defined in claim 1) ] which comprises the reductive amination of a compound of the formula : 7Γ Mr - 39620/2 [wherein- R is as defined in claim 1 and R^ represents one of the following groups in the meta-or para- position to the imidazolidinone ring:- -CH0 -CHR.-C H ,0 or 1. n 2n-l -0-CH*. -CHR.-C KL ,0 ,e i n n-i (in which R^ & as defined in claim 1 and n is an integer from 1 to 4)] with an amine of the formula - H-A II (wherein A represents the radica in which R.. and R^ are as defined in claim 1).

30. A process as claimed in claim 29 wherein the - & - 1(o V 39620/2 reductive amination is effected by the use of hydrogen in the presence of a hydrogenation catalyst.

31. A process as claimed in claim 29 or claim 30 for the preparation of compounds of formula la as defined in claim 3 which comprises the reductive amination o.f a compound of the formula: [wherein Κχ is as defined in claim 3 and R ^ represents the group -CHR' -C H .0 6 n 2n-l or -0-CH. -CHR' -C H„. .0 c 6 n 2n-l (in which R' , ±s as defined in claim 3 and n is 1 to 4) in the meta- or para- position to the imidazolidinone ring] with an amine of the formula 39620/2 ( herein R' η and Rg are as defined in claim 3).

32. A process for the preparation of compounds of formula I as defined in claim 1 [wherein-R1 represents the radical -CHOH-Q-A (in which Q and A are as defined in claim 1) in the meta- or. para- position to the imidazolidinone ring] which comprises reducing a compound of the formula: 0 (wherein R, Q and A are as defined in claim 1)

33. A process as claimed in claim 32 wherein' the reduction is effected by the use of an appropriate hydride.

34. A process as claimed in claim 33.wherein the appropriate hydride comprises sodium borohydride.

35. A process as claimed in claim 32 wherein the reduction is effected by the use of hydrogen in the presence of a hydrogenation catalyst. - iQt - 39620/2

36. A process as claimed in any of claims . 32 to 35 for the preparation of compounds of formula la as defined in claim 3 wherein a compound of the formula : (wherein 11χ .

37. Q, R1 η and Rg are as defined in claim 3) is reduced. , t 37 · process for the preparation of compounds of formula la as defined in Claim 3 (wherein 'g represents a hydrogen atom) in which a compound of the formula [wherein R is as defined in claim 3 and R x xc represents the group or 39620/2 (in. which R' η , Rg, and Q are as defined in claim 3) ' in the meta- or para- position to the imidazolidinone ring] is dehydroxylated.

38. A process as claimed in claim 37 wherein the dehydroxylation is effected by chlorinating the compound of formula VII" with an appropriate chlorinating agent and subsequently hydrogenating the compound thus formed whereby a compound of formula I is obtained.

39. A process as claimed in claim 38 wherein the appropriate chlorinating agent comprises SOC^ or PCI5.

40. A process for the preparation of compounds of formula I (in* which R^, where present, represents a hydroxyl group) which comprises reacting a compound of the formula: IX 39620/2 [wherein R is as defined in claim 1 and R^ represents one of the radicals :- - Rfi I -CH— C — R ' or 0 \ (wherein ^ and R^, which may be. the same of different, each represents a hydrogen atom or an alkyl group with up to three carbon atoms) in the meta- or para-position to the imidazolidinone ring] with an amine of the formula: ' H-A (wherein A is as defined in claim 1).

41. · A process as claimed in claim' 40 for the preparation of compounds of formula la as defined in claim 3 (in which R' ^ represents a hydroxyl group) wherei'n a compound of the formula: 39620/2 Λ [wherein Rx is as defined in claim 3 and Rxd represents one of the radicals ■ ' ' ■ - x6 ■CH — C — V/ (in which R and ^xyt which may be the same or different each represents a hydrogen atom or an alkyl group with up to 3 carbon atoms) in the meta- or para- position to the imidazol- idinone ring] with an amine of the formula: (in which R' η and Rg are as defined in claim 3).

42. process for the preparation of compounds of formula I [in which R^ where present represents a hydrogen atom, a lower alkyl group or the group -9-CO-R-j. (wherein R-. represents an alkyl group)] which comprises reacting a compound of the formula — ,86> — 39620/2 0 [wherein R and R' are as hereinbefore defined with the proviso that R^, where present, represents a hydrogen atom and represents an alkali metal cation] with a compound of the formula HX " (wherein' X represents j an atom or group removable as an anion).

43. A process for the preparation of compounds of formula I as defined' in claim 1 [in which R' ■ represents the radical -0-CH≥' -CH2-Q-A (wherein Q and A are as defined in claim 1) in the eta- or para- position to the imidazolidinone ring] which comprises reacting a compound of the fo 39620/2 (wherein R is " as defined in claim 1 and the phenolic -OH group is in the meta- or para-position to the imidazolidinone ring) with a compound of the formula: X - CH2 -CH2-Q-A (wherein X, Q and A are as defined in claim 1) in the presence of an acid binding agent.

44. A process as claimed in claim 43 wherein the acid binding agent comprises sodium or potassium carbonate.

45. , A process as claimed in claim 43 or claim44 for the preparation. of compounds of formula la as defined in claim 3 [wherein R'^ represents the radical: 39620/2 (in which Q, R' and Rg are as defined in claim 3)] wherein a compound of the formula: which R is as defined in claim 3) is reacted with a compound of the formula: (wherein Q, R' and Rg are as defined in claim 3 and X represents an atom or group removable as an anion). =6.6.72

46. A process for the preparation of compounds for Claims 46-57. 39620/2 of formula I [in which R^ represents an alkoxy group or the group -0-CO-R,. (wherein R^ is as defined in 1giro l) ! which comprises the etherification or esterifi-cation of a compound of the formula: - 0 [wherein R is - as defined in claim 1 with the proviso that1 RQ represents' the radical: -CH0H - Q - A or ' -0-CH 2 - CHOH-Q-A (in which Q and A are as defined in claim 1) in the meta- or para- position to the imidazolidinone ring] with a compound capable of replacing the hydrogeo of the -OH group with an alkyl group or the group 8t 39620/2 -CO-R^ (wherein R.. is as defined in claim 1).

47. A process as claimed in claim 6 "wherein the etherification is effected by the .use of an appropriate alkylating agent.

48. A process as claimed in claim 47 wherein the alkylating agent comprises an alkyl halide, a dialkyl sulphate or a sulphonic acid ester.

49. A process as claimed in claim.48 wherein the etherification is effected in the presence of an alkali.

50. process as claimed in claim 46 wherein the compound of formula XII is chlorinated, whereby the -OH group is replaced by a chlorine atom, and the compound thus formed is reacted with an alkali metal alkoxide whereby a compound of formula I is obtained. 51· A process as claimed in claim 50 wherein the chlorination is effected by the use of SOC^ or PCl^. 52. process as claimed in claim 6 wherein the esterification is effected by the use of an appropriate acylating agent. 53, A process as claimed in claim 52 wherein the appropriate acylating agent comprises an acid chloride, ' ' . -■ JMr - carbamoyl chloride or an anhydride, '54· A process as claimed in claim 46 for the preparation of compounds of formula I as defined in claim 1 (wherein R represents an alkyl group) wherein a compound of formula XII is reacted with an appropriate acid. 55. A process as claimed in claim 54 wherein the reaction is effected in the presence of a condensing agent. 56. A process as claimed in claim 55 wherein the condensing agent comprises dicyclohexyl carbodiimide or ,Ν' -carbonyl diimidazole. 57. A process as claimed in claim 46 for the prepare of a compound of formula I as defined in claim 1 [in whi' .. represents the group -0-C0-R5 (wherein R5 represents a methyl, or monoalkylamino group)] wherein the compound of formula XII is reacted with ketene, or a lower alkylisocyanate. 58. A process as claimed in any of claims 10 to 57 ■ 39620/2 In which the compound of formula I obtained is converted into a physiologically compatible acid addition salt* 59· A process as claimed In any of Claims 10 to 57» in which a compound of formula I or an acid addition salt thereof is obtained as a racemic mixture which is subsequently resolved Into its optically active isomers* 60* A process as claimed in any of Claims 10 to 57* substantially as herein described in any of Examples 1 to 21. 61. A process for the preparation of compounds as claimed in Claim 3, substantially as herein described in any of Examples 1 to 9· 62* Compounds as claimed in Claim 1 when prepared by a process as claimed in any of Claims 10 to 60 or 61* 63· Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as claimed 6.6.72 for in Claim 1 or a physiologically compatible acid addition the same meanings as salt thereof in association with a pharmaceutical carrier in Claim 1. or excipient. 64* Compositions as claimed In Claim 63 in a form suitable for oral* nasal, parenteral or rectal administration. 39620/2 65. Compositions as claimed In Claim 63 or Claim 64 n the form of dosage units. 66· Compositions as claimed in Claim 65 wherein each dosage unit contains from 2 to 100 mg of the said active ingredient. 67· Compositions as claimed in Claim 66 wherein each dosage unit contains from 5 to 50 mg of the aaid active Ingredient. 68. Pharmaceutical compositions as claimed in any of Claims 63 to 67 wherein the active ingredient is a compound of formula Za as defined in Claim 3 o a physiologically compatible acid addition salt thereof. 69· Compositions as claimed in Claim 63 substantially as herein described. 70; Compositions as claimed in Claim 68 substantially as,herein described. 71. Pharmaceutical compositions substantially as herein described in Examples 20 to 23L. PC/rb