IE37812B1

IE37812B1 - Substituted phenylimidazolidinones the acid addition salts thereof and processes for their preparation

Info

Publication number: IE37812B1
Application number: IE791/72A
Authority: IE
Original assignee: Boehringer Sohn Ingelheim
Priority date: 1971-06-07
Filing date: 1972-06-07
Publication date: 1977-10-26
Also published as: SU493067A3; AR202903A1; CH589646A5; IL39620A; FR2140492B1; DD101403A5; NL7207701A; SE392902B; ZA723840B; SU505358A3; ES403542A1; CH590269A5; AR205522A1; IL39620A0; GB1391491A; AR202904A1; NO136841C; SU498907A3; AR200112A1; SU453839A3

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]