NZ231950A

NZ231950A - Amidine and guanidine derivatives, medicaments

Info

Publication number: NZ231950A
Application number: NZ231950A
Authority: NZ
Inventors: Balasubramanian Gopalan
Original assignee: Boots Co Plc
Priority date: 1989-01-02
Filing date: 1989-12-21
Publication date: 1992-05-26
Also published as: GB2226562A; CA2006577C; KR0168398B1; KR900012933A; AU4703789A; IE62023B1; GB2226562B; GB8929260D0; HU900008D0; CA2006577A1; IE894039L; HUT58693A; AU632778B2

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £31 950 2 3 19 5 0 I Pooritv : : D~ T 8P| , —• r~ ' *«• * r* C ko ^ .K 5.Ji .onDa-3 3./^Q.><.CCllVZa J. I ) .cOT1D.XO 7../^^ r-C^-f .£ .O.^.C\U..O. ' t J% UAU AAM / »>. A ?$ HAY 992 A* Clasr. Cent' i __ .. .).3.5G ^ dec vss- / . O V OMi ^ U c o n c. .^.l.Cj 11S .fCCxTio x.U>5./_5o A .la l k-^. I I .0.5 i UrO. <k. \D.>. U-W^, 535|JO- 2 T * *:?. r/\#v N ®V la\|GS NEW ZEALAND PATENTS ACT, 1953 Dale. COMPLETE SPECIFICATION THERAPEUTIC AGENTS 9 y] We, TUE BOOTS COMPANY PLC, a British Company o£ 1 Thane Road Nest, Nottingham, England, J hereby declare the invention for which^7 we pray that a patent may be granted to jrr£7us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page 1A) - lA - 2 3 19 5 0 Therapeutic Agents This invention relates to novel therapeutic agents useful as antidiabetic agents, particularly as hypoglycaemic agents, to processes for the preparation of such agents and to pharmaceutical compositions containing them. The present invention provides compounds of formula I: and their pharmaceutically acceptable salts in which n = 0 or 1; in which R-^ and R? , which are the same or different, are (a) an aliphatic group containing 1 to 3 carbon atoms, said aliphatic group being optionally substituted by methoxv (b) a cycloalkyl group containing 3 to 7 carbon atoms or (c) and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring of formula II ^ CHR„ 0 \ -N B ^ CH, ^ 11 in which Rg represents H or an alkyl group containing 1 to 3 carbon atoms and B represents an alkylene group of 2 to A carbon atoms optionally interrupted by oxygen, by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms or the substituents on two adjacent carbon atoms of the alkylene group form a benzene ring or B represents an alkenylene group of 3 carbon atoms; R^ is a straight or branched alkyl group containing 1 to 7 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms or a group of formula III in which R, and R' , , which are the same or different, H «-r are H or an alkyl group containing 1 to A carbon atoms; in which R^ is H or a straight or branched aliphatic group of 1 to A carbon atoms, said aliphatic group being optionally substituted by methoxy; in which Rg is (a) H, (b) a straight or branched aliphatic group of 1 to 6 carbon atoms optionally substituted by hydroxy or an acylated derivative thereof, by an alkoxy group containing 1 to 3 carbon atoms, by an alkylthio group containing 1 to 3 carbon atoms, by an optionally alkylated amino group, by a carbocyclic group containing 3 to 7 carbon atoms or by cyano or (c) a cycloalkyl ring containing 3 to 7 carbon 3. tiouts j sulphur, sulphinyl or NH optionally substituted N III / 24 r. - 3 - 2 3 1 9 5 or Che group and the group together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV R9 0 \ / C ::r:=:: C- D IV ^ I R6 in which R^ is as hereinbefore defined, Rg and R-j q , which are the same or different, are H or an alkyl group of 1 to 4 carbon atoms optionally substituted by methoxy and D is an oxyethylene group in which the oxygen atom is bonded to the carbon atom carrying the groups Rg and R-j q or an alkylene group of 2 to 5 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms; or the group R^ and the group R^ together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V in which is as hereinbefore described, in which R-j i is H or an alkyl group containing 1 or 2 carbon atoms, and E is an alkylene group of 2 to A carbon atoms optionally substituted by one or more alkyl groups - A - 2 3 1 9 5 containing 1 to 3 carbon atoms; or Rcj and together with the nitrogen atom to which they are attached form a heterocyclic ring of formula in which G is an alkylene group of A or 5 carbon atoms optionally interrupted by oxygen, sulphur or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; and Ry represents H or one or more optional substituents selected from halo, alkyl groups containing 1 to A carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkvlthio groups containing 1 to 3 carbon atoms, alkylsulphiny1 groups containing 1 to 3 carbon atoms, alkylsulphonyl groups containing 1 to 3 carbon atoms, alkoxycarbonyl groups containing a total of 2 or 3 carbon atoms, trifluoromethyl or cyano. In preferred compounds of formula I in which n = 0, R-j and R2. which may be the same or different, are selected from (a) alkyl groups of 1 to 3 carbon atoms optionally substituted by methoxy (b) allyl groups or (c) cvclohexyl groups. In particularly preferred compounds of formula I in which n = 0 , R^ and are both alkyl, allyl or 2-methoxyethvl or R^ is methyl and R2 is 2-methoxyethy1 or cyclohexyl. In especially preferred compounds of formula I in which n = 0 , the group NR-j R2 is dimethylamino, die thy lamino, diallyl-amino, (2-methoxyethyl)methylamino, cvclohexylmethyl- VI G 2 3 19 5 0 '"■"i ~,y amino or bis ( 2-methoxvcthvl) amino In preferred compounds of formula I in which n = 0 and in which the group MR, R0 is a heterocyclic ring represented by formula II, Rg represents H or methyl 5 and B represents a group selected from -(CH0)0-, -CHMeCH0-, o-phenylene, -CH9CHMeCH9-, -(CH0)a-. -CH90CH2-, -CHMeOCHMe-, -CH9SCH2-, -CH-,S(0)CH0-, -CH?NMeCK9- or -CH=CHCH9-. In especially preferred compounds of formula I in which n = 0 and the 10 group NR|R9 is a group of formula II, the group NR^R9 is 1-pyrrolidinvl, 2-methyl-l-pyrrolidinyl, piperidino, 4-methvlpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethvlmorpholino, thiamorpholino , thiamorpho1ino- 1 -oxide, 2-isoindolinv1, U-methyl-1-piperazinyl or 15 1-(1.2,5,6-tetrahydro)pyridvl. In preferred compounds of formula I in which n = 1 , the group NR-j R2 is morpholino or thiamorpho1ino. In preferred compounds of formula I in which R^ is an alkyl group, the group R^ contains 1 to 5 carbon 20 atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, _t-butyl or pentyl). In preferred compounds of formula I in which the group is a cycloalkyl group, the cycloalkyl group is cvclohexyl. In preferred compounds or formula I in which R2 is 25 a group of formula III, R^ and R^ ' are H, methyl or ethyl (for example R^ is amino, methylamino, dimethvl-amino or ethvlamino). In preferred compounds of formula I in which the group Rj- does not form part of a heterocyclic ring, the 30 group R<- is H or an alkyl group containing 1 to 3 carbon atoms (eg methyl or ethyl) optionally substituted by methoxy (og is mechoxyethyl) or allyl. In preferred compounds of formula I, Rg is H or a straight or branched alkyl group containing 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropvl, butyl, isobutyl, sec-butyl, tert-bucv1 or pentvl) optionally substituted by hydroxy (e.g. Rg is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropy1, 2-hydroxybuty1, 2-hvdroxy-2-methylpropy1, or 2,3-dihvdroxypropyl), by an acylatec derivative of hydroxy such as acetyloxy or bennoyloxy (e.g. Rg is 2-acety loxyethy I or Z-ber.zoy loxyethvl) by methoxy (e.g. Rg is 2-methoxvethy1) . by methylchio (eg Rg is 2-methy Ithioethy 1) , by dime thy lamir.c (e.g. Rg is 2-dimethylam: r.ce chy!) , by phenyl (e.g. Rg is benr.yl or 2-Dhenvlethvl) or bv cvano (e.g. is 2-cvanoethvl) or 0 Rg is a straight or branched alkeriyl group containing 3 to 6 carbon atoms (e. g. Rg is ally! or 2-me chy 1- In preferred compounds of formula I in which R,- is r • c a cycloalkyl group. Rg contains 5 or 6 carbon atoms (e.g. Rg is cyclopentvl or cyclohexyl). In particularly preferred compounds of formula I in which the groups R^ and R^ together with the nitrogen and carbon atoms to which they are attached do not form a heterocyclic ring, the group -^CCR^NR^Rg is : - acetamidino, N-methylacetamidino, N,N-dimethylace tamidino, N,N-diethylacetamidino, N-(2-acetyloxyethy!)acetamidino, allyl). N-butylacetamidino, N-pentylacetamidino, o\\ N-me thyIprop ionamidino, N,N-dimethylpropionamidino N-ethvlpropionamidino, butyramidirto , N-mechylbutvramidino, N,N-dimechylbutvramidino, N-ethvlbutyramidino, isobutyramidino, N-mechy1 isobutyramidino, N,N-dimethylisobutyramidino, valeramidino, N-methylvaleramidino, N,N-dimethvlvaleramidino, pivalamidino, N-methyIpivalamicino, N,N-dimethyIpivalamidino, N-methyleaproamidino N-methyleyelohexanecarboxamidino, diaminomethyleneamino, N-methylguanidino, N,N-dimethylguanidino, N,N'-dimethvlguanidino, N-ethvlguanidino, N-butylguanidino, N-ethyl-N-methylguanidino, N,N-diethylguanidino, N,N1-diethylguanidino, N,N',N'-trimethylguanidino, 1,1,3,3-tetramethylguanidino, N-ethy1-N'-methylguanidino, 1-ethyl-1,3,3-trimethylguanidino, 1-butyl-1,3,3-trimethylguanidino, N-methyl-N-propylguanidino, N-butyl-N-methylguanidino, N-sec-butyl-N'-methylguanidino, N-tert-butyl-N'-methylguanidino, - 8 - 23195 N-isobutvl-H'-methylguanidino. N-butyl-N'-methylguanidino, N-butyl-N'-ethylguanidino, N-methy1-N'-pentvlguanidino, 5 N-cvclopentyl-N'-methylguanidino, N-(2-methoxyethy 1)guanidino, N-(2-methoxyethyl)-N-methylguanidino, N-(2-methoxyethyl)-N'-methylguanidino, N-ethyl-N-(2-methoxyethy 1)guanidino, 10 N,M-bis(2-methoxyethyl)guanidino, N-methyl-N-(2-me thy1thicethy 1)guanidino , N-allyl-N-methyLguanidino, N-allyl-N'-methylguanidino, 1 -allyl-1 .3,3-trimethylguanidino, 15 N,N-diallylguanidino, In one group of preferred compounds of formula I in which the groups and R^ together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV, Rg and R-jg, which may 20 be the same or different, are H or alkyl groups containing 1 to 3 carbon atoms (for example methyl, ethyl or isopropyl) optionally substituted by methoxy (eg Rg and/or R-| q are methoxyethyl) , D is selected from -(CH2)o- , -(CH2)3-, -(CK9)4-, -(CH2)5 - , -CH2CMe2- or 25 -0(CH2)2- and the group Rg is preferably H, methyl, ethyl, isopropyl, cvclohexyl, 2-cyanoethyl, 2-acetoxyethyl or 2-methoxyethyl. In particularly preferred compounds of formula I, formula IV represents:- 30 2-pvrrolidinylidene, 1-methyl-2-pyrrolidinylidene, 3-methyl-2-pyrrolidinylidene, 1-ethvl-2-pyrrolidinylidene, 1-isopropyl-2-pyrrolidinylidene, 35 1-cyclohexyl-2-pyrrolidinylidene, - Q - 2 3 1 Q z 1 w •.> 1 -(2-methoxyethv1)-2-pyrrolidinyXidene, 1 ,3-dimethy 1-2-pyrrolidinylidene, 5,5-dimethy 1-2-pyrrolidinylidene , 1 ,3,3-trimethy 1-2-pvrrolidinylidene , 5 1 ,5,5-trimethyl-2-pyrrolidinylidene, 3-isopropvl-l-methy1-2-pyrrolidinylidene, 1-ethyl-3 , 3-dimethyI-2-pyrro1idinylidene, 3,3-diethyl-l-methyl-2-pyrrolidinylidene, 2-piperidinylidene, 10 1-methyl-2-piperidinylidene, 1,3-dimethvlpiperidinylidene, 1-ethyl-2-piperidinylidene, 1-isopropyl-2-piperidinylidene, 1 -(2-cyanoethy1)-2-piperidinyLidene, 15 1 -(2-acetoxvethy1)-2-piperidinv1idene, 3-(2-methoxyethyl)-1-methyl-2-piperidinylidene, 2-hexahydroazepinylidene, 1-methyl-2-hexahydroazepinylidene, 2-octahydroazocinvlidene or 20 3-morpholinvlidene. In a second group of preferred compounds of formula I in which the groups and together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V, 25 E is -CH9CH2-, -CMe2CH0-. -CHMeCHMe-, -(CH9)3~, CH>!eCH9- or ~(CH9)Zi, R-j -j is H, methyl or ethyl and R& is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethvl, 2-acetoxvethyl, 2-benzovloxvethyl, 2-methoxyethyl, 30 cyclohexyl, benzyl, phenethyl, 3-hydroxypropyl, 2-hydroxvpropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-butvl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl. In particularly preferred compounds of formula I, formula V represents:- - 10 - 2-imidazolidiny1idene, 1-methyl-2-imidazolidinylidene, A-methyl-2-imidazolidinylidene, A , A - dime thy 1-2 - imidazolidiny lidene . 5 A,5-dime thy 1-2-imidazolidiny1idene. 1-echv1-2-imidazolidinylidene, 1-propyl-2-imidazolidinylidene, 1-isopropyl-2-imidazolidinvlidene, l-(n-butvl)-2-imidazolidinylidene, 10 1-isobutyl-2-imidazolidinvlidene, 1-pentyl-2-imidazolidinylidene , 1-ally 1-2-imidazo1idiny1idene, 1 -(2-me thy la 1!y1)-2 -imidazo1idiny1idene, 1 -(2-hydroxye chy1)-2 -imidaz olidiny1idene, 15 1 -(2-hydroxyethyI)-3-me thy 1- 2 -imidazo1idinylidene, 1 -(2-ace toxye chy1)-2 -imidazo1idiny1idene, 1 -(2-benzoyloxye thy1)-2 -imidazolidiny1i dene, 1 -(2-benzovloxyethy1)-3-methy1-2-imidazolidinvlidene, A,5-dime thy 1-1 -(2-hydroxye chyI)-2-imidazolidinylidene, 20 1 -(2-methoxyechv1)-2-imicazolidinylidene, 1 - (2 - me thoxye thy 1) -3 -me thy 1 -2 - imidazo 1 idiny l.i dens . 1-cyclohexyl-2-imidazolidinylidene, 1-benzyl-2-imidazolidinvlidene , 1 -(2-phenylethyl)-2-imidazolidinylidene , 25 1 - ( 2-dimethylaminoechyl) -2-ir.idazolidinylidene , 1 -(3-hydroxvpropyl)-2-imidazo1idinylidene, 1 -(2-hydroxvpropyl)-2 -imidazoIidiny1idene, 1 -(2-hydroxy-2-methyIpropyl)-2-imidazolidinylidene, 1 -(2-hydroxybuty1)-2-imidazolidinylidene, 30 1 -(2,3-dihydroxvpropy1)-2-imidazolidinylidene, 1 ,3-dime thy1-2-imidazolidinylidene, 1 ,3-diethyl-2-imidazolidinylidene, 1 -ethyl-3-methyl-2-imidazolidinylidene, 1 -butyl-3-methyl-2-imidazolidinylidene, -•~3'5~~,">lvrisopropyl-A , A -dimethyl-2-imidazolidinylidene , T'-miethyl-2-perhydropyrimidinylidene or 1 , ?r-diazacycloheptane-2-yl idene. 4 SEP 19 9 ir ■ <r. /' -11- 2 3 1 9 5 In preferred compounds of formula I In which and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI, G represents a group selected from -(CH9)^-, -(CH0)^-, -(CH9)20(CH9)9-, -(CH9)9S(CH9)9-, -(CH0)9NMe(CH~)2-, - (CHo ) .-,CHMe (CH9 ) 0 - or -CH9CHMeOCHMeCH9*~- . *" In particularly preferred compounds, the group NR^Rg is 1-pvrrolidinyl, piperidino, 4-methyIpiperidino , morpholino, 2,6-dime thylmorpholino, thiamorpholino or 4-methyl-1-piperaziny1. In particularly preferred compounds of formula I in which R^ and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI, the group -N=C(R„)NR,R, is:-j 5 6 N ,N- (3-oxapentar.ethvlene ) guar, id ino , 1 ,1 -dimethyl-3,3-(3-oxapentame thylene)guanidino, N,N-(2,4-dime thy 1-3-oxapentame thylene)guanidino, N,N-(3-thiapentame thylene)guanidino, M,N-(3-methylpentame thylene)guanidino, N,N-(N-methyl-3-azapentamethvlene)guanidino, N-methyl-N',N'-tetramethyleneguanidine, N,N-pentamethyleneguanidino, 1 ,1-dimethyl-3,3-pentamethyleneguanidino. In preferred compounds of formula I, Ry represents H or one or more substituents (preferably one or two substituents) selected from fluoro, chloro, methyl, ethyl, isobutyl . nethylthiomethyl, methoxy, dimethoxy, methoxycarbonyl , methvlthio, methylsulphinyl, methyl-sulphonyl, trifluoromethv1 or cyano. Specific compounds of formula I are 4 - [ 2 - (2-piper id iny lideneamino) phenyl ] rr.orpholine 4 -[2-(1 -methyl-2-piperidinylideneamino)phenyl]-morpholine 4 - ( 2 - (1-e thy1-2-piperidinylideneamino)phenyl]-morpholine 4 - [ 2-(1 - isopropy 1-2-piperidinylideneamino)phenyl]-morpholine 4 -[2 -(2-hexahydroasepinylideneamino)phenyl]norpholine 4-[2-(1-me thy1-2-hexahydroazepinylideneamino)phenyl]-morpholine 4 -[2-(2-oc tahydroazoc inylideneamino)phenyl]morpholine 4-[2-(2-pyrrolidinylideneamino)phenyl]morpholine 4 -[2 -(1-methy1-2-pyrrolidiny1ideneamino)phenyl]-morpho1ine 4 -[2-(1 ,3-dimethy1-2-pyrrolidinylideneamino)- phenyl]morpholine 4 - [ 2 - M .3,3 -trime thy1-2-pyrrolidinylideneamino)- phenyl]morpholine 4 -f 2- (1-ethy 1-2-pyrrolidiny1ideneamino)phenyl]-morpholine 4 - £ 2-[1 -(2-methoxyethyl)-2-pyrrolidiny1ideneamino]- pheny1)morpholine 4 -[2-(1-cvclohexv1-2-pyrrolidinylideneamino)phenyl] -morpholine 4-[2-(3,3-dimethyl-l-ethyl-2-pyrrolidinylideneamino) phenyl]morpholine 4 -[2 -(3 ,3-diethyl-l-methyl-2-pyrrolidinylideneamino)- pheny1]morpho1ine 4 -[2 -(3-isopropyl-1-methy1-2-pyrrolidinylideneamino) phenyl]morpholine 4-[2-(1 , 3-dimethy1-2-piperidinylideneamino)phenyl]-morpholine 4 -[3-methy 1-2-(2-piperidinylideneamino)phenyl]-morpholine 4 -[3-methy1-2 -(1-methyl-2-piperidinylideneamino) phenyl]morpholine 4 -[4-methyl-2-(2-piperidiny1ideneamino)phenyl]-morpholine 4 -[4-methyl-2 -(1-methy1-2-piperidinylideneamino)-phenyl]morpholine m - 13 - 23105 4-[5-methyl-2-( 2 - p iper idinv 1 ideneamino) pheny 1 ] -morpholine 4-[6-methvl-2-(2-piperidinylideneamino)phenyl]-morpholine 5 4-[4-ethyl-2-(2-piperidinylideneamino)pheny1] morpholine 4-[3-chloro-2-(2-piperidiny1ideneamino)phenyl]-morpholine 4-[4-chloro-2-(2-piperidinylideneamino)phenyl]-10 morpholine 4-[A-chloro-2-(l-methy 1-2-piperidiny1ideneamino) pheny1]morpholine 4 - [ 5-chloro-2-(2-piperidinylideneamino)pheny1]-morpholine 15 4-[6-chloro-2-(2-piperidiny1ideneamino)phenyl]-morpholine 4-(4-fluoro-2-(2-piperidinylideneamino)pheny1]-morpholine 4-[4-fluoro-2-(1-methyl-2-piperidinylideneamino)-20 phenyl]morpholine 4-[4-methoxy-2-(2-piperidinylideneamino)phenyl]-morphol ir.e 4 -[4-methoxvcarbonyl-2-(2-piperidinylideneamino) phenyl]-morpholine 25 4 -[4-methylsulphonyl-2-(2-piperidinylideneamino) pheny1]morpholine 4_(2 -[1 -(2-acetoxyethvl)-2-piperidinylideneamino]- phenyl)morpholine 4 - (2-[ 1 -methy1-3-(2-methoxyethyl)-2-piperidinylidene■ 30 amino]phenyljmorpholine 4 -[2 -(3-methy1-2-pyrrolidinylideneamino)phenyl]-morpholine N-methyl-N'-(2-morpholinophenyl)acetamidine N-(2-morpholinophenyl)-N'-propvlacetamidine 35 N-(n-butyl)-N'-(2-morpho1inopheny1)acetamidine - 14 - 2 3 1 " N-(n-pentvl)-N'-(2-morpholinophenvl)acetamidine N-(2-ace toxyethy1)-N'-(2-morphoIinophenvl)-ace tamidine N,N-dimethy1-N'-(2-morpholinophenvl)acetamidine N,N-diethyl-N1-(2-morpholinopheny1)acetamidine N-methy1-N'-(2-morpholinopheny1)propicnamidine N-ethyl-N'-(2-morpholinophenvl)prop ionamidine N,N-dime thyl-N'-(2-morpholinophenvl)propionamidine N-methy1-N'-(2-morpho1inopheny1)butvramidine N-ethy1-N1 -(2-morpholinopheny1)butyramidine N,N-dimethyl-N ' -(2-morpho1inopheny1)butyramidine N-methy1-N'-(2-morpholinopheny1)-2-methvl- prop ionami dine N,N-dimethyl-N'-(2-morpholinopheny1)-2-methvl- prop ion ami dine N-methy1-N'-(2-morpholinopheny1)valeramidine N,M-dimethy1-N'-(2-morpholinophenvl)valeramidine N-methy1-N'-(2-morpholinopheny1)pivalamidine N,N-dimethy1-N1 -(2-morpho1inophenvl)pivalamidine N-methy1-N'-(2-morpholinopheny1)hexaramidine N-methy1-N'-[2-(1 -pyrro1idiny1)phenyl]butyramidine N-methy1-N'-[2-(1 -pyrro1idiny1)phenyl]pivalamidine N-methyl-N'-(2-morpholinophenyl)cyclohexane carboxamidine N-methyl-N'-(2-piperidinopheny1)pivalamidine l-[2-(2-piperidinylideneamino)phenyl]pyrrolidine 1 -[2-C1-methy1-2-piperidinylideneamino)phenyl]-pyrrolidine 1 -[2-f1-ethy1-2-piperidinylideneamino)phenyl]-pyrrolidine 1 -[4-chloro-2-(1-methyl-2-piperidinylideneamino)- phenyl]pyrrolidine 1 -[3-methy1-2-(1 -methyl-2-piperidinylideneamino)- phenyl]pyrrolidine 1 -[2-(1-methy1-2-pyrrolidinylideneamino)phenyl]-pyrrolidine - 15 - 2 3 19 10 1 5 20 25 30 35 -[2-(1 , 3 -dime thy 1-2 -pyrrol iciiny lideneamino) pheny I] -pyrrolidine -[2 -(1-methy I-2-hexahvdroazepiny1ideneamino)pheny1]-pyrrolidine -[4-methyl-2-(2-piperidinylideneamino)phenyl]-pyrrolidine -[4-chloro-2-(2-piperidinvlideneamino)phenyl]-pyrrolidine -[3-methy1-2-(2-piperidinylideneamino)phenyl]-pvrrolidine -[6-tnethvl-2-( 2-piperidinv 1 ideneamino)phenvl ] -pyrrolidine -[2-(2-piperidinylideneamino)pheny1]thiamorpholine -[2-(2-piperidinylideneamino)phenyl]piperidine -[2-(l-methyl-2-piperidinylideneamino)phenyl]-piperidine 1 -[2-(2-piperidinylideneamino)pheny1]hexahydroazepine 2,6-dimethyl-4-[2-(2-piperidinylideneamino)pheny1]- morpholine 4-methy 1-1 -[2 -(2-piperidinylideneamino)phenyl]-piperidine 1-[2-(2-piperidinvlideneamino)pheny1]-1,2,5,6-tetrahydrcpvridine 2-methyl-l-[2-(2-piperidiny1ideneamino)pheny1]-pyrrolidine 2 -[2-(2-piperidinylideneamino)pheny1]isoindoline 4 -[2-(1-methy1-2-piperidinylideneamino)phenyl 1 - thiamorpholine 4 -[4-methyl-2-(2-piperidiny1ideneamino)- phenyl]thiamorpholine N-(2-methoxyethyl)-N-[2-(2-piperidinylideneamino)- pheny1]me thylamine N-[2-(2-piperidinylideneamino)phenyl]dimethylamine N-[2-(2-piperidinylideneamino)phenyl]diallylamine N-cyclohexyl-N-[2-(2-piperidinylideneamino)phenyl]-methylamine \ - 16 2 3 1 95 N- [ 2-(2-piperidinylidineamir.ophenyl) -bis- (2-methoxy-ethyUamine A -(2-(1 ,3,3 -trime thy1-2-pyrro1idiny1 idineamino)-phenyl]thiamorpholine 5 1 - [ 2- (1 ,3,3-trimethyl-2-pyrrolidinylidineamino) -pheny L ] p iperidir.e 1 - [ 2 - (1 ,3 , 3-trirr.ethyl-2-pyrrol idiny 1 id ine amino) phenyl ] 4-methvIpiperacine 1 - [2-(1 ,3,3-trimethy 1-2-pyrro1idinylidineamino)-10 phenyl]pyrrolidine 4-[4-mechvl-2-(l ,3,3-trimethy 1-2-pyrrolidiny 1 ideneamino) phenyl]morpholine 1 -[2-(1-methy1-2-pyrrolidiny1ideneamino)phenyl ] -piperidine 15 1 - [ 2- (1 , 3 - dime thy 1 - 2 - pyrrolidir.vlideneamino)pheny 1 ] -piperidine 4 -[2-(5,5-dimethy 1-2-pvrrolidinylideneamino)phenyl]-morpholine 4 -[1 ,5,5-trimethy1-2-pyrrolidinylideneamino)phenyl]-20 morpholine N —[2 — (1 ,3,3-trimethy1-2-pvrrolidinylideneamino)phenyl] bis-(2-methoxyethvl)amine N-(2-morpholinopheny!)acetamidine N-(5-methy1-2-morpholinophenvl)acetamidine 25 N-(2-morpholinophenyl)propionamidine N-(2-morpholinopheny1)butyramidine N-(2-morpholinophenvl)isobutvramidine N-(5-me thylthio-2-morpholinopheny1)isobutyramidine N-(5-fluoro-2-morpholinopheny1)isobutyramidine 30 N-(2-morpholinophenyl)valeramidine N-(2-morpholinophenyl)pivalamidine 4-(2-[1 -(cyanoethyl)-2-piperidinylideneamino] phenyl)-morpholine 4 -[2-(3-morpholiny!ideneamino)phenyl]morpholine 35 4 -[2-(2-piperidinylideneamino)benzyl] morpholine 4-[2-(1-methy1-2-pyrro1idinylideneamino)benzyl] -morpholine -17- 23 19 4-[4-chloro-2-(2 -piperidinylideneamino)benzy1 ] -morpholine 4 -(2 -(1 ,3,3 -trimeChy1-2-pyrrolidinylideneamino)- benzyl]morpholine N-mechy1-N'-(2-morpholinomethy1pheny1)pivalamidine A - [ 2 - (1 , 3-dime thv 1.-2 -imidazol idiny lidene amino) phenyl ] -morpholine A -[2 - (1 ,3-dime thy1-2-imidazolidinylideneamino)-A - fluorophenyl]morpholine A -[2 - (1 ,3-dimethy1-2-imidazolidinylideneamino)-3- methy 1pheny1]morpholine A -[2 -(1 , 3-dime thy1-2 -imidazolidinylideneamino) - A - methylpheny1]morpholine 4 -(2 -(1 ,3-dimethyl-2-imidazolidiny1ideneamino) - 5 - methylphenyl]morpholine 4 -[4-chloro-2-(1 ,3-dimechy1-2-imidazolidinylideneamino) phenyl]morpholine 4 - [ 2 - (1 ,3-dimethyl-2-imidazolidiny1ideneamino)-A - methoxvpheny1]morpholine 4 — [4,5-dimethoxv-2-(1 ,3-dimethvl-2-imidazolidinylidene amino)phenyl]morpholine 1 -[2 -(1 ,3-dimeChy1-2-imidazolidinylideneamino)phenyl]-pyrrolidine 1 -[2 -(1 ,3-dimeChy1-2-imidazolidinylideneamino)-3-me thy1pheny1]pyrrolidine 1 -[2 -(1 ,3-dimeChy1-2-imidazolidinylideneamino)phenyl]-piperidine 4-[2-(l ,3-dimeChy1-2-imidazolidinylideneamino)phenyl]- Chiamorpholine 2,6-dimeChy1-4 -[2-(1 ,3-dimeChy1-2-imidazolidinylideneamino) phenyl ] morpholine N-[2-(1,3-dimethy1-2-imidazolidinylideneamino)phenyl]-diechylamine 1 -[2 -(1 ,3-dimeChy1-2-imidazolidinylideneamino)phenyl]-2-meChylpyrrolidine - 18 - 2 3 19 4-[3-chloro-2-(1,3-dimechy1-2-imidazolidinylidene- amino)phenyl]morpholine 1 - [2- (1 ,3-dimeChy1-2-imicazolidinylideneamino)-4- ne thy1pheny1]pyrrolidine N-[2-(1,3-dimechy1-2-imidazolidinylideneamino )phenyl]-bis-(2-mechoxyethyl)amine 4 -[2-(1 ,3-diethyl-2-imida-olidiny1ideneamino)phenyl morpholine 4 -[2 -(1 .3-dime thy 1-2-imidazo1idiny1ideneamino)-6- rr.e thyl pheny 1 ] pyrrolidine 4 -[2 -(1 -ethy 1-3-me thy 1-2-imidazolidiny1ideneamino)- phenyl]morpholine 4 -[2 -(1-n-buty1-3-me thy1-2-imidazolidiny1ideneamino phenyl]morpholine 4 - £ 2 - [1-(2-benzoyloxyethyl)-3-methvl-2-imidazolinyl ideneamino]pheny1)morpholine 2-(2-morpholinophenyl)-1 ,1 ,3 , 3-tetramethylguanidine 1-echvl-2-(2-morpholinophenyl)-1 ,3,3-trimethvl-guanidine 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethy1-guanidine 1-n-buty1-2-(2-morpholinopheny1)-1 ,3,3-trime thy1-guanidine 1-pentyl-2-(2-morpholinophenyl)-1 ,3 , 3-trimethyl-guanidine 4-^2-[1-methy1-3-(2-methoxyethyl)-2-imidazolidinylidene amino ]phenyl)morpholine 4 - f 2 - [1-methvl-3-(2-hydroxyethy1)-2-imidazolidinylidene amino ]phenyl)morpholine N,N-dimethy1-N1 -(2-morpho1inophenvl)morpholine-4 - carboxamidine N,N-dimethy1-N'-(2-morpho1inopheny1)piperidine-1- carboxamidine 4 -[2-(1 ,3-dimethy1-2-imidazolidinylideneamino) phenyl]thiamorpholine-1-oxide 4 -[2 -(2-imidazolidinylideneamino)phenyl]morpholine - 19 - 2 3 19 5 A -[2-(1-meChy1-2-imidazolidiny1ideneamino)phenyl1 -morpholine 4 -[2-(1-ethyl-2-imidazolidiny1ideneamino)phenyl]-morpholine 4 -[2-(1-n-propvl-2-imidazolidinylideneamino)phenyl]-morpholine 4 - [ 2 - (1 -i.sopropyl-2- imidazol idiny lideneamino) pheny 1 ] -morpholine 4 - [2 -(1-n-bucy1-2-imidazolidinvlideneamino)phenyl]-morpholine 4 -[2-(1-isobutyl-2-imidazolidinylamino)phenvl]-morpholine 4 -[2-(1-pency1-2-imidazolidinylamino)phenyl]-morpholine 4 -[2-(1-a 1ly1-2-imidazolidiny1ideneamino)phenyl]- 4 -(2 -[1 -(2-hydroxvethy 1)-2-imidazolidinylideneamino] phenyl)morpholine 4 -^ 2 -[1-(2-hydroxvechy1)-2-imidazolidinylideneamino]-3- me chyIphenv1)morpholine 4 -(2 -[1 -(2-mechoxyechy1)-2 -imidazolidiny1ideneamino] phenyl)morpholine 4 -[2 -(1-cyclohexy1-2-imidazolidinylideneamino)pheny1]-morpholine 4 -[2 -(1-benzyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-(2-[1 -(2-phenvleChyl)-2-imidazolidinylideneamino]- phenyl)morpholine 4-f 2-[1 -(2-dimeChylaminoechyl)-2-imidazolidinylideneamino ]phenyl)morpholine 4-(2-[1 -(2,3-dihydroxypropy1)-2-imidazo1idinylideneamino ]phenyl)morpholine 4-(2-[ 1 -(2-methylallyl)-2-imidazolidinylideneamino]- phenyl)morpholine N-[2-(1-methy1-2-imidazolidinylideneamino)phenyl]bis- (2-methoxyethy1)amine N-(2-[1 -(2-hydroxyethyl)-2-imidazolidinylideneamino]-phenyl)bis-(2-methoxyethyl)amine 2 319 A-[2-C1-meChy1-2 -imidazolidinylideneamino)phenyl ] chiamorpholine 1 -[2 -C1-mechyl-2-imidazolidinvlideneamino)phenyl] pyrrolidine 5 A - f2-(1-n-bucy1-2-imidazolidinylideneamino)phenyl ] -Chiamorpholine A-[2-(1-mechyI-2-imidazolidinvlideneamino)- 3-mechy1-pheny1]morpho1ine -—v A - [ 2 -(1 -meChy1-2-imidazo1idinylideneamino)-A-methyl- 10 phenyllmorpholine 1 -^ 2 -[1 -(2-hydroxyethyl)-2-imidazolindinylideneamino] phenyl)pyrrolidine 1 -(2 -[ 1 -(2-hydroxve chy1)-2 -imidazolindinylideneamino] pheny1)- 2-me chylpvrrolidine 15 A -[A-mechy1-2 -(1-n-bucy1-2-imidazolidinylidene) -phenyl]morpholine 1 -[2-(2-imidazolidinylideneamino)phenyl]piperidine 1 -[2-(1-methy 1-2-imidazolidiny1ideneamino)phenyl] -piperidine 20 1 -[2-(1 -meChyl-2-imidazolidinylideneamino)-3-methyl-phenvl]piperidine A -{ 2-[1 -(2-hydroxvethy1)-2-imidazolidinylideneamino ]phenyl)thiamorpholine 1 -(2-[1 - (2-hydroxyethyl)-2-imidazolidiny1idene-25 amino]pheny1)piperidine A-(2-[ 1 -(3-hydroxypropy1)-2-imidazolidinylideneamino] phenyl)morpholine A -[ 2 -[1 -(2-hydroxypropy1)-2-imidazolidinylideneamino] phenyl)morpholine 30 A -^ 2-[1 -(2-hvdroxybutyl)-2-imidazolidinylideneamino] -phenyl)morpholine A -(2-[ 1 -(2-hydroxy-2-meChylpropyl)-2-imidazolidinylideneamino] phenyl)morpholine A -[2-(A-meChy1-2 -imidazolidinylideneamino)phenyl ] -35 morpholine - 21 - 23 1 g 5 A -[2-(4,5-dimechyL-2-imidazolidinylideneamino)phenyl] morpholine 4 - f 2 - [ 4,5-dime thy I-1-(2-hydroxyethyl)-2-imidazolidinyl ideneamino]pheny1)morpholine 5 4-[2-(1-isopropyl-4i4-dime chy1-2-imidazolidinylideneamino) pheny 1 ] morpholine 4 -[2 -(1-meChylperhydropvrimidin-2-ylideneamino)- phenyl]morpholine 2 -(2-morpholinophenylimino)-1 ,3-diazacyclohepcane 10 1,1-dimeChvl-2-(2-morpholinophenyl)guanidine 1,3-dimeChyl-2-(2-morpholinophenyl)guanidine 1,3. 3-CrimeChy1-2-(2-morpholinopheny1)guanidine 1-eChy1-2-(2-mornholinophenvl)-3-methyl-guanidine 15 1,3-diechy1-2-(2-morpholinopheny1)guanidine 4 -f 2-[1 -(2-acecyloxyechy1)-2 -imidazolidiny1ideneamino] phenyl)morpholine 4 - (2 - [1-(2-benzcvloxye Chyl)-2-imidazc1idinylideneamino] pheny1)morpholine 20 1-(n-butyl)-2-(2-morpholinophenvl)-3-methyl-guanidine 1 -(2-mechoxyeChyl)-2-(2-piperidinophenyl)guanidine 1 - (2 -me chy lchioe chy 1) - 2- (2. -mo rpho lino pheny 1) guanidine 1 -(2-mechoxyechyl)-2-(2-morpholinephenv1)guanidine 25 1 -(n-propvl)-2-(2-morpholinophenyl)-3-methyIguanidine 1 -(2-mechoxyechyl)-3-meChy1-2 -(2-morpholinophenyl) guanidine 1-cyclopencyl-2-(2-morpholinopheny1)-3-meChy1-guanidine 30 N-methy1-N'-(2-morpholinophenvl)pyrrolidine-1 -carboxamidine 1 -(n-butyl)-2-(2-morpholinophenvl)-3-ethyIguanidine 1,3-dimethy1-2-(5-chloro-2-morpholinophenyl)guanidine 1-allyl-2-[2-(1-pyrrolidinyl)phenyl]-3-35 methylguanidine 1,3-dimethyl-2-(5-methy1-2-morpholinophenvl)- 22 10 15 20 25 30 35 9 7'i i 9 5 guanidine 4 - f 2 - [ 1 -(2-hydroxvechy1)-2 -imidazo1idiny1ideneamino]-4-mechy1pheny1)morpho Line -meChyL-2-(2-morphoLinophenyL)-3-(n-penCvL)guanidine -(n-butyL)-2-(5-me chy L-2-morphoLinophenyL)-3 - meChylguanidine -(n-bucyL)-2-(6-mechvL-2-morphoLinopheny1) - 3 - meChylguanidine -(n-bucyl)-2-(5-fluoro-2-morpholinopheny1)-3 -me ChyIguanidine -(n-buCyl)-2-(5-meChylchio-2-morpholinophenyl)-3-mechyIguanidine -isobutvl-?. - (2 -morphol inopheny 1) -3-me Chy Iguanidine -sec-buCvl-2-(2-morpho1inophenvl)-3-meChyIguanidine -cert-bucyl-2-(2-morpholinophenyl)-3-mechyIguanidine -allyl-2-(2-morpholinophenyL)-3-meChvLguanidine -(n-buCvL)-2-(2-chiamorphoLinophenvl)-3-meChylguanidine ,1-dimechyL-2-(2-morphoLino-5-CrifiuoroneChvL-phenyl)guanidine , 1 - dimeChy1-2 -(5-cvano-2-morpho1inopheny1)guanidine ,3-di-(n-propy1)-2-(2-morpholinophenvl)guanidine -(2-morpholinopheny1)guanidine ,1-dimeChyl-2-(5-meChyL-2-morpholinophenvl)-guanidine ,1-dimeChy1-2-(6-mechy1-2-morpholinophenyl)-guanidine ,1-dimeChyl-2-(4-chloro-2-morpholinophenvl) guanidine ,1-dimeChyl-2-(3-chloro-2-morpholinophenvl)-guanidine , 1 -dimechyl-2-(5-meChoxv-2-morpholinophenyl)-guanidine ,1-dimeChy1-2-(5-methylchio-2-morpholinophenyl)-guanidine 1 ,1 -dimeChyl-2-(4-mechyl-2-morpholinophenyl)guanidine 2 ^ 1 n R 1 ,1 -dime Chy I-.? - (5-eChyl-2-morpholinophenyl) guanidine 1 ,1 -dimeChyL-2-( 5-me chy 1 chiorr.e chy 1-2-morpho 1 inopheny 1) guan idine 1 ,1 -dieChyl-2-(2-morpholinophenyl)guanidine 5 1 -(n-bucyl) -1 -methyl-2-(2-morpholinophenyl)guanidine 1,1-bis(2-meChoxvechy1)-2-(2-morpholinophenyl)-guanidine N-(2-morpholinophenyl)morpholine-4-carboxamidine N - ( 2 -morpho lino pheny Dpvrrolidine-1 - carboxamidine 10 1 ,1-dimeChyl-2-(2-piperidinophenyl)guanidine 1 ,1 -dimeChy1-2-[ 2 - (1-pyrrolidinyl)phenyl]guanidine 1,1-dimeChvl-2-(2-chiamorpholinophenyl)guanidine 1 ,1 -dimethyl-2-(2-dimechylaminophenyl)guanidine 1 ,1 -dime thy 1-2-(2-[N-(2-methoxvethy 1)-N-methylamino] 15 pheny1Iguanidine 1 ,1 -dimeChy1-2 -[2 -(4-meChy1-1 -piperazinyl)phenyl] guanidine N-(2-piperi dinopheny1)morpholine-4-carboxamidine N-(2-piperidinophenyl)piperidine-1 -carboxamidine 20 1,1-dimethvl-2-(5-methoxycarbonvl-2-morpholino-phenyDguanidine 1 -methy 1-2-(2-morpho1inopheny1)guanidine 1 -echy1-2-(2-morpholinophenyl)guanidine 1 -buty1-2-(2-morpholinophenyl)guanidine 25 1 -ethyl-1-methy1-2-(2-morpholinophenyl)guanidine 1 -methyl-1-(2-methylthioethyl)-2-(2- morpholinopheny1)guanidine 1 -(2-methoxyethyl)-1-meChy1-2-(2-morpholinophenyl) guanidine 30 1 -ally1-1-methy1-2-(2-morpholinopheny1)guanidine 1 -eChy1-1-(2-meChoxyeChyl)-2-(2-morpholinophenyl) guanidine 1 ,1 -diallvl-2-(2-morpholinophenyl)guanidine N-(2-morpholinophenyl)-4-methylpiperazine-l-35 carboxamidine 23 1950 N-(2-morpholinopheny1)-2,6-dimeChylmorpholine-4- carboxamidine N-(2-morpho1inophenvl)chiamorpholine-4-carboxamidine N-(2-morpholinophenvl)-4-mechylpiperidine-1-carboxamidine N - (2-morpholinipheny1)chiamorpho1ine-1-carboxamidine 1,1-dimeChyl-2-(5-chloro-2-morpholinophenyl)guanidine 1 ,1-dimeChy1-2 -(5-fluoro-2-morpholinopheny1)guanidine 1,1-ditneChyl-2-(3-mechyl-2-morpholinophenyl)guanidine 1,1-aimechy1-2-(4-mechoxv-2-morpholinophenvl)guanidine 1,1-dimeChy1-2-(5-isobuCy1-2-morpholinophenvl) guanidine 1,1-dimeChvl-2-(5-mechyIsulphiny1-2-morpholinopheny 1)guanidine 4 - [ 2 -(1 ,3-dimechy1-2-imidazolidinylideneamino)- benzyl]morpholine 4-[A-chloro-2-(l,3-dimechy1-2-imidazolidinvlideneamino) benzyl]morpholine N,N-dimeChy1-N'-(2-morpholinomechy1phenyl)guanidine N-(2-morpholinomechylphenyl)morpholine-4 -carboxamidine and pharmaceuCicallv accepcable sales chereof. One group of preferred compounds of formula I includes compounds of formula I in which n = 0, -NR-jR^ is morpholino, chiamorpholino, piperidino or 1-pyrrolidiny 1, is -N^, R^ is an aliphatic group containing 1 Co 4 carbon atoms (eg methyl, ethyl or allyl), Rg is an aliphatic group of 1 to 4 carbon atoms optionally substituted by methoxy or methylthio (eg methyl, ethyl, allyl, methoxyethyl or methylthioethyl) or R^ and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI (e.g. morpholino or thiamorpholino) and R^ is H, fluoro, chloro, methyl, ethyl, mechylchiomechyl or meChylChio. - 25 - 23 1 9 5 Specific compounds falling within this one group of preferred compounds include:- 1 ,1-dimethy1-2 -(2-morpho1inopheny1)guan idine 1 ,1-dime thy 1-2 -(5-fluoro-2-morpholinophenvl)guanidine 5 1,1-dimethy1-2-(5-chloro-2-morpholinophenyl)guanidine 1 ,1-dimethy1-2 -(5-methy 1-2-morphoIinophenvl)guanidine 1 ,1-dimethy1-2-(6-me thy1-2-morpholinophenyl)guanidine 1 ,1-dimethy 1-2 -(5-e thy 1-2 -morpholinopheny1)guanidine 1 ,1-dimethvl-2-(5-methylthiomethyl-2-morpholinophenyl) 10 guanidine 1 ,1-dimethy 1-2-(5-me thylthio-2-morpholinophenvl) guanidine 1-ethy1-1-methyl-2 -(2-morpholinopheny1)guanidine 1 ,1-diethy1-2-(2-morpholinophenyl)guanidine 15 1 -(2-methoxyethyl)-1-methy 1-2 -(2-morpholinophenvl) guanidine 1 -methyl -1 - ( 2-methy1thioethy 1)-2 -(2-morpholinophenvl)-guanidine 1 ,1-dime thyl-2-(2-thiamorpholinopheny1)guanidine 20 1,1-dimethyl-2-(2-piperidinopheny1)guanidine 1 ,1 -dimethyl-2- [ 2- (1 -pvrrolidinyDphenyl] guanidine N-(2-morpho1inopheny1)morpholine-4 -carboxamidine N-(2-morpholinopheny1)thiamorpholine-4-carboxamidine and pharmaceutically acceptable salts thereof. 25 A second group of preferred compounds of formula I includes compounds of formula I in which n = 0, -NR-j is morpholino or thiamorpholino, R~ is a group of formula III in which R^ is an alkyl group containing 1 to 4 carbon atoms (eg methyl) and R^' is H, R^ is H, Rg 30 is an aliphatic group containing 1 to 4 carbon atoms (eg methyl, butyl or _t-butyl) optionally substituted by methoxy (e.g. Rg is methoxvethyl) and is H, fluoro, methyl, methylthio or methylthiomethv1. 23 195 Specific compounds falling within this second group of preferred conpounds include:- 1-butyl-3-me thy 1-2-(2-morpholinophenvl)guanidine 1-methy1-3-tert-butyl-2-(2-morpholinophenyl)guanidine 5 1-methyi-3-tert-buty1-2-(4-fluoro-2-morpholinophenyl) guan idine 1-me thy1-3-tert-butvl-2-(4-me thy1-2-morpholinophenvl) guanidine 1-methyl-3-tert-butyl-2-(4-methyIthio-2-morpholino-10 phenyl)guanidine 1-me thy 1-3-tert-butyl-2-(4-me thylthiomethy1-2- morpholinopheny1)guanidine 1 -(2-methoxyethy 1)-3-methy 1-2 -(2-morpho1inophenvl) guanidine 15 1,3-dimethyl-2-(2-thianorpholinophenyl)guanidine 1-methyl-3-tcrt-butvl-2-(2-thiamorpholinopheny1) guanidine and pharmaceutically acceptable salts thereof A further group of preferred compounds of formula 20 I includes compounds of formula I in which n = 0, -NR-jR.2 is morpholino, thiamorpholino, morpholinomethy 1 or thiamorpholinomethvl, is an alkyl group of 1 Co 4 carbon atoms (eg methyl and t-butyl), R^ and Rg are H and Ry is H, fluoro, methyl, methylthio or 25 meChylChiomeChyl. Specific compounds falling within this further group of preferred compounds include:- 30 N-(2-morpholinophenyl)acetamidine N-(4-fluoro-2-morpholinophenyl)aceCamidine N-(4-meChyl-2-morpholinophenyl)acetamidine - 27 - 23195 N-(4-mechvlchio-2-morpholinophenyl)acetamidine N-(4-methy1thiomethy 1-2-morpholinophenyl)acetamidine N-(2-thiamorpholinophenvl)acetamidine N-(2-morpholinomethyIpheny1)acetamidine 5 N-(2-morpholinophenyl)pivalamidine N-(2-morpholinome thyIpheny1)p ivalamidine and pharmaceutically acceptablc salts thereof. Compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such 10 salts include hydrochlorides, hvcrobromides, hvdro-iodides, sulphates, nitrates, maleates, acetates, citrates, fumarates, tartrates, succinates, ben~oates , pamoates and salts with acidic amino acids such as glutamic acid. Compounds of formula I and their salts 15 may exist in the form of solvates (for example hydrates). Some compounds of formula I contain one or more asymmetric carbon atoms and exist in different optically active forms. When the compounds of formula 20 I contain one chiral centre the compounds exist in two enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof. When the compounds of formula I contain more than one chiral centre, the compounds may exist in diastereoisomeric 25 forms. The present invention includes each of these diastereoisomeric forms and mixtures thereof. The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I together with a 30 pharmaceutically acceptable diluent or carrier. In therapeutic use, the active compound may be administered orally, rectally, parenterally or 2 3195 - 2S - topically, preferably orally. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. 5 Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-90" by weight of active compound. The compositions cf the invention are generally prepared in unit desase form. w Compositions for oral administration are the preferred compos *. tior.s cf the invention and these are the knovr. pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oilv suspensions. The excipier.ts used in the preparation cf these compositions are the excipients Kr.ovn i.n tne or.armacists ' art. laoiets may oe preparec bv mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in 10 the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known , methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or 15 soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 50 to 500 mg of 20 the active compound. Other compositions for oral administration include, for example, aqueous solutions , £ N / v.. .... , containinS t^ie active compound, aqueous suspensions "C- v J. 's \ 24 SEP 1991 'Jj Continued on page 28a - 28a - 251950 containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethvlceLlulose, and oily suspensions containing a compound of the present; invention in a suitable vegetable oil, for example arachis oil. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling. In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. \ \ o - 29 - 2 3 19 5 5 10 15 20 The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat hvperglycaemia in human beings. In such treatment the amount of the compound of formula I administered per day is in the range 50 to 3000 mg. The preferred administration route is oral adminis trat ion. Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention. Compounds of formula I may be prepared by the reaction of an aminophenyl compound of formula VII with an amide or a urea of formula R^.CO.NR^R^ in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulphonvl chloride. Compounds of formula I in which the groups R^ and R^ together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula IV may be prepared by the reaction of an aminophenyl compound of formula VII with a) a lactam of formula VIII - 30 - 2 3 1 9 $ q in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, cyanuric chloride, phosgene, carbon tetrachloride/triphenyl-phosphine, phosphorus pentachloride or benzenesulphonvl chloride. b) a compound of formula IX in which ? is chloro, -O-POCI2, -0-S0C1, -0C0C1 or -OSC^Ph and B~ is an anion such as halo (e.g. CI ) or poci4", c) a compound of formula X Rq \ . R. 10 R13°-1 0 G N - 31 - 23 1§50 in which is an alkyl group and B~ is an anion such as fluoroborate or methosulphate. d) when R.- is H, a ketoxime of formula XI in the presence of a sulphonyl chloride (for example bencene sulphonyl chloride). Compounds of formula I in which the groups R^ and R^ together wich the carbon and nitrogen atoms to which they are attached form a ring represented by formula V may be prepared by the reaction of an aminophenyl compound of formula VII with a urea of formula XII in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulphonyl chloride. Compounds of formula I in which the groups R^ and R^ together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula V may be prepared by the reaction of a compound of formula XIII - 3: 23 19 5 XIII optionally in the form of a salt (e.g. a hvdroiodide salt) in wl formula XIV salt) in which R-^ and R^ are H with a diamine of R]]NHENHRg XIV 5 Compounds of formula I in which R^ is a straight or branched alkyl group of 1 to 7 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms and the group NR^Rg is may be prepared by the reaction of a compound of formula VII optionally in the form of a 10 salt (e.g. a hydrochloride salt) with a cyano compound of formula R^CN, optionally in the presence of aluminium chloride. Compounds of formula I in which the group R^ is NH2 may be prepared by the reaction of a compound of 15 formula VII optionally in the form of a salt (e.g. a hydrochloride salt) with a cvanamide compound of formula R^R^NCN. The reaction may be performed in a liquid reaction medium (for example m-cresol) or by heating the reactants together in the absence of a 20 liouid carrier. Compounds of formula I in which the group R^ is NH2 may be prepared by the reaction of compounds of formula XV - 33 - 2 3 1 9 5 0 (! i ) N ?.. R - v r*i n XV NHCN with amines of formula NKR^Rg optionally in a liquid reaction medium (for example ethanol). Compounds of formula I in which R^ is a group of formula III in which R^ is alkyl and R^ ' is K or alkyl may be prepared by the reaction of a compound of formula XIII in which R^ is the group R^ and R^ is the group R^1 with an amine of formula HNR^R^. The reaction may be performed in an alcoholic medium (e.g. ethanol or n-butanol) optionally in the presence of a base such as pyridine or triethv lamine or in the presence of potassium hydroxide and lead acetate. When HNR,-R, is ammonia, the ammonia may be dissolved in the alcoholic medium and the reaction may be performed under elevated pressure in a sealed reaction vessel. Compounds of formula I in which R^ is a group of formula III in which R^ is alkyl and R^1 is K or alkyl may be prepared by the reaction of a thiourea of formula XVI (CH-JnNR!R2 XVI NK.CS.N \ 23 1n5o in which R-j ^ is the group RA and is the group R^ ' with an amine of formula HNRCR.. . The reaction mav be 5 6 performed in the presence of a base (such as potassium hydroxide or potassium carbonate) and lead acetate. When HNR^Rg is ammonia, the ammonia may be dissolved in an alcoholic medium (e.g. ethanol) and the reaction may be performed under elevated pressure in a sealed reaction vessel. Compounds of formula I in which R^ is a group of formula III in which is alkyl and R^ ' is H and in which R,- is H may be prepared by the reaction of a carbodiimide of formula XVII with an amine of formula F^NRg. Compounds of formula I in which n = 0 and NR-j R2 is a morpholino, thiamorpholino, 1-pyrrolidinyl or piperidino group may be prepared by the reaction of a compound of formula XVIII "35" 231 9 z.n with a disubstLtuted compound of formula XIX K(CH9)9L(CH2')2:< XIX in which K is a leaving group such as halo (e.g. bromo or chloro) or tosvloxy and L is -0-, -S-, a direct bond 5 or ~CH2-. /-s, Compounds of formula I in which is a group of formula III in which R^ is propyl and R^' is H and in which R,. is H and Rg is propyl may be prepared by the reaction of an amine of formula H0NRg in which Rg is 10 propyl with a thiourea of formula XVI in which R^ and R^ are both methyl in the presence of potassium hydroxide and lend acetate. In this reaction the amino group -NHRg replaces both the thioxo group and the dimethylamino group. 15 Compounds of formula I in which R^ is a group of formula III and in which R^ is methyl and R^' is H and in which R^ is H and Rg is methyl may be prepared by the reaction of an amine of formula F^NRg in which Rg is methyl with a compound of formula XIII in which the 20 group NR^R-j ^ is butvlamino. In this reaction the amino group -NHRg replaces both the methylthio group and the amino group -NR^R^. Compounds of formula I in which NR-j R2 is a thiamorpholino-1-oxide group may be prepared by the 25 oxidation (for example using sodium metaperiodate) of a compound of formula I in which -NR-j R2 is thiamorpholino. Compounds of formula I in which Rg is substituted by an acyloxy group may be prepared by acylation (e.g. 30 acetylation or benzoylation) of the corresponding 36 - 23 19 5 compound of formula I in which is substituted by hydroxy. Compounds of formula I in which R^ is an alkylsulphinyl group may be prepared by oxidation (for example using sodium metaperiodate) of compounds of formula I in which is an alkvlthio group. Compounds of formula VII may be prepared by the reduction of the nitro group in a compound of formula XX 10 for example (a) using hydrogen and a Ranev nickel catalyst, (b) hydrogen and a palladium/carbon catalyst, (c) sodium sulphide, (d) stannous chloride dihydrate in hydrochloric acid, ethyl acetate or ethanol or (e) iron in the presence of acid. 15 Compounds of formula IX in which R-j 9 is a group of formula 0P0C19, 0S0C1, OCOC1 and OSO<,Ph may be prepared by the reaction of compounds of formula VIII with w' phosphorus oxychloride, thionyl chloride, phosgene or benzenesulphony1 chloride respectively. 20 Compounds of formula X may be prepared by the reaction of compounds of formula VIII with alkylating agents such as dialkylsulphate, trialkyloxonium fluoroborate or borontrifluoride etherate/diazoalkanes followed by basification with sodium carbonate or 25 sodium hydroxide solution. - 37 - 23 195 0 Compounds of formula XIIT may be prepared by the reaction of methyl iodide with thioureas of formula XVI. Compounds of formula XV may be prepared by the 5 reaction of potassium hydroxide with compounds of formula XIII in which and R^ are both H or in which R^ is benzoyl and R-j ^ is H in the presence of z-s lead acetate. Compounds of formula XV may be prepared by the 10 reaction of thioureas of formula XVI in which R,, and I <4 R-| 2 are H with sodium chlorite in the presence of a base such as sodium carbonate and a copper catalyst such as a mixture of cuprous and cupric chlorides. Thioureas of formula XVI in which R-| ^ and R-j ^ are 15 H may be prepared by the reaction of ammonia with an isothiocyanate of formula XXI (CH-) NR R 2 n 12 XXI NCS Compounds of formula XVI in which R^ is an alkyl group and R-j ^ is H may be prepared by the reaction of an aminophenyl of formula VII with an 20 alky lisothiocyanate of formula R^NCS. Carbodiimides of formula XVII may be prepared by the reaction of a thiourea of formula XVI in which R-j ^ is the group R^ and R-| ^ is H with sodium chlorite. - 38 - 231950 Compounds of formula reduction for example by compounds of formula XXII XVIII may be prepared bv the hydrogen and Raney nickel of Compounds of formula XX in which n = 0 and NR-| R2 is a morpholino, thiamorpholino, 1-pvrrolidiny1 or piperidino group may be prepared by the reaction of a 2-nitroaniline with a compound of formula XIX. Compounds of formula XX in which n = 0 and -NR-|R9 is morpholino, thiamorpholino, 1-pvrrolidiny1, piperidino, 1-hexa-hvdroazepinv1 or A-methvl-1 -piperazinyl may be prepared by the reaction of morpholine, thiamorpholine, pyrrolidine, piperidine, 1-hexahydroazepine and 4-methy1-1-piperazine respectively with a halonitro-benzene (e.g. 2-fluoronitrobenzene or 2-chloronitro-benzene) in the absence or presence of a solvent such as benzene, ethanol or acetonitrile. Compounds of formula XXI may be prepared by the reaction of a compound of formula VII with thiophosgene in a liquid reaction medium such as dioxan. Compounds of formula XXII may be prepared by the reaction of an amide or urea of formula R^.CO.NR^Rg with a 2-nitroaniline in the presence of a condensing agent (such as phosphorus oxychloride or thionylchloride). Compounds of formula XXII may be prepared by the reaction of an amidine or guanidine of 39 2319 £ -J 5 /•""V 10 15 20 ."■a formula R^.CNH.NR^R^ with a 2-halonitrobenzene (e.g. 2-fluoronitrobenzene or 2-chloronitrobenzene). The hypoglycaemic activity of the compounds of formula I which are given in the following Examples has been demonstrated by the following test. Rats weighing between 150 and 200 g were fasted for 18 hours and then were subcutaneously injected with glucose (800 mg/4 ml/kg) followed by an oral dose of the compound to be tested (x mg in either 4 or 5 ml of 0.2% Agar/kg). After 2 and 4 hours blood was collected by orbital bleeding and the plasma glucose estimated on a Beckman glucose analyser using the specific glucose oxidase method (Kadish A H, Little R L and Sternberg J C, Clin chem J_4_ 116 [1968]). The percentage reduction of plasma glucose when compared to control animals which had not been given the compound to be tested, but which had been given 0.2" Agar homogenate, was then calculated. Compounds are considered to have hypoglycaemic activity in this test if they show a 15% or greater reduction in plasma glucose at any value of x up to 200 at either or both of 2 and 4 hour's. The results obtained at any value of x in the above tests were then reviewed and the hypoglycaemic activity of each compound was classified on the following scale. Where more than one set of results is available at a particular value of x, the mean value of the % reduction is used to classify the activity of the compounds. A greater than 25% reduction at both 2 and 4 hours. 30 B greater than 25% reduction at 2 hours but less than 25% reduction at 4 hours. - 40 - 2 3" r ~ n C reduction in the range 15 to 25" at 2 hours but greater than 251 reduction at 4 hours. D reduction in the range 15 to 25% at both 2 and 4 hours. 5 E reduction in the range 15 to 25% at 2 hours but less than 152 reduction at 4 hours. F less than 15% reduction at 2 hours but greater than 15% reduction at 4 hours. The activities of the compounds described in the 10 Examples given hereinafter are given below in Table A. Table A Example x Activity Example x Activity 1 25 A 2 25 B 3 25 B 4 25 B 5 25 A 6 25 E 7 25 B 8 36 B 9 200 E 1 0 25 B 1 1 25 A 12 25 A 1 3 50 D 14 200 A 1 5 1 00 E 16 25 D 1 7 50 B 18 25 E 1 9 40 A 20 25 A 21 25 C 22 25 B 23 50 A 24 25 B 25 25 D 26 25 B 27 25 A 28 25 A 29 25 E 30 25 D 31 50 D 32 25 D -41 - Table A continued 2 3 195 o Example X Activity Example V Activ: 33 25 B 34 25 B 5 35 25 D 36 200 F 37 200 E 3S 200 D 39 200 A 40 200 A 41 200 A 42 36 D A3 25 B 44 200 A 10 45 200 D 46 36 B 47 37 B 48 200 A 49 38 E 50 36 A 51 200 D 52 36 B 53 36 B 54 37 B 15 55 36 A 56 35 A 57 25 A 58 25 B 59 35 A 60 37 E 61 36 D 62 25 C 63 1 00 A 64 25 B 20 65 25 A 66 36 D 67 200 A 68 25 C 69 43 D 70 36 A 71 36 A 72 25 B 73 25 A 74 25 A 25 75 50 F 76 25 D 77 25 E 78 25 F 79 200 A 80 25 D 81 200 D 82 50 E 83 25 A 84 25 E 30 85 25 D 86 25 F 87 200 D 88 200 F Example x Table A concinued Activity Example x Activity 89 200 C 90 25 E 5 91 200 A 92 25 B 93 25 C 94 200 C 95 25 E 96 25 F 97 50 D 98 50 A 99 25 A 100 25 B 10 101 25 B 1 02 200 A 103 25 B 1 04 27 A 1 05 37 E 1 06 37 E 107 25 B 108 25 B 1 09 25 B 110 36 B 15 1 11 25 B 1 1 2 36 B 1 13 25 D 1 14 25 E 115 25 D 11 6 25 B 117 25 B 118 25 A 119 25 D 120 25 B 20 121 25 E 1 22 25 A 1 23 38 B 1 24 37 B 1 25 36 B 126 200 A 1 27 25 E 1 28 25 A 1 29 25 B 1 30 100 B 25 131 50 B 1 32 200 A 1 33 25 B 134 25 A 135 25 A 136 25 B 1 37 25 B 1 38 25 B 1 39 25 B 140 100 A 30 141 25 E 142 25 A \ 43 Table A continued 9 ^ 1 n ; -c 0 ' c/ J Example x Activity Example x Activity 143 25 B 1 44 25 B 5 145 25 C 1 46 200 A 147 36 D 1 48 25 D 149 36 D 1 50 68 F 151 25 C 1 52 25 D 153 25 B 1 54 39 D 10 155 1 33 B 1 56 25 D 157 25 A 1 58 25 A 159 50 D 1 60 26 D 161 34 A 162 35 B 163 25 B 164 25 D 15 165 200 B 1 66 25 D 167 25 B 168 25 B 1 69 25 A 1 70 25 A 171 25 D 1 72 25 D 173 25 D 1 74 25 B 20 175 25 B 1 76 35 C 177 25 B 1 78 200 A 179 25 D 180 25 E 181 43 D 182 25 D 183 25 D 184 34 F 25 185 200 D 1 86 25 A 187 25 A 188 25 B 189 25 A 1 90 25 A 191 36 D 1 92 25 B 193 25 A 1 94 200 C 30 195 12.5 A 1 96 25 A " 44 " ? ? " 0 Table A continued Example x Activity Example x Activity 1 97 25 D 1 98 25 A 5 199 25 E 200 25 A 201 25 E 202 25 B 203 100 A 204 200 A 205 200 A 206 200 C 207 50 A 208 30 D 10 209 25 B 210 30 D 21 1 36 A 212 25 F 213 50 D 214 25 E 215 25 E 216 35 A 217 30 E 218 200 D 15 219 200 D 220 36 A 221 200 A 222 35 A 223 35 D 224 35 C 225 25 B 226 200 A 227 25 F 228 35 A 20 229 35 A 230 35 C 231 35 F 232 25 B 233 25 B 234 25 B 235 34 A 236 38 C 237 35 A 238 35 A 25 239 35 A 240 36 A 241 34 A 242 200 A 243 200 B 244 200 E 245 25 B 246 200 D 247 37 A 248 36 A 30 249 36 B 250 25 E 251 35 E 252 200 A 253 35 A 254 36 B 45 - n -r 2 3 1 n r Table A continued Example X Activity Example X Activity 255 36 A 256 34 B 5 257 36 A 258 35 E 259 34 D 260 35 B 261 36 C 262 37 B 263 38 B 264 36 B 265 200 E 266 200 E 10 267 200 E 268 35 B 269 35 B 270 25 B 271 25 B 272 25 B 273 200 C 274 1 28 D 275 25 E 276 36 B 15 277 34 B 278 35 B 279 25 B 280 35 B 281 35 A 282 200 C 283 200 E 284 200 E 285 200 B 286 35 B 20 287 36 B 288 38 E 289 200 A 290 25 D 291 25 B 292 85 C 293 35 A 294 25 B 295 25 B 296 25 D 25 297 35 B 298 35 E 299 34 E 300 200 A 301 25 B 302 38 A 303 39 B 304 40 B 305 28 A 306 29 A 30 307 30 B 308 NT 309 100 D 310 200 D 311 200 E 312 200 E NT = Not Tested - 46 - 2 3 19 5 0 The present invention will be illustrated by the following Examples which are given by way of example only. The final product of each of the Examples was characterised by elemental analyses. Example 1 A solution of de lta-valerolactam (24 g) in dry benzene (100 ml) was cooled to 10°C in ice-water and treated with freshly distilled phosphorus oxychloride (22.2 ml) under nitrogen over a period of 10-15 minutes. The initial white solid formed changed to a clear yellow oil over 3 hours. A solution of 4-(2-aminophenyl)morpholine (36 g) in dry benzene (150 ml) was added and the mixture heated at 65°C with stirring for 32 hours. The benzene layer was decanted, the oil washed twice with benzene (2 x 40 ml), ether (100 ml) was added and the mixture cooled in ice treated with 10" aqueous sodium hydroxide solution to alkaline pH, with stirring. The aqueous layer was extracted with ether (2 x 100 ml) and the combined ether extracts washed with water, brine and dried. The solution was filtered and the solvent removed to give a thick oil which solidified on trituration with hexane. The crude solid was crystallised from hot hexane to yield 4 -[2-(2-piperidinylideneamino)phenyl]morpholine (m.p. 89-90°C). Example 2 A solution of the product of Example 1 (10.2 g) in dry methanol (30 ml) was treated with fumaric acid (4.6 g). The resulting solid was filtered and crystallised from methanol to yield 4-[2-(2-piperi-dinylideneamino)phenyl]morpholine fumarate as a colourless crystalline solid [m.p. 210°C (dec)]. - 47 - 23 19 5 0 Examples 3 to 35 In a similar manner to that described above in Example 1 the compounds listed in Table I were prepared by the reaction of an aminophenyl compound of formula VII in which NR-| is morpholino (A grammes in B ml benzene) with a compound of formula VIII (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-70°C. Notes to Table I (1) Product recrystallised from hexane. (2) The product was purified by chromatography on an alumina column using a 1:1 mixture of dichloromethane and hexane as eluant. (3) Product isolated as its hydroiodide salt which was recrystallised from a 1:1 mixture of methanol and ether. (4) Coupling reaction performed at ambient temperature. (5) Product recrystallised from ether. (6) The compound of formula VIII was dissolved in a mixture of benzene (60ml) and acetonitrile (40ml). (7) The product was purified by chromatography on an alumina column using the following eluants sequentially:- hexane, a 1:9 mixture of dichloromethane and hexane, a 3:7 mixture of dichloromethane and hexane, a 1:1 mixture of dichloromethane and hexane and dichloromethane. - 48 - 9 31 0 5 0 (8) The produce was isolated as its monofumarate s;n.r~' which was recrystallised from 1:1 mixture of methanol and ether. (9) The product was isolated as its monohydroiodide salt which was recrystallised from a 2:3 mixture of methanol and ether. (10) Coupling reaction performed at ambient temperature for 24 hours and at 70°C for 8 hours. (11) Product isolated as its fumarate salt which was recrystallised from propan-2-ol. (12) Product isolated as its sesquifumarate salt which was recrystallised from a 1:1 mixture of methanol and ether. (13) The compound of formula VIII was dissolved in acetonitrile (120 ml). (14) The product was purified by chromatography on an alumina column using a 99:1 mixture of dichloromethane and methanol as eluant. The product was recrystallised from a 1:1 mixture of dimethoxyethane and hexane. o LO o> NO CNJ 5 10 Ex. A 3 17 .8 4 5 .3 5 5 .4 6 5 7 5 .4 8 10 9 3 . 6 10 10 .7 11 3 .6 B C 75 16 .4 20 5 . 7 25 6 .3 25 4 30 7 .5 25 12 .7 10 2 60 7 .2 10 2 .8 ,1 r '• »■ ( - 49 - Table I & •» |l / CKoR 1D \ i\ 1 < / 'n xs - c_ (c. \ v rvj .— v- v ) '"a K D E F m R7 R9 R10 R6 tnp(°C) Notes 100 13. 3 6 3 H H H Me 1 30 (1) 40 4. 1 4 3 H H H Et 92-93 (1) 50 4 . 1 2 3 H H H i-Pr 104-105 (1 ) 25 3. 3 40 4 H H H H 96-98 (1)(2) 50 5. 5 6 4 H H H Me 79-80 (1) 50 9 6 5 H H H H 231-232 (3) 20 2 . 4 6 2 H H H H 143 (1) 120 7. 2 8 2 H H H Me 89-90 (1) 20 2. 4 6 2 H Me H Me 105-107 (1) (4) o ur> NO Ex. A B C D E 12 3.6 10 3.2 30 2.4 13 A.5 10 3.5 25 3 5 14 3.6 25 4.3 50 2.7 15 7.1 80 10 40 5.5 16 3.5 10 3.4 30 2.4 1 7 3.6 30 3.8 15 2.4 18 3.4 15 3.3 25 2.4 10 19 2.5 30 1 .9 60 1 .4 20 6.8 30 8 50 7.3 21 3.1 25 2.7 25 2.2 22 6.8 30 8 50 7.3 23 3.8 25 2.7 25 2.2 15 24 6 30 6.3 50 5.8 25 2.5 10 3 20 2.7 26 4.1 20 4 30 3.7 - 50 - Table I cont. F m R7 R9 R10 R6 mp(°C) Notes 14 2 H Me Me Me 72-75 (1) 5 2 H H H Et 94-96 (1 ) 5 2 H H H CH2CH2OMe 140-142 (7) (9) 8 2 H H H cyclohexyl 110-112 (1) 5 2 H Me Me Et 72-74 (1) 2 H Et Et Me 190 (10)(11 ) 1 2 2 H i- Pr H Me 70 (1 ) 10 3 H Me H Me 184 02) 5.5 3 3-Me H H H 167-168 (1 ) 4 3 3-Me H H Me 110-111 O) 4.5 3 4-Me il H H 114 0) 4 3 4 -Me H H Me 108-109 (1 ) 10 3 5-Me H H H 119 (1) 10 3 6 -Me H H H 98 0) 5 3 4-Et H H H 204-205 (7)(8) o LO C\J 10 Ex. A B C D E 27 3 10 3 20 2.7 28 5 40 5.25 30 3.4 29 4.2 25 2.7 25 2 . 2 30 6.3 25 6 50 5.5 31 6.3 20 6 40 5.8 32 5 50 6 30 5.6 33 3.7 25 2.7 25 2.2 34 3.1 20 3 30 2.7 35 4.6 4 40 3.6 36 5.1 8 60 2.2 37 6.3 30 6.8 40 3.4 - 51 - Table I cont. m R. R9 R10 R6 mp(°C) Notes 5 3 3-Cl H H H 166-167 8 3 4 -CI H H H 109-110 4 3 4 -CI H H Me 108-109 4. ,5 3 5-Cl H H H 140-141 4 3 6-C1 H H H 115-116 5 3 4-F H H H 82-83 4 3 4-F 11 H Me 110-111 5 3 4-OMe h H H 103-104 4 3 4-COOMe H H h 112-114 3 3 4-S02Me h H H 151-152 7 3 h H H ch2ch2oac 66-67 23 195 0 Example 38 In a similar mariner Co chat described in Examples 1 and 2, 1-meChy1-3-(2-mechoxyechy1)-2-piperidone (2.56 g) in benzene (30 ml) was reacCed wich 4-(2-5 aminophenyl)morpholine (2.49 g) in benzene (30 ml) in the presence of phosphorus oxychloride (1.37 ml) for 12 hours aC 70°C. The resulting product was 4-(2-[l~ methy1-3-(2-mechoxyechy1)-2-piperidinylideneamino]-pheny1jmorpholine sesquifumarace (m.p. 174°C) which was 10 recrysCallised from a 1:1 mixCure of mechanol and e Cher. Example 39 In a similar manner to that described in Example 1, 1-benzyl-3-methvl-2-pyrrolidone (14.17 g) in benzene 15 (80 ml) was reacted with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (30 ml) in che presence of phosphorus oxychloride (6.86 ml) for 24 hours aC 70°C to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinyl- ideneamino)phenyl Jmorpholine (m.p. 96-97°C) which was 20 recrystallised from hexane. The recrystallised product (2 g) from the previous paragraph was heated at reflux with cyclohexene (6 ml), 10" Pd/C (1.5 g) and methanol (100 ml) for 4 hours to give 4-[2-(3-methyl-2-pyrrolidinylidene-25 amino)phenyl]morpholine as an oil. This oil (1 g) was dissolved in methanol (20 ml) and a solution of fumaric acid (0.47 g) in methanol was added to yield 4-[2-(3-methy1-2-pyrrolidinylideneamino)phenyl]-morpholine fumarate (m.p. 185°C) which was 30 recrystallised from an 1:1 mixture of methanol and ether. Examples 40-62 In a similar manner to that described in Example 1 the compounds listed in Table II were prepared by Che - 53 - 2 3 19 5 0 reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with an amide of formula R^.CO.NR^Rg (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-70°C. Notes to Table II Notes (1) and (8) has the meaning given in respect of Table I (15) The product was isolated as its monofumarate salt which was recrystallised from methanol. (16) Coupling reaction performed at 80°C. (17) Coupling reaction performed at 75°C. (18) Product obtained as a monohydrate. (19) Product recrystallised twice from n-pentane. (20) The product was obtained as an oil, the boiling point of which was not determined. The oil was purified by chromatography on an alumina column using the following eluants sequentially:-hexane, a 1:1 mixture of dichloromethane and hexane and dichloromethane. LO o> NO OJ - 54 - Table II H ft., R., "ft* Ex. A B C D E F NRiRz R3 R5 R6 R7 mp(°C) Notes 40 7 . 1 30 7.3 50 9, . 1 6 morpholino Me H Me H 132-133 (1) 41 6 .3 35 4 25 3, .5 10 morpholino Me H Pr H 78-79 (1) 42 7 .2 35 5.1 25 4 9 morpholino Me H n-Bu H 178-179 (15) 43 7 .2 35 5.7 25 4 9 morpholino Me H n-C^ Hi, H 163-164 (15) 44 10 .8 40 10 50 6 .3 18 morpholino Me H <ch2) 2OAc H 185-186 (15) 45 3 .5 20 2.5 20 2 .3 8 morpholino Me Me Me H 68-70 (1) 46 3 .5 20 3 20 2 .3 40 morpholino Me Et Et H 166-168 (8) 47 8 .9 30 6.5 70 6 .9 12 morpholino Et h Me H 70 (8) 48 5 .3 30 4 20 3 .7 5 morpholino et h Et h 105-107 (1)(16) o 10 G") No Ex. A B 49 8 .9 30 50 8 .9 30 51 5 .3 30 52 8 .9 30 53 8 .9 30 54 8 .9 30 55 7 .2 30 56 8 .9 30 57 5 .3 30 58 5 20 59 8 .9 50 60 8 .1 50 61 3 .7 20 62 5 30 - 55 Table II C D E F NRiR2 7. 6 70 6, ,9 12 morphoLino 7 . 6 75 6. ,9 45 morpholino 4 . 5 20 3. .7 3 morpholino 8 . 6 75 6. .9 45 morphoLino 7 . 6 70 6. .9 12 morpholino 8. 6 70 6, ,9 12 morpholino 5 . 1 35 4 16 morphoLino 1C 1.7 80 6, .9 1 2 morphoLino 5. 2 40 4 , , 1 8 morpholino 5 . 5 20 4 14 morphoLino 9. 7 100 6, .9 10 morpholino 7 80 6 .4 8 1-pyrrol-idinyi 3. 9 30 3 .1 8 1-pyrrol-idinyL 4 . .3 25 2 .6 9 morpholino Cont. R3 R5 R6 R7 mp(°C) Notes Et Me Me H 170 (8)(17)(18) Pr H Me H 180 (8) Pr H Et H 75-77 (16) (19) Pr Me Me H 135-137 (8) i-Pr H Me H 220 (8) (17) i-Pr Me Me H 156-160 (8)07) Bu H Me H 168-169 (17) Bu Me Me H 121 -122 (8) -CMe3 H Me H 128-129 O) -CMe3 Me Me H (20) penty1 H Me H 1 34-1 35 (8) Pr 11 Me H 135-137 (8) -CMe3 H Me H 193-194 (8) cyclo hexyl H Me H 93-94 0) - 56 - 2 319 50 Example 63 A mixture of N-methyIpivalamide (11.5 g) in benzene (120 ml) and phosphorus oxychloride (9.2 ml) was stirred at room temperature for 3 days. A solution of 1-(2-aminophenyl)piperidine (14 g) in benzene (80 ml) was added and the mixture heated at 65-70°C for four days to give N-methyl-N'-(2-piperidinophenv1)pivalamidine (m.p. 78°C) which was recrystallised from hexane. The product was obtained as a 0.25 hydrate. Examples 64-75 In a similar manner to that described in Example 1 the compounds listed in Table III were prepared by the reaction of an aminophenyl compound of formula VII in which NR-jR^ is 1-pyrrolidinyl (A grammes in B ml benzene) with a compound of formula VIII (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range of 60-70°C. Notes to Table III Notes (1), (4) and (8) have the meaning given in respect of Table I. (21) The product was isolated as its monofumarate salt which was recrystallised from a 1:2 mixture of methanol and ether. (22) The product was isolated as its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether. Q O K) CNJ Ex. A B C 64 3.2 20 3 65 3 25 2.7 66 4.9 20 5.7 67 4 25 2.7 68 3.5 25 4 69 4 25 3 70 4.8 25 4 71 4.8 20 5.7 72 8.8 90 10 - 57 Table D E F m 20 2.8 6 3 25 2.2 5 3 30 4.1 7 3 25 2.2 6 3 25 3.3 14 3 25 2.7 8 2 30 3.3 8 2 30 4.1 8 4 60 9.2 8 3 III NJ ^ I R7 R9 R10 R6 H H H H H H H Me H H H Et 4 -CI H H Me 3-Me H H Me H H H Me H Me H Me H H H Me 4-Me H H H mp(°C) Notes 82-84 (1) 99-101 (1) 143-144 (21) 77-78 (1) 92-93 (1) 157-158 (8) 152-154 (22) 159-160 (21) 112-113 (1) o LO ho Ex. A B C D E CNJ 73 1 .8 30 2 20 1 .8 74 8.8 60 10 60 9.2 5 75 k 30 4.5 30 4.2 r ( - 58 - Table III cont. F tn R7 R9 R10 R6 tnp( °C) Notes 24 3 4 -CI H H H 138-139 (1) 5 3 3-Me H H H 113-115 (1) 14 3 6-Me H H H 83-85 (1)(4) " 59 " 2 * ^ ^ r* ^ J Examples 76-91 In a similar manner to that described in Example 1 the compounds listed in Table IV were prepared by the reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with a 2-piperidone (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-70°C. Notes to Table IV 10 Note (1), (8), (11) and (21) have the meaning given for Tables I and III (23) Coupling reaction performed at 75-80°C. (24) Product isolated as its monofumarate salt which was recrystallised from methanol. 15 (25) Product was recrystallised from a 1:2 mixture of dimethoxyethane and hexane. (26) Product recrystallised from hexane and then a mixture of dimethoxyethane and hexane. (27) Product was purified by column chromatography on 20 an alumina column using a 49:1 mixture of dichloromethane and methanol as eluant. The product was isolated as its dihydroiodide salt which was recrystallised from a 1:1 mixture of ethanol and ether. 25 (28)Coupling reaction performed at 90-100°C. o LO i-O CNJ Ex. A B C D E 76 3.5 10 2.4 20 2.4 77 H 40 16 120 15.2 5 78 3.4 25 2.7 25 2.2 79 2.8 25 3 30 2.7 80 5 25 5 50 4 7 0 81 7.6 40 8 60 7.3 82 5 25 6 50 5.5 / I - 60 -Table IV nr]r2 5 thiamorpholino 12 piperidino 8 piperidino 5 1-hexahydro-azepinyl 4 2,6-dimethyl-morpholino 7 4-methyl-piperidino 7 1 - (1 , 2 , 5 ,6-tetra-hydro)pyridyl Ry Rg mp(°C) Notes H H H H H H H H H ii 215-217 70-72 Me 87-89 152-153 H 132-135 H 1A5-H6 H 62 (8) (1) (1)(23) (18) (1 ) (24) (1) ) o ld O5 Table NO C\J Ex. A B C D E F 83 5.3 15 6 30 6 24 5 84 2.8 40 3 20 2.7 4 85 3.7 25 2.6 25 2.2 6 86 4.2 60 4 40 3.6 5 87 7.2 30 8 40 7.3 7 88 5.4 30 8 40 7.3 5 10 89 4.2 20 4 .6 40 4.3 4 90 6.1 25 4.5 50 4.2 14 91 4.2 25 2.7 25 2.2 8 61 - IV cont. nr1r2 2-methyl-l-pyrrolidiny1 2-isoindolinyl thiamorpholino thiamorpholino N(Me)CH2CH2OMe NMe2 N(allyl)2 N(Me)cyclohexyl N(CH2CH2OMe)2 R7 R6 mp(0 C) Notes H H 71 (1) H H 124-125 (25) H Me 124-125 (1) 4 -Me 11 150-151 (26) H H 135-136 (27) H H 175-176 (8) H H 62-63 (1 ) H H 183-185 (11) (28) H Me 129-130 (21) -"-s - 62 - 2 3 | 9 5 Examples 92-101 In a similar manner Co chac described in Example 1, Che compounds lisCed in Table V wore prepared by Che reacCion of an aminophenyl compound of formula VII (A grammes in B ml benzene) wich a methyl-subsCiCuCed-2-pyrrolidinone (C grammes in D ml benzene) in Che presence of phosphorus oxychloride (E ml) for F hours aC a CemperaCure in the range 60-70°C. Notes Co Table V 10 Noces (1) and (4) has Che meaning given for Table I (29) Produce isolaCed as iCs dihydroiodide sale which was recrysCallised from a 1:1 mixture of meChanol and echer. (30) Coupling reacCion performed aC ambienC 15 cemperacure for F hours. (31 ) Produce isolated as its dihydroiodide salt which was recrystallised from a 1:3 mixture of ethanol and ether. CD to o> hO CNJ m==c TNJ \ R, < 10 ex. a b c d e f NR-j R2 a g R6 R7 mp(°C) Notes 92 2 .5 20 2 20 1 .5 4 thiamorpholino CMe2 ch2 Me h 120-122 (1) 93 3 .6 20 3. 2 20 2 .4 1 7 piperidino CMe2 ch2 Me h 62-63 (1) 94 4 . 7 10 3. 9 30 3 6 4-methyl-1-piperaziny1 CMe2 ch2 Me h 280 (29) 95 4 .8 20 4 . 6 40 2 .8 8 1-pyrrolidinyl CMe2 ch2 Me h 85-86 (1) 96 8 80 7. 2 70 5 .2 20 morpholino CMe2 ch2 Me 4 -Me 182-183 (11) 97 6 10 4. 2 20 7 .4 4 piperidino ch2 ch2 Me h 65-66 (1)(4)(30) 98 3 .5 20 2. 8 20 2 .4 5 piperidino CHMe ch2 Me h 75-76 (1)(4)(30) 99 7 . 1 40 6. 8 40 5 .5 18 morpholino ch2 CMe2 h h 130-131 (1) 100 7 .1 50 6. 1 25 4 .4 4 morpholino ch2 CMe2 Me h 63-64 (1) 101 4 .4 10 3. 1 20 2 .4 20 N(CH2CH20Me)2 CMe2 ch2 Me h 178 (31) r - 64 - ^ ^ 1 9 5 0 Example 102 A mixture of 4-(2-aminopheny1)morpholine (5.34 g), acetonitrile (4.52 ml) and anhydrous aluminium chloride (12 g) was heated at 1 60-1 70 °C for 4 hours to yield N-(2-morpholinopheny1)acetamidine (m.p. 140-141°C) which was recrystallised from hexane. Example 103 A mixture of 4-(2-amino-4-methvIpheny1)morpholine (5.76 g), acetonitrile (3.5 g) and anhydrous aluminium chloride (12 g) was heated at 160-170°C for 5 hours to yield N-(5-methy1-2-morpholinopheny1)acetamidine (m.p. 121°C) which was recrystallised from hexane. Example 104 A mixture of 4-(2-aminophenyl)morpholine (5.34 g), propionitrile (4.7 g) and anhydrous aluminium chloride (12 g) was heated at 150-170°C for six hours to yield N-(2-morpholinophenyl)propionamidine (m.p. 114°C) which was recrystallised from hexane. Example 105 A mixture of 4 -(2-aminophenyl)morpholine hydrochloride (7.5 g) and n-butyronitrile (20 ml) was heated at 170°C in a sealed stainless steel pressure vessel for 60 hours. Excess n-butyronitrile was removed and the residue dissolved in water, basified with 10% aqueous sodium hydroxide solution to pH 12 and extracted with dichloromethane. The extract was washed with water and then brine, dried and the solvent removed. The residue was purified by chromatography on a neutral alumina column. Elution with a 1:1 mixture of dichloromethane and hexane removed unreacted starting material and then elution with a 1:99 mixture of methanol and dichloromethane yielded a solid which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give N-(2-morpholinophenyl)- 2 3 1 9 5 0 - 65 - butyramidine monofumarate (m.p. 168-170°C) which was recrystallised from a 1:2 mixture of methanol and e ther. Example 106 Powdered anhydrous aluminium chloride (12 g) was added portion-wise to a stirred slurry of 4-(2-amino-phenvDmorpholine (5.34 g) and n-butyronitrile (6 g) at 40-50°C. The mixture was then heated at 160-170°C for 6 hours, allowed to cool and then digested with 40% aqueous sodium hydroxide solution. The solution was extracted with ether and the extract washed with water and brine and dried. Removal of the solvent gave a residue which was crystallised from a 1:1 mixture of ethylacetate and hexane to give N-(2-morpholinophenyl)-butyramidine (m.p. 131°) which was converted into its monofumarate salt (m.p. 173°C) which was recrystallised from propan-2-ol. Example 107 A mixture of 4-(2-aminophenyl)morpholine hydrochloride (10 g) and isobutyronitrile (60 ml) was heated at 165°C for 26 hours in a sealed stainless steel pressure vessel to yield N-(2-morpholinophenyl)-isobutyramidine (m.p. 140-141°C) which was recrystallised from hexane. Example 108 A mixture of 4-(2-aminophenyl)morpholine (5.34 g), isobutyronitrile (6 g) and anhydrous aluminium chloride (12 g) was heated at 1 60-1 70°C for 6 hours to give N-(2-morpholinophenyl)isobutyramidine (m.p. 138°C) which was recrystallised from a 1:1 mixture of ethylacetate and hexane. 4 - 66 - 23 1 9 5 Example 109 A mixture of 5-methylthio-2-morphoiinoaniline (1.8 g), isobutyronitrile (1.66 g) and anhydrous aluminium chloride (3.2 g) was heated at 140°C for 2 5 hours to give N-(5-methylthio-2-morpho1inopheny1) isobutyramidine (m.p. 155°C) which was recrystallised from hexane. Example 110 A mixture of 5-fluoro-2-morpholinoaniline 10 (1.96 g) isobutyronitrile (2 g) and anhydrous aluminium chloride was heated at 150°C for four hours to give N-(5-fluoro-2-morpholinophenyl) isobutyramidine (m.p. 142°C) which was recrystallised from hexane and converted into its fumarate salt (m.p. 15 172°C) which was recrystallised from a 1:1 mixture of methanol and ether. Example 111 A mixture of 4-(2-aminophenyl)morpholine hydrochloride (6.5 g) and valeronitrile (35 ml) were 20 heated at 160-165°C under nitrogen for 25 hours and then cooled. The mixture was treated with aqueous sodium hydroxide and the basified mixture was extracted with dichloromethane. The solvent was removed by evaporation and the residue distilled under a pressure 25 of 50mm Hg to remove half the unreacted valeronitrile. A solid separated on cooling which was separated by filtration, washed with hexane (50 ml) and recrystallised from hexane to give N-(2-morpholinophenyl )valeramidine. (m.p. 135-136°C). 30 Example 112 A mixture of 4-(2-aminophenyl)morpholine (3.56 g), pivalonitrile (5 g) and anhydrous aluminium chloride (8 g) was heated at 160-1 70°C for six hours to yield N-(2-morpholinophenyl)pivalamidine (m.p. 126°C) which - 67 - 23 195 0 was recrysCallised from hexane and converted into its monofumarate salt (m.p. 211°C) which was recrystallised from methanol. Examples 113-125 In a similar manner to that described in Example 2, the compounds prepared in the Examples listed below were converted into their fumarate salts which were recrystallised from the solvents given below:- mp of Starting Recrystallisation fumarate Ex. Example solvent salt (°C) 113 20 methanol 212 114 22 methanol 229-230 115 32 methanol 213 116 34 methanol 180(dec) 117 64 methanol 197(dec) 118 72 methanol 188 119 73 methanol:ether(1:2) 208-210 1 20 99 methanol:ether(1:2) 204-205 121 100 methanol 117-118 122 74 methanol:etherd:2) 179-180 123 102 methanol:ether(1:1) 189 1 24 107 methanol:ether(1:1) 162-163 125 111 isopropanol 1 56-158 Example 126 The product of Example 1 (2.6 g) was reacted at room temperature with excess acrylonitrile (5 ml). The product was recrystallised from ethylacetate to give 4-f 2-[1 -(2-cyanoethyl)-2-piperidinylideneamino] phenyl)morpholine. (m.p. 148°C). - 68 - 23195 Example 127 A mixture of 3-morpholinone (4 g) in dry acetonitrile (40 ml), 4-(2-aminophenyl)morpholine 'mS (3.6 g) in dry acetonitrile (20 ml) and phosphorous 5 oxychloride (3.6 ml) was heated for 40 hours at 65-70°C to give oil which was purified by column chromatography on neutral alumina (72 g) using (a) hexane, (b) dichloromethane:hexane (1:1) and (c) dichloromethane as eluant. The resulting oil was treated with a saturated 10 solution of hydrogen chloride in methanol (25 ml) to give a pale yellow solid which was recrystallised from a 1:1 mixture of methanol and ether to give 4 - [2-(3-morpholinylideneamino)phenyl]-morpholine hydrochloride (m.p. 262-263°C). 15 Example 128 A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4-(2-aminobenzyl)morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65-70°C for 48 hours to yield 4-[2-(2-piperidinyl-20 ideneamino)benzyl]morpholine (m.p. 108-110°C) which was recrystallised from hexane. Example 1 29 A mixture of 2-piperidone (6 g) in benzene (50 ml), 4-(2-amino-4-chlorobenzyl)morpholine (6.8 g) 25 in benzene (50 ml) and phosphorus oxychloride (5.5 ml) was heated at 60-65°C for 5 hours to give 4-[4-chloro-^ 2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 121-122°C) which was recrystallised from hexane. Example 130 30 A mixture of 1-methyl-2-pyrrolidone (4.8 g) in benzene (20 ml), 4-(2-aminobenzyl)morpholine (7.6 g) in benzene (50 ml) and phosphorus oxychloride (4.8 ml) was heated at 65-70°C for 18 hours to yield an oil which was dissolved in methanol (30 ml). Treatment with 57% - 69 - 23195 hvdroiodic acid (10.L ml) gave A-[2-(1-methy1-2-pyrrolidiny1ideneamino)benzyl]morpholine dihydro iodide (m.p. 230-232°C) which was recrystallised from ethanol. Example 131 A mixture of 1,3,3-trimethyl-2-pyrrolidinone (3 g) in benzene (20 ml), A-(2-aminobenzyl)morpholine (3.8 g) in benzene (10 ml) and phosphorus oxychloride (2.1 ml) was allowed to stand at room temperature for 28 hours and then heated at 60-65°C for 14 hours to yield an oil (2.9 g) which was dissolved in methanol (15 ml). Treatment with 57Z hvdroiodic acid (2.8 ml) gave A-(2-(1,3,3-trimethyl-2-pyrrolidinylideneamino)benzyl] morpholine dihydroiodide (m.p. 256-258°C) which was recrystallised from a 1:1 mixture of ethanol and ether. Example 132 A mixture of N-methylpivalamide (6.2 g) in benzene (50 ml), A-(2-aminobenzy1)morpholine (9 g) in benzene (AO ml) and phosphorus oxychloride (5 ml) was heated at 80-85°C for 12 hours to yield a solid which was dissolved in methanol (25 ml) and treated with fumaric acid (l.A g) to give N-methyl-N1-(2- morpholinomethylphenyl)pivalamidine monofumarate (m.p. 167-168°C) which was recrystallised from propan-2-ol. 2 3 1 9 5 ZJ - 70 - Example 133 A mixture of 1 ,3-dime thy 1-2-imidazolidinone (7 g) in benzene (45 ml), phosphorus oxychloride (6 ml) and -(2-aminophenyl)morpholine (8.5 g) in benzene (30 ml) 5 was heated for 30 hours at 65-70°C. The product was recrystallised from hexane to give 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 133-1 34 °C). Examples 134 to 154 10 In a similar manner to that described in Example 133 the compounds listed in Table VI were prepared by the reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with a compound of formula VIII (C grammes in D ml benzene) in the presence of 15 phosphorus oxychloride (E ml) for F hours at a temperature in the range 65-70°C. Notes to Table VI (32) Product recrystallised from hexane. (33) Coupling reaction performed at 90-95°C. 20 (34) Coupling reaction performed at 70-75°C. (35) Coupling reaction performed at 60-65°C. (36) The product was isolated as its fumarate salt which was recrystallised from a 2:1 mixture of isopropanol and ether. 25 (37) Coupling reaction performed at 75-80°C. (38) The product was isolated as its monofumarate salt which was recrystallised from a 1:2 mixture of methanol and ether. - 71 - 9 3 1 o 5 (39) The produce was isolated as its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether. (40) Coupling reaction performed at 80-85°C. (41) The product was purified by column chromatography on an alumina column using dichloromethane as eluant. (42) Coupling reaction performed at 80-85°C for 48 hours and at 90-95°C for 14 hours. The product 10 was purified by column chromatography on an alumina column using a 99:1 mixture of dichloromethane and methanol as eluant. 15 (43) The product was isolated as its sesquifumarate salt which which was recrystallised from a 1:2 mixture of methanol and ether. ) - 72 -Table VI NR.Rj, Ex. A B C D E F NR-j R2 R6 R11 R7 mp(°C) Notes 134 3.8 25 2.7 40 2.1 21 morpholino Me Me 4-F 115-117 (32) 135 9.8 25 12.6 10 7.3 50 morpholino Me Me 3-Me 85-86 (32) 136 2.9 30 2.6 30 2.1 23 morpholino Me Me 4 -Me 105-106 (32)(33) 137 5 25 4.2 35 3.7 35 morpholino Me Me 5-Me 109-110 (32)(34) 138 8.5 40 9.1 60 7.3 18 morpholino Me Me 4 -CI 103-104 (32) 139 4 40 2.7 30 2.2 23 morpholino Me Me 4-OMe 79-80 (32) 140 3.5 30 2.5 30 2.3 6 morpholino Me Me 4,5-(OMe)2 117-118 (32) (35) 141 3.2 20 2.7 30 2.2 28 1-pyrrolidiny1 Me Me H 162-163 (36) 142 5.2 30 5.1 30 4.1 70 1-pyrrolidinyl Me Me 3-Me 75-76 (32) 143 8.8 60 8.5 50 6.8 10 piperidino Me Me H 61 (32) PO Cn| CO cn o ( Ex. A B C 144 Ln OO 50 5.1 145 8.2 80 6.8 146 6.3 30 6.8 147 3.6 60 3.4 148 5.3 25 4.3 149 4.8 40 5.1 150 8.9 50 6.8 151 5.2 40 6.4 152 7.6 30 6.8 153 7.1 60 7.6 154 4.4 20 5.9 (.} - 73 -Table VI Cont e f nr]r2 4 26 thiamorpholino 5. 4 14 2 ,6-dimethyl-morpholino 5. 4 28 NEt2 2. 7 90 2-methy1-1 -pyrrolidinyl 3. 4 80 morpholino 4. 8 24 1-pyrrolidinyl 5. 4 12 N(CH2CH2OMe)2 4. 3 48 morpholino 5. 5 14 morpholino 5. 6 70 morpholino 4. 4 60 morpholino D 60 40 40 40 25 40 50 30 30 80 50 J R6 R11 R7 Me Me H Me Me H Me Me H Me Me H Me Me 3 -CI Me Me 4 -Me Me Me H Et Et H Me Me 6 -Me Et Me H Bu Me H mp(°C) 96-98 86-86 164-165 183-184 86-88 165-167 105-106 154-155 106-108 75-76 135-136 Notes (32) (32)(37) (38)(37) (39)(40) (32)(33)(41) (38) (40) (38)(37) (A2)(38) (40) (32) (40)(32) ^ (40) (41 ) (43) —J. CO cri - 7 A - ? 3 1 .9 5 0 Example 155 A mixture of N-(2-hydroxyethy1)ethylenediamine (31.2 g), urea (23.A g) and water (3 ml) was heated at 130°C for 3 hours and at 210°C for 8 hours arid then 5 distilled directly from the reaction mixture to give 1 -(2-hydroxyethy1)-2-imidazolidinone (30 g) as an oil [(b.p. 150-160°C (0.2 mm)] which solidified to give a solid (m.p. 50-51 ) . A mixture of 1-(2-hydroxyethy1)-2-imidazolidinone 10 (2.28 g), benzoic anhydride (A. 5 g) , triethylamine (2.A g), A-dimethylaminopyridine (0.1 g) and 1,2-dimethoxyethane (20 ml) was stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (15 ml) was added and the mixture extracted with 15 dichloromethane (100 ml). The extract was washed with water, brine and then dried and filtered. The solvent was removed to give 1-(2-benzoyloxyethyl)-2-imidazolidinone (m.p. 130-132°C) which was recrystallised from ethylacetate. 20 A mixture of 1 -(2-benzoyloxyethyl)-2- imidazolidinone (2.3 g) and methyl-A-toluenesulphonate (2 g) was heated at 90-95°C for A8 hours. The reaction mixture was then cooled to room temperature, treated with saturated sodium bicarbonate solution (10 ml) and 25 extracted with ethyl acetate (6 x 20 ml). The extract was washed with water and brine and then dried and filtered. The solvent was removed to give an oily residue (2 g) which was purified by column chromatography on silica gel (80 g, 100-200 mesh) using 30 a 1:1 mixture of ethylacetate and hexane as eluant to give 1 -(2-benzoyloxyethyl)-3-methy1-2-imidazolidinone as an oil. In a similar manner to that described in Example 133 , 1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidone - 75 - 2 3 19 5 (8.8 g) in benzene (30 ml) was reacted with 4-(2-amino-phenyl )morpholine (5.2 g) in benzene (20 ml) in the presence of phosphorus oxychloride (3.3 ml) for 35 hours at 80-85°C to yield an oil. The oil was 5 dissolved in methanol (10 ml) and treated with fumaric acid (1.8 g) . The solvent was removed by evaporation and the residue washed with ether and then dissolved in water. The aqueous solution was basified with aqueous sodium carbonate solution to pH 9-10 and extracted with 10 ether to yield an oil which was purified by chromatography on an alumina column using dichloromethane as eluant. The purified base (0.8 g) in methanol (10 ml) was treated with fumaric acid (0.23 g) to give 4-f2-[1 -(2-benzoyloxyethyl)-3-methyl- 15 2-imidazolidiny1ideneamino]phenyljmorpholine mono fumarate (m.p. 132-133°C) which was recrystallised from a 1:2 mixture of methanol and ether. Example 156 Reaction of tetramethylurea (10.4 g, 10.7 ml) in 20 dry benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.2 g) in dry benzene (100 ml) in the presence of phosphorus oxychloride (8.3 ml) for 30 hours at 65-70°C gave an oil which was purified by column chromotography on a neutral alumina column (100 g) eluted with hexane 25 to give as an oil. A solution of this base (2.5 g) in methanol (10 ml) was treated with 57% hydroiodic acid (1.3 ml) to give 2-(2-morpholinophenyl)-1 ,1,3,3-tetramethylguanidine hydroiodide as a pale yellow crystalline solid (m.p. 215-216°C) which was 30 recrystallised from a 2:3 mixture of methanol and ether. Example 157 Reaction of 3-ethyl-l ,1 ,3-trimethylurea (6.57 g) in benzene (70 ml) with 4-(2-aminophenyl)morpholine 35 (6 g) in benzene (30 ml) in the presence of phosphorus - 76 - 23 19 50 oxychloride (A.71 ml) for 45 hours at 65-70°C gave l-ethyl-2-(2-morpholinophenyl)-l,3,3-trimethvl-guanidirie (bp. 140°C at 0.2 mm Hg) . \ Example 158 5 Reaction of 3-ally1-1 ,1 ,3-trimethylurea (7.17 g) in benzene (50 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus -n. oxychloride (4.71 ml) for 45 hours at 70°C gave 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethy1-10 guanidine (bp. 1 48-1 50°C at 0.2 mm Hg) . Example 159 Reaction of 3-n-butyl-l ,1 ,3-trimethylurea (7 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (7.2 g) in benzene (30 ml) in the presence of 15 phosphorus oxychloride (4 ml) for 18 hours at 80-85°C gave 1-n-buty1-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (bp. 162-163°C at 0.7 mm Hg). Example 160 Reaction of 3-pentyl-l , 1 ,3-trimethylurea (7.5 g) 20 in benzene (80 ml) with 4-(2-aminophenyl)morpholine (6.46 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.06 ml) for 45 hours at 70°C gave 1-pentyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (b.p. 98°C at 1.5 mm Hg). •— 25 Example 161 Reaction of 1 -(2-hydroxyethyl)-2-imidazolidinone (13 g) in dry dimethylformamide (125 ml) with sodium hydride (50% suspension in paraffin oil 12 g) at 10°C for 3 hours was followed by treatment with methyl 30 iodide (35.5 g) over a period of one hour. The mixture was stirred at ambient temperature for 18 hours gave 1 -methy1-3 -(2-methoxyethyl)-2-imidazolidinone (b.p. 110-114°C at 0.4 mm). 2 3/950 - 77 - Reaction of 1-methyl-3-(2-methoxyethyl)-2-imidazolidinone (11.4 g) in benzene (60 ml) with 4-(2-aminopheny1)morpho1ine (8.9 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7.2 ml) for 5 30 hours at 80-85°C gave an oil a portion of which (1.8 g) was dissolved in methanol (10 ml) and treated with fumaric acid (0.9 g) to give 4-f2-[1-methy 1-3-(2-methoxyethyl)-2-imidazolidinylideneamino]phenyl)-morpholine monofumarate (m.p. 127-129°C) which was 10 recrystallised from propan-2-ol. Example 162 Reaction of 1-methyl-3-(2-hvdroxyethyl)-2-imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromethane (60 ml) in the presence of 15 triethylamine (9 g) and 4-dimethylaminopyridine (0.1 g) for 18 hours at ambient temperature gave 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone as an oil. Reaction of 1 -methyl-3-(2-acetoxyethyl)-2- 20 imidazolidinone (13.4 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.6 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7 ml) for 30 hours at 80-85°C gave 4 — ^2-[1-methyl-3-(2-acetoxy-ethyl)-2-imidazolidinylideneamino]phenyl) morpholine. 25 Reaction of 4-(2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolidinylideneamino]phenyljmorpholine (2.7 g) in dimethylformamide (10 ml) with sodium hydroxide (0.4 g) in water (10 ml) for one hour at 10°C gave an oil which was dissolved in methanol (10 ml) and treated with 30 fumaric acid (0.4 g) to give 4-^2 — [ 1 -methyl-3-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl) morpholine (m.p. 129-131°C) which was recrystallised from a 1:2 mixture of methanol and ether. - 78 2 3 1 9 5 Example 163 ReacCion of 4-dimeChylcarbamoylmorpho1ine (3.8 g) in benzene (25 ml) with 4-(2-aminopheny1)morpholine (3.5 g) in Che presence of phosphorus oxychloride 5 (2.1 ml) for AO hours aC 80-85°C gave N,N-dimethyl-N ' -(2-morpholinopheny1)morpholine-A-carboxamidine (m.p. 126-128°C) which was recrysCallised from hexane. Example 16A ReacCion of 1 -dimethylcarbamoylpiperidine (3.7 g) 10 in benzene (25 ml) wich 4-(2-morpholinophenyl)-morpholine (3.5 g) in che presence of phosphorus oxychloride for 35 hours aC 80-85°C gave N,N-dimeChyl-N'-(2-morpholinophenyl)piperidine -1 -carboxamidine (m.p. 88-90°C) which was recrysCallised from pecroleum ether 15 (b.p. 40-60°C) Example 165 ReacCion of 4-[2-(1,3-dimeChyl-2-imidazolidinyl-ideneamino)pheny1]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and 20 sodium metaperiodate (1 .4 g) in water (4 ml) for 4 hours at 10°C yielded 4-[2-(1,3-dimethyl-2-imidazol-idinylideneamino)phenyl]thiamorpholine-1 -oxide monohydrate (m.p. 103-105°C) which was recrystallised from a 1:1 mixture of 1 ,2-dimethoxyethane and hexane. 25 Example 166 A solution of 2-morpholinophenyl isothiocyanate (2.3 g) was treated with a saturated solution of ammonia in ethanol (20 ml) and the reaction mixture was stirred at room temperature for 3 hours. The resulting 30 solid was filtered, washed with ethanol and dried to give 1-[2-(4-morpholino)phenyl]thiourea (m.p. 1 94-195 °C). - 79 - 23 1950 A solution of 1 -(2-morpho1inopheny1)thiourea (7.2 g) in dry methanol (30 ml) was heated at reflux with methyliodide (4.2 g) for 2 hours. The solvent was removed under reduced pressure and dry ether (15 ml) was added and on scratching gave 2-methyl-l-(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (m.p. 151-152°C). A mixture of 2-me thy1-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (5 g) and ethylenediamine (2.4 g) , in dry ethanol (50 ml) was heated at reflux for 6 hours, the solvent removed under reduced pressure to give an oil which was dissolved in dichloromethane (50 ml), cooled, basified with 20% sodium hydroxide and the organic layer was washed successively with water, brine and dried (Na2SO^), filtered and the solvent removed to get a solid (4 g) which on recrystallisation from ethyl acetate gave 4 -[2-(2-imidazolidinylidene-amino)phenyl]morpholine (m.p. 185-186°C). Example 167 A mixture of 2-methyl-l-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3 g prepared as described in Example 166), N-methylethylenediamine (2 ml) and absolute ethanol (35 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from ethyl acetate to give 4-[2-(1-methyl-2-imidazoli-dinylideneamino)phenyl]morpholine (m.p. 156°C). Examples 168 to 202 In a similar manner to that described in Example 167, the compounds listed in Table VII were prepared by heating a mixture of a compound of formula XIII in which and R-j ^ are H, (G grammes), an N-substituted ethy 1-enediamine of formula ) 2^HRg (H grammes) in dry ethanol (I ml) under reflux for J hours. - 80 - 23 19 5 Note to Table VII Notes (32), (38), (39) and (41) has the meaning given with respect to earlier Tables. (44) Product recrystallised from ethylacetate. 5 (45) Product isolated as its monofumarate salt which was recrystallised from methanol. (46) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure A. 10 (47) Product isolated as its fumarate salt which was recrystallised from a 1:2 mixture of methanol and propan-2-ol. (48) Product recrystallised from a 1:4 mixture of 1 ,2-dimethoxyethane and petroleum ether (b.p. 1 5 40-60°C) . (49) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure B. (50) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure C. 20 (51 ) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure D. (52) Product recrystallised from a 1:2 mixture of ethylacetate and hexane. 25 (53) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure E. - 81 - 2 3 1 .9 5 0 (54) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure F. (55) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure G. 5 (56) Product was purified by chromatography on an alumina column using the following eluents sequentially:- hexane, a 1:1 mixture of dichloromethane and hexane and then dichloromethane. 10 (57) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure H. (58) Product recrystallised from a 1:1 mixture of ethylacetate and hexane. i u - 82 - Table VII R. H nJ. \fsj^ I Ex, H NRlR2 R, 168 3 .8 2.7 4 5 8 morpholino Et 169 2 .8 2.6 35 1 0 morpholino Pr 5 170 3 .8 3 45 14 morpholino i-Pr 171 5 .7 5.2 65 7 morpholino Bu \ * \ <& ^72 —* tl 3 .8 3.5 45 12 morpholino i-Bu -^173 n •'/ 7 .5 7.8 90 14 morpholino penty1 o -^''Am si Ky/ 3 .8 3 50 8 morpholino allyl - •:; 175 3 .8 3.1 45 25 morpholino ch2ch2oh f Ry mp(°C) Notes H 107-109 (32) H 131-132 (32) H 121-122 (32) H 88-89 (32) H 136-138 (32) H 72-74 (32) H 126-128 (32) H 131-132 (44) ro oj vo O ex. 1 76 177 178 1 79 180 181 182 183 184 185 186 187 188 189 - 83 - Table VII Cont. G H I J nr]r2 r6 r7 mp(°C) 7.9 6. .2 90 150 morpholino ch2ch2oh 3- Me 198-199 3.8 3, ,8 45 9 morpholino CH2CH2OMe h 74-75 3.8 4 , .2 40 24 morpholino cyclohexyl H 189-189 5.7 6, .75 70 12 morpholino CH2Ph H 96-97 7.6 9, .8 90 8 morpholino CH2CH2Ph h 106-108 11.4 8 , .3 150 24 morpholino ch2ch2nme2 h 151 5.7 6 70 24 morpholino ch2chohch2oh H 144-145 3.8 3 .4 45 18 morpholino CH2C(Me)=CH2 H 141-143 4.2 2 .4 45 8 N(CH2CH2OMe)2 Me h 140-141 3.0 2 o . ^ 30 40 N(CH2CH2OMe)2 ch2ch2oh H 110-111 7.9 4 .4 90 8 thiamorpholino Me H 115-117 5.4 3 .3 70 10 1-pyrrolidinyl Me H 117-118 3.9 3 .5 45 8 thiamorpholino Bu H 106-108 7.8 4 .4 90 75 morpholino Me 3- ■Me 120-121 9.8 5 .9 115 12 morpholino Me 4- ■Me 122-123 LO o> v— ho Ex. G H I J 191 7 . 2 6 .4 90 24 192 3. 7 3.1 45 32 193 5. 9 5.2 75 1 2 194 7 . 5 3.6 150 24 195 7 . 5 5.5 90 14 196 5. 9 3.4 70 70 197 2. ,8 2.2 40 24 198 3. 7 3.1 45 18 199 5. ,6 5.3 65 39 200 5, .9 3.4 70 70 201 7 , .6 8 90 23 202 3, .8 3.9 45 14 € (. - 84 -Table VII Cont. nr]r2 R6 R7 mp(°C) Notes 1-pyrrolidinyl ch2ch2oh h 166-167 <38)<51) 2-methyl-l -pyrrolidinyl ch2ch2oh h 81 (32)(54) morpholino Bu 4 -Me 114-116 (32) piperidino h H 163 (38X55) piperidino Me h 75-76 (41 )(32) (55) piperidino Me 3-Me 86-87 (56)(32)(57) thiamorpholino ch2ch2oh h 99-101 (58X50) piperidino ch2ch2oh H 105-107 (32) (55) morpholino (ch2)3oh H 139-140 (44) morpholino CH2CH(0H)Me H 147-148 (44) morpholino CH2CH(0H)Et H 112-113 (56) morpholino CH2C(OH)Me2 H 132-133 (44) ) - 85 2 3 19 5 Preparative Procedure A Reaction of 6-methyl-2-morpholinoaniline (9.6 g) in dioxan (25 ml) and water (100 nil) with thiophosgene (5.7 ml) at 0°C for 30 minutes and at room temperature 5 for 3 hours gave 6-methyl-2-morpholinophenyl isothiocyanate as an oil. Reaction of 6-methyl-2-morpholinophenvl isothiocyanate (8.8 g) with 33Z alcoholic ammonia solution (60 ml) at room temperature for 5 hours gave 10 1 -(6-methvl-2-morpholinophenyl)thiourea (9 g) as a pale yellow solid, m.p. 199°C which was recrystallised from a 1:1 mixture of ethylacetate and hexane. A mixture of 1-(6-mechyl-2-morpholinophenyl)-thiourea (9 g) and methyl iodide (2.5 ml) in dry 15 acetone (100 ml) was heated at reflux at 90-95°C for 2.5 hours to give 2-methyl-l-(6-methyl-2-morpholino-phenyl)-2-thiopseudourea hydroiodide. Preparative Procedure B A solution of N,N-bis(2-methoxyethyl)benzene-1 ,2-—- 20 diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been cooled to 0°C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice water (50 ml) was added and w 25 the mixture extracted with ether (3 x 20 ml) . The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to give a residue which was heated at 45 °C under vacuum (100 mm/Hg) to give 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate as an 30 oil. A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of - 86 - 23 19 5 10 2-[b is(2-methoxyechyl)amino]phenyl isothiocyanate (7.5 g) and ethanol (10 ml) which had been cooled to 10°C. The mixture was scirred aC 0°C for 8 hours and Chen sCirred wichouc cooling for 16 hours. The solvenc was Chen removed by evaporacion and the residue purified by chromatography on a silica column eluted with a 1:4 mixture of ethyl acetate and hexane and then a 1:1 mixture of ethyl acetate and hexane to give 1 - f 2-[ bis (2-methoxyethyl )amir.o] pheny 1) thiourea (m.p. 118-119 °C). 15 A mixture phenyl)thiourea acetone (25 ml) Removal of the triturated with of 1 -(2-[bis(2-methoxyethyl)amino] (5 g), methyl iodide (1.4 ml) and was heated at 40°C for 2 hours, solvent gave a residue which was ether to give 2-methyl-l-^2-[bis(2- hydro- methoxyethyl)amino]phenyl)-2-thiopseudourea iodide (m.p. m-112°C). Preparative Procedure C A solution of 2-thiamorpholinoaniline (14.6 g) in 20 dioxane (10 ml) was added over 15 minutes to a mixture of .thiophosgene (8.77 ml) and water (120 ml) which had been cooled to 0°C. The mixture was stirred and its temperature was allowed to rise to ambient. The mixture was then stirred for 4 hours and ice/water 25 (200 ml) was added. The mixture was extracted with ether (2 x 100 ml) and the extracts washed with water (50 ml) and then brine (100 ml) and the solvent removed by evaporation to give a residue which was heated at 40-45°C under vacuum (100 mm/hg) for two hours to give 30 2-thiamorpholinophenyl isothiocyanate (m.p. 55-56°C). 25Z Aqueous ammonia solution (100 ml) was added to a mixture of 2-thiamorpholinophenyl isothiocyanate (14 g) and ethanol (40 ml) at 10°C. The mixture was - 87 - 23 19 5 0 stirred at 30°C for 24 hours and then cooled to 10°C. 1-(2-thiamorpholinophenyl)thiourea was collected by filtration, washed with water (100 ml) and dried (m.p. 170-171°C). 5 A mixture of 1-(2-thiamorpholinophenyl)thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90-95°C for 2% hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-l-(2-thiamor-10 pholinophenyl)-2-thiopseudourea hydroiodide (m.p. 1 76-1 77 °C). Preparative Procedure D Benzoylisothiocyanate (10 ml) was added over 30 minutes to a mixture of 2-(1-pyrrolidinyl)aniline 15 (10.6 g) and dichloromethane (30 ml). The mixture was then stirred at 30°C for 4 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) for 30 minutes and triturated with ether. 3-Benzoyl-1 -[2 - (1 -pyrrolidinyDphenyl] thiourea 20 was collected by filtration, washed with ether and dried (m.p. 172-173°C). A mixture of 3-benzoyl-1-[2-(1-pyrrolidinyl)-phenyl]thiourea (18.1 g) , sodium hydroxide (5 g) and water (50 ml) was heated at 90-95°C for 4 hours. Ice 25 and then 50% aqueous hydrochloric acid were added. The mixture was filtered and the filtrate treated with saturated sodium bicarbonate solution to pH 8. l-[2-(1-PyrrolidinyDphenyl] thiourea was collected by filtration, washed with water and dried (m.p. 30 185-186°C). A mixture of 1 - [2-(1 -pyrrolidinyDphenyl] thiourea (12.2 g) , acetone (100 ml) and methanol (20 ml) was 88 - 2 3 19 5 0 heated to 90-95°C. Methyl iodide (8.36 g) was added and the mixture heated under reflux for 3 hours. The solvent was removed by evaporation to give a residue which was dried under vacuum (5 mm/Hg) to give 5 2-methyl-l-[2-(1-pyrrolidinyl)phenyl]-2 -thiopseudourea hydroiodide (m.p. 139-141°C). Preparative Procedure E Reaction of 5-methyl-2-morpholinoaniline (20 g) in dioxan (80 ml) and water (200 ml) at 0°C for 30 10 minutes and at room temperature for 2 hours gave 5-methyl-2-morpholinophenyl isothiocyanate, (m.p. 91-92°C). Reaction of 5-methyl-2-morpholinophenyl isothiocyanate (15 g) with 33" ethanolic ammonia 15 solution for 48 hours at room temperature gave 1-(5-methyl-2-morpholinophenyl)thiourea as a pale yellow solid (m.p. 181-182°C). A mixture of 1 -(5-methyl-2-morpholinophenyl)-thiourea (14 g), methyl iodide (7.9 g) in methanol 20 (50 ml) was heated at reflux for 2 hours to give 2-methyl-1-(5-methy1-2-morpholinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, m.p. 157-159°C. Preparative Procedure F A mixture of 2-methyl-l-(2-aminophenyl) 25 pyrrolidine (9.1 g) and benzoyl isothiocyanate (9.2 g) 7.7 ml) and dichloromethane (100 ml) was stirred at room temperature for 8 hours and left overnight. Removal of the solvent and trituration with ether gave 1-benzoyl-3-[2-methyl-l-pyrrolidinyl) phenyl]thiourea, 30 (m.p. 105-106°C). - 89 - 2 3 19 5 0 A mixture of 1-bervzoyl-3-[ 2-( 2-me thy 1-1-pyrrolidiny L) pheny L ] thiourea (9 g), sodium hydroxide (1 g, as pellets) and water (10 ml)' was heated at 90-95°C for 48 hours to give 1 -[2-(2-methyl-1 -pyrrolidinyDphenyl] 5 thiourea (m.p. 145-148°C) which was purified by column chromatography on silica gel using a 1:1 mixture of ethylacetate and hexane as eluant. A mixture of 1-[ 2-(2-methyl-1-pyrrolidiny 1) phenyl ] thiourea (3.4 g) and methyl iodide (2.1 g) in acetone 10 (60 ml) was heated at 90-95°C for 3 hours and the solvent removed to give 2-methy1-1 -[2-methyl-1 -pyrrolidinyDphenyl] -2-thiopseuaourea hydroiodide (3.7 g) as a thick oil. Preparative Procedure G 15 A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 ml) was added over 25 minutes to a mixture of thiophosgene (10.2 ml) and water (200 ml) which had been cooled to 0°C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred 20 for 4 hours. Ice (200 g) and water (200 ml) were added r) and the mixture extracted with ether (6 x 50 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried and evaporated to give a residue which purified by chromatography on a silica column 25 eluted with hexane to give 2-piperidinophenyl '.w/ isothiocyanate as an oil. 25% Aqueous ammonia solution (60 ml) was added to a mixture of 2-piperidinophenyl isothiocyanate (12 g) and ethanol (25 ml) which had been cooled to 10°C. The 30 mixture was stirred at 30°C for 24 hours and then cooled to 10°C. 1-(2-Piperidinophenyl)thiourea was collected by filtration, washed with water and dried (m.p. 143-145°C). - 90 - 2 3 1 9 5 A mixture of 1 -(2-piperidinophenyl)thiourea (10.1 g), methyl iodide (5.35 g) and methanol (50 ml) was heated at 50-55°C for 2 hours. The solvent was removed by evaporation and the residue dried under 5 vacuum (5 mm/Hg) to give 2-methyl-l-(2-piperidinophenyl )-2-thiopseudourea hydroiodide (m.p. 160-1 62°C). Preparative Procedure H Reaction of 6-methvl-2-piperidinoaniline (6.4 g) in dioxan (20 ml) and water (65 ml) with thiophosgene 10 (5.7 g) at 0°C for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothiocyanate as an oil. Reaction of 6-methyl-2-piperidinophenyl isothiocyanate (6.8 g) with 25Z aqueous ammonia solution 15 (65 ml) in ethanol (20 ml) for 8 hours at room temperature gave 1 -(6-methyl-2-piperidinophenyl) thiourea as a pale yellow solid (m.p. 197-198°C). A mixture of 1 -(6-methyl-2-piperidinophenyl)-thiourea (7 g) and methyl iodide (4.38 g) in dry 20 methanol (100 ml) was heated under reflux for 3 hours to give 2-methyl-l-(6-methyl-2-piperidinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, (m.p. 204-205°C). Example 203 25 A mixture of 2-methyl-l-(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 2-methylethylenediamine (2.2 g) and ethanol (45 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from 30 ethyl acetate to give 4-[2-(4-methyl-2-imidazol-idinylideneamino)phenyl]morpholine (m.p. 173-174°C). - 91 - 2 3 19 5 Example 20A A mixture of 2-me thy1-1 -(2-morpholinopheny1)-2-thiopseudourea hydroiodide (7.6 g prepared as described in Example 166), 1,2-dimethylethylenediamine (5.3 g) 5 and ethanol (90 ml) was heated under reflux for 70 hours to give a solid which was recrystallised from ethylacetate to give 4 - [2-(4,5-dimethy1-2-imidaz-olidinylideneamino)phenyl]morpholine (m.p. 142-1A3°C). Example 205 10 Ethylene oxide generated from 2-chloroethanol (36 g) and potassium hydroxide pellets (20 g) in methanol (60 ml) was reacted with 1 ,2-dimethylethylene-diamine (22.6 g) in methanol (50 ml) at -15°C to give N-(2-hydroxyethyl)-1,2-dimethylethylenediamine as a 15 colourless liquid (b.p. 89-91°C at 1 mmHg) . A mixture of 2-methyl-1 -(2-morpholinophenyl)-2-thiopseudourea (12.5 g) and N-(2-hydroxyethyl)-1,2-dimethylethylenediamine (8 g) in dry ethanol (150 ml) was heated under reflux at 90-95°C for 6 days to give a 20 dark brown oil which was purified by column chromatography on neutral alumina (250 g) using a 1:9 mixture of dichloromethane and hexane to give A-^2-[A,5-dimethy1-1 -(2-hydroxyethyl)-2-imidazolidinylidene-amino]phenyl)morpholine as a colourless solid (m.p. 25 108-109°C) which was recrystallised from hexane. Example 206 A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), N'-isopropyl-2-methyl-l,2-30 propanediamine (3.95 g) and ethanol (45 ml) was heated under reflux for 28 hours to yield an oil which was purified by column chromatography on a neutral alumina - 92 - 2 3 19 5 column using dichloromethane as eluant. The resultant oil (1.5 g) was dissolved in methanol (10 ml) and fumaric acid (0.5 g) was added to give A-[2-(l-iso-propyl-A,A-dime thy 1-2-imidazolidinvlidenamino)phenyl]-5 morpholine monofumarate (mp 206-208°C) which was recrystallised from a 1:3 mixture of methanol and ether. Example 207 A mixture of 2-me thy 1-1 -(2-morpholinopheny1)-10 2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 3-methylaminopropylamine (2.6 g) and absolute ethanol (AO ml) was heated under reflux for 6 hours to give a solid which was recrystallised from ether to give A-[2-(1-methylper-15 hydropyrimidin-2-ylideneamino)phenyl]morpholine (m.p. 138-139°C). Example 208 A mixture of 2-methyl-l-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (7.6 g) and 20 1,A-diaminobutane (5.3 g) in ethanol (150 ml) was heated under reflux for 60 hours to give a white solid (m.p. 135°C) which was recrystallised from ethyl acetate. The solid (2.7 g) was dissolved in methanol (20 ml) and treated with fumaric acid to give 25 2-(2-morpholinophenylimino)-1,3-diazocycloheptane fumarate (m.p. 220-222°C) which was recrystallised from a 1:1 mixture of methanol and ether. Example 209 A mixture of 2-methyl-l-(2-morpholinophenyl)-30 2-thiopseudourea hydroiodide (1 g), dimethylamine (1 ml of a 33% solution in ethanol) and ethanol (2 ml) was kept at ambient temperature for A8 days. The mixture was then cooled in an ice bath. The resulting solid was separated by filtration, treated with dilute 23 1 q yJ I 9 1 - 93 - K aqueous sodium hydroxide solution (5 ml) and the resulting mixture extracted with dichloromethane (2 x 50 ml). The extract was washed with brine, dried and the solvent removed by evaporation to give 5 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 143-144°C) which was recrystallised from hexane. Example 210 """ A solution of A-(2-aminophenyl) morpholine (5.3g) in dichloromethane (25 ml) was treated with methyl 10 isothiocyanate (3.2g) and the mixture stirred at room temperature for 36 hours to yield 1 -(2-morpholino phenyl)-3-methylthiourea (m.p. 115-116°C) which was recrystallised from a A:1 mixture of ethyl acetate and hexane. 15 A mixture of 1 -(2-morpholinophenyl)-3-methyl thiourea (5 g) and methyliodide (2.8 g) in acetone (30 ml) was heated at reflux for 4 hours to yield 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (m.p. 163-164°C) which was recrystallised from a 20 1:3 mixture of methanol and ether. A mixture of 2-methyl-l-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g) and 337. methylamine in solution in absolute ethanol (40 ml) was heated for 28 hours at 50-55°C to yield 1,3-25 dimethyl-2-(2-morpholinophenyl)guanidine which was ^ recrystallised from hexane (m.p. 137-138°C). Example 211 A mixture of 2-methyl-l-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared 30 as described in Example 210) and dimethylamine (25 ml of a 33Z solution in ethanol) was kept at ambient temperature for 25 days. Removal of the solvent gave a - 94 - 23 19 5 0 residue which was purified by chromatography on an alumina column using a 1:49 mixture of methanol and dichloromethane as eluant. The resulting solid was dissolved in methanol and treated with fumaric acid to 5 give 1 ,3,3-trimethyl-2-(2-morpholinophenyl)guanidine monofumarate (m.p. 192-194°C) which was recrystallised from a 1:2 mixture of methanol and ether. Example 21 2 Reaction of 2-morpholinophenyl isothiocyanate (3.3 10 g) with ethylamine generated from ethylamine hydrochloride (12.18 g) and sodium methoxide [generated from sodium (3.5 g) and methanol (100 ml)] gave 1-ethyl-3-(2-morpholinophenyl)thiourea (m.p. 118-120°C) which was recrystallised from a 1:1 mixture 15 of ethylacetate and hexane. A mixture of 1-ethyl-3-(2-morpholinophenyl) thiourea (3.2 g) and methyliodide (2 g) in acetone (25 ml) was heated at reflux for 4 hours to yield 2-methyl-3-ethyl-l -(2-morpholinophenyl)-2-thiopseudourea 20 hydroiodide as a pale yellow solid (m.p. 170°172°C) which was recrystallised from acetone. A mixture of 2-methy1-3-ethyl-l-(2-morpholinophenyl) -2-thiopseudourea hydroiodide (6 g) and 33£ methylamine in absolute ethanol solution (250 ml) was 25 heated initially for 24 hours at 45°C and then left at room temperature for 14 days to yield 1-ethyl-2-(2-morpholinophenyl)-3-methyIguanidine as a colourless solid (m.p. 118—119°C) which was recrystallised from hexane. 30 Example 213 Sodium (23 g) was added to ethanol (300 ml) and the resulting solution of sodium ethoxide was reacted with ethylamine hydrochloride to give a solution of Hfth. J 23 1 9 - 95 - ethylamine which was stirred at room temperature for 30 days with 2-methyl-3-ethyl-l-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (6 g prepared as described in Example 212) to yield 1 ,3-diethyl-2-(2-morpholino-5 phenyl)guanidine (m.p. 101-102°C) which was recrystallised from hexane. Example 214 Reaction of 4-f2-[1-(2-hydroxyethy1)-2-imidazolidiny lideneamino]pheny1)morpholine (3 g prepared as 10 described in Example 175) in dichloromethane (20 ml) with acetic anhydride (0.86 g) yielded A-^2-[l—(2— acetyloxyethyl)-2-imidazolidinylideneamino]phenyl)-morpholine (m.p. 89-91°C) which was recrystallised from hexane. 15 Example 215 Reaction of 4-f2-[1 -(2-hydroxyethyl)-2-imidazol-idinylideneamino]phenyl)morpholine (2.9 g prepared as described in Example 175) in dichloromethane (60 ml) with benzoic anhydride (2.4 g) in the presence of dry 20 triethylamine (2 ml) and 4-dimethylaminopyridine (50 mg) gave an oil which was purified by chromatography on an alumina column using dichloromethane as eluant to give 4-f2-[1-(2-benzoyloxyethyl)-2-imidazolidinylideneamino]phenyl)morpholine 25 (m.p. 92-94°C) which was recrystallised from a 1:1 mixture of ethyl acetate and hexane. Example 216 A solution of 4-(2-aminophenyl)morpholine (5.8 g) in dichloromethane (60 ml) was treated with n-butyl 30 isothiocyanate (5 g) and mixture stirred at room temperature for 4 days to yield 1 -(n-butyl)-3-(2-morpholinophenyl)thiourea as a pale yellow solid (m.p.105 °C). m - 96 - 2 3 t 9 5 A mixture of 1 -(n-buty1)-3-(2-morphoIino pheny 1) thiourea (5.8 g) and methyliodide (3.1 g) in acetone (25 ml) was heated at reflux for 4 hours to yield 2-methyl-3 -(n-buty1)-1 -(2-morpholinophenyl)- 5 2-thiopseudourea hydroiodide as a colourless solid m.p 1 54-156°C. A mixture of 2-methyl-3-(n-buty1)-1-(2-morpholinophenyl) -2-thiopseudourea hydroiodide (4.0 g) and 33Z methylamine in absolute ethanol solution (200 ml) was 10 heated intially for 24 hours at 45° and then left at room temperature for 21 days to yield 1-(n-butyl)-2 — (2-morpholinophenyl)-3-methylguanidine as an oil; a solution of which in methanol (25 ml) on treatment with fumaric acid (0.7 g) gave a colourless solid which was 15 recrystallised from a 1:1 mixture of methanol and ether to give 1-(n-butyl)-2-(2-morpholinophenyl)-3-methyl-guanidine monofumarate (m.p. 170-172°C). Example 217 A mixture of 2-methyl-1-(2-piperidino)phenv1]-20 2-thiopseudourea hydroiodide (7.5 g prepared as described in Preparative Procedure G) , 2-methoxyethvl-amine (2 ml) and ethanol (40 ml was stirred at ambient temperature for 20 days. Removal of the solvent gave a residue which was dissolved in methanol and treated 25 with fumaric acid to give 1-(2-methoxyethyl)— 2 — (2 — piperidinophenyl)guanidine hemifumarate (m.p. 218-220°C) which was recrystallised from a 1 :2 mixture of methanol and ether. Example 218 30 A mixture of 2-methyl-l-(2-morpholinophenyl)-2- thiopseudourea hydroiodide (1.7 g) prepared as described in Example 166, 2-methylthioethylamine (1.8 g) and ethanol (25 ml) was heated at 90-95°C for 22 hours to give 1 -(2-methylthioethyl)-2-(2- - 97 - 2 3 ; 9 t morpholinophenyl) guanidine' (m.p. 115-1 16°C) which was recrysCallised from hexane. Example 219 A mixcure of 2-meChy1-1 -(2-morpholinopheny1)-2-5 Chiopseudourea hydroiodide (7.6 g), 2-meChoxyeChylamine (2 ml) and echanol (45 ml) was scirred ac ambienc CemperaCure for 14 days Co give 1 -(2-mechoxyechyl)-2-(2-morpholinophenyDguanidine (m.p. 1 25-1 28°C) which was recrysCallised from 1,2-dimechoxyechane and 10 converced inco ics fumarace sale (m.p. 136-138°C) which was recrysCallised from a 1:2 mixture of mechanol and echer. Example 220 A mixcure of 2-mechyl-l-(2-morpholinophenyl)-3-15 mechyl-2-chiopseudourea hydroiodide (7.8 g prepared as described in Example 210), n-propylamine (1.3 g) and echanol (50 ml) was scirred ac ambienc temperaCure for 45 days Co yield an oil which was purified by chromaCography on a neuCral alumina column using a 1 :99 20 mixcure of mechanol and dichloromethane as eluenC. The resulcing oil was dissolved in mechanol and Created wich fumaric acid to give 1 -(n-propyl)-2-morpholinophenyl) -3-methylguanidine monofumarate (m.p. 187-188°C) which was recrystallised from a 1:2 mixture of methanol 25 and ether. Example 221 A mixture of 2-methyl-l-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), 2-methoxyethylamine (0.82 g) 30 and ethanol (25 ml) was stored at ambient temperature for three months to yield an oil which was dissolved in methanol and treated with fumaric acid to give 1-methyl-2-(2-morpholinophenyl)-3-(2-methoxyethyl)-guanidine monofumarate (m.p. 158-160°C) which was - 98 - 2 3 1 .9 5 recrystallised from a 1:2 mixture of methanol and ether. Example 222 A mixture of 2-methvl-1-(2-morpholinophenyl)-3-5 methyl-2-thiopseudourea hydriodide (7.86 g prepared as described in Example 210), cyclopentylamine (2.9 g) , anhydrous sodium carbonate (6.36 g) and ethanol (100 ml) was heated in a stainless steel pressure vessel in an oil bath at 110°C for 24 hours. The 10 reaction mixture was cooled, filtered and the solvent was partially removed. The residue was poured onto ice and the resulting mixture extracted with dichloromethane. The extract was dried, filtered and the solvent removed to give a residue which was treated 15 with fumaric acid to give 1-cyclopenty1-2-(2-morpholinophenyl)-3-methylguanidine monofumarate (m.p. 220°C) which was recrystallised from a 1:1 mixture of methanol and ether. Example 223 20 A mixture of 2-methyl-1-(2-morpholinopheny1)-3- methyl-2-thiopseudourea hydriodide (3.9 g prepared as described in Example 210), pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux for two weeks to yield an oil which was purified by chromatography on 25 a neutra alumina column eluted with a 1:1 mixture of dichloromethane and hexane and then a 1:9 mixture of methanol and dichloromethane to give N-methyl-N1-(2-morpholinophenyl)pyrrolidine-l-carboxamidine which was converted into its monofumarate salt (m.p. 168-171°C) 30 which was recrystallised from propan-2-ol. Example 224 A mixture of 2-methyl-l-(2-morpholinophenyl)-3-ethyl-2-thiopseudourea hydriodide (10 g prepared as described in Example 212), n-butylamine (2.7 g) and -99 - 2 3 19 5 t-butanol (75 ml) was heated at 90-95°C for 172 hours to yield 1 -(n-butyl)-2-(2-morpholinophenyl)-3-ethyl-guanidine which was converted into its monofumarate salt (m.p. 159-160°) which was recrystallised from a 5 1:2 mixture of methanol and ether. Example 225 Reaction of 5-chloro-2-morpholinoaniline (2.8 g) with n-butyl isothiocyanate (1.5 g) in ethanol (20 ml) at room temperature for 60 days yielded 1 -(n-buty1)-3-10 (5-chloro-2-morpholinophenyl)thiourea (m.p. 150-152°C). A mixture of 1-(n-butyl)-3-(5-chloro-2-morphol-inophenyl)thiourea (2.6 g) , methyl iodide (1.4 g) and acetone (20 ml) was heated under reflux for 3 hours to give 2-methyl-l-(5-chloro-2-morpholinophenyl)-3-(n- 15 butyl)-2-thiopseudourea hydroiodide (m.p. 130-132°C). A mixture of 2-methyl-l-(5-chloro-2-morpholinophenyl) -3-(n-butyl)-2-thiopseudourea hydroiodide (3.4 g) and a 33% ethanolic solution of methylamine (10 ml) were stored at ambient temperature in a sealed 20 container for 8 months to yield 1,3-dimethyl-2-(5-chloro-2-morpholinopheny1)guanidine (m.p. 145-146°C) which was recrystallised from hexane. In this reaction the butylamino and the methylthio group of the starting material are replaced by a methylamino group. 25 Example 226 Reaction of 1-(2-aminophenyl)pyrrolidine (10 g) with methyl isothiocyanate (6.3 g) in dichloromethane (45 ml) at room temperature for 4 days gave 1-methyl-3-[ 2 - (1 -pyrrolidinyDphenyl] thiourea (m.p. 125-1 26°C). 30 A mixture of 1-methyl-3-t2-(1-pyrrolidinyl)- phenyl]thiourea (18.5 g) and methyl iodide (12.3 g) and - 100 - 2 3 ■; 9 5 acetone (100 ml) was heated under reflux for 2.5 hours to give 2-methyl-l-[2-(1-pyrrolidiny1)phenyl ] - 3-methyl-2-thiopseudourea hydroiodide (m.p. 161-162°C). A mixture of 2-me thy 1-1-[2-(1-pyrrolidinyl)-5 phenyl]-3-methyl-2-thiopseudourea hydroiodide (14.7 g), allylamine (4.45 g) and ethanol (65 ml) was stored at ambient temperature for 50 days and was then heated under reflux for 20 hours to give an oil which was treated with fumaric acid to give 1-allyl-2-[2-10 (1-pyrrolidinyl)phenyl]-3-methylguanidine monofumarate (m.p. 162-163°C) which was recrystallised from a 1:2 mixture of methanol and ether. Example 227 A solution of 4-(2-amino-4-methylphenv1)morpholine 15 (5.7 g) in dichloromethane (30 ml) was treated with methylisothiocyanate (2.8 g) and the reaction mixture kept at room temperature for 6 days to yield 1-methyl-3-(5-methy1-2-morpholinophenv1)thiourea as a colourless solid (m.p. 107°C). 20 A mixture of 1-methy1-3-(5-methy1-2-morpholino- phenyl) thiourea (6.4 g) and methyl iodide (3.8 g) in acetone (60 ml) was heated at reflux for 4 hours to give 2-methyl-l -(5-methyl-2-morpholinophenyl)-3- methyl-2-thiopseudourea hydroiodide as a pale yellow 25 solid (m.p. 160-161°C) . A mixture of 2-methy1-1 -(5-methy1-2-morpholino-phenyl)-3-methyl-2-thiopseudourea hydroiodide (6 g) and 33£ methylamine in absolute ethanol solution (250 ml) was kept at room temperature for 21 days to yield 1,3-30 dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine as an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g) to give 1 ,3-dimethyl-2-(5-methyl-2-morpholinophenvl)guanidine fumarate (1.2 g) as - 101 - 2319 a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether (m.p.201-202°C). Example 228 A mixture of 2-methy1-1-(5-methy1-2-morpholino-5 phenyl)-3-methyl-2-thiopseudourea hydroiodide (8.4 g prepared as described in Example 227), N-(2-hydroxy-ethvl)ethylenediamine (6.8 ml) and ethanol (80 ml)) was heated under reflux for 30 hours to give an oil which was treated with fumaric acid in methanol to give 4-(2-10 [ 1 -(2-hydroxyethyl)-2-imidazolidinylideneamino] -4- methylphenyljmorpholine sesquifumarate (m.p. 135-1 36 °C). Example 229 A mixture of 2-methyl-l-(2-morpholinophenyl)-3-15 methy1-2-thiopseudourea (4 g prepared from the hydroiodide salt described in Example 210), potassium hydroxide (1.7 g), n-pentylamine (2.1 g), lead acetate trihydrate (5.8 g) and ethanol (20 ml) were heated at 90-95°C for 40 minutes to yield an oil which was 20 extracted with hexane to give 1-methyl-2-(2-morpholinophenyl) -3-(n-pentyl)guanidine which was converted into its monofumarate salt (m.p. 148-149°C) which was recrystallised from a 3:5 mixture of methanol and ether. 25 Example 230 A mixture of 2-methyl-l-(5-methyl-2-morpholino-phenyl)-3-methyl-2-thiopseudourea hydroiodide (12.2 g prepared as described in Example 227), n-butylamine (2.4 g) and ethanol (80 ml) was stored at ambient 30 temperature for 4 months. Lead acetate trihydrate (9 g) was then added and the mixture heated under reflux for one hour to yield 1 -(n-butyl)-2-(5-methyl-2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 150°C) which was - 102 - 2 3 19 5 recrysCallised from a 1:2 mixcure of mechanol and eCher. Example 231 ReacCion of 6-meChyl-2-morpholinoaniline (8.75 g) 5 wich mechyl isochiocvanace (A. 7 g) in dichloromeChane (50 ml) aC room CemperaCure for four days yielded N-mechy1-N'-(6-mechy1-2-morpholinophenyl)chiourea (m.p. 182-183°C). A mixcure of N-meChyl-N'-(6-methyl-2-morpholino-10 pheny1)chiourea (11.5 g) , mechyl iodide (6.75 g) and aceCone (100 ml) was heaced under reflux for 2.5 hours Co give 2-methyl-l-(6-methyl-2-morpholinophenyl)-3-meChyl-2-chiopseudourea hydroiodide (m.p. 187-188°C). A mixcure of 2-methyl-l-(6-methyl-2-morpholino-15 phenyl)-3-meChyl-2-chiopseudourea hydroiodide (17.8 g) , n-bucylamine (6.A g) and echanol (60 ml) was scored aC ambienc temperature for 60 days. Pocassium hydroxide (2.2 g) and Chen lead aceCaCe CrihydraCe (7.6 g) were added and the mixture was heated under reflux for 5 20 hours to yield 1 -(n-butyl)-2-(6-methyl-2-morpholino-phenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 203-20A°C) which was recrystallised from a 1:2 mixture of methanol and ether. 25 Example 232 Reaction of N-(2-morpholinophenyl) isothiocyanate (A g) in ethanol (10 ml) with 331 ethanolic dimethyl-amine solution (15 ml) at 15°C for four hours gave 1 ,1-dimethyl-3-(2-morpholinophenyl)thiourea (m.p. 30 150-152°C). A mixture of 1,1-dimethyl-3-(2-morpholinophenyl)-thiourea (7.5 g) , methyl iodide (1.7 ml) and acetone 103 2 3 1 9 5 0 was heated under reflux for 2 hours to give 2-methyl-l-(2-morpholinophenyl)-3,3-dime thy1-2-thiopseudourea (m.p. 162-163°C). A mixture of 2-methyl-l-(2-morpholinophenyl)-3 , 3-5 dimethyl-2-thiopseudourea hydroiodide (2 g), a saturated ethanolic ammonia solution (10 ml) and pyridine (10 ml) was heated at 90-95°C for 19 hours in a sealed stainless steel pressure vessel. Pyridine was removed by evaporation under reduced pressure and the 10 residue suspended in water. 1 ,1-Dimethyl-2-(morpholinophenyl) guanidine (m.p. 142-143°C) was collected by filtration, washed with water, dried and recrystallised from hexane. Example 233 15 A mixture of 2-methyl-l-(2-morpholinophenyl)-2- thiopseudourea hydroidide (3.8 g), a 332 ethanolic solution of dimethylamine (5 ml) and pyridine (25 ml) was heated at 80 °C for 6 hours. Pyridine was removed by evaporation under reduced pressure and the residue 20 treated with a mixture of ice and water to give 1,1 — dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142-144°C) which was recrystallised from hexane. Example 234 A mixture of 2-methyl-l-(2-morpholinophenyl)-2-25 thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and triethylamine (25 ml) was heated at 80°C for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to 30 give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141-143°C) which was recrystallised from hexane. -10* - 2 3 19 5 Examples 235 Co 241 The compounds of formula I lisCed in Table VIII were prepared by heaCing a mixCure of a Chiourea of formula XVI in which is mechyl and R-| ^ is H (A g) , pocassium hydroxide (B g) , an amine of formula I^NRg (C g), lead aceCaCe crihydrace (D g) and echanol (E ml) aC 90-95°C for F hours Co yield an oil which is dissolved in mechanol and creaced with fumaric acid Co give the monofumarate salt of the compounds of formula I. The melting point of the monofumarate salt is given in the column headed "m.p." and the solvent from which the salt was recrystallised is identified by the following Notes. 23 19 - 105 - Notes to Table VIII (59) Salt recrystallised from mechanol. (60) The thiourea starting material was prepared by the reaction of 4-(2-amino-4-fluoropheny1)morpholine (6 g) with methyl isothiocyanate (2.6 g) in dichloromethane (50 ml) at room temperature for 25 days to give 1 -methyl-3-(5-fluoro-2-morpholino-phenyl)thiourea (m.p. 145-148°C). (61) The free base was purified by chromatography on a neutral alumina column using dichloromethane as eluent. (62) The thiourea starting material was prepared by the reaction of 4-(2-amino-4-methylthiophenyl)-morpholine (9.5 g) with methyl isothiocyanate (3.1 g) in dichloromethane (100 ml) at room temperature for 30 days to give l-methyl-3-(5-methylthio-2-morpholinophenyl)thiourea (m.p. 132-133°C). (63) Salt recrystallised from a 1:2 mixture of methanol and ether. (64) Salt recrystallised from propan-2-ol. ( -106- ) ) * Table VIII R- N=^ 3^- fvl H N^\ q_ kim r, Ex A B C D E F NR1R2 R6 R7 mp(°C) Notes 235 5 . 4 2.2 2.2 7.4 40 2 morpholino n-Bu 4-F 212(dec) (59)(60) 236 5. 9 2.24 2.2 7.6 60 1 .5 morpholino n-Bu 4-SMe 120-122 (61)(62)(63) 237 5 2.2 2.9 7.6 50 2 morpholino i-Bu 11 157-158 (64) 238 2. 5 1 .1 1 3.7 20 2 morpholino s -Bu H 170(dec) (63) ro 239 5 2.2 2.93 7.6 50 3 .5 morpholino t-Bu H 182-184 (63) CM 240 5 2.2 2.3 7.6 50 4 .5 morpholino allyl H 189-190 (63) 241 3. 9 1 .64 2.1 5.5 50 2 .5 thiamorpholino n-Bu H 162-163 (59) CO CJl o 2319 Example 24 2 ReacCion of 2-morpho1ino-5-trifluoromeChylaniline (12 g) wich chiophosgene (8.6 g) in dioxan (30 ml) and wacer (100 ml) at 0°C for 30 minuces and Chen ac room 5 CemperaCure for 2 hours yielded a residue which was exCracCed wich dichloromechane Co give 2-morpholino-5-crifluoromechylpheny1 isochiocyanate as a yellow oil. Reaction of 2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) with 33" 10 ethanolic ammonia solution (50 ml) at room temperature for 2 hours gave 1-(2-morpholino-5-trifluoromethylphenyl) thiourea (m.p. 196-197°C). A mixture of 1-(2-morpholino-5-trifluoromethylphenyl) thiourea (6.1 g) , potassium hydroxide (2.2 g), a 15 33% ethanolic solution of dimethylamine (5.6 ml), lead acetate trihydrate (7.5 g) and ethanol (40 ml) was heated at 90-95°C for 2 hours to yield 1 ,1-dimethy1-2-(2-morpholino-5-trifluoromethylphenyl)guanidine (m.p. 132-135°C) which was recrystallised from ethylacetate 20 and converted into its fumarate salt (m.p. 228-230°C) which was recrystallised from a 1:2 mixture of methanol and ether. Example 243 Reaction of 5-cyano-2-morpholinoaniline (2 g) with 25 thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) at 0°C for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 5-cyano-2-morpholinophenyl isothiocyanate as an oil. 30 Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with 251 aqueous ammonia solution (1 ml) at room temperature for 231 9 3 hours gave 1 -(5-cyano-2-morpholinophenyl)Chiourea (m.p. 1 93-1 94 °C). A mixture of 1 - (5-cyano-2-morpholinophenyl)-thiourea (5.2 g), potassium carbonate (8.3 g) , a 33" ethanolic solution of dimethylamine (15 ml), lead aceCaCe CrihydraCe and echanol (25 ml) was heaCed under reflux for 3 hours Co yield 1 ,1-dimethyl-2-(5-cvano-2-morpholinophenyl)guanidine (m.p. 125-127°C) which was converced into its monofumarate salt [m.p. 223-225°C (dec)] which was recrystallised from methanol. Example 244 A mixture of 1 ,1-dimethyl-3-(2-morpholinophenyl)-thiourea (2.65 g prepared as described in Example 232), n-propylamine (1.6 ml), lead acetate trihydrate (3.8 g), potassium hydroxide (1.2 g) and ethanol (25 ml) was heated under reflux for 4 hours. A further amount of n-propy lamine (1.6 ml) was added and the mixture heated under reflux for a further 8 hours. The reaction mixture yielded a residue which was extracted with ether. The extract was decolourised with charcoal, filtered and the solvent removed to leave a sticky solid which was dissolved in methanol (10 ml) and treated with fumaric acid to give l,3-di-(n-propyl)-2-(2-morpholinophenyl)guanidine hemifumarate (m.p. 212-214°C) which was recrystallised from a 1:2 mixture of methanol and ether. Example 245 A mixture of 1 ,1-dimethyl-3-(2-morpholinophenyl) thiourea (2.65 g prepared as described in Example 232), lead acetate trihydrate (3.8 g) , saturated ethanolic ammonia solution (25 ml), potassium hydroxide (1.12 g) and ethanol (20 ml) where heated at 90-95°C is a sealed stainless steel pressure vessel for 5 hours. -1»® - 2 3 1 9 5 0 The reaction mixture was filtered and the solid collected washed with ethanol. The washings were added to the filtrate and the volume reduced by evaporation. Ice was added and the resulting solid was collected by 5 filtration, washed with water and dried to give 1,1 -dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141-142°C) which was recrystallised from hexane. Examples 246 to 269 Reaction of a compound of formula VII in the form 10 of its hydrochloride salt (K grammes) and a compound of formula NC-NR^R^ (L grammes) in m-cresol (M ml) was heated at 90-95°C for N hours to give the compounds identified in Table IX. Notes to Table IX 15 Notes (32),(38), (44) and (45) have the meaning given hereinbefore. Reaction performed at 110°C. The product was isolated as its monofumarate salt which was recrystallised from a 1:1 mixture of methanol and ether. (65) (66) 20 (67) Reaction performed at 90-95°C for 8 hours and then at 115-120°C for 4 hours. (68) Reaction performed at 120-125°C. (69) The reaction mixture was heated at 90-95°C for 9 25 hours and then at 120°C for 21 hours. (70) The reaction mixture yielded an oil which was extracted with boiling hexane to yield the free 10 - 23 19 base which was converted into its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether. The reaction mixture yielded an oil which was extracted with hexane to yield the free base as an oil which was purified by chromatography on a neutral alumina column using the following eluents sequentially:- hexane, a 1:1 mixture of dichloromethane and hexane, dichloromethane and a 1:99 mixture of methanol and dichloromethane to give the base which was converted into its monofumarate salt which was recrystallised from 2:7 mixture of methanol and ether. Ex 246 247 248 249 250 251 252 253 254 ' > ) - m - Table IX li> Ki = C. \ Nj H K L M N NR-j R2 R5 R6 R7 mp(°C) Notes 6 .4 1 .8 25 3.5 morpholino H H H 189 (44) 19 .2 9 .45 80 5 morpholino Me Me H 215-216 (45) 7 .4 5 .5 25 5.5 morpholino Me Me 4 -Me 122-123 (32) 10 .8 5 45 10 morpholino Me Me 3-Me 230-231 (45)(65) 7 .3 3 .54 50 42 morpholino Me Me 5-Cl 152 (44) 7 .2 3 .54 50 50 morpholino Me Me 6-C1 190-192 (45) 6 .3 2 .7 25 18 morpholino Me Me 4 -OMe 220 (45) 6 .8 4 .25 40 18 morpholino Me Me 4-SMe 220(dec)(45) 5 .7 2 .93 25 6 morpholino Me Me 5-Me 225-226 (45) o J - 112 - Table IX continued Ex K L M N NR1R2 R5 R6 R7 mp(°C) Notes 255 4.9 2.1 25 9 morpholino Me Me 4 -Et 217-218 (45) 256 5.4 5.4 40 20 morpholino Me Me 4- CH2SMe 198-200 (38) 5 257 8.6 5.9 30 15 morpholino Et Et H 193-194 (45) 258 8.6 6.7 40 8 morpholino Me Bu H 187-188 (45) 259 8.1 8.8 50 - morpholino (CH2)2OMe (CH2) 2 OMe H 160-162 (66)(67) 260 6.5 5 20 7 morpholino -(CH2)2O(CH2) 2" H 202-203 (4 5) 261 10.2 6.8 40 12 morpholino -<CH2>4- H 237-238 (45) 10 262 10.6 5.25 30 16 piperidino Me Me 11 189-190 (68)(45) 263 8.2 4.3 40 pyrrolidinyl Me Me H 201-202 (45)(69) 264 4.6 2.1 25 1 thiamorpholino Me Me H 209-210 (45) 265 4.5 2.3 50 6 NMe2 Me Me H 188 (70) 266 4.33 1 .75 10 8 N(Me)CH2CH2OMe Me Me H 162-163 (71) 15 267 11 .38 3.52 20 8 4-methyl-1-piperaziny1 Me Me H 205-206 (38) 268 7 5.5 25 10 piperidino -(CH2)20(CH2) 2" H 208-209 (68)(45) 269 7.5 5.8 25 13 morpholino -(ch2)5- H 216-217 (45) ro Osf CO cn o -in- 2 3 1 9 5 0 Example 270 A mixture of 4 - (2-aminophenyl)morpholine hydrochloride (2.1 g) and N,N-dimethyIcvanamide (7 ml) was heated under nitrogen at 165-170°C for 12 hours. The reaction mixture was cooled to 10°C and the precipitate collected by filtration, washed with ether and stirred with 40% aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane and the extract washed with brine and dried. Removal of the solvent yielded a residue which was recrystallised from hexane to give 1,1-dimethyl-2 (2-morpholinophenyl)guanidine (m.p. 144-145°C). Example 271 A mixture of 4-(2-amino-4-methoxycarbonylphenyl)-morpholine (2.7 g), N,N-dimethyl cyanamide (1 g) and m-cresol (15 ml) was heated at 90-95°C for 10 hours. Ice was added and the reaction mixture acidified to pH 4 by the addition of 2N hydrochloric acid and the resultant mixture extracted with ether. The aqueous layer was cooled, basified to pH 8 by the addition of solid sodium bicarbonate and then extracted with dichloromethane. The extract was dried and the solvent removed to yield an oily residue which was purified by chromatography on a neutral alumina column eluted with a 1:99 mixture of methanol and dichloromethane to give 1 ,1 - dimethyl-2-(5-methoxycarbonyl-2-morpholinopheny1-guanidine (m.p. 152-154°C). Example 272 1 -(2-morpholinophenyl)thiourea (10.6 g) was suspended in boiling water (80 ml) and a solution of potassium hydroxide (25.2 g) in hot water (70 ml) was added. The mixture was heated to 90°C and aliquot portions of a hot solution of lead acetate trihydrate (17.5 g) in water (80 ml) added and the mixture heated under reflux for 10 minutes and cooled to ambient 23 19 - 114 - ^ temperature. The mixture was filtered and the filtrate acidified with acetic acid to pH 6. The solid which formed was separated by filtration, washed with water and recrystallised from ethylacetate to give N-(2-5 morpholinopheny1)cyanamide (m.p. 175-176°C). N-(2-morpholinophenyl)cyanamide (2 g) was heated under reflux with a 337. solution of dimethylamine in ethanol (15 ml) for 4 hours. The mixture was then cooled and the solvent removed by evaporation to give a 10 residue which was suspended in 20% aqueous sodium hydroxide solution. The suspension was extracted with dichloromethane (3 x 25 ml) and the extracts were washed with water, and then brine, dried and evaporated to give 1,1-dimethyl-2-(2-morpholinophenyl) guanidine 15 (m.p. 142-143°C) which was recrystallised from hexane. Examples 273-285 In a similar manner to that described in Example 272, N-(2-morpholinophenyl)cyanamide (P g) was heated under reflux with an amine of formula HNR^Rg (Q g) and 20 ethanol (R ml) for T hours to give the compounds listed in Table X. -115 - 2 3 19 5 Notes to Table X Notes (32), (38), (44) and (45) have the meaning given hereinbefore (72) A 33Z ethanolic solution of methylamine (25 ml) was used as reactant. (73) Reaction performed at 90-95°C. (74) Product isolated as its monofumarate salt which was recrystallised from a 2:3 mixture of methanol and ether. (75) Product recrystallised from a 1:1 mixture of hexane and ethyl acetate. (76) Reaction performed at ambient temperature for 2 hours and then at 90-95°C for 20 minutes. (77) Product recrystallised from a 3:7 mixture of ethylacetate and hexane. (78) Reaction performed at ambient temperature for 4 hours and then heated under reflux for 4 hours. vN. Ex P Q R T 273 2.5 2 274 2 1 .3 15 1 275 2 2.2 15 3 276 2 3.4 20 277 4 6 25 1 278 3 4.6 30 1 .25 279 2 2.2 10 1 .5 280 4 6.2 30 1 .5 281 4 2.5 25 2 J - 116 - Table X O M * - \ R5 R6 mp(°C) Notes II Me 171-172 (72) (73)(74 ) H Et 103-105 (75) H Bu 114-116 (44)(73) Me Et 130-132 (76)(32) Me CH2CH2SMe 230(dec) (45)(73) Me CH2CH2OMe 192-193 (38) Me allyl 125 (73)(77) Et CH2CH2OMe 168-170 (38) allyl allyl 188-190 (73)(38) no CaJ CO en CD (. Ex P Q R T 282 5 5 50 2 283 2 1.7 20 6 284 4 4.1 40 3 285 3 22 40 - 117 - Table X Continued R5 R6 -(CH2)2NMe(CH2)2- -CH2CHMeOCHMeCH2- -(CH2)2CHMe(CH2)2- -(ch2)2s(ch2)2- ) mp(°C) Notes 146-1 A 7 (32) 175-177 (44) 133-135 (32) 148-150 (32)(78) ro Ovi —i CO Ol - "8 - 2 3 19 Example 286 Reaction of 4-(2-amino-4-chloropheny1)morpholine (8.5 g) with thiophosgene "(4.6 ml) in dioxan (25 ml) and water (100 ml) for 30 minutes at 0°C and for 3 5 hours at room temperature gave 5-chloro-2-morpholino-phenyl isothiocyanate as a pale yellow solid (m.p. 86-87°C). Reaction of 5-chloro-2-morpholinophenyl isothiocyanate (10 g) with 33% alcoholic ammonia solution 10 (60 ml) at room temperature for 14 hours gave 1 -(5-chloro-2-morpholinopheny1)thiourea as a yellow solid (m.p. 174-175°C). A mixture of 1 -(5-chloro-2-morpholinophenyl) thiourea (5.97 g) suspended in water (40 ml), lead 15 acetate trihydrate (8.75 g) in water (40 ml) and potassium hydroxide (12.6 g) in water (35 ml) was heated under reflux for 15 minutes to give N-(5-chloro-2-morpholinophenyl)cyanamide as a white solid (m.p. 305-308°C). 20 In a similar manner to that described in Example 272, N-(5-chloro-2-morpholinophenyl)cyanamide (2.3 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) were heated under reflux for 4 hours to give 1,1-dimethyl-2-(5-chloro-2-morpholino-25 phenyl)guanidine (m.p. 135-138°C) which was recrystallised from hexane and then was converted into its monofumarate salt (m.p. 223-225°C) which was recrystallised from methanol. Example 287 30 A mixture of 5-fluoro-2-morpholino aniline (6 g) and thiophosgene (5.2 g) in dioxan (20 ml) and water (40 ml) was stirred at 0°C for 15 minutes and at room temperature for one hour to yield a residue which was -119- 23 19 extracted with dichloromethane to give an oil which was purified by chromatography on a silica gel column (mesh 100-200) using a 1:9 mixture of ethylacetate and hexane as eluant to give 5-fluoro-2-morpholinophenyl 5 isothiocyanate as an oil. Reaction of 5-fluoro-2-morpholinophenyl isothiocyanate (5.8 g) with 33% ethanolic ammonia solution (30 ml) at room temperature for 3 hours gave l-(5-fluoro-2-morpholinophenyl)thiourea as a white solid 10 (m.p. 195-196). A mixture of 1-(5-fluoro-2-morpholinopheny1)-thiourea (5.1 g) suspended in water (36.5 ml), lead acetate trihydrate (7.95 g) in water (36 ml) and potassium hydroxide (11.45 g) in water (32 ml) was 15 heated under reflux for 25 minutes to give N-(5-fluoro-2-morpholinopheny1)cyanamide as a white solid (m.p. 168-170°C). In a similar manner to that described in Example 286, N-(5-fluoro-2-morpholinophenyl)cyanamide (2.2 g) 20 in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) was heated under reflux for 20 minutes to give 1 ,1-dimethyl-2-(5-fluoro-2-morphol-inophenyl)guanidine (m.p. 137-138°C) which was recrystallised from hexane and converted into its 25 fumarate salt (m.p. 222-224°C) which was recrystallised from methanol. Example 288 Reaction of 3-methyl-2-morpholinoaniline (9.4 g) with thiophosgene (6 ml) in dioxane (50 ml) and water 30 (200 ml) at 0°C for 30 minutes and at room temperature for 2 hours gave a product which was extracted with m - 120 - 2 3 7 9 5 dichloromethane to give 3-methyl-2-morpholinophenyl isothiocyanate as a red oil. Reaction of 3-methvl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) with a saturated 5 solution of ammonia in ethanol (60 ml) at room temperature for 4 hours gave 1-(3-methy1-2-morpholinophenyl) thiourea (m.p. 178-179°C). A mixture of 1-(3-methy1-2-morpholinophenyl)-thiourea (6 g) suspended in water (40 ml), lead acetate 10 trihydrate (9 g) in water (40 ml), potassium hydroxide (13.5 g) in water (35 ml) was heated at 90-95°C for 1 hour to give N-(3-methy1-2-morpholinophenyl)cyanamide (m.p. 137-138°C) which was recrystallised from ethyl acetate. 15 In a similar manner to that described in Example 286, N-(3-methyl-2-morpholinophenyl)cyanamide (2.5 g) in ethanol (8 ml) and a 33% ethanolic solution of dimethylamine (3.5 ml) were heated under reflux for 1 hour. A further amount of the 33% ethanolic solution 20 of dimethylamine (3.5 ml) was added and the mixture heated under reflux for a further hour to give 1,1-dimethy1-2-(3-methy1-2-morpholinophenyl)guanidine (m.p. 100°C) which was recrystallised from hexane and converted into its monofumarate salt (m.p. 180°C) which 25 was recrystallised from a 1:1 mixture of methanol and ether. Example 289 Reaction of 4-methoxy-2-morpholinoaniline (4.7 g) and thiophosgene (2.9 ml) in dioxan (25 ml) and water 30 (75 ml) for 30 minutes at 0°C and 3 hours at room temperature yielded a residue which was extracted with dichloromethane to give 4-methoxy-2-morpholinophenyl isothiocyanate as an oil. - 121 - 23195 ReacCion of ' 4-mechoxy-2-morpholinophenyl isochiocyanace (4.1 g) wich a sacuraced solucion of ammonia in echanol (30 ml) for 24 hours aC room ****) temperac ure gave 1 -(4-meChoxy-2-morpholinophenyl)- 5 Chiourea (m.p. 175°C). A mixcure of 1-(4-methoxy-2-morpholinophenyl) -Chiourea (3.8 g) suspended in waCer (26 ml), lead acetate Crihydrate (5.7 g) in water (26 ml) and pocassium hydroxide (8.4 g) in wacer (24 ml) was heaCed 10 ac 90-95°C for 30 minuces Co give N-(4-methoxy-2-morpho1inopheny1)cyanamide. A mixcure of N-(4-methoxv-2-morpholinophenyl)-cyanamide (1.9 g) and 33% echanolic dimechylamine solucion (2.5 ml) was heaCed under reflux for 15 15 minuces Co give 1,1-dimethyl-2-(4-methoxy-2-morphol-inophenyl)guanidine (m.p. 135°C) which was recrysCallised from hexane. Example 290 A mixcure of 5-isobuCyl-2-morpholinoaniline 20 hydrochloride (4.1 g) , N,N-dimeChylcyanamide (1.77 g) and m-cresol (15 ml) was heaCed aC 90-95°C for 6 hours to yield a residue which was extracted with hot hexane, decolourised with charcoal and purified by chromatography on an alumina column eluted with a 2:98 25 mixture of methanol and dichloromethane. The resulting product was crystallised from a 1:3 mixture of ethylacetate and hexane. The initial precipitate was removed by filtration and the filtrate evaporated to dryness to give a residue which was recrystallised 30 from a 1:3 mixture of ethylacetate and hexane to give 1,1-dimethyl-2-(5-isobutyl-2-morpholinophenyl)-guanidine. - 122 - 2 3 1 9 5 Example 291 Sodium chlorite (5.6 g), cuprous chloride (0.2 g), cupric chloride dihydrate (0.34 g) were added to a solution of sodium carbonate (3.75 g) in water (25 ml). The mixture was cooled to 20°C and a solution of N-(2-morpholinophenyl)thiourea (6 g) in dichloromethane (45 ml) was added over 15 minutes. The temperature was raised to 40°C and maintained at this level for 4.5 hours. Water (100 ml) and dichloromethane (200 ml) were added and the mixture stirred for ten minutes. The organic layer was separated and the aqueous layer washed with dichloromethane. The combined organic layer was washed with brine and dried. Removal of the solvent gave a residue which was stirred with 20% aqueous sodium hydroxide solution (100 ml) and heated on a steam bath and then filtered. The filtrate was washed with ether, acidified to pH 4 with acetic acid and extracted with dichloromethane. The extract was washed with brine, dried and the solvent removed to give a residue which was purified by chromatography on a silica column which was eluted with hexane to which ethylacetate (up to 30%) was added progressively to raise the polarity. N-(2-morpholinophenyl)cyanamide (m.p. 175-176°C). k mixture of N-(2-morpholinophenyl)cyanamide (1.5 g) and a 33% ethanolic solution of dimethylamine (12 ml) was heated under reflux for 4 hours. Removal of solvent gave a residue to which was added dichloromethane (100 ml) and brine (50 ml). The mixture was stirred for 5 minutes and the organic layer separated and dried. Removal of the solvent gave 1,1 -dimethyl-2-(2-morpholinophenyl)guanidine (m.p. ]44-145°C) which was recrystallised from hexane. 23195 Example 292 1 ,1-dimethy 1-2-(5-methylthio-2-morpholinophenvl)-guanidine in the form of its free base (1.3 g) obtained from the product of Example 253, sodium metaperiodate 5 (1 g), methanol (10 ml) and water (4 ml) were stored at ambient temperature for 20 hours to yield 1,1-dimethyl-2-(5-methyIsulphiny1-2-morpholinopheny1)guanidine (m.p. 160-161°C) which was recrystallised from ethyl acetate. Example 293 10 A solution of 1 -methy1-2-(2-morpholinopheny1)- thiourea (6.2 g) in dichloromethane (30 ml) was added over 15 minutes to a stirred mixture of aqueous sodium carbonate solution (3.75 g in 25 ml), sodium chlorite (5.6 g), cuprous chloride (0.2 g), cupric chloride 15 dihydrate (0.34 g) and benzyltrimethylammonium chloride (0.6 g). The resulting mixture was stirred for 2 hours and then sodium chlorite (2.4 g) and benzyltrimethyl-ammonium chloride (0.4 g) were added and the mixture stirred for 1% hours. Dichloromethane (200 ml) and 20 water (50 ml) were added and the aqueous layer extracted with dichloromethane (2 x 100 ml). The extracts were combined, washed with brine, dried and filtered. Removal of the solvent gave a residue which was purified by chromatography on a silica gel column 25 using hexane and then a 1:4 mixture of ethyl acetate and hexane as eluant to give N-methyl-N'-(2-morpholinophenyl)carbodiimide (m.p. 67-68°C). A mixture of N-methyl-N'-(2-morpholinopheny1)-carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol 30 (5 ml) was heated at 90-95 °C for four hours. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and the resulting solution was washed with water, dried and filtered. Removal of the solvent gave 1-(n-butyl)-2-(2-morphol- - 1 24 2 3 1 I 9 5 inophenvl)-3-meChylguanidine which was converted inco ics monofumarate sale (m.p. 17S-179°C). Examples 294 to 300 In a similar manner to that described in Example 2 the products of the Examples set out below were converted into their fumarate salts which were recrvstallised from the solvent shown:- l 0 Example Starting Example Recrystallisation Solvent M.P. of fumarate Salt(°C) 15 294 295 296 297 298 299 300 133 1 34 167 1 75 200 201 204 1:2 methanol:ether 173-175 1:2 methanol:ether 183-184 2:1 methanol:ether 192-193 1:1 methanol:ether 159-160 propan-2-ol 142-143 1:1 methanol:ether 151-152 1:2 methanol:ether 170-171 Example 301 A mixture of 2-morpholinoaniline hydrochloride 20 (19.2 g) , m-cresol (80 ml) and dimethylcyanamide (9.45 g) was heated at 100°C for five hours, cooled and added to a mixture of 40% aqueous sodium hydroxide solution (300 ml) and ice (300 g). Water (300 ml) was added and the resulting solid separated by filtration, 25 washed with water and dissolved in dichloromethane. The solution was dried and the solvent removed to give a residue which was recrystallised from hexane to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142-143°C). 125 - 23 1 9 5 Example 303-304 Reaction of the products of Examples 175, 248 and 300 in the form of its free base respectively in methanol with L( + ) tartaric acid gave the following 5 compounds which were recrystallised from methanol. 301 4-^2—[1—(2-hydroxye thy 1)-2-imidazolidinylideneamino] phenyl)morpholine monotartrate (m.p. 1 47-1 48°C). 303 1 ,1 -dimethyl-2-(5-methyl-2-morpholinophenyl)-10 guanidine monotartrate (m.p. 183-184°C). 304 1,1-dimethyl-2-(2-morpholinophenyl)guanidine monotartrate (m.p. 184-185°C). Examples 305 and 306 Methanol and acetylchloride were reacted for 30 15 minutes to give hydrogen chloride which was reacted with the products of Example 248 and 301 respectively to give the products identified below. The products were recrystallised from the solvents given in parenthesis. 20 305 1,1 -dimethyl-2-(5-methyl-2-morpholinophenyl) - guanidine monohydrochloride (m.p. 161-162°C) (a 1:1 mixture of isopropanol and ether). 306 1,1-dimethyl-2-(2-morpholinophenyl)guanidine monohydrochloride (m.p. 200-201°C) (isopropanol). 25 Example 30 7 Reaction of the product of Example 301 in acetone with concentrated sulphuric acid gave 1 ,1-dimethyl-2-( 2-morpholinophenyl)guanidine hemisulphate (m.p. 234-235°C) which was recrystallised from a 1:1 mixture 30 of methanol and ether. - 126 - Example 308 23 1 9 5 ReacCion of pamoic acid wich chc produce of Example 301 in pyridine yielded 1 ,1-dimechy1-2- ( 2- morpholinopheny 1) guanidine hemipamoaCe (m.p. 5 158-160°C). Example 309 A mixcure of 1 ,3-dimeChyl-2-imidazolidinone (4.6 g) in benzene (40 ml), 4-(2-aminobenzy1)-morpholine (3.8 g) in benzene (20 ml) and phosphorus 10 oxychloride (3.6 ml) was heaCed aC 65-70°C for 20 hours Co yield 4 - [2-(1 ,3-dimethvl-2-imidazolidinyl- ideneamino)benzyl]morpholine (m.p. 56-58°C) which was recrysCallised from hexane. Example 310 15 A mixcure of 1 ,3-dimeChyl-2-imidazolidinone (10.95 g) in benzene (100 ml), 4 - ( 2-amino-4-chloro-benzyl)morpholine (13.6 g) in benzene (50 ml) and phosphorus oxychloride (8.8 ml) was heaCed ac 60-65°C for 8 hours Co yield an oil which was purified by 20 column chromaCography on an alumina column using hexane, a 9:1 mixture of hexane and dichloromethane, a 1:1 mixture of hexane and dichloromethane and then dichloromethane as eluant. The resulting product (3.2 g) was dissolved in methanol (50 ml) and treated 25 with fumaric acid (1.2 g) to yield 4 - [4-chloro-2-(1 , 3-dimethyl-2-imidazolidinylideneamino)benzyl ] -morpholine monofumarate (m.p. 169-170°C) which was recrystallised from a 1:1 mixture of methanol and ether. 30 Example 311 A mixture of 4-(2-aminobenzyl)morpholine dihydrochloride (10.6 g) and N,N-dimethylcyanamide (4.2 g) in m-cresol (40 ml) was heated at 90-95°C for 13 hours to yield a solid (m.p. 120-121°C) a portion of - 127 - 2 5 1 9 5 which (2 g) was dissolved in mechanol (15 ml). Treatment wich fumaric acid (0.9 g) gave N,N-dimethyl-N'-[2-morpholinomethylphenyl)guanidine monofumaraCe (m.p. 164-165°C) which was recrysCallised from propan-2-ol. Example 312 A mixcure of A-(2-aminobenzy1)morpholine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heaCed aC 90-95°C for 12 hours co yield N-(2-morpholinomechyIpheny1)morpholine-4-carboxamidine (m.p. 118-119°C) which was recrysCallised from hexane and Chen converced into its difumarate salt (m.p. 166-167°C) which was recrystallised from propan-2-ol. Example 313 The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples. a) Capsules In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound. b) Tablets Tablets are prepared from the following ingredients. </div>

Claims

<div id="claims" class="application article clearfix printTableText"> - 1 2S 23195 Pares bv weight Active compound prepared as in Example 1 1 0 Lactose 190 Maine starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated wich a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit cose or a part of a unit dose of active compound. (c) Enteric coated tablets Tablets are prepared (b) above. The tablets conventional manner using acetate phthalate and ethanol:dichloromethane (1: d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient. by the method described m are enteric coated in a a solution of 20% cellulose 3Z diethyl phthalate in 1 ) - - U9 2519:0 WHAT 37WE CLAIM IS: Gla L ;■!>■&- 1 . Compounds of formula I and their pharmaceutically acceptable salts in which n = 0 or 1 ; 5 in which and R2 , which are the same or different, are (a) an aliphatic group containing 1 to 3 carbon atoms, said aliphatic group being optionally substituted by methoxy (b) a cycloalkyl group containing 3 to 7 carbon atoms or (c) R-| and R^ 10 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring of formula II CHRs ""N -N B CH. II in which Rg represents H or an alkyl group containing 1 to 3 carbon atoms and B represents an alkylene group of 15 2 to 4 carbon atoms optionally interrupted by oxygen, sulphur, sulphinyl or NH optionally substituted r ^ v. •- I , by an alkyl group containing 1 to 3 carbon atoms, said ^ \\ o 24SEP1991 ,£N /<?. - .,<<• // - 130 ? 3 1 Q alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms or the substituents on two adjacent carbon atoms of the S alkylene group form a benzene ring or B represents an 5 alkenylene group of 3 carbon atoms; is a straight or branched alkyl group containing 1 to 7 carbon atoms or a cycloalkyl group containing "3 to 7 carbon atoms or a group of formula III 10 - N III in which R^ and which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms; in which R^ is H or a straight or branched aliphatic 15 group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy; in which R^ is (a) H, (b) a straight or branched aliphatic group of 1 to 6 carbon atoms optionally substituted by hydroxy or an acylated derivative 20 thereof, by an alkoxy group containing 1 to 3 carbon atoms, by an alkylthio group containing 1 to 3 carbon atoms, by an optionally alkylated amino group, by a carbocyclic group containing 3 to 7 carbon atoms or by cyano or (c) a cycloalkyl ring containing 3 to 7 carbon 25 atoms; or the group R^ and the group R^ together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV -131 - 2 31 9 5 0 0 in which Rg is as hereinbefore defined, Rq and R-j g, which are the same oi* different, are H or an alkyl group of 1 to A carbon atoms optionally substituted by methoxy, and D is an oxvethylene group in which the oxygen atom is bonded to the carbon atom carrying the groups Rg and R-j q or an alkylene group of 2 to 5 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms; or the group R^ and the group R,. together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V in which Rg is as hereinbefore described, in which R^ is H or an alkyl group containing 1 or 2 carbon atoms, and E is an alkylene group of 2 to 4 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; or R^ and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI 1 - I 0 ■ 0 - 132 - VI in which G is an alkylene group of k or 5 carbon atoms optionally interrupted by oxygen, sulphur or NH optionally substituted by an alkyl group containing 1 5 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing '1 to 3 carbon atoms; and Ry represents H or one or more optional substituents selected from halo, alkyl groups containing 1 to 4 10 carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms, alkvlsulphinyl groups containing 1 to 3 carbon atoms, alkylsulphonvl groups containing 1 to 3 carbon atoms, alkoxycarbonyl 15 groups containing a total of 2 or 3 carbon atoms, trifluoromethvl or cyano.
2. Compounds of formula I as claimed in claim 1 in which n = 0, R-j and R2, which are the same or different, are selected from (a) alkyl groups of 1 to 3 20 carbon atoms optionally substituted by methoxy (b) allyl groups or (c) cyclohexyl groups.
3. Compounds of formula I as claimed in claim 2 in which R-| and R2 are both alkyl, allyl or 2-methoxyethyl or R1 is methyl and R2 is 2-methoxyethyl or 25 cyclohexyl. A.
Compouds of formula I as claimed in claim 2 in which the group NR-j R2 is dimethylamino, diethyl-amino, diallylamino, (2-methoxyethyl)methylamino, cyclohexylmethylamino or bis(2-methoxyethyl)amino. - 133 - ? 5 i 9 50
5. Compounds of formula I as claimed in claim 1 in which n = 0, the group NRjR0 is a heterocyclic ring represented by formula II,' Rg represents H or methyl and B represents a group selected from -(CH9)2-, 5 -CKMeCH2-, o-phenylene, -(CH^-, -CH0CHMeCHo -, -(CH2)^-, -CH9OCH7-, -CHMeOCHMe- , -CH9SCH2-, -CK2S(0)CH2-, -CrL, NMeCH.-, - or -CH=CHCH2~.
6. Compounds of formula I as claimed in claim 5 in which the group NR-j R2 is 1-pyrro 1 idiny 1, 2-methyl-l- 10 pyrrolidinyl, piperidino, 4-methyl-piperidino, 1-hexa-hydroazepinyl, morpholino, 2 , 6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide , 2-isoindoliny1, 4-tnethyl-l-piperaz iny 1 or 1 -(1 ,2,5,6-tetrahvdro)-pvridvl. 15
7. Compounds of formula I as claimed in claim 1 in which n = 1 and the group NR-j R9 is morpholino or thiamorpholino.
8. Compounds of formula I as claimed in claim 1 in which R, is methyl, ethyl, propyl, isopropyl, butyl 20 t-butyl, pentyI, cyclohexyl, amino, methylamino. dimethylamino or ethylamino.
9. Compounds of formula I as claimed in claim 1 in which R<j is H, methyl, ethyl or methoxyethyl. 25
10. Compounds of formula I as claimed in claim 1 in which Rg is H or a straight or branched alkyl group containing 1 to 5 carbon atoms optionally substituted by hydroxy, by an acylated derivative of hydroxy, by methoxy, by methylthio, by dimethylamino, by phenyl or by cyano, Rg is a straight or branched alkenyl group containing 3 to 6 carbon atoms or Rg is a cycloalkyl group containing 5 or 6 carbon atoms. 24 SEP 1991" ^31950 m 134 10 15 20 25 "J 30 35
11 . Compounds of formula I as claimed in claim 10 in which Rg is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-hydroxy-ethyl, 3-hydroxvpropyl, 2-hydroxypropy1, 2-hydroxy-butyl, 2-hydroxy-2-methylpropvl, 2 , 3-dihydroxypropy1, 2-acetyloxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, 2-methvlthioethy1, 2-dime thylaminoethy1, benzyl, 2-phenylethyl, 2-cyanoethyl, allyl, 2-methylal'lyl, cyclopentvl or cyclohexyl.
12. Compounds of formula I as claimed in claim 1 in which the group -N=C()NR^Rg is:- acetamidino, N-methylacetamidino, N,N-dimethylacetamidino, N , N-diethylace tanidino, N- (2-scetyloxyethyl)acetamidino, N-butylacetamidino, N-pentylace tanidino, N-methylpropionamidino, N,N-dimethylpropionamidino N-ethylpropionamidi.no , butvramidino, N-methyIbutyramidino, N,N-dimethyIbutyramidino, N-ethvIbutyramidino, isobutyramidino, N-methylisobutvramidino, N,N-dimethylisobutyramidino, valeramidino, N-methylvaleramidino, N,N-dimethylvaleramidino, pivalamidino, N-methylpivalamidino, N,N-dimethylpivalamidino, N-methylcaproamidino t V - 135 - 23 19 N-methyleyelohexanecarboxamidino, diaminomethyleneamino, N-methylguanidino, N,N-dimethylguanidino, 5 N,N'-dimethylguanidino, N-ethylguanidino, N-butylguanidino, N-ethyl-N-methylguanidino, N,N-die thylguanidino, 10 N,N'-diethylguanidino, N,N',N'-trimethylguanidino, 1 ,1 ,3,3-tetramethvlguanidino, N-ethyl-N'-methylguanidino, 1-ethy1-1,3,3-trimethylguanidino, 15 1 -butyl-1 ,3,3-trimethylguanidino, N-methyl-N-propylguanidino, N-butyl-N-methylguanidino, N-sec-butyl-N'-methylguanidino, N-tert-butyl-N'-methylguanidino, 20 N-isobutyl-N1-methylguanidino, N-buty1-N'-methylguanidino, N-butyl-N1-ethylguanidino, N-methyl-N1-pentylguanidino, N-cyclopentyl-N'-methylguanidino, 25 N-(2-methoxyethyl)guanidino, N-(2-methoxyethyl)-N-methylguanidino, N-(2-methoxyethyl)-N'-methylguanidino, N-ethyl-N-(2-methoxyethyl)guanidino, N,N-bis(2-methoxyethyl)guanidino, 30 N-methyl-N-(2-methylthioethyl)guanidino, N-ally1-N-methylguanidino, N-allyl-N'-methylguanidino, 1-allyl-1,3,3-trimethylguanidino, N,N-diallylguanidino, 35
13. Compounds of formula I as claimed in claim 1 in which the groups and together with the carbon and - 136 - 2 3 1 9 5 0 nitrogen atoms to which they are attached form a heterocyclic ring of formula IV, Rg and R^g. which are the same or different, are H or alkyl groups containing 1 to 3 carbon atoms optionally substituted by methoxy, 5 D is selected from -(CH^)^-. -(CH0)^-, -(C^)^-, -CH9CMe9- or -0(CH9)9- and the group R^ is H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethy1 or 2-methoxyethyl.
14. Compounds of formula I as claimed in claim 13 in 10 which formula IV represents:- 2-pvrrolidinylidene, 1-methyl-2-pyrrolidinvlidene, 3-methyl-2-pyrrolidinvlidene, 1-ethy1-2-pyrrolidinylidene, 15 1 - isopropyl-2-pyrrolidinylidene, 1-cyclohexyl-2-pyrrol idinylidene, 1 -(2-methoxyethyl)-2-pyrrolidinylidene, 1 ,3-dimethy1-2-pyrrolidinylidene, 5,5-dimethy1-2-pyrrolidinylidene, 20 1 ,3,3-trimethyl-2-pyrrolidinylidene, 1 ,5,5-trimethyl-2-pyrrolidinylidene, 3-isopropy1-1-methyl-2-pyrrolidinylidene, 1-ethyl-3,3-dimethyl-2-pyrrolidinylidene, 3,3-diethyl-l-methyl-2-pyrrolidinylidene, 25 2-piperidinylidene, 1-methyl-2-piperidinylidene, 1 ,3-dimethylpiperidinylidene, 1 -ethy1-2-piperidinylidene, 1 - isopropyl-2-piperidinylidene, 30 1 -(2-cyanoethyl)-2-piperidinylidene, 1 -(2-acetoxyethyl)-2-piperidinylidene, 3-(2-methoxyethyl)-1-methy1-2-piperidinylidene, 2-hexahydroazepinylidene, 1-methyl-2-hexahydroazepinylidene, 35 2-octahydroazocinylidene or 3-morpholinylidene. iljk - 137 - 2 3 19 5
15. Compounds of formula I as claimed in claim 1 in which Che groups and together wich che carbon and nicrogen acoras Co which ' Chev are accached form a ■""N hecerocvclic ring of formula V, E is -CF^CH.-,-, 5 -CMe9CH2-, -CHMeCHMe-, -(CH0)3-t CHMeCH9- or -(CH9)4, R-j ^ is H, methyl or echvl and R^ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylally1, 2-hydroxyethyl, 2-acetoxyeChyl, 2-benzovloxyethyi, 2-methoxyethyl, cyclohexyl, benzyl, 10 phenechyl, 3-hydroxypropyl, 2-hydroxypropy1, 2-hydroxy-2-meChvIpropvl, 2-hydroxvbuty1, 2,3-dihydroxypropy1 or 2-dimeChvlaminoeChy1.
16. Compounds of formula I as claimed in claim 15 in which formula V represents:- 15 2-imidazolidinylidene, 1-meChyl-2-imidazolidinvlidene, A-meChvl-2-imidazolidinylidene, 4.4-dimeChy1-2-imidazolidinylidene, 4.5-dimeChy1-2-imidazolidinylidene, 20 1-echy1-2-imidazolidinylidene, 1-propyl-2-imidazolidinylidene, 1-isopropyl-2-imidazolidinylidene, 1 -(n-buCy1)-2-imidazolidinylidene, 1-isobuCyl-2-imidazolidinylidene, 25 1-penCyl-2-imidazolidinylidene, 1-allyl-2-imidazolidinvlidene, 1 -(2-meChylallyl)-2-imidazolidinylidene, w* 1 -(2-hydroxyeChyl)-2-imidazolidinylidene, 1-(2-hydroxyethyl)-3-methyl-2-imidazolidinylidene, 30 1 -(2-acetoxyethyl)-2-imidazolidinylidene, 1 -(2-benzoyloxyethyl)-2-imidazolidinylidene, 1 -(2-benzoyloxyethyl)-3-methyl-2-imidazolidinylidene, 4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinylidene, 1-(2-methoxyethyl)-2-imidazolidinylidene, 35 1 -(2-methoxyethyl)-3-methy1-2-imidazolidinylidene, ?31950 n - 13 3 - 10 15 -eye 1ohexy1-2-imidazolidinylidene, -benzyl-2-imidazolidinylidene, -(2-phenvlechyl)-2-imidazolidinylidene, -(2-dimeChylaminoethyl)-2-imidazolidinylidene, -(3-hydroxypropy1)-2-imidazolidinylidene, -(2-hydroxypropy1)-2-imidazolidinylidene, -(2-hydroxy-2-mechyIpropy1)-2-imidazolidinylidene, -(2-hydroxvbucyl)-2-imidazolidinylidene, -(2,3-dihydroxypropy1)-2 -imidazolidiny1idene, ,3-dimeChy1-2 -imidazolidinylidene, ,3-dieChy1-2-imidazolidiny1idene, -eChv1-3-meChvl-2-imidazolidinylidene, -buCy1-3-me chy1-2 -imidazolidinylidene, -isopropyl-A ,A-dimechy1-2-imidazolidiny1idene, -meChy1-2-perhydropyrimicinvlidene or , 3-diazacycloheptsne-2-yl idene.
17. Compounds of formula I as claimed in claim 1 in which R^ and Rg cogecher wich che nitrogen atom Co which Chey are aCtached form a heCerocvclic ring of 20 formula VI and G represents a group selected from -(CH9)a-, -(CH9)5-, -CCK9)?0(CK9)2-, -(CH9)9S(CH9)9-, -(CH2)9NMe(CH9)9 - , -(CH9)9CHMe(CK2)9- or -CH2CHMeOCHMeCH9- .
18. Compounds of formula I as claimed in claim 1 7 in 25 which the group NR^Rg is 1-pyrrolidinyl, piperidino, A-methvlpiperidino, morpholino, 2,6-dimethylmorpholino, thiamorpholino or A-methyl-1-piperazinvl.
19. Compounds of formula I as claimed in claim 17 in which the group -N=C(R^)NR^Rg is :-30 N,N-(3-oxapentamethylene)guanidino, 1,1-dimethyl-3,3-(3-oxapentamethylene)guanidino, N,N-(2,A-dimethy1-3-oxapentamethylene)guanidino, N,N-(3-thiapentamethylene)guanidino, t 1 ■^Vv N,N-(3-methvlpentamethylene) guanidino, .1 n "24SEP1991^/ .-o , •/ 231950 N,N-(N-methy1-3-azapentamethylene)guanidino, N-methyl-N' ,N1 -tetramethvleneguanidine, N,N-pentamethyleneguanidino, 1,1-dimethyl-3,3-pentamethyleneguanidino. 5
20. Compounds of formula I as claimed in claim 1 in which Ry represents H or one or more substituents selected from fluoro, chloro, methyl, ethyl, isobu'tyl, methylthio-methyl, methoxy, dimethoxy, methoxycarbonvl, methylthio, methylsulphinyl, methylsulphonyl, tri-10 fluoromethyl or cvano.
21 . Compounds of formula I as claimed in claim 1 in which n = 0, -NR-|R9 is morpholino, thiamorpholino, piperidino or 1-pyrrolidiny 1, R^ is -NH^, R^ is an aliphatic group containing 1 to A carbon atoms Rg is an 15 aliphatic group containing 1 to A carbon atoms optionally substituted by methoxy or methylthio or R^ and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI and R~ is H, fluoro, chloro, methyl, ethyl, methylthio-20 methyl or methylthio.
22. Compounds of formula I as claimed in claim 21 in which is methyl, ethyl or allyl, Rg is methyl, ethyl, allyl, methoxyethyl or methylthioethyl or the group -NR^Rg is morpholino or thiamorpholino and Ry is 25 H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.
23. Compounds of formula I as claimed in claim 1 in which n = 0, -NR^R2 is morpholino or thiamorpholino, R^ is a group of formula III in which R^ is an alkyl group 30 containing 1 to A carbon atoms and R^' is H, R,- is H, Rg is an aliphatic group containing 1 to A carbon atoms optionally substituted by methoxy and Ry is H, fluoro, methyl, methylthio or methylthiomethyl. 2A .
Compounds of formula I as claimed in claim 23 in which is methyl, R^' is H, R^ is H and R^ is methyl, butyl, t_-butyl or methoxyethyl.
25. Compounds of formula I as claimed in claim 1 in 5 which n = 0, -NR^R2 is morpholino or thiamorpholino, R3 is an alkyl group of 1 to A carbon atoms, R^ and R^ are ft and Ry is H, fluoro, methyl, methylthio or methylthiomethyl. 1 0
26. Compounds of formula I as claimed in claim 1 selected from: ,1-dimethyl-2-(2-morpholinophenyl)guanidine ,1-dimethyl-2-(5-fluoro-2-morpholinopheny1)guanidine ,1-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine 15 1,1-dimethyl-2-(5-methvl-2-morpholinophenyl)guanidine ,1-dimethyl-2-(6-methyl-2-morpholinophenvl)guanidine ,1-dimethyl-2-(5-ethy1-2-morpholinophenyl)guanidine ,1-dimethyl-2-(5-methylthiomethyl-2-morpholinophenyl) guanidine 20 1,1-dimethyl-2-(5-methylthio-2-morpholinophenyl) guanidine -ethyl-1-methy1-2-(2-morpholinophenyl)guanidine ,1-diethyl-2-(2-morpholinophenyl)guanidine -(2-methoxyethyl)-1-methyl-2-(2-morpholinophenyl) 25 guanidine -methyl-1-(2-methylthioethyl)-2-(2-morpholinophenyl)-guanidine ,1-dimethyl-2-(2-thiamorpholinophenyl)guanidine ,1-dimethyl-2-(2-piperidinophenyl)guanidine 30 1 ,1 -dimethyl-2-[2-(l -pyrrolidinyDphenyl]guanidine N- (2 -morpho1inopheny1)morpho1ine-A -carboxamidine N-(2-morpholinophenyl)thiamorpholine-A-carboxamidine 1-butyl-3-methyl-2-(2-morpholinophenyl)guanidine 1-methyl-3-tert-buty1-2-(2-morpholinophenyl)guanidine I j - 141 - ? 3-1 9 - 0 10 15 1 , 3 - dime Chy 1-2- ( 2-chiamorp.hol inopheny 1) guanidine N-(2-morpholinophenyl)aceCamidine N-(4-meChy1-2-morpholinophenyl)aceCamidine N-(2-morpholinophenyl)pivalamidine and pharmaceucically accepcable sales Chereof.
27. Pharmaceucical composicions comprising ' a cherapeucically active amount of a compound of formula I as claimed in any one of the preceding claims in combination with a pharmaceutically accepcable diluent or carrier.
28 . The use of compounds of formula I as claimed in any one of claims 1 to 26 in the manufacture of a medicament for the treatment of disbeces.
29 . The use of compounds of formula I as claimed in any one of claims 1 to 26 in the manufacture of a medicament for the treatment of hyperglycaemia.
30 . A process for preparing compounds of formula I as claimed in claim 1 comprising the reaction of an aminophenyl compound of formula VII VII / : o", 24 SEP J99] 251950 - 1-12 - wich an amide or a urea of formula R^-CO.NR^R^ in che presence of a condensing agenc such as phosphorus oxychloride, Chionyl chloride, phosgene, phosphorus pencachloride or benzenesulphonyl chloride.
31. A process as claimed in claim 30 for preparing compounds of formula I as claimed in claim 1 wherein Che compound of formula VII is reacCed wich a) a lacCam of formula VIII C =C VIII in Che presence of a condensing agenc such as 10 phosphorus oxychloride. Chionyl chloride, cvanuric chloride, phosgene, carbon CeCrachloride/Criphenyl-phosphino, phosphorus pencachloride or benzenesulphonyl chloride; b) a compound of formula IX \ L ft; i S tr I99J Sc< R 10 I R-12-C 0 G IX - 143 - ->319:0 in which 9 is chloro, -O-POCl^, -O-SOCl, -0C0C1 or -OSO^Ph and B is an anion such as halo (e.g. Cl~) or POCl^-, c) a compound of formula X R9n^ /SR10 ,c —^ r, ,0 - c 1 J> % n © G 5 in which R-j ^ is an alkyl group and B~ is an anion such as fluoroborace or mechosulphace: d) when R^ is H, a keCcxime of formula XI in Che presence of a sulphonyl chloride (for example benzene sulphonyl chloride) or 10 e) a urea of formula XII ,-;p & /v . °! \ 24 SEP J99}1 ■N _ a* 144 - i ?"0 xi r R, in Che presence of a condensing agenc such as phosphorus oxychloride, chionyl chloride, phosgene, phosphorus pencachloride or benzenesulphonyl chloride.
32 . A process for preparing compounds of formula I as 5 claimed in claim 1 in which and cogecher wich Che carbon and nicrogen acorns Co which they are accached form a ring represenced by formula V, said process comprising reacCion of a compound of formula XIII opcionally in Che form of a sale in which R-j ^ and 10 are K wich a diamine of formula XIV R11NHENHR6 XIV 15
33. A process for preparing compounds of formula I as claimed in claim 1 in which R.^ is a scrai.ghc or branched alkyl group of 1 Co 7 carbon aComs or a cycloalkyl group of 3 Co 7 carbon atoms and the group NR^Rg is NH2, said process comprising Che reacCion of a compound of formula VII \ 24 SEP 199'," • (CH2)nNRiR2 optionally in the form of a VII sale with a cyano compound cf formula R^CN, optionally in the presence of aluminium chloride. is NH o < said
34. A process for preparing compounds of formula I as claimed in claim 1 in which the group process comprising the reaction of formula VII a compound of 1 0 (cfy„Nv2 vri optionally in the form of a salt with a cyanamide compound of formula R^R^NCN.
35. A process for preparing compounds of formula I as claimed in claim 1 in which the group is NH^, said process comprising the reaction of compounds of formula XV with amines of formula NHR^R^.
36. A process for preparing compounds of formula I as claimed in claim 1 in which is a group of 15 formula III in which R^ is alkyl and R^1 is H or alkyl, said process comprising the reaction of a compound of formula XIII u'" ' 0 in which R^ is the group and R^ is ["24 SEH199] / ' .04/ - 146 - with an amine of formula hnr5R6 Che group R^ optionally in the presence of a base or in the presence of potassium hydroxide and lead acetate.
37. A process for preparing compounds of formula I as claimed in claim 1 in which R^ is a group of formula III in which R^ is alkyl and R^1 is H and in which R^ is H may be prepared by the reaction of a thiourea of formula XVI (C:VnNRlR2 NH.CS.
N /R14 XR15 XVI in which R-j ^ is the group R^ and R^ is the group R^( ' with an amine of formula hnr5r6 ontionallv in the presence of a base and lead acetate. 10 38 A process for preparing compounds of formula I as claimed in claim 1 in which R^ III in which R^ is alkyl and R^ n xniu. ^ is H, said process comprising the reaction of a carbodiimide of formula XVII is a group of formula is H and in which R, CH.) NR R 2 n 12 N = C= NR XVII with an amine of formula J^NRg.
39 . A process for preparing compounds of formula I as claimed in claim 1 in which n = 0 and NR-jR9 is morpholino, thiamorpholino, 1-pyrrolidinyl or fcu 5 piperidino, said process comprising the reaction of a ^ °*\ comPounc* formula XVIII { 24S£p|99j'Ty - 147 - 951950 wich a disubscicuted compound of formula XIX K(CH2)2L(CH2)9K XIX in which K is a leaving group and L is -0-, -S-, a direcC bond or -CH9- respectively.
40. Compounds of formula I as defined in claim 1 or their pharmaceutically acceptable salts substantially as herein described with reference to any example thereof.
41. Pharmaceutica] compositions as defined in claim 27 substantially as herein described with reference co any example thereof.
42. A process as defined in any one of claims 30 and 3Z to 39 for preparing compounds of formula I substantially as herein described with reference to any example thereof.
43. Compounds of formula 1 when produced in accordance with the processes of any one of claims 30 or 32 to 39. /' //v -o\\ fa»SEP,99lH A. </div>