CA2006577C - Hypoglycaemic phenylamidines and phenylguanidines - Google Patents

Hypoglycaemic phenylamidines and phenylguanidines

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Publication number
CA2006577C
CA2006577C CA002006577A CA2006577A CA2006577C CA 2006577 C CA2006577 C CA 2006577C CA 002006577 A CA002006577 A CA 002006577A CA 2006577 A CA2006577 A CA 2006577A CA 2006577 C CA2006577 C CA 2006577C
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Prior art keywords
methyl
morpholinophenyl
guanidine
carbon atoms
formula
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CA002006577A
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French (fr)
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CA2006577A1 (en
Inventor
Balasubramanian Gopalan
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Boots Co PLC
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Boots Co PLC
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Priority claimed from IN1/BOM/89A external-priority patent/IN169912B/en
Priority claimed from GB898903592A external-priority patent/GB8903592D0/en
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Publication of CA2006577A1 publication Critical patent/CA2006577A1/en
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/16—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract

Compounds of formula I

(see formula I) and their salts in which n = 0 or 1, R1 and R2 are each aliphatic or cycloalkyl or NR1R2 is an optionally substituted heterocyclic ring, R3 is alkyl, cycloalkyl or optionally substituted amino, R5 is an aliphatic group, R6 is H, an optionally substituted aliphatic group or a cycloalkyl group, or R3 and R5 together with the nitrogen and carbon atoms to which they are attached form an optionally substituted heterocyclic ring or R5 and R6 together with the nitrogen to which they are attached form a heterocyclic ring optionally substituted by alkyl and R7 is optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkoxycarbonyl, trifluoromethyl or cyano have utility as hypoglycaemic agents.

Description

f This invention relates to novel therapeutic agents useful as antidiabetic agents, particularly as hypoglycaemic agents, to processes for the preparation of such agent s and to pharmaceutical compositions containing them.
The present invention provides compounds of formula I:
/. ICH2)~NR~ R2 N'C ~ R! R5 NwRg I
and their pharmaceutically acceptable salts in which n = 0 or 1;
in which R1 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) R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring of formula II
CHRg _N 8 in which R8 represents H or an alkyl group containing 1 to 3 carbon atoms and B represents a straight chain alkylene group of 2 to 4 carbon atoms optionally interrupted by oxygen, sulphur, sulphinyl or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted ty one or more alkyl groups containing 1 to 3 carboy. 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;
R3 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

i Irr ~ R' in which R4 and R'4, which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms;
in which R5 is H or a straight or branched aliphatic group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy;
in which R6 is (a) H, (b) a straight or branched aliphatic gr~~up 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 atoms;
provided that, when NR1R2 is dialkylamino and R3 is a group of formula III, at least one of R4, R4', R5 or R6 is other than H;
A

~~~E~ i'~''7 or the group R3 and the group R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV
R9\ ~ 10 ~C~
/ '~' D I V
N

in which R6 is as hereinbefore defined, R9 and R10' ' 5 which are the same or different, are H or an alkyl group of 1 to 4 carbon atoms optionally v substituted by methoxy and D is an oxyethylene group in which the oxygen atom is bonded to the carbon atom carrying the groups R9 and R10 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 R3 and the group R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V

N
- C/ g V
\N

in which R6 is as hereinbefore described, in which R11 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 2t.~()~ i'T'~

containing 1 to 3 carbon atoms;
or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI
N G
VI
in which G is an alkylene group of 4 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 R~ represents H or one or more optional substituents selected l groups containing 1 to 4 from halo, alky carbon atoms optionally substituted by methylthio, alkoxy groups containing to 3 carbon atoms, alkylthio groups containing 1 to carbon atoms, alkylsulphinyl groups containing 1 to carbon atoms, alkylsulphonyl groups containing 1 to carbon atoms, alkoxycarbonyl groups containing a tota l of 2 or 3 carbon atoms, trifluorom~=_thyl or cyano.

In preferred compounds of formula I in which n =
0 , R1 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) a11y1 groups or (c) cyclolzexyl groups. In particularly preferred compounds of formula I in which n - 0, R1 and R2 are both alkyl, allyl or 2-methoxyethyl or R1 is methyl and R2 is 2-methoxyethyl or cyclohexyl. In especially preferred compounds of formula I in which n - 0, the group NR1F;2 is dimethylamino, diethylamino, diallyl-amino, (2~-methoxyethyl)methylamino, cyclohexylmethyl-~oo~.s~~
amino or bis(2-methoxvethyl)amino.
In preferred compounds of formula I in which n =
0 and in which the group NR~R2 is a heterocyclic ring represented by formula II, R8 represents H or methyl and B represents a group selected from -(CH2)2 ' -CHMeCH~-, o-phenylene, -(CH2)3-, -CH2CHMeCH2-, -(CH2)4-, -CH20CH2-, -CHMeOCHMe-, -CH2SCH2-, -CH2S(0)CH2-, -CH2NMeCH2- or -CH=CHCH2-. In especially preferred compounds of formula I in which n = 0 and the 1 0 group NR~ R.2 is a group of formula II , the group NR~ R2 is 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, piperidino, 4-methylpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl or 1-(1,2,5,6-tetrahydro)pyridyl. In preferred compounds of formula I in which n - 1, the group NR~R2 is morpholino or thiamorpholino.
In preferred compounds of formula I in which R3 is an alkyl group, the group R3 contains 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl). In preferred compounds of formula I
in which the group R3 is a cycloalkyl group, the cyclo-alkyl group is cyclohexyl.
In preferred compounds of formula I in which R3 is a group o:E formula III, R4 and R4' are H, methyl or ethyl (for example R3 is amino, methylamino, dimethyl-amino or ethylamino).
In preferred compounds of formula I in which the group R5 does not form part of a heterocyclic ring, the group R5 is H er an alkyl group containing 1 to 3 carbon atoms (eg methyl or ethyl) optionally ~0~~ i'~'~
substituted by methoxy (eg R5 is methoxyethyl) or a11v1.
In preferred compounds of formula I, R6 is H or a straight or branched alkyl group containing 1 to 5 carbon atoms (e. g. methvl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl) optionally substituted by hydroxy (e.g. R6 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hvdroxybutyl, 2-hydroxy-2-methylpropyl, or 2,3-dihydroxypropyl), by an acylated derivative of hydroxy such as acetyloxy or benzoyloxy (e.g. R6 is 2-acetyloxyethyl or 2-benzoyloxyethyl) by methoxy (e. g.
R6 is 2--methoxyethyl), by methylthio (eg R6 is 2-methylthioethyl), by dimethylamino (e.g. R6 is 2-dimethylaminoethyl), by phenyl (e.g. R6 is benzyl or 2-phenylet'.zyl) or by cyano (e.g. R6 is 2-cyanoethyl) or R6 is a straight or branched alkylene group containing 3 to 6 c~.rbon atoms (e. g. R6 is allyl or 2-methyl-allyl).
In preferred compounds of formula I in which R6 is a cycloalk:yl group, R6 contains 5 or 6 carbon atoms (e. g. R6 is cyclopentyl or cyclohexyl).
In particularly preferred compounds of formula I
in which the groups R3 and R5 together with the nitrogen and carbon atoms to which they are attached do not form a heterocyclic ring, the group -N=C(R3)NR5R6 is:
acetamidino, N-methylac~~tamidino, N,N-dimeth:ylacetamidino, N,N-diethyLacetamidino, N-(2-acetyloxyethyl)acetamidino, N-butylacetamidino, N-pentylac~~tamidino, ~0(~~ x'7'7 N-methylpr~~pionamidino, N,N-dimeth:ylpropionamidino N-ethylpropionamidino, butyramidi:zo , N-methylbutyramidino, N,N-dimeth;ylbutyramidino, N-ethylbut:yramidino, isobutyramidino, N-methylis~~butyramidino, N,N-dimeth:ylisobutyramidino, valeramidino, N-methylvaLeramidino, N,N-dimeth:ylvaleramidino, pivalar-midino , td-methylpivalamidino, 1'd,N-dimeth:ylpivalamidino, N-methylcap roamidino N-methylcy~~lohexanecarboxamidino, diaminometlzyleneamino, N-methylgu;~.nidino, N, N-dimeth:;~lguanidino , N,N'-dimetlzylguanidino, N-ethylguanidino , N-butylguanidino, N-ethyl-N-methylguanidino, N,N-diethy:Lguanidino, N,N' -dieth:,~lguanidino, N,N',N'-tr:imethylguanidino, 1,1,3,3-te~_ramethylguanidino, N-ethyl-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-but~,~l-N'-methylguanidino, , __ I~'GW ~~~~
_ g _ N-isobutyl-T1'-methylguanidino, N-butyl-N'-methylguanidino, N-butyl-N'-ethylguanidino, N-methyl-N'-pentylguanidino, N-cyclopentyl-N'-methylguanidino, N-(2-metho:xyethyl)guanidino, N-(2-metho:Kyethyl)-N-methylguanidino, N-(2-metho:Kyethyl)-N'-methylguanidino, N-ethyl-N-(2-methoxyethyl)guanidino, N,N-bis(2-methoxyethyl)guanidino, N-methyl-N-(2-methylthioethyl)guanidino, N-a11y1-N-methylguanidino, N-a11y1-N'-methylguanidino, 1-allyl-1,:3,3-trimethylguanidino, N,N-diallyLguanidino, In one group of preferred compounds of formula I
in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a heterocycl:ic ring of formula IV, R9 and R10, which may 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 R9 and/or R10 are methoxyethyl), D is selected from -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH2CMe2- or -0(CH2)2- and the group R6 is preferably H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyev=hyl or 2-metho:~yethyl. In particularly preferred compounds of formula I, formula IV
represents:-2-pyrrolid:Lnylidene, 1-methyl-2~-pyrrolidinylidene, 3-methyl-2~-pyrrolidinylidene, 1-ethyl-2-pyrrolidinylidene, 1-isopropy:L-2-pyrrolidinylidene, 1-cyclohexyl-2-pyrrolidinylidene, w-- I
_ 9 _ 1-(2-metho:Yyethyl)-2-pyrrolidinylidene, 1,3-dimethyl-2-pyrrolidinylidene, 5,5-dimeth;yl-2-pyrrolidinylidene, 1,3,3-trim~ethyl-2-pyrrolidinylidene, 1,5,5-trimethyl-2-pyrrolidinylidene, 3-isopropyl-1-methyl-2-pyrrolidinylidene, 1-ethyl-3,3-dimethyl-2-pyrrolidinylidene, 3,3-diethyl-1-methyl-2-pyrrolidinylidene, 2-piperidi:zylidene, 1-methyl-2-piperidinylidene, 1,3-dimeth:ylpiperidinylidene, 1-ethyl-2-yiperidinylidene, 1-isopropyl-2-piperidinylidene, 1-(2-cyano~~thyl)-2-piperidinylidene, 1-(2-aceto:~yethyl)-2-piperidinylidene, 3-(2-metho:xyethyl)-1-methyl-2-piperidinylidene, 2-hexahydroazepinylidene, 1-methyl-2-hexahydroazepinylidene, 2-octahydr~~azocinylidene or 3-morpholinylidene.
In a second group of preferred compounds of formula I in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V, E is -CH2CH2-, -CMe2CH2-, -CHMeCHMe-, -(CH2)3 ' CHMeCH2- or -(CH2)4, Rll is H, methyl or ethyl and R6 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, cyclohexyl, benzyl, phenethyl, 3-hydroxypropyl, 2-hydroxyp:ropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-butyl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl. In particularly preferred compounds of formula I, formula V represents:-20065'1 2-imidazolid~.'_nylidene, 1-methyl-2-im.idazoiidinylidene, 4-methyl-2-i~r~.idazoii dinyl idene, 4,4-dimethyl-2-imidazolidinylidene, S 4,5-dimethyl-~-imidazolidinylidene, 1 -er~~yl-2-il«idazoli d=nylidene, 1-propyl-2-i~nidazolidinylidene, 1-isopropyl-~-imidazolidinylidene, 1-(n-butyl)-2-imidazolidinylidene, 1-isobutyl-2-imidazolidinylidene, 1-per:tyl-2-imidazolidinylidene, 1-allyl-2-imidazolidinylidene, 1-(~-methylallyl)-2-imidazolidinylidene, 1-(2-hydroxyethyl)-2-imidazolidinylidene, 1-(2-hydroxrethyl)-3-methyl-2-imidazolidinylidene, 1-(2-acetoxyethyl)-2-imidazolidinylidene, 1-(2-benzoyloxyethyl)-2-imidazolidinylidene, 1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidinylidene, 4,S-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinylidene, 1-(2-methoxyethyl)-2-imidazolidinylidene, 1-(2-methoxyethyl)-3-methyl-2-imidazolidinylidene, 1-cyclohexyl-2-imidazolidinylidene, 1-benzyl-2-imidazolidinylidene, 1-(2-phenylethyl)-2-imidazolidinylidene, 1-(2-dimethylaminoethyl)-2-imidazolidinylidene, 1-(3-hydroxypropyl)-2-imidazolidinylidene, 1-(2-hydroxypropyl)-2-imidazolidinylidene, 1-(2-hydroxy-2-methylpropyl)-2-imidazolidinylidene, 1-(2-hydroxybutyl)-2-imidazolidinylidene, 1-(2,3-dihydroxypropyl)-2-imidazolidinylidene, 1,3-dimethyl-2-imidazolidinylidene, 1,3-diethyl-2-imidazolidinylidene, 1-ethyl-3-met;zyl-2-imidazolidinylidene, 1-butyl-3-methyl-2-imidazolidinylidene, 3S 1-isopropyl-4,4-dimethyl-2-imidazolidinylidene, 1-methyl-2-pe:rhydropyrimidinylidene or 1,3-diazacycl«heptan-2-ylidene.

-~~-In preferred compounds of formula I in which R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI, G
represents a group selected from -(CH2)4-, -(CH2)5-, -S (CH2 ) 20 (CH2 ) ~;-, - (CH2 ) 2S (CH2 ) 2-, - (CHI ) 2NMe (C::2 ) 2 -, _ (CH2 ) 2CHMe (C~i2 ) 2- or -C H3C:~'~IeOCHMeCH2-. In particularly preferred cornpcunds, the group NRSR6 is 1-pyrrolidiny~~, piperidino, 4-methylpiperidino, mcrpholiro, 2,0-dimethylmorpr:ol ino, t::iamorphclir_o or 4-T~et:-ryl-1-?0 piperazinyl. In part=cvlarly preferred compounds of formula I in which RS and R6 together with the nitroge.~.
atom to whic~i they are attacred form a heterocyclic ring' of formula VI, the group -N=C(R3)NR5R6 is:-N,N-(3-oxaper..tamethylene)guanidino, l,l-dimethyl-3,3-(3-15 oxapentamethylene)guanidino, N,N-(2,4-dimethyl-3-oxa-pentamethyle:~e)guanidino, N,N-(3-thiapentamethylene)-guanidino, D1,N-(3-methylpentamethylene)guanidino, N,N-(N-methyl-3-a.zapentamethylene)guanidino, N-methyl-N',N'-tetramethylen.eguanidine, N-pentamethyleneguanidino, 1,1-20 dimethyl-3,3-pentamethyleneguanidino.
In preferred compounds of formula I, R~ represents H or one or more substituents (preferably one or two substituents) selected from fluoro, chloro, methyl, ethyl, isobu.tyl, methylthiomethyl, methoxy, methoxy-25 carbonyl, methylthio, methylsulphinyl, methyl-sulphonyl, trifluorometh.yl or cyano.
Specific compounds of formula I are 4-[2-(2-piperidinylideneamino)phenyl]morpholine 4-[2-(1-methyl-2-piperidinylideneamino)phenyl]
30 morpholine ~:; w ..' 2Q~~~'~'7 4-[2-(1-et:hyl-2-piperidinvlideneamino)phenyl]-morpholine 4-(2-(1-is~~propyl-2-piperidinylideneamino)phenyl]-morpho l ine 4-[2-(2-he:xahydroazepinylideneamino)phenyl]morpholine 4-[2-(1-methyl-2-hexahydroazepinylideneamino)phenyl]-morpholine 4-[2-(2-octahydroazocinylideneamino)phenyl]morpholine 4-[2-(2-py:rrolidinylideneamino)phenyl]morpholine 4-(2-(1-methyl-2-pyrrolidinylideneamino)phenvl]-morpho l ine 4-(2-(1,3-~3imethyl-2-pyrrolidinylideneamino)-phenyl]m~~rpholine 4-[2-(1,3,:3-trimethyl-2-pyrrolidinylideneamino)-phenyl]morpholine 4-(2-(1-ethyl-2-pyrrolidinylideneamino)phenyl]-morpho l ine 4-~2-[1-(2-methoxyethyl)-2-pyrrolidinylideneamino]-phenyl)morpholine 4-[2-(1-cyclohexyl-2-pyrrolidinylideneamino)phenyl]-morpholine 4-(2-(3,3-dimethyl-1-ethyl-2-pyrrolidinylidene-amino)phenyl]morpholine 4-[2-(3,3-diethyl-1-methyl-2-pyrrolidinylideneamino)-phenyl]morpholine 4-(2-(3-isopropyl-1-methyl-2-pyrrolidinylidene-amino)phenyl]morpholine 4-[2-(1,3-dimethyl-2-piperidinylideneamino)phenyl]-morpho l ine 4-[3-methy:L-2-(2-piperidinylideneamino)phenyl]-morpho l ine 4-[3-methy:L-2-(1-methyl-2-piperidinylideneamino) phenyl]morpholine 4-[4-methy:L-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-methy:L-2-(1-methyl-2-piperidinylideneamino)-phenyl]morpholine ,~c,~~5'7'7 4-[5-methyl-2-(2-piperidiriylideneamino)phenyl]-morpholine 4-[6-methyl-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-ethyl-2-(2-piperidinylideneamino)phenyl]
morpholine 4-[3-chloro-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-chloro-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-chloro-2-(1-methyl-2-piperidinylideneamino) phenyl]morpholine 4-[5-chloro-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[6-chloro-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-fluoro-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-fluoro-2-(1-methyl-2-piperidinylideneamino)-phenyl]morpholine 4-[4-methoxy-2-(2-piperidinylideneamino)phenyl]-morpholine 4-[4-methoxycarbonyl-2-(2-piperidinylideneamino) phenyl]-~morpholine 4-[4-methylsulphonyl-2-(2-piperidinylideneamino) phenyl]morpholine 4-(2-[1-(2-acetoxyethyl)-2-piperidinylideneamino]-phenyl~morpholine 4-(2-[1-methyl-3-(2-methoxyethyl)-2-piperidinylidene-amino]phenyl~morpholine 4-[2-(3-methyl-2-pyrrolidinylideneamino)phenyl]-morpho 1 irne N-methyl-N'-(2-morpholinophenyl)acetamidine N-(2-morpholinophenyl)-N'-propylacetamidine N-(n-butyl)-N'-(2-morpholinophenyl)acetamidine ~0~65'~'~

N-(n-pentyl)-N'-(2-morpholinophenyl)acetamidine N-(2-acetoxyethyl)-N'-(2-morpholinophenyl)-acetamid.ine N,N-dimethyl-N'-(2-morpholinophenyl)acetamidine N,Pd-diethyl-N'-(2-morpholinophenyl)acetamidine N-methyl-N'-(2-morpholinophenyl)propionamidine N-ethyl-N'-(2-morpholinophenyl)propionamidine N,N-dimethyl-N'-(2-morpholinophenyl)propionamidine N-methyl-1'd'-(2-morpholinophenyl)butyramidine N-ethyl-Pd'-(2-morpholinophenyl)butyramidine N,N-dimethyl-N'-(2-morpholinophenyl)butyramidine N-methyl-N'-(2-morpholinophenyl)-2-methyl-propionamidine N,N-dimethyl-N'-(2-morpholinophenyl)-2-methyl-propionamidine Td-methyl-N'-(2-morpholinophenyl)valeramidine N,N-dimethyl-N'-(2-morpholinophenyl)valeramidine N-methyl-N'-(2-morpholinophenyl)pivalamidine N,N-dimethyl-N'-(2-morpholinophenyl)pivalamidine N-methyl-N'-(2-morpholinophenyl)hexar_amidine N-methyl-N'-[2-(1-pyrrolidinyl)phenyl]butyramidine N-methyl-N'-[2-(1-pyrrolidinyl)phenyl]pivalamidine N-methyl-N'-(2-morpholinophenyl)cyclohexane carboxamidine N-methyl-N'-(2-piperidinophenyl)pivalamidine 1-[2-(2-piperidinylideneamino)phenyl]pyrrolidine 1-[2-(1-methyl-2-piperidinylideneamino)phenyl]-pyrrolidine 1-[2-(1-ethyl-2-piperidinylideneamino)phenyl]-pyrrolidine 1-[4-chlor~~-2-(1-methyl-2-piperidinylideneamino)-phenyl]p:yrrolidine 1-[3-methyl-2-(1-methyl-2-piperidinylideneamino)-phenyl]p:yrrolidine 1-[2-(1-methyl-2-pyrrolidinylideneamino)phenyl]-pyrrolidine m_. 2(;~~c;;~'T~

1-[2-(1,3-dimethyl-2-pyrrolidinylideneamino)phenyl]-pyrrolidine 1-[2-(1-methyl-2-hexahydroazepinylideneamino)phenyl]-pyrrolidine 1-[4-methyl-2-(2-piperidinylideneamino)phenyl]-pyrrolidine 1-[4-chloro-2-(2-piperidinylideneamino)phenyl]-pyrrolidine 1-[3-methyl-2-(2-piperidinylideneamino)phenyl]-pyrrolidine 1-[6-methyl-2-(2-piperidinylideneamino)phenyl]-pyrrelidine 4-[2-(2-piperidinylideneamino)phenyl]thiamorpholine 1-[2-(2-piperidinylideneamino)phenyl]piperidine 1-[2-(1-methyl-2-piperidinylideneamino)phenyl]-piperidi~ne 1-[2-(2-piperidinylideneamino)phenyl]hexahydroazepine 2,6-dimethyl-4-[2-(2-piperidinylideneamino)phenyl]-morpho 1 i~ne 4-methyl-1-[2-(2-piperidinylideneamino)phenyl]-piperidine 1-[2-(2-piperidinylideneamino)phenyl]-1,2,5,6-tetrahydropyridine 2-methyl-1-[2-(2-piperidinylideneamino)phenyl]-pyrrolidine 2-[2-(2-pi~peridinylideneamino)phenyl]isoindoline 4-[2-(1-methyl-2-piperidinylideneamino)phenyl]-thiamorp~ho 1 ine 4-[4-methyl-2-(2-piperidinylideneamino)-phenyl]t~hiamorpholine N-(2-metho:Kyethyl)-N-[2-(2-piperidinylideneamino)-phenyl]m~ethylamine 1'T-[2-(2-pi~peridinylideneamino)phenyl]dimethylamine N-[2-(2-pi:peridinylideneamino)phenyl]diallylamine N-cyclohex:yl-N-[2-(2-piperidinylideneamino)phenyl]-methylamine ~~t~~~'~~

N-[2-(2-piperidinylidineaminophenyl)-bis-(2-methoxy-ethyl)amine 4-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino)-phenyl]thiamorpholine 1-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino)-phenyl]piperidine 1-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino)phenyl]-4-methylpiperazine 1-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino)-phenyl]pyrrolidine 4-[4-methyl-2-(1,3,3-trimethyl-2-pyrrolidinylidene-amino)phenyl]morpholine 1-[2-(1-methyl-2-pyrrolidinylideneamino)phenyl]-piperidine 1-[2-(1,3-dimethyl-2-pyrrolidinylideneamino)phenyl]-piperidine 4-[2-(5,5-dimethyl-2-pyrrolidinylideneamino)phenyl]-morpholine 4-[1,5,5-trimethyl-2-pyrrolidinylideneamino)phenyl]-morpholine rd-[2-(1,3,3-trimethyl-2-pyrrolidinylideneamino)phenyl]-bis-(2-m.ethoxyethyl)amine N-(2-morpholinophenyl)acetamidine N-(5-methyl-2-morpholinophenyl)acetamidine N-(2-morpholinophenyl)propionamidine N-(2-morpholinophenyl)butyramidine N-(2-morpholinophenyl)isobutyramidine N-(5-methylthio-2-morpholinophenyl)isobutyramidine N-(5-fluoro-2-morpholinophenyl)isobutyramidine N-(2-morpholinophenyl)valeramidine N-(2-morpholinophenyl)pivalamidine 4-t2-[1-(cyanoethyl)-2-piperidinylideneamino]phenyl~-morpholine 4-[2-(3-morpholinylideneamino)phenyl]morpholine 4-[2-(2-piperidinylideneamino)benzyl]morpholine 4-[2-(1-methyl-2-pyrrolidinylideneamino)benzyl]-morpholine ~QiJ65'~'~

4-[4-chloro-2-(2-piperidinylideneamino)benzyl]-morpholine 4-[2-(1,3,3-trimethyl-2-pyrrolidinylideneamino)-benzyl]morpholine N-methyl-N'-(2-morpholinomethylphenyl)pivalamidine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-4-fluorophenyl]morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-3-methylphenyl]morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-4-methylphenyl]morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-5-methylphenyl]morpholine 4-[4-chloro-2-(1,3-dimethyl-2-imidazolidinylidene-amino)phenyl]morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-4-methoxyphenyl]morpholine 4-[4,5-dimethoxy-2-(1,3-dimethyl-2-imidazolidinylidene-amino)phenyl]morpholine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]-pyrrolidine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-3-methylphenyl]pyrrolidine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]-piperidine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]-thiamorpholine 2,6-dimeth;yi-4-[2-(1,3-dimethyl-2-imidazolidinylidene-amino)phenyl]morpholine N-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]-diethylamine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]-2-methyl~pyrrolidine w 2(~~6 ~"'~"~

4-[3-chloro-2-(1,3-dimethyl-2-imidazolidinylidene-amino)phenyl]morpholine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-4-methylphenyl]pyrrolidine N-[2-(1,3-dimethyl-2-imidazolidinylidene-amino)phenyl)-bis-(2-methoxyethyl)amine 4-[2-(1,3-diethyl-2-imidazolidinylideneamino)phenyl)-morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-6-methylphenyl]pyrrolidine 4-[2-(1-et''~yl-3-methyl-2-imidazolidinylideneamino)-phenyl]m~~rpholine 4-[2-(1-n-butyl-3-methyl-2-imidazolidinylideneamino)-phenyl_ ] m~~rpholine 4-~2-[1-(2-benzoyloxyethyl)-3-methyl-2-imidazolinyl-ideneamino]phenyl)morpholine 2-(2-morpholinophenyl)-1,1,3,3-tetramethylguanidine 1-ethyl-2-(2-morpholinophenyl)-1,3,3-trimethyl-guanidine=_ 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethyl-guanidine 1-n-butyl-:Z-(2-morpholinophenyl)-1,3,3-trimethyl-guanidine 1-pentyl-2-(2-morpholinophenyl)-1,3,3-trimethyl-guanidine 4-~2-[1-methyl-3-(2-methoxyethyl)-2-imidazolidinyl-ideneamino)phenyl)morpholine 4-(2-[1-methyl-3-(2-hydroxyethyl)-2-imidazolidinyl-ideneamino]phenyl7morpholine N,N-dimeth;~l-N'-(2-morpholinophenyl)morpholine-4-carboxam:idine Pd,N-dimeth:;~l-N'-(2-morpholinophenyl)piperidine-1-carboxam:idine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino) phenyl)thiamorpholine-1-oxide 4-[2-(2-im:idazolidinylideneamino)phenyl]morpholine ~O~Ei a'7'~

4-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-[2-(1-ethyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-[2-(1-n-propyl-2-ir~idazolidinylideneamino)phenyl]-morpho l ine 4-[2-(1-isopropyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-[2-(1-n-butyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-[2-(1-isobutyl-2-imidazolidinylamino)phenyl]-morpholine 4-[2-(1-pentyl-2-imidazolidinylamino)phenyl]-morpholine 4-[2-(1-allyl-2-imidazolidinylideneamino)phenyl]-4-~2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]
phenyl7morpholine 4-(2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-3-methylphenyl7morpholine 4-~2-[1-(2-methoxyethyl)-2-imidazolidinylideneamino]
phenyl~morpholine 4-[2-(1-cyclohexyl-2-imidazolidinylideneamino)phenyl]-morpholine ' 4-[2-(1-be'nzyl-2-imidazolidinylideneamino)phenyl]-morpholine 4-(2-[1-(2-phenylethyl)-2-imidazolidinylideneamino]-phenyl)morpholine 4-(2-[1-(2-dimethylaminoethyl)-2-imidazolidinylidene-amino]phenyl~morpholine 4-(2-[1-(2,3-dihydroxypropyl)-2-imidazolidinylidene-amino]phenyl~morpholine 4-t2-[1-(2-methylallyl)-2-imidazolidinylideneamino]-phenyl~morpholine N-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]his-(2-metho:xyethyl)amine N-~2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-phenyl)bis-(2-methoxyethyl)amine ~af~~ 5'~'~

4-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]
thiamorpholine 1-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]
pyrrolidine 4-[2-(1-n-butyl-2-imidazolidinylideneamino)phenyl]-thiamorpholine 4-[2-(1-methyl-2-imidazolidinylideneamino)-3-methyl-phenyl]m~~rpholine 4-[2-(1-methyl-2-imidazolidinylideneamino)-4-methyl-phenyl]morpholine 1-~2-[1-(2-hydroxyethyl)-2-imidazolindinylideneamino]-phenyl7p:yrrolidine 1-~2-[1-(2-hydroxyethyl)-2-imidazolindinylideneamino]-phenyl~-.2-methylpyrrolidine 4-[4-methyl-2-(1-n-butyl-2-imidazolidinylidene)-phenyl]m~~rpholine 1-[2-(2-im:idazolidinylideneamino)phenyl]piperidine 1-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]
piperidine 1-[2-(1-methyl-2-imidazolidinylideneamino)-3-methyl-phenyl]p:iperidine 4-~2-[1-(2-hydroxyethyl)-2-imidazolidinylidene-amino]phc~nyl~thiamorpholine 1-~2-[1-(2~-hydroxyethyl)-2-imidazolidinylidene-amino ] phen_,~1 ~ p iperidine 4-(2-[1-(3~-hydroxypropyl)-2-imidazolidinylideneamino]-phenyl~morpholine 4-~2-[1-(2~-hydroxypropyl)-2-imidazolidinylideneamino]-phenyl)morpholine 4-(2-[1-(2~-hydroxybutyl)-2-imidazolidinylideneamino]-phenyl7morpholine 4-(2-[1-(2~-hydroxy-2-methylpropyl)-2-imidazolidinyl-ideneamino]phenyl7morpholine 4-[2-(4-methyl-2-imidazolidinylideneamino)phenyl]-morpholine 2Q~~5'~''7 4-[2-(4,5-dimethyl-2-imidazolidinylideneamino)phenyl]
morpholine 4-~2-[4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinyl-ideneamino]phenyl7morpholine 4-[2-(1-isopropyl-4,4-dimethyl-2-imidazolidinylidene-amino)phenyl]morpholine 4-[2-(1-methylperhydropyrimidin-2-ylideneamino)-phenyl]morpholine 2-(2-morpholinophenylimino)-1,3-diazacycloheptane 1,1-dimethyl-2-(2-morpholinophenyl)guanidine 1,3-dimethyl-2-(2-morpholinophenyl)guanidine 1,3,3-trimethyl-2-(2-morpholinophenyl)guanidine 1-ethyl-2-(2-morpholinophenyl)-3-methyl-guanidine 1,3-diethyl-2-(2-morphelinophenyl)guanidine 4-(2-[1-(2-acetyloxyethyl)-2-imidazolidinylidene-amino]phenyl7morpholine 4-~2-[1-(2-benzoyloxyethyl)-2-imidazolidinylidene-amino]phenyl)morpholine 1-(n-butyl)-2-(2-morpholinophenyl)-3-methyl-guanidine 1-(2-methoxyethyl)-2-(2-piperidinophenyl)guanidine 1-(2-methylthioethyl)-2-(2-morpholinophenyl)guanidine 1-(2-methoxyethyl)-2-(2-morpholinephenyl)guanidine 1-(n-propyl)-2-(2-morpholinophenyl)-3-methylguanidine 1-(2-methoxyethyl)-3-methyl-2-(2-morpholinophenyl) guanidine 1-cyclopentyl-2-(2-morpholinophenyl)-3-methyl-guanidine N-methyl-N'-(2-morpholinophenyl)pyrrolidine-1-carboxamidine 1-(n-butyl)-2-(2-morpholinophenyl)-3-ethylguanidine 1,3-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine 1-allyl-2-[2-(1-pyrrolidinyl)phenyl]-3-methylguanidine 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl)-2~~~'~S'~'~

guanidine 4-~2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-4-methylphenyl~morpholine 1-methyl-2-(2-morpholinophenyl)-3-(n-pentyl)guanidine 1-(n-butyl)-2-(5-methyl-2-morpholinophenyl)-3-methylguanidine 1-(n-butyl)-2-(6-methyl-2-morpholinophenyl)-3-methylguanidine 1-(n-butyl)-2-(5-fluoro-2-morpholinophenyl)-3-methylgu.anidine 1-(n-butyl)-2-(5-methylthio-2-morpholinophenyl)-3-methylgu,~nidine 1-isobutyl-2-(2-morpholinophenvl)-3-methylguanidine 1-sec-butyl-2-(2-morpholinophenyl)-3-methylguanidine 1-tert-but:yl-2-(2-morpholinophenyl)-3-methylguanidine 1-a11y1-2-(2-morpholinophenyl)-3-methylguanidine 1-(n-butyl)-2-(2-thiamorpholinophenyl)-3-methyl-guanidine 1,1-dimeth:~l-2-(2-morpholino-5-trifluoromethyl-phenyl)guanidine 1,1-dimeth:~l-2-(5-cyano-2-morpholinophenyl)guanidine 1,3-di-(n-propyl)-2-(2-morpholinophenyl)guanidine 2-(2-morpholinophenyl)guanidine l,l-dimeth:;~1-2-(5-methyl-2-morpholinophenyl)-guanidine 1,1-dimeth:,~l-2-(6-methyl-2-morpholinophenyl)-guar_idine 1,1-dimeth:,~l-2-(4-chloro-2-morpholinophenyl) guanidine 1,1-dimeth~,~l-2-(3-chloro-2-morpholinophenyl)-guanidinE~
1,1-dimeth~~l-2-(5-methoxy-2-morpholinophenyl)-guanidinE~
1,1-dimeth~~l-2-(5-methylthio-2-morpholinophenyl)-guanidinE~
1,1-dimethyl-2-(4-methyl-2-morpholinophenyl)guanidine ..: ~~~6~"~"7 1,1-dimeth;yl-2-(5-ethyl-2-morpholinophenyl)guanidine l,l-dimeth:yl-2-(5-methylthiomethyl-2-morpholino-phenyl)guanidine 1,1-diethyl-2-(2-morpholinophenyl)guar_idine 1-(n-butyl)-1-methyl-2-(2-morpholinophenyl)guanidine 1,1-bis(2-methoxyethyl)-2-(2-morpholinophenyl)-guanidine N-(2-morph~~linophenyl)morpholine-4-carboxamidine N-(2-morph~~linophenyl)pyrrolidine-1-carboxamidine 1,1-dimeth:yl-2-(2-piperidinophenyl)guanidine 1,1-dimeth:yl-2-[2-(1-pyrrolidinyl)phenyl]guanidine l,l-dimeth:yl-2-(2-thiamorpholinophenyl)guanidine 1,1-dimeth:~1-2-(2-dimethylaminophenyl)guanidine 1,1-dimeth:yl-2-~2-[N-(2-methoxyethyl)-N-methylamino]
phenyl)guanidine 1,1-dimeth:~1-2-[2-(4-methyl-1-piperazinyl)phenyl]
guanidine N-(2-piper:idinophenyl)morpholine-4-carboxamidine N-(2-piper:idinophenyl)piperidine-1-carboxamidine 1,1-dimeth:;~l-2-(5-methoxycarbonyl-2-morpholino phenyl)guanidine 1-methyl-2~-(2-morpholinophenyl)guanidine 1-ethyl-2-(2-morpholinophenyl)guanidine 1-butyl-2-(2-morpholinophenyl)guanidine 1-ethyl-1-methyl-2-(2-morpholinophenyl)guanidine 1-methyl-1~-(2-methylthioethyl)-2-(2-morpholinophenyl)guanidine 1-(2-methoayethyl)-1-methyl-2-(2-morpholinophenyl) guanidine.
1-allyl-1-methyl-2-(2-morpholinophenyl)guanidine 1-ethyl-1-(2-methoxyethyl)-2-(2-morpholinophenyl) guanidine:
1,1-dially:l-2-(2-morpholinophenyl)guanidine N-(2-morpholinophenyl)-4-methylpiperazine-1-carboxam:idine 2~0!~ i'~'~

Pd-(2-morpholinophenyl)-2,6'-dimethylmorpholine-4-carboxam:idine N-(2-morpholinophenyl)thiamorpholine-4-carbox-amidine N-(2-morpholinophenyl)-4-methylpiperidine-1-carboxam_edine N-(2-morpholiniphenyl)thiamorpholine-1-carboxamidine 1,1-dimeth~~l-2-(5-chloro-2-morpholinophenyl)guanidine 1,1-dimethyl-2-(5-fluoro-2-morpholinophenyl)guanidine 1,1-dimeth~~l-2-(3-methyl-2-morpholinophenyl)guanidine 1,1-dimeth~T1-2-(4-methoxy-2-morpholinophenyl)guanidine 1,1-dimethyl-2-(5-isobutyl-2-morpholinophenyl) guanidinE~
1,1-dimethyl-2-(5-methylsulphinyl-2-morpholino-phenyl)guanidine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-benzyl]morpholine 4-[4-chloro-2-(1,3-dimethyl-2-imidazolidinylidene-amino)benzyl]morpholine N,N-dimeth;~l-N'-(2-morpholinomethylphenyl)guanidine N-(2-morpholinomethylphenyl)morpholine-4-carboxam~_dine and pharmaceutically acceptable salts thereof.
One group of preferred compounds of formula I
includes compounds of formula I in which n = 0, -NR1R2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, R3 is -NH2, R5 is an aliphatic group containing 1 to 4 carbon atoms (eg methyl, ethyl or allyl), R6 is an aliphatic group of 1 to 4 carbon atoms optionally substituted by methoxy or methylthio (eg methyl, ethyl, allyl, methoxyethyl or methylthioethyl) or R5 and R6 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, methylthiomethyl or methylthio.

~"~0~'~5'7''7 Specific compounds falling within this one group of preferred ~~ompounds include:-1,1-dimeth;~l-2-(2-morpholinophenyl)guanidine 1,1-dimeth:,~l-2-(5-fluoro-2-morpholinophenyl)guanidine 1,1-dimeth:;~l-2-(5-chloro-2-morpholinophenyl)guanidine 1,1-dimeth:~l-2-(5-methyl-2-morpholinophenyl)guanidine 1,1-dimeth:,~1-2-(6-methyl-2-morpholinophenyl)guanidine 1,1-dimeth~,~l-2-(5-ethyl-2-morpholinophenyl)guanidine 1,1-dimeth:,~l-2-(5-methylthiomethyl-2-morpholinophenyl) guanidine 1,1-dimeth:,~l-2-(5-methylthio-2-morpholinophenyl) guanidine 1-ethyl-1-methyl-2-(2-morpholinophenyl)guanidine 1,1-diethy:L-2-(2-morpholinophenyl)guanidine 1-(2-metho:~yethyl)-1-methyl-2-(2-morpholinophenyl) guanidine 1-methyl-1~-(2-methylthioethyl)-2-(2-morpholinophenyl)-guanidinc:
1,1-dimeth~~l-2-(2-thiamorpholinophenyl)guanidine 1,1-dimeth~~1-2-(2-piperidinophenyl)guanidine 1,1-dimeth~~l-2-[2-(1-pyrrolidinyl)phenyl]guanidine N-(2-morpholinophenyl)morpholine-4-carboxamidine N-(2-morpholinophenyl)thiamorpholine-4-carboxamidine and pharmaceutically acceptable salts thereof.
A second group of preferred compounds of formula I
includes compounds of formula I in which n = 0, -NR1R2 is morphol.ino or thiamorpholino, R3 is a group of formula III in which R4 is an alkyl group containing 1 to 4 carbon atoms (eg methyl) and R4' is H, R5 is H, R6 is an aliphatic group containing 1 to 4 carbon atoms (eg methyl,, butyl or t-butyl) optionally substituted by methoxy (e. g. R6 is methoxyethyl) and R~ is H, fluoro, methyl, met:hylthio or methylthiomethvl.

2Q~D~~'~'~

Specific compounds falling within this second group of preferred compounds include:-1-butyl-3-rnethyl-2-(2-morpholinophenyl)guanidine 1-methyl-3--tert-butyl-2-(2-morpholinophenyl)guanidine 1-methyl-3--tert-butyl-2-(4-fluoro-2-morpholinophenyl) guanidinE:
1-methyl-3--tert-butyl-2-(4-methyl-2-morpholinophenyl) guanidine 1-methyl-3--tert-butyl-2-(4-methylthio-2-morpholino-phenyl)guanidine 1-methyl-3--tert-butyl-2-(4-methylthiomethyl-2-morpholinophenyl)guanidine 1-(2-metho~;yethyl)-3-methyl-2-(2-morpholinophenyl) guanidine 1,3-dimeth5~1-2-(2-thiamorpholinophenyl)guanidine 1-methyl-3-~tert-butyl-2-(2-thiamorpholinophenyl) guanidine and pharmaceutically acceptable salts thereof A furi:her group of preferred compounds of formula I includes compounds of formula I in which n - 0, -NR1R2 is morpholino, thiamorpholino, morpholinomethyl or thiamorpholinomethyl, R3 is an alkyl group of 1 to 4 carbon atoms (eg methyl and t-butyl), R5 and R6 are H
and R~ is H, fluoro, methyl, methylthio or methylthiomethyl.
Specific compounds falling within this further group of preferred compounds include:-N-(2-morpholinophenyl)acetamidine N-(4-fluoro-2-morpholinophenyl)acetamidine N-(4-methyl.-2-morpholinophenyl)acetamidine :000 S'7'~

N-(4-methy=Lthio-2-morpholinophenyl)acetamidine N-(4-methy:Lthiomethyl-2-morpholinophenyl)acetamidine N-(2-thiamo rpholinophenyl)acetamidine N-(2-morpholinomethylphenyl)acetamidine N-(2-morpholinophenyl)pivalamidine N-(2-morpholinomethylphenyl)pivalamidine and pharmaceutically acceptable salts thereof.
Compounds of formula I may exist as salts with pharmaceut~:cally acceptable acids. Examples of such salts inc~_ude hydrochlorides, hydrobromides, hydro-iodides, sulphates, nitrates, maleates, acetates, citrates, fumarates, tartrates, succinates, benzoates, pamoates and salts with acidic amino acids such as glutamic ac=id. Compounds of formula I and their salts 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 I contain ~me chiral centre the compounds exist in two enantiomeri_c forms and the present invention includes both enanti_omeric forms and mixtures thereof. When the compounds of formula I contain more than one chiral centre, the compounds may exist in diastereoisomeric forms. Th.e present invention includes each of these diastereoi:comeric 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 pharmaceutically acceptable diluent or carrier.
In therapeutic use, the active compound may be administerE:d orally, rectally, parenterally or ~00~~~'~'7 topically, preferably orally. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, reci=al, parenteral or topical administration.
Pharmaceutically acceptable carriers suitable for use in such compositions are well known. in the art of 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 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 soft gelatin capsules, containing the active compound with or w:Lthout 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 the active compound. Other compositions for oral administra~~ion include, for example, aqueous solutions containing the active compound; aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vE~getable 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.

~~~~a~~

The pharmaceutical ~ compositions containing a therapeutically effective amount of a compound of formula I may be used to treat hyperglycaemia in human beings . :CrL 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 administration.
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 ~~f an aminophenyl compound of formula VII
(CH2)nNRlR2 R~

VII
with an arnide or a urea of formula R3.CO.NR5R6 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 R3 and R5 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

~Q~~ a'~'7 R9\ / R10 0 = C 1D
~N

in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, cyanuric chloride, phosgene, carbon tetrachloride/triphenyl phosphine, phosphorus pentachloride or benzene sulphonyl chloride.
b) a compound of formula IX
R9\ / R10 'C
I / _ N ~ ~ IX

in which F:12 is chloro, -0-POC12, -0-SOCl, -OCOC1 or -OS02Ph and B is an anion such as halo (e.g. C1 ) or POC14-, c) a compound of formula X
R9~ ~ R10 C
R 0-C~ D B

N

_a 2~~~;~'7'7 in which R.~3 is an alkyl group and B is an anion such as fluoroborate or methosulphate.
d) when R6 is H, a ketoxime of formula XI

9~C%
~1 HON = C ~ XI
D
in the presence of a sulphonyl chloride (for example benzene sul_phonyl chloride).
Compounds of formula I in which the groups R3 and R5 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 an aminophenyl compound of formula VII with a urea of formula XII
j11 ~N

\N~

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 R3 and R5 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 XI7=I

~~~f J'O'B

(CH2)nNRlR2 R~ \ I / She XIII

N
\ R15 optionally in the form of a salt (e. g. a hydroiodide salt) in which R14 and R15 are H with a diamine of formula XI'J
R11NHENHR~ XIV
Compo,inds of formula I in which R3 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 NR5R6 is NH2 may be prepared by the reaction of a compound of formula VII optionally in the form of a salt (e. g. a hydrochloride salt) with a cyano compound of formula R3CN, optionally in the presence of aluminium ~=hloride.
Compounds of formula I in which the group R3 is NH2 may be prepared by the reaction of a compound of formula VII optionally in the form of a salt (e.g. a hydrochloride salt) with a cyanamide compound of formula R5R6NCN. The reaction may be performed in a liquid re~.ction medium (for example m-cresol) or by heating the reactants together in the absence of a liquid carrier.
Compounds of formula I in which the group R3 is NH2 may be prepared by the reaction of compounds of formula XV

2~0~ ~'~'7 (CH2)nNRlR2 NHCN
with amines of formula NHR5R6 optionally in a liquid reaction medium (for example ethanol).
Compounds of formula I in which R3 is a group of formula IIL in which R4 is alkyl and R4' is H or alkyl may be prepared by the reaction of a compound of formula XIII in which R14 is the group R4 and R15 is the group R4' with an amine of formula HNR5R6. The reaction m,~y be performed in an alcoholic medium (e. g.
ethanol or n-butanol) optionally in the presence of a base such as pyridine or triethylamine or in the presence o:E potassium hydroxide and lead acetate. When HNR5R6 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 R3 is a group of formula II:L in which R4 is alkyl and R4' is H or alkyl may be prepared by the reaction of a thiourea of formula XV:
(CH')nNRlR2 XVI
R~ ~ / Rl~
NH.CS.N
\ R1~

~Q~~~'~'7 in which R.14 is the group R4 and R15 is the group R4' with an arsine of formula HNR5R6. The reaction may be performed in the presence of a base (such as potassium hydroxide or potassium carbonate) and lead acetate.
When HNRSR~ 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.
Comp ounds of formula I in which R3 is a group of formula III in which R4 is alkyl and R4' is H and in which R5 is H may be prepared by the reaction of a carbodiimide of formula XVII
(CH2 ) nNRlR2 R.~
XVII
N= C-NR4 with an amine of formula H2NR6.
Compounds of formula I in which n = 0 and NR1R2 is a morpholino, thiamorpholino, 1-pyrrolidinyl or piperidino group ma~~ be prepared by the reaction of a compound of formula XVIII
NHZ
R7 \ I / R3 XVIII
~N C
N ~ R5 R

~.~~~J~~'7 with a disubstituted compound of formula XIX
K(CH2)2L(CH2~)2K XIX
in which K is a leaving group such as halo (e. g. bromo or chloro) or tosyloxy and L is -0-, -S-, a direct bond or -CH2-.
Compounds of formula I in which R3 is a group of formula III in which R4 is propyl and R4' is H and in which RS is H and R6 is propyl may be prepared by the reaction of an amine of formula H2NR6 in which R6 is propyl with a thiourea of formula XVI in which R14 and R15 are Moth methyl in the presence of potassium hydroxide and lead acetate. In this reaction the amino group -NHR.6 replaces both the thioxo group and the dimethylam_Lno group .
Compounds of formula I in which R3 is a group of formula II:C and in which R4 is methyl and R4' is H and in which R5 is H and R6 is methyl may be prepared by the reaction of an amine of formula H2NR6 in which R6 is methyl 'with a compound of formula XIII in which the group NR14R15 is butylamino. In this reaction the amino group -NHR6 replaces both the methylthio group and the amino group -NR14815' Compounds of formula I in which NR1R2 is a thiamorpho:Lino-1-oxide group may be prepared by the oxidation ;for example using sodium metaperiodate) of a compound of formula I in which -NR1R2 is thiamorpho:Lino.
Compounds of formula I in which R6 is substituted by an acyloxy group may be prepared by acylation (e. g.
acetylation or benzoylation) of the corresponding 36 _ 2 0 o s 5 7 ~
compound of formula I in' which R6 is substituted by hydroxy.
Compounds of formula I in which R~ is an alkvlsulphinyl group may be prepared by oxidation (for example u;;ing sodium metaperiodate) of compounds of formula I :in which R~ is an alkylthio group.
Compounds of formula VII may be prepared by the reduction of the vitro group in a compound of forr_mula XX
(CHZ)nNRlR2 XX
R, I

for example (a) using hydrogen and a Raney~nickel catalyst, (b) hydrogen and a palladium/carbon catalyst, (c) sodium sulphide, (d) stannous chloride dehydrate in hydrochloric acid, ethyl acetate or ethanol or (e) iron in the presence of acid.
Compounds of formula IX in which R12 is a group of formula OPC~Cl2, OSOCl, OCOC1 and OS02Ph may be prepared by the reaction of compounds of formula VIII with phosphorus oxychloride, thionyl chloride, phosgene or benzenesulphonyl chloride respectively.
Compounds of formula X may be prepared by the reaction of compounds of formula VIII with alkylating agents such as dialkylsulphate, trialkyloxonium fluoroborave or borontrifluoride etherate/diazoalkanes followed by basification with sodium carbonate or sodium hydroxide solution.
B

_. ~~~0~~~7'7 Compounds of formula ~ XIII may be prepared by the reaction of methyl iodide with thioureas of formula XVI.
Compounds of formula XV may be prepared by the reaction of potassium hydroxide with compounds of formula XIII in which R14 and R15 are both H or in which R14 is benzoyl and R15 is H in the presence of lead acetate .
Compounds of formula XV may be prepared by the reaction of thioureas of formula XVI in which R14 and R15 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 formulaXVI in which R14 and R15 are H may be prepared by the reaction of ammonia with an isothiocyanate of formulaXXI

(CH2)nNRlR2 R~ XXI
NCS
Compounds of formula XVI in which R14 is an alkyl group and R15 is H may be prepared by the reaction of an aminophenyl of formula VII with an alkylisoth:~ocyanate of formula R14NCS.
Carbociiimides of formula XVII may be prepared by the reacti~~n of a thiourea of formula XVI in which R14 is the group R4 and R15 is H with sodium chlorite.

. _ 38 _ 2006577 .
Compounds of formula XVIII may be prepared by the reduction for example by hydrogen and Raney~nickel of compounds of formula XXII
NO~
R7 \ / R3 - XXII
N C
N ~ R~
~ R

Compounds of formula XX in which n - 0 and NR1 P.2 is a morpholino, thiamorpholino, 1-pyrrolidinyl or piperidino group may be prepared by the reaction of a 2-nitroani:Line with a compound of formula XIX.
Compounds of formula XX in which n - G and -NR1R2 is morpholino, thiamorpholino, 1-pyrrolidinyl, piperidino, 1-hexa-hydroazepinyl or 4-methyl-1-piperazinyl may be prepared b5~ the reaction of morpholine, thiamorpholine, pyrrolidinE~, piperidine, 1-hexahydroazepine and 4-methyl-1-~piperazine respectively with a halonitro-benzene (e. g. 2-fluoronitrobenzene or 2-chloronitro-benzene) lIl 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 R3.C0.1'1R5R6 with a ?.-n:~troaniline in the presence of a condensing agent (such as phosphorus oxychloride or thionylchloride). Compounds of formula y:XII may be prepared by the reaction of an amidine or guanidine of B

~.~~~ i'~'7 formula R3.CNH.NR5R6 with a 2-halonitrobenzene (e. g.
2-fluoronit=robenzene or 2-chloronitrobenzene).
The hypoglycaemic activity of the compounds of formula I which are given in the following Examples has been demon:~trated 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 m1/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 blE~eding 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 ch~:m 14 116 [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 hours.
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 ~;cale. Where more than one set of results is available s:t a particular value of x, the mean value of the 7 reduction is used to classify the activity of the compounds.
A greater than 25~ reduction at both 2 and 4 hours.
B greater than 25~ reduction at 2 hours but less than 25~' reduction at 4 hours.

~.(~~~5'~'7 C reduction in the range 15 to 25~ at 2 hours but greater than 25~' reduction at 4 hours.
D reduction in the range 15 to 25~ at both 2 and 4 hours.
E reduction in the range 15 to 25~ at 2 hours but less 'than 15~ 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 Examples given hereinafter are given below in Table A.
Table A
Example x Activity Example x Activity 9 :Z00 E 10 25 B

xoos5 ~~

Table A continued Example x Activity Example x Activity 67 :?00 A 68 25 C

79 a'_00 A 80 25 D

81 a?00 D 82 50 E

20065'Tl Table A continued Example x Activity Example x Activity 89 ;?00 C 90 25 E

zooss~~

Table A continued Example x Activity Example x Activity 155 '133 B 156 25 D

159 50 D i60 26 D

165 ~?00 B 166 25 D

185 a'_00 D 186 25 A

195 12.5 A 196 25 A

zooss~

Table A continued Example x Activity Example x Activity zooss~

Table A continued Example X Activity ~ Example X Activity 309 '100 D 310 200 D

311 ;?00 E 312 200 E

NT - Not Tested zooss~~

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 delta-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-amino;~henyl)morpholine (36 g) in dry benzene (150 ml) was added and the mixture heated at 65°C with stirring f~~r 32 hours. The benzene layer was decanted, the oil w~~shed 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 F>H, 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 metharLOl (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-dinylidene,amino)phenyl]morpholine fumarate as a colourless crystalline solid [m.p. 210°C (dec)].

Examples 3 to 37 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 NR1R2 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 rEac~ystallised from hexane.
(2) The produ~zt was purified by chromatography on an alumina column using a 1:1 mixture of dichlorome:thane 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 (60m1) and acetonitrile (40m1).
(7) The product was purified by chromatography on an alumina ~~olumn using the following eluants sequentially:- hexane, a 1:9 mixture of dichloro-methane and hexane, a 3:7 mixture of dichloro-methane and hexane, a 1:1 mixture of dichloromethane and hexane and dichloromethane.
A

20065'~"~
(8) The product was isolated as its monofumarate salt which was recrystallised from 1:1 mixture of methanol and ether.
(9) The F~roduct was isolated as its monohydroiodide salt which was recrystallised from a 2:3 mixture of methanol and ether.
(10) Coup ling reaction performed at ambient temperature for 24 hours and at 70°C for 8 hours.
(11) Produ~~t isolated as its fumarate salt which was recry;stallised from propan-2-ol.
(12) Produ~~t 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 dimetlzoxyethane and hexane.

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Example 38 In a similar manner to that described in Examples 1 and 2, 1-methyl-3-(~2-methoxyethyl)-2-piperidone (2.56 g) :gin benzene (30 ml) was reacted with 4-(2-aminophenyl)morpholine (2.49 g) in benzene (30 ml) in the presence of phosphorus oxychloride (1.37 ml) for 12 hours at 70°C. The resulting product was 4-~2-[1-methyl-3-(2-methoxyethyl)-2-piperidinylideneamino]-phenyl~morpholine sesquifumarate (m.p. 174°C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 39 In a similar manner to that described in Example 1, 1-benzyl-3-methyl-2-pyrrolidone (14.17 g) in benzene (80 ml) wasreacted with 4-(2-aminophenyl)morpholine (8.9 g) i.n benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70°C
to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinyl ideneamino)phenyl]morpholine (m.p. 96-97°C) which was recrystallised from hexane.
The r~ecrystallised product (2 g) from the previous paragraph was heated at reflux with cyclohexene (6 ml), 107 Pd/C (1.5 g) and methanol (100 ml) for 4 hours to give 4-[2-(3-methyl-2-pyrrolidinylidene-amino)phen;yl]morpholine as an oil. This oil (1 g) was dissolved in methanol (20 ml) and a solution of fumaric acid (0.4.7 g) in methanol was added to yield 4-[2-(3-methyl-2-pyrrolidinylideneamino)phenyl]-morpholine fumarate (m.p. 185°C) which was 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 the zooss~~

reaction of an aminophenyl compound of formula VII (A
grammes in B ml benzene) with an amide of formula R3.CO.NRSRE~ (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 sale= 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.

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Example 63 A mixture of N-methylpivalamide (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 :Eor four days to give N-methyl-N'-(2 piperidinophenyl)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 NR1R2 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 F~roduct was isolated as its monofumarate salt which was recrystallised from a 1:2 mixture of methanol and ether.
(22) The ~~roduct was isolated as its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether.

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~ v v n v 20065'7'7 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
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 r~ecrystallised from methanol.
(25) Product was recrystallised from a 1:2 mixture of dimet:hoxyethane and hexane.
(26) Product recrystallised from hexane and then a mixtvure of dimethoxyethane and hexane.
(27) Product was purified by column chromatography on 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.
(28)Coupli:ng reaction performed at 90-100°C.

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v 20065'x'7 Examples 92-101 ' In a similar manner to that described in Example 1, the compounds listed in Table V were prepared by the reaction of an aminophenyl compound of formula VII (A
grammes in B ml benzene) with a methyl-substituted-2-pyrrolidinone (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 T;~ble V
Notes (1) and (4) has the meaning given for Table I
(29) Product isolated as its dihydroiodide salt which was recrystallised from a 1:1 mixture of methanol and ether.
(30) Coup:Ling reaction performed at ambient temperature for F hours.
(31) Product isolated as its dihydroiodide salt which was recrystallised from a 1:3 mixture of ethanol and ether.

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Example 10:'_ A mixture of 4-(2-aminophenyl)morpholine (5.34 g), acetonitri:Le (4.52 ml) and anhydrous aluminium chloride (12 g) was heated at 160-170°C for 4 hours to yield N-(2-morpholinophenyl)acetamidine (m.p. 140-141°C) which was recrystallised from hexane.
Example 103 A mixture of 4-(2-amino-4-methylphenyl)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-methyl-2-morpholinophenyl)acetamidine (m. p.
121°C) which was recrystallised from hexane.
Example 10~E
A mixture of 4-(2-aminophenyl)morpholine (5.34 g), propionitri:le (4.7 g) and anhydrous aluminium chloride (12 g) was heated at 160-170°C for six hours to yield N-(2-morpholinophenyl)propionamidine (m. p. 114°C) which was recryst:allised from hexane.
Example 10-'i 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. 7.'he 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)-20065'x'7 butyramidine monofumarate' (m.p. 168-170°C) which was recrystall:~sed from a 1:2 mixture of methanol and ether.
Example lOfi Powdered anhydrous aluminium chloride (12 g) was added portion-wise to a stirred slurry of 4-(2-amino-phenyl)morpholine (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 monofumarata salt (m. p. 173°C) which was recrystallised from propan-2-ol.
Example 10'1 A mixture of 4-(2-aminophenyl)morpholine hydrochlor:Lde (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) isobutyram:Ldine (m.p. 140-141°C) which was recrystall:Lsed from hexane.
Example 103 A mix~~ure of 4-(2-aminophenyl)morpholine (5.34 g), isobutyron:itrile (6 g) and anhydrous aluminium chloride (12 g) was. heated at 160-170°C for 6 hours to give N-(2-morpholinophenyl)isobutyramidine (m.p. 138°C) which was recrystallised from a 1:1 mixture of ethylaceta~=a and hexane.

2ooss~~

Examp 1 a 1 0 ~) A mixture of 5-methylthio-2-morpholinoaniline (1.8 g), isobutyronitrile (1.66 g) and anhydrous aluminium chloride (3.2 g) was heated at 140°C for 2 hours to give N-(5-methylthio-2-morpholinophenyl) isobutyramidine (m. p. 155°C) which was recrystallised from hexanE:.
Example 110 A mixture of 5-fluoro-2-morpholinoaniline (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) isobutyram:idine (m. p. 142°C) which was recrystallised from hexane and converted into its fumarate salt (m. p.
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 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 dich:loromethane. The solvent was removed by evaporation and the residue distilled under a pressure 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 recrystall:ised from hexane to give N-(2-morpholino-phenyl)valeramidine. (m. p. 135-136°C).
Example 11:?
A mixture of 4-(2-aminophenyl)morpholine (3.56 g), pivalonitr:ile (5 g) and anhydrous aluminium chloride (8 g) was heated at 160-170°C for six hours to yield N-(2-morpholinophenyl)pivalamidine (m. p. 126°C) which 20065'~'~

was recrystallised from hexane and converted into its monofumaravte 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 recrystall:ised from the solvents given below:-mp of St;~rting Recrystallisation fumarate Ex. Example solvent salt (C) 113 20 methanol 212 114 ;?2 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) 208-210 120 !39 methanol:ether(1:2) 204-205 121 100 methanol 117-118 122 '74 methanol:ether(1:2) 179-180 123 102 methanol:ether(1:1) 189 124 107 methanol:ether(1:1) 162-163 125 111 isopropanol 156-158 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-(2-[1-(2-cyanoethyl)-2-piperidinylideneamino]
phenyl~mor~pholine. (m. p. 148°C).

20065'~"~

Exampla 127 ' A mixture of 3-morpholinone (4 g) in dry acetonitri:Le (40 ml), ~~4-(2-aminophenyl)morpholine (3.6 g) in dry acetonitrile (20 ml) and phosphorous oxychloride (3.6 ml) was heated for 40 hours at 65-70°C
to give oi:L 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 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-mo:rpholinylideneamino)phenyl]-morpholine hydrochloride (m. p. 262-263°C).
Example 128 A mi:~ture 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-ideneamino)benzyl]morpholine (m.p. 108-110°C) which was recrystallised from hexane.
Examp 1 a 12'~
A mixture of 2-piperidone (6 g) in benzene (50 ml), 4-(2-amino-4-chlorobenzyl)morpholine (6.8 g) 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 A mi:~ture 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 579 20065'x'7 hydroiodic acid (10.1'ml) gave 4-[2-(1-methyl-2-pyrrolid:inylideneamino)benzyl]morpholine dihydro-iodide (m. p. 230-232°C) which was recrystallised from ethanol.
Example 13'1 A mixture of 1,3,3-trimethyl-2-pyrrolidinone (3 g) in benzene (20 ml), 4-(2-aminobenzyl)morpholine (3.l8 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 57~ hydroiodic acid (2.8 ml) gave 4-[2-(1,3,:3-trimethyl-2-pyrrolidinylideneamino)benzyl]
morpholine dihydroiodide (m.p. 256-258°C) which was recrystall:ised from a 1:1 mixture of ethanol and ether.
Example 132 A mixture of N-methylpivalamide (6.2 g) in benzene (50 ml), 4-(2-aminobenzyl)morpholine (9 g) in benzene (40 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 1;1.4 g) to give N-methyl-N'-(2-morpholinomethylphenyl)pivalamidine monofumarate (m. p.
167-168°C) which was recrystallised from propan-2-ol.

2ooss~~

Example 133 A mixture of 1,3-dimethyl-2-imidazolidinone (7 g) in benzene (45 ml), phosphorus oxychloride (6 ml) and 4-(2-aminophenyl)morpholine (8.5 g) in benzene (30 ml) 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. 133-134°C).
Examples 1:34 to 154 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 phosphorus oxychloride (E ml) for F hours' at a temperature in the range 65-70°C.
Notes to Table VI
(32) Produ~~t recrystallised from hexane.
(33) Coupling reaction performed at 90-95°C.
(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 isopr~~panol and ether.
(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.

20065'~'~
(39) The product was isolated as its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether.
(40) Coupl:i.ng reaction performed at 80-85°C.
(41) The product was purified by column chromatography on an alumina column using dichloromethane as a luanl_ .
(42) Coupling reaction performed at 80-85°C for 48 hours and at 90-95°C for 14 hours. The product was 'purified by column chromatography on an alumina column using a 99:1 mixture of dichloro-methane and methanol as eluant.
(43) The product was isolated as its sesquifumarate salt which which was recrystallised from a 1:2 mixture of methanol and ether.

20065'~'~
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Examp 1 a 15 .'i A mixture of N-(2-hydroxyethyl)ethylenediamine (31.2 g), urea (23.4 g) and water (3 ml) was heated at 130°C for 3 hours and at 210°C for 8 hours and then distilled directly from the reaction mixture to give 1-(2-hydroayethyl)-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-hydroxyethyl)-2-imidazolidinone (2.2$ g), benzoic anhydride (4.5 g), triethylamine (2.4 g), 4-dimethylaminopyridine (0.1 g) and 1,2-dimethoxyeohane (20 ml) was stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (15 ml) was added and the mixture extracted with dichloromev=bane (100 ml). The extract was washed with water, brine and then dried and filtered. The solvent was remc>ved to give 1-(2-benzoyloxyethyl)-2-imidazolid:inone (m.p. 130-132°C) which was recrystall:~sed from ethylacetate.
A mixture of 1-(2-benzoyloxyethyl)-2-imidazolid:inone (2.3 g) and methyl-4-toluenesulphonate (2 g) was heated at 90-95°C for 48 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 chromatogr;~.phy on silica gel (80 g, 100-200 mesh) using a 1:1 mixture of ethylacetate and hexane as eluant to give 1-(:?-benzoyloxyethyl)-3-methyl-2-imidazolidinone as an oil.
In a similar manner to that described in Example 133, 1~-(2-benzoyloxyethyl)-3-methyl-2-imidazolidone 20065'T~

(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 dissolved :in methanol (10 ml) and treated with fumaric acid ( 1 .8 ~) . The solvent was removed by evaporation and the re:~idue 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 ether to yield an oil which was purified by chromatography on an alumina column using dichloro-methane a~~ eluant. The purified base (0.8 g) in methanol (10 ml) was treated with fumaric acid (0.23 g) to give 4-(2-[1-(2-benzoyloxyethyl)-3-methyl-2-imidazol~_dinylideneamino]phenyl)morpholine mono-fumarate (m. p. 132-133°C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example lSEi Reaction of tetramethylurea (10.4 g, 10.7 ml) in dry benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.2 g) i.n dry benzene (100 ml) in the presence of phosphorus oxychloride (8.3 ml) for 30 hours at 65-70°C
gave an oi~_ which was purified by column chromotography on a neutral alumina column (100 g) eluted with hexane 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-tetramethy~_guanidine hydroiodide as a pale yellow crystalline' solid (m.p. 215-216°C) which was recrystall~:sed from a 2:3 mixture of methanol and ether.
Example 157 React~_on of 3-ethyl-1,1,3-trimethylurea (6.57 g) in benzenE~ (70 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus 20065'x'7 oxychloride (4.71 ml) for 45 hours at 65-70°C gave 1-ethyl-2-1;2-morpholinophenyl)-1,3,3-trimethyl-guanidine I;bp. 140°C at 0.2 mm Hg).
Example lSFi Reaction of 3-allyl-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 oxychloridE: (4.71 ml) for 45 hours at 70°C gave 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethyl-guanidine I;bp. 148-150°C at 0.2 mm Hg).
Example 15~~
React~:on of 3-n-butyl-1,1,3-trimethylurea (7 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (7.2 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4 ml) for 18 hours at 80-85°C
gave 1-n--butyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (bp. 162-163°C at 0.7 mm Hg).
Example 160 Reaction of 3-pentyl-1,1,3-trimethylurea (7.5 g) in benzenf~ (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).
Example 1611 Reaction of 1-(2-hydroxyethyl)-2-imidazolidinone (13 g) in dry dimethylformamide (125 ml) with sodium hydride (50Z suspension in paraffin oil 12 g) at 10°C
for 3 hours was followed by treatment with methyl iodide (35..5 g) over a period of one hour. The mixture was stirred at ambient temperature for 18 hours gave 1-methyl-3~-(2-methoxyethyl)-2-imidazolidinone (b. p. 110-'Il4°C at 0.4 mm).

. 2006,,' _ 77 _ Reaction of 1-methyl=3-(2-methoxyethyl)-2-imidazolidinone (11.4 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7.2 ml) for 30 hours a.t 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-(2-[1-methyl-3-(2-methoxyeth~~l)-2-imidazolidinylideneamino]pheny l -morpholine monofumarate (m.p. 127-129°C) which was recrystallised from propan-2-ol.
Example 16:?
Reaction of 1-methyl-3-(2-hydroxyethyl)-2-imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromei=bane (60 ml) in the presence of triethylamina (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-imidazolidinone (13.4 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.6 g) in benzene (80 ml) in the prE~sence of phosphorus oxychloride (7 ml) for hours at 80-85°C gave 4-~2-[1-methyl-3-(2-acetoxy-ethyl)-2-imidazolidinylideneamino]phenyl~morpholine.
25 React:Lon of 4-(2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolid:Lnylideneamino]phenyl)morpholine (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-hydroxyeth~~l)-2-imidazolidinylideneamino]phenyl morpholine (m. p. 129-131°C) which was recrystallised from a 1:2 mixture of methanol and ether.

20065'~'~
- 78 _ Example 16:3 Reaction of 4-dimethylcarbamoylmorpholine (3.8 g) in benzen~a (25 ml) with ~4-(2-aminophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride (2.1 ml) for 40 hours at 80-85°C gave N,N-dimethyl-N'-(2-morpholinophenyl)morpholine-4-carboxamidine (m. p.
126-128°C) which was recrystallised from hexane.
Example 164 Reaction of 1-dimethylcarbamoylpiperidine (3.7 g) in benze~ze (25 ml) with 4-(2-morpholinophenyl) morpholine (3.5 g) in the presence of phosphorus oxychlorid~~ for 35 hours at 80-85°C gave N,N-dimethyl N'-(2-morplholinophenyl)piperidine-1-carboxamidine (m. p.
88-90°C) which was recrystallised from petroleum ether (b.p. 40-60°C) Example 16.5 Reaction of 4-[2-(1,3-dimethyl-2-imidazolidinyl-ideneamino)phenyl]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and 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.
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 solid was filtered, washed with ethanol and dried to give 1-[2-(4-morpholino)phenyl]thiourea (m. p.
194-195°C).

2006~'T'~

A solution of 1-(2-morpholinophenyl)thiourea (7.2 g) in dry methanol (30 ml) was heated at reflux with methy~_iodide (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-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (m. p.
151-152°C)..
A mixture of 2-methyl-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 20Z sodium hydroxide and the organic layer was washed successively with water, brine and dried (Na2S04), 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-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3 g prepared as described in Example: 166), N-methylethylenediamine (2 ml) and absolute e~=hanol (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 1 Ei8 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 R14 and R15 are H, (G grammes), an N-substituted ethyl-ened~amine of formula H2N(CH2)2NHR6 (H grammes) in dry ethanol (I ml) under reflux for J hours.

20065'~'~
- so -Note to Table VII
Notes (32), (38), (39) and (41) has the meaning given with respe~~t to earlier Tables.
(44) Product recrystallised from ethylacetate.
(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.
(47) Product isolated as its fumarate salt which was rec:rystallised 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.
40-60°C).
(49) The preparation of the compound of formula XIV
is ;liven hereinafter as Preparative Procedure B.
(50) The preparation of the compound of formula XIV
is ;liven hereinafter as Preparative Procedure C.
(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 eth:ylacetate and hexane.
(53) The preparation of the compound of formula XIV
is liven hereinafter as Preparative Procedure E.

zooss~~
- 8, -(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.
(56) Product was purified by chromatography on an aluTnina column using the following eluents sequentially:- hexane, a 1:1 mixture of dichloromethane and hexane and then dichloromethane.
(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 ethvlacetate and hexane.

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., .. .. .. .. .. .. .. .. .., .. .. z m n ~ ~ W w n ~ w W w w o l~O~ L~ .~ N 00 Q~ J Oo N N 00 f't v ~r v v ~r v ~r ~r v ~ ~r v (p n U'tVi W W lr V7 V7 In O N N Vi v ~r v v ~r v ~r n V ll1 v ~r ~,~~6~Jrf Preparative Procedure A ' React:LOn of 6-methyl-2-morpholinoaniline (9.6 g) in dioxan (25 ml) and water (100 ml) with thiophosgene (5.7 ml) at 0°C for 30 minutes and at room temperature for 3 hours gave 6-methyl-2-morpholinophenyl isothiocyanate as an oil.
React:LOn of 6-methyl-2-morpholinophenyl isothio-cyanate (E~.8 g) with 33~ alcoholic ammonia solution (60 ml) at room temperature for 5 hours gave 1-(6-methy:L-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-methyl-2-morpholinophenyl)-thiourea (9 g) and methyl iodide (2.5 ml) ~in dry acetone (100 ml) was heated at reflux at 90-95°C for 2.5 hours to give 2-methyl-1-(6-methyl-2-morpholino-phenyl)-2-thiopseudourea hydroiodide.
Preparative Procedure B
A solution of N,N-bis(2-methoxyethyl)benzene-1,2-diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been c~~oled 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 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 oil.
A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of 2p06J'~'~

2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate (7.5 g) and ethanol (10 ml) which had been cooled to 10°C. The mixture was stirred at 0°C for 8 hours and then stirred without cooling for 16 hours. The solvent was then removed by evaporation 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 togive 1-~2-[bis(?-methoxyethyl)amino]phenyl) thiourea (m. p.
118-119°C).
A m:~xture of 1-~2-[bis(2-methoxyethyl)amino]
phenyl)thiourea (5 g), methyl iodide (1.4 ml) and acetone (:25 ml) was heated at 40°C for 2 hours.
Removal o:E the solvent gave a residue which was triturated with ether to give 2-methyl-1-~2-[bis(2-methoxyeth~~l)amino]pheny l -2-thiopseudourea hydro-iodide (m.p. 111-112°C).
Preparative Procedure C
A solution of 2-thiamorpholinoaniline (14.6 g) in 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 (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 2-thiamorpholinophenyl isothiocyanate (m. p. 55-56°C).
257 Adueous 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 2oos~~~
- $7 _ stirred at 30°C for 24 hours and then cooled to 10°C.
1-(2-thiamorpholinophenyl)thiourea was collected by filtration, washed with water (100 ml) and dried (m. p.
170-171°C).
A mi;iture of 1-(2-thiamorpholinophenyl)thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90-95°C for 22 hours. The solvent was removed b5~ evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-thiamor-pholinophenyl)-2-thiopseudourea hydroiodide (m. p.
176-177°C).
Preparative Procedure D
Benzo:~lisothiocyanate (10 ml) was added over 30 minutes to a mixture of 2-(1-pyrrolidinyl)aniline (10.6 g) and dichloromethane (30 ml). The mixture was then stirred at 30°C for 4 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) for 30 minutes and triturated with ether. 3-Benzoyl-1-[2-(1-pyrrolidinyl)phenyl]thiourea was collected by filtration, washed with ether and dried (m. p. 172-173°C).
A mixture of 3-benzoyl-1-[2-(1-pyrrolidinyl)-phenyl]thi~~urea (18.1 g), sodium hydroxide (5 g) and water (50 ml) was heated at 90-95°C for 4 hours. Ice and then S~D~ aqueous hydrochloric acid were added. The mixture was filtered and the filtrate treated with saturated sodium bicarbonate solution to pH 8. 1-[2 (1-Pyrrolidinyl)phenyl]thiourea was collected by filtration, washed with water and dried (m. p.
185-186°C).
A mixaure of 1-[2-(1-pyrrolidinyl)phenyl]thiourea (12.2 g), acetone (100 ml) and methanol (20 ml) was ~ooss~~
_ 8$ _ 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 2-methyl-1~-[2-(1-pyrrolidinyl)phenyl]-2-thiopseudourea hydroiodidE~ (m. p. 139-141°C).
PreparativE= Procedure E
React:LOn of 5-methyl-2-morpholinoaniline (20 g) in dioxan (80 ml) and water (200 ml) at 0°C for 30 minutes and at room temperature for 2 hours gave 5-methyl-2~-morpholinophenyl isothiocyanate, (m. p.
91-92°C).
React:LOn of 5-methyl-2-morpholinophenyl isothiocyanate (15 g) with 337 ethanolic ammonia solution for 48 hours at room temperature gave 1-(5-methy:L-2-morpholinophenyl)thiourea as a pale yellow sol:Ld (m. p. 181-182°C).
A mixture of 1-(5-methyl-2-morpholinophenyl)-thiourea x;14 g), methyl iodide (7.9 g) in methanol (50 ml) was heated at reflux for 2 hours to give 2-methyl-1-(.'i-methyl-2-morpholinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, m.p. 157-159°C.
Preparative Procedure F
A mixture of 2-methyl-1-(2-aminophenyl) pyrrolidine (9.1 g) and benzoyl isothiocyanate (9.2 g) 7.7 ml) and dichloromethane (100 ml) was stirred at room temp=rature for 8 hours and left overnight.
Removal of the solvent and trituration with ether gave 1-benzoyl-:3-[2-methyl-1-pyrrolidinyl) phenyl]thiourea, (m. p. 105-'106°C).

2p(~..,t"''~'7 A mi:~ture of 1-benzoyl-3-[2-(2-methyl-1-pyrrol-idinyl)phenyl]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-pyrrolidinyl)phenyl]
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-pyrrolidinyl)phenyl]
thiourea (3.4 g) and methyl iodide (2.1 g) in acetone (60 ml) was heated at 90-95°C for 3 hours and the solvent 'removed to give 2-methyl-1-[2-methyl-1-pyrrolidin,yl)phenyl]-2-thiopseudourea hydroiodide (3.7 g) as a thick oil.
Preparative Procedure G
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 for 4 hours. Ice (200 g) and water (200 ml) were added 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 eluted with hexane to give 2-piperidinophenyl 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 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).

2ooss~~

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 b5~ evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-piperidino-phenyl)-2-~~hiopseudourea hydroiodide (m. p. 160-162°C).
Preparative Procedure H
Reaction of 6-methyl-2-piperidinoaniline (6.4 g) in dioxan (20 ml) and water (65 ml) with thiophosgene (5.7 g) at 0°C for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothio-cyanate as an oil.
Reaction of 6-methyl-2-piperidinophenyl isothio-cyanate (6.8 g) with 257 aqueous ammonia solution (65 ml) in ethanol (20 ml) for 8 hours at room temperature gave 1-(6-methyl-2-piperidinophenyl) thiourea a;s 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 methanol (100 ml) was heated under reflux for 3 hours to give 2-methyl-1-(6-methyl-2-piperidinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, (m. p. 204-205°C).
Example 20:3 A mixture of 2-methyl-1-(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 ;dive a solid which was recrystallised from ethyl acE~tate to give 4-[2-(4-methyl-2-imidazol-idinyliden~eamino)phenyl]morpholine (m. p. 173-174°C).

2ooss~~

Example 204 A mi~~ture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide '(7.6 g prepared as described in Examples 166), 1,2-dimethylethylenediamine (5.3 g) and ethanol (90 ml) was heated under reflux for 70 hours to give a solid which was recrystallised from ethylacetai:e to give 4-[2-(4,5-dimethyl-2-imidaz-olidinylidsmeamino)phenyl]morpholine (m. p. 142-143°C).
Example 20_'i EthylE~ne oxide generated from 2-chloroethanol (36 g) an~3 potassium hydroxide pellets (20 g) in methanol (fi0 ml) was reacted with 1,2-dimethylethylene-diamine (22.6 g) in methanol (50 ml) at -15°C to give N-(2-hydro~~yethyl)-1,2-dimethylethylenediamine as a colourless liquid (b. p. 89-91°C at 1 mmHg).
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseu<iourea (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 dark broom oil which was purified by column chromatography on neutral alumina (250 g) using a 1:9 mixture of dichloromethane and hexane to give 4-~2-[4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinylidene-amino]phen~~l~morpholine as a colourless solid (m. p.
108-109°C) which was recrystallised from hexane.
Example 20Ei A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), N'-isopropyl-2-methyl-1,2-propanediamine (3.95 g) and ethanol (45 ml) was heated under reflux for 28 hours to yield an oil which was purified b:~ column chromatography on a neutral alumina column using dichloromethane as eluant. The resultant oil (1.5 ~;) was dissolved in methanol (10 ml) and fumaric acid (0.5 g) was added to give 4-[2-(1-iso-propyl-4,4-dimethyl-2-imidazolidinylidenamino)phenyl]-morpholine monofumarate (mp 206-208°C) which was recrystalli.sed from a 1:3 mixture of methanol and ether.
Example 20i A mixture of 2-methyl-1-(2-morpholinophenyl) 2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 3-methylaminopropylamine (2.6 g) and absolute ethanol (40 ml) was heated under reflux fo-.r 6 hours to give a solid which was recrystallised from ether to give 4-[2-(1-methylper hydropyrimidin-2-ylideneamino)phenyl]morpholine' (m. p.
138-139°C).
Example 20FS
A mixture of 2-methyl-1-(2-morpholinophenyl) 2-thiopseudourea hydroiodide (7.6 g) and 1,4-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 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 20~~
A mixture of 2-methyl-1-(2-morpholinophenyl) 2-thiopseudourea hydroiodide (1 g), dimethylamine (1 ml of a 33~ solution in ethanol) and ethanol (2 ml) was kept at ambient temperature for 48 days. The mixture was then cooled in an ice bath. The resulting solid was separated by filtration, treated with dilute 2pp6a T'~

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 1,1-dimeth:~l-2-(2-morpholinophenyl)guanidine (m. p.
143-144°C) which was recrystallised from hexane.
Example 210 A solution of 4-(2-aminophenyl)morpholine (5.3g) in dichloromethane (25 ml) was treated with methyl 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 recrystall:ised from a 4:1 mixture of ethyl acetate and hexane.
A mixture of 1-(2-morpholinophenyl)-3-methyl-thiourea (5 g) and methyliodide (2.8 g) in acetone (30 ml) was he;~ted at reflux for 4 hours to yield 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydro-iodide (m.p. 163-164°C) which was recrystallised from a 1:3 mixture of methanol and ether.
A mixture of 2-methyl-1-(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-dimethyl-2~-(2-morpholinophenyl)guanidine which was recrystall:ised from hexane (m. p. 137-138°C).
Example 21 '1 A mixture of 2-methyl-1-(2-morpholinophenyl) 3-methyl-2~-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210) and dimethylamine (25 ml of a 337 solution in ethanol) was kept at ambient temperature for 25 days. Removal of the solvent gave a __ 20065'T7 residue which was purified by chromatography on an alumina column using a 1:49 mixture of methanol and dichloromet=bane as eluant.'~ The resulting solid was dissolved :in methanol and treated with fumaric acid to give 1,:3,3-trimethyl-2-(2-morpholinophenyl)guanidine monofumaral=a (m. p. 192-194°C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 21:?
React_Lon of 2-morpholinophenyl isothiocyanate (3.3 g) with ethylamine generated from ethylamine hydrochlor-.Lde (12.18 g) and sodium methoxide [generated from sodi~im (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 of ethylacE~tate 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-1-~;2-morpholinophenyl)-2-thiopseudourea hydroiodidE: as a pale yellow solid (m.p. 170°172°C) which was recrystallised from acetone.
A mixture of 2-methyl-3-ethyl-1-(2-morpholino-phenyl)-2-1=hiopseudourea hydroiodide (6 g) and 339 methylamine in absolute ethanol solution (250 ml) was 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-methylguanidine as a colourless solid (m. p. 118-119°C) which was recrystallised from hexane.
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 ~006~'~

ethylamine which was stirred at room temperature for 30 days with ~'_-methyl-3-ethyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodid'e (6 g prepared as described in Example 212) to yield 1,3-diethyl-2-(2-marpholino-phenyl)guanidine (m.p. 101-102°C) which was recrystall:Lsed from hexane.
Example 21 ~~
Reaction of 4-f2-[1-(2-hydroxyethyl)-2-imidazol idinylidenE~amino]phenyl~morpholine (3 g prepared as described in Example 175) in dichloromethane (20 ml) with acet_Cc anhydride (0.86 g) yielded 4-~2-[1-(2-acetyloxye~=hyl)-2-imidazolidinylideneamino]phenyl~-morpholine (m. p. 89-91°C) which was recrystallised from hexane.
Example 21.'i Reaction of 4-(2-[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 triethylam:ine (2 ml) and 4-dimethylaminopyridine (50 mg) gave an oil which was purified by chromatogr;~phy on an alumina column using dichloro-methane as eluant to give 4-~2-[1-(2-benzoyloxyethyl)-2-imidazol:idinylideneamino]phenyl~morpholine (m.p. 92-94°C) which was recrystallised from a 1:1 mixture of ethyl acetate and hexane.
Example 21 i5 A solution of 4-(2-aminophenyl)morpholine (5.8 g) in dichloromethane (60 ml) was treated with n-butyl isothiocyanate (5 g) and mixture stirred at room temperature for 4 days to yield 1-(n-butyl)-3-(2-morpholino;phenyl)thiourea as a pale yellow solid (m.p.105°C).

~ooss~

A mixture of ~ 1-(n-butyl)-3-(2-morpholino phenyl)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-butyl)-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide as a colourless solid m.p 154-156°C.
A mixture of 2-methyl-3-(n-butyl)-1-(2-morpholino-phenyl)-2-thiopseudourea hydroiodide (4.0 g) and 33~
methylamin~~ in absolute ethanol solution (200 ml) was 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 o:E which in methanol (25 ml) on treatment with fumaric acid (0.7 g) gave a colourless solid which was 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 21 '7 A mixture of 2-methyl-1-(2-piperidino)phenyl]
2-thiopseudourea hydroiodide (7.5 g prepared as described in Preparative Procedure G), 2-methoxyethyl 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 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_ A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (1.7 g) prepared as described in Example 166, 2-methylthioethylamine (1.8 g) anal ethanol (25 ml) was heated at 90-95°C for 22 hours to give 1-(2-methylthioethyl)-2-(2-2ooss~~

morpholinophenyl)guanidine (m.p. 115-116°C) which was recrystall:ised from hexane.
Example 21 !a A mi:~ture of 2-methyl-1-(2-morpholinophenyl)-2 thiopseudourea hydroiodide (7.6 g), 2-methoxyethylamine (2 ml) and ethanol (45 ml) was stirred at ambient temperature= for 14 days to give 1-(2-methoxyethyl)-2 (2-morphol:inophenyl)guanidine (m. p. 125-128°C) which was recr;ystallised from 1,2-dimethoxyethane and converted :into its fumarate salt (m. p. 136-138°C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 220 A mi:~ture of 2-methyl-1-(2-morpholinophenyl)-3 methyl-2-tlziopseudourea hydroiodide (7.8 g prepared as described in Example 210), n-propylamine (1.3 g) and ethanol (50 ml) was stirred at ambient temperature for 45 days to yield an oil which was purified by chromatography on a neutral alumina column using a 1:99 mixture of methanol and dichloromethane as eluent. The resulting oil was dissolved in methanol and treated with fumaric acid to give 1-(n-propyl)-2-morpholino phenyl)-3-methylguanidine monofumarate (m.p. 187-188°C) which was :recrystallised from a 1:2 mixture of methanol and ether.
Example 221 A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-t'hiopseudourea hydroiodide (3.9 g prepared as described in Example 210), 2-methoxyethylamine (0.82 g) 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 2ooss~~

recrystallised from a 1:2 mixture of methanol and ether.
Example 222 A mi~aure of 2-methyl-1-(2-morpholinophenyl)-3 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 reaction mixture was cooled, filtered and the solvent was partially removed. The residue was poured onto ice and the resulting mixture extracted with dichloro-methane. The extract was dried, filtered and the solvent removed to give a residue which was treated with fum<iric acid to give 1-cyclopentyl-2-(2-morpholinophenyl)-3-methylguanidine monofumarate (m. p.
220°C) whi~~h was recrystallised from a 1:1 mixture of me thano 1 arid a they .
Example 223 A mi~~ture of 2-methyl-1-(2-morpholinophenyl)-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 am oil which was purified by chromatography on a neutra a.lumina column eluted with a 1:1 mixture of dichlorome~=have and hexane and then a 1:9 mixture of methanol a.nd dichloromethane to give N-methyl-N'-(2-morpholinophenyl)pyrrolidine-1-carboxamidine which was converted into its monofumarate salt (m.p. 168-171°C) which was recrystallised from propan-2-ol.
Example 22~+
A mi:~ture of 2-methyl-1-(2-morpholinophenyl)-3-ethyl-2-th:~opseudourea hydriodide (10 g prepared as described in Example 212), n-butylamine (2.7 g) and 20065'~'~

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 1:2 mixturc= of methanol and ether.
Example 22_'i React:~on 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-butyl)-3-(5-chloro-2-morpholinophenyl)thiourea (m. p. 150-152°C).
A mi:cture of 1-(n-butyl)-3-(5-chloro-2-morphol-inophenyl)thiourea (2.6 g), methyl iodide (1.4 g) and acetone (2~0 ml) was heated under reflux for 3 hours to give 2~-methyl-1-(5-chloro-2-morpholinophenyl)-3-(n-butyl)-2-thiopseudourea hydroiodide (m. p. 130-132°C).
A mixture of 2-methyl-1-(5-chloro-2-morpholino-phenyl)-3-(n-butyl)-2-thiopseudourea hydroiodide (3.4 g) ar,.d a 33~ ethanolic solution of methylamine (10 ml) were stored at ambient temperature in a sealed container for 8 months to yield 1,3-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine (m.p. 145-146°C) which was :recrystallised from hexane. In this reaction the butylamino and the methylthio group of the starting material a:re replaced by a methylamino group.
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-pyrr~~lidinyl)phenyl]thiourea (m. p. 125-126°C).
A mixture of 1-methyl-3-[2-(1-pyrrolidinyl)-phenyl]thi~~urea (18.5 g) and methyl iodide (12.3 g) and zooss~
- ,00 -acetone (11)0 ml) was heated under reflux for 2.5 hours to give 2-methyl-1-[2-(1-pyrrolidinyl)phenyl]-3-methyl-2--thiopseudourea hydroiodide (m. p. 161-162°C).
A m:Lxture of 2-methyl-1-[2-(1-pyrrolidinyl)-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-(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-methylphenyl)morpholine (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-methy:L-2-morpholinophenyl)thiourea as a colourless solid (m. p,. 107°C).
A mi:~ture of 1-methyl-3-(5-methyl-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-1-(5-methyl-2-morpholinophenyl)-3 methyl-2-thiopseudourea hydroiodide as a pale yellow solid (m. p. 160-161°C).
A mixture of 2-methyl-,-(5-methyl-2-morpholino-phenyl)-3-methyl-2-thiopseudourea hydroiodide (6 g) and 339 methylamine in absolute ethanol solution (250 ml) was kept at room temperature for 21 days to yield 1,3-dimethyl-2~-(5-methyl-2-morpholinophenyl)guanidine as an oil which Haas dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g) to give 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine fumarate (,.2 g) as 20065'~'~
- l of -a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether (m.p.201-202°C).
Example 22Fs A mi~;ture of 2-methyl-1-(5-methyl-2-morpholino phenyl)-3-Methyl-2-thiopseudourea hydroiodide (8.4 g prepared as described in Example 227), N-(2-hydroxy ethyl)ethyl_enediamine (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 [1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-4-methylphenyl)morpholine sesquifumarate (m. p.
135-136°C),.
Example 22~~
A mi~cture of 2-methyl-1-(2-morpholinophenyl)-3 methyl-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 far 40 minutes to yield an oil which was extracted with hexane to give 1-methyl-2-(2-morpholino-phenyl)-3-(n-pentyl)guanidine which was converted into its monofumarate salt (m.p. 148-149°C) which was recrystall-.Lsed from a 3:5 mixture of methanol and ether.
Example 230 A mixture of 2-methyl-1-(5-methyl-2-morpholino-phenyl)-3-methyl-2-thiopseudourea hydroiodide (12.2 g prepared a.s described in Example 227), n-butylamine (2.4 g) and ethanol (80 m1) was stored at ambient 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 recrystall:i.sed from a 1:2 mixture of methanol and ether.
Example 231 Reaction of 6-methyl-2-morpholinoaniline (8.75 g) with methyl isothiocyanate (4.7 g) in dichloromethane (50 ml) ai. room temperature for four days yielded N-methyl-N'-(6-methyl-2-morpholinophenyl)thiourea fm. p.
182-183°C).
A mi~aure of N-methyl-N'-(6-methyl-2-morpholino-phenyl)thiourea (11.5 g), methyl iodide (6.75 g) and acetone (100 ml) was heated under reflux for 2.5 hours to give 2-methyl-1-(6-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (m. p. 187-188°C).
A mixture of 2-methyl-1-(6-methyl-2-morpholino-phenyl)-3-methyl-2-thiopseudourea hydroiodide (17.8 g), n-butylamine (6.4 g) and ethanol (60 ml) was stored at ambient temperature for 60 days. Potassium hydroxide (2.2 g) and then lead acetate trihydrate (7.6 g) were added and the mixture was heated under reflux for 5 hours to yield 1-(n-butyl)-2-(6-methyl-2-morpholino-phenyl)-3-methylguanidine which was converted into its monofumarai_e salt (m.p. 203-204°C) which was recrystall:ised from a 1:2 mixture of methanol and ether.
Example 23;?
Reaction of N-(2-morpholinophenyl) isothiocyanate (4 g) in ethanol (10 ml) with 33~ ethanolic dimethyl amine solution (15 ml) at 15°C for four hours gave 1,1-dimeth:;~l-3-(2-morpholinophenyl)thiourea (m. p.
150-152°C).
A mixture of 1,1-dimethyl-3-(2-morpholinophenyl)-thiourea (7.5 g), methyl iodide (1.7 ml) and acetone 20065'x'7 was heated under reflux fo.r 2 hours to give 2-methyl-1-(2-morphol~_nophenyl)-3,3-dimethyl-2-thiopseudourea (m.p. 162-"63°C). .
A mixture of 2-methyl-1-(2-morpholinophenyl)-3,3-dimethyl-2--thiopseudourea hydroiodide (2 g), a saturated ethanolic ammonia solution (10 ml) and pyridine (10 m1) was heated at 90-95°C for 19 hours in a sealed si=ainless steel pressure vessel. Pyridine was removed by evaporation under reduced pressure and the residue suspended in water. 1,1-Dimethyl-2-(morphol-inophenyl)~;uanidine (m.p. 142-143°C) was collected by filtration, washed with water, dried and recrystallised from hexanE~ .
Example 233 A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroidide (3.8 g), a 337 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 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 23~+
A mi:~ture of 2-methyl-1-(2-morpholinophenyl)-2 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 give 1,1-d:imethyl-2-(2-morpholinophenyl)guanidine (m. p.
141-143°C) which was recrystallised from hexane.

Examples 2.35 to 241 The compounds of formula I listed in Table VIII
were prep~~red by heating a mixture of a thiourea of formula XVI in which R14 is methyl and R15 is H
(A g), potassium hydroxide (B g), an amine of formula H2NR6 (C g), lead acetate trihydrate (D g) and ethanol (E mI) at 90-95°C for F hours to yield an oil which is dissolved in methanol and treated with fumaric acid to give the m.onofumarate 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 .

20065'x'7 Notes to Table VIII
(59) Salt :.ecrystallised frbm methanol.
(60) The thiourea starting material was prepared by the reaction of 4-(2-amino-4-fluorophenyl)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 tlziourea starting material was prepared by the reaction of 4-(2-amino-4-methylthiophenyl)-morph~~line (9.5 g) with methyl isothiocyanate (3.1 ;~) in dichloromethane (100 ml) at room temperature for 30 days to give 1-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.

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- l07 -Example 242 Reaction of 2-morpholino-5-trifluoromethylaniline (12 g) with thiophosgene ($.6 g) in dioxan (30 ml) and water (100 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 2-morpholino-5-trifluoromethylphenyl isothiocyanate as a yellow oil.
React~'_on of 2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) with 337 ethanolic ,ammonia solution (50 ml) at room temperature for 2 hours gave 1-(2-morpholino-5-trifluoromethyl-phenyl)thiourea (m. p. 196-197°C).
A mi~~ture of 1-(2-morpholino-5-trifluoromethyl-phenyl)thiourea (6.1 g), potassium hydroxide (2:2 g), a 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-dimethyl-2-(2-morpholino-5-trifluoromethylphenyl)guanidine (m. p.
132-135°C) which was recrystallised from ethylacetate and converted into its fumarate salt (m.p. 228-230°C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 24:3 Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) a~~ 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.
Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with 257 aqueous ammonia solution (1 ml) at room temperature for 2ooss~
- los -3 hours gave 1-(5-cyario-2-morpholinophenyl)thiourea (m. p. 193-194°C).
A m::xture of 1-(5-cyano-2-morpholinophenyl)-thiourea (5.2 g), potassium carbonate (8.3 g), a 33~
ethanolic solution of dimethylamine (15 ml), lead acetate tr:uhydrate and ethanol (25 ml) was heated under reflux for 3 hours to yield 1,1-dimethyl-2-(5-cyano-2~-morpholinophenyl)guanidine (m.p. 125-127°C) which was converted into its monofumarate salt [m. p.
223-225°C (dec)] which was recrystallised from methanol.
Example 24~~
A mixture of 1,1-dimethyl-3-(2-morpholinophenyl) thiourea x;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) wa:~ heated under reflux for 4 hours. A further amount of n-propylamine (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 1,3-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 24.'i A mi~aure 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.

20065'x'7 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 filtration., washed with water and dried to give 1,1-dimethvl-2-(2-morpholinophenyl)guanidine (m. p.
141-142°C) which was recrystallised from hexane.
Examples 2~E6 to 269 Reaction of a compound of formula VII in the form of its hydrochloride salt (K grammes) and a compound of formula NC;-NR5R6 (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
Notes (32),(38), (44) and (45) have the meaning given hereinbefore .
(65) Rea~:tion performed at 110°C.
(66) The product was isolated as its monofumarate sale= which was recrystallised from a 1:1 mixture of methanol and ether.
(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 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 2ooe~s~~
-"o-basE~ which was converted into its monofumarate salt. which was recrystallised from a 1:3 mixture of methanol and ether.
(71) 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 eluE~nts sequentially:- hexane, a 1:1 mixture of dichloromethane and hexane, dichloromethane and a 1:99 mixture of methanol and dichloromethane to ;dive the base which was converted into its monofumarate salt which was recrystallised from 2:7 mixture of methanol and ether.

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Example 27~~ ' A mixture of 4-(2-aminophenyl)morpholine hydrochloride (2.1 g) and N,N-dimethylcyanamide (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 407 aqueous sodium hydroxide solution.
The res~slting 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-morphol:inophenyl)guanidine (m. p. 144-145°C).
Exampla 271 A mixture of 4-(2-amino-4-methoxycarbonylphenyl) morpholine (2.7 g), N,N-dimethyl cyanamide (l~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 tree 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 dichlorome~thane. 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-dimeth:~l-2-(5-methoxycarbonyl-2-morpholinophenyl-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 ref:Lux for 10 minutes and cooled to ambient ._ 200b5'~'~

temperaturE~. The mixture faas 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-morpholinophenyl)cyanamide (m. p. 175-176°C).
N-(2-morpholinophenyl)cyanamide (2 g) was heated under reflex with a 33% solution of dimethylamine in ethanol (15 ml) for 4 hours. The mixture was then cooled and the solvent removed by evaporation to give a residue which was suspended in 20% aqueous sodium hydroxide solution. The suspension was extracted with dichloromet:hane (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 (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-vmorpholinophenyl)cyanamide (P g) was heated under reflex with an amine of formula HNR5R6 (Q g) and ethanol (R ml) for T hours to give the compounds listed in Table X.

20065'~'~

Notes to Table X
Notes (32) , (38) , (44) and (45) have the meaning given hereinbefora (72) A 33T ethanolic solution of methylamine (25 ml) was u:~ed as reactant .
(73) Reaction performed at 90-95°C.
(74) Product isolated as its monofumarate salt which was rc:crystallised 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.

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Example 28fi ' Reaction of 4-(2-amino-4-chlorophenyl)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 hours at room temperature gave 5-chloro-2-morpholino-phenyl isothiocyanate as a pale yellow solid (m. p.
86-87°C).
React:~on of 5-chloro-2-morpholinophenyl isothio-cyanate (10 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 14 hours gave 1-(5-chloro-2-morpholinophenyl)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 acetate t:rihydrate (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-:i08°C) .
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-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 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 2006J'~

extracted with dichloromet~hane to give an oil which was purified b;y 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 isothiocya:nate as an oil.
Reaction of 5-fluoro-2-morpholinophenyl isothio cyanate (_'i.8 g) with 33~ ethanolic ammonia solution (30 ml) at. room temperature for 3 hours gave 1-(5 fluoro-2-m~~rpholinophenyl)thiourea as a white solid (m. p. 195-196).
A mixture of 1-(5-fluoro-2-morpholinophenyl)-thiourea 1:5.1 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 heated under reflux for 25 minutes to give N-(5-fluoro-2-m~~rpholinophenyl)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) in ethanol_ (10 ml) and a 337 ethanolic solution of dimethylamine (6 ml) was heated under reflux for 20 minutes to give 1,1-dimethyl-2-(5-fluoro-2-morphol-inophenyl);~uanidine (m.p. 137-138°C) which was recrystallised from hexane and converted into its fumarate salt (m. p. 222-224°C) which was recrystallised from methanol.
Example 28~~
Reaction of 3-methyl-2-morpholinoaniline (9.4 g) with thiophosgene (6 ml) in dioxane (50 ml) and water (200 ml) at 0°C for 30 minutes and at room temperature for 2 hovers gave a product which was extracted with dichloromel=have to give' 3-methyl-2-morpholinophenyl isothiocyanate as a red oil.
Reaction of 3-methyl-2-morpholinophenyl isothio-cyanate (8 g) in ethanol (5 ml) with a saturated solution of ammonia in ethanol (60 ml) at room temperaturE~ for 4 hours gave 1-(3-methyl-2-morpholino-phenyl)thiourea (m. p. 178-179°C).
A mixture of 1-(3-methyl-2-morpholinophenyl)-thiourea (fi g) suspended in water (40 ml), lead acetate trihydrate (9 g) in water (40 ml), potassium hydroxide (13.5 g) i:n water (35 ml) was heated at 90-95°C for 1 hour to give N-(3-methyl-2-morpholinophenyl)cyanamide (m. p. 137-138°C) which was recrystallised from ethyl acetate.
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 of dimethylamine (3.5 ml) was added and the mixture heated under reflux for a further hour to give 1,1-dimethyl-2--(3-methyl-2-morpholinophenyl)guanidine (m. p.
100°C) which was recrystallised from hexane and converted :Lnto its monofumarate salt (m. p. 180°C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 28~~
React:Lon of 4-methoxy-2-morpholinoaniline (4.7 g) and thiophosgene (2.9 ml) in dioxan (25 ml) and water (75 ml) fc~r 30 minutes at 0°C and 3 hours at room temperaturE~ yielded a residue which was extracted with dichloromei=have to give 4-methoxy-2-morpholinophenyl isothiocyanate as an oil.

2t'~6~''~'l React:~on of ' 4-methoxy-2-morpholinophenyl isothiocyanate (4.1 g) with a saturated solution of ammonia in ethanol (30 ml) for 24 hours at room temperaturE~ gave 1-(4-methoxy-2-morpholinophenyl) thiourea (m. p. 175°C).
A mixture of 1-(4-methoxy-2-morpholinophenyl)-thiourea (3.8 g) suspended in water (26 ml),lead acetate trihydrate (5.7 g) in water (26 ml) and potassium hydroxide (8.4 g) in water (24 ml) was heated at 90-95°C for 30 minutes to give N-(4-methoxy-2-morpholinophenyl)cyanamide.
A mixture of N-(4-methoxy-2-morpholinophenyl)-cyanamide (1.9 g) and 337 ethanolic dimethylamine solution x;2.5 ml) was heated under reflux for 15 minutes to give 1,1-dimethyl-2-(4-methoxy-2-morphol-inophenyl));uanidine (m.p. 135°C) which was recrystallised from hexane.
Example 290 A mixture of 5-isobutyl-2-morpholinoaniline hydrochloride (4.1 g), N,N-dimethylcyanamide (1.77 g) and m-cres~~l (15 ml) was heated at 90-95°C for 6 hours to yield a residue which was extracted with hot hexane, dE~colourised with charcoal and purified by chromatography on an alumina column eluted with a 2:98 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 from a 1:3 mixture of ethylacetate and hexane to give 1,1-dimeth~il-2-(5-isobutyl-2-morpholinophenyl)-guanidine.

200~5'~'7 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 zaashed 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 res:~due which was purified by chromatography on a silica c~~lumn which was eluted with hexane to which ethylacetat:e (up to 30~) was added progressively to raise the polarity. N-(2-morpholinophenyl)cyanamide (m. p. 175-176°C).
A mixture of N-(2-morpholinophenyl)cyanamide (1.5 g) and a 33X ethanolic solution of dimethylamine (12 ml) was heated under reflux for 4 hours. Removal of solvent gave a residue to which was added dichloromet:hane (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.
144-145°C) which was recrystallised from hexane.

20065'T7 Example 292 1,1-dimethyl-2-(5-methylthio-2-morpholinophenyl)-guanidine in the form of its free base (1.3 g) obtained from the product of Example 253, sodium metaperiodate (1 g), methanol (10 ml) and water (4 ml) were stored at ambient temperature for 20 hours to yield 1,1-dimethyl-2-(5-methylsulphinyl-2-morpholinophenyl)guanidine (m. p.
160-161°C) which was recrystallised from ethyl acetate.
Example 29:3 A solution of 1-methyl-2-(2-morpholinophenyl)-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), ~~uprous chloride (0.2 g), cupric chloride dehydrate (0.34 g) and benzyltrimethylammonium chloride (0.6 g). 'The resulting mixture was stirred for 2 hours and then :>odium chlorite (2.4 g) and benzyltrimethyl-ammonium chloride (0.4 g) were added and the mixture stirred for 1~ hours. Dichloromethane (200 ml) and 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 using hexane and then a 1:4 mixture of ethyl acetate and hexane as eluant to give N-methyl-N'-(2-morpholino~~henyl)carbodiimide (m. p. 67-68°C).
A mixture of N-methyl-N'-(2-morpholinophenyl)-carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol (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 ~~as washed with water, dried and filtered.
Removal of the solvent gave 1-(n-butyl)-2-(2-morphol-. _ . 2p06;;'T'~

inophenyl)--3-methylguanidine which was converted into its monofumarate salt (m. p. 178-179°C).
Examples 2~~4 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 recrystall~_sed from the solvent shown:
M.P. of Starting Recrystallisation fumarate Example Example Solvent Salt(C) 294 133 1:2 methanol:ether 173-175 295 134 1:2 methanol:ether 183-184 296 167 2:1 methanol:ether 192-193 297 175 1:1 methanol:ether 159-160 298 200 propan-2-of 142-143 299 201 1:1 methanol:ether 151-152 300 204 1:2 methanol:ether 170-171 Example 301 A min;ture of 2-morpholinoaniline hydrochloride (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, 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-dimeth5~1-2-(2-morpholinophenyl)guanidine (m. p.
142-143°C).

.w. 200b5'~'~

Example 30:3-304 Reaction of the products of Examples 175, 248 and 300 in tree form of its ~~free base respectively in methanol with L(+) tartaric acid gave the following compounds which were recrystallised from methanol.
301 4-~2-[1-(2-hydroxyethyl)-2-imidazolidinylidene-amino]phenyl7morpholine monotartrate (m. p.
147-'148°C).
303 1,1-dimethyl-2-(5-methyl-2-morpholinophenyl)-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 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 parenthesi;~ .
305 1,1-dimethyl-2-(5-methyl-2-morpholinophenyl)-guan:idine monohydrochloride (m.p. 161-162°C) (a 1:1 mixture of isopropanol and ether).
306 1,1-dimethyl-2-(2-morpholinophenyl)guanidine monollydrochloride (m. p. 200-201°C) (isopropanol).
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 of methanol and ether.

20065'T7 Example 30.3 ' Reaction of pamoic acid with the product of Example 301 in pyridine - yielded 1,1-dimethyl-2-(2 morpholinophenyl)guanidine hemipamoate (m. p.
158-160°C).
Example 30!a A mixture of 1,3-dimethyl-2-imidazolidinone (4.6 g) in benzene (40 ml), 4-(2-aminobenzyl)-morpholine (3.8 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65-70°C for 20 hours to yield 4-[2-(1,3-dimethyl-2-imidazolidinyl-ideneamino;)benzyl]morpholine (m.p. 56-58°C) which was recrystall:ised from hexane.
Example 311) ' A mixture of 1,3-dimethyl-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 heated at 60-65°C
for 8 hours to yield an oil which was purified by column chromatography on an alumina column using hexane, a 9:1 mixture of hexane and dichloromethane, a 1:1 mixture of hexane and dichloromethane and then dichloromei_hane as eluant. The resulting product (3.2 g) was dissolved in methanol (50 ml) and treated with -fuma~~ic 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 recrystall:ised from a 1:1 mixture of methanol and ether.
Example 31 'I
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 ~~6J

which (2 g) was dissolved in methanol (15 m1).
Treatment 'with fumaric acid (0.9 g) gave N,N-dimethyl N'-[2-morplzolinomethylphenyl)guanidine monofumarate (m. p. 16~~-165°C) which was recrystallised from propan-2-oL.
Example 312 A mixture of 4-(2-aminobenzyl)morpholine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heated at 90-95°C for 12 hours to yield N-(2-morpholinomethylphenyl)morpholine-4-carboxamidine (m. p. 118-119°C) which was recrystallised from hexane and then converted into its difumarate salt (m. p.
166-167°C) which was recrystallised from propan-2-ol.
Example 31:3 ' 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 o:E the invention but particularly any compound which is the final product of one of the preceding Examples.
a) Ca su:Les 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) Tablev~s Table=s are prepared from the following ingredients .

2ooss~
-, Parts by weight Active compound prepared as~ in Example 1 10 Lactose 190 Maize sts:rch 22 Polvvinyl.pyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture i.s granulated with a solution of the polyvinyl-pyrrolidone in ethanol. The dry granulate is blended with the: magnesium stearate and the rest of the starch. The mixture is then compressed in a tablettin.g machine to give tablets each containing a unit dose: or a part of a unit dose of active compound.
(c) Enteric coated tablets Tablets are prepared by the method described in (b) above. The tablets are enteric coated in a conventional manner using a solution of 207 cellulose acetate phthalate and 37 diethyl phthalate in ethanol:a:ichloromethane (1:1).
d) SupFositories In t:he 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.

Claims (34)

1. A compound of formula I

or a pharmaceutically acceptable salt thereof in which n = 0 or 1;

in which the group NR1R2 is selected from the group consisting of 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, piperidino, 4-methylpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl and 1-(1,2,5,6-tetrahydro)pyridyl;

R3 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 R4 and R'4, which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms;

-130-~

in which R5 is H or a straight or branched aliphatic group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy;

in which R6 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 atoms;

R7 represents H or one or more optional substituents selected from halo, alkyl groups containing 1 to 4 carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms, alkylsulphinyl 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.
2. A compound of formula I as claimed in claim 1 in which n = 1 and the group NR1R2 is morpholino or thiamorpholino.
3. A compound of formula I as claimed in claim 1 in which R3 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, cyclohexyl, amino, methylamino, dimethylamino or ethylamino.
4. A compound of formula I as claimed in claim 1 in which R5 is H, methyl, ethyl or methoxyethyl.
5. A compound of formula I as claimed in claim 1 in which R6 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, R6 is a straight or branched alkylene group containing 3 to 6 carbon atoms or R6 is a cycloalkyl group containing 5 or 6 carbon atoms.
6. A compound of formula I as claimed in claim 5 in which R6 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-hydroxy-ethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-butyl, 2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 2-acetyloxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, benzyl or 2-phenylethyl 2-cyanoethyl, allyl, 2-methylallyl, cyclopentyl or cyclohexyl.
7. A compound of formula I as claimed in claim 1 in which the group -N=C(R3)NR5R6 is:
acetamidino, N-methylacetamidino, N,N-dimethylacetamidino, N,N-diethylacetamidino, N-(2-acetyloxyethyl)acetamidino, N-butylacetamidino, N-pentylacetamidino, N-methylpropionamidino, N,N-dimethylpropionamidino N-ethylpropionamidino, butyramidino, N-methylbutyramidino, N,N-dimethylbutyramidino, N-ethylbutyramidino, isobutyramidino, N-methylisobutyramidino, N,N-dimethylisobutyramidino, valeramidino, N-methylvaleramidino, N,N-dimethylvaleramidino, pivalamidino, N-methylpivalamidino, N,N-dimethylpivalamidino, N-methylcaproamidino N-methylcyclohexanecarboxamidino, diaminomethyleneamino, N-methylguanidino, N,N-dimethylguanidino, N,N'-dimethylguanidino, N-ethylguanidino, N-butylguanidino, N-ethyl-N-methylguanidino, N,N-diethylguanidino, N,N'-diethylguanidino, N,N',N'-trimethylguanidino, 1,1,3,3-tetramethylguanidino, N-ethyl-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, N-isobutyl-N'-methylguanidino, N-butyl-N'-methylguanidino, N-butyl-N'-ethylguanidino, N-methyl-N'-pentylguanidino, N-cyclopentyl-N'-methylguanidino, 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, N-methyl-N-(2-methylthioethyl)guanidino, N-allyl-N-methylguanidino, N-allyl-N'-methylguanidino, 1-allyl-1,3,3-trimethylguanidino, N,N-diallylguanidino.
8. A compound of formula I as claimed in claim 1 in which R7 represents H or one or more substituents elected from fluoro, chloro, methyl, ethyl, isobutyl, methylthiomethyl, methoxy, methoxycarbonyl, methylthio, methylsulphinyl, methylsulphonyl, trifluoromethyl or cyano.
9. A compound of formula I as claimed in claim 1 in which n - 0, -NR1R2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, R3 is -NH2, R5 is an aliphatic group containing 1 to 4 carbon atoms R6 is an aliphatic group containing 1 to 4 carbon atoms optionally substituted by methoxy or methylthio and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or ethylthio.
10. A compound of formula I as claimed in claim 9 in which R5 is methyl, ethyl or allyl, R6 is methyl, ethyl, allyl, methoxyethyl or methylthioethyl and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.
11. A compound of formula I as claimed in claim 1 in which n - 0, -NR1R2 is morpholino or thiamorpholino, R3 is a group of formula III in which R4 is an alkyl group containing 1 to 4 carbon atoms and R4' is H, R5 is H, R6 is an aliphatic group containing 1 to 4 carbon atoms optionally substituted by methoxy and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
12. A compound of formula I as claimed in claim 11 in which R4 is methyl, R4' is H, R5 is H and R6 is methyl, butyl, t-butyl or methoxyethyl.
13. A compound of formula I as claimed in claim 1 in which n = 0, -NR1R2 is morpholino or thiamorpholino, R3 is an alkyl croup of 1 to 4 carbon atoms, R5 and R6 are H and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
14. A compound of formula I as claimed in claim 1 selected from:
1,1-dimethyl-2-(2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-fluoro-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(6-methyl-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-ethyl-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-methylthiomethyl-2-morpholinophenyl) guanidine;
1,1-dimethyl-2-(5-methylthio-2-morpholinophenyl) guanidine;
1-ethyl-1-methyl-2-(2-morpholinophenyl)guanidine;
1,1-diethyl-2-(2-morpholinophenyl)guanidine;
1-(2-methoxyethyl)-1-methyl-2-(2-morpholinophenyl) guanidine;
1-methyl-1-(2-methylthioethyl)-2-(2-morpholinophenyl)-guanidine;
1,1-dimethyl-2-(2-thiamorpholinophenyl)guanidine;
1,1-dimethyl-2-(2-piperidinophenyl)guanidine;
1,1-dimethyl-2-[2-(1-pyrrolidinyl)phenyl]guanidine;
1-butyl-3-methyl-2-(2-morpholinophenyl)guanidine;
1-methyl-3-tert-butyl-2-(2-morpholinophenyl)guanidine;
1,3-dimethyl-2-(2-thiamorpholinophenyl)guanidine;
N-(2-morpholinophenyl)acetamidine;
N-(4-methyl-2-morpholinophenyl)acetamidine;
N-(2-morpholinophenyl)pivalamidine;

and pharmaceutically acceptable salts thereof.
15. 1,1-Dimethyl-2-(2-morpholinophenyl)guanidine in the form of its fumarate salt in accordance with claim 1.
16. A pharmaceutical composition comprising a hypoglycemically effective amount of a compound of formula I
or a pharmaceutically acceptable salt thereof in which n = 0 or 1;
in which they group NR1R2 is selected from the group consisting of 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, piperidino, 4-methylpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl and 1-(1,2,5,6-tetrahydro)pyridyl;
R3 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 R4 and R'4, which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms;
in which R5 is H or a straight or branched aliphatic group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy;
in which R6 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 croup containing 3 to 7 carbon atoms or by cyano or (c) a cycloalkyl ring containing 3 to 7 carbon atoms;
R7 represents H or one or more optional substituents selected from halo, alkyl groups containing 1 to 4 carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms, alkylsulphinyl 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, together with a pharmaceutically acceptable diluent or carrier.
17. A pharmaceutical composition as claimed in claim 16 in which n = 1 and the group NR1R2 is morpholino or thiamorpholino.
18. A pharmaceutical composition as claimed in claim 16 in which R3 is methyl, ethyl, propyl, isopropyl, butyl t-butyl, pentyl, cyclohexyl, amino, methylamino, dimethylamino or ethylamino.
19. A pharmaceutical composition as claimed in claim 16 in which R5 is H, methyl, ethyl or methoxyethyl.
20. A pharmaceutical composition as claimed in claim 16 in which R6 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, R6 is a straight or branched alkylene group containing 3 to 6 carbon atoms or R6 is a cycloalkyl group containing 5 or 6 carbon atoms.
21. A pharmaceutical composition as claimed in claim 20 in which R6 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2,3-di-hydroxypropyl, 2-acetyloxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, benzyl or 2-phenylethyl 2-cyanoethyl, allyl, 2-methylallyl, cyclopentyl or cyclohexyl.
22. A pharmaceutical composition as claimed in claim 16 in which the group -N=C(R3)NR5R6 is:
acetamidino, N-methylacetamidino, N,N-dimethylacetamidino, N,N-diethylacetamidino, N-(2-acetyloxyethyl)acetamidino, N-butylacetamidino, N-pentylacetamidino, N-methylpropionamidino, N,N-dimethylpropionamidino N-ethylpropionamidino, butyramidino, N-methylbutyramidino, N,N-dimethylbutyramidino, N-ethylbutyramidino, isobutyramidino, N-methylisobutyramidino, N,N-dimethylisobutyramidino, valeramidino, N-methylvaleramidino, N,N-dimethylvaleramidino, pivalamidino, N-methylpivalamidino, N,N-dimethylpivalamidino, N-methylcaproamidino N-methylcyclohexanecarboxamidino, diaminomethyleneamino, N-methylguanidino, N,N-dimethylguanidino, N,N'-dimethylguanidino, N-ethylguanidino, N-butylguanidino, N-ethyl-N-methylguanidino, N,N-diethylguanidino, N,N'-diethylguanidino, N,N',N'-trimethylguanidino, 1,1,3,3-tetramethylguanidino, N-ethyl-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, N-isobutyl-N'-methylguanidino, N-butyl-N'-methylguanidino, N-butyl-N'-ethylguanidino, N-methyl-N'-pentylguanidino, N-cyclopentyl-N'-methylguanidino, 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, N-methyl-N-(2-methylthioethyl)guanidino, N-allyl-N-methylguanidino, N-allyl-N'-methylguanidino, 1-allyl-1,3,3-trimethylguanidino, N,N-diallylguanidino.
23. A pharmaceutical composition as claimed in claim 16 in which R7 represents H or one or more substituents selected from fluoro, chloro, methyl, ethyl, isobutyl, methylthiomethyl, methoxy, methoxycarbonyl, methylthio, methylsulphinyl, methylsulphonyl, trifluoromethyl or cyano.
24. A pharmaceutical composition as claimed in claim 16 in which n - 0, -NR1R2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, R3 is -NH2, R5 is an aliphatic group containing 1 to 4 carbon atoms R6 is an aliphatic group containing 1 to 4 carbon atoms optionally substituted by methoxy or methylthio and R7 is H, fluoro, chloro, methyl, ethyl, methyl-thiomethyl or methylthio.
25. A pharmaceutical composition as claimed in claim 24 in which R5 is methyl, ethyl or allyl, R6 is methyl, ethyl, allyl, methoxyethyl or methylthioethyl and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.
26. A pharmaceutical composition as claimed in claim 16 in which n = 0, -NR1R2 is morpholino or thia-morpholino, R3 is a group of formula III in which R4 is an alkyl group containing 1 to 4 carbon atoms and R4' is H, R5 is H, R6 is an aliphatic group containing 1 to 4 carbon atoms optionally substituted by methoxy and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
27. A pharmaceutical composition as claimed in claim 26 in which R4 is methyl, R4' is H, R5 is H and R6 is methyl, butyl, t-butyl or methoxyethyl.
28. A pharmaceutical composition as claimed in claim 16 in which n = 0, -NR1R2 is morpholino or thia-morpholino, R3 is an alkyl group of 1 to 4 carbon atoms, R5 and R6 are H and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
29. A pharmaceutical composition as claimed in claim 16 wherein the compound of formula I is selected from:
1,1-dimethyl-2-(2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-fluoro-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(6-methyl-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-ethyl-2-morpholinophenyl)guanidine;
1,1-dimethyl-2-(5-methylthiomethyl-2-morpholinophenyl) guanidine;
1,1-dimethyl-2-(5-methylthio-2-morpholinophenyl) guanidine;
1-ethyl-1-methyl-2-(2-morpholinophenyl)guanidine;
1,1-diethyl-2-(2-morpholinophenyl)guanidine;
1-(2-methoxyethyl)-1-methyl-2-(2-morpholinophenyl) guanidine;
1-methyl-1-(2-methylthioethyl)-2-(2-morpholinophenyl)-guanidine;
1,1-dimethyl-2-(2-thiamorpholinophenyl)guanidine;
1,1-dimethyl-2-(2-piperidinophenyl)guanidine;
1,1-dimethyl-2-[2-(1-pyrrolidinyl)phenyl]guanidine;
1-butyl-3-methyl-2-(2-morpholinophenyl)guanidine;
1-methyl-3-t-butyl-2-(2-morpholinophenyl)guanidine;
1,3-dimethyl-2-(2-thiamorpholinophenyl)guanidine;

N-(2-morpholinophenyl)acetamidine;
N-(4-methyl-2-morpholinophenyl)acetamidine;
N-(2-morpholinophenyl)pivalamidine;
and pharmaceutically acceptable salts thereof.
30. A pharmaceutical composition as claimed in claim 16 wherein the compound of formula I is 1,1-dimethyl-2-(2-morpholinophenyl)guanidine in the form of its fumarate salt.
31. Compounds of formula I as claimed in any one of claims 1 to 15 for use as antidiabetic agents.
32. Compounds of formula I as claimed in any one of claims 1 to 15 for use as hypoglycaemic agents.
33. The use of compounds of formula I as claimed in any one of claims 1 to 15 in the manufacture of a medicament for the treatment of diabetes.
34. The use of compounds of formula I as claimed in any one of claims 1 to 15 in the manufacture of a medicament for the treatment of hyperglycaemia.
CA002006577A 1989-01-02 1989-12-22 Hypoglycaemic phenylamidines and phenylguanidines Expired - Fee Related CA2006577C (en)

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IN1/BOM/89 1989-01-02
IN1/BOM/89A IN169912B (en) 1989-01-02 1989-01-02
GB898903592A GB8903592D0 (en) 1989-02-16 1989-02-16 Therapeutic agents
GB8903592.7 1989-02-16

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IN172842B (en) * 1990-05-17 1993-12-11 Boots Pharmaceuticals Limited
AU671071B2 (en) * 1990-08-30 1996-08-15 State of Oregon, acting by and through The Oregon State Board of Higher Education, acting for and on behalf of The Oregon Health Sciences University, Portland, Oregon, and The University of Oregon, Eugene, Oregon, Johnson Hall, Substituted amidines having high binding to the sigma receptor and the use thereof
WO1994021621A1 (en) * 1993-03-23 1994-09-29 Astra Aktiebolag Guanidine derivatives useful in therapy
CZ29996A3 (en) * 1993-08-12 1996-09-11 Astra Ab Amidine derivatives with activities of nitrogen oxide sythetase
ATE182889T1 (en) * 1994-05-07 1999-08-15 Astra Ab BICYCLIC AMIDEINE DERIVATIVES AS NO-SYNTHETASE INHIBITORS
DE69708198T2 (en) * 1996-04-30 2002-03-28 Pfizer Inc., New York Muscarinic receptor agonists
GB9626265D0 (en) * 1996-12-18 1997-02-05 Knoll Ag Medical treatment
WO2003000659A1 (en) * 2001-06-26 2003-01-03 Nissan Chemical Industries, Ltd. Heterocycloiminophenyl compounds and fungicides and insecticides for agricultural and horticultural use
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CA2006577A1 (en) 1990-07-02
NZ231950A (en) 1992-05-26
KR0168398B1 (en) 1999-03-20
KR900012933A (en) 1990-09-03
HUT58693A (en) 1992-03-30
HU900008D0 (en) 1990-03-28
GB2226562B (en) 1992-07-08
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GB2226562A (en) 1990-07-04

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