HYPOGLYCAEMIC PHENYLAMIDINES AND PHENYLGUANIDINES

PHENYLAMIDINES ET PHENYLGUANIDINES HYPOGLYCEMIQUES

English 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.

Claims

-129-
Claims
1. A compound of formula I
<IMG>
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
<IMG>
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.

-131-
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,

-132-
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,

-133-
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.

-134-
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;

-135-
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
<IMG>
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
<IMG>

-136-
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.

-137-
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,

-138-
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,

-139-
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

-140-
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;

-141-
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.

Description

CA 02006577 1999-09-16
- 1 -
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
CH2 II
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

-2- 2006577
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
R4
i
Irr
~ R'
4
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
- 3 -
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
R6
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
11
N
- C/ g V
\N
R6
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'~
- 4 -
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
1
groups containing 1 to carbon atoms, alkylsulphinyl
3
groups containing 1 to carbon atoms, alkylsulphonyl
3
groups containing 1 to carbon atoms, alkoxycarbonyl
3
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~~
- 5 -
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'~'~
- 6 -
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
- 10 -
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
- 12 -
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
- 13 -
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'~'~
- 14 -
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~
- 15 -
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~~~'~~
- 16 -
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'~'~
- 17 -
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 ~"'~"~
- 18 -
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'~
- 19 -
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'~'~
- 20 -
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
- 21 -
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'~'~
- 22 -
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
- 23 -
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'~'~
- 24 -
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
- 25 -
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~~'~'~
- 26 -
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'~
- 27 -
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
- 28 -
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~~
- 29 -
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~
NH2
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
- 30 -
R9\ / R10
C1
0 = C 1D
~N
R6 VIII
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 / _
R12 C D B
N ~ ~ IX
R6
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
13
N
R6 - X

_a 2~~~;~'7'7
- 31 -
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
R R10
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
0 C E XII
\N~
R6
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
- 32 -
(CH2)nNRlR2
R~ \ I / She XIII
N C / R14
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
- 33 -
(CH2)nNRlR2
R7 XV
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
- 34 -
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
6

~.~~~J~~'7
- 35 -
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
N02
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
- 37 -
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
6
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
- 39 -
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
- 40 -
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
1 25 A 2 25 B
3 25 B 4 25 B
5 25 A 6 25 E
7 25 B 8 36 B
9 :Z00 E 10 25 B
11 25 A 12 25 A
13 50 D 14 200 A
15 100 E 16 25 D
17 50 B 18 25 E
19 40 A 20 25 A
21 25 C 22 25 B
23 50 A 24 25 B
25 25 D 26 25 B
27 25 A 28 25 A
29 25 E 30 25 D
31 50 D 32 25 D

xoos5 ~~
- 41 -
Table A continued
Example x Activity Example x Activity
33 25 B 34 25 B
35 25 D 36 200 F
37 200 E 38 200 D
39 200 A 40 200 A
41 200 A 42 36 D
43 25 B 44 200 A
45 200 D 46 36 B
47 37 B 48 200 A
49 38 E 50 36 A
51 200 D 52 36 B
53 36 B 54 37 B
55 36 A 56 35 A
57 25 A 58 25 B
59 35 A 60 37 E
61 36 D 62 25 C
63 -100 A 64 25 B
65 25 A 66 36 D
67 :?00 A 68 25 C
69 43 D 70 36 A
71 36 A 72 25 B
73 25 A 74 25 A
75 50 F 76 25 D
77 25 E 78 25 F
79 a'_00 A 80 25 D
81 a?00 D 82 50 E
83 25 A 84 25 E
85 25 D 86 25 F
87 200 D 88 200 F

20065'Tl
- 42
Table A continued
Example x Activity Example x Activity
89 ;?00 C 90 25 E
91 200 A 92 25 B
93 25 C 94 200 C
95 25 E 96 25 F
97 50 D 98 50 A
99 25 A 100 25 B
101 25 B 102 200 A
103 25 B 104 27 A
105 37 E 106 37 E
107 25 B 108 25 B
109 25 B 110 36 B
111 25 B 112 36 B
113 25 D 114 25 E
115 25 D 116 25 B
117 25 B 118 25 A
119 25 D 120 25 B
121 25 E 122 25 A
123 38 B 124 37 B
125 36 B 126 200 A
127 25 E 128 25 A
129 25 B 130 100 B
131 50 B 132 200 A
133 25 B 134 25 A
135 25 A 136 25 B
137 25 B 138 25 B
139 25 B 140 100 A
141 25 E 142 25 A

zooss~~
- 43 -
Table A continued
Example x Activity Example x Activity
143 25 B 144 25 B
145 25 C 146 200 A
147 36 D 148 25 D
149 36 D 150 68 F
151 25 C 152 25 D
153 25 B 154 39 D
155 '133 B 156 25 D
157 25 A 158 25 A
159 50 D i60 26 D
161 34 A 162 35 B
163 25 B 164 25 D
165 ~?00 B 166 25 D
167 25 B 168 25 B
169 25 A 170 25 A
171 25 D 172 25 D
173 25 D 174 25 B
175 25 B 176 35 C
177 25 B 178 200 A
179 25 D 180 25 E
181 43 D 182 25 D
183 25 D 184 34 F
185 a'_00 D 186 25 A
187 25 A 188 25 B
189 25 A 190 25 A
191 36 D 192 25 B
193 25 A 194 200 C
195 12.5 A 196 25 A

zooss~
- 44 -
Table A continued
Example x Activity Example x Activity
197 25 D 198 25 A
199 25 B 200 25 A
201 25 E 202 25 B
203 100 A 204 200 A
205 200 A 206 200 C
207 50 A 208 30 D
209 25 B 210 30 D
211 36 A 212 25 F
213 50 D 214 25 E
215 25 E 216 35 A
217 30 E 218 200 D
219 200 D 220 36 A
221 200 A 222 35 A
223 35 D 224 35 C
225 25 B 226 200 A
227 25 F 228 35 A
229 35 A 230 35 C
231 35 F 232 25 B
233 25 B 234 25 B
235 34 A 236 38 C
237 35 A 238 35 A
239 35 A 240 36 A
241 34 A 242 200 A
243 200 B 244 200 E
245 25 B 246 200 D
247 37 A 248 36 A
249 36 B 250 25 E
251 35 E 252 200 A
253 35 A 254 36 B

zooss~
- 45
Table A continued
Example X Activity ~ Example X Activity
255 36 A 256 34 B
257 36 A 258 35 E
259 34 D 260 35 B
261 36 C 262 37 B
263 38 B 264 36 B
265 200 E 266 200 E
267 200 E 268 35 B
269 35 B 270 25 B
271 25 B 272 25 B
273 200 C 274 128 D
275 25 E 276 36 B
277 34 B 278 35 B
279 25 B 280 35 B
281 35 A 282 200 C
283 200 E 284 200 E
285 200 B 286 35 B
287 36 B 288 38 E
289 200 A 290 25 D
291 25 B 292 85 C
293 35 A 294 25 B
295 25 B 296 25 D
297 35 B 298 35 E
299 34 E 300 200 A
301 25 B 302 38 A
303 39 B 304 40 B
305 28 A 306 29 A
307 30 B 308 NT
309 '100 D 310 200 D
311 ;?00 E 312 200 E
NT - Not Tested

zooss~~
- 46 -
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)].

- 47 -
2006577
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'~"~
- 48 -
(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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20065'~'~
- 52 -
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~~
- 53 -
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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J J J J J J ,J J
~O W W N N O~ 01 W v
-W ! In ~ N v0 O V
.. ~. .. .. .. .. .. .. ~. .. .. .. .. .. z
Oo Oo 0o N J Oo -~ Oo Oo Oo -~ Oo Oo O
~r v v ~r O v v V ~r v v
~ rt
'. '. ~ .~ v
J J
V V -~ V
~r v ~p v
J
v

_. 20065'~"~
- 56 -
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.

-- 20065'x"7
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20065'x'7
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20065'7'7
- 59 -
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.

2pp65~"~
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2p065'~'~
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v ~ v v (p
N
v

20065'x'7
- 62 -
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.

20065'~'~
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20065'T~
- 64 -
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
- 65 -
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~~
- 66 -
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'~'~
- 67 -
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'~"~
- 68 -
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
- 69 -
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~~
- 70 -
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'~'~
- 71 -
(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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20065'~'~
- 74 -
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~
- 75 -
(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
- 76 -
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'~
- 79 -
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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~,~~6~Jrf
- 85 -
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'~'~
- 86 -
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
- 89 -
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~~
- 90 -
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~~
- 91 -
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

2
- 92 -
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'~
- 93 -
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
- 94 -
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~'~
- 95 -
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~
- 96 -
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~~
- 97 -
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~~
- 98 -
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'~'~
- 99 -
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

- 102 -
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
- 103 -
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.

- 104 -
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
- 105 -
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.

.o. 200~'T7
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- 20
- 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
- 109 -
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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20065'~'~
- 113 -
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'~'~
- 114 -
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'~'~
- 115 -
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.

.. 20065'~'~
..
..
.. .. .. .. .. ..
M M N M 1~ 00
(~ 1~ M I~ i~ M
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2ooss~~
- 118 -
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'~
- 119 -
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

- 120 -
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
- 121 -
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
- 122 -
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
- 123 -
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'~
- 124 -
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'~'~
- 125 -
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
- 126 -
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
- 127 -
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.

Representative Drawing