This invention relates to amidine derivatives which are histamine H-2 antagonists and which inhibit gastric acid secretion. According to the invention there is provided a guanidine derivative of the formula I: ##STR1## in which R.sup.1 is hydrogen or a 1-10C alkyl, 3-8C cycloalkyl, 4-14C cycloalkylalkyl, 3-6C alkenyl, 3-6C alkynyl, 1-6C alkanoyl, 6-10C aryl, 7-11C aralkyl or 7-11C aroyl radical, the latter three being optionally substituted; ring X is a heterocyclic ring as defined in the specification; A is phenylene or 5-7C cycloalkylene or a 1-8C alkylene chain into which is optionally inserted one or two groups; and R.sup.2 and R.sup.3 are a variety of radicals described in the specification: and the pharmaceutically-acceptable acid-addition salts thereof. Manufacturing processes and pharmaceutical compositions are also described.

This invention relates to amidine derivatives which are histamine H-2 
antagonists and which inhibit gastric acid secretion. 
It is postulated that the physiologically-active compound histamine, which 
occurs naturally within the animal body, is able to combine, in the course 
of exerting its activity, with certain specific receptors of which there 
are at least two distinct and separate types. The first has been named the 
H-1 receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27, 427) and the 
action of histamine at this receptor is blocked (antagonised) by classical 
"antihistamine" drugs such as mepyramine. The second histamine receptor 
has been named the H-2 receptor (Black et al., Nature, 1972, 236, 385) and 
the action of histamine at this receptor is blocked by drugs such as 
cimetidine. It is known that one of the results of the blockade of the 
action of histamine at the H-2 receptor is the inhibition of the secretion 
of gastric acid and a compound which possesses this ability is therefore 
useful in the treatment of peptic ulcers and other conditions caused or 
exacerbated by gastric acidity. 
In UK Patent Applications Nos. GB2052478A and GB2055800A there are 
described histamine H-2 receptor antagonists which are 2-guanidinothiazole 
derivatives carrying a side chain in the 4-position to the end of which is 
attached a substituted amidine group. It has now been discovered that if 
the thiazole ring is replaced by one of a variety of 5- and 6-membered 
heterocycles, there are obtained potent histamine H-2 receptor 
antagonists. 
According to the invention there is provided a guanidine derivative of the 
formula I: 
##STR2## 
in which R.sup.1 is a hydrogen atom or a 1-10C alkyl, 3-8C cycloalkyl, 
4-14C cycloalkylalkyl, 3-6C alkenyl, 3-6C alkynyl, 1-6C alkanoyl, 6-10C 
aryl, 7-11C aralkyl or 7-11C aroyl radical, the aryl, aralkyl and aroyl 
radicals being optionally substituted on the aryl ring by one or two 
substituents selected from halogen atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C 
alkylthio, trifluoromethyl, hydroxy and amino radicals; in ring X the 
dotted line is a double bond on one side of the nitrogen atom and Z is a 
carbon or nitrogen atom such that ring X is a 1,2,3-triazole, 
1,2,4-triazole, pyrazole, pyrazine, pyridine, pyrimidine or 1,3,5-triazine 
ring, which ring may, where possible, carry one or two optional 
substituents, the optional substituents on ring X being selected from 
fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 
trifluoromethyl, hydroxy and amino radicals; A is a phenylene or a 5-7C 
cycloalkylene radical or a 1-8C alkylene chain which is optionally 
substituted by one or two 1-3C alkyl radicals and into which is optionally 
inserted, as part of the backbone of the chain, one or two groups selected 
from oxygen and sulphur atoms and NH, 1-6C N-alkyl, cis and trans 
vinylene, ethynylene, phenylene and 5-7C cycloalkylene radcials, provided 
that the shortest link between ring X and C(R.sup.3).dbd.NR.sup.2 is of at 
least 3 atoms, provided that when an optional insertion is made in chain A 
which results in the inserted group being directly attached to 
C(R.sup.3).dbd.NR.sup.2 the inserted group is other than an NH or N-alkyl 
radical, and provided that no two insertions selected from oxygen and 
sulphur atoms and NH and N-alkyl radicals are directly attached one to the 
other; R.sup.2 is a hydrogen atom or a 1-6C alkyl, 3-8C cycloalkyl, 4-14C 
cycloalkylalkyl, 1-6C haloalkyl, 1-6C hydroxyalkyl, 1-6C aminoalkyl, 2-10C 
alkylaminoalkyl, 3-14C dialkylaminoalkyl, 2-6C carboxyalkyl, 1-6C 
alkanoyl, 7-11C aroyl, 6-10C aryl, 7-11C arylalkyl, 2-6C alkenyl, 2-6C 
alkynyl, 2-6C haloalkanoyl, 1-6C thioalkanoyl, 7-11C thioaroyl, cyano, 
carbamoyl, thiocarbamoyl, 2-6C alkylcarbamoyl, 3-10C dialkylcarbamoyl, 
2-6C alkylthiocarbamoyl, 3-10C dialkylthiocarbamoyl, carboxy, 2-6C 
alkoxycarbonyl, 2-6C alkoxythiocarbonyl, oxamoyl, sulphamoyl, 1-6C 
alkylsulphamoyl, 2-10C dialkylsulphamoyl, 6-10C arylsulphamoyl, 7-11C 
aralkylsulphamoyl, 1-6C alkanesulphonyl, 6-10C arenesulphonyl, hydroxy, 
1-6 C alkoxy, amino, 1-6C alkylamino, 2-10C dialkylamino, 6-10C arylamino, 
2-6C alkoxycarbonylamino, 7-11C aryloxycarbonylamino, 1-6C alkanoylamino, 
7-11C aroylamino, 1-6C thioalkanoylamino, 7-11C thioaroylamino, 
heteroarylcarbonylamino, heteroaryl-(1-6C)alkylcarbonylamino, 1-6C 
alkanesulphonylamino, 6-10C arenesulphonylamino, ureido, thioureido, 
oxamoylamino, heteroaryl or heteroaryl-(1-6C)alkyl radical;R.sup.3 is a 
radical of the formula HNR.sup.4 in which R.sup.4 is a hydrogen atom or a 
1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, cyano, 1-6C alkanoyl, carbamoyl, 
2-6C alkylcarbamoyl or 1-6C alkanoylamino radical; or R.sup.2 and R.sup.4 
are joined to form, together with the N--C.dbd.N chain to which they are 
attached, a monocyclic or bicyclic heterocyclic ring system composed of 5- 
and/or 6- membered rings, which ring system may be partially unsaturated 
or fully unsaturated, which ring system may optionally include additional 
hetero atoms selected from oxygen, nitrogen and sulphur atoms and which 
ring system may, where possible, carry one, two or three optional 
substituents selected from fluorine, chlorine and bromine atoms and 1-6C 
alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy, amino, 6-10C 
aryl, 7-11C arylalkyl, carboxy, 2-6C carboxyalkyl, 2-6C alkoxycarbonyl, 
3-10C alkoxycarbonylalkyl, 1-6C hydroxyalkyl, heteroaryl-(1-6C)alkyl, 
furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, 
oxadiazolyl, triazolyl, pyrazolyl and pyrimidyl radicals; or R.sup.2 is a 
hydrogen atom or a 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl radical and 
R.sup.3 is a carboxy radical; and wherein when R.sup.2 is or contains a 
heteroaryl radical and when R.sup.2 and R.sup.4, when joined, is 
substituted by a heteroarylalkyl radical, that heteroaryl radical is a 5- 
or 6- membered heterocyclic ring which contains 1, 2, 3 or 4 heteroatoms 
selected from oxygen, nitrogen and sulphur atoms, such ring being 
optionally substituted by one or two substituents selected from methyl and 
amino radicals; or R.sup.2 and R.sup.4 are joined to form, together with 
the N--C.dbd.N chain to which they are attached, a ring of the formula II: 
##STR3## 
in which R.sup.5 is a hydrogen atom or a 1-4C alkyl radical and R.sup.6 is 
a furan-2-yl or thien-2-yl radical substituted in the 5-position, a phenyl 
radical substituted in the 3- or 4- position, a pyrid-3-yl radical 
substituted in the 5- or 6- position, a pyrid-4-yl radical substituted in 
the 2-position, or a pyrid-2-yl radical substituted in the 4- or 5- 
position, the substituent on R.sup.6 being a radical of the formula III: 
EQU R.sup.7 R.sup.8 N--(CH.sub.2).sub.m -- III 
in which R.sup.7 and R.sup.8 are 1-4C alkyl radicals or R.sup.7 and R.sup.8 
are joined to form, together with the nitrogen atom to which they are 
attached, a pyrrolidine, piperidine or morpholine ring and m is 1 to 4: 
and the pharmaceutically-acceptable acid-addition salts thereof. 
It is to be understood that, in the above formula I and throughout this 
specification, although the double bonds in both groups attached to ring X 
have been inserted in particular positions, other tautomeric forms are 
possible, and this invention includes such tautomeric forms within its 
scope, both in terms of the compounds of the invention and in terms of the 
manufacturing processes. Similarly, when R.sup.2 and R.sup.4 are joined to 
form a heterocyclic ring which is substituted by a hydroxy radical,that 
radical may exist in the tautomeric keto form. It is also to be understood 
that when A is or contains a cycloalkylene radical the groups attached to 
this radical may be in the cis or trans configuration. When A is or 
contains a cycloalkylene radical and/or when A is an alkylene chain 
substituted by one or two alkyl radicals, the compound of the formula I 
will, in most instances, contain at least one asymmetric centre. In such 
cases the compound of the formula I will therefore exist in at least two 
enantiomeric forms, the precise number being determined by the number of 
asymmetric centres. The biological activity, as hereinafter defined, of 
these enantiomeric forms may differ, and it is therefore to be understood 
that this invention encompasses the racemate of the formula I, including 
any possible diastereoisomeric forms, and any enantiomeric form which 
possesses the disclosed biological activity, it being a matter of common 
general knowledge to one skilled in the art how to separate 
diastereoisomeric forms and how to separate a racemate into its 
enantiomers and determine the biological activity of each. 
A particular value for R.sup.1 is a hydrogen atom or a methyl, ethyl, 
propyl, isopropyl, butyl, cyclohexyl, cyclohexylmethyl, allyl, propargyl, 
acetyl, phenyl, benzyl or benzoyl radical, the phenyl, benzyl and benzoyl 
radicals being optionally substituted on the benzene ring by one or two 
substituents selected from fluorine, chlorine and bromine atoms and 
methyl, methoxy, methylthio, trifluoromethyl, hydroxy and amino radicals. 
A particular value for the optional substituent on ring X is one or two 
substituents selected from fluorine, chlorine and bromine atoms and 
methyl, methoxy, trifluoromethyl, hydroxy and amino radicals. 
A particular value for --A-- is a phenylene, cyclopentylene, cyclohexylene, 
trimethylene, tetramethylene, pentamethylene, thioethylene, 
thiotrimethylene, thiotetramethylene, thiopentamethylene, oxyethylene, 
oxytrimethylene, oxytetramethylene, methylenethiomethylene, 
methylenethioethylene, methylenethiopropylene, methyleneoxymethylene, 
methyleneoxyethylene, ethyleneoxyethylene, oxy-2-methylethylene, 
thiopropylenethiomethylene, oxypropyleneoxy, oxyethyleneoxymethylene, 
oxyethylenethio, oxypropylenethio, iminoethylene, iminopropylene, 
vinylenepropylene, oxymethylenevinylene, 1,3-phenylene, 
1,3-cyclopentylene, methylene-1,4-phenylene, 
ethyleneoxymethylene-1,4-phenylene, oxy-1,3-phenylenemethylene or 
thiomethylene-ethynylenemethylene radical. These values for --A-- are 
written reading from left to right in formula I such that the first named 
part of the radical is attached to ring X and the last named part of the 
radical is attached to C(R.sup.3).dbd.NR.sup.2. Thus, for example, when 
--A-- is a thiotrimethylene radical, the compound of the formula I 
contains the part structure IV: 
##STR4## 
A particular value for R.sup.2 is a hydrogen atom or a methyl, cyclohexyl, 
cyclobutylmethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-aminoethyl, 
2-methylaminoethyl, 2-dimethylaminoethyl, 2-carboxyethyl, acetyl, benzoyl, 
phenyl, benzyl, allyl, propargyl, trifluoroacetyl, thioacetyl, 
thiobenzoyl, cyano, carbamoyl, thiocarbamoyl, methylcarbamoyl, 
dimethylcarbamoyl, methylthiocarbamoyl, dimethylthiocarbamoyl, carboxy, 
methoxycarbonyl, methoxythiocarbonyl, oxamoyl, sulphamoyl, 
methylsulphamoyl, dimethylsulphamoyl, phenylsulphamoyl, benzylsulphamoyl, 
methanesulphonyl, benzenesulphonyl, hydroxy, methoxy, amino, methylamino, 
dimethylamino, phenylamino, methoxycarbonylamino, phenoxycarbonylamino, 
acetylamino, benzoylamino, thioacetylamino, thiobenzoylamino, 
heteroarylcarbonylamino, heteroarylacetylamino, methanesulphonylamino, 
benzenesulphonylamino, ureido, thioureido, oxamoylamino, heteroaryl or 
heteroarylmethyl radical wherein the heteroaryl part is a furyl, thienyl, 
pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, 
triazolyl, pyrazolyl, pyridyl or pyrimidyl radical which is optionally 
substituted by one or two substituents selected from methyl and amino 
radicals. 
A particular value for R.sup.3 is a radical of the formula NHR.sup.4 in 
which R.sup.4 is a hydrogen atom or a methyl, allyl, propargyl, cyano, 
acetyl, carbamoyl, methylcarbamoyl or acetylamino radical. A further 
particular value for R.sup.3 is a carboxy radical when R.sup.2 is a 
hydrogen atom or a methyl, allyl or propargyl radical. 
A particular value for the ring system formed when R.sup.2 and R.sup.4 are 
joined is an imidazole, imidazoline, triazole, pyrimidine, oxadiazole, 
thiadiazole, 1,3,5-triazine, 1,2,4-triazine, benzimidazole, quinazoline or 
purine (linked through the 2- or 8- position) ring system each of which 
ring systems may, where possible, carry one, two or three optional 
substituents selected from fluorine, chlorine and bromine atoms and 
methyl, ethyl, propyl, butyl, methoxy, methylthio, trifluoromethyl, 
hydroxy, amino, phenyl, benzyl, carboxymethyl, methoxycarbonyl, 
methoxycarbonylmethyl, hydroxymethyl, furyl, thienyl, pyrrolyl, thiazolyl, 
oxazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyrazolyl and 
pyrimidyl radicals and heteroarylmethyl and 2-heteroarylethyl radicals in 
which the heteroaryl part is a furyl, thienyl, pyrrolyl, thiazolyl, 
oxazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyrazolyl, 
pyridyl or pyrimidyl radical, each optionally substituted by one or two 
substituents selected from methyl and amino radicals. 
A further particular value for the ring formed when R.sup.2 and R.sup.4 are 
joined is a ring of the formula II given above in which R.sup.5 is a 
hydrogen atom or a methyl radical and R.sup.6 is a furan-2-yl or 
thien-2-yl radical substituted in the 5-position, a phenyl radical 
substituted in the 3- or 4- position, a pyrid-3-yl radical substituted in 
the 5- or 6-position, a pyrid-4-yl radical substituted in the 2-position 
or a pyrid-2-yl radical substituted in the 4- or 5-position, the 
substituent on R.sup.6 being a radical of the formula III given above in 
which R.sup.7 and R.sup.8 are methyl radicals or are joined to form, 
together with the nitrogen atom to which they are attached, a pyrrolidine, 
piperidine or morpholine ring and m is 1 to 4, preferably 1. 
The following are eight preferred features of the guanidine derivative of 
the formula I. When any one of these features is taken, either singly or 
in combination, with the other general or particular features of the 
guanidine derivative of the formula I listed above,there are obtained 
preferred sub-groups of compounds within the above general definition. 
1. R.sup.2 is a cyano radical and R.sup.3 is a radical of the formula 
NHR.sup.4 in which R.sup.4 is a hydrogen atom. 
2. R.sup.2 and R.sup.4 are joined to form an optionally-substituted 
imidazole, triazole or pyrimidine ring. 
3. R.sup.2 and R.sup.4 are joined to form an unsubstituted imidazole ring, 
a triazole ring substituted in the 5-position by a 1-6C alkyl radical or a 
pyrimidine ring substituted in the 4-position by a hydroxy radical and in 
the 5-position by a 1-6C alkyl radical. 
4. R.sup.2 and R.sup.4 are joined to form a triazole ring substituted in 
the 5-position by a methyl radical or a pyrimidine ring substituted in the 
4-position by a hydroxy radical and in the 5-position by a methyl or ethyl 
radical. 
5. R.sup.1 is an ethyl or propyl radical. 
6. Ring X carries no optional substituent. 
7. Ring X is a 1,2,3-triazole, or pyrimidine in which A is linked at the 
2-position, ring. 
8. --A-- is a tetramethylene or thiotrimethylene radical. 
Specific compounds of the invention are described in the Examples. The 
following is a preferred group of compounds: 
N-cyano-4-(4-[2-propylguanidino]pyrimid-2-ylthio)butanamidine (Example 1); 
N-cyano-5-(4-[2-propylguanidino]pyrimid-2-yl)valeramidine (Example 2); 
5-methyl-3-(3-[4-(2-propylguanidino)pyrimid-2-ylthio]propyl)-1,2,4-triazole 
(Example 4); 
2-[4-(4-[2-propylguanidino]pyrimid-2-yl)butyl]-5-ethyl4-hydroxypyrimidine 
(Example 5); 
2-[4-(4-[2-propylguanidino]pyrimid-2-yl)butyl]-5-methyl-4-hydroxypyrimidine 
(Example 6); 
3-methyl-5-(4-[4-(2-ethylguanidino)-1,2,3-triazol-2-yl]butyl)-1,2,4-triazol 
e (Example 10); 
and the pharmaceutically-acceptable acid-addition salts thereof. 
Of this group the compounds of Examples 1 and 4 are particularly preferred. 
A suitable pharmaceutically-acceptable acid-addition salt of the guanidine 
derivative of the invention is, for example, a salt formed with 
hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, citric or maleic 
acid. 
The guanidine derivative of the invention may be manufactured by methods in 
which the actual chemical reactions involved are known in themselves. The 
following processes, R.sup.1, R.sup.2, R.sup.3, A and ring X having the 
meanings stated above, unless indicated otherwise, are therefore provided 
as further features of the invention. 
The process of the invention is characterised by: 
(a) for those compounds in which R.sup.3 is a radical of the formula 
NHR.sup.4 and R.sup.2 and R.sup.4 are not joined, reaction of a compound 
of the formula V: 
##STR5## 
in which R.sup.9 has one of the values given above for R.sup.2 or R.sup.4 
and R.sup.10 is a displaceable radical with a compound of the formula VI: 
EQU R.sup.11 --NH.sub.2 VI 
in which R.sup.11 has one of the values given above for R.sup.4 or R.sup.2 
respectively. When R.sup.11 is a hydrogen atom, that is the compound of 
the formula VI is ammonia, it is convenient to use it in the form of a 
salt such as ammonium chloride. R.sup.10 may, for example, be a 1-6C 
alkoxy radical, for example a methoxy or ethoxy radical. The reaction may 
be carried out in a diluent or solvent, for example methanol or ethanol. 
The reaction generally proceeds at ambient temperature, but may, in 
certain instances, require acceleration or completion by the application 
of heat, for example by heating to the boiling point of the diluent or 
solvent. 
(b) for those compounds in which R.sup.3 is a radical of the formula 
NHR.sup.4 in which R.sup.2 and R.sup.4 are joined to form a heterocyclic 
ring system, reaction of a compound of the formula VII: 
##STR6## 
in which R.sup.10 is a displaceable radical, with a compound containing a 
2-, 3- or 4-atom chain, two adjacent members of which may be incorporated 
into a 5- or 6-membered carbocyclic or heterocyclic ring, and in which the 
chain is functionalised in such a way that a cyclised amidine is formed. 
R.sup.10 may, for example be an amino or 1-6C alkoxy, for example methoxy 
or ethoxy, radical. The following examples illustrate this general 
reaction for specific ring systems. When the ring to be formed is an 
optionally-substituted imidazole ring, the compound of the formula VII in 
which R.sup.10 is a displaceable radical is reacted with a compound of the 
formula VIII: 
##STR7## 
in which R.sup.11, R.sup.12 and R.sup.13 are hydrogen atoms or the 
optional substituents on the heterocyclic ring system and R.sup.14 and 
R.sup.15 are 1-6C alkyl, for example methyl or ethyl, radicals, or 
R.sup.14 and R.sup.15 are joined to form an ethylene or propylene radical. 
When the ring to be formed is an optionally-substituted 1-imidazoline 
ring, the compound of the formula VII in which R.sup.10 is a displaceable 
radical is reacted with a compound of the formula IX: 
EQU HNR.sup.11 --CHR.sup.12 --CHR.sup.13 --NH.sub.2 IX 
in which R.sup.11, R.sup.12 and R.sup.13 have the meanings given above. 
When the ring to be formed is an optionally substituted pyrimidine ring 
which carries a hydroxy radical in the 4-position, the compound of the 
formula VII in which R.sup.10 is an amino radical is reacted with a 
compound of the formula X: 
EQU R.sup.14 OCO--CHR.sup.12 --CO--R.sup.13 X 
in which R.sup.12, R.sup.13 and R.sup.14 have the meanings given above, for 
example as illustrated in Examples 5 and 6. When the ring to be formed is 
a pyrimidine ring which carries an amino radical in the 4-position, the 
compound of the formula VII in which R.sup.10 is an amino radical is 
reacted with 2-chloroacrylonitrile. The process of the invention may be 
conducted in a diluent or solvent, such as methanol or ethanol, and be 
accelerated or completed by the application of neat, for example by 
heating to the boiling point of the diluent or solvent. When using the 
compound of the formula VIII the reaction may conveniently be conducted in 
two stages, the second stage being initiated by the addition of a mineral 
acid, for example HCl. When using 2-chloroacrylonitrile as starting 
material, the reaction may be conducted in the presence of triethylamine. 
(c) for those compounds in which R.sup.3 is a radical of the formula 
NHR.sup.4 in which R.sup.2 and R.sup.4 are joined to form a 1,2,4-triazole 
ring substituted in the 5-position by an alkyl, trifluoromethyl, hydroxy, 
aryl, arylalkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, 
heteroarylalkyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imdazolyl, 
thiadiazolyl, oxadiazolyl, triazolyl, pyrazolyl or pyrimidyl radical, 
cyclisation of a compound of the formula XI: 
##STR8## 
in which R.sup.16 is a 1-6C alkyl, trifluoromethyl, hydroxy, 1-6C alkoxy, 
6-10C aryl, 7-11C arylalkyl, 2-6C carboxyalkyl, 2-6C alkoxycarbonyl, 3-10C 
alkoxycarbonylalkyl, 1-6C hydroxyalkyl, heteroaryl-(1-6C) alkyl, furyl, 
thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, 
oxadiazolyl, triazolyl, pyrazolyl or midyl radical. The process may be 
carried out by heating the compound of the formula XI in the absence of a 
diluent or solvent, for example at a temperature of between 50.degree. and 
200.degree. C. Alternatively, the process may be conducted in a diluent or 
solvent, for example ethanol, at the boiling point of the diluent or 
solvent. 
(d) for those compounds in which R.sup.2 is a carbamoyl radical, hydrolysis 
of the corresponding compound in which R.sup.2 is a cyano radical. The 
process may, for example, be carried out in an alcoholic diluent or 
solvent such as methanol or ethanol, or mixtures of these with chloroform, 
containing dissolved HCl gas, and in the presence of at least one 
equivalent of water. 
(e) for those compounds in which the group inserted into A is an oxygen or 
sulphur atom or an NH or N-alkyl radical, reaction of a compound of the 
formula XII or XIII: 
##STR9## 
with a compound of the formula XIV or XV respectively: 
##STR10## 
in which G is an oxygen or sulphur atom or an NH or N-alkyl radical, 
R.sup.10 is a displaceable radical and A.sup.1 and A.sup.2 are fragments 
of A, including direct bonds, and are such that A.sup.1 --G--A.sup.2 falls 
within the general definition of A given above. R.sup.10 is, for example, 
a halogen atom, for example a chlorine, bromine or iodine atom. When 
R.sup.10 is directly attached to ring X, R.sup.10 may, for example, be a 
methylsulphinyl or methylsulphonyl radical. The process may be conducted 
in a diluent or solvent, for example t-butanol, and the reaction may be 
accelerated or completed by the application of heat, for example by 
heating to the boiling point of the diluent or solvent. When G is an 
oxygen or sulphur atom it is advantageous to conduct the reaction in the 
presence of a base. When the diluent or solvent is t-butanol, the base may 
be sodium t-butoxide. 
(f) for those compounds in which R.sup.3 is a radical of the formula 
NHR.sup.4 in which R.sup.4 is a hydrogen atom, reaction of a compound of 
the formula XVI: 
##STR11## 
with a compound of the formula XVII: 
EQU R.sup.2 --NH.sub.2 XVII 
The reaction may be conducted in a diluent or solvent, for example 
n-propanol or t-butanol,and may be accelerated or completed by the 
application of heat, for example by heating to the boiling point of the 
diluent or solvent. 
(g) for those compounds in which Z is a nitrogen atom, reaction of a 
compound of the formula XVIII: 
##STR12## 
with a compound of the formula XIX: 
##STR13## 
in which R.sup.10 is a displaceable radical. R.sup.10 is, for example, a 
halogen atom, for example a chlorine, bromine or iodine atom. 
(h) construction of the guanidine radical attached to ring X by reaction of 
the appropriate thiourea, or a 1-6C S-alkyl (e.g. S-methyl) or S-benzyl 
derivative thereof, or a salt of such a derivative, with the appropriate 
amine. The guanidine radical in the compound of the formula I contains 
three nitrogen atoms, each of whicn carries different substituents. The 
appropriate amine for use in this reaction may therefore be ammonia, an 
amine of the formula R.sup.1 NH.sub.2 or an amine of the formula XX: 
##STR14## 
The reaction may be conducted in a diluent or solvent such as methanol or 
ethanol. In many cases it is advantageous to use a catalyst such as lead 
oxide, mercuric oxide or sodium hypochlorite. The reaction may be 
conducted at ambient temperature or it may be accelerated or completed by 
the application of heat, for example by heating to the boiling point of 
the diluent or solvent. 
(i) construction of the guanidine radical attached to ring X by reaction of 
the appropriate cyanamide with the appropriate amine. Since the guanidine 
radical in the compound of the formula I contains only one unsubstituted 
nitrogen atom there are two appropriate amines, namely the amine of the 
formula R.sup.1 NH.sub.2 or of the formula XX given above. 
(j) for those compounds in which R.sup.3 is a radical of the formula 
NHR.sup.4 in which R.sup.2 and R.sup.4 are joined to form a 1,2,4-triazole 
ring substituted in the 5-position by an amino or hydroxy radical, br a 
1,3,5-triazine ring substituted in the 4-position by an amino or hydroxy 
radical and in the 6-position by a hydrogen atom or an alkyl, 
trifluoromethyl, aryl, arylalkyl, alkoxycarbonylalkyl, hydroxyalkyl, 
heteroarylalkyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, 
imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyrazolyl, or pyrimidyl 
radical, reaction of a compound of the formula XXI: 
##STR15## 
in which R.sup.10 is a displaceable radical with hydrazine or with a 
compound of the formula XXII: 
##STR16## 
respectively in which R.sup.17 is a hydrogen atom or a 1-6C alkyl, 
trifluoromethyl, 6-10C aryl, 7-11C arylalkyl, 2-6C alkoxycarbonylalkyl, 
1-6C hydroxyalkyl, heteroaryl-(1-6C)alkyl, furyl, thienyl, pyrrolyl, 
thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, 
pyrazolyl or pyrimidyl radical, whereafter, if desired, the amino radical 
on the 1,2,4-triazole or 1,3,5-triazine ring so formed is transformed to a 
hydroxy radical by standard methods. R.sup.10 may, for example, be a 1-6C 
alkoxy radical, for example a methoxy radical. The subsequent 
transformation of amino radical to hydroxy radical may be carried out, for 
example, by hydrolysis or by diazotisation followed by hydrolysis. 
(k) for those compounds in which ring X is a thiazole ring, reaction of a 
compound of the formula XXIII: 
##STR17## 
with a compound of the formula XXIV: 
##STR18## 
in which Hal is a chlorine or bromine atom and R.sup.18 is a hydrogen atom 
or the optional substituent on the thiazole ring. The reaction may be 
conducted in a diluent or solvent such as acetone and may be accelerated 
or completed by the application of heat, for example by heating to the 
boiling point of the diluent or solvent. 
When the process of the invention manufactures the compound of the formula 
I in the form of the free base and an acid-addition salt is required, the 
compound of the formula I in the free base form is reacted with an acid 
which affords a pharmaceutically-acceptable anion. 
A critical intermediate for preparing the starting materials for several of 
the processes of the invention is the starting material of the formula XVI 
for use in process (f). This starting material may be prepared by separate 
construction of the two side chains on the appropriate ring X. Thus the 
left hand side chain may be constructed by reduction of a nitro group to 
an amino group, reaction of this amino group with an isothiocyanate of the 
formula R.sup.1 N.dbd.C.dbd.S. and finally reaction of the resulting 
thiourea with ammonia in the presence of mercuric oxide. The method of 
construction of the right hand side chain may vary depending on the nature 
of ring X, the nature of the atom in ring X to which A is attached (carbon 
or nitrogen) and the presence or absence of inserted atoms or groups in 
chain A. When A contains no inserted group, or the inserted group is a 
phenylene radical and Z is a carbon atom, it is preferable to construct 
ring X with the right hand side chain already in place. Thus, for example, 
when ring X is a pyrimidine ring, it may be formed by reaction of a 
suitably substituted amidine with 2-chloroacrylonitrile to give the 
corresponding 4-aminopyrimidine derivative. When the inserted group in A 
is a cycloalkylene radical, the chain A may be constructed by a conjugate 
addition to the corresponding cycloalk-2-enone. When the inserted group in 
A is a vinylene or ethynylene radical, A may be introduced by formation of 
the double or triple bond by standard coupling methods. When the inserted 
group in A is an oxygen or sulphur atom or an NH or N-alkyl radical, the 
right hand side chain may be built up by a method similar to that in 
process (e), for example as illustrated in Example 1. When Z is a nitrogen 
atom, the right hand chain may be formed by a method similar to that in 
process (g), for example as illustrated in Example 7. 
The starting material of the formula V for use in process (a) in which 
R.sup.9 is a hydrogen atom and R.sup.10 is an alkoxy radical, or of the 
formula VII for use in process (b) in which R.sup.10 is an alkoxy radical, 
may be prepared from the starting material of the formula XVI by treatment 
with anhydrous HCl in a diluent or solvent of the formula R.sup.10 --OH, 
for example as illustrated in Examples 1, 2, 7, 8 and 9. 
The starting material of the formula XI for use in process (c) may be 
prepared from the starting material of the formula VII in which R.sup.10 
is a displaceable radical by reaction with a compound of the formula XXV: 
EQU H.sub.2 NNHCOR.sup.16 XXV 
The starting material of the formula XII or XIII for use in process (e) and 
the starting material of the formula XIII for use in process (g) may be 
prepared by construction of the substituted guanidine radical on a 
suitably- substituted ring X. 
The starting material of the formula XX for use in process (h) or (i) may 
be prepared by the methods described above for the preparation of 
compounds of the formula V or VII in which the right hand chain is 
constructed first, followed by use of one of the processes (a) or (b). 
The cyanamide corresponding to the amine of the formula XX for use in 
process (i) may be prepared by reaction of the compound of the formula XX 
with cyanogen bromide. 
The starting material of the formula XXI for use in process (j) may be 
prepared by reaction of the compound of the formula V in which R.sup.9 is 
a hydrogen atom and the nitrogen to which it is attached is in the 
protonated form with cyanamide. 
As noted above, the guanidine derivative of the invention is a histamine 
H-2 antagonist, inhibits the secretion of gastric acid in warm-blooded 
animals and is therefore useful in the treatment of peptic ulcers and 
other conditions caused or exacerbated by gastric acidity, including 
stress ulcers and gastrointestinal bleeding due to trauma. 
The histamine H-2 antagonist activity may be demonstrated on standard 
tests, for example by the ability of the compound of the formula I to 
inhibit the histamine-induced uptake of aminopyrine into the acid space of 
parietal cells. 
The test is carried out as follows: 
Gastric mucosa from the New Zealand white rabbit is removed from the 
underlying muscle and washed in Buffer 1 [containing per liter NaCl; 
(8.007 g.), KCl (0.201 g.), Na.sub.2 HPO.sub.4 (0.113 g.), KH.sub.2 
PO.sub.4 (0.204 g.), CaCl.sub.2.2H.sub.2 O (0.132 g.), MgCl.sub.2 (0.101 
g.) and glucose (1 g.), adjusted to pH 7.4 with NaOH]. The tissue is 
finely chopped, suspended in Buffer 1 and washed three times with Buffer 
1. The tissue is then suspended in dispersion medium collagenase (Sigma 
Chemical Co., Type V; 100 mg.) and bovine serum albumin (Miles 
Laboratories Ltd., Fraction V; 100 mg.) in Buffer 1 (100 ml.); 50 ml. per 
10 g. net weight of tissue]and incubated at 30.degree. C. and pH 7.4 
(maintained by continuous monitoring) with stirring under an oxygen 
atmosphere. After 30 minutes the tissue is allowed to settle and the 
supernatant liquid is removed. Fresh dispersion medium (50 ml. per 10 g. 
wet weight of tissue) is added and incubation is continued with the tissue 
being largely dispersed into glands and whole cells after 40-60 minutes. 
Any remaining large pieces of tissue are removed by filtration through 
nylon mesh. The mixture of glands and cells is collected by centrifugation 
at 200 x g. and suspended in Buffer 1 containing 1% bovine serum albumin 
(Miles Laboratories Ltd., Fraction V). Finally the cells and glands are 
washed 3 times with Buffer 1 and suspended in Buffer 2 [containing Eagles 
MEM (500 ml.), Aprotinin (Sigma Chemical Co., 10 mg.) and HEPES 
(2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulphonic acid; 150 mM., 20 
ml.) adjusted to pH 7.4 with NaOH; 150 ml. per 10 g. net weight of 
tissue]. The tissue suspension is stirred under an oxygen atmosphere at 
32.degree. C. for at least 1 hour before use. The tissue suspension is 
incubated with the test compound and aminopyrine (10 .mu.M) labelled with 
C.sup.14 on the dimethylamino group (0.1 .mu.Ci/ml.) for 20 minutes. The 
uptake of the aminopyrine is then stimulated by addition of histamine and 
the phosphodiesterase inhibitor ICI 63197 (Biochem. Soc. Special 
Publication 1, 1973, pp 127-132) to final concentrations of 10.sup.-5 M. 
and 5.times.10.sup. -7 M respectively. After 18 minutes the cells/glands 
are separated from the incubation medium by filtration of the suspension 
through glass microfibre filters. The cells/glands are quickly ( &lt;10 
seconds) washed three times with ice-cold Buffer 1. The C.sup.14 
aminopyrine retained by the tissue is measured on a scintillation counter 
and the degree of inhibition of uptake by the test compound is calculated 
by reference to a control sample. The concentration of test compound 
giving 50% inhibition is then calculated graphically from a series of 
tests run at different concentrations. 
All the compounds exemplified in this specification gave a 50% inhibition 
of uptake of aminopyrine at or below a concentration of 3 .mu.M. 
The inhibition of the secretion of gastric acid may be demonstrated in 
standard tests, for example by the ability of the compound of the formula 
I, when dosed intravenously, intragastrically or orally, to inhibit the 
secretion of acidic gastric juice in, for example, rats,or dogs provided 
with denervated fundic pouches, and whose gastric secretion is stimulated 
by administration of a secretagogue, for example histamine, pentagastrin, 
bethanechol or food. 
The test in rats is carried out as follows: 
Female rats (200-230 g.) are anesthetized by intramuscular administration 
of urethane (1.5 g/kg.) anc the trachea cannulated. A soft tuue is passed 
down tne oesophagus into the stom.ach and secured by a tie in the neck 
region. A multi-orifice plastic tube (3 mm. diameter) is passed into the 
antral region of the stomach, via an incision in the duodenum, and tied in 
place by means of a ligature around the pylorus. Saline (9 g./1. NaCl) is 
perfuseu through the stomach via the oesophageal cannula at a rate of 7 
ml./minute and collected into beakers from the pyloric outlet over periods 
of 10 minutes. Acid secretion is stimulated by subcutaneous administration 
of the specific h-2 agonist dimaprit in a loading dose of 10 mg./kg. 
followed by an infusion of 30 mg./kg./hour. Acid output is computed by 
titration of the 10 minute samples to an end point of ph 6.4 with 20 mM. 
NaOH. When secretion has reached a plateau (three consecutive readings 
within 5%) the test compound is administered intravenously via a cannula 
placed in the left external jugular vein. Secretion is then measured for a 
further 2 hours. A stock solution of each test compound is prepared (10 
mg./ml. in DMSO) and appropriate dilution made with saline to enable 
injection in a dose volume of 1 ml./kg. (DMSO &lt;2%). 
The test in dogs provided with denervated fundic pouches is carried out as 
follows: 
Male beage dogs (14-22 kg.) are prepared with vagally denervated pouches of 
the fundic gland area by the method of Rudick et al. (J. Surg. Res. 1967, 
7, 383). The animals are allowed 4-6 weeks to recover from surgery and a 
further period of 2-3 months prior to routine use, to allow for table 
training and standardization of secretory responses. The dogs are starved 
for 23 hours before use water ad lib) and during experiments they are 
lightly restrained in cloth slings. After rinsing the pouch with warm 
water, histamine is infused subcutaneously at a rate of 10 .mu.g./minute. 
This dose of agonist produces a submaximal (60-90% of maximum) increase in 
acid output in all dogs used. Pouch secretions are collected over 15 
minute periods into graduated glass test-tubes and the volume measured to 
the nearest 0.1 ml. A 500 .mu.l sample is diluted with 5 ml. of saline and 
titrated to pH 7.0 with 100 mM.NaOH. Total acid output is computed from 
the product of acid concentration and volume of juice secreted. Compounds 
are administered intravenously (0.1 ml./kg.) via a cephalic vein or orally 
in a gelatin capsule when a secretory plateau (3 consecutive readings 
within 10%) has been attained. Secretion is measured for a period of 3 
hours following administration of test compound. 
The results obtained in the aminopyrine test are predictive of activity in 
the rat and dog tests. 
No overt toxicity or side effects were noted during the rat or dog tests. 
The compounds N-cyano-5-(4-[2-propylguanidino]pyrimid-2-yl)valeramidino 
was administered intravenously to groups of two anaesthetised rats and 
four conscious mice at doses which were respectively ten times and one 
hundred times the dose, in mg./kg., which produced an approximate 50% 
inhibition of gastric secretion in the anaesthetised rat. No toxic 
symptoms were noted in any of the dosed animals. 
A number of compounds exemplified in this specification exhibit inhibition 
of acid secretion which shows little or no decline from peak inhibition 
for several hours. 
The N-methylcyanoguanidine group in known L-2 receptor antagonists is 
potentially changeable into the carcinogenic N-nitroso 
N-methylcyanoguanidine group in the mammalian body (Pool et al., 
Toxicology, 1979, 15, 69). The corresponding group in the compounds of the 
present invention, C(R.sup.3).dbd.NR.sup.2, is resistant to reaction with 
nitrous acid over the pH range 1-4 (Baum et al., J. Chem. Research (S), 
1980, 212-213) when R.sup.4 is NHR.sup.7 and R.sup.3 and R.sup.7 are 
joined to form a triazole, imidazole or 4-hydroxypyrimidine ring. 
According to a further feature of the invention there is provided a 
pharmaceutical composition which comprises a guanidine derivative of the 
invention in association with a non-toxic pharmaceutically-acceptable 
diluent or carrier. 
The pharmaceutical composition may, for example, be in a form suitable for 
oral, rectal, parenteral or topical administration, for which purposes it 
may be formulated by means known to the art into the form of, for example, 
tablets, capsules, aqueous or oily solutions or suspension, emulsions, 
dispersible powders, suppositories, sterile injectable aqueous or oily 
solutions or suspensions, gels, creams, ointments or lotions. 
In addition to the guanidine derivative of the formula I, the 
pharmaceutical composition of the invention for oral, rectal or parenteral 
administration may also contain, or be co-administered with, one or more 
known drugs selected from antacids, for example aluminium hydroxide - 
magnesium hydroxide mixtures; antipepsin compounds, for example pepstatin; 
other histamine H-2 antagonists, for example cimetidine or ranitidine, 
ulcer healing agents, for example carbenoxolone or bismuth salts; 
anti-inflammatory agents, for example ibuprofen, indomethacin, naproxen or 
aspirin, prostaglandins, for example 16,16-dimethylprostaglandin E.sub.2 ; 
classical antihistamines histamine H-1 antagonists), for example 
m.epyramine or diphenhydramine; anticholinergic agents, for example 
atropine or propantheline bromide; anxiolytic agents, for example 
diazepam, chlordiazepoxide or phenobarbital. 
The pharmaceutical composition of the invention for topical administration 
may also contain, in addition to the guanidine derivative, one or more 
classical anti-histamines (histamine H-1 antagonists), for example 
mepyramine or diphenhydramine and/or one or more steroidal 
anti-inflammatory agents, for example fluocinolone or triamcinolone. 
A topical formulation may contain 1-10% w/w of the guanidine derivative of 
the invention. A preferred pharmaceutical composition of the invention is 
one suitable for oral administration in unit dosage form, for example a 
tablet or capsule which contains between 15 mg. and 500 mg. of the 
guanidine derivative, or one suitable for intravenous, subcutaneous or 
intramuscular injection, for example a sterile injectable containing 
between 0.1% and 10% w/w of the guanidine derivative. 
The pharmaceutical composition of the invention will normally be 
administered to man for the treatment of peptic ulcers and other 
conditions caused or exacerbated by gastric acidity in the same general 
manner as that employed for cimetidine, due allowance being made in terms 
of dose levels for the potency and duration of action of the guanidine 
derivative of the present invention relative to cimetidine. Thus each 
patient will receive an oral dose of between15 mg. and 1500 mg., and 
preferably between 20 mg. and 200 mg. of guanidine derivative or an 
intravenous, subcutaneous or intramuscular dose of between 1.5 mg. and 150 
mg., and preferably between 5 mg. and 20 mg. of the guanidine derivative, 
the composition being administered 1 to 4 times per day. The rectal dose 
will be approximately the same as the oral dose. The composition may be 
administered less frequently when it contains an amount of guanidine 
derivative which is a multiple of the amount which is effective when given 
1-4 times per day. 
The invention is illustrated, but not limited, by the following Examples. 
The n.m.r. spectra are quoted in .delta. relative to tetramethylsilane 
(.delta.=O) as internal standard (s=singlet, d=doublet, t=triplet, 
q=quartet, m=multiplet, br=broad). The temperatures are in degrees 
Centigrade. The following contractions are used: 
HOAc=acetic acid 
DMF=dimethyl formamide 
ether=diethyl ether 
DMSO=dimethylsulphoxide 
MeOH=methanol 
EtOH=ethanol 
THF=tetrahydrofuran 
EtOAc=ethyl acetate 
Attention is drawn to the fact that 4-nitrotriazole (Example 7) is an 
explosion hazard.

EXAMPLE 1 
To a mixture of 4-(4-[2-propylguanidino]pyrimid-2-ylthio)butyronitrile (0.8 
g.) in MeOH (7 ml.) and CHCl.sub.3 (7 ml.) at 0.degree. was added dry HCl 
gas until the mixture was saturated. The resulting solution was allowed to 
stand at 0.degree. for 2.5 days and then evaporated to dryness. To the 
residue of the imino-ether was added potassium carbonate (anhydrous, 4 g.) 
and water (10 ml.). The resulting mixture was extracted with CHCl.sub.3 
(3.times.20 ml.) and the CHCl.sub.3 extracts washed with water (5 ml.), 
dried over magnesium sulphate, filtered and evaporated to dryness to give 
a crude sample of the imino-ether (0.60 g.). Without further purification 
the imino-ether (0.30 g.) was added to a mixture of cyanamide (0.04 g.) 
and MeOH (5 ml.) and the mixture stirred at room temperature for 2.5 
hours, then evaporated to dryness. The residue was triturated with MeOH (5 
ml.) and filtered to give N-cyano-4-(4 -[2 
propylguanidino]pyrimid-2-ylthio)butanamidine (0.23 g.) as a white 
crystalline solid, m.p. 210.degree.-215.degree.. 
The starting material may be obtained as follows: 
4-Chlorobutyronitrile (0.23 g.) in EtOH (2 ml.) was added to a solution of 
2-thiocytosine (0.25 g.) in 0.5N aqueous NaOH (5 ml.) and the mixture 
stirred for 18 hours. A further portion of 4-chlorobutyronitrile (0.23 g.) 
was added and the mixture stirred a further 24 hours. The solution was 
concentrated in vacuo to 2 ml. and cooled and the crystalline precipitate 
collected to give 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.3 g.), m.p. 
99.degree.-100.degree.. 
A mixture of 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.75 g.), 
propylisothiocyanate (0.8 g.) and pyridine (5 ml.) was heated at 
130.degree. for 2 hours and then heated under reflux for 18 hours. The 
solvent was removed by evaporation in vacuo and the residual oil was 
purified by medium pressure chromatography on silica using CHCl.sub.3 
/MeOH 9.75:0.25 v/v as eluant. A portion of the purified product (0.3 g.) 
and EtOH (5 ml.) was added to EtOH saturated with ammonia (10 ml.) and 
mercuric oxide (0.22 g.). After 15 minutes the reaction mixture was 
filtered through diatomaceous earth and the filtrate was evaporated to 
give a white semi-crystalline solid which was purified by medium pressure 
chromatography on silica using CHCl.sub.3 /MeOH/aqueous ammonia (s.g. 
0.880) 9:1:0.1 v/v/v as eluant. There was thus obtained 
4-(4-[2-propylguanidine pyrimid-2-ylthio)butyronitrile (0.18 g.) which was 
used without further purification. 
EXAMPLE 2 
To a mixture of 5-(4-[2 propylguanidino]pyrimid-2-yl)valeronitrile (0.60 
g.) in MeOH (5 ml.) and CHCl.sub.3 (5 ml.) at 0.degree. was added dry HCl 
gas until the mixture was saturated. The resulting solution was allowed to 
stand at Oo for 2.5 days and then evaporated to dryness. The residue was 
taken up in a mixture of anhydrous potassium carbonate (3 g.) and water 
(10 ml.) and extracted with CHCl.sub.3 (3.times.15 ml.). The CHCl.sub.3 
extracts were combined, washed with water (5 ml.) dried over magnesium 
sulphate, filtered and evaporated to dryness. To the residual imino-ether 
(0.25 g.) was added MeOH (5 ml.) and cyanamide (0.04 g.) and the mixture 
was stirred at room temperature for 3 hours, then evaporated to dryness 
and the residue purified by medium pressure (20-40 lb/in.sup.2) liquid 
chromatography on silica using CHCl.sub.3 /MeOH/aqueous ammonia (s.g. 
0.880) 9:1:0.1 v/v/v as eluant to give N-cyano-5 
-(4-[2-n-propylguanidino]pyrimid-2-yl-valeramidine (0.20 g.) as a white 
cyrstalline solid, m.p. 202.degree.-205.degree.. 
The starting material may be prepared as follows: 
A mixture of 2-(4-cyanobutyl)-4-aminopyrimidine (1.2 g.) and 
propylisothiocyanate (0.9 g.) was heated under reflux in pyridine (3 ml.) 
for 22 hours. The mixture was then evaporated to dryness and the residue 
purified by medium pressure chromatography using CHCl.sub.3 /MeOH/aqueous 
ammonia (s.g. 0.880) 19:1:0.05 v/v/v as eluant. The appropriate fraction 
was evaporated to dryness and the residue treated in concentrated 
ethanolic ammonia with mercuric oxide (2.2 g.). After 1 hour the mixture 
was filtered and the filtrate evaporated to dryness. Recrystallisation of 
the residue from acetone/petroleum ether (b.p. 60.degree.-80.degree.) gave 
0.8 g. of 5-(4-[2-propylguanidino]pyrimid-2-yl)valeronitrile which was 
used without further purification. 
EXAMPLE 3 
To a solution of 
1-imino-1-methoxy-4-(4-[2-propylguanidino)pyrimid-2-ylthio)butane (0.41 
g.) in MeOH (8 ml.) was added acethydrazide (0.136 g.) in one portion. The 
reaction mixture was stirred at room temperature for 3 hours and the 
solution was evaporated to dryness. The residue was triturated with ether 
and acetonitrile to give 
N-acetyl-4-(4-[2-propylguanidino]pyrimid-2-ylthio)butyramidrazone as a 
white solid (0.307 g.), m.p. 179.degree.-181.degree.. 
EXAMPLE 4 
N-Acetyl-4-(4-[2-n-propylguanidino]pyrimid-2-ylthio)butyramidrazone (0.25 
g.) was heated in an oil bath at 190.degree. for 10 minutes. The resulting 
glass was purified by medium pressure chromatography using 
EtOAc/MeOH/aqueous ammonia (s.g. 0.880) 6:1:0.5 v/v/v as eluant. The main 
peak was dissolved in acetone and added to an acetone solution of maleic 
acid (0.15 g.). The precipitate was collected and washed with acetone to 
give 
5-methyl-3-(3-[4-(2-propylguanidino)pyrimid-2-ylthio]propyl-1,2,4-triazole 
dimaleate (0.(825 g.), m.p. 150.degree.-153.degree.. 
EXAMPLE 5 
A mixture of 5-(4-[2-propylguanidino]pyrimid-2-yl)valeramidine 
hydrochloride (0.4 g.) and the sodium salt of ethyl 2-formylbutyrate (1.5 
g.) in MeOH (5 ml.) was heated under reflux for 4 hours. The solvent was 
evaporated in vacuo and the residue was partitioned between water (pH 7) 
and EtOAc. The EtOAc layer was separated, dried (MgSO.sub.4) and 
evaporated in vacuo to give 
2-[4-(4-(2-propylguanidino]pyrimid-2-yl)butyl]-5-ethyl-4-hydroxypyrimidine 
as an oil (0.13 g.) which was characterised by conversion to the bis 
hydrogen maleate salt (0.11 g.), m.p. 140.degree.-142.degree.. 
The starting material may be prepared as follows: 
A mixture of methyl 5-(4-[2-propylguanidino]pyrimid-2-yl)valerimidate (0.4 
g.) and ammonium chloride (0.076 g.) in MeOH (20 ml.) was stirred at 
ambient temperature for 1 hour and the solvent evaporated in vacuo to give 
5-(4-[2-propylguanidino]pyrimid-2-yl)valeramidine hydrochloride (0.4 g.) 
as an oil which was used without further purification. 
EXAMPLE 6 
The process of Example 5 was repeated using ethyl 2-formylpropionate in 
place of ethyl 2-formylbutyrate to give 
2-[4-[4-[2-propylguanidino]pyrimid2-yl)butyl]-5-methyl-4-hydroxypyrimidine 
, m.p. 213.degree.-215.degree. (yield 15%). 
EXAMPLE 7 
Crude N-acetylamino-5-[4-(2-methylguanidino)1,2,3-triazol-2-yl]valeramidine 
(0.54 g.) in EtOH (15 ml.) was heated under reflux for 18 hours. The 
solvent was evaporated and the residue converted to the maleate salt in 
acetone to give 
3-methyl-5-(4-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]butyl)-1,2,4-triaz 
ole dihydrogen maleate as a white solid (0.454 g.), m.p. 
143.degree.-145.degree. (yield 49%). 
The starting material may be prepared as folllows: 
A stirred solution of 4-nitro-1,2,3-triazole (23.0 g.) in dry DMF (135 ml.) 
was treated at room temperature with a dispersion of sodium hydride [4.8 
g.) in mineral oil (4.8 g.). The mixture was stirred for 30 minutes then 
treated with 5-bromovaleronitrile (33.0 g.). The mixture was stirred 
overnight at room temperature then poured into water. The product was 
extracted into EtOAc and purified by column chromatography on silica gel 
(1 kg.) eluted with EtOAc/petroleum ether (b.p. 60.degree.-80.degree.) 1:1 
v/v to give 22.3 g. of 5-(4-nitro-1,2,3-triazol-2-yl)valeronitrile as an 
oil. 
A suspension of palladium on charcoal (5% w/w; 0.5 g.) in a solution of 
5-(4-nitro-1,2,3-triazol-2-yl)valeronitrile (1.0 g.) in HOAc (20 ml.) was 
stirred under one atmosphere of hydrogen until 420 ml. of hydrogen had 
been absorbed. The mixture was filtered and evaporated to give 0.85 g. of 
5-(4-amino-1,2,3-triazol-2-yl)valeronitrile as an oil. 
A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (1.65 g.) in 
acetonitrile (5 ml.) and methylisothiocyanate (0.73 g.) was stirred for 18 
hours at ambient temperature and then heated under reflux for 6 hours. The 
solvent was evaporated and the residue was triturated with ether/EtOH to 
give 5-[4-(3-methylthioureido)-1,2,3-triazol-2-yl]valeronitrile as a white 
solid. 
A solution of 5-[4-(3-methylthioureido)1,2,3-triazol-2-yl]valeronitrile in 
methanolic ammonia (6M; 15 ml.) was treated with mercuric oxide (1.1 g.) 
and tne mLxture stirred for 3 hours at room temperature. The resulting 
suspension was filtered through diatomaceous earth and the filtrate 
evaporated to give 
5-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeronitrile as a yellow oil. 
A solution of 5-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeronitrile 
(0.8 g.) in a mixture of chloroform (15 ml.) and MeOH (5 ml.) was 
saturated at 0.degree. with hydrogen chloride gas and the mixture 
maintained at 0.degree. for 3 days. The mixture was evaporated to dryness 
and the residue basified with cold sodium carbonate solution and extracted 
witn chloroform. The extract was dried and evaporated to give methyl 
5-[4-(2-methylguanidino)1,2,3-triazol-2-yl]valerimidate as a yellow oil 
(1.07 g.). 
Methyl 5-[4-[2-methylguanidino)-1,2,3-triazol2-yl]valerimidate (1.0 g.) in 
MeOH (12 ml.) was treated with acethydrazide (0.22 g.) and the solution 
stirred for 18 nours. Evaporation of the solvent and trituration of the 
resioue with ether/EtOH gave 
N-acetylamino-5[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeramidine as a 
yellow sticky solid [0.54 g.) which was used without further purification. 
EXAMPLE 8 
Crude methyl 5-(4-guanidino-1,2,3-triazol-2-yl)valerimidate hydrochloride 
(0.42 g.) in MeOH (8 ml.) was treated with triethylamine (0.35 g.) 
followed after 0.5 hours by acethydrazide (0.13 g.). After a further 0.5 
hours the solution was heated under reflux for 6 hours then evaporated to 
dryness. The residue was purified by medium pressure chromatography using 
chloroform/MeOH/aqueous ammonia (s.g. 0.880) 8:2:0.1 v/v/v as eluant to 
give a gum which was converted to the fumarate in MeOH. The solid was 
filtered and washed with warm MeOH to give 
3-methyl-5-[4-(4-guanidino-1,2,3-triazol-2-yl)butyl]-1,2,4-triazole 
fumarate (yield 19%) having the following n.m.r. in d.sub.6 DMSO:- 1.4-2.1 
(m, 4H); 2.15 (s, 3H); 2.61 (t, 2H); 4.4 (t, 2H); 6.68 (s, 1H); 7.08 (s, 
1H); 7.26 (br s, 4H). 
The starting material may be prepared as follows: 
A solution 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile hydrochloride (2.01 
g.) in EtOH (15 ml.) was treated with cyanamide (0.42 g.) and the solution 
heated under reflux for 4.5 hours. A further 0.1 g. of cyanamide was added 
and heating under reflux was continued for 2 hours. The solution was 
evaporated and the residue basified with ammonia and continuously 
extracted for 24 hours with EtOAc to give a yellow oil which was purified 
by medium pressure chromatography using chloroform/MeOH/aqueous ammonia 
(s.g. 0.880) 8:2:0.1 v/v/v as eluant to give 
5-(4-guanidino-1,2,3-triazol-2-yl)valeronitrile as a colourless oil (0.45 
g.). 
A solution of 5-(4-guanidino-1,2,3-triazol-2-yl)valeronitrile (0.41 g.) in 
chloroform (15 ml.) and MeOH (4 ml.) was saturated at 0.degree. with 
gaseous hydrogen chloride and the solution kept at 0.degree. for 3 days. 
Lvaporation gave methyl 5-(4-guanidino-1,2,3-triazol-2-yl)valerimidate 
hydrochloride which was used without further purification. 
EXAMPLE 9 
A solution of methyl 
5-[4-(2-ethylguanidino)-1,2,3-triazol-2-yl]valerimidate (1.57 g.) in MeOH 
(6 ml.) was treated with acethydrazide (0.42 g.) and the solution allowed 
to stand for 18 hours. Evaporation gave a brown gum which was triturated 
with ether/EtOH to give 
N-acetylamino-4-[4-(2-ethylguanidino)-1,2,3-triazol-2-yl]valeramidine as a 
white solid (1.1 g.), m.p. 136.degree.-138.degree. (yield 60%). 
The starting material may be prepared as follows: 
A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (1.65 g.) in 
acetonitrile (6 ml.) was treated with ethylisothiocyanate (0.87 g.) and 
the solution stirred for 2.5 days then heated under reflux for 4.5 hours. 
Evaporation of the solvent gave 
5-[4-(3-ethylthioureido)-1,2,3-triazol-2-yl]valeronitrile. 
A solution of 5-[4-(3-ethylthioureido)-1,2,3-triazol-2-yl]valeronitrile 
(2.2 g.) in methanolic ammonia (6M; 20 ml.) was treated with yellow 
mercuric oxide (2.08 g.) and the resulting suspension stirred at room 
temperature for 18 hours. The suspension was filtered through diatomaceous 
earth and the filtrate evaporated to give an oil which was purified by 
medium pressure chromatography using EtOAc then MeOH/EtOAc 1:1 v/v as 
eluants to give 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile 
(1.35 g.). 
A solution of 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile 
(1.35 g.) in MeOH (5 ml.) and chloroform (20 ml.) was saturated with 
gaseous HCl at 0.degree. and the solution kept at 0.degree. for 2.5 days. 
Evaporation of the solvent gave an oil which was basified with cold 
potassium carbonate solution and then extracted with chloroform to give 
methyl 5-[4-(2-ethylguanidino)1,2,3-triazol-2-yl]valerimidate (1.57 g.) 
which was used without further purification. 
EXAMPLE 10 
The process of Example 7 was repeated using the product of Example 9 as 
starting material to give 
3-methyl-5-(4-[4-(2-ethylguanidino)-1,2,3-triazol-2-yl]butyl)-1,2,4-triazo 
le maleate, m.p. 129.degree.-132.degree. (yield 50%). 
EXAMPLE 11 
A tablet containing 200 mg. of 
N-cyano-4-(4-[2-propylguanidino]pyrimid-2-ylthio)butanamidine may be 
prepared using ingredients in the following proportions: 
______________________________________ 
mg./tablet 
______________________________________ 
(a) Tablet Core 
Active agent 200 
Lactose 68.5 
Calcium carboxymethylcellulose 
22.5 
Polyvinylpyrrolidone 
6.0 
Magnesium stearate 3.0 
(b) Tablet Coat 
Hydroxypropylmethylcellulose 
4.5 
Polyethylene glycol 0.9 
Titanium dioxide 1.35 
______________________________________ 
The active agent, lactose and calcium carboxymethylcellulose are mixed. An 
aqueous solution of polyvinylpyrrolidone is added, and the mass is then 
mixed until it is suitable for granulation. The mass is then granulated 
and dried. The magnesium stearate is blended with the dried granules and 
the resulting mixture is compressed into tablets. The tablets are 
film-coated using an aquous or solvent suspension of 
hydroxypropylmethylcellulose, polyethylene glycol and titanium dioxide.