1,2,4-Triazole-3-amine and 1,2,4 triazole-3,5-diamine compounds and their pharmaceutical use

The invention provides compounds of the general formula (I) ##STR1## and physiologically acceptable salts, hydrates and bioprecursors thereof, in which the substituents are defined later. The compounds show pharmacological activity as selective histamine H.sub.2 -antagonists.

This invention relates to novel heterocyclic derivatives having action on 
histamine receptors, to processes for the preparation thereof, to 
pharmaceutical compositions containing them and to their use in 
therapeutics. 
Certain novel heterocyclic derivatives have now been found which have 
potent activity as H.sub.2 -antagonists. These compounds, which are more 
particularly described below, for example show inhibition of the secretion 
of gastric acid when this is stimulated via histamine receptors (Ash and 
Schild, Brit. J. Pharmacol. Chemother, 1966, 27, 427). Their ability to do 
so can be demonstrated in the perfused rat stomach using the method 
described in German Offenlegungsschrift No. 2,734,070, modified by the use 
of sodium pentobarbitone (50 mg/kg) as anaesthetic instead of urethane, 
and in conscious dogs equipped with Heidenhain pouches using the method 
described by Black et al, Nature 1972 236, 385. Furthermore the compounds 
antagonise the effect of histamine on the contraction frequency of 
isolated guinea pig right atrium but do not modify histamine induced 
contractions of isolated gastrointestinal smooth muscle which are mediated 
via H.sub.1 -receptors. 
Compounds with histamine H.sub.2 -blocking activity may be used in the 
treatment of conditions where there is an advantage in lowering gastric 
acidity, particularly in gastric and peptic ulceration, as a prophylactic 
measure in surgical procedures, and in the treatment of allergic and 
inflammatory conditions where histamine is a known mediator. Thus they may 
be used for example, either alone or in combination with other active 
ingredients in the treatment of allergic and inflammatory conditions of 
the skin. 
The present invention provides compounds of the general formula (I) 
##STR2## 
and physiologically acceptable salts, hydrates and bioprecursors thereof, 
in which 
R.sub.1 represents C.sub.1-14 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, 
trifluoroalkyl, heteroaralkyl or alkyl substituted by cycloalkyl, hydroxy, 
alkoxy, amino, alkylamino or dialkylamino; and 
R.sub.2 represents hydrogen or a C.sub.1-4 alkyl group; 
or R.sub.1 and R.sub.2 together with the nitrogen atom to which they are 
attached form a 5-10 membered ring which may be saturated or may contain 
at least one double bond, may be unsubstituted or may be substituted by 
one or more C.sub.1-3 alkyl groups, e.g. methyl, or a hydroxy group and/or 
may contain another heteroatom selected from oxygen and sulphur; 
Alk represents a straight or branched alkylene chain of 1 to 6 carbon 
atoms; 
Q represents a furan or thiophen ring in which incorporation into the rest 
of the molecule is through bonds at the 2- and 5- positions, the furan or 
thiophen ring optionally bearing a further substituent R.sub.5 adjacent to 
the group R.sub.1 R.sub.2 N-Alk, or Q represents a benzene ring in which 
incorporation into the rest of the molecule is through bonds at the 1- and 
3- or 1- and 4- positions; 
R.sub.5 represents halogen or C.sub.1-4 alkyl which may be substituted by 
hydroxy or C.sub.1-4 alkoxy; 
X and Y, which may be the same or different each represent oxygen, sulphur, 
methylene or a bond; 
n represents zero, 1, 2 or 3 and m represents an integer from 2 to 5 with 
the provisos that (a) the total number of atoms in the chain 
X(CH.sub.2).sub.n Y(CH.sub.2).sub.m is an integer from 3 to 8 and (b) when 
X and Y represent oxygen or sulphur then n is 2 or 3; 
R.sub.3 represents alkyl, alkenyl, aralkyl, hydroxy-C.sub.2-6 alkyl or 
alkoxy-C.sub.2-6 alkyl; and 
R.sub.4 represents hydrogen, alkyl, alkenyl, aralkyl, acyloxyalkyl, 
alkylthioalkyl, arylthioalkyl, aryloxyalkyl, aralkyloxyalkyl, or the group 
(CH.sub.2).sub.q R.sub.6 where q is zero, 1,2,3,4,5 or 6 and the alkylene 
chain (CH.sub.2).sub.q may be straight or branched, and 
R.sub.6 is hydroxy, alkoxy, nitro, cyano, heteroaryl or CH.sub.2 
NHC(.dbd.A)NHR.sub.7 where A is NCN, NSO.sub.2 Methyl, NSO.sub.2 Phenyl or 
CHNO.sub.2, and R.sub.7 is alkyl; 
or R.sub.6 is the group NR.sub.8 R.sub.9 where R.sub.8 is hydrogen or 
alkyl; and R.sub.9 is hydrogen, alkyl, alkenyl, aryl, aralkyl or 
heteroaralkyl, or R.sub.9 is the group SO.sub.2 R.sub.10 where R.sub.10 is 
alkyl or aryl; or R.sub.9 is the group COR.sub.11 where R.sub.11 is 
hydrogen, alkyl, aryl, aralkyl, alkoxy, halomethyl, heteroaryl, 
heteroaralkyl or the group NHR.sub.12 where R.sub.12 is hydrogen, alkyl, 
cycloalkyl, aryl or aralkyl; or R.sub.8 and R.sub.9 together represent the 
group .dbd.CR.sub.13 R.sub.14 where R.sub.13 represents aryl or heteroaryl 
and R.sub.14 represents hydrogen or alkyl; 
or R.sub.6 is the group SO.sub.2 R.sub.15 in which R.sub.15 is hydroxy, 
alkyl, aryl or the group NR.sub.16 R.sub.17 where R.sub.16 and R.sub.17, 
which may be the same or different, each represent hydrogen or alkyl; 
or R.sub.6 is the group COR.sub.18 where R.sub.18 is hydrogen, hydroxy, 
alkoxy, aryloxy, aralkyloxy, alkyl, aryl, aralkyl or the group NR.sub.19 
R.sub.20 where R.sub.19 is hydrogen or alkyl optionally substituted by a 
hydroxy or alkoxy group; and R.sub.20 is hydrogen, alkyl (optionally 
substituted by a hydroxy or alkoxy group), alkenyl, aryl, aralkyl or 
cycloalkyl, or NR.sub.19 R.sub.20 forms a 5 to 8 membered ring which may 
contain another heteroatom, e.g. oxygen, or a double bond and/or may be 
substituted by hydroxy or one or two C.sub.1-3 alkyl (e.g. methyl) groups; 
or R.sub.6 is the group CR.sub.21 .dbd.NR.sub.22 where R.sub.21 is 
hydrogen, alkyl, aryl or aralkyl and R.sub.22 is hydroxy, alkoxy, 
aralkyloxy or --NHC(.dbd.B)NH.sub.2 where B is oxygen or sulphur; 
with the proviso that when the group R.sub.6 contains a carbon atom through 
which it is linked to the alkylene group (CH.sub.2).sub.q then the total 
number of carbon atoms in the resulting chain is not greater than 6 (i.e. 
q is not greater than 5); 
or R.sub.3 and R.sub.4 together represent the group --CH.dbd.CH--.sub.2 or 
--(CH.sub.2).sub.4 --. 
The term "alkyl" as a group or part of a group means that the group is 
straight or branched, and unless otherwise stated, has preferably 1 to 6 
carbon atoms and in particular 1 to 4 carbon atoms, e.g. methyl or ethyl, 
and the terms "alkenyl" and "alkynyl" mean that the groups preferably 
contain 3-6 carbon atoms. The term "cycloalkyl" means that the group has 3 
to 8 carbon atoms. The term "halomethyl" means a mono-, di- or trihalo 
substituted methyl group, e.g. trifluoromethyl. The term "aryl" as a group 
or part of a group preferably means phenyl or substituted phenyl, for 
example phenyl substituted with one or more C.sub.1-3 alkyl or alkoxy 
groups or halogen atoms, e.g. fluorine. The acyl portion of an 
acyloxyalkyl group means an aroyl, aralkanoyl or C.sub.1-6 alkanoyl group. 
Examples of acyloxyalkyl groups include acetoxymethyl, formyloxymethyl, 
benzoyloxymethyl and phenylacetoxymethyl. The term "heteroaryl" as a group 
or part of a group means a 5 or 6 membered monocyclic ring containing 1 to 
3 heteroatoms selected from oxygen, nitrogen and sulphur, e.g. thienyl, 
pyridyl, furyl or thiazolyl. The heteroaryl ring may be unsubstituted or 
substituted by C.sub.1-3 alkyl, C.sub.1-3 alkoxy, hydroxy, hydroxyalkyl, 
aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The alkyl 
portion of a heteroaralkyl group is a straight or branched C.sub.1-4 alkyl 
chain, and the heteroaryl ring is linked to the alkyl portion through 
either a carbon or nitrogen atom. 
According to one aspect the invention provides compounds of formula (I) in 
which 
R.sub.4 represents hydrogen, alkyl, alkenyl, aralkyl, acyloxyalkyl, 
aryloxyalkyl, aralkyloxyalkyl, or the group (CH.sub.2)qR.sub.6 where 
R.sub.6 represents hydroxy or alkoxy, or R.sub.6 is NR.sub.8 R.sub.9 where 
R.sub.9 represents hydrogen or alkyl; 
or, when q is zero, 
R.sub.6 represents NR.sub.8 R.sub.9 where R.sub.9 is alkenyl, aralkyl or 
heteroaralkyl, or R.sub.9 is the group SO.sub.2 R.sub.10 or the group 
COR.sub.11 (where R.sub.11 is other than halomethyl); or R.sub.8 and 
R.sub.9 together represent .dbd.CR.sub.13 R.sub.14. 
According to another aspect the invention provides compounds of formula (I) 
in which 
R.sub.4 represents alkylthioalkyl or arylthioalkyl, or the group 
(CH.sub.2)qR.sub.6 where R.sub.6 is nitro, cyano, heteroaryl, or CH.sub.2 
NHC(.dbd.A)NHR.sub.7 ; or R.sub.6 represents CH.sub.2 NR.sub.8 R.sub.9 
where R.sub.9 is aryl, aralkyl, alkenyl, or heteroaralkyl, or R.sub.9 is 
the group SO.sub.2 R.sub.10 or COR.sub.11, or R.sub.8 and R.sub.9 together 
represent .dbd.CR.sub.13 R.sub.14 ; or R.sub.6 represents SO.sub.2 
R.sub.15, COR.sub.18 or CR.sub.2] .dbd.NR.sub.22 ; 
or R.sub.3 and R.sub.4 together represent --CH.dbd.CH--.sub.2 or 
--(CH.sub.2).sub.4 -- 
Examples of suitable meanings for the groups R.sub.1 to R.sub.4 are as 
follows: 
R.sub.1 : alkyl containing up to 14 carbon atoms (e.g. methyl, ethyl, 
propyl, butyl, pentyl, hexyl, heptyl or decyl), C.sub.5-7 cycloalkyl (e.g. 
cyclopentyl, cyclohexyl or cycloheptyl), alkenyl, (e.g. allyl or 
3,3-dimethylallyl), aralkyl (e.g. phenylalkyl such as benzyl or 
phenethyl), C.sub.1-4 alkyl substituted by a trifluoromethyl group (e.g. 
2,2,2-trifluoroethyl), hydroxy C.sub.2-4 alkyl (e.g. 3-hydroxypropyl), 
C.sub.1-3 alkoxy C.sub.2-4 alkyl (e.g. methoxyethyl or ethoxyethyl), or 
di-C.sub.1-3 alkylamino C.sub.2-4 alkyl (e.g. dimethylaminoethyl, 
diethylaminoethyl or dimethylaminopropyl), or heteroaralkyl where the 
heterocyclic portion represents for example a furyl, thienyl, pyrrolyl, 
pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl or thiazolyl ring 
and the alkyl portion is for example a methyl, ethyl or propyl grouping; 
R.sub.2 : hydrogen, methyl or ethyl; or 
R.sub.1 R.sub.2 N may represent a 5-8 membered ring optionally containing 
one double bond and/or substituted by one or two C.sub.1-3 alkyl (e.g. 
methyl) groups or a hydroxy group and/or containing an oxygen or sulphur 
atom (e.g. pyrrolidino, piperidino, hexamethylenimino, heptamethylenimino, 
tetrahydropyridino, 4-hydroxypiperidino, 4-C.sub.1-3 alkylpiperidino (e.g. 
4-methylpiperidino), morpholino, 2,6-di-C.sub.1-3 alkylmorpholino (e.g. 
2,6-dimethylmorpholino), or thiamorpholino; 
R.sub.3 : C.sub.1-4 alkyl (e.g. methyl, ethyl or propyl) or hydroxy 
C.sub.2-4 alkyl) (e.g. 2-hydroxyethyl); 
R.sub.4 : hydrogen, hydroxy, C.sub.1-4 alkyl (e.g. methyl, ethyl, or 
isobutyl), hydroxy C.sub.1-4 alkyl (e.g. hydroxymethyl, 2-hydroxyethyl or 
1-hydroxy-1-methylethyl), C.sub.1-3 alkoxy C.sub.1-4 alkyl (e.g. 
methoxymethyl or methoxyethyl), phenyl C.sub.1-3 alkyl (e.g. benzyl or 
phenethyl), C.sub.2-4 alkanoyloxy C.sub.1-4 alkyl (e.g. acetoxymethyl), 
amino C.sub.1-4 alkyl (e.g. aminomethyl), C.sub.1-3 alkylthio C.sub.1-4 
alkyl (e.g. methylthiomethyl), amino, C.sub.1-4 alkylamino (e.g. 
methylamino or ethylamino) or di-C.sub.1-4 alkylamino (e.g. dimethylamino, 
diethylamino or dipropylamino), phenyl C.sub.1-3 alkylamino (e.g. 
benzylamino), or a heteroaryl C.sub.1-3 alkylamino group where the 
heteroaryl ring contains one heteroatom (e.g. 3- or 4-pyridylmethyl); or 
R.sub.4 represents the group N.dbd.CHR.sub.13 where R.sub.13 is a phenyl or 
pyridyl (e.g. 3- or 4- pyridyl) group; or 
R.sub.4 represents (CH.sub.2).sub.q R.sub.6 where q is zero, 1, 2, or 3; 
and R.sub.6 is nitro, cyano, heteroaryl (e.g. pyridyl or thienyl), 
--CH.sub.2 NHC(.dbd.A)NHR.sub.7 where A is NCN or CHNO.sub.2 and R.sub.7 
is C.sub.1-3 alkyl (e.g. methyl); or the group SO.sub.2 R.sub.15 where 
R.sub.15 is hydroxy, C.sub.1-3 alkyl (e.g. methyl), or aryl (e.g. phenyl); 
or the group COR.sub.18 where R.sub.18 is hydrogen, hydroxy, C.sub.1-3 
alkoxy (e.g. ethoxy), C.sub.1-3 alkyl (e.g. methyl) or the group NR.sub.19 
R.sub.20 where R.sub.19 and/or R.sub.20 are hydrogen or C.sub.1-3 alkyl 
(e.g. methyl), or NR.sub.19 R.sub.20 forms a 5- or 6-membered ring (e.g. 
pyrrolidino); or the group CH.dbd.NR.sub.22 where R.sub.22 is hydroxy or 
C.sub.1-3 alkoxy (e.g. methoxy): or R.sub.6 is the group NHR.sub.9 where 
R.sub.9 is the group SO.sub.2 R.sub.10 where R.sub.10 represents 
C.sub.1-3 alkyl (e.g. methyl), or phenyl optionally substituted by a 
C.sub.1-3 alkyl (e.g. methyl) or C.sub.1-3 alkoxy (e.g. methoxy) group; or 
R.sub.9 represents COR.sub.11 where R.sub.11 represents hydrogen, 
C.sub.1-3 alkyl (e.g. methyl or ethyl), C.sub.1-3 alkoxy (e.g. methoxy or 
ethoxy), halomethyl (e.g. trifluoromethyl), phenyl C.sub.1-3 alkyl (e.g. 
benzyl), furyl, pyridyl, thiazolyl, thienyl, phenyl optionally substituted 
by a C.sub.1-3 alkyl (e.g. methyl) or C.sub.1-3 alkoxy (e.g. methoxy) 
group, or NHR.sub.12 where R.sub.12 is C.sub.1-3 alkyl (e.g. methyl), 
C.sub.5-7 cycloalkyl (e.g. cyclohexyl) or phenyl optionally substituted by 
a C.sub.1-3 alkyl (e.g. methyl) or C.sub.1-3 alkoxy (e.g. methoxy) group; 
or R.sub.3 and R.sub.4 together represent --CH.dbd.CH--.sub.2 or 
--(CH.sub.2).sub.4 --. 
In particular the groups R.sub.1 to R.sub.4 may have the meanings as 
follows: 
R.sub.1 : C.sub.1-7 alkyl, C.sub.1-4 alkyl substituted by trifluoromethyl, 
C.sub.2-4 alkyl substituted by hydroxy or di-C.sub.1-3 alkylamino, 
C.sub.5-7 cycloalkyl, alkenyl, phenyl C.sub.1-3 alkyl or heteroaryl 
C.sub.1-3 alkyl where the heteroaryl ring contains one heteroatom (e.g. 
furylmethyl); 
R.sub.2 : hydrogen or methyl; or 
R.sub.1 R.sub.2 N may represent a 5 to 7 membered ring optionally 
containing a double bond or an alkyl (e.g. methyl) substituent; preferably 
R.sub.1 R.sub.2 N represents dimethylamino or piperidino; 
R.sub.3 : methyl, ethyl or 2-hydroxyethyl, preferably methyl; 
R.sub.4 : hydrogen, C.sub.1-4 alkyl, nitro, C.sub.1-3 alkylthiomethyl, 
C.sub.1-3 alkoxy C.sub.1-4 alkyl, C.sub.2-4 alkanoyloxy C.sub.1-4 alkyl, 
phenyl C.sub.1-3 alkyl, heteroarylmethyl (e.g. pyridylmethyl), the group 
N.dbd.CHR.sub.13 where R.sub.13 is phenyl or pyridyl, or the group 
(CH.sub.2).sub.q R.sub.6 where q is zero, 1, 2 or 3, and R.sub.6 is 
hydroxy, cyano, CH.sub.2 NHC(.dbd.A)NHR.sub.7 (where A is NCN or 
CHNO.sub.2 and R.sub.7 is C.sub.1-3 alkyl); or R.sub.6 represents the 
group NHR.sub.9 where R.sub.9 is hydrogen, SO.sub.2 R.sub.10 where 
R.sub.10 is C.sub.1-3 alkyl, or COR.sub.11 where R.sub.11 is hydrogen, 
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, benzyl, phenyl or NHR.sub.12 (where 
R.sub.12 is phenyl); or R.sub.6 represents the group SO.sub.2 R.sub.15 
where R.sub.15 is C.sub.1-3 alky or aryl; or R.sub.6 represents the group 
COR.sub.18 where R.sub.18 is hydrogen, hydroxy or NR.sub.19 R.sub.20 where 
R.sub.19 and/or R.sub.20 are hydrogen or C.sub.1-3 alkyl, or NR.sub.19 
R.sub.20 forms a 5- or 6- membered ring; or R.sub.6 represents 
--CH.dbd.NOH; or R.sub.3 and R.sub.4 together represents 
--CH.dbd.CH--.sub.2 or --(CH.sub.2).sub.4 --. 
The group Alk preferably contains 1-4 carbon atoms and may be for example a 
methylene, ethylene or propylene group. More preferably Alk represents 
methylene. 
Q is preferably a benzene ring in which incorporation into the rest of the 
molecule is through bonds at the 1- and 3- positions, or a furan ring 
optionally containing a further substituent R.sub.5 or a thiophen ring 
containing a further substituent R.sub.5, where R.sub.5 is C.sub.1-4 alkyl 
(e.g. methyl); more preferably Q is a benzene ring which is incorporated 
into the rest of the molecule through bonds in the 1- and 3- positions. 
Preferably the chain --X(CH.sub.2).sub.n Y(CH.sub.2).sub.m -- contains from 
4 to 6 atoms. When Q is an optionally substituted furan or thiophen, X 
preferably represents a bond and either Y is --S-- or --CH.sub.2 --, n is 
1 and m is 2 or Y is --O--, n is 1 and m is 3. More preferably Q is furan 
without a further substituent R.sub.5, Y is --S--, n is 1 and m is 2. When 
Q is benzene, e.g. 1,3-benzene, X preferably represents a bond, Y is 
--O--, n is zero and m is 3, 4 or 5, or X and Y both represent --O-- and n 
and m are both 2; more preferably Y is --O--, n is zero and m is 3 or 4. 
A preferred group of compounds of formula (I) are those of formula (II). 
##STR3## 
where R.sub.1 and R.sub.2 are methyl groups or together with the nitrogen 
atom to which they are attached form a pyrrolidino, piperidino or 
hexamethylenimino group (more preferably piperidino); m is 3 or 4, R.sub.3 
is methyl and R.sub.4 is hydrogen, C.sub.1-4 alkyl (e.g. methyl), 
C.sub.2-4 alkanoyloxyalkyl (e.g. acetoxymethyl), C.sub.1-3 alkylthiomethyl 
(e.g. methylthiomethyl), cyanoalkyl (e.g. cyanomethyl), or the group 
(CH.sub.2).sub.q R.sub.6 where q is zero, 1 or 2, and R.sub.6 is hydroxy, 
CH.sub.2 NHC(.dbd.CHNO.sub.2)NHR.sub.7 (where R.sub.7 is C.sub.1-3 alkyl 
e.g. methyl), or the group NHR.sub.9 where R.sub.9 is hydrogen, SO.sub.2 
R.sub.10 (where R.sub.10 is C.sub.1-3 alkyl e.g. methyl) or COR.sub.11 
(where R.sub.11 is C.sub.1-3 alkyl e.g. methyl) or R.sub.6 is the group 
SO.sub.2 R.sub.15 where R.sub.15 is C.sub.1-3 alkyl (e.g. methyl) or 
R.sub.6 is the group COR.sub.18 where R.sub.18 is hydrogen, hydroxy or 
amino; or R.sub.6 is the group CH.dbd.NOH; or R.sub.3 and R.sub.4 together 
represent --CH.dbd.CH--.sub.2 or --(CH.sub.2)--.sub.4. 
Particularly preferred compounds are: 
4-methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]4H-1,2,4-triazole-3-am 
ine 
4-methyl-5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino-4H-1,2,4-triazole 
-3-methanol 
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2,4-triazolo[4,3-a]pyridine- 
3-amine 
4-methyl-5-[[3-[3(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triazo 
le-3-acetamide 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-methanol 
4-methyl-5-(methylsulphonyl)methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]pro 
pyl]-4H-1,2,4-triazole-3-amine and their physiologically acceptable salts. 
The invention includes the compounds of formula (I) in the form of 
physiologically acceptable salts with inorganic and organic acids. 
Particularly useful salts include hydrochlorides, hydrobromides, 
sulphates, methanesulphonates, acetates, maleates, succinates citrates, 
tartrates, fumarates and benzoates. The compounds of formula (I) and their 
salts may also form hydrates, which hydrates are also to be considered as 
part of the invention. The compounds of formula (I) can exhibit 
tautomerism and the formula is intended to cover all tautomers. Where 
optical isomers may exist the formula is intended to cover all 
diastereoisomers and optical enantiomers. 
The compounds according to the invention, preferably in the form of a salt 
may be formulated for administration in any convenient way and the 
invention includes within its scope pharmaceutical compositions containing 
at least one compound according to the invention adapted for use in human 
or veterinary medicine. Such compositions may be formulated in a 
conventional manner using one or more pharmaceutically acceptable carriers 
or excipients. Such compositions may also contain if required other active 
ingredients e.g. H.sub.1 -antagonists. 
Thus the compounds according to the invention may be formulated for oral, 
buccal, topical, parenteral or rectal administration. Oral administration 
is preferred. 
For oral administration, the pharmaceutical compositions may take the form 
of for example, tablets, capsules, powders, solution, syrups or 
suspensions prepared by conventional means with acceptable excipients. For 
buccal administration the composition may take the form of tablets or 
lozenges formulated in conventional manner. 
The compounds of the invention may be formulated for parenteral 
administration by bolus injection or continuous infusion. Formulations for 
injection may be presented in unit dosage form in ampoules, or in 
multi-dose containers, with an added preservative. The compositions may 
take such forms as suspensions, solutions or emulsions in oily or aqueous 
vehicles, and may contain formulatory agents such as suspending, 
stabilising and/or dispersing agents. Alternatively, the active ingredient 
may be in powder form for reconstitution with a suitable vehicle, e.g. 
sterile pyrogen-free water before use. 
The compounds of the invention may also be formulated in rectal 
compositions such as suppositories or retention enemas, e.g. containing 
conventional suppository bases such as cocoa butter or other glyceride. 
For topical application, the compounds of the invention may be formulated 
as ointments, creams, gels, lotions, powders or sprays in a conventional 
manner. 
For internal administration a convenient daily dosage regime of the 
compounds according to the invention would be 1 to 4 doses to the total of 
some 5 mg to 1 g per day, preferably 5 to 250 mg per day, dependent upon 
the condition of the patient. 
It will be appreciated that in the methods for the preparation of compounds 
of formula (I) given below, for certain reaction steps it may be necessary 
to protect various reactive substituents in the starting materials for a 
particular reaction and subsequently to remove the protecting group. Such 
protection and subsequent deprotection may be particularly pertinent where 
R.sub.1 and/or R.sub.2 in intermediates used to prepare compounds of 
formula (I) are hydrogen atoms and/or when R.sub.3 in intermediates is an 
alkyl group bearing a hydroxy substituent and/or when R.sub.4 in certain 
intermediates is an alkyl group bearing a hydroxyl or a primary or 
secondary amino substituent. Standard protection and deprotection 
procedures can be employed. For example an amino group may be protected by 
formation of a phthalimide which may subsequently be cleaved by treatment 
with a hydrazine e.g. hydrazine hydrate or a primary amine, for example 
methylamine. 
In describing the processes which may be used for preparing the compounds 
of formula (I) or intermediates useful in the preparation thereof, any of 
R.sub.1 to R.sub.22, Alk, Q, X, Y, n and m in the various formulae are as 
defined in formula (I) unless otherwise stated. 
Compounds of formula (I) in which R.sub.4 is other than 
(CH.sub.2)qN.dbd.CR.sub.13 R.sub.14, alkoxy, acyloxyalkyl, nitro, SO.sub.2 
R.sub.15, COR.sub.18 (where R.sub.18 is hydrogen, aryl or aralkyl) or the 
group CR.sub.21 .dbd.NR.sub.22 may be prepared by cyclisation of a 
compound of formula (III) 
##STR4## 
in which V is oxygen, sulphur or NH. When V represents sulphur then 
tautomerism with the adjacent NH group is possible (i.e. 
##STR5## 
and the --SH group may be alkylated under standard conditions to form the 
group 
##STR6## 
the S-alkylated compound may also be used in the cyclisation process. 
The cyclisation may be carried out in the absence or presence of a solvent 
(e.g. dimethylformamide), or under basic conditions (e.g. using aqueous 
potassium hydroxide), at elevated temperatures (e.g. within the range 
80.degree.-150.degree. C.). 
In a convenient embodiment of the cyclisation process the intermediate 
(III) in which V is oxygen may be formed in situ by reacting an 
aminoguanidine of formula (IV) 
##STR7## 
with an acid R.sub.4 CO.sub.2 H or an activated derivative thereof such as 
an acid halide (e.g. R.sub.4 COCl) or a trialkylorthoester (e.g. R.sub.4 
C(OEt).sub.3). The reaction may be carried out as described above, and 
under these conditions cyclisation occurs to give a compound of formula 
(I). 
In another embodiment of the cyclisation process an aminoguanidine of 
formula (IV) may be reacted with an alkali metal (E.g. potassium) 
isocyanate or isothiocyanate in a solvent such as acetonitrile at for 
example 20.degree. C. to give an intermediate of formula (III) in which 
R.sub.4 is amino and V is respectively oxygen or sulphur. Subsequent 
cyclisation then affords a compound of formula (I) in which R.sub.4 is 
amino. 
Compounds of formula (I) in which R.sub.4 is other than 
(CH.sub.2)qN.dbd.CR.sub.13 R.sub.14 may be prepared by reducing a compound 
of formula (V) 
##STR8## 
in which D.sup.a may represent R.sub.1 R.sub.2 NAlk or a group convertible 
thereto under reducing conditions; 
D.sup.b represents --CH.sub.2 NH--, --CONH-- or --CH.dbd.N; and 
D.sup.c represents R.sub.4 or a group convertible thereto under reducing 
conditions, provided that at least one of D.sup.a, D.sup.b and D.sup.c 
represents a reducible group and the other(s) take the appropriate meaning 
corresponding to formula (I). 
Thus for example compounds of formula (I) may be prepared by reduction of a 
compound of formula (V) in which D.sup.a is R.sub.1 R.sub.2 NAlk, D.sup.b 
is --CONH-- or --CH.dbd.N-- and D.sup.c represents R.sub.4 or a group 
convertible thereto under the conditions of the reduction reaction such as 
an ester group (CH.sub.2).sub.q-1 CO.sub.2 R.sup.a where R.sup.a is alkyl. 
Reduction may for example be carried out with lithium aluminium hydride in 
a suitable solvent such as tetrahydrofuran at for example 20.degree. C. to 
reflux, or with sodium borohydride in a suitable solvent such as ethanol 
at 20.degree.-50.degree. C. 
Compounds of formula (I) in which R.sub.4 is the group (CH.sub.2).sub.q 
R.sub.6 where R.sub.6 is NR.sub.8 COR.sub.11, NR.sub.8 SO.sub.2 R.sub.10, 
CH.sub.2 NHC(.dbd.A)NHR.sub.7 or N.dbd.CR.sub.13 R.sub.14 may be prepared 
by treating an aminoalkyltriazole of formula (VI) 
##STR9## 
in which R.sub.1, R.sub.2 and R.sub.3 are as defined in formula (I) or are 
groups readily convertible thereto, and R.sub.23 is the group 
(CH.sub.2).sub.q NHR.sub.8, the group (CH.sub.2).sub.q+1 NH.sub.2 or the 
group (CH.sub.2).sub.q NH.sub.2, with a compound capable of replacing the 
hydrogen atom in the group NHR.sub.8 by the group COR.sub.11 or SO.sub.2 
R.sub.10 or a hydrogen atom in the group NH.sub.2 of the group 
(CH.sub.2).sub.q+1 NH.sub.2 by the group C(.dbd.A)NHR.sub.7 or both 
hydrogen atoms in the group NH.sub.2 of the group (CH.sub.2).sub.q 
NH.sub.2 by the group .dbd.CR.sub.13 R.sub.14. 
Thus for example the aminoalkyltriazole (VI) in which R.sub.23 is the group 
(CH.sub.2).sub.q NHR.sub.8 may be reacted with an isocyanate R.sub.12 ' 
NCO in which R.sub.12 ' has any of the meanings defined for R.sub.12 in 
formula (I) except hydrogen or represents an alkali metal atom such as 
potassium or sodium, or with an activated derivative of either a 
carboxylic acid R.sub.11 COOH (in which R.sub.11 is other than the group 
NHR.sub.12) or a sulphonic acid R.sub.10 SO.sub.3 H to give a compound of 
formula (I) in which R.sub.6 is respectively the group NR.sub.8 
CONHR.sub.12, NR.sub.8 COR.sub.11 (in which R.sub.11 is other than 
NHR.sub.12), or NR.sub.8 SO.sub.2 R.sub.10. 
Suitable activated derivatives include acid halides e.g. acid chlorides, 
alkylchloroformates, acid anhydrides including mixed anhydrides (e.g. 
acetic formic anhydride), and esters such as alkyl esters and ortho 
esters. 
The reaction with an acid halide is preferably carried out in the presence 
of a base e.g. an inorganic base such as sodium hydroxide or an organic 
base such as triethylamine or pyridine. The reaction with an 
alkylchloroformate is preferably carried out in the presence of a base, 
e.g. potassium carbonate or triethylamine, in a solvent such as 
dimethylformamide. The reaction with an acid anhydride may be carried out 
in the absence of presence of solvent such as pyridine. 
In the reaction with an isocyanate compound of formula (I) in which 
R.sub.12 is other than hydrogen are conveniently prepared by carrying out 
the reaction in a solvent such as acetonitrile at temperatures from 
ambient to reflux. Compounds of formula (I) in which R.sub.12 is hydrogen 
may be prepared by heating a salt e.g. hydrochloride of the aminotriazole 
(VI) with an aqueous solution of an appropriate cyanate e.g. potassium 
cyanate. 
As a further embodiment of this process an aminoalkyltriazole (VI) in which 
R.sub.23 is the group (CH.sub.2).sub.q+1 NH.sub.2 may be treated with a 
compound of formula LC(.dbd.A)NHR.sub.7 where L is a leaving group (e.g. 
methylthio) to give a compound of formula (I) in which R.sub.6 is CH.sub.2 
NHC(.dbd.A)NHR.sub.7. The reactants may for example be mixed in an aqueous 
solution at room temperature to 100.degree. C. 
In yet another embodiment of this process an aminoalkyltriazole (VI) in 
which R.sub.23 is the group (CH.sub.2).sub.q NH.sub.2 is treated with an 
appropriate aromatic aldehyde, e.g. benzaldehyde, or a ketone R.sub.13 
R.sub.14 CO optionally in the presence of a catalyst (e.g. 
p-toluenesulphonic acid) to give a product in which R.sub.6 is 
N.dbd.CR.sub.13 R.sub.14. 
Compounds of formula (I) in which R.sub.4 is an acyloxyalkyl group may be 
prepared by treating the corresponding hydroxyalkyl compound with an 
activated derivative (e.g. an acid chloride) of an appropriate acid. The 
reaction may be carried out at room temperature, optionally in the 
presence of a solvent (e.g. pyridine, tetrahydrofuran, acetone or 
dimethylformamide), and preferable in the presence of a base (e.g. 
pyridine, triethylamine or an alkali metal carbonate such as potassium 
carbonate). 
Compounds of formula (I) in which R.sub.4 is a nitro group or R.sub.3 and 
R.sub.4 together represent --CH.dbd.CH--.sub.2 may be prepared by heating 
a diamine of formula (VII) 
EQU R.sub.1 R.sub.2 NAlkQX(CH.sub.2).sub.n Y(CH.sub.2).sub.m NH.sub.2 (VII) 
with an appropriate triazole of formula (VIII) 
##STR10## 
where P is a leaving group such as halogen, e.g. bromine, and R.sub.4 
represents nitro, or R.sub.3 and R.sub.4 together represent 
--CH.dbd.CH--.sub.2. The reaction may be carried out in the absence or 
presence of a solvent such as acetonitrile or an alcohol (e.g. ethanol). 
The nitrotriazoles (VIII, R.sub.4 .dbd.NO.sub.2), such as the 
bromonitrotriazole in which P is bromine, may be prepared from the 
corresponding triazole of formula (VIII) in which P is hydrogen, for 
example by treatment with bromine. 
Compounds of formula (I) in which R.sub.3 and R.sub.4 together represent 
--(CH.sub.2).sub.4 -- may be prepared by reduction of the corresponding 
compound in which R.sub.3 and R.sub.4 together represent 
--CH.dbd.CH--.sub.2 using for example hydrogen and a metal catalyst (e.g. 
platinum) in a solvent such as ethanol. 
Compounds of formula (I) in which R.sub.4 is the group (CH.sub.2).sub.q 
R.sub.6 in which R.sub.6 is COR.sub.18 (where R.sub.18 is hydrogen, alkyl, 
aryl or aralkyl) or SO.sub.2 R.sub.15 may be prepared by oxidation of the 
corresponding compound in which R.sub.4 is the group (CH.sub.2).sub.q 
CHR.sub.18 OH, (CH.sub.2).sub.q SR.sub.15 (where R.sub.15 is other than 
hydroxy) or (CH.sub.2).sub.q SH. 
Thus aldehydes and ketones of formula (I) in which R.sub.4 is the group 
(CH.sub.2).sub.q COR.sub.18 where R.sub.18 is hydrogen, alkyl, aryl or 
aralkyl may be prepared by oxidising the corresponding hydroxyalkyl 
compound in which R.sub.4 is (CH.sub.2).sub.q CHR.sub.18 OH using for 
example oxalyl chloride and dimethylsulphoxide in a solvent such as 
dichloromethane at reduced temperature (e.g. -50.degree. C.) or using 
activated manganese dioxide in a solvent such as chloroform at for example 
room temperature. 
Compounds of formula (I) in which R.sub.4 is the group (CH.sub.2).sub.q 
SO.sub.2 R.sub.15 may be prepared by oxidising the corresponding compound 
in which R.sub.4 is either --(CH.sub.2).sub.q SR.sub.15 (where R.sub.15 is 
other than hydroxy) or (CH.sub.2).sub.q SH with for example peracetic acid 
or nitric acid. The reaction may be carried out in a solvent such as 
acetic acid, at room temperature. 
The starting material in which R.sub.4 is (CH.sub.2).sub.q SH where q is 
other than zero may be obtained by alkaline hydrolysis of the 
corresponding isothiourea, which may in turn be prepared by alkylating 
thiourea with an appropriate compound of formula (I) in which R.sub.6 is a 
leaving group e.g. halo. 
The thiol starting material in which R.sub.4 is SH may be prepared by 
diazotisation of the corresponding aminotriazole followed by treatment 
with an alkali metal (e.g. potassium) salt of ethyl xanthate to give a 
xanthate in which R.sub.4 is the group --SC(.dbd.S)OEt, which is 
subsequently hydrolysed (for example by heating with ethanolic potassium 
hydroxide) to give the starting thiol in which R.sub.4 is the group SH. 
The above oxidation process is particularly applicable to the preparation 
of compounds of formula (I) in which Q is a benzene or furan ring, X and Y 
are each oxygen, methylene or a bond, and there is no unsaturation within 
the groups R.sub.1 and R.sub.3. 
Compounds of formula (I) in which R.sub.4 is (CH.sub.2).sub.q CR.sub.21 
.dbd.NR.sub.22 may be prepared by reacting the corresponding carbonyl 
compound i.e. a compound of formula (I) in which R.sub.4 is 
(CH.sub.2).sub.q COR.sub.21, with an appropriate reagent H.sub.2 NR.sub.22 
in a suitable solvent such as ethanol, optionally with heating. 
Compounds of formula (I) in which R.sub.4 is (CH.sub.2).sub.q R.sub.6 where 
R.sub.6 is SO.sub.2 NR.sub.16 R.sub.17 or CONR.sub.19 R.sub.20 may be 
prepared by reacting an activated derivative of the corresponding 
carboxylic acid or sulphonic acid, i.e. compounds of formula (I) in which 
R.sub.4 is (CH.sub.2).sub.q R.sub.6 where R.sub.6 is CO.sub.2 H or 
SO.sub.3 H, with ammonia or an appropriate amine HNR.sub.16 R.sub.17 or 
HNR.sub.19 R.sub.20. Suitable activated derivatives include those referred 
to previously e.g. acid chlorides and esters. 
Compounds of formula (I) in which R.sub.4 is (CH.sub.2).sub.q R.sub.6 where 
R.sub.6 is --CONH.sub.2 or --CO.sub.2 H may be prepared by hydrolysis of 
the corresponding nitrile. 
Compounds of formula (I) in which R.sub.4 is (CH.sub.2).sub.q R.sub.6 where 
R.sub.6 is cyano may be prepared by heating the corresponding oxime of 
formula (I) in which R.sub.6 is --CH.dbd.NOH with a dehydrating agent such 
as acetic anhydride. 
Aldehydes of formula (I) in which R.sub.4 is (CH.sub.2).sub.q R.sub.6 where 
R.sub.6 is CHO may be prepared by reducing the corresponding nitrile in 
which R.sub.4 is (CH.sub.2).sub.q CN with for example hydrogen in the 
presence of Raney nickel. The resulting aldehyde may be conveniently 
isolated as its semicarbazone, from which the desired aldehyde may be 
generated by treatment with hydrochloric acid and aqueous formaldehyde. 
The aminoguanidine (III) may be prepared, for example by reacting a diamine 
of formula (VII) with a compound of formula (IX) 
##STR11## 
where L is a leaving group such as thioalkyl, e.g. thiomethyl. 
The triazoles of formula (V) may be prepared by reacting a triazole of 
formula (X) 
##STR12## 
with a compound of formula (XI) 
EQU D.sup.a --QX(CH.sub.2).sub.n Y(CH.sub.2).sub.m-1 G (XI) 
where G is CO.sub.2 H or CHO. 
The triazoles of formula (X) may in general be prepared by the method 
described by C. F. Kroger, Chem. Berichte, 1964, 97, 396. 
Amines of formula (VII) may be made by methods analogous to those described 
in German Offenlegungsschrifts 2734070, 2821410 and 2821409 and in 
European Patent Specification publication No. 0029306. 
Where the product of any of the above processes is a free base and a salt 
is required, the salt may be formed in a conventional manner. Thus, for 
example, a generally convenient method of forming the salts is to mix 
appropriate quantities of the free base and the acid in an appropriate 
solvent(s) e.g. an alcohol such as ethanol or an ester such as ethyl 
acetate. 
The invention is illustrated but not limited by the following Examples and 
Preparations. 
PREATION 1 
N-Amino-N'-methyl-N"-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine 
hydroiodide 
A mixture of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (12.4 g) and 
methyl N-methylhydrazine carboximidothioate (12.55 g) were heated as a 
solution in water (40 ml) at 65.degree. for 6 h. The cooled mixture was 
stirred, and purged with nitrogen for 14 h. The water was decanted from 
the solid which was dissolved in ethyl acetate (50 ml) and saturated 
sodium carbonate solution (50 ml). The aqueous solution was further 
extracted with ethyl acetate. The combined organic extracts were dried and 
evaporated to leave a red oil. This oil was triturated with cyclohexane to 
give the title compound as a pale pink solid (11.8 g) 
m.p.=104.degree.-108.degree. C. 
PREATION 2 
Methyl, 5-amino-4-methyl-4H-1,2,4-triazole-3-carboxylate 
N-amino-N'-methyl guanidine hydroiodide (4.3 g) and oxalic acid dihydrate 
(2.5 g) were heated at reflux in water (25 ml) for 3.5 h. The reaction was 
cooled, basified with excess solid potassium hydroxide, and heated on a 
steambath for 2 h. The reaction was cooled and acidified to pH 3 with 
conc. hydrochloric acid to produce a white solid (1.6 g) which was used 
without further purification. This solid (8 g), in dry methanol (100 ml) 
was saturated with hydrogen chloride gas at 5.degree., and then heated at 
reflux for 4 h. The solvent was evaporated and the residue was dissolved 
in water. The pH of the solution was adjusted to pH 7 with solid potassium 
carbonate to precipitate the title compound as a white solid (2.7 g) which 
was crystallised from methanol, m.p. 208.degree.-9.degree.. 
PREATION 3 
Methyl 
4-methyl-5-[[1-oxo-4[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-4H-1,2,4- 
triazole-3-carboxylate 
Thionyl chloride (2.5 ml) was added to a solution of 
4-[3-(1-piperidinylmethyl)phenoxy]butanoic acid (2.77 g) in dry 
dichloromethane (30 ml) and dry dimethylformamide (6 drops). The reaction 
was stirred at room temperature for 2 h, and the solvent was removed in 
vacuo. Excess thionyl chloride was removed by azeotropic distillation with 
toluene (3.times.15 ml). The residue was dissolved in dry 
dimethylformamide (50 ml), and methyl 
5-amino-4-methyl-4H-1,2,4-triazole-3-carboxylate (1.53 g) was added. The 
solution was stirred at room temperature for 18 h, heated at 60.degree. 
for 3 h, and the solvent removed under reduced pressure to leave a brown 
gum. This gum was partitioned between aqueous sodium carbonate solution 
and ethyl acetate. Evaporation of the organic phase gave a viscous oil 
which was triturated with a mixture of ether and light petroleum b.p. 
60.degree.-80.degree. to give a solid. This solid was recrystallised from 
a mixture of ethyl acetate and light petroleum b.p. 60.degree.-80.degree. 
to give the title compound as an off-white solid (0.68 g) m.p. 
108.degree.-109.5.degree.. 
PREATION 4 
Methyl 
N'-[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N-methylcarb 
amimidothioate 
A solution of 
N-[2-[[5-[(dimethylamino)methyl]-2-furanmethyl]thio]ethyl]-N'-methylthiour 
ea (5.75 g) in methanol (30 ml) was just acidified with hydrogen chloride 
in ether. The ether was evaporated in vacuo, methyl iodide (3.12 g) added 
and the solution heated under reflux for 1.25 hours. The solution was 
evaporated in vacuo, the oily residue dissolved in water (30 ml) and an 
excess of anhydrous sodium carbonate added. The oily suspension was 
extracted with ethyl acetate (2.times.40 ml), dried (MgSO.sub.4), 
decolorised with charcoal, filtered and evaporated to give the title 
compound (5 g) as an oil. 
Found: C, 52.0; H, 7.9; N, 13.9 C.sub.13 H.sub.23 N.sub.3 O S.sub.2 
requires C, 51.8; H, 7.7; N, 14.0%

EXAMPLE 1 
4-Methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-4H-1,2,4-triazole-3-a 
mine 
A mixture of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (2.48 g) and 
methyl N-methyl hydrazine carboximidothioate (2.48 g) was heated as a melt 
at 60.degree. during 4 h. The residue was dissolved in formic acid (50 ml) 
and the solution was heated under reflux during 12 h. The cooled solution 
was diluted with water (100 ml) and the pH was adjusted to pH 9 with 
anhydrous potassium carbonate. The mixture was extracted with ethyl 
acetate. The combined extracts were evaporated to give an orange oil. The 
oil was heated at 150.degree. during 0.5 h and the unwanted material 
distilled off a 180.degree. C. 0.06 mm Hg leaving a yellow oil. 
This oil was crystallised from ethyl acetate. The solid was discarded. The 
mother liquors were concentrated to give an orange oil which was 
triturated in a mixture of ethyl acetate (10 ml) and ether (20 ml) to give 
the title compound as a white powder (200 mg) m.p. 118.degree.-9.degree.. 
Assay Found: C, 65.87; H, 8.23; N, 20.99, C.sub.18 H.sub.27 N.sub.5 O 
Requires: C, 65.65; H, 8.21; N, 21.28%. 
EXAMPLE 2 
4,5-Dimethyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-4H-1,2,4-triazole 
-3-amine 
N-Amino-N'-methyl-N"[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine 
hydroiodide (3.19 g) and glacial acetic acid (50 ml) were heated at reflux 
for 2 h. The cooled reaction solution was basified with 2N sodium 
hydroxide, and extracted with ethyl acetate. The organic extracts were 
evaporated to leave a pale yellow oil. This oil was extracted with boiling 
cyclohexane (150 ml) and insoluble solid that remained was further 
extracted with boiling ether (50 ml) to leave a crystalline white solid. 
This solid was recrystallised from ethyl acetate to give the title 
compound as a white solid (0.46 g) m.p.=143.degree.-4.degree. C. 
Assay Found: C, 65.92; H, 8.34; N, 19.96, C.sub.19 H.sub.29 N.sub.5 O 
Requires: C, 66.44; H, 8.51; N, 20.39. 
EXAMPLE 3 
4-Methyl-5-[[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-4H-1,2,4-triazo 
le-3-methanol 
Lithium aluminium hydride (0.46 g) was added to a solution or methyl 
4-methyl-5-[[1-oxo-4[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-4H-1,2,4- 
triazole-3-carboxylate (0.58 g) in dry tetrahydrofuran (20 ml) under an 
atmosphere of dry nitrogen. The grey suspension was stirred at room 
temperature for 3.5 h before adding water (0.5 ml), 15% aqueous sodium 
hydroxide (1.0 ml), water (0.5 ml) and ethyl acetate (20 ml). The 
suspension was filtered and the filtrate was evaporated under reduced 
pressure to give a solid which was recrystallised from ethyl acetate (5 
ml) to give the title compound as a white solid (0.04 g) m.p. 
128.degree.-30.degree.. 
Analysis Found: C, 63.7; H, 8.2; N, 18.4; C.sub.20 H.sub.31 N.sub.5 O.sub.2 
requires: C, 64.3; H, 8.4; N, 18.7%. 
EXAMPLE 4 
(a) 
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2,4-triazolo-[4,3-a]pyridin 
e-3-amine 
3-Bromo-1,2,4-triazolo[4,3-a]pyridine (2.5 g), 
3-[3-(1-piperidinylmethyl)phenoxy]propanamine (9 g) and ethanol (20 ml) 
were heated in an autoclave at 110.degree. for 24 h and then at 
150.degree. for 36 h. The mixture was evaporated in vacuo (200.degree., 
0.1 mm Hg) and the residue (2.3 g) was chromatographed on silica using 
dichloromethane:ethanol:880 ammonia (100:8:1) to give a gum which was 
crystallised from methyl acetate-petroleum ether (b.p. 
60.degree.-80.degree.) to give the title compound (0.8 g) as white 
crystals, m.p. 150.degree.-151.degree.. 
Found: C, 69.0; H, 7.4; N, 19.1; C.sub.21 H.sub.27 N.sub.5 O requires: C, 
69.0; H, 7.45; N, 19.2%. 
(b) In a similar manner 3-bromo-1,2,4-triazolo[4,3-a]pyridine (0.8 g) and 
3-[3-(dimethylaminomethyl)phenoxy]propanamine (0.92 g) gave 
N-[3-[3-(dimethylaminomethyl)phenoxy]propyl]-1,2,4-triazolo[4,3-a]pyridine 
-3-amine (67 mg) as white crystals, m.p. 143.degree.-45.degree.. 
NMR (CDCl.sub.3): 2.2, dd, (1H); 2.5, dd, (1H); 2.65-3.5, m, (6H); 5.86, t, 
(2H); 6.22, q, (2H); 6.62, s, (2H); 7.73, s, (6H); 7.75, m, (2H). 
EXAMPLE 5 
N-[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]-(5,6,7,8-tetrahydro-1,2,4-tria 
zolo[4,3-a]pyridine)-3-amine hydrate (4:1) 
A solution of 
N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2,4-triazolo[4,3-a]pyridine 
-3-amine (475 g) in ethanol was hydrogenated at atmospheric pressure over 
platinum on carbon. The resulting mixture was filtered and evaporated to a 
gum which crystallised from isopropanol/ethyl acetate to give the title 
compound as fibrous white needles (382 mg) m.p. 164.degree.-5.degree.. 
Analysis Found: C, 67.5; H, 8.5; N, 18.5; C.sub.21 H.sub.31 N.sub.5 
0.1/4H.sub.2 O requires: C, 67.4; H, 8.6; N, 18.7%. 
EXAMPLE 6 
(a) 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-acetonitrile dioxalate sesquihydrate 
A mixture of N-amino-N'-methyl-N"[3-[3-(1-piperidinylmethyl) 
phenoxy]propyl]guanidine hydroiodide (4.5 g) and cyanoacetic acid (1.7 g) 
was heated at 100.degree.-125.degree. for 7 h. The cooled reaction mixture 
was basified with sodium carbonate and extracted with chloroform. The 
organic extract was evaporated to leave an oil which was chromatographed 
on silica using methanol. The resulting oil (0.56 g) was dissolved in 
ethanol and treated with an ethanolic solution of oxalic acid. 
Recrystallisations of the solid from a mixture of ethanol and water gave 
the title compound (0.45 g) as a white powder. m.p. 93.degree.-97.degree.. 
Analysis Found: C, 50.0; H, 5.8; N, 14.2; C.sub.20 H.sub.28 N.sub.6 
0.2H.sub.2 C.sub.2 O.sub.4 11/2H.sub.2 O requires: C, 50.1; H, 6.1; N, 
14.6%. 
(b) In a similar manner 
N-amino-N'-methyl-N"-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine. 
hydroioidide (4.5 g) and methylthioacetic acid (2.13 g) gave, after 
chromatography on silica using ethylacetate:isopropanol:water:0.88 ammonia 
(25:15:8:2), 4-methyl-5-(methylthio) 
methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-4H-1,2,4--triazole-3-a 
mine (0.48 g) as a white solid, m.p. 104.degree.-5.degree.. 
Analysis Found: C, 61.7; H, 8.0; N, 17.7; C.sub.20 H.sub.31 N.sub.5 OS 
requires: C, 61.7; H, 8.0; N, 18.0%. 
EXAMPLE 7 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-acetamide 
A solution of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-acetonitrile dioxalate (0.05 g) in 35% hydrochloric acid (1 ml) was 
heated at 40.degree. C. for 3 h. The mixture was basified with sodium 
hydroxide and extracted with chloroform. Evaporation of the organic 
solution gave the title compound (0.01 g) as a white powder. 
TLC Silica.Ethyl acetate:isopropanol:water:ammonia (25:15:8:2)R.sub.f 0.45 
NMR (CDCl.sub.3):2.53, br.s, (1H): 2.78, t, (1H); 3.00-3.3, m, (3H); 3.73, 
br.s, (1H); 4.72, br.t, (1H); 5.90, t, (2H); 6.3-6.63 s+q+s+s, (9H); 
7.5-7.72, m+m, (6H); 8.30-8.65, m, (6H). 
EXAMPLE 8 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-methanol 
N-Amino-N'-methyl-N"-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine 
hydroiodide (2.24 g) and glycolic acid (1.52 g) were heated together for 3 
h in dry benzene (25 ml) at reflux. The benzene was decanted from the 
residual oil, which was partitioned between ethyl acetate and aqueous 1N 
sodium hydroxide solution. The organic phase was chromatographed on silica 
using methanol to give a white solid. This solid was washed with boiling 
ethyl acetate to leave the title compound as a white solid (0.013 g) m.p. 
151.degree.-2.degree.. 
NMR (CDCl.sub.3 /DMSO): 2.8, t, (1H); 3.1-3.4, m, (3H); 5.1, t, (1H); 5.42, 
s, (2H); 6.0, t, (2H); 6.5, q, (2H); 6.6, s, (3H); 6.63, s, (2H); 7.7, m., 
(4H); 7.9, m, (2H); 8.5, m, (6H). 
EXAMPLE 9 
4-Methyl-5-(methylsulphonyl)methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]pro 
pyl-4H-1,2,4-triazole-3-amine 
Peracetic acid (0.82 ml of 6.1M) in acetic acid (4.5 ml) was added at 
0.degree. to a solution of 
4-methyl-5-(methylthio)methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] 
-4H-1,2,4-triazole-3-amine (0.63 g) and sodium acetate (0.39 g) in acetic 
acid (8 ml). The mixture was stirred at room temperature for 18 h. Excess 
peracetic acid was decomposed with sodium sulphite (1g) and the resulting 
suspension was evaporated. The residue was treated with water (10 ml), 
neutralised with sodium bicarbonate solution and extracted with ethyl 
acetate. The extract was evaporated to give the title compound as a white 
solid (0.58 g), m.p. 121.degree.-3.degree. C. 
NMR (CDCl.sub.3): 2.77, dd, (1H); 3.00-3.35, m, (3H); 5.50, t, (1H); 5.65, 
s, (2H); 5.83, t, (2H); 6.35, q, (2H); 6.56-6.58, s+s, (5H); 7.04, s, 
(3H); 7.60-7.83, m, (6H); 8.25-8.70, m, (6H). 
EXAMPLE 10 
4,5-Dimethyl-N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-4 
H-1,2,4-triazole-3-amine.dimaleate 
A mixture of methyl 
N'-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N-methylcarb 
amimidothioate (4.5 g) and acetic acid hydrazide (0.89 g) was heated at 
90.degree. for 24 h. Column chromatography on silica using 
dichloromethane:ethanol:0.88 ammonia (100:8:1) gave a viscous oil (2.8 g). 
A portion of this oil (0.4 g) was treated with excess maleic acid in 
acetone to give the title compound as a white solid (0.35 g) m.p. 
93.degree.5.degree.. 
NMR (D.sub.2 O): 3.33, d, (1H); 3.63-3.70, d+s, (5H); 5.70, s, (2H); 6.20, 
s, (2H); 6.50-6.56, t+s, (5H); 7.15-7.18, s+t, (8h); 7.58, s, (3H). 
EXAMPLE 11 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-acetic acid monopotassium salt.dihydrate 
A solution of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-acetonitrile. dioxalate (0.4 g) in 35% hydrochloric acid (10 ml) was 
heated at 40.degree. for 3 h. The cooled solution was basified with 10% 
aqueous sodium carbonate solution and washed with chloroform. The aqueous 
solution was saturated with potassium carbonate and extracted with 
isopropanol. The extract was washed with saturated potassium carbonate, 
dried, and evaporated to leave a residue which was crystallised from ethyl 
acetate and methanol to give the title compound (0.16 g) as a white 
powder, m.pt. 166.degree.-169.degree.. 
Analysis Found: C, 52.30; H, 6.77; N, 15.20; C.sub.20 H.sub.28 N.sub.5 
O.sub.3 K.2H.sub.2 O requires: C, 52.05; H, 6.98; N, 15.18%. 
EXAMPLE 12 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-(2-ethanamine), trihydrochloride, monohydrate 
A solution of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-acetonitrile dioxalate (0.65 g) in ethanol (25 ml) and 0.88 ammonia 
(2.5 ml), was hydrogenated at 70 p.s.i. over 5% rhodium on alumina (4 g) 
for 18 h. The mixture was filtered through `hyflo`, and the filtrate was 
evaporated. The residue was chromatographed on silica using methanol and 
0.88 ammonia, to give a yellow gum (400 mg). A portion of this gum (200 
mg) was dissolved in methyl acetate and ethanol, and treated with ethereal 
hydrogen chloride to precipitate a white solid which was recrystallised 
from isopropanol and ethanol to give the title compound as a white powder 
(87 mg) m.p. 221.degree.-223.degree.. 
Analysis Found: C, 47.7; H, 7.2; N, 16.4; C.sub.20 H.sub.32 N.sub.6 
0.3HCl.H.sub.2 O Requires: C, 48.0; H, 7.5; N, 16.8%. 
EXAMPLE 13 
N-[2-[4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4 
-triazol-3-yl]ethyl]acetamide 
A mixture of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino-4H-1,2,4-triaz 
ole-3-(2-ethanamine) (0.16 g) and acetic anhydride (0.1 ml) in pyridine (10 
ml) was stirred at 5.degree. for 1 h. Evaporation gave an oil which was 
chromatographed on silica using methanol: 0.88 ammonia (79:1) to provide 
the title compound as a semi-solid (0.085 g) 
NMR (CDCl.sub.3): 2.78, dd, (1H); 3-3.34, m, (3H); 5.70-5.90, 2xt, (3H); 
6.2-6.6, 2xt, (4H); 6.60, s, (2H); 6.75, s, (3H); 7.30, t, (2H); 7.6-7.87, 
2xm, (7H); 8.10, s, (3H); 8.40-8.60, m, (6H); 
TLC: Methanol: 0.88 Ammonia (79:1) Rf 0.41. 
EXAMPLE 14 
N-[2-[4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4 
-triazol-3-yl]ethyl]methanesulphonamide 
A mixture of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl]phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-(2-ethanamine) (0.38 g) and methanesulphonyl chloride (0.1 g) in dry 
pyridine was stirred at room temperature for 18 h. The mixture was diluted 
with ethanol evaporated in vacuo and the residue was partitioned between 
aqueous potassium carbonate and ethyl acetate. The organic layer was 
washed with brine and evaporated to give a brown gum which was 
chromatographed on alumina using dichloromethane:ethanol:0.88 ammonia 
(75:8:1) to give a gum. This gum on trituration with diethyl ether gave 
the title compound (0.13 g) as off-white solid. m.p. 
105.degree.-6.degree.. 
NMR (CDCl.sub.3): 2.78, t, (1H); 3.00-3.33, m, (3H); 3.65, b, (1H); 5.68, 
t, (1H); 5.91, t, (2H); 6.20-6.55+6.59, m+s, (6H); 6.75, s, (3H); 7.05, s, 
(3H); 7.18, t, (2H); 7.50-8.0, m, (6H); 8.3-8.7, m, (6H): 
EXAMPLE 15 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-carboxaldehyde 
Activated manganese dioxide (20 g) and 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-triazole-3 
-methanol (2g) were stirred in chloroform (50 ml) at room temperature for 
12 h. The mixture was filtered and the filtrate was evaporated to give an 
oil which was chromatographed on silica using ethyl acetate: ethanol (9:1) 
to give a gum. This gum was crystallised from methyl acetate:light 
petroleum (b.p. 60.degree.-80.degree.) (1:2) to give the title compound as 
white crystals (0.25 g) m.p. 157.degree.-158.degree.. 
NMR (CDCl.sub.3): 0.15, s, (1H); 2.8, t, (1H); 3-3.4, m, (3H); 4.7, brt, 
(1H); 5.93, t, (2H); 6.27-6.37, q+s, (5H); 6.6, s, (2H); 7.65-7.85, m, 
(6H); 8.55, m, (6H). 
EXAMPLE 16 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triaz 
ole-3-methanol acetate(ester) 
Acetyl chloride (0.18 g) was added dropwise to a stirred solution of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-methanol (0.7 g) in pyridine (5 ml), and the reaction mixture was 
stirred at room temprature for 18 h. The solution was evaporated, excess 
aqueous sodium carbonate was added, and the mixture was extracted with 
ethyl acetate. The extract was washed with water, dried and evaporated to 
give the title compound as a white solid, (0.54 g) m.p. 
95.degree.-97.degree.. 
NMR (CDCl.sub.3): 2.7-3.5, m, (4H); 4.94, s, (2H); 5.15, t, (1H); 5.95, t, 
(2H); 6.42, q, (2H); 6.61, s, (2H); 6.68, s, (3H); 7.5-8.0, m, (6H) 
overlain by 7.95, s, (3H); 8.3-8.6, m, (6H). 
EXAMPLE 17 
N-Methyl-N'-[2-[4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino 
]-4H-1,2,4-triazol-3-yl]ethyl]-2-nitro-1,1-ethenediamine. 
A solution of 4-methyl-5-[[3-[3-(1-piperidinylmethyl) 
phenoxy]propyl]amino]-4H-1,2,4-triazolo-3-(2-ethanamine) (0.38 g) and 
methyl N-methyl-2-nitroimidothioate (0.29 g) in methanol (5 ml) and water 
(10 ml) was stirred at room temperature for 24 h, and then at 50.degree. 
for 5 h. The resulting solution was evaporated, treated with aqueous 
potassium carbonate and extracted with a mixture of ethyl acetate and 
isopropanol. The extract was washed with brine and evaporated to leave a 
gum which was chromatographed on alumina using 
dichloromethane:ethanol:0.88 ammonia (75:8:1) to give a gum. This gum on 
trituration with diethyl ether gave the title compound as an off-white 
solid. (0.06 g) m.p. 110.degree.-112.degree. 
NMR (CDCl.sub.3): 1.18, br.s, (2H); 2.78, t, (1H); 3.0-3.6, m+m, (4H); 
5.48, br.t, (1H); 5.89, t, (2H); 6.15, m, (2H); 6.42, q, (2H); 6.58, s, 
(2H); 6.70, s, (3H); 7.15, m, (5H); 7.62-7.85, m+m, (6H); 8.3-8.65, m, 
(6H). 
EXAMPLE 18 
4-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]4H-1,2,4-triazo 
le-3-carboxaldehyde oxime 
A solution of hydroxylamine hydrochloride (0.13 g) in ethanol (10 ml) was 
treated with potassium hydroxide (0.11 g). A solution of 
4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-tria 
zole-3-carboxaldehyde (0.54 g) in ethanol (10 ml) was added. The mixture 
was stirred at room temperature for 15 min and then filtered. The filtrate 
was evaporated and the residue was crystallised from a mixture of ethanol 
(5 ml) and ethyl acetate (5 ml) to give the title compound as a white 
crystalline solid (0.21 g) m.p. 187.degree.-188.degree.. 
NMR (DMSO): -1.6, br.s, (1H); 1.92, s, (1H); 2.75, t, (1H); 3.0-3.3, m, 
(3H); 3.60, br.t, (1H); 5.91, t, (2H); 6.39, s, (3H); 6.50, q, (2H); 6.62, 
s, (2H); 7.50-7.78, m, (4H); 7.78-8.05, m, (2H); 8.30-8.65, m, (6H). 
EXAMPLES OF PHARMACEUTICAL COMPOSITIONS 
______________________________________ 
Tablets mg/tablet mg/tablet 
______________________________________ 
Active ingredient 
20.0 40.0 
Microcrystalline 99.5 199.0 
cellulose BPC 
Magnesium stearate 
0.5 1.0 
B.P. 
Compression weight 
120.0 240.0 
______________________________________ 
The drug is sieved through a 250 .mu.m sieve, blended with the excipients 
and compressed using 6.5 mm and 8.0 mm diameter punches for the 20 and 40 
mg strengths respectively. Tablets of other strengths may be prepared by 
increasing the compression weight and using punches to suit. 
The tablets may be film coated with suitable film forming materials, e.g. 
methyl cellulose, ethyl cellulose or hydroxypropylmethyl cellulose, using 
standard techniques. Alternatively the tablets may be sugar coated. 
INJECTION FOR INTRAVENOUS ADMINISTRATION 
______________________________________ 
% w/v 
______________________________________ 
Active ingredient 0.25 
Water for Injections BP to 
100.00 
______________________________________ 
Sodium chloride may be added to adjust the tonicity of the solution and the 
pH may be adjusted to that of maximum stability using dilute acid or 
alkali or suitable buffer salts. 
The solution is prepared, clarified and filled under nitrogen into 
appropriate sized ampoules sealed by fusion of the glass. The injection is 
sterilised be heating in an autoclave using one of the acceptable cycles. 
Alternatively the solution may be sterilised by filtration and filled into 
sterile ampoules under aseptic conditions.