GB2116178A - Heterocyclic derivatives - Google Patents

Abstract

Compounds of the formula (I):- <IMAGE> and physiologically acceptable salts, hydrates and bioprecursors thereof have been found to show pharmacological activity as selective histamine H2-antagonists. In formula (I> R1 represents hydrogen, C1-14 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl or substituted alkyl; and R2 represents hydrogen or C1-4 alkyl; or R1 and R2 together complete an optionally substituted 5 to 10 membered ring; Alk represents C1-3 alkylene; Q represents a furan or thiophene bonded via the 2- and 5- positions, the furan or thiophene ring optionally bearing a further substituent R4 adjacent to the group R1R2N-Alk-; or Q represents a thiophene ring bonded via the 2- and 4- positions, the thiophene ring optionally bearing a further substituent R4 adjacent to the group R1R2NAlk with the proviso that when the group R1R2 NAlk is in the 4- position then the group R4 is in the 5-position; or Q represents a benzene ring bonded via the 1- and 3- or 1- and 4-positions; R4 represents halogen or C1-4 alkyl which may be substituted by hydroxy or C1-4 alkoxy; X represents oxygen, sulphur-, -NH-, methylene or a bond; Y represents oxygen, sulphur, methylene or a bond; n represents zero, 1, 2 or 3 and m is an integer from 2 to 5, with the provisos that (a) the total number of atoms in the chain X(CH2)nY(CH2)m is an integer from 3 to 8, (b) when X and Y represents oxygen or sulphur then n is 2 or 3, (c) when X represents -NH- then Q is a benzene ring and Y represents methylene or a bond, and (d) when Q represents a benzene ring, X represents oxygen, and n represents 1, then m may additionally represent 1 and Y may additionally represent -CHOR14 where R14 represents hydrogen or acyl; and R3 represents hydrogen, alkyl, alkenyl, aralkyl, or C2-6 alkyl substituted by hydroxy or alkoxy; either A represents N and B min represents CR5; or A represents CR5 and B represents N; and R5 represents one of various defined substituents.

Description

SPECIFICATION Heterocyclic derivatives This invention relates to heterocyclic derivatives having action on histamine receptors, to processes for the preparation of the said heterocyclic derivatives, to pharmaceutical compositions containing the said derivatives and to the use of these derivatives in therapeutics.

Certain heterocyclic derivatives have now been found to possess potent activity as H2antagonists. 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 British Patent Specification No. 1 565966 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 methods described by Black et al, Nature 1 972 236, 385. Furthermore the compounds antagonise the effect of histamine on the contraction frequency of isolated guinea pig right atrium.

Compounds with histamine H2-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)

and physiologically acceptable salts, and hydrates thereof, in which R, represents hydrogen, C, ,4 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl; and R2 represents hydrogen or C,~4 alkyl; or R, and R2 may together with the nitrogen atom to which they are attached form a 5 to 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,~3 alkyl e.g. methyl, groups 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 3 carbon atoms, Q represents a furan or thiophene ring in which incorporation into the rest of the molecule is through bonds at the 2- and 5- positions, the furan or thiophene ring optionally bearing a further substituent R4 adjacent to the group R,R2N-Alk-;; or Q represents a thiophene ring in which incorporation into the rest of the molecule is through bonds at the 2- and 4- positions, the thiophene ring optionally bearing a further substituent R4 adjacent to the group R,R2NAlk with the proviso that when the group R,R2NAlk is in the 4-position then the group R4 is in the 5-position; 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; R4 represents halogen or C,~4 alkyl which may be substituted by hydroxy or C,~4 alkoxy; X represents oxygen, sulphur, -NH-, methylene or a bond; Y represents oxygen, sulphur, methylene or a bond;; n represents zero, 1, 2 or 3, and m is an integer from 2 to 5, with the provisos that (a) the total number of atoms in the chain X(CH2)nY(CH2)m is an integer from 3 to 8, (b) when X and Y represent oxygen or sulphur then n is 2 or 3, (c) when X represents -NH- then Q is a benzene ring and Y represents methylene or a bond, and (d) when Q represents a benzene ring, X represents oxygen, and n represents 1, then m may additionally represent 1 and Y may additionally represent -CHOR14 where R,4 represents hydrogen or acyl; and R3 represents hydrogen, alkyl, alkenyl, aralkyl, or C26 alkyl substituted by hydroxy or alkoxy; either A represents N and B represents CR5; or A represents CR5 and B represents N; and R5 represents (i) a C25 straight or branched alkyl group substituted by two or three hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group may form a cyclic acetal or cyclic ketal structure of the formula

where p is zero or 1 and Re and R7 which may be the same or different, each represents hydrogen, a C1 ~, alkyl group or a phenyl group; or (ii) the group (CH2)qZ(CH2)rR8, where q represents an integer from 1 to 4 inclusive, r represents an integer from 1 to 6 inclusive, Z represents oxygen or sulphur and when r represents 1, R8 represents the group CH = CH2, alkenyl or the group COR9 where R9 is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the group NR,o R" where R10 is hydrogen or alkyl and R" is hydrogen or alkyl and when r represents an integer from 2 to 6, R8 has any of the meanings given above or may additionally represent hydroxy, alkoxy, aryloxy or the group NR,2R,3 where R,2 is hydrogen or alkyl and R,3 is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulphonyl or arylsulphonyl, with the proviso that the total of q and r is preferably 6 or less; or (iii) the group (CH2)xS(CH2)yR15, where x represents 1 or 2, y represents zero or 1, and R,s represents a heteroaryl group; or (iv) an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy, alkoxy or acyloxy.

In the above formula (I) the term "alkyl" as a group or part of a group means that the group is straight or branched and, unless otherwise stated, contains 1 to 6 carbon atoms, and in particular 1 to 4 carbon atoms, e.g. methyl or ethyl, and the term "alkenyl" means that the group has preferably 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 3 to 8 carbon atoms. 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,~3 alkyl or C,~3 alkoxy groups, or halogen atoms, e.g. fluorine. The term "acyl" means an aroyl, aralkanoyl or C16 alkanoyl group, e.g. acetyl, formyl, phenylacetyl or benzoyl.The term "heteroaryl" as a part of a group within the definition of R, means a 5 or 6 membered monocyclic ring containing 1 to 3 heteroatoms selcted from oxygen, nitrogen and sulphur, e.g. thienyl, pyridyl, furyl or thiazolyl.

The heteroaryl ring may be unsubstituted or substituted by C,~3 alkyl, C,~3 alkoxy, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The term "heteroaryl" as part of a group within part (iv) of the definition of R5 means a 5 or 6 membered monocyclic ring containing one heteroatom selected from oxygen, nitrogen and sulphur, e.g. thienyl, pyridinyl or furyl, optionally substituted by a C,~3 alkyl group. The alkyl portion of a heteroaralkyl group is a straight or branched C14 alkyl chain, and the heteroaryl ring is linked to the alkyl portion through a carbon atom.The term "heteroaryl" within the definition of R,s means a monocyclic or bicyclic unsaturated ring containing from 5 to 10 atoms selected from carbon, oxygen, nitrogen or sulphur. If the heteroaryl ring is monocyclic it preferably contains 5 or 6 members and if it is bicyclic it preferably contains 9 or 10 members. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isoquinolyl, quinolyl, indolyl or benzoxazolyl. The ring structure may be unsubstituted or substituted by one or more groups selected from C,~3 alkyl, C,~3 alkoxy or hydroxy.

One aspect of the invention relates to compounds of formula (I) in which R, R2 R3 Alk, Q, X, Y, n and m are as defined above but excluding the additional possibilities for m and Y given by proviso (d), and A represents N and B represents CR5 or A represents CR5 and B represents N where R5 is as defined in possibility (i) above or in possibility (ii) above (except that q can only represent 1 or 2).

Another aspect of the invention relates to compound of formula (I) in which R, R2,R3, Alk, Q, X, Y, n and m are as defined above but excluding the additional possibilities for m and Y given by proviso (d), and A represents N and B represents CR5 or A represents CR5 and B represents N where R5 is as defined in possibility (iv) above.

Preferred compounds of formula (I) are those in which R, represents C1 -e alkyl (e.g. methyl, propyl, butyl or heptyl), C1 ~, alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), C24 alkyl substituted by hydroxy or a di C13 alkyl amino group (e.g. 3-hydroxypropyl or dimethylaminoethyl), C57 cycloalkyl (e.g cyclohexyl), C35 alkenyl (e.g. allyl), phenyl C13 alkyl (e.g. benzyl), or a heteroaryl C13 alkyl group where the heteroaryl ring contains one heteroatom (e.g. 2-furylmethyl); R2 represents hydrogen or methyl; or R,R2N represents a 5-8 membered ring optionally containing a double bond, an oxygen atom or an alkyl (e.g. methyl) substituent (e.g. piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethylenimino or tetrahydropyridino); Alk represents methylene; Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1 - and 3- positions; or a furan ring incorporated into the rest of the molecule through bonds at the 2- and 5positions optionally bearing a substituent R4 adjacent to the group R1R2NAlk where R4 is C,~4 alkyl (e.g. methyl); or a thiophene ring incorporated into the rest of the molecule through bonds at the 2- and 4- positions with the substituent R,R2NAlk in the 2- position; with the provisos that when Q is a benzene ring as just defined, then X is a bond, n is zero, Y is oxygen and m is 3, 4 or 5, or X and Y both represent oxygen and n and m are both 2, or X is oxygen, Y is CHOH and n and m are both 1; and when Q is a furan or thiophene ring as just defined, then X is a bond and either Y is sulphur or CH2, n is 1 and m is 2, or Y is oxygen, n is 1 and m is 3; R3 represents hydrogen or alkyl (e.g methyl); R5 represents a C24 alkyl group substituted by two hydroxy groups, or a 2,2-di C,~3 alkyl (e.g. dimethyl)-l ,3-dioxolan-4-yl group or R5 represents phenyl C,~3 alkyl (e.g. benzyl) or heteroaryl C,~3 alkyl (e.g. furylmethyl or pyridylmethyl) in which the alkyl portion is substituted by hydroxy, C1-4 alkanoyloxy (e.g.

acetyloxy) or C1 -2 alkoxy (e.g. methoxy); or R5 represents the group (CH2)qZ(CH2)rR8, in which q is 1, r is 1 to 4 when Z is oxygen, or r is 1 when Z is sulphur, and R8 is hydroxy, the group -CH = CH2, di C13 alkylamino (e.g.

dimethylamino), or the group COR9, where R9 is C1 -4 alkoxy (e.g. ethoxy) or the group NHR" where R" is C,~3 alkyl (e.g. methyl); or R5 represents the group (CH2)xS(CH2)yR15, in which x represents 1 and the heteroaryl group R,5 is tetrazolyl or thiadiazolyl each of which is substituted by C, -3 alkyl (e.g. methyl), or R,5 is furyl; more preferably y is zero and R,5 is 1-methyl-1 H-tetrazol-5-yl.

Within the preferred meaning of R5 compounds in which R5 is defined as follows can be regarded as a separate aspect of the invention.

R5 represents a C24 alkyl group substituted by two hydroxy groups, or a 2,2-di C13 alkyl (e.g. dimethyl)- 1 ,3-dioxolan-4-yl group; or R5 represents phenyl C,~3 alkyl (e.g. benzyl) in which the alkyl portion is substituted by C,~4 alkanoyloxy (e.g. acetyloxy) or C1-2 alkoxy (e.g. methoxy), or heteroaryl C13 alkyl (e.g.

furylmethyl or pyridylmethyl) in which the alkyl portion is substituted by hydroxy, C1-4 alkanolyoxy (e.g. acetyloxy) or C1-2 alkoxy (e.g. methoxy); or R5 represents the group (CH2)qZ(CH2)rR8, in which q is 1, r is 1 to 4 when Z is oxygen, or r is 1 when Z is sulphur, and R8 is hydroxy, the group -CH = CH2, di C13 alkylamino (e.g.

dimethylamino), or the group COR9 where R9 is C, ~4 alkoxy (e.g. ethoxy) or the group NHR" where R1, is C13 alkyl (e.g. methyl) or; R5 represents the group (CH2)xS(CH2)yR15, in which x represents 1 and the heteroaryl group R,5 is tetrazolyl or thiadiazolyl each of which is substituted by C,~3 alkyl (e.g. methyl), or R,5 is furyl; more preferably y is zero and R,5 is 1-methyl-1 H-tetrazol-5-yl.

A particularly preferred group of compounds are those of formula (II)

in which R,R2N represents diC1-3 alkylamino (e.g. dimethylamino), furylmethylamino, or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleimino, more preferably piperidino; A represents N and B represents CR5, or A represents CR5 and B represents N, where R5 represents C24 alkyl substituted by two hydroxy groups, 2,2-di C13 alkyl (e.g. dimethyl)1,3-dioxolan-4-yl, (1-methyl-1 H-tetrazol-5-yl)thiomethyl, or R5 represents phenyl C13 alkyl (e.g. benzyl) or heteroaryl C13 alkyl (e.g. furylmethyl or pyridylmethyl) in which the alkyl portion is substituted by hydroxy, or phenyl C,~3 alkyl (e.g.

benzyl) in which the alkyl portion is substituted by C1 - alkanoyloxy (e.g. acetyloxy) or C, -2 alkoxy (e.g. methoxy), or R5 represents the group CH2Z(CH2)rR8 where, R8 is hydroxy or di C13 alkylamino (e.g.

dimethylamino), Z is oxygen and r is 4; or R8 is the group -CH = CH2 or the group COR9 where R9 is C1 ~, alkoxy (e.g. ethoxy), Z is oxygen or sulphur and r is 1; and either Q is 1,3-benzene, and X is a bond, n is zero, Y is oxygen and m is 3 or 4, more preferably 3; or X is oxygen, n is 1, Y is -CHOH- and m is 1; or O is 2,5-furan or 2,4thiophene, Xis a bond, Y is sulphur, n is 1 and m is 2; with the proviso that R,R2N is di C13 alkylamino when Q is a furan or thiophene ring.

A further particularly preferred group of compounds are those of formula (II), in which either R,R2N is dimethylamino, Q is a 2,5-furan, X is a bond, Y is sulphur, n is 1 and m is 2; or R,R2N is methylamino or pyrrolidino, piperidino, or hexamethylenimino, more preferably piperidino, Q is a 1,3-benzene, X is a bond, Y is oxygen, n is zero, and m is 3 or 4, more preferably 3; and A represents N and B represents CR5, or A represents CR5 and B represents N, where R5 is benzyl in which the methylene group is substituted by hydroxy; with the proviso that, when Q is a furan ring, then preferably A is N and B is CR5.

Particularly preferred compounds are 5-((2-[[[5-(di methylamino)methyl]-2-furanyljmethyl]- thio]ethyl]amino]- 1 -methyl-a-phenyl- 1 H-i , 2,4-triazole-3-methanol, 1 -methyl-3-[[(1 -methyl-l H-tetrazol-5-yl)thio]methyl]-N-[3-[3-(1 -piperidinylmethyl)phenoxy]pro- pyl]-i H-l ,2,4-triazol-5-amine, 1 -methyl-cy-phenyl-5-C[3-C3-(1 -piperid inylmethyl)phenoxy]propyl]amino]- 1 H- 1,2,4-triazole-3- methanol, 4-methyl-a-phenyl-5-([3-(3-( 1 -piperidinylmethyl)phenoxy]propyl]amino]-4H- 1, 2,4-triazole-3- methanol, 1 -methyl-5-(3-[(( 1 -piperidinylmethyl)phenoxy]propyl]amino]-i H- ,2,4-triazole-3-ethane-l 1,2- diol, an( 1 -methyl-5-[[3-[3-(1 -piperid inyl methyl)phenoxy]propyl]ami no]- 1 H- , 2,4-triazole-3-yl]-2-pyri- dinemethanol, 5-[[2-hydroxy-3-[3-( 1 -piperidinyl methyl)phenoxyjpropyl]am ino]- 1 -methyi-a-phenyl- 1 H-1,2,4-tri- azole-3-methanol, 5-([3-(3-[(dimethylamino)methyl]phenoxy]prnpyl]amino]- 1 -methyl-a-phenyl- 1 H-i , 2,4-triazole- 3-methanol, 5-[[2-[[[5-[(d imethylam i no)methyl]-3-thienyl]methyl]thio]ethyl]amino]- 1 -methyl-a-phenyl- 1 H 1,2,4-triazole-3-methanol, 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, hydro bromides, sulphates, methanesulphonates, acetates, maleates, succinates, citrates, tartrates, fumarates and benzoates. The compounds of formula (I) and their salts may also form hydrates, and the hydrates of the compounds of formula (I) are also to be considered as part of the invention. The compounds of formula (I) can exhibit tautomerism and the formulae are intended to cover all tautomers. Where optical isomers may exist the formulae are intended to cover all diastereoisomers and optical enantiomers. It should be understood that the present invention includes bioprecursors of the compounds of formula (I).The term bioprecursors means compounds which have a structure different to that of the compounds of formula (I) but which, upon administration to the animal or human being, are converted in the body into a compound of formula (I).

The compounds of formula (I) 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 formula (I) 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,-antagonists.

Thus the compounds of formula (I) may be formulated for oral, buccal, topical, parenteral or rectal aministration. Oral administration is preferred.

For oral administration, the pharmaceutical composition may take the form of for example, tablets, capsules, powders, solutions, 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 formula (I) 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 multidose 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 soluble vehicle e.g.

sterile pyrogen-free water before use.

The compounds of formula (I) may also be formulated in rectal compositions ch as suppositories or retention enemas, e.g. containing conventional suppository base such as cocoa butter or other glycerides.

For topical application, the compounds of formula (I) 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 500 mg per day, dependent upon tha 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, and R2 are hydrogen atoms and/or when R3 is an alkyl group bearing a hydroxy substituent and/or when R5 contains a hydroxy or amino group. Standard protection and deprotection procedures can be employed, for example amines may be protected by formation of a phthalimide group 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 R1 to R15, A, B, Alk, Q, X, Y, Z, n, m, p, q, r, x and y in the various formulae are as defined in formula (I) unless otherwise stated.

Compounds of formula (I) in which R5 represents the group (CH2)qZ(CH2)rR8 or (CH2)xS(CH2)yR15 may be prepared by reaction of a triazole of formula (I) in which R5 represents the group R5a where R5a is -(CH2)qL or -(CH2)XL and L is a leaving group such as halogen, mesyloxy or tosyloxy, with an anion 6Z(CH2)rR8 or aS(CH2)yR15. The anion may be generated from the corresponding alcohol by treatment with sodium or a strong base such as sodium hydride in the absence or presence of a solvent, for example dimethylformamide, at a temperature in the range from 20 to 120o, or from the corresponding thiol by treatment with a base such as potassium or sodium carbonate in the presence of a solvent, for example acetone, at a temperature within the above range.

The intermediates of formula (I) in which R5 represents the group R5a where R5a is -(Ch2) L or -(CH2)XL may be prepared by reacting the corresponding compound in which R58 is ~(Ch2)qOH or -(CH2)XOH with an acid chloride such as thionyl chloride, methanesulphonyl chloride or ptoluenesulphonyl chloride.

The intermediates of formula (I) in which R5 represents the group R5a where R5, is (CH2)qOH or (CH2)xOH may be prepared as described in British Patent Specification No. 2047238A and European published specification No. 48555.

Compounds of formula (I) may also be prepared by cyclisation of an appropriate intermediate.

Thus compounds of formula (I) in which R5 is other than a C26 straight or branched alkyl group substituted by two or three acyloxy groups, or a dihydroxyalkyl group forming a cyclic acetal or cyclic ketal structure or an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group or Y is other than CHOR14 where R14 is acyl can be prepared by cyclisation of a compound of formula (III)

in which R16 is a group as defined for R3, V' is

is hydrogen where V is oxygen or sulphur and R5, is a group as defined for R5 or a group convertible thereto under the conditions of the cyclisation reaction; or V' is NH, R,6 is a group as defined for R3 and Y' is

where Y" is sulphur, oxygen or NH; or V' is sulphur or oxygen, Y' is

and R,6 is a group as defined for R3; or V' is NR3, R,6 is hydrogen and Y' is

where Y" is as defined above.

Thus for example in one embodiment of the cyclisation process a compound of formula (I) in which A is N and B is the group CR5 may be prepared by cyclisation of a compound of formula (IV)

where V represents sulphur or more preferably oxygen and U represents two hydrogen atoms, in the absence or presence of a solvent, e.g. a hydrocarbon such as toluene, a ketone such as acetone, or water, and optionally with heating, for example, within the range 50" to 90 .

It may be convenient to prepared in situ compounds of formula (IV) in which U represents two hydrogen atoms by treating a compound of formula (IV) where U represents a divalent protecting group which can readily be removed to yield two hydrogen atoms, for example a benzylidene group, with an acid, e.g. hydrochloric acid, preferably with heating, and under such conditions cyclisation to give the corresponding compound of formula (I) will normally occur.

In a further embodiment of the cyclisation of compounds of formula (III), compounds of formula (I) may be prepared by cyclisation of a compound of formula (V)

where R,6 is a group as defined for R3, and either V' is NH and Y" is sulphur, oxygen or NH, or V' is sulphur or oxygen and Y" is NH; or Rie is hydrogen, V' is NR3 and Y" is sulphur.

When Y" represents sulphur then tautomerism with the adjacent NH group is possible

and the -SH group may be alkylated under standard conditions. The S-alkylated compound may also be used in the cyclisation process.

The cyclisation may be carried out by heating the compound (V) (e.g. within the range 80 to 150 ) in the absence or presence of a solvent (e.g. acetonitrile or dimethylformamide), or under basic conditions (e.g. using aqueous potassium hydroxide).

In a convenient embodiment of this process an intermediate of formula (V) in which R,6 is a group as defined for R3, V' is NH and Y" is oxygen; or R,6 is hydrogen, V' is NR3 and Y" is oxygen may be prepared in situ by the reaction of an aminoguanidine (VI)

with an acid R5COOH or with an activated derivative thereof. Suitable activated derivatives include acid halides, e.g. acid chlorides, alkylchloroformates, acid anhydrides including mixed an hydrides (e.g. acetic formic anhydride), esters such as alkyl esters, ortho esters (such as trialkylorthoesters, e.g. R5C(OEt)3) and (1 -alkyl-2-pyridinyl) esters, or derivatives formed from a coupling agent such as carbonyldiimidazole or a carbodiimide such as dicyclohexylcarbodiimide.

The acid and the aminoguanidine (VI) may be heated together, under which conditions cyclisation of the intermediate (V) takes place directly to give a compound of formula (I). In the case of an activated derivative, an aprotic solvent, e.g. tetrahydrofuran may be used at temperatures from ambier.t to reflux. When using an acyl chloride as the activated derivative the reaction may also be carried out in the presence of a base, e.g. a tertiary amine such as pyridine, which may also be used as the softens.

In general intermediates of formula (IV) may be prepared from the appropriate diamines by methods analogous to those described in British Patent Specification No. 2047238A, and intermediates of formula (V) may be prepared from the appropriate diamines by methods analogous to those described in British Patent Specification No. 20231 33A and in European Patent Specification No. 48555. The aminoguanidines (VI) may be prepared as described in British Patent Specification No. 2023133A, and European Patent Specification No. 48555.

Compounds of formula (I) in which Alk is CH2 may be prepared by treating an aldehyde of formula (VII)

with an amine R,R2NH, for example in a solvent such as tetrahydrofuran or an alkanol, e.g.

ethanol, followed by reduction using for example a hydride reducing agent such as an alkali or alkaline earth metal borohydride, e.g. sodium borohydride or lithium aluminium hydride, or hydrogen and a metal catalyst- such as palladium or platinum. The reactions may be carried out at a temperature of 0" to 80"C.

The intermediates of formula (VII) may be prepared from compounds of formula (VIII) WOX(CH2)nY(CH2)rnNH2 (VIII) in which W represents a protected aldehyde group, e.g. a cyclic acetal such as an ethylene acetal, by methods analogous to those described herein for preparing compounds of formula (I) from the appropriate diamine.

Compounds of formula (I) in which R5 is an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy may be prepared by reacting the appropriate aldehyde or ketone with an organolithium compound ArLi or a Grignard reagent ArMgHal where Ar is an appropriate aryl, aralkyl, heteroaryl or heteroaralkyl group and Hal is halogen. The reaction may be carried out in a suitable solvent such as an ether e.g. diethylether, tetrahydrofuran or a mixture thereof at a temperature of from - 70" to 50", preferably at - 70 to 20" for the reaction with ArLi and at O to 50" for the reaction with ArMgHal. The aldehyde or ketone starting material may be prepared as described in British Patent Specification No. 2075007A and European Patent Specification No. 48555.

Compounds of formula (I) in which R5 has one meaning may be converted into compounds of formula (I) in which R5 has another meaning using standard methods of interconversion.

Thus, compounds in which R5 represents a C26 atraight or branched alkyl group substituted by two or three acyloxy groups, or R5 represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group, or Y represents CHOR,4 where R,4 is acyl, may be prepared by reacting the corresponding alcohol with an activated derivative (e.g. an acid chloride or an acid an hydride) 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 preferably in the presence of a base (e.g. pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate).

Compounds in which R5 represents a C26 straight or branched alkyl group substituted by two or three alkoxy groups, or R5 represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an alkoxy group may be prepared from the corresponding alcohol by treatment with an halogenating agent, for example thionyl chloride, followed by reaction of the resulting halocompound with an appropriate alkanol in the presence of sodium at a temperature within the range 20-50". Alternatively the intermediate halocompound may be treated with an appropriate alkanol in a solvent such as dimethylformamide, in the presence of a strong base such as sodium hydride, at a temperature within the range 20-100".

Compounds in which R5 represents the group (CH2)qZ(CH2)rR8 where R8 is NR,2R,3 and R,2 and R,3 each represent hydrogen or alkyl may be prepared from the corresponding alcohol in which R8 is hydroxy by treatment with a reagent capable of converting the group R8 into a leaving group, for example thionyl chloride, followed by reaction of the resulting compound of formula (I) in which R5 represents (CH2)qZ(CH2)rL where L is a leaving group e.g. halogen with ammonia or an appropriate amine R,2R,3NH preferably in a solvent such as an alkanol, e.g.

ethanol at a temperature within the range 80-120".

Compounds in which Re is the group NHR,2 may be converted into compounds in which R5 is the group NR,2R,3 where R,3 is either an acyl group or an aryl- or alkylsulphonyl group, by reaction with an activated derivative of the appropriate carboxylic or sulphonic acid.

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 is carried out in the absence or presence of a solvent such as pyridine.

Compounds in which R8 is the group -CONR,oR1, may be prepared by reacting an activated derivative of the corresponding carboxylic acid in which R8 is the group -CO2H, e.g. an ester with ammonia or an appropriate amine HNR,OR" in a suitable solvent (e.g. an alcohol such as ethanol) at a temperature of from 20"C to 1 20"C.

Compounds in which R5 includes the group

may be converted into the corresponding compounds in which R5 includes the group

by reaction with an aldehyde or ketone R6R7CO, e.g. acetone in the presence of an acid, e.g. ptoluenesulphonic acid. The reaction is carried out in the absence or presence of a solvent, e.g.

benzene, at a temperature between room temperature and reflux.

Where the product of any of the above processes is a free base and an acid addition salt, in particular a physiologically acceptable salt is required, the salt may be formed in 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 also includes interconversion of one salt of the compound of formula (I) into another.

The invention is illustrated but not limited by the following Examples and Preparations, in which temperatures are in "C.

Unles otherwise stated the silica used for column chromatography was Merck Kieselgel 60 (7734).

T.l.c. refers to thin layer chromatography and this and preparative chromatography were carried out on silica using, unless otherwise stated, one of the following solvent systems: System A: Dichloromethane:ethanol:0.88 ammonia (50:8:1) System B: Dichloromethane:ethanol:0.88 ammonia (25:8:1) System C: Dichloromethane:ethanol:0.88 ammonia (100:8:1) System D: Ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) System E: Dichloromethane:ethanol:0.88 ammonia (75:8:1) Preparation 1 Methyl N-[2, 3-diacetyloxypropionyl]- l-methyl-2-(phenylmethylene)hydrazine carboximidothioate Di-acetyl glyceric acid (13.8 9) was heated under reflux in thionyl chloride (50 ml) for 4 h.

The solution was evaporated in vacuo and azeotroped with toluene (3 X 50 ml) to give an oil which was used without further purification. This oil was dissolved in dichloromethane (100 ml) and added dropwise to a solution of methyl 1 -methyl-2-(phenylmethylene)hydrazine carboximi dothioate hydrochloride (15.4 g) in dichloromethane (250 ml) and triethylamine (19.3 ml) which had previously been stirred at 20" for 0.5 h. The reaction was stirred at 20" for 1 5 h before adding water. The organic phase was separated, dried (MgSO4) and evaporated to leave a residue (7 g) which was chromatographed using ether as eluent to give the title compound as a yellow waxy solid (4.6 g).

NMR (CDCl3): 2.16, s, (1H); 2.2-2.7. m, (3H); 4.58-5.45, m, (3H); 6.57, s, (3H); 7.67, s, (3H); 7.85, s, (3H); 7.93, s, (3H).

Preparation 2 Methyl N-(2-acetyloxy-(2-(phen yl)-acetyljj- 1 -meth yl-2-(phenylmeth ylene)h ydrazine carboximidothioate A solution of acetyl chloride (11.35 9) in dry ether (50 ml) was slowly added to a solution of mandelic acid (20 g) in ether (100 ml). The solution was heated at reflux for 3 days, before it was evaporated to leave a pale yellow oil. This oil was heated at reflux for 3h with thionyl chloride (31 g). The thionyl chloride was removed by azeotropic distrillation with toluene to leave an oil (27.7 g) which was used without further purification.

This oil was dissolved in toluene (50 ml) and added to a suspension of triethylamine (5.8 9) and methyl 1 -methyl-2-(phenylmethylene)hydrazine carboximidothioate hydrochloride (6.9 g) in dry toluene (180 ml). The reaction was stirred at room temperature for 1 5 h, poured onto water and extracted with ether. The organic extract was dried (MgSO4) and evaporated to give the title compound as a cream solid (6.3 9).

NMR (CDCl3): 2.25, s, (1H); 2.3-2.8, m, (10H); 3.95, s, (1H); 6.7, s, (3H); 7.8, s, (3H); 7.9, s, (3 H).

Preparation 3 (i) 2-[2-Hydroxy-3-[3-( 1 -piperidinylmethyl)phenoxy]propyl]- 1 H-isoindole- 1, 3-(2H)-dione A mixture of 2-(oxiranylmethyl)-l H-isoindole-l ,3-(2H)-dione (9.10 g) and 3-(l-piperidinylme- thyl)phenol (8.55 g) was heated at 1 30"C under nitrogen for 10 minutes. The resulting mixture was dissolved in chloroform (100 ml), washed with 1 N sodium hydroxide (2 x 25 ml), dried (MgS04) and evaporated to give the title compound as a gum (17.65 9).

T.l.c. system C; Rf 0.60.

(i i) 1 -Amino-3-(3-(( 1 -piperidinylmethyl)phenoxy]-2-propanol A solution of 2-[2-hydroxy-3-3-( 1 -piperidinylmethyl) phenoxy]propyl]- 1 H-iosindole-l, 3-(2H) dione (17.6 9) and hydrazine hydrate (2.5 g) in ethanol (60 ml) was heated under reflux for 3 h.

The resulting mixture was evaporated to a solid residue which was suspended in 1 N hydrochloric acid (30 ml) and filtered. The filtrate was basified with an excess of potassium carbonate and extracted with isopropanol (3 X 40 ml). The isopropanol extracts were dried (Na2CO3) and evaporated to a gum which was chromatographed using System A. Crystallisation of the product from n-hexane:ether (20:1) gave the title compound as colourless grains (7.7 g), m.p. 74-76.5".

Preparation 4 5-[[3-(3-Formylphenoxy)propyl]amino]- 1 -methyl-phenyl- 1 H- 1,2, 4-triazole-3-methanol acetate (ester).

A solution of 3-(3-(i ,3-dioxolan-2-yl)phenoxy]propanamine (6.0 g) and compound A(11.33 g) in toluene (300 ml) was stirred at 20" for 4 h, 5N hydrochloric acid (30 ml) was added and the mixture was stirred at 20" for a further 18h. The acidic layer was separated, washed with toluene basified with 2N sodium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to give a gum (9.0 g) which was chromatographed on activated alumina [Phase Separations Ltd (UG1)1 using ether:ethyl acetate:methanol 50:50:1 as eluent to give the title compound (1.4 9) as a foam.

T.l.c. System C Rf 0.7.

*Compound A = methyl-N-12-acetyloxy-[2-phenyl)-acetyl] 1 -methyl-2-(phenylmethylene) hydra zine carboximidothioate Example 1 1 -Methyl-5-f3-((( 1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H- 1,2, 4-triazole-3-ethane- 1, 2-diol, hemicitrate To a mixture of methyl N-[2, 3-diacetyloxypropionyl]- 1 -methyl-2-(phenylmethylene)hydrazine carboximidothioate (2.69 9) in toluene (100 ml) was added 3-[3-(1-piperidinylmethyl)phenoxy]- propanamine (1.5 9) and the resulting solutions stirred at 20" for 16 h before 5N hydrochloric acid (25 ml) was added and the two phase mixture stirred vigorously for a further 16h. The acidic layer was separated and the toluene layer washed with 2N hydrochloric acid.The combined acidic layers were washed with toluene before being basified and subsequently saturated with solid sodium carbonate. The basic solution was extracted with ethyl acetate and the combined organic extracts dried (MgSO4) and evaporated. The residue (2.0 g) was chromatographed using chloroform:methanol (5:1) as eluent to give a foam (0.6 9). The foam was dissolved in ethyl acetate (20 ml). with the aid of methanol (4 ml) and treated with a stoichiometric amount of citric acid in ethyl acetate (20 ml), under nitrogen. The suspension was stirred 20" for 0.5 h, the compound was collected and dried in vacuo to give the title compound as a white solid (0.53 g), m.p. 73-74" softens: T.l.c. System D.Rf. 0.46 Example 2 (a) 5-rC2-Hydroxy-3-f3-( 1 -piperidinylmethyl)phenoxyjpropyljaminoj- 1 -methyl-er-phenyl- 1 H- 1,2, 4-triazole-3-methanol A solution of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol (2.0 g) and methyl-N-(2- acetyloxy-[2-(phenyl)-acetyl]]- 1 -methyl-2-(phenylmethylene) hydrazine carboxim idothioate, compound A (3.19 g) in toluene (60 ml) was stirred at 20" for 4h, 5N hydrochloric acid (9 ml) was added and the mixture was stirred at 20" for 1 6h and heated on a steam bath for 1 5 min.The acidic layer was separated, washed with toluene, basified with saturated aqueous sodium bicarbonate, washed with toluene, and the aqueous layer basified with 5N sodium hydroxide.

The basic layer was extracted with hot 4-methyl-2-pentanone (3 X 100 ml) and the extracts washed with brine, dried, and concentrated in vacuo to a volume of 1 50 ml whereupon crystallisaion occured. The resulting solid (1.2 g) was collected on a filter and recrystallised from 2-propanol to give the title compound (0.63 g) as a white solid m.p. 154-157".

Found: C, 66.2; H, 7.2; N, 15.2; C25H33N505 requires: C, 66.5; H, 7.4; N, 15.5% Example 2 (b) Similarly prepared from Compound A (1.5 g) and 3-[3-(dimethylamino)methyl]phenoxy]propa- namine (0.74 g), except that the 4-methyl-2-pentanone extract was evaporated in vacuo and the residue (1.3 g) was chromatographed using System A as eluent, was 5-[[3-[3-[(dimethylamino) methyl]phenoxy]propyljamino]- 1 -methyl-a-phenyl-i H- , 2,4-triazole-3-methanol hydrate (0.31 g) as a white foam.

Found: C, 63.7; H, 7.3 ; N, 16.6; C22H29N5O2.iH2O requires: C, 63.9; H, 7.59; N, 16.9% N.m.r. (CDCI3-DMSO): 2.4-2.92, m, (6H); 3.05-3.33, m, (3H): 4.4, s, (1 H); 4.65, s(br), (1 H); 5.58, s, (br), (1 H); 5.98, t, (2H); 6.4-6.75, s + s + q, (7H); 7.85, s, (6H); 8.0, quintet, (2H).

Example 2 (c) Similarly prepared from Compound A (1.5) and 2-(2-[3-(i-piperidinylmethyl)phenoxy]ethoxy]e- thanamine (0.99 g), with exceptions that the aqueous phase was extracted with hot ethyl acetate (6 x 50 ml) at pH 7 and chromatographed using dichloromethane:ethanol:0.88 ammonia (80:8:1) was 1 -methyl-a-phenyl-5-[[2-[2-[3-( 1 -piperidinylmethyl)phenoxyjethoxy]ethyl]ami no]iH-i,2,4-triazole-3-methanol (0.45 g) as a clear gum.

Found: C, 66.95; H, 7.75; N, 14.65; C26H35N503 requires: C, 67.07; H, 7.58; N, 15.04% N.m.r. (CDCl3): 2.4-2.9, m, (6H); 3-3.35, m, (3H); 4.3, s, (1H); 5.6, t, (1H); 5.95, m, (2H); 6.27-6.8, m, (5H); 6.67, 2 xs, (6H); 7.75, m, (4H); 8.56, m, (6H).

Example 2 (d) 5-2-5-Dimeth ylam in o)meth yl]- 3-th ien yl]meth yl]th io]eth yl]am in o]- 1 -m eth yl-a-phen yl-l H 1,2, 4-triazole-3-methanol A solution of 4-[[[2-(aminoethyl)]thio]methyl]-N, N-dimethyl-2-thiophene-methanamine (1.09 g) and compound A (2 g) in toluene (40 ml) was stirred at 20" for 4 h. 5N hydrochloric acid (5 ml) was added and the mixture was stirred at 20" for 16h, then heated on the steam bath for 10 min. The acidic layer was basified to pH 3 with sodium bicarbonate, washed with toluene, basified to pH 9 with sodium carbonate and extracted with ethyl acetate. The ethyl acetate extract was dried, and evaporated to give a gum which was chromatographed using System C as eluent to give the title compound (0.45 g) as a fawn coloured foam.

N.m.r. (CDCI3 + DMSO): 2.35-2.85, m, (5H); 3.01, s, (1 H); 3.12, s, (1 H); 4.33, s, (1 H); 4.62, t, (1 H); 5.75, br, (1 H); 6.40, s, (2H); 6.45, s, (2H); 6.55, s, (3H); 6.5-6.7, t, (2H); 7.35, t, (2H); 7.75, s, (6H).

T.l.c. System A. Rf 0.5.

Example 3 (a) 1-Methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-3-[(2-propenyloxylmethyl]- 1 H- 1,2,4- triazol-5-amine 1-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1 H- , 2,4-triazole-3-methanol (3.59 9) was dissolved in thionyl chloride (10 ml) and heated at reflux for 15 min. The orange solution was evaporated under reduced pressure to leave a gum which was stirred in water (35 ml) at 20". Sodium bicarbonate and sodium carbonate (3 9) were added, and the suspension was stirred with ethyl acetate. The organic phase was separated, dried for 1 h with sodium carbonate and evaporated in vacuo to give an oil. This oil was dissolved in allyl alcohol (10 ml) and added to a solution of sodium (0.3 9) in allyl alcohol (8 ml).The reaction mixture was heated on a steam-bath for 6h, poured into water and extracted with ethyl acetate. The organic phase was extracted with 2N hydrochloric acid. The acidic extract was basified to pH 9 with potassium carbonate and extracted with ethyl acetate. Evaporation of the organic extracts gave an oil (1.1 9) which was chromatographed using dichloromethane:ethanol:ammonia: (70:8:1) as eluent to give the title compound as an oil (0.4 9) Assay Found: C, 65.64; H, 8.46; N, 17.44; C22H33N502 requires: C, 66.14; H, 8.33; N, 17.53.

T.l.c. System C Rf 0.4 (b) Similarly prepared by this procedure from 1 -methyl-S-[[3-(3-( 1 -piperid i nylmethyl)phenoxy]- proply]amino]-1H-1,2,4-triazole-3-methanol (3.59 9) and thionyl chloride (10 ml), followed by addition of a solution of sodium (0.3 g) in butane-i,4-diol (109) was 4-((i-methyl-5-([3-[3-(i- piperidinylmethyl)phenoxy]propyl]amino-1 h-i , 2,4-triazol-3-yl]methoxy]butanol compound with ethanol (2:1) (0.87 9).

Assay Found: C, 63.12; H. 8.81; N, 15.56; Q3H27N503+C2H5OH requires: C, 63.40; H, 8.87; N, 15.41; NMR (CDCl3): 2.8, t, (1 H); 3.0-3.3, m, (3H); 5.4, br.t, (1 H); 5.62, s, (2H); 5.95, t, (2H); 6.4, m, (6H); 6.5, s, (3H); 6.6, s, (2H); 7.0, br, (1H); 7.6, m, (4H); 7.9, m, (2H); 8.1-8.7, m, (1 OH).

Example 4a Ethyl ff1 -Methyl-5-ff3-( 1 -piperidinylmethyl)phenoxyjpropyljaminoj- 1 H- 1,2,4, triazol-3-yl]methyl] thio]acetate hemihydrate 1 -Methyl-5-((3-[3-( 1 -piperidinylmethyl)phenoxy]propyl]aminoj- 1 h-i , 2 ,4-triazole-3-methanol, compound B, (7.2 9) was dissolved in thionyl chloride (30 ml) at 20" and heated under reflux for 15 min. The cooled solution was evaporated in vacuo and the oil dissolved in water (30 ml), cautiously basified with solid sodium bicarbonate, sodium carbonate (39) added, and the mixture extracted with ethyl acetate. The extract was dried (Na2CO3), 1 h) and evaporated to give an oil.

The resulting oil was dissolved in acetone (100 ml) and heated under reflux for 16 h with anhydrous potassium carbonate (2.76 9) and ethyl mercaptoacetate (2.4 g). The mixture was partitioned between aqueous potassium carbonate and ethyl acetate. The ethyl acetate extract was dried and evaporated and the residue (5.1 9) was chromatographed using System E as eluent to give the title compound (2.9 9) as a pale yellow oil.

Found: C, 58.7; H, 7.6; N, 14.8; C2sH35NsO3S.+H2O requires: C, 58,7; H, 7.7; N, 14.9% N.m.r. (CDCl3): 2.75, dd, (1 H); 3-3.33, m, (3H); 5.45, t, (1 H); 5.66-6, q + t, (4H); 6.23-6.7, s + s + q + s + s, (1 1H); 7.61-7.86, m, (6H); 8.45, m, (6H); 8.7, t, (3H).

The following compounds were similarly prepared from the compound B and the appropriate starting materials.

4 (b) Compound B (1.41 9), 5-mercapto-1-methyltetrazole (0.506 9) and potassium carbo nate (0.54 9) with the exceptions that the mixture was chromatographed using System C to give an oil (1.0 9) which was dissolved in ethyl acetate and treated with excess ethereal hydrochloric acid, gave 1 -methyl-3-[[(1 -methyl-l H-tetrazol-5-yl)thio]methyl]-N-[3-[3-(1 -piperidinylmethyl)phe- noxy]propyl]-1 K1 ,2,4-triazol-5-amine dihydrochloride sesquihydrate (0.6 9) as a white powder m.p. slowly softens above 40".

N.m.r. (D20): 2.6, 2.9-3.0, m, (4H); 5.7-5.9,m, (6H), 6.04, s, (3H): 64-6.6, s + m, (7H); 7.05, t, (2H); 7.9-8.6, m, (8H).

4 (c) Compound B (1.41 9), 2-mercapto-5-methyl-1,3,4-thiadiazole (0.52 9) and potassium carbonate (0.54 9), with the exception that the mixture was chromatographed using System C.

gave 1 -methyl-3-[((5-methyl- 1,3,4-th iadiazol-2-yl)th io]methyl]-N-[3-[3-(1 -piperidinyl methyl)phe noxy]propyl]-1 K1 ,2,4-triazol-5-amine (0.62 9) as a white powder m.p. 63 softens melts 72-74", Found: C, 55.9; H. 6.7; N, 20.7; C22H3,N70S2 requires: C, 55.8; H, 6.6; N, 20.7% Example 5 3-r4-(oimethylamino)butoxy]methyl]- 1 -meth yl-Nj3j3-( 1 -piperidin ylmethyl)phenoxyjpropylj- I H- 1,2, 4-triazole-5-amine 4-([i -Methyl-5-[[3-(3-( 1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H- , 2,4-triazol-3-yljme thoxy]butanol (0.5 9) was dissolved in thionyl chloride (10 ml) and stirred at 20" for 1.5 h.The solution was evaporated in vacuo and the residue dissolved in water (20 ml), basified with solid sodium bicarbonate and sodium carbonate (-2 g). The mixture was extracted with ethyl acetate, the extract dried (Na2CO3, 1 h), evaporated and the residual oil was dissolved in ethanolic dimethylamine (33%, 1 S ml) and the solution was heated in an autoclave at 80" for 8h. The solution was evaporated and the residual oil (0.3 9) was chromatographed using System A as eluent to give the title compound (0.2 9) as a pale yellow oil.

N.m.r. (CDCl3): 1.74, dd, (1 H); 3-3.32, m, (3H); 5.48, t, (1 H); 5.58, s, (2H); 5.86, t, (2H); 6.24-6.64, s+s+m, (9H); 7.48-8, m+s, (14H); 8.21-8.68, m, (10H).

T.l.c. System B Rf 0.55.

Example 6 &alpha;-(2-Furanyl)-1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]- 1 H- 1,2,4-triazole-3- methanol n-Butyllithium (1.55M in n-hexane, 5.96 ml) was added dropwise to a stirred solution of furan (0.61 ml) in anhydrous tetrahydrofuran (20 ml), under nitrogen at - 40". The stirred solution was allowed to warm slowly to 20", heated under reflux for 3h, added dropwise at 0 to a solution of 1 -methyl-5-([3-(3-( 1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H-i , 2, 4-triazole- 3-carboxaldehyde (1.0 9) in tetrahydrofuran (10 ml), and the resulting solution was stirred at 20" for 18h. Water (20 ml) was added, the mixture concentrated, extracted with ethyl acetate and the extract was dried and evaporated.The residual oil (0.9 9) was chromatographed using System E to give the title compound (0.1 6 9) as a brown oil.

N.m.r. (CDCl3): 2.6, m. (1 H); 2.76, t (1 H); 3.06-3.08, m, (2H); 3.23, m, (1 H); 3.65, m, (2H); 4.25, s, (1 H); 5.48, t, (1 H); 5.86, t, (2H); 6.38, q, (2H); 6.45, s, (3H): 6.56, s, (2H); 7.62, m, (4H); 7.88, quintet, (2H); 8.36, m, (6H).

T.l.c. System A Rf 0.7.

Example 7 3-(2, 2-Dimethyl- 1, 3-dioxolan-4-yl)- 1-methyl-N-[3-[3-(1 -piperidinylmethyl-phenoxy]propyl]- 1 H 1,2, 4-triazol-5-amine A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]- 1 H-1,2,4-triazole- 3-ethane-1,2-diol (0.08 9), 2,2-dimethoxypropane (2.0 ml) and 4-toluenesulphonic acid (0.03 g) in acetone (10 ml) was stirred at 20" for 16 h, evaporated and partitioned between 2N sodium carbonate and ethyl acetate. The ethyl acetate extract was dried and evaporated and the resulting oil (0.07 9) was chromatographed using System E as eluent to give the title compound (0.025 9) as an amber gum.

N.m.r. (CDCl3): 2.78, t, (1 H); 3.08-3.23, m, (3H); 4.96, dd, (1 H); 5.48, t, (iH & 5.72, dd, (1 H); 5.80, t, (1 H); 5.88, t, (2H); 6.37, q, (2H); 6.46, s, (3H); 6.55, s, (2H); 7.62, m, (4H); 7.87, m, (2H); 8.4-8.6, m, (9H).

T.l.c. System D Rf 0.7.

Example 8 N-Methyl rcc 1 -meth y1-5-FE3-F3-( 1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H- 1,2, 4-triazol-3-yl- ]methyl]thio]acetamide A solution of ethyl [([1 -methyl-S-([3-(3-( 1 -piperidinylmethyl]phenoxy]propyl]amino]- 1 H-i ,2,4- triazol-3-yl]methyl]thio]acetate (0.4 9) in ethanolic methylamine (33%, 20 ml) under nitrogen, was heated under reflux for 30 h, cooled, evaporated in vacuo, the residue dissolved in 2N hydrochloric acid (20 ml), and washed with ethyl acetate.The acidic layer was basified with potassium carbonate extracted with ethyl acetate and the extract was dried and evaporated to give an oil (0.28 9) which was chromatographed using System E as eluent to give the title compound (0.139) as an oil.

N.m.r. (CDCl3): 2.46, s(br), (1 H); 2.79, t, (1 H); 3.07, m, (2H); 3.22, dd, (1 H); 5.34, t, (1 H); 5.85, t, (2H); 6.4, s+q, (4H); 6.46, s, (3H); 6.56, s, (2H); 6.72, s, (2H); 7.19, d, (3H); 7.63, m, (4H); 7.86, m, (2H); 8.42, m, (4H); 8.57, m, (2H).

T.l.c. System A, Rf 0.7.

Example 9 1 -Methyl-a:-phenyl-5-[[3-[3-( 1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H- 1,2, 4-triazole-3-methanol compound with fumaric acid and ethyl acetate: 40:56:5 3-[3-(1-Piperidinylmethyl)phenoxy]propanamine (0.72 9) and methyl N-[2-acetyloxy-[2-(pheny l)acetyl]]-i -methyl-2-(phenylmethylene)hydrazine carboximidothioate (1.1 9) were heated together as a melt for 2h at 60" to give a gum. This gum was dissolved in toluene and stirred for 15 h with 5N hydrochloric acid. The pH of the aqueous phase was adjusted to pH 7 with sodium carbonate and washed with toluene and ethyl acetate. The aqueous phase was basified to pH 10 with sodium carbonate and extracted with ethyl acetate. The organic extracts at pH 10 were dried (MgSO4) and evaporated to leave an oil (1.1 9).This oil was chromatographed using dichloromethane:ethanol:0.88 ammonia (150:8:1) as eluent to give a white solid (0.259) m.p.

42-52". This solid (0.112 9) was dissolved in ethyl acetate and treated with a solution of furmaric acid (0.03 9) in ethyl acetate to precipitate the title compound which was collected as a white solid (0.095 9) m.p. 80".

NMR (CDCl3) of free base 2.4-2.9, m, (6H); 3.0-3.4, m, (3H); 4.31, s, (1 H); 5.56, t, (1 H); 5.93, t, (2H); 6.3-6.7, q + s + s, (7H); 7.5-7.75, m, (4H); 7.92, m, (2H); 8.3-8.7, m, (6H).

Example 10 4-Methyl-&alpha;-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2, 4-triazole-3-meth- anol A mixture of DL mandelic acid (30.4 9) and N-amino-N-methyl-N-[3-[3-(1-piperidinylme- thyl)phenoxy]propyl]guanidine hydroiodide (22.35 9) was heated from 40 to 125" and maintained at 1 25" as a melt for 6h.

The hot melt was extracted with hot water (250 ml) and the aqueous extract was basified to pH 8 with solid sodium carbonate, and extracted into ether. The ether extract was cooled at 5" to give a white solid which was washed with boiling ethyl acetate to leave the title compound as a white solid (0.18 9) m.p. 186-8".

Assay Found: C, 68.9; H, 7.7; N, 16.0; C25H33N502 requires: C, 68.9; H, 7.6; N, 16.1% Example 11 f4-Methyl-a-phenyl-5jC3j3-( 1 piperidinylmethyl)phenoxyjpropyljaminoj-4H- 1,2, 4-triazole-3 methanol]acetate (ester) hydrate A solution of 4-methyl-&alpha;-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H- 1 ,2,4-triazole-3-methanol (0.10 g) and acetic acid anhydride (0.03 ml) in pyridine (2 ml) was stirred at room temperature for 16h. Saturated sodium carbonate solution was added and the suspension was extracted with ethyl acetate. The organic phase was washed with water and brine, and evaporated under reduced pressure. The residue was crystallised from isopropyl acetate to give the title compound as a white solid (0.074 9), m.p. 89-91 C.

Assay Found: C, 64.9; H, 7.5; N, 13.8; C27H35NsO3H2O requires: C, 65.3; H, 7.4; N, 14.1% Example 12 &alpha;-[1-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazol-3-yl]-2-pyridi- nemethanol n-Butyllithium (1.6M in n-hexane, 8.1 2 ml) was added dropwise during 15 min to a stirred solution of 2-bromopyridine (1.869, 1.12ml) in anhydrous ether (10 ml) at - 70", under nitrogen.The brown solution was stirred at - 70" for 0.5h before a solution of i-methyl-5-[[3- [3-( 1 piperidinylmethyl)phenoxy]propyl]amino]- 1 K1, 2,4-triazole-3-carboxaldehyde (2.0 9) in anhydrous tetrahydrofuran (20 ml) was added dropwise at - 70" and the solution was stirred at - 40" for 2 h before water (20 ml) was added and the mixture was allowed to stand overnight at 20". The mixture was concentrated extracted with ethyl acetate and the extract was dried and evaporated to give an oil (2.5 9) which was chromatographed using System E as eluent to give a solid (0.48 9). This was crystallised from ethyl acetate to give the title compound (0.25 9) as a white powder m.p. 1 52-1 54" (d).

Found: C, 65.9; H, 7.4; N, 19.1; C24H32N602 requires: C, 66.0; H, 74; N, 19.2% Example 13 5-2-5-Dimeth ylamino)meth yl]-2-furan yl]meth yl]thio]eth yl]am ino]- 1 -methyl-a-phenyl- 1 H 1,2, 4-triazole-3-methanol dihydrochloride A solution of 2-[[[S-((dimethylamino)methyl]-2-furanyl]methyl]thoo]ethanamine (3.09 9) and methyl-N-(2-acetyloxy-[2-(phenyl)acetyl-]]- 1 -methyl-2-(phenylmethylene)hydrazine-carboximidoth ioate (5.9 9) in toluene (110 ml) was stirred at room temperature for 3h.A further quantity of methyl-N-[2-acetyloxy-[2-(phenyl)acetyl]]- 1 -methyl-2-(phenylmethylene)hydrazine-carboximidoth ioate (0.3 9) was added and the mixture stirred at room temperature for 1.5 h. 2M hydrochloric acid (22.5 ml) was then added to the reaction mixture and the mixture heated on a steam bath for 1 h. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with toluene (2 X 30 ml). The acidic aqueous layer was basified with potassium carbonate and extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried and evaporated to give a brown gum, which was chromatographed on silica using dichloromethane: ethanol:ammonia (65:8:1) to give a brown gum (1.35 9).This was dissolved in methyl acetate and treated with ethereal hydrogen chloride to give a white solid which was triturated with dry ether to give the title compound (1.3 9) as a fine white solid, mp 55-60" softens.

Nmr(CD3OD): 2.5, m, (5H); 3.3, d, (1 H); 3.6, d, (1 H); 4.i5,s, (1 H); 5.6, s, (2H); 6.3, m, (7H); 7.15, m, (8H).

Example 14 5jC3jU2-Furnn ylmeth yl)aminoJmethyljphenoxyjpropyljaminoj- 1 -meth yl-a-phenyl- 1 H- 1,2, 4-tria zole-3-methanol A solution of 5[[3-(3-formylphenoxy)propyl]amino]- 1 -methyl-a-phenyl-i K1,2,4-triazole-3- methanol acetate (ester) (1.0 9) and furfurylamine (5 ml) in ethanol (30 ml) was stirred at 21 for 1.5 h before a suspension of sodium borohydride (1.3 9) in ethanol (10 ml) was added and stirring was continued for a further 1 6h at 21". Water (20 ml) was added, the mixture concentrated to remove ethanol and the aqueous residue extracted with 4-methylpentan-2-one.

The extract was dried and evaporated to give an oil. Excess furfurylamine was removed in vacuo and the residue was dissolved in 2N hydrochloric acid, the acidic layer washed with ethyl acetate, basified (pH 9) with sodium carbonate, and extracted with 4-methylpentan-2-one. The extract was washed with water, dried and evaporated to give a brown gum (0.65 9) which was chromatographed on silica (Merck No. 7729) using System C as eluent to give the title compound (0.5 9) as a pale orange gum.

T.l.c. System C Rf 0.35.

N.m.r. (CDCl3) 2.50, db, (2H); 2.6-2.84, m, (5H); 3.14-3.4, m, (2H); 3.24, d, (1H); 3.70, dd, (1 H); 3.82, dd, (1 H); 4.28, s, (1 H); 5.5, t, (1 H); 5.92, t, (2H); 6.23, s, (2H); 6.25, s, (2H); 6.44 q(dt) (2H); 6.56, s, (3H); 6.6-8, m, (2H); 7.94, m, (2H).

Example 15 3-[[[(2-Furanyl)methyl]thio]methyl]- 1 -methyl-N3-( 1 -piperidinylmethyl)phenoxyjpropylj- 1 H- 1, 2, 4- triazol-5-amine A solution of 1 -methyl-5-[[3-[3-(1 -piperidinylmethyl)phenoxy]propyl]amino]-i K1,2,4-triazole- 3-methanol (3.59 9) in thionyl chloride (10 ml) was heated on a steam bath for 10 min. The solution was evaporated to dryness and the residue was dissolved in water. Sodium bicarbonate was added to the solution until no more effervescence occurred. Sodium carbonate (39) was added, and the suspension was extracted with ethyl acetate. The organic extract was dried and evaporated to give a brown oil (4.1 9).

A portion of this oil (3.2 9) was dissolved in absolute ethanol (40 ml) and added dropwise at 5" to a solution of furfurylmercaptan (1.14 9) and sodium (0.34 9) in absolute ethanol (20 ml).

The suspension was allowed to stand at room temperature for 18h, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in 0.2N hydrochloric acid, washed with ethyl acetate, and basified with excess solid sodium carbonate. The basic solution was extracted with ethyl acetate. The organic extract was dried and evaporated to give an oil (2.2 9) which was purified by column chromatography using chloroform as eluent to give the title compound as an oil (1.29).

T.l.c. System C Rf 0.45.

N.m.r. (CDCl3) 2.7, d, (1H); 2.8, t, (1H); 3.0-3.4, m, (3H); 3.8, m, (2H); 5.5, t, (1H); 5.95, t, (2H); 6.25, s, (2H); 6.3-6.7, m, (9H); 7.5-8.1, m, (6H); 8.5, m, (6H).

Example 16 5-(Methoxyphenylmethyl)-4-methyl-N-(f3-f3-( 1 -piperidinylmethyl)phenoxy]propyl]-4H- 1,2, 4-triazol-3-amine compound with tartaric acid (1:1) A solution of 4-methyl-a-phenyl-5-([3-[3-( 1 -piperidi nyl methyl)phenoxy]propyl]aminoj-4 K 1 ,2,4-triazole-3-methanol (0.37 9) in thionyl chloride (3.0 ml) was stirred at room temperature for 0.5h. The solvent was removed in vacuo. The residual pink foam was dissolved in dry methanol (10 ml) and added dropwise to a solution of sodium (0.17 9) in dry methanol (10 ml).

The reaction solution was stirred at room temperature for 0.5h, poured onto water, and extracted with ethyl acetate. The organic extract was dried and evaporated to give a gum (0.3 g). This gum was dissolved in ethyl acetate and treated with an excess of tartaric acid in ethyl acetate to give the title compound as a white solid (0.26 9), m.p. = 88" softens.

N.m.r. (CD3OD) 2.5-3.1, m, (9H); 4.5, s, (1H); 5.6, s, (2H); 5.8, s, (2H); 5.9, t, (2H); 6.48, t, (2H); 6.60, s, (3H); 6.80, s, (3H); 6.85, m, (4H); 7.85, m, (2H); 8.2, m, (6H).

Example 17 5-2-5-Dimeth ylamino)meth yl]-2-furan yl]meth yl]thio]eth yl]a mino]- 1 -meth yl-a-phen yl- 1 H 1,2, 4-triazole-3-methanol A solution of 2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethanamine (3.09 9) and methyl-N-[2-acetyloxy-[2-(phenyl)acetyl]]- 1 -methyl-2-(phenylmethylene)hydrazinecarboxi midothioate (compound A) (5.9 9) in toluene (110 ml) was stirred at room temperature for 3h and a further quantity of compound A (0.3 9) was added. The mixture was stirred at room temperature for a further 1.5 h, 2M hydrochloric acid (22.5 ml) was added, and the mixture was heated on a steam bath for 1 h. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with toluene.The acidic aqueous layer was then basified with potassium carbonate and extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried and evaporated to leave a brown gum which was chromatographed using dichloromethane:ethanol ammonia (65:8:1) to give a brown gum (1.95 9). A portion of this gum (0.5 9) was dissolved in dry tetrahydrofuran and filtered through "Florisil" (an activated magnesium silicate). The filtrate was concentrated to a small volume to give the title compound (0.32 9) as a white solid, m.p.

121-122.5".

Found: C, 60.0; H, 6.9; N, 17.3; C20H27N502S requires: C, 59.8; H, 6.8; N, 17.4% Examples of Pharmaceutical Compositions Tablets mg/tablet Active ingredient 5.0 to 125.0 Microcrystalline Cellulose USP 293.5 to 173.5 Magnesium Stearate BP 1.5 Compression weight 300.0 The drug is sieved though a 250 ym sieve, blended with the excipients and compressed using 9mm diameter punches. Other strengths may be prepared by altering the compression weight and using punches to suit.

The tablets may be film coated using suitable film forming polymers such as hydroxypropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.

Capsules mg/capsule Active ingredient 5.0 to 125.0 Starch 1500"(USP) 243.5 to 123.5 Magnesium Stearate BP 1.5 Fill weight 250.0 *A form of directly compressible starch The active ingredient is sieved through a 250,um sieve and blended with the excipients. The mix is filled into No. 2 hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight, and, if necessary, changing the capsule size.

Injection for Intravenous Administration % w/v Active ingredient 0.20 to 0.50 Water for Injection B.P. to 100.0 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability using either dilute acid or alkali. The solution is prepared, clarified and filled under nitrogen, or other inert gas, into appropriate sized ampoules sealed by the fusion of glass. The injection is sterilised by 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.

Syrup mg/5 ml dose Active ingredient 5.0 to 250.0 Sucrose 2795.0 to 2550.0 Glycerine 500.0 Buffer Flavour as necessary Colour Distilled water to 5.0 ml The active ingredient, buffer, flavour, preservative and colour are dissolved in some of the water. The remainder of the water is heated to approximately 80"C and the sucrose is dissolved in this water and cooled. The two solutions are mixed, adjusted to volume and clarified by filtration. Alternatively, the active ingredient, sucrose, buffer, flavour, colour and preservative may be mixed and the powder filled into bottles for later reconstitution by the addition of water.

In the above examples the active ingredient is preferably 5-[[2-[((5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethyl]amino]- 1 -methyl-a-phenyl- 1 H-i , 2, 4-triazole-3-methanol in the form of a physiologically acceptable salt, for example the hydrochloride.

Claims (10)

CLAIMS:

1. Compounds of the general formula (I)

and physiologically acceptable salts and hydrates thereof, in which R, represents hydrogen, C,~4 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl; and R2 represents hydrogen or C1 - alkyl; or R1 and R2 may together with the nitrogen atom to which they are attached form a 5 to 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 C1 -3 alkyl groups 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 3 carbon atoms, Q represents a furan or thiophenering in which incorporation into the rest of the molecule is through bonds at the 2- and 5- positions, the furan or thiophene ring optionally bearing a further substituent R4 adjacent to the group R1R2N-Alk-; or Q represents a thiophene ring in which incorporation into the rest of the molecule is through bonds at the 2- and 4- positions, the thiophene ring optionally bearing a further substituent R4 adjacent to the group R,R2NAlk with the proviso that when the group R,R2NAlk is in the 4- position then the group R4 is in the 5-position; or Q represents a benzene ring in which incorporation into the rest of the molecule is though bonds at the 1- and 3- or 1- and 4- positions; R4 represents halogen or C,~4 alkyl which may be substituted by hydroxy or C1 -4 alkoxy; X represents oxygen, sulphur, -NH-, methylene or a bond; Y represents oxygen, sulphur, methylene or a bond;; n represents zero, 1,

2 or 3, and m is in integer from 2 to 5, with the provisos that (a) the total number of atoms in the chain X(CH2)nY(CH2)m is an integer from 3 to 8, (b) when X and Y represent oxygen or sulphur then n is 2 to 3, (c) when X represents -NH- then Q is a benzene ring and Y represents methylene or a bond, and (d) when Q represents a berzene ring, X represents oxygen, and n represents 1, then m may additionally represent 1 and Y may additionally represents -CHOR,4 where R,4 represents hydrogen or acyl; and R3 represents hydrogen, alkyl, alkenyl, aralkyl, or C28 alkyl substituted by hydroxy or alkoxy; either A represents N and B represents CR5; or A represents CR5 and B represents N; and R5 represents (i) a C28 straight or branched alkyl group substituted by two or three hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group may form a cyclic acetal or cyclic ketal structure of the formula

where p is zero or 1 and R6 and R7, which may be the same or different, each represents hydrogen, a C14 alkyl group or a phenyl group; or (ii) the group (CH2)qZ(CH2)rR8, where q represents an integer from 1 to 4 inclusive, r represents an integer from 1 to 6 inclusive, Z represents oxygen or sulphur and when r represents 1, R8 represents the group CH = CH2, alkenyl or the group COR9 where R9 is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the group NR,oR1, where R10 is hydrogen or alkyl and R" is hydrogen or alkyl and when r represents an integer from 2 to 6, Re has any of the meanings given above or may additionally represent hydroxy, alkoxy, aryloxy or the group NR,2R,3 where R,2 is hydrogen or alkyl and R,3 is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulphonyl or arylsulphonyl; or (iii) the group (CH2)xS(CH2)yRi5, where x represents 1 or 2, y represents zero or 1, and R5 represents a heteroaryl group; or (iv) an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy, alkoxy or acyloxy.

'2. Compounds as claimed in claim 1 in which: R, represents C,-8 alkyl, C,~4 alkyl substituted by a trifluoromethyl group, C24 alkyl substituted by hydroxy or a di C1 -3 alkyl amino group, C57 cycloalkyl, C35 alkenyl, phenyl C13 alkyl, or a heteroaryl C1 -3 alkyl group where the heteroaryl ring contains one heteroatom; R2 represents hydrogen or methyl; or R,R2N represents a 5-8 membered ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Alk represents methylene; Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1- and 3- positions; or a furan ring incorporated into the rest of the molecule through bonds at the 2- and 5- positions optionally bearing a substituent R4 adjacent to the group R,R2NAlk where R4 is C1 -4 alkyl; or a thiophene ring incorporated into the rest of the molecule through bonds at the 2- and 4- positions with the substituent R,R2NAlk in the 2- position; with the provisos that when Q is a benzene ring as just defined, then X is a bond, n is zero, Y is oxygen and m is 3, 4 or 5, or X and Y both represent oxygen and n an m are both 2, or X is oxygen, Y is CHOH and n and m are both 1; and when Q is a furan or thiophene ring as just defined, then X is a bond and either Y is sulphur or CH2, n is 1 and m is 2, or Y is oxygen, n is 1 and m is 3; R3 represents hydrogen or alkyl; R5 represents a C24 alkyl group substituted by two hydroxy groups, or a 2,2-di C,~3 alkyl 1,3-dioxolan-4-yl group; or R5 represents phenyl C13 alkyl or heteroaryl C13 alkyl in which the alkyl portion is substituted by hydroxy, C,~4 alkanoyloxy or C1 -2 alkoxy; or R5 represents the group (CH2)qZ(CH2)rR8, in which q is 1, r is 1 to 4 when Z is oxygen or r is 1 when Z is sulphur, and R8 is hydroxy, the group -CH = CH2 di C,~3 alkylamino, or the group COR9 where R9 is C,~4 alkoxy or the group NHR11 where R11 is C,~3 alkyl; or R5 represents the group (CH2)xS(CH2)yR15 in which X represents 1 and the heteroaryl group R15 is tetrazolyl or thiadiazolyl each of which is substituted by C,~3 alkyl, or R15 is furyl.

3. Compounds as claimed in claim 1 in which R1 represents C1 -e alkyl, C1 -4 alkyl substituted by a trifluoromethyl group, C24 alkyl substituted by hydroxy or a di C13 alkyl amino group, C57 cycloalkyl, C35 alkenyl, phenyl C1-3 alkyl, or a heteroaryl C1 -3 alkyl group where the heteroaryl ring contains one heteroatom, R2 represents hydrogen or methyl; or R,R2N represents a 5-8 membered ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Alk represents methylene; Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1- and 3- positions; or a furan ring incorporated into the rest of the molecule through bonds at the 2- and 5- positions optionally bearing a substituent R4 adjacent to the group R,R2NAlk where R4 is C,~4 alkyl; or a thiophene ring incorporated into the rest of the molecule through bonds at the 2- and 4- positions with the substituent R,R2NAlk in the 2- positon; with the provisos that when Q is a benzene ring as just defined then X is a bond, n is zero, Y is oxygen and m is 3, 4 or 5, or X and Y represent oxygen and n and m are both 2, or X is oxygen, Y is CHOH and n and m are both 1; and when Q is a furan or thiophene ring as just defined, then X is a bond and either Y is sulphur or CH2, n is 1 and m is 2, or Y is oxygen, n is 1 and m is 3; R3 represents hydrogen or alkyl; R5 represents a C24 alkyl group substituted by two hydroxy groups, or a 2,2- di C,~3 alkyl1,3-dioxolan-4-yl group; or R5 represents phenyl C,~3 alkyl in which the alkyl porton is substituted by C,~4 alkanoyloxy or C12 alkoxy, or heteroarly C13 alkyl in which the alkyl portion is substituted by hydroxy, C14 alkanoyloxy or C1-2 alkoxy; R5 represents the grou (CH2)qZ(CH2)rR5, in which q is 1, r is 1 to 4 when Z is oxygen or r is 1 when Z is sulphur, and R8 is hydroxy, the group -CH =CH2, di C13 alkylamino, or the group COR9 where R9 is C1-4 alkoxy or the group NHR11 where R11 is C,~3 alkyl; or R5 represents the group (CH2)xS(CH2)yR15 in which x represents 1 and the heteroaryl group R15 is tetrazolyl or thiadiazolyl each of which is substituted by C1-3 alkyl, or R15 is furyl.

4. Compounds of general formula (II)

and physiologically acceptable salts and hydrates thereof in which R,R2N represents di C13 alkylamino, furylmethylamino, or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethylenimino; A represents N and B represents CR5, or A represents CR5 and B represents N, where R5 represents C24 alkyl substituted by two hydroxy groups, 2,2- di C13 alkyl-1,3-dioxolan-4yl, (1-methyl-1 H-tetrazol-5-yl)thiomethyl, or R5 represents phenyl C,~3 alkyl or heteroaryl C,~3 alkyl in which the alkyl portion is substituted by hydroxy, or phenyl C1-3 alkyl in which the alkyl portion is substituted by C1-4 alkanoyloxy or C1-2 alkoxy, or R5 represents the group CH2Z(CH2),R8 where Re is hydroxy or di C1-3 alkylamino, Z is oxygen and r is 4; or R5 is the group -CH = CH2 or the group COR9 where R9 is C1-4 alkoxy, Z is oxygen or sulphur and r is 1; and either Q is 1,3-benzene and X is a bond, n is zero, Y is oxygen and m is 3 or 4; or X is oxygen, n is 1, Y is -CHOH- and mis 1; or Q is 2,5-furan or 2,4-thiophene, X is a bond, Y is sulphur, n is 1 and m is 2; with the proviso that R,R2N is di C, -3 alkylamino when Q is a furan or thiophene ring.

5. Compounds of general formula (II)

and physiologically acceptable salts and hydrates thereof in which either R,R2N is dimethylamino, Q is 2,5-furan, X is a bond, Y is sulphur, n is 1 and m is 2; or R,R2N is dimethylamino or pyrrolidino, piperidino, or hexamethylenimino, Q is 1,3 benzene, X is a bond, Y is oxygen, n is zero, and m is 3 or 4; and A represents N and B represents CR5, or A represents CR5 and B represents N, where R5 is benzyl in which the methylene group is substituted by hydroxy.

6. S[[2-[[[5-[(Dimethylamino)methyl]-24uranyl]methyl]thio]ethyl]amino]-i -methyl-a-phenyl- 1 H-l ,2,4-triazole-3-methanol and physiologically acceptable salts thereof.

7. Compounds as claimed in claim 1 which are: 1 -methyl-3-[[(1 -methyl-1 H-tetrazol-S-yl)th io]methyl]-N-[3-[3-( 1 -piperid inyl methyl)phenoxy]pro- pyl]-H-i ,2,4-triazol-S-amine 1 -methyl-a-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3- methanol 4-methyl-oc-phenyl-5-[[3-[3-(1 -piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triazole-3- methanol and physiologically acceptable salts thereof.

8. Compounds as claimed in claim 1 which are: 1 -methyl-5-[3-[[(1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H-1,2,4-triazole-3-ethane-1,2,- diol a-[i -methyl-S-[[3-(3-( 1 -piperidinylmethyl)phenoxy]propyl]amino]- 1 H- , 2,4-triazole-3-yl]-2-pyri- dinemethanol 5-[[2-hydroxy-3-[3-( 1 -piperidinyl methyl)phenoxy]propyl]am i no]- 1 -methyl-a-phenyl- 1 H-1,2,4-tri- azole-3-methanol 5-[[3-(3-[(dimethylamino)methyl]phenoxy]propyl]amino]- 1 -methyl-&alpha;-phenyl-1H-1,2,4-triazole- 3-methanol 5-[[2-[[[5-[(d imethylamino)methyl]-3-thienyl]methyl]thio]ethyl]am ino]- 1 -methyl-o-phenyl- 1 H1,2,4-triazole-3-methanol an physiologically acceptable salts thereof.

9. A process for the preparation of compounds of formula (I) as defined in claim 1 which comprises (a) for the preparation of compounds in which R5 represents the group (CH2)qZ(CH2)rR8 or (CH2)xS(CH2)yR15, reacting a triazole of formula (I) in which R5 represents the group R5a where R5a is ~CH2)qL or -(Ch2)XL and L is a leaving group with an anion eZ(CH2),R8 or sS(CH2)yR15;; (b) for the preparation of compounds in which R5 is other than a C25 straight or branched alkyl group substituted by two or three acyloxy groups, or a dihydroxyalkyl group forming a cyclic acetal or cyclic ketal structure, or an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group or Y is other than CHOR,4 where R,4 is acyl, cyclising a compound of formula (III).

in which R,6 is a group as defined for R3, V' is

and Y' is hydrogen where V is oxygen or sulphur and R5C is a group as defined for R5 or a group convertible thereto under the conditions of the cyclisation reaction; or V' is NH, R,6 is group as defined for R3 and Y' is

where Y" is sulphur, oxygen or NH; or V' is sulphur or oxygen, Y' is

and R15 is a group as defined for R3; or V' is NR3, R,6 is hydrogen and Y' is

where Y" is as defined above; (c) for the preparation of compounds in which Alk is CH2, treating an aldehyde of formula

with an amine R,R2NH followed by reduction (d) for the preparation of compounds in which R5 is an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy, reacting the appropriate aldehyde or ketone with an organolithium compound ArLi or a Grignard reagent ArMgHal where Ar is an appropriate aryl, aralkyl, heteroaryl or heteroaralkyl group and Hal is halogen;; (e) for the preparation of compounds in which R5 represents a C2e straight or branched alkyl group substituted by two or three acyloxy groups, or R9 represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group, or Y represents CHOR,4 where R,4 is acyl, reacting the corresponding alcohol with an activated derivative of an appropriate acid; (f) for the preparation of compounds in which R5 represents a C28 straight or branched alkyl group substituted by two or three alkoxy groups, or R5 represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an alkoxy group, treating the corresponding alcohol with an halogenating agent followed by reaction of the resulting halocompound with an appropriate alkanol;; (g) for the preparation of compounds in which R5 represents the group (CH2)qZ(CH2)rR8 where R8 is NR,2R,3 and R,2 and R,3 each represent hydrogen or alkyl, treating the corresponding alcohol in which Re is hydroxy with a reagent capable of converting the group R8 into a leaving group, followed by reaction of the resulting compound of formula (I) in which R5 represents (CH2)qZ(CH2),L where L is a leaving group with ammonia or an appropriate amine R,2R,3NH; (h) for the preparation of compounds in which R8 is the group NR,2R,3, where R,3 is an acyl group or an aryl or alkylsulphonyl group, reacting the corresponding compound in which Re is the group NHR,2 with an activated derivative of the appropriate carboxylic or sulphonic acid; ; (i) for the preparation of compounds in which Re is the group -CONR,oR1" reacting an activated derivative of the corresponding carboxylic acid in which R8 is -CO2H, with ammonia for an appropriate amine HNRaoR11; or (j) for the preparation of compounds in which R5 includes the group

reacting the corresponding compound in which R5 includes the group

with an aldehyde or ketone R6R7 CO in the presence of an acid; and optionally converting the compound of formula (I) produced into a salt.

10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 together with at least one pharmaceutically acceptable carrier or diluent.