NZ203384A - Heterocyclic compounds and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £03384 2 033 84 .riority Date(s): .2.4. -2.-S2 -^2 If. - «. -g3 Complete Specification Filed: Class: . ., c&j D.tt-faS-.i... „ ' ri 6 AU61985 Publication Date: P.O. Journal, No: 1"73 No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION [*24 FEB 1983 Sbwi?* HETEROCYCLIC DERIVATIVES +/We, GLAXO GROUP LIMITED, a British Company, of Clarges House, 6/12 Clarges Street, London, W1Y 8DH, ENGLAND hereby declare the invention for which t / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) 7//- ;"> - u 203384 -lar Heterocyclic Derivatives This invention relates to heterocyclic derivatives having action on histamine receptors, to processes for the 5 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 ^"antagonists. 10 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, 21_, 427). Their ability to do so can be demon-15 strated in the perfused rat stomach using the method described in New Zealand Patent Specification No. 184759 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 20 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.

Compounds with histamine I^-blocking activity 25 may be used in the treatment of conditions where there is an advantage in lowering gastric-acidity^iparticularly in gastric and peptic ulceration, as a prophylactic measure in surgical procedures, and in the treatment of allergic and inflammatory conditions where histamine 30 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 35 general formula (I) {6MAYI9S, *3 \ ,N A / v\ R1R2N-Alk-Q-X-(CH2)nY(CH2)mNH /B <1> and physiologically acceptable salts, and hydrates thereof, in which R^ represents hydrogen, alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl, 4 > ' /\ "T or alkyl substituted by hydroxy, alkoxy, amino, alkyl-amino, dialkylamino or cycloalkyl; and R2 represents hydrogen or alkyl; or R^ and R2 may together with the nitrogen atom to which they are attached form a 5 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 alkyl e.g. methyl, groups or a hydroxy group and/or may contain another heteroatom selected from oxygen and sulphur; 10 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 15 ring optionally bearing a further substituent R^ adjacent to the group R^^N-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 R^ adjacent 20 to the group R^R2NAlk with the proviso that when the group R^R2NAlk is in the 4- position then the group R^ 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; 25 R^ represents halogen or alkyl which may be substituted by hydroxy or 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(CH0) Y(CH~) is v 2'n 2'm an integer from 3 to 8, (b) when X and Y represent 35 oxygen or sulphur then n is 2 or 3, (c) when X represents -NH- then Q is a benzene ring and Y ~ ' g <[ 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 -CHOR^. where R^ represents 5 hydrogen or acyl; and R3 represents hydrogen, alkyl, alkenyl, aralkyl, or alkyl substituted by hydroxy or alkoxy; either A represents N and B represents CR^; or A represents CR^ and B represents N; and R^ represents 10 i) a C2_g straight or branched alkyl group substituted by two or three hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group maycform a cyclic acetal or cyclic ketal structure of the formula /(CH2>p\ -CH CH- 0 ^ „ 0 R6 R7 where p is zero or 1 and Rg and R7, which may be the same or different, each represents hydrogen, a C^_4 alkyl group or a phenyl group; or ii) the group (CH0) Z(CH„) R0, where q represents d. q z r o 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, Rg represents the group CH=CH2f alkenyl or the group COR^ where R^ is hydrogen, 30 hydroxy, alkyl, aralkyl, alkoxy or the group nriqR11 where R^Q is hydrogen or alkyl and R^ is hydrogen or alkyl and when r represents an integer from 2 to 6, Rg has any of the meanings given above or may additionally 35 represent hydroxy, alkoxy, aryloxy or the group NR^2R13 where R12 is hydrogen or alkyl and R^ 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)r where x represents 5 1 or 2, y represents zero or 1, and represents a heteroaryl group; or iv) an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy, alkoxy or acyl-oxy.

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 15 "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 20 substituted with one or more alkyl or alkoxy groups, or halogen atoms, e.g. fluorine. The term "acyl" means an aroyl, aralkanoyl or C, _ alkanoyl 1—o group, e.g. acetyl, formyl, phenylacetyl or benzoyl. The term "heteroaryl" as a part of a group within the 25 definition of R^ 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 alkyl, c^_3 alkoxy, hydroxy, hydroxy- alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The term "heteroaryl" as part of a group within part (iv) of the definition of R^ means a 5 or 6 membered monocyclic ring containing one heteroatom selected from oxygen, nitrogen and sulphur, e.g. thienyl, pyridinyl 35 or furyl, optionally substituted by a alkyl group.

The alkyl portion of a heteroaralkyl group is a straight 7 ^ or branched alkyl chain, and the heteroaryl ring is linked to the alkyl portion through a carbon atom. The term "heteroaryl" within the definition of R^,- means a monocyclic or bicyclic unsaturated ring containing 5 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, 10 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 alkyl, C-^_2 alkoxy or hydroxy.

One aspect of the invention relates to compounds of formula (I) in which R^, R2, R^, Alk, Q, X, Y, n and m are as defined above butexcluding the additional possibilities for m and ¥ given by proviso d), and A represents N and B represents CR^ or A represents CR^ and B represents 20 N where R^ 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, R^, Alk, Q, X, Y, n arid m 25 are as defined above but excluding the additional possibilities for m and Y given by proviso d), and A represents N and B represents CR^ or A represents CR^ and B represents N where R,. is as defined in possibility (iv) above.

Preferred compounds of formula (I) are those in which R-^ represents C^_g alkyl (e.g. methyl, propyl, butyl or heptyl), C^_4 alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoro-ethyl), C2_4 alkyl substituted by hydroxy or 35 a di alkyl amino group (e.g. 3-hydroxy- propyl or dimethylaminoethy1), C5_7 cycloalkyl /] *1 (e.g. cyclohexyl), C3_5 alkenyl (e.g. allyl), phenyl alkyl (e.g. benzyl), or a heteroaryl C^_2 alkyl group where the heteroaryl ring contains one heteroatom (e.g. 2-furylmethyl); 5 1*2 represents hydrogen or methyl; or R1R2N rePresents a 5-8 membered ring optionally containing a double bond, an oxygen atom or an alkyl (e.g. methyl) substituent (e.g. pipetidino, morpholino, 4-methylpiperidino, pyrrolidino, 10 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 5- positions optionally bearing a substituent adjacent to the group R^R2NAlk where R^ is alkyl (e.g. methyl); or a thiophene ring incorporated into 20 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, 25 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 30 oxygen, n is 1 and m is 3; R^ represents hydrogen or alkyl (e.g. methyl); Rg represents a C2_^ alkyl group substituted by two hydroxy groups, or a 2,2-di alkyl (e.g. di- : methyl)-1,3-dioxolan-4-yl group or 35 R^ represents phenyl alkyl (e.g. benzyl) or heteroaryl alkyl (e.g. furylmethyl or pyridylmethyl) in which the alkyl portion is substituted by hydroxy, C^_4 alkanoyloxy (e.g. acetyloxy) or C^_2 alkoxy (e.g. methoxy); or Rg represents the group (CH2)(CH2)rRg, in which q is 1, r is 1 to 4 when Z is oxygen, or r is 1 when Z is sulphur, and Rg is hydroxy, the group --CH=CH2, di C1-3 alkylamino (e.g. dimethylamino), or the group CORg, where Rg is C^_4 alkoxy (e.g. ethoxy) or the group NHR^ where R^ is C^_3 10 alkyl (e.g. methyl); or Rg represents the group (CH2)(CH2)^R^g, in which x represents 1 and the heteroaryl group R^g is tetrazolyl or thiadiazolyl each of which is substituted by C-^_3 alkyl (e.g. methyl) ,;>or 15 R^g is furyl; more preferably y is zero and R-^g is Vl-methyl-lH-tetrazol-5-yl.

Within the preferred meaning of Rg compounds in which Rg is defined as follows can be regarded as a separate aspect of the invention, Rg represents a C2_4 alkyl group substituted by two hydroxy groups,or a 2,2-di alkyl (e.g. dir methyl)-l,3-dioxolan-4-yl group; or Rg represents phenyl C-^_3 alkyl (e.g. benzyl) in which the alkyl portion is substituted by C^_4 alkanoyl-25 oxy (e.g.acetyloxy) or alkoxy (e.g. methoxy), or heteroaryl C^_3 alkyl (e.g. furylmethyl or vpyridylmethyl) in which the alkyl portion is substituted by hydroxy, C^_4 alkanoyloxy (e.g. acetyloxy) or C^_2 alkoxy (e.g. methoxy) ; or 30 Rg represents the group (CH2)^Z(CH2)rRg, in which q is 1, r is 1 to 4 when Z is oxygen, or r is 1 when Z is sulphur, and Rg is hydroxy, the group -CH=CH2, di C^_2 alkylamino (e.g. dimethylamino), or the group CORg where Rg is C^_4 alkoxy (e.g. 35 ethoxy) or the group NHR^ where R^ is C^_3 alkyl (e.g. methyl) or; \o 203384 R5 represents the group (CH2) (CH2) ^R^, in which x represents 1 and the heteroaryl group R.. c is lo tetrazolyl or thiadiazolyl each of which is substituted by C^_3 alkyl (e.g. methyl), or R^ is furyl; more preferably y is zero and R^ is l-methyl-lH-tetrazol-5-yl.

A particularly preferred group of compounds are those of formula (II) Me I /N"^ A R1R2NCH2QX(CH2)nY(CH2)mNH"4 'I (II) N "B in which R^R2N represents diC^_3 alkylamino (e.g. dimethylamino), furylmethy1amino, or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethylen-imino, more preferably piperidino; A represents N and B represents CR^, or A represents CR^ and B represents N, where Rg represents C2_^ alkyl substituted by two hydroxy groups, 2,2-di C1-3 alkyl (e.g. dimethyl)-1,3r dioxolan-4-yl, (l-methyl-lH-tetrazol-5-yl)thio-methyl, or Rg 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, or phenyl C^_3 alkyl (e.g. benzyl) in which the alkyl portion is substituted by alkanoyloxy (e.g. acetyloxy) or C^_2 alkoxy (e.g. methoxy), or R5 represents the group CH22(CH2)rRg where, Rg is hydroxy or di C1-3 alkylamino (e.g. dimethylamino), Z is oxygen and r is 4; or Rg is the group -CH=CH2 or the group CORg where Rg is 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 203384 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 Q is 2r5-furan or 2,4—thiophene, X is a bond, Y is sulphur, n is 1 and m is 2; with the proviso that R1R2N "*"s ^ *"1-3 alkYlamino w^en Q is a furan or thiophene ring.

A further particularly preferred group of compounds are those of formula (II) , in which either R-j_R2N ^s dimethylamino, Q is a 2,5-furan, X is a bond, Y is sulphur, n is 1 and m is 2; or * R1R2N is dimethylamino 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 CR,., or A represents CRg and B represents N, where R^ 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 CR^.

Particularly preferred compounds are 5—[[2—[[[5—[(dimethylamino)methyl]-2-furanyl]methyl]thio] ethyl]amino]-1-methyl-a-pheny1-1H-1,2,4-triazole-3-methanol, l-methyl-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] -1H-1,2,4-triazol-5-amine, l-methyl-a-phenyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy] propyl]amino]-1H-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-methy 1-5-[[3-[3-( 1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-ethane-l:,'2—didl, ; a-[l-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-1H-1,2,4-triazole-3-yl]-2-pyridinemethanol, -[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-1-methyl-a-phenyl-lH-l,2,4-triazole-3-methanol, r>> —[C3—[3—C(dimethylamino)methyl]phenoxy]propyl]amino]-1-methy1-a-phenyl-lH-l,2,4-triazole-3-methanol, 5-[[2-[[[5-[(dimethylamino)methyl]-3-thienyl]methyl]thio] ethyl]amino]-1-methyl-a-phenyl-lH-l,2,4-triazole-3-5 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 10 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, and the hydrates of the compounds of formula 15 (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. 20 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, 25 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 30 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 pharmaceutical^ acceptable carriers or excipients. Such compositions may also contain if 35 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 203384 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 soluble vehicle e.g. sterile 10 pyrogen-free water before use.

The compounds of formula ( I) 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 15 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 the condition of the patients 25 It will be appreciated that in the methods for the preparation of compounds of formula (l) 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 30 protecting group. Such protection and subsequent deprotection may be particularly pertinent where and R2 are hydrogen atoms and/or when R^ is an alkyl group bearing a hydroxy substituent and/or when R^ contains a hydroxy or amino group. Standard protection and de-35 protection procedures can be employed, for example amines may be protected by formation of a phthalimide group ? n'U ,'Mv Va>- -- ' 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^ to R-|.5' A, B, Alk, Q, X, Y, Z, n, m, p, q, x, x and y in the various formulae are as defined in formula (I ) unless otherwise stated.

Compounds of formula ( I ) in which Rg represents the group (CH2)gZ (CH2)rRg or (CH2) XS yR15 may ^ prepared by reaction of a triazole of formula ( I ) in which Rg represents the group Rg3 where Rg3 is -(CH2)gL or -(CH,) L and L is a leaving group such as halogen, 0 mesyloxy or tosyloxy, with an anion Z(CH2)rRg or eS(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 120°, 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 represents the group Rg3 35 -(CH,) L may be prepared m X compound in which R^a is of formula (I ) in which Rg where Rg3 is -(CH2)qL or by reacting the corresponding -(CH0) OH or —(CH») OH with an 2'q 2'x gio^s*-203384 acid chloride such as thionyl chloride, methanesulphonyl chloride or p-toluenesulphonyl chloride.

The intermediates of formula (I) in which represents the group R^a where R^a is (CH2)gOH or 5 (CH„) OH may be prepared as described in. New Zealand Patent, ~ i..... . — ' Specification No. 19 3 009 and European published i specification No. 48555.

Compounds of formula ( I ) may also be prepared by cyclisation of an appropriate intermediate. Thus compounds of formula ( I ) in which R^ is other than a C- straight or branched alkyl group substituted by 2 — 6 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^ where R ^ is acyl^ can be prepared by cyclisation of a compound of formula (III) ?16 RJLR2NAlkQX (CH2 ) nY (CH2) ^NH-C-NNHY • (III) V1 in which R16 is a group as defined for R_, V1 is NCR,.0 ■3 ii 5 V and Y* is hydrogen where V is oxygen or sulphur and RgC is a group as defined for R^ or a group convertible thereto under the conditions of the cyclisation reaction; or V* is NH, R16 is a group as defined for R- and Y' is CR. where ^ II J Y" Y" is sulphur, oxygen or NH; or V' is sulphur or oxygen, 1* V./F Y* is CRg and R^g is a group as defined for R^; or V' NH is NR^ / R-^g is hydrogen and Y' is CR^ where Y" is as Y" 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 CR^ may be prepared by cyclisation of a compound of formula (IV) R3 R^NAlkQX (CH2) nY (CH2) mNHC-N-N=U (IV) N-CRcC i. 3 V where V represents sulphur or more preferably oxygen and 15 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 prepare in situ compounds 20 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 25 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) 30 may be prepared by cyclisation of a compound of formula (V) ,16 R, R9NAlkQX (CH,) Y (CH-) NHCNNHC-Rt-x ^ ^ n iu ft d V' Y" (V) where R-^g is a group as defined for R^r and either V' is NH and Y" is sulphur, oxygen or NH, or VI is sulphur or oxygen and Y" is NH; or R^g is hydrogen, V' is NR^ and Y" is sulphur.

When Y" represents sulphur then tautomerism with the adjacent NH group is possible (i.e. -N=CR,-) and the I ^ SH -SH group may be alkylated under standard conditions. The S-alkylated compound may also be used in the cyclisa-10 tion 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. 15 using aqueous potassium hydroxide).

In a convenient embodiment of this process an intermediate of formula (V) in which R^g is a group as defined for R^, V' is NH and Y" is oxygen; or R^g is hydrogen, V" is NR^ and Y" is oxygen may be prepared in 20 situ by the reaction of an aminoguanidine (VI) ?16 Rj^R2NAlkQX (CH2) nY (CH 2) mNH-C-N-NH2 (VI) V' with an acid R^COOH or with an activated derivative 25 thereof. Suitable activated derivatives include acid halides, e.g. acid chlorides, alkylchloroformates, acid anhydrides including mixed anhydrides (e.g. acetic formic anhydride), esters such as alkyl esters, ortho esters (such as trialkylorthoesters, e.g. RgC(OEt)3) and 30 (l-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 35 the intermediate (V) takes place directly to give a compound of formula (I). In the case of an activated 203^1^ derivative, an aprotic solvent, e.g. tetrahydrofuran may be used at temperatures from ambient to reflux.

When using an acyl chloride as the activated derivative the reaction may also be carried out in the presence 5 of a base, e.g. a tertiary amine such as pyridine, which may also be used as the solvent.

In general intermediates of formula (IV) may be prepared from the appropriate diamines by methods analogous to those described in New Zealand Patent Specifi- ' 10 cation No. 193009, (and intermediates of formula (V) may be prepared from the appropriate diamines by methods analogous to those described in New Zealand Patent Specifi- \ cation No.190299 and in European Patent Specification No. 48555. The aminoguanidines (VI) may be prepared as 15 described in New Zealand Patent Specification No. 190299, \ and European Patent Specification No. 48555.

"V \\ V 1 1 *1 / Compounds of formula ( I ) in which Alk is CH2 may be prepared by treating an aldehyde of formula (VII) OHC-QX(CH2)nY(CH2)mNH (VII) with an amine R^R^H, 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 15 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. in which W represents a protected aldehyde group, e.g. a cyclic acetal such as an ethylene acetal, by methods 25 analogous to those described herein for preparing compounds of formula (I) from the appropriate diamine.

Compounds of formula (I ) in which R^ is an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy may be prepared by reacting 30 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. 35 diethylether, tetrahydrofuran or a mixture thereof at a temperature of from -70° to 50°, preferably at -70 to The intermediates of formula (VII) may be prepared from compounds of formula (VTII) WQX(CH2)nY(CH2)mNH 2 m 2 (VIII) 203384 to 20° for the reaction with ArLi and at 0 to 50° for the reaction with ArMgHal. The aldehyde or ketone starting material may be prepared as described in New Zealand Patent Specification No. 196365 and European Patent Specifica- -5 tion No. 48555.

Compounds of formula (I) in which Rg has one meaning may be converted into compounds of formula (I) in which Rg has another meaning using standard methods of interconver-s ion.

Thus, compounds in which Rg represents a C2-6 straight or branched alkyl group substituted by two or * three acyloxy groups, or Rg represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group, or Y represents CH0R^4 where 15 R is acyl, may be prepared by reacting the corresponding alcohol with an activated derivative (e.g. an acid chloride or an acid anhydride) of an appropriate acid. The reaction may be carried out at room temperature, optionally in the presence of a solvent (e.g. pyridine, tetrahydrofuran, 20 acetone or dimethyIformamide), and preferably in the presence of a base (e.g. pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate).

Compounds in which Rg represents a C2_g straight or branched alkyl group substituted by two or three alkoxy 2 5 groups, or Rg 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 halo-30 compound 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 dimethylform-amidg, in the presence of a strong base such as sodium 35 hydride, at a temperature within the range 2 0-100°.

Compounds in which Rg represents the group I (CH2) cjZ (CH2) rRs wliere R8 is NR12R13 and R12 and R13 each represent hydrogen or alkyl may be prepared from the corresponding alcohol in which Rg is hydroxy by treatment with a reagent capable of converting the group Rg into a leaving group, for example thionyl chloride, followed by reaction of the resulting compound of formula (I) in which R_ represents (CH0) Z(CH_) L where L is a leaving group 3 £. g £ r e.g. halogen with ammonia or an appropriate amine R12R13NH Preferably in a solvent such as an alkanol, 10 e.g. ethanol at a temperature within the range 80-120°.

Compounds in which Rg is the group NHR^ maY converted into compounds in which Rg is the group NRi2Ri3 where R^ is either an acyl group or an aryl-or alkylsulphonyl group, by reaction: with an activated 15 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 20 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 25 as triethylamine or pyridine. The reaction with an alkyl-chloroformate 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 30 presence of a solvent such as pyridine.

Compounds in which Rg is the group -CONR^qR^ may be prepared by reacting an activated derivative of the corresponding carboxylic acid in which Rg is the group -CC^H, e.g. an ester with ammonia or an appropriate 35 amine HNR^gR^ in a suitable solvent (e.g. an alcohol such as ethanol) at a temperature of from 20°C to 120°C.

Compounds in which Rg includes the group -CHCCH.,) CH- may be converted into the corresponding i ^ Pi OH OH compounds in which R,- includes the group -CH(CH~) CH D | c p | 0 yO \ / 6 7 by reaction with an aldehyde or ketone R^R^CO, e.g. acetone in the presence of an acid, :e.g.;pttoluene-sulphonic 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. 15 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, fdr example, a generally convenient method of forming the salts is 20 to mix appropriate quantities of the free base and the acid in an apppropriate 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.

Unless 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: Dichloromethane:ethanol:0.88 ammonia (50:8:1) Dichloromethane:ethanol:0.88 ammonia (25:8:1) Dichloromethane:ethanol:0.88 ammonia (100:8:1) Ethyl lacefeate:isopropanol:water:0.88 ammonia (25 115:8:2) System E: Dichloromethane:ethanol:0.88 ammonia (75:8:1) System A System B 10 System C System D Preparation 1 Methyl N- [2 , 3-diacetyloxypropionyl] -l-methyl-2- (phenyls-methylene) hydrazine carboximidothioate Di-acetyl glyceric acid (13.8 g) was heated under reflux in thionyl chloride (50 ml) for 4 h. The solution was 20 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 carboximidothioate 25 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 15 h before adding water. The organic phase was separated, dried (MgS04) and evaporated to leave a 30 residue (7 g) which was chromatographed using ether as eluent to give the title compound as a yellow waxy solid (4.6 g).

NMR (CDC13): 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); 35 7.93, s, (3H). 2 A Preparation 2 Methyl N-[2-acetyloxy-[2-(phenyl)-acetyl]]-l-methyl-2-(phenylmethylene)hydrazine carboximidothioate A solution of acetyl chloride (11.35 g) in dry ether 5 (50 ml) was slowly added to a solution of mafldelic 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 10 removed by azeotropic distillation 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 g) and 15 methyl l-methyl-2-(phenylmethylene)hydrazine carboximidothioate hydrochloride (6.9 g) in dry toluene (180 ml). The reaction was stirred at room temperature for 15 h, poured onto water and extracted with ether. The organic extract was dried (MgSO^) and evaporated to give 20 the title compound as a cream solid (6.3 g).

NMR (CDC13): 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, (3H).

Preparation 3 (i) 2-[2-Hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]-lH-isoindole-l,3-(2H)-dione A mixture of 2-(oxiranylmethyl)-lH-isoindole-l,3-(2H)-dione (9.10 g) and 3-(1-piperidinylmethyl)phenol (8.55 g) was heated at 130°C under nitrogen for 10 minutes. The 30 resulting mixture was dissolved in chloroform (100 ml) , washed with IN sodium hydroxide (2 x 25 ml), dried (MgSO^) and evaporated to give the title compound as a gum (17.65 g).

T.l.c. system C; Rf 0.60. (ii) l-Airtino-3-[3-[ (1-piperidinylmethyl)phenoxy] -2-propanol A solution of 2-[2-hydroxy-3-[3-(l-piperidinylmethyl) 2 033 84 phenoxy]propyl]-lH-isoindole-1,3-(2H) dione (17.6 g) 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 IN hydro-5 chloric 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 (Na2C02) and evaporated to a gum which was chromatographed using System A. Crystallisat-10 ion 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 -£ f3-(3-Formylphenoxy)propyl]amino]-1-methyl-a-phenyl-15 ltj-1, 2 , 4-triazole-3-methanol acetate (ester).

A solution of 3-[3-(l,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 20 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 (UGl)] using ether:ethyl 25 acetate:methanol 50:50:1 as eluent to give the title compound (1.4 g) as a foam.

T.l.c. System C Rf 0.7.

* Compound A = methyl-N-[2-acetyloxy-[2-(phenyl)-acetyl]]- 3° l-methyl-2-(phenyMethylene)hydrazine carboximidothioate Example 1 1-methyl-5-[ [3-[3-'( l-piperidinylmethyl) phenoxy] propyl] amino] -ljj-1,2,4-triazole-3-ethane-l, 2-diol, hemicitrate To a mixture of methyl N-[2,3-diacetyloxypropionyl]-1-5 methyl-2-(phenylmethylene)hydrazine carboximidothioate (2.69 g) in toluene (100 ml) was added 3-[3-(1-piperidinylmethyl) phenoxy]propanamine (1.5 g) and the resulting solutions stirred at 20° for 16 h before 5N hydrochloric acid (25 ml) was added and the two phase mixture 10 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 15 solution was extracted with ethyl acetate and the combined organic extracts dried (MgSO^) and evaporated. The residue (2.0 g) was chromatographed using chloroform: methanol (5:1) as eluent to give a foam (0.6 g). The foam was dissolved in ethyl acetate (20 ml) with the aid 20 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° 25 softens: T.l.c. System D. Rf. 0.46 Example 2 (a) -[[2-Hydroxy-3-C3-(1-piperidinylmethyl)phenoxy]propyl] 30 amino]-1-methyl-g-phenyl-lS-l,2,4-triazole-3-methanol A solution of l-amino-3-[3-(1-piperidinylmethyl)phenoxy]- 2-propanol (2.0 g) and methyl-N-[2-acetyloxy-[2-(phenyl)-acetyl]]-l-methyl-2-(phenylmethylene) hydrazine . carboximidothioate, compound.A (3.19 g) in toluene 35 (60 ml) was stirred at 20° for 4h, 5N hydrochloric acig^^^^1^^^ (9 ml) was added and the mixture was stirred at 20° for 16h and heated on a steam bath for V.V I 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 5 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 150 ml whereupon crystallisaion occured. The resulting solid (1.2 g) was collected on a filter and recrystallised from 2-propanol to give the 10 title compound (0.63 g) as a white solid m.p. 154-157°.

Found: C, 66.2; H, 7.2; N, 15.2; C25H33N5O3 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]propanamine (0.74 g), except that the 4-methyl-2-pentanone extract was evaporated in vacuo and the residue (1.3 g) was chromato-20 graphed using System A as eluent, was 5-[[3-[3-[(dimethylamino) methyl] phenoxy] propyl] amino] -1-methyl-Xrphenyl-1H-1,2,4-triazole-3-methanol hydrate (0.31 g) as a white foam.

Found: C, 63.7; H, 7.3; N, 16.6; C22H29N5°2"1H2° re<3uires: C' 63.9; H, 7.59; N, 16.9% N.m.r. (CDC13~DMS0): 2.4-2.92, m, (6H); 3.05-3.33, m, (3H); 4.4, s, (1H); 4.65, s(br), (1H); 5.58, s, (br), 30 (1H); 5.98, t, (2H); 6.4-6.75, s+s+q, (7H); 7.85, s, (6H); 8.0, quintet, (2H).

^ /■* 'V* 4 - 28" Example 2 (c) Similarly prepared from Compound A (1.5) and 2-[2-[3-(l-piperidinylmethyl)phenoxy]ethoxy]ethanamine (0.99 g), with exceptions that the aqueous phase was extracted 5 with hot ethyl acetate (6 x 50 ml) at pH 7 and chromatographed using dichloromethane:ethanol:0.88 ammonia (80:8:1), was l-methyl-a-phenyl-5-[[2-[2-[3-(1-piperidinylmethyl)phenoxy]ethoxy]ethyl]amino]-1H-1,2,4-triazole-3-methanol (0.45 g) as a clear gum.

Found: C, 66.95; H, 7.75; N, 14.65; C,,Hoi:N.O, requires: C, 67.07; H, 7.58; N, 15.04% ZD JJ D J N.m.r. (CDC13): 2.4-2.9, m, (6H); 3-3.35, m, (3H); 15 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) -[[2-[[[5-[(Dimethylamino)methyl]-3-thienyl]methyl]thiol 20 ethyl]amino]-1-methyl-a-phenyl-lff-l,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 25 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. (CDC13 +■DMSO): 2.35-2.85, m, (5H) ; 3.01, S, (1H); 3.12, s, (1H); 4.33, s, (1H); 4.62, t, (1H); 5.75, br, (1H) ; 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-propenyloxy)methyl]-1H-1,2,4-triazol-5-amine l-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl} 15 amino]-lH-l,2,4-triazole-3-methanol (3.59 g) 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 20 (3 g) were added, and the suspension was stirred with ethyl acetate. The organic phase was separated, dried for lh 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 g) in allyl alcohol 25 (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. 30 Evaporation of the organic extracts gave an oil (1.1 g) which was chromatographed using dichloromethane:ethanol: ammonia: (70:8:1) as eluent to give the title compound as an oil (0.4 g) Assay Found: C, 65.64; H, 8.46; N, 17.44; C22H33N5°2 re<3uires: c> 66.14; H, 8.33; N, 17.53. T.l.c. System C Rf 0.4 7 (b) Similarly prepared by this procedure from 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (3.59 g) and thionyl chloride (10 ml), followed by addition of a solution of sodium 5 (0.3 g) in butane-1,4-diol (10 g) was 4-[[l-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino-lH-1,2,4-triazol-3-yl]methoxy]butanol compound with ethanol (2:1) (0.87 g).

Assay Found: C, 63.12; H. 8.81; N, 15.56; C23H27N5°3^C2H5OH requires: C, 63.40; H, 8.87; N, 15*41; NMR (CDC13): 2.8, t, (1H); 3.0-3.3, m, (3H); 5.4, br.t, (1H) ; 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); 15 7.9, m, (2H); 8.1-8.7, m, (10H).

Example 4a Ethyl [[[1-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino]-1H-1>2,4-triazol-3-yl]methyl]thio]acetate 20 hemihydrate l-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-lH-l,2,4-triazole-3-methanol, compound B, (7.2 g) was dissolved in thionyl chloride (30 ml) at 20° and heated under reflux for 15 min. The cooled solution was 25 evaporated in vacuo and the oil dissolved in water (30 ml), cautiously basified with solid sodium bicarbonate, sodium carbonate (3g) added, and the mixture extracted with ethyl acetate. The extract was dried (Na2C03, lh) 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 g) and ethyl mercaptoacetate (2.4 g). The mixture was partitioned between aqueous potassium 35 carbonate and ethyl acetate. The ethyl acetate extract was dried and evaporated and the residue (5.1 g) was chromatographed using System E as eluent to give the title compound (2.9 g) as a pale yellow oil.

Found: C, 58.7; H, 7.6; N, 14.8; C25H35N5°3S*^H2° re<3u;*-res: C' 58,7; H, 7.7; N, 14.9% N.m.r. (CDClg): 2.75, dd, (1H); 3-3.33, m, (3H); 5.45, t, (1H) ; 5.66-6, q+t, (4H) ; 6.23-6.7, s+s+q+s+s, (11H) ; 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 g), 5-mercapto-l-methyltetrazole (0.506 g) and potassium carbonate (0.54 g) with the 15 exceptions that the mixture was chromatographed using System C to give an oil (1.0 g) which was dissolved in ethyl acetate and treated with excess ethereal hydrochloric acid, gave l-methyl-3-[[(1-methyl-lH -tetrazol-5-yl)thio] methyl]-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-20 1,2,4-triazol-5-amine dihydrochloride sesquihydrate (0.6 g) 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): 6.4-6.6, s+m, (7H); 7.05, t, (2H); 25 7.9-8.6, m, (8H). 4 (c) Compound B (1.41 g), 2-mercapto-5-methyl-l,3,4-thiadiazole (0.52 g) and potassium carbonate (0.54 g), with the exception that the mixture was chromatographed using 30 System C, gave l-methyl-3-[[(5-methyl-l,3,4-thiadiazol-2-y1)thio]methyl]-N-[3-[3-(1-piperidinylmethyl)phenoxy] propyl]-1H-1,2,4-triazol-5-amine (0.62 g) as a white powder m.p. 63° softens melts 72-74°, Found: C, 55.9; H. 6.7; N, 20.7; C22H31N7OS2 re(3uires : c> 55.8; H, 6.6; N, 20.7% Example 5 3 — T T4 — (Dimethylamino) butoxy]methyl] -l-methyl-?N-E3-E;3-rXl-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-5-amine 4-[[l-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-1H-1,2,4-triazol-3-yl]methoxy]butanol (0.5 g) 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 10 sodium bicarbonate and sodium carbonate (^-2 g). The mixture was extracted with ethyl acetate, the extract dried (Na2C03, lh), evaporated and the residual oil was dissolved in ethanolic dimethylamine (33%, 15 ml) and the solution was heated in an autoclave at 80° for 8h. 15 The solution was evaporated and the residual oil (0.3 g) was chromatographed using System A as eluent to give the title compound (0.2 g) as a pale yellow oil.

N.m.r. (CDCl3): 1.74, dd, (1H); 3-3^32, m, (3H); 5.48, 20 t, (1H); 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 a-(2-Furanyl)-l-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-lfl-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 30 -40°. The stirred solution was allowed to warm slowly to 20°, heated under reflux for 3h, added dropwise at 0° to a solution of l-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (1.0 g) in tetrahydrofuran (10 ml), and the resulting 35 solution was stirred at 20° for 18h. Water (20 ml) was added, the mixture concentrated, extracted with ethyl 4* i/ acetate and the extract was dried and evaporated. The residual oil (0.9 g) was chromatographed using System E to give the title compound (0.16 g) as a brown oil.

N.m.r. (CDClg): 2.6, m, (1H); m, (2H); 3.23, m, (1H); 3.65, .48, t, (1H); 5.86, t, (2H); 6.56, s, (2H); 7.62, m, (4H); m, (6H).

T.l.c. System A Rf 0.7. 2.76, t, (1H); 3.06-3.08, m, (2H); 4.25, s, (1H); 6.38, q, (2H); 6.45, s, (3H): 7.88, quintet, (2H); 8.36, Example 7 3-(2,2-Dimethyl-l,3-dioxolan-4-yl)-1-methyl-N-[3-[3-(1-piperidinylmethyl-phenoxy] propyl] -lij-1,2 ,4-triazol-5-amine A solution of l-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-1H-1,2,4-triazole-3-ethane-l,2-diol (0.08 g), 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 g) was chromatographed using System E as eluent to give the title compound (0.025 g) as an amber gum.

N.m.r. (CDC13): 2.78, t, (1H); 3.08-3.23, m, (3H); 4.96, dd, (1H) ; 5.48, t, (1H) ; 5.72, dd, (1H); 5.80, t, (1H) ; 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 [[[l-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino]-1H-1,2,4-triazol-3-yl]methyl]thio]acetamide A solution of ethyl [[[l-methyl-5-[[3-[3-(1-piperidinylmethyl )phenoxy]propyl]amino]-1H-1,2,4-triazol-3-yl]methyl] thio]acetate (0.4 g) 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 g) which was chromatographed using System E as eluent to give the title compound (0.13 g) as an oil.

N.m.r. (CDC13): 2.46, S(br), (1H); 2.79, t, (1H); 3.07, m, (2H); 3.22, dd, (1H); 5.34, t, (1H); 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, 15 (4H) ; 8.57, m, (2H) .

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

Example 9 l-Methyl-a-phenyl-5-C[3-[3-(1-piperidinylmethyl)phenoxy] 20 propyl] amino]-llj-l, 2,4-triazole-3-methanol compound with fumaric acid and ethyl acetate: 40;56;5 3-[3-(1-Piperidinylmethyl)phenoxy]propanamine (0.72 g) and methyl N-[2-acetyloxy-[2-(phenyl)acetyl]]-l-methyl-2-(phenylmethylene)hydrazine carboximidothioate (1.1 g) 25 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 30 phase was basified to pH 10 with sodium carbonate and extracted with ethyl acetate. The organic extracts at pH 10 were dried (MgSO^) and evaporated to leave an oil (1.1 g). This oil was chromatographed using dichloromethane : ethanol: 0.88 ammonia (150:8:1) as eluent to give 35 a white solid (0.25 g) m.p. 42-52°. This solid (0.112 g) was dissolved in ethyl acetate and treated with a solution »*-v> of furmaric acid (0.03 g) in ethyl acetate to precipitate the title compound which was collected as a white solid (0.095 g) m.p. 80°.

NMR (CDClg) of free base 2.4-2.9/ m, (6H); 3.0-3.4, m, (3H); 4.31, s, (1H); 5.56, t, (1H); 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-a-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy] propyl] amino] -4H.-1 r 2 ,4-triazole-3-methanol A mixture of DL mandelic acid (30.4 g) and N-amino-N^-methyl-N"'"''"-[3-[3- (1-piperidinylmethyl) phenoxy] propyl] 15 guanidine hydroiodide (22.35 g) was heated from 40° to 125° and maintained at 125° 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 20 carbonate, and extracted into ether. The ether extract was cooled at 5° £0 give a white solid which was washed with boiling ethyl acetate to leave the title compound as a white solid (0.18 g) m.p. 186-8°.

Assay Found: C, 68.9; H, 7.7; N, 16.0; C25H33N5°2 rec3uires: C' 68.9; H, 7.6; N, 16.1% Example 11 r4-Methyl-g-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino]-4jj-l,2,4-triazole-3-methanol]acetate (ester) 30 hydrate A solution of 4-methyl-g-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 35 sodium carbonate solution was added and the suspension was extracted with ethyl acetate. The organic phase was 8 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 g), m.p. 89-91°C.

C27H35N5°3H2° re(3uireS: c' 65.3; H, 7.4; N, 14.1% Example 12 g-[l-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl] 10 amino] -llj-l, 2 ,4-triazol-3-yl] -2-pyridinemethanol n-Butyllithium (1.6M,in.n-hexane? 8.12 ml) was added drop-wise during 15 min to a stirred solution of 2-bromopyridine (1. 86§, 1.12ml) iin anhydrous ether (10 ml) at -70^, under nitrogen. The brown solution was stirred at - 70° for 15 0.5h before a solution of l-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carbox-aldehyde (2.0 g) 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 20 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 g) which was chromatographed using System E as eluent to give a solid (0.48 g). This was crystallised 25 from ethyl acetate to give the title compound (0.25 g) as a white powder m.p. 152-154° (d).

Found: C, 65.9; H, 7.4; N, 19.1; C24H32N6°2 rec3u;i-res: C' 66.0; H, 7.4; N, 19.2% Example 13 -[[2-[[[5— C(Dimethylamino)methyl]-2-furanyl]methyl]thio] ethyl]amino]-1-methyl-g-phenyl-lH-l,2,4-triazole-3-methanol dihydrochloride A solution of 2-[[[5-[(dimethylamino)methyl]-2-furanyl] 35 methyl]thio]ethanamine (3.09 g) and methyl-N-[2-acetyloxy-[2-(phenyl)acetyl-]]-l-methyl-2-(phenylmethylene)hydrazine- Assay Found: C, 64.9; H, 7.5; N, 13.8; 2 033 84 carboximidothioate (5.9 g) in toluene (110 ml) was stirred at room temperature for 3h. A further quantity of methyl-N-[2-acetyloxy~[2-(phenyl)acetyl]]-l-methyl-2-(phenylmethylene)hydrazine-carboximidothioate (0.3 g) 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 lh. 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 g).

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 g) as a fine white solid, mp 55-60° softens.

Nmr (CD30D): 2.5, m, (5H); 3.3, d, (1H); 3.6, d, (1H); 4.15, s, (1H); 5.6, s, (2H); 6.3, m, (7H); 7.15, m, (8H).

Example 14 -[[3-C 3 — Cf(2-Furanylmethyl)amino]methyl]phenoxy]propyl] amino]-1-methyl-g-phenyl-lH-l,2,4-triazole-3-methanol A solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-a-phenyl-lH-1,2,4-triazole-3-methanol acetate (ester) (1.0 g) and furfurylamine (5 ml) in ethanol (30 ml) was stirred at 21° for 1.5 h before a suspension of sodium borohydride (1.3 g) in ethanol (10 ml) was added and stirring was continued for a further 16h at 21°. Water (20 ml) was added, the mixture concentrated to remove ethanol and the aqueous residue extracted with 4-methyl-pentan-2-one. The extract was dried and evaporated to x. give anloil. 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 g) which was chromatographed on silica (Merck No. 7729) using System C as eluent to give the title compound (0.5 g) as a pale orange gum.

T.l.c. System C Rf 0.35.

N.m.r. (CDC13) 2.50, db, (2H); 2.6-2.84, m, (5H); 3.14-3.4, m, (2H); 3.24, d, (1H); 3.70, dd, (1H); 3.82, dd, (1H); 4.28, s, (1H); 5.5, t, (1H); 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-CCT (2-Furanyl)methyl] thio]methyl"! -l-methyl-Nr3-[3-(l-piper idinylmethyl) phenoxy] propyl] -1H.-1,2,4-t.Txa.7.ol-5^ amine A solution of l-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino]-1H-1,2,4-triazole-3-methanol (3.59 g) 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 25 added to the solution until no more effervescence occurred. Sodium carbonate (3g) was added, and the suspension was extracted with ethyl acetate. The organic extract was dried and evaporated to give a brown oil (4.1 g).

A portion of this oil (3.2 g) was dissolved in absolute ethanol (40 ml) and added dropwise at 5° to a solution of furfurylmercaptan (1.14 g) and sodium (0.34 g) in absolute ethanol (20 ml). The suspension was allowed to stand at room temperature for 18h, filtered, and the filtrate was 35 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 g) which was purified by column chromatography using chloroform as eluent to give the title compound as an oil (1.2 g). T.l.c. System C Rf 0.45.

N.m.r. (CDC13) 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 -(Methoxyphenylmethyl)-4-methyl-N-[r3-f3-(1-piperidinylmethyl) phenoxy] propyl] -4fl-l,2,4-triazol-3-amine compound with tartaric acid (1:1) A solution of 4-methyl-a-phenyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy] propyl]amino]-4H-1,2,4-triazole-3-methanol (0.37 g) 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 20 methanol (10 ml) and added dropwise to a solution of sodium (0.17 g) 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 25 (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 g) , m.p. = 88° softens.

N.m.r. (CD3OD) 2.5-3.1, m, (9H); 4.5, s, (1H); 5.6, s, 30 (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) .

' - V 41 Example 17 -f f2-f f[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio] ethyl]amino]-1-methyl-a-phenyl-lH-l,2,4-triazole-3-methanol A solution of 2-[[5-[(dimethylamino)methyl]-2-furanylmethyl] thio]ethanamine (3.09 g) and methyl-N-[2-acetyloxy-[2-(phenyl)acetyl]] -l-methyl-2-(phenylmethylene)hydrazine-carboximidothioate (compound A) (5.9 g) in toluene (110 ml) was stirred at room temperature for 3h and a further 10 quantity of compound A (0.3 g) 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 lh. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with 15 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 20 (65:8:1) to give a brown gum (1.95 g). A portion of this gum (0.5 g) 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 g) as a white 25 solid, m.p. 121-122.5°.

Found: C, 60.0; H, 6.9; N, 17.3; C20H27N5°2S re<3uires: 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 through a 250 Jim sieve, blended 10 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 15 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 yim 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

Claims (2)

1. -42- 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 5 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. 10 Syrup mg/5 mlodose Active ingredient 5.0 to 250.0 Sucrose 2795.0 to 2550.0 Glycerine 500.0 Buffer ) 15 Flavourj as necessary Colour ) Distilled water to 5.0 ml The active ingredient, buffer, flavour, preservative 20 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, 25 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] 30 methyl]thio]ethyl]amino]-1-methyl-a-phenyl-lH-l,2,4-triazole-3-methanol in the form of a physiologically acceptable salt, for example the hydrochloride. 35 -43- yyHM +/WE CLAIM; IS. CLAIMS? 1. Compounds of the general formula (I) R„ R1R2N-Alk-Q-X-(CH2)nY(CH2)inNH-^. /B (I) and physiologically acceptable salts and hydrates thereof, in which 10 R^ represents hydrogen, C^_-^ 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 15 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 groups or a hydroxy group and/or may contain another heteroatom 20 selected from oxygen and sulphur; Alk represents a straight or branched alkylene chain of 1 >tt> 3 carbon atoms, Q represents a furan or thiophenering in which incorporation into the rest of the molecule is through 25 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 thiophenering in which incorporation into the rest of the molecule is through bonds at the 2- and 4- positions, 30 the thiophenering optionally bearing a further substituent R^ adjacent to the group R^R2NAlk with the proviso that when the group R^R2NAlk is in the 4- position then the group R^ is in the 5- position; or Q represents a benzene ring in which incorporation into the rest of the 35 molecule is through bonds at the 1- and 3~ or 1- and 4-positions; -44- represents halogen or C^_4 alkyl which may be substituted by hydroxy or alkoxy; X represents oxygen, sulphur, -NH-, methylene or a bond; 5 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) is an integer 10 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 15 and Y may additionally represent -CHOR^ where R^ represents hydrogen or acyl; and R^ represents hydrogen, alkyl, alkenyl, aralkyl, or alkyl substituted by hydroxy or alkoxy; either A represents N and B represents CR,-; 20 or A represents CR^ and B represents N; and R^ represents i) a C2_g straight or branched alkyl group substituted by two or three hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group may form a cyclic 25 acetal or cyclic ketal structure of the formula (CH0) ■/ P\ -CH CH- 30 35 where p is zero or 1 and Rg and R^, which may be the same or different, each represents hydrogen, a alkyl group or a phenyl group; or -45- ii) the group (CI^) gZ (CI^) rRg r 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 5 when r represents 1, Rg represents the group CH=CH2/ alkenyl or the group COR^ where Rg is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the group NR]_oRll where R^q is hydrogen or alkyl and R^ is hydrogen or alkyl and 10 when r represents an integer from 2 to 6, Rg has any of the meanings given above or may additionally represent hydroxy, alkoxy, aryloxy or the group NRi2Ri3 where R^ is hydrogen or alkyl and R^ is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulphonyl 15 or arylsulphonyl; or iii) the group (CI^) XS (CH2) yR]_5 / where x represents 1 or 2, y represents zero or 1, and R^^ represents a heteroaryl group; or iv) an aralkyl or heteroaralkyl group in which the 20 alkyl portion is substituted by hydroxy, alkoxy or acyloxy.

2. Compounds as claimed in claim 1 in which: R^ represents C^_g alkyl, alkyl substituted by a trifluoromethyl group, C2-4 substituted 25 by hydroxy or a di alkyl amino group, cycloalkyl, Cg_5 alkenyl, phenyl C^_g alkyl, or a heteroaryl alkyl group where the heteroaryl ring contains one heteroatom; R2 represents hydrogen or methyl; or 30 RiR2N 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 35 rest of the molecule through bonds at the 1- and 3- positions; or a furan ring incorporated into the -46- 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- positioas with the substituent R^^NAlk 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 ra is 3; represents hydrogen or alkyl; represents a C2_4 alkyl group substituted by two hydroxy groups, or a 2,2-di C1-3 alkyl-l,3-dioxolan-4-yl group; or represents phenyl C1-3 alkyl or heteroaryl C1-3 alkyl in which the alkyl portion is substituted by hydroxy, C-j._4 alkanoyloxy or C^_2 alkoxy; or represents the group (CH2)gZ(CH2)rRg, in which q is 1, r is 1 to 4 when Z is oxygen or r is 1 when Z is sulphur, and Rg is hydroxy, the group -CH=CH2, di ci_3 alkylamino, or the group CORg where Rg is C1-4 alkoxy or the group NHR^ where R^ is C-^_3 alkyl; or 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 R^5 is furyl. Compounds as claimed in claim 1 in which represents C1_g alkyl, C1-4 alkyl substituted by a trifluoromethyl group, C2_4 alkyl substituted by -47- hydroxy or a di C^_g alkyl amino group, Cg_7 cycloalkyl, Cg_g alkenyl, phenyl alkyl, or a heteroaryl alkyl group where the heteroaryl ring contains one heteroatom, 5 R2 represents hydrogen or methyl; or represents a 5-8 membered ring optionally containing a double bond, an oxygen atom or an alkyl V; ; substituent; Alk represents methylene; 10 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 15 adjacent to the group R^R2NAlk where R^ 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- position; with the provisos that when Q 20 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 oxy gen, 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 25 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; Rg represents hydrogen or alkyl; R5 represents a C2_4 alkyl group substituted by two hydroxy groups^ or a 2,2- di alkyl-1,3- 30 dioxolan-4-yl group; or Rg represents phenyl C1_g alkyl in which the alkyl portion is substituted by C^_4 alkanoyloxy or C^_2 alkoxy,or heteroaryl C1_g alkyl in which the alkyl portion is substituted by hydroxy, C1-4 35 alkanoyloxy or C1-2 alkoxy; R5 represents the group JCH^) (CI^ty^Rg r in which. 9 203384 -4S- 10 15 q is 1, r is 1 to 4 when Z is oxygen or r is 1 when Z is sulphur, and Rg is hydroxy, the group -CH=CH2, di C^_2 alkylamino, or the group CORg where Rg is C1-4 alkoxy or the group NHR^ where R^1 is alkyl; or Rg represents the group >(GH2)(CH2)yR^g in which x represents 1 and the heteroaryl group R-^g is tetrazolyl or thiadiazolyl each of which is substituted by alkyl, or R^g is furyl. 4. Compounds of general formula (II) Me XN—A R1R2NCH2QX(CH2)nY(CH2)mNH-^N^B (II) and physiologically acceptable salts and hydrates thereof in which RlR2N represents di alkylamino, furylmethylamino, or pyrrolidino^. piperidino, 4-methylpiperidino, tetra-20 hydropyridino or hexamethylenimino; A represents N and B represents CR,., or A represents D CRg and B represents N, where Rg represents C2_4 alkyl substituted by two hydroxy groups, 2,2- di' C^^ alky1-1,3-dioxolan-4-25 yl, (l-methyl-lH-tetrazol-5-yl)thiomethyl, or Rg represents phenyl alkyl or heteroaryl C^ ^ alkyl in which the alkyl portion is substituted by hydroxy, or phenyl alkyl in which the alkyl portion is substituted by C^-4 alkanoyloxy or 30 Ci-2 alkoxy' or Rg represents the group CH2Z(CH2)rRg where Rg is hydroxy or di alkylamino, Z is oxygen and r is 4; or Rg is the group -CH=CH2 or the group CORg where Rg is C^_4 alkoxy, Z is oxygen or 35 sulphur and r is 1; and either Q is 1,3-benzene and X is a bond, n is zero, \ % - *;£ ^;10;-49-;Y is oxygen and m is 3 or 4; or X is oxygen^ n is 1, Y is -CHOH- and m is 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 alkylamino when Q is a furan or thiophene ring.;5. Compounds of general formula (II);Me;R1R2NCH2QX(CH2)nY(CH2)mNH /B (II);and physiologically acceptable salts and hydrates thereof in which;15 either is dimethylamino, Q is 2,5-furan, X is a bond;Y is sulphur, n is 1 and m is 2;;or RiR2N 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;;20 and A represents N and B represents CR^, or A represents CRg and B represents N, where R^ is benzyl in which the methylene group is substituted by hydroxy.;6. 5- [ [2- [ [ [5- [ (Dimethylaminojmethyl] -2-furanyl] 25 methyl] thio] ethyl] amino] -1-methyl-a-phenyl-lH-l,2 ,4*> triazole-3-methanol and physiologically acceptable salts thereof. 7. Compounds as claimed in claim 1 which are: 30 l-methyl-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl] N- [3- [3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazol-5-amine l-methyl-a-phenyl-5- [ [3- [3-(1-piperidinylmethyl) phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol 35 4-methyl-a-pheny1-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-4H-1,2,4-triazole-3-methanol and physiologically acceptable-salts thereof. 203384 -50- 8. Compounds as claimed in claim 1 which are: l-methyl-5-[ [3-[3-( 1-piperidinylmethyl) phenoxy]propyl] aminc]>-lH-l,2 ,4-triazole-3-ethane-l,2 ,-diol a-[l-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy] 5 Propyl] amino] -1H-1,2 , 4-triazole-3-yl] -2-pyridineimethanol 5-[[2-hydroxy-3- [3-(1-piperidinylmethyl)phenoxy] propyl]amino]-1-methy1-a-phenyl-lH-l,2,4-triazole-3-methanol 5- [ [3- [3- [ (dimethylamino) methyl] phenoxy] propyl] 10 amino]-1-methyl-a-phenyl-lH-l,2,4-triazole-3-methanol 5- [ [2- [ [ [5- [ (dimethylamino) methyl] -3-thienyl]methyl] thio] ethyl] airtino] -1-methy 1-a-phenyl-lH-l,2 ,4-triazole-3-methanol and physiologically acceptable salts thereof. 15 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 R,. represents the group (CH2)gZ(CH2)rRg or (CH2)xS(CH2)yR15/ 20 reacting a triazole of formula (I) in which Rc represents a a 5 the group R where R,- is -(CH„) L or -(CH0) L and L is 5 J 0 ^3 0^ a leaving group with an anion Z(CH0) R0 or S(CH ) R ; z r a i y 15 (b) for the preparation of compounds in which R^ is other than a C2_6 straight or branched alkyl group 2 5 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 R^4 is acyl, cyclising a compound of formula (III) ?16 R1R2NAlkQX(CH2)nY (CH2 ) ^NH-C-NNHY 1 (III) V' in which R^g is a group as defined for R , V1 is NCR_° J it D v and Y' is hydrogen where V is oxygen or sulphur and R_c 5 is a group as defined for R$ or a group convertible thereto A) -51- 10 under the conditions of the cyclisation reaction; or V'. is NH, R... is a group as defined for R_ and Y' is CR,. lb J »f 5 Y" where Y" is sulphur, oxygen or NH; or V' is sulphur or oxygen, Y' is CRc and R1t is a group as defined for R_; ii J J.D j NH or V' is NR~, R is hydrogen and Y' is CR_ where Y" is ■J 10 ti D Y " as defined above; (c) for the preparation of compounds in which Alk is CH2, treating an aldehyde of formula (VII) R3 ! OHC-QX(CH~) Y(CH ) NH-/ if (VII) z n 2 m v 15 N B with an amine R^R2NH followed by reduction d) for the preparation of compounds in which R^ 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 R^ represents a C2-6 straight or branched alkyl group substituted by two or three acyloxy groups, or represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy groupj or Y represents CHOR^ where R^ is acyl, reacting the corresponding alcohol with an activated derivative of an appropriate acid; f) for the preparation of compounds in which R^ represents a C_ ^ straight or branched alkyl group Z""D substituted by two or three alkoxy groups, or R^ 35 represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an alkoxy group, 20 25 30 10 -5 2- 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 represents the group (CH2^qZ^H2^rR8 w^ere Rs NR12R13 and R12 an<^ R13 6aC^ rePresent hydrogen or alkyl, treating the corresponding alcohol in which Rg is hydroxy with a reagent capable of converting the group Rg into a leaving group, followed by reaction of the resulting compound of formula (I) in which R^ represents " (CH2)qZ(CH2>rL where L is a leaving group with ammonia or an appropriate amine R^R-j^NH/ h) for the preparation of compounds in which Rg is the group NR12R13' where Ri3 is an acY! group or an 15 aryl or alkylsulphonyl group, reacting the corresponding compound in which Rg is the group NHR^ with an activated derivative of the appropriate carboxylic or sulphonic acid; i) for the preparation of compounds in which Rg 20 is the group -CONR^qR.^ , reacting an activated derivative of the corresponding carboxylic acid in which Rg is -CO^E, with ammonia for an appropriate amine HNR^qR^; or j) for the preparation'of compounds in which Rj. includes the group 25 -CH(CH )CH— I 2 P| 0 0 C R6 7 30 reacting the corresponding compound in which R^ includes the group -CH-(CH9) -CH- with an aldehyde or ketone i Pi OH OH RgR^CO in the presence of an acid; 35 and optionally converting the compound of formula (I) produced into a salt. -53- 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. -»AT£D this 2IDAT of £ebru3fij A. J. PARK & SON PER fid# AG8NTS FOR THE APPLICAHTE. , 4