CA1188689A - 1,2,4-triazole derivatives as histamine h.sub.2- antagonists - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention disclosure novel heterocyclic derivatives, the processes for their production and pharmeceutical compositions containing same. In particu1ar, it disclosures compounds of the general formula (I) and physiologically acceptab1e salts, hydrates and bio-precursors thereof, in which Rl and R2 which may be the same or diffcrent, each represent hydrogen, Cl-10 alkyl, cycloalkyl, alkenyl, aralkyl, trifluoroalkyl, or alkyl, substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino, or Rl and R2 may together with the nitroqen atom to which they are attached form a 5 to 10 membered ring which may be sat-urated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more Cl-3 alkyl groups or a hydroxy group and/or may contain another heteroatom which i8 oxygen or sulphur;
Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms Q represent3 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 ring option-ally bearing a further substituent R6 adjacent to the group RlR2N-Alk-, or Q represents a benzene ring in which incorp-oration into the reet of the molecule is through bonds at the 1- and 3- or 1- and 4- positions;
R6 represents halogen or Cl-4 alkyl which may be substituted by hydroxy or Cl-4 alkoxy;
X represents -CH2-, -O-,-S- or -N- where R5 represents hydrogen or methyl; n represents zero,1 or 2, m represents 2,3 or 4;
R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy-alkyl with at least two carbon atoms, alkoxyalkyl or aryl;
and R4 represents hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryl-oxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen.
These compounds show pharmacological activity as selective histamine H2-antagonists.

Description

1 This is a divisional application of Canadian paten-t application serial number 346,685 filed on February 29, 1980.
This inven-tion relates to novel heterocyclic S derivatives having action on histamine receptors, to processes Eor the preparation thereoE, to pharmaceutical compositions containing them and to their use in thera-peutics.
Certain novel he-terocyclic derivatives have now been found which have potent activity as H2 ~ antagonists.
These compounds, which are more particularly described be-low, for example show inhibi-tion of the secretion of gas-tric acid when this is stimulated via histamine - recep-tors (~sh and Schild, Brit, J. Pharmacol. Chemother, 1966, 27, 427). Their ability to do so can be demonstrated in the perfused rat stomach using the method described in German Offenlegungsschrift No. 2,734,070, modified by the use of sodium pentobarbitone (50 mg/kg) as anasthetic in-stead of urethane, and in conscious dogs equipped with ~eidenhain pouches using the method described by Black et al, Nature 1972 236, 3~5. Furthermore the compounds antagonise the effect of histamine on the contraction frequency of isolated guinea pig right atrium but do not modify histamine induced contractions of isolated gastrointestinal smooth muscle which are mediated via El - receptors. ~ertain com-pounds according to the invention have the advantage of an extended duration of action.
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 , ~.

- ~ -1 inflammatory conditions where histamine ls a known mediator.
Thus -they may be used :Eor example, either alone or in comb:i.nation with o-ther ac-tive ingredlen-ts .in the treatmen-t o:E aller~.ic and inflammatory conditions of the skin.
S ~rhe present invention provides compounds o:E the general :Eormula (I) R3\
~_ N

~ N ~ R
1 2N Alk-Q-(C~2)nx CH2)mNH 4 and physiologically acceptable salts, hydrates and bio-precursors thereof, in which Rl and R2 which may be the same or diEferent, each represent hydrogen, Cl 10 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamlno or cycloalkyl or Rl and R2 may together with the ni-txogen 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 Cl 3 alkyl groups, e.g. methyl or a hydroxy group and/
or may contain another heteroatom, e.gO oxygen or sulphur;
Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, Q represents a furan or thiophen ring in which incorporation into the rest of the molecule is through bonds at the 2- and 5- positions, the furan ring optional-ly bearing a further substituent R6 adjacent to the group RlR2N-Alk-, or Q represents`a ben~ene ring in which incor~oration into the rest of the molecule is through bonds at the 1-and 3- or 1- and ~- positions;
R6 represents halogen or Cl 4 alkyl which may be substituted by hydroxy or Cl 4 alkoxy;

1 X represents -CH2-, -O-, -S- or -N-where R5 repxesents hydrogen or methyl;
n represents zero, 1 or 2;
m xepresents 2,3 or ~;
R3 represell-ts hydrogen, alkyl, alkenylr a.ralkyl, hydroxyalk~l with at least -two carbon atoms, alkoxy-alkyl or aryl; and R~ represents hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, acyloxyalkyl,alkoxyalkyl, or arylox-yalkyl, aralky]oxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen, or the group NR7R8 where R7 represents hydrogen, alkyl, alkenyl or aralkyl, and R8 represents the group CORg where Rg represen-ts hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or monocyclic heteroarylalkyl or R8 represents the group SO2Rlo where Rlo represents alkyl or aryl, or R8 represents the group ICI-NHRll where Y is oxygen or sulphur and Y
Rll represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl. -N-When X represents an oxygen atom I and n is zero, then Q preferably represents benzene.
In particular, the present invention is directed to a compound of the general formula (I) 3\
/N-N~ ~

1 2N Alk Q-(cH2)nx(cH2)mN~ N ~ (I) 1 and physiologically acceptable sal-ts, hydrates and bio-precursors thereoE, in which Rl and R2 which may be the same or difEerentr each represent hydrocJen, CL 10 alkyl, cycloalkyl, alkenyl, ara1.kyl, trl:Eluoroalkyl, or alkyl~ substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino, or Rl and R2 may together wi-th the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturat-ed or may con-tain at least one double bond, may be un-substituted or may be substituted by one or more Cl 3 alkyl groups or a hydroxy group and/or may contain another heteroatom which is oxygen or sulphur;
Al.k represents a straight or branched alkylene chain of 1 to 6 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 ring option-ally bearing a :Eurther substituent R6 adjacent to the group RlR2N-Alk-, or Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4- posi-tions;
R6 represents halogen or Cl 4 alkyl which may be substituted by hydroxy or Cl 4 alkoxy;
X represents -CH2-, -0-, -S- or -N- where R5 represents hydrogen or methyl; n represents zero, 1 or 2, m represents 2,3 or 4;
R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy-alkyl with at least two carbon atoms, alkoxy-alkyl or aryl; and R4 represents hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxy-alkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, di-alkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen.

- ~La -1 To this end, in one of its aspects, the inven-tion provides a process for the preparation of compounds of the general :~ormula (I) R3 N_ N
/ ~ (I) ~ N '~\
RLR2N-Alk-Q-(CH2)nX(CH2)mNH R~

and physioloyically acceptable salts, hydrates and bio-precursors thereof, in which Rl and R2 which may be the same or different, each represent hydrogen, Cl 10 alkyl, cycloalkyl, alkenyl, aralkyl, trifluoroalkyl, or alkyl, suhstituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino, or Rl 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 a-t least one double bond, may be unsub-stituted or may be substituted by one or more Cl 3 alkyl groups or a hydroxy group andfor may contain another heteroatom which is oxygen or sulphur;
Alk represents a straight or branched alkylene chain oE 1 to 6 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 ring optionally bearing a further substituent R6 adjacent to the group RlR2N-Alk-, or Q represents a benzene ring in which incorp-oration into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4- positions;
R6 represents halogen or Cl ~ alkyl which may be substituted by hydroxy or Cl 4 alkoxy;
X represents -CH2-, -O-, -S- or -N- where . R5 - 4b -1 R5 represen-ts hydrogen or me-thyl; n represents zero, 1 or 2, m represents 2,3 or 4;
R3 represen-ts hydrogen, alkyl, alkenyl, aralkyl, hydroxy-alkyl with at leas-t two carbon atoms, alkoxyalkyl or aryl;
and R~ represen-ts hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, acyloxyal]cyl, alkoxyalkyl, ary]oxy-alkyl, aralky].oxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen, which comprises selecting a process from the group of processes consisting of:
(a) for the production of compounds in which R~ represents a halogen atom or a hydrogen atom, converting the group -N-N Y in a diazonium salt (III) R
IN~ N~
RlR2 N-Alk-Q~(CH2)nx(~H2)m ~ N ~ N--N Y ~III) in which Rl, R2 and R3 are as defined in formula (I) or are groups convertible thereto, Alk, Q, n, X and m as defined in formula (I) and Y is the anion corresponding to the acid used in the diazotisation reaction, into a halogen atom or a hydrogen atom;
(b) for the production of compounds in which R4 is other than a halogen atom or an alkoxy, alkythio or acyloxy-alkyl group, cylising a compound of formula (V) R

RlR2N-Alk-Q-(CH2)nX (CH2)mNH-I_NNHY' (V) in which Rl, R2, Alk, Q, X, R3n and m are as defined in formula (I) and V' is NCR~' and Y' is hydrogen where V is oxygen or sulphur and R4 is a group as - 4c -1 defined for R~ or a group conver-tlble thereto under the conditions of the cyclisation reac-tion or represents halo-gen or alkoxy; or V' is NH and Y' is CR~ where Y

is sulphur, oxygen or Nll, except that when R~ is halogen or ~lkoxy Y cannot be NM, or V' is sulphur or oxygen and Y' is C~, with optional protection and subsequen-t de-N~l protection of any reactive groups in -the starting material if clesired;
(c) reducing a compound of formula (XV) Da_Q- (C~I2)nX(CH2)m~ DC (~V) in which Q, n, X, m and R3 are as defined in formula (I), at least one of Da, Db and Dc represents a reducible group and the other(s) take the appropriate meaning corresponding to formula (I), D represents RlR2NAlk- or a group convertible thereto under reducing conditions where Rl, R2 and Alk are as defined in formula (I);
Db represents -CH2NH-, -CONH- or -CH=N-D represents R~ as defined in formula (I) or a group conver~ible thereto under reducing conditions, with optional protection and subsequent deprotection of any reactive groups in the starting material if desired;
(d) reacting a co~pound of formula (XX) R1R2NAlkQE . (XX) in which E represents (CH2)nX(CH2)mP or CH2P where P
and pl are leaving groups, with a triazole of the formula (XVII) - 4d -U ~ ~ ~ R~ (XVII) N
where U represents amino, I-IS (CF12)mNEI or EIO (Cll2)mNH, and R~ ls as deEined l.n formula (I) or is a group convertible thereto wi.th optional protection and sub~
sequent depro-tection of any reac-tive groups in -the s-tarting material if desired;
(e) in-troducing the group RlR2N-Alk into the group Q
presen-t in a suitable intermediate or converting another group already present into a group RlR2N-Alk- with option-al protection and subsequen-t deprotection of any reactive groups in the starting material if desired;
(f) for the production of compounds in which R4 is a secondary or tertiary hydroxyalkyl group, treating the corresponding compound where R4 is the group (CH2)q lCHO, (CH2)q_lCO2R12 or (CEI2)rCOR12 in which q is an integer from 1 to 6 inclusive, r is 0 to 4 and R12 is an alkyl group, with an organometallic derivative;
(g) reacting a compound of formula (XXII) - 3~ ~ N
/ ~ (XXII) L Alk Q (CH2)nX (CH2)m NH ~ N ~ Lb where eithe~ L is RlR2N and Lb is the group (CH2) L or La is a group Ld and Lb is R4, where Lc and L are leaving groups and q is an integer from 1 to 6 inclusive, with a compound capable of replacing La by RlR2N or L
so as to convert Lb into the group R4 with optional ~rotection and subsequent deprotection of any reactive groups in the starting material if desired;

- 4e -l. (h) converting a compound of formula (I) in which R4 has a particular meaning into ano-ther compound of Eoxmula (I) in which R4 has a di:E:Eerent meaning by standard methods o:E interconversion;
(i) :Eor the produc-tion of compounds in which R~ is an acyloxyalkyl group, treating the corresponding hyclroxy-alkyl compound with an appropriate acid at elevated temperature; or (j) for the production of compounds in which R4 is a hydroxyalkyl group removing a hydroxyl protecting group from the hydroxyl group; and (h) for the production of a sal-t of the compound of the general formula (I), relating a process from the group of processes consisting of the processes defined in parts (a) to (j) hereinbefore, and converting the free base into a salt.
The term "alkyl" as a group or a part of a group means that the group is straight or branched and, unless otherwise stated, has preferably l to 6 carbon atoms, and in particular l to 4 carbon atoms, e.g. methyl or ethyl, and the terms "alkenyl" and "alkynyl" 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 subs-tituted phenyl, for example phenyl substituted with one or more Cl 3 alkyl or alkoxy groups h logeeng-;tfolrnUs~i~e~he acyl portion of an acyloxyalkyl group means an aroyl, aralkanoyl or Cl 6 alkanoyl group.
Examples oE acyloxy,lkyl groups include acetoxymethyl, formyloxyme-thyl, benzoyloxymethyl and phenylacetoxymethyl.
The term "heteroaryl" generally means a 5 or 6 membered monocyclic ring or 9 or 10 membered bicyclic ring either of which may contain 1 or more heteroatoms selected from oxygen, nitrogen and sulphur, e.g. furyl,pyridyl, thiazolyl, quinolinyl~ indolyl or thienyl.
According to one aspect the invention provides compounds according to formula (I) and physiologically acceptable salts, hydrates and bioprecursors thereof, in which Rl and R2 are as defined in formula (I) except alkynyl or al]cyl substituted by cycloalkyl;
R4 represents the group NR7R8 where R7 and R8 are as defined in formula (I) except that Rg is other than heteroaryl and Rll is other than cycloalkyl; or more preferab]y R4 represents hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy or halogen; provided that when X represents an oxygen atom or -NR5- and when n is zero then Q represents benzene.
The invention includes the compounds of formula (I) in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include hydrochlorides, hydrobromides, sulphates, methanesulphona~,acetates, maleates, succinates, citrateS~tartratest fumarates and be~oates. The compounds of formu]a ~I) and their salts may also form h~dra-tes, which hydrates are also to be considered as part of the invention. The compounds of Eormula (I) can exhibit tautomerism and the formula .is intended to cover aLl tautomers. Where optical isomers may e~ist the formula is intended to cover all diastereoisomers and op-tical enantiomers.
The compounds accordiny to the invention, preferably .in the form of a salt, may be formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such composi-tions may also contain if required other active ingredients e.g. H1-antagonists.
Thus the compounds according to the invention may be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is

2- preferred.
For oral administration, the pharmaceutical composition may take the form of for e~ample, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
25. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional mannerO
The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion~ Formulations for injection may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions -7~ &~

1 may take such forms as suspensions, solu-tions or emulsions in oily or aqueous vehicles, and may contain Eormulatory agen-ts such as suspending, s-tabilising andJor disperslng agents. ~l-ternatively, the active ingredient may be in powder form for reconstitu-tion with a sui-table vehicle e.g.
sterile pyrogen-free water beEore use.
r~'he compounds of -the invention may also be Eormu-lated in rectal compositions such as suppos:itories or retention enemas, e.g. con-taining L0 conventional supposi-tory bases such as cocoa butter or other glyceride.
For topical application, the compounds of the invention may be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner.
For internal administration a convenient daily dosage regime of the compounds according to the invention would be 1 to 4 doses to the total of some 5mg. to lg per day, preferably 5 to 250mg per day, dependant upon the condition of the patient.
In the compounds according to the invention, preferably the total of m + n is 3 or 4.
Preferably Q is benzene incorporated into the rest of the molecule through bonds at the 1- and 3- positions.
In the case where Q is benzene, preferably n is zero, X is oxygen and m is 3 or 4. If ~ is furan, substituted furan or thiophen, preferably n is 1, X is sulphur and m is 2.
Preferably Rl represents hydrogen or Cl ~ alkyl and R2 represents C3_5 alkenyl, C5_7 cycloalkyl, benzyl, Cl alkyl or Cl 4 alkyl substituted by Cl 3 alkoxy, hydroxy, di-Cl 3 alkylamino or trifluoromethyl or Rl and R2 together with the nitrogen atom to which they are attached form a ring with 5 to 8 members and optionally containing one double bond and/or substituted by hydroxy or one or two Cl 3 alkyl group(s). More preferably Rl and R2 are Cl 3 alkyl, e.g. methyl or Rl and R2 together with the nitrogen atom to which they are attached form a he-terocyclic ring 1 which is pyrrolidine, piperidine optionally subs-tituted in the 4- position by Cl 3 alkyl e.g. me-thyl or hydroxy, tetrahydropyridine, morpholine, 2,6-dialkylmorpholine, hexamethyleneimine or hep-tamethylenimine. ~ost preferably the he-terocyclic ring is piperidine.
Preferably R3 represen-ts hydrogen, alkyl or C2 4 hydroxyal]cyl. More preEerab]y R3 represents methyl.
PreEerably R~ represents hydrogen, al]cyl, hydroxy-al]cyl, alkoxyalkyl, acylo~yal]cyl, aralkyl or hydroxy or the yroup N~ICORg where Rg represen-ts hydrogen, alkyl, aryl, he-teroaryl, or alkoxy, or the group NHCONHRll where R
represents alkyl, aryl or cycloalkyl. More preferably R~
is hydroxyalkyl, e.g. hydroxymethyl, benzyl, hydroxy, alkoxyalkyl, e.g. methoxymethyl or -the group/NHCORg where R9 is hydrogen, aryl e.g. phenyl, alkyl e.g. methyl, or alkoxy e.g. ethoxy; or the group NHCONHRll where Rll is aryl, e.g. phenyl. Most preferably R4 is hydroxymethyl, -formylamino or acetylamino.
Pre-ferably Alk is CH2.
A particularly preferred group of compounds of formula (I) are those of formula (II) RlR2NCH2 _ ~ O-(CH2)m-NH ~ ~ R4 (II) where Rl and R2 are methyl groups or together with the nitrogen atom to w'nich they are attached form a pyrrolidino, piperidino or hexamethyleneimino group; m is 3 or 4, R3 is hydrogen or methyl; and R4 is a hydroxyalkyl, alkoxy-alkyl, benzyl, formamido, alkanoylamino, alkoxycarbonyl-amino, hydroxy, aroylamino or phenylcarbamoylamino group Particularly preferred compounds are (1) 1-methyl-5-[[4-[3~(1-piperidinylmethyl) phenoxy]
butyl]amino]-lH-1,2,4- triazole -3-methanol 2) 1-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-lH-1,2,4-triazole-3-me-thanol.

3) N-[l-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-lH- 1,2,4 triazol-3--yl] formamide

4) 3-methoxy--methyl-1-methyl-5-[[4-[3-(1-piper-idinyl me-thyl) phenoxy]butyl]amino]-lE~-1,2,4-triazole S) 3-phenylmethyl-N-[3-[3-(dimethylaminomethyl) phenoxy]propyl]-l~I-1,2,4-triazole-5-amine 6) 5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]
amino-lH-1,2,4-triazole-3-methanol 7) 3-phenylmethyl-N-[3-[3-ll-piperidinylmethyl) phenoxy]propyl]-lH-1,2,4-triazole-5-amine 8) Ethyl l-methyl-5-[[3-[3-[(dimeth~tlamino)methyl]
phenoxy]propyl]amino]-lH-1,2,4-triazole-3-carbamate 9) N-[5-[[3-[3-[(dimethylamino)methyl]phenoxy]
propyl]amino3-1-methyl-lH-1,2,4-triazole~3~yl]
benzamide 10) N-[5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino] l-methyl-lH-1,2,4-triazole-3-yl]-N -phenylurea 25 11) 5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino~-lH-1,2,4-triazole-3-one and their physiologically acceptable salts.
Of the above mentioned compounds, compounds Nos(l) (2), (3) and (4) and their salts are particularly preferred.
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 ~or a particular reaction and subsequently to remove the protecting group. ~uch protection and subsequent depro-tecticn may ~e particularly pertinent where Rl and/or ~2 in intermediates used to prepare compounds o:E formula (l) are hydrogen atoms and/or when ~3 in in-termediates is an alkyl group bearing a hydroxy subst:ituent and/or when R~ in certaln intermediates is an a:lky:l group bearing a hydroxyl or a primary or secondary amino substituent. Standard protection and deprotection procedures can be employed, for example formation of phthalimide (in the case of primary amines), benzyl, benzyloxycarbonyl or trichloroethoxy-carbonyl derivatives. Subsequent cleavage of the protecting group is achieved by conventional procedures.
Thus a phthalimide group may be cleaved by treatment with a hydrazine e.g. h~drazine hydrate or a prima.-y amine, for example methylamine; benzyl or benzyloxy-carbonyl derivatives may be cleaved by hydrogenolysis in the presence of a catalyst,e.g. palladium, and trichlor-oethoxycarbonyl derivatives may be cleaved by treatment with zinc dust.
In describing theproces~swhich may be used for preparing the compounds of formula (l) or intermediates useful in the preparatio.n thereof, any of Rl to Rll, Alk,Q,X,Y,nandmin the various formulae are as defined in formula (l) unless otherwise stated.
Compounds according to formula (I) in which R4 represents a halogen atom or a hydrogen atom may be prepared from the corresponding diazonium salt (III) RlR2 N-Alk-Q-(c~2)nx(cH2)m ~ ~ N-N Y
(III~

1 in which Rl, R2 anc1 R3 are as defined in formula (I) or are groups conver-tib~e there-to and Y is the anion corresponding to the acid in the diazotisatiorl reaction.
Thus treatment of the diazonium salt (III) with a concentrated mineral acid such as sulphuric acid or hypophosphorous acid in a solven-t such as ethanol gives the compound of Eormula (I) in which R~ represents hydro-gen. Simllar]y the reaction of the diazonium salt (III) with hydrochloric acid in the presence of chloride ions e.g. aqueous cuprous chloride, at eleva-ted temperature glves the compound of formula (I) in which R4 represents a chlorine atom.
Compounds of formula (I) in which R4 iS the group NR7R8 may be prepared by treating an amino triazole (IV) \ N-N
1 2 NAlk Q-(cH2)nx(cH2)mNH ~ ~ NH R (IV) in which Rl, R2, R3 and R7 are as deEined in formula (I) or are groups readily conver-tible -thereto with a reagent capable of replacing the hydrogen atom in the group NHR7 by the group R8 where R8 is as defined in formula (I).
Thus for example the aminotriazole (IV) may be reacted with an activated derivative of either a carboxylic acid RgCOOH or a sulphonic acid RloSO3H or the aminotriazole (IV) may be reacted with an isocyanate or isothiocyanate RilNCY in which Rll has any of the meanings defined for Rll in formula (I) except hydrogen or represents an alkali metal atom such as potassium or sodium or an alkoxycarbonyl group, e.g. ethoxycarbonyl, to give a compound of formula (I) in which R8 (:

is respective~ the group CORg, SO2Rlo or C-NII Rll.

Suit~bLe act1vated deriva-tives include acid halides e.g. acid chlorides, alkylchloroformates, acid arlhydr:ides inclu~ing mi~ed anhydrides (e~g. acetic formic anh~clride),esters such as alkyl esters, ortho esters and (l~a]kyl-2-pyridinyl~ esters, or derivatives ~ormed frorn a coupling agent such as carbonyldiimidazole or a carbodiimide such as dicyclohexylcarbodiimide.
The reaction with an acid halide is preferably carried out in the presence of a ~se e.g. an inorganic base such as sodium hydroxide or an organic base such as triethylamine or pyridine. The reaction with an alkylchloroformate is pre~erably carried out in the 15 presence of a base, e.g. potassium carbonate or triethylamine, in a solvent such as dimethylformamide.
The reaction with an acid anhydride may be carried out in the absence or presence of solvent such as pyridine.
Formylation may be effected by heating the amino-triazole (IV) in dime-thylformamide in the presence of a base, e.g. sodium hydride.
In the reaction with an isocyanate or isothio-cyanate compounds of formula (I) in which Rll is other than hyârogen are conveniently prepared by carrying out the reaction in a solvent such as acetonitrile at an elevated temperature,e.g. reflux. Compounds of formula (I) in which Rll is hydrogen may be prepared by heating the aminotriazole (IV) with an appropriate organic isocyanate or isothiocyanate such as ethylcarbonisothio-cyanatidate, at an elevated temperature followed byhydrolysis of the resulting ester, for example with a base such as aqueous ethanolic sodium hydroxide.

.

Compounds of formula (I) in which R4 is other than a halogen atom or an alkoxy, alkylthio or acyloxy-alkyl group may be prepared by cyclisation of a compound of formula (V) 1 2 N Alk Q (C~12)nX(CH2)mNH~C-N N~-IY' (V) V' in which V' is N~R'4 and Y' is hydrogen where V is oxygen V
or sulphur and R4' is a group as defined for R4 or a group convertible thereto under the conditions of the cyclisation reaction or represents halogen or alkoxy;
or V' is NH and Y' is C R'4 y where Y is sulphur, oxygen or NH except that when R4' is halogen or alkoxy Y cannot be NH; or V' is sulphur or oxygen and Y' is CIR4.
NH
The above process is partieularly suitable for the produc-tion of compounds of formula (I) in which R4 is other than NR7 R8. It should be noted that when V' is sulphur in compound (V) this eompound is tautomerie with the thiol (V1`).

RlR2N-Alk-Q-(CH2)nX(CH2)m N=IC-N NH ~ (Vl) S~
and the corresponding S-alkyl,e.gOS-methyl, derivatives may also be used in the cyelisation.
Thus for example compounds according to formula (I) in whieh R4 is other than a halogen atom or an alkoxy, alkythio, or acyloxyalkyl group may be prepared by thermal 3S eyclisation of a eompound of formula (Vll) .

1 2 N ~lk Q(~H2)nx(cH2)mNHc N N=z ~Vll) N-CR
V
whcre V repre~ents sulphur or more preferably oxygerl and Z represents two hyclrogen atoms~
in the absence ~r presence o:. a solvent, e.g. acetone or water.
It may be convenient to prepare compounds of formula (Vll) in which Z represents two hydrogen atoms in situ by treating a compound of formula (Vll) where Z 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 compounds of formula (I) will normally occur.
In a method for preparing the intermediate (Vll) a compound of formula (Vlll) RlR2NAlk Q (CEl2)nX (CH2)m NHIClL
NIClR4 (Vlll) V

where V is oxygen or sulphur and L is a leaving group such as alkylthio may be reacted with hydrazine R3NE~N=Z
where Z is as defined above, followed by removal of the protecting group where necessary. Compounds of formula (Vlll) may be prepared by treating a diamine of formula (lX) lR2NAlk Q (CH2)nX(CH2)m NH2 (lX) with a compound of formula (X) NCR4 (~) V
, where L and V are as defined, above.
As a Eur-ther possibility the diamine of formula (lX) m~y be reactecl with a compound of Eormula (Xl) l3 LCNN=Z
~vR4 (Xl) where L, V and Z are as defined above~ in the absence or presence of a solvent such as acetone or acetonitrile at a temperature oE ~rom room temperature to 70~C.
Subsequent removal of the protecting group where approp-riate then gives the intermediate (Vll).
Compounds of formula (Xl) may be prepared by acylating a compound of formula (Xll) LCNN=Z (Xll) NEI
with for examplean acid chloride R4COCl. The compound of formula (Xll) may be prepared by treating a compound LCL with the appropriate hydrazine NH
R3NHN=Z.
When preparing compounds of formula (I) in which R4 is a hydroxyalkyl group it is preferabie that in the intermediates (Vll), (Vlll~ and (Xl) the hydroxy groupis~protected form,e.g. as an acyloxy derivative such as an alkanoyloxy or aroyloxy derivative. The protecting group will normally be removed during the cyclisation process.
In a further embodiment of the cyclisation of compounds of formula (V) compounds of formula (I)-B~9 in which R~ is other than a halogen atom, or an alkoxy, alkylthio or acyloxyalkyl may also be prepared by cyclisation of a compound of formula (Xlll) l3 1 2NAlk Q(CH2)nX(CH2)mNHICINNHCR~ (Xlll) where V i5 NH and Y is sulphur, oxygen or NH, or V
is sulphur or oxygen and Y is NH. The reaction is preferably carried out by heating the compound (Xlll) in a suitable solvent such as acetonitrile or dimethyl-formamide.

In general intermediates of formula (Xlll) may be prepared by methods analogous to those described in British Patent Specification No.2023133. A.
In a particularly convenient embodiment of -the above process an intermediate of formula (X]ll) in whicl~ V is N~l and Y is oxygen may be prepared in situ by the reaction oE an aminoguanidine (XlV) l3 RlR2 N-~lk-Q-~CH2)nX (CH2)mNHICl-N-NH2 NH
(XlV) with an acid ~ COO~ or with an activated derivative thereof as defined above.
The acid and the amino guanidine (XlV) may be heated together, under which conditions cyclisation of the intermediate (Xlll) 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 temperaturesfrom ambient to re~lux. When using an acyl chloride as the activated derivative the reaction may also be carried out in the presence of a base e.g. potassium hydroxide.
Compounds_of formula (I) may be prepared by reducing a compound of formula (XV).

Da-Q-(C~2)nX(CH2)m-1 ~ N (XV

in which at least one of Da, D and Dc represents a reducible group and the other(s) take the appropriate meaning corresponding to formula (I).

~ f Thus D may represent RlR2NAlk or a group convertible ther~?to under reducing conditions;
D represents -CEI2NI1-, CONII- or -CH=N-;
and S D represents R~ or a group conver-t.ible thereto under reduc:ing condit:ions.
Examples oE the type of group that may be reduced are an amide, imide, imine, ester, aldehyde,ketone or nltrile group. Examples of the type of group D
which may be conver-ted into the group RlR2N.~lk under reducing conditions are: an amide grouping P~lR2~CO(CH2)p where p is 0,1,2,3,4 or 5 or Rl CONR2 ~lk - where Rl CO
represents a group which is reducible into Rl; an aralkylidenaminoalkyl grouping; a nitrile group NC(CH2)p where p is 0,1,2,3,4 or 5;ora~aldehyde group, When D
is analdehyde group the conversion into RlR2NAlk under reducing conditions is carried out in the presence of an appropriate amine RlR2NH, the reaction proceeding by reductive alkylation, Examples of the group Dc which may be converted into R4 under reducing conditions are: an amide grouping -(CH2)q lCO NRaRC where Ra represents hydrogen, alkyl, or aralkyl~ Rc represents hydrogen or alkyl and q is an integer from 1 to 6 inclusive with the possibility that the alkylene chain (CH2)q_l may be straight or branched, or an amide grouping ~(CH2)qNRaCORb where Ra is as defined above, Rb is alkyl and CORb is a group which is reducible into Rb and qisasdefined above with the possibility that the alkylene chain (CH2)q may be straight or branched; a nitrile group -(CH2)~ lCN;
an aldehyde group ~(CH2)q lCHOjan ester group ~(C~2)q 1 CO2R12 where q is as defined above and R12 is an alkyl group,oraketone group -(CH2)rCOR12 where r`is 0 to 4 and R12 is an alkyl group and the total number of carbon atoms in (CH2)r and R12 is not more than 5.

~ 9 ~

1 Da and/or D may also represent an aminoalkyl group, in which case the compound of formula (XV) is reacted with an appropriate aldehyde or ketone under reclucing conditions to give the group RlR2NAlk- and/or R~, -the reaction proceeding by reductive alkylation.
~ variety of reducing agents may be used in the above process.
Thus amides, imides, imines, esters, aldehydes, ketones and nitriles may conveniently be reduced using for example lithium aluminium hydride or aluminium hydride in a solvent such as tetrahydro~uran, dioxan or diethyl ether.
Imines, aldehydes and ketones may be reduced using an alkali or alkaline earth metal borohydride e.g. sodium borohydride or by treatment with hydrogen and a suitable metal catalyst such as platinum, palladium or Raney nickel, in a suitable solvent such as an alkanol e.g. methanol or ethanol. Imines may also be reduced using ~ormic acid.
In the particular process involving reductlve alkylation of an amine with an aldehyde or ketone the reaction is conveniently carried out without isolation o~ the intermediate which is subsequently reduced using ~or example sodium borohydride, or hydrogen in the presence o~ a suitable catalyst.
Thus in one embodiment of the reduction process compounds of ~ormula (I) in which R4 is other than -the group NR7R8 or acyloxyalkyl may be prepared by reduction of an amide of ~ormula (XV) in which Da representS RlR2NCO(CI12)P
R~CONR2Alk, Db represents -CH2NH- and D represents R4;
or b) Da represents RlR2NAlk, D represents -CONH- and D represents R~; or c) Da represents RlR2NAlk, D represents -CH2NH- and Dc represents (CH2)q lCONRaRC
or (CH2)qNHCORb ; where p,q,Ra,R and Rb are fi~ ~

~o as defined above, with a suitable reducing agent such as lithium aluminium hydride or an aluminium hydride in a solvent such as tetrahydrofuran, dioxan ox ~iethylether.
S A particularly useful amide of formula (XV) is that in which D represents RlR2NAlk, D represents ~-CONEI~ and D represents R4.
In a further embodiment of the reduction process a compound of formula (xv) in which Da or Dc is a cyanoalkyl group NC(CH2)p or (CH2)q lCN respectively may be reduced to a compound of formula (I) in which RlR2NAlk is a primary aminoalkyl group or R4 is a primary aminoalkyl group (CH2)q 1CH2NH2. Reduction may be effected using for example lithium aluminium hydride in a solvent such as diethyl ether or tetrahydrofuran.
In a further embodiment of the reduction process compounds of formula (I) may be prepared by reduction of an imine of formula (XV) in which a) Da represents an aralkylidenaminoalkyl group, D represents -CH2NH- and D represents R4; or b) D represents RlR2NAlk, D represents -CH=N- and Dc represents R4; with a suitable reducing agent such as a metal hydride, e.g. an alkali or alkaline ~rthmetal borohydride, such as sodium borohydride, in a solvent such as an alkanol, e.g. methanol or ethanol, or aluminium hydride or lithium aluminium hydride in a solvent such as tetrahydrofuran or dioxan. The imine (X~7) may also be reduced with hydrogen and a suitable metal catalyst such as platinum, in a solvent such as an alkanol e.g. methanol or ethanol.
A particularly useful imine of formula (XV) is that in which Da is RlR2NAlk, D is -CEI=N- and Dc is R4.
In the above process a borohydride reducing agent is prefera~ly used when preparing compounds in which R4 is the group NR7R8.

~L~h3~

The process involving reductive alkylation of an amine with an aldehyde or ketone to give the compounds of Eormula ~I),without isolation of any intermediate, is also part oE this embodiment. Thusl fox example compounds oE formula (I) ln which Alk represents CH2 may be prepared from the compound (XV) in which Da represents CHO, D represents -CH2NH- and Dc represents R4, by reaction with ammonia or an amine RlR2NH in a solvent,e.g.
tetrahydrofuran or an alkanol such as ethanol or methanol, followed by reduction e.g. with a hydride reducing agent such as an alkali or alkaline earth metal borohydride, e.g.
sodium borohydride, or aluminium hydride or lithium aluminium hydride or with hydrogen and a metal catalyst e.g. palladium or platinum.
In another embodiment of the reduction process, a compound of formula (I) in which R4 represents a hydroxyalkyl group may be prepared from a compound of formula (XV) in which Dc is a group that may be reduced to a hydroxyalkyl group,e.g. an ester, aldehyde, or ketone, Da is RlR2N~lk and D is -CH2N~ . Thus a compound of formula (XV) in which Dc has the meaning (CH2)q 1 CO2R12 may be reduced using for example li-thium aluminium hydride to give a compound of formula (I) in which R4 is the group ~(CH2)q 1 CH2OII. Compounds of formula 25 (XV) in which D has the meaning (CH2)q 1 CHO or (CH2)rCOR12 may be reduced using for instance sodium borohydride or lithium aluminium hydride to give a compound of formula (I) in which R4 is the group (CH2)q_lCH2OH or (CH2)r CHOH R12 where q,r and R12 are as defined above.
In certain instances it is convenient to reduce for example more than one of the groups Da, Db and Dc simultaneously. Thus for example compounds of formula (X~) in which D represents (CH2)q_lCO2R12 or (CH2)q_l CONRaRC and D is the group -CONH- and D is RlR2NAlk may be reduced using for example lithium aluminium hydride to give compounds of formula (I~ in which R4 is the group (CH2)~OH or (CH~)qNRaRC respectively, where q, Ra and R are d~fined above.
c Amides and imines of formula (XV) where Db is -CON~I- or -CH-N-, Da is RlR2NAlk and Dc is R~ or a group convertible thereto may be prepared by the reaction of an activated deriva-tive of a carboxylic acid or aldehyde (XVl) RlR2N-~l]c-Q-(cH2)nx(cH2)m-l G (XVl~

where G is CO2H or CHOrespectively wi-th the appropriate amino triazole (XVll) R3 ~ _ U ~ ~ 4 (XV~I) where U is NH2 and R4 is as defined in formula (I) or is a group convertible thereto,using methods analogous to those described in British Patent Specification No. 2023133 A.
Aldehydes and carboxylic acids of formula (XVI) may be prepared from an appropriate starting material (XVIII) RlR2N Alk Q (CH2)nXH (XVIII) in which X is other than CH2.

Thus for example a compound RlR2NAlk Q OH
may be -treated with a haloalkyl nitrile Elal (CH2)m lCN
in a solvent such as dimethylformamide and in -the presence of a base e.g. sodium hyclricle, to give the corresponding compound RlR2NAlk Q O (CH2)m lCN.
Subsecfuent reduction usiny for example hydrogen in the presence oE E~aney Nickel aEfords the corresponding aldehyde which may conveniently be isolated as its semicarbazone. The desired aldehyde (XVI) may then be generated by treatmen-t with hydrochloric acid and aqueous formaldehyde.
Alternatively txeatment of the compound RlR2-NAlk Q OII with an alkyl haloester Hal (CH2)m 1CO2Alk affords the ester RlR2NAlk Q O(CH2)m_l 2 then be hydrolysed (e.g. by using potassium hydroxide in aqueous ethanol) to give the corresponding carboxylic acid (XVI).
The triazole (XVII) may be prepared by standard methods such as those described by F.Kurzer and L.E.A. Godfrey, Angew.Chem.International Edition 2, 459-476 (1963) and K.T.Potts, Chem.Reviews 61,87 (1961).
The compounds of formula (XV) in which Da represents RlR2NCO(CH2)p or CHO, D represents -CEI2NH
and D represents R4 may be prepared from an amine of formula (XIX)-W~Q-(CH2)nX-(cH2)m N~2 (XIX) in which W represents the group RlR2NCO(CH2)p or a protected aldehyde group e.g. a cyclic ketal such as an ethylene ketal, by methods analagous to those already described for preparing the corresponding compounds of formula (I).
The compounds of formula (XV) in which Da has the meaning RalCONR~lk- and/or Dc has the meaning (C~i2)qNRaCORb may be prepared by treati.ng the correspondirlg compouncls in which D is IINR2~1k- and/
or Dc is (CH2)~N~I~a with an activated clerivative oE the appropria-te acid RlCO21l or Rb CO2~1.
Compounds oE formula (XV) in which Da is aralk~liclenaminoalkyl may be prepared from the correspondin~ amine by standard procedures.
Compounds oE formula (I) can be produced by reacting a compound of formula (XX) RlR2NAlk Q E (XX) in which E represents (Cll2)nX(CH2)mP or CH2P where P
and P' are leaving groups, with a triazole oE the formula (XVII) whe,re U represents amino, HS(C~12)mNH or HO(CH2)m NH, and R4 is as defined in formula (I) or is a group convertible thereto.
Thus for example compounds of formula (I) may be prepared by reacting a compound of formula (XX) in which E represents (CH2)nX(~H2~mP and P represents a leaving group such as halogen, e.g. chlorine or bromine, sulphonyloxy,e.g. mesyloxy or tosyloxy with the triazole (XVII) in which U represents an amino group, the reaction being carried out in a suitable solvent such as dimethylformamide or aceto~trile.
Compounds of formula (I) may also be prepared by introducing the group RlR2NAlk- into the group Q
present in a suitable intermediate or converting another group already present into a groupRlR2NAlk. Thus compounds of formula (I) in which Alk represents a methylene group and Q represents a furan or substituted furan ring as defined in formula (I) may be prepared from a compound of formula (XXI) \, Q-(CH2)n-x-(CH2)mNH ~ (XXI) in which Q represerlts a furan or substituted furan riny as clefined in formula (I), by means of a Mannich reaction with forrnaldehyde and an amine RlR2NH or a salt ther~of. The reaction may be carried out by reacting the amine salt with aqueous formaldehyde and the compound (XXI) or by refluxing the amine salt with paraformaldehyde and compound (XXI) in a suitable solvent such as ethanol.
Compounds of formula (I) in whichRl and R2 are both methyl, ~lk is methylene and Q represents a thio-phen ring, a furan ring or a substituted furan ring as defined in formula (I) may be prepared from compound (XXI) in which Q may additionally represent a ~ Q
thiophen ring, by reaction with a compound (CH3)2N=CH2Cl in a solvent such as acetonitrile at an elevated temperature, e.g. reflux. The compounds of formula (XXI) may be prepared by methods analogous to those already described for the compounds of formula (I).
Compounds of formula (I) in which R4 is a secondary or tertiary hydroxyalkyl group may be prepared by treating the corresponding compound where R4 is the 2 q~ 2)q_lC02R12 or (CH2)rCORi2 in which q,r and R12 as defined previously with an organometallic derivative such as a Grignard reagent,e.g. a Cl 5alkyl magnesium halide or an organolithium,e.g. alkyl lithium reagent in a suitable solvent such as diethyl ether or tetrahydco Intermediates in preparing the compounds of furan formula (I) wherein R4 is a group convertible into R4 as defined in formula (I) include aldehydes, ketones, es~ers, amides and nitriles~ Such intermediate~ may be prepared by methods analogous to -those already described for preparing compounds of formula (I).

1 Compoun~s o~ formula (I) may be prepared by reactin~ a compound of formula (XXII) ~3 /N~I\
LaAlkQ(cH2)nx(cH2)m ~ \ ~ Lb (XXII) where either L is RlR2N and Lb ls the group (CFI2) Lc or I,'l is a group Ld ancl I,b is R~ where Lc and Ld are leavi~g groups~ with a compound capable of replacing La by RlR2N or Lc so as -to convert Lb into the group R4.
Examples of the leaving group L include halogen, e.g.
chlorine or bromine, or qua-ternary ammonium, e.g. trimethyl-ammonium and examples of the leaving group Lc include halogen, e.g. chlorine or bromine.
The leaving group Ld may be displaced by -treatment with an amine RlR2NH to give a compound oE formula (I).
The leaving group Lc may be displaced by treating the compound of formula tXXII) with either ammonia or a primary or secondary amine to give a compound of formula (I) in which R~ is an aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl group or wi-th the anion of an appropriate alcohol or phenol, e.g. with alkoxide, to give a compound of formula (I) in which R~ is an ether group, e.g.
alkoxyalkyl.
The displacement of halide ions with ammonia or an amine may be carried out in the absence or presence of a solvent such as acetonitrile. Displacement with the anion of an appropriate alcohol or phenol may be effected by treatment with a suitable alkali metal derivative, e.g. sodium methoxide, in a suitable solvent e.g. dimethylformamide, or the alcohol corresponding to the anion. Displacement of a quaternary ammonium group may be effected by heating with an excess of the appropriate amine.

Compounds oE formula (I) in which R4 has a particular meaniny may be converted into other compounds of the invention by standard methods of interconversion.
Thus a compound in which R4 is an alkoxyalkyl group may be prepared by treating a corresponding compound of formula (I) in which R~ is a hydroxyalkyl group with for example an alkyl halide in a suitable solvent such as dimethylformamide in the presence oE a base e.g.
sodium hydride.
According to a further possibility alkylation (e.g. methylation) of a compound in which R4 is aprimary orsec-ondary aminoalkyl group may be effected by treatment with formaldehyde and formic acid (the Eschweiler-Clarke procedure).
Compounds of formula (I) in which R4 is an acyloxyal]cyl group may be prepared by treating the corresponding hydroxyalkyl compound with an appropriate acid, e.g. acetic or benzoic acid at elevated temperatures e.g. 80-120C in the absence or presence of a solvent such as toluene.
Compounds of formula (I) in which R4 is an alkenyl group may be prepared from the corresponding hydroxyalkyl compound by heating with an acid,e.g. toluene sulphonic acid, in a suitable solvent,e.g. acetonitrile.
Compounds of formula (I) in which R4 represents a hydroxyalkyl group may be prepared by removal of a suitable hydroxyl protecting group. Examples of such protected hydroxyl groups include ethers, such as trialkylsilyl e.g. trimethyl silyl, aralkyl such as benzyl, benzhydryl or trityl, tetrahydro pyranyl or alkoxymethyl, e.g.
methoxymethyl ethers, or esters of carboxylic acids such as alkanoic acids e.g. formic acid or acetic acid, or aromatic acids such as benzoic acid, or aralk~noic acids e.g. phenylacetic acid or haloalkanoic acids such as trifluoroacetic acid or trichloropropionic acid.

The pro-tecting groups may be removed by conventional procedures c.E. Protective Groups in Organic Chemistry 1973 eclited by J.F.I~ lcOmie.For example benzy1 and benzhydryl ether groups may be S removed by catalytlc hyclrogenolysls wlth for example hydrogen ancl a pallad:ium catalyst;the -trityl, tetrahydropyranyl,alkoxymethyl and trialkylsllyl ether groups may be removed by acid hydrolysls.
The esters may be cleaved by acid or alkallne hydrolysis.
The dlazonium salts (III), the aminotrlazoles (IV~, -the amlnoguanldines (XIV) and the compounds of formula (XX) in which E represents (CH2)nX(CE12)mP may be prepared as described in British Patent Specification 1~o.2023133A.
~ here the product of any of the above processes is a free base and a salt is required, the salt may be formed in a conventional manner. Thus for example, a generally convenient method of forming the salts is to mix approprlate quantities of the free base and the acid in an approprlate solven-t(s) e.g. an alcohol such as ethanol or an ester such as ethyl acetate.
The invention is illustrated but not limited by the following Examples and preparatiOnS.

In the Eollowing examples tempera-tures ~re in C
"T.l.c " refers to thin layer chromatography carried out on silica usin~, unless otherwise stated, one of the following solvent systems:
System A methanol 0.88 ammonia (79.1) System B ethyl acetate: water: isopropanol-0.88 ammonia ( 25:8:15:2) System C ethyl acetate : ethanol :
0.88 ammonia (20:3:2) Preparative chroma-tography was carried out on silica using methanol as eluant unless otherwise stated.
Preparation 1 a) 4-[3~ piperidinylmethyl)phenoxy]butanal 4-[3~ piperidinylmethyl)phenoxylbutannitrile A mix-ture o~ sodlum hydride (1.5g) and 3-(1-piperidinylmethyl)phenol (11.2g) in dimethylformamide (60 ml) was stirred at room temperature for 5h. 4-Bromobutannitrile (9~Og) was added, and stirring was continued for a further 2~h. The mixture was poured onto ice and extracted with ethyl acetate which was washed with water and brine, and distilled to give the title compound as a colourless oil (14.78g) b.p.
200,0.08 mm; tlc system A Rf 0.8 4-[3-~-piperidinylmethyl)~henoxy~butanal semi-carbazone -A solution o~ 4-L3-(1-piperidinylmethyl)phenoxy]
butannitrile (51.6g) sodium acetate (73.8g) and semi-carbazide hydrochloride (77.6g) in 50~ aqueous ethanol (lL) was hydrogenated over Raney Nickel (50g). The cata-lyst was removed by filtration. The filtrate was partially evaporated, made basic with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated to leave an oil which was puri~ied by column -3~
ch~omatography to give the title compound asa pale yellow oil (48.6CJ); tlc Sys-tem B, R~ 0.8.

N.M.R. (CDC13) 0.28, brs, (l~I); 2.6,s, (lI-I);
2.9,t, (lH); 3-3.4,m,(3H); 4.4, brs, (2H); 6.02,t, (2H);6.57,s, (2il); 7.4-7.8,m, (4H); 7.95, m (2H); 8.2-8.9,m, (8H).

4-[3-(1-piperidinylmethyl)~henoxy]butanal 4-~3-(1-piperidinylmethyl)phenoxy]butanal semi-carbazone (9.43g) and 37~ formaldehyde (80 ml) in 2N
hydrochloric acid (80 ml) were stirred at room temperature for 2.5h and then diluted with water. The solution was basified with sodium carbonate and extracted with ether.
The organic extract was washed with brine, and distilled to give the title compound as a colourless oil (5.59g) .

b.p. 200, 0~06mm; tlc methanol Rf 0.7.
.
b) Similarly prepared from 3-[~dimethylamino)methyl]
phenol (12.08g) was 4-~3-[(dimethylamino)methyl]
phenoxy]butanal (1.05g) as a colourless oil b.p. 150, 0.06 mm; tlc System A, Rf 0.59.

Preparation 2 4-C3~ piperidinylmethyl)phenoxy~butanoic acid Ethy~ 4-[3-(1-p~peridinYlmethy~lphenoxy]butanoa_e A mixture of 3-~1-piperidinylmethy])phenol (11.2g) sodium hydride (1.5g) and ethyl 4-bromobutyrate (11.7g) in dimethylformamide (60 ml) was stirred at 25 during 20h. The mixture was poured onto ice (300g) and extracted with ethyl acetate (3 x 100 ml). The combined ext ~lCts were distilled to give the title compound as a colourless oil (16.9g) b.p. 250, 0.1 mm; tlc System B, ~f 0.9 4-~3-(1-pi~_idinylme-thyl)phenox~]butanoic acid A solution of e-thyl-4-l3-(1-piperidinylmethyl) phenoxy~butanoate (~.lg) an~ potassium hydroxide (6.0g) in et}lanol (50 ml) and water (50 ml) w~s heated under reflux durlng 0.5h. The cool solution was neutralised to p~l 7 with 5N hydrochloric acid, and evaporated to dryness under reduced pressure. The residue was dissolved in ethanol (100 ml), filtered and the Eiltrate was evaporated to leave a residue whichwas crystallised from a mixture of methanol and ether to give the title com~ound as a white crystalline solid (4.91g~ m.p. 73.5; tlc Sys-tem B, RE 0 3 Preparation 3 Methyl 5-amino-1-meth~l-lH-1,2,4-triazole-3-carboxylate A stirred suspension of 5-amino-1-methyl-lH-l, 2,4-triazole-3-carboxylic acid (9.lOg) in methanol (100 ml?
was saturated with dry hydrogen chloride, and heated under reflux for 4.5h. The cooled solution was partially evaporated, diluted,wth water (100 ml) and the pH was adjusted to pH 7 with potassium carbonate. The solution was filtered, and the filtrate partially evaporated to give the title compound as a white solid (4.60g) m.p.
190-1; tlc System B, Rf 0.6 Preparation 4 3-[3-(1-piperidinylmethyl~phenoxy]propanoic acid _C3-~1-piperidinylmethyl~phenoxy]propannitrile A solution of 3-(1-piperidinylmethyl)phenol (26g), acrylonitrile (100 ml) and benzyltrimethylammonium hydroxide (40~ methanolic solution, 5 ml) was heated at reflux for 4Oh. The mixture was evaporated in vacuo, diluted with ether (300 ml) and filtered. The fil-trate was washecl with 2N so~ium hydroxide, water and distilled to give the title ~ ound as a colourless oil (17.5g~
b~p. 170, 0.07 mm; tlc sys-tem B, Rf 0.8 3-[3~ piperidinylme-thyl)phenox~ propionic acid A solution of 3-C3-(1-piperidinylmethyl)phenoxy propannitrile (1.5y) in 2N sulphuric acid (115 ml) was heatecl under reflux for 72h. The p~l of the coolecl solution was adjusted to pH 7 and the suspension was treated with ethanol, filtered and evaporated to dryness. The resulting residue was extracted with hot ethanol. Ether was added to the cooled extract to give the title compound as a white solid (12g) m.p.l78.5-179.5; tlc System B, Rf 0.4 Pre~ation 5 a) Meth 1 N-r2-~acetvloxv)acetvl1-1-me-thyl-2-Y . . ~ ~ ~ ~ ~ _ ~henvlmethYlene)hydrazinecarboximidothioate MethYl l-methyl-2-(phenYlme-thylene)hydrazine-carboximidothioate hydroiodide A mixture of dimethyl dithiocarbamate hydroiodide (lOg) and l-methyl-2-(phenylmethylene) hydrazine (5.4g) was heated at 60 under water pump pressure for lh. The residue was triturated with hot ethyl acetate (20ml) to give the ~ (13.3g) as a yellow solid, m.p.l83.4 tlc System A Rf 0.75 Methyl N-C2-(acetyloxy)acetyl~-l-methyl-2-(phenylmethylene)hydrazinecarboximidothioate Methyl l-methyl-2-(phenylmethylene)hydrazine-carboximidothioatel hydroiodide (1.34g) was dissolved in saturated potassium carbonate solution and extracted with ether. The combined organic extracts were dried and evaporated to give an off-white solid which was dissolved in acetone (25 ml) and treated with potassium carbonate (l~lg) followed by (acetyloxy)acetyl chloride (0.85g).
The suspension was stirred at room temperature for 2h and evaporatecl ir, vacuo. The residue was suspended in __ water (50 ml) and fi:Ltered to c~ive the title com~ound (1.01g) which was recrystallised from ethanol, m.p.

Found: C, 54.7; H; 5.6; N,13.4;
C14H17N3 3 q C, 54.7; H; 5.6; N,13.7%
The following compounds were similarly prepared from the corresponding methyl-l-alkyl-2-(phenylmethylene) hydrazinecarboximidothioate hydroiodide (A) and the correspondlng acid chloride.

5 b) A (3.4g) and phenyl acetyl chloride (1.6g) gave methyl-l-methyl-N-phenylacetyl-2-(phenylmethylene)hydrazinecarboximidothioate (1.3g) m.p. 147-8 tlc. silica; ethyl acetate Rf 0.75 preparation 6 Followiny the method of Prepara-tion 5, methyl l-methyl-2-(pheny`me hylene) hydrazinecarboximidothioate (20g)and ethyl malonyl chloride ~12g) gave ethyl 3-[[[1-methyl-2-(phenylmethylene)hy~razino](methylthio) methylene]amino~-3-oxopropanoate (5.6g)m.p. 74-5 N.m.r. (CDC13~ 2.2,s,(lH); 2.2-2.4,m,(2H); 2.5-2.7,m, 13H); 5.82,q,(2H); 6.49,s,(2H); 6.52,s,(3H3 7.6,s,~3H) 8.73,t,(3EI).
~ .
l~he following compound was prepared using the method of Example 16:
3-[3-(1-piperidinylmethyl)phenoxy~propananamine (3.61g) and ethyl 3-[[[1-methyl-2-(phenymethylene)hydrazino~

&~

-3~

(methylthio) methylellelamino]-3-oxopropanoate(4.7g) gave ethyl 3-[[[1-methyl-2-(phenylmethylene)hydrazino]
[[3-[3-(1-piper:iclinylmethyl)phenoxy]propyl]amino]me-thylene]
amino]-3-oxopropanoate (7.3g) Nmr. (CDC13) 2.1,br, (11l); 2.23,s, (lH); 2.3-2.5,m,(2H);
2.55-2.7,m,(311); 2,83,t,tlH), 3-3.3,m,(3H); 5.8,q,(2H) 5.9,t, (2H); 6.4,m,(2H); 6.53,2,(3H); 6.55,s,(2H); 6.68,s, (2H); 7.5-8,m, (6H)i 8.5,m,(6H); 8.7,t,(3H); t.l.c. System A Rf 0.65 10 The above ethyl ester (1.84gl was acidi~ied to give e-thyl l-methyl-5~[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]
-lH-1,2,4-triazole-3-acetate (0.5g) N.m.r- (CDC13) 2.77,t r (lH); 3-3.3,m, (31-1); 5.4,t,(lH); 5.8,q,(2H); 5.9,t,(2H)

6.3-6.6,3xs-~q, (9H); 7.6,m, (4H); 8.5,m,(6H), 8.2,t,(3H);
15 T.l.c. System A Rf 0.63 -34a-Prepara-tion 8 5-C[3-(3-Form~ nox~propyl~amirlol-l-metilyl-lH-1,2,4-tr ~o~ 3-me~h~lnol e~Ll ~y~acetyl1-N'-~3-~3~ 3-dioxolan-2-y~ henoxxl~r-opyl~-l-methx---2-(ph-enylmethylene)-hydrazine -arboximidalllide A mixture of 3-[3-(1,3-dio~olan-2-yl)phenoxy]propanatnine (2.9g~ and methyl-N-~2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene) hydra~inecarboximidothioate (4g) was heated at 60 under water pump vacuum for 3h to give a glass which was triturated with ether to give the title compound as a white solid (5.39g) m.p. 78-80 t.l.c. silica methanol Rf 0.8 5-c[3-(3-Formylphenoxy)propyl~amino~-l-n-l-et-yl~ L~ ~-triazole-3-methanol .

A suspension of N'-[2-[(acetyloxy)acetyl]-N'-[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene)-hydrazinecarboximidamide (Sg) in 2N hydrochloric acid (lOOml) and ethanol (25ml ) was stirred at room temperature for 16 h. The solution was neutralised to pH 7 with potassium carbonate, treated with potassium hydroxide (1.7g) diluted with ethanol (50 ml) and stirred for a further 15 min. The pH
of the solution was adjusted to pH 7 with 2N hydrochloric acid, and the solvent was partially evaporated to leave an aquecus solution which was extracted with ethyl acetate. The combined organic extracts were dried and evaporated to give the title compound as a foam 12.63~) t.l.c. silica ethyi acetate:methanol: 2:1 Rf 0.5,nmr (CDC13) O.OO,s, (lH);
2.5 - 2.9,m, (4H); 5.4,t, (lH); 6.4,q,(2H); 6.50,s,(3H);

7.85,m, (2H).

1 E a ple 1 a) 3-me-thyl-N-[3-[3-(N,N~dimethylaminomethyl) ___ __ phenoxy]propyl]-EI-1,2,_-triazole-5-amine A mixture of 3-~3-am;nopropoxy)-N,N-dime-thyl-benzencmethanamine (A) (2.0g) and methylisothio semicarbazide hydroioclicle (2.24g) was heated at 40 Eor 6h. The residual gum was dissolved in ethanol and treated with a solution oE tartaric acid in ethyl aceta-te. The solid that precipitated was filtered oEf and heated under reflux in glacial acetic acid (lS ml) for 4 h. The mixture was cooled, basified with potassium carbonate and extracted with ether. The organic extract was purified by column chromatography to give -the title compound after recrystal-lisation from a mixture of ethyl acetate and light petroleum (b.p. 60-80) as a buEf solid (0.8g) m.p.
133-133.5 . tlc System A,Rf 0.58.
The following were similarly prepared from the appropriate acid, the appropriate diamine and methylisothiosemicarbazide hydroiodide (B).
b) Diamine A (1.46g), B (2.75g) and phenyl acetic acid (3.0g) carrying out the reaction with the acid in refluxing ethanol (50 ml) for 72 hr, gave 3-phenylmethyl-N-[3-~3-[(dimethylamino)methyl]phenoxy]propyl~-lH-1,2,4-triazole-- 5-amine (0.06g) m.p. 140-141. tlc System A,Rf 0.49 c) Diamine A (1.46g), B (1.73g) and benzoic acid (5.g) carrying out the reaction with the acid by heating at 140 for 12 hr gave 3-phenyl-N-[3-[3-~(dimethylamino)methyl]
phenoxy]propyl]-1~-1,2,4-triazole-5-amine (0.62g) m.p.
126.5-127.5 tlc System A,Rf 0.48.
d) 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (4.96g), B(4.94g) and phenyl acetic acid (8.16g) carrying out the reaction with the acid in refluxing toluene (20ml) for 6 hr gave 3-phenylmethyl-N-~3-[3-(1-piperidinylmethyl) phenoxy]
propyl]-lH-1,2,4-triazole-5-amine (1.3g) m.p. 143-4 tlc System A,Rf 0.5.

Example 2 a) I-(N, _ imethylaminomethyl) pheno~ylprop~ ,2,4-triazole -5-amine ___ _.
A sollltion of sodium nitrite (1.74y) in water (15 ml) was adc1ed clropwise to a solution of l-methyl-N -C3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl] lEI
-1,2,4-triazole-3,5-diamine (Sg) in concentrated sulphuric acid (3.6~g) and ethanol (200 ml). The reaction mixt~re was heated at 65 for 4h, cooled, treated with saturated brine (100 ml) and extracted with ethyl acetate. Evaporation of the organic extract gave a re~ oil which was extracted with ether.
Distillation of the ether extracts gave the title compound as a pale yellow oil (1.8g) b.p. 190 (0.04 mm). tlc System A,Rf 0.6.
The following compounds were similarly prepared:
b) l-methyl-N5-[3-[3-(1-piperidinylmethyl)phenoxy]
propyl]-lH~1,2,4-triazole-3,5-diamine (1.72g) gave l-methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy~propyl~
-lE~-1,2,4-triazole-5-amine (1.25g) as a yellow oil;b.p.
220, 0.08 mm; tlc System B, Rf 0.5.
c) l-methyl-N5-[3-[3-[(hexamethyleneiminyl)methyl]
phenoxy]propyl-lH-1,2,4-triazole-3,5-diamine (1.79g) gave l-me-thyl-N-[3-[3-[(hexamethyleneiminyl)methyl]
phenoxy]propyl]-lH-1,2,4--triazole-5-amine (500 mg) b.p. 240 0.15 mm; tlc System B, Rf 0.75.

Exam~le_3 a) 3-chloro-1-methyl-N-~[3-(N,N-dimethylaminomethyl ~noxylpro~l]-lH-l,2,4-triazole-5-amine . _ A solution of sodium nitrite -(0.46g) in wa-ter (1.5 ml) ~as added dropwise to a solution of 1-methyl-N5-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl~
-1~l-1,2,4-triazole-3,5-diamine (2.0g ) in concentrated hydrochloric acid a-t 5. This solution of the diazoniurn salt w~s ac1decl to a solution o~ cuprous chloride at 75 [prepared by adding a solution of sodium metabisulphi-te (0.41g) and sodium hydroxide (0.27g) in w~ter (3 ml) to a hot solu-tion of copper sulphate (1.89g) and sodium chloride (1.61g) in water (6 Ml) ].
Concentrated hydrochloric acid (S4 ml) was added to the reaction mixture which was allo~ed to stand at 25 for 12h, cooled, basified with sodium bicarbonate and extracted with ethyl acetate. Distillation of the organic extract gave the title compound as a pale yellow oil (1.23 g) b.p. 225 (0.04 mm). tlc System A,Rf 0.64.
b) Similarly prepared from l-methyl-N5-[3-[3~1-pip eridinylmethyl)phenoxy~ propyl]-l~I-1/2,4-triazole-3,5-diamine (11.3g) was 3-chloro-1-methyl-N-L3~[3-(1-piperidinylmethyl)phenoxy]propyl]-lH-1,2,4-triazole-5-amine (3.05y) b.p. 250, 0.06 mm, tlc System B,Rf 0.8 Example 4 a) N-[~-~3-[(dimethylamino)methyl]phenoxy]butyl7-- 3-phenylmethyl-lH-1,2,4-triazole-5-amine A solution of 4-~3-[(dimethylamino)methyl]phenoxy]
butanal (0.5g) and 3-phenyl methyl-1~-1,2,4-triazole -5-amine ~0.39g~ in dry toluene (60 ml) was heated under reflux during 3h. The solvent was evaporated and replaced with methanol (50 ml). Sodium borohydride (0O4g) was added and the mixture was stirred at 20 during 2h. The methanol was evaporated and the residue partitioned between water and ethyl acetate. The organic extract was evaporated and the residue was purified by column chromatography to give the title compound, which ~39-crystallised from a mixture oE ethyl aceta-te and cyclohexane as pale yellow crystals (0.09g) m.p.
131--3; tlc system A,Rf 0.6.
The Eollowing compounds were similarly prepared frorn the appropriate aldehyde and aminotriazole:
b) 4-[3-(l~piperidinylmethyl)phenoxy]butanal (0.4g), 3-methyl~ 1,2,4-triazole -5-amine (0.15g) and sodium borohydride (0.4g) gave 3-methyl-N-[4-~3-(1-piper-idinylmethyl)phenoxy~butyl]-lH-1,2,4-triazole-5-amine t50 mg) m.p. 138-9; tlc System A, Rf 0.64 c ) 4 - L 3-(1-piperidinylmethyl)phenoxy]butanal (0.5g) 3-phenylmethyl-lH-1,2,4-triazole-5-amine (0.33g) and sodium borohydride (0.4g) gave 3-phenylmethyl~N-~4-[3-(1-pipericlinylmethyl)phenoxy]butyl~-lH-1,2,4-triazole-5-amine (0.16g) m.p. 145-6 tlc. System A, Rf 0.6.

Example 5 -a) 3-(2-phenylethy~-N-[4-~3-(1-piperidinylmethyl) henoxvlbutYll-lH-~2,4-triazole-5-amine ~ ~
~3-(~Phenvleth~l)-lH-1,2,4-triazol-5-Y11-4r3-~ ~ , ~
( i eridinvlmethYl) phenoxYlbutanamide P- P ~ _ ~
A solution of 4-[3-(1-piperidinylmethyl)phenoxy]
butanoic acid (l.Og)~ thionyl chloride (1 29g) and dimethylformamide (6 drops) in methylene chloride (50 ml) was stirred at 25 during 5h. The solvent was evaporated and the residue was dissolved in methy]ene chloride (50 ml). 3-phenylethyl-lH-1,2,4-triazole -5-amine (0.68g) was added and the mixture was stirred at 25 during l~h. The solvent was removed and the residue was diluted with water (50 ml). The pH of the aqueous solution was adjusted to pH8with sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were evaporated and the residue was heated at 155 during 2il. The resulting solic~ was triturated under ho-t methanol to give the title compound (0.5g) as a white powder m.p. 192-3 tlc 'iystem A,R~ 0.62 3-(2-phe~ t~ )-N-~4-[3-(1-piperidinylmethyl) ~henoxxI~ _ ~ Il-1,2,4-triazole-5-amine ~ suspension of N-[3-(2-phenylethyl)-lEI-1,2,4-triazol-5 yl]-4-L3-(1 piperidirlylmethyl)phenoxy]
butanamide (0.4g) and lithium aluminium hydride ~0.33g) in dioxan (50 ml) was heated under reflux in a nitrogen atmosphere during 12h. The cool mixture was quenched with water (50 ml) and extracted with ethyl acetate.
The combined organic extracts were evaporated and the residue was crystallised from ethyl acetate to give the title compound as a white solid (0.23g) m.p. 146-7 tlc System A, Rf 0.71.
The following compounds were similarly prepared from 4-[3~ piperidinylmethyl)phenoxy]butanoic acid (A) and the corresponding tria201es:
b) A (l.Og) and 3-methylthio-lH-1,2,4-triazole-5-amine (0.47g) gave 3-methylthio-N-[4-[3-~1-piper-idinylmethyl)phenoxy]butyl]-lH-1,2,4-triazole -5-amine (O.lg)~ m.p. 122-3 tlc System A R~ 0.73 c) A (l.Og) and 3-(2-methylpropyl)-lH-1,2,4-triazole-5-amine (0.68g) gave 3-(2-methylpropyl)~N-[4-~3-(1-piperidinylmethyl)phenoxy]butyl]-lH-1,2,4-triazole-5-amine (0.08g), m.p. 141-142~.
N.m.r. (CDC13) 2.78,t,(1H); 3.0-3.3,m,(3H); 5.02, br, (lH); 6.0, m,(2H);6.60, s+m, (4H); 7.2-8.8, m,(l8EI); 9.05,d,(6H)~

_40-_a 5-~4-[~ dinylmethyl)~henoxyI~utyl~amino~
l.l~-1,2,4-triazole~3-methanol ~ [3-(1-p.iperidin~lmethyl)~henoxy~bu-tyl]
ami.no-llH,~,4-triazole-3-carbox~late Methyl 5-amino-1ll-1,2,4--triazole-3-carboxylate (0.568g) and 4-[~-(1-piperidinylmethyl)phenoxy~butanal in ethanol (40 ml) were heated at reflux for 2h. The cooled reaction mix-ture was treated with sodium boro hydride ~0.4g) and stirred at room termperature for 15h.
The solvent was evaporated and the residue was dissolved in 2N hydrochloric acid which was washed with ethyl acetate, basified with sodium carbonate and extracted with ethyl acetate. The'combined organic extracts were evaporated to yield the title compound as a white solid which was recrystallised from a. mixture of ethyl acetate and ethanol (1:1) .(0.5g) m.p. 170-1 dec.; tlc System B, Rf 0.8.
~ 4-[3~ iperidinylmethyl)phenoxyl_ut~l~amino-lH-1,2,4-triazole-3-methanol A mixture of ethyl 5-[4-[3-(1-piperidinylmethyl) phenoxy]butyl~amino-lH-1,2,4-triazole-3-carboxylate (0.3g) and lithium,aluminium hydride (O.lg) in tetra-hydrofuran (50 ml) was stirred at room temperature for 0.5h, then quenched with water. The solid was-filtered off and washed with methanol. The filtrate and washings were evaporated to leave a residue which was extracted with hot ethyl acetate. Evaporation of the extract gave an oil that solidified. It was crystallised from ethyl acetate to give the title compound as an off-white solid (0.094g) m.p. 127-8 dec. tlc System B, Rf 0.7 Example 7 l-meth~ 5-C~4-~3~(1-piperidirlv _~'. y ]
butyl]amino~ 1,2,4-triazole-3 methanol Methyl l-methyl-5-~[l-oxo-4-c3~ E~r 1DYI-methyl)phenox ~ yl~aminoJ-lEI-1,2,4-triazole -3 ~
A solution of A-[3-(1-piperidiny:Lmethyl)phenoxy3 butanoic acid (2.77q), thionyl chloride (2.5 ml) and dimethylformamide (6 drops) in methylene chloride (80 ml) was stirred at room temperature for 2h. The mixture was evaporated in vacuu. The resulting solid was dissolved in dimethylformami~e (50 ml) and treated with methyl 5-amino-1-methyl-lH-1,2,4-triazole-3-carboxylate (1.56g) After 18h at room temperature, the mixture was evap-orated in vacuo and the residue was dissolved in water.
The combined organic extracts were washed with water and evaporated in vacuo. The resulting solid was recrystall-ised from a mixture of ethyl acetate and cyclohexane to yield the title compound as a white powder (2.0g) m.p. 108-10 tlc System B, Rf 0.7 l-Methyl-5-[[4-[3-(1-piperidirlylmethyl?phenoxy~
butyl] amino~-lH-1,2,4-triazole-3-methanol A suspension of methyl l-methyl-5-~[1-oxo-4-[
3-(1-piperidinylmethyl)phenoxy3butyl]amino~-lH-1,2,4-triazole-3-carboxylate (1.25g) and lithium aluminium hydride (l.Og) in tetrahydrofuran (30 ml) was stirred under nitrogen at room temperature for Sh, cooled to 0 and quenched with water. The mixture was diluted with ethyl acetate, filtered and the filtrate was evaporated in vacuo. The residue was chromatographed to give an oil, which crystallised on trituration with ether to yield the title compound as a white solid ~0.33g) m.p. 84-5, tlc System B,Rf 0.6 Exam~l~ 8 1 ethyl ~ piperidinylmethyl)phenox~7 -1,2,4-triazole-3-methallol ~ stirred suspension oE 3-C3-(1-pipericlinylmethyl) phcnoxy]propano:ic acicl (].34g~ :in methylene chloride (50 ml) and dimethylformamide (5 drops) was treated with thionyl chloricle (2.0 ml). The solution was maintained for 2h at room temperature and then evaporated ln vacuo. The oily product was dissolved in dimethyl-10 ~ formamide (50 ml) and treated with methyl-5-amino-1-methyl~lH-1,2,4-triazole-3-carboxylate (1.09g). The reaction mixture was stirred at room temperature for 16h, evaporated in vacuo, the residue was dissolved in 8% sodium bicarbonate solu-tion and washed with ethyl acetate. The organic extracts were washed with water and evaporated in vacuo to give methyll-methyl-5-[[1-oxo ' ~4-[3-(1-piperidinylmethyl)phenoxy]propyl]amino-lH-l, 2,4-triazole-3-carboxylate as an oil (0.832g) which was dissolved in tetrahydrofuran (30 ml) and treated with lithium aluminium hydride (0.6g) at 0, The mix-ture was stirred at room temperature for 6h, then quenched with water, diluted with ethyl acetate and filtered.
The filtrate was evaporated in vacuo to yield an oil (0.586g), which was purified by colun~nchromatography to give an oil, which crystallised on trituration with ether to yield the title compound (0.136 mg) as a white solid m.p. 118-9 tlc System B, Rf 0.7 Exam~e 9 a) N-[5-[~3-[3-~(dimethylamino)methy~l~henoxy~
pro~yl] amino~-l-methyl lH=1~,4-triazol-3-yl]-N'-methylthiourea A solution of l-methyl-N5-[3-~3-~,(dimethylamino) -~3- ~

1 methyl]phenoxy]propyl]-lH-1,2,4-triazole-3,5-diamine (A) (l.Og) and methyl isothiocyanate (0.24g) in dry ace-toni-trile was heated under reflux for 48 houxs. rl'he solvent was removed and the residual oil purified by colum chromatography The residue was dissolved ln ethyl aceta-te. A solution oE tartaric acid in ethyl aceta-te was added to give -the title compound as the tartrate salt as a white powder (0.22g). tlc System A Rf 0.51. NMR
(free base) CDC13, 0.4 brs. (lH); 2.78 t (lH); 3.0-3.3 m (3H); 4.77 t (lH); 5.90 t (2H); 6.46 s-~q (5H); 6.60 s (2M); 6.~0 d (3H); 7.76 s (6H); 7.90 m (2H).
The following compounds were similarly prepared from the appropriate aminotriazole and isocyanate.
b) Aminotriazole (l.Og) and methylisocyanate (0.2g) gave N-[5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]
amino]-l-methyl-lH-1,2 r 4-triazol-3-yl]-N'-methylurea tartrate (1.2g). tlc System A, Rf 0.55. NMR (free base) (CD C13) 1.48,s, (lH); 2.10,q,(lH); 2.77,t, (lH);
3.0-3.3,m, (3H); 5.0,t, (lH); 5.9,t, (2H); 6.43,q,(2H);
6.48,s, (3H); 6.62,s,(2H); 7.15,d,(3H); 7.77,s,(6H);
7.9,m, t2H) c) l-methyl-N5-~3-[3-(1-piperidinylmethyl)phenoxy]
propyl]-lH-1,2,4-triazole-3,5-diamine (B) (1.5g) and phenylisocyanate (0.52g) gave N-[5-[[3-[3-(1-piperidinyl-methyl) phenoxy]propyl]amino]-1-methyl-lH-1,2,4-triazol-3-yl]-M'-phenylurea (1.07g) m.p. 137-9 (from ethyl acetate) tlc System A, Rf 0.57.
d) Aminotriazole (B) (1.5g) and cyclohexylisocyanate (0.64g) gave N-[5-[[3-[3-(1-piperidinylmethyl)phenoxy]
propyl]amino]-1-methyl-lH-1,2,4-triazol-3-yl]-N'cyclo-hexylurea (0.43g) m.p. 129-130 (from cyclohexane). tlc System B, Rf 0.6.

1 e) l-methyl~ 2-[[[5-[ldime-thylamino)methyl]-~-methyl-2-f~lranyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3, 5-diamine ~lg) and phenylisocyana-te (0.35 ml) gave N-[5-[[2-[[[5-[(dimethylamino)me-thyl]-4-me-thyl-2-Euranyl~
methyl]thio]ethyl]amino]-1-methyl-lH-1,2,~-triazol-3-yl]-N'-phenyLIlrea (0.65g) m.p. 166-7 (from acetonitrlle methanol) tlc System ~ (79.1) Rf 0.5 f) l-methyl-N5-[2-[[15-(dimethylamlno)methy]]-2-Euranyl]
methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine (3 1g) and methyl isocyanate (O.g7g) gave N-methyl-N'-[l-methyl-5-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]me-thyl]thio]
ethyl]amino~-lH-1,2,4-triazole-3-yl]urea as a gum (2.5g) tlc. System C Rf 0.41. NMR (CDC13) 1.70,s,(lH); 2.15, br q (lH); 3.92,s,(2H); 5.06,t,(lH); 6.52,s,(3H); 6.63, s~q, (4H), 7.20,d-~t,(5H);7.80,s, (6H).

Example 10 Ethyl l-methyl-5-[[3-[3-(N,N-dimethylami'nome'thyl) phenoxy]propyl]amino]-lH-1,2,4-triazole-3-carbamate, -tartrate A solution of ethyl chloroformate (0.6 ml) and 1-methyl-N5-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl]
~lH-1,2,4-triazole-3, 5-diamine (2.0g) in dry dimethylformamide (30 ml) was stirred at 25 for 12 h.
The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were evaporated to lea~e a yellow oil which was triturated with'a mixture of ether, ethyl acetate and light petroleum ~b.p. 60-80 ).
Insoluble material was filtered off and the residual oil dissolved in ethyl acetate. A saturated solution of tartaric acid in ethyl acetate was added until no more precipitate ~as formed, to give the title com~ound as a white solid ~Or88g) m.p. 110-115 tlc Sys-tem A, Rf 0~61.
b) Similarly prepared from l~me-thyl-N5-~3-r3-(1-piperidinylmethyl)phenoxy]propyl]~lH-1,2,4-triazole-3,5-diamine (5g) and ethyl chloroformate (1.56g) was e-thyl [l-mel:hyl-5-C~3--~3-(1-piperidinylmethyl)phenoxy]propyl amino~-lH-1,2,4-tr:iazol-3-yl]carbamate tartrate (0.85g) m.p. 82 N.m.r. (D20) 2.51,m, (lH); 2.7-3.1,m, (3H);
5.42,s,(2H); 5.5-6,m, (6H); 6.3-6.7 m-~s, (7H); 6.8-7.3, m, (2H); 7.6-8.6,m, (8H); 8.71,t, (3H).

_xam~e 11 a) ~ [3-~(dimethylamino)methyl]phenoxy]
~r ~ n~ -1-methyl-lH-1,2,4-triaæol-3-yl] acetamide, tartra_ Acetlc anhydride (0.35g) was added dropwise to a solution of l-methyl-N5-[3-[3-[(dimethylamino)methyl]
phenoxy]propyl]-lH-1,2,4-triazole-3,5-diamine (A) (lg) in dry pyridine and the reaction was stirred at 25~ for 12h. Solveni was removed and the residue was dissolved in ethyl acetate, washed with aqueous saturated sodium caxbonate solution, dried and evaporated. The residual oil was puri~ied by chromatography and treated with a solution of tartaric acid in ethyl acetate to give the title com~und (1.2g)m.p. 103-5 tlc System A,Rf 0.5 The following compound~ were similarly prepared from the appropriate diamine:
b) 1-methyl-N5-C3-[3-~-piperidinylmethyl)phenoxy]
propyl]-lH-1,2,4-triazole-3,5-diamine (B) (2.5g) and acetic anhydride (0.75g) gave N-[5-~3-[3-~(1-piperidinylmethyl)phenoxy]propyl]amino~-l-methyl-lH-l, 2,4-triazole-3-yl]acetamide, tartrate (2.7g) m.p. 90 ~6 (softens) tlc System A, Rf 0.6.
c) Diamine (~) (l.Og) and me-thanesulphonic anhydride (0.59g) gave 5-[[3-C3-(1-p:iperidinylme-thyl) phenoxy]propyl]amino~-l-methyl-lH-1,2,~-triazole-3-sulphamic acid, methyl es-ter, methane sulphonate (1.2g) m.p. 130-1~. tlc Systern A, RE 0 54 d) Diamine (A) (lg) and benzoic anhydride (0.8g) gave N-[$~[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]
-l-methyl-lH-1,2,4-triazol-3-yl]benzamide, tartrate ~0.48g) m.p. 126-130. tlc System A,Rf 0.47.
e) l-methyl-N -[2-[[[5-[(dimethylamino)methyl]
2-furanyl]methyl]thio]ethyl~-lH-1,2,4-triazole-3,5-dia-mine (1.9g) and benzoic anhydride (1.2g) gave N-[l-methyl-5--[[2-[[~ 5-[(dimethylamino)methyl]-2-furanyl]
methyl]thio]ethyl]amino]-lH-1,2,4-trlazol-3yl]
benzamide (0.95g). tlc System C, R~ 0.45.
Found: C, 57.7; H, 6.4; N, 19.8 C20~I26N6 2 q C, 58.0; H, 6.3; N, 20.3~
f) 1-methyl-N5-[2-[[[5-[(dimethylamino)methyl]-4-methyl-2-furanyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine (0.96g) and benzoic anhydride (l.OgJ gave N-[l-methyl-5-[[2-[[[-5-[(dimethylamino)methyl]-4-methyl-2-furanyl]methyl]thio~ethyl]amino]-lH-1,2,4-triazol-3-yl~benæamide (0.6g). tlc System C, R~ 0.42 N.m.r. (CDC13) O.90,s, (lH); 2.10,m,(2H); 2.5,m,(3H); 4.06,s,(lH);
5.10,t,(lH); 6.43,s,(2H); 6.52,s,(3H); 6.68,s+q,(4H);
7.32,t,(2H); 7.82,s,(6H); 8.10,s, ~3H) g) l-methyl-N5-C2-~[5-~(dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine (0.98g) and benzoic anhydride (l.Og) gave ~7_ N-[l-methyl-5-[[2 ~[[5-[(dime-thylamino)methyl]-2-thienyl]methyl]thio]ethyl] amino]-l~l-l,2,4-triazol-3-yl]benzam:ide (0.5g). tlc Sys-te~ C, Rf 0.46 N.m.r. (C~Cl3) l.021br.s,(lH); 2.07,m,(2~1); 2.5,m,(3H);
3.30,m, (2H); 5.43,t, (lH); 6.18,s,(2M); 6.5,2s-~q, (711); 7~28,t,(2EI); 7.77,s,(6H).
Exarnple 12 N~ methyl-5-[~3 13-1l piperidinylmethyl) phenoxy~propyl~amino~-lH-l~2~4-tr_azol-3-y ~ormamlcle A mixture of sodium hydride (0.72g) and l-methyl-N5-[3-[3-(l-piperidinylmethyl) phenoxy3propyl]-lH-l, 2,4-triazole-3,5-diamine (3.44g) in dimethylformamide (50 ml) was heated under reflux for 8h. The reaction mixture was cooled, poured onto water (300 ml) and extracted with ether. Evaporation of the organic extract gave a yellow oil, which was extracted with boiling cyclohexane (500 ml). As the cyclohexane extract cooled a brown oil precipi-tated out. This oil was discarded and the supernatant solution was cooled to room ternperature to give the title compound which was recrystallised from a mixture of ethyl aceta-te and light petroleum (b.p.60-80) as a pale yellow solid (0.35g) m.p. 68-75 (decomposition). tlc, System C Rf 0.6 Example 13 N-[l-methyl-5-~2-~[C5-[(dimethylamino)methyl~ --2-uranylLmethylLthio]ethyl]amino~_lH_l~,4-triazol-3- ~ rormamide A stirred suspension of l-methyl-N -[2-[[[5-tdimethylamino)methyl -2-furanyl]methyl]thio3ethyl]-lH-l,2,4-triazole~3,5-diamine, dihydrochloride (3.83g' and potassium carbonate (3.04g) in acetone (60 ml) was heated at reflux for 30 min, and then cooled to 5C. Aceticformic _~8~
anhydride (1.32g) was added and the suspension was allowed to warm up to room -tempera-ture~ The inorganic material was ~iltered off and the solution evaporated to give an oil which was chromatoyraphed. I'he resulting oil was dissolved in ethyl ace-tate, washed with saturatecl aqueous sodium bicarbonate and evaporatecl to aEforcl the ~ _d (0.47g) as a colourless oil~ tlc System B, R~ 0.61.Nmr. (CDC13) 0.28 brd, (lH); 0.93 d, (lH); 3.81,s,(2H);
5.25, brt (lH); 6.28,s, (2H); 6.47,s,(3H); 6.52 s~m (2H~; 7.16,t, (2H) 7.74,s, (6H).

Fxam~le 14 N-El-methyl-5-~C3- L3-(1-piperidinylmethyl)~henoxy]
~op~l~amino~-lH-1,2,4-triazol-3-~1]-2-furancarb-oxamide a) A solution oE l-methyl-N~-[3-[3-(1-piperidinyl-methyl)phenoxy]propyl]-lH-1,2,4-triazole-3,5-diamine (A) (l.Og) and 2-furancarboxylic acid, chloride (0.42g) in pyridine (25 ml) was kept at ambient temperature for lh. The pyridine was evaporated in vacuo and the residue was azeotropically distilled with toluene to give an oil which was partitioned between ethyl acetate and 2M hydrochloric acid. The pH of the aqueous extract was adjusted to pH 9 and it was extracted with ethyl acetate. The organic extracts were evaporated to a gum which was chromatographed on silica using ethyl acetate:
methanol (9:1) to give the title compound (0.30g) as a - glassy solid. tlc System B, Rf 0.57. Nmr (CDC13~
1.5,brs, (lH); 2.53,m, (lH); 2.75,t-~m, (2H); 3.0-3.3-~, (3H); 3.5,dd (lH); 5.31,t, (lH); 5.92,t, (2H);
6.42,q,(2H); 6.50,s,(3H); 6.59,s,(3H); 7.6,brs;(4H);
7.9,m,(2H); 8.5,m,(6H).
.

, ~9 b) Similarly prepared from diamine (A) (lg) and 3-pyridinecarbo~ylic acid, chloride, hydrochloride (0.57g) was N-[l-methyl~5-[C3-[3-(l-piperidinylmethyl) phenoxy]propyl]aminol-lH-1,2,4-triazol-3-yl¦-3-pyridinecarboxamide (0~98g). tlc System B, Rf 0.64.
Nmr (CDC13) 0.85,d, (lH); 1.07,brs,(1H); 1.22,dd (1~1); 1.78,m, (lH); 2.62,q,(lH); 2.77,t, (lH); 3.0-3.3, m,(3H); 5.35,t, (lH); 5.92,t,(2H); 6.48,s,(3H)i 6.50,m (2H) 6.55,s, (2H); 7.5-7.7,m, (4H); 7.90,m, (2H); 8.3-8.
m, (6H).

lhe following compounds were similarly prepared from the appropriate aminotriazOle and acid chloride c) The triazole ~A) (2.00g) and 4-methoxybenzoic acid, chloride (l.lOg) gave 4-methoxy-N-[l-methyl-5-[[3-~3-(1-piperidinylmethyl)phenoxy]propyl]amino]-lH-l, 2,4-triazol-3-yl]benzamide (2.00g),m.p. 93.5-97~.
tlc. System B Rf 0.78 Found : C, 65.0; H, 7.0;N.17.9;
2634 6 3 requires : C, 65.2; H, 7.1;N,17.5 d) The triazole (A) (2.00g) and 4-methylbenzene-sulphonic acid, chloride~1.22gjwas 4-methyl-N~l-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-lH-l, 2,4-triazol-3-yl]benzenesulphonamide (1.58g) m.p. 100.5-Found: C, 57.1, H,6.7;N,15.7 C25H34N6o3S.32-H2o requires C,57.1; H,7.1;N,16.0%

Exam~le 15 5-- U3-~3~ idinylmethyl)phenoxy]propyl L
aminol-lM-1,2,4-triazole-3-one .- _ A solution of 3-[3-(1-piperidinylme-thyl)phenoxy]
propanarnine (1.76g) in tetrahydrofuran (70 ml) was treatecl with dimethyl N-methoxycarbonylcarbonimidodi-thioate (1.27g) at room temperature, and the mixture was stirred for 6h. Hydra~ine hydrate (2g) was added, and the mixture was heated under re~lux for 18h.
The solution was evaporated, and the residue was chrom-atographed to give the title compound (250mg) as a colourless oil. tlc. System B, Rf 0.5. Nmr (D2O) 2~5,t, (lH); 2.8-3.0,m,(3H); 5.72,s,(1H); 5 8,t, (3H); 6.5,m, (2H); 6.65,t, (2H); 7.05,br.t, (2H);
7.7-8.6,m, (8H).

Example 16 l-methyl~3-phenylmethyl-N-[3-[3-(1-piperidinyl-_thyl ? phenoxy~propyl~-lH-1,2 ! 4 -triazole-5-amine, tartrate N-[[l-methyl-2-~phenylmethylene)hydrazinol r C3-[3-(l~piperidinylmeth~l~phenoxylpropyl]amino]meth-ylene~benzeneacetamide A mi~ture of 3-~3-(1-piperidinylmethyl)phenoxy~
propanamine (0:38g) and methyl l-methyl-N-phenylacetyl-2-(phenylmethylene) hydrazinecarboximidothioate (0.5g) was hea-ted at 50 under water pump vacuum during 4h.
The residue was dissolved in c~clohexane (20 ml) and light petroleum (b.p. 60-~0) was added. The precipitate was removed by filtration and the ~iltrate was evaporated to give the title compound (0.65g) as a colourless oil.
tlc. System A R~ 0.7.
N.m.r. (CDC13) 2.2-3.0,m, (12H); 3.0-3.3,m~(3H); 6.01,t, (2H); 6.30,s, (2H); 6.55rbr.q., (2H); 6.62,s, (3H); G.66,s (2H); 7.65,m, (4H); 8.00,m, (2H); 8.3-8.6,m,(6H).

1 ethyl-3-~enylmethyl~N-[ _ ~lpiperidinylmeth~) phenoxy~pro ~
A solution of N-[[l-methyl-2-(phenylmethylene) hydrazino ]~3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino]methylene~benzeneacetamide (0.65g) in acetone (50 ml) was acidified to pII 1 with 2N hydrochloric acid ancl heated under reflux during 4h. The solution was washed with ethyl acetate, basified with potassium carbonate and extracted with ethyl acetate. The combined organic extracts were dried and evaporated to give a residue which was purified by column chromatography.
The resulting oil (0.4g) was dissolved in ethyl acetate (10 ml), and a solution of tartaric acid (125 mg) in ethyl acetate (50 ml) was added to give the title com~ound (0.42g) as a white powder.
tlc System A, Rf 0.65 N.m.r. (CDC13) (free base) 2.6-3.0,m,(6H); 3.0-3.4, m,(3H); 5.65,t, (lH);
5.95,t,~2H); 6.12,s,~2H); 6.47,q,~2H); 6.57,brs, ~5H);
7O67,m~ (4H); 7.93,m,(2H); 8.3-8.6,m, (6H).
Exam~e _ 5-~[2-[~5-[(dimethylamino)methyl]-2-furanyl~
meth~ thio~ethyl~amino]-l-meth~-lH-1,2,4-triazole-3-methanol 2-(~c-etyloxy)-N-[~[2-[[c5-L(dimethylamino) methyl]-2-furanyl]methyllthio~ethyl~amino ~l-methyl(2-phenylmethylene)hydrazino]
methylene]acetamide A mixture of methyl ~-[2-(acetyloxy)acetyl]-1-methyl-2~(phenylmethylene) hydrazinecarboximidothioate (0.92g) and 5- [[(2-aminoethyl)thio]methyl]-N, N-dimethyl-2-furanmethanamine ~0.64g) in aceto~trile ~5 ml) was stirred at room temperature for 3h. The solution was evaporated in vacuo. The oily residue was suspended in ether (20 ml), filtered and the solid which crystallised was collected to give the title compound (0.8g), m.p. 78-80 tlc. System A Rf 0.65 ~ me-thy ~ furanyl]
meth ~ e ~ 4-triaæole-3-methanol A solution of 2-(acetylo~y)-N-[[[2-[[[5~~(di -methylamino)mel:hyl]-2-furanyl]methyl]thio~ethyl]amino]
[l-methyl-2-(phenylmethylene)hydrazino]methylene]
acetamide (0.74y) in 2~ hydrochloric acid was heated at 98-100~ for lh. Water (5 ml) was added to the cooled solution which was washed with ethyl acétate.
The aqueous fraction was made alkaline with sodium carbonate and the solution was evaporated to dryness in vacuo. The residue was suspended in ethyl acetate (20 ml), excess anhydrous sodium carbonate and decolourising charcoal were added. The suspension was boiled for 10 mins, cooled, filtered and the filtrate was evaporated in vacuo. The residual oil was chroma-tographed on silica using methanol:0.88 ammonia, (79:1) to give the title compound (0.35g) as a pale brown oil.
tlc. System A Rf 0.6 N.m.r.~CDC13) 3.92,s,(2H); 5.18,t,5.32,b~, 5.49,s, (4H); 6.33,s,(2H); 6.51,s,6.61,s~q,(7H); 7.23,t,(2H~;
7.78,s,(6H).
Example 18 l~~ethyl~5-[[4~ 1-piperidinylmethylLphenoxy~
butyll~ino]-lH-1,2_4~triazole-3-methanol acetate A solution of l-methyl-5-[[4-[3~-piperidinylmethyl) phenoxy]butyl]amino]-lH-1,2,4-triazole-3-methanol (100 mg) in glacial acetic acid (S ml) was heated under reflux for 8h. The mixture was evaporated and -the residue was tri-turated with ether to give the title compound as a white solid (97 mg) m.p. 119 20.
tlc. System ~,R~ 0.8 E mple 19 3-Methoxymethyl-l-methy]-5-[[4-[3 _l-piper~
~ ~ o~lH-l,2,4-_ iazol A solution of l~methyl~3-[[4-[3-~1-piperid-inylmethyl)phenoxy]bu-tyl~amino~-lH-1~2,4-triazOle-3-me-thanol ~149mg~ and thionyl chloricle (3 ml) was stirred at room temperature Eor 0.5h and evaporated.
The residue was dissolved in methanol (5 ml) and added to a solution of sodium hydride (200 mg) in methanol (5 ml). The mixture was stirred at room temperature for 18h, evaporated, and the residue was partitioned between ethyl acetate and water. The organic extracts were dried and evaporated to give an oil which was chromatographed on silica using ethyl acetate:
isopropanol:water: 0.88 ammonia (25:15:8:2), to yield the title compound (108 mg).
tlc. System B, Rf 0.6. N.M.R. (CDC13) 2.8,t,(lH);
3.0-3.3,m,(4H); 5.67,s,(2H): 5.72,t,(1H); 6.00,br t, (2H); 6.3-6 6,m,(lOH); 7.6,m,(4H); 8.0-8.7,m,(lOH~

Example 20 1,3-dimethyl-N-[4-[3-(~ iperidinylmethyl) phenoxy~but~-lH-1,2,4-triazole-5-amine A stirred suspension of 4-[3-(1-piperidinyl-methyl)phenoxy]butanoic acid (4.0g) in methylene chloride (100 ml) and dimethylformamide (24 drops) was treated with thionyl chloride (5.16g). The solution was stirred at room temperature for 18h and evapora-ted in vacuo, to give a pale yellow solid which was dissolved in methylene chloride (100 ml) and treated with 5-amino-1,3-dimethyl~1,2,4-triazole (1.61g).

_54-The reaction mixture was stirred at room temperature for 2~h and evaporated in vacuo. The residue was dissolvecl in aqueous sodi~lm bicarbonate solution and extracted with ethyl aceta-te. The organic extracts were ~Iried and evaporated to give a brown oil which was dissolved in tetrahydrofuran (500ml), treated with lithiurn aluminium hydride (3.04g), s-tirred at room temperat~efor 18h and refluxed for 3h. The cooled reac-tion mixture was quenched l~ith water (300 ml) and extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated in vacuo to give an oil which ~as distilled to give the title compound (1~7g) as a pale yellow oil, b.p. 230/
__ _ 0.06mm N.m.r. 2.80,t, (lH); 3.0-3.3,m, (3H); 5.82,t,(lH) 6.02,m, (2EI); 6.58,s,s-~m, (7H); 7.65,7.77m,s,(7H)

8.0-8.7,m, (lOEI).

The following compounds were prepared using the method of Example 2:
l-methyl- N5-t2-[[[5-[(dimethylamino)methyl]-2-furanyl3 methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine(l.Og) gave 1-methyl-N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-lH,1,2,4-triazole-S-amine(0.32g) T.l.c. System C P~f 0.54.N.m.r. (CDC13); 2.50,s,(lH);
3 90,s,(2H); 6.30,s,(2H); 6.5,2s+q, (7H); 7.18,t,(2H) 7.79,s,(6H).
b) 1-methyl-N5-[2-[[~5-[(dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3, S-diamine (l.Og) gave l-methyl-N-[2-[[[S-[(dimethylamino)methyl]
-2-thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-5-amine (0.31g) T.l.c. System C Rf 0.52.N.m.r. (CDC13): 2.57,s,(lH);

-5~-3.3,m,(2H); 5.58,br,s,(lH)i 6~16,s,(2I-I); 6.48,2s+q,t7H)i 7.20,m, (2H); 7.76,s,(6H).

E n~le 2 ~ 3-C3-(1-pi~erldinylmethyl)phe}loxy~propyl~
ami ~ H-1,2,4-triazole-3-ethanol tartra-te salt A suspension of ethyl l-methyl-5-[[3 [3-(1-piperidinylmethyl)phenoxy]propyl]amino]-lH-1,2,4-triazole-3-acetate (0.3g)and lithium aluminium hydride (lOOmg) in tetrahydrofuran (50 ml) was stirred at 25 under nitrogen during 24h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were evaporated and the residue was chroma-tographed to give a pale yellow oil which dissolved in boiling cyclohexane. The hot solution was allowed to cool to room temperature, and the oil that precipitated was treated with a saturated ~lution of (d)-tartaric acid in ethyl acetate to give the title compoun~ as a white powder (80 mg).
N.m.r. (free base) (CDC13); 2.8,t,(lH); 3-3.3,m,( 3H);
5.3,t,(lH); 5.9,t, (2II); 6.13,t,(2H); 6.0,br,s,(lH) 6.4,q,(2H); 6.52,s,(3H)-6.57,s,(2H); 7.2,t,(2H);
7.65,m,(4H); 7.88,m,(2H); 8.5,m,(6H) T.l.c. System A Rf 0.55 Example 23 a) 5-[2-r~L~[(dimethylamino)methyl]-2-thienyl]methyll thiol~_hyl~-l-methyl-3-phenylmethyl-lH-1,2,4-triazole-5-amine 2-(~henyl)-N[~[2-~U5-[(dimethylamino)methy~-2-thienyl~methyl~thio~ethyl]amino]cl-methyl-2-(phenylmethylene)hydrazino]methylene]acetamide .
A mixture of 5-[[[2-(amino)ethyl]thio]methyl] N, -5~-N-dimethyl-2--thiopI-Iene methanamine(c) (l.Og) ancl methyl l-methyl N phenylacetyl-2-(phenylmethylene) hydrazinecarboximidothioate (A) (1.42g) was heated at 60 under wa-ter-pump vacuum during 3h. to gi~e the title co~ uncl (1.9g) as a colourless oil.
T.]..C. System A RE 0.61 N-m-r- (CDC13) 2 19br,m, (lEI); 2.2-2.4m (3H);
2.5-2.85,m,~8H); 3.3,dd (2EI); 6.18,s,(2EI); 6.33,s,(2H) 6.48,s,(2H); 6.68-6.70rm,(5H); 7.4,t,(2H); 7.78,s,(6H);

5-[2-~C[~I(dimethylamino)methyl]-2-thienyl~methyll thio~ethyl~ methvl-3-~henvlmethvl-lH-1,2,4-triazole -5-amine 2N hydrochloric acid (5ml) was added to a solution of 2-(phenyl)-N-[[[2-[[[5-~(dimethylamino) methyl]-2-thienyl]methyl]thio]ethyl]amino][l-methyl-2-(phenylmethylene)hydrazino]me-thylene]acetamide (1.9g) in toluene (20ml) and the mixture was heated on a steam bath for 30 min. The aqueous layer was washed with toluene, treated with po-tassium carbonate, ar,d evaporated in vacuo.The residue was dissolved in ethyl acetate, filtered and the filtrate was evaporated to yield an oil which was chromatographed to give the title compound (0.47g) as a pale orange 25 oil.
T.l.c. System A. Rf 0.55.
Found C, 60.0; H,6.8; N,17.1;
C20 27 5 2 q C, 59.8; H,6.8; N,17.4 8S~ ( The followinc3 compouncls were similarly prepared from -the ap~ropriate methyl l-m~-th~l M-acyl-2-(phenylmethylene~
hydrazinecar~oximidothioa-te ~nd the correspondiIl~ diamine b) A (0.5g) an~ 5[[(2~aminoethyl)thio]methyl~-N,N-dimethyl--2-fu~anmethanamine (0.33g) gave 5-[2-[[[5-[(d.imethylamlno)me~hyl~-2-Eurar~yl]methyl]thio]e-thyl]-1-methyl-3-phenylmethyl-liI-1,2,4-triazole-~5-amine (0.21g)~
T.l.c. System ~ Rf 0~61 N.m.r. (CDC13): 2.6-2.8,m,(5H); 3~95,s,(2H); 5.60,t,(lH);
6.12,s,(2H); 6.32,s,(2H); 6.55-6.63,m,(7H); 7.25,t,(2H);
7.79,s,(6H).
c) ~ (1.21g) and 5-[C(2-aminoethyl)thio]methyl]-3 -N,N-trimethyl-2-furanmethanamine (0.85g) gave 5-[2-[[t5-[(dimethYlamino)methyl]-4-methyl-2-furany]]methyl]
thio]ethyl~-l-methyl-3-phenylmethyl-lH-1,2,4-triazole-5-amine (0.42g) as a pale yellow oil.
T.l.c. System A Rf 0.58 N.m.r. (CDC13): 2.6-2.9,m, (5H); 4.06,s,(lH): 6.16,s,(2H);
5.53,t,(1~I); 6.40,s,(2H), 6.58-6.61,m,~7~1); 7.27,t,(2H);
7.8,s,(6H); 8.1,s,(3H);
d) N-[2~(acetyloxy)acetyl]-1-methyl-2-phenylmethylene) hydrazinecarboximidothioate (B) (0.75g) and 3-[3-[(1-hexamethyleneiminyl) methyl~phenoxy~propanamine (0.64g) gave 1-methyl-5-[3-[3-[(1-hexamethyleneiminyl)methyl]
phenoxy]propyl]amino-lH-1,2,4-triazole-3-methanol (0.32g), m.p. 80-82 N-m-r- (CDC13); 2.8,t,(1H); 3.0-3.3m, (3H); 5.42-5.45,m, (3H); 5.88-7.0,m,(llH); 7.4,m,(4H); 7.9,m,(2H); 8.4,m,(8H).
e) B (1.37g) and diamine C ~l.Og) gave 5-[[2-[[[5-[(dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]amino]
-l-methyl-lH-1,2,4-triazole-3-methanol (0.2g) T.l.c. System B. Rf 0.48 N.m.r. (CDC13); 3.25,m,(2H); 5.1,m,(2H); 5.5,s,(2H);
6.16,s,(2H); 6.35-6.5,m, (7H); 7.22,t,(2H) 7.77,s,(6H).

f) B (0.75g) and 3- L3- ( l-pyrrolidinylmethyl)phenoxy]
propanamiIle (0.57g) gave 1-me-thyl-5-[ 3 - [ 3-(1-pyrrolidinyl-methyl)phenoxy]propyl]amino]~EI-1,2,4-tria,.ole-3-methanol (0.4~) m~p. 105-7C.
Fo~nd: C, 62.9; H, 7.9; N, 20.7 C18~l27Ns2 ~equ:lres : C, 62.6; ~I, 7.9; M, 20.3~
g) B (0.75~) and 5-[[(2-aminoethyl)thio]methyl~-3-N, N-trimeth~1-2-furclnmethanamine (0.5g) gave 5-[[2-[[[5~ L (dimethylamino)methyl]-4-methyl-2-furanyl]methyl~
10 thio]ethyl]amino]-1-me-thyl--lH-1,2,4-triazole-3-methanol (0.32g~ T.l.c. System B Rf 0.53. N.m.r. (CDC13~ 4.02,s, (lH~; 5.32-5.48,m,(3H~; 6.37,s, (2H); 6.50~6.7,m,(7H~;
7.25,t, (2H~; 7.82,s,(6H~; 8.08,s,(3H).
~
~,l-trimethyl-5-[~4-~3-(1-pi~eridinylmethyl~phenoxy]
_tyl]amino]-lH-1,2,4-triazole-3-methanol N-[3-(1-h~droxy-1-methylethyl)-1-methyl-lH-1,2,4-triazole-5-yl]-4-[3-(1-piperidin~lmethyl)phenoxy~
butanamide A solution of methyl l-methyl-5-[[1-oxo-4-[3-(l-piperidinylmethyl~phenoxy]butyl~amino~-lH-1,2,4-triaæole -3-carboxylate (508 mg~ in tetrahydrofuran (10 ml) at -78 was treated with a solution of methyl magnesium iodine [(1.6 ml~ o~ a solution prepared from magnesium turnings (400 mg) and methyl iodine (0.7 ml) in ether (10 ml~].
The mixture was maintained at -78 for 0.5h. allowed to reach room temperature and quenched with water. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide, the aqueous layer was extracted with ethyl acetate, and the combined organic extracts were dried and evaporated in VaGUO. The residue was chromatographed to give the title compound (358 mg) as an oil.
T.l.c. System B. R~ 0.8 N.m.r. (CDC13): 2.82,t,(lH); 3.0-3.3,m,(4H~; 6.0,t,(2H);
6.20,s,(lH~; 6.32,s,(3II~; 6.60ls, (2H~; 7.3,m,(2H);
7.5-8.0,m,(6H); 8.45,S,(6H~; 8.5,m/(6H~.

a,~ trimeth~1-5-r[4-r3-(1-pi~eridinylmethyl)phenox~]
amino~lM-1,2,4-triazole-3-methanol A stirrecl solution oE ~ [3-(1-hyclroxy-1-me-thylethyl) -l-~ethyl-lH-1,2,~triazol-5-yl~-4-[3--(1-plperidinylmethyl) pheno~y]blltanam:ide (30~mq)in tetrahydroEuran (20 ml) under nitrogell was -treated, with lithium aluminium hydride (0.5g) in an ice-bath. The mixture was stirred at room temperature Eor 24h, quenched with wa-ter and extracted with ethyl acetate. The comblned organic extracts were dried and evaporated to give an oil (300 mg) which was chromatographed on silica using ethyl acetate:
isopropanol:wa-ter: 0.~8 ammonia (25:15:8:2) to give the title compounct (224 mg) as an oil. T.l.c. System B
Rf 0.7. N.m.r. (CDC13): 2.80,t,(lH); 3.0-3.3,m,(3H);
~5.65,t,(lH); 6.02,s, (2H); 6.52,m,(7H); 7.60,m,(4H);
8.0-~.7,m,(10M); 8.46,s,(6H).

Example 25 1 _ hyl-5-~C~-[3-(1-piperidinylmethyl)phenox~lbut~
aminol-lH-l 2 4-triazole-3- methanamine ' ' A solution of methyl l-methyl-5-[[1-oxo-4-[3-(l-piperidinylmethyl)phenoxy]butyl]amino]-lH-1,2,4-triazole -3-carboxylate (1.94g) in 0.8~ ammonia was stirred at room temperature for 18h. The mixture was evaporated to yield a yellow foam, which was triturated with ether to give a yellow solid (1.56g) which was used without further purification. A portion of this solid (1.20g) was suspended in tetrahydrofuran (50 ml) and treated at room temperature with lithium aluminium hydride (l.Og).
The mixture was heated under reflux for 24h, cooled and quenched with water. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were evaporated to yield an oil (0.9Og) which was chromatographed to give the title compound as an oil (210mg) T.l.c. Systern B Rf 0.5. N~m.r. (D20); 2.5,t,(1II);
2~8--3.0,m,(3EI); 5.43,s,(4H); 5.72,s,(21I); 5.8,t,(2H);
5.~6,s,(2H); 6.47,s,(3EI); 6.6,m,(~EI); 7.05,bt,(2H);
8.0-8.6,m~(10H3.

E _ ~le 26 a) N,N,l-Tr~ 5- r r 4 - ~ 3-(1-piperidinylmethyl) phenoxy~butyl]amino~-lH-:l,2,4--triazole-3--methanamine A solution of l-methyl-5-[[4-[3-5L-piperidinylmethyl) phenoxy]butyl~amino]-lE~-1,2,4-triazole-3-methanol (200mg) in thionyl chloride (4 ml) was stirred at room temperature fox 0.5h. The mixture was evaporated to give a white foam which was used without further purification, and dissolved in a 33~ solution of dimethylamine in ethanol (25 ml). The resulting solution was maintained at room temperature for 16h, and evaporated to give an oil which was chromatographed on silica using ethyl acetate:isopro-panol:water:O.88 ammonia (25:~5:8:2) to give the title compound (132mg) as an oil. T.l.c. System B. Rf 0.6 N.m.r. (CDC13): 2.8,t,(lH); 3.0-3.3,m,(3H); 5.66,t,51H);
6.02,t,(2H); 6.4-6.7,m, (9H); 7.6,m,(4H)i 7.7,s.(6H);
8.0-8.7,m, (lOH).

b) Similarly prepared from the same triazole methanol (l5omg)l thionyl chloride ~3 ml) and 0.88 aqueous ammonia (50 ml) was 1-methyl-5-[C4-[3-(1-piperidinyl-methyl) phenoxy]butyl]amino]-lH-1,2,4-triazole-3-methana-mine (109mg). T.l.c. System B and n.m.r. (D20) were the same as for the product of Example 25.

Exam~le 27 ~ . .
l-meth~1-5- ~ 3-(1-piperidinylmethyl)phenoxy~butyl~
amino~ l-1,2,4-triazole-3-methanol A stirrecl solution of 1-methyl-5-[[~-[3-(1-p:iperidinylmethyl)phenoxy~butyl]amino]-lH-1,2,~-triazole -3-methanoll acetate (5mg) in ethanol (1 ml) w~s treated with 2N sodium hydroxide solution (0.5 ml). The mixture was maintained at room temperature for 2h, - evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The aquous layer was extracted with ethyl acetate and the combined organic extracts were dried and evaporated in vacuo to yield the title compound ~4 mg) as a white solid,m.p. 82-83.
T.l.c. System B, Rf identical to product of Example 7.
Example 28 l-methyl-5-[[3-r3-[(1-piperidinyl)methy~]phenoxylpropyl~
aminol,-lH-1,2,~-triazole-3-methanol 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (1.2~g) and N-~2-acetyloxy) acetyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximidothioate (1.535g) were heated together at 50 for 3h. The residual oil was used without purification, and dissolved in acetone (30 ml). 2N
hyarochloric acid (5 ml) was added, the solution was stirred at room temperature for 1.5h and left overnight without stirring. A further quantity of 2N hydrochloric acid (5 ml) was added and -the solution was heated a~
reflux for 2h. Water (50 ml) was added, the aqueous solution was washed with ethyl acetate, and basified with excess solid sodium carbonate. The basic solution was extracted with ethyl acetate, and the organic extracts we~e evaporated to give the title compound as a white solid (l.lg) m.p. 119.
T.l.c. System B, ~f 0.7 Exam~le 29 Eollowing the method of Example 9, l-methyl N5-[2-r~[5~ imethylamino) methyl]-2-thienyl]
methyl] thio] ethyl]-lH 1,2,4-triazo]e-3,5-diamin~ (0.67g) and methyl isocyanate (0.17 ml) gave N-[5-[[2-[[[5-[(climethylamino)methyl]-2-thienyl]me-thyl]thio]ethyl]
amino]-l-methyl-lH-,2,4-triazol--3-yl]-N'-methyl urea (0.4g).
N-m-r- (CDC13). 3-23,q, (2H); 6.02,s,(2H); 6.4-6.5,s-~s+t, (7H); 7.1-7.2,s-~s,(5H); 7.75,s,(6H). T.l.c. System B
R~ 0.55.

Example 30 The following compounds were prepared using the method of Example 11 a ) l-methyl-N5- [2- ~ [ [~5~ L (dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine (0.5g) and methane sulphonic anhydride (0.3g) gave N-[l-methyl-5-[[2-[[~5-[(dimethylamino)methyl]-2-thienyl]methyl]
thio]ethyl]amino]-lH-1,2,4-triazol-3-yl]methane sulphonamide tO-05g)- N-m-r- (CDC13): 3.22,q,(2H); 4.28,t,(lH); 6.10,s, (2H); 6.4-6.5,m,(7H); 6.80,s,(ca 3H); 1.28,t,(2H); 7-73,s~
(6H). T.l.c. System B Rf 0.25.
b) l-methyl-N -[2-[~[5-[(dimethylamino)methyl~-2-furanyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine (1.55g) and acetic anhydride (0.5g) gave N-~l-methyl-5-[ [2- [ [ [5-[(dimethylamino)methyl]~2-furanyl]methyl]thio]
ethyl~amino]-lH,1,2,4-triazol-3-yl]acetamide, oxalate (1 ! 3g) m.p. 132-4~
N.m.r. (D2O): 3.30,d,(lH); 3.60,d,(lH); 5.67,s,(2H);
6.13,s,(2H); 6.45, s+t, (5H); 7.15,s~t, (8H) 7.80,s,(3H) c) l-methyl-N5-[2-[[[5-[(dimethylamino)methyl]-4-methyl-2-furanyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3, 5-diamine (lg) and acetic anydride (0.32 ml ) ga~e N-[l-methyl-5-[[2-[[~5-[(dimethylamino)me-thyl]-4-methyl-2-furanyl]methyl~-thio]ethyl]amino]-lH-1,2,4-triazol-3-yl]
acet~mide (0.5g).
T.l.c. System B Rf 0.4 N.m.r. (CDC13): 1.2,br.s.(lH); ~.05,s,(lH); 5.2,t,(1H);
6.4,s,(2H); 6.5-6.7,m,(7H); 7.25,t,(2H); 7.75,s,(9H);
8.10,s,(3TI).
d) l-methyl-N5-[3-[~ piperidinylmethyl)phenoxy]
propyl]-lEI-1,2,4-triazole-3,5-diamine(0.5g) and acetic anhydride (157mg) gave 1-methyl-N-[5-[C3-~4-(l-piperidinylmethyl)phenoxy]propyl]amino]-lH-1,2,4-triazol-3-ylJacetamide (0.58g).
N.m.r. (CDC13): 2.75,d,(2H); 3.18,d,(2H); 5.95,t,(2EI);
6.4-6.7,m,(2H); 6.55,s,(3H); 6.60,s,(2H) 7.5-8.1,m,(6.El);
7.87,s,(3H);8.3-8.7m,(6H) T.l.c. System A,R~ 0.52 Example 31 The following compounds were prepared using the method of Example 14:
a) l-methyl-N5~[3~3-(1-piperidinylmethyl)phenoxy]
propyl]-lH-1,2,4-triazole-3,5-diamine (A) (2.00g) and phenylacetylchloride(0.99g) ga~e N-[l-methyl-5-~[3-~3-(l-piperidinylmethyl)phenoxy]propyl]amino]-lH-1,2,4-triazol-3-yl~benzeneacetamide (0.92g) N.m.r. (CDC13): l.9,br,s, (lH); 2.70,2.80,s-~t,(6H);
3.0-3.3,m, (3H); 5.30,t,(lH); 5.98,t,(2H); 6.28,br.s,(2H) 6.55,s+s~q, (7H); 7.65,m,(4H); 8.0,m, (2H); 8.5,m,(6H).
T.l.c. System ~ r Rf 0.71 b) The trlazole (A) (2.00g) and benzoyl chloride (0.9Og) gave N-[l-methyl-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]-lH-1,2,4-triazole-3-yl~benzamide (1.05g) 6~-N.m.r. (CDC13): O.9,br,s,(lH); 2.00-2.25,m,(2Hl, 2O4-2~7,2.8,m~t, (4~1); 3.00-3.35,m,(3H); 5.22,t,(lH) 5.98,t,(2H); 6.50,6~55,6.60,s-~s-~q,(71-1); 7.60,m,(4H) 8.0,m,(2~1); 8.5,m,(6H);
Found: C, 66.77; 1l, 7.30; N,18.72;
C25~32 6 2 q C, 66.94; H, 7.19; N,18.74~6 F,xample 32 N-methyl-N'-[l~nethy ~ [3-[3-(1-piperidinylmethyl) ~
A mixture of l-methyl-N5-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]~lH-1,2,4-triazole-3~5-diamine (2.00g) and methylisocyanate (1~2g) in dry acetonitrile (60 ml) was heated at reflux for 2h. and allowed to cool. The precipitated solid was collected and recrystallised from methanol to give the title compound (1.9g) T.l.c. System B: Rf 0.71 N.m.r. (CDC13): 1.22,s,(lH); 2.07,q,(lH); 2.78,t,(lH);
3.00-3.30,m, (3H); 4.90,t,(lH); 5.90,t,(2H); 6.42,6.48, 20 6.58,q~s+s, (7H); 7.10,d,(3H); 7.60,7.90,m+m,(6H);
8~50,m,(6H).

Example 33 Ethyl- rS-u2-r ~rs-r (dimeth~ylamino~methyl]-2-thien~l~
meth llthiolethYllamino~ methYl-lH-l~2~4-triazole~3 Y_J
yl]carbamate A cooled mixture of ethylchloroformate (0.45g) in pyridine was trea-ted with a solution of N5-[2-[rr5-[(dimethylamino)methyl]-2-thienyl]methyl~thio]ethyl]-1-30 methyl-lH-1,2,4-triazole-3,5-diamine (0.7g) in pyridine (8 ml). Sodium carbonate (2g) and water (10 ml) were added and the mixture evaporated in vacuo. The residue was dissolved in water (15 ml) and extracted with hot isopropanol (30 ml). The extract was evaporated and the i8~ -residue puxified by column chromatography ~silica:methanol:
0.88 arnmonia; 79:l) to give the ~ (0.48g) T.l.c. System A Xf 0.6 N.m.r. (CDCl3) 1.8, brs (lH); 3.25,m,(2~I); 5.47,brt (l~1); 5.~8,q, (211); 6.13,s,(2~1); 6.~7,2s ~q, (711); 7.2~,t,(2H); 7.75,s,(6H); 8.73,t,(3H).

Example 34 The following compound was prepared using -the method of Example l6:
3-[4-~l-piperidinylmethyl)phenoxylpropanamine (0.61g) and methyl N-C2-(acetyloxy) acetyl~-l-methyl-2-(phenylmethylene) hydrazinecarboximidothioate (0.75g) gave 2-(acetyloxy)-N-[C[3-[4-(l-piperidinylmethyl) phenoxy]propyl]amino] [l-methyl-(2-phenylmethylene) hydrazino~methylene]acetamide (l,2g) T.l.c. System A RE 0 59 N.m.r. (CDCl3) 2.2,s,(lH); 2.3-2.45,m, (2H); 2.5-2.75,m, (3H); 2.85,d,(2H); 3.2,d,(2H); 5.4,s,(2H); 5.9,t,(2H), 6.45,q,(2H); 6.6,s,(3H); 6.64,s,(2H); 7.55-7.~,m,(6H) 7.85,s,(3H3; 8.3-8.6,m,(6H) The above acetamide (1.2g) was acidified to give l-methyl-N-[[3-C4-(l-piperidinylmethyl)phenoxy]
propyl]amino]-lH-l,2,4-triazole-3-methanol T.l.c. System A. Rf 0.6. N.m.r. (CDCl3) 2.?8,d,(2H) 3.20,d, (2H); 5.48,s, (2H); 5.94,t,(2H); 6.42,q,(2H);
6.52,s,(3H); 6.62,s,(2H~; 6.8,br,s,(lH); 7.68,m,(4H) 7.9,m,(2H); 8.3-8.7,m, (6H).

a,l-dimeth~l-N-[ L4-[3-(l-piperidinylmethyl) phenoxy]butyl]amino~ lH-l,2,4-triazole-3=methanol l-Methyl-N-C[4-[3-(l-piperidinylmethyl)phenoxy ]
~ amino] -lH-l,2,4-triazole-3-carbaldehyde Dimethyl sulphoxide (304mg) was added to a solution of oxalyl chloride (254mg) in dichloromethane (20ml) a-t -60 under nitrogen. The solution was stirred at -50 to -60 for 2 min and a solu-tion of l-methyl--N-[~4-c3-(l-piperidinylmethyl)phenoxy]butyllamino]
-1~-1-1,2,4 triazole-3-methanol (0.5g) in dichloromethane (lOml) was added. The mixture was stirred at -50 to -60 for 15 min and then quenched with triethylamine (657mg). The solution was allowed to warm to 25 and was diluted with water. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried and evaporated to leave the t le compound as a pale yellow oil (0.4g). N.m.r.
CDC13 0.2,s,(lH); 2.78,t,(lH), 3.0-3.3,m,(3H);
5.25,br,t, (lH); 6.06, br t, (2H); 6.40,s,(3H);
Ç.5,q, (2H); 6.60,s, (2~1); 7.68,br, (4H); 8.0-8.6,m, (lOH)~ Tlc System A Rf 0.55 a,l-dimethyl-N-C~4-~3-(l-pi~èridinylmethyl)phenoxyl_ butyl~amino~-lEI-1,2,4-triazole-3-methanol A solution of methyl lithium [(0.6m in ether), lOml] was added to a solution of the above carbaldehyde (0.4g) in -tetrahydrofuran (20ml) a-t 25 under nitrogen.
The mixture was stirred for 12 h, quenched with water and extrac-ted with ethyl acetate. The combined organic extracts were evaporated to give a yellow oil ~0.3g) Tlc System C Rf 0.3.

Example 36 Following the method of Example 23, N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximidothioate (0.75g) and 3-[3-[1-(4-hydroxypiperidinyl)methyl]phenoxy~propanamine (0.65g) gave 1-methyl-5-{[3-[3-[1-(4-hydroxypiperidinyl) methyllphenoxy]propyl]amino]-lEI-1,2,4-triazole-3-methanol (0.3g), -tlc Systern B Rf 0.~. NMR(CDC]3) 2.80,-t,(ll-I); 3~0-3O3,m,(3H); 4.63,t,(lH); 5.52,s,(2H);
5.8-6.1,m,(5H); 6.3-6.7,m,(7~1); 7.1-7.4,m,(2H) 7.7-8.7,m, (8H).

xam~ 37 l~me~yl-[5-[[3-[3 _l p~e _ inylmethyl)phenoxylpropyl~
amino]-lH-1,2,4-triazole--3-one The ~ollowing compound was prepared using the method of preparation 5:me-thyl 1-methyl-2-(phenylmethylene) hydrazinecarboximido thioate hydroiodide (2.35g) and methylchloro~ormate (0.58 ml) gave methyl-N-methoxycarbonyl-l-methyl-2-(phenylmethylene)hydrazinecarboximido-thioate (0.65g),m.p. 85-6.

The ~ollowing compound was prepared using the method o~ Example 16:
3-[3-(1-piperidinylmethyl)phenoxy]propanamine (0.62g) and methyl-N-methoxy carbonyl-l-methyl-2-(phenylmethylene) hydrazinecarboximidothioate (0.59g) gave methyl[[l-methyl-2-(phenylmethylene)hydrazino][[3-[3-(1-piperidinylmethyl) phenoxy]propyl]amino]methylene]carbamate (0.9g).
~lc silica; methanol. R~ 0.35.
The above carbamate (0.6g) was acidi~ied to give l-methyl-[5-~[3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino~-lH-1,2,4-triazole-3-one tartrate (0.03g);
Tlc System B. R~ 0.23 NMR (D20); 2.50,t,(lH); 2.8-3.0,m,(3H); 5.45,s,(2H);
5.8,s+m,(4H); 6.4-6.6,m,(4H); 6.73,s,(3H); 7.05,t,(2H);
7.7-8.6,m,(~H).

&~

-67a-3xample 38 The following compound was prepared using the me-thod of Example 23:
Methyl-N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximiclothioate (0.75g) and 3-~3 aminopropoxy) -N,N-climethylbenzenemethanamine tO.51g) gave l-methyl-5-[~3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino~
-lH-1,2,4-trazole-3-methanol (0.3g).
T.l.c. System B. Rf 0.52 N.m.r. (CDC13); 2.76,t,(lH); 3-3.3,m,(3H); 5.4-5.9,m, (6H); 6.42-6.64,m, (8H); 7.8-7.9,m,(8H).

-67b-Fxample ~9 .S-r~7)-r~-r(Phenylmethylamino~methrllphenox~ ro~yllamino~ 2,~L-A solution o~ 5-[[3-(3-formyl phenoxy)propyl]amino]-1-methyl-lE-1,2,4-triazole-3~e-thanol (532 mg) in e-thanol (15 ml) was treated with ben~ylamine (5 ml) and stirred at roorn temperat~re for 1.5h. ~he solution was -treated with sodiurn borohydride (500 mg) and stirred at room tempera-ture for 16h.
'~he mixture was evaporatbd, and the residue partitioned between 2~ hydrochloric acid and ethyl acetate. ~he aqueous layer was washed with e-thyl acetate, neu-tralised with potas~ium carbanate, and extracted with ethyl acetate. ~he combined extracts were dried and evaporated in vacuo to yield an oil. ~his oil was chroma-tographed on silioa gel, using a mixture of methanol-ethyl acetate (1:1) to give -the title compound as an oil (315 mg).
T.l.c. silica: methanol, Rf 0.5 N.m.r (CDCl3): 2.72,s+t,(6E); 3.0-3.3,m,(3H); 5.24,br.t,(1E); 5.52,s,(2E);
5.98,t9(2E); 6.1-607,m,~8E); 6.60,s,(3H); 7.98,m,(2H).

me following compound was similarly prepared from the above aldehyde (A) and l-heptylamine.
(1) A (558 mg) and l-heptylamine (5 ml) gave 5-[[3-[3-[(1-heptylamino)methyl~ ~, pheno~y]propyl]amino]-lE-1,2,4-tria~ole-3-methanol, as an oil (153 mg).
T.l~c. Silica; methanol Rf 0.3 . . .
N.m.r. (CDCl3): 2.80,t,(1E); 3.1-3.3,m,(3E); 5.50,9+m,(3E); 5.97,t,(2H);

6.30,s,(2H); 6.50,q9(2H); 6~58,s,(3H); 6.90,b9,(2E); 7.41,-t,(2H);

7.96,m,(2E); 8.3-8.9,m,(10); 9.2,bt,(3H).

1.

_. .. ~ .

-67c-Ex~nple ~0 N-rr)~rr4-r5-r(Dime-th~yla~nino~r~et~11-2-fura~yllbutyllarninol-l ~et~yl-lH-1,2 triazol-~-yl ~N ~phenyl urea N -~4-rS-r ~Tnet~ylarnino~met;~ -2-fura~yllbu-tyll l~n~thyl-1~-1,? 4-triazole-~, r)-diarninc-~, ~ mixture of N-cyano-l-methyl-2-~phenylmethylene)-hyclrazine carboxirnidothioic acid methyl es-ter (2.32g~ and 4-[5-[(aimethylaTnino)methyl]-2-furanyl]butana~ine (1.96g) was hea-ted at 60D under reduced water-pump pressure for lh. The residual oil was used without further purifica-tion, and stirred with 2N hydrochloric acid (lO ml~ ~
for 005h. me pE of the acidic solution was adjusted -to pH ~ wi-th potassiurn carbonate, and washed with toluene. ~n excess of potassium carbonate was added to the aqueous phase which was then extracted with e-thyl acetate. me organic extracts were dried and evaporated to give a solid which was recrystallised frome-thyl acetate to give the title com~ound as a white solid (2.1g), m.p. 105 C.

.
~sing -the method of Example 9:
-[4-[5-[(Dimethylamino)methyl]-2-~uranyl]bu-tyl]-l~ne-thyl-lE-1,2,4-tria~ole-3,5-diaTnine (0.73g) and phenylisocyanate (0025 ml) gave N-[5-[[4-[5-[(aimethylamino~
methyl]-2-furanyl]butyl~amino]-l~nethyl-1~-1,2,4-tria~ol-3-yl]-~ -phenyl urea (o.67g), m.p. 124-5.
T.l.c. system C~ Rf 0.42 ' ' ' ' , " '` ' '' '~ " ' ,' , ' '' ' .

., ' ' ; ''' ' ' . ~.
. .

-67d-Example 41 ~he following compound~ were prepared ueing the method of Example 23.
a) 4-~5-[(dimethylami~o)methyl~-2-furanyl]bu-tananline (1.96g) and me-thyl l~nethyl-N-phenyl-ace-tyl-2-(phenylme-thylene)hydrazinecarboximidothioate (3.25g) gave 5-[4-[5-[(dimethylamino)methyl]-2-furanyl]butyl]-l~nethyl-3-phenylm2thyl-lH-1,2,4-triazole-5-amine (2.0g).
rr l.c. cystem ~, ~ 0 52.
N.m.r. (CDC13): 2.6-2.9;m,(5~); 3.98,d,(1H); 4.13,d,(1~); 5.80,t~(1E);
6.13,s,(2H); 6.13,s,(Za); 6.60-6.65,m~(7H); 7.38,t,(2H); 7.80,a,(6H);
8.3.m.(4~)-b) 4-[5~[(Dimethylamino)methyl]-2-furanyl~bu-tanamine (l.lg) and N-~2-(acetyloxy)acetyl~-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate (1.9g) gave 5-[[4-[-[(dimethylamino~methyl~-2-furanyl]butyl]amino]-1-methyl-1~-1,2,4--triazole-3-methanol (0.5g).m.p.88-90 .
r~ 1 C. System C, Rf 0.34-.

, . ~ .

.

. _ _ _ _ . _ __ ~ __ , .. . . ..... _ __ _ _ ___ _ .... . ,. . .. _, . . . . . . .. . . . ...
.. . . . . . . ....

~7e-Example 42 ~ ethyl-5-~c3-[3~ ridin~]methyl)phenoxyJ~_op amlno-l~l 1,2,4-triazole-3-methanol,sulpha-te (1:1) l-Methyl-5-[[3-[3~ piperidinylme-thyl)phenoxy]propyl]
amino]-1~ 1,2,4-triazole-3-metilanol(300mg) was dissolved in ethyl aceta-te ;20ml) with heating and the addition of a few drops of ethanol to give a clear solution.
A 0.45 ml aliquot oE a hot solution of concentrated sulphuric acid (1~1) in ethanol (9ml) was added dropwise.
The solid which separated on cooling and standing was filtered off, washed with diethyl ester and dried in vacuo to give the title compound as a white crystalline solid (400mg)m.p. 170.

In a similar manner:

(b) A solution of the free base (300 mg) as in (a) above was treated with a hot solution of tartaric acid (125mg) in ethanol (lOml) to give the tartrate salt (2:1) as a white crystalline solid (50 mg), m.p~ 144 (c) A solution of free base (300 mg) as in (a) above was treated with ho-t solution of succinic acid (99mg) in ethanol (lOml) to give the succinate salt (2:1) as a white crystalline solid (150mg). m.p. 137.

1 Examples oE Pharmaceu-tical compositions according to the invention are as follows:
(a) TABLETSmg/-tablet mg/tablet Active incredient20.0 40-0 Microcrystalllne99.5 199.0 cellulose BPC
Magneslum stearate B.P. 0.5 1-0 Compression weight 120.0 240.0 The drug is seived through a 250 ~m sieve, blended with the excipients and compressed using 6.5 mm and 8.0 mm diameter punches for the 20 and ~0 mg strengths respectively.
Tablets of other streng-ths may be prepared by increasing the compression weight and using punches to suit.
The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose, ethyl cellulose or hydroxypropylmethyl cellulose, using standard techniques.
Alternatively the tablets may be sugar coated.
` (b) CAPSULES mg/capsule Active ingredient 20.0 **Sta-Rx 1500 Starch 79.5 Magnesium Stearate B.PØ5 Fill weight100.0 ** A form of directly compressible starch supplied by Colorcon Ltd. Orpington, Kent.
The active ingredien-t is sieved through a 250 ~Im sieve and blended with other materials. The mix is filled into No. 3. hard gelatin capsules using a suitable filling machine. Other doses may be prepared by increasing the fill weight and if necessary changing the ~ Trade Mark - ~9 - ~

l capsule size to accommoda-te the increase.
(c) SUSTAINED RELF,ASE TABLETS mg/-tablet Active ingredient ~0 *Cutina HR 25 I,actose B.P. 142.5 MacJnesium Steara-te B . P . 2.5 Compression weight 250.0 *Cutlna HR is a grade of microfine hydrogenated castor oil supplied by Sipon Products Ltd., London.
The drug is sieved through a 250 ~m sieve and blended with Cutina HR~ and lactose. The mixed powders are moistened with Industrial Methylated Spirits 74 O.P., granules are made, dried, screened and blended with the magnesium stearate. The lubricated granules are compressed using ~.5 mm punches to produce tablets with a hardness of not less than 10 Xp (Schleuniger tester).
(d) IN~ECTION FOR INTR~VENOUS ADMINISTRATION
% w/v Active ingredient 0.25 Water for Injections BP to 100.00 Sodium chloride may be added to adjust -the tonicity of the solution ana 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 into appropriate sized ampoules sealed by fusion of the 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.

~ Trade Mark -~Q-(e) SYRUP mg/5ml dose Active ingredient 20.0 mg Sucrose 2750.0 mg Glycer:ine 500.0 mg BufEer Flavour ) as necessary Colour Preservative ) 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 80C and the sucrose is dissolved in this and cooled. The two solutions are mixed, adjusted to volume and clarified by filtration.

Claims (58)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds of the general formula (I) and physiologically acceptable salts and hydrates thereof, in which Rl and R2 which may be the same or different, each respresent hydrogen, Cl-10 alkyl, cycloalkyl, alkenyl, aralkyl, trifluoroalkyl, or alkyl, substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino, or Rl 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 Cl-3 alkyl groups or a hydroxy group and/or may contain another heteroatom which is oxygen or sulphur;
Alk represents a straight or branched alkylene chain of 1 to 6 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 ring optionally bearing a further substituent R6 adjacent to the group RlR2N-Alk-, or Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4- positions;

Claim 1 continued...

RG represents halogen or C1-4 alkyl which may be substituted by hydroxy or Cl-4 alkoxy;
X represents -CH2-, -O-, -S- or -N- where R5 represents hydrogen or methyl; n represents zero, 1 or 2, m represents 2, 3 or 4;
R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl with at least two carbon atoms, alkoxyalkyl or aryl; and R4 represents hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino-alkyl, hydroxy, alkoxy, alkylthio or halogen, which comprises selecting a process from the group of processes consisting of:
(a) for the production of compounds in which R4 represents a halogen atom or a hydrogen atom, converting the group in a diazonium salt (III) (III) in which Rl, R2 and R3 are as defined in formula (I) or are groups convertible thereto, Alk, Q, n, X and m are as defined in formula (I) and Y is the anion corresponding to the acid used in the diazotisation reaction, into a halogen atom or a hydrogen atom;
(b) for the production of compounds in which R4 is other than a halogen atom or an alkoxy, alkythio or acyloxyalkyl Claim 1 continued...
group, cyclising a compound of formula (V) (V) in which Rl, R2, Alk, Q, X, R3, n and m are as defined in formula (I) and V' is and Y' is hydrogen where V is oxygen or sulphur and R4 is a group as defined for R4 or a group convertible thereto under the conditions of the cyclisation reaction or represents halogen or alkoxy;
or V' is NH and Y' is CR4 where Y
is sulphur, oxygen or NH, except that when R4 is halogen or alkoxy Y cannot be NH, or V' is sulphur or oxygen and Y' is CR4, with optional protection and subsequent deprotection of any reactive groups in the starting material if desired;
(c) reducing a compound of foxmula (XV) (XV) in which Q,n,X,m and R3 are as defined in formula (I), at least one of Da, Db and Dc represents a reducible group and the other(s) take the appropriate meaning corresponding to formula (I), Da represents R1R2NAlk- or a group convertible thereto under reducing conditions where R1, R2 and Alk are as defined in formula (I);
Db represents -CH2NH-, -CONH- or -CE=N-Dc represents R4 as defined in formula (I) or a Claim 1 continued...

group convertible thereto under reducing conditions, with optional protection and subsequent deprotection o any reactive groups in the starting material if desired;

(d) reacting a compound of formula (XX) RlR2NAlkQE (XX) in which E represents (CH2)nX(CH2)mP or CH2P'where P
and P' are leaving groups, with a triazole of the formula (XVII):

(XVII) where U represents amino, HS (CH2)mNH or H0 (CH2)mNH, and R4 is as defined in formula (I) or is a group convertible thereto with optional protection and subsequent deprotection of any reactive groups in the starting material if desired;

(e)(i) for the production of compounds of the general formula (I) wherein Alk represents a methylene group and Q represents a furan or substituted furan ring as defined in formula (I), subjecting a compound of the general formula (XXI):

(XXI) in which Q represents a furan or substituted furan ring as defined in formula (I) and n, m, X, R3 and R4 are as defined hereinbefore, to a Mannich reaction with formaldehyde and an amine RlR2NH or a salt thereof;

Claim 1 continued...

(ii) for the production of compounds of the general formula (I) wherein Rl and R2 are both methyl, Alk is methylene and Q represents a thiophene ring, a furan ring or a substituted furan ring as defined in formula (I), reacting a compound of the formula (XXI) as defined in Claim l(e) in which Q may additionally represent a thiophene ring, with a compound (f) for the production of compounds in which R4 is a secondary or tertiary hydroxyalkyl group, treating the corresponding compound where R4 is the group (CH2)q-lCHO, (CH2)q-lC02R12 or (CH2)rCOR12 in which q is an integer from 1 to 6 inclusive, r is O to 4 and R12 is an alkyl group, with an organometallic derivative;

(g) reacting compound of formula (XXII) (XXII) where either La is RlR2N and Lb is the group (CH2)qL or La is a group Ld and Lb is R4, where Lc and Ld are leaving groups and q is an integer from 1 to 6 inclusive, with a compound capable of replacing La by RlR2N or Lc so as to convert Lb into the group R4 with optional protection and subsequent deprotection of any reactive groups in the starting material if desired;
(h)(i) for the production of compounds of the general formula (I) in which R4 is an alkoxyalkyl group, treating a corresponding compound of formula (I) in which R4 is a hydroxyalkyl group with an appropriate alkylating agent;
1. Claim 1 continued ..
   
   (ii) for the production of compounds of the general formula (I) in which R4 is a dimethylaminoalkyl or methylalkylaminoalkyl group, treating a corresponding compound of formula (I) in which R4 is a primary or secondary aminoalkyl group with formaldehyde and formic acid;
   (i) for the production of compounds in which R4 is an acyloxyalkyl group, treating the corresponding hydroxyalkyl compound with an appropriate acid at elevated temperature;
   or (j) for the production of compounds in which R4 is a hydroxyalkyl group removing a hydroxyl protecting groùp from the hydroxyl group; and (k) for the production of a physiologically acceptable salt of the compound of the general formula (I), as defined hereinbefore, selecting a process from the group of processes consisting of the processes defined in parts (a) to (j) and converting the free base into a physiologically acceptable salt.
2. 2. Compounds of the general formula (I) as defined in claim 1 and the physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
3. 3. A process as claimed in claim l(a).
4. 4. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim l(a), whenever prepared by the process as claimed in claim 3 or an obvious chemical equivalent thereof.
5. 5. A process as claimed in claim l(b).
6. 6. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim l(bl, whenever prepared by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. 7. A process as claimed in claim l(c).
8. 8. Compounds of the general formula (I) as defined in claim 1 whenever prepared by the process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. 9. A process as claimed in claim l(d).
10. 10. Compounds of the general formula (I) as defined in claim 1 whenever prepared by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. 11. A process as claimed in claim l(e).
12. 12. Compounds of the general formula (I) as defined in claim l(e) whenever prepared by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. 13. A process as claimed in claim l(f).
14. 14. Compounds of the general formula ()~ as defined in claim 1 wherein R4 is defined in claim 1 (f) whenever prepared by a process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. 15. A proeess as claimed in claim l(g).
16. 16. Compounds of the general formula (I) as defined in claim 1 whenever prepared by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. 17. A process as claimed in claim l(h).
18. 18. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim l(h) whenever prepared by a process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. 19. A process as claimed in claim l(i).
20. 20. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim l(i) whenever prepared by a process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. 21. A process as claimed in claim l(j).
22. 22. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim l(j) whenever prepared by a process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. 23. A process as claimed in claim l(k).
24. 24. Physiologically acceptable salts of the compounds of the general formula (I) as defined in claim 1 whenever prepared by the process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. 25. A process as claimed in claim 1 wherein R4 represents hydrogen, alkyl, alkenyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy or halogen; provided that when X represents an oxygen atom or -NR5- and when n is zero then Q represents benzene.
26. 26. Compounds of the general formula (I) as defined in claim 1 and the physiologically acceptable salts thereof wherein R4, X and n and Q are defined in claim 25 whenever prepared by a process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. 27. A process as claimed in claim 1 wherein Q
    represents benzene incorporated into the molecule through bonds at the 1- and 3- positions, n is zero and X is oxygen.
28. 28. Compounds of the general formula (I) as defined in claim 1 and the physiologically acceptable salts thereof whenever prepared by the process as claimed in claim 27 or an obvious chemical equivalent thereof.
29. 29, A process as claimed in claim 1 wherein m+n is 3 or 4.
30. 30. Compounds of the general formula (I) as defined in claim 1 and the physiologically acceptable salts thereof whenever prepared by the process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. 31. A process as claimed in claim 1 wherein Alk is -CH2-.
32. 32. Compounds of the general formula (I) as defined in claim 1 and the physiologically acceptable salts thereof whenever prepared by the process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. 33. A process as claimed in claim 1 wherein R 1 represents hyclrogen or C1-4 alkyl and R2 represents C3-5 alkenyl, C5-7 cycloalkyl, benzyl, Cl-8 alkyl or Cl-4 alkyl substituted by Cl-3 alkoxy, hydroxy, di-Cl-3 alkylamino or trifluoromethyl or Rl and R2 together with the nitrogen atom to which they are attached form a ring with 5 to 8 members and optionally containing one double bond and/or substituted by hydroxy or one or two methyl group(s).
34. 34. Compounds of the general formula (I) as defined in claim 1 wherein Rl and R2 are defined in claim 33 and the physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. 35. A process as claimed in claim 1 wherein Rl and R2 represent Cl-3 alkyl, or Rl and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring which is pyrrolidine, piperidine optionally substituted in the 4-position by methyl or hydroxy, tetrahydropyridine, morpholine,2,6-dimethylmorpholine, hexamethyleneimine or heptamethyleneimine.
36. 36. Compounds of the general formula (I) as defined in claim 1 wherein Rl and R2 are defined in claim 35 and the physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 35 or an obvious chemical equivalent thereof.
37. 37. A process as claimed în claim 1 wherein R3 represents hydrogen, alkyl or C2-4 hydroxyalkyl.
38. 38. Compounds of the general Eormula (I) as defined in claim 1 wherein R3 is defined in claim 37, wherein the physiologically acceptable salts thereof, whenever prepared by the process as claimed in claim 37 or an obvious chemical equivalent thereof.
39. 39. A process as claimed in claim 1 wherein R4 represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, aralkyl or hydroxy.
40. 40. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim 39, and the physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 39 or an obvious chemical equivalent thereof.
41. 41. A process as claimed in claim 1 wherein R4 represents hydroxyalkyl, hydroxy, alkoxyalkyl or benzyl.
42. 42. Compounds of the general formula (I) as defined in claim 1 wherein R4 is defined in claim 41, and the physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 41 or an obvious chemical equivalent thereof.
    
    ~\~
43. 43. A process as claimed in claim 1 for the preparation of compounds of the general formula (II):
    
    (II) where R1 and R2 are methyl groups or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexamethylenemino group; m is 3 or 4; R3 is hydrogen or methyl, and R4 is a hydroxyalkyl, alkoxy-alkyl, benzyl or hydroxy group.
44. 44. Compounds of the general formula (II) as defined in claim 43 and the physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 43 or an obvious chemical equivalent thereof.
45. 45. A process as claimed in claim 1 which comprises treating l-methyl-5-[[1-oxo-4-[3-(1-piperidinylmethyl)-phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxylate with a reducing agent.
46. 46. 1-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]
    propyl]amino)-]-1H,2,4,-triazole-3-methanol and physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 45 or an obvious chemical equivalent thereof.
47. 47. A process as claimed in claim 1 which comprises treating the product formed from the reaction of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine with methyl N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)hydrazine-carboximidothioate, with an acid to effect cyclisation.
48. 48. l-Methyl-5-[[3-[3-(l-piperidinylmethyl)phenoxy]
    propyl]amino]-l?-l,2,4-triazole-3-methanol and physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 47 or an obvious chemical equivalent thereof.
49. 49. A process as claimed in claim l for the preparation of l-methyl-5-[[3-[3-(l-piperidinylmethyl)-phenoxy]propyl]amino]-lH-1,2,4-triazole-3-methanol as its sulphate, tartrate or succinate salt which comprises treating l-methyl-5-[[3-[3-(l-piperidinylmethyl)phenoxy]-propyl]amino]-lH,1,2,4-triazole-3-methanol with sulphuric acid, tartaric acid or succinic acid.
50. 50. l-Methyl-5-~[3-[3-~l-piperidinylmethyl)phenoxy]-propyl]amino]-l~-1,2,4-triazole-3-methanol as its sulphate, tartrate or succinate salt whenever prepared by a process as claimed in claim 49 or an obvious chemical equivalent thereof.
51. 51. A process as claimed in claim 1 which comprises treating 2-(acetyloxyl)-N-[[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]amino]-l-methyl-2-(phenylmethylene)-hydrazino]methylene]acetamide with an acid to effect cyclisation.
52. 52. 5-[[2-[[[5-[(Dimethylamino)methyl]-2-furanyl)methyl]
    thio]ethyl]amino]-l-methyl-lH-1,2,4-triazole-3-methanol and physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 51 or an obvious chemical equivalent thereof.
53. 53. A process as claimed in claim 1 which comprises treating the product formed from the reaction of 5-[[(2-aminoethyl)-thio]methyl]-3,N,N-trimethyl-2-furan-methanamine with methyl N-[2-(acetyloxy)acetyl]-1-methyl-2(phenylmethylene)hydrazinecarboximidothioate, with an acid to effect cyclisation.
54. 54. 5-[12-[[[5-[(Dimethylamino]methyl]-4-methyl-2-furanyl]methyl]thio]ethyl]amino]-l-methyl-lH-1,2,4-triazole-3-methanol and physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 53 or an obvious chemical equivalent thereof.
55. 55. A process as claimed in claim 1 which comprises treating the product formed from the reaction of 3-(3-aminopropoxyl)-N,N-dimethyl-benzenemethanamine with methyl N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)-hydrazine carboximidothioate, with an acid to effect cyclisation.
56. 56. 1-Methyl-5-[[3(~3-[(dimethylamino)methyl]phenoxy]
    propyl]amino]-lH-1,2,4-triazole-3-methanol and physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 55 or an obvious chemical equivalent thereof.
57. 57. A process as claimed in claim 1 which comprises treating the product formed from the reaction of 3-(3-(.1-piperidinylmethyl)phenoxy]propanamine with dimethyl N-methoxycarbonylcarbonimidothioate, with hydrazine hydrate to effect cyclisation.
58. 58. 5-[[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]-amino]-lH-1,2,4-triazole-3-one and physiologically acceptable salts thereof, whenever prepared by a process as claimed in claim 57 or an obvious chemical equivalent thereof.