HETEROCYCLIC DERIVATIVES

Abstract: The invention relates to compounds of the general formula (I) and physiologically acceptable salts, hydrates and bioprecur­ sors thereof, in which R₁ represents hydrogen, C₁₋₁₄ alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroaralkyl or alkyl substi­ tuted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino; and R₂ represents hydrogen or C₁₋₄ alkyl group; or R₁ and R₂ together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C₁₋₃ alkyl groups or a hydroxy group and/or may contain another heteroatom selected from oxygen or sulphur: Alk represents a straight or branched alkylene chain of 1 to 3 carbon atoms; 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: R₅ represents hydrogen or acyl; n and m, which may be the same or different, are each 1 or 2; Z represents one of the groups where X represents NCN, NSO₂Methyl, NSO₂Phenyl or CHNO₂; R₈ represents alkyl; A represents N and B represents CR₇; or A represents CR₇ and B represents N; or A and B both represent N; R₃ represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy C₂₋₆ alkyl, alkoxy C₂₋₆ alkyl or C₁₋₄ alkanoyloxy C₂₋₆ alkyl;

Description: Heterocyclic Derivatives This invention relates to novel heterocyclic derivatives having action on histamine receptors, to processes for the preparation thereof, to pharmaceutical compositions containing them and two their use in therapeutics. Certain novel heterocyclic derivatives have now been found which have potent activity as H2-antagonists. These compounds, which are more particularly described below, for example show inhibition of the secretion of gastric acid when this is stimulated via histamine receptors (Ash and Schild, Brit. J. Pharmacol. Chemother, 1966, 27, 427). Their ability to do so can be demonstrated in the perfused rat stomach using the method described in British Patent Specification Number 1565966, modified by the use of sodium pentobarbitone (50 mg/kg) as anaesthetic instead of urethane, and in conscious dogs equipped with Heidenhain pouches using the method described by Black et al, Nature 1972 236, 385 Furthermore, the compounds antagonise the effect of histamine on the contraction frequency of isolated guinea pig right atrium. Compounds with histamine 112-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 treatr-nt of allergic and inflammatory conditions where histamine is a known mediator. Thus they may be used for exarele, either alone or in combination with other active ingrenients in the treatment of allergic and inflammatory conditions of the skin. The present invention provides compounds of the general formula (I). EMI2.1 and physiologically acceptable salts, hydrates and bioprecursors thereof, in which R1 represents hydrogen, C1-14 alkyl, cycloalkyl alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroaralkyl or alkyl substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylainino or dialkylamino; and R2 represents hydrogen or C1-4 alkyl group; or R1 and R2 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 C13 alkyl groups, e.g. methyl, or a hydroxy group and/or may contain another heteroatom selected from oxygen or sulphur; Alk represents a straight or branched alkylene chain of I to 3 carbon atoms; Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1and 3- or l- and 4- positions; R5 represents hydrogen or acyl; n and m, which may be the same or different, are each 1 or 2; ; Z represents one of the groups EMI2.2 whre X represents NCN, NSO2 Methyl, -32 Phenyl or CHNO2; R8 represents alkyl; A represents N and B represents CR7; or A represents CR7 and B represents N; or A and B both represent N; R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy C2-6 alkyl, alkoxy C26 alkyl or C1-4 alkanoyloxy C2-6 alkyl; ; R7 represents hydrogen, alkyl, alkenyl, aralkyl, acyloxyalkyl, alkylthioalkyl, arylthioalkyl, aryloxyalkyl, aralkyloxyalkyl, or the group (CH2)qR6 where q is zero, 1, 2, 3, 4, 5 or 6 and the alkylene chain (CH2)q may be straight or branched, and R6 is hydroxy, alkoxy, nitro, heteroaryl, tetrahydropyranyloxy or CH2NHC (=X)NHR9 where X is as defined above and Rg is alkyl; or R6 is the group NRloRll where R10 is hydrogen or alkyl; and R11 is hydrogen, alkyl, alkenyl, aryl, aralkyl, or heteroaralkyl, or R11 is the group SO2R12 where R12 is alkyl or aryl; or R11 is the group COR13 where Rl3 is hydrogen, alkyl, aryl, aralkyl, alkoxy, halomethyl, heteroaryl, heteroaralkyl or the group NHR14 where R14 is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; or R10 and R11 together represent the group =CR15Rl6 where R15 represents aryl or heteroaryl and R16 represents hydrogen or alkyl; or R6 is the group S02R17 in which R17 is hydroxy, alkyl, aryl or the group NR18R19 here Rl8 and R19, which may be the same or different, each represent hydrogen or alkyl; or R6 is the group COR20 where R20 is hydrogen, hydroxy, alkoxy, arylo::y, aralkyloxy, alkyl, aryl, aralkyl or the group NR21R22 where R21 is hydrogen or alkyl optionally substituted by a hydroxy or alkoxy group; and R22 is hydrogen, alkyl (optionally substituted by a hydroxy or alkoxy group), alkenyl, aryl, aralkyl or cycloalkyl, or NR21R22 forms a 5 to 8 membere. ring which may contain another heteroatom, e.g. oxygen, or a double bond and/or may be substituted by hydroxy or one or two C13 alkyl (e.g. methyl) groups; or R6 is the group CR23=NR24 where R23 is hydrogen alkyl, aryl or aralkyl and R24 is hydroxy, alkoxy, aralkyloxy or -NHC(=Y)NH2 where Y is oxygen or sulphur; or when A represents CR7 and B represents N, the groups R3 and R7 taken together represent (CH=CH)2 or -(CH2)4-; with the proviso that when the group R6 contain a carbon atom through which it is linked to the alkylene group (CH2) q then the total number of carbon atoms in the resulting chain is not greater than 6 (i. e. q is not greater than 5); R4 represents phenyl, phenoxy or pyridinyl which may optionally be substituted by one or more halogen, alkyl, alkoxyalkyl or alkoxy groups or by a methylenedioxy group; p represents an integer which is 1, 2 or 3. The term "alkyl" as a group or part of a group means that the group is straight or branched, and unless otherwise stated, has preferably I to 6 carbon atoms and in particular 1 to 4 carbon atoms, e.g. methyl or ethyl; and the terms 11alkenyl" and "alkynyl" mean that the groups preferably contain 3 to 6 carbon atoms. The term "cyclo- alkyl" means that the group has 3 to 8 carbon atoms. The term "halomethyl'! means a mono-, di- or trihalo substituted methyl group, e.g. trifluoromethyl. The term "aryl" as a group or part of a group preferably ans phenyl or substituted phenyl, for example phenyl substituted with one or more C13 alkyl or alkoxy group or halogen atoms, e.g. fluorine. The term acyl or the acy' portion of an acyloxyalkyl group-means an aroyl, arali-anoyl or C16 alkanoyl group. Examples of acyloxyalkyl groups include acetoxymethyl, formyloxymethyl, benzoyloxymethyl and phenylacetoxymethyl. The term heteroaryl as a group or part of a group means a 5 or 6 membered monocyclic ring containing from l to 3 heteroatoms selected from oxygen, nitrogen and sulphur, e.g. thienyl, pyrrolyl, pyridyl, furyl or thiazolyl. The heteroaryl ring may be unsubstituted or substituted by C1-3 alkyl, C1-3 alkoxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen, for example, the heteroaryl ring may be thienyl or furyl substituted by C13 alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl. or hydroxyalkyl, pyrrolyl substituted by C1-3 alkyl, pyridyl substituted by C1-3 alkyl, C1-3 alkoxy, halogen or hydroxyalkyl or thiazolyl substituted by C1-3 alkyl or hydroxyalkyl The alkyl portion of a heteroaralkyl group is a straight or branched C14 alkyl chain, and the heteroaryl ring is linked to the alkyl portion through a carbon atom. According to one aspect the invention provides compounds of formula (I) in which Z is EMI5.1 R5 represents hydrogen or a C1-4 alkanqyl group; R4 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy C2-6 alkyl, or alkoxy C26 alkyl; R7 is as defined in formula (I) except that R6 does not represent tetrahydropyranyloxy; and R1, R2, Alk, Q,n and m are as defined in formula (I) According to a second aspect the invention provides compounds of formula (I) in which Z is EMI5.2 R5 represents hydrogen or a C14 alkanoyl group; and R1, R2, R3, Alky Q, m and n are as defined in formula (I). According to a third aspect the invention provides compounds of formula (I) in which Z is EMI6.1 R5 represents hydrogen or a C1-4 alkanoyl group; and R1, R2r R4, Alk, Q, m, n and p are as defined in formula (I). According to a fourth aspect the invention provides compounds of formula (I) in which z is EMI6.2 R5 represents hydrogen or a C1-4 alkanoyl group; R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy C2-6 alkyl or alkoxy C26 alkyl; R7 is as defined in formula (I) except that R; does not represent tetrahydropyranyloxy; and R1, R2, Alk, Q, n and m are as defined in formula (I). Preferred compounds of formula (I) are those in which R1 represents C1-8 alkyl (e.g. methyl, propyl, butyl or heptyl), C1-4 alkyl substituted by a trifluoro methyl group (e.g. 2,2,2-trifluoroethyl), C2-4 alykl substituted by hydroxy or a di C1-3 alkyl amino group (e.g. 3-hydroxypropyl or dimethylamino ethyl), C5-7 cycloalkyl (e.g. cyclohexyl), C35 alkenyl (e.g. allyl), phenyl C1-3 alkyl (e.g. benzyl), or a heteroaryl C1-3 alkyl group where the heteroaryl ring contains one heteroatom (e.g. 2-furylmethyl); R2 represents hydrogen or methyl; or R1R2N represents a 5 to 7 membered.ring optionally containing a double bond, an oxygen atom or an alkyl (e.g. methyl) substituent (e.g. piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethylenimino or tetrahydropyridino); Alk represents methylene; R3 represents hydrogen, alkyl (e.g. methyl-or ethyl), hydroxy C2 2-4 alkyl (e.g. hydroxyethyl) or, when A is the group CR7, then R3 and R7 taken together represent EMI7.1 or -(CH2)4-; or Q ° represents a benzene ring incorporated into the rest of the molecule through bonds at the 1- and 3- positions; R5 represents hydrogen or alkanoyl (e.g. acetyl ); n and m both represent 1 or one of n and m represents 2; R7 represents alkoxyalkyl, alkylthioalkyl, alkanoyl oxyalkyl, benzyl, or -CH=NOH; or R7 represents the group (CH2)qR6 where q is zero, 1, 2 or 3,and R6 represents hydroxyl, CH2NHSO2R12 (where Rl2 is alkyl), CH2NHC(=X)NHCH3 (where X=NCN or CHNO2), SO2Rl7 (where R17 is alkyl), or R6 represents COR20 where R20 is hydroxyl or NR21R22 and R21 and R22 indepenenily represent hydrogen or C1-3 alkyl or R21 and R22 together with the nitrogen atom to which they are attached represent a pyrrolidino ring, or R6 represents the group NR10R11 where Rio represents hydrogen and R11 is hydrogen or COR131 where R13 represents hydrogen, alkyl, phenyl, benzyl, alkoxy, NH phenyl, or R10 and R11 together represent the group =CHR15 where R15 is phenyl or pyridyl; R4 represents pyridinyl (e.g. 3-pyridinyl) optionally substituted by an alkyl (e.g. methyl) group; or a phenyl group optionally substituted by an alkoxy (e.g. methoxy) group; p represents 1; R8 represents alkyl (e.g. methyl); X represents CHNO2. When Z represents the group EMI8.1 then preferably A is N and B is CR7 or A and B are both N. A further preferred class of compounds of formula (I) are those of formula (II) EMI8.2 in which R1R2N is dimethylamina, pyrrolidino, piperidino or hexamethylenimino, more preferably piperidino and Z represents EMI8.3 where, when B represents CR7, then R3 is hydrogen or methyl and R7 is hydroxymethyl, amino, alkanoyloxyalkyl (preferably acetoxymethyl), N = CHPh, (CH2)3 NHC(=CHN02)NHMe, aminopropyl, methylsuiphonylmethyl or acetylamino; or when A is CR7 then R3 is methyl and R7 is amino or R3 and R7 together form the group tCH-Ht2 or (CH2)4; or when A and B both represent N then R3 is methyl; and R4 is 3-pyridinyl, 6-methyl-3-pyridinyl or 4-methoxyphenyl Particularly preferred compounds are 1-[(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)amino]-3-[3 (1-piperidinylmethyl)phenoxy]-2-propanol; 5-[r2-hydroxy-3-[3-(l-piperidinvlmethyl)phenoxygpropyl] amino]-l-methyl-lH-1,2,4-triazole-3-methanol; l-r(l-methyl-lH-tetrazol-5-yl)amino]-3-[3-(l-piperidinyl- methyl) -phenoxy] -2-propanol; 2- r [ 2-hydroxy-3-[3-(l-piperidinylmethyl)phenoxy]propyl] amino]-5-[(6-methyl-3-pyridinyl)methyl]-4-(3H)-pyrimidinone; 2-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-5-(3-pyridinylmethyl)-4(3H)-pyrimidinone; 2-[t2-hydroxy-3- r 3-(l-piperidinylmethyl)phenoxy]propyl] amino]-5-[(4-methoxyphenyl)methyl]-4(3H)-pyrimidinone; and physiologically acceptable salts thereof. The invention includes the compounds of formula (I) in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, acetates; maleates, succinates, citrates, tartrates, fumarates and benzoates. The compounds of formula (I) and their salts may also form hydrates, which hydrates are also to be considered as part of the invention. The compounds cf formula (I) can exhibit tautomerism and the formula is intended to cover all tautomers. Where optical isomers may exist the formula is intended to cover all diastereoisomers and optical enantiomers. The term bioprecursnrs as used nerein means compounds which have a structure different to that of the compounds or formula (I) but which, upsn administration to the animal or human being are converted in the body into a compound of formula (I). The compounds according to the invention preferably in the form of a salt may be formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such compositions may also contain if requid 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 preferred. For oral administration, the pharmaceutical compositions may take the form of for example, tablets, capsules, powders, soluticns, syrups or suspensions prepared by conventional means with acceptable excipients. For buccal administration the composition may take the 43rm of tablets or lozenges formulated in conventional manner. The compounds of the invention may be forirralated for parenteral administration by bolus injection or continuous infusion. Formulations for inJection may be presented in unit dosage form in ampoules, or in multi- dose containers, with an added preservative. The compositions may take such forms as suspenions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder. form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free.water forte use. The compound of the invention ray also be formulates in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride. For topical application, the compounds of the invention may be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner. For internal administration a convenient daily dosage regime of the compounds according to the invention would be 1 to 4 doses to the total of some 5 mg to 1.5 g per day, preferably 5 to 500 mg per day dependent upon the condition of the patient. It will be appreciated that in the methods of the preparation of compounds of formula (I) given below, for certain reaction steps it may be necessary to protect various reactive substituents in the starting materials for a particular reaction artd subsequently to remove the protecting group. Such protection and subsequent deprotection may be particularly pertinent where R1 and/or R2 in intermediates used to prepare compounds'of formula (I) are hydrogen atoms and/or when R3 in intermediates is an alkyl group bearing a hydroxy substituent and/or when R7 in certain intermediates is an alkyl group bearing a hydroxy or primary or secondary amino substituent and/or when R5 in intermediates is a hydrogen atom. Standard protection and deprotection procedures can be empolyed. For example an amino group may be protected by formation of a phthalimide which may subsequently be cleaved by treatment with a hydrazine e.g. hydrazine hydrate or a primary amine, for example methylamine; or by formation of a benzyl derivative which may subsequcntly be cleaved by hydrogenolysis in the presence of a catalyst e.g. palladium. When A and B both represent N and R3 is hydrogen, this may be protected by formation of a Nalkoxyalkyl (e.g. ethoxymethyX derivative which may subsequently be cleaved by treatment with dilute acid. The hydroxyl group OR5 where R5 is hydrogen may be protected, for example as an acyloxy grt or as an ether group such as trialkylsilyl e.g. trimethylsilyl, aralkyl such as benzyl, benzhydryl or trityl, tetrahydropyranyl or alkoxymethyl, e.g methoxymethyl ethers. Such protecting groups may be removed by conventional procedures cf JFW McOmie. For example, benzyl and benzhydryl ether groups may be removed by catalytic hydroqenolysis with for example hydrogen and a palladium catalyst, and trityl, tetrahydropyranyl, alkoxymethyl and trialkylsilyl ether groups may be removed by acid hydrolysis. In describing the processes which may be used for preparing the compounds of formula (I) or intermediates useful in the preparation thereof, any of R1 to R24 Alk, Q, Z, p, n and mare as"defined in formula (I) unless otherwise stated. Compounds of formula (I) may be prepared by cyclisation of an appropriate intermediate. Thus, compounds of formula (I) in which R5 represents hydrogen and Z represents the group EMI12.1 where either A represents CR7 and B represents N or A represents N and B represents CR7, and R7 is other than acyloxyalkyl, alkoxy, nitro, (CH2)gN=CRl,Rl6, SQ2Rl7, COR20 (where R20 is hydrogen, aryl or aralkyl) or CR23=NR24, or when A represents CR7 and B reprezents N then R3 and R7 may not represent the group fCH=CHt2 or -(CH2)4- may be prepared by cyclising a compound of formula (III) EMI12.2 in which R25 is as defined for R3., V' is EMI13.1 or NCN and Y' is hydrogen where V is oxygen or sulphur and R7'is a group as defined for R7 or a group convertible thereto under the conditions of the cyclisation reaction or R7' represents halogen or alkoxy; or V' is NR3, R25 is hydrogen and Y' is EMI13.2 where.Y" is sulphur, -oxygen or NH. Thus for example in one embodiment of the cyclisation process a compound of formula (I) in which A is N and B is the group CR7 may be prepared by cyclisation of a compound of formula (IV) EMI13.3 in which V' is-NCN or NC(=V)R7' where R7' is as defined above, V represents sulphur or more preferably oxygen and U represents two hydrogen atoms, in the absence or, presence of a solvent, e.g. acetone or water, and optionally with heating. It may be convenient to prepare in situ compounds of formula (IV) in which U represents two hydrogen atoms -by treating a compound of formula (IV) where U represents a divalent protecting group which can readily be removed to yield two hydrogen atoms, for example a benzylidene group, with an acid, e.g. hydrochloric acid, optionally in the presence of an additional solventr e.g. toluene and conveniently at a temperature of 10-500C. Under such conditions cyclisation to give thc orresponding compound of formula (I) will normally occur. In general the intermediate of formula (IV) may be prepared from the appropriate diamines by methods analogous to those described in British Patent Specifications Numbers 2047238A, 2023133A and 2075007A. In another embodiment of the cyclisation process; compounds bf formula (I) in which A is :e group CR7 and B is N may be prepared by cyclisation of a compound of formula (V) EMI14.1 in which Y" .is oxygen. The cyclisation may be carried out in the absence or presence of a solvent (e.g. dimethylformamide), at elevated temperatures (e.g. within the range 80-3500) optionally in the presence of a base e.g. aqueous potassium hydroxide. In a convenient embodiment of the cyclisation process the intermediate (V) may be formed in situ by reacting an aminoguanidine of formula (VI) EMI14.2 with cyanogen bromide or with an acid R7CO2H or an activated derivative thereof, such as an acid halide (e.g. R7COCl) or a trialkylorthoester (e.g. R7C(OEt)3). The reaction may be carried out by heating the acid and the aminoguanidine (VI) under which conditions cyclisation of the intermediate (V) takes place-directly to give a compound of formula (I). In the case of an activated derivative an aprotic'solvent, e.g. tetrahydrofuran may be used at temperatures from ambient to reflux. When using an acyl chloride as the activated derivative the reaction may also be carried out in the presence of a base, e.g. a tertiary amine such as pyridine, which may also be used as the solvent. The reaction with cyanogen bromide may be carried out with heating, optionally in the presence of a solvent such as an alkanol e.g methanol. The aminoguanidine (VI) may be prepared, for example by reacting a diamine of formula (VII) EMI15.1 with a compound of formula (VIII) EMI15.2 where L is a leaving group suchas throalkyl, e.g. thiomethyl. Compounds of formula (I) in which R5 is hydrogen and Z is as defined in formula (I) except C(=X)NHR8 and except that when A or B represents the group CR7 then R7 represents nitro or when A represents CR7 then R3 and R7 together represents the group EMI15.3 may be prepared by heating the diamine (VII) in which R5 represents hydrogen with a compound of formula (IX) or (X) EMI15.4 in which R3' is the group R3 or a group convertible thereto, and P and P' are leaving groups. Examples of the leaving group P are halogen e.g. bromine and P' are nitroamino and alkylthio e.g. methylthio. The reaction may be carried out iri the absence or presence of a solvent such as acetonitrile, water or an alcohol (e.g. ethanol) at for example 80 - 1500C, and optionally in a sealed vessel. In a particular embodiment of the process, triazoles in which R7 is NO2, i.e q is zero and R6 is NO2, may be prepared by heating a diamine of formula (VII) with a triazole of formula (IX) in which R7 is NO2. Compounds of formula (IX) in which A is N and B is CR7 or in which A is CR7 and B is N and P is bromine may be prepared from the corresponding triazole (IX) in which P is hydrogen by treatment with bromine. Compounds of formula (IX) in which A and B are both N are either known compounds or may be prepared by methods analogous to those described in British Patent Specification No. 1364917 and G.B. Barlin, J. Chem. Soc. (B) 1967, 641. Compounds of formula (I) where Z represents EMI16.1 and R5 represents hydrogen, may he made by reacting an amine of the formula (XI) R26NH2 (XI) with a compound of general formula (XII) EMI16.2 wherein one of -the groups R26 and R27 represents the group EMI16.3 and the other represehts the group R81 , and L is a leaving group such as halogen, thioalkyl (preferably thiomethyl) or alkoxy. Compounds of formula (XII) may be prepared by reacting the amine (XI) with a compound nf formula (XIII) EMI16.4 where L is as defined in formula (XII). The above reaction may be effected in the absence or presence of a solvent e.g ethanol or water at a temperature from ambient to reflux preferably at room temperature. In the absence of a solvent the reaction may be carried out by heating a mixture of the reactants at for example 100-120 C. Compounds of formula (I) in which R5 represents hydrogen, A represents N and B represents CR7 or A represents CR7 and B represents N, where R7 is the group (CH2)qR6 where R6 is NR10COR13, NR10SO2R12, CH2NHC(=X)NHR9 or N=CR15R16 may be prepared by treating an aminoalkyltriazole of formula (XIV), EMI17.1 in which R1, R2 and R3 are as defined in formula (I) or are groups readily convertible thereto, A represents N and B represents CR28 or A represents CR28 and B represents N, where R28 is the group (CH2)qNHR10, the group (CH2)q+1NH2 or the group (CH2)qNH2, with a compound capable of replacing the hydrogen atom in the group NHR10 by the group COR13 or SO2R12 or a HYDROGEN atom in the group NH2 of the group (CH2)q11NH2 by the group C(=X) NHR9 or both hydrogen atoms in the group NH2 of the group (CH2)qNH2 by the group =CR15R16. Thus for example the aminoalkylthiazole (XIV) in which R28 is the group (CH2)qNHR10 may be reacted with an isocyanate R14'NCO in which R14 has any of the meanings defined for R14 in formula (I) except hydrogen or represents an alkali metal atcm such as potassium or sodium, or with an activated derivative of either a carboxylic acid R13COOH (in Which R13 is other than the group NHR14) or a sulphonic acid R,2SO3H to give a compound of formula (I) in which R6 is respectively the group NR10CONHR14, NR10COR13 (in which R13 is other than NHR14), or NR10SO2R12 Suitable activated derivatives include acid halides e.g. acid chlorides, alkylchloroformates, acid anhydrides including mixed anhydrides (e.g. acetic formic anhydride), esters such as alkyl esters, ortho esters and -tl-alkyl-2-pyridinyl) esters. The reaction with an acid halide is preferably carried out in the presence of a base e.g an inorganic base such as sodium hydroxide or an organic base such as triethylamine or pyridine. The redaction with an alkylchloroformate is preferably carried out in the presence of a base, e.g. potassium carbonate or triethylamine, in a solvent such as dimethylformamide. The reaction with an acid anhydride may be carried out in the absence or presence of solvent such as pyridine. In the reaction with an isocyanate, compounds of formula (I) in which R14 is other than hydrogen are conveniently prepared by carrying out the reaction in a solvent such as acetonitrile at temperatures from ambient to reflux. Compounds of formula (I) in which R14 is hydrogen may be prepared by heating a salt e.g. hydrochloride.of the aminotriazole (XIV) with an aqueous solution of an appropriate cyanate, e.g. potassium cyanate. -As a further embodiment of this process an amino- alkyltriazole (XIV) in which R28 is the group (CH)q+lNH2 may be treated with a compound of forms LC(--X)NHR9 where L1 is a leaving group (e.g. methylthio) to give a compound of formula (I) in which R6 is CH2NHC(=X)NHR9. The reactants may for example be mixed in an aqueous solution at room temperature. In yet another embodiment of this process an aminoalkyltriazole (XIV) in which R28 is the group (CH2)qNH2 is treated with an appropriate aromatic aldehyde, e.g. benzaldehyde, or a ketone R15R16CO to give a product in which R6 is N=CR15R16. The reaction may conveniently be carried out in.the presence of a solvent e.g. benzene, preferably with heating e.g. at reflux. Compounds of formula' (I) in which R5 is hydrogen and R7 is the group (CH2)qR6 in which R6 is COR20 (where R20 is hydrogen, alkyl, aryl or aralkyl), or S02R17 may be prepared by oxidation of the corresponding compound in which R7 is the group (CH2)qCHR20OH, (CH2) qSR17 (where R17 is other than hydroxy) or (CH2)SH. Thus aldehydes and ketones of formula (I) in which R5 is hydrogen and R7 is the group (CH2)qCOR20 where R20 is hydrogen, alkyl, aryl or aralkyl may be prepared by oxidising the corresponding hydroxyalkyl compound in which R7 is (CH2)qCHR20OH using for example oxalyl chloride and dimethylsulphoxyde, or activ'ated manganese dioxide in a solvent such as dichloromethane. Compounds of formula (I) in which R5 is hydrogen and R7 is the group (CH2)qSO2R17 may be prepared by oxidising the corresponding compound in which R7 is either (CH2)qSR17 (where R17 is other than hydroxy) or (CH2)qSH with for example peracetic acid. The reaction may be carried out in a. solvent such as acetic acid, at room temperature. The starting material in which R, is (CH2)qSH where q is other than zero may be obtained by alkaline hydrolysis of the corresponding isothiourea, which may in turn be prepared by alkylating thio with an appropriate compound of formula (I) in ch R6 is a leaving group e.g. halo. The thiol starting material in which R7 is SH may be prepared by diazotisation of the corresponding aminotriazole followed by treatment with an alkali metal (e.g. potassium) salt of ethyl xanthate to give a xanthate in which R7 is the group -SC(=S)OEt, which is subsequently hydrolysed (for example by heating with ethanol potassium hydroxide) to give the starting thiol in which R7 is the group SH. The above oxidation process is particularly applicable to the preparation of compounds of formula (I) in which there is no unsaturation within the groups R1 and R3. Compounds of formula (I) in which R5 is hydrogen and R7 is (CH2)qCR23=NR24 may be prepared by reacting the corresponding carbonyl compound i.e. compound of formula (I) in which R7 is (CH2)qCOR23, with an appropri ate reagent H2NR in a suitable solvent such as ethanol, 24 optionally with heating. Compounds of formula (I) in which R5 is hydrogen, R7 is (CH ) R where R6 is SO2NR18Rl9 or CONR21R22 may be prepared by reacting an activated derivative of the corresponding carboxylic acid or sulphonic acid, i.e. compounds of formula (I) in which R7 is (CH2) qR6 where R6 is CO2H or SO3H, with ammonia or an appropriate amine HNR18Rl9 or 'HNR21R22 Suitable activated derivatives include those referred to previously;e.g. acid chlorides and esters. Compounds of formula (I) in which R7 is an acyloxyalkyl group and/or R5 is acyl may be prepared by treating the corresponding compound of formula (I) in which R7 is a hydroxyalkyl group and/or R5 represents hydrogen with either an appropriate aciz or an activated derivative thereof (e g. an acid anhydride or acid chloride). The reaction may be carried ! t at room temperature optionally in the presence of a solvent (e.g. pyridine, tetrahydrofuran, acetone or dimethylformamide), and preferably in the presence of a base (e.g. pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate). Compounds of formula (I) in which R5 is hydrogen and A is CR7 and B is N, and R3 and R7 together represent -(CH2)4- may be prepared by reduction of the corresponding compound in which R3 and R7 together represent fCH=CHt2 using for example hydrogen and a metal catalyst (e.g. platinum) in a solvent such as ethanol. Compound's of formula (I) in which Z is EMI21.1 Alk is CH2 and R5 is hydrogen may be prepared-by treating an aldehyde of formula (XV) EMI21.2 with an amine R1R2NH in a solvent such as tetrahydrofuran or an alkanol, e.g. methanol, followed by reduction using for example a hydride reducing agent such as an alkali or alkaline earth metal borohydride e.g. sodium borohydride or lithium aluminium hydride', or hydrogen and a metal catalyst such as palladium or platinum. The reactions may be carried out at a temperature of 0 to 300C. The intermediates of formula (X1') may be prepared from compounds of formula (XVIa EMI21.3 in which W represents a protected aldehtrle group, e.g. a cyclic'acetal such as an ethylene acetl, by methods analogous to those described herein for r-eparing compounds of formula (I) from the amine of formula (VII). Compounds of formula (I) in which R5 is hydrogen and R6 is tetrahydropyranyloxy may be prepared by-reacting the corresponding hydroxyalkyltriazole of formula (I) with dihydropyran. The reaction maybe carried out in a solvent, e.g. dichloromethane or dimethylformamide, at low temperature e.g. -100 to 0 C, in the presence df a catalyst, e.g. paratoluenesulphonic acid. In the above discussion of the processes available for the production of compounds according to the invention reference has been made to the primary amines of formula (VII). These amines are novel compounds and the invention includes such compounds. These intermediates may be made by a number of processes which are described below. Diamines of formula (VII) in which R5 is. hydrogen and n is 1 may be prepared by reacting a compound of formula (XVII) R1R2NAlkQOH (XVII) with an epoxide of formula (XVIII) EMI22.1 to produce a diamine of formula (XIX) EMI22.2 The reaction may be carried out in the absence or Presence of a solvent such as dimethylformamide, preferably at elevated temperature, and optionally in the presence of a base, e.g. sodium hydride or potassium butoxide. The protecting group may be removed from the compound of formula (XIX) by reaction with a hydrazine, e.g. hydrazine hydrate, or a primary amine, e.g. methylamine. Diamines of formula (VII) in which R5 is hydrogen and m is 1 may be prepared by reacting an epoxide of formula (XX) EMI23.1 with an azide, e.g. sodium azide to produce a compound of formula (XXI) EMI23.2 which may be reduced to produce a diamine of formula (VII) where m is 1. The reaction with the azide may be carried out in a suitable solvent, e.g. aqueous ethanol in the presence of ammonium chloride, preferably at reflux temperature. Reduction of the compound of formula (XXI) may be carried out for example, with lithium aluminium hydride in a suitable solvent, e.g. tetrahydrofuran, or catalytically using for example platinum oxide or palladium oxide as catalyst. Diamines of formula (VII) in which R5 is hdyrogen and m is 2 may be prepared by reacting the epoxide of formula (XX) with a cyanide, e.g. sodir cyanide, to produce a compound of formula (XXII) EMI23.3 which may be reduced produce a compound cf formula (VII) in which m is 2. The reaction wir,i the cyanide may be carried out in a suitable solvent, e.g. aqueous ethanol preferably at reflux temperature. Reduction of the compound of formula (XXII) may be carried out, for example with lithium aluminium hydride in a suitable solvent, e.g. tetrahydrofuran. Alternatively the epoxide of formula (XX) may be reacted with nitromethane to produce a compound of formula (XXIII) EMI24.1 which may be reduced to produce a compound of formula (VII) in which m is 2. The reaction with nitromethane may be carried out in a suitable solvent, e.g. dimethyl- formamide, preferably in the presence of a-base, e.g. sodium hydride. Reduction of the compound of formula (XXIII) may be carried out for example as described above for reduction of the compound of formula (XXII) or using hydrogen in the presence of a catalyst. The intermediate oxides of formula (XX) may be prepared by alkylation of an appropriate alkali metal phenolate, e.g. sodium phenolate with a halohydrin (X,-:IV) EMI24.2 The intermediate epoxide of formula (XVIII) may b prepared by alkylation of an alkali metal, phthalimide, e.g. potassium phthalimide with a halohydrin (XXV) EMI24.3 Where the pro -ict of any of title cve processes is a ree base and a ':alt is required, the salt may be formed in conventional manner. Thus, for example, a generally convenient method of forming the salts is to mix appropriate quantities of the free base and the acid in an appropriate solvent (s) e.g. an a1 -'iol such as or an ester such as ethyl aceto The invention is illustrated but not limited by the following Examples. In the following Examples and Preparations temperatures are in OC. T.l.c. refers to thin layer chromatography and this and preparative chromatography were carried out on silica using, unless otherwise stated, one of the following solvent systems. System A: Dichloromethane:ethanol:0.88 ammonia (50:8:1) System B: Dichloromethane:ethanol:0.8*8 ammonia (100:8:1) System C: Methanol:0.88 ammonia (200:1). Preparation 1 2-[2-Hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]1H-isoindole-1,3-(2H)dione A mixture of 2-(oxiranylmethyl)-1H-isoindole-1,3- (2H)-dione (9.10 g) and 3-(1-piperidinylmethyl)phenol. (8.55 g) was heated at 1300C under nitrogen for 10 minutes. The resulting mixture was dissolved in chloroform (100 ml), washed with 1N sodium hydroxide (2 x 25 ml), dried (MgSO4) and evaporated to give the title compound as a gum (17.65 g). T.l.c. system B, Rf 0.60 b) Similarly prepared by this procedure from 2-[2oxiranylethyl]-1H-isoindole-1,3-(2H)dione (19.7g) and 3-(l-piperidinylmethyl)phenol (17.4 g) except that the crude compound was distilled, was 2-[3-hydroxy-4-[3-(1- piperidinylmethyl)phenoxy]butyl]-1H-isoindole-1,3 (2H)-dione (16.5 g) as an orange oil, b.p. 1800C (0.05 mm) N. m. r. (CDC13):2.0-2;35 ,m(4H); 2.8,t,(dd),(1H); 3.33,m, (3H); 5.8-6.2, m, (5H); 6.54, s, (2H); 6.95, br, (1H), 7.5-7.7, m, (4H); 7.8-8.2, m, (2H); 8.2-8.7, m, (6H). Preparation 2 l-Amino-3-[3- r (l-piperidinylmethylOphenoxy-3-2-propanol A solution of 2-[2-hydroxy-3-[3-(1-piperidinyl- methyl)phenoxy]propyl]-1H-isoindole-1,3-(2H) dione (17.6 g) and hydrazine hydrate (2.5 g) in ethanol (60 ml) was heated under reflux for 3 h. The rr wilting mixture was evaporated to a solid residue which w s suspended in 1N hydrochloric acid (30 ml) and filtered The filtrate was basified with an excess of potassium carbonate and extracted with isopropanol t3 x 40 ml). The isopropanol extracts were dried (Na2C03) and evaporated to a gum which was chromatographed using System A Crystallisation of the product from n-hexane:ethet (20: gave the title compound as colourless grains (7.7 g), m.p. 74-76.5 . b) Similarly prepared by this procedure from 2-j3-hydroxy- 4-r3-(1-piperidinylmethyl)phenoxy]butyl]-lH-isoindole- 1,3-(2H dione (16.5 g) and hydrazine hydrate (4.35 g) (except that the crude product was distilled [b.p. 200 (0.06 mm)]) was 4-amino-1-[3-(1-piperidinylmethyl)phenoxy] -2-butanol (7.2 g) as a white solid, m.p. 59 . c) Similarly prepared by this procedure from 2-[3-[3 (dimethylaminomethyl)phenoxy]-2-hydroxy-propyl]-lH-isoindole-1,3-(2H)-dione (13.0 g) and hydrazine hydrate (2.1 g) except the crude product was distilled [b. p. 2000, 0.2 mmHg] was 1-amino-3-[3-(dimethylaminoethyl)phenoxy] -2-propanol (3.8 g) as a pale yellow solid. n.m.r. (CDCl3): 2.7, t, (1H); ca. 3.2,m,(3H); ca. 6.05,m,(3H); 6.63, s, (2H); 7.15, m, (2H); 7.53, br, m, (2H); 7.78, s, (6H); 7.0-8.3, br, s, (1H). Preparation 3 2-[3- r 3-(Dimethylaminomethyl)phenoxy]-2-hydroxy-propyl]- lH-isoindole-1,3-(2H)-dione A solution of 2-(oxiranylmethyl)-lH-isoindole-1,3 (2H) -dione (20.3 g) and 3- (dimethylaminomethyl)phenol (22.3g) in dimethylformamide (200 ml) with a catalytic amount of sodium hydride (0.2 g) was heated for 6 h at 1000 under N2. The solvent was evaporated to give an oil which was dissolved in chloroform and washed with 26- sodium hydroxide and water. The organic solution was evaporated to give an oil (14 g). A portion of the oil (0.8 g) was distilled to give the title compound (0.6 g) as an oil, b.p. 2500 (0.08 mmHg! Found: C, 67.4; ' H, 6.3; N, 7.8; C20H22N2O4 requires: C, 67.8; H, 6.3; :;, 7.98 Preparation 4 5-Bromo-l-ethyl-lH-tetrazole A solution of bromine 3.34 g) in chloroform (2 ml) was added dropwise over 0.25 h to a ref fluxing solution of l-ethyl-lH-tetrazole (980 mg) -in acetic acid (8 ml) and chloroform (16 ml). The mixture was ref fluxed for 16 h, was cooled and evaporated to give an oil which was distilled to give the title compound (1.28 g) as an orange oil b.p. 100-110 (0.08 mm). n.m.r (CDC13): 5.53,q,(2H); 8.40,t,(3H). Preparation 5 l-Amino-4- r3- (1-piperidinylmethyl)phenoxy]-2-butanol. (a) 1-[[3-(2-Oxiranylethoxy)phenyl]öethyl]piperidine A mixture of 3-(1-piperidinylmethyl)phenol (19.1 g) and flaked potassium hydroxide (6.1 g) in acetonitrile (350 ml) was stirred at room temperature for 16h. The mixture was warmed to give a uniform solution to which (2-bromoethyl)oxirane (20 g) was added. Atter 3.5 h at ambient temperature, the solvent was evaporated orf and the residue partitioned between diethyl ether (400 ml) and water(100 ml). The organic phase was washed with 1M sodium hydroxide, dried and evaporated at 500 (0.01 mm) to give the title compound (18 g) as a light brown oil. m.n.r. (CDCl3): 2.7-3.4,t+m, (4H); 5.93,t,(2H); 6.6,s,(2H)i 6.9,m, (1H); 7.23+7.47, t+dd, (2H); ca. 7.65,m, (4H), ca. 8.0,m,(2H); ca 8.6,m,(6H). (b) 1-Azido-4-[3-(1-piperidinylmethyl)methyl]phenoxy]-2-butanol A solution ot 1-[[3-(2-oxiranylethoxy]phenyl]methyl] piperidine (17 g), sodium azide (5.1 g) and ammonium chloride (2.73 g) in 25% aqueous ethanol (200 ml) was rerluxed ror bh and concentrated to ca. 130 ml. The ccncentrate was diluted with water (50 ml), saturated witn potassium carbonate and extracted with isopropanol. The extract was dried and evaporated to give an oil (20 g) which was chromatographed on silica using dicnloromethane:ethanol: ammonia (200:8:1) to give the title compound (10.u g) as a colourless oil. n.m.r. (CDC13): 2.75,t,(1H); 3.0-3.3,m,(3H); ca. 5.85,m,(3H); 6.53,s,(2H); 6.58,d,(2H); 7.2,br s,(lH); 7.65,m,(4H); 8.05,m,(2H); ca. 8.5,m,(6H). (c) l-Amino-4-[3-(1-piperidinylmethyl)phenoxy]-2-butanol A solution of l-azido-4[3-(1-piperidinylmethyl) phenoxy]-2-butanol (10 g) in dry tetrahydrofuran (100 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (4g) in tetrahydrofuran (200 ml) under nitrogen. The resulting mixture was stirred at room temperature forms h and quenched with water (4 ml), followed by 15% sodium hydroxide (4 ml) and water (12 ml). The mixture was then filtered and the residue washed with tetrahydrofuran (50 ml). The combined filtrate was evaporated to give the title compound (7.5 g) as a pale pink oil. n.m.r. (CDC13): 2.78,t,(1H); 3.0-3.32,m,(3H); 5.88,t,(2H); 6.22,m,(lH), 6.58,s,(2H); 7.0-7.5,ABX,(2H), 7.6,m,(4H), 7.73,brs,(3H); 8.l,m,(2H); ca. 8.5,m,.(6H). EXAMPLE 1 1-[(3-Amino-1-,ethyl-1H-1,2,4-triazol-5-yl)amino-3-[3 (1-piperidinylmethyl)phenoxy]-2-propanol, maleate (1:2) A mixture of l-amino-3-[(1-piperidinylmethyl) phenoxy]-2-propanol (1.32 g) and methyl N-cyano-l-methyl 2-(phenylmethylene)hydrazine-carboximidothioate (1.16 g) was heated as a melt at 800C under water pump vacuum until bubbling ceased (20 minutes). The resulting mixture was stirred with toluene (20 ml) and 1N hydrochloric acid (10 ml) for 30 minutes. The aqueous phase. was diluted with water (30 ml), brought to pH 9 by addition of potassium carbonate, and washed with toluene (2 x 40 ml). The aqueous layer was treated with an excess of potassium carbonate and extracted with ethyl acetate (3 x 25 ml). The ethyl acetate extracts were dried (Na2SO4) and evaporated to a gum which was purified by column chromatography using System A. The resulting gum was treated with an excess of maleic acid in iso propanol to yield the title compound as its white solid (1.52 g), m.p 145-7 . Found: C, 52.4; H, 6.1; N, 13.9; C26H36N6Olo requires: C, 52.9; H, 5.8; N, 14 2% EXAMPLE 2 5-Ct2-hydroxv-3- r 3= piperidinylmethyl)phenoxyJpropyl] amino]-1-methyl-1H-1,2,4-triazole-3-methanol A solution of l-amino-3-[(1-piperidinylmethyl) phenoxy]-2-propanol (compound A) (1.32 g) and methyl N [2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)-hydra zinecarboximidothioate (Compound B) (1.61 g ) in toluene was stirred at 250C for 4h. The resulting solution was treated with 5N hydrochloric acid and stirred for 18 h. The aqueous layer was adjusted to pH 9 by addition of sodium hydroxide and washed with toluene. The aqueous layer was treated with an excess of sodium hydroxide and extracted with hot methyl isobutyl ketone which on cooling gave a white precipitate. RecrystallisatiQn from isopropanol gave the title compound as a white solid (0.81 g) m.p. 170-2 . Analysis Found C, 60.8; H, 7.7, N, 18.3; C19H29N503 requires: C, 60.8; H, 7.8; N, 18-78 b) Similarly prepared by this procedure from compound A (0.8 g) and methyl l-methyl-N-[(methylsulphonyl)acetyl]- 2-(phenylmethylene)hydrazine-carboximidothioate (1.1 g), except that the methyl isobutyl ketone extract was evaporated to give a residue which was chromatographed using system A to give a gum which crystallised from methyl acetate - light petroleum (b.p. 60-80 ), was 1-r-(1-methyl-3-methylsulphonylmethyl-lH-Friazol-S-yl) amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol, (0.49 g) as a white solid m.p. 680. N.m.r. (CDCl3): 2.8,t, (1H); 2.95-3.35,m, (3H); 5.22,t, (1H); 5.78,s,(2H); 5.97,d, (2H) ; 5.9,m, (lH) ; 6.3,d, (2H); 6.43,s, )3H); 6.55,s, (2H); 6.9,s, (3H); 7.6,m, (4H); 8.45,m, (6H). c) Similarly prepared by this procedure from 4-amino-1- [3-(1-piperidinylmethyl)phenoxy]-2-butanol (2.0 g) and compound B (2.4 g), was 1-methyl-5-[3-hydroxy-[4-[3-(1- piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole3-methanol (1.7 g) as a white solid, m.p. 1280. Found: C, 61.7; H, 8.0; N, 17.7; C20H31N5O3 requires: C, 61.7; H, 8.0; N, 18.0%. d3 Similarly prepared by this procedure from I-amino3- [3- (dimethylaminomethyl) phenoxy3 -2-propanol (1.5 g) and compound B (2.25 g) except that the methyl isobutyl ketone extract was evaporated to give a solid which was washed with diethyl ether and then recrystallised from methyl acetate was 5-[[3-[3-(dimethylaminomethyl)phenoxy]- 2-hydroxy-propylamino]-1-methyl-lH-1,2,4-triazole-3- methanol (250 mg) m.p. 104-109 . Nm.r, (CD3Ou): 2.7-3.55,m,(4H); 5.7,s,(2H); 5.8-6.3,m, (3H); 6.45-6.75,m, (7H); 7.9,s, (6H) EXAMPLE 3 1-S3-(3-Aminopropyl)-l-methyl-lE-l2,4-triazol-5-yl] anino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol 2-[3-[5-[[2-Hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino}-1-methyl-1H-1,2,4-triazol-3-yl]propyl] lH-isoindole-1,3v2H)-dione A solution of methyiN-[4-(l,3-dihydro-l,3- dioxo-2H-isoindol-2-yl)-1-oxobutyl]-1-methyl-2-(phenyl methylene)hydrazinecarboximidothioate, (2.1 g) and 1amino-3-[(1-piperidinylmethyl)phenoxy]-2-propanol (1.32 g) in toluene (10 ml) was stirred at room terperature 6H. The mixture was then treated with 5N hyrlro-chloric acid (10 ml) at room temperature for 21h and a further quantity of SN hydrochloric acid (5 ml) was added and stirred for further 20h. The reaction mixture was then washed with toluene, basified with sodium bicarbonate (pH 9) and extracted with ethyl acetate. The extract was dried and evaporated to leave a light brown gum (1.9 g) which was chromatographed using system A to give the title compound (0.8g) as a yellow gum. n.m.r. (CDC13): 2.2,m,(4H); 2.84,t,(lH); 3-3.35,m,(3H); 5.25,t, )1H); 4.6-5.8,br, (1H); 57-6.8,m, (12H); 7.25-8.15,m,(8H); 8.2-8.7,m,(6H). 1-[[3-(3-Aminopropyl)-1-methyl-1H-1,2,4-triazol-5-yl] amino]-3-[3- piperidinylmethyl)phenoxy]-2-propanol A solution of 2-[3-[5-[[2-hydroxy-3-[3-(1- piperidinylmethyl)phenoxy]propyl]amino]-l-methyl-lH- 1,2,4-triazol-3-yl]propyl]-1H-isoindole-1,3-(2H)-dione (0;8 g) and hydrazine hydrate (0.5 ml), in ethanol (60 ml) was stirred at room temperature for 4h and the solvent removed in vacuo.,The white solid residue was partitioned between diethyl ether (100 ml) and 5M sodium hydroxide (50 ml). The alkaline aqueous phase was further extracted with ethyl acetate. The organic extracts were combined, washed with SM sodium hydroxide (50 ml), driedland evaporated to give a yellow gum (0.65 g) which was chromatographed on silica using methanol: 0.88 ammonia (80:1) to give the title compound (0.25 g) as a light brown gum. n. m. r. (CDCi3): 2.8-,dd(t), (lH); 3.01-3.33,m,(3H); 5.37,t, (lH); 5.8-6.16,m,(3H); 6.3-6.62,m,(6H); 7.05-7.8,m,(12H); 8.2-8.72, m, (8H) i.r. (CHCl3): 3600, 3445, 2800, 2755, 2720, 1595cm EXAMPLE 4 5-[2-acetyloxy-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-1-methyl-1H-1,2,4-triazole-3-methanol acetate (ester) A solution of 5-C2-hydroxy-C3-13-(l-piperidinyl- methyl)phenoxy]propyl]amino]-1-methyl-1H-1,2,4-triazole 3-methanol (0.75 g) in acetic acid (30 m1) was refluxed for 48h. The solution was evaporated to leave a pale yellow oil. Aqueous sodium bicarbonate solution (2M, 100 ml) was added and the mixture was extracted with ethyl acetate. The extract was dried ar-1 evaporated to give the title compound (0.89 g) as a yellow gum. N.m.r. (CDC13); 2,78,t,(dd),(lK); 3.0-3.35,m, (3H); 4.65,m, (1H); 5.03,s, (2H); 5.51,t, (1H); 5.82,d, (2H); 6.16.3,m, (2H); 6.45,s, (3H); 6.58,s, (2H); 7.5-7.7,m, (4H); 7.90,s, (6H); 8.3-8.7,m, (6H). I.r. (CHBr3) : 3440, 1740, 2800, 2760, 2720 cm EXAMPLE 5 1-[(3-Amino-1H-1,2,4-triazol-5-yl)amino]-3-[3-(1piperidinylmethyl)phenoxy]-2-propanol hemihydrate Methyl N-cyano-[2-hydroxy-3-[3-[(1-piperidinyl)methyl] phenoxy]propyl]carbamimidothioate A solution of l-amino-3-[(1-piperidinylmethyl) phenoxy]-2-propanol (2.6 g) in ether (50 ml) and methanol (10 ml) was added dropwise to a solution of dimethyl cyanocarbonimidodithioic acid (1.5 g) in ether (30 ml) and the mixture was stirred at room temperature for 18h. The mixture was filtered and the filtrate was evaporated to give a gum which was chromatographed using System B to give the title compound (1.32 g) as a pale yellow gum. N.m.r. (CDC13): 2.8,t,(1H); 2.9-3.4,m,(3H); 4.8,m, (1H); 5.8,m,(2H); 6.1,m,(2H); 6.3,s,(2H); 7.35,s, (3H); 7.6,m, (4H); ca. 8.5,m, (6H). 1-[(3-Amino-1H-1,2,4-triazol-5-yl)amino]-3-[3-(1piperidinylmethyl)phenoxy]-2-propanol hemihydrate Hydrazine hydrate (0.9 ml, 18.5 mmol) was added to a stirred solution of methyl N-cyano-[2-hydroxy-3-[3-(1- piperidinyl)methyl]phenoxy]propyl]carbamimidothioate (1.25 g, 3.5 mmol) in ethanol (10 ml). After 18h at room temperature the mixture was evaporated to give a gum (1.3 g) which was chromatographed on cilica using methanol:0.88 ammonia (100:1) to give the title compound (0.96 g) as a solid white foam, m.p. 57 'softens). N.m.r. (CD3OD):2.82,t, (dd), (1H); 3.0-3.3,m, (3H); 5.8-6.15, m, (3H); 6.60,s, (2H); 6.7,m, (2H); 7.60,m, (4H); 8.3-8.7,m, (6H). EXAMPLE 6 1-[3-(1-piperidinylmethyl)phenoxy]-3-[(1,2,4-triazolo [4,3,&alpha;] pyridin-3-y1) amino] -2-propanol A solution of l-amino-3-[3-(l-piperidinylmethyl) phenoxy]-2-propynol (1.6 g) and 3-bromo-1,2,4-triazolo [4,3 -a]pyridine (1.2 g) in absolute ethanol (5 ml) was heated in an autoclave at 1400 for 42 h. Aqueous 2 M sodium carbonate (15 ml) was added to the reaction mixture and the solvent was evaporated to leave a dark brown solid. This solid was extracted with hot ethyl acetate. The ethyl acetate extract was cooled and partitioned with dilute hydrochloric acid (lM; 50 ml). The acidic aqueous layer was basified with excess aqueous sodium carbonate, washed with diethyl ether (50 ml) and then extracted with diethyl ether. The organic extracts were combined, dried (Na2S04) and evaporated to leave a brown semi-solid gum. This gum was triturated with dry diethyl ether to precipitate a white solid (0.75 g) which was recrystallised from a mixture of ethyl acetate and methanol to give the title compound (0.15 g) as a white solid m.pX 160-161 . Analysis Found: C, 66.1; H, 6.9; N, 18.2; C21H27N502 requires: C 66.1; H, 7.1; N, 18.4% EXAMPLE 7 1-[(1-Methyl-1H-tertazol-5-yl)amino]-3-[3-(1-piperidinyl methyl)phenoxy3-2-propanol A solution of 1-amino-3-[3-(1-piperidinylmethyl)- phenoxy]-2-propanol (1.19 g) and 5-bromo-1-methyl-1Htetrazole (0.735 g) in absolute ethanol [5 ml) was heated in an autoclave at 1250 for 18h. The mixture was cooled, evaporated, saturated with sodium carbonate solution (30 ml) and ethyl acetate (30 ml) added. The mixture was stirred for 15 min. and filtered to give a white solid (830 mg) which was recrystallised from ethyl acetate (20 ml) to give the title compound (0.58 g) as white micro-crystals, m.p. 156-7 . Analysis Found: C, 58.73; H, 7.60; N, 24.24; CS7H26N602 requires: C, 58.94; H, 7.57; N, 24-26t EXAMPLE 8 2-[[2-Hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-5-[(6-methyl-3-pyridinyl)methyl]-4-(3H)-pyrimidinone A mixture of 5-(6-methyl-3-pyridinylmethyl)-2- methylthio-4(3H)-pyrimidinone (1.24 g) and 1-amino-3-[3 [1-piperidinylmethyl)phenoxy]-2-propanol (Compound A) (1.32 g) was heated at 1200 for 1.5 h and then at 1301400 for 2.5 h. The resulting brown glass was dissolved in chloroform (25 ml) and added to stirred dry diethyl ether (250 ml) to precipitate a white solid (1.5 g). This solid was recrystallised from ethyl acetate to give the title compound (0.9 g) as a white solid, m.p. 115-117 . N.r.r (CDC13): 1.0-3.0, v,.br.,(3H); l.5,d, (lH); 2.53-2.59, s + dd, (2H); 2,82, t, (1H); 2.99, d, (lH); 3.10-3.3, m, (3H); 5.8-6.1. m, (3H); 6.25-6.58, ABq + s, (6H) ; 7.54, s, (3H); 7.65, br, (4H); 8.4-8.6, br, (6H). Similarly prepared by this procedure were: b) From compound A (0.9g) and 5-(3-pyridinylmethyl)- 2-methylthio-4(3H)-pyrimidinone (0.8 g), except that the mixture was heated at 125-1300 for 2.5h and subsequently at 140-150 for 3h and the crude product (0.92 g) was chromatographed using System C was hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino] 5-(3-pyridinylmethyl)-4(3H)-pyrimidinone monohydrate (0.42 g) as a buff solid m.p. (78-82 ) (softens). Found: C, 64.3; H, 6.9; N, 14.6 CH25H31N5O3.H2O requires: C, 64.2; H, 7.1; N, 15.0% c) From compound A (0.4 g) and 5-[(4 methoxy phenyl) methyl]-2-(methylthio)-4(3H)-pyrimidinone (0.42 g), except that the crude product was chromatographed using System C and then crystallised from methyl acetate and light petroleum (b.p. 60-80 ), was 2-[[2-hydroxy-3 [3-(1-piperidinylmethyl)phenoxy]propyl]amino]-5-[(4methoxyphenyl)methyl]-4(3H)-pyrimidinone (0.26 g) as a white solid, m.p. 112-116 . n.m.r (CDC13): 2.2-3.4,m,(12H); 2.7-3,4,m,(9H); 5.956.15,m+d, (3H); 6.3,s,(3H); 6.6,m,(GH); 7.7,m,(4H); 8.6,m,(6H). EXAMPLE 9 1-[[1-(Methylamino)-2-nitroethenyl]amino]-3-[3-(1piperidinylmethyl)phenoxy]-2-propanol A solution of 1-amino-3-[(1-piperidinylmethyl) phenoxy] -2-propanol (1.32 g) and N-methyl-l-(methylthio)- 2-nitroethenamine (1.04 g) in water (25 ml) was stirred at 250 for 24h. The resulting mixture was treated with glacial acetic acid (2 ml) and was washes with ethyl acetate. The aqueous phase was basified with excess potassium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to give a gum which was crystallised from acetone to give the title compound (820 mg) as a white solid, m.p. 104-5 . N.m.r. (CDCl3-DMSO): -0.3,br,s, (1H); 2.81,dd, (1H); 3.0-3.5,m, (4H); 5.7-6.1,m, (3H); 6.4-6.6,m, (2H); 6.6,s, (2H) 7.2,br s,(3H); 7.5-7.8,m,(4H); 8.3-8.7,m,(6H). b) Similarly prepared by this procedure from 4-amino- 1-[3-(1-piperidinylmethyl)phenoxy]-2-butanol (2 .0g) and N mcthyl-l-(methylthio)-2-nitroethenamine (1.5 g) except that the gum was chromatographed using system B was 4-[[1-(methylamino)-2-nitroethenyl]amino]-1-[3-(1piperidinylmethyl)phenoxy]-2-butanol (1.1 g) as a white foam, m.p. 45-50 . n.m.r. (CD30D): -0.2,br, (1H); 0.32,br,(lH); 2.85,t,l1H); 3.0-3.5,m+s, (4H); 5.9-6.2,m, (3H); ca. 6.6,m+s, (4H); 7.2, brs, (3H); 7.7,m,(4H); 8.2,m,(2H); ca. 8.6,m, (6H). EXAMPLE 10 1-fr3-(Acetylamino)-l-methyl-lH-l24-triazol-s-ylgamin 3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol acetate (ester) A solution of 1-[(3-amino-1-methyl-1H-1,2,4- triazol-3-yl]amino]-3-[3-(1-piperidinylmethyl)phenoxy]2-propanol(l.Og) and acetic anhydride (0.52g) in pyridine (30ml) was stirred at 230C for 18h. The solvent was evaporated to give a gum, which was dissolved in ethyl acetate. This solution was washed with saturated sodium carbonate solution, dried and evapcrated to give a foam, which was chromatographed using system B to give the title compound (0.5g) as a white foam. n.n.r. (CD30D): 2.7-3.3,m, (4H); 4.6,m,(lI{); 5.9,m,(2H); 6.25-6.65,m,(7H); 7.6,m,(4H); 7.9-8.0,s+s,(6H); 8.5,m, (6H). i.r. (CHBr3); 3425, 3405, 2800, 2760, 2720, 1735, 1708, 1678, 1610cm-1 EXAMPLE 11 N-[5-[[2-Hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] propylgamino]-l-methyl-lH-1,2,4-triazol-3-ylJacetamide hemihydrate A solution of l-[[3-(acetylamino)-l-methyl-lH- 1,2,4-triazol-5-yl]amino]-3-[3-(1-piperidinylmethyl) phenoxy]-2-propanol acetate (ester) (0.32g) and 0.9M aqueous potassium hydroxide (l.Oml) in ethanol (25ml) was stirred for 0.5h at 230. The ethanol was evaporated, and the residue was suspended in sodium carbonate solution. This solution was extracted with methyl acetate. The extract was-dried, and evaporated to give a gum, which was chromatographed using system A to give the title compound (0.25g) as a white foam. Found: C,58.5; H,7.7, N,20.1; C20H30N6O3.O.5H2O requires: C,58.4;H,7.6; N,20.4% N.n.r. (CDCl3): 2.6-3.3,m, (4H); 5.7-6.15,m, (7H); 6.4-6.6,m,(7H); 7.6,m,(4H); 7.9,s,(3H); 8.5,m,(6H). EXAMPLE 12 1-[(5t6t7t8-Tetrahydro-1t24-triazolo[4x3-agpyridin-3 yleamino}3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol A solution of 1-[3-(1-piperidinylmethyl)phenoxy]- 3-[(1,2,4-triazolo[3,4-a]pyridin-3-yl)amino]-2-propanol (252mg) in absolute ethanol (25 ml) was hydrogenated over a 58 platinium on carbon catalyst (150mg). After 8h, additional catalyst (200mg) was added and the mixture was hydrogenated for a further 8h. The mixture was filtered through hyflo and the filtrate was evaporated to give a white solid which was recrystallised from ethyl acetatemethanol to give the title compound (182ng) as white microcrystals, m.p. 141-2 . Found: C,65.1; H,8.1; N,18.?; C21H31N5O2 requires: C,65.4; H,8.1; N,18.2% EXAMPLE 13 1-[[1-Methyl-3-[3-[[1-(methylamino)-2-nitroethenyl] amino]propyl]-1H-1,2,4-triazol-5-yl]amino]-3-[3-(1-piper idinylmethyl)phenoxy]-2-propanol A solution of 1-[[3-(3-aminopropyl)-1-methyl- 1H-1,2,4-triazol-5-yl]amino]-3-[3-(1-piperidinylmethyl) phenoxy]-2-propanol (0.25g) and N-methyl-1-(methylthio) 2-nitroethenamine (0.1g) in water (6ml) and methanol (6ml) was stirred at room temperature for 24h. A further quantity of N-methyl-1-(methylthio)-2-nitroethenamine 'O Olg) was added and the mixture stirred for a further 3h. The reaction mixture was concentrated to ca. 6ml, diluted with water (10ml), acidified to pH3 with acetic acid and washed with ethyl acetate. The aqueous solution was basified with excess potassium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to leave a brown gum which was chromatographed on silica using methanol:ammonia (250:1) to give a gum which was dissolved in hot ethyl acetate and cooled to precipitate a gum. This gum was dissolved in chloroform and filtered through florosil and hyflo. The filtrate was evaporated to give the title compound (0.12g) as a solid white foam m.p. 60-63 (softens). n.m.r. (CDCl3): -0.2,brs,'1H), 2.25,brs,(lH); 2.8,t,(19 3.1, m, (2H); 3,24, dd, (1H); 3.28-3.45, m, (2H); 4.4, brs, (1H); 5.75, brs, (1H); 5.95, m, (2H); 6.1-6.9, m, (9H); 7.0-7.5,m, (5H); 7.63, m, (4H); 8.05, m, (2H); 8.4-7.8, m, (6H). EXAMPLE 14 1-[[1-Methyl-3-[(phenylmethylene)amino]-1H-1,2,4-triazol5-yl]amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol A solution of 1-[(3-amino-1-methyl-1H-1,2,4- triazol-5-yl)amino]-3[3-(1-piperidinylmethyl)phenoxy]-2propanol (0.47g! and lenzaldehyde (0.2a :n benzene (lSml) was ref fluxed for 18h and evaporate to leave a brown gum (0.65g). This gum (0.33g) was chromatographed on alumina using diethyl ether:ethyl acetate:methanol (20:20:1) to give the title compound (0.09g) as a yellow foam. m.p. 53-57 (softens). n.m.r (CDC13): 0.9,s,(lH); 2.1-2.6,m+m,(5H); 2.8,t,(lH); 3.0-3.35, m, (3H); 5.15, brt, (1H); 5.4-6.1, m, (4H); 6.2-6.6, m, (7H); 7.5, m, (4H); 8.5, m, (6H). EXAMPLE 15 1-[(1-Ethyl-1H-tetrazol-5-yl)amino]-3-[3-(1-piperidinylmethyl) phenoxy] -2-propanol A mixture of l-amino-3-[3-(l-piperidinylmethyl) phenoxy]-2-propanol (1.06 g) and 5-bromo-l-ethyl-lH- tetrazole (0.7 g) in water (20 ml) was stirred at reflux for 18 h. Excess potassium carbonate was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to give an oil which was crystallised from methyl acetate-light petroleum (b.p. 60-80 ) to give the title compound (530 mg) as white microcrystals, m. p. 111-13 . Found: C, 59.9; H, 7.8; N, 23.0; C18H28N602 requires: C, 60.0; H, 7.8; M, 23.3% EXAMPLE 16 N-Cyano-N'-[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] propyl] -N" -methylguan idine A mixture of 1-amino-3[(1-piperidinylmethyl) phenoxy]-2-propanot (1 g) and methyi N-cyano- N'-methyl-carbamimidothioate (0.49 g) was heated at 100 under water pump vacuum for 4 h. The resulting brown glass was chromatographed on silica using dichloromethane: ethanol:ammonia (100:8.1) to give a brown gum (0.75 g) This gum was further purified by chromatography using methanol:ammonia (250:1) to give the title compound (0.27 g) as a white solid foam, m.p. 45-7 softens. n. m. r. (CDCl3): 2.8, t, (1H); 3.03-3.37, m, (3H); 3.63, q, (1H); 3.91,t,(1H); 5.8-6.2m,(3H); 6.47-6.79,m,(4H); 7.22,d,(3H); 7.68,m,(4H); 8.52,m,(6H). EXAMPLE 17 1-[(1-Methyl-1H-tetrazol-5-yl)amino]-4-[3-(1-piperidinyl methyl) phenoxy -2-butanol A solution of 1-amino-4-[3-(1-piperidinylmethyl) phenoxyl-2-butanol (1.39 g) and 5-bromo-1-methyl-lH- ttrazole (0.82 g) in absolute ethanol (10 ml) was heated in an autoclave at 1250 for 18 h. The solution was evaporated and. the residue dissolved in 1M hydrochloric acid (25 ml). The acidic solution was washed with ethyl acetate, basified with excess sodium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to leave a solid which was triturated with dry diethyl ether to give a white solid (1.0 g). This solid was recrystallised from methyl acetate-light petroleum (b.p. 60-80 ) to give the title compound (0-6 g) as white crystals , m.p. 138-90. Found: C, 59.8; H, 7.9, N, 23.2; C18H28N6O2 requires: C, 60.0; H, 7.8; N. 23.3% EXAMPLE 18 5-[[2-Hydroxy-4-[3-(1-piperidinylmethyl)phenoxy]-butyl] amino]-1-methyl-1H-1,2,4-triazole-3-methanol A solution of 1-amino-4-[3-(1-piperidinylmethyl) phenoxy]-2-butanol (1.4 g) and methyl N-[2-(acetyloxy)acetyl, -1-methyl-2-(phenylmethylene)-hydrazine-carboximodothioate (1.61 g) in toluene (20 ml) was stirred at 250 for 3 h. The solution was treated with 5N hydrochloric acid (10 ml) and stirred for 16 h. The phases were separated, the aqueous phase was washed with toluene, basified with excess 2N sodium hydroxide and ethyl acetone (50 ml) was added. T: liquid plases were decanted o'.'f from the resulting white solid which was recrystallised from ethyl acetate-n. ethanol to give the title compound (193 mg) as white crystals, m.p. ;47.5-148 . Found: C, 51.6; H, 8.1; N, 17.8. C20H31N5O3 requires: C, 51.7; H, 8.0; N, 18.0% Examples of Pharmaceutical Compositions 1. Tablets mg/tablet Active ingredient 5.0 to 25.0 Lactose 131.5 to 111.5 Pregelatinised maize starch 7.5 Sodium starch glycollate 4.5 Magnesium stearate 1.5 Compression weight 150.0 The active ingredient is sieved through a 250 pm sieve and blended with the lactose and pregelatinised maize starch. This mix is granulated by the addition of water. The granules are dried, screened and blended with the sodium starch glycollate and magnesium stearate. The lubricated granules are compressed into tablets using 8.0 mm diameter punches. 2. Injections % w/v Active ingredient 0.5 Water for injection B.P. to 100.0 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability using dilute acid or alkali or by the addition of suitable buffer salts. The solution is prepared, clarified and filled 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 in sterile ampoules under aseptic conditions. The solution may be packed nder an inert atmosphere of nitrogen or other suitable gas. The ability of the compounds to inhibit histamine induced gastric acid secretion was demonstrated in the perfused rat stomach test preferred to above For example the compounds of Examples 1 to 9(a) have ED50 values within the range of 0,05-0,74 mg/kg in the perfused rat stomach test. The compounds of the invention have in general low toxicity at doses at which they effectively inhibit gastric acid secretion. Thus for example the compound of Example 4 produced no toxic effects when administered intravenously to anaesthetised rats at a dose of at least 4 times its ED50 value.

Claims: CLAIMS: 1. Compounds of the general formula (I) EMI45.1 and physiologically acceptable salts, hydrates, and bioprecursors thereof, in which R1 represents hydrogen, C114 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroaralkyl or alkyl substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino; and R2 represents hydrogen or C 1-4 alkyl group ; or R1 and R2.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 C13 alkyl groups or a hydroxy group and/or may contain another heteroatom selected from oxygen or sulphur; Alk represents a straight or branched alkylene chain of 1 to 3 carbon atoms; Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1and 3- dr 1- and 4-positions; R5 represents hydrogen or acyl; n and m, which may be the same or different, are each 1 or 2; Z represents one of the groups; ; EMI45.2 where X represents NCN, NSO2Methyl, NSO2Phenyl or CHNO2; R8 represents alkyl; A represents N and B represents CR7; or A represents CR7 and B represents N; or A and B both represent N; R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy C26 alkyl, alkoxy C26 alkyl or C1-4 alkanoyloxy C26 alkyl; R7 represents hydrogen, alkyl, alkenyl, aralkyl, acyloxyalkyl, alkylthioalkyl, arylthioalkyl, aryloxyalkyl, aralkyloxyalkyl, or the group (CH2)qR6 where q is zero, 1, 2, 3, 4, 5 or 6 and the alkylene chain (CH2)q may be straight or branched, and R6 is hydroxy, alkoxy, nitro, heteroaryl, tetrahydropyranyloxy, or CH2NHC(=X)NHR9 where X is as defined above and R9 is alkyl; ; or R6 is the group NRloRllr where R10 is hydrogen or alkyl; and R11 is hydrogen, alkyl, alkenyl, aryl, aralkyl, or heteroaralkyl, or R11 is the group S02R12 where R12 is alkyl or aryl; or R11 is the group COR13 where R13 is hydrogen, alkyl, aryl, aralkyl, alkoxy, halomethyl, heteroaryl, heteroaralkyl or the group NHR14 where R14 is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; or R10 and R11 together represent the group =CR15R16 where R15 represents aryl or heteroaryl and R16 represents hydrogen or alkyl; or R6 is the group SO2R17 in which R17 is hydroxy, alkyl, aryl or the group NRl8R19 where R18 and R19, which may be the same or different, each represent hydrogen or alkyl; or R6 is the group COR20 where R20 is hydrogen, hydroxy,- alkoxy, aryloxy, aralkyloxy, alkyl, aryl, aralkyl, or the group NR21R22 where R21 is hydrogen or alkyl optionally substituted by a hydroxy or alkoxy group; and R22 is hydrogen, alkyl (optionally substituted by a hydroxy or alkoxy group), alkenyl, aryl, aralkyl or cycloalkyl, or NR21R22 forms a 5 to 8 membered ring which may contain another heteroatom, e.g. oxygen, or a double bond and/or may be substituted by hydroxy or one or two C13 alkyl groups; or R6 is the group CR23=NR24 where R23 is hydrogen, alkyl, aryl or aralkyl and R24 is hydroxy, alkoxy, aralkyloxy or -NHC(=Y)NH2 where Y is oxygen or sulphur; or when A represents CR7 and B represents N, the groups R3 and R7 taken together represent EMI47.1 or -(CH2)4-; with the proviso that when the group R6 contains a carbon atom through which it is linked to the alkylene group (CH2) q then the total number of carbon atoms in the resulting chain is not greater than 6 (i.e. q is not greater than 5); - R4 represents phenyl, phenoxy or pyridinyl which may optionally be substituted by one or more halogen, alkyl, alkoxyalkyl or alkoxy groups or by a methylenedioxy group; p represents an integer which is 1, 2 or 3. 2. Compounds as claimed in claim 1 in which R1 represents C1-8 alky, C1-4 alkyl substituted by a trifluoromethyl group, C2-4 alkyl substituted by hydroxy or a di C13 alkyl amino group, C57 cycloalkyl, C35 alkenyl, phenyl C13 alkyl, or a heteroaryl C 1-3 alkyl group where the hetero aryl ring contains one heteroatom; R2 represents hydrogen or methyl; or R1R2N represents a S to 7 membered ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Alk represents methylene; R3 represents hydrogen, or alkyl, or hydroxy C24 alkyl or when A is the group CR7 then R3 and R7, taken together, represent EMI48.1 or -(CH2)4-; or Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1 and 3- positions; R5 represents hydrogen or alkanoyl n and m both represent 1, or one of n and m represents 2; R7 represents alkoxyalkyl, alkylthioalkyl,. alkanoyl oxyalkyl, -benzyl, or -CH=NOH; or R7 represents the group (CH2)qR6 where q is zero, 1, 2 or 3, and R6 represents hydroxyl, CH2NHS02R12 (where R12 is alkyl), CH2NHC(=X)NHCH3 (where X=NCN or CHNO2), 502R17 (where R17 is alkyl), or R6 represents COR20 where R20 is hydroxyl or NR21R22 and R21 and R22 independently represent hydrogen or C13 alkyl or R21 and R22 together with the nitrogen atom to whichthey are attached represent a pyrrolidino ring, or R6 represents the group NR10R11 where R10 represents hydrogen and R11 is hydrogen or COR13, where R13 repre sents hydrogen, alkyl, phenyl, benzyl, alkoxy, NH phenyl, or R10 and R11 together represent the group =CHR15 where R15 is phenyl or pyridyl; R4 represents pyridinyl optionally substituted by an alkyl group; or a phenyl group optionally substituted by an alkoxy group; p represents 1; R8 represents alkyl; X represents CHNO2 3. Compounds as claimed in claim 1 of fic general formula (II) EMI48.2 in which R1R2N is dimethylamino, pyrrolidino, piperidino or hexamethylenimino; and Z represents EMI49.1 where, when B represents CR7, then R3 is hydrogen or methyl and R7 is hydroxymethyl, amino, alkanoyloxyalkyl N=CHPh, (CH2)3 NHC(=CHNO2)NHMe, aminopropyl, methylsulphonyl or acetylamino; or when A is CR7 then R3 is methyl and R7 is amino or R3 and R7 together form the group EMI49.2 or (CH2)4; or when A and B both represent N then R3 is methyl; and R4 is 3pyridinyl, 6-methyl-3-pyridinyl or 4-methoxyphenyl. 4. 1-[(3-Amino-1-methyl-1H-1,2,4-triazol-5-yl)amino] -3-[3-1-piperidinylmethyl)phenoxy]-2-propanol; 5-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino] -l-methyl-lH-l , 2 ,4-triazole-3-methanol; 1-[(1-methyl-1H-tetrazol-5-yl)amino]-3-[3-(1-piperidinylmethyl)-phenoxy]-2-propanol; 2-[E2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxyzpropyl] amino]-5-[(6-,methyl-3-pyridinyl)methyl]-4-(3H)pyrimidinone; 2-Et2-hydroxy-3-[3-(1-piperidinylmethylOphenoxy]propyl] amino]-5-(3-pyridinylmethyl)-4(3H)-pyrimidinone; 2-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl] amino]-5-[(4-methoxyphenyl)methyl]-4-(3H)-pyrimidinone; and physiologically acceptable salts thereof. 5 A process for the preparation of compounds as claimed in claim 1 which comprises: a) for the preparation of compounds of formula (I) in which R5 represents hydrogen and Z represents the group EMI50.1 where either A represents CR7 and B represents N or A represents N and B represents CR7, and R7 is other than acyloxyalkyl, alkoxy, nitro, (CH2)qN=CR15R16, S02R17, COR20 (where R20 is hydrogen, aryl or aralkyl) or CR23= NR24, or when A represents CR7 and B represents N then R3 and R7 may not represent the group EMI50.2 or -(CH2)4¯r cyclising a compound of formula (IEI) EMI50.3 in which R25 is as defined in claim 1 for R3, V' is NCR71 or NCN and Y' is hydrogen where V is oxygen or í TT sulphur and R7 ' is a group as defined in claim 1 for R or a group convertible thereto under the conditions 7 of the cyclisation reaction or R7' represents halogen or alkoxy; or V' is NR3, R25 is hydrogen and Y' is EMI50.4 where Y" is sulphur, oxygen or NH; b) for the preparation of compounds of formula (I) in which R5 is hydrogen and Z is as defined in claim 1 except C(=X)NHR8: :and except that when A or B represent the group CR7 then R7 represents nitro or when A represents CR7 then R3 and R7 together represent the group (CH=CH2), heating the diamine (VII) EMI50.5 in which R5 represents hydrogen with a compound of formula (IX) or (X) EMI51.1 in which R3' is the group R3 or a group convertible thereto, and P and P'fare leaving groups; (c) for the production of compounds of'formula (I) in which Z represents EMI51.2 and R5 represents hydrogen, reacting an amine of the formula (XI) R26NH2 (XI) with a compound of general formula (XII) EMI51.3 where one of the groups rX26 and R27 represents the group EMI51.4 and the other represents the group R8, and L is a leaving group; ; d) for the production of compounds of formula (I) in which R5 represents hydrogen and A represents N and B represents CR7 or A represents CR7 and B represents N, where R7 is the group (CH2)gR6 where R6 is NR10COR13, NR10SO2R12, CH2NHC(=X)NHR9 or N=CR15R16 treating an aminoalkyltriazole of formula (XIV) EMI52.1 in which R1, R2 and R3 are as defined in claim 1 or are groups readily convertible thereto, A represents N and B represents CR28 or A represents CR28 and B represents N, where R28 is the group (CK2) NHRlo the group (CH2) q+1NH2 or the group (CH2)qNH2 with a compound capable of replacing the hydrogen atom in the group NHR10 by the group COR13 or S02R12 or a hydrogen atom in the group NH2 of the group (CH2)q+1NH2 by the group C(=X)NHR9 or both hydrogen atoms in the group NH2 of the group (CH2)qNH2 by the group =CR15R16; e) for the production of compounds of formula (I) in which R7 is an acyloxyalkyl group and/or R5 is acyl, treating the corresponding compound of formula (I) in which R7 is hydrosyalkyl group and/or R5 is hydrogen with either an appropriate acid or an activated derivative thereof; f) for the production of compounds cf formula (I) in which A is CR7 and H is N, R3 and R7 together represent -(CH2)4- and R5 is hydrogen, reducing the corresponding compound in which R3 and R7 together represent EMI52.2 g) for the production of compounds of formula (I) in which Z is EMI53.1 Alk is CH2 and R5 is hydrogen treating analdehyde of formula ) EMI53.2 with an amine R1R2NH, followed by reduction; h) for the production of compounds of formula (I) in which R5 is hydrogen and R6 is tetrahydropyranyloxy, reacting the corresponding hydroxyalkyltriazole of formula (I) with dihydropyran; i) for the production of a compound of formula (I) in the form of a physiologically acceptable salt, converting the compound of formula (I) in the form of the free base into a physiologically acceptable salt. 6. A pharmaceutical composition which comprises a compound as claimed in any of claims 1 to 4 together with at least one inert pharmaceutically acceptable carrier or diluent. 7. Compounds cf the general formula (VII) EMI53.3 in which R1 R2 Alk, g, R5, n and m are as defined in claim 1. 8. Compounds as claimed in claim 7 in which R1, R2, Alk, Q, R5, n and m are as defined in claim 2. 9. Compounds as claimed in claim 7 in which R1, R2, Alk, Q, R R5, n and m are as defined in claim 3. CLAIMS: (AUSTRIA) 1. A process for the production of compounds of the general formula (I) EMI55.1 and physiologically acceptable salts, hydrates and bioprecursors thereof, in which R1 represents hydrogen, C1-14 alkyl, cycioalkyi, aikenyl, alkynyl, aralkyl, trifluoroalkyl, hetercaralkyl or alkyl substituted by cycloalkyl, hydroxy, alkcxy, amino, alkylamino or dialkylaminc; and R2 represents hydrogen or C1-4 alkyl grop; or R1 and R2 together with the nitrogen tom no which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least ore double bond, may be unsubstituted or may De substituted by one or more C1-3 alkyl groups or a hydroxy group and/ or may contain another heteroatom select from oxygen or sulphur; Alk represents a straight or branched alkylene chain of I to 3 carbon atoms; Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1and 3- or 1 and 4- positions; ; R represents hydrogen or acyl n and m, which may be he satne ?iffernt are each 1 or 2; Z represents one the groups EMI55.2 wnere X represents NCN, NSO2Methyl, NSO2 Phenyl or CHN02; R8 represent alkyl; A represents N and B represents CR7; or A represents CR7 and B represents N; or A and B both represent N; R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy C2-6 alkyl, alkoxy C26 alkyl or C1-4 alkanoyloxy C2-6 alkyl; R7 represents hydrogen, alkyl, alkenyl, aralkyl, acyloxyalkyl, alkylthioalkyl, arylthioalkyl, aryloxyalkyl, aralkyloxyalkyl., or the group (CH2)qR6 where q is zero, 1, 2, 3, 4, 5 or 6 and the alkylene chain (CH2)q may be straight or branched, and R6 is hydroxy, alkoxy, nitro, heteroaryl, tertahydropyranyloxy, CH2NHC(=X)NHRg where X is as defined above and Rg is alkyl; or R6 is the group NRloRll, where R10 is hydrogen or alkyl; and R11 is hydrogen, alkyl, alkenyl, aryl, aralkyl, or heteroaralkyl, or R11 is the group SO2R12 where R12 is alkyl or aryl; or R11 is the group COR13 where R13 is hydrogen, alkyl, aryl, aralkyl, alkoxy, halomethyl, heteroaryl, heteroaralkyl or the group NHR14 where R14 is hydrogen, alkyl, cycloalkyl, aryl or aralkyl; or R10 and R11 together represent the group =CR15Rl6 where R15 represents aryl or heteroaryl and R16 represents hydrogen or alkyl; or R6 is the group S02R17 in which R17 is hydroxy, alkyl, aryl or the group NR18Rl9 where R18 and R19, which may be the same or different, each represents hydrogen or alkyl; or R6 is the group COR20 where R20 is hydrogen, hydroxy, alkoxy, aryloxy, aralkyloxy, alkyl, aryl, aralkyl or the group NR21R22 where R21 is hydrogen or alkyl optionally substituted by a hydroxy or alkoxy group; and R2, is hydrogen, alkyl (optionally substituted by a hydroxy or alkoxy group), alkenyl, aryl, aralkyl or cycloalkyl, or NR21R22 forms a 5 to 8 membered ring which may contain another heteroatom, e.g. oxygen, or a double bond and/or may be substituted by hydroxy or one or two C1-3 alkyl groups; or R6 is the group CR23=NR24 where R23 is hydrogen, alkyl, aryl or aralkyl and R24 is hydroxy, alkoxy, aralkyloxy or -NHC(=Y)NH2 where Y is oxygen or sulphur; or when A represents CR7 and B represents N, the groups R3 and R7 taken together represent EMI57.1 or -(CH2)4-; with the proviso that wnen the yroup R6 contains a carbon atom through which it is linked to the alkylene group (CH2)q then the total number of carbon atoms in the resulting chain is not greater than 6 (i.e. q is not yreater than 5); R4 represents phenyl, phenoxy or pyridinyl which may optionally be substituted by one or more halogen, alkyl, alkoxyalkyl or alkoxy groups or by a methylenedioxy group; p represents an integer which is 1, 2 or 3; which comprises: a) for the preparation of compounds of formula (I) in which R5 represents hydrogen and Z represents the group EMI57.2 where eithcr A represents CR7 and B represents N or A represents N and B represents CR7, and P is other than acyloxyalkyl, alkoxy, nitro, (CH2)qN=CR15R16, SO2R17, COR20 (where R20 is hydrogen, aryl or aralkyl) or CR23= NR24, or when A represents CR7 and B represents N then R3 and R7 may not represent the group -CH=CH2) or -(CH2)4-, cyclising a compound of formula (III) EMI58.1 in which R25 is as defined for R31 V' is; ; EMI58.2 or NCN and Y is hydrogen where V is oxygen or sulphur and R,' is a group as defined for R7 or a group convertible thereto under the conditions of the cyclisation reaction or R7' represents halogen or alkoxy; or B' is NR3, R25 is hydrogen and Y' is EMI58.3 where Y" is sulphur, oxygen or NH; b) for the preparation of compounds or formula (I) in which R5 is hydrogen and Z is as defined except C(=X)NHR8 and except that when A or B represent the group CR7 then R7 represents nitro or when A represents CR7 then R3 and R7 together represent the group EMI58.4 heating the diamine (VII) EMI58.5 in which B represents hydrogen with a compound offormula (IX) or (X) EMI58.6 in which R3' is the group R or a group convertible thereto, and P and P' are leaving groups; ; for the production of compounds of formula (I, in which Z represents EMI59.1 and R5 represents hydrogen, reacting an amine of the formula (XI) R26NH2 (XI) with a compound of general formula (XII) EMI59.2 where one of the groups R26 and R27 represents the group EMI59.3 and the other represents the group R8, and L is a leaving group; ; dl for the production of compounds of formula (I) in which R5 represents hydrogen and A represents N and B represents CR7 or A represents CR7 and B represents N, where R7 is the group (CH2)qR6 where R6 is NR10COR13, NRloS02R12, CH2NHC(=X)NHR9 or'N=CR15R16 treating an aminoalkyl triazole of formula (XIV) EMI59.4 in which R1, R2 and P3 are as defined in claim 1 or are groups readily convertible thereto, A represents N and B represents CR28 or A represents CR28 and B represents N, where R28 is the group (CH2)qNHR10 the group (CH2)q+1NH2 or the group (CH2)qNH2, with a compound capable of replacing the hydrogen atom in the group NHR10 by the group COR13 or S02R12 or a hydrogen atom in the group NH2 of the group (CH2)q+1NH2 by the group C(=X)NHR9 or both hydrogen atoms in the group NH2 of the group (CH2?qNH2 by the group =CR15R16; e) for the production of compounds of formula (I) in which R7 is an acyloxyalkyl group and/or B5 is acyl, treating the corresponding compound of formula (I) in which R7 is a hydroxyalkyl group and/or B5 is hydrogen with an appropriate acid or an activated derivative thereof; f) for the production of compounds of formula (I) in which A is CR7 and B.is N, R3 and R7 together represent -(CH2)4- and B5 is hydrogen, . reducing the corresponding compound in which R3 and R7 together represents EMI60.1 g) for the production of compounds of formula (I) in which Z is EMI60.2 Alk is CH2 and R5 is hydrogen treating an aldehyde of formula (XV) EMI60.3 with an amine R1R2NH, followed by reduction; h) for the production of compounds of formula (I) in which R5 is hydrogen and R6 is tertahydropyranyloxy, reacting the corresponding hydroxyalkyltriazole or formula (I) with dihydropyran; ; i) for the production of a compound of formula (I) in the form of a physiologically acceptable salt, converting the compound of formula (I) in the form of the free base into a physiologically acceptable salt. 2. A process as claimed in claim 1 for the production of compounds of formula (I) in which R1 represents C1-8 alkyl, C1-4 alkyl substituted by a trifluoromethyl group, C2-4 alkyl substituted by hydroxy or a di C1-3 alkyl amino group, C57 cycloalkyl, C35 alkenyl, phenyl C1-3 alkyl, or a heteroaryl C13 alkyl group where the heteroaryl ring contains one heteroatom; R2 represents hydrogen or methyl; or R1R2N represents a 5 to 7 membered ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Alk represents methylene; R3 represents hydrogen, alkyl, or hydroxy C2-4 alkyl or when A is the group CR7, then R3 and R7, taken together, represent EMI61.1 -or -(CH2)4-; or Q represents benzene ring incorporated into the rest of the molecule through bonds at the 1- and 3- positions, R5 represents hydrogen or alkanoyl; n and m both represent 1, or one of n and m represents 2; R7 represents alkoxyalkyl, alkylthioalkyl, alkanoyl oxyalkyl, benzyl, or -CH=NOH; or R7 represents the group (CH2)qR6 where q is zero, 1, 2 or 3, and R6 represents hydroxyl, CH2NHSO2R12 (where R12 is alkyl), CH2NHC(=X!NtICH3 (where X=NCN or CHNO2), S02R17 (where B17 is alkyl), or R6 represents COR20 where B20 is hydroxyl or NR21R22 and R21 and R22 independently represent hydrogen or C13 alkyl or R21 and R22 together with the nitrogen atom to which they are attached represent a pyrrolidino ring, or R6 represents the group NR10R11 where R10 represents hydrogen and R11 is hydrogen or COR13, where R13 represents hydrogen, alkyl, phenyl, benzyl, alkoxy, NH phenyl, or R10 and R11 together represent the group =CHR15 where R15 is phenyl or pyridyl; R4 represents pyridinyl optionally substituted by an alkyl group; or a phenyl group optionally substituted by an alkoxy group; p represents 1; R5 represents alkyl; X represents CHNO2. 3. A process as claimed in claim 1 for the production of compounds of the general formula (II) EMI62.1 in which R1R2N is dimethylamino, pyrrolidino, piperidino or hexamethylenimino; and Z represents EMI62.2 where, when B represents CR7, then R3 is hydrogen or methyl and R7 is hydroxymethyl, amino, alkanoyloxyalkyl N = CHPh, (CH2)3 NHCt=CHN02)NHMe, aminopropyl, rnethylsulphonylmethyl or acetylamino; or when A is CR7 then R3 is methyl and R7 is amino or R3 and R7 together form the group EMI63.1 or (CH2,)4; or when A and B both represent N then R3 is methyl; and R4 is 3-pyridinyl, 6-methyl-3-pyridinyl or 4-methoxyphenyl. 4. A process as claimed. in claim 1 for the production of the compounds 1-[(3-Amino-1-methyl-1H-1,2,4-triazol-5-yl) amino3-3-[3-(l-piperidinylmethyl)phenoxy]-2-propanol; 5-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanol; 1-[(1-methyl-1H-tetrazol-5-yl)amino]-3-(3-(1piperidinylmethyl)phenoxy]-2-propanol; 2-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino3-5-[(6-methyl-3-pyridinyl)methyl]-4-(3H)- pyrimidinone; 2-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] proyl]amino3-5-(3-pyridinylmethyl)-4(3H)-pyrimiGinone; 2-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy] propyl]amino]-5-[(4-methoxyphenyl)methyl]-4(3H) pyrimidinone; and physiologically acceptable salts th^-eef.

Inventors: BAYS, DAVID EDMUND, BLATCHER, PHILIP, CAREY, LINDA, HAYES, ROGER, MACKINNON, JOHN WILSON MACFARLANE
Applicants: GLAXO GROUP LIMITED
Application year: 1982
Main classification: C07C129
IPC codes: C07D401, C07D249, C07C279, C07D471, C07D295, C07D239, C07D257