AMINOALKYL COMPOUNDS, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: The invention provides compounds of the general formula (I) R₁R₂N-Alk-Q-X(CH₂) n Y(CH₂) m NH-B (1) and physiologically acceptable salts, hydrates and bio­ precursors thereof, e.g. N-[5-[3-(1-piperidinyl-methyl)phen­ oxy]pentyl]-N¹-methyl-2-nitro-1,1-ethene-diamine. The com­ pounds of formula (I) show activity as histamine H₂-antagon­ ists.

Description: This invention relates to novel heterocyclic derivatives having action on histamine receptors, to processes for the preparation thereof, to pharmaceutical compositions containing them and to their use in therapeutics. Certain novel heterocyclic derivatives have now been found which have potent activity as t12-antagonists. These compounds, which are more particularly described below, for example show inhibition of the secretion of gastric acid when this is stimulated via histamine receptors (Ash and Schild, Brit. J. Pharmacol. Chemother, 1966, 27, 427). Their ability to do so can be demonstrated in the perfused rat stomach using the method described in German Offenlegungsschrift No. 2,734,070, modified by the use of sodium pentobarbitone (50 mg/kg) as anaesthetic instead of urethane, and in conscious dogs equipped with Heidenhain pouches using the method described by Black et al, Nature 1972 236, 585. 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 111 receptors. Compounds with histamine H2-blocking activity may be used in the treatment of conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration, as a prophylactic measure in surgical procedures, and in the treatment of allergic and inflammatory conditions where histamine is a known mediator. Thus they may be used for example, either alone, or in combination with other active ingredients in the treatment of allergic and inflammatory conditions of the skin. The present invention provides compounds of the general formula (I) R1R2N - Alk - Q - X (C112)n Y (Gil2) rn Nil - (I) and physiologically acceptable salts, hydrates and bioprecursors thereof in which B represents either the group EMI2.1 or the group EMI2.2 ; ; R1 represents hydrogen, cycloalkyl, aralkyl, tri fluoroalkyl, heteroaralkyl or C16 alkyl substituted by cycloalkyl or a C1,16 straight or branched saturated or unsaturated alkylene chain optionally substituted by a hydroxy, amino, alkylamino, dialkylamino, ester (-C02R where R6 is a C13 alkyl group) or carboxamide (CONH2) group, or R1 represents a C1 16 straight or branched saturated or unsaturated alkylene chain interrupted by an oxygen atom, sulphur atom-, sulphoxide, sulphone, amide (-CONH- or -MICO-) or ester (-COO- or -OCO-) group with the proviso that when the alkylene chain is interrupted by an oxygen or sulphur atom, or the sulphoxide, -CONlI- or -COO- group then there must be at least two carbon atoms between that group and the nitrogen atom to which the group R1 is attached; R2 represents hydrogen or a C14 alkyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5-10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1 3 alkyl groups e.g. methyl or a hydroxy group and/or may contain another heteroatom, e.g. 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 optionally bearing a further substituent R7 adjacent to the group R1R2-N-Alk-, or Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4- positions; R7 represents halogen,or C1-4 alkyl which may be substituted by hydroxy or C1-4 alkoxy; X and Y, which may be the same or different, each represent oxygen or sulphur, or one of X and Y represents -CH2- and the other represents oxygen or sulphur; n and m, which may be the same or different, each represent 2 or 3; R3 represents hydrogen, alkyl, alkenyl, alkynyl, aralkyl or alkoxyalkyl; ; Z represents CHNO2 or NR8 where R8 is nitro, cyano, alkylsulphonyl or aryl sulphonyl; R4 represents hydrogen, alkyl, alkenyl, aralkyl, or C2-6 alkyl substituted by hydroxy or alkoxy; and R5 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy or alkoxy or the group NR9R10 where R9 represents hydrogen, alkyl, alkyl substituted by hydroxy or C1-5 alkoxy, alkenyl, aralkyl or heteroaralkyl and R10 represents any of the groups defined for R9 or may represent the group COR11 where R11 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or monocyclic heteroaralkyl or R10 represents the group SO2R12 where R12 represents alkyl or aryl, or R10 represents the group EMI3.1 where E is oxygen or sulphur R13 represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl, or 119 and R10 taken together may represent the group =CRlliRl5 where R14 represents aryl or heteroaryl and Rl5 represents hydrogen or alkyl. The term "alkyl" as a group or part or a group means that the group is straight or branched and has unless otherwise stated preferably 1 to 6 carbon atoms, and in particular 1 to 4 carbon atoms, e.g. methyl or ethyl, and the term "alkenyl" means that the group has preferably 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 5 to 8 carbon atoms. The acyl portion of the acyloxyalkyl group means an aroyl, aralkanoyl or C1-6 alkanoyl group. Examples of acyloxy- alkyl groups include acetoxymethyl, formyloxymethyl, benzoyloxymethyl and phenylacetoxymethyl. The term "aryl" as a group or part of a group preferably means phenyl or substituted phenyl, for example phenyl substituted with one or more C1-3 alkyl or C1-3 alkoxy groups or halogen atoms. The term "heteroaryl" as a group or part of a group when applied to the group R5 means a 5 or 6 membered monocyclic unsaturated ring which may contain one or more heteroatoms selected from oxygen, nitrogen and sulphur, e.g. furyl, pyridyl, tiliazolyl or thienyl. The term 11heteroaralkyl1' as applied to the group R1 means that the group is made up of a heterocyclic part which is a mono or bicyclic, unsaturated, substituted or unsubstituted ring containing from 5 to 10 atoms selected from carbon, oxygen, nitrogen and sulphur, and an alkyl part which is a straight or branched alkylene chain with 1 to 4 carbon atoms, the heterocyclic ring being linked to the alkylene chain either through carbon or nitrogen and when the heterocyclic ring is substituted the substituent being chosen from C13 alkyl, C1 1-5 alkoxy, hydroxy, ambioalkyl and halogen. If the heterocyclie ring is monocyclic it preferably contains 5 or 6 members and if it is bicyclic it preferably contains 9 or 10 members. The term "unsaturated" in relation to an alkylene chain means that it contains at least one -C=Cor -C#C- grouping. The invention includes the compounds of formula (I) in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include hydrocillorides, hydrobromides and sulphates, methanesulphonates, acetates, maleates, succinates, tartrates, benzoates, citrates and fumarates. The compounds of formula (I) and their salts may also form hydrates, which hydrates are also to be considered as part of the invention The compounds of formula (I) can exhibit tautomerism and the formula is iiiteiided to cover all tautomers. 91ere optical isomers may exist the formula is intended to cover all diastereoisomers and optical enantiomers. The term bioprecursors as used herein means compounds which have a structure different to that of the compounds of formula (I) but which, upon administration to an 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 tiie invention iiicludes wiX1in its scope pharmaceutical compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such compositions may also contain if required other active ingredients, e.g. 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, tii e pharmaceutical composition may take the form of for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. The compounds of 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 multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water before use. The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride. For topical application, the compounds of tie 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 I to 4 doses of the total of some 5 mg to 2 g per day, preferably 5 to 500 mg per day dependent upon the condition of the patient. Examples of suitable meanings for the groups R1, R2 and R7 are as follows: Rl: alkyl containing up to 16 carbon atoms (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or decyl), and optionally containing an ester or amide grouping, C57 cycloalkyl (e.g. cyclopentyl, cyclo hexyl or cycloheptyl), alkenyl (e.g. allyl or S dimethylallyl), aralkyl (e.g. phenylalkyl such as benzyl or phenethyl), C1-4 alkyl substituted by a trifluoromethyl group (e.g. 2,2,3-trifluoroethyl), hydroxy C2-4 alkyl (e.g. 3-hydroxypropyl), C1-3 alkoxy C2-4 alkyl (e.g. methoxyethyl or ethoxyethyl), or di-C1-3 alkylaminoalkyl (e.g. dimethylaminoethyl, diethylaminoethyl or dimethylaminopropyl), or heteroaralkyl where the heterocyclic portion represents for example a furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl, thiazolyl, isoquinolinyl, quinolinyl or indolyl ring and the alkylene portion is for example methylene, ethylene or propylene; R2 hydrogen or C14 alkyl (e.g. methyl or ethyl); or R1R2N may represent a 5-8 membered ring optionally containing one double bond and/or substituted by one or two C13 alkyl (e.g. methyl) groups or a hydroxy group and/or containing an oxygen or sulphur atom (e.g. pyrrolidino, piperidino, hexa methylenimino, heptamethylenimino, tetrahydro pyridino, 4-hydroxypiperidino, 4-Cl 3 alkylpiper idino (e.g. 4-methylpiperidino), morpholino, 2,6 di-C 3 alkylmorpholino (e.g. 2,6-dimethylmorpholino) or thiomorpholino); bromine atom or a C1-3 alkyl group e.g. methyl, ethyl or isopropyl) or a C1-3 alkoxy C1-3 alkyl group (e.g. methoxymethyl). When 13 represents the group EMI7.1 examples of suitable meanings for 113 and Z are as follows: R3: hydrogen,C1-4 alkyl (e.g. methyl or ethyl) or C1-3 alkoxy C2-4 alkyl (e.g. methoxy ethyl) CHNO2 or NR8 where R8 is nitro, cyano or C1-4 alkylsulphonyl (e.g. methylsulphonyl). When B represents the group EMI7.2 examples of suitable meanings for R4 and R5 are as follows: hydrogen, C1-4 a alkyl (e.g. methyl, ethyl or propyl) or hydroxy C2-4 alkyl (e.g. 2-hydroxyethyl); R5: hydrogen, hydroxy, C1-4 alkyl (e.g. methyl, ethyl or isobutyl), hydroxy C1-4 alkyl (e.g. hydroxy methyl, 2-hydroxyethyl or 1-hydroxy-1-methylethyl), C1-3 alkoxy C1-4 alkyl (e.g. methoxymethl or methoxyethyl), phenyl C1-3 alkyl (e.g. benzyl or phenethyl), C2-4 alkannoyloxy C1-4 alkyl (e.g. acetoxymethyl), amino C1-4 alkyl (e.g. aminomethyl), amino, C1-4 alkylamino (c.g. methylamino or ethylamino) or di-Cl 1 alkylamino (e.g. dimethyl amino, diethylamino or dipropylamino), phenyl C1-3 alkylamino (e.g. henzylamino), or a heteroaryl C1-3 alkylamino group where the heteroaryl ring is 5 or 6 membered and contains one heteroatom (e.g. 3 or 4- pyridylmethyl); or the group NHCOR11 where R11 represents hydrogen, C1-3 alkyl (e.g. methyl or ethyl), C1-3 alkoxy (e.g. methoxy or thoxy), furyl, pyridyl, thiazolyl, thienyl, or phenyl optionally substituted by a C1-3 alkyl (e.g. methyl) or C1-3 alkoxy (e.g. methoxy) group; or te group NHS02R12 where R12 represents C1-3 alkyl (e.g. methyl), or phenyl optionally substituted by a C1-3 alkyl (e.g. methyl) or C1-3 alkoxy (e.g. methoxy) group; or the group -NHCONHR13 where 11 13 is C1-3 alkyl (e.g. methyl), C57 cycloalkyl (e.g. cyclohexyl), or phenyl optionally substituted by a C1-3 alkyl (e.g. methyl) or C1-3 alkoxy (e.g. methoxy) group, or the group N=CHR14 where R14 is a phenyl or pyridyl (e.g. - or 4 pyridyl) group0 The group Alk may be for example the group (CH2)p where p is l, 2 or 3. In particular the groups R1 and R2 may have meanings as follows: R1: $C1-7 alkyl (e.g. methyl, propyl, butyl, isobutyl, or lieptyl), C1-4 alkyl substituted by a trifluoromethyl group (e.g. 2,2, 2-trifluoroethyl), C2-4 alkyl substituted by hydroxy or a di C1-3 alkylamino group (e.g. 3-hydroxypropyl or dimethylaminoethyl), C5-7 cycloalkyl (e.g. cyclohexyl), alkenyl (e.g. allyl), phenyl C1-3 alkyl (e.g. benzyl), or a heteroaryl C1-3 alkyl group where the heter oaryl ring is 5 or 6 membered and contains one heteroatom (e.g. 2 furylmethyl); R2: hydrogen or methyl; or R1R2N may represent a 5 to 7 membered ring optionally containing a double bond or an alkyl (e.g. methyl substituent (e.g. piperidino, 4-methylpiperidino pyrrolidino, hexamethylenimino or tetrahydro- pyridino. When B represents the group EMI9.1 R3 and Z may, in particular, have meanings as follows: R3: hydrogen or C1-3 alkyl (e.g. methyl) Z: CHNO2 or NR8 where RB is cyano, nitro or methyl su lphonyl. When B represents the group EMI9.2 R4 and R5 may, in particular, have meanings as follows: R4: hydrogen, methyl, ethyl or 2-hydroxyethyl; R5: hydroxy, phenyl C1-3 alkyl (e.g. benzyl), C1-4 alkyl substituted by hydroxy, C1-3 alkoxy, C2-4 alkanoyloxy or amino (e.g. hydroxymethyl, 2-hydroxy ethyl, acetoxymethyl or aminomethyl); amino, di-C1-4 alkylamino (e.g. diethylamino), NHCOR11 where 1111 represents hydrogen, C1-3 alkyl, (e.g. methyl), C1-3 alkoxy (e.g. ethoxy) or phenyl; -NHCONHR13 where R13 represents phenyl; or N=CHR14 where 1314 is phenyl or pyridyl (e.g. 4-pyridyl). Alk is particularly a methylene or ethylene group, more particularly methylene. Tile group Q is preferably a benzene ring in which incorporation into the rest of the molecule is ttlrougi bonds at the 1- and 3-position. One of X and Y is preferably oxygen and the other is preferably oxygen or methylene. n and m are preferably both two. When B represents the group EMI10.1 z is preferably CHNO2 and R3 is more particularly alkyl (e.g. methyl). A preferred group of triazoles of formula (1) are those of formula (II) EMI10.2 where R1 and R2 are methyl groups or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, hexamethylenimino,tetrahydropyridino or 4-methylpiperidino group; R4 is hydrogen or methyl; and R5 is an amino, hydroxyalkyl, alkanoylamino, alkanoyloxyalkyl, alkoxyalkyl, aminoalkyl, benzyl, formamido, alkoxycarbonylamino, hydroxy, aroylamino or phenylcarbamoylamino group; and Y represents oxygen or methylene. A further preferred group of compounds of formula (I) are those of formula (III) EMI10.3 in which R1R2N forms a pyrrolidino, piperidino, hexamethyl enimino, t etrahydropyridino or 4-methyl- piperidino group; Z represents CHNO2 or N1t8 where R8 is methylsulphonyl, more preferably CHNO2; and R3 represents hydrogen, C1-4 alkyl or C1-3 alkoxy C2-4 alkyl, more preferably 1-4 alkyl e.g. methyl. A particularly preferred compound is N- [5- [3-(1 piperidinylmethyl)phenoxy]pentyl]-NÚ-methyl-2-nitro-1,1ethenediamine and its physiologically acceptable salts. According to one aspect i,lie invention provides compounds of formula (I) in which B represents EMI11.1 R1 represents hydrogen, cycloalkyl, aralkyl, trifluoroalkyl, heteroaralkyl or C1-6 alkyl substituted by cycloalkyl, amino, alkylamino or dialkylamino; or R1 represents a C1-16 straight or branched saturated or unsaturated alkylene chain which may be optionally substituted by a hydroxy, ester (CO2R6where R6 is a C1-3 alkyl group) or carboxamide (CONH2) group; or R1 represents a C1-16 straight or branched saturated or unsaturated alkylene chain interrupted by an oxygen atom, sulphur atom, sulphoxide sulphone, amide (-COMI- or -NHCO-) or ester (-COO- or -OCO-) group, with the proviso that when the alkylene chain is interrupted ly an oxygen or sulphur atom, or the sulphoxide, -COMI- or -COO- group then there must be at least two carbon atoms between that group and the nitrogen atom to which the group itl is attached. R2 represents hydrogen or a C1-4 alkyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5-10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1-3 alkyl groups or a hydroxy gro and/or may contain another heteroatom; and R9 and R10 represent hydrogen, alkyl, alkyl substituted by hydroxy or C1-3 alkoxy, alkenyl, aralkyl or heteroaralkyl or R9 and 1110 together represent the group =CRl4Rl5 where Rl4 represents aryl or heteroaryl and R15 represents hydrogen or alkyl. According to another aspect the invention provides compounds of formula (I) in which B represents EMI12.1 ; R1 represents hydrogen, cycloalkyl, aralkyl, trifluoroalkyl, heteroaralkyl or C16 alkyl substituted by cycloalkyl, amino, alkylamino or dialkylamino; or R1 represents a C1-16 straight or branched saturated or unsaturated alkylene chain which may be optionally substituted by a hydroxy, ester (CO2R6 where R6 is a C1-3 alkyl group) or carboxamide (CONH2) group; or R1 represents a C1-16 straight or branched saturated or unsaturated alkylene chain interrupted by an oxygen atom, sulphur atom, sulphoxide, sulphone, amide (-conh- or -NHCO-) or ester (-COO- or -OCO-) group, with the proviso that when the alkylene chain is interrupted by an oxygen or sulphur atom, or the sulphoxide, -CONH- or -COO- group then there must be at least two carbon atoms between that group and the nitrogen atom to which the group R1 is attached; R2 represents hydrogen or a C1-4 alkyl group; or 111 and R2 together with the nitrogen atom to which they are attached form a 5-10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1-3 alkyl groups or a hydroxy group and/or may contain another heteroatom. It will be appreciated in the methods for tie preparation of the compounds of formula (I) given below that for certain reaction steps it may be necessary to protect various reactive substituents ill the starting marterials for a particular reaction and subsequently to remove the protecting group. Such protection and subsequent deprotection may be particularly pertinent when R1 and/or 112 and/or R3 are hydrogen, and/or when n4 is an alkyl group bearing a hydroxy substituent and/or 115 is an alkyl group bearing a hydroxy 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 trichloroet}1oxyearbonyl 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. hydrazine hydrate or a primary amine for example methylamine, benzyl or benzyloxycarbonyl derivatives may be cleaved by hydrogenolysis in the presence of a catalyst, e.g. palladium, and trichloroethoxycarbonyl derivatives may be cleaved by treatment with zinc dust. In describing the processes which may be used for preparing the compounds formula (I) or intermediates useful in tie preparation thereof, any of R1 to R15' Alk, Q, X, Y, Z, E, n and m are as defined in formula (I) unless otherwise stated. Compounds of formula (I) where B represents the group -CNHR3 may be made by reacting an amine of the " Z formula R16NH2 (IV) with a compound of general formula (v) EMI13.1 wherein one of the groups 1116 and Rl7 represents the group R1R2NAlkQX(CH2)nY(CH2)m- and the other represents the group R¯, and P is a leaving group such as halogen, thioalkyl (preferably thiometliyl) or alkoxy. Compounds of formula (V) may be prepared by reacting the amine (IV) with a eompound of formula (VI) EMI14.1 where P is as defined in formula (V). The above reactions may be effected in the absence or presence of a solvent e.g. ethanol, dioxan, acetonitrile, water or aqueous ethanol at a temperature from ambient to reflux. 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 B represents the group EMI14.2 where R@ is other than an alkoxy or acyloxyalkyl group or the group -N = CR14Rl5 may be prepared by cyclisation of a compound of formula (VII) EMI14.3 in which V1 is EMI14.4 or NCN and YÚ is hydrogen, where V is oxygen or sulphur and R51 is a group as defined in formula (I) for R5 or a group convertible thereto under the conditions of the cyclisation reaction or represents halogen or alkoxy; or VÚ is NH and YÚ is . EMI14.5 . In a particular embodiment of the above process compounds of formula (I) in which the group B represents EMI14.6 where R5 is amino, hydroxy or a carbon-linke(i group may conveniently be prepared by cyclisation of a compound of formula EMI15.1 where V11 represents the group NCN or EMI15.2 and Z represents two hydrogen atoms. The reaction may be carried out in the absence or presence of a suitable solvent, for example, toluene, ethanol, methanol, isopropanol, acetonitrile or water, at a temperature from room temperature to reflux. It may be convenient to prepare in situ compounds of formula (VIII) in which Z1 represents two hydrogen atoms by treating a compound of formula (VIII) where Zl 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. When preparing compounds of formula (I) in which R5 is a hydroxyalkyl group it is preferable that in the intermediate (VIII) the hydroxy group is in 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. Compounds of formula (I) where Alk represents CIIS and where B represents the group EMI15.3 in which R5 is other than the group -N = CRl4Rl5 may be prepared by reducing the intermediate formed from reacting a cdmpound of formula (IX) EMI16.1 in which W represents the group -CIIO with a reagent R1R2NH. Reaction may be effected by treatment with ammonia or an amine R1R2NHI 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 metal 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, Alternatively, for the production of compounds of formula (I) in which R5 is other than -N=CR14R15, a compound of formula (I) in which R1 is hydrogen may be 1 1 reacted with an aldehyde Rl-CIIO under the reducing conditions described above; the group 111 having a meaning such that the resultant group R1CH2 represents a group R1 as defined above. This method applies particularly to the preparation of compounds of formula (I) in which R1 is heteroaralkyl or an optionally substituted alkyl chain containing up to 16 carbon atoms. In certain instances compounds of formula {I) where B represents the group EMI16.2 may be prepared by methods involving interconversion of the substituent R5. Thus compounds in which R5 is an acyloxyalkyl 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. 80-1200C in tie absence or presence of a solvent such as toluene. Compounds of formula (I) in which R5 represents the group -N=CR14R15 may be prepared from compounds of Iormula (I) in which R5 is a NH2 group by reaction with an aldehyde or ketone R14R15CO in a solvent such as benzene, ethanol, or methanol. The reaction is preferably carried out with heating, e.g at reflex. Compounds of formula (I) in which R5 is the group NR9R10 where R10 is -COR11, -SO2R12 or -C(=E)NHR13 may be prepared by treating a compound of formula (I) in which R5 is the group -M 29 and Rl, R2, 114 and R9 are as defined in formula (I) or are groups readily convertible thereto with a reagent capable of replacing the hydrogen atom in the group NHR9 by the group R10 where R10 is as defined above. Thus for example reaction with an activated derivative of either a carboxylic acid R11COOH or a suiphonic acid R12SO3H, or reaction with an isocyanate or isothiocyanate R13NCE in which R131 has any of the meanings defined for R13 in formula (I) except hydrogen or represents an alkali metal atom such as potassium or sodium or an alkoxycarbonyl group, e.g. ethoxycarbonyl, gives a compound of formula (I) in which 1110 is respectively the group COR11, SO2R12 or C(=E)NHR13. Suitable activated derivatives include acid halides e.g. acid chlorides, alkylchloroformates, acid anhydrides including mixed anhydrides (e.g. acetic formic anhydride), or esters such as alkyl esters, orthoesters and (l-alkyl2-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 pyridineO The reaction with an alkylchloroformate is preferably carried out in the presence of a base, e.g. potassium carbonate or triethylamine, in a solvent such as dimethylformamide. The reaction with an acid anhydride may be carried out in the absence or presenceof a solvent such as pyridine. In the reaction with an isocyanate or isothio cyanate compounds of formula (I) in which Rl3 is other than hydrogen 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 1113 is hydrogen may be prepared by heating with an appropriate organic isocyanate or isothiocyanate such as ethylcarbonisothiocyanatidate, at an elevated temperature followed by hydrolysis of the resulting ester, for example with a base such as aqueous ethanolic sodium llydroxide . Amines of the formula (IV) where Rl6 represents the group RlR2NAlkQX(CH2)nY(CH2)m- may be made by methods analogous to those described in German Offenlegungsschrifts 2,734,070, 2,821,410 and 2,821,409. For example, amines of formula (IV) in which X is oxygen or sulphur may be prepared by reacting a compound of formula (X) R1R2NAlkQ-XH (X) with the phthalimide derivative (xi) EMI18.1 where Hal is chlorine or bromine, in the presence of a base followed by removal of the phthalimide protecting group. Amines of formula (IV) in which X is -CR2- may be prepared by reacting a compound of formula (XII) with a compound of formula (XIII) R1R2NAlkQch2(CH2)nJ (XII) EMI18.2 where either J is a leaving group e.g. halogen and G is a hydroxyl or thiol group, or J is a hydroxyl or thiol group and G is a leaving group e.g. halogen. The reaction is carried out in the presence of a base e.g. sodium hydride or potassium carbonate, in a solvent such as dimethylformamide or acetone respectively, to give an intermediate of formula (XIV) EMI19.1 from which the amine (IV) in which X is -CIO- may be formed by cleavage of the phthalimide protecting group. The intermediates of formulae (VII) and (VIII) may be prepared by methods analogous to those described in British Patent Specification No. 2023l3A and European Patent Specification publication No. 0016565. Where the product of any of the above processes is a free base and a salt is required, the salt may be formed in a conventional manner. Thus, for example, a generally convenient method of forming tiie salts is to mix appropriate quantities of tiie free base and the acid in an appropriate solvent (s), e.g. an alcohol such as ethanol or an ester such as methyl acetate. The invention is illustrated by tie following examples. In the following examples t.l.c. refers to thin layer chromatography carried out on silica using unless otherwise stated one of the following solvent systems: A: ethyl acetate/water/isopropanol/0.88 ammonia (25:8:15:2) B: methanol/0.88 ammonia (80.1). Column chromatography was earried out on silica using methanol as eluent unless otherwise stated. Preparation 1 6-[3-(1-Piperidinylmethyl)phenoxy]hexanamine A -suspension of 3-(1-piperidinylmethyl)phenol (3.9 g) and sodium hydride (0.49 g) in dry dimethylformamide (70 ml) was stirred at 250 for 6h. 2-(6-Bromohexyl)1H-isoindole- 1,3-(2H)-dione (604g) was added and the solution was stirred at 25 for 16h. The mixture was poured onto water and extracted with ethyl acetate. The organic extract was evaporated to leave a dark brown oil (8.6g) which was used without further purification. A solution of the oil and hydrazine hydrate (l.5g) in ethanol (200 ml) was heated at reflux for 8h. Ether was added to the cooled solution and the precipitate was removed by filtration. The filtrate was distilled to give the title compound as a pale yellow oil (2.5g) b.p. 1700/0.1 mm. The following compounds were similarly prepared from v-(l-piperidinylmethyl)phenol [A] and the corresponding 2-(halosubstituted alkyl)-1H-isoindole-1,3-(2H)-dione. (b) A (5.2g) and 2-(5-Bromopentyl)-1H-isoindole-1,3- (2H)-dione (8g) gave 5-[3-(l-piperidinylmethyl)- phenoxy]pentanamine as a colourless oil (4.3g) b.p. 1500 (0.1 mm). (c) A (2.7g) and 2-[2-(2-Chloroethoxy)ethyl]-1H- isoindole-l,3-(211)-dione (5.6g) gave piperidinylmethyl)phenoxy]ethoxy]ethanamine as an oil (2g), b.p. 1800 (0.1 mm). Preparation 2 2-[5-[3-Formylphenoxy]pentyl]-1H-isoindole-1,3-dione 3-Hydroxybenzaldehyde (6048g) and sodium hydride (80 1.65g) in dry dimethylformamide (120 ml) were stirred together at room temperature for 5h. N-(5-Bromopen.tyl)- phthalimide (14.3g) was added and the mixture was stirred at 200 during 18h. The reaction mixture was poured onto water and extracted with ether. Evaporation of the ether gave the title compound (9.5g) as a wiiite solid. T.1.c.silica; ethyl acetate Rf 0.7. N.m.p. (CDCl5) 0.0, s, (1H); 2.05-2.4, m, (4H); 2.5-2.7,m, (3H); 2.75-2.95,m, (1H); 6.0, t, (2H); 6.25, t, (2H); 7.8-8.7, m, (6H). 5-[3-(1,3-dioxolan-2-yl)phenoxy]pentanamine A solution of 2-[5-[3-formylphenoxy]pentyl]-1H-isoindole 1,3-dione (9.5g), ethane-1,2-diol (2,4g) and p-toluenesulphonic acid, monollydrate (75 mg) in benzene (150 ml) was heated under reflux using a l)ean-Stark separator for 24h. Tlie cooled solution was washed successively with sodium carbonate solution, water, sodium chloride solution, and evaporated in vacuo. The resulting oil was dissolved in tetrahydrofuran (150 ml) and stirred with hydrazine hydrate (4.9g) at room temperature for 24h. The mixture was diluted with ether, filtered and the filtrate was distilled to give the title compound as a colourless oil (3.42g) b.p. 185-189 (0.1 mm). T°l.c. silica; methanol:ammonia 79:1 11± 0.4 5-[[5-(3-Formylphenoxy)pentyl]amino]-1-methyl-1H-1,2,4 triazole-3-methanol 5-[3-(1,3-dioxolan-2-yl)phenoxy]pentanamine (3.26g) and methyl N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximidothioate (3.98g) were heated at 700 under water-pump vacuum for 3h. The resulting glass was dissolved in ethanol (25 ml) and stirred with 2N hydrochloric acid (100 ml) a-t room temperature for 18h. The solution was neutralised to pH 7 with potassium carbonate, and extracted with ethyl acetate to give a brown oil which was purified by column chromatography on silica using ethyl acetate followed by - ethyl acetate:methanol (3:1) to give the title compound as a yellow solid. T.l.c. silica; ethyl acetate:methanol 2:1 Rf 0.5. N.m.r. (CDCl3) 0.0, s, (1H); 2.5-5.0,m, (4H); 5.47, s, (2H); 5.8, t, (1H); 6.0, t, (2H); 6.55, s, (3H); 6.6, q, (2H); 6.6, s, (1H); 8-8.6, m, (6H). EXAMPLE 1 1-Methyl-N5-[6-[3-(1-piperidinylmethyl)phenoxy]hexyl]1H-1,2,4-triazole-3,5-diamine 6-[3-(1-Piperidinylmethyl)phenoxy]hexanamine (0.5g) and methyl-N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (0.4g) were heated at 60 under water pump pressure for 4h. The resulting glass was dissolved in acetone, and the 1)11 of the solution was adjusted to pH 1 with 2N hydrochloric acid. The solution was stirred at 250 for lh, diluted with water and washed with ethyl acetate. The aqueous phase was basified with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated and the residual oil was triturated with cyclohexane to give the title compound as a white crystalline solid (0.41g) m.p. 71 - 4 . T.l.c. system A, Rf 0.5. The following compounds were similarly prepared from the corresponding diamines and methyl-N- cyano-l-methyl-2- (pilenylmethyl ene )hydrazine carboximido- thioate [A]. (b) 5-[3-(1-Piperidinylmethyl)phenoxy]pentanamine (0.5g) and A (0.42g) gave 1-methyl-N'-[5-[3-(1-piperidinyl- methyl) phenoxy]pentyl]-1H-1,2,4-triazole-3,5-diamine as a pale yellow oil (0.35g) purified by column chromatography. T.l.c. system A,Rf 0.6. N.m.r. (CDCl3) 2.8, t, (1H); 3.05 - 3.3,m, (3H); 6.04, s, (2H); 6.06,t, (2H); 6.54,s, (3H); 6.62,s, (2H); 6.6, q, (2H); 7.6,m, (4H) 8.0 - 8.7,m, (12H). (c) 2-[2-[3-(1-Piperidinylmethyl)phenoxy]ethoxy]ethanamine (1.0g) and A (0.84g) gave 1-methyl-N5-[2-[2 [3-(1-piperidinylmethyl)phenoxy]ethoxy]ethyl]-1H-1,2,4 triazole-3,5-diamine (0.25g) as a pale yellow oil, purified by column chromatography. T.l.c. system 13, Rf 0.58. N.m.r. (CDCl3) 2.8,t, (III); 3 - 3.3,m, (3H); 5.54,t, (III); 5.8 - 6.6,m, (10H); 6.57,s, (2H): 6.7,s, (5H); 7.65,m, (4H); 8.5,m, (6H). EXAMPLE 2 1-Methyl-5-[[5-[3-(1-piperidinylmethyl) phenoxy]pentyl]amino]-1H-1,2,4-triazole-3-methanol 5-[3-(1-Piperidinylmethyl) phenoxy]pentanamine (0.75g) and methyl N-[(2-acetyloxy)acetyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximidothioate (0.84g) were heated together, with stirring, at 800 for 2h under water pump vacuum to give an oil which was used without further purification. The oil was dissolved in toluene (15 ml) and, treated with 2N hydrochloric acid (5 ml). The resultant suspension was heated at 80 - 900 for 0.5h and stirred for 17h at 200. The acidic layer was separated, washed with toluene and basified with potassium carbonate. The basic mixture was extracted wiih ethyl acetate and the organic extract was purified by column chromatography on silica using methanol, ethyl acetate (1:9) to give the title compound as a white solid (0.'5g) m.p. 82.5 - 83.5 . Assay found: C, 65.0; II, 8.2; N, 17.5; C21I133N502 requires: C, 65.1; H, 8.6; N, 18.1% (b) In a similar manner, 2-[2-[3-(l-piperidinyl methyl)phenoxy]ethoxy]ethanamine (0.95g) and methyl N-L(2-acetyloxDT)acetyl]-l-methyl-2-(phenylmethylene)- hydrazinecarboximidothioate (0.94g) gave 1-methyl 5-[[2-[2-[3-(1-piperidinylmethyl)phenoxy]ethoxy] ethyl]amino]-1H-1,2,4-triazole-3-methanol (0.3g) as a pale yellow oil. T.l.c. system A. Rf 0.5 N.m.r. (CDCl3) 2.76, t, (1H); 3.0 - 3.3,m. (3H); 5.30, t, (1H); 5.47,s, (2H); 5.90,m, (3H); 6.1 - 6.6,m,(llH); 7.60,m, (4H); 8.3 - 8.8,m, (611). EXAMPLE 3 N-[1-Methyl-5-[[5-[3-(piperidinylmethyl)phenoxy]pentyl]amino]-1H-1,2,4-triazole-5-yl]acetamide Acetic anhydride (1 ml) was added to a solution of 1methyl-N5-[5-[3-(1-piperidinylmethyl)phenoxy]pentyl]1H-1,2,4-triazole-3,5-diamine (0.7 g) in dry pyridine (15 ml) and the mixture was heated at 80 for 2h. Water was added followed by excess potassium carbonate and the mixture was stirred at 20D for 3h. The product was extracted into ethyl acetate and the combined organic extracts were evaporated to give the title compound as a yellow foam (0.4g). T.l.c. silica; ethyl acetate/ethanol/0.88 ammonia (20::2) Rf 0.5 N.m.r. (CDCL3) 1.7,s, (1H); 2.8,t, (1H): 3 - 3.3,m, (3H); 5.8 - 6.07,m, (311); 6.4 - 6.8,m, (711); 7.5 - 8.0,m. (7H); 8.0 - 8.7,m, (12H). EXAMPLE 4 3-Phenylmethyl-5-[[2-[2-[3-(1-piperidinylmethyl)phenoxy]ethoxy]ethyl]amino]-1H-1,2,4-triazole Dimethyldithio-N-phenacylcarbonimidinothioate A suspension of potassium carbonate (14.1g) and dimethyl dithiocarbonimidinothioate hydroiodide (10.2g) in acetone (150 ml) was stirred at 200 during 2h. Phenylacetyl chloride (6.8g) was added dropwise aiid stirring was continued for 17h at 200. The mixture was partially evaporated, diluted with water (300 ml) and extracted with ethyl acetate. The combined organic extracts were evaporated to give the title compound as a pale green oil (7,9g) b.p. 160 - 164 , o.o6 mm. T.l.c. silica; ethyl acetate Rf 0.8 3-Phenylmethyl-5-[ [[2-[ 2-F 3- (1-piperidinylme thyl ) phenoxy i ethoxy]ethyl]amino]-1H-1,2,4-triazole A solution of 2-[2-[3-(1-piperidinylmethyl)phenoxy]ethoxy] ethanamine (1.5g) in tetrahydrofuran (10 ml) was added dropwise to a solution of dimethyldithio-N-phenacylcarbon- imidinothioate (1.3g) in tetrahydrofuran (20 ml) during lh at 0 and the mixture was stirred at 200 for 16h. Hydrazine hydrate (0.42g) was added and the mixture was stirred at 200 for 17h, then heated under reflux for 3h. The mixture was partially evaporated, diluted with water and extracted with ethyl acetate. The organic extracts were evaporated to give an oil which was purified by column chromatography on silica using chloroformmethanol (9:1) to give the title compound as a white solid (0.3g) m.p. 82.5 - 84.50. Assay Found: C. 66.8; H 7.4; N, 15.3; C25H33N5O2.0.75H2O requires: C. 66.8; II 7.7; N, 15.6 EXAMPLE 5 N-Methyl-NÚ-[2-[2-]3-(1-piperidinylmethyl)phenoxy]ethoxy] ethyl]-2-nitro-1,1-ethenediamine A solution of 2-[2-[3-(1-piperidinylmethyl)phenoxy]ethoxy] ethanamine (0.4g) and N-methyl-1-methylthio-2-nitro- etheneamine (0.24g) in water (20ml) and ethanol (20ml) was stirred at 500 for Sh. The solution was diluted with water (20ml) acidified to pH 1 with dilute llydro- chloric acid and washed with ethyl acetate (2x50ml). The aqueous solution was basified to pH 9 with potassium carbonate and extracted with ethyl acetate (3x50ml). Evaporation of these organic extracts gave a yellow oil which solidified when triturated with cyclohexane. The solid was recrystallised from ethyl acetate (10ml) to give the title compound as a white powder (0.17g) m.p. 125.5 - 126.5 Assay Found: C, 60.28; IT, 7.98; N, 14.64 C19H30N4O4 Requires: C, 60.32; H, 7.94; N, 14.81% EXAMPLE 6 N-[5-[3-(1-Piperidinylmethyl)phenoxy]pentyl]-NÚmethyl2-nitro-1,1-ethenediamine A solution of 5-[3-(1-piperidinylmethyl)-phenoxy]- pentanamine (1.0g) and 1-methylthio-1-methylamino-2nitroethene (0.53g) in water (20ml) was stirred overnight at room temperature The water was removed in vacuo and the resulting oil triturated with ethyl acetate to give a yellow solid which was dissolved ill isopropanol:ethyl acetate (75:25). Addition of ether to the solution afforded tie title compound (0.16g) as a white crystalline solid, m.p. 112-113 . Found: C,61.3; H,8.3; N, 14.0 C20H32H4O3.1H2O requires: C,60.9; H,8.7; N..14.2%. EXAMPLE 7 5-[[5-[3-[(2-Furanmethylamino)methyl]phenoxy]pentyl]amino]1-methyl-1H-1,2,4-triazole-3-methanol 5-[ [5-(3-Formylphenoxy)pentyl]amino]-l-methyl-lR-1, 2,4- triazole-3-methanol (0.46g) and 2-fdranmethanamine (3.42g) in ethanol (20 ml) were stirred together at 200 for 5h. Sodium borohydride (0.37g) was added and tile mixture stirred at 200 for 16h. The mixture was evaporated and the residue partitioned between 2N hydrochloric acid and ethyl acetate0 The aqueous layer was washed with ethyl acetate, neutralised with potassium carbonate, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo, and the residual oil was chromatographed on silica gel using a mixture of methanol-ethyl acetate (1:1) to give the title compound as an oil (O.2g). T.l.c. silica:methanol Rf 0.5. N.m.r. (CDCl3) 1.6,m, (1H); 2.75,t, (1H); 3.0-3.3,m, (3H); 3.67.3.8,m, (2H); 5.4,s, (2H); 5.7,m, (1H); 6.2-6.8,m, (11H); 8.0-8.6,m, (6H). Examples of Pharmaceutical Compositions TABLETS mg/tablet Active ingredient 100.00 Microcrystalline Cellulose BPC 198.50 Magnesium stearate BP 1.50 Compression weight 300000 The active ingredient is sieved through a 250 /um sieve, blended with the excipients and compressed using 9.5mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit. The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxypropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated. njection for Intravenous Administration % w/v Active ingredient 1.00 Water for injections B.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using either dilute acid or alkali. 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 into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen. EXAMPLE 8 2-[3-[2-(N, N-Dimethylamino)methyl]phenyl]propyl]ethyl] N'-methyl-2-nitro-1,1-ethenediamine 3-[3-[2-Aminoethoxy]propyl]N,N-dimethyl-benzenemethanamine A suspension of 3-[(N,N-dimethylamino)methyl]benzene propanol (2.5g), potassium tertiary butoxide (o.56g), 2-chloroethylamine hydrochloride (0.59g) in dimethylformamide (10 ml) was stirred at 0-5 under a nitrogen atmosphere for 24h. The mixture was poured onto water (1 1) and extracted with ethyl acetate. The organic extract was evaporated to leave a yellow oil which was purified by column chromatography using methanol followed by methanol: 0.880 ammonia; (20:1) to give tile title compound as a brown oil (73 mg). T.l.c. system B Rf 0.2 2- 3-[ 2- (N, N-Dimethyl amino )methyl 1 phenyl 1 pro pyl 1 ethyl 1 - N' -methyl-2-nitro-l , l-ethenediamine Following the method of Example 6, 3-[3-[2-aminoethoxy] propyl]N,N-dimethyl-benzenemethanamine (7) mg) gave the title compound as a white powder (38 mg). T.l.c. system B Rf 0.35 N.mr. (CDCl3) -1 to 0, br.s., (1H); 2.7-5.1, m, (4H); 3.1-3.5, br.s., (1H); 3.41, s, (1H); 6.3 6.7, m, (6H); 6.62, s, (2H); 7.20, br.s., (3H); 7.35, m, (2H); 7.80, s, (6H); 8.12, m,(2H) The ability of the compounds of the invention to inhibit histamine induced gastric acid secretion has been demonstrated in the perfused rat stomach preparation referred to previously; the effectiveness of a compound conveniently being expressed in terms of its ED50 (mg/kg) value. Tile results obtained for a representative number o-f compounds according to the invention are given below: 1(b) 0.19 2(a) 0.2 3 0.22 0.17 5(b) 0.027 The compounds of the invention have in general low toxicity at doses at which they effectively inhibit gastric acid secretion. Thus for instance the compounds listed above produced no toxic effects when admisistered intravenously to anaesthetised rats at does in excess of 4 times their ED50 values.

Claims: CLAIMS: 1. Compounds of the general formula (I) RlR2N-Alk-Q-X(CH2)nY(CH2)mNH-B (i) and physiologically acceptable salts, hydrates and bioprecursors thereof in which B represents either the group EMI30.1 or tile EMI30.2 ; ; R1 represents hydrogen, cycloalkyl, aralkyl, trifluoroalkyl, heteroaralkyl or C16 alkyl substituted by cycloalkyl or a C1-16 straight or branched saturaled or unsaturated alkylene chain optionally substituted by a hydroxy, amino, alkylamino, dialkylamino, ester (-CO2R6 where R6 is a C13 alkyl group) or carboxamide (CONH2) group, or R1 represents a C1-16 straight or branched saturated or unsaturated alkylene chain interrupted by an oxygen atom, sulphur atom, sulphoxide, sulphone, amide (-CONH- or -NHCO-) or ester (-COO- or -OCO-) group with the proviso that when the alkylene chain is interrupted by an oxygen or sulphur atom, or a sulphoxide, -CONH- or -COO- group then there must be at least two carbon atoms between that group and the nitrogen atom to which the group R1 is attached; R2 represents hydrogen or a C1,4 alkyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5-10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1-3 alkyl groups or a hydroxy group and/or may contain another heteroatom selected from oxygen and sulphur; Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms; ; Q represents a furan or thiophen ring in which incorporation into the rest of the molecule is through bonds at the 2- and 5- positions, the furan ring optionally bearing a further substituent R7 adjaceiit to the group RlR2-N-Alk-, or Q represents a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4- positions; R7 represents halogen or C1-4 alkyl which may be substituted by hydroxy o C1-4 alkoxy; X and Y, which may be the same or different, each represent oxygen or sulphur, or one of X and Y represents -CR2- and the other represents oxygen or sulphur; n and m, which may be the same or different, each represent 2 or 3; ; R3 represents hydrogen, alkyl, alkenyl, alkynyl, aralkyl or alkoxyalkyl; Z represents CIINO, or NR8 where R8 is nitro, cyano, alkylsulphonyl or arylsulphonyl; represents hydrogen, alkyl, alkeiiyl, aralkyl,or 2-6 alkyl substituted by hydroxy or alkoxy; and R5 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy or alkoxy or the group NR9R10 where R9 represents hydrogen, alkyl, alkyl substituted by hydroxy or C1-3 alkoxy, alkenyl, aralkyl or heteroaralkyl and R10 represents any of the groups defined for R9 or may represent the group C0H11 where R11 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or monocyclic heteroaralkyl or R10 represents the group SO2R12 where R12 represents alkyl or aryl, or P10 represents the group EMI31.1 where E is oxygen or sulphur and represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl, or R9 and R10 taken together represent the group =CR14R15 where R14 represents aryl or heteroaryl and R15 represents hydrogen or alkyl. 2. Compounds as claimed in Claim 1, in wiicll tile groups R1, R2 and R7 have the following meanings: R1: alkyl containing up to 16 carbon atoms all optionally containing an ester or amide grouping, C5-7 cycloalkyl, alkenyl, aralkyl, C1-4 alkyl substituted by a trifluoromethyl group, hydroxy 2-4 alkyl, C1-3 alkoxy C2-4 alkyl, or di-Cl 3 alkylaminoalkyl, or heteroaralkyl where the hetero cyclic portion represents a furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl, thiazolyl, isoquinolinyl, quinolinyl or indolyl ring and the alkylene port ion is methylene, ethylene or propylene; R2: hydrogen or C1-4 alkyl; or R1R2N may represent a 5-8 membered riiig optionally containing one double bond and/or substituted by one or two C1-3 alkyl groups or a hydroxy group and/or containing an oxygen or sulphur atom; R7: bromine atom or a C1-3 alkyl group or a C13 alkoxy C1-3 alkyl group; and B represents the group EMI32.1 in which R3 and Z have the following meanings: hydrogen, C1-4 alkyl or C1-3 alkoxy C2-4 alkyl; CHNO2 or NR8 where R8 is nitro, cyano or C1-4 alkylsulphonyl; or B represents the group EMI32.2 in which R4 and R have the following meanings: R4: hydrogen, C1-4 alkyl or hydroxy C2-4 alkyl; hydrogen, hydroxy, C1 4 alkyl, hydroxy C1-4 alkyl, C 1-3 alkoxy C1 alkyl, phenyl C1-3 alkyl, C2-4 alkanoyloxy C1-4 alkyl, amino C1-4 alkyl, amino, C 1-4 alkylamino, di-C1-4 alkyl- amino, phenyl C1-3 alkylamino, or a heteroaryl C1-3 alkylamino group where the heteroaryl ring is 5 or 6 membered and contains one heteroatom; ; or the group NHCOR11 where R11 represents hydrdgen, C1 3 alkyl, C1-3 alkoxy, furyl, pyridyl, thiazolyl, thienyl, or phenyl optionally substituted by a C1-3 alkyl or C13 alkoxy group; or the group NHS02R12 where R12 represents C1-3 alkyl, or phenyl optionally substituted by a C1-3 alkyl or C1-3 alkoxy group; or the group -NHCONHR13 where R13 is C1-3 alkyl, C5 cycloalkyl, or phenyl optionally substituted by a C1-3 alkyl or C 1-3 alkoxy group; or the group N=CHR14 where R14 is a phenyl or pyridyl group; and tbe group Alk is the group (CH2)p where P is 1, 2 or 3. 30 Compounds as claimed in Claim 1 or 2 in which the group Q is a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3positions;one of X and Y is oxygen and the other is oxygen or methylene; and n and m are both two. 4. Compounds as claimed in Claim 1 corresponding to formula (III) EMI33.1 in which R1R2N forms a pyrrolidino, piperidino, hexamethylenimino, tetrahydropyridino or 4-methylpiperidino group; Z represents CHNO2 or NR8 where R8 is methylsulphonyl; and R3 represents hydrogen, C1-4 alkyl or C13 alkoxy C2-4 alkyl. 50 Compounds as claimed in Claim 1 corresponding to formula (II) EMI34.1 where R1 and R2 are methyl groups or together with tile nitrogen atom to which they are attached form a pyrrolidino, piperidino, hexamethylenimino, tetrahydropyridino or 4-methylpiperidino group; R4 is hydrogen or methyl; and R5 is an amino, hydroxyalkyl, alkanoylamino, alkanoyloxyalkyl, alkoxyalkyl, aminoalkyl, benzyl, formamido, alkoxycarbonylamino, hydroxy, aroylamino or phenylcarbamoylamino group; and Y represents oxygen or methylene. 6. A compound as claimed in Claim 1, which is N-[5-L3-(1-piperidinylmetilyl)phenoxy]pentyl]-Nl-methyl-2- nitro-l,l-ethenediamine or a physiologically acceptable salt thereof. 7. Compounds as claimed in Claim 1 in which B represents EMI34.2 R1 represents hydrogen, cycloalkyl, aralkyl, trifluoroalkyl, heteroaralkyl or C16 alkyl substituted by cycloalkyl, amino, alkylamino or dialkylamino; or R1 represents a C1,16 straight or branched saturated or unsaturated alkylene chain which may be optionally substituted by a hydroxy, ester (CO2R6 where 116 is a C1-3 alkyl group) or carboxamide (CONH2) group; or R1 represents a C1-16 straight or branched saturated or unsaturated alkylene chain interrupted by an oxygen atom, sulphur atom, sulphoxide, sulphone, amide (-CONH- or -NHCO-) or ester (-COO- or -OCO-) group, with the proviso that when the alkylene chain is interrupted by an oxygen or sulphur atom, or the sulphoxide, -COMIor -COO- group then there must be at least two carbon atoms between that group and the nitrogen atom to which the group R1 is attached; Ho represents hydrogen or a C14 alkyl group; ; or 111 and R2 together with the nitrogen atom to which they are attached form a 5-10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C 3 alkyl groups or a hydroxy group and/or may contain another heteroatom; and R9 and 1110 represent hydrogen, alkyl, alkyl substituted by hydroxy or C1-3 alkoxy, alkenyl, aralkyl or heteroaralkyl or R9 and R10 together represent the group =CR14R15 where H14 represents aryl or heteroaryl and R R15 represents hydrogen or alkyl. 8. A process for the production of compounds of formula (I) as defined in Claim 1, characterised in that a) for the production of compounds in wiiich B represents the group EMI35.1 a a primary amine of formula R16MI2 (IV) is reacted with a compound of general formula (V) EMI35.2 in which one of the groups R16 and R17 represents the group R1R2NAlkQX(CH2)nY(CH2)m- and the other represents the group R3, and P is a leaving group. b) for the production of compounds in which B represents the group. EMI36.1 where R@ is other than an alkoxy or acyloxyalkyl group, or the group -N=CR14R15, a compound of formula (VII) EMI36.2 in which V1 is EMI36.3 or NCN and YÚ is hydrogen,where V is oxygen or sulphur and H5 is a group as defined for R5 or is a group convertible thereto under the conditions of the reaction or represents halogen or alkoxy, or V1 is NH and YÚ os EMI36.4 , is cyclised; e) for the production of compounds in which Alk is CH2 and B represents the group EMI36.5 in which R5 is other than the group -N=CR14R15, an intermediate formed by reacting a compound of formula (IX) EMI36.6 in which W represents the group -CI-IO, with a reagent R1R2NH, is reduced: d) for the production of compounds in which B represents the group EMI37.1 in which R5 is other than the group -N=CR14-R15, a compound of formula (I) in which B represents the group EMI37.2 in which R5 is other than the group -N=CR14Rl5 and in which R1 is hydrogen is reacted with an aldehyde R1-CHO under reducing conditions, the group R1 having a R1 meaning such that the resultant group R1CH2 represents a group R1 as defined in formula (I); e) for the production of compounds in which B represents the group EMI37.3 in which R5 is an acyloxyalkyl group, the corresponding hydroxyalkyl compound is treated with an appropriate acid at elevated temperature; f) for the production of compounds in which B represents the group EMI38.1 in which the group R5 represents the group -N=CR14Rl5, a compound of formula (I) in which R5 is an N112 group is reacted with an aldehyde or ketone R14R15 CO; g) for the production of compounds in which B represents the group EMI38.2 in which R5 is the group NH9R10 where R10 is -CORll, -S02R12 or -C(=E)NHR13, a compound of formula (I) in which R5 is the group -NHR9 and R1, R2, R4 and R9 are as defined in formula (I) or are groups readily convertible thereto is treated with a reagent capable of replacing the hydrogen atom in the group NHR9 by the group R10; ; and where the compound of formula (I) is produced in the form of a free base, optionally converting the free base into a salt. 9. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 7 together with at least one pharmaceutically acceptable carrier or diluent, and optionally one or more further acting ingredients0 10. Compounds as claimed in Claim 1 in which B is CNHR3 where Z is CHNO2. " Z 11. Compounds as claimed in Claim 5 in which R5 is amino, alkanoylamino, hydroxyalkyl or benzyl.

Inventors: BRADSHAW, JOHN, CAREY, LINDA, CLITHEROW, JOHN WATSON, HAYES, ROGER, MACFARLANE MACKINNON, JOHN WILSON
Applicants: GLAXO GROUP LIMITED
Application year: 1980
Main classification: C07C87
IPC codes: C07D249, C07D317, C07D295, C07D209