GB2063875A

GB2063875A - Heterocyclic derivatives: Processes for the production thereof and pharmaceutical compositions containing them

Info

Publication number: GB2063875A
Application number: GB8034212A
Authority: GB
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1979-10-23
Filing date: 1980-10-23
Publication date: 1981-06-10
Also published as: GB2063875B

Abstract

The invention relates to compounds of the general formula (I> <IMAGE> and physiologically acceptable salts, hydrates and bioprecursors thereof in which one of R1 and R2 represents hydrogen, halogen or a C1-4 alkyl group which may be optionally substituted by hydroxy or C1-4 alkoxy, and the other represents the group R4R5NAlk- in which R4 represents hydrogen, C1-10 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, and R5 represents hydrogen or a C1-4 alkyl group, or R4 and R5 may, together with the nitrogen atom to which they are attached, form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1-3 alkyl groups e.g. methyl, or a hydroxy group and/or may contain another hetero- atom, 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; R3, which may be in either the 2- or 3-position, represents the group -(CH2)nX(CH2)mNH-Z where X represents -CH2-, -O- or -S- n represents zero, 1 or 2; m represents 2, 3 or 4; and Z represents either the group <IMAGE> or the group <IMAGE> where Y represents S, O, CHNO2 or NR9 where R9 is nitro, cyano, alkylsulphonyl or arylsulphonyl; R6 represents hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl or aralkyl; R7 represents hydrogen, alkyl, alkenyl, aralkyl, or C2-6 alkyl substituted by hydroxy or alkoxy; and R8 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy or alkoxy, or the group NR10R11 where R10 represents hydrogen, alkyl, alkyl substituted by hydroxy or C1-3 alkoxy, alkenyl, aralkyl or heteroaralkyl, and R11 represents any of the groups defined for R10 or may represent COR12 where R12 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or heteroaralkyl or R11 represents the group SO2R13 where R13 represents alkyl or aryl, or R11 represents the group <IMAGE> where E represents oxygen or sulphur, and R14 represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl, or R10 and R11 taken together represent the group =CR15R16 where R15 represents aryl, or heteroaryl and R16 represents hydrogen or alkyl, with the provisos that where R2 represents the group R4R5NAlk then R3 is in the 2-position; and where R2 represents hydrogen then R3 is in the 3-position. The compounds of formula (I) show pharmacological activity as selective histamine H2-antagonists.

Description

SPECIFICATION Heterocyclic derivatives, processes for the production thereof and pharmaceutical compositions containing them The 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 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 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 1972236385. 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 gastro-intestinal smooth muscle which are mediated via H1-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)

and physiologically acceptable salts, hydrates and bioprecursors thereof, in which one of R1 and R2 represents hydrogen, halogen or a C1.4 alkyl group which may be optionally substituted by hydroxy or CIA alkoxy, and the other represents the group R4R5NAlk in which R4 represents hydrogen, C 0 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, and R5 represents hydrogen or a C1.4 alkyl group, or R4 and R5 may, together with the nitrogen atom to which they are attached, form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1.3 alkyl groups, 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; R3,which may be in either the 2- or 3- position, represents the group -(CH2)nX(CH2)mNH-Z where X represents -CH2-, -O- or -S-; n represents zero, 1 or 2; m represents 2, 3 or 4; and Z represents either the group

or the group

where Y represents S, O, CHNO2 or NR9 where R9 is nitro, cyano, alkylsulphonyl or arylsulphonyl; R6 represents hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl or aralkyl; R7 represents hydrogen, alkyl, alkenyl, aralkyl or C2.6 alkyl substituted by hydroxy or alkoxy; and R8 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy or alkoxy, or the group NRloR11 where Rlo represents hydrogen, alkyl, alkyl substituted by hydroxy or Cur 3 alkoxy, alkenyl, araikyl or heteroaralkyl, and R11 represents any of the groups defined for Rlo or may represent COR12 where R12 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or heteroaralkyl, or R11 represents the group SO2R13 where R13 represents alkyl or aryl, or R11 represents the group

where E represents oxygen or sulphur, and R14 represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl, or Rao and R taken together represent the group =CR15R16 where R5 represents aryl or heteroaryl and R16 represents hydrogen or alkyl, with the provisos that where R2 represents the group R4R5NAlk then R3 is in the 2- position; and where R2 represents hyrogen then R3 is in the 3- position.

The term "alkyl" as a group or part of a group means that the group is straight or branched and has unless otherwise stated 1 to 6 carbon atoms, and in particular 1 to 4 carbon atoms e.g. methyl or ethyl and the terms "alkenyl" and "alkynyl" means that the group has 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 3 to 8 carbon atoms. The term "aryl" as a group or part of a group preferably means phenyl or substituted phenyl, for example phenyl substituted with one or more C1.3 alkyl or C1.3 alkoxy groups or halogen atoms e.g. fluorine. The acyl portion of an acyloxyalkyl group means an aroyl, aralkanoyl or C1.8 alkanoyl group. Examples of acyloxyalkyl groups include acetoxymethyl, formyloxymethyl, benzoyloxymethyl and phenylacetoxymethyl.The term "heteroaryl" as a group or part of a group within the definition of R4 and R8 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, thiazolyl or thienyl. The heteroaryl ring may be unsubstituted or substituted by C1.3 alkyl, C1.3 alkoxy, hydroxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The alkyl portion of a heteroaralkyl group is a straight or branched C, 4 alkyl chain, and the heteroaryl ring is linked to the alkyl portion through either a carbon or nitrogen atom.

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, tartrates, citrates, benzoates 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 intended to cover all tautomers. Where 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 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 required other active ingredients, e.g. Hr 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 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 multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a 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 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 2 to 4 doses to the total of some 5 mg. to 2 g per day, preferably 5 to 500 mg. per day, dependant upon the condition of the patient.

Examples of suitable meanings for the groups R1, R2, R4, R5, R6, R7, R8, Y and Alk are as follows: R1 or R2 (when other than the group R4R5NAlk): bromine atom or a C1.3 alkyl group (e.g. methyl, ethyl or isopropyl) or a R1-3 alkoxy C, 3 alkyl group (e.g.

methoxymethyl) or a hydroxy C, 3 alkyl group (e.g. hydroxymethyl); or, when R1 or R2 is the group R4R5NAlk, R4: alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or decyl), C5-7 cycloalkyl (e.g. cyclopentyl, cyclohexyl or cycloheptyl), alkenyl (e.g. allyl or 3,3-dimethylallyl), aralkyl (e.g. phenylalkyl such as benzyl or phenethyl), CiA alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), hydroxy C2-4 alkyl (e.g.

3-hydroxypropyl), C1-3 alkoxy C2-4 alkyl (e.g. methoxyethyl or ethoxyethyl), 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 or thiazolyl ring and the alkylene portion is for example a methylene, ethylene or propylene grouping; and Fl5: hydrogen ora methyl or ethyl group; or R4R5N may represent a 5-8 membered ring optionally containing one double bond and/or substituted by one or two C1-3 alkyl (e.g. methyl) groups or a hydroxy group and/or containing an oxygen or sulphur atom (e.g. pyrrolidino, piperidino, hexamethylenimino, heptamethylenimino, tetrahydropyridino, 4hydroxypiperidino, 4-C1.3 alkylpiperidino (e.g. morpholino, 2,6-di-C1.3 alkylmorpholino (e.g. 2,6-dimethylmorpholino), orthiamorpholino); Rs: hydrogen, C, 4 alkyl (e.g. methyl or ethyl) or C1.3 alkoxy -methylpiperidino), alkyl (e.g. methoxyethyl); Y:CHNO2 or NRg where Rg is nitro, cyano, C2-4 alkylsulphonyl (e.g.methylsulphonyl) or arylsulphonyl (e.g. phenylsulphonyl); R7: hydrogen, C1.4 alkyl (e.g. methyl, ethyl or propyl), or hydroxy-C24 alkyl (e.g. 2-hydroxyethyl); C1-4 hydrogen, hydroxy, R8: alkyl (e.g. methyl, ethyl or isobutyl), hydroxy C, 4 alkyl (e.g. hydroxymethyl, 2-hydroxyethyl or 1-hydroxy-1-methylethyl), C1 3 alkoxy C1-4 alkyl (e.g. methoxymethyl or methoxyethyl), phenyl C1-4 alkyl (e.g. benzyl or phenethyl), C1-3 alkanoyloxy C, 4 alkyl (e.g. acetoxymethyl), amino C, 4 alkyl (e.g. aminomethyl), amino, C, 4 alkylamino (e.g. methylamino or ethylamino) or di-C1.4 alkylamino (e.g.

dimethylamino, diethylamino or dipropylamino), phenyl C2-4 alkylamino (e.g. benzylamino), or a heteroaryl C, 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 C1-3 where R,2 represents hydrogen, C, 3 alkyl (e.g. methyl or ethyl), C1.3 alkoxy (e.g. methoxy or ethoxy), furyl, pyridyl, thiazolyl, thienyl, or phenyl optionally substituted by a C, 3 alkyl (e.g. methyl) or NHCOR12 alkoxy (e.g. methoxy) group; or the group NHS02R13 where R13 represents C1-3 alkyl (e.g. methyl), or phenyl optionally substituted by a C1-3 alkyl (e.g. methyi) or C1-3 alkoxy (e.g. methoxy) group; or the group C1-3 R14 is NHCONHR14 where 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 C1-3 where R15 is a phenyl or pyridyl (e.g. 3- or 4- pyridyl) group. The group Alk may be for example the group (CH2)p where P is 1, 2 or 3.In particular the groups RX, R2, R4, R5, N-CHR15 R7, R6 and Y may have the following meanings: R8 or R2 (when other than the group R1 hydrogen or R4R5NAlK): alkyl (e.g. methyl); C1-4 C17 alkyl (e.g. methyl, propyl, butyl, isobutyl or heptyl), R4: alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), C1-4 alkyl substituted by a hydroxy or di C2-4 alkylamino group (e.g.

3-hydroxypropyl or dimethylaminoethyl), C57 cycloalkyl (e.g. cyclohexyl), alkenyl (e.g. allyl), phenyl C1-3 C1-3 alkyl (e.g. benzyl), or a heteroaryl C1-3 alkyl group where the heteroaryl ring is 5 or 6 membered and contains one heteroatom (e.g. furylmethyl); R5: hydrogen or methyl; or R4R5N may represent a 5 to 7 membered ring, optionally containing a double bond or an alkyl (e.g. methyl) group (e.g. piperidino, 4-methylpiperidino, pyrrolidino, hexamethylenimino or tetrahydropyridino); R6: hydrogen or C1-3 alkyl (e.g. methyl) Y:CHNO2 or NRg where Rg is nitro or methylsulphonyl; R7: hydrogen, methyl, ethyl or 2-hydroxyethyl; R8: hydroxy, phenyl C1-3 alkyl (e.g. benzyl), C, 4 alkyl substituted by hydroxy, C1-3 alkoxy, C2 4 alkanoyloxy or amino (e.g. hydroxymethyl, 2-hydroxyethyl, acetoxymethyl or aminomethyl); amino, di-01.4 alkylamino (e.g. diethylamino); NHCOR12 where Rq2 represents hydrogen, C1-3 alkyl (e.g. methyl), 01.3 alkoxy (e.g.

ethoxy), or phenyl; NHCONHR14 where R14 represents phenyl; or N =CHR15 where R15 is phenyl or pyridyl (e.g. 4-pyridyl).

Alk is particularly a methylene or ethylene group, more particularly methylene.

When R3 is in the 3-position preferably R2 represents hydrogen.

When R3 is in the 2-position preferably R2 represents alkyl (e.g. methyl).

When Xis sulphur, n is preferably 1 and m is preferably 2.

Three preferred groups of compounds are as follows: (i) compounds in which R3 is in the 3- position and R1 is the group R4R5NAlk, and R2 is more particularly hydrogen; (ii) compounds in which R3 is in the 2-position and R2 is the group R4R5NAlk; (iii) compounds in which R3 is in the 2- position and R1 is the group R4R5NAlk, and R2 is more particularly alkyl (e.g. methyl).

A preferred group of compounds of formula (I) where Z represents the group

are those in which Y represent the group CHNO2 and R6 is more particularly alkyl (e.g. methyl).

A preferred group of compounds of formula (I) where Z represents the group

are those in which R7 is hydrogen or methyl, and Rs is amino, hydroxyalkyl, alkoxyalkyl, benzyl, formamido, alkanoylamino, aminoalkyl, alkanoyloxyalkyl, hydroxy, aroylamino or phenylcarbamoylamino.

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

where R4and R5 are methyl groups or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexamethyleneimino group, and Z represents either

where Rg is methyl, or the group

where R7 is hydrogen or methyl, and R8 is amino, hydroxyalkyl, alkoxyalkyl, benzyl, formamido, alkanoylamino, aminoalkyl, alkanoyloxyalkyl, hydroxy, aroylamino or phenylcarbamoylamino.

The following compoounds and their physiologically acceptable salts are particularly preferred: N-methyl-N-[2[[5-(dimethylaminomethyl)-3-thienylmethyl]-thio]ethyl-2-nitro-1,1-ethenediamine N-methyl-N'-[2-[[5-(1-pyrrolidinylmethyl)-3-thienylmethyl]-thio]ethyl-2-nitro-1,1-ethenediamine N-methyl-N'-[2-[[5-(1-piperidinylmethyl)-e-thienylmethyl]-thio]ethyl-2-nitro-1,1-ethenediamine N-[2-[[5-(dimethylaminomethyl)-4-methyl-2-thienylmethyl]-thio]ethyl-2-nitro-1,1ethenediamine N-[2-[[5-(dimethylaminomethyl)-3-thienylmethoxy]propyl]-N'-methyl-2-nitro-1,1-ethenediamine 1-methyl-N5-[2-[[5-[(dimethylamino)methyl]-4-mjethyl-2-thienylmethyl]thio]ethyl-1H-1,2,4-triazole-3,5diamine 1-methyl-5-[[2-[[5-(dimethylaminomethyl)-3-thienylmethyl]-thio]ethyl]amino]-1H-1,2,4-triazole-3methanol 5-[[2-[[[5-(dimethylaminomethyl)-4-methyl]-2-thienylmethylj-thio]ethyljaminoj-1 -methyl-1 H-1,2,4-triazole- 3-methanol 5-[[2-[[5-(dimethylaminomethyl)-34hienyl]methyl]thio]ethyl]amino-3-phenylmethyl1 H-1,2,4-triazole.

According to one aspect the invention provides compounds of formula (I) in which one of R1 and R2 represents hydrogen and the other represents R4R5NAlk and R3 represents

except that Y does not represent NRg where Rg is alkylsulphonyl or arylsulphonyl.

According to another aspect the invention provides compounds of formula (I) in which one of R1 and R2 represents hydrogen and the other represents R4R5NAlK and R3 represents

where R8 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, alkoxyalkyl, hydroxy or alkoxy or R8 represents the group NR10R11 where R10 represents hydrogen, alkyl, hydroxyalkyl, alkenyl or aralkyl and R11 represents hydrogen, alkyl, hydroxyalkyl, or the group COR 12 where R12 represents hydrogen, alkyl, aryl, aralkyl, or alkoxy, or R11 represents the group SO2R13 where Ra3 represents alkyl or aryl, or R10 and R11 taken together represent the group = CR15R16 where R15 represents aryl and R16 represents hydrogen or alkyl.

According to a further aspect the invention provides compounds of formula (I) in which R1 is R4R5NAlK-, R2 is halogen or a C1-4 alkyl group which may be optionally substituted by hydroxy or C1-4 alkoxy and R3, which is in the 2- position represents

except that R4 and R5 do not represent alkynyl or heteroaralkyl and R4RsN does not represent a 9 or 10 membered ring.

According to a still further aspect the invention provides compounds of formula (I) in which R1 is R4R5NAlk-, R2 is halogen or a C1 4 alkyl group which may be substituted by hydroxy or C1 4 alkoxy and R3, which is in the 2- position represents

except that R4 and R5 do not represent alkynyl or heteroaralkyl and R4R5N does not represent a 9 or 10 membered ring.

It will be appreciated in the methods for the preparation of the compounds of formula (I) given below, that for certain reaction steps it may be necessary to protect various reactive substituents in the starting materials for a particular reaction and subsequently to remove the protecting group. Such protection and subsequent deprotection may be particularly pertinent when R4 and Rg and/or Rg are hydrogen, and/or when R7 is an alkyl group bearing a hydroxy substituent and/or R8 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, with subsequent cleavage by treatment with a hydrazine e.g. hydrazine hydrate or a primary amine for example methylamine.

In describing the processes which may be used for preparing the compounds for formula (I) or intermediates useful in the preparation thereof, any of R1 to R16, Alk, X, Y, Z, E, n and m are as defined in formula (I) unless otherwise stated.

Compounds of formula (I) where Z represents the group

may be made by reacting an amine of the formula R17NH2 (III) with a compound of general formula

wherein one of the groups R17 and R18 represents the group

and the other represents the group Rs, and P is a leaving group such as halogen, thioalkyl (preferably thiomethyl) or alkoxy.

Compounds of formula (IV) may be prepared by reacting the amine (III) with a compound of formula (V)

where P is as defined in formula (IV).

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 Z represents the group

where R8 is other than an alkoxy or acyloxyalkyl group or the group = CR15R16 may be prepared by cyclisation of a compound of formula (Vl)

in which V1 is

or NCN andY1 is hydrogen where V is oxygen or sulphur and R8 is a group as defined in formula (I) for R8 or a group convertible thereto under the conditions of the cyclisation reaction or represents halogen or alkoxy; or V1 is NH and Y' is

In a particular embodiment of the above process compounds of formula (I) in which the group Z represents

where R8 is amino, hydroxy or a carbon-iinked group may conveniently be prepared by cyclisation of a compound of formula (VII)

where V represents the group NCN or

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 (VII) in which Z1 represents two hydrogen atoms by treating a compound of formula (VII) where Z1 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 R8 is a hydroxyalkyl group it is preferable that in the intermediate (VII) 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 CH2 and where Z represents the group

in which R8 is other than the group -N = CR15R16 may be prepared by reducing the intermediate formed from reacting a compound of formula (VIII)

in which one of R1 and R2 represents hydrogen, halogen or a C1 4 alkyl group which may be optionally substituted by hydroxy or C, 4 alkoxy and the other represents the group -CHO with a reagent R4R5NH.

Reaction may be effected by treatment with ammonia or an amine R4R5NH 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 R8 is other than - N =CR15R16, a compound of formula (I) in which R4 is hydrogen may be reacted with an aldehyde Fl41-CHO under the reducing conditions described above, the group R1 having a meaning such that the resulting group R4CH2 represents a group R4 as defined above. This method applies particularly to the preparation of compounds of formula (I) in which R4 is heteroaralkyl or an optionally substituted alkyl chain containing up to 10 carbon atoms.

In certain instances compounds of formula (I) where Z represents the group

may be prepared by methods involving interconversion of the substituent R8.

Thus compounds in which R8 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.

80-120 C in the absence or presence of a solvent such as toluene.

Compounds of formula (I) in which R8 represents the group -N=CFl15Fl15 may be prepared from compounds of formula (I) in which R8 is an NH2 group by reaction with an aldehyde or ketone R15R16CO in a solvent such as benzene, ethanol, or methanol. The reaction is peferably carried out with heating, e.g. at reflux.

Compounds of formula (I) in which R8 is the group NFl10Fl11 where R11 is -C0R12, -S02Fl13 or -C(=E)NHR14 may be prepared by treating a compound of formula (I) in which R8 is the group -NHFl10 and Fl1, R2, R7 and Rr0 are as defined in Formula (I) or are groups readily convertible thereto with a reagent capable of repiacing the hydrogen atom in the group NHFl10 by the group R11 where R11 is as defined above.

Thus, for example, reaction with an activated derivative of either a carboxylic acid R12COOH or a sulphonic acid R3SO3H or reaction with an isocyanate or isothiocyanate R14NCE in which R14 has any of the meanings defined for Rt4 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 R11 is respectively the group COR,2, S02Fl13 or C(=E)NHR14.

Suitable activated derivates 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 (1 -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 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 presence of solvent such as pyridine.

In the reaction with an isocyanate or isothiocyanate 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 an elevated temperature, e.g. reflux. Compounds of formula (I) in which R14 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 hydroxide.

Compounds of formula (I) may also be prepared by treating a compound of formula (I) in which the group R4R5N is replaced by a quaternary ammonium group (e.g. a trimethylammonium group) with an amine R4R5NH. The reaction may be carried out by heating the quaternary ammonium compound in the amine (e.g.

at 100 to 120 C) or the reaction may be carried out in the presence of a solvent such as an alkanol (e.g.

ethanol) at reflux. This process is particularly applicable to compounds in which Alk is CH2.

Amines of formula (III) may be made by a number of methods depending on the precise structure of the compound.

Thus amines of formula (IX)

in which n is 1 or 2 and X is oxygen or sulphur may be prepared from the corresponding alcohol of formula (X)

in which n is 1 or 2.

For example amines of formula (IX) in which n is 1 and Xis sulphur may be prepared by reacting an alcohol of formula (X) in which n is 1 with an appropriate aminoalkane thiol salt (e.g. cysteamine hydrochloride) in a concentrated mineral acid (e.g. hydrochloric acid).

Amines of formula (IX) in which n is 2 and Xis sulphur may be prepared by converting an alcohol of formula (X) in which n is 2 into the corresponding haloalkyl compound using for example thionyl chloride or phosphorus tribromide, or mesylate by reaction with methanesulphonylchloride, followed by treatment with an appropriate aminoalkylthiol (e.g. cysteamine) in a solvent such as ethanol and in the presence of a base (e.g. sodium ethoxide).

Amines of formula (IX) in which n is 1 or 2 and Xis oxygen may be prepared by treating an alcohol of formula (X) in which n is 1 or 2 with a suitable base (e.g. potassium t- butoxide) in a solvent (.e.g.

dimethylformamide) followed by the addition of an appropriate haloalkylamine (e.g. chloropropylamine).

The alcohols of formula (X), as well as the intermediates (XXII) and (XXIV) below, may be made by a variety of processes based on conventional methods in thiophene chemistry (Advances in Heterocyclic Chemistry Volume 1, 1963, page 2-116, Ed. A.R. Katritzky, Academic Press, London and New York; and Comprehensive Chemistry Volume 4, page 787, Ed. P.G. Sammes, Pergamon Press, Oxford). Some representative routes and reagents are given in each case.

Alcohols of formula (X) in which R1 is the group R4R5NCH2, n is 1 and the hydroxymethyl substituent is in either the 2- or 3- position may be prepared by treating a compound of formula (Xl)

with an amine R4RSNH under reducing conditions as described previously for the preparation of compounds of the invention, to give a thiophenemethanamine of formula (XII) which may be subsequently reacted with paraformaldehyde in a concentrated mineral acid (e.g. hydrochloric acid) and acetic acid to introduce the hydroxymethyl group at either the 2- or 3- position.

Alcohols of formula (X) in which R2 is the group R4R5NCH2, n is 1 and the hydroxymethyl substituent is at the 2- position may be prepared by reacting a compound of formula (XIII)

with for example oxalyl chloride in a solvent (e.g. benzene) and preferably in the presence of a catalyst (e.g.

pyridine) followed by treatment with an amine R4R5NH to give an amide of formula (XIV) which is subsequently reduced with a complex metal hydride e.g. lithium aluminium hydride in a solvent such as tetrahydrofuran to give a compound of formula (XV).

The 2- hydroxymethyl group is then introduced by reacting the compound of formula (XV) with formaldehyde or a precursor of formaldehyde such as paraformaldehyde, in a concentrated mineral acid, e.g. hydrochloric acid or acetic acid.

Alcohols of formula (X) in which R1 is the group R4R5NCH2, R2 is hydrogen, n is 1 and the hydroxymethyl substituent is in the 3- position may be prepared from a thiophene 3- carboxylate of formula (XVI)

where R19 is an alkyl group. This compound is halomethylated e.g. chloromethy!ated using for example formaldehyde, or a precursor of formaldehyde such as paraformaldehyde, and gaseous hydrogen chloride in a solvent such as chloroform and in the presence of zinc chloride to give a compound of formula (XVII).

The amino group R4R5N- iS then introduced into the compound offormula (XVII) by reaction with an amine R4R5NH, in a suitable solvent such as ether, to give a compound of formula (XVIII)

Introduction of the 3- hydroxymethyl group is effected by reduction of the 3- carboxylate using for example lithium aluminium hydride in a suitable solvent such as ether.

Alcohols of formula (X) in which n is 2 may be prepared by lithiating a halothiophene of formula (XIX)

(where Hal is halogen e.g. bromine) using n- butyl lithium in a suitable solvent (e.g. tetrahydrofuran) at a low temperature (e.g. -78"), followed by treatment of the resulting lithio derivative (XX) with ethylene oxide in a solvent such as tetrahydrofuran, to give the desired hydroxyethyl compound (X, n=2).

In a modification of this process a halothiophene of formula (XIX) in which R1 is a group convertible to R4R5NCH2- (e.g. an aldehyde grouping protected as an acetal) and the group Hal is at the 3- position may be lithiated and treated with ethylene oxide as described above to give a hydroxyethyl compound of formula (XXI).

Subsequent treatment with an amine R4R5NH under reducing conditions as described previously for preparing compounds of the invention affords an alcohol of formula (X) in which R1 is the group R4R5NCH2, n is 2 and the hydroxyethyl substituent is at the 3- position.

Amines of formula (IX) in which X is CH2 may be prepared from an appropriate haloalkylthiophene of formula (XXII)

(in which Hal is halogen) by treatment with for example potassium phthalimide in a solvent (e.g.

dimethylformamide), followed by deprotection of the phthalimido derivative using for example hydrazine hydrate.

The haloalkylthiophenes of formula (XXII) may be prepared for example by treating a lithio derivative of formula (XX) with an a,o) - dihaloalkane (e.g. Br(CH2)n+m+ Br) in a solvent such as tetrahydrofuran to give an intermediate of formula (XXII).

Amines of formula (IX) in which Xis CH2 may also be prepared by methods involving conventional homologation of an alkyl chain. Thus for example a haloalkyl (e.g. chloroethyl) thiophene of formula (XXIII)

may be treated with for example sodium cyanide in dioxan to give the corresponding cyanoethyl compound, which may then be reduced (using for example lithium aluminium hydride in tetrahydrofuran) to give the corresponding aminopropyl compound.

Alternatively a chioroethyl compound of formula (XXIII) may be treated with malonic ester to give, after decarboxylation, the corresponding butyric acid derivative. This may be treated with thionyl chloride for example, followed by treatment with ammonia, to give the corresponding amide which may then be reduced using for example lithium aluminium hydride to give the corresponding aminobutyl compound.

Amines of formula (IX) in which n is zero and X is oxygen may be prepared from an appropriate alkoxythiophene (XXIV)

where W is a halogen atom (e.g. chlorine or bromine) or a leaving group (e.g. mesylate), by a similar method to that described above for the preparation of amines of formula (IX) in which Xis CH2 from the corresponding haloalkyl thiophene.

Alkoxythiophenes of formula (XXIV) may be prepared for example by treating a halo (e.g. bromo) thiophene of formula (XIX) with a diol HO(CH2)mOH in the presence of a base (e.g. sodium hydride)) and cuprous oxide, and preferably with the addition of potassium iodide, to give a hydroxyalkoxy compound of formula (XXV)

which may be treated with for example, thionyl chloride, phosphorus tribromide or methanesulphonyl chloride to give the alkoxythiophene of formula (XXIV).

Amines of formula (IX) in which n is zero and X is sulphur may be prepared by treating a lithio derivative of formula (XX) with elemental sulphur, followed by reaction with an appropriate haloalkylamine (e.g.

chloropropylamine) preferably in protected form, e.g. as a phthalimide with subsequent cleavage of the phthalimide group using for example hydrazine hydrate.

Compounds of formula (I) and amines of formula (IX) in which Alk is an alkylene group other than CH2 may be prepared from the intermediates described above in which Alk is CH2 or a group convertible thereto (e.g.

an ester group) by conventional means for ascending a homologous series. Thus for example a hydroxymethyl group may be converted into a chloromethyl group, which may then be converted into an aminoethyl or aminopropyl group by methods analogous to those decribed for amines of formula (IX) in which X is CH2, and thence into the group R4R5NAlk where Alk contains two or three methylene groups.

Intermediates of formula (VI) and (VII) may be prepared from amines of formula (IX) by methods analogous to those described in British Patent Specification No. 2023133Aand European Patent Specification Publication No. 0016565.

Intermediates of formula (VIII) in which the aldehyde grouping is preferably in protected form (e.g. as an acetal) may be prepared by the methods described above for preparing compounds of the invention except that in the appropriate intermediates the group R4R5NAlk is replaced by a protected aldehyde group (e.g. an acetal grouping).

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 the salts is to mix appropriate quantities of the free base and the acid in an appropriate solvent (s), e.g. an alcohol such as ethanol or an ester such as ethyl acetate.

The invention is illustrated by, but not limited to, the following Examples and Preparations. In the exemplification temperatures are in "C and t.l.c. refers to thin layer chromatography carried out on silica using one of the following solvent systems unless otherwise stated.

System A: Methanol: 0.88 ammonia (79:1) System B: Ethyl acetate: isopropanol: water: 0.88 ammonia (25:15:8:2) PREPARATION 1 (a) Methyl 5-{dimethylaminomethyl)-3-thiophene carboxylate A solution of methyl 5-(chloromethyl)-3-thiophenecarboxylate (1.9g) in dry diethylether (100ml) was treated with anhydrous dimethylamine (5ml). After 6 hours the solvent was removed in vacuo and the residue was dissolved in 5M hydrochloric acid (20 ml). The aqueous solution was washed with diethylether, basified with 5M sodium hydroxide (30ml) and extracted with ether. The ethereal extracts were evaporated to give an oily residue which was distilled to yield the title compound as a colourless oil (1.6g) b.p.

120-130 /0.5mm.

The picrate salt was formed in and recrystallised from ethanol.m.p. 165".

The following compounds were similarly prepared from methyl-5-(chloromethyl)-3-thiophenecarboxylate (A) and the corresponding amines: (b) A (79) and pyrrolidine (10ml) gave methyl 5-(1-pyrrolidinylmethyl)-3-thiophene carboxylate (3.3g), Picrate saltm.p. 122-3' (c) A (6g) and piperidine (10ml) gave methyl 5-(1-piperidinylmethyl-3-thiophenecarboxylate (3.6g), Picrate saltm.p. 186'.

PREPARATION 2 (a) 5-(DimethylaminomethylJ-3-thiophenemethanol A solution of methyl 5-(dimethylaminomethyl)-3-thiophenecarboxylate (1.5g) in diethylether (50ml) was treated with lithium aluminium hydride (0.219). After 1 hour water (2ml) was added and the solution was filtered through diatomaceous earth. Evaporation of the filtrate gave an oily residue which distilled to give the title compound as an oil (1.29) b.p. (120 /0.1 mm).

The oxalate salt was formed in and recrystallised from ethanol m.p. 107-8'.

The following compounds were similarly prepared from the corresponding ester.

(b) Methyl 5-(1 -pyrrolidinylmethyl)-3-thiophenecarboxylate (3.2g) gave 5-(1 -pyrrolidinylmethyl)-3- thiophenemethanol (2.49) Oxalate salt m.p. 111-2 .

(c) Methyl 5-(1-piperidinylmethyl)-3-thiophenecarboxylate (3.6g) gave 5-(1 -piperidinylmethyl)-3- thiophenemethanol (2.9g). Oxalate salt m.p. 115-7 C.

PREPARATION 3 Methyl 5-(hydroxymethyl)-3-thiophenecarboxylate A solution of methyl 5-(chloromethyl)-3-thiophenecarboxylate (1.79) in 50% aqueous acetone (60ml) was treated with silver nitrate (1.52g). After 2h the resulting precipitate was filtered and the filtrate was evaporated. The residue was extracted with diethyl ether, and the ethereal extract was washed with water.

Evaporation of the solvent gave an oily residue, which was chromatographed on silica with ethyl acetate-light petroleum 60-80 ; (1:1) to give the title compound as an oil (0.39) b.p. 110/0.imm m.p. 38-40'.

PREPARATION 4 5-(Hydroxymethyl)-N,N-dimethyl-3-thiophenecarboxamide A mixture of methyl 5-(hydroxymethyl)-3-thiophenecarboxyiate (39), sodium methoxide (0.29) and excess anhydrous dimethylamine in dry methanol (20ml) was stirred for 24h at ambient temperature. The solvent was removed in vacuo, water was added and the product was extracted with ethyl acetate. The organic extract was evaporated to leave an oily residue which was chromatographed on silica with ethyl acetate-light petroleum 40-60 ; (1:1) to give the title compound (1.3g).I.R. (CHBr3) OH 3,595cm-1; C = 0 1,620cm- PREPARATION 5 4-(Dimethylaminomethyl)-2-thiophenemethanol A solution of 5-(hydroxymethyl)-N,N-dimethyl-3-thiophenecarboxamide (1.7g) in dry tetrahydrofuran (1 50ml) was treated with a 0.5M solution of aluminium hydride in tetrahydrofuran (26ml) After 2h at room temperature, water (5ml) was cautiously added and the mixture was filtered through diatomaceous earth.

The filtrate was evaporated to leave an oily residue, which was dissolved in 2M hydrochloric acid (20ml). The aqueous solution was washed with diethyl ether, basified with 5M sodium hydroxide and extracted with ethyl acetate.

The organic extract was distilled to give the title compound as an oil (1g) b.p.110/0.1mm 1.R. (CHBr3) OH 3585cm-1; Me2NCH2 2,775cm~1 and 2,820cm-1 PREPARATION 6 1-(3-Methyl-2-thienylmethyl)piperidine A mixture of 3-methyl-2-thiophenecarboxaldehyde (20g), formic acid (6ml) and N-formyl piperidine (44.4ml) was heated under reflux for 12 h. Water (50 ml) and 2 M hydrochloric acid (30ml) were added; and the aqueous solution was washed with ether. The solution was basified to pH 10 with 2M sodium hydroxide (30ml) and extracted with ether. The organic extract was evaporated to give a brown oil which was distilled to afford the title compound as a colourless oil (11 .8g) b.p.70 /0.4mm.

NMFl (CDCl3) 2.9,d, (1 H); 3.27,d, (1 H); 6.48,s, (2H); 7.6,m, (4H); 7.83,s, (3H); ca 8.5,m, ( > 6H).

PREPARATION 7 5- (Dimeth ylaminometh yl)-4-meth yl-2-thiophen em ethanol A solution of N,N-3-trimethyl-2-thiophenemethanamine (1.5g) in dry tetrahydrofuran (50ml) was treated with a solution of n-butyl lithium (1.6M; 7ml) at room temperature, under nitrogen. After 4h, gaseous formaldehyde (excess) was added and the mixture was heated at 40 C for 20h.

Water (100ml) and chloroform (1 00m1) were added and the organic solution evaporated in vacuo to leave an oily residue which was dissolved in ethanol (50ml) and treated with sodium borohydride (0.lg), followed by acetic acid (1 Oml). The reaction mixture was evaporated to dryness and the residue was dissolved in sodium carbonate solution (8%,50ml) and extracted with chloroform. The organic extract was distilled to give the title compound as a colourless oil (0.65g) b.p. 120 /0.1mm.

The oxalate salt was formed in and recrystallised from a mixture of ethanol and ethyl acetate m.p.116-7 C.

(b) Similarly, 1-(3-methyl-2-thienylmethyl)piperidine (39) gave 4-methyl-5-(1 -piperidinylmethyl)-2- thiophenemethanol as an oil (2.4g) b.p. 120 /0.2mm.

N.m.r. (CDCI3) 3.32,s,(lH); 5.32,s,(2H); 6.48,s, (2H); 7.38,brs,(lH); 7.50-7.7,m,(4H); 7.89,s,(3H); 8.30 8.80,m.(6H).

PREPARATION 8 (a) 4-[[2-(Amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine A mixture of 5-(dimethylaminomethyl)-3-thiophenemethanol (1 g) and 2-aminoethanethiol hydrochloride (0.67g) was stirred in concentrated hydrochloric acid (7ml) at 0 C for 2 hours; and then at room temperature for 48 hours. Solid anhydrous sodium carbonate was added and the product was extracted into ethyl acetate.

The organic extract was distilled to give the title compound as a colourless oil (0.759 b.p.130 /0.05mm.

The oxalate salt was formed in ethanol and recrystallised from ethanol and water m.p. 178-9 .

The following compounds were similarly prepared from 2-aminoethanethiol hydrochloride (A) and the corresponding thiophenemethanol.

(b) A(1.5g) and 5-(1 -pyrrolidinylmethyl)-3-thiophenemethanol (2.49) gave 2[[4-(1 -pyrrolidinylmethyl)-2- thienylmethyllthio]ethanamine (1.49).

Oxalate salt m.p. 162-4 .

(c) A(1.6g) and 5-(1 -piperidinylmethyl)-3-thio-phenemethanol (2.99) gave 2-[[4-(1 -pyrrolidinylmethyl)-2- thienylmethyl]thio]ethanamine (2.29), Oxaiate salt m.p. 89-91 (d) A (0.659) and 4-(dimethylaminomethyl)-2 -thiophenemethanol (0.9g) gave 5-[[2 aminoethyl]thio]methyl-N,N-dimethyl-3-thiophenemethanamine (0.8g) b.p. 130 /0.1mm. Oxalate salt m.p. 151-2 .

(e) A (0.6g) and 5-(dimethylaminomethyl)-4-methyl-2-thiophenemethanol (0.6g) gave 5-[[2-aminoethyl] thio]methyl-N,N,3-trimethyl thiophenemethanamine as a colourless oil (0.69g) b.p. 1500/0.lmm. Oxalate salt m.p. 212 dec.

(f) A (1.119) and 4-methyl-5-(l -piperidinylmethyl)-thiophene-2-methanol (2.29) gave 2-[[4-methyl-5-(1 piperidinylmethyl)-2-thienylmethyl]thio]-ethanamine as a yellow viscous oil (1.889) b.p.170 /0.05mm.

(g) A (1.29) and 4-(1 -pyrrolidinylmethyl)-2-thiophenemethanol (1.7g) gave 2[[4-(1 -pyrrolidinylmethyl)-2- thienylmethyl]-thio]ethanamine. b.p.165 /0.02mm. Oxalate salt m.p. 147-8 .

(h) A (1.3g) and 5-methyl-4-(dimethylaminomethyl)-2-thiophenemethanol (2g) gave 5-[[2-(aminoethyl)]- thio]methyl-N,N,2-trimethyl-3-thiophenemethanamine (1.9g). Oxalate salt m.p. 146-7 .

PREPARATION 9 4-(1-Pyrrolidinylmethyl)-2-thiophenemethanol 1-(3-Thienylcarbonyl)pyrrolidine A mixture of 3-thiophenecarboxyiic acid (15g) oxalylchloride (15ml) and pyridine (0.05ml) in toluene (100ml) was heated at reflux for 2 hours. The excess reagent was removed in vacuo and the toluene solution was added to a solution of dry pyrrolidine (25ml) in drytoluene (100ml). After 2h the reaction mixture was washed with dilute hydrochloric acid, 8% aqueous sodium carbonate, saturated brine and water. The organic solution was dried and evaporated to give the title compound (1.89) as a white crystalline solid m.p. 70-73'.

1-(3- Thienylmethyl)pyrrolldine A solution of 1-(3-thienylcarbonyl) pyrrolidine (129) in dry diethylether (200ml) was added to a slurry of lithium aluminium hydride (2.69) in dry diethylether (1 00ml). The mixture was stirred for 1 hour, and aqueous 5M sodium hydroxide (20ml) was added. The mixture was filtered and the filtrate was distilled to give the title compound (9.89) as a colourless oil.b.p. 120/15mm.

4-(1-Pyrrolidinylmethyl)-2-thiophenemethanol A solution of paraformaldehyde (1.59) in conc. hydrochloric acid (15ml) and acetic acid (30ml) was treated with 1-(3-thienylmethyl)-pyrrolidine (2.7g), and the mixture was stirred for 18 hours, at room temperature.

The mixture was poured onto saturated aqueous sodium carbonate and extracted with chloroform. The chloroform solution was extracted with dilute hydrochloric acid. The aqueous extract was basified with anhydrous sodium carbonate and extracted with chloroform. The chloroform extract was dried and evaporated to give an oil which was purified firstly by thin layer chromatography on silica with a mixture of ethyl acetate: ethanol: 0.88 ammonia (40:3:2) as eluant, and finally by distillation to give the title compound (0.89) as a colourless oil.b.p. 140/0.02mm.

PREPARATION 10 5-(Dimethylaminomethyl)-3-thiophenemethanol.

Methyl 5-[(dimethylamino)carbonyl]-3-thiophenecarboxylate A mixture of methyl 3-thiophenecarboxylate (2.89) and N,N-dimethylcarbonyl chloride (2.0ml) was treated with stannic chloride for 5 minutes and the mixture was stirred for 20 hours. Chloroform and iced water were added. The organic solution was washed with 8% aqueous sodium carbonate, dried and evaporated to give a viscous oil. This oil was heated at 70 in vacuo and the residue was dissolved in methyl acetate. Petroleum ether was added to give the title compound(1 .1 g) as a crystalline solid m.p. 51-2 C.

5-(Dimethylaminomethyl)-3-thiophenemethanol A solution of methyl 5-[(dimethylamino)carbonyl]-3-thiophenecarboxylate (0.5g) in dry diethylether (50ml) was added to a slurry of lithium aluminium hydride (0.39) in dry diethylether(l 00ml). The mixture was stirred for 3 hours at room temperature. Water was cautiously added, the mixture was filtered and the filtrate was evaporated to give the title compound (0.4g) as a colourless oil b.p. 120 /0.1mm. The oxalate was formed in and recrystallised from ethanol m.p. 107-8'.

PREPARATION 11 5-Methyl-4-(dimethylaminomethyl)-2-thiophenemethanol N,N,3-trimethyl-3-thiophene carboxamide A mixture of 2-methyl-3-thiophene carboxylic acid (29) and oxalyl chloride (2ml) in drytoluene (20ml) was heated under reflux and was treated with pyridine (0.05ml). The reaction mixture was heated at reflux for 1 h, cooled and partially evaporated. The residue was added to a solution of dimethylamine in toluene at 0 to S'C.

After 2 hours water and diethyl ether were added. The organic phase was washed with dilute hydrochloric acid, sodium hydroxide and water dried and evaporated to an oil which was distilled to give the title compound (1.49) as a colourless oil b.p. 100'/0.1 mm.

N,N,2-Trimethyl-3-thiophenemethanamine A solution of N,N,3-trimethyl-3-thiophene carboxamide (1.39) in dry diethylether (50ml) was added to a slurry of lithium aluminum hydride (0.39) in dry diethylether (100ml) at room temperature. The mixture was stirred for 1 hour and then water was added. The mixture was filtered and the filtrate was evaporated to give the title compound (0.75g) as a colourless oil. The picrate salt was formed in ethanol m.p. 155 .

5-Methyl-4-(dimethylaminomethyl)-2-thiophenemethanol A mixture of N,N,2-trimethyl-3-thiophenemethanamine (6.lg),paraformaldehyde (3.09) in conc. hydrochloric acid (20ml) and acetic acid (45ml) was stirred at 0 to 5 C for 1 hour, and at 8 for 72 hours. The mixture was added to an ice-cold, saturated solution of sodium carbonate. Aqueous 5M sodium hydroxide was added and the mixture was stirred for 20 hours. The solution was extracted with chloroform and the organic extract was washed with dilute sodium hydroxide and saturated brine, dried and evaporated to leave an oil.

This residue was distilled to give the title compound (6g) as a pale yellow oil b.p. 1 20'/0.1 mm. The oxalate salt was formed in ethanol and ethyl acetate m.p. 129-131'C.

PREPARATION 12 3-[5-(Dimethylaminomethy/J-3-thiophenemethoxyjpropanamine dioxalate salt To a solution of 5-(dimethylaminomethyl)-thiophene-3-methanol (5.29) and potassium tertiary-butoxide (3.4g) in dry dimethylformamide (100ml) was added 3-chloropropylamine hydrochloride (7.89) in dimethylformamide (10ml). The mixture was stirred at 20 for 3h. A further portion of potassium tertiarybutoxide (6.8g) was added followed by 3-chloropropylamine hydrochloride (7.89) in dimethylformamide (10 ml) and the reaction was stirred at 20 for 1 8h. The mixture was concentrated in vacuo, tetrahydrofuran (10G ml) was added followed by potassium carbonate and the mixture was filtered.The filtrate was concentrated, and purified by column chromatography on silica using methanol and methanol: ammonia (79:1) to give an oil (2.29). Addition of oxalic acid to a solution of oil in ethanol gave the title compound as an off-white solid, m.p. 176-178 (d).

Analysis Found: C, 43.6; H, 5.8; N, 6.6; C15H24N2O9S requires: C, 44.1; H, 5.9; N, 6.9% PREPARATION 13 Dimethyldithio-N-phenacylcarbonimidinothioate A suspension of potassium carbonate (14.1g) and dimethyl dithiocarbonimidinothioate hydroiodide (10.29) in acetone (150 ml) was stirred at 20 during 2h. Phenylacetyl chloride (6.89) was added dropwise and stirring was continued for 17h at 20 . 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 /0.06 mm. T.l.c. ethyl acetate Rf0.8.

PREPARATION 14 4-[3-rAminoJpropoxyl-N,N-dimethyl-2-thiophenemethanamine 4-Bromo-N,N-dimethyl-2-thiophenemethanamine A mixture of 4-bromo-2-thiophenecarboxaldehyde (4.89), dry dimethylformamide (4.3 ml) and 98% formic acid (1.4 ml), was heated at 120 for 30h. The cooled mixture was poured into water (100 ml) and basified with anhydrous sodium carbonate. Diethyl ether (2 x 100 ml) was added and the ethereal solution was extracted with dilute hydrochloric acid (50 ml). The aqueous solution was basified with anhydrous sodium carbonate and extracted with diethyl ether (200 ml). The ethereal extracts were distilled to give the title compound (2.5g) as a colourless oil, b.p. 70'/0.1 mm.

3-[5-(Dimethylaminomethyl)-3-thienyloxy]-1-propanol A mixture of 1,3-propanediol (20 ml) and sodium hydride (1g) was stirred at 80 for 1 h. Copper (II) oxide (1.3g), sodium iodide (0.05g) and 4-bromo-N,N-dimethyl-2-thiophenemethanamine (5g) were added and heating was continued for 2 days. Dilute hydrochloric acid (60 ml) was added and the aqueous solution was washed with diethyl ether (50 ml), basified with aqueous sodium hydroxide and extracted with chloroform (200 ml).The organic extract was distilled to give the title compound (1.79 as an off-white wax. m.p. 32-4" 3-[5-(Dimethylaminomethyl)-3-thienyloxy]- 1-propanol methanesulphonate, hydrochloride A solution of 3-[5-(dimethylaminomethyl)-3-thienyloxy]-1-propanol (0.259) and methanesulphonyl chloride (0.1 mi) in dry dichloromethane (10 ml) at 0-5 was stirred for 1 h. The mixture was poured onto an ice cold 4% aqueous solution of sodium carbonate (50 ml). The solution was extracted with dichloromethane (20 ml).

The organic extract was evaporated to give the title compound (0.059) as a white solid.

I.R. (Nujol) 2,550; 2,450, 1,350, 1,170 and 1,195 cm-5 N.m.r. (CdCl3) of base: 3,40,brs(1 H); 3.82,d,(lH); 5.62,t,(2H); 5.98,t,(2H); 6.50,s,(2H); 7.01,s,(3H); 7.75 7.80,s+m, (8H).

2-[3-[[5-(Dimethylaminomethyl)-3-thienyloxy]propyl]]-(1H)-isoindole-1,3-(2H)dione A solution of 3-[5-(dimethylaminomethyl)-3 thienyloxy]-1 -propanol methanesulphonate hydrochloride (6g) in dichloromethane (200 ml) was washed with dilute sodium hydroxide (50 ml). The organic solution was dried (Na2SO4), filtered and evaporated leaving an oil. This oil was dissolved in dry dimethylformamide (100 ml), and potassium phthalimide (3.79) was added. The mixture was stirred for 72h. The excess solvent was removed in vacuo and the residue was dissolved in diethylether (1 I) and washed with water (2 1). The ethereal solution was dried (Na2SO4), filtered and evaporated to give the title compound (4.89) as an amber oil.

I.r. (CHBr3) 2,780,2,820, 1,770, 1,710 cm- 4-[3-(Amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine A solution of 2-[3-[[5-(dimethylaminomethyl)-3-thienyloxy]propyl]]-(1H)-isoindole-1,3(2H)-dione (4.69) was dissolved in a 30% solution of methylamine in ethanol (100 ml). The mixture was stirred at room temperature for 4h and heated on a steam-bath for 2h. The solvent was evaporated and the residue was dissolved in dilute hydrochloric acid (20 ml). The aqueous solution was basified with anhydrous sodium carbonate, washed with diethyl ether (150 ml) and extracted with toluene (200 ml). The toluene solution was distilled to give the title compound (1.69) as a colourless oil, b.p. 1 20'/0.06 mm.

The oxalate salt was formed in and recrystallised from ethanol and water m.p. 150-2 PREPARATION 15 5-[[3-Aminopropyl)thio]-N,N,3-trimethyl-2-thiophenemethanamine N-[3-[[5-(Dimethylamino)methyl-4-methyl-2-thienyloxy]propyl]]-isoindole-1,3(2H)-dione A solution of N,N,3-trimethyl-2-thiophenemethanamine (6.29) in dry tetrahydrofuran (100 ml) was treated with a solution of n-butyl lithium in hexane (1.6M, 27.5 ml) at 0 , under nitrogen. After 1 h, sulphur (1.49) was added. After further G.5h a solution of N-(3-bromopropyl)-isoindole-1 ,3(2H)-dione (11 .8g) in dry tetrahydrofuran (50 ml) was added and the mixture was stirred at room temperature for 18h. Water (100 ml) was added and the mixture extracted with ether.The organic extract was evaporated to give the title compound as a yellow oil (15.3g).

I.r. (CHBr3) 2820,2775, 1770, 1705, 1392 cm-7 5-[[3-Aminopropyl)thio)-N,N,-3-trimethyl-2-thiophenemethanamine N-[3-[[5-(Dimethylamino)emthyl-4-methyl-3-thienyl]thio]propyl]isoindole-1,3(2H)-dione (15.29) and hydrazine hydrate (8 ml) were stirred at room temperature in tetrahydrofuran (150 ml) for 48h. The mixture was filtered and the filtrate was distilled to give the title compound as an orange oil (6.9g), b.p. 160-1 70'/0.04 mm.

PREPARATION 16 5-J4-J(3-Hydroxymethyl- 1-methyl- iN- 1,2,4-triazol-5-yl)amino]butyl]-3-methyl-2-thiophenecarboxaldehyde 2-/3-Methyl-2-thienylI- 1,3-dioxolane 3-Methyl-2-thiophenecarboxaldehyde (12g), 1,2-ethanediol (20 ml) and a trace oftoluene-p-sulphonic acid were heated at reflux in toluene (250 ml) under Dean and Stark conditions for 4h. The reaction mixture was cooled and washed with 5% aqueous sodium carbonate solution and water. The toluene solution was evaporated to give an oil which was distilled to give the title compound as a pale yellow oil (14.59), b.p.

95 /0.1 mm.

2-[5-(4-Bromobutyl)-3-methyl-2-thienyl]-1,3-dioxolane A solution of 2-(3-methyl-2-thienyl)-1,3-dioxolane (12.39) in dry tetrahydrofuran (150 ml) was treated with a solution of n-butyl lithium in hexane (1.6M, 50 ml) at -60 , under nitrogen. After 1 h, 1 ,4-dibromobutane (17.39) was added and the mixture was stirred at -50" for 3h and at room temperature for 18h. Water (75 ml) was added and the mixture extracted with ether.The organic extract was distilled to give the title compound as a light brown oil (15.1 g) b.p.250 /0.15 mm N-N-[[5-(1,3-Dioxolan-2-yl)-4-methyl-2-thienyl]-4-butyl]-ixoindole-1,3(2H)-dione 2-[5-(4-Bromobutyl)-3-methyl-2-thienyl]-1,3-dioxolane(13.3g) and potassium phthalimide (8.9g) were stirred at 50 in dry dimethylformamide (130 ml) for 4h and then at room temperature for 18h. The mixture was poured into water (1500 ml) and extracted with ether.The organic extract was evaporated to give the title compound as a light yellow oil (16.19) I.r. (CHBr3) 1770, 1710, 1395, 1070, 1033, 720 cm-1 4-[5-(1,3-Dioxolan-2-yl)-4-methyl-2-thienyl]-butanamine N-[[5-(1,3-Dioxolan-2-yl)-4-methyl-2-thienyl]-4-butyl]-isoindole-1,3(2H)-dione(16.1g) and hydrazine hydrate (8 ml) were stirred at room temperature in tetrahydrofuran (150 ml) for 24h. The mixture was filtered and the filtrate was distilled to give the title compound as a red-brown oil (5.349), b.p. 230'/0.1 mm.

5-(4-[(3-Hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)-amino]butyl]-3-methyl-2-thiophenecarboxaldehyde A mixture of 4-[5-(1,3-dioxolan-2-yl)-4-methyl-2-thienyl]-butanamine (2.739) and methyl N-[2-(acetoxy)acetyl]-1 -methyl-2-(phenylmethylene)-hydrazine-carboximidothioate (3.389) was heated at 60 for 2 h.

Toluene (20 ml) and 5N hydrochloric acid (12 ml) were added and the mixture stirred at room temperature for 18h. The mixture was basified to pH 8, washed with toluene, basified to pH 10 and extracted with ethyl acetate. The extract was evaporated to give an oil which was purified by column chromatography on silica using 3:1 ethyl acetate;methanol as eluent to give the title compound as pale yellow solid (0.6g) m.p.

118-121 (softens).

EXAMPLE 1 (a) N-Methyl-N-[2-[[5-dimethylaminomethyl)-3-thienylmethyl]-thio]ethyl]-2-nitro- 1, l-ethenediamine A mixture of 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophene methanamine (0.35g) and N methyl-1-(methylthio)-2-nitroethenamine (0.239) in water (5ml) was stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration and recrystallised from methanol and water to give the title compound as an off-white solid (0.27 g) m.p. 143 .

Assayfound:- C,47.3; H,6.7; N, 16.8% C13H22N402S2 requires: C, 47.3; H, 6.7; N, 17.0% The following compounds were similarly prepared from N-methyl-1-(methylthio)-2-nitroethenamine[A] and the appropriate diamine.

(b) A (0.45g) and 2-[[4-(1-pyrrolidinylmethyl)-2-thienyl methyl]thio]ethanamine (0.759) gave N-Methyl-N' [2-[[5-(1-pyrrolidinylmethyl)-3-thienylmethyl]thio]-ethyl]-2-nitro-1,1-ethenediamine(0.72g), m.p. 128-130 .

Assayfound: C,50.4; H,6.7; N,15.15; C15H24N402S2 requires: C, 50.5; H, 6.8; N, 15.7% (c) A (0.23g) and 5-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-3-thiophenemethanamine (0.35g) gave N methyl-N-[2-[[4-(dimethylaminomethyl )-2-thienyl methyl]thio]ethyl]-2-nitro-l ,1 -ethenediamine, carbonate salt as a white solid (0.29) m.p. 99-100 .

Assay found: C,44.93; H,6.46; N,15.45 Ca3H22N402S21/2H2CO3requires C, 44.85; H, 6.41; N, 15.50% (d) A (0.28g) and 2-[[5-(1-piperidinylmethyl)-3-thienylmethyl]thio]ethanamine (0.5g) gave N-methyl-N'-[2-[[5- 1-piperidinylmethyl)-3-thienylmethyl]thio]ethyl]-2-nitro-1,1,-ethenediamine as a white solid (0.49) m.p.101-3O.

Assayfound:- C, 51.93; H,7.03; N, 15.09 C16H26N4O2S2 requires C, 51.87; H, 7.02; N, 15.13% (e) A (0.29) and 5-[[[2-(amino)ethyl]thio]methyl]-N,N,3-trimethylthiophenemethanamine (0.3g) gave N-[2-[[5- Dimethylaminomethyl)-4-methyl-2-thienylmethyl]-thio]ethyl]N'-methyl 2-nitro-1,1,-ethenediamine (which was purified by column chromatography on silica using methanol as eluant) as a white solid (0.38g) m.p.

82-3 .

Assayfound: C,48.6; H,7.0; N,15.9 C14H2402S2 requires C, 48.8; H, 7.0; N, 16.3% (f) A (0.279) and 2-[[4-methyl-5-(1-piperidinylmethyl)-2-thienylmethyl]thio]ethanamine (0.5g) gave N-methyl N'-[2-[[4-methyl-5-(1-piperidinylmethyl)-2-thienylmethyl]-thio]ethyl]-2-nitro-1,1-ethanediamine as a white solid, recrystallised from methyl acetate-light petroleum b.p. 60-80 (1:3), (0.lg) m.p. 81 .

Assay found:- C, 53:11; H, 7.38; N, 14.52 C17H28N402S2 requires C, 53.11; H, 7.34; N, 14.58% (g) A (0.259) and 2-[[4-(1-pyrrolidinylmethyl)-2-thienyl-methyl]thio]ethanamine (0.49) gave N-Methyl-N'-[2 [[4-(1-pyrrolidinylmethyl)-2-thienylmethyl]thio]ethyl]-2-nitro-1,1-ethenediamine as a white solid (0.259) m.p.

109-111 .

Assay found: C, 50.25; H, 6.75; N, 15.4 C,5H24N402S2 requires C, 50.55; H, 6.8: N, 15.7 (h) A (0.269) and 5-[[2-(amino)ethyl]thio]methyl-N,N,2-trimethyl-3-thiophenemethanamine (0.49) gave N-Methyl-N'-2-[[4-(dimethylaminomethyl)-5-methyl-2-thienylmethyl]thio]ethyl]-2-nitro]-1,1-ethenediamine as a white solid (0.259) m.p. 100-101 .

Assayfound: C, 48.65; H, 6.85; N, 16.10 C14H24N4O2S2 requires C, 48.80; H, 7.0; N, 16.25 (i) A (0.279) and 3-[5-(dimethylaminomethyl)-3-thiophenemethoxy]propanamine (0.49) gave N-[2-[[5- (dimethylaminomethyl)-3-thienylmethoxy]propyl]-N'-methyl-2-nitro-1,1-ethenediamine (0.429) as a pale orange oil.

T.l.c. System B Rf 0.43 N.M.R. (CDCl3) 0.0,br,(1H); 3.9,br,(1H); 2.88,s, (1H); 3.12,s,(1H); 3.45,s,(1H); 5.59,s,(2H); 6.3,m,(2H); 6.43,s,(2H); 6.7,m,(2H); 7.40,d,(3H); 7.75,s,(6H); 8.08,m,(2H).

(j) A (0.359) and 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine (0.5g) gave N-[3-[5- (dimethylaminomethyl)-3-thienyloxy]propyl]-N'-methyl-2-nitro-1,1-ethenediamine (0.35g), which was purified by column chromatography and crystallised from methyl acetate m.p. 113 N.m.r. (CDCl3) -0.4,brs,(1H); 34.0,brs,(3H); 3.82,d,(1H); 6.00,t,(2H); 6.50-6.55,s+br,(4H); 7.1,brs,(3H); 7.75-7.9,s+m,(8H).

(k) A (0.4g) and 5-[[3-aminopropyl)thio]-N,N,3-trimethyl-2-thiophenemethanamine gave N-[3-[[5 (dimethylamino)methyl-4-methyl-2-thienyl]thio]propyl]-N'-methyl-2-nitro-1,1,-ethenediamine which was purified by column chromatography as a light brown oil (0.353g).

N.m.r. (CDCI3) : -0.25 br.s. (1H); 3.18,s,(1H); 3.4,br.s,(1H) overlain by 3.4,s,(1 H); 6.53s,(2H); 6.55,q,(2H); 7.1,m,(3H); 7.18,t,(2H); 7.72,s,(6H); 7.9,s,(3H); 8.05,m,(2H).

Found: C,48.8; H,7.0; N,16.2; C14H24N4O2S2 requires: C, 48.8; H, 7.1; N, 15.8%.

EXAMPLE 2 (a) N5-[2-[[5-(Dimethylaminomethyl)-3-thienylmethyl]-thio]ethyl]-1-methyl-1H-1,2,4,-triazole-3,5-diamine A mixture of 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (0.3759) and methyl N-cyano-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate (0.359) was heated at 60 in vacuo for 1 hour. The resulting oil was dissolved in toluene (30 ml) and 2M hydrochloric acid (2ml) was added.

After 3 hours at room temperature 8% aqueous sodium bicarbonate (20ml) was added and the resulting aqueous solution was washed with toluene. The aqueous solution was further basified with 5M sodium hydroxide (30ml) and the product was extracted with ethyl acetate. The organic solution was evaporated to give the title compound as an amber oil (0.39).

NMR (CDCl3)3.0,s, (1 H); 3.1,s (1 H); 5.6,t, (1 H); 6.0,brs,(2H); 6.4,s (2H); 6.5,s, (2H); 6.6,s + q, (5H); 7.4,t,(2H); 7.8,t (6H).

T.l.c. System A Rf 0.5. The following compounds were similarly prepared from methyl N-cyano-1 -methyl-2- (phenylmethylene)hydrazinecarboximidothioate (A) and the appropriate diamine.

(b) A (0.42g) and 5-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-3-thiophenemethanamine (0.49) gave N5-[2 [[4-(Dimethylaminomethyl)-2-thienylmethyl]thio]ethyl]-1-methyl-1H-1,2,4-triazole-3,5-diamine (0.3g).

Assay found:- C, 45.3; H, 7.1; N, 24.1 C13H22N5S2H2O requires C, 45.4; H, 7.0; N, 24.4% NMR (CDCI3) 2.98, 2s (2H); 5.4-5.9, br, (3H); 6.13, s, (2H); 6.55,6.61, 2s + m, (7H); 7.28, b, (2H); 7.7, s, (6H).

(c) A (0.439) and 2-[[4-(1-pyrrolidinylmethyl)-2-thienylmethyl]thio]ethanamine (0.45g) gave N5-[2-[[5-(1pyrrolidinylmethyl)-3-thienylmethyl]thio]ethyyl]-1-methyl-1 H-l ,2,4-triazole-3,5-diamine as an amber gum (0.49).

Assay found: C,49.79; H,6.81; N,22.83 C15H24N5S2.H2O requires C, 49.82; H, 6.97; N, 23.24% NMR (CDCl3) 3.0-3.1, 2s, (2H); 5.6,brt, (1 H); 6.05, br, (2H);6.23, s, (2H); 6.33, s, (2H); 6.52, s + m, (5H); 7.31, t, (2H); 7.4, m. (4H); 8.25, m, (4H).

(d) A (0.3g) and 5-[[2-(amino)ethyl]thio]methyl]-N,N,3-trimethyl-2-2-thiophenemethanamine (0.3g) gave 1-methyl-N5-[2-[[5-[(dimethylamino)methyl]-4-methyl-2-thienylmethyl]thio]ethyl]-1H-1,2,4-triazole-3,5diamine as an amber gum (0.159).

T.l.c. System A RfO.5 N.m.r. (CDCI3) 3.4, s, (1 H); 5.7-6.1, t + brs + s, (5H); 6.5 - 6.6,s + + s + m, (7H);7.2,m,(2H); 7.8, s, (6H); 7.9,s, (3H).

EXAMPLE 3 N-[[[2-[[5-(Dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]amino](methylamino)-methylene]methanesulphonamide A mixture of 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (0.4g) and S,S'dimethyl-N-(methylsulphonyl)-dithio-carbonimidic acid (0.359) in ethanol (lOmi) was heated at 60"C for 1 hour. A 33% solution of methylamine in ethanol (1 Oml) was added and the mixture was stirred for 20h. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica using methanol to give the title compound (0.5g) as an amber gum.

Assayfound:- C, 41.0; H, 6.6; N, 14.7 C13H24N402S3 requires C, 40.8; H, 6.9; N, 14.5% N,m.r. (CDCl3) : 2.9, s, (1 H); 3.09, s, (1 H); 3.25, brs, (1 H); 4.30, brs. (1 H); 6.28, s, (2H); 6.39, s, (2H); 6.61, q, (6.61); 7.08, s, (3H); 7.16, d, (3H); 7.36,t, (2H); 7.73, s, (6H).

EXAMPLE 4 N''-Cyano-N-[2-[[5-[(dimethylamino)emthyl]-4-methyl-2-thienylmethyl]thio]ethyl]-N'-methylguanidine 5-[[2-(Amino)ethyl]thio]methyl-N,N,3-trimethylthiophenemethanamine (0.5g) and methyl N-cyano-N'methylcarbonimidothioate (0.27g) were heated at 110-130 in vacuo for 7 h. The resulting mixture was purified by column chromatography on silica using methanol to give the title compound as a brown oil (0.359).

T.l.c. System A Rf. 0.52 N.m.r. (CDC13) 3.57,s,(1H); .16,br.q,(1H); 4.55,br,t,(1H); 6.17,s,(2H); 6.52,s,(2H); 6.63,q,(2H); 7.17,s,(3H); 7.30,t,(2H); 7.75,s,(6H); 7.9,s,(3H).

EXAMPLE 5 (a) 1-methyl-5-[[2-[[5-(Dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]amino]-1H-1,2,4-triazole,3methanol dihydrochloride A mixture of 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (0.4g) and methyl N-[2-(acetoxy)-acetyl]-1-methyl-2-(phenylmethylene)-hydrazinecarboximidothioate (0.56g) was heated at 60 for 1 h. Toluene (25 ml) and dilute hydrochloric acid (3 ml) were added and the mixture was stirred for 3h at room temperature and then heated for 30 min. on a steam-bath. Anhydrous sodium bicarbonate was added and the mixture was washed with toluene. The aqueous solution was basified with sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract was dried [Na2SO4] filtered, and evaporated to give an oil, which was purified by column chromatography on silica using methanol to give a gum.

This gum was dissolved in methylacetate (10 ml) and treated with 8% ethereal hydrogen chloride (5 ml). The resulting solid was crystallised from ethanol to give the title compound (0.29) as white needles m.p. 182-4 C.

N.m.r. (D2O) 2.50,2.66,2xm,(2H); 5.35,s,(2H); 5.50,s,(2H); 6.19,s,(2H); 5.50,s,(2H); 6.19,s,(2H); 6.38-6.42, s+t,(5H); 7.11-7.20,s+t,(8H).

The following compounds were similarly prepared from methyl N-[2-(acetoxy) acetyl]-1-methyl-2 (phenylmethylene)-hydrazinecarboximidothioate [B] and the appropriate diamine.

(b) [B] (1.01 g) and 2-[[5-(dimethylaminomethyl)-4-methyl]2-thienylmethyl[thio]ethanamine (0.89) gave 5-[[2-[[[5-(dimethylaminomethyl)-4-methyl]-2-thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4 triazole-3-methanol (0.739) as a pale yellow oil.

N,m.r. (CDC13) 3.36,s,(1 H); 5.45,s+t,(3H); 6.18,s,(2H); 6.46,s+m.(8H); 7.16,t,(2H); 7.72,s,(6H); 7.88,s,(3H).

The free base was converted to its citrate salt in dry ethyl acetate.

m.p. 45-50 (softens).

Analysis Found: C, 44.3: H, 6.1; N, 11.5; C15H25N5OS2C5H8O7.H2O C, 44.6; H, 6.2; N, 11.4% (c) [B] (0.62g) and 2-[[4-(1 pyrrolidinylmethyl]-2-thienylmethyl]thio]ethanamine (0.51g) gaqve 1-methyl-5-[[2 [[[4-(1-pyrroolidinylmethyl)]-2-thienylmethyl]thio]ethyl]amino]-1H-1,2,4-triazole-3-methanol (0.24g) as a pale yellow gum.

Analysis Found: C, 51.9; H, 6.9; N, 18.4; C15H25N5OS20.2S H2O requires: C, 51.65; H, 6.91; N, 18.83% N.m.r. (CDC13) 3.05,br.s,(1H); 5.30,t,(2H); 5.52,s,(2H); 6.20,s,(2H); 6.55,m,(7H); 7.32,t,(2H); 7.55,m,(4H); 8.30,m,(4H); (d) [B] (0.70g) and 2-[[[4-(Dimethylaminomethyl)-5-methyl]-2-thienylmethyl]thio]ethanamine (0.5g) gave 1 -methyl-5-[[2-[[[4-(dimethylaminomethyl)-5-methyl]-2-thienylmethyl]thio]ethyl]amino]-1 11-1,2,4- triazole-3-methanol (0.229) as a brown gum.

Analysis Found: C, 50.3; H, 7.1; N, 20.2; C15H25N5OS2 requires: C, 50.7; H, 7.1; N, 19.7% N.m.r. (CDCI3) 3.13,s,(1H); 5.25-5.50,br.t,s,br.s,(4H); 6.23,s,(2H); 6.50-6.72, s.q,s,(7H); 7.30,t,(2H); 7.70-7.78, 2,xs,(9H) (e) [B] (1.019) and 3-[[5-(Dimethylmainomethyl)]-3-thienylmethoxy]propanamine (0.759) gave 5-[[3-[[5 (dimethylaminomethyl)j-3-thienylmethoxy]propyl]-amino]-111-1 ,2,4-triazole-3-methanol tO.4g) as a pale yellow oil.

T.lc. System B Rf 0.54 Analysis Found: C, 50.4; H, 7.3; N, 19.1; C,5H25N502S.1 H2O requires: C, 50.4; H, 7.6; N, 19.6% (f) [B] (492 mg) and 2-[[[5-(1-Piperidinylmethyl)]-3-thienylmethyl]thio]ethanamine (417 mg) gave 1-methyl-S- [[2-[[[5-(1 -Piperidinylmethyl)]-3-thienylmethyl]-thio]ethyl]amino]-1 H-1 ,2,4-triazole-3-methanol (500 mg) as a pale yellow gum.

T.l.c. 1:1 ethyl acetate-methanol, Rf 0.3 N,m.r. (CDCl3) 3.02,d,(1H); 3.12,d,(1H); 5.46,s,(2H); 5.5,t,(1H); 6.0,br.s.(1H); 6.36,s,(2H); 6.4s,(2H), 6.5,s,(3H); 6.5,q,(2H); 7.3,t,(2H); 7.6,m,(4H); 8.5,m,(6H).

(g) [B] (0.57g) and 2-[[4-Methyl-[5-(1-piperidinylmethyl)]-2-thienylmethyl]thio]ethanamine (0.509) gave 1-methjyl-5-[[2-[[[4-methyl-5-(1-piperidinylmethyl)]-2-thienylmethyl]thio]ethyl]amino]-1H-1,2,4-thiazole 3-methanol (0.129) as a cream coloured solid, m.p. 55 .

N.m.r. (CDCI3) 3.4 s,(1 H); 5.47-5.58,t & ,(3H); 6.2,s,(2H); 6.48-6.8,2xs,q.br.s,(8H); 7.2,m,(2H); 7.6,m,(4H); 7.9,s,(3H); 8.5,m,(6H).

(h) [B] (0.75g) and 4-(3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine (0.5g) gave 5-[3-[[5 [(dimethylamino)methyl]-3-thienyloxy]propyl]amino]-1 -methyl-i 11-i ,2,4-triazole-3-methanol (0.29) m.p.

99-100'T.l.c. System B Rf 0.55 (i) [B] (0.9059) and 5-[[3-aminopropyl)thio]-N,N,3-trimethyl-2-thiophenemethanamine (0.729) gave 5-[3-[[5 [(dimethylamino)-methyl]-4-methyl-2-thienyl]thio]propyl]amino-1-methyl-1H-1,2,4-triazole-3-methanol (0.359) as a pale yellow oil.

T.l.x. system B Rf 0.6 N.M.R. (CDCl3) 3.i8,s,(iH); 5.45,s,(2H); 5.60,s+ br.t,(2H); 6.50,s,(3H), 6.52,q,(2H); 6.54,s,(2H); 7.19,t,(2H); 7.75,s,(6H); 7.90,s,(3H); 8.10,m,(2H): EXAMPLE 6 (a) 5-[[2-[[5-(Dimethylaminomethyl)-3-thienyl]methyl]-thio]ethyl]amino-3-phenylmethyl- 7H- 1,2,4-triazole To dimethyl dithio-N-phenacylcarbonimidinothioate (1.189) in tetrahydrofuran (20 ml) was added 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (1.139) in tetrahydrofuran (10 ml) and the reaction mixture stirred at 20 for 5 h.Hydrazine hydrate (2.59) was added and the mixture was stirred overnight at 20". 2N Hydrochloric acid (10 ml) was added and after stirring for 3h at 20 , the acidic layer was basified with potassium carbonate and extracted with ethyl acetate.The ethyl acetate extracts were evaporated and the residual oil purified by column chromatography on silica using chloroform followed by chloroform: methanol (19:1) to give the title compound (0.2g) as a white solid m.p. 113' after recrystallisation from a mixture of ethyl acetate and light petroleum, b.p. 60-80 Analysis Found: C, 58.6; H, 6.5; N, 17.9; C19H25N5S2 requires: C, 58.9; H, 6.5; N, 18,1% (b) Similarly prepared from 5-[[2-(amino)ethyl]thio]methyl-N,N,3-trimethyl-2-thiophenemethanamine (1.0g), dimethyl dithio-N-phenacylcarbonimidinothioate (0.98g) and hydrazine hydrate (2.1g) was 5-[[2-[[[5 (dimethylaminomethyl)-4-methyl-2-thienyl]methyl]thio]-ethyl]amino]-3-phenylmethyl-1H-1,2,4-triazole (0.2g) as a white solid m.p. 116-117 (d) Analysis Found: C, 59.7; H, 6.9: N, 17.2; C20H27N5S2 requires:C, 59.8; H, 6.8; N, 17.4% EXAMPLE 7 (a) N-[5-[[2-[[[5-[(Dimethylamino)methyl]-4-methyl-2-thienyl]methyl]thio]ethyl]amino]-1-methyl-1H-1,2,4 triazol-3-yllacetamide A solution of N5-[2-[[[S-[(dimethylamino)methyl]4-methyl]-24hienyl]methyI]thio]ethyl]1 -methyl-i H 1,2,4-triazole-3,5-diamine (1.56g) and acetic anhydride (0.529) in pyridine (20 ml) was stirred at room temperature for 24h. The solution was evaporated to dryness in vacuo and the residual yellow gum was dissolved in water (60 ml). The solution was extracted with ethyl acetate, and to the aqueous fraction was added an hydros sodium carbonate (39). The solution was extracted with ethyl acetate (3 x 50 ml). The organic extracts were evaporated in vacuo to give the title compound (1.1 7g) as a yellow gum.

Analysis Found: C 50.0; H, 6.9; N, 21.7; S,i6.8; C16H26N6OS2 requires: C 50.2; H, 6.9; N, 22.0; 5, 16.8% N.m.r. (CDCl3) 1.0,br,(1H); 3.4,s,(1H); 5.2,t,(1H); 6.2,s,(2H); 6.5,s,6.55,s,ca.6.5,s,(7H); 7.27,t,(2H); 7.75,m,7.9,s,(12H).

(b) In a similar manner,5-[2-[[5-[(dimethylamino)-methyl]-3-thienyimethyl]thio]ethyl]-1-methyl-1H-1,2,4- triazole-3,5,diamine (1.15g) and acetic anhydride (0.35 ml) gave N-[5-[[2-[[5-[(dimethylamino)methyl]-3- thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole-3-yl]acetamide as a yellow foam (1.1 g).

T.l.c. System A Rf 0.53 N.m.r. (CDCl3) 1.6,br,(1H); 2.98,d,(1H); 3.1,d,(1H); 5.47,t,(1H); 6.3,s,(2H); 6.47,s,(3H); 6.53,q,(2H); 7.3,t,(2H); 7.7,m.(9H).

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS Tablets: mgitablet Active ingredient 100.00 Microcrystalline Cellulose BPC 198.50 Magnesium stearate BP 1.50 Compression weight 300.00 The active ingredient is sieved through a 250 ijm sieve, blended with the excipients and compressed using 9.5 mm 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.

Injection 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 fiitration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen.

EXAMPLE 8 (a) 5-[[2-[[5-[[[2-Furanylmethyl)amino]methyl]-3-thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole3-methanol 4-[[[2-[(3-Hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)amino]ethyl]thio]methyl]-N,N,N-trimethyl-2thiophenemethanium iodide To a solution of 5-[[2-[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]amino]-1 -methyl]-i H-1,2,4- triazole-3-methanol (3.729) in acetone (50 ml) was added a solution of methyl iodide (1.94g) in acetone (1 0 ml).After stirring at room temperature for 3h, the oil which separated was triturated to give the title compound (4.65g) m.p. 146-149 5-[[2-[[5-[[[2-Furanylmethyl)amino]methyl]-3-thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole-3methanol Amixture of 4-[[[2-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)amino]ethyl]thio]methyl]-N,N,Ntrimethyl-2-thiophenemethanium iodide (1.12g) and 2-furanmethanamine (2.25g) was heated at 140-160 for 2h. The oily residue was washed with diethyl ether (5 x 15 ml) and suspended in water (30 ml) containing anhydrous sodium carbonate (2g). The suspension was extracted with ethyl acetate (3 x 30 ml), the combined extract dried and evaporated in vacuo. The oily residue was chromatographed (silica/ethyl acetate-methanol, 1:1) to give the title compound (0.27g) as an oil.

T.l.c. ethyl acetate:methanol, 1:1 Rf 0.65.

N.m.r. (CDCl3) 2.60,m,(1H); 3.00,brs,(1H); 3.09,brs,(1H); 3.70,dd,(1H); 3.80,d,(1H); 5.50,s+t,(3H); 6.13,s,(2H); 6.23,s,(2H); 6.36,s, 6.52,s+q,(7H); 6.83,brs,(2H); 7.31,t,(2H).

(b) Prepared in a similar manner was: 5-[[2-[[5-['[(Phenylmethyl)amino]methyl]-3-thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole-3 methanol (0.40g) as an oil from 4-[[[2-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5- yl)amino]ethyl]thio]methyl]-N,N,N-trimethyl-2-thiophenemethanium iodide (1.8g) and benzenemethana mine (1.0g) at 120 for 4h followed by evaporation of the mixture with water (3 x 20 ml) in vacuo and column chromatography (silica; ethyl acetate-methanol, 3:1) T.l.c. ethyl acetate-methanol, 1:1 Rf 0.55 N.m.r. (CDCl3) 2.70,m,(5H); 3.03,brs,(1H); 3.13,brs,(1H); 5.49,s, 5.50,t,(3H); 6.10,s,(2H); 6.20,s,(2H); 6.38,s, 6.54,s+q,(7H); 6.90,brs,(2H); 7.32,t,(2H).

(c) Prepared in a similar way was: 5-[[2-[[5-[(Heptylamino)methyl]-3-thienylmethyl]thio]-ethyl]amino]-1-methyl-1 H-1,2,4-triazole-3- methanol (0.3g) from 4-[[[2-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazole-5-yl)amino]ethyl]thio]methyl] N,N,N trimethyl-2-thio-phenemethanium iodide (1.89) and heptanamine(2.15g) at 120 for ih and 140 for 4h followed by evaporation of the residue with water (4 x 20 ml) in vacuo and column chromatography on the residue (silica/methanol-acetyl acetate, 3:1 then silica/ethanol) N.m.r. (CDC13) : 3.03,d,(1H); 3.13,d,(1H); 5.36,t,(1H); 5.5,s,(2H); 6.15,m,(2H); 6.38,s,(2H); 6.53,s,(3H); 6.55,q,(2H); 6.75,s,(br),(2H); 7.3 m,(4H); 8.3-9.0,m,(10H); 9.13 t,(3H).

T.l,c ethanol Rf 0.32 EXAMPLE 9 5-64-[[5-zDimethylaminoJmethyl-4-methyl-2-thienyllbutyll-amino]- 1-methyl- 1H- 1,2,4-triazole-3-methanol A mixture of 5-[4-[(3-hydroxymethyl-1-methyl-1H-1,2,4-triazol-5-yl)amino]butyl-3-methyl-2thiophenecarboxaldehyde [0.55g) and dimethylamine in industrial methylated spirits (33% w/w) 8 ml was heated at 50 for 18h. The mixture was cooled and sodium borohydride 90.5g) was added. The mixture was stirred at room temperature for 2h, acidified with 2N hydrochloric acid and washed with ethyl acetate. The aqueous phase was basified with sodium carbonate solution and extracted with ethyl acetate. The organic extract was evaporated to give an oil which was purified by column chromatography on silica using 2:1 ethyl acetate-methanol as eluent to give the title compound as a light brown oil (0.22g).

N.m.r. (CDCl3): 3.68,s,(1H); 5.47,s,(2H); 5.90; t,(1H); 6.3,br.s,(1H); 6.5-6.7,m,7H; 7.25,m,(2H); 7.78,s, (6H); 7.90,s,(3H); 8.3,m,(4H).

I.r. (CHBr3): 3585,3420,2820,2770 1530cm- .

Claims

1. Compounds ofthe general formula (I)

and physiologically acceptable salts, hydrates and bioprecursors thereof, in which one of R1 and R2 represents hydrogen, halogen ora C1 4 alkyl group which may be optionally substituted by hydroxy or CiA alkoxy, and the other represents the group R4RsNAlk- in which R4 represents hydrogen, C,10 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, and RB represents hydrogen or a C1.4 alkyl group, or R4 and RB may, together with the nitrogen atom to which they are attached, form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C, 3 alkyl 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; R3, which may be in either the 2- or 3- position, represents the group -(CH2)nX(CH2)mNH-Z where X represents -CH2-, -O- or -S-; n represents zero, 1 or 2; m represents 2,3 or 4; and Z represents either the group

or the group

where Y represents S, O, CHNO2 or NRg where Rg is nitro, cyano, alkylsulphonyl or arylsulphonyl; Rg represents hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl or aralkyl; R7 represents hydrogen, alkyl, alkenyl, aralkyl, or C2-6 alkyl substituted by hydroxy or alkoxy; and R8 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, or alkoxy, or the group NR10R11 where R10 represents hydrogen, alkyl, alkyl substituted by hydroxy or C103 alkoxy, alkenyl, aralkyl or heteroaralkyl, and R11 represents any of the groups defined for Ra0 or may represent COR12 where R12 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryi or heteroaralkyl, or R11 represents the group SO2R13 where Ra3 represents alkyl or aryl, or R" represents the group

where E represents oxygen or sulphur, and R14 represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl, or R10 and R11 taken together represent the group = CR15R16 where R15 represents aryl or heteroaryl and R16 represents hydrogen or alkyl, with the provisos that where R2 represents the group R4R5NAlK then R3 is in the 2- position; and where R2 represents hydrogen then R3 is in the 3- position.

2. Compounds as claimed in Claim 1, characterised in that the groups R,,R2, R4, RB, R6, R7, R8, Y and Alk have the following meanings: R1 or R2(where other then the group R4R5NAlK): bromine atom or a C1 3 alkyl group or a C1-3 alkoxy C1.3 alkyl group or a hydroxy C1-3 alkyl group; or, when R1 or R2 is the group R4Rs Alk, R4: alkyl, C5-7 R7 cycloalkyl, alkenyl, aralkyl, C1 4 alkyl substituted by a trifluoromethyl group, hydroxy C2-4 alkyl, C, 3 alkoxy C2A alkyl di-C1-3 alkylaminoalkyl, or heteroaraikyl where the heterocyclic portion represents a furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl, or thiazolyl ring and the alkylene portion is a methylene, ethylene or propylene grouping, and Rg: hydrogen or a methyl or ethyl group; or R4R5N may represent a 5-8 membered ring optionally containing one double bond and/or substituted by one or two C, 3 alkyl groups or a hydroxy group and/or containing oxygen or sulphur atom; Rg: hydrogen, C, 4 alkyl or C1.3 alkoxy C2.4 alkyl; Y:CHNO2 or NR9 where R9 is nitro, cyano, C1.4 alkylsulphonyl or arylsulphonyl; R7: hydrogen, C1-4 alkyl or hydroxy -C2A alkyl; R8: hydrogen, hydroxy, C1-4 alkyl, hydroxy C1-4 alkyl, C1-3 alkoxy C1-4 alkyl, phenyl C1-3 alkyl, C2-1 alkanoyloxy C1-4 alkyl, amino C1-4 alkyl, amino, C1-4 alkylamino or di-C1-4 alkylamino, phenyl C1-3 alkylamino, or a heteroaryl C, 3 alkylamino group where the heteroaryl ring is 5 or 6 membered and contains one heteroatom; or represents the group NHCOR12 where Ra2 represents hydrogen, C1-3 alkyl, C1-3 alkoxy, furyl, pyridyl, thiazolyl, thienyl, or phenyl optionally substituted by a C1.3 alkyl or C1.3 alkoxy group; or represents the group NHSO2R13 where R1B represents C, 3 alkyl or phenyl optionally substituted by a C1 3 alkyl or C1-3 alkoxy group; or represents the group NHCONHR14 where R14 is C1-3 alkyl, C5-7 cycloalkyl or phenyl optionally substituted by a C1 3 alkyl or C1 3 alkoxy group, or represents the group N=CHR15 where R15 is a phenyl or pyridyl group; Alk is (CH2)p where P is 1 to 3.

3. Compounds as claimed in Claim 1 or 2 characterised in that R3 is in the 3- position and R1 is the group R4R5NalK.

4. Compounds as claimed in any of Claims 1 to 3, characterised in that Z represents the group

where Y respresents the group CHNO2.

5. Compounds as claimed in any of Claims 1 to 3 characterised in that Z represents the group

6. Compounds as claimed in Claim 1, characterised in that they correspond to formula (II)

where R4 and R5 are methyl groups ortogetherwith the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexamethylenimino group, and Z represents either

where R5 is methyl, or the group

9. Compounds as claimed in Claim 1 which are: N-methyl -N- [2[[5-(dimethylaminomethyl)-3-thienylmethyl]thio]ethyl]-2-nitro-i ,i-ethenediamine N-methyl-N'-[2-[[5-(1-pyrrolidinylmethyl)-3-thienylmethyl]thio]ethyl]-2-nitro-1,1-ethenediamine N-methyl -N'-[2-[[S-(i -piperidinylmethyl)-34hienylmethyl]thio]ethyl]-2-nitro-1 ,i -ethenediamine N-[2-[[5-(dimethylaminomethyl)-4-methyl-2-thienylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine N-2-[[5-(dimethylaminomethyl)-3-thienylmethoxy]prppyl]-N'-methyl-2-nitro-1,1-ethenediamine 1-methyl-N5-[2-[[5-[(dimethylamino)methyl]-4-methyl-2-thienylmethyl]thio]ethyl]-1H-1,2,4-triazole-3,5diamine 1 -methyl-5-[[2-[[5-(dimethylam inomethyl)-3-thienylmethyl]th io]ethyl]amino]-1 H-1,2,4-triazole-3methanol 5-[[2-[[[5-(dimethylaminomethyl)-4-methyl]-2-thienylmethyl]thio]ethyl]amino]-1-methyl-1H-1,2,4-triazole-3methanol 5-[[2-[[5-(dimethylaminomethyl)-3-thienyl]methyl]thio]ethyl]amino-3- phenylmethyl -l H- 1,2,4- triazole and their physiologically acceptable salts.

8. Compounds of formula (I) as defined in Claim 1 characterised in that one of R1 and R2 represents hydrogen and the other represents R4RsNAlk and R3 represents

except that Y does not represent NRg where Rg is alkylsuiphonyl or arylsulphonyl.

9. Compounds of formula (I) as defined in Claim 1, characterised in that one of R1 and R2 represents hydrogen and the other represents R4RsNAlk and R3 represents

where R8r represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, alkoxyalkyl, hydroxy or alkoxy or R8 represents the group NR10R11@ where R1o represents hydrogen, alkyl, hydroxyalkyl, alkenyl oraralkyl and R11r represents hydrogen, alkyl, hydroxyalkyl, or the group COR12 where R12 represents hydrogen, alkyl, aryl, aralkyl or alkoxy, or R11 represents the group SO2R13 where Ra3 represents alkyl or aryl, or R10 and R11 taken together represent the group =CR15R16 where R15 represents aryl and R16 represents hydrogen or alkyl.

10. 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 which Z represents the group

an amine of formula R17NH2(111) is reacted with a compound of general formula (IV)

in which one of the groups R17 and R,8 represents the group

and the other represents the group R6, and P is a leaving group; b) for the production of compounds in which Z represents the group

where R8 is other than an alkoxy or acyloxyalkyl group, or the group -N=CR15R15, a compound of formula (Vl)

in which Vi is

or NCN andY1 is hydrogen where V is oxygen or sulphur and r8 is a group as defined for r8 or is a group convertible thereto under the conditions of the reaction or represents halogen or alkoxy, or V' is NH and Y' is

is cyclised;; c) for the production of compounds in which Alk is CH2 and Z represents the group

in which R8 is other than the group -N=CR15R16, an intermediate formed by reacting a compound of formula (VIII)

in which one of R11 and R12 represents hydrogen, halogen or a C1-4 alkyl group which may be optionally substituted by hydroxy or C1-4 alkoxy and the other represents the group -CHO, with a reagent R4R6NH, is reduced.

d) for the production of compounds in which R8 is other than -N=CR15R16, a compound of formula (I) in which R4 is hydrogen is reacted with an aldehyde R4 -CHO under reducing conditions, the group R4 having a meaning such that the resulting group R14CH2 represents a group R4 as defined; e) for the production of compounds in which Z represents the group

in which R8 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 Z represents the group

in which the group R6 represents the group -N=CR15R16, a compound of formula (I) in which 1 R8 is an NH2.

group is reacted with an aldehyde or ketone R15R16CO; g) for the production of compounds in which Z represents the group

in which R8 is the group NR10R11 where R11 is -COR12, -SO2R13 or -C(=E)NHR14, a compound offormula (I) in which R8 is the group -NHR10 and R1, R2, R7 and R10 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 NHRlo by the group Fl11; h) treating a compound of formula (I) in which the groups R4R5N is replaced by a quaternary ammonium group with an amine R4RsNH; and where the compound of formula (I) is produced in the form of a free base, optionally converting the free base into a salt.

11. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 14, together with at least one pharmaceutically acceptable carrier or diluent, and optionally one or more further active ingredients.

12. Compounds as claimed in Claim 5, characterised in the R8 represents amino, hydroxyalkyl, alkanoylamino or benzyl.