IE44103B1 - Heterocyclic thioalkyl-amines,-guanidines and thioureas - Google Patents

Abstract

Compounds are disclosed which may be represented by the formula: wherein Het1 and Het2 may each be imidazole which may be substituted by methyl or bromo, pyridine which may be substituted with hydroxyl, methoxy, chloro or bromo, thiazole or isothiazole; X is sulphur, NH2, NOH, NCN, or CHNO2; B1 and B2 are lower alkylene groups such that either B1 is (CH2)2 or (CH2)3 and B2 is -CH2CHR-, -CHRCH2-, , or wherein R is methyl or ethyl or B1 and B2 are both selected from and . The compounds are useful in blocking histamine H2-receptors and act to inhibit the biological actions of histamines which are not inhibited by "antihistamines". The compounds find use for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system.

Description

This invention relates to pharmacologically active compounds which block histamine Hg-receptors, to methods for their preparation and to pharmaceutical compositions containing them. The compounds of the invention can exist as acid addition salts and/or hydrates but, for convenience, reference will be made throughout this specification to the parent compounds.

Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors. Histamine is such a substance and has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called antihistamines of which mepyramine is a typical example, and diphenhydramine and chlorpheniramine are other examples are mediated through histamihe, H^-receptors (Ash and Schild, Brit. 2- Pharmac. Chewother, 27, 427 (1966)). However, other of the biological actions of histamine are not inhibited by antihistamines and actions of this type which are inhibited by a compound described by Black et al (Nature, 236, 395 (1972)) and called burimamide, are mediated through receptors which are defined by Black et al as histamine Hg-receptors. Thus histamine Hg-receptors are histamine receptors which are blocked by burimamide but not mepyramine. Compounds which block histamine Hg-receptors are referred to as histamine Hg-antagonists.

Blockade of histamine H2-recePtors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines. Histamine Hg-antagonists are therefore useful for example, as inhibitors of gastric acid secretion, and antiinflammatory agents and as agents which act on the cariovascular system, for example as inhibitors of the effects of histamine on blood pressure. In the treatment of certain conditions, for example inflammation and in inhibiting the actions of histamine in blood pressure, a combination of histamine H-j- and H2- antagonists is useful.

According to the present invention there is provided a compound of formula I: X I Het1-CH2-S-B1-NH-C-NH-B2S-CH2-Het2 I where Het( and Het2 are the same or different and are imidazole optionally substituted by methyl or bromo; pyridine optionally substituted by hydroxyl, methoxy, chloro or bromo; thiazole or isothiazole; X is sulphur, NH, NOH, NCN, or CHNO2; and B^ and B2 are lower alkylene groups such that either B] is -{CHZ)2- or -(CH2)3- and B2 is -CHgCHR-, -CHRCHg-, -CHCH2CH2-, or -CH2CH2^Hch3 ch3 where R is methyl or ethyl or and B2 are both selected from -CH9CH- and CHCH, I ! ch3 ch3 4410 3 The compounds of the invention are histamine Hg antagonists.

It will be understood that compounds of the invention may exhibit tautomerism and all such tautomeric forms are within the scope of the present invention. Throughout the present specification by the term "lower alkyl, we mean an alkyl group containing from 1 to 4 carbon atoms.

In one preferred group of compounds B^ is (CHg)g- and Bg is -CHgCH-. In particular Het-j and Hetg are selected from ch3 4- imidazolyl optionally substituted by 5-methyl or 5-bromo; 2-pyridyl optionally substituted by 3-hydroxy, 3-methoxy, 3-bromo or 3-chloro; Z-thiazolyl and 3-isothiazolyl.

Preferably Heti and Hetg are both 4-imidazolyl substituted by - methyl.

X is preferably NH, NCN, sulphur or CHNOg.; Examples of particular acid addition salts include those with hydrochloric, hydroiodic, sulphuric and maleic acids. These particular acid addition salts are examples of salts which are also pharmaceutically acceptable.

Specific compounds falling within the scope of the present invention are: X. *4103 Ν-β2- ((4-methyl -5-imi dazolyl Jmethyl thi o)propyfj -Ν' -[2- ((4methyl-5-imidazolylJmethylthiojethyl]guanidine and N,N- bis[2-((4-methyl-5-inndazolylJmethylthio)propyl]-guanidine.

The invention further provides a process for the preparation of 5 compounds of formula I where an amine of formula Ila or lib: He^-CHgS-BI-NHg Ila Het2-CH2S-B2-NH2 lib where Hetp Het2, and B2 have the same significance as in formula I, is reacted respectively with a compound of formula Ilia or Illb:X' Het-pCHgS-B^NH-C^ Het2-CH2S-B2-NH-Q // X' SA SA Ilia Illb where Het-j, Het2> B^ and B2 are as previously defined, X' is sulphur, NH, NCN or CHN02 and when X1 is sulphur optionally reacting the product with a lower alkyl halide to yield the corresponding isothiourea which is then reacted with hydroxylamine and thereafter where desired converting the compound of formula I into a salt.

Acid addition salts can be conveniently formed by standard procedures for example by reacting a corresponding base of formula I with an acid in lower alkanol or by use of an ion exchange resin to form the required salt either directly from the base or from a different addition salt.

Production of the compound of formula I where X is NH results from the reaction of an amine of formula Ila or lib with an isothiourea of formula IIIc or Illd: • SA Het2-CH2S-B2-NH-C NH IIIc SA Hetj-CHgS-Bj-NH-C NH Hid where Hetp Het2> and B2 have the above significance and A is lower alkyl, the isothiourea of formula Ilia is formed from the corresponding amine of formula Ila by reaction of the latter with benzoyl isothiocyanate to give a compound of formula IV: He^-CHgS-B^NH-C Iy ^NHQ where Het^ and have the above significance and Q is benzoyl, hydrolysis of this compound to yield the corresponding thiourea where Q is hydrogen; and reaction of the latter with a lower alkyl halide such as lower alkyl iodide. Similarly the isothiourea of formula Illb can be prepared from the amine of formula lib.

Alternatively the compounds of formula I where X is NH can be produced by reaction of a compound of formula V; (AS)2C = X1 V where A is lower alkyl and X1 is NQ, Q being benzoyl, first with an equimolar amount of one of the amines of formula Ila or formula lib and then reacting the resultant product with the other amine of formula lib or Ila. Finally the benzoyl group is removed by hydrolysis. In this case, where it is desired to produce the compound of formula I where each Het-| and B^ is identical to the corresponding Het2 and B2, the compound of formula V may be reacted in a single stage reaction with two or more equivalents of the amine of formula Ila. In a variation of this method, the compound of formula V can be replaced by a compound of the formula ClgC = X^ wherein X1 has the above significance. 441° 3 The reactions described in the preceding paragraph can also be used for the production of compounds of formula I where X is N.CN or CHNOg. In this X^ in formula V is N.CN or CHNOg and the final hydrolysis The compounds of formula I by reacting the amine of formula ester of formula VIb or Via. step is not of course necessary. where X is sulphur can be produced Ila or lib with a dithiocarbamic SA SA Het0-CH,S-B,-NH-C VIb Het.-CH-S-Bn-C X S Via where Het^, Hetg, and Bg have the above significance and 10 A is lower alkyl. The dithiocarbamic esters of formual Via and VIb can be formed from the corresponding amines of formula Ila and lib by reaction of the latter with carbon disulphide and a lower alkyl halide or sulphate. When Het^B^ is identical to HetgBg the required compounds of formula I where X is sulphur can be produced directly by the reaction of carbon disulphide with two equivalents of the amine of formula II.

The compounds of formula I where X is N.OH can be formed from those where X is sulphur by reacting the latter with a lower alkyl halide to yield the corresponding isothiourea and then reacting 20 this isothiourea with hydroxylamine.

The amines of formula II can be produced by the reaction of a compound of formula VII.

Het-CH2L VI1 where Het has the same significance as Het^ and Het2 in formula I and L is hydroxyl, halogen or methoxy, with an aminethiol of formula VIII.

HS-B^NH 2 VIII where B1 has the same significance as B1 and B2 in formula I. The aminethiols of formula VIII are known compounds.

The compounds of formula I block histamine H2-reactors that is they inhibit the biological actions of histamine which are not inhibited by antihistamines such as mepyramine but are inhibited by burimamide.

For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs or rats anaesthetised with urethane, at doses of from 0.5 to 256 micromoles per kilogram intravenously. This procedure is referred , to in the above mentioned paper of Ash and Schild. The activity of these compounds as histamine H2-anatagonists is also demonstrated by their ability to inhibit other actions of histamine which, according to the above-mentioned paper of Ash and Schild, are not mediated by histamine ^-receptors. For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food. 44ΐθ3 In addition, the compounds of this invention show anti-inflammatory activity in conventional tests, for example, the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume is reduced by subcutaneous injection of doses of a compound of formula I. In a conventional test, for example the measurement of blood pressure in the anaesthetised rat, the action of the compounds of this invention in inhibiting the vasodilator action of histamine can also be demonstrated.

The level of activity of the compounds of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secretion in the anaesthetised rat and the dose producing 50% inhibition of histamine-induced tachycardia in the isolated guinea pig atrium.

In order to use the compounds of the present invention as histamine Hg-receptor antagonists they will normally be administered in a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in the basic form or in the form of a pharmaceutically acceptable acid addition salt and in association with a pharmaceutical carrier.

Accordingly the invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formual I or a pharmaceutically acceptable acid addition salt thereof.

The pharmaceutical carrier employed can be solid or liquid.

Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, or stearic acid. Exemplary of liquid carriers are syrup, peanut oil, olive oil and Zb water. 4410 3 The composition is presented for administration in a variety of pharmaceutical forms. Thus if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.

The amound of solid carrier can be varied widely but preferably will be from 25 mg to 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or, non-aqueous liquid suspension.

The active ingredient will be present in the compositions in an effective amount to block histamine Hg-receptors. The route of administration may be oral or parenteral.

Advantageously the composition will be made up in a unit dosage form for example as a tablet or capsule. ζ Preferably, each dosage unit will contain the active ingredient in an amount of from 50 mg to 250 mg.

The active ingredient will preferably be administered one to six times per day. The daily dosage regimen will preferably be from 150 mg to 1500 mg.

The pharmaceutical compositions can be prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate.

The invention is illustrated by the following examples: EXAMPLE I N-|j-(4-Methyl-5-imi dazolylmethylthio) ethylj -N'- jj- (4-methyT5-imi dazolylmethyl thio)propyl J guanidine tri hydrochloride. (i) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (14.8 g) and 2-mercaptopropylamine hydrochloride (12.8 g) in aqueous hydrobromic acid (48%, 100 ml) was heated under reflux for hours, concentrated and recrystallised from ethanol-ether to give 2-jj4-methyT5-imidazolylmethylthi0] -propylamine di hydrobromide (30.0 g), m.p. 177-8°. (ii) A solution of N-jj-((5-methyT4-imidazolyl)methylthio)-ethylJ thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at room temperature for 18 hours affording S-methyl-N[?-((5-methyl-4-imidazolyl) methylthio) etbylj-thiouronium iodide (2.3 g), m.p. 128-131°. The iodide was converted into the corresponding sulphate by ion-exchange on ari ion-exchange resin (IRA 401) in the sulphate form. (iii) A solution of 2j_4-methyl-5-imidazolylmetbylthiJ-N[j-((4-methyl-5-imidazolyl) methylthio) ethylj thiouronium sulphate (3.35 g) in water 25 ml) was heated under reflux for 4 hours.

Concentration, followed by purification on ion exchange resin C.G.50(H+), with elution by 0.02N hydrochloric acid, treatment with sodium hydroxide and picrolonic acid accorded N-j2-(4-methyl-5imidazolylmethylthio) - ethylj -N‘-jj-(4-methyT5-imidazoly1methylthio) propyfjguanidine tripicrolonate (1.75 g. m.p. 173-175°, from aqueous dimethylformamide).

(Found: C, 46.9; H, 4.5; N, 21.9; S, 5.1% C16H27N7S23 01θΗ8Ν405 requires C, 47.1; H, 4.4; N, 22.7; S, 5.57, The tripicrolonate was suspended in aqueous ethanol and treated with ion-exchange resin; IRA 400 (CT) and acidified with the hydrochloric acid to form the corresponding trihydrochloride salt.

(Found: Cl, 22.1%. C16H27N7S2 . 3HC1 requires: Cl, 21.7%) EXAMPLE 2 Ν,Ν'-bis-[2-(4-Methyl-5-imidazolylmethylthio)propylIguanidine. trihydrochloride (i) A solution of 2~[4-methyl-5-imidazolylmethylthio]~ propylamine (from the dihydrobromide, 13.0 g) in ethanol (50 ml) was cooled to 0° and stirred during the gradual addition of benzoylimino dichloromethane (3.78 g). After addition the reaction mixture was set aside at room temperature for 2 hours and heated on the steam bath for 0.5 hours. Following addition to water and removal of insoluble material by filtration, the filtrate was adjusted to pH 9. The crude product obtained was purified by chromatography on a column of alumina followed by chromatographic purification on a column of silica gel (chloroform-methanol) to give N-benzoyl-N',-N-biS-[2-(4-methyl-5-imidazolylmethylthio) propylJguanidine. (ii) The benzoyl compound (3.2 g) was hydrolysed in concentrated hydrochloric acid (40 ml) at steam bath temperature for 5 hours. Following cooling, dilution with water and extraction with ether to remove benzoic acid, the product was purified as in Example 1 and concentrated to the picrolonate (1.35 g), m.p. 230°(decomp).

The picrolonate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 401 (Cl-) and acidified with hydrochloric acid to give N.N*-bis~r2-(4-methyl-5-imidazolylmethylthio)propyl] guanidine trihydrochloride.

The NMR spectrum of a solution in DgO recorded at 100 mHz showed the following resonances: imidazole-2H imidazole-CHgsinglet o 8.60 singlet S3.94 integral 2.0 calculated 2 integral 4.4 calculated 4 protons 0 protons protons 0 protons NH - CHg ch„-ch-s Z | — : doublet S3.39 ) : multiplet S3.04) integral 6.6 protons calculated 6.0 protons imidazole-CH3 : SingletS 2.37 integral 6.0 protons -CH- : doublet Si.34 (internal standard) I ch3 EXAMPLE 3 N-[l-((4-Methyl-5-imidazolyl)methylthio)but-2-yl]-N'~ [2-((4-methyl-5-iBidazolyl)methylthio)ethyl(guanidine trihydr oehloride IS Reaction of 4-hydroxymethyl-5-methylimidazole and 1-mercapto2-aminobutane in the procedure of Example l(i) yields 4-methyl5-[(2-aminobutyl)thiomethyl]imidazolyl and, when this is reacted with S-methyl~N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouronium sulphate in the procedure of Example l(iii), the title compound is produced.

EXAMPLE 4 When 4-hydroxymethyl-5-methylimidazole is reacted in the procedure of Example 1 with the following aminethiols: 2- mercaptobutylamine, 1-mere apt o-2-aminopropane, 3- mercaptobutylamine and 1- mercapto-3-aminobutane 30 the following amines are produced respectively: 2- [(4-methyl-5-imidazolyl)methylthio]butylamine, 4- methyl-5-'[(2-aminopropyl)thiomethyl]imidazole, 3-[ (4-methyl-5-imidazolyl)nethylthio]butylamine and 4-methyl-5-[(3-aminobutyl)thiomethyl]imidazole, which, on reaction with S-methyl-N-[2-((4-methyl~5-imidazolyl)methylthio)ethyl]thiouronium sulphate according to the J 410 3 procedure of Example l(iii), yield the following compounds respectively: N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-(2-((4methyl-5-imidazolyl)methylthio)butyl]guanidine trihydrochloride, N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N * -[1-((4methyl-5-imidazolyl)methylthio)prop-2-yl]guanidine trihydrochlorid· N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[3-((4methyl-5-imidazolyl)methylthio)butyl]guanidine trihydrochloride and N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl ]—— ((4methyl-5-i»idazolyl)methylthi o)but-3-yl]guanidine tri hydrochl ori de.

EXAMPLE 5 N-Cyano-N1-[2-(4-methyl-5-lmldazolylmethylthio)ethyI]-N-[2(4-methyl-5-lmidazolylmethylthio)propyljguanidine A mixture of 2-(4-methyl-5-iraidazolylmethylthio)propylamine (3.7 g. 0.2 mole) and N-cyano-N'-[2-((4-raethyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g. 0.1 mole) was heated at 130-140° for 6 hours. The cooled mixture Was treated with picrolinic acid in ethanol, and the resulting solid was recrystallised from dimethylformamide/ethanol to give the picrolonate salt of the title canpound (3.5 g) m.p. 217-219°.

The picrolonate salt was suspended in aqueous methanol and stirred with ion-exchange resin IRA 401 (Cl-) until the yellow colour disappeared. The mixture was filtered and the filtrate was evaporated to give the dihydrochloride of the title compound. 60 mHz n.m.r. in DgO:1.35 multiplicity d assignment CHg -s4ih-ch2integral observed calculated partially obscured 2.33 s CHg-imidazole 6.0 ref 2.5 - 3.75 Ώ1 -SCH2CH2 ) m -NCH„- ) 7.73 7 —2 ) ) ) m. CH2SCH 3.90 s (b) imidazole -CH2S- 4.18 4 8.40 s (b) 1.58 2 H The dihydrochloride was dissolved in isopropanol and was treated with one equivalent of sodium ethoxide in ethanol. The mixture was evaporated to dryness and the solid residue extracted with isopropanol. The isopropanol extract was evaporated to dryness to give the title compound as a foam.

EXAMPLE 6 1-Nltro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-225 [2-((4-methyl-5-imidazolyl)methylthio)propylamino]ethylene A mixture of 2-[(4-methyl-5-imidazolyl)methylthio]propylamine (0.46 g) and l-nitro-2-methylthio-2-[2-((4-methyr-5-imidazolyl)methylthio)ethylamino]ethylene (0.72 g) is heated on a steam bath for two hours and the cooled melt recrystailised to give the title product.

EXAMPLE 7 N-[2-((4-Methyl-5-imidazolyl)methylthlo)ethyl]-N,-[2-((4-methyl5-xmidazolyl)methylthio)propylJthiourea dihydrochloride A solution prepared from S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]dithiocarbamate hydrochloride (0.69 g) and ;16 110 3 2-[(4-methyl-5-imidazolyl)methylthio]propylamine (0.37 g) in ethanol containing sodium (0.05 g) was heated under reflux for 20 hours. Concentration followed by chromatographic purification of the product on a column- of silica gel gave the title compound.

EXAMPLE 8 N-Hydroxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]Nt-[2-((4-methyl-5-imldazolyl)methylthio)propyl]guanidine dihydrochloride Dry hydrogen chloride was passed into a solution of N-[2((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((4-methyl5-imidazolyl)methylthio)propyl]thiourea (0.23 g) in methanol (10 ml) and the mixture was refluxed for 5 hours. Concentration yielded S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]N'-[2-((4-methyl-5~imidazolyl)methylthio)propyl]isothiourea dihydrochloride. A mixture of the isothiourea dihydrochloride, hydroxylamine hydrochloride, potassium hydrogen carbonate and anhydrous dimethyl formamide was stirred vigorously for 4 hours at 85°C. Cooling and concentration of the product yielded the title compound.

EXAMPLE 9 When the procedure of Example 1 is carried out,using in place of 4-hydroxymethyl-5-methylimidazole hydrochloride, the hydrochlorides of the following compounds: 4-hydroxymethyl~5-bromoimidazole, 4-hydroxymethylimidazole, 2- hydroxymethylpyridine, 3- hydroxy-2-hydroxymethylpyridine, 3-methoxy-2-hydroxymethylpyridine, 3-chloro-2-hydroxymethylpyridine, 3-bromo-2-hydroxymethylpyridine, 2- hydroxymethylthiazole and 3- hydroxymethylisothiazole the trihydrochlorides of the following products are respectively produced: N-[2-((4-bromo-5-imidazolyl)methyltbio)propyl]—N'—[2— ((4methyl-5-iJuidazolyl)inethylthio) ethyl] guanidine, N-[2-(4-imidazolylmethylthio)propyl] -N'-[2-((4-methyl-5imidazolyl)methylthio)ethyl]guanidine, N-[2-(2-pyridylmethylthio)propyl]-N,"(2-((4-methyl-5imidazolyDmethylthio) ethyl] guanidine, N-[2-((3-hydroxy-2-pyridyl)methylthio)propyl]-N'-(2-((4methyl-5-imidazolyl)methylthio)ethyl]guanidine, N-[2-((3-methoxy-2-pyridyl)methylthio)propyl]-Ν'-(2-((4methyl-5-imidazolyl)methylthio)ethyl]guanidine, N-[2-((3-chloro-2-pyridyl)methylthio)propyl]-Ν' -(2-((4methyl-5-imidazolyl)methyIthio) ethyl ] guanidine, N-[2-((3-bromo-2-pyridyl)methylthio)propyl]-N'-[2-((4methyl-5-imidazolyl)methylthio)ethyl]guanidine, N-[2-(2-thiazolylmethylthio)propyl]-N'-[2-((4-methyl-5imidazolyl)methylthio)ethyl]guanidine and N-f2-(3-isothiazolyl)methylthio)propyl]-N'-[2-((4-methyl-5 imidazolyl)methylthio)ethyl]guanidine.

Claims (4)

1. A compound of the formula: X if Het ] -CH 2 S-B 1 -NH-C-NH-BgS-CHg-Hetg where Het-j and Het 2 are the same or different and are 5 imidazole optionally substituted by methyl or bromo, pyridine optionally substituted by hydroxyl, methoxy, chloro or bromo; thiazole or isothiazole; X is sulphur, NH, NOH, NCN, or CHNO 2 ; and Β-j and B 2 are lower alkylene groups such that either B 1 is -(CH 2 ) 2 · Of (CH 2 ) 3 “ and 10 B 2 is -CHgCHR-. -CHRCHg-, -CHCHgCHg-, or “CHgCHg-CHCH 3 CH 3 where R is methyl or ethyl or and B 2 are both selected from and -CHCH, Z l j Z CH 3 ch 3

2. A compound according to claim 1 wherein B-j is -(CH 2 ) 2 - and B 2 is -CH 2 CHl ch 3

3. A compound according to claim 1 or claim 2 wh ere Het^ and 15 Het 2 are selected from 4-imidazolyl optionally substituted by 5-methoxy, 3-bromo or 3-chloro; 2-thiazolyl and 3-isothiazolyl. 4. A compound according to claim 3 where Het^ and Het 2 are both 4-imidazolyl substituted by 5-methyl. 5. A compound according to any one of the preceding claims where X is sulphur, NH, NCN or CHNOg. 6. N-[l·-((4-Methyl-5-imidazolylJmethylthioJpropylj-N'-[2-((4-methyl5-imidazolyl)methylthio)ethylj guanidine. 5 7. N, N'-bis-j_2-((4-Methyl-5-imidazolyl) methyl thio) propyl]-guanidine 8. A process for the preparation of a compound according to claim 1 in which a compound of formula Het^HgSB^H- X or Het-CH-SB-NH-C Xa where Hetp Het,,, B-j and B 2 have the same significance as in claim 1, A is lower alkyl and X^ is sulphur, NH, N.CN or CHN0 2 is reacted 10 respectively with an amine of the formula: Het 2 CH 2 SB 2 NH 2 or He^CHgSB^ and when X^ is sulphur, optionally reacting the product with a lower alkyl halide to yield the corresponding isothiourea which is then reacted with hydroxylamine. 15 9. A process for the production of a compound according to claim 1 as described in any one of the Examples. 10. A compound according to claim 1 whenever produced by a process according to claim 8 or claim 9.

4. 4103 Π. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or 10 and a pharmaceutically acceptable carrier. Dated this 26th day of October 1976,