GB1573611A

GB1573611A - Heterocyclic thioalkyl-amines-guanidines and -thioureas

Info

Publication number: GB1573611A
Application number: GB46732/75A
Authority: GB
Original assignee: Smith Kline and French Laboratories Ltd
Current assignee: Smith Kline and French Laboratories Ltd
Priority date: 1975-11-12
Filing date: 1975-11-12
Publication date: 1980-08-28
Also published as: DK503176A; IL50748A0; FR2331342B1; ZA766201B; NL7611590A; DE2649546A1; IE44103L; AT350583B; JPS5262274A; SU634668A3; PT65759A; HU175667B; LU76162A1; ATA819776A; ES453263A1; IE44103B1; AU1890076A; PT65759B; AU508143B2; BE848108A

Description

(54) HETEROCYCLIC THIOALKYL -AMIN ES, -GUANIDIN ES AND ) -THIOUREMS (71) We, SMITH KLINE & FRENCH LABORATORIES LIMITED of Mundells, Welwyn Garden City, Hertfordshire, England, a British company do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to pharmacologically active compounds which block histamine H2-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 diDhenhyd ramine and chlorpheniramine are other examples are mediated through histamine H receptors (Ash and Schild, Brit. J. Pharmac. Cltemother, 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 (Naturc, 236, 385 (1972)) and called burimamide. are mediated through receptors which are defined by Black et al as histamine H2-recetors. Thus histamine H2-receptors are histamine receptors which are blocked by burimamide but not mcpyramine. Compounds which block histamine H2- receptors are referred to as histamine H2-antagonists.

Blockade of histamine H2-receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2-antagonists are therefore useful for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cariovascular system, for example as inhibitors of the cffccts of histamine on blood pressure. In the treatment of certain conditions, for example inflammation and in inhbiiting the actions of histamine in blood pressure, a combination of histamine Hl- and H2- antagonists is useful.

According to the present invention there is provided a compound of formula 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; Xis sulphur, NH, NOH, NCN, or CHNO2; and B1 and B2 are lower alkylene groups such that either B1 is -(CH2)2- or -(CH2)3- and B2 is -CH2CHR-,

where R is methyl or ethyl or B1 and B2 are both selected from

The compounds of the invention are histamine H2 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 B1 is -(CH2)2- and B2 is

In particular Hetl and Het2 are selected fr6m 4-imidazolyl optionally substituted by 5-methyl or 5-bromo; 2-pyridyl optionally substituted by 3-hydroxyl, 3-methoxy,3-bromo or 3-chloro; 2-thiazolyl and 3-isothiazolyl.

Preferably Hetl and Het2 are both 4-imidazolyl substituted by 5-methyl.

X is preferably NH, NCN, sulphur or CHIN02.

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: N-[2-((4-methyl-5-imidazolyl)methylthio)propylj-N'- [2-((4-methyl-5-imidazolyl)methyl thio)ethyl jguanidine and N,N-'bis-[2-((4-methyl-5-imidazolyl)methylthio)propyll- guanidine.

The invention further provides a process for the preparation of compounds of formula 1 where an amine of formula IIa or IIb: Het1-CH2S-B 1-NH2 Het2-CH2S-B2-NH2 IIa IIb where Het,, Het2, B1 and B2 have the same significance as a formula I, is reacted respectively with a compound of formula IIIa or IIIb:

where Hetl, Het2, B1 and B2 are as previously defined, X' is sulphur, NH, NCN or CRNO2 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 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 IIa or IIb with an isothiourea of formula IIIc or IIId:

S 10 15 20 25 30 35 40 45 50 55 60

where Heel, Het2, B1 and B2 have the above significance and A is lower alkyl, the isothiourea of formula IIIa is formed from the corresponding amine of formula IIa by reaction of the latter with benzoylisothiocyanate to give a compound of formula IV:

where Hetl and B1 have the above significance and Q isbenxoyl; 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 IIIb can be prepared from the amine of formula IIb.

Alternatively the compounds of formula I where X is NH can be produced by reaction of a compound of formula V: (AS)2C = X 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 IIa or formula IIb and then reacting the resultant product with the other amine of formula IIb or IIa. Finally the benzoyl group is removed by hydrolysis. In this case. where it is desired to produce the compound of formula I where each Hctl and B1 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 Cl2C=X1 wherein Xl has the above significance.

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 CHIN02. In this X1 in formula V is N.CN or CHNO2 and the final hydrolsis step is not of course necessary.

The compounds of formula I where X is Xis sulphur can be produced by reacting the amine of formula IIa or IIb with a dithiocarbamic ester of formula VIb or VIa.

where Heel. Rest2, B1 and B2 have the above significance and A is lower alkyl. The dithiocarbamic esters of formula VIa and VIb can be formed from the corresponding amincs of formula IIa and IIb by reaction of the latter with carbon disulphide and a lower alkyl halide or sulphate. When HetlB1 is identical to Hct2B2 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 isothiourca and then reacting this isothiourea with hydroxylamine.

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

Het-CH2L VII where Het has the same significance as Het1 and Het2 in formula I and L is hydroxyl, halogen or methoxy, with an aminethiol of formula VIII.

HS-B l-NH2 VIII where B l 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-receptors 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 of 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 R2-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 H1-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.

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 H2-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 formula 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 water.

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 amount 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 inectable liquid contained for example in an ampoule, or an aqueous or nonaqueous liquid suspension.

The active ingredient will be present in the compositions in an effective amount to block histamine H2- 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.

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 1 N- [2- (4Methyl-S-imidazolylmethylthio) ethyl ]-N'- [2- (4-methyl-5-imidazolylmethylthio) proyliguanidine trEhydrochloride.

(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 6 hours, concentrated and recrystallised from ethanol-ether to give 2-[4-methyl-5-imidazolylmethylthio]-propylamine dihydrobromide (30.0 g), m.p.

177-178 .

(ii) A solution of N-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl] 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- [2-((5-methyl-4-imidazolyl) methylthio)ethyl]-thiouronium iodide (2.3 g), m.p. 128-131". The iodide was converted into the corresponding sulphate by ion-exchange on an ion-exchange resin (IRA 401) in the sulphate form.

(iii) A solution of 2-[4-methyl-5-imidazolymethylthio]-N-[2-((4-methyl-5-imidazolyl) methylthio)ethyl]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 afforded N-[2-(4-methyl-5-imidazolylmethylthio) -ethyl]-N'-[2-(4-methyl-5 -imidaxolymethylthio)propyl]guanidine tripicrolonate (1.75 g, m.p.173-175 , from aqueous dimethylformamide).

(Found(found (Found(found C, 46.9; H, 4.5; N, 21.9; S, 5.10/OC16H27N7S2 3 Cl0H8N405requires: C, 47.1; H, 4.4; N, 22.7; S, 5.5%).

The tripicrolonate was suspended in aqueous ethanol and treated with ion-exchange resin IRA 400 (cm ) (cm ) and acidified with the hydrochloric acid to form the corresponding trihydrochloride salt.

(Found: Cl, 22.1C/ C6H2,N,S2. 3HCl requires: Cl, 21.7%) EXAMPLE 2 N, N'-bis- I-(4-Methyl-5- imidazolymethylthio)propyl ]guanidine. trihydrochloride (i) A solution of 2- [4-methyl-5-imidazolymethylthio] -propylamine (from the dihydrob romide, 13.0 g) in ethanol (50 ml) was cooled 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) -propyl]guanidine.

(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- (4-methyl-5-imidazolyl -methylthio)propyl]guanidine trihydrochloride.

The NMR spectrum of the solution in D2O recorded at 100 mRz showed the following resonances: imidazole-2H singlet 8 8.60 integral 2.0 protons calculated 2.0 protons imidazole-CH2- : singlet 8 3.94 integral 4.4 protons calculated 4.0 protons NH - CH2- : doublet 8 3.69 ) integral 6.6 protons CH2-CH-S : multiplet 8 3.04 calculated 6.0 protons imidaz'ole-CH3 singlet 8 2.37 integral 6.0 protons (internal standard)

: doublet 3 1.34 EXAMPLE 3 N-[1-((4-Metllyl-5-rtlidazolyl)methylthio)but-2-yl]-N'-[2-((4-methyl-S-imidazolyl)-N- [1 -((4-MethyP5-inzidazolyi) inedylio) but-2-yl]-N'- [2-((4-nethyl-5-imidazoly() - N-[1-((4-Metllyl-5-rtlidazolyl)methylthio)but-2-yl]-N'-[2-((4-methyl-S-imidazolyl)-N- [1 -((4-MethyP5-inzidazolyi) inedylio) but-2-yl]-N'- [2-((4-nethyl-5-imidazoly() - tl eth llho) etizyl ]gtian idiii e trihydroclz bride Reaction of 4-hydroxymethyl-5-methylimidazole and 1-mercapto-2-aminobutane in the procedure of Example l(i) yields 4-methyl-5- [(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-mercapto-2-aminopropane, 3-mercaptobutylamine and 1-mercapto-3-aminobutane the following amines are produced respectively: 2-[(4-methyl-5-imidazolyl)methylthio]butylamine, 4-methyl-5- [(2-aminopropyl)thiomethyl] imidazole, 3-[(4-methyl- 5-[(-5- imidazolyl)methylthio]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 procedure of Example 1(iii), yield the following compounds respectively: N-[2- ((4-methyl-5-imidazolyl)methylthio)ethyl N'-[2- ((4-methyl-5 imidazolyl)methylthio)ethyl] -N'- [1 -((4-methyl-S-imidazolyl)methylthio)prop-2-yl]-.

guanidine trihydrochloride -5-imidazolyl)methylthio)prop-2-yl]guanidine trihydrochloride N- [2-((4- methyl-5-imidazolyl)methylthio)ethyl] -N'- [3- ((4-methyl5-5imidazolyl)- methylthio) butyl] guanidine trihydrochloride and N-[2-((4- methyl-5-imidazolyl)methylthio)ethyl]-N' -[1-((4 -methyl -5-imidazolyl)methylthio) but-3-yl]guanidine trihydrochloride.

EXAMPLE 5 N-Cyano-N'- [2-(4- methyl- 5-imidazolylmethylthio) ethyl] -N"- [2-(4 -methyl- 5 imidazolymethylthio)propyl]guanidine A mixture of 2-(4-methyl- S-imidazolylmethylthio)propylamine (3.7 g. 0.2 mole) and N-cyano-N'-[2-((4-methyl-5- imidazolyl)-methylthio)ethyl]-S-methylisothiourea (2.69 g.

0.1 mole) was heated at 130-1400 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 compound (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 D2O: integral 8 multiplicity assignment observed calculated

1.35 d H3 partially obscured -S-CH-CH2 2.33 5 CH3-imidazole 6.0 ref 6 2.5 - 3.75 m -SCH2CH2 ) m -NCH2- ) 7.73 7 m CH2SCH 3.90 s (b) imidazole 4.18 4 -CH2S 8.40 s (b) NltN 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 I-Nitro-2- [2-((4-methyl- 5-imidazolyl)methylthio) ethylamino]- 2-[2- ((4-methyl-S -imidazolyl) methylthio)p ropylamino ]ethylene A mixture of 2-[(4-methyl -5-imidazolyl)methylthio] propylamine (0.46 g) and 1-nitro-2 methylthio-2-[2- ((4-methyl-5-imidazolyl) -methylthio)ethylamino] ethylene (0.72 g) is heated on a steam bath for two hours and the cooled melt recrystallised to give the title product.

EXAMPLE 7 N- [2-((4- Methyl-5-imidazolyl)methylthio)ethyl] -N'- [2-((4-methyl- 5-imidazolyl)methylthio) propyl]thiourea dihydrochloride A solution prepared from S-methyl-N -[2-((4-methyl- 5-imidazolyl) -methylthio) ethyl]dithiocarbamate hydrochloride (0.69 g) and 2-[(4 -methyl-5-imidazolyl)methylthio]propylamine (0.37 g) in ethanol containing sodium (0.5 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-ffydroxy-N'-[2-((4- methyl-5-imidazolyl) ethylthio) ethyl] -N'-[2-((4- methyl- 5- imidazolyl) methylthio)propyl]guanidine dihydrochloride Dry hydrogen chloride was passed into a solution of N-[2-((4 -methyl-5-imidazolyl)methylthio) ethyll-N'-[2- ((4-methyl-5- 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 4hydroxymethyl-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)methylthio)propyl] -N'- [2- ((4-methyl- 5-imidazolyl) methyl- thio)ethyl]guanidine, N-[2- (4-imidazolymethylthio)propyl]-N'- [2-methyl -5-imidazolyl)methylthio) ethyl]guanidine.

N-[2-(9 -pyridylmethylthio)propyl]-N' -[2-((4- methyl-5-imidazolyl)methylthio)- ethyl]guanidine.

N-[2-((3-hydroxy -2-pyridyl)methylthio) propyl]-N' - [2-((4 -methyl-5- imidazolyl)methylthio) ethyl guanidine N-[2-((3-methoxy -2-pyridyl)methylthio) propyl]-N'- [2-((4- methyl-5- imidazolyl) methylthio)ethyl]guanidine, N-[2- ((3-chloro-2-pyridyl)methylthio)propyl] -N'-[2- ((4-methyl-5- imidazolyl)methylthio) ethyl]guanidine.

N-[2-(3-bromo -2-pyridyl)methylthio)propyl] -N'-[2- ((4-methyl-5- imidazolyl) methylthio)ethyl]guanidine.

N-[2-(2- thiazolylmethylthio) propyl]-N'-[2- ((4-methyl- 5-imidazolyl) methyl thio)ethyl]guanidine and N-[2-(3-isothiazolyl)methylthio)propyl] -N'-[2-((4- methyl-5-imidazolyl) methylthio)ethyl]guanidine.

WHAT WE CLAIM IS: 1. A compound of the formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

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 I-Nitro-2- [2-((4-methyl- 5-imidazolyl)methylthio) ethylamino]- 2-[2- ((4-methyl-S -imidazolyl) methylthio)p ropylamino ]ethylene A mixture of 2-[(4-methyl -5-imidazolyl)methylthio] propylamine (0.46 g) and 1-nitro-2 methylthio-2-[2- ((4-methyl-5-imidazolyl) -methylthio)ethylamino] ethylene (0.72 g) is heated on a steam bath for two hours and the cooled melt recrystallised to give the title product.

EXAMPLE 7 N- [2-((4- Methyl-5-imidazolyl)methylthio)ethyl] -N'- [2-((4-methyl- 5-imidazolyl)methylthio) propyl]thiourea dihydrochloride A solution prepared from S-methyl-N -[2-((4-methyl- 5-imidazolyl) -methylthio) ethyl]dithiocarbamate hydrochloride (0.69 g) and 2-[(4 -methyl-5-imidazolyl)methylthio]propylamine (0.37 g) in ethanol containing sodium (0.5 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-ffydroxy-N'-[2-((4- methyl-5-imidazolyl) ethylthio) ethyl] -N'-[2-((4- methyl- 5- imidazolyl) methylthio)propyl]guanidine dihydrochloride Dry hydrogen chloride was passed into a solution of N-[2-((4 -methyl-5-imidazolyl)methylthio) ethyll-N'-[2- ((4-methyl-5- 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 4hydroxymethyl-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)methylthio)propyl] -N'- [2- ((4-methyl- 5-imidazolyl) methyl- thio)ethyl]guanidine, N-[2- (4-imidazolymethylthio)propyl]-N'- [2-methyl -5-imidazolyl)methylthio) ethyl]guanidine.

N-[2-(9 -pyridylmethylthio)propyl]-N' -[2-((4- methyl-5-imidazolyl)methylthio)- ethyl]guanidine.

N-[2-((3-hydroxy -2-pyridyl)methylthio) propyl]-N' - [2-((4 -methyl-5- imidazolyl)methylthio) ethyl guanidine N-[2-((3-methoxy -2-pyridyl)methylthio) propyl]-N'- [2-((4- methyl-5- imidazolyl) methylthio)ethyl]guanidine, N-[2- ((3-chloro-2-pyridyl)methylthio)propyl] -N'-[2- ((4-methyl-5- imidazolyl)methylthio) ethyl]guanidine.

N-[2-(3-bromo -2-pyridyl)methylthio)propyl] -N'-[2- ((4-methyl-5- imidazolyl) methylthio)ethyl]guanidine.

N-[2-(2- thiazolylmethylthio) propyl]-N'-[2- ((4-methyl- 5-imidazolyl) methyl thio)ethyl]guanidine and N-[2-(3-isothiazolyl)methylthio)propyl] -N'-[2-((4- methyl-5-imidazolyl) methylthio)ethyl]guanidine.

WHAT WE CLAIM IS: 1. A compound of the formula:

where Hetl 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 B1 and B2 are lower alkylene groups such that either B1 is (CH2)2 or (CH2)3 and

where R is methyl or ethyl or B1 and B2 are both selected from
2. A compound according to claim 1 wherein B1 is -(CH2)2- and B2 is
3. A compound according to claim 1 or claim 2 where Hetl and Het2 are selected from 4-imidazolyl optionally substituted by 5-methoxy, 3-bromo or 3-chloro; 2-thiazolyl and 3-isothiazoly.
4. A compound according to claim 3 where Hetl and Het2 are both 4-imidazolyl substituted by methyl.
5. A compound according to any one of the preceding claims where X is sulphur, NH, NCN or CHNO2.
6. N-[2-((4-Methyl-5-imidazolyl)methylthio)propyl]-N' [2-((4-methyl-5-imidazolyl) methylthio)ethyl guanidine.
7. N N'-bis- 2-((4-Methyl-5-imidazolyl) methylthio)propyl]-guanidine.
8. A process for the preparation of a compound according to claim 1 in which a compound of formula:

where Rest1, Het 2. B1 and B2 have the same significance as in claim 1, A is lower alkyl and X' is sulphur, NH. N.CN or CRNO2 is reacted respectively with an amine of the formula: Het2CH2SB2NH2 or HetlCH2SB1NH2 and when X l is sulphur, optionally reacting the product with a lower alkyl halide to yield the corresponding isothiourea which is then reacted with hydroxylamine.
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.
11. 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.