CA1070316A - Pharmacologically active bis imidazolyl guanidines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

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 substi-tuted 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

1 This invention relates to pharmacologically active compounds, to methods for preparing these compounds, to ~
pharmaceutical compositions containing these compounds and to methods ol' blocking histamine ~2-receptors by admini terlng these co~pounds. The compounds oi' the S invention can exist a~ acid addition salts and/or hydrates but, l'or convenience, re~erence will be made throughout this speci~ication to the parent compound-~.

~any phrslologically active substances elicit their biological actions by interaction with speci~ic qites known as receptors. Histamine is such a substance and has a number o~ biological actions. Those biological action~ oi' histamine which are inhibited by drugs commonly called "antihistamines" oi which mepyramine is a typical e~ample, and diphenhydramine and chlorpheniramine are other examples are mediated through histamine Hl-receptors (AF,h and Schild, Brit. J. Pharmac. Chemother, 27, 427, (1966)). ~owever, other oi' the biologlcal actions oi hi~tamlne are not inhibited by "antihistæmines" and actions oi' thi~ type which are inhibited by a compound described by Black et. al (Nature, 236, 385 (1972)) and called burimamid~ are medlated through receptors ~hich are dei'ined C ~ by Black et al. as histamine ~2-receptors. Thu-~ histamine ~2-receptors may be de~ined as those histamine receptors ~hich are not blocked by mepyramine but are blocked by burimamide. Compounds ~hich block hlstamine H2-receptors are re~erred to as histamine H2-antagonists.

Blockade ol' histamine ~2-receptors is oi' utility in inhibitlng the biological actions oi histamine which are not inhibited by "antihistaminea". Histami~e ~2-antagonists are thereiore useiul i'or example, as inhibitors of gastric acid secretion, as anti-ini'lam~atory agents and as agents which act on the cardiovascular system, l'or example as inhibitors o~ the el'l'ects oi' histamine on blood pressure. In the treatment oi' certain conditions, l'or example inl'lammation and in ` -2- ~

. ., . . .. . . . . - .
- : :- , , -107()316 1 inhibiting the actions o~ histamine on blood pressure, a combination o~ histamine H1- and H2-antagonists is useful.

The compounds of this invention are histamine H2-antagonists.
These compounds are represented by the i'ollowing Formula 1:

Hetl-CH2 S Bl-NH C NH-B2S CH2-Het2 FO~MULA 1 .

wherein Hetl and Het2 may each be 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 CHN02: and Bl and B2 are lower alkylene~groups such that either Bl is - (CH2)2 or (CH2)3 and B2 i9 -CH2CHR-, -CHR~H2-- -1CHCH2CH2-~ or -CH2CH2¦H-ao CH3 CH3 R is ~ethy} or ethy or ~ r~ both_se~ec~2~ ~rom -CHaCH- and CHCH2-CH~ CH3 It wlll be understood that the structure illustrated in Formula 1 is only one o~ several possible representations and that other tautomeric i'orms are also covered by the present invention.
Throughout the present speci~ication by the term "lower alkyl", we mean an alkyl group containing from 1 to 4 carbon atoms.
In one pre~erred group o~ compounds Bl is (CH2)i2 and B2 is -CH21CH-. It is also pre~erred that Hetl and Het2 are selected ~rom 4-imidazolyl optionally substituted by 5imethyl or 5-bromo; 2-pyridyl optionally substituted by 3-hydroxyl,3-methoxy ...-' -- 1070316 - ~

1 3-bromo or 3-chloro; 2-thiazolyl and 3-isothiazolyl.
X is preferably NH, N.CN, sulphur or CHN02.

Specific compounds falling within the scope of the present invention include:
. N-~2-((4-methyl-5-imidazolyl)methylthio)propyl]-N'-~2-((4-methyl-5-imidazolyl-)methylthio)ethyl]guanidine a~d N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)prQpyl]guanidine.

The compounds of Formula 1 may be prepared ~rom the correspond1n3 a~ines o~ Formulae IIa and IIb.

~Ietl-CH2S~Bl N~2 Het2-CH25~B2-NH2 FORMULA IIa - FOR~ULA IIb '~
wherein Het1, Het2, Bl and B2 have the same significance as in Formula I.

Production of the compound of Formula I wherein X is NH
results ~rom the reaction of the amine of Formula IIa or IIb with the lsothiourea of Formula IIIb or IIIa:

2 2 B2 Nll C

_RM~LA IIIb ~ SA
Hetl-C~2S-Bl_NH_C

FORMULA IIIa ,~ .
... .. .

1 wberein Hetl, Het2, Bl and B2 have the above significance and A is lower alkyl, The is~thiourea of Formula IIIa is formed from the corresponding amine of Formula IIa by reaction of the latter with benzoylisothiocyanate to give the compound of Formula IV:
S
Hetl - CH2S - Bl - NH - C
NHQ

FORMULA IV

wherein Hetl and Bl have the above significance and Q is ( benzoyl; hydrolysis of this compound to yield the corresponding thiourea wherein Q is hydrogen; and reaction of the latter with a lower alkyl halide such as lower alkyl iodide. Similarly the isothiourea of Formula IIIb may be prepared from th~ amine of Formula IIb.

Alternatively the compounds of ~ormula I wherein X is NH
may be produced by reaction of a compound o~ Formula V:

(AS)2C = X
~ FORMULA V

( 25 wherein A i~ lower alkyl and Xl is NQ, Q being benzoyl, ~irst ~ith an equimolar amount o~ one of the amines of Formula IIa or Formula IIb and then reacting the re~ultant product with the other amine of Formula IIb or IIa. Finally the benzoyl group is removed by hydrolysis. In this case, where it i8 desired to produce the compound oi' Formula I
wherein each Hetl and Bl 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 ---r amine of Formula IIa. In a variation of this method, the compound of Formula V may be replaced by a compound of the i'ormula C12C~Xl wherein Xl has the above signi~icance.

- -- - , .-. ~- - ,., .. ~ .; .

~071 )3~6 1 The reactions described in the preceding paragraph may also be used for the production of compounds o~ Formula I wherein X is N.CN or CHN02. In this case Xl in Formula V is N.CN or CHN02 and the final hydrolysis step is not of course necessary.

The compounds o~ Formula I wherein X is sulphur are produced by reacting the amine of Formula IIa or IIb with a dithiocarbamic ester o~ Formula VIb or VIa.
~ SA ~ SA
Het2-l~H2s-B2-NH-c ~etl-cH2s-Bl-NH-c S ' S

FORMULA VIb FORM~LA VIa wherein Hetl, Het2, ~ and B2 have the above significance and A is lower alkyl. The dithiocarbamic esters of Formula VIa and VIb are ~ormed from the corresponding amines of Formula IIa and IIb by reaction o~ the latter with carbon . 20 di~ulphide and a lower alkyl halide or sulphate. When HetlB
is identical to Het2B2 the required compounds of Formula I
wherein X is sulphur can be produced directly by the reaction of carbon disulphide with two equivalents o~ the amine of Formula II.

The compound~ o~.Formula I wherein X is N.OH may be ~ormed ~om those wherein X is sulphur by reaçting the latter with a lower alkyl halide to yield the corresponding isothiourea and then reacting this isothiourea with hydroxylamine.

The amines o~ Formula II may be produced by the reaction of a compound o~ FormulaVII.

H~t - CH2L

FORMULAVII

1 wherein Het has the same signiflcance as ~etl and Het2 in Formula I and L is hydroxyl, halogen or methoxy, with an aminethiol of Formula VIII.

FORMULA VIII

wherein Bl has the same significance as Bl and B2 in Formula I. The aminethiols of Formula XI are known compounds.
The compounds o~ Formula I block histamine H2-receptors that is they inhibit the biological actions o~ histamine whieh are not inhibited by "antihistamines" such as mepyramine but are inhibited by burimamide. For example, the eompounds o~ this invention have been iound to inhibit histamine-stimulated secretion o~ gastrlc acid ~r~m the lumen-per$used stomachs o~ rats anaesthetised 2 with ur~thane, at doses oi ~rom 0.5 to 256 micromoles per kilogram intravenously. This procedure is referred to in the above mentioned paper oi' Ash and Schild. The activlty oi these eompounds a histamine H2-antagonists is also demonstrated by their ability to inhibit other aetions o~ histamlne whieh, aeeording to the above-mentioned paper o~ Ash and Sehild, are not mediated by histamine Hl-reeeptors. For example, they inhibit the actions o~ hi~tamine on the isolated guinea pig atrium and isolated rat uterus.

The eompounds o~ this invention inhibit the basal seeretion o~ gastrie aeld and also that stimulated by pentagastrin or by iood.

In addition, the eompounds oi' this invention show anti-in~lammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume is redueed by subcutaneous injeetion of doses o~ a eompound o~ Formula I. In a - ; , :. , ~. .

10~70316 conventional test, such as the measurement o~ blood pressure ~ in the anaesthetised rat, the action o~ thé compounds o~ this invention in inhibiting the vasodilator action oi' histamine can also be demonstrated. The level oi' activity of the compounds of this ~nvention is illustrated by the effective dose producing ~0% 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.

For therapeutic use, the pharmacologically active compounds , .... .. ..... . . ........ . . . .. . . . . . .
o~ the present invention will normally be administered as a pharmaceutical compositiQn comprising as the or an essential active ingredient at lea.st one such compound in the basic ~orm or in the ~orm o~ an addition salt with a pharmaceutically acceptable acid and in associated with a pharmaceutical carrier there~or. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and may conveniently be ~ormed ~rom the corresponding bases of Formula I by standard procedures, ~or example by treating the base with an acid in a lower alkanol or by the use o~ ion exchange resins to iorm the required salt either directly i'rom the base or ~rom a dii'~erent addition salt.

Pharmaceutical compositions comprising a pharmaceutie21-carrier and a compound o~ Formula I or a pharmaceutically acceptable acid addition salt thereo~ and methods o~
blocking histamine H2-receptors which comprise administering

3 a compound o~ Formula I or a pharmaceutically acceptable acid addition salt thereoi are also objects o~ this invention.
The pharmaceutical carrier employed may be, ~or example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
Exemplary o~ liquid carriers are syrup, peanut oil, olive oil, water and the l~ke.
.

- 10703~6 1 A wide variety of pharmaceutical forms can be employed. Thus i~ a solid carrier ~ 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 will vary widely but pre~erably will be ~rom about 25 mg to about 1 g. I~ a liquid carrier is used, the preparation may be in-the form o~ a syrup, emulsion, soft gelatin capsule, sterile in~ectable liquid contained i'or ~ example in an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in an e~fective amount to block h~stamine H2-receptors.
The route of administration may be oral or parenteral.

Preierably, each dosage unit will contain the active *
ingredient in an amount o~ ~rom about 50 mg to about 250 mg.
The active ingredient will pre~erably be administered one to six times per day. The daily dosage regimen will pre~erably be i'rom about 150 mg to about 1500 mg.

Advantageously the composition will be made up in a dosage i'orm appropriate to the desired mode oi' administration, ~or example as a tablet, capsule, inJectable solution or as a cream or ointment ~or topical application.
, The invention is illustrated but in no Wdy limited by the ~ollowing examples:

: . ,... . ~ . . . .. :

`. 1070316 `

1 EgAMPLE 1 N-~2-(4-Methyl-5-imidazolylmethylthio)ethyl]-N'-~2-(4-methyl 5-imidazolylmethylthio)propyl~guanidine trihydrochloride.
-(i) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (14.8 g) and 2-mercaptopropylamine hydrochloride (12.8 g) in aqueous hydrobromic acid (48~o~ 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 Por 18 hours affording S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiouronium iodide (2.3 g), m.p. 128-i31. The iodide was.
converted into the corresponding sulphate by ion-exchange ' on an ion-exchange resin (IRA 401) in the sulphate ~orm.
(iii) A solution of 2-[4-methyl- ~imidazolylméthylthio]-propylamine (4.0 g., from the dihydrobromide) and S-methyl-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(~+), with-elution by 0.02N
hydrochloric acid, treatment with sodium hydroxide and picrolonic acid a~forded N-~2-(4-methyl-5-imidazolylmethylthio)-propyl]guanidine tripi$rolonate (1.75 g, m.p. 173-175, from ~;
aqueous dimethylformamide).
tFound: C, 46.9; H, 4.5; N, 21.9; S, 5.1% C16H27N7S2 3 CloH8N405 requires: C, 47.1; H, 4.4; N, 22.7; S, 5.5%).

The tripicrolonate was suspended in aqueous ethanol and treated with io~-exchange resin IRA 400 (Cl ) and acidified with the hydrochloric acid to form the corresponding trihydrochloride salt.
(Found: Cl, 22.1%. Cl ~27N7S2. 3HCl requires: Cl, 21.7%) L~
., ., ~. -10703~6 N,N'-bis-[2-(4-Methyl-5-imidazolylmethylthio)propyl]guanidine.
trihydrochloride (i) A solution o~ 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). A~ter addition the reaction mixture was set aside at r~om temperature for 2 hours and heat~d 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 chromatog aphy on a column of alumina ~ollowed by chromatographic puriiication on a column o~ -~ilica 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 ior S hours. Following cooling, dilution ~ith water and extraction with ether to remove benzoic acid, the product was puri~ied as in Example 1 and cQ~centrated to the picrolonate (1.35 g), m.p. 230(decomp).

The picrolonate was disQolved in aqueous methanol and treated with ion~exchange resin IRA 401 (Cl ) and acidiiied with hydrochloric acid to give N,N'-bis-[2-(4-methyl-5-imidazolyl-methylthio)propyl]guanidine trihydrochloride.

The NMR spectrum o~ a solution in D20 recorded at 100 mHz sho~ed the iollowing resonances:

imidazole-2H : singlet ~8.60 integral 2.0 protons calculated 2.0 protons imidazole-CH2- : singlet ~3.94 integral 4.4 protons calculated 4.0 protons ., - ,-~ :. , .. .. . . , . ; , . -.............. . .
- , . .
- . . . . , , -- ..
, NH - CH2 - : doublet ~3.39 ~ integral 6.6 protons CH2-CH-S : multiplet ~3.04 calculated 6.0 protons imidazole-CH3: singlet ~2.37 integral 6.0 protons (internal standard) -CH- : doublet ~1.34 N-11-((4-Methyl-5-imidazolyl)methylthio)but-2-yl]-N'-[2-((4-meth~yl-5-i~idazolyl)methylthio)ethyl]guanidine trihydrochloride Reaction of 4-hydroxymethyl-5-methylimidazole and l-mercapto-2-aminobutane in the procedure o~ Example l(i) Yields 4-methyl-5-[(2-aminobutyl)thiomethyl]imidazolyl and, when ~his is r~acted with S-methyl-N-[2-((4-methyl-5-imidazolyl)'methylthio)ethyl]-thiouronium ~ulphate in ~he procedure of Example l(iii), the title compound is produced.
EXA~PLE 4 ' W~n~-hydroxyme~hyl-5-methylimidazole is reacted in the procedure oi Example 1 with the ~ollowing aminethiols:
2-mercaptobutylamine, l-mercapto-2-aminopropane, 3-mercaptobutylamine and l-mercapto-3-aminobutane ; 30 the ~ollowing amines are produced respectively:

2-[(4-methyl-5-imidazolyl)methylthio]butylamine,

4-methyl-5-'[(2-aminopropyl)thiomethyl]imidazole, 3-[(4-methyl-5-imidazolyl~ethylthio]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 :, . - ....... . .,: . .. - ;;
:. : :; . . - - .. - - .. - . . ;. : .:.... -, . . . .

. 1070316 1 procedure of Example l(iii), yield the following compounds respectively:
N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((4-, methyl-5-imidazolyl)methylthio)butyl]guanidine trihydrochloride, N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[1-((4-methyl-5-imidazol`yl)methylthio)prop-2-yl]guanidine trihydrochlorid~
~-[2-((4-methyl-5-imidazolyl)methylthio3ethyl]-N~-[3-((4-methyl-5-imidazolyl)methylthio)butyl]guanidine trihydrochloride and N-[2-((4-methyl-5-imidazolyl)methiylthio)ethyl~NL;1-((4- , , methyl-5-imidazolyl)methylthio)but-S-yl]guanidine trihydrocyloride.

N-Cyano-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]-N"-[2-(4-methyl-5-imidazolylm,ethylthio)propyl~guanidine A mixture of 2-(4-methyl-5-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 130-140 i'or 6 hours. The coo~ed mixtura was treated with picroliDic acid in ethanol, and the resulting 2S solid was recrystal]ised i'rom dimethylformamide/ethanol to give the picrolonate salt oi' the titls compou~,d (3.5 g) m.p.
217-219.

The picrolonate salt was suspended in a~ueous methanol and stirred with ion-exchange resin IRA 401 (Cl ) until the yellow colour disappeared. The mixture wai $iltered and the filtrate was evaporated to give the dihydrochloride of the title compound.

. -,,: ~ , , - , , . -, . ~ - . . . ..

,. . ~. - , , : , . .

`` 11D70316 1 60 mHz n.m.r. in D20:-integral ~ multiplicity assignment observed calculated 1.35 d CH3 partially ob~cured -S-~H-CH2-2.33 s CH3 imidazole 6.0 ref 6 2.5 - 3.75 m -SCH2C~2 m ~NC-2 m CH2SCH
3.90 s (b~ imidazole 4.18 4 8.40 ~ (b) N~rO N 1.58 The dihydrochloride was dissolved in iscpropanol and was treated with one equivalent oi sodium ethoxide in ethanol. The mixture was ~-20- evap~rated-t~-dryne~s-and~he-s~lid--reæidue extracted with iso-propanol. The lsopropanol extract was evaporated to dryness to glve , the title compound as a ~oam.
.. . . _............................. .
EXA~PLE_6 l-Nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-~2-((4-methyl-5-imidazolyl)methylthio)propylamino]ethylene A mixture o~ 2-1(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 ~or two hours and the cooled melt recrystallised to give the title product.

3S N-~2-((4-Methyl-5-imidazolyl)methylthio)ethyll-N'-L2-((4-methyl-

5-imidazolyl)methylthio)propyl]thiourea dihydrochloride A solution prepared ~rom S-methyl-N-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]dithiocarbamate hydrochloride (0.69 g) and - .. - . ... ` . . .- . - . . , - . .

' ' 1071V316 1 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.

EXAMP,LE 8 N-Hydroxy-N'-~2-~(4-methyl-5-imidazolyl)methylthio)ethyl~-N'-[2-((4-methyl-5-inlidazolyl)methylthio)propyl]guanidine dihydrochloride - ~
Dry hydrogen chloride was passed into a solution o~ N-[2-((4-methyl-5-lmidazolyl)methylthio)ethyl]-N'-[2-(t4-methyl-5-imidazolyl)~ethylthio)propyl]thiourea (0.23 g) in methanol (10 ml) and the mixture was refluxed for 5 hours. Concentration yielded S-methyl-N-[2-((4-mèthyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)propyl]isothiourea dihydrochloride. A mixtur~ o~ the isothiourea dihydrochloride, h ydroxylamine hydrochloride, potassium hydrogen carbonate and anhydrous dimethyl formamide was ~tirred vigorously for 4 hours at 85C, Cooling and concentration o~ the product yielded the title compound.

EXA~PLE 9 When the procedure o~ Example 1 is carried out,using in place oi 4-hydroxymethyl 5-~ethylimidazole hydrochloride, the hydrochlorides o~ the ~ollowing 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, , .: , .
.,: - - , -~, . , ~ , . - .
, . .. .. . ~ . -`` 107V316 1 2-hydroxymethylthiazole and 3-hydroxymethylisothiazole the trihydrochlorides of the ~ollowing products are 5 respectively produced:

N-[2-((4-bromo-5-imidazolyl)methylthio)propyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, N [2-(4-imidazolylmethylthio)propyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]~uanidine, .. -N-[2-(2-pyridylmethylthio)propyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, ---N-[2-((3-hydroxy-2-pyridyl)methylthio3propy.1]-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]~uanidine, N-[2-((3-chloro-2-pyridyl~methylthio)propyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, N-[2-((3-bromo-2-pyridyl)methyithio)propyl]-N'-[2-((4-. 20 methyl-5-imidazolyl)methylthio)ethyl]guanidine, N-[2-(2-thiazolylmethylthio)propy}]-N'-[2-((4-methyl-5-lmidazolyl)methylthio)ethyl]guanidine and N-[2-(3-isothiazolyl)methylthio)propyl]-N'-[2-((4-methyl-5-imidazoly-l)me~hylthio~ethyl]guanlidine.

Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the general formula:
wherein Het1 and Het2 may each be imidazole optionally substituted by methyl, X is NH or NCN; and B1 and B2 are lower alkylene groups such that either B1 is (CH2)2 or (CH2)3 and wherein R is methyl or ethyl or B1 and B2 are both selected from and which comprises reacting a compound of the formula:

or wherein Het1, Het2, B1 and B2 have the same significance as above, A is a lower alkyl and X1 is NH or NCN with an amine of the formula:
Het2CH2SB2NH2 or Het1CH2SB1NH2.

2. The process according to Claim 1 for the preparation of N-[2-(4-methyl-5-imidazolyl methylthio)ethyl]-N'-[2-(4-methyl-5-imidazolyl methyl thio)propyl] guanidine which comprises reacting 2-[4-methyl-5-imidazolyl methylthio]-propyl amine with S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio) ethyl]thiouronium sulphate.

3. A compound of the formula:

wherein Het1 and Het2 may each be imidazole optionally sub-stituted by methyl, X is NH or NCN; and 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 whenever prepared or produced by the process of Claim 1 or by any chemical equivalent thereof.

4. N-[2-((4-Methyl 5-imidazolyl)methylthio)propyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, whenever prepared or produced by the process of Claim 2 or by any chemical equivalent thereof.