GB2038825A - Heterocyclic compounds substituted by heterocyclyl-alkylthia groups - Google Patents

Abstract

Novel heterocyclic compounds have the formula I X-A-S-Y (I) wherein X is a radical selected from imidazolyl, pyridyl, quinolyl, hydrogenated pyridyl or piperidyl any of which may be substituted and Y is any of the above radicals or an optionally substituted pyridinium radical, A is optionally substituted C1-6-alkylene. Most of the compounds are anti-ulcer agents but some have anti-hypertensive activity, eg where X is quinolyl. Pharmaceutical compositions are also described.

Description

SPECIFICATION Heterocyclic Compounds The invention relates to novel heterocyclic compounds which have anti-ulcer, anti-secretory, and/or anti-hypertensive activity.

During the course of our search for novel anti-ulcer agents we have found that certain novel compounds which have two particular heterocyclic rings (identified below) linked by an alkylene chain containing a sulphur atom, possess anti-ulcer and/or anti-secretory activity. Some of the compounds also have anti-hypertensive activity. Many of the compounds of our invention contain an imidazolyl ring.

Some related nitroimidazoles have been disclosed recently in Arzneimittel Forschung 1978,351-366 These compounds have been investigated for activity against various protozoa but so far as we are aware there has been no report of any investigation for anti-ulcer activity. The related compounds of our invention are distinguished from those of this publication by the absence of a nitro group.

German Offenlegungsschrift 2,504,252 discloses a wide range of heterocyclic compounds which are said to either inhibit or stimulate gastric secretion. The compounds of our invention are distinguished from those of this German publication by having different combinations of heterocyclic radicals.

According to the present invention, in one aspect, there is provided a compound of the formula I X-A-S-Y (I) wherein X is a heterocyclic radical of the formula

wherein R is hydrogen or lower alkyl, R1 is hydrogen, loweralkyl, hydroxylower alkyl, loweralkoxyloweralkyl, loweralkoxy, halogen, formyl, phenyl, phenylalkyl or acetal lCH(OR4)2 where R4 lower alkyl or two R4 radicals are joined to form a lower alkylene chain, R2 is hydrogen, lower alkyl, aryl arylloweralkyl, halogen, nitro, loweralkoxy, hydroxy, amino, loweralkylamino, diloweralkylamino, trifluoromethyl or two R2 radicals form a loweralkylene dioxygroup, n is 1, 2 or 3, m is 1 or 2, the dotted lines in formula V represent an optional double bond in one of the indicated positions, A is a saturated or unsaturated alkylene radical having from 1 to 6 carbon atoms, which may be substituted b lower alkyl of 1 to 6 carbon atoms, phenyl, oxo, or hydroxy; S is sulphur; Y is a heterocyclic radical of formula 11 to V as defined above, or of formula VII as defined below:

wherein R' and m are as defined above, R3 is loweralkyl, phenyl or aralkyl of 7 to 12 carbon atoms, and Z- is an anion, and acid addition salts thereof, with the provisos that:: (1) when X and Y are both radicals of formula II at least one substituent R in X or Y is lower alkyl; (2) when X is a radical of formula II and Y is a radical of formula Ill and both R7 substituents are hydrogen then R is other than methyl, (3) when Xis a radical of formula Ill, then Y is a radical of formula Ill, IV, V or VII, (4) when X is a 2-quinolyl radical and Y is a radical of formula 11, III, IV, or V then the Y radical is linked to S at a position other than the 2-position, (5) when Xis a radical of formula II and Y is a radical of formula VII then A is CH2, (6) when more than one R1 radical is present in the molecule then the R' radicals may be the same or different, and (7) when more than one R2 radical is present in the molecule then the R2 radicals may be the same or different.

Preferably Y is a radical of formula (VII), especially when Xis a radical of formula II.

The radical A is preferably a saturated or unsaturated alkylene radical of 1 to 6 carbon atoms which is unsubstituted. A may be methylene, ethylene, propylene, butylene, pentylene, or hexylene.

Alternatively A may be unsaturated containing at least one double bond eg -OH = CHCH2-. A radicals containing 1 to 4 carbon atoms are preferred, especially H2-.

The anion Z is preferably halide, namely fluoride, bromide, chloride or iodide or loweralkyl-, arylor aralkylsulphonate, eg methyl sulphonate (mesyl) or ptoluene sulphonate (tosyl).

In this specification when a group is substituted by alkyl, this is preferably lower alkyl of 1 to 6 carbon atoms e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl. An alkoxy substituent is preferably lower alkoxy in which the alkyl portion is as defined for a lower alkyl group. Whenever the term lower aikyl is used as part of another radical e.g. arylloweralkyl, the lower alkyl portion has 1 to 6 carbon atoms.

The acid addition salts of compounds of formula I may be of an organic or inorganic acid e.g.

hydrochloric, hydrobromic, phosphoric, sulphuric, nitric, citric, acetic, formic, fumaric, maleic, tartaric, embonic, methane sulphonic and p-toluene sulphonic acids.

The invention includes a pharmaceutical composition comprising a compound of formula I as defined above where proviso (2) does not apply or an acid addition salt thereof, and a pharmaceutically acceptable carrier.

For the pharmaceutical carrier any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid, or a mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilizers suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers, which is thus in association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be disso!ved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil.

Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient: the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 10 to 500 mg or more e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orally in either liquid or solid composition form. These compositions may include one or more antacid ingredients e.g. aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbonate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Specification No.

1,284,394.

Anti-ulcer activity was determined by the stress-induced erosion test of Senay 8 Levine, Proc.

Soc. Exp. Biol. Med., 124,1221-3(1967) and anti-secretory activity by the test of H. Shay, D. Sun and H. Greenstein, Gastro-enterology, 1954, 26, 90313 as exemplified by Beattie etalj. Med. Chem., 20, 714 (1977). Compounds which possess one or both these activities are considered to be anti-ulcer agents which can be used for the treatment of ulcers or hypersecretion in mammals. Nearly all compounds of formula I which we have tested possess one or both of the above activities. However, some compounds show activity in tests for anti-hypertensive activity.

In another aspect the invention provides as an anit-ulcer agent a compound of formula I or an acid addition salt thereof as defined above, wherein proviso (2) does not apply, X is other than formula (IV), and if X has formula Ill then A is at the 2-position of radical III.

The compounds may be prepared by methods known for analogous compounds. The invention includes methods of preparing the novel compounds of the invention. For example a particularly useful method according to the invention comprises reacting a compound of formula VIII X--AA-Hal (VIII) where X and A are as defined above and Hal is a halogen atom, especially chlorine, bromine or iodine, with a thiol compound of formula Y-SH where Y is as defined above and provisos 1-5 apply or an alkali-metal derivative (where possible) of said thiol compound except when Y is VII. The thiol compound may be in the form of a tautomeric thione in suitable cases.

The invention includes a method of preparing novel compounds of formula I wherein Y is a radical of formula VII and R3 is alkyl or aralkyl which method comprises reacting a corresponding compound of formula I wherein Y is a radical of formula Ill, with an alkylating or araikylating agent containing the groups R3 and Z, eg with an alkyl or aralkyl halide or a lower alkyl or aralkyl ester of an organic sulphonic acid such as a loweralkylaralkyl- or aryl- sulphonic acid.

A compound I in which Z is one particular anion may be converted to another in which Z is a different anion by anion exchange, eg chloride may be exchanged for iodide by reaction of a chloride of formula l.with sodium iodide in ethanol or other suitable solvent.

The following examples illustrate the invention: EXAMPLE 1 1 -Methyl-2 (4-[5-methyli midazolyl] methylthio)pyridi nium chloride 1 -Methyl-2-pyridothione (0.63 g, 0.005 mole) in hot ethanol (3 ml) was added to a refluxing solution of 4-chloromethyl-5-methylimidazole, hydrochloride (0.83 g, 0.005 mole) in ethanol (4 ml).

The solution was warmed on a steam bath for 5 minutes and allowed to crystallise. The crystals were removed by filtration, washed with ethanol and diethyl ether and dried to give the title compound as the hydrochloride salt (0.75 g) mp > 2600C. (Found: C,44.9; H, 5.35; N, 14.6. C11H14CIN3S, HCI requires C, 45.2; H, 5.2; N, 14.4%).

EXAMPLE 2 1 -Methyl-2 ((2-pyridyl) methylthio)pyridini urn chloride 1-methyl-2-pyridothione (1.1 g) was added to a solution of 2-chloromethylpyridine, hydrochloride (1.28 g) in acetonitrile (10 ml). The solution was warmed 10 minutes on a steam bath and allowed to crystallise. The crystals were removed by filtration, washed with ether and dried to give the title compound as the hydrochloride salt (2.0 g) mp 1900C decomp. (Found: C, 49.4; H, 4.8; N, 9.4.

Cr2H13N2SCI.HCI requires C,49.8; H, 4.9; N,9.7%).

EXAMPLE 3 1 -Methyl-2(4-imidazolylmethylthio)pyridinium chloride 4-Chloromethylimidazole, hydrochloride (1.5 g) in ethanol (5 ml) was treated with 1 -methyl-2pyridothione (1.25 g) in ethanol (5 ml) and the mixture was heated on a steam bath for 5 minutes. The solution was allowed to stand for 2 hours, scratched to induce crystallisation and ether (20 mli was added. The crystals were removed by filtration, washed with ether and dried to give the title compound as the hydrochloride salt (1.5 g) mp 228--90C (Found: C,43.1: H, 4.7: N, 15.1. C,OH12N3SCI, HCI requires C,43.2; H, 4.7; N, 15.1%).

EXAMPLE 4 1 -Methyl-2(4-[5-methylimidazolyl] methylthio)imidazole A solution of 4-chloromethyl-5-methylimidazole, hydrochloride (1.67 g) in hot ethanol (12 ml) wasfiltered and treated with a solution of 2-mercapto-1-methylimidazole (1.14 g) in hot ethanol (4 ml).

The mixture was heated on a steam bath for 2 hours and then allowed to cool. The resulting solid was removed by filtration and washed with diethyl ether, followed by absolute ethanol and dried to give the title compound as the dihydrochloride monohydrate (lAg, 46%) mp 1 1 4--7 OC. (Found: C,36.15; H, 5.5; N, 19.1%. C9H12N4S.2HCl.H20 requires: C, 36.1; H, 5.4; N, 18.7%).

EXAMPLE 5 1 -Methyl-2-(3-pyridylmethylthio)pyridiniu m chloride A solution of 1 -methyl-2-pyridothione (1.25 g) and 3-chloromethylpyridine, hydrochloride (1.66 g) in ethanol (10 ml) was heated under reflux for 5 hours. The product was induced to crystallise by scratching, removed by filtration, washed with ether and dried to give the title compound as the hydrochloride salt (2.2 g) mp 210--20C. (Found: C, 44.9; H, 5.2; N, 9.6. C12H13CIN2S.HCI requires C, 49.8; H, 4.9; N, 9.7%).

EXAMPLE 6 2-(4-[5-Methylimidazolylj methylthio)pyridine A solution of 4-chloromethyl-5-methylimidazole, hydrochloride (1.67 g) in hot ethanol (20 ml) was filtered and treated with a solution of 2-mercaptopyridine (1.1 g) in hot ethanol (10 ml). The mixture was refluxed for 3 hours and then cooled to room temperature. Diethyl ether was added and the resulting solid was removed by filtration and dried to give the title compound as the dihydrochloride salt (1.78 g, 64%) mp 203--60C. (Found: C, 42.8; H, 4.9; N, 15.45%. C1oH11N3S.2HCI requires: C, 43.2: H, 4.7; N, 15.1%).

EXAMPLE 7 4-(4-[5-Methyli midazolyl] methylthio)pyridine A solution of 4-chloromethyl-5-methylimidazole, hydrochloride (1.67 g) in hot ethanol (25 ml) was filtered and then added to a solution of 4-mercaptopyridine (1.1 g) in hot ethanol (25 ml)under nitrogen. The mixture was refluxed under nitrogen for 2 hours. After cooling to room temperature, a solid was precipitated out by the addition of diethyl ether. This was removed by filtration and dried to give the title compound as the dihydrochloride, hemihydrate (1 g, 35%) mp 240--40C. (Found: C, 41.55 H, 4.7: N, 14.6%. C10H11N3S.2HCI. > H20 requires: C, 41.8; H, 4.9; N, 14.6%).

EXAMPLE 8 2-(4-lmidazolylmethylthio)pyridine A solution of 4-chloromethylimidazole, hydrochloride (3.8 g) in hot ethanol (25 ml) was treated with a solution of 2-mercaptopyridine (2.759) in hot ethanol (25 ml). The mixture was heated under reflux for 1 hour and then allowed to cool to room temperature. The resulting solid was removed by filtration and dried to give the title compound as the dihydrochloride salt (5.2 g, 79%) mp 224--60C.

(Found: C, 41.0; H, 4.3; N, 15.9. CgHgN3Ss2HCI requires: C, 40.9; H, 4.2; N, 15.9%).

EXAMPLE 9 1 -Methyl-2-( [(4-pyridyl)methyl]thio) pyridinium chloride 1-Methyl-2-pyridothione (1.25 g) was added to a solution of 4-picolyl chloride, hydrochloride (1.64 g) in hot isopropyl alcohol (20 ml). The. mixture was heated under reflux for 2 hours and then allowed to coot to room temperature. The resulting solid was removed by filtration and dried to give the title compound as the hydrochloride salt, three quarter hydrate (2.5 g; 83%) mp 178--830C decomp.

(Found: C, 47.75; H, 5.4: N, 9.1%. C12H13CIN2. HCl.aH,O requires: C, 47.6; H, 5.2: N, 9.25%).

EXAMPLE 10 1-Methyl-2([(2-quinolyl)methyl]thio)pyridinium chloride 1-Methyl-2-pyridothione (1.25 g) was added to a solution of 2-(chloromethyl)quinoline (2.14 g) in hot acetonitrile (35 ml). The mixture was heated under reflux for 3 hours. It was then allowed to cool to room temperature and was evaporated to dryness under reduced pressure. The residue was triturated with a small amount of hot acetonitrile. The resulting solid was removed by filtration and dried to give the title compound as the hydrochloride salt, monohydrate (1.8 g; 50%) mp 142--450C. (Found: C, 53.9; H, 5.15; N, 8.0%. C1,NHr5CIN2S.HCi.H20 requires: C, 53.8; H, 5.1; N, 7.8%).

EXAMPLE 11 1 -Methyl-2-[(2-piperidionethyl)thio]pyridinium chloride A solution of N-(2-chloroethyl)piperidine, hydrochloride (1.84 g) in ethanol (20 ml) was treated with 1 -methyl-2-pyridothione (1.25 g) and the mixture was heated in a stainless steel bomb at 1200C for 5 hours. It was then allowed to cool to room temperature and the solvent was removed by evaporation. The residue was triturated with ether and the resulting solid was removed by filtration and dried to give the title compound as the hydrochloride, one and one half hydrate (2.7 g; 80%) mp 188--900C. (Found: C, 46.7; H, 7.1; N, 8.3%. C,3H21CIN2S.HCI.1TH20 requires: C, 46.4; H, 7.5; N, 8.3%).

EXAMPLE 12 Using the method of example 2, 2-chloromethylpyridine is reacted with the following pyridothiones to give the product indicated: Pyridothione Product a) 3-hydroxymethyl-1 - 3-hydroxymethyl-1 -phenyl phenyl-2-pyridothione -2-((2-pyridyl)methylthio) pyridinium chloride b) 3-hydroxy-2-pyridothione 3-hydroxy-2-((2-pyridyl) methylthio)pyridine c) 1 ,4-dimethyl-2-pyridothione 1 1,4-dimethyl-2-((pyridyl) methylthio)pyridinium chloride.

d) 3-(2-phenylethyl)-2 3-(2-phenylethyl)-2-((2 pyridothione pyridyl)methylthio) pyridine e) 3-phenyl-2-pyridothione 3-phenyl-2-((2-pyridyl) methylthio)pyridine f) 5-chloro-2-pyridothione 5-chloro-2-((2-pyridyl) methylthio)pyridine g) 3-formyl-1 -methyl-2- 3-formyl-1 -methyl-2- pyridothione (((2-pyridyl)methyl)thio) pyridinium chloride h) 3-hydroxymethyl-1 -methyl 3-hydroxymethyl-1 -methyl 2-pyridothione 2-(((2-pyridyl)methyl)thio) pyridinium chloride i) 3-diethoxymethyl-1 -methyl- 3-diethoxymethyl-1 -methyl- 2-pyridothione 2-( ((2-pyridyl) methyl)thio) pyridinium chloride EXAMPLE 13 Using the method of example 2, 1-methyl-2-pyridothione is reacted with the following starting materials to give the product indicated: Starting Material Product a) 2-chloromethyl-6- 2-((2-(6-methyi)pyridyl) methylpyridine methylthio)- 1-methyl pyridinium chloride b) 2-bromomethyl-6- 2-(2-(6-chloro)pyridyl) chloropyridine methylthio)-1 -methyl- pyridinium bromide c) 2-chloromethyl-4-(4- 2-({2-(4-(4-chlorophenyl)) chlorophenyl)pyridine pyridyl) methylthio)- 1 methylpyridinium chloride Pharmacological Test Results

Compound Stress- iriduced erosion Anti-secretory [Product of Example Noel I Dose % inhibition Dose % change mg/kg r mg/kg in volume 1 100 69 30 65 10 -43 2 100 50 30 31 3 100 67 30 -71 10 -43 4 100 83 30 67 30 58 10 33 5 100 58 30 -55 6 10 68 30 - 3 56 7 100 87 30 60 8 100 79 30 - 30 70 11 100 - 30 35 Antihypertensive Activity Some compounds of the invention were tested for anti-hypertensive activity by the following procedures.

Procedure A Systolic pressure of male spontaneously hypertensive rats is measured by an indirect technique using the Decker Caudal Plethylsmograph or other appropriate sensor. Groups usually consist of 4 rats.

Drugs are usually administered orally. Pressures are usually read prior to drug administration and at 1.5, 4 and 24 hours thereafter. This schedule may be altered depending upon the behaviour of the drug.

Compounds of the following examples showed activity in this test at the dose stated. 75mg/kg orally; Examples 3 and 5. 50 mg/kg orally; Examples 9 and 10.

The compound of Example 6 was inactive in this test at 75 mg/kg.

Procedure B Female rats are rendered hypertensive by unilateral nephrectomy and the s.c. implantation of a pellet containing 30 mg of deoxycorticosterone acetate. The drinking water is replaced by normal saline at lib for the first four weeks following preparation. Blood pressures stabilise at a hypertensive level after 6 weeks. Systolic pressure is measured indirectly before dosing with a test compound using an E and M pneumatic pulse transducer and a Devices MX2 recorder. Groups of 4 rats are dosed orally with suspensions or solutions of the test compound in 0.5% hydroxypropyl-methyl-cellulose 0.9% saline vehicle. Blood pressures are recorded again at 2, 6 and 24 hours and the results, expressed as a percentage of the pre-dose value compared with those of a similar group of rats receiving vehicle alone.

The compound of Example 4 was active in this test at 50 mg/kg orally. The compounds of examples 1 and 7 were inactive in this test at 50 mg/kg orally.

Pharmaceutical Compositions The following examples illustrate the preparation of unit dosage form of pharmaceutical compositions according to the invention.

EXAMPLE A Antacid Tablet (chewabie) Saccharin 1.0 mg.

Hydrated alumina sucrose powder 750.0 mg.

N-Methyl-2(4-[5-methylimidazolyl]- methylthio)pyridinium chloride 1 00.0 mg.

Mannitol B.P. 170.9 mg.

Maize starch B.P. dried 30.0 mg.

Talc. purified B.P. 28.0 mg.

Magnesium stearate B.P. 20.0-mg.

Peppermint oil B.P. 1.0 mg.

1100.0 mg.

Antacid tablets of the above formulation are prepared by the following procedure. Triturate peppermint oil with talc (screen 40 mesh). Add the triturate, and other ingredients to a blender and mix thoroughly.

Slug the powder to large hard slugs. Granulate the slugs through a 14 mesh screen. Compress the granules on a suitable compression machine to give tablets of the required size.

EXAMPLE B Anti-ulcer tablet (without antacid) mg/tablet N-Methyl-2(4-[5-methylimidazol.yl)methyl pyridinium chloride 100 mg.

Celutab 147.5 mg.

Mg. Stearate 2.5 mg.

250.0 mg.

The tablets are prepared by the following method. Blend the ingredients in a suitable blender. t;ompress the blended ingredients on a suitable compresssion machine to form tablets of the above composition.

Celutab is a commercial product comprising 902% dextrose, 3-5% maltose, the remainder being higher glucose saccharides. The product is spray crystallized.

EXAMPLES C to F Example A is repeated but replacing N-methyl-2 (4-[5-methylimidazolyU-methylthio)py?idiniu m chloride with 100 mg of the products of Examples 3, 4, 5 and 7 respectively.

EXAMPLES G to H Example B is repeated but replacing N-methyl-2(4-15-methylimidazolyl]-methylthio)pyridinium chloride with 100 mg of the products of Examples 3, 4, 5 and 7 respectively.

Claims (33)

1. A compound of the formula I X-A-S-Y V (I) wherein X is a heterocyclic radical of the formula

wherein R is hydrogen or lower alkyl, R1 is hydrogen, lower alkyl, hydroxylower alkyl, loweralkoxyloweralkyl, loweralkoxy, halogen, formyl, phenyl, phenylalkyl or acetal [CH(OR4)2 where R4 is lower alkyl or two R4 radicals are joined to form a lower alkylene chain], R2 is hydrogen, lower alkyl, aryl, arylloweralkyl, halogen, nitro, loweralkoxy, hydroxy, amino, loweralkylamino, diloweralkylamino, trifluoromethyl or two R2 radicals form a loweralkylene dioxygroup, n is 1,2 or 3, m is 1 or 2, the dotted lines in formula V represent an optional double bond in one of the indicated positions, A is a saturated or unsaturated alkylene radical having from 1 to 6 carbon atoms, which may be substituted by lower alkyl of 1 to 6 carbon atoms, phenyi, oxo or hydroxy, S is sulphur; Y is a heterocyclic radical of formula II to V as defined above, or of formula VII as defined below:

wherein R' and m are as defined above, R3 is loweralkyl, phenyl or aralkyl of 7 to 12 carbon atoms, and Z is an anon, and acid addition salts thereof, with the provisos that (1) when X and Y are both radicals of formula 11 at least orie stubstituent R in X or Y is lower alkyl;; (2) when X is a radical of formula II and Y is a radical of formula Ill and both R' substituents are hydrogen then R is other than methyl, (3) when X is a radical of formula Ill, then Y is a radical of formula III, IV, V or VII, (4) when X is a 2-quinolyl radical and Y is a radical of formula 11, III, IV, or V then the Y radical is linked to S at a position other than the 2-position, (5) when X is a radical of formula II and Y is a radical of formula VII then A is CH2, (6) when more than one R1 radical is present in the molecule then the R' radicals may be the same or different, and (7) when more than one RZ radical is present in the molecule then the R2 radicals may be the same or different.

2. A compound as claimed in claim 1, wherein A is an alkylene radical of 1 to 4 carbon atoms.

3. A compound as claimed in claim 2 wherein A is CH2.

4. A compound as claimed in claim 3, wherein X is a radical of formula II and Y is a radical of formula VII.

5. A compound as claimed in claim 2 or claim 3, wherein X is a radical of formula Ill and Y is a radical of formula VII, radicals Ill and VII being as defined in claim 1.

6. A compound as claimed in claim 2, or claim 3, wherein X and Y are radicals of formula II, as defined in claim 1, and at least one substituent R in X and Y is lower alkyl.

7. A compound as claimed in claim 6, wherein both substituents R are lower alkyl.

8. A compound as claimed in claim 7, wherein R is methyl.

9. A compound as claimed in claim 2, or claim 3, wherein X is a radical of formula II and Y is a radical of formula lil, formulae II and Ill being as defined in claim 1, and at least one R1 substituent in II or Ill is loweralkyl.

10. A compound as claimed in claim 2 or claim 3, wherein X is a radical of formula VI and Y is a radical of formula VII, radicals VI and VII being as defined in claim 1.

11. 1 -Methyl-2 (4-[5-methylimidazolyl] methylthio)pyridinium chloride.

12. 1 -Methyl-2((2-pyridyl)methylthio)pyridiniui . chloride.

13. 1 -Methyl-2(4-imidazolylmethylthio)pyridinium chloride.

14. 1 -Methyl-2(4-[5-methylimidazolyl)methylthio)imidazole or a pharmaceutically acceptable acid addition salt thereof.

1 5. 1 -Methyl-2-(3-pyridylmethylthio)pyridinium chloride.

1 6. 2-(4-[5-Methylimidazolyl]methylthio)pyridine or a pharmaceutically acceptable acid addition salt thereof.

17. 4-(4-[5-Methylimidazolyl] methylthio)pyridine or a pharmaceutically acceptable acid addition salt thereof.

18. 2-(4-lmidazolylmethyithio)pyridine or a pharmaceutically acceptable acid addition salt thereof.

1 9. 1 Methyl-2-[(2-piperidinoethyl)thioj pyridinium chloride.

20. A pharmaceutical composition comprising a compound as claimed in claim 1, wherein proviso (2) does not apply, and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition as claimed in claim 20, in unit dosage form.

22. As an anti-ulcer agent, a compound as claimed in claim 1 wherein X is a radical of formula II, III, V orVI and Y is a radical of formula II, Ill, V or VII and provisos (1), (3), (5) and (6) apply with the further proviso that when X has formula Ill then A is at the 2-position of radical III.

23. As an anti-ulcer agent a compound as defined in any one of claims 11 to 1 9.

24. An anti-ulcer composition comprising an anti-ulcer agent as claimed in claim 22 or claim 23 and a pharmaceutically acceptable carrier.

25. An anti-ulcer composition as claimed in claim 24, which also includes an antacid ingredient,

26. A pharmaceutical composition substantially as hereinbefore described with reference to any one of Examples A to H.

27. 1 -Methyl-2([(4-pyridyl)methyl]thio)pyridiniu m chloride.

28. 1 -Methyl-2([(2-quinolyl)methyl]thio)pyrid chloride.

29..A method for preparing a compound as claimed in claim 1, wherein provisos (1) to (7) apply, which method comprises reacting a compound of formula VIII X-A-Ha I (Vill) wherein X and A are as defined in claim 1, and Hal is chlorine bromine or iodine, with a thiol compound of formula Y-SH, wherein Y is as defined in claim 1, or an alkali-metal derivative of said thiol compound (where possible) except when Y is VII.

30. A method for preparing a compound of formula I as claimed in claim 1, wherein Y is a radical of formula VII and R3 is alkyl or aralkyl and provisos (5), (6) and (7) apply, which method comprises reacting a corresponding compound of formula I wherein Y is a radical of formula III, with an alkylating or aralkylating agent containing the groups'R3 and Z.

31. A method as claimed in claim 30, wherein the alkylating or aralkylating agent is an alkyl or aralkyl halide or a loweralkyl or aralkyl ester of an organic sulphonic acid.

32. A method as claimed in claim 29 substantially as hereinbefore described in any one of Examples 1 to 13.

33. A compound of formula I whenever prepared by a method as claimed in any one of claims 29 to 32.