BENZIMIDAZOLES

Abstract: Compounds of structure (I) and pharmaceutically acceptable salts thereof, in which R⁵ and R⁶ are the same or different and are each hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl or together with the nitrogen atom to which they are attached form an acetidino, pyrrolidino, piperidino, piperazino, N-C 1-4 alkylpiperazino or morpholino group and one of R⁷ and R⁸ is halogen, and the other is hydrogen, halogen or C 1-6 alkyl; processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion.

Description: The present invention relates to novel substituted benzimidazole derivatives, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy. Substituted benzimidazole derivatives that are capable of inhibiting gastric acid secretion are known in the art. For example, GB 1500043 and GB 1525958 disclose a series of 2-pyridylalkylthio- and 2-pyridylalkylsulphinyl benzimidazoles in which the pyridyl group is optionally mono-substituted by an alkyl or a halogen group. Further, EP 5129B, 74341A and 80602A disclose series of 2-pyridylalkylsulphinyl- and 2-pyridylalkylthio-benzimidazoles in which the pyridyl group is optionally substituted by 1 to 3 substituents selected from methyl, ethyl, methoxy, ethoxy, methoxyethoxy or ethoxyethoxy; and GB 2134523A discloses further such compounds in which the pyridyl group is optionally substituted by 1 to 3 groups. Such compounds are believed to exert their effects by inhibition of the gastro-intestinal H⁺-K⁺ ATPase enzyme (Fellenius E., Berglindh, T., Sachs, G., Olke, L., Elander, B., Sjostrand, S.E. and Wallmark B., 1981, Nature , 290 , 159-61). In addition, US 4359465 discloses the cytoprotective action of certain 2-pyridylalkylthio- and 2-pyridylalkylsulphinyl benzimidazoles and their use in the treatment or prevention of gastro-intestinal inflammatory disease. The compounds of the present invention are 2-pyridylalkylsulphinyl- and 2-pyridylalkylthio-benzimidazoles in which the 2-pyridyl group is substituted in the 4-position by an optionally substituted amino group, and are inhibitors of potassium stimulated H⁺-K⁺ ATPase activity. The present invention therefore provides, in a first aspect, a compound of structure (I) in which, R¹ to R⁴ are the same or different and are each hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, RCF₂O, an ethoxy group substituted by 3 to 5 fluorine atoms, or R² and R³ together form a group -O(CR₂) m O-; R is hydrogen or fluorine; m is 1 or 2; n is 0 or 1; R⁵ and R⁶ are the same or different and are each hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl or R⁵ and R⁶ together with the nitrogen atom to which they are attached form an azetidino, pyrrolidino, piperidino, piperazino, N-C 1-4 alkylpiperazino or morpholino group; and one of R⁷ and R⁸ is halogen, and the other is hydrogen, halogen or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof. Suitably, R¹ to R⁴ are all hydrogen. Preferably R¹ and R⁴ are hydrogen, one of R² and R³ is hydrogen and the other is halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxycarbonyl or C 1-6 alkanoyl. More preferably, R¹ and R⁴ are hydrogen, one of R² and R³ is hydrogen and the other is C 1-6 alkoxy, RCF₂O or an ethoxy group substituted by 3 to 5 fluorine atoms; or, R¹ and R⁴ are hydrogen and R² and R³ together form a group -O(CR₂) m O-. Suitably, ethoxy groups substituted by 3 to 5 fluorine atoms are, 2,2,2-trifluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy, 1,2,2,2-tetrafluoroethoxy and perfluoroethoxy. Preferably ethoxy groups substituted by 3 to 5 fluorine atoms are 1,1,2,2-tetrafluoroethoxy. Suitably, groups -O(CR₂) m O- in which m is 1 are methylenedioxy (-OCH₂O-); preferably difluoromethylenedioxy (-OCF₂O-). Suitably, groups -O(CR₂) m O- in which m is 2 are ethylenedioxy (-OCH₂CH₂O-); preferably, trifluoroethylenedioxy (-OCHFCF₂O-). Suitably n is 0. Preferably n is 1. Suitably one of R⁵ and R⁶ is hydrogen and the other is C 3-6 cycloalkyl. Preferably R⁵ and R⁶ are the same or different and are each hydrogen or C 1-6 alkyl. Suitably R⁵ and R⁶ together with the nitrogen to which they are attached form an azetidino group. Preferably, R⁵ and R⁶ together with the nitrogen to which they are attached form a morpholino, pyrrolidino, piperazino, N-C 1-4 alkylpiperazino or a piperidino group. Suitably R⁷ and R⁸ are both halogen. Preferably, one of R⁷ and R⁸ is halogen and the other is hydrogen or C 1-6 alkyl. C 1-6 Alkyl groups alone or as part of another group (for example C 1-6 alkoxy, C 1-6 alkoxycarbonyl or C 1-6 alkanoyl), can be straight or branched, for example methyl, ethyl, n-propyl, i-propyl, i-butyl, s-butyl, n-butyl, n-pentyl, i-pentyl or n-hexyl. Preferably C 1-6 alkyl groups are methyl or ethyl. Preferably, C 1-6 alkoxy groups are methoxy or ethoxy. Preferably C 1-6 alkoxycarbonyl groups are methoxycarbonyl or ethoxycarbonyl. Preferably C 1-6 alkanoyl groups are methanoyl or ethanoyl. C 3-6 Cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably, C 3-6 cycloalkyl groups are cyclopentyl or cyclohexyl. Halogen groups are fluorine, chlorine, bromine or iodine. Preferably halogen groups are chlorine or bromine. Preferred compounds of the present invention include (i) compounds of structure (I) in which R⁵ and R⁶ are both C 1-6 alkyl, for example, 2-(5-chloro-4-dimethylamino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(3-chloro-4-dimethylamino-2-pyridylmethylsulphinyl)-5-methoxy -(1H)-benzimidazole 2-(3-methyl-5-chloro-4-dimethylamino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-dimethylamino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole 2-(5-bromo-4-dimethylamino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole (ii) compounds of structure (I) in which R⁵ and R⁶ together form a morpholino, pyrollidino, piperazino, N-C 1-4 alkylpiperazino or piperidino group, for example, 2-(3-chloro-4-morpholino-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole 2-(3-chloro-5-methyl-4-morpholino-2-pyridylmethylsulphinyl)- 5-methoxy-(1H)-benzimidazole 2-(5-chloro-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole 2-(3-chloro-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole 2-(3-methyl-5-chloro-4-piperidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(5-chloro-4-pyrrolidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(3-chloro-4-pyrrolidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole 2-(3-methyl-5-chloro-4-pyrrolidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-pyrrolidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(5-bromo-4-pyrrolidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(3-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole 2-(3-methyl-5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole 2-(5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole. (iii) compounds of structure (I) in which the substituent on the benzimidazole ring is a 1,1,2,2-tetrafluoroethoxy group or a difluoromethylenedioxy group, for example 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)- 5-(1,1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)- 4,5-difluoromethylenedioxy-(1H)-benzimidazole 2-(3-chloro-4-piperidino-2-pyridylmethylsulphinyl)-5- (1,1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole 2-(3-chloro-4-piperidino-2-pyridylmethylsulphinyl)-4,5- difluoromethylenedioxy-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-pyrollidino-2-pyridylmethylsulphinyl)-5- (1,1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-pyrollidino-2-pyridylmethylsulphinyl)-4,5- difluoromethylenedioxy-(1H)-benzimidazole 2-(3-chloro-5-methyl-4-dimethylamino-2-pyridylmethysulphinyl)-5- (1,1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole, and 2-(3-chloro-5-methyl-4-dimethylamino-2-pyridylmethysulphinyl)-4, 5-difluoromethylenedioxy-(1H)-benzimidazole 2-(3-methyl-5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5- (1,1,2,2-tetrafluoroethoxy-(1H)-benzimidazole 2-(3-methyl-5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-4,5- difluoromethylenedioxy-(1H)-benzimidazole 2-(3-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-(1,1,2,2- tetrafluoroethoxy)-(1H)-benzimidazole 2-(5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-(1,1,2,2- tetrafluoroethoxy)-(1H)-benzimidazole 2-(3-bromo-4-piperidino-2-pyridylmethylsulphinyl)-4,5- difluoromethylenedioxy-(1H)-benzimidazole 2-(5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-4,5- difluoromethylenedioxy-(1H)-benzimidazole and (iv) the corresponding thioethers of the foregoing preferred compounds ie the analogous compounds of structure (I) in which n is 0. Compounds of structure (I) in which n is 0, can form pharmaceutically acceptable acid addition salts with suitable organic and inorganic acids, the nature of which will be apparent to persons skilled in the art. For example, pharmaceutically acceptable salts can be formed by reaction with hydrochloric, sulphuric, sulphonic or phosphonic acids; aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulphonic acids; methionine, tryptophan, lysine or arginine and the like. Compounds of structure (I) in which n is 1 can also form pharmaceutically acceptable acid addition salts, but in aqueous solution the salts are less stable than those formed with the compounds of structure (I) in which n is 0. Compounds of structure (I) in which n is 1 can form basic salts by reaction with an appropriate base. Such salts include, for example, the sodium, potassium, lithium, calcium and magnesium salts which can be prepared by methods well known to those skilled in the art for example, the sodium, potassium and lithium salts can be prepared by reaction with sodium, potassium or lithium hydroxide in an aqueous or non- aqueous medium; and the calcium salts can be prepared by reaction with calcium chloride in an aqueous or non-aqueous medium. Compounds of structure (I) in which n is 0 can also form basic salts but such salts are less stable than those prepared from compounds of structure (I) in which n is 1. Compounds of structure (I) in which n is 1 have an asymmetric centre at the S atom and are thus optically active compounds. As such, these compounds exist as two optical isomers (enantiomers). In addition, compounds of structure (I) in which one or more of R¹ to R⁸ is a branched C 3-6 alkyl group (either alone or as part of another group) may contain an additional asymmetic centre(s) due to the presence of the C 3-6 alkyl group(s). Again, such compounds will exist as two (or more) optical isomers. Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the present invention. Further, all diasteriomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention. It should be noted that for all the compounds of the present invention, the substituents R¹ and R⁴ as well as R² and R³ are considered to be equivalent at room temperature in solution. This is due to the tautomerism of the benzimidazole nucleus causing an equilibrium between the 2 possible forms. In a further aspect the present invention provides a process for the preparation of a compound of structure (I) or a pharmaceutically acceptable salt thereof which comprises a) reacting a compound of structure (II) with a compound of structure (III) in which R¹ to R⁸ are as described for structure (I) and one of L¹ and L² is SH and the other a leaving group displaceable by a mercaptan; (b) reacting a compound of structure (IV) in which R¹ to R⁴ are as described for structure (I), with a compound of structure (V) in which R⁵ to R⁸ are as described for structure (I), X is CO₂H or CSX¹ and X¹ is halogen or C 1-4 alkoxy; (c) reacting a compound of structure (VI) in which R¹ to R⁴ are as described for structure (I), R⁹ is hydrogen or a protecting group and M is an alkali metal atom, with a compound of structure (VII) in which R⁵ to R⁸ are as described for structure (I), Z is a leaving group and p is 0 or 1; (d) reacting a compound of structure (VIII) in which R¹ to R⁴ are as described for structure (I), R⁹ is hydrogen or a protecting group and Y is a leaving group, with a compound of structure (IX) in which R⁵ to R⁸ are as described for structure (I), p is 0 or 1 and M' is an alkali metal atom or the equivalent of an alkali metal atom, and, optionally, where desired : (i) oxidising a compound of structure (I) so formed in which n is 0 to a compound of structure (I) in which n is 1; (ii) reducing a compound of structure (I) so formed in which n is 1 to a compound of structure (I) in which n is 0; (iii) forming a pharmaceutically acceptable salt. Suitable leaving groups L¹ displaceable by mercaptan include halogen, for example chloro, bromo or iodo, aryl sulphonyloxy for example toluenesulphonyloxy, alkylsulphonyloxy for example methanesulphonyloxy, alkylmercapto, for example methylmercapto, or alkylsulphinyl, for example methylsulphinyl. Suitable leaving groups L² are as described for L¹, and may also be C 1-4 acyloxy, for example acetoxy, or hydroxy. Suitable alkali metal atoms include, for example lithium, sodium or potassium. Suitable leaving groups Z include, for example, halogen (preferably chloro) and hydroxy activated by esterification with, for example, an aryl or alkane sulphonic acid. Suitable sulphonic acids will be apparent to those skilled in the art, for example p-toluenesulphonic acid or methanesulphonic acid. Suitable leaving groups Y are those groups which form a reactive sulphinic acid derivative together with the sulphinyl group to which it is attached, and include for example, C 1-4 alkoxy, di-C 1-4 alkylamino and C 1-4 alkyl-mercapto. Suitable groups M' which are equivalent to a metal atom include, for example, alkali earth metal atoms, (for example magnesium) which are substituted by a halogen atom (for example, bromine). Suitable protecting groups R⁹ are those conventional in the art for example as described in "Protective Groups in Organic Synthesis" T.W. Greene 1981 (Wiley). It will be appreciated that the group R⁹ should not be cleavable under the conditions of reaction of compounds of structure (VIII) and (IX). Such groups include for example benzyl or trityl groups. The reaction between compounds of structure (II) in which L¹ is SH and compounds of structure (III) in which L² is a leaving group can be carried out under basic conditions in the presence of an inert solvent at a temperature between ambient and the reflux temperature of the solvent. Suitable solvents include lower alkanols, for example methanol or ethanol, mixtures of lower alkanols with water, or ethers for example dimethoxyethane or tehrahydrofuran. Suitable bases will be apparent to those skilled in the art and include for example, alkali metal hydroxides, for example, sodium or potassium hydroxide, alkali metal alkoxides, for example potassium t-butoxide, alkali metal hydrides, for example sodium or potassium hydride, or organic tertiary amines, for example triethylamine. Preferably the reaction is carried out at ambient temperature in ethanol as solvent, in the presence of sodium hydroxide solution. It is to be noted, and will be apparent to persons skilled in the art that under basic conditions L² should be a group other than hydroxy or acetoxy, for example halogen, preferably chlorine. Further, the reaction can be carried out under neutral conditions in the presence of an inert solvent at the reflux temperature of the solvent. Suitable solvents include those hereinbefore described. Alternatively, when L² is hydroxy or C 1-4 acyloxy, for example acetoxy, the reaction can be carried out under acidic conditions. Suitable acidic conditions will be well known to those skilled in the art, for example, under reflux in hydrobromic acid, optionally in the presence of acetic acid. The reaction between compounds of structure (II) in which L¹ is a leaving group and compounds of structure (III) in which L² is SH can be carried out under basic conditions as described for the reaction between compounds of structure (II) in which L¹ is SH and compounds of structure (III) in which L² is a leaving group. The reaction between compounds of structure (IV) and compounds of structure (V) can be carried out under acidic conditions in a suitable solvent at a temperature between ambient and reflux temperature of the solvent used. Suitably the reaction is carried out in polar solvents, for example, lower alkanols, dimethyl sulphoxide, acetone, dimethylformamide or acetonitrile, optionally in the presence of water. Preferably the reaction is carried out in ethanol. Suitably the reaction is carried out in the presence of a strong acid, for example hydrobromic or hydrochloric acid. Preferably the reaction is carried out in the presence of hydrochloric acid. Preferably the reaction is carried out at the reflux temperature of the solvent. The reaction between a compound of structure (VI) and a compound of structure (VII) can be carried out in an inert solvent at ambient or elevated temperature depending on the nature of groups M and Z. Suitable solvents include those solvents usually employed for the reaction of enolate ions with alkylating agents for example, benzene or toluene. Preferably, when M is lithium and Z is chlorine, the reaction is conducted in benzene at reflux temperature. The reaction between a compound of structure (VIII) and a compound of structure (IX) can be carried out under conditions normally used for organometallic reactions as will be well known to those skilled in the art. The products of reactions (a) to (c) are compounds of structure (I) in which n is 0. These products can be oxidised to compounds of structure (I) in which n is 1 by reaction with an oxidising agent. Suitable oxidising agents include, for example, nitric acid, hydrogen peroxide, peracids, peresters, ozone, dinitrogen tetroxide, iodosobenzene, N-halosuccinamide, 1-chlorobenzotriazole, hypohalites, for example sodium hypochlorite or t-butyl hypochlorite, diazabicylo [2,2,2]- octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, ceric ammonium nitrate, bromine, chlorine, or sulphuryl chloride. Preferably the oxidising agent is m-chloroperbenzoic acid. The oxidation reaction is carried out under conditions known in the art for the oxidation of thiols to sulphoxides. Suitably, the reaction is carried out in an inert solvent at a temperature of between -70° and the boiling point of the solvent used. Suitable solvents include aromatic or chlorinated hydrocarbons, for example benzene, toluene dichloromethane or chloroform, esters, for example ethyl acetate, or ethers, for example dioxan. Preferably, the reaction is carried out in dichloromethane at a temperature of between -50° and +20°C. The compounds of structure (I) are obtained either as the free base, or in the form of a salt depending on the choice of starting materials and reaction conditions. If the free compound is obtained it can be converted into a salt by standard techniques well-known to those skilled in the art, for example by dissolving the compound in a suitable solvent and adding the desired acid or base; alternatively, if a salt is obtained it can be converted into the free compound, again by standard techniques, for example by treatment with an appropriate acid or base. Racemic mixtures may be produced and can be separated by standard techniques e.g. recrystallisation from optically active solvent or by high performance liquid affinity chromatography as described by S. Allenmark, B. Bomgren, H. Baren and P-O Lagerstrom in Analytical Biochemistry, 136 , 293-7, 1984. The intermediate of structure (IV) and the intermediate benzimidazole structures (II), (VI) and (VIII) are known and can be prepared by methods analogous to those known in the art. For example, compounds of structure (II) in which L¹ is SH can be prepared by reacting the corresponding compounds of structure (IV) with carbon disulphide in the presence if alkali metal hydroxides, or with potassium ethylxanthate (Org. Syn., 30 , 56) or thiophosgene. Compounds of structure (II) in which L¹ is a leaving group, for example halogen can be obtained from the corresponding compounds of structure (II) in which L¹ is hydroxy by treatment with for example, phosphorous oxychloride. The compounds of structure (II) in which L¹ is hydroxy can be prepared by reacting compounds of structure (IV) with phosgene. Compounds of structure (IV) can be prepared by methods analogous to those described in EP 127763A, DE 2848531, CA, 60 , 13352h, 1964 and Liebigs Ann.Chem., 730 , 16-30, 1969. Compounds of structure (VI) can be prepared by methylation, oxidation and subsequent deprotection of compounds of structure (II) in which L¹ is SH using, for example, alkali metal hydroxides or alcoholates. The intermediates of structures (III), (V), (VII) and (IX) are novel and provide a further aspect of the invention. They can be prepared by methods analogous to those well known in the art as described in "The Chemistry of Heterocyclic Compounds - Pyridine and its Derivatives", Pts. 2 and 3, E. Klingsberg Ed., Interscience Publishers, 1962. For example, (i) compounds of structure (III) in which L² is hydroxy and R⁵ and R⁶ are not both hydrogen can be prepared by the reactions outlined in Scheme 1. Scheme 1 In Scheme 1, the 3- or 5-halo compounds of structure (X) are known or can be prepared by standard methods. (ii) compounds of structure (III) in which L2 is hydroxy, R⁵ and R⁶ are not both hydrogen, one of R⁷ and R⁸ is bromine and the other is hydrogen or C 1-6 alkyl can also be prepared by the methods outlined in Scheme 2. Scheme 2 Separation of the 3- and 5-bromo intermediates (XVIII) and (XIX) followed by oxidation to the corresponding N-oxides and rearrangement using, for example, acetic anhydride gives the required compounds of structure (III) in which one of R⁷ and R⁸ is bromine and the other is hydrogen. If, in the starting material of structure (XV) one of R⁷ and R⁸ is C 1-6 alkyl and the other is hydrogen, then the bromination reaction gives essentially a single product, namely the 3- bromo-5-alkyl compounds (XVIII, R⁸ = C 1-6 alkyl) or 3-alkyl-5-bromo compounds (XIX, R⁷ = C 1-6 alkyl). These products can be oxidised and rearranged as hereinbefore described to the desired compounds of structure (III) in which one of R⁷ and R⁸ is bromine and the other is C 1-6 alkyl. (iii) compounds of structure (III) in which L² is hydroxy, R⁵ and R⁶ are not both hydrogen, R⁷ is chlorine and R⁸ is hydrogen or C 1-6 alkyl can be prepared by the reactions outlined in Scheme 3. Scheme 3 (iv) compounds of structure (III) in which L² is hydroxy and R⁵ and R⁶ are both hydrogen can be prepared by reduction of compounds of structure (XII) using for example Raney Nickel/hydrazine, followed by rearrangement of the 4-amino-N-oxide intermediate so formed, with, for example acetic anhydride. Treatment of the compounds of structure (III) in which L² is OH with halogenating agents such as thionyl chloride or O-acylating agents such as p-toluenesulphonyl chloride gives the required compounds of structure (III) in which L² is halogen or sulphonyloxy respectively. Compounds of structure (III) in which L² is SH can be prepared from compounds of structure (III) in which L² is a leaving group for example halogen, by reaction with, for example, NaSH. Compounds of structure (V) can be prepared from the corresponding compounds of structure (III); for example, compounds of structure (V) in which X is CSCl can be prepared by reaction of a compound of structure (III) in which L² is SH with thiophosgene. Compounds of structure (VII) can be prepared by methods analogous to those described in Roszniki Chem., 35 , 475, 1961. In a further aspect the present invention provides compounds of structure (I) and pharmaceutically acceptable salts thereof for use in therapy. The compounds of structure (I) and their pharmaceutically acceptable salts inhibit exogenously and endogenously stimulated gastric acid secretion and are useful in the treatment of gastro-intestinal diseases in mammals, in particular humans. Such diseases include, for example, gastric and duodenal ulcers, and Zollinger-Ellison Syndrome. Further, the compounds of structure (I) can be used in the treatment of other disorders where a cytoprotective and/or anti- secretory effect is desirable for example in patients with gastritis, NSAID induced gastritis, gastric ulcers, acute upper intestinal bleeding, and in patients with a history of chronic and excessive alcohol consumption. It is believed that, after administration to mammals, compounds of structure (I) in which n is 0 exert their anti-secretory and cytoprotective activities after conversion into compounds of structure (I) in which n is 1. Furthermore it is believed that compounds of structure (I) in which n is 1, after administration to mammals, exert their anti-secretory activity after transformation under acid conditions into another chemically reactive species. Active species so generated from compounds of structure (I) are within the scope of the present invention. In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Compounds of structure (I) in which n is 1 are susceptible to decomposition in acid media, and thus tablets and capsules containing such compounds are preferably provided with an enteric coating to protect the compound from acid degradation in the stomach or capsules used which are inherently acid resistant. Alternatively, the enteric coating can be provided by coating pellets containing the active ingredient before filling them into the hard gelatin capsule. Suitable enteric coating materials are those well known in the art of pharmacy and include for example shellac or anionic-film forming polymers such as cellulose acetate phthalate and hydroxypropylmethyl cellulose phthalate and the like, optionally in the presence of a plasticizer. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats. Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The present invention also provides a method of inhibiting gastric acid secretion which comprises administering to a mammal in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable compounds of the invention will normally be administered to a subject for the treatment of gastro intestinal diseases and other conditions caused or exacerbated by gastric acidity. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. In addition, the compounds of the present invention can be co- administered with further active ingredients, such as antacids (for example magnesium carbonate or hydroxide and aluminium hydroxide), non steroidal anti- flammatory drugs (for example indomethacin, aspirin or naproxen), steroids, or nitrite scavengers (for example ascorbic acid or aminosulphonic acid), or other drugs used for treating gastric ulcers (for example pirenzipine, prostanoids for example 16,16 dimethyl PGE₂, or histamine H₂-antagonists (for example, cimetidine). The following examples illustrate the invention. Temperatures are recorded in degrees centigrade. Example 1A Preparation of 5-bromo-2-methyl-pyridine-N-oxide To a solution of 5-Bromo-2-methyl-pyridine (71.35 g, 0.41M) in dichloromethane (350 ml) was added a solution of m-chloroperbenzoic acid (78.83 g, 0.46M) in dichloromethane (1100 ml), over a period of 2.5 hours. The reaction mixture was stirred at ambient temperature for a further 20 hours, cooled (ice/salt bath) and anhydrous ammonia bubbled into it for 1 hour during which time a white precipitate formed and the temperature of the solution was not allowed to rise above 15°. The reaction mixture was allowed to warm to room temperature, filtered and washed with dichloromethane. The filtrate and washings were combined and washed with Na₂SO₃ (5%) solution (2 x 200 ml), water (2 x 150 ml), dried (phase separating paper) and evaporated to dryness in vacuo to give an off white solid. Recrystallisation from ethyl acetate gave 5-bromo-2-methylpyridine-N-oxide as white crystals, 65.66 g, 84%, m.p. 116-118°. Example 1B Preparation of 5-bromo-4-nitro-2-methylpyridine-N-oxide The product of 1(A) (59.89 g, 0.32M) was added in portions, over 45 minutes to a nitrating mixture consisting of conc. sulphuric acid (100 ml) and conc. nitric acid (100 ml). The reaction mixture was heated at 60°C with stirring for 20 hours, allowed to cool and poured on to ice with stirring so that its temperature did not rise above 10°. Sodium hydroxide solution (10N) was then added to give a final volume of 1700 ml at pH 12 (again, during addition of NaOH, the temperature not allowed to rise above 25°). The solution was then extracted with ethyl acetate (4 x 1000 ml), the extracts combined dried and evaporated in vacuo to give a suspension ( 400 ml). The suspension was heated, filtered and allowed to cool to give crystals (yellow needles) of the title compound 65.00 g, m.p. 137-8°. Example 1C Preparation of 5-Bromo-4-amino-2-methylpyridine-N-oxide To a suspension of the product of example 1(B) (5.00 g, 0.02M) in ethanol (100 ml) under an atmosphere of nitrogen was added Raney Nickel, followed by hydrazine hydrate (1.6 ml, 0.03M) in ethanol (10 ml). The reaction mixture was stirred under nitrogen for 2.5 hours, a further portion of hydrazine hydrate (0.8 ml, 0.015 M) in ethanol (5 ml) added and the mixture stirred for a further 21 hours at ambient temperature. The mixture was filtered, washed through with ethanol, and the combined filtrates evaporated to dryness to give a brown oil. Column chromatography, using chloroform: methanol (30:1) as eluant gave the title compound 0.96 g, 25%, m.p. 212-215° (decomp). Example 1D Preparation of 5-Bromo-4-amino-2-hydroxymethylpyridine The product of example 1(C) (0.83 g, 0.0041M) was heated under reflux in acetic anhydride (25 ml) for 2 hours. The mixture was evaporated to dryness, taken up in 2N HCl (10 ml) and heated over a steam bath for 1 hour. The solution was cooled, extracted with chloroform and the aqueous layer basified to pH 11.5 with sodium hydroxide solution (ice bath) and extracted with ethyl acetate (5 x 50 ml). The combined extracts were evaporated to dryness to give, as an off-white glass, the title compound, 0.56 g. Example 1E Preparation of 5-Bromo-4-amino-2-chloromethylpyridine hydrochloride 5-Bromo-4-amino-2-hydroxymethylpyridine (0.60 g, 0.003M) in chloroform (15 ml) was cooled to -10° and thionyl chloride (0.64 ml, 1.05 g, 0.0089M) in chloroform (5 ml) added dropwise over 20 minutes so that the temperature of the reaction mixture did not rise above -10°. The reaction mixture was stirred for 1 hour at -10° and then allowed to warm to room temperature and stirred for 21 hours (if the reaction is not complete at this stage, further portions of thionyl chloride can be added (at -10°), followed by reflux if necessary). Excess thionyl chloride was destroyed by the dropwise addition of methanol and the mixture evaporated to dryness in vacuo to give the title compound as a brown glass, 0.76 g. Example 1F Preparation of 2-(4-amino-5-bromo-2-pyridylmethylthio)-5- methoxy-(1H)-benzimidazole The product of example of 1E (0.73 g, 0.0028M) and 5-methoxy-2- mercapto-benzimidazole (0.51 g, 0.0028M) were dissolved in ethanol (30 ml) and 5N sodium hydroxide solution added (1.2 ml). The reaction mixture was stirred at room temperature for 22 hours and then evaporated to dryness in vacuo. The residue was dissolved in water (30 ml) and then basified with concentrated NaOH solution to pH 14. The solution was extracted with chloroform (3 x 100 ml), the organic layers dried, and then evaporated to dryness in vacuo, to give 2-(4-amino-5- bromo-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole 0.66 g, m.p. 183-4°. Example 2 Preparation of 2-(4-amino-5-bromo-2-pyridyl-methyl- sulphinyl)-5-methoxy-(1H)-benzimidazole 2-(4-amino-5-bromo-2-pyridylmethylthio)-5-methoxy-(1H)- benzimidazole (0.58 g, 0.0016M) was dissolved in dichloromethane (160 ml) and cooled to -40°. m-Chloroperbenzoic acid (0.33 g, 0.0019M) in dichloromethane (10 ml) was added dropwise over 20 mins, keeping the temperature at -30 to -40°. The solution was stirred at -30° for 1 hour and then stored at -20° overnight, or until reaction was complete. Ammonia was then bubbled through the solution at 5°, the mixture allowed to warm up to room temperature, and then filtered. The filtrate and washings were washed with 10% Na₂CO₃ (10 ml) an dried. Back extraction of the aqueous layers with dichloromethane (3 x 100 ml) gave further organic layers which were dried and combined with layers obtained from the first extraction. Evaporation of the combined organic layers gave a brown solid. Purification, by heating in presence of decolouring charcoal in ethyl acetate/methanol, followed by recrystallisation from methanol gave 2-(4-amino-5-bromo-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 0.21 g, m.p. 130-132°. Example 3A Preparation of 4-amino-3-chloro-2-picoline Precondensed chlorine (ca. 20 ml) was evaporated into a stirred, ice cooled solution of 4-amino-2-picoline (44g) in sulphuric acid (1l, 50% v/v) in a flask fitted with a dri-cold trap. After stirring for a further 2 hours the solution was basified (NaOH) and extracted with ether. The extract was dried (K₂CO₃), treated with charcoal and reduced to a small volume. Pet. ether (40/60) was added to give a solid which was recrystallised from chloroform/pet. ether (60/80) to give 4-amino-3-chloro-2-picoline, 37.2g, m.p. 116-18°. Example 3B Preparation of 3,4-dichloro-2-picoline Sodium nitrite (36g) was added in portions to a stirred solution of 4-amino-3-chloro-2-picoline (24.85g) in conc. hydrochloric acid (750 ml) cooled to 0-5°. After 1 hour at 0-5° and a further 2 hours at room temperature the mixture was basified (NaOH), allowing the temperature to rise to ca. 50°, and extracted with ether. After drying (K₂CO₃), the extract was evaporated to dryness to give 3,4-dichloro-2-picoline (26.5g) as a low melting solid. Example 3C Preparation of 3,4-dichloro-2-hydroxymethylpyridine m-Chloroperbenzoic acid (32.63g) in dichloromethane (400 ml) was added dropwise to a solution of 3,4-dichloro-2-picoline (25.53 g)in dichloromethane (100ml) maintaining the temperature at 20-25°. After standing for 16 hours at room temperature the solution was washed with 1N NaOH, dried (K₂CO₃) and filtered to give a pale yellow solution. Trifluoroacetic anhydride (30 ml) was added dropwise to this solution maintaining the temperature at 15-20°. After standing for 2 days at room temperature, methanol (100 ml) was added and the solution evaporated under reduced presure. The residue was treated with aqueous sodium carbonate and extracted into dichloromethane. After drying (K₂CO₃) and removal of solvent, the residue was recrystallised from pet. ether (60/80) to give 3,4-dichloro-2-hydroxymethylpyridine, 15.76 g, m.p. 66-8°. Example 3D Preparation of 4-morpholino-3-chloro-2-hydroxymethylpyridine Morpholine (7.34 ml) and 3,4-dichloro-2-hydroxymethylpyridine (3.0 g) were heated together in a bomb at 180° for 4 hours. After cooling, the mixture was taken up in ethanol and evaporated under reduced pressure to remove excess amine. The residue was taken up in water and extracted with chloroform. After drying (K₂CO₃) and removal of solvent, the residue was chromatographed (silica gel, CHCl₃) to give an oil which was crystallised from petroleum ether (60/80) to give 4-morpholino-3-chloro-2-hydroxymethylpyridine, 3.24 g, m.p. 80-2°. Example 3E Preparation of 4-morpholino-3-chloro-2-chloromethylpyridine hydrochloride Thionyl chloride (3 ml) in chloroform (25 ml) was added dropwise to a solution of 4-morpholino-3-chloro-2-hydroxymethylpyridine (3.09 g) in chloroform (25 ml) cooled in an ice/salt bath. Following the addition the ice bath was removed and the mixture stirred for a further 1.5 hours. The volume of the solution was reduced and ether added to give 4- morpholino-3-chloro-2-chloromethylpyridine hydrochloride, 3.77 g, m.p. 200-2°. Example 3F Preparation of 2-(4-morpholino-3-chloro-2-pyridylmethylthio)-5- methoxy-(1H)-benzimidazole 5N Sodium hydroxide (5.68 ml) was added dropwise to a stirred solution of 4-morpholino-3-chloro-2-chloromethyl- pyridine hydrochloride (3.66 g) and 5-methoxy-2-mercapto- benzimidazole (2.33 g). After standing overnight the solution was evaporated under reduced pressure and the residue triturated with water. The solid thus obtained was recrystallised from ethanol to give 2-(4-morpholino-3-chloro-2- pyridyl-methylthio)-5-methoxy-(1H)-benzimidazole, 4.38 g, m.p. 124-25°. Example 4 Preparation of 2-(4-morpholino-3-chloro-2-pyridylmethyl- sulphinyl)-5-methoxy-(1H)-benzimidazole A solution of m-chloroperbenzoic acid (1.61 g) in dichloromethane (75 ml) was added dropwise to a stirred solution of 2-(4- morpholino-3-chloro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (3.35 g) in dichloromethane (150 ml) cooled to -35°. After 1 hour, ammonia was passed through the solution for 5 minutes and the precipitate filtered off. The solution was evaporated under reduced pressure and the residue chromatographed (silica gel, 2% CHCl₃/MeOH-NH₃) to give an oil which was crystallised from ethanol to give 2-(4-morpholino-3-chloro-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, (2.6 g). C₁₈H₁₉ClN₄O₃S Found C 53.39, H 4.79, N 13.62, S 7.75, Cl 8.84 Requires C 53.13, H 4.71, N 13.77, S 7.88, Cl 8.71 Example 5A Preparation of 4-amino-3-chloro-2,5-dimethylpyridine Substituting 4-amino-2,5-dimethylpyridine (35 g) for 4-amino-2 -picoline and using corresponding molar proportions of the other reagents in the method of Example 3A gave 4-amino-3-chloro-2,5-dimethylpyridine, 26 g, m.p. 82-3°. Example 5B Preparation of 3,4-dichloro-2,5-dimethylpyridine Substituting 4-amino-3-chloro-2,5-dimethylpyridine (26 g) for 4 -amino-3-chloro-2-picoline and using corresponding molar proportions of the other reagents in the method of Example 3B gave 3,4-dichloro-2,5-dimethylpyridine, 26.8 g, as an oil. Example 5C Preparation of 3,4-dichloro-5-methyl-2-hydroxymethylpyridine Substituting 3,4-dichloro-2,5-dimethylpyridine (26.8 g) for 3,4-dichloro-2-picoline and using corresponding molar proportions of the other reagents in the method of Example 3C gave 3,4-dichloro-5-methyl-2-hydroxymethylpyridine, 22.5g, m.p. 77-8° from ether/pet. ether (40/60). Example 5D Preparation of 4-morpholino-3-chloro-5-methyl-2- hydroxymethylpyridine Substituting 3,4-dichloro-5-methyl-2- hydroxymethylpyridine (4 g) for 3,4-dichloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents, in the method of Example 3D gave 4-morpholino- 3-chloro-5-methyl-2-hydroxymethylpyridine, 4.49 g, m.p. 54-5° from pet. ether (60/80). Example 5E Preparation of 4-morpholino-3-chloro-5-methyl-2- chloromethylpyridine Hydrochloride Substituting 4-morpholino-3-chloro-5-methyl-2- hydroxymethylpyridine (4.0 g) for 4-morpholino-3-chloro-2- hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3E gave 4-morpholino-3-chloro-5-methyl-2- chloromethylpyridine hydrochloride, 4.9 g, m.p. 176-9°. Example 5F Preparation of 2-(4-morpholino-3-chloro-5-methyl-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole Substituting 4-morpholino-3-chloro-5-methyl-2- chloromethylpyridine hydrochloride (4.0g) for 4-morpholino-3- chloro-2-chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F gave 2-(4-morpholino-3-chloro-5- methyl-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole, 3.96g, m.p. 162-4° from acetonitrile. Example 6 Preparation of 2-(4-morpholino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole Substituting 2-(4-morpholino-3-chloro-5-methyl-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (3.8g) for 2-(4- morpholino-3-chloro-2-pyridylmethylthio)-5-methoxy-(1H)- benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave, after chromatography (alumina CHCl₃/MeOH 0-1%), 2-(4-morpholino- 3-chloro-5-methyl-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole, 1.09 g, m.p. 147-48° from acetonitrile. C₁₉H₂₁ClN₄0₃S Found C 54.25, H 5.08, N 13.25, S 7.6, Cl 8.68 Requires C 54.22, H 5.03, N 13.31, S 7.62, Cl 8.42 Example 7A Preparation of 4-piperidino-3-chloro-5-methyl-2- hydroxymethylpyridine Substituting piperidine for morpholine in the method of Example 5D, gave 4-piperidino-3-chloro-5-methyl-2- hydroxymethylpyridine (80%) as an oil. Example 7B Preparation of 4-piperidino-3-chloro-5-methyl-2- chloromethylpyridine hydrochloride Substituting 4-piperidino-3-chloro-5-methyl-2- hydroxymethylpyridine (2.9g) for 4-morpholino-3-chloro-5-methyl- 2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 5E gave 4-piperidino-3-chloro-5-methyl-2- chloromethylpyridine hydrochloride, 3.5g, m.p. 178-80° Example 7C Preparation of 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole Substituting 4-piperidino-3-chloro-5-methyl-2- chloromethylpyridine hydrochloride (3 g) for 4-morpholino-3- chloro-2-chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 5F gave 2-(4-piperidino-3- chloro-5-methyl-2-pyridylmethylthio)-5-methoxy-(1H)- benzimidazole, 3.1 g, m.p. 154-56° from acetonitrile. Example 8 Preparation of 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylsulpinyl)-5-methoxy-(1H)-benzimidazole Substituting 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio) -5-methoxy-(1H)-benzimidazole (2.3 g) for 2-(4-morpholino-3 -chloro-5-methyl-2-pyridylmethylthio)-5- methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents, in the method of Example 6, gave 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 0.78 g, m.p. 151-52° from acetonitrile. C₂₀H₂₃ClN₄O₂S Found C 57.17, H 5.47, N 13.33, S 7.6, Cl 8.54 Requires C 57.34, H 5.53, N 13.37, S 7.65, Cl 8.46 Example 9A Preparation of 4-piperidino-3-chloro-2-hydroxymethylpyridine Substituting piperidine (7.17 g) for morpholine and using corresponding molar proportions of the other reagents, in the method of Example 3D, gave 4-piperidino-3-chloro-2- hydroxymethyl pyridine, 2.7 g, m.p. 68-70° from pet. ether (40/60). Example 9B Preparation of 4-piperidino-3-chloro-2-chloromethylpyridine hydrochloride Substituting 4-piperidino-3-chloro-2-hydroxymethyl pyridine (3.43 g) for 4-morpholino-3-chloro-2-hydroxymethyl pyridine and using corresponding molar proportions of the other reagents in the method of Example 3E, gave 4-piperidino-3 -chloro-2-chloromethyl pyridine hydrochloride, 4.02 g, m.p. 192-4°. Example 9C Preparation of 2-(4-piperidino-3-chloro-2-pyridylmethylthio) -5-methoxy-(1H)-benzimidazole Substituting 4-piperidino-3-chloro-2-chloromethylpyridine hydrochloride (3.87 g) for 4-morpholino-3-chloro-2-chloromethyl pyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F, gave 2-(4-piperidino-3 -chloro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole, 4.53 g, m.p. 145-7°. Example 10 Preparation of 2-(4-piperidino-3-chloro-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole Substituting 2-(4-piperidino-3-chloro-2-pyridylmethylthio)- 5-methoxy-(1H)-benzimidazole (4.12 g) for 2-(4-morpholino- 3-chloro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents, in the method of Example 4, gave 2-(4-piperidino- 3-chloro-2-pyridylmethylsulphinyl)-5-methoxy-(1H)- benzimidazole, 1.51 g. C₁₉H₂₁ClN₄O₂S Found C 56.72, H 5.28, N 13.80, S 7.79, Cl 8.67 Requires C 56.36, H 5.23, N 13.84, S 7.92, Cl 8.76 Example 11A Preparation of 4-pyrrolidino-3-chloro-2-hydroxymethylpyridine Substituting pyrrolidine (5.99 g) for morpholine and using corresponding molar proportions of the other reagents, in the method of Example 3D, gave 4-pyrrolidino-3-chloro-2- hydroxymethylpyridine, 3.0 g, m.p. 85-6°. Example 11B Preparation of 4-pyrrolidino-3-chloro-2-chloromethylpyridine hydrochloride Substituting 4-pyrrolidino-3-chloro-2-hydroxymethyl pyridine (2.96g) for 4-morpholino-3-chloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents, in the method of Example 3E, gave 4-pyrrolidino-3 -chloro-2-chloromethylpyridine hydrochloride, 3.68g, m.p. 184-5°. Example 11C Preparation of 2-(4-pyrrolidino-3-chloro-2-pyridylmethylthio) -5-methoxy-(1H)-benzimidazole Substituting 4-pyrrolidino-3-chloro-2-chloromethylpyridine hydrochloride (3.68 g) for 4-morpholino-3-chloro-2- chloromethyl pyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F gave 2-(4-pyrrolidino-3-chloro-2-pyridylmethylthio) -5-(1H)-benzimidazole, 4.14 g, m.p. 131-3°. Example 12 Preparation of 2-(4-pyrrolidino-3-chloro-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole Substituting 2-(4-pyrrolidino-3-chloro-2-pyridylmethylthio)-5 -methoxy-(1H)-benzimidazole (4.11 g) for 2-(4-morpholino-3-chloro-2-pyridylmethylthio)-5-methoxy-(1H) -benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave 2-(4 -pyrrolidino-3-chloro-2-pyridylmethyl-sulphinyl)-5-methoxy-(1H) -benzimidazole, 1.92 g. C₁₈H₁₉ClN₄O₂S Found C 54.98, H 4.90, N 14.15, S 8.28, C l9.25 Requires C 55.31, H 4.90, N 14.33, S 8.20, C l9.07 Example 13A Preparation of 4-pyrrolidino-3-chloro-5-methyl-2-hydroxymethylpyridine Substituting pyrrolidine for morpholine in the method of Example 5D gave 4-pyrrolidino-3-chloro-5-methyl-2- hydroxymethylpyridine (50%) as an oil. Example 13B Preparation of 4-pyrrolidino-3-chloro-5-methyl-2- chloromethyl hydrochloride Substituting 4-pyrrolidino-3-chloro-5-methyl-2-hydroxymethylpyridine (2.1 g) for 4-morpholino-3-chloro-5-methyl-2 -hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 5E gave 4-pyrrolidino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride, 2.38 g, m.p. 180-182°. Example 13C Preparation of 2-(4-pyrrolidino-3-chloro-5-methyl-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole Substituting 4-pyrrolidino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride (2.2 g) for 4-morpholino-3- chloro-5-methyl-2-chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 5F gave 2-(4-pyrrolidino-3-chloro-5-methyl-2-pyridylmethylthio)- 5 -methoxy-(1H)-benzimidazole, 3.01 g, m.p. 152-158° from acetonitrile. Example 14 Preparation of 2-(4-pyrrolidino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole Substituting 2-(4-pyrrolidino-3-chloro-5-methyl-2-pyridyl- methylthio)-5-methoxy-(1H)-benzimidazole (2.3 g) for 2-(4-morpholino-3 -chloro-5-methyl-2-pyridylmethylthio)-5- methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 6 gave 2-(4-pyrrolidino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 1.74 g, m.p. 145-146° from acetonitrile. C₁₉H₂₁ClN₄O₂S Found C 56.51, H 5.31, N 13.97, S 7.91, Cl 8.92 Requires C 56.36, H 5.23, N 13.84, S 7.92, Cl 8.76 Example 15A Preparation of 4-dimethylamino-3-chloro-5-methyl-2- hydroxymethylpyridine 3,4-dichloro-5-methyl-2-hydroxymethylpyridine (4 g) was dissolved in 33% dimethylamine in ethanol (17 ml), placed in a sealed vessel and heated to 200°C for 4 hours. On cooling, the reaction mixture was evaporated under reduced presure and the residue dissolved in water (15 ml) and ether extracted. Etherial extracts were dried (K₂CO₃), filtered and stripped to yield 4-dimethylamino-3-chloro-5- methyl-2-hydroxymethylpyridine, 4.08 g as an oil. Example 15B Preparation of 4-dimethylamino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride Substituting 4-dimethylamino-3-chloro-5-methyl-2-hydroxymethylpyridine (3.5 g) for 4-morpholino-3-chloro-5-methyl- 2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 5E gave 4-dimethylamino-3-chloro-5-methyl-2-chloro- methylpyridine hydrochloride, 4.0 g, m.p. 162-163°. Example 15C Preparation of 2-(4-dimethylamino-3-chloro-5-methyl-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole Substituting 4-dimethylamino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride (3.9 g) for 4-morpholino-3-chloro-5-methyl-2 -pyridylmethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 5F gave 2-(4-dimethyl- amino-3-chloro-5 -methyl-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole, 4.2 g, m.p. 109-110° from acetonitrile. Example 16 Preparation of 2-(4-dimethylamino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole Substituting 2-(4-dimethylamino-3-chloro-5-methyl-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (1.6 g) for 2-(4 -morpholino-3-chloro-5-methyl-2-pyridylmethyl-thio)-5-methoxy-(1H) -benzimidazole and using corresponding molar proportions of the other reagents, in the method of Example 6, gave 2-(4-dimethylamino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 0.94 g, m.p. 147-149° (from acetonitrile). C₁₇H₁₉ClN₄O₂S Found C 53.69, H 5.02, N 14.70, Cl 9.37, S 8.43 Requires C 53.89, H 5.05, N 14.79, Cl 9.36, S 8.46 Example 17A Preparation of 4-Piperidino-2-picoline Piperidine (31.7 ml) and 4-chloro-2-picoline (13.65 g) were heated together in a bomb at 170° for 4.5 hours. After cooling, the mixture was taken up in water and extracted with ether. After drying (K₂CO₃) and stripping, the residue was distilled to give 4-piperidino-2-picoline, 15.45 g. b.p. 105-10° (0.1mm). Example 17B Preparation of 4-piperidino-5-bromo-2-picoline and 4-piperidino-3-bromo-2-picoline A solution of bromine (9.3 ml) in dimethylformamide (50 ml) was added dropwise to a stirred mixture of 4-piperidino-2-picoline (15 g), potassium carbonate (23.5 g) in dimethylformamide (50 ml) at 25-30°. After 3.5 hours, the mixture was stripped and the residue taken up in water, adjusted to pH13 with 40% aqueous NaOH, and extracted with ether. After drying (K₂CO₃) and stripping, the residue was chromatographed (silica gel, n-hexane:ether) to give 4-piperidino-5-bromo-2-picoline, 11.18 g, as an oil and 4-piperidino-3-bromo-2-picoline, 3.5 g, as an oil. Example 17C Preparation of 4-piperidino-5-bromo-2-picoline-N-oxide m-Chloroperbenzoic acid (7.3 g) in dichloromethane (100 ml) was added dropwise to a stirred solution of 4-piperidino-5- bromo-2-picoline. After 16 hours, the solution was washed with 10% aqueous sodium carbonate, dried (K₂CO₃) and stripped. The residue was chromatographed (silica gel, chloroform:methanol) to give 4-piperidino-5-bromo-2- picoline-N-oxide, 6.79 g, m.p. 115-6° from ether. Example 17D Preparation of 4-piperidino-5-bromo-2-hydroxymethylpyridine 4-piperidino-5-bromo-2-picoline-N-oxide (4.66 g) and acetic anhydride (25 ml) were heated at 100° for 1.25 hours. The solution was stripped, treated with toluene (30 ml) and stripped again. 2N Hydrochloric acid (35 ml) was added and the mixture heated at 100° for 2 hours. After cooling, 40% aqueous NaOH was added to pH13 and the solution extracted with ether. After drying (K₂CO₃) and stripping, the residue was chromatographed (silica gel, chloroform:methanol) to give 4 piperidino-5-bromo-2- hydroxymethylpyridine, 2.38 g, m.p. 118-9°, from ether. Example 17E Preparation of 4-piperidino-5-bromo-2-chloromethylpyridine hydrochloride Substituting 4-piperidino-5-bromo-2-hydroxymethylpyridine (3.0 g) for 4-morpholino-3-chloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3E gave 4-piperidino-5- bromo-2-chloromethyl pyridine hydrochloride, 3.47 g, m.p. 155-7° by ether trituration. Example 17F Preparation of 2-(4-piperidino-5-bromo-2-pyridylmethylthio) -5-methoxy-(1H)-benzimidazole Substituting 4-piperidino-5-bromo-2-chloromethyl pyridine hydrochloride (3.44g) for 4-morpholino-3-chloro-2- chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F gave after chromatography (silica gel, chloroform:methanol) 2-(4-piperidino-5-bromo-2 -pyridylmethylthio) -5-methoxy-(1H)-benzimidazole, 4.39 g, as an oil. Example 18 Preparation of 2-(4-piperidino-5-bromo-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole Substituting 2-(4-piperidino-5-bromo-2-pyridylmethylthio)- 5-methoxy-(1H)-benzimidazole (3.83 g) for 2-(4-morpholino- 3-chloro-2-pyridylmethylthio-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave after chromatography (silica gel, chloroform:methanol-ammonia) 2-(4-piperidino-5-bromo-2 -pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 3.15 g, m.p. 114-8°C, from ether. C₁₉H₂₁BrN₄O₂S Found C 50.48, H 4.78, N 12.30, S 7.13, Br 17.44 Requires C 50.78, H 4.71, N 12.47, S 7.14, Br 17.78 Example 19A Preparation of 4-piperidino-3-bromo-2-picoline-N-oxide Substituting 4-piperidino-3-bromo-2-picoline (3.46 g) for 4-piperidino-5-bromo-2-picoline and using corresponding molar proportions of the other reagents in the method of Example 17C gave 4-piperidino-3-bromo-2-picoline-N-oxide, 2.5 g, m.p. 98-100° from pet. ether (60/80). Example 19B Preparation of 4-piperidino-3-bromo-2-hydroxymethylpyridine Substituting 4-piperidino-3-bromo-2-picoline-N-oxide (2.42 g) for 4-piperidino-5-bromo-2-picoline-N-oxide and using corresponding molar proportions of the other reagents in the method of Example 17D gave 4-piperidino-3-bromo-2-hydroxymethylpyridine, 1.19 g, m.p. 51-3° from pet. ether (40/60). Example 19C Preparation of 4-piperidino-3-bromo-2-chloromethylpyridine hydrochloride Substituting 4-piperidino-3-bromo-2-hydroxymethylpyridine (0.96 g) for 4-morpholino-3-chloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3E gave 4-piperidino-3- bromo-2 -chloromethylpyridine hydrochloride, 1.08 g, m.p. 182-4°C by ether trituration. Example 19D Preparation of 2-(4-piperidino-3-bromo-2-pyridylmethylthio) -5-methoxy-(1H)-benzimidazole Substituting 4-piperidino-3-bromo-2-chloromethylpyridine hydrochloride (1.07g) for 4-morpholino-3-chloro-2- chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F gave 2-(4-piperidino-3-bromo-2-pyridylmethylthio)- 5-methoxy-(1H)-benzimidazole, 1.34 g, as an oil. Example 20 Preparation of 2-(4-piperidino-3-bromo-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole Substituting 2-(4-piperidino-3-bromo-2-pyridylmethylthio)-5 -methoxy-(1H)-benzimidazole (1.34 g) for 2-(4-morpholino-3-chloro-2 pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave after chromatography (silica gel:2% methanol:chloroform) 2-(4-piperidino-3-bromo-2-pyridylmethyl-sulphinyl)-5- methoxy-(1H)-benzimidazole, 0.62 g, from ether. C₁₉H₂₁BrN₄O₂S.H₂O Found C 48.53, H 4.58, N 11.75, S 6.80, Br 17.02 Requires C 48.82, H 4.96, N 11.99, S 6.86, Br 17.10 Example 21A Preparation of 5-bromo-2,3-lutidine-N-oxide m-Chloroperbenzoic acid (71.42 g) in dichloromethane (1l) was added dropwise to a stirred solution of 5-bromo-2,3- lutidine (70.0g) over 1 hour. After 23 hours the solution was cooled to 15° and ammonia gas bubbled through to give a white precipitate, which was filtered off. The filtrate was washed with 5% aqueous sodium sulphite, dried, and stripped to give 5-bromo-2,3-lutidine-N-oxide, 61.78 g, m.p. 80-2°, from ethyl acetate. Example 21B Preparation of 5-bromo-4-chloro-2,3-lutidine 5-bromo-2,3-lutidine-N-oxide (30.31g) was added in portions to phosphorus oxychloride (41.3 ml) at 30-40°. The mixture was heated to 50°, when an exothermic reaction raised the temperature to reflux. After 30 minutes the solution was cooled and poured onto ice to give a white solid, which was filtered off and discarded. The filtrate was extracted with ether then treated with 40% aqueous sodium hydroxide to pH 7, and extracted again with ether. The latter extract was dried (MgSO₄) and stripped to give 5-bromo-4- chloro-2,3-lutidine, 12.0 g as a low melting solid. Example 21C Preparation of 4-piperidino-5-bromo-2,3-lutidine Substituting 5-bromo-4-chloro-2,3-lutidine (8.0 g) for 3,4-dichloro-2-hydroxymethyl pyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave, after chromatography (silica gel, chloroform), 4-piperidino-5-bromo-2,3- lutidine, 7.88 g, as an oil. Example 21D Preparation of 4-piperidino-5-bromo-2,3-lutidine-N-oxide Substituting 4-piperidino-5-bromo-2,3-lutidine (8.3 g) for 4-piperidino-5-bromo-2-picoline and using corresponding molar proportions of the other reagents in the method of Example 17C gave 4-piperidino-5-bromo -2,3-lutidine-N-oxide, 5.31 g, m.p. 103-5°, from ether. Example 21E Preparation of 4-piperidino-5-bromo-3-methyl-2-hydroxymethylpyridine Substituting 4-piperidino-5-bromo-2,3-lutidine-N-oxide (4.71 g) for 4-piperidino-5-bromo-2-picoline-N-oxide and using corresponding molar proportions of the other reagents in the method of Example 17D gave 4-piperidino-5-bromo-3-methyl-2-hydroxymethylpyridine, 2.34 g, m.p. 80-1°, from pet. ether (60/80). Example 21F Preparation of 4-piperidino-5-bromo-3-methyl-2-chloromethylpyridine hydrochloride Substituting 4-piperidino-5-bromo-3-methyl-2-hydroxymethylpyridine (2.25g) for 4-morpholino-3-chloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3E gave 4-piperidino-5-bromo-3-methyl-2-chloromethylpyridine hydrochloride, 2.68 g, m.p. 177-9°, by ether trituration. Example 21G Preparation of 2-(4-piperidino-5-bromo-3-methyl-2-pyridylmethylthio) -5-methoxy-(1H)-benzimidazole Substituting 4-piperidino-5-bromo-3-methyl-2-chloromethylpyridine hydrochloride (2.65 g) for 4-morpholino-3-chloro- 2-chloromethylpyridine hydrochloride and using the corresponding molar proportions of the other reagents in the method of Example 3F gave 2-(4-piperidino-5-bromo-3-methyl-2-pyridylmethylthio)-5-methoxy-(1H) -benzimidazole, 2.97 g, m.p. 90-2° from isopropanol/water. Example 22A Preparation of 2-(4-piperidino-5-bromo-3-methyl-2- pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole Substituting 2-(4-piperidino-5-bromo-3-methyl-2-pyridyl-methylthio -5-methoxy-(1H)-benzimidazole (2.9 g) for 2-(4-morpholino-3-chloro-2 -pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave 2-(4-piperidino-5-bromo-3-methyl-2-pyridyl-methylsulphinyl)-5-methoxy-(1H) -benzimidazole, 1.83 g, m.p. 157-9° (dec), from acetonitrile. C₂₀H₂₃BrN₄O₂S Found C 51.81, H 5.01, N 11.95, S 6.85, Br 17.18 Requires C 51.84, H 5.00, N 12.09, S 6.92, Br 17.24 Example 23A Preparation of 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio) -5-(1,1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole 5N Sodium hydroxide (2 ml) was added to a stirred suspension of 4-piperidino-3-chloro-5-methyl-2-chloromethylpyridine hydrochloride (1.6 g) and 5-(1,1,2,2-tetrafluoroethoxy)-2 -mercaptobenzimidazole (1.5 g) in ethanol at room temperature. After standing over night an additional quantity of sodium hydroxide (1 ml) was added and after a further 1 hour the mixture was evaporated at reduced pressure. The residue was chromatographed (silica gel chloroform/methanol 2%) and crystallised from acetonitrile to give 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio)-5-(1,1,2,2 -tetrafluoroethoxy)-(1H)- benzimidazole, 1.66 g, m.p. 170-71°. Example 23B Preparation of 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-(1,1,2,2-tetrafluoroethoxy)-(1H)- benzimidazole m-Chloroperbenzoic acid (0.75 g total) in dichloromethane (40 ml) was added to a solution of 2-(4-piperidino-3- chloro-5-methyl-2-pyridylmethylthio)-5-(1,1,2,2-tetrafluoroethoxy)-(1H) -benzimidazole (1.5 g) in dichloromethane (30 ml) at -40 to -50° over a period of 2.5 hours. After a further 0.5 hour ammonia was passed through the solution and the precipitate filtered off and washed well with dichloromethane. The filtrates were evaporated under reduced pressure to give an oil which, on treatment with acetonitrile, gave 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-5-(1,1,2,2-tetrafluoroethoxy)-(1H)- -benzimidazole, 0.77g, m.p. 155-56° (dec). C₂₁H₂₁ClF₄N₄OS Found C 49.70, H 4.12, N 10.93, S 6.63 Requires C 49,95, H 4.19, N 11.10, S 6.35 Example 24A Preparation of 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylthio)-4,5-difluoromethylenedioxy-(1H)- benzimidazole Substituting 4,5-difluoromethylenedioxy-2-mercapto- benzimidazole (1.5 g) for 5-(1,1,2,2-tetrafluoroethoxy)- 2-mercaptobenzimidazole and using corresponding molar proportions of the other reagents in the method of Example 23A gave 2-(4-piperidino-3-chloro 5-methyl-2-pyridyl- methylthio)-4,5-difluoromethylenedioxy-(1H) -benzimidazole, 2.12 g, m.p. 198-99° from acetonitrile. Example 24B Preparation of 2-(4-piperidino-3-chloro-5-methyl-2- pyridylmethylsulphinyl)-4,5-difluoromethylenedioxy-(1H)- benzimidazole Substituting 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio) -4,5-difluoromethylenedioxy-(1H)-benzimidazole (2 g) for 2-(4-piperidino-3-chloro-5-methyl-2-pyridyl- methylthio)-5-(1,1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 23B gave 2-(4-piperidino- 3-chloro-5-methyl-2-pyridylmethylsulphinyl)-4,5-difluoromethylenedioxy (1H)-benzimidazole, 1.05 g, m.p. 169-70° (dec) from acetonitrile. Example 25A Preparation of 4-chloro-5-bromo-2-picoline-N-oxide A solution of 5-bromo-4-nitro-2-picoline-N-oxide (30.0 g) in dichloromethane (250 ml) was cooled at 10°, and a solution of phosphoryl chloride (35.5 ml) in dichloromethane (200 ml) added over 15 minutes. The mixture was heated under reflux for 5 hours, allowed to cool to ambient temperature, and allowed to stand for 16 hours. After pouring onto ice (300 ml) and stirring for 15 minutes, the mixture was basified to pH 10 using concentrated aqueous sodium hydroxide. The organic phase was separated off, and the aqueous phase further extracted with chloroform (2x100 ml). The combined organic phases were dried (K₂CO₃) and stripped to a solid, which was triturated with petroleum ether (40-60), filtered, washed and dried to yield 4-chloro-5-bromo-2-picoline-N-oxide, 24.08 g, m.p. 121-4°C. Example 25B Preparation of 4-chloro-5-bromo-2-hydroxymethylpyridine A solution of 4-chloro-5-bromo-2-picoline-N-oxide (23.9 g) in dichloromethane (250 ml) was cooled to 10° and trifluoroacetic anhydride (25 ml) added over 20minutes. The mixture was allowed to warm to ambient temperature, and stand for 7 days. After cooling to 10°, methanol (100 ml) was added, and the solution stripped. The residue was treated with water (150 ml), basified with saturated aqueous sodium carbonate to pH 10, and extracted with ethyl acetate (2x150 ml). The combined extracts were dried (MgSO₄), stripped, and triturated with ether to give 4-chloro-5-bromo-2-hydroxymethylpyridine, 16.58 g, m.p. 109-10°. Example 25C Preparation of 4-dimethylamino-5-bromo-2-hydroxymethylpyridine Substituting 33% w/w dimethylamine in ethanol (15 ml) for morpholine and 4-chloro-5-bromo-2-hydroxymethylpyridine (5 g) for 3,4-dichloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave after chromatography (silica, chloroform:methanol, 98:2) 4-dimethylamino-5 -bromo-2-hydroxymethylpyridine, 3.62 g, as an oil. Example 25D Preparation of 4-dimethylamino-5-bromo-2-chloromethyl-pyridine hydrochloride Substituting 4-dimethylamino-5-bromo-2-hydroxymethylpyridine (3.42 g) for 4-morpholino-3-chloro-2-hydroxy-methylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3E gave 4-dimethylamino-5-bromo-2-chloromethylpyridine hydrochloride, 4.11 g, m.p. 184-5° (dec.). Example 25E Preparation of 2-(4-dimethylamino-5-bromo-2-pyridyl-methylthio)-5 -methoxy-(1H)-benzimidazole Substituting 4-dimethylamino-5-bromo-2-chloromethylpyridine hydrochloride (3.96 g) for 4-morpholino-3- chloro-2-chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F gave after chromatography 2-(4-dimethylamino-5-bromo-2-pyridylmethylthio)-5-methoxy (1H)-benzimidazole, 5.23 g, as a foam. Example 25F Preparation of 2-(4-dimethylamino-5-bromo-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole Substituting 2-(4-dimethylamino-5-bromo-2-pyridylmethylthio)-5 -methoxy-(1H)-benzimidazole (5.02 g) for 2-(4-morpholino-3-chloro-2 pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave 2-(4-dimethylamino-5-bromo-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 3.8 g. C₁₆H₁₇BrN₄O₂S Found C 47.18, H 4.14, N 13.60, S 7.81, Br 19.34 Requires C 46.95, H 4.19, N 13.69, S 7.83, Br 19.52 Example 26A Preparation of 4-pyrrolidino-5-bromo-2-hydroxymethylpyridine Substituting pyrrolidine (7.4 ml) for morpholine and 4-chloro-5- bromo-2-hydroxymethylpyridine (4 g) for 3,4-dichloro-2-hydroxypyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave 4-pyrrolidino-5-bromo-2-hydroxymethylpyridine, 2.28 g, m.p. 108-10°C, from ether. Example 26B Preparation of 4-pyrrolidino-5-bromo-2-chloromethylpyridine hydrochloride Substituting 4-pyrrolidino-5-bromo-2-hydroxymethylpyridine (2.17 g) for 4-morpholino-3-chloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3E gave 4-pyrrolidino-5-bromo-2-chloromethylpyridine hydrochloride, 2.6 g, m.p. 197-200° (dec.). Example 26C Preparation of 2-(4-pyrrolidino-5-bromo-2-pyridylmethylthio)-5 -methoxy-(1H)-benzimidazole Substituting 4-pyrrolidino-5-bromo-2-chloromethylpyridine hydrochloride (2.48 g) for 4-morpholino-3-chloro-2-chloromethylpyridine hydrochloride and using corresponding molar proportions of the other reagents in the method of Example 3F gave 2-(4-pyrrolidino-5-bromo-2-pyridylmethylthio)-5-methoxy- (1H)-benzimidazole, 3.37 g, as an oil. Example 26D Preparation of 2-(4-pyrrolidino-5-bromo-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole Substituting 2-(4-pyrrolidino-5-bromo-2-pyridylmethylthio)-5- methoxy-(1H)-benzimidazole (3.23 g) for 2-(4-morpholino-3-chloro-2- pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding proportions of the other reagents in the method of Example 4 gave 2-(4-pyrrolidino-5 -bromo-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 2.6 g, m.p. (dec. ca. 144°). Example A A tablet for oral administration is prepared by combining into a 9 mm tablet. If the active ingredient is a compound of structure (I) in which n is 1 then the tablet is provided with an enteric coating. Example B A pellet formulation for oral administration may be prepared by formulating the following into pellets by standard techniques If the active ingredient is a compound of structure (I) in which n is 1, the pellets are first enteric coated before being filled into hard gelatin capsules. Example C An injection for parenteral administration is prepared by combining The solution is then sterilised and sealed into 2 ml and 5 ml ampoules and vials. Example D A reconstitutable lyophilisate for parenteral administration is prepared from: The solution is sterilised by aseptic filtration, 5 ml portions dispensed into 15 ml vials and the solution lyophilised. The lyophilisate can be reconstituted with 10 ml H₂O. Biological Data A. K⁺ Stimulated ATPase Activity. The effects of a single high concentration (1mM) of a compound of structure (I) on H⁺-K⁺ ATPase were determined at pH 6.1 and pH 7.4. Preferred compounds of structure (I) were also tested over a range of concentrations to determine IC₅₀ values at pH 6.1 and 7.4. (i) Preparation of Lyophilised Gastric Vesicles (H⁺-K⁺-ATPase) H⁺-K⁺-ATPase was prepared from the lyophilised gastric vesicles of pig fundic mucosa after the method of Saccomani et. al. (Biochem and Biophys. Acta., 465 , 311, 1977). (ii) K⁺ Stimulated ATPase Activity Compounds of structure (I) were pre-incubated with H⁺-K⁺-ATPase preparation 30µg protein/ml from (i) in 10 mM Pipes/Tris buffer pH 6.1 and pH 7.4. After 30 min at 37° the pre-incubation was diluted 5-fold with assay buffer to start the ATPase reaction. The conditions in the assay are 100mM Pipes/Tris, 2mM MgCl₂, 10mM KCl, 5ug/ml nigericin, 2mM Na₂ATP, pH 7.0. After an incubation at 37° for 15 min the inorganic phosphate released was determined by the method of Yoda & Hokin (Biochem. Biophys. Res. Com. 40 , 880, 1970). Nigericin was dissolved in methanol, which at the final concentration of 0.5%, did not affect the enzyme activity. The effect of the same concentration of compound of structure (I) (pre-incubated with H⁺-K⁺-ATPase preparation at pH 7.4 as described above) on the recovery of 100nmole of inorganic phosphate was also determined. Compounds of structure (I) were initially dissolved in dimethyl sulphoxide, polyethylene glycol (Type 400) or Pipes/Tris buffer. None of these solvents affects K⁺-ATPase activity at the concentrations used. All data refer to the concentration of compound present in the pre-incubation before dilution with assay buffer. (iii) Results The compounds of Examples 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 23, 24, 25 and 26 were all found to inhibit potassium stimulated ATPase activity in the above preparations at pH 6.1 and 7.4. B. Aminopyrine (AP) accumulation in intact gastric glands. The effect of a single concentration (100µm) of a compound of structure (I) on dibutyryl cAMP stimulated AP metabolism in rabbit intact gastric glands was determined. Preferred compounds of structure (I) were tested over a range of concentrations to determine the IC₅₀ value. (i) Preparation of intact gastric glands. Intact gastric glands were prepared from New Zealand white rabbits by the method of Berghindh et al. (Acta. Physio. Scand. 96, 150, 1976). Gastric mucosal scrapings were digested at 37°C for 45-60 min. with Collagenase (100 U, Type 1, Sigma), and glands harvested by coarse filtration and sedimentation. (ii) AP accumulation Test compound was incubated with glands and 300 µM dibutyryl cAMP for 30 minutes at 37°C. Incubating medium contained 132.5 mM NaCl, 5.4 mM KCl, 1.0 mM NaH₂PO₄, 5.0 mM Na₂HPO₄, 1.2 mM MgSO₄, 1.0 mM CaCl₂, 11.1 mM glucose, 2.0 mg/ml rabbit albumin, 10µg/ml phenol red, approximately 0.3 µM[¹⁴C] aminopyrine (110 mCi/mmole), pH 7.4. After incubation, glands were centrifuged and the supernatant removed. The glands were dried, weighed and dissolved in NaOH. The distribution of radioactivity between the supernatant and glands is then used to calculate the AP ratio after the method of Berglindh et al. (Acta. Physiol. Scand. 97 , 401, 1976). The IC₅₀ value is the amount of compound required to inhibit the histamine stimulated accumulation of aminopyrine by 50%. C. Rat : Lumen perfused stomach (histamine stimulated gastric acid secretion). Using a modification of the procedure described by Ghosh and Schild (Br. J. Pharmacology, 13 , 54, 1958), ED₅₀ values after either intraduodenal (i.d) or intravenous (i.v) administration were obtained as follows: No overt signs of toxicity were observed in any of the foregoing tests.

Claims: 1. A compound of structure (I) in which, R¹ to R⁴ are the same or different and are each hydrogen, halogen, trifluoromethyl, C1-6alkyl, C1-6alkoxy, C1-6alkanoyl or C1-6alkoxycarbonyl, RCF₂O, an ethoxy group substituted by 3 to 5 fluorine atoms, or R² and R³ together form a group -O(CR₂)mO-; R is hydrogen or fluorine; m is 1 or 2; n is 0 or 1; R⁵ and R⁶ are the same or different and are each hydrogen, C1-6alkyl or C3-6cycloalkyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form an azetidino, pyrrolidino, piperidino, piperazino, N-C1-4alkylpiperazino or morpholino- group; and one of R⁷ and R⁸ is halogen, and the other is hydrogen, halogen or C1-6alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1 in which R⁵ and R⁶ together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, piperazino, N-C1-4alkylpiperazino or morpholino group. 3. A compound as claimed in claim 1 or claim 2 in which n is 1. 4. A compound as claimed in claim 1 which is:- 2-(5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole, 2-(3-chloro-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-methyl-5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(5-bromo-4-pyrrolidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-chloro-4-pyrrolidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-pyrrolidino-2-pyridylmethylsulphinyl) -5-methoxy-(1H)-benzimidazole, 2-(3-chloro-4-morpholino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-chloro-5-methyl-4-morpholino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)- 5-(1,1,2,3-tetrafluoroethoxy)-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)-4,5 -difluoromethylenedioxy-(1H)-benzimidazole. 5. A pharmaceutical composition comprising a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier. 6. A pharmaceutical composition as claimed in claim 5, in which n is 1. 7. A pharmaceutical composition as claimed in claim 6, in a form suitable for oral administration. 8. A pharmaceutical composition as claimed in claim 7, provided with an enteric coating. 9. A compound as claimed in any one of claims 1 to 4 for use as a therapeutic agent. 10. A compound as claimed in any one of claims 1 to 4 for use in the treatment of gastro-intestinal diseases caused or exacerbated by gastric acidity. 11. A process for the preparation of a compound as claimed in claim 1, which comprises a) reacting a compound of structure (II) with a compound of structure (III) in which R¹ to R⁸ are as described for structure (I), one of L¹ and L² is SH and the other is a leaving group displaceable by a mercaptan; (b) reacting a compound of structure (IV) in which R¹ to R⁴ are as described for structure (I), with a compound of structure (V) in which R⁵ to R⁸ are as described for structure (I), X is CO₂H or CSX¹ and X¹ is halogen or C1-4alkoxy; (c) reacting a compound of structure (VI) in which R¹ to R⁴ are as described for structure (I), R⁹ is hydrogen or a protecting group and M is an alkali metal atom, with a compound of structure (VII) in which R⁵ to R⁸ are as described for structure (I), Z is a leaving group and p is 0 or 1; (d) reacting a compound of structure (VIII) in which R¹ to R⁴ are as described for structure (I), R⁹ is hydrogen or a protecting group and Y is a leaving group, with a compound of structure (IX) in which R⁵ to R⁸ are as described for structure (I), p is 0 or 1 and M' is the equivalent of a metal atom, and, optionally where desired, (i) oxidising a compound of structure (I) in which n is 0 so formed to a compound of structure (I) in which n is 1; (ii) reducing a compound of structure (I) so formed in which n is 1 to a compound of structure (I) in which n is 0; (iii) forming a pharmaceutically acceptable salt. 12. A compound of structure (III) in which R⁵ to R⁸ are as described for structure (I) and L² is SH or a leaving group displaceable by mercaptan. 13. A compound of structure (V) in which, R⁵ to R⁸ are as described for structure (I), and X is CO₂H or CSX¹ and X¹ is halogen or C1-4alkoxy. Claims for Contracting State: AT. 1. A process for the preparation of a compound of structure (I) in which, R¹ to R⁴ are the same or different and are each hydrogen, halogen, trifluoromethyl, C1-6alkyl, C1-6alkoxy, C1-6alkanoyl or C1-6alkoxycarbonyl, RCF₂O, an ethoxy group substituted by 3 to 5 fluorine atoms, or R² and R³ together form a group -O(CR₂)mO-; R is hydrogen or fluorine; m is 1 or 2; n is 0 or 1; R⁵ and R⁶ are the same or different and are each hydrogen, C1-6alkyl or C3-6cycloalkyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form an azetidino, pyrrolidino, piperidino, piperazino, N-C1-4alkylpiperazino or morpholino- group; and one of R⁷ and R⁸ is halogen, and the other is hydrogen, halogen or C1-6alkyl; or a pharmaceutically acceptable salt thereof, which comprises a) reacting a compound of structure (II) with a compound of structure (III) in which R¹ to R⁸ are as described for structure (I), one of L¹ and L² is SH and the other is a leaving group displaceable by a mercaptan; (b) reacting a compound of structure (IV) in which R¹ to R⁴ are as described for structure (I), with a compound of structure (V) in which R⁵ to R⁸ are as described for structure (I), X is CO₂H or CSX¹ and X¹ is halogen or C1-4alkoxy; (c) reacting a compound of structure (VI) in which R¹ to R⁴ are as described for structure (I), R⁹ is hydrogen or a protecting group and M is an alkali metal atom, with a compound of structure (VII) in which R⁵ to R⁸ are as described for structure (I), Z is a leaving group and p is 0 or 1; (d) reacting a compound of structure (VIII) in which R¹ to R⁴ are as described for structure (I), R⁹ is hydrogen or a protecting group and Y is a leaving group, with a compound of structure (IX) in which R⁵ to R⁸ are as described for structure (I), p is 0 or 1 and M' is the equivalent of a metal atom, and, optionally where desired, (i) oxidising a compound of structure (I) in which n is 0 so formed to a compound of structure (I) in which n is 1; (ii) reducing a compound of structure (I) so formed in which n is 1 to a compound of structure (I) in which n is O; (iii) forming a pharmaceutically acceptable salt. 2. A process a claimed in Claim 1 in which L¹ is SH and L² is a leaving group. 3. A process as claimed in Claim 2 in which L² is chlorine. 4. A process as claimed in any one of claims 1 to 3 when used to prepare a compound as claimed in claim 1 in which n is 1. 5. A process as claimed in any one of Claims 1 to 4 when used to prepare a compound of claim 1 in which R⁵ and R⁶ together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, piperazino, N-C1-4alkylpiperazino or morpholino- group. 6. A process as claimed in any one of claims 1 to 5 when used to prepare 2-(5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-chloro-4-piperidino-2-pyridylmethylsulphinyl)- 5-methoxy-(1H)-benzimidazole, 2-(3-methyl-5-bromo-4-piperidino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(5-bromo-4-pyrrolidino-2-pyridylmethylsulphinyl)-5-methoxy-(1H) -benzimidazole, 2-(3-chloro-4-pyrrolidino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-pyrrolidino-2-pyridylmethyl- sulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(3-chloro-4-morpholino-2-pyridylmethylsulphinyl)-5- methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-morpholino-2-pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)-5- (1,1,2,3-tetrafluoroethoxy)-(1H)-benzimidazole, 2-(3-chloro-5-methyl-4-piperidino-2-pyridylmethylsulphinyl)- 4,5-difluoromethylenedioxy-(1H)-benzimidazole, or a pharmaceutically acceptable salt thereof. 7. A process for preparing a pharmaceutical composition which comprises bringing into association a compound as claimed in claim 1 and a pharmaceutically acceptable carrier. 8. A process as claimed in Claim 7 in which n is 1. 9. A process as claimed in Claim 8 in which the composition is further provided with an enteric coating.

Inventors: IFE, ROBERT JOHN
Applicants: SMITH KLINE & FRENCH LABORATORIES LIMITED
Application year: 1985
Main classification: C07D401
IPC codes: C07D401, C07D213, C07D491