GB2194230A - Thiazolo-and thiazino-benzimidazoles - Google Patents

Abstract

Compounds of formula <IMAGE> [wherein R<1>, R<2>, R<3> and R<4> are defined substituents; R<5> is a substituted aryl or heteroaryl radical; m is 0 or 1; and -B-B<1>- represent a chain of formula -(CHR<6>)n-CHR<7>- (Ia) -CR<6>=CR<7>- (Ib) or -(CHR<6>)n-CR<7>= (Ic) (wherein n is 0 or 1; and R<6> & R<7> are hydrogen or alkyl)], and pharmaceutically acceptable salts thereof, are useful for the treatment of ulcers and hypersecretion.

Description

SPECIFICATION Thiazolo- and thiazino-benzimidazoles This invention relates to heterocyclic compounds, more particularly to thiazolo- and thiazinobenzimidazoles, to processes for their preparation and to pharmaceutical compositions containing them.

2,3-Dihydrothiazino-benzimidazoles having hypotensive activity are disclosed in Japanese Kokai 8118989 (Chemical Abstracts 95: 80996d). Krasovskii OM in Farm. Zh (Kiev) 1979, (4) 33036 disclosed naphth1',2':4,5]imidazo[2,1-bj-thiazoles in a study (no data) of compounds with antibacterial and antifungal activities.

Thiazolo[3,2-albenzimidazoles are described in the following Chemical Abstracts references: 72:43565s; 76:52165w; 81:151141v; 73:109740z; 71:22067v; 71:13065r; 76:153678w; 76:153679x and 92:41839y; but no pharmaceutical activity is ascribed to the compounds.

Thiazolo- and thiazino- benzimidazoles possessing antiulcer activity and/or antisecretory activity are are also disclosed in our GB Patent Publication No. 2141429.

In one aspect this invention provides a compound of formula

or a pharmaceutically acceptable salt thereof wherein -B-B'- represents a chain of formula -(CHR6)n-CHR7- la -CR6=CR7- Ib or -(CHR6)n-CR7= Ic;; R5 represents an aryl or heteroaryl radical carrying at least one substituent (R'O) selected from 1piperidinyl, 4-morpholinyl, 4-(C1-C6 alkyl)-piperazinyl, 1-pyrrolidinyl, OR8 (wherein R8 is C2-C6 alkenyi, C3-Cqo cycloalkyl, aryl, aralkyl or aryl or aralkyl in which the aryl portion carries 1 to 3 substituents selected from C,-C6 alkyl, halogen, nitro, C,-C6 haloalkyl, hydroxy or C,-C6 alkoxy) or SR9 wherein R9 is R8 as hereinbefore defined or C,-C6 alkyl;; R5 optionally carrying further substituents in one or more vacant ring positions selected from lower alkyl, lower alkoxy, halogen, alkanoyloxy of 2 to 7 carbon atoms, lower alkoxycarbonyl, halolower alkyl, hydroxy, cyano, amino, mono- or diloweralkyl amino, lower alkanoylamino, carboxy, carboxyloweralkyl, hydroxylower alkyl, carbamoyl, carbamoyloxy, lower alkyl- or arylcarbonyl, (loweralkoxy)- lower alkoxy, and phenyl optionally substituted by a substituent as hereinbefore defined excepting phenyl, R', R2, R3 and R4 each independently represent hydrogen or a substituent as mentioned above in connection with R5; R6 and R7 independently represent hydrogen or lower alkyl; n and m independently represent 0 or 1.

The group R5 is exemplified by (1) aryl radicals e.g. those having 6 to 10 carbon atoms such as phenyl or naphthyl which are substituted by at least one R'O group as listed above and (2) heteroaryl radicals especially those having 5 or 6 ring atoms and one or more heteroatoms selected from oxygen, nitrogen and sulphur, such as pyridyl (e.g. pyrid-2-yl, pyrid-3-yI), thienyl (e.g. thien-2-yl) furyl (e.g. fur-2-yl), thiazolyl e.g. thiazol-2-yl), or bicyclic groups of up to 10 ring atoms such as quinolyl, isoquinolyl or indolyl, which groups are also substituted by one or more R'O substituents as listed above.

The term "lower" as used herein to qualify a group means such a group contains 1 to 6 carbon atoms.

Examples of (a) any one of R'-4 when substituents and (b) optional substituents for R5 are:methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, chlorine, bromine, fluorine, acetoxy, propionyloxy, butyryloxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, trifluoromethyl, hydroxy, cyano, amino, methylamino, dimethylamino, ethylamino, acetylamino, carboxy, carboxymethyl, hydroxymethyl, hydroxyethyl, carbamoyl, carbamoyloxy, acetyl, benzoyl, phenyl, halophenyl, methoxymethoxy and methoxyethoxy.

When an R'O substituent is OR8 values for R8 include vinyl; 1-propenyl; 3-butenyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; cyclooctyl; cyclononyl; cyclodecyl; 2-methylcyclopropyl; 2,2-dimethylcyclopropyl; 2-methylcyclobutyl; 2-methylcyclopentyl, 2-methylcyclohexyl; phenyl; o- m-orp-tolyl; o-, m- or p-ethylphenyl; 2,3-, 3,4-, 3,5- or 2,5-dimethylphenyl; 2,3,5-, or 3,4,5-triethylphenyl; 2-,3- or 4-chlorophenyl; 2-,3- or 4-fluorophenyl; 2,3-. 3,4- or 2.4-dichlorophenyl; o,- m- or p- methoxyphenyl; 2,3-, 3,4-, or 2,4-dimethoxyphenyl; 2-chloro-3-methylphenyl; 2-chloro-4-methoxyphenyl; benzyl or 2-chlorobenzyl.

When an R'O substituent is SR9, values for R9 include those listed above for R8 and also methyl, ethyl, propyl, butyl, pentyl and isomeric forms thereof e.g. isopropyl, t-butyl.

In a preferred embodiment this invention provides compounds of formula

wherein -B-B'- and m are as hereinbefore defined, R'3 and R'4 are independently hydrogen, methyl, methoxy, chloro, fluoro, trifluoromethyl, hydroxy or hydroxymethyl, R'O represents SR9 wherein R9 is as defined above and R" and R12 are independently hydrogen, lower alkyl or lower alkoxy.

Preferred values for R'O are methylthio, ethylthio and propylthio. Preferred values for R" and R12 are methyl, ethyl, propyl and hydrogen.

Examples of acid addition salts are those formed from inorganic and organic acids, in particular pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, sulphonate (such as the methanesulphonate and p-toluenesulphonate) acetate, maleate, citrate, fumarate, tartrate, malonate and formate. The salts also include quaternary ammonium salts such as those formed from alkyl or aralkyl halides.

The compounds of formula I possess antiulcer and/or anti-secretory activity as measured by standard test procedures and accordingly are useful for the treatment of ulcers or hypersecretion in mammals.

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

Soc. Exp.Biol.Med., 124, 1221-3 (1967). The procedure used is as follows.

Male rats, weighing between 80 and 120 gms. were fasted overnight with water ad lib. The rats were then divided into groups of six and doses orally with the test drug in the form of a solution or with the vehicle alone, 0.5% carboxymethylcellulose, in a volume of 10ml/kg.

After 30 minutes the rats were inserted into aluminium restraining tubes measuring 1% inches in diameter by 5 inches and placed in the cold (4+ 1 C) for 3 hours. Immediately after cold exposure the rats were killed with intracranial alcohol and their stomachs excised and opened along the greater curvature. Each stomach was washed gently free of contents with warm tap water and pinned out on a board.The condition of the gastric mucosa was then scored from 0 to 6 on the followin-g scale: Ulcers 0-6 0 =No ulcers 1 Pin point haemorrhaqic site

2 l Several discrete pin point 3 J=haemorrhagic sites

5 =Large eroded sites with haemorrhage 6 J The maximum possible score for each animal was 6 and for the group 36. Decrease in ulcer formation is calcuiated as a percentage of the control score, i.e.

Mean Control group score Mean Test group scorex 100 Percentage Inhibition= Mean Control group score The statistical significance of the effect is assessed by Student's t-test. Experience has shown that +45% inhibition may be taken as a threshold value below which compounds can be regarded as inactive or not sufficiently active to be considered further.

Antisecretory activity is demonstrated by the test of H.Shay, D.Sun and H.Gruenstein, Gastroenterology. 1954, 26, 903-13 as exemplified by Beattie et al, J.Med. Chem. 20, 714 (1977).

Anti-secretory activity for compounds of formula I is demonstrated by their ability to inhibit the highly specific proton transporting enzyme H+/K+ ATPase.

Potential H+/K+ ATPase inhibitors are evaluated by a technique involving the measurement of aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine accumulates in acidsecreting cells; therefore, uptake of aminopyrine is increased by secretagogues and an inhibitor of acid secretion will reduce the response to one or more secretagogues depending upon its site of action. Compounds which reduce the response to dibutyryl cyclic adenosine monophosphate (DBcAMP) stimulation are assumed to have an intracellular site of action, and those which reduce the response to both DBcAMP and high potassium ion concentration (K+) are thought to have an intracellular site of action at the secretory surface of the parietal cell, involving the highly specific proton-transporting enzyme, H+/K+ ATPase.

The following test procedure is used: Rabbit gastric glands are isolated from gastric mucosa from the corpus region of the stomach by a method based on one described by Berglindh T., Obrink K.J., Acta Physiol. Scand. 96, 150-159 (1976). Measurement of aminopyrine uptake is carried out using a procedure based on the method described by Berglindh T., Hellander H.F., Obrink K.J. (ibid.97, 401-414, 1976).

Compounds are tested at a concentration of 10-4M, initially, and in some cases at lower concentrations, for their ability to inhibit t4C-aminopyrine uptake in gastric glands, stimulated by DBcAMP and high K+ respectively. Results are expressed as the % inhibition of the maximum response to the secretagogue induced by the test compound. An inhibitor of H+/K+ ATPase would be expected to reduce the response to both secretagogues.

This invention also provides processes for preparing the novel compounds of formula I. In general the compounds may be prepared by processes which are known or are analogous to known processes-see literature references hereinbefore disclosed.

A first process for preparing compounds of formula I comprises cyclising a compound of formula

whereinin -B-B'-, n, m, R', R2, R3, R4, R, R6 and R7 are as defined above, and X is OH or a leaving group such as halogen or an aryl-, alkyl- or aralkyl-sulphonyloxy group thqt couples B to nitrogen, providing that (i) when -B-B'- has formula la and n is O or 1, or formula Ic and n is 1 then X is not OH; and (ii) when -B-B'- has formula Ib or IC and n is 0 then X is OH.

This cyclisation is conveniently carried out in a suitable solvent if desired under basic conditions (e.g triethylamine, potassium carbonate) and with heating if required. When X is enolic OH the cyclisation may be carried out in acidic solvent such as acetic anhydride.

Compounds of formula II can in general be prepared by reacting an appropriate 2-chlorobenzimidazole with a compound of formula

wherein R5, -B-B1- and X are as hereinbefore defined and if desired oxidising the product, e.g.

using a peroxyorganic acid such as peroxybenzoic acids.

Compounds of formula II as hereinbefore defined wherein X is OH, -B-Ba- has the formula Ic wherein n is O (enol form of ketone) or formula Ib may be prepared by reacting the appropriate 2-mercaptobenzimidazole with a haloketone or aldehyde of formula Illa or Illb.

wherein R5, R6 and R7 are as defined above and hal is a halogen. Using this reaction it is possible to go directly to the corresponding compounds of formula I without isolating the intermediates of formula II.

In a preferred process for preparing the compounds of formula I wherein -B-B'- has formula la the compounds of formula II wherein m is 0 are prepared and cyclised without isolation is a single step process by reacting an appropriate 2-mercaptobenzimidazole of formula

wherein R1, R2, R3 and R4 are as defined above with a compound of formula

wherein R5 R6 R7 and n are as hereinbefore defined, the X groups being the same or different halogens. This reaction is conveniently carried out by heating in a suitable solvent, e.g. dimethylformamide, if desired in the presence of base. When n is 0, and X is bromine then it is possible to isolate from such a reaction a corresponding compound of formula I wherein -B-B'- is -(CHR6)n-CR7 wherein n is 0.

It should be noted that due to tautomerism certain ring substituted 2-mercaptobenzimidazole starting materials are mixtures and hence mixtures of final products are obtained. For example 2mercapto-5-methylbenzimidazole is tautomeric with 2-mercapto-6-methylbenzimidazole and the final product will be a mixture of compounds where R2 or R3 is methyl.

A further process for preparing the compounds of formula I wherein m is 0 comprises cyclising a compound of formula

wherein -B-B', n, R', R2, R3, R4, R5, R6 and R7 are as hereinbefore defined and one of A and B2 is -SH, the other is a leaving group providing that when A is SH then B2 may also represent OH.

When A or B2 is a leaving group the cyclisation is generally carried out by heating if desired in the presence of base, e.g. triethylamine, K2CO3, NaOH, etc. When B2 is OH the cyclisation may be carried out in the presence of a strong acid, e.g. HCI or polyphosphoric acid.

Compounds of formula VI wherein A is SH and B2 is OH may be prepared by (a) reacting an appropriate 2-chlorobenzimidazole with a compound of formula

wherein -B-B'-, X, R5, R6 and R7 are as hereinbefore defined to give a compound of formula VIII

wherein -B-B1-, R', R2, R3, R4, Re, R6 and R7 are as hereinbeforn defined and (b) reacting the compound of formula VIII with thiourea and to give a 2-isothiouronium compound and treating this with an alkali metal hydroxide or ammonium hydroxide under mild conditions, e.g. reacting at room temperature or without heating.

Compounds of formula VIII wherein -B-B'- is -(CHRs)n-CR7=may be reacted in step (b) above under more vigorous conditions, e.g. reflux in a solvent such as a solvent with a boiling point above 50"C, to give a corresponding compound of formula I directly.

Compounds of formula VI wherein A is SH and B2 is a leaving group and -B-B'- has formula la or Ib may be prepared from the corresponding compounds of formula VI wherein B2 is OH by known methods e.g. halogenation, sulphonylation to convert OH to a leaving group.

Compounds of formula VI wherein A is a leaving group such as halogen and B2 is SH may be prepared by building up the molecule from appropriate starting materials wherein the -SH is protected by a thiol protecting group and removing the protecting group as the final step.

Compounds of formula I wherein m is 0, -B-B'- has formula la and either n is 1 and R6 is hydrogen or n is 0 and R7 is hydrogen may also be prepared by a process which comprises reducing a compound of formula

wherein R', R2, R3, R4 and R7 are as hereinbefore defined and p is O or 1.

This reduction may be carried out using a metal hydride, e.g. lithium aluminium hydride.

The compounds of formula IX may be prepared by cyclising a corresponding compound of formula X

wherein p, R', R2, R3, R4 and R7 are as defined above.

Compounds of formula X may be prepared by reacting the appropriate 2-mercaptobenzimidazole with a haloacid of formula R5CHBR(CHR7)pCOOH (R5, R7 and p as defined herein) and converting the acid to the acid chloride.

In yet a further process the compounds of formula I wherein m is 0 may be prepared by reacting a compound of formula

wherein -B-B'-, hal, n,R', R2, R3, R4, Re, R6 and R7 are as hereinbefore defined with (i) an alkali metal sulphide or hydrosulphide, (ii) ammonium sulphide or polysulphide or (iii) H2S in the presence of a tertiary amine.

Compounds of formula I as hereinbefore defined wherein -B-B' is -CR6=CR7 or -(CHRs)n-CR7=may be prepared by reacting a compound of formula XII or XIII

in which formulae one of D and E is hydroxy or a leaving group such as hereinbefore defined, the other of D and E being hydrogen, to remove the elements of DE, e.g. dehydrohalogenation, dehydration, etc.

Yet a further process for preparing compounds of formula I wherein -B-B'- is -(CHR6)n-CR7= comprises cyclizing a compound of formula

wherein R', R2, R3, R4, Re, R6, R7 and n are as hereinbefore defined. The cyclisation may be conveniently carried out under condensation conditions such as treatment with mixed base/acid systems, e.g. sodium formate/formic acetic anhydride or sodium acetate/acetic anhydride, or by treatment with base followed by subsequent dehydration under acid conditions.

Compounds of formula I wherein m is 0 and 1 may be interconverted. For example when m is 0 the compounds may be oxidised to the corresponding oxides of formula I wherein m is 1 by treatment with suitable oxidising agents e.g. hydrogen peroxide, sodium periodate, peroxy acids such as peroxybenzoic acids and peroxyalkanoic acids. When m is 1 the compound of formula I may be reduced to the corresponding compound where m is 0 using a reducing agent such as a metal or boron hydride, e.g. BHCl2. Compounds of formula I in which -B-B'- does not contain a double bond may be oxidised to compounds of formula I in which a double bond is present and vice versa by reduction. Accordingly compounds of formula I are intermediates for other compounds of formula I.

The compounds of formula I possess one or more asymmetric centres and hence optical isomers and mixtures thereof are possible. All such isomers and mixtures thereof are included within the scope of this invention. Where any reaction process produces mixtures of such isomers standard resolution techniques may be applied to separate a specific isomer.

In any of the aforementioned reactions compounds of formula I may be isolated in free base form or as acid addition salts as desired. Quaternary ammonium salts may be prepared by reaction with an appropriate halide.

This invention also provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a composition, the carrier may be a solid, liquid or 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, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be 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 dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. Other 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 subdivided 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 adminsitered 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 carbo nate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Specification No. 1,284,394.

In another aspect the invention provides as an anti-ulcer agent a compound of formula I or a pharmaceutically acceptable salt thereof as defined above.

The following Examples illustrate the invention: Example I 2-(4-Ethylthio-3-methylpyrid-2-yl) -2, 3-dihydrorhiazolo[3,2-a]benzimidazole (a) 2-Chlorobenzimidazole is reacted with 2-bromoacetyl-4-ethylthio-3-methylpyridine in the presence of K2CO3 to give 2-chloro- 1 -[2-[4-ethylthio-3-methylpyridyl])-2-oxoethyl]benzimidazole. This is reacted with thiourea and treated with NH40H to give 2-mercapto-1-(2-(2-(4-ethylthio-3-methylpyridyl))-2-oxoethyl)benzimidazole. Reduction of this product using NaBH4 gives 1-[2-hydroxy-2-(4ethylthio-3-methylpyrid-2-yl)ethyl]-2-mercaptobenzimidazole.

(b) 1 -[2-Hydroxy-2-(4-ethylthio-3-methylpyrid-2-yl)ethyl]-2-mercaptobenzimidazole (0.01 mole) is dissolved in polyphosphoric acid (10g) and the mixture heated at 100"C for 2 hours with stirring.

The mixture is then neutralised with sodium hydroxide solution and the product extracted with chloroform. Purification by column chromatography on silica gives the title compound.

Example 2 2-(4-Ethylthio-3-methylpyrid-2-yl)-2, 3-dThydrothiazolo[3,2-a]benzimidazole- 1-oxide A solution of 2-(4-ethylthio-3-methylpyrid-2-yl)-2,3-dihydrothiazolo[3 ,2-a]benzimidazole (0.01 mole) is dissolved in CH2CI2 solution (100 ml) at 0 C and treated with m-chloroperoxybenzoic acid (0.01 mole) for 0.5 hours. The solution is then washed with sodium carbonate solution and dried (MgS04). Purification by chromatography on silica gives the title compound.

Example 3 In a manner analogous to Example 1 the following compounds of formula (Ib) are prepared according to the reaction scheme:

Ra Rb Rc Rd Ra H H MeO SEt H H H Me SMe H H H Me SnPr H OMe H Me SEt H H OMe Me Set H H H Et OPh H H H H OCH2Ph H H H Et 4-morpholinyl H H H Et 1-piperidinyl H CF3 H Me SEt H H H Me SEt Me H H H SPh Me H H Me SCH=CH2 H H H Me SCH=CHCH3 H H H Me SC6H12 H H H H HSEt OMe which compounds are converted to the sulphoxides in a procedure analogous to Example 2.

Example 4 2- (4-Ethylthio-3-methylpyrid-2-yl) thiazolo[3, 2-a]benzimidazole A solution of 2-mercapto- 1 -(2-(2-(4-ethylthio-3-methylpyridyl))2-oxoethyl)benzimidazole in polyphosphoric acid is heated at 140"C for 1 hour. The solution is neutralised with Na2CO3 solution and extracted into EtoAc. The extracts are dried and evaporated and the residue purified by chromatography on silica to give the title compound.

Claims (12)

1. A compound of formula

or a pharmaceutically acceptable salt thereof wherein -B-B1- represents a chain of formula: -(CHR5)n-CHR7- la -CR6=CR7- Ib or -(CHR6)n-CR7= Ic; Re represents an aryl or heteroaryl radical carrying at least one substituent selected from 1 - piperidinyl 4-morpholinyl, 4-(CI-C6alkyl)-piperazinyl,1-pyrrolidinyl, OR8 (wherein R9 is C2-C6 alkenyl, C3-CIO cycloalkyl,aryl, aralkyl or aryl or aralkyl in which the aryl portion carries 1 to 3 substituents selected from C1-C6 alkyl, halogen, nitro, C1-C6 haloalkyl, hydroxy or C1-C6 alkoxy) or SR9 wherein R9 is R6 as hereinbefore defined or C1-C6 alkyl; R6 optionally carrying further substituents in one or more vacant ring positions selected from lower alkyl, lower alkoxy, halogen, alkanoyloxy of 2 to 7 carbon atoms, lower alkoxy-carbonyl, halolower alkyl, hydroxy, cyano, amino, mono- or diloweralkyl amino, lower alkanoylamino, carboxy, carboxyloweralkyl, hydroxylower alkyl,carbamoyl, carbamoyloxy, lower alkyl- or arylcarbonyl, (loweralkoxy)-lower alkoxy and phenyl optionally substituted by a substituent as hereinbefore defined excepting phenyl, R', R2, R3 and R4 each independently represent hydrogen or a substituent as mentioned above in connection with R5; R6 and R7 independently represent hydrogen or lower alkyl; n and m independently represent 0 or 1.

2. A compound as claimed in Claim 1 wherein -B-B1- has the formula la or Ic and n is 0.

3. A compound as claimed in Claim 1 or Claim 2 wherein R represents a phenyl, naphthyl, pyridyl, thienyl, furyl, thiazolyl, quinolyl, isoquinolyl or indolyl group substituted as defined in Claim 1.

4. A compound as claimed in Claim 1 or Claim 2 wherein R represents phenyl, pyrid-2-yl or pyrid-3-yl each substituted as defined in Claim 1.

5. A compound as claimed in any one of Claims 1 to 4 wherein the substituent R10 is OR8 or SR9 where R9 and R9 are each selected from: vinyl; 1-propenyl; 3-butenyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl;cyclooctyl; cyclononyl; cyclodecyl;2-methylcyclopropyl; 2,2-dimethylcyclopropyl; 2-methylcyclobutyl; 2methylcyclopentyl,2-methylcyclohexyl; phenyl; o-, m-orp-tolyl; o-,m- or p-ethylphenyl; 2,3-,3,4 ,3,5- or 2,5-dimethylphenyl; 2,3,5-, or 3,4,5-triethylphenyl; 2-,3- or 4-chlorophenyl; 2-,3- or 4fluorophenyl; 2,3-, 3,4- or 2,4-dichlorophenyl; o-, m- or p- methoxyphenyl; 2,3-, 3,4-, or 2,4dimethoxyphenyl; 2-chloro-3-methyl-phenyl; 2-chloro-4-methoxyphenyl; benzyl or 2-chlorobenzyl; or R9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl.

6. A compound as claimed in any one of Claims 1 to 5 wherein R2 and R3 are selected from hydrogen, lower alkyl, alkoxycarbonyl of 2 to 7 carbon atoms, halogen lower alkoxy, hydroxylower alkyl or trifluoromethyl.

7. A compound of formula

wherein -B-B1- and m are as defined in Claim 1, R'3 and R14 are independently hydrogen, methyl, methoxy, chloro, fluoro, trifluoromethyl, hydroxy or hydroxymethyl, R'O represents SR9 wherein R9 is as defined in Claim 1 or Claim 5 and R11 and R12 are independently hydrogen, lower alkyl or lower alkoxy.

8. A compound as claimed in Claim 7 wherein R10 is methylthio, ethylthio, propylthio,methyl, ethyl, propyl and hydrogen.

9. A compound as claimed in any one of Claims 1 to 8 when in the form of a salt of an acid selected from hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric, methanesulphonic, p-toluenesulphonic, acetic, maleic, citric, fumaric, tartaric, malonic and formic.

10. A process for preparing a compound of formula I as claimed in Claim 1 characterised in that (a) a compound of formula II

wherein -B-B1-, n, m, R, R', R2, R3, R4 and Re are as defined in Claim 1 and X is OH or a leaving group, providing that (i) when -B-Ba- has formula la and n is O or 1, of formula Ic and n is 1 then X is not OH; and (ii) when -B-B1- has formula Ib then X is OH; is cyclised; or (b) a compound of formula (IV)

is reacted with a compound of formula (V)

in which formulae R, Ra, R2, R3, R4, R, R6, R7 and n are as defined in Claim 1, the X groups being the same or different halogens, to give a compound of formula I wherein -B-B1- has formula la and additionally when X is bromine and n is O in the compound of formula V to give a compound of formula I wheren -B-Bt- has formula Ic wherein n is O or (c) a compound of formula

wherein -B-B1-, n, R, R1, R2, R3, R4, R5, R6 and R7 are as defined in Claim 1 and one of A and B2 is -SH, the other is a leaving group providing that when A is SH then B2 may also represent OH, is cyclised to give a compound of formula I wherein m is O;; (d) a compound of formula VIII

wherein -B-B1-, Rr, R2, R3, R4 and Re are as defined in Claim 1 is reacted with thiourea followed by heating in the presence of an alkali metal hydroxide or NH4OH to give a compound of formula I wherein -B-B1 has formula Ic; (e) a compound of formula

wherein R, R', R2, R3, R4, Rye and R7 are as defined in Claim 1 and p is O or 1 is reduced to give a compound of formula I wherein m is 0, -B-B'-has formula la and either n is 1 and Rs is hydrogen or n is 0 and R7 is hydrogen; or (f) a compound of formula

wherein -B-B'-, hal, n, R, R1, R2, R3, R4 and Re are as defined in Claim 1, is reacted with (i) an alkai metal sulphide or hydrosulphide (ii) ammonium sulphide or polysulphide or (iii) H2S in the presence of a tertiary amine; to give a compound of formula I wherein m is O; or (g) a compound of formula XII or Xlil

in which formulae, R, R', R2, R3, R4, Re, R6, R7 and m are as defined in Claim I and one of D and E is hydroxy or a leaving group, the other of D and E being hydrogen, is reacted to remove the elements of DE, to give a compound of formula I wherein -B-B'- has formula Ib or Ic; or (h) a compound of formula

wherein R, R', R2, R3, R4, R5, R6, R7, m and n are as herein defined in Claim 1, is cyclised to give a compound of formula I wherein -B-B' has formula Ic; or (i) a compound of formula I wherein m is O is oxidised to the corresponding oxide of formula I wherein m is 1 or the compound of formula I wherein m is 1 is reduced to give a compound of formula I where m is 0, or (j) a compound of formula I in which -B-B'- does not contain a double bond is oxidised to a compound of formula I in which a double bond is present or vice versa by reduction; or (k) a compound of formula I in free base form is converted to an acid addition or quaternary ammonium salt or an acid addition salt is neutralized to give the free base form.

11. A compound of formula I as claimed in Claim 1 whenever prepared by a process as claimed in Claim 10.

12. A pharmaceutical composition comprising a compound of formula I as claimed in any one of Claims 1 to 9 and a pharmaceutically acceptable carrier.