GB2172285A - Dibenzoimidazothiazepines - Google Patents

Description

1 GB2172285A 1

SPECIFICATION

Dibenzoimidazothiazepines This invention relates to heterocyclic compounds, more particularly to dibenzoimidazothiazepines, 5 to processes for preparing them and to pharmaceutical compositions containing them.

In UK Patent Publication No. 2141429 there are described a series of tricyclic thiazolo- and thiazinobenzimidazoles possessing pharmaceutical activity, in particular antiulcer and antisecretory activity. The thiazolo and thiazino-benzimidazoles are useful as antiulcer agents or for the treat ment of gastric hypersecretion and particularly for the treatment of peptic ulcer disease.

We have now found a novel series of tetracyclic dibenz[d,h]imidazo thiazepines possessing pharmaceutical activity in particular antisecretory activity and hence are also useful for the treatment of gastric hypersecretion and as antiulcer agents especially in the treatment of peptic ulcers.

Accordingly this invention provides compounds of formula:

R (0) m. R R 2 N S R 6 R 3 N 7 R 4 R 8 I or a pharmaceutically acceptable salt thereof wherein R', R2, R3, R4 independently represent 25 hydrogen or a substituent selected from lower alkyl, lower alkoxy, halogen, alkanoyl of 2 to 7 carbon atoms, lower alkoxycarbonyl, halolower alky], hydroxy, cyano, amino, mono- or diloweral kyl amino, C2-C7 alkanoylamino, carboxy, carboxylower alky], hydroxyloweralkyl, carbamoyl, car bamoyloxy, lower alkyl- or aryl-carbony], (lower alkoxy)-1ower alkoxy, phenyl or a phenyl group itself optionally substituted by a substituent as hereinbefore defined excepting phenyl, or an 30 adjacent pair of R 1-4 together with the carbon atoms to which they are attached complete a six membered unsaturated carbocyclic or nitrogen containing heterocyclic ring, optionally substituted by one or more of the substituents listed above for R,, m represents 0 or 1; and R5, R6, R' and R' independently represent hydrogen or a substituent selected from lower alkyl, lower alkoxy, halogen, alkanoyloxy of 2 to 7 carbon atoms, lower alkoxycarbonyl and hydroxy.

The term---lower-as used herein to qualify a group means such a group contains 1 to 6 carbon atoms. Examples of any one of R 1 4 when substituents are methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, chlorine, bromine, fluorine, acetoxy, propionyloxy, butryloxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, trifluoromethyl, hy droxy, cyano, amino, methylamino, dimethylamino, ethylamino, acetylamino, carboxy, carboxyme- 40 thy], hydroxymethyl, hydroxyethyl, carbamoy], carbamoyloxy, acetyl, benzoyl or phenyl.

When any adjacent pair of R', R2, R3 and R 4 complete a fused ring examples of the additional rings are benzo- and pyrido-fused rings. For example when R2 and R3 form a benzo fused ring the compound of formula 1 has the general formula R' (0 R 5 6 C. _11 C N R 7 R 4 R 8 Examples of any one of R5-8 when substituted are methyl, ethyl, propyl, fluorine, methoxy, ethoxy, chlorine, bromine, acetoxy, propionyloxy, methoxycarbonyl, ethoxycarbonyl and hydroxy. 55 Preferred compounds of this invention are: 8,13-Dihydrodibenzo[d, hlimidazo[2,1-b][1,3]thiazep- ine, 8,13-dihydro-4,5-dimethyidibenzo[d,hlimidazo[2,1-bl[1,3]thiazepine.

8,13-dihydro-4-methoxydibenzo[d,hlimidazo[2,1-bl[1,3]thiazepine and 8,13-dihydro-5-methoxydibenzo[d,hlimidazo[2, 1 -bl[ 1,3]thiazepine.

Examples of acid addition salts of the compounds of the invention 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.

2 GB2172285A 2 Compounds of formula 1 were tested for anti-secretory activity by their ability to inhibit the effect of one or two secretagogues on, isolated gastric glands.

Potential inhibitors of the highly specific proton transporting enzyme W/K+ ATPase were evaluated by'a technique involving the measurement of aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine accumulates in acid-secreting 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 side 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 10 action at the secretory surface of the parietal cell, involving the highly specific proton transporting enzyme, HI/K, ATPase.

The following procedure is used:

Rabbit glands are isolated from gastric mucosa from the corpus region of the stomach by a method based on one described by Berglindh T_ Obrink KA, Acta Physiol. Scand. 96, 150-159 15 (1976). Measurement of aminopyrine uptake is carried out using a procedure based on the method described by Berlindh T_ Hellander H.F., Obrink KA (ibid. 97 401- 414, 1976).

Compounds are tested at a concentration of 10 4M, for their ability to inhibit C-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 com- 20 pound.

In the above test the following representative compounds of formula 1 gave the results shown:

Compound 8,13-Dihydrodibenzo[d,hl imidazo[2,1-bl [1,31 thiazepine 8,13-Dihydro-4,5-dimethyl dibenzo[d,hlimidazo[2,1-bl [1,31thiazepine A 60:40 mixture of 8,13-Dihydro-4-methoxydibenzo[d,hlimidazo[2,1-bl[1, 3]thiazepine % Inhibition stimulation by: 25 to D13cAMP K+ 32% at 10-4 m 94% at 10- 4 m ns at. 10 -4 m 80% at 10- 4 m ns at 10-6M 108% at 10-4M 8,13-Dihydro-5-methoxydibenzo45 [d,h]imidazo[2,1-b][,1,3]thiazepine 8,13-Dihydrodi.beifzold,hlimidazo- 3.1%alt 10-4 m [2,1-b-1[1,3]thiazepinel.-oxide ns = not significant ns at 10-4 m This invention also provides processes for preparing the compounds of formula 1. A first process for preparing the compounds of formula 1 comprises cyclising a compound of formula R 1 (0) m R 5 R 2 N r S op, 16 R 3 CH.-, R 7 R 4 X,., 2 R 8 (11) 3 GB2172285A 3 wherein R1-8 and m are as defined above and X represents OH or a leaving group such as halogen or an organic sulphonyloxy group such as alkyi-, aryl- or aralkyl- sulphonyloxy group (e.g. tosyloxy, mesyloxy). The cyclisation is conveniently carried out in an inert solvent if desired under basic conditions (e.g. triethylamine, potassium carbonate) with heating if required. When X 5 is OH the cyclisation may be carried out in acidic solvent such as acetic anhydride.

Compounds of formula 11 may be prepared by reacting an appropriate 2chlorobenzimidazole with a compound of formula R 5 6 HS-CH2 - 1 7 X-CH2- R R 8 III wherein X and R5-11 are as hereinbefore defined and if desired oxidising the product e.g. using a peroxyorganic acid such Ss a peroxybenzoic acid.

Compounds of formula 11 wherein m=0 may also be prepared by coupling an alkali metal salt of 2-mereaptobenzimidazole, e.g. the sodium salt with a compound of formula 15, hal-CH 2, 6 1 X-CH 2 - Z1 7 1 R 5 IV where X and R5-11 are as hereinbefore defined and hal is a halogen such as chlorine.

A second process for preparing compounds of formula 1 wherein m is 0 comprises cyclising a 30 compound of formula R 1 R 5 R 2 N A B- R 6 7 R 3 4 N R R 8 (V) wherein R"' are as hereinbefore defined and one of A and B is -SH, the other is a leaving group such as radicals mentioned above providing that when A is -SH then B may also represent OH. When either of A and B is a leaving group the cyclisation is conveniently carried out by heating if desired in the presence of base (e.g. triethylamine, potassium carbonate etc.). When B is OH the cyclisation may be carried out in the presence of a strong acid e.g. HCl or 45 polyphosphoric acid.

Compounds of formula V where B is OH and A is SH may be prepared by reacting an appropriate 2-chlorobenzimidazoie with a compound of formula HO-CH 2 R R 6 X'-CH 2 7 R VI to give a compound of formula R R 2 c R 6 1 HOCH 2 R 3 R VII 4 R 5 R R in which formulae R", are as hereinbefore defined and X' is a leaving group, e.g. halogen and 65 4 GB2172285A 4 then reacting the compound of formula VII with thiourea to give a 2isothiouronium compound.

The product is treated with an alkali metal hydroxide or ammonium hydroxide under mild conditions, e.g. without heating.

Compounds of formula V wherein A is SH and B is a leaving group may be prepared from the corresponding compounds of formula VI wherein B is OH by known methods e. g. halogenation, 5 sulphonylation to convert OH to a leaving group.

Compounds of formula V wherein A is a leaving group such as halogen and B 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 may also be prepared by a process which comprises 10 reducing a compound of formula R 2 R R - R 6 R 3: - 2 -'C -R 7 R 4 11 R 8 Viii wherein W-% are as hereinbefore defined.

This reduction may be carried out using a metal hydride, e.g. lithium aluminium hydride. The compounds of formula Vill may be prepared by cyclising a corresponding compound of formula lX 1 R 2 R R 5 6 c 1 5:P1 1,.R R 3 NH z 7 1 cl R 4 8 R 1X wherein R' 11 are as defined above.

Compounds of formula IX may be prepared by reacting the appropriate 2mercaptobenzimida- 35 zole with a halo-acid of formula R 5 BrCH R 6 HOOC,:C R7 R 8, (R5 11 as defined herein) and converting the acid to the acid chloride.

In yet a further process the compounds of formula 1 wherein m is 0 may be prepared by reacting a compound of formula R 1 hal R 5 50 R 2: N R 6 R 3 R 7 R 4 8 wherein hal and W-8 are as hereinbefore defined with (i) an alkali metal sulphide or hydrosulphide, 60 (ii) ammonium sulphide or polysulphide or (iii) H,S in the presence of a tertiary amine.

In a preferred process for preparing the compounds of formula 1 the compounds of formula 11 wherein m is 0 are prepared and cyclised without isolation in a single step process by reacting an appropriate 2mercaptobenzimidazole of formula GB 2 172 285A 5 R R 2 N VE -NH R R wherein R', R2, R3 and R 4 are as defined above with a compound of formula R 5 X 1 CH 6 X 1 CH 2 7 R wherein R5-8 are as hereinbefore defined, the X' groups being the same or different halogens. 20 This reaction is conveniently carried out by heating in a suitable solvent, e.g. dimethylformamide, if desired in the presence of base.

It should be noted that due to tautomerism certain ring substituted 2mercaptobenzimidazole starting materials are mixtures and hence mixtures of final products are obtained. For example 2mercapto-5-methylbenzimidazole is tautomeric with 2-mercapto-6methyibenzimidazole and the 25 final product will be a mixture of compounds where R2 or R3 is methyl.

Compounds of formula 1 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 1 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 1 30 may be reduced to the corresponding compound where m is 0 using a reducing agent such as a metal or boron hydride, e.g. BI-IC'2. Accordingly compounds of formula 1 are intermediates for other compounds of formula 1.

The compounds of formula 1 which are sulphoxides possess an asymmetric centre 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 1 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.

The invention further provides a compound of formula (1) or a pharmaceutically acceptable acid addition salt for use as a pharmaceutical.

The invention also provides a pharmaceutical composition comprising a compound of general formula (1) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient.

Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxyimethyl cellulose, polyvinyl pyrrol idine, low melting waxes and ion exchange resins.

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 60 other carriers is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a 65 6 GB2172285A 6 mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweet eners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral adminis tration include water (particularly containing additives as above e.g. cellulose derivatives, prefera- 5 bly sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhy dric alcohols e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compo sitions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. 15 In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orally in either liquid or solid composition form. These compositions may include one or more antacid ingredients, e.g. alumi- 25 nium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbo nate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Specifica tion 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.

Based on the isolated tissues experiments detailed hereinabove the dosage range for the treatment of humans using a compound of formula I will be in the range from about 5mg to about 1000mg per day depending on the activity of the compound and the degree of inhibition desired.

The following Examples illustrate the invention:

EXAMPLE 1

8, 13-Dihydrodibenzo[dhlimidazo[2, 1-bl[1,3]thiazepine a,(x'-Dibromo-o-xylene (39.39) was added to 2-mercaptobenzimidazole (25g) in dimethylfor mamide (200 m]) and the mixture was stirred at ambient temperature for 18 hours and was then 4G heated at 100'C for 5 hours. The product was removed by filtration and was recrystallised from methanol/ethyl acetate four times to give the title compound as the hydrobromide 1 hydrate 4 salt, (1.39) mp 265.5-7'C. decomp.

Analysis Found: C. 53.6; H, 3.85; N, 8.4; C,,H,^S.H13r.1H,0 requires C, 53.3; H, 3.9; N, 8.3%.

4 EXAMPLE 2

8, 13-Dihydro-4,5-dimethyldibenzo[dh]imidazo[2, 1-b][1,3fthiazepine 5,6-Dimethyl-2-mercaptobenzimidazole (1.7g) was added to a,a'-dibromo-oxylene (2.7g) in 50 ethanol (100 ml) and the mixture was heated at reflux for 6 hours.

The solvent was removed under reduced pressure and the residue washed with 2N HCI. The solid obtained was suspended in saturated sodium carbonate solution and was removed by filtration. The residue was suspended in chloroform and filtered. The organic layer was dried (MgSOJ and evaporated. The residue was recrystallised twice from ethanol to give the title compound 0.46g, mp. 228-230'C. Analysis Found: C, 72.6; H, 5.8; N, 9.7; C,7H,6N,S requires: C, 72.8; H, 5.75; N, 10.0%.

EXAMPLE 3 8, 13-Dihydro-4-methoxydibenzo[dhlimidazo[2, 1-bl[1, 3]thiazepine and 8, 13-Dihydro-5-methoxydibenzo[d,hlimidazo[2, 1-bl[1, 3]thiazepine 5-Methoxy-2-mercaptobenzimidazole (3.69) was added to a,a-dibromo-o- xylene (5.39). in etha- nol (100 mi) and the mixture was heated at reflux 4 hours.

7 GB2172285A 7 The reaction mixture was allowed to cool and was filtered. The filtrates were evaporated under reduced pressure and the residue was purified by chromatography on alumina using dichloromethane as eluent. The solvent was removed under reduced pressure and the residue was crystallised using ether. The product was isolated by filtration to give a 60:40 mixture respectively of the title 4- and 5- methoxy compounds, 0.3g mp. 144-146'C. Analysis Found: C, 68.0; H, 5.0; N, 9.6; C,J-1,1\120S requires: C, 68.0; H,5.0; N, 9.95%.

EXAMPLE 4 4,5-Dichloro-8, 13-clihydrodibenzo[dhlimidazo[2, 1-bl[1, 3]thiazepine 4,5-Dichloro-2-mercaptobenzimidazole (29) was added to a, a'-dibromo-o- xylene (2.7g) in ethanol (100 mi) and was heated at reflux for 6 hours. The solvent was removed under reduced pressure and the residue was suspended in 2N HCL The aqueous mixture was filtered and the material obtained was washed with water, saturated Na2C03 solution and then again with water.15 The product was dried under vacuum and was recrystallised from ethanol to give the title compound (1.2g) mp 243.5-245'C. Analysis Found: C, 56.2; H, 3.0; N, 8.6; Cl,H1OC12N2S requires C, 56.1; H, 3.1; N, 8.7%.

EXAMPLE 5

8, 13-Dihydrodibenz[dhlimidazo[2, 1-bl[1,3]thiazepine- 1-oxide 8,13-Dihydrodibenzo[d,hlimidazo[2,1-bl[1,3]thiazepine, free base, (1.89) was dissolved in ethyl acetate and cooled to -30'C. m-Chloroperoxybenzoic acid (1.29) was added as a solid and the 25 mixture allowed to warm over 1 hour to - WC when a saturated solution of sodium carbonate (5 mi) was added. The mixture was filtered and dried (M9SOJ and the solvent removed to give a white solid, this was extracted with ethyl acetate (15 mi). The ethyl acetate soluble material was purified by chromatography on Fluorisil using ethyl acetate as eluent to give the title compound as the 1 hydrate, (350 mg), mp. 210.5-212'C decomp.

4 Analysis Found: C, 65.7; H, 4.4; N, 9.9; C,H,N20S. 1. H,0 requires C, 66.0; H, 4.6; N, 10.3%.

4 EXAMPLE 6-17

Using a procedure analogous to Example 1 the following compounds of formula 1 may be prepared according to the reaction scheme R 1 R 2 1 N Y SH + R 3 NH 4 R R 5 BrCH 2 R 6 BrCH 2 R 7 R R 5 R 2 NY S R 3 N 7 4 R 8 R wherein 8 GB2172285A 8 R R 2 R 3 R 4 R 5 R 6 R 7 R 8 H H H H H H cl H 5 H H H H H cl H H H Me me H H H me H H Me me H H Me H H 10 H H H H H H Meo H H H H H H Meo H H H H H H H H CH 3 CO- H 15 H H H H H CH 3 CO- H H H H H H H CH30C0 H H H H H H H H CH 3 OCO- H 20 H Cl30CO- CH 3 OCO- H H H H H H MeO MeO H H H H H 25

Claims (12)

1. A compound of formula:

R 1 5 30 2 N (0) R 6 R R 4 R R 8 (I) or a pharmaceutically acceptable salt thereof wherein R1, R2, R 3, R 4 independently represent hydrogen or a substituent selected from lower alkyl, lower alkoxy, halogen, alkanoyl of 2 to 7 carbon atoms, lower alkoxycarbonyl, halolower alkyl, hydroxy, cyano, amino, mono- or di loweralkyl amino, C2_C7 alkanoylamino, carboxy, carboxylower alkyl, hydroxyloweralkyl, carba moyl, carbarnoyloxy, lower alkyl- or aryl-carbonyl, (lower alkoxy)-lower alkoxy, phenyl and a phenyl itself optionally substituted by a substituent as hereinbefore defined excepting phenyl, or an adjacent pair of R' -4 together with the carbon atoms to which they are attached complete a six membered unsaturated carbocyclic or nitrogen containing heterocyclic ring, optionally substi45 tuted by one or more of the substituents listed above for RI; m represents 0 or 1; and R5, R6, RI and R8 independently represent hydrogen or a substituent selected from lower alkyl, lower alkoxy, halogen, alkanoyloxy of 2 to 7 carbon atoms, lower alkoxycarbonyl and hydroxy and the term 'lower' means a group containing 1 to 6 carbon atoms.

2. A compond as claimed in Claim methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 1 wherein any one of R1, R2, R3 and R4 is hydrogen, 50 butoxy, chlorine, bromine, fluorine, acetoxy, propionyloxy, butyryloxy, methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, CF,-, HO-, NH2_, MeNH-, Me2N-, EtNH-, cyano, acetylamino, carboxy, carboxymethyl, hydroxymethyl, hydroxyethyl, carbamoyl, carbarnoyloxy, acetyl, benzoyl or phenyl.

3. A compound as claimed in Claim 1 or Claim 2 wherein any one of R1, R 6, R 7 and R8 is 55 methyl, ethyl, propyl, fluorine, chlorine, bromine, methoxy, ethoxy, acetoxy, propionyloxy, me thoxycarbonyl, ethoxycarbonyl or hydroxy.

4. 8,13-Dihydrodibenzo[d,h]imidazo[2,1-b][1,3]thiazepine or a pharmaceutically acceptable salt thereof.

5. 8,13-Dihydro-4,5-dimethyidibenzo[d,h]imidazo[2,1-b][1,3]thiazepine or a pharmaceutically ac- 60 ceptable salt thereof.

6. 8,13-Dihydro-4-methoxydibenzo[d,h]imidazo[2,1-b][1,3]thiazepine or a pharmaceutically ac ceptable salt thereof.

7. 8,13-Dihydro-5-methoxydibenzo[d,h]imidazo[2,1-bl[1,3]thiazepine or a pharmaceutically ac- ceptable salt thereof.

9 GB2172285A 9

8. A process -for preparing _a compound of formula 1 claimed in Claim 1 which comprises one of the following a) cyclising a compound of formula R 2 R 1 rN (0)m R 5 - 6 R 3 1 T 5 1 R R NH,CH, 7 R 4 X 2 R 8 (II) wherein R"' and m are as defined in Claim 1 and X represents OH or a leaving group; b) cyclising a compound of formula 1 R 5 R 2 6 1 'v 7 1 R N:,-, R 7 R R (V) wherein R'-" are as defined in Claim 1 and one of A and B is -SH, the other is a leaving group providing that when A is -SH then B may also represent OH to give a compound of formula 1 wherein m is zero; c) reducing a compound of formula 1 RS R 2 1 N; S 1 6 R 3 N, c:X,!: 7 R 4 11 R 8 0 (VIII) wherein R' 11, are as defined in Claim 1 to give a compound of formula 1 wherein m is zero; or 35 d) reacting a compound of formula R N,hal 6 3 N R 4 R wherein hal is a halogen and W-" are as hereinbefore defined with (i) an alkali metal sulphide or hydrosulphide, (ii) ammonium sulphide or polysulphide or (iii) H2S is the presence of'a tertiary amine; or e) reacting a 2-mercaptobenzimidazole of formula R 2 R CN SH R 3 NH R 4 wherein R', R2, R3 and R4 are as defined in Claim 1 with a compound of formula GB2172285A 10 R 5 X CH 2 6 X CH 21 7 R 8 wherein 135-11 are as defined in Claim 1 the XI groups being the same or different halogens to give a compound of formula I wherein m is zero; or f) oxidising a compound of formula I wherein m is 0 is to give the corresponding oxide of formula I wherein m is 1; or g) reducing a compound of formula I wherein m is 1 is to give the corresponding compound of formula I wherein m is 0; or h) converting a compound of formula I in free base form to an acid addition or quaternary 15 ammonium salt or converting an acid addition salt of a compound of formula I to the free base form.

9. A process as claimed in Claim 8 for preparing a compound of formula I substantially as hereinbefore described with reference to any one of Examples 1 10 17.

10. A compound of formula I as claimed in Claim 1 whenever prepared by a process as 20 claimed in Claim 8 or Claim 9.

11. A compound of formula I or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof as defined in Claim 1 for use as a pharmaceutical.

12. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in Claim 1 and a pharmaceutically acceptable carrier.

Printed in the United Kingdom for Her Majesty's Stationery Office. Dd 8818935, 1986, 4235. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 'I AY, from which copies may be obtained.