GB2141429A - Thiazolo - and thiazino-benzimidazoles - Google Patents

Abstract

Pharmaceutical compositions comprising compounds of formula <IMAGE> or a pharmaceutically acceptable salt thereof wherein -B-B<1>- represents a chain of formula -(CHR<5>)n-CHR<6> (Ia) or -CR<5>=CR<6> (Ib) or -(CHR<5>)n-CR<6>= (Ic); R represents an optionally substituted aryl or heteroaryl radical, R<1>, R<2>, R<3> und R<4> independently represent hydrogen or a defined substituent or any adjacent pair of R<1>, R<2>, R<3> und R<4> together with the carbon atoms to which they are attached complete a five or six membered saturated or unsaturated carbocyclic or heterocyclic ring, said ring being optionally substituted by a defined substituent and said heterocyclic ring having at least one heteroatom selected from oxygen, nitrogen and sulphur; R<5> and R<6> independently represent hydrogen or lower alkly; n and m independently represent 0 or 1, providing that then -B-B<1>- has formula Ia, n is 1 and m is 0 then R is heteroaryl, the term "heteroaryl" means a monovalent aromatic heterocyclic group in which the ring heteroatom or atoms is/are selected from oxygen, nitrogen and sulphur; and a pharmaceutically acceptable carrier which have anti-ulcer and/or anti-secretory activity. Novel compounds of formula I are also disclosed together with processes for preparing them.

Description

or or 1 GB 2 141 429 A 1

SPECIFICATION

Thiazolo- and thiazino-benzimidazoles This invention relates to pharmaceutical compositions containing heterocyclic compounds, more particular- 5 ly benzimiclazoles, to novel compounds contained in these compositions and their preparation.

2,3-Dihydrothiazino-benzamidazoles having hypotensive activity are disclosed in Japanese Kokai 8118989 (Chemical Abstracts 95: 80996d). Krasovskii OM in Farm. Zh (Kiev) 1979, (4) 33036 disclosed naph th[1',2':4,5]imidazo[2,1 -b]-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; 81:151141 v; 73:109740z; 71:22067v; 71:13065r; 76:153678w; 76:153679x and 92:41839y; but no pharmaceutical activity is ascribed to the compounds.

We have now found a series of thiazolo- and thiazino- benzimiclazoles which possess pharmaceutical activity, in particular antiulcer activity and/or antisecretory activity and hence are useful as antiulcer agents or forthe treatment of gastric hypersecretion. In particular the compounds are useful in the treatment of 15 peptic ulcer disease. The compounds are also useful as intermediates to other compounds in the series.

Accordingly in one aspect this invention provides a pharmaceutical composition comprising a compound of formula R 2 R' Orn Sr R 1 - N,B ' 4 1 B (1).25 R or a pharmaceutically acceptable salt thereof wherein -13-131represents a chain of formula -(CHR5)n-CHR 6_ -CR 5= CR 6_ -(CHR5)n-CR 6= (1a) (1 b) (Ic) R represents an aryl or heteroaryl radical each optionally substituted by one or more substituents selected from lower alkyl, lower alkoxy, halogen, alkanoyloxy of 2 to 7 carbon atoms, lower alkoxycarbonyl, halo-lower alkyl, hydroxy, cyano, amino, mono- or di-loweralkyl amino, lower alkanoylamino, carboxy, carboxyloweralkyl, hydroxylower alkyl, carbamoyl, carbarnoyloxy, lower alkyl- or aryl-carbonyl, (loweral koxy)lower alkoxy, or phenyl, or a phenyl group itself optionally substituted by a substituent as hereinbefore defined excepting phenyl; R', R 2, Wand R 4 independently represent hydrogen, or a substituent as mentioned above in connection with the group R, or any adjacent pair of R1, R 2, R 3 and R'together with the carbon atoms to which they are attached complete a five or six membered saturated or 45 unsaturated carbocyclic or heterocyclic ring, said ring being optionally substituted by a substituent as defined above in connection with the group R, said heterocyclic ring having at least one heteroatom selected from oxygen, nitrogen and sulphur; RI and R 6 independently represent hydrogen or lower alkyl; n and m independently represent 0 or 1, providing that when -B-BI has formula I(a), n is 1 and m is 0 then R is heteroaryl, heteroaryl means a monovalent aromatic heterocyclic group in which the ring heteroatom or atoms is/are selected from 0, N and S, the term'lower' means a group containing 1 to 6 carbon atoms; and a pharmaceutically acceptable carrier.

In a second aspectthis invention provides novel compounds of formula I as shown hereinabove or salts thereof, wherein R, R1, R 2, R 3, R 4, m and -13-131 - have the meanings given above with the provisos:

(i) when -B-B1 is a chain of formula la, n is 1 and m is 0 then R is optionally substituted heteroaryl, (ii) when - B-B'- is a chain of formula la, n is 0, R1 and R 2 together with the carbon atoms to which they are attached represent a 6 membered unsaturated carbocyclic ring and R is phenyl or p-nitrophenyl then m is 1, or (iii) when -B-Bl- is a chain of formula]c, n is 0, R' and R 2 together with the carbon atoms to which they 60 are attached represent a 6-membered unsaturated carbocyclic ring and R is phenyl 2-thienyl, p methoxyphenyl or p-bromophenyl then m is 1.

or 0v) when -B-B' is a chain of formula lc, n is 0, R6 is hydrogen or lower alkyl and R', R' and R 4 are hydrogen,R 3 is hydrogen or hydroxy and R is phenyl, p-chloropheny], p- bromopheny], p-tolyl, p- methoxyphenyl, p-phenyl phenyl, 1 -na phthyl or 2-thienyl, then m is 1.

2 GB 2 141 429 A 2 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, methoxycarbonyi, ethoxycarbonyl, propoxycarbonyl, trifluoromethyl, hydroxy, cyano, amino, methylamino, 5 dimethylamino, ethylamino, acetylamino, carboxy, carboxymethyl, hydroxymethyl, hydroxyethyl, carba- moyl, carbamoyloxy, acetyl, benzoyl or phenyl.

The group R is exemplified by (1) aryl radicals such as phenyl or naphthyl which can be substituted by one or more groups as listed above for any one of R' -4, and (2) heteroaryl radicals especially those having one or more heteroatoms selected from oxygen, nitrogen and sulphur, such as pyridyl (e.g. pydrid-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 such as quinoly], isoquinolyl or indolyl, which groups can be substituted by one or more groups as listed above for any one of R 1-4. Examples of substituents for R also include (lower alkoxy)- lower alkoxy (e.g. methoxymethoxy, methoxy, and ethoxyethoxy,) phenyl,halophenyl, loweralkylphenyl and loweralkoxyphenyL When any adjacent pair of R', R 2, R 3 and R' complete a fused ring examples of the additional rings are benzo- and pyrido-fused rings. For example when R 2 and R 3 form a benzo fused ring the compound of formula 1 has the general formula R' (0)m N.S,rR 20 N, B,B' 4 R 25 Examples of R 5 and R' when lower alkyl are methyl, ethyl, propyl.

In the compounds of formula 1 preferred values for -B-B' - are formula [a or]c, especiallywhere n is 0.

Preferably R represents a phenyl or pyridyl group, e.g. pyrid-2- or 3-yl which may be substituted by substituents as hereinbefore described especially lower alkyl, lower alkoxy, and halogen, phenyl, halophenyl, lower alkyl phenyl or lower alkoxyphenyl. Preferably m is 1. Preferably either or both R 2 and R 3 30 represent substituents selected from lower alkyl (e.g. methyl or ethyl) lower alkoxycarbonyl, (e.g.

methoxycarbonyl); halogen (e.g. chlorine or bromine) or R 2 and R 3 are both hydrogen.

A preferred group of compounds for use in the composition of this invention has the general formula ld (0)m 35 R 40 and salts thereof, wherein [Arl represents R 8 R 8 1 or 45 9 50 the dotted line represents an optional double bond, R' is a phenyl or a pyridyl group either of which may be substituted; R8 and R9 independently represent hydrogen or a substituent selected from lower alkyl, lower alkoxy, halogen, cyano, carboxy, loweralkoxycarbonyl, alkanoyloxy of 2 to 7 carbon atoms, carbamoy], carbamoyloxy, hydroxy, hydroxyalkyl, haloloweralkyl, amino; R 6 is as hereinbefore defined and m is 0 or 1.

Preferred compounds of the invention include 2,3-dihydro-2-(2pyridyl)thiazolo[3,2-albenzimidazole-l- 55 oxide; 6,7-clich 1 oro-2,3-dihyd ro-2-(2-m ethyl pyrid-5-y1)th iazo 1 o-[3,2-a] benzi m idazo 1 e; 2,3-dihydro-6,7-dimethyi-2-(2 pyridyi)-thiazolo[3,2-al-benzimidazole-1 -oxide; 6 or 7-chloro-2,3dihydro-2-(2-pyridyi)thiazolo[3,2-al- benzimidazole-1 -oxide; 2-(2-(5-ethylpyridyl-thiazolo[3,2-a]- benzimidazole, and 6or7-ethoxy-2-(2- pyridyi)thiazolo-[3,2-al-benzimidazole.

Examples of acid addition salts are those formed from inorganic and organic acids, in particular pharmaceutical ly acceptable acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, sulphonate (such as the methanesu 1 phonate and p-to luenesu 1 phonate) acetate, maleate, citrate, fumarate, tartrate, malonate and formate. The salts also include quaternary ammonium salts such as those formed from alkyl or aralkyl halides.

3 GB 2 141 429 A -3 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 was determined by the stress-induced erosion test of Senay and Levine, Proc. Soc. Exp.

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

Male rats, weighing between 80 and 120 gms, were fasted overnight with water adlib. The rats were then 5 divided into groups of six and dosed orally with the test drug in the form of a solution or with the vehicle alone, 0.5% carboxym ethylcel I u lose, in a volume of 1 OmI/kg.

After 30 minutes the rats were inserted into alum! nium restraining tubes measuring 15/a inches in diameter by 5 inches and placed in the cold (4:t VC) 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 following scale:

Ulcers 15 0-6 0 = No ulcers 1 = Pinpoint haemorrhagic site 2) = Several discrete pin point 20 3) haemorrhagic sites 4) 5) = Large eroded sites with 6) haemorrhage 25 The maximum possible score for each animal was 6 and forthe group 36. Decrease in ulcer formation was calculated as a percentage of the control score, i.e.

Mean Control group score - Percentage Inhibition Mean Test group score X 100 Mean Control group score The statistical significance of the effect is assessed by Student's Mest. 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.

In the above mentioned test the following representative compounds of formula 1 were particularly active giving results as shown:

Dose (mg/kg) Inhibition 45 2,3-dihydro-2-(2-pyridyi)- 100 75% thiazolo[3,2-albenzimidazole 30 86% 2,3-dihydro-6,7-dimethyi-2- 100 82% 50 (2-pyridyi)thiazolo[3,2-al benzimidazole 2,3-dihydro-2-phenyithiazolo74% 55 [3,2-a]benzimidazole Antisecretory activity was demonstrated by the test of H. Shay, D.Sun and H. Gruenstein, Gastroenterolo gy. 1954,26,903-13 as exemplified by Beattie etal, J.Med, Chem. 20,714 (1977). In this test the following 60 representative compounds of formula 1 were particularly active:

(a) 2,3-dihydro-2-(2-pyridyl)thiazolo[3,2-a]benzimidazole and its 1-oxide.

(b) 2,3-dihydro-6 or 7-methyl-2-(2-pyridyi)thiazolo[3,2-a]-benzimidazole.

(c) 2,3-d i hyd ro-6,7-d i methyl -2-(2-pyri dyl)th iazo 1 o [3,2-a]-be nzi m i dazo 1 e and its 1 -oxide.

(d) 2,3-dihydro-6 or 7-methyl-2-(2-pyridyl)thiazolo[3,2-al-benzimidazole1 -oxide.

4 GB 2 141 429 A 4 (e) 2,3-dihydro-6- or 7-chloro-2-(2-pyridyl)thiazolo-[3,2-al- benzimidazole-1 -oxide.

Compounds of formula 1 were also tested for anti-secretory activity by their ability to inhibit the highly specific proton transporting enzyme H'/C ATPase.

Potential W/K' ATPase inhibitors were evaluated by a technique involving the measurement of aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine accumulates in acid-secreting 5 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 havean intracellular site of action, and those which reduce the response to both DBcAMP and high potassium ion concentration (C) are thought to have an intracellular site of action at the secretory surface of the parietal 10 cell, involving the highly specific proton -transporting enzyme, W/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. 1, 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., 15 Hellander H.F., Obrink K.J. (ibid.97,401-414,1976).

Compounds are tested at a concentration of 10-4 M, initially, and in some cases at lower concentrations, for their ability to inhibit 14 Caminopyrine 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 W/K' ATPase would be expected to reduce the response to both secretagogues.

In the above testthe following compounds of formula 1 were particularly active giving the results shown:

Compound % Inhibition to stimulation by: 25 DBcAMP K' 2,3-dihydro-2-(2-pyridyi)- 74% at 10-4M 91% at 10-4M thiazolo[3,2-a]benzimi- 73% at 10-5M 26% at 10-5m dazole-l-oxide 30 6,7-dichloro-2,3-dihydro- 90% at 10-4M 187% at 10-4M 2-(6-m ethyl pyrid-3-yl) thiazolo[3,2-a] benzimidazole 35 6,7-dichloro-2,3-dihydro50.5% at 10-4M 74% at 10-4M 2-(2-pyridyl-thiazolo [3,2-al-benzimidazole 2,3-dihydro-6,7-dimethy]-2- 30% at 10-4M 209% at 10-4M 40 (2-pyridyi)thiazolo[3,2-al benzimidazole-1 -oxide 2-(2-(5-ethylpyridyi)56% at 10-4M 142% at 10-4M thiazolo[3,2-albenzimida- 45 zole 6- or 7-ethoxy-2-(2-pyridyl)- 68% at 10-4M 162% at 10-4M thiazolo[3,2-a]-benzimidazole 50 2-[2-(6-Phenylpyridyll- 22% at 10-4M 381 % at 10-4M thiazolo[3,2-al benzimidazole This invention also provides processes for preparing the novel compounds of formula 1. In general the 55 compounds may be prepared by processes which are known or are analogous to known processes - see literature references hereinbefore disclosed.

4 GB 2 141 429 A A first process for preparing compounds of form u [a 1 comprises cyclisin g a compound of formula 2 R1 (0)m 1 N Y S --i R 5 R 3 N B' - 4 H / R X (11) 10 wherein -B-B'-, n, m, R, R', R 2, R 3 R 4, R5 and R6 are as defined above, and X is OH or a leaving group such as halogen or an aryi-, alkyl- or aralkyl-sulphonyloxy group that couples B to nitrogen, providing that 15 (i) when -B-B' - has formula [a and n is 0 or 1, or formula lc and n is 1 then X is not OH; and (ii) when -B-B'- has formula lb 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.

Compound of formula 11 can in general be prepared by reacting an appropriate 2-chlorobenzimidazole with a compound of formula HS R 20 B1 1 '(J11) L3 1 X wherein R, -B-B'- and X are as hereinbefore defined and if desired oxidising the product, e.g. using a peroxyorganic acid such as peroxybenzolc acids.

Compounds of formula 11 as hereinbefore defined wherein X if OH, -B-Elhas the formula ic wherein n us 0 (enol form of ketone) or formula lb may be prepared by reacting the appropriate 2-mercapto-benzimidazole 35 with a haloketone or aldehyde of formula Ilia or Hib.

k.1 H R k,,1 H 40 6 0 H 0 (111o.) (1116) 45 wherein R, R5 and R' are as defined above and hal is a halogen. Using this reaction it is possible to go directly to the corresponding compounds of formula 1 without isolating the intermediates of formula 11.

In a preferred process for preparing the compounds of formula 1 wherein B-B'- has formula la the 50 compounds of formula 11 wherein m is 0 are prepared and cyclised without isolation in a single step process by reacting an appropriate 2-mercaptobenzimidazole of formula R 2 N, SH p 3, NH (N) 6 GB 2 141 429 A 6 wherein R', R2, R 3 and R 4 are as defined above with a compound of formula X-,./'R ['H 5 (V) H X(CHRSn R6 10 1 wherein R, R5 R 6 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 15 corresponding compound of formula 1 wherein -B-Bl- is -(CHR'),,-CFt-wherein n is 0.

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 2-mercapto-5methyl benzimidazole is tautomeric with 2-mercapto-6-methyibenzimidazole and the final product will be a mixture of compounds where R 2 or R' is methyl.

Afurther process for preparing the compounds of formula 1 wherein m is 0 comprises cyclising a 20 compound of formula R 2 R' N A B2 R Y - 3 1 - N, R 4 B R (V1) wherein -B-BI- n, R, W, R 2, R 3, R 4, R 5 and R 6 are as hereinbefore defined and one of A and B 2 is -SH, the 30 other is a leaving group providing that when A is SH then B 2 may also represent OH.

When A or B 2 is a leaving group the cyclisation is generally carried out by heating if desired in the presence of base, e.g. triethylamine, K2C03, NaOH, etc. When B 2 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 B 2 is OH may be prepared by (a) reacting an appropriate 2-chforobenzimidazole with a compound of formula H0,1Y R B' 40 1 (V11) X 45 wherein -B-B'-, X, R, R' and R' are as hereinbefore defined to give a compound of formula Vill 2 R' 50 R N CL HO,,R 1 'T' ' 11 -N 'B,B 4 55 P, M11) wherei n - B - B'-, R', R 2, R 3, R 4, R5 and RI are as hereinbefore 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 60 room temperature or without heating.

Compounds of formula VIII wherein -B-B1 - is -(CHR5)n-CRI= 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 B 2 is a leaving group and -B131- has formula la or lb may 65 7 GB 2 141 429 A 7 be prepared from the corresponding compounds of formula VI wherein B 2 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 B 2 is SH may be prepared by building up the molecule from appropriate starting materials wherein the -SH is protected by a thiol 5 protecting group and removing the protecting group as the final step.

Compounds offormula 1wherein m isO, -B-Bl- hasformula [a and eithern is land R 5 is hydrogen or n is 0 and R 6 is hydrogen may also be prepared by a process which comprises reducing a compound of formula R1 R2 N, S R Y 6 3 - N, ACHR p R' -14 CO R (1x) wherein R, W, R 2, R 3, R 4 and R' are as hereinbefore defined and p is 0 or 1 with the proviso that when p is 1, R is heteroaryl, 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 R Y R 6 25 -3 NH /CHR R 4 0 CD p (X) R 30 wherein p, R, W, R 2, R 3, R 4 and R 6 are as defined above.

Compounds of formula X may be prepared by reacting the appropriate 2mercaptobenzimidazole with a halo-acid of formula RCHBr(CHR6)pCOOH (R, R' and p 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 35 compound of formula 2 R1 R NR k.L hol R y 3 N, 'BI R 4 B R (xl) wherein -B-B'-, hal, n, R, R', R 2, R3, R 4, R 5 and R 6 are as hereinbefore defined with (i) an alkali metal suphide or hydrosulphide, (5) ammonium sulphide or polysulphide or (iii) H2S in the presence of a tertiary amine. Compounds of formula 1 as hereinbefore defined wherein -B- B-Lis -CR5=CRAor -(CHRI)r,-CR'= may be 50 prepared by reacting a compound of formula XII orXIII 2 R PM R N S R D E N i R CH R 5)n R6 (X11) R 2 or R1 (OL - R N S R H R3 N R6 D 4 R (X111) R 8 GB 2 141 429 A 8 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 1 wherein -BBlis -(CHR 5)n-CR'= comprises cyclizing a compound of formula 1_) (q)rn R N S, Y- CH2R 0 XIV 3 N 10 R '-'(C H R 5 - li R6 9n C wherein R, R', R 2, R 3, R4, R5, R 6 and n are as hereinbefore defined. The cyclisation may be conveniently carried out under condensation conditions such as treatment with mixed baselacid 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 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 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-IC12.

Compounds of formula 1 in which -B-B' - does not contain a double bond may be oxidised to compounds of formula 1 in which a double bond is present and vice versa by reduction. Accordingly compounds of 25 formual 1 are intermediates for other compounds of formula 1.

The compounds of formula 1 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 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.

Processes as described hereinabove which prepare novel compounds of formula 1 are within the scope of this invention.

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 40 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 sub-divided in unit 55 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 maybe varied or adjusted from 10 to 500 mg or more, e.g. 25 mg to 250 mg, according to the particular need 60 and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orally in either liquid or solid composition form. These compositions may include one or more antacid ingredients, e.g. aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbonate, 9 GB 2 141 429 A 9 magnesium trisilicate, sodium bicarbonate orthe 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 1

Dihydro-2-(2-pyridyl)thiazolo[3,2-albenzimidazole To 2-(1-,2-dibromoethyl)pyridine hydrobromide (10g) dissolved in dimethyl formamide (250m1) was added 0 2-mercaptobenzimidazole (7g) and the mixture was stirred at WC for 36 hours. The solvent was removed 10 under reduced pressure and the residue diluted with 2N HCl (250mi) to give a slight precipitate. This was removed by filtration and the filtrate washed with ether (3 X 150mi), basified (Na2C03) and extracted with CH2C12 (4 x 1 Oomi). The extracts were dried (MgS04) and the solvent removed under reduced pressure. The residue was dissolved in EtOAc to give a slight precipitate which was removed by filtration. The filtrate was concentrated under reduced pressure and the residue dissolved in xylene (500mi) to give a slight 15 precipitate which was removed by filtration. The filtrate was concentrated under reduced pressure and the residue dissolved in methanol (500mi) and treated with decolourising charcoal for 18 hours. The solution was then filtered and the filtrate concentrated under reduced pressure. The residue was purified initially by chromatography on silica using EtOAc as eluent, and finally by h.p.l.c. using 40% EtOAc in CH2C12. The purified material was treated with ethereal hydrogen chloride and recrystallised from propan-2-ol to give the 20 title compound as the di-HCI salt (1.8g) mp 226-229'C decomp. Analysis: Found: C, 51.1; H, 4.1; N, 13.05 C14H1IN3S.21-10 requires: C, 51.5; H, 4. 0; N, 12.9% EXAMPLE 2

2,3-Dihydro-2-(2-pyridyl)thiazolo[3,2-albenzimidazole-l-oxide 25 2,3-Dihydro-2-(2-pyridyl)thiazolo[3,2albenzimidazole. (2g) was dissolved in ethyl acetate (150m1) and the solution cooled to -50'C. A solution of m-chloroperoxy-benzoic acid (1. 7g) in ethyl acetate (30mi) was added and the temperature of the mixture allowed to rise to ambient temperature. The mixture was washed with saturated sodium carbonate solution (5m[) and dried (M9S04). The solvent was concentrated under reduced pressure keeping the temperature below WC. The title compound precipitated out as the 1/4 hydrate, (0.9g). 30 mp 177'C decomp.

Analysis:

Found: C,61.6; H,4.2; N, 15.6 C14H11N3OW/4H20 requires C, 61.35; H, 4.2; N, 15.35% EXAMPLE 3 2,3-Dihydro2-phenylthiazolo[3,2-albenzimidazole(1,2-Dibromoethyl)benzene (21 g) was treated with 2-mercaptobenzimidazole (17g) in dimethylformamicle (100mi) and the mixture was heated at 1OWC for 36 hours. On cooling, the solid material was removed by filtration and recrystallised from methanol and ethyl acetate to give the title compound as the hydrobromide salt (13.68g). mp 207-210'C.

Analysis:

Found: C,518; H,4A; N,8.5C151-112N2S.HI3r requires C, 54.1; H, 3.9; N, 8. 4% EXAMPLE 4

2,3-Dihydro-2-phenylthiazolo[3,2-albenzimidazole-l-oxide 2,3-Dihydro-2-phenylthiazolo[3,2-a]benzimidazole (4.25g) was dissolved in ethyl acetate (250mi) and cooled to -50'C. Solid m-chloroperoxybenzoic acid was added and the mixture allowed to warm to -30'C, at which point saturated sodium carbonate solution (1 Orni) was added and allowed to freeze.

On reaching ambient temperature the reaction mixture was filtered and dried (M9S04) and the solvent removed by evaporation to give a white residue. This was recrystallised twice from ethyl acetate to give the so title compound as the 114 hydrate (0.75g) mp 162.5-163'C.

Analysis:

Found: C,653; H,43; N,10.0 C15H12N2OS1/41-120 requires C,66.0; H,4.6; N, 10.3%.

EXAMPLE 5

2,3-Dihydro-2-(6-methylpyrid-3-yl)thiazolo[3,2-a]benzimidazole 3-0,2-Di bro m oethyl)-6-m ethyl pyri d in e hydrobromide (2.5g) was added to 2-mercaptobenzimidazole (1.25g) in dimethy[formamide (50mi). The mixture was stirred at ambient temperature for 4 days and then heated at 1 OWC for a further 2 days. The solvent was removed under reduced pressure and the residue diluted with 2N HCI, filtered and extracted with ethyl acetate. The aqueous layer was basified with sodium 60 hydroxide and extracted with ethyl acetate (3 x 1 00m1), dried (M9S04) and the solvent removed. The residue was purified by chromatography on Fluorisil using 10% cyclohexane in ethyl acetate as eluent. The solvent was removed and the residue dissolved in 25mi ether and ethereal HQ added. The solid obtained was GB 2 141 429 A recrystallised from methanol/ethyl acetate to give the title compound asthe dihydrochloride, hydrate salt (1.3g) mp greater than 2700C.

Analysis:

Found: C,49.9; H,4A5; N,11.65C,5H13N3S.2HCI.H20 requires C, 50.3; H,4.8; N, 11.7%.

EXAMPLE 6

6,7-Dichloro-2,3-dihydro-2-(6-methylpyrid-3-yl)thiazolo-[3,2albenzimidazole To 5,6-dichloro-2-mercaptobenzimidazole (7.5g) in dimethylformamide (200mi) was added 3-(1,2dibromoethyl)-6-methylpyridine hydrobromide (7.5g), The mixture was stirred at ambient temperature for 3 days, and then heated at 1 OWC for 3 days. The solventwas removed by evaporation and the residue diluted with 2N HCl, filtered through keiseighur and extracted with chloroform (3 x 125m1). The aqueous solution was then basified with N2.2C03 and extracted with dichforomethane (3 x 300mi). The extracts were dried (M9S04) and the solvent removed under reduced pressure. The residue was washed with ethyl acetate (5 x 2mi), dissolved in hot propan-2-ol and ethereal HCI was added. The solid obtained was recrystallised from methanol/ethyl acetate to give the title compound as the dihydrochloride, 1/4 hydrate salt (3.1g) mp >32WC.15 Analysis:

Found: C,419; H,14; N, 10.00 C15H11C12N3S.2HCLIAH20 requires C,43.55; H, 3.3; N, 10.2% EXAMPLE7

2,3-Dihydro-6-methyl-2-(2-pyricfyl)thiazolo[3,2-albenzimidazote and 2,3Dihydro-7-methyl-2-(2-pyridyl) thiazolo[3,2-albenzimidazole 2-(1,2-Dibromoethyi)pyridine hydrobromide (9.5g) was added to 5-methyl-2mercaptobenzimidazole (59) in dimethylformamide (100m1) and the mixture stirred at ambient temperature for 3 hours and then heated at 1OWC for 24 hours. The solvent was removed and the residue was dissolved in 2N HCLThe resulting solution was filtered through keiseighur and then extracted with ethyl acetate. The aqueous layer was basified (Na2C03) and extracted with chloroform. The extracts were dried (M9S04) and the solvent removed under reduced pressure. The residue was purified by chromatography on fluorisil with 25% v/v chloroform in ethylacetate and then on silica using 10% v/v hexane in ethylacetate. The solvent was removed and the residue dissolved in hot propan-2-ol and ethereal HCI was added. The product obtained was recrystallised from methanollethylacetate to give a mixture of the title compounds as the dihydrochloride hemihydrate salts (1.249) mp 212-214'C decomp.

Analysis Found: C.51.4; H,4A5; N, 12.0C15H13N3S.2HCLY2H20 requires C,51.6; H, 4.6; N, 12.0%.

t EXAMPLE 8

6,7-Dichloro-2,3-dihydro-2-(2-pyridyl)thiazolof3,2-al)benzimidazole 2-(1,2-Dibromoethyl)pyridine hydrobromide (10.1g) was added to 5,6dichloro-2-mercaptobenzimidazole (7.1 g) in dimethylformamide and the mixture left at ambient temperature for 24 hours, after which it was heated at 1OWC for 3 days. The solvent was removed under reduced pressure and the residue dissolved in 2N HCI and extracted with ethyl acetate. The aqueous layer was basified (Na2C03) and extracted with ethyl 40 acetate. The organic extracts were dried (MgS04) and the solvent removed under reduced pressure. The residue was purified by chromatography on fluorisil using 30% v/v chloroform in ethyl acetate and then on fluorisil using ethyl acetate as eluent. The solvent was removed under reduced pressure and the residue washed with a small volume of ethyl acetate. The residue was then dissolved in hot propan-2-ol and ethereal HCI was added. The solid obtained was filtered and dried to give the title compound as the dihydrochloride 45 sa It (1.3g) m p 233-2350C.

Analysis:

Found: C.42.5; H,11; N, 10.5C141-19C12N3S.21-IC1 requires Q42.6; H, 2.8; N, 10.6%.

EXAMPLE 9

2,3-Dihydro-6,7-dimethyl2-(2-pyridyl)thiazolo[3,2-albenzimidazole (5.3g) in methanol (100mi) and the mixture was heated at reflux for 18 hours, after which time the solvent was removed under reduced pressure. The residue was treated with saturated sodium carbonate solution and extracted into dichloromethane. The extracts were dried (M9S04) and evaporated and the residue was 55 purified by chromatography on silica using ethyl acetate as eluent. The solvent was removed under reduced pressure and the residue dissolved in hot propan-2-ol and ethereal HU was added. The product obtained was recrystallised from methanol and ethyl acetate to give the title compound as the clihydrochloride, hernihydrate (0.759,7.35%) mp 222'C decomp.

Analysis:

Found: C,510; 1H1,4.8;N,11.3C16H15N3S.2HCL1/21H120 requires C. 52.9; H, 5. 0; N, 11.6%.

4 11 GB 2 141 429 A 11 EXAMPLE 10

2,3-Dihydro-6-methyl-2-(2-pyridyl)thiazolo[3,2-albenzimidazole-1-oxide and 2,3-Dihydro-7-methyl2-(2pyridyl)thiazolo[3,2-albenzimidazole- 1-oxide A mixture of 6- and 7-m ethyl -2,3-d i hyd ro-2-(2-pyri dyi)th i azo 1 o [3,2-al be nzi m idazo 1 es (1.57g) was dissolved in ethyl acetate (120mi) and cooled to O'C. m-Chloroperoxybenzoic acid (1. 09g) was added and the mixture stirred for 1 hour. More m-chloroperoxybenzoic acid (0.1g) was added and the mixture was left a further 1/2 hour. Saturated sodium carbonate solution was added and the reaction mixture was filtered. The organic layer was dried (M9S04) and evaporated to low volume. Acetonitrile (0. 5mi) was added and the product crystallised. The solid was isolated by filtration and was washed with acetonitrile and with ether to give a mixture of the quaterhydrates of the title compounds (1g) mp 153'C.

Analysis:

Found: C,62.5; H,4.6; N, 14.3 C151-113N30S.141-120 requires C,62.6; H,4.8; N, 14.6%.

EXAMPLE 11

2,3-Dihydro-6-methoxycarbonyl-2-(2-pyridyl)thiazolo[3,2-a]benzimidazole and 2,3-Dihydro-7 methoxycarbonyl-2-(2pyridyl)thiazolo[3,2a]benzimidazole Methyl 2-mereaptobenzimidazole-5-carboxylate (13.18g) was suspended in 2methylpropan-2-ol (180mi) and potassium tert-butoxide (7.08g) was added. The mixture was left to stir 1 hour and then 2-(1,2-dibromoethyl)pyridine hydrobromide (21.82g) was added. Stirring continued for 1 hour at ambient temperature and then 2 hours at reflux.

The mixture was filtered and the solid obtained washed with ether. The filtrate was evaporated to dryness and the residue combined with the solid obtained by filtration and the combined material was dissolved in 2N HCI. The aqueous solution was extracted with ethyl acetate, basified (Na2C03) and then extracted with dichloromethane. The organic layer was dried (M9S04) and evaporated to dryness. The residue was purified by chromatography on fluorisil using chloroform as eluent and then on silica using 1: 1 v/v methyl acetate 25 and chloroform. The solvent was removed and the residue recrystallised from methyl acetate/cyclohexane to give a mixture of the title compounds (5.30g) mp 12WC.

Analysis:

Found: C,611.9; H,4.4; N,13.3C16HI3N302S requires C, 613; H,4.2; N, 13.5%.

EXAMPLE 12

2,3-Dihydro-6-methoxycarbonyl-7-methyl-2-(2-pyridyl)thiazolo[3,2albenzimida zole and2,3dihydro-7 methoxycarbonyl-6-methyl-2-(2-pyridyl)thiazolo[3,2-albenzimidazole 2-Mercapto-5-methoxycarbonyl-6-methyibenzimidazole (2.8g) was suspended in 2-methyl-2-propanol (50mi) and potassium tert-butoxide (1.41g) was added. The reaction mixture was stirred under nitrogen for 35 one hour at WC. Then 2-(1,2-dibromoethyl)pyridine hydrobromide (4.36g) was added all at once and the reaction mixture stirred at WC for 1 hour and then at reflux for 2.5 hours.

The solvent was removed under reduced pressure and the resulting residue treated with 2N HCI (1 Omi) and water (1 00mi). Insoluble solid was filtered off. The resulting filtrates were washed with ethyl acetate and basified (2N NaOH) and extracted with dichloromethane. The dichloromethane extract was dried (M9S04) 40 and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography, first, on alumina (grade 111) using dichloromethane as the eluent and then on silica using CH2C12/MeOAc (1.1 v/v) as the eluent. The solvents were removed under reduced pressure and the resulting residue treated with methyl acetate (1 mi), hexane, (1 m]) and diethyl ether (1 m[). The resulting solid was removed by filtration, washed with a small amount of ether and dried to give a mixture of the title compounds (0.759) mp 104-106'C.

Analysis:

Found: C,62.7,1-1,4A; N, 12.6C17H15N302S requires C, 62.75; H,4.65; N, 12. 9%.

EXAMPLE 13 2,3-Dihydro-6,7-dimethyl2-(2pyridyl)thiazolo[3,2albenzimidazole-l-oxice In a manner analogous to Example 10 2,3-Dihydro-6,7-dimethyl-2-(2- pyridyl)thiazolo[3,2-albenzimidazole (2.63g) was reacted with m- chloroperoxybenzoic acid (1.45g) to give the title compound as the 1/4 hydrate, mp 177-WC decomp. 55 Analysis:

Found: C,64.0; H,5.1; N,13.7 C161-115N,30S.1/41-120 requires C,633; H, 5. 2; N, 13.9%.

EXAMPLE 14 6-Chloro-2,3-dihydro-2-(2-pyridyl)thiazolo[3,2-a]benzimidazole and 7-Chloro-2,3-dihydro-2-(260 pyridyl)thiazolo[3,2-ajbenzimidazole 5-Chloro-2-mercaptobenzimidazole (9.25g) was added to a solution of sodium (1.1 5g) in ethanol (200ml) and was stirred for 5 minutes. 2-(1,2Dibromoethyl)pyridine hydrobromide (17.3g) was added and the mixture was heated at reflux for 1.25 hours. Further sodium ethoxide 0 equiv.) was added and the mixture heated at reflux for 3 hours. The reaction mixture was filtered and the solvent evaporated under reduced 65 pressure. The residue was.clissolved in chloroform (200ml) and was washed with 2% sodium hydroxide 12 GB 2 141 429 A solution (200m) and brine and then dried (M9S04). The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and filtered. Thefiltrate was evaporated under reduced pressure and the residue purified by repeated chromatography on silica using ethyl acetate as eluent. The solventwas removed under reduced pressure and the solid obtained was dried under vacuum to give a mixture of the 5 title compounds (1.4g) mp 89.5-93'C.

Analysis: Found: C,58.8; H,3.6; N, 14.5C14H1OCIN3S requires C, 58.4; H,15; N, 14.6%.

12 EXAMPLE 15

7-Ethoxy-2,3-dihydro-2-(2-pyridyl)thiazolo[3,2-albenzimidazole 5-Ethoxy-2-mercaptobenzimidazole (6.03g) was suspended in 2-m ethyl pro pa n-2-ol (100mi) at 500C. Potassium tert-butoxide (3.48g) was added and the mixture stirred for 1 hour. The temperature was allowed to fall to WC and 2-(1,2-dibromoethyl)pyridine hydrobromide (1 0.76g) was added. The resulting mixture was stirred for 1 hour at WC and then 2 hours at reflux.

The reaction mixture was filtered and the solid washed with ether. The mother liquors were evaporated 15 under reduced pressure and the residue was combined with the solid obtained by filtration. The combined solids were dissolved in 2N HCI and washed with ethyl acetate (4 x 75mi), basified (Na2C03) and extracted with dichloromethane (3 x 1 00mi). The organic layer was dried (M9S04) and evaporated under reduced pressure. The residue was purified by chromatography on fluorisil using chloroform as eluent. The solvent was removed under reduced pressure when the residue crystallised to give the title compound (1.2g) mp 20 164-166'C.

Analysis:

Found:C,64.4;H,52;N,14.3 C161-115N30S requires C, 64.6; H, 5.1; N, 14.1%.

EXAMPLE 16

2-3-Dihydro-7-methoxycarbonyl-6-methyl-2-(2-pyridyl)thiazolo[3,2albenzimida zole-l-oxide and2,3 dihydro-6-methoxycarbonyl-7-methyl-2-(2-pyridyl)thiazolo[3,2albenzimidazole - 1-oxide In a manner analogous to Example 10 a solution of 2,3-dihydro-6- methoxycarbonyi-7-methyi-2-(2pyridyl)thiazolo[3,2-albenzimidazole and 2,3-dihydro-7-methoxycarbonyi-6methyi-2-(2-pyridyl)- thiazolo[3,2-a]benzimidazole (0.65g) in dichloromethane (15mi) was reacted with rn-chloroperoxybenzoic 30 acid (0.43g) to give a mixture of the title compounds (1 17mg) 150-151'C.

Analysis:

Found: C,59.7;1-1,43; N,12.40 C17H15N303S requires C,592; H,4.4; N, 12.3%.

EXAMPLE 17 2,3-Dihydro-6-methoxycarbonyl2-(2-pyridyl)thiazolo[3,2albenzimidazole- 1-oxide and2,3-dihydro-7methoxycarbonyl-2-(2pyridyl)thiazolo[3,2-albenzimidazolel-o xide In a manner analogous to Example 10 a mixture of 2,3-clihydro-6-[and 71-methoxycarbonyl-2(2pyridyi)thiazolo[3,2-albenzimidazole (prepared according to Example 12, 1.81 g) was reacted with m- chloroperoxybenzoic acid (1.16g) to give a mixture of the title compounds (50Orng) mp 128-35'C.

Analysis:

Found: C,58.5; H,4.3; N,12.6 C16N13N303S requires C, 58.7; H, 4.0; N, 12. 8%.

EXAMPLE 18

6-Chloro-2,3-dihydro-2-(2-Pyridyl)thiazolo[3,2-albenzimidazole-l-oxide and 7-chforo-2,3-dihydro-2-(2 pyridyl)-thiazolo[3,2-albenzimidazole- 1- oxide In a manner analogous to Example 10 a mixture of 6- and 7-chloro-2,3dihydro-2-(2-pyridyl)-thiazolo[3,2a]benzimidazole (prepared according to Example 13, 2.629) was reacted with rn-chloroperoxybenzoic acid (1.81 g) to give a mixture of the title compounds (1.9g) mp 163.5-4.5'C.

Analysis:

C,55.6;H,16;N,14.0C14H1OCIN3OS requires C, 55.4; H, 3.3; N, 13.8%.

C 13 GB 2 141 429 A 13 EXAMPLE 19

Using a procedure analogous to Example 1 involving reaction of compounds of formulae IV and V R 2 1 S H N R R 4 (IV) X R + 5:

X (CHR) n R 6 (V) wherein X is Cl or Br, the following compounds of formula 1 wherein m is 0 and -B-B'- is -(CHR 5), -CHR 6 - are prepared R' R 2 R 3 R 4 R n R 6 R 5 H H H H 2-pyridyl 1 H H Me H H Me 2-pyridyl 0 H H C02Me C02Me H 2-pyridyl 0 H - 20 H H H H 4-chloro-2- 0 H - pyridyl H H H H 2-thienyl 0 H - H H H H 4-pyridyl 0 H - H H H H 2-pyrimidinyl 0 H - 25 H H H H 3-chlorophenyl 0 H - H H H H 4-methylphenyl 0 H - H H H H 4-methoxyphenyl 0 H - H H H H 4-methoxycarbonyl- 0 H - phenyl 30 H H H H 2-acetoxyphenyl 0 H which compounds are all converted to their S-oxides by a method analogous to Example 2.

EXAMPLE 20

2,3-Dihydro-5-metl7yl-2-(2-pyridyl)thiazolo[3,2-albenzimidazole 4-Methyi-2-mercaptobenzimidazole (13.32g) was suspended in 2-methylpropan2-ol (150mi) and potas sium tert-butoxide (9.04g) added. The mixture was stirred for 2 hours and 2-(1,-2-dibromoethyl)pyridine 40 hydrobromide (27.68g) added. The mixture was stirred at ambient temperature for 1 hour and then at reflux for 2 hours. The reaction mixture was filtered and the solid washed with ether. The filtrate was evaporated to dryness under reduced pressure and the residue combined with the first solid obtained. The combined material was dissolved in 2N HCl (1 00mi). The aqueous solution was extracted with ethyl acetate, basified (Na2C03) and extracted with dichloromethane. The organic layer was dried (M9S04) and the solvent removed under reduced pressure. The residue was purified on Florisil using chloroform as eluent and on silica using ethyl acetate as eluentto give the title compound (1.55g) mp 128-130'C Analysis:

Found: C,67.1; H,5.0; N, 16.1; C151-113N3S requires: C,67.4; H,4.9; N, 15. 7%.

EXAMPLE 21

2,3-Dihydro-8-methyl-2-(2-pyridyl)thiazolo[3,2-albenzimidazole Also isolated from the purification step in Example 20 was the title compound (1.5g) m.p. WC.

Analysis:

Found: C,67.05; H,4.9; N,153; C151-113N3S requires: C,67.4; H,4.9; N, 15. 7% EXAMPLE 22 2,3-Dihydro-5-methyl-2-(2-pyridyl)thiazolo[3,2-albenzimidazole- l-oxide In a similar mannerto Example 4 2,3-dihydro-5-methyl-2-(2pyridyl)thiazolo[3,2-a]-benzimidazoie (1.07g) was reacted with rn-chloroperoxybenzoic acid to give the title compound (0.749,70%) mp 148.5'C.

Analysis: Found: C,614; H,4.6; N, 143;C151-113N3OS requires: C,616; H,4.6; N, 14.8%.

14 GB 2 141 429 A EXAMPLE 23 2,3-Dihydro-8-methyl-2-(2-pyridyl)thiazolo[3,2-albenzimidazole- l-oxide In a manner analogous to Example 4 2,3-d i hyd ro-8-m ethyl -2-(2- pyridyl)th iazo lo[3,2-al-benzi m idazo le (1.04g) was reacted with mchloroperoxybenzoic acid (0.859) to give the title compound (0.839, 80%) mp 182'C decomp.

Analysis:

Found: 63.2; H,4.6; N, 15.0;C151-113N3OS requires C,616; H,4.6; N, 14.8%.

14 EXAMPLE 24

6-Ethoxy-2-(2-pyridyl)thiazolo[3,2-al-benzimidazole and 7-ethoxy-2(2pyridyl)thiazolo[3,2-albenzimidazole 10 5-Ethoxy-2-mercaptobenzimidazole (10.43g) was dissolved in 2-methyl-2- propanol (250m1) at3O'C. Potassium tert-butoxide (5.95g) was added and the mixture was left to stir for 1 hour. 2-(1,2Dibromoethyl)pyridine hydrobromide (1 8.4g) was added and the mixture was stirred at WC for 1 hour and at reflux for 2 hours.

The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was 15 combined with the first solid obtained and was dissolved in 2NI-ICI. The aqueous solution was extracted with ethyl acetate, basified (NaC03) and extracted with dichloromethane. The organic layer was dried (M9S04) and the solvent removed under reduced pressure. The residue was purified by chromatography on Florisil using chloroform as eluent and then on silica using ethyl acetate as eluent. The solvent was removed to give a mixture of the title compounds (0.2g) mp 150-151'C.

Analysis:

Found: C,653; H,4.1; N,14.6; C161-113N3OS requires: C,65.11; H,4.4; N, 14. 2%.

EXAMPLE 25 25 7-Ethoxy-2,3-dihydro-2-(2-Pyridyl)thiazolo[3,2albenzimidazole-l-oxide In a manner analogous to Example 4 7-ethoxy-2,3dihydro-2-(2-pyridyi)thiazolo[3,2-al-benzimidazole (1.659) was reacted with m-chloroperoxy benzoic acid (1.25) to give the title compound (0.569, mp 145-147'C. Analysis: 30 Found: C.61.3; H,4.8; N,117; C16H15N302S requires: C,613; H,4.8; N, 13.4%.

EXAMPLE 26

2,3-Dihydro-2-(2-(5-ethylp thiazolo[3,2-albenzimidazole a) 5-Ethyl-2-vinylpyridine (12.0g) (J.Amer,Chem.Soc., 681368 (1946)) was dissolved in dichloromethane (40mi) and cooled to ice temperature with stirring. Then bromine (15.8g) dissolved in dichloromethane 35 (30mi) was added dropwise over a period of 5 minutes and the reaction mixture stirred forfurther 10 minutes at ice tem peratu re.

Anhydrous HBr gas was bubbled through the reaction solution in excess amount and solventwas removed under reduced pressure. The resulting residue wastreated with propan-2-ol (10mi) and the resulting yellow solid filtered, washed with ether and dried to yield 2(1,2-dibromoethyi)-5-ethylpyridine 40 hydrobromide (29.0g) (86%).

b) 2-Mercaptobenzimidazole (10.84g) was suspended in 2-methylpropan-2-ol (170m1) and potassium tert-butoxide (8.1g) in 2-methylpropan-2-ol (70m1) added and the reaction mixture stirred under nitrogen for 1 hour at WC. The reaction was then cooled to room temperature and 2-(1,2dibromoethyl)-5-ethylpyridine hydrobromide (27.0g) was added at once and the reaction mixture stirred at room temperature for 2 hours 45 and then refluxed for 2 hours. Further potassium tert-butoxide (8.19) was added and the reaction mixture refluxed for 2.5 hours.

The solvent was removed under reduced pressure and the resulting residue treated with 2N HCI (200 mi) and water (100 mO and the insoluble solid filtered off. The resulting filtrate was washed with ethyl acetate and basified (2N NaOH) and extracted with dichloromethane. The dichloromethane extracts were dried 50 (M9S04) and evaporated to dryness under reduced pressure.

The resulting residue was purified by column chromatography, first, on alumina (grade 111) using dichloromethane as the eluent and then on silica using ROAc/hexane (85:15 vlv) as the eluent. The solvents were removed under reduced pressure from the fractions having Rf value about 0.29 and the resulting residue treated with methyl acetate (2 mi). The resulting white solid was removed by filtration, washed with 55 a small amount of hexane and dried to give the title compound (7.4g). m.p. 101-102'C.

Analysis:

Found: C,68.6; H,5.4; N,14.7.C16H15N3S requires C, 68.3; H, 5.4; N, 14.9%.

C c GB 2 141 429 A - 15 EXAMPLE 27 2-(2-(5-Ethylpyridyl))thiazolo[3,2-albenzimidazole Solvent was removed from the fractions from the previous example having an Rf value about 0.44 and the resulting residue treated with methyl acetate (2m]). The resulting solid was removed by filtration, washed 5 with small amount of hexane and dried to give title compound (0.4g) m.p. 174-175'C.

Analysis:

Found: C,683; H,4.9; N,14.7. C161-113N3S requires C, 68.8; 1-1,43; N, 15. 0%.

EXAMPLE 28 10 2,3-Dihydro-2-(2-(5-ethylpyridyl))thiazolo[3,2a]benzimidizole-loxide In a manner analogous to Example 4 2,3-dihydro-2-(2-(5-ethylpyridyi)) thiazolo[3,2-al benzimidazole was reacted with m-chloroperoxybenzoic acid (1.2g) to give the title compound (0.91 g) m.p. 154-155'C.

Analysis:

Found: C,64.5; 1-1,53; N, 133; C161-115N3OS requires C, 64.6; H, 5.1; N, 14.1%.

EXAMPLE 29

6-Cyano-2,3-dihydro-2-(2-pyridyl)thiazolo[3,2a]benzimizazole and 7-Cyano2,3-dihydro-2-(2 pyridyl)thiazolo[3,2-albenzimidazole In a man ner analogous to Example 12, 5-cyano-2-mercaptobenzimidazole (1 0.46g) was reacted with 2-(1,2-dibromoethyi)pyridine hydrobromide (20.769) in the presence of potassium tert-butoxide (15.46g) to 20 give the title compound (0.24g), m.p. 158-160'C.

Analysis:

Found: C,64.4; H,3.6; N,19.85; C151-11ON4S requires: C,643; H,3.6; N,20. 1%.

EXAMPLE 30

2,3-Dihydro-2-[2-(4-methoxypyridyl)lthiazolo[3,2-albenzimidazole (a) 2-Bromoacetyl-4-.methoxypyridine (1 1.5g, 0.05) and 2- chlorobenzimidazole (7.5g, 0.05 mole) were dissolved in dimethylformamide (75mi) and cooled to 2'C. K2C03 (12g, 0.08 mole) was added and the temperature rose to 9'C as the suspension was stirred for 1/2 hour. The mixture was added to H20 (200 m]) giving a solid which was removed by filtration. The mother liquors were extracted with ethyl acetate and the 30 solid was dissolved in the extracts. The organic solution was washed (brine) and dried (M9S04) and purified by passage down a silica column and evaporated to dryness to give a sticky solid. Trituration with propan-2-ol/di-isopropyl ether gave 2-chloro-l-[2-(2-[4-methoxypyridyll)- 2-oxoethyi]benzimidazole (7.2g).

(b) A mixture of the product of step (a) (7.2g) and thiourea (2.4g) in ethanol (50mi) was stirred at ambient temperature for 1/4 hour and treated at WC for 2 hours. The solution was filtered and evaporated and the 35 residue was dissolved in water and treated to excess with NH40H to give a solid which was purified by chromatography on silica with ethyl acetate to give 2-mercapto-l-(2-(2-(4- methoxypyridyi))-2- oxoethyl)benzimidazole (2g).

(c) The product of step (b) was dissolved in 0.1 N NaOH (70 mi) and ethanol (30 mO and the solution was treated with NaBH4 (0.3g.). After stirring at ambient temperature for 1 hour, the resulting solution was 40 treated with charcoal, filtered and evaporated to low volume. The residue was acidified to pl-15 with acetic acid and the aqueous solution decanted. The residue was crystallised from propan-2-ol to give 1-[2-hydroxy-2-(2-(4-methoxypyridyl))ethyll-2-mercaptobenzimidazole (1.1. 9j.

(d) The product of step (c) (0.5g.) was dissolved in polyphosphoric acid (1.7g) and was heated at 12WC for 11/2 hour with stirring. Further 1-[2-hydroxy-2-(2-(4- methoxypyridyl)ethyll-2-mercaptobenzimidazole (0.5g.) 45 was added and the heating continued 11/2 hours. The solution was basified with Na2C03 solution to give a solid which was extracted with ethyl acetate. The extracts were dried (M9S04) and evaporated and the residue triturated with di-isopropyl ether to give the title compound (0. 85g.) mp 107-8'C.

Analysis:

Found: C,615; H,4.8; N,14.5;C15H13N3OS requires C,616; H,4.6; N, 14.8%.

EXAMPLE 31

2-(2-Pyridyl)thiazolo[3,2a-Ibenzimidazole A solution of 2-mercapto-l-[2-oxo-2-(2-pyridyi)ethyllbenzimidazole (lg.) in polyphosphoric acid was heated at 14WC for 1 hour. The solution was'neutralised with Na2C03 solution and extracted into EtOAc (700 55 mi). The extracts were dried (M9S04) and evaporated to give a solid which was recrystallised from EtOAc/EtOH to give the title compound (0.35g.) mp 222-4'C.

Analysis:

Found: C,673; H,3.5; N,16.4. C14H9N3S requires C, 66.9; H, 3.6; N, 16.7%.

EXAMPLE 32

2,3-Dihydro-2-[2-(6-methylpyridyllthiazolo [3,2-a]benzimidazole In a manner analogous to Example 30 steps a) -> d) 2-bromoacety]-6methylpyridine (11.49) was reacted with 2-chlorobenzimidazole (8.29) to give 1 -[2-(6-m ethyl pyrid-2-yl)-2- oxoethyl]-2-ch 1 o robe nzi mid azo 1 e (8.4g). This was reacted with thiourea, then NH40H to give 1-[2-(6methylpyrid-2-yi)2-oxoethyll-2- 16 GB 2 141 429 A mercaptobenzimidazole (6.9g.); which compound was reduced with NaBH4tO give 1-[2-hydroxy-2-(6methyl pyrid-2-yi)ethyll-2-mercaptobenzim idazole (5.0g.). Treatment of this with polyphosphoric acid gave the title compound (2.1 g.) m.p. 79-81'C.

Analysis:

Found: C,67.0; H,4.8; N,15.6%. C151-113N3S requires: C,67.4; H,4.9; N, 15. 7%.

EXAMPLE 33 2,3-Dihydro-2-[2-(6-methylpyridyl)lthiazolo[3,2albenzamidazole- 1-oxide In a manner analogous to Example 4 2,3-d i hyd ro-2-[2-(6-m ethyl pyridyl)thiazo lo [3,2-al benzim idazo le (1.0g.) was reacted with m-chloroperoxybenzoic acid (0.71g.) to give the title compound as the quaterhydrate, 0.9 g, m.p. 175-177'C.

Analysis:

Found: C,62.2; H,4.4; 14.4%. C151-113N30S.1/41-120 requires: C,62.6; H,4. 7; N, 14.6%.

EXAMPLE 34

2-[2-(6-Methylpyridyl)jthiazolo[3,2-albenzimidazole In a manner analogous to Example 31 1-[2+M ethyl pyrid-2-yl)-2-oxoethy]-2- merca ptobenzimidazol e (1.7g) (prepared according to Example 32) was reacted with polyphosphoric acid (20g) to give the title compound as the 1/4 hydrate, (0.8gJ, m.p. 235-7'C Analysis:

Found: C,67.15; H,4A; N, 15.4% C151-111N3S. 1/41-120 requires: C,66.8; 11,43; N, 15.6%.

EXAMPLE 35

2,3-Dihydro-2-(2-pyridyl)naphth[2',3'.4,5Jimidazo-[2, 1-b1thiazole In a manner analogous to Example 30 steps a) --> d) 2-chloro-1 Hnaphtho[2,3-d]imidazole (7.5g) was 25 reacted with 2-bromoacetylpyricline (8.7g) to give 2-chloro-l-(2-oxo-2-(2- pyridyl)ethyl)naphtho[2,3d1imiclazole (9g), This was reacted with thiourea (5.5g) then NH40H solution (100 ml) to give 2-mercapto-1 (2-oxo-2-(2-pyridyl) ethyl) nap hth o [2,3-d] i m i d azo; which compound was reduced with NaBH4tO give 2-mercapto-l-(2-hydroxy-2-(2-pyridyl)ethyl)naphtho[2,3-alimidazole (1.3g). Treatment of this with polyphos- phoric acid (23g) gave the title compound (0.75g.) mp 197.5-198.5'C.

Analysis:

Found: C,71.2; H,4.25; N,13.5; Cj8H13N3S requires: C,71.3; H,4.3; N,13. 85%).

EXAMPLE 36

2,3-Dihydro-2-[2-(6-phenylpyridyl)]thiazolo[3,2-albenzimidazole In a similar manner to Example 30 steps a)--> d) 2-bromoacetyl-6-phenylpyridine (14.1 g,) is converted to the title compound via the following intermediates: 1-[2-(6-phenylpyrid-2-yi)-2-oxoethyll-2chlorobenzimidazole, 1-[2-(6-phenylpyrid-2-yi)-2-oxoethyll-2-mercaptobenzimidazole and 1-[2hydroxy-2-(6phenyl pyrid-2-yi)ethyll-2-merca pto benzim idazole, m.p. of the title compound = 145-147'C.

Analysis: Found: C,73.25; H,4.9; N,13.1% C20H15N3S requires C,72.9; H,4.6; N, 12.75%.

16 7 EXAMPLE 37

2-[2-(6-Phenylpyridyl)lthiazolo[3,2.-albenzimidazole In a manner analogous to Example 31 1-[2-(6-Phenylpyrid-2-yl)-2-oxoethyll2-mercaptobenzimidazole 45 (2.0g) (prepared as intermediate in Example 36) is reacted with polyphosphoric acid to give the title compound (1.79j m.p. 267-268'C.

Analysis:

Found: C,733; HA.0; N, 12.5%C20H13N3S requires: C, 73.4, H,4.0: N, 12.8%.

EXAMPLE 38

2-(2-Pyridyl)naphth[2'13'.4,5]imidazo[2, 1-blthiazole In a manner analogous to Example 31 1-(2-(2-pyridyi)-2-oxoethyi)-2mercaptonaphtho[2,3-dlimidazole (19) prepared as an intermediate in Example 35 was reacted with polyphosphoric acid to give the title compound (290 mg) mp 261.WC. decomp.

Analysis:

Found: C,71.6; H.3.6; N,133;C181-111N3S requires C, 713; H, 33; N, 13.9%.

EXAMPLE 39 (RRJ-2,3-dihydro-2-(4-methoxypyrid-2-yl)thiazolo-[3,2-albenzimidazole- 1oxide and its (RIS) isomer 60 A solution of 2,3-dihydro-2-[2-(4-methoxypyridyi)lthiazolo[3,2- albenzimidazole (.06g) in CH2C12 (30mi) was cooled to 0'. Purified m-chloroperoxybenzole acid (0.4g) was added and the mixture was stirred 11/2 hr.

Further rn-chloroperoxybenzoic acid (0.05g) was added and the mixture was stirred 1 hour and washed (Na2C03 solution and brine) dried (M9S04) and evaporated. The residue was purified by chromatography on C c X 17 GB 2 141 429 A 17 silica with ROH/ROAc as eluentfollowed by recrystallisation from acetonitrileto give as afirst productthe RR isomerof the title compound (105mg) mp 193-5'C.

Analysis:

Found: C,60.5; H,4.5; N,14.1; C15H13N302S requires: C,60.2; N,4A; H, 14. 0%.

A further component of lower Rf was isolated and recrystallised from acetonitrile to give the corresponding RS isomer of the title compound (90% pure) (115 mg) mp 172-70C.

EXAMPLE40 2,3-Dihydro-2-(2-pyridyl)thiazino[3,2-albenzimidazole 10 a) 3(2- Benzi mid azo lyith i o)-3-(2-pyridyl) pro pion ic acid (3.7g) was suspended in dichloromethane (100 mi) 10 and was cooled to O'C. N,N'Dicyclohexylcarbodiimide (2.559) was added and the mixture was left to stir until Ll.c. showed no starting material. The solvent was removed under reduced pressure and the residue suspended in acetone and filtered. The solvent was removed under reduced pressure and the residue was dissolved in chloroform. The organic 15 solutions was washed with dilute sodium hydrogen carbonate solution then water and was dried (M9S04). 15 The residue was purified on silica using chloroform as eluentto give 2,3 dihydro-2-(2-pyridyi)-[1,31thiazino[3,2-albenzimidazol-4-one 1/4 hydrate (1.8g,) mp 165.5-167.WC decomp. Analysis: Found: C,610; H,42; N,14.7; C15H11N30S.1/41-120 requires: c,63.0; H,4A; N, 14.7%). 20 (b) The product of step a) is reduced using diborane to give the title compound.

EXAMPLE 41 Using a procedure analogous to those hereinbefore described the following compounds of formula 1 are prepared: 25 a) 6,7-dichloro-2(2-(3,5-dimethylpyridyi))thiazolo[3,2-albenzimidazole; b) 6,7-dichloro-2(2-(4-methoxypyridyi))thiazolo[3,2-albenzimidazole; c) 6,7-dichloro-2-(2(3,5-dichloropyridyi))thiazolo[3,2-a]benzimidazole; d) 6,7-dichloro-2-(2pyridyl)thiazolo[3,2-a]benzimidazole; e) 2-(2-(4-methoxypyridyl)-6,7dimethoxythiazolo[3,2-albenzimidazole; 30 f) 2-(2-(3,5-dichloropyridyl)-6, 7-dimethoxythiazolo[3,2-albenzimidazole; g) 2-(2-pyridyl)-6,7dimethoxythiazolo[3,2-albenzimidazole; h) 6,7-di methyl-2-(2-(3,5-di methyl pyridyl))thiazolo [3,2-al benzimidazole; i) 2-(2-(3,5dichloropyridyl))-6,7-dimethyithiazolo[3,2-albenzimidazole j) 2-(2pyridyl)-6,7-dimethy[thlazolo[3,2-albenzimidazole; 35 k) 2-(2-(3,5-cli methyl pyridyl))th iazolo [3,2-al benzim idazole; 1) 2-(2-(4methoxypyridyi))thiazolo[3,2-albenzimidazole; m) 2-(2-(3,5dichloropyridyl))thiazolo[3,2-albenzimidazole; n) 2-(2-(4-m ethyl pyridyl))th iazo 1 o [3,2-al be nzi m idazo 1 e; o) 2-(2-(3hydroxypyridyi))thiazolo[3,2-albenzimidazole; 40 p) 2-(2-(4-methoxy-3,5dimethyl))thiazolo[3,2-albenzimidazole; cl) 2,(2-(3methylpyridyl))thiazolo[3,2-albenzimidazole; r) 2-(2-(4phenylpyridyi))thiazolo[3,2-albenzimidazole; s) 2-(2-(6-cyanopyridyi))-2, 3-dihydrothiazolo[3,2-albenzimidazole or its S-oxide; t) 6- or 7-methoxy2-(2-pyridyl)thiazolo[3,2-albenzimidazole; 45 u) 2-(2-(6carbamoylpyridyi))-2,3-dihydrothiazolo[3,2-albenzimidazole or its S-oxide; v) 6- or 7-trifluoromethyi-2-(2-pyridyl)-thiazolo[3,2-albenzimidazole.

18 GB 2 141429 A 18

Claims (43)

1. A pharmaceu fical composition comprising a compound of formula 1 2 R (0) m 5 R S R 3 m 11 /B1 R B 10 4 z or a pharmaceutically acceptable saItthereof wherein -B-131- represents a chain of formula -(CHR5),,-CHR6or or -CR5=CR 6_ -(CHR 5)n-CR6= (1a) (Ib) (1c) 25 R represents an aryl or heteroaryl radical each optionally substituted by one or more substituents selected from lower alky], lower alkoxy, halogen, alkanoyloxy of 2 to 7 carbon atoms, lower alkoxycarbonyl, halo-lower alkyl, hydroxy, cyano, amino, mono- or di-lower alkyl amino, lower alkanoylamino, carboxy, carboxyloweralkyl, hydroxylower alkyl, carbamoyl, carbamoyloxy, lower alkyl- or aryl-carbonyl, (loweral koxy) lower alkoxy, or phenyl, or a phenyl group itself optionally substituted by substituents as hereinbefore defined excepting phenyl; W, R 2, R 3 and R 4 independently represent hydrogen, or a substituent as mentioned above in connection with the group R, orany adjacent pairof W, R 2, R'and R 4 together with the carbon atoms to which they are 35 attached complete a five or six membered saturated or unsaturated carbocyclic or heterocyclic ring, said ring being optionally substituted by a substituent as defined above in connection with the group R, said heterocyclic ring having at least one heteroatom selected from oxygen, nitrogen and sulphur; R' and R' independently represent hydrogen or lower alkyl; n and m independently represent 0 or 1, providing that when -B-Bl-has formula 1 (a), n is 1 and m is 0 then R is heteroaryl, the term "heteroaryV 40 means a monovalent aromatic heterocyclic group in which the ring heteroatom or atoms islare selected from oxygen, nitrogen and sulphur, the term 'lower'means a group containing 1 to 6 carbon atoms; and a pharmaceutically acceptable carrier.

2. A composition as claimed in Claim 1 wherein -B-Eghas formula]a or]c and n is 0.

3. A composition as claimed in Claim 1 or Claim 2 wherein R represents a phenyl, naphthy], pyridyl, thienyi, furyl, thiazolyl, quinolyl, isoquinolyl or indolyl group each optionally substituted as defined in Claim 1.

4. A composition as claimed in Claim 1 or Claim 2 wherein R represents phenyl, pyrid-2-y] or pyrid-3-y] each optionally substituted by lower alkyl, lower alkoxy, halogen, phenyl, halopheny], lower alkylphenyl or lower alkoxyphenyl.

5. A composition as claimed in anyone of Claims 1 to 4wherein R2and R 3 are selected from hydrogen, lower alkyl, alkoxycarbonyl of 2 to 7 carbon atoms, halogen or lower alkoxy.

6. A compound of formula 1 as shown in Claim 1 or a pharmaceutically acceptable saitthereof wherein R, W, R2, R 3, R 4, m and -B-B' - are as defined in any one of Claims 1 to 5 for use as an anti-ulcer or anti-secretory agent.

7. A compound of formula 1 as shown in Claim 1 or a saitthereof wherein R, W, R 2 R 3 R 4, m and -B-Bl are as defined in any one of Claims 1 to 5 with the provisos (i) when -B-E3-is a chain of formula la, n is 1 and m is 0 then R is heteroaryl, or (ii) when -B-Bi-is a chain of formula la, n is 0 R' and R 2 together with the carbon atoms to which they are attached represent a 6 membered unsaturated carbocyclic ring and R is phenyl or p-nitrophenyl then m is 60 1, or (iii) when -B-Blis a chain of formula [c, n is 0 R' and R 2 togetherwith the carbon atoms to which they are attached represent a 6-membered unsaturated carbocyclic ring and R is phenyl, 2-thienyl, p methoxyphenyl or p-bromophenyl then m is 1, or (iv) when -B-B-is a chain of formula lc, n is 0 R6 is hydrogen or lower alkyl and W, R 2 and R 4 are 65 1 4 19 GB 2 141 429 A 19 hydrogen, R' is hydrogen or hydroxy and R is phenyl, p-chloropheny], p- bromophenyl, p-tolyl, p methoxyphenyl, p-phenylpheny], l-naphthyl or 2-thienyl, then m is 1.

8. A compound as claimed in Claim 7 wherein -B-B-1-has formula la or le and n is 0.

9. A compound as claimed in Claim 7 or Claim 8 wherein R represents a phenyl, naphthyl, pyridyi, thienyi, furyl, thiazolyl, quinoly], isoquinolyl or indolyl group each optionally substituted as defined in Claim 5 7.

10. A compound as claimed in Claim 7 or Claim 8 wherein R represents phenyl, pyrid-2-yl or pyrid-3-yl each optionally substituted by lower alkyl, lower alkoxy, halogen, phenyl, halophenyl, lower alkylphenyl or lower alkoxyphenyl.

11. Acompound as claimed in anyone of Claims 7 to 10wherein R 2 and R 3 are selected from hydrogen, 10 lower alkyl, alkoxycarbonyl of 2 to 7 carbon atoms, halogen or lower alkoxy.

12. 2,3-Dihydro-2-(2-pyridyi)thiazolo[3,2-albenzimidazole-1 -oxide.

13.

14.

15.

16.

17.

18.

19.

20.

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22.

23.

24.

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31.

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36.

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38.

39.

6,7-Dich 1 o ro-2,3-d i hyd ro-2-(6-m ethyl pyri cl-3-y1)th i azo 1 o-[3, 2-al be nzi m idazol e. 2,3-Dihydro-6,7-dimethyi-2-(2-pyridyi)-thiazolo[3,2-albenzimidazole-1 -oxide. 6-Chloro-2,3-dihydro-2-(2pyridyi)thiazolo[3,2-albenzimidazole-1 -oxide. 7-Chloro-2,3-dihydro-2-(2pyridyi)thiazolo[3,2-albenzimidazole-1 -oxide. 2-(2-(5Ethylpyridyl))thiazolo[3,2-a)benzimidazole. 7-Ethoxy-2-(2pyridyi)thiazolo[3,2-albenzimidazole. 6-Ethoxy-2-(2-pyridyl)thiazolo[3,2albenzimidazole. 6,7-Dichloro-2,3-dihydro-2-(2-pyridyl)thiazolo[3,2-albenzimidazole. 2,3-Dihydro6-methy]-2-(2-pyridyl)thiazolo[3,2albenzimidazole-1 -oxide. 2,3-Dihydro-7-methy]-2-(2-pyridyl)thiazolo[3,2albenzimidazole-1 -oxide. 2,3-Di hyd ro-7-m ethoxyca rbo nyi-6-m ethyl -2(2-pyridyi)-th iazo 1 o [3,2-al be nzi m idazo 1 e- 1 -oxide. 2,3-Di hyd ro-6-m ethoxyca rbo nyi-7-m ethyl -2-(2-pyri dyi)-th iazo 1 o [3,2-al be nzi mid azo 1 e- 1 -oxide; 2,3-Dihydro-6-methoxycarbonyi-2-(2-pyridyl)thiazoio[3,2-al-benzimidazole-1 -oxide. 2,3-Dihydro-7-methoxycarbonyl-2(2-pyridyi)-thiazolo[3,2-a]-benzimidazole-1 -oxide. 2,3-Dihydro-2-[2-(6phenylpyridyi)jthiazolo[3,2-al-benzimidazole. 2,3-Dihydro-2-(2pyridyl)thiazolo[3,2-al-benzimidazole. 2,3-Dihydro-2-phenyithiazolo[3,2albenzimidazole. 2,3-Dihydro-2-phenylthiazolo[3,2-albenzimidazole-1 oxide. 2,3-Di hyd ro-2-(6-m ethyl pyri d-3-yl)th iazo 1 o [3,2-a 1 benzi mid azo 1 e. 2,3-Dihydro-6-methyi-2-(2-pyridyl)thiazolo[3,2albenzimidazole. 2,3-Di hyd ro-7-m ethyl 21(2-pyri dyi)-th i azo 1 o [3,2a 1-benzi mid azo 1 e. 2,3-Dihydro-6,7-dimethyi-2-(2-pyridyl)thiazolo[3,2al-benzimidazole. 2,3-Dihydro-5-methyl-2-(2-pyridyi)thiazolo[3,2-albenzimidazole. 2,3-Dihydro-8-methyl-2-(2-pyridyi)thiazolo[3,2-albenzimidazole. 2,3-Dihydro-8-methyl-2-(2-pyridyi)thiazolo[3,2-a]benzimidazole-1 -oxide. 2,3-Dihyd ro-2-[2-(6-m ethyl pyridyl)th iazo lo [3,2-al-benzimidazole-1 -oxide. A compound as claimed in any one of Claims 7 to 38 when in the form of a salt of an acid selected 40 from hydrocholoric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric, methanesulphonic, ptoluenesulphonic, acetic, maleic, citric, fumaric, tartaric, malonic and formic.

40. A pharmaceutical composition comprising a compound as claimed in anyone of Claims 12to 38 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

41. A process for preparing a compound of formula 1 as claimed in Claim 7 characterised in that 45 a) a compound of formula 11 _) R' (0)m R 1 N,,: S,1,1,R 50 R 3 N B' 4 H R X (11) 55 2 3 4 wherein -B-B'-, n, m, R, W, R, R, R, R 5 and R' are as defined in Claim 7, and X is OH or a leaving group, providing that (i) when -B-B'- has formula la and n is 0 or 1, or formula lc and n is 1 then X is not OH; and 60 (ii) when -B-B' - has formula lb then X is OH; is cyclised; or GB 2141 429 A (b) a compound of formula (IV) R 1 SH R 3, NH 4 R (IV) 10 is reacted with a compound of formula (V) X R H 15 (V) ik H 5 20 X(CHR)n F in which formulae R, W, R 2, R 3, R 4, R5, R' and n are as defined in Claim 7 the X groups being the same or different halogens, to give a compound of formula 1 wherein -B-B' - has formula]a and additionally when Xis bromine and n is 0 in the compound of formula Vto give a compound of formula 1 wherein -B-B'- has 25 formula]c wherein n is 0; or c) a compound of formula R 2 P11 NA B2 R Y ' - - 1 30 3 - N, R B R (V1) wherein -B - B' -, n, R, W, R 2, R 3, R 4, R' and R' are as defined in Claim 7 and one of A and B 2 is -SH, the other is a leaving group providing that when A is SH then B 2 may also represent OH, is cyclised to give a compound of formula 1 wherein m is 0; d) reacting a compound of formula VIII R 2 R1 N, CL HO,, R 40 f..11 j 'E3,,B 45 4 P, (Vill) wherein -B-B'-, W, R 2 R 3 R 4, R5 and R' are as defined in Claim 7, with thiourea followed by heating in the 50 presence of an alkali metal hydroxide or NH40H to give a compound of formula 1 wherein -B-B' has formula lc; or e) a compound of formula R 2 R' N S R 55 6 3 N, ACHR), R CO 60 P, (1x) wherein R, W, R 2, R3, R 4 and R 6 are as defined in Claim 7 and p is 0 or 1 with the proviso that when p is 1, R is heteroaryl, is reduced to give a compound of formula 1 wherein m is 0, -B- Bl- has formula la and either n 65 v v 21 is 1 and R5 is hydrogen or n is 0 and R' is hydrogen; or GB 2 141 429 A 21 f) a compound of formula 2 RI R N l-a hol R 1 y 5 R - 3 N, B' 4 B R w) wherein -B- B' -, hal, n, R, R', R 2, R 3, R 4, R' and R' are as defined in Claim 7, is reacted with (i) an alkali 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 1 wherein m is 0; or g) a compound of formula X11 or X111 2 R PM N, S R D 20 R 3 3 N E R CMR 5)n R6(X' 1) R 2 or R (0)m 25 R N S R H R6 3 5 D 30 4 R E (X111) R in which formulae R, R', R 2, R3, R 4, R5, R' and m are as defined in Claim 7 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 35 compound of formula 1 wherein -B-B'- has formula lb or lc; or h) a compound of formula - R' R 2 N (0)m 40 1 'S"CH2R 0 (XIV) 3 1 N 1-111A R 4- (C H R 9n - C R'-j 45 R 2 4 6 wherein R, R', R, R3, R, Rs, R, m and n are as herein defined in Claim 7, is cyclised to give a compound of formual 1 wherein -B-Bl-has formula lc; or i) a compound of formula 1 wherein m is 0 is oxidised to the corresponding oxide of formula 1 wherein m is 50 1 or the compound of formula 1 wherein m is 1 is reduced to give a compound of formula 1 where m is 0; or j) a compound of formula 1 in which -B-B'- does not contain a double bond is oxidised to a compound of formula 1 in which a double bond is present or vice versa by reduction; or k) a compound of formula 1 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.

42. A process as claimed in Claim 41 for preparing a compound of formula 1 substantially as hereinbefore described with reference to any one of Examples 1 to 18; 20 to 25, 26(b), 27 to 29; 30; (d); 31; 32 step (d); 33; 34; 35 step (d); 36 step (d); 37; 38; 39 and 40 (b).

43. A compound of formula 1 as claimed in Claim 7 whenever prepared by a process as claimed in Claim 41 or Claim 42.

Printed in the UK for HMSO, D8818935, 10184, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.