NO882321L - CONNECTIONS. - Google Patents

Abstract

Compounds of the formula :. wherein A is an S- or 6-membered, completely unsaturated,. karboeyk Angry or heterocyclic ring. B is a 5- or 6-membered, completely unsaturated, nitrogen-containing heterocyclic ring, X is KR. 0 is S, R is hydrogen or alkyl optionally substituted with -OCOR, n is 0 or 1, R, R, R, R (,, R, R, R <j and Ro have different meanings. R , or together with the ring carbon atoms to which they are attached form a benzene or pyridine ring, which ring carries substituents R5, R17, R17 and R5- wherein R8 has different meanings, with certain reservations. pharmaceutical preparations Containing these compounds, eg for the treatment of conditions Including excessive gastric acid secretion are also described.

Description

The present invention relates to new compounds, methods for their production and pharmaceutical preparations containing the compounds.

According to the invention, compounds of the formula are provided:

where A is a 5- or 6-membered, fully unsaturated, carbocyclic or heterocyclic ring,

B is a 5- or 6-membered, fully unsaturated, nitrogen-containing heterocyclic ring,

X is NRig, 0 or S,

R-L9 is hydrogen or alkyl, optionally substituted with

-OCOR,

n is 0 or 1,

<R>3,<R>4,<R>5, Rfc, R7, R8, Rg and Rio»which may be the same or different, are selected from hydrogen, alkyl, halogen, -SR, benzoyl, —NO2, — N<R>2o<R>21»—COOH or an ester or amide thereof, or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group, or

in addition to the meanings given above, an adjacent pair of R 3 to R 2 , or R 7 to R 2 q together with the

ring atoms to which they are attached form a 5- or 6-membered, fully unsaturated, carbocyclic or heterocyclic ring bearing substituents Rn,<R>12»R13°S<R>14»

R11»<R>12»<R>13 °S R14 which may be Uke or different, is selected from hydrogen, alkyl, alkoxy, halogen, -SR, benzoyl, -NO2, -NR2oR21 or -CO2H or an ester or an amide thereof ,

with the exception that when ring A, ring B or the ring formed by an adjacent pair of R3 to R5 or R7 to R^q is 5_ membered, then R5, R^q or R14 respectively have no meaning,

R 1 and R 2 , which may be the same or different, are selected from hydrogen or alkyl, or may, together with the ring carbon atoms to which they are attached, form a benzene or pyridine ring, which ring carries substituents R 15 ,<R>16»<R >17 and R^g, R15'<R>16»<R>17 °S<R>18» which may be the same or different, are selected from hydrogen, alkyl, halogen, -SR, benzoyl, alkoxy, -NO2, —NR20,<R>21 or —CO2H or an ester or an amide thereof, or

in addition to the meanings given above, an adjacent pair of R 15 , R 16 , R 17 and R 18 , together with the ring carbon atoms to which they are attached, can form a 5- or 6-membered, carbocyclic or heterocyclic ring,

R2Q and<R>2i»which may be the same or different, are selected from hydrogen, alkyl, phenyl or may, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring, which ring may contain a further heteroatom, R is hydrogen, phenyl or alkyl, optionally substituted with phenyl,

provided that when R^ and R2 together with the ring carbon atoms to which they are attached form a benzene ring, A is a benzene ring, and B is a pyridine ring, then

i) when R 3 to R^ and R 7 to<R> 10 are each different from alkoxy substituted by OH or by an optionally protected oxo group, and either an adjacent pair of R 3 to R^ or of R 15 to R 18 does not form a 5-membered fully unsaturated carbocyclic or nitrogen-containing heterocyclic ring or a 5- or 6-membered fully unsaturated oxygen- or sulfur-containing heterocyclic ring, or an adjacent pair of R7 to R10 does not form a 5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring, and each of R3 to R6, R7 to<R> 10 and <R>15 to <R>18 are different from NR20<R>21», where R20 and R21», together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring, which ring may contain an additional heteroatom, then at least one of R3 to R-^g is selected from alkyl, alkoxy, SR or N<R>2oR21nvor<R>20°S R21' which may be Uke or different, may be hydrogen, alkyl or phenyl, and

ii) when X is NR-^g, R1, R3 to R^ and R15 to R^g are each hydrogen, and one of R7 to R^q is a methoxy group positioned para to the ring nitrogen atom, then the remainder of R7 to R^q is not each hydrogen,

and pharmaceutically acceptable salts thereof.

According to the invention, a method for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided, which includes

a) selective oxidation of a compound of formula (I) where n is 0, to a corresponding compound of formula (I)

where n is 1,

b) modification of a compound of formula (I) containing one or more groups which can be converted into a

group —NH2, —CH2OH or C=0, to a compound of formula (I) Containing a group —NH2-, CH2OH or C=0,

c) reacting a compound of formula (I) where X is N<R>^g where R^g is hydrogen, with a compound R22Z where R22

is as defined for R^g above, except that it cannot be hydrogen, and Z is a good leaving group,

d) conversion of a compound of the formula:

where R 1 , R 2 and X have the meanings given above, with a

where R3, R4, R5, R6, R7, R8, Rg, Rio»A and B have the meanings given above, and

one of D and E is -SH or S", and the other is a good leaving group, or

e) reaction of a compound with the formula:

where % to R 5 , n, X and A have the meanings given above, with a compound of the formula:

where R7 to R10 and B have the meanings given above,

and, if desired or necessary, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof, or vice versa.

The selective oxidation in method a) can be carried out in a solvent which is inert under the reaction conditions, e.g. ethyl acetate, dichloromethane, chloroform or a mixture thereof. The reaction is preferably carried out at below room temperature, e.g. from -20 to +20°C. Suitable oxidizing agents for use in the reaction are hydrogen peroxide; peracids, e.g. m-chloroperbenzoic acid; or t-butyl hydroperoxide in the presence of a suitable catalyst, e.g. vanadyl acetylacetonate, or periodates, e.g. Natrlum periodate in aqueous alcohol, e.g. methanol.

The modification of one group to another in method b) can be selective reduction, e.g. -NO2 to -NH2 or HC=0 to CH2-OH, or selective hydrolysis, e.g. of a protected carbonyl group to C=0. The selective reduction of —N02 to NH2 can e.g. is carried out chemically under basic conditions, e.g. using hydrazine and Raney nickel, but is preferably carried out using hydrogen and a catalyst, e.g. PtO 2 in ethanol, as reaction medium. The selective reduction of CH=0 to CHqH can e.g. unreduced by the use of sodium borohydride. The selective hydrolysis is preferably carried out in an aqueous solution under acidic conditions.

In method c), the good leaving group can e.g. be halogen (chlorine or lead), and the reaction can be carried out in a solvent or solvent mixture which is inert under the reaction conditions, e.g. dimethylformamide, in the presence of a base, e.g. potassium carbonate and at a temperature in the range 15-35°C, e.g. at 20-25°C.

For method d), a good leaving group can be a sulfone, e.g. —SO 2 Me, or a halogen, e.g. chlorine or bromine. The reaction can be carried out in any suitable solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide or methanol, at a possibly elevated temperature, and can take place in the presence of a catalyst, e.g. Cu or an acid acceptor, e.g. potassium carbonate. It is preferred that D is a good leaving group, and E is SH or S-.

The reaction in method e) can be carried out in any suitable solvent, e.g. water, and at a temperature in the range 50-100°C, e.g. at approx. 80°C.

The compounds of formula (II) can be prepared from known compounds using conventional techniques known per se, e.g. the compounds of formula (II) where X is NH, and D is SH or S", can be prepared, for example, by reacting a compound with the formula:

where R 2 and R 2 have the meanings given above, with CS 2 . The reaction is preferably carried out under nitrogen and at a temperature in the range 50-80°C. The compounds of formula (II) where D is a sulfone, e.g. -SO 2 Me, can be prepared from the corresponding thiol compound, e.g. by reaction first with methyl iodide and potassium carbonate in dimethylformamide at a

temperature in the range 0-50°C followed by treatment with Okson (registered trademark of DuPont Co, peroxy monosulfate) in aqueous methanol at a temperature in the range 0-50°C.

The compounds of formula (III) can be prepared from known compounds using conventional techniques known per se, e.g. the compounds of formula (III) where E is

—SH or S", can be prepared using the following reaction-

road :

where R 3 to Rio, A and B have the meanings given above.

The oxidation in step (I) can be carried out as described for method

a) above. Step 2 can be carried out e.g. with trifluoroacetic acid and triethylamine in methanol. Under oxidation conditions

(e.g. in the presence of air) a disulfide may be a by-product in step 2. The disulfide may be converted to the corresponding sulfide by reduction. Suitable reagents for this reduction are sodium borohydride and sodium cyanoborohydride.

The compounds of formula (VIII) can be prepared by a coupling or ring closure reaction as shown below.

a) Coupling

Reaction of a compound of the formula: where R 3 to R 5 and A have the meanings given above, and G is a metal ion (e.g. lithium) or a Grignard reagent (e.g. MgBr), with a compound of formula (Va) or its N-oxide or ortho-halo (e.g. o-fluoro) derivative,

where R 7 to R 7 and B have the meanings given above,

b) Looping

Reaction of a compound with the formula:

where Z is a good leaving group, e.g. chlorine, with e.g.

i) when ring B is pyridine, CH3-C(0 )-CH=CH-OMe, followed by NH3, or

ii) when ring B is imidazole, NH2C(R7 ) = C(R8)NH2, where R7 and Rg have the above meanings.

The compounds of formula (IV) can be prepared by diazotization of a compound of the formula:

where R 1 to R 5 , X, n and A have the meanings given above. The diazotization can be carried out in any suitable solvent, e.g. water, in the presence of acid, e.g. hydrochloric acid, at a temperature in the range 0-15°C, e.g. below 5°C, with an alkali metal nitrite, e.g. sodium nitrite.

The compounds of formula (VI) are either known or can be prepared by conventional processes known per se, e.g. by processes analogous to methods a), b), c) or d) described above for the preparation of compounds of formula

(IN).

The compounds with formulas (V), (Va), (VII), (IX) and (X) are either known or can be prepared by conventional processes known per se.

The compounds of formula (I) and their intermediates can be isolated from their reaction mixtures using conventional techniques.

Some of the compounds of formulas (III), (VIII) and (Villa) are new, and these new compounds are provided for use as intermediates in the synthesis of compounds of formula (I) as defined above.

In particular, compounds with the formula:

where Ea is SH, S~, SMe or SOMe, ring A is a benzene or thiophene ring, R3 to R^ have the meanings given above, and ring B is either a pyridine ring bearing substituents R7 to Rig as defined above, except that an additional opposing pairs of R7 to R^q cannot together with the carbon atoms to which they are attached form a ring, or ring B and an adjacent pair of R7 to R^q form a 1-isoquinolinyl-, 2-imidazo(l,2-a )pyridine- or 2-N-alkylated-benzimidazolyl group, new and are provided for use as intermediates in the synthesis of compounds of formula (I) as defined above.

Pharmaceutically acceptable salts of the compounds of formula (I) include salts with suitable organic or inorganic acids, e.g. with a hydrohalic acid, sulfuric acid, alkanesulfonic acid, tartaric acid or citric acid. When the compound of formula (I) carries a —COH or other acidic group, salts with suitable organic and inorganic bases are also provided, e.g. ammonium, alkali metal1, alkaline earth metal, alkylamino, etc. salts. The benzimidazole nucleus itself is acidic and can form salts with appropriate bases as indicated above. The compounds of formula (I) and pharmaceutically acceptable salts thereof are also provided for use as pharmaceuticals, e.g. for use as cytoprotective agents, in the treatment or prophylaxis of inflammatory conditions, as mucosal protective agents, or in the prevention or inhibition of gastric acid secretion.

The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful because they possess pharmacological activity in animals, in particular they are useful because they have cytoprotective properties, are useful in the treatment or prophylaxis of inflammatory conditions and/or to prevent or inhibit gastric acid secretion, e.g. in the test indicated Am. J. Physiol., 1982, 243(6), G505-510. The compounds of formula (I) are also useful as intermediates in the synthesis of other chemicals.

The new compounds are thus indicated for use in preventing or inhibiting gastric acid secretion, and/or conditions that normally involve strong gastric acid secretion, e.g. peptic, duodenal, gastric, recurrent or storm ulceration, dyspepsia, duodenitis, Zollinger-Ellison syndrome, reflux oesophagitis and bleeding, e.g. from erosion of ulcers in the upper part of the gastrointestinal tract, especially when a major blood vessel is not involved. The compounds can also be used to treat gastritis or dyspepsia associated with the administration of non-steroidal anti-inflammatory drugs, in the prophylaxis of bleeding in the gastrointestinal tract from stress ulceration in severely ill or burned patients, in the prophylaxis of recurrent bleeding in patients with bleeding peptic ulcer, before general anesthesia of the patients at risk of acid aspiration syndrome (Mendelson's syndrome) and to reduce the chance of bleeding in patients with leukaemia, host disease In connection with transplantation or with severe hepatic failure. The conditions mentioned above can be treated whether they are associated with excessive gastric acid secretion or not.

The compounds can also be used to treat cholera, para-typhoid, tourist's diarrhoea, toxin-induced diarrhea and local gastric catarrh.

The new compounds are also indicated for use as cytoprotective agents, especially for the gastrointestinal tract, and can be used for the treatment or prevention of a non-gastric acid-induced, non-traumatically induced, non-neoplastic gastrointestinal inflammatory disease, e.g. e.g. Crohn's disease, inflammatory bowel disease, infectious enteritis, colitis, ulcerative colitis, pseudomembranous colitis, diverticulitis and allergic and radiological inflammatory diseases.

The compounds are also indicated for use in the treatment or prophylaxis of inflammatory conditions in mammals, including humans, especially those involving lysozymal enzymes. Conditions that can be particularly mentioned are: rheumatoid arthritis, gout, eczema, polyserositis and allergic alveolitis.

Patterns of therapeutic use that can be mentioned are:

a) a high dose to begin with, in e.g. 2-4 weeks, followed by continued therapy at a lower dose after the condition

has improved, e.g. the stomach ulcer has healed,

b) as in a) above, but the continued therapy includes another cytoprotective agent, e.g. a PGE_

derivative,

c) combination therapy using a low dose of the compound of the present invention in conjunction with a

low, well-tolerated dose of another cytoprotective agent and/or antacid, d) intermittent dosing, e.g. every 2 days, may be appropriate as continued therapy.

For the above applications, the dose administered will naturally vary with the compound used, the method of administration and the desired treatment. In general, however, satisfactory results are obtained when the compounds are administered at a dose of from 10~^M to 10"^M in the test set forth in Am. J. Physiol , 1982, 243 (6), G505-G510. For man, the indicated total daily dose is in the range of from about 1 mg to 3000 mg, preferably to 500 mg, and -more preferably from about 10 mg to 200 mg, which can be administered in divided doses from 1 to 6 times daily or in a sustained release form. calculated for administration thus comprises from about 1.0 mg to 600 mg of the compound mixed with a solid or liquid pharmaceutically acceptable diluent, carrier or excipient.

The compounds of formula (I) and pharmaceutically acceptable salts thereof have one or more of the following advantages. They are absorbed more easily, have increased bioavailability, are more stable around neutral pH, are less irritating to the gastrointestinal tract, are more specific in their effect, have less toxic side effects, are more easily activated by acid, e.g. stomach acid, are more stable against acid, e.g. stomach acid, gives beneficial results, e.g. in the "Shay rat test" as described by H. Shay et al. in Gastroenterology, 5 43-61 (11945) or has other advantageous properties compared to known compounds with a similar structure.

Ring A may be carbocyclic or a heterocycle containing O, S or N. When ring A is a heterocyclic ring, it is preferred that it contains a heteroatom. Specific groups that ring A may represent include furan, pyridine, benzene or thiophene. It is preferred that ring A is a benzene or tipophene ring. When ring A is a pyridine ring, it may be attached to the -S(0)n group in the 4-position, and to ring B in the 3-position, or it may be attached to the -S(0)n group in the 3 - position and to ring B in the 2 position. When ring A is a thiophene ring, it may be attached to the —S(0)n group at the 2-position and to ring B at the 3-position, or it may be attached to the —S(0 )n group at the 3- the position and to ring B at the 2 position.

Ring B may contain one or two further heteroatoms and preferably one or two further nitrogen atoms. It is particularly preferred that ring B is a pyridine or imidazole ring. When ring B is an imidazole ring, it may be attached to ring A at its 2- or 4-position. When ring B is an imidazole ring, it may be N-substituted, e.g. N-alkylated. When ring B is an imidazole ring linked to ring A at its 2-position, it is preferred that it be an N-methylated imidazole.

It is preferred that X is 0 or more preferably NR-2g. R-^g can be methyl or preferably hydrogen.

It is preferred that n is 1.

When any of R 3 to R 3 is halogen, it may be chlorine or fluorine.

When any of R 1 to R 22 or R 2 represents or contains a carbonaceous group, it is preferred that the group contains up to and including 10, and preferably up to and including 6, carbon atoms.

When any one of R 3 to R 4 represents an ester, it is preferred that it is derived from a C 1 -C 4 alcohol, e.g. that it is a methyl or ethyl ester.

Specific groups R3, R4, R5, R6, R7, Rg, Rg and R10 include hydrogen, methyl, ethyl, chlorine -NR20<R>21, methoxy, ethoxy, propyloxy, isopropyloxy, ethoxy substituted with OH, with oxo group and with a protected oxo group, e.g. a ketal, especially ethylenedioxy.

When an adjacent pair of R 3 to R 1 or R 7 to R 1 together with the ring carbon atoms to which they are attached form a ring, it is preferred that this ring be a carbocyclic ring and more particularly a benzene ring. When an adjacent pair R 7 to R 8 forms such a ring, it is preferred that ring B is a pyridine or imidazole ring. When an adjacent pair of R7 to R-Lg forms a ring, it is particularly preferred that those with ring B form a 1-isoquinolinyl-, 2-imidazo(1,2-a)-pyridine- or more particularly a 2-benzimidazolyl- group.

Specific groups<R>n,<R>12»<R>13or R14 include hydrogen, halogen (eg chlorine) or alkoxy.

It is preferred that R 1 and R 2 , together with ring carbon atoms to which they are attached, form a benzene ring.

Specific groups R15, <R>16, R17 and R18 include hydrogen, methyl, methoxy, ethoxy, chlorine -NO2, -NR20<R>21, benzoyl, methoxycarbonyl and ethoxycarbonyl.

When an adjacent pair of R 15 to R 15 forms a 5- or 6-membered ring, it may be saturated, partially unsaturated or fully unsaturated, and may contain 0, 1 or 2 heteroatoms. It is preferred that the ring is carbocyclic, or that it is an oxygen-containing heterocyclic ring. It is particularly preferred that the ring is a benzene ring or a 1,3-dioxylan ring.

It is preferred that R 15 to R 18 are selected from hydrogen, alkyl or alkoxy.

Specific groups R 20 and<R> 21 include hydrogen, methyl and phenyl.

When R 20 and R 21 , together with the nitrogen atom to which they are attached, form a ring containing a further hetero atom, it is preferred that the hetero atom is oxygen. When R 20 and R 21 , together with the nitrogen atom to which they are attached, form a ring, it is preferred that the ring is a pyrrolidino or morpholino ring.

When R-L and R2 form a benzene ring, A is a benzene ring and B is a pyridine ring, it is preferred that at least one of R3 to Rfc, R7 to R10 and Rn to R14 is selected from methyl, ethyl, methoxy, ethoxy, propyloxy, isopropyloxy, ethoxy substituted with OH , with an oxy group or with a protected oxo group, or -N<R>2o<R>21where R 20 and R 2 ^ represent methyl, phenyl or, together with the nitrogen atom to which they are attached, form a pyrrolidino or morpholino ring.

When ring A is a benzene ring attached to the —S(0 )n group in the 2-position and to ring B in the 1-position, it is particularly preferred that the substituent in the 4-position (i.e. para to the position for attachment of ring B ) is selected from alkyl, —SR, —NR 20 R 2 I or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group.

When ring B is a pyridine ring attached to ring A in the 2-position, it is preferred that the substituent in the 4-position (i.e. para to the ring N atom) is selected from alkyl, —SR, —NR2fjR21 or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group.

Particularly preferred are compounds of formula (I) where Ri and R2, together with the ring carbon atoms to which they are attached, form a benzene ring which benzene ring carries substituents Rifc, Ri6»R17°g R18»x is NR19»R19 is hydrogen, n is 1, A is a benzene ring, and ring B is a pyridine ring attached to ring A in the 2 position and has a substituent para to the ring N atom selected from alkyl, —SR, —NR2qR21 or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group, or that ring B is an imidazole ring attached to ring A in the 2-position, and where the substituents in the 4- and 5-style rings, together with the ring carbon atoms to which they are attached, form a benzene ring, which benzene ring carries substituents Rj^, Ri2><R>13°S<R>14*

Specific groups of compounds of formula (1) include:

where at least one of R5a, R6a,<R>7a,<R>8a,<R>ga,<R>10a, Rlla and R12a is selected from alkyl, alkoxy, or -NR20<R>21, °& the rest of R5a to' Ri 2 ah is hydrogen, halogen, —NO 2 , or —COOH or an ester or amide thereof,

<R>la><R>2a»<R>3a °§<R>4a»which may be the same or different, each being hydrogen, halogen, alkyl, alkoxy, -NO2, -NRaR14a or -COOH or an ester or amide thereof,

<R>19><R>20 °S<R>21when the meanings given above,

Ra and<R>i4a, which may be the same or different, are each hydrogen, phenyl, or alkyl;

provided that when Rla,<R>2a,<R>3a, R4a, R5a,<R>6a, R7a,<R>ga><R>ga,<R>lla»<R>12a°S<R> 15aaile is hydrogen, then Rioa is not methoxy,

where Atø represents a 5- or 6-membered nitrogen, oxygen or sulfur-containing fully unsaturated heterocyclic ring which is connected to the —SO group through a ring carbon atom, and which may be fused to a benzene ring,

Etø represents a 5- or 6-membered nitrogen-containing fully unsaturated heterocyclic ring, which may be fused to a benzene ring,

R^bog R2b»which may be the same or different, each is hydrogen or alkyl, or may, together with the carbon atoms to which they are attached, form a benzene or pyridine ring which in turn may be substituted with one or more substituents<R> ia,<R>2a><R>3a><R>4as defined above,

Rio has the meaning set out above,

where at least one adjacent pair of Rgc, Rifjc» Rllc °g R12c» together with the ring atoms to which they are attached, form a

5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring,

and the remainder of Rgctil Ri2cer as defined for R^ao above,

A is a 5- or 6-membered fully unsaturated nitrogen-containing heterocyclic ring,

<R>19a«<R>la»<R>2a»R3a°S R4anar the meanings given above,

R5c<R>6c«<R>7c °S<R>8c have the meanings given for R^a to R4ao above, and, in addition, an adjacent pair of R5c»<R>6c»R7c°S R8c• together with the ring atoms to which they are attached, form a 5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring.

According to the present invention, there is also provided a pharmaceutical preparation including (preferably a smaller proportion of) a compound of formula (1), or a pharmaceutically acceptable salt thereof, as active ingredient, in admixture with a pharmaceutically acceptable aid, diluent or carrier . Examples of suitable aids, diluents or carriers are: - for tablets and dragées; lactose, starch, talc or stearic acid; for capsules, tartaric or lactose; for suppositories, natural or hardened oils or waxes; and for injections (i.m. or i.v.) or enema water, surfactants and preservatives. The compounds can also be administered transdermally, e.g. in an ointment base. The compound of formula (I) or the pharmaceutically acceptable salt thereof preferably has an average mass diameter of 0.01-10 µm. The compound with such a particle size can be produced by crushing or grinding followed, if necessary, by particle size classification using e.g. of a term. The preparations may also contain suitable preserving, stabilizing and wetting agents, solubilizing agents, sweetening, coloring and flavoring agents. The preparations can, if desired, be formulated in a form with a long-term release effect.

The compounds may, if desired, be co-administered with (eg as admixture with) an antacid buffer.

Preparations which are intended for ingestion or rectally and which release their contents in the intestine are preferred. Preparations which will pass through the acidic parts of the gastrointestinal tract unaffected, e.g. enteric-coated preparations.

Some of the compounds of formula (I) are optically active and can be resolved into their optical isomers using conventional techniques known per se. The invention therefore provides the compounds as their optical isomers, or as mixtures, e.g. racemic mixtures thereof.

The compounds of formula (I) can exist in tautomeric forms, and these tautomeric forms are included in the definition of the compounds of formula (I). In particular, when X is R19, and R1 is hydrogen, the imidazole nucleus can exist in tautomeric forms.

The invention is illustrated, but not limited in any way, by the following examples in which temperatures are in degrees Celcius.

Example 1

2- r4- dimethylamino- 2-( 4- methoxy- 2- pyridinyl) phenylsulfinyl- 1H- benziraidazole

a) 2-(2-hydroxy-5-nitrophenyl)-4-methoxypyridine

4-Nitrobenzenediazonium tetrafluoroborate (65.8 mmol) was added

portionwise while stirring at room temperature to a dissolve-

ing of 4-methoxypyridine-N-oxide (50 mmol) in acetonitrile (150 ml). The mixture was stirred overnight at room temperature, treated with triethylamine (100 mmol), and the spent solution was heated under reflux for 15 min.

The solvent was removed in a rotary evaporator and the residue flame chromatographed on silica eluting with chloroform to give the sub-title compound.

b) 2-(2-hydroxy-5-nitrophenyl)-4-methoxypyridln-N.N-dimethylthiocarbamate

The compound from step a) above (24.2 mmol), N,N-dimethylaminothiocarbamoyl chloride (37 mmol) in dimethylformamide (250 ml) was stirred rapidly in the presence of potassium carbonate (60 mmol) for 24 hours, as more potassium carbonate (1 g) was added after 18 hours. The mixture was acidified (to pH 4) with dilute hydrochloric acid and extracted with ethyl acetate (3 times). The combined extracts were washed with water (x), dried (anhydrous sodium sulfate) and evaporated to give a brown solid, which was triturated with ether and filtered to afford the sub-title compound.

' HNMR (CDCl 3 ) S (d), 8.61 (d, 1H), 8.52 (d, 1H), 8.28 (dd, 1H), 7.33 (d, 1H), 7.22 ( d, 1H), 6.65 (m, 1H), 3.86 (S, 3H), 3.38 & 3.26 (NMe26H).

c) 2-(2-mercapto-5-nitrophenyl)-4-methoxypyridine-N.N-dimethylcarbamate

The compound from step a) above (13.5 mmol) in 2,2'-oxybis-ethanol (130 ml) was heated under nitrogen at 175° for 2 hours. The mixture was cooled, poured into water and extracted with ethyl acetate (3 times). The combined extracts were washed with water (3 times), dried (anhydrous sodium sulfate) and evaporated to give a dark brown oil, flash chromatographed on silica and crystallized on standing under ether 1 freezer. The subtitle mixture was filtered off and obtained as a yellow solid.

m/z (FOB) 334 (M+1), 289, 247, (base peak, bp) 72.

d) 2 - ( 5- amino- 2- mecapto)- 4- methoxypyridln- N. N- dlmethylcarbamate

The compound from step c) above (3.75 mmol) was hydrogenated

at room temperature at 3.33 atmospheres for 6 days in the presence of 10$ palladium on charcoal (150 mg) in ethanol (150 ml) as solvent. The mixture was filtered and evaporated to give the sub-title compound as a pale yellow foam. m/z 303 (M+), 283, (bp) 231.

e) 2-(5-N.N-dimethylamino-2-mercapto)-4-methoxypyridln-N. N-dimethylcarbamate

The compound from step d) above (2.97 mmol) in acetonitrile (15 mL) and formaldehyde solution (2.4 mL, ca. 30 mmol) was treated portionwise with sodium cyanoborohydride (7.1 mmol) and stirred with the addition of acetic acid of and to (to maintain the pH value of approx. 5). After the addition, stirring was continued for 1 hour when the mixture was poured into dilute aqueous sodium bicarbonate solution and extracted with ethyl acetate, dried (sodium sulfate), flame chromatographed on silica, eluted with ethyl acetate to give the title compound as a pale yellow solid.

m/z (minor base peak) 331, (bp) 259.

f) Disulfide of 2-(5-N.N-dlmethylamino-2-mercapto)-4-methoxypyridine

The compound from step e) above (110 mg, 0.33 mmol) in methanol (3 mL) was heated under reflux in the presence of sodium hydroxide (0.4 mmol) for 8 h. An additional aliquot of NaOH (0.4 mmol) was added and heating was continued for 15 h. The mixture was poured into water, acidified with dilute aqueous HCl, and the pH was then brought back to 8 with dilute aqueous sodium bicarbonate.

The aqueous solution was extracted with ethyl acetate (3 times) and the extracts washed with water (2 times), dried (anhydrous sodium sulfate) and evaporated to give the sub-title compound as a yellow oil.

m/z 259 (MW/Z), 244, 228

g) 2- r4-Dimethylamino-2-(4-Methoxy-2-pyridinyl)1-1H-benzenemidazole

2-Chlorobenzimidazole (700 mg) and the compound from step f) above (1.2 g) were heated under reflux with sodium cyanoborohydride (290 mg) in isopropanol (33 ml) and acetic acid (7 ml) for 2 hours. The solvent was removed on a rotary evaporator and the residue evaporated with dilute aqueous sodium bicarbonate and extracted with CHCl 3 in the usual manner, dried (Na 2 SO 4 ) and recrystallized from ethyl acetate to give the subtitle compound as a white solid, m.p. 218-220°.

h ) 2- r 2 - dlmethylamino- 2-( 4 - methoxy v - 2- pyr idinylsulf lnyl )~ 1 - 1H-benzlmldazole

The compound from step g) above (2.39 mmol) in methylene chloride (40 ml) was treated portionwise with m-chloroperbenzoic acid (500 mg of 8556, 2.46 mmol) at -10° with stirring over 15 min. Stirring was continued for an additional 1 hour, after which the mixture was worked up to give, after trituration with ether, the title compound as a gray solid.

m/z FAB 393 (M?l), 275 (bp).

Example 2

5-Methoxy-2-f2-(4-Methoxy-2-pyridinyl)phenyl1sulfinyl1-1H-benzimldazole

a) 4-Methoxy-2-(2-methylthiophenyl)pyridine

Under a nitrogen atmosphere, 2-bromothioanisole (9.6 g) was dried

ether (20 ml) added dropwise to magnesium (1.15 g) in ether (5 ml) containing lead (a small crystal). The reaction was initiated by the addition of methylmagnesium iodide (0.1 mL of 3.0 M ether). The mixture was heated under reflux for 1.5 hours to give a clear solution of the Grignard reagent (20 mL). 4-Methoxypyridine-N-oxide (2 g) in dry tetrahydrofuran (50 mL) was mechanically stirred, and ethyl chloroformate (1.52 mL) was added dropwise. The stirred mixture was cooled to -78° and treated with the above Grignard solution (7.5 mL). After stirring for 2 hours, the mixture was allowed to warm to room temperature. The mixture was poured into dilute hydrochloric acid and washed with ethyl acetate. Ethyl acetate was extracted with dilute hydrochloric acid. The aqueous solution was washed with chloroform, then basified and re-extracted with ethyl acetate. The ethyl acetate was washed with saline, where-

after drying and evaporation to form the sub-title compound as a light brown oil MS MW 231 bp 216.

b) 4-Methoxy-2-(2-methylsulfinylphenyl1-pyridine).

The product from step a) above (750 mg) in ethyl acetate (7 ml)

was cooled to -10° and treated with a solution of m-chloroperbenzoic acid (660 mg) in ethyl acetate (4 ml). After 1 hour, the solution was washed with sodium bicarbonate solution, sodium bisulfate solution and saline solution, and then dried and evaporated. The residue was flame chromatographed (ethyl acetate) to give the sub-title compound as a clear oil MS (FAB) M+1 at 248 bp 32.

c) 5-Methoxy-2-r2-(4-Methoxy-2-pyridinyl)phenylthiol-1H-benzimidazole

The product from step b) above (180 mg) was treated with trifluoroacetic anhydride (1.5 ml) and heated under reflux for 1 hour. The solvent was removed in vacuo and the residue treated with methanol (10 mL) and triethylamine (10 mL). The mixture was concentrated in vacuo and the residue taken up in dichloromethane. The solution was washed with ammonium chloride solution, then dried and evaporated. The residue was taken up in dry dimethylformamide and 2-chloro-5-methoxy-1H-benzimidazole (133 mg) and potassium carbonate (101 mg) added. The mixture was heated at 90-95° for 1 hour, then poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated. Flame chromatography gave the subtitle compound as a bright red foam MS MW 363 bp 216.

d) 5- me toc sy- 2- f 2- ( 4- methoxy- 2- pyridlnyl) phenylsulfinyl - 1H- benzimidazole

The product from step c) above (103 mg) was dissolved in ethyl acetate (7.5 ml) and stirred at -10°. A solution of m-chloroperbenoic acid (58 mg of 85$) in ethyl acetate (0.5 ml) was added and the mixture stirred for 50 min. The solution was washed with sodium bicarbonate solution, sodium bisulfite solution, water and brine, then dried and evaporated. After trituration with ether, the solid was dried to give the title compound MS (FAB) M+1 at 380.

Example 3

By procedures analogous to those of Example 2, using appropriate starting materials, the following compounds were prepared.

Example 4

2-f(5-Methoxy-2-(4-Methoxy-2-pyrldlnyl)phenylsulfinyl-1H-benzlmidazole

a) 0-(2-bromo-5-methoxyphenyl)-N.N-dlmethylthiocarbamate

2-Bromo-5-methoxyphenol (29 g) was dissolved in dry dimethylformamide (100 ml) and cooled to 0°. Anhydrous potassium carbonate (21.7 g) was added and the mixture stirred for 15 min. A solution of dimethylthiocarbamoyl chloride (22.1 g) in dry dimethylformamide (50 ml) was added and the mixture was allowed to warm to room temperature. After stirring for 5 hours, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water, dilute sodium hydroxide solution, again with water, then dried and evaporated. Flash chromatography (10% ethyl acetate/petroleum ether) gave the subtitle compound as a colorless solid, NMR (CDCl 3 ) d 7.45 (dod, 1H) 6.72 (m, 2H) 3.79 (s, 3H) 3.40 (s, 3H).

b ) S-(2-bromo-5-methoxyphenyl)-N.N-dimethylthiocarbamate

The product from step a) above (32.5 g) was dissolved in diethylaniline (330 ml) and the solution heated under reflux for 4 hours. The cooled mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with dilute hydrochloric acid, water and saline, and then dried and evaporated to obtain a brown gum. Flame chromatography (10% ethyl acetate/petroleum ether) gave the subtitle compound as a brown solid. MW M+l at 288/290 bp 72.

c) 2-bromo-5-methoxythiophenol

The product from step b) above (200 mg) was dissolved in methanol

(4 ml). Aqueous sodium hydroxide solution (1.4 mL of 10$) was added and the mixture heated under reflux under nitrogen atmosphere for 2 hours. The mixture was cooled, poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to give the sub-title compound as an oil MS MW 218/220 bp 218.

d) 1- bromo- 4- methoxy- 2- methylthiobenzene

The product from step c) above (140 mg) was dissolved in dry

dimethylformamide (2 mL). Potassium carbonate (114 mg) was added followed by methyl iodide (47 mL). The mixture was stirred for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to give the sub-title compound as a light brown oil MS MW 232/4 bp 232.

e) 4- methoxy- 2-( 4- methoxy- 2- methylthiophenyl) pyridine

A Grignard reagent was prepared from the product of step d)

above (12.3 g), magnesium (1.28 g) and lead (1 crystal) in dry tetrahydrofuran (150 ml). 4-Methoxypyridine (5.76 g) was dissolved in dry tetrahydrofuran (300 mL) and stirred under nitrogen. The solution was cooled to -70° and processed

with the above Grignard solution in one portion. After stirring for 10 min, phenyl chloroformate (6.6 ml) was added dropwise. After stirring at -70° for 30 min. the mixture was allowed to warm to room temperature. After stirring for 90 min. the mixture was poured into water and extracted with ether. The ether was washed with water and brine, then dried and evaporated. The residue was taken up in toluene (250 ml) and stirred at room temperature. Erti!? solution of 3,4,5,6-tetrachloro-1,2-benzoquinone (13.0 g) in acetic acid (120 ml) was added dropwise. When the addition was-! completely, the mixture was stirred for an additional 18 h. The mixture was ice-cooled and treated with a cold solution of sodium hydroxide (700 mL of 10%). After stirring 2i0 min. the mixture was filtered and separated. The aqueous filtrates were extracted with ether and the combined organic filtrates were extracted with dilute hydrochloric acid. The extracts were combined and basified with sodium hydroxide solution. The mixture was extracted with ether and the combined extracts washed with brine, then dried and evaporated. Flash chromatography (1:1 ethyl acetate/petroleum ether) gave the subtitle compound as a clear oil (5.4 g). NMR (CDCl 3 ) d 8.50 (d, 1H), 7.39 (d, 1H), 760 (d, 1H), 6.85 (d, 1H), 6.77 (m, 2H), 3, 88 (p, 3H), 3.86 (p, 3H ), 2.40 (p, ; 3H).

■

The title compound was prepared using methods analogous to example 2b), c) and d) via: f) 4- methoxy- 2-( 4- methoxy- 2- methylsulflnylphenyl) pyridine MS M<+>277 g) 2- r5- Methoxy-2-(4-methoxy-2-pyrridine)phenylthiol-1H-benzlmidazole; MS M<+>363. h) 2-r5-methocrsv-2-(4-methoxyv-2-pyridinvl)phenylsulfinvll-1H-benzimldazole, rsmp. 204-207°.

r;

Example 5

Using procedures analogous to those in Example 1 4 above and using the appropriate starting materials, the following compounds were prepared:

Example 6

5, 6- dlmethoxy- 2- r5- methoxy- 2-( 2- pyrldinyl) phenylsulfinyl- 1H- benzimidazole

a) 5,6-dimethoxy-2-(5-methoxy-2-nitriofenyl 11o)-1H-benzimldazole

5,6-dimethoxybenzimidazol-2-thione (4.0 g), 2-chloro-4-methoxynitrobenzene (3.6 g), and potassium carbonate (2.65 g) were stirred together in dry dimethylformamide (30 mL) at 95° for 3 days. The cooled mixture was poured into water (300 mL) and the precipitate collected. The solid was washed with water and dried to afford the sub-title compound as a pale yellow solid, MS 361 bp 2207.

b) 2- f 5 , 6- dimethoxy-2- 1H- benzimidazolyItio]- 4- methoxybenzene-amine

The product from step a) above (6.3 g), iron powder (6.3 g) and ammonium chloride (6.3 g) were stirred together with ethanol (63 ml) and water (120 ml) and heated under reflux for 1 hour . The hot mixture was filtered and the residue washed with hot ethyl acetate (500 mL). The combined filtrates were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, then dried and evaporated to a foam. Trituration with ether gave the subtitle compound as a gray solid, MS MW bp 331.

c) 5.6-dimethoxy-2- r5-methoxy-2-(2-pyridinyl)phenylthiol-1H-benzimldazole

The product from step b) above (500 mg) was treated with concentrated hydrochloric acid (0.8 ml) and water (0.8 ml) to form a paste. The paste was stirred at 0-10° and a solution of sodium nitrite (105 mg) in water (0.5 ml) was added dropwise. After stirring for 40 min. the resulting solution was added slowly to pyridine (5 mL), stirred at 80°. The mixture was stirred for an additional 40 min. and then concentrated in vacuo. The residue was slurried with 0.880 ammonium hydroxide, and the mixture again concentrated in vacuo. The residue was slurried with water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to form a brown gum. Flame chromatography gave the desired product as a light brown solid, MS MW 393 bp 216.

d ) 5 , 6- dimethoxy-2- r5- methoxy- 2-( 2- pyridlnyl) phenylsulfinyl - 1H- benzimidazole

The product from step c) above (370 mg) was dissolved in ethyl acetate (90 ml) and cooled to -10°C. To the stirred solution was added a solution of m-chloroperbenzoic acid (191 mg of 85%) in ethyl acetate (10 ml). After stirring for 1 hour, the solution was washed with sodium bicarbonate solution, sodium metabisulfite solution, water and brine and then dried and evaporated. The residue was flame chromatographed to give the title compound as a light brown solid, m.p. 208-210°.

Example 7

By procedures analogous to those of Example 6 and using the appropriate starting materials, the following compounds were prepared:

Example 8

2-f2-(1H-benzimidazol-2-yl-sulfinyl)fenvl"1-1-methyl-1H-benzimidazol

a) 2-(2-methylthiophenyl)-1H-benzimldazole

2-methylthiobenzoic acid chloride (4 g), o-phenylenediamine (2.32 g) and

polyphosphoric acid (64 g) was heated at 135° with stirring for 24 hours. The reaction mixture was poured onto ice, basified with sodium hydroxide solution and extracted with ethyl acetate which was washed with brine, dried over magnesium sulfate and evaporated to dryness to give the sub-title compound as a pale yellow solid, MS MW 240 bp 225.

b) 1-methyl-2-(2-methylthiophenyl)-1H-benzimldazole

The product from step a) above (3.25 g), methyl iodide (1.92 g)

and potassium carbonate (5.2 g) were stirred together in dry dimethylformamide (50 mL) at room temperature for 24 hours. The reaction mixture was poured into brine and extracted into ethyl acetate, the extract was washed with excess brine, dried over magnesium sulfate and evaporated to dryness in vacuo, and the residue was purified by flame chromatography (SiOg/-CH2CI29:1 ethyl acetate) to afford the sub-title compound as a yellow solid , MS MW 254 bp 239.

c) 1- methyl- 2-( 2- methylsulfinylphenyl)- 1H- benzlmldazole

The product from step b) above (2 g) was dissolved in dichloromethane (50 ml) and cooled to 10° with stirring. 85% m-chloroperbenzoic acid (1.6 g) was added portionwise. The reaction mixture was slowly warmed to room temperature, and after 3 hours the reaction was complete. The reaction mixture was washed with aqueous metabisulphite solution, then bicarbonate solution and finally brine, dried over magnesium sulfate and evaporated to dryness in vacuo, after which the residue was purified by flame chromatography (SiCl 2 /ethyl acetate 3:2 CH 2 Cl 2 ) to obtain the sub-title compound as a yellow, crystalline solid, m.p. 157-159°.

d) 2 - 12 - 1 1H- benzimidazole- 2- vl- tlo) phenvll- 1- metvl- 1H- benzimidazole

The product from step c) above (1.83 g) was heated at reflux with trifluoroacetic anhydride (10 ml) and dry dichloromethane (15 ml) for 30 min. The whole was evaporated to dryness and the resulting oil was dissolved in dry methanol (220 mL) and triethylamine (20 mL). 2-(Phenylsulfonyl)-1H-benzimidazole (1.75 g) was added to the solution and the whole was heated at 70° for 15 min. before evaporation to dryness.

The pale yellow residue was dissolved in iso-propanol (50 ml) and heated at reflux temperature for 30 min. before the addition of sodium borohydride (0.26 g) and further heating for 1 hour at reflux temperature and 18 hours at 50°.

The volume of isopropanol was reduced to approx. 5 ml, and the reaction mixture was poured into brine, extracted with dichloromethane, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by flame chromatography (SO 2 /ethyl acetate 1:9 CH 2 Cl 2 ) to give the sub-title compound as a white powder, m.p. 246-247°.

e) 2 -\ 2 -( 1H- benzimldazol- 2- vl- sulfinvl) phenvlll- 1- methyl- 1H- benzimidazole

The product from step d) above (0.99 g) was dissolved in dichloromethane (60 ml) and methanol (5 ml) and cooled to -10°. 85% m-chloroperbenzoic acid (0.56 g) was added and the whole was slowly warmed to room temperature with stirring. After 2 hours, the reaction mixture was washed with metabisulfate solution, then bicarbonate solution and finally with brine, dried over magnesium sulfate and evaporated to dryness in vacuo, and the residue was purified by flame chromatography (S102/CH2C122:3 ethyl acetate) to give the title compound as a white solid, m.p. 164°.

Example 9

By methods analogous to those in Example 8, the following compounds were prepared:

Example 10

2- r2-(6.7- dlmethoxy-l- isoclnolnlvl) fenvlsul flnvil - 1H-benimidazole

a) N- (3, 4- dimethoxyphenyl) ethyl]- 2- methylthiobenzamide

2-(3,4-dimethoxyphenyl)ethylamine (4.8 mL), poly(4-vinylpyridine)

(PVP) (5.7 g) and 2-methylthiobenzoyl chloride (5.3 g) were stirred in dichloromethane (50 ml) under cooling in a water bath at 20° overnight. The PVP material was filtered off and washed with CHCl 3 . Evaporation of the extracts followed by flame chromatography in (ethyl acetate/petroleum ether) gave the sub-title compound, m.p. 94-95°.

b) 6. 7- dimethoxysv-l- r(2- metvltlo) phenyl- 33. 4- dihydroisoquinoline

The product from step a) above was heated with phosphorus pentoxide (6 g) in dry acetonitrile (500 ml) under reflux with stirring for 2 hours. The mixture was cooled, carefully treated with water and neutralized with solid NaHCO 3 and extracted with ethyl acetate, which on evaporation gave the subtitle compound as an oil, MS electron estimate (EI) 298 { 100%, M-15 ).

c) 6.7-Dimethoxy(2-methylthio)phenyl]isoquinoline

the product from step b) above (3.4 g) was treated with

sulfur (2 g) under reflux in xylene (80 mL), while additional amounts of sulfur (0.2 g) were added every 3 days for 2 weeks. The solvent was evaporated and the residue was chromatographed (ethyl acetate petroleum ether) to give the sub-title compound as an oil, MS 311 (M.556), 296 (M-15, 10056).

d) 6.7-dimethoxy-l-r(2-methylsulfinyl)phenyl1isoquinoline

The product from step c) above was treated with 85% m-chloroperbenzoic acid (1.58 g) in ethyl acetate to give, after chromatography, the sub-title compound, m.p. 64°.

e) Bisr2-(6.7-dimethoxy-1-isoquinolinyl)phenyldisulfide

The product from step d) above (1.14 g) and trifluoroacetic anhydride (0.98 ml) was treated in CH 2 Cl 2 (20 ml) solution at reflux for 1 hour. The solvent was evaporated and the resulting gum was heated in triethylamine (5 mL) and methanol (25 mL) under reflux for 1 hour. The solvent was removed and the residue chromatographed (ethyl acetate/petroleum ether) to give the sub-title compound as a white solid, MS 593 (M + 1.5%), 296 (10056).

f) 2-f 2-(6.7-dimethoxy-1-isoquinolinyl)phenylthiol-1H-benzimidazole

The product from step e) above (59 mg) was heated with sodium cyanoborohydride (6 mg) in the presence of 2-chlorobenzimidazole (31 mg) in acetic acid (1 ml) and isopropanol (5 ml) for 1 hour under nitrogen at 80°. The product was neutralized with aqueous NaHCO 3 and extracted with ethyl acetate to give the subtitle compound as a solid, MS 413 (M, 70%), 296 (10056).

g) 2 - f 2-(6.7-dimethoxy-1-isoquinolinyl)phenylsulfinyl1-1H-benzimidazole

The product from step f) above was dissolved in 1:1•CH2Cl2-CHCl3 (10 mL), treated with 8556 m-chloroperbenzoic acid (24 mg) at -5°, and worked up in aqueous NaHCO3 to give the title compound, NMR (CDCl3)d , 8.5 (d, 1H), 8.35 (dd, 1H), 7.26 (1H, s), 7.21 (1H, s), 7.7-7.2 (complex, 8H), 4.30 (s, 3H), 3.85 (s, 3H) ppm, m.p. 250° (d).

Example 11

2- f 2-( 4- methoxy- 2- pyridine )- 3- 1-phenylsulfinyl 1- 1H- benzimidazole

a) 4-methoxy-1-phenoxycarbonyl-22-(2-thienyl)-1.2-dlhydro-pyridine

2-Iodothiophene (21 g) was reacted with magnesium (2.43 g) in dry diethyl ether (200 ml) and a crystal of lead under reflux in a nitrogen atmosphere for 1 hour. The solution was decanted into a solution of 4-methoxypyridine (7.94 g) in dry tetrahydrofuran (200 mL) at -225° with vigorous stirring. After 5 min. phenyl chloroformate (9.17 ml) was added dropwise and the mixture was allowed to warm to room temperature overnight. Aqueous work-up and ethyl acetate extraction gave the subtitle compound as a brown oil, MS (EI) 313 (M, 20$), 230

(7096) , 220 ( 10056 ).

b) 4-Methoxy-2-(2-thienyl)pyridine

The product from step a) above (24 g) was dissolved in toluene

(240 ml) at room temperature and treated with tetrachloro-1,2-benzoquinone (18.9 g) in a solution of acetic acid (90 ml) dropwise over 1/2 hour and stirred overnight. Ice was added and the mixture was basified with 4056 aqueous NaOH, which gave a black precipitate. The mixture was filtered, washed with toluene, then CH 2 Cl 2 . The combined filtrates were cooled, and extracted with concentrated HCl acid (6 x 100 mL). Neutralization of the aqueous solution with NaHCO 3 (solid) and ethyl acetate extraction and chromatography gave the sub-title compound m.p. 43-45°.

c) 4-Methoxy-2-(3-methylthio-2-thienylpyridine).

The product from step b) above (5 g) dissolved in dry diethyl ether (100 ml) was cooled to -50° and treated with butyllithium in hexane (2.2 M, 13 ml) dropwise over 1/2 hour. The mixture was heated to -10° for 10 min., then cooled to -30°. Dimethyl sulfide (3.5 mL) was then added dropwise. The mixture was kept at -30° for 1/2 hour, then warmed to room temperature over several hours. Aqueous work-up and ethyl acetate extraction gave the subtitle compound as an oil.

d) 4- methoxy- 2-( 3- methylsulfInyl- 2- thienyl) pyridine

The product from step c) above was dissolved in ethyl acetate (100

ml) and cooled to -10°. m-chloroperbenzoic acid (2.98 g) was added and after 1.5 hours the mixture was worked up and then chromatographed (ethyl acetate) to give the sub-title compound as a solid, m.p. 103-105°).

e) r2-(4-Methoxys-2-pyridinyl)-3- trienyl disulfide

The product from step d) above (1.61 g) and trifluoroacetic anhydride (1.79 ml) were heated under reflux in dichloromethane (50 ml) to give an abundant white precipitate over 1.5 hours. The solvent was evaporated and the residue heated under reflux with methanol (10 mL) and triethylamine (10 mL) for 0.5 h. Evaporation to dryness in vacuo, aqueous workup, extraction into ethyl acetate and chromatography gave the sub-title compound as a gum. MS (FAB) 445 (M +1), 5%), 222 ($100).

f) 2- r2-(4- methoxy-2- pyridine )- 3- ethylene thiol- 1H- benzimildazole

The product from step e) above was reacted with sodium cyanoborohydride (0.236 g) and 2-chlorobenzimidazole (1.14 g) in isopropanol (20 ml) and acetic acid (5 ml) at 80° for 1 hour. Cooling, NaHCO 3 workup, ethyl acetate extraction and washing with diethyl ether gave the sub-title compound as a white solid, MS (EI) 339 (M, 100$), 306 (80%).

g) 2- \ 2 -( 4- methoxy- 2-pyrrlidlnyl )- 3- thienylsulf lnyl - 1H- benzlmldazole

The product from step f) above (1.25 g) was dissolved in chloroform (500 ml). The stirred solution was cooled to -5° and m-chloroperbenzoic acid (85%, 0.75 g) was added portionwise over 10 min. After 1 hour, NaHCO 3 workup and chromatography gave the title compound, m.p. 192°.

Example 12

By methods analogous to those in Example 11, the following compounds were prepared: i) 5-methyl-2-[3-(2-pyridinylthien-2-yl-thio]-1H-benzimidazole, MS m/e 323 (70%, M <+>) bp 290.

11) 5-methyl-2-[3-(2-pyridinylthien-2-yl-sulfinyl]-1H-benzlmidazole, mp 100° (d).

Example 13

2- f 2 - ( 4- methoxy- 2- pyridinyl)- phenylsulfInyl 1- 1H- benzimldazol-5- amine

The compound 1 example 5 b) 11) was hydrogenated over a 10% palladium-carbon catalyst at 3 atmospheres pressure in ethanol. The catalyst was filtered off and the ethanol was evaporated to give the title compound, m.p. 192-193°.

Example 14 1-\2-\2-(1H-2-benzylimidazolylsulfinyl)phenyl-4-pyridinyloxyl-propan-2-ol, (FAB ms M2+ +1).

The title compound was obtained from the compound of Example 2 m) above using a standard NaBE 2 /ethanol reduction.

Example 15

2-(2-1H-benzimidazol-2-yl-sulfinyl)phenylimidazoTl. 2- alpyridine

a) 2-( 2- bromophenyl Umldazofl . 2- alpyridine

A solution of 2-aminopyridine (1.63 g) and 2-bromo-1-(2-bromo-phenyl)-ethanone (4.8 g) in dry ethanol (40 ml) was heated under reflux for 1 hour. The mixture was concentrated in vacuo. The residue was treated with dilute sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated. Flame chromatography gave the subtitle compound as a light gray oil. MS MW 272/274 bp 272.

b) 2-(2-methylthiophenyl Umldazofl. 2-alpyridine

The product in step a) above (546 mg) was dissolved in dry ether

(10 ml) and stirred under a nitrogen atmosphere at -60°. A solution of n-butyllithium (1.25 mL of 1.6 M) was added dropwise. After stirring for 5 min. methyl disulfide (179 ml) was added dropwise and the mixture stirred for a further 45 min. The mixture was allowed to warm to room temperature and was then quenched with water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic solution was washed with water and brine, then dried and evaporated to give the sub-title compound as a gum. MS MW 240 bp 207.

c) 2-(2-methylsulfinyl)imidazole" 1.2-alpyridine

The subtitle compound was prepared from the product of step b) above using a method analogous to that of Example 8

c) above. MS MW 257 bp 78.

d) 2-(2-1H-benzimidazol-2-yl-tlo)phenylimidazolium. 2-alpyridine The subtitle compound was prepared from the product from step c) above using a method analogous to that in Example 8

d) above. MS MW 342 bp 225.

e) 2 - (2-lH-benzimidazol-2-yl-suIfinyl)phenyl-Imidazo-f 1.2-al-<pyr>idine

The title compound was prepared from the product of step b) above using a method analogous to that in Example 18 e) above. MS (FAB) M+ 1/bp 359.

Claims (14)

1. Compound, characterized by the formula: where A is a 5- or 6-membered, fully unsaturated, carbocyclic or heterocyclic ring, B is a 5- or 6-membered, fully unsaturated, nitrogen-containing heterocyclic ring, X is NRi g, 0 or S, R^ g is hydrogen or alkyl optionally substituted with —OCOR, n is 0 or 1, <R>3 , <R>4 , R5 , Rf c , R7 , R3 , Rg and Rio , which are the same or different, are selected from hydrogen, alkyl, halogen, —SR, benzoyl, —NO2 , —N <R> 20 <R>21» —COOH or an ester or amide thereof, or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group, or in addition to the meanings given above, an adjacent pair of R 3 to R 5 or R 7 to R 5 , together with the ring atoms to which they are attached, may form a 5- or 6-membered fully unsaturated, carbocyclic or heterocyclic ring which carries substituents Rn, ^12»<R>1 3 °S R14 » R11» R12 » R13 °g R14» which may be the same or different, are selected from hydrogen, alkyl, alkoxy, halogen, —SR, benzoyl, —NO2 , —NR20 R21 or —CO2 H or an ester or amide thereof, except when ring A, ring B or the ring formed by an adjacent pair of R3 to R5, or R7 to R^q is 5-membered, then R^, R^q or R14 respectively have no significance, R 1 and R 2 , which may be the same or different, are selected from hydrogen or alkyl, or may, together with the ring carbon atoms to which they are attached, form a benzene or pyridine ring, which ring carries substituents R 15 , R 16 » <R> 17 and Ride <g> . <R>15 » <R>16> R17 °g R18« which may be or be different, is selected from hydrogen, alkyl, halogen, —SR, benzoyl, alkoxy, —NO2 , — <NR>20<R>21 or -CO2 H or an ester or amide thereof, or in addition to the meanings indicated above, an adjacent pair of R15, R16, R17, and R18, together with the ring carbon atoms to which they are attached, can form a 5- or 6-membered carbocyclic or heterocyclic ring, <R> 20 °g R21 • which may be Uke or different, is selected from hydrogen, alkyl, phenyl or may, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring, which ring may contain an additional heteroatom, R is hydrogen, phenyl or alkyl optionally substituted with phenyl, provided that when R^ and R2 together with the ring carbon atoms to which they are attached form a benzene ring, A is a benzene ring, and B is a pyridine ring, then i) when R 3 to R 6 and R 7 to <R> 10 are each different from alkoxy substituted by OH or by an optionally protected oxo group, and either an adjacent pair of R 3 to R^ or of R^ 5 to R^ g does not form a 5-membered fully unsaturated carbocyclic or nitrogen-containing heterocyclic ring or a 5- or 6-membered fully unsaturated oxygen- or sulfur-containing heterocyclic ring, or an adjacent pair of R7 to R-10 does not form a 5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring, and each of R3 to R6 , R7 to <R>10 and <R>15 to <R>18 is different from NR20<R> 21> where R20 and R21» together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring, which ring may contain an additional heteroatom, then at least one of R3 to <R>10 is selected from alkyl, alkoxy, SR or NR2 o <R>21 where R2 q and R21" as may be the same or different, is hydrogen, alkyl or phenyl, and li) when X is NR 1 , R 19 , <R> 3 to R 6 and R 15 to R 18 are each hydrogen, and one of R 7 to R 10 is a methoxy group positioned para to the ring nitrogen atom, then the rest of R 7 to R 1 o are not each hydrogen, and pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, character r i-sertvedatnerl. 3. Compound according to claim 1 or 2, characterized in that Ri and R2, together with the ring carbon atoms to which they are attached form a benzene ring, which benzene ring carries substituents R 15 , <R> ifc, <R> i7 and Ri g. 4. Compound according to claim 1, 2 or 3, character -rised in that ring A is a benzene or thiophene ring. 5. Compound according to any one of the preceding claims, characterized in that ring B is a pyridine or imidazole ring. 6. Compound according to any one of the preceding claims, characterized in that X is NRig . 7. Compound according to claim 1, characterized in that R-^ and Rg, together with the ring carbon atoms to which they are attached, form a benzene ring, which benzene ring carries substituents R15 , <R>i6 » <R>17 °S <R>18 » ^ is NR^g, R^g is hydrogen, n is 1, A is a benzene ring, and ring B is a pyridine ring attached to ring A at the 2-position and has a substituent para to the ring N atom selected from alkyl , —SR, —NR2 or R21 or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group 1 , or ring B is an imidazole ring attached to ring A in the 2-position and in which the substituents in the 4- and 5-positions, together with the ring carbon atoms to which they is attached, forms a benzene ring, which benzene ring carries substituents Rn, R12» R13 °S <R> 14. 8. Connections, characterized in that they consist of: 2-[4-dimethylamino-2-(4-methoxy-2-pyridinylthio]-1H-benzimidazole, 2-[4-dimethylamino-2-(4-methoxy-2-pyridinylsulfinyl)]-1H-benzimidazole, 2-[5-methoxy-2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[5-methoxy-2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(1H-benzimidazol-2-yl-thio)phenyl]-1-methyl-1H-benzimidazole, 2 - [2-(1H-benzimidazol-2-yl-sulfinyl)phenyl]-1-methyl-1H-benzimidazole, or a pharmaceutically acceptable salt of any of these compounds. 9. Compounds, characterized in that they consist of 5-methoxy-2-[2-(4-methoxy-2-pyridyl)phenylthio]-1H-benzimidazole, 5-me took sy-2-[2-(4-methoxy-2-pyridyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-ethyl-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(ethyl-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, methyl-2 - [2-(4- methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole-5-carboxylate, methyl 2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole-5-carboxylate, 5-methyl-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 5-methyl-2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-methyl-2-pyridinyl)phenylthio]benzoxazole, 2-[2-(4-methyl-2-pyridinyl)phenylsulfinyl]benzoxazole, 2-[2-(4-methoxy-2-pyridinyl) phenylthio]benzoxazole, 2-[2-(4-methoxy-2-pyridyl)phenylsulfinyl]-benzoxazole, 2-[5-ethoxy-2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole, 2 - [ 5 -methyl sy-2-( 4 -methyl 1 - 2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-[2-methyl-1,3-dioxolan-2-yl-methoxy]-2-pyridinyl)-phenylthio]-1H-benzimidazole, 2-[2-(4-[2-methyl-1,3-dloxol an-2-yl-methoxy-2-pyridinyl)-phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-Methoxy-2-pyridinyl)phenylthio-1H-naphtho[2,3-d]imidazole, 2-[2-(4-methoxy-2-pyridinyl)phenylthio-1H-naphtho[ 2,3-d]-imidazole, 5-methoxy-2-[2-(4-methoxy-2-pyridinyl)-5-methoxyphenylthio]-1H-benzimidazole, 5-methoxy-2-[2-(4-methoxy-2-pyridinyl)-5-methoxyphenylsulfinyl]-1H-benzimidazole, 2-[2-(1H-2-benzimidazolylthio)phenyl]-N-methyl-1-N-phenyl-4-pyridinamine, 2-[2-(1H-2-benzimidazolylsulfinyl)phenyl]-N-methyl-N-phenyl-4-pyridinamine, 2-[5-methoxy-2-(2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[5-methoxy-2-(2-pyridinyl)phenylsulfinyl-1H-benzimidazole, 1- [2-(2-(1H-2-benzimidazolylthio)phenyl1-4-pyridinyloxy]propane- 2- wed. 1- [2-( 2-( 1H-2-benzimidazolylsulfinyl)phenyl-4-pyridinyloxy]-propan-2-one, 4-methoxy-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 4-Methoxy-2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(5-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(5-methyl-2-pyridinyl)phenylsulfinyl-1H-benzimidazole, 2-[2-(4-Metocy-6-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(4-methoxy-6-methyl-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(3-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(3-methyl-2-pyridinyl)phenylsulfinyl]-11H-benzimidazole, 2-[2-(4-methoxy-2-pyridinyl)phenyl]-4,5-dimethyl-1H-benzimidazole, 2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-4,5-dimethyl-1H-benzimidazole, 2-[2-(4-methoxy-2-pyridinyl)phenylthio]-5-nitro-1H-benzimidazole, 2 - [2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-5-nitro-11H-benzimidazole, 5-chloro-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 5-chloro-2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]- 1H-benzimidazole, 5,6-dimethoxy-2-[2-(4-methoxy-2-pyridinyl)phenyl]-1H-benzimidazole, 5.6-dimethoxy-2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, ethyl - 6-ethoxy-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole-5-carboxylate, ethyl 6-ethoxy-2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole-5-carboxylate, 4.7-dimethoxy-2-[2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 4,7-dimethoxy-2-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-ethoxy-2-pyridinyl)phenylthio-1H-benzimidazole, 2-[2-(4-ethoxy-2-pyridinyl)phenylsulfinyl-1H-benzimidazole, 2-[2-(4-(l -methylethoxy)-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(4-(1-methylethoxy)-2-pyridinyl)phenylsulfinyl]-1H-imidazole, 2-[2-(4-(4-morpholinyl)-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(4-(4-morpholinyl)-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(1H-benzimidazol-2-yl-thio])phenyl]-N,N-dimethyl-4-pyrimidinemine, 2-[2-(1H-benzimidazol-2-yl-sulfinyl)phenyl]-N,N-diraethyl-4-pyridinamine, 6-[2-( 4-methoxy-2-pyridinyl )phenylthio-2H,5H-dioxolo[4,5-f]-benzimidazole, 6-[2-(4-methoxy-2-pyridinyl)phenylsulfinyl-2H,5H-dioxolo-[4,5-f]benzimidazole, 2-[2-(4-propyloxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(4-propyloxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[5-chloro-2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 2 - [5-chloro-2-(4-methoxy-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[5-methoxy-2-(4-methoxy-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[5-methoxy-2-(4-methoxy-2pyridinyl)phenylsulfinyl]-1H-benzimidazole, methyl 2-(2-(4-methoxy-2-pyridinyl)phenylthio-6-methyl-1H-benzimidazole-5-carboxylate, methyl 2-(2-(4-methoxy-2-pyridinyl)phenylsulfinyl-6-methyl-1H-benzimidazole-5-carboxylate, 5,6-dimethoxy-2-[5-methoxy-2-(2-pyridinyl)phenylthio]-1H-benzimidazole, 5,6-dimethoxy-2-[5-methoxy-2-(2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole, 2-[2-(4-methyl-2-pyridinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(2- pyridinyl-5-(1-pyrro1idinyl)phenylthio]-1H-benzimidazole, 2-[2-(2-pyridinyl-5-(1-pyrro-1-di-inyl)-phenylsulfinyl]-1H-benzimidazole, 5-methoxy-2-[2-(4-methyl-2-pyridinyl)phenylthio]-1H-benz-imidazolol, 5-Methoxy-2-[2-(4-methyl 1-2-pyridinyl)phenylsulfinyl]-1H-benzlmidazole, methyl 2-[2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole-5-carboxylate, methyl 2-[2-(4-methyl-2-pyridine)phenylsulfinyl]-1H-benzimidazole-5-carboxylate, 2-[2-(2-pyridinyl)phenylthio]-1H-imidazole, 2-[2-(2-pyridinyl)phenylsulfinyl]-1H-imidazole, 2 - [2 - (1H-2-benzimidazolylthio)phenyl)-6-chloro-1-methyl-1H-benzimidazole, 2 - [2-(1H-2-benzimidazolylsulfinyl)phenyl]-6-chloro-1-methyl-1H-benzimidazole, 2 - [2-(1H-2-benzimidazolylthio)phenyl]-5-chloro-1-methyl-1H-benzimidazole, 2 - [2-(1H-2-benzimidazolylsulfinyl)phenyl]-5-chloro-1-methyl-1H-benzimidazole, 2 - [2-(1H-2-benzimidazolylthio)phenyl]-5,6-dichloro-1-methyl-1H-benzimidazole, 2 - [2-(1H-2-benzimidazolylsulfinyl)phenyl]-5,6-dichloro-1-methyl-1H-benzimidazole, 2-[2-(5-methoxy-1H-2-benzimidazolylthiophenyl]-1-methyl-1H-benzimidazole, 2-[2-(5-methoxy-1H-2-benzimidazolylsulfinyl)phenyl]-1-methyl-1H-benzimidazole, methyl 2-[2-(1-methyl-1H-2-benzimidazolyl)phenyl]-1H-benzimidazol-5-carboxylate, methyl 2-[2-(1-methyl-1-1H-2-benzimidazolyl)phenylsulfinyl]-1H-benzimidazole-5-carboxylate, 2-[2-(6,7-dimethoxy-1-isoquinolinyl)phenylthio]-1H-benzimidazole, 2 - [2-(6,7-dimethoxy-1-isoquinolinyl)phenylsulfinyl]-1H-benzimidazole, 2-[2-(4-methoxy-2-pyridinyl)-3-thienylthio]-1H-benzimidazole, 2-[2-(4-methoxy-2-pyridinyl)-3-thienylsulfinyl]-1H-benzimidazole, 5-methyl-2-[3-(2-pyridinyl-thien-2-yl-thio]-1H-benzimidazole, 5-methyl-2-[3- (2-pyridinyl-thien-2-yl-sulfyl 1]-1H-benzimidazole, 2-[2-(4-methoxy-2-pyridinyl)-phenylsulfinyl]-1H-benzimidazol-5-amine, 1-[2-[2-(1H-2-benzimidazolylsulfinyl)phenyl-4-pyridinyloxy]-propan-2-ol, 2-(2-1H-benzimidazol-2-ylthio)phenyl-imidazo[1,2-a]pyridine, 2-(2-1H-benzimidazol-2-yl-sulfinyl)phenyl-imidazo-[1,2- a] - pyridine, or a pharmaceutically acceptable salt of any of these compounds. 10. Pharmaceutical preparation, characterized in that it comprises a compound with the formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in mixture with a pharmaceutically acceptable aid, diluent or carrier. 11. Pharmaceutical use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof. 12. Use of a compound of formula (I) as defined in claim 1 for the preparation of a medicinal product for use as a cytoprotective agent, in the treatment or prophylaxis of inflammatory conditions or for the prevention or inhibition of gastric acid secretion. 13. Process for producing a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that one: a) selectively oxidizes a compound of formula (I) where n is 0, to a corresponding compound of formula (I) where n is 1, b) modifies a compound of formula (I) containing one or more groups that can be converted into a group —NH 2 . —CH2 0H or C=0, to a compound of formula (I) containing a group —NH2 , -CH2 0H or C=0, c) reacts a compound of formula (I) where X is NR^ g, where R^ g is hydrogen, with a compound R 22 Z where R 22 is as defined for R^ g above, except that it cannot be hydrogen, and Z is a good breakout group, d) conversion of a compound of the formula: where R 1 , R 2 and X have the meanings given above, with a compound of the formula: where R3 , R4 , R5 , Rfc, Ry, Rg, Rg, Rig» A and B have the meanings indicated above, and one of D and E is —SH or S~, and the other is a good leaving group, or e) reaction of a compound with the formula: where Ri to R^ , n, X and A have the meanings given above, with a connection of the formula: where Ry to Riq and B have the above meanings, and, if desired or necessary, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof or vice versa. 14. Connection, characterized by the formula: where Ea is SH, S~ , SMe or SOMe, ring A is a benzene or thiophene ring, R3 to R^ have the meanings given above, and ring B is either a pyridine ring bearing substituents R7 to R^O as defined in claims 11, except that an adjacent pair of R 7 to R 1 q cannot, together with the carbon atoms to which they are attached, form a ring, or ring B and an adjacent pair of R 7 to R 10 form a 1-isoquinolinyl-, 2-imidazole [1,2-a]-pyridine or 2-n-alkylated-benzimidazolyl group, for use as an intermediate in the synthesis of a compound of formula (I) as defined in claim 1.