GB2219584A

GB2219584A - Phosphates of benzimidazole-methanols

Info

Publication number: GB2219584A
Application number: GB8911302A
Authority: GB
Inventors: Stig Ake Ingemar Carlsson; Per Lennart Lindberg
Original assignee: Hassle AB
Current assignee: Hassle AB
Priority date: 1988-05-20
Filing date: 1989-05-17
Publication date: 1989-12-13
Also published as: SE8801907D0; GB8911302D0

Abstract

Novel compounds of the formula <IMAGE> and therapeutically acceptable salts thereof particularly phosphate esters of 1-hydroxymethyl-2-organo-sulphonyl- benzimidazoles, are useful in therapy, particularly as inhibitors of gastric acid secretion and in the treatment of gastrointestinal inflammation, where D is a mono-, di-, or tri-phosphate group; X is SO or S; y is O or I; R<c> is (a) a mono or bicyclic aromatic heterocyclic structure which may be substituted or (b) a benzene or 5- or 6- membered heterocyclic ring linked via a C atom and containing as an alpha -substituent an N-containing group; A is a fused ring system; and R<1>, R<2>, R<3>, R<4> and R<5> are H or substituents.

Description

Novel Pharmacological Compounds DESCRIPTION Field of the invention The object of the present invention is to provide novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the-prevention and treatment of peptic ulcer.

The present invention relates to the use of the compounds of the invention, especially therapeutically acceptable salts thereof, for inhibiting gastric acid secretion in mammals and man. In a more general sense, the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals and man, such as gastritis, gastric ulcer, duodenal ulcer, and reflux esophagitis. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding.

They may also be used in patients in intensive care situations, and preand postoperatively to prevent acid aspiration and stress ulceration.

The invention also relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient. In a further aspect, the invention relates to processes for preparation of such new compounds, to novel intermediates in the preparation of the compounds of the invention, and to the use of the active compounds for-the preparation of pharmaceutical compositions for the medical use indicated above.

Prior art and background of the invention Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in numerous patent documents. Among these can be mentioned GB 1500043, GB 1 525 958, US 4 182 766, EP 0 005 129, and BE 890 024.

Benziriiidazole derivatives proposed for use in the treatment or prevention of special gastrointestinal inflammatory diseases are disclosed in EP-A-O 045 200. N-substituted 2-(pyridylalkylenesulfinyl)benzimidazoles are disclosed in EP-A-O 176 308.

For certain pharmaceutical usage forms there is a great need for high water solubility of the compound to be used. For instance, for intravenous and intramuscular injection formulations, the dose is to be dissolved in a small volume of an aqueous medium. This, of course, requires a high aqueous solubility. However, a high aqueous solubility is often a great advantage also in other cases e.g. for oral formulations.

The compounds in the prior art generally have a low water solubility, which does not admit manufacture of such highly concentrated water solution which are needed for intravenous and intramuscular injections.

For example the compounds presented in the European patent application, publication no. 0176308, disclosing N-substituted benzimidazole derivatives, have low water solubility and are thus not suitable for the above-mentioned parenteral use.

The invention It has been found that the compounds of the following formula I are effective as inhibitors of gastric acid secretion in mar1nnals and man, and that the said compounds I exhibit an unexpectedly high solubility in water compared with compounds in the prior art.

The compounds of the invention wherein X is SO generally show higher chemical stability in water solutions at the pH where they exhibit optimal stability compared to the corresponding compounds without the N-l substitution, at the same pH. Some of the compounds of the invention show exceedingly high chemical stability in solution. The compounds of the formula I are therefore particularly suitable for parenteral, especially intravenous and intramuscular administration. The high solubility and chemical stability also render the compounds of the invention suitable for other administration routes, such as for instance oral and rectal administration.

The compounds of the invention are of the following formula I:

and terapeutically acceptable salts thereof, in which formula X is -S- or -SO-; y is O or 1; A is a benzene ring or a heterocyclic 5- or 6-membered ring which may contain 1-2 hetero atoms selected from sulfur and nitrogen.;; R1, R2, R3 and R4, which are the same or different, are a) H, b) alkyl containing 1-6 carbon atoms, c) cycloalkyl containing 3-7 carbon atoms, d) alkoxy containing 1-6 carbon atoms, e) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part, f) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part, g) halogen, h) -CN, i) -CF3, ji -N02, k) -COR , where R6 is (1-6c) alkyl, (1-6c) alkoxy), or aryl 1) alkylthio containing 1-6 carbon atoms, m) alkylsulfinyl containing 1-7 carbon atoms, n) aryl, o) arylalkyl containing 1-6 carbon atoms in the alkyl part, p) aryloxy, q) arylalkoxy containing 1-6 carbon atoms in the alkyl part or r) R1 and R2, R2 and R3 or R3 and R4, when A is a benzene ring, together with the adjacent carbon atoms in the benzimidazole ring form one or more 5-, 6- or 7-mebered rings, which each may be saturated or unsaturated and may contain 0-3 hetero atoms selected from N, S and 0, and whereby each ring may be optionally substituted with 1-10 substituents selected from alkyl groups with 1-3 carbon atoms, or two or four of the mentioned substituents togetherform one or two oxo groups

whereby if R1 and R2, R2 and R3 or R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring form two rings, the rings may be condensed with each other;; R5 is a) H b) alkyl containing 1-4 carbon etoms Rc is, when y=l, a mono or bicyclic and, when y=O, a bicyclic aromatic heterocyclic structure, wherein one of the rings may be saturated, containing 5-12 atoms, optionally substituted by 0-5 substituents, which are the same or different and selected from a) alkyl containing 1-4 carbon atoms, b) alkoxy containing 1-3 carbon atoms, c) amino, mono- or dialkylamino containing 1-3 carbon atoms in the alkyl part(s), d) alkylthio, alkylsulfinyl or alkylsulfonyl containing 1-3 carbon atoms, e) aryl, f) arylalkyl containing 1-2 carbon atoms in the alkyl part, g) aryloxy, h) arylthio, i) arylalkoxy containing 1-2 carbon atoms in the alkoxy part, j) halogen,

1) fluoroalkyl containing 1-4 carbon atoms and 1-7 fluorine atoms, m) alkanoyl containing 2-5 carbon atoms, n) arylcarbonyl, o) nitro, p) acylamino containing 1-4 carbon atoms, q) carboxy or an ester or amide thereof, r) cyano whereby the heterocyclic structure Rc may contain 1-4 hetero atoms selected from nitrogen, oxygen and sulfur, however, in all cases with a nitrogen atom separated from the -X- group in formula I by two or three atoms, one of which namely that one connected to the -X- group, is a carbon atom;; Rc also designates a ring structure of formula II

in which B represents a benzene ring, or a 5- or 6- meinbered nitrogen or sulfur-containing heterocyclic ring which is connected to the (CH2)y group through a ring carbon atom, L is an alkylene group containing 1 or 2 carbon atoms or a single bond, R11 and R12, which may be the same or different, are each hydrogen, (1-6c)-alkyl, phenyl or cycloalkyl, each of which optionally is substituted by phenyl, the phenyl groups in turn optionally being substi\tSg by (l-6c)-alkyl, or Rill is as defined above and R12 is -OR13 or -NR R , wherein R13, R14 and R15, which may be the same or different, are each hydrogen, cycloalkyl, alkanoyl, pyridyl, phenyl or alkyl optionally substituted by halogen or by an oxo gruop= O, or R12 is as defined above and, when L is a group containing 1 or 2 carbon atoms, R11 forms part of a double bond with L, or R11 and R12, together with the nitrogen atoni to which they are attached, form a 4 to 8 inclusive membered ring which optionally contains 0, 1 or 2 further hetero atoms, which ring carries substituents selected from the definitions of R1 to R4; or, provided that L is not a single bond, the group -LNRllRl2 forms a 5or 6- meribered nitrogen containing heterocyclic ring, which ring carries substituents R16 to R23; R7 to R10 and R16 to R23, which may be the same or different, and each are hydrogen, halogen, phenoxy, alkyl, fluoroalkyl, alkanoyl, benzoyl, RS(O)n, -N02, -NR24R25, morpholino, -NHCOR24, -COOH or an ester or amide thereof, or alkoxy optionally substituted by phenyl and in addition, an adjacent pair of R7, R8, R9 and R10 may together forM a chain -(CH2)X or together with the carbon atoms to which they are attached, form a 6-membered carbocyclic or nitrogen heterocyclic ring; n is 0, 1 or 2; x is 3, 4 or 5; R24 and R25, which may be the same or different are each hydrogen, phenyl and (1-6c) alkyl optionally substituted by phenyl, the phenyl groups in turn optionally being substituted by (1-6c) alkyl;

in which formulas Re is a) H b) (1- 6alkyl c) aryl (0-3C)alkyl whereby the aryl group is optionally substituted by 1-3 substituents, the same or different and selected from halogen, CF3, N02, (1-5C)alkyl and (l-5C)alkoxy; s is O or 1; and the group D preferably is in the form of a mono-, di-, tri- or tetra-ionic salt containing a physiologically acceptable counter cation, and wherein R is (1-6C) alkyl or aryl.

provided that Rc is other than pyridyl when the ring structure A represents a benzene ring as definded above.

It should be understood that the expressions "alkyl" and "alkoxy" include straight, branched and cyclic structures including cycloalkylalkyl and cycloalkylalkoxy, respectively.

The number of carbon atoms in a given radical is in this specification either expressly stated or given in abbreviated form within parentheses such as (1-3C)alkyl.

The compounds of the invention that are sulfoxides have an asymnetric centre in the sulphur atoni, i.e. these compounds exist as two opticaT isomers (enantiomers), or if they also contain one or more asymmetric carbon atoms the compounds have two or more diastereomeric forms, each existing in two enantionieric forms.

Both the pure enantiomers, racemic mixtures (50 % of each enantioer) and unequal mixtures of the two are within the scope of the present invention. It should be understood that all the diastereomeric forms possible (pure enantiomers or racemic mixtures) are within the scope of the invention.

The compounds of the invention that are sulphides (X=S) may be asymmetric due to one or more asymmetric carbon atoms, as described above. The different diastereomeric forms possible as well as the pure enantiomers and racemic mixtures are within the scope of the invention.

Illustrative examples of the various radicals in the formula I are as follows. These illustrative examples will be applicable to the different radicals depending on the number of carbon atoms prescribed for each radical.

The group alkyl in the definitions of R1, R2, R3, R4, R5, R6, R7, R8 R9, R10 Rll R12, R13 R14 R15 R16 R17 18 R19, R20 R21 R22, R23, R24, R25 and Re are exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylr,1ethyl, cyclopentylniethyl, cyclopentylethyl, and cyclohexylmethyl. Lower alkyl groups containing 1-4 carbon atoms are especially preferred.

The group alkoxy in the defintions of R1, R2, R3, R4, R6, R7, R8,R9, R10, R16 R17 R18, R19, R20 R21 R22 and R23 are exemplified by methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, cyclopropoxy, cyclopentoxy, cyclohexoxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclopentylethoxy, and cyclohexylmethoxy. Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms, preferably a lower alkoxy group having especially preferred 1-3 carbon atoms, e.g. methoxy, ethoxy, n-propoxy or isopropoxy.

Halogen in the definitions of R1, R2, R3 R4 R7, R8 R9 R10, R16 R17, R18 R19, R20, R21 , R22 and R23 is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.

In R2 R3 R4 R7 R8 R9 R1O R16 R17 R R and R23 when representing alkylthio or alkylsulfinyl is the alkyl preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methylthio, methylsulfinyl, ethylthio, ethylsulfinyl, isopropylthio, n-butylsulfinyl or isobutylthio.

The group aryl when present in R1, R2, R3, R4, R6, and Re has preferaDly up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.

7 R2, R3, R4, R7, R8, R9, R10, R16, R17 R18,R19 R20, R21 R22 and R23 representing an aryloxy or arylthio group have preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy or phenylthio group.

The groups arylalkyl, arylalkoxy, and arylalkylthio, when present in R, R2, R3, R4 and Re have preferably up to 10 carbon atoms in the aryl group. Especially preferred are 6 carbon atoms in the aryl group and 1-3 carbon atoms in the alkyl group or alkoxy group, respectively, e.g.

phenylmethyl, phenylethyl, phenylmethoxy, phenylethoxy, phenylpropyl, phenylisopropoxy, phenylmethylthio, and phenylethylthio.

R1, R2, R3 and R4 representing an alkoxy alkyl or alkoxyalkoxy group are exemplified by methoxymethyl methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxyethyl, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy.

Illustrative examples of ring structures formed by R1 and R2, R2 and R3 and R3 and R4 are -CH2CH2CH2-, -CH2CH2CH2CH2 -CH2C(CH3)2CH2-, -(CH2)5-, -CH=CH-CH=CH-, -CH2COCH2-, -OCH20-, -OCH2CH20-, -OCH2CH2CH20-, -OCH2CH2-, -CH2CH2NH-, -CH=CH-CH=N-, -COCH2CO-, -SCH2CH2-, -SCH2S-, -SCH2CH2S-, -C(CH3)2-CO-C(CH3)2-, -OCF20-, -OCF2CHFO-, -OCF2CF2O-, and -OCF2CFC 10-.

For the compounds with the general formula I containing an asymmetric centre, both the pure enantiomers and the acetic mixtures are within the scope of the present invention.

Further illustrative examples of the radicals in the formula I are given in the examples and lists of specific compounds given elsewhere in this specification.

It is believed that compounds of formula I are metabolized before exerting their effect. Such metabolism may occur in the N-substituent in position 1 in the benzimidazole nucleus. Moreover, compounds of the invention wherein X is S are believed to exert their antisecretory activity after metabolism to compounds wherein X is SO. Preparation A.For the preparation of compounds of the formula I wherein R5 is H, reacting a compound of the formula III

wherein R1, R2, R3, R4, Rc, Y, A and X are as defined under formula I, and Z is halogen such as C1, Br or I or a functionally equivalent group, with a compound of the formula IV, V, VI, VII, VIII or IX:

wherein s and Re are as defined under formula I above, RP is a suitable protecting group such as cyanoethyl, benzyl or p-nitrophenyl, and M is a counter ion such as Na+, K+, Ag+ or trialkylammonium. In the case where a protecting group is used, such protecting group is removed after the coupling reaction (see under D below).

B. Oxidizing a compound of the formula I

wherein X is S, R1, R2, R3, R4, R5, R , A, Y and D have the meanings given, to give a compound of the same formula I wherein X is SO. This oxidation may be carried out by using an oxidizing agent selected from the group consisting of nitric acid, hydrogen peroxide, peracids, peresters, oxone, dinitrogentetraoxide, iodosobenzene, N-halosuccinimide, l-chlorobenzotriazole, t-butylhypochlorite, diazabicyclo-[2,2,2] -octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine, and sulfuryl chloride. The oxidation usually takes place in a solvent wherein the oxidizing agent is present in some excess in relation to the product to be oxidized.

The oxidation may also be carried out enzymatically by using an oxidating enzyme or microbiotically by using a suitable microorganism.

C. Reacting a compound of the formula IIIA

wherein R1, R2, R3, R4, R5, Roc, X and A are as defined under formula I with a suitable activated phorphoric acid moiety such as

wherein S is for instance C1, Br, imidazolyl or triazolyl if desired in the presence of a suitable base, whereupon the intermediate formed is hydrolyzed, preferably in alkaline solution.

D. Removal of a protective group in the D substituent is done by methods well known in the art. Thus, for instance, the phosphates may be protected as dibenzyl- or diphenyl esters, which can be cleaved by sodium iodide in acetone or by basic hydrolysis. The cyanoethyl protecting group may be removed by treatment with a base such as NaOH.

Depending on the process conditions and the starting materials, the end products of the formula I are obtained either in neutral or salt form.

Both the neutral compounds and the salts of these end products are included within the scope of the invention. Thus. salts may be obtained as well as hemi, mono, sesqui or polyhydrates.

Acid addition salts of the amino-containing compounds may in a manner known per se be transformed into free base using basic agents such as alkali or by ion exchange. The free bases obtained may then be converted into salts with organic or inorganic acids. In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts.Examples of such acides are hydrohalogen acids, sulfonic acid, phosphoric acid, nitric acid, and perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, napthylsulfonic acid or sulfanilic acids, methionine, tryptophane, lysine or arginine.

Base addition salts of the carboxylic acid - or phosphorous - containing compounds may in a corresponding way be transformed into the acid form, and then reconverted to a therapeutically suitable salt such as sodiurn and potassium salts.

Racemates obtained can be separated according to known methods, e.g.

recrystallization from an optically active solvent.

In the case of diastereomeric mixtures (racemate mixtures) these may be separated into stereoisomeric (diastereomeric) pure racemates by means of chromatography or fractional crystallization.

The starting materials utilized in the methods A-D are in some cases novel. These novel starting materials may, however, be obtained according to processes known per se.

Starting materials of the formula III A are obtained by reaction of the corresponding compound carrying H in the N-l position with an aldehyde R5CHO.

Starting materials of the formula III are novel and constitute as such part of the invention. Compounds of the formula III wherein Z is C1 are prepared by reaction of a compound of the formula III A with a chlorinating agent such as SOC12 in the presence of a suitable base such as triethylamine in a suitable solvent such as CH2C12, toluene, acetonitrile, tetrahydrofuran or mixtures thereof. For the preparation of compounds of the formula III wherein Z is Br or I, analogous methods are used utilizing suitable reagents containing bromine, such as BBr3, or iodine.

The starting materials having X=S, utilized in Method B may be obtained according to Method A, or Method C.

In a further aspect, the invention relates to the use, as means for increasing the aqueous solubility of gastric acid-inhibiting compounds, of a radical of the formula

where D and R5 are as defined in formula I, as substituent in position N-l of the ii,lidazolyl riny of the heterocyclic nucleus of compound I as defined in claim I.

The preferred meanings of D and R5 are as stated elsewhere in this specification.

For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. It is especially preferred to formulate the compounds of the invention into pharmaceutical formulations for parenteral administration. The pharmaceutical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier.

The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the anount of active compounds is between 0.1-95% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration.

In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylo pectin, cellulose derivatives, gelatin, or another suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleng glycol waxes. The mixture is then processed into granules or pressed into tablets.

Granules and tablets containing sulfoxides may be coated with an enteric coating which protects the active compound form acid catalyzed degradation as long as the dosage form remains in the stomach. The enteric coating is chosen among pharmaceutically acceptable entericcoating materials e.g. beeswax, shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To this coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules may also be enteric-coated as described above. Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatine. The hard gelatine capsules may be entericcoated as described above.

Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.

Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different unit dose ampoules or vials.

Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.

The invention is illustrated by the following examples.

Example 1 Preparation of Phosphoric acid, ethyl-2-E2-(2-pyri dyl )- phenylsulfinyl]-H-benzimidazole-1-yl]methyl ester, sodium salt.

1-Chloromethyl-2-t2-(2-pyridyl)-phenylsulfinyl3-lH-benz- i mi dazol e (20mg,0.055 mrnol )and the ditri butyl ammoni um salt of phosphoric acid acid mono ethyl ester (1.8nl1l0.52mlol)were mixed together with tributylamine and methylene chloride ( 1 ml ). The solvent was evaporated and the residue heated on a water bath at 600C for 5 min. Methylene chloride was added, distilled off and the product was heated for 5 min at 60 0C . This procedure was repeated four times until the reaction was completed. The residue was dissolved in methylene chloride and washed with three portions of water. The organic layer was dried, filtered and evaporated.The crude mixture of tri butyl ammoni um salts was dissolved in methylene chloride and water was added. A solution of sodium hydroxide was added until pH 10. The mixture was centrifuged and the aqueous layer washed with three portions of methylene chloride. Yielding a fixture containing the title compound.

Example 2 Preparation of Phosphoric acid, 2-12-(2-pyridyl )-phenyl- sulfinyl]-lH-benzimidazole-l-yl methyl ester disodium salt

Tributylamine (0.3ml,1.13mmol)was added with stirring to a solution of phosphoric acid, 85 per cent b.o4mlso.o6mrolfin ethanol ( 1 ml ). The solvent was evaporated and the residue taken up in methylene chloride ( 2 ml ). The organic phase was dried over sodium sulphate, filtered and evaporated. 1-Chloromethyl-2-[2-(2-pyridyl)-phenylsulfinyl] - iH-benzi mi dazol e (2O#%,O.054T.0J'1) and the tri butyl ammonium salt of phosphoric acid, prepared above, were dissolved in methylene chloride ( 1 ml ).The methylene chloride was distilled off and the residue was treated on a water bath for 5 min at 6O0C. The residue was dissolved in methylene chloride ( 1 ml ) and again the methylene chloride was distilled off and the oily product was heated on a water bath for 5 min at 60 0C. This procedure was repeated four times until the reaction was completed. The residue wasdissolved in methylene chloride and washed with three portions of water. The organic layer was dried, filtered and evaporated. The mixture of tributylammonium salts was dissolved in methylene chloride ( 1 ml ) and water ( 1 ml ) was added. A solution of sodium hydroxide was added with stirring while pH of the aqueous layer was carefully controlled. When pH reached 9.0-9.5 in the aqueous phase the mixture was centrifuged. The aqueous layer was washed with three portions of ( 1 ml methylene chloride, yielding a mixture containing the title co; ound.

Example 3 Preparation of Phosphoric acid, 2-[[4-(2,3,4 heptaflurobutoxy) -2-picolylsulfinyl 1 -1H-thjeno 3,4 -d 1 imidazole-l-yl)methyl ester, disodium salt.

1-Chloromethyl-2-[[4-(2,3,4-heptafluorobutoxy)-2-picolyl- sulfinyl]-1H-thieno[3,4-d] imidazole (30 mg, 0.62 mmol) was dissolved in a 1:1 mixture of ethylacetate and methylene chloride (30 ml). A solution of bis(tri- n-butyl-ammonium hydrogen)phosphate (1.5 ml, 0.7M) in methylene chloride was added and the mixture was concentrated in a water bath at reduced pressure at 60eC. The residue was dissolved in methylene chloride (10 ml) and the solution was concentrated as above. According to TLC (SiO2/EtoAc:MeOH:H2O; 20:4:2) the reaction was by then completed. The residue was taken up in methylene chloride (6 ml) and the solution was washed with water (4x2 ml).Sodium hydroxide (0.1 M) was then added during violent stirring while the pH value of the water phase was carefully controlled. At pH 10 the phases were separated by centrifugation and the water phase was freeze dried. The crude product contains about 0.5 mg of the title compound.

NMR analysis: 1H NMR in D2O; 6 4.2-4.4 (2 H, m, CH2CF2), 5.0-5.1 (2 H, m, CH2SO), 5.5-5.8 (2 H, m, CH2OP), 6.4-7.1 (4 H, m, aromatic protons), 8.19 (1 H, d; J=6.2 Hz, aromatic proton) Pharmaceutical preparations containing a compound of the invention as active ingredient are illustrated in the following formulations.

Syrup A syrup containing 1 X (weight per volume) of active substance was prepared from the following ingredients: Active compound 1.0 g Sugar. powder 30.0 g Saccharine 0.5 g Glycerol 5.0 g Flavouring agent 0.05 g Ethanol 96 X 5.0 g Distilled water q.s. to a final volume of 100 ml Sugar and saccharine were dissolved in 60 g of warm water. After cooling the active compound was added to the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.

Enteric-coated tablets An enteric coated tablet containing 20 mg of active compound was prepared from the following ingredients: I Active compound 200 g Lactose 700 g Methyl cellulose 6g Polyvinylpyrrolidone cross-linked 50 g Magnesium stearate 15 g Sodium carbonate 6g Distilled water q.s.

II Cellulose acetate phthalate 200 g Cetyl alcohol 15 g isopropanol 2900 g Methylene c'oride 205r 9 I Active coln?ounds powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet mass was forced through a sieve and the granulate dried in an oven. After drying the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was pressed into tablet cores (10 000 tablets), each tablet containing 20 mg of active substance, in a tabletting machine using 6 rrwn diameter punches.

II A solution of cellulose acetate phthalate and cetyl alcohol in isopropanol/methylene chloride was sprayed onto the tablets I in an Accela CotaR, Manesty coating equipment. A final tablet weight of 110 mg was obtained.

Solution for intravenous administration A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients: Active compound 4g Sterile water to a final volume of 1000 ml The active compound was dissolved in water to a final volume of 1000 ml.

The solution was filtered through a 0.22 pm filter and immediately dispensed into 10 ml sterile ampoules. The ampoules were sealed.

Tablets Tablets containing 30 mg of active compound were prepared from the following ingredients: Active corilpound 300 g Lactose 700 9 Methyl cellulose 6g Polyvinyl pyrrolidone, cross-linked (PVP-XL) 62 g Di sodium hydrogen phosphate 2 g Magnesium stearate 30 g Purified water q.s.

The active compound was mixed with lactose and part of the PVP-XL and granulated with a solution of methyl cellulose and disodium hydrogen phosphate. The wet mass was forced through a screen and dried in a fluidized bed dryer. After adding magnesium stearate and the remainder in PYP-XL and mixing, the drug mixture was compressed into tablets with a mean weight of 110 mg, each tablet containing 30 mg of the active compound Enteric coated tablets 500 g of the tablets above were enteric-coated. A solution of the composition below was sprayed onto the tablets in a fluidized bed apparatus using Wurster coating technique.

Coating solution: Cellulose acetate phthalate 40 g Cetyl alcohol 2g Isopropanol 400 g Dichloromethane 400 g The final coated tablet weighed 117 mg.

Suppositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.

Active compound 4g Witepsol H-15 180 g The active compound was homogenously mixed with Witepsol H-15 at a temperature of 41"C. The molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed. Each suppository contained 40 mg of active compound.

Just before use, the active compound dissolved in 10 ml of sterile water is transferred into 100 ml of normal saline solution for infusion to give a total volume of about 110 ml. The solution is administered as an intravenous infusion during a time period of about 30 minutes.

Syrup A syrup containing 1X of active substance was prepared from the following ingredients: Active compound 1.0 g Sugar, powder 30.0 g Saccharine 0.6 g Flavouring agent 0.05 g Ethanol 96X 5.0 g Purified water q.s. to 100 ml Sugar and saccharine were dissolved in 60 g of warm water. After cooling the active compound was added to the sugar solution and a solution of flavouring agents dissolved in ethanol was added. The mixture was diluted with water to a final volume of 100 ml.

Solution for intravenous or intramuscular injection Active compound 60 g Water for injection to make 1000 ml The active compound was dissolved in water to a final volume of 1000 ml.

The solution was filtered through a sterile 0.22 pm filter and aseptically dispensed into 1 ml sterile ampoules. The ampoules were sealed.

Formulation for intravenous infusion Active compound 60 mg Sterile injection vials and stoppers Active compound, 60 mg, was dispensed into 10 ml sterile injection vials. The vials were stoppered with sterile rubber stoppers.

The vokale filling operation was performed under aseptic conditions in a sterile production area under vertical laminar flow.

Preparation of l-chloromethyl-2-2-(2-pyridyl )-phenylsulfinyl)-lH- benzimidazole as starting material for examples 1 and 2 2-G2-(2-pyridyl)-phenyl sulfinyll-1H-benzimidazoie (110 mg, 0.35 mmole) was dissolved in 5 ml of CH2C12 , 5 mg 4-dimethylaminopyridine was added and the mixture was stirred with 1 ml of 5 M HCHO for 2 min. The layers were separated and the CH2C12 layer was dried and evaporated. The residue was dissolved in 10 ml of CH2C12. Triethylamine (150 mg, 15 mmole) was added followed by SOCl2(60 mg, 0.5 mmole) dissolved in 2 ml of CH2Cl2.

Yield: 40 mg.

NMR (500 MHz, CDCl3,oC): 6.34 (d, 1H), 6.52 (d, 1H), 7.13-7.95 (m, lOH), 8.52 (d, 1H), 8.63 (d, 1H).

Claims

What we claim is: 1. A compound of the formula and therapeutically acceptable salts thereof in which formula X is -S- or -SO-; y is O or 1; A is a benzene ring or a heterocyclic 5- or 6-niembered ring which may contain 1-2 hetero atoms selected from sulfur and nitrogen.;; R1, R2, R3 and R4, which are the same or different, are a) H, b) alkyl containing 1-6 carbon atoms, c) cycloalkyl containing 3-7 carbon atoms, d) alkoxy containing 1-6 carbon atoms, e) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part, f) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part, g) halogen, h) -CN, i) -CF3, j i -NO2, k) -COR6, where R6 is (1-6c) alkyl, (1-6c) alkoxy), or aryl 1) alkylthio containing 1-6 carbon atoms, m) alkylsulfinyl containing 1-7 carbon atoms, n) aryl, o) arylalkyl containing 1-6 carbon atoms in the alkyl part, p) aryloxy, q) arylalkoxy containing 1-6 carbon atoms in the alkyl part or r) R1 and R2, R2 and R3 or R3 and R4, when A is a benzene ring, together with the adjacent carbon atoms in the benzimidazole ring for one or more 5-, 6- or 7-membered rings, which each may be saturated or unsaturated and may contain 0-3 hetero atoms selected from N, S and 0, and whereby each ring may be optionally substituted with 1-10 substituents selected from alkyl groups with 1-3 carbon atoms, or two or four of the mentioned substituents togetherform one or two oxo groups whereby if R1 and R2, R2 and R3 or R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring form two rings, the rings may be condensed with each other;; R5 is a) H b) alkyl containing 1-4 carbon atoms R c is, when y=l, a mono- or bicyclic and, when y=O, a bicyclic aromatic heterocyclic structure, wherein one of the rings may be saturated, containing 5-12 atoms, optionally substituted by 0-5 substituents, which are the same or different and selected from a) alkyl containing 1-4 carbon atoms, b) alkoxy containing 1-3 carbon atoms, c) amino, mono- or dialkylamino containing 1-3 carbon atoms in the alkyl part(s), d) alkylthio, alkylsulfinyl or alkylsulfonyl containing 1-3 carbon atoms, e) aryl, f) arylalkyl containing 1-2 carbon atoms in the alkyl part, g) aryloxy, h) arylthio, i) arylalkoxy containing 1-2 carbon atoms in the alkoxy part, j) halogen,

1) fluoroalkyl containing 1-4 carbon atoms and 1-7 fluorine atoms, (n) alkanoyl containing 2-5 carbon atoms, n) arylcarbonyl, o) nitro, p) acylamino containing 1-4 carbon atoms, q) carboxy or an ester or amide thereof, r) cyano whereby the heterocyclic structure Rc may contain 1-4 hetero atoms selected from nitrogen, oxygen and sulfur, however, in all cases with a nitrogen atom separated from the -X- group in formula I by two or three atoms, one of which namely that one connected to the -X- group, is a carbon atomj Rc also designates a ring structure of formula II

in which B represents a benzene ring, or a 5- or 6- mernbered nitrogen or sulfur-containing heterocyclic ring which is connected to the -(CH2)y~ group through a ring carbon atom, L is an alkylene group containing 1 or 2 carbon atoms or a single bond, and and R12, which may be the same or different, are each hydrogen, (1-6c)-alkyl, phenyl or cycloalkyl, each of which optionally is substituted by phenyl, the phenyl groups in turn optionally being substi\4tSg by (l-6c)-alkyl, or R11 is as defined above and R12 is -OR13 or -NR R , wherein R13, R14 and R15, which may be the same or different, are each hydrogen, cycloalkyl, alkanoyl, pyridyl, phenyl or alkyl optionally substituted by halogen or by an oxo gruop= 0, or R12 is as defined above and, when L is a group containing 1 or 2 carbon atoms, Rll forms part of a double bond with L, or R11 and R12, together with the nitrogen atoms to which they are attached, form a 4 to 8 inclusive membered ring which optionally contains 0, 1 or 2 further hetero atoms, which ring carries substituents selected from the definitions of R1 to R4; or, provided that L is not a single bond, the group -LNR11R12 forms a 5or 6- mebered nitrogen containing heterocyclic ring, which ring carries substituents R16 to R23; R7 to R10 and R16 to R23, which may be the same or different, and each are hydrogen, halogen, phenoxy, alkyl, fluoroalkyl, alkanoyl, benzoyl, RS(O)n, -N02, -NR24R25, morpholino, -NHCoR24, -COOH or an ester or amide thereof, or alkoxy optionally substituted by phenyl and in addition, an adjacent pair of R7, R8, R9 and R10 may together form a chain -(CH2) or together with the carbon atoms to which they are attached, form a 6-me-abered carbocyclic or nitrogen heterocyclic ring; n is 0, 1 or 2;R is 1-6C alkyl or aryl; x is 3, 4 or 5; R24 and R25, which may be the same or different are each hydrogen, phenyl and (l-6c) alkyl optionally substituted by phenyl, the phenyl groups in turn optionally being substituted by (1-6c) alkyl;

in which formulas Re is a) H b) (1- 6C)alkyl c) aryl (0-3C)alkyl whereby the aryl group is optionally substituted by 1-3 substituents, the same or different and selected from halogen, CF3, N02, (1-5C)alkyl and (l-SC)alkoxy; s is O or 1; and the group D preferably is in the form of a mono-, di-, tri- or tetra-ionic salt containing a physiologically acceptable counter cation, provided that Rc is other than pyridyl when the ring structure A represents a benzene ring as definded above.

2. A compound according to claim 1 hereinbefore specifically mentioned.

3. A compound of the formula

or a physiologically acceptable saltthereof.

4. A compound of the formula

or a physiologically acceptable salt thereof.

5. A pharmaceutical composition containing as active ingredient a compound according to any of claims 1-4.

6. A composition according to claim 5 substantially as hereinbefore described.

7. A compound as defined in any of claims 1-4 for use in therapy.

8. A compound as defined inany of claims 1-4 for use in inhibiting gastric acid secretion in mammals and man.

9. A compound as defined in any of claims 1-4 for use in the treatment of gastrointestinal inflammatory diseases in mammals and man.

10. A compound according to any of claims 1-4 for use in the manufacture of a medicament for inhibiting gastric secretion in mammals and man.

11. A compound according to any of claims 1-4 for use in the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases in mammals and man.

12. A process for the preparation of a compound according to formula I as defined in claim 1, by A. for the preparation of compounds of the formula I wherein R5 is H, reacting a coinpound of the formula III

wherein R1, R2, R3, R4, Rc, Y, A and X are as defined under formula I, and Z is halogen such as C1, Br or I or a functionally equivalent group, with a compound of the formula IV, V, VI, VII, VIII or IX::

wherein s and Re are as defined under formula I above, RP is a suitable protecting group such as cyanoethyl, benzyl or p-nirophenyl, and M is a counter ion such as Na+, K+, Ag+ or trialkylammonium; B. oxidizing a compound of the formula I

wherein X is S, R1, R2, R3, R4, R5, Rc, A, Y and D have the meanings given, to give a compound of the same formula I wherein X is SO; ; C. reacting a compound of the formula IIIA

wherein R1, R2, R3, R4, R5, R , X and A are as defined under formula I with a suitable activated phosphoric acid moiety such as

wherein S is for instance C1, Br, imidarolyl vr triazolyl if desired in the presence of a suitable base, whereupon the intermediate formed is hydrolyzed; whereafter, if necessary, protecting groups are reriloved and the compound obtained if desired is converted to a physiologically accetable salt.

13. A process according to claim 12 substantially as hereinbefore described.