WO1995032957A1

WO1995032957A1 - Novel ethoxycarbonyloxymethyl derivatives of substituted benzimidazoles

Info

Publication number: WO1995032957A1
Application number: PCT/SE1994/000512
Authority: WO
Inventors: Sverker Von Unge
Original assignee: Astra Aktiebolag
Priority date: 1994-05-27
Filing date: 1994-05-27
Publication date: 1995-12-07

Abstract

The novel optically pure compounds, i.e. the single enantiomeric compounds, (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H)-benzimidazole-1-ylmethyl ethyl carbonate, (-)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate, (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate and (+)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate, processes for the preparation thereof and pharmaceutical preparations containing the compounds as active ingredients, as well as the use of the compounds in pharmaceutical preparations and intermediates obtained by preparing the compounds.

Description

NOVEL ETHOXYCARBONYLOXYMETHYL DERIVATIVES OF SUBSTITUTED BENZIMIDAZOLES

Field of the invention

The present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation.

Background of the invention

The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]- sulfinyl]-lH-benzimidazole, having the generic name omeprazole is described in EP 5129. Omeprazole is an effective gastric acid secretion inhibitor, and is useful as an antiulcer agent.

A number of alkoxycarbonyloxymethyl derivatives of omeprazole are disclosed in EP 0233284. The compounds, omeprazole as well as its N-substituted derivatives, being sulfoxides, have an asymmetric center in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as lower degree of interindividual variation. The present invention provides such compounds, which are novel single enantiomers of ethoxy- carbonyloxymethyl derivatives of omeprazole.

The separation of the enantiomers of omeprazole in analytical scale is described in e.g. J. Chromatography, 532 (1990), 305-19 and in a preparative scale in DE 4035455. The latter has been done by using a diastereomeric ether which is separated and thereafter hydrolysed in an acidic solution.

There is no example given in the prior art of the isolated and characterized compounds of the invention.

Detailed description of the invention

The present invention refers to the new single enantiomers of 5-methoxy-2-[[(4- methoxy-3 ,5-dimethyl-2-pyridinyl)rnethyl] sulfinyl] - 1 H-benzimidazole- 1 -ylmethyl ethyl carbonate according to compounds la and lb

SUBSTITUTE SHEET

la (+)-enantiomer lb (-)-enantiomer

as well as the new single enantiomers of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfmyl]-lH-benzirnidazole-l-ylmethyl ethyl carbonate according to compounds Ha and lib.

Ila (+)-enantiomer lib (-)-enantiomer

The invention also refers to the new single enantiomers of the regioisomeric mixture

SUBSTITUTE SHEET of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyτidinyl)methyl]sulfιnyl]-l_i- benzimidazole- 1 -ylmethyl ethyl carbonate and 6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]suirιnyl]-lH-benzimidazole-l-ylmethyl ethyl carbonate according to compounds Ilia and Illb, wherein the methoxy substituent in the benzimidazole moiety is in position 5 or 6.

Ilia (+)-enantiomer nib (-)-enantiomer

With the expression "optically pure compound of the invention" is meant the (+)- enantiomer of said compound (or compounds) essentially free of the corresponding (-)-enantiomer and the (-)-enantiomer essentially free of the corresponding (+)- enantiomer, respectively.

It is believed that the compounds of invention is metabolized into the corresponding compounds, carrying H in the N-l position in the benzimidazole nucleus (compounds A and B, i.e. the single enantiomers of omeprazole) before exerting its effect.

SUBSTITUTE SHEET

A (+)-omeprazole B (-)-omeprazole

Single enantiomers of omeprazole in neutral form (i.e. not as salts thereof) have hitherto only been obtained as syrups and not as crystalline products. However, the optically pure N-ethoxycarbonyloxymethyl derivatives, both the single enantiomers of pure regioisomers (i.e. the 5-methoxy-2-[[(4-methoxy-3,5-dirnethyl-2- pyτidinyl)methyl]sulfιnyl]-lH-benzimidazole-l-ylmethyl ethyl carbonate isomer and the 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfιnyl]-lH- benzimidazole- 1 -ylmethyl ethyl carbonate isomer) as well as the single enantiomers of regioisomeric mixtures are obtained as crystalline products.

Therefore, it is possible to obtain crystalline products, which would be easier to handle (use) in the preparation of pharmaceutical formulations than a syrup of the single enantiomers of omeprazole in neutral form.

Further, it is possible to use the single enantiomers of ethoxycarbonyloxymethyl derivatives of omeprazole to obtain the single enantiomers of omeprazole in neutral form in a higher purity.

The optically pure compounds do not undergo directly racemization in neutral pH, which was surprising since N-substituted omeprazole derivatives, catalyzed by protons, are converted to achiral sulfenic acids which easily undergo the reverse reaction back to sulfoxides (see e.g. Brandstrδm et al. Acta Chemica Scandinavica 43 (1989) 587). It is obvious that such a reversible reaction from an achiral sulfenic acid back to a sulfoxide would cause a racemic compound. This high stability towards

SUBSTITUTE SHEET racemization in neutral pH combined with the assumption that the compounds will be dissolved and converted to optically pure omeprazole in the intestine but not in the acidic compartments of the stomach makes it possible to use a single enantiomeric compound of invention in therapy.

The compounds according to the invention may be used for inhibiting gastric acid secretion in mammals and man. In a more general sense, the single enantiomeric compounds of the invention may be used for the treatment of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable e.g. in patients on NSAID therapy, in patients with gastrinomas, and in patients with accute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration. The compound of the invention may also be used for treatment or prophylaxis of inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be specifically mentioned are rheumatoid arthritis and goat. The compounds of the invention may also be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections.

Preparation

The optically pure compounds of the invention, i.e. the single enantiomers may be prepared according to one of the following methods a), b) or c) described below.

a) Reacting a compound of the formula IV a) or IVb).

SUBSTITUTE SHEET IVa (+)-enantiomers IVb (-)-enantiomers

wherein the methoxy substituent in the benzimidazole moiety is in position 5 or 6 and wherein Z is either a metal cation such as Na⁺, K⁺, Li⁺ or Ag⁺ or a quaternary ammonium ion, such as tetrabutylammonium, with chloromethyl ethyl carbonate.

b) Reacting a compound of the formula IVa) or IVb) either in the form of a pure regioisomer or as a regioisomeric mixture, wherein Z is hydroxymethyl, with a compound of the formula V,

X-C(O)-O-CH2CH3 V

wherein X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group, in the presence of a suitable base such as trietylamine.

c) Oxidizing a compound of the formula VI either as a pure regioisomer or as a regioisomeric mixture, wherein the methoxy substituent in the benzimidazole moiety is in position 5 or 6.

This oxidation may be carried out by using a chiral inducing oxidizing agent or by using an oxidizing agent with a chiral catalyst or any other chiral enviroment such as e.g. chiral solvents.

The oxidation may also be carried out enzymatically by using an oxidizing enzyme or

SUBSTITUTE SHEET microbiologically by using a suitable microorganism.

The reactions according to methods a) and b) above are suitably carried out under protective gas in the absence of water. Suitable solvents are acetonitrile, l-methyl-2- pyrrolidinone, acetone or dimethyl formamide or hydrocarbons such as toluene or benzene or halogenated hydrocarbons such as methylene chloride or chloroform. The reactions may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.

The starting compounds IVa) and IVb), respectively, being salt of the single enantiomers of omeprazole, can be prepared by separating the two stereoisomers of a diastereomeric mixture of the following type 5- or 6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfιnyl]-l-[acyloxymethyl]-lH-benzimidazole, formula VII

wherein the methoxy substituent in the benzimidazole moiety is in position 5 or 6, and wherein the Acyl radical is as defined below, followed by a solvolysis of each separated diastereomer in an alkaline solution. The formed single enantiomers of omeprazole are then isolated by neutralizing aqueous solutions of the salts of the single enantiomers of omeprazole with a neutralizing agent which can be an acid or an ester such as methyl formate.

The Acyl moiety in the diastereomeric ester may be a chiral acyl group such as mandeloyl, and the asymmetric center in the chiral acyl group can have either R or S configuration.

The diastereomeric esters can be separated either by chromatography or fractional

SUBSTITUTE SHEET crystallization.

The solvolysis usually takes place together with a base in a protic solvent such as alcohols or water, but the acyl group may also be hydrolysed off by a base in an aprotic solvent such as dimethylsulfoxide or dimethylformamide. Th reacting base may be OH" or R^O" where R^ can be any alkyl or aryl group.

To obtain the sodium salt of single enantiomers of omeprazole, the resulting compound is treated with a base, such as NaOH, in an aqueous or nonaqueous medium, or with NaOR^ where R^ is an alkyl group containing 1-4 carbon atoms, or with NaNH2- In order to obtain the crystalline form of the Na⁺ salt, addition of NaOH in a non-aqueous medium such as a mixture of 2-butanone and toluene, is preferred.

When rnixtures of regioisomers are obtained in any of the above methods, a pure regioisomer of a single enantiomer of the invention can be isolated by means of crystallization or chromatography.

In those cases when a mixture of the two enantiomers are obtained, the single enantiomers can be separated according to known methods, e.g. by crystallisation from different solvents.

In some cases the starting materials utilized in the methods a)-c) are unknown. These unknown starting materials may be obtained from known compounds by utilizing processes known per se.

Chloromethyl ethyl carbonate may be obtained from ethanol by treatment with chloromethyl chloroformate in the presence of pyridine.

Intermediates of formula IV, wherein Z is hydroxymethyl are obtained by reaction of the corresponding single enantiomer of omeprazole with formaldehyde.

Starting materials of the formula V may be obtained by known methods, e.g. from ethanol by treatment with phosgene or l,l'-carbonyl diimidazole or p-nitrophenyl chloroformate.

Starting materials of formula IV and VI can be obtained from the regioisomeric mixtures of the corresponding compounds by means of crystallization or

SUBSTITUTE SHEET chromatography.

For clinical use the single enantiomers, i.e. the optically pure compounds, of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other modes of administrations. The pharmaceutical formulations contain the single enantiomers of the invention normally in combination with a pharmaceutically acceptable carrier. The carrier may be in form of a solid, semi-solid or liquid diluent, or capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1-95% by weight of the preparation, and between 1-50% by weight in preparations for oral administration.

In the preparation of pharmaceutical formulations in form of dosage units for oral administration the optically pure compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatin or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes. The mixture is then processed into granules or pressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalysed degradation as long as the dosage form remains in the stomach. The enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different amounts of the active compound present.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound, 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 derivates or gelatin. The capsules may be enteric -coated as described above.

Dosage units for rectal administration may be prepared in the form of suppositories

SUBSTITUTE SHEET 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/or 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 dry powder to be reconstituted with a suitable solvent prior to use.

The typical daily dose of the active compound 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 (-)-5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyPmethvHsulfinyll-lH-benzimidazole-l-ylmethyl ethyl carbonate and (-)-6- methoxy-2-rr(4-methoxy-3.5-dimethyl-2-pyridinyl methyllsulfιnvn-lH- benzimidazole-l-ylmethyl ethyl carbonate

(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyτidinyl)methyl]sulfinyl]-lll- benzimidazole sodium salt 3.0 g (8.2 mmol) was dissolved in water (200 ml). The solution was neutralized with an aqueous solution of ammonium chloride and thereafter extracted with methylene chloride. The organic phase was dried over Na2SO4, filtered and then removed by film evaporation. The oily residue containing (-)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH- benzimidazole was dissolved in acetonitrile (50 ml). Potassium carbonate (1.2 g, 9.0 mmol) together with chloromethyl ethyl carbonate (1.2 g, 9.0 mmol) was added and the mixture was stirred over night After evaporation the residue was partitioned between water and methylene chloride. The aqueous phase was pH adjusted to pH 9

SUBSTITUTE SHEET with aqueous ammonia. The layers were separated and the organic phase was dried over Na2SO4. After filtration the solvent was evaporated off. The product which consisted of approximately equal amounts of the two regioisomers was crystallized when a small amount of acetonitrile was added. There was obtained 3.3 g (90%) of the title compounds as white crystals m.p. 81-96°C. [α]²0_D=-121.4 (c=l%, chloroform).

NMR data are given below

Example 2. Preparation of (H^-5-methoxy-2-IT(4-methoxy-3.5-dimethyl-2- pyτidinyl)methyllsulfinyll-lH-benzimidazoIe-l-ylmethyl ethyl carbonate and (+V6- methoxy-2-rr(^"4-methoxy-3.5-dimethyl-2-pyridinvπmethyl1sulfinyl1-lH- benzimidazole-1-ylmethyl ethyl carbonate

(-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-l-H- benzimidazole sodium salt 3.0 g (8.2 mmol) was dissolved in l-methyl-2- pyrrolidinone (50 ml). Chloromethyl ethyl carbonate (1.2 g, 9.0 mmol) was added and the mixture was stirred over night. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed repeatedly with water and then dried over Na2SO4. After evaporation the product was purified by flash chromatography on silica gel with a mixture of acetonitrile/methylene chloride as eluent. The solvents were removed by film evaporation and there was obtained 2.4 g (66%) of the title compounds as white crystals m.p. 83-100°C. [α]²⁰D=+122.8 (c=l%, chloroform).

NMR data are given below

Example 3. Preparation of (-)-5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyDmethyllsulfinyll- 1 H-benzimidazole- 1 -ylmethyl ethyl carbonate

Starting from 2.9 g of the regioisomeric mixture of (-)-5-methoxy-2-[[(4-methoxy- 3,5-dlmethyl-2-pyridinyl)methyl]sulfinyl]-l-H-benzimidazole-l-ylmethyl ethyl carbonate and (-)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulf-nyl]-l -H-benzimidazole- 1-ylmethyl ethyl carbonate from Example 1 the regioisomers of the (-)-enantiomer was separated by repeated recrystallisations from 2-propanol in which the title compound was somewhat less soluble. 76 mg of the title compound containing less than 8% of the other regioisomer was isolated. The product was obtained as white crystals,

SUBSTITUTE SHEET m.p. 115-1 19°C.

NMR data are given below.

Example 4. Preparation of -6-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyl)methyllsulfinyll-l H-benzimidazole- 1-ylmethyl ethyl carbonate

Starting from 2.9 g of the regioisomeric mixture of (-)-5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]- 1 -H-benzimidazole- 1 -ylmethyl ethyl carbonate and (-)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-l -H-benzimidazole- 1 -ylmethyl ethyl carbonate from Example 1 the regioisomers of the (-)-enantiomer was separated by repeated recrystallisations from 2-propanol in which the title compound was somewhat more soluble. 30 mg of the title compound containing less than 8% of the opposite regioisomer was isolated. The product was obtained as white crystals, m.p. 97-100°C.

NMR data are given below.

Table 1.

Ex. Solvent NMR data δ ppm

1. CDCI3 1.3 (m, 3H), 2.2-2.3 (m, 6H), 3.71 (s, 3H), 3.86 and 3.90 300 MHz (two singlets, 3H), 4.18-4.27 (m, 2H), 4.88 (d, 1H), 4.98 (d, lH),6.37-6.42 (m, 1H), 6.51-6.58 (m, 1H), 6.96-7.26 (m, 2H),

7.53 and 7.67 (two doublets, 1H), 8.16 (s, 1H).

2. CDCI3 1.3 (m, 3H), 2.2-2.3 (m, 6H), 3.70 (s, 3H), 3.84 and 3.89 300 MHz (two singlets, 3H), 4.17-4.26 (m, 2H), 4.87 (d, 1H), 4.97 (d, 1H), 6.36-6.42 (m, 1H), 6.50-6.57 (m, 1H), 6.95-7.26 (m, 2H),

7.53 and 7.67 (two doublets, 1H), 8.15 (s, 1H).

CDCI3 1.28 (s, 3H), 2.20 (s, 3H), 2.24 (s, 3H), 3.69 (s, 3H),

300 MHz 3.84 (s, 3H), 4.21 (q, 2H), 4.87 (d, 1H), 4.97 (d, 1H),

6.38 (d, 1H), 6.52 (d, 1H), 7.05 (dd, 1H), 7.24 (d, 1H),

7.53 (d, 1H), 8.15 (s, 1H).

SUBSTITUTE SHEET 4. CDCI3 1.30 (s, 3H), 2.22 (s, 3H), 2.24 (s, 3H), 3.70 (s, 3H),

500 MHz 3.90 (s, 3H), 4.23 (q, 2H), 4.88 (d, 1H), 4.97 (d, 1H), 6.41 (d, 1H), 6.55 (d, 1H), 6.98 (dd, 1H), 7.10 (d, 1H), 7.67 (d, 1H), 8.16 (s, 1H).

Preparation of the starting compounds used in Examples 1 and 2 are described in the following examples. Further some intermediates used in said preparation of the starting compounds are described by examples.

Example 5. Preparation of (+)-5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyl)memyllsi_l_-nyl1-lH-rjen-irnidazole sodium salt

100 mg (0.3 mmol) of (-)-5-me oxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl] sulfinyl]- 1 H-benzimidazole (contaminated with 3% of the (+)-isomer) was dissolved in 1 ml of 2-butanone with stirring. 60 μl of an aqueous solution of 5.0 M sodium hydroxide and 2 ml of toluene were added. The resultant mixture was non- homogeneous. In order to obtain a clear solution, more 2-butanone was added (ca 1 ml) and the mixture was stirred at ambient temperature over night. The formed precipitate was filtered off and washed with ether. There was obtained 51 mg (46%) of the title compound as white crystals m.p. (decomposition) 246-248°C. The optical purity (e.e.) which was analyzed by chiral column chromatography was >99.8%. [α]20_D= +42,8° (c=0.5%, water).

NMR data are given below.

Example 6. Preparation of (-)-5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridiny memyllsiilflnyll-lH-benzirn dazole sodium salt

100 mg (0.3 mmol) of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridlnyl)- methyl]sι_l__nyl]-lH-benzlmldazole (contaminated with 3% of the (-)-isomer) was dissolved in 1 ml of 2-butanone with stirring. 60 μl of an aqueous solution of 5.0 M sodium hydroxide and 2 ml of toluene were added. The resultant mixture was non- homogeneous. In order to obtain a clear solution, more 2-butanone was added (ca 1 ml) and the mixture was stirred at ambient temperature over night. The formed precipitate was filtered off and washed with ether. There was obtained 56 mg (51%) of the title compound as white crystals m.p. (decomposition) 247-249°C. The optical purity (e.e.) which was analyzed by chiral column chromatography was >99.8%.

SUBSTITUTE SHEET [α]²⁰D= -44.1° (c=0.5%, water).

NMR data are given below.

Table 2

Ex. Solvent NMR data pp

DMSO-d₆ 2.20 (s, 3H), 2.22 (s, 3H), 3.69 (s, 3H), 3.72 (s, 3H), 4.37 500 MHz (d, 1H), 4.75 (d, 1H), 6.54 (dd, 1H), 6.96 (d, 1H) 7.30 (d, 1H), 8.21 (s, 1H).

6. DMSO-d₆ 2.20 (s, 3H), 2.22 (s, 3H), 3.69 (s, 3H), 3.72 (s, 3H),

500 MHz 4.38 (d, 1H), 4.73 (d, 1H), 6.54 (dd, 1H), 6.96 (d, 1H), 7.31 (d, 1H), 8.21 (s, 1H).

Example 7. Preparation of 6-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridlnyl methyll-(R/S)-sulfinyll- 1 -r(R)-mandeloyIoxymethyll- 1 H-benzimidazole

A solution of 3.4 g sodium hydroxide in 40 ml water was added to a mixture of 14.4 g (42 mmol) tetrabutylammonlum hydrogen sulphate and 6.4 g (42 mmol) (R)-(-)- mandelic acid. The mixture was extracted with 400 ml chloroform. After separation, the organic extract was heated to reflux with 16.6 g (42 mmol) of the racemate of 6- methoxy-2-[[(4-methoxy-3,5-cu^ethyl-2-pvridinyl)methyl]-s_-finyl]-l-[chloromethyl]- lH-benzimldazole. Evaporation of the solvent was followed by dilution with 100 ml dichloromethane and 700 ml ethyl acetate. The mixture was washed with 3 x 200 ml water and the organic solution was dried over MgSO4 and then evaporated. The crude material was purified by recrystallization from 100 ml acetonitrile, giving 8.1 g of the title compound (38%) as a diastereomeric mixture.

NMR data are given below.

Example 8. Separation of the more hydrophilic diastereomer of 6-methoxy-2-riY4- methoxy-3.5-dimethyl-2-pyridinyl)methvfl-(R/S)-sulfinvπ- 1 -\(R)- mandeloyloxymethyπ- 1 H-benzimidazole

The diastereomers of the title compound in Example 7 were separated using reversed

SUBSTITUTE SHEET phase chromatography (HPLC). Approximately 300 mg of the diastereomeric mixture was dissolved in 10 ml hot acetonitrile which was diluted with 10 ml of a mixture of aqueous 0.1 M ammoniumacetate and acetonitrile (70/30). The solution was injected to the column and the compounds were eluted with a mixture of aqueous 0.1 M ammoniumacetate and acetonitrile (70/30). The more hydrophilic isomer was easier to obtain pure than the less hydrophilic one. The work up procedure for the fraction which contained pure isomer was as follows; extraction with dichloromethane, washing the organic solution with aqueous 5 % sodium hydrogen carbonate solution, drying over Na2SO4 and evaporation of the solvent on a rotavapor (at the end of the evaporation the removal of acetonitrile was facilitated by adding more dichloromethane). Using 1.2 g of the diastereomeric mixture with the above mentioned technique, the more hydrophilic isomer, 410 mg, was obtained in a pure state as a colourless syrup.

NMR data are given below.

Example 9. Preparation of 6-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyl)methyll-(R/S)-sulfmyll-l-r(S)-mandeloyloxymethvU-lH-benziιτιidazole

The product was obtained from 8.1 g (202 mmol) sodium hydroxide in 100 ml water,

34.4 g (101 mmol) tetrabutylammonium hydrogen sulfate, 15.4 g (101 mmol) (S)-(+)- mandellc acid and 39.9 g (101 mmol) of the racemate of 6-methoxy-2-[[(4-methoxy- 3,5-dimemyl-2-pyridinyl)methyl]-sulfinyl]-l-[chloromethyl]-lH-ber_zimidazole using the same procedure as in Example 7. Recrystallization from 100 ml acetonitrile yielded 21.3 g, i.e. 41 % of the title compound as a diastereomeric mixture.

NMR data are given below.

Example 10. Separation of the more hydrophilic diastereomer of 6-methoxy-2-rF(4- methoxy-3.5-dimethyl-2-pyridlnyl methvn-(R S -sulfιnyll-l-r(S - mandeloyloxymethyll - 1 H-benzimidazole

The diastereomers of the title compound in Example 9 were separated using reversed phase chromatography (HPLC) in the same way as In Example 8, but using the diasteromeric mixture of 6-methoxy-2-[[(4-methoxy-3,5-dlmethyl-2-pyridlnyl)methyl]- (I S)-sulf_nyl]-l-[(S)-mandeloyloxymeΛyl]-lH-ber__imidazole instead of the (R)- mandelic ester used in Example 8. Using 2.1 g of the diastereomeric mixture, the more hydrophilic isomer, 760 mg, was obtained in a pure state as a colourless syrup.

SUBSTITUTE SHEET NMR data are given below.

Example 11. Preparation of (- -5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyl methyll-sulfmyll-lH--^nzimidazole

0.23 g (0.45 mmol) of the more hydrophilic diastereomer of 6-methoxy-2-[[(4- methoxy-3,5-cUmethyl-2-pyridlnyl)methyl]sulf_nyl]- 1 -[(R)-mandeloyloxymethyl]- 1H- benzimldazole was dissolved in 15 ml methanol. A solution of 36 mg (0.9 mmol) sodium hydroxid in 0.45 ml water was added, and after 10 minutes the mixture was evaporated on a rotavapor. The residue was partitioned between 15 ml water and 15 ml dichloromethane. The organic solution was extracted with 15 ml water and to the combined aqueous solutions was added 85 μl (1.4 mmol) methyl formate. After 15 minutes the mixture was extracted with 3x10 ml dichloromethane. The organic solution was dried over Na2SO4 and then evaporated. There was obtained 0.12 g

(77%) of the title compound as a colourless syrup. The optical purity (e.e.) which was analyzed by chiral column chromatography was 94%.

-155° (c=0.5%, chloroform).

NMR data are given below

Example 12. Preparation of (+)-5-methoxy-2-rr(4-methoxy-3.5-dlmethyl-2- pyridinyl)memyl1-sulfinyll-lH-ben__rnidazole

0.76 g ( 1.5 mmol) of the more hydrophilic diastereomer of 6-methoxy-2-[[(4- methoxy-3,5-c_methyl-2-pyri___ιyl)methyl]su_finyl]-l-[(S)-mandeloyloxymethyl]-lH- benzlmidazole was dissolved in 50 ml methanol. A solution of 0.12 mg (3.0 mmol) sodium hydroxid In 1.5 ml water was added, and after 10 minutes the mixture was evaporated on a rotavapor. The residue was partitioned between 25 ml water and 25 ml dichloromethane. The organic solution was extracted with 25 ml water and to the combined aqueous solutions was added 200 μl (3.2 mmol) methyl formate. After 15 minutes the mixture was extracted with 3x25 ml dichloromethane. The organic solution was dried over Na2SO4 and then evaporated. There was obtained 0.42 g (81%) of the title compound as a colourless syrup. The optical purity (e.e.) which was analyzed by chiral column chromatography was 98%. [α]20_j)= +157° (c=0.5%, chloroform).

NMR data are given below

SUBSTITUTE SHEET Table 3.

Ex. Solvent NMR data ppm

7. CDC1₃ 2.18 (s, 3H), 2.20 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H),

500 MHz 3.77 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 4.80 (d, IH), 4.88 (d, IH), 5.0 (m, 2H), 5.34 (s, 2H), 6.43 (d, IH), 6.54 (d, IH), 6.6-6.7 (m, 2H), 6.90 (d, IH), 6.95-6.98 (m, 2H), 7.01 (d, IH), 7.2-7.3 (m, 6H), 7.37 (m, 2H), 7.44 (m, 2H), 7.58 (d,

IH), 7.62 (d, IH), 7.95 (s, IH), 7.97 (s, IH).

8. CDCI3 2.20 (s, 3H), 2.36 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H),

500 MHz 4.80 (d, IH), 5.00 (d, IH), 5.35 (d, IH), 6.43 (d, IH), 6.63 (d, IH), 6.90 (d, IH), 6.97 (dd, IH), 7.2-7.3 (m, 3H), 7.37 (m,

2H), 7.62 (d, IH), 7.97 (s, IH).

9. CDCI3 2.19 (s, 3H), 2.20 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H), 3.77 500 MHz (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.80 (d, IH), 4.88 (d, IH), 5.0 (m, 2H), 5.34 (s, 2H), 6.43 (d, IH), 6.54 (d,

IH), 6.6-6.7 (m, 2H), 6.90 (d, IH), 6.96-6.98 (m, 2H), 7.01 (d, IH), 7.2-7.3 (m, 6H), 7.37 (m, 2H), 7.44 (m, 2H), 7.58 (d, IH), 7.62 (d, IH), 7.95 (s, IH), 7.97 (s, IH).

10. CDCI3 2.20 (s, 3H), 2.36 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 4.80

500 MHz (d, IH), 5.00 (d, IH), 5.35 (d, IH), 6.43 (d, IH), 6.63 (d, IH), 6.90 (d, IH), 6.97 (dd, IH), 7.2-7.3 ( , 3H), 7.37 (m, 2H), 7.62 (d, IH), 7.97 (s, IH).

11. CDCI3 2.18, (s, 3H), 2.22 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H),

300 MHz 4.77 (m, 2H), 6.93 (dd, IH), =7.0 (b, IH), =7.5 (b, IH), 8.19 (s, IH).

12. CDCI3 2.21 (s, 3H), 2.23 (s, 3H), 3.69 (s, 3H), 3.84 (s, 3H), 4.76 (m, 2H), 6.94 (dd, IH), =7.0 (b, IH), =7.5 (b, IH), 8.20 (s, IH).

The best mode of carrying out the invention known at present is to use the compounds described In Example 3 and Example 4.

SUBSTITUTE SHEET Pharmaceutical preparations containing the compounds of the invention as active ingredient are illustrated In the following formulations.

Syrup

A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:

Compounds according to Example 1 1.0 g

Sugar, powder 30.0 g

Saccharine 0.6 g

Glycerol 5.0 g

Flavouring agent 0.05 g Ethanol 96% 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 compounds 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.

Tablets

A tablet containing 50 mg of active compound was prepared from the following

Ingredients:

I Compounds according to Example 2 500 g

Lactose 700 g

Methyl cellulose 6 g

Polyvlnylpyrrolidone cross-linked 50 g

Magnesium stearate 15 g

Sodium carbonate 6 g Distilled water q.s.

I Hydroxypropyl methylcellulose 3 g Polyethylene glycol 19 g

SUBSTITUTE SHEET Colour Titanium dioxide 4 g

Purified water 313 g

I Compounds according to Example 2 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 polyvinylpyiTolidone and magnesium stearate. The dry rriixture was pressed into tablet cores (10 000 tablets), each tablet containing 50 mg of active substance, in a tabletting machine using 7 mm diameter punches.

II A solution of hydroxypropyl methylcellulose and polyethylene glycol In purified water was prepared. After dispersion of titanium dioxide the solution was sprayed onto the tablets I in an Accela CotaR, Manesty coating equipment. A final tablet weight of 125 mg was obtained.

Capsules

Capsules containing 30 mg of active compound were prepared from the following ingredients:

Compounds according to Example 2 300 g

Lactose 700 g

Microcrystalline cellulose 40 g Hydroxypropyl cellulose low-substituted 62 g

Disodium hydrogen phosphate 2 g

Purified water q.s.

The active compound was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate. The wet mass was forced through an extruder and spheronized and dried in a fluidlzed bed dryer.

500 g of the pellets above were first coated with a solution of hydroxypropyl methylcellulose, 30 g, In water, 600 g, using a fluidized bed coater. After drying, the pellets were coated with a second coating as given below:

Coating solution:

SUBSTITUTE SHEET Hydroxypropyl methylcellulose phthalate 70 g

Cetyl alcohol 4 g

Acetone 600 g Ethanol 200 g

The final coated pellets were filled into capsules.

Suppositories

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

Compounds according to Example 1 4 g 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.

SUBSTITUTE SHEET

Claims

1. Single enantiomeric compounds having the formula Ilia and Illb

Ilia (+)-enantiomer Ulb (-)-enantiomer

wherein the methoxy substituent in the benzimidazole moiety is in position 5 or 6.

2. Compounds according to claim 1, characterized in that the compounds are (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH- benzimidazole- 1 -ylmethyl ethyl carbonate, (-)-6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]- IH-benzimidazole- 1 -ylmethyl ethyl carbonate,

(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfιnyl]-lJi- benzimidazole- 1 -ylmethyl ethyl carbonate and (+)-6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]- 1 H-benzimidazole- 1 -ylmethyl ethyl carbonate.

3. Compounds according to claim 1 characterized in that the compounds are (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]- IH- benzimidazole- 1 -ylmethyl ethyl carbonate and (-)-6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]- 1 H-benzimidazole- 1-ylmethyl ethyl carbonate.

4. Compounds according to claim 1 characterized in that the compounds are (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridlnyl)methyl]-sulfinyl]-lH- benzimidazole- 1-ylmethyl ethyl carbonate and (+)-6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]- IH-benzimidazole- 1-ylmethyl ethyl carbonate.

SUBSTITUTE SHEET 5. Compound according to claim 1 characterized in that the compound is

(-)-5-methoxy-2-[[(4-methoxy-3,

5-dimethyl-2-pyridinyl)methyl]sulfιnyl]-lH- benzimidazole- 1-ylmethyl ethyl carbonate substantially free of its (+)-enantiomer.

6. Compound according to claim 1 characterized in that the compound is

(-)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]- IH- benzimidazole- 1-ylmethyl ethyl carbonate substantially free of its (+)-enantiomer.

7. Compound according to claim 1 characterized in that the compound is

(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]- IH- benzimidazole- 1 -ylmethyl ethyl carbonate substantially free of its (-)-enantiomer.

8. Compound according to claim 1 characterized in that the compound is (+)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyrid_nyl)methyl]sulfinyl]- IH- benzimidazole- 1-ylmethyl ethyl carbonate substantially free of its (-)-enantiomer.

9. A process for the preparation of compounds according to claim 1 characterized by

a) reacting a compound of the formula IVa) or IVb)

IVa, (+)-enantiomers IVb, (-)-enantiomers

SUBSTITUTE SHEET wherein the methoxy substituent in the benzimidazole moiety is in position 5 or 6, and wherein Z is either a metal cation such as Na⁺, K⁺, Li⁺ or Ag⁺ or a quaternary ammonium ion, such as tetrabutylammonium, with chloromethyl ethyl carbonate,

X-C(O)-O-CH2CH3 V

wherein X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group, in the presence of a suitable base such as triethylamine, or

c) oxidizing a compound of the formula VI either as a pure regioisomer or as a regioisomeric mixture,

and when mixtures of regioisomers are obtained in any of the above methods the pure regioisomeric compound is isolated by crystallisation or chromatography.

10. Pharmaceutical preparation comprising a single enantiomeric compound according to any of claims 1-8 as active ingredient.

11. Single enantiomeric compounds according to any of claims 1-8 for use in therapy.

SUBSTITUTE SHEET

12. Use of a single enantiomeric compound according to any of claims 1-8 in the manufacture of a pharmaceutical formulation for inhibiting gastric acid secretion.

13. Use of a single enantiomeric compound according to any of claims 1-8 for the manufacture of a pharmaceutical formulation for the treatment of gastrointestinal inflammatory diseases.

14. A method for inhibiting gastric acid secretion comprising administration to a mammal including man in need of such treatment an effective amount of an enantiomeric compound according to any of claims 1-8.

15. A method for the treatment of gastrointestinal inflammatory diseases comprising administration to a mammal including man In need of such treatment an effective amount of an enantiomeric compound according to any of claims 1-8.

SUBSTITUTE SHEET