WO1991019711A1

WO1991019711A1 - Substituted benzimidazoles, process for their preparation and their pharmaceutical use

Info

Publication number: WO1991019711A1
Application number: PCT/SE1991/000415
Authority: WO
Inventors: Arne Elof BRÄNDSTRÖM; Per Lennart Lindberg; Gunnel Elisabeth SUNDéN
Original assignee: Aktiebolaget Astra
Priority date: 1990-06-20
Filing date: 1991-06-11
Publication date: 1991-12-26
Also published as: FI925766A; HUT62881A; ZA914297B; LT3952B; HU9204033D0; CS189491A3; YU104191A; NO924775L; IL98470A0; AU649453B2; EP0535081A1; TNSN91049A1; RO110493B1; IE912025A1; ZA914296B; MA22199A1; LV10953A; JPH05507713A; LTIP1713A; SE9002206D0

Abstract

The novel compounds of formula (I), wherein R?1 and R2¿, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R6; one of R1 or R2 is always selected from the group -C(O)-R6; wherein R6 is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms, R3 is the group -CH¿2OCOOR?7, wherein R7 is alkyl containing 1-6 carbon atoms or benzyl; R?4 and R5¿ are the same or different and selected from -CH¿3?, -C2H5, (a), (b) and -CH2CH2OCH3, or R?4 and R5¿ form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R?4 and R5¿ is -CH¿2?CH2CH2-, -CH2CH2- or -CH2- as well as pharmaceutical compositions containing such compounds as active ingredient, and the use of the compounds in medicine.

Description

Substituted benzimidazoles. process for their preparation and their pharmaceutical use

DESCRIPTION

Field of the invention The object of the present invention is to provide novel compounds, 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 also relates to the use of the compounds of the invention for inhibiting gastric acid secretion in mammals including 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 including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome. 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 pre- and postoperatively to prevent acid aspiration and stress ulceration. The compounds 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 gout. The compounds may also be useful in the treatment of diseases related to bone metabolism disorders as well as the treatment of glaucoma. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as active ingredient. In a further aspect, the invention relates to processes for preparation of such new compounds and to the use of the active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.

It is a specific primary object of the invention to provide compounds with a high level of biovailability. The compounds of the invention will also exhibit good

stability properties at neutral and acidic pH and a good potency in regard to inhibition of gastric acid

secretion. The compounds of the invention will not block the uptake of iodine into the thyroid gland. It has earlier been disclosed in several lectures from the company, where the inventors are working that thyroid toxicity depends on if the compounds are lipophilic or not. The inventors have now unexpectedly found that it is not the lipophilicity that is the critical parameter. The claimed compounds, which include rather hydrophilic compounds, do not give any thyroid toxic effect and have at the same time high acid secretion inhibitory effect, good bioavailability and stability.

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 1 500 043, GB 1 525 958, US 4 182 766, US 4 255 431, US 4 599 347, BE 898 880, EP 124 495, EP 208 452, EP 221 041, EP 279 149, EP 176 308 and Derwent abstract 87-294449/42. Benzimidazole

derivatives proposed for use in the treatment or

prevention of special gastrointestinal inflammatory diseases are disclosed in US 4 359 465. The invention

The compounds of the formula I are effective as

inhibitors of gastric acid secretion in mammals including man and in addition do not block the uptake of iodine into the thyroid gland. It has also been found that the compounds of the following formula I show high

bioavailability. Further, the compounds of the invention exhibit a high chemical stability in solution at neutral and acidic pH. The high chemical stability also at acidic pH makes the compounds useful for non-enteric coated peroral formulations. The compounds of the invention are of the following formula I:

wherein

R¹ and R², which are different, is each H, alkyl

containing 1-4 carbon atoms or -C(O)-R ⁶, one of R¹ or R² is always selected from the group -C(O)-R⁶; wherein

R⁶ is alkyl containing 1-4 carbon atoms or alkoxy

containing 1-4 carbon atoms

R 3 is the group -CH₂OCCOR⁷, wherein R⁷ is alkyl containing

1-6 carbon atoms or benzyl;

R ⁴ and R⁵ are the same or different and selected from

and R⁵ form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R⁴ and R⁵ is -CH₂CH₂CH₂-, -CH₂CH₂- or -CH₂-.

It should be understood that the expressions "alkyl" and "alkoxy" include straight and branched structures.

The structural isomers of the invention described in examples 1-6 may be used separately, or in equal or unequal mixtures.

The compounds of the invention of the formula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers) or if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each existing in the two enantiomeric forms. Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are within the scope of the present invention. It should also be understood that all the diastereomeric forms possible (pure enantiomers or racemic mixtures) are within the scope of the invention.

Preferred groups of compounds of the formula I are: 1. Compounds, wherein R³ is -CH₂OCOOCH₂CH₃.

2. Compounds, wherein R¹ and R² are selected from H, methyl or -C(O)-R⁶, wherein R⁶ is alkyl containing 1-

4 carbon atoms or alkoxy containing 1-4 carbon atoms.

3. Especially preferred benzimidazole structures are:

4. Especially preferred are compounds, wherein R⁴ and R⁵ are methyl.

5. Especially preferred specific compounds of the

invention are the compounds listed in the following tabulation

CH₃ C(O)OCH₃ CH₂OCOOCH₂CH₃ CH₃ CH₃ C(O)OCH₃ CH₃ CH₂OCOOCH₂CH₃ CH₃ CH₃

CH₃ C(O)CH₃ CH₂OCOOCH₂CH₃ CH₃ CH₃

C(O)CH₃ CH₃ CH₂OCOOCH₂CH₃ CH₃ CH₃

It is believed that compounds of formula I are metabolized into the corresponding compounds, wherein R³ is H before exerting their effect.

Preparation

The compounds of the invention may be prepared according to the following methods: a) Reacting a compound of the formula II

wherein R¹, R², R⁴ and R⁵ are as definedw under formula I, and Z, is either a metal cation such as Na+, K+, Li+ or Ag+ or a quaternary ammonium ion, such as tetrabutylammonium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate.

b) Reacting a compound of the formula II, wherein R ¹ , R², R ⁴ and R⁵ are as defined under formula I and Z is

hydroxymethyl with a compound of the formula III,

X-C(O)-O-R⁷ III wherein R⁷ is as defined above and X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group, in the presence of a suitable base such as triethylamine.

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

c) Oxidizing a compound of the formula IV

wherein R¹, R², R³, R⁴ and R⁵ are as defined under formula I.

This oxidation may be carried out by using an oxidizing agent such as nitric acid, hydrogen peroxide, (optionally in the presence of vanadium compounds), peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, Nhalosuccinimide, 1-chlorobenzotriazole, tbutylhypochlorite, 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 such as halogenated hydrocarbons, alcohols, ethers, ketones.

The oxidation may also be carried out enzymatically by using an oxidizing enzyme or microbiotically by using a suitable microorganism. The structural isomers obtained, may be separated by means of crystallization or

chromatography. Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent. In the case of racemic diastereomeric mixtures these may be separated into diastereomeric pure enantiomers by means of chromatography or fractional crystallization. The starting materials utilized in the methods a)-c) are in some cases unknown. These unknown starting materials may, be obtained according to processes known per se.

Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate may be obtained from the pertinent alcohol by treatment with chloromethyl chloroformate in the presence of pyridine.

Intermediates of the formula II, wherein Z is hydroxymethyl are obtained by reaction of the corresponding benzimidazole compound carrying H in the N-1 position with formaldehyde.

Starting materials of the formula III may be obtained by known methods, e.g. from an alcohol HOR⁷ by treatment with phosgene or 1,1¹-carbonyldiimidazole or p-nitrophenyl chloroformate.

For clinical use a compound of the invention is formulated into pharmaceutical formulations for oral, rectal, or other modes of administration. The pharmaceutical formulation contains a compound of the invention normally in combinatio 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 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

containing a compound of the present invention in the form of dosage units for oral administration a compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch,

amylopectin, cellulose derivatives, 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 catalyzed 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 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 the 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 an active compound 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, amylopection, cellulose

derivatives or gelatine. The hard gelatine capsules may be enteric-coated as described above. Dosage units for rectal administration may be prepared in the form of suppositories which contain an 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 a dry powder to be reconstituted with a suitable solvent prior to use.

The typical daily dose of the active substance 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 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-carbomethoxy-6-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1- ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate, as an isomeric mixture. To a suspension of 0.45 g (1.1 mmol) of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole and 0.25 g (1.8 mmol) of potassium

carbonate anhydrous in 45 ml of dry acetonitrile, 0.21 g (1.5 mmol) of chloromethyl ethyl carbonate dissolved in 5 m of acetonitrile was added. The reaction mixture was stirred at room temperature over night. The solvent was then removed in vacuo and the residue was diluted with methylene chloride and water. The organic solvent was dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave the crude product, which was chromatographed with silica gel and eluted with ethyl acetate to provide 0.94 g of a yellow oil which slowly crystallized. Recrystallizatio with ethanol yielded 0.25 g (44 %) of the title compounds a an isomeric mixture.

NMR data for the products are given below.

Example 2. Preparation of 6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1ylmethyl ethyl carbonate.

The title compound was obtained by crystallizing the isomeric mixture given in example 1 from ethanol.

NMR data are given below. Example 3. Preparation of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1- ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2-[[(3,4-dimethoxγ-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1- ylmethyl ethyl carbonate, as an isomeric mixture.

To a magnetically stirred suspension of potassium carbonate anhydrous (0.48 g, 3.47 mmol) in 80 ml of dry acetonitrile 0.80 g (2.14 mmol) of 5-acetyl-6-raethyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and 0.39 g (2.8 mmol) of chloromethyl ethyl carbonate dissolved in 10 ml of acetonitrile was added dropwise. Stirring was

continued at room temperature for 20 hours. The solvent was removed in vacuo, the residue diluted with methylene

chloride, the methylene chloride solution washed with water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave the crude product which was

chromatographed with silica gel and eluted with ethyl acetate to yield 0.63 g of an almost white crystalline solide. The product was recrystallized from ethyl acetate to give 0.50 g (49 %) of the title compounds as an isomeric mixture.

NMR data for the products are given below.

Example 4. Preparation of 5-acetyl-6-methγl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1ylmethyl ethyl carbonate.

The title compound was isolated from the isomeric mixture given in example 3 by chromatography on a silica column with methylene chloride - acetonitrile (ratio 6:4) as eluent. The title compound was crystallized from ethanol.

NMR data are given below.

Example 5. Preparation of 6-acetyl-5-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1- ylmethyl ethyl carbonate.

The title compound was isolated from the isomeric mixture given in example 3 by chromatography on a silica column with methylene chloride-acetonitrile (ratio 6:4) as eluent. The title compound was crystallized from ethanol.

NMR data are given below. Example 6 Preparation of 5-carbethoxy-2-[[(3,4-diιnethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benziraidazole-1-ylmethyl ethyl carbonate and 6-carbethoxy-2-{[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate, as an isomeric mixture.

To a suspension of 0.28 g (0.72 mmol) 5-carbethoxy-2-[[(3,4 dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole and 0.16 g (1.2 mmol) anhydrous potassium carbonate in 20 ml of dry acetonitrile 0.16 g (1.2 mmol) chloromethyl ethyl carbonate dissolved in 2 ml dry acetonitrile was added. The mixture was stirred at ambient temperature over night. The solvent was evaporated off and the crude product was

chromatographed on a silica column using ethyl acetate as eluent. Crystallizing from ethanol gave the title compounds as an isomeric mixture, (0.13 g, 37%).

NMR data for the products are given below. Table 1

Ex. Solvent NMR data δ ppm

CDCl₃ 1.20-1.30 (m, 3H), 2.70 (s,1.8H), (300 MHz) 2.75 (s, 1.2H), 3.85-3.95 (m,9H),

4.15-4.25 (m,2H), 4.85-5.05 (m,2H), 6.40-6.55 (m,2H), 6.75 (d,1H), 7.45 (s, 0.6H), 7.65 (s, 0.4 H), 8.10 (d, 1H), 8.20 (s, 0.4 H), 8.40 (s, 0.6 H).

CDCl₃ 1.30 (t, 3H), 2.70 (s, 3H)

(300 MHz) 3.90 (s,3H), 3.90 (s, 3H), 3.95 (s,

3H), 4.25 (q, 2H) , 4.95 (d, 1H), 5.05 (d, 1H), 6.50 (m, 2H), 6.75 (d, 1H), 7.65 (s, 1H), 8.10 (d, 1H), 8.20 (s. 1H)

CDCl₃ 1.30 (t, 3H) 2.60-2.70 (m, 6H), (303 MHz) 3.85-3.90 (m, 6H), 4.25 (q,2H),

4.85-5.05 (m, 2H), 6.75 (d,1H), 7.45 (s, 0.7 H), 7.60 (s, 0.3H), 8.05 (s, 0.3H), 8.10 (d, 1H), 8.20 (s, 0.7H)

CDCl₃ 1.30 (t, 3H), 2.60 (s, 3H), 2.70 (300 MHz) (s, 3H), 3.90 (s, 3H), 3.90 (s, 3H),

4.20 (q, 2H), 4.90 (d, 1H), 5.05 (d, 1H), 6.50 (m, 2H), 6.80 (d, 1H),

7.50 (s, 1H), 8.15 (d, 1H), 8.20 (s, 1H)

CDCl₃ 1.30 (t, 3H), 2.60 (S, 3H), 2.70 (300 MHz) (s, 3H), 3.90 (s, 3H), 3.90 (s, 3

H), 4.25 (q, 2H), 4.90 (d, 1H), 5.05 (d, 1H), 6.55 (m, 2H), 6.80 (d, 1H), 7.60 (s, 1H), 8.05 (s, 1 H), 8.15 (d, 1H)

CDCl₃ 1.30 (m, 3H), 1.45 (m, 3H), 3.90 (300 MHz) (s, 3H), 3.90 (s, 3H), 4.25 (m,

2H), 4.45 (m, 2H), 5.00 (m, 2H), 6.55 (m, 2H), 6.80 (d, 1H), 7.70 (d, 0.55H), 7.80 (d, 0.45H), 8.10 (m, 2H), 8.35 (s, 0,45H), 8.50 (d, 0.55H). Preparation of intermediates

Example I 1 Preparation of 5-carbomethoxy-6-methyl-9-[[(3,4-dimethoxy-

2-pyridinyl)methyl]thio]-1H-benzimidazole

5-carbomethoxy-6-methyl-2-mercapto-1H-benziraidazole (0.67 g, 0.003 mol) and NaOH (0.12 g, 0.003 mol) in H₂O (0.6 ml) were dissolved in CH₃OH (15 ml). 3,4-dimethoxy-2chloromethylpyridine hydrochloride, (=0.0036 mol) as a crude material in CH₃OH (10 ml) and NaOH (0.144 g, 0.0036 mol) in H₂O (0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH₃OH was evaporated off and the crude material was purified by chromatography on a silica column using CH₂Cl₂-CH₃OH (98-2) as eluent, giving (1.03 g, 92%) of the pure title compound.

NMR data are given below.

Example I 2

Preparation of 5-carbomethoxy-6methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.03 g, 0.00276 mol) was dissolved in CH₂Cl₂ (30 ml). NaHCO₃ (0.46 g,

0.0055 mol) in H₂O (10 ml) was added and the mixture was cooled to +2°C. m-chloroperbenzoic acid 69.5% (0.62 g,

0.0025 mol) dissolved in CH₂Cl₂ (5 ml) was added dropwise under stirring. Stirring was continued at +2ºC for 15 min. After separation the organic layer was extracted with an aqueous 0.2 M NaOH solution (3x15 ml, 0.009 mol). After separation the aqueous solutions were combined and

neutralized with methyl formate (0.56 ml, 0.009 mol) in the presence of CH₂Cl₂ (25 ml). After separation the organic layer was dried over Na₂SO₄ and evaporated under reduced pressure. The residue was crystallized from CH₃CN (10 ml) giving the title compound (0.68 g, 70 %).

NMR data are given below.

Example I 3 Preparation of 5-acetyl-6-m_et_h_yl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole

5-acetyl-6-methyl-2-mercapto-1H-benzimidazole (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) in H₂0 (1 ml) were dissolved in 60 ml ethanol. 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈17 mmol) as a crude material was added and the mixture was heated to boiling. NaOH (0.7 g, 17 mmol) in H₂0 (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na₂SO. and the solvent was removed under reduced pressure. Crystallizing from acetonitrile gave the title compound, (3.75 g, 62%). NMR data are given below.

Example I 4

Preparation of 5-acetyl-6-m_et_h__yl-2-[[(3,4-di__methoa_y-2- pyridinyl)methyl]sulfinyl3-lH-benzimidazole

5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]thio]-1H-benzimidazole (3.75 g, 10 mmol) was dissolved in CH₂Cl₂ (70 ml). NaHC0₃ (1.76 g, 21 mmol) in H₂O (25 ml) was added and the mixture was cooled to ≈+3°C. m-Chloroperbenzoic acid 69.5% (2.43 g, 9.8 mmol) dissolved in CH₂Cl₂ (20 ml) was added dropwise under stirring.

Stirring was continued for 10 min. The phases were separated and the organic phase was dried over Na₂SO. and evaporated under reduced pressure. The residue was crystallized from CH₃CN giving the title compound (2.25 g, 60%).

NMR data are given below.

Example I 5

Preparation of 5-carbethoxy-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]thio]-1H-benzimidazole

5-carbethoxy-2-mercapto-1H-benzimidazole (2.0 g, 9 mmol) and NaOH (0.36 g, 9 mmol) in H₂O (1 ml) were dissolved in ethanol (30 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈6.6 mmol) as a crude material were added and the mixture was heated to boiling. NaOH (0.26 g, 6.6 mmol) in H₂O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na₂SO₄ and the solvent removed under reduced pressure. Crystallizing from CH₃CN gave the desired product (1.75 g, 71 %).

NMR data are given below.

Example I 6 Preparation of 5-carbethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

5-carbethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (95.2% pure) (1.4 g, 0.0036 mol) was dissolved in CH₂Cl₂ (30 ml). NaHCO₃ (0.6 g, 0.0072 mol in H₂O (10 ml) was added and the mixture was cooled to +2°C. m-Chloroperbenzoic acid 69.5 % (0.87 g, 0.0035 mol)

dissolved in CH₂Cl₂ (5 ml) was added dropwise under

stirring. Stirring was continued at +2°C for 10 rain. The phases were separated and the organic phase was dried over Na₂SO₄ and evaporated under reduced pressure. The residue was crystallized from CH₃CN (15 ml ) giving the title compound (0.76 g, 54 %).

NMR data are given below.

Table 2

Ex Solvent NMR data δ ppm I 1 CDCl₃ 2.70 (s, 3H), 3.90 (s, 3H),

(300 MHz) 3.95 (s, 3H), 4.00 (s, 3H),

4.40 (s, 2H), 6.90 (d, 1H),

7.35 (s, 1H), 8.20 (s, 1H),

8.25 (d,1H).

I 2 CDCl₃ 2.70 (s, 3H), 3.85 (s, 3H),

(500 MHz) 3.90 (s, 3H), 3.95 (s, 3H),

4.70 (d, 1H), 4.90 (d, 1H),

6.8 (d, 1H), 7.30 (b, 1H), 8.20 (d, 1H), 8.35 (b, 1H).

I 3 CDCl₃ 2.60 (s, 3H), 2.65 (s, 3H), 3.90

(300 MHz) (s, 3H), 3.90 (s, 3H), 4.35 (s, 2H

6.85 (d, 1H), 7.25 (s,0.6H), 7.40 (s, 0.4H), 7.85 (s, 0.4H), 8.05 (s, 0.6H), 8.30 (m, 1H)

I 4 CDCl₃ 2.60 (s, 6H), 3.85 (s, 3H), 3.85

(300 MHz) (s, 3H), 4.70 (d, 1H), 4.90

(d, 1H), 6.80 (d, 1H), 7.30

(b, 1H), 8.15 (d, 1H), 8.20 (b, 1H I 5 CDCl₃ 1.40 (m, 3H), 3.90 (s, 3H), 3.90 (300 MHz) (s, 3H), 4.40 (m, 4H), 6.90

(dd, 1H), 7.45 (d, 0.4H), 7.60 (d, 0.6H), 7.90 (m, 1H), 8.20 (s, 0.6H), 8.25 (m, 1H), 8.25 (s, 0.4H)

I 6 CDCl₃ 1.45 (t, 3H), 3.85 (s, 3H),

(300 MHz) 3.90 (s, 3H), 4.40 (q, 2H),

4.65 (d, 1H), 4.40 (d, 1H),

6.80 (d, 1H), 7.507.80 (b, 1H) 8.05 (d, 1H), 8.20 (d, 1H),

8.25, 8.55 (b, 1H)

The best mode of carrying out the invention known at present is to use the compound mixture according to Example 3 and the compound according to Example 4.

Table 3

Examples of compounds included in the formula I are given in the following table.

Ident. Re¬

Example R¹ R² R³ R⁴ R⁵ Yield % data marks 1 C(O)OCH₃ CH₃ CH₂OCOOC₂H₅ CH₃ CH₃ 44 NMR Isomeric

CH₃ C(O)OCH₃ mixture 2 CH₃ C(O)OCH₃ CH₂OCOOC₂H₅ CH₃ CH₃ NMR Isolated isomer 3 C(O)CH₃ CH₃ CH₂OCOOC₂H₅ CH₃ CH₃ 49 NMR Isomeric

CH₃ C(O)CH₃ mixture 4 C(O)CH₃ CH₃ CH₂OCOOC₂H₅ CH₃ CH₃ NMR Isolated isomer 5 CH₃ C(O)CH₃ CH₂OCOOC₂H₅ CH₃ CH₃ NMR Isolated isomer 6 C(O)OCH₂CH₃ H CH₂OCOOC₂H₅ CH₃ CH ₃ 37 NMR Isomeric

H C(O)OCH₂CH₃ mixture

Syrup

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

A compound according to Example 4 1. 0 g Sugar, powder 30. 0 g Saccharine 0.6 g Glycerol 5. 0 g Tween 1.0 g

Flavouring agent 0. 05 g

Ethanol 96% 5. 0 g

Distilled water q.s. to a final volume of 100 ml A solution of the compound mixture according to Example in ethanol and Tween was prepared. Sugar and saccharine were dissolved in 60 g of warm water. After cooling the

solution of 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.

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

I Compound mixture according to

Example 3 500 g

Lactose 700 g

Methyl cellulose 6 g

Polyvinylpyrrolidone cross-linked 50 g

Magnesium stearate 15 g

Sodium carbonate 6 g

Distilled water q.s. II Hydroxypropyl methylcellulose 36 g

Polyethylene glyco 19 g

Colour Titanium dioxide 4 g

Purified water 313 g

I Compound mixture according to Example 3, 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 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 Cota , 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:

A compound according to Example 4 300 g

Lactose 700 g Miσrocrystalline cellulose 40 g

Hydroxypropyl cellulose low-substituted 62 g

Purified water q.s.

The active compound mixture 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 fluidized 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:

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.

Compound mixture according to Example 4 4 g Witepsol H-15 180 g

The active compound mixture 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. BiologicalEffects

Biovailability

Bioavailability, is assessed by calculating the quotient between the areas under plasma concentration (AUC) curve of a compound of the formula I wherein R³ is hydrogen

(herein defined as compound A), following 1) intraduodenal (id) or oral (po) administration of the corresponding compound according to the invention and 2) intravenous

(iv) administration of compound A, from the rat and the dog. Low, therapeutically relevant doses, were used. Data are provided in Table 4.

Potency for inhibition of acid secretion

The potency for inhibition of acid secretion is measured in the female rat orally and in the dog both

intraduodenally and orally.

Potency data are provided in Table 4.

Effects on the uptake of iodine into the thyroid gland.

The effect of a compound within the invention of the formula I on the uptake of iodine into the thyroid gland is measured as an effect on the accumulation of ¹²⁵I in the thyroid gland of the corresponding compound of the formula I, wherein R³ is hydrogen, that is a metabolized compound of the formula I.

Biological Tests Inhibition of Gastric Acid Secretion in the Conscious Female Rat. Female rats of the Sprague-Dawley strain are used. They are equipped with cannulated fistulae in the stomach (lumen), for collection of gastric secretions. A fourteen days recovery period after surgery is allowed before testing is commenced.

Before secretory tests, the animals are deprived of food but not water for 20 h. The stomach is repeatedly washed through the gastric cannula, and 6 ml of Ringer-Glucose given s.c. Acid secretion is stimulated with infusion during 2.5 h (1.2 ml/h, s.c.) of pentagastrin and

carbachol (20 and 110 nmol/kg h, respectively), during which time gastric secretions are collected in 30-min fractions. Test substances or vehicle are given orally 120 min before starting the stimulation, in a volume of 5 ml/kg. Gastric juice samples are titrated to pH 7.0 with NaOH, 0.1 mol/L, and acid output is calculated as the product of titrant volume and concentration. Further calculations are based on group mean responses from 4-7 rats. Percentage inhibition is calculated from absolute rates of acid output. ED_CQ" values are obtained from graphical interpolation on log dose-response curves, or estimated from single-dose experiments assuming a similar slope for all dose-response curves. The results are based on gastric acid secretion during the third hour after drug/vehicle administration.

Bioavailability in the Male Rat.

Male adult rats of the Sprague-Dawley strain were used. One day, prior to the experiments, all rats were prepared by cannulation of the left carotid artery under

anaesthesia. The rats used for the intravenous

experiments, were also cannulated in the jugular vein. (Ref. V Popovic and P Popovic, J Appl Physiol 1960;15,727-728). The rats used for the intraduodenal experiments, were also cannulated in the upper part of the duodenum. The cannulas were exteriorized at the nape of the neck. The rats were housed individually after surgery and were deprived of food, but not water, before administration of the test substances. The same dose (4 μmol/kg) were given iv and id as a bolus for about one minute (2 ml/kg). Blood samples (0.1-0.4 g) were drawn repeatedly from the carotid artery at intervals up to 4 hours after given dose. The samples were frozen as soon as possible until analysis of the test compound. The area under the blood concentration vs time curve, AUC, for the compound A, determined by the linear trapezoidal rule and extrapolated to infinity by dividing the last determined blood concentration by the elimination rate constant in the terminal phase. The systemic

bioavailability (F%) of the compound A following

intraduodenal administration of compounds of the

invention of formula I was calculated as

Inhibition of Gastric Acid Secretion and Bioavailability in the Conscious Dog

Harrier dogs of either sex were used. They were equipped with a duodenal fistula for the administration of test compounds or vehicle and a cannulated gastric fistula or a Heidenhain-pouch for the collection of gastric secretions. Before secretory tests the animals were fasted for about 18 h but water was freely allowed. Gastric acid secretion was stimulated by a 4 h infusion of histamine

dihydrochloride (12 ml/h) at a dose producing about 80% of the individual maximal secretory response, and gastric juice collected in consecutive 30-min fractions. Test substance or vehicle was given orally, id or iv 1 h after starting the histamine infusion, in a volume of 0.5 ml/kg body weight. In the case of oral administration, it should be pointed out that the test compound is administered to the acid secreting main stomach of the Heidenhain-pouch dog. The acidity of the gastric juice samples were determined by titration to pH 7.0, and the acid output calculated. The acid output in the collection periods after

administration of test substance or vehicle were

expressed as fractional responses, setting the acid output in the fraction preceding administration to 1.0.

Percentage inhibition was calculated from fractional responses elicited by test compound and vehicle. ED₅₀-values were obtained by graphical interpolation on log dose - response curves, or estimated from single-dose experiments under the assumption of the same slope of the dose-response curve for all test compounds. All results reported are based on acid output 2 h after dosing.

Blood samples for the analysis of test compound

concentration in plasma were taken at intervals up to 3 h after dosing. Plasma was separated and frozen within 30 min after collection and later analyzed. AUC (area under the plasma concentration - time curve) from time zero to 3 h after dose for compound A, was calculated by the linear trapezoidal rule. The systemic bioavailability (F%) of the compound A after oral or id administration of compounds of the invention was calculated as described above in the rat model. Effect on the accumulation of ¹²⁵I in the thyroid gland The accumulation of 125I in the thyroid gland was studied in male, Sprague-Dawley rats which were deprived of food for 24 hours before the test. The experimental protocol of Searle, CE et al. (Biochem J 1950; 47:77-81) was followed.

Test substances, suspended in 0.5% buffered (pH 9)

methocel, were administerd by oral gavage in a volume of 5 ml/kg body weight. After 1 hour, ¹²⁵I (300kBq/kg, 3ml/kg) was administered by intraperitoneal injection. Four hours after 125I-administration, the animals were killed by

C0₂-asphyxiation and bled. The thyroid gland together with a piece of the trachea was dissected out and placed in a small test tube for the assay of radioactivity in a gamma counter (LKB-Wallac model 1282 Compugaiuna). Percentage inhibition was calculated according to the formula 100 (1-T/P), where T and P is the mean radioactivity of thyroid glands from animals treated with test agent and placebo (buffered methocel), respectively. The statistical

significance for a difference between test agent- and placebo-treated animals was assessed with the Mann-Whitney U-test (two-tailed). P<0.05 was accepted as significant.

Chemical Stability

The chemical stability of the compounds of the invention has been followed kinetically at low concentration at 37°C in aqueous buffer solution at different pH values. The results in Table 5 show the half life (t 1/2) at pH 7, that is the time period after which half the amount of the original compound remains unchanged, and 10% at pH 2, that is the time period after which 10% of the original compound has decomposed. Results of biological and stability tests

Table 4 and 5 give a sumnary of the test data available for the compounds of the invention.

Table 5 , stability Data

Test compound Chemical

Example No. stability at

pH 7 pH 2 t 1/2 (h) t 10% (h)

1 87 9.5 2 50 6.5 3 51 7.5 4 82 13 5 60 7 6 63 13

Claims

CLAIMS:

1. Compounds of the formula I

wherein

R ¹ and R², which are different, is each H, alkyl containing

1-4 carbon atoms or -C(O)-R ⁶; one of R¹ or R² is always selected from the group -C(O)-R⁶; wherein

R⁶ is alkyl containing 1-4 carbon atoms or alkoxy containing

1-4 carbon atoms. R³ is the group -CH₂OCOOR⁷, wherein R⁷ is alkyl containing

1-6 carbon atoms or benzyl;

R ⁴ and R⁵ are the same or different and selected from -CH₃, and - or R⁴ and R⁵

form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R ⁴ and R⁵ is -CH₂CH₂ - CH₂-, -CH₂CH₂- or -CH₂-.

2. Compounds according to formula I of claim 1, namely a mixture of 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-H-benzimidazole-1-ylmethyl ethyl carbonate.

3. Compounds according to formula I of claim 1, namely mixture of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2-[[(3,4-dimethoxy- 2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.

4. A compound according to claim 1, namely 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole-1-ylmethyl ethyl carbonate.

5. A compound according to claim 1, namely 6-carbomethoxy- 5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]sulfinyl]- 1H-benzimidazole-1-ylmethyl ethyl carbonate.

6. A compound according to claim 1, namely 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate.

7. A compound according to claim 1, namely 6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)-methyl]sufinyl]-1Hbenzimidazole-1-ylmethyl ethyl carbonate.

8. A compound according to claim 1, wherein R³ is the group

CH₂OCOOCH₂CH₃.

9. A compound according to claim 1, wherein R ¹ and R² is each H, methyl or -C(O)R⁶, wherein R⁶ is alkyl containing 1

4 carbon atoms or alkoxy containing 1-4 carbon atoms.

10. A pharmaceutical composition containing as active ingredient a compound according to claim 1.

11. A compound as defined in claim 1 for use in therapy.

12. A compound as defined in claim 1 for use in inhibiting gastric acid secretion in mammals including man.

13. A compound as defined in claim 1 for use in the treatment of gastrointestinal inflammatory deseases in mammals including man.

14. A method for inhibiting gastric acid secretion by administering to mammals including man a compound as defined in claim 1.

15. A method for the treatment of gastrointestinal

infammatory diseases in mammals including man by

administering a compound as defined in claim 1.

16. Use of a compound according to claim 1 in the

manufacture of a medicament for inhibiting gastric acid secretion in mammals including man.

17. Use of a compound according to claim 1 in the

manufacture of a medicament for the treatment of

gastrointestinal inflammatory diseases in mammals including man.

18. A process for the preparation of a compound of the formula I according to claim 1, by

a) reacting a compound of the formula II

wherein R¹, R², R⁴ and R⁵ are as defined under formula I a Z is either a metal cation such as Na+, R+, Li+ or Ag+ or quaternary ammonium ion, such as tetrabutylammonium with alkyl chloromethyl carbonate or benzyl chloromethyl

carbonate or; b) reacting a compound of the formula II, wherein R¹, R², R⁴ and R⁵ are as defined under formula I and Z is

hydroxymethyl with a compound of the formula III

X-C(O)-O-R⁷ wherein R⁷ is as defined above and 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 IV

wherein R¹, R², R³, R⁴ and R⁵ are as defined under

formula I.