AU665043B2 - Substituted benzimidazoles, process for their preparation as well as their use - Google Patents

Description

I

4

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ii

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.1 OPI DATE 19/07/93 APPLN. ID 31752/93 .111 I AOJP DATE 16/09/93 PCT NUMBER PCT/SE92/00844 111 I1111AIIIIII III AU9331752 ILKNAIUNAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) F(51) International Patent Classification 5 (11) International Publication Number: WO 93/12124 C07F 3/65,C740/2A (43) International Publication Date: 24 June 1993 (24.06.93) (21) International Application Number: PCT/SE92/00844 (74) Agents: DANIELSSON, Sten et al.; AB Astra, Patent Department, S-151 85 S6dertiilje (SE).

(22) International Filing Date: 8 December 1992 (08.12.92) (81) Designated States: AT, AU, BB, BG, BR, CA, CH, CS, (30) Priority data: DE, D-k ES, Fl, GB, HU, JP, KP, KR, LK, LU, MG, 9103776-2 19 December 1991 (19.12.91) SE MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE, UA, European patent (AT, BE, CH, DE, DK, ES, FR, GB, OGk&"c Gk~tijxkAa;ci GR, JE, IT, LU, MC, NL, PT, SE), QAPI patent (BF, (71) Applicant: A4-AS1U.A [SE/SE]; S-1 55S6dert4lje BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD, TG).

(72) Inventors: HOLSTEIN, Karl, Bj6rn, Christer Grdskarsgatan 144, S-421 59 Viistra Fr6lunda SUNDEN, Published Gunnel, Elisabeth ;Frigdngsgatan 10, S-413 01 G6te- With international search report.

borg (SE).

1004 (54) Title: SUBSTITUTED BENZIMIDAZOLES, PROCESS FOR THEIR PREPARATION AS WELL AS THEIR USE OCH's >~OC4 3 N'

CH

2

N~N

o-J 41 0 4P\ 0M (57) Abstract The novel compounds of formu~la wherein RI and R 2 which are different, are each methyl, -C(O)-CH 3 Or

-C(O)-OCH

3 and whereby one of R 1 or R2 is always methyl; and M is a physiologically acceptable counter cation, as well as processes for the preparation of said compounds, pharmaceutical compositions containing said compounds as active ingredient, and the use of the compounds in medicine.

I f^ ME C WO 93/12124 PCT/SE92/00844 SUBSTITUTED BENZIMIDAZOLES, PROCESS FOR THEIR PREPARATION AS WELL AS THEIR 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 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 r WO93/12124 PCT/SE92/00844 2 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.

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.

The compounds of the invention will also exhibit a high solubility and a high chemical stability in water.

Background of the invention i Similar disubstituted 2-[[(3,4-dialkoxy-2-pyridinyl)methyllsulfinyl]-lH-benzimidazole-l-yl compounds are described in PCT/SE91/00415, which was not publically available at the time of filing the basic application in Sweden, but was published shortly thereafter.

i Prior art 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 WO 93/12124 PCT/SE92/00844 3 use in the treatment or prevention of special gastrointestinal inflammatory diseases are disclosed in US 4 359 465.

The invention The compounds of the invention 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.

Further, the compounds of the invention exhibit a high solubility and a high chemical stability in water.

The compounds of the invention 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:

OCHS

OCH3 N H N I O\ OM i o-\M i WO 93/12124 93/12124 PCT/SE92/00844 4 wherein 1 2 R and R which are different, is each methyl,

CH

3 or -C(O)-OCH 3 and whereby one of R or R is always methyl, and M is a physiologically acceptable counter cation.

The structural isomers of the compounds of the formula I 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). 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 is believed that compounds of formula I are metabolized before exerting their effect. Such metabolism occur in the N-substituent, the phosphorous containing group, in position 1 in the benzimidazole nucleus.

Preparation The compounds of the invention may be prepared according to the following methods: a) Reacting a compound of the formula II i 1 4 1 1

,I

4WO 93/12124 PCT/SE92/00844

OCH

3

OCHCH

2

Z

NX 1 I

N-^

2R I 1 0 wherein R and R are as defined under formula I, and i Z, is halogen such as Cl, Br or I or a functionally I equivalent group, with a compound of the formula III 0 HO-P-0 Q III HOP- Q. II 0 Q.

wherein Q is a counter ion such as Na K Ag or I 20 trialkylarmonium.

Salts obtained may be transformed to a therapeutically suitable salt such as sodium and potassium salts, by addition of NaOH and KOH, respectively or by ion exchange.

b) Oxidizing a compound of the formula IV 0 OCH 3 N RI

OM

NQ

NCH2-S-^ ^^Y 0 M IV 0 \M I _i l WO 93/12124 PCT/SE92/00844 6 1 2 wherein R R and M have the meanings given, to give a compound of 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, N-halosuccinimide, 1chlorobenzotriazole, t-butylhypochlorite, diazabicyclc- [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 crystallizat-ion or chromatography.

Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent. i For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. It 4 WO 93/12124 PCT/SE92/00844 7 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 amount 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, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, 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 containing sulfcxides 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 phtalate, hydroxlpropylmethylcellulose phthalate, partly methyl esterified methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To this WO 93/12124 PCT/SE92/00844 8 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 enteric-coated 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 WO 93/12124 PCT/SE92/00844 9 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 prio 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, 6-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl]methyl ester, disodium salt or phosphoric acid, methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]- WO 93/12124 PCT/SE92/00844 1H-benzimidazole-1-yl]methyl ester, disodium salt.

Tributylamine (1.7 ml, 7.0 mmol) was added with stirring to a solution of phosphoric acid, 85 per cent (0.24 ml, 3.6 mmol) in ethanol (2 ml). The solvent was evaporated and the residue taken up in methylene chloride (2.5 ml). The organic phase was dried over sodium sulphate, filtered and evaporated. chloromethyl-6-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-1H-benzimidazole or 6acetyl-l-chloromethyl-5-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-1H-benzimidazole (0.12 g, 0,28 mmol) and the tributylam- nium salt of phosphoric acid, prepared above, were dissolved in methylene chloride (6 ml). The methylene chloride was distilled off and the residue was heated on a waterbath for minutes at 60 0 C. The residue was dissolved in methylene chloride (6 ml) and again the methylene chloride was distilled off and the oily product mixture was heated on a waterbath for 5 minutes at 60°C. This procedure was repeated four times until the reaction was completed. The residue was dissolved in methylene chloride (4 ml) and washed with three (4 ml) portions of water. A solution of sodium hydroxide was added to the organic phase with stirring while pH of the aqueous layer was carefully controlled. When pH reached 9-9.5 in the aqueous phase the mixture was centrifuged. The aqueous layer was washed with three portions (4 ml) of methylene chloride and then freeze dried to give 40 mg, 27% of the title compound.

NMR data are given below.

Example 2. Preparation of phosphoric acid, WO 93/12124 PCT/SE92/00844 11 methoxy-6-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-yl]methyl ester, disodium salt or phosphoric acid, [6carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-IH-benzimidazole-1-yl]methyl ester, disodium salt.

Tributylamine (1.8 ml, 7.8 mmol) was added with stirring to a solution of phosphoric acid, (0.26 ml, 3.9 mmol) in ethanol (2.5 ml). The solvent was evaporated and the residue taken up in methylene chloride (3 ml). The organic phase was dried over sodium sulphate, filtered and evaporated. carbomethoxy-l-chloromethyl-6-methyl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole or 6-carbomethoxy-l-chloromethyl-5-methyl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyl]-iH-benzimidazole (0.14 g, 0.32 mmol, and the tributylammonium salt of phosphoric acid, prepared above, were dissolved in methylene chloride (6.5 ml). The methylene chloride was distilled off and the residue was heated on a waterbath for 5 minutes at 60*C. The residue was dissolved in methylene chloride (6.5 ml) and again the methylene chloride was distilled off and the oily product mixture was heated on a waterbath for 5 minutes at 60 0 C. This procedure was repeated four times until the reaction was completed. The residue was dissolved in methylene chloride (4 ml) and washed with three (4 ml) portions of water. A solution of sodium hydroxide was added to the organic phase with stirring while pH of the aqueous layer was carefully controlled. When pH reached 9-9.5 in the aqueous phase the mixture was centrifuged. The aqueous layer was washed with three portions (4 ml) of methylene chloride and then freeze dried to give 11 mg, 6% of the title compound.

4 WO 93/12124 WO 9312124PCI'/SE92/00844 NMR date are given below.

Table 1 Protons in water set to 4.80.

Ex. Solve~nt NMR data 8 ppm

D

2 0 (300 MHz) D 2 0 (300 M4Hz) 2.67 2.78 3H), 3.85 3H), 3.98 3H), 4.98 1H), 5.08 (d, 1H), 5.98 (mn, 2H), 7.15 1H), 7.78 1H), 8.12 1H), 8.18 1H).

2.75 3H), 3.83 3H), 3H), 4.05 3H), 4.98 1H), 1H), 5,95 (mn, 2H), 7.15 (d, 1H), 8.15 1H), 8.28 3.97 (s, 5.08 (d, 1H) 7.83 1H) Preparation of intermediates Example 1 1 Preparation of 5-acetyl-l-hydroxyraethyl-6-iuethyl-2- [E(3,4dimethoxy-2-pyridinyl )methyl] suif inyl] -1H-benzimidazole or 6-acetyl-1-hydroxymethyl-5-metyl-2- 4-dimethoxy-2-pyridinyl )methyllsulfinyl] -1H-benzimidazole To a mixture of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2- WO 93/12124 PCT/SE92/00844 13 pyridinyl)methyllsulfinyll-1H-benzimidazole (2.00 g, 5.4 mmol) and methylene chloride (100 ml) aqueous 5 M formaldehyde (5.0 ml, 25 mmol) was added. The mixture was shaken for 3 minutes. After separation the organic solution was dried over Na 2

SO

4 and evaporated under reduced pressure giving a red syrup (1.7 g, The product consisted mainly of one of the structure isomers of the title compound as well as small amounts of starting material.

NMR data are given below.

Example I 2 Preparation of 5-acetyl-1-chloromethyl-6-methyl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole or 6-acetyl-1-chloromethyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyllsulfinyl]-1H-benzimidazole A suspension of 5-acetyl-l-hydroxymethyl-6-methyl-2-[[(3,4dimethoxy-2-pyridinyl)methyl]sulfinyll-1H-benzimidazole and 6-acetyl-1-hydroxymethyl-5-methyl-2-[[(3,4-dimethoxy-2pyridinyl)methyl]sulfinyl]-1H-benzimidazole (1.7 g, 4.2 mmol) in acetonitrile (40 ml) was chilled to -15 0

C.

Thionyl chloride (0.50 g, 4.2 mmol) and triethylamine (0.50 g, 4.2 mmol) were added dropwise in the given order.

The mixture was stirred at room temperature for five minutes and then evaporated under reduced pressure. The residue was chromatographed on silica gel (70 g) using a raixture of ethyl acetate and methylene chloride as eluent.

The amount of ethyl acetate was increased during the chromatography. The product 0.14 g consisted mainly of one of the structure isomers.

NMR data are given below.

WO 93/12124 PCI'/SE92/00844 14 Example 1 3 Preparation of 5-c arbomethoxy-l1-hydroxymethyl- 6-methyl- 2- C 4-dimethoxy-2-pyridinyl)uethyl] suif iny.] -1Hbenz imidazole or 6-carbomethoxy-l-hydroxymethyl-5-methyl- 2- ,4-dimethoxy-2-pyridinyl )methyl] suli nyl] -1Hbenz imidazole To a solution of 5-carbornethoxy-6-methyl-2-[[(3,4dimethoxy-2-pyridinyl )methyl lsuif inyl -lH-benzimidazole (0.34 g, 0.87 mmol) in methylene chloride (25 ml) 5 M aqueous formaldehyde (1.7 ml, 8.5 mmol) was added. The mixture was shaken for 3 minutes. After separation the organic solution was dried over Na SO 4 and evaporated under.

2$1 reduced pressure giving a red syrup (0.36 g, 100%). The product consisted mainly of one of the structure isomers of the title compound as well as small amounts of starting material.

NM4 data are given below.

Example 1 4 Preparation of 5-carboinethoxy-l-chloroinethyl-6-methyl-2- (C 4-diiethoxy-2-pyridinyl )methyl] sulfinyl] -lHbenzimidazole or 6 -carbomethoxy-l1-chioromethyl- 5-methyl- 2- 4-dinethoxy-2-pyridinyl )methyl] aulfinyl] -lHbenzimidazole A solution of 5-carbomethoxy-l-hydroxym-ethyl-6-methyl-2- [C 4-dimethoxy-2-pyridinyl )methyl] sulf inyll -lHbenzimidazole and 6-carbomethoxy-1-hydroxymethyl-5-methyl- 2- C C(3, 4-dimethoxy-2-pyridinyl )methyl Isuif inyl]I-lHbenzimidazole (0.36 g, 0.87 mnrol) in acetonitril (20 ml) was chilled to -200C. Thionyl, chloride (0.066 ml, WO 93/12124 PCTr/SE92/00844 0.90 inmol) and triethylamine (0.10 g, 1.0 mmol) were added dropwise in the given order. The mixture was stirred at room temperature for five minutes and then evaporated under reduced pressure. The residue was chromatographed on silica gel (20 g) using a mixture of ethyl acetate and methylene chloride as eluent. The amount of ethyl acetate was increased during the chromatography. The product 0.16 g consisted mainly of one of the structure isomers.

NI4R data are given below.

Table 2 Ex Solvent NMR data 8 ppm 1 1 CDC1 3 1 2 CDC1 3 2.60 3.95 1H), 1H), 7.90 2.66 3.91 6.23 7.39 2.75 2H) 6.75 8.30 2.79 3.93 6.23 7.39 3H), 3H), 6.10 (d, 1H), 8.10 1H).

(5, (s, (d, (5, 3H), 3H) 1H), 1H), 2.72 3H), 3.90 3H), 4.91 1H), 5.02 1H), 6.55 1H), 6.80 1H), 8.15 1H), 8.20 1H1).

3.8-4.0 (in, 9H), 4.7-5.1 (in, 1H), 6.10 1H), 7.40 1H), 7.90 1H), 2.70(s, 3H), 3.90 (sr 3H), 4.8-5.1 (mn, 2H), 5.70 (d, 1H) 6.75 1H), 7.40 (s, 1 3 CDC1 3 3H) 5. 75 (d, 1H), 1H).

1 4 CDC1 3 (d, (s, 3H), 3H), 1H), 1H), 3.89 3H), 3.91 3H), 4.90 1H1), 5.02 1H), 6.57 6.80 1H), 8.15 1H), 8.40 1H).

WO 93/12124 W093/2124PCT/SE92/00844 Table 3 Examples of compounds included in in the following table.

the formula I are given Example R1 Yield

M

Ident.

data Remarks CH 3 C (0)CH 3 Na NMR Isolated isomer C (0)CH 3 CH 3

CH

3 C (0)OCR 3 Na NMR Isolated isomer C OCR 3 C CH 3 or CH 3 CH 3 Na Isolated isomer CH 3 C CH 3 C OCR 3 or CH 3 Isolated isomer C OCH 3

CH

3

CH

3 C CH 3 Na Isomeric mixture C (0)CH 3 CH 3 WO 93/12124 PCr/SE92/00844 17 6 CH3

C(O)OCH

3 Na+ Isomeric

C(O)OCH

3

CH

3 mixture The best mode of carrying out the invention known at present is to use a compound according to Example 2.

Pharmaceutical preparations containing a compound 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: Compound 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 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 frcm the following ingredients: WO 93/12124 PCT/SE92/00844 18 I Compound mixture according to Example 2 200 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 Cellulose acetate phthalate 200 g Cetyl alcohol 15 g Isopropanol 2000 g Methylene chloride 2000 g I Compound according to Example 1, 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 mm diameter punches.

II A solution of cellulose acetate phthalate and cetyl alcohol in isopropanol/methylene chloride was sprayed onto the tablets in an Accela CotaR, Manesty coating equipment. A final tablet weight of 110 mg was I 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: WO 93/12124 PCT/SE92/00844 19 Compound according to Example 2 4 g 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 um 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: Compound according to Example 3 in Table 3 300 g Lactose 700 g Methyl cellulose 6 g Polyvinyl pyrrolidone, cross-linked (PVP-XL) 62 g Disodium 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 PVP-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 WO 93/12124 PCT/SE92/00844 tablets in a fluidized bed apparatus using Wurster coating technique.

Coating solution: Cellulose acetate phthalate 40 g Cetyl alcohol 2 g 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.

Compound mixture according to Example 4 in Table 3 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 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 minutes.

~1 WO 93/12124 PC/SE92/00844 21 Syrup A syrup containing 1% of active substance was prepared from the following ingredients: Compound according to Example 3 in Table 3 Sugar, powder Saccharine Flavouring agent Ethanol 96% Purified water q.s.

1.0 g 30.0 g 0.6 g 0.05 g 5.0 g 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 Compound according to Example 1 Water for injection to make 60 g 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 im filter and aseptically dispensed into 1 ml sterile ampoules. The ampoules were sealed.

Formulation for intravenous infusion Sterile compound according to Example 2 Sterile injection vials and stoppers 60 mg WO 93/12124 PCT/SE92/00844 22 Sterile active compound, 60 mg, was dispensed into ml sterile injection vials. The vials were stoppered with sterile rubberstoppers. The vokale filling operation was performed under aseptic conditions in a sterile production area under vertical laminar flow.

Biological Effects 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 active compounds generated in the metabolism of the compounds within the invention.

Effect on the accumulation of 125 in the thyroid gland Effect on the accumulation of I in the thyroid gland '125 The accumulation of I 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 administered by oral gavage in a volume 125 of 5 ml/kg body weight. After 1 hour, 125 (300kBq/kg, 3ml/kg) was administered by intraperitoneal injection.

125 i Four hours after I-administration, the animals were killed by CO 2 -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 WO 93/12124 PCT/SE92/00844 23 iadioactivity in a gamma counter (LKB-Wallac model 1282 Compugamma). Percentage inhibition was calculated according to the formula 100 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 placebotreated animals was assessed with the Mann-Whitney Utest (two-tailed). P<0.05 was accepted as significant.

Results of biological tests Table 4 give the test data available for the compounds of the invention.

Table 4, Biological Test Data Test compound Per cent inhibition of (number of animals) 400 umol/kg on the uptake of 125I in the thyroid gland Active metabolite of2 Examples No 1, 3 and (n 5) -7 Active metabolite of Examples No 2, 4 and 6 (n 5) 0

Claims (12)

1. Compounds of the formula I 00H 3 OCH 3 N CH 2 I N R2 101 0 wherein R1and R 2 which are different, is each methyl, -C(o)-CH3 or -c(O)-0d11 3 and whereby one of R 1or R 2is always methyl and M is a physiologically acceptable counter cation.

2. A compound according to claim 1 wherein M is Na, K, Ag or trialkylamtonium.

3. Compounds according to formula I of claim 1, namely a mixture of phosphoric acid, r5-acetyl-6-methyl-2-

4-dimethoxy-2--pyridinyl)methyllsulfinyl]-lH- benzimidazole-l-yl)methyl ester, disodiui salt and phosphoric acid, [6-acetyl-5-methyl-2-[ (3 ,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-lH-benzirnidazole-1-yllmethyl ester, disodium salt. 4. Compounds as according to formula I of claim 1, namely a mixture of phosphoric acid, [5-carbomethoxy-6- methyl-2-[ 4-dimethoxy-2-pyridinyl)methyllsulfinylj- 1H-benzimidazole-l-yllmethyl ester, disodium salt and phosphoric acid, [6-carbomethoxy-5-methyl-2-[[(3,4-I y7 WO 93/12124 PCT/SE92/00844 dimethoxy-2-pyridinyl)methylsulfinyl] -lH-benzimidazole- 1-yl]methyl ester, disodium salt. A compound according to claim 1, namely phosphoric acid, (5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)- methyl]sulfinyl]-lH-benzimidazole-l-yl]methyl ester, disodium salt.

6. A compound according to claim 1, namely phosphoric acid, [6-acetyl-5-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)- methyl]sulfinyl]-1H-benzimidazole--ylmethyl ester, disodium salt.

7. A compound according to claim 1 namely phosphoric 15 acid, [5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl-lH-benzimidazole-1-yl]methyl ester, disodium salt.

8. A compound according to claim 1, namely phosphoric acid, (6-carbomethoxy-5-methyl-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-yl]methyl ester, disodium salt.

9. A pharmaceutical composition containing a compound according to claim 1 as active ingredient, together with a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound according to any one of claims 2 and 5-8 as active ingredient, together with a pharmaceutically acceptable carrier.

11. A pharmaceutical composition containing a mixture according to claim 3 or 4 as active ingredient, together with a pharmaceutically acceptable carrier. WO 93/12124 PCT/SE92/00844 26

12. A method for inhibiting gastric acid secretion by administering to mammals including man a compound as defined in any one of claims 1, 2 and 5-8, or a mixture as defined in claim 3 or 4, or a composition as defined in any one of claims 9 to 11.

13. A method for the treatment of gastrointestinal inflammatory diseases in mammals including man by administering a compound as defined in any one of claims 1, 2 and 5-8, or a mixture as defined in claim 3 or 4, or a composition as defined in any one of claims 9 to 11. St 14. Use of a compound according to claim 1 in formulating a medicament composition suitable for inhibiting gastric S' acid secretion in mammals including man, or for the treatment of gastrointestinal inflammatory diseases in mammals including man. 1, IS. 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 SO 0CH 3 SO O C H 3 0 II N CH 2 I R2 CH 2 Z wherein R 1 and R 2 are as defined under formula I and Z is halogen such as Cl, Br or I or a functionally equivalent I group, with a compound of the formula III 7 WO 93/12124 PCr/SE92/0044 0 11 HO-P-a Q IQ III wherein Q is a counter ion such as N, Ag or tri- alkylammoniun, or b) oxidizing a compound of the formula IV LO 00H 3 OC 0H 3 'CH2- I r t~C SC It t 0 M 0O0M I 1 2 wherein R, R and M have the meanings given, to give a compound of formula I. 25 16. A compound of the formula II II WO 93/12124 PCF/SE92/OO844 28 wheeinRiand R 2 are as defined under formula I and Z is halogen, such as Cl, Br or I or a functionally eqivalent group.

17. A compound according to claim 16, wherein R 1and R 2are as defined above and Z is Cl or OH. DATED 'T-his 18th day of September 1995 ASTRA AKTIEBOLAG, By its Patent Attorneys, E. F. WELLINGTON CO., (B .Wellingto/ *3S RJ(B S .S Rl '4/4/1 1 4 Stn~ INTERNATIONAL SEARCH REPORT International application No. PCT/SE 92/00844 c cc~- A. CLASSIFICATION OF SUBJECT MATTER IPC5: C07F 9/6558, C07D 401/12, A61K 31/675 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07F C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched SE,DK,FI,NO classes as above Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS-ONLINE C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP, A2, 0279149 (AKTIEBOLAGET HASSLE), 1-12,15-19 24 August 1988 (24.08.88), see especially pages 1-8, 13-14 and examples 130-131 A GB, A, 2219584 (AKTIEBOLAGET HASSLE), 1-12,15-19 13 December 1989 (13.12.89) Further documents are listed in the continuation of Box C. 5 See patent family annex. Special categories of cited documents:. T' later docu.net published after the international filing date or priority document d the geral stat of thedate and not in conflict with the application but cited to understand tA" document deni e eneral n of the art which is not ondd the principle or theory underlying the invention eriier document but published on or after the international filing date document of particular relevance: the claimed invention cannot be document which may throw doubts on priority claim(s) or which is considered novel or cannot be onsidered to involv an inventive cited to establish the publication date of another citation or other tep whe the document i taken alone special reason (as specified) document of particular relevance: the claimed invention cannot be document referring to an oral disclosure, use, ehibition or other considered to involve an inventive step when the document is means combined with one or more other such documents, such combination document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 17 February 1993 -ur* Name an nailing address of the ISA/ Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM GOran Karlsson Facsimile No. +46 8 666 02 86 Telephone No. +46 8 782 25 00 Form PCT/ISA/210 (second sheet) (July 1992) 7 ~an I lt---1141 Itn ~an~aaljo INTERNATIONAL SEARCH REPORT PCT/SE 92/00844 I Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claims Nos.: 13-14 because they relate to subject matter not required to be searched by this Authority, namely: See PCT Rule 39.1(iv): Methods for treatment of the human or animal body by surgery or therapy, as well as diagnostic methods. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Clams Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II ObservLtions where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. As .lI required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. O As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. D As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest |The additional search fee were accompanied by the applicant's protest. S'No protest accompanied the payment of additional search fees. Form PCT/ISAI210 (continuation of first sheet (July 1992) 1 i i1 i i j