RO110493B1 - Benzimidazole derivates and preparation processes therefor - Google Patents

Abstract

The novel compounds of formula (I), wherein R<1> and R<2>, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R<6>; one of R<1> or R<2> is always selected from the group -C(O)-R<6>; wherein R<6> is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms, R<3> is the group -CH2OCOOR<7>, wherein R<7> is alkyl containing 1-6 carbon atoms or benzyl; R<4> and R<5> are the same or different and selected from -CH3, -C2H5, (a), (b) and -CH2CH2OCH3, or R<4> and R<5> 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 R<5> is -CH2CH2CH2-, -CH2CH2- or -CH2- as well as pharmaceutical compositions containing such compounds as active ingredient, and the use of the compounds in medicine.

Description

The invention relates to novel benzimidazole derivatives and processes for their preparation, compounds that inhibit secretion of exogenously and endogenously stimulated gastric acid and thus may be used in the prevention and treatment of peptic ulcer for inhibiting gastric acid secretion in mammals, including humans.

Benzimidazole derivatives known to inhibit gastric acid secretion are known. These include patents: GB 15OOO43, GB 1526358, US 4182766, US 4255431, US 4599347, SE 898880, EPO 124495, EPO 208452, EPO 22104, EPO 279149, EPO 176308 and Derwent summary 87-294440 / 92. Benzimidazole derivatives for use in the treatment or prevention of special inflammatory gastrointestinal disorders are described in US 4359465.

2- (pyridylalkylene-sulfinyljbenzimidazole derivatives of the formula are known)

wherein, X is S or SO, D is 2-pyridyl and A, B, G and R ₁₀ have different meanings, these compounds having gastric acid inhibition effects. Procedures for the preparation of these compounds by treating compounds of the formula are also claimed:

CH -OH an anhydride or acid containing -C0R _e , -COPhX, -CO (CH _a ) _m , C0 _a R ₃ or COCHgPhX and a catalytic amount of Ν, Ν-dimethyl-aminopyridine (EP 0176308).

Benzimidazole derivatives of the formula are also known:

wherein, R ₅ -R ₃ and X have different meanings, compounds having therapeutic properties.

Also described are processes for the preparation of these compounds (EP 0221041).

The object of the invention H is new benzimidazole derivatives of general formula (I):

o * 5

wherein, R, and R _a , which are different, are each hydrogen, alkyl containing 1-4 carbon atoms or -C (0) -R ₆₁ one of R, or R ₂ is always selected from the group -C ( 0) -R ₆ , wherein R ₆ is alkyl containing 1-4 carbon atoms or alkoxy with 1-4 carbon atoms, R ₃ is the group -CH ₂ 0C00R ₇ , wherein R ₇ is alkyl containing 1- 6 carbon or benzyl atoms; R ₄ and R _s are the same or different and are chosen from -CH ₃ , -0C ₂ H ₅ , -CH _a - -O. -CH _a - <z> and -CH ₂ CH _a = 0CH ₃ , or R ₄ and R ₅ together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms of the pyridine ring a ring, wherein the part consisting of R ₄ and R ₅ is -CHgCHgCHg, -CH _of CH _a - or -CH _a -,

Preferred benzimidazole derivatives are, in particular, a mixture of 5-carbomethoxy-6-methyl-2 - ((((3,4-dimethoxy-2-pyridyl nyl) methyl) sulfuryl) -1H-benzimidazole-1-ylmethyl ethyl carbonate and 6-. carbomethoxy-5-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfur ni) -1H-benzimidazole-1-ylmethylethyl carbonate or are in particular a mixture of 5-acetyl-6- methyl-2 - ((((3,4-dimethoxy-2-pyridyl) methylsulfonyl) -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.

Other importing benzimidazole derivatives are, in particular, 5-carbomethoxy-6-methyl -2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl} -1H-benzimidazoH-ylmethyl ethyl

CH— R

I 'o — c— ^R _t

II

EN 110493 Bl halogenates, acetone, acetonitrile or dimethylformamide, at the temperature between ambient temperature and boiling temperature of the reaction mixture.

Another process is that a compound of formula (IV) is oxidized:

carbonate, or 6-carbomethoxy-5-methyl-2 ((((3,4-d imethoxy-2-pyridinyl) methyl) sulfinyl] -1H-benzimidazoH-ylmethyl ethyl carbonate, or

5-acetyl-6-methyl-2 - ((((3,4-dimethoxy-2-pyridinylmethyl Jsulf inyl) -1H-benzimidazole-1 * ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2 ([(3,4 -dimethoxy-2-pyridinyl] methyl) sulfinyl} -1 HbenzimidazoH-ylmethyl ethyl carbonate.

Also, compounds of formula (I), wherein R ₃ is a CH ₂ 0C00CH ₂ CH ₃ or R ₃ and R ₂ are each hydrogen, matyl or -C (0) R ₆ , wherein R ₆ is important alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms.

These benzimidazole derivatives are used in the form of pharmaceutical compositions for inhibiting gastric acid secretion in mammals, including humans and in treating inflammatory gastrointestinal disorders in mammals, including humans.

Another object of the invention is a process for the preparation of benzimidazole derivatives of general formula (I) by treating a compound of general formula (II):

wherein, R _v R ₂ , R ₃ and R ₄ have the above meanings and Z is a metal cation such as Na *, K *. Li * or a quaternary ammonium ion, such as tetrabutylammonium, with chloromethylalkyl carbonate or chloromethylbenzyl carbonate; or a compound of formula (II) is treated wherein: R _v R _2> Rj and 1¾ have the above meanings and Z is a hydroxymethyl, with a compound of formula (III):

X - C (0) -0- R ₇ (III) wherein, R ₇ has the above meanings and X is chloro or imidazole or pnitrophenoxy or an equivalent functional group, in the presence of an appropriate base such as triethylamine, both phases having under protective gas in the absence of water, in suitable solvents such as hydrocarbons such as toluene or benzene, or hydrocarbons

(IV) wherein, R _1t R _a , R ₃ , R ₄ and R ₅ have the above meanings, with an oxidizing agent such as nitric acid, oxygenated water, possibly in the presence of vanadium, peracids, peresters, ozone compounds , dinitrogentetraoxide, iodobenzene, N-halosuccinimides, 1-chlorobenzotriazole, t-butylhydrochlorite, diazabicyclo- (2,2,2) -octan complex bromide, sodium metaperiodate, selenium dioxide, magnesium dioxide, chromic acid, chromium nitrate sulfuryl bromide or chloride, in a solvent such as halogenated hydrocarbons, alcohols, esters, ketones.

The invention has advantages in that it makes compounds that are effective as inhibitors of gastric acid secretion in mammals including humans and in addition do not block iodine uptake into the thyroid gland. Also, the compounds of general formula (I), indicate a high bio-usefulness and have a high chemical stability in acidic, neutral pH solution. High chemical stability at acidic pH also makes the compounds useful for non-enteric peroral coating formulations.

The compounds of the invention of formula (I) have an asymmetric center in a sulfur atom; for example, there are 2 optical isomers, enantiomers or also if they contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each existing in two enantiomeric forms. Both pure enantiomers, as well as racemic mixtures, 50% of each enantiomer as well as the unequal mixtures of the two are within

RO 110493 Bl

(W> in which, R _v R ₂ , R ₃ , R ₄ and R ₅ have the above meanings.

This oxidation can be accomplished by using an oxidizing agent such as nitric acid or oxygenated water, possibly in the presence of vanadium compounds, peracids, peresters, ozone, din trogentetraoxide, iodobenzene, N-halosuccinimides, 1-chlorobenzotriazole, t-butylhydrochloride, dia-butylhydrochlorite, (2,2,2) -octane complex bromide, sodium metaperiodate, selenium dioxide, magnesium dioxide, chromic acid, cericammonium nitrate, bromide, or sulfuryl chloride, in a solvent such as halogenated hydrocarbons, alcohols, ethers, ketones.

Oxidation can also be performed enzymatically by using an oxidation enzyme or microbiologically by using a suitable microorganism. The obtained structural isomers can be separated by crystallization or chromatography. The racemates obtained can be separated by known methods, for example reclistalization between an optically active solvent. In the case of racemic diastereomeric mixtures, they can be separated into pure diastereomeric enantiomers by means of chromatography or fractional recrystallization.

The starting materials used are in a somewhat unknown case and can be obtained by known procedures per se.

Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate can be obtained with chloromethyl chloroformate in the presence of pyridine.

Intermediates of formula (II), wherein Z is hydroxymethyl were obtained by reacting the corresponding hydrogen-bearing benzimidazole compound at the N-1 formaldehyde position.

The starting materials of formula (III) can be obtained by methods known, for example, from an alcohol H0R ₇ by treatment with phosgene or 1,1-carbonyldiimidazole or pnitrophenyl chloroformate.

The following are examples of embodiments of the invention:

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) methylsuffinyl) -1H-benzimidazole-1-ylmethyl ethyl carbonate, as an isomeric mixture. O, 45 g (1.1 mmol) of 5-carbomethoxy-6-methyl is suspended. 2 - ((((3,4-dimethoxy-2-pyridinyl] methyl) sulfinyl) -1 H-benzimidazole and □, 25 g (1.8 mmol) anhydrous potassium carbonate in 45 ml dry acetonitrile, 0.21 g (1.5 mmol ) of chloromethylethyl carbonate dissolved in 5 ml of acetonitrile. The reaction mixture is stirred overnight at room temperature. The solvent is then removed in vacuo and the remainder diluted with methylene chloride and water. The organic solvent is dried over anhydrous sodium sulfate. Removing the solvent in vacuo yields a crude product which is chromatographed with silica gel and eluted with ethyl acetate to obtain O, 94 g of a yellow oil which is easily crystallized. Ethanol staining produces O, 25g (44%) of the title products as an isomeric mixture. The MRI data for the products are given in table (1) below.

Example 2. Preparation of 6-Carbomethoxy-6-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl) methylsulfuryl I) -1H-benzimidazole-1-ylmethyl ethyl carbonate. The title compound was obtained by crystallizing the isomeric mixture, given in Example (1), with 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-Dimethoxy-2-pyridinyl] methyl] sulfinyl) -1H-benzimidazo-1-ylmethyl ethyl carbonate, as an isomeric mixture. A suspension of O, 48g (3.47 mmol) of carbonate is prepared. anhydrous potassium in 80ml dry acetonitrile 0.8 (¾ (2.14 mmol) 5-acetyl-6RO 110493 Bl-methyl-2 - ((((3,4-dirnetoxy-2-pyridinyl) methyl) sulfinyl) -1H- benzimidazole which is magnetically stirred and 0.39g (2.8 mmol) of chloromethethyl carbonate dissolved in 10 ml of acetonitrile is added dropwise. Stirring 5 is continued at room temperature for 20 h. The solvent is removed in vacuo, the rest is diluted with methylene chloride, the solution of methylene chloride is washed with water and dried over anhydrous sodium sulphate.When removing the solvent under vacuum, a crude product is obtained which is chromatographed on silica gel and eluted with ethyl acetate for water. O rod, 63g of white crystals almost 15 solids. The product is recrystallized from ethyl acetate to obtain O, 5Og (49%) of the title compounds as an isomeric mixture. The MRI data for the products are given in table (1) below. 20

Example 4. Preparation of 5-acetyl-

6-methyl-2 - ([(3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole-1-ylmethyl ethyl carbonate. The title compounds were isolated as the isomeric mixture given in Example 3 25 by chromatography on a silica gel column with methylene chloride-acetonitrile (ratio 6: 4) as eluent. The title compound was crystallized from ethanol. MRI data are given in table (1) 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 gel column with methylene chloride-acetonitrile (ratio 6: 4) as eluent. The title compound is crystallized from ethanol. MRI data are given in table (1) below.

Example 6. Preparation of 5-carbomethoxy-2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole-1-ylmethyl ethyl carbonate and 6-carbomethoxy-2 - (((3, 4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole-1-ylmethyl ethyl carbonate as an isomeric mixture. At a suspension of O, 26 g (0.72 mmol) of 5-carbomethoxy-2 - ((((3,4 dimethoxy-2-pyridinyl) methyl) sulfinyl] -1 Hbenzimidazole O, 16 g (1.2 mmol) potassium carbonate anhydrous in 20 ml of dry acetonitrile was added D, 16g (1.2 mmol) chloromethylethyl carbonate dissolved in 2 ml of dry acetonitrile The mixture was stirred overnight at room temperature The solvent was evaporated off and the crude product was chromatographed on a column with silica gel using ethyl acetate as the eluent Crystallize from ethanol to give 0.13g (37%) of the title compounds as an isomeric mixture NMR data for the products are given in Table 1.

Table 1

Ex. solvent MRI or ppm data 1 cdci ₃ (300 MHz) 1.20-1.30 [m, 3H); 2.70 (s.l, 8H); 2.75 (s.l, 2H); 3.85-3.95 (m, 9H); 4.15-4.25 (m, 2H}; 4.85- 5.05 (m, 2H); 6.40 ^, 55 (m, 2H); 6.75 (d. 1H); 7.45 (s, 0.6H); 7.65 (s, 0.4H); 8.10 (d, 1H); 8.20 (s. 0.4H); 8.40 (s, 0.6H); 2 cdci ₃ [300 MHz) 1.30 (t. 3H); 2.70 (s, 3H); 3.90 (s, 3H); 3.95 (s, 3H); 4.25 (q, 2H); 4.95 (h, 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); 3 cdci ₃ (300 MHz) 1.30 (t. 3H]; 2.80-2.70 (m. 6H); 3.85-3.90 (m. 6H); 4.25 (q, 2H); 4.85-5.05 (m, 2H); 6.75 (d, 1H): 7.49 (s, 0.7H); 7.60 (s. 0.3H); 8.09 [s, 0.3H); 8.10 (d, 1H): 8.20 [s, 0.7).

RO 110493 Bl

12

Table 1 (continued)

4 cdci ₃ (300 MHz) 1.30 (t, 3H); 2.60 (3H s); 2.70 (3H s); 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 (1H). 5 cdci ₃ (300 MHz) 1.30 (t. 3H); 2.60 (s. 3H); 2.70 (3H s); 3.90 (s. 3H); 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, 1H); 8.15 (d. 1H). 6 CDCI, (300 MHz) 1.30 (m, 3H); 1.45 (m, 3H); 3.90 (s, 3H); 4.25 (m, 2H); 5, CD [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).

Procedures 15 for the preparation of intermediaries are given below

a) preparation of 5-carbomethoxy-6-methyl-24 ((3,4-dimethoxy-2-pyridinyl] methyl] thio) 1H-benzimidazole. O, 67g [3 mmol) 5-carbomethoxy-6-methyl-2-mercapto- 1H- 20 benzimidazole and □, 12g (3 mmol) NaOH in □, 5ml water were dissolved in 615ml CH ₃ OH. To (3.6 mmol) 3.4-dimethoxy-2-chloromethylpyridine hydrochloride as crude material in 10ml methyl alcohol was added 25 0.144g (0.036 mol) NaOH in 0.72ml water. The mixture is heated to reflux and reflux is continued for one hour. The methyl alcohol is evaporated off and the crude material is purified by chromatography on a silica gel column using CH ₂ Cl ₂ -CH ₃ O (98-2) as eluent to give 1, O 3 g (92%) of the title compound . MRI data are given in Table 2 below. 35

b) Preparation of 5-carbomethoxy-6-ethyl 2 - ((((3,4-dimethyl-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole. 1.03g (2.76 mmol) of 5-carbomethoxy-6-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl] methyl) thio) - 40 1H-benzimidazole in 30ml methylene chloride, 0.46g (5.5 mmol) of sodium bicarbonate in 10ml of water is added and the mixture is cooled to + 2 ° C, O, 62g (2.5mmol) of m-chloro-45 perbenzoic acid is added 69.5%, dissolved in methylene chloride as a dropwise stirring. Stirring is continued at + 2 ° C for 15 min. After separation of the organic layer, an aqueous solution of 50 3x15ml (9 mmol) NaOH 0.2 M is extracted. After separation, the aqueous solutions are extracted. combine and neutralize with 0.56 ml (9 mmol) of methyl formate in the presence of 25 ml of methylene chloride. After separation of the organic layer, dry over Na ₂ SO ₄ and evaporate under reduced pressure. The residue is crystallized from 10 ml CH ₃ CN giving O, 68g, 70% MRI data are given in table 2 below.

c) Preparation of 5-acetyl-6-methyl-2 (((3,4-dimethoxy-2-pyridinyl) methyl) thio) -1H-benzimidazole. 4.2g (20 mmol) 5acetyl-6-methyl-2-mercapto-1H-benzimidazole and 0.8g (20mmol) NaOH In 1ml water dissolve in 60ml ethanol (317mmol) 3,4-dimethoxy hydrochloride -2-chloromethylpyridine as crude material is added and the mixture is heated to boiling, O, 7 g (17 mmol) NaOH in 1 ml water is added and reflux is continued for 5 h. The solvent is separated by evaporation and the residue is diluted with chloride of methylene and water The organic phase is dried over Na ₂ SO ₄ and the solvent is removed under reduced pressure Crystallizing from acetonitrile gives the title compound 3.75g (62%). The NMR data are given in the table below.

d) Preparation of 5-acetyl-6-methyl-2 ((((3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl) -1Hbenzimidazole 3.75g (10 mmol) 5acetyl-6-methyl-2 - ((((( 3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole is dissolved in 70ml CH ₂ Cl _2. 1.76g (21 mmol] sodium bicarbonate in 25ml water is added and the mixture is cooled to + 3 ° C 2.43g (9.8 mmol) m-chloroperbenzoic acid 69.5% dissolved in 20ml methylene chloride was added dropwise with stirring, stirring continued for 10 min. The phases were separated and the organic phase was dried over Na ₂ SO ₄ and evaporate below

RO 110493 Bl reduced pressure. The residue was crystallized from acetonitrile to give 2.25g of the title compound 60%. The MRI data are shown in table 2 below.

e) Preparation of 5-carbomethoxy-2- 5 ([(3,4-dimethoxy-2-pyridinyl) methyl) -thio) -1H-benzimidazole. 2.0g (9 mmol) of 5-carbomethoxy-2-mercapto-1H-benzimidazole and 0.36 (9 mmol) of sodium hydroxide in 1ml of water were dissolved in 30ml of ethanol. 6.6 mmol 10 3,4-dimethoxy-3-chloromethylpyridine hydrochloride as crude material is added and the mixture is heated to boiling. O, 26 g (6.6 mmol) of sodium hydroxide in 1 ml of water is added and reflux is continued for 6 h. The solvent is evaporated off and the residue is diluted in methyl chloride and water. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. Crystalline lysate from acetonitrile yields 1.75g the desired product, 71%. MRI data are presented in Table 2 below.

f) Preparation of 5-carbetoxy-2 - {(((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole. 1.4g (3.6 mmol) 5-carbetoxF24 ((3,4-dimethoxy-2-pyridinyl) methylthio) 1H-benzimidazole 95.2% purity was dissolved in 30ml methylene chloride. Add 6 g (7.2 mmol) of sodium bicarbonate in 10 ml of water and cool to + 2 ° C. 0.87g (3.5 mmol) of chlorooperbenzoic acid 69.5% dissolved in 5ml methylene chloride is added dropwise under stirring. Stirring is continued at + 2 ° C for 10 min. The phases are separated and the organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from acrylonitrile to afford O, 76g (54%) of the title compound. MRI data are presented in Table 2 below.

Table 2

Ex. Solvent MRI or ppm data of cdci ₃ (300 MHz) 2.70 (3H s); 3.90 (3H s); 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). b CDCIg (300 MHz) 2.70 (3H s); 3.85 (s, 3H); 3.90 (s, 3H); 3.95 (s, 3H); 4.70 (d. 1H); 4.90 (d. 1H); 6.80 (d, 1H); 7.3 (b, 1H); 8.20 (d, 1H); 8.35 (b, 1H); c CDCIg (300 MHz) 2.60 (s, 3H); 2.65 (3H s); 3.90 (s, 3H); 3.90 (3H s); 4.35 (s, 2H); 6.85 (d, 1H); 7.25 (s, 0.6H); 7.40 (s, 0.4H) 7.85 (s, 0.4HJ; 8.05 (s, 0.6H); 8.30 (m, 1H). d CDCIg (300 MHz) 2.60 (s, 6H); 3.85 (s. 3H); 3.85 (s, 3H); 4.7 (d, 1H); 4.90 (d, 1H); 6.80 (d, 1H); 7.30 (b. 1H); 8.15 [d, 1H); 8.20 (b, 1H); e CDCIg (300 MHz) 1.40 (m, 3H); 3.90 (s, 3H); 3.90 (s, 3H); 4.4 (m, 4H); 6.90 [d, 1H); 7.45 (d, 0.4H); 7.60 (d, 0.6H); 7.90 (m, 1H); S, 20 (s, 0.6H); 8.25 (m, 1H); 8.25 (s, 0.4H). f CDCl 1.45 (t, 3H); 3.85 (s. 3H); 3.90 (s, 3H); 4.4 (q, 2H); 4.65 (d. 1H); 4.40 (d. 1H); 6.80 (d. 1H); 7.50-7.80 (b, 1H); 8.05 (d. 1H); 8.20 (d, 1H); 8.25-8.55 (b, 1H).

In Table 3, examples of compounds of formula (I) are given in Table 3:

Table 3

ex R! r ₂ r ₃ r ₄ r ₅ Of course Identity dates Obs. 1 C [0) 0CH ₃ ch ₃ ch ₃ C [0] 0CH ₃ ch ₂ ocooc ₂ h ₅ ch ₃ ch ₃ 44 NMR isomeric mixture 2 ch ₃ C (0) 0CH ₃ CH _s 0C00C ₂ H _e ch ₃ ch ₃ NMR isolated isomer 3 C (0) CH ₃ ch ₃ ch ₃ C (0) 0CH ₃ ch ₂ ocooc ₂ h ₅ ch ₃ ch ₃ 49 NMR mixture of isomers 4 C (0) CH ₃ ch ₃ ch ₂ ocooc ₂ h ₅ ch ₃ ch ₃ NMR isolated isomer 5 ch ₃ C (0) CH ₃ ch ₂ ocooc ₂ h ₅ ch ₃ ch ₃ NMR isolated isomer 6 C (0) 0CH ₂ -ch ₃ H H C [0] QCH ₂ '-ch ₃ ch ₂ ocooc ₂ h ₅ ch ₃ ch ₃ 37 NMR mixture of isomers

The compounds of the invention can be used to prevent and treat inflammatory gastrointestinal disorders and gastric acid disorders in mammals, including humans, such as gastritis, gastric ulcer, duodenal ulcer, 30 reflux esophagitis, and Zollingen-Ellison syndrome. Furthermore, the compounds may be used for the treatment of other gastrointestinal disorders where the gastric antisecretory effect is desirable, for example, in 35 patients with gastrinoma and in the patient with acute upper gastrointestinal bleeding. They can also be used in patients in special care situations to prevent acid aspiration, stress ulceration. The compounds of the invention can also be used for the treatment or prophylaxis of inflammatory conditions in mammals, including humans, in particular those involving lysozyme enzymes. The conditions that need to be mentioned in particular are gout and rheumatoid arthritis. The compounds can also be used in the treatment of disorders related to metabolism disorders in 50 bones as well as in the treatment of glaucoma. It also relates to pharmaceutical compositions containing compounds of the invention, as active ingredient. In a further aspect, the invention relates to the use of active compounds for the preparation of active compositions for the preparation of pharmaceutical compositions for the medical use indicated above.

It is an object, by specific, of the invention to obtain compounds with a high level of bio-utility. The compounds of the invention also have good stability properties at neutral pH or acid and a good ability to inhibit gastric acid secretion The compounds of the invention cannot block the elevation of iodine in the thyroid gland. In some works of the company or described earlier how inventors work so that thyroid toxicity depends on whether the compounds are lipophilic or not. Now it has been found that lipophilicity is not a critical parameter. The claimed compounds, which do not include hydrophilic compounds, do not have any thyroid toxic effect and at the same time have particular effects of inhibiting acid secretion, good biotility and stability.

For clinical use the compounds of the invention are formulated in pharmaceutical formulations for oral administration,

RO 110493 Rectal bl or other modes. The pharmaceutical formulation contains a compound of the invention in combination with an acceptable pharmaceutical carrier. The carrier may be in the form of a liquid, semi-liquid or solid diluent, or a capsule. These pharmaceutical preparations are another object of the invention. Typically, the amount of active compound is between 0.1 and 95% by weight of the preparation and between 1 and 50% by weight in the 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 selected compound may be mixed with a powder carrier, solid such as lactose, sucrose, sorbitol, mannitol, starch, amiiopectin, cellulose derivatives, gelatin or another corresponding carrier, which stabilizes substances such as alkali compounds, for example, carbonates, hydroxides and sodium oxides, potassium, calcium, magnesium, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium fumarate stearyl and polyethylene glycol waxes . The granules and tablets may be coated with an enteric protective coating that protects the active compound from catalytic acid degradation as long as the dosage form remains in the stomach. the enteric protective coating is selected from pharmaceutically acceptable enteric protective materials, for example, beeswax, shellac or anionic film-forming polymers such as cellulose acetylphthalate, hydroxypropyl-methylcellulose phthalate, polymers of methacrylic acid partially esterified with methyl and the like prefers in combination with a suitable plasticizer. For coating, different dyes can be added to distinguish the other tablets and granules with different active compounds or with different amounts of the present active compound.

Soft gelatin capsules may be prepared with capsules containing a mixture of an active compound of the invention, vegetable oil, fat or other suitable carrier for soft gelatin capsules. Soft gelatin capsules may also be enteric coated as described above. Hard gelatin capsules may also contain the active compound in combination with a solid carrier in the form of powder such as lactose, sucrose, sorbitol, corn starch.amiiopectin, cellulose derivatives or gelatin. The hard gelatin capsules may be enteric coated as described above. Dosage units for rectal administration may be prepared in the form of suppositories containing an active substance mixed with a natural fat base, or may be prepared in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, oil of paraffin or other carrier suitable for rectal gelatin capsules, or may be prepared in the form of a ready-prepared microclism, or may be prepared in the form of a dry microclism formulation to be reconstituted into a suitable solvent just prior to administration.

The liquid preparation for oral administration may be prepared in the form of syrup or suspension, for example, solutions or suspensions containing from 0.2 to 20% by weight of the active ingredient and the remainder consisting of sugar or sweet alcohol (baby alcohol) and a mixture of ethanol, water. glycerol, propylene glycol and / or polyethylene glycol. If desired, each of the liquid preparations may contain flavoring agents, saccharin and carboxymethylcellulose 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 substance will depend on different factors such as, for example, the individual need of each patient, the route of administration and the condition. In general, oral doses will be in the range of 5-500mg / day of active substance.

Following are given ways

RO 110493 Bl (weight by volume) of the active substance was prepared from the following ingredients:

conditioning of the compounds according to the invention.

Syrup

A syrup containing 1%

A compound according to Example 4 1.0g Powdered sugar 30, Og saccharine O.6g glycerol 5 Og Tween 1.0g Flavor agent O O5g ethanol 5 Og Distilled water to the final volume of 1OOml

Prepare a solution of the mixture of the compound of Example 1 in ethanol and Tween. Dissolve sugar and saccharin in 60ml hot water. After cooling the solution of the active compound is added to the solution of sugar and glycerol and 20 flavoring agents dissolved in ethanol are added. The mixture is diluted with water to a final volume of 1OOml.

tablets

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

1). Compound mixture according to Example 3 500g Lactose 700g methylcellulose 6g Reticular polyvinylpyrrolidine 50g Magnesium stearate 15g sodium carbonate Sg Distilled water qs II). hydroxypropyl 36g polyethylene 19g Titanium dioxide color 4g Purified water 313g

I. The mixture of compound according to 40 of Example 3, powder, is mixed with lactose and granulated with an aqueous solution of methylcellulose and sodium carbonate. The wet mass is passed through a sieve and the granulate is dried in an oven. 45 After drying the granulate is mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture is pressed into tablet cores (1OOOO tablets) each tablet contains 50mg of 50 active substance, in a tablet machine using a 7mm diameter changer.

II. Prepare a solution of hydroxyprolylmethylcellulose and polyethylene glycol in purified water. After titanium dioxide dispersion, the solution is sprayed onto tablets (I) in a coating equipment. Accela Cota ”Manestry. Finally, 125mg tablets are obtained.

RO 110493 Bl

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

A compound according to Example 4 3OOg Lactose 7OOg Microcrystalline cellulose 40g Poorly substituted hydroxypropyl cellulose 62g Purified water qs

The mixture of active compound is mixed with dry ingredients and granulated with a solution of sodium mono acid phosphate. The wet mass is passed through an extruder and spheronized and dried in a fluidized drying bed. 5DOg of the above tablets is first coated with a solution of hydroxypropylmethylcellulose, 3Og, in water, 6OOg, using a fluidizing coating bed. After drying, the tablets are coated with a second coating as shown below:

Coating solution Hydroxypropylmethylcellulose phthalate 7Og All alcohol 4g Acetone 6OOg ethanol 2OOg

The coated tablets are finally inserted into the capsules.

suppositories

The suppositories are prepared from the following ingredients using a welding process. Each suppository contains 40mg of active compound.

- Compound mixture according to example 4 ................ 4g;

- Witepsol H-15 .................................. 180g.

The mixture of the active compound is mixed homogeneously with Witepsol H-15 at a temperature of 41 ° C. The melted mass is placed in prefabricated suppository packages at a net weight of 1.84g. After cooling, the packages were heat sealed. Each suppository contains 40mg of active compound.

The biological effects of the compounds according to the invention are presented below. 50

The bioavailability is evaluated by calculating the coefficient between the areas under the plasma concentration curve (AUC) of a compound of formula (I) wherein R ₃ is hydrogen, defined here as compound A, following (1) intraduodenal (id) or oral ( po) of the corresponding compound according to the invention and (2) intravenous administration (iv) of compound A, from rats and dogs. Relatively low therapeutic doses are used. The data are presented in Table 4.

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24

Table 4

Biological tests

Test composed of ex Inhibition of acid secretion oral administration ED ₅₀ pmol / kg Inhibition of acid secretion administered to dog ED _5Q pmol / kg Bioavailability F% % inhibition of 400 pmol / kg growth in the thyroid gland dog rat dog rat adm adm adm oral id id 1 2 3 4 5 6 1 O ⁶ ) 1.5 ^bl 2.2 ^b) 1.5 ^bl 0.9 1.3 ^a) 1.3 ^ai 0.8 ^b) 51 ^bl 51 ^b) 35 ^bl 5O ^fal 66 ^b) 106 99 0 0 -7 -7 -7 -6 a) gastric fistula in the dog b) Heidenhein dog

The potential for inhibition of acid secretion 20 is measured by mouth in the rat and dog, both by mouth and by intraduodenal route. Potential data are presented in Table 4 above. 25

The effect of a compound of the invention of formula (I) on the rise of iodine in the thyroid gland is measured as an effect on the accumulation of 125 in the thyroid gland of the compound corresponding to the formula (I), wherein R ₃ is hydrogen, which is a compound metabolized by formula (I).

Further biological tests are given below. 35

Inhibition of gastric acid secretion in the conscious female rat. SpragueDawley female rats are used. They are endowed with cannulated fistulas in the stomach (lumen), for the collection of gastric secretions. A period of 14 days after surgery is considered before the start of the test.

Prior to secretion tests, age-45 hips are retained from food but not from water for 2D h. The stomach is repeatedly washed through the gastric cannula and given 6ml Ringer-Glucose sc The acid secretion is stimulated with infusion for 2, 5 h (1.2 ml / h, sc) of pentagastrin and carbachol (20 and 110 nmol / kg h, respectively), during which gastric secretions are collected in fractions of 30 min. The test substances or the carrier are given orally for 120 minutes, before starting stimulation, in a volume of 5ml / kg. The gastric juice samples were titrated to pH 7.0 with NaOH, 0.1 mol / l and the acid removed was calculated as the product of the concentration and volume of the titrate. The following calculations are based on the main group of responses from 47 rats. The percentage of inhibition is calculated from the absolute ratios of eliminated acid. The ED ₅₀ values are obtained by graphically interpolating the intersection of dose-response curves, or they are estimated from single-dose experiences by summing a similar slope for all dose-response curves. The results are based on gastric acid secretion during the one hour after drug / transporter administration.

Bioavailability in the male rat.

Male rats are used

RO 110493 Adults of the Sprague-Dawley breed. One day, before the experience, all rats prepare for the left carotid cannulation for anesthesia. The rats used for intravenous experiments also cannulated in the jugular vein. (Ref. V Popovic and Popovic P, <J. Appl Physiol 1960, 15, 727-728). The rats used for intradodenal experiences.

It is also cannulated in the upper 10 of the duodenum. The cannulae are externalized at the neck of the neck. After the operation, the rats were housed individually and were whipped for food, but not for water, before administering sub-15 test rooms.

The same dose (4 pmol / kg) is given iv and id as a large pill for about 1 minute (2ml / kg).

Blood samples (0.1-0.4g) leak repeatedly from the carotid artery at intervals greater than 4 hours after receiving the dose. Samples are cooled as quickly as possible until analysis of the test compound.

The area under type vs blood concentration, AUC, for compound A, determined by the trapezoidal linear rule and extrapolated to infinity by dividing the last blood concentration determined by the constant of the elimination ratio in the terminal phase.

The systemic bioavailability (F%) of compound A after intraduodenal administration of the compounds of the invention of formula (I) is calculated as follows:

AUC (compound A)

F (%) = ----- 1 --- L ---- L

AUC (compound

Inhibition of gastric acid secretion 25 and bioavailability in conscious dogs. Harrier dogs of both sexes are used. They were endowed with a duodenal fistula for administration of test compounds or carrier and 30 □ cannulated gastric fistula or a Heidennain bag for collecting gastric secretions. Before the secretion tests the animals were starved for almost 18h, but they were given fresh water. Gastric acid secretion is stimulated by an infusion of 4 h histamine hydrochloride (12ml / h), at a dose that produces almost 80% of the maximum individual secretion response, 40 and gastric juice is collected in consecutive fractions at 30 min. The test substance or transporter is given by mouth, ed or iv one hour after the start of the histamine infusion, in a volume of O, 5ml / kg 45 body weight. In the case of oral administration, it can be shown that the test compound administered to the stomach secretes, in particular, acid in the Heidenhain pouch in dogs.

The acidity of samples id (compound of the invention)% (compound J) of gastric juice was determined, by titration at pH = 7.0 and the eliminated acid was calculated. Acid removed during collection periods after administration of the test substance or carrier was expressed as fractional responses, placing the eliminated acid in the fraction preceding administration at 1.O. '

The percentage inhibition was calculated from the fractional responses obtained by the test compound and carrier. EDgo values were obtained by graphical interpolation on the dose-response cross-curves, either estimated from single-dose experiments under the sum of the same dose-response inclination for all tested compounds. All reported results are based on acids removed 2 h after dosing.

Blood samples for analysis of plasma test compound concentration are taken at intervals greater than 3 h after dosing. The plasma is separated and cooled within 30 minutes after collection and analyzed subsequently. AUC (area under the plasma concentration-time curve) from time zero to 3 h after the dose for the compound

RO 110493 Bl

A, is calculated by the trapezoidal linear rule. The systemic bioavailability (P%) of compound A after the appearance or id of the compounds of the invention is calculated as described above in model 5 rats.

Effect on 125 _t accumulation in the thyroid gland.

The 125 _t accumulation in the thyroid gland is studied in 10 Sprague-Dawley male rats that were detained for 24 h before testing. The experimental protocol after Searle, EC et al. (Bichem J 1950; 47;

77-81) is the following. Test substances, suspended in 0.5% buffered methylcellulose (pH 9), are administered orally in a volume of 5ml / kg body weight. After one hour, 125 _((300kBq / kg, 3ml / kg) was administered 20 by intraperitoneal injection. Four hours after administration of 125, the animals are killed by asphyxiation with C0 ₂ and bleeding. The thyroid gland together with a piece of the trachea was cut and 25 is placed in a small test tube for analyzing radioactivity in a gamma container [LKB

Wallac model 1282 Compugamma). The inhibition percentage is calculated according to the formula 100 (1-T / P), where T and P is the main radioactivity of the thyroid glands from animals treated with test and placebo (methylcellulose buffered), respectively. The statistical significance for a difference between the animals treated with test agent and placebo is analyzed with Mann-Whitney U-test (2 heads) P 0.05 is accepted as significant.

Chemical stability

The chemical stability of the compounds of the invention is followed by kinetics 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, which is the time period after which half of the amount of the original compound remains unchanged, and 10% at pH = 2, which is the time period after which 10% of the original compound is decomposed.

Table 5

Stability data

The compound tested example no. pH = 7 t Vz (h) pH = 2 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 (12)

Claims • 1 Results of biological and stability tests: Tables 4 and 5 summarize the availability test data for the compounds of the invention. wherein, R-, and R ₂ , which are different, are each hydrogen, alkyl containing 1-4 carbon atoms or -C [O] ~ R _S ; one of the R ₅ or R ₂ being always chosen from the group -C [0) -R ₆ ; Wherein R _s is alkyl containing 1-4 carbon atoms or 1. Benzimidazole derivatives, characterized in that they have the general formula (I): RO 110493 Alkoxy containing 1-4 carbon atoms; R ₃ is a group -CH _s 0C00R ₇ wherein R ₇ is alkyl containing 1-6 carbon or benzyl atoms; R ₄ and R ₅ are the same or different and are selected from -CH _a , C ₂ H ₅ , -ch ₂ -CH ₂ CH ₂ 0CH ₃ , or R ₄ and R ₅ together with the adjacent oxygen atoms attached to the ring. pyridine and carbon atoms in the pyridine ring a ring. wherein the part consisting of R ₄ and R _s is a group -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ -, or CH _a - 2. The benzimidazole derivatives according to claim 1. characterized in that they are, in particular, 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] -1H-benzimidazole-1-ylmethyl ethyl carbonate. The benzimidazole derivatives according to claim 1, characterized in that they are, in particular, a mixture of 5-80βί ^ 6-ηηβϋ1-2 - (((3,4-άΪΓΤΐβίοχϊ-2-ρΐπdinyl) methyl) sulfinyl) - 1H-benzimidazole-1-ylmethyl ethyl carbonate and B-acetyl-5-methyl-2 (((3,4-dimethoxy-2-pyridinyl) rnetyl) sulfinyl] -1H-benzimidazole-1-ylmethyl ethyl carbonate. A benzimidazole derivative according to claim 1, characterized in that it is in particular 5-carbomethoxy-6-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole-1-ylmethyl ethyl carbonate. A benzimidazole derivative according to claim 1, characterized in that it is, in particular, 6-carbomethoxy-5-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H- benzimidazole-1-ylmethyl ethyl carbonate. A benzimidazole derivative according to claim 1, characterized in that it is, in particular, 5-acetyl-6-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -! H-benzimidazole-1-ylmethyl ethyl carbonate. A benzimidazole derivative according to claim 1, characterized in that it is, in particular, 6-acetyl-5-methyl-2 - ((((3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl) -1H- benzimidazole-1-ylmethyl ethyl carbonate. A benzimidazole derivative according to claim 1, characterized in that in the compounds of formula (I), R ₃ is a CH ₂ 0C00CH ₂ CH _{3 group} . 9. Benzimidazole derivatives according to claim 1, characterized in that in the compounds of formula (I), R, and R ₂ are each hydrogen, methyl or C (O) R _e , wherein R ₆ is alkyl containing 1-. 4 carbon atoms or alkoxides containing 1-4 carbon atoms. The benzimidazole derivatives according to claim 1, characterized in that it is used in the form of pharmaceutical compositions for inhibiting gastric acid in mammals, including humans and in treating inflammatory gastrointestinal disorders in mammals, including humans. 11. Process for the preparation of some benzimidazole derivatives of the general formula (I) above, characterized in that a compound of general formula (II) is treated: Z (ti) in which, R _1t R ₂ , Rg and R ₄ have the above meanings and Z is a matical cation such as Na *, K ⁺ , Li ⁺ or Ag * or a quaternary ammonium ion, such as tetrabutylammonium, with chloromethylalkyl carbonate or chloromethylbenzyl carbonate; or a compound of formula (II) is treated, wherein: R _v R ₂ . R ₄ and 1¾ have the above meanings and Z is hydroxymethyl with a compound of formula (III): X - C (0) - O - R ₇ (III) wherein, R ₇ has the above meanings and X is chlorine or imidazole or pnitrophenoxy or an equivalent functional group, in the presence of a suitable base such as triethylamine, both reactions under protective gas in the absence of water. in suitable solvents such as hydrocarbons such as toluene or benzene or hydrocarbons EN 110493 Bl halogenates or acetone, acetonitrile or dimethylformamide at the temperature between ambient temperature and boiling temperature of the reaction mixture. 12. Process for preparing 5 benzimidazole derivatives of the general formula (I) above, characterized in that a compound of formula (IV) is oxidized: wherein: R _p R ₂ , R ₃ , R ₄ and R ₅ have the above meanings, with an oxidizing agent such as nitric acid, oxygenated water, possibly in the presence of vanadium compounds, peracids, peresters, ozone, dinitrogentetraoxide, iodobenzene , N-halosuccinimides, 1-chloroenzotriazole, t-butyl hypochlorite complex, diazabicyclo- (2,2,2) octane bromide, sodium metaperiodate, selenium dioxide, magnesium dioxide, chromic acid, cericammonium acetate, bromide or sulphide chloride , in a solvent such as halogenated hydrocarbons, alcohols, esters, ketones.