HU196997B - Process for producing pyridine derivatives and pharmaceuticals comprising these compounds as active ingredient - Google Patents

Description

The present invention relates to novel pyridine derivatives and to pharmaceutical compositions containing them as active ingredients. The above compounds have anti-ulcer activity and are thus useful as pharmaceutical compositions for the prevention and treatment of gastrointestinal ulcers.

Pyridine derivatives having anti-ulcer activity are described in Japanese Patent Laid-open Nos. 141783/1979 and 135881/1983.

However, the above known compounds are not considered to be suitable anti-ulcer compounds because, although they inhibit gastric secretion, they do not possess adequate gastric mucosal protection. In addition, they have the disadvantage of being unstable and easily degradable. For these reasons, there is a need for compounds which possess not only gastrointestinal secretion inhibitory activity but also gastric mucosal protective activity.

The pyridine derivatives disclosed in German Patent No. 3,404,610 differ from the compounds of the present invention in that they do not contain an alkoxy substituent at the 3-position of the pyridine ring.

U.S. Patent No. 4,255,431 (the equivalent of European Patent No. 5,129) and European Patent Nos. 7,441,441 and Hungarian Patent Specification 190,408 generally disclose compounds of Formula I which are pyridine ring compounds.

They may be substituted at the 3- and 4-positions with methoxy or ethoxy, but no examples of compounds containing a methoxy or ethoxy substituent at each of positions 3 and 4 of the pyridine ring are disclosed. In our pharmacological studies, however, compounds containing a lower alkoxy substituent at both the 3 and 4 positions of the pyridine ring exhibit significantly greater gastric mucosal protective activity than compounds containing only one of the two alkoxy substituents.

In our studies, we have found that certain pyridine derivatives, in addition to having an adequate level of inhibition of gastric secretion, also possess gastric mucosal protective activity and thus exhibit excellent anti-ulcer activity. The above compounds are represented by the general formula (I)

R ¹ is hydrogen, fluoro, methoxy or trifluoromethyl,

R ² is lower alkyl,

R ³ is lower alkyl optionally fluorinated with 2 to 8 fluorine atoms and n is 0 or 1.

The process of the present invention thus relates to the preparation of compounds of formula I by reacting a compound of formula II with a compound of formula III: in the latter formulas, R ¹ , R ² and R ³ are as defined above, and

X ¹ mercapto ports,

X ² represents a leaving group - and the resulting compound is oxidized, if desired.

The active ingredient of formula (I) obtained by the above process is admixed with a pharmaceutically acceptable carrier and / or other excipients to provide a pharmaceutical composition suitable for the prevention and treatment of gastrointestinal ulcers.

The leaving group represented by X ^{2 in} formula (III) is, for example, a halogen atom, preferably a chlorine, bromine or iodine atom;

an ester-activated hydroxy group such as an arylsulfonyloxy group, i.e. an organic sulfonic acid residue (e.g., p-toluenesulfonyloxy group, benzenesulfonyloxy group), a C 1-4 alkylsulfonyloxy group (e.g., methanesulfonyloxy); or an organic phosphoric acid residue such as diphenylphosphoryloxy, dibenzylphosphoryloxy or di (C 1-4) alkylphosphoryloxy (e.g. dimethylphosphoryloxy).

The lower alkyl group represented by R ² may be a C 1 -C 6 group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, with C 1 -C 4 being preferred.

The lower alkyl group represented by R ³ , optionally substituted with 2 to 8 fluorine atoms, may be a C 1-6 alkyl group as defined above. Examples of fluorinated alkyl include 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl.

1- (trifluoromethyl) -2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,4,4,4-heptafluorobutyl, and 2,2,3,3,4,4,5,5-octafluoropentyl, of which C2-C4 fluorinated alkyl groups are preferred.

The sulfide derivatives (I) (n = 0) are prepared by reacting a compound (II) with a compound (III).

The above reaction is preferably carried out in the presence of a base. As the base, for example, alkali metal hydrides such as potassium hydride, alkali metals such as metal sodium, sodium alcoholates such as sodium methoxide or sodium ethoxide, alkali metal carbonates such as potassium carbonate or sodium carbonate, for example triethylamine. Suitable solvents are, for example, alcohols such as methanol or ethanol or dimethylformamide. The base is generally used in an amount slightly greater than one equivalent in the above reaction, but may also be used in a large excess, i.e., the amount of the base is about. 1-10 equivalents, preferably close to 1-4 equivalents. Reaction temperature-23

The amount of 196,997 usually ranges from 0 'C to the boiling point of the solvent used, preferably from 20 to 80' C. The reaction time is approx. 0.2-24 hours, preferably 0.5-2 hours.

The sulfinyl derivatives of formula I (n = 1) may be prepared by oxidation of compounds of formula I wherein n is 0. The oxidizing agent is, for example, peracids such as meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid or permaleic acid. Hydrogen peroxide, sodium bromide or sodium hypochlorite may be used. Solvents include, for example, halogenated hydrocarbons such as chloroform or dichloromethane, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, alcohols such as ethanol, isopropanol or tert-butanol, or water, or mixtures of the above solvents. you can use. In some cases, a catalyst such as vanadium pentoxide or tungstic acid may also be used. The above oxidizing agents are preferably ca. is used in an equivalent amount, or in a small excess, based on the compound of general formula (I) (n = 0), e.g.

1-3, more preferably 1-1.5 equivalents of oxidizing agent are used. The reaction temperature may range from the temperature of the ice bath to room temperature, preferably 0 to 10 ° C. The reaction time is usually 0.1 to 24 hours, more preferably 0.1 to 4 hours.

The starting compounds of formula (III) wherein X ² is a leaving group are

Scheme 1 may be prepared as follows.

The maltol of formula (IV) is reacted with an alkyl halide of formula R ² X, for example in the presence of silver oxide. The resulting compound (V) is reacted with aqueous ammonia to give compound (VI). The compound of formula (VI) is directly alkylated with an alkyl halide (VII) with a compound of formula, or a halogenating agent - for example, phosphorus oxychloride - treated converted into halo compound of formula (VIII), and the obtained (VIII) with a compound of the formula R ³ Reaction with an alcohol of formula OH in the presence of a base yields the product of formula VII. The compound of formula (VII) is either directly converted to the compound of formula (III) by halogenation with N-bromosuccinimide or chlorine gas or by treatment with an oxidizing agent such as m-chloroperbenzoic acid to form the compound of formula IX followed by the reaction with acetic anhydride. and hydrolyzing the resultant compound (X) to compound (XI) which is then treated with a halogenating agent such as thionyl chloride to give compound (III).

The alkyl halide used in the preparation of compounds of formulas (V) and (VIII) may be, for example, methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, pentyl iodide, or hexyl iodide.

1 to 10 equivalents. The base used is, for example, silver oxide, potassium carbonate or sodium carbonate, and the solvent used is, for example, dimethylformamide or dimethylacetamide. The reaction is usually carried out at room temperature. The halogenating agent used in the preparation of compounds of formula (VIII) may be, for example, phosphorus oxychloride, phosphorus pentachloride or phosphorus tribromide in amounts of one equivalent to a large excess. The reaction temperature is approximately 50-150 ° C.

The alcohol used to convert the compound (VIII) to the compound (VIII) is, for example, methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, 2,2,2-trifluoroethanol,

2,2,3,3,3-pentafluoropropanol, 2,2,3,3-tetrafluoropropanol, 1- (trifluoromethyl) -2,2,2-trifluoroethanol,

2,2,3,3,4,4,4-heptafluorobutanol, or

2,2,3,3,4,4,5,5-octafluoropentanol may be present in an amount equivalent to a large excess. The bases used are, for example, sodium or potassium alcoholates of the above alcohols, potassium tert-butoxide or sodium hydride in the above reaction. The reaction temperature may be between room temperature and the boiling point of the alcohol used.

The bromination of the compounds of formula (VII) with N-bromosuccinimide is conveniently carried out by irradiation in a solvent such as carbon tetrachloride, chloroform or tetrachloroethane.

Oxidizing agents such as peracids such as meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, or permaleic acid, or hydrogen peroxide may be used as oxidizing agents for the oxidation of compounds of formula VIII to compounds of formula IX. Suitable solvents for the reaction are, for example, halogenated hydrocarbons such as chloroform or dichloromethane, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, acetic acid or water, individually or in combination. The amount of oxidizing agent may vary from one equivalent to an excess of the compound of formula VII, preferably from 1 to 10 equivalents. The reaction temperature may range from the temperature of ice cooling to the boiling point of the solvent used. The reaction time is usually 0.1 to 24 hours, more preferably 0.1 to 4 hours.

The compound of formula (X) is prepared from the compound of formula (IX) by heating the compound of formula (IX) in the presence of acetic anhydride or in the presence of a mineral acid such as sulfuric acid or perchloric acid for about 10 minutes. 80-120'C C. The reaction time is usually 0.1 to 10 hours.

Compounds of formula XI are prepared from compounds of formula X by alkaline hydrolysis using, for example, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate. Suitable solvents are, for example, methanol, ethanol or water. The reaction temperature is usually between 20 and 60 ° C and the reaction time is about 1 hour. It may take from 0.1 to 2 hours.

Compounds of formula (III) may be prepared from compounds of formula (XI), a chlorinating agent such as thionyl chloride, or an acid chloride of an organic sulfonic acid or organic phosphoric acid,

196,997 using, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride or diphenylphosphoryl chloride. When thionyl chloride is used as the chlorinating agent, the chlorinating agent is used in an amount in the equivalent amount to a large excess relative to the compound of formula XI. Suitable solvents are, for example, chloroform, dichloromethane or tetrachloroethane. The reaction temperature is ca. The reaction temperature may range from about 20 to about 80 ° C. Between 0.1 hours and 2 hours. When the acid chloride of an organic sulfonic acid or an organic phosphoric acid is used as the halogenating agent, the amount of the halogenating agent may vary from one equivalent to a small excess of the compound of formula XI and the reaction is usually carried out in the presence of a base. The bases used are, for example, organic bases such as triethylamine or tributylamine, or inorganic bases such as sodium carbonate, potassium carbonate or sodium bicarbonate in amounts ranging from one equivalent to a small excess. Examples of the solvent include chloroform, dichloromethane, carbon tetrachloride and acetonitrile. The reaction temperature may range from the temperature of ice cooling to the boiling point of the mixture and may be from a few minutes to several hours.

Compounds of formula (I) may also be prepared by methods described, inter alia, in Japanese Patent No. 192,880/1983, wherein a compound of formula (XII) wherein R ¹ is as defined above is coupled with a compound of formula (XIII) - wherein R ² and R ³ are as defined above - are reacted, then the resultant compound is oxidized, if desired, or a compound of formula (XIV): - wherein ^R? is as defined above and M is potassium, sodium or lithium atom - with a compound of formula (XV) - wherein the meaning of R ² and R ³ are as defined above and X ³ represents one of the X ¹ to X ² report of a leaving group - with.

The compounds of formula (I) obtained by the above processes may be isolated and purified by conventional means, for example, by recrystallization or chromatography.

The pharmacological activity of the compounds of formula (I) obtained by the process of the invention is described below.

The role of acid in the development of gastric and duodenal ulcers has long been well known, but the importance of the protective capacity of the gastric mucosa has only recently been explored (Miller T. A .: Am. J. PhysioL 245, G601 (1983)).

A commonly used method for determining gastric mucosal protection is ethanol-induced gastric mucosal injury [Robert

A .: Gastroenterology 77, 761 (1979)]. The compounds of the present invention were also tested for their activity by this method.

Male Spargue-Dawley rats, fasted for 7 weeks, were used for the assay. The animals are administered the test compounds via the stomach tube. After 30 minutes, 1 ml of 100% ethanol was administered orally. 60 minutes after ethanol administration, the animals are sat on carbon dioxide. The stomach is removed along with the lower portion of the inguinal tube and the duodenum. The esophagus was squeezed, 10 ml of a 1% formalin solution in the duodenum was instilled into the stomach and the duodenum was suctioned. The whole stomach is immersed in 1% formalin solution. After about 15 minutes, the stomach is incised along a greater curvature. The length of gastric mucosal lesions was measured under a dissecting microscope using a square grating lens (10x magnification). In each animal, the sum of the lesion lengths from each lesion is determined and the mean values are calculated for each group. The degree of inhibition in each group

Table I. Gastric mucosal protective effects of compounds of formula Ij

Gyomomyál-

R ' R ² ' R ³ R ' card vi effect ID, (mg / kg, p. H —OCH, —CH, Η 3.2 -cf ₃ -OCH ₃ -ch ₃ Η 3.0 H -och ₃ -ch ₂ cf ₃ Η 6.2 -och ₃ -ch ₃ -ch ₃ —CH ₃ ^(b) 22.0 -cf ₃ -ch ₃ -ch ₃ H ^c > 24.0

a) 6 animals per group were used, test compounds were dosed at 3, 10 and 30 mg / kg to determine the IDj ₀

b) the compound of Example 23 of U.S. Patent 4,255,431 (Japanese Patent Application No. 141783/1979).

(c) Example 3 of U.S. Patent 4,472,409 (Japanese Patent Application No. 135881/1983).

II. spreadsheet. The gastric mucosal lesion inhibitory activity of the compounds of formula (V) in rats was 10 mg / kg p.o. in 6 animals per group

R ¹ R ² ' R ³ R ⁴ Inhibitory effect (%) Η ~ OCH ₃ -C ₃ H ₇ H 56 ** H -och ₃ c ₂ h ₃ H 69 *** -och ₃ -ch ₃ -ch ₃ -ClÍ ₃ »> 2 -cf ₃ -ch ₃ -CHj H ^b > 30

a) The compound of Example 23 of U.S. Patent 4,255,431

b) the compound of Example 3 of U.S. Patent 4,472,409, ♦ * p <0.01, ♦ ** p <0.001 compared to control (Student's t-test)

Calculated as the difference between the mean of 196,997 and the mean of the control group,%. The test compounds are suspended in a 5% gum arabic solution in animals at a dose volume of 2 ml / kg. The experimental results are shown in Figs

II. See Table 1.

From the above results it can be seen that the compounds of the present invention have a significantly higher gastric mucosal protective activity than the known compounds. In addition, the compounds of formula I have an excellent inhibitory effect on gastric juice secretion, protect the gastric mucosa and prevent ulcer formation.

In view of the toxicity of the compounds of formula I, the compounds tested in the above experiment for gastric mucosal protection (R '= H, R ^J = CH ³ , R ³ = CH ³ ; and R * = H, R ² = CH 3). R ³ = CH ₂ CF ₃ ) when administered orally to mice, even at a dose of 500 mg / kg, the compounds of formula I are generally of low toxicity.

As mentioned above, the compounds of the present invention have excellent gastric mucosal secretion, gastric mucosal and anti-ulcer activity. rabbit, dog, cat and human) because of their low toxicity.

For the treatment of gastrointestinal ulcers, mammals may be administered orally the compounds of Formula I in various dosage forms, such as capsules, tablets, and granules, which are prepared by incorporating the active ingredient into pharmaceutically acceptable carriers such as lactose, starch, sucrose. Disintegrating agents such as starch, carboxymethylcellulose calcium salt, and the like. Lubricants such as magnesium stearate, talcunim, etc. Binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, and the like. And other similar excipients and shaping it to the desired composition. The dosage may be from about 0.01 to about 30 mg / kg / day, more preferably from about 0.1 to about 3 mg / kg / day.

Compounds of formula (I) wherein n is 0 may be used as starting materials for the preparation of compounds of formula (I) wherein n is 1.

The compounds of the present invention possess not only gastric secretion inhibitory activity but also gastric mucosal protective activity and therefore exhibit excellent anti-ulcer activity. The compounds of formula (I) are thus useful in the prevention and treatment of gastric ulcer, duodenal ulcer, gastritis, and the like.

The preparation of starting materials for the preparation of the compounds of formula (I) and the preparation of the compounds of formula (I) are described in detail by the following reference examples and examples, but are not intended to be limiting.

Reference Example 1

- Preparation of methoxy -2-methyl-4-propoxypyridine

1.39 g of 3-methoxy-2-methyl-4 (1H) -pyridine and 2.0 ml of propyl iodide are dissolved in 20 ml of dimethylformamide, 2.31 g of silver oxide are added in small portions and the mixture is stirred at room temperature. Stir vigorously for 5 hours. The reaction mixture was diluted with 1 (X) ml of chloroform, washed with water, dried and evaporated. The residue was purified by silica gel flash chromatography eluting with chloroform. 1.7 g of the title compound are obtained in the form of a pale bamboo oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

1.06 (3H, d, J = 7Hz), 1.86 (2H, m), 2.45 (3H, s), 3.81 (3H, s), 3.96 (2H, d, J) = 7Hz), 6.66 (1H, d, J = 6Hz), 8.06 (1H, d, J = 6Hz).

Reference Example 2

Preparation of chloro - 3 - methoxy - 2 - methylpyridine

5.6 g of 3-methoxy-2-methyl-4 (1H) -pyridine are suspended in 50 ml of phosphorus oxychloride and refluxed for 10 hours and then concentrated. Toluene was added to the residue and the remaining phosphorus oxychloride was evaporated under reduced pressure. To the resulting oily substance was added chloroform and water and the chloroform phase was separated. The aqueous phase was made basic with potassium carbonate and extracted with chloroform. The resulting chloroform solutions were combined, washed with water, dried and evaporated. The residue was purified by silica gel column chromatography.

4.8 g of the title compound are obtained in the form of a pale bamboo oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

2.53 (3H, s), 3.84 (3H, s), 7.14 (1H, d, J = 6Hz), 8.12 (1H, d, J = 6Hz).

Reference Example 3

Preparation of 3,4 - Dimethoxy - 2 - methylpyridine

To a solution of 3.2 g of 4-chloromethoxy-2-methylpyridine in 5 ml of methanol is added dropwise, under ice-cooling, 20 ml of 28% sodium methoxide in methanol and the mixture is refluxed for 10 hours and then evaporated to dryness. . To the residue was added 10 ml of ice water followed by addition of 100 ml of chloroform, the chloroform layer was separated, washed with water, dried and evaporated. The residue was purified by silica gel column chromatography. 2.95 g of the title compound are obtained in the form of a pale bama oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

2.46 (3H, s), 3.79 (3H, s), 3.86 (3H, s), 6.18 (1H, d, J = 6Hz), 8.11 (1H, d, J) -6 Hz).

196,997

Reference Example 4

Preparation of ethoxy - 3 - methoxy - 2 - methylpyridine

4-Chloro-3-methoxy-2-methylpyridine (3.14 g) was added to a solution of sodium (2.0 g) in ethanol (30 ml) and the mixture was heated under reflux for 10 hours. The solvent was evaporated and the residue was added to ice water, then extracted with chloroform, washed with water, dried and evaporated. The residue was purified by silica gel column chromatography. 2.6 g of a compound of the formula (cfm) are obtained in the form of a pale bama oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

1.45 (3H, t, J = 8Hz), 2.46 (3H, s), 3.81 (3H, s), 4.10 (2H, q, J-8Hz), 6.66 ( 1H, d, J = 5Hz), 8.06 (1H, d, J = 5Hz).

Reference Example 5

Preparation of - (bromoethyl) -3-methoxy-4-propoxypyridine

To a solution of 1.0 g of 3-methoxy-2-methyl-4-propoxypyridine in 70 ml of carbon tetrachloride was added 1.0 g of N-bromosuccinimide and the mixture was heated under reflux for 2 hours while under an infrared light ( Toshiba, 100V, 375WR). The insoluble material was filtered off, the filtrate was concentrated and purified by silica gel column chromatography. 0.4 g of the title compound is obtained in the form of a reddish-brown oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

1.06 (3H, t, J = 7Hz), 1.87 (2H, m), 3.98 (3H, s), 4.01 (2H, t, J-7Hz), 4.58 ( 2H, s), 6.77 (1H, d, J = 6Hz), 8.16 (1H, d, J-6Hz).

Reference Example 6

(a) Preparation of 2- (bromomethyl) -3,4-dimethoxypyridine

Starting from 3,4-dimethoxy-2-methylpyridine, the procedure of Reference Example 5 gave the title compound as a reddish-brown oil.

(b) Preparation of 2- (bromoethyl) -4-ethoxy-3-methoxypyridine

Starting from ethoxy-3-methoxy-2-methylpyridine, the procedure of Reference Example 5 gave the title compound as a reddish-brown oil.

Reference Example 7

- Preparation of methoxy-2-methyl-4- (2,2,2-trifluoroethoxy) pyridine

A mixture of 7.8 g of 4-chloro-3-methoxy-2-methylpyridine, 24.7 g of 2,2,2-trifluoroethanol and 27.76 potassium tert-butoxide was heated at 110 ° C for 18 hours, then concentrated, diluted with water and extracted twice with chloroform. The extract was dried, the chloroform was evaporated and the residue was purified by column chromatography on silica gel, eluting with chloroform / methanol (400: 9 by volume). 5.12 g of compound am are obtained as a white or pale yellow solid.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

2.49 (3H, s), 3.84 (3H, s), 4.42 (2H, q, J = 8Hz), 6.67 (1H, d, J = 5.5Hz), 8, 14 (1H, d, J = 5.5 Hz).

Reference Example 8

- Preparation of methoxy-2-methyl-4- (2,2,3,3,3-pentafluoropropoxy) pyridine per ml of 2,2,3,3,3-pentafluoropropanol in small portions of 23.6 g of potassium butoxide, then

7.5 g of 4-chloro-3-methoxy-2-methylpyridine are added. The mixture was refluxed for 40 hours, cooled, ethyl acetate was added and the insoluble material was cooled. The filtrate was concentrated and purified by column chromatography. 1.7 g of the title compound are obtained in the form of a pale yellow oil, and 4.1 g of starting material are recovered.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

2.48 (3H, s), 3.81 (3H, s), 4.49 (2H, t, J = 12Hz), 6.67 (1H, d, J = 5.5Hz), δ, 14 (1H, d, 3-5.5 Hz).

Example 1

Preparation of - [(3,4-Dimethoxypyrid-2-yl) methylthio] benzimidazole

To a mixture of 1.45 g of potassium salt of 2-mercapto-benzimidazole, 1.0 g of potassium carbonate and 10 ml of dimethylformamide, while stirring, 1.18 g of 2-bromomethyl-3,4-dimethoxy-pyridine in 2 ml A solution of dimethylformamide was added, the reaction mixture was stirred at room temperature for 30 minutes, and then chloroform (100 mL) was added. The mixture was quenched with water, 1N sodium hydroxide solution and again

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The mixture was washed with water (196,997), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 50: 1). 1.08 g of the title compound are obtained in the form of a pale yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.80 (3H, s), 3.82 (3H, s), 4.43 (2H, s), 6.70 (1H, d, J-6Hz), 7.0-7.2 (2H) , m), 7.4-7.6 (2H, m), 8.13 (1H, d, J-6Hz).

Example 2

Preparation of - [(3-Methoxy-4-propoxy-pyrid-2-yl) -methyl-thio] -benzimidazole

To a solution of 0.4 g of 2-mercapto-benzimidazole potassium salt in 5 ml of dimethylformamide was added dropwise a solution of 0.4 g of 2-bromomethyl-3-methoxy-4-propoxy-pyridine in dimethylformamide and the mixture was added at room temperature 1. stir for 1 hour. The reaction mixture was diluted with chloroform (50 mL), washed with water, dried and evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 50: 1). 0.35 g of a compound of the formula (cfm) was obtained as a pale bama oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

1.06 (3H, t), 1.87 (2H, m), 3.91 (3H, s), 3.99 (2H, m), 4.41 (2H, m), 6.88 (1H , d, J-6Hz), 7.1-7.65 (2H, m), 8.16 (1H, d, J-6Hz).

Example 3

Preparation of 2 - [(4-Ethoxy-3-methoxypyrid-2-yl) methylthio] benzimidazole

To a suspension of 1.3 g of 2-mercapto-benzimidazole potassium salt and 1.0 g of potassium carbonate in 15 ml of dimethylformamide was added 1.6 g of 2-bromomethyl-4-ethoxy-3-methoxy-pyridine in 5 ml. a solution of dimethylformamide was added and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 50 µl of chloroform, washed with water, 1N sodium hydroxide solution, then again with water, dried and evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 50: 1). 1.4 g of the title compound are obtained in the form of a pale yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

1.46 (3H, t), 3.9 (3H, s), 4.12 (2H, q), 4.40 '(2H, s), 6.79 (1H, d, J-5Hz) , 7.1-7.3 (2 H, m),

7.45-7.65 (2H, m), 8.19 (1H, d, J-5Hz).

Example 4

Preparation of 2 - [(3,4-Dimethoxypyrid-2-yl) methylthio] -5- (trifluoromethyl) benzimidazole

To a mixture of 1.10 g of 5- (trifluoromethyl) -2-mercaptobenzimidazole in 7.2 ml of 1N sodium hydroxide solution and 5 ml of methanol is added 1.3 g of 2- (bromomethyl) 3,4-dimethoxy. - a solution of pyridine in 35 ml of methanol was added at room temperature for 10 minutes. The mixture was stirred for 1 hour and extracted with chloroform. The organic layer was washed with 1N sodium hydroxide solution, then water, dried and evaporated. The residue was purified by silica gel column chromatography, eluting with chloroform: ethyl acetate: acetone = 1: 1: 0.1; 310 mg of the title compound are obtained in the form of white crystals.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.95 (6H, s), 4.43 (2H, s), 6.87 (1H, d, J-6Hz), 7.41 (1H, dd, J-1.5 and 9Hz), 7.60 (1H, d, J-9Hz), 7.80 (1H, bs), 8.27 (1H, d, J-6Hz).

Example 5. Preparation of 2 - [(3,4-Dimethoxypyrid-2-yl) methylthio] -5-methoxybenzimidazole

Starting from methoxy-2-mercaptobenzimidazole and 2- (bromomethyl) -3,4-dimethoxypyridine, the title compound was obtained in the same manner as in Example 4, in the form of a resin.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.77 (3H, s), 3.86 (6H, s), 4.41 (2H, s), 6.75 (1H, d, J-6Hz), 6.78 (1H, dd), 7.03 (1H, d, J-3Hz), 7.40 (1H, d, J-9Hz), 8.17 (1H, d, J-6Hz).

Example 6

Preparation of - [(3,4-Dimethoxy-pyrid-2-yl) -methylsulfinyl] -benzimidazole

To a solution of 1.08 g of 2 - [(3,4-dimethoxypyrid-2-yl) methylthio] benzimidazole in 30 ml of methylene chloride was added 0.79 gm-chloroperbenzoic acid in small portions, Below C. After completion of the reaction, the reaction mixture was diluted with methylene chloride (70 mL), washed with aqueous potassium carbonate solution, then water, dried and evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 40: 1). The material was recrystallized from a mixture of acetone and diethyl ether to give the title compound (670 mg) as a pale bama crystalline solid, m.p. 149-151 ° C (with decomposition).

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196,997

Example 7

Preparation of 2 - [(3-Methoxy-4-propoxypyrid-2-yl) methylsulfinyl] -benzimidazole

From [(3-methoxy-4-propoxy-pitid-2-yl) methyl-thio] -benzimidazole as described in Example 6, recrystallization from acetone-diethyl ether-hexane gave the title compound as a crystalline solid, m.p. -111'C.

Example 8

Preparation of - [(4-Ethoxy-3-methoxy-pyridin-2-yl) -methylsulfinyl] -benzimidazole

Starting from [(4-ethoxy-3-methoxypyrid-2-yl) methylthio) benzimidazole, the title compound was obtained in the same manner as in Example 6 as an amorphous powder.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

1.40 (3H, t), 3.80 (3H, s), 4.03 (2H, q), 4.81 (2H, s), 6.67 (1H, d, J-6Hz), 7.15-7.35 (2H, m), 7.40-7.65 (2H, m), 8.08 (1H, d, J-6Hz).

Example 11

- Preparation of methoxy-2 -1- [3-methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2-yl] methylthio] benzimidazole

A mixture of 1.1 g of 3-methoxy-2-methyl-4- (2,2,2-trifluoro cloxy) pyridine and 0.89 g of N-bromosuccinimide in 100 ml of carbon tetrachloride was refluxed for 2 hours, infrared radiation. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was immediately dissolved in diethyl ether (10 mL). The ethereal solution was added to a solution of 2-mercapto-5-methoxybenzimidazole (0.9 g) in 2N sodium hydroxide (2.5 mL) in methanol (20 mL) and stirred at room temperature for 50 min. The solvent was evaporated and the residue was purified by column chromatography and recrystallized from ethyl acetate-hexane. 989 mg of the title compound are obtained in the form of yellow crystals, m.p. 149-150'C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.82 (3H, s), 3.94 (3H, s), 4.34 (2H, s), 4.45 (2H, q, J = 8Hz), 6.79 (d, J-6H) ), 6.79 (d-like, J-8 Hz), 7.02 (1H, d, J-8 Hz), 7.39 (1H, d, J-8 Hz),

8.26 (1H, d, J-6 Hz).

Example 9

Preparation of - [(3,4-Dimethoxypyrid-2-yl) methylsulfinyl] 5- (trifluoromethyl) benzimidazole

- [(3,4-Dimethoxy-pyrid-2-yl) -methyl-thio] -5- (trifluoromethyl) -benzimidazole, as described in Example 6, recrystallization from chloroform-ethanol gave the title compound as a crystalline solid. 158-161 ° C (with decomposition).

Example 10

Preparation of -1 (3,4-Dimethoxy-pyrid-2-yl) -methylsulfinyl] -5-methoxy-benzimidazole

Starting from - [(3,4-dimethoxypyrid-2-yl) methylthio] 5-methoxybenzimidazole, the title compound was obtained as an amorphous powder as described in Example 6.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.83 and 3.85 (9H), 4.83 (2H, s), 6.76 (1H, d, J = 6 and 9 Hz), 6.93 (1H, dd, J = 2 and 9 Hz), 7.02 (1H,

d), 7.55 (1H, d, J-6Hz), 8.19 (1H, d, J-6Hz).

Example 72

Preparation of 2-1 / 3-methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2-yl] methylthio) -5-trifluoromethylbenzimidazole

A mixture of 1.1 g of 3-methoxy-2-methyl-4- (2,2,2-trifluoroethoxy) pyridine and 0.89 g of Ν-bromosuccinimide in 100 ml of carbon tetrachloride was refluxed for 2 hours, infrared radiation. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate and then concentrated. The residue was immediately dissolved in 10 ml of diethyl ether. The ethereal solution was added to a solution of 654 mg of 2-mercapto-5- (trifluoromethyl) benzimidazole, 1.5 ml of 2N sodium hydroxide and 10 ml of methanol and stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by silica gel column chromatography. Recrystallization from chloroform gave 690 mg of the title compound as a white crystalline solid, m.p. 80-82'C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.98 (3H, s), 4.45 (2H, s), 4.50 (2H, q, J = 8Hz),

6.86 (1H, d, J-5.5 Hz), 7.44 (1H, dd, J-32 and 9 Hz), 7.63 (1H, d, J-9 Hz), 7.83 ( IH, s-like), ca. 8.0 (1H, broad), 8.30 (111, d, J-5.5 Hz).

-815

196,997

Example 13

Preparation of 2 - (β-Methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2-yl] methylthio) benzimidazole

Starting from methoxy-2-methyl-4- (2,2,2-trifluoroethoxy) pyridine and 2-mercaptobenzimidazole, the title compound was obtained in the same manner as in Example 12 in crystalline form, m.p. 113-115 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.97 (3H, s), 4.43 (2H, s), 4.46 (2H, q, J = 8Hz),

6.81 (1H, d, J = hHz), 7.09-7.30 (2H, m),

7.46-7.63 (2 H, m), 8.29 (1H, d, J-6 Hz).

Example 14

Preparation of 2 - ((3-Methoxy-4- (2,2,3,3,3-pentafluoropropoxy) pyrid-2-yl] methylthio] benzimidazole

A mixture of 0.85 g of 3-methoxy-2-methyl-4- (2,2,3,3,3-pentafluoropropoxy) pyridine and 638 mg of N-bromosuccinimide in 70 ml of carbon tetrachloride was refluxed for 2 hours. boil under infrared radiation. The reaction mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was immediately dissolved in diethyl ether (6 mL) and added to a solution of 2-mercaptobenzimidazole (576 mg) and 2N sodium hydroxide (1.9 mL) in methanol (15 mL). The reaction mixture was stirred at room temperature for 15 minutes, evaporated, water was added and the mixture was extracted with ethyl acetate. The extract was washed with nearly 0.5 N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography and recrystallized from isopropyl ether / ethyl acetate. 710 mg of a compound of the formula (cfm) are obtained in the form of white crystals, m.p.

Nuclear Magnetic Resonance Spectrum (CDCl ·) δ:

3.93 (3H, s), 4.41 (2H, s), 4.52 (2H, t, J = 12Hz),

6.81 (1H, d, J = 5.5Hz), 7.05-7.3 (2H, m), 7.35-7.7 (2H, m), 8.27 (1H, d, J = 5.5 Hz), 12.52 wide s).

3.95 (3H, s), 4.42 (2H, s), 4.53 (2H, t, 1 = 12 Hz),

6.89 (III, d, J-5.5 Hz), 7.40 (J1, dd, J-8 and 1.5 Hz), 7.59 (1H, d, J-8 Hz), 7, 80 (1H, s-like), 8.29 (1H, d, J = 5.5 Hz).

Example 16

- Preparation of methoxy-2 - ((3-methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2-yl] methylsulfinyl) benzimidazole

989 mg of 5-methoxy-2 ()) 3-methoxy-4- (2,2,2-trifluoroethoxy-pyrid-2-yl) -methyl-thio) -benzimidazole are dissolved in 30 ml of chloroform and added under ice-cooling, 503 mg of m - chloroperbenzoic acid, dissolved in 8 ml of chloroform, are added dropwise over 5 minutes. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, then with a saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography. 712 mg of the title compound are obtained in the form of a pale pale yellow powder, m.p. 36-46 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.82 (6H, s), 4.33 (2H, q, J = 8Hz), 4.82 (2H, s),

6.70 (1H, d, J-36 Hz), 6.85-7.15 (111, broad), 6.92 (111, dd, J-9 and 2 Ilz), 7.85 (III, broad) ), 8.12 (111, d, J-6Hz), 12.47 (broad).

Example 17

Preparation of 2 - ((3-Methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2-ylmethylsulfinyl) -5- (trifluoromethyl) benzimidazole

2-1) starting from 3-methoxy-4- (2,2,2-trifluoro-ethoxy) -pyrid-2-yl] -methyl-thio) -5-trifluoromethyl-benzimidazole according to the procedure of Example 16; m.p. 147-149 ° C recrystallized from ethyl acetate-hexane.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:

3.80 (3H, s), 4.31 (2H, q, J = 8Hz), 4.88 (2H, s-like), 6.69 (1H, d, J = 5.5Hz), 7.38-7.98 (3H, m), 8.07 (1H, d, J = 5.5 Hz).

Example 15

2 - ((3-Methoxy-4- (2,2,3,3,3-pentafluoropropoxy)

- Pyrid-2-yl] -methylthio) -5- (trifluoromethyl) benzimidazole

starting from mercapto-5- (trifluoromethyl) benzimidazole and 3-methoxy-2-methyl-4- (2,2,3,3,3-pentafluoropropoxy) pyridine to give the title compound according to the procedure of Example 14. m.p. 127-128 ° C after recrystallization from isopropyl ether.

Nuclear Magnetic Resonance Spectrum (CDCl3) δ:

Example 18

2 - ((3-Methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2)

- yl] - (methylsulfinyl) -benzimidazole

2-1) starting from 3-methoxy-4- (2,2,2-trifluoroethoxy) pyrid-2-yl] methylthio) benzimidazole

Example 16 gave the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ·) δ:.

3.82 (3H, s), 4.31 (2H, q, J = 8Hz), 4.88 (2H, s),

6.70 (1H, d, J = 6Hz), 7.20-7.40 (2H, m), 7.49-7.73 (2H, m), 8.14 (1H, d, J = 6 Hz).

-917

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150 mg / capsule

Example 19

2 - (β-Methoxy-4- (2,2,3,3,3-pentafluoropropoxy)

Preparation of Pi - ₂ - yl - Methylsulphinobenzimidazole 1 / 4H ₂ O

Starting from {[3-methoxy-4- (2,2,3,3,3-pentafluoropropoxy) pyrid-2-yl] methylthio) benzimidazole, the title compound was obtained according to the procedure of Example 16, as a white powder, m.p. 59-65 ° C.

NMR (CDQ ₃₎ Ö:

3.79 (3H, s), 4.37 (2H, t, J-12Hz), 4.83 (2H, s-sr), 6.69 (111, d, J-5.5Hz), 7.27 (211, m), 7.57 (2H, m), 8.10 (1H, d, J-5.5 Hz).

Example 20

Preparation of 2 - (/ - Methoxy-4- (2,2,3,3,3-pentafluoropropoxy) pyrid-2-yl) methyl-stdfinyl] -5- (trifluoromethyl) benzimidazole

Starting from {[3-methoxy-4- (2,2,3,3,3-pentafluoropropoxy) pyrid-2-yl) methylthio) -5- (trifluoromethyl) benzimidazole; The title compound of Example 1 was used to obtain the title compound as a light tan powder, m.p. 52-56 ° C.

NMR (cd0 ₃₎ δ:

3.83 (3H, s), 4.39 (2H, t, J = 12Hz), 4.79 (1H, d, J = 14Hz), 4.87 (1H, d, J = 14Hz) , 6.74 (1H, d,

1.5-5 Hz), 7.4-8.1 (3H, m), 8.13 (1H, d, J-5.5 Hz).

Example 21

Tablet Preparation (1) Prepared according to Example 6

compound 50 mg (2) corn starch 20 mg (3) lactose 65.2 mg (4) microcrystalline cellulose 60 mg (5) Pure anhydrous silica 1.8 mg (6) magnesium stearate 3.0 mg 200 mg / tablet

Components (1), (2) and (3) are mixed together, half of components (4), (5) and (6) are mixed. The mixture is dried on a granulator! (Roller Compacter, Freund Industrial, Co., Ltd., Japan) is pressed and molded. The resulting cylindrical granulate is crushed in a mortar, sieved through a 1.41 mm mesh sieve, the other half of components (4), (5) and (6) is added to the resulting granulate and mixed. The mixture is then compressed into a 200 mg tablet on a rotary tabletting machine (Kikusui Seisakusho Ltd., Japan).

Example 22

Preparation of the capsule (1) 9. Prepared Example 30 30 mg (2) Corn Starch 40 mg (3) Lactose 74 mg (4) Hydroxypropyl Cellulose 6 mg (5) Water (0.1 mL)

Components (1), (2), (3) and (4) are mixed together. Water was added to the resulting mixture. The mixture was kneaded and dried at 40 ° C under vacuum for 16 hours. The dry mass is chopped in a mortar and sieved through a 1.41 mm mesh sieve. The resulting granulate is filled into gelatin capsules (# 3).

Example 23

Preparation of granules (1) Compound prepared according to Example 18 30 mg (2) Corn starch 80 mg (3) Microcrystalline cellulose 20 mg (4) Carboxymethylcellulose calcium salt 10 mg (5) Hydroxypropyl cellulose 10 mg (6) Pluronic F-68 (Asahi Denka Kogyo, Japan) 4 mg (7) lactose 46 mg

The above components (1) to (7) are mixed. Water was added to the resulting mixture. The wet mass is extruded on an extruder (Kikusui Seisakusho Ltd., Japan, sieve diameter 1.0 mm). The granules are spherical, appropriately sized (Marumerizer, Fuji Paudal Ltd., Japan), dried at 40 ° C under vacuum for 16 hours, and finally sieved to give 0.35-1.41 mm diameter granules.

Claims (3)

Claims A process for the preparation of a pyridine derivative of the Formula I in the Formula I R * is hydrogen, fluoroatoin, ethoxy or trifluoromethyl; R ² is C 1-6 alkyl, R ³ is a C 1 -C 6 alkyl group optionally substituted with 2 to 8 fluorine atoms, and n is 0 or 1, characterized in that a compound of formula II is a compound of formula III in which: -1019 196,997 R ^l, R ² and R ³ have the meanings as defined above, and X ¹ mercapto group and X ² a leaving group - was reacted, and the product obtained - wherein n is 0 - optionally oxidized to a compound wherein n is the first 2. A process according to claim 1 wherein the starting compound is a compound of formula III wherein X ² is halogen. 3. A process for the preparation of a pharmaceutical composition comprising the steps of: R ¹ , R ² , R ³ and n are as defined in claim 1, when mixed with excipients and / or other excipients commonly used in pharmaceutical preparation to form a pharmaceutical composition.