Derivatives of 5-pyrrolyl-2-pyridylmethylamine and the retrieval method (variants)

 

(57) Abstract:

Usage: as an anti-ulcer drug. 2-{[(4-methoxy-3-methyl)-2-pyridinyl] methylthio} -5-(1H-pyrrol-1-yl)-1H-benzimidazole, yield 85%, so pl. 191 - 193oC; sodium salt of 2-{[(4-methoxy-3-methyl)-2-pyridinyl] methylsulfinyl}-5-(1H-pyrrol-1-yl)-1H-benzimidazole, yield 85%, so pl. 230 - 232oC. 10 C.p. f-crystals, 8 PL.

The invention relates to new derivatives of 5-pyrrolyl-2-pyridylmethylamine. More Concerto, the present invention relates to new derivatives of 5-pyrrolyl - 2-pyridylmethylamine represented by the following General formula:

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and their salts, in which: X represents S, SO or SO2,

R1and R2independently from each other represent hydrogen or C1-C8-alkyl,

R3represents hydrogen, C1-C8-alkyl, -or SIG6,

where: R6represents C1-C4-alkyl, C2-C5-foralkyl;

R4and R5independently from each other represent hydrogen or C1-C5-alkyl.

The present invention also relates to a method for obtaining compounds of formula (I) defined above, and to the use of compounds of the formula ludka and duodenal ulcers are gastro-intestinal disease, due to various factors, for example, mental stress, food habits, consumption of irritating food, etc. are the Direct cause of peptic ulcers is the risk for gastric membranes due to excessive secretion of gastric acid. Therefore, therapeutic agents that are commonly used to treat ulcers, include, for example, antacid to neutralize stomach acid, antipathies means, means for protecting the gastric mucous membrane, protivoallergicheskoe means for inhibiting gastric secretion, parasympatholytics funds antagonists H2-receptor, etc., At the present time, since it was found that antacids and antiulcer means acting on the Central nervous system, provide only unsatisfactory therapeutic effect and can cause unwanted actions when they are accepted for a long time, the antagonists H2-receptor as a means to treat ulcers of the stomach and duodenum increased.

In addition, recently developed and demonstrated as an effective antiulcer tools 5-methoxy-2-[(4-is fully superior action compared with the traditional antagonists H2-receptor, for example, cimetidine, famotidine, ranitidine, etc., See: description of the U.S. patent N 4255431, 4337257, 4508905, 4758579, the United Kingdom patent N 2134523, European patent N 0005129 and 0268956. Therefore, Omeprazole is widely used in various kinds of medicines from the point of view of the mechanism of action, which is opposite to the conventional antagonists H2receptors Omeprazole blocks the proton pumping H+, K+-ATP-ases present in a good shell for the inhibition of gastric secretion. In addition, omeprazole has also the advantage consisting in a more prolonged effect compared to conventional antiulcer agents.

To create a new antiulcer means the present inventors worked for a long period of time. So there was synthesized a new compound, having the General formula (1), which is defined above, and then found that the compound of formula (1) has excellent antiulcer effects in comparison with omeprazole.

The purpose of the present invention to provide new derivatives of 5 - pyrrolyl - 2 - pyridylmethylamine with following the tion.

Preferred compounds of formula (1) in accordance with the present invention include those in which:

X represents S, SO or SO2;

R1and R2independently of one another represent hydrogen or methyl;

R3represents hydrogen, methyl, methoxy or ethoxy group, 2,2,2-triptoreline or 3,3,3,2,2-pentafluoropropane;

R4hydrogen or methyl;

R5hydrogen, methyl or ethyl.

C2-C5-foralkyl may include 2,2,2-triptorelin, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1-(trifluoromethyl)-2,2,2-triptorelin, 2,2,3,3,4,4,4-heptafluorobutyl, 2,2,3,3,4,4,5,5-octafluoropentyl etc.

More preferred compounds of formula (I) in accordance with the present invention include, for example, such that:

X is SO,

R1and R2represent hydrogen,

R3represents methoxy or ethoxy,

R4and R5independently represent hydrogen, methyl or ethyl.

Compounds of the present invention of formula (I):

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in which X, R1-R5have the meanings indicated above, and their salts can be obtained by the reaction of compounds of General formula (II):

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in which R1and R2opredelen R5defined as they described previously;

Y represents halogen, etherified hydroxy or acyloxy group

in an organic solvent in the presence of a base, or by reaction of compounds of General formula (IV):

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in which R1and R2defined as they described previously, t is 1 or 2, M represents an alkali metal, with a compound of General formula (V):

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in which R3, R4and R5defined as they described previously, or by the reaction of compounds of General formula (VI):

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in which R1and R2defined as previously described, with a compound of General formula (VII):

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in which R3, R4and R5defined as they described previously, or by the reaction of compounds of General formula (VIII):

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in which R1and R2defined as they described previously, with a compound of General formula (IX):

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in which R3, R4and R5defined as they described previously, in a polar solvent in the presence of sulfuric acid.

Obtaining compounds of formula (I) by reaction of compounds of formula (II) with the compound of the formula (III) in an organic solvent in the presence of a base shown in the following reaction shamley as in the compound of formula (1), above, and Y represents halogen, etherified hydroxy, acyloxy group.

In the reaction solvent used may include conventional organic solvent, for example, low alkanol, such as methanol, ethanol etc., acetone, simple ether, tetrahydrofuran, methylene chloride, acetonitrile, dimethylsulfoxide or dimethylformamide, to which may not necessarily be added to the water. The reaction temperature is usually in the range of 0 - 150oC, preferably in the range from 50 to 100oC.

As grounds for this reaction can be used hydroxides, carbonates or hydrides of alkali metal or tertiary amines, examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, calcium carbonate, sodium methoxide, sodium bicarbonate, potassium hydride, sodium hydride, pyridine, triethylamine, ethyldiethanolamine or etc.

The compound of formula (I) in accordance with the present invention can be obtained by oxidation of compounds of formula (Ia) corresponding quantity of oxidant, as shown in the above reaction scheme (A). In this case, the obtained compound of formula (I) may be either sulfoxide (-SO-) connection of the x2">

The oxidant used for this purpose, includes: m-chloroperoxybenzoic acid, hydrogen peroxide, peroxyoctanoic acid, cryptocercidae acid, 3,5-dinitropropanol acid, proximality acid, Penta-vanadium oxide, nitric acid, ozone, dinitrogen tetroxide, iodosobenzene, N-glowczewski, 1-chlorobenzotriazole, tributylphosphate, diazabicyclo[2,2,2] -octane, metaperiodate sodium, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine, sulfurylchloride etc.

The reaction may preferably takes place in an inert solvent, e.g. an aromatic hydrocarbon such as benzene or toluene; chlorinated hydrocarbons, such as chloroform or methylene chloride; or acetone.

In this case, the reaction temperature is usually in the range from -70oC to the boiling point of the used solvent, preferably in the range from -50oC to -20oC.

Obtaining compounds of formula (I) in accordance with the present invention by the interaction of the compounds of formula (IV) with the compound of the formula (V) shown in the following reaction scheme (B):

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In the above reaction scheme, X, R

This reaction can preferably be implemented in a conventional inert solvent mentioned above.

In addition, the reaction is usually carried out at a temperature of 0 120oC, preferably at the boiling temperature of solvent used here. The compound of formula (V), which is used as starting material in the method in accordance with the reaction scheme (I) to obtain the compounds of formula (I) of the present invention can be obtained by reacting the intermediate compounds of the pyridine-N-oxide with conventional gloriouse agent, for example, phosphorus oxychloride, pentachloride phosphorus, etc.

The alternate connection of the formula (I) in accordance with the present invention can be also obtained by reacting the compounds of formula (VI) with the compound of the formula (VII), as shown in the following reaction scheme (C):

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In the above reaction scheme, X, R1, R2, R3, R4and R5defined as they are defined in the compound of formula (I) above.

In this reaction, the reaction conditions are essentially identical reaction conditions reaction in sooome this, the compound of formula (Ia) obtained in the above manner, can be oxidized under the same conditions as in the reaction scheme (A) above, to obtain compounds of formula (I) in accordance with the present invention.

In addition, the compound of formula (I) in accordance with the present invention can be obtained by reacting the compounds of formula (VIII) with the compound of the formula (IX) in a polar solvent in the presence of a strong acid, as shown in the following reaction scheme (D):

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In the above reaction scheme, X, R1, R2, R3, R4and R5defined as they are defined in the compound of formula (I) above.

In this reaction, the polar solvent may also contain water.

The reaction in accordance with reaction scheme (D) can be carried out at the boiling temperature of solvent used here.

The compound of formula (I), which can be obtained here in accordance with the reaction schemes (C) and (D) may be oxidized in accordance with the same method as in reaction scheme (A) to obtain the compounds of formula (I) of the present invention.

Echoee known and can be obtained in accordance with known methods.

The compound of formula (I) obtained by the above methods in accordance with the present invention can be separated and cleaned in accordance with generally accepted working methods or you can turn it into a pharmaceutically acceptable salt form in accordance with conventional ways.

The compound of formula (I) in accordance with the present invention can be used for the prevention and treatment of gastric ulcers and duodenal ulcers. The compound of formula (I) has a chemical structure similar to the chemical structure of known manufacturing means of omeprazole, and, therefore, shows the mechanism of pharmacological action of omeprazole. In addition, as demonstrated by in vitro tests, the pharmacological efficacy of the compounds of formula (I) in accordance with the present invention is about 7 times higher pharmacological efficacy of omeprazole. In addition, in vivo tests on animals have also shown that the compound of formula (1) has a strong pharmacological effect, 2.5-3 times the pharmacological effects of omeprazole. In addition, in accordance with pharmacological toxicity tests, it was found that soedinenii the Central nervous system.

Therefore, new compounds of formula (I) in accordance with the present invention are excellent antiulcer agent, which has an excellent pharmacological action significantly better than the known pharmacological action anti-ulcer remedies, and also prolonged period.

The compound of formula (I) in accordance with the present invention may be injected or oral or parenteral. The preferred method of administration is oral administration.

The compound of formula (I) in accordance with the present invention can be entered by itself or in the form of its pharmaceutically acceptable salts. Suitable examples of such salts of compounds of formula (I) include acid salt of accession and the salt of an alkali metal. As salts of the alkali metal can be mentioned sodium salt, magnesium salt, calcium salt or alkylamine salt. As the acid, which can form an acid salt of joining the compounds of formula (1), may be mentioned the following compounds:

sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, Perlina acid, formic acid, acetic acid, propiona acid, ascorbic acid, maleic acid, ximalayasha acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-oxybenzone acid, salicylic acid, p-aminosalicylic acid, methanesulfonate acid, econsultancy acid, oxetanemethanol acid, atlantogenata acid, toluensulfonate acid, neftenalivnoy acid, sulfanilic acid, camphorsulfonic acid, Hinn acid, o-methyleneindoline acid, proton benzolsulfonat acid, methionine, tryptophan, lysine, arginine, picric acid or d-o-trillina acid.

The compound of formula (I) in accordance with the present invention can be applied in the appropriate pharmaceutically acceptable composition, which is obtained by using pharmaceutically acceptable additives and corresponding media using methods well known to experts in the related field. Although this composition includes various pharmaceutically acceptable formulation, e.g., capsules, tablets, coated in sugar, syrups or injections are preferred for administration are capsules, coated enteric monasteries, i.e. pharmaceutically acceptable organic or inorganic carriers suitable for parenteral, small bowel (e.g. oral) administration, which do not destroy in the interaction of active compounds. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, gum Arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, scented oil, monoglycerides and diglycerides of fatty acids, fatty acid esters and pentaerythrol, hydroxymethylcellulose, polyvinylpyrrolidone, etc.

The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary substances such as preservatives, stabilizers, emulsifiers, salts for influencing osmotic pressure, buffers, dyes, chemicals, improves taste and/or aroma substances, etc. which do not destroy in the interaction of the active substance. They can also be combined with other active agents, for example, vitamins.

For parenteral administration, in particular p is e suspension emulsions or implants, including suppositories. Appropriate standardized doses are capsules.

For enteral application, particularly suitable are tablets, pills, liquids, drops or capsules. When used sweetened filler, you can use the syrup, elixir, or etc.

The dose of the compounds in accordance with this invention is usually 1 to 1000 mg/day, preferably 3 to 100 mg/day when administered to adult patients for the prevention and treatment of gastric ulcers and duodenal ulcers. As specialists in this area, the dose can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the discussed compounds and known means, for example, by an appropriate conventional pharmacological Protocol.

The present invention will be more specifically illustrated by the following examples. However, it is clear that the present invention is not limited to these examples.

Example 1. Getting 2-[[(4-methoxy-3-methyl)-2-pyridinyl]methylthio]-5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 1). 2 g (9.3 mmole) of 5-(1H-pyrrol-1-yl)-2-mercaptobenzoic the obtained solution was added to 1.9 g (1 EQ. weight) 4-methoxy-3-methyl-2-chloro-methylprednisolone and the mixture is then left to interact for 3 hours at a temperature of 50 60oC, and then filtered to remove precipitated inorganic material. Under reduced pressure the solvent was removed and simple ether to obtain 2.7 g (85%) of the desired compound crystallized residue.

Melting point: 191 193oC.

1H-NMR [DMSO-d6] 2,3 (s, 3H), at 3.9 (s, 3H), and 4.8 (s, 2H), 6,3 (t, 2H), 7,0 (d, 1H), and 7.4 (t, 2H), and 7.6 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), and 8.3 (d, 1H).

Example 2. Getting 2-[[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl] -5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 2). 6.7 g (19 mmol) of the compound obtained in example 1 was dissolved in 150 ml of chloroform and then cooled to a temperature of -40oC. thereto dropwise slowly added m-chloroperoxybenzoic acid (1 EQ. weight), dissolved in chloroform, and the mixture is then mixed for 20 min at -40oC. the Reaction mixture was diluted with chloroform and washed with sodium bicarbonate and saturated saline solution. A solution of chloroform was dried with sodium sulfate. After removal of the solvent under reduced pressure, the obtained crude product was dissolved in ethyl acetate and then was led CLASS="ptx2">

1H-NMR (d [DMSO-d6] 2,3 (s, 3H), and 3.8 (s, 3H), 4,7-4,9 (s, 2H), 6,3 (t, 2H), 7,0 (d, 1H), and 7.4 (t, 2H), and 7.6 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), and 8.3 (d, 1H).

Compound 3 12 listed in the following tables 1 and 2, can be obtained in accordance with the same methodology described in example 2.

Example 3. Getting 2-[[(4-(2,2,2-triptoreline)-3-methyl)-2-pyridinyl] -5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 13). 2 g (9.3 mmole) of 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole dissolved in a solution of 0.74 g (2 EQ. weight) of sodium hydroxide in 100 ml of methanol. To the resulting solution was added 2.6 g (1 EQ. weight) of 4-(2,2,2-triptoreline)-3-methyl-2-chloromethylpyridine and the mixture is then left to interact for 3 hours at a temperature of 50 60oC. After removal of the solvent under reduced pressure, the obtained product was dissolved in 150 ml of chloroform and then cooled to -40oC. To this reaction solution was slowly dropwise added m-chloroperoxybenzoic acid (1 EQ. weight), dissolved in chloroform, and the mixture is then mixed for 20 min at -40oC, diluted with chloroform and washed with sodium bicarbonate and saturated saline solution. A solution of chloroform was dried with sodium sulfate. After removal of the solvent under reduced TableName 3.6 g (8,8%) of the desired compound.

Melting point: 156 157oC.

1H-NMR (d [DMSO-d6] 2,2 (s, 3H), 4,3 (q, 2H), 4,6-4,9 (dd, 2H), 6,3 (t, 2H), and 6.6 (d, 1H), and 7.1 (t, 2H), and 7.3 (d, 1H), and 7.4 (s, 1H), and 7.7 (d, 1H), and 8.3 (d, 1H).

Example 4. Getting 2-[[(4-(2,2,3,3,3-pentafluoropropane)-3-methyl)-2-pyridinyl] methylsulfinyl] -5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 14). 2 g (9.3 mmole) of 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole dissolved in a solution of 0.74 g (2 EQ. weight) of sodium hydroxide in 100 ml of methanol. To the resulting solution was added 3 g (1 EQ. weight) of 4-(2,2,3,3,3-pentafluoropropane)-3-methyl-2-chloromethylpyridine, and the mixture is then left to interact for 3 hours at a temperature of 50 60oC. After removal of the solvent under reduced pressure, the obtained product was dissolved in 150 ml of chloroform and then cooled to -40oC. To this reaction solution was slowly dropwise added m-chloroperoxybenzoic acid (1 EQ. weight), dissolved in chloroform, and the mixture is then mixed for 20 min at -40oC, diluted with chloroform and washed with sodium bicarbonate and saturated saline solution. A solution of chloroform was dried with sodium sulfate. After removal of the solvent under reduced pressure, the obtained crude product was dissolved in ethyl acetate and then was led from the eff is UP>1H-NMR (d [DMSO-d6] 2,2 (s, 3H), 4,7-4,9 (dd, 2H), 5,0 (t, 2H), 6,3 (t, 2H), and 7.1 (d, 1H), and 7.4 (t, 2H), and 7.6 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), and 8.3 (d, 1H).

Example 5. Getting 2-[[(4-methoxy-3-methyl)-2-pyridinyl]-methylsulfinyl] -5-(1H-2,5-dimethylpyrrole-1-yl)-1H-benzimidazole (Compound 15). 2 g (8.2 mmole) 5-(2,5-dimethylpyrrole-1-yl)-2-mercaptobenzimidazole dissolved in a solution of 0.66 g (2 EQ. weight) of sodium hydroxide in 100 ml of methanol. To the resulting solution was added 1.7 g (1 EQ. weight) 4-methoxy-3-methyl-2-chloromethylpyridine, and the mixture is then left to interact for 3 hours at a temperature of 50 - 60oC. After removal of the solvent under reduced pressure, the obtained product was dissolved in 150 ml of chloroform and then cooled to -40oC. Into this reaction solution was slowly dropwise added m-chloroperoxybenzoic acid (1 EQ. weight), dissolved in chloroform, and the mixture is then mixed for 20 min at -40oC. After removal of the solvent under reduced pressure the residue was subjected to silicagel chromatography using as an eluent of ethyl acetate, was obtained 1.4 g (10%) of the desired compound.

Melting point: 94 96oC.

1H-NMR (d [DMSO-d6] of 1.9 (s, 6H), 2,1 (s, 3H), and 3.8 (s, 3H), 4,5-4,8 (dd, 2H), and 5.8 (d, 2H), 4,9 (d, 1H), 7.2 sulfinyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole. 1 g (2.7 mmole) of the compound obtained in example 2 was dissolved in 15 ml of methylene chloride and then thereto was added 0.1 g (2.7 mmole) of sodium hydroxide dissolved in 10 ml of water. The mixture is vigorously mixed. The aqueous layer was separated, washed several times with methylene chloride and then was liofilizovane to obtain 0.9 g (85%) of the desired compound.

Melting point: 230 232oC.

1H-NMR (d [DMSO-d6] 2,0 (s, 3H), at 3.9 (s, 3H), 4,5-4,9 (dd, 2H), 6,4 (t, 2H), 6,9 (d, 1H), and 7.4 (t, 2H), and 7.5 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), and 8.2 (d, 1H).

Example 7. Getting 2-[[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl] -5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 2). 2 g to (7.9 mmole) of 2-(latinatranny)-5-(1H-pyrrol-1-yl) benzimidazole was dissolved in 100 ml of benzene and then added to 1.25 g (1 EQ. weight) of 2-chloro-(4-methoxy-3-methyl)pyridine. The reaction mixture was heated in a flask under reflux for 2 h and filtered to remove lithium chloride. After removal of the solvent under reduced pressure, the obtained crude product was dissolved in ethyl acetate and then was led from simple ether to obtain 2.1 g (84%) of the desired compound.

Melting point: 102 123oC.

1H-NMR (d [DMSO-d6] 2,3 (s, 3H), and 3.8 (s, 3H), 4,7-4,9 (dd, 2H), 6,3 (t, 2H), 7,0 (d]-5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 1). 2 g (9.2 mmole) of 4-methoxy-3-methyl-2-dimethylpyridine dissolved in a solution of 0.4 g (1 EQ. weight) of sodium hydroxide in 100 ml of ethanol. To the resulting solution was added 2 g (1 EQ. weight) of 2-chloro-5-(1H-pyrrol-1-yl)benzimidazole, and then the reaction mixture was heated in a flask under reflux for 2 hours After removal of the solvent under reduced pressure the product was led from ether to obtain 2.7 g (85%) of the desired compound.

Melting point: 191 193oC.

1H-NMR (d [DMSO-d6] 2,3 (s, 3H), at 3.9 (s, 3H), 4,8 (dd, 2H), 6,3 (t, 2H), 7,0 (d, 1H), and 7.4 (t, 2H), and 7.6 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), and 8.3 (d, 1H).

Example 9. Getting 2-[[(4-methoxy-3-methyl)-2-pyridinyl]methylthio]-5-(1H-pyrrol-1-yl)-1H-benzimidazole (Compound 1). 17.3 g (0.1 mmole) 2-[[(4-methoxy-3-methyl)-2-pyridinyl] methylthio] formic acid and 21.3 g (1 EQ. weight) o-[5-(1H-pyrrol-1-yl)]phenylenediamine was heated in a flask under reflux in 100 ml of 4N HCl for 40 min, the Reaction mixture was cooled and then neutralized by ammonia water. The solution was treated with activated charcoal and then was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was led from simple ether to obtain 8.8 g (25%) of the desired compound.

The fact is t, 2H), and 7.6 (d, 1H), and 7.7 (s, 1H), and 7.8 (d, 1H), and 8.3 (d, 1H).

Physico-chemical properties of the compounds obtained under essentially the same methodology as the compounds in the examples above, are described in the table. 1 and 2.

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The antiulcer activity of the compounds of formula (1) defined above, in accordance with the present invention was illustrated through various experiments, including inhibition of enzyme activity, effect on the inhibition of the secretion of gastric acid and acidity, ED50and so on, test Methods and results follow.

Test 1: Inhibition of enzyme activity. Inhibition of H+/K+-ATP-ases compounds of formula (1) according to the present invention was demonstrated by in vitro tests.

In this test, the control connection is used omeprazole [5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole]

The rabbit was removed gastric mucosa and then centrifuged 77,000 g, using the ultracentrifuge for separating microsome fraction, which was used as the source of enzyme H+/K+-ATP-ASE for this test. In teenies) 60 g H+/K+-ATP-ases and then to it was added 4 mm ATP as a nutrient medium and 4 mm Mg++, 20 mm K+as coenzymes. Then using a spectrophotometer at 660 nm was determined the number thus obtained inorganic phosphorus and turned it into a protein. The concentration of a compound that inhibits enzyme activity by 50% i.e., IC50was calculated from the values of percent concentration for inhibition of enzyme activity, which are received from 3 to 5 test tubes containing various concentrations of the test compounds according to the method of Litchfield-Wilcoxon (Litchfield-Wilcoxon). The results described in table. 3.

Test 2. Effect on inhibition of gastric secretion and acidity (in vivo). As a second test in vivo, were testing the inhibition of gastric secretion and acidity in rats using the method Shay (Neck), and the results were compared with normal control group and the group of omeprazole. Specific test methods are as follows:

Male SD rats (20020 g) fasted for 24 h, except that they were given water, then they were anestesiologi simple ether. Cut open the abdominal cavity and then the ligated pylorus is preserved (narrowing part of the stomach is datepart intestine. After the solution has soaked up into the abdominal cavity of rats was kept for 5 h and then slew simple ether. Rats have removed the stomach and collected gastric juice. Gastric juice was centrifuged at HD for 10 min at 4oC to remove the sediment. The amount of gastric juice and the acidity was determined using a 0.02 N NaOH to create a pH of 7.0 at the endpoint of the analysis and then calculated the total amount of acid. The results described in table. 4 and 5.

As you can see from the above test results, among the compounds of formula (1) in accordance with the present invention compounds 2, 4, 5, 8 10, 12, 13, 15 18 show the activity of the enzyme, similar or superior to the activity of known anti-ulcer remedies omeprazole, and compounds 2, 5, 8, 9, 16 and 17 show a good effect on the inhibition of gastric secretion and decrease acidity. In particular, it is found that compounds 2 and 5 among the compounds of formula (1) in accordance with the present invention show a strong inhibition of gastric secretion and the effect of reducing the high acidity even at a lower dose than the dose known antiulcer tools, and ED50connection 2 for impact is in the surrounding area it was 1.6 mg/kg

Test 3. Test acute toxicity. In the cage for breeding animals within one week of pre-weaned at five weeks mice (males and females) and then randomly selected and used in this test, the animals gained weight. The number of the tested compounds, the input of experimental animals established based on the maximum dose of 4000 mg/kg in normal ratio equal to 1.5.

Compound in powder form suspended in 0.5% methylcellulose and introduced orally when using a 1 ml syringe. Other particular conditions the introduction is described in the following table. 6.

In the above test, the control group received only 0.5% methylcellulose.

Clinical symptoms and death in experimental animals caused by the test compounds was observed immediately after administration of the tested compounds and during the entire test period, with changes in body mass were recorded three times: i.e., the day of the introduction, a week after the introduction and the last day of the test.

After completion of testing of all experimental animals slew simple ether and observed changes in the internal and external organs of powiatu this test, shown above, it is possible to establish that the connector 2 in accordance with the present invention is a very safe compound that has a value of LD50equal to 4000 mg/kg or more, it does not affect the normal changes in the body weight of experimental animals and, moreover, does not affect the internal and external organs of experimental animals.

1. Derivatives of 5-pyrrolyl-2-pyridylmethylamine General formula I

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where X is S, SO or SO2;

R1and R2independently from each other hydrogen or C1- C8-alkyl;

R3hydrogen, C1WITH8-alkyl, -OR6where R6WITH1WITH4-alkyl, C2WITH5-foralkyl;

R4and R5independently from each other hydrogen or C1- C5-alkyl,

or their salts.

2. The compound of formula I under item 1, where X is S, SO or SO2, R1and R2independently from each other hydrogen or C1- C8-alkyl, R3hydrogen, C1WITH8-alkyl, -OR6where R6WITH1WITH4-alkyl, C3- C8-foralkyl, R4and R5independently from each other hydrogen or C1WITH5-alkyl.

3. The compound of formula I on p. 2, where X C, SO or SO4hydrogen or methyl and R5hydrogen, methyl or ethyl.

4. The compound of formula I under item 1, where X SO that R1and R2both hydrogen, R3methoxy or ethoxy and R4and R5independently from each other hydrogen, methyl or ethyl.

5. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula II

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where R1and R2are specified in paragraph 1 values

subjected to reaction with the compound of the formula III

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where R3, R4and R5are specified in paragraph 1 values;

Y is halogen, etherified hydroxy or alloctype,

in an organic solvent in the presence of a base.

6. The method of obtaining the compounds of formula I on p. 5, characterized in that the compound of formula IV

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where R1and R2are specified in paragraph 1 values;

t is 1 or 2;

M is alkali metal,

subjected to reaction with the compound of the formula V

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where R3, R4and R5are specified in paragraph 1.

7. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula VI

< / BR>
where R1and R2are specified in paragraph 1 values

8. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula VIII

< / BR>
where R1and R2are specified in paragraph 1 values

subjected to reaction with the compound of the formula IX

< / BR>
where R3, R4and R5are specified in paragraph 1 values

in polar solvent in the presence of a strong acid.

9. The method according to p. 5, characterized in that the interaction of the compounds of formula II with the compound of the formula III is carried out at a temperature of 0 to 150oC.

10. The method according to p. 5, characterized in that the resulting product is further oxidized.

11. The method according to p. 10, characterized in that the oxidation reaction is carried out at a temperature from -70oC to the boiling point of the used solvent.

12. The method according to p. 6, characterized in that the interaction of the compounds of formula IV with the compound of the formula V is carried out at a temperature of 0 120oC.

 

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< / BR>
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< / BR>
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< / BR>
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10 cl, 3 tbl

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