Imidazopyridine, the method of production thereof, pharmaceutical composition and a method of obtaining a pharmaceutical composition

 

(57) Abstract:

Imidazopyridine formula I, where R0is methyl or hydroxymethyl, R1, R2- C1- C4-alkyl; R3- C1- C4-alkoxy; And a is oxygen or NH, and their salts can inhibit gastric secretion in the absence of significant side effects. 4 C. and 5 C.p. f-crystals, 1 PL.

The present invention relates to new imidazopyridine, which are intended for use in the pharmaceutical industry as active compounds in the manufacture of medicinal preparations.

Known imidazo[1,2-a] pyridine with the aryl substituent in position 8 represents preferably phenyl, thienyl or peredelnyj radicals or phenyl radical, which is substituted by an atom of chlorine, fluorine, methyl, tert-butilkoi, triptoreline groups, methoxy or cyano groups, which are described in European patent application EP-A-0033094. The aforementioned aryl radicals are phenyl, o - or p-florfenicol, p-chloraniline or 2,4,6-trimethylphenyl groups, of which the most preferred are phenyl, o - or p-triptoreline and 2,4,6-tryptophanyl is a saturated aliphatic radical, in particular alkynylaryl radical. In European patent application EP-A-O 226890 describes imidazo[1,2-a]pyridine, substituted in position 8 alkenylphenol, alkyl or cycloalkylation group.

The present invention is the creation of new imidazopyridine, possessing valuable pharmacological properties, namely the ability to inhibit gastric secretion, high selectivity, long action, absence of significant side effects and a wide interval of therapeutic action.

This object is achieved by the new imidazopyridine General formula I with substituents in the 3-or 8-position

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where substituent R0represents a methyl or hydroxymethyl, Deputy R1is a 1-4C-alkyl, the substituent R2is a 1-4C-alkyl, the substituent R3is a 1-4C-alkoxygroup and fragment A represents O (oxygen) or H, and their salts.

1-4C-Alkyl represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms. Examples of such radicals are butyl, ISO-butyl, sec-butyl, tert-butyl, propyl, ISO-propyl, ethyl and CCA is above 1-4C-alkyl radicals. Preferred is a methoxy group.

Acceptable salts of the compounds of formula I are preferred, all acid-salt additive. Especially preferred pharmacologically compatible salts of inorganic and organic acids, which are commonly used in pharmacology. Pharmacologically incompatible salts, which can be, for example, the starting products in the process of producing compounds of the present invention on an industrial scale, are converted into pharmacologically compatible salts by methods known from qualified professionals. Acceptable salts are water-soluble and water-insoluble acid additive salts with such acids, such as hydrochloric acid, bromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluensulfonate, methansulfonate acid or 3-hydroxy-2-naphthoic, and chimaeric, depending on whether acid mono - or polonovski and depending on the salt, you want to get.

Examples of preferred compounds are the following compounds:

3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2 - methylimidazo[1,2-a]pyridine;

3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2 - methylimidazo[1,2-a]pyridine;

8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a] pyridine and

8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a] pyridine, as well as their salts.

The above compound was prepared as follows:

a) to obtain compounds of the formula I in which the substituent R0represents hydroxymethylene group, carry out the restoration of compounds of the formula II (see attached page of formulas, where the substituents R1, R2, R3and A take the above values;

or

b) for compounds of formula I in which the substituent R0represents a methyl group, conduct the interaction of compounds of formula III (see attached page of formulas, where the substituents R1and A accept the above-mentioned meanings, with compounds FoA, the Deputy X represents a suitable removable group;

or

to obtain compounds of the formula I in which the substituent R0represents a methyl group, conduct the interaction of compounds of formula V (see attached page of formulas, where the substituents R1, R2and A accept the above-mentioned meanings, with compounds of formula VI (see attached page formula), where the substituent R3adopts the above-mentioned values, and Deputy Y represents a suitable removable group;

and, if necessary, subsequent conversion of the obtained compounds of formula I and their salts,

or, if necessary, subsequent release of compounds I from the resulting salts of the compounds I.

The recovery of the compounds II are conducted by known methods. It is carried out in an inert solvent, for example lower aliphatic alcohols, using, for example, a suitable hydride, for example sodium borohydride, adding water if necessary.

The interaction of compounds III with compounds IV is conducted according to known methods, for example by methods similar to the methods described in European patent applications EP-A-O 033094 or EP-A-O 308917. sulfonyloxy. The reaction is carried out with good results in the presence of a base (for example, an inorganic hydroxide, such as sodium hydroxide, or an inorganic carbonate, for example potassium carbonate, or organic nitrogen bases, such as triethylamine, pyridine, kallidin or 4-dimethylaminopyridine), and the reaction can be facilitated by the addition of catalysts, such as alkali metal iodide or tetrabutylammonium.

The interaction of compounds V and VI compounds are also carried out by known methods, which are usually used for obtaining aromatic urethanes, preferably in the interaction of the compounds V with halogenfree (Y = halogen), for example, chloroformiate, in inert solvents. The reaction was successfully carried out in the presence of the agent linking the acid (proton acceptor). As the proton acceptor may be used, for example, carbonates of alkali metals (e.g. potassium carbonate or bicarbonate (e.g. sodium bicarbonate) or tertiary amines (e.g. triethylamine).

Compounds of the present invention is isolated and purified in accordance with techniques which are in themselves known, such as those recristallization of a suitable solvent or purified by one of the conventional methods, for example, column chromatography on a suitable carrier.

Acid additive salts receive by dissolving the free base in an acceptable solvent such as a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a lower aliphatic alcohol (ethanol, isopropanol) ketone (e.g. acetone) or an ether (e.g. tetrahydrofuran or diisopropyl ether), which contains the desired acid, or to which you then add the acid.

The resulting salt allocate by filtration, the resultant deposition rates, deposition with solvent, nerastvorim acid additive salt, or by evaporation of the solvent. The resulting salts with alkalis, for example using an aqueous solution of ammonia can be converted into a free base, which, in turn, can be converted into an acid additive salt. In accordance with such methodology may become pharmaceutically incompatible salts in a pharmaceutically compatible acid additive salt.

Starting compound II can be obtained by methods which are in themselves known, for example in the interaction of compound VII with compounds VIII (see attached page of formulas), DG is an appropriate leaving group, for example, a halogen atom (preferably chlorine atom or bromine), or by methods analogous to methods described, for example, in European patent applications EP-A-0033094 or EP-A-0308917.

Starting compound III is described in European patent application EP-A-0299470, and the starting compound IV in European patent application EP-A-O 308917.

The following examples serve for a detailed explanation of ways to produce compounds of the present invention. In particular, these examples serve to describe the reaction in accordance with process variants a, b and C, as well as to describe receiving the selected source connections. Similarly, other compounds of formula I, as well as other source connections, which are not included in the examples, can be synthesized by similar methods or by methods known to a skilled in this area specialists using conventional technologies. Abbreviations: h = hours, so pl. is the melting temperature, decomp. - decomposition.

Example 1. 3-Formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino) -2-methylimidazo[1,2-a]pyridine.

A suspension of 400 mg of the industrial 80% sodium hydride in 10 ml of dry tetrahydrofuran at room temperature dobavlenie 50oC is accompanied by the rapid evolution of gas. After the gas evolution, the reaction mixture was cooled to 0oC and added dropwise a solution of 3.9 g of 2-methoxycarbonylamino-6-methylbenzylamine in 40 ml of dry tetrahydrofuran. The mixture is again heated to 50oC and kept at this temperature for 3 h, and then poured into ice water, neutralized with a small amount of diluted hydrochloric acid and extracted four times with ethyl acetate. The combined organic phases are washed with water and dried with sodium sulfate. The solvent is evaporated in vacuum and the resulting dark brown viscous residue chromatographic on silica gel (eluent - ethyl acetate : petroleum ether, 1: 1). After recrystallization from isopropanol obtain 2.5 g of the named compound, so pl. 188-190oC (decomp.).

Example 2. 3-Hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2 - methylimidazo[1,2-a]pyridine.

In 30 ml of methanol at room temperature suspended 2 g of 3-formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo [1,2-a]pyridine and portions add 0.2 g of sodium borohydride, the mixture was stirred at room temperature for 1 h Then evaporated half of the solvent Eoliano acid and extracted four times with ethyl acetate. The combined organic phases are washed with water and dried with sodium sulfate. The solvent is evaporated in vacuum. The obtained yellowish residue over time completely crystallized. After recrystallization from ethyl acetate to obtain 1.3 g of the named compound, so pl. 170-172oC.

Example 3. 3-Formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo [1,2-a]pyridine.

In 50 ml of dry acetonitrile at 50oC dissolved 2.6 g of 3-formyl-8-hydroxy-2-methylimidazo [1,2-a] pyridine with the Department of moisture. After cooling to room temperature, add 2.8 g industrial potassium fluoride (50% wt.) on kieselguhr (e.g., Celite). Then added dropwise a solution of 3.6 g of 2-methoxycarbonylamino-6-methylbenzylamine in 50 ml of acetonitrile and the mixture was incubated at 70oC for 6 hours After cooling to room temperature the mixture was poured into ice water, adjusted pH to 9 with a few drops of 6 n sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases are washed with water and dried with sodium sulfate. After distillation under vacuum of the solvent and stirring in a small amount of cold methanol to obtain 3.2 g of the named compound, so pl. 196-198

According to the method of example 2 from 3 g of 3-formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo [1,2-a]pyridine and 400 mg of sodium borohydride obtain 2.1 g of the named compound, so pl. 185-187oC.

Example 5. 8-(2-Methoxycarbonylamino-6-methylbenzylamino)- 2,3-dimethylimidazo[1,2-a]pyridine.

To a solution of a 4.03 g of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine and 6,41 g 2 methoxycarbonylamino-6-methylbenzylamine in 400 ml of dry acetone is added 4.5 g of sodium iodide and 6,63 g of dry sodium carbonate. The resulting mixture is boiled for 6 hours After cooling to room temperature, add 400 ml of water and the acetone evaporated in vacuo using a water-jet pump. The aqueous residue is then extracted three times with ethyl acetate (200 ml). The combined organic extracts are washed with 300 ml of water, dried with magnesium sulfate and concentrate. The resulting residue is purified by chromatography on silica gel (eluent - toluene : dioxane, 9:1). Fractions with Rf= 0,2, concentrated and then recrystallized from diisopropyl ether. Get 4.71 g (yield 56 %) of these connections, so pl. 136 - 138oC.

a) In the interaction of these compounds are dissolved in acetone, with 12 N. hydrochloric acid is obtained hydrochloride is voennogo in tetrahydrofuran, with methansulfonate get methanesulfonate these compounds, so pl. 181-182oC (decomp.).

C) In the interaction of these compounds are dissolved in acetone, with fumaric acid get profumata these compounds, so pl. 191-192oC (decomp.)

Example 6. 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a]pyridine.

To a suspension of 7.2 g of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine in 130 ml of dry acetonitrile, to which was added 8 g of industrial potassium fluoride (50% wt. ) diatomaceous earth (e.g., CeliteR) dropwise at room temperature, add a solution of 9.5 g of 2-methoxycarbonylamino-6-methylbenzylamine in 150 ml of dry acetonitrile. The mixture was incubated at 70oC for 9 h After cooling to room temperature the mixture was poured into 1 l of ice water and extracted three times with ethyl acetate. The combined organic extracts washed with distilled water and dried with sodium sulfate. After distillation of the organic solvent in vacuo the precipitation is filtered off, washed with a small amount of ethyl acetate and ether and dried. After recrystallization from isopropanol obtain 2.2 g of the named compound, so pl. 176-177oC.

Example 8. 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-2,3 - dimethylimidazo[1,2-a]pyridine.

A named connection receive according to the method described in example 1, using 8-amino-2,C-dimethylimidazo[1,2-a]pyridine (4.8 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (9.2 grams), sodium iodide (5.5 g) and sodium carbonate (8.0 g) in acetone (250 ml). Cleaning chromatographytandem on silica gel (eluent - toluene : dioxane, 20:1) and kristallizatsii-Butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine.

A named connection receive according to the method described in example 7, using 2,3-dimethyl-8-hydroxyamide[1,2-a] pyridine (1.6 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (3,1), sodium iodide (1.8 g) and sodium carbonate (2.7 g) in acetone (350 ml). Cleaning chromatographytandem on silica gel (eluent - toluene : dioxane, 5:1) and crystallization from cyclohexane gives 3.0 g (78%) of these connections, so pl. 128-131oC.

Example 10. 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino) -3-formyl-2-methylimidazo[1,2-a]pyridine.

A named connection receive according to the method described in example 7, using 8-amino-3-formyl-2-methylimidazo[1,2-a] pyridine (4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (7.0 g), sodium iodide (4.1 g) and sodium carbonate (6,1 g) in acetone (250 ml). Cleaning chromatographytandem on silica gel (eluent-toluene : dioxane, 9:1) and crystallization from diisopropyl ether yields of 7.3 g (81 %) of these connections, so pl. 210-212oC.

Example 11. 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2 - methylimidazo[1,2-a]pyridine.

a) In a mixture of Vilsmeier containing 20 ml of dimethylformamide and 2.3 ml of phosphorylchloride, at 60oC for 2.5 h mix 4.77 g of 8-benzyloxy-2-m which are square-8-benzyloxy-2-methylimidazo[1,2-a] pyridine-3 - carboxaldehyde, so pl. 105-106oC (from isopropyl ether), which are dibenzylamino according to the method described by Kaminski et al., J. Med. Chem., 28, 876 (1985), method H, receive 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine, T. pl. 251-252oC.

b) a Named connection receive according to the method described in example 7, using 3-formyl-8-hydroxy-2-methylimidazo[1,2-a] pyridine (2.4 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (4,2 g), sodium iodide (2.5 g) and sodium carbonate (3.7 g) in acetone (400 ml). Crystallization from a mixture of diisopropyl ether-ethyl acetate to give 4.4 g (80%) of the named compound, so pl. 189-191oC

Example 12. 8-(2-Amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine.

Method A:

A solution of 8-(6-methyl-2-nitrobenzylamine)-2,3-dimethylimidazo [1,2-a]pyridine (61 g) in methanol (5.5 l) is treated with a catalyst, 15 g of palladium on coal (5%), and hydronaut at atmospheric pressure at room temperature for 1.5 hours the Catalyst is filtered off and evaporated the solvent. The residue is dissolved in boiling ethyl acetate (2.7 l). After cooling to room temperature emit 51 g (82%) of these connections, so pl. 206-208oC.

Method B:

To the mixture triperoxonane acid (30 ml) and anisole (3 m is pyridine (6.7 g). After stirring for 30 min at room temperature the resulting solution was added to water with ice (100 ml) and then treated with 6 N. solution of sodium hydroxide (75 ml). The precipitate is filtered off and purified by chromatography on silica gel (eluent - toluene : dioxane, 8: 1). After crystallization from ethyl acetate to obtain 3.1 g (62 %) of these connections, so pl. 206-208oC.

Example 13. 8-(2-Amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a] pyridine.

According to the method described in example 12 (method B), using 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo [1,2-a] pyridine (5.0 g) and triperoxonane acid (40 ml) to obtain 3.57 g (96%) of these connections, so pl. 144-150oC (decomp.).

Example 14. 8-(2-Ethoxycarbonyl-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a]pyridine.

To a solution of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine (0,98 g) in methylene chloride (50 ml) add ethylchloride (0.65 g) dissolved in methylene chloride (10 ml) and stirred for 18 h at room temperature. Then the resulting solution is extracted with saturated aqueous sodium bicarbonate (40 ml), washed with water (40 ml) and evaporated. The residue is recrystallized ptx2">

Example 15. 8-(2-Solutionline-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a]pyridine.

A named connection receive according to the method described in example 14, using isobutylphthalate (0.3 g) and 8-(2-amino-6-methylbenzylamino-2,3-dimethylimidazo[1,2-a] pyridine (0.56 g) in methylene chloride (50 ml). Get 0,22 g (29%) of these connections, so pl. 144-146oC.

Example 16. 8-(2-Isopropoxycarbonyl-6-methylbenzylamino - 2,3-dimethylimidazo[1,2-a]pyridine.

A named connection receive according to the method described in example 14, using isopropylcarbamate (1.5 g) and 8-(2-amino-6-methylbenzylamino-2,3-dimethylimidazo[1,2-a] pyridine (0,98 g) in methylene chloride (50 ml). Obtain 0.32 g (25%) of the named compound.

Example 17. 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3 - hydroxymethyl-2-methylimidazo[1,2-a]pyridine.

A named connection receive according to the method described in example 2, using 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a] pyridine (0.15 g) and sodium borohydride (15 mg) in methanol (15 ml). Obtain 0.12 g of the named compound, so pl. 102-104oC.

Example 18. 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino) -3-hydroxymethylcytosine 8-(2-tert-butoxycarbonylamino-6-methyl-benzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine (0.20 g) and sodium borohydride (19 mg) in methanol. Obtain 0.17 g of the named compound, so pl. 140-142oC.

The compounds of formula I and their salts possess significant pharmacological properties, which determine their potential industrial applications. In particular, they have the ability to inhibit gastric secretion and excellent protective effect on the stomach and intestines of warm-blooded animals. In addition, the compounds of the present invention have high selectivity, relatively long action, good efficiency in the small intestine, the absence of significant side effects and a wide interval of therapeutic action.

The term "protective effect on the stomach and intestines" understand the prevention and treatment of gastrointestinal disorders, in particular gastrointestinal inflammatory diseases and lesions (such as gastric ulcer, duodenal ulcer, gastritis, functional gastropathy caused by high acidity or drugs), which may be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (for example, some anti-inflammatory and Antirheumatic agents), chemicals (for example, the th of the invention, as it turned out unexpectedly markedly superior to known compounds of the prior art in various models, which define antiulcer and protivozachatochnye properties. Due to these properties, the compounds of the present invention of the formula I and their pharmaceutically compatible salts can be widely used in the treatment of humans and animals. Especially it is recommended for the treatment and/or prevention of diseases of the stomach and/or intestines.

Thus, the invention also relates to compounds of the present invention for use in the treatment and/or prophylaxis of the aforementioned diseases.

The invention also includes the use of compounds of the present invention for the production of drugs that are used for treatment and/or prevention of the above diseases.

In addition, the invention also includes the use of compounds of the present invention for the treatment and/or prevention of the above diseases.

In addition, the invention relates to pharmaceutical preparations which contain one or more compounds of formula 1 and/or their pharmaceutically acceptable salts.

Pharmaceutical preparations for the active substance) of the present invention are used by themselves or, preferably, in combination with acceptable pharmaceutical substances or fillers in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, where the content of the active compound is in the range from 0.1 to 95% and where, by appropriate selection of excipients and carriers can be obtained pharmaceutical formulation (e.g., formulation with prolonged release of active compounds or the formula for the small intestine), which corresponds exactly to the active compound and/or to the desired onset of action.

Specialists know which of the excipients and fillers can be used for the desired pharmaceutical formulations. In addition to solvents, geleobrazovanie, candle bases, excipients for tablets and other fillers for the active compounds, may use, for example, antioxidants, dispersants, emulsifiers, antifoaming agents, flavorings, preservatives, solubilization, dyes, or, in particular, penetration promoters and complexing agents (e.g. cyclodextrins).

The active compounds can pry effect is achieved by oral application of the active substance or substances in a daily dose of approximately 0.01 to 20, preferably from 0.05 to 5, and especially preferably from 0.1 to 1.5 mg/kg of body weight when when taken for several times, preferably 1-4 times, achieved the desired result. When parenteral application is possible using the same doses, or as a rule (especially when administered intravenously active substances), lower doses. A qualified technician can easily determine the optimal dosage and method of application active substances required in each case.

If compounds and/or salts in accordance with the present invention can be used for treatment of the above diseases, the pharmaceutical preparations can also contain one or more pharmacologically active components from another group of drugs, such as antacids, for example aluminum hydroxide, magnesium aluminate, tranquilizers, such as benzodiazepines, for example diazepam; antispasmodic, such as, for example, becamevery, camylofin; anticholinergic agents such as, for example, occidentalis, fingerbone; local anesthetics, such as, for example, tetracaine, procaine; also in the formulation may include enzymes, vitamins or amino acids.

2-blockers (e.g. cimetidine, ranitidine), inhibitors of H+/K+- ATP-ases (e.g., omeprazole, pantoprazole) or with so-called peripheral anticholinergic agents (for example, pirenzepine, telenzepine), and afganistani gastrin to strengthen primary action in accordance with the additive or vergadain scheme and/or eliminate or reduce side effects, or, alternatively, the combination with substances having antibacterial activity (such as, for example, cephalosporins, tetracyclines, nalidixic acid, penicillin, or in addition, salts of bismuth) with the purpose of killing Helicobacter pyroli.

Pharmacology.

Excellent protective effect on the stomach and inhibitory effect on gastric secretion of compounds of the present invention can be shown in animal studies as experimental models. Compounds of the present invention investigated on the model, described below, have numbers that correspond to the numbers of examples, which received these compounds.

Study of the inhibition of the secretion of action on perfesional the rat stomach.

The influence of the marrying using pentagastrin, in perfesional the stomach of rats in vivo are presented in table. 1.

Method.

Shot rats (rats CD, female, 200-250 g, 1.5 g/kg urethane intramuscularly) is subjected to tracheotomy and then open the abdomen through a midline epigastric dissection and fixed PVC catheter through the mouth into the esophagus, and the other through the pylorus so that the ends of the tubes only acted in the stomach cavity. A catheter extending from the pylorus, leads out through a hidden hole in the right wall of the abdominal cavity. After a full wash (about 50-100 ml) of the stomach continuously transmit the physiological NaCl solution temperature 37oC (0.5 ml/min, pH 6.8 or 6.9; Brun-Unita 1). The resulting stream is collected (in the measuring cylinder 25 ml) at intervals of 15 min each, and determine the pH (pH meter 632, glass electrode EA 147; diameter = 5 mm, Metrohm) and by titration of the liberated HCl relative to freshly prepared in 0.01 n NaOH solution to pH 7 (Dosimat 655 Metrohm).

Gastric secretion stimulated by continuous intravenous infusion of pentagastrin rate of 1 mcg/kg (= 1.65 ml/h, the left femoral vein) approximately 30 minutes after the end of the operation (that is, after determining 2 preliminary STI rate of 1 ml/kg over 60 min after continuous infusion of pentagastrin.

Body temperature constant support of 37.8-38oC using infrared radiation and heated cushions (automatic speed control through the rectal temperature sensor).

Dose, which leads to maximum inhibition of acid secretion at 100%, are shown in the table.

Examples of the preparation of pharmaceutical forms.

Tablet containing 40 mg of active substance.

20 kg of 3-hydroxymethyl-8-(2-methoxycarbonylamino-6 - methylbenzylamino)-2-methylimidazo[1,2-a] pyridine, 40 kg of milk sugar, 26 kg of corn starch, 3 kg of polyvinylpyrrolidone moisturize 20 l of water and granularit through a sieve with a mesh size of 1.25 mm Granulate is dried to a relative humidity of 50-60% in the dryer with psevdoozhizhennom layer and then added to the mixture of 8 kg of sodium carboxymethyl cellulose, 2 kg of talc and 1 kg of magnesium stearate. The finished granulate is pressed into tablets weighing 200 mg and a diameter of 8 mm

Capsules containing 30 mg of active substance.

300 mg of 3-hydroxymethyl-8-(2-methoxycarbonylamino-6 - methylbenzylamino)-2-methylimidazo[1,2-a] pyridine, 695 g of microcrystalline cellulose and 5 g of amorphous silicic acid are crushed, thoroughly mixed, and this mixture of zapolneniya-6-methylbenzylamino)-2,3 - dimethylimidazo[1,2-a]pyridine, 895 g of microcrystalline cellulose and 5 g of amorphous silicic acid are crushed, thoroughly mixed, and this mixture is filled gelatin capsules.

Ampoules containing 10 mg of active substance.

Dissolve and 3.16 g of 8-(2-methoxycarbonylamino-6-methylbenzylamino)- 2,3-dimethylimidazo[1,2-a] pyridine hydrochloride, is dissolved in the solution, 165.5 g of mannitol and 0.5 g of sodium carbonate in 1300 ml of distilled water, then the volume of the mixture was adjusted to 1500 ml and sterile filtered. This solution is dosed at 5 ml in 15-ml vessels. The lyophilisate can be further diluted with 10 ml of water.

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n

1. Imidazopyridine formula I:

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where substituent R0represents a methyl or hydroxymethyl;

Deputy R1represents a C1- C4-alkyl;

Deputy R2represents a C1- C4-alkyl;

Deputy R3represents a C1- C4-alkoxygroup;

fragment A represents O (oxygen) or NH,

and also their salts.

2. Imidazopyridine formula I under item 1, characterized in that the substituent R0represents methyl.

3. Imidazopyridine formula I under item 1, of the p. 1, characterized in that they are chosen from the group comprising: 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo [1,2-a] pyridine, 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo [1,2-a] pyridine, 8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine, 8-(2-tert.-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine, 8-(2-tert. -butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine, 8-(2-ethoxycarbonyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine, 8-(2-isobutylacetophenone-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine, 8-(2-isopropoxycarbonyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine, 8-(2-tert.-butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a] pyridine and 8-(2-tert. -butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine or its salt.

5. 8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine or its salt.

6. The method of producing imidazopyridines formula I under item 1, in which R0represents methyl, and their salts, the interaction of compounds of formula III

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where R1and A at the note, specified in paragraph 1;

X represents a suitable delete group

followed, if required, prevrasheniem of the compounds obtained into their salts, or, if required, subsequent to the release of the compounds of formula I obtained from salts of compounds of formula I.

7. The pharmaceutical composition inhibiting gastric secretion, comprising an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains an effective amount of imidazopyridine formula I or its pharmaceutically joint of salt.

8. Connection on p. 1 or its pharmacologically compatible salts with inhibiting gastric secretion activity.

9. A method of obtaining a pharmaceutical composition inhibiting gastric secretion, characterized in that conduct the mixture of imidazopyridine formula I with a pharmaceutically acceptable carrier, auxiliary substances.

Priority signs:

15.02.93 R0is methyl;

29.06.93 R0- hydroxymethyl, R1, R2, R3and A are specified in paragraph 1 values.

 

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3 ex

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