Derivatives imidazopyridine, method of their production and intermediate compounds, pharmaceutical drugs based on them (options), the method of inhibiting the secretion of gastric acid and a method of treatment of conditions involving infection by h. pylori

 

(57) Abstract:

Describes derivatives of imidazopyridine General formula I

or their pharmaceutically acceptable salts, where R1represents N, CH3or CH2OH; R2represents CH3or CH2CH3; R3represents N or C1-C6alkyl; R4represents N or C1-C6alkyl; R5represents H or halogen; R6and R7independently represent H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, halogenated C1-C6alkyl, phenyl, possibly substituted by one or more than one Deputy, selected from C1-C6of alkyl, C1-C6alkoxy, (C1-C6alkyl)2-N or NH2SO2, aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one or more than one Deputy, selected from C1-C6alkoxy or OH, R8-(C1-C6)alkyl-, in which R8represents NH2C=O, C1-C6alkyl-NHC=O-, (C1-C6alkyl)2NC=O-, C1-C6the alkyl, gidroksilirovanii C1-C6the alkyl or C1-C6alkoxy-substituted C1-C6by alkyl; and X represents NH or O; and intermediate compounds, pharmaceutical preparations on their basis, the method of inhibiting the secretion of gastric acid and a method of treatment of conditions involving infection by H. YLORI. The new compounds inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases. 9 N. and 6 C.p. f-crystals.

TECHNICAL AREA

The present invention relates to new compounds and their pharmaceutically acceptable salts, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases. Other aspects of this invention relate to compounds according to the invention for use in therapy, to methods of producing such novel compounds, to pharmaceutical compositions containing as active ingredient at least one compound according to the invention or the s funds for the above medical use. The invention also relates to novel intermediate compounds for obtaining these new compounds.

Description of the prior art

Replaced imidazo[1,2-a]pyridine, useful in the treatment of stomach ulcers, known for example from EP-B-0033094 and US 4450164 (Schering Corporation), from EP-B-0204285 and US 4725601 (Fujisawa Pharmaceutical Co.) and from publications of J. J. Kaminski et al. in Journal of Medical Chemistry (vol.28, 876-892, 1985; vol.30, 2031-2046, 1987; vol.30, 2047-2051, 1987; vol.32, 1686-1700, 1989 and vol.34, 533-541, 1991).

Overview of issues related to the pharmacology of the gastric acid pump (N+TO+-ATPase), can be found in Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.

Description of the INVENTION

It has been unexpectedly found that the compounds of formula I, which is derived from imidazopyridine, in which the phenyl group is substituted, and imidazopyridine group substituted at the 6th position carboxamide group, are particularly effective as inhibitors of gastrointestinal N+TO+-ATPase and therefore as inhibitors of secretion of gastric acid. Carboxamide group in the 6th position may be chosen so to give the compounds of formula I with a molecular weight of not more than 600.

Thus, one aspect of this izobreteny the m salts,

where R1represents the

N

CH3or

CH2OH;

R2represents the

CH3or

CH2CH3;

R3represents the

N or

C1-C6alkyl;

R4represents the

N or

C1-C6alkyl;

R5represents the

N or

halogen;

R6and R7independently represent

N

C1-C6alkyl,

gidroksilirovanii C1-C6alkyl,

C1-C6alkoxy-substituted C1-C6alkyl,

halogenated C1-C6alkyl,

aryl, where aryl represents phenyl, possibly substituted by one or more than one Deputy, selected from C1-C6of alkyl, C1-C6alkoxy, (C1-C6alkyl)2-N or NH2SO2,

aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one or more than one Deputy, selected from C1-C6alkoxy or OH,

R8-(C1-C6)alkyl-, in which R8represents NH2alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-C=O-, ArCONH-, Ar(C1-C6alkyl)CONH, ArC=O, NH2CONH-, C1-C6alkyl-NHCONH-, (C1-C6alkyl)2-NCONH-, ArNHCONH-, gidroksilirovanii C1-C6alkyl-O - or morpholinyl; where Ar represents a phenyl, pyridyl or naphthyl;

C7-C12alkyl,

OH,

where R9and R10independently represent H,

R11-(C1-C6)alkyl-COO-(C1-C6)alkyl-, where R11represents HOOC-, or

R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring may contain one or more than one additional heteroatom, such as morpholine, piperazine, pyrrolidine, piperidine, possibly substituted by one or more than one Deputy, selected from halogen, C1-C6of alkyl, C1-C6alkoxy, CF3, OH, phenyl, NH2CO-, C1-C6alkyl-CO-,

provided that at least one of R6and R7can not be H, C1-C6the alkyl, gidroksilirovanii C1Preferred compounds according to the invention are those compounds of formula I in which R1represents CH3or CH2OH; R2represents CH3or CH2CH3; R3represents CH3or CH2CH3; R4represents CH3or CH2CH3; R5represents H, Br, Cl or F; R6and R7independently represent

N

C1-C6alkyl,

gidroksilirovanii C1-C6alkyl,

C1-C6alkoxy-substituted C1-C6alkyl,

halogenated C1-C6alkyl,

aryl, where aryl represents phenyl, possibly substituted by one or more than one Deputy, selected from C1-C6of alkyl, C1-C6alkoxy, (C1-C6alkyl)2-N or NH2SO2,

aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one or more than one Deputy, selected from C1-C6alkoxy or OH,

R8-(C1-C6)alkyl-, in which R8represents NH2C=O, C1-C6alkyl-NHC=O-, (C1-C66alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-C=O-, ArCONH-, Ar(C1-C6alkyl)CONH, ArC=O, NH2CONH-, C1-C6alkyl-NHCONH-, (C1-C6alkyl)2-NCONH-, ArNHCONH-, gidroksilirovanii C1-C6alkyl-O - or morpholinyl, where Ar represents a phenyl, pyridyl or naphthyl;

C7-C12alkyl,

OH,

where R9and R10independently represent H,

R11-(C1-C6)alkyl-COO-(C1-C6)alkyl-, where R11represents HOOC-, or

R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring may contain one or more than one additional heteroatom, such as morpholine, piperazine, pyrrolidine, piperidine, possibly substituted by one or more than one Deputy, selected from halogen, C1-C6of alkyl, C1-C6alkoxy, CF3, OH, phenyl, NH2CO-, C1-C6alkyl-CO-,

provided that at least one of R6and R7can not be H, C1-C6the alkyl, gidroksilirovanii C1-C6the alkyl or C1-C6alaxis is sustained fashion the compounds according to the invention are those compounds of formula I, in which R1represents CH3or CH2OH; R2represents CH3; R3represents CH3or CH2CH3; R4represents CH3or CH2CH3; R5represents H, Br, Cl or F; R6and R7independently represent

N

C1-C6alkyl,

gidroksilirovanii C1-C6alkyl,

C1-C6alkoxy-substituted C1-C6alkyl,

halogenated C1-C6alkyl,

aryl, where aryl represents phenyl, possibly substituted by one or more than one Deputy, selected from C1-C6of alkyl, C1-C6alkoxy or (C1-C6alkyl)2-N-aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one or more than one Deputy, selected from C1-C6alkoxy or OH,

R8-(C1-C6)alkyl-, in which R8represents NH2C=O, C1-C6alkyl-NHC=O-, (C1-C6alkyl)2NC=O-, C1-C6alkyl-OOC-, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C6alkyl)CONH, ArC=O, NH2CONH-, C1-C6alkyl-NHCONH-, (C1-C6alkyl)2-NCONH-, ArNHCONH-, gidroksilirovanii C1-C6alkyl-O - or morpholinyl, where Ar represents a phenyl, pyridyl or naphthyl;

C7-C12alkyl,

OH,

R11-(C1-C6)alkyl-COO-(C1-C6)alkyl-, where R11represents HOOC-, or

R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring may contain one or more than one additional heteroatom, such as morpholine, piperazine, pyrrolidine, piperidine, possibly substituted by one or more than one Deputy, selected from halogen, C1-C6of alkyl, C1-C6alkoxy, CF3, OH, phenyl, NH2CO-, C1-C6alkyl-CO-,

provided that at least one of R6and R7can not be H, C1-C6the alkyl, gidroksilirovanii C1-C6the alkyl or C1-C6alkoxy-substituted C1-C6the alkyl.

The most preferred compounds according to the invention are:

- 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-6-(morpholinomethyl)-imidazo[1,2-a]pyridine;- (8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridinyl)(4-methylpiperazine)methanon;

- 1-((8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)-carbonyl)-2-(s)-pyrrolidinecarboxamido;

- 8-(2-ethyl-6-methylbenzylamino)-N-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide;

- (2-ethyl-6-methylbenzylamino)-N-(2-(2-hydroxyethoxy)ethyl)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxamide;

- (8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)(3-hydroxy-1-pyrrolidinyl)methanon;

- N-(3,4-dihydroxyphenyl)-8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide;

- 8-(2-ethyl-6-methylbenzylamino-3-(hydroxymethyl)-2-methyl-6-(morpholino-carbonyl)-imidazo[1,2-a]pyridine;

- N-((8-(2-ethyl-6-methylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)-carbonyl)guanidine;

- 4-(2-(((8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)-carbonyl)amino)ethoxy)-4-oxobutanoic acid.

Preferred compounds are compounds as hydrochloride salts or mesilate.

The present invention also relates to a combined preparation for the prevention or treatment of gastrointestinal inflammatory diseases in concurrent, repairable agent.

The present invention also relates to a method of obtaining compounds of General formula I, where X and R1-R7such as defined for formula I, which consists in the fact that the compound of General formula II

where R1-R5have the above values, hydrolyzing under standard conditions with obtaining a carboxylic acid of General formula III

which is subjected to interaction with aminoguanidinium formula IV

where R6and R7such as defined for formula I, in the presence of the agent combinations in standard conditions in an inert solvent.

Convenient is the realization of this interaction in an inert solvent, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide, in the presence or in the absence of base. The base can be, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide, a carbonate of an alkali metal such as potassium carbonate and sodium carbonate, or an organic amine, such as triethylamine.

According to another aspect of this invention relates to pharmaceutical preparations possessing inhibiting the secretion of gastric acid activestyle diluent or carrier.

In addition, according to this invention proposed a compound of formula I for the manufacture of medicaments for the inhibition of the secretion of stomach acid or for the treatment of gastrointestinal inflammatory diseases.

According to another aspect, the present invention relates to a method of inhibiting secretion of gastric acid, in which the mammal, including man, in need of such inhibition is administered an effective amount of the compounds according to the invention.

The present invention also relates to a method of treatment or prophylaxis of conditions involving infection by Helicobacter pylori infection of the gastric mucosa of a mammal, including humans, in which the specified mammal in need of such treatment is administered an effective amount of the compounds according to the invention in combination with at least one antimicrobial agent.

In addition, the present invention relates to a pharmaceutical preparation for inhibiting secretion of gastric acid, in which the active ingredient is a compound according to the invention.

This invention also relates to a pharmaceutical preparation for the treatment or prevention cotingidae represents a connection according to the invention, in combination for simultaneous, separate or sequential use with at least one antimicrobial agent.

Another aspect of the present invention are new intermediate compounds useful for the synthesis of compounds according to the invention is:

the compound of formula III

where R1, R2, R3, R4, R5and X are such as defined for formula I.

Used in this application, the term “C1-C6alkyl” means a straight or branched alkyl group containing from 1 to 6 carbon atoms. Examples specified WITH1-C6of alkyl include methyl, ethyl, N.-propyl, isopropyl, N.-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl and hexyl straight and branched chain.

The term “halogen” includes fluorine, chlorine, bromine and iodine.

As pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of this invention. It should be understood that all possible diastereomers form (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of this invention. This invention also covers made in the STV.

In addition, specialists clear that although derivatives of compounds of formula I may not possess pharmacological activity as such, they may be administered parenterally or orally, and thereafter be subjected to metabolism in the body with the formation of the pharmacologically active compounds according to the invention. Therefore, such derivatives can be described as “prodrugs”. All prodrugs of the compounds of formula I are included within the scope of this invention.

Depending on the conditions of the method of obtaining the final products of formula I are produced either in a neutral form or in salt form. As free base and salts of these end-products are within the scope of this invention.

Salt accession acids new compounds known per se can be converted into a free base or with the use of basic reagents such as alkali, or by ion exchange. In addition, the obtained free base can also form salts with organic and inorganic acids.

Upon receipt of salts accession acids are preferably used such acids which form suitable pharmaceutically acceptable salts. PR is th acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleimide acid, pyruvic acid, p.-hydroxybenzoic acid, albanova acid, methanesulfonate acid, econsultancy acid, hydroxyethanesulfonic acid, halogenosilanes acid, toluensulfonate acid or naphthalenesulfonate acid.

Compounds according to this invention can be used for prevention and treatment in mammals, including humans, gastrointestinal inflammatory diseases and diseases caused by exposure to gastric acid, such as gastritis, gastric ulcer, duodenal ulcer, gastroesophageal reflux and the syndrome of Zollinger-Ellison. Moreover, these compounds may be used for treatment of other gastrointestinal disorders, where desirable gastric antisecretory effect, for example, in patients with gastrinom intensive therapy patients and in pre - and post-operative period to prevent acid aspiration and education ulcers as a result of stress.

A typical daily dose of the active substance varies in a wide range and will depend on various factors, such as, for example, the individual requirements of each patient, the route of administration and the disease itself. Usually oral and parenteral doses of the active substance will be in the range from 5 to 1000 mg per day.

In addition, the compounds according to the invention can be used in the preparations together with other active ingredients, such as antibiotics, such as amoxicillin.

For clinical use of the compounds according to the invention is made in the form of pharmaceutical preparations for oral, rectal, parenteral or other routes of administration. The pharmaceutical preparation contains at least one compound according to the invention in combination with one or more pharmaceutically acceptable ingredient. The carrier may be in the form of solid, semi-solid or liquid diluent or in the form of capsules. These pharmaceuticals are another object of the present invention. Usually the number of active compounds is 0.1-95% by weight of the preparation, preferably 0.1 to 20% by weight of the preparation for parenteral use and preferably between aderrasi compound of the present invention, in the form of dosage units for oral administration selected compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polietilenglikolya wax. The mixture is then made in the form of granules or pressed into tablets.

Soft gelatin capsules can be obtained in the form of capsules containing a mixture of active compound or compounds according to the invention, vegetable oil, fat or other suitable filler for soft gelatin capsules. Hard gelatin capsules may contain granules of the active compound. In addition, hard gelatin capsules can contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Unit dosing for rectal injection can be obtained (1) in the form of suppositories which contain the active weselne substance in a mixture with a vegetable oil, liquid paraffin or other suitable filler for gelatin rectal capsules; (3) in the form of ready-to-use micro; or (4) in the form of a dry preparation for micro, which should pererastaet in a suitable solvent just before the introduction.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing from 0.1 to 20 wt.% the active ingredient and the remainder composed of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, corrigentov, saccharin and carboxymethyl cellulose or other thickener. In addition, liquid preparations for oral administration can be prepared in the form of a dry powder, which should be pererastaet in a suitable solvent before use.

Solutions for parenteral administration can be obtained in the form of a solution of the compounds according to the invention in a pharmaceutically acceptable solvent, preferably in a concentration of from 0.1 to 10 wt.%. In addition, these solutions may also contain stabilizing ingredients and/or tabularasa ingledove injection can also be prepared in the form of a dry preparation which should pererastaet in a suitable solvent immediately prior to use.

In addition, the compounds of the present invention can be used for simultaneous, separate or sequential use drugs in combination with other active ingredients, for example, for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori infection of the gastric mucosa of man. These other active ingredients may be antimicrobial agents, in particular:

- -lactam antibiotics, such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime;

- macrolides, such as erythromycin or clarithromycin;

the tetracyclines, such as tetracycline or doxycycline;

- aminoglycosides, such as gentamicin, kanamycin or amikacin;

- quinolones such as norfloxacin, ciprofloxacin or enoxacin;

other agents such as metronidazole, nitrofurantoin, or chloramphenicol; or

- preparations containing bismuth salt such as bismuth citrate core, bismuth salicylate main, bismuth carbonate basic, bismuth nitrate basic or bismuth gallate main.

The AOC is high or sequential applications with antacids, such as aluminum hydroxide, magnesium carbonate and magnesium hydroxide or alginic acid, either together or in combination for simultaneous, separate or sequential use in pharmaceuticals that inhibit the secretion of acid, such as H2 blockers (e.g. cimetidine, ranitidine), inhibitors of N+/K+-ATPase (e.g., omeprazole, pantoprazole, lansoprazole or rabeprazole), either together or in combination for simultaneous, separate or sequential use gastroprokinetic (such as cisapride or mosapride).

EXAMPLES

1. Obtaining the COMPOUNDS ACCORDING to the INVENTION

Example 1.1

Synthesis of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-6-(morpholinomethyl)-imidazo[1,2-a]pyridine

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g; 0.44 mmol) and o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0.14 g; 0.44 mmol) are added to a methylene chloride (10 ml). Add morpholine (0.12 g; 1.4 mmol) and the reaction mixture stirred at ambient temperature for 1.5 hours, the Reaction mixture was applied on a column of silica gel and purified by chromatography, using as eluent the UB>): 1.2 (t, 3H), 2.32 (s, 3H), 2.35 (s, 3H), 2.37 (s, 3H), 2.7 (q, 2H), 3.7 (s, 8H), 4.35 (d, 2H), 4.95 (bs, 1H), 6.15 (s, 1H), 7.0-7.2 (m, 3H), 7.4 (s, 1H).

Example 1.2

Synthesis of N-(4-ethoxyphenyl)-8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g; 0.44 mmol) and o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0.14 g; 0.44 mmol) are added to a methylene chloride (10 ml). Add 4-ethoxyaniline (0,19 g; 1.4 mmol) and the reaction mixture stirred at ambient temperature for 72 hours, the Solvent is evaporated under reduced pressure, the residue applied to a column of silica gel and purified by chromatography, using as eluent a mixture of methylene chloride:methanol (95:5). The residue is treated with hot hexane:ethyl acetate (2:1), the product is filtered and dried, obtaining 0.14 g (74%) of the desired compound as white crystals.

1H-NMR (300 MHz; CDCl3): 1.2 (t, 3H), 1.4 (t, 3H), 2.35 (s, 9H), 2.65 (q, 2H), 4.0 (q, 2H), 4.35 (d, 2H), 4.9 (t, 1H), 6.55 (s, 1H), 6.85 (d, 2H), 7.0-7.2 (m, 3H), 7.5 (d, 2H), 7.9 (s, 1H), 8.15 (s, 1H).

Example 1.3

Synthesis of N-[2-(dimethylamine)-2-oxoethyl]-8-(2-ethyl-6-methylbenzylamino)-N,2,3 trimethylimidazo[1,2-a]pyridine-6-carboxamide

2,3-Dimethyl-8-(2-eh is trimethylenetrinitramine (TBTU) (0.12 g; 0.38 mmol) are added to a methylene chloride (10 ml). Add N,N-dimethyl-2-methylamino-ndimethylacetamide (0,088 g; 0.38 mmol) and the reaction mixture stirred at ambient temperature for 1 h the Solvent is evaporated under reduced pressure, the residue is purified column chromatography, using as eluent a mixture of methylene chloride:methanol (95:5), which gives 80 mg (48%) specified in the header of the product.

1H-NMR (500 MHz; CDCl3): 1.2 (t, 3H), 2.3 (s, 6H), 2.35 (s, 3H), 2.65 (q, 2H), 2.75 (s, 6H), 2.95 (s, 3H), 3.15 (s, 2H), 4.35 (bs, 2H), 4.85 (bs, 1H), 6.25 (s, 1H), 7.0-7.2 (m, 3H), 7.45 (s, 1H).

Example 1.4

Synthesis of (8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-yl)(4-methylpiperazin)methanone

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.5 g, 1.48 mmol) and o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0,48 g; 1.5 mmol) are added to a methylene chloride (20 ml) and the mixture stirred for 5 minutes Add N-methylpiperazine (0.16 g; 1.6 mmol) and the reaction mixture stirred at ambient temperature overnight. The solvent is evaporated under reduced pressure, and purification of the residue column chromatography on silica gel using as eluent a mixture of methylene chloride:IU who 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.47 (bs, 4H), 2.71 (q, 2H), 2.80 (s, 3H), 3.65 (bs, 4H), 4.36 (d, 2H), 4.94 (t, 1H), 6.19 (s, 1H), 7.04-7.18 (m, 3H), 7.42 (s, 1H).

Example 1.5

Synthesis of 1-((8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)carbonyl)-2-(s)-pyrrolidinecarboxamido

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g; 0.44 mmol), o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0.14 g; 0.45 mmol) and triethylamine (0.05 g; 0.5 mmol) are added to a methylene chloride (10 ml) and the mixture is stirred for 10 minutes Add (S)-prolinamide (0,016 g; 0.45 mmol) and the reaction mixture stirred at ambient temperature for 1 h the Solvent is evaporated under reduced pressure, purification of the residue column chromatography on silica gel using as eluent a mixture of methylene chloride: methanol (9:1) and crystallization from diethyl ether to give 0.07 g (36%) specified in the connection header.

1H-NMR (500 MHz; CDCl3): 1.21 (t, 3H), 2.1-2.2 (m, 4H), 2.33 (s, 3H), 2.35 (s, 3H), 2.37 (s, 3H), 2.70 (q, 2H), 3.65-3.75 (m, 2H), 4.36 (d, 2H), 4.80 (bs, 1H), 4.94 (bs, 1H), 5.88 (s, 1H), 6.33 (s, 1H), 6.98 (s, 1H), 7.04-7.19 (m, 3H), 7.54 (s, 1H).

Example 1.6

Synthesis of 8-(2-ethyl-6-methylbenzylamino)-N-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

2,3-Dimer Is,N’-tetramethylethylenediamine (TBTU) (0.14 g; 0.45 mmol), triethylamine (0.1 g; 0,99 mmol) and hydroxylamine hydrochloride (0,031 g; 0.46 mmol) in dimethylformamide (5 ml).

Specified in the header connection receive in accordance with example 1.5 (output: 0,016 g; 10%).

1H-NMR (500 MHz; CDCl3): 1.15 (bs, 3H), 2.25 (bs, 9H), 2.6 (bs, 2H), 4.25 (bs, 2H), 4.95 (bs, 1H), 6.45 (bs, 1H), 6.9-7.1 (m, 3H), 7.75 (bs, 1H).

Example 1.7

Synthesis of (2-ethyl-6-methylbenzylamino)-N-(2-(2-hydroxyethoxy)ethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g; 0.88 mmol), o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0,29 g; 0.90 mmol) and 2-(2-aminoethoxy)ethanol (0.2 g, 1.9 mmol) in methylene chloride (10 ml).

Specified in the header connection receive in accordance with example 1.5 (yield: 0.24 g; 80%).

1H-NMR (500 MHz; CDCl3): 1.25 (t, 3H), 2.25 (s, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.75 (q, 2H), 3.4-3.45 (m, 2H), 3.55-3.7 (m, 6H), 4.35 (d, 2H), 5.05 (t, 1H), 6.45 (s, 1H), 7.0-7.2 (m, 4H), 7.5 (s, 1H).

Example 1.8

Synthesis of (8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)(3-hydroxy-1-pyrrolidinyl)methanone

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g; 0.44 mmol), o-benzotriazol-1-yl-N,N,N’,N’-tetracosane header connection receive in accordance with example 1.4. Crystallization from a mixture of ethyl acetate:hexane (2:1) (yield: 0.24 g; 80%).

1H-NMR (300 MHz; CDCl3): 1.23 (t, 3H),1.93 (bs, 2H), 2.33 (s, 3H), 2.34 (s, 3H), 2.41 (s, 3H), 2.70 (q, 2H), 3.51-3.89 (m, 4H), 4,35 (d, 2H), 4.38-4.55 (m, 1H), 5 .04 (bs, 1H), 6.35 (s, 1H), 7.01-7.16 (m, 3H), 7.51 (s, 1H).

Example 1.9

Synthesis of N-(3,4-dihydroxyphenyl)-8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g; 0.44 mmol) and o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0.14 g; 0.45 mmol) are added to a dimethylformamide (10 ml) and the mixture stirred for 5 minutes Add 3,4-dihydroxyphenethylamine (0.27 g; 1.4 mmol) and triethylamine (0.28 g; 1.4 mmol) and the reaction mixture stirred at ambient temperature for 72 hours, the Solvent is evaporated under reduced pressure, purification of the residue column chromatography on silica gel using as eluent a mixture of methylene chloride:methanol (9:1) and crystallization from acetonitrile give 0,059 g (28%) specified in the connection header.

1H-NMR (400 MHz; DMSO-d6): 1.15 (t, 1H), 2.22 (s, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 2.65-2.74 (m, 4H), 3.41 (q, 2H), 4.37 (d, 2H), 4.85 (t, 1H), 6.48 (dd, 1H), 6.63-6.66 (m, 2H), 6.70 (d, 1H), 7.07-7.21 (m, 3H), 8.04 (d, 1H), 8.49 (t, 1H), 8.63 (s, 1H), 8.75 (s, 1H).

8-(2-Ethyl-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0,012 g; 0,034 mmol), o-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0,011 g; 0,034 mmol) and morpholine (0,009 g; 0.1 mmol) in methylene chloride (1 ml).

Specified in the header connection receive in accordance with example 1.1 (output: 0.008 g; 56%).

1H-NMR (300 MHz; DMSO-d6): 1.23 (t, 3H), 2.33 (s, 3H), 2.39 (s, 3H), 2.72 (q, 2H), 3.74 (bs, 8H), 4.37 (d, 2H), 4.85 (s, 2H), 5.02 (t, 1H), 6.27 (d, 1H), 7.06-7.22 (m, 3H), 7.75 (d, 1H).

Example 1.86

Synthesis of N-((8-(2-ethyl-6-methylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)carbonyl)guanidine

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.5 g, 1.5 mmol), diisopropylethylamine (0,57 g; 1.5 mmol) and guanidine carbonate (0,53 g; 2.9 mmol) are added to a dimethylformamide (10 ml). Add on-benzotriazol-1-yl-N,N,N’,N’-tetramethylethylenediamine (TBTU) (0,48 g; 1.5 mmol) and the reaction mixture is stirred at 50aboutC for 3 hours the Solvent is evaporated under reduced pressure, purification of the residue column chromatography on silica gel using as eluent a mixture of methylene chloride: methanol (100:15) and crystallization from diethyl ether to give 0.12 g (21%) specified in (bs, 1H), 6.9 (s, 1H), 7.05-7.2 (m, 3H), 8.25 (s, 1H).

Example 1.87

Synthesis 4-(2-(((8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)carbonyl)amino)ethoxy)-4-oxobutanoic acid

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-hydroxyethylamide[1,2-a]pyridine-6-carboxamide (250 mg; to 0.263 mmol) and succinic anhydride (100 mg; 1.00 mmol) are added to 7 ml of acetone. The mixture is refluxed for 48 hours Precipitated precipitated product is filtered and washed with acetone and ether, receiving 288 mg (91%) specified in the connection header.

1H-NMR (500 MHz; DMSO): 1.16 (t, 3H), 2.24 (s, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 2.48-2.58 (m, 4H), 2.70 (q, 2H), 3.54 (q, 2H), 4.19 (t, 2H), 4,39 (d, 2H), 4.90 (t, 1H), 6.72 (s, 1H), 7.09-7.22 (m, 3H), 8.08 (s, 1H), 8.59 (t, 1H), 12,25 (s, 1H).

Compounds of examples 11-85 receive in parallel syntheses using is shown in scheme 1 way.

Solution: 0,149 mmol in 1 ml of dimethylformamide.

Solution B (TBTU): 0,297 mmol in 1 ml of dimethylformamide.

Solution C+D: Amin (C) (0,297 mmol in 1 ml of dimethylformamide) + TEA (D) (0,594 mmol in 1 ml of dimethylamine).

To a solution (300 ál) add solution B (150 μl) and solution C + D (150 ál). The reaction mixture was stirred by shaking at room temperature overnight. The solvent is evaporated at what likehell (100 g); the gel is washed with a mixture of dichloromethane/methanol (9/1) (0.5-1.0 ml). The filtrate is evaporated under reduced pressure, obtaining the desired connection. (If necessary, the compounds purified using preparative HPLC).

Analysis of the compounds of the examples are carried out with HPLC and compounds identified using LC-mass spectrometry. All the compounds obtained in examples 11-85 show mass spectra, confirming the proposed structure.

As the initial compounds And reactions using the following connections:

As the parent compound C in the reaction using the following amines:

Compounds of examples 11-85 receive in accordance with scheme 1.

Primary or secondary amine nitrogen is a nitrogen involved in the interaction.

For example, A1+Spriter 27

2. The INTERMEDIATE COMPOUNDS

Example 2.1

Synthesis of 8-(2-ethylbenzylamine)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid

8-(2-Ethylbenzylamine)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (1.0 g; 0,0031 mol) and sodium hydroxide (1.2 g; 0,031 mol) is dissolved in ethanol (95%-sq; 30 ml) and refluxed for Noetherian HCl (2.6 ml), and fell in the sludge solids are separated by filtration, washed with water and dried, obtaining 1.0 g (99%) specified in the connection header.

1H-NMR (300 MHz; DMSO-d6): 1.2 (t, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.7 (q, 2H), 4.45 (d, 2H), 6.3 (s, 1H), 6.45 (t, 1H), 7.05-7.25 (m, 4H), 7.95 (s, 1H).

Example 2.2

Synthesis of 8-(2,6-diethylaniline)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid

8-(2,6-Diethylaniline)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (1.5 g; 0,0043 mol) and sodium hydroxide (1.7 g; 0,043 mol) is dissolved in ethanol (95%; 30 ml).

Specified in the header connection receive in accordance with example 1.4 (yield: 1.5 g; 99%).

1H-NMR (400 MHz; DMSO-d6): 1.14 (t, 6H), 2.22 (s, 3H), 2.37 (s, 3H), 2.67 (q, 4H), 4.37 (d, 2H), 4.89 (t, 1H), 6.68 (s, 1H), 7.11 (d, 2H), 7.23 (t, 1H), 8.09 (s, 1H).

Example 2.3

Synthesis of 8-(2,6-dimethyl-4-forbindelsen)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid

8-(2,6-Dimethyl-4-forbindelsen)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (1.47 g; 0,0034 mol) and sodium hydroxide (1.7 g; 0,034 mol) is dissolved in ethanol (95%; 30 ml).

Specified in the header connection receive in accordance with example 2.1 (yield: 1.1 g; 95%).

1H-NMR (400 MHz; DMSO-d6): 2.23 (s, 3H), 2.34 (s, 6H), 2.36 (s, 3H), 4.31 (d, 2H), 5.04 (bs, 1H), -a]pyridine-6-carboxylic acid

8-(2-Isopropyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (1.2 g; 0,0027 mol) and sodium hydroxide (1.1 g; or 0.027 mol) is dissolved in ethanol (95%; 25 ml).

Specified in the header connection receive in accordance with example 2.1 (yield: 1.1 g; 95%).

1H-NMR (300 MHz; DMSO-d6): 1.69 (d, 6H), 2.74 (s, 3H), 2.85 (s, 3H), 2.89 (s, 3H), 3.73 (m, 1H), 4.90 (d, 2H), 5.48 (t, 1H), 7.19 (s, 1H), 7.55-7.61 (m, 1H), 7.70-7.76 (m, 2H), 8.60 (s, 1H).

Example 2.5

Synthesis of 8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid

8-(2-Ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (11,0 g; 0,025 mol) and sodium hydroxide (7.0 g; to 0.17 mol) is dissolved in ethanol (95%; 120 ml) and refluxed for 20 hours, the Solvent is evaporated under reduced pressure and to the residue is added water (150 ml). pH down to 5 by adding concentrated HCl and acetic acid, and precipitated in the sludge solids are separated by filtration, washed with water and acetone and dried, obtaining 7.6 g (88%) specified in the connection header.

1H-NMR (500 MHz; DMSO-d6): 1.15 (t, 3H), 2.26 (s, 3H), 2.34 (s, 3H), 2.39 (s, 3H), 2.69 (q, 2H), 4.38 (d, 2H), 5.2 (bs, 1H), 6.73 (s, 1H), 7.07-7.2 (m, 3H), 8.12 (s, 1H).

Example 2.6

Synthesis of 8-(2-ethyl-6-methylbenzenamine-2-methylimidazo[1,2-a]pyridine-6-carboxamide (0.02 g; 0,057 mmol) and sodium hydroxide (0.02 g; 0.29 mmol) dissolved in ethanol (95%; 1 ml) and refluxed for 20 hours, the Solvent is evaporated under reduced pressure and to the residue is added water (1 ml). pH down to 5 by adding acetic acid, and precipitated in the sludge solids are separated by filtration, washed with water and dried, obtaining 0,012 g (60%) specified in the connection header.

1H-NMR (300 MHz; DMSO-d6): 1.14 (t, 3H), 2.22 (s, 3H), 2.33 (s, 3H), 2.67 (q, 2H), 4.33 (d, 2H), 4.55 (bs, 1H), 4.67 (s, 2H), 6.83 (s, 1H), 7.06-7.24 (m, 3H), 8.15 (s, 1H).

BIOLOGICAL TESTS

1. Experiments in vitro

Inhibition of acid secretion in isolated gastric glands of the rabbit

Inhibitory effect on the secretion of acid in vitro in isolated gastric glands of the rabbit was measured as described Berglindh et. al. (1976) Acta Physiol. Scand. 97, 401-414.

The determination of the activity of N+TO+-ATPase

Membrane vesicles (2.5 to 5 μg) incubated for 15 min at +37aboutWith 18 mm Pipes/Tris buffer pH 7.4 containing 2 mm MgCl2, 10 mm KCl and 2 mm ATP. The ATPase activity is being assessed by the release of inorganic phosphate from ATP, as described by LeBel et al. (1978) Anal. Biochem. 85, 86-89.

2. Experiments in vivo

Ingibirujut the x secrets and the introduction of the test substances they enter kanilirovannoy the fistula into the stomach lumen) and the upper part of the duodenum, respectively. The recovery period after surgery before testing is 14 days.

Before conducting tests on the secretion of animals at 20 h are deprived of food, but not water. The stomach repeatedly washed through the gastric cannula tap water (+37aboutC) and subcutaneously injected with 6 ml of glucose ringer (Ringer-Glucose). Acid secretion stimulated by infusion for 2.5-4 h (1.2 ml/h, subcutaneously) of pentagastrin and carbachol (20 and 110 nmol/AU, respectively) and during this period of time taken gastric secrets in the form of 30-minute fractions. Test substance or filler give or 60 minutes after the beginning of stimulation (intravenous and intraduodenal dosing, 1 ml/kg), or for 2 h before stimulation (oral dosing, 5 ml/kg, gastric cannula is closed). The time interval between dosing and stimulation can be increased with the aim of the study duration. Samples of gastric juice is titrated to pH 7.0 using 0.1 M NaOH, and the output of acid calculated as the product of the volume of the titrant concentration.

Further calculations are based on average group responses 4-6 rats. In the case when the introduction is carried out during the period of stimulation, the output Kikot, taking the exit acid in 30-minute period prior to the introduction 1.0. The percentage of inhibition calculated from the fractional responses caused by the test compound and filler. In the case when the introduction is carried out prior to stimulation, the percentage of inhibition calculated directly from the output of acid, registered after the introduction of the test compound and filler.

Bioavailability in rats

Use of adult rats Sprague-Dawley. For one to three days before the experiments, all rats under anesthesia introduce the cannula into the left carotid artery. Rats used for intravenous experiments also introduce a cannula in the jugular vein (Popovic (1960) J. Appl. Physiol. 15, 727-728). Cannula output on the back of the head.

Blood samples (0.1-0.4 g) repeatedly at intervals of time selected from the carotid artery for 5.5 hours after administration of the dose. Samples frozen until analysis tested the connection.

Bioavailability was assessed by calculating the ratio between the areas under the curves of the concentration in the blood/plasma (AUC) after (1) intraduodenal (I. D.) or orally (p. O.) introduction and (2) intravenous (centuries) administration to rats or dogs, respectively.

The area under crapulent to infinity as the result of dividing the latter concentration, certain blood on the rate constant of elimination in the final phase. Systemic bioavailability (F%) after intraduodenal and oral administration calculated as F (%)=AUC (p. O. or I. D.)/AUC (centuries))100.

Inhibition of the secretion of gastric acid and bioavailability of conscious dogs

Use of hunting dogs Labrador and hound dogs of both sexes. They enter the duodenal fistula required for insertion of test compounds or filler, and kanalirovanie gastric fistula or bags Heidenheim (Heidenhaim-pouch) to collect gastric secretion.

Before conducting tests on the secretion animals are starving for approximately 18 h with free access to water. Gastric acid secretion stimulated by infusion of histamine hydrochloride (12 ml/h) (up to 6.5 h) in the dose that causes about 80% of the individual maximal secretory response, and the gastric juice is collected in the form of a consecutive 30-minute fractions. Substance or filler give oral, I. D. or centuries after 1 or 1.5 h after the beginning of histamine infusion in a volume of 0.5 ml/kg of body weight. It should be noted that in the case of oral administration, the test compound is injected into secreting ka is determined by titration to pH 7.0 and calculate the output acids. The release of acid into the collection periods after administration of test compound or filler is expressed as the fractional answers, taking the output of the acid in the fraction preceding the introduction, for 1.0. The percentage inhibition is calculated from the fractional responses caused by the test compound and filler.

Blood samples for analysis of concentration of test compound in plasma taken at intervals of time up to 4 h after dosing. Plasma was separated and frozen within 30 min after collection and later analysis. Systemic bioavailability (F%) after oral or I. D. introduction calculated as described above for the model in rats.

1. Derivatives imidazopyridine General formula I

or their pharmaceutically acceptable salt,

where R1represents N, CH3or CH2OH;

R2represents CH3or CH2CH3;

R3represents N or C1-C6alkyl;

R4represents N or C1-C6alkyl;

R5represents H or halogen;

R6and R7independently represent H, C1-C6alkyl, gidroksilirovanii C1alkyl, aryl, where aryl represents phenyl, possibly substituted by one or more than one Deputy, selected from C1-C6of alkyl, C1-C6alkoxy, (C1-C6alkyl)2-N or NH2SO2, aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one or more than one Deputy, selected from C1-C6alkoxy or OH, R8-(C1-C6)alkyl-, in which R8represents NH2C=O, C1-C6alkyl-NHC=O-, (C1-C6alkyl)2NC=O-, C1-C6alkyl-OOC-, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-C=O-, ArCONH-, Ar(C1-C6alkyl)CONH, ArC=O, NH2CONH-, C1-C6alkyl-NHCONH-, (C1-C6alkyl)2-NCONH-, ArNHCONH-, gidroksilirovanii C1-C6alkyl-O - or morpholinyl; where Ar represents a phenyl, pyridyl or naphthyl; C7-C12alkyl, OH,

where R9and R10independently represent H, R11-(C1-C6)alkyl-COO-(C1-C6)alkyl-, where R11represents HOOC-,saturated ring, may contain one or more than one additional heteroatom, such as morpholine, piperazine, pyrrolidine, piperidine, possibly substituted by one or more than one Deputy, selected from halogen, C1-C6of alkyl, C1-C6alkoxy, CF3, OH, phenyl, NH2CO-, C1-C6alkyl-CO-, provided that at least one of R6and R7can not be H, C1-C6the alkyl, gidroksilirovanii C1-C6the alkyl or C1-C6alkoxy-substituted C1-C6by alkyl; and

X represents NH or O.

2. The compound of formula I under item 1, where R1represents CH3or CH2OH; R2represents CH3or CH2CH3; R3represents CH3or CH2CH3; R4represents CH3or CH2CH3; R5represents H, Br, Cl or F; R6and R7independently represent H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, halogenated C1-C6alkyl, aryl, where aryl represents phenyl, possibly substituted by one or more than one replace theSO2, aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one or more than one Deputy, selected from C1-C6alkoxy or OH, R8-(C1-C6)alkyl-, in which R8represents NH2C=O, C1-C6alkyl-NHC=O-, (C1-C6alkyl)2NC=O-, C1-C6alkyl-OOC-, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-C=O-, ArCONH-, Ar(C1-C6alkyl)CONH, ArC=O, NH2CONH-, C1-C6alkyl-NHCONH-, (C1-C6alkyl)2-NCONH-, ArNHCONH-, gidroksilirovanii C1-C6alkyl-O - or morpholinyl; where Ar represents a phenyl, pyridyl or naphthyl; C7-C12alkyl,OH,

where R9and R10independently represent H, R11-(C1-C6)alkyl-COO-(C1-C6)alkyl-, where R11represents HOOC-, or R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring may contain one or more than one additional heteroatom, such as morpholine,halogena, C1-C6of alkyl, C1-C6alkoxy, CF3, OH, phenyl, NH2CO-, C1-C6alkyl-CO-, provided that at least one of R6and R7can not be H, C1-C6the alkyl, gidroksilirovanii C1-C6the alkyl or C1-C6alkoxy-substituted C1-C6the alkyl, or its pharmaceutically acceptable salt.

3. The compound of formula I under item 1 or 2, where R1represents CH3or CH2OH; R2represents CH3; R3represents CH3or CH2CH3; R4represents CH3or CH2CH3; R5represents H, Br, Cl or F; R6and R7independently represent H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, halogenated C1-C6alkyl, aryl, where aryl represents phenyl, possibly substituted by one or more than one Deputy, selected from C1-C6of alkyl, C1-C6alkoxy or (C1-C6alkyl)2-N-aryl-substituted C1-C6alkyl in which aryl represents phenyl, imidazolyl, possibly substituted by one who, the where R8represents NH2C=O, C1-C6alkyl-NHC=O-, (C1-C6alkyl)2NC=O-, C1-C6alkyl-OOC-, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-C=O-, ArCONH-, Ar(C1-C6alkyl)CONH, ArC=O, NH2CONH-, C1-C6alkyl-NHCONH-, (C1-C6alkyl)2-NCONH-, ArNHCONH-, gidroksilirovanii C1-C6alkyl-O - or morpholinyl; where Ar represents a phenyl, pyridyl or naphthyl; C7-C12alkyl, OH, R11-(C1-C6)alkyl-COO-(C1-C6)alkyl-, where R11represents HOOC-, or R6and R7together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring may contain one or more than one additional heteroatom, such as morpholine, piperazine, pyrrolidine, piperidine, possibly substituted by one or more than one Deputy, selected from halogen, C1-C6of alkyl, C1-C6alkoxy, CF3, OH, phenyl, NH2CO-, C1-C6alkyl-CO-, provided that at least one of R6and R7can not be H, C1-C6the alkyl.

4. Connection PP.1-3, representing

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-6-(morpholinomethyl)-imidazo[1,2-a]pyridine;

N-(4-ethoxyphenyl)-8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide;

N-[2-(dimethylamine)-2-oxoethyl]-8-(2-ethyl-6-methylbenzylamino)-N,2,3 trimethylimidazo[1,2-a]pyridine-6-carboxamide;

(8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-yl)(4-methylpiperazine)methanon;

1-((8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)carbonyl)-2-(s)-pyrrolidinecarboxamido;

8-(2-ethyl-6-methylbenzylamino)-N-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide;

(2-ethyl-6-methylbenzylamino)-N-(2-(2-hydroxyethoxy)ethyl)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxamide;

(8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)(3-hydroxy-1-pyrrolidinyl)methanon;

N-(3,4-dihydroxyphenyl)-8-(2-ethyl-6-methylbenzylamino)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxamide;

8-(2-ethyl-6-methylbenzylamino-3-(hydroxymethyl)-2-methyl-6-(morpholinomethyl)-imidazo[1,2-a]pyridine;

N-((8-(2-ethyl-6-methylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridine-6-yl)carbonyl)guanidine;

4-(2-(((8-(2-ethyl-6-methylbenzylamino)-2,3-priemlemuyu salt.

5. The compound according to any one of paragraphs.1-4 in the form of a hydrochloride salt or mesilate.

6. Combination drug for the prevention or treatment of gastrointestinal inflammatory diseases in simultaneous, separate or sequential use, containing a compound according to any one of paragraphs.1-5 and at least one antimicrobial agent.

7. The method of obtaining compounds of General formula I according to any one of paragraphs.1-5, where X and R1- R7are specified in paragraph 1 values, which consists in the fact that the compound of General formula II

where R1- R5have the above values, hydrolyzing under standard conditions with obtaining a carboxylic acid of General formula III

which is subjected to interaction with aminoguanidinium formula IV

where R6and R7are specified in paragraph 1 values, in the presence of the agent combinations in standard conditions in an inert solvent.

8. The compound according to any one of paragraphs.1-5 for use in the treatment of gastrointestinal diseases.

9. Pharmaceutical drug, possessing inhibiting the secretion of gastric acid activity, containing as active ingredient a compound according to any one of paragraphs.1-5 in combination with FAA drugs for inhibiting secretion of gastric acid.

11. Method of inhibiting secretion of gastric acid, in which the mammal, including man, in need of such inhibition is administered an effective amount of a compound according to any one of paragraphs.1-5.

12. The method of treatment or prophylaxis of conditions involving infection by Helicobacter pylori infection of the gastric mucosa of a mammal, including humans, in which specified a mammal in need of such treatment is administered an effective amount of a compound according to any one of paragraphs.1-5 in combination with at least one antimicrobial agent.

13. Pharmaceutical preparation for inhibiting the secretion of gastric acid, in which the active ingredient is a compound according to any one of paragraphs.1-5.

14. Pharmaceutical preparation for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori infection of the gastric mucosa of man, in which the active ingredient is a compound according to any one of paragraphs.1-5 in combination for simultaneous, separate or sequential use with at least one antimicrobial agent.

15. The compound of the formula

where R1, R2, R3, R4, R5and X

 

Same patents:

The invention relates to 7-chloro-4-hydroxy-2(2-chloro-4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione, its pharmaceutically acceptable salts, methods for treating pain, when administered pain relieving effective amount of this compound, and pharmaceutical compositions containing this compound

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to compounds of General formula I:

where n is 1, 2 or 3; R1and R2independently selected from hydrogen and alkyl; R3represents alkyl; R4-R7independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio, aaltio, alkylsulfonyl, alkylsulfonyl, arysulfatase, arylsulfonyl, amino, monoalkylamines, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarboxylic, arylcarbamoyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, alkoxycarbonyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, monoalkylammonium, dialkylaminomethyl, or R5and R6together form a carbocyclic or heterocyclic ring, its pharmaceutically acceptable salts and prodrugs and a method of treatment and pharmaceutical compositions having the properties of agonist 5-HT2

The invention relates to the field of medicine and organic chemistry and relates to new derivatives of azobenzenes formula I, II or III, modulating the function of serine/threonine protein kinases, methods of modulating the function of serine/threonine protein kinases, the method of identifying compounds modulating the function of serine/threonine protein kinase, the method of treatment-related serine/threonine protein kinase pathological conditions using such compounds, methods of synthesis of the above on the basis of the compounds of formula I, II or III

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to cavemosum derivative of formula (1) with a broad spectrum of antibacterial activity against different species of pathogenic bacteria, including MRSA

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where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity
The invention relates to biology and biotechnology, in particular to new compounds isolated from plant cells, and can be used in medicine and veterinary medicine as a drug enhancing regenerative repair processes in the mucous membrane of the gastrointestinal tract, as well as in biology and medicine for research purposes

The invention relates to the field of chemistry, particularly the proton pump inhibitors
The invention relates to medicine and can be used in cardiology and gastroenterology

The invention relates to the field of medicine and for farmcampsite for the treatment of ulcers, containing the compounds of formula (a) and (b) and organic compounds containing-ONO2group, or inorganic compounds containing-NO-group

The invention relates to the field of pharmacy, in particular, to herbal medicine and can be used for treatment of ulcer patients with Helicobacter pylori (HP)

The invention relates to thermostable antacid suspension capable of posteritati at a temperature in the range of 60-100oWith, including one or more neutralizing acid and carminative compounds in liquid water suspension containing as a suspending agent is hydroxyethyl cellulose
The invention relates to biotechnology

The invention relates to organic chemistry and can find application in medicine
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