Derivatives imidazopyridine, methods for their preparation and intermediate compounds, pharmaceutical drugs based on them (options), the method of inhibiting the secretion of gastric acid, the method of treatment of gastrointestinal inflammatory diseases and method of treating conditions in which involved infection with h. pylori

 

(57) Abstract:

The invention relates to the derivatives of imidazopyridine formula

or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases. Also describes the methods for their preparation, intermediate compounds, pharmaceutical preparations on their basis, methods of inhibiting the secretion of gastric acid, treatment of gastrointestinal inflammatory diseases and treatment of conditions involving infection by H. PYLORI. 18 N. and 8 C.p. f-l is Eski 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 the invention relate to compounds according to this 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 a therapeutically acceptable salt, as well as to the use of the active compounds in pharmaceuticals for the above medical use. The invention also relates to novel intermediate compounds for obtaining these new compounds.

Background of the invention

Replaced imidazo[1,2-a]pyridine, useful in the treatment of peptic ulcers, known in this field, for example, from EP-B-0033094 and US 4450164 (Schering Corporation), from EP-B-0204285 and US 4725601 (Fujisawa Pharmaceutical Co.), as well as publications (J. J. Kaminski et al. in the 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).

Review of the pharmacology of the gastric acid pump (N+TO+-ATPase), see Sachs et al. (1995). Annu. Rev. Pharmacol. Toxicol. 35:277-305.

+TO+,-ATPase and in view of this as inhibitors of secretion of gastric acid.

In one aspect, the invention thus relates to compounds of General formula I

or their pharmaceutically acceptable salts,

where R1represents the

(a) N

(b) CH3or

(in) CH2HE;

R2represents the

(a) CH3,

(b) CH2CH3;

R3represents the

(a) N

(b)1-C6alkyl,

(C) gidroksilirovanii C1-C6alkyl,

(g) halogen;

R4represents the

(a) N

(b)1-C6alkyl,

(C) gidroksilirovanii1-C6alkyl or

(g) halogen;

R5represents the

(a) N or

(b) halogen;

R6, R7are the same or different

(a) N

(b)1-C6alkyl,

(C) hydroxyle is SS="ptx2">X represents

(a) NH or

(6) O.

Used herein, the term “C1-C6alkyl” means a linear 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, pentyl with linear and branched chain and hexyl.

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

In the scope of the present invention is included as pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers. It should be understood that all possible diastereomers form (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) included in the scope of this invention. In the present invention also includes derivatives of compounds of formula I which possess the biological activity of the compounds of formula I, such as prodrugs.

The person skilled in the art should also understand 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 education is but can be described as “prodrugs”. All prodrugs of the compounds of formula I included in the scope of the present 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 final products included in the scope of the present 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. The obtained free base can also form salts with organic or inorganic acids.

Upon receipt of salts accession acids are preferably used such acids which form suitable therapeutically acceptable salt. Examples of such acids are halogenation acid, such as hydrochloric acid, sulfuric acid, phosphoric 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 is Leonova acid, pyruvic acid, para-hydroxybenzoic acid, albanova acid, methanesulfonate acid, econsultancy acid, hydroxyethanesulfonic acid, halogeenvalgusega acid, toluensulfonate acid or naphthalenesulfonate acid.

Preferred compounds according to the invention are those compounds of formula I, where R1represents CH3or CH2HE; R2represents CH3or CH2CH3; R3represents CH3or CH2CH3; R4represents CH3or CH2CH3; R5represents H, Br, Cl or F.

Particularly preferred compounds according to the invention are

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-propylimidazol[1,2-a]pyridine-6-carboxamide,

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

2,3-dimethyl-8-(2,6-dimethylbenzylamine)-N-hydroxyethylamide[1,2-a]pyridine-6-carboxamide,

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

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

8-(2-ethyl-6-methylbenzylamino)-N,N,2,3-Tetra is camid,

2,3-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxamide mesilate,

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

2,3-dimethyl-8-(2,6-dimethyl-4-forbindelsen)imidazo[1,2-a]pyridine-6-carboxamide mesilate,

2,3-dimethyl-8-(2-methyl-6-isopropylbenzylamine)imidazo[1,2-a]pyridine-6-carboxamide mesilate,

2,3-dimethyl-8-(2,6-diethylaniline)imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethylbenzylamine)imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-hydroxyethylamide[1,2-a]pyridine-6-carboxamide,

N-(2,3-dihydroxypropyl)-2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-[1,2-a]pyridine-6-carboxamide,

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

2-methyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-bromo-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-(2-hydroxyethyl)-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxamide,

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

8-(2-ethyl-6-methylbenzylamino)-N-(2-hydroxyethyl)-N,2,3-crimetime.

The most preferred compounds according to the invention are

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

2,3-dimethyl-8-(2,6-dimethylbenzylamine)-N-hydroxyethylamide[1,2-a]pyridine-6-carboxamide,

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

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

2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyridine-6-carboxamide,

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

2,3-dimethyl-8-(2,6-dimethyl-4-forbindelsen)imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2,6-diethylaniline)-imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-hydroxyethylamide[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-(2-methoxyethyl)imidazo[1,2-a]pyridine-6-carboxamide.

Obtaining

The present invention also proposed the following methods a, B and In the production of compounds of General formula I.

Method AND

Method And production of compounds of General formula I, where X represents NH, containing the following stage.

where R6and R7are as defined for formula I, to obtain the corresponding amide of formula IV. The interaction may be carried out under standard conditions in an inert solvent.

b) compounds of General formula IV

can be subjected to interaction with ammonia to obtain compounds of General formula V

where R6and R7are as defined for formula I.

The reaction can be performed under standard conditions in an inert solvent.

C) the compounds of formula V can be recovered, for example, by using hydrogen and a catalyst such as Pd/C, to obtain the compounds of formula VI

where R6and R7are as defined for formula I.

The reaction can be performed under standard conditions in an inert solvent.

g) Imidazo[1,2-a]pyridine compounds of formula VIII can be obtained by reacting compounds of General formula VI with compounds of General formula VII

where R2is as defined for formula I and Z represents a leaving group such as halogen, mesyl, tosyl, and R9represents N, CH3elitnyh conditions in an inert solvent, such as acetone, acetonitrile, ethanol, dimethylformamide and so on, in the presence or in the absence of a base.

d) the compounds of formula VIII can be subjected to interaction with compounds of formula IX

where R3, R4and R5are as defined for formula I, a Y is a leaving group such as halide, tosyl or mesyl,

to obtain compounds of the formula X

where R2, R3, R4, R5, R6and R7are as defined for formula I, and R9represents N, CH3or ester group, such as SOOSN3, COOC2H5and so on.

Suitable for carrying out this reaction are inert solvents, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide, in the presence or in the absence of base. The base is a hydroxide of an alkali metal 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.

e) Recovery of the compounds of General formula X, where R9represents ECAC tetrahydrofuran or diethyl ether, obtaining compounds of General formula I, where R1represents CH2HE.

Method B

Method B the production of compounds of General formula I, where R1represents N or CH3and X represents NH, contains the following stage.

a) compounds of General formula II

can be subjected to interaction with alcohol of General formula R10-OH, where R10represents an alkyl group such as methyl, ethyl and so on, to obtain the corresponding ester of formula XI.

The reaction can be performed under standard conditions.

b) compounds of General formula XI can be subjected to interaction with ammonia to obtain compounds of General formula XII

where R10represents an alkyl group such as methyl or ethyl, and so on.

The reaction can be performed under standard conditions in an inert solvent.

C) the compounds of formula XII can be recovered, for example, by using hydrogen and a catalyst such as Pd/C, to obtain the compounds of formula XIII

where R10represents an alkyl group such as methyl, ethyl and so on.

The reaction may pray XV, where R10represents an alkyl group such as methyl, ethyl, and so forth, can be obtained by reacting compounds of General formula XIII compounds of General formula XIV

where R2is as defined for formula I, Z represents a leaving group such as halogen, mesyl or tosyl, and R11represents N or CH3.

The reaction is carried out under standard conditions in an inert solvent, such as acetone, acetonitrile, ethanol, dimethylformamide and so on, in the presence or in the absence of a base.

d) the compounds of formula XV can be subjected to interaction with compounds of formula IX

where R3, R4and R5are as defined for formula I, a Y is a leaving group such as halide, tosyl or mesyl, to obtain the compounds of formula XVI

where R2, R3, R4and R5are as defined for formula I, R10represents an alkyl group such as methyl, ethyl, and R11represents N or CH3.

Comfortable is to conduct this reaction in an inert solvent, for example, Aceto the cation. The base is a hydroxide of an alkali metal 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.

(e) Compounds of formula XVI may be subjected to interaction with amino compounds of General formula III

where R6and R7are as defined in formula I,

to obtain the corresponding amide of formula I, where R1represents N or CH3and X represents NH. This reaction can be conducted by heating the interacting substances in pure aminosidine or in an inert solvent under standard conditions.

Method IN

Method of production of compounds of General formula I contains the following stage.

a) Treating the compounds of formula XVII

where R1, R2, R3, R4, R5and X are as defined in formula I, a R10represents an alkyl group such as methyl, ethyl and so on, with an acid or a base under standard conditions, it is possible to hydrolyze them to obtain the corresponding compounds of formula XVIII, representing the FDS is UP>5and X are as defined in formula I, can be subjected to interaction with amino compounds of formula III in the presence of the agent in combination with obtaining the corresponding amide compounds of formula I. the Reaction can be carried out in an inert solvent under standard conditions.

Medical use

In an additional aspect, the invention relates to compounds of formula I for use in therapy, in particular for applications from the gastro-intestinal inflammatory diseases. The invention also suggested the use of the compounds of formula I in the manufacture of medicaments for the inhibition of the secretion of stomach acid or for the treatment of gastrointestinal inflammatory diseases.

Thus, the compounds of the present invention can be used for the prevention and treatment of gastrointestinal inflammatory diseases and diseases caused by exposure to gastric acid, in mammals, including humans, such as gastritis, gastric ulcer, duodenal ulcer, gastroesophageal reflux syndrome Zollinger-Ellison. Moreover, these compounds can be used for treatment of other gastrointestinal disorders, in which the upper gastro-intestinal bleeding. They can also be used in intensive care patients, as well as in pre - and postoperative periods to prevent acid aspiration and stress ulceration.

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

Pharmaceuticals

In another aspect this invention relates to pharmaceutical compositions containing as active ingredient at least one compound according to the invention or a therapeutically acceptable salt.

Compounds according to the invention can also be used in 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 way of introduction. The pharmaceutical preparation contains at least one with Sitel may be in the form of a solid, semi-solid or liquid diluent or in the form of capsules. These pharmaceutical drugs represent another objective of the invention. Usually the number of active compounds is 0.1-95% by weight of the preparation, preferably 0.1 to 20% by weight in preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration.

In the preparation of pharmaceutical preparations containing the compound of the present invention, in the form of dosage units for oral administration, the 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 fumarate and polietilenglikolya waxes. This mixture is then processed into 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. t also 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 substance is mixed with a neutral fat base; (2) in the form of a gelatine rectal capsule which contains the active substance in a mixture with 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 be dissolved 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% by weight of 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. Liquid preparations for oral administration can the physical alteration.

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% by weight. These solutions may also contain stabilizing ingredients and/or tabularasa ingredients, and they can be represented in standard doses in the form of ampoules or vials. Solutions for parenteral administration can also be prepared in the form of a dry preparation, which should be dissolved in a suitable solvent immediately before use.

Compounds of the present invention can also be used in preparations for simultaneous, separate or sequential use in conjunction or 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;

tetracyclines, such as tetany, such as norfloxacin, ciprofloxacin or enoxacin;

others, such as metronidazole, nitrofurantoin, or chloramphenicol, or preparations containing bismuth salt such as bismuth subcitrate, bismuth subsalicylate, subcarbonate bismuth, subnitrate bismuth or subgallate bismuth.

Compounds of the present invention can also be used for simultaneous, separate or sequential use in conjunction or in combination with antacids such as aluminum hydroxide, magnesium carbonate and magnesium hydroxide or alginic acid, or for simultaneous, separate or sequential use in conjunction or in combination with pharmaceutical drugs, which inhibit the secretion of acid, such as H2 blockers (e.g. cimetidine, ranitidine), inhibitors of H+/K+-ATPase (e.g., omeprazole, pantoprazole, lansoprazole or rabeprazole), or for simultaneous, separate or sequential use in conjunction or in combination with gastroprokinetic (e.g., cisapride or mosapride).

Intermediate compounds

An additional aspect of the present invention are new intermediate compounds useful for the synthesis of compounds OYe R2, R6and R7are as defined for formula I, a R9represents N, CH3or ester group, such as SOOSN3, SOOS2H5and so forth;

(b) a compound of the formula X

where R2, R3, R4, R5, R6and R7are as defined for formula I, a R9represents an ester group, such as SOOSN3, COOC2H5and so forth;

(C) a compound of formula XV

where R2is as defined for formula I, R10represents an alkyl group, and R11represents N or CH3;

(g) compound of formula XVI

where R2, R3, R4and R5are as defined for formula I, R10represents an alkyl group, and R11represents N or CH3;

(d) a compound of formula XVIII

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

EXAMPLES

1. Obtaining the COMPOUNDS ACCORDING to the INVENTION

Example 1.1

Synthesis of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-propylimidazol[1,2-a]pyridine-6-carboy acid (0.12 g, 0.33 mmol), Propylamine (1.0 g, 17 mmol) and a catalytic amount of sodium cyanide was heated under reflux in methanol (20 ml) for 24 hours. Added more Propylamine (1.0 g, 17 mmol) and the reaction mixture is boiled under reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using diethyl ether as eluent. Crystallization from diethyl ether gave 0,053 g (42%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 1.0 (t, 3H), 1.2 (t, 3H), 1.65-1.75 (m, 2H), 2.3 (s, 3H), 2.35 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 3.4-3.5 (m, 2H), 4.35 (d, 2H), 4.9 (bs, 1H), 6.2 (bs, 1H), 6.35 (s, 1H), 7.0-7.2 (m, 4H), 7.85 (s, 1H).

Example 1.2

Synthesis of 8-(2-ethyl-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine-6-carboxamide

Ethyl ester of 6-(aminocarbonyl)-8-(2-ethyl-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (280 mg, 0.71 mmol) and borohydride lithium (16 mg, 0.71 mmol) was added to tetrahydrofuran (10 ml) and the reaction mixture is boiled under reflux for 70 minutes. Added additional lithium borohydride (16 mg) and methanol (45 mg, of 1.42 mmol) and this mixture was boiled with about the a (22 mg, 71 mmol) and this mixture was boiled under reflux for 4 hours. The reaction mixture was left to cool to room temperature, and water (1 ml) and methanol (5 ml) and was stirred for 40 minutes at room temperature. The solvent was evaporated under reduced pressure and the residue added to water and was stirred for 80 minutes. The crystals were filtered off and washed with water, ethyl acetate/ethanol and diethyl ether to give the desired product (115 mg, 46%).

1H-NMR (300 MHz, DMSO-d6): 1.15 (t, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.7 (q, 2H), 4.35 (d, 2H), 4.75 (d, 2H), 4.85 (t, 1H), 5.1 (t, 1H), 6.8 (s, 1H), 7.1-7.25 (m, 3H), 7.4 (bs, 1H), 8.05 (bs, 1H), 8.3 (s, 1H).

Example 1.3

Synthesis of 2,3-dimethyl-8-(2,6-dimethylbenzylamine)-N-hydroxyethylamide[1,2-a]pyridine-6-carboxamide

Methyl ester of 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyridine-6-carboxylic acid (0.12 g, 0.33 mmol), ethanolamine (0.2 g, 3.3 mmol) and sodium cyanide (10 mg, 0.2 mmol) was boiled under reflux in dimethoxyethane (2 ml) for 20 hours. The solvent was evaporated under reduced pressure. Purification of the residue via column chromatography on silica gel using a mixture of methylene chloride and methanol in a ratio of 92:8 as eluent gave prodr>1H-NMR (300 MHz, CDCl3): 2.3 (s, 6H), 2.35 (s, 6H), 3.5-3.6 (m, 2H), 3.75-3.8 (m, 2H), 4.3 (d, 2H), 4.95 (t, 1H), 6.4 (s, 1H), 6.85 (t, 1H), 7.07.2 (m, 3H), 7.75 (s,1H).

Example 1.4

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

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (3,3 g, 16.2 mmol), 2-ethyl-6-methylbenzylamine (2,73 g, 16.2 mmol), potassium carbonate (8.0 mg, 58 mmol) and potassium iodide (1.1 g, 6.6 mmol) was added to an acetone (150 ml) and boiled under reflux for 20 hours. Added additional amount of 2-ethyl-6-methylbenzylamine (1.0 g, 5.9 mmol) and the reaction mixture is boiled under reflux for 7 hours. Added methylene chloride (60 ml) and methanol (30 ml). The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio of 100:7 as eluent. Crystallization from ethyl acetate gave 2.8 g (50%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 1.2 (t, 3H), 2.34 (s, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 4.4 (d, 2H), 4.9 (bs, 1H), 6.0 (bs, 2H), 6.45 (s, 1H), 7.0-7.2 (m, 3H), 7.9 (s, 1H).

Example 1.5

Synthesis of 8-(2-ethyl-6-methylbenzylamino)-N,2,3 trimethylimidazo[1,2-a]Peralta (0.15 g, 0.44 mmol) and tetrafluoroborate ortho-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (TBTU) (0.14 g, 0.44 mmol) was added to methylene chloride (10 ml) and the reaction mixture was stirred at room temperature for 15 minutes. Added methylamine (0.1 g, 3.2 mmol) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methylene chloride in the ratio of 1:1 as eluent. The resulting product was treated with diethyl ether to obtain 40 mg (26%) of the desired product.

1H-NMR (300 MHz, CDCl3): 1.2 (t, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 3.05 (d, 3H), 4.35 (d, 2H), 4.9 (t, 1H), 6.3 (bs, 1H), 6.4 (s, 1H), 7.0-7.2 (m, 3H), 7.85 (s, 1H).

Example 1.6

Synthesis of 8-(2-ethyl-6-methylbenzylamino)-N,N,2,3 tetramethylenebis[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 tetrafluoroborate ortho-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (TBTU) (0.14 g, 0.44 mmol) was added to methylene chloride (10 ml). Added dimethylamine (0,063 g, 1.4 mmol) and the reaction mixture was stirred at the ambient temperature t is Noah temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography using a mixture of methylene chloride and methanol in the ratio 9:1 as eluent. The oily product was treated with heptane and the solid which formed was filtered to obtain 0.1 g (62%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 1.2 (t, 3H), 2.35 (s, 6N), 2.4 (s, 3H), 2.7 (q, 2H), 3.15 (s, 6H), 4.4 (d, 2H), 4.9 (t, 1H), 6.25 (s, 1H), 7.0-7.2 (m, 3H), 7.45 (s, 1H).

Example 1.7

Synthesis of 2,3-dimethyl-8-(2,6-dimethylbenzylamine)imidazo[1,2-a]pyridine-6-carboxamide

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (0.6 g, 2.9 mmol), 2,6-dimethylbenzylamine (0.45 g, 2.9 mmol), sodium carbonate (1.0 g, 9.4 mmol) and potassium iodide (0.2 g, 1.3 mmol) was added to an acetone (25 ml) and boiled under reflux for 19 hours. Added methylene chloride and filtered inorganic salts. This solution was washed with bicarbonate solution, the organic layer was separated, dried and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio of 100:5 as eluent, and the product washed with diethyl who .33 (s, 3H), 2.4 (s, 6H), 2.42 (s, 3H), 4.4 (d, 2H), 2.95 (bs, 1H), 6.45 (s, 1H), 7.05-7.15 (m, 3H), 7.95 (s, 1H).

Example 1.8

Synthesis of 2,3-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxamide nelfinavir

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (0.7 g, 1.9 mmol), 2-ethyl-4-fluoro-6-methylbenzylamine (0.26 g, 1.9 mmol) and diisopropylethylamine (0.54 g, 4.2 mmol) was added to dimethylformamide (5 ml) and stirred at room temperature for 1 hour. To the reaction mixture were added methylene chloride and water, the organic layer was separated, dried and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and ethanol and added methanesulfonyl acid (0.2 g, 2 mmol). This product was filtered and dissolved in a mixture of methylene chloride and methanol in the ratio of 2:1 and excess potassium carbonate. The solids were filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio of 10:1 as eluent. The residue was dissolved in ethyl acetate and added methanesulfonyl acid (0.04 g, 0.4 mmol). This salt was filtered to obtain 0.2 g (23%) of the connection specified in the header.

1Example 1.9

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

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (1.0 g, 2.7 mmol), a-chloro-ortho-xylene (or 0.38 g, 2.7 mmol) and diisopropylethylamine (0,76 g, 5.9 mmol) in dimethylformamide (7 ml) was stirred at 50 ° C for 7 hours and at room temperature for 72 hours. The solvent was evaporated, and the residue was treated with a mixture of methylene chloride, water and a small amount of diisopropylethylamine. The solid which formed was isolated by filtration and washed with ethyl acetate to obtain 0.11 g (13%) of the connection specified in the header.

1H-NMR (300 MHz, DMSO-d6): 2.3 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 4.45 (d, 2H), 6.3-6.4 (m, 2H), 7.1-7.25 (m, 4H), 7.3 (bs, 1H), 7.85 (bs, 1H), 8.05 (s, 1H).

Example 1.10

Synthesis of 2,3-dimethyl-8-(2,6-dimethyl-4-forbindelsen)imidazo[1,2-a]pyridine-6-carboxamide nelfinavir

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (5.0 g, a 13.4 mmol), 2,6-dimethyl-4-florantyrone (2.91 in g, a 13.4 mmol), diisopropylethylamine (3.8 g, 29.5 mmol) and a catalytic amount of potassium iodide was stirred in dimethylformamide (20 ml) at room temperature over night. To realsystem pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio 9:1 as eluent. This product was dissolved in isopropanol and added methanesulfonyl acid (0.3 g). The formed salt was isolated by filtration and washed with isopropanol and diethyl ether to obtain 1.4 g (24%) of the connection specified in the header.

1H-NMR (500 MHz, DMSO-d6): 2.25 (s, 3H), 2.35 (s, 6N), 2.4 (s, 3H), 2.5 (s, 3H), 4.4 (d, 2H), 6.1 (bs, 1H), 7.0 (d, 2H), 7.35 (s, 1H), 7.8 (bs, 1H), 8.3 (bs, 1H), 8.45 (s, 1H).

Example 1.11

Synthesis of 2,3-dimethyl-8-(2-methyl-6-isopropylbenzylamine)imidazo[1,2-a]pyridine-6-carboxamide nelfinavir

Used 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (3.0 g, 8.0 mmol), 2-methyl-6-isopropylbenzylamine (1.47 g, 8.0 mmol), diisopropylethylamine (2.4 g, to 18.6 mmol) and a catalytic amount of potassium iodide in dimethylformamide (15 ml). The connection specified in the header, was obtained in accordance with example 1.10 (output 1.3 g, 36%).

1H-NMR (300 MHz, DMSO-d6): 1.2 (d, 6H), 2.25 (s, 3H), 2.4 (s, 3H), 2.45 (s, 3H), 2.5 (s, 3H), 3.2 (m, 1H), 4.45 (d, 2H), 6.15 (bs, 1H), 7.15-7.3 (m, 3H), 7.4 (s, 1H), 7.85 (bs, 1H), 8.35 (bs, 1H), 8.45 (s, 1H).

Example 1.12

Synthesis of 2,3-dimethyl-8-(2,6-diethylaniline)imidazo[1,2-a]mmol), 2,6-diethylaniline (1.8 g, 9.9 mmol), diisopropylethylamine (3.0 g, with 23.3 mmol) was stirred in dimethylformamide (20 ml) at 50 ° C overnight and at 70 C for 3 hours. Added water (60 ml) and methylene chloride, and the organic layer was separated, dried and evaporated under reduced pressure. The residue was treated with diethyl ether, and the product was filtered to obtain 1.7 g (45%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 1.2 (t, 6H), 2.35 (s, 3H), 2.4 (s, 3H), 2.7 (q, 4H), 4.4 (d, 2H), 4.95 (bs, 1H), 6.15 (bs, 2H), 6.5 (s, 1H), 7.05-7.25 (m, 3H), 7.95 (s, 1H).

Example 1.13

Synthesis of 2,3-dimethyl-8-(2-ethylbenzylamine)imidazo[1,2-a]pyridine-6-carboxamide

Used 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (4.0 g, is 10.7 mmol), 2-ethylbenzylamine (1,65 g of 10.7 mmol), diisopropylethylamine (3.0 g, with 23.3 mmol) in dimethylformamide (20 ml).

The connection specified in the header, obtained according to example 1.12 (yield of 1.15 g, 26%).

1H-NMR (300 MHz, CDCl3): 1.2 (t, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.75 (q, 2H), 4.5 (d, 2H), 6.3 (t, 1H), 6.4 (s, 1H), 7.05-7.25 (m, 4H), 7.3 (bs, 1H), 7.85 (bs, 1H), 8.05 (s, 1H).

Example 1.14

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

2,3-Dimethyl-8-(2-ethyl-6-meth is N,N,N’,N’-tetramethylurea (TBTU) (0.29 grams, 0.90 mmol) was added to methylene chloride (15 ml) and this mixture was stirred for 5 minutes. Added ethanolamine (0.11 g, 1.8 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio 9:1 as eluent. Crystallization from diethyl ether gave 0,2 (59%) of the desired product.

1H-NMR (500 MHz, CDCl3): 1.2 (t, 3H), 2.3 (s, 6H), 2.35 (s, 3H), 2.7 (q, 2H), 3.55-3.6 (m, 2H), 3.8-3.85 (m, 2H), 4.35 (d, 2H), 4.9 (t, 1H), 6.4 (s, 1H), 6.85 (t, 1H), 7.05-7.2 (m, 3H), 7.75 (s, 1H).

Example 1.15

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

Applied 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g, 0.88 mmol), tetrafluoroborate ortho-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (TBTU) (0,29 g, 0.90 mmol) and 3-amino-1,2-propandiol (0.16 g, is 1.81 mmol) in dimethylformamide (10 ml).

The connection specified in the header, obtained in accordance with example 1.14 (yield 0.2 g, 54%).

1H-NMR (500 MHz, CDCl3): 1.2 (t, 3H), 1.82-1.85 (m, 1H), 2.32 (s, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.7 (q, 2H), 3.5-3.65 (m, 4H), 3.72-3.7 shall imethyl-8-(2-ethyl-6-methylbenzylamino)-N-(2-methoxyethyl)-imidazo[1,2-a]pyridine-6-carboxamide

Applied 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol), tetrafluoroborate ortho-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (TBTU) (0.14 g, 0.44 mmol) and 2-methoxyethylamine (0.11 g, 1.4 mmol) in methylene chloride (10 ml).

The connection specified in the header, obtained in accordance with example 1.14.

Crystallization from a mixture of hexane and ethyl acetate (yield 0.09 g, 53%).

1H-NMR (400 MHz, CDCl3): 1.22 (t, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.71 (q, 2H), 3.42 (s, 3H), 3.6-3.72 (m, 4H), 4.38 (d, 2H), 4.91 (t, 1H), 6.42 (s, 1H), 6.58 (t, 1H), 7.04-7.2 (m, 3H), 7.88 (s, 1H).

Example 1.17

Synthesis of 2-methyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxamide

8-Amino-2-methylimidazo[1,2-a]pyridine-6-carboxamide (3.8 g, 20 mmol), 2-ethyl-6-methylbenzylamine (2.8 g, 17 mmol), potassium carbonate (5.5 g, 40 mmol) and sodium iodide (0.1 g, 0.6 mmol) was added to dimethylformamide (75 ml) and this mixture was stirred at 50C for 4 hours and at room temperature for 48 hours. The reaction mixture was filtered through silica gel and the gel was rinsed with methylene chloride. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride compounds specified in the header.

1H-NMR (400 MHz, CDCl3): 1.15 (t, 3H), 2.31 (s, 6H), 2.64 (q, 2H), 4.32 (d, 2H), 4.89 (bs, 1H), 6.36 (s, 1H), 7.0-7.15 (m, 3H), 7.23 (s, 3H), 8.03 (s, 1H).

Example 1.18

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

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesilate (1.0 g, 5.0 mmol), 2-bromo-6-methylbenzylamine (45%) (3.0 g, 5.0 mmol) and diisopropylethylamine (2.2 g, 17 mmol) was added to dimethylformamide (50 ml) and stirred at 50C for 48 hours. To the reaction mixture were added methylene chloride and water, the organic layer was separated, washed with saturated sodium chloride, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel, using a mixture of methylene chloride and methanol in the ratio of 10:1 and ethyl acetate as eluent, gave 0.18 g (1%) of the desired product.

1H-NMR (300 MHz, CDCl3): 2.28 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 4.48 (d, 2H), 5.0 (bs, 1H), 6.05 (bs, 2H), 6.41 (d, 1H), 6.95-7.1 (m, 2H), 7.37 (d, 1H), 7.87 (d, 1H).

Example 1.19

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

2,3-Dimethyl-8-(2-(2-(benzyloxy)ethyl)-6-methylbenzylamino)imidazo[1,2-a]Piri is ü boiled under reflux during the night. Added additional amount of cyclohexene (1 ml) and Pd(OH)2(cat., 25 mg) and the mixture was boiled under reflux for 4 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio 9:1 as eluent. Treatment of the residue with chloroform and filtering gave 0.1 g (99%) of the connection specified in the header.

1H-NMR (400 MHz, CD3OD): 2.29 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.94 (t, 2H), 3.74 (t, 2H), 4.47 (s, 2H), 6.83 (d, 1H), 7.11-7.20 (m, 3H), 8.12 (d, 1H).

Example 1.20

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

Applied 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g, 0.88 mmol), tetrafluoroborate ortho-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (TBTU) (0.3 g, were 0.94 mmol) and diethanolamine (0.2 g, 1.9 mmol) in methylene chloride (10 ml).

The connection specified in the header, obtained in accordance with example 1.14 (output 0,19 g, 50%).

1H-NMR (400 MHz, Dl3): 1.2 (t, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 2.7 (q, 2H), 3.65 (bs, 4H), 3.9 (bs, 4H), 4.35 (d, 2H), 4.95 (bs, 1H), 6.35 (s, 1H), 7.0-7.2 (m, 3H), 7.7 (s, 1H).

Example 1.21

Synthesis premanjali 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g, 0.88 mmol), tetrafluoroborate ortho-benzotriazol-1-yl-N,N,N’,N’-tetramethylurea (TBTU) (0.3 g, were 0.94 mmol) and 2-(methylamino)ethanol (0.2 g, of 2.66 mmol) in methylene chloride (10 ml).

The connection specified in the header, obtained in accordance with example 1.14 (yield 0.25 g, 71%).

1H-NMR (600 MHz, CDCl3): 1.2 (t, 3H), 2.25 (s, 6N), 2.35 (s, 3H), 2.7 (q, 2H), 3.15 (s, 3H), 3.65 (bs, 2H), 3.9 (bs, 2H), 4.35 (d, 2H), 5.0 (bs, 1H), 6.25 (bs, 1H), 7.0-7.25 (m, 3H), 7.45 (bs, 1H).

Example 1.22

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

6-Amino-5-(2-ethyl-6-methylbenzylamino)nicotinamide (0.14 g, 0.49 mmol), 3-bromo-2-butanone (0.075 g, 0.49 mmol) and sodium bicarbonate (0.1 g, 1.2 mmol) was added to acetonitrile (3 ml) and boiled under reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio 9:1 as eluent. Crystallization from acetonitrile gave 0,058 g (35%) of the connection specified in the header.

1H-NMR (300 MHz, DMSO-d6): 1.14 (t, 3H), 2.24 (s, 3H), 2.33 (s, 3H), 2.40 (s, 3H), 2.69 (q, 2H), 5.25 (s, 2H), 7.1-7.3 (m, 4H), 7.51 (bs, 1H), 8,08 (bs, 1H), 8.42 (s, 1H).

2. The INTERMEDIATE COMPOUNDS

Example 2.1

The synthesis is given to 5C. Within 30 minutes was added dropwise methanol and the reaction mixture was stirred for 60 minutes. The temperature was not allowed to rise above 10C. To the reaction mixture was added dropwise to the ammonium hydroxide (25%, 400 ml) and the mixture was stirred at room temperature for 20 hours. The product was filtered, washed with water and dried to obtain 9.0 g (45.9 per cent) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 3.95 (s, 3H), 6.3 (bs, 1H), 8.0 (bs, 1H), 8.95 (s, 1H), 9.05(s, 1H).

Example 2.2

Synthesis of methyl ester of 5,6-diaminotoluene acid

Methyl ester of 6-amino-5-nitronicotinic acid (9.0 g, 46 mmol) and a small amount of Pd/C catalyst was added to methanol (200 ml) and this mixture was hydrogenosomal at room temperature and atmospheric pressure until, until stopped absorption of hydrogen. After filtration through celite, the methanol was evaporated under reduced pressure to get the connection specified in the header, 7.0 g (92%).

1H-NMR (300 MHz, CDCl3): 3.3 (s, 2H), 3.9 (s, 3H), 4.75 (s, 2H), 7.45 (s, 1H), 8.35 (s, 1H).

Example 2.3

Synthesis of methyl ester of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid

Methyl ester of 5,6-diaminotoluene acid (0m within 24 hours. Upon cooling was filtered certain amount of product in the form of hydrobromide salt. 20 ml of the filtrate was evaporated under reduced pressure and added to diethyl ether. An additional amount of product was filtered as hydrobromide salt. This salt was dissolved in methylene chloride and washed with a solution of bicarbonate. The organic layer was separated, dried over PA2SO4and evaporated under reduced pressure to obtain 0.7 g (59%) of the desired compound.

1H-NMR (300 MHz, Dl3): 2.4 (s, 6N), 3.9 (s, 3H), 4.5 (s, 2H), 6.85 (s, 1H), 8.1 (s, 1H).

Example 2.4

Synthesis of methyl ester of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxylic acid

Methyl ester of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid (0.7 g, 3.2 mmol), 2-ethyl-6-methylbenzylamine (0.54 g, 3.2 mmol), potassium carbonate (0.9 g, 6.4 mmol) and a catalytic amount of potassium iodide were added to acetonitrile (20 ml) and boiled under reflux for 6 hours. After filtration of the acetonitrile was evaporated under reduced pressure to obtain oil. The oily residue was dissolved in methylene chloride and washed with water. The organic layer was separated, dried over Na2SO4and evaporated under reduced with Dablam mixture of methylene chloride and ethyl acetate in a ratio of 10:1 as eluent gave 0,42 g (38%) compound specified in the header.

1H-NMR (500 MHz, CDCl3): 1.15 (t, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 2.43 (s, 3H), 2.75 (q, 2H), 4.0 (s, 3H), 4.25 (d, 2H), 4.9 (bs, 1H), 6.8 (s, 1H), 7.05-7.2 (m, 3H), 8.1 (s, 1H).

Example 2.5

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

Methyl ester of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (0.4 g, 1.1 mmol) was added to a mixture of 1,4-dioxane (6 ml) and 2 M NaOH (6 ml) and boiled under reflux for 30 minutes. The dioxane was evaporated under reduced pressure and the aqueous solution was acidified by addition of 2 M HCl. The acidic aqueous solution was podslushivaet by adding a saturated solution of bicarbonate, and the resulting solid was isolated by filtration to obtain 0.35 g (91%) of the connection specified in the header.

1H-NMR (400 MHz, DMSO-d6): 1.15 (t, 3H), 2.2 (s, 3H), 2.35 (s, 6H), 2.7 (q, 2H), 4.35 (d, 2H), 4.65 (t, 1H), 6.8 (s, 1H), 7.05-7.2 (m, 3H), 7.95 (s, 1H).

Example 2.6

Synthesis of ethyl ester of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid

Ethyl ester of 5,6-diaminotoluene acid (1.4 g, 7.7 mmol) and 3-bromo-2-butanone (1,16 g, 7.2 mmol) was added to 1,2-dimethoxyethane (50 ml) and boiled under reflux for 20 hours. The solvent operandum sodium bicarbonate and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio of 10:1 as eluent, to obtain 0.3 g (17%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 1.4 (t, 3H), 2.4 (s, 6H), 4.35 (q, 2H), 4.6 (s, 2H), 6.75 (s, 1H), 8.2 (s, 1H).

Example 2.7

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

Ethyl ester of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid (0.7 g, 3.0 mmol), 2-ethyl-6-methylbenzylamine (0.5 g, 3.0 mmol), sodium carbonate (0.64 g, 6.0 mmol) and a catalytic amount of potassium iodide was added to an acetone (50 ml) and boiled under reflux for 20 hours. After filtration, the acetone was evaporated under reduced pressure to obtain oil. The oily product was purified by column chromatography on silica gel using a mixture of diethyl ether and petroleum ether in the ratio 1:1 as eluent, to obtain 0.12 g (9%) of the connection specified in the header.

1H-NMR (500 MHz, CDCl3): 1.25 (t, 3H), 1.5 (t, 3H), 2.35 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 2.75 (q, 2H), 4.45-4.5 (m, 4H), 4.9 (bs, 1H), 6.8 (s, 1H), 7.05-7.2 (m, 3H), 8. the orida (38 g, 0.2 mol) in tetrahydrofuran (500 ml) was stirred at 5 ° C and ammonia were barbotirovany in the solution. The reaction mixture was left to warm to room temperature over 1 hour and the ammonia was barbotirovany in the solution for an additional 2.5 hours. The reaction mixture was stirred at room temperature for 20 hours. Solids were removed by filtration, thoroughly washed with water and dried under reduced pressure to obtain 18.5 g (51%) of the connection specified in the header.

1H-NMR (400 MHz, DMSO-d6): 7.4 (s, 1H), 8.05 (s, 1H), 8.3 (s, 2H), 8.8 (s, 2H).

Example 2.9

Synthesis of 5,6-diaminononane

A suspension of 6-amino-5-nitronicotinic (18 g, 99 mmol) and catalytic amount of Pd/C in methanol (600 ml) and this mixture was hydrogenosomal at room temperature and atmospheric pressure until, until stopped absorption of hydrogen. After filtration through celite, the methanol was evaporated under reduced pressure to get the connection specified in the header, 14.5 g (96%).

1H-NMR (300 MHz, DMSO-d6): 5.0 (bs, 2H), 6.1 (bs, 2H), 6.9 (bs, 1H), 7.15 (s, 1H), 7.55 (bs, 1H), 7.9 (s, 1H).

Example 2.10

Synthesis of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

5,6-Diaminononane (12.5 g, 82 mmol), 3-the additional amount of 3-bromo-2-butanone (4.0 g, of 26.5 mmol) and the reaction mixture is boiled under reflux for 5 hours. When cooled, the solids were removed by filtration. Solids added to methylene chloride (150 ml), methanol (150 ml) and potassium carbonate (22 g, 160 mmol) and was stirred for 30 minutes. Solids were removed by filtration, and evaporation of the solvents under reduced pressure gave an oily residue. Purification using column chromatography on silica gel with elution with a mixture of methylene chloride and methanol in the ratio of 5:1, gave 3.3 g (20%) of the connection specified in the header.

1H-NMR (400 MHz, DMSO-d6): 2.25 (s, 3H), 2.35 (s, 3H), 5.6 (s, 2H), 6.65 (s, 1H), 7.15 (bs, 1H), 7.85 (bs, 1H), 8.05 (s, 1H).

Example 2.11

Synthesis of ethyl ester of 8-amino-6-(aminocarbonyl)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid

5,6-Diaminononane (2.0 g, a 13.4 mmol), ethyl ester of 2-chloroacetoacetic acid (2.38 g, 14.4 mmol) and ethanol (40 ml) was boiled under reflux for 20 hours. The precipitate was isolated by filtration and washed with ethanol and diethyl ether. Solids suspended in water, podslushivaet the sodium hydroxide solution and was isolated by filtration. Washing solids with water and diethyl EF 6.9 (s, 1H), 7.35 (bs, 1H), 8.0 (bs, 1H), 9.0 (s, 1H).

Example 2.12

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

Ethyl ester of 8-amino-6-(aminocarbonyl)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0,41 g, 1.6 mmol), 2-ethyl-6-methylbenzylamine, sodium carbonate (0.7 g, 6.6 mmol), sodium iodide (0.15 g, 1.0 mmol) and acetone (20 ml) was boiled under reflux for 44 hours. Added methylene chloride and removing the solids by filtration. The filtrate was evaporated under reduced pressure and purification of the residue via column chromatography on silica gel with elution with a mixture of methylene chloride and methanol in the ratio of 100:4 gave 0.35 g (56%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 1.25 (t, 3H), 1.45 (t, 3H), 2.35 (s, 3H), 3.65 (s, 3H), 2.7 (q, 2H), 4.4-4.45 (m, 4H), 5.0 (t, 1H), 6.95 (s, 1H), 7.0-7.2 (m, 3H), 9.2 (s, 1H),

Example 2.13

Synthesis of 8-amino-2-methylimidazo[1,2-a]pyridine-6-carboxamide nelfinavir

5,6-Diaminononane (10 g, 66 mmol), chloroacetone (6,1 g, 66 mmol) and sodium bicarbonate (11.2 g, 132 mmol) was added to dimethylformamide (200 ml) and this mixture was stirred for 72 hours at room temperature. A large part of the solvent is evaporated under pengendali under reduced pressure and to the residue was added ethanol. When heated the mixture up to 60C product crystallized in the form of salt and was filtered to obtain 6 g (32%) of the connection specified in the header.

1H-NMR (400 MHz, CDCl3): 2.3 (s, 6H), 7.25 (s, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.75 (s, 1H), 7.85 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.6 (s, 1H).

Example 2.14

Synthesis of 1-bromo-2-isopropyl-6-methylbenzoyl

2-Isopropyl-6-methylaniline (14.9 g, 0.1 mol) was dissolved in concentrated Hydrobromic acid (40 ml) and this mixture was cooled to 5C. Sodium nitrite (7.0 g, 0.1 mol) in water (15 ml) was added so that the temperature was below 10C. To the reaction mixture was added a solution of copper bromide (I) in concentrated Hydrobromic acid (10 ml) and left, so that the temperature rose to room. This mixture was stirred for 1 hour at room temperature and for 30 minutes at 40C. Added hexane, and the organic layer was separated and evaporated under reduced pressure. Purification using column chromatography on silica gel using hexane as eluent gave 6.9 g (32%) of the compound indicated in the title, in the form of butter.

1H-NMR (300 MHz, CDCl3): 1.23 (d, 6H), 2.43 (s, 3H), 3.4-3.55 (m, 1H), 7.05-7.2 (m, 3H).

Example 2.15

Synthesis of 2-isopropyl-6-methylbenz the magnesium shavings (0.9 g, 37 mmol) and this mixture was boiled under reflux in a nitrogen atmosphere until then, until the reaction had begun, and then stirred over night at room temperature. Within 10 minutes was added dropwise dimethylformamide (4 ml) and this mixture was stirred for 30 minutes. Added a saturated solution of ammonium chloride (30 ml) and this mixture was stirred for 1 hour. The organic layer was separated, was filtered and was evaporated under reduced pressure. Purification using column chromatography on silica gel using a mixture of hexane and methylene chloride in a ratio of 3:2 as eluent gave 1.75 g (33%) of the connection specified in the header.

1H-NMR (500 MHz, CDCl3): 1.25 (d, 6H), 2.55 (s, 3H), 3.7-3.8 (m, 1H), 7.1-7.4 (m, 3H), 10.65 (s, 1H).

Example 2.16

Synthesis of 2-isopropyl-6-methylbenzylamino alcohol

To a solution of 2-isopropyl-6-methylbenzaldehyde (1,75 g to 10.8 mmol) in methanol (15 ml) was added borohydride sodium (0.35 g, 9.5 mmol) and the mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure and to the residue was added hexane and water. The organic layer was separated and evaporated under reduced pressure to obtain 1.73 g (98%) of the connection specified in Savolainen 2.17

Synthesis of 2-isopropyl-6-methylbenzylamine

To a solution of 2-isopropyl-6-methylbenzylamino alcohol (1.7 g, 10.4 mmol) in methylene chloride (20 ml) was added thionyl chloride (1.7 g, 14 mmol) and this reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the residue was filtered through silica gel, using methylene chloride as eluent. The solvent was evaporated under reduced pressure to get to 1.83 g (96%) of the compound indicated in the title, in the form of butter.

1H-NMR (500 MHz, CDCl3): 1.25 (d, 6H), 2.45 (s, 3H), 3.25-3.35 (m, 1H), 4.75 (s, 2H), 7.05-7.25 (m, 3H).

Example 2.18

Synthesis of 2-bromo-6-methylbenzylamine

A mixture of 3-bromo-ortho-xylene (15 g, 81 mmol), N-bromosuccinimide (15,1 g of 85.1 mmol), dibenzoylperoxide (0.65 g) and carbon tetrachloride (150 ml) was boiled under reflux for 5 hours. After filtration, the filtrate was washed with acidic sodium sulfite and water. The organic layer was dried over sodium sulfate and evaporated under vacuum. Chromatography (SiO2, petroleum ether : ethyl acetate, 100:4) gave a 16.8 g of fraction a mixture containing 45% of the connection specified in the header. This mixture was used without further purification.

1H-NMR (300 MHz, CDCl31H-NMR (500 MHz, CDCl3): 2.44 (s, 3H), 3.86 (s, 2H), 7.22-7.37 (m, 3H).

Example 2.20

Synthesis of 2-(2-bromo-3-were)acetic acid

2-(2-Bromo-3-were)acetonitrile (8.0 g, of 0.038 mol) was added to a mixture of water (60 ml) and sulfuric acid (50 ml) and this mixture was boiled under reflux overnight. After cooling to room temperature, added water (200 ml) and this mixture was extracted twice with methylene chloride. Methylenechloride extracts were combined, washed twice with water, dried and evaporated under reduced pressure to obtain 7.9 g (90,8%) of the connection specified in the header.

1H-NMR (400 MHz, CDCl3): 2.42 (s

2-(2-Bromo-3-were)acetic acid (7.9 g, 0,034 mol) and sulfuric acid (0.1 ml) was added to ethanol (25 ml) and this mixture was boiled under reflux overnight. The solvent was evaporated and to the residue was added saturated sodium carbonate. The aqueous solution was extracted twice with diethyl ether, the organic extracts were combined, washed twice with water, dried and evaporated under reduced pressure to give the desired product as oil (8.5 g, 97.7 per cent).

1H-NMR (400 MHz, CDCl3): 1.24 (t, 3H), 2.40 (s, 3H), 3.78 (s, 3H), 4.16 (q, 2H), 7.06-7.14 (m, 3H).

Example 2.22

Synthesis of 2-(2-bromo-3-were)-1-ethanol

LiAlH4(3.1 g, 0,083 mol) is suspended in dry tetrahydrofuran (100 ml) in an argon atmosphere. Added ethyl ester 2-(2-bromo-3-were)acetic acid (8.5 g, 0,033 mol) dissolved in dry tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 4 hours. This mixture was cooled on ice and was added dropwise to 3.1 ml of water, then with 3.1 ml of 15% sodium hydroxide and then with 9.3 ml of water. After 15 hours, the solids were removed by filtration and thoroughly washed with tetrahydrofuran. The filtrate was removed under reduced pressure. Purification of the residue by filtration through selegiline, specified in the header, in the form of butter.

1H-NMR (400 MHz, Dl3): 2.39 (s, 3H), 3.00 (t, 2H), 3.81 (t, 2H), 7.04-7.10 (m, 3H).

Example 2.23

Synthesis of benzyl-2-bromo-3-methylpentylamino ether

Sodium hydride (50% in oil) (1.7 g, being 0.036 mol) is suspended in dry tetrahydrofuran (75 ml) in an argon atmosphere. For 30 minutes at room temperature was added dropwise 2-(2-bromo-3-were)-1-ethanol (7.0 g, 0,033 mol) dissolved in tetrahydrofuran (25 ml). Added benzylbromide (6.2 g, being 0.036 mol) and this reaction mixture was stirred at room temperature overnight. Carefully added water (1.0 ml) and the solvent was evaporated under reduced pressure. The residue was distributed between water and diethyl ether and the aqueous layer was twice extracted with diethyl ether. The ether extracts were combined, washed twice with water and evaporated under reduced pressure. Purification of the residue via column chromatography on silica gel using a mixture of heptane and methylene chloride in the ratio of 7:3 as eluent gave 7.5 g (74.3 per cent) of the connection specified in the header.

1H-NMR (400 MHz, Dl3): 2.38 (s, 3H), 3.10 (t, 2H), 3.69 (t, 2H), 4.51 (s, 2H), 7.04-7.08 (m, 3H), 7.21-7.30 (m, 5H).

Example 2.24

Synthesis of 2-[2-(benzyloxy)ethyl]-6-METI is wound in a nitrogen atmosphere at-65S added tert-utility (1.7 M in pentane) (10.5 ml, 0.018 mol) and this mixture was stirred at-20C for 30 minutes. Under-65S was added dropwise dimethylformamide (1.5 g, 0,021 mol) and this mixture was stirred at-20C for 30 minutes and at room temperature for 1 hour. To the solution were carefully added water and 2M HCl to acidify it, and the mixture was stirred for 30 minutes. To this mixture was added diethyl ether (50 ml), the organic layer was separated, washed with saturated sodium carbonate and water. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue via column chromatography on silica gel using a mixture of heptane and methylene chloride in the ratio of 2:8 as eluent gave 1.0 g (38.5 percent) of the connection specified in the header.

1H-NMR (300 MHz, Dl3): 2.55 (s, 3H), 3.23 (t, 2H), 3.66 (t, 2H), 4.46 (s, 2H), 7.05-7.31 (m, 8H), 10.54 (s, 1H).

Example 2.25

Synthesis 8-((2-[2-(benzyloxy)ethyl]-6-methylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

To a solution of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide nelfinavir 1.4 g (0,0038 mol) in methanol (20 ml) under nitrogen atmosphere was added zinc chloride (1.0 g, to 0.0039 mol) dissolved in methanol (10 ml) and this mixture was stirred for 30 minutes. To this mixture was added 2-[2-(b whom or under reflux overnight. The reaction mixture was cooled to room temperature, was added triethylamine (4 ml), the mixture was stirred for 30 minutes and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol in the ratio 9:1 as eluent. The residue was dissolved in diethyl ether was treated with diethyl ether/Hcl and the precipitated product was filtered in the form of cleaners containing hydrochloride salt. This salt was dissolved in methylene chloride and washed with saturated sodium carbonate. The organic layer was separated, washed with water, dried and evaporated under reduced pressure obtaining of 0.13 g (7.7 g) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 2.31 (s, 3H), 2.33 (s, 3H), 2.34 (s, 3H), 2.98 (t, 2H), 3.66 (t, 2H), 4.37 (d, 2H), 4.46 (s, 2H), 5.02 (bs, 1H), 6.29 (bs, 2H), 6.47 (s, 1H), 7.03-7.26 (m, 8H), 7.91 (s, 1H).

Example 2.26

Synthesis of 2-ethyl-6-methylbenzylamino ester 5-(2-ethyl-6-methylbenzylamino)-6-nitronicotinic acid

5-Hydroxy-6-nitronicotinic acid (1 g, 5 mmol), 2-ethyl-6-methylbenzylamine (1.85 g, 11 mmol), N,N-Diisopropylamine (1.75 g, 14 mmol) and tetrabutylammonium iodide (0.1 g) were added to acetonitrile (10 ml) and boiled under reflux for 3 hours. the organic layer was separated, was dried and evaporated under reduced pressure. Purification of the residue via column chromatography on silica gel using a mixture of n-hexane and methylene chloride in the ratio of 1:1 as eluent gave 0.7 g (29%) of the connection specified in the header.

1H-NMR (300 MHz, CDCl3): 6 1.2 (t, 3H), 1.25 (t, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 2.7 (q, 2H), 2.8 (q, 2H), 5.25 (s, 2H), 5.55 (s, 2H), 7.05-7.3 (m, 6N), 8.2 (s, 1H), 8.65 (s, 1H).

Example 2.27

Synthesis of 6-amino-5-(2-ethyl-6-methylbenzylamino)nicotinamide

2-Ethyl-6-methylbenzylamine ester 5-(2-ethyl-6-methylbenzylamino)-6-nitronicotinic acid (0.7 g, 2 mmol) was added to a solution of ammonia in methanol (5-10%, 40 ml) and the mixture was stirred at 35C within 96 hours. The solvent was evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel using mixtures of ethyl acetate and methylene chloride in the ratio of 1:1 mixture of methanol and methylene chloride in the ratio of 1:9 as eluent gave 0.14 g (31%) of the connection specified in the header.

1H-NMR (500 MHz, CDCl3): 1.21 (t, 3H), 1.87 (s, 2H), 2.37 (s, 3H), 2.72 (q, 2H), 5.11 (s, 2H), 5.99 (bs, 2H), 7.1-7.3 (m, 3H), 7.67 (d, 1H), 8.09 (d, 1H).

BIOLOGICAL TESTS

1. Experiments in vitro.

Inhibition of acid secretion in isolated zielasek rabbit was determined, 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) were incubated for 15 minutes at C 18 mm Pipes buffer/Tris, pH of 7.4, containing 2 mm gl2, 10 mm KCl and 2 mm ATP. The ATPase activity was assessed by the release of inorganic phosphate from ATP, as described LeBel et al. (1978). Anal. Biochem. 85, 86-89.

2. Experiments in vivo.

Inhibitory effect on the secretion of acid in female rats

Used female rats Sprague-Dawly. Collection of gastric secretions and the introduction of the test substances were introduced kanilirovannoy the fistula into the stomach lumen) and in the upper part of the duodenum, respectively. The recovery period after surgery before testing was 14 days.

Before conducting tests on the production of animals for 20 hours were deprived of food but not water. The stomach repeatedly washed through the gastric cannula tap water (S) and subcutaneously injected 6 ml glucose ringer (Ringer-Glucose). The acid secretion stimulated by infusion of pentagastrin and carbachol (20 and 110 nmol/AU, respectively) for 2.5-4 hours (1.2 ml/h, subcutaneously), and during this time he collected the gastric secrets in the form of 30-gtreverse and intraduodenal dosing, 1 ml/kg), or for 2 hours 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 was titrated to pH 7.0 using 0.1 M NaOH and the acid output was calculated as the product of the volume of the titrated solution and concentration.

Further calculations were based on average group responses 4-6 rats. In the case of the introduction during stimulation of the release of acid during the periods after the introduction of the test substance or solvent were expressed as fractional answers, taking the exit acid in 30-minute period preceding the introduction, for 1.0. The percentage of inhibition was calculated from the fractional responses caused by the test compound and the solvent. In the case of the introduction to stimulation the percentage of inhibition was calculated directly from the output of acid, registered after the introduction of the test compound and solvent.

Bioavailability in rats

Used adult rats Sprague-Dawly. For 1-3 days before the experiments, all rats under anesthesia was administered cannula into the left carotid artery. Rats used for inside the and back of the neck.

Blood samples (0.1-0.4 g) were repeatedly collected from the carotid artery for 5.5 hours after administration of the dose. Samples were frozen until analyzed test the connection.

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

The area under the curve concentration in the blood AUC from time was determined using the logarithmic/linear trapezoid and extrapolated to infinity by dividing the last of a certain blood concentration on the rate constant of elimination in the final phase. Systemic bioavailability (F %) after intraduodenal or oral administration was calculated as F (%)=AUC (p. O. or I. D.)/ AUC (century))100.

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

Used hunting dogs of the Labrador breed, or dogs of both sexes. They were introduced duodenal fistula required for insertion of test compounds or solvent, and kanalirovanie gastric fistula or bag HEIDENHAIN the hours were deprived of food with free access to water. The secretion of gastric acid stimulated up to 6.5 hours infusion of histamine dihydrochloride (12 ml/h) dose that causes about 80% of the individual maximal secretory response and gastric juice was collected as successive 30-min fractions. The test substance or solvent gave oral, I. D., or centuries after 1 or 1.5 hours after the start of infusions of histamine in the amount 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 acid the main stomach of a dog with a bag of HEIDENHAIN.

The acidity of the samples of gastric juice was determined by titration to pH 7.0 and expected output acids. The release of acid into the collection periods after administration of the test substance or solvent were expressed as fractional answers, taking the output of the acid in the fraction preceding the introduction, for 1.0. The percentage of inhibition was calculated from the fractional responses caused by the test compound and the solvent.

Blood samples for analysis of concentration of test compound in the plasma was collected at intervals of time up to 4 hours after dosing. Plasma was separated and frozen within 30 minutes after collection and later an is as described above for the model in rats.

1. Derivatives imidazopyridine General formula I

or their pharmaceutically acceptable salt,

where R1represents (a) H, (b) CH3or (C) CH2HE;

R2represents (a) CH3(b) CH2CH3;

R3represents (a) H, (b) C1-C6alkyl; (C) gidroksilirovanii C1-C6alkyl; (d) halogen;

R4represents (a) H, (b) C1-C6alkyl, (C) gidroksilirovanii C1-C6alkyl or (g) halogen;

R5represents (a) H or (b) halogen;

R6and R7are the same or different (a) H, (b) C1-C6alkyl, (C) gidroksilirovanii C1-C6alkyl, (g) C1-C6alkoxy-substituted C1-C6alkyl;

X represents (a) NH or (b) O.

2. Connection on p. 1, where R1represents CH3or CH2HE; R2, R3and R4independently represent CH3or CH2CH3and R5represents H, Br, Cl or F.

3. Connection under item 1 or 2, which is a

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

8-(2 is milleniumiso)-N-hydroxyethyl-imidazo[1,2-a]pyridine-6-carboxamide,

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

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

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

2,3-dimethyl-8-(2,6-dimethylbenzylamine)-imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide mesilate,

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

2,3-dimethyl-8-(2,6-dimethyl-4-fluoro-benzylamino)-imidazo[1,2-a]pyridine-6-carboxamide mesilate,

2,3-dimethyl-8-(2-methyl-6-isopropylbenzylamine)-imidazo[1,2-a]pyridine-6-carboxamide mesilate,

2,3-dimethyl-8-(2,6-diethyl-benzylamino)-imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethylbenzylamine)-imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethyl-6-methyl-benzylamino)-N-hydroxyethyl-imidazo[1,2-a]pyridine-6-carboxamide,

N-(2,3-dihydroxypropyl)-2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2-ethyl-6-methyl-benzylamino)-N-(2-methoxyethyl)-imidazo[1,2-a]pyridine-6-carboxamide,

2-methyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide,

2.3 methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide,

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

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

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide, or its pharmaceutically acceptable salt.

4. Connection under item 1 or 2, which is a

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

2,3-dimethyl-8-(2,6-dimethylbenzylamine)-N-hydroxyethyl-imidazo[1,2-a]pyridine-6-carboxamide,

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

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

2,3-dimethyl-8-(2,6-dimethylbenzylamine)-imidazo[1,2-a]pyridine-6-carboxamide,

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

2,3-dimethyl-8-(2,6-dimethyl-4-fluoro-benzylamino)-imidazo[1,2-a]pyridine-6-carboxamide,

2,3-dimethyl-8-(2,6-diethylaniline)-imidazo[1,2-a]pyridine-6-carboxamide,

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

2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-(2-matokie according to any one of paragraphs.1-4 in the form of cleaners containing hydrochloride or mesilate salt.

6. Products containing at least one compound according to any one of paragraphs.1-4 and at least one antimicrobial agent as a combined preparation for simultaneous, separate or sequential use for the prevention or treatment of gastrointestinal inflammatory diseases.

7. Products containing at least one compound according to any one of paragraphs.1-4 and at least one proton pump inhibitor as a combined preparation for simultaneous, separate or sequential use for the prevention or treatment of gastrointestinal inflammatory diseases.

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

subjected to interaction with the compound of General formula III

where R6and R7are as defined in paragraph 1,

in an inert solvent to obtain compounds of General formula IV

which is subjected to interaction with ammonia in an inert solvent to obtain compounds of General formula V

which, in its the materials of the VI

which is then subjected to interaction with the compound of General formula VII

where R2is as defined in paragraph 1;

Z represents a leaving group;

R9represents N, CH3or ester group,

in an inert solvent in the presence or in the absence of a basis of obtaining compounds of General formula VIII

with the subsequent interaction of the latter with a compound of General formula IX

where R3, R4and R5are as defined in paragraph 1;

Y represents a leaving group,

in an inert solvent in the presence or in the absence of a basis of obtaining compounds of General formula X

that is, if R9represents an ester group, is transferred to the target product, where R1represents CH2HE, by restoring in an inert solvent.

9. The method of obtaining compounds of General formula I according to any one of paragraphs.1-5, where X represents NH, R1represents N or CH3, a R2-R7are specified in paragraph 1 values, which consists in the fact that the compound of formula II

subjected to the interaction of the x with obtaining compounds of General formula XI

which is subjected to interaction with ammonia under standard conditions in an inert solvent to obtain compounds of General formula XII

which in turn restores under standard conditions in an inert solvent, and the compound obtained of General formula XIII

subjected to interaction with the compound of General formula XIV

where R2is as defined in paragraph 1;

Z represents a leaving group;

R11represents N or CH3,

in an inert solvent in the presence or in the absence of a basis of obtaining compounds of General formula XV

which, in turn, is subjected to the interaction with the compound of General formula IX

where R3, R4and R5are as defined in paragraph 1;

Y represents a leaving group,

in an inert solvent in the presence or in the absence of a base and the compound obtained of General formula XVI

subjected to interaction with the compound of General formula III

where R6and R7are as defined in paragraph 1,

under standard conditions.

10. SPO is tion, it lies in the fact that the compound of General formula XVII

where R1-R5and X are as defined in paragraph 1;

R10represents an alkyl group,

treated with acid or base under standard conditions to obtain compounds of General formula XVIII

which, in turn, is subjected to the interaction with the compound of General formula III

where R6and R7are as defined in paragraph 1,

under standard conditions in an inert solvent in the presence of the agent combinations.

11. The compound according to any one of paragraphs.1-5 for use in therapy.

12. 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 a pharmaceutically acceptable diluent or carrier.

13. The compound according to any one of paragraphs.1-5 for the production of medicaments for the inhibition of the secretion of gastric acid.

14. The compound according to any one of paragraphs.1-5 for the production of drugs for the treatment of gastrointestinal inflammatory diseases.

15. The compound according to any one of paragraphs.1-5 for the production of medications for leelavati, intended for administration in combination with at least one antimicrobial agent.

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

17. The method of treatment of gastrointestinal inflammatory diseases in which the mammal, including man, in need of such treatment is administered an effective amount of a compound according to any one of paragraphs.1-5.

18. 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 the specified 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.

19. Pharmaceutical formulation for use in inhibiting the secretion of gastric acid, where the active ingredient is a compound according to any one of paragraphs.1-5.

20. Pharmaceutical formulation for use for the treatment of gastrointestinal inflammatory diseases, where the active ingredient is sobouti States, involving infection by Helicobacter pylori infection of the gastric mucosa of man, where the active ingredient is a compound according to any one of paragraphs.1-5 for simultaneous, separate or sequential use in combination with at least one antimicrobial agent.

22. The compound of formula VIII

where R2, R6and R7are as defined in paragraph 1;

R9represents N, CH3or ester group.

23. The compound of the formula X

where R2-R7are as defined in paragraph 1;

R9represents an ester group.

24. The compound of formula XV

where R2is as defined in paragraph 1;

R10represents an alkyl group;

R11represents N or CH3.

25. The compound of formula XVI

where R2- R5are as defined in paragraph 1;

R10represents an alkyl group;

R11represents N or CH3.

26. The compound of the formula

where R1-R5and X are as defined in paragraph 1.

 

Same patents:

The invention relates to a method for producing 7-aminopyrido[1,2-a][1,3]benzimidazole of the formula (1), which can be used as an intermediate in the synthesis of fluorescent and biologically active substances

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 new compounds of General formula

which have the properties of receptor antagonists neirokinina-1(NK-1)

The invention relates to the treatment of chronic gastritis with high acidity and its consequences, peptic ulcer disease and, in particular, gastric ulcers
The invention relates to medicine, in particular to a gastroenterologist, and for the prevention of relapse of erosive or ulcerative bleeding ulcers stomach and duodenal ulcers associated with Helicobacter pylori

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 pharmaceutical industry and relates to inhibitors lks-channel simultaneous action as inhibitors KQT1 channel to obtain drugs for the treatment of diseases caused by helminths and ectoparasites, while inhibitors KQT1 channel have high selectivity and are non-toxic to warm-blooded animals and humans
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