MXPA99007650A - Compounds for inhibition of gastric acid secretion - Google Patents

Abstract

The present invention relates to imidazo pyridine derivatives of the formula (I), in which the phenyl moiety is substituted with lower alkyl in 2- and 6-position, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

Description

COMPOUNDS FOR INHIBITING THE SECRETION OF GASTRIC ACID Field of Invention The present invention relates to novel compounds and therapeutically acceptable salts thereof, which inhibit the secretion of gastric acid exogenously or endogenously and can thus be used in the prevention and treatment of gastrointestinal inflammatory disorders. In additional aspects, the invention relates to compounds of the invention for use in therapy; to processes for the preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as an active ingredient; and to the use of the active compounds in the manufacture of medicines for use in the medicine indicated below.

Ref: 030911 Background of the Invention Imidazo [1,2-substituted ajpyridines, useful in the treatment of peptic ulcer disorders, for example EP-B-0033094 and US 4,450,164 (Schering Corporation); are known in the art; of EP-B-0204285 and US 4,725,601 (Fujisawa Pharmaceutical Co.); and those published by J.J. Kaminski et al., In the Journal of Medical Medical Sciences (vol.28, 876-892, 1985; vol 30, 2031-2046, 1987; vol 30, 2047-2051, 1987; vol 32, 1686-1700; 1989 and vol.33, 533-541, 1991).

An imidazo pyridine derivative which is substituted at position 8 with 2, 4, 6- (CH3) 3-C6H2CH20 is described in EP-B-0033094 and a "Compound No. 49" in Kaminski et al., J. Med. Chem. Vol. 28, 876-892, 1985. However, according to the last publication, said compound does not show favorable characteristics when tested as an inhibitor of gastric acid secretion.

For an analysis of the pharmacology of gastric acid pumping (H +, K + -ATPase), see Sachs et al. to the. (1995), Annu. Rev. Pharmacol. Toxicol 35 277-305.

Description of the invention.

Surprisingly it has been found that compounds of Formula I, which are substituted imidazo pyridine derivatives which the phenyl portion is substituted with a lower alkyl at positions 2 and 6, are particularly effective as inhibitors of the gastrointestinal H +, K + -ATPase. and therefore as inhibitors of gastric acid secretion.

In one aspect, the invention thus relates to the compounds of general Formula I: or a pharmaceutically acceptable salt thereof, wherein R1 is CH3 or CH2OH; R2 is lower alkyl; R3 is lower alkyl; R4 is H or halogen; R5 is H, halogen, or lower alkyl; X is NH or O.

As used herein, the term "lower alkyl" denotes a long or branched chain alkyl group having from 1 to 6, preferably from 1 to 4, carbon atoms. Examples of "lower alkyl" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and hexyl and pentyl of branched chain. Preferably, "lower alkyl" means methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.

The term "halogen" includes fluoro, chloro, bromo and iodo.

Both pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It will be understood that all possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Also included in the invention are derivatives of the compounds of Formula I which have the biological function of the compounds of Formula I.

Depending on the process conditions and the final products of Formula I, it is obtained either in neutral form or in salt form. Both the free base and the salts of these final products are within the scope of the invention.

The acid addition salts of the novel compounds can, in a manner known per se, be transformed into the free base using basic agents such as alkaline or by ion exchange. The obtained free base can form salts with organic or inorganic acids.

In the preparation of the addition salts, preferably such acids are used to form appropriate therapeutically acceptable salts. Examples of such acids are hydrogenated acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric, aliphatic, alicyclic, aromatic, or carboxyl heterocyclic 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, hydroxymalonic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulonic acid, hydroxyethanesulonic acid, halogenbenzenesulfonic acid, toluenesulphonic acid or phonic naphthalenesul acid.

Preferred compounds according to the invention are those of Formula I wherein R2 is CH3 or CH2CH3; R3 is CH3 or CH2CH3; R4 is H, Br, Cl or F; and R5 is H, CH3, Br, Cl or F, more preferably H, CH3, or F.

Particularly preferred compounds according to the invention are: • 8- (2,6-dimethylbenzylamino) -2,3,6-trimethylimidazo [1,2-a] pyridine; • 8- (2,6-dimethylbenzylamino) -3-hydroxymethyl-2-ethylimidazo [1,2-a] pyridine; • 2,3-dimethyl-8- (2,6-dimethyl-4-fluorobenzylamino) imidazo [1,2-a] pyridine; • 2,6-dimethyl-1 - 8 - (2,6-dimethyl-il-benzylamino) -3-hydroxymethyl imidazo [1,2-a] pyridine; • 2,6-dimethyl-8- (2,6-dimethyl-4-fluorobenzylamino; 3-hydroxymethylimidazo [1,2-a] pyridine; • 8- (2,6-dimethyl-4-fluorobenzylamino) -2, 3 6-trimethyl imidazo [1,2-a] pyridine; • 2,3-dimethyl-8- (2,6-dimethyl-4-chlorobenzylamino) imidazo [1,2-a] pyridine; • 2,6-dimethyl -8- (2-ethyl-6-methylbenzylamino) -3-hydroxymethylimidao [1,2-a] pyridine; • 8- (2,6-diethylbenzylamino) -2,6-dimethyl-3-hydroxymethyl-1 imidazo [1 , 2-a] pyridine; • 8- (2-ethyl-6-methylbenzylamino) -2,3,6-trimethylimidazo [1,2-a] pyridine; • 8- (2,6-dimethyl-4-fluorobenzyloxy) -3-hydroxymethyl-2-methylimidazo [1,2-a] pyridine; • 2,6-dimethyl-8- (2,6-dimethylbenzyloxy) -3-hydroxymethyl imidazo [1,2-a] pyridine; • 2,6-dimethyl-8- (2-ethyl-4-fluoro-6-methylbenzyl-lamino) -3-hydroxymethylimidao [1, 2-a] pyridine; • 8- (2-ethyl-4-fluoro-6-methylbenzylamino) -2, 3, 6-trimetho-limidazo [1,2-a] pyridine.

Preparation .

The present invention also provides the following processes A, B, C, D, and E for the manufacture of the compounds with the general Formula I.

Process A.

Process A for the manufacture of the compounds with General Formula I comprises the following steps: Compounds of General Formula II wherein X1 e s NH2 or OH, and R1 and RE are as defined by Formula I, can react with compounds of general Formula III wherein R2, R3 and R4 are as defined by Formula I and Y is a starting group, such as a halide, tosyloxy or mesyloxy, for the compounds of Formula I.

It is convenient to conduct this reaction in an inert solvent, for example, acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without base. The base is, for example, an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.

Pro ces or B.

Process B for the manufacture of the compounds with the general Formula I, wherein X is NH, comprises the following steps: Compounds of General Formula IV wherein R1 and R5 are as defined by Formula I, they can react with compounds of the general Formula V wherein R, R3 and R4 are as defined by Formula I, in the presence of a Lewis acid, for example, zinc chloride, for the compounds of Formula VI wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined by Formula I, after which the compounds of the general Formula VI are reduced, for example, by using sodium hydrobromide or sodium-sodium hydrobromide, to the compounds of General Formula I wherein X is NH. The reactions can be carried out under standard conditions in an inert solvent, for example, methanol or ethanol.

Process C Process C for the manufacture of the compounds with the general Formula I, wherein R 1 is CH OH, comprises the following steps: Compounds of General Formula VII wherein X 1 is NH 2 or OH and R 5 is as defined by Formula I, can react with compounds of General Formula III wherein R2, R3 and R4 are as defined by Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, for the compounds of Formula VIII wherein R2, R3, R4, R5 and X are as defined by Formula I It is convenient to conduct this reaction in an inert solvent, for example, acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without base. The base is, for example, an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.

The reduction of the compounds of the general Formula VII, for example, using lithium aluminum hydride in tetrahydrofuran or products of ether to the compounds of the general Formula I wherein R1 is CH20H.

Pro ces or D.

Process D for the manufacture of the compounds with the general Formula I, wherein R1 is CH20H and X is NH, comprises the following steps: Compounds of Formula IX wherein R is as defined by Formula I, can react with the compounds of general Formula V wherein R2, R3 and R4 are as defined by Formula I, in the presence of a Lewis acid, for example, zinc chloride, for the compounds of Formula VI wherein R2, R3, R4 and R5 are as defined by Formula I, after which the compounds of the general Formula X are reduced, for example, using sodium hydrobromide or sodium-cyanohydrobromide for the compounds of the general Formula XI XI wherein R2, R3, R4 and R5 are as defined by Formula I. The reactions can be carried out under standard conditions in an inert solvent, for example methanol or ethanol.

The reduction of the compounds of the general Formula XI, for example, using lithium aluminum hydride in tetrahydrofuran or ether products to the compounds of the general Formula I wherein R1 is CH20H and X is NH.

Process E.

Condensation of the compounds of general Formula XII wherein R2, R3, R4, and R5 are as defined by Formula I, with α-halocarbonyl intermediates of the general formula CH3C0CH (Z) C00H2CH3 wherein Z is Br or Cl, in an inert solvent, for example, acetonitrile or ethanol resulting in the formation of compounds of the general Formula XIII wherein R2, R3, R4 and R5 are as It was defined by Formula I: The reduction of the compounds of the general Formula XII, for example, by the use of lithium aluminum hydride in tetrahydrofuran or ether products to the compounds of the general Formula I wherein R1 is CH2OH and X is O.

Us or Médi co.

In a further aspect, the invention relates to the compounds of the formula I for the use in therapy, in particular for use against gastrointestinal disorders. The invention also provides the use of a compound of formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory disorders.

The compounds according to the invention can be used for the prevention and treatment of gastrointestinal inflammatory disorders, and disorders related to gastric acid in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux of the esophagus and Zollinger syndrome. -Ellison. In addition, the compounds can be used for the treatment of other gastrointestinal disorders wherein the effect of gastric antisecretion is desirable, for example, in a patient with gastrinomas, and in patients with acute gastrointestinal bleeding. These can also be used in patients in intensive care situations, and in pre- and post-operations to prevent acid aspiration and tension ulceration.

The typical daily dose of the active substance varies within a wide range and will depend on several factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral doses may be in the range of 5 to 1000 mg per day of the active substance.

Form ula ci on es fa rma cé u t i ca s In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as an active ingredient.

The compounds of the invention can also be used in formulations together with other active ingredients, for example, antibiotics such as amoxicillin.

For clinical use, the compounds of the invention are formulated in pharmaceutical formulations for oral, rectal or another way of it. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier can be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are also the object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in the preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration.

In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of unit doses for oral administration, the selected compound can be mixed with a solid, powdered ingredients, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other appropriate ingredients, as well as with disintegrating agents and lubricating agents such as magnesium stearate, stearate calcium, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into pellets or pressed into tablets.

Soft gelatine capsules can be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for the soft gelatine capsules. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Unit doses for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for the rectal gelatin capsules; (iii) in the form of a micro enema already prepared; or (iv) in the form of a dry micro-enema formulation to be reconstituted in a suitable solvent just prior to administration.

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 consisting of sugar or sugar alcohols and a mixture of ethanol , water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration can also be prepared in the form of a dry powder to be reconstituted with an appropriate solvent before use.

Solutions for parenteral administration can be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight.

These solutions may also contain stabilizing ingredients and / or regulatory ingredients and are dispersed in the unit doses in the form of small vials or vials. Solutions for parenteral administration can also be prepared as a dry preparation to be reconstituted with a suitable extemporaneously solvent before use.

The compounds according to the invention can also be used in formulations together with other active ingredients, for example, for the treatment or prophylaxis of conditions involving an infection by Hel i coba c t er pyl ori of the human gastric mucosa. Such other active ingredients may be antimicrobial agents, in particular: • ß-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; • macrolides such as erythromycin, or clarithromycin; • tetracyclines such as tetracycline or doxycycline; aminoglycosides such as gentamicin, canapucin or amicacma; • quinolones such as norfloxacin, ciprofloxacin or enoxacin; • others such as etronidazole, nor do they rofuran tinoin or chloramphenicol; or • preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.

EXAMPLES 1. PREPARATION OF THE INVENCON COMPOUNDS.

Example 1.1 Synthesis of the hydrochloride of 8- (2, dimethyl-ylbenzylamine) -2,3,6-trimethyl imidazole [1,2-a] pyridine.

A stirred mixture of 8-amino-2,3,6-trimethylimidazo [1,2-a] pyridine (0.9 g, 5.1 mmol), zinc chloride (II) (0.84 g, 6.2 mmol) and 2.6- timebenzaldehyde (0.83 g, 6.2 mmol) in methanol (50 ml) was treated with sodium cyanoborohydride (0.39 g, 6.2 mmol) and refluxed for 3 hours. The methanol was vaporized under reduced pressure and the residue was dissolved in methylene chloride and 2 M sodium hydroxide (40 ml). The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure.

The residue was purified twice by column chromatography on silica gel, using a) ethyl acetate: methylene chloride (1: 2) and b) methanol: methylene chloride (1:20) as eluent. The oily product was dissolved in diethyl ether, treated with diethyl ether / HCl and the precipitate salt was filtered off to give 0.6 g (36%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 2.33 (s, 3H), 2.38 (s, 3H), 2.45 (s, 6H), 2.50 (s, 3H), 4.40 (d, 2H), 6.40 bs, 1H), 7.95-7.15 (m, 4H).

Example 1.2 Synthesis of 2,3-dimethyl-8- (2,6-dimethenobenzylamino) -6-fl uoroimide zo [1,2-a] pir idina A stirred mixture of 8-amino-2,3-dimethyl-6-fluoroimidazo [1,2-a] pyridine (0.16 g, 0.89 mmol), zinc chloride (II) (0.14 g, 1.04 mmol) and 2 , 6-dimethylbenzaldehyde (0.14 g, 1.04 mmol) in methanol (50 ml), treated with sodium cyanoborohydride (0.065 g, 1.04 mmol) and refluxed for 7 hours. The cooled reaction mixture was added to 0.5 M NaOH (20 ml) and the precipitated solids were completely filtered and purified by column chromatography on silica gel, using methanol: methylene chloride (1:10) as eluent. Crystallization from petroleum ether gave 0.1 g (38%) of the title compound. 1 H-NMR (300 MHZ, CDC13): d 2.30 (s, 3H), 2.34 (s, 3H), 2.40 (s, 6H), 4.35 (d, 2H), 4.95 (bs, 1H), 6.15 (dd, 1H), 7.0-7.20 (m, 4H).

Example 1.3.

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

Amino-2,3-dimethyl-imidazo [1, 2-a] pyridine (0.33 2.0 mmol, 2,6-diethylbenzaldehyde (0.36 g, 2.2 mmol) in methanol (7 ml) was dissolved in. ZnCl 2 was added in small portions. (0.30 g, 2.2 mmoles) and subsequently NaBH3CN (0.14 g, 2.2 mmol) and the mixture was refluxed under argon for 3 hours, cooled and then poured into an aqueous solution of 1M NaOH (10 mL). The resulting yellow suspension was extracted with DCM (3x25 ml) and the combined organic solutions were washed with brine, dried over Na 2 SO 4 and then removed. The oily residue (0.4 g) was purified by flash chromatography (DCM-EtOAc 0% -20% EtOAc) to give 0.34 g. Treatment of this oily product with hexane (2 ml) provided 0.14 g (23%) of quenched white crystals. 1 H-NMR (300 MHZ, CDC13): d 7.2-7.3 (2H, m), 7.1 (2H, d), 6.7 (1H, t), 6.2 (1H, d), 4.8 (1H, b), 4.4 ( 2H, d), 2.7 (4H, q), 2.3 (6H, two singlets), 1.2 (6H, t).

Example 1.4 Synthesis of 8 - (2,6 -dimethyl-il-benzyloxy) -3-hydroxymethyl-2-methyl-yl-imide zol [1,2-a] pyridine.

A mixture of 8-hydroxy-3-hydroxymethyl-2-methyl-idazo [1,2-a] pyridine (0.89 g, 5.0 mmol), sodium carbonate (1.5 g), sodium iodide (0.4 g), 2, 6-Dimethyl-benzylchloride (0.7 g, 4.5 mmol) and acetone (60 mL) was stirred overnight. More sodium carbonate (1.0 g) was added. The reaction mixture was refluxed for 2 hours. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was suspended in CH2Cl2 / MeOH (100: 5) and filtered. Evaporation under vacuum of the solvent gave a residue which was purified by flash chromatography eluting with CH2Cl-MeOH (100: 4), collecting the fractions, and recrystallizing from CH2C12 / CH3CN to give 0.37 g of the title compound. 1 H-NMR (300 MHZ, CDC13): d 7.87 (d, J = 7.6 Hz, 1H), 7.15-7.08 (m, 1H), 7.0 (d, J = 7.6 Hz, 2H), 6.73 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.83 (s, 2H), 2.4 (s, 6H), 2.28 (s, 3H).

Example 1.5 Synthesis of 2,3-dimethyl-8- (2,6-dimethyl t -benzyllamino) imidazo [1,2-a] pyridine.

A mixture of 8-amino-2, 3-dimethyl-thymidazo [1,2-a] pyridine (0.7 g, 4.34 mmol), sodium carbonate (2.0 g), sodium iodide (0.3 g), 2,6-dimethylbenzyl chloride (0.671) g, 4.34 mmole) and acetone (30 ml) was stirred overnight. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and washed with aqueous NaHCO 3. The organic layer was separated and the solvent was evaporated. The crude product was purified by flash chromatography eluting with CH2Cl2 / MeOH to give 0.7 g of the title compound.

XH-NMR (300 MHZ, CDC13): d 7.25 (d, J = 7.7 Hz, 1H), 7.14-7.09 (m, 1H), 7.03 (d, J = 7.7 Hz, 2H), 6.73 (t, J = 7.7 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 4.79 (br "t", 1H), 4.34 (d, J = 4.5 Hz, 2H), 2.38 (s, 6H), 2.34 (s, 6H).

Example 1.6 Synthesis of 2,3-dimethyl '- (2,6-dimethylbenzyloxy) imidazo [1,2-a] pyridine.

A mixture of 8-hydroxy-2,3-dimethylimidazo [1,2-a] pyridine (1.2 g, 7.41 mmol), 2,6-dimethyl-benzylchloride (1145, 7.41 mmol), sodium iodide (0.3 g), Sodium carbonate (2.0 g) and acetone (50 ml) was refluxed for 3 hours. After the addition of methylene chloride, the reaction mixture was filtered. The solvent was removed in vacuo. The residue was dissolved in CH2C12, washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue is chromatography on silica, eluting with CH2Cl2-MeOH (100: 5) to give 0.70 g of the desired product (from ethyl acetate-ether).

XH-NMR (300 MHZ, CDC13): d 7.56 (d, J = 6.6 Hz, 1H), 7.1 (t, J = 6.6 Hz, 1H), 6.94-6.85 (m, 3H), 6.73 (d, J = 6.6 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.24 (s, 6H).

Example 1.7 Synthesis of 2,3-dimethyl-8 - (2-ethyl-6-methybenzyllamino) imidazo [1, 2-a] pyridine. 8-amino-2,3-dimethylimide zo [1,2-a] pyridine (0.3 g, 1.86 mmol) and 2-ethyl-6-methylbenzylchloride (0.31 g, 1.84 mmol) were dissolved in 5 ml of dimethoxyethane. Potassium iodide (0.2 g, 1. 2 mmol) and Na 2 CO 3 (0.3 g, 2.8 mmol) and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (60:40) as eluent. 230 mg (42%) of the title compound were obtained. 1 H-NMR (300 MHZ, CDC13): d 1.22 (t, 3H), 2.35 (s, 6H), 2.39 (s, 3H), 2.70 (q, 2H), 4.35 (d, 2H), 4.81 (t, 1H), 6.21 (d, 1H), 6.73 (t, 1H), 7.01-7.10 (m, 2H), 7.13-7.19 (m, 1H), 7.24 (d, 1H).

Example 1.8 Synthesis of 6-bromo-2, 3-dimethyl-8- (2,6-dimethenobenzylamino) imide zo [1,2-a] pyridine.

A mixture of 8-amino-6-bromo-2,3-dimethylimidazo [1,2-a] pyridine (1.2 g, 5.0 mmol), 2,6-dimethylbenzylchloride (0.772 g, 5.0 mmol), sodium carbonate ( 0.8 g), sodium iodide (0.2 g) and acetone (45 ml) was stirred overnight. More 2,3-dimethylbenzylchloride (0.285 g) was added and the reaction mixture refluxed for 5 hours. After adding the acetone, the reaction mixture was filtered. The solvent was removed in vacuo and the residue was dissolved in CH2C12, washed with NaHCO3, dried over Na2SO4 and evaporated. The crude product was dissolved in ethyl acetate and petroleum ether was added. Filtration and evaporation of the solvent gave a residue which was recrystallized from ethyl acetate to give 1.45 g of the title compound. 1 H-NMR (300 MHZ, CDC13): d 7.37 (d, J = 1.5 Hz, 1H), 7.15-7.09 (m, 1H), 7.04 (d, J = 7.5 Hz, 2H), 6.28 (d, J = 1.5 Hz, 1H), 4.88 ("t", 1H), 4.33 (d, J = 4.13 Hz, 2H), 2.38 s, 6H), 2.3 (s, 3H), 2.29 (s, 3H).

Example 1.9 Synthesis of 8- (2,6-dimethybenzylamino) -3-hydroxymethyl-2-methylimide zo [1,2-a] pyridine.

A solution of vitride (40 ml, 136 mmol) in toluene (25 ml) was added dropwise to a solution purged with nitrogen of 3-carboethoxy-8 - (dimethylbenzylamino) -2-methylimidazo [1,2-a] pyridine. (8.0 g, 23.71 mmoles) in toluene (100 ml). The ice bath was removed and the reaction mixture was stirred at room temperature for 105 minutes. The reaction mixture was cooled to 0 ° C and quenched by the addition of water (36 ml). The mixture was filtered and the organic layer was washed with aqueous NaHCO 3, dried over Na 2 SO and concentrated. Acetonitrile (20 ml) was added and the product was collected by filtration. The crystalline product is washed twice with acetonitrile and dried in vacuo. Yield 5.6 g.

XH-NMR (300 MHZ, CDC13): d 7.58 (d, J = 7.1 Hz, 1H), 7.15-7.1 (m, 1H), 7.05 (d, J = 7.1 Hz, 2H), 6.74 (t, J = 7.1 Hz, 1H), 6.28 (d, J = 7.1 Hz, 1H), 4.84 (br t, J = 4.5 Hz, 1H), 4.8 (s, 2H), 4.35 (d, J = 4.5 Hz, 2H), 2.4 (s, 6H), 2.2 (s, 3H).

Example 1.10 Synthesis of 6-chloro-2,3-dimethyl-8- (2,6-dimethyl-il-benzylamino) imidazo [1,2-a] -pyrin.

A mixture of 8-amino-6-chloro-2,3-dimethylimidazo [1,2-a] pyridine (0.894 g, 4.57 mmol 2, 6-dimethyl thiolbenzaldehyde (0.77 5.7 mmol), ZnCl2 (1.08 g, 7.92 mmol ), NaB (CN) H3 (0.36 g, 5.7 mmol) and MeOH (35 mL) was refluxed for 3.5 hours. More 2,6-dimethylbenzaldehyde (0.25 g in 4 ml of MeOH), ZnCl 2 (0.55 g) and NaB (CN) H 3 (0.35 g) were added. The reaction mixture was refluxed for an additional 4 hours. Subsequent work by the addition of 1M NaOH (150 ml), and water (50 ml), followed by extraction of the mixture with CH2C12, drying, and evaporation of the solvent, gave a solid residue. The crude product was dissolved in ethyl acetate and ether was added. Filtration and evaporation of the solvent gave a residue which was recrystallized from ethyl acetate to give 0.52 g of the product.

XH-NMR (300 MHZ, CDC13): d 7.28 (d, J = 1.7 Hz, 1H), 7.15-7.1 (, 1H), 7.04 (d, J = 12 Hz, 2H), 6.2 (d, J = 1.7 Hz, 1H), 4.89 (br "t", 1H), 4.33 (d, J = 4 Hz, 2H), 2.37 (s, 6H), 2.33 (s, 3H), 2.32 (s, 3H).

Example 1.11 Synthesis of 2, 3-dimethyl-8- (2, β-dimethyl-4-f luor ob ene i lamí) imidazo [1,2-a] pyridine. 8-amino-2,3-dimet and limidazo [1,2-a] pyridine (0.5 g, 3.1 mmol) was dissolved in acetonitrile (6 ml). To the solution was added 2,6-dimethyl-4-fluoro-benzylbromide (0.67 g, 3.1 mmol) and potassium carbonate (0.47 g, 3.4 mmol). The mixture was refluxed for 16 hours. Methylene chloride (12 ml) and a solution of sodium chloride (20 ml) was added. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography (ethyl acetate: petroleum ether 1: 1). 400 mg of the title compound was obtained as a solid.

XH-NMR (300 MHZ, CDC13): d 2.3 (s, 6H), 2.3 (s, 6H), 4.2 (d, 2H), 4.65 (b, 1H), 6.15 (d, 1H), 6.65-6.75 ( m, 3H), 7.2 (d, 1H).

Example 1.12 Synthesis of 2,6-dimethyl-8- (2,6-dimethylbenzylamino) -3-hydroxymethyl imidazo [1,2-a] pyridine.

A solution of 3-carboethoxy-2,6-dimethyl-il - 8 - (2,6-dimethylbenzylamino) imidazo [1,2-a] pyridine (0.4 g, 1.1 mmol) in 10 ml of toluene was cooled with ice water, 65% Red-Al in toluene (2.1 g, 6.6 mmol) was added after 30 minutes. The solution was stirred for 2 hours at room temperature. 10 ml of Rochelle saline solution (potassium sodium tartrate tetrahydrate, 35 g / 250 ml of water) was added dropwise, 10 ml of toluene was added, the organic layer was separated and washed with water, dried over sulphate of sodium and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with dichloromethane: methanol 9: 1, to give 0.21 g, (62%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 1.65 (s, 1H), 2.30 (d, 6H), 2.38 (s, 6H), 4.37 (d, 2H), 4.75 (s, 1H), 4.85 (s, 2H), 6.15 (s, 1H), 7.0-7.15 (m, 3H), 7.40 (s, 1H).

Example 1.13 Synthesis of 2,6-dimethyl-8- (2,6-dimet-il-4-fl uorobenzyllamino) -3-hydroxymethylimide zo [1,2-a] pyridine.

A solution of 0.4 g (1.1 mmol) of 3-carboethoxy-2,6-dimethyl-8- (2,6-dimethyl-4-) fluorobenzylamino) -imidazo [1, 2-a] pyridine in 10 ml of toluene was cooled with ice water, (2.1 g, 6.6 mmoles). Red-AL 65% in toluene was added after 30 minutes. The solution was stirred for 2 hours at room temperature. 10 ml of Rochelle saline solution (potassium sodium tartrate tetrahydrate, 35 g / 250 ml of water) was added dropwise, water was added, 10 ml of toluene was added, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol 95: 5, to give 0.3 g (83%) of the title compound.

XH-NMR (300 MHZ, CDC13): d 2.26 (s, 3H), 2.33 (s, 3H), 2.37 (s, 6H), 4.28 (d, 2H), 4.70 (s, 1H), 4. 82 (s, 2H), 6.14 (s, 1H), 6.75 (d, 2H), 7.42 (s, 1H).

Example 1.14 Synthesis of the hydrochloride of 8 - (2,6-dimet-il-4-fluoro-ene-lamino) -2,3,6-tr imet-1-imidazo [1,2-a] pyridine.

A stirred mixture of 8-amino-2,3,6-trimethylimidazole [1,2-a] pyridine (0.5 g, 2.85 mmol is), 2,6-dimethyl-4-fluorobenzylbromide (0.7 g, 3. 4 mmol), potassium carbonate (0.6 g, 4.6 mmol), sodium iodide (0.1 g), 15 mL of acetonitrile, refluxed overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane: ethyl acetate. ethyl 2: 1. The oil produced was dissolved in diethyl ether, treated with diethyl ether / HCl and the precipitated salt was filtered off to give 0.55 g (56%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 2.22 (s, 3 H), 2.30 (d, 12 H), 4.23 (d, 2 H), 4.68 (s, 1 H), 6.05 (s, 1 H), 6.70 (d, 2H), 7.00 (s, 1H).

Example 1.15 Synthesis of 2,3-dimethyl-8- (2,6-dimet-il-4-c-or n-n-ylamino) imidazo [1,2-a] pyridine.

A mixture of 4-chloro-2,6-dimethylobenzylbromo and 2-chloro-4,6-dimethylbenzylbromo (1.1 g, 4.68 mmol) and 8-amino-2,3-dimetimididazo [1, 2- a] pyridine (4.65 mmol) was dissolved in 15 ml of dimethoxyethane. Potassium iodide (0.5 g, 3.0 mmol) and Na C03 (1 g, 9.4 mmol) were added. The mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel. The product was eluted with a mixture of methylene chloride and ethyl acetate (70:30). 70 mg of the title compound was obtained. aH-NMR (300 MHZ, CDC13): d 2.35 (s, 6H), 4.29 (d, 2H), 4.74 (t, 1H), 6.19 (d, 1H), 6.72 (t, 1H), 7.04 (s, 2H), 7.25 (d, 1H).

Example 1.16 Synthesis of 2,6-dimethyl-8- (2-yl-6-methylbenzylamino) -3-hr idr or imeylimide zo [1,2-a] pyridine. 3-Carboethoxy-2,6-dimethyl-8 - (2-yl-6-methylbenzylamino) imidazo [1, 2-a] pyridine (1.0 g, 2.8 mmol) was added to tetrahydrofuran (25 ml) and stirred at + 5 ° C. Lithium aluminum hydride (0.5 g, 13 mmol) was added in portions for 1.5 hours until the temperature remained below 10 ° C. After stirring the mixture at room temperature for an additional 1 hour, 0.5 ml of water was added dropwise, followed by 0.5 ml of 15% sodium hydroxide and then 1.5 ml of water. The solids were removed by filtration and washed thoroughly with tetrahydrofuran and methylene chloride. The filtrate and washings were combined and dried and the solvents were removed under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate: methylene chloride (1: 1) as eluent. Crystallization from petroleum ether: diethyl ether (1: 1) gave 0.37 g (41%) of the title compound. 1 H-NMR (300 MHZ, CDC13): d 1.25 (t, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.70 (q, 2H), 4.35 (d, 2H), 4.75 (bs, 1H), 4.80 (s, 2H), 6.15 (s, 1H), 7.05-7.25 (m, 3H), 7.40 (s, 1H).

Example 1.1 Synthesis of 8- (2,6-diethylbenzylamino) -2,6-dimethyl-3-hydroxymethyl imidazo [1,2-a] pyridine.

A solution of 3-carboe-toxy-2,6-dimethyl-8- (2,6-diethylbenzylamino) imidazo [1,2-a] pyridine (1.75 g, 4.6 mmol) in 30 ml of tetrahydrofuran was treated with hydride. Lithium aluminum (0.7 g, 18.5 mmol) at room temperature for 3.5 hours. The reaction was completed after 4 hours and carefully quenched by the dropwise addition of water (0.7 ml), aqueous sodium hydroxide. (0.7 ml, 15%) and again water (2 ml). The mixture was extracted with chloroform and the organic layer was concentrated. The residue was recrystallized from ethanol and the white crystalline product was filtered, washed with diethyl ether and dried in vacuo, which yielded 1.5 g (96%) yield. 1 H-NMR (500 MHz, CDC13): d 1.23 (t, 6H), 1.99 (s, 1H), 2.25 (s, 3H), 2.33 (s, 3H), 2.73 (q, 4H), 4. 34 (d, 2H), 4.80 (s, 3H), 6.13 (s, 1H), 7.09 (d, 2H), 7.22 (t, 1H), 7.40 (s, 1H).

Example 1.1 Synthesis of 8- (2,6-diethylbenzylamino) 2, 3, 6-trimethyl imide zo [1,2-a] pyridine.

A stirred mixture of 8-amino-2,3,6-trimethylimidazo [1,2-a] pyridine (0.5 g, 2.8 mmol), 2,6-diethylbenzaldehyde (0.7 g, 4.3 mmol) and zinc chloride (II) (0.44 g, 3 mmol) in 50 ml of methanol was treated with sodium cyanoborohydride (0.19 g, 3 mmol) and then refluxed for 20 hours. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethylene and water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with dichloromethylene, first, and then with dichloromethylene: ethyl acetate (1: 1) which yielded 0.42 g of the title compound.

^ • H-NMR (300 MHZ, CDC13): d 1.25 (t ', 6H), 2.28 (s, 3H), 2.30 (s, 3H), 2.33 (s, 3H), 2.71 (q, 4H), 4.36 (d, 2H), 4.84 (s, 1H), 6.10 (s, 1H), 7.04-7.23 (m, 4H).

Example 1.19 Synthesis of 8- (2-ethyl-6-methylbenzylamino) -2, 3,6-trimethyl imidazo [1,2-a] pyridine.

A stirred mixture of 8-amino-2,3,6-trimethylimidazo [1,2-a] pyridine (0.5 g, 2.8 mmol), 2-ethyl-6-methyl-methylbenzaldehyde (0.45 g, 3 mmol) and zinc (II) (0.4 g, 3 mmol) in 50 ml of methanol was treated with sodium cyanoborohydride (0.19 g, 3 mmol) and reflux for 20 hours. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethylene and water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with dichlormethylene: methanol (10: 1) which afforded 0.28 g (33%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 1.22 (t, 3H), 2.32 (s, 6H), 2.34 (s, 3H), 2.38 (s, 3H), 2.72 (q, 2H), 4. 33 (d, 2H), 4.77 (s, 1H), 6.08 (s, 1H), 7.03 '7.19 (m, 4H).

Example 1.20 Synthesis of 8- (2,6-dimethyl-4-fluorobenzyloxy) -3-hydroxymethyl-2-methyl imidazo [1,2-a] pyridine.

Lithium aluminum hydride (0.31 g, 8.4 mmol) was added to tetrahydrofuran (30 mL) and 3-carboethoxy-8- (2,6-dimethyl-4-fluorobenzyloxy) -2-methyl imidazo [1,2-a was dissolved ] pyridine (1.5 g, 4.2 mmol) in tetrahydrofuran (30 ml) was added dropwise over 30 minutes. 0.31 ml of water was added dropwise, followed by 0.31 ml of 15% sodium hydroxide and then 0.93 ml of water. The solids were removed by filtration and washed thoroughly with methanol: methylene (1: 1). The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Treating the residue with acetonitrile gave 0.9 g (69%) of the title compound.

XH-NMR (300 MHz, DMSO-d6): d 2.25 (s, 3H), 2.35 (s, 6H), 4.85 (d, 2H), 5.1 (t, 1H), 5.2 (s, 2H), 6.8- 7.05 (m, 4H), 7.95 (d, 1H).

Example 1.21 Synthesis of 6-bromo-8 - (2,6-dimethyl-4-f-luorobenzylamino) -3-hydroxymethyl-2-methyl-imidazo [1,2-a] pyridine.

LiBH (70 mg) was added in portions over 4 hours to a refluxing solution of 6-bromo-3-carboethoxy-8- (2,6-dimethyl-4-fluorobenzylamino) -2-methylimidazo [1,2-a] ] pyridine (100 mg, 0.23 mmol) in THF. The reaction mixture was quenched by the addition of dilute HCl and methylene chloride was added. The organic layer was separated, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel, using methylene chloride: ethyl acetate (100: 10) as eluent to give 40 mg (44%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 7.72 (s, 1H), 6.75 (d, 2H), 6.35 (s, H), 4.9 (t, 1H), 4.8 (s, 2H), 4.3 (d, 2H), 2.35 (s, 6H), 2.25 (s, 3H).

Ex empl o 1.22 Synthesis of 2,6-dimethyl-8- (2,6-dimethyl-il-benzyloxy) -3-hydroxy-ethyl-imidazo [1,2-a] pyridine.

A mixture of vitride (3 ml, 10.2 mmol) in toluene (3 ml) was added dropwise to a nitrogen purged solution of 3-carboe-toxy-2,6-dimethyl-8 - (2,6-dimethylbenzyloxy) imidazole [1,2-a] pyridine (0.68 g, 1.93 mmol) in toluene (15 ml). The ice bath was stirred and the reaction mixture was stirred at room temperature for 2 hours and 15 minutes. The reaction mixture was cooled to 0 ° C and quenched by the addition of water (6 ml). Methylene chloride / methanol was added and the reaction mixture was filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, using methylene chloride: methanol (100: 5) as eluent to give 0.35 g (58%) of the title compound.

XH-NMR (300 MHZ, CDC13): d 7.65 (s, 1H), 7.10 (t, 1H), 7.0 (d, 2H), 6.50 (s, 1H), 5.2 (s, 2H), 4.8 (s, 2H), 2.4 (s, 6H), 2.35 (s, 3H), 2.25 (s, 3H).

Example 1.23 Synthesis of 8- (2,6-dimethyl-4-fluorobenzylamino) -3-hydroxymethyl-2-methyl-imidazo [1,2-a] pyridine.

A solution of 0.6 g (1.7 mmol) of 3-carboe toxi-8 - (2,6-dimethyl-4-fluorobenzylamino) -2-methylimdazo [1,2-a] pyridine in 30 ml of toluene was cooled with water with ice. 2.1 g of Red-Al 65% (6.6 mmoles) in toluene was added over 30 minutes. The solution was stirred 1 hour at room temperature. 25 ml of Rochelle saline solution (35 g of sodium potassium tartrate tetrahydrate / 250 ml of water) was added dropwise and the organic layer was separated. The water layer was washed with methylene chloride which was separated. The combined organic solvents were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: me tanol 95: 5, to give 0.42 g, (79%) of the title compound.

^ • H-NMR (300 MHz, CDC13): d 2.15 (s, 3H), 2.35 (s, 6H), 4.30 (d, 2H), 4.75 (s, 2H), 4.85 (t, 1H), 6. 25 (d, 1H), 6.70-6.80 (m, 3H), 7.55 (d, 1H).

Example 1.24 Synthesis of 2,6-dimethyl-8 - (2-yl-4-fluoro-6-methyl-ylbenzylamino) -3-hr-idronene-imidazo [1, 2-a] pyridine.

To a mixture of LiAlH (0.08 g, 2.1 mmol) in tetrahydrofuran (15 ml) was added 3-carboe-toxy-2,6-dimethyl-8- (2-ethyl-4-fluoro-6-methylbenzylamine) imide zo [1, 2 -a] i ridine (0.4 g, 1.0 mmol) in tetrahydrofuran (15 ml). After stirring the mixture at room temperature for 4 hours, 0.1 ml of water was added dropwise, followed by 0.1 ml of 15% sodium hydroxide and then 0.3 ml of water. The solids were removed by filtration and washed thoroughly with tetrahydrofuran. The filtrate and washings were combined and dried and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Crystallization from acetonitrile gave 0.32 g (89%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 1.2 (t, 3H), 2.2 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 2.75 (q, 2H), 4.3 (d, 2H), 4.75 (bs, 3H), 4.75 (bs, 3H), 6.15 (s, 1H), 6.75-6.85 (m, 2H), 7.45 (s, 1H).

Example 1.25 Synthesis of 8- (2-ethyl-4-fluoro-6-methylbenzylamino) -2,3,6-trimethyl imidazo [1,2-a] pyridine. 8-amino-2, 3, 6- 1 rimet, limidazo [1,2-a] pyridine (0.38 g, 2.16 mmol) and 2-ethyl-4-fluoro-6-methylbenzylbromo (0.50 g, 2.16 mmol) were dissolved in 10 ml of dimethoxyethane. Potassium iodide (0.2 g, 1.2 mmol) and Na 2 CO 3 (0.4 g, 3.8 mmol) were added and the mixture was refluxed for 6 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (60:40) as eluent. 203 mg (29%) of the title compound was obtained.

XH-NMR (300 MHz, CDC13): d 1.21 (t, 3H), 2.32 (s, 6H), 2.33 (s, 3H), 2.37 (s, 3H), 2.71 (q, 2H), 4.28 (d, 2H), 4.68 (t, 1H), 6.06 (s, 1H), 6.73-6.80 (m, 2H), 7.05 (s, 1H).

Example 1.26 Synthesis of 2,3-dimethyl-8 (2,6-dimethyl-4-fluorobenzyl oxy) imide zo [1,2-a] pyridine. 2,3-Dimethyl-8-hydroxyimidazo [1,2-a] pyridine (1.7 g, 10 mmol), 2,6-dimethyl-4-fluorobenzylbromo (2.3 g, 10 mmol), sodium iodide ( 0.5 g, 0.3 mmol) and sodium carbonate (2.6 g, 28 mmol) were added to acetone (75 ml) and the mixture was refluxed for 6 hours. Methylene chloride was added and the mixture was filtered and the solvents were evaporated under reduced pressure. Purification by column chromatography on silica gel, using methylene chloride: ethyl acetate (1: 2) as eluent gave the title compound as a white powder (0.85 g, 28%). 1 H-NMR (300 MHz, CDC13): d 2.36 (s, 3H), 2.38 (s, 9H), 5.15 (s, 2H), 6.57 (d, 1H), 6.68-6.75 (m, 3H), 7.46 ( d, 1H).

Example 1.21 Synthesis of 2,3-dimethyl (2-ethyl-6-methylbenzyloxy) imide zo [1, 2-a] pyridine. 2, 3-Dimethyl-8-hydroxyimidazo [1,2-a] pyridine (0.8 g, 5 mmol), 2-ethyl-6-methylbenzyl chloride, sodium iodide (0.25 g, 1.7 mmol) and sodium carbonate were added. sodium (1.2 g, 11 mmol) to acetone (40 ml) and the mixture was refluxed for 5 hours.

The acetone was evaporated and the residue was dissolved in methylene chloride and washed with water. The organic solvent was dried and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel using (a) methyl chloride: ethyl acetate (1: 2), (b) methylene chloride: ethyl acetate (2: 1), as eluent to give the title compound (0.02 g, 1.4%). 1 H-NMR (300 MHz, CDC13): d 1.2 (t, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 2.74 (q, 2H), . 21 (s, 2H), 6.59 (d, 1H), 6.7 (t, 1H), 7.04 (m, 2H), 7.17 (t, 1H), 7.45 (d, 1H).

Example 1.28 Synthesis of 8- (2-yl-6-methylbenzoyloxy) -3-hydroxymethyl-2-methyldiazo [1,2-a] pyridine.

To a mixture of LiAlH (0.08 g, 2.1 mmol) in tetrahydrofuran (25 ml) was added 3-carboethoxy-8 - (2-ethyl-6-methylbenzyloxy) -2-methyl imidazo [1,2-a] pyridine (1.0 g, 2.8 mmol) in tetrahydrofuran (25 ml). After stirring the mixture at temperature At room temperature for 2 hours, 0.2 ml of water was added dropwise, followed by 0.2 ml of 15% sodium hydroxide and then 0.6 ml of water. The solids were removed by filtration and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Crystallization from diethyl ether gave 0.52 g (60%) of the title compound.

^ -H-NMR (300 MHz, CDCl 3): d 1.2 (t, 3H), 2.25 (s, 3H), 2.4 (s, 3H), 2.75 (q, 2H), 4.75 (s, 2H), 5.2 ( s, 2H), 6.65-6.75 (m, 2H), 7.0-7.2 (m, 3H), 7.85 (d, 1H).

TABLE 1 Summary of the compounds according to Examples 1.1 to 1.28.

PREPARATION OF INTERMEDIARIES.

Example 2.1 Synthesis of 2,6-dimethyl-4-fluorobenzylbromo.

A mixture of 3,5-dimethyl-fluorobenzene (5 g, 0.04 mol), paraformaldehyde (15 g), hydrobromic acid (70 ml) (30% in acetic acid) and acetic acid (25 ml) was stirred at room temperature. environment for 4.5 hours. Water and petroleum ether were added to the mixture and the organic layer was separated by drying over sodium sulfate and carefully evaporating under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether as eluent to give the desired product (3.7 g, 43%).

XH-NMR (300 MHz, CDC13): d 2.5 (s, 6H), 4.55 (s, 2H), 6.75 (d, 2H).

Example 2.2 Synthesis of 2-ethyl-6-methylbenzylchlor 2-Ethyl-6-methylbenzylalcohol (1.0 g, 6.67 mmol) was dissolved in 10 ml of methylene chloride. Thionyl chloride (1.0 g, 8.5 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was dissolved in methylene chloride and filtered through 5 g of silica gel. The filtrate was evaporated. 1.0 g (89%) of the title compound (oil) was obtained.

XH-NMR (300 MHz, CDC13): d 1.29 (t, 3H), 2.46 (s, 3H), 2.76 (q, 2H), 4.71 (s, 2H), 7.0-7.2 (m, 3H).

Example 2.3 Synthesis of 8-amino-2, 3,6-trimethylimide zo [1,2-a] pyridine.

To a solution of 2, 3-diamino-5-met ilpyridine (2.0 g, 16 mmol) in ethanol (100 ml) was added 3-bromo-2-butanon (2.4 g, 16 mmol). The reaction mixture was refluxed for 16 hours. An additional amount of 3-bromo-2-butanon (1.0 g, 6.7 mmol) and triethylamine (1.0 g, 9.9 mmol) was added and the mixture was refluxed for 2 hours. He Ethanol was evaporated under reduced pressure and the residue was treated with methylene chloride and a sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel, using methanol: methylene chloride (1:20) as eluent, to give the desired product (1.05 g, 37%). 1 H NMR (300 MHz, DMSO-d 6): d 2.15 (s, 3H), 2.3 (s, 3H), 5.45 (bs, 2H), 6.05 (s, 1H), 7.20 (s, 1H).

Ex empl o 2. 4 Syn is is of 2-amino-5-fluoro-3-n i t ropi rine.

To a solution of 2-amino-5-fluoropyridine (8.6 g, 77 mmol) in concentrated sulfuric acid (40 ml), steaming nitric acid (3.25 ml, 77 mmol) was added dropwise (30 minutes) at a temperature of + 3 ° C. The reaction mixture was stirred at room temperature for 1 hour and at + 55 ° C for 1 hour. The mixture was emptied on ice and neutralized with 10 M sodium hydroxide and extracted with methylene chloride. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel, using (i) methanol: methylene chloride (1:20) and (ii) diethyl ether: petroleum ether (1: 1) as eluent to give the compound of the title (0.44 g, 3.6%). 1 H-R N (300 MHz, CDC13): d 6.65 (bs, 2H), 8.20 (dd, 1H), 8.35 (d, 1H).

Ex empl o 2. 5 No more than 2, 3-diam in or -5-fl uoropi r i dina.

To a solution of 2-amino-5-fluoro-3-nitropyridine (0.42 g, 2.3 mmol) and iron powder (1.6 g, 28 mmol) in ethanol (10 ml), water (0.5 ml, 28 mmol) was added. ) and hydrochloric acid (27 μl, 0.32 mmol). The mixture was refluxed for 1 hour. An additional amount of iron powder (0.2 g, 3.6 mmol) was added and the mixture was refluxed for 30 minutes. The reaction mixture was filtered through celite and evaporation under reduced pressure of the solvent gave 0.3 g (100%) of the desired product. 1 H-NMR (300 MHz, CDC13): d 3.55 (bs, 2H), 4.1 (bs, 2H), 6.7 (dd, 1H), 7.5 (d, 1H).

Example 2.6 Synthesis of 8-amino-2,3-dimethyl-6-fluoroimidazo [1,2-a] pyridine.

A mixture of 2,3-diamino-5-fluoropyridine (0.3 g, 2.4 mmol) and 3-bromo-2-butanon (0.36 g, 2.4 mmol) in ethanol (20 mL) was refluxed for 10 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride and treated with a bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with me tanol: methylene chloride (1:20) as eluent, to give 0.16 g (37%) of the title compound.

XH-NMR (300 MHz, CDC13): d 2.3 (s, 3H), 2.4 (s, 3H), 4.6 (bs, 2H), 6.2 (dd, 1H), 7.2 (dd, 1H).

Example 2.7 Synthesis of -amino-6-bromo-2,3-dimetylimida zo [1, 2-a] pir idina A solution of 2,3-diamino-5-bromopyridine (4.0 g, 21.29 mmol) and 3-bromo-2-butanone (3.7 g, 24.48 mmol) in ethanol (40 mL) was refluxed overnight. After cooling to room temperature, the crystalline product was filtered and washed with ethanol and ether. The crystals were dissolved in methylene chloride and neutralized by aqueous NaHCO 3. The organic layer was separated, dried over Na 2 SO and evaporated in vacuo. Yield 2.3 g.

XH-NMR (300 MHz, CDC13): d 7.39 (d, J = 1.7 Hz, 1H), 6.36 (d, J = 1.7 Hz, 1H), 4.5 (br s, 2H), 2.35 (s, 3H), 2.3 (s, 3H).

Example 2.8 Synthesis of 3-carboethoxy-8- (dimethylbenzylamino) -2-methylimide zo [1,2-a] pyridine.

A mixture of 8-amino-3-carboethoxy-2-methylimidazo [1,2-a] pyridine (6.08 g, 27.74 mmol), 2,6-dimethyl-il-benzylchlor (4.5 g, 29.13 mmol), sodium carbonate (4.32 g) , 43.7 mmoles), sodium iodide (0.7 g) and acetone (120 ml) was stirred for 30 hours and the crystalline product was filtered off completely. The yield was dissolved in filtered dichloromethane and the solvent was evaporated under reduced pressure to give the title product (7.0 g).

XH-NMR (300 MHz, CDC13): d 8.66 (d, J = ll Hz, 1H), 7.16-7.1 (m, 1H), 7.05 (d, J = ll Hz, 2H), 6.87 (t, J = 11 Hz, 1H), 6.45 (d, J = ll Hz, 1H), 4.86 ("t", 1H), 4.4 (q, J = 7 Hz, 2H), 4.35 (d, J = 3.6 Hz, 2H) , 2.65 (s, 3H), 2.35 (s, 6H), 1.4 (t, J = 7 Hz, 3H).

Example 2.9 Synthesis of 8-amino-6-chloro-2,3-dimethyl-imidazo [1,2-a] pyridine.

A mixture of 2,3-diamino-5-chloropyridine (5.26 g, 36.64 mmole) and 3-bromo-2-butanone (6.2 g, 41.06 mmole) in ethanol (60 ml) was refluxed overnight. After cooling to room temperature, the crystalline product was filtered and washed with ethanol and ether. The crystals were dissolved in methylene chloride and neutralized by aqueous NaHCO 3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. Performance 3.0 g.

X H-NMR (300 MHz, CDCl 3): d 7.29 (d, J = 1.5 Hz, 1 H), 6.26 (d, J = 1.5 Hz, 1 H), 4.55 (br s, 2 H), 2.4 (s, 3 H), 2.3 (s, 3H).

Ex empl o 2.10 Synthesis of 8-amino-3-ca-r-ethoxy-2,6-dimethyl-i-da z or [1, 2-a] pyridine.

A stirred mixture of 2,3-diamino-5-me t-ylpyridine (4.0 g, 32.5 mmol) and ethyl chloroacetate (5.9 g, 36.0 mmol) in 75 mL absolute ethanol was refluxed overnight. The ethanol was evaporated under reduced pressure. The residue was dissolved in 2M HCl and washed 3 times with diethyl ether, adjusting the pH to 9 and extracting 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel with dichloromethane: methanol 95: 5 as eluent to give 2.0 g of the title product (28%).

XH-NMR (300 MHz, CDC13): d 1.42 (t, 3H), 2.28 (s, 3H), 2.65 (s, 3H), 4.40 (q, 2H), 4.47 (s, 2H), 6.40 (s, 1H), 8.55 (s, 1H).

Example 2.11 Synthesis of 3-carboethoxy-2,6-dimethyl-8- (2,6-dimethyl-il-benzylamino) imidazo [1,2-a] -pyrin.

A mixture of 8-amino-2,6-dimethexididazole [1, 2-a] pyridine (1.2 g, 5.1 mmol), zinc chloride (II) (0.84 g, .6.2 mmol) and 2,6-dimethylbenzaldehyde (0.84 g, 6.2 mmol) in 50 ml of methanol, was treated with sodium cyanoborohydride. (0.39 g, 6.2 mmol) and refluxed for 5 hours. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethane and 40 ml of 2 M sodium hydroxide. The organic layer was separated, dried over sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum ether (40-60) isopropyl ether 8: 2, in yield of 0.8 g (44%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 1.44 (t, 3H), 2.35 (d, 9H), 2.60 (s, 3H), 4.33 (d, 2H), 4.40 (q, 2H), 4.6 (s, 1H), 6.60 (s, 1H), 7.10 (d, 2H), 7.25 (m, 1H), 8.50 (s, 1H).

Example 2.12 Synthesis of 3-carboethoxy-2,6-dimethyl-8- (2,6-dimethyl-il-benzylamino) -imidazo [1, 2-a] -pyridine.

A stirred mixture of 8-amino-2,6-di-ethylimidazole [1,2-a] pi-ridine (1.2 g, 5.1 mmol), zinc chloride (II) (0.84 g, 6.2 mmol) and 2,6-dime The lbenzaldehyde (0.84 g, 6.2 mmol) in 50 ml of methanol was treated with sodium cyanoborohydride (0.39 g, 6.2 mmol) and refluxed for 5 hours. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethane and 40 ml of 2 M sodium hydroxide. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum ether (40 60): isopropyl ether 8: 2, in 0.8 g yield, (44%) of the title compound.

XH-NMR (300 MHz, CDC13): d 1.44 (t, 3H), 2.35 (d, 9H), 2.60 (s, 3H), 4.33 (d, 2H), 4.40 (q, 2H), 4.6 (s, 1H), 6.60 (s, 1H), 7.10 (d, 2H), 7.25 (m, 1H), 8.50 (s, 1H).

Ex empl o 2.13 Synthesis of 3-carboethoxy -2,6-dimet-il- 8 - (2,6-dimethyl-4-f-luorobenzyl amino) -imidazo [1,2-a] pyridine.

A stirred mixture of 8-amino-3-carboe-toxy-2, -dimethylimidazo [1,2-a] pyridine (1.1 g, 4.7 mmol), 2,6-dimethyl-4-fluorobenzylbromo (1.2 g, 5.7 mmol) ), potassium carbonate (1.0 g, 7.5 mmol) and sodium iodide (0.1 g) in 15 ml of acetonitrile were refluxed overnight. After evaporation of the solvent under reduced pressure, the residue was dissolved in dichloromethane and washed with water, the organic layer was separated and dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum ether (40-60) isopropyl ether 7: 3, to give 0.8 g (47%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 1.42 (t, 3H), 2.36 (s, 9H), 2.62 (2, 3H), 4.45 (d, 2H), 4.48 (q, 2H), 4. 54 (s, 1H), 6.30 (s, 1H), 6.75 (d, 2H), 8.55 (s, 1H).

Ex empl o 2. 1 4 Sins of 4 - cl gold -2, -dim e t i lben ci lb rom 4-Chloro-3,5-dimethylbenzene (1.42 g, 0.01 mol) and paraformaldehyde (0.31 g, 0.01 mol) were added to 2 ml of bromohydrogen (33%) in acetic acid. The mixture was stirred overnight at + 70 ° C. The reaction mixture was poured into 25 ml of water and the product was extracted with diethyl ether. The organic layer was washed with water. The organic layer was dried (Na2SO4) and evaporated. 1.1 g of the product (oil) was obtained. The 1 H-NMR spectrum showed that the substance was a mixture of the title compound and 2-chloro-4,6-dimethylbenzylbromo. The product was used as such without any further purification in the next synthesis step (E j. 1.15). 1 H-NMR (300 MHz, CDC13): d 2.28 (s, 6H), 4.51 (s, 2H), 7.04 (s, 2H).

Example 2.15 Synthesis of 3-carboethoxy-2,6-dimethyl-l- 8- (2-yl-6-methylenbenzylamino) -imidazo [1,2-a] pyridine.

A mixture of 8-amino-3-carboe-toxi-2,6-dimethyl-thymidazo [1,2-a] pyridine (1.4 g, 6 mmol), 2-ethyl-6-methyl-ylbenzaldehyde (0.9 g, 6.5 mmol), ZnCl 2 (1.0 g, 7.4 mmol), NaB (CN) H 3 (0.41 g, 6.5 mmol) and MeOH (30 mL) were refluxed for 5 hours. More ZnCl2 (0.2 g) and NaB (CN) H3 (0.1 g) were added. The reaction mixture was refluxed for an additional 2 hours. Triethylamine (2 ml) was added and the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride as eluent. 1.1 g (50%) of the title compound was obtained. 1 H-NMR (300 MHz, CDC13): d 1.25 (t, 3H), 1.45 (t, 3H), 2.30 (s, 6H), 2.6 (s, 3H), 2.75 (q, 2H), 4.35 (d, 2H), 4.45 (q, 2H), 4.85 (bs, 1H), 6.35 (s, 1H), 7.0-7.25 (m, 3H), 8.5 (s, 1H).

Example 2.16 Synthesis of 3-carboethoxy-2,6-dimethyl-8- (2,6-diethylbenzylamino) imidazo [1,2-a] pyridine.

A stirred mixture of 8-amino-3-carboe t-oxy-2,6-dimethylimidazo [1,2-a] pyridine (2.02 g, 8.6 mmol), zinc chloride (II) (1.48 g, 10.8 mmol) and 2 g. , 6-diethylbenzaldehyde (2.17 g, 13.4 mmol) in 50 ml of methanol was treated with sodium cyanoborohydride (0.65 g, 10.3 mmol) and refluxed overnight. The mixture was allowed to cool and then was poured over 80 ml of 1M sodium hydroxide. The precipitate formed was filtered and washed with water and then purified by column chromatography on silica gel with dichloro ethanol: methanol (95: 5) as eluent. The yield was 2.1 g (64%) of the title compound.

XH-NMR (500 MHz, CDC13): d 1.23 (t, 6H), 1.42 (t, 3H), 2.38 (s, 3H), 2.61 (s, 3H), 2.72 (q, 4H), 4.34 (d, 2H), 4.40 (q, 2H), 4.83 (t, 1H), 6.32 (s, 1H) ), 7.11 (d, 2H), 7.24 (t, 1H), 8.51 (s, 1H).

Example 2.11 Synthesis of 3-carboethoxy-8 - (2,6-dimet-il-4-f-luorob-ncyloxy) -2-methyl-imidazo [1,2-a] -pyridine.

A mixture of 3-carboethoxy-8-hydroxy-2-methylimidazo [1, 2-a] pi ridine (1.5 g, 6.8 mmol), 2,6-dimethyl-4-fluorobenzylbromo (1.6 g, 7.5 mmol), iodide Sodium (0.1 g), potassium carbonate (1.9 g, 13.6 mmol) and acetonitrile (50 ml) were refluxed overnight. The solvent was removed in vacuo. The residue was dissolved in CH C12, washed with water, dried over Na2SO and evaporated. The residue was chromatographed on silica gel, eluting with heptane: isopropyl ether (1: 2) to give 2.0 g (83%) of the desired product. 1 H-NMR (300 MHz, CDC13): d 1.45 (t, 3H), 2.4 (s, 6H), 2.7 (s, 3H), 4.45 (q, 2H), 5.2 (s, 2H), 6.7-6.9 ( m, 4H), 9.0 (d, 2H).

Example 2.18 Synthesis of 8-amino-6-bromo-3-carboethoxy-2-methylimidazo [1,2-a] pyridine.

A mixture of 2,3-diamino-5-bromopyridine (2.5 g, 13.31 mmol) and ethyl 2-chloroacetoacetate (2.41 g, 14.64 mmol) in 35 mL of absolute ethanol was refluxed for 14 hours. The ethanol was evaporated under reduced pressure. The residue was dissolved in methylene chloride and neutralized by aqueous NaHCO 3. The organic layer was separated, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride: methanol (100: 3.5) as eluent to give 1.55 g (39%) of the title compound.

XH-NMR (300 MHz, CDC13): d 8.6 (s, 1H), 6.65 (s, 1H), 4.6 (bs, 2H), 4.4 (q, 2H), 2.65 (s, 3H), 1.4 (t, 3H).

Example 2.19 Synthesis of 6-bromo-3-carboethoxy-8- (2,6-dimethyl-4-f-luorobenzylamino) -2-methyl-imidazo [1, 2-a] -pyridine.

A mixture of 8-amino-6-bromo-3-carboethoxy-2-methylimidazo [1,2-a] pyridine (2.06 g, 6.91 mmol), 2,6-dimethyl-4-fluorobenzylbromide (1.05 g, 4.48 mmoles), sodium iodide (0.45 g), sodium carbonate (2.2 g) and acetone (40 ml) was refluxed for 22 hours. The reaction mixture was filtered. The filtrate was washed with CH2C12. The methylene chloride solution was washed with water, dried and evaporated in vacuo. The residue was suspended in ethanol / ether and filtered to give 1.15 g (56%) of the title compound.

^ -NMR (300 MHz, CDC13): d 8.85 (s, 1H), 6.8 (d, 2H), 6.55 (s, 1H), 4.9 (t, 1H), 4.4 (q, 2H), 4.3 (d, 2H), 2.6 (s, 3H), 2.4 (s, 6H), 1.45 (t, 3H).

Example 2.20 Synthesis of 3- (2,6-dimethylbenzyloxy) -5-methyl-2-nit rop ir idina To 0.52 g (8.02 mmol) of 87% KOH and 0.15 g of q-iodide in 6 ml of 95% ethanol was added a solution of 3-hydroxy-5-methyl-2-ni t ropyridine. (1.2 g, 7.79 mmol) in 25 ml of ethanol. To the resulting suspension of potassium salt was added dropwise a solution of 2,6-dimethylbenzylchloride (1.24 g, 8.02 mmol) in 13 g. ml of ethanol. The reaction mixture was refluxed for 1 hour. Additional 87% KOH (0.16 g) and 2,6-dimethylbenzylchloride (0.38 g) were added. The reaction mixture was refluxed for an additional 70 minutes. The mixture was filtered and the inorganic salts were washed with ethanol and methylene chloride. The organic layer was evaporated in vacuo. The residue was dissolved in methylene chloride, washed with aqueous aHC03, dried and evaporated in vacuo. The residue was suspended in ether / isopropanol and filtered to give 1.72 g (81%) of the title compound. 1 H-NMR (500 MHz, CDC13): d 7.94 (s, 1H), 7.46 (s, 1H), 7.19 (t, 1H), 7.08 (d, 2H), 5.18 (s, 2H), 2.47 (s, 3H), 2.4 (s, 6H).

Example 2.21 Synthesis of 2-amino-3- (2,6-dimethylbenzyloxy) -5-methylpyr idine.

A mixture of 3- (2,6-dimethylbenzyloxy) -5-methyl-2-nor tropiridine (1.9 g, 6.99 mmol), iron powder (6.4 g), concentrated HCl (0.15 ml), water (1.5 ml) and 95% ethanol (35 ml) was refluxed for 1.0 hour. The reaction mixture was filtered over celite and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, using methylene chloride: methanol (100: 4) as eluent to give 1.56 g (92%) of the title compound. 1 H-NMR (500 MHz, CDC13): d 7.57 (s, 1H), 7.2 (t, 1H), 7.09 (d, 2H), 6.95 (s, 1H), 5.02 (s, 2H), 4.45 (bs, 2H), 2.4 (s, 6H), 2.24 (s, 3H).

Example 2.22 Synthesis of 3-carboethoxy-2,6-dimethyl-8- (2,6-dimethyl-ylbenzyloxy) imide zo [1,2-a] pyridine.

A mixture of 2-amino-3- (2,6-dimethyl-t-ylbenzyloxy) -5-methy1pi-lyridine (1.0 g, 4.13 mmol) and ethyl 2-chloroacetate (0.79 g, 4.55 mmol) in 20 ml of absolute ethanol , went to reflux for 19 hours. More ethyl 2-chloroacetate (0.25 g) was added. The reaction mixture was refluxed for an additional 23 hours. The solvent was evaporated in vacuo and the residue dissolved in methylene chloride and washed with aqueous NaHCO3. The organic layer was dried and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using methylene chloride: ethyl acetate (100: 10) as eluent to give 0.68 g (47%) of the title compound.

XH-NMR (500 MHz, CDC13): d 8.8 (s, 1H), 7.15 (t, 1H), 7.04 (d, 2H), 6.71 (s, 1H), 5.22 (s, 2H), 4. 41 (q, 2H), 2.67 (s, 3H), 2.41 (s, 6H), 2.39 (s, 3H), 1.42 (t, 3H).

Example 2.23 Synthesis of 3-carboethoxy-8- (2,6-dimethyl-4-fluoro-benzylamino) -2-methyl-yl-imide zo [1,2-a] pyridine.

A stirred mixture of 8-amino-3-carboethoxy-2-methylimidazo [1,2-a] pyridine (1.0 g, 4.7 mmol), 2,6-dimethyl-1-4-fluorobenzylbromide (1.2 g, 5.7 mmol), Potassium carbonate (1.0 g, 7.5 mmol) and sodium iodide (0.1 g) in 15 mL of acetonitrile was refluxed overnight. After evaporation of the solvent under reduced pressure, the The residue was dissolved in dichloromethane and washed with water, the organic layer was separated and dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum ether (40-60) isopropyl ether 7: 3 to give 1.2 g (75%) of the title compound.

XH-NMR (300 MHz, CDC13): d 1.45 (t, 3H), 2.35 (s, 6H), 2.65 (s, 3H), 4.40 (d, 2H), 4.40 (q, 2H), 4. 85 (t, 1H), 6.40 (d, 1H), 6.75 (d, 2H), 6.85 (t, 1H), 8.70 (d, 1H).

Example 2.24 Synthesis of 2-yl-4-fluoro-6-methylbenzylbromide A mixture of 3-ethyl-1-fluoro-5-me t -ylbenzene (1.1 g, 0.008 mol), paraformaldehyde (1.5 g, 0.05 mol), hydrobromic acid (4.1 ml, 0.017 mol) (4.1 M in acetic acid) and Acetic acid (2.5 ml) was stirred at room temperature for 40 hours. To the mixture was added water and petroleum ether (40-60) and the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate and it was evaporated carefully under reduced pressure. The desired product was obtained as a yellow oil (1.3 g, 72%).

XH-NMR (300 MHz, CDC13): d 1.2 (t, 3H), 2.35 (s, 3H), 2.7 (q, 2H), 4.50 (s, 2H), 4.50 (s, 2H), 6.7-6.85 ( m, 2H).

Example 2.25 Synthesis of 3-carboethoxy-2,6-dimet-il-8- (2-yl-4-fl uoro-6-methybenzyl-amino) imidazo [1,2-a] pyridine.

A stirred mixture of 8-amino-3-ca rboe toxy -2,6-dimethylimidazo [1,2-a] pyridine (0.7 g, 3.0 mmol), 2-ethyl-4-fluoro-6-? T? Et, and il-benzyl bromide (0.8 g, 3.5 mmol), potassium carbonate (0.7 g, 4.8 mmol) and sodium iodide (0.1 g) in 15 mL of acetonitrile was refluxed overnight. After evaporation of the solvent under reduced pressure, the residue was dissolved in dichloromethane and washed with water, the organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by gel column chromatography of silica, eluting with petroleum ether (40-60), isopropyl ether 7: 3 to give 0.4 g, (35%) of the title compound. 1 H-NMR (300 MHz, CDC13): d 1.25 (t, 3H), 1.45 (t, 3H), 2.4 (s, 6H), 2.65 (s, 3H), 2.75 (q, 2H), 4.3 (d, 2H), 4.4 (q, 2H), 4.75 (bs, 1H), 6.3 (s, 1H9, 6.75-6.85 (m, 2H), 8.5 (s, 1H).

Example 2.26 Synthesis of 3-carboethoxy-8- (2-yl-6-methylbenzyloxy) -2-methylodazole [1,2-a] pyridine.

A stirred mixture of 3-carboe-toxy-8-hydroxy-2-methylimidazo [1,2-a] pyridine (0.92 g, 4.2 mmol), 2-ethyl-6-methyl-t-methylbenzylchloride (0.7 g, 4.2 mmol), Sodium carbonate (1.0 g, 9.4 mmol) and a catalytic amount of potassium iodide in acetonitrile (40 mL) was refluxed for 4 hours. After filtration and evaporation of the solvent under reduced pressure the residue was purified by column chromatography on silica gel using methylene chloride: ethyl acetate. as eluent to give 1.0 g (68%) of the title compound.

X H-NMR (300 MHz, CDCl 3): d 1.2 (t, 3 H), 1.4 (t, 3H), 2.4 (s, 3H), 2.65 (s, 3H), 2.75 (q, 2H), 4.4 (q, 2H), 5.25 (s, 2H), 6.85-6.9 (, 2H), 7.05-7.25 (m, 3H), 8.95 (dd, 1H).

Ex empl o 2. 21 Symptoms of 3 -e t il -l -fl uoro -5-me t i lben cen o.

Methyl lithium (40 ml, 64 mmol) was added dropwise at 0 ° C to a copper (I) iodide syrup (6.42 g, 33.6 mmol) in diethyl ether (20 ml). After the stirring was started at 0 ° C for 30 minutes, the clear colorless homogeneous cuprous solution was cooled to -78 ° C where the 3-bromomethyl-1-fluoro-5-methylbenzene (5.15 g, 25.4 mmoles) in 10 g. ml of diethyl ether was added. The temperature was allowed to increase slowly. The reaction was turned off at -50 ° C with NH4C1 / NH3-s buffer solution (50 ml). It was extracted with diethyl ether (3 x 50 ml), brine (1 x 100 ml). The organic layer was dried over MgSO4, filtered and the solvents they were removed to yield 3.3 g (94%) of the title compound. 1 H-NMR (500 MHz, CDC13): d 1.22 (t, 3H), 2.32 (s, 3H), 2.60 (q, 2H), 6.69 (d, 2H), 6.78 (s, 1H).

BIOLOGICAL TESTS. 1. In vitro experiments.

Inhibition of acid secretion in isolated rabbit gastric glands.

The inhibitory effects on acid secretion in vivo in isolated rabbit gastric glands was measured as described by Berglidh et al., (1979) Acta Physio. Scand., 97, 401-414.

Determination of the activity H +, K + ATPase.

Preparation of gastric membrane vesicles: Gastric membrane vesicles containing H +, K + -ATPase were prepared from pig stomachs as previously described by Saccomani et al., (1977) Biochim. Biophys. Acta 465, 311-330.

Permeable vesicles: The membrane fraction was diluted with 1 mM PIPES / Tris, pH 7.4, to obtain a concentration of 1% sucrose, homogenized and centrifuged at 100,000 x g for 2 hours. The resulting pellet was suspended in water and lyophilized twice.

Determination of H +, K + -ATPase activity: Permeable membrane vesicles (2.5-5 μg) were incubated for 15 minutes at 37 ° C in an 18 mM PIPES / Tris buffer solution, pH 7.4, containing 2 mM MgCl 2, 10 mM KCl and 2 M ATP. The ATPase activity was estimated as the release of the inorganic phosphate from ATP, as described by LeBel et al., (1978) Anal. Biochem., 85, 86-89. 2. Experiments in vivo.

Inhibitory effect on acid secretion in female rats.

Female rats of the Sprague-Dawly strain were used. These were equipped with a cannulated fistula in the stomach (opening) and the upper part of the duodenum, to collect the gastric secretions and administer the test substances, respectively. A recovery period of 14 days was allowed after the surgery before beginning the test.

Before the secretion tests, the animals were deprived of food, but not of water for 20 hours. The stomach was repeatedly washed through the gastric cannula with tap water (+ 37 ° C), and 6 ml of Glucose-Ringer was given subcutaneously. The secretion of the acid was stimulated with the infusion for 2.5-4 hours (1.2 ml / h, subcutaneously) of pentagastrin and carbachol (20 and 110 mmol / kg.h, respectively), during which time the gastric secretions were collected in fractions of 30 minutes. The test substances or vehicle were given either 60 minutes after starting the stimulation (intravenous or intraduodenal doses, 1 ml / kg), or 2 hours after initiating the stimulation (oral dose, 5 ml / kg, closed gastric cannula). ). The time interval between the dose and the stimulation can be increased in order to study the duration of the action. Samples of gastric juices were titrated until a pH of 7.0 with NaOH, 0.1 m, and an acid output calculation as the product of the titrated volume and concentration.

Additional calculations are based on a group of 4 to 6 rats with significant responses. In the case of administration during stimulation; the acid exit during the periods after the administration of the test substance or vehicle are expressed as fractional responses, establishing the acid exit in the period of 30 minutes preceding the administration at 1.0. Percent inhibition was calculated from the fractional responses obtained by the test compound and the vehicle. In the case of administration before stimulation; the percent inhibition was calculated directly from the acid output recorded after the test compound and the vehicle.

Biodi spon ibi l i da d en ra t a s Adult rats of the Sprague-Dawley strain were used. One to three days before the experiments, all the rats were prepared by Cannulation of the left carotid artery under anesthesia. The rats used for the intravenous experiments were also cannulated in the jugular vein (Popovic (1960) J. Appl. Physiol., 15, 727-728). The cannulas were exteriorized at the nape of the neck.

Blood samples (0.1 - 0.4 g) were taken repeatedly from the carotid artery at intervals of more than 5.5 hours after the dose was given. The samples were frozen until the analysis of the test compound.

Bioavailability was evaluated by calculating the arithmetic quotient between the area under the blood / plasma concentration curve (AUC) followed by (i) int radoudenal (id) or oral (po) administration and (ii) intravenous (iv) administration to the rat or the pig, respectively.

The area under the curve of blood concentration versus time, AUC, is determined by the linear / logarithmic trapezoid rule and extrapolated to infinity by dividing the last blood concentration determined by the rate of blood. constant elimination in the terminal phase. The systemic bioavailability (F%) following the intoduodenal or oral administration is calculated as F (%) = (AUC (p.o. or i.d.) / AUC (i.v.)) x 100.

Inhibition of gastric acid secretion and bioavailability in the conscient dog.

Labrador Retriever or Harrier dogs of either sex were used. These were equipped with a duodenal fistula for the administration of the test compounds or vehicle and a cannulated gastric fistula or a Heidenhaim bag to collect the gastric secretion.

Before the secretory tests, the animals fasted for about 18 hours but were allowed water freely. The secretion of gastric acid was stimulated for more than 6.5 hours by the infusion of histamine dihydrochloride (12 ml / h) at a dose producing about 80% of the individual maximum secretion response, and gastric juices were collected in fractions of 30 consecutive minutes. The test substance or vehicle was given orally, i.d or i.v., 1 or 1.5 hours after initiating the histamine infusion, in a volume of 0.5 mg / kg of body weight. In the case of oral administration, it may be noted separately that the test compound is administered to the secretion of the main stomach acid from the dog's Heidenham pouch.

The acidity of the gastric juice samples was determined by titration up to a pH of 7.0 and the acid output was calculated. The acid exit in the collection periods after the administration of the test substance or vehicle is expressed as a fractional response, establishing the exit of the acid in the fraction preceding the 1.0 administration. Percent inhibition was calculated from fractional responses obtained by the test compound and the vehicle.

Blood samples for analyzes of the concentration of test compound in the plasma were taken at intervals of more than 4 hours after dosing. The plasma was separated and frozen within 30 minutes after the collection and subsequently analyzed. The bioavailability systemic (F%) after oral administration or i.d. was calculated as described above in the rat model.

It is stated that in relation to this date. The best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (35)

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, characterized in that R1 is CH3 or CH20H; R2 is lower alkyl; R3 is lower alkyl; R4 is H or halogen; R5 is H, halogen, or lower alkyl; X is NH or O.

2. A compound according to claim 1, characterized in that R 2 is C 1 -C 4 alkyl; R 3 is C 1 -C 4 alkyl; R 5 is halogen, H, or C 1 -C 4 alkyl; Y R, R4 and X are as defined in the claim 1.

3. A compound according to claim 1 or 2, characterized in that R2 is CH3 or CH2CH3; R3 is CH3 or CH2CH3; R4 is H, Br, Cl or F; R5 is H, CH3, Br, Cl or F; and R1 and X are as defined in claim 1.

4. A compound according to claim 3, characterized in that R5 is H, CH3, or F; and R1, R2, R3, R4 and X are as defined in claim 3.

5. The compound according to any of claims 1 to 4, characterized in that it is the compound 8- (2,6-dimethylbenzylamino) -2,3,6-trimethylimidazo [1,2- a] pyridine, or a pharmaceutically salt acceptable of it.

6. The compound according to any one of claims 1 to 4, characterized in that it is the compound 8- (2,6-dimethybenzlamino) -3-hydroxymethyl-2-methylimidazo [1,2- a] pyridine, or a salt pharmaceutically acceptable thereof.

7. The compound according to any of claims 1 to 4, characterized in that it is the compound 2,3-dimethyl-8- (2,6-dimethyl-4-fluorobenzylamino) imidazo [1,2-a] pyridine, or a salt pharmaceutically acceptable thereof.

8. The compound according to any of claims 1 to 4, characterized in that it is the compound 2,6-dimethyl-8- (2,6-dimethenobenzylamino) -3-hydroxymethyl imidazo (1, 2-a] pyridine, or a pharmaceutically acceptable salt thereof.

9. The compound according to any of claims 1 to 4, characterized in that it is the compound 2,6-dimethyl-8- (2,6-dimethyl-4-fluorobenzylamino) -3- hydroxymethylimidazo [1,2-a] pyridine, or a pharmaceutically acceptable salt thereof.

10. The compound according to any of the rei indications 1 to 4, characterized in that it is the compound 8- (2,6-dimethyl-4-fluorobenzylamino) -2, 3,6-trimethyl imidazo [1,2- a] pyridine, or a pharmaceutically acceptable salt thereof.

11. The compound according to any of claims 1 to 4, characterized in that it is the compound 2,3-dimethyl-8- (2,6-dimethyl-4-chlorobenzylamino) imidazo [1,2- a] pyridine, or a salt pharmaceutically acceptable thereof.

12. The compound in accordance with any. of claims 1 to 4, characterized in that it is the compound 2,6-dimethyl-8- (2-ethyl-6-methylbenzylamino) -3-hydroxymethylimide zo [1, 2 -a] pi ridine, or a pharmaceutically acceptable salt of the same.

13. The compound according to any of claims 1 to 4, characterized in that it is the compound 8- (2,6-diethylbenzylamino) -2,6-dimethyl-3-hydroxymethylidazo [1,2-a] pyridine, or a salt pharmaceutically acceptable thereof.

14. The compound according to any of claims 1 to 4, characterized in that it is the compound 8- (2-ethyl-6-methylbenzylamino) -2, 3, 6-t rimet -limidazo [1,2-a] pyridine, or a pharmaceutically acceptable salt.

15. The compound according to any of claims 1 to 4, characterized in that it is the compound 8- (2,6-dimethyl-4-fluorobenzyloxy) -3-hydroxymethyl-2-methylimidazo [1,2-a] pyridine, or a pharmaceutically acceptable salt thereof.

16. The compound according to any of claims 1 to 4, characterized in that it is the compound 2,6-dimethyl-8- (2,6-dimethyl-t-benzenediol) -3- hydroxymethylimidazo [1,2-a] pyridine, or a pharmaceutically acceptable salt thereof.

17. The compound according to any of claims 1 to 4, characterized in that it is the compound 2,6-dimethyl-8- (2-ethyl-4-fluoro-6-methylbenzylamino) -3-hydroxymethylimidazo [1,2-a] pyridine, or a pharmaceutically acceptable salt thereof.

18. The compound according to any of claims 1 to 4, characterized in that it is the compound 8- (2-ethyl-4-fluoro-6-metylbenzylamine) -2,3,6-trimethylimidazo [1,2-a] pyridine , or a pharmaceutically acceptable salt thereof.

19. A hydrochloride salt of a compound according to any of claims 1 to 18.

20. The compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, characterized in that it is used in therapy.

21. A process for the preparation of a compound according to any of claims 1 to 18, characterized in that it comprises reacting a compound of the general Formula II wherein X1 is NH2 or OH, and R1 and R5 are as defined by Formula I, they can react with compounds of the general Formula III where R2, R3 and R4 are as defined by the Formula I and Y is a starting group, in an inert solvent with or without a base, for the compounds of Formula I.

22. The process for the preparation of a compound according to any of claims 1 to 18, wherein X is NH, characterized in that it comprises a) reacting a compound of Formula IV wherein R1 and R5 are as defined by Formula I, with compounds of Formula V wherein R2, R3 and R4 are as defined by Formula I, preferably in the presence of a Lewis acid, in an inert solvent for compounds of Formula VI VI wherein R1, R2, R3, R4, R5 are as defined by Formula I; (b) reducing the compounds of Formula VI in an inert solvent under standard conditions for compounds of general Formula I wherein X is NH.

23. The process for the preparation of a compound according to any of claims 1 to 18, wherein R1 is CH20H, characterized in that it comprises (a) reacting a compound of Formula VII wherein X1 is NH2 or OH and R5 is as defined by Formula I, with compounds of the general Formula III wherein R2, R3 and R4 are as defined by Formula I and Y is a starting group, in an inert solvent with or without base, for compounds of Formula VIII, Vffl wherein R2, R3, R4, R5 and X are as defined by Formula I; (b) reducing the compounds of Formula VIII in an inert solvent under standard conditions for compounds of the general Formula I wherein R 1 is CH OH.

24. The process for the preparation of a compound according to any of claims 1 to 18, wherein X is NH and R1 is CH2OH, characterized in that it comprises (a) reacting a compound of general Formula IX wherein R5 is as defined by Formula I, with compounds of Formula V wherein R2, R3 and R4 are as defined by Formula I, preferably in the presence of a Lewis acid, in an inert solvent for compounds of general Formula X where R2, R3, R4 and R5 is as defined by the Formula I; (b) reducing compounds of Formula X in an inert solvent under standard conditions for compounds of Formula XI R4 xi wherein R2, R3, R4 and R5 are as defined by Formula I, (c) reducing the compounds of the general Formula XI in an inert solvent under standard conditions for a compound of the general Formula I wherein X is NH and R1 is CH20H.

25. The process for the preparation of a compound according to any of claims 1 to 18, wherein X is O and R1 is CH2OH, characterized in that (a) reacting a compound of general Formula XII wherein R2, R3, R4, and R5 are as defined by Formula I, with compounds of the general formula CH3COCH (Z) COOCH2CH3 wherein Z is Br or Cl, in an inert solvent, for compounds of the general Formula XIII wherein R2, R3, R4, and R5 are as defined by Formula I; (b) reducing the compounds of the general Formula XIII in an inert solvent under standard conditions for compounds of the general Formula I, wherein R1 is CH2OH and X is 0.

26. A pharmaceutical formulation, characterized in that it comprises a compound according to any of claims 1 to 18 and further comprises a pharmaceutically acceptable carrier.

27. The use of a compound according to any of claims 1 to 18, for the manufacture of a medicament for inhibiting the secretion of gastric acid.

28. The use of a compound according to any of claims 1 to 18, for the manufacture of a medicament for the treatment of gastrointestinal inflammatory disorders.

29. The use of a compound according to any of claims 1 to 18, for the manufacture of a medicament for the treatment or prophylaxis of conditions involving an infection by Hel i coba c t er pyl ori of human gastric mucosa, wherein the salt is adapted to be administered in combination with at least one antimicrobial agent.

30. A method for inhibiting gastric acid secretion, characterized in that it comprises administering to a mammal, including man, in need of such inhibition, an effective amount of a compound according to any of claims 1 to 18.

31. A method for the treatment of gastrointestinal inflammatory disorders, characterized in that it comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any of claims 1 to 18.

32. A method for the treatment or prophylaxis of conditions that involve infection by Hel i coba c t er pyl ori of human gastric mucosa, characterized in that it comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound as claimed in any of claims 1 to 18, wherein the salt is administered in combination with at least one antimicrobial agent.

33. A pharmaceutical formulation for use in the inhibition of gastric acid secretion, characterized in that the active ingredient is a compound according to any of claims 1 to 18.

34. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory disorders, characterized in that the active ingredient is a compound according to any of claims 1 to 18.

35. A pharmaceutical formulation for use in the treatment or prophylaxis of conditions involving an infection by Hel i coba c t er pyl ori of the human gastric mucosa, characterized in that the active ingredient is a compound in accordance with any of the claims 1 to 18 in combination with at least one antimicrobial agent.