Imidazolidinedione, their salts and drug

 

(57) Abstract:

Imidazolidinedione formula I, where R0 - (C1-C4)alkyl, hydroxymethyl or halogen; R1 is - (C1-C4)alkyl; R2, R3, R4, R5 is hydrogen or (C1-C4)alkyl; R3' is hydrogen, (C1-C4)alkyl or (C1-C4)alkyl substituted by 1-2 halogen or (C1-C4)alkoxy; And - O or NH; Y Is O or CH2and their salts, can be used for the prevention and treatment of diseases of the gastrointestinal tract. 2 S. and 4 C.p. f-crystals, 2 tab.

The invention relates to new imidazolidinedione intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines.

In European application EP-A-0033094 describes imidazo-[1,2-a] pyridine containing in position 8 aryl Deputy, preferably represents a radical of the following: phenyl, thienyl, pyridyl or substituted by chlorine, fluorine, stands, tert-bootrom, trifluoromethyl, methoxy group or a cyanide phenyl. As a particularly interesting aryl radicals in EP-A-0033094 named phenyl, o - or p-forfinal, p-chlorophenyl and 2,4, 6-trimetilfenil, of which especially preferred by imidazo [1,2-a] pyridine, containing in position 3 unsaturated aliphatic radical, primarily (substituted) alkynylaryl radical. In European application EP-A-0266890 describes imidazo [1,2-a] pyridine, substituted in position 8 alkenyl, alkyl or cycloalkylcarbonyl radical.

The present invention is the development of new derivatives of imidazopyridine with antiulcer and antisecretory properties, and the development of new drugs based on them.

The problem is solved is described in more detail below compounds different from the compounds of the prior art primarily by the substitution in position 8, which have surprising and particularly positive properties.

Thus, the object of the invention is imidazolidinedione formula I

< / BR>
where R0 denotes (C1-C4)alkyl, hydroxymethyl or halogen,

R1 means (C1-C4)alkyl,

R2 means hydrogen or (C1-C4)alkyl,

R3 means hydrogen or (C1-C4)alkyl,

R3' is hydrogen, (C1-C4)alkyl or (C1-C4)alkyl, substituted by one or two identical or different substituents, wybranej,

R5 means hydrogen or (C1-C4)alkyl,

A means O (oxygen) or NH, and

Y represents O (oxygen) or CH2,

and their salts.

In addition to the above values, R0 may additionally mean thiocyanate, R2 - (C1-C4)alkoxy, halogen or trifluoromethyl.

This group of substituents in R3' when he means substituted (C1-C4)alkyl, optionally may include (C1-C4)alkoxy (C1-C4)alkoxy, R4 may additionally denote a (C1-C4)alkoxy, halogen or trifluoromethyl, and R5 is halogen.

(C1-C4)alkyl represents remotemachine or branched alkyl radicals with 1-4 carbon atoms. As examples of such radicals can be called butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl.

Halogen in the context of the present invention means bromine, fluorine and especially chlorine.

(C1-C4)alkoxy represents an oxygen atom bound to one of the above (C1-C4)alkyl radicals. As examples metaxylene and ethoxyline radicals.

(C1-C4)alkoxy-(Cdisplaced in turn by another (C1-C4)CNS radical. As an example, you can call methoxyethoxy radical.

Salts of compounds of the formula I can preferably include all of the acid additive salt. Among these one should mention first of all pharmacologically acceptable salts of inorganic and organic acids commonly used in Galenika. Pharmacologically unacceptable salts, which may be formed as a primary product upon receipt of the compounds according to the invention on an industrial scale, using methods known to the person skilled in the art can be converted into pharmacologically acceptable salts. As such suitable water-soluble and water-insoluble acid additive salts with such acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-Glukhova acid, benzoic acid, 2-(4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, albanova acid, stearic kisenyi salts depending on use, whether one - or polybasic acid, and a salt is required to obtain the acid used in equimolar or in some other proportion.

Among the compounds of formula I should highlight those that

R0 means (C1-C4)alkyl, hydroxymethyl or halogen,

R1 means (C1-C4)alkyl,

R2 means (C1-C4)alkyl,

R3 means hydrogen or (C1-C4)alkyl,

R3' is hydrogen, (C1-C4)alkyl or (C1-C4)alkyl, substituted Deputy selected from the group comprising halogen and (C1-C4)alkoxy,

R4 means hydrogen,

R5 means hydrogen,

A means O (oxygen) or NH, and

Y represents O (oxygen) or CH, and their salts.

Particularly preferred compounds of formula I are those in which

R0 denotes methyl, hydroxymethyl, chlorine or fluorine,

R1 means methyl,

R2 means (C1-C4)alkyl,

R3 means hydrogen or (C1-C4)alkyl,

R3' is hydrogen, (C1-C4)alkyl or (C1-C4)alkyl, substituted (C1-C4)alkoxygroup,

R4 means hydrogen,

R5 oznachaet is sustained fashion are further such compounds of the formula I, where

R0 denotes methyl, hydroxymethyl or chlorine,

R1 means methyl,

R2 means (C1-C4)alkyl,

R3 means hydrogen or (C1-C4)alkyl,

R3' is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl,

R4 means hydrogen,

R5 means hydrogen, A stands for O (oxygen) or NH

Y represents O (oxygen) or CH,

and their salts.

Examples according to the invention compounds are presented in table 1 (see tab. 1 in the end of the description).

These examples include salts represented in the connection table.

The compounds of formula I in positions in which the attached substituents R3, respectively R3' may respectively have a center of chirality. The invention includes in accordance with this, in the case of chiral compounds as pure enantiomers and diastereomers and their mixtures in any ratio of 15 components, including the racemates.

The compounds of formula I according to the invention can be obtained in the following ways

a) to obtain compounds of the formula I in which R0 denotes hydroxymethyl, compounds of formula II

< / BR>
where R1, R2, R3, R3', R4, R5, A and Y have the above values of p is s higher than the value and X is an appropriate leaving group is subjected to cyclization with elimination of HX,

or, if necessary, the obtained compound of formula I transferred into their salts, or, if necessary, from the obtained salts of compounds 1 then release the compounds of formula I.

The recovery of the compounds of the formula II is carried out but the methods known to the person skilled in the art. The reaction is carried out in inert solvents, for example lower aliphatic alcohols, for example, using the corresponding hydrides, such as, in particular, as borohydride sodium, optionally with the addition of water.

The cyclization of compounds of the formula III is carried out according to the methods known to the person skilled in the technical field, for example, as described in the examples below, in inert solvents and in the presence of an acid binding agent (proton acceptor). As acceptors of protons can be called, among other things, hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide, or metal hydrides such as sodium hydride. Appropriate leaving group is, for example, halogen atom (preferably chlorine or bromine) or methansulfonate the t on the basis of their knowledge and experience.

Isolation and purification of the compounds according to the invention is conducted according to known methods, for example by distillation of the solvent under vacuum and recrystallization of the resulting residue from a suitable solvent, or one of the usual methods of treatment, such as, for example, column chromatography on acceptable material.

An acid additive salt is obtained by dissolving the free base in a suitable for this purpose solvent, for example water, a chlorinated hydrocarbon, such as methylene chloride or chloroform, in a lower aliphatic alcohol (ethanol, isopropanol), a ketone such as acetone, or in a simple ether, such as THF or diisopropyl ether, containing the desired acid, or to which is added then the desired acid.

Salt is obtained by filtering the resultant deposition rates, deposition using herstories salt accession, or by evaporation of the solvent. The obtained salt by alkalizing, for example, an aqueous solution of ammonia, to translate into the free base, which in turn can be converted to an acid additive salt. In this way pharmaceutically unacceptable acid additive salts can be converted into fertilizatio compounds of formula III, in which R0 is set to CHO.

The compounds of formula III receive, for example, the interaction of the compounds of formula IV

< / BR>
where R0, Rl, R2, R4, R5 and a have the abovementioned meanings, with compounds Hal-CO-Y-CHR3'-CHR3-X, where R3, R3', Y and X have the above values, a Hal represents a halogen atom (preferably chlorine or bromine).

The initial compounds of formula IV are known from European application EP-A-0268989 and EP-A-0308917 or they can be obtained as described in these publications methodology. Thus, in particular, the parent compound IV can be obtained by known methods from the corresponding nitro compounds by recovery or by hydrolysis of the corresponding N-ACI-derivatives.

Getting proposed according to the invention compounds is explained more in the following examples. First of all these examples serve to selectively describe the process and methods of producing compounds of the formula I, as well as some of the parent compounds. Similarly, according to the same method or technique known to a person skilled in the art using conventional techniques can be obtained from other compounds of formula I, as well as other source compounds derived hour(s) min - minute (s), tPLthe melting temperature, tKip- boiling point, decomp. - decomposition.

Examples

The final products

1.3- [2-(2.3-dimethylimidazo[1.2-a]pyridine-8-illuminometer)-3-were] oxazolidin-2-he

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

To a solution of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (19,65 g, 70 mmol) in anhydrous dichloromethane (600 ml) at RT for about 30 min added dropwise 2-chlorotalonil ether of Harborview acid (12.4 g, 81 mmol) dissolved in dichloromethane (40 ml). Then stirred for 16 h at RT, and then extracted with a solution of sodium bicarbonate (g ml). After extraction of the aqueous phase with dichloromethane (200 ml) the combined organic extracts washed with water (I ml), dried over magnesium sulfate and concentrated. The crude product (33, 9 g) is directly used in the subsequent reaction in example 1B.

b) 3-[2-(2,3-dimethylimidazo[1,2-a}pyridine-8-illuminometer)-3-were] oxazolidin-2-he

To a solution of the crude product from example 1A (33,8 g) in anhydrous ethanol (800 ml) under vigorous stirring are added in several portions during pre CT, then add portions of water (200 ml) and the ethanol is distilled off using a rotary evaporator. The precipitate is sucked off, washed with water and dried under vacuum. The crude product is purified by chromatography on silica gel (solvent system: toluene-dioxane= 4: 1). After combining fractions with Rf=0.15 and crystallization from ethyl acetate-diisopropyl ether allocate specified in the header connection (13,6 g, 63%) as a solid beige color. tPL139-140oC.

the Interaction between dissolved in acetone compounds specified in the header, with methansulfonate get methanesulfonate specified in the connection header with tPL232-235oC.

2. 3- [2-(3-chloro-2-methylimidazo[1.2-a]pyridine-8-illuminometer) -3-were]oxazolidin-2-he

a) 8- [2-(2-chlorocarbonate)-6-methylbenzylamino] -3-chloro-2-methylimidazo[1,2-a]pyridine

As described in example 1A, the method of 8-(2-amino-6-methylbenzylamino)-3-chloro-2-methylimidazo[1,2-a] pyridine (0.27 g) and 2-hloretilova ether Harborview acid (0.18 g) in dichloromethane (30 ml) receive specified in the title compound as a brown oil, which was directly used in the subsequent reaction in 2B.

b) 3-[2-(3-chloro-2-methylimidazo the frame of the product 2A (0,37 g) and sodium hydride (0.45 g, 80% in paraffin) in anhydrous ethanol (20 ml) after crystallization from ethyl acetate-petroleum ether get mentioned in the title compound (70 mg, 21%) as a solid beige color, tPL137-139oC.

3. 3- [2-(3-hydroxymethyl-2-methylimidazo[1.2-a]pyridine-8-illuminometer) -3-were]oxazolidin-2-he

a) 8-[2-(2-chlorocarbonate)-6-methylbenzylamino]-3-formyl-2 - methylimidazo[1,2-a]pyridine

As described in example 1A, the method of 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a] pyridine (2,03. g) and 2-hloretilova ether Harborview acid (1.01 g) in dichloromethane (120 ml) receive specified in the title compound as a brown oil, which was directly used in the subsequent reaction in example 3b.

b) 3-[2-(3-formyl-2-methylimidazo[1,2-a]pyridine-8-illuminometer)- 3-were]oxazolidin-2-he

As described in example 1B to the methodology of the crude product 3A (0.12 g) and sodium hydride (0.01 g, 80% in paraffin) in anhydrous ethanol (10 ml) after crystallization from ethyl acetate-diisopropylamido ether get mentioned in the title compound (80 mg, 73%) as a solid beige color, tPL196-197oC.

C) 3- [2-(3-hydroxymethyl-2-matrimid the DIN-8-illuminometer)-3 - were] oxazolidin-2-it (0.18 g, 0,49 mmole) and boronate sodium (19 mg, 0.5 mmole) in anhydrous ethanol (20 ml) is stirred for 30 min at RT. Then add water (75 ml), ethanol is distilled off using a rotary evaporator and the aqueous residue extracted with ethyl acetate (CH ml). The organic extracts washed with water (50 ml), dried over magnesium sulfate and concentrated. After crystallization from diisopropyl ether get mentioned in the title compound (120 mg, 66%) as a solid beige color, tPL152-157oC.

4.3- [2-(3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine-8-intoximeter) -3-were]oxazolidin-2-he

a) 8-[2-(2-chlorocarbonate)-6-methylbenzylamino] -3-formyl-2 - methylimidazo[1,2-a]pyridine

As described in example 1A, the method of 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a] pyridine (2,36 g) and 2-hloretilova ether Harborview acid (1.3 g) in dichloromethane (150 ml) receive specified in the title compound as a brown oil, which was directly used in the reaction of 4B.

b) 3-[2-(3-formyl-2-methylimidazo[1,2-a]pyridine-8-intoximeter)-3 - were]oxazolidin-2-he

As described in example 1B to the methodology of the crude product 4A (1,14 g) and sodium hydride (0,13 g, 80% in paraffin) in the head of the compound (0.7 g, 67%) as a solid beige color, tPL242-244oC.

C) 3-[2-(3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine-8-intoximeter) -3-were] oxazolidin-2-he

A solution of 3-[2-(3-formyl-2-methylimidazo[1,2-a] pyridine-8-intoximeter)-3 - were] oxazolidin-2-it (1.39 g, 3.8 mmole) boronate sodium (0,19 g, 4.75 mmole) in anhydrous ethanol (125 ml) is stirred for 1.5 h at RT. Then add water (100 ml), ethanol is distilled off using a rotary evaporator and the aqueous residue is stirred for 30 min at 4oC. the Precipitate is filtered off, washed with cold water and dried under vacuum. This way, get listed in the title compound (1.28 g, 91%) as a solid beige color, tPL190-193oC.

5. 5-chloromethyl-3-[2-(2.3-dimethylimidazo [1.2-a] pyridine-8-illuminometer)-3-were] oxazolidin-2-he

a) To 591 ml (1,14 mole) of a solution of phosgene in toluene (1.93 and mol/l) for 2 h at 5-8oC added dropwise a mixture of 150 g (1,14 mole) of 1,3-dichloropropanol and 90.2 g (1,14 mole) of pyridine and stirred for 24 h at 20oC. Then pass the gas stream N2sucked hydrochloride of pyridine, washed with water, dried over magnesium sulfate and after fractional distillation 102 g (47%within 2 days at RT was stirred solution of 2.0 g (7,13 mmol) of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a] pyridine and 1.5 g (7.84 mmol) obtained in stage a) compound in 80 ml of dichloromethane. The organic solution was washed with saturated sodium carbonate solution and water, dried with magnesium sulfate and concentrate under vacuum. This way obtain 3.4 g of the crude 8-12- [(2-chloro-1-chloromethylene)carbylamine]-6-methylbenzylamino) -2,3-dimethylimidazo[1,2-a] pyridine in the form of oils, which are used at a later stage.

To the solution obtained in stage b) compound in 30 ml of ethanol at 20oC added dropwise a solution of 0.48 g of 85% potassium hydroxide in 4 ml of ethanol and stirred for 5 hours Then concentrated under vacuum, mixed with water, extracted with dichloromethane and dried with magnesium sulfate the organic layer concentrated under vacuum. The residue is mixed with 5 ml of ethanol and cooled in an ice bath. In this way receive 1.2 g specified in the connection header, tPL141-143oC.

6. Hydrochloride 3-[2-(2,3-dimethylimidazo[1.2-a]pyridine-8-illuminometer)-3-were] -5-methyloxazolidine-2-it

a) Analogously to example 5A 2-chloro-1-propanol and phosgene receive (2-chloro-1-metaliteracy ether) Harborview acid, tKip55-56oC/17 mbar.

b) Analogously to example 5B is subjected to interaction 2.0 g (7,13 mmol) of 8-(2-amino-6-methylbenzylamino)-2,3-Demetrio 8-{2- [(2-chloro-1-methylethoxy) carbylamine]-6-methylbenzyl-amino]-2,3-dimethylimidazo[1,2-a] pyridine in the form of an amorphous mass.

To 2.9 g obtained in stage b) compound in 15 ml of ethanol at RT are added dropwise a solution of 0.48 g of 85% KOH in 15 ml of ethanol and stirred for further 12 hours and Then concentrated under vacuum, mixed with water, extracted with dichloromethane and dried with magnesium sulfate the organic layer concentrated under vacuum. The residue is mixed with 0.3 ml of concentrated hydrochloric acid and acetone, to deliver 1.5 g specified in the connection header, tPL274-275oC (decomp.).

7. 3-[2-(2.3-dimethylimidazo [1.2-a]pyridine-8-illuminometer)-3-were] -4-methyloxazolidine-2-he

a) Analogously to example 5B (2-chloropropylene ether) Harborview acid and 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a] pyridine receive 8-[2-(2-chloropropiophenone)-6-methylbenzylamino] -2,3-dimethylimidazo[1,2-a]pyridine.

b) obtained in (a) connection and a solution of potassium hydroxide in ethanol analogously to example 5B receive specified in the header of the connection.

8. 3- [2-(2.3-dimethylimidazo [1.2-a]pyridine-8-illuminometer)-3-were] -5-ethoxyethylacetate-2-he

a) Analogously to example 5B (1-chloromethyl-2-methoxyethanol ether) Harborview acid (see Helv. Chim. Acta 44, 105, 1961) and 8-(2)-6-methylbenzylamino] -2,3-dimethylimidazo[1,2-a]pyridine.

b) obtained in (a) connection and a solution of potassium hydroxide in ethanol analogously to example 5B receive specified in the header of the connection.

9. 1-[2-(2.3-dimethylimidazo [1.2-a] pyridine-8-illuminometer)-3-were] pyrrolidin-2-he

a) 8-[2-(4-chloroethylamino)-6-methylbenzylamino] -2,3-dimethylimidazo[1,2-a]pyridine

To a solution of 2.2 g (a 7.85 mmol) of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine and 0.63 ml (a 7.85 mmol) of pyridine in 30 ml dichloromethane at 0-5oC under stirring is added dropwise to 0.88 ml (a 7.85 mmol) of 4-chlorobutyronitrile and continue stirring for another 2 h at 0-20oC. and Then mixed with water and potassium bicarbonate to pH 7, extracted by shaking, the organic layer dried with magnesium sulfate and concentrate under vacuum. The residue is recrystallized from toluene and petroleum ether (50/70oC). This way obtain 2.6 g ( 86%) indicated in the title compound, tPL138-140oC.

b) 1-[2-(2,3-dimethylimidazo[1,2-a]pyridine-8-illuminometer)- 3-were] pyrrolidin-2-he

To a solution of 2.4 g (6,24 mmol) obtained in (a) compound in 60 ml of ethanol at RT is added dropwise a solution of 0.41 g (6.25 mmol) of 85% KOH in 15 ml of ethanol and stirred for 4 h Then the m shaking with ethyl acetate. The organic layer is dried with magnesium sulfate, concentrated under vacuum and the residue crystallized diisopropyl ether. This way obtain 2.0 g (92%) indicated in the title compound, tPL138-141oC.

10. 1-[2-(3-chloro-2-methylimidazo[1.2-a] pyridine-8-illuminometer)-3-were] pyrrolidin-2-he

a) 8-[2-(4-chloroethylamino)-6-methylbenzylamino] -3-chloro-2-methylimidazo [1,2-a]pyridine

As described in example 9a methodology the interaction of 8-(2-amino-6-methylbenzylamino)-3-chloro-2-methylimidazo [1,2-a] pyridine with 4-chlorobutyryl-chloride after crystallization from ethyl acetate-cyclohexanone get mentioned in the title compound in the form of a powder beige. Yield 66%; tPL127-130oC.

b) 1-[2-(3-chloro-2-methylimidazo[1,2-a] pyridine-8-illuminometer)- 3-were] pyrrolidin-2-he

As described in example 9b method interaction obtained in (a) compounds with potassium hydroxide in ethanol and subsequent crystallization from diisopropyl ether get mentioned in the title compound in the form of a powder beige. Yield 77%; tPL265-267oC.

The source connection

A1. 3-chloro-2-methyl-8-pihlajaniemi[1.2-a]pyridine

In the icy vinegar (20 ml) restauraut [1,2-a] pyridine and pivaloyloxy, tPL229-230oC, and 15oC slowly pass chlorine gas until completion of the reaction, which is defined by TX (about 20 min). The solvent is then distilled off, the residue is dissolved in ethyl acetate-water (respectively 30 ml), saturated solution of sodium bicarbonate establish a basic pH and extracted. Then re-extracted with ethyl acetate (CH ml). The combined organic extracts washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (solvent system: toluene-dioxane= 9:1). After concentration of fractions with Rf=0,2 receive specified in the title compound (4.1 g, 83%) as a colourless solid, tPL117-118oC.

A2. 8-amino-3-chloroimidazo[1,2-a]pyridine

A suspension of 3-chloro-2-methyl-8-pihlajaniemi[1,2-a] pyridine (4.0 g, 15 mmol) in 60% sulfuric acid (25 ml) is heated for 1 h at 100oC. After cooling to CT add water (100 ml) and 10H sodium hydroxide pH adjusted to 10. Then extracted with ethyl acetate (CH ml). The combined organic extracts washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is dissolved in boiling what about the substance of beige. The output of 1.9 g (70%), tPL126-127oC.

B1. 8-(6-methyl-2-nitrobenzylamine)-2.3-dimethylimidazo[1.2-a]pyridine

To a solution of 8-amino-2,3-dimethylimidazo [1,2-a] pyridine (14,7 g) and 6-methyl-2-nitrobenzylamine (18.6 g) in 100 ml of acetone was added when CT 15.0 g of sodium iodide and 31.0 g of sodium carbonate and then heated under reflux for 6 h to a boil. After cooling the solution to CT and concentration the residue is dissolved in a mixture of 200 ml of ethyl acetate and 200 ml of water and the organic phase is separated. After carrying out the subsequent three-fold extraction with 100 ml of ethyl acetate, respectively, are combined organic extracts are dried over magnesium sulfate and then concentrated to a volume of 80 ml of 12.1 g specified in the header of the compounds crystallize in the form of solids, slightly colored in yellow. The mother liquor is concentrated. After chromatographic purification of the residue on silica gel (solvent system: toluene-dioxane=6:1) receive an additional 14 g of crystalline product. After recrystallization of both fractions from ethyl acetate get a 21.5 g (76%) specified in the connection header with tPL160-162oC.

B2. 8-(6-methyl-2-nitrobenzyloxy)-2,3-dimethylimidazo [1,2-a] pyridineoC. Then filtered light brown precipitate, which is washed with water and dried under vacuum. Subsequent cleaning is performed by chromatography on silica gel (solvent system: toluene-dioxane= 5:1). Fractions with Rf=0,2 concentrated and recrystallized from ethyl acetate-cyclohexane. Specified in the title compound is isolated in the form of a yellow solid. Output 8,31 g (58%), tPL168-171oC.

B3. 3-chloro-2-methyl-8-(6-methyl-2-nitrobenzylamine)imidazo[1.2-a] pyridine

On the basis of 8-amino-3-chloroimidazo[1,2-a] pyridine (9,26 g), 6-methyl-2-nitrobenzylamine (10.5 g), sodium carbonate (13,7 g) and sodium iodide (8,55 g) in acetone (380 ml), as described in example B1 technique after chromatography on silica gel (solvent system: toluene-dioxane=20:1) and crystallization from ethyl acetate-cyclohexane obtain 10.6 g (63%) specified in the connection header with tPL142-144oC.

B4. 8-(2-tert-butoxy is iridin (4.8 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (9.2 grams), sodium iodide (5.5 g) and sodium carbonate (8.0 g) in acetone (250 ml), according to the method similar to that described in example B1, after chromatography on silica gel (solvent system: toluene-dioxane= 20: 1) and recrystallization from diisopropyl ether get 7,1 g (62%) specified in the connection header with tPL149-152oC.

B5. 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo [1.2-a]pyridine

On the basis of 8-hydroxy-2,3-dimethylimidazo[1,2-a] pyridine (1.6 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (3.1 g), sodium iodide (1.8 g) and sodium carbonate (2.7 g) in acetone (350 ml), according to the method similar to that described in example B1, after chromatography on silica gel (solvent system: toluene-dioxane= 5:1) and recrystallization from cyclohexane obtain 3.0 g (78%) specified in the connection header with tPL128-131oC.

B6. 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl - 2-methylimidazo[1.2-a]pyridine

On the basis of 8-amino-3-formyl-2-methylimidazo[1,2-a] pyridine (4.0 g) 2-tert-butoxycarbonylamino-6-methylbenzylamine (7.0 g), sodium iodide (4.1 g) and sodium carbonate (6,1 g) in acetone (250 ml), according to the method similar to that described in the example is saprophilous ether gain of 7.3 g (81%) specified in the connection header with tPL210-212oC.

B7. 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2 - methylimidazo[1.2-a]pyridine

On the basis of 3-formyl-8-hydroxy-2-methylimidazo [1,2-a] pyridine (2.4 g), 2-tert-butoxycarbonylamino-6-methylbenzylamine (4,2 g), sodium iodide (2.5 g) and sodium carbonate (3.7 g) in acetone (400 ml), according to the method similar to that described in example B1, after recrystallization from diisopropyl ether-ethyl acetate to obtain 4.4 g (80%) specified in the connection header with tPL189-191oC.

B1. 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1.2-a]pyridine

Method A

A solution of 8-(6-methyl-2-nitrobenzylamine)-2,3-dimethylimidazo[1,2-a]pyridine (61 g) in methanol (5.5 l) hydronaut in the presence of 15 g of palladium on charcoal (5%) as catalyst at RT and at atmospheric pressure for 1.5 hours After filtering off the catalyst and concentrating the residue is dissolved in boiling ethyl acetate (2.7 l). After cooling to CT allocate 51 g (82%) specified in the connection header with tPL206-208oC. Method B

6.7 g of 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo [1,2-a]pyridine at 25-30C are added in several portions to a mixture triperoxonane acid (30 ml) and anisole (3 ml). PEFC is atra. The precipitate is filtered off and purified by chromatography on silica gel (solvent system: toluene-dioxane = 8:1). After recrystallization from ethyl acetate to obtain 3.1 g (62%) specified in the connection header with tPL206-208oC.

B2. 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine

On the basis of 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2 - methylimidazo[1,2-a] pyridine (3.6 g), triperoxonane acid (15 ml) and anisole (5 ml), but the procedure described in example 1 (method B), after chromatography on silica gel (solvent system: toluene-dioxane=9:1) and crystallization from ethyl acetate-cyclohexane obtain 2.3 g (76%) specified in the connection header with tPL230-234oC.

B3. 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1.2-a] pyridine

On the basis of 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2 - methylimidazo [1,2-a] pyridine (5.0 g) and triperoxonane acid (40 ml), according to the method similar to that described in example 1 (method B) obtain 3.57 g (96%) specified in the connection header with tPL144-150oC (decomp.).

B4. Hydrochloride 8-(2-amino-6-methylbenzylamino)-3-chloro-2-methylimidazo [1.2-a] pyridine

A solution of 8-(2-nitro-6-methylbenzene the Oia with platinum catalyst on coal (5%) and hydronaut for 2 h at RT and at atmospheric pressure. After 2 hours add 2H hydrochloric acid (5 ml) and re-hydronaut for 1 h in the same conditions. Then the catalyst is filtered off, the pH of the filtrate 2H sodium hydroxide was adjusted to 8.5 and the solvent is distilled off using a rotary evaporator. The residue is dissolved in boiling ethyl acetate (400 ml). After cooling to CT added diisopropyl ether (250 ml) and to complete crystallization is stirred for 30 min at 4oC. Then the precipitate is sucked off, washed with diisopropyl ether and dried under vacuum. Specified in the title compound (1.66 g, 92%) was isolated as solids beige, tPL243-246oC.

Industrial applicability

The compounds of formula I and their salts have valuable pharmacological properties, which provide the possibility of their industrial applicability. First of all, they exhibit a pronounced inhibitory effect on the secretion of gastric acid and is an excellent action for the protection of the stomach and intestines of warm-blooded. In this connection according to the invention are highly selective action, the relatively long duration of action, good enteral efficiency, absence of substantial pobo the communication refers to the prevention and treatment of diseases of the gastrointestinal tract, first of all inflammations and lesions of the gastrointestinal tract (such as, for example, gastric ulcer, duodenal ulcer, gastritis, hyperacid or drug irritable stomach), which can be caused, for example, by microorganisms (particularly bacteria Helicobacter pylori), bacterial toxins, medicaments (for example, certain anti-inflammatory drugs and Antirheumatic drugs), chemicals (e.g. ethanol), gastric acid or stress conditions. Compounds according to the invention have also proprioceptive activity against the microorganism Helicobacter pylori.

Its excellent properties, the compounds according to the invention, held pilot-tested on various models, where they were antiulcer and antisecretory properties, unexpectedly were significantly higher than the compounds known from the prior art. Due to these properties, the compounds of formula I and their pharmacologically acceptable salts are suitable for high performance applications in medicine and veterinary medicine, primarily they can be used for the treatment and/or prevention of diseases of the stomach and/or intestines.

Another abheri the treatment and/or prophylaxis of the aforementioned diseases.

The invention further includes the use of the proposed compounds for the manufacture of medicinal products intended for the treatment and/or prophylaxis of the aforementioned diseases.

The invention further includes the use of the proposed compounds for the treatment and/or prophylaxis of the aforementioned diseases.

Another object of the invention is a medicinal product intended for the prevention and treatment of diseases of the gastrointestinal tract caused by bacteria Helicobacter pylori or increased secretion of gastric acid, containing one or more compounds of the formula I and/or its pharmacologically acceptable salt.

Medications manufactured using conventional methods known to the person skilled in the art. In the quality of medicines proposed according to the invention pharmacologically effective compounds (which are the active ingredients) used either individually or preferably in combination with suitable for this purpose pharmaceutical auxiliary agents and/or fillers in the form of tablets, pills, capsules, suppositories, patches (e.g. in the form of percutaneous existing therapeutic is sustained fashion from 0.1 to 95% and with an appropriate choice of auxiliary agents and fillers, taking into account characteristics of the active substance and/or the desired effect can be obtained ready for use herbal medicines (for example, the form of prolonged action or form, are resistant to gastric juice).

The choice of auxiliary agents, respectively fillers suitable for the desired pharmaceutical composition, defines himself an expert on the basis of their knowledge and experience. Along with solvents, geleobrazovanie, the main components of suppositories, excipients for tablets and other fillers of active substances can also be used, for example, antioxidants, dispersants, emulsifiers, antispyware, korrigentami taste, preservatives, agents, solubility, dyes, or first of all promoters, improving permeability, and complexing agents (in particular cyclodextrins).

The active substances can be administered orally, parenterally or transdermally.

As a rule, in medicine to achieve the desired effect was suitable active substance, respectively, of active substances in oral introduction to appoint at a daily dosage of from about 0.01 to about 20, preferably from 0.05 to 5, especially 0.1 to 1.5 mg/kg body weight, splitting if necessary, the daily dose into several doses, the advantage is the maintenance of existing substances), generally, lower doses. The definition is necessary in each specific case, the optimal dosage, as well as the method of introduction of active substances can easily spend every specialist on the basis of their knowledge and experience.

When using compounds according to the invention and/or their salts for the treatment of the aforementioned diseases, the pharmaceutical compositions can contain one or more pharmacologically active ingredients from other groups of drugs, such as antacids, for example aluminum hydroxide, magnesium aluminate; tranquilizers, such as benzodiazepines, for example diazepam; antispasmodic, such as becamevery, camylofin; anticholinergics, such as, for example, oxyphencyclimine, fingerbone; local anesthetics, such as tetracaine, procaine; if necessary, also enzymes, vitamins or amino acids.

In this regard, should be allocated primarily to the combination of the compounds according to the invention with pharmaceuticals that inhibit the secretion of acid, such as H2-blockers (in particular cimetidine, ranitidine), applications anticholinergic agents (as, for example, pirenzepine, telenzepine), as well as antagonists of gastrin, which aims to strengthen the total or sverhsummarny the main action and/or to eliminate or reduce side effects, or further the possibility of combining with substances that have antibacterial efficiency (such as cephalosporins, tetracyclines, Kalinicheva acid, penicillin or salts of bismuth), to fight with the bacteria Helicobacter pylori.

Pharmacology

High efficiency of the compounds according to the invention for protection of the stomach and their inhibitory action on the secretion of gastric acid can be confirmed by the results of research carried out in experiments on animal models. Compounds according to the invention, held pilot-tested the following models have the same sequence number as the compounds mentioned in the examples.

Test suppresses the secretion of action on perponderance the rat stomach

In the following table 2 shows the in vivo effect of the compounds according to the invention after intravenous injection on-stimulated pentagastrin the secretion of acid in perponderance the rat stomach.

Technique

In the AI section along the middle line was opened upper abdominal part of the stomach through the mouth and was introduced into the esophagus PVC catheter, and another catheter in the gatekeeper, locking them so that the ends of the tubes included in the lumen of the stomach. The catheter leading from the pylorus, went through a lateral incision in the right wall of the abdomen to the outside.

After thorough rinsing (about 50-100 ml) through the stomach continuously missed having a temperature of 37oC the physiological NaCl solution (0.5 ml/min, pH 6.8 or 6.9; firm Braun-Unita 1). In collected every 15 min affliate (expiring liquid) was determined by the pH (pH meter 632, glass electrode EA 147; diameter 5 mm, Metrohm, and was found by titration with a freshly prepared 0,01 H NaOH to pH 7 (measuring device Dosimat 665 Metrohm) allocated HCl.

Stimulation of gastric secretion was carried out by continuous intravenous infusion of 1 mcg/kg (equivalent of 1.65 ml/h) of pentagastrin (left femoral vein) after approximately 30 min after the end of the operation (i.e., after identifying the two preliminary fractions). The subjects of the substance was injected intravenously with a liquid volume of 1 ml/kg over 60 min after the start of a prolonged infusion of pentagastrin.

The body temperature of experimental animals by infrared radiation and the use of heaters (automatic, stepless regulation of h is cousin dosage, for maximum suppression of acid secretion of the order of 100%.

Determination of the General level of toxicity in the most preferred compounds, in particular compounds of example 1 gives the following indicators of toxicity LD50for this connection:

mice (oral administration) > 750 mg/kg

rats (oral administration) > 500 mg/kg,

mouse (intravenous) about 80 mg/kg)

rats (intravenous) 70 mg/kg

Examples of obtaining drugs:

a) Tablets containing 40 mg of active ingredient: 20 kg of 3-[2-(2,3-dimethylimidazo[1,2-a] pyridine-8-illuminometer)-3-were]oxazolidin-2-it, 40 kg of milk sugar, 26 kg of corn starch and 3 kg of polyvinylpyrrolidone moisturize 20 l of water and passed through a special sieve with the hole diameter of 1.25 mm, to obtain pellets. The obtained granules are dried in a rotary drying apparatus until the moisture content of 50-60%, and then mixed with 8 kg of sodium carboxymethyl cellulose, 2 talc and 1 kg of magnesium stearate. The finished granulate is formed into tablets of 200 mg and a diameter of 8 mm

b) Capsules containing 30 mg of active ingredient: 300 g of 3-[2-(2,3-dimethylimidazo[1,2-a] pyridine-8-and what the notes ground to powder, mix thoroughly and placed in gelatin capsules having a size of 4.

) Capsules containing 10 mg of active ingredient: 100 g of 3- [2- (2,3-dimethylimidazo [1,2-a]pyridine-8-illuminometer) -3 - were]oxazolidin-2-it, 895 g of microcrystalline cellulose and 5 g of amorphous silicic acid pounded into powder, thoroughly mixed and placed in gelatin capsules having a size of 4.

g) Ampoules containing 10 mg of active substance: Dissolved and 3.16 g methansulfonate 3-[2-(2,3-dimethylimidazo[1,2-a] pyridine - 8-illuminometer)-3-were] oxazolidin-2-it solution containing 165,5 g mannitol and 0.5 g of sodium carbonate in 1300 ml of distilled water, add distilled water to the mark 1500 ml and filtered. The resulting solution was dosed at 5 ml in 15 ml vials and subjected to lyophilization. The lyophilisate can be mixed with 10 ml of water to obtain the desired concentration.

1. Imidazolidinedione formula I

< / BR>
where R0 denotes (C1-C4)alkyl, hydroxymethyl or halogen;

R1 means (C1-C4)alkyl;

R2 means hydrogen or (C1-C4)alkyl;

R3 means hydrogen or (C1-C4)alkyl;

R3' is hydrogen, (C1-C4)alkyl Lieb is from the group comprising halogen and (C1-C4)alkoxy;

R4 means hydrogen or (C1-C4)alkyl;

R5 means hydrogen or (C1-C4)alkyl;

A represents O (oxygen) or NH;

Y represents O (oxygen) or CH2,

and their salts.

2. The compounds of formula I on p. 1, where R0 means (C1-C4)alkyl, hydroxymethyl or halogen, R1 means (C1-C4)alkyl; R2 means (C1-C4)alkyl; R3 means hydrogen or (C1-C4)alkyl; R3' is hydrogen, (C1-C4)alkyl or (C1-C4)alkyl, substituted Deputy selected from the group comprising halogen and (C1-C4)alkoxy; R4 means hydrogen; R5 means hydrogen, a represents O (oxygen) or NH, and Y represents O (oxygen) or CH2and their salts.

3. The compounds of formula I on p. 1, where R0 denotes methyl, hydroxymethyl, chloro or fluoro; R1 means methyl; R2 means (C1-C4)alkyl; R3 means hydrogen or (C1-C4)alkyl; R3' is hydrogen, (C1-C4)alkyl or (C1-C4)alkyl, substituted (C1-C4)alkoxygroup; R4 means hydrogen; R5 means hydrogen; a represents O (oxygen) or NH, and Y represents O (oxygen) or CH2and their salts.1
-C4)alkyl; R3 means hydrogen or (C1-C4)alkyl; R3' is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl; R4 means hydrogen; R5 means hydrogen; a represents O (oxygen) or NH, and Y represents O (oxygen) or CH2and their salts.

5. The compound of formula I on p. 1, representing 3-[2-(2,3-dimethylimidazo[1,2-a]pyridine-8-illuminometer)-3-were]oxazolidin-2-one or its salts.

6. A drug intended for the prevention and treatment of diseases of the gastrointestinal tract caused by bacteria Helicobacter pylori or increased secretion of gastric acid containing compound under item 1 or its pharmacologically acceptable salt and pharmaceutical auxiliary agents and/or fillers.

 

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