EP0773945A1

EP0773945A1 - Acyl imidazopyridines

Info

Publication number: EP0773945A1
Application number: EP95927726A
Authority: EP
Inventors: Wolfgang-Alexander Simon; Richard Riedel; Stefan Postius; Gerhard Grundler; Georg Rainer; Jörg Senn-Bilfinger
Original assignee: Byk Gulden Lomberg Chemische Fabrik GmbH
Current assignee: Takeda GmbH
Priority date: 1994-07-28
Filing date: 1995-07-26
Publication date: 1997-05-21
Also published as: NZ290819A; CA2196076A1; JPH10505332A; WO1996003404A1; AU702166B2; AU3166195A

Abstract

The invention concerns compounds of formula (I), wherein the substituents and symbols have the meanings indicated in the description, and the use of these compounds in the treatment of gastro-intestinal diseases.

Description

Acyli idazopyridlne

Field of application of the invention

The invention relates to new acylimidazopyridines which are to be used in the pharmaceutical industry as active ingredients for the production of medicaments.

Known technical background

European patent application EP-A-0033094 describes imidazo [1,2-a] pyridines which carry an aryl substituent in the 8-position which preferably has a phenyl, thienyl, pyridyl or chlorine, fluorine, Methyl, tert-butyl, trifluoromethyl, methoxy or cyano-substituted phenyl radical. Particularly interesting aryl radicals in EP-A-0033094 are the radicals phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl, of which the radicals phenyl, o- or p-fluorophenyl and 2,4,6-tri ethylphenyl are particularly preferred. - In the European patent applications EP-A-0204285, EP-A-0228006, EP-A-0268989 and EP-A-0308917 imidazo [1,2-a] pyridines are described which have an unsaturated in the 3-position saturated aliphatic radical, especially a (substituted) alkynyl radical. - European patent application EP-A-0266890 describes imidazo [1,2-a] pyridines which are substituted in the 8-position by an alkenyl, alkyl or cycloalkylalkyl radical.

Description of the invention

It has now been found that the compounds described in more detail below, which differ from the compounds of the prior art in particular by the substitution in the 3- or in the 8-position, have surprising and particularly advantageous properties.

The invention relates to compounds of the formula I (see attached formula sheet), in which R0 1-4C-alkyl, hydroxymethyl, halogen or thiocyanate,

Rl 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R3 amino, pyridyl, 1-4C-alkoxy substituted by halogen or substituted 1-4C-alkyl with one or two identical or different substituents selected from the group consisting of hydroxy, oxo, 1-4C-alkylcarbonyloxy, carboxy, halogen, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, 1-4C-alkylcarbonylamino and 1-4C-alkoxycarbonyl ino,

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen and

A means 0 (oxygen) or NH, and their salts.

1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical.

Halogen in the sense of the invention is bromine, chlorine and fluorine.

1-4C-Alkoxy stands for an oxygen atom to which one of the 1-4C-alkyl radicals mentioned above is bound. For example, the methoxy and ethoxy radicals may be mentioned.

1-4C-Alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkyl radicals mentioned above. For example, the acetyl radical may be mentioned in particular. The acetoxy radical may be mentioned as the preferred 1-4C-alkylcarbonyloxy radical.

1-4C-Alkoxycarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the 1-4C-alkoxy radicals mentioned above. For example, the methoxycarbonyl and the ethoxycarbonyl radical may be mentioned.

Examples of the 1-4C-alkylcarbonylamino radical are the propionylamino and in particular the acetylamino radical. Examples of the l-4C-alkoxycarbonylamino radical are methoxycarbonylamino, ethoxycarbonylamino and in particular t-butoxycarbonyla amino radical.

Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically tolerable salts of the inorganic and organic acids usually used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, maleic acid Lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids during salt production - depending on whether it is a mono- or is multi-base acid and, depending on which salt is desired, be used in an equi o¬ lar or a different ratio.

Compounds to be emphasized are those of the formula I in which

RO 1-4C-alkyl, hydroxymethyl or halogen,

Rl 1-4C-alkyl,

R2 1-4C-alkyl or halogen,

R3 amino, pyridyl, 1-4C-alkoxy substituted by halogen or substituted 1-4C-alkyl with a substituent selected from the group consisting of hydroxy, oxo, 1-4C-alkylcarbonyloxy, halogen, 1-4C-A1k-oxy , Amino, 1-4C-alkylcarbonylamino and 1-4C-alkoxycarbonylamino,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH, and their salts.

Particularly noteworthy compounds are those of the formula I in which RO is methyl, hydroxymethyl or chlorine, Rl methyl,

R2 1-4C-alkyl, chlorine or fluorine,

R3 amino, chlorine-substituted 1-4C-alkoxy or substituted 1-4C- -alkyl with a substituent selected from the group consisting of hydroxy, oxo, 1-4C-alkylcarbonyloxy, chlorine, 1-4C-alkoxy, amino, 1- 4C-alkylcarbonylamino and 1-4C-alkoxycarbonylamino,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH, and their salts.

Preferred compounds are those of the formula I in which

RO methyl or hydroxymethyl,

Rl methyl,

R2 1-4C-alkyl,

R3 amino, 1-hydroxyethyl, 1-acetoxyethyl, 1-oxoethyl, acetoxymethyl, 2-0xopropyl, 2-hydroxypropyl, 1-butoxycarbonylaminomethyl, acetaminomethyl, aminomethyl, 3-chloropropyl, methoxymethyl or 2-chloroethoxy,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH, and their salts.

Exemplary compounds according to the invention are listed in Table 1 below:

Table 1

Compounds of the formula I (see attached formula sheet) with Rl-CH, R4-H, R5-H and the following further substituent meanings:

RO R2 R3

CH ₃ CH (0H) CH ₃ NH

CH ₃ CH (0H) CH ₃ 0

Cl CH (0H) CH ₃ NH

Cl CH (0H) CH ₃ 0

Cl CH ₃ CH (0H) CH ₃ NH Continuation of table 1

RO R2 R3 A

Cl CH ₃ CH (OH) CH ₃ 0

Cl Cl CH (0H) CH ₃ NH

Cl Cl CH (0H) CH ₃ 0

F CH ₃ NH ₂ NH

F CH ₃ NH ₂ 0

F Cl NH ₂ NH

F Cl NH ₂ 0

Cl CH ₃ NH ₂ NH

Cl CH ₃ NH ₂ 0

Cl Cl Nil NH

Cl Cl NH 0

CH ₃ Cl CH (OH) CH NH

CH ₃ Cl CH (0H) CII ₃ 0

CH OH Cl CH (OH) CH ₃ NH

2

CH OH Cl CH (OH) CH 0

and the salts of the compounds listed in the table.

Compounds of the formula I can have a chiral center in the substituent R3. In the case of the chiral compounds, the invention therefore encompasses both the pure enantiomers and their mixtures in any mixing ratio, including the racemates.

The invention further relates to a process for the preparation of the compounds of the formula I and their salts. The method is characterized in that

a) for the preparation of compounds of the formula I in which RO is hydroxymethyl, compounds of the formula II (see attached formula sheet), in which R 1, R 2, R 3, R 4, R 5 and A have the meanings given above, or that b) in compounds of the formula III (see attached formula sheet), in which RO, Rl, R2, R4, R5 and A have the meanings given above, the radical R3-C0- in a suitable manner and, if desired, then the radical R3 in another R3 transfer, or that one

c) for the preparation of compounds I in which R3 is amino, reacting compounds of the formula III (see attached formula sheet) in which RO, R1, R2, R4, R5 and A have the meanings given above, with alkali metal cyanate,

and that, if desired, the compounds I obtained are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained.

The compounds II are reduced in a manner known per se to the person skilled in the art. It takes place in inert solvents, e.g. never their aliphatic alcohols, e.g. using suitable hydrides, such as sodium borohydride, if necessary with the addition of water.

The introduction of the radical R3-C0- into the compounds III takes place in a manner known per se to the person skilled in the art, for example as described in the examples below or using methods analogous to those described in European patent application EP-A-0308917 .

The reaction according to process variant c) is also carried out in a manner known per se to the person skilled in the art, as is known for the production of urea derivatives from amines, for example by adding an aqueous solution of an alkali metal anyanate (for example potassium cyanate) to a solution or suspension of the compound III in acid.

The person skilled in the art is familiar with the reaction conditions which are required for carrying out the process in detail on the basis of his specialist knowledge. The substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or using one of the customary purification methods, such as column chromatography on a suitable support material, submits.

Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in water, in a chlorinated hydrocarbon, such as methylene chloride or chloroform, a lower aliphatic alcohol (ethanol, isopropanol), a ketone, such as acetone, or an ether, such as THF or diisopropyl ether, which contains the desired acid, or which contains the desired acid Acid is then added.

The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.

The starting compounds II can be prepared in a manner known per se, for example by reacting the compounds IV with the compounds V (see attached formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings indicated above and X has one suitable leaving group, e.g. represents a halogen atom (preferably chlorine or bromine), or using analogous methods such as those described, for example, in European patent applications EP-A-0268989 or EP-A-0308917.

The starting compounds III are known from EP-A-0308917 or they can be prepared in an analogous manner to that described there.

For example, the starting compounds III can be prepared in a manner known per se from the corresponding nitro compounds by reduction. The following examples serve to explain the preparation of the compounds according to the invention in more detail. In particular, the examples also serve to describe, by way of example, the preparation of the compounds of the formula I and the preparation of selected starting compounds. Likewise, further compounds of the formula I and further starting compounds, the preparation of which is not explicitly described, can be prepared in an analogous manner or in a manner familiar to the person skilled in the art using customary process techniques. The abbreviation RT stands for room temperature, h stands for hour (s), min for minute (s), mp for melting point, dec. for decomposition.

Examples

End products

1. 8-f2- (2 (S) -acetoxypropionylamino) -6-methyl-benzylaminol-2.3-dimethv1-imida-ZQπ,? - alpyridiη

O-acetyl-L-lactic acid chloride (0.34 g, 2.25 mol), dissolved in anhydrous dichloromethane (5 ml), becomes a solution of 8- (2-amino-6-methyl-benzylamino) -2 at RT , 3-dimethyl-imidazo [1,2-a] pyridine (0.56 g, 2.2 mmol) was added dropwise in water-free dichloromethane (25 ml). The solution is then stirred at RT for 2 h and then extracted with aqueous sodium hydrogen carbonate solution (3 × 15 ml). The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene / dioxane 9: 1). After concentration of the fractions with Rf 0.2 and crystallization from diisopropyl ether, the title compound (0.76 g, 96%) is obtained as a colorless crystallizate. 177-178'C, rotation (589 nm, 22 ^* C): -37'C (c-1, CHC1 ₃ ).

2. 8-r2- (2 (R) -acetoxypropionylamino) -6-methyl-benzylaminol-2,3-dimethyl-imidazoπ.2-a1pyridine

According to the procedure given in Example 1, O-acetyl-D-lactic acid chloride and 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine are obtained Title compound of mp 177-179 ^* C. Rotary value (589 nm, 22 ^* C): + 40'C (c-1, CHC1 ₃ ).

3. 8-r2- (2 (S) -acetoxypropionv1amino) -6-methv1-benzylamino1-3-formv1-2-methv1-imidazoπ.2-a1pyridine

According to the procedure given in Example 1, O-acetyl-L-lactic acid chloride and 8- (2-amino-6-methyl-benzylamino) -3-formyl-2-methyl-1midazo [1,2-a] pyridine are obtained Crystallization of the crude product from ethyl acetate / - diisopropyl ether, the title compound of mp. 132-136'C. 4. 8- [ ^" 2- (2 (R) -acetoxypropionyl ami no) -6-methyl-benzyl mi no1 -3-formyl -2-methv1 - imidazoπ .2-a1pyridine

The procedure given in Example 1 is followed by chromatography from O-acetyl-D-iic acid chloride and 8- (2-amino-6-methyl-benzylamino) -3-formyl-2-methylimidazo [1,2-ajpyridine Silica gel (eluent: toluene / dioxane - 9: 1) and crystallization from ethyl acetate / cyclohexane, the title compound of mp. 131-134'C.

5. 8-r2- (2 (S) -hydroxypropionylamino) -6-methyl-benzylamino! -2.3-dimethyl-imidazoπ.2-alpyridine

A solution of 8- [2- (2 (S) -acetoxypropionylamino) -6-methyl-benzylamino] - 2,3-dimethyl-imidazo [1,2-a] pyridine (0.70 g, 1.77 mmol) in methanol (15 ml), sodium methoxide (0.2 ml of 30% solution in methanol) is added and the mixture is stirred at RT for 30 min. Then water (20 ml) is added and the methanol is distilled off on a rotary evaporator. The precipitate which has precipitated in the aqueous residue is filtered off, washed with water and dried in vacuo. The crude product is purified by chromatography on silica gel (eluent: ethyl acetate / methanol = 9: 1). After concentration of the fractions with Rf = 0.25 and crystallization from ethyl acetate / diisopropyl ether, the title compound (0.5 g) is isolated as beige crystals. 185-186 ^* C, rotation (589 nm, 22 ^* C): -41'C (c-1, CHC1 ₃ ).

6. 8-T2- (2 (R) -Hydroxypropionylamino) -6-methyl-benzylamino! -2.3-dimethyl-imidazof1.2-alpyridine

According to the procedure given in Example 5, 8- [2- (2 (R) -acetoxypropionylamino) -6-methyl-benzylamino] -2,3-dimethyl-imidazo [1,2-a] pyridine and sodium methoxide are obtained the title link. Mp 178-180'C, rotation (589 nm, 22 ^* C): +37 ^* C (c-1, CHC1 ₃ ).

7. 8-T2- ((Sl-Hvdroxypropionylamino) -6-methyl-benzylamino! -3-hvdroxyme-thv1-2-methyl-imidazori.2-alpyridine

A suspension of 8- [2- (2 (S) -acetoxypropionylamino) -6-methyl-benzylamino] -3-formyl-2-methyl-imidazo [1,2-a] pyridine (0.51 g, 1 , 25 mmol) in water Free methanol (40 ml) is stirred with sodium methoxide (0.1 ml of a 30% solution in methanol) for 2 h at RT. Sodium borohydride (0.55 g, 1.4 mmol) is then added to the yellow solution and the mixture is stirred at RT for a further hour. Then water (50 ml) is added and the methanol is distilled off on a rotary evaporator. The precipitate formed in the aqueous residue is filtered off, washed with water and dried in vacuo. The crude product is purified by chromatography on silica gel (eluent: ethyl acetate / methanol 20: 1 to 10: 1). After concentration of the fractions with Rf-0.3 and crystallization from ethyl acetate / cyclohexane, the title compound (0.26 g, 47%) is obtained as a beige powder. 164-168'C (dec.).

8. 8-r2- (2 (R) -hydroxypropionylamino) -6-methyl-benzylaminol-3-hvdroχyme-ethyl-2-methv1-imidazori.2-alpyridine

According to the procedure given in Example 7, 8- [2- (2 (R) -acetoxypropionylamino) -6-methylbenzylamino] -3-formyl-2-methylimidazo [1,2-a] pyridine is obtained from 8- [2- (2 (R) - acetoxypropionylamino) , Sodium methoxide and sodium borohydride the title compound as a beige powder. M.p. 166-170'C.

9a. 8-r2-f2-chloroacetylamino) -6-methyl-benzylamino1-2.3-dimethyl-imidazo- π.2-alpvridine

A solution of 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine (0.28 g, 1 mmol) in anhydrous dichloromethane (15 ml) is added treated with 1.1 equivalents of chloroacetyl chloride and stirred at RT for 2 h. It is then extracted with aqueous sodium carbonate solution (3 × 15 ml). The organic phase is washed with water (15 ml), dried over magnesium sulfate and concentrated. After crystallization from ethyl acetate / diisopropyl ether, the title compound (0.35 g, 84% of theory) is isolated as a beige solid. M.p. 159-162'C.

Following the procedure described in Example 9a, 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine or 8- (2-amino- 6-methyl-benzylamino) -3-chloro-2-methyl-imidazo [1,2-a] pyridine with the corresponding acid chlorides or the chloroformic acid esters, the following compounds are prepared: 9b. 2,3 dimethyl-8- [6-methyl-2- (2-oxo-propionylamino) benzylamino] imidazo [1,2-a] pyridine. Mp 156-158 ^* C (crystallization from ethyl acetate / diisopropyl ether).

9c. 8- [2- (2-Acetoxy-acetylamino) -6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine. 96-98'C.

9d. 8- [2- (2-Chloroethoxycarbonylamino) -6-methyl-benzylamino] -2,3-dimethyl-imidazo [1,2-a] pyridine hydrochloride. Extraction with water instead of sodium carbonate solution. Mp 199-202'C (crystallization from ethyl acetate).

9e. 8- [2- (2-Chloroethoxycarbonylamino) -6-methyl-benzylamino] -3-chloro-2-methyl-imidazo [1,2-a] pyridine. 136-139'C.

9f. 8- [2- (4-Chlorobutyrylamino) -6-methyl-benzylamino] -2,3-dimethyl-imidazo [1,2-a] pyridine. M.p. 138-140'C.

9g. 8- [2- (4-Chlorobutyrylamino) -6-methylbenzylamino] -3-chloro-2-methylimidazo [1,2-a] pyridine. M.p. 130-132'C.

9h. 8- [2- (2-Methoxyacetylamino) -6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine. M.p. 130-131'C.

10a. 8-T2- (2-acetylamino-acetylamino) -6-methyl-benzylaminol-2.3-dimethyl-imidazoπ.2-alpyridine

A solution of N-acetylglycine (0.36 g, 3.0 mmol) in anhydrous dichloromethane (20 ml) is mixed at -10 ° C. with N-methylmorpholine (034 g, 3.0 mmol) and 1 h stirred. Isobutyl chloroformate (0.4 ml, 3.0 mmol), dissolved in 5 ml dichloromethane, is then added dropwise and the mixture is stirred again at -10 ° C. for 1 h. A solution of 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2a] pyridine (0.43 g, 1.5 mmol) in dichloromethane (30 ml ) added dropwise. The solution is then warmed to RT, stirred for 20 h and then extracted with water (4 × 50 ml). The organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: ethyl acetate / methanol 10: 1). The fractions with Rf-0.15 are concentrated and crystallized from ethyl acetate / diisopropyl ether. The title compound (0.14 g, 26%) is isolated as a beige solid. Mp 192-195 ^* C. Following the procedure described in Example 10a, the following compounds are prepared by reacting various carboxylic acids with isobutyl chloroformate and the correspondingly substituted imidazopyridines:

10b. 8- [2- (2-Acetylamino-acetylamino) -6-methyl-benzylamino] -3-formyl-2-methyl-imidazo [1,2-a] pyridine. 150-154'C. 10c. 8- [2- (2-tert-Butyloxycarbonylamino-acetylamino) -6-methyl-benzyla i-no] -2,3-dimethyl-imidazo [1,2-a] pyridine. 172-174'C. lOd. 8- [2- (2-tert-Butyloxycarbonylaminoacetylamino) -6-methyl-benzylamino] -3-formyl-2-methylimidazo [1,2-a] pyridine. M.p. 112-116'C. lOe. 2,3-Dimethyl-8- {2 - [(pyridine-2-carbonyl) amino] -6-methyl-benzylamino} - imidazo [1,2-a] pyridine. M.p. 178-179 * C. lOf. 2,3-dimethyl-8- {2 - [(pyridine-3-carbonyl) amino] -6-methyl-benzylamino) imidazo [1,2-a] pyridine. 119-121'C.

11. 8-r2- (2-amino-acetylamino) -6-methyl-benzylaminol-2,3-dimethyl-imidazo-fl, 2-a1pγr1d1n

8- [2- (2-tert-Butyloxycarbonylamino-acetylamino) -6-methyl-benzylamino] -2,3-dimethyl-imidazo [1,2-a] pyridine (0.44 g, 1 mmol) is at RT added in portions to a solution of anisole (2 ml) in trifluoroacetic acid (10 ml) and stirred for 30 min. The reaction mixture is then poured into 2 N sodium hydroxide solution (50 ml) and stirred at 4'C for 15 min. The precipitate is filtered off, washed with water, stirred in diisopropyl ether and dried. The title compound (0.29 g, 85%) is isolated as a beige solid. Mp 134-136 ^* C.

12. 8-T2- (2-amino-acetylamino) -6-methyl-benzylaminol-3-formyl-2-methyl-1mi- dazoπ.2-alpyridine

The procedure given in Example 11 gives 8- [2- (2-tert-butyloxycarbonylaminoacetylamino) -6-methylbenzylamino] -3- formyl-2-methylimidazo [1,2-a] pyridine the title compound as a beige solid. 149-15rc. 13. 8-T2-.2-amino-acetylamino) -6-methyl-benzylamino! -3-hydroxymethyl-2-methyl-imidazofl.2-alpyridine

A solution of 8- [2- (2-aminoacetylamino) -6-methyl-benzylamino] -3-formyl-2-methylimidazo [1,2-a] pyridine (0.24 g, 0.68 mmol ) in anhydrous ethanol (25 ml) is mixed with sodium borohydride and stirred at RT for 30 min. Then water (50 ml) is added and the ethanol is distilled off on a rotary evaporator. The precipitate in the aqueous residue is filtered off, washed with water and dried. The solid is then extracted again from diisopropyl ether and dried again. The title compound (0.29 g, 85%) is isolated as a beige solid. Mp 134-136 ^* C.

14. 8-r2- (2-acetv! Amino-acetylamino) -6-methyl-benzylaminol-3-hydroxymethyl-2-methyl-imidazoπ.2-alpyridine

Following the procedure given in Example 13, the title compound is obtained starting from 8- [2- (2-acetylamino-acetylamino) -6-methyl-benzylamino] -3-formyl-2-methylimidazo [1,2-a] pyridine as a beige solid. M.p. 162-167'C.

15. 2.3-Dimethyl-8-r6-methyl-2- (3-oxo-butyry1amino) -benzylaminol-imidazo- π, 2-alpγridine

To a suspension of 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine (1.0 g, 3.5 mmol) and 4-dimethylaminopyridine (10 mg) in anhydrous acetone (30 ml), a solution of diketene (0.7 ml 50% solution in acetone, 3.5 mmol) in 2 ml acetone is added dropwise at RT. The mixture is stirred at RT for a further 1 h. The solvent is then distilled off on a rotary evaporator and the remaining oil is recrystallized from ethyl acetate. The title compound (0.31 g, 10%) is isolated as a beige product. M.p. 133-135'C.

16. 2.3-Dimethv1-8-r6-methy1-2- (3-oxo-butyrylamino) -benzyloχyl-imidazo- fl.2-alpyridine

The procedure described in Example 15 gives diketene starting from 8- (2-amino-6-methyl-benzyloxy) -2,3-dimethyl-imidazo [1,2-a] pyridine and 4-dimethylaminopyridine the title compound (49%) as a beige powder. 174-175'C.

17. 3-Formv1-2-methyl-8-f6-methyl-2- (3-oxo-butyrylamino) benzyloxyl-imidazo-π.2-alpyridine

According to the procedure described in Example 15, the title compound is obtained starting from 8- (2-amino-6-methyl-benzyloxy) -3-formyl-2-methyl-imidazo [1,2-a] pyridine, diketene and 4-dimethylaminopyridine (49%) as a beige powder. 174-175 ^# C.

18. 8-r2- (3-Hvdroχy-butyrv1amino) -6-methyl-benzyloxyl-3-hvdroχymethyl-2-methyl-imidazoπ.2-alpyridine

A solution of 3-formyl-2-methyl-8- [6-methyl-2- (3-oxobutyrylamino) benzyloxy] imidazo [1,2-a] pyridine (0.8 g, 2 , 1 mmol) in tetrahydrofuran (80 ml) and ethanol (80 ml), sodium borohydride (80 mg) is added and the mixture is stirred at RT for 30 min. The mixture is then neutralized with acetic acid, the solvent is distilled off and the residue is chromatographed on silica gel (mobile phase: ethyl acetate / methanol = 10: 1). The fractions with Rf-0.15 are concentrated and crystallized from ethyl acetate. The title compound (0.52 g, 65%) is isolated as a beige solid. M.p. 168-169 ^* C.

19. 2.3-Dimethyl-8- (6-methyl-2-ureido-benzylamino) imidazori.2-alpyridine

To a suspension of 8- (2-amino-6-methyl-benzylamino) -2,3-dimethyl-imidazo [1,2-a] pyridine (0.56 g, 2 mmol) in 80% acetic acid ( 25 ml), a solution of potassium cyanate (0.33 g, 4 mmol) in 8 ml of water is slowly added dropwise at RT. The solution is stirred at RT for a further 2 h. Then water (80 ml) is added and extracted with ethyl acetate (4 x 75 ml). The organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is crystallized from diisopropyl ether / ethyl acetate. The title compound (0.18 g, 28%) is isolated as a beige solid. Mp 280 ^* C dec.). 20. 3-Formyl- - ethyl-8- (6-methyl-2-ureido-benzylamino) -imidazor1.2-al-pyridine

Following the procedure given in Example 19, starting from 8- (2-amino-6-methyl-benzylamino) -3-formyl-2-methyl-imidazo [1,2-a] pyridine and potassium cyanate, the title compound (94%) as a beige powder. 292-292'C

21. 3-Hroxroxymethyl-2-methyl-8- (6-methv1-2-ureidobenzylamino) imidazo π, 2-al-pγridine

A solution of 3-formyl-2-methyl-8- (6-methyl-2-ureido-benzylamino) imidazo [1,2-a] pyridine (0.27 g, 0.8 mmol) in ethanol (20 ml) is mixed with sodium borohydride (30 mg, 0.8 mmol) and stirred at RT for 1 h. Water (50 ml) is then added and the ethanol is distilled off on a rotary evaporator. The precipitate in the aqueous residue is filtered off, washed with water and dried in vacuo. The crude product is purified by chromatography on silica gel (eluent: dichloromethane / methanol = 10: 1). After concentration of the fractions with Rf = 0.3 and crystallization from diisopropyl ether, the title compound (0.11 g, 41%) is isolated as a beige solid. 247'C (dec.).

22. 3-Chloro-2-methyl-8- (6-methyl-2-ureido-benzylamino) imidazo ^" 1,2-al-pyridine

Using the procedure given in Example 19, starting from 8- (2-amino-6-methyl-benzylamino) -3-chloro-2-methylimidazo [1,2-a] pyridine and potassium cyanate, the title compound (72% ) as a beige powder. Mp 265-267 ^* C. Output connections

AI. 8- (2-tert-Butoxycarbonylamino-6-methyl-benzylamino) -2.3-dimethyl-imidazoπ.2-alpyridine

To a solution of 8-amino-2,3-dimethylimidazo [1,2-a] pyridine (4.8 g) and 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (9.2 g) in acetone (250 ml) 5.5 g of sodium iodide and 8.0 g of sodium carbonate are added at RT and the mixture is then heated to boiling under reflux for 6 h. After the solution has been cooled to RT and concentrated, the residue is dissolved in a mixture of 200 ml of ethyl acetate and 200 ml of water and the organic phase is separated off. After three further extractions, each with 100 ml of ethyl acetate, the combined organic phases are dried over magnesium sulfate and then concentrated. The title compound crystallizes as a pale yellow solid. After chromatographic purification on silica gel (eluent: toluene / dioxane = 20: 1) and recrystallization from diisopropyl ether, 7.1 g (62%) of the title compound of mp 149-152 ^* C are obtained.

A2. 8- (2-tert-Butoxycarbonylamino-6-methyl-benzylamino) -3-formyl-2-methv1-imidazoπ.2-a1pyridine

Starting from 8-amino-3-formyl-2-methylimidazo [1,2-a] pyridine (4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (7.0 g), sodium iodide (4.1 g) and sodium carbonate (6.1 g) in acetone (250 ml) are obtained in analogous application of the process from Example AI after chromatography on silica gel (eluent toluene / dioxane 9: 1) and recrystallization from diisopropyl ether 7 , 3 g (81%) of the title compound of mp 210-212'C.

A3. 8- (2-amino-6-methylbenzylamino) -2,3-dimethyl-i idazof1.2-alpyridine Method A:

A solution of 8- (6-methyl-2-nitrobeι.zylamino) -2,3-dimethylimidazo [1,2-a] - pyridine (61 g) in methanol (5.5 l) is in the presence of 15 g palladium hydrogenated on activated carbon (5%) as a catalyst at RT and under atmospheric pressure for 1.5 h. After filtering off the catalyst and concentrating, the residue is dissolved in boiling ethyl acetate (2.7 l). After cooling to RT, 51 g (82%) of the title compound are isolated from the mp. 206-208'C. Method B:

6.7 g of 8- (2-tert-butoxycarbonylamino-6-methylbenzylamino) -2,3-dimethylimidazo [1,2-a] pyridine are added in portions at 25-30 "C to a mixture of trifluoroacetic acid (30 ml ) and anisole (3 ml) After 30 minutes of stirring at RT, the solution is poured into 100 ml of ice water and then mixed with 75 ml of 6N sodium hydroxide solution. The precipitate is filtered off and purified chromatographically on silica gel (solvent: toluene / dioxane 8: 1) After recrystallization from ethyl acetate, 3.1 g (62%) of the title compound of mp 206-208'C are obtained.

A4. 8- (2-Amino-6-methyl-benzylamino) -3-for yl -2-methyl-imidazoπ, 2-alpyridine

Starting from 8- (2-tert-butoxycarbonylamino-6-methyl-benzylamino) -3-formyl-2-methyl-imidazo [1,2-a] pyridine (3.6 g), trifluoroacetic acid (15 ml) and anisole (5 ml) are obtained according to the procedure described for Example A3 (method B) after chromatography on silica gel (eluent: toluene / dioxane - 9: 1) and crystallization from ethyl acetate / cyclohexane 2.3 g (76%) of the Ti ¬ tel connection from mp. 230-234'C.

Bl. 8- (2-Amino-6-methyl-benzylamino) -3-chloro-2-methyl-imidazoπ.2-aloyridine-hydrochloride

A solution of 3-chloro-2-methyl-8- (6-methyl-2-nitro-benzylamino) -imidazo [1,2-a] pyridine (2.0 g, 6 mmol) in methanol (175 ml ) and dioxane (175 ml) is mixed with platinum-on-carbon catalyst (5%) and hydrogenated at RT and atmospheric pressure for 2 h. After 2 h, 2 N hydrochloric acid (5 ml) is added and the mixture is hydrogenated again for 1 h under the same conditions. The catalyst is then filtered off, the filtrate is adjusted to pH 8.5 with 2 N sodium hydroxide solution and the solvent is distilled off on a rotary evaporator. The residue is dissolved in boiling ethyl acetate (400 ml). After cooling to RT is added diisopropyl propyl ether (250 ml) and tion to complete the Kristallisa¬ 30 min at 4 ^* C stirred. The precipitate is then filtered off, washed with diisopropyl ether and dried in vacuo. The title compound (1.66 g, 92%) is isolated as a beige solid. 243-246'C. B2. 3-Chloro-2-methyl -8- (6-methyl -2-nitro-benzylamino) -imidazoπ, 2-alpyridine

Starting from 8-amino-3-chloro-imidazo [1,2-a] pyridine (9.26 g), 6-methyl-2-nitrobenzyl chloride (10.5 g), sodium carbonate (13.7 g) and sodium iodide ( 8.55 g) in acetone (380 ml) is obtained according to the procedure given in Example AI after chromatography on silica gel (eluent: toluene / dioxane - 20: 1) and crystallization from ethyl acetate / cyclohexane 10.6 g (63%) Title compound of mp 142-144'C.

B3. 8-amino-3-chloro-imidazofl .2-alpyridine

A suspension of 3-chloro-2-methyl-8-pivaloylamino-imidazo [l, 2-a] pyridine (4.0 g, 15 mmol) in 60 sulfuric acid (25 ml) for 1 h at 100 ^* C ge stirs. After cooling to RT, water (100 ml) is added and the pH is adjusted to 10 using 10 N sodium hydroxide solution. Then it is extracted with ethyl acetate (3 x 50 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is taken up in boiling toluene, clarified with silica gel and crystallized. The title compound is isolated as a beige solid. Yield 1.9 g (70%), m.p. 126-127'C.

B4. 3-chloro-2-methyl-8-pivaloylamino-imidazofl, 2-alpyridine

5.0 g (18.6 mmol) of 2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine hydrochloride, prepared from 8-amino-2-methyl-imidazo [1,2-a], are dissolved. pyridine and pivaloyl chloride, mp. 229-230'C, in glacial acetic acid (20 ml) and slowly introduces chlorine gas at 15 ^* C until the reaction is complete after TLC control (approx. 20 min). Then the solvent is distilled off, the residue is taken up in ethyl acetate / water (in each case 30 ml), made basic with saturated sodium bicarbonate solution and extracted. The mixture is then extracted again with ethyl acetate (3 x 30 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene / dioxane = 9: 1). After concentration of the fractions with Rf 0,2 0.2, the title compound (4.1 g, 83) is obtained as a colorless solid. M.p. 117-118'C. Industrial applicability

The compounds of the formula I and their salts have valuable pharmacological properties which make them commercially usable. In particular, they have a pronounced inhibition of gastric acid secretion and an excellent gastric and intestinal protective effect in warm-blooded animals. The compounds according to the invention are distinguished here by a high degree of selectivity of action, a comparatively long duration of action, good enteral activity, the absence of essential side effects and a large therapeutic breadth.

"Stomach and intestinal protection" in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms ( eg Helicobacter pylori), bacterial toxins, medications (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), gastric acid or stressful situations. The compounds of the invention also have an intrinsic activity against the Helicobacter pylori germ.

In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art on various models in which the antiulcerogenic and the antisecretory properties are determined. On the basis of these properties, the compounds of the formula I and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and / or prophylaxis of diseases of the stomach and / or intestine.

The invention therefore furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases. The invention also includes the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.

The invention further comprises the use of the compounds according to the invention for the treatment and / or prophylaxis of the abovementioned diseases.

The invention further relates to medicaments which contain one or more compounds of the formula I and / or their pharmacologically tolerable salts.

The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as pharmaceuticals either as such or preferably in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions used, the active substance content advantageously being between 0.1 and 95% and the galenical dosage form (for example a slow release form or a pharmaceutical form) which is precisely adapted to the active substance and / or to the desired onset of action due to the appropriate choice of auxiliaries and carriers. genetically resistant form) can be achieved.

The person skilled in the art is familiar with the auxiliaries and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active ingredients, for example antioxidants, dispersants, emulsifiers, defoamers, flavor correcting agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins) can be used.

The active ingredients can be administered orally, parenterally or percutaneously.

In ullijυiiiυIni-n u-. --Uli In er lliim.iium.- l / In al-> vur -l I uM. proven, «Ion« xlor <llo Wlrkstoffo bot oral f.aho in ol or li-'i-srinsls from olwa 0.01 up to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight, optionally in the form of several, preferably 1 to 4, individual doses to achieve the desired result. In the case of parenteral treatment, similar or (in particular when the active compounds are administered intravenously) generally lower doses can be used. Any person skilled in the art can easily determine the optimum dosage and mode of application of the active ingredients required on the basis of his or her specialist knowledge.

If the compounds and / or salts according to the invention are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also comprise one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics, e.g. Bietamiverin, Camylofin, Anticholinergica, e.g. Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.

In this context, the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H blockers (for example cimetidine, ranitidine), H ⁺ / K ⁺ -ATPase inhibitors (for example omeprazole, pantoprazole), or also with, should be emphasized So-called peripheral anticholinergics (eg pirenzepin, telenzepin) and with gastrin antagonists with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or furthermore the combination with antibacterial substances ¬ zen (such as cephalosporins, tetracyclines, nalidixic acid, penicillins or bismuth salts) to combat Helicobacter pylori. pharmacology

The excellent gastric protective effect and the gastric acid secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on animal experimental models. The compounds according to the invention investigated in the model listed below have been given numbers which correspond to the numbers of these compounds in the examples.

Testing the secretion-inhibiting effect on the perfused rat stomach

Table A below shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.

Table A

No dose inhibition of acid excretion iv

5 3 96

6 3 94

19 3 100

methodology

After tracheotomy, anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened with a median upper abdominal incision and a PVC catheter transorally in the esophagus and another one after tracheotomy fixed via the pylorus in such a way that the tube ends just protruded into the stomach lumen. The catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall. After thorough rinsing (about 50-100 ml) of the stomach with 37 ^* C, warm physiological NaCl solution was continuously passed through (0.5 ml / min, pH 6.8-6.9; Braun-Unita I). The pH value (pH meter 632, glass electrode EA 147; $ - 5 mm, Metrohm) and the titration with a freshly prepared 0.01 N NaOH to pH 7 (Dosimat 665 Metrohm) determines the secreted HC1.

Gastric secretion was stimulated by continuous infusion of 1 μg / kg (- 1.65 ml / h) IV. Pentagastrin (V. fern, sin.) Approx. 30 min after the end of the operation (i.e. after the determination of 2 pre-fractions). The substances to be tested were administered intravenously in 1 ml / kg liquid volume 60 min after the start of the continuous pentagastrin infusion.

The body temperature of the animals was by infrared irradiation and Heiz¬ pads (automatic, stepless control via rectal temperature sensor) at a constant 37.8-38 ^β C.

The table shows the dose which led to a maximum inhibition of acid secretion by approximately 100%.

Claims

claims

1. Compounds of the formula I

(I)

wherein

RO 1-4C-alkyl, hydroxymethyl, halogen or thiocyanate,

Rl 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R3 amino, pyridyl, 1-4C-alkoxy substituted by halogen or substituted 1-4C-alkyl with one or two identical or different substituents selected from the group consisting of hydroxy, oxo, 1-4C-alkylcarbonyloxy, carboxy, halogen, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, 1-4C-alkylcarbonylamino and 1-4C-alkoxycarbonylamino,

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen and

A means 0 (oxygen) or NH, and their salts.

2. Compounds of formula I according to claim 1, wherein

RO 1-4C-A1 yl, hydroxymethyl or halogen,

Rl 1-4C-alkyl,

R2 1 -4C-alkyl or halogens, R3 amino, pyridyl, halogen-substituted 1-4C-alkoxy or substituted 1-4C-alkyl with a substituent selected from the group consisting of hydroxy, oxo, 1-4C-alkylcarbonyloxy, halogen, 1-4C-A1-oxy , Amino, 1-4C-al ylcarbonylamino and 1-4C-alkoxycarbonylamino,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH, and their salts.

3. Compounds of formula I according to claim 1, wherein RO is methyl, hydroxymethyl or chlorine,

Rl methyl,

R2 1-4C-alkyl, chlorine or fluorine,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH, and their salts.

4. Compounds of formula I according to claim 1, wherein RO is methyl or hydroxymethyl,

Rl methyl,

R2 1-4C-alkyl,

R3 amino, 1-hydroxyethyl, 1-acetoxyethyl, 1-oxoethyl, acetoxymethyl, 2-oxopropyl, 2-hydroxypropyl, 1-butoxycarbonylaminomethyl, acetaminomethyl, aminomethyl, 3-chloropropyl, methoxymethyl or 2-chloroethoxy,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH, and their salts.

5. Compounds of formula I according to claim 1, wherein RO is fluorine.

6. A process for the preparation of the compounds of formula I according to claim 1 and their salts, characterized in that

a) for the preparation of compounds of the formula I in which RO is hydroxymethyl, compounds of the formula II (see attached formula sheet), in which R 1, R 2, R 3, R 4, R 5 and A have the meanings given in claim 1, or that one

b) in compounds of the formula III (see attached formula sheet) in which RO, Rl, R2, R4, R5 and A have the meanings given in claim 1, the radical R3-C0- is introduced in a suitable manner and, if desired, the radical is then subsequently introduced R3 transferred to another R3 residue, or that one

c) for the preparation of compounds I in which R3 is amino, reacting compounds of the formula III (see attached formula sheet) in which RO, R1, R2, R4, R5 and A have the meanings given in claim 1, with alkali metal cyanate,

7. Medicament containing a compound according to claim 1 and / or a pharmacologically acceptable salt thereof together with conventional pharmaceutical auxiliaries and / or carriers.

8. Compounds according to claim 1 and their pharmacologically acceptable salts for use in the prevention and treatment of gastrointestinal diseases.

9. Use of compounds according to claim 1 and their pharmacologically acceptable salts for the manufacture of medicaments for the prevention and treatment of gastrointestinal diseases.