AU702166B2 - Acylimidazopyridines - Google Patents

Description

WO 96/03404 PCT/EP95/02953 1 Acylimidazopyridines Field of application of the invention The invention relates to novel acylimidazopyridines which are intended to be used in the pharmaceutical industry as active compounds for the production of medicaments.

Known technical background European Patent Application EP-A-0 033 094 describes imidazo[1,2-a]pyridines which in the 8-position carry an aryl substituent which is preferably a phenyl, thienyl, pyridyl, or chlorine-, fluorine-, methyl-, tert-butyl-, trifluoromethyl-, methoxy- or cyano-substituted phenyl radical. As aryl radicals of particular interest, EP-A-0 033 094 mentions 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-trimethylphenyl are particularly preferred. European Patent Applications EP-A-0 204 285, EP-A-0 228 006, EP-A-0 268 989 and EP-A-0 308 917 describe imidazo[l,2-a]pyridines which in the 3-position carry an unsaturated aliphatic radical, in particular a (substituted) alkynyl radical.

European Patent Application EP-A-0 266 890 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 greater detail below, which in particular differ from the compounds of the prior art by the substitution in the 3- or 8-position, have surprising and particularly advantageous properties.

WO 96/03404 PCT/EP95/02953 2 The inventions [sic] relates to compounds of the formula I (see attached formula sheet), in which RO is l-4C-alkyl, hydroxymethyl, halogen or thiocyanate, R1 is l-4C-alkyl, R2 is hydrogen, l-4C-alkyl, l-4C-alkoxy, halogen or trifluoromethyl, R3 is amino, pyridyl, halogen-substituted l-4C-alkoxy or substituted l-4C-alkyl having one or two identical or different substituents selected from the group consisting of hydroxyl, oxo, l-4C-alkylcarbonyloxy, carboxyl, halogen, l-4C-alkoxy, 1-4Calkoxycarbonyl, amino, l-4C-alkylcarbonylamino and l-4C-alkoxycarbonylamino, R4 is hydrogen, 1-4C-alkyl, l-4C-alkoxy, halogen or trifluoromethyl, is hydrogen, l-4C-alkyl, l-4C-alkoxy or halogen and A is O (oxygen) or NH, and their salts.

l-4C-Alkyl is straight-chain or branched alkyl radicals [sic] having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tertbutyl, propyl, isopropyl, ethyl and, in particular, the methyl radical.

Halogen within the meaning of the invention is bromine, chlorine or fluorine.

l-4C-Alkoxy is an oxygen atom to which one of the abovementioned l-4C-alkyl radicals is bonded. Examples which may be mentioned is [sic] the methoxy and the ethoxy radicals.

1-4C-Alkylcarbonyl is a radical which, beside the carbonyl group, contains one of the abovementioned l-4C-alkyl radicals. An example which may be mentioned WO 96/03404 PCT/EP95/02953 3 in particular is the acetyl radical. A preferred 1-4Calkylcarbonyloxy radical which may be mentioned is the acetoxy radical.

l-4C-Alkoxycarbonyl is a radical which, beside the carbonyl group, contains one of the abovementioned l-4C-alkoxy radicals. Examples which may be mentioned is [sic] the methoxycarbonyl and the ethoxycarbonyl radicals.

l-4C-Alkylcarbonylamino radical [sic] which may be mentioned, for example, is [sic] the propionylamino and, in particular, the acetylamino radicals.

l-4C-Alkoxycarbonylamino radicals which may be mentioned, for example, are the methoxycarbonylamino, the ethoxycarbonylamino and, in particular, the t-butoxycarbonylamino radicals.

Suitable salts of compounds of the formula I are preferably all acid addition salts. Particular mention may be given to the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Pharmacologically nontolerable salts which can initially be obtained as process products, for example, in the preparation of the compounds according to the invention on the industrial scale, are converted into pharmacologically tolerable salts by the processes known to the person skilled in the art. Very suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, 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, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or WO 96/03404 PCT/EP95/02953 4 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparation depending on whether it is a monoor polybasic acid and depending on which salt is desired in an equimolar quantitative ratio or one differing therefrom.

Compounds to be emphasized are those of the formula I, in which RO is l-4C-alkyl, hydroxymethyl or halogen, R1 is l-4C-alkyl, R2 is l-4C-alkyl or halogen, R3 is amino, pyridyl, halogen-substituted l-4C-alkoxy or substituted l-4C-alkyl having a substituent selected from the group consisting of hydroxyl, oxo, l-4C-alkylcarbonyloxy, halogen, l-4C-alkoxy, amino, l-4C-alkylcarbonylamino and l-4C-alkoxycarbonylamino, R4 is hydrogen, is hydrogen and A is 0 (oxygen) or NH, and their salts.

Compounds to be particularly emphasized are those of the formula I, in which RO is methyl, hydroxymethyl or chlorine, R1 is methyl, R2 is l-4C-alkyl, chlorine or fluorine, R3 is amino, chlorine-substituted l-4C-alkoxy or substituted l-4C-alkyl having a substituent selected from the group consisting of hydroxyl, oxo, l-4C-alkylcarbonyloxy, chlorine, 1-4C-alkoxy, amino, l-4C-alkylcarbonylamino and l-4C-alkoxycarbonylamino, R4 is hydrogen, R5 is hydrogen and A is 0 (oxygen) or NH, and their salts.

WO 96/03404 PCT/EP95/02953 5 Preferred compounds are those of the formula I, in which

RO

R1 R2 R3 is methyl or hydroxymethyl, is methyl, is l-4C-alkyl, is amino, l-hydroxyel 1-oxoethyl, acetoxyme thyl, thyl, l-acetoxyethyl, 2-oxopropyl, arbonylaminomethyl, 3-chloropropyl, 2-hydroxypropyl, 1-butoxyc; acetaminomethyl, aminomethyl, methoxymethyl or 2-chloroethoxy, R4 is hydrogen, is hydrogen and A is 0 (oxygen) or NH, and their salts.

Exemplary compounds according to the invention are listed in Table 1 which follows: Table 1 Compounds of the formula I (see attached formula sheet) with R1=CH 3 R4=H, R5=H and the following further substituent meanings: RO R2 R3 A

CH

3

CH

3 Cl Cl

CH

3

CH

3 Cl Cl

CH

3

CH

3 Cl Cl CH (OH) CH 3 CH (OH) CH 3 CH (OH) CH 3 CH (OH) CH 3 CH (OH) CH 3 CH (OH) CH 3 CH (OH) CH 3 CH (OH) CH 3

NH

2

NH

2

NH

2

NH,

WO 96/03404 PCT/EP95/02953 6 Continuation of Table 1 RO R2 R3 A C1 CH 3

NH

2

NH

C1 CH 3

NH

2 0 C1 C1 NH 2

NH

C1 C1 NH 2 0

CH

3 Cl CH(OH)CH 3

NH

CH

3 Cl CH(OH)CH 3 0

CH

2 OH C1 CH(OH)CH 3

NH

CH

2 OH C1 CH(OH)CH 3 0 and the salts of the compounds mentioned in the table.

Compounds of the formula I can each have a chiral center in the substituent R3. The invention therefore includes under the chiral compounds 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 process comprises a) for the preparation of compounds of the formula I in which RO is hydroxymethyl, reducing compounds of the formula II (see attached formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings indicated above, or b) introducing the radical R3-CO- into compounds of the formula III (see attached formula sheet), in which RO, R1, R2, R4, R5 and A have the meanings indicated above, in a suitable manner and if desired then converting the radical R3 into another radical R3, or WO 96/03404 PCT/EP95/02953 -7c) 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, and A have the meanings indicated above, with alkali metal cyanate, and if desired then converting the compounds I obtained into their salts, or if desired then liberating the compounds I from salts of the compounds I obtained.

The reduction of the compounds II is performed in a manner customary per se to the person skilled in the art. It is carried out in inert solvents, e.g. lower aliphatic alcohols, e.g. using suitable hydrides, such as, for example, sodium borohydride, if desired with addition of water.

The introduction of the radical R3-CO- into the compounds III is carried out in a manner familiar per se to the person skilled in the art, for example as described in the following examples or analogously using those processes such as are described in European Patent Application EP-A-0 308 917.

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

The person skilled in the art is familiar on the basis of his expert knowledge with the reaction conditions which are specifically necessary for carrying out the process.

WO 96/03404 PCT/EP95/02953 8 -8- The isolation and purification of the substances according to the invention is carried out in a manner known per se, for example, in such a way that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on suitable support material.

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 to which the desired acid is then added.

The salts are obtained by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted by basification, e.g. with aqueous ammonia solution, into the free bases, which in turn can be converted into acid addition salts. In this manner, pharmacologically nontolerable acid addition salts can be converted into pharmacologically tolerable acid addition salts.

The starting compounds II can be prepared in a manner known per se, for example by reaction of the compounds IV with the compounds V (see attached formula sheet), in which RI, R2, R3, R4, R5 and A have the meanings indicated above and X is a suitable leaving group, e.g.

a halogen atom (preferably chlorine or bromine), or analogously using those processes such as are described, for example, in European Patent Applications EP-A-0 268 989 or EP-A-0 308 917.

WO 96/03404 PCT/EP95/02953 9 The starting compounds III are disclosed in EP-A-0 308 917 or they can be prepared in a manner analogous to that described there.

For example, the starting compounds III can be prepared by reduction in a manner known per se from the corresponding nitro compounds.

The following examples serve to illustrate in greater detail the preparation of the compounds according to the invention. 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 whose preparation is not described explicitly can be prepared in a manner which is analogous or in a manner which is familiar per se to the person skilled in the art using customary process techniques. The abbreviation RT stands for room temperature, h stands for hour(s), min stands for minute(s), m.p. for melting point and dec. for decomposition.

WO 96/03404 PCT/EP95/02953 10 Examples Final products 1. 8-[2-(2(S)-Acetoxypropionylamino)-6-methylbenzylaminol-2.3-dimethylimidazofl.2-alpyridine O-Acetyl-L-lactoyl chloride (0.34 g, 2.25 mmol), dissolved in anhydrous dichloromethane (5 ml), is added dropwise at RT to a solution of 8-(2-amino- 6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.56 g, 2.2 mmol) in anhydrous dichloromethane ml). The solution is subsequently stirred at RT for 2 h and then extracted with aqueous sodium hydrogen carbonate solution (3 x 15 ml). The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene/dioxane After concentration of the fractions of Rf 0.2 and crystallization from diisopropyl ether, the title compound (0.76 g, 96%) is obtained as a colorless crystallizate. M.p. 177-178 0

C,

specific rotation (589 nm, 22 0 -37 0 C (c 1, CHC1 3 2. 8-[2-(2(R)-Acetoxypropionylamino)-6-methylbenzylaminol-2.3-dimethylimidazo l.2-alpyridine According to the procedure indicated in Example 1, O-acetyl-D-lactoyl chloride and 8-(2-amino- 6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine give the title compound of m.p. 177-1790C. Specific rotation (589 nm, 22°C): +40 0 C (c 1, CHC1 3 3. 8- 2-(2(S)-Acetoxypropionylamino)-6-methylbenzylaminol-3-formyl-2-methylimidazo l.2-alpyridine According to the procedure indicated in Example 1, O-acetyl-L-lactoyl chloride and 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine WO 96/03404 PCT/EP95/02953 11 give, after crystallization of the crude product from ethyl acetate/diisopropyl ether, the title compound of m.p. 132-136°C.

4. 8-[2-(2(R)-Acetoxypropionylamino)-6-methylbenzylaminol-3-formyl-2-methylimidazo[l.2-alpyridine According to the procedure indicated in Example 1, O-acetyl-D-lactoyl chloride and 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[l,2-a]pyridine give, after chromatography on silica gel (eluent: toluene/dioxane 9:1) and crystallization from ethyl acetate/cyclohexane, the title compound of m.p. 131- 134oC.

5. 8- 2-(2(S)-Hydroxypropionylamino)-6-methylbenzylaminol-2.3-dimethylimidazorl.2-alpyridine A solution of 8-[2-(2(S)-acetoxypropionylamino) 6-methylbenzylamino]-2,3-dimethylimidazo[l,2-a]pyridine (0.70 g, 1.77 mmol) in methanol (15 ml) is treated with sodium methoxide (0.2 ml of 30% strength solution in methanol) and stirred at RT for 30 min. Water (20 ml) is then added and the methanol is distilled off on a rotary evaporator. The precipitate deposited 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 After concentration of the fractions of Rf 0.25 and crystallization from ethyl acetate/diisopropyl ether, the title compound (0.5 g) is isolated as a beige crystallizate. M.p. 185-1860C, specific rotation (589 nm, 220C): -410C (c 1, CHC1 3 6. 8- 2-(2(R)-Hydroxypropionylamino)-6-methylbenzylaminol-2.3-dimethylimidazorl.2-alpyridine According to the procedure indicated in Example 8-[2-(2(R)-acetoxypropionylamino)-6-methylbenzylamino]- WO 96/03404 PCT/EP95/02953 12 2,3-dimethylimidazo[1,2-a]pyridine and sodium methoxide give the title compound. M.p. 178-1800C, specific rotation (589 nm, 22 0 +370C (c 1, CHC1 3 7. 8- -Hydroxypropionylamino)-6-methylbenzylaminol-3-hydroxymethyl-2-methylimidazoFl.2alpyridine A suspension of 8-[2-(2(S)-acetoxypropionylamino)- 6-methylbenzylamino]-3-formyl-2-methylimidazo- [1,2-a]pyridine (0.51 g, 1.25 mmol) in anhydrous methanol (40 ml) is stirred at RT for 2 h with sodium methoxide (0.1 ml of a 30% strength solution in methanol). Sodium borohydride (0.55 g, 1.4 mmol) is then added to the yellow solution and it is stirred at RT for a further hour. Water (50 ml) is then added and the methanol is distilled off on a rotary evaporator.

The precipitate deposited 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 of Rf 0.3 and crystallization from ethyl acetate/cyclohexane, the title compound (0.26 g, 47%) is obtained as a beige powder. M.p. 164-1680C (dec.).

8. 8-[2-(2(R)-Hydroxypropionylamino)-6-methylbenzylaminol-3-hydroxymethyl-2-methylimidazo[1.2alpyridine According to the procedure indicated in Example 7, 8-[2-(2(R)-acetoxypropionylamino)-6methylbenzylamino]-3-formyl-2-methylimidazo[1,2a]pyridine, sodium methoxide and sodium borohydride give the title compound as a beige powder. M.p. 166-1700C.

WO 96/03404 PCT/EP95/02953 13- 9a. 8-r2- (2-Chloroacetylamiflo) -6-methylbenzylaminol 2,.3 -dimethylimidazo rl. 2 -a1pyridine A solution of 8- (2-amino-6-methylbenzylamino) 2,3-dimethylimidazo[l,2-alpyridile (0.28 g, 1 mmol) in anhydrous dichloromethane (15 ml) is treated with 1.1 equivalents of chioroacetyl chloride and stirred at RT for 2 h. It is then extracted with aqueous sodium carbonate solution (3 x 15 ml) The organic phase is washed with water (15 ml), dried over magnesium sulfate and concentrated. After crystallization from ethyl acetate /di isopropyl ether, the title compound (0.35 g, 84*- of theory is isolated as a beige solid. M.p. 159- 162 0

C.

According to the procedure described in Example 9a, reaction of 8- (2-amino-6-methylbenzylamino) -2,3dimethylimidazo pyridine or of 8- (2-amino- 6-methylbenzylamino) -3-chloro-2-methylimidazo pyridine gives the following compounds: 9b. 2, 3-Dimethyl-8- [6-methyl-2- (2-oxopropionylamino) benzylaminolimidazo[1,2-a]pyridine. M.p. 156-l580C (crystallization from ethyl acetate/diisopropyl ether).

9c. 8- (2-Acetoxyacetylamino) -6-methylbenzylamino) 2,3-dimethylimidazo[l,2-alpyridine. M.p. 96-98 0

C.

9d. 8- (2-Chloroethoxycarbonylamino) -6-methylbenzylamino] 3-dimethylimidazo pyridine hydrochloride. Extraction with water instead of with sodium carbonate solution. M.p. 199-202 0 C (crystallization from ethyl acetate).

9e. 8- (2-Chloroethoxycarbonylamino) -6-methylbenzylamino] -hoo--ehlmiao12alyiie M.p. 136-139 0

C.

9f. 8- (4-Chlorobutyrylamino) -6-methylbenzylaminol -2,3- S. dimethylimidazo[1,2-alpyridine. M.p. 138-1400C.

WO 96/03404 PCT/EP95/02953 14 9g. 8-[2-(4-Chlorobutyrylamino)-6-methylbenzylamino]- 3-chloro-2-methylimidazo[1,2-a]pyridine. M.p. 130- 1320C.

9h. 8-[2-(2-Methoxyacetylamino)-6-methylbenzylamino)-2,3dimethylimidazo[1,2-a]pyridine. M.p. 130-1310C.

8-[2-(2-Acetylaminoacetylamino)-6-methylbenzylaminol- 2.3-dimethylimidazo [12-alpyridine A solution of N-acetylglycine (0.36 g, 3.0 mmol) in anhydrous dichloromethane (20 ml) is treated at -100C with N-methylmorpholine (034 [sic] g, 3.0 mmol) and stirred for 1 h. Isobutyl chloroformate (0.4 ml, mmol), dissolved in 5 ml of dichloromethane, is then added dropwise and the mixture is again stirred at for 1 h. A solution of 8-(2-amino-6methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.43 g, 1.5 mmol) in dichloromethane (30 ml) is then added dropwise. The solution is then warmed to RT, stirred for 20 h and then extracted with water (4 x 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 of Rf 15 are concentrated and crystallized from ethyl acetate/diisopropyl ether. The title compound (0.14 g, 26%) is isolated as a beige solid. M.p. 192-1950C.

According to the procedure described in Example reaction of various carboxylic acids with isobutyl chloroformate and the appropriately substituted imidazopyridines gives the following compounds: 8-[2-(2-Acetylaminoacetylamino)-6-methylbenzylamino]-3-formyl-2-methylimidazo[1,2-a]pyridine.

M.p. 150-154 0

C.

WO 96/03404 PCT/EP95/02953 15 8- (2-tert-Butyloxycarbonylaminoacetylamino) 6-methylbenzylaminol -2,3-dimethylimidazo'[1,2Z-a] pyridine. M.p. 172-1740C.

8- (2-tert-Butyloxycarbonylaminoacetylamino) 6-methylbenzylamino] -3-f ormyl- 2-methylimidazo[1,2-alpyridile. M.p. 112-116 0

C.

2,3-Dimethyl-8- [(pyridine-2-carbonyl) amino] 6-methylbenzylamino) imidazo pyridine.

M.p. 178-1790C.

10f. 2,3-Dimethyl--8-(2-[(pyridine-3-carbol)aminol- 6-methylbenzylamino) imidazo pyridine.

M.p. 119-1210C.

11. 8- F2- (2-aminoacetylamino) -6-methylbenzylaminol 2.3-dimethylimidazorl.2-alpyridile 8- (2-tert-Butyloxycarbonylaminoacetylamino) 6-methylbenzylamino] 3-dimethylimidazo pyridine (0.44 g, 1 mmol) is added in portions at RT to a solution of anisole (2 ml) in trifluoroacetic acid ml) and the mixture is stirred for 30 min. The reaction mixture is then added to 2 N sodium hydroxide solution (50 ml) and stirred for 15 min at 40C. The precipitate is filtered off, washed with water, precipitated with stirring in diisopropyl ether and dried. The title compound (0.29 g, 850-) is isolated as a beige solid. M.p. 134-1360C.

12. 8- F2- (2-Aminoacetylamino) -6-methylbenzylaminol 3-formyl-2-methylimidazo Fl.2-al pyridine According to the procedure indicated in Example 11, starting from 8- (2-tert-butyloxycarbonylaminoacetYlamino) -6-methylbenzylaminol -3-formyl-2-methylimidazo- [1,2-alpyridine gives the title compound as a beige solid. M.p. 149-151 0

C.

WO 96/03404 PCT/EP95/02953 16 13. 8-[2-(2-Aminoacetylamino)-6-methylbenzylaminol- 3-hydroxymethyl-2-methylimidazo l,2-apyridine A solution of 8-[2-(2-aminoacetylamino)-6-methylbenzylamino]-3-formyl-2-methylimidazo[1,2-a]pyridine (0.24 g, 0.68 mmol) in anhydrous ethanol (25 ml) is treated with sodium borohydride and stirred at RT for 30 min. Water 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.

The solid is then again precipitated with stirring from diisopropyl ether and dried again. The title compound (0.29 g, 85%) is isolated as a beige solid. M.p. 134- 136oC.

14. 8-[2-(2-Acetylaminoacetylamino)-6-methylbenzylaminol-3-hydroxymethyl-2-methylimidazorl.2-alpyridine According to the procedure indicated in Example 13, starting from 8-[2-(2-acetylaminoacetylamino)-6-methylbenzylamino]-3-formyl-2-methylimidazo[1,2-a]pyridine gives the title compound as a beige solid. M.p. 162- 1670C.

2,3-Dimethyl-8-r6-methyl-2-(3-oxobutyrylamino)benzylaminolimidazo.l,2-alpyridine A solution of diketene (0.7 ml of 50% strength solution in acetone, 3.5 mmol) in 2 ml of acetone is added dropwise at RT to a suspension of 8-(2-amino- 6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine g, 3.5 mmol) and 4-dimethylaminopyridine (10 mg) in anhydrous acetone (30 ml). The mixture is stirred at RT for a further 1 h. The solvent is then distilled off on a rotary evaporator and the residual oil is recrystallized from ethyl acetate. The title compound WO 96/03404 PCT/EP95/02953 17 (0.31 g, 10%) is isolated as a beige product. M.p. 133- 1350C.

16. 2,3-Dimethyl-8-f6-methyl-2-(3-oxobutyrylamino)benzyloxylimidazo[l.2-alpyridine According to the procedure described in Example starting from 8-(2-amino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine, diketene and 4-dimethylaminopyridine gives the title compound as a beige powder.

M.p. 174-1750C.

17. 3-Formyl-2-methyl-8-[6-methyl-2-(3-oxobutyrylamino)benzyloxylimidazo l.2-alpyridine According to the procedure described in Example starting from 8-(2-amino-6-methylbenzyloxy)-3-formyl-2methylimidazo[1,2-a]pyridine, diketene and 4-dimethylaminopyridine gives the title compound as a beige powder. M.p. 174-1750C.

18. 8-[2-(3-Hydroxybutyrylamino)-6-methylbenzyloxyl- 3-hydroxymethyl-2-methylimidazo l,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) is treated with sodium borohydride mg) and stirred at RT for 30 min. It is then neutralized with acetic acid, the solvent is distilled off and the residue is chromatographed on silica gel (eluent: ethyl acetate/methanol 10:1). The fractions of 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. 168-1690C.

WO 96/03404 PCT/EP95/02953 18 19. 2.3-Dimethyl-8-(6-methyl-2-ureidobenzylamino)imidazoil.2-a1pyridine A solution of potassium cyanate (0.33 g, 4 mmol) in 8 ml of water is slowly added dropwise at RT to a suspension of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[l,2-a]pyridine (0.56 g, 2 mmol) in strength acetic acid (25 ml). The solution is stirred at RT for a further 2 h. Water (80 ml) is then added and the mixture is extracted with ethyl acetate (4 x 75 ml). The organic extracts are washed with water 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. M.p. 280 0 C dec.).

3-Formyl-2-methyl-8-(6-methyl-2-ureidobenzylamino)imidazorl.2-alpyridine According to the procedure indicated in Example 19, starting from 8-(2-amino-6-methylbenzylamino)-3-formyl- 2-methylimidazo[1,2-a]pyridine and potassium cyanate gives the title compound as a beige powder.

M.p. 291-2920C.

21. 3-Hydroxymethyl-2-methyl-8-(6-methyl-2-ureidobenzylamino)imidazo1.l2-alpyridine A solution of 3-formyl-2-methyl-8-(6-methyl-2-ureidobenzylamino)imidazo[1,2-a]pyridine (0.27 g, 0.8 mmol) in ethanol (20 ml) is treated with sodium borohydride mg, 0.8 mmol) and stirred at RT for 1 h. Water 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 After concentration of the fractions of Rf 0.3 WO 96/03404 PCT/EP95/02953 19 and crystallization from diisopropyl ether, the title compound (0.11 g, 41%) is isolated as a beige solid.

M.p. 247 0 C (dec.).

22. 3-Chloro-2-methyl-8-(6-methyl-2-ureidobenzylamino)imidazorl.2-alpyridine According to the procedure indicated in Example 19, starting from 8-(2-amino-6-methylbenzylamino)-3-chloro- 2-methylimidazo[l,2-a]pyridine and potassium cyanate gives the title compound as a beige powder.

M.p. 265-2670C.

Starting compounds Al. 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-2.3-dimethylimidazo[l.2-alpyridine g of sodium iodide and 8.0 g of sodium carbonate are added at RT to a solution of 8-amino-2,3dimethylimidazo[l,2-a]pyridine (4.8 g) and 2-tertbutoxycarbonylamino-6-methylbenzyl chloride (9.2 g) in acetone (250 ml) and the mixture is then heated to boiling under reflux for 6 h. After cooling the solution to RT and concentrating, 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 with 100 ml of ethyl acetate in each case, the combined organic phases are dried over magnesium sulfate and then concentrated. The title compound crystallizes as a slightly yellow solid.

Chromatographic purification on silica gel (eluent: toluene/dioxane 20:1) and recyrstallization from diisopropyl ether gives 7.1 g of the title compound of m.p. 149- S1520C.

I

WO 96/03404 PCT/EP95/02953 20 A2. 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazofl.2-alpyridine Starting from 8-amino-3-formyl-2-methylimidazo[l,2-a]pyridine (4.0 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (7.0 sodium iodide (4.1 g) and sodium carbonate (6.1 g) in acetone (250 ml) analogously using the process of Example Al gives, after chromatography on silica gel (eluent: toluene/dioxane 9:1) and recrystallization from diisopropyl ether, 7.3 g of the title compound of m.p. 210-212 0

C.

A3. 8-(2-Amino-6-methylbenzylamino)-2.3-dimethylimidazorl.2-alpyridine Method A: A solution of 8-(6-methyl-2-nitrobenzylamino)-2,3dimethylimidazo[1,2-a]pyridine (61 g) in methanol (5.5 1) is hydrogenated at RT and under atmospheric pressure for 1.5 h in the presence of 15 g of palladium on active carbon as catalyst. After filtering off the catalyst and concentrating, the residue is dissolved in boiling ethyl acetate (2.7 After cooling to RT, 51 g of the title compound of m.p.

206-2080C are isolated.

Method B: 6.7 g of 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine are added at 25-30 0 C in portions to a mixture of trifluoroacetic acid (30 ml) and anisole (3 ml). After stirring at RT for 30 minutes, the solution is poured into 100 ml of ice-water and then treated with 75 ml of 6 N sodium hydroxide solution. The precipitate is filtered off and purified chromatographically on silica gel (solvent: toluene/dioxane Recrystallization from ethyl WO 96/03404 PCT/EP95/02953 21 acetate gives 3.1 g of the title compound of m.p.

206-2080C.

A4. 8-(2-Amino-6-methylbenzylamino)-3-formyl-2-methylimidazo Fr2-alpyridine Starting from 8-(2-tert-butoxycarbonylamino-6methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine (3.6 trifluoroacetic acid (15 ml) and anisole (5 ml) according to the procedure described for Example A3 (Method B) gives, after chromatography on silica gel (eluent: toluene/dioxane 9:1) and crystallization from ethyl acetate/cyclohexane, 2.3 g of the title compound of m.p. 230-234°C.

Bl. 8-(2-Amino-6-methylbenzylamino)-3-chloro-2-methylimidazofrl2-alpyridine hydrochloride A solution of 3-chloro-2-methyl-8-(6-methyl-2-nitrobenzylamino)imidazo[1,2-a]pyridine (2.0 g, 6 mmol) in methanol (175 ml) and dioxane (175 ml) is treated with platinum-on-carbon catalyst strength) and hydrogenated at RT under atmospheric pressure for 2 h.

After 2 h, 2 N hydrochloric acid (5 ml) is added and the mixture is hydrogenated under the same conditions again for 1 h. The catalyst is then filtered off, the filtrate is adjusted to pH 8.5 using 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, diisopropyl ether (250 ml) is added and, to complete crystallization, the mixture is stirred at 4°C for min. The precipitate is then filtered off with suction, washed with diisopropyl ether and dried in vacuo. The title compound (1.66 g, 92%) is isolated as a beige solid. M.p. 243-2460C.

WO 96/03404 PCT/EP95/02953 22 B2. 3-Chloro-2-methyl-8-(6-methyl-2-nitrobenzylamino)imidazo[1.2-alpyridine Starting from 8-amino-3-chloroimidazo[1,2-a]pyridine (9.26 6-methyl-2-nitrobenzyl chloride (10.5 g), sodium carbonate (13.7 g) and sodium iodide (8.55 g) in acetone (380 ml) according to the procedure indicated in Example Al gives, after chromatography on silica gel (eluent: toluene/dioxane 20:1) and crystallization from ethyl acetate/cyclohexane, 10.6 g of the title compound of m.p. 142-144°C.

B3. 8-Amino-3-chloroimidazorl,2-alpyridine A suspension of 3-chloro-2-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine (4.0 g, 15 mmol) in 60% strength sulfuric acid (25 ml) is stirred at 100 0 C for 1 h.

After cooling to RT, water (100 ml) is added and the mixture is adjusted to pH 10 using 10 N sodium hydroxide solution. It is then 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, and the solution is clarified with silica gel and crystallized. The title compound is isolated as a beige solid. Yield 1.9 g m.p. 126-127°C.

B4. 3-Chloro-2-methyl-8-pivaloylaminoimidazo l.2-alpvridine g (18.6 mmol) of 2-methyl-8-pivaloylaminoimidazo- [1,2-a]pyridine hydrochloride, prepared from 8-amino-2methylimidazo[1,2-alpyridine and pivaloyl chloride, m.p. 229-2300C, are dissolved in glacial acetic acid (20 ml) and chlorine gas is slowly passed in at until the reaction has ended according to TLC checking (about 20 min). The solvent is then distilled off, the residue is taken up in ethyl acetate/water (in each WO 96/03404 PCT/EP95/02953 23 case 30 ml), and the mixture is rendered basic using saturated sodium hydrogencarbonate solution and extracted. It 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 Concentration of the fractions of Rf 0.2 gives the title compound (4.1 g, 83%) as a colorless solid.

M.p. 117-1180C.

Commercial utility The compounds of the formula I and their salts have useful pharmacological properties which make them commercially utilizable. In particular, they have a marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warmblooded mammals. The compounds according to the invention are distinguished here by a high selectivity of action, a comparatively long duration of action, a good enteral activity, the absence of significant side effects and a large therapeutic breadth.

"Gastric and intestinal protection" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, hyperacidic or medicament-related functional gastropathy), which can be caused, for example, by microorganisms Helicobacter pylori), bacterial toxins, medicaments certain antiinflammatories and antirheumatics), chemicals ethanol), gastric acid or stress situations. The compounds according to the invention in this case also have an intrinsic action against the microorganism Helicobacter pylori.

WO 96/03404 PCT/EP95/02953 24 The compounds according to the invention surprisingly prove clearly superior to the compounds known from the prior art in their excellent properties in various models in which the antiulcerogenic and the antisecretory properties are determined. On account of these properties, the compounds of the formula I and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine.

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

The invention likewise comprises the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases.

The invention furthermore 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 medicaments are prepared by processes known per se, which are familiar to the person skilled in the art. As medicaments, the pharmacologically active compounds according to the invention active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries or excipients, in the form of tablets, coated tablets, capsules, suppositories, patches, as TTS) emulsions sus- WO 96/03404 PCT/EP95/029-53 25 pensions or solutions, the active compound content advantageously being between 0.i and 95% and it being possible to achieve by the appropriate choice of the auxiliaries and excipients a pharmaceutical administration form exactly suited to the active compound and/or to the desired onset of action a sustained-release form or an enteric form) The person skilled in the art is familiar on the basis of his expert knowledge with the auxiliaries and excipients which are suitable for the desired pharmaceutical formulations. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents cyclodextrins) can be used.

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

In general, it has proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, preferably 0.05 to in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 4, individual doses to achieve the desired result. In the case of a parenteral treatment, similar or (in particular in the case of intravenous administration of the active compounds), as a rule, lower doses are used.

Any person skilled in the art can easily fix the required optimum dose and manner of administration of the active compounds in each case on the basis of his expert knowledge.

WO 96/03404 PCT/EP95/02953 26 If the compounds and/or salts according to the invention are to be employed for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other pharmaceutical groups, such as antacids, for example aluminum hydroxide, magnesium aluminate; tranquilizers, such as benzodiazepines, for example diazepam; spasmolytics, such as, for example, bietamiverine, camylofin, anticholinergics, such as, for example, oxyphencyclimine, phencarbamide; local anesthetics, such as, for example, tetracaine, procaine; and optionally also enzymes, vitamins or amino acids.

Emphasis is to be given in this connection in particular to the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H 2 blockers (e.g.

cimetidine, ranitidine), H ATPase inhibitors (e.g.

omeprazole, pantoprazole), or furthermore with socalled peripheral anticholinergics pirenzepine, telenzepine) and also with gastrin antagonists with the aim of potentiating the main action in an additive or superadditive sense and/or of eliminating or of lowering the side effects, or furthermore the combination with substances having antibacterial activity (such as, for example, cephalosporins, tetracyclines, nalidixic acid, penicillins or alternatively bismuth salts) for the control of Helicobacter pylori.

Pharmacology The excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be detected in investigations on animal experimental models. The compounds according to the invention investigated in the model mentioned below have been provided with numbers which WO 96/03404 PCT/EP95/02953 27 correspond to the numbers of these compounds in the examples.

Testing the secretion-inhibiting action on the perfused rat stomach Table A which follows shows the effect of the compounds according to the invention after intravenous administration on the pentagastrin-stimulated acid secretion of the perfused rat stomach in vivo.

Table A No. Dose Inhibition of acid secretion (gmol/kg) i.v.

3 96 6 3 94 19 3 100 Methodology After tracheotomy, the abdomen of anesthetized rats (CD rats, female, 200-250 g; 1.5 g/kg i.m. urethane) was opened by a median upper abdominal incision and a PVC catheter was fixed transorally in the esophagus and a further one via the pylorus in such a way that the tubing ends just projected into the gastric lumen. The catheter leading from the pylorus led outwards via a side opening in the right abdominal wall.

After thorough irrigation (about 50-100 ml), warm physiological NaC1 solution at 37 0 C was continuously passed through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I) In the effluate in each case collected WO 96/03404 PCT/EP95/02953 28 at an interval of 15 minutes, the pH (pH meter 632, glass electrode EA 147; 4 5 mm, Metrohm) and, by titration with a freshly prepared 0.01 N NaOH to pH 7 (Dosimat 665 Metrohm), the secreted HC1 were determined.

The stimulation of gastric acid secretion was effected by continuous infusion of 1 pg/kg 1.65 ml/h) of i.v.

pentagastrin (left femoral vein) for about 30 min after the end of the operation after determination of 2 initial fractions). The substances to be tested were administered intravenously in 1 ml/kg of liquid volume min after beginning the pentagastrin continuous infusion.

The body temperature of the animals was kept at a constant 37.8-380C by infrared irradiation and heating pads (automatic, continuous regulation by means of a rectal temperature sensor).

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

Claims (9)

1. A compound of the formula I R2 R NHCO-R3 (1) in which RO is 1-4C-alkyl, hydroxymethyl, halogen or thiocyanate, R1 is l-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, or trifluoromethyl, R3 is amino, pyridyl, halogen- substituted 1-4C- alkoxy or substituted 1-4C-alkyl having one or two identical or different substituents selected from the group consisting of hydroxyl, oxo, 1- 4C- alkylcarbonyloxy, carboxyl, halogen, 1-4C-alkoxy, 1-4C-alkoxy- carbonyl, amino, 1-4C-alkylcarbonylamino and 1 -4C-alkoxycarbonylamino, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl, is hydrogen, 1-4C-alkyl, 1-4c--alkoxy or halogen and A is 0 (oxygen) or NH, or its salts. 30

2. A compound of the formula I as claimed in claim 1, in which RO is l-4C-alkyl, hydroxymethyl or halogen, R1 is l-4C-alkyl, R2 is l-4C-alkyl R3 is amino, pyridyl, halogen-substituted 1-4C- alkoxy or substituted l-4C-alkyl having a substituent selected from the group consisting of hydroxyl, oxo, l-4C-alkyl- carbonyloxy, halogen, l-4C-alkoxy, amino, l-4C-alkylcarbonylamino and l-4C-alkoxy- carbonylamino, R4 is hydrogen, 15 R5 is hydrogen and A is 0 (oxygen) or NH, or its salts. .9 *9

3. A compound of the formula I as claimed in claim 1, in which RO is methyl or hydroxymethyl or chlorine, R1 is methyl, i. R2 is l-4C-alkyl, R3 is amino, chlorine-substituted l-4C-alkoxy or 25 substituted l-4C-alkyl having a substituent selected from the group consisting of hydroxyl, oxo, l-4C-alkylcarbonyloxy, chlorine, l-4C-alkoxy, amino, l-4C-alkyl- carbonylamino and l-4C-alkoxycarbonylamino, R4 is hydrogen, is hydrogen and A is 0 (oxygen) or NH, or its salts.

4. A compound of the formula I as claimed in claim 1, in which RO is methyl or hydroxymethyl, Rqzl R1 is methyl, WO 96/03404 PCT/EP95/02953 31 R2 is l-4C-alkyl, R3 is 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, is hydrogen and A is 0 (oxygen) or NH, or its salts.

A compound of the formula I as claimed in claim 1, in which RO is fluorine.

6. A process for the preparation of the compounds of the formula I as claimed in claim 1 and their salts, which comprises a) for the preparation of compounds of the formula I in which RO is hydroxymethyl, reducing compounds of the formula II (see attached formula sheet), in which Ri, R2, R3, R4, R5 and A have the meanings indicated in claim 1, or b) introducing the radical R3-CO- into compounds of the formula III (see attached formula sheet), in which RO, Ri, R2, R4, R5 and A have the meanings indicated in claim 1, in a suitable manner and if desired then converting the radical R3 into another radical R3, or 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 indicated in claim 1, with alkali metal cyanate, 32 and if desired then converting the compounds I obtained into their salts, or if desired then liberating the compounds I from salts of the compounds I obtained.

7. A medicament comprising a compound as claimed in claim 1 and/or a pharmacologically tolerable salt thereof together with customary pharmaceutical auxiliaries and/or excipients.

8. Use of a compound as claimed in claim 1 or its pharmacologically tolerable salts in the prevention and treatment of gastrointestinal diseases.

9. Method of treating gastrointestinal diseases 15 comprising administering a compound as claimed in claim 1 or its pharmacologically tolerable salts to a subject in need of such treatment. The use of compounds as claimed in claim 1 and 20 their pharmacologically tolerable salts for the production of medicaments for the prevention and treatment of gastrointestinal diseases. Dated this 14th day of December 1998 BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent Attorneys of Australia H:\PClarke\Keep\specis\31661.95.byk.cm.doc 14/12/98