AU700737B2

AU700737B2 - Benzylimidazopyridines

Info

Publication number: AU700737B2
Application number: AU31660/95A
Authority: AU
Inventors: Gerhard Grundler; Stefan Postius; Georg Rainer; Richard Riedel; Jorg Senn-Bilfinger; Wolfgang-Alexander Simon
Original assignee: Byk Gulden Lomberg Chemische Fabrik GmbH
Current assignee: Takeda GmbH
Priority date: 1994-07-28
Filing date: 1995-07-26
Publication date: 1999-01-14
Anticipated expiration: 2015-07-26
Also published as: AU3166095A; EP0773944A1; NZ290818A; CA2196077A1; JPH10505331A; WO1996003403A1

Description

WO 96/03403 1 PCT/EP95/02952 Benzylimidazopyridines Field of application of the invention The invention relates to novel benzylimidazopyridines 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[1,2-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 96/03403 2 PCT/EP95/02952 The inventions relate [sic] to compounds of the formula I (see attached formula sheet), in which RO is methyl or hydroxymethyl, R1 is l-4C-alkyl, R2 is hydrogen, l-4C-alkyl, l-4C-alkoxy, halogen or trifluoromethyl, R3 is l-4C-alkoxy, R4 is hydrogen, l-4C-alkyl, l-4C-alkoxy, halogen or trifluoromethyl, R5 is hydrogen, l-4C-alkyl, l-4C-alkoxy or halogen and A is O (oxygen) or NH, where R4 and R5 are not simultaneously hydrogen if R2 is l-4C-alkyl, and their salts.

l-4C-Alkyl is straight-chain or branched alkyl radical [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.

l-4C-Alkoxy is an oxygen atom to which one of the abovementioned l-4C-alkyl radicals is bonded. The methoxy radical is preferred.

Halogen within the meaning of the invention is bromine, fluorine and, in particular, chlorine.

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 processes known to the person skilled in the art. Those suitable WO 96/03403 3 PCT/EP95/02952 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 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 of the formula I to be emphasized are those in which RO is methyl or hydroxymethyl, R1 is l-4C-alkyl, R2 is hydrogen, l-4C-alkyl, l-4C-alkoxy, chlorine or fluorine, R3 is l-4C-alkoxy, R4 is hydrogen, l-4C-alkyl or l-4C-alkoxy, is hydrogen and A is 0 (oxygen) or NH, where R4 is not hydrogen if R2 is l-4C-alkyl, and their salts.

Compounds of the formula I to be particularly emphasized are those in which RO is methyl or hydroxymethyl, R1 is methyl, R2 is chlorine, R3 is l-4C-alkoxy, R4 is hydrogen, is hydrogen and A is 0 (oxygen) or NH, and their salts.

WO 96/03403 4 Wa 960340 -4-PCT/EP95/02 952 Exemplary compounds according to the invention are listed in the following tables: Table 1 Compounds of the formula I with R1=CH 3 A=O (oxygen) substituent meanings: (see attached formula sheet) and the following further

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

2 0H

H

F

OCH

3

CH

3 Cl

H

CH

3 Cl

CH

3

CH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3 0C 2

H

5

OCH

3

OCH

3 5-CH 3

H

3 OCH 3

H

3-CH 3 3 CH 3

H

5-CH 3 Table 2 Compounds of the formula I (see attached formula sheet) with Rl=CH., A=NH and the following further substituent meanings: RO R2 R3 R4

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

2 0H

CH

3

H

F

OCH

3

CH

3

H

CH

3 Cl

CH

3

CH

3 Cl

OCH

3

OCH

3

OCH

3 0CH 3

OCH

3

OCH

3 0C 2

H

5

OCH

3

OCH

3 OC (CH 3 3 5 CH 3

H

3-0CH 3 3 -CH 3 3 CM 3

H

5-CM 3 5-CH 3

H

WO 96/03403 5 PCT/EP95/02952 Continuation of Table 2: RO R2 R3 R4

CH

3 C1 OCH(CH 3 2 5-CH3 H

CH

3 F OCH 3 H H

CH

3

CH

3

OCH

3 5-C1 H

CH

3

CH

3

OCH

3 5-Br H and the salts of the compounds mentioned in the tables.

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 the attached formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings indicated above, or b) for the preparation of compounds of the formula I in which RO is methyl, reacting compounds of the formula III (see the attached formula sheet), in which R1 and A have the meanings indicated above, with compounds of the formula IV (see attached formula sheet), in which R2, R3, R4 and R5 have the meanings indicated above and X is a suitable leaving group, or c) for the preparation of compounds of the formula I in which RO is methyl, reacting compounds of the formula V (see attached formula sheet), in which R1, R2, R4, R5 and A have the meanings indicated above, with compounds of the formula VI (see attached formula sheet), in which R3 has the meanings indicated above and Y is a suitable leaving group, WO 96/03403 6 PCT/EP95/02952 and if desired then converting the compounds I obtained according to b) or c) into their salts, or if desired then liberating the corrmpounds I from salts of :he 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 reaction of the compounds III with the compounds IV is carried out in a manner familiar per se to the person skilled in the art, for example analogously using those processes such as are described in European Patent Applications EP-A-0 268 989 or EP-A-0 308 917.

A suitable leaving group is, for example, a halogen atom (preferably chlorine or bromine) or a methanesulfonyloxy group. The reaction is advantageously carried out in the presence of a base of an inorganic hydroxide, such as sodium hydroxide, or of an inorganic carbonate, such as potassium carbonate, or of an organic nitrogen base, such as triethylamine, pyridine, collidine or 4-dimethylaminopyridine), it being possible to promote conduct of the reaction by addition of catalysts, such as alkali metal iodide or tetrabutylammonium bromide.

The reaction of the compounds V with the compounds VI is likewise carried out in a manner known per se to the person skilled in the art, such as is customary for the preparation of aromatic urethanes, preferably by reaction of the compounds V with haloformic acid esters (Y halogen), such as chloroformic acid esters, in inert solvents. The reaction is advantageously carried out in the presence of an acid-binding agent (proton acceptor). Proton acceptors which may be mentioned are, WO 96/03403 7 PCT/EP95/02952 for example, alkali metal carbonates (such as potassium carbonate) or hydrogen carbonates (such as sodium hydrogen carbonate) or tertiary amines (such as triethylamine) 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.

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.

WO 96/03403 8 PCT/EP95/02952 The starting compounds II can be prepared in a manner known per se, for example by reaction of the compounds VII with the compounds IV (see attached formula sheet), in which R1, 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.

The starting compounds III are disclosed in European Patent Application EP-A-0 299 470; the starting compounds IV can be prepared in an analogous manner as described in European Patent Application EP-A-0 308 917.

The starting compounds V can be prepared in a manner known per se from the corresponding nitro compounds by reduction or by hydrolysis of suitable N-acyl derivatives. The nitro compounds, for their part, can be prepared from the compounds III and appropriate nitro compounds corresponding to the compounds IV.

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 reactions according to process variants a, b and c, 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 for minute(s), m.p. for melting point and dec. for decomposition.

I I WO 96/03403 9 PCT/EP95/02952 Examples Final products 1. 8- (6-Chloro-2-methoxycarboflylaminobenzlaminO) 2 -methyl imidazo [1.2-al pyridine-3 -methanol 1.6 g of 8- (6-chloro-2-methoxycarbonylaminobenzylamino) -2-methylimidazo 11,2-al pyridine-3-carboxaldehyde and 0.16 g of sodium borohydride are stirred at in 100 ml of methanol until the thin-layer chromatogram indicates complete conversion. The mixture is concentrated in a rotary evaporator to about 20 ml, treated with water and cooled in an ice bath. The precipitate is filtered, washed with water and recrystallized from acetonitrile. 1.5 g of the title compound are obtained. M.p. 167-168 0 C (dec.).

The compounds of Examples 2 10 are prepared in an analogous manner, it being possible in the case of more easily soluble derivatives to reduce the amount of solvent and the temperature.

2. 8- (6-Fluoro-2-methoxycarbonylaminobenzylamino) 2-methylimidazorl,2-alpyridine-3-methanol.

M.p. 155-156 0 C (from dichioromethane/petroleum ether).

3. 8- (2-Methoxycarbonylamino-3-methylbenzylamino) 2-methylimidazorl,2-alyridine3methanol.

M.p. 170-172 0 C with dec. (from toluene).

4. 8- (2-Methoxycarbonylamino-5-methylbenzylamino) 2-methylimidazo [1.2-al pyridine-3-methanol.

M.P. 187-188 0 C (dec.).

8- (2-Methoxvcarbonylamino-3 .6-dimethylbenzylamino)- -2 methyimidazoF.2-alpyridine3methanol.

M.p. 179-1800C (from toluene/diisopropyl ether).

WO 96/03403 10 PCT/EP95/02 952 6. 8- (3-Methoxy-2-methoxycarbonylamino-6-methylbenzylamino) -2-methylimidazo [1.2-al pyridine- 3-methanol. M.p. 118-1220C (dec.).

7. 8- (6-Chloro-2-methoxycarbony-laminobenzyloxy) 2-methylimidazo [1.2-al pyridine-3-methanol.

M.p. 184-186-C with dec. (from acetonitrile).

8. 8- (6-Methoxy-2-methoxycarbonylaminobenzylamino) 2-methylimidazofl.2-alipyridine-3-methanol.

M.p. 159-161 0

C.

9. 8- (6-Fluoro-2-methoxycarbonylaminobenzyloxy) 2-methylimidazo p1.2-al pyridine-3-methaniol.

M.P. 175-176 0 C (dec.).

8- (2-Methoxycarbonylamino-3 .5-dimethylbenzyloxcy) 2-methylimidazo p1.2-al pyridine-3-methanol.

M.p. 155 0 C with dec. (from toluene/petroleum ether).

11. 8- (6-Chloro-2-methoxycarbonylaminobenzylamino) 2. 3-dimethylimidazo [1.2-al oyridine A mixture of 1.98 g of 8-amino-2,3-dimethylimidazo- 11,2-alpyridine, 2.5 g of methyl (3-chloro-2-chloromethylphenyl)carbamate, 2.6 g of anhydrous sodium carbonate and 0.4 g of sodium iodide in 50 ml of acetone is stirred at RT for 30 h. The mixture is filtered hot and the filtrate is treated with a solution of 0.7 g of fumaric acid in 70 ml of acetone.

It is allowed to crystallize for 5 h with stirring and cooling and the hemifumarate of the title compound 191-192 0 C, dec.) is separated off. It is suspended in water/acetone and the mixture is adjusted to PH 10 with dilute sodium hydroxide solution. The mixture is then extracted by shaking with dichloromethane, the extract is concentrated in a rotary evaporator and the residue is recrystallized WO 96/03403 11 PCT/EP95/02952 from ethyl acetate/petroleum ether. The title compound is obtained in 65% yield 146-147°C, dec.).

Starting compounds A. Methyl (3-chloro-2-chloromethylphenyl)carbamate a. 100 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran are added dropwise to a suspension of 17.2 g of 2-amino-6-chlorobenzoic acid in 300 ml of ether with stirring at 5 0 C in the course of 1 h (evolution of H 2 The mixture is stirred for a further 0.5 h, 6 ml of water, 6 ml of 15% strength sodium hydroxide solution and 16 ml of water are added dropwise and the mixture is stirred for a further 1 h at 0°C. The salts are filtered off and washed with ether, the filtrates are concentrated in vacuo and the residue is crystallized from petroleum ether (100/1400C).

9.6 g of 2-amino-6-chlorobenzyl alcohol of m.p. 81-82 0 C are obtained.

b. 4.41 ml of methyl chloroformate are added dropwise at 0-5 0 C in the course of 10 min to 9.0 g of the preceding compound and 4.6 ml of pyridine in 200 ml of dichloromethane and the mixture is stirred for a further 2 h in an ice bath. The organic solution is washed with water, mixed with ml of petroleum ether (100-1400C) and concentrated on a rotary evaporator to about 50 ml, and 11.5 g of methyl (3-chloro-2-hydroxymethylphenyl)carbamate of m.p. 126-127 0 C are obtained.

c. 3.9 ml of thionyl chloride are added dropwise to 11.0 g of the preceding compound in 150 ml of dichloromethane and the mixture is stirred for a further 4 h at 35-40 0 C. 50 ml of petroleum ether (100/1400C) are added, the mixture is concentrated WO 96/03403 12 PCT/EP95/02952 on a rotary evaporator to about 50 ml, and the residue is stirred for a further 2 h and washed with petroleum ether (40C) 10.6 g of the title compound of m.p. 136-1370C are obtained.

B. Methyl (2-chloromethyl-3-fluorophenyl)carbamate a. Analogously to Example Aa, 2-amino-6-fluorobenzoic acid and lithium aluminum hydride give, in 81% yield, 2-amino-6-fluorobenzyl alcohol of m.p. 87-88°C.

b. Analogously to Example Ab, the preceding compound and methyl chloroformate give, in 92% yield, methyl (3-fluoro-2-hydroxymethylphenyl)carbamate of m.p. 92-94 0

C.

c. Analogously to Example Ac, the preceding compound and thionyl chloride give, in 92% yield, the title compound of m.p. 113-114°C.

C. Methyl (2-chloromethyl-6-methylphenyl)carbamate Analogously to Example A, 2-amino-3-methylbenzyl alcohol and methyl chloroformate give methyl (2-hydroxymethyl-6-methylphenyl)carbamate of m.p. 90-910C and, furthermore from this, with thionyl chloride the title compound of m.p. 115-116 0

C.

D. Methyl (2-chloromethyl-4-methylphenyl)carbamate Analogously to Example A, 2-amino-4-methylbenzyl alcohol and methyl chloroformate give, after chromatography on silica gel using ethyl acetate, methyl (2-hydroxymethyl-4-methylphenyl)carbamate as an oil and, furthermore from this, with thionyl WO 96/03403 13 PCT/EP95/02952 chloride the title compound of m.p. 126-127°C (from diisopropyl ether).

E. Methyl (2-chloromethyl-3.6-dimethylphenyl)carbamate a. 0.36 ml of methyl chloroformate in 2 ml of dichloromethane is added dropwise at 0-5 0 C in the course of 20 min to 0.70 g of 2-amino-3,6-dimethylbenzyl alcohol and 0.37 ml of pyridine in ml of dichloromethane, the mixture is stirred for a further 0.5 h and washed 3 x with water, and the solution is dried and concentrated in vacuo.

The residual oil is crystallized using diisopropyl ether and petroleum ether (40 0 0.79 g of methyl (2-hydroxymethyl-3,6-dimethylphenyl)carbamate of m.p. 94-95 0 C is obtained.

b. 0.26 ml of thionyl chloride is added dropwise to 0.75 g of the preceding compound in 20 ml of dichloromethane at 0-5 0 C, the mixture is stirred for a further 15 min and concentrated in vacuo, the residue is chromatographed on silica gel by means of ethyl acetate and the product is crystallized from diisopropyl ether. 0.52 g of the title compound of m.p. 127-128 0 C is obtained.

F. Methyl (2-chloromethyl-6-methoxy-3-methylphenyl)carbamate a. 15 g of 7-methoxy-4-methylindole-2,3-dione (Houben-Weyl VII/4, 17) and 150 ml of 10% sodium hydroxide solution are heated to 100 0 C and 75 ml of 30% hydrogen peroxide solution are added dropwise in the course of 30 min. The mixture is stirred for a further 15 min at 100 0 C and adjusted to pH 4 with half-concentrated hydrochloric acid, wo 96/03403 14 PCT/EP95/02952 and the aqueous solution is extracted with isopropyl acetate. The organic solution is dried and concentrated, and the residue is chromatographed on silica gel using e:hyl acetate/isopropanol 1 g of 2-amino- 3-methoxy-6-methylbenzoic acid of m.p. 118-120 0

C

(dec.) is obtained after triturating with petroleum ether.

b. 0.85 g of the preceding compound is reduced in ml of tetrahydrofuran using 11.7 ml of 1 M lithium aluminum hydride in tetrahydrofuran analogously to Example Aa). 0.64 g of 2-amino- 3-methoxy-6-methylbenzyl alcohol of m.p. 70-72 0

C

is obtained, crystallized from petroleum ether (50/700C).

c. Reaction of the preceding compound analogously to Example Ea gives, after crystallizing from petroleum ether (50/70°C) in 89% yield, methyl (2-hydroxymethyl-6-methoxy-5-methylphenyl)carbamate of m.p. 89-93 0

C.

d. Reaction of the preceding compound analogously to Example Ec gives, after concentrating on a rotary evaporator, the title compound as a crude product which is employed directly in Example Ie.

G. Methyl (2-chloromethyl-3-methoxyphenyl)carbamate a. A mixture of 10 g of 2-[(2,2-dimethyl-l-oxopropyl)amino]-6-methoxybenzoic acid Org. Chem.

718, 1985), 20 ml of water and 45 ml of concentrated sulfuric acid is heated for 8 h at 70 0 C, added to ice and adjusted to pH 5 using sodium hydrogen carbonate. The mixture is extracted with isopropyl acetate, the organic phase is concentrated in vacuo and the residue is recrystallized from toluene/petroleum ether WO 96/03403 15 PCT/EP95/02952 0 C) 4.6 g of 2-amino-6-methoxybenzoic acid of m.p. 79-81 0 C are obtained.

b. The preceding compound is reduced analogously to Example Fb and gives in 55% yield 2-amino-6-methoxybenzyl alcohol of m.p. 59-60 0 C (from diisopropyl ether/petroleum ether (40 0 c. Reaction of the preceding compound analogously to Example Ea with methyl chloroformate gives methyl (2-hydroxymethyl-3-methoxyphenyl)carbamate of m.p. 94.5-96 0

C.

d. Starting from the preceding compound analogously to Example Ab with thionyl chloride gives, in 84% yield, the title compound of m.p. 131-133°C (from diisopropyl ether).

H. 8-(6-Chloro-2-methoxycarbonylaminobenzylamino)- 2-methylimidazofl.2-alpyridine-3-carboxaldehyde A mixture of 1.2 g of 8-amino-2-methylimidazo- [1,2-a]pyridine-3-carboxaldehyde, 1.7 g of methyl (3-chloro-2-chloromethylphenyl)carbamate, 1.5 g of fine-grained anhydrous sodium carbonate and 0.2 g of sodium iodide in 40 ml of acetone is stirred for 7 h at 0 C. It is mixed with 60 ml of ice/water, then [lacuna] to pH 7.5 with glacial acetic acid, and stirred for a further 30 min. The mixture is filtered, the solid is washed with water and dissolved in 300 ml of isopropyl acetate, and the solution is dried with magnesium sulfate and clarified with active carbon. It is then concentrated to about 80 ml and cooled in ice.

1.8 g of the title compound of m.p. 194-196 0 C are obtained.

I. Reaction analogously to Example H of 8-amino- 2-methylimidazo[l,2-a]pyridine-3-carboxaldehyde with WO 96/03403 16 PCT/EP95/02952 methyl (2-chloromethyl-3-fluorophenyl) carbamate, methyl (2-chloromethyi-6-methylphenyl) carbarnate, methyl (2-chloromethyl-4-methylphenyl) carbamate, methyl (2-chloromethyl-3, 6-dimethyiphenyl) carbamate, methyl (2-chloromethyl-6--methoxy-3-methylphenyl) carbamate, and methyl (2-chloromethyl-3-methoxyphelyl) carbamate gives a. 8- (6-Fluoro-2-methoxycarbonylaminobenzylaio) 2-methylimidazo F .2-al pyridine-3-carboxaldehyde.

M.p. 142-144 0 C (from diisopropyl ether after chromatography on silica gel using ethyl acetate).

b. 8- (2-Methoxycarbonylamino-3-methylbelzylamilo) 2-methylimidazo ri.2-al pyridine-3-carboxaldehyde.

M.p. 195-196 0 C with dec. (from toluene/petroleum ether).

C. 8- (2-Methoxycarbonylamino-5-methylbelzylamilo) 2 -methylirnidazoF 1. 2-al pyridine-3 -carboxaldehyde.

M.P. 144-1460C (from toluene/petroleum ether after chromatography on silica gel using ethyl acetate).

d. 8- (2-Methoxycarbonylamino-3. G-dimethylbenzylamino) -2-methylimidazo [1.2-al pyridine-3-carboxaleyQ M.p. 170-170.50C (from toluene /petroleum ether after chromatography on silica gel using ethyl acetate).

e. 8- (3-Methoxy-2-methoxycarboflylamfiflo-6-methyli benzvlamino) -2-methyl imidazofl,2-alpvridine-3-carboxaldehyde. M.p. 176-1780C (from toluene/petroleum ether after chromatography on silica gel using ethyl acetate).

f. 8- (6-Methoxv-2-methoxycarbonlamilobefzl~amino 2-methylimidazo fi.2-al pyridine-3-carboxaldehyde WO 96/03403 17 PCT/EP95/02952 M.p. 146-149 0 C (from toluene after chromatography on silica gel using ethyl acetate).

K. Reaction analogously to Example H of 8-hydroxy- 2-methylimidazo[l,2-a]pyridine-3-carboxaldehyde with methyl (3-chloro-2-chloromethylphenyl)carbamate, methyl (2-chloromethyl-3-fluorophenyl)carbamate, and methyl (2-chloromethyl-3,6-dimethylphenyl)carbamate gives a. 8-(6-Chloro-2-methoxycarbonylaminobenzyloxy)- 2-methylimidazo[l.2-alpyridine-3-carboxaldehyde.

M.p. 233-234 0 C (from acetonitrile).

b. 8-(6-Fluoro-2-methoxycarbonylaminobenzyloxy)- 2-methylimidazo l.2-alpyridine-3-carboxaldehyde.

M.p. 214-216 0 C (from toluene/petroleum ether).

c. 8-(2-Methoxycarbonylamino-3.6-dimethylbenzyloxy)- 2-methylimidazo[l.2-alpyridine-3-carboxaldehyde.

M.p. 171-172 0 C (after chromatography on silica gel using ethyl acetate).

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.

4 WO 96/03403 18 PCT/EP95/02952 "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.

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.

WO 96/03403 19 PCT/EP95/02952 The invention further relates to medicaments which contain one or more compounds of the formula I and/cr 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, suspensions or solutions, the active compound content advantageously being between 0.1 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 WO 96/03403 20 PCT/EP95/02952 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 can be 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.

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 /K 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 WO 96/03403 21 PCT/EP95/02952 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 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 (Amol/kg) i .v.

1 6 97 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 outward via a side opening in the right abdominal wall.

22 After thorough irrigation (about 50-100 ml), warm physiological NaCl solution at 37cC 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 at an interval of 15 minutes, the pH (pH meter 632, glass electrode EA 147; 5 mm, Metrohm) and, by :itration with a freshly prepared 0.01 N NaOH to pH 7 (Dosimat 665 Metrohm), the secreted HCl were determined.

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

pentagastrin (left femoral vein) for about 30 min after 15 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 60 min after beginning the pentagastrin continuous infusion.

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

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

Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in a nonexclusive sense.

Claims

2. A compound of the formula I as claimed in claim 1, in which RO is methyl or hydroxymethyl, R1 is 1-4C-alkyl, R2 is hydrogen, l-4C-alkyl, 1-4C-alkoxy, chlor- mne or fluorine, R3 is i-4C-alkoxy, R4 is hydrogen, l-4C-alkyl or 1-4C-alkoxy, WO 96/03403 24 PCT/EP95/02952 is hydrogen and A is 0 (oxygen) or NH, where R4 is not hydrogen if R2 is 1-4C-alkyl, or its salts.
3. A compound of the formula I as claimed in claim 1, in which RO is methyl or hydroxymethyl, R1 is methyl, R2 is chlorine, R3 is l-4C-alkoxy, R4 is hydrogen, is hydrogen and A is 0 (oxygen) or NH, or its salts.
4. 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 com- pounds of the formula II (see the attached formula sheet), in which RI, R2, R3, R4, R5 and A have the meanings indicated in claim 1, or b) for the preparation of compounds of the formula I in which RO is methyl, reacting compounds of the formula III (see the attached formula sheet), in which Ri and A have the meanings indicated in claim 1, with compounds of the formula IV (see attached formula sheet), in which R2, R3, R4 and R5 have the meanings indicated in claim 1 and X is a suitable leaving group, or c) for the preparation of compounds of the formula I in which RO is methyl, reacting compounds of the formula V (see attached 25 formula sheet), in which Rl, R2, R4, R5 and A have the meanings indicated in claim 1, with compounds of the formula VI (see attached formula sheet), in which R3 has the meanings indicated in claim 1 and Y is a suitable leaving group, and if desired then converting the compounds I obtained according to b) or c) into their salts, or if desired then liberating the compounds I from salts of the compounds I obtained.
5. A medicament containing a compound as claimed in claim 1 and/or a pharmacologically tolerable salt thereof together with customary pharmaceutical 15 auxiliaries and/or excipients.
6. A compound as claimed in claim 1 and its pharmacologically tolerable salts when used in the prevention and treatment of gastrointestinal 20 diseases.
7. The use of compounds as claimed in claim 1 and their pharmacologically tolerable salts for the production of medicaments for the prevention and treatment of gastrointestinal diseases. Dated this 13th day of November 1998 BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent Attorneys of Australia H:\Simeona\Keep\3166O 95.doc 13/11/98