WO1996003403A1

WO1996003403A1 - Benzyl-imidazopyridines

Info

Publication number: WO1996003403A1
Application number: PCT/EP1995/002952
Authority: WO
Inventors: Georg Rainer; Jörg Senn-Bilfinger; Gerhard Grundler; Richard Riedel; Stefan Postius; Wolfgang-Alexander Simon
Original assignee: Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date: 1994-07-28
Filing date: 1995-07-26
Publication date: 1996-02-08
Also published as: AU3166095A; JPH10505331A; AU700737B2; NZ290818A; EP0773944A1; CA2196077A1

Abstract

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

Description

Benzylimidazopyridines

Field of application of the invention

The invention relates to new benzylimidazopyridines 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. In EP-A-0033094, the residues phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl are mentioned as particularly interesting aryl residues, of which the residues phenyl, o- or p-fluorophenyl and 2,4,6-trimethylphenyl are particularly preferred. - In the European patent applications EP-A-0204285, EP-A-0 228006, EP-A-0268989 and EP-A-0308917 imidazo [1,2-a] pyridines are described which have one unsaturated in the 3-position ¬ termed aliphatic radical, in particular 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 is methyl or hydroxymethyl,

Rl 1-4C-alkyl,

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

R3 1-4C-alkoxy,

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 denotes 0 (oxygen) or NH, where R4 and R5 do not simultaneously denote hydrogen if R2 denotes 1-4C-alkyl, 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.

1-4C-Alkoxy stands for an oxygen atom to which one of the 1-4C-alkyl radicals mentioned above is bound. The methoxy radical is preferred.

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

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, ebonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a or multi-base acid and, depending on which salt is desired, be used in an equimolar or a different ratio. Compounds of formula I to be emphasized are those in which

RO methyl or hydroxymethyl,

Rl 1 -4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, chlorine or fluorine,

R3 1-4C-alkoxy,

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

R5 hydrogen and

A is 0 (oxygen) or NH, where R4 is not hydrogen if R2 is 1-4C-alkyl, and their salts.

Particularly noteworthy compounds of formula I are those in which

RO methyl or hydroxymethyl,

Rl methyl,

R2 chlorine,

R3 1-4C-alkoxy,

R4 is hydrogen,

R5 hydrogen and

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

Exemplary compounds according to the invention are listed in the following tables:

Table 1

Compounds of the formula I (see attached formula sheet) with R1-CH ₃ , A-0 (oxygen) and the following further substituent meanings:

RO R2 R3 IM R5

CH, HHO OCCHH33 5-CH ₃ H

CH, F F O OCHH33 H H

CH ₃ 0 OCCHH ₃ 3 O OCCHH3 HH

CH ₃ CCHH, ₃ , OOCCHH, 3 3-OCH3 H CH ₃ CCII O0CCHH ₃ , HH CH ₃ HH OOCCHH3, 3-CH, H Continuation of table 1:

RO R2 R3 R4 R5

CH ₃ CH, 0CH ₃ 5-CH ₃ H

CH ₂ 0H CH ₃ 0CH ₃ 5-C1 H

Table 2

Compounds of formula I (see attached formula sheet) with R1 = CH ,, A = NH and the following further substituent meanings:

RO R2 R3 R4 R5

CH ₃ 0CH ₃ 0CH ₃ HH

CH ₃ Cl OC ₂ H ₅ HH

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 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 the enclosed formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings given above , reduced, or that one

b) for the preparation of compounds of the formula I in which RO is methyl, compounds of the formula III (see the attached formula sheet), in which Rl and A have the meanings given above, with compounds of the formula IV (see attached formula sheet ), in which R2, R3, R4 and R5 have the meanings given above and X represents a suitable leaving group, or that

c) for the preparation of compounds of the formula I in which RO is methyl, compounds of the formula V (see attached formula sheet), in which R 1, R 2, R 4, R 5 and A have the meanings indicated above, with compounds of the formula VI (see attached formula sheet), in which R3 has the meanings given above and Y represents a suitable leaving group

and that, if desired, the compounds I obtained according to a), b) or c) 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. nie¬ their aliphatic alcohols, e.g. using suitable hydrides, such as sodium borohydride, if necessary with the addition of water.

The reaction of the compounds III with the compounds IV is carried out in a manner known per se to the person skilled in the art, for example using methods analogous to those described in European patent applications EP-A-0268989 or EP-A-0308917.

A suitable leaving group is, for example, a halogen atom (preferably chlorine or bromine) or a methanesulfonyloxy group. The implementation takes place advantageously in the presence of a base (for example an inorganic hydroxide, such as sodium hydroxide, or an inorganic carbonate, such as potassium carbonate, or an organic nitrogen base, such as triethylamine, pyridine, collidine or 4-dimethylaminopyridine), with the addition of catalysts, such as Alkali iodide or tetrabutylammonium bromide, the reaction can be favored.

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 as is customary for the production of aromatic urethanes, preferably by reaction of the compounds V with halogen formic 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). Examples of proton acceptors are 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 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, e.g. such 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 a 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 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 by alkalization, for example 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 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 has one suitable leaving group, e.g. represents a halogen atom (preferably chlorine or bromine), or using methods analogous to those described, for example, in European patent applications EP-A-0 268989 or EP-A-0308917.

The starting compounds III are known from European patent application EP-A-0299470, the starting compounds IV can be prepared in an analogous manner to that described in European patent application EP-A-0308917.

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 in turn can be prepared from the compounds III and corresponding nitro compounds corresponding to the compounds IV.

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 exemplify 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, 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. In game e

End products

1.8- (6-chloro-2-methoxycarbonv1 amino-benzylamino) -2-methyl1-imidazoπ .2-a1-pyridine-3-methanol

1.6 g of 8- (6-chloro-2-methoxycarbonylamino-benzylamino) - -methyl-imidazo [1,2-a] pyridine-3-carboxaldehyde and 0.16 g of sodium borohydride are dissolved in 100 ml of methanol at 40- Stirred 50 ^* C until the thin layer chromatogram shows complete conversion. It is concentrated in a rotary evaporator to about 20 ml, water is added and the mixture is cooled in an ice bath. It is filtered, washed with water and the precipitate is recrystallized from acetonitrile. 1.5 g (94%) of the title compound are obtained. M.p. 167-168'C (dec.).

The compounds of Examples 2-10 are prepared in an analogous manner, the amount of solvent and the temperature being able to be reduced in the case of more readily soluble derivatives.

2. 8- (6-fluoro-2-methoxycarbonylamino-benzylamino) -2-methv1-imidazori.2-al-pyridine-3-methanol. 155-156'C (from dichloromethane / petroleum ether).

3. 8- (2-methoxycarbonylamino-3-methyl-benzylamino) -2-methyl-imidazo-fK2-alpyridine-3-methanol. Mp 170-172'C under dec. (from toluene).

4. 8- (2-methoxycarbonylamino-5-methyl-benzylamino) -2-methyl-imidazo-π.2-alDyridine-3-methanol. M.p. 187-188'C (dec.).

5. 8- (2-methoxycarbonylamino-3.6-dimethyl-benzylamino) -2-methyl-imidazo π, 2-alpyridine-3-methano1. Mp 179-180'C (from Toiuol / diisopropyl ether).

6. 8- (3-methoxy-2-methoxycarbonylamino-6-methyl-benzylamino) -2-methylimidazofl, 2-alpyridine-3-methanol. 118-122'C (dec.).

7. 8- (6-chloro-2-methoxycarbonylamino-benzyloxy) -2-methyl-imidazoπ.2-al-pyridine-3-methanol. Mp 184-186'C under dec. (from acetonitrile). 8. 8- (6-methoxy-2-methoxycarbonylamino-benzylamino) -2-methyl-imidazo-π.2-alpyridine-3-methanol. M.p. 159-161'C.

9. 8- (6-fluoro-2-methoxycarbonylamino-benzyloxy1-2-methylimidazoπ.2-al-pyridine-3-methanol. Mp 175-176 ^β C (dec.).

10. 8- (2-methoxycarbonylamino-3,5-dimethyl-benzyloxy) -2-methyl-i idazo-π.2-alpyridine-3-methanol. Mp 155 "C with decomposition (from toluene / petroleum ether).

11. 8- (6-Chloro-2-methoxycarbonylamino-benzylamino) -2,3-dimethyl-imidazo-f1.2-alpyridine

A mixture of 1.98 g of 8-amino-2,3-dimethyl-imidazo [1,2-a] pyridine, 2.5 g of (3-chloro-2-chloromethyl-phenyl) carbamic acid, 2, 6 g of anhydrous sodium carbonate and 0.4 g of sodium iodide in 50 ml of acetone for 30 h at RT. The mixture is filtered while hot and a solution of 0.7 g of fumaric acid in 70 ml of acetone is added to the filtrate. The mixture is left to crystallize for 5 hours with stirring and cooling and the hemifumarate of the title compound (mp. 191-192'C, dec.) Is separated off. It is suspended in water / acetone and adjusted to pH 10 with dilute sodium hydroxide solution. Then it is shaken out with dichloroethane, concentrated in a rotary evaporator and the residue is recrystallized from ethyl acetate / petroleum ether. The title compound is obtained in 65% yield (mp. 146-147'C, dec.).

Output connections

A. (3-chloro-2-chloromethyl-phenyl) carbamic acid methyl ester

a. 100 ml of a 1 m solution of lithium aluminum hydride in tetrahydrofuran (H ₂ evolution) 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'C in 1 h. The mixture is stirred for a further 0.5 h, 6 ml of water, 6 ml of 15% 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, washed with ether and the filtrates are concentrated in vacuo one and crystalline siert the residue from petroleum ether (100 / 140'C). 9.6 g (61%) of 2-amino-6-chlorobenzyl alcohol of melting point 81-82 ^* C are obtained.

b. 4.41 ml of methyl chloroformate are added dropwise to 0-9 ° C. in 9 min to 9.0 g of the above compound and 4.6 ml of pyridine in 200 ml of dichloroethane, and the mixture is stirred for 2 hours in an ice bath. Organi¬ the specific solution is washed with water, treated with 50 ml of petroleum ether (100-140 ^* C), concentrated on a rotary evaporator to about 50 ml and obtains 11.5 g (93.4%) (3-chloro-2 -hydroxymethyl-phenyl) carbamic acid methyl ester of mp. 126-127'C.

c. It is added dropwise to 11.0 g of the above compound in 150 ml of dichloromethane, 3.9 ml of thionyl chloride and the mixture is stirred for a further 4 h at 35-40'C. 50 ml of petroleum ether (100 / 140'C) are added, the mixture is concentrated to approx. 50 ml on a rotary evaporator, the mixture is stirred for a further 2 h and washed with petroleum ether (40 ^* C). 10.6 g (88.8%) of the title compound of mp 136-137 * C are obtained.

B. (2-chloromethyl -3-fluorophenv1) carbamic acid methyl ester

a. Analogously to example Aa, 2-amino-6-fluorobenzoic acid and a melting point of 87-88'C are obtained in 81% yield from 2-amino-6-fluorobenzoic acid and lithium aluminum hydride.

b. Analogously to Example Ab, the above compound and methyl chloroformate are obtained in 92% yield (methyl 3-fluoro-2-hydroxymethylphenyl) carbamic acid, melting point 92-94'C.

c. Analogously to Example Ac, the title compound of mp 113-114'C is obtained from the above compound and thionyl chloride in 92% yield.

C. (2-Chloromethyl-6-methylphenyl) carhamidic acid methyl ester

Analogously to Example A, 2-amino-3-methylbenzyl alcohol and chloroformic acid methyl ester (2-hydroxymethyl-6-methylphenyl) carboxylic acid methyl ester of mp 90-9TC and further therefrom with thionyl chloride gives the title compound of mp 115-116'C . D. (2-chloromethyl -4-methylphenyl) carbamic acid methyl ester

Analogously to Example A, 2-amino-4-methylbenzyl alcohol and methyl chloroformate are obtained after chromatography on silica gel with ethyl acetate (2-hydroxymethyl-4-methylphenyl) carbamic acid ethyl ester as an oil and further therefrom with thionyl chloride the title compound of mp 126 -127'C (from diisopropyl ether).

E. (2-chloromethyl-3,6-dimethylphenyl carbamic acid methyl ester

a. 0.36 ml of methyl chloroformate in 2 ml of dichloromethane is added dropwise to 0.70 g of 2-amino-3,6-dimethylbenzyl alcohol and 0.37 ml of pyridine in 20 ml of dichloromethane in 20 min at 0-5'C in 20 min , 5 h, wash 3 times with water, dry the solution and concentrate in vacuo. The remaining oil is brought to crystallization with diisopropyl ether and petroleum ether (40'C). 0.79 g (82%) (2-hydroxymethyl-3,6-dimethylphenyl) carbamic acid methyl ester of mp 94-95 ^* C. is obtained.

b. 0.25 ml of thionyl chloride is added dropwise to 0.75 g of the above compound in 20 ml of dichloromethane at 0-5'C, the mixture is stirred for a further 15 min, concentrated in vacuo, chromatographed on silica gel using ethyl acetate and crystallized from diisopropyl ether. 0.52 g of the title compound of mp 127-128 ^* C is obtained.

F. (2-Chloromethv1-6-methoxy-3-methylphenyl) carbamic acid methyl ester

a. 15 g of 7-methoxy-4-methylindole-2,3-dione (Houben-Weyl VI1 / 4, 17) and 150 ml of 10% sodium hydroxide solution are heated to 100 ° C. and 75 ml of 30% hydrogen peroxide solution are added dropwise in 30 minutes. The mixture is stirred for a further 15 min at 100 ° C., adjusted to pH 4 with half-concentrated hydrochloric acid and the aqueous solution is extracted with isopropyl acetate. The organic solution is dried and concentrated, and the residue is chromatographed on silica gel with ethyl acetate / isopropanol (4: 1). 1 g of 2-amino-3-methoxy-6-methylbenzoic acid of mp. 118-120'C (decomp.) Is obtained after rubbing with petroleum ether. b. 0.85 g of the above compound is reduced in 10 ml of tetrahydrofuran with 11.7 ml of 1 M lithium aluminum hydride in tetrahydrofuran as in Example Aa). This gives 0.64 g (82%) of 2-amino-3-methoxy-6-methylbenzyl alcohol mp. 70-72 ^* C, crystallized from petroleum ether (50 / 70'C).

c. By reaction of the above compound analogously to Example Ea, after crystallization from petroleum ether (50 / 70'C), methyl (2-hydroxymethyl-6-methoxy-5-methylphenyl) carbamate of mp 89-93'C is obtained in 89% yield.

d. By reacting the above compound analogously to Example Ec, after concentration on a rotary evaporator, the title compound is obtained as a crude product which is used directly in Example Ie.

6. (2-Chloromethyl-3-methoxyphenyl) carbamic acid methyl ester

a. A mixture of 10 g of 2 - [(2,2-dimethyl-l-oxopropyl) - amino] -6-methoxybenzoic acid (J.Org.Chem. 50, 718, 1985), 20 ml of water and 45 ml of concentrated sulfuric acid is heated 8 C, to ice and, with sodium bicarbonate to pH 5. It is extracted pylacetat h at 70 ^* with isopropyl, and the organic solution is concentrated in vacuo and crystallized from Toiuol / petrol (40'C) to. 4.6 g (69%) of 2-amino-6-methoxybenzoic acid, mp. 79-81 ^* C., are obtained.

b. Reducing the foregoing compound analogously to Example Fb and receives in 55% yield 2-amino-6-methoxybenzyl alcohol mp. 59-60'C (from diisopropyl ether / petroleum ether (40 ^* C)).

c. By reacting the above compound analogously to Example Ea with methyl chloroformate, methyl (2-hydroxymethyl-3-methoxyphenyl) carbamate of mp 94.5-96'C is obtained.

d. The title compound of mp 131-133'C (from diisopropyl ether) is obtained from the above compound analogously to Example Ab with thionyl chloride in 84% yield. H. 8- (6-chloro-2-methoxycarbonylamino-benzylamino) -2-methyl-imidazoπ.2-al-pyridine-3-carboxaldehvd

A mixture of 1.2 g of 8-amino-2-methylimidazo [1,2-a] -pyridine-3-carboxaldehyde and 1.7 g of (3-chloro-2-chloromethyl-phenyl) carbamide acid methyl is stirred - ester, 1.5 g of fine-grained anhydrous sodium carbonate and 0.2 g of sodium iodide in 40 ml of acetone for 7 hours at 50'C. 60 ml of ice / water are added, then glacial acetic acid to pH 7.5 and stirring is continued for 30 min. It is filtered, washed with water, dissolved in 300 ml of isopropyl acetate, dried with magnesium sulfate and clarified with activated carbon. Then concentrate to about 80 ml and cool in ice. 1.8 g (76%) of the title compound of mp 194-196'C are obtained.

I. By reaction analogous to Example H of 8-amino-2-methyl-imidazo [1,2-a] - pyridine-3-carboxaldehyde

(2-chloromethyl-3-fluorophenyl) carbamic acid methyl ester, (2-chloromethyl-6-methylphenyl) carbamic acid methyl ester, (2-chloromethyl-4-methylphenyl) carbamic acid methyl ester, (2-chloromethyl-3,6-dimethylphenyl) carbamic acid methyl ester, (2 -6-methoxy-3-methylphenyl) carbamic acid methyl ester and (2-chloromethyl-3-methoxyphenyl) carbamic acid methyl ester are obtained

a. 8- (6-Fluoro-2-methoxycarbonv1amino-benzylamino) -2-methy1-imidazoπ.2-al-pyridine-3-carboxaldehvd. Mp 142-144'C (from diisopropyl ether after chromatography on silica gel with ethyl acetate).

b. 8- (2-methoxycarbonylamino-3-methylbenzylamino) -2-methylimidazo-f1.2-alpyridine-3-carboxaldehvd. 195-196 ^* C under dec. (from toluene / petroleum ether).

c. 8- (2-methoxycarbonylamino-5-methyl-benzylamino) -2-methyl-i idazo-π.2-a1pyridine-3-carboxaldehvd. Mp 144-146'C (from toluene / petroleum ether after chromatography on silica gel with ethyl acetate).

d. 8- (2-Methoxycarbonylamino-3,6-dimethv1-benzylamino) -2-methyl-i idazone-2-alpyridine-3-carboxaldehvd. Mp 170-170.5 ^* C (from toluene / petroleum ether after chromatography on silica gel with ethyl acetate). e. 8- (3-methoxy-2-methoxycarbonylamino-6-methyl-benzylamino) -2-methyl-imidazo [1,2-alpyridine-3-carboxal ehyd. Mp 176-178'C (from toluene / petroleum ether after chromatography on silica gel with ethyl acetate).

f. 8- (6-methoxy-2-methoxycarbonylamino-benzylamino) -2-methyl-i idazo-π.2-alpyridine-3-carboxaldehvd. 146-149'C (from toluene after chromatography on silica gel with ethyl acetate).

K. By reaction analogous to Example H of 8-hydroxy-2-methyl-imidazo [1,2-a] pyridine-3-carboxaldehyde

(3-Chloro-2-chloromethyl-phenyl) carbamic acid methyl ester, (2-chloromethyl-3-fluorophenyl) carbamic acid methyl ester and (2-chloromethyl-3,6-dimethylphenyl) carbamic acid methyl ester are obtained

a. 8- (6-chloro-2-methoxycarbonylamino-benzyloxy) -2-methyl-imidazof1.2-al-pyridine-3-carboxaldehvd. Mp 233-234 ^* C (from acetonitrile).

b. 8- (6-fluoro-2-methoxycarbonylamino-benzyloxy) -2-methyl-imidazof1.2-al-pyridine-3-carboxaldehvd. 214-216 ^* C (from toluene / petroleum ether).

c. 8- (2-methoxycarbonylamino-3,6-dimethyl-benzyloxy) -2-methyl-imidazo-π.2-a1pyridine-3-carboxaldehvd. Mp 171-172'C (after chromatography on silica gel with ethyl acetate).

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 substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, colorants or in particular performance promoters and complexing agents (e.g. cyclodextrins) can be used.

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

In general, it has proven advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 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. Bieta iverin, Camylofin, Anticholinergica, such as e.g. Oxyphencycl i in, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.

In this connection, the combination of the compounds according to the invention with Phar aka which inhibit acid secretion, such as, for example, H ₂ blockers (for example cimetidine, ranitidine), H ⁺ / K ⁺ -ATPase inhibitors (for example omeprazole, pantoprazole), or should be emphasized in particular furthermore with 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 effective substances (such as cephalosporins, tetracyclines, nalidixic acid, penicillins or bismuth salts) for combating 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.

97

methodology

After tracheotomy, anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened by a median upper abdominal incision and a PVC catheter transorally in the esophagus and a white ¬ fixed via 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; ψ = 5 mm, Metrohm) and the titration with a freshly prepared 0.01 N NaOH to pH 7 (Dosimat 665 Metrohm) were measured in the effluate collected every 15 minutes. the secreted HC1 determined.

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 kept at a constant 37.8-38 ^* C by infrared radiation and heating pad (automatic, stepless regulation via rectal temperature sensor).

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

Claims

claims

1. Compounds of formula I.

(I)

wherein RO is methyl or hydroxymethyl, Rl 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl, R3 1-4C-alkoxy,

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 0 (oxygen) or NH, where R4 and R5 are not at the same time mean hydrogen when R2 is 1-4C-alkyl, and their salts.

2. Compounds of formula I according to claim 1, in which

RO methyl or hydroxymethyl,

Rl 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, chlorine or fluorine,

R3 l -4C-alkoxy, R4 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,

R5 hydrogen and

A is 0 (oxygen) or NH, where R4 is not hydrogen if R2 is 1-4C-A1 yl and their salts.

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

Rl methyl,

R2 chlorine,

R3 1-4C-alkoxy,

R4 is hydrogen,

R5 hydrogen and

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

4. 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 the enclosed formula sheet), in which R 1, R 2, R 3, R 4, R 5 and A have the meanings given in claim 1 , reduced, or that one

b) for the preparation of compounds of the formula I in which RO is methyl, compounds of the formula III (see the attached formula sheet), in which Rl and A have the meanings given in claim 1, with compounds of the formula IV (see enclosed formula sheet), wherein R2, R3, R4 and R5 have the meanings given in Claim 1 and X represents a suitable leaving group, or that

c) for the preparation of compounds of the formula I in which RO is methyl, compounds of the formula V (see attached formula sheet), in which R 1, R 2, R 4, R 5 and A have the meanings given in claim 1, with compounds of the formula VI (see attached formula sheet), in which R3 has the meanings given in claim 1 and Y represents a suitable leaving group and that, if desired, the compounds I obtained according to a), b) or c) are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained.

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

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

7. 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.