AT390438B - Novel imidazo(1,2-a)pyridine derivatives and their preparation and pharmaceutical preparations containing them - Google Patents

Abstract

Novel imidazo(1,2-a)pyridine derivatives and their pharmaceutically acceptable salts which have an H+,K+ adenosine triphosphatase-inhibitory effect and which are useful as prophylactic and therapeutic active substances for gastric disorders are described. Also indicated are pharmaceutical preparations which contain these compounds, and processes for preparing these compounds. The compounds have the general formula I. <IMAGE>

Description

No. 390 438

The present invention relates to new imidazo [1,2-a] pyridine derivatives of the general formula (1) below and their pharmaceutically acceptable salts. The compounds of the invention have an H +, K + adinosine triphosphatase inhibitory activity and are useful as prophylactic and therapeutic agents for gastric diseases.

The invention further relates to pharmaceutical preparations containing the compounds according to the invention.

Finally, the invention also relates to processes for the preparation of the compounds according to the invention.

The compounds according to the invention have the general formula (I) O-R 1

(D

In this formula means an alkyl group having 4 to 6 carbon atoms or an alkyl group having 1 to 10 carbon atoms, which is optionally substituted by a cycloalkyl group. R represents a hydroxy group, a lower alkoxycarbonyl group, a lower alkyl group which may be substituted by a hydroxy group, a lower alkoxy group or a lower alkoxycarbonyl group, a phenyl group which may be substituted by a lower alkoxy group, or a lower acyloxyalkyl group which may be substituted by a low acyloxy group. R ^ represents hydrogen, a lower alkyl group, a lower haloalkyl group, a lower alkoxyalkyl group, a hydroxy lower alkyl group, a cyano lower alkyl group, a mono- or di-lower alkylamino lower alkyl group, an amino group, a Mono- or di-lower alkylamino group, a nitroso group, a lower alkoxycarbonyl group, a lower acylamino group, a lower alkylsulfunoylamino group, a group of the formula

-CH wherein D is NH or sulfur, E, nitrogen or CH, and R ^ and R ^ have the same or different meanings and hydrogen can be a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, a group of the formula

-ch2l 2 \ nh2 where X is oxygen, sulfur or N-R ^, where is a sulfamoyl group, a lower acylamino group or a lower alkynyl group, or a group of the formula -2-

No. 390 438 -ch2-y-r8 where Y is oxygen or sulfur and R8 is a cyano-lower alkyl group or a lower alkynyl group 5 is 8-aralkyl (or aryl) oxyimidazo [1,2-a] pyridines which may be attached to the Phenyl group are disclosed in European patents 33094 and 68378. It is described that these pyridines are useful anti-secretion agents and cell protection agents.

The compounds of the present invention are new compounds which have different substituents from these known compounds and which have an excellent H *, K * adenosine triphosphatase inhibitory activity.

In the present context, the term &quot; low &quot; a straight or branched carbon chain of up to 6 carbon atoms unless otherwise stated. Accordingly, a lower alkyl group means a straight or branched alkyl group of 1 to 6 carbon atoms. Examples of lower 15 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2- Dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2- Trimethylpropyl, 1,2,2-trimethylpropyI, l-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl etc. 20 Lower alkoxy groups are straight or branched alkoxy groups with 1 to 6 carbon atoms, examples are: methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and isohexyloxy and the like. the like

A lower alkynyl group is a straight or branched alkynyl group with 2 to 6 carbon atoms. Examples are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 25 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3rd -Methyl-l-butynyl, 2-methyl-3-butynyl, l-methyl-2-butynyl, l-methyl-3-butynyl, l, l-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3rd -Hexynyl, 4-hexynyl, 5-hexynyl, etc.

As the alkyl group of the substituent R1, a straight or branched alkyl group having 1 to 10 carbon atoms is preferred. Examples of the alkyl group are, in addition to the above-mentioned examples of the lower alkyl group, heptyl, 5-methylhexyl, l-methylhexyl, 3-ethylpentyl, 2-propylbutyl, octyl , 30 6-methylheptyl, nonyl, 7-methyloctyl, decyl, 8-methylnonyl etc.

Preferred examples of alkenyl groups with 4 to 6 carbon atoms are 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2,2-dimethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 4-methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, 4-methyl-35 4-pentenyl 3-methyl-2-pentenyl, etc.

Groups with 3 to 6 carbon atoms are preferred as the cycloalkyl group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

As the acyl group of acyloxy or acyl-lower alkyl groups, a lower alkanoyl group and an arylcarbonyl group, in particular a straight-chain or branched alkanoyl group with 2 to 40 6 carbon atoms, or the benzoyl group are preferred. Examples of the alkanoyl group are acetyl,

Propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. the like

Alkyl groups with a lower alkoxy or a cycloalkyl substituent are groups in which any water surge in the alkyl group described above is substituted by a lower alkoxy group or a cycloalkyl group. Representative examples of the lower alkoxy substituted alkyl group are 45 methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, Äthoxypropyl, Äthoxybutyl, Äthoxypentyl, propoxymethyl, Propoxyäthyl, propoxypropyl, propoxybutyl, propoxypentyl, isopropoxymethyl, Isopropoxyäthyl, isopropoxypropyl, Isopropoxybutyl, Isopropoxypentyl, Isopropoxyhexyl, butoxymethyl, Butoxyäthyl, butoxypropyl, butoxybutyl, isobutoxymethyl, Isobutoxyäthyl, Isobutoxypropyl, isobutoxybutyl, etc. Specific examples of cycloalkyl-substituted alkyl groups are 50 cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclope ntylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, cyclohexylhexyl etc.

A lower alkoxy-substituted phenyl group is a group in which the water atom in the ortho, 55 para or meta position of the phenyl group is substituted by one of the lower alkoxy groups described above. Preferred examples are ortho- or para-methoxyphenyl, ethoxyphenyl, Propoxyphenyl and isopropoxyphenyl groups.

Preferred halogen atoms are fluorine, chlorine and bromine.

Thus, a halogen-substituted lower alkoxy group is a group in which any one to three arbitrary 60 hydrostatic atoms in one of the lower alkyl groups described above is (are) substituted by one or more of the above halogen atoms. Taking chlorine as an example, examples of these are -3-

No. 390 438

Groups chloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, l-chloropropyl, 2-chloropropyl, 3-chloropropyl, 2-chloro-2-methylethyl, 1-chlorobutyl, 2-chlorobutyl, 3-chlorobutyl, 4-chlorobutyl , 5-chloropentyl, 6-chlorohexyl etc.

A hydroxy lower alkoxy group is a group in which any hydrogen atom of one of the lower alkyl groups described above is substituted by a hydroxy group. Examples are straight-chain or branched hydroxyalkyl groups with 1 to 6 carbon atoms, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-l-methylethyl, 2-hydroxy-1-methylethyl , 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, l-hydroxy-2-methylpropyl, 2-hydroxy 2-methylpropyl, 3-hydroxy-2-methylpropyl, 1-hydroxypentyl, 2-hydroxypentyl, 3- Hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxy-4-methylpentyl, etc.

Examples of cyano-substituted lower alkyl groups are cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, 3-cyanopropyl, 1-cyano-l-methylethyl, 2-cyano-l-methylethyl, 1-cyanobutyl, 2-cyanobutyl, 3-cyanobutyl, 4-cyanobutyl, 1-cyano-l-methylpropyl, 2-cyano-l-methylpropyl, 3-cyano-l-methylpropyl, l-cyano-2-methylpropyl, 2-cyano-2- methylpropyl, 3-cyano-2-methylpropyl, 1-cyanomethylpropyl, 1-cyanopentyl, 2-cyanopentyl, 3-cyanopentyl, 4-cyanopentyl, 5-cyanopentyl, l-cyano-3-methylbutyl, 2-cyano-3-methylbutyl, 1-cyanomethylbutyl, 1-cyanohexyl, 2-cyanohexyl, 3-cyanohexyl, 4-cyanohexyl, 5-cyanohexyl, 6-cyanohexyl, etc.

A mono- or di-lower alkylamino group is a group in which one or two hydrogen atoms of an amino group is substituted by one of the lower alkyl groups described above. Examples are mono-alkylamino groups with a 1 - 6 straight or branched alkyl group with 1 to 6 carbon atoms, such as methylamines, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino and hexylamino. Symmetrical dialkylamino groups with straight-chain or branched alkyl groups with 1 to 6 carbon atoms, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino and dihexylamino. Asymmetric dialkylamino groups with different straight-chain or branched alkyl groups with 1 to 6 carbon atoms, such as ethylmethylamino, methylpropylamino, ethylpropylamino, butylmethylamino, butylethylamino and butylpropylamino.

A mono- or di-lower-alkylamino-substituted lower alkyl group is a group in which at least any hydrogen atom of one of the lower alkyl groups described above is substituted by one of the mono- or di-lower-alkylamino groups described above. Taking the diethylamino group as an example, examples are diethylaminomethyl, 2- (N, N-diethylamino) ethyl, 3- (N, N-diethylamino) propyl, 4- (N, N-diethylamino) butyl, 5- (N , N-diethylamino) pentyl 6- (N, N-diethylamino) hexyl, etc. However, these groups are not limited to those substituted with the diethylamino group. As examples of lower alkoxycarbonyl groups, there can be mentioned monovalent groups which are obtained by esterification between a straight-chain or branched alcohol having 1 to 6 carbon atoms and a carboxy compound, such as, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl , Isopentyloxycarbonyl, neopentyloxycarbonyl, terL-pentyloxycarbonyl, and hexyloxycarbonyl.

Some compounds of the present invention have stereo isomers such as optical isomers, tautomers, etc.

The present invention also includes pure isomers and mixtures thereof.

The compounds of the general formula I can also form salts. The present invention also encompasses the salts of the compounds of the general formula I, in particular their pharmaceutically acceptable salts.

Examples of such salts are acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and with organic acids such as formic acid, acetic acid, oxalic acid, citric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, methanesulfonic acid and ethanesulfonic acid. Depending on the substituents of the compound of general formula I, these can also form salts with bases such as sodium, potassium and quaternary ammonium salts with halogenated, lower alkyl groups.

The compounds of the present invention can be prepared in various ways. Representative examples of the methods are given below. All processes according to the invention optionally also include the step of converting the product into a salt and reversing it -4-

No. 390 438

there)

Process I;

In this formula, the substituents have R * and the meanings given above. R a represents a halogen, a lower alkoxycarbonyl group, a lower alkyl group which may be substituted by a lower alkoxycarbonyl group or a phenyl group which may be substituted by a lower alkoxy group. R ^ a represents hydrogen, a lower alkyl group, a cyano-lower alkyl group or a lower alkoxycarbonyl group. X represents halogen or an organic sulfonic acid residue

The compounds of the general formula Ia can be prepared by reacting amino-substituted pyridyl ethers of the general formula II with compounds of the general formula III. In the reaction scheme given above, examples of the halogen X are iodine, bromine, chlorine, etc. Examples of the organic Sulfonic acid residues are alkanesulfonic acid residues such as the methanesulfonyloxy and ethanesulfonyloxy group etc., and aromatic sulfonic acid residues such as benzenesulfonyloxy and toluenesulfonyloxy groups etc.

The reaction can advantageously be carried out by using the compounds II and III either in approximately equimolar amounts or with a slight excess of compound II or compound ΠΙ in an inert solvent, preferably in the presence of a base at room temperature or with heating, preferably with heating Reflux cooling. As an inert, organic solvent, ether, benzene,

Toluene, xylene and the like. Like. Be used with advantage when R a is halogen. If R a has a meaning other than halogen, an alcohol such as methanol, ethanol, isopropanol or the like or benzene, toluene, xylene or the like is advantageously used.

If a base is used, it is preferred to use trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc.

Procedure 2:

O-R1 O-R1

-5-

No. 390 438

In this formula scheme has the meaning given above. R ^ b is a lower alkyl group, R ^ b means a group which can be converted into a hydroxy-lower alkyl group or an amino group by reduction. R ^ b represents a hydroxy lower alkyl group, a cyano lower alkyl group or an amino group.

The compounds of the present invention represented by the general formula Ib or I'b can be prepared by reducing the compounds represented by the general formula IV or IV.

As a group which can be converted into a hydroxy-lower alkyl group by reduction, nicdrig-alkoxycarbonyl-lower alkyl groups (C3 to C ^) or a hydroxy-lower alkyl group in which the hydroxy group is protected can be mentioned. As a protecting group for the hydroxy group, benzyl, p-methoxybenzyl and benzyloxycarbonyl groups, protecting groups of the acetal type, acelyl and benzoyl groups and the like. Like. Be mentioned.

As a group which can be converted into a cyano-nicdrigalkyl group by reduction, the (C1 -Cg-alkylJC ^ NC ^ groups which

NC, CH - (Cj-Cg alkyl) groups CH3S ', etc. may be mentioned.

As a group which can be converted into an amino group by reduction, there can be mentioned the cyano, nitro, Nilroso and protective amino groups similar to those described above.

The reduction of these compounds can be mentioned by catalytic reduction in the presence of various catalysts by chemical reduction with various hydrides or metals and acids or liquid ammonia and metallic sodium or the like and a reductive dehydration carried out by phosphorus trichloride in pyridine.

In order to reduce the protective group, for example a hydroxyl or amino group, in order to remove it, a catalytic reduction using palladium-carbon as a catalyst is advantageously used in a conventional manner.

In order to reduce a lower alkoxycarbonyl group into the hydroxymethyl group, the reaction with lithium aluminum hydride in an organic solvent such as ether, dioxane, tetrahydrofuran is preferred. The reaction can be conveniently carried out under anhydrous conditions in an inert gas atmosphere.

In order to convert a nitro or Nilroso group or the like into an amino group, it is advantageous to carry out a catalytic reduction using palladium-carbon, Raney nickel, palladium-bog, etc. as the catalyst. Another group of the formula

CN

-CH ^ SCH to convert to a cyanomethyl group, a catalytic reduction in which Raney nickel or the like is used as a catalyst is preferred. In order to convert a nitromethyl group to a cyano group, it is advantageous to use reductive dehydration by reaction with phosphorus trichloride in pyridine. A chemical reduction with lithium aluminum hydride is suitable for the reduction of a cyano group to an aminomethyl group.

If there are two or more substituents that need to be reduced, these reductions can be carried out by reducing all of the substituents either simultaneously or in stages by selecting the conditions accordingly. A suitable choice of conditions can also reduce some or some of the subscribers. -6-

No. 390 438 .VgrfatygnJ;

halogenating aoens, (ic) 1 0-R ~ i

&gt; (id)

In this Foimel scheme, R1 2 has the meaning given above. R ^ c represents a lower alkyl group or a phenyl group which may be substituted by a lower alkoxy group. R ^ c means a hydroxy-nicdrig-alkyl grappc. R ^ d means a Halogcnonicdrig-alkyl group.

Of the compounds according to the invention, the imidazopyridine derivatives (Id) in which the 3-position is a halogeno-nicdrig alkyl group can be prepared by reacting a halogenating agent with the corresponding compound (Ic) containing a hydroxy-lower alkyl group .

As the halogenating agent, there can be mentioned: hydrogen halides such as hydrogen fluoride, hydrogen bromide, etc .; Thionyl halides such as thionyl chloride, etc .; Alkali halides such as sodium bromide, etc .; Phosphorus halides, phosphorus oxyhalides, triphenylphosphonate alkali halides, triphenylphosphine tetrachloromethane, triphenylphosphine dihalides, diphenyltrihalophosphoranes, triphenylphosphonate dihalides, sulfonyl halides, sulfonium halides, etc.

The reaction changes depending on the starting compounds, the desired compounds and the type of halogenation ice cream. For example, if thionyl halides, such as thionyl chloride, or thionyl bromide are used as halogenating agents, it is preferred to use a primary or secondary alcohol as the starting compound. The reaction can be carried out by mixing one of the compounds (Ic) or a salt thereof with the halogenating agent in almost equimolar amounts or with an excess of one of the compounds, preferably in the absence of a solvent or in an organic solvent such as methylene chloride, ether, dioxane , Tetrahydrofuran with cooling or at room temperature. Depending on the reaction conditions, it may be appropriate in some cases to carry out the reaction in the presence of amines such as pyridine, etc.

Method 4: O-R1 O-R1

Ci ^ 2 cyano group-forming agent R3e or dehydrating agent (V) (Ie) -7- 1 *) 2

In this reaction scheme, R has the meaning given above. R e represents a lower alkyl group which may be substituted by a lower alkoxy group or a phenyl group which may be substituted by a lower 3

Alkoxy group can be substituted. R ^ means a residue that is in a cyano-lower alkyl group

No. 390 438 can be converted. R ^ e represents a cyano lower alkyl group.

The compounds of the general formula (Ie) according to the invention which contain a cyano group can be prepared by reacting cyano group-introducing agendas or dehydrating agendas with the compounds of the general formula V.

As the radical which can be converted into the cyano-lower alkyl group, there are atoms or groups corresponding to cyano, hydrogen, halogen, an organic sulfonic acid base and trialkylsilyl, lower alkoxy, phenoxy, trialkylammonium, carbamoyl, formyl, lower alkoxycarbonyl, carboxy, aminomethyl , Aminocarboxymethyl,

JCOOH (-CH), nh2 and hydroxyiminomethyl (-CH = N-OH) groups etc.

Methods for converting these residues into the cyano group include nucleophilic substitution, dehydration, oxidation and the like. Like., With which the agent forming the cyano groups changes in the respective reaction. For example, in the nucleophilic substitution, alkali metal cyanides such as sodium cyanide, potassium cyanide, metal cyanides such as silver cyanide, copper cyanide, cyano-coordinated transition metal complexes and the like. Like., Cyanic acid, etc. can be used. A dehydrating agent is used in the formation of the cyano group by dehydration of an amide or the hydroxyiminomethyl group. The above-mentioned cyanogen-forming agent is also said to include a dehydrating agent. As a dehydrating agent in such a reaction, phosphorus oxyphide, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, trifluoroacetic anhydride, triphenylphosphine, tris (triphenylphosphine) chlororrhodium, phosphonitrile chloride, thionyl chloride, phosgene, aluminum chloride, dodecylimidyl chloride, dicyclimyl chloride, dicyclimidyl chloride, dicyclimyl chloride, Trichlorotriazine, etc. can be used.

The aldehyde and carboxy are reacted with hydroxylamine or amine to form the oxime or amide which is reacted with the dehydrating agent described above to form the cyano group.

Methods of forming the cyano group by oxidation include reacting with an aminomethyl compound in the presence of lead tetraoxide or nickel peroxide, reacting sodium hypochlorite, hypobromite or N-bromosuccinimide with an amino acid salt, and reacting with a primary alcohol or aldehyde together with nickel / alumina, Cuprichloride or the like in the presence of ammonia. These agents are defined by the term &quot; cyano group-introducing agent &quot; subsumed

The reaction conditions change depending on the agent introducing cyano groups, the starting compounds and the desired compounds. For example, when the residue corresponding to the cyano group is an atom or a group such as halogen, an organic sulfonic acid residue or the like which is split off by substitution, cs is advantageous to use a compound of the general formula V with an equimolar or excess amount of the alkali metal cyanide based on the compounds V, in an inert, organic solvent, such as dimethyl sulfoxide, dimethylformamide, etc., with cooling or at room temperature, preferably in an inert gas atmosphere, under anhydrous conditions.

When the residue corresponding to the cyano group is a group such as an amide, an oxime or the like, which is converted into the cyano group by dehydration, it is advantageous to use a compound of the general »! React Formula V in an organic solvent such as benzene, toluene, xylene, mesitylene, pyridine, chloroform, dichloromethane, dichloroethane, etc. with the above-described dehydrating agent in an amount slightly larger than the theoretical amount.

The oxidation can be carried out by using the oxidizing agent described above in an organic solvent such as an alcohol, e.g. B. methanol, ethanol or the like. Benzene, toluene, xylene, dichloromethane, dichloroethane, etc. is implemented. -8th-

No. 390 438

Procedure 5:

In this reaction scheme has the meaning given above. R ^ g is a lower alkyl group or a phenyl group which may be substituted by a lower alkoxy group. R ^ represents an alkali metal, hydrogen or a lower alkyl group. The compounds of the invention which have a nitroso group in position 3 can be prepared by the imidazopyridine derivatives (IQ &gt; which have hydrogen in position 3) with a nitroso agent (VI) such as nitrous acid or a lower ester of nitrous acid, etc. implemented, manufactured.

The reaction is carried out by mixing the compounds (10 with the compounds (VI) in an equimolar amount or in an amount based on (10 excess) either in an organic solvent such as ether, dioxane, tetrahydrofuran, acetic acid or the like or in Hydrochloric acid is reacted at room temperature or with heating.

Procedure 6:

1 9

In this reaction scheme, R has the meaning given above. R f represents a lower alkyl group. M means an alkali metal.

The compounds of the general formula (Ih) according to the invention can be prepared by reacting the amino-substituted pyridine ethers of the general formula (II) with aldehydes (VII) and alkali metal cyanides (VIII).

Examples of alkali metals M in the above reaction scheme are sodium, potassium, lithium, etc.

It is advantageous if the reaction of the compounds (II), (VII) and (VIII) in equimolar amounts or slightly excess amounts of (VI0 and (VIII), in water as a solvent and in the presence of sodium bisulfite at room temperature or with heating is preferably carried out with heating under reflux.

Other procedures:

Further compounds according to the invention can be prepared by further converting the substituents in the compounds described above. 9 o

The conversion of the substituents R or RJ which has not been described previously can be carried out as described below. -9-

No. 390438 a) Compounds which contain the cyano-lower alkyl group can, for example, be further converted in accordance with the reaction scheme below to prepare other compounds according to the invention:

O-R

CH2CN

HCl-EtOH

H2S

KL · R T-X H /

O-R 2 -NH2 OII CH 3CNHNH2 ^ NH .N ^ CH2CC0Et

HC = CCH2NH2

O-R

^ “7cH2c 9 '^ NNECCH.

CH2C <; NCH2C EC: H2NCH2CH (OEt) 2

i u II

CH3CCH2Ci 'V

O-R

CK3 ψ

O-R &quot;

Η2-ν · Ν -10-

No. 390 438 b) By N-alkylation of the compounds containing an amino group, other compounds which contain a mono- or di-lower alkylamino group can be prepared. c) By reacting the compounds containing a halogeno-lower alkyl group with thiohamstoffF and then reacting them with alkalis and alkyl halides, compounds can be prepared which contain a lower alkyl group which are substituted with SR **. R ** represents a cyano-nicdrigc-alkyl group or a lower alkynyl group. d) By reacting the compounds containing a halogeno-lower alkyl group with lower metal alcoholates, compounds can be obtained which contain a lower alkyl group which are substituted with a lower alkoxy group. e) By reacting compounds containing a hydroxy lower alkyl group with lower acyl halides, which may be substituted with a lower acyloxy group, compounds can be prepared which contain a lower acyloxyalkyl group, which is optionally substituted with a lower acyloxy group. f) By carrying out the Mannich reaction on compounds which have hydrogen in the imidazole ring, compounds can be prepared which contain a di-lower alkylaminomethyl group. These compounds can also be reacted with lower alkyl halides to produce the quaternary ammonium salts of the compounds. g) By reacting compounds containing an amino group with low acyl halides or halosulfonic acid-low-alkyiestem, compounds can be prepared which contain a low-acylamino or a nicdrig-alkylsulfonylamino group.

The compounds of the present invention, which have been prepared by the processes described above, can be separated off by conventional chemical processes such as extraction, crystallization, recrystallization, column chromatography, etc. and presented in pure form.

The compounds of the general formula (I) and their salts according to the invention have an activity which inhibits the acidic acid protection, an activity which protects the gastric mucous membrane (cytoproleclive activity) and an activity against ulcers. The compounds according to the invention are useful as preventive and therapeutic agents for gastric diseases, e.g. B. as active ingredients for inhibiting gastric acid secretion or as a prophylactic and treatment agent for gastric ulcers.

The activity of the compounds according to the invention in inhibiting gastric acid secretion and the activity against ulcers was confirmed by the inhibitory activity (IC ^ q, 50% inhibitory concentration) against H +, K + adenosine triphosphatase (see Biochimica et Biophysica Acta, 728.31-38 (1983))

The gastric acid secretion inhibiting activity was further confirmed by the experiment below.

Six male beagles (13-17 kg) with well-developed Heidenhain pockets were used to plot gastric acid secretion response curves. No food was given 18 hours before each experiment, but water was allowed. One hour after drug administration, histamine (60 pg / kg / hour) was administered subcutaneously. The pocket secretion was drained into a collection jar which was replaced every 15 minutes. The volume of gastric juice was recorded and the acid concentration determined by titration with 0.05 N NaOH up to pH 7.0, using an automatic titrator (Hiranuma Sangyo Co., COMTITE-7).

The results obtained are summarized in the following table:

Compound Table: H +, K + -ATPase gastric acid inhibition known compound A Hcmmaktiviläl IC50 (M) (%) pocket dog 3 mg / kg p.o. ° CH2-Ö fYlf CH3 6.5 x 10 &quot; 7 36 CH2CN -11-

connection

known compound B

Examples 16 and 38

Example 11

Example 12 o (ch2) 4ch3

ch2cn

No. 390 438 Table (continued): H +, K + -ATPase inhibitory activity ic50 (M) 5.4 x IO’4 2.9 x ΙΟ'6 6.2 x 10 * 6

Gastric acid inhibitory effect (%) pocket dog 3 mg / kg p.o. 21 82 67 -12-

No. 390 438

Known Compound A: Compound of European Patent 33094

Known Compound B: Compound of European Patent 68378

The compounds of the general formula (I) according to the invention and their salts can be used as such or as pharmaceutical preparations which have been prepared by mixing with conventional pharmaceutically acceptable carriers, auxiliaries, etc. Administration can be oral (by tablets, capsules, powder, granules, pills or the like) or parenteral (by injections, syrups, ointments, supposiloricn, etc.).

The dosage may be changed depending on the patient concerned, the mode of administration and the condition of the patient, but generally daily total amounts of 200 to 400 mg are administered for a 10 adults, which are administered in 2 to 4 single doses.

The invention is explained in more detail below by the following, non-limiting rules and examples.

At least some of the starting compounds used in accordance with the present invention are new and included in the invention. The manufacture of some of these new connections is explained in the IS regulations.

In the examples, Fp, Mass or * HNMR means the melting point, the mass spectrum or the 1 H-Kcmrcsonanzspcklrum.

An aqueous, physiological saline containing 1000 mg / kg of the test compound, 3-cyanomethyl-2-methyl-8 - [(3-methyl'2-butenyl) -oxy] imidazo [1,2-a] pyridine (prepared according to Example 16) was orally administered to a group of three male and two female Fischer rats (5-7 weeks old). These were observed for 24 hours, but no death was found. This means that the LD ^ q (p.o.) of the compound is over 1000 mg / kg.

Procedure 1: 25 2-Amino-3-hexyloxypyridine:

30 35

2 g of sodium hydroxide in 50 ml of methanol were released in an atmosphere of flowing nitrogen. Then 5.5 g of 2-amino-3-hydroxypyridine were added to the solution with water cooling and dissolved therein. The solvent was then evaporated to dryness under reduced pressure. 70 ml of dry dimethyl sulfoxide were added to the residue under a stream of nitrogen, and 9.08 g of hexyl bromide were added to the resulting suspension with water cooling, and the mixture was then stirred at room temperature overnight. The solution was poured onto 400 ml of water. The mixture was extracted with ether (400 ml and 300 ml). After washing with 300 ml of water, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with hexane. 6.69 g of the product were obtained. 45 mp 55-56 ° C; Mass (El) m / z 194 (M +).

The following connections were made in a similar manner

Instructions 2: 2-Amino-3- (2-butenyloxy) pyridine: 50 55

NH 2 60 mp: 79-80 ° C / recrystallized from hexane; Mass (EI) m / z 164 (M +). -13-

No. 390 438

Procedure 3: 2-Amino-3- (3-methyl-2-butenyloxy) pyridine:

NH. 0 c

Mp 66-67 ° C / hexane; Mass (EI) m / z 178 (M +).

Procedure 4: 2-amino-3-pentyloxypyridine:

NH.

Mp 50-51 ° C / Hcxan; Mass (EI) m / z 180 (M +).

Procedure 5: 2-Amino-3- (cyclohexylmethoxy) pyridine:

2nd

NH

Mp 116-117 ° C / ether; Mass (EI) m / z 206 (M +). -14- 5 No. 390 438

Procedure 6: 2-amino-3-butoxypyridine:

2 10 15

Mp 53-54 ° C / hexane; Mass (EI) m / z 166 (M +).

Procedure 7: 20 2-Amino-3-octyloxypyridine:

2nd

25 30 35

Mp 56-57 ° C / hexane; Mass (EI) m / z 222 (M +).

Regulation.g.;. 40 2-Amino-3- (1-methylbutoxy) pyridine: 45 50

2nd

SH 55 oily substance; Mass (EI) m / z 180 (M +),! HNMR (CDC13, Sigma) 0.8-1.1 (m, 3H), 1.32 (d, 3H), 1.2-1.9 (m , 4H), 4.32 (dt, 1H), 6.54 (dd, 1H), 6.88 (dd, 1H), 7.62 (dd, 1H) -15- 60

No. 390 438

Regulation 9: 2-amino-4- (2-ethylbutoxy) pyridine: \

2 oily substance; Mass (EI) m / z 194 (M +), * HNMR (CDC13, Sigma) 0.92 (t, 6H), 1.1-1.8 (m, 5H), 3.86 (d, 2H), 6.56 (dd, 1H), 6.89 (dd, 1H), 7.62 (dd, 1H)

Regulation 10: 2-amino-3- (ethoxy) pyridine:

OH &quot; NH.

EtBr

NaOK - ~ 7

East I

1.80 g of sodium hydroxide and 50 ml of methanol were dissolved in 3 ml of water. 5.0 g of 2-amino-3-hydroxypyridine were added to the solution thus obtained. After stirring at room temperature for 5 minutes, the methanol was removed by distillation under reduced pressure. After evaporation to dryness, 100 ml of dimethyl sulfoxide was added to the residue, and 5 g of ethyl bromide were added to the mixture thus obtained. The mixture was then stirred at room temperature for 24 hours. The reaction mixture was poured into 200 ml of water. The mixture was extracted with chloroform. The chloroform phase was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and then with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was mixed with n-hexane and the crystals formed were filtered off. 3.40 g of 2-amino-3-ethoxypyridine were obtained.

Mp 76-77 ° C; Mass (EI) m / z 138 (M +).

The following compounds were made in a similar manner.

Regulation 11: 2-amino-3-propoxypyridine: OPr-n

Mp 54-55 ° C; Mass (EI) m / z 152 (M +). -16- 5

No. 390 438

Regulation 12: 2-Amino-3- (2-melhylpropoxy) pyridine:

10 15

Mp 45-46 ° C / hexane; Mass (El) m / z 166 (M4). 20 Regulation 13: 2-amino-3- (2-cyclohexylälhoxy) pyridine: 25 OCH2CK2

2nd

NH 30 35

Mp 99-100 ° C mass (El) m / z 220 (M +).

Example 1; 40 OPr-n O OPr-n

50

24 g of ethyl 2-chloroacetoacetate were dissolved in 200 ml of ethanol and 11.1 g of 2-amino-55 3-propoxypyridine were introduced into the solution. After addition of 6.2 g of sodium hydrogen carbonate, the mixture was heated under reflux for 16 hours and finally the solvent was distilled off. The. The residue was mixed with 100 ml of water and the mixture thus obtained was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography using hexane: ethyl acetate (1: 1). 4.0 g of 60 3-ethoxycarbonyl-2-methyl-8-propoxyimidazo [1,2-a] pyridine were obtained.

Mp 56-57 ° C; Mass (EI) m / z 262 (M +). -17-

No. 390 438 Example 2:

1 g of ethyl 2-chloroacetoacetate and 0.8 g of 2-amino-3- (2-methylpropoxy) pyridine were dissolved in 30 ml of ethanol, and 0.50 g of triethylamine was then introduced into the solution. After refluxing for 6 hours, 1.0 g of ethyl 2-chloroacetoacetate was added to the mixture, followed by refluxing for 16 hours. After cooling, the ethanol was distilled off under reduced pressure. The residue was dissolved in chloroform. The solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography using hexane / ethyl acetate (4: 1). 0.45 g of 3-ethoxycarbonyl-2-methyl-8- (2-methylpropoxy) imidazo [1,2-a] pyridine was obtained.

Mp 59-60 ° C; Mass (EI) m / z 276 (M +).

Elemental analysis (C15H20N2O3) C H N Calculated: (%) 65.20 7.30 10.14 Found: (%) 64.98 7.38 10.12 Example 3:

OCH

nh2

O CI CH3C-CHCOOC2K5

5.76 g of 2-amino-3-cyclohexyl methoxypyridine, 5.0 g of ethyl 2-chloroacetoacetate and 3.09 g of triethylamine were dissolved in 100 ml of toluene. The solution was refluxed for 24 hours. 100 ml of ether were added to the reaction solution. The mixture was washed with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off. Recrystallization from ether n-hexane gave 5.67 g of 8-cyclohexylmethoxy-3-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine with a melting point of 108-109 ° C.

Dimension (FAB) m / z 317 (M ++ 1),

Elemental analysis (CjgH ^ NjO ^ C H N Calculated: (%) 68.33 7.65 8.85 Found: (%) 68.21 7.67 8.79 -18-

No. 390438

The following connection was made using a procedure similar to Example 3:

Example 4: 0- (ch2 &gt; jch3 ^ • N \ coost 3-ethoxycarbonyl-2-methyl-8-pentyloxyimidazo [l, 2-a] pyridine, mp 59-60 ° C; Mass (FAB) m / z 291 (M + + 1).

Example 5:

Under flowing argon gas, 30 ml of anhydrous tetrahydrofuran was added to 0.78 g of lithium aluminum hydride. The mixture was stirred and cooled to a temperature between 0 and 10 ° C with ice water. A solution of 5.48 g of 8-cyclohexylmethoxy-3-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine in 50 ml of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred at a temperature between 0 and 10 ° C for 1 hour. Excess lilhium aluminum hydride was destroyed by careful addition of 7 ml of water, and 100 ml of ether was added to cool to room temperature, after which insoluble matters were filtered off. After washing with a saturated aqueous sodium chloride solution, the filtrate was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ether n-hexane. 4.22 g of 8-cyclohexylmethoxy-3-hydroxymethyl-2-methylimidazo [1,2-a] pyridine with a melting point of 146 ° C. were obtained.

Mass (FAB) m / z 275 (M + +1), elemental analysis (CjgH ^^ C ^) CHN Calculated '(%) 70.04 8.08 10.21 Found: (%) 70.06 8.09 10, 18 The following examples worked in a similar way to Example 5 -19-

No. 390 438 Example 6:

3-hydroxymethyl-2-methyl-8-pentyloxyimidazo [l, 2-a] pyridine mp 116-117 ° C, mass (FAB) m / z 249 (M + + 1), elemental analysis (C14H20N2O2) CHN 20 calculated (% ) 67.72 8.12 11.28 Found: (%) 67.62 8.09 11.19 Example 7; CPr-n

CH, OH 35 3-hydroxymelhyl-2-methyl-8-propoxyimidazo [lt2-a] pyridine mp 136-137 ° C, mass (EI) m / z 220 (M +). 40 Elemental analysis (C j 2H j g ^ C ^) C H N Calculated: (%) 65.43 7.32 12.72 Found: (%) 65.26 7.28 12.68 45 Example 8:

50 55 60 3-hydroxymethyl-2-methyl-8- (2-methylpropoxy) imidazo [1,2-a] pyridine -20-

No. 390 438

Mp 130-132T, mass (EI) m / z 234 (M +).

Elemental Analysis (C ^ Hjg ^ C ^) C H N Calculated; (%) 66.64 7.74 11.96 Found: (%) 66.46 7.72 11.79

Example 9: 3.3 g of 8-cyclohexylmethoxy-3-hydroxy-methyl-2-methylimidazo [1,2-a] pyridine were treated with HCl in ethanol to form the hydrochloride.

The hydrochloride was dissolved in 30 ml of thionyl chloride and the solution was stirred at room temperature for 3 hours.

The excess thionyl chloride was distilled off under reduced pressure and the residue was washed with ethanol-ether. 3.69 g of 3-chloromethyl-8-cyclohexylmethoxy-2-methylimidazo [1,2-a] pyridine hydrochloride with a melting point of 144-146 ° C. were obtained.

Example 10:

A procedure similar to Example 9 gave 3-chloromethyl-2-methyl-8-pentyloxyimidazo [1,2-a] pyridine hydrochloride with a melting point of 96-98 ° C.

Example 11:

-21-

No. 390 438

2.19 g of sodium cyanide were introduced into 20 ml of anhydrous dimethyl sulfoxide. A solution of 3.69 g of 3-chloromethyl-8-cyclohexylmethoxy-2-methylimidazo [1,2-a] pyridine hydrochloride in 30 ml of anhydrous dimethyl sulfoxide was added dropwise to the mixture while cooling with ice. It was cooled back to room temperature, followed by stirring for 3 hours.

The reaction solution was introduced into 300 ml of an aqueous 3% sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3x150 ml). After washing with water, the organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate-n-hexane. Recrystallization from elder-n-hexane gave 1.3 g of 3-cyanomethyl-8-cyclohexylmcthoxy-2-methylimidazo [1,2-a] pyridine with a melting point of 145-146 ° C. Mass (EI) m / z 283 (M +).

Elemental analysis (Cjyf ^ jNßO) H N 7.47 14.83 7.47 14.71 Example 12:

C.

Calculated: (%) 72.06

Found: (%) 72.09 o- (ck2) 4ch3 CH.

CU

^ N p

CK2CN

A procedure similar to Example 11 was used to prepare 3-cyanomethyl-2-methyl-8-penlyloxyimidazo- [1,2-ajpyridine.

Mp 124-125 ° C, mass (EI) m / z 257 (M +).

Elemental analysis (CjgHj ^ NjO)

Calculated: (%) Found: (%) 70.01 69.79 7.44 7.46 16.33 16.05

Example 13:

CK

c: -: 2c: ·

To 5 ml of thionyl chloride, 1.78 g of 3-hydroxymethyl-2-methyl-8- (2-methylpropoxy) imidazo [1,2-a] pyridine hydrochloride was added. The mixture was stirred at room temperature for 5 hours. The excess thionyl chloride was distilled off under reduced pressure. Ether was added to the residue for crystallization. 1.20 g of sodium cyanide was dissolved in 30 ml of dimethyl sulfoxide, and a solution of the crude crystals previously obtained in dimethyl sulfoxide was added dropwise to the solution while cooling with ice under an argon gas atmosphere. The mixture was stirred at room temperature for 3 hours. The -22-

No. 390 438

The reaction mixture was introduced into 300 ml of an aqueous 3% strength sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography using ethyl acetate as a developing solvent. Recrystallization from hexane-ethyl acetate gave 0.50 g of 3-cyanomelhyl-2-melhyl-8- (2-melhylpropoxy) imidazo [1,2-a] pyridine.

Mp 113-114 ° C, mass (EI) m / z 243 (M +).

Elemental analysis (C ^ H ^ N-jO) C H N Calculated: (%) 69.11 7.04 17.27 Found: (%) 69.00 7.08 17.07

Example 14:

1.32 g of 3-chloro-4-oxopentanenitrile and 1.55 g of 2-amino-3-hexyloxypyridine and then 0.81 g of triethylamine were introduced into 40 ml of ethanol under flowing nitrogen. After stirring overnight under reflux, the solvent was distilled off under reduced pressure. An aqueous sodium carbonate solution was added to the residue, and the solution was extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography and recrystallized from ether. 1.30 g of 3-cyanomethyl-8-n-hexyloxy-2-methylimidazo [1,2-a] pyridine were obtained.

Mp 119-120 ° C, mass (EI) m / z (M +).

Elcm clear analysis (Cig ^ jN ^ O) C H N Calculated (%) 70.82 7.80 15.48 Found: (%) 70.59 7.75 15.38

The following compounds were made in a similar manner

Example 15: 8 - ((E) -2-butenyloxy) -3-cyanomethyl-2-methylimidazo [1,2-a] pyridine: (E) och2ch * chch3

CHjCN -23-

No. 390 438

Mp 93-95 ° C / ethyl acetate ether, mass (EI) m / z 241 (M +). Elemental analysis (C ^ H ^ NjO) C H N Calculated (%) 69.69 6.27 17.41 5 Found: (%) 69.54 6.30 17.36

Example 16: 3-cyanomethyl-2-methyl-8 - [(3-methyl-2-butenyl) -oxy] imidazo [1,2-a] pyridine: 10

20th

Mp 118-119 ° C / ether, mass (EI) m / z 255 (M +). Elemental analysis (Cj ^ Hj ^ NgO) C H N Calculated (%) 70.56 6.71 16.46 25 Found: (%) 70.45 6.77 16.41

Example 17; 3-cyanomethyl-2-melhyl-8- (l-methylbutoxy) imidazo [1,2-a] pyridine2 / 3-fumarate 30 CH, I 3 35

.2 / 3 fumarate 40

Mp 135-140 ° C / ethanol ether, mass (EI) m / z 257 (M +). Elemental analysis (CjgH | gNg0.2 / 3 (C4H4O4)) C H N 45 Calculated (%) 63.40 6.52 12.55 Found: (%) 63.46 6.58 12.73

Example 18: 50 3-cyanomethyl-8 - [(2-ethylbutoxy)] imidazo [1,2-a] pyridine: och2ch (c2h5) 2

55 -24- 60

No. 390 438

Mp 123-124 ° C / year, mass (El) m / z 271 (M +). Elemental Analysis (C16H21N3O) C H N Calculated; (%) 70.82 7.80 15.48 Found: (%) 70.64 7.78 15.42

Example 19: 8-Butoxy-3-cyanomcthyl-2-mclhylimidazo [1,2-a] pyridine:

Mp 105-107 ° C / ether, mass (EI) m / z 243 (M +). Elementary analysis (C ^ H ^ NjO) C H N Calculated: (%) 69.11 7.04 17.27 Found: (%) 69.13 7.13 17.23

Example 20: 3-Cyanomethyl-2-methyl-8-octyloxyimidazo [1,2-a] pyridine: 0 (CH2) 7CH3 CH.

CH2CN

Mp 90.5-91.5 ° C / ether hexane, mass (EI) m / z 299 (M +). Elemental analysis (Cjgl ^ j ^ O) C H N Calculated (%) 72.21 8.42 14.03 Found: (%) 72.18 8.40 14.01

Example 21: 3-Cyanomethyl-8- (2-cyclohexylethoxy) -2-methyl-imidazo [1,2-a] pyridine:

-25-

No. 390 438 0 (CH2) 4CH3

II; i \

0 (ch2) 4ch3 'V 3

Mp 142-144T, mass (EI) m / z 297 (M +). Elemental Analysis (CjgHjgNgO) C H N Calculated (%) 72.70 7.80 14.13 Found: (%) 72.65 7.75 14.06

Example 22: 3.60 g of 2-amino-3-pentyloxypyridine and 2 ml of bromoacetone were introduced into 30 ml of ethanol. After refluxing for 2 hours, 1 ml of bromoacetone was added to the mixture with water cooling, followed by refluxing overnight. The solvent was distilled off under reduced pressure. An aqueous sodium carbonate solution was added to the residue, followed by extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography and then recrystallized from hexane. 2.04 g of 2-methyl-8-pentyloxyimidazo [1,2-a] pyridine was obtained.

Mp 68-69 ° C, mass (EI) m / z 218 (M +).

Example 23: 8- (Cyclohexylmethyloxy) -2-melhylimidazo [1,2-a] pyridine was synthesized similarly to Example 22.

3 v N 1 oily substance, mass (EI) m / z 244 (M +), ^ HNMR (CDCI3, Sigma) 0.8-2.1 (m, 11H), 2.48 (s, 3H), 3, 89 (d, 2H), 6.36 (dd, 1H), 6.60 (dd, 1H), 7.28 (s, 1H), 7.64 (dd, 1H) 'Example 24: 8- (Cyclohexylethylamine) ) -2-methyl-3-nitrosoimidazo [1,2-a] pyridine: OCH, -®

-26-

No. 390 438

2.8 g of 8- (cyclohexylmethyloxy) -2-melhyIimidazo [1,2-a] pyridine were added to 28 ml of dioxane. After 20.75 g of isoamyl nitrite had been added over a period of 5 minutes at 50 ° C., the mixture was boiled under reflux with stirring for 25 minutes. After concentration, the concentrate was purified by column chromatography and crystallized from hexane. 1.27 g of the desired product were obtained.

Mp 88-89 ° C, mass (EI) m / z 273 (M +).

Example 25: 2-Methyl-3-nitroso-8-penteneoxyimidazo [1,2-a] pyridine: 0 (CK2) 4Cii3

c CH- s

KO

This compound was synthesized in a manner similar to Example 24. Mp 67-68 ° C / hexane, mass (EI) m / z 247 (M +).

Example 26: 3-Amino-8- (cyclohexylmethyloxy) -2-methylimidazo [1,2-a] pyridine fumarate:

. Fumarate

1.27 g of 8- (cyclohexylmethyloxy) -2-methyl-3-nitrosoimidazo [1,2-a] pyridine was dissolved in a mixture of 14.5 ml of acetic acid and 11.5 ml of water. After zinc powder was added to the solution over about 30 minutes, stirring was continued for 30 minutes. Insoluble matters were filtered off through Celite and the filtrate was evaporated to dryness. An aqueous solution of sodium carbonate was added to the residue, followed by extraction with methylene chloride. After drying, the solvent was distilled off. The residue was dissolved in a little ethanol and a solution of 0.45 g of fumaric acid in ethanol was added to the solution. The salt formed was filtered off and dried. 0.85 g of the desired product was obtained.

Mp 188-190 ° C.

Elemental analysis (C15H21N3O.C4H4O4) C H N Calculated: (%) 60.79 6.71 11.19 Found: (%) 60.53 6.69 11.00 -27-

No. 390 438

Example 27: 3-Amino-2-methyl-8-pentyloxyimidazo [1,2-a] pyridine fumarate:

. Fumarate

This compound was synthesized in a manner similar to Example 26, mp. 183-185 ° C / methanol-ethanol, mass (EI) m / z 233 (NT **)

Elemental Analysis (C13H19N3O.C4H4O4) C H N Calculated: (%) 58.44 6.64 12.03 Found: (%) 58.35 6.61 11.97 Example 28: 0 {CH2) 4CH3

+ MeO - ^ - CCK2Br o (ch2) 4ch3 tisHCO.

'«' Ύο- · OMe

1.8 g of 2-amino-3-pentyloxypyridine, 2.29 g of 4-methoxyphenacyl bromide and 0.84 g of sodium bicarbonate were dissolved in 30 ml of ethanol. The mixture was heated under reflux for 2 hours

The solvent was distilled off under reduced pressure. After washing the obtained crystals with water, the mixture was recrystallized from ethyl acetate. 0.8 g of 2- (p-methoxyphenyl) -8-pentyloxyimidazo [1,2-a] pyridine with a melting point of 118-119 ° C. was obtained.

Mass (EI) m / z 310 (M +).

Elemental analysis (Cjgl ^^ C ^) C H N Calculated: (%) 73.52 7.14 9.03 Found: (%) 73.65 7.11 9.11

Example 29:

Using 2-bromo-3-butanone (o Br

II I ch3-c-ckck3) Instead of 4-methoxyphenacyl bromide, 2,3-dimethyl-8-pentyloxyimidazo [1,2-a] pyridine was used

3 -28- 3

No. 390 438 obtained in an example 28 similar procedure.

Mp 53-55 ° C, mass (EI) m / z 232 (M +), 175.162.

Example 30:

.1 / 2 fumarate

1.0 g of 8-propoxy-3-chloromethyl-2-methylimidazo [1,2-a] pyridine hydrochloride was dissolved in a solution of 250 mg of sodium metal in 30 ml of ethanol. The mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane as the developing solution. Treatment of the compound obtained with fumaric acid gave 0.2 g of 8-propoxy-3-ethoxymethyl-2-methylimidazo [1,2-a] pyridine 1/2 fumarate with a melting point of 160-161 ° C.

Mass (EI) m / z 248 (M +).

Elemental analysis (^ 14 ^ 20 ^ 2¾- ^ C4H4O4) C H N Calculated: (%) 62.73 7.24 9.14 Found: (%) 62.60 7.08 9.53 Example 31:

1.50 g (9.8 mmol) of 2-amino-3-n-propyloxypyridine and 2.0 g (15.2 mmol) of 3-chloro-4-oxopentanenitrile in 40 ml of Äüianol were mixed with 1.0 g for 16 hours (9.8 mmol) triethylamine heated under reflux. Then the ethanol was distilled off and the residue was separated by silica gel column chromatography (CHCl 3) and recrystallized from hexane-ethyl acetate. 0.30 g (13.3%) of 3-cyanomethyl-2-methyl-8-n-propyloxyimidazof 1,2-a] pyridine was obtained.

Mp 106-107 ° C, mass (EI) m / z 229 (M +).

Elemental analysis (C ^ H ^ N ^ O) C H N Calculated: (%) 68.10 6.59 18.33 Found: (%) 61.92 6.59 18.21 29-

No. 390438 Example 32:

0 (CH2) 4CH3 o o KH. + ErCH2C-CO £ t

j COOEt. 10 g (55.48 mmol) of 2-amino-3-n-pentyloxypyridine, 12.98 g (66.56 mmol) of ethyl bromopyruvate and 7.0 g (83.33 mmol) of sodium bicarbonate were at room temperature for 2 hours stirred in 200 ml of ethanol and then heated under reflux for a further 2 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in ether and the solution was washed with water. After drying over anhydrous magnesium sulfate, the ether phase was evaporated to dryness under reduced pressure. 8 g (yield 52.2%) of 8-n-pentyloxy-2-ethoxycarbonylimidazo [1,2-a] pyridine were obtained in the form of crystals with a melting of 120-121 ° C.

Mass (EI) m / z 276 (M +), 231,219.206.

Example 33; o- (ch2) 4ch3 CH2COOEt. 1/2 fumarate

Using the procedure of Example 32, ethyl (8-n-pentyloxyimidazo [1,2-a] pyridin-2-yl) acctate 1/2 fumarate was obtained.

Mp 78 ° C. C H N Calculated; (%) 62.05 6.94 8.04 Found: (%) 61.97 6.88 8.03 Example 34:

Elemental analysis (Cigf ^^ Oß.l # C4H4O4)

-30-

No. 390 438

0.72 g of 2-amino-3-cyclohexylmethoxypyridine was dissolved in 5 ml of dry ether. After adding 0.28 g of pyridine to the solution, a solution of 0.34 ml of 2-chloropropanoyl chloride in 2 ml of ether was added to the mixture at -10 ° C. After stirring at -10 ° C for one hour, the reaction mixture was washed with cold water and dried. Then the solvent was distilled off under reduced pressure. 5 The residue was recrystallized from ether-hexane. The 2-chloro (N-cyclohexylmethoxy-2-pyridyl) propanamide hydrochloride thus obtained was reacted with heating at 120 ° C for 2 hours. The residue was recrystallized from ethanol-ether. 0.35 g of 8-cyclohexyl-methoxy-2-hydroxy-3-methylimidazo [1,2-a] pyridine hydrochloride was obtained.

Mp 167-169 ° C, mass (EI) m / z 260 (M +). 10 Elcmcntaranalysc (Cis ^ o ^ O ^ HCl.lM H2O) CHN CI Calculated: (%) 59.79 7.19 9.30 11.75 Found: (%) 59.75 7.12 9.22 11.65 15 Example 35:

20 25

8.0 g (34.4 mmol) of 8-iso-hexyloxy-2-methylamidazo [1,2-a] pyridine and 68.5 ml (0.51 mol) of isoamyl nitrite were introduced into 150 ml of dioxane. After refluxing for 30 minutes, the solvent was distilled off. The residue was mixed with 200 ml of acetic acid and 100 ml of water. 9.0 g (0.137 mol) of zinc were added to this mixture at room temperature. After stirring for 4 hours, the mixture was filtered and the filtrate evaporated to dryness. Chloroform and water were added to the residue. The mixture was made alkaline with an aqueous sodium hydroxide solution and filtered. The filtrate was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate), and finally 0.75 g (6.5 mmol) of fumaric acid was added to form the fumarate. After recrystallization from methanol, 1.20 g (9.6%) of 3-amino-8-iso-hexyIoxy-2-methyItmidazo [1,2-a] pyridine fumarate was obtained.

Mp 194-196 ° C, mass (EI) m / z 247 (M +). 50 Elemental analysis (C14H21N3O.C4H4O4) C H N Calculated (%) 59.49 6.93 11.56 Found: (%) 59.51 6.91 11.58 55 31 60

No. 390 438

Example 36:

. Fumarate

1.90 g (7.71 mmol) of 8-n-heptyIoxy-2-methylimidazo [1,2-a] pyridine were dissolved in 60 ml of dioxane, and 20.7 ml (0.154 mol) of isoamyl nitrite were added to the solution. After refluxing for 30 minutes, the solvent was distilled off under reduced pressure and 30 ml of acetic acid and 10 ml of water were added to the residue. 2.1 g (32.1 mmol) of zinc were added to the mixture. After stirring at room temperature for 2 hours, the solvent was distilled off. 50 ml of methylene chloride and 20 ml of water were added to the residue. The reaction mixture was made alkaline with sodium hydroxide solution. After filtration through Celite, washing with methanol and concentration, the concentrate was extracted with methyl chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography. The purified compound was converted into the fumarate in a conventional manner and recrystallized from ethanol. 0.40 g (20%) of 3-amino-8-n-heptyloxy-2-methyl-imidazo [l »2-a] pyridine fumarate was obtained.

Mp 171-173 ° C, mass (EI) m / z 261 (M +). Elemental Analysis (C15H23N3O.C4H4O4) C H N Calculated: (%) 60.46 7.21 11.13 Found: (%) 60.49 7.26 11.12 Example 37; 0 (CH2) 4CH3

N-COOC2H5 LiAiH, HCl 0 (CH2) {CH3 (Vir "’ "N-. HCl -32-

No. 390 438

1.3 g (39.5 mmol) of lithium aluminum hydride were suspended in 100 ml of dry tetrahydrofuran in an argon gas stream and a solution of 16 g (57.9 mmol) of 8-n-pentyloxy-2-ethoxycarbonylimidazo [1,2- a] pyridine added dropwise in 300 ml of dry tetrahydrofuran. After stirring at room temperature for 30 minutes, the mixture was heated to 65 ° C for 20 minutes. About 15 ml of water were carefully added dropwise to the reaction mixture 5. Insoluble parts were filtered off. After the solvent was distilled off under reduced pressure, the residue was treated with ethanolic hydrochloric acid and recrystallized from acetone. 13.9 g (yield 88.7%) of 8-n-pentyloxy-2-hydroxymethylimidazo [1,2-a] pyridine hydrochloride with a melting point of 102-103 ° C. were obtained.

Elemental analysis (C ^ Hjg ^ OjHCl) 10 C H N CI Calculated (%) 57.67 7.07 10.35 13.09 Found: (%) 57.67 7.06 10.36 13.33 20 25

30 a) 248 g of 3-carbamoyl-2-methyl-8 - [(3-methyl-2-butenyl) oxy] imidazo-35 [1,2-a] pyridine and 204 ml of pyridine were added to 2.5 1 of methylene chloride . Then 297 ml were added to the mixture at 0 ° C

Trifluoroacetic anhydride added dropwise. After the reaction was completed, the reaction mixture was poured into 51 cold, saturated, aqueous sodium hydrogen carbonate solution and then fractionated. After drying over anhydrous magnesium sulfate, the organic phase was evaporated to dryness under reduced pressure. The residue was recrystallized from methylene chloride ether. 198 g of 40 3-cyanomethyl-2-methyl-8 - [(3-methyl-2-butenyl) oxy] imidazo [1,2-a] pyridine were obtained.

The product thus obtained had the same properties as the compound prepared according to Example 16. The starting compound used in this example was prepared as follows: b) -1 (Chem. Abs., Vol. 102,148704c is referred to).

715 g of methyl levulinate were dissolved in 5.5 l of dry ether. A catalytic 45 amount of acetic acid hydrogen bromide was added to the solution. The mixture was cooled to 5 ° C or below. 283 ml of bromine were added dropwise to the mixture at an internal temperature between 2 and 5 ° C. This dropping was carried out by taking care that the red color caused by the addition of bromine disappeared. After the reaction was completed, the reaction mixture was poured into 6 liters of ice water, followed by fractionation. After washing with a saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was distilled (boiling point 92-96 ° C. at about 10 mm Hg). 642 g of methyl 3-bromolaevulinate (purity determined by gas chromatography, about 85%) were obtained. b) -2 430 g of 2-amino-3 - [(3-methyl-2-butenyl) oxy] pyridine and 488 g of triethylamine were introduced into 4.3 l of isopropyl alcohol. 870 g of methyl 3-bromolaevulinate 55 (gas chromatographic purity 85-90%) were then added to the mixture, followed by stirring under reflux for 2.5 hours. After the solvent was distilled off under reduced pressure, 5 liters of water was added, followed by extraction with 61% ethyl acetate. After washing with 51 water and then with 51 a saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. 60 3-methoxycarbonylmethyl-2-methyl-8 - [(3-methyl-2-butenyl) oxy] imidazo [1,2-a] pyridine were obtained. b) -3 The compound thus obtained was dissolved in 2.5 l of methanol. Ammonia gas was then bubbled through the solution for 10 hours. 21 ether were added to the solution while cooling with ice. The -33-

No. 390,438 crystals formed were filtered off and 248 g of 3-carbamoylmethyl-2-methyl-8 - [(3-methyl-2-butenyl) oxy] imidazo [1,2-a] pyridine were obtained.

Example 39:

A mixture of 4.0 g (8.94 mmol) (8-n-penlyloxy-2-methoxymethylimidazo [1,2-a] pyridin-3-yl) methyltrimethylammonium iodide and 0.47 g (9.59 mmol) sodium cyanide was added at 99 ° C for one hour in 25 ml of dimethylformamide. The reaction solution was carefully poured into 150 ml of ice water, followed by extraction with methyl chloride. After drying over magnesium sulfate, the extract was concentrated under reduced pressure. Purification by silica gel column chromatography using chloroform-ethyl acetate as the developing solvent gives 0.7 g (yield 27.3%) of 8-n-pentyloxy-2-methoxymethyl-3-cyanomethylimidazo [1,2-a] pyridine with a melting point of 101-102 ° C.

Elementalanalysc (^ 16¾ ^ 3 (¾) C H N Calculated (%) 66.88 7.37 14.62 Found: (%) 66.65 7.30 14.50 Example 40:

A solution of 0.95 g of 8-cyclohexylmethoxy-2-methyl-3-methoxycarbonylmethylimidazo [1,2-a] pyridine in 5 ml of tetrahydrofuran, which was obtained similarly to Example 38 b) -2, was 0.17 g of lithium aluminum hydride in 5 ml of tetrahydrofuran entered. The mixture was stirred at room temperature for 3 hours. While cooling, 2 ml of ethyl acetate and then a saturated aqueous sodium sulfate solution were added to the reaction mixture. Then ether was added and decanted twice. After the solvent was distilled off under reduced pressure, ethanolic hydrochloric acid was added to form the hydrochloride. After recrystallization from acetonitrile-tetrahydrofuran, 0.58 g of 8-cyclohexyethylene methoxy-3- (2-hydroxyethyl) -2-methylimidazo [1,2-a] pyridine hydrochloride (i. -34-

No. 390 438

Mp 147-149T, mass (El) m / z 288 (M +). Elemental analysis (C17H24N2O2 HCl O.IH2O) C H N CI Calculated (%) 62.51 7.78 8.58 10.85 Found: (%) 62.45 7.80 8.36 10.71

Example 41;

CH ° &lt; CB2,3CH3

ch3cko

NaHSO, ... · * \

NaCN 0 (ch2) 3ch3 &gt;

NH 3 2 5 ml of water were added with 2.7 g (18.2 mmol) of the salt of acetaldehyde and NaHSO ^ and to the mixture thus obtained 1.0 g (6.0 mmol) of 2-amino-3-n- butyloxypyridine added. After refluxing for one hour, the reaction mixture was cooled with ice and a solution of 0.95 g (19.3 mmol) of NaCN in 1.6 ml of water was added dropwise. After refluxing for 2 hours, 4 ml of methanol was added to the reaction mixture. After refluxing for 6 hours, the reaction mixture was cooled and extracted with chloroform. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate. 0.25 g (19.2%) of 3-amino-8-n-butyloxy-2-methylimidazo [1,2-a] pyridine was obtained.

Mp 106-107 ° C, mass (EI) m / z 219 (M +).

Elemental Analysis (C12H17N3O) C H N Calculated: (%) 65.73 7.81 19.16 Found: (%) 65.54 7.78 19.06

Example 42:

3 o (ch2) 5ch3

CHjCKO, NaHS03 --— y

NaCN -35- 2

No. 390 438

0.43 g of sodium hydrogen sulfite was dissolved in 1 ml of water and 0.23 ml of acetaldehyde was added to the solution. The mixture was stirred at room temperature for one hour. Then 0.8 g of 2-amino-3-hexyloxypyridine was added to the mixture at 95 ° C. After stirring at room temperature for 1 hour, an aqueous solution of 0.40 g of sodium cyanide in 0.7 ml of water was added, followed by stirring for 2 hours. After cooling, it was extracted with chloroform. After washing the extract with water, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography and then washed with hexane. 50 mg of 3-amino-8-n-hexyloxy-2-methylimidazo [1,2-a] pyride were obtained.

Mp 45-65 ° C, mass (EI) m / z 247 (M +).

Elemental analysis (C14H21N3O) H N 8.56 16.99 8.47 16.88 Example 43:

C.

Calculated: (%) 67.98

Found: (%) 67.62 0 (CH2) 4CH3

ch2cn

20 g (77.72 mmol) of 8-n-pentyloxy-2-methyl-3-cyanomethyIimidazo [1,2-a] pyridine were dissolved in 50 g of pyridine and 7.85 g of triethylamine. Hydrogen sulfide was bubbled into the solution for 4 hours while cooling with water. Then the reaction mixture was carefully poured into 300 ml of ice water, followed by stirring. The crystals formed were filtered off. Recrystallization from ethanol gave 15.11 g (yield 66.7%) (8-n-pentyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) thioacetamide with a melting point of 157-159 ° C. .

Elemental Analysis (Cl ^ HjjNgOS 0.1H20) C H N S Calculated (%) 61.44 7.29 14.33 10.94 Found: (%) 61.45 7.28 14.28 10.77 Peigpiei44;

-36-

No. 390 438

After 1.0 g (3.43 mmol) (8-n-pentyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) thioacetamide and 0.35 g (3.78 mmol) chloroacetone in 15 ml After refluxing ethanol for one hour, the solvent was distilled off under reduced pressure. The residue was dissolved in water and potassium carbonate was added to the solution to make it alkaline. Then it was extracted with chloroform. The chloroform phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform-ethyl acetate as a developing solvent and converted to fumarate in acetone. 1.11 g (yield 73%) of 8-n-pentyloxy-2-methyl-3- (4-methyl-2-thiazolyl) methylimidazo [1,2-a] pyridine fumarate with a melting point of 117-118 ° C. were obtained .

Elemental analysis (C ^ gl ^ NjOS.C ^ C ^) C H N S Calculated: (%) 59.30 6.10 9.43 7.19 Found: (%) 59.15 6.09 9.34 7.16

The following compounds were made in a similar manner.

Example 45:

8-n-pentyloxy-2-methyl-3- (4,5-dimethyl-2-thiazolyl) methyliinidazo [1,2-a] pyridine hydrobromide mp 166-167T

Elemental analysis (C ^ l ^ NjOS.HBr) CHNS Br Calculated: (%) 53.77 6.17 9.90 7.56 18.83 Found: (%) 53.68 6.11 9.86 7.60 18 , 98

Example;

8-n-pentyloxy-2-methyl-3- (4-methyl-5-n-propyl-2-thiazolyl) methyliinidazo [1,2-a] pyridine hydrobromide mp 162-164 ° C -37-

No. 390 438

. Fumarate

Elemental analysis (C21H29N3OS.HBrO.2H2O) C H N S Br Calculated: (%) 55.30 6.71 9.21 7.03 17.52 Found: (%) 55.34 6.55 9.25 7.30 17.76

Example 47:

8-n-pentyloxy-2-methyl-3- (5-methyl-4-phenyl-2-thiazolyl) methylimidazo [1,2-a] pyridine fumarate mp 126-127 ° C

Elemental analysis (C24H27N3OS.C4H4O4.O.25H2O) C H N S Calculated (%) 63.92 6.03 7.98 6.09 Found: (%) 63.75 5.90 7.77 6.05 Example 48:

COOC2Hs CK3. KCl

8-n-Pentyloxy-2-methyl-3- (5-ethoxycarbonyl-4-methyl-2-thiazolyl) methylimidazo [1,2-a] pyridine hydrochloride, mp 160-163 ° C

Elemental analysis (C21H27N3O3S.HCI.O.4H2O) CHNS CI Calculated (%) 56.66 6.52 9.44 7.20 7.96 Found: (%) 56.70 6.46 9.39 7.18 8. 22 -38-

No. 390 438 Example 49:

.2 / 3 fumarate

a) 10.0 g (38.86 mmol) of 8-n-pentyloxy-2-methyl-3-cyanomethylimidazo [1,2-a] pyridine were dissolved in a mixture of 5 ml of dry ethanol and 150 ml of dry chloroform. The solution was cooled to a temperature between 0 and 10 ° C. After bubbling hydrogen chloride gas into the solution for two hours, the reaction mixture was left at about 4 ° C for 2 days. The reaction mixture was then carefully poured onto ice water in which an excess of potassium carbonate had been dissolved to fractionate the organic phase. The aqueous phase was extracted with chloroform. The extracts were then combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. 10.1 g (yield 93%) of oily ethyl (8-n-pentyloxy-2-methyl-imidazo [1,2-a] pyridin-3-yl) acetimide were obtained

The imidate was used without purification b) After 1.5 g (4.94 mmol) of ethyl (8-n-pentyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) acetimidate and 0.3 g (5.44 mmol) of propargylamine had been stirred in 30 ml of ethanol at room temperature for 18 hours, the mixture was left to react for another hour at 65 ° C. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methyl alcohol as a developing solvent, and converted to the fumarate in acetone. This gave 1.1 g of N-propargyl (8-n-pentyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) acetamidine 3/2 fumarate

Elemental analysis (CigH24N40.3 / 2 C4H404.l / 4 H20) C H N Calculated: (%) 58.70 6.26 11.41 Found: (%) 58.69 6.37 11.32

The following compounds were obtained in a similar manner, using the amidine from Example 49 a).

Example 50: N-sulfamoyl- (8-n-pentyloxy-2-methylimidazo [l ^ -a] pyridin-3-yl) acetamidine with a melting point of 194-196 ° C was obtained in a manner similar to Example 49 , using sulfamide instead of propargylamine.

O-CCHj) ^ 1- CH

^ .NSO-KH. CH-C ^ 2 2 '&quot; NHj, -39- 5

No. 390 438

Elemental analysis (C15H23N5O3S) C H N S Calculated: (%) 50.97 6.56 19.81 9.07 Found: (%) 51.07 6.61 19.23 8.90

Example 51; N-Acetyl (8-n-pentyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) acetamidorazone with a melting point of 195-196 ° C was similarly obtained using acetohydrazide instead of propargylamine. 10? - &lt; Ca2 &gt; 4Ca3 15

Cpr "

Ck2cn 20 nnecoch3 nh2

Elemental Analysis (C17H25N5O2) 25 C H N Calculated: (%) 61.61 7.60 21.13 Found: (%) 61.67 7.64 21.07

Example 52: 30 35 40? - (CS2 "4C" 3rYV; ^ N- ^ NNKCOCH, CH.C 3 “&quot; NH2 o- (ch2) 4ch3

45 0.8 g (2.4 mmol) of N-acetyI- (8-n-penteneoxy-2-methylimidazo [1,2-a] pyridin-3-yl) acetamidorazone was heated at 200 ° C. for 3 minutes. Recrystallization from ethanol ether gave 0.37 g (yield 48.9%) of 50 3- (8-n-pentyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) methyl-5-methyltriazole with a melting point of 187-188 ° C.

Elemental analysis (C17H23N5O) C H N Calculated: (%) 65.15 7.40 22.35 55 Found: (%) 65.07 7.40 22.33 40-60

No. 390 438 Example 53:

0-ICH2) 4CH3 ch2- &lt; s * N - '

After 1.5 g (4.94 mmol) of the ethyl (8-n-penteneoxy-2-methylimidazo [1,2-a] pyridin-3-yl) acetimidate synthesized according to Example 49 a) and 0.72 g (5th , 40 mmol) of aminoacetaldehyde diethyl acetal had been stirred in 30 ml of ezlhanol at room temperature for 18 hours, the mixture was stirred at 65 ° C. for another hour. The solvent was distilled off under reduced pressure and 15 ml of concentrated hydrochloric acid were added to the residue. The mixture was stirred at 100 ° C for 90 minutes and made alkaline with an aqueous solution of potassium carbonate with ice cooling, followed by extraction with chloroform. After drying over anhydrous magnesium sulfate, the chloroform phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methyl alcohol as a developing solvent. 0.7 g (yield 47.6%) of 8-n-pentyloxy-2 * methyl-3- (2-imidazolyl) methylimidazo [1,2-a] pyridine with a melting point of 148-149 ° C. were obtained.

Elemental analysis (C C H N Calculated: (%) 67.61 7.47 18.55 Found: (%) 67.97 7.49 18.16 Example 54:

A drop of concentrated sulfuric acid was added to a mixture of 1.35 g of 3-amino-8-cyclohexylmethoxy-2-methylimidazo [1,2-a] pyridine and 1.65 g of ethyl orthoformate. The mixture was heated to 150 ° C with stirring for one hour. After cooling, chloroform was added to the mixture. After washing with an aqueous sodium hydrogen carbonate solution and drying, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of tetrahydrofuran and a solution 0.40 g of lithium aluminum hydride in 10 ml of tetrahydrofuran was added, followed by stirring under reflux for 1.5 hours. After cooling, 1 ml of ethyl acetate and then a saturated aqueous sodium sulfate solution was carefully added to the reaction mixture. The -41-

No. 390 438

Mixture was added ether and then decanted twice. The solvent was then distilled off under reduced pressure. The residue was treated by column chromatography and then recrystallized from ether-hexane. 0.31 g of 8-cyclohexylmethoxy-2-methyl-3-methylaminoimidazo [1,2-a] pyridine was obtained.

Mp 133-135 ° C, mass (EI) m / z 273 (M +)

Elemental analysis (C ^ H ^ N ^ O) C H N Calculated: (%) 70.30 8.48 15.37 Found: (%) 70.19 8.43 15.20

Example 55;

0.91 g of 3-amino-8-cyclohexylmethoxy-2-methylimidazo [1,2-a] pyridine and 0.36 g of triethylamine were dissolved in 10 ml of dry ether. A solution of 0.25 ml of acetyl chloride in 5 ml of ether was added dropwise to the solution thus obtained at 0.degree. After stirring for one hour, chloroform was added to the solution. After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-ether. The crystals thus obtained were introduced into a solution of 0.14 g of lithium aluminum hydride in tetrahydrofuran under an argon gas atmosphere, followed by stirring under reflux for 1.5 hours. After cooling, 1 ml of ethyl acetate and then a saturated aqueous sodium sulfate solution were gradually added to the reaction mixture. Ether was added to the reaction mixture, followed by decanting twice. Then the solvent was distilled off under reduced pressure. The residue was treated by column chromatography and then recrystallized from ether-hexane. 0.36 g of 8-cyclohexylmethoxy-3-ethylamino-2-methylimidazo [1,2-a] pyridine was obtained.

Mp 89-90 ° C, mass (EI) m / z 287 (M +). Elemental analysis (CjyH ^ N ^ O) C H N Calculated: (%) 71.05 8.77 14.62 Found: (%) 71.03 8.70 14.38 Example 56:

-42-

No. 390 438

1.0 g (3.3 mmol) of 8-n-pentyloxy-3-chloromethyl-2-methylimidazo [1,2-a] pyridine hydrochloride was dissolved in 50 ml of ethanol and 0.25 g was added to the solution thus obtained (3.3 mmol) thiourea added. After refluxing for 2 hours, the ethanol was distilled off. The residue was dissolved in 30 ml of ethanol and 30 ml of water and 0.22 ml (3.42 mmol) of chloroacetonitrile was added to the solution thus obtained. With ice cooling, an aqueous solution of 0.40 g (10 mmol) of sodium hydroxide in 5 ml of water was added added dropwise under an argon gas stream. The mixture was stirred for 40 minutes and then the ethanol was distilled off. Water was added to the residue, followed by extraction with ethyl acetate. After drying over anhydrous magnesium sulfate, the ethyl acetate was distilled off. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 4: 1) and recrystallized from hexane-ethyl acetate. 0.30 g (30%) of 3- [cyanomethyl) thio] methyl-2-methyl-8-n-pentyloxyimidazo [1,2-a] pyridine were obtained.

Mp 94-95 ° C, mass (EI) m / z 303 (M +).

Elemental Analysis (C ^ HjjNgOS) C H N S Calculated (%) 63.33 6.98 13.85 10.57 Found: (%) 63.21 6.94 13.76 10.63

Example 57:

The following connection was made in a similar manner o (ce2) 4ch3 ca,

. Fumarate "CECH 2-methyl-8-pentyloxy-3- (2-propynylthio) methylimidazo [1,2-a] pyridine fumarate mp 127-128 ° C, mass (EI) m / z 302 (M +).

Elemental analysis (C ^^ jNjOS.C ^ O ^ C H N S Calculated (%) 60.27 6.26 6.69 7.66 Found: (%) 60.32 6.35 6.65 7.76

Example 58:

-43-

No. 390 438

In an argon gas stream, 10.6 g (39.15 mmol) of 8-n-pentyloxy-2-hydroxymethylimidazo [1,2-a] pyridine hydrochloride was added to 70 ml of ice-cooled thionyl chloride. After warming to room temperature, stirring was continued for 2 hours. The thionyl chloride was then distilled off under reduced pressure. The residue was dissolved in 200 ml of methyl alcohol, and 5.3 g of sodium methoxide was added to the resulting solution under ice-cooling, followed by stirring at room temperature for 20 hours has been. The solvent was distilled off under reduced pressure. The residue was dissolved in ether and the solution washed with water. After drying over anhydrous magnesium sulfate, the ether phase was concentrated under reduced pressure. The crystals formed were washed with a mixture of ether and n-hexane and filtered. 7.8 g (yield 80.4%) of 8-n-pentyloxy-2- methoxymethylimidazo [1,2-a] pyridine with a melting point of 50 ° C.

Elemental Analysis (C ^ I ^ q ^ C ^) C H N Calculated (%) 67.72 8.12 11.28 Found: (%) 67.67 8.05 11.21 B-eisoiel-59; o (ck2) 4ch3 ch2oh 0 (CH,), CH, Ο O 'J 4 3 II II * CH2OCCH2OCCH3 -. 1/2 fumarate

KCl

1.5 g (5.54 mmol) of 8-n-pentyloxy-2-hydroxymethylimidazo [1,2-a] pyridine hydrochloride were suspended in 30 ml of melylene chloride in an argon gas stream. The suspension was cooled to -20 ° C in a dry ice-acetone bath. 1.3 g (12.87 mmol) of triethylamine were added to the suspension and 0.83 g (6.07 mmol) of acetoxyacetyl chloride were added dropwise. The temperature was allowed to gradually rise to room temperature, at which temperature the mixture was stirred for one hour. The reaction mixture was washed with water. After drying the methylene chloride phase over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was treated with fumaric acid in ethanol to give 1.2 g (yield 55.3%) of 8-n-pentyloxy-2-acetoxyacetoxymethylimidazo [1,2-a] pyridine 1/2 fumarate with a melting point of 97 ° C.

Elemental analysis (C17H22N2O5.1 / 2 C4H4O4) C H N Calculated (%) 58.16 6.16 7.14 Found: (%) 58.06 6.12 7.13 Example 60: o (ch2) 4ch3

. KCl +

* 2www ** 3 1/2 fumarate 0 (CH2J4CH3

-44-

No. 390 438 8-n-pentyloxy-2-acetoxymeihylimidazo [1,2-a] pyridine 1/2 fumarate with a melting point of 101-102 ° C. was prepared in a similar manner to that described in Example 58, using acetyl chloride instead of acetoxyacetyl chloride has been.

Elemental analysis (C15H20N2O3.I / 2 € 411404) C H N Calculated: (%) 61.07 6.63 8.38 Found: (%) 60.95 6.63 8.25 Example 61:

fVjr ^ N 0 (C32) 4CH3 CH, OCH, 0 ^ V- CEjOCHΛ. ^ CH'2N®K £ 3i 'In 70 ml of methyl alcohol 5.0 g (20.13 mmol) of 8-n-pentyloxy-2-methoxymethylimidazo [l, 2-a] pyridine, 1.8 g (22.07 mmol) of dimethylamine hydrochloride and 0.66 g (21.98 mmol) of paraformaldehyde for 10 hours under reflux. Then 0.9 g (11.03 mmol) of dimethylamine hydrochloride and 0.33 g (10.99 mmol) of paraformaldehyde were added to the reaction mixture, followed by heating under reflux for 5 hours. Some of the solvent was distilled off under reduced pressure. The residue was dissolved in water. After washing with ether, the solution was made alkaline with potassium carbonate and extracted. After the ether phase was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of ethanol and 3.7 g (26.05 mmol) of methyl iodide were added to the solution thus obtained. The mixture was stirred at room temperature for 18 hours. The crystals formed were filtered off. 7.71 g (yield 5.7%) (8-n-pentyloxy-2-methoxymethylimidazo (1,2-a] pyridin-3-yl) methyltrimethylammonium iodide with a melting point of 155-156 ° C. were obtained.

Elemental Analysis (CigHggNjC ^ J.l # H2O) C H N Calculated: (%) 47.37 6.84 9.20 Found: (%) 47.58 6.63 9.02 Example 62: c (ck2) 4ch3

. 1/2 fumarate -45-

No. 390 438

1 g of 3-amino-2-methyl-8-n-pentyl-oxyimidazo [1,2-a] pyridine was dissolved in 10 ml of ether and 0.43 g of triethylamine was added to the solution thus obtained. At a temperature of 5 ° C or below, 0.30 ml of acetyl chloride was added to the solution. After stirring at room temperature for one hour, the solvent was distilled off under reduced pressure. After treatment by column chromatography, the residue was converted to the fumarate. The compound was recrystallized from ethanol-ethyl acetate and 031 g of 3-acctylamino-2-methyl-8-n-pentyloxyimidazo [1,2-a] pyridine 1/2 fumarate was obtained.

· &Gt; 0 (ch2) 4ck3

2 2

Mp 183-186 ° C, mass (EI) m / z 275 (M +). Elemental Analysis C4H4O4) C H N Calculated; (%) 61.25 6.95 12.60 Found: (%) 60.98 6.96 12.46

Example 63:

1 g of 3-amino-2-methyl-8-n-penteneoxyimidazo [1,2-a] pyridine was dissolved in 10 ml of ether and 0.43 g of triethylamine was added to the solution thus obtained. At a temperature of 5 ° C or below, 0.4 ml of ethyl sulfonyl chloride was further added to the solution. The mixture was stirred at room temperature for one hour. Then ethyl acetate was added and then washed with water. The solvent was then distilled off under reduced pressure. After refluxing in saturated hydrogen chloride-ethanol, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetal isopropyl ether. 0.13 g of 3-ethylsulfonylamino-2-methyl-8-n-pentyloxyimidazo [1,2-a] pyride was obtained.

Mp 114-115 ° C, mass (EI) m / z 325 (M +).

Elemental analysis (C15H23N3O3S) C H N S Calculated (%) 55.36 7.12 12.91 9.85 Found: (%). 55.57 6.96 12.80 9.83 46-

Claims (10)

00 wherein R * has the meaning given above in claim 1, and R ^ g is a C ^ -Cg alkyl group or a phenyl group which is optionally substituted by a C j -Cg alkoxy group, with a -52- No. 390 438 nitrosilation agent of the general formula (VI) R9ONO (VI), 5 in which R9 is an alkali metal, hydrogen or a C 1 -C 6 -alkyl group, and that one is obtained by one of processes (a) to (d) At most, the compound is converted into a salt or vice versa. No. 390 438 PATENT CLAIMS 1. New imidazo [1,2-a] pyridine derivatives of the general formula (I). O-R &quot; 0) or a salt thereof, in which an alkenyl group having 4 to 6 carbon atoms or an alkyl group having 1 to 10 carbon atoms, which is optionally substituted by a cycloalkyl group, a hydroxy group, a (C j-Cg-alkoxy) carbonyl group, a Cj-Cg Alkyl group which is optionally substituted by a hydroxyl group, a Cj-Cg-alkoxy group or a (Cj-Cg-alkoxy) carbonyl group, a phenyl group which is optionally substituted by a Cj-Cg-alkoxy group, or a (Ci Cg-acyloxyjalkyl group, which is optionally substituted by a C2-Cg-acyloxy group, and RJ hydrogen, a C j -Cg alkyl group, a halogeno (C j -Cg alky l) group, a (Cj-Cg alkoxy) alkyl group, a hydroxy (Cj-Cg-alkyl) group, a cyano (Cj-Cg-alkyl) group, a mono- or di (Cj-Cg-alkyl) amino (Cj-Cg-alkyl) group, an amino group, a mono- or di (C j -Cg-alkyl) amino group, a nitroso group, a (Cj-Cg-alkoxy) carbonyl group, a C2-Cg-acylamino group, ei ne Cj-Cg-alkylsulfonylamino group, a group of the formula R '-CH / Dr-I 2% V, (where D is NH or sulfur, E is nitrogen or CH, and and R® have the same or different meaning and hydrogen, one C j -Cg alkyl group, a (C | -Cg-alkoxy) carbony l group or a phenyl group), a group of the formula -ch2c / \ NH <i -47- No. 390 438 7 7 (in which X is oxygen, sulfur or NR ', in which R' is a sulfamoyl group, represents a C2-Cg-acylamino group or a Cj-Cg-alkynyl group), or a group of the formula: ch2-y-r8 (in which Y is oxygen or sulfur, and R8 is a cyano (C j-Cg-alkyl) group or represents a C 1 -C 6 alkynyl group). 2. A compound according to claim 1, wherein R ^ is a Cj-Cg-alkyl group which is optionally substituted by a hydroxy group, a Cj-Cg-alkoxy group, or a (Cj-Cg-alkoxy) carbonyl group, or a (C2- Cg-acyl) oxyalkyl group, which is optionally substituted by a C2-Cg-acyloxy group, and R8 is a C j -Cg alkyl group, a halogeno (C | -Cg-alkyl) group, a (Cj-Cg-alkoxy) alkyl group , a hydroxy (Cj-Cg-alkyl) group, a cyano (Cj-Cg-alkyl) group, an amino group, a mono- or di (Cj-Cg-alkyl) amino group, a nitroso group or a (C 2 -Cg-alkoxy) carbonyl group. 3. A compound according to claim 1, wherein R ^ is a C2-Cg-alkyl group and R ^ is a cyano- (C2-Cg-alkyl) group. 4.3- Cyanomethyl-2-methyl-8 - [(3-methyl-2-butenyl) -oxy] imidazo [1,2-a] pyridine and its salts. 5.3- Cyanomethyl-8-cyclohexylmethoxy-2-melhyl-imidazo [1,2-a] pyridine and its salts. 6.3- Cyanomethy 1-2-methyl-8-pentyloxyimidazo [1,2-a] pyridine and its salts. 7. Process (a) for the preparation of a new imidazopyridine derivative of the general formula (Ia) Oa) or a pharmaceutically acceptable salt thereof, characterized in that an amino-substituted pyridyl ether of the general formula (II) 0D -48- No. 390 438 with a compound of the general formula (III) o R2 «. CH / \ X R3a m, wherein R1 and R2 have the meaning given above in claim 1 and R2a halogen, a (Ci-Cg-Alkoxyjcarbonylgruppe, a Cj-Cg-alkyl group, which may be replaced by a (C i -Cg-alkoxy ) carbonyl group, or a phenyl group which is optionally substituted by a Cj-Cg-alkoxy group, R ^ a is hydrogen, a Cj-Cg-alkyl group, a cyano- (C2-C5-alkyl) group, or a (C | -Cg-alkoxy) carbonyl group and X is a halogen or an organic sulfonic acid radical and that the product is at most converted into a salt or vice versa; or that b) for the preparation of an imidazopyridine derivative of the formula (Ih) or a pharmaceutically acceptable salt thereof, an amino-substituted pyridine ether of the general formula (II) T O-R “NK. (Π) with an aldehyde of the general formula (VII) R2 f-CHO m and an alkali metal cyanide of the formula (VIII) MCN (vm) -49- No. 390 438 1 ο, wherein R has the meaning given in claim 1 above , R f is a C j-Cg alkyl group and M is an alkali metal, and that the product is converted into a salt or vice versa. 8. Process for the preparation of an imidazopyridine derivative (a) of the general formula (Ib) O-R R3b or (Ib ') or a pharmaceutically acceptable salt thereof, characterized in that a compound of the general formula (IV) or (IV) OR 1 -50- No. 390 438 wherein R * has the meaning given above in claim 1, R ^ b is a Cj-Cg-alkyl group, R ^ b is a hydroxy (Cj-Cg-alkyl) group, a cyano (C j-Cg-alkyl) group or an amino group and R ^ b is a group which can be reduced to a hydroxy- (Cj-Cg-alkyl) group or an amino group, reduced, that (b) to prepare an imidazopyridine derivative of the general formula (Id ) 1 O-R &quot; m or a pharmaceutically acceptable salt thereof, a compound of the general formula 0c) 0c) wherein R ^ has the meaning given above in claim 1, R ^ c is a Cj-Cg-alkyl group or a phenyl group which is optionally substituted by a Cj-Cg-alkoxy group, R ^ d is a halogeno- (C | -Cg -alkyl) group and R ^ c denotes a hydroxy (C j -Cg-alkyl) group, reacted with a halogenating agent that (c) for the preparation of an imidazopyridine derivative of the general formula 0e) 0e) -51- (V) No. 390 438 or a pharmaceutically acceptable salt thereof, a compound of the formula (V) R2e 1 0 wherein R has the meaning given in claim 1 above, R e is a Cj-Cg-alkyl group which is optionally substituted by a Cj-Cg-alkoxy group, or a phenyl group which is optionally substituted by a C | -Cg-alkoxy group, R ^ e is a cyano- (Cj-Cg-alkyl) group and R ^ is a group which can be converted into a cyano- (Cj-Cg-alkyl) group, with one forming a cyano group «! Agent or a dehydrating agent, or that (d) for the preparation of an imidazopyridine derivative of the general formula (lg) NO dg) or a pharmaceutically acceptable salt thereof, a compound of the general formula (10 9. A process for the preparation of a compound according to claim 1, characterized in that one carries out a process according to claim 7 or 8, that one converts another 10 substituent in the product of the formula (I) thus obtained, and that the compound thus obtained Formula (I) at most converted into a salt or vice versa. 10. Pharmaceutical preparation, characterized by a pharmaceutically effective content of an imidazo [l, 2-a] pyridine derivative or a pharmaceutically acceptable salt thereof according to one of claims 1 to 6 and a pharmaceutically acceptable carrier. -53-