CA1263390A - 3-(acylaminomethyl)imidazol[1,2-a]pyridine derivatives, their preparation and their application in therapy - Google Patents

Abstract

ABSTRACT

3-(ACYLAMINOMETHYL)IMIDAZO[1,2-a]PYRIDINE DERIVATIVES, THEIR
PREPARATION AND THEIR APPLICATION IN THERAPY

A compound which is a 3-(acylaminomethyl)-imidazo[1,2-a]pyridine derivative of formula (I) (I) in which R1 denotes hydrogen; linear or branched C1-C4 alkyl; or benzyl:
R2 denotes linear or branched C1-C6 alkyl; cyclohexyl;
trichloromethyl; 1-propenyl; allyl; phenyl; 4-chlorophenyl;
or benzyl:
or R1 and R2 together denote a C3-C5 aliphatic chain:
and either a) X1 and X2 both denote hydrogen, X3 denotes halogen; C1-C3 alkyl; methylthio;
trifluoromethyl; optionally esterified carboxy of formula -COOR in which R denotes hydrogen or C1-C6 alkyl; cyano;
optionally mono- or dialkylated aminocarbonyl of formula -CONR3R4 in which R3 and R4 independently denote hydrogen or C1-C4 alkyl or together denote a chain of formula -(CH2)2-Z-(CH2)2- in which Z denotes a direct bond, oxygen, sulphur, or a divalent group of formula -CH2-, -NH- or -N(C1-C4 alkyl)-; alkylamino of formula NHR5 in which R5 denotes C2-C6 alkyl; or dialkylamino of formula -NR6R7 in which R6 and R7 independently denote C2-C6 alkyl or together denote a chain of formula -(CH2)2-Z-(CH2)2- in which z denotes a direct bond, oxygen, sulphur, or a divalent group of formula -CH2-, -NH- or -N(C1-C4 alkyl)-: and Y denotes hydrogen; halogen; methyl; trifluoromethyl;
optionally esterified carboxy of formula -COOR8 in which R8 denotes hydrogen or C1-C6 alkyl; cyano; optionally mono- or dialkylated aminocarbonyl of formula -CONR9R10 in which R9 and R10 independently hydrogen or C1-C4 alkyl; or optionally mono- or dialkylated amino of formula -NR11R12 in which R11 and R12 independently denote hydrogen or C1-C4 alkyl:
with the exclusion, in case (a), of compounds in which X3 denotes halogen; alkyl; or methylthio and Y denotes hydrogen; halogen; or methyl:
or b) X1, X2 and X3 independently denote hydrogen; halogen;
C1-C4 alkyl; methoxy; methylthio; ethylthio;
methylsulphonyl; nitro; amino; methylamino; dimethylamino;
acetylamino; or diacetylamino: and Y denotes hydrogen; chlorine; or methyl:
with the exclusion, in case (b), of compounds in which X1 and X2 both denote hydrogen:
or a pharmacologically acceptable acid addition salt is useful in therapy.

Description

339(3 3-(ACYLAMINOMETHYL)IMIDAZO[1,2-a]PYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION IN THERAPY

The present invention provides compounds which are 3-~acylaminomethyl)imidazo[1,2-a]pyridine derivatives of formula ( I) given in the scheme givsn below, in which 5 R1 denotes hydrogen; linear or branched Cl-C4 alkyl; or benzyl:
R2 denotes linear or branched Cl-C6 alkyl; cyclohexyl;
trichloromethyl; l-propenyl; allyl; phenyl; 4-chlorophenyl;
or benzyl:
lO or alternativel~ R1 and R2 together denote a C3-Cs aliphatic chain:
and either a) X~ and X2 both denote hydrogen, X3 denotes halogen; Cl-C3 alkyl; methylthio;
15 trifluoromethyl; optionally esterified carboxy group of formula COOR in which R denotes hydrogen or Cl-C6 alkyl;
cyano; optionally mono- or dialkylated aminocarbonyl of formula CONR3R6 in which R3 and R4 independently denote hydrosen or C1-C4 alkyl or together denote a chain cf 20 formula -(CH2)2-Z-(CH2)2- in which Z denotes a direct bond, oxygen, sulphur or a divalent group of formula -CH2-, -NH-or -N~C1-C4 alkyl)-; alkylamino of formula NHRs in which Rs denotes C2-C6 alkyl; or a dialkylamino of formula NR6R7 in which R6 and R7 independently denote C2-C6 alkyl or together 25 denote a chain of formula -(CH2)2-Z-(CH2)2- in which Z

~J~
-3;~

denotes a direct bond, oxygen, sulphur or a divalent group of formula -CH2-, -NH- or -N(C1-C4 alkyl)-: and Y denotes hydrogen; halogen; methyl; trifluoromethyl;
5 optionally esterified carboxy of formula COOR3 in which ~
denotes hydrogen or Cl-C6 alkyl; cyano; optionally mono- or dialkylated amino carbonyl of formula CO~RgR1o in which Rg and Rlo independently denote hydrogen or C1 -C4 alkyl; or optionally mono- or dialkylated amino of formula NR1lR1 2 in 10 which R11 and R~ 2 independently denote hydrogen or C1-C4 alkyl;
with the exclusion, in case ~a), of compounds in which X3 denotes halogen; alkyl; or methylthio and Y denotes hydrogen; halogen or methyl:
15 or b) X1, X2 and X3 independently denote hydrogen; halogen;
C1-C4 alkyl; methoxy; methylthio; ethylthio;
methylsulphonyl; nitro; amino; methylamins; dimethylamino;
acetylamino; or diacetylamino: and 20 Y denotes hydrogen; chlorine; or methyl:
with the exclusion, in case (b), of compounds in which X
and X2 both denote hydrogen:
or their pharmacologically acceptable acid addition salts.
The preferred compounds are those in which R
25 denotes hydrogen or methyl and R2 denotes propyl or isobutyl.

~3~

The compounds of the invention can be prepared according to the scheme on the following page.
A 2-aminopyridine of formula (II), bearing a substituent Y, is reacted with a 2-bromoethanone of formula 5 (III) bearing the substituents xl, x2 and X3, preferably in a protic solvent such as an aliphatic alcohol and in a heated state and in the absence or presence of a base such as an alkali metal carbonate or hydrogen carbonate. The imidazo[l,2-a]pyridine of formula (IV) thereby obtained is 10 hydroxymethylated, for example by means of formaldehyde in a solvent of the carboxylic acid type, such as acetic acid, or any other equivalent means, to obtain an alcohol of formula (V) .
The alcohol of formula (V) can also be obtained 15 from the imidazo[l,2-a]pyridine of formula (IV) in two stages, the first being a formylation, for exa~ple by means of a reagent which can be obtained by the action of oxalyl chloride on dimethylformamide. After hydrolysis, an aldehyde is obtained which, in the second stage, is reduced 20 to the corresponding alcohol of formula (V), in a known manner, for example by the action of an alkali metal borohydride.

3~

SCHEME
Xl x2 + Br~x3 (II) / (~II) y~ X3 y~ i ~X3 (IV) (v) ., I ~ 1 Xl X2 Xl X2 ~ ~\~N ~
J~N ,/~=~_X3 ~ J~ ~ X3 Rl - N HN
o~~ R2 o~ R2 lI) (Ia) i~6~3~

The alcohol (V) is then reacted with a nitrile of formula R2-CN in an acid medium, for example an acetic or sulphuric acid medium, preferably at a temperature of from 0 to 150C, depending on the nitrile used. After hydrolysis, 5 a compound of formula (Ia), in which the substituent R1 is hydrogen, is obtained. If desired, it is possible to alkylate or benzylate this compound in a known manner, for example with a halide of formula R1-hal in the presence of an alkali metal hydride, and in a suitable solvent such as lO tetrahydrofuran, to yield a compound of formula (I) in which Rl i5 an alkyl or benzyl group.
The compounds of formula (I) can also be prepared in two stages by reacting the imidazopyridine of formula (IV) with an amide of formula R2~ _Rl in which R1 and R2 are as defined above. The reaction is generally performed at room temperature, preferably in the presence of concentrated sulphuric acid and optionally with a cosolvent such as glacial acetic acid.
It i~ also possible to prepare compounds of formula (Ia) by reactin~ the imidazopyridine of formula (IV) with a nitrile of formula R2-CN and paraformaldehyde, generally in the heated state, preferably in acetic acid medium and in the presence of sulphuric acid.
The compound (Ia) obtained after hydrolysis can 3~

then, if so desired, be alky:Lated or benzylated as described above.
The compounds of formula (I) in which Xl ~ X2 ~ X3 and/or Y denote an amino group may be obtained by reduction 5 of the corresponding nitro compounds, for example using a metal such as iron or zinc, in a protic or acidic solvent such as ethanol or acetic acid, or alternatively with tin derivatives such as stannous chloride.
The compounds of formula (I~ in which Xl ~ X2 ~ X3 10 and/or Y denote an alkylamino or dialkylamino group may be obtained, either by alkylation of the primary amine, for example by means of an alkyl halide in the presence of a tertiary base, or by reductive amination, for example by means of an aldehyde and alkali metal borohydride in a 15 netural or acid protic medium.
These amino derivatives can, of course, also be obtained directly from the compounds of formulae (II) and ~III) in which X3 denotes NHRs or NR6R~ and Y denotes NR11Rl2 from the outset, as specified in the reaction scheme 20 above.
The compounds of formula (I) in which X3 and/or Y
denote cyano can be obtained by reaction of the compounds of formula (I), in which X3 and/or Y denote halogen, especially iodine, with a cyanide, for example a metal cyanide such as cuprous cyanide, generally in an organic solvent such as pyridine or dimethylformamide. They can also be obtained f~2~ t~3~3~

directly from the compounds of formulae (II) and (III) in which X3 and/or Y denote cyano from the outset, as specified in the reation scheme above.
The compounds of formula (I) in which X3 and/or Y
5 denote carboxylate of formula C02R can be obtained by reaction of the compounds of formula (I) in which X3 and/or Y denote cyano with gaseous hydrochloric acid in the corresponding alcohol of formula ROH as solvent, followed by hydrolysis. They can also be obtained directly from the 10 compounds of formulae (II) and (III) in which X3 and/or Y
denote carboxylate from the outset, as specified in the reaction scheme above.
The compounds of formula (I) in which X3 and/or Y
denote carboxyl or carboxamide may be obtained by 15 hydrolysi5, preferably acid hydrolysis, of the corresponding compounds of formula (I) in which X3 and/or Y denote cyano.
The hydrolysis can be carried out, for example, in an hydrochloric acid medium, in the heated state, alone or with an acidic organic cosolvent such as acetic acid, and at a 20 temperature of from 60 to 120C.
The compounds of formula (I) in which X3 denotes a group CONR3R4 and/or Y denotes a group CONRgRl~ can be obtained by amidation of the corresponding acids, for example by reaction of the compounds of formula (I), in 25 which X3 and/or Y denote a group of formula CO2H, with carbonyldiimidazole in an inert solvent such as ~i33~

tetrahydrofuran, followed by aminolysis of the intermediate imidazolide obtained in situ by means of an amine of formula R3R4HN or RgR1oNH respectively, in which the substituents R3, R4, Rg and R1o correspond to the definitions given 5 above.
More especially, the compounds of formula ~I) in which X3 and/or Y denote CON~2 can also be prepared, either by partial hydrolysis of the corresponding nitriles, or by reaction of the same nitriles, for example with gaseous lO hydrochloric acid in formic acid.
The examples which follow illustrate the preparation of a few compounds according to the invention.
The microanalyses and the IR and NMR spectra confirmed the structures of the products obtained.
Example 1 N-{l2-(4-Methylphenyl)-6-trifluoromethylimidazoll,2-a]-pyrid-3-yl]methyl~-N,3-dimethylbutanamide.
1.1. 2-(4-Methylphenyl)-6-trifluoromethyl-imida~oll,2-a]-pyridine.
10 g (0.0616 mole) of 2-amino-5-trifluoromethyl-pyridine and 17.5 g (0.0616 mole) of 1-bromo-2-(4-methyl-phenyl)-2-ethanone are mixed in 200 ml of n-propanol and the solution is heated to reflux. At the end of the reaction, the reaction mixture is concentrated under reduced pressure and the evaporation residue taken up with water and treated with an excess of ammonia solution until the pH i~ basic.

3~

~he imida~opyridine is extracted with dichloromethane and puri4ied by chromatography. 11.95 9 (56~) of white solid are obtained.
M.p. 187-188C.
5 1.2. 2-(4-Methylphenyl)-6-trifluoromethyl-imidazo[1,2-a]-pyridine-3-methanol.
13.~ 9 (0.0463 mole) of im;dazopyridine prepared according to 1.1. and 32 ml of 37% strength formaldehyde in water are dissoLved in 160 ml of acetic acid. This 10 solution is maintained at 6~C for 3 hours and the solvent is then driven off under reduced pressure. The evapor-ation residue is taken up ~ith 70 ml of water, 21 ml of caustic soda and 260 ml of dichloromethane. The two-phase mixture is stirred for 1 hour and the insoLuble material 15 is then separated by filtration, ~ashed ~ith acetone and then ether and dr;ed. 6.17 9 of the expected alcohol ~44~) are~obtained.
M.p. 216-218C.
1.3. N-~t2-(4-Methylphenyl)-6-trifluoromethylimidazo-20 t1,2-a]pyrid-3-yl~rethyl}-3-methylbutanamide.
6.1 9 (0.02 mole) of the alcohol obtained accord-ing to 1.2. 3nd 40 ml of isovaleronitrile are intrDduced into a 250-ml round-bottomed flask. The suspension ;s heated to 100C snd 5.7 ml of concentrated sulphuric 25 acid are added to it dropvise. All the reagen~s go into solution, and a precipitate then appears. Ice is then added and the 0edium is diLuted uith uater and treated uith ~mmoni~ solution (until pH > 8), and the amide is e~tracted ~ith dichloromethane.
5.9 9 (80X) of product are finally collerted.

M.p. 212-213C.

. .

~P63~3~

1.4. N-{r2-(4-Methylphenyl)-6-trifLuoromethyLimidazo-t1,2-a]pyrid-3-yL]methyL}-N,3-dimethylbutanamide.
1.23 9 (0.0256 mole) of SOX strength sodium hy-dride in oil is suspended in 40 ml of tetrahydrDfuran 5 with 2 ml of dimathylformamide. There is added to this a solution of 60 ml tetrahydrofuran and 3 ml of dimethyl-formamide containing 5 9 (0.0128 moLe) of amide prer,ared according to 1~3. and 1.6 ml of methyl iodide. The mix-ture is stirred until the evolution Df gas has ceased, lO and then for a further 1 hour, and is concentrated under reduced pressure. The evaporation residue is taken up with water and the tertiary amide extracted uith dichloro-methane. After drying, 5 9 (96%) of amide are obtained.
M.p. 196-197C.
15 Example ~
N-~t2-(4-MethyLphenyL)-6-nitroimidazo~1,2-a]pyrid-3-yL]-methyl}-N,3-dimethylbutanamide.

2.1. 2-(4-~ethylphenyl)-6-nitroimidazo[1,2-a]pyridine.
81 9 (D.38 mole) of 1-bromo-2-(4-methyLphenyL)-20 2-ethanone and 53 9 (û.38 moLe) of 2-amino-5-nitropyridine are reacted in 9ûO ml of n-propanol. The soLution is ~aintained under ref;ux, the reaction being foLLowed by thin lsyer chromatographyv ~hen there is no further change, the mixture is evapora~ed to dryness. The resi-25 due is t~ken up uith water and treated uith am~onia solutionuntil the pH >8. The insoluble ~aterial is filtered off snd dried, and then treated with dichloromethane. The insoluble portion is recrystallized in ethyl acet2te, uhich yields ~ first crop. The mother liquors are then combined with the portion soluble in dichloromethane, the mixture is concentrated and a second crop of product is obtained. The two crops are purified separately by chromatography. 22 9 (23%) of yellow solid are obtained overall.
M.p. 2D5-206C.
2.2. 2-(4-Methylphenyl)-6-nitroimidazo[1,2-a]pyridine-

3-methanol.
14 9 (0.056 mole) of imidazopyridine prepared ac-10 cording to 2.1. and 45 ml of 37% strength aqueous formal-dehyde are added successively to 200 ml of acetic acid.
The solution is heated to 60C for 4 hours. At the end of the reaction, the solvent is evaporated off under re-duced pressure and the solid residue treated with 76 ml 15 of water, 25 ml of caustic soda and 310 ml of dichloro-methane. This tvo-phase mixture is stirred for 1/2 hour, then treated with an excess of ammonia solution and stirred for a further 1/2 hour~ The insoluble material is collected by filtration and washed with water, then 20 ethyl acetate and ether. 11.5 9 ~73~) of alcohol are obtained.
M.p. 236-238C.
2.3. N-{[2-(4-Methylphenyl)-6-nitroimidazo~1,2-a]pyrid-3-yl]methyl}-3-methylbutanamide.
6.88 9 (0.0242 mole) of alcohoL prepared according to 2.2. and 40 ml of isovaleronitrile are introduced into a 100-ml round-bottomed flask, and the solution is brought to 100C. 6.7 ml of suLphuric acid are added dropwise to this suspension and the mixture is left with stirring until 2 phases are obtained. The upper phase is removed and the remainder of the reaction mixture treated with ice, then diluted with water and treated with concentrated ammonia solution untiL the pH > 8. The inso~uble materia~
is filtered off and washed with dichLoromethane and then with water, acetone and finally ether.
6.92 g of pure product are obtained.
2.24 g are recovered by partial evaporation of the dichloromethane. The two batches are combined and the product is recrystallized in ethyl acetate.
M.p. 239-241C.
Example 3 N-{~Z-(4-Methylphenyl)-6-aminoimidazo[1,2-a]pyrid-3-yL~-methyL}-3-methyLbutanamide.
1 g (0.0026 moLe) of amide prepared according to 2.3. and 2.5 g of stannous chloride are introduced into 25 ml of ethanol. The mixture is heated to 7ûC for 3 h, and then evaporated to dryness. The residue is taken up with water and 1 N ammonia solution and the product extracted with dichloromethane. The organic phase ;s dried over sodium sulphate, f;ltered and evaporated under reduced pressure. The evaporation residue is pur;f;ed by column chromatography.
M.p. 245-247C.

Example ~
N-{~6-MethyL-2-(4-trifLuoromethy~phenyl)imidazo[1,2~a]-pyrid 3-yl]methyl}-~,3-dimethyLbutanamide.

4.1. 6-Methyl-2-(4-trifLuoromethyLphenyl)imidazo[1,2-a]-pyridine.
24 9 (0.077 moLe) of 1-bromo-2-(4-trifluoromethyl-phenyl)-2-ethanone, 8.4 9 tO.077 mole) of 2-amino-5-methyl-pyridine and 13 9 of sodium bicarbonate are mixed in Z10 mL
of 95X strength ethanol, and this suspension is heated under reflux until the evoLution of gas has ceased. The soLvent is then evaporated off under reduced pressure and the evaporation residue is taken up with ~ater and di-chloromethane. The organic phase is decanted and dried over magnesium suLphate, and the soLvent is removed by evaporation under reduced pressure. The residue is puri-fied by column chromatography.
18.4 9 t78~ of imidazopyridine are obtained.
M.p. 216-217C~
4.2. 6-Methyl-2-(4-trifluoromethylohenyL)imida2O[1,2-a]-pyridine-3-methanol.
1B 9 (0.065 mole) of imidazopyridine obtained according to 4.1. and 46 ml of 37~ strength formaldehyde in water are dissolved in 230 ml of acetic acid. The mixture is ma;ntained at 60C until the starting sub-stance has disappeared (followed by th;n layer chroma-tography), and is then concentrated under reduced pres-sure. The residue ;s taken up with 9û ml of water, 29 ml of caustic soda and 360 ml of dichloromethane, and the mi~ture is stirred for 1/4 hour. The inso~uble material is coLlected by filtration and washed with water, acetone and ether. 14 9 (70%~ of alcohol are obtained.
M.p. 225-226C
4 3. N-{[6-Methyl-2-(4-trif~uoromethyLphenyl)i~idazo[1,Z-a]-pyrid-3-yl~methyl}-3-methylbutanamide.
7 9 (0.0228 mole) of alcohol obtained according to 4.2. and 40 ml of isovaleronitrile are introduced into a 250-ml round-bottomed flask. This suspension is heated to 100C and 6.5 ml of sulphuric acid are added to it drop~ise. All the reagents go into solution, and a pre-cipitate then appears. The medium is diluted ~ith ice and then water, and the solution is then treated with ammonia solution until the pH >8 and finally with 2D0 ml of dichloromethane. The organic ,ohase is decanted and dried over sodium sulphate.
After filtration and evaporation of the sr,lvent, 8 9 (90%) of amide are obtained.
M.p. 200-202C.
4.4. N-{[6-Methyl-2-(4-trifluoromethylphenyl)imidazo-~1,2-a]-pyrid-3-yl~methyl}-N,3-dimethylbutanamide.
S ~ (0.128 mole) of the secondary amide obtained according to 4.3. and 1.6 ml of methyl iodide dissolved in 63 ml of a tetrahydrofuran/dimethylformamide (~5:5) mixture are added to a suspension of 1.23 9 (000256 mole) of 50% strength sodium hydride in oil in a mixture of 40 ml 33~

of tetrahydrofuran and 2 ml of dimethylformamide. After the evolution of gas has ceased, stirrins is maintained for 1 hour and 1 ml of methanol is then added. The solvent is evaporated off under reduced pressure, the evaporation residue taken up with water and the tertiary amide extracted with dichloromethane.
4.5 9 (87%) of tertiary amide are obtained.
M.p. 1Z9-130C.
~xample S
Ethyl 4-{6-methyl-3-[(3-methylbutanoyl)aminomethyl]imidazo-[1,2-a]pyrid-2-yl}benzoate.

5.1. Ethyl 4-(6-methyLimidazo[1,2-a]pyrid-2-yl)benzoate.
67 9 (0.62 mo(e) of Z-amino-5-methylpyridine, 86 9 (1.02 mole) of sodium bicarbonate and 143 9 (0.527 mole) of ethyl 4-(2-bromoacetyl)benzoate are introduced into 1 l of ethanol. The mixture is brought to reflux for 3 hours and left standing for 19 hours, and the solid formed is recovered by fiLtration, washed copiously with ~ater and dried. It is recrystallized in a dichloromethane/
methanol mixture.
M.p. 228-230C.
5.2. Ethyl 4-(3-hydroxymethyl-6-methylimidazo[1,2-a]pyrid-2-yl)benzoate.
31 g (0.1 mole) of the benzoate obtained acçord-ing to S.1. and 81 9 (1 mole) of 37% strength formaldehydein ~ater are added successively to 200 ml of acetic acid.

Stirring is maintained for several hours and the acetic `3~

- '0 -acid is then evaporated off The evaporation residue is taken up with water and then with an excess of ammonia solution until the pH is basic. The solid is extracted with dichloromethane and recrystallized in a dichLoro-methane/ether mixture.
M.p. 157-159C.
5.3. Ethyl 4-{6-methyl-3-t~3-methylbutanoyl)aminomethyl]-imidazo[1,2-a]pyrid-2-yl}benzoate.
20 ml of isovaleronitrile and 5 9 (0.016 mole~ of 1û alcohol Drepared according to 5.2. are mixed, 4 ml of concentrated sulphuric acid are then added dropwise and the reaction medium is heated to 100C unt;l 2 phases are formed. The lower phase is treated with 100 9 of ice, and diluted with water or treated with ammonia so-lution until the pH is basic. ~he amide is extractedwith dichLoromethane and purified by chromatographyO A
white solid is obtained.
M.p. 230-231C.
Example 6 N-~C6-Methyl-2-~4-(1-piperidyl)phenyl]imidazol1,2-a]pyrid-3-yl}methyl]-N,3-dimethylbutanamide.

6.1. 6-Methyl-2-(4-nitrophenyl~imidazo~1,2-a~pyridine.
59.5 9 (0.2 mole) of 1-bromo-2-t4-nitrophenyl)-2-ethanone, 21.6 9 (û.2 mole) of 2-amino-5-methylpyridine and 34 9 of sodium bicarbonate are reacted in 200 ml of 95% strength ethanol. Stirring and refl~xing are main-tained for 3 hours, and the reaction mixture is then cooled and the ethanol evaporated off under reduced pressure.
The evaDoration residue is stirred in 700 ml of ~ater at 70C for 3 hours, and the insoluble material is then filtered off, ~ashed with S0 m( of ethanol and then ether and dried.
M p 237-239C
6.2. 6-Methyl-2-(4-nitrophenyl)imidazoC1,2-a]pyridine-3-methanol.
50 9 (0.2 mo!e) of imidazopyridine obtained ac-cording to 6.1. and 140 ml of 37% strength aqueous for-maldehyde are mixed in 700 ml of glacial acetic acid, and the solution is brought to 60C for 3 hours. The solvent is then evaporated off under reduced pressure and the evaporation residue taken up with ~ater, treated with ammonia solution until the pH >8, and taken up between water and dichLoro-methane. The insoluble material is separated by fil-tration and washed w;th ether. It is recrystallized in a mixture of methanol and ethanol.
36 9 (64%) of product are obtained.
M.p. 237-238C.
6.3. N-{[6-Methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyrid-3-yl~methyl~-3-methylbutanamide.
0.8 ml of concentrated sulphuric acid is introduced drop~ise and with stirring into 2û ml of isovaleronitrile containing 2 9 (0.0076 mole) of alcohol obtained according to 6.2. The suspension is then heated until tuo phases are formed. The supernatant liquid is removed and the 63~

remainder of the liquid hydrolysed and then treated with an excess of ammonia solution unt;l the pH >8. The in-soluble material is extracted with dichloromethane; after drying, filtration and evaporation of the solvent, 9.1û 9 (88%) of secondary amide are obtained.
M.p. 221-222C.
6.4. N-{[6-Methyl-2-(4-nitrophenyl)imidazoL1~2-a]pyrid 3-yl]methyl}-N,3-dimethylbutanamide.
A solution of 85 ml of tetrahydrofuran/dimethyl-formamide (95:5) containing 7 9 (0.019 mole) of amide ob-tained according to 6.3. and 2.4 ml of methyl iodide is added to a suspension of 1.83 9 (0.07c, mole) of sodium hydride (at 50~ strength in oil) in S0 ml of a tetrahy-drofuran/dimethylformamide (95:5) mixture. The suspension is maintained with stirring until 1 hour after the evo-lution of gas has ceased. The excess sodium hydride is destroyed with methanol and the sr,lvents are then evapo-rated off under reduced pressure. The solid residue is taken up with water and dichloromethane. The organic phase is decanted, dried over sodium sulphate and filtered, and the solvent evaporated off. The solid obtained is purified on a chromatography column and then by recry-stallization in a mixture of ethyl acetate and cyclo-hexane.
4.7 9 (65%) of product are obtained.
M.p. 157-159C.

3~
_ 19 _ 6.5. N-{~6-Methyl-2-(4-aminophenyl)imidazo~1,2-a]pyrid-3-yl]methyl}-N,3-dimethylbutanamide.
3.5 9 (0.0144 mole) of amide obtained according to 6.4., 3.42 9 of powdered iron and 6 9 of acetic acid S are reacted in 100 ml of absolute ethanoL. The suspension is heated under refLux for 4 hours 30 min and then cooLed.
The ethanol and the acetic acid are driven off under re-duced pressure, the residue is treated with 350 ml of water and the product is extracted with dichloromethane.
After purification by chromatography, 4.4 9 (87~) of product are obtained.
M.p. 178-179C.
6.6. N-[~6-Methyl-2-[4-(1-piperidyl)phenyl]imidazo[1,2-a]-pyrid-3-yl}methyl]-N,3-dimethylbutanamide.
1.7 9 (0.00485 mole) of amide obtained according to 6.5., 120 ml of dry toluene, 0.56 9 (0.00243 mole) of 1,5-dibromopentane and 0.75 9 (0.0058 mole) of ethyldi-isopropylamine are introduced successively into a 250-ml round-bottomed flask. The mixture is heated under re-flux for 13 hours and then concentrated under reduced pressure. The oily residue is purified directly by chromatography.
A yellowish oil is obtained, the hydrochloride of which is prepared in a mixture of isopropyl alcohoL and ether.
M.p. 116-118~C.

Example 7 N-{[6-Methyl-2-(4-diethylaminophenyl)imidazo[1,2-a]pyrid-3-yL]methyl}-N,3-dimethylbutanamide.
1.3 9 (0.0037 mole) of amide obtained according to 6.5. is dissolved in 25 ml of methanol containing 0.6 9 (0.0013 mole) of acetaldehyde in a round-bottomed flask maintained under argonO A solution of 0.5 9 (0.0079 mole) of sodium cyanoborohydride and 0.55 9 (0.0039 mole) of zinc chloride in 8 ml of methanol is added to this mixture.
After 1 hour's react;on, 0.5 ml of acetic acid is added and stirring is maintained for a further 2 hours at room temperature, and then overnight at 50C. The re-action mixture is then treated with 20 ml of 0.1 N sodium hydroxide and the solvents are driven off under reduced pressure. ~he evaporation residue is treated with di-chloromethane, and the organic phase is ~ashed with water, decanted and dried.
After evaporation of the solvent, the product obtained is purified by chromatography.
An oil is obtained, the dihydrochloride of which is prepared in a mixture of isopropyl aLcohol and ether.
M.p. 158-160C.
ExampLe 8 N-{C2-(3,4-DimethyLphenyl~-6-methyLimidazo[1,2-a]pyrid-3-yl~methyl}-N,3-dimethylbutanam;de.
8.1. 2-(3,4-Dimethylphenyl)-6-methylimidazo[1,2-a]pyridine.
20.5 9 ~0.188 mole) of 2-amino-5-methylpyridine 3~1~

and 32 9 (0.381 mole) of sodium bicarbonate are added to a solution of 42 9 (û.188 mole) of 1-(3,4-dimethylphenyl)-2-bromoethanone in 4ûO ml of 95~ strength ethanol. The suspension is heated to the refluxing temperature for 6 S hours, and then cooled and cc,ncentrated under reduced pressure. The residue is washed with water and then treated with an ether/ethanol mixture and then ~ith an ether/acetone mixture, and finally with ether.
A yellow powder is obtained, of sufficient purity 1û to continue the synthesis~
M.p. 157-160C.
8.2. 2-(3,4-Dimethylphenyl)-6-methylimidazoC1,2-a]pyridine-3-methanol.
13.5 9 (0.057 mole) of the imidazopyridine ob-tained above are dissolved in 80 mL of acetic acid con-taining 2Q ml of 37% strength formaldehyde in water. The solution is brought to 55C for 4 hours and then con-centrated under reduced pressure. The evaporation resi-due is taken up with water and then treated with an exress of ammonia solution until the pH is basic. The suspension formed is stirred for 24 hours in the presence of 200 ml of dichloromethane, and the insoluble material is then filtered ûff on sintered glass and washed with water and then ether.
After drying under vacuum, an amorphous ~hite powder is obtained.
M.p. 20~-210C.

8.3. N-{t2-(3,4-~imethylphenyl)-6-me~hylimidazo[1,2-a]-pyrid-3-yl]methyl}-3-methylbutanamide.
3.5 ml of concentrated sulphuric acid are slowly added dropwise to a solution of 20 ~l of isovaleronitrile containing 3.5 9 ~0.0131 mole) of the alcohol obtained above. Stirring is maintained for 1 hour 30 min at room temperature, and then for 2 hours at 110C. The suspension is cooled, and treated ~ith 100 9 of ice and then an excess of ammonia solution until the pH is basic.
7he insoluble material is extracted with dichloro-methane and purified by chromatography on silica. The secondary amide (Ia) is obtained in the form of a viscous oil, the hydrochLoride of ~hich is prepared.
M.p. 217-218C.
8.4. N-~[2-t3,4-Dimethylphenyl~-6-methylimidazoC1,2-a]-pyrid-3-yl]methyl}-N,3-dimethylbutanamide.
3.53 9 (0.001 moLe) of the secondary amide obtained above, dissolved in 35 ml of tetrahydrofuran, are added to a suspension of 1.16 9 (0.0024 mole) of sodium hydride (at 50X strength in oiL) in 20 ml of tetrahydrofuran con-taining 1.26 ml, equivalent to 2.87 9 (O.û02 mole)~ of iodomethane. Stirring is maintained for 3 hours. The suspens;on is treated uith 1 ml of methanùl and then con-centrated under reduted pressure. The residue is taken up vith uster, and the insoluble material extracted Lith dichLoro~ethane and purified by chromatography on silica.
M.p. 1û3-4C.

3~

The hydrochloride of the compound melts at 162.5-163.5~
ExamDle C,' N-{[2-(3,4-Dimethylphenyl)-6-methylimidazo[1,2-a]pyrid-3-yl]methyl}-N-methylbutanamide.
9.1. N-{[2-(3,4-dimethylphenyl)-6-methylimidazo[1,2-a]-pyrid-3-yl]methyl}butanamide.
6 9 (0.022 mole) of the alcohol obtained according to 8.2. are suspended in 50 ml of butyronitrile and 6 ml of concentrated sulphuric acid are then added sLowLy The mixture is stirred at room temperature for 1 hour 30 min, and then brought for 1/2 nour to 140C. After being cooled, the lower phase is treated with ice, the super-natant portion having been removed. After complete dis-soLution of the gum, the solution is treated with an ex-cess of ammonia solution until the pH is strongLy basic.
The insoluble material is extracted with dichloromethane and purified by recrystallization in a cyclohexane/ethyl acetate mixture.
The secondary amide ~Ia) is obtained, the hydro-chloride of which is prepared.
M.p. 219-Z20C.
9.2. N-{C2-(3,4-dimethylphenyl)-6-methylimidazoC1,2-a]-pyrid-3-yl]methyL}-N-methylbutanamide.
Z5 3.49 9 (0.0104 mole) of the amide obtained above are added to a suspension o~ 1.19 9 of sodium hydride (at 50% strength in oil) in 20 ml of dry tetrahydrofuran .

~-p~

containing 1.29 ml equivalent to 2.~5 9 (0.0208 mole), of iodomethane. The reaction medium is diluted with 30 ml of tetrahydrofuran. Stirring is maintained for 2 hours and then, after the addition of 1 ml of methanol, the mixture is concentrated under reduced Dressure. The residue is treated with water and the insoluble material extracted with dichloromethane and then chromatographed on silica.
An oil is obtained, ;he hydrochloride of which is prepared.
M.p. 181.5-182C.
Example 10 N-{[6-Dimethylamino-2-(4-methylphenyl)imidazoC1,2-a~pyrid-3-yl]methyl}-N,3-dimethylbutanamide.
15 10.1. N-{[6-Dimethylamino-2-(4-methylphenyl)imidazo[1,2-a]-pyrid-3-yl~methyl}-3-methylbutanamide.
8 ml (0.0025 mole) of 3M sulphuric acid and 6 ml (û.072 mole) of formaldehyde in 40X strength aqueous solution are introduced into 83 ml of tetrahydrofuran.
20 4 9 (0.0118 mole) of amine prepared according to 3 are added to this solution, and the mixture is Left stirred for 20 min. It is cooled in a bath of ice-cold ~ater and 3.12 9 (0.0826 mole) of sodium borohydride are then added in small portions.
The pH of the solution shouLd remain in the region of 4; if required, 3M sulphuric acid is added. At the end of the reaction, the mixture is treated L ith potassium carbonate in aqueous solution and the product is extracted with dichloromethane. The organic phase is washed and dried and the solvent is evaporated off. The evaporation residue is purified by column chromatography and then S taken up with ether. 2.3 g (53%) of solid are obtained M.p. 173-175C.
1û.2. N-{[6-DimethyLamiro-2-(4-methylphenyl)imida2O[1,2-a]-pyrid-3-yl]methyl}-N,3-dimethylbutanamide.
2 9 (û.û054 moLe) of amide prepared according to 1û 10.1. and 1.56 9 (0.0109 mole) of methyl iodide dissolved in a mixture of 25 ml of tetrahydrofuran and 2.5 ml of dimethylformamide are added to a suspension of û.S26g (û.0109 mole) of 50% strength sodium hydride in oil in a mixture of 20 ml of tetrahydrofuran and 2 ml of dimethyl-formamide. After the evolution of gas has ceased, stirringis maintained for 1 hour and 1 ml of methanol is then added to destroy the excess sodium hydride. The solvent is evaporated off under reduced pressure, the evaporation residue taken up with ~ater and the tert;ary amide ex-tracted with dichloromethane. The product is purifiedby flash column chromatography, and its hydrochloride is then prepared and recrystallized ;n methyl ethyl ketone.
0.6 9 (27%~ of salt is thereby obtained.
M.p. 200-2û2C.
Example 11 3-{CMethyl-(3-methylbutanoyl)amino]methyl}-2 (4-methyl-phenyl)imidazo[1,2-a~pyridine-6-carbonitrile.

3~ .

3.7 9 (0.041 mole) of cuprous cyanide and 19 9 (0.041 mole) of N-{[6-iodo-2-(4-methylphenyl)imidazo-[1,2-a]pyrid-3-yl]methyl}-N,3-dimethylbutanamide, pre-pared according to the process described in European Patent Application No. 0,172,096, are introduced into 100 ml of dimethylformamide. The mixture is heated under reflux for 4 hours and the solvent then evaporated off under reduced pressure. The residue is taken up with water and dichloromethane and the mixture treated with ammonia solution. The organic phase is washed with water and dried, and the solvent evaporated off. The residue is purified by column chromatography and taken up with pentane. 14.4 9 (96%) of white solid are obtained.
M.p. 151-153C.
ExampLe 12 3-{~Methyl-(3-methyLbutanoyl)amino]methyL}-2-~4-methyL-phenyL)imidazo[1,2-a~pyridine-6-carboxamide.
3.6 9 (0.01 moLe) of nitrile prepared accord;ng to 11 are introduced into 36 ml of formic acid, and a stream of dry gaseous hydrochloric acid is then passed through the mixture at room temperature until conversion of the nitrile is complete. When the reaction is f;n;shed, the solut;on ;s poured ;nto 200 ml of uater, ammon;a so-lution is added and the amide ;s extracted w;th d;chloro-methane~ It is recrystall;zed ;n methyl ethyl ketone.2.4 9 (64Z) of am;de are obta;ned.
M.p. 231-233C.

Example 13 Ethy~ 3-{[methyL-(3-methylbutanoyl)amino~methyl}-2-(4-methylphenyl~imidazo[1~2-a]Dyridine-6-carboxylate~
3.6 g (0.01 mole) of nitrile prepared according to 11 are introduced into 36 ml of dry ethanol, and this solution is then saturated with gaseous hydrochloric acid, stirring for several hours. The solution is then treated with ~ater for 5 hours and alkalinized with sodium bi-carbonate The ester is extracted ~ith dichLoromethan~
and purified by column chromatography. 1.53 9 (38X) of white solid is obtained.
M.p. 158-160C.
Example 14 -3-{[Methyl-(3-methylbutanoyl)amino]methyl}-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-6-carboxylic acid.

7.2 9 (O.û2 mole) of nitrile prepared according to 11 are introduced into a mixture of 35 ml of acetic acid and 35 ml of concentrated hydrochloric acid. This solution is heated under reflux for seYeral hours and then cooled, and it is evaporated to dryness under reduced pressure. The evaporation residue is taken up uith water and brought to pH 5 by means of atetic ac;d. The pre-cipitate is separated by filtration, uashed with water and then acetone and dried. It is rerrystallized in methanol. 6.5 9 (85%) of acid are obtained.

M.p. ~27-229C.

;~7.~

Example 15 N-methyl-3-{[methyl-(3-methylbutanoyl)amino]methyl}-2-(4-methylphenyl)imidazo[1,2-a~pyridine-6-carboxamide.
1.6 9 (0.0042 mole) of acid prepared according to 14, 0.82 9 (0.005 mole) of carbonyldiimidazole and 20 ml of dry tetrahydrofuran are introduced into a round-bot-tomed flask flushed with argon. The solution is stirred for 1 hour at 40C, and then cooled and saturated with a stream of dry gaseous methylamine Stirr;ng is maintained overnight and the solvent then evaporated off. The evap-oration residue is taken up with water and dichloromethane, the organic phase is separated, washed with water and dried, and the solvent is evaporated off. The evaporation residue is purified by chromatography. 0.~4 9 (57%) of amide is obtained.
M.p. 183-185C.
Example 16 N,N-DimethyL-3-~[methyL-t3-methylbutanoyl)amino]methyl}-2-t4-methylphenyl)imidazo~1,2-a~pyridine-6-carboxamide.
1.6 9 (0.0042 mole) of acid prepared according to 14, 0.82 9 (0.005 mole) of carbonyldiimidazole and 2û mL
of dry tetrahydrofuran are introduced into a round-bot-tomed flask flushed with argon. The suspension is heated to 40C for 2 h, and then cooled and saturated with a stream of gaseous dimethylamine. At the end of the re-action, the solution is evaporated under reduted pressure and the residue taken up with water and dichloromethane.

~ ~33~

The organic phase is separated and dried and the solvent evaporated off~ The residue is purified by column chroma-tography. 0.89 9 (52%) of amide is obtained.
M.p. 134-136C
Example 17 4-{6-Methyl-3-[(3-methylbutanoyl)aminomethyL]imidazo[1,2-a]-pyrid-2-yl}benzonitrile.
17 1 4-(6-MethyLimidazo[1,2-a~pyrid-2-yL)benzo-nitrile.
70 9 (0.647 mole) of 5-methyl-2-pyridamine, 145 9 (0.647 mole) of 4-(2-bromoacetyl)benzonitrile and 110 9 (1.294 mole) of sodium bicarbonate are introduced into 1.Z l of 95~ strength ethanol. The suspension is heated under reflux for 2 h and then filtered and evaporated to dryness. The residue is taken up with water and treated with dichloromethane. The organic phase is separated and dried, and the solvent evaporated off. The residue is taken up ~ith ether. 107 g (71X~ of imidazopyridine are obtained.
M.p. 2Z8-230C.
17.2. 4-[6-Methyl-3-(hydroxymethyl)imidazot1,2-a]pyrid-2-yl~benzonitrile.
70 g ~0.3 mole) of imidazopyridine prepared ac-cording to 17.1., 1.5 l of acetic acid and 210 ml of for-maldehyde in 37% strength soLution in water are introducedinto a 2-l three-necked rsund-bottomed flask. The mixture is stirred for 3 h at 50C and the acetic acid and water 33g(~

are then evaporated off. The residue is taken up with water and dichloromethane and then treated with an excess of ammonia solution, and the alcohol precipitates. It is filtered off, washed with acetone and dried under vacuum.
52 9 (66%) of alcohol are obtained.
17.3. 4-{6-Methyl-3-[(3-methylbutanoyl~aminomethyl]-imidazo[1,2-a]pyrid-2-yl}benzonitrile.
5ûO ml of isovaleronitrile and 50 9 (0.189 mole) of aLcohol prepared according to 17.2. are introduced in-to a 250-ml round-bottomed flask, and 57 ml of contentrated sulphuric acid are added rapidly to this mixture. The suspension is heated until two liquid phases are obtained.
The two-phase mixture is hydrolysed with ice and then treated with an excess of ammon;a solution. The precipi-tate formed is filtered off, washed with water and driedunder vacuum. It is purified by column chromatography.
Z4 9 (37~) of product are obtained.
M.p. 231-233C.

The table which follows illustrates the structures and physical properties of some compounds according to the invention~

3~

Table X1 X2 `>~X3 N y, ( I ) Rl__N/
\

o~ R2 tomD~u~d - Xl X~ X3 Rl R2 ~l ~ ( D C ~
1 ~E~. 1.3~ CF3 H B C~3 B iC4 ~ 212-213 2 (E~. 1.4) C~3 ~ H ~ C~3 CH3 iC4~9 196-197 3 C~3 H H SC~3 ~ i~4~9 231-232 4 c~3 ~ ~ SC~3 C~3 lC4~9 180-182 S (Ex 2 3) N02 B ~ CB3 B iC4~9 239-241 6 (Ex. 3) N~2 B B c~3 ~ iC,,Hg 245-247 7 (Es. 4.3) C~3 ~ B CF3 ~ iC4 ~ 200^202

8 (E~. 4-6) ca3 H ~ CF3 C~3 lC4 ~ 123-130

9 (Es. 5.3) C~ ~ B CO2C2~s H iC6Bg 230-231

10 (E~. 6.6) C~3 H ~ N ~ C83 iC4 ~ 116-118

11 C~3 ~ H N ~ O C~3 iC4~9 137.5-138

12 (Ex. 7) C83 ~ ~ N(C2~5)2 C~3 iC4 ~ 158-160**

13 c~3 ~ ~ N~C2~5 C~3 iC4~g 173-174

14 C~3 B B N ~ C~3 iC4~g 153-154 N~C~3 ~ ~ c~3 ~ iC~g 252-256 16 (Ex. 10.1) N(C~3)2 B B C~3 ~ iC4H9 173-175 17 CB3 Cl H Cl Ca3 nC3~7 146-167*
18 C~3 ~ Cl Cl CB3 n53H7 126-125 __ _ _ __ __ _, 3~
.

Ta!~le (continued) , _~ _. . I_ __ . . ___ C~r.Dound Y Xl lx2 X3 Rl R2 ~1 D' (CC) ~__ ~ _ _ _ _ 19 C~3 H C1 H c~3 nC3~7 84-85 CR3 Cl 8 H C~3 nC3~7 185-186 21 CH3 H c~3 H C~3 nC3H7 94 5_95 22 C~3 H OC~3 H C~3 nC3~7 165-166*
23 c~3 C83 H C~3 C~3 nc3H7 129-129,5 24 (Ex 9 2) CH3 H CH3 C~3 CH3 n~3H7 181.5-182*
CH3 C~3 8 C83 C~3 iC4H9 111-112*
26 (Ex. 8.4) C~3 ~ C~3 C~3 C~3 iC4~g 162.5-163.5*
27 C~3 H C~3 OC~3 C~3 nc3H7 168-168 5*
28 Cl ~ C~3 C~3 C~3 nC3H7 126.5-125 29 CH3 Cl 8 Cl H nc3~7 160-161 CH3 ~ Cl Cl H nc3~7 160-161 31 C~3 ~ C1 H ~ nc3~7 154-155 32 c~3 Cl H H H nc3~7 178-179 33 CR3 H CR3 H H nc3~7 141-142 34 c~3 H 0583 H H nc3H7 137.5-188.5 ca3 ca3 ~ CH3 H nC3~7 16U-161 36 (E~. g.l) ce3 ~ CH3 C~3 H nC3H7 219-220*
37 C83 C83 h CR3 H iC4Hg 166-167 38 (Ex. 8.3) CH3 H CH3 CR3 h iC4~9 217-218*
39 C~3 ~ OCa3 C~3 ~ ~C3~7 ~00-201*
Cl H C83 Ch3 H nC3~7 154.5-155 41 H 8 C~3 Ca3 H nC3~7 146.5-147 42 ~ ~ C~3 C~3 C~3 ~C3~7 136-137*
43 N8CR3 H h C~3 CH3 iC4H9 175-177 44 (~. 10.2) N(C~3)2 h H C~3 C~3 ~C4~9 200-202 45 (Ex. 11) CN ~ ~ C~3 C~3 iC4~g lS1-15~
46 (E~. 12) CON~2 H 8 c~3 o~3 iC4Hg 231-233 47 (Ex. 13) C02C28s H H C83 C~3 iC4~9 158-160 48 (E~. lS) CON8CH3 8 8 C~3 C~3 1~4~9 183-185 49 (Ex. 14) co2~ H ~ C83 C~3 i~4Hg 227-229 S0 (Es. 16) CON(C83)2 H 3 ~63 CH3 iC4Hg 134-136 :~6~

Ta~l~ (continued) _ . ._ _ _ _ Cotppund --Xl X2 X3 R1 R2 N P ( t) 51 (~. 17.3) C~3 H .~ oN H iC4~9 231-233 52 CH3 H H CN C~3 iC4~9 147-149 53 C~3 ~ ~ ~ON~2 ~ iC4~9 271-272 54 C~3 ~ ~ CON~2 C~3 l~4~g 225-227 C~3 ~ ~ C02C2~5 C~3 ~C~g 113-115 56 C~3 ~ ~ CONaC~3 C~3 iC4~9 189-190 57 C~3 H H CON(C~3)2 C~3 iC4~9 116-118 53 33 2 3 C023 C~3 iC4~9 240-242 * . hydrochloride ** ~ dihydrochloride ~3~

The compounds of the present invention were sub~ected to pharmacological trials to demonstrate their therapeutic acitivites.
Acute toxicity.
This was determined intraperitoneally in mice.
The LDso values are greater than 500 mg/kg.
Antagonism towards clonic convulsions induced by Cardiazol (Trade Mark) in mice.
~ trial which was modelled on the procedure lO described by Goodman et al., J. Pharm. Exp. Ther., (1953), 108, 16a-176 was carried out on mice. Mice received the test products, or, as a control, the solvent alone, intraperitoneally 30 minutes before the intravenous injection of 35 mg/kg of Cardiazol. The animals were then observed for one hour and, for each batch, the percentage of mice showing clonic convulsions was noted t100% of clonic convulsions and 10 to ~0% of tonic convulsions in the control animals).
For each dose, the percentage protection relative to the control animals was calculated, and the ADso~ the dose which protects 50~ of the animals as regards the convulsion effects of Cardiazol, was determined graphically.
The ADso of the compounds of the invention are from 0.1 to more than 30 mg/kg.

3~~

Action on the electrocorticogram of ventilated curarized rats.
The sedative or hypnotic acitivity of the compounds was determined by observing their action on the 5 electrocorticogram of rats according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and ~y ~. Depoortere and M. Decobert, J. Pharmacol.
(Paris), 14, 2, 195-265 (1983).
The test compounds were administered lO intraperitoneally at increasing doses from 1 to 30 mg/kg.
They induced sleep traces from doses ranging from 0.01 to 30 mg/kg.
Effects on the duration of "sleep" induced by sodium 4-hydroxybutyrate.
This action was determined by the influence of a compound on the duration of "sleep" induced by sodium 4-hydroxybutyrate (GHB) in curarized rats.
The animals used were male Charles River strain rats weighing 200 + 20 g. The animals, curarized with 20 alloferin in the proportion of 1 mg/kg i.p., were placed under artificial respiration using a mask applied over the muzzle (breathing rate - 50/minute; respiratory volume - 14 ml).
The oesophagus was ligated beforehand in order to 25 prevent the entry of air into the stomach.

~;3~

Frontoparietal and occipital cortical electrodes were used to enable the electrocorticographic activity to be recorded on a Grass 79 P (Trade Mark) polygraph at a speed of 6 mm/s. The preparation of the animal was performed 5 under local anaesthesia (2% strength xylocaine). The rats were maintained throughout the experiment at constant temperature (37.5C). Ten minutes after completion of the preparation of each rat, a dose of 200 mg/kg of sodium 4-hydroxybutyrate was injected intravenously in its tail.
A dose of 10 mg/kg of the test compound was administered intrperitoneally 3 minutes after the administration of the sodium 4-hydroxybutyrate.
Assessment of the traces was performed on the basis of 15-minute periods during 75 minutes after the

15 injection of GHB. During this period of analysis, the total duration of the "sleep" was determined. A series of 15 controls enabled the duration of the "GHB sleep" to be precisely defined.
Statistical analysis of the results was carried 20 out using the Mann-Whitney "~" test.
Some compounds reduced the effects of GHB (up to 40~ decrease in the duration of the sleep at a dose of 10 mg/kg), while others boosted these effects ~up to 25~
increase in the duration of the sleep at a dose of lO
25 ~g/kg). It was also found that the effects can be opposite, according to whether the compounds were administered at high ~33~

or low doses.
Drinking conflict test in rats.
This test is described by Vogel J.R., ~eer ~. and Clody D.E. in Psychopharmacologica, 21, 1-7, (1971).
Male Wistar rats (IFFA Credo) were used. Their drinking water was withdrawn 24 hours before the test. On the day of the test, 30 minutes after intraperitoneal treatment wlth the ~ompounds of the invention, each rat was placed in a transparent plastic cage (24 x 20 x 21 cm) 10 having a meshwork floor which could be electrified.
Drinking water was distributed via a pipette projecting 2 cm from one wall of the cage and placed 3 cm above the floor of the cage.
After a 10 to 90 second exploration, the rats 15 found the pipette and started to drink. After giving 20 licks with the tongue (recorded by an Omnitech (Trade Mark) anxiometer), the rat received an electric shock of 0.07 mA
applied to its tongue (delivered by the anxiometer), which stopped when the rat left the pipette. This test then 20 continued for 3 minutes after the first shock; the animals continued to receive a shock every 20 licks until they stopped or until the end of the session.
Under these experimental conditions, the control animals accepted, on average, 3 to 6 shocks. The number of 25 shocks obtained with the treated animals was noted, and this number was compared with that of the control animals by a 3~6~

Dunett test. The MED, the minimal effective dose, which is the first dose which significantly increases the number of shocks accepted by an animal relative to the control animals, was determined in this manner.
The MED values of the compounds are from 1 to 100 mg/kg intraperitoneally.
Analgesic activity.
This was shown by using the test of ~oster et al.
(acetic acid "writhing" test in mice), Fed. Proc., 18, 412, The test compound, dissolved in Tween 80 (Trade Mark) at a concentration of 1%, was administered orally to fasted mice in a proportion of 0.2 ml per 20 g of bodyweight; after 30 min, acetic acid (dissolved at a 15 concentration of 0.6% in a mixture of carboxymethylcellulose and Tween 80, in a proportion of 10 ml per kg of bodyweight) was administered intraperitoneally. The total number of contortions was noted during 15 min.
The percentage protection relative to a control 20 batch was determined, and the ADs D was calculated graphically (dose which protects 50% of the animals).
The AD50 of the compounds of the invention ranges from 5 to 50 mg/kg p.o.
Stress ulceration.
The technique used is that of Senay and Levine, Proc. Soc. Exp. Biol. 1967, 124, 1221-1223, Peptic Ulcers.

33~

The test was carried out on female Wistar rats weighing 180-210 g, kept fasted for 20 hours and distributed in randomized groups.
The animals were held in restraint in cylindrical 5 boxes 20 cm x 5 cm, and placed in a cold room at from 2 to 4C.
The test compounds were administered orally in a proportion of 10, 30 and 100 mg/kg immediately before the restraints, the c~ntrol rats receiviny only placebo. 2 lO hours later, the animals were sacrificed by inhalation of chloroform.
The stomachs were removed and the degree of ulceration noted.
The compounds of the invention significantly 15 decreased the amount of stress ulceration, at doses ranging from 0.1 to 10 mq/kg orally.
The results of these different tests show that the compounds nf the invention possess at least one anxiolytic, sleep-inducing, hypnotic, anticonvulsant, analgesic or 20 stress-ulceration inhibitory property. The compounds of the invention are useful for, example, in the treatment of anxiety states, sleep disorders and other neurological and psychiatric conditions, disorders of altertness, and can be especially useful for combating behavioural disorders which 25 can be ascribed to cerebral vascular damage and to cerebral sclerosis in geriatrics, for treating temporary loss of ?~

consciousness due to cranial trauma and for treating metabolic encephalopathies, as well as for treating pain, various aches and stress ulcers.
The compounds of the invention can be presented in any form suitable for oral or parenteral administration, for example in the form of tablets, dragees, gelatin capsules, solutions to be taken by mouth or injectable solutions in combination with any pharmaceutically suitable excipient.
The daily dosage can range from 0.1 to 500 mg.

Claims (20)

The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:

1. A process for preparing a compound which is a 3-(acylaminomethyl)imidazo[1,2-a]pyridine derivative of formula (I) (I) in which R1 denotes hydrogen; linear or branched C1-C4 alkyl; or benzyl:
R2 denotes linear or branched C1-C6 alkyl; cyclohexyl;
trichloromethyl; 1-propenyl; allyl; phenyl; 4-chlorophenyl;
or benzyl:
or alternatively R1 and R2 together denote a C3-C5 aliphatic chain:
and either a) X1 and X2 both denote hydrogen, X3 denotes halogen; C1-C3 alkyl; methylthio;
trifluoromethyl; optionally esterified carboxy of formula COOR in which R denotes hydrogen or C1-C6 alkyl; cyano;
optionally mono- or dialkylated aminocarbonyl of formula CONR3R4 in which R3 and R4 independently denote hydrogen or C1-C4 alkyl or together denote a chain of formula -(CH2)2-Z-(CH2)2- in which Z denotes a direct bond, oxygen, sulphur, or a divalent group of formula -CH2-, -NH- or N(C1-C4 alkyl)-; alkylamino of formula NHR5 in which R5 denotes C2-C6 alkyl; or a dialkylamino of formula NR6R7 in which R6 and R7 independently denote C2-C6 alkyl or together denote a chain of formula -(CH2)2-Z-(CH2)2- in which Z
denotes a direct bond, oxygen, sulphur, or a divalent group of formula -CH2-, -NH- or -N(C1-C4 alkyl)-: and Y denotes hydrogen; halogen; methyl; trifluoromethyl;
optionally esterified carboxy of formula COOR8 in which R8 denotes hydrogen or C1-C6 alkyl; cyano; optionally mono- or dialkylated aminocarbonyl of formula CONR9R10 in which R9 and R10 independently denote hydrogen or C1-C4 alkyl; or optionally mono- or dialkylated amino of formula NR11R12 in which R11 and R12 independently denote hydrogen or C1-C4 alkyl:
with the exclusion, in case (a), of compounds in which X3 denotes halogen; alkyl; or methylthio and Y denotes hydrogen; halogen; or methyl:
b) X1, X2 and X3 independently denote hydrogen; halogen;
C1-C4 alkyl; methoxy; methylthio; ethylthio;
methylsulphonyl; nitro; amino; methylamino; dimethylamino;

acetylamino; or diacetylamino: and Y denotes hydrogen; chlorine; or methyl:
with the exclusive, in case (b), of compounds in which X1 and X2 both denote hydrogen:
or a pharmacologically acceptable acid addition salt, in which an alcohol of formula (V) (V) in which X1, X2, X3, and Y are as defined above is reacted with a nitrile of formula R2-CN in which R2 is as defined above and the reaction product is hydrolysed to obtain a compound of formula (I) in which R1 is hydrogen and, if desired, the compound of formula (I) in which R1 denotes hydrogen is alkylated or benzylated to form a compound of formula (I) in which R1 is linear or branched C1-C4 alkyl or benzyl, - 43a -or reacting a compound of formula (IV) (IV) is reacted with a nitrile of formula R2-CN in which R2 and with paraformaldehyde and, if required, the thus obtained compound of formula (I) in which R1 denotes hydrogen is alkylated or benzylated to form a compound of formula (I) in which R1 is linear or branched C1-C4 alkyl or benzyl, or reacting a compound of formula (IV) (IV) with an amide of formula

2. A process according to claim 1 in which the alcohol of formula (V) is reacted with the nitrile in an acid medium at a temperature of from 0 to 150°C.

3. A process according to claim 1 in which the alcohol of formula (V) has been obtained by hydroxymethylation of a compound of formula (IV) (IV) in which X1, X2, X3 and Y are as defined in claim 1.

4. A process according to claim 3 in which the hydroxymethylation is carried out using formaldehyde in a solvent of the carboxylic acid type.

5. A process for preparing a compound of formula (I) as defined in claim 1 or a pharmacologically acceptable acid addition salt in which a compound of formula (IV) (IV) in which X1, X2, X3 and Y are as defined in claim 1 is reacted with a nitrile of formula R2-CN in which R2 is as defined in claim 1 and with paraformaldehyde and, if desired, the thus obtained compound of formula (I) in which R1 denotes hydrogen is alkylated or benzylated to form a compound of formula (I) in which R1 is linear or branched C1-C4 alkyl or benzyl.

6. A process according to claim 5 in which the reaction of the compound of formula (IV) with the nitrile and paraformaldehyde is carried out in an acetic acid medium and in the presence of sulphuric acid.

7. A process according to claim 1 or 5 in which the alkylation or benzylation is carried out using a halide of formula R1-hal in which hal denotes halide and R1 is as defined in claim 1 with the exception of hydrogen, in a solvent and in the presence of an alkali metal hydride.

8. A process for preparing a compound of formula (I) as defined in claim 1 or a pharmacologically acceptable acid addition salt in which a compound of formula (IV) (IV) in which X1, X2, X3 and Y are as defined in claim 1 is reacted with an amide of formula in which R1 and R2 are as defined in claim 1.

9. A process according to claim 8 which is carried out at room temperature and in the presence of concentrated sulphuric acid.

10. A process according to claim 3 in wherein the compound of formula (IV) has been obtained by reacting a 2-aminopyridine of formula (II) (II) in which Y has the same meaning as in claim 3 with a 2-bromoethanone of formula III

(III) in which X1, X2, and X3 have the same meanings as in claim 3.

11. A process according to claim 10 in which the compounds of formulae (II) and (III) are reacted in a heated state and in a protic solvent.

12. A process according to claim 1 for preparing a compound of formula (I) as defined in claim 1 or a pharmaco-logically acceptable acid addition salt in which X3 and/or Y
denote cyano which comprises reacting a compound of formula (I) in which X3 and/or Y denote halogen with a cyanide in an inert solvent.

13. A process according to claim 1 for preparing a compound of formula (I) as defined in claim 1 or a pharmaco-logically acceptable acid addition salt in which X3 and/or Y
denote carboxylate which comprises reacting a compound of formula (I) in which 3 and/or Y denote cyano with gaseous hydrochloric acid in an alcohol of formula ROH wherein R is as defined in claim 1 followed by hydrolysis.

14. A process according to claim 1 for preparing a compound of formula (I) as defined in claim 1 or a pharmaco-logically acceptable acid addition salt in which X3 and/or Y
denote carboxyl or carboxamide which comprises hydrolysing a compound of formula (I) in which X3 and/or Y denote cyano.

15. A process according to claim 14 in which the hydrolysis is carried out in an acid medium at a temperature of from 60 to 120°C.

16. A process according to claim 1 for preparing a compound of formula (I) as defined in claim 1 or a pharmaco-logically acceptable acid addition salt in which X3 and/or Y
denote carboxamide which comprises amidating a compound of formula (I) in which X3 and/or Y denote carboxyl group.

17. A process according to claim 16 in which the amidation is carried out using carbonyldiimidazole and the intermediate imidazolide thereby obtained is reacted with an amide of formula R3R4NH or R9R10NH in which R3, R4, R9 and R10 are as defined in claim 1.

18. A process according to claim 1 wherein R1 ~
denotes hydrogen or methyl and R2 denotes propyl or isobutyl.

19. A compound of formula (I) as defined in claim 1 or a pharmacologically acceptable acid addition salt thereof.

20. A compound of formula (I) as defined in claim 1 or a pharmacologically acceptable acid addition salt thereof wherein R1 denotes hydrogen or methyl and R2 denotes propyl or isobutyl.