CA1263389A - Imidazo[1.2-a]quinoline derivatives, their preparation and pharmaceutical compositions containing them - Google Patents
Imidazo[1.2-a]quinoline derivatives, their preparation and pharmaceutical compositions containing themInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
ABSTRACT
IMIDAZO[1.2-a]QUINOLINE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Compounds which are imidazo[1.2-a]quinoline derivatives of general formula (I)
IMIDAZO[1.2-a]QUINOLINE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Compounds which are imidazo[1.2-a]quinoline derivatives of general formula (I)
Description
3~
"IMIDAZO[1.2-a~Q~INOLINE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to imidazo[l.2-a]-quinoline derivatives.
According to the invention there are provided compounds which are imidazo[l;2-a]quinolines of the general formula (I) 7 0~
~N _ R
in which X is hydrogen, halogen, methyl, methoxy, methylthio or methylsulphonyl, Y is hydrogen, halogen or methyl in position 6, 7 or 8, and Rl and R2, which may be the same or different, each is hydrogen, methyl or ethyl or Rl and R2 together form a tetramethylene, pentamethylene~
3-methyl-3-azapentamethylene, 3-ethoxycarbonyl-3-azapenta-methylene or 3-oxapentamethylene group, and their pharmacologically acceptable acid addition salts.
The compounds of the invention can be prepared according to the scheme illustrated on the following page.
A quinoline of formula (II~ or a 2-aminoquinoline of forrnula (IV) is first subjected to the action of an a~bromo-acetophenone carrying the substituent X defined above.
In the case of a quinoline (II), the reaction is suitably carried out hot in a solvent such as methylene chloride or 1,2-dichloroethane. An ionic compound of formula (III) is thus obtained, which is cyclized hot in the presence of ammonium acetate and ferric chloride to produce a compound of formula (V).
In the case of a 2-aminoquinoline of formula (IV), the compound of formula (V) is obtained directly, suitably by carrying out the reaction :~p~
Y~ Scheme I ' ~2 Y~ X--Y ~ ~ Y
( II I) y~ X'' y ,~J~ X
I
~x~ X
NC (VIII) ( IX) ~ ~ O H
o~X
9 ~> ( I ) ~N P 2 ~ J~ 9 in the presence of a base and in an alcoholic solvent.
A formylation of the compound (V) thus produced is then carried out, for example by means of the reagent which is produced by the reaction of oxalyl chloride with dimethylformamide, and then hydrolysis of this adduct.
The aldehyde (VI) thus obtained is then reduced to an alcohol of formula (VII), in a known manner, for example by reaction with sodium or potassium borohydride.
The alcohol (VII) is then converted to the nitrile of formula (VIII). This can be done by subjecting the alcohol (VII) firstly to a tosylation, for example by means of para-toluenesulphonyl chloride, in the presence of pyridine, and then to the action of sodium or potassium cyanide in an aqueous medium.
lS The nitrile (VIII) is then hydrolysed to a carboxylic acid in a known manner, for example by heating in a hydrochloric acid medium, to produce the acid of formula (IX).
From this acid (IX), the corresponding amide of formula (I) is finally prepared. ~his can be done by subjecting the acid (IX) firstly to the action of carbonyldiimidazole, and then to the action of an amine of formula Rl-NH-R2 in which Rl and R2 are as defined above.
In the case of the unsubstituted amide of formula (I) in which both Rl and R2 are hydrogen, the final compound may be produced directly by partial hydrolysis of the nitrile (VIII) in an aqueous basic meidum.
Lastly, it should be noted that the N,N-dimethylated amides can also be produced by methylation of the 3i~
unsubstituted amide (~l=R2=H) by means of iodomethane in the presence of sodium hydride.
Examples A and B below illustrate the two alternative ways of preparing the compound of formula (V).
The following Examples illustrate the preparation of some compounds according to the invention. The structures of the compounds were confirmed by microanalyses and IR and NMR
spectra.
Example A.
"IMIDAZO[1.2-a~Q~INOLINE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to imidazo[l.2-a]-quinoline derivatives.
According to the invention there are provided compounds which are imidazo[l;2-a]quinolines of the general formula (I) 7 0~
~N _ R
in which X is hydrogen, halogen, methyl, methoxy, methylthio or methylsulphonyl, Y is hydrogen, halogen or methyl in position 6, 7 or 8, and Rl and R2, which may be the same or different, each is hydrogen, methyl or ethyl or Rl and R2 together form a tetramethylene, pentamethylene~
3-methyl-3-azapentamethylene, 3-ethoxycarbonyl-3-azapenta-methylene or 3-oxapentamethylene group, and their pharmacologically acceptable acid addition salts.
The compounds of the invention can be prepared according to the scheme illustrated on the following page.
A quinoline of formula (II~ or a 2-aminoquinoline of forrnula (IV) is first subjected to the action of an a~bromo-acetophenone carrying the substituent X defined above.
In the case of a quinoline (II), the reaction is suitably carried out hot in a solvent such as methylene chloride or 1,2-dichloroethane. An ionic compound of formula (III) is thus obtained, which is cyclized hot in the presence of ammonium acetate and ferric chloride to produce a compound of formula (V).
In the case of a 2-aminoquinoline of formula (IV), the compound of formula (V) is obtained directly, suitably by carrying out the reaction :~p~
Y~ Scheme I ' ~2 Y~ X--Y ~ ~ Y
( II I) y~ X'' y ,~J~ X
I
~x~ X
NC (VIII) ( IX) ~ ~ O H
o~X
9 ~> ( I ) ~N P 2 ~ J~ 9 in the presence of a base and in an alcoholic solvent.
A formylation of the compound (V) thus produced is then carried out, for example by means of the reagent which is produced by the reaction of oxalyl chloride with dimethylformamide, and then hydrolysis of this adduct.
The aldehyde (VI) thus obtained is then reduced to an alcohol of formula (VII), in a known manner, for example by reaction with sodium or potassium borohydride.
The alcohol (VII) is then converted to the nitrile of formula (VIII). This can be done by subjecting the alcohol (VII) firstly to a tosylation, for example by means of para-toluenesulphonyl chloride, in the presence of pyridine, and then to the action of sodium or potassium cyanide in an aqueous medium.
lS The nitrile (VIII) is then hydrolysed to a carboxylic acid in a known manner, for example by heating in a hydrochloric acid medium, to produce the acid of formula (IX).
From this acid (IX), the corresponding amide of formula (I) is finally prepared. ~his can be done by subjecting the acid (IX) firstly to the action of carbonyldiimidazole, and then to the action of an amine of formula Rl-NH-R2 in which Rl and R2 are as defined above.
In the case of the unsubstituted amide of formula (I) in which both Rl and R2 are hydrogen, the final compound may be produced directly by partial hydrolysis of the nitrile (VIII) in an aqueous basic meidum.
Lastly, it should be noted that the N,N-dimethylated amides can also be produced by methylation of the 3i~
unsubstituted amide (~l=R2=H) by means of iodomethane in the presence of sodium hydride.
Examples A and B below illustrate the two alternative ways of preparing the compound of formula (V).
The following Examples illustrate the preparation of some compounds according to the invention. The structures of the compounds were confirmed by microanalyses and IR and NMR
spectra.
Example A.
2-(4-Chlo~ophenyl)imidazo[1.2-a]quinoline.
17.7 9 (0.123 mole) of 2-aminoquinoline, 28.7 g (1 equivalent of d-bromo-p-chloroacetophenone and 20.6 g (2 equivalents) of sodium bicarbonate are mixed in 180 ml of n-propanol and heated under reflux for 20 hours. The precipitate obtained is filtered off, washed with ethanol and water and dried. A white solid is obtained which is recrystallized from nitromethane.
M.p. = 206-208 C.
Example B.
2-(4-Chlorophenyl)imidazo[1.2-a]quinoline.
23.3 g (0.1 mole) of d-bromo-p-chloroacetophenone and 13 ml (1.1 equivalent) of quinoline are mixed with 100 ml of methylene chloride. They are heated under reflux for 1 hour and then 100 ml of ether are added to the rea_tion mixture, which is cooled. The yellow precipitate obtained is filtered off and dried.
38.3 9 (0.105 mole) of the above quaternary ammonium, 48.6 9 (0.63 mole) of ammonium acetate, and 55 9 (0.34 moLe) of ferric chloride are mixed with 270 ml of acetic acid in a 1 litre autoclave, and are heated at 140C for 13 hours. The solid obtained is filtered off, S washed ~ith acetic acid and then with water; it is dried, and recrystall;zed from ethanol and then from n;tromethane.
Example 1 2-(4-Chlorophenyl)-1-im;dazoC1.2-a~qu;nolylacetamide.
a) ?-(4-Chlorophenyl)-1-imidazoC1.2-a~quinolylcarboxalde-hyde.
150 ml of dry dimethylformamide are cooled to-20C and 17.4 ml tO~2 mole) of oxalyl chloride are added dropwise. 13.6 9 (0.05 mole) of the compound obtained accord;ng to Example A or B are then added and the mixture ;s stirred for 15 hours at amb;ent temperature and 15 hours at 55C.
The mixture ;s then poured ;nto 1 l;tre of ~ater, the precipitate is filtered off and made aLkaline, and washed uith ~ater to a neutral pH and dr;ed. It is re~
crystallized from nitromethane.
M.p. = 199-20QC.
b) 1-Hydroxymethyl-2-(4-chlorophenyl)imidazo[1.2-a~quinoline.
13.3 9 (0.043 mole) of the above aldehyde are sus-pended in 300 nl of dry absolute ethanol.
To this are added 825 mg (0.5 equivalent) of sodium borohydride and the mixture is st;rred for 18 hours at ambient temperature. It is then evaporated to dryness, ~b~33æs - the residue is taken up with ~ater the pH is adjusted to 8 ~ith dilute hydrochlor;c acid and the prec;p;tate is filtered off washed with water acetone and then with ether and dried.
M.p. = 236 237C tdecomposition).
c) 1-Cyanomethyl-2-(4-chlorophenyl)im;dazoC1.2-a~quinoline.
7.8 g (0.025 mole) of the above a~cohoL and 5.3 9 (1.1 equivalent~ of p-toluenesulphonyl chloride are mixed in 100 ml of pyrid;ne. The react;on m;xture ;s heated at 40C for 8 hours and then st;rred at ambient temperature for 60 hours. It is then taken ap with 700 ml of ~ater and 300 ml of methylene chlor;de the prec;pitate between the two phases ;s f;ltered off and ;s dropped into 400 ml of water conta;n;ng 3.7 9 (0.075 mole) of sod;um cyan;de and 2~1 9 (0.025 mole) of sod;um bicarbonate~ The m;xture is heated under reflux for 15 hours and ;s then cooled and f;ltered. The precipitate is washed w;th water and extrac-ted with methylene chlor;de and the extract ;s dr;ed over sod;um sulphate. The n;tr;le ;s purif;ed by chromatography on sil;ca gel.
After crystall;zat;on from ether and dry;ng a wh;te sol;d ;s obta;ned.
M.p. = 221-223C.
d) 2-(4-Chlorophenyl)-1-;midazoC1.2-a~quinolylacetam;de.
7 9 (0.022 mole) of the above nitr;le and 6 9 t5 equivalents) of potass;um hydrox;de are m;xed in 200 ml of ethanol and 50 ml of water and heated for 3 hours under ~3 reflux. The mixture is then evaporated to dryness, the residue ;s taken up with water, filtered, washed with water to a neutral pH and dried.
M.p. = 298-300C.
Example 2 2-(4-ChLorophenyl)-1-;m;dazoC1.2-a]qu;noLyL-N-methy~acet-amide.
a) 2-(4-Chlorophenyl)-1-imidazo~1.2-a]qu;nolylacetic acid.
17.7 9 (0.123 mole) of 2-aminoquinoline, 28.7 g (1 equivalent of d-bromo-p-chloroacetophenone and 20.6 g (2 equivalents) of sodium bicarbonate are mixed in 180 ml of n-propanol and heated under reflux for 20 hours. The precipitate obtained is filtered off, washed with ethanol and water and dried. A white solid is obtained which is recrystallized from nitromethane.
M.p. = 206-208 C.
Example B.
2-(4-Chlorophenyl)imidazo[1.2-a]quinoline.
23.3 g (0.1 mole) of d-bromo-p-chloroacetophenone and 13 ml (1.1 equivalent) of quinoline are mixed with 100 ml of methylene chloride. They are heated under reflux for 1 hour and then 100 ml of ether are added to the rea_tion mixture, which is cooled. The yellow precipitate obtained is filtered off and dried.
38.3 9 (0.105 mole) of the above quaternary ammonium, 48.6 9 (0.63 mole) of ammonium acetate, and 55 9 (0.34 moLe) of ferric chloride are mixed with 270 ml of acetic acid in a 1 litre autoclave, and are heated at 140C for 13 hours. The solid obtained is filtered off, S washed ~ith acetic acid and then with water; it is dried, and recrystall;zed from ethanol and then from n;tromethane.
Example 1 2-(4-Chlorophenyl)-1-im;dazoC1.2-a~qu;nolylacetamide.
a) ?-(4-Chlorophenyl)-1-imidazoC1.2-a~quinolylcarboxalde-hyde.
150 ml of dry dimethylformamide are cooled to-20C and 17.4 ml tO~2 mole) of oxalyl chloride are added dropwise. 13.6 9 (0.05 mole) of the compound obtained accord;ng to Example A or B are then added and the mixture ;s stirred for 15 hours at amb;ent temperature and 15 hours at 55C.
The mixture ;s then poured ;nto 1 l;tre of ~ater, the precipitate is filtered off and made aLkaline, and washed uith ~ater to a neutral pH and dr;ed. It is re~
crystallized from nitromethane.
M.p. = 199-20QC.
b) 1-Hydroxymethyl-2-(4-chlorophenyl)imidazo[1.2-a~quinoline.
13.3 9 (0.043 mole) of the above aldehyde are sus-pended in 300 nl of dry absolute ethanol.
To this are added 825 mg (0.5 equivalent) of sodium borohydride and the mixture is st;rred for 18 hours at ambient temperature. It is then evaporated to dryness, ~b~33æs - the residue is taken up with ~ater the pH is adjusted to 8 ~ith dilute hydrochlor;c acid and the prec;p;tate is filtered off washed with water acetone and then with ether and dried.
M.p. = 236 237C tdecomposition).
c) 1-Cyanomethyl-2-(4-chlorophenyl)im;dazoC1.2-a~quinoline.
7.8 g (0.025 mole) of the above a~cohoL and 5.3 9 (1.1 equivalent~ of p-toluenesulphonyl chloride are mixed in 100 ml of pyrid;ne. The react;on m;xture ;s heated at 40C for 8 hours and then st;rred at ambient temperature for 60 hours. It is then taken ap with 700 ml of ~ater and 300 ml of methylene chlor;de the prec;pitate between the two phases ;s f;ltered off and ;s dropped into 400 ml of water conta;n;ng 3.7 9 (0.075 mole) of sod;um cyan;de and 2~1 9 (0.025 mole) of sod;um bicarbonate~ The m;xture is heated under reflux for 15 hours and ;s then cooled and f;ltered. The precipitate is washed w;th water and extrac-ted with methylene chlor;de and the extract ;s dr;ed over sod;um sulphate. The n;tr;le ;s purif;ed by chromatography on sil;ca gel.
After crystall;zat;on from ether and dry;ng a wh;te sol;d ;s obta;ned.
M.p. = 221-223C.
d) 2-(4-Chlorophenyl)-1-;midazoC1.2-a~quinolylacetam;de.
7 9 (0.022 mole) of the above nitr;le and 6 9 t5 equivalents) of potass;um hydrox;de are m;xed in 200 ml of ethanol and 50 ml of water and heated for 3 hours under ~3 reflux. The mixture is then evaporated to dryness, the residue ;s taken up with water, filtered, washed with water to a neutral pH and dried.
M.p. = 298-300C.
Example 2 2-(4-ChLorophenyl)-1-;m;dazoC1.2-a]qu;noLyL-N-methy~acet-amide.
a) 2-(4-Chlorophenyl)-1-imidazo~1.2-a]qu;nolylacetic acid.
3.5 9 (0.011 mole) of the nitrile obtained accord-;ng to Example 1c) are dropped ;nto a m;xture of 10 mL ofconcentrated hydrochloric acid and 20 ml of acetic acid.
Th;s react;on m;xture is heated under reflux for 8 hours, and then a further 10 ml of concentrated hydrochloric acid are added and heating under reflux is continued for 8 hours.
The m;xture ;s then evaporated to dryness, the residue is taken up with water, and the precipitate is filtered off.
The prec;pitate ;s resuspended ;n water, the pH is adjusted to 5 with dilute sodium hydroxide, it is filtered, washed with ethanol, acetone and ether and is dried.
M.p. = 246-248C ~decomposit;on).
b) 2-(4-Chlorophenyl)-1-imidazoC1.2-a~quinolyl-N-methyl-acetam;de.
2.5 9 (O.û074 mole) of the above ac;d are suspended in 50 ml of dry tetrahydrofuran, 1.4 9 (1.2 equivalent) of carbonyldiimidazole are added, and the mixtùre is heated at about 40C for 2 hours.
Methylamine is then bubbled through the mixture for 3~
30 m;nutes and stirring is continued for 15 hours.
The mixture ;s evaporated to dryness, the residue is taken up ~ith water and with methylene chloride, the organic phase is separated off, washed with ~ater, dried and evaporated down. The residue is purified by chromato-graphy and left to crystallize from ether.
M.p. = 289-292C (decomposition).
Example 3 2-t4-Chlorophenyl)-1-imidazoC1.2-a~quinolyl-N,N-dimethyl-acetamide.
To a suspension of 3.35 9 ~0.09 mole) of the com-pound obta;ned according to Example 1d) in 200 ml of tetra-hydrofuran are added 1.05 9 (0.022 mole) of sodium hydride at a concentration of 50X in oil, 0.1 ml of d;methylform-am;de and then, rap;dly, 1.9 ml (3 equivalents) of ;odo-methane. The mixture is stirred for 15 hours under argon at amb;ent temperature, and is then evaporated to dryness, the residue is taken up ~ith water and with methylene chloride, the organ;c phase is ~ashed ~ith ~ater, dried and evaporated down. The residue ;s purified by chromatography.
M.p. = 190-191.5C.
Example 4 2-(4-Chlorophenyl)-1-;midazoC1.2-a]quinolyl-N,N-tetra-methyleneacetam;de.
2.5 9 (0.0074 mole) of the ac;d obtained according to Example 2a) are suspended in 50 ml of dry tetrahydro-furan, 1.4 9 (1.2 equivalents) of carbonyldiimidazole are 33~
added, and the m;xture is heated at about 40C for 2 hours.
0.63 9 (1.2 equ;valent~ of pyrrolid;ne are then added and st;rring ;s cont;nued at amb;ent temperature for 15 hours. The m;xture is evaporated to dryness, the res;-due is taken up with water and methylene chlor;de, the organ;c phase is separated off, washed w;th water, dried and evaporated down. The residue is purifled by chromato-graphy and left to crystall;ze from ether.
M.p. = 217-218C.
The following table illustrates the structures and the phys;caL propert;es of the compounds of the invent;on.
~,. 6~
Table ~= X
9 0 ~
3 ~ (I) ,,N R 2 _ _ __ . _ _ C~ounc L x Rl ~Z ~as /
l(Ex.l) H4-Cl H H . 00 298-300 2(Ex.2) H. 4-Cl H rH3~ oo 289-292 3~Ex.3) H4-Cl ICH3 CH3 00 190-191,5
Th;s react;on m;xture is heated under reflux for 8 hours, and then a further 10 ml of concentrated hydrochloric acid are added and heating under reflux is continued for 8 hours.
The m;xture ;s then evaporated to dryness, the residue is taken up with water, and the precipitate is filtered off.
The prec;pitate ;s resuspended ;n water, the pH is adjusted to 5 with dilute sodium hydroxide, it is filtered, washed with ethanol, acetone and ether and is dried.
M.p. = 246-248C ~decomposit;on).
b) 2-(4-Chlorophenyl)-1-imidazoC1.2-a~quinolyl-N-methyl-acetam;de.
2.5 9 (O.û074 mole) of the above ac;d are suspended in 50 ml of dry tetrahydrofuran, 1.4 9 (1.2 equivalent) of carbonyldiimidazole are added, and the mixtùre is heated at about 40C for 2 hours.
Methylamine is then bubbled through the mixture for 3~
30 m;nutes and stirring is continued for 15 hours.
The mixture ;s evaporated to dryness, the residue is taken up ~ith water and with methylene chloride, the organic phase is separated off, washed with ~ater, dried and evaporated down. The residue is purified by chromato-graphy and left to crystallize from ether.
M.p. = 289-292C (decomposition).
Example 3 2-t4-Chlorophenyl)-1-imidazoC1.2-a~quinolyl-N,N-dimethyl-acetamide.
To a suspension of 3.35 9 ~0.09 mole) of the com-pound obta;ned according to Example 1d) in 200 ml of tetra-hydrofuran are added 1.05 9 (0.022 mole) of sodium hydride at a concentration of 50X in oil, 0.1 ml of d;methylform-am;de and then, rap;dly, 1.9 ml (3 equivalents) of ;odo-methane. The mixture is stirred for 15 hours under argon at amb;ent temperature, and is then evaporated to dryness, the residue is taken up ~ith water and with methylene chloride, the organ;c phase is ~ashed ~ith ~ater, dried and evaporated down. The residue ;s purified by chromatography.
M.p. = 190-191.5C.
Example 4 2-(4-Chlorophenyl)-1-;midazoC1.2-a]quinolyl-N,N-tetra-methyleneacetam;de.
2.5 9 (0.0074 mole) of the ac;d obtained according to Example 2a) are suspended in 50 ml of dry tetrahydro-furan, 1.4 9 (1.2 equivalents) of carbonyldiimidazole are 33~
added, and the m;xture is heated at about 40C for 2 hours.
0.63 9 (1.2 equ;valent~ of pyrrolid;ne are then added and st;rring ;s cont;nued at amb;ent temperature for 15 hours. The m;xture is evaporated to dryness, the res;-due is taken up with water and methylene chlor;de, the organ;c phase is separated off, washed w;th water, dried and evaporated down. The residue is purifled by chromato-graphy and left to crystall;ze from ether.
M.p. = 217-218C.
The following table illustrates the structures and the phys;caL propert;es of the compounds of the invent;on.
~,. 6~
Table ~= X
9 0 ~
3 ~ (I) ,,N R 2 _ _ __ . _ _ C~ounc L x Rl ~Z ~as /
l(Ex.l) H4-Cl H H . 00 298-300 2(Ex.2) H. 4-Cl H rH3~ oo 289-292 3~Ex.3) H4-Cl ICH3 CH3 00 190-191,5
4(Ex.4) H4-Cl -~CI i2)4 00 217-218 H4-Cl -(CH2)5- 00 . 163-164 6 H4-Cl _(CH2)2-NI-(cH2)2 15 162-165 7 H4-Cl _(CH2)2-N-(CH2)2- 00 180-190 . a H 4-Cl _(CH2)2-0-(cH2)2 00 . 228-232 9 H 4-CL ¦ 2 5 00 263-270 = free base 15 = methanesulphonate Table tcontinued) Compound I _ Rl R2 I aase/ M~p. (C) . . . s~Lt~`
8-Cl 4-Cl H CH3 00 290,5-291 11 - 8-Cl 4-Cl CH3 CH3 00 259-260 12 7-Cl 4-Cl H CH3 no 300~302 1} 7-Cl 4-Cl CH3 CH3 00 24~-250 14 6-Cl 4-C1 H CH3 00 306-307 . 6-C.1 4-Cl CH3 CH3 00 248-249 16 7-~ 4-Cl H CH3 00 }04-3û5 17 7-CH3 4-Cl H CH3 ûO 269-271 19 H 4-CH3 CH3 CH3 00 181-182,5 H h-OCH3 H CH3 00 264-265 23 H 4-SCH3 CHt CH3 00 172-173 24 H 3-Cl L CH3 00 261-262 00 = free base ~6~
Table (cont;nued) . . . _ ~
Conpoun iY X Rl R2 Base/ M.p.(C) , H 3-Cl CH3 CH3 133-140 26 H 2-Cl H CH3 no 222-224 27 H 2-Cl CH3 CH3 00 165-167 3n H 4-502CH3 H CH3 279-280 31 H 4-502CH3 !CH3 - CH~ 00 244-245 (*) : 00 = free base The compounds of the invention have been the sub-ject of pharmacological tests which have demonstrated their interest as substances ~ith therapeutic activities.
Antagonism towards cLon;c convu~sions ;nduced by Cardiazo ~ in the mouse.
The test is prompted by the protocol described by Goodman et al., J. Pharm. Exp. Ther., 108~ 168~176r The m;ce rece;ve the products to be tested, or the solvent alone, 30 m;nutes (;.p. route) or 60 minutes toral route) before the ;nject;on of 35 mg/kg of Cardiazol~ by ;ntravenous route. The animals are then observed for one hour and, for each batch, the percentage of mice presenting clon;c con-vuls;ons ;s noted (100X of clonic convulsions and 10 to 20Xof tonic convulsions in the control an;mals). The percent-age of protect;on ;n compar;son w;th the control an;mals is calculated for each dose, ~hich makes it possible to deter-mine graphically the AD50, the dose which protects 50% of the animals aga;nst the convulsion-inducing action of Cardia7Ol~. The AD50s of the compounds of the invention are between 0.1 and 30 mg/kg for the intraperitoneal route and between 0.1 and 30 mg/kg for the oral route.
"8urying test" in the mouse~
This test ;s prompted by the method described by - ~4 -J.P.J. Pinel, D. Treit, F. Ladak and A.J. MacLennan in Animal learning and behavior, 8, 447-451, (1980).
The presence of foreign bodies in the usual environment of an animal forms an aversive situation to which the animal reacts by burying the aggressive object (glass beads) in the sa~dust in its cage.
The effect of anx;olytics is to reduce the fear caused by the foreign presence: the animals bury less.
The number of unburied beads which remain is then counted.
The products to be studied are administered to male CD1 strain (Charles River) mice 30 minutes ~intraperitoneal route) or 60 minutes (oral route) before the latter are placed in cages containing 25 glass beads~ After 30 minutes the number of beads remain;ng unbur;ed ;s counted. A
percentage is calculated for the treated animals and the controL animals.
In this way the AD50 is determined, the 50X active dose, which is the dose of the compound (in mg/kg) reducing by half the number of bur;ed beads, in compar;son ~;th the control an;mals. The AD50s of the compounds of the inven-tion are between 0.3 and 30 mg/kg by ;ntraper;toneal route.
The dr;nk conflict test ;n the rat.
This test is descr;bed by J.R. Vogel, B. Beer and D.E. Clody in Psychopharmacologia, 21, 1-7, (1971) Male Wistar rats (~FFA Credo) are employed. Their 3~
drinking water is withdrawn 24 h before the test. On the day of the test, 30 minutes after treatment with the com-pounds of the ;nvention by intraperitoneal route, each rat is placed ;n a transparent plastic cage (24 x 20 x Z1 cm)
8-Cl 4-Cl H CH3 00 290,5-291 11 - 8-Cl 4-Cl CH3 CH3 00 259-260 12 7-Cl 4-Cl H CH3 no 300~302 1} 7-Cl 4-Cl CH3 CH3 00 24~-250 14 6-Cl 4-C1 H CH3 00 306-307 . 6-C.1 4-Cl CH3 CH3 00 248-249 16 7-~ 4-Cl H CH3 00 }04-3û5 17 7-CH3 4-Cl H CH3 ûO 269-271 19 H 4-CH3 CH3 CH3 00 181-182,5 H h-OCH3 H CH3 00 264-265 23 H 4-SCH3 CHt CH3 00 172-173 24 H 3-Cl L CH3 00 261-262 00 = free base ~6~
Table (cont;nued) . . . _ ~
Conpoun iY X Rl R2 Base/ M.p.(C) , H 3-Cl CH3 CH3 133-140 26 H 2-Cl H CH3 no 222-224 27 H 2-Cl CH3 CH3 00 165-167 3n H 4-502CH3 H CH3 279-280 31 H 4-502CH3 !CH3 - CH~ 00 244-245 (*) : 00 = free base The compounds of the invention have been the sub-ject of pharmacological tests which have demonstrated their interest as substances ~ith therapeutic activities.
Antagonism towards cLon;c convu~sions ;nduced by Cardiazo ~ in the mouse.
The test is prompted by the protocol described by Goodman et al., J. Pharm. Exp. Ther., 108~ 168~176r The m;ce rece;ve the products to be tested, or the solvent alone, 30 m;nutes (;.p. route) or 60 minutes toral route) before the ;nject;on of 35 mg/kg of Cardiazol~ by ;ntravenous route. The animals are then observed for one hour and, for each batch, the percentage of mice presenting clon;c con-vuls;ons ;s noted (100X of clonic convulsions and 10 to 20Xof tonic convulsions in the control an;mals). The percent-age of protect;on ;n compar;son w;th the control an;mals is calculated for each dose, ~hich makes it possible to deter-mine graphically the AD50, the dose which protects 50% of the animals aga;nst the convulsion-inducing action of Cardia7Ol~. The AD50s of the compounds of the invention are between 0.1 and 30 mg/kg for the intraperitoneal route and between 0.1 and 30 mg/kg for the oral route.
"8urying test" in the mouse~
This test ;s prompted by the method described by - ~4 -J.P.J. Pinel, D. Treit, F. Ladak and A.J. MacLennan in Animal learning and behavior, 8, 447-451, (1980).
The presence of foreign bodies in the usual environment of an animal forms an aversive situation to which the animal reacts by burying the aggressive object (glass beads) in the sa~dust in its cage.
The effect of anx;olytics is to reduce the fear caused by the foreign presence: the animals bury less.
The number of unburied beads which remain is then counted.
The products to be studied are administered to male CD1 strain (Charles River) mice 30 minutes ~intraperitoneal route) or 60 minutes (oral route) before the latter are placed in cages containing 25 glass beads~ After 30 minutes the number of beads remain;ng unbur;ed ;s counted. A
percentage is calculated for the treated animals and the controL animals.
In this way the AD50 is determined, the 50X active dose, which is the dose of the compound (in mg/kg) reducing by half the number of bur;ed beads, in compar;son ~;th the control an;mals. The AD50s of the compounds of the inven-tion are between 0.3 and 30 mg/kg by ;ntraper;toneal route.
The dr;nk conflict test ;n the rat.
This test is descr;bed by J.R. Vogel, B. Beer and D.E. Clody in Psychopharmacologia, 21, 1-7, (1971) Male Wistar rats (~FFA Credo) are employed. Their 3~
drinking water is withdrawn 24 h before the test. On the day of the test, 30 minutes after treatment with the com-pounds of the ;nvention by intraperitoneal route, each rat is placed ;n a transparent plastic cage (24 x 20 x Z1 cm)
5 with -a gridded f Loor ~hich can be eLectr;fied. Drinking ~ater is distributed by means of a pipette projecting 2 cm from a cage wall and placed 3 cm above the cage floor~
After an exploration lasting 10 to 90 seconds, the animal f;nds the p;pette and beg;ns to drink. After having made 20 flicks of the tongue ~which are recorded by an Omnitech anxiometer), the rat receives a 0.07 mA electric shock (delivered by the anxiometer) at the tongue, which ceases when the rat leaves the pipette. A 3-minute session begins after a first shock, the animal continuing to receive a shock every 20 flicks of the tongue until it stops or unt;l the end of the sess;on.
Under these experimental conditions, the control animals tolerate, on average, 3 to 6 shocks. The number of shocks obta;ned w;th the treated an;mals ;s noted, and this number is compared ~ith that for the control animals using a Dunett test. This is usd to determine the MED~, the minimum effective dose, ~hich is the first dose which ;ncreases significantly the number of shocks tolerated by an animal, relative to the controls. The MEDs are bet~een 3 and 100 mg/k3 by an intraperitoneal route.
~3~
Effect on the electrocorticogram of the ventilated curarised rat.
The sedative or hypnotic activity of the compounds has been determined by observing the;r effect on the electrocorticogram of the rat according to the method des-cribed by H. Depoortere, Rev. E.E~G. Neurophysiol., 10, 3, Z07-214 t1980) and by H. Depoortere and M. Decobert, J.
Pharmacol. (Paris~, 14, 2, 195-265 ~1983).
The products to be studied were adm;nistered by the intraperitoneal route in doses increasing fr~m 1 to 30 mg/kgO
They induce sleep traces starting ~ith doses rang-;ng from 3 to 30 mg/kg.
Effects on the duration of "sleep" induced by sodium 4-hydroxybutyrate.
Th;s act;on was determined by the effect of a com-pound on the duration of "sleep" induced by sod;um 4-hydroxybutyrate (GHB) in the curarized rat.
The animals employed are Charles River strain male rats 200 + 20 9 in weight. The animals, curarized ~ith Alloferin in a dose of 1 mg/kg by i.p. route, are placed under artific;al respiration with the aid of a mask placed over the muzzle (frequency of resp;ration = 50/minute;
respiratory volume = 14 ml3.
~2~
The oesophagus is ligatured beforehand to prevent the entry of air into the stomach.
Frontoparietal and occipital cort;cal electrodes make it possible to record the electrocorticographic S activity on 3 Grass multipoint recorder modeL 79 P at a speed of 6 mm/s.
The preparation of the animal is carried out under local anaesthesia (2X Xylocaine). The rats are kept at a constant temperature (37.5C) throughout the exper;ment.
Ten minutes after the rat's preparation has been completed a 2ûO mg/kg dose of sodium 4-hydroxybutyrate is injected by intravenous route at the tail.
A 10 mg/kg dose of the compound under study is administered by intraperitoneal route 3 minutes after the administration of sodium 4-hydroxybutyrate.
The evaluation of the traces is carried out over 15-minute periods for 75 minutes after the injection of GH~.
During this analysis period, the total duration of "sleep"
is determined. A series of 15 controls makes it poss;ble 2û to establish precisely the duration of "GH8 sleep".
Statistical analysis of the results is carried out using the Mann-Whitney "U" test.
Some compounds reduce the effects of GH8 (up to 24X
reduction in the duration of sleep at a dose of 10 mg/kg), wh;le others ;ntens;fy these effects ~up to 18% ;ncrease in the duration of sleep at a dose of 10 mg/kg, or 3ûX at a dose of 30 mg/kg). It is also found that the effects can ~633 be opposite, depending on whether the compounds are adminis-tered in high doses or in low doses.
The results of these various tests sho~ that the compounds of the invention have anxiolytic, sleep-induc;ng, hypnotic and anticonvulsant properties; the compounds of the invent;on are useful for the treatment of anx;ety states, disturbances of sleep and other neurological and psychiatric disorders, for the treatment of disturbances of vigilance, in particular for combating behaviour disturbances attributable to cerebral vascular damage and to cerebral scleros;s in geriatrics, and for the treatment of absences due to cranial traumas and for the treatment of metabolic encephalopath;es.
The compounds of the ;nvention may be presented in any form suitable for administration by oral or parenteral rou~e, for example in the form of tablets, pills, gelatine capsules, drinkable or injectable solutions, and the like, in combination ~ith any suitable excipient.
The daily dosage can range from 1 ts 100 mg.
After an exploration lasting 10 to 90 seconds, the animal f;nds the p;pette and beg;ns to drink. After having made 20 flicks of the tongue ~which are recorded by an Omnitech anxiometer), the rat receives a 0.07 mA electric shock (delivered by the anxiometer) at the tongue, which ceases when the rat leaves the pipette. A 3-minute session begins after a first shock, the animal continuing to receive a shock every 20 flicks of the tongue until it stops or unt;l the end of the sess;on.
Under these experimental conditions, the control animals tolerate, on average, 3 to 6 shocks. The number of shocks obta;ned w;th the treated an;mals ;s noted, and this number is compared ~ith that for the control animals using a Dunett test. This is usd to determine the MED~, the minimum effective dose, ~hich is the first dose which ;ncreases significantly the number of shocks tolerated by an animal, relative to the controls. The MEDs are bet~een 3 and 100 mg/k3 by an intraperitoneal route.
~3~
Effect on the electrocorticogram of the ventilated curarised rat.
The sedative or hypnotic activity of the compounds has been determined by observing the;r effect on the electrocorticogram of the rat according to the method des-cribed by H. Depoortere, Rev. E.E~G. Neurophysiol., 10, 3, Z07-214 t1980) and by H. Depoortere and M. Decobert, J.
Pharmacol. (Paris~, 14, 2, 195-265 ~1983).
The products to be studied were adm;nistered by the intraperitoneal route in doses increasing fr~m 1 to 30 mg/kgO
They induce sleep traces starting ~ith doses rang-;ng from 3 to 30 mg/kg.
Effects on the duration of "sleep" induced by sodium 4-hydroxybutyrate.
Th;s act;on was determined by the effect of a com-pound on the duration of "sleep" induced by sod;um 4-hydroxybutyrate (GHB) in the curarized rat.
The animals employed are Charles River strain male rats 200 + 20 9 in weight. The animals, curarized ~ith Alloferin in a dose of 1 mg/kg by i.p. route, are placed under artific;al respiration with the aid of a mask placed over the muzzle (frequency of resp;ration = 50/minute;
respiratory volume = 14 ml3.
~2~
The oesophagus is ligatured beforehand to prevent the entry of air into the stomach.
Frontoparietal and occipital cort;cal electrodes make it possible to record the electrocorticographic S activity on 3 Grass multipoint recorder modeL 79 P at a speed of 6 mm/s.
The preparation of the animal is carried out under local anaesthesia (2X Xylocaine). The rats are kept at a constant temperature (37.5C) throughout the exper;ment.
Ten minutes after the rat's preparation has been completed a 2ûO mg/kg dose of sodium 4-hydroxybutyrate is injected by intravenous route at the tail.
A 10 mg/kg dose of the compound under study is administered by intraperitoneal route 3 minutes after the administration of sodium 4-hydroxybutyrate.
The evaluation of the traces is carried out over 15-minute periods for 75 minutes after the injection of GH~.
During this analysis period, the total duration of "sleep"
is determined. A series of 15 controls makes it poss;ble 2û to establish precisely the duration of "GH8 sleep".
Statistical analysis of the results is carried out using the Mann-Whitney "U" test.
Some compounds reduce the effects of GH8 (up to 24X
reduction in the duration of sleep at a dose of 10 mg/kg), wh;le others ;ntens;fy these effects ~up to 18% ;ncrease in the duration of sleep at a dose of 10 mg/kg, or 3ûX at a dose of 30 mg/kg). It is also found that the effects can ~633 be opposite, depending on whether the compounds are adminis-tered in high doses or in low doses.
The results of these various tests sho~ that the compounds of the invention have anxiolytic, sleep-induc;ng, hypnotic and anticonvulsant properties; the compounds of the invent;on are useful for the treatment of anx;ety states, disturbances of sleep and other neurological and psychiatric disorders, for the treatment of disturbances of vigilance, in particular for combating behaviour disturbances attributable to cerebral vascular damage and to cerebral scleros;s in geriatrics, and for the treatment of absences due to cranial traumas and for the treatment of metabolic encephalopath;es.
The compounds of the ;nvention may be presented in any form suitable for administration by oral or parenteral rou~e, for example in the form of tablets, pills, gelatine capsules, drinkable or injectable solutions, and the like, in combination ~ith any suitable excipient.
The daily dosage can range from 1 ts 100 mg.
Claims (4)
1. A process for preparing imidazo[1.2-a]quinolines of the general formula (I) (I) in which X is hydrogen, halogen, methyl, methoxy, methylthio or methylsulphonyl, Y is hydrogen, halogen or methyl in position 6, 7 or 8, and R1 and R2, which may be the same or different, each is hydrogen, methyl or ethyl or R1 and R2 together form a tetramethylene, pentamethylene, 3-methyl-3-azapentamethylene, 3-ethoxycarbonyl-3-azapenta-methylene or 3-oxapentamethylene group, and their pharmacologically acceptable acid addition salts which process comprises:-(a) - either reacting a quinoline of formula (II) (II) with an .alpha.-bromoacetophenone carrying the substituent X, to produce an ionic compound of formula (III) (III) and cyclising the ionic compound (III) in the presence of ammonium acetate and ferric chloride to produce a compound of formula (V) (V) - or reacting a 2-aminoquinoline of formula (IV) (IV) with an .alpha.-bromoacetophenone carrying the substituent X to produce said compound of formula (V) (b) formylating said compound of formula (V) to produce an aldehyde of formula (VI) (VI) (c) reducing said aldehyde of formula (VI) to an alcohol of formula (VII) (VII) (d) converting said alcohol of formula (VII) to a nitrile of formula (VIII) (VIII) and (e) converting said nitrile of formula (VIII) into an amide of formula (I) either directly by partial hydrolysis in the case of an amide in which both R1 and R2 are hydrogen or by hydrolysis to an acid of formula (IX) (IX) and conversion of the acid to the amide of formula (I) by reaction with an amine of formula R1-NH-R2, the resulting amide of formula (I) optionally being converted, in manner known per se, into an acid addition salt.
2. A process according to claim 1, wherein the amide of formula (I) in which R1 and R2 are both hydrogen is prepared by partial hydrolysis of the nitrile of formula (VIII) in an aqueous basic medium.
3. A process according to claim 1 or 2 wherein an amide of formula (I) in which R1 and R2 are both methyl is prepared by direct methylation of an amide of formula (I) in which both R1 and R2 are hydrogen.
4. Imidazo[1.2-a]quinolines of the general formula (I) as defined in Claim 1, in which X is hydrogen, halogen, methyl, methoxy, methylthio or methylsulphonyl, Y is hydrogen, halogen or methyl in position 6, 7 or 8, and R1 and R2, which may be the same or different, each is hydrogen, methyl or ethyl or R1 and R2 together form a tetramethylene, pentamethylene, 3-methyl-3-azapentamethylene, 3-ethoxycarbonyl-3-azapentamethylene or 3-oxapentamethylene group, and their pharmacologically acceptable acid addition salts.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8412446A FR2568879B1 (en) | 1984-08-07 | 1984-08-07 | IMIDAZO (1,2-A) QUINOLINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR8412446 | 1984-08-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1263389A true CA1263389A (en) | 1989-11-28 |
Family
ID=9306855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000488164A Expired CA1263389A (en) | 1984-08-07 | 1985-08-06 | Imidazo[1.2-a]quinoline derivatives, their preparation and pharmaceutical compositions containing them |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0172097B1 (en) |
| JP (1) | JPS6147484A (en) |
| KR (1) | KR860001814A (en) |
| AR (1) | AR240674A1 (en) |
| AT (1) | ATE41001T1 (en) |
| AU (1) | AU573880B2 (en) |
| CA (1) | CA1263389A (en) |
| DE (1) | DE3568430D1 (en) |
| DK (1) | DK161963B (en) |
| ES (1) | ES8604593A1 (en) |
| FI (1) | FI79314C (en) |
| FR (1) | FR2568879B1 (en) |
| GR (1) | GR851929B (en) |
| HU (1) | HU199838B (en) |
| IL (1) | IL76019A0 (en) |
| MX (1) | MX161035A (en) |
| NO (1) | NO162188C (en) |
| NZ (1) | NZ213014A (en) |
| PT (1) | PT80920B (en) |
| ZA (1) | ZA855937B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2593179B1 (en) * | 1986-01-22 | 1988-04-01 | Synthelabo | IMIDAZO (1,2-A) QUINOLEINS DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2606410B1 (en) * | 1986-11-07 | 1989-02-24 | Synthelabo | IMIDAZOPYRIDINES, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS |
| FR2707987B1 (en) * | 1993-07-22 | 1995-09-08 | Synthelabo | 9H-imidazo [1,2-a] benzimidazole-3-acetamide derivatives, their preparation and their therapeutic use. |
| FR2700547B1 (en) * | 1993-01-15 | 1995-02-17 | Synthelabo | Imidazo [2,1-b] benzoselenazole-3-acetamide derivatives, their preparation and their therapeutic use. |
| EP0607076A1 (en) * | 1993-01-15 | 1994-07-20 | Synthelabo | 9H-Imidazo 1,2-a benzimidazole derivatives with GABA activity |
| FR2700544B1 (en) * | 1993-01-15 | 1995-02-17 | Synthelabo | 9H-imidazo [1,2-a] benzimidazole-3-acetamide derivatives, their preparation and their therapeutic use. |
| FR2719843B1 (en) * | 1994-05-10 | 1996-06-07 | Synthelabo | Derivatives of 5,6-dihydro-4h-imidazo [2 ', 1': 2,3] imidazo- [4,5,1-ij] quinoline and 4,5-dihydroimidazo [1,2-a] pyrrolo- [1,2,3-cd] benzimidazole, their preparation and their therapeutic application. |
| FR2722501B1 (en) * | 1994-07-13 | 1996-08-09 | Synthelabo | 9H-IMIDAZO (1,2-A) BENZIMIDAZOLE-3-ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2492382A1 (en) * | 1980-10-22 | 1982-04-23 | Synthelabo | IMIDAZO (1,2-A) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF |
-
1984
- 1984-08-07 FR FR8412446A patent/FR2568879B1/en not_active Expired
-
1985
- 1985-07-30 DE DE8585401555T patent/DE3568430D1/en not_active Expired
- 1985-07-30 AT AT85401555T patent/ATE41001T1/en not_active IP Right Cessation
- 1985-07-30 EP EP85401555A patent/EP0172097B1/en not_active Expired
- 1985-08-06 ZA ZA855937A patent/ZA855937B/en unknown
- 1985-08-06 KR KR1019850005659A patent/KR860001814A/en not_active Application Discontinuation
- 1985-08-06 DK DK356985A patent/DK161963B/en not_active IP Right Cessation
- 1985-08-06 AR AR30120285A patent/AR240674A1/en active
- 1985-08-06 NO NO853099A patent/NO162188C/en unknown
- 1985-08-06 MX MX206216A patent/MX161035A/en unknown
- 1985-08-06 AU AU45814/85A patent/AU573880B2/en not_active Ceased
- 1985-08-06 ES ES545929A patent/ES8604593A1/en not_active Expired
- 1985-08-06 FI FI853027A patent/FI79314C/en not_active IP Right Cessation
- 1985-08-06 GR GR851929A patent/GR851929B/el unknown
- 1985-08-06 CA CA000488164A patent/CA1263389A/en not_active Expired
- 1985-08-06 NZ NZ213014A patent/NZ213014A/en unknown
- 1985-08-06 IL IL76019A patent/IL76019A0/en not_active IP Right Cessation
- 1985-08-06 JP JP60173976A patent/JPS6147484A/en active Pending
- 1985-08-06 HU HU852992A patent/HU199838B/en not_active IP Right Cessation
- 1985-08-06 PT PT80920A patent/PT80920B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0172097A1 (en) | 1986-02-19 |
| NO162188B (en) | 1989-08-14 |
| ES545929A0 (en) | 1986-02-01 |
| EP0172097B1 (en) | 1989-03-01 |
| GR851929B (en) | 1985-12-09 |
| FR2568879A1 (en) | 1986-02-14 |
| FI79314B (en) | 1989-08-31 |
| DE3568430D1 (en) | 1989-04-06 |
| DK356985D0 (en) | 1985-08-06 |
| NO162188C (en) | 1989-11-29 |
| PT80920B (en) | 1987-12-30 |
| HUT38636A (en) | 1986-06-30 |
| MX161035A (en) | 1990-07-11 |
| AU573880B2 (en) | 1988-06-23 |
| FI853027A0 (en) | 1985-08-06 |
| ZA855937B (en) | 1986-03-26 |
| ES8604593A1 (en) | 1986-02-01 |
| AU4581485A (en) | 1986-02-13 |
| KR860001814A (en) | 1986-03-22 |
| NO853099L (en) | 1986-02-10 |
| NZ213014A (en) | 1988-05-30 |
| ATE41001T1 (en) | 1989-03-15 |
| JPS6147484A (en) | 1986-03-07 |
| FR2568879B1 (en) | 1986-12-12 |
| DK161963B (en) | 1991-09-02 |
| DK356985A (en) | 1986-02-08 |
| HU199838B (en) | 1990-03-28 |
| PT80920A (en) | 1985-09-01 |
| AR240674A1 (en) | 1990-08-31 |
| FI853027L (en) | 1986-02-08 |
| IL76019A0 (en) | 1985-12-31 |
| FI79314C (en) | 1989-12-11 |
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