CA1286668C - Imidazo[1,2-a]quinoline derivatives, their preparation and their application in therapy - Google Patents
Imidazo[1,2-a]quinoline derivatives, their preparation and their application in therapyInfo
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Abstract
ABSTRACT
IMIDAZO[1,2-a]QUINOLINE DERIVATIVES, THEIR PREPARATION AND
THEIR APPLICATION IN THERAPY
Compounds of formula (I)
IMIDAZO[1,2-a]QUINOLINE DERIVATIVES, THEIR PREPARATION AND
THEIR APPLICATION IN THERAPY
Compounds of formula (I)
Description
~Z86668 IMIDAZO[1,2-a] QUINOLINE DERIVATIVES, THEIR PREPARATION AND
THEIR APPLICATION IN THERAPY
The present invention provides compounds for use in therapy.
The present invention provides a compound which is an imidazo[1,2-a]quinoline of formula (I) ~1) ~ 2 Rl in which X denotes hydrogen or a halogen or a ~Cl 4)alkyl, (Cl 4)-alkoxy, (Cl 4)alkylthio, methylsulphonyl, amino, (Cl 4)-alkylamino, di(Cl 4)alkylamino, nitro or trifuloroalkyl 10 group, Y denotes hydrogen or a halogen or a methyl group and is attached to the aryl ring at position 6, 7 or 8, and Rl and R2, which may be identical or different, each denote hydrogen or a (Cl 6)alkyl group, or Rl and R2 together form ~.Z8~
a tetramethylene, pentamethylene, 3-methyl-3-azapentamethylene or 3-oxapentamethylene divalent group, or a pharmaceutically acceptable addition salt thereof.
The preferred compounds of the invention are those 5 for which X denotes chlorine, or a methyl or methylthio group attached for the aryl ring at the para position, Y
denotes hydrogen, and R1 and R2, which may be identical or different, denote hydrogen or a methyl group.
The present invention also provides a process 10 for the preparation of a compound of formula (I) as shown in the attached drawing.
A quinoline of formula (II) is reacted with an -bromoacetophenone bearing the substituent X as defined above. The reaction preferably occurs with heating in a 15 solvent such as methylene chloride or 1,2-dichloroethane.
An ionic compound of formula (III) is obtained, which is then cyclized, preferably in the presence of ammonium acetate in an acidic organic solvent such as acetic or propionic acid at a temperature of about 90C, to obtain a 20 compound of formula (IV). This compound is then reacted with glyoxylic acid, preferably in a solvent such as acetic acid at 80C. A hydroxy acid of formula (V) is obtained which is acetylated, for example using acetic anhydride in the presence of pyridine, and then converted to an 25 a-acetoxyacetamide of formula (VI) via the imidazolide, 128~i~68 which is produced in situ.
The compound of formula (VI ) is deacetylated to an ~-hydroxyacetamide of formula (VII), preferably by treatment with potassium carbonate in ethanol.
The compound of formula (VII ) is chlorinated, preferably with sulphonyl chloride (SOC12) in a chlorinated solvent such as dichloromethane, to obtain a chlorinated compound of formula (VIII ), which is finally dechlorinated to the compound ( I ), for example using sodium formaldehyde 10 sulfoxylate (Rongalite - Trade Mark) in methylene chloride.
The examples which follow further illustrate the invention.
Microanalyses and the IR and NMR spectra confirm the structure of the compounds of formula (I).
l5 Example 1 Preparation of N-methyl-a=~2-(4-methylphenyl)-4,5-dihydro-imidazo-l1,2-a]quinol-1-yl}acetamide 1.1 1-[2-(4-methylphenyl)-2-oxoethyl]quinolinium bromide 110 g (0.516 mol) of a-bromo-para-methylaceto-phenone and 61 ml (0.516 mol) of quinoline were dissolved in 500 ml of methylene chloride. The solution was heated to the reflux temperature for 1 hour and then diluted with 300 ml of ether and cooled.
After filtration and drying of the precipitate, a yellow solid was obtained of melting point 220-221C.
128666t3 1.2. 2-(4-methylphenyl)-4,5-dihydroimidazo[1,2-a]quinoline.
17.1 g (0.05 mol) of quaternary salt obtained in 1.1. and 25 g of ammonium acetate were mixed in 50 ml of acetic acid. This suspension was heated for 3 hours to 90C, and then cooled and diluted with 200 ml of water. The brown precipitate formed was filtered off and taken up between water and methylene chloride.
This two-phase mixture was treated with an excess of 1 N NaOH until the pH was at least 8. The organic phase was then decanted, dried over Na2SO4 and filtered, and the filtrate concentrated under reduced pressure. The evaporation residue was recrystallized in pentane.
THEIR APPLICATION IN THERAPY
The present invention provides compounds for use in therapy.
The present invention provides a compound which is an imidazo[1,2-a]quinoline of formula (I) ~1) ~ 2 Rl in which X denotes hydrogen or a halogen or a ~Cl 4)alkyl, (Cl 4)-alkoxy, (Cl 4)alkylthio, methylsulphonyl, amino, (Cl 4)-alkylamino, di(Cl 4)alkylamino, nitro or trifuloroalkyl 10 group, Y denotes hydrogen or a halogen or a methyl group and is attached to the aryl ring at position 6, 7 or 8, and Rl and R2, which may be identical or different, each denote hydrogen or a (Cl 6)alkyl group, or Rl and R2 together form ~.Z8~
a tetramethylene, pentamethylene, 3-methyl-3-azapentamethylene or 3-oxapentamethylene divalent group, or a pharmaceutically acceptable addition salt thereof.
The preferred compounds of the invention are those 5 for which X denotes chlorine, or a methyl or methylthio group attached for the aryl ring at the para position, Y
denotes hydrogen, and R1 and R2, which may be identical or different, denote hydrogen or a methyl group.
The present invention also provides a process 10 for the preparation of a compound of formula (I) as shown in the attached drawing.
A quinoline of formula (II) is reacted with an -bromoacetophenone bearing the substituent X as defined above. The reaction preferably occurs with heating in a 15 solvent such as methylene chloride or 1,2-dichloroethane.
An ionic compound of formula (III) is obtained, which is then cyclized, preferably in the presence of ammonium acetate in an acidic organic solvent such as acetic or propionic acid at a temperature of about 90C, to obtain a 20 compound of formula (IV). This compound is then reacted with glyoxylic acid, preferably in a solvent such as acetic acid at 80C. A hydroxy acid of formula (V) is obtained which is acetylated, for example using acetic anhydride in the presence of pyridine, and then converted to an 25 a-acetoxyacetamide of formula (VI) via the imidazolide, 128~i~68 which is produced in situ.
The compound of formula (VI ) is deacetylated to an ~-hydroxyacetamide of formula (VII), preferably by treatment with potassium carbonate in ethanol.
The compound of formula (VII ) is chlorinated, preferably with sulphonyl chloride (SOC12) in a chlorinated solvent such as dichloromethane, to obtain a chlorinated compound of formula (VIII ), which is finally dechlorinated to the compound ( I ), for example using sodium formaldehyde 10 sulfoxylate (Rongalite - Trade Mark) in methylene chloride.
The examples which follow further illustrate the invention.
Microanalyses and the IR and NMR spectra confirm the structure of the compounds of formula (I).
l5 Example 1 Preparation of N-methyl-a=~2-(4-methylphenyl)-4,5-dihydro-imidazo-l1,2-a]quinol-1-yl}acetamide 1.1 1-[2-(4-methylphenyl)-2-oxoethyl]quinolinium bromide 110 g (0.516 mol) of a-bromo-para-methylaceto-phenone and 61 ml (0.516 mol) of quinoline were dissolved in 500 ml of methylene chloride. The solution was heated to the reflux temperature for 1 hour and then diluted with 300 ml of ether and cooled.
After filtration and drying of the precipitate, a yellow solid was obtained of melting point 220-221C.
128666t3 1.2. 2-(4-methylphenyl)-4,5-dihydroimidazo[1,2-a]quinoline.
17.1 g (0.05 mol) of quaternary salt obtained in 1.1. and 25 g of ammonium acetate were mixed in 50 ml of acetic acid. This suspension was heated for 3 hours to 90C, and then cooled and diluted with 200 ml of water. The brown precipitate formed was filtered off and taken up between water and methylene chloride.
This two-phase mixture was treated with an excess of 1 N NaOH until the pH was at least 8. The organic phase was then decanted, dried over Na2SO4 and filtered, and the filtrate concentrated under reduced pressure. The evaporation residue was recrystallized in pentane.
2-(4-methylphenyl)-4,5-dihydroimidazo[1,2-a]quino-line (IV) was thereby obtained, of melting point 91-92C (decomposition).
1.3. -hydrox~ ~-{2-(4-methylphenyl)-4~5-dihydroimidazo-1,2-a]quinol-1-yl}acetic acid.
A mixture of 29 g (0.112 mol) of 4,5-dihydroimidazo[1,2-a]quinoline, obtained in 1.2., 16.3 g (0.225 mol) of glyoxylic acid and 550 ml of acetic acid was heated at 80C for 6 hours. The solution was concentrated under reduced pressure and the evaporation residue taken up with water. The acid crystallized and was filtered off, washed with water, THF and ether and dried under vacuum. An a-hydroxy acid (V) was obtained of melting point lX866~;8 178-181C (decomposition) 1.4. -hydroxy-N-methyl-a-{2-~4-methylphenyl)-4,5-dihydro-imidazo[1,2-a]quinol-1-yl}acetamide 1.4.1. 16.5 g (0.049 mol) of a-hydroxy acid was dissolved in 300 ml of a 50:50 mixture of pyridine and acetic anhydride. This mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The evaporation residue crystallized on treatment with ether to give a product which was used directly for the following stage.
1.4.2. 16.5 g (0.045 mol) of a-acetoxy acid obtained in 1.4.1 and 9.5 g (0.058 mol) of carbonyldiimidazole were reacted in 200 ml of dry THF. When the evolution of gas had ceased, the solution was brought to 50C for 1 hour and then cooled and treated with an excess of dry gaseous methylamine. The reaction mixture was concentrated under reduced pressure, the residue taken up between water and methylene chloride and treated with K2CO3. This mixture was stirred for 3 hours at room temperature and then decanted. The organic phase was dried with Na2SO4, filtered, and the filtrate evaporated under reduced pressure to obtain a mixture which was then purified by chromatography on silica and crystallized in ether to lX86668 provide an a-acetoxyacetamide (VI), which was deacetylated directly without further purification.
1.4.3. The a-acetoxyacetamide (VI) produced in 1.4.2 was treated with 25 g of K2CO3 in 100 ml of 50% strength aqueous methanol with stirring which was maintained overnight. The solution was concentrated, the solid residue taken up with water, filtered off, washed with water until the pH of the washing liquors was neutral, and then washed with ether and dried. The a-hydroxyacetamide (VII) is obtained of melting point 209-211C.
1.5. N-methyl-a-{2-(4-methylphenyl)-4,5-dihydroimidazo [1,2-a]quinol-1-yl}acetamide 4.0 g (0.0115 mol) of a-hydroxyacetamide (VII) produced in 1.4 was treated with 25 ml of SOC12 in 125 ml of methylene chloride at room temperature overnight. The volatile residues were evaporated off and the hydrochloride of the a-chloroacetamide (VIII) was obtained. 100 g (0.0115 mol) of this compound was dissolved in 150 ml of CH2Cl2 and the resulting solution treated with 5.3 g (0.0345 mol) of Rongalite (Trade Mark) at room temperature for 24 hours. At the end of the reaction, the mixture was filtered, the filtrate concentrated under reduced pressure, and the evaporation residue treated with aqueous NaHCO3.
After several washings with water, the solid residue was filtered off and dried and the crude mixture was 1~8~6~8 purified by chromatography and recrystallized in acetonitrile. The amide (I) was obtained of melting point 226-8C.
Example 2 5 N,N-dimethyl-a-{2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-a]quinol-1-yl}acetamide 2.1. a-hydroxy-N,N-dimethyl-a-{2-(4-methylphenyl)-4,5-dihydroimidazo[1,2-a]quinol-1-yl}acetamide.
2.1.1. 16.5 g (0.049 mol) of a-acetoxy acid obtained in 1.4.1 was reacted with 9.5 g (0.0585 mol) of carbonyldiimidazole in 200 ml of dry THF. When the evolution of gas had ceased, the solution was brought to 50C for 1 hour, and then cooled and treated with an excess of dry gaseous dimethyl amine. The mixture was stirred for several hours and then concentrated under reduced pressure. The resulting evaporation residue was treated with aqueous NaHCO3 and the a-acetoxyamide extracted with CH2Cl2, which was purified by chromatography on silica to provide an oil.
2.1.2. The oil obtained in 2.1.1 above was treated with 45 g of K2CO3 dissolved in 100 ml of CH30H at room temperature for 40 hours. After evaporation of the water and methanol, the residue was taken up between water and methylene chloride. The organic phase was ~X8666~
decanted, dried with Na2SO4 and filtered and the filtrate concentrated under reduced pressu,e. The residual oil was crystallized in ether to provide the a-hydroxyamide (VII) of melting point 169-70C.
5 2.2. N,N-dimethyl-a-{2-(4-methylphenyl)-4,5-dihydro-imidazo[1,2-a]quinol-1-yl}acetamide.
4 g (0.0115 mol) of -hydroxyacetamide (VII) was treated with 25 ml of SOCl2 in 125 ml of CH2Cl2 at room temperature overnight. After evaporation of the solvent and excess SOCl2, the crude hydrochloride of the a-chloroacetamide was obtained, which was dissolved in 150 ml of CH2Cl2. This solution was then treated with 5.3 g (0.0345 mol) of Rongalite (Trade Mark) at room temperature for 24 hours. At the end of the reaction, the suspension was filtered, the filtrate concentrated under reduced pressure, the evaporation residue treated with aqueous NaHCO3, the insoluble solid extracted with CH2Cl2 and then purified by chromatography (silica). It was recrystallized in ethyl acetate to provide the acetamide (I) of melting point 206-207C.
Five compounds of the present invention were subjected to pharmacological trials to demonstrate their therapeutic activities. These compounds used are defined (with reference to formula (I)) in the following table lZ86~i6~
..
Compound Y _ 1 R2 M.p. ( C) 1 H Para-CH3 H CH3 226-8 2 H Para-cH3 CH3 CH3 206-7 3 H para-C1 H CH3 236-7 4 H para-Cl CH3 CH3 193-4 H Para-SCH3 H C~3 245-7 Antagonism towards clonic convulsions induced by Cardiazol (Trade Mark~ in mice.
A trial, which was modelled on the procedure described by Goodman et al., J. Pharm. Exp. Ther., 108, 168-176, was carried out on mice. Mice either 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 15 observed for one hour and, for each batch, the percentage of mice showing clonic convulsions was noted (100~ of clonic convulsions ahd 10 to 20% of tonic convulsions in the control animals).
For each dose, the percentage protection relative 20 to the control animals was calculated, and the AD50, the dose which protects 50~ of the animals as regards the lX86668 convulsant effects of Cardiazol, was determined graphically.
The AD50 values of the compounds of the invention are from 0.1 to 30 mg/kg intraperitoneally and from 0.1 to 30 mg/kg orally.
5 "surying" test in mice.
A test which was modelled on the method described by Pinel J.P.J., Treit D., Ladak F. and MacLennan A.J. in Animal learning and behavior, 8, 447-451, (1980) was carried out.
The presence of foreign bodies in the usual environment of an animal represents an aversive situation, to which the animal reacts by burying the subject of the attack (in this case glass balls in the sawdust in its cage).
Anxiolytic substances reduce the apprehension caused by the presence of the foreign bodies and the animals engage in less burying.
The test products were administered to male CD1 strain mice (Charles River) 30 minutes (intraperitoneally) 20 or 60 minutes (orally) before they were placed in cages containing 25 glass balls. After 30 minutes, the number of balls remaining unburied was counted and a percentage calculated between the treated animals and the control animals.
lX86668 The AD50, the 50% active dose, which is the dose of compound (in mg/kg) which reduces by one half the number of balls buried, by comparison with the control animals, was determined in this manner. The AD50 values of the compounds 5 of the invention are from 0.3 to 30 mg/kg intraperitoneally.
Drinking conflict test in rats.
This test is described by Vogel J.R., seer s. and Clody D.E. in Psychopharmacologia, 21, 1-7, (1971).
Male Wistar rats (IFFA Credo) were used. Their l0 drinking water was withdrawn 24 hours before the test. On the day of the test, 30 minutes after intraperitoneal treatment with the compounds of the invention, each rat was placed in a transparent plastic cage (24 x 20 x 21 cm) having a meshwork floor which could be electrified.
l5 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 exploration for from 10 to 90 seconds, the rats found the pipette and started to drink. After giving 20 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 continued for 3 minutes after the first shock; the animals ~X86668 received 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 5 shocks obtained with the treated animals was noted, and this number was compared with that of the control animals by a 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 10 animals, was determined in this manner.
The MED values are from 3 to 100 mg/kg intraperitoneally.
Action on the electrocorticogram of ventilated curarized rats.
The sedative or hypnotic activity of the compounds was determined by observing their action on the electrocorticogram of rats according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and by H. Depoortere and M. Decobert, J. Pharmacol.
(Paris), 14, 2, 195-265 (1983).
The test compounds were administered intraperitoneally at increasing doses of from 1 to 30 mg/kg.
They induced sleep traces with doses ranging from 3 to 100 mg/kg.
1~86668 Koster's test The analgesic activity was shown using the test of Koster et al. (acetic acid "writhing" test in mice), Fed.
Proc., 18, 412, 1959.
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 body weight. After 30 min, acetic acid (dissolved at a concentration of 0.6% in a mixture of carboxymethyl-10 cellulose and Tween 80, in a proportion of 10 ml per kg of body weight) was administered intraperitoneally. The total number of contortions was noted during 15 min.
The percentage protection relative to a control batch was determined, and the AD50 was calculated 15 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 inhibition test The test used the technique described in Senay and 20 Levine, Proc. Soc. Exp. Biol. 1967, 124, 1221-1223, Peptic Ulcers, 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 boxes 20 cm x 5 cm, and placed in a cold room at from 2 to 4C.
The test compounds were administered orally in the proportion of 10, 30 and 100 mg/kg immediately before the 5 restraint; the control rats received only placebo. 2 hours later, the animals were sacrificed by inhalation of chloroform.
The stomachs were removed and the degree of ulceration was noted.
The compounds of the invention significantly decreased the amount of stress ulceration.
The results of these different tests show that the compounds of the invention possess at least one anxiolytic, sleep-inducing, hypnotic, anticonvulsant, analgesic or anti-15 ulcerative property; the compounds of the invention are, forexample, useful in the treatment of anxiety states, sleep disorders and other neurological and psychiatric conditions, disorders of alertness, and can be especially useful for combatting behavioural disorders ascribed to cerabral 20 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 aches, pain and ulcers.
The compounds of the invention can be presented in 1~:86668 any form suitable for oral or parenteral administration, for example in the form of tablets, dragées, gelatin capsules, solutions to be taken by mouth or injectable solutions, in combination with any pharmaceutically acceptable excipient.
5 The daily dosage can range from 1 to 100 mg.
1.3. -hydrox~ ~-{2-(4-methylphenyl)-4~5-dihydroimidazo-1,2-a]quinol-1-yl}acetic acid.
A mixture of 29 g (0.112 mol) of 4,5-dihydroimidazo[1,2-a]quinoline, obtained in 1.2., 16.3 g (0.225 mol) of glyoxylic acid and 550 ml of acetic acid was heated at 80C for 6 hours. The solution was concentrated under reduced pressure and the evaporation residue taken up with water. The acid crystallized and was filtered off, washed with water, THF and ether and dried under vacuum. An a-hydroxy acid (V) was obtained of melting point lX866~;8 178-181C (decomposition) 1.4. -hydroxy-N-methyl-a-{2-~4-methylphenyl)-4,5-dihydro-imidazo[1,2-a]quinol-1-yl}acetamide 1.4.1. 16.5 g (0.049 mol) of a-hydroxy acid was dissolved in 300 ml of a 50:50 mixture of pyridine and acetic anhydride. This mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The evaporation residue crystallized on treatment with ether to give a product which was used directly for the following stage.
1.4.2. 16.5 g (0.045 mol) of a-acetoxy acid obtained in 1.4.1 and 9.5 g (0.058 mol) of carbonyldiimidazole were reacted in 200 ml of dry THF. When the evolution of gas had ceased, the solution was brought to 50C for 1 hour and then cooled and treated with an excess of dry gaseous methylamine. The reaction mixture was concentrated under reduced pressure, the residue taken up between water and methylene chloride and treated with K2CO3. This mixture was stirred for 3 hours at room temperature and then decanted. The organic phase was dried with Na2SO4, filtered, and the filtrate evaporated under reduced pressure to obtain a mixture which was then purified by chromatography on silica and crystallized in ether to lX86668 provide an a-acetoxyacetamide (VI), which was deacetylated directly without further purification.
1.4.3. The a-acetoxyacetamide (VI) produced in 1.4.2 was treated with 25 g of K2CO3 in 100 ml of 50% strength aqueous methanol with stirring which was maintained overnight. The solution was concentrated, the solid residue taken up with water, filtered off, washed with water until the pH of the washing liquors was neutral, and then washed with ether and dried. The a-hydroxyacetamide (VII) is obtained of melting point 209-211C.
1.5. N-methyl-a-{2-(4-methylphenyl)-4,5-dihydroimidazo [1,2-a]quinol-1-yl}acetamide 4.0 g (0.0115 mol) of a-hydroxyacetamide (VII) produced in 1.4 was treated with 25 ml of SOC12 in 125 ml of methylene chloride at room temperature overnight. The volatile residues were evaporated off and the hydrochloride of the a-chloroacetamide (VIII) was obtained. 100 g (0.0115 mol) of this compound was dissolved in 150 ml of CH2Cl2 and the resulting solution treated with 5.3 g (0.0345 mol) of Rongalite (Trade Mark) at room temperature for 24 hours. At the end of the reaction, the mixture was filtered, the filtrate concentrated under reduced pressure, and the evaporation residue treated with aqueous NaHCO3.
After several washings with water, the solid residue was filtered off and dried and the crude mixture was 1~8~6~8 purified by chromatography and recrystallized in acetonitrile. The amide (I) was obtained of melting point 226-8C.
Example 2 5 N,N-dimethyl-a-{2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-a]quinol-1-yl}acetamide 2.1. a-hydroxy-N,N-dimethyl-a-{2-(4-methylphenyl)-4,5-dihydroimidazo[1,2-a]quinol-1-yl}acetamide.
2.1.1. 16.5 g (0.049 mol) of a-acetoxy acid obtained in 1.4.1 was reacted with 9.5 g (0.0585 mol) of carbonyldiimidazole in 200 ml of dry THF. When the evolution of gas had ceased, the solution was brought to 50C for 1 hour, and then cooled and treated with an excess of dry gaseous dimethyl amine. The mixture was stirred for several hours and then concentrated under reduced pressure. The resulting evaporation residue was treated with aqueous NaHCO3 and the a-acetoxyamide extracted with CH2Cl2, which was purified by chromatography on silica to provide an oil.
2.1.2. The oil obtained in 2.1.1 above was treated with 45 g of K2CO3 dissolved in 100 ml of CH30H at room temperature for 40 hours. After evaporation of the water and methanol, the residue was taken up between water and methylene chloride. The organic phase was ~X8666~
decanted, dried with Na2SO4 and filtered and the filtrate concentrated under reduced pressu,e. The residual oil was crystallized in ether to provide the a-hydroxyamide (VII) of melting point 169-70C.
5 2.2. N,N-dimethyl-a-{2-(4-methylphenyl)-4,5-dihydro-imidazo[1,2-a]quinol-1-yl}acetamide.
4 g (0.0115 mol) of -hydroxyacetamide (VII) was treated with 25 ml of SOCl2 in 125 ml of CH2Cl2 at room temperature overnight. After evaporation of the solvent and excess SOCl2, the crude hydrochloride of the a-chloroacetamide was obtained, which was dissolved in 150 ml of CH2Cl2. This solution was then treated with 5.3 g (0.0345 mol) of Rongalite (Trade Mark) at room temperature for 24 hours. At the end of the reaction, the suspension was filtered, the filtrate concentrated under reduced pressure, the evaporation residue treated with aqueous NaHCO3, the insoluble solid extracted with CH2Cl2 and then purified by chromatography (silica). It was recrystallized in ethyl acetate to provide the acetamide (I) of melting point 206-207C.
Five compounds of the present invention were subjected to pharmacological trials to demonstrate their therapeutic activities. These compounds used are defined (with reference to formula (I)) in the following table lZ86~i6~
..
Compound Y _ 1 R2 M.p. ( C) 1 H Para-CH3 H CH3 226-8 2 H Para-cH3 CH3 CH3 206-7 3 H para-C1 H CH3 236-7 4 H para-Cl CH3 CH3 193-4 H Para-SCH3 H C~3 245-7 Antagonism towards clonic convulsions induced by Cardiazol (Trade Mark~ in mice.
A trial, which was modelled on the procedure described by Goodman et al., J. Pharm. Exp. Ther., 108, 168-176, was carried out on mice. Mice either 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 15 observed for one hour and, for each batch, the percentage of mice showing clonic convulsions was noted (100~ of clonic convulsions ahd 10 to 20% of tonic convulsions in the control animals).
For each dose, the percentage protection relative 20 to the control animals was calculated, and the AD50, the dose which protects 50~ of the animals as regards the lX86668 convulsant effects of Cardiazol, was determined graphically.
The AD50 values of the compounds of the invention are from 0.1 to 30 mg/kg intraperitoneally and from 0.1 to 30 mg/kg orally.
5 "surying" test in mice.
A test which was modelled on the method described by Pinel J.P.J., Treit D., Ladak F. and MacLennan A.J. in Animal learning and behavior, 8, 447-451, (1980) was carried out.
The presence of foreign bodies in the usual environment of an animal represents an aversive situation, to which the animal reacts by burying the subject of the attack (in this case glass balls in the sawdust in its cage).
Anxiolytic substances reduce the apprehension caused by the presence of the foreign bodies and the animals engage in less burying.
The test products were administered to male CD1 strain mice (Charles River) 30 minutes (intraperitoneally) 20 or 60 minutes (orally) before they were placed in cages containing 25 glass balls. After 30 minutes, the number of balls remaining unburied was counted and a percentage calculated between the treated animals and the control animals.
lX86668 The AD50, the 50% active dose, which is the dose of compound (in mg/kg) which reduces by one half the number of balls buried, by comparison with the control animals, was determined in this manner. The AD50 values of the compounds 5 of the invention are from 0.3 to 30 mg/kg intraperitoneally.
Drinking conflict test in rats.
This test is described by Vogel J.R., seer s. and Clody D.E. in Psychopharmacologia, 21, 1-7, (1971).
Male Wistar rats (IFFA Credo) were used. Their l0 drinking water was withdrawn 24 hours before the test. On the day of the test, 30 minutes after intraperitoneal treatment with the compounds of the invention, each rat was placed in a transparent plastic cage (24 x 20 x 21 cm) having a meshwork floor which could be electrified.
l5 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 exploration for from 10 to 90 seconds, the rats found the pipette and started to drink. After giving 20 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 continued for 3 minutes after the first shock; the animals ~X86668 received 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 5 shocks obtained with the treated animals was noted, and this number was compared with that of the control animals by a 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 10 animals, was determined in this manner.
The MED values are from 3 to 100 mg/kg intraperitoneally.
Action on the electrocorticogram of ventilated curarized rats.
The sedative or hypnotic activity of the compounds was determined by observing their action on the electrocorticogram of rats according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and by H. Depoortere and M. Decobert, J. Pharmacol.
(Paris), 14, 2, 195-265 (1983).
The test compounds were administered intraperitoneally at increasing doses of from 1 to 30 mg/kg.
They induced sleep traces with doses ranging from 3 to 100 mg/kg.
1~86668 Koster's test The analgesic activity was shown using the test of Koster et al. (acetic acid "writhing" test in mice), Fed.
Proc., 18, 412, 1959.
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 body weight. After 30 min, acetic acid (dissolved at a concentration of 0.6% in a mixture of carboxymethyl-10 cellulose and Tween 80, in a proportion of 10 ml per kg of body weight) was administered intraperitoneally. The total number of contortions was noted during 15 min.
The percentage protection relative to a control batch was determined, and the AD50 was calculated 15 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 inhibition test The test used the technique described in Senay and 20 Levine, Proc. Soc. Exp. Biol. 1967, 124, 1221-1223, Peptic Ulcers, 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 boxes 20 cm x 5 cm, and placed in a cold room at from 2 to 4C.
The test compounds were administered orally in the proportion of 10, 30 and 100 mg/kg immediately before the 5 restraint; the control rats received only placebo. 2 hours later, the animals were sacrificed by inhalation of chloroform.
The stomachs were removed and the degree of ulceration was noted.
The compounds of the invention significantly decreased the amount of stress ulceration.
The results of these different tests show that the compounds of the invention possess at least one anxiolytic, sleep-inducing, hypnotic, anticonvulsant, analgesic or anti-15 ulcerative property; the compounds of the invention are, forexample, useful in the treatment of anxiety states, sleep disorders and other neurological and psychiatric conditions, disorders of alertness, and can be especially useful for combatting behavioural disorders ascribed to cerabral 20 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 aches, pain and ulcers.
The compounds of the invention can be presented in 1~:86668 any form suitable for oral or parenteral administration, for example in the form of tablets, dragées, gelatin capsules, solutions to be taken by mouth or injectable solutions, in combination with any pharmaceutically acceptable excipient.
5 The daily dosage can range from 1 to 100 mg.
Claims (4)
1. A process for preparing a compound which is an imidazo[1,2-a]quinoline of formula (I) (I) in which X denotes hydrogen or a halogen or a (C1-4)alkyl, (C1-4)-alkoxy, (C1-4)alkylthio, methylsulphonyl, amino, (C1-4)-alkylamino, di(C1-4)alkylamino, nitro or trifluoroalkyl group, Y denotes hydrogen or a halogen or a methyl group and is attached to the aryl ring at position 6, 7 or 8, and R1 and R2, which may be identical or different, each denote hydrogen or a (C1-6)alkyl group, or R1 and R2 together form a tetramethylene, pentamethylene, 3-methyl-3 azapentamethylene or 3-oxapentamethylene divalent group, or a pharmaceutically acceptable addition salt thereof which comprises dechlorinating a compound of formula (VIII) (VIII) wherein X, Y, R1 and R2 are as defined above.
2. A process according to claim 1, wherein X
denotes chlorine, a methyl or methylthio group, attached to the aryl ring in the para position, Y denotes a hydrogen atom, and R1 and R2, which may be identical or different, denote hydrogen or a methyl group.
denotes chlorine, a methyl or methylthio group, attached to the aryl ring in the para position, Y denotes a hydrogen atom, and R1 and R2, which may be identical or different, denote hydrogen or a methyl group.
3. A process according to claim 1 wherein the compound of formula (VIII) has been obtained by reacting a quinoline of formula (II) (II) with an .alpha.-bromoacetophenone bearing the substituent X as defined in claim 1 to obtain an ionic compound of formula (III);
(III) cyclizing the ionic compound of formula (III) to obtain a compound of formula (IV);
(IV) reacting the compound of formula (IV) with glyoxylic acid to obtain an .alpha.-hydroxy acid of formula (V);
(V) acetylating the .alpha.-hydroxy acid of formula (V) and then converting it, via the imidazolide, to an .alpha.-acetoxyacetamide of formula (VI);
(VI) deacetylising the compound of formula (VI) to the .alpha.-hydroxyacetamide of formula (VII);
(VII) and chlorinating the compound of formula (VII) to obtain the chlorinated compound of formula (VIII).
(III) cyclizing the ionic compound of formula (III) to obtain a compound of formula (IV);
(IV) reacting the compound of formula (IV) with glyoxylic acid to obtain an .alpha.-hydroxy acid of formula (V);
(V) acetylating the .alpha.-hydroxy acid of formula (V) and then converting it, via the imidazolide, to an .alpha.-acetoxyacetamide of formula (VI);
(VI) deacetylising the compound of formula (VI) to the .alpha.-hydroxyacetamide of formula (VII);
(VII) and chlorinating the compound of formula (VII) to obtain the chlorinated compound of formula (VIII).
4. A compound which is an imidazo[1,2-a]quinoline of formula (I) (I) in which X denotes hydrogen or a halogen or a (C1-4)alkyl, (C1-4)alkoxy, (C1-4)alkylthio, methylsulphonyl, amino, (C1-4)alkylamino, di-(C1-4)alkylamino, nitro or trifluoroalkyl group, Y denotes hydrogen or a halogen or a methyl group and is attached to the aryl ring at position 6, 7 or 8, and R1 and R2, which may be identical or different, each denote hydrogen or a (C1-6)alkyl group, or R1 and R2 together form a tetramethylene, pentamethylene, 3-methyl-3 azapentamethylene or 3-oxapenta-methylene divalent group, or a pharmaceutically acceptable addition salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8600834 | 1986-01-22 | ||
| FR8600834A FR2593179B1 (en) | 1986-01-22 | 1986-01-22 | IMIDAZO (1,2-A) QUINOLEINS DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1286668C true CA1286668C (en) | 1991-07-23 |
Family
ID=9331353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000527831A Expired - Fee Related CA1286668C (en) | 1986-01-22 | 1987-01-21 | Imidazo[1,2-a]quinoline derivatives, their preparation and their application in therapy |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0233800B1 (en) |
| JP (1) | JPS62169783A (en) |
| AT (1) | ATE50578T1 (en) |
| AU (1) | AU585688B2 (en) |
| CA (1) | CA1286668C (en) |
| DE (1) | DE3761770D1 (en) |
| DK (1) | DK31887A (en) |
| ES (1) | ES2014306B3 (en) |
| FI (1) | FI85476C (en) |
| FR (1) | FR2593179B1 (en) |
| GR (1) | GR3000463T3 (en) |
| HU (1) | HU194232B (en) |
| IE (1) | IE59173B1 (en) |
| IL (1) | IL81335A (en) |
| NO (1) | NO164596C (en) |
| NZ (1) | NZ219008A (en) |
| PT (1) | PT84159B (en) |
| ZA (1) | ZA87442B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2593180B1 (en) * | 1986-01-22 | 1990-10-26 | Synthelabo | IMIDAZO (1,2-A) QUINOLEINS ACYLAMINOMETHYL-1 DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| DK0833638T3 (en) * | 1995-06-15 | 2002-05-21 | Upjohn Co | Use of imidazo [1,5-a] quinolones as neuroprotective agents |
| FR2759700B1 (en) * | 1997-02-20 | 1999-03-19 | Synthelabo | IMIDAZO [2,1-C] [1,4] BENZOTHIAZINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2783828B1 (en) * | 1998-09-29 | 2000-11-10 | Synthelabo | 5,6-DIHYDRO-4H-IMIDAZO [1,2-A] [1] BENZAZEPINE -1-ACETIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| ES2320758T3 (en) | 2002-12-18 | 2009-05-28 | Mallinckrodt Inc. | SYNTHESIS OF HETEROARIL ACETAMIDAS. |
| US7498439B2 (en) * | 2004-06-22 | 2009-03-03 | Mallinckrodt Inc. | Synthesis of heteroaryl acetamides from reaction mixtures having reduced water content |
Family Cites Families (3)
| 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 |
| FR2568879B1 (en) * | 1984-08-07 | 1986-12-12 | Synthelabo | IMIDAZO (1,2-A) QUINOLINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2593180B1 (en) * | 1986-01-22 | 1990-10-26 | Synthelabo | IMIDAZO (1,2-A) QUINOLEINS ACYLAMINOMETHYL-1 DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
-
1986
- 1986-01-22 FR FR8600834A patent/FR2593179B1/en not_active Expired
-
1987
- 1987-01-14 DE DE8787400073T patent/DE3761770D1/en not_active Expired - Fee Related
- 1987-01-14 AT AT87400073T patent/ATE50578T1/en not_active IP Right Cessation
- 1987-01-14 ES ES87400073T patent/ES2014306B3/en not_active Expired - Lifetime
- 1987-01-14 EP EP87400073A patent/EP0233800B1/en not_active Expired - Lifetime
- 1987-01-21 HU HU87175A patent/HU194232B/en not_active IP Right Cessation
- 1987-01-21 PT PT84159A patent/PT84159B/en unknown
- 1987-01-21 IE IE15587A patent/IE59173B1/en not_active IP Right Cessation
- 1987-01-21 DK DK031887A patent/DK31887A/en not_active Application Discontinuation
- 1987-01-21 IL IL81335A patent/IL81335A/en not_active IP Right Cessation
- 1987-01-21 FI FI870252A patent/FI85476C/en not_active IP Right Cessation
- 1987-01-21 NZ NZ219008A patent/NZ219008A/en unknown
- 1987-01-21 AU AU67898/87A patent/AU585688B2/en not_active Ceased
- 1987-01-21 JP JP62013280A patent/JPS62169783A/en active Pending
- 1987-01-21 ZA ZA87442A patent/ZA87442B/en unknown
- 1987-01-21 CA CA000527831A patent/CA1286668C/en not_active Expired - Fee Related
- 1987-01-21 NO NO870249A patent/NO164596C/en unknown
-
1990
- 1990-04-30 GR GR90400260T patent/GR3000463T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3761770D1 (en) | 1990-04-05 |
| DK31887D0 (en) | 1987-01-21 |
| FI85476B (en) | 1992-01-15 |
| FI870252A (en) | 1987-07-23 |
| EP0233800B1 (en) | 1990-02-28 |
| PT84159B (en) | 1989-07-31 |
| IL81335A (en) | 1990-07-12 |
| ES2014306B3 (en) | 1990-07-01 |
| PT84159A (en) | 1987-02-01 |
| IL81335A0 (en) | 1987-08-31 |
| NO164596B (en) | 1990-07-16 |
| FR2593179B1 (en) | 1988-04-01 |
| DK31887A (en) | 1987-07-23 |
| ZA87442B (en) | 1987-09-30 |
| AU585688B2 (en) | 1989-06-22 |
| FI870252A0 (en) | 1987-01-21 |
| IE59173B1 (en) | 1994-01-26 |
| NO870249D0 (en) | 1987-01-21 |
| EP0233800A1 (en) | 1987-08-26 |
| NO164596C (en) | 1990-10-24 |
| FR2593179A1 (en) | 1987-07-24 |
| FI85476C (en) | 1992-04-27 |
| HU194232B (en) | 1988-01-28 |
| GR3000463T3 (en) | 1991-06-28 |
| NZ219008A (en) | 1989-08-29 |
| JPS62169783A (en) | 1987-07-25 |
| ATE50578T1 (en) | 1990-03-15 |
| AU6789887A (en) | 1987-07-23 |
| NO870249L (en) | 1987-07-23 |
| IE870155L (en) | 1987-07-22 |
| HUT43063A (en) | 1987-09-28 |
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