NO164596B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOKINOL INGREDIATES. - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Imidazo[1,2-_a]quinoline derivatives corresponding to the formula (I) see diagramm : EP0233800,P14,F1 in which X denotes hydrogen, 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, a halogen or a methyl group at position 6, 7 or 8, and R1 and R2, taken separately, each denote hydrogen or a (C1-6 )alkyl group, or alternatively R1 and R2 together form a tetramethylene, pentamethylene, 3-methyl-3-azapentamethylene or 3-oxapentamethylene chain, as well as their addition salts which are acceptable in pharmacology. 1. Claims for the Contracting States : AT, ES, GR Process for the preparation of imidazo[1,2-_a]quinoline derivatives corresponding to the formula (I) see diagramm : EP0233800,P16,F1 in which X denotes hydrogen, 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, a halogen or a methyl group at position 6, 7 or 8, and R1 and R2, taken separately, each denote hydrogen or a (C1-6 )alkyl group, or alternatively R1 and R2 together form a tetramethylene, pentamethylene, 3-methyl-3-azapentamethylene or 3-oxapentamethylene chain, which process is characterized in that the quinoline of formula (II) see diagramm : EP0233800,P16,F2 is first subjected to the action of an alpha-bromoacetophenone bearing the substituent X defined above, in the heated state in a solvent such as methylene chloride or 1,2-dichloroethane ; an ionic compound of formula (III) see diagramm : EP0233800,P16,F3 is obtained, which is cyclized in the presence of ammonium acetate, in an acidic organic solvent such as acetic or propionic acid, at a temperature of 90 degrees C, to obtain the compound of formula (IV) see diagramm : EP0233800,P16,F4 the compound obtained (IV) is reacted with glyoxylic acid in a solvent such as acetic acid at 80 degrees C ; the alpha-hydroxy acid obtained (V) see diagramm : EP0233800,P17,F1 is acetylated using acetic anhydride in the presence of pyridine, and then converted to the alpha-acetoxyacetamide see diagramm : EP0233800,P17,F2 via the imidazolide, which is prepared in situ ; the compound (VI) is deacetylated to the alpha-hydroxyacetamide (VII) see diagramm : EP0233800,P17,F3 by treatment with potassium carbonate in ethanol ; the compound (VII) is reacted with sulphonyl chloride SOCl2 in a chlorinated solvent such as dichloromethane, to obtain the chlorinated compound (VIII) see diagramm : EP0233800,P17,F4 which is reduced using Rongalite**(r) in methylene chloride to the compound (I).

Description

The present invention relates to an analogue method for the production of therapeutically active imidazo-thi,2-a]-quinoline derivatives of formula (I)

in which

X stands for a halogen, (Ci-4)alkyl or (Ci-4)alkylthio,

R1 and R2 each represent hydrogen or (C1~6)alkyl,

as well as their pharmacologically tolerable addition salts,

and the invention is characterized in that the quinoline with formula

(II)

is subjected to the action of α-bromo-acetophenone with substituent X indicated above by heating in a solvent such as methylene chloride or 1,2-dichloroethane to obtain an ionic compound of formula (III) which is cyclized in the presence of ammonium acetate in an organic acidic solvent as acetic acid or propionic acid at a temperature of 90°C, to obtain the compound of formula (IV) which is reacted with glyoxylic acid in a solvent such as acetic acid at 80°C, to form the ct-hydroxy acid (V) which is acetylated by means of acetic anhydride in the presence of pyridine and converted to the α-acetyloxyacetamide via the imidazolide prepared in situ, deacetylated to the α-hydroxyacetamide (VII) by treatment with potassium carbonate in ethanol, the obtained compound (VII) is reacted with sulfonyl chloride SOCI2 in a chlorinated solvent such as dichloromethane to obtain the chlorinated compound (VIII)

and this is reduced by means of sodium sulphoxylate formaldehyde in methylene chloride to the compound (I) and,

if desired, a free base obtained is converted in a known manner into its pharmacologically tolerable addition salts.

The compounds that are preferred are those in which X stands for a chlorine atom, the methyl group or the methylthio group in the 4-position.

The compounds that can be produced by the invention are produced by means of the reactions that appear from the reaction scheme listed at the end of the description.

First, the quinoline of formula (II) is subjected to the action of an α-bromo-acetophenone bearing the substituent X defined above. The reaction takes place in a solvent such as methylene chloride or 1,2-dichloroethane. An ionic compound of formula (III) is obtained which is cyclized in the presence of ammonium acetate in an acidic organic solvent such as acetic acid or propionic acid at a temperature of 90°C to obtain the compound of formula (IV). The obtained compound (IV) is reacted with glyoxylic acid in a solvent such as acetic acid at 80°C. The obtained hydroxy acid (V) is acetylated using acetic anhydride in the presence of pyridine and converts the hydroxy acid (VI) to α-acetoxyacetamide (VI) via the imidazolide produced in situ.

The compound (VI) is deacetylated to the α-hydroxyacetamide

(VII) by treatment with potassium carbonate in ethanol.

The compound (VII) is then reacted with sulfonyl chloride SOCI2 in a chlorinated solvent such as dichloromethane to obtain the chlorinated compound (VIII) which is reduced by means of "Rongalite" in methylene chloride to the compound (I).

("Rongalite" is a sodium sulfoxylate-formaldehyde).

The following examples illustrate the invention.

Microanalyses and IR and NMR spectra confirm the structure of the compounds (I).

Example 1

N-methyl-2-4-(methylphenyl)-4,5-dihydro-imidazo-[1,2-a]-quinoline-1-acetamide.

1.1. 1-2-[4-(methylphenyl)-2-oxo-ethyl]-quinolinium bromide.

110 g (0.516 mol) of α-bromo-para-methylacetophenone and 61 ml (0.516 mol) of quinoline are dissolved in 500 ml of methylene chloride.

The solution is heated at the reflux temperature for 1 hour, after which it is diluted with 300 ml of ether and cooled. After filtering and drying the precipitate, a yellow solid is obtained.

Temp. = 220-221°C.

1.2. 2-(4-methylphenyl)-4,5-dihydro-imidazo-[1,2-f]-quinoline.

In 50 ml of acetic acid, 17.1 g (0.05 mol) of the quaternary salt obtained under 1.1 and 25 g of ammonium acetate are mixed. The suspension is heated for 3 hours at 90°C, after which it is cooled and diluted using 200 ml of water. The brown precipitate formed is filtered and shaken between water and methylene chloride. This two-phase mixture is treated with an excess of 1N NaOH to pH 2 8, the organic phase is poured off, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure. The evaporation residue is recrystallized from pentane.

2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-fi]-quinoline (IV) is then obtained. Temp. = 91-92°C (decomposition).

1.3. α-Hydroxy-2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-fl]-quinoline-1-acetic acid.

For 6 hours at 80°C, a mixture of 29 g (0.112 mol) of 4,5-dihydroimidazo-[1,2-fi]-quinoline obtained under 1.2 is heated,

further 16.3 g (0.225 mol) glyoxylic acid and 550 ml acetic acid. The solution is concentrated under reduced pressure and the evaporation residue is taken up in water. The crystallized acid filter-

res, washed with water and then with THF and ether. The acid is dried under vacuum. The α-hydroxy acid (V) is obtained.

Temp. = 178-181°C (decomposition).

1.4. α-Hydroxy H-methyl 2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-f]-quinoline-1-acetamide.

1—4.1. 16.5 g (0.049 mol) of the α-hydroxy acid is dissolved in 300 ml of a 50/50 mixture of pyridine and acetic anhydride. The mixture is stirred overnight at ordinary temperature, after which it is concentrated under reduced pressure. The evaporation residue is crystallized by treatment with ether and a product is obtained which is used directly in the following step.

1.4.2. 16.5 g (0.045 mol) of the obtained α-acetyloxy acid and 9.5 g (0.058 mol) carbonyldiimidazole are reacted in 200 ml of dry THF. After gas evolution has ended, the solution is kept for one hour at 50°C, after which it is cooled and treated with an excess of dry gaseous methylamine. The reaction mixture is concentrated under reduced pressure, the residue is shaken between water and methylene chloride and treated with K2CO3. The mixture is stirred for 3 hours at normal temperature, after which it is allowed to settle. The organic phase is dried over Na2SC>4, filtered and the filtrate is evaporated under reduced pressure. The resulting mixture is purified by chromatography on silica and crystallized in ether. The α-acetyloxyacetamide (VI) is obtained, which is deacetylated directly without further purification.

1.4.3. The α-acetyloxyacetamide (VI) is treated with 25 g of K2CO3 in 100 ml of 50% aqueous methanol. The stirring is maintained throughout the night. The solution is concentrated, the solid residue is taken up in water, filtered and washed with water to neutral pH in the wax water, after which the residue is washed with ether and dried.

The α-hydroxyacetamide (VII) is obtained.

Temp. = 209-211°C.

1.5. N-methyl-2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-s]-quinoline-1-acetamide.

4.0 g (0.0115 mol) of α-hydroxyacetamide (VII) is treated with 25 ml of SOCI2 in 125 ml of methylene chloride at room temperature overnight. The volatile residues are evaporated and the hydrochloride of the α-chloroacetamide (VIII) is obtained. 100 g (0.0115 mol) of this compound are dissolved in 150 ml of CH 2 Cl 2 . This solution is treated with 5.3 g (0.0345 mol) "Rongalite" at room temperature for 24 hours. At the end of the reaction, the mixture is filtered, the filtrate is concentrated under reduced pressure and the evaporation residue is treated with aqueous NaHCO 3 . After several washings with water, the solid residue is filtered and dried. The crude mixture is purified by chromatography after which it is recrystallized from acetonitrile. The amide (IV) is obtained.

Temp. = 226-8°C.

Example 2

N_,N-dimethyl-2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-f]-quinoline-1-acetamide.

2.1. α-Hydroxy-N,N-dlmethyl-2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-f]-quinoline-1-acetamide.

2.1.1. 16.5 g (0.049 mol) of the α-acetyloxy acid obtained under 1.4.1. is reacted with 9.5 g (0.0585 mol) of carbonyldiimidazole in 200 ml of dry THF. After gas evolution has ended, the solution is kept at 50°C for 1 hour, after which it is cooled and treated with an excess of dry gaseous dimethylamine. The mixture is stirred for several hours, after which it is concentrated under reduced pressure. The evaporation residue is treated with aqueous NaHCO 3 and the α-acetyloxyamide is extracted with CH 2 Cl 2 . This is purified by chromatography on silica. An oil is obtained.

2.1.2. The previously obtained oil is treated with 45 g of K2CO3 dissolved in 100 ml of CH3OH at ordinary temperature for 40 hours. After evaporation of the water and methanol, the residue is shaken between water and methylene chloride. The organic phase is allowed to settle, dried over Na 2 SO 4 and filtered. The filtrate is concentrated under reduced pressure. The remaining oil is crystallized from ether and the -hydroxyamide (VII) is obtained. Temp. = 169-70°C.

2.2. H,N-dimethyl-2-(4-methylphenyl)-4,5-dihydroimidazo-[1,2-fl]-quinoline-1-acetamide. 4 g (0.0115 mol) of the α-hydroxyacetamide (VII) is treated with 25 ml SOCI 2 in 125 ml CH 2 Cl 2 at ordinary temperature overnight. After evaporation of the solvent and excess of SOCI2, the hydrochloride of the crude α-chloroacetamide is obtained which is dissolved in 150 ml of CH2CI2. This solution is treated with 5.3 g (0.345 mol) "Rongalite" at room temperature for 24 hours. At the end of the reaction, the suspension is filtered, the filtrate is concentrated under reduced pressure and the evaporation residue is treated with aqueous NaHCC>3. Insoluble solid is extracted with CH2CI2 and purified by chromatography (silica). It is recrystallized from ethyl acetate and the acetamide is obtained

(IN).

Temp. = 206-207°C.

The compounds that can be prepared by the invention were subjected to pharmacological tests which show their interest as substances with therapeutic effects.

Antagonism of clonic convulsions induced with "Cardiazole" in mice.

The experiment was arranged based on the protocol described by

Goodman et al., J. Pharm. Exp. Ther., 108, 168-176. The mice received the test products or only the solvent 30 minutes (i.p. administration) before injection of 35 mg/kg "Cardiazol" by intravenous administration. The animals were then observed for 1 hour and for each group the percentage of mice with clonic convulsions was noted (100% clonic convulsions and 10 to 20% tonic convulsions in the control animals).

For each dose, percentage protection is calculated in relation to the control animals and this allows graphical determination of the AD50, which is the dose that protects 50% of the animals against the convulsive effects of "Cardiazol". The AD50 of the compounds that can be prepared by the invention is between 0.1 and 30 mg/kg when administered intraperitoneally and between 0.1 and 30 mg/kg when administered orally.

Test with "burying" in mice ("Burying test").

This test is adapted from 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).

The presence of foreign bodies in the usual environment for an animal constitutes an unfamiliar situation to which the animal reacts by burying the object of aggression (glass balls) in the sawdust at the bottom of the cage.

Anxiolytic agents act to reduce the attention caused by the presence of the foreign body by the animals burying them to a lesser extent. The number of balls that are left unburied is then counted.

The products examined are administered to male mice of the strain CD1 (Charles River) 30 minutes (intraperitoneal administration) or 60 minutes (oral administration) before the animals are placed in the cages

containing 25 glass balls. After 30 minutes, the number of balls left unburied is counted. A percentage calculated

nes for the treated animals and the control animals.

The AD50, 50% active dose, is then determined, which is the dose of the compound (in mg/kg) that reduces the number of buried balls to half compared to the control animals. The AD50 of the compounds that can be prepared by the invention is between 0.3 and 30 mg/kg when administered intraperitoneally.

Drinking conflict in rats.

This test is described by Vogel J.r., Beer B. and Clody D.E. in Psychoparmacologia, 21, 1-7, (1971).

Male Wistar rats (IFFA Credo) are used. Their drinking water is withdrawn 24 hours before the test. On the test day, 30 minutes after intraperitoneal administration of the compounds that can be produced by the invention, each rat is placed in a cage of transparent plastic material (24 x 20 x 21 cm) with a grid bottom to which electric current can be applied. The drinking water is distributed using a pipette that comes out 2 cm from the cage wall and is placed 3 cm above the cage bottom.

After an investigation for 10 to 90 seconds, the animal finds the pipette and begins to drink. After 20 sips (recorded using an OMNITECH anxiometer), the rat receives a 0.07 mA electric shock in the tongue (delivered by the anxiometer) which ceases when the rat leaves the pipette. A 3-minute period begins after an initial shock and the animal continues to receive a shock for every 20 sips until it stops drinking or until the end of the period.

Under the experimental conditions, the control animals receive an average of 3 to 6 shocks. The number of shocks obtained with the treated animals is recorded and this number is compared with the control animals by a Dunett test.

One then determines the MED, minimum effective dose, which is the first dose that clearly increases the number of shocks accepted by an animal, compared to the control animals.

The MED is between 3 and 100 mg/kg when administered intraperitoneally.

Effect on the electrocorticogram of the curarized rat supplied with air.

The sedative or anesthetic effect of the compounds is determined by observing their effect on the electrocorticogram in rats according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 207-214 (1980) and by H. Deportere and M. Decobert, J. Pharmacol. (Paris), 14, 2, 195-265 (1983).

The products under investigation are administered intraperitoneally in increasing doses from 1 to 30 mg/kg. They easily induce sleep from doses from 3 to 100 mg/kg.

Koster test.

The analgesic effect is shown by the test of Koster et al.

("twist test" using acetic acid in mice), Fed. Proe., 18, 412, 1959.

Young mice are orally administered the test compound in solution in "Tween 80" with a 1% concentration, in an amount of 0.2 ml per 20 g body weight. After 30 minutes, the acetic acid (in a 0.6% solution in a mixture of carboxymethyl cellulose and "Tween 80" in an amount of 10 ml per kg of body weight) is added by intraperitoneal injection. The total number of twists during 15 minutes is noted.

The percentage protection in relation to a control group is determined and the AD50 is calculated graphically (the dose that protects 50% of the animals).

The AD50 of ae by the invention preparable compounds is from 5 to 50 mg/kg p.o.

Anti-ulcer test for stress.

The technique used is in accordance with Senay and Levine, Proe. Soc. Exp. Biol. 1967, 124, 1221-1223, Peptic Ulcers, with female Wistar rats weighing 180-210 g, fasted for 20 hours and assigned to random groups.

The animals are placed in cylindrical containers 20 cm x 5 cm and placed in a cold room where the temperature is kept between 2 and 4°C.

The compounds being tested are administered orally in amounts of 10, 30 and 100 mg/kg immediately before the animals are placed in the container and the control group receives only placebo. 2 hours later, the animals are killed by inhalation of chloroform.

The stomachs are removed and the degree of ulceration is determined.

The compounds that can be produced by the invention clearly reduce the formation of wounds due to stress.

The results of these various tests show that the compounds that can be produced by the invention have anxiolytic properties and induce sleep, and can be used as anaesthetics, anticonvulsants, anesthetics and anti-stomach ulcer agents and can be used in anxiety states, sleep disorders and other neurological and psychiatric conditions for the treatment of vigilance disorders, in particular to combat behavioral disorders caused by damage to vessels in the brain and cerebral sclerosis in geriatrics, for the treatment of fainting caused by skull injuries and for the treatment of metabolic encephalopathies as well as for the treatment of anxiety, pain and ulcers.

The compounds that can be prepared by the invention can be supplied in any suitable form for oral or parenteral administration, e.g. in the form of tablets, dragees, drinkable or injectable solutions, etc., possibly in connection with usual excipients. Daily dose can be from 1 to 100 mg.

In connection with the invention, comparisons were made between the compounds that can be produced by the invention and the compounds that are known from European patent document 50563 (corresponding to Norwegian patent document 155664) in an anticonvulsant test similar to that described earlier in the description (bottom of page 8 and further on page 9).

For each new compound (NO), at least one known compound (EP) with the same substituents X and R2 was selected. Known compounds strictly corresponding to the new compounds (Y=H) were available for comparison only with the new compounds 3 and 4 prepared according to the present invention. Therefore, data are also given for known compounds where Y is not H, but X, R 1 and R 2 are identical to the corresponding substituents in the new compounds produced by the invention.

In the following table, the first column indicates known "(EP)" or new "(NO)" compounds according to compounds disclosed in EP-50563 or compounds prepared according to the present invention, and the numbers refer to the respective table. The numbers corresponding to EP-50563 are given in brackets, while the numbers corresponding to the present invention are underlined. The last column indicates the ADc« values of the compounds, administered intraperitoneally (i.p.) or by oral administration (p.o.).

The comparison results can be commented on as follows:

In each group of compounds with the same X and R2 substituents, the new compounds (NO) are unexpectedly more active than corresponding known compounds (EP), with the exception of the new compound 4 which is less active than the known compounds (44) and (26). However, the new compound 4 is more active than the strictly corresponding (Y=H) known compound (2), the latter having an AD,-q (i.p.) of 4.5 mg/kg, while the new compound has an AD ^q (i.p.) 3 mg/kg.

In summary, it is concluded that the replacement of the pyridine ring with a quinoline ring is an improvement that leads to surprisingly better properties.

In what follows, the reaction scheme for the alternative synthesis routes corresponding to those stated in the patent claim is given.

Claims (1)

Analogous process for the preparation of therapeutically active imidazo-[1,2-aj-quinoline derivatives of formula (I) in which X stands for a halogen, (Ci-4)alkyl or (Ci-4)alkylthio, R1 and R2 each represent hydrogen or (C^-6) alkyl, as well as their pharmacologically tolerable addition salts, characterized in that the quinoline of formula (II) is subjected to the action of α-bromo-acetophenone with substituent X indicated above by heating in a solvent such as methylene chloride or 1 ,2-dichloroethane to obtain an ionic compound of formula (III) which is cyclized in the presence of ammonium acetate in an organic acidic solvent such as acetic acid or propionic acid at a temperature of 90°C, to obtain the compound of formula (IV) which is reacted with glyoxylic acid in a solvent such as acetic acid at 80°C, to form the α-hydroxy acid (V) which is acetylated with the help of acetic anhydride in the presence of pyridine and converted to the α-acetyloxyacetamide via the imidazolide prepared in situ, is deacetylated to the α-hydroxyacetamide (VII) by treatment with potassium carbonate in ethanol, the obtained compound (VII) is reacted with sulfonyl chloride SOCI2 in a chlorinated solvent such as dichloromethane to obtain the chlorinated compound (VIII) and this is reduced by means of sodium sulphoxylate formaldehyde in methylene chloride to the compound (I) and, if desired, a free base obtained is converted in a known manner into its pharmacologically tolerable addition salts.