DK161963B - 2-PHENYL-IMIDAZOOE1,2-AAAQUINOLINE DERIVATIVES AND PROCEDURES FOR PREPARING IT AND A PHARMACEUTICAL PREPARATION CONTAINING SUCH COMPOUNDS - Google Patents

Description

DK 161963 B

The present invention relates to novel 2-phenyl-imidazole [1,2-a] quinoline derivatives and to a process for the preparation of such compounds. The compounds of the invention have the general formula (I) shown in the following reaction scheme in which formula: X represents a hydrogen atom, a halogen atom or a methyl group, a methoxy group, a methylthio group or a methylsulfonyl group, Y represents a hydrogen atom , a halogen atom or a methyl group at positions 6, 7 or 8, and R 1 and R 2 each represent a hydrogen atom or a methyl group an ethyl group, or and R 2 together form a tetramethylene chain, a pentamethylene chain, a 3- methyl 3-aza-pentamethylene chain, a 3-20 ethoxycarbonyl-3-aza-pentamethylene chain or a 3-oxa-pentamethylene chain.

The invention further includes acid addition salts of these compounds.

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EP 50 563 discloses imidazole [1,2-a] pyridines having anticonvulsant activity homologous to the subject 2-phenyl-imidazole [1,2-a] quinoline derivatives. In addition to the difference in chemical structure, the compounds of the invention also have a different pharmacological profile, the compound of the invention, in addition to an anticonvulsant action, acting less sleep-inducing than the known compounds.

The disclosed 2-phenyl-imidazole [1,2-a] quinoline derivatives are characterized by the method of claim 1. They are prepared by a method which is

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2 as claimed in claim 2.

Pharmaceutical preparations containing an active compound of formula I are also the subject of the invention, cf. claim 3.

The compounds of the invention can be prepared according to the reaction scheme shown below.

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3

(Scheme)

. · \ Γ ^ NH

5

XpUX, - XXXX

10 Y kJ φ xx * 'KJ (*> (III)' r .. yp> Q, - ΧΧχΟ., HO '(VII) CH ° (VI) 20 JCtt-XXhCk.

25 Y --- \ Y-t- \ NC / (VIII) 0_ / (IX) \ - "* ™" Λ \ l> 1 \ \

/ OH

jl 3 ^ Ln), 7 o ^ / 8 X (I) 35; X 2

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In the first step, the quionoline compound of formula (II) or the 2-aminoquinoline compound of formula (IV) is subjected to a reaction with an α-bromoacetophenone containing the substituent X as defined above.

In the case of the quinoline (II), the reaction takes place in a warm state in a solvent such as methylene chloride or in 1,2-dichloroethane. An ionic compound of formula (III) is obtained, which is cyclized in hot state in the presence of ammonium acetate and of ferric chloride to give the compound of formula (V).

In the case of the 2-aminoquinoline (IV), direct compound of formula (V) is obtained, carrying out the reaction in the presence of a base and an alcoholic solvent.

A formulation of the compound (V) thus obtained, e.g. by a reaction component obtained by the action of oxalyl chloride on dimethyl formamide, upon which this adduct is hydrolyzed.

Then the aldehyde (VI) thus obtained is reduced to an alcohol of formula (VII) in a manner known per se, e.g. by the action of sodium or potassium borohydride.

Then the alcohol (VII) is first subjected to tosylation, e.g. by means of paratoluene sulfonyl chloride in the presence of the pyridine, and then the action of sodium cyanide or of potassium cyanide in aqueous medium to give the nitrile of formula (VIII).

This nitrile is then hydrolyzed to a carboxylic acid in a manner known per se, e.g. in hot state and in a hydrochloric acid medium to give the compound of formula (IX).

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5

Finally, the corresponding amide is prepared, subjecting first to the acid (IX) action of carbonyldi-imidazole, and then the action of an amine of the formula R 1 -NH-R 2 wherein and R 2 have the meaning given above.

In the case of an unsubstituted amide of formula (I) (R1 = R2 = H), the final product is formed by partial direct hydrolysis of the nitrile (VIII) in a basic aqueous medium.

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Finally, the N, N-dimethylated amides are obtained by methylation of the unsubstituted amide (R1 = R2 = H) by iodomethane in the presence of sodium hydride.

The following Examples A and B illustrate the two variants of the process for preparing the compound of formula V. The following examples illustrate the preparation of some compounds of the invention. By microelementary analysis and IR and NMR spectra, the structure of the compounds is confirmed.

EXAMPLE A

2- (4-Chlorophenyl) imidazo [1,2-a] quinoline 25

17.7 g (0.123 mol) of 2-aminoquinoline, 28.7 g (1 equivalent) of α-bromo-p-chloroacetophenone and 20.6 g (2 equivalents) of sodium hydrogen carbonate 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 with water and then dried. There is thus obtained a solid white substance which is recrystallized from nitromethane. Mp. 206-208 ° C.

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6

EXAMPLE B

2- (4-Chlorophenyl) imidazo [1,2-a] quinoline Mix 23.3 g (0.1 mole) of a-bromo-p-chloroacetophenone and 13 ml (1.1 equivalent) of quinoline with 100 ml methylene chloride. Reflux for 1 hour, then add 100 ml of ether to the reaction mixture and cool. The resulting yellow precipitate is filtered and dried. In a 1 liter autoclave 38.3 g (0.105 mole) of the quaternary ammonium compound obtained, 48.6 (0.63 mole) of ammonium acetate, 55 g (0.34 mole) of ferric chloride are mixed in 270 ml of acetic acid. and heated to 140 ° C for 13 hours. The obtained solid is filtered off, washed with acetic acid and then with water. The product is dried and recrystallized from ethanol and then from nitromethane.

EXAMPLE 1 2- (4-Chlorophenyl) imidazo [1,2-a] quinoline acetamide a) 2- (4-Chlorophenyl) imidazo [1,2-a] quinoline-1-carboxaldehyde

Cool 150 ml of dry dimethylformamide to -20 ° C and drop by drop of 17.4 ml (0.2 mole) of oxalyl chloride. Then 13.6 g (0.05 mole) of the compound obtained in the above Example A or B are added, and stirred for 15 hours at ambient temperature and for 15 hours at 55 ° C.

Then the mixture is poured into 1 liter of water. After filtration, the precipitate is made alkaline and washed with water 35 to neutral pH and then dried. It is recrystallized from nitromethane. Mp. = 199-200 ° C.

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B) 1-hydroxymethyl-2- (4-chlorophenyl) imidazo [1,2-a] quinoline

13.3 g (0.043 mol) of the aldehyde prepared above are suspended in 300 ml of dry absolute ethanol.

825 mg (0.5 equivalents) of sodium borohydride is added and stirred for 18 hours at ambient temperature.

Then, evaporate to dryness and dissolve the residue in water. The pH is adjusted to 8 by dilute hydrochloric acid and the precipitate is filtered and washed with water, then with acetone and finally with ether, then dried. Mp. ® 236-237 ° C (decomposition).

C) 1-cyanomethyl-2- (4-chlorophenyl) -imidazo [1,2-a] quinoline

7.8 g (0.025 mol) of the alcohol prepared above and 5.3 g (1.1 equivalent) of p-toluenesulfonyl chloride are mixed in 100 ml of pyridine. The reaction mixture is heated to 40 ° C for 8 hours, then stirred at ambient temperature for 60 hours. Then redissolve with 700 ml of water and 300 ml of methylene chloride and filter off the precipitate between the two phases and pour it into 400 ml of water containing 3.7 g (0.075 mol) of sodium cyanide and 2.1 g (0.025 mol) sodium bicarbonate. The mixture is heated at reflux for 15 hours, then cooled and filtered. The precipitate is washed with water and extracted with methylene chloride and the extract is dried over sodium sulfate. The Ni-tril is purified by chromatography over silica gel.

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After recrystallization from ether and drying, a solid white substance is obtained. Mp. = 221-223 ° C.

d) 2- (4-Chlorophenyl) imidazo [1,2-a] quinoline-1-acetamide

7 g (0.022 mol) of the above-prepared nitrile and 6 g (5 equivalents) of potassium carbonate are mixed in 200 ml

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8 ethanol and 50 ml of water, then reflux for 3 hours. Then it is evaporated to dryness and the residue is redissolved in water, filtered, washed with water to neutral pH and dried. Mp. = 298-300 ° C.

EXAMPLE 2 2- (4-Chlorophenyl) -N-methylimidazo [1,2-a] quinoline-1-acetamide 10 a) 2- (4-Chlorophenyl) imidazo [1,2-a] quinoline -L-acetic acid

3.5 g (0.011 mol) of the above nitrile obtained in Example 1 is poured into a mixture of 10 ml of concentrated 15 hydrochloric acid and 20 ml of acetic acid. This reaction mixture is heated under reflux for 8 hours, then an additional 10 ml of concentrated hydrochloric acid is added and refluxed under reflux for 8 hours. It is then evaporated to dryness and the residue is redissolved in water, 20 and the precipitate is filtered off. The precipitate is suspended in water, the pH is adjusted to the value of 5 by means of dilute sodium hydroxide, filtered and washed with ethanol, acetone and ether and then dried. Mp. = 246-248 ° C (decomposition).

B) 2- (4-Chlorophenyl) -N-methyl-imidazo [1,2-a] quinoline-1-acetamide

2.5 g (0.0074 mol) of the above prepared acid is suspended in 50 ml of dry tetrahydrofuran, 1.4 g (1.2 equivalents) of carbonyl diimidazole is added and the mixture is heated to 40 ° C. for 2 hours.

Then, methylamine is bubbled for 30 minutes and stirring is continued for 15 hours. The mixture is evaporated to dryness, the residue is redissolved in water and methylene chloride, the organic phase is separated, washed

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9 with water and dried, then evaporated. The residue is purified by chromatography and then recrystallized from ether. Mp. = 289-292 ° C (decomposition).

EXAMPLE 3 2- (4-Chlorophenyl) -N, N-dimethyl-imidazo [1,2-a] quinoline-1-acetamide A suspension of 3.35 g (0.01 mole) of Example 1 d) obtained compound in 200 ml of tetrahydrofuran 1.05 g (0.022 mol) of sodium hydride with the strength 50% in oil, 0.1 ml of dimethylformamide, to which 1.9 ml (3 equivalents) of iodomethane is rapidly added.

15 Stir for 15 hours under argon at ambient temperature and evaporate to dryness. The residue is redissolved in water and methylene chloride, the organic phase is washed with water, dried and evaporated. The residue is purified by chromatography. Mp. = 190-20 191.5 ° C.

Example 4 2- (4-Chlorophenyl) -N, N-tetramethylene-imidazo [1,2-a] quinoline-1-acetamide

2.5 g (0.0074 mol) of the acid obtained in the above Example 2 a) is suspended in 50 ml of dry tetrahydrofuran and 1.4 g (1.2 equivalents) are added.

30 carbonyldiimidazole and then the mixture is heated to 40 ° C

for 2 hours. Then 0.63 g (1.2 equivalents) of pyrrolidine is added and stirring is continued at ambient temperature for 15 hours. The mixture is evaporated to dryness and the residue is redissolved with water and methylene chloride, the organic phase is separated and washed with water, dried and evaporated. The residue is purified by chromatography and recrystallized

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10 ether. Mp. = 217-218 ° C.

The following Table 1 shows the structures and physical properties associated with the compounds of the invention.

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11 TABLE 1

5 X 10 X

8 (I) R-, n2 10 -1

Combine-Y X R- ^ R2 Base / m.p. (° C) separation salts (1) 15 '' 1 (ex H 4-Cl HH 00 298-300 1) 2 (ex H .: 4-C1 H CH 00 289-292 2) ^ 3 ( ex .. H 4-Cl CHV CHT 00 190-191.5 20 3) 33 4 (ex H 4 Cl - (CH0), - 00 217-218 4) 24 5 H 4-C1 - (CH) - 00 163-164 6 H 4-Cl - (CH) -N- (CH) - 162-165

Δ l I L L

CH

n3 7 H 4-Cl - (CH) -N- (CH) 0- 00 188-190

L L \ L L

COOC ^ H ^ 8 H 4-Cl - (CW2) 2-0- (CH) - 00 228-232 9 H 4-Cl H C H 00 268-270 35 ______: 00 = free base 15 = methanesulfonate

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TABLE 1 (continued)

Eorbin-Y X R-, R2 Base / m.p. (° C) part Se 3alt (*) 5________ 10 8-C1 4-C1 H CH3 00 290.5-291 11 8-Cl 4-C1 CH3 CH3 00 259-260 10 12 7-C1 4-C1 H CH3 00 300 -302 13 7-C1 4-C1 CH3 CH3 00 248-250 14 6-Cl 4-C1 H CH 00 306-307 15 -5 15 '6-Cl 4-C1 CH3- CH3 00 248-249 16 7-F 4-C1 H CH3 00 304-305 20 17 7-CH3 4-C1 H CH3 00 269-271 18 H 4-CH3 H CH3 00 265-266 25 19 - H 4-CH3 CH3 CH3 00 181-182.5 20 H 4-0CH3 H CH3 00 264-265 21 H 4-0CH3 CH3 CH3 00 194-196 30 22 H 4-SCH3 H CH3 00 284-287 23 H 4-SCH 3 CH3 CH3 00 172-173 35 24 H 3- C1 H CH3 00 261-262 (*): 00 = free base

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TABLE 1 (continued)

Combine Y X R R Base / mp (° C) partition * salt (it) 5 -----, ---- 25 H 3-C1 CH ^ CH ^ 00 138-140 26 H 2-C1 H CH3 00 | 222-224 10 27 H 2-C1 CH3 CH3 00 165-167 i 28 HH H CH3 00 264-266 29 HH CH3 CH3 00 | 173-175 15 30 H 4-SO2CH3 H CH3 00 279-280 31 H 4-SO2CH3 CH3 CH3 00 244-245 20 (A): 00 = free base

Compounds of the invention have been subjected to 25 pharmacological studies which have shown their importance as substances with therapeutic activities.

Antagonism to clonic convulsions induced by "Cardiazol®" in mice 30

This experiment is inspired by the test manual described by Goodman et al., J. Pharm. Exp. Ther., 108, 168-176.

The mice received the products to be tested or the solvent alone 30 minutes (by intraperitoneal administration) or 60 minutes (by oral administration) before the injection of 35 mg / kg Cardiazol® by intravenous administration.

The animals were then observed for 1 hour, and for each team

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14, the percentage of mice exhibiting clonic convulsions was noted (100% clonic convulsions and 10-20% tonic convulsions in the control animals). For each dose, the percentage protection relative to the control animal is calculated, which makes it possible to determine graphically the value of DA ^ q, the dose that protects 50% of the test animals against the convulsant-forming effects of Cardiazol®. The values of DA ^ q for the compounds of the invention are between 0.1 and 30 mg / kg 10 for intraperitoneal administration and between 0.1 and 30 mg / kg for oral administration.

"Burying test" in mice ("Burying test") 15 This test is inspired by a method described by Pinel JPJ, Treit D., Ladak F. and MacLennan AJ in Animal learning and behavior, 8 ^, 447-451 (1980).

The presence of foreign bodies in the usual environment of an animal presents a frightening situation to which the animal responds by burying the aggressive object (glass balls) in the sawdust in the cage.

The anxiolytic agents have the effect of reducing the anxiety caused by the foreign presence. The animals' propensity for burial is reduced. The number of spheres remaining in the un-buried state is then counted.

The products to be examined are administered to male mice by the GDI strain (Charles River) and 30 minutes (by intraperitoneal administration) or 60 minutes (by oral administration) before the latter were placed in cages containing 25 glass beads. After 30 minutes, the number of spheres remaining in the un-buried state is counted.

A percentage ratio is calculated between the treated animals and the control animals.

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In this way, the value of DA 2 -q, the dose that is 50% active, is the dose of the compound (expressed in mg / kg) which decreases by half the number of buried bullets compared to the control animals.

The values of DA 1 for the compounds of the invention are between 0.3 and 30 mg / kg by intraperitoneal administration.

Testing of the conflict when drinking in rats 10

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

Male rats of the strain "Wistar" (IFFA Credo) are used.

15 Your drinking water is withheld 24 hours before the test.

On the day of the test, 30 minutes after treatment by intraperitoneal administration with the compounds of the invention, each rat is placed in a cage of transparent plastic material (24 x 20 x 21 cm) and with a grid-shaped 20 floor which can be supplied with electricity. The drinking water is distributed by means of a pipette protruding 2 cm from one of the cage walls and placed 3 cm above the cage floor.

After an exploration of 10-90 seconds, the animal finds the pi-25 cap and starts drinking. After performing 20 shocks with the tongue (which is detected by a so-called omnitech anxiometer), the rat receives near the tongue an electric shock of 0.07 mA (delivered through the anxiometer) and stops when the rat leaves the pi-30 Petten. A trial period of 3 minutes begins after an initial shock, with the animal continuing to receive a shock for every 20 movements of the tongue until it stops or until the end of the trial period.

35 Under these experimental conditions, the experimental animals in the control team accept an average of 3 to 6 electric shocks. The number of shocks obtained with the treated 16 is noted

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This number is compared to the number of control animals using the Dunette test. In this way, the value of DEM is determined, the minimum effective dose, which is the first dose, which significantly increases the number of shocks accepted by an animal relative to the control animals. The value for DEM is between 3 and 100 mg / kg at intraperitoneal administration.

10 Impact on the electrocardiogram of rats that are curare-treated and ventilated

The sedative activity or hypnotic activity of the compounds was determined by observing their effect on the electrocardiogram of rats according to the method described by H. Depoorter, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and by H. Depoortere M. Decobert, J. Pharmacol. (Paris), 14, 2, 195-265 (1983).

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The products to be investigated were administered by intraperitoneal administration at doses ranging from 1 to 30 mg / kg. The evoked traces of sleep ranged from 3 to 30 mg / kg.

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Effects of duration of "sleep" induced by sodium 4-hydroxybutyrate

This effect was determined by the influence of one of the 30 compounds on the duration of the "sleep" induced by sodium 4-hydroxybutyrate (GHB) on rats treated with curare.

The experimental animals used were male rats of the Charles 35 River strain weighing 200 + 20 g. The animals, which were curare-treated with the drug alloferin in an amount of 1 mg / kg by intraperitoneal administration, were placed under artificial re-

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17 germination using a mask placed on their muzzle (respiratory rate = 50 / minute; respiratory volume = 14 ml).

5 Oesophagus was previously provided with a ligature to avoid the entry of air into the stomach.

Cerebral electrodes in the front parietal and occipital positions allowed recording of electrocardiographic activity on a polygraph of the "Grass" model 79 P make at a speed of 6 mm / sec.

The preparation of the animal was carried out under local anesthesia (xylocaine with the strength 2%). The rats were kept at constant temperature (37.5 ° C) throughout the test. Ten minutes after completion of rat preparation, a dose of 200 mg / kg sodium 4-hydroxybutyrate was injected intravenously at the tail level.

A dose of 10 mg / kg of the compound to be tested was administered intraperitoneally 3 minutes after administration of sodium 4-hydroxybutyrate.

Assessment of the plotted curves was performed for 15-minute periods of 15 minutes through 75 minutes after the injection of GHB. During this analysis period, the total duration of "sleep" is determined. A series of 15 control trials makes it possible to clarify the duration of "GHB sleep".

30 Statistical analysis of the results was carried out using the so-called "U" test by Mann-Whitney.

Some compounds reduce the effects of GHB (up to 24% decrease in sleep duration at a dose of 35 10 mg / kg), while others potentiate these effects (up to 18% increase in sleep duration at a dose of 10 mg / kg), or 30% at a dose of 30 mg / kg). You

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18 also finds that the effects may be opposite depending on whether the compounds are administered at high doses or at low doses.

The results obtained from these various tests show that the compounds of the invention possess anxiolytic properties, sleep elicitation properties, hypnotic properties and anticonvulsant properties. The compounds of the invention are useful in the treatment of anxiety disorders, of sleep disorders and of other neurological and psychiatric illnesses, in the treatment of insomnia problems, in particular to combat the behavioral difficulties attributable to vascular cerebral damage and to the cerebral 15 sclerosis in old age, as well as in the treatment of absenteeism due to cranial trauma and in the treatment of metabolic encephalopathies.

The compounds of the invention may be in any form suitable for oral or parenteral administration, e.g. in the form of tablets, of dragees, of gelatin capsules, of solutions for drinking or for injection etc., in combination with any suitable excipient.

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The daily posology can range from 1 to 100 mg.

Comparison of the activity of some of the compounds of the present invention with closely related compounds 30

Compounds 2, 3 and 6 of Table 1 are compared with three compounds described in EP 50 563 (refs. 1, 2 and 5 of the table, page 6 of the patent) and a closely related isomer which has been synthesized for the purpose, but is not -35 taken by the invention.

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Thus, the effective dose of DA 1 -q in mg / kg is determined by intraperitoneal administration in trials of antagonism to clonic convulsions, induced on mice by Cardiazol® by the above-described experimental technique (experiment ACS).

Furthermore, determined doses in mg / kg by intraperitoneal administration, which produce sleep signs by electrocardiograms in rats, are in accordance with the above test technique (Experiment ECoG).

The results are shown in the following Table 2. The structure of the formulas for the test compounds is given. Column 1 lists No. on the compound in question (cf. Table 1). The term "Ref." refer to the table in EP 50 563 and "Isomer" is the related isomer of the given formula.

In column 2, designations 00 and 15 denote free base and methanesulfonate, respectively. Columns 3 and 4 indicate the measured values of the samples described.

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TABLE 2 ζΨ> 20 V ^ R.Rj tø ?, Ri n {ch ^

Compound Reference Isomer DA50 15 Base mg / Rg or by ACP

Compound salt ^ R1R2 trial ECoG

No. 200 0.15 10-30 - -NHCH

Ref. 1 00 1 1 20 -----

No. 3 00 1 30

Ref. 200 -N (CHq) 0 0.7 10 15 * 1

No. 6 15 j- \ 1 10-30 25 Ref. 5 00 _NX ^ n “ch3 22 20

Isomer 15 -NfCH ^^> * 30 * 30 30/35 21

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It can be seen from the table, see column 4, that both the compounds of the invention and the known compounds are potent anti-convulsive agents, with the exception of ref. 5, which is less active.

5

However, from column 5 of the table, it appears that the compounds of the invention are substantially less sleep-inducing than the reference compounds.

10 The closely related "Isomer" has surprisingly low anti-convulsive activity (DA 2 -q is more than 30 times as high).

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Claims (4)

X (V) wherein X and Y are as defined in claim 1, or subject to the 2-aminoquinoline compound of formula: Y-- (IV) 10 wherein Y is as defined in claim 1; the effect of an α - bromocyte t ophenone which is the carrier of a substituent X as defined in claim 1, thereby obtaining a compound of formula: Yu 20 wherein X and Y have the meaning of claim 1, which compound is subjected to a formylation to give the aldehyde of formula: CO-O, Wherein Y and Y are as defined in Claim 1, reducing this compound to an alcohol of the formula: H / where X and Y has the meaning of claim 1, which compound is converted to a nitrile of the formula: wherein X and Y have the meaning of claim 1, which compound is hydrolyzed to obtaining the acid of the formula: <c ^ 'X (ix) v4f- i \ XX, whereby this latter compound is finally converted to amide by reacting it with an amine of the formula R 1 -NH-1 2, wherein R 2 and R 2 have the meaning set forth in claim 1, or, if desired, convert the reaction product to a pharmaceutically acceptable acid addition salt thereof, or, to prepare the amide of formula (I) wherein R 1 and R 2 each represent hydrogen, the nitrile of formula (VIII) is hydrolyzed or to prepare, for the preparation of the amide of formula 10 (I) wherein R 1 and R 2 are each a methyl group, and the amide of formula (I) wherein and R 2 is each represents hydrogen is a direct methylation. Pharmaceutical composition, characterized in that it contains a 2-phenyl-imidazo [1,2-a] quinoline derivative according to claim 1, combined with an appropriate excipient. 20 25 30 35 /