FI85476B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYTICAL PRODUCTS 2-PHENYL-4,5-DIHYDRO-IMIDAZO- / 1,2-A / QUINOLIN-1-ACETAMID DERIVATIVES. - 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

1 85476

A process for the preparation of therapeutically useful 2-phenyl-4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide derivatives The present invention relates to a process for the preparation of therapeutically useful 2-phenyl-4,5-dihydroimidazo [1,2- a) for the preparation of quinoline-1-acetamide derivatives of the formula (I) 10 / == \, XXHi "is. (i) R1 <N-CW3 wherein Rx is a hydrogen atom or a methyl group and X is a chlorine atom or a methyl or methyl mercapto group , and pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention are prepared by patent. . as described in the claim according to the following diagram.

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C/O

10 φ (ιν) (III) «R1 CH3 ^ / NR1'CH3. HCl O; 5 J * 3 _ .. · .: 35 e JC \, 0 ^ \ ^^;. i s ^ '· Oj ^ j /. ·; ·. »I <N CK3 3 S5476 α-Bromoacetophenone having a substituent X as defined above is first reacted with a quinoline of formula (II). The reaction takes place in a hot solvent such as methylene chloride or 1,2-dichloro-5 ethane. An ionized compound of formula (III) is obtained which is cyclized in the presence of ammonium acetate in an organic acid solvent such as acetic or propionic acid at a temperature of 90 ° C to give a compound of formula (IV). The obtained compound (IV) 10 is reacted with glyoxylic acid in a solvent such as acetic acid at 80 ° C. The resulting hydroxy acid (V) is acetylated with acetic anhydride in the presence of pyridine and converted to α-acetoxyacetamide (VI) via an in situ prepared imidazole.

Compound (VI) is deacetylated to α-hydroxyacetamide (VII) by treatment with potassium carbonate in ethanol. Compound (VII) is reacted with sulfonyl chloride SO 2 Cl 2 in a chlorinated solvent such as dichloromethane to give chlorinated compound (VII) which is reduced by Rongalite® in methylene chloride to compound (I).

The following examples illustrate the invention.

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

Example 1 N-Methyl-2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide 1.1 1- [2- (4-methylphenyl) -2-oxoethyl] quinoline -umbromidi.

. : Dissolve 110 g (0.516) of α-bromo-para-methylacetophenone and 61 ml (0.516 mol) of quinoline in 500 ml of methylene chloride. Heat the solution at reflux for 1 hour, dilute with 300 ml of ether and cool. After filtration and drying of the precipitate, a yellow solid is obtained.

: Sp. = 220-221 ° C.

4 B b 4 7 6 1.2. 2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline.

Mix in 50 ml of acetic acid 17.1 g (0.05 mol) of the quaternary salt obtained in 1.1 and 25 g of ammonium acetate. Heat this suspension for 3 hours at 90 ° C, cool and dilute with 200 ml of water. The brown precipitate formed is filtered off and mixed with water-methylene chloride. This biphasic mixture is treated with excess 1-N NaOH until pH 8; The organic phase is decanted, dried over Na 2 SO 4, filtered and the filtrate is concentrated under reduced pressure. The evaporation residue is recrystallized from pentane. There is thus obtained 2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline (IV). Sp. - 91-92 ° C (decomposes).

15 1.3. α-Hydroxy-2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline-1-acetic acid

Heat a mixture of 29 g (0.112 mol) of the 4,5-dihydroimidazo [1,2-a] quinoline obtained in 1.2, 16.3 g (0.225 mol) of glyoxylic acid, for 6 hours at 80 ° C. and 550 ml of acetic acid. Concentrate the solution under reduced pressure and stir the evaporation residue in water. The acid crystallizes, is filtered, washed with water, then with THF and ether. Dry in vacuo. Α-Hydroxy acid (V) is obtained. Sp. - 178-181 ° C (decomposes).

‘25 1.4. α-Hydroxy-N-methyl-2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide 1.4.1. Dissolve 16.5 g (0.049 mol) of α-hydroxy acid in 300 ml of a 50/50 mixture of pyridine and acetic anhydride. This mixture is stirred overnight at ambient temperature and then concentrated under reduced pressure. The evaporation residue is crystallized by treatment with ether. A product is obtained which is used immediately in the next step.

1.4.2. 16.5 g (0.045 mol) of the 35 α-acetyloxy acid thus obtained and 9.5 g (0.058 mol) of carbonyl- 85476 diimidazole are reacted in 200 ml of dry THF. After gas evolution, the solution is kept at 50 ° C for 1 hour, cooled and treated with excess dry gaseous methylamine. The reaction mixture is concentrated under reduced pressure, the residue is taken up in a mixture of water and methylene chloride and treated with K2CO3. This mixture is stirred for 3 hours at ambient temperature, then decanted. The organic phase is dried over Na2SO4, filtered and the filtrate is evaporated under reduced pressure. The resulting mixture 10 is purified by silica chromatography and recrystallized from ether. Α-Acetyloxyacetamide (VI) is obtained, which is deacetylated immediately without further purification.

1.4.3. α-Acetyloxyacetamide (VI) is treated with 25 g of K 2 CO 3 in 100 ml of 50% aqueous methanol. 15 Stir overnight. The solution is concentrated, the solid residue is taken up in water, filtered and washed with water until the pH of the washings is neutral, then washed with ether and dried. O-Hydroxyacetamide (VII) is obtained. Sp. - 209-211 ° C.

20 1.5. N-methyl-2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide Treat 4.0 g (0.0115 moles) of α-hydroxyacetamide ( VII) 25 ml of SO 2 in 125 ml of methylene chloride at ambient temperature overnight. Evaporate the residue. Obtain α-chloroacetamide hydrochloride (VIII). Dissolve 100 g (0.0115 mol) of this compound in 150 ml of CH2Cl2. Treat this solution with 5.3 g (0.0345 moles) of Rongalite® at ambient temperature for 24 hours. After completion of the reaction, the mixture is filtered, the filtrate is concentrated under reduced pressure and the evaporation residue is treated with aqueous NaHCO 3 solution. After washing the residue several times with water, it is filtered and dried. The crude mixture is purified by chromatography and recrystallized from acetonitrile. The amide (I) is obtained.

35 Sp. = 226-8 ° C.

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Example 2 N, N-Dimethyl-2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide.

2.1. α-Hydroxy-N, N-dimethyl-2- (4-methylphenyl) -5,5-dihydroimidazo [1,2-a] quinoline-1-acetamide 2.1.1. 16.5 g (0.049 mol) of the α-acetyloxy acid obtained in 1.4.1 and 9.5 g (0.0585 mol) of carbonyldiimidazole are reacted in 200 ml of dry THF. After gas evolution, the solution is kept at 50 ° C for 1 hour 10, cooled and treated with excess 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 solution and the α-acetyloxamide is extracted with CH 2 Cl 2. It is purified by silica chromatography. An oil is obtained.

2.1.2. Treat the previously obtained oil with 45 g of K 2 CO 3 dissolved in 100 ml of CH 3 OH at ambient temperature for 40 hours. After evaporation of the water and methanol, the residue is stirred in a water-methylene chloride mixture. The organic phase is decanted, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residual oil is crystallized from ether. Α-Hydroxyamide (VII) is obtained.

2.2. N, N-Dimethyl-2- (4-methylphenyl) -4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide 4 g (0.0115 moles) of α-hydroxyacetamide (VII) treated with 25 mL of SO 2 in 125 mL of CH 2 Cl 2 at ambient temperature overnight. Evaporation of the solvent and excess SO 2 Cl 2 gives crude α-chloroacetam-30 dihydrochloride, which is dissolved in 150 ml of CH 2 Cl 2 at ambient temperature overnight. Evaporation of the solvent and excess SO 2 Cl 2 gives crude α-chloroacetamide hydrochloride which is dissolved in 150 ml of CH 2 Cl 2. This solution is treated with 5.2 g (0.0345 moles) of 35 Rongalite® at ambient 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 NaHCO3 solution. The insoluble solid is extracted with CH2Cl2 and purified by chromatography (silica). It is recrystallized from ethyl acetate. Acetamide (I) is obtained. Sp. = 206-207 ° C.

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Table 5 o ^ y ri '^ ”^ ch3 10

Compound X Mp (° C) 15 1 CH 3 H 226-8 2 CH 3 CH 2 206-7 3 Cl H 236-7 20 * / .: 4 Cl CH 3 193-4 * • • a: 5 SCH 3 H 245-7 * * 9 35476

The compounds of the invention have been subjected to pharmacological experiments which have shown their usefulness as therapeutically active substances.

Action against convulsions induced by Cardiazol® in mice.

The experiment is derived from Goodman et al., J. Pharm. Esp. Ther. 108, 168-176. Mice receive test products or solvent alone intraperitoneally 30 minutes prior to intravenous injection of 35 10 mg / kg Cardiazol®. The animals are then observed for one hour and the percentage of mice with convulsions is recorded for each batch (100% of the control animals with convulsions and 10-20% of persistent convulsions. For each dose 15, the percentage protection compared to control animals is calculated to allow graphical determination of AD50 A dose that protects 50% of animals from the anticonvulsant effects of Cardiazol® The AD50 values of the compounds of the invention range from 0.1 to 30 mg / kg when administered traperitoneally and from 0.1 to 30 mg / kg orally. administration.

"Burying test" in rats This experiment is derived from J.P.J. Pinelin, D. Treitin, F. Ladakin, and A.J. From the method described in MacLennan's article Animal 25 learning and behavior, 8, 447-451 (1980). The presence of foreign objects in the animal's normal environment is a disgusting situation to which the animal responds by burying an interfering object (glass beads) in sawdust in its cage. Sedatives reduce the fear caused by 30 foreign objects; the animals bury them less. The number of beads left in the non-burial towers is counted. The test products are administered to male CD1 (Charles River) mice 30 minutes (intraperitoneally) or 60 minutes (orally) before being placed in cages with 25 glass beads. After 30 minutes ίο 8 5 4 76, the number of unearthed beads remaining is calculated. The percentage is calculated for treated and control animals. This determines the AD50 value, a 50% effective dose, which is a dose of compound 5 (mg / kg) that halves the number of buried beads compared to the control helium. The compounds of the invention have AD50 values between 0.3 and 30 mg / kg when administered intraperitoneally.

Drinking test in rat 10 This experiment has been described by Vogel J.R., Beer B. and Cloudy D.E. in Psychopharmacologia 21, 1-7 (1971).

Male Wistar (IFFA Credo) rats are used. They are prevented from receiving drinking water 24 hours before the test. On the day of the experiment, 30 minutes after the rats have been treated intraperitoneally with the compounds of the invention, each of them is placed in a transparent plastic cage (24 x 20 x 21 cm) with an electrified lattice floor. Drinking water is given with a pipette that extends 2 cm from one wall and is placed 3 cm above the floor of the cage. After 10-20 90 seconds of examination, the animal finds a pipette and begins to drink. After the rat has slipped its tongue 20 times (recorded with an OMNITECH anxiometer), it receives a 0.07 mA electric shock to the tongue (given with an anxiometer) that stops when the rat detaches from the pipette. After the first stroke, 1 25 begins a 3-minute period, during which the animal is continuously struck every 20 tongues of the tongue until it stops or until the end of the period.

Under these experimental conditions, control animals tolerated an average of 3-6 shocks. The number of shocks received by the treated animals is recorded and this number is compared to the corresponding reading of the control animals by the Dunett test. This determines MED, the lowest effective dose, which is the first dose that significantly increases the number of shocks tolerated by the animal compared to control animals. MED values range from 3 to 100 mg / kg when administered intraperitoneally.

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Effect on curl-treated, ventilated rat electrocorticogram

The sedative or hypnotic effect of the compounds was determined by observing their effect on the rat electrocorticogram in H. Depoorter's article Rev.

ELECTROENCEPHALOGRAM. Neurophyciol., 10, 3, 207-214 (1980) and in the article by J. Depoorteren and M. Decobert in J. Pharmacol. (Paris), 14, 2, 195-265 (1983).

The test products were administered intraperitoneally in doses of 1 to 30 mg / kg of Kas-10 Vavi. They cause sleep symptoms starting at doses between 3 and 100 mg / kg.

Koster test

The analgesic effect was demonstrated by the Koster et al test (acetic acid "Writhing test" in the mouse), Fed. 15 Proc., 18, 412, 1959. Fasting mice are orally administered the test compound in Tween 80 as a 1% solution in a ratio of 0.2 ml per 20 kg of body weight: after 30 minutes, acetic acid (0.6% solution of carboxymethylcellulose) is administered. and Tween 80, 20 in a ratio of 10 ml per kg body weight) intraperitoneally. The total number of twists during 15 min is calculated.

Determine the percentage protection relative to the control group and calculate ADS0 graphically (dose that protects 50% of the animals). The ADSO value of the compounds according to the invention varies between 5 and 50 mg per kg of body weight.

The test describes the anti-ulcer effect of stress.

30 The experiment is used in an article by Senay and Levine

Proc. Soc. Exp. Biol. 1967, 124, 1221-1223, Peptic Ulcers, and 180-210 g female Wistar rats fasted for 20 hours and divided into random groups. The animals are enclosed in cylindrical 20 x 5 cm jars and placed in a cold room.

i2 8 5 4 7 6 with a temperature maintained between 2-4 ° C. Test compounds are administered orally at 10, 30 and 100 mg / kg immediately before sealing in jars, control rats receive placebo only.

5 2 hours later, the animals are killed by allowing chloroform to be inhaled. The stomachs are removed and the degree of ulceration is recorded. The compounds of the invention significantly reduce stress-induced ulcers.

The results of these various tests show that the compounds of the invention have sedative, hypnotic, hypnotic, anticonvulsant, analgesic and antiulcer properties; The compounds of the invention are useful in the treatment of pain conditions, sleep disorders and other neurological or psychiatric disorders, in the treatment of alertness disorders, in particular in the treatment of cerebrovascular damage and in trust.

The compounds of the invention may be in a form suitable for oral or parenteral administration, for example tablets, granules, beads, drinkable or injectable solutions, etc., together with any suitable excipient. The daily dosage may vary between 1 and 100 mg.

To demonstrate the inventiveness of the compounds of formula (I), comparative experiments were also carried out to investigate the anti-convulsive effect of Cardiazol aiheutt in mice. The experiments were performed using the technique described above on page 9.

Compounds known from EP patent 50,563 (corresponding to FI patent 71,143) were used as reference compounds. The results for '35 are shown in the following table.

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Comparative experiments X_ ^ r \ -Q_x ρ> θ- »n" R2 / N ^ R2 <R1 EP-50563 (known) New

Well. Y X R3 R2 AD50 i.p. po

known (81) 6-CH3 CH3 H CH3 20 known (49) 6-C1 "" "5 new 1 H n" H 273 Γ74 ssssssassssssssssssssssBsasssssassssssssssssassssrssssssssssastssss known (50) 6-C1 CH3 CH3 CH3 15 new 2 H! i 15 B 3 7: known (69) 8-CH3 Cl H CH3 20 known (41) 6-CH3 "" "2.8 known (9) 6-C1" "" 0.6 known (1) H un · g new 3 H 5 B n Ö75 Γ76

. . aBaaBaBassassasaaaaaBssBasaBaaaaaaaaaaaBBaBaaaaBsaaaeaasB

known (68) 7-CH3 Cl CH3 CH3> 30 known (44) 6-CH3 "" "2.5 known (26) 6-C1" "" 0.3 * known (2) H "" "4.5 new 4 H 5 s B 3 16 aaaaaaasssasasaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa known (92) 6-CH3 SCH3 H CH3 1

new 5 H 15 5 B ÖTT5 ÖTT

* - - aaaaaaassBsasasaaaaaaasaaaaaaaaaaaaaaaaaaaaaaaaasaa

Claims (2)

A process for the preparation of therapeutically useful 2-phenyl-4,5-dihydroimidazo [1,2-a] quinoline-1-acetamide-5 derivatives of formula (I). Wherein R 1 is a hydrogen atom or a methyl group and X is a chlorine atom or a methyl or methyl mercapto group, and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that quinoline of formula (II) is reacted with α-bromoacetophenone which is substituted by the radical X, which has the same meaning as above, by heating in a solvent such as methylene chloride or 1,2-dichloroethane to give an ionized compound of formula (III) I- (5¾. (III) is 85476 and cyclized with anunonium acetate in the presence of an organic acid solvent such as acetic acid or propionic acid at a temperature of 90 ° C to give a compound of formula (IV) which is reacted with glyoxyl with acetylic acid at 80 ° C to give an α-hydroxy acid of formula (V) 20 U-H-25 which is acetylated with acetic anhydride in the presence of pyridine and then converted by reaction with an amine of formula R 1 -NH-CH 2. with, where Rx is as defined above, α-acetyloxyacetamethyldehyde of formula (VI) 30 XXHD "prepared from In sltu. ·· 35 il V-OAC; ·; <vn NRj_CH3 16 85476 which compound (VI) is deacetylated to α-hydroxyacetamide of formula (VII) by treatment with potassium carbonate in ethanol, which compound (VII) is reacted with a sulfonyl chloride SOCl2 in a chlorinated solvent such as dichloromethane to give a compound of formula (VIII) which is reduced with sodium formaldehyde sulfoxylate in methylene chloride, and the resulting compound of formula (I) is converted into a pharmaceutically acceptable compound if desired. 17 85476 For the preparation of therapeutically active compounds 2-phenyl-4,5-dihydroimidazo [1,2-a] quinoline-1-acet-5-amide derivatives of formula (I) i 3 \ —X • 'o — y • (i) Rl * ^ 15 for Rj är en väteatom eller en methylyl och and X är en chloro eller en methyl- eller methylmercaptogrupp, samt farmaceutiskt godtagbara syraaadditionssalter därav, kännetecknat därav, att e n quinoline with -20 mein (II) 00 <in:. : 25 ometts med α-bromoacetophenone, with a substituent mediated by radical X, with a single addition of the same, a genomic up-and-coming mixture, methylene chloride or 30 1,2-dichloroethane, in the form of an amine-free form , 6VO- · (III) ie 85476 and with a cyclic mixture of ammonium acetate and organic syrups, acetic acid or propionic acid, at a temperature of 90 ° C, for use in the preparation of form (IV) UV) and with the addition of glyoxylic acid to the solution, at -15 ° C, at 80 eC, for a mixture of α-hydroxys, to form (V), XXhCX. ) -OH? with formula (VI) 30 v = rv "vA-« AJx ~ \ j. 35 o ^ Acvn NR1CH3 i9 85476 for the formation of (VI) deacetylers to α-hydroxyacetamide with formula (VII) [f "ay-OH Oxs-S ( VII) 10 NRx Ch3 genome behaving with callus carbonate 1 ethanol, one or more of the sulfonyl chlorides S0C12 i and chlorinated in the form of a solution, with the addition of dichloromethane, for 15 times with the formulation of formula (VIII) 20 (fjT at night ^ 0 === Λ (VIII) NR 2 CH 3. «Cl 25 and somehow reducing with sodium formaldehyde sulfoxylate and methylene chloride, and if the same is obtained, the compound of formula (I) is used in the form of a pharmaceutical compound.