FR2593817A1 - 5,6,7,8-Tetrahydroimidazo[1,2-a]pyridine derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds of formula I: in which X represents a halogen, an alkyl or an alkoxy, Y represents hydrogen or an alkyl, R1 and R2 each represent hydrogen or an alkyl or together form an alkylene chain optionally containing an oxygen or nitrogen atom. Application in therapeutics.

Description

The present invention relates to derivatives of tetrahydro-5,6,7,8-imidazo [1,2-a] pyridine, their preparation and their therapeutic application.

The compounds of the invention correspond to the general formula (I) given in the scheme below, in which formula
X represents a halogen atom or a (C1 4) alkyl or (C1 4) alkoxy group,
Y represents a hydrogen atom or a (C1 4) alkyl group, and R1 and R2 each represent, independently of one another, a hydrogen atom or a (C1 4) alkyl group, or together form an alkylene chain (C3-C6) optionally containing a heteroatom such as an oxygen atom or an NH or N (C1 4) alkyl group.

The compounds of the invention may be in the form of pure enantibodies or mixtures thereof, and in the form of free bases or addition salts with pharmaceutically acceptable acids.

The preferred compounds of the invention are those in the form of which X represents a halogen atom or a methyl or methoxy group, Y represents a hydrogen atom or a methyl group, and R1 and R2, each separated, represent a a hydrogen atom or a methyl group or together a tetramethylene, pentamethylene, hexamethylene, 3-oxa-pentamethylene, 3-aza-pentamethylene or 3-methyl-3-aza-pentamethylene group. The compounds in the formula of which R 1 and R 2 each represent a methyl group are most preferred.

According to the invention, the compounds of formula (I) can be prepared by hydrogenation of the compounds of formula (II), in which the symbols X, v, R1 and R2 are as defined above.

The compounds of formula (II) are described in European Patent No. 50,563.

Diagram

The hydrogenation is of the catalytic type under pressure, that is to say that it is carried out for example in the presence of palladium on carbon or rhodium on alumina, the starting compound (II) being either in the form of the dissolved base in a solvent such as acetic acid or an alcohol such as methanol or ethmol, or in the form of a salt such as the hydrochloride in one of the solvents mentioned above.

The following examples illustrate the preparation of some compounds according to the invention. Analyzes and IR and NMR spectra confirm the structures of the products obtained.

Example 1 (4-Methoxyphenyl) -2,5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-acetamide, hydrochloride.

2.6 g (0.008 mole) of 4- (4-methoxyphenyl) imidazol, 2-a] pyridine-3-acetamide are dissolved in 200 ml of glacial acetic acid, and the solution is hydrogenated in a reaction apparatus.
Parr in the presence of 1.5 g of 10X PcLÇ on charcoal. At the end of absorption, the catalyst is filtered, the acetic acid is removed under reduced pressure and the residue is taken up in 100 ml of a 10% solution of sodium bicarbonate in water. The insoluble material is filtered, dried and recrystallized from acetonitrile. Mp: 205-206 C.

The hydrochloride is prepared in isopropyl alcohol.

Mp 254-2550 ° C.

Example 2 (4-methyl-phenyl) -2,6-dimethyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-3-acetamide hydrochloride.

5.82 g (0.0189 mol) of 2- (4-methyl-phenyl) -N, 6-dimethyl-imidazo [1,2-a] pyridine-3-acetamide are dissolved in 180 ml of 95% ethanol, 20 ml of 1N aqueous hydrochloric acid and 1.53 g of 10% Pd on charcoal are added thereto, followed by hydrogenation at 0.4 MPa. At the end of the absorption, the catalyst is removed by filtration, the filtrate is concentrated to dryness, the residue is recrystallized from acetone and dried.

F = 21151C.

Example 3 (4-Chloro-phenyl) -2 N, N, 6-trimethyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-3-acetamide, hydrochloride.

4 g (0.0122 mol) of (4-chlorophenyl) imidazo [1,2-a] pyridine-3-acetamide are dissolved in 200 ml of glacial acetic acid, and 1 g of 5 S rhodium is added thereto. on alumina and is hydrogenated at a pressure of 0.3 to 0.4 MPa. At the end of absorption, the catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is taken up in 200 ml of water and ammonia is added thereto. The amide is extracted with methylene chloride and then purified by chromatography on a silica column. The hydrochloride is prepared from the purified base in hydrochloric isopropyl alcohol.

F = 238239CC.

The following table illustrates the structures and physical properties of some compounds according to the invention.

BOARD

<tb> Compound <SEP> X <SEP> Y <SEP> R1 <SEP> R2 <SEP> Sel <SEP> or <SEP> F (OC)
<tb><SEP> base (t)
<tb><SEP> 1 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> H <SEP> 10 <SEP> 274-276
<tb><SEP> 1 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> H <SEP> 10 <SEP> 274-276
<tb><SEP> 2 (Ex.2) <SEP> CH3 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> 10 <SEP> 215-216
<tb><SEP> 3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> 10 <SEP> 201-203
<tb><SEP> 4 <SEP> CH3 <SEP> CH3 <SEP> - (CH2) 4- <SEP> 10 <SEP> 206-207
<tb><SEP> 5 <SEP> CH3 <SEP> CH3 <SEP> - (CH2) 6- <SEP> 10 <SEP> 236-238
<tb><SEP> 6 <SEP> CH3 <SEP> CH3 <SEP> - (CH2) 2-k- (CH2) 2- <SEP> 10 <SEP> 213-215
<tb><SEP> H
<tb><SEP> 7 <SEP> CH3 <SEP> CH3 <SEP> - (CH2) 2-N- (CH2) 2- <SEP> 00 <SEP> 183-185
<tb><SEP> CH3
<tb><SEP> 8 <SEP> CH3 <SEP> CH3 <SEP> - (CH2) 2-O- (CH2) 2- <SEP> 10 <SEP> 196-197
<tb><SEP> 9 <SEP> CH3 <SEP> H <SEP> H <SEP> H <SEP> 10 <SEP> 223-224
<tb> 10 <SEP> CH3 <SEP> H <SEP> H <SEP> CH3 <SEP> 10 <SEP> 255-256
<tb> 11 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 10 <SEP> 257-259
<tb> 12 (Ex.1) <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> 10 <SEP> 254-255
<tb> 13 <SEP> 0CH3 <SEP> H <SEP> H <SEP> CH3 <SEP> 10 <SEP> 218-220
<tb> 14 <SEP> OCH3 <SEP> CH3 <SEP> H <SEP> H <SEP> 10 <SEP> 235-237
<tb> 15 <SEP> OCH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> 10 <SEP> 238-240
<tb> 16 <SEP> C1 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 10 <SEP> 264-265
<tb> 17 (Ex. 3) <SEP> C1 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> 10 <SEP> 238-239
<tb> (*) 00: base
10: hydrochloride.

The compounds of the invention have been the subject of pharmacological tests which have revealed their interest as active substances of medicaments.

Their acute toxicities determined in mice are between 30 and 300 mg / kg intraperitoneally.

Antagonism against cardiazolX-induced clonic convulsions in mice.

The test is based on the protocol described by Goodman et al.
J. Pharm. Exp. Ther., 108, 168-176. The mice receive the products to be tested, or the solvent alone, intraperitoneally 30 minutes before the injection of 35 mg / kg of intravenous cardiazol. The animals are then observed for one hour and, for each lot, the percentage of mice with clonic convulsions is noted (100 y of clonic convulsions and 10-20 S of tonic convulsions in the control animals).

For each dose, the percentage of protection relative to the control animals is calculated, which makes it possible to graphically determine the DA50, a dose which protects 50% of the animals against the convulsive effects of Cardiazol.

The DA50s of the compounds of the invention are between 0.5 and 30 mg / kg intraperitoneally and are of the order of 4 mg / kg for some of them orally.

"Burial" test in the mouse ("8urying test").

This test is inspired by the 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 constitutes an aversive situation to which the animal reacts by burying the object of aggression (glass beads) in the sawdust of its cage.

Anxiolytics have the effect of reducing the apprehension caused by the foreign presence: the animals bury less. We then count the number of logs that have not been buried.

The test products are administered to male CD1 strain (Charles River) mice for 30 minutes (intraperitoneal route) or 60 minutes (orally) before they are placed in cages containing 25 glass beads.

After 30 minutes count the number of logs not buried. A percentage is calculated between the treated animals and the control animals.

Thus, the active dose 50, which is the dose of compound (in mg / kg), is reduced by halving the number of buried beads in comparison with the control animals.

The DA50s of the compounds range from 5 to 30 mg / kg intraperitoneally and are of the order of 10 to 20 mg / kg for some of them orally.

Action on the electrocorticogram of the ventilated rat.

The sedative or hypnotic activity of the compounds was determined by observation of their action on the electrocorticogram of the rat according to the method described by H. Depoortere,
Rev. EEG Neurophysiol., 10, 3, 207-214 (1980) and by
H. Depoortere and M. Decobert, D. Pharmacol. (Paris), 14, 2, 195-265 (1983).

The products to be studied were administered intraperitoneally at increasing doses of 1 to 30 mg / kg.

They induce sleep patterns from doses ranging from 1 to 30 mg / kg.

Effects on the duration of "sleep" induced by 4-hydroxy sodium butyrate.

This action was determined by the influence of a compound on the duration of "sleep" induced by 4-hydroxy-sodium butyrate (GHB) in the curarized rat.

The animals used are male rats of Charles strain
River of 200 + 20 g. The animals, curarized with alloferin at a dose of 1 mg / kg ip, are placed under artificial respiration using a mask applied to the muzzle (respiratory rate = 50 / minute, respiratory volume = 14 ml). .

The esophagus is first ligated to prevent the entry of air into the stomach.

Front-parietal and occipital cortical electrodes allow electrocorticographic activity to be recorded on a Grass Model 79 P polygraph at a rate of 6 mm / sec.

The preparation of the animal is carried out under local anesthesia (xylocaine at 20). The rats were maintained throughout the experiment at constant temperature (37.50C). Ten minutes after completion of the rat preparation, a dose of 200 mg / kg of sodium 4-hydroxy-butyrate is injected intravenously at the tail.

A dose of 10 mg / kg of the test compound is administered intraperitoneally 3 minutes after the administration of sodium 4-hydroxybutyrate.

The evaluation of the tracings is done in 15-minute periods for 75 minutes after the injection of GHB. During this analysis period, the total duration of "sleep" is determined. A series of 15 witnesses makes it possible to specify the duration of the "GHB sleep".

The statistical analysis of the results is performed using the Mann-Whitney "U" test.

Some compounds reduce sleep time (up to 30 at a dose of 10 mg / kg), while others increase it slightly.

The results of these various tests show that the compounds of the invention possess anxiolytic, sleep-inducing, hypnotic and anticonvulsant properties. The compounds of the invention are useful for the treatment of anxiety states, sleep disorders and other disorders. neurological and psychiatric disorders, for the treatment of vigilance disorders, in particular for combating behavioral disorders attributable to cerebrovascular damage and cerebral sclerosis, in geriatrics, as well as for the treatment of absences due to head trauma and for the treatment of metabolic encephalopathies.

The compounds of the invention may be presented in any form suitable for oral or parenteral administration, for example in the form of tablets, lozenges, capsules, oral or injectable solutions, etc., in combination with any suitable excipient. .

The daily dosage can range from 0.1 to 100 mg.

Claims (6)

claims 1. Compound as pure enantiomer or enan mixture  tiomers, characterized in that it meets the formula  general I

 pharmacology.  as well as its addition salts with acceptable acids in  oxygen or an NH or N (C14) alkyl group,  possibly containing a heteroatom such as an atom  or together form a chain (C3-C6) alkylene  the other, a hydrogen atom or a (C1 4) alkyl group,  1 and P2 represent each independently  alkyl, and  Y- represents a hydrogen atom or a group (C14)  or (C1 4) alkoxy,  X represents a halogen atom or a (C1 4) alkyl group  in which 2. Compound according to claim 1, characterized in that,  in formula I, X represents a halogen atom or a  methyl or methoxy group, Y represents a hydro atom  gene or a methyl group, and RI and R2, separated, represented  each feel a hydrogen atom or a methyl group  or together, a tetramethylene group, pentamethyl  lene, hexamethylene, oxa-3 pentamethylene, aza-3 penta  methylene, or 3-methyl-3-aza-pentamethylene. 3. Compounds according to claim 2, characterized in that  in the formula (I), R1 and R2 each represent a  methyl group. 4. Process for the preparation of the compounds according to the claims  cations 1 and 2, characterized in that a compound is  of formula II

 to a catalytic hydrogenation under pressure. 5. Drug, characterized in that it consists of a compound  according to one of claims 1 and 2. 6. Pharmaceutical composition, characterized in that  contains a compound according to one of claims 1 and 2,  in combination with any suitable excipient.