FR2593181A1 - Derivatives of 3-(acylaminomethyl)imidazo[1,2-a]pyridines, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds corresponding to the general formula I: in which X1, X2 and X3 each represent, independently of each other, hydrogen, a halogen or a C1-C4 alkyl, methoxy, methylthio, ethylthio, methylsulphonyl, nitro, amino, methylamino, dimethylamino, acetylamino or diacetylamino group, Y represents hydrogen, chlorine or a methyl group, R1 represents hydrogen or a linear or branched C1-C4 alkyl group or a benzyl group, R2 represents a linear or branched C1-C6 alkyl group, or a cyclohexyl, trichloromethyl, 1-propenyl, allyl, phenyl, 4-chlorophenyl or benzyl group, or else R1 and R2 together represent a C3-C5 aliphatic chain, as well as their addition salts which are acceptable in pharmacology. Application in therapeutics.

Description

The present invention relates to 3-acylaminomethylimidazo [1,2-a] pyridines derivatives, their preparation and their therapeutic application.

The compounds of the invention correspond to the formula (I) given in the scheme on the following page, in which formula X1, X2 and X3 each represent, independently of one another, hydrogen, a halogen or a C1-C4 alkyl, methoxy, methylthio, ethylthio, methylsulfonyl, nitro, amino, methylamino, dimethylamino, acetylamino or diacetylamino,
Y represents hydrogen, chlorine or a methyl group, R1 represents hydrogen or a linear or branched C1-C6 alkyl group, or a benzyl group,
R2 represents a linear or branched C1-C6 alkyl group, a cyclohexyl, trichloromethyl, propenyl, allyl, phenyl, 4-chlorophenyl or benzyl group, or else
R1 and R2 together represent an alienic chain in
C3-C5, with the exception of the compounds for which x3 has the definitions given above when X1 and X2 are each a hydrogen atom and the other radicals have the definitions given above.

The compounds of the invention may be in the form of free bases or addition salts with pharmaceutically acceptable acids.

Preferred compounds are those in formula (I) of which
X1, X2 and X3 are chlorine, methyl or methoxy, Y is hydrogen or chlorine or methyl, R1 is hydrogen or methyl, and R2 is propyl or isobutyl.

The compounds of the invention may be prepared according to the scheme on the following page.

Diagram

The starting compound is a 2-phenylimidazo [1,2-a] pyridine of formula (II) bearing the substituents X1, X2, X3 and Y as defined above.

Formylation of this compound (II) can be carried out first, for example by means of the reagent which is obtained by the action of oxalyl chloride on dimethylformamide. After hydrolysis, an aldehyde of formula (III) is obtained which is reduced to the corresponding alcohol of formula (IV) in a known manner, for example by the action of an alkali metal borohydride. The alcohol (IV) can be obtained by direct hydroxymethylation of the imidazo C12-a] pyridine (II) by means of aqueous formaldehyde in acetic acid.

This alcohol (IV) is then reacted with a nitrile
R2-CN in sulfuric medium. Thus, after hydrolysis, a compound of formula (Ia) is obtained, the substituent R1 of which is necessarily hydrogen. If desired, it is then possible to alkylate or benzylate this compound in known manner, for example with an iodide of formula R1-I in the presence of sodium hydride, to give a compound of formula (I) in which R1 is a alkyl or benzyl group.

dans laquelle R1 et R2 sont tels que définis ci-dessus.The compounds of formula (I) can also be prepared in a single step, by reacting the starting compound (II) with an amide of formula

wherein R1 and R2 are as defined above.

The reaction is carried out at room temperature in the presence of concentrated sulfuric acid and optionally with a cosolvent such as glacial acetic acid.

Finally, it is also possible to prepare compounds of formula (Ia) by reacting the starting compound (II) with a nitrile of formula R2-CN and paraformaldehyde, under hot conditions, in an acetic medium and in the presence of sulfuric acid.

The compound (I) obtained after hydrolysis can, if desired, then be alkylated or benzylated as indicated above.

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

Example 1 N - [[(3,4-dimethyl-phenyl) -6-methyl-imidazo [1,2-a] pyridin-3-yl] methyl] -3-dimethyl-butanamide.

1.1. (3,4-Dimethylphenyl) -2-methylimidazo1,2-a]
pyridine.

To a solution of 42 g (0.188 mole) of (3,4-dimethyl)
phenyl-1-bromo-2-ethanone in 400 ml of ethanol
95%, 20.5 g (0.188 mole), 2-amino-5-methyl are added.
pyridine and 32 g (0.381 mol) of NaHCO3. We heat the
suspension at reflux temperature for 6 hours
then cools it and concentrates it under pressure
scaled down. The residue is washed with water and then treated with
an ethanol-ethanol mixture and then by a mixture
ether-acetone and finally by ether.

A yellow powder of sufficient purity is obtained
to continue the synthesis.

 r = 157-1600C.

1.2. (3,4-Dimethylphenyl) -2-methylimidazo [1,2-a]
pyridine-3-methanol.

13.5 g (0.057 mol) of the imidazopyridine are dissolved
previously obtained in 80 ml of acetic acid,
containing 20 ml of 37% formalin in water. We wear
the solution at 55C for 4 hours then the concentrate
under reduced pressure. We take the residue
evaporation with water, then treat it with excess
ammonia to basic pH. The suspension is shaken
formed 24 hours in the presence of 200 ml of CH2Cl2 then
the insoluble material is sintered and washed with water
then to the ether.

After drying under vacuum, a white powder is obtained
amorphous.

 F: 209-210 C.

1.3. N - [[(3,4-dimethylphenyl) -2-methyl] imidazo [1,2-a]
3-pyridinyl] methyl] 3-methylbutanamide
To a solution of 20 ml of isovaleronitrile containing
3.5 g (0.0131 mol) of the alcohol obtained previously,
add drop by drop, slowly, 3.5 ml of acid
concentrated sulfuric. Stirring is maintained for
1 hour 30 to room temperature, then 2 hours to
110 C. Cool the suspension, milking with 100 g
ice and then an excess of ammonia to basic pH.

The insoluble material is extracted with CH2Cl2 and purified by
silica chromatography. We get the amide
secondary (Ia) in the form of a viscous oil
the hydrochloride melts at 217-8C.

1.4. N - [[(3,4-dimethylphenyl) -2-methyl] imidazo [1,2-a]
pyridinyl-3] methyl] N, 3-dimethyl-butanamide
To a suspension of 1.16 (0.0024 mol) of NaH (at 50 S
in oil) in 20 ml THF containing 1.26 ml, either
2.87 g (0.002 mol) of CH3I is added 3.53 g (0.001 g).
mole) of the secondary amide obtained previously, in
solution in 35 ml of THF. We maintain the agitation
during 3 hours. The suspension is treated with 1 ml of
methanol and then concentrated under reduced pressure. We
take up the residue with water, extract the insoluble
CH2Cl2 and purify by chromatography on silica.

The compound (I) F = 103-4 C is obtained
The hydrochloride of the compound melts at 162.5-163.5 C.

Example 2 N - [[(3,4-Dimethyl-phenyl) -6-methyl-imidazo [1,2-a] p; yridin-3-yl] methyl] N -methyl-butanamide 2.1. N - [[(3,4-Dimethyl-phenyl) -2-methyl-imidazo] 21.2-4
pyridinyl-3] methyl] -butanemide
6 g (0.022 mol) of the alcohol are suspended
obtained under 1.2. in 50 ml of butyronitrile then
slowly add 6 ml concentrated H2504. We shake the
mixed at room temperature for 1 hour 30 minutes,
then take it 1/2 hour at 1400C. After
cooling, the phase is treated with ice
lower, the supernatant having been eliminated.

After complete dissolution of the gum, treat the
solution with an excess of NH40H up to pH strongly
basic. The insoluble material is extracted with CH2Cl2 and purified
by recrystallization from a cyclohexane /
ethyl acetate.

The secondary amide (Ia) whose hydrochloride is obtained
background at 219-220C.

2.2. N - [[(3,4-Dimethyl-phenyl) -2-methylimidazo [1,2-a]
pyridinyl-3] methyl] N-methyl-butanamide
To a suspension of 1.19 g of NaH (at 50 S in
the oil) in 20 ml of dry THF containing 1.29 ml is
2.95 g (0.0208 mol) of CH3I is added 3.49 g (0.0104).
mole) of the amide obtained previously. We dilute the
reaction medium with 30 ml of THF. We keep
stirring for 2 hours then after addition of 1
ml of methanol, the mixture is concentrated under pressure
scaled down. The residue is treated with water and extracted
the insoluble with CH2C12 then the chromatography on
silica.

 An oil is obtained whose hydrochloride melts at 181.5-1820C.

Board

<tb> Compound <SEP> Y <SEP> X1 <SEP> X2 <SEP> X3 <SEP> R1 <SEP> R2 <SEP> F (C)
<tb><SEP> 1 <SEP> CH3 <SEP> Cl <SEP> H <SEP> Cl <SEP> CH3 <SEP> nC3H7 <SEP> 146-147 *
<tb><SEP> 2 <SEP> CH3 <SEP> H <SEP> Cl <SEP> Cl <SEP> CH3 <SEP> nC3H7 <SEP> 124-125
<tb><SEP> 3 <SEP> CH3 <SEP> H <SEP> Cl <SEP> H <SEP> CH3 <SEP> nC3H7 <SEP> 84-85
<tb><SEP> 4 <SEP> CH3 <SEP> Cl <SEP> H <SEP> H <SEP> CH3 <SEP> nC3H7 <SEP> 185-186
SEP> CHP <CH>
<tb><SEP> 6 <SEP> CH3 <SEP> H <SEP> OCH3 <SEP> H <SEP> CH3 <SEP> nC3H7 <SEP> 165-166 *
<tb><SEP> 7 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> nC3H7 <SEP> 129-129.5
<tb><SEP> 8 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> nC3H7 <SEP> 181,5-182 *
<tb><SEP> 9 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> iC4H9 <SEP> 111-112 *
<tb><SEP> 10 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> iC4H9 <SEP> 162.5-163.5 *
<tb><SEP> 11 <SEP> CH3 <SEP> H <SE> OCH3 <SEP> OCH3 <SEP> CH3 <SEP> nC3H7 <SEP> 168-168.5 * <SEP>
<tb><SEP> 12 <SEP> Cl <SEP> H <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> nC3H7 <SEP> 124.5-125
<Tb>
Table (continued)

<tb> Compound <SEP> Y <SEP> X1 <SEP> X2 <SEP> X3 <SEP> R1 <SEP> R2 <SEP> F (C)
<tb><SEP> 13 <SEP> CH3 <SEP> Cl <SEP> H <SEP> Cl <SEP> H <SEP> nC3H7 <SEP> 160-161
<tb><SEP> 14 <SEP> CH3 <SEP> H <SEP> Cl <SEP> Cl <SEP> H <SEP> nC3H7 <SEP> 160-161
<tb><SEP> 15 <SEP> CH3 <SEP> H <SEP> Cl <SEP> H <SEP> H <SEP> nC3H7 <SEP> 154-155
<tb><SEP> 16 <SEP> CH3 <SEP> Cl <SEP> H <SEP> H <SEP> H <SEP> nC3H7 <SEP> 178-179
<tb><SEP> 17 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> H <SEP> H <SEP> nC3H7 <SEP> 141-142
<tb><SEP> 18 <SEP> CH3 <SEP> H <SEP> OCH3 <SEP> H <SEP> H <SEP> nC3H7 <SEP> 187.5-188.5 * <SEP>
<tb><SEP> 19 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> H <SEP> nC3H7 <SEP> 160-161
<tb><SEP> 20 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> H <SEP> nC3H7 <SEP> 219-220 <SEP>
<tb><SEP> 21 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> H <SEP> iC49H <SEP> 166-167
<tb><SEP> 22 <SEP> CH3 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> H <SEP> iC4Hg <SEP> 217-218 * <SEP>
<tb><SEP> 23 <SEP> CH3 <SEP> H <SEP> OCH3 <SEP> OCH3 <SEP> H <SEP> nC3H7 <SEP> 200-201 * <SEP>
<tb><SEP> 24 <SEP> Cl <SEP> H <SEP> CH3 <SEP> CH3 <SEP> H <SEP> nC3H7 <SEP> 154.5-155
<tb><SEP> 25 <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> H <SEP> nC3H7 <SEP> 146.5-147
SEP> CHP <CH>
<tb> * = hydrochloride.

The compounds of the invention have been the subject of pharmacological tests which have demonstrated their interest as substances with therapeutic activities.

Acute toxicity.

It was determined in the mouse intraperitoneally. LD 50 are greater than 500 mg / kg.

Antagonism against clonic convulsions induced by Cardiazols 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 test products, or the solvent alone, intraperitoneally 30 minutes before the injection of 35 mg / kg of CardiazolX intravenously. The animals are then observed for one hour and, for each lot, the percentage of mice with clonic convulsions is noted (100% of clonic convulsions and 10% to 20% of tonic convulsions in the control animals).

For each dose, the percentage of protection against plant 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®.

DA50 of the compounds of the invention are between 0.1 and 30 mg / kg.

Landfill test in mice ("Burying 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 products to be studied are administered to CD1 (Charles River) male 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.

In this way, the active dose LD50 (50%) is determined, which is the dose of compound (in mg / kg) which reduces by half the number of buried beads, in comparison with the control animals.

The DA50s of the compounds of the invention are between 0.1 and 30 mg / kg intraperitoneally.

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, J. 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 0.01 to 30 mg / kg.

Koster test.

The analgesic activity of the compounds of the invention has been shown in the Koster et al ("writhing test with acetic acid in mice"), Fed Proc., 18, 412, 1959.

The test compound dissolved in Tween 80 at 1 Z is orally administered to the fasting mice at the rate of 0.2 ml per 20 g of body weight; after 30 minutes, acetic acid (in a solution of 0.6% in a mixture of carboxymethylcellulose and tween 80 at the rate of 10 ml per kg of body weight) is administered intraperitoneally.

The total number of contortions is recorded for 15 minutes.

The percentage of protection is determined relative to a control group and the DA 50 is calculated graphically (a dose which protects 505 of the animals).

The DA 50 of the compounds of the invention ranges from 5 to 50 mg / kg p.o.

Stress ulcer
The technique used is that of Senay and Levine, Proc.

Soc. Exp. Biol. 1967, 124, 1221-1223, Peptic Ulcers, on female Wistar rats weighing 180-210 g, fasted for 20 hours, divided into randomized blocks.

The animals are put in contention in cylindrical boxes of 20 cm x 5 cm and placed in a cold room whose temperature is maintained between 2 and 40C.

The compounds to be studied are administered orally at a rate of 10, 30 and 100 mg / kg immediately before the compression, the control rats receiving only placebo.

2 hours later, the animals are sacrificed by inhalation of chloroform.

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

The compounds of the invention significantly reduce stress ulcers.

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

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 (5)

claims 1. 3-Acylaminomethyl imidazo [1,2-a] pyridine derivatives,  according to the general formula (I)

 acceptable.  as well as their addition salts with pharmaceutic acids  given above,  hydrogen atom and the other radicals have the definite  given above when X1 and X2 are each a  with the exception of compounds for which X3 has the challenge  C3-C5  R1 and R2 together represent an aliphatic chain in  or even  benzyl,  propenyl, allyl, phenyl, 4-chlorophenyl or  branched, cyclohexyl, trichloromethyl,  R2 represents a linear C1-C6 alkyl group or  linear or branched, or a benzyl group,  R1 represents hydrogen or a C1-C4 alkyl group  Y represents hydrogen, chlorine or a methyl group,  diacetylamino,  nitro, amino, methylamino, dimethylamino, acetylamino or  the other, hydrogen, halogen, C 1 -C 4 alkyl, methoxy, methylthio, ethylthio, methylsulfonyl,  X1, X2 and X3 each independently represent one of  in which 2. Derivatives according to claim 1, characterized by the  X1, X2 and X3 represent the chlorine, the group  methyl or methoxy, Y represents a hydrogen atom or  of chlorine or a methyl group, R1 represents hydrogen  or a methyl group, and R2 represents a propyl group  or isobutyl. 3. Process for preparing the compounds of the claim  1, characterized in that one carries out a  formylation of the compound of formula (II)

  in a known manner, for example by the action of an alkali metal borohydride (alcohol (IV) can also be obtained directly by hydroxymethylation of imidazo pyridine (II)); This alcohol (IV) is then reacted with a R2-CN nitrile in a sulfuric medium and the compound of formula (Ia) is obtained after hydrolysis.

 reduced to the corresponding alcohol of formula (IV)

 after hydrolysis, an aldehyde of formula (III) is obtained  for example by means of the reagent obtained by the action of oxalyl chloride on dimethylformamide,  benzyl.  of formula (I) wherein R1 is an alkyl group or  the presence of sodium hydride, to result in a compound  known, for example with an iodide of formula R1-I in  this compound can then be alkylated or benzylated  whose substituent R1 is hydrogen; if you wish, 4. Medicinal product, characterized in that it consists of a  compound according to any one of claims 1 and 2. 5. Pharmaceutical composition, characterized in that  contains a compound according to any one of the  1 and 2, in combination with an excipient  appropriate.