FR2647451A1 - Imidazole[1,2-a]pyridine derivatives, process of preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The subject of the invention is imidazole[1,2-a]pyridine derivatives of general formula: These compounds are active as pharmacological agents especially by their bradycardiac, hypotensive, antiadrenergic, calcium translocation inhibiting and local anaesthetic properties.

Description

 The present invention relates generally. to new heterocyclic derivatives and more particularly to new imidazo [1,2-a] pyridine derivatives as well as their preparation process.

dans laquelle
R est choisi parmi les groupes alkyle en C2-C6 linéaire ou ramifié, cycloalkyle en C3-C6 et phényle non substitué ou substitué par un ou plusieurs substituants identiques ou différents, sélectionnés parmi les atomes d'halogène, par exemple fluor, chlore ou brome et les groupements alkyle en C1-C4 alkoxy en
C1-C4 et nitro,
R1 et R2 qui sont identiques ou différents. sont choisis parmi l'hydrogène, le radical méthyle, le radical méthoxy et un atome d halogène tel que chlore.Consequently. The subject of the invention is the novel imidazo [1,2-a] pyridine derivatives of the general formula

in which
R is selected from linear or branched C 2 -C 6 alkyl, C 3 -C 6 cycloalkyl and phenyl unsubstituted or substituted by one or more identical or different substituents selected from halogen atoms, for example fluorine, chlorine or bromine; and C 1 -C 4 alkyl groups alkoxy in
C1-C4 and nitro,
R1 and R2 which are the same or different. are chosen from hydrogen, the methyl radical, the methoxy radical and a halogen atom such as chlorine.

bromine or iodine,
R3 is selected from hydrogen, a halogen atom such as bromine chlorine or iodine, a hydroxy radical.

C1-C4 alkyl, C1-C4 alkoxy and benzyloxy.

A represents a C2-C6 alkylene radical, linear or branched. preferably the propylene radical,
R4 is chosen from a linear or branched C3-C6 alkyl radical and a radical of formula
-Alk-R6 in which Alk represents a single bond or a linear or branched C1-C5 alkylene radical. and R6 is selected from a pyridyl radical. phenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl and a phenyl group substituted with one or more identical or different substituents selected from halogen atoms, alkyl groups,
C1-C4 and C 1 -C 4 alkoxy groups,
R5 is selected from hydrogen and a C3-C6 alkyl radical or R4 and R5 when taken together. represent a C3-C6 alkylene or alkenylene radical optionally substituted by a phenyl radical or optionally interrupted by -O-. -NH-. -N = or -N-R7, R7 being chosen from a C1-C4 alkyl radical and phenyl radical.

In formula I above. R or the aminoalkoxybenzoyl chain can be in position 2 or 3: when R is in position 2, the aminoalkoxybenzoyl chain is in position 3 and the reverse,
In this context. both in the description and in the claims, the terms below have the following meaning: "C2-C6 alkyl" means the radicals of saturated aliphatic hydrocarbons, linear or branched, having from 2 to 6 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl. isobutyl. tert-butyl, n-pentyl, neopentyl, n-hexyl, "C3-C6 alkyl" refers to linear or branched saturated aliphatic hydrocarbon radicals having from 3 to 6 carbon atoms such as n-propyl, isopropyl, n- butyl, isobutyl. tert-butyl, n-pentyl.

neopentyl or n-hexyl, "C1-C4 alkyl", refers to the residues of saturated aliphatic hydrocarbons having up to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or 1-methylpropyl.

"C3-C6 cycloalkyl" denotes an alicyclic radical having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, "C1-C4 alkoxy" denotes a hydroxy group substituted by a C1-C6 alkyl group; C4 as defined above.

So, taking into account the meanings given above
R represents in particular an ethyl radical. n-propyl, isopropyl. n-butyl, isobutyl. tert. methyl
-1 propyl. n-pentyl, neopentyl, phenyl. mono fluoro-. mono-chloro or mono-bromo-phenyl, di-fluoro, di-chloro- or dibromo-phenyl, mono-methyl-, or di-methyl-phenyl, mono-methoxy- or di-methoxy-phenyl or a methyl- phenyl substituted with a halogen atom.

A in particular represents a 1,2-ethylene chain; propylene-1,3; 2-methylpropylene-1,3; 1,4-tetramethylene or 1,5-pentamethylene.

R3 represents in particular a methyl, ethyl group.

n-propyl. n-butyl, methoxy or ethoxy.

R 4 represents in particular an n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or 1-methylpropyl radical. n-pentyl, n-hexyl, phenyl. benzyl. phenethyl dimethoxyphenethyl, for example 3,4-dimethylphenethyl, trimethoxyphenethyl, dimethoxybenzyl, pyridylethyl or a phenethyl radical substituted in the aromatic portion by methyl or methoxy radicals.

R5 represents in particular an n-propyl, isopropyl or n-butyl radical. isobutyl, tert-butyl, n-pentyl, neopentyl or n-hexyl.

 R4 and R5, taken together, especially represent a 1,4-tetramethylene radical; pentamethylene-1 .5; 3-oxo-1,5-pentamethylene; aza-3 pentamethylene-1,5; 3-methylaza-1,5-pentamethylene; 3-phenylaza pentamethyl-1,5-one. pyrrolidinyl. piperidinyl. morpholinyl.

piperazinyl. 4-methylpiperazinyl. 4-phenylpiperazinyl or imidazolyl,
Among the compounds of formula I, those in which R represents a C2-C6 alkyl radical constitute a preferred class.

The invention also relates to pharmaceutically acceptable salts of compounds of formula
I formed from an organic or inorganic acid.

 Examples of organic salts of this type include oxalate, maleate, fumarate, methanesulfonate, benzoate, ascarbate, pamoate, succinate. hexanate, bismethylenesalicylate. ethanedisulfonate. acetate. propionate. tartrate, salicylate, citrate, gluconate, lactate. malate, cinnamate, mandelate, citraconate. aspartate. palmitate, stearate, itaconate. glycolate, p-aminobenzoate, glutamate, ben zeonfulfonate and theophillin acetate as well as salts formed from an amino acid such as lysine or histine salt.

 Examples of inorganic salts of this kind include hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate.

 It has been found that the imidazo-pyridine derivatives of the invention possess remarkable pharmacological properties, especially bradycardic, hypotensive properties. antiadrenergic agents, inhibitors of calcium translocation and local anesthetics.

 These properties are capable of rendering the compounds in question very useful in the treatment of certain pathological syndromes of the cardiovascular system, in particular in the treatment of angina pectoris, hypertension, arrhythmia and cerebral circulatory insufficiency. .

 Depending on the chosen route of administration, the daily dosage for a human weighing 60kg will be between 2 and 500mg of active ingredient.

 Similarly, the compounds of the invention may be used alone or in combination with an anti-inflammatory agent to reduce and / or control excessive intraocular pressure. For this purpose, the corposés of the invention may be used for the treatment of pathological diseases ocular especially in the treatment of glaucoma.

 Generally, 5ng to 0.5mg of active ingredient according to the invention will be administered to each eye, the daily frequency of administration depending on the severity of the condition to be treated.

 Accordingly, the invention also relates to pharmaceutical or veterinary compositions containing as active principle, at least one imidazol derivative, 2-ajpyridine of formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutical vehicle or a suitable excipient.

dans laquelle R, R1 et R2 ont la même signification que précédemment, R'3 a la même signification que R3 précédemment à l'exception du groupe hydroxy et X est choisi parmi un atome d'halogene, de préférence le chlore et le brome, un groupement alkysulfonyloxy en C1 -C4 tel que méthanesulfonyloxy et un groupement arylsulfonyloxy en C6-C10 tels que benzénesulfonyloxy et p-toluènesulfonyloxy, avec une amine de formule générale ::

dans laquelle R 4 et R ont la méme signification que précédemment pour obtenir des dérivés d imidazo/1,2- pyridine de formule I sous forme de base libre, et en soumettant éventuellement le composé obtenu dans lequel R'3 représente un groupe benzyloxy à une hydrogénation catalytique par exemple sur charbon palladié, pour former le dérivé d'imidazo[1,2-a]pyridine de formule I, dans laquelle R3 représente le groupe hydroxy, sous forme de base libre.The compounds of formula I can be prepared by condensing, in an inert solvent such as an alcohol, for example n-butanol or a ketone such as methyl-ethyl ketone, a derivative of alkoxy benzoylimidazo [1], 2-a) pyridine of the general formula

in which R, R1 and R2 have the same meaning as before, R'3 has the same meaning as R3 previously except for the hydroxyl group and X is selected from a halogen atom, preferably chlorine and bromine, a C 1 -C 4 alkysulphonyloxy group such as methanesulphonyloxy and a C 6 -C 10 arylsulphonyloxy group, such as benzenesulphonyloxy and p-toluenesulphonyloxy, with an amine of general formula:

wherein R 4 and R have the same meaning as above to obtain imidazo / 1,2-pyridine derivatives of formula I in free base form, and optionally subjecting the obtained compound wherein R '3 represents a benzyloxy group to a catalytic hydrogenation, for example on palladium on carbon, to form the imidazo [1,2-a] pyridine derivative of formula I, in which R 3 represents the hydroxyl group, in free base form.

Generally, the condensation takes place by heating the reactants to a temperature between 80 and 100 ° C in the presence of a base,
The compounds of formula II may be prepared according to the processes listed below with respect to their chemical structure.

dans laquelle R a la même signification que précédemment, avec un dérivé d'halogénoacétophénone de formule générale

dans laquelle Hal représente un atome d'halogène de préférence le clore ou le brome, R1 et R2 ont la même signification que précédemment et Y est cnoi- sinsrrni'tn radical alkylsulfonyle en C1-C4 par exemple méthanesulfonyle,
un radical arylsulfonyle en C6-C10 par exemple benzènesulfonyle ou
p-toluènesulfonyle , et un radical -AX dans lequel A et X ont la même signification que précédemment, ce qui fournit les dérivés
N-phénacyl-alkanoyl-1 pyridinone-2 imine de formule générale

dans laquelle R, R1, R2 et Y ont la même signification que précédemment.I. When R is located in position 2 of the imidazo [1,2-a] pyridine ring, the mixture is refluxed in a suitable medium, for example benzene or toluene. a 2-amido pyridine derivative of general formula

in which R has the same meaning as above, with a haloacetophenone derivative of the general formula

in which Hal represents a halogen atom, preferably one which terminates it or bromine, R 1 and R 2 have the same meaning as above and Y is, for example, C 1 -C 4 alkylsulfonyl radical, for example methanesulfonyl,
a C 6 -C 10 arylsulfonyl radical, for example benzenesulphonyl or
p-toluenesulfonyl, and a radical -AX in which A and X have the same meaning as above, which provides the derivatives
N-phenacyl-alkanoyl-1-pyridinone-2 imine of the general formula

wherein R, R1, R2 and Y have the same meaning as above.

 The compounds of formula VI are then cyclized in an alkaline medium and at a temperature of between 0 ° C. and room temperature. according to a reaction scheme described in the literature by K. SCHILLING, F.

KRÔHNKE and B. KICKÖFEN in Chem. Ber. 88, 1093 (1955), the cyclization being followed when Y represents an alkylsulfonyl or arylsulfonyl radical firstly by a basic hydrolysis, then by an alkylation with a dihaloalkane of general formula
Hal-A-Hal VII in which A and Hal have the same meaning as above, in a suitable solvent such as for example dichloroethane and in the presence of a basic agent, for example an alkali metal carbonate such as sodium carbonate, which provides the desired compound of formula II.

The compounds of formula V, for their part, can be obtained in the following manner: when Y represents an alkylsulphonyl or arylsulphonyl radical, in
reacting a halide of the general formula
Hal-W VIII
wherein W is selected from a C 1 -C 4 alkylsulfonyl radical, by
example methanesulfonyl and a C 6 -C 10 arylsulfonyl radical, for example
benzenesulfonyl or p-toluenesulfonyl, in an acceptor solvent
acid, for example pyridine, with a ketone of general formula

in which R1 and R2 have the same meaning as previously
then halogenating, for example by brominating, the derivative thus obtained.

in an appropriate solvent such as acetic acid, the disulphide of
carbon or ether, which provides the desired derivative of formula V.

b) when Y represents a radical --X in which X represents a
halogen atom, by reacting a ketone of formula IX with
a haloalkane of formula VII and then halogenating, for example
by brominating the haloalkoxyacetophenone thus obtained, which furnishes
nitrate the desired compound of formula V, c) when Y represents a radical -AX in which X represents a
alkylsulfonyloxy or arylsulfonyloxy group by reacting a
ketone of formula IX first with a hydroxy-haloalkane of
general mule
Hal-A-OH X
in which Hal and A have the same meaning as before.

then with a halide of formula VIII and then halogenating by
example by bromination of the sulfonyloxyacetophenone obtained, to give
the desired compounds of formula V.

Acetophenones of formula IX are known compounds or
be prepared by known methods.

dans laquelle R'3 a la même signification que précédemment, avec le N,Ndiméthylformamide, le diméthylacétal ou le triéthylorthoformiate dans un solvant approprié tel que le benzène, le toluène ou le xylène ce qui fournit les composés de formule générale

dans laquelle R et R' ont la même signification que précédemment.II - When R is located at the 3-position of the imidazoel (2-a) pyridine ring,
An aminopyridine of general formula is reacted

wherein R'3 has the same meaning as above, with N, Ndimethylformamide, dimethylacetal or triethylorthoformate in a suitable solvent such as benzene, toluene or xylene which provides the compounds of general formula

in which R and R 'have the same meaning as above.

dans laquelle R1. R2 et Hal ont la même signification que précédemment pour donner les dérivés hydroxy-4 phényle de formule générale

dans laquelle R, R1 R2 et R'3 ont la même signification que précédemment.The compounds of formula XII are then condensed at reflux with an α-haloketone of general formula

in which R1. R2 and Hal have the same meaning as above to give the 4-hydroxyphenyl derivatives of the general formula

in which R, R1 R2 and R'3 have the same meaning as above.

The 4-hydroxyphenyl derivatives of formula XIV may be subsequently treated a) with a haloalkane of formula VII. which provides the desired compound
of formula II wherein X represents a halogen atom b) with a hydroxy-haloalkane of formula X and then with a halide of formula VIII to give the desired compounds of formula II wherein X represents an alkylsulfonyloxy or arylsulfonyloxy group.

dans laquelle R1 et R2 ont la même signification que précédemment.The α-halokoketones of formula XIII can be produced by reacting at urep-hydroxyacetophenone reflux of general formula

wherein R1 and R2 have the same meaning as above.

with a halogen for example brominated bromine, in a suitable solvent. such as an ether. glacial acetic acid or carbon disulfide.

dans laquelle R, R1, R2 et R'3 ont la même signification que précédemment avec un composé de formule générale

dans laquelle R4 et R5 ont la même signification que précédemment et
X a la même signification que précédemment et représente de préférence le chlore ou un radical benzènesulfonyloxy ou p-toluènesulfonyloxy la réaction ayant lieu au reflux et dans un solvant polaire telle que la méthyl-éthyl-cétone pour obtenir les dérivés d'imidazo[l,2-a)pyridine de formule I sous forme de base libre et en soumettant éventuellement le composé obtenu dans lequel R'3 représente un groupe benzyloxy à une hydrogénation catalytique pour former le dérivé d'imidazo[1,2-a]pyridine de formule I dans laquelle R3 représente le groupe hydroxy, sous forme de base libre.According to a variant of S, the imidazo [1,2-aipyridine of formula I can also be obtained by reacting. in the presence of a basic agent such as an alkali metal carbonate, for example potassium carbonate. an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal hydride such as sodium hydride or an alkali metal alkoxide for example sodium methoxide or ethylate. a benzoyl derivative of general formula

in which R, R1, R2 and R'3 have the same meaning as above with a compound of the general formula

in which R4 and R5 have the same meaning as before and
X has the same meaning as before and preferably represents chlorine or a benzenesulphonyloxy or p-toluenesulphonyloxy radical, the reaction being carried out under reflux and in a polar solvent such as methyl-ethyl-ketone to obtain the imidazo [1 derivatives, 2-a) pyridine of formula I in free base form and optionally subjecting the obtained compound wherein R '3 represents a benzyloxy group to a catalytic hydrogenation to form the imidazo [1,2-a] pyridine derivative of the formula Wherein R3 represents the hydroxy group, in free base form.

dans laquelle R et R'3 ont la même signification que précédemment, avec un halogénure d'acyle de formule générale

dans laquelle Hal, R1 et R2 ont la même signification que précédemmen. The compounds of formula XVI may be obtained by heating under reflux in a suitable medium, for example toluene or xylene and in the presence of an acid acceptor, for example triethylamine, an imidazo-pyridine derivative of general formula

in which R and R'3 have the same meaning as above, with an acyl halide of general formula

in which Hal, R1 and R2 have the same meaning as above.

and Y 'represents a C1-C4 alkylsulfonyl radical or a C6-C10 arylsulphonyl radical, the reaction taking place in the presence of an a = XFblr acid such as triethylamine, and then hydrolyzing in the presence of an alkaline agent such as an alkali metal hydroxide, for example sodium hydroxide, and reacting the salt thus obtained with a strong acid, for example hydrochloric acid, to obtain the desired poses of formula XVI
The compounds of formulas XVIII and XIX are known compounds which can be prepared according to known methods.

According to another method, the compounds of formula
I or XVI in which R 1 and R 2 are respectively at the 3 'and 5' positions and each represents a chlorine, bromine or iodine atom, by reacting a compound of formula I in which
R 1 and R 2 each represent hydrogen or a compound of formula XVI in which R 1 and R 2 each represent hydrogen a) or with N-chlorosuccinimide, the reaction taking place in a
appropriate medium such as dichloroethane between O "C and tempe
ambient, to obtain the desired derivative in the form of a base
free radical in which R 1 and R 2 each represent chlorine, b) either with bromine or iodine, the reaction taking place in a solvent
suitable as dioxane or N, N-dimethylformamide and in pre
the presence of an alkali metal acetate, for example sodium acetate,
to obtain the desired derivative, in free base form, in which
R1 and R2 each represent bromine or iodine.

 The compounds of formula I thus obtained in free base form can then be converted into pharmaceutically acceptable salts by reaction with a suitable organic or inorganic acid, for example oxalic acid, maleic acid, fumaric acid, methanesulphonic acid, benzoic acid, ascorbic acid, pamoic acid or succinic acid. , hexamic, bismethylenesalicylic, ethanedisulfonic, acetic, propionic, tartaric, salicylic.

citric, gluconic, lactic, malic, cinnamic, mandelic, citraconic, aspartic, palmitic, stearic, itaconic, glycolic.

 p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic.

lysine or histidine.

dans laquelle X est choisi parmi l hydrogene, un radical hydroxy. alkoxy en C1 -C3. benzyloxy et alkyle en
C1-C6; R' est choisi parmi l'hydrogène et un groupement Ar; R 1 est choisi parmi l'hydrogène. un groupement méthyle et Ar: Ar représentant un groupement

dans lequel R 2 représente un radical alkyle en C1-C6.EP-A-0 261 912 describes derivatives aryl-2 or -3 imidazo [1,2-a] pyridine having the general formula

wherein X is selected from hydrogen, a hydroxy radical. C1-C3 alkoxy. benzyloxy and alkyl
C1-C6 alkyl; R 'is selected from hydrogen and an Ar group; R 1 is selected from hydrogen. a methyl group and Ar: Ar representing a grouping

in which R 2 represents a C 1 -C 6 alkyl radical.

n 'is 0 or 1 when R' is Ar or n 'is 1 when R 1 is Ar; m is an integer from 2 to 6, provided that one of R or R'1. but not both simultaneously. represents the group
Ar.

 These compounds are mentioned as having, in particular, anticalcic properties.

 Surprisingly, it has been found that the compounds of the invention, while having an anti-calcium activity, are also endowed with important antiadrenergic properties which are not possessed by the previous compounds or only at derisory levels.

 These antiadrenergic properties effectively complement the spectrum of cardiovascular activity exhibited by the compounds of the invention giving them indisputable advantages over previous compounds as will be explained later.

 It has been reported in detail by R. CHARLIER in "Bruxelles Medical", No. 9, September 1969, pages 543-560. that an anti-anginal medication must be capable in particular of antagonizing cardiovascular reactions of the adrenergic type.

 For this purpose. agents capable of blocking alpha receptors have been proposed.

 However. the clinical application of such compounds to the treatment of angina was unsuccessful most probably due to the fact that the receptor antagonists induce only a very partial neutralization of the adrenergic system, the activity of the ss receptors being respected.

 However, the most undesirable hemodynamic manifestations that occur in the angina during painful accesses are primarily cardiac and thus reveal SS receptors.

 In parallel. antagonistic adrenergic receptor medications have been proposed. These compounds, of real clinical interest, reduce angina attacks by reducing cardiac work by slowing down the heart rate. However, there is no fall of peripheral arterial resistances - but on the contrary an elevation by release of the tone.

 These treatments, however, modify certain hemodynamic parameters in a sense that. fundamentally, is an adverse counterpart to the angina pectoris in particular and the cardiac in general.

 If we consider the anti-adrenergic appearance of A-blockers, it becomes clear that only tachycardia and increased cardiac contractility are likely to be neutralized, arterial hypertension being a function of stimulation of alpha-receptors; on which the antagonists have no action.

 Or. If the cardiovascular disturbances caused by the stimulation of the receptors are the most prejudicial to angina. there is nothing left of it except that arterial hypertension also plays a role which is not negligible.

 In addition. the blocking of the receptors carries a risk depriving the cardiac insufficiency of a compensating mechanism which it normally puts into play to limit its circulatory insufficiency.

 This reflex mechanism whose main component borrows the path of the ss-adrenergic system results notably in an increase in the power and velocity of the cardiac contraction. Therefore, if this system is blocked. heart failure is aggravating its functional failure. It is therefore logical to consider that the use of a ss-blocker whose action is pure and complete will always involve a cardiac risk.

 it therefore seems desirable not to seek antagonistic properties α or ss complete, given the side effects they can cause in clinic. It seems more logical to aim at amortizing rather than suppressing the dive-scala disturbances that characterize hyperstimulation of the adrenergic system as a whole.

 The compounds of the invention meet this objective since they have antiadrenergic properties of 0k and ss incomplete type. They can therefore be considered. not as anti-blockers but as adreno-drugs. i.e., partial antagonists of the adrenergic reactions α andp potentially lacking the disadvantages listed above for A -blockers.

In addition. the calcium inhibitory component demonstrated in the compounds of the invention will remarkably supplement their cardiovascular pharmacological spectrum.
We know, indeed. that the translocation of calcium ions is one of the essential components of the action potential in cardiac cells and that. as such. it plays a key role in electrical conduction as well as in its possible disorders (arrhythmia). In addition. it is known that calcium ions are involved in excitation-contraction coupling which control. at the level of smooth musculature. the degree of vasoconstriction and.

at the same time plays a critical role in the angina pectoris crisis.

 Calcium antagonist compounds act at the level of the cell membrane by selectively preventing calcium from intervening in the contraction process within the arterial cell.

 Now, it appears more and more obvious, at present. that the clinical results provided by a combination of calcium channel blockers and β-adrenergic inhibitors are better than when each inhibitor is used alone [J.A.M.A. 1982, 247, pages 1911-1917).

 It seems, moreover. that it does not exist at present. no ss-blocker exerting in addition an appreciable inhibitory action at the level of the calcium translocation.

 From this point of view. the compounds of the invention having both an antiseptic component and an antiadrenergic component α and r will be of primary interest as they are likely to have broader therapeutic applications than an isolated -blocker or isolated calcium channel blocker. By way of example, mention may be made of 2-ethyl-3- [3- (3-di-n-butylamino) -propoxy) benzoyl] imidazo [1,2-a] pyridine, n-butyl-2 - ( 3-di-n-butylamino-3-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine.

2-phenyl-3,5-dibromo-3- (3-di-n-propylamino-propoxy) benzoyl] imidazo [1,2-a] pyridine.

The results of pharmacological tests carried out to determine the cardiovascular properties of the compounds of the invention are listed below.
I. Calcium inhibitory properties
The inhibitory properties of calcium translocation at the membrane level exhibited by the compounds of the invention have been demonstrated by measuring their antagonistic action with respect to the contractile response to dyarisatioe for the assiun on the isolated acrte of rat. It is well established that the depolarization of the membrane of a smooth muscle by potassium makes the latter permeable to extracellular calcium and causes muscle contraction.

Therefore, the measure of the inhibition of the contractile response to potassium depolarization or the measurement of relaxation of tonic contraction to potassium depolarization may be an assessment of the potency of a compound as a potency inhibitor. membrane permeability to Ca ions
The technique used is the following
In male Wistar rats weighing about 300 g, the aorta is removed and cut into strips of about 40 mm in length and 3 mm in width. These fragments are placed in a 25 ml isolated organ container containing Krebs-bicarbonate solution. modified (112 mM NaCl, 5 mM KCl, 25 mM NaHCO 3, 1 mM KH 2 PO 4, 1.2 mM MgSO 4, 2.5 mM CaCl 2, 11.5 mM glucose, distilled water up to 1000 ml), followed by a stream of carbogen and maintained at 37 C. The preparation is connected to a force microsensor and the contractile response is recorded after amplification on a recorder.

A voltage of 2 g is applied to the preparation. This is maintained for 60 minutes in the modified Krebs-bicarbonate solution and the contractions are then induced by replacing the Krebs-bicarbonate solution with a Krebs-potassium solution (17 mM NaCl, 100 mM KCl;
25 mM NaHCO3; 1mM KH2PO4; 1.2 mM MgSO4; 2.5 mM CaCl2; 11.5-mM glucose; distilled water up to 1000 ml). When the contractile response of the preparation has become reproducible, a given amount of a compound of the invention is introduced into the bath. Sixty minutes later a new spasm is caused by potassium depolarization.

 The results obtained on the tested aorta are then expressed as 7. of the maximal contracting effect before the incubation with the substance to be tested.

a) s la dose de 10-7M

As examples, the following results were obtained

a) s the dose of 10-7M

<tb> Compounds <SEP> R <SEP> R1 <SEP> R2 <SEP> | <SEP> R4 <SEP> R5 <SEP> 7. <SEP> of <SEP> the effect
<tb><SEP> contracting
<tb><SEP> maximum
<tb><SEP> Ex. <SEP> 1 <SEP> C2H5 <SEP> H <SEP> H <SEP> n-c4H9 <SEP> n-C4Hg <SEP> 76.5
<tb><SEP> Ex. <SEP> 6 <SEP> n-C4H9 <SEP> H <SEP> F. <SEP> n-C4Hg <SEP> n-C4Hg <SEP> 45.1
<tb> Ex. <SEP> 9 <SEP> ~ <SEP> O <SEP> H <SEP> H <SEP> n-C4Hg <SEP> n-C4H9 <SEP> 70
<tb><SEP> Ex.13 <SEP><9<SEP> Br <SEP> Br <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 60
<tb> b) At the dose of lG M

<tb> Ex. <SEP> 6 <SEP> n-C4H9 <SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 88.9
<tb> II. Antiadrenergic properties
The purpose of this test is to determine the ability of the compounds of the invention to reduce the increase in the blood pressure induced by epinephrine (anti-effect) and the acceleration of the isoprenaline-induced heart rate (effect anti-ss) in dogs previously anesthetized with pentobarbital and atropine.

 The dose of epinephrine (between 3 and 10 μg / kg) is first determined for each dog, which causes a reproducible increase in blood pressure of approximately 133 × 10 2 Pa and the dose of isoprenaline (1 which causes a reproducible increase in the heart rate is approximately 70 beats / minute, the dose of epinephrine and isoprenaline thus determined is injected alternately every ten minutes and after obtaining two successive reference responses, an amount of the test compound is administered intravenously. .

- Anti-a-effect
The percentage reduction in hypertension caused by the test compound is recorded as compared to the reference hypertension obtained previously (approximately 100 nm Hg).

-Effect anti-6
The percentage reduction in the heart rate acceleration caused by the test compound compared to the previously measured baseline tachycardia (approximately 70 beats) is recorded.

In both cases, the results of the reduction in blood pressure or heart rate were expressed as follows
+ for a discount <50%
++ for a reduction> 50%
+++ for a sub-total reduction (almost complete reduction)
The following results were recorded

Compounds <SEP> R <SEP> R1 <SEP> R2 <SEP> R4 <SEP> R5 <SEP> Dose <SEP> Effect <SEP> anti- &alpha;<SEP> Effect <SEP> anti-ss
<tb><SEP> (mg / kg)
<tb> Ex. <SEP> 1 <SEP> -C2H5 <SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 10 <SEP> ++ <SEP> ++
<tb> Ex. <SEP> 3 <SEP> n-C3H7 <SEP> H <SEP> H <SEP> n-C3H7 <SEP> n-C4H9 <SEP> 10 <SEP> +++ <SEP> ++ +
<tb> Ex. <SEP> 4 <SEP> n-C3H7 <SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C3H7 <SEP> 10 <SEP> +++ <SEP> ++ +
<tb> Ex. <SEP> 5 <SEP> n-C4H9 <SEP> H <SEP> H <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 6 <SEP> ++ <SEP> ++
<tb> Ex. <SEP> 6 <SEP> n-C4H9 <SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 3 <SEP> ++ <SEP> ++
<tb> Ex. <SEP> 10 <SEP>#<SEP> H <SEP> H <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 10 <SEP> + <SEP> +
<tb> Ex. <SEP> 11 <SEP>#<SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 10 <SEP> ++ <SEP> +++
<tb> Ex. <SEP> 18 <SEP>#<SEP> H <SEP> H <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 5 <SEP> + <SEP> +
<Tb>

Ex. <SEP> 13 <SEP>#<SEP> Br <SEP> Br <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 10 <SEP> +++ <SEP> +++
<tb> Ex. <SEP> 14 <SEP>#<SEP> Br <SEP> Br <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 10 <SEP> ++ <SEP> +
<tb> Ex. <SEP> 12 <SEP>#<SEP> Br <SEP> Br <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 10 <SEP> + <SEP> +
<tb> Ex. <SEP> 19 <SEP>#<SEP> Br <SEP> Br <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 10 <SEP> + <SEP> +
<tb> Ex. <SEP> 20 <SEP>#<SEP> Br <SEP> Br <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 5 <SEP> + <SEP> +
For comparison, the anti-adrenergic effects of the compounds of formula I 'below, compounds covered by EP-A-0261912, have been determined.

Compounds <SEP> R <SEP> R1 <SEP> R2 <SEP> R4 <SEP> R5 <SEP> Dose <SEP> Effect <SEP> anti- &alpha;<SEP> Effect <SEP> anti-ss
<tb><SEP> (mg / kg)
<tb> A <SEP> H <SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 10 <SEP> 0 <SEP> 0
<tb> B <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 10 <SEP> 0 <SEP> 0
<tb> C <SEP> CH3 <SEP> H <SEP> H <SEP> C2H5 <SEP> C2H5 <SEP> 10 <SEP> 0 <SEP> 0
<tb> D <SEP> CH3 <SEP> H <SEP> H <SEP> n-C3H7 <SEP> n-C3H7 <SEP> 10 <SEP> 0 <SEP> 0
<tb> E <SEP> CH3 <SEP> H <SEP> H <SEP> n-C4H9 <SEP> n-C4H9 <SEP> 10 <SEP> + <SEP> 0
<Tb>
These results show that the compounds of the invention have antiadrenergic properties undoubtedly more interesting than the previous compounds.

Iii. Toxicity
The toxicity revealed by the compounds of the invention has proved compatible with their use in therapy.

 The therapeutic compositions according to the invention may be presented in any form suitable for administration in human or veterinary therapy. As regards the administration unit, this may take the form of, for example, a tablet, a dragee, a capsule, a capsule, a powder, a suspens ion or syrup for oral administration, suppository for rectal administration or solution or suspension for parenteral administration.

 The therapeutic compositions of the invention may comprise, per unit of administration, for example from 50 to 500 mg by weight of active ingredient for oral administration, from 50 to 2 mg of active ingredient for rectal administration and from 50 to 500 mg of active ingredient for oral administration. at 150mg of active ingredient for parenteral administration.

 Depending on the route of administration chosen, the therapeutic or veterinary compositions of the invention will be prepared by combining at least one of the compounds of formula I or a pharmaceutically acceptable salt of this compound with a suitable excipient, the latter possibly consisting of, for example, at least one ingredient selected from the following substances: lactose, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or sweetening agents.

The following nonlimiting examples illustrate the invention
EXAMPLE 1
Preparation of 2-ethyl 2- (3-di-n-butylamino-3-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine oxalate (LB 31468) a) (3-chloro-propoxy) hydrobromide phenacyl] -In-propionyl
pyridone 2 imine.

 To 45 g (0.3 mol) of propionylamino-2-pyridine dissolved in 500 ml of benzene, 87 g (0.3 mol) of 3- (3-chloro-propoxy) -bromoacetophenone are added. The reaction mixture is then refluxed for 24 hours and then cooled to room temperature. The desired hydrobromide is thus precipitated and this precipitation is completed with petroleum ether. The hydrobromide is filtered, dried and used as is in the next step.

Using the same process as above, the following compounds were prepared:
compounds
E-4- (3-chloro-propoxy) -phenacyl) -N-butyroyl-pyridone-2-imine hydrobromide.

4 - [(3-chloro-propoxy) phenacyl] -1-N-valeroyl-pyridone-2-imine hydrobromide.

[(3-Bromo-4-propoxyphenacyl] -1-N-propionyl-2-pyridone imine hydrobromide.

b) 2-ethyl-3- (3-chloro-propoxy) benzoyl] imidazo [1,2-a] pyridine
To a solution of 105 g (0.23 mol) of 4 - [(3-chloro-propoxy) phenacyl] -1-N-propionyl-2-pyridone imine hydrobromide in a mixture of water and methanol previously cooled to 0 ° C. 181 ml (0.35 mol) of 2N potassium carbonate are added dropwise. Stirring is maintained for about 8 hours and then the precipitate formed is filtered, dried and purified by dry column chromatography on silica using ethyl acetate as eluent. The collected product is filtered and then recrystallized from cyclohexane.

 Of this. In this way, 2-ethyl-3- (3-chloro-propoxy) benzoyl-3-imidazo (1,2-a) pyridine is obtained in 38% yield.

PF: 82 ° C
Using the same process as above, the following compounds were prepared:
Compound n-Propyl-2 - ((3-chloro-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine
Mp: 66 C (cyclohexane) n-Butyl-2 - [(3-chloro-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine
Oil
Ethyl-2 - [(3-bromo-propoxy) -4-benzoyl-imidazo [1,2-a] pyridine
Mp: 155 C (methanol) (c) 2-ethyl-2- (3-di-n-butylamino-propoxy) benzoyl] -3-imiazo oxalate
[1,2-a] pyridine.

 To a solution of 6.25 g (0.02 mole) of 2-ethyl-3- (3-chloro-propoxy) benzoyl-3-imidazo [1,2-a] pyridine in 120 ml of n-butanol, 13 5 ml (0.08 mol) of di-n-butylamine and the reaction medium is heated at 85 ° C. for 20 hours. The solution is then evaporated to dryness, the oily residue is dissolved in ethyl ether and washed with a dilute solution of sodium hydroxide and then with water.

The organic phase is evaporated to dryness and the residue obtained is taken up in acetone, to which a methanolic solution of oxalic acid is added. The desired oxalate which has precipitated is then recrystallized from an acetone / methanol mixture.

 In this way, 2-ethyl-2- (3-di-n-butylamino-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine oxalate is obtained.

M.p .: 88 C.

Following the same procedure as described above, the following compounds were prepared:
compounds
2-ethyl-2 - [(di-n-propylamino) -3-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine oxalate (LB 31469) (Example 2)
PF: 157 C (acetone)
2- (3-Di-n-propylamino-3-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine oxalate (LB 31276) (Example 3)
PF: 146 C (acetone / methanol)
2-N-propyl-2- (3-di-n-butylamino-3-propoxy) oxaloyl 3-benzoyl imidazo [1,2-a] pyridine (LB 31277) (Example 4)
PF: 86 C (acetone / methanol)
2-N-Butyl-2 - [(3-di-n-propylamino-3-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine oxalate (LB 31470) (Example 5)
PF: 143 C (acetone)
2-N-butyl-2 - [(3-di-n-butylamino-3-propoxy) benzoyl] -3-imidazc [1,2-a] pyridine oxalate (LB 31392) (Example 6)
PF: 84 C (acetone)
EXAMPLE 7
Preparation of (4-chloro-phenyl) -2 - [(3-di-n-butylamino-3-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine hydrochloride (LB 32367) a) (4-chlorophenyl) 2- (4-tosyloxy-benzoyl) -3-imidazo [1,2-a] pyridine
2.28 g (0.01 mole) of (4-chlorophenyl) imidazo [1,2-a] pyridine, 4.37 g (0.014 mole) of 4-tosyloxy benzoyl chloride and 3 ml (0.02 mole) of triethylamine in 30 ml of xylene.

 The solution is boiled for one hour and then the triethylamine hydrochloride formed is filtered off. The solution is washed with water, dried over calcium chloride and evaporated to dryness.

The residue obtained is then recrystallized from dichloroethane.

 In this way, (4-chloro-phenyl) -2- (4-tosyloxybenzoyl) imidazo [1,2-a] pyridine is obtained with a yield of 7C%.

M.p .: 208 C.

Using the same process as above, the following compounds were prepared:
compounds
Phenyl-2 (tosyloxy-4-benzoyl) -3-imidazo [1,2-a] pyridine
Mp: 190 ° C (ethyl acetate)
Phenyl-2 (3-bromo-4-tosyloxy-benzoyl) -3-imidazo [1,2-a] pyridine
PF: 100 C.

(4-Bromo-phenyl) -2- (4-tosyloxy-benzoyl) -3-imidazo [1,2-a] pyridine
PF: 2100c (methanol) (4-fluoro-phenyl) -2 (tosyloxy-4-benzoyl) -3-imidazo [1,2-a] pyridine
Mp: 2126C (chloroform) b) (4-chloro-phenyl) -2- (4-hydroxybenzoyl) -3-imidazo [1,2-a] pyridine
50 g (0.1 mole) of 2- (4-chlorophenyl) (4-tosyloxybenzoyl) imidazo (112-a) pyridine dissolved in 920 ml of ethanol are added 28 g (0.7 mole) of hydroxide. of sodium dissolved in the prelude in 150ml of water. The mixture is refluxed for 24 hours and then the solution is brought to room temperature. It is neutralized by addition of hydrochloric acid and precipitation of the hydroxyl compound is observed which is filtered and dried.

 In this way, 4- (4-chlorophenyl) (4-hydroxy benzoyl) imidazo [1,2-a] pyridine is obtained in 90% yield.

M.p .: 250 C.

Following the same procedure as above, the following compounds were prepared:
compounds
Phenyl-2 (4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
PF:> 225 C
Phenyl-2 (3-bromo-4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
Mp: 256 C (4-Bromo-phenyl) -2 (4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
PF:> 260 C.

(4-Fluoro-phenyl) -2- (4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
PF:> 260 ° C.

2-Ethyl-3-bromo-4-hydroxy-benzoyl-3-imidazo [1,2-a] pyridine
M.p. 260 ° C.

c) (4-Chloro-phenyl) -2 - [(3-chloro-propoxy) benzoyl] -3-imidazo [1,2-a]
pyridine.

 To 10.4 g (0.03 mol) of 4- (4-chlorophenyl) -2- (4-hydroxybenzoyl) imidazo [1,2-a] pyridine in 200 ml of methyl ethyl ketone, 102 g of sodium carbonate are added. potassium.

The mixture is heated for one hour at 90 ° C. and then, with stirring, it is poured into a solution of 6.5 ml of 1-bromo-3-chloropropane in 30 ml of methyl ethyl ketone. Heating is continued for 20 hours and then the reaction medium is cooled. Filter, wash with water and evaporate to dryness. The residue is then recrystallized from a benzene / hexane mixture.

In this way, 2- (4-chlorophenyl) - [(3-chloro-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine is obtained with a yield of 78%.
PF: 125 ° C.

Using the same process as above, the following compounds were obtained:
compounds
Phenyl-2 - [(3-chloro-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine
PF: 113 C (benzene / hexane) (4-bromo-phenyl) - [(3-chloro-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine
Mp: 1260C (hexane / dichloroethane) d) 4- (4-chloro-phenyl) -2- [(di-n-butylamino-propoxy)] hydrochloride
benzoyl] -3 imidazo [1,2-a] pyridine.

 In 40 ml of n-butanol, 3.2 g (0.0075 mol) of 4- (chloro-4-phenyl) -2- (3-chloro-propoxy) benzoyl] -3-imidazo (1,2-a) pyridine are dissolved in 7.95ml of di-n-butylamine. The reaction mixture is heated at 95 ° C for 24 hours and then the solvent is removed. The oily residue is taken up in ethyl ether and the organic phase is washed with dilute hydrochloric acid. The aqueous phase is neutralized and extracted with ethyl ether. The ether solution is evaporated to dryness and the desired compound is thus obtained in free base form. The corresponding hydrochloride is then formed by dissolving the base in diisopropyl ether and adding a stoichiometric amount of 1N hydrochloric acid.

 In this manner, (4-chloro-phenyl) -2- (3-di-n-butylaminopropoxy) benzoyl-3-imidazo [1,2-a] pyridine hydrochloride was collected in 69% yield after purification.

M.p .: 120 C.

Following the same procedure as above, the following compounds were prepared:
compounds
2-phenyl-2 - [(3-di-n-propylamino-3-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine oxalate (LB 31272) (Example 8)
PF: 141 C.

2-phenyl-2 - [(3-di-n-butylamino-3-propoxy) benzoyl-3-imidazo [1,2-a] pyridine oxalate (LB 31273) (Example 9)
Mp: 115 ° C (acetone / methanol)
4- (4-Bromo-phenyl) -2 - [(3-di-n-propylamino-3-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine oxalate (LB 32126) (Example 10)
Mp: 89 C (acetone) (4-bromo-phenyl) -2 - [(3-di-n-butylamino-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine (LB 32127) (Example 11)
PF: 77 C.

EXAMPLE 12
Preparation of (4-bromo-phenyl) -2-dibromo-3,5-di-n-butylamino-3-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine hydrochloride (LB 32274) a) (Bromo-4) phenyl) -2 (3,5-dibromo-4-hydroxybenzoyl) -3-imidazo [1,2-a]
pyridine
To a solution of 6.5 g (0.016 mole) of 4- (4-bromo-phenyl) -2- (4-hydroxy benzoyl) imidazo [1,2-a] pyridine in 1 g of N, N-dimethylformamide and 35 ml of dioxane, containing 3.4 g of sodium acetate, a solution of 1.8 ml of bromine in 20 ml of N, N-dimethylformamide is introduced dropwise and with stirring. After the addition, the reaction medium is left at room temperature for 2 hours and then filtered and washed with water the precipitate formed. The dibromo compound is then purified by recrystallization from a dichloroethane / ethanol mixture.

 In this way, 4- (4-bromo-phenyl) (3,5-dibromo-4-hydroxybenzoyl) imidazo [1,2-a] pyridine is obtained in 75% yield.

M.p .:> 260 C.

Following the same procedure as previously described, the following compounds were prepared:
compounds
Phenyl-2 (3,5-dibromo-4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
Mp: 269 C (chloroform / ethanol) (4-chloro-phenyl) -2 (3,5-dibromo-4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
Mp: 260 C (dichloroethane / ethanol) (4-Fluoro-phenyl) -2 (3,5-dibromo-4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine
PF: 246 C.

b) (4-Bromo-phenyl) -2 [3,5-dibromo-3- (3-chloro-propoxy) benzoyl] -3
imidazo [1,2-a] pyridine
The (4-bromo-phenyl) -2 (3,5-dibromo-4-hydroxy-benzoyl) -3-imidazo [1,2-a] pyridine alkylation was carried out with 1-bromo-3-chloropropane according to the method described in US Pat. Example 2c).

 In this manner, 2- (4-bromo-phenyl) [3,5-dibromo-3- (3-chloro-propoxy) benzoyl] imidazo [1,2-a] pyridine was obtained in 85% yield.

PF: 151 C (benzene)
Using the same method as that described above, 2-phenyl-3,5-dibromo-3- (3-chloro-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine was prepared.

Mp: 144 C (benzene / hexane) c) 4- (bromo-4-phenyl) -hydrochloride [3,5-dibromo-di-n-butylamino]
propoxy) -4-benzoyl] -3-imidazo [1,2-a] pyridine.

 This compound was prepared from 2- (3-bromo-phenyl) [3,5-dibromo-3- (3-chloro-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine and di-n-butylamine. according to the method described in Example 2d).

 In this manner, 2- (bromo-4-phenyl) -2-dibromo-3,5-di-n-butylamino-3-propoxy-4-benzoyl-3-imidazo [1,2-a] pyridine hydrochloride is obtained with a yield of 23%.

PF: 90 C (isopropanol)
Using the same method as that described above, the following compounds were prepared:
compounds
2-Phenyloxalate [3,5-dibromo-3- (3-di-n-propylaminopropoxy) benzoyl] imidazo [1,2-a] pyridine (LB 31961 (Example 13)
PF: 87C (acetonelmethanol)
2- (3,5-Dibromo-3- (3-di-n-butylamino-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine oxalate (LB 31962) (Example 14)
PF: 76 C (acetone / methanol)
4- (4-Bromo-phenyl) hydrochloride [3,5-dibromo-3- (3-propynaphtinopropoxy) benzoyl) -3-imidazo [1,2-a] pyridine (LB 32273) (Example 15)
PF: 163 C (isopropanol)
EXAMPLE 16
Preparation of 2- (4-chloro-phenyl) hydrochloride [3,5-dibromo-3- (3-di-n-butylamino) -propoxy) benzoyl-3-imidazo [1,2-a] pyridine (LB 32419)
5 g (0.01 mol) of 4- (4-chloro-phenyl) -3-dibromo-4-hydroxy-benzoyl-3-imidazo [1,2-a] pyridine and 5.5 g of potassium carbonate are refluxed. in 60ml of dichloroethane.

To this medium is then added 3 μg (C, 015 mol) of chloro-1-di-n-butylamino-3 propane dissolved in 1 ml of dichloroethane and 3 ml of water.
The refluxing is continued for 2.5 hours and then the reaction medium is washed with water. The organic phase is dried over magnesium sulfate and then evaporated to dryness.

It is then resumed in isopropanol. the oily residue containing the desired product under free base and then a stoichiometric amount of 1N hydrochloric acid is added. The precipitated hydrochloride is then recrystallized from ethyl acetate.

 In this way, 2- (4-chloro-phenyl) [3,5-dibromo-3- (3-di-n-butylamino-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine hydrochloride is obtained with 75% yield.

M.p .: 168 C.

Following the same process as that described above, the following compounds were prepared:
compounds
2- [4-Chlorophenyl] hydrochloride [3,5-dibromo-3- (3-propylaminopropoxy) benzoyl] imidazo [1,2-a] pyridine (LB 32418) (Example 17)
Mp: 176 C (ethyl acetate)
3- [4-Fluoro-phenyl] -2- [(3-di-n-propylamino-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine hydrochloride (LB 32476) (Example 18)
Mp: 104 C (isopropanol / ethyl acetate)
2- (4-Fluoro-phenyl) hydrochloride [3,5-dibromo-3- (3-di-n-propylamino) propoxy) benzoyl] imidazo [1,2-alpyridine (LB 32476) (Example 19)
Mp: 161 C (ethyl acetate)
4- (4-Fluoro-phenyl) -4-tetbromo-3,5-di-n-butylamino-propoxy) benzoyl] -3-imidazo [1,2-aipyridine hydrochloride (LB 32477) (Example 20s)
Mp: 168 C (ethyl acetate)
2- [3-Bromo-3- (3-di-n-propylamino-3-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine sesquioxalate (-B 32219) (Example 21)
PF: 154-155 ° C (isopropanol)
2- (3-Bromo-3- (3-di-n-butylamino-3-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine oxalate (LB 32220) (Example 22)
PF: 120-122 C (isopropanol)
2-ethyl-3- [3-bromo-3- (3-di-n-propylamino-propoxy) benzoyl) -3-imidazo [1,2-a] pyridine hydrochloride (LB 32486) (Example 23)
PF: 1690C (ethyl acetate)
2-ethyl-3- [3-bromo-3- (3-di-n-butylamino-propoxy) benzoyl] -3-imidazo [1,2-a] pyridine hydrochloride (LB 32487) (Example 24)
M.p .: 122-124C (ethyl acetate)
EXAMPLE 25
According to known pharmaceutical techniques, capsules containing the following ingredients have been prepared. Ingredient
Compound of the invention 100
Starches 99.5
Colloidal silica 0.5
200.0
EXAMPLE 26
In accordance with known pharmaceutical techniques, suppositories containing the following ingredients have been prepared
Ingredient
Compound of the invention 10G
Mixture of mono- and di-glycerides of saturated acids (C12 to C18) 1400
1500

Claims (12)

R3 is selected from hydrogen, halogen. R1 and R 2 'identical or different. are chosen from hydrogen, methyl, methoxy and a halogen atom, R is selected from linear or branched C 2 -C 6 alkyl, C 3 -C 6 cycloalkyl and phenyl unsubstituted or substituted by one or more identical or different substituents selected from halogen atoms and C 1 -C 6 alkyl groups; -C4, C1-C4 alkoxy and nitro,  in which

 1, imidazo [1,2-a] pyridine derivatives of general formula:  C1-C4 and C1-C4 alkoxy groups.  among halogen atoms. alkyl groups  identical or different substituents selected R4 is chosen from a linear or branched C3-C6 alkyl radical and a radical of formula -Alk-R6 in which Alk represents a single bond or a linear or branched C1-C5 alkylene radical and R6 is chosen from a radical pyridyl, phenyl, 2,3-methylenedenedioxyphenyl, 3,4-methylenedioxyphenyl and a phenyl group substituted with one or more A represents a linear or branched C2-C6 alkylene radical, a hydroxy, C1-C4 alkyl, C1-C4 alkoxy and benzyloxy radical,  ceptable.  phenyl. as well as their pharmaceutically ac  being chosen from a C 1 -C 4 alkyl radical and  optionally substituted by a phenyl radical or optionally interrupted by -O-, -NH-, -N = or -N-R7, R7  a C3-C6 alkylene or alkenylene radical  or R4 and R5. when taken together, represent  in C3-C6,  R5 is chosen from hydrogen and an alkyl radical 2. Imidazo [1,2-a] pyridine derivatives of formula I as claimed in claim 1  in which A represents the propylene radical. 3. Imidazo [1,2-a3pyridine derivatives of formula I as claimed in claim 1  wherein R3 is hydrogen. 4. Imidazo [1,2-a] pyridine derivatives of formula I as claimed in claim 1  in which R represents an ethyl, n-propyl or isopropyl radical,  n-butyl, isobutyl, tert-butyl, methyl-1-propyl, n-pentyl, neo  pentyl, phenyl, mono-fluoro-, mono-chloro- or mono-bromo-phenyl,  di-fluoro-, di-chloro- or dibromo-phenyl, mono-methyl- or di  methyl-phenyl, mono-methoxy- or di-methoxy-phenyl or a radical  methyl-phenyl substituted with a halogen atom. 5. ImidazoFl, 2.a) pyridine derivatives of the formula I as claimed in claim 1  in which R4 and R5, which are identical or different, are chosen from  an n-propyl and n-butyl radical. 6. Imidazo1,2-a) pyridine derivatives selected from the following compounds  2-ethyl-3- (3-di-n-butylaminopropoxy) benzoyl) -3-imidazo [1,2-a]  pyridine; n-butyl-2 [(3-di-n-butylamino-3-propoxy) benzoyl] -3 imidazo  [1,2-a] pyridine; 2-phenyl-3,5-dibromo (3-di-n-propylamino-3-propoxy)  benzoyl) -3 imidazo [1,2-a] pyridine, and their pharmaceutically acceptable salts  acceptable. 7. Imidazo (1,2-a) pyridine derivatives according to one of the claims  1-6 characterized in that the pharmaceutically acceptable salt  is oxalate or hydrochloride. 8. Process for the preparation of imidazo [1,2-a] pyridine derivatives of formula  according to Claim 1, characterized in that it is condensed. in  an inert solvent, a 4-alkoxy benzoylimidazo [1,2-a] pyridine derivative  of general formula

 wherein R, R1 and R2 have the same meaning as in Claim 1, R'3 has the same meaning as R3 in Claim 1 except for hydroxy and X is selected from halogen, C1-C4alkylsilyloxy or C6-C10 arylsulfonyloxy. with an amine of general formula

 pharmaceutically acceptable.  with an appropriate organic or inorganic acid to form a salt  free base thus obtained being, if desired, treated  of the formula wherein R 3 is hydroxy, in the form of a base  catalytic genesis to form the imidazoEl, 2-a) pyridine derivative  the compound obtained in which R'3 represents a benzyloxy group with a hydro-  formula I as a free base, and possibly submitting  cation 1 to obtain dtimidazo [1,2-a] pyridine derivatives of  in which R4 and R5 have the same meaning as in Reven 9. Process for preparing imidazo [1 2-a] pyridine derivatives of formula  I according to Claim 1, characterized in that the reaction is carried out,  in the presence of a basic agent, a benzoyl derivative of general formula

 wherein R, R1 and R2 have the same meaning as in Claim 1 and R'3 has the same meaning as R3 in the Claim 1 with the exception of the hydroxy group, with a compound of the general formula:

  wherein R, R3, R4, R5 and A have the same meaning as in Claim 1 and R1 and R2, which are the same, represent an atom selected from chlorine, bromine and iodine, characterized in that a compound of general formula is reacted

 general mule  table; 10.Process for the preparation of imidazo [1,2-a) pyridine derivatives of  inorganic material suitable for forming a pharmaceutically acceptable salt  obtained being, if desired, treated with an organic acid or  has the hydroxy group, in free base form, the free base and  imidazoE1,2-alpyridine derivative of formula I, wherein R3 is  present benzyloxy to a catalytic hydrogenation to form the  by optionally subjecting the compound obtained in which R'3  imidazo [1,2-a] pyridine of formula I in free base form, and  reflux and in a polar solvent to obtain derivatives  C 1 -C 4 sulfonyloxy or C 6 -C 10 arylsulfonyloxy, the reaction having  1 and X is selected from a halogen atom or an alkyl radical  in which R4 and R5 have the same meaning as in Reven  ceutically acceptable.  organic or inorganic acid suitable for forming a pharma salt  the free base thus obtained being, if desired, treated with a  iodine,  in which R1 and R2 each represent bromine or  obtain the imidazoC1,2-apyridine derivative, in base form  appropriate and in the presence of an alkali metal acetate, to  (b) with bromine or iodine, the reaction taking place in soil  in which R1 and R2 each represent chlorine,  obtain the imidazo [1,2-a] pyridine derivative in base form  medium and between G'C and room temperature. for  a) with N-chlorosuccinimide, the reaction taking place in a  in which R, R3.R4, R5 and A have the same meaning as previously 11. Pharmaceutical or veterinary compositions comprising as prin  at least one imidazo [1,2-a] pyridine derivative according to one of the  Claims 1 to 7 in association with a pharmaceutical vehicle  or a suitable excipient. 12. Pharmaceutical or veterinary compositions comprising as prin  at least one derivative of imidazo [1,2-a] pyridine according to  Claim 6 or 7.