FR2700337A1 - Imidazopyridin-2-one derivatives, process for their preparation and their use in therapy - Google Patents

Abstract

The present invention relates to compounds of formula (CF DRAWING IN BOPI) in which - R1 represents a hydrogen atom, a group of (CF DRAWING IN BOPI) R4 being a group selected from amino, amidino, guanidino, pyrazinyl, imidazolyl and pyrimidinyl, - R2 represents a group - (CH2) n -COOH with n = 1 to 3, or when R1 is not a hydrogen atom R2 can represent a hydrogen atom, - R3 represents an indolyl group or a phenyl group optionally substituted by one or more methoxy, nitro or halogen groups, and their pharmaceutically acceptable salts. These compounds can be used as inhibitors of platelet aggregation.

Description

 The present invention relates to novel imidazopyridine-2-one derivatives, to a process for their preparation and to their therapeutic use, in particular as inhibitors of platelet aggregation.

- R1 représente un atome d'hydrogène, un groupe de formule

ou un groupe de formule

The subject of the present invention is therefore compounds of formula in which

R1 represents a hydrogen atom, a group of formula

or a group of formula

Wherein R.sup.4 is a group selected from amino, amidino, guanidino, pyrazinyl, imidazolyl and pyrimidinyl; R2 is - (CH2) n -COOH with n = 1 to 3, or when R1 is not hydrogen R2 can represent a hydrogen atom, - R3 represents an indolyl group or a phenyl group optionally substituted by one or more methoxy groups, nitro or halogen atoms, and their pharmaceutically acceptable salts.

 The term "pharmaceutically acceptable salts" denotes the addition salts which the compounds of formula (I) form with pharmaceutically acceptable acids, as well as the salts which the compounds of formula (I) with acidic groups form with pharmaceutically acceptable bases.

 The "pharmaceutically acceptable acid addition salts" refer to the salts which give the biological properties of the free bases without undesirable effects. These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, tartaric acid and pamoic acid.

 Similarly, "salts with pharmaceutically acceptable bases" refer to salts which do not modify the biological properties of the free acids. These salts may be especially those formed with mineral bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, or organic bases such as glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, N-methylmorpholine, tris (hydroxymethyl) methylamine and lysine.

A particular group of compounds of formula I are compounds of formula I in which
R1 is a group

 Another particular group of compounds of formula I are compounds of formula I wherein R 3 is selected from phenyl, indolyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl and 4-chlorophenyl.

par réaction avec le phosgène, conduisant à un composé de formule

et éventuellement conversion du composé de formule III en un composé de formule

In general, compounds of formula
I can be prepared by cyclization of a compound of formula

by reaction with phosgene, resulting in a compound of formula

and optionally converting the compound of formula III to a compound of formula

avec une amine de formule
H2N-(CH2)2-R3 VI conduisant à un composé de formule

puis réduction du composé de formule VII en un composé de formule

In the case where R 1 is a hydrogen atom, the compounds of formula II can themselves be obtained by reaction of a compound of formula

with an amine of formula
H2N- (CH2) 2 -R3 VI leading to a compound of formula

and then reducing the compound of formula VII to a compound of formula

avec une amine de formule VI conduisant à un composé de formule

puis conversion en un composé de formule

et réduction en un composé de formule Il. In the case where R is other than a hydrogen atom, the compounds of formula I may be obtained by reaction of a compound of formula

with an amine of formula VI leading to a compound of formula

then conversion to a formula compound

and reduction to a compound of formula II.

 The conversion of a compound of formula III into a compound of formula IV may be obtained by reaction, for example with ethyl bromoacetate, and then hydrolyzing the ester function.

 The following examples illustrate the preparation of compounds of formula I.

EXAMPLE 1 1,3-dihydro-1- (carboxymethyl) -3- (phenethyl) imidazo [4, S-b] pyridin-2-one (CRL 41835)
a) Preparation of 2-phenethylamino-3-nitropridine
60 mmol of 2-chloro-3-nitropyridine (9.51 g) are dissolved in 100 ml of DMF. 10.6 g of sodium carbonate and the equivalent of phenethylamine (7.27 g) are added. After stirring for one hour at 90 ° C., the mixture is cooled before being poured into 100 ml of water The crystals are washed with water, dried and then recrystallized from 2-propanol.

 13.1 g of the nitro derivative are obtained, ie a yield of 9%.

 M.p. = 88 ° C.

b) Preparation of 1,3-dihydro-3- (nethylethyl) imidazo [4,5-b] pyridin-2-one (CRL 41833)
20 mmol of the nitro derivative obtained in a) (4.86 g) dissolved in 250 ml of methanol are subjected to a catalytic hydrogenation at atmospheric pressure, in the presence of 500 mg of Pd / C. After 16 hours of reaction, the catalyst is filtered and the solution is decolorized in the presence of vegetable charcoal.

After evaporation of the methanol, the amine is taken up in 200 ml of toluene. At 0 C, 11.5 ml of a solution of phosgene dissolved in toluene (1.93
M) are added dropwise. After 12 hours of stirring, the solvent is evaporated and the reaction crude is dissolved in ethyl acetate. This organic phase is washed with water and then with an N HCl solution before being dried (saturated solution of NaCl and MgSO 4).

 The compound is recrystallized from ethyl acetate.

 The yield of both steps is 70% (4.8 g).

 Mp = 164 ° C.

c) Preparation of 1,3-dihydro-1- (carboxymethyl) -3- (phenethyl) imidazo [4,5-b] pyridin-2-one (CRL 41835)
4 mmol of the imidazolone derivative obtained in b) (956 mg) are suspended in 50 ml of anhydrous acetone. After adding 490 mg of KOH, the mixture is stirred under nitrogen for 30 minutes. 5 mmol of ethyl bromoacetate are added dropwise and the whole mixture is stirred for 3 hours.

The reaction crude is suspended in water and filtered.

 930 mg of ester are obtained, a reaction yield of 71%.

 The ester is quantitatively hydrolyzed to acid by a 2N sodium hydroxide solution.

 M.p .: 218 C.

 EXAMPLE 2 1,3-dihydro-1- (carboxymethyl) -3- (phenethyl) -5- (4-amidino phenyl) amino imidazo [4,5-b] pyridin-2-one.

a) Preparation of 2-phenethylamino-3-nitro-6-chloropyridine
On 15 mmol of 2,6-dichloro-3-nitropyridine dissolved in 25 ml of DMF and 2.65 g of sodium carbonate, one equivalent of phenethylamine is added dropwise. After stirring for one hour at 25 ° C., the whole is poured into 25 ml of water. The solution is filtered and the crystals are washed with water and then dried under vacuum. The product is purified by flash chromatography on silica gel, using a mixture of hexane and ethyl acetate.

 2.7 g of product are thus recovered, ie a yield of 75%.

 Mp = 90 C.

b) Preparation of 2-phenethylamino-3-nitro-6 (4-amidinophenyl) amino-pyridine
1 mmol (273 mg) of 2-phenethylamino-3-nitro-6-chloropyridine and 233 mg of sodium carbonate are suspended in 25 ml of DMF. An equivalent of para-amino benzamidine is added. The whole is heated at reflux for 12 hours. Poured cold over 25 ml of water, the crystals are filtered, washed, dried and chromatographed on silica gel, using a gradient gradient of ethyl acetate / hexane.

 This purification makes it possible to obtain 207 mg of the benzamidine derivative, ie a yield of 55.

 M.p .: 80 C.

 c) Preparation of 1,3-dihydro-1- (carboxymethyl) -3- (phenethyl) -5- (4-amidino phenyl) amino imidazo [4,5-b] pyridin-2-one.

 The nitro derivative described above is subjected to a catalytic hydrogenation under pressure, in the presence of Pd / C. The amine obtained is cyclized with phosgene dissolved in toluene.

 The introduction of the carboxymethyl group is carried out according to the procedure described above in Example 1 c).

 EXAMPLE 3 1,3-dihydro-1- (carboxymethyl) -3- (phenethyl) -5- (4-amidino phenyl) carboxamido-imidazo [4,5-b] acridin-2-one.

 5 mmol of 2-phenethylamino-3-nitro-6-chloropyridine (1.38 g) are dissolved in liquid ammonia and stirred under pressure for 12 hours.

 The amino derivative is isolated quantitatively.

 M.p .: 137 C.

 On 5 mmoles of para-amidinobenzoic acid, dissolved in 25 ml of methylene chloride, 1.1 equivalents of dicyclohexylcarbodiimide and one equivalent of triethylamine are added.

 5 mmol of the amine derivative previously obtained, dissolved in 25 ml of CH 2 Cl 2, are added dropwise to the mixture. After stirring for 12 hours at room temperature, the solution is filtered. The organic phase is washed with water and then dried over sodium sulfate. The product is purified by chromatography on silica gel (AcOEt / Hexane gradient).

 The reduction of the nitro function, the cyclization to imidazolone and the alkylation of the nitrogen are carried out according to the method described above.

PHARMACOLOGICAL TRIALS
Inhibitory Activity of Platelet Approval
Platelets are isolated from human venous blood mixed with ACD anticoagulant buffer at 1 volume buffer for 6 volumes of blood (ACD buffer formula = trisodium citrate 5H2O: 5.95 g, citric acid: 3.41 g dextrose: 5 g, HO: qs 250 ml). The blood is then centrifuged for 20 min at 1000 rpm. The PRP (platelet-rich plasma) is decanted and added with 0.1 μM PGE and then centrifuged for 15 minutes at 2000 rpm. The platelets obtained in the centrifugation pellet are resuspended in 1 ml of tyrode-albumin buffer pH 7.2.

 The effect of the compounds of formula I on platelet aggregation is studied with ADP 5.10-6M as activator. The results indicate an inhibitory activity of the compounds for concentrations between 10-6M and 10-9M.

 The compounds of formula I can be used especially for the treatment and prevention of thromboses, in particular in pre-thrombotic states to block platelet aggregation. These same compounds can also exert an inhibitory effect on the adhesion of platelets to endothelial cells and vascular walls, atherogenesis, the development of metastases of tumor cells, cellular adhesion phenomena during the inflammatory reaction. More generally, the compounds can inhibit integrin receptor-dependent cellular adhesion phenomena interacting with, for example, fibrinogen, vitronectin, fibronectin, thrombospondin, von Willebrand factor, thrombin, bone sialoprotein , proteins of the extracellular matrix.

 The therapeutic compositions according to the invention can be administered to humans or animals orally or parenterally or transdermally. They can be in the form of solid, semi-solid or liquid preparations. Examples include tablets, capsules, solutions or injectable suspensions. In these compositions the active ingredient is generally mixed with one or more usual pharmaceutically acceptable excipients well known to those skilled in the art. The amount of active ingredient administered obviously depends on the patient being treated, the nature of the disease, the severity of the disease. It is usually 1 to 5000 mg.

Claims (5)

 or a group of formula

 R1 represents a hydrogen atom, a group of formula

I - Compounds of formula in which Wherein R 4 is a group selected from amino, amidino, guanidino, pyrazinyl, imidazolyl and pyrimidinyl, - R2 is - (CH 2) n -COOH with n = 1 to 3, or when R 1 is not an atom of hydrogen R 2 may represent a hydrogen atom; R 3 represents an indolyl group or a phenyl group optionally substituted with one or more methoxy, nitro or halogen groups, and their pharmaceutically acceptable salts.  2 - Compounds of formula I according to claim 1, wherein R1 is a group

 Compounds of formula I according to claim 1 or claim 2, wherein R3 is selected from phenyl, indolyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl and 4-chlorophenyl.  4 - Process for preparing a compound of formula I according to claim 1, wherein a compound of formula

 by reaction with phosgene, resulting in a compound of formula

 and optionally converting the compound of formula III to a compound of formula

 5 - Therapeutic composition containing, as active principle, a compound according to any one of claims 1 to 3.