EP1242381A2

EP1242381A2 - 2-phenyl-quinoline derivatives, preparation method and therapeutic use thereof

Info

Publication number: EP1242381A2
Application number: EP00988917A
Authority: EP
Inventors: Philippe R. Bovy; Alain Braun; Christophe Philippo
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1999-12-17
Filing date: 2000-12-14
Publication date: 2002-09-25
Also published as: JP2003516969A; WO2001044197A2; FR2802532A1; US20030097000A1; AU2526001A; WO2001044197A3

Abstract

The invention concerns compounds of general formula (I) wherein: A represents a hydrogen atom or a hydroxy; B represents a hydrogen atom or a C1-C3 alkyl group; R1 represents a phenyl optionally substituted with a halogen, a hydroxy, a C1-C3 alkoxy, C1-C3 alkyl, C1-C3 fluoroalkyl or C1-C2 perfluoroalkyl group; R2, R3 and R6, identical or different, represent each a hydrogen atom, a halogen, a C1-C6 alkyl, C2-C6 alkenyl group; R4 and R5, identical or different, represent each a hydrogen atom, a C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl group, or R4 and R5 together form a C2-C6 alkylene, C3-C6 alkenylene chain to form with the nitrogen whereto they are bound a heterocycle, said heterocycle being optionally substituted with a C1-C4 alkyl group. The invention has therapeutic applications.

Description

2-PHENYL-QUINOLElNE DERIVATIVES, THEIR PREPARATION AND THEIR

THERAPEUTIC APPLICATION

The present invention relates to 2-phenyl-quinoline derivatives, their preparations and their therapeutic applications.

The document “Chemical Abstracts vol. 104, n ° 13 of March 31, 1986 "quotes the compounds RN69758-24-3, 6957-69-3 and 35871-03-5 of formula (I)

( in which

• A represents a hydroxy;

B represents a hydrogen atom; Ri represents 4-chlorophenyl; R ₂ represents a hydrogen atom; R ₃ represents hydrogen;

R ₄ and R ₅ both represent ethyl; and R ₆ represents a 6-chloro or

• A represents a hydroxy; B represents a hydrogen atom; R-i represents phenyl;

R ₂ and R ₃ each represents a hydrogen atom; R ₄ and R ₅ together form a C ₆ alkylene chain; and R ₆ represents a hydrogen atom or a 6-methyl.

These compounds are active in the treatment of malaria. The document by J-Gillepsie, JR et al. "Antimalarials. II. 8-quinolinemethanols "(JOURNAL OF MEDICINAL CHEMISTRY., Vol. 13, n ° 5 -1970, pages 860-864) discloses in its table III the compounds 1 b, 3a, 3b, 5b and of formula (I) in which:

• A represents a hydroxy; B represents a hydrogen atom; Ri represents 4-chlorophenyl; R ₂ represents a hydrogen atom; and ^* Rβ represents a 6-chloro, R ₃ represents a hydrogen and

R4 and R5 both represent ethyl or butyl; or

* R ₆ represents a 6-chloro, R ₃ represents a methyl and R ₄ and R ₅ both represent a butyl; or

^* Rβ represents a hydrogen atom, R ₃ represents a hydrogen and R ₄ and R ₅ both represent a butyl; or

* R ₆ represents 5-chloro, R ₃ represents methyl and R and R ₅ both represent butyl.

These compounds are active in the treatment of malaria.

The subject of the present invention is the 2-phenyl-quinoline derivatives, corresponding to the following general formula (I)

in which: - A represents a hydrogen atom or a hydroxy,

- B represents a hydrogen atom or a Cι _-3 alkyl group,

- Ri represents a phenyl optionally substituted by a halogen, a hydroxy, a group C * ι _-3 alkoxy, Cι _-3 alkyl, Cι _-3 fluoroalkyle or Cι _-2 perfluoroalkyle.

- R ₂ , R ₃ and Rβ, identical or different, each represent a hydrogen atom, a halogen, a hydroxy, a Ci-β alkyl group, C _2- β alkenyl,

- R ₄ and R ₅ , identical or different, each represent a hydrogen atom, a group C1. ₆ alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, or R and R ₅ , together form a chain C ₂ -β alkylene, C ₃ -6 alkenylene to give with the nitrogen to which they are attached a heterocycle such as , for example, a piperidyl, azetidinyl or pyrrolidyl, this heterocycle being optionally substituted by one or two C-alkyl groups; and their salts or hydrates, excluding the compounds for which: • A represents a hydroxy; B represents a hydrogen atom; Ri represents 4-chlorophenyl;

R ₂ represents a hydrogen atom; and

^* R ₆ represents a 6-chloro, R ₃ represents a hydrogen and R ₄ and R ₅ both represent an ethyl or a butyl; or

^* Rβ represents 6-chloro, R ₃ represents methyl and R and R5 both represent butyl; or

^* R ₆ represents a hydrogen atom, R ₃ represents a hydrogen and

R ₄ and R ₅ both represent butyl; or

^* R ₆ represents 5-chloro, R ₃ represents methyl and R and R5 both represent butyl; and • A represents a hydroxy; B represents a hydrogen atom; R1 represents phenyl;

R ₂ and R ₃ each represents a hydrogen atom; R and R5 together form a C _2- β alkylene chain; and

R ₆ represents a hydrogen atom or a 6-methyl.

The preferred compounds according to the invention are those, as defined above, for which A represents a hydroxy and more particularly the compounds for which A represents a hydroxy and B represents a hydrogen atom.

Among these, subgroups of compounds comprising radicals having the following meanings are preferred:

* Ri represents a phenyl optionally substituted by a halogen, a C * ι _-3 alkyl, Cι _-3 alkoxy or C * ι _-2 perfluoroalkyl group, or

* R ₂ and R ₃ represent, each independently of one another, a hydrogen atom or a C-alkyl group, more preferably methyl or ethyl, or

* R ₄ and R ₅ each represent a C-alkyl group, more preferably a methyl, ethyl, propyl or iso-propyl group, or

R and R ₅ , together form a C _2- s alkylene chain to give, with the nitrogen to which they are attached, a heterocycle, preferably an azetidinyl or a piperidyl, this heterocycle being optionally substituted by a Cι _-2 alkyl group; or * R ₆ represents a hydrogen atom.

More particularly, the subgroup of preferred compounds is that in which A represents a hydroxy, B represents a hydrogen atom and Ri, R ₂ , R ₃ , R ₄ , R ₅ and R are as defined in the sub- preferred compound groups.

In particular, in the context of the present invention, the compounds in the table are preferred and more particularly the following:

- 2-Phenyl-3-methyl-8- (2-diethylamino-1-hydroxyethyl) quinoline,

- 2-Phenyl-8- (2-ethyl- / so-propylamino-1-hydroxyethyl) quinoline and - 2-Phenyl-3-methyl -8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl] quinoline On the other hand, in the context of the present invention, the following definitions are understood:

- C * ι.z (C _2- z or Ca-z). where z can take the values from 2 to 6, a carbon chain being able to have from 1 (2 or 3) to z carbon atoms, - alkyl, a linear or branched saturated aliphatic group; for example, a C-ι-6 alkyl group represents a carbon chain of 1 to 6 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc; preferably methyl, ethyl, propyl and isopropyl, - fluoroalkyl, an alklyl ^"in which one or two hydrogen atoms have been substituted by a fluorine atom,

- perfluoroalkyle, an alklyl in which all the hydrogen atoms have been substituted by a fluorine atom,

cycloalkyl, a cyclic alkyl, for example, a C ₃ - ₆ cycloalkyl group represents a cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl,

- alkenyl, a linear or branched mono or poly-unsaturated aliphatic group, preferably comprising 1 or 2 ethylenic unsaturations,

- alkylene and alkenylene, respectively a divalent alkyl and alkenyl,

- alkoxy, an alkyloxy group with a saturated, linear or branched aliphatic chain, and

- halogen atom, fluorine, chlorine, bromine or iodine.

The term “protective group Pg” is intended to mean a group which allows on the one hand to protect a reactive function such as a hydroxy or an amine during a synthesis and on the other hand to regenerate the reactive function intact at the end of the synthesis. Examples of protective groups as well as methods of protection and deprotection are given in Protective groups in Organic Synthesis, Greene et al., 2 ^nd Ed. (John Wiley & Sons, Inc., New York). On the other hand, in the case where for example R ₂ , R ₃ and R represent such reactive functions, the latter can be protected before reaction and deprotected according to these methods, the person skilled in the art will easily determine the cases where this protection is necessary.

The term “leaving group” is intended to mean a group which can be easily cleaved from a molecule, with the departure of an electronic pair, by breaking a heterolytic bond. This group can thus be easily replaced by another group during a substitution reaction for example. Such leaving groups are, for example, halogens, or an activated hydroxy group such as a mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups as well as preparation references are given in "Advanced Organic Chemistry", J. March, 3 ^rd Edition, Wiley Interscience, p 310-316.

The compounds of general formula (I) may have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including ^* the racemic mixtures are part of the invention.

When a compound according to the invention has a stereoisomerism, for example of the axial-equatorial or Z-E type, the invention comprises all the stereoisomers of these compounds.

The compounds of general formula (I) can be in the form of free base or of addition salts with acids, which also form part of the invention. These salts, according to the present invention, include those with mineral or organic acids which allow proper separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, by example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphosulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the maleate, the fumarate, pamoate, 2-naphthalenesulfonate, paratoluenesulfonate.

Although the pharmaceutically acceptable salts are preferred, the other salts are part of the present invention. These salts can be prepared, according to methods known to a person skilled in the art, for example, by reaction of the compound of formula (I) in base form with the acid in an appropriate solvent, such as an alcoholic solution or a organic solvent, then separation of the medium which contains it by evaporation of the solvent or by filtration.

A second subject of the present invention is processes for preparing the 2-phenyl-quinoline derivatives of formula (I) according to the invention. They can be prepared according to various methods, in particular those described below. 1. The compounds of formula (I), in particular those for which A represents a hydroxy group, can be prepared according to reaction scheme 1.

Diagram 1

According to this process, an aldehyde of formula II is reacted with a stannate derivative of formula III. This reaction can be carried out according to the method described by A.R. Katrizky et al. (Synthesis 1994; 907) in an ethereal organic solvent such as ether or tetrahydrofuran (THF), in the presence of n-butyl lithium. The reaction is preferably carried out at -78 ° C.

The meanings of Ri, R ₂ , R ₃ , R-., R5, R and B of the compounds of formula II or III are those indicated in formula I.

The compounds of formula II can be prepared, according to scheme 2, by a reaction for formylation of a quinoline derivative of formula IV, in which R 1, R ₂ , R ₃ and R ₆ are as defined in formula (I) and Y represents a leaving group such as for example a halogen, or an activated hydroxy group such as a triflate group. The reaction can be carried out by means of a palladium catalysis according to the process described by Kotsuki H. et al. (Synthesis 1996, 470-472) or alternatively, by lithiation of the quinoline derivative of formula IV and treatment with N, N-dimethylformamide (DMF). Diagram 2

The compounds of formula III can be prepared by a person skilled in the art according to the method described by A.R. Katrizky et al. (Synthesis 1994; 907).

The compounds of formula IV can be synthesized according to methods known to those skilled in the art, in particular those described in patent application PCT / FR99 / 02129. Other methods which have been employed make use of the methods described below. Thus, the compounds of formula IV can be prepared by a Skraup or Doebner-Miller reaction, according to reaction scheme 3.

According to this scheme and under the conditions defined by Belser P. Tetrahedron 1996Nol 52, Ν ° 8, 2937-2944 or advantageously under the conditions defined by Z. Song J. Heterocyclic Chem. 1993, 30, 17-21, an aniline of formula VII, for which Z represents a hydroxy or methoxy group, and an α, β-unsaturated aldehyde or ketone of formula VI are heated in the presence of a dehydrating agent such as l sulfuric acid and an oxidant such as sodium iodide to form a quinoline derivative of formula V substituted in position 8 with a group Z. This compound is then treated with a phenyllithian derivative of formula VIII in a solvent such as toluene to give the compound of formula IX. The group Z of the compound thus obtained is then transformed into a leaving group according to methods known to those skilled in the art. For example, when Z represents a methoxy group, this is first transformed into a hydroxy group, for example in the presence of boron tribromide in a chlorinated solvent such as dichlorormethane or chloroform, then in a leaving group according to methods known to those skilled in the art to give the compound of formula IV in which Y represents a leaving group. The meanings of Ri, R ₂ , R ₃ and R ₆ of the compounds of formula IV, V, VI and VII, VIII and IX are those indicated in formula I.

Diagram 3

IX IV

On the other hand, the compounds of formula IV can be prepared by a Friedlander condensation reaction.

According to this process described in reaction scheme 4 and under the conditions defined by RP Thummel et al J. Org. Chem. 1993, 58, 1666-1671, the heating of a phenylketone of formula XI, for which Y is as defined above, with an acyl-2-aniline of formula X, in a solvent with high boiling point, such as toluene, and in the presence of alcoholic potash provides the compounds of formula IV. The meanings of Ri, R ₂ , R ₃ and R of the compounds of formula IV, X and XI are those indicated in formula I. Diagram 4

2. The compounds of formula (I) according to the invention, for which A is a hydroxy group, can also be prepared according to reaction scheme 5.

Diagram 5

XIV XIII

According to this scheme, an ethenyl quinoline derivative of formula XIV is reacted with an oxidant such as sodium periodate, osmium tetroxide (in racemic or chiral series by using AD-mix-α or AD -mix-β) or metachloroperbenzoic acid followed by hydrolysis in basic or acidic medium, so as to form a diol of formula XIII in which W represents a hydroxy. The hydroxy group twin to group B of the diol thus obtained can then be optionally selectively activated, in a manner known to those skilled in the art, so as to obtain the compound of formula XIII, in which W represents a leaving group, such as a tosyle group, an acetyl group or a bromine atom. The compound of formula (I) according to the invention is then prepared from the compound of formula XIII, by reacting the latter with an amine NHR.4R5. The meanings of R * ι, R ₂ , R ₃ , R ₄ , R5, Rβ and B in each of the compounds of formula XIV or XIII and of the amine NHR R ₅ , are those indicated in formula (I). The ethenyl quinoline derivative of formula XIV can itself be prepared by palladic coupling of Stille, under the conditions defined by DR Me Kean et ai. (J. Org. Chem., 52; 1987: 492), from a derivative of formula IV as defined above for which Y represents a leaving group, such as a halogen or an activated hydroxy group, such than a triflate group.

Alternatively, the ethenyl quinoline derivative of formula XIV can be prepared from an aldehyde derivative of formula II as defined above, by a Wittig reaction with the corresponding (Pphenyl) ₃ P ⁺ - ^" CHB, under conditions conventional for those skilled in the art.

3. The compounds of formula (I), in particular those for which A represents a hydroxy group, can also be prepared, according to scheme 6, from a quinoline derivative of formula XV, for which Y represents a leaving group such that a halogen, such as bromine, iodine or chlorine or an activated hydroxy group such as a triflate group, by a palladic coupling, for example a Stille or Suzuki reaction, respectively with a compound of formula RιSn (nC ₄ Hg) ₃ or R * ιB (OH) ₂ , to give an intermediate compound of formula XVI, then by opening the epoxide of the latter compound according to methods known to those skilled in the art, for example in a solvent such than acetonitrile at temperatures between 20 and 80 ° C. The meanings of B, Ri, R ₂ , R ₃ , R _4ι R ₅ and Rβ of the amine XII, of the compound of formula XV and of the compounds of formula R * ιSn (nC Hg) ₃ or RιB (OH) ₂ are those indicated in formula I.

Diagram 6

1) Pd °

The compound of formula XV can itself be obtained according to reaction scheme 7.

According to this scheme, a quinoline of formula XVII is oxidized, by methods known to those skilled in the art, to an N-oxide compound of formula XVIII which in the presence of acetic anhydride, and under the conditions defined in the Tzeng patent , C et al US 5,646,164, rearranges into a 2-acetoxy quinoline compound of formula XIX. The hydroxy group in position 8 of the latter is converted into a leaving group such as a triflate group, then is reacted with a vinylstannan compound of formula BCH = CH-Sn (nC H ₉ ) ₃ under the conditions defined by Me Kean, DR; Parinello, G. Renaldo, AF; Stille, JK, J. Org. Chem., 52, 1987, 492, to provide the ethenyl derivative of formula XX, the acetoxy group of which in position 2 is then converted into a leaving group Y, such as a halogen, such as bromine, iodine or chlorine, or an activated hydroxy group such as a triflate group, to give the ethenyl derivative of formula XXI. The quinoline derivative of formula XV can then be prepared by the action of a peracid such as metachloroperbenzoic acid on the quinoline of formula XXI. The reaction can be carried out under conditions known to those skilled in the art, for example in a chlorinated solvent such as dichloromethane or chloroform, preferably at temperatures of 20 to 80 ° C. The meanings of R ₂ , R ₃ , Rβ and B of the compounds of formula XV, XVII, XVIII, XIX, XX and XXI are those indicated in formula I.

Diagram 7

4. The compounds of formula (I) according to the invention, for which A represents a hydrogen atom, can be prepared by dehydroxylation of a compound of formula (I) corresponding, where A is a hydroxy group.

The dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with triethylsilane and trifluroacetic acid or according to the method described by A. G. Myers et al. (J. Am. Chem. Soc. 1997; 119: 8572-8573).

5. The compounds of formula (I) according to the invention, for which A is hydrogen, can also be prepared according to the methods described in PCT / FR99 / 02129.

The starting compounds, in particular the compounds of formula VII, X, XI, XII and XVI are commercially available or can be prepared according to methods known to those skilled in the art. The following examples are intended to illustrate the present invention without, however, limiting its scope.

Example 1: 2-Phenyl-3-methyl-8- (2-diethylamino-1-hvdroxyethvπquinoline. Hydrochloride

Rι = Phenyl; R ₂ = CH ₃ ; R ₃ = H; R ₄ = R ₅ = C ₂ H ₅ ; R ₆ = H; A = OH; B = H

(1) 3-Methoxy-2-aminobenzaldehyde

In a solution of 100 ml of ethanol, 100 ml of acetic acid and, 50 ml of water, are dissolved 5 g of 3 - methoxy 2-nitrobenzaldehyde. After addition of 1.4 g of iron and 1.4 ml of concentrated hydrochloric acid, the reaction medium is heated at reflux for 10-15 minutes. After cooling the reaction medium, 150 ml of water are added and the reaction mixture is extracted with 3 x 200 ml of dichloromethane. The organic phases are combined, washed with 500 ml of a saturated solution of sodium hydrogencarbonate, dried over magnesium sulfate, filtered and evaporated in vacuo to provide 4.17 g of 3-methoxy-2-aminobenzaldehyde in the form of a colorless oil, used without purification for the next step. (Yield: quantitative)

(2) 2-Phenyl-3-methyl-8-methoxyquinoline

15.3 g (101 moles) of 3-methoxy 2-amino benzaldehyde and 14 ml (105 moles) of propiophenone are dissolved in 400 ml of ethanol. 1.4 g (25 moles) of potassium hydroxide are added to the reaction mixture and the latter is brought to 100 ° C. for 8 hours. After cooling the reaction medium, the latter is concentrated under vacuum and added with 200 ml of water. A yellow precipitate forms after a few minutes. The medium is filtered and the yellow precipitate is taken up in a mixture of 300 ml of ethyl ether and 200 ml of a 1 N solution of hydrochloric acid. The aqueous phase is extracted with 2 x 100 ml of ethyl ether. Then after adding 300 ml of methylene chloride, 100 ml of a 3N sodium hydroxide solution are added to the aqueous phase. The latter is then extracted with 3 x 200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. 21.2 g of 2-phenyl-3-methyl-8-methoxyquinoline are obtained in the form of a pale yellow solid - mp = 105 ° C. (Efficiency: 85%) (3) 2-Phenyl-3-methyl-8-hydroxyquinoline

To a solution of 21.2 g (85 mmol) of 2-phenyl-3-methyl-8-methoxyquinoline in 500 ml of methylene chloride are added dropwise, at -30 ° C, 17.6 ml (180 mmoles) of boron tribromide. The cooling bath is then removed and the reaction medium is stirred for 3 hours until it returns to ambient temperature. Then, the reaction mixture is poured onto ice and the medium is basified using sodium hydrogen carbonate. The latter is then extracted with 3 x 200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane 3/7) to give 12.7 g of 2-phenyl-3-methyl-8-hydroxyquinoline in the form of a colorless oil. (Yield: 64%)

(4) 2-Phenyl-3-methyl-8-trifluoromethanesulfonatequinoline

To a solution of 12.5 g (53 mmol) of 2-phenyl-3-methyl-8-hydroxyquinoline in 150 ml of pyridine are added dropwise at 0 ° C, 16.9 ml (110 mmol) of trifluoromethane sulfonic anhydride. The reaction mixture is then stirred for 16 hours at room temperature. After evaporation of the pyridine, the residue is taken up in 200 ml of water and 100 ml of ethyl acetate. The aqueous phase is extracted with 2 x 100 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane 37) to give 17.8 g of 2-phenyl-3-methyl-8- trifluoromethanesulfonatequinoline in the form of a beige solid - PF = 85 ° C. (Yield: 91%)

(5) 2-Phenyl-3-methyl-8-vinylquinoline

To a solution of 17.7 g (48 mmol) of 2-phenyl-3-methyl-8-trifluoromethanesulfonatequinoline in 250 ml of dioxane degassed beforehand using a stream of nitrogen are added sequentially at room temperature 6, 3 g (150 mmol) of lithium chloride, 16.8 ml (57 mmol) of tributylvinyltin, and 1.6 g (1.5 mmol) of Pd (PPh ₃ ) ₄ . The reaction medium is then heated to 110 ° C for 16 hours. After evaporation of the dioxane, the residue is taken up in 200 ml of water and 200 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane 37) to provide 11.3 g of 2-phenyl-3-methyl-8-vinylquinoline in the form of a colorless oil. (Yield: 96%)

(6) 2-Phenyl-3-methyl-8-oxiranequiπoleine

0.5 g of 2-phenyl-3-methyl-8-vinylquinoline (20.3 mmol) and 10 ml of chloroform are placed in a 100 ml flask. The solution is cooled to 0 ° C., in an ice bath, and 0.6 g (3.46 mmol) of meta-chloroperbenzoic acid is added. Stirring is continued for 2 h at 0 ° C. and 15 ml of a saturated sodium carbonate solution are added. Extraction is carried out with 3 × 50 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, concentrated in vacuo. The residue is purified by a chromatographic column on silica (elution solvent cyclohexane: ethyl acetate 95: 5) to provide 0.263 g of 2-phenyl-3-methyl-8-oxiranequinoline in the form of a colorless oil. (Yield 50%)

(7) 2-Phenyl-3-methyl-8- (2-diethylamino-1-hydroxyethyl) quinoline

0.120 g of 2-phenyl-3-methyl-8-oxiranequinoline (0.46 mmol), 1 ml of diethylamine and 5 ml of chloroform are placed in a 100 ml three-necked flask fitted with a condenser. The solution is heated at reflux for 4 h then concentrated in vacuo. The residue is purified by chromatographic column on silica (elution solvent dichloromethane: methanol 95: 5) to provide 0.124 g of 2-phenyl-3-methyl-8- (2-diethylamino-1-hydroxyethyl) quinoline in the form of a wax; yield 81%. (8) 2-Phenyl-3-methyl-8- (2-diethylamino-1-hydroxyethyl Oquinoleine, hydrochloride

To 0.116 g (0.347 mmol) 2-phenyl-3-methyl-8- (2-diethylamino-1-hydroxyethyl) quinoline obtained in step (7) is added to 3.116 g, 3.1 ml of hydrochloric acid in solution 0, 1 M in isopropanol and the salt is concentrated under vacuum. The residue is taken up in a minimum of ethyl ether then filtered and dried in a desiccator under vacuum over phosphoric anhydride. 0.1 g of 2-hényl-3-methyl-8- (2-diéthylamino-1 -hydroxyéthyOquinoleine, hydrochloride - PF: 208-210 ° C is obtained.

Example 2: 2-Phenyl-8-r2- (ethyl-iso-propylamino) -1-hvdroxyethvn quinoline, pamoate

R * ι = Phenyl; R ₂ = R ₃ = H; R ₄ = Et, R ₅ = iC ₃ H ₇ ; R ₆ = H; A = OH; B = H

(1) 8-Hydroxyquinoline N-Oxide

In a 1 L flask, 59.74 g (411 mmol) of 8-hydroxyquinoline, 350 ml (822 mmol) of dichloromethane, 82.2 ml of 35% hydrogen peroxide and 0.52 g (2, 5 mmol) of methylrhenium trioxide (MTO). The reaction mixture is stirred at room temperature (25 ° C) for 24 h then 80 ml of hydrogen peroxide and 0.32 g of manganese dioxide are successively added. The mixture is stirred for 1 hour 30 minutes then decanted. The aqueous phase is extracted with dichloromethane (2x200 ml). The organic phases are combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide 64 g of 8-hydroxyquinoline N-oxide in the form of an orange solid - mp = 112 ° C. (97% efficiency)

(2) 2-Acetoxy-8-hydroxyquinoline

64 g (397 mmol) of 8-hydroxyquinoline N-oxide, 550 ml of acetic anhydride and 40 ml of acetic acid are placed in a 1 L flask. The reaction mixture is heated at reflux (135 ° C) for 24 h then 40 ml of acetic acid are added again and the heating is continued for 1 h 30 min. The reaction mixture is allowed to return to room temperature and 400 ml of toluene are added. A precipitate appears and is filtered. 400 ml of toluene and we filter. The precipitate is washed with 200 ml of ethyl ether and is dried in a desiccator under vacuum over phosphoric anhydride to provide to provide 70.5 g of 2-acetoxy-8-hydroxyquinoline in the form of a brown solid - mp = ° C. (88% yield)

(3) 2-Acetoxy-8-trifluoromethanesulfoπatequinoline

36 g (176 mmol) of 2-acetoxy-8-hydroxyquinoline and 300 ml are placed in a 1L flask. The reaction mixture is cooled by an ice bath and 62.3 ml (370 mmol) of trifluoromethanesulfonic anhydride are added dropwise and stirring is continued at 0 ° C for 3 h. The reaction mixture is poured onto a mixture of 200 ml 3M hydrochloric acid and ice. A brown precipitate appears and is filtered then washed with 3 × 50 ml of water and is dried in a desiccator under vacuum over phosphoric anhydride to provide, to supply 56.6 g of 2-acetoxy-8-trifluoromethanesulfonatequinoline as a brown solid - PF = 90 ° C. (Yield 96%)

(4) 2-Acetoxy-8-vinyiquinoiéine

33.6 g (100 mmol) of 2-acetoxy-8-trifluoromethanesulfonatequinoline, 12.7 g of LiCl (300 mmol) 34.9 g (110 mmol) are placed in a 1 L flask containing 300 ml of previously degassed dioxane ) of tributylvinyltin and 5.8 g of tetrakis (triphenylphosphine) palladium. The mixture is heated at reflux for 4 h then concentrated under vacuum and hydrolyzed by the addition of 200 ml of water. The aqueous phase is extracted with ethyl acetate (4x200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by a chromatographic column on silica (eluent: cyclohexane / ethyl acetate 95/5) to provide a fraction containing 2-hydroxy-8-vinylquinoleole and 18.6 g of 2-acetoxy-8-vinylquinoline in the form of a yellow oil. (Yield = 87%)

(5) 2-Hydroxy-8-vinylquinoline

In a 1 L flask, 18.6 g (87.3 mmol) of 2-acetoxy-8-vinylquinoline, 290 ml of water and 290 ml of methanol are placed. The reaction mixture is heated at 55 ° C for 2 hours then the methanol is evaporated in vacuo. An extraction is carried out with ethyl acetate (2 × 200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 15.0 g of 2-hydroxy-8-vinylquinoline in the form of a yellow solid - mp = 96 ° C. (Quantitative return)

(6) 2-Trifluoromethanesulfonate-8-vinylquinoline

7.5 g (43.86 mmol) of 2-hydroxy-8-vinylquinoline, 5.32 ml of pyridine (65.78 mmol) and 100 ml of dichloromethane are placed in a 250 ml flask. The mixture is cooled to 0 ° C. in an ice bath and 11.10 ml (65.78 mmol) of trifluoromethanesulfonic anhydride are added dropwise. Stirring is continued at 0 ° C for ^Λ A h and the reaction mixture is hydrolyzed by adding 100 ml of water. An extraction is carried out with dichloromethane (3 × 150 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by a chromatographic column on silica (eluent: 1/1 heptane / dichloromethane) to provide 7.2 g of 2-trifluoromethanesulfonate-8-vinylquinoline in the form of a yellow oil. (Yield = 52%)

(7) 2-Trifluoromethanesuifonate-8-oxiranequinoline

1.85 g (6.1 mmol) of 2-trifluoromethanesulfonate-8-vinylquinoline and 2.7 g (12.2 mmol) of meta-chloroperbenzoic acid are dissolved in δ ml of chloroform in a 100 ml flask. The mixture is heated at 60 ° C for 24 h and then thrown onto a saturated sodium bicarbonate solution. . An extraction is carried out with dichloromethane (3 × 150 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.75 g of 2-trifluoromethanesulfonate-8-oxiranequinoline in the form of an oil. (Yield = 83%) (9) 2-Phenyl-8-oxiranequinoline

A previously degassed solution of 0.319 g (1.0 mmol) of 2-trifluoromethanesulfonate-8-oxiranequinoline in 10 ml of toluene, 243 mg (2.0 mmol) of phenyl acid is introduced into a 20 ml three-necked flask boronic, 207 mg (1.5 mmol) of potassium carbonate and 35 mg (0.3 mmol) of tetrakistriphenylphosphine palladium. The mixture is heated in an oil bath at 60 ° C for 4 h and 30 ml of water are added. An extraction is carried out with ethyl acetate and the organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by a chromatographic column on silica (eluent: ethyl acetate / cyclohexane 2/8) to provide 140 mg 2-phenyl-8-oxiranequinoline in the form of a colorless oil. (Yield = 55%)

(10) 2-Phenyl-8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl Oquinoleine

In a 100 ml three-necked flask fitted with a condenser, 0.110 g of 2-phenyl-8-oxiranequinoline (0.44 mmol), 1.2 ml of ethyl- / so-propylamine and 10 ml of chloroform are placed. The solution is heated at 60 ° C for 4 h and then concentrated in vacuo. The residue is purified by chromatographic column on silica (elution solvent dichloromethane: methanol 95: 5) to provide 0.140 g of 2-phenyl-8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl] quinoline in the form a wax. (Yield = 95%)

(11) 2-Phenyl-8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl] quinoline, pamoate

To a solution of 120 mg (0.33 mmol) of 2-phenyl-8- (1-diethylamino-2-hydroxyethyl) quinoline in 2 ml of DMF is added a solution of 129 mg (0.33 mmol) of acid pamoic in 2 ml of DMF. The solution is stirred for 15 min and then 15 ml of distilled water are added. The yellow precipitate obtained is filtered, washed with 5 x 10 ml of distilled water and then dried in a desiccator under vacuum over phosphoric anhydride to provide 248 mg of 2-phenyl-8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl] quinoline. pamoate in the form of a yellow solid - mp = 110 ° C. (Quantitative return) The following table illustrates the chemical structures and the chemical properties of certain compounds of formula (I) according to the invention. These compounds were synthesized according to the methods described above. Board

In this table:

- pam. represents a salt of pamoic acid,

- HCI represents a hydrochloride,

- "-" represents a compound in free form,

- Ph represents a phenyl

- i-Pr represents an iso-propyl group

- And represents an ethyl group,

- Me represents a methyl group. The compounds of the invention were subjected to biological tests intended to demonstrate their selective smooth muscle contracting activity.

1. The in vitro activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles.

These tests were carried out on female New Zealand rabbits weighing 3 to 3.5 kg. The animals were killed by vertebral dislocation, and then rings of tissue from the mesenteric arteries and urethra were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated with a mixture of 95% O ₂ and 5% CO ₂ . Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / response curve was established. After rinsing the samples, the compound to be studied was introduced at cumulative doses and the dose / response curve established. The contractile effect of each compound is evaluated by calculating pD ₂ (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the Maximum effect representing the percentage of the maximum contraction obtained with the phenylephrine (% E _ma ).

The results obtained show that the compounds in accordance with the invention have:

* a pD2 urethra greater than 2.5, usually between 4 and 8, more generally between 5 and 8,

^* a pD2 artery less than 3,

^* a% E _max urethra greater than 30, usually between 40 and 90,

^* a% Emax route equal to zero.

2. The in vivo activity of the compounds of the invention on the blood and urethral pressure was studied in the amyele rat and the rabbit, according to the following protocols: * Demedulated rats

Wistar rats are anesthetized and demedulated (according to the technique described by Gillespie, MacLaren A. and Polock D., A method of stimulating different segments of the autonomy outflow from the spinal column to various organs in the pithed cat and rat Br. J. Pharmacol., 1970, 40: 257-267).

The catheters are introduced through the aorta and a jugular vein. Another catheter is introduced into the urethra through an incision made in the bladder. The test compounds are administered in increasing doses by intravenous infusion.

The results are expressed in doses (μg / kg) necessary to increase the urethral pressure by 10 cm of water (PU10) or the blood pressure by 10 mm Hg (PA10) or 50 mm Hg (PA ₅ o) * The compounds of the invention thus tested, made it possible to obtain:

- PU-io with doses less than 100 μg / kg, usually between 20 and 100 μg / kg,

- a PA-io with doses greater than 110 μg / kg, usually between 130 and 250 μg / kg,

- PA ₅₀ could not be reached.

* Rabbits

The experiments are carried out on female New Zealand rabbits weighing between 3 and 4 kg, anesthetized with pentobarbital. The catheters are introduced for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the neck of the bladder). The test compounds are administered 5 to 15 days after the operation, by intravenous administration (i.v.).

The compounds are administered iv over 5 minutes in a single dose (100 μg / kg) * We measured here the increase in urethral pressure (PU) and blood pressure (PA), compared to basal pressure, urethral and arterial respectively.

The results obtained are expressed as a percentage of premedication values at 5 minutes after dosing.

The compounds of the invention thus tested, allowed an increase in the PU greater than 70%, usually between 90 and 125%. The increase in BP was always less than 10%, usually it was 0%.

All of the above results show that the compounds of the invention have a strong urethral action and a weak arterial action.

They can be used as a medicament, in particular as a contracting agent for smooth muscles, and more particularly still, in the treatment of urinary incontinence, in particular stress urinary incontinence. In this indication, the compounds according to the invention exhibit good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the arteries.

The compounds of the invention were subjected to biological tests intended to demonstrate their venoconstrictor activity.

The in vitro activity of the compounds of the invention was studied on the saphenous veins of Yucatan micro-pigs. The tissue is cut in a helix and mounted in a tank with isolated organs in a modified Krebs solution oxygenated with a mixture of 95% O ₂ and 5% CO ₂ maintained at 37 ° C. The vessel is connected to an isometric sensor at a basal voltage of 1 g and connected to a polygraph allowing the recording of blood pressure variations. The viability of each preparation is tested by pre-stimulation with noradrenaline 3μM. After rinsing, the compound to be studied is introduced and its concentration-response curve constructed cumulatively until a maximum response is obtained. The contractile effect of each compound is evaluated by calculation of the EC ₅₀ (concentration producing 50% of the maximum response). The compounds of the invention have made it possible to obtain a venoconstrictor activity with an EC50 value usually between 1 μM and 100 μM.

The compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer.

The compounds according to the invention can also be used for the treatment of migraine, gastrointestinal disorders and as a vasoconstrictor of the "nasal mucosa.

The use of the compounds according to the invention for the preparation of a medicament intended to treat the pathologies mentioned above forms an integral part of the invention.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.

Thus, these pharmaceutical compositions contain an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutical excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, its salt or hydrate, if any, can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal administration. For topical application, you can use the compounds according to the invention in creams, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.1 μg and 50 mg per kg of body weight per day. Although these dosages are examples of an average situation, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.

Each unit dose can contain from 0.1 to 1000 mg, preferably from 1 to 500 mg of active ingredient in combination ^'with a pharmaceutical excipient. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

For example, when preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative, or other materials. The tablets can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.

According to a second example, a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.

The present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a compound according to the invention or one of its salts or hydrates.

Claims

1. Compound of formula (I)

in which :

- A represents a hydrogen atom or a hydroxy,

- B represents a hydrogen atom or a C * ι _-3 alkyl group,

- Ri represents a phenyl optionally substituted by a halogen, a hydroxy, a group Cι _-3 alkoxy, C * ι _-3 alkyl, Cι _-3 fluoroalkyle or C _1-2 perfluoroalkyle.

- R ₂ , R ₃ and R ₆ , identical or different, each represent a hydrogen atom, a halogen, a hydroxy, a Ci-β alkyl group, C _2-6 alkenyl,

- R ₄ and R ₅ , identical or different, each represent a hydrogen atom, a C-ι- ₆ alkyl group, C _2- β alkenyl, C3-6 cycloalkyle, or R ₄ and R ₅ , together form a chain C _2-6 alkylene, C ₃ ^ alkenylene to give, with the nitrogen to which they are attached, a heterocycle, this heterocycle being optionally substituted by one or two C-alkyl groups; and its salts or hydrates excluding the compounds for which: • A represents a hydroxy; B represents a hydrogen atom; Ri represents 4-chlorophenyl; R ₂ represents a hydrogen atom; and

^* Rβ represents a 6-chloro, R ₃ represents a hydrogen and R ₄ and R ₅ both represent an ethyl or a butyl; or * R ₆ represents a 6-chloro, R ₃ represents a methyl and

R and R ₅ both represent butyl; or

^* Rβ represents a hydrogen atom, R ₃ represents a hydrogen and R and R ₅ both represent a butyl; or

^* R ₆ represents a 5-chloro, R ₃ represents a methyl and R ₄ and R ₅ both represent a butyl; and * A represents hydroxy;

B represents a hydrogen atom; R1 represents phenyl; R ₂ and R ₃ each represents a hydrogen atom; R ₄ and R ₅ together form a C _2-6 alkylene chain; and R ₆ represents a hydrogen atom or a 6-methyl.

2. Compound of formula (I) according to claim 1, characterized in that * A represents a hydroxy,

* B represents a hydrogen atom

* Ri represents a phenyl optionally substituted by a halogen, a C-ι group. ₃ alkyl, C ₁ . ₃ alkoxy or C-ι. ₂ perfluoroalkyl,

* R ₂ and R ₃ represent, each independently of one another, a hydrogen atom or a C1.4 alkyl group,

* R ₄ and R ₅ each represent a C-alkyl group O or R ₄ and R 5, together form a C _2- alkylene chain to give with the nitrogen to which they are attached an azetidinyl or a piperidyl, this an azetidinyl or piperidyl being optionally substituted with a C _1-2 alkyl group; and ^* Rβ represents a hydrogen atom.

3. Compound of formula (I) according to one of claims 1 or 2 characterized in that it consists of:

- 2-Phenyl-3-methyl-8- (2-diethylamino-1-hydroxyethyl Oquinoleine or - 2-Phenyl-8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl] quinoline or

- 2-Phenyl-3-methyl -8- [2- (ethyl-iso-propylamino) -1-hydroxyethyl] quinoline.

4. Process for the preparation of a compound of formula (I) according to one of claim 1 or 2, characterized in that an aldehyde of formula II is reacted

with a stannate derivative of formula III

R.

. N Sn (n-

R5 CW ₄ H ' ₉ 9)' 3

B

III

the meanings of R * ι, R ₂ , R ₃ , R, R _5τ R ₆ and B of the aldehyde of formula II and of the stannate derivative of formula III being those defined for the compound of formula (I) according to claim 1 , to give the compound of formula (I) in which A represents a hydroxy group, and optionally dehydroxyl to give the compound of formula (I) in which A represents a hydrogen atom.

5. Process for the preparation of a compound of formula (I), according to claim 1, in which A is a hydroxy group, characterized in that an oxirane derivative of formula XVI is reacted

with an amine NHR4R5, the meanings of Ri, R ₂ , R ₃ , Rβ and B of the oxirane of formula XVI and of R4 and R _{5 of} said amino, being those defined for the compound of formula (I) according to claim 1 .

6. Process for the preparation of a compound of formula (I), according to claim 1, in which A represents a hydroxy, characterized in that a compound of formula XIII is reacted,

XIII in which W represents an activated hydroxy group, with an amine NHR4R5, the meanings of Ri, R ₂ , R ₃ , R, R ₅ , Rβ and B of the compound of formula XIII and of said amine, being those defined for the compound of formula (I) according to claim 1.

7. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1, 2 or 3 and one or more suitable excipients.

8. Use of a compound according to one of claims 1, 2 or 3, or of a compound of formula (I), according to claim 1, in which • A represents a hydroxy; B represents a hydrogen atom; Ri represents 4-chlorophenyl;

R ₂ represents a hydrogen atom; and

* Rβ represents a 6-chloro, R ₃ represents a hydrogen and R4 and R5 both represent an ethyl or a butyl; or

^* R ₆ represents a 6-chloro, R ₃ represents a methyl and 4 and R5 both represent a butyl; or

^* R ₆ represents a hydrogen atom, R ₃ represents a hydrogen and R4 and R5 both represent butyl; or

^* R ₆ represents a 5-chloro, R ₃ represents a methyl and R4 and R ₅ both represent a butyl; and • A represents a hydroxy;

B represents a hydrogen atom;

R-i represents phenyl;

R ₂ and R ₃ each represents a hydrogen atom;

R ₄ βt R ₅ , together form a chain C ₂ -β alkylene; and Rβ represents a hydrogen atom or a 6-methyl; for the preparation of a medicinal product intended for the treatment of urinary incontinence, venous insufficiency, migraine or gastrointestinal disorders.