EP1131293A1

EP1131293A1 - 1-aminoethylquinoline derivatives for treating urinary incontinence

Info

Publication number: EP1131293A1
Application number: EP99972204A
Authority: EP
Inventors: Christophe Philippo; Patrick Mougenot; Gérard Defosse; Alain Braun; Philippe R. Bovy
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1998-11-17
Filing date: 1999-11-10
Publication date: 2001-09-12
Also published as: FR2785903A1; JP2002529533A; AU1166000A; FR2785903B1; WO2000029379A1; US6331549B1

Abstract

The invention concerns compounds of general formula (I) wherein: A represents a hydrogen atom, an azido, a halogen, a hydroxy, a thiol, an amino, a phenyl, a C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, hydroxylamine, C1-C6 alkyl hydroxylamine, N, O-C1-C6 dialkyl hydroxylamine, C1-C6 alkoxy or C1-C6 alkylsulphanyl group; B and D represent independently of each other a hydrogen atom, a phenyl, a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 fluoroalkyl or C1-C6 perfluoroalkyl group, or together form an oxo; R1 represents a hydrogen atom, a halogen, a carbonyl, a cyano, a carboxamide, a C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxycarbonyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C2 perfluoroalkyl or CF3(OH)CH group, or R1 and R2 together form, with the carbons whereto they are bound a phenyl; R5 and R6 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cyloalkenyl, C1-C6 fluoroalkyl, C1-C2 perfluoroalkyl group or R5 and R6 together form a C2-C6 alkylene, C3-C6 alkenylene chain to produce with the nitrogen whereto they are bound a heterocycle, said heterocycle being optionally substituted by a C1-C4 alkyl group. The invention has therapeutic applications.

Description

1-AMΓNOETHYLQUINOLEINE DERIVATIVES FOR THE TREATMENT OF URINARY INCONTINENCE

The subject of the present invention is 1-amino ethylquinoline derivatives, their preparation and their therapeutic use.

The publication Chemical Abstracts, vol. 83, no. 9 (1/9/1975) discloses 8- (1-aminoethyl) quinoline and describes only its process for obtaining.

According to one aspect of the invention, it relates to the compounds corresponding to the general formula (I)

in which : * A represents a hydrogen atom, an azido, a halogen, a hydroxy, a thiol, an amino, a phenyl, a C ^ .g alkyl group, C _x _ ₆ alkyla ino, di (C _x _ ₆ alkyl) amino, hydroxylamine, C ₁ . ₆ alkyl hydroxylamine, dialkyl hydroxylamine, C _x _ ₆ alkoxy or alkylsulfanyl,

* B and D represent, independently of one another, a hydrogen atom, a phenyl, a group C _λ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ^ g fluoroalkyle or _λ . ₂ perfluoroalkyl, or together form an oxo,

* R _x represents a hydrogen atom, a halogen, a carbonyl, a hydroxycarbonyl, a cyano, a carboxamide, a group C ^ g alkyl, C ₂ _ ₆ alkenyl, C ₃ _ ₆ cycloalkyle, C _ ₆ alkoxycarbonyle, C _λ _ ₆ hydroxyalkyl, C ₁ . ₆ alkoxy, C ₁ _ ₆ alkoxy C ^ alkyl, C _λ _ ₆ fluoroalkyle, C _x _ ₂ perfluoroalkyle or CF ₃ (OH) CH, or R _x and R _{2 /} together, form a chain C ₃ _ ₅ alkylene, C ₃ _ ₅ alkenylene or form, with the carbons to which they are attached, a phenyl, * R _{2 /} R ₃ and R ₄ represent, independently of each other, a hydrogen atom, a halogen or a C ^ ₆ alkyl group, or R ₂ and R ₃ together, form a chain C ₃ _ ₅ alkylene, C ₃ _ ₅ alkenylene or R _x and R _{2 /} together, are as defined above, and

* R ₅ and R ₆ represent, independently of one another, a hydrogen atom, a group C ^ g alkyl, C ₂ _ ₆ alkenyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkenyl, C ^ g fluoroalkyle, C ^ perfluoroalkyle or R ₅ and R _6f together, form a chain C ₂ _ ₆ alkylene, C ₃ _ ₆ alkenylene to give with the nitrogen to which they are attached a heterocycle such as, for example, a piperidyle, azétidinyle or pyrrolidyl, this heterocycle being optionally substituted by a C _x _ ₄ alkyl group, and their salts.

The preferred compounds according to the invention are chosen from the following subgroups, in which:

* A represents a halogen, a hydroxy, a thiol, a phenyl, a group C ^ ₆ alkyl, hydroxylamine, C _x _ ₆ alkyl hydroxylamine, IS ^ OC ^ g dialkyl hydroxylamine, C _x _ ₆ alkoxy or C _λ _ ₆ alkylsulfanyl , and more particularly a hydroxy, a phenyl, a C _λ _ ₆ alkyl group, IS ^ OC- ^ g dialkyl hydroxylamine or C _t _ ₆ alkoxy; or

* B and D represent, independently of one another, a hydrogen atom, a phenyl, a C _λ _ ₆ alkyl group or together form an oxo; or

* R _x represents a group. ₅ alkyl, C ₂ - ₆ alkenyl, C _x _ ₆ fluoroalkyle, C _x _ ₂ perfluoroalkyle more particularly C _x _ ₆ alkyl, C _± _ ₂ perfluoroalkyle, or CF ₃ (OH) CH, or R _x and R _{2 /} together , form a C ₃ _ ₅ alkylene or C ₃ _ ₅ alkenylene chain, more particularly a C ₃ _ ₅ alkylene chain, or R _x and R ₂ form, with the carbons to which they are attached, a phenyl; or

* R ₅ and R ₆ represent, independently of one another, a C _x _ ₆ alkyl group, C ₂ _ ₆ alkenyl, or R ₅ and R _{6 /} together, form a chain C ₂ _ ₆ alkylene, C ₃ _ ₆ alkenylene to give with the nitrogen to which they are attached a heterocycle, this heterocycle being optionally substituted by a C _x _ ₄ alkyl group, more particularly C _x _ ₂ alkyl.

A particularly preferred subgroup of compounds of formula (I) is that in which A, B, D, R _x , R ₅ and R ₆ are as defined above in the subgroups of preferred compounds and, R _{2 /} R ₃ and R ₄ are as defined above.

In particular, the following subgroup of compounds is particularly preferred:

* A represents hydroxy, phenyl, C _x _ ₃ alkyl, N, O-C ₁ _ ₃ dialkyl hydroxylamine or C _x _ ₃ alkoxy;

* B and D represent, independently of one another, a hydrogen atom, a phenyl, a C _x _ ₃ alkyl group or together form an oxo;

* R _x represents a C _x _ ₃ alkyl, C _x _ ₂ perfluoroalkyl or R _x and R _{2 group;} together form a C ₃ _ ₅ alkylene chain, or R _x and R ₂ together with the carbons to which they are attached form phenyl;

* R _{2 /} R ₃ and R ₄ represent, independently of one another, a hydrogen atom, a halogen or a C _x _ ₃ alkyl group, or R ₂ and R _3ι together form a chain C ₃ _ ₅ alkylene, or R _x and R _{2 /} together, are as defined above,

* R ₅ and R ₆ represent, independently of one another, a C _x _ ₆ alkyl group, or R ₅ and R _6; together, form a piperidyle, this piperidyle being optionally substituted by a C _x _ ₂ alkyl group.

In this application:

- C _x _ _z (or C ₂ _ _z or C ₃ _ _z ), where z can take the values between 2 and 6, represents a carbon chain which can have from 1 (or 2 or 3) to z carbon atoms, the term alkyl, alkenyl or alkoxy represents respectively an alkyl, alkenyl or alkoxy with a linear or branched carbon chain,

the term alkylene or alkenylene represents respectively a divalent alkyl or alkenyl with a linear or branched carbon chain,

- Pg represents a protective group; examples of protective groups as well as methods of protection and deprotection are given in Protective groups in Organic Synthesis Greene et al., 2nd Ed. (John iley & Sons, Inc., New York), and

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

The compounds of general formula (I) may contain 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 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, 2-naphthalenesulfonate, palmoate, 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 base with the acid in an appropriate solvent, such as an alcoholic solution or an organic solvent, then separation of the medium which contains it by evaporation of the solvent or by filtration.

The compounds of the invention can be prepared according to methods illustrated by the schemes which follow. The preparation methods are part of the present invention.

1. The compounds of formula (I), in particular those for which A represents a hydroxy group, can be prepared according to the process described in scheme 1.

According to this process, an ethenyl derivative of formula IV is reacted with an oxidant, such as sodium periodate, osmium tetroxide or metachloroperbenzoic acid, in basic or acidic medium so as to form a diol of formula III. The hydroxy group twinned with group B (or D) is selectively protected by a protective group Pg, in a manner known to a person skilled in the art, for example by the formation of a silylated ether, so as to obtain the compound of formula II. The hydroxy group carried by the alpha carbon of the heterocycl of the compound thus obtained, is activated, in a manner known to those skilled in the art, so as to obtain a nucleophuge group, such as a mesyl, tosyle group or an atom of bromine. The compound of formula (I) according to the invention is then prepared from this compound by reacting it with an amine NHR ₅ R ₆ in excess, in an organic solvent such as chloroform, acetonitrile or tetrahydrofuran. Preferably, the reaction is carried out in dicoromethane in the presence of triethylamine. This reaction is followed by deprotection according to methods known to those skilled in the art, for example in the case of a sylated ether, the hydroxy group is deprotected by tert-butylammonium fluoride action. The meanings of R _x , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , B and D in each of the compounds of formulas II, III, IV and of the amine NHR ₅ R ₆ , are those indicated for the formula (I).

The ethenyl derivative of formula IV can itself be prepared from a quinoline derivative of formula V, where Y represents a nucleofuge group such as a halogen, or a hydrox group activated, for example, in triflate, by palladic coupling of Stille with a compound of formula VI, B and D having the same meanings as for the compounds of formula (I), under the conditions defined by DR Me Kean et al. (J. Org. Chem. 1987; 52: 492).

Alternatively, the ethenyl derivative of formula IV can be prepared from an aldehyde derivative of formula XIV, by a Wittig reaction under conditions standard for a person skilled in the art. The compounds of formula XIV can themselves be prepared by formylation of a halogen derivative of formula V, Y representing halogen, in the presence of N, N-dimethylformamide and butyl lithium. The formylation reaction can be carried out in an organic solvent such as tetrahydrofuran, N, N-dimethylformamide or a mixture of these solvents, according to the following reaction scheme (2): Diagram 2

V XIV IV

The compounds of formula XIV can also be prepared by a reaction for formylation of a quinoline derivative of formula V, carried out by means of a catalysis with palladium according to the method described by H. Kotsuki et al (Synthesis 1996: 470-472 ).

There are many preparations, known to those skilled in the art, of the compounds of formula V according to the invention, among these, some which have been used use the methods below.

Thus, the compounds of formula V can be prepared, according to scheme 3, by a Skraup or Doebner-Miller reaction. The reaction conditions used are those defined by P. Belser (Tetrahedron 1996; 52: 2937-2944) or by Z. Song (J. Heterocyclic Chem. 1993; 30: 17-21).

Diagram 3

VII VIII V

According to this scheme, an aniline of formula VII, for which Y represents a halogen, a hydroxy or a methoxy, is heated with an aldehyde or a β-unsaturated ketone of formula VIII in the presence of a dehydrating agent, such as sulfuric acid, and an oxidant, such as iodide sodium, to form a quinoline derivative of formula V substituted in position 8 by the group Y. The meanings of R _x , R ₂ , R ₃ and R ₄ of the compounds of formula V, VIII and VII are those indicated in formula I.

Alternatively, the compounds of formula V for which Y represents a hydroxy group can be prepared by an intramolecular cyclization reaction under the conditions defined by Uchiyama K. et al (Synlett 1997; 445-446), according to scheme 4.

Diagram 4

According to this process, the cyclization is obtained by treating a phenethyl ketone oxime of formula IX in the presence of sodium hydride and an oxidant such as 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ). The oxime of formula IX originating from the condensation, known to a person skilled in the art, between the phenethyl ketone of formula X and the hydroxylamine of formula XI. The meanings of R _x , R ₂ , R ₃ and R ₄ of the compounds of formula V, IX, X and XI are those indicated in formula I.

On the other hand, the compounds of formula V can be prepared, according to scheme 5, by a condensation reaction of a β-ketoester of formula XIII, in which R represents a C _x _ ₄ alkyl group, on an aniline of formula VII, wherein Y represents an O-CH _{3 group} , by heating in a high boiling solvent, such as diphenyl ether, to give a quinol-4-one of formula XII. This compound is then flavored in a manner known to those skilled in the art, to provide the compounds of formula V. The meanings of R _x , R ₂ , R ₃ and R ₄ of the compounds of formula V, VII, XII and XIII are those indicated in the formula (I ',

Diagram 5

The compounds of formula V for which R _x represents a methyl can be derivatized to give other compounds of formula V in which R _x represents a carbonyl, a cyano, a carboxamide, a C _x _ ₆ alkoxycarbonyl group, C _x _ ₆ hydroxyalkyl, hydroxycarbonyl, C _x _ ₆ alkoxyalkyl. To do this, the methyl in position 2 of the quinoline can be selectively oxidized and then derivatized. The oxidation reaction is carried out by treatment with selenium dioxide in a solvent such as dioxane (under the conditions defined by Ferranti, A. Farmaco. 1993, 48 (11), 1547-1553), which leads to compounds of formula V for which R _x represents an aldehyde. From this aldehyde, numerous functionalizations known to those skilled in the art, such as the addition of an organomagnesium or the oxidation to acid and the derivatization of the latter to esters, amides or nitrile have provided compounds of formula V for which RI represents a cyano, a carboxamide, a hydroxycarbonyl, a C _x _ ₆ alkoxycarbonyl group, C _x _ ₆ hydroxyalkyl or C _x _ ₆ alkoxy-C _x _ ₃ alkyl.

2. Alternatively, the compounds of formula (I), in which A is a C _x _ ₆ alkoxy group and, B and D, together, an oxo group according to the invention, can be prepared according to the following reaction scheme (6) : Diagram 6

(I) A = OH, B = D = H 0)

According to this process, a metallation of a halogen derivative of formula V is carried out, where Y represents a halogen, as defined above, for example by means of butyl lithium, then this product is reacted with the alkyl glyoxylate of formula XV. The reaction can be carried out in an organic solvent such as tetrahydrofuran. The hydroxy group of the compound of formula XVI can be activated by methods known to those skilled in the art, so as to obtain a nucleophuge group, such as a mesyl, tosyl group or a bromine atom, and it is then reacted with a amine NHR ₅ R ₆ , as defined above.

The compounds of formula (I), in which A is a C _x ₆ alkoxy group, B and D an oxo group according to the invention, can also be prepared by reaction of an organozinc of the halogen derivative of formula V with a compound previously obtained by reaction of a secondary ine of formula HNR ₅ R ₆ , for which the meanings R ₅ and R ₆ are those indicated for formula (I) except the hydrogen atom, with benzotriazole and alkyl glyoxylate of formula XV or the monoacetal of glyoxale, according to the method described by Katrizky et al. (Synthesis 1989, 323; Synthesis 1990, 1173).

3. The compounds of formula (I), in which A is a C _x ₆ alkoxy group, B and D an oxo group, can be reduced, by conventional methods known to those skilled in the art, to give the compounds of formula (I) in which A is a hydroxy group, B and D a hydrogen. Such methods are described for example in Advanced Organic chemistry (J. March, 3 ^rd Ed., John Iiley & Sons, Inc., New York, p. 1101). For example, the reaction can be carried out by the action of mixed lithium aluminum hydride in an organic solvent such as tetrahydrofuran.

4. On the other hand, the compounds of formula (I) according to the invention, for which A is not a hydroxy group, can also be prepared from the compound of formula I, where A is a hydroxy group, by activation of this group, in a manner known to a person skilled in the art, so as to obtain a nucleophuge group W, such as a mesyl, tosyle group or a bromine atom and from this compound by reacting the latter with a group nucleophile "A", "A" representing the nucleophile corresponding to A, the meaning of which is indicated for formula (I), according to the following reaction scheme (7):

(XVII (D

5. Alternatively, the compounds of formula (I) according to the invention, for which A is a hydrogen atom, can also be prepared by dehydroxylation of a corresponding compound of formula (I), where A is a group hydroxy. The dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with triethylsilane and trifluroacetic acid.

The compounds of formula (I) according to the invention, for which A is a hydrogen atom, can also be prepared according to the following reaction scheme (8):

Diagram 8

According to this process, the compound of formula (I) is prepared by reacting a nucleophilic derivative of formula B (D) -CHMX for which M represents a metal, Y represents a halogen, B and D have the meaning indicated for formula ( I), such as for example an organomagnesium or an organolithium, with an imine derivative of formula XVIII obtained by reaction of a secondary amine of formula NHR ₅ R ₄ , for which the meanings of R ₄ and R ₅ are those indicated for the formula (I) except the hydrogen atom, with an aldehyde of formula XIV. The meanings of R _x , R ₂ , R _3; R ₄ , B and D are those indicated for formula (I).

The starting materials for the syntheses of the compounds of formula (I) are directly commercially available, are known in the literature or can be synthesized by conventional methods known to those skilled in the art.

The following examples illustrate the methods and techniques suitable for the preparation of this invention, without however limiting the scope of the claim. Microanalyses and NMR and IR spectra confirm the structures of the compounds. Example 1: 2, 3-Dimethyl-8- (1-diethylamino-2-hydroxyethyl) - quinoline, pamoate

(1) 2, 3-Dimethyl-4-hydroxy-8-methoxyquinoline

12.3 g of 2-methoxyaniline, 14.2 g of ethyl 2-methylacetoacetate and 3 drops of IN HCl are introduced into a 250 ml three-necked flask fitted with a Dean-Stark and a condenser. The mixture is stirred for 1 night. 100 ml of toluene are added and the mixture is brought to reflux until complete distillation of the toluene / water azeotrope. The toluene is then evaporated and 100 ml of diphenyl ether are added. The mixture is heated for 1 hour at 200 ° C. 50 ml of diphenyl ether are evaporated and the mixture is cooled to ambient temperature. 20 ml of petroleum ether are added and the product which crystallizes is filtered. 2.1 g are obtained (Yield: 10%) of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline - M:> 290 ° C.

(2) 2, 3-Dimethyl-4-chloro-8-methoxyquinoline

2.09 g of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline, 10 ml of phosphorus oxychloride and 0.43 g of phosphorus pentachloride are introduced into a 25 ml two-necked flask fitted with a condenser. . The mixture is refluxed for 1 h. The reaction medium, cooled to room temperature, is poured onto 100 g of ice and extracted with ethyl acetate (2x100 ml). The organic phases are combined, washed with saturated sodium bicarbonate solution (200 ml), dried over magnesium sulfate and concentrated. The residue is purified by a chromatographic column on silica (dichloromethane elution solvent). 0.85 g is obtained (Yield: 37%) of 2, 3-dimethyl-4-chloro-8-methoxyquinoline - M: 130 ° C.

(3) 2, 3-Dimethyl-8-methoxyquinoline

1.23 g of 2,3-dimethyl-4-chloro-8-methoxyquinoline, 1 g of ammonium acetate, 20 ml are introduced into a Parr bottle. acetic acid and 1.2 g of palladium on charcoal (5%). The mixture is subjected to a hydrogen pressure of 50 psi for 4 h. The reaction medium is filtered and neutralized with 75 ml of 1N sodium hydroxide. Extraction is carried out with ethyl acetate (2 x 75 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. 1.32 g are obtained (Yield: 77%) of 2,3-dimethyl-8-methoxyquinoline - M: 138-139 ° C

(4) 2, 3-Dimethyl-8-hydroxyquinoline

1.25 g of 2,3-dimethyl-8-methoxyquinoline and 10 ml of 48% hydrobromic acid are introduced into a 25 ml two-necked flask fitted with a condenser. It is heated at 100 ° C for 24 h. The reaction mixture, cooled to room temperature, is neutralized with a concentrated solution (30%) of sodium hydroxide. 100 ml of water are added and the mixture is extracted with ethyl acetate (2 x 100 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. 0.79 g is obtained (Yield: quantitative) of 2, 3-dimethyl-8-hydroxyquinoline - M: 170 ° C

(5) 2, 3-Dimethyl-8-trifluoromethanesulfonatequinoline

0.79 g of 2,3-dimethyl-8-hydroxyquinoline, 8 ml of dimethylformamide, 1.21 g of 4-nitrophenyl trifluoromethanesulfonate and 0.62 g of potassium carbonate are introduced into a 25 ml two-necked flask. The reaction medium is stirred for 2 h and then poured onto 100 ml of ethyl acetate. The organic phase is decanted and successively washed with water (50 ml) and brine (3 x 50 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatographic column on silica (elution solvent ethyl acetate: cyclohexane 1:20). 0.396 g is obtained (Yield: 29%) of 2, 3-dimethyl-8-trifluoromethanesulfonatequinoline (purity: 84%) in the form of an oil. (6) 2, 3-Dimethyl-8-vinylquinoline

0.38 g of 2,3-dimethyl-8-trifluoromethanesulfonatequinoline, 10 ml of dioxane, 0.44 ml of tributylvinyltin, 0.19 g of lithium chloride and 0 are introduced into a 25 ml two-necked flask fitted with a condenser. .08 g of tetrakistriphenylphosphine palladium. The reaction medium is degassed by bubbling nitrogen for 30 minutes and then refluxed for 3 h. The solvent is evaporated off and the residue is purified by a chromatographic column on silica (elution solvent ethyl acetate: cyclohexane 1:40). 0.169 g is obtained (Yield: 68%) 2, 3-dimethyl-8-vinylquinoline in the form of an oil.

(4) 2,3-dimethyl-8- (1,2-dihydroxyethyl) quinoline

1.17 g (10 mmol) of N-methyl-N-oxide-morpholine, 10 ml of water and 30 ml of acetone are placed in a 100 ml three-necked flask. 0.4 mol of a 1% by mass solution of osmium tetroxide in tert-butanol is added dropwise, followed by a solution of 1.4 g (7.6 mmol) of 2.3. dimethyl-8-vinylquinoline in 10 ml of acetone. The reaction mixture is stirred for 2 hours at room temperature. 50 ml of water are added and extraction is carried out with ethyl acetate (3 × 100 ml). The organic phases are combined, washed with 100 ml of a 1% solution of sodium bisulfite and 100 ml of a 1% solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent 30% ethyl acetate in cyclohexane). 1.34 g are obtained (Yield: 81%) of 2, 3-dimethyl-8- (1, 2-dihydroxy ethyl) quinoline in the form of a white solid. M = 120 ° C.

(5) 2,3-dimethyl-8- (1-hydroxy-2- [tert-butyldimethyl silyloxy] ethyl) quinoline

1.32 g (6.1 mmol) of 2, 3-dimethyl-8- (1, 2-dihydroxy-ethyl) quinoline, 0.2 ml of N, N-dimethylformamide are placed in a 100 ml flask. 50 ml of dichloromethane and 0.612 g (9 mmoles) of imidazole. The mixture is cooled to 0 ° C, 1.0 g (6.6 mmol) of tert-butyldimethylchlorosilane is added and the mixture is stirred for 2 hours at 0 ° C. 50 ml of water are added and extraction is carried out with ethyl acetate (3 x 100 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent 10% ethyl acetate in hexane). 1.68 g are obtained (yield: 83%) of 2,3 dimethyl-8- (2- [tert-butyldimethyl silyloxy] -1-hydroxyethyl) quinoline in the form of an oil.

(6) 2,3-dimethyl-7- (1-diethylamino-2- [tert-butyl dimethyl silyloxy] -ethyl) -quinoline

1.04 g (3.15 mmol) of 2,3-dimethyl-8-1-hydroxy-2- [tert-butyldimethylsilyloxy] -1-hydroxyethyl) quinoline, 20 ml of are introduced into a 100 ml flask. ethyl ether and 0.53 ml (3.77 mmol) of triethylamine. The mixture is cooled to -30 ° C by a dry ice bath in acetone and 0.30 ml (3.9 mmol) of esyl chloride is added. The cooling bath is removed and the reaction mixture is allowed to return to room temperature for 30 minutes. 100 ml of water are added and extraction is carried out with ethyl ether (3 x 100 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is transferred without further purification into a 25 ml three-necked flask fitted with a condenser. 6.5 ml (63 mmol) of diethylamine, 5 ml of chloroform are added and the mixture is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature, it is concentrated under vacuum, 50 ml of water are added and extraction is carried out with ethyl acetate (3 x 50 ml). The organic phases are combined, dried over magnesium sulfate, and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent 10% methanol in dichloromethane). 0.64 g (yield 53%) of 2, 3-dimethyl-8- (1-diethylamino-2- [tert-butyldimethylsilyloxy] ethyl) quinoline is obtained in the form of an oil. (7) 2, 3-Dimethyl-8- [1-diethylamino-2-hydroxyethyl) quinoline.

0.60 g (1.55 mmol) of 2,3-dimethyl-8- [1-diethylamino-2- [tert-butyldimethyl silyloxy] ethyl] quinoline and 5 ml of tetrahydrofuran are introduced into a 50 ml flask. The mixture is cooled to 0 ° C. in an ice bath and a solution of 0.60 g (2.3 mmol) of tert-butylammonium fluoride trihydrate in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 0 ° C for 1 hour and at room temperature for 16 hours. 50 ml of water are added and extraction is carried out with ethyl ether (3 x 50 ml). The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 5% methanol in dichloromethane). 0.4 g (yield: 95%%) of 2,3-dimethyl-8- (1-diethylamino-2-hydroxyethyl) quinoline is obtained in the form of an oil.

(8) 2,3-dimethyl-8- (1-diethylamino-2-hydroxyethyl) quinoline pamoate.

To the 2,3-dimethyl-8- (1-diethylamino-2-hydroxyethyl) quinoline is added an equivalent of pamoic acid and the mixture is triturated in acetone and then filtered. Water is added to the filtrate, filtered and the precipitate is dried in a desiccator over P ₂ 0 ₅ to give the 2,3-dimethyl-8- (1-diethylamino-2-hydroxyethyl) quinoline pamoate as a yellow solid - F: 228 ° C.

Example 2: Asymmetric synthesis of (+) -2-ethyl-3-methyl-8- (1 (R) -diethylamino-2-hydroxyethyl) quinoline, hydrochloride

(1) (+) -2-Ethyl-3-methyl-8- (1 (S), 2-dihydroxyethyl) quinoline

2.0 g of 2-ethyl-3-methyl-8-vinylquinoline, 65 ml of t-butanol, 65 ml of water are introduced into a 250 ml flask. The solution is cooled to 0 ° C. in an ice bath and 16.8 g of AD-mix-α (complex based on K ₂ Os0 ₂ (OH) ₄ , Fe (CN) ₆ and, in addition, are added. as a ligand, dihydroquinidine 1,4- phthalazinediyl diether). Stirring is continued for 18 h at 0 ° C. and a solution of 12.6 g of sodium sulfite in 30 ml of water is added. The mixture obtained is stirred for 1 h at room temperature, then extraction is carried out with ethyl acetate (2 × 200 ml). The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by a chromatographic column on silica (elution solvent ethyl acetate / heptane 3/7). 2.0 g (yield: 86.5%) of (+) - 2-Ethyl-3-methyl-8- (1 (S), 2-dihydroxyethyl) quinoline are obtained in the form of a white solid.

F: 66 ° C, [] ²⁰ _D = + 33.9 ° (C = 1, methanol), enantiomeric excess: 95% by chiral HPLC.

(2): (+) - 2-Ethyl-3-methyl-8- (1 (S) -hydroxy-2- [tert-butyldimethylsilyloxy] ethyl) quinoline.

1.72 g (7.45 mmol) of (-) -2-ethyl-3-methyl-8- (1 (R), 2-dihydroxyethyl) quinoline, 25 ml of dichloromethane are introduced into a 100 ml flask and 0.75 g imidazole. The mixture is cooled to 0 ° C., 1.12 g (7.45 mmol) of tert-butyl dimethyl chlorosilane are added and the mixture is stirred for 2 hours at 0 ° C. 50 ml of water are added and extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent 10% ethyl acetate in hexane). 1.85 g are obtained (Yield: 72%) of (+) - 2- ethyl-3-methyl-8- (1 (S) -hydroxy-2- (tert-butyldimethylsilyloxy] ethyl) quinoline in the form of a oil.

(3) (+) -2-Ethyl-3-methyl-8- (1 (R) -diethylamino-2- [tert-butyl dimethyl silyloxy] -ethyl) quinoline

1.85 g (5.35 mmol) of (+) -2-ethyl-3-methyl-8- (1 (S) -hydroxy-2- [tert-butyldimethylsilyloxy] ethyl are introduced into a 250 ml flask ) quinoline, 65 ml of ethyl ether and 1.33 ml (9.6 mmol) of triethylamine. The mixture is cooled to -30 ° C by a dry ice bath in acetone and 0.67 g (8.53 mmol) of mesyl chloride is added. The cooling bath is removed and the reaction mixture is allowed to return to room temperature for 30 minutes. 100 ml of water are added and extraction is carried out with ethyl ether (3 x 50 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. Part of the residue (0.8 g of the 2.5 g obtained) is transferred without additional purification to a 50 ml three-necked flask fitted with a condenser. 2.5 ml (34.6 mmol) of diethylamine, 3 ml of chloroform are added and the mixture is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature, it is concentrated under vacuum, 50 ml of water are added and extraction is carried out with ethyl ether (3 x 30 ml). The organic phases are combined, dried over magnesium sulfate, and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent 10% methanol in dichloromethane). 0.45 g is obtained (yield 60%) of (+) - 2-ethyl-3-methyl-8- (1 (R) -diethylamino-2- [tert-butyl dimethyl silyloxy] -ethyl) quinoline in the form of 'an oil.

(4): (+) - 2-Ethyl-3-methyl-8- (l (R) -diethylamino-2-hydroxyethyl) quinoline

0.40 g (1.0 mmol) of (+) -2-ethyl-3-methyl-8- (1-diethylamino-2- [tert-butyl dimethyl silyloxy] -ethyl is introduced into a 50 ml flask ) quinoline and 5 ml of tetrahydrofuran. The mixture is cooled to 0 ° C. in an ice bath and a solution of 0.40 g (1.52 mmol) of tert-butylammonium fluoride trihydrate in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 45 ° C for 3 hours. 50 ml of water are added and extraction is carried out with ethyl acetate (3 x 50 ml). The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 5% methanol in dichloromethane). 0.25 g is obtained (Yield: 87.4%%) of (+) -2-ethyl-3-methyl-8- (1 (R) -diethylamino-2-hydroxyethyl) quinoline in the form of an oil. (5) (+) -2-Ethyl-3-methyl-8- (1 (R) - diethylamino-2-hydroxyethyl) quinoline hydrochloride

250 mg of (+) -2-ethyl-3-methyl-8- (1 (R) - diethylamino-2-hydroxyethyl) quinoline is added to an equivalent of a 0.1 N hydrochloric acid solution in the isopropanol. The isopropanol is evaporated and recrystallized from acetone. 0.20 g of (+) -2-ethyl-3-methyl-8- (1 (R) -diethylamino-2-hydroxyethyl) quinoline, hydrochloride, are obtained in the form of a white solid - M: 187 ° C. [α] ²⁰ _D = +2.01 ° (C = l, methanol)

Example 3

Using essentially the same method as that of Example 1, using an adequate amine in step (6), other compound of formula (I) according to the invention was prepared. These compounds are those of the table below.

In this Table: - pam. represents a pamoic acid salt,

HC1 represents a hydrochloride,

"-" represents a compound in free form, nPr represents a linear propyl group, cPr represents a cyclopropyl group, i-Pr represents an iso-propyl group,

And represents an ethyl group, - Me represents a methyl group. In column B (D), D is indicated when it does not represent hydrogen. Furthermore, the compounds whose number is accompanied by a " ^* " are in chiral form for the carbon carrying the amine. (R) and (S) indicate the R or S configuration of the carbon to which it is attached. All the other compounds in the table are racemates.

The compounds of the invention were subjected to biological tests intended to demonstrate their contractile activity on the urethral and arterial smooth muscles.

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 by a mixture of 95% of 0 ₂ and 5% of 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 the 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 _raax ).

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

* a pD ₂ urethra, usually between 4 and 8

* a pD ₂ artery usually less than 3,

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

a% E _raax artery usually less than 5

2. 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 is mounted in a tank with organs isolated in an oxygenated modified Krebs solution by a mixture of 95% 0 ₂ and 5% C0 ₂ maintained at 37 ° C. The vessel is connected to an isometric sensor at a basal voltage of 1 g and is 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 EC ₅₀ 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.

3. 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 femoral artery 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 (PU ₁₀ ) or the blood pressure of 10 mm Hg (PA ₁₀ ) or 50 mm Hg (PA ₅₀ ) •

The compounds of the invention thus tested, made it possible to obtain:

- PU ₁₀ with doses less than 500 μg / kg, usually between 5 and 200 μg / kg,

- a PA ₁₀ with doses greater than 600 μg / kg, usually between 600 and 2000 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 a mixture of Ketamine and Xylazine. 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 (i.v.) administration in 5 minutes, and in a single dose (10 or 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 intravenous administration (i. V.).

The compounds of the invention thus tested, allowed an increase in the PU greater than 50%, usually between 50 and 350% after intravenous administration, and usually between 50 and 200% after gavage. The increase in BP was always less than 10%, usually 0%.

All of the above results show that the compounds of the invention have a strong urethral contractile action and a weak arterial contractile 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 stress urinary incontinence. In this indication, the compounds according to the invention have good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the cardiovascular system, in particular the arterial beds.

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

The use of the compounds according to the invention for the preparation of medicaments 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, solvate or hydrate thereof, and one or more suitable 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 ingredients of formula (I) above or their salts, solvates or hydrates, if appropriate be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, 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, the compounds according to the invention can be used in creams, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active ingredient can vary between 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 mode of administration, the pea and the response of said patient.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. 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 the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. One can coat the tablets ^{^} sucrose, a cellulose derivative or other materials.

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.

The present invention according to another of its aspects, also relates to a method of treatment of the above pathologies which comprises administering a compound according to the invention.

Claims

claims

1. Compound of formula (I]

in which :

* A represents a hydrogen atom, an azido, a halogen, a hydroxy, a thiol, an amino, a phenyl, a group C ₁ . ₆ alkyl, C _λ _ ₆ alkylamino, di (C ^ g alkyl) amino, hydroxylamine, C ₁ . ₆ alkyl hydroxylamine, I ^ OC ^ g dialkyl hydroxylamine, C ^ g alkoxy or C ₁ . ₆ alkylsulfanyl,

* B and D represent, independently of one another, a hydrogen atom, a phenyl, a group C ^ g alkyl, C ₂ _ ₆ alkenyl, C ^ g fluoroalkyle or C ^ perfluoroalkyle, or together form a oxo,

* R _λ represents a hydrogen atom, a halogen, a carbonyl, a hydroxycarbonyl, a cyano, a carboxamide, a group C ^ g alkyl, C ₂ _ ₆ alkenyl, C ₃ _ ₆ cycloalkyl, C ^ g alkoxycarbonyl, C ^ g hydroxyalkyl, C ^ g alkoxy, C ^ g alkoxy C _x _ ₃ alkyl, C ₁ . ₆ fluoroalkyle, C _λ _ ₂ perfluoroalkyle or CF ₃ (OH) CH, or R _λ and R _2f together, form a chain C ₃ _ ₅ alkylene, C ₃ _ ₅ alkenylene or form, with the carbons to which they are attached, a phenyl,

* R _2r R ₃ and R ₄ represent, independently of one another, a hydrogen atom, a halogen or a group C ^ g alkyl, or R ₂ and R _{3 #} together, form a chain C ₃ _ ₅ alkylene, C ₃ _ ₅ alkenylene or R _x and R _{2 (} together, are as defined above,

* R ₅ and R ₆ represent, independently of one another, a hydrogen atom, a group _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkenyl, C ₁ . ₆ fluoroalkyle, C ^ perfluoroalkyle or R ₅ and R _{6 #} together, form a chain C ₂ _ ₆ alkylene, C ₃ _ ₆ alkenylene to give with the nitrogen to which they are attached a heterocycle, this heterocycle being optionally substituted by a C _x _ ₄ alkyl group, and its salts, with the exception of 8- (1-aminoethyl) quinoline.

2. Compound according to claim 1, characterized in that:

* A represents a hydroxy, a phenyl, a C ^ alkyl, N, O-C ₁ _ ₃ dialkyl hydroxylamine or C ^ alkoxy group;

* B and D represent, independently of one another, a hydrogen atom, a phenyl, a C ^ alkyl group or together form an oxo;

* R _x represents a C ^ alkyl group, C ^ perfluoroalkyle or R ₁ and R _2j together, form a C ₃ _ ₅ alkylene chain, or R _λ and R ₂ form, with the carbons to which they are attached, a phenyl;

* R ₂ , R ₃ and R ₄ represent, independently of each other, a hydrogen atom, a halogen or a C _x _ ₃ alkyl group, or R ₂ and R _3r together form a chain C ₃ . ₅ alkylene, or R _x and R _2; together, are as defined above,

* R ₅ and R ₆ represent, independently of one another, a group C ^ g alkyl, or R ₅ and R _{6 /} together, form a piperidyle, this piperidyle being optionally substituted by a group C ^ alkyl.

3. Compound according to one of claims 1 or 2, characterized in that it consists of: - 2,3-Dimethyl-8- (l-diethylamino-2-hydroxyethyl) -quinoline, or

- (+) -2-ethyl-3-methyl-8- (1 (R) -diethylamino-2-hydroxyethyl) quinoline.

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

in which R _1r R ₂ , R _3, R ₄ , B and D are as defined in claim 1 and Pg is a protective group, with an amine of formula HNR ₅ R ₆ in which R ₅ and R ₆ are such that defined in claim 1, followed by deprotection,

5. Process for the preparation of the compound of formula (I), according to claim 1, in which A is a Cι_ ₆ alkoxy group, B and D, together, an oxo group, by reaction of a compound of formula XVI

in which R _lr R ₂ , R ₃ and R ₄ are as defined in claim 1, A is a Cι_ ₆ alkoxy group, B and D represent an oxo group, with an amine of formula HNR ₅ R ₆ in which R ₅ and R ₆ are as defined in claim 1.

6. Process for preparing the compound of formula (I), according to claim 1, in which A is not a hydroxy group, characterized in that a compound of formula XVII is reacted

wherein R _1r R ₂ , R ₃ , R ₄ , R _{5 /} R ₆ , B and D are as defined in claim 1 and W is a nucleophuge group, with a nucleophilic group A as defined in claim 1.

7. Medicament, characterized in that it consists of a compound according to claim 1, it being understood that 8- (l-aminoethyl) quinoline is not excluded.

8. Pharmaceutical composition characterized in that it comprises a compound according to claim 1, it being understood that 8- (1-aminoethyl) quinoline is not excluded, and one or more suitable excipients.