Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
  • C07D219/02—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with only hydrogen, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system

Definitions

• the subject of the present invention is 1-amino ethylquinoline derivatives, their preparation and their therapeutic use.
• * 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 ⁇ _ 6 alkyl, C 2 _ 6 alkenyl, C ⁇ g fluoroalkyle or ⁇ . 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 ⁇ _ 6 hydroxyalkyl, C 1 .
• 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, azatterdinyle or pyrrolidyl, this heterocycle being optionally substituted by a C x _ 4 alkyl group, and their salts.
• a heterocycle such as, for example, a piperidyle, azatterdinyle or pyrrolidyl, this heterocycle being optionally substituted by a C x _ 4 alkyl group, and their salts.
• 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 ⁇ _ 6 alkylsulfanyl , and more particularly a hydroxy, a phenyl, a C ⁇ _ 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 ⁇ _ 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.
• 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 3 ⁇ 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.
• alkyl, alkenyl or alkoxy represents respectively an alkyl, alkenyl or alkoxy with a linear or branched carbon chain
• 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.
• 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 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.
• 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.
• 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.
• an oxidant such as sodium periodate, osmium tetroxide or metachloroperbenzoic acid
• 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.
• 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.
• the reaction is carried out in dicoromethane in the presence of triethylamine.
• 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).
• 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
• 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 ).
• 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).
• an aniline of formula VII for which Y represents a halogen, a hydroxy or a methoxy, is heated with an aldehyde or a ⁇ -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.
• a dehydrating agent such as sulfuric acid
• an oxidant such as iodide sodium
• 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.
• 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).
• DDQ 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone
• 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.
• the compounds of formula V can be prepared, according to scheme 5, by a condensation reaction of a ⁇ -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 ',
• 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.
• R x represents a carbonyl, a cyano, a carboxamide
• a C x _ 6 alkoxycarbonyl group C x _ 6 hydroxyalkyl, hydroxycarbonyl, C x _ 6 alkoxyalkyl.
• 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.
• 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).
• 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).
• the reaction can be carried out by the action of mixed lithium aluminum hydride in an organic solvent such as tetrahydrofuran.
• 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):
• 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 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).
• Example 1 2, 3-Dimethyl-8- (1-diethylamino-2-hydroxyethyl) - quinoline, pamoate
• 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).
• (+) -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.
• HC1 represents a hydrochloride
• nPr represents a linear propyl group
• cPr represents a cyclopropyl group
• i-Pr represents an iso-propyl group
• the compounds of the invention were subjected to biological tests intended to demonstrate their contractile activity on the urethral and arterial smooth muscles.
• 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 ).
• a% E raax artery usually less than 5
• 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 3 ⁇ M.
• 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 ⁇ M and 100 ⁇ M.
• the compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer.
• 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 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).
• 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 ⁇ g / kg).
• 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%.
• the compounds according to the invention 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.
• 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 present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.
• 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.
• 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.
• the compounds according to the invention can be used in creams, ointments or lotions.
• the dose of active ingredient can vary between 1 ⁇ g 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.
• the main active ingredient is mixed with a pharmaceutical vehicle, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• 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.

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• Organic Chemistry (AREA)
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• Animal Behavior & Ethology (AREA)
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