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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • 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
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • 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
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • 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
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

• the present invention relates to 2-phenyl-quinoline derivatives, their preparations and their therapeutic applications.
• 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.
• A represents a hydroxy
• B represents a hydrogen atom
• Ri represents 4-chlorophenyl
• R 2 represents a hydrogen atom
• * R ⁇ represents a 6-chloro
• R 3 represents a hydrogen
• R4 and R5 both represent ethyl or butyl
• R 6 represents a 6-chloro
• R 3 represents a methyl and R 4 and R 5 both represent a butyl
• R ⁇ represents a hydrogen atom
• R 3 represents a hydrogen and R 4 and R 5 both represent a butyl
• R 6 represents 5-chloro
• R 3 represents methyl
• R and R 5 both represent butyl.
• the subject of the present invention is the 2-phenyl-quinoline derivatives, corresponding to the following general formula (I)
• - A represents a hydrogen atom or a hydroxy
• - B represents a hydrogen atom or a C ⁇ -3 alkyl group
• - Ri represents a phenyl optionally substituted by a halogen, a hydroxy, a group C * ⁇ -3 alkoxy, C ⁇ -3 alkyl, C ⁇ -3 fluoroalkyle or C ⁇ -2 perfluoroalkyle.
• R 2 , R 3 and R ⁇ identical or different, each represent a hydrogen atom, a halogen, a hydroxy, a Ci- ⁇ alkyl group, C 2- ⁇ 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 - ⁇ 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
• R 6 represents a 6-chloro
• R 3 represents a hydrogen
• R 4 and R 5 both represent an ethyl or a butyl
• R ⁇ represents 6-chloro
• R 3 represents methyl and R and R5 both represent butyl
• R 6 represents a hydrogen atom
• R 3 represents a hydrogen
• R 4 and R 5 both represent butyl
• 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- ⁇ 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.
• * Ri represents a phenyl optionally substituted by a halogen, a C * ⁇ -3 alkyl, C ⁇ -3 alkoxy or C * ⁇ -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 C ⁇ -2 alkyl group; or * R 6 represents a hydrogen atom.
• 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.
• 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- ⁇ -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,
• cycloalkyl a cyclic alkyl, for example, a C 3 - 6 cycloalkyl group represents a cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl,
• alkylene and alkenylene respectively a divalent alkyl and alkenyl
• protection 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).
• 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.
• 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.
• 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, pamoate, 2-naphthalenesulfonate, paratoluenesulfonate.
• 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.
• 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 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).
• 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.
• 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.
• 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.
• the compounds of formula IV can be prepared by a Friedlander condensation reaction.
• 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- ⁇ or AD -mix- ⁇ ) 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.
• an oxidant such as sodium periodate, osmium tetroxide (in racemic or chiral series by using AD-mix- ⁇ or AD -mix- ⁇ ) 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.
• 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 * ⁇ , R 2 , R 3 , R 4 , R5, R ⁇ 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.
• 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.
• 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 R ⁇ Sn (nC 4 Hg) 3 or R * ⁇ B (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.
• a halogen such as bromine, iodine or chlorine
• an activated hydroxy group such as a triflate group
• the compound of formula XV can itself be obtained according to reaction scheme 7.
• 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.
• 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.
• 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.
• a chlorinated solvent such as dichloromethane or chloroform
• R 2 , R 3 , R ⁇ and B of the compounds of formula XV, XVII, XVIII, XIX, XX and XXI are those indicated in formula I.
• 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).
• - pam. represents a salt of pamoic acid
• - Me represents a methyl group.
• the compounds of the invention were subjected to biological tests intended to demonstrate their selective smooth muscle contracting activity.
• the in vitro activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles.
• 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 ).
• 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 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 ⁇ g / kg) * We measured here the increase in urethral pressure (PU) and blood pressure (PA), compared to basal pressure, urethral and arterial respectively.
• PU urethral pressure
• PA blood pressure
• 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%.
• 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 urinary incontinence, in particular stress urinary incontinence.
• 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 3 ⁇ M. 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 ⁇ M and 100 ⁇ M.
• 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 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 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.
• 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.
• the dose of active principle can vary between 0.1 ⁇ 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 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.
• the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• 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.
• 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.
• aqueous suspensions, isotonic saline solutions or sterile injectable solutions 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.

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• 1999
  • 1999-12-17 FR FR9915934A patent/FR2802532A1/fr not_active Withdrawn
• 2000
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