EP2854758A1 - Pharmazeutische zusammensetzung mit einem papillomavirus-inhibitor - Google Patents

Pharmazeutische zusammensetzung mit einem papillomavirus-inhibitor

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Publication number
EP2854758A1
EP2854758A1 EP13721713.9A EP13721713A EP2854758A1 EP 2854758 A1 EP2854758 A1 EP 2854758A1 EP 13721713 A EP13721713 A EP 13721713A EP 2854758 A1 EP2854758 A1 EP 2854758A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
group
composition according
weight
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13721713.9A
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English (en)
French (fr)
Inventor
Marta Blumenfeld
Delphine Compere
Patricia FRANCON
Michel HUTIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anaconda Pharma SAS
Original Assignee
Anaconda Pharma SAS
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Filing date
Publication date
Application filed by Anaconda Pharma SAS filed Critical Anaconda Pharma SAS
Publication of EP2854758A1 publication Critical patent/EP2854758A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants

Definitions

  • the present invention relates to a pharmaceutical composition of compounds useful for the treatment and prevention of infections related to the papillomavirus, described in particular in the application WO 2007/135106.
  • A represents an optionally substituted aryl, cycloalkyl, cycloalkenyl or heterocycle group
  • B represents an aryl or an optionally substituted heterocycle
  • R1 and R2 independently represent a hydrogen atom or various substituents
  • R3 represents an acid function or a prodrug radical or a bioisostere of this function
  • Gi represents a bond or a hydrocarbon chain
  • R represents a hydrogen atom or various substituents
  • W representing O, S or NH
  • G representing a bond or a hydrocarbon chain.
  • compositions of very simple preparation allow rapid and high release of the active principle.
  • the subject of the present invention is therefore a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I):
  • ⁇ G is a bond or a hydrocarbon chain, linear or branched, saturated or unsaturated, comprising 1 to 4 carbon atoms, optionally substituted by one or two alkyl groups, preferably identical,
  • ⁇ A represents an aryl group such as phenyl, optionally substituted:
  • ⁇ B represents an aryl group, preferably phenyl, substituted in the ortho position with a heterocycle, preferably a N-cycloalkyl, such as a group piperidin-l-yl, and optionally substituted at ortho 'position with an alkyl group, such as methyl,
  • ⁇ n is an integer between 1 and 4, preferably between 1 and 2, and more preferably is 1, ⁇ RI represents an alkoxy group such as methoxy, preferably in the position ortho to R3,
  • ⁇ R2 represents a hydrogen or halogen atom, such as chlorine or bromine, or an alkyl group such as methyl, preferably in meta position with respect to R3, and
  • ⁇ R 3 is an acid or ester group, and preferably acidic
  • the term "pharmaceutically acceptable” means that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither logically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.
  • salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound.
  • Such salts include:
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, acid methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid trimethylacetic acid, trifluoroacetic acid and the like; and
  • a metal ion for example an alkali metal ion (Na + , K + or Li + for example), an alkaline metal ion; earthy (such as Ca 2+ or Mg 2+ ) or an ion aluminum; either coordinates with an organic or inorganic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • halogen means a fluorine, bromine, chlorine or iodine atom.
  • fluorine bromine or chlorine atom.
  • alkyl group is meant, in the sense of the present invention, a saturated hydrocarbon chain, linear or branched, comprising from 1 to 6 carbon atoms, in particular the methyl, ethyl, n-propyl, isopropyl, n-propyl groups. butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
  • it is methyl.
  • cycloalkyl group is intended to mean a monocyclic or polycyclic, preferably mono-, bi- or tri-cyclic, saturated system comprising from 3 to 12 carbon atoms, the cycles being able to be two or more carbon atoms. two fused or bridged, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decalinyl or norbornyl.
  • N-cycloalkyl is meant, in the sense of the present invention, a cycloalkyl group as defined above for which a carbon atom has been substituted by a nitrogen atom, the bond with the molecule being by this nitrogen atom. It is advantageously a piperidin-1-yl or pyrrolidin-1-yl group.
  • acyl is meant, within the meaning of the present invention, a group of formula -C (O) -Z, where Z represents an alkyl group as defined above. or phenyl. It may advantageously be an acetyl, ethylcarbonyl or benzoyl group.
  • alkoxy group is meant, in the sense of the present invention, an alkyl group as defined above bonded to the molecule through an oxygen atom. It may be in particular a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy or tert-butoxy group.
  • haloalkoxy group is meant, in the sense of the present invention, an alkoxy group as defined above substituted with one or more halogen atom (s) as defined above.
  • it will be fluoroalkoxy, that is to say an alkoxy group substituted by one or more fluorine atom (s), such as a group -OCF 3 or -OCH 2 CF 3 .
  • aryl group is meant, in the sense of the present invention, an aromatic group, preferably comprising from 5 to 10 carbon atoms and comprising one or more contiguous rings, such as for example a phenyl or naphthyl group.
  • aryl is meant, in the sense of the present invention, an aromatic group, preferably comprising from 5 to 10 carbon atoms and comprising one or more contiguous rings, such as for example a phenyl or naphthyl group.
  • it is phenyl.
  • heterocycle is intended to mean a monocyclic or polycyclic, and preferably mono- or bi-cyclic, saturated, unsaturated or aromatic system comprising from 3 to 12 ring members, the rings being two fused, spiro-fused or bridged, and comprising 1 to 4 heteroatoms, identical or different, selected from O, S and N, and optionally comprising one or two oxo or thioxo groups, being understood only in the case of a polycyclic system one of the cyles may be aromatic while the other may be aromatic, saturated or unsaturated.
  • these will be piperidyl, piperazyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyradizinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo [l, 2, 5] thiadiazolyl, benzo [1,2,5] oxadiazolyl, [1,2,3] triazolyl and [1,2,4] triazolyl.
  • arylalkyl is meant, in the sense of the present invention, an aryl group as defined above linked to the molecule through an alkyl group as defined above. Preferably, it is a benzyl group.
  • acylaminoalkyl means a group of formula -Alk-NHCO-Alk ', in which Alk and Alk' represent, independently of one another, an alkyl group as defined herein. -above.
  • the term "acid” means a COOH group.
  • esters is meant, within the meaning of the present invention, a -CO-O-Alk group, where Alk represents an alkyl group as defined above.
  • viscosifying agent is intended to mean a compound which makes it possible to increase the viscosity of a fluid, such as a liquid. This thus makes it possible to modify the rheological properties of the fluid, which then becomes more viscous.
  • composition according to the invention will comprise 0.01 to 10%, especially 2 to 8%, preferably about 5% by weight of a compound of formula (I) relative to the total weight of the composition.
  • the viscosifying agent may be hydroxypropylcellulose, hydroxypropylmethylcellulose or a carbomer.
  • the viscosifying agent could also be in the form of a mixture thereof.
  • the viscosifying agent will be hydroxypropylcellulose.
  • composition according to the invention may comprise 0.01 to 50%, in particular 0.05 to 10%, especially 0.5 to 5%, preferably 1 to 5% by weight of this viscosifying agent relative to the total weight of the composition.
  • composition according to the invention will also advantageously comprise a solvent such as propylene glycol, glycerol or polyethylene glycol.
  • a solvent such as propylene glycol, glycerol or polyethylene glycol.
  • the solvent could also be in the form of a mixture thereof.
  • the solvent will be propylene glycol.
  • composition according to the invention may comprise 40 to 99.9%, in particular 80 to 99.5%, especially 85 to 99%, preferably 90 to 95% by weight of this solvent relative to the total weight of the composition.
  • composition according to the present invention will advantageously comprise, and preferably will consist of, a compound of formula (I), a viscosifying agent and a solvent.
  • This pharmaceutical composition may in particular comprise or be constituted by (the percentages by weight being expressed relative to the total weight of the pharmaceutical composition):
  • this pharmaceutical composition will comprise or consist of (the percentages by weight being expressed relative to the total weight of the pharmaceutical composition):
  • a viscosifier selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, a carbomer and mixtures thereof, and
  • a solvent selected from propylene glycol, glycerol, polyethylene glycol and mixtures thereof.
  • composition according to the present invention will comprise, and preferably will consist of, a compound of formula (I), hydroxypropylcellulose and propylene glycol.
  • composition according to the invention will thus have in particular the following composition, with respect to the total weight of the composition:
  • composition according to the invention will be in particular in gel form.
  • the gel will have in particular a viscosity of 5,000 to 50,000 mPa.s, in particular 15,000 to 25,000 mPa.s, measured according to the standards of European Pharmacopoeia 2.2.10.
  • the viscosity is measured more particularly at 25 ° C. using a Brookfield model HDBV + apparatus or equivalent, with a No. 21 needle for a rotation speed of 10 rpm. The values are determined after 1 minute of rotation.
  • G 1 represents a bond and a linear and saturated hydrocarbon-based chain comprising 1 to 4 carbon atoms, and preferably represents a bond.
  • the radical A defined above is an aryl, preferably a phenyl, substituted in meta or para, preferably para, with an alkoxy group, such as methoxy, or with an aryl or arylalkyl group, such as phenyl or benzyl, optionally substituted with one or two substituents, identical or different, such as an acyl or alkoxy group.
  • B represents an aryl group, preferably a phenyl, substituted in the ortho position by a heterocycle, preferably an N-cycloalkyl, such as a piperidin-1-yl group, and optionally substituted in the ortho 'position by an alkyl group. , such as methyl.
  • R2 represents a halogen atom, such as a bromine atom, preferably in the meta position relative to R3.
  • the compound of formula (I) has the following characteristics:
  • A represents a phenyl group substituted in the para position by a benzyl group
  • B represents a phenyl group substituted in the ortho position by a piperidin-1-yl group and in the ortho-position with a methyl group, Gl represents a bond, and
  • R1, R2, R3 and n are as defined above.
  • the compound of formula (I) is 4- [N '- (4-benzylphenyl) -N' - (2-methyl-6-piperidin-1-yl-phenyl) -hydrazinocarbonylmethyl] - 5-bromo-2-methoxy-benzoic acid or a pharmaceutically acceptable salt thereof, and in particular its potassium salt.
  • the potassium salt makes it possible to increase the solubility of this compound, especially in comparison with its hydrochloride, and to facilitate the formulation of the product.
  • the subject of the present invention is therefore also the potassium salt of 4- [N '- (4-benzyl-phenyl) -N' - (2-methyl-6-piperidin-1-yl-phenyl) -hydrazino acid. carbonylmethyl] -5-bromo-2-methoxybenzoic acid.
  • the present invention also relates to this particular salt for use as a medicament, especially for preventing or treating an infection with the papilloma virus, and in particular HPV6 or HP VI 1.
  • This potassium salt makes it possible in particular to prevent or treat lesions or diseases associated with papillomavirus infections, and in particular ano-genital warts, such as condyloma acuminata and flat condyloma, laryngeal, conjunctival or oral papillomas, recurrent respiratory papillomatosis, low-grade and high-grade intraepithelial neoplasia, bowenoid papulosis, vulvar, plantar, myrmcial, superficial or flat warts, verruciform epidermodysplasias, and carcinomas, especially anogenital.
  • ano-genital warts such as condyloma acuminata and flat condyloma, laryngeal, conjunctival or oral papillomas, recurrent respiratory papillomatosis, low-grade and high-grade intraepithelial neoplasia, bowenoid papulo
  • the present invention also relates to any pharmaceutical composition comprising this potassium salt in combination with at least one pharmaceutically acceptable excipient.
  • the present invention also relates to a composition according to the present invention for its use as a medicament, in particular for preventing or treating an infection with the papilloma virus, and in particular HPV6 or HP VI 1.
  • the present invention also relates to the use of a composition according to the invention for the preparation of a medicament useful for preventing or treating an infection with the papilloma virus, and in particular HPV6 or HP VI 1.
  • the present invention also relates to a method for preventing or treating an infection with the papilloma virus, and in particular HPV6 or HPV11, comprising administering an effective amount of a composition according to the invention to a person in need.
  • composition will be used in particular topically, especially in gel form, oral administration may also be considered.
  • topical is meant, in the sense of the present invention, a local application.
  • This application can be performed on the skin or the mucous membranes (external or internal) such as the respiratory tract, the oral cavity or the ano-genital area. It could also be performed by local injection in or around a lesion or tumor. Preferably, it is carried out on the skin and / or the mucous membranes, and in particular in the ano-genital zone.
  • composition according to the present invention makes it possible in particular to prevent or treat lesions or diseases associated with papillomavirus infections, and in particular ano-genital warts, such as condyloma acuminata and flat condyloma, laryngeal, conjunctival papillomas or oral, recurrent respiratory papillomatosis, low-grade and high-grade intraepithelial neoplasia, bowenoid papulosis, vulvar, plantar, myrmcial, superficial or flat warts, verruciform epidermodysplasias, and carcinomas, especially anogenital.
  • ano-genital warts such as condyloma acuminata and flat condyloma, laryngeal, conjunctival papillomas or oral, recurrent respiratory papillomatosis, low-grade and high-grade intraepithelial neoplasia, bowenoid
  • composition according to the present invention will in particular be useful for the treatment of lesions caused in particular by HPV6 and HPV11 virus infections, in particular warts and condylomas.
  • compositions according to the present invention can be prepared by mixing the different ingredients.
  • the present invention therefore also relates to a method for preparing a composition according to the present invention comprising a compound of formula (I), a viscosifying agent and a solvent, comprising the following steps:
  • step (iii) mixing solutions A and B to give the composition according to the invention.
  • step (i) will be carried out at room temperature.
  • step (ii) will be carried out hot to obtain a homogeneous solution of the viscosifying agent.
  • This step will in particular be carried out at a temperature between 60 and 100 ° C, preferably between 70 and 80 ° C.
  • Solution B will then be cooled before being used in step (iii).
  • step (iii) will be carried out at a temperature of between 20 and 40 ° C.
  • the reactor containing solution A will be transferred to the reactor containing solution B, or vice versa.
  • the reactor thus transferred may also be rinsed with a little solvent according to common practice.
  • the present invention will be better understood in the light of the nonlimiting examples which follow.
  • FIGURE
  • FIG. 1 represents the diagram of the process for manufacturing a composition according to the invention.
  • the active ingredient used in the examples is the potassium salt of 4- [N '- (4-benzyl-phenyl) -N' - (2-methyl-6-piperidin-1-yl-phenyl) -hydrazinocarbonylmethyl) 5-bromo-2-methoxy-benzoic (compound (la)).
  • One of the methods for obtaining the potassium salt of the active ingredient is based on the transformation of the neutral form of the compound of interest solubilized in ethanol with ethanolic potassium hydroxide.
  • the neutral form is itself obtained from the washing with water of the compound in hydrochloride form as claimed in the patent WO 2007/135106.
  • compositions according to the invention with 5% by weight of active principle in the form of a gel
  • the pharmaceutical composition is a gel containing 5% by weight of compound (Ia). Hydroxypropylcellulo is:
  • the active ingredient (Ia) is dissolved in a propylene glycol fraction. Hydroxypropylcellulo was dispersed in "cold" propylene glycol and the mixture was then heated to dissolve the viscosifier. When the gel is cooled to 40 ° C, the active ingredient solution (1a) in propylene glycol is added (the container having contained this solution is rinsed with a little propylene glycol) and the mixture is homogenized. Stirring is maintained until room temperature.
  • the active ingredient is dissolved in about 750 g of propylene glycol for a batch of 5000 g gel at room temperature.
  • the hydroxypropylcellulose is dispersed in about 3,600 g of propylene glycol.
  • the mixture is heated with stirring at 75 ⁇ 5 ° C until a homogeneous gel is obtained.
  • the preparation is allowed to cool to 40 ° C or lower while maintaining agitation.
  • the active ingredient in solution is poured into the hydroxypropylcellulose solution and the container with the remaining propylene glycol (250 g) is rinsed.
  • the final gel is allowed to cool to 30 ⁇ 5 ° C with stirring before conditioning.
  • the pharmaceutical composition obtained is a viscous gel, translucent, colorless to pale yellow.
  • the kinetics of the diffusion of the compound (Ia) through the membrane was monitored for 6 h. At the end of kinetics, more than 20% of the active ingredient was released from the pharmaceutical composition.
  • Biological activity of the pharmaceutical composition The activity against papillomavirus of an active ingredient can be evaluated in various in vitro and cellular assays such as those described by Chiang et al. (1992), Proc. Natl. Acad. Sci. USA, 89: 5799-5803, by White et al. (2003), Journal of Biological Chemistry, 278: 26765-26772, or by Fradet-Turcotte et al. (2010), Virology, 399: 65-76.
  • E1 / E2 interaction test evaluates the interaction between HPV (human papillomavirus) proteins El and E2 in human cells.
  • a second test measures the replication of viral genomic DNA in human cells.
  • the interaction test between El and E2 is similar to tests often called 'mammalian 2 Hybrid'. It is based on the co-transfection of a reporter vector containing DNA binding sites for HPV E2 protein in the promoter controlling the expression of the reporter gene, and expression vectors encoding the E1 proteins and E2 HPV, the El protein being fused to the transactivator domain VP16. This test makes it possible to follow the interaction between the proteins El and E2, this interaction being a necessary step for the replication of the HPV genome.
  • a reporter vector containing several DNA binding sites for the E2 protein (palindrome 5 'ACCGNNNNCGGT-3') upstream of the minimal promoter MLP (Adenovirus Major) was constructed. Late Promoter) controlling transcription of the gene encoding firefly luciferase.
  • N-terminal fused HPV E1 expression vectors were also constructed with the HSV-1 virus transactivator domain VP16. Co-transfection into cell lines of this reporter vector containing E2 sites and HPV E2 protein expression vectors leads to a marginal increase in luciferase activity.
  • the viral genomic DNA replication test is based on the co-transfection of a reporter vector containing an HPV viral origin of replication (ori) and expression vectors encoding the HPV El and E2 proteins. It makes it possible to follow all the biological functions of El and E2 necessary for the replication of the HPV genome.
  • ori HPV viral origin of replication
  • a 'replicon' reporter vector containing the origin of HPV11 / HPV6 viral replication also called LCR, which carries HPV E1 and E2 binding sites
  • LCR which carries HPV E1 and E2 binding sites
  • the activity of the compound (Ia) was measured by studying the biological activity against the virus of the papilloma, either pharmaceutical compositions (a), (d), (f) and (g) according to the invention, or of the compound (la) in a Tris-DMSO buffer solution (25 mM Tris, pH 8.0, % DMSO) freshly prepared.
  • the pharmaceutical compositions (a), (d), (f) and (g) were diluted in the same buffer solution to be tested at the same concentrations as the active ingredient, namely in a range of 0.25 to 40 ⁇ .
  • the compound (Ia), either in solution or in the pharmaceutical compositions (a), (d), (f) and (g), was evaluated for its inhibitory activity of the interaction between HPV11 proteins E1 and E2.
  • HPV6 in human cell lines derived from renal epithelial cells or cervical carcinoma.
  • Various doses (0.25-40 ⁇ l) were incubated in the cell medium for 2 days after transfection and luciferase activity was measured to determine the ICso of the compound on the interaction between the E1 and E2 proteins of the cells. HPV.
  • HPV 6 in human cell lines derived from renal epithelial cells or cervical carcinoma.
  • the pharmaceutical compositions described above have the same biological activity as the compound (Ia) in solution (not formulated).
  • the compound (Ia) in solution and the pharmaceutical compositions (a), (d), (f) and (g) both inhibit the interaction between the HPV 11 / HPV6 E1 and E2 proteins in the cells, as well as the replication. viral, dependent on proteins El and E2 of HPV11 in cells, with an IC 50 of the order of 1 ⁇ .
  • the percutaneous absorption of the compound (Ia) from the pharmaceutical composition (g) was studied after the application of a dose of 10 mg / cm 2 on human skin mounted in Franz's cell. This study was done by comparing percutaneous absorption on healthy skin and delaminated skin, as a model of the weak keratinization of the anogenital area.
  • the amount of the compound (Ia) present in each layer of the skin (stratum corneum, epidermis, dermis), as well as what passed through the skin (receiving fluid ) is quantified by HPLC.
  • the results obtained after 8 hours of diffusion are presented in the table below.
  • the horny layer of non-delaminated skin is removed from the epidermis by adhesive peeling.
  • the latter is applied to the skin surface under a constant and controlled pressure.
  • the concentrations of the compound (la) measured in the skin after 8 hours of diffusion correspond to a local concentration of 100 (healthy skin) to 1000 times (delaminated skin) activity of the active ingredient (IC 50 ) measured in cellulo. Similar results were obtained after 24 hours of diffusion. Similarly, similar results have been observed in in vitro percutaneous absorption studies on miniporc skin, a highly predictive animal model of the behavior of human skin.
  • the percutaneous absorption of the compound (Ia) from the pharmaceutical composition (g) was also measured in vivo during a toxicokinetic study, performed by twice-daily application of a dose of 10 mg / cm 2 on the flank. minipigs for 42 days.
  • limit of detection 0.5 ng / ml
  • a very good tolerance to the pharmaceutical composition (g) has been demonstrated both in the miniporc during a preclinical toxicity study and in the healthy volunteer during a Phase I clinical study.
  • a dose of 10 mg / cm 2 was applied twice daily to 25, 125 or 250 cm 2 on the flank of the animals for 42 days. Regardless of the surface treated, a high tolerance to the pharmaceutical composition has been observed.
  • a very good tolerance to the pharmaceutical composition was demonstrated at twice-daily application for 7 days at a dose of 10 mg / cm 2 on a 25 cm 2 surface on the lower back of healthy volunteers. No local reactions or adverse effects were observed in the 8 healthy volunteers treated.
  • the stability of the pharmaceutical composition (g) was studied on a 5 kg laboratory batch.
  • test methods are those used routinely and include:
  • the viscosity remains stable whatever the conditions and duration of storage.
  • the dosage of the active ingredient (Ia) and the appearance of the gel remain in the expired standards, regardless of the conditions and duration of storage, demonstrating the stability of the gel on storage.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Otolaryngology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP13721713.9A 2012-05-07 2013-05-07 Pharmazeutische zusammensetzung mit einem papillomavirus-inhibitor Withdrawn EP2854758A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1254186A FR2990134B1 (fr) 2012-05-07 2012-05-07 Composition pharmaceutique d'un inhibiteur du virus du papillome
PCT/EP2013/059475 WO2013167583A1 (fr) 2012-05-07 2013-05-07 Composition pharmaceutique d'un inhibiteur du virus du papillome

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EP2854758A1 true EP2854758A1 (de) 2015-04-08

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EP (1) EP2854758A1 (de)
JP (1) JP2015522529A (de)
CN (1) CN104427971B (de)
AR (1) AR090965A1 (de)
CA (1) CA2872832A1 (de)
FR (1) FR2990134B1 (de)
HK (1) HK1206273A1 (de)
RU (1) RU2661007C2 (de)
WO (1) WO2013167583A1 (de)

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RU2595832C9 (ru) * 2015-08-26 2016-10-27 Андрей Дмитриевич Протасов Способ достижения длительной клинической ремиссии хронической впч-инфекции, проявляющейся остроконечными кондиломами аногенитальной области

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DE2730645A1 (de) 1977-07-07 1979-01-25 Henkel Kgaa Verwendung von telomerisaten aus mercaptanen mit acrylverbindungen als steinschutz- und/oder korrosionsschutzmittel
EP0000430B1 (de) 1977-07-15 1981-08-12 Ici Australia Limited Verfahren zur Polymerisation von Vinylhalogeniden
US5093133A (en) * 1990-01-24 1992-03-03 Mcneil-Ppc, Inc. Method for percutaneous delivery of ibuprofen using hydroalcoholic gel
RU2196568C1 (ru) * 2001-08-08 2003-01-20 Киселев Всеволод Иванович Фармацевтическая композиция для профилактики и лечения дисплазий и рака шейки матки и папилломатоза гортани, а также способ профилактики и лечения этих заболеваний на ее основе
FI20041425A0 (fi) * 2004-11-05 2004-11-05 Orion Corp Transmukosaalinen veterinäärinen koostumus
AU2006210392A1 (en) * 2005-02-04 2006-08-10 Coley Pharmaceutical Group, Inc. Aqueous gel formulations containing immune response modifiers
FR2901273B1 (fr) * 2006-05-19 2010-12-24 Anaconda Pharma Inhibiteurs du virus du papillome humain et les compositions pharmaceutiques les contenant
MX2009004038A (es) * 2006-10-17 2009-08-24 Nuvo Res Gel de diclofenaco.
FR2923825B1 (fr) * 2007-11-20 2013-05-03 Anaconda Pharma Nouveaux inhibiteurs du virus du papillome humain et les compositions pharmaceutiques les contenant.

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See also references of WO2013167583A1 *

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CN104427971A (zh) 2015-03-18
HK1206273A1 (en) 2016-01-08
WO2013167583A1 (fr) 2013-11-14
FR2990134B1 (fr) 2014-11-21
US9670159B2 (en) 2017-06-06
US20150152051A1 (en) 2015-06-04
CN104427971B (zh) 2018-04-20
CA2872832A1 (fr) 2013-11-14
FR2990134A1 (fr) 2013-11-08
JP2015522529A (ja) 2015-08-06
RU2661007C2 (ru) 2018-07-11
AR090965A1 (es) 2014-12-17
RU2014148528A (ru) 2016-06-27

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