EP2981521A1 - Novel chalcone derivatives having an anti-allergic activity - Google Patents

Novel chalcone derivatives having an anti-allergic activity

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Publication number
EP2981521A1
EP2981521A1 EP14720658.5A EP14720658A EP2981521A1 EP 2981521 A1 EP2981521 A1 EP 2981521A1 EP 14720658 A EP14720658 A EP 14720658A EP 2981521 A1 EP2981521 A1 EP 2981521A1
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EP
European Patent Office
Prior art keywords
compounds according
manifestations
compound
compounds
group
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.)
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EP14720658.5A
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German (de)
French (fr)
Inventor
Charles Dumontet
Ahcène BOUMENDJEL
Guillaume Monneret
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Centre National de la Recherche Scientifique CNRS
Universite Claude Bernard Lyon 1 UCBL
Hospices Civils de Lyon HCL
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite Claude Bernard Lyon 1 UCBL
Hospices Civils de Lyon HCL
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Publication of EP2981521A1 publication Critical patent/EP2981521A1/en
Withdrawn legal-status Critical Current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
    • C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention relates to novel chalcone derivatives having anti-allergic activity, as well as pharmaceutical compositions containing such compounds and compounds for their use as medicaments. as an anti-allergic medicine,
  • Patent application WO 2007/083060 describes a chalcone family having anti-tumorotic activity, the results being presented on a cycle test corresponding to the analysis of the G2 / M phase blocking of a blood line.
  • human leukemia cells evaluated by flow cytometry *
  • the compounds described could be used for the treatment of manifestations secondary to hypersensitivity, for example rhinitis, conjunctiva and allergic asthma, eczema,
  • the inventors of the present patent application have tested several of the described compounds on the degranulation of normal human basophils and the tested compounds showed no activity. These results will be presented later in the examples.
  • WO 01/98291 describes, for its part, a large family of chalcone-type compounds, presented as being useful for treating VCAM-I mediated disorders (vascular eye adhesion molecule-1). Among the long list of pathologies mentioned, are some allergic diseases. In order to verify the inactivation of the compounds described in the treatment of allergies, among the 655 examples given in this patent application, the inventors of the present patent application tested the compound described on page 9.
  • the invention relates to the compounds of formula
  • R 2f R and 3 ⁇ 4 identical or different, represent a hydrogen, chlorine, bromine, iodine or fluorine atom, or a -OH or -O-alkyl group comprising from 1 to 6 carbon atoms;
  • - R.2 f and RV identical or different, represent a hydrogen atom, or a group QH or -O-aikyie comprising 1 to 6 carbon atoms; 2 and / or '4 which represented nt) n methoxy;
  • n is equal to 1, 2 or 3;
  • R 7 represents a hydrogen atom or an alkyl group comprising from 1 to 6 carbon atoms
  • the compounds of formula (I), optionally in the form of hydrates f f solvates or pharmaceutically acceptable salts have any of the following characteristics or a combination of several of these characteristics, , or all these features:
  • R 7 represents a methyte group
  • At least two of the groups R3 ⁇ 4 * and R3 ⁇ 4 and in particular R 2 and R 6 are different from hydrogen;
  • R 2f RA and R3 ⁇ 4 which may be identical or different, represents a hydrogen atom, a chlorine atom or a methoxy group.
  • alkyl group is meant a saturated linear or branched hydrocarbon-based chain.
  • alkyl group comprising from 1 to 6 carbon atoms, mention may be made, in particular, of the methyte (denoted Me), ethyl, // -propyl, / sylpropyl, t-butyl, t-butyl and , n-butyl, n-pentyl, n-hexyl,
  • the invention also relates to the compounds defined in the context of the invention for their use as medicaments and in particular for their use as an anti-allergic medicine. Such use is preferably implemented in humans,
  • Salts of compounds according to the invention are prepared according to techniques well known to those skilled in the art.
  • the salts of the compounds of formula (I) according to the present invention include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), as well as pharmaceutically acceptable salts.
  • Suitable acids include: oxalic acid or an optically active acid, for example tartaric acid, dibenzoyitartric acid, mandelic acid or camphorsulfonic acid, and those which form physiologically such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulionate, paratoluenesulfonate.
  • solvate is meant a form of the compound associated with one or more molecules of solvent, especially used during its synthesis or during its purification, without being in solution in the latter.
  • the optical isomers of this compound form an integral part of the invention.
  • the present invention comprises the compounds of formula (I) in the form of pure isomers but also in the form of a mixture of isomers in any proportion, the compounds (I) are isolated in the form of pure isomers by standard separation techniques: it is possible to use, for example, fractional recalibrations of a salt of racenic acid with an acid or an optically active base whose principle is well known or the conventional techniques of chromatography on chiral or non-chiral phase,
  • the functional groups optionally present in the molecule of the compounds of formula (I) and in the reacturized intermediates can be protected, either in permanent form or in temporary form, by means of protective groups that provide a unambiguous synthesis of the expected compounds.
  • the protection and deprotection reactions are carried out according to techniques well known to those skilled in the art.
  • the temporary protecting group of amines, alcohols or carboxylic acids is meant to include protecting groups such as those described in Profeetive Groups in Organic Synthesis, Greene TW and Wirts PGM, ed John Wiiey and Sons, 1991 and in Protectlng Groups, Kodenski PJ. , 1994, Georg Thieme Veriag,
  • the compounds of formula (I) according to the invention are obtained by aidoiic condensation of an acetophenone of formula (II) and a benzaldehyde of formula ( ⁇ ), as illustrated in the examples.
  • the present invention also relates to the use of the compounds defined in the context of the invention for the manufacture of a medicament, and preferably a medicament for the treatment of allergies.
  • medicaments are intended for the treatment of humans.
  • the compounds according to the invention are more particularly suitable for the treatment of a pathology of allergic origin such as pulmonary manifestations, such as allergic asthma; cutaneous allergy manifestations such as eczema, drug allergy, contact reactions to environmental products; digestive manifestations including food allergies; other mucous manifestations such as rhinitis and conjunctivitis; allergic joint manifestations; local and systemic manifestations resulting from contact with a food product, cosmetic, hygienic, professional, drug or toxic environment, microbiota or parasites; manifestations of autoimmune diseases; Quincke's edema.
  • the antiallergic activity of the compounds was demonstrated by studying the ability of the compounds of the invention to Inhibit degranulation of normal human basophils by conducting tagging studies in cytométxie flow.
  • the compounds according to the invention possess an important activity of protection against the degranulation of normal human basophils, such as can be evaluated by the overexpression of CD203c and CD63 after exposure to an anti-IgE antibody.
  • the concentration of compound according to the invention for obtaining a protective effect of 50% belongs to the range from 1 to 100 micromofôires.
  • compositions comprising a compound according to the invention, in combination with at least one pharmaceutically acceptable excipient, are also an integral part of the invention In such compositions, the compound according to the invention is present in a therapeutically effective amount.
  • treatment means any prophylactic or suppressive therapeutic measure of a disease or disorder, leading to a desirable clinical effect or any beneficial effect, including in particular the suppression or decrease of one or more symptoms, regression, slowing or stopping the progression of the disease or disorder associated therewith.
  • “Therapeutically effective amount” refers to any amount of a composition that improves one or more of the characteristic parameters of the condition being treated.
  • the compounds of formula (I), their pharmaceutically acceptable salts, solvates and hydrates are not cytotoxic.
  • the compounds of formula (1) described above, as well as their salts, solvates and hydrates can be used for the manufacture of a medicament for treating an allergic disease, and in particular a pathology of allergic origin.
  • pulmonary manifestations such as allergic asthma
  • cutaneous manifestations of allergy such as eczema, drug allergy, contact reactions to environmental products
  • other mucosal manifestations such as rhinitis and conjunctivitis
  • allergic joint manifestations local and systemic manifestations resulting from contact with a food product .
  • cosmetic, hygienic, professional drug or toxic., microbiota or parasites; manifestations of autoimmune diseases; Quincke's edema,
  • the present invention also relates to the pharmaceutical compositions administered to animals and, in particular to humans, containing a therapeutically effective dose of a compound of formula (I), or a salt, a solvate or a a pharmaceutically acceptable hydrate thereof and one or more suitable excipients according to the European Pharmacopoeia in particular? ems edition.
  • the invention thus relates to pharmaceutical compositions comprising: a compound according to the invention, with at least one pharmaceutically acceptable excipient.
  • excipients present in the pharmaceutical compositions according to the invention are chosen according to the pharmaceutical form and the desired mode of administration.
  • the active ingredients of formula (I) in any proportion, or their salts, solvates and hydrates, may be administered in unit dosage form, in admixture with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of the above diseases.
  • Suitable unit dosage forms include oral forms, such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, oral, tracheal intravenous, intranasal, forms of subcutaneous, intramuscular, intra-cartilage or intravenous administration in the forms of rectal administration.
  • oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions
  • sublingual, oral, tracheal intravenous, intranasal forms of subcutaneous, intramuscular, intra-cartilage or intravenous administration in the forms of rectal administration.
  • the compounds according to the invention can be used in creams, ointments, patches or lotions.
  • the compound of the invention will be present in the composition at a therapeutically effective dose.
  • the dose of active ingredient varies, for example, between 0.1 and 100 mg per kg of body weight per day.
  • a solid composition in tablet form When a solid composition in tablet form is prepared, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • Sucrose tablets can be coated, a cellulose derivative or other appropriate substances or else they can be treated such that they have a prolonged or delayed activity and release qulls û'une continuously a predetermined quantity of active ingredient.
  • a capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • compositions containing a compound of formula (I), or a salt thereof, solvates or hydrates may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable examples are water, organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions, in water.
  • a syrup or syrup preparation or drop administration may contain the active ingredient together with a sweetener, acaloric, antiseptic, as well as a flavoring agent and a suitable colorant.
  • the water dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinyl pyrrolidone, as well as with sweeteners or taste correctors. .
  • Figures I and 2 show the results obtained at 100 ⁇ on dégranulatlon basophils by flow cytometry, respectively with the CD63 and CD203c markers for compounds according to the invention and other similar structure compounds.
  • Figures 3 and 4 present the results of a dose-effect study conducted with the compounds (1.1), (1.2) and (1.3) on a number of 4 donors, with the markers CD63 and CD203c.
  • the Igra S shows the non-invasive plethysrnography response to increasing doses of methacholine for all groups u day after the last OVA challenge.
  • the Fifpre ⁇ shows the intra-bronchial focus concentration of all the groups one day after the last OVA challenge
  • the figures ? and S show the cytokines obtained by the flow cytometry analyzes in the lungs and the LBA of all the groups one day after the last OVA challenge.
  • chalcones were synthesized according to Scheme I F cl following wherein X .. n, R3 ⁇ 4 R4 and Rg, and FV are as defined for compounds of formula (3 ⁇ 4, by aldol condensation between that an acetophenone derivative ( II) and a benzaldehyde derivative (II),
  • the experimental protocol is as follows: A solution of acetophenone ( ⁇ ) in ethanol. or methane! (10 mg / mmol of acetophenone) is added successively the benzaldehyde derivative (III) it and a potassium hydroxide solution (KOH, 50% in H 2 Q), The solution was stirred at reflux of the solvent for 24 h, ethanol or methanol is evaporated and water is added to the remaining residue . The solution is filtered under reduced pressure and the balance obtained is washed successively with water and with ether. The purity of the product is analyzed by TLC. The majority of the chalcones were obtained pure at this stage. If the CC reveals the presence of impurities, purification by silica gel chromatography column eluted with ethyl acetate / cyclohexane (1/4 to 1/1, v / v) is carried out.
  • acetoprenone derivative required for its preparation of chalcones was synthesized according to the method described in; Liu et al. Bioorgank at Medicinal Chemistry, 2007, 15, 7021-7034, Benzahyde derivatives are commercial.
  • This test consists of analyzing by flow cytometry CD203c and CD63 mernbran markers on normal human basophils.
  • blood from healthy donors is exposed to an antibody against immunoglobulin E (IgE) which leads to basophll activation and degranulation, causing an increase in the expression of CD203c and CD63, in order to demonstrate
  • IgE immunoglobulin E
  • they are co-incubated with the basophites and the snti-IgE antibody and the samples are analyzed to demonstrate a lower level of expression of CD2 ⁇ 3c and CD63.
  • the compounds of interest are dissolved in dimethylsulfoxide (DMSO) a control is also carried out by incubating the basophiies in the presence of DMSO without active principle.
  • DMSO dimethylsulfoxide
  • the protocol comprises
  • mice were divided into 3 groups:
  • a compound group (L1) (n 10), an i-cm group (cromoglycate, n-10) and a ⁇ -PBS group (n-10).
  • the compound (Ll) is dissolved in a solution of D SO. This stock solution is then diluted in a solution vol: vol ethartol.PBS before intra-perioneal administration.
  • the compound (L1) solubilizes poorly which may explain the variability found in some of the experiments.
  • Figure S shows the non-invasive plethysmographic response to increasing doses of methacholine for all groups one day after the last OVA challenge.
  • Penh enhanced pause
  • Penh values calculated from the pleitiysmography measurements, reflect lengthening of the Expiratory pause time observed in subjects with reduced caliber bronchial and are correlated with respiratory resistance. A decrease in Penh values therefore corresponds to a protective effect vis-à-vis OVA-induced bronchoconstruction.
  • Figure 6 shows the concentration of intra-bronchial infiltrate of all groups one day after the last QVA challenge.
  • Figures 7 and 8 show the cytokines obtained by flow cytometric analyzes in the lungs and L8 of all groups one day after the last OVA challenge.
  • the control group sensitized and chaliengé with OVA and injected with PBS shows all the signs of allergic asthma to IOVA with a high Penh, and all the more that the dose of methacholine is important, a strong intrabronchial infiltrate and strong eosinophilia.
  • This group served as a reference for all the results,
  • mice treated with cromoglycate showed the same increases in Penh in response to increasing doses of methacholine as the control mice treated with PB8.
  • the difference was significant from the dose when compared with the compound .l). Comparing to the control group injected with PBS f the difference is not significant for the dose to 40 mg / ml.
  • mice injected with PBS show a large inflammatory infiltrate.
  • the cromoglycate group did not show a significant difference with the buffer group.
  • the group treated with compound (11) showed a significant decrease in intracranial infiltrate compared with PBS and cromoglycate-S! we look at the composition level of this infiltrate (Figure 7), we have a composition quite in line with an OVA model with strong eosinophilia and little increase of other cell types.
  • Intra-pupal inflammation does not show large variations compared to bronchial infiltrate. Eryosinophilia was observed for all groups, but it was much less important in the group of the compound (L1), including Se group cromogylate with a decrease in these eosinophils in the group of the compound (L1).

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  • Physical Education & Sports Medicine (AREA)
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  • Hydrogenated Pyridines (AREA)

Abstract

The present invention concerns compounds of formula (I); in which; - R2, R4 and R6, identical or different, represent a hydrogen, chlorine, bromine, iodine or fluorine atom, or an -OH or -O-alkyl group comprising 1 to 6 carbon atoms; -R2 and R4, identical or different, represent a hydrogen atom, or an --OH or -Q-alkyl group comprising 1 to 6 carbon atoms; in which R2' and/or R4' represent(s) a methoxy group; - n is equal to 1, 2 or 3; - X = CH2, G, S or N(R7); and - R7 represents a hydrogen atom or an alkyl group comprising 1 to 6 carbon atoms; and the pharmaceutically acceptable hydrates, solvates and salts thereof.

Description

iteyveaus iérâé de ctaioMe présentant une activité anti- La présente invention concerne de nouveaux dérivés de chalcone présentant une activité anti-allergique, ainsi que les compositions pharmaceutiques contenant de teis composés et de tels composés pour leur utilisation en tant que médicaments., et e particulier en tant que médicament anti-allergique,  The present invention relates to novel chalcone derivatives having anti-allergic activity, as well as pharmaceutical compositions containing such compounds and compounds for their use as medicaments. as an anti-allergic medicine,
De nombreux travaux ont déjà été réalisés sur des dérivés de chaicone. A titre iliustratif, on peut citer les publications de Starkhov S,P. correspondant à XP 0009171181 et XP 009171188, qui décrivent certains dérivés de chalcone,. sans en spécifier une quelconque activité. Différentes activités ont déjà été rapportées pour des dérivés de chalcone. On peut citer le brevet US 6,462,075 qui décrit des dérivés de chalcon présentant une activité d'inhibition de Tangiogénèse. Ces composés sont présentés comme pouvant être utilisés comme agents anti-tumoraux, anti-cancéreux, pour traiter les maladies anglogénlques de la peau et les maladies inflammatoires chroniques. La publication X, L Llu dans Eur« 3, Med, Chem,, 43 (2008), 1681-1587, décrit des dérivés de chalcone présentés comme des agents a nti bactériens de Staphyioœccus Aureus*  Much work has already been done on derivatives of chaicone. Illustratively, the publications of Starkhov S, P. corresponding to XP 0009171181 and XP 009171188, which describe some chalcone derivatives ,. without specifying any activity. Various activities have already been reported for chalcone derivatives. US Pat. No. 6,462,075, which describes chalcon derivatives having a tangiogenesis inhibition activity. These compounds are shown to be useful as anti-tumor, anti-cancer agents, to treat English skin diseases and chronic inflammatory diseases. The publication X, L Llu in Eur. 3, Med. Chem. 43 (2008), 1681-1587, discloses chalcone derivatives presented as bacteriostatic agents of Staphylococcus aureus *.
La demande de brevet WO 2007/083060, quant à elle, décrit une famille de chalcone présentant une activité anti-rnstotique des résultats étant présentés sur un test de cycle correspondant à l'analyse du blocage en phase G2/M d'une lignée de cellules leucémiques humaines, évalué par cytométrie de flux* Bien qu'il soit mentionné dans cette demande de brevet que les composés décrits pouvaient être utilisés pour le traitement de manifestations secondaires à une hypersensibilité, par exemple rhinite, conjonctive et asthme allergiques,, eczéma, allergies médicamenteuses, les inventeurs de la présente demande de brevet ont testés plusieurs des composés décrits, sur la dégranulation de basophiies humains normaux et les composés testés n'ont pas montré d'activité, Ces résultats seront présentés ultérieurement dans les exemples. Le document WO Oi/98291 décrit, quant à lui, une large famliie de composés de type chalcone, présentés comme utiles pour traiter les désordres médiés par VCAM-I (« vascular œil adhésion molécule- 1 »). Parmi la longue liste de pathologies citées, figurent certaines maladies allergiques. Afin de vérifier iactivlté des composés décrits dans le traitement des allergies, parmi les 655 exemples donnés dans cette demande de brevet es inventeurs de la présente demande de brevet ont testé ie composé décrit page 9? de ce document, sous la référence 8 et, le composé décrit page 137 sous la référence 359, afin de vérifier s'ils présentaient une activité, à 100 μΜ, sur la dégranulation de basophiles humains normaux CD 63 selon le protocole décrit à partir de ia page 12 de ia présente demande de brevet, qui est un modèle reconnu pour évaluer une activité anti-allergique (Clin Mol Allergy. 2005 Jun 3Q;3;9. The basophii activation test by flow cytometry: récent developments in dinicai studies, standardizatior; and errterging perspectives. BourrHza R, Debard AL, onneret G,)- Ces deux composés peuvent être considérés comme inactifs, au vu des résultats obtenusf et présentés dans les exemples comparatifs de ia présente demande de brevet» Selon la présente invention., les inventeurs ont maintenant développé une nouvelle série de chaicones présentant un intérêt dans ie traitement des affections allergiques. Patent application WO 2007/083060, for its part, describes a chalcone family having anti-tumorotic activity, the results being presented on a cycle test corresponding to the analysis of the G2 / M phase blocking of a blood line. human leukemia cells, evaluated by flow cytometry * Although it is mentioned in this patent application that the compounds described could be used for the treatment of manifestations secondary to hypersensitivity, for example rhinitis, conjunctiva and allergic asthma, eczema, For example, the inventors of the present patent application have tested several of the described compounds on the degranulation of normal human basophils and the tested compounds showed no activity. These results will be presented later in the examples. WO 01/98291 describes, for its part, a large family of chalcone-type compounds, presented as being useful for treating VCAM-I mediated disorders (vascular eye adhesion molecule-1). Among the long list of pathologies mentioned, are some allergic diseases. In order to verify the inactivation of the compounds described in the treatment of allergies, among the 655 examples given in this patent application, the inventors of the present patent application tested the compound described on page 9. of this document, under the reference 8 and the compound described on page 137 under the reference 359, in order to verify whether they exhibited an activity, at 100 μl, on the degranulation of normal human basophils CD 63 according to the protocol described starting from page 12 of the present patent application, which is a recognized model for evaluating anti-allergic activity (Clin Mol Allergy, 2005 Jun 3Q, 3, 9. The basophii activation test by flow cytometry: recent developments in dinicai studies, standardizatior .; and errterging prospects BourrHza R Debard AL onneret G) - These two compounds can be considered inactive, given the results obtained f and presented in the comparative examples of the present patent application "According to the present invention. the inventors have now developed a new series of chaicones of interest in the treatment of allergic diseases.
Dans ce contexte, linvention concerne les composés de formule ÇI) :  In this context, the invention relates to the compounds of formula
dans laquelle : in which :
- R2f R et ¾, Identiques ou différents, représentent un atome d'hydrogène, chlore, brome, iode ou fluor, ou un groupe -OH ou -O-alkyie comprenant de 1 à 6 atomes de carbone ; - R.2f et RV, identiques ou différents, représentent un atome d'hydrogène, ou un groupe™QH ou -O-aikyie comprenant de 1 à 6 atomes de carbone ; avec 2 et/ou '4 qui représentée nt) n groupe méthoxy ; R 2f R and ¾, identical or different, represent a hydrogen, chlorine, bromine, iodine or fluorine atom, or a -OH or -O-alkyl group comprising from 1 to 6 carbon atoms; - R.2 f and RV, identical or different, represent a hydrogen atom, or a group QH or -O-aikyie comprising 1 to 6 carbon atoms; 2 and / or '4 which represented nt) n methoxy;
- n est égai à 1,, 2 ou 3 ;  n is equal to 1, 2 or 3;
- X = CH2f 0, S ou N(R7); et X = CH 2f 0, S or N (R 7 ); and
- R7 représente un atome d'hydrogène ou un groupe alkyie comprenant de 1 à 6 atomes de carbone ; - R 7 represents a hydrogen atom or an alkyl group comprising from 1 to 6 carbon atoms;
ainsi que ieurs hydrates, soivats et sels pharmaceutiquement acceptables.  as well as their hydrates, soivates and pharmaceutically acceptable salts.
Selon des aspects préférés de l'invention, les composés de formule (ï), éventuellement sous forme dfhydratesf solvats ou sels pharmaceutiquement acceptables,, présentent l'une quelconque des caractéristiques ci-après ou une combinaison de plusieurs de ces caractéristiques,, voire toutes ces caractéristiques : According to preferred aspects of the invention, the compounds of formula (I), optionally in the form of hydrates f f solvates or pharmaceutically acceptable salts ,, have any of the following characteristics or a combination of several of these characteristics, , or all these features:
- X~N(R7) ; en particulier, R7 représente un groupe méthyte ; - X ~ N (R 7 ); in particular, R 7 represents a methyte group;
~ n~2 ;  ~ n ~ 2;
- R et R ' sont différents de l'hydrogène ; en particulier ? et R*' représentent un groupe méthoxy ;  - R and R 'are different from hydrogen; in particular ? and R * 'represent a methoxy group;
- au moins deux des groupes R¾ * et R¾ et notamment R2 et R6, sont différents de l'hydrogène ; at least two of the groups R¾ * and R¾ and in particular R 2 and R 6 are different from hydrogen;
- R2f RA et R¾ identiques ou différents,, représenten un atome d'hydrogène, un atome de chlore ou un groupe méthoxy. R 2f RA and R¾, which may be identical or different, represents a hydrogen atom, a chlorine atom or a methoxy group.
Dans tous les composés de formule (I), Sa configuration autour de la double liaison α,β est trans comme indiqué sur îa formule développée (I), Par groupe alkyie., on entend une chaîne hydrocarbonée, saturée,, linéaire ou ramifiée, A titre d'exemples de groupe alkyie comprenant de 1 à 6 atomes de carbone, on peut citer, notamment, les groupes méthyte (noté Me), éthyle, //-propyle, /sopropyie, /ï-butyie, fe t-butyle, sar-butyie, n~ pentyle, n-hexyle,  In all the compounds of formula (I), its configuration around the α, β double bond is trans as indicated in structural formula (I). By alkyl group is meant a saturated linear or branched hydrocarbon-based chain. By way of examples of an alkyl group comprising from 1 to 6 carbon atoms, mention may be made, in particular, of the methyte (denoted Me), ethyl, // -propyl, / sylpropyl, t-butyl, t-butyl and , n-butyl, n-pentyl, n-hexyl,
Les composés de formule (I), ci-après, dans lesquels R?~méthylef ainsi que leurs hydrates, solvats ou sels pharmaceutiquement acceptables, sont particulièrement préférés. En particulier, l'invention concerne les composés : 2 ~Hydroxy-2,4f6,4'i6'~pent^ The compounds of formula (I), hereinafter, wherein R? F ~ methyl and their hydrates, solvates or pharmaceutically acceptable salts, are particularly preferred. In particular, the invention relates to the compounds: 2 ~ Hydroxy-2,4 f 6,4 ' i 6' ~ pent
composé (Li) compound (Li)
2f~Hydrox7~2A- ',6M:etr3m 2 f ~ Hydrox7 ~ 2A- ', 6M: etr3m
composé (1.2) compound (1.2)
~ 2?6-Diehloro^'f6,~diméthoxy-2i¾^ ~ 2 ? 6-Diehloro ^ 'f 6 ~ dimethoxy-2 i ^ ¾
compo compo
ainsi que leurs hydrates, solvats ou sels pharmaceutiquement acceptables.  as well as their hydrates, solvates or pharmaceutically acceptable salts.
Une étude de modélisation moléculaire a été réalisée et montrent notamment que la présence de hétérc ycle azoté est déterminante pour l'activité anti-allergique.  A molecular modeling study has been carried out and show in particular that the presence of nitrogenous heterocycle is critical for the anti-allergic activity.
L'invention concerne également les composés définis dans le cadre de l'invention pour leur utilisation en tant que médicament et en particulier pour leur utilisation en tant que médicament anti-allergique. Une telle utilisation est, de préférence,, mise en œuvre chez l'être humain, The invention also relates to the compounds defined in the context of the invention for their use as medicaments and in particular for their use as an anti-allergic medicine. Such use is preferably implemented in humans,
Les sels des composés selon l'Invention sont préparés selon des techniques bien connues de l'homme de l'art. Les sels des composés de formule (I) selon la présente Invention comprennent ceux avec des acides minéraux ou organiques qui permettent une séparation ou une cristallisation convenable des composés de formule (I), ainsi que des sels pharrnaceutiquement acceptables. En tant qu'acide approprié, on peut citer: l'acide pioîque l'acide oxalique ou un acide optiquement actif, par exemple un acide tartrlque, un acide dibenzoyitartrïque, un acide mandélique ou un acide camphosulfonique, et ceux qui forment des seis physiologiquement acceptables, tels que le chlorhydrate, le bromhydrate, le sulfate, l'hydrogénosulfate, le dîhydrogénophosphate,, le maléate, le fumarate, le 2- naphtalènesulionate, le paratoluènesuifonate. Salts of compounds according to the invention are prepared according to techniques well known to those skilled in the art. The salts of the compounds of formula (I) according to the present invention include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), as well as pharmaceutically acceptable salts. Suitable acids include: oxalic acid or an optically active acid, for example tartaric acid, dibenzoyitartric acid, mandelic acid or camphorsulfonic acid, and those which form physiologically such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulionate, paratoluenesulfonate.
Comme composés sous forme hydratée, on peut citer, a titre d'exemples. Ses semi~nydratesf monohydrates et poSyhydrates, As compounds in hydrated form, there may be mentioned, by way of examples. His semi ~ f nydrates monohydrate and poSyhydrates,
Par solvat, on entend une forme du composé associé à une ou plusieurs moiécules de solvant, notamment utilisé lors de sa synthèse ou lors d sa purification, sans pour autant être en solution dans ce dernier.  By solvate is meant a form of the compound associated with one or more molecules of solvent, especially used during its synthesis or during its purification, without being in solution in the latter.
Lorsqu'un composé selon l'invention présente un ou plusieurs carbones asymétriques, les isomères optiques de ce composé font partie intégrante de .Invention. La présente invention comprend les composés de formule (I) sous forme d'isomères purs mais également sous forme de mélange d'isomères en proportion quelconque, tes composés (I) sont isolés sous forme d'isomères purs par les techniques classiques de séparation: on pourra utiliser, par exemple des recnstalllsations fractionnées d'un sel du racérnique avec u acide ou une base optiquement active dont le principe est bien connu ou les techniques classiques de chromatographies sur phase chirale ou non chirale,  When a compound according to the invention has one or more asymmetric carbons, the optical isomers of this compound form an integral part of the invention. The present invention comprises the compounds of formula (I) in the form of pure isomers but also in the form of a mixture of isomers in any proportion, the compounds (I) are isolated in the form of pure isomers by standard separation techniques: it is possible to use, for example, fractional recalibrations of a salt of racenic acid with an acid or an optically active base whose principle is well known or the conventional techniques of chromatography on chiral or non-chiral phase,
Les groupes fonctionnels éventuellement présents dans la molécule des composés de formule (I) et dans les intermédiaires réacttonneis peuvent être protégés, soit sous forme permanente, soit sous forme temporaire, par des groupes protecteurs qui assurent une synthèse univoque des composés attendus. Les réactions de protection et déprotection sont effectuées selon des techniques bien connues de l'homme de l'art. Pa groupe protecteur temporaire des aminés, alcools ou des acides carboxylîques, on entend les groupes protecteurs tels que ceux décrits dans Profeetive Groups in Organic Synthesis, Greene T.W. et Wirts P.G.M., ed John Wiiey et Sons, 1991 et dans Protectlng Groups, Kodenski PJ., 1994, Georg Thieme Veriag, The functional groups optionally present in the molecule of the compounds of formula (I) and in the reacturized intermediates can be protected, either in permanent form or in temporary form, by means of protective groups that provide a unambiguous synthesis of the expected compounds. The protection and deprotection reactions are carried out according to techniques well known to those skilled in the art. The temporary protecting group of amines, alcohols or carboxylic acids is meant to include protecting groups such as those described in Profeetive Groups in Organic Synthesis, Greene TW and Wirts PGM, ed John Wiiey and Sons, 1991 and in Protectlng Groups, Kodenski PJ. , 1994, Georg Thieme Veriag,
Les composés de formule (I) selon l'invention sont obtenus par condensation aidoiique d'une acétophénone de formule (II) et d'un benzaldéhyde de formule (ΠΧ), comme illustré dans les exemples.  The compounds of formula (I) according to the invention are obtained by aidoiic condensation of an acetophenone of formula (II) and a benzaldehyde of formula (ΠΧ), as illustrated in the examples.
La présente Invention a également pour objet l'utilisation des composés définis dans le cadre de l'Invention., pour la fabrication d'un médicament, et de préférence d'un médicament destiné au traitement des allergies. En particulier,, de tels médicaments sont destinés au traitement de l'être humain, Les composés selon l'invention sont plus particulièrement appropriés pour le traitement d'une pathologie d'origine allergique telles que ies manifestations pulmonaires, comme l'asthme allergique ; tes manifestations cutanées d'allergie comme l'eczéma, l'allergie médicamenteuse, les réactions de contact à des produits de l'environnement ; ies manifestations digestlves y compris les allergies alimentaires ; les autres manifestations muqueuses telles que les rhinites et les conjonctivites ; les manifestations articulaires allergiques ; les manifestations locales et systémiques résultant d'un contact avec un produit alimentaire, cosmétique, hygiénique, du milieu professionnel, médicamenteux ou toxique, le microbiote ou des parasites ; les manifestations de maladies auto-immunes ; l'œdème de Quincke.  The present invention also relates to the use of the compounds defined in the context of the invention for the manufacture of a medicament, and preferably a medicament for the treatment of allergies. In particular, such medicaments are intended for the treatment of humans. The compounds according to the invention are more particularly suitable for the treatment of a pathology of allergic origin such as pulmonary manifestations, such as allergic asthma; cutaneous allergy manifestations such as eczema, drug allergy, contact reactions to environmental products; digestive manifestations including food allergies; other mucous manifestations such as rhinitis and conjunctivitis; allergic joint manifestations; local and systemic manifestations resulting from contact with a food product, cosmetic, hygienic, professional, drug or toxic environment, microbiota or parasites; manifestations of autoimmune diseases; Quincke's edema.
L'activité anti-allergique des composés a été mise en évidence en étudiant la capacité des composés selon l'invention à Inhiber la dégranulation de basophiles humains normaux en réalisant des études de marquage en cytométxie en flux. Les composés selon l'invention possèdent une activité importante de protection vis-à-vis de la dégranuiation de basophiles humains normaux, telle qu'elle peut être évaluée par la surexpression de CD203c et de CD63 après exposition à un anticorps anti-IgE, En particulier, la concentration en composé selon l'invention permettant d'obtenir un effet protecteur de 50% (par rapport à une valeur de 100% correspondant au contrôle réalisé en l'absence de composé selon l'invention) appartient à la gamme allant de 1 à 100 micromofôires. The antiallergic activity of the compounds was demonstrated by studying the ability of the compounds of the invention to Inhibit degranulation of normal human basophils by conducting tagging studies in cytométxie flow. The compounds according to the invention possess an important activity of protection against the degranulation of normal human basophils, such as can be evaluated by the overexpression of CD203c and CD63 after exposure to an anti-IgE antibody. particular, the concentration of compound according to the invention for obtaining a protective effect of 50% (relative to a value of 100% corresponding to the control carried out in the absence of compound according to the invention) belongs to the range from 1 to 100 micromofôires.
Par contre, contrairement aux composés décrits dans la demande WO On the other hand, unlike the compounds described in the WO application
2007/083060., Ses composés selon l'invention, lorsqu'ils sont testés seuls, ne présentent pas d'activité significative sur différents modèles cancéroSogiques étudiés, 2007/083060., Its compounds according to the invention, when tested alone, show no significant activity on different carcinological models studied,
Les compositions pharmaceutiques comprenant un composé selon l'invention, en association avec au moins un excipient pharmaceutiquement acceptable, font également partie intégrante de (Invention. Dans de telles compositions, Se composé seSon l'invention est présent en quantité thérapeutiquement efficace»  Pharmaceutical compositions comprising a compound according to the invention, in combination with at least one pharmaceutically acceptable excipient, are also an integral part of the invention In such compositions, the compound according to the invention is present in a therapeutically effective amount.
Le terme « traitement » désigne toute mesure thérapeutique prophylactique ou suppressive d'une maladie ou désordre, conduisant à un effet clinique souhaitable ou à tout effet bénéfique,, incluant notamment la suppression ou la diminution d'un ou plusieurs symptômes, la régression, le ralentissement ou la cessation de la progression de la maladie ou du désordre qui y est associé.  The term "treatment" means any prophylactic or suppressive therapeutic measure of a disease or disorder, leading to a desirable clinical effect or any beneficial effect, including in particular the suppression or decrease of one or more symptoms, regression, slowing or stopping the progression of the disease or disorder associated therewith.
Far « quantité thérapeutiquement efficace », on désigne toute quantité d'une composition qui améliore un ou plusieurs des paramètres caractéristiques de l'affection traitée.  "Therapeutically effective amount" refers to any amount of a composition that improves one or more of the characteristic parameters of the condition being treated.
Les composés de formule (I), leurs sels, solvats et hydrates pharmaceutiquement acceptables ne sont pas cytotoxiques. De par leur activité, les composés de formule (1) précédemment décrits, ainsi que leurs sels, solvats et hydrates, peuvent être utilisés pour la fabrication d'un médicament destinés à traiter une affection allergique, et en particulier une pathologie d'origine allergique choisie parmi les manifestations pulmonaires,, comme l'asthme allergique ; les manifestations cutanées d'allergie comme l'eczéma, l'allergie médicamenteuse, les réactions de contact à des produits de l'environnement ; les manifestations digestives y compris les allergies alimentaires ; les autres manifestations muqueuses telles que les rhinites et les conjonctivites ; les manifestations articulaires allergiques ; les manifestations locales et systémiques résultant d'un contact avec un produit alimentaire., cosmétique, hygiénique, du milieu professionnel, médicamenteux ou toxique., le microbiote ou des parasites ; les manifestations de maladies auto-immunes ; l'œdème de Quincke, The compounds of formula (I), their pharmaceutically acceptable salts, solvates and hydrates are not cytotoxic. By their activity, the compounds of formula (1) described above, as well as their salts, solvates and hydrates, can be used for the manufacture of a medicament for treating an allergic disease, and in particular a pathology of allergic origin. selected from pulmonary manifestations, such as allergic asthma; cutaneous manifestations of allergy such as eczema, drug allergy, contact reactions to environmental products; digestive manifestations including food allergies; other mucosal manifestations such as rhinitis and conjunctivitis; allergic joint manifestations; local and systemic manifestations resulting from contact with a food product . , cosmetic, hygienic, professional, drug or toxic., microbiota or parasites; manifestations of autoimmune diseases; Quincke's edema,
La présente invention a également pour objet les compositions pharmaceutiques administra bîes aux animaux et, en particulier à l'homme, contenant une dose thérapeutiquement efficace d'un composé de formule (I), ou d'un sel, d'un solvat ou d'un hydrate pharmaceullquement acceptable de celui-ci^ et un ou des excipients convenables selon notamment la Pharmacopée Européenne ?ems édition. L'invention concerne donc les compositions pharmaceutiques comprenant: un composé selon l'invention, avec au moins un excipient pharmaceutiquement acceptable. The present invention also relates to the pharmaceutical compositions administered to animals and, in particular to humans, containing a therapeutically effective dose of a compound of formula (I), or a salt, a solvate or a a pharmaceutically acceptable hydrate thereof and one or more suitable excipients according to the European Pharmacopoeia in particular? ems edition. The invention thus relates to pharmaceutical compositions comprising: a compound according to the invention, with at least one pharmaceutically acceptable excipient.
Les excipients présents dans les compositions pharmaceutiques selon l'invention sont choisis selon la forme pharmaceutique et le mode d'administration souhaité. Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intra-veineuse, întracartiiage, topique, intratrachéale, intranasale, transdermique, rectale ou intraoculaire, les principes actifs de formule (I), en toute proportion,, ou leurs sels, solvats et hydrates éventuels, peuvent être administrés sous forme unitaire d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains pour la prophylaxie ou le traitement des maladies ci-dessus. Les formes unitaires d'administration appropriées comprennent les formes par voie orale, telles que les comprimes, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, Intra trachéale, intra nasale, les formes d'administration sous- cutanée, intramusculaire, intra cartilage ou intraveineuse e les formes d'administration rectale. Pour l'application topique, on peut utiliser les composés selon S Invention dans des crèmes, pommades, patches ou lotions.  The excipients present in the pharmaceutical compositions according to the invention 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, intrathecal, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active ingredients of formula (I), in any proportion, or their salts, solvates and hydrates, may be administered in unit dosage form, in admixture with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of the above diseases. Suitable unit dosage forms include oral forms, such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, oral, tracheal intravenous, intranasal, forms of subcutaneous, intramuscular, intra-cartilage or intravenous administration in the forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments, patches or lotions.
Afin d'obtenir l'effet souhaité, le composé selon l'Invention sera présent dans la composition à une dose thérapeutiquement efficace. La dose de principe actif varie, par exemple, entre 0,1 et 100 mg par kg de poids du corps et par jour. In order to achieve the desired effect, the compound of the invention will be present in the composition at a therapeutically effective dose. The dose of active ingredient varies, for example, between 0.1 and 100 mg per kg of body weight per day.
Lorsqu'on prépare une composition solide sous forme de comprimés., on mélange l'ingrédient actif principal avec un véhicule pharmaceutique, tel que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique ou analogues. On peut enrober les comprimés de saccharose, d'un dérivé cellulosique, ou d'autres matières appropriées ou encore on peut les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qulls libèrent û'une façon continue une quantité prédéterminée de principe actif, On obtient une préparation en gélules en mélangeant Ilngrédient actif avec un diluant et en versant te mélange obtenu dans des gélules molles ou dures. When a solid composition in tablet form is prepared, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. . Sucrose tablets can be coated, a cellulose derivative or other appropriate substances or else they can be treated such that they have a prolonged or delayed activity and release qulls û'une continuously a predetermined quantity of active ingredient. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
Les compositions pharmaceutiques contenant un composé de formule (I), ou d'un de ses sels, solvats ou hydrates, peuvent aussi se présenter sous forme liquide, par exemple, des solutions, des émulsions, des suspensions ou des sirops» Les supports liquides appropriés peuvent être, par exemple, l'eau, les solvants organiques tels que le glycérol ou les glycois, de même que leurs mélanges, dans des proportions variées, dans l'eau.  The pharmaceutical compositions containing a compound of formula (I), or a salt thereof, solvates or hydrates, may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable examples are water, organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions, in water.
Une préparation sous forme de sirop ou d'éiixfr ou pour l'administration sous forme de gouttes peut contenir l'ingrédient actif conjointement avec un éduicorant, acalorique, un antiseptique, ainsi qu'un agent donnant du goût et un colorant approprié. Les poudres ou ies granules dispersibles dans l'eau peuvent contenir Ilngrédient actif en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, comme la polyvinySpyrralidone, de même qu'avec des édulcorants ou des correcteurs de goût.  A syrup or syrup preparation or drop administration may contain the active ingredient together with a sweetener, acaloric, antiseptic, as well as a flavoring agent and a suitable colorant. The water dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinyl pyrrolidone, as well as with sweeteners or taste correctors. .
D'une façon générale, les mêmes variantes que celles indiquées précédemment pour les composés (I) sont applicables mutaù's mutandis aux médicaments, compositions et utilisations mettant en œuvre ces composés, Les exemples ci-après, en référence aux Figures annexées, permettent d'illustrer l'invention, mais n'ont aucun caractère limitatif. ίθ In general, the same variants as those indicated above for the compounds (I) are applicable Mutau's mutandis to drugs, compositions and uses employing such compounds, the following examples with reference to the accompanying Figures, allow to illustrate the invention, but have no limiting character. ίθ
Les Figures I et 2 montrent les résultats obtenus à 100 μ sur la dégranulatlon des basophiles par cytométrie en flux, respectivement avec les marqueurs CD63 et CD203c pour des composés selon l'Invention et d'autres composés de structure proche. Figures I and 2 show the results obtained at 100 μ on dégranulatlon basophils by flow cytometry, respectively with the CD63 and CD203c markers for compounds according to the invention and other similar structure compounds.
Les Figures 3 et 4 présentent les résultats d une étude effet-dose menée avec les composés (1.1), (1.2) et (1.3) sur un nombre de 4 donneurs, avec les marqueurs CD63 et CD203c.  Figures 3 and 4 present the results of a dose-effect study conducted with the compounds (1.1), (1.2) and (1.3) on a number of 4 donors, with the markers CD63 and CD203c.
Les iguras S à S présenten des résultats obtenus avec le composé The iguras S to S present in results obtained with the compound
(Ll) dans un modèle d'asthme chez la souris. (Ll) in a model of asthma in mice.
La îg ra S montre la réponse en plethysrnographie non invasive à des doses croissantes de métacholine pour l'ensemble des groupes u jour après le dernier challenge OVA.  The Igra S shows the non-invasive plethysrnography response to increasing doses of methacholine for all groups u day after the last OVA challenge.
La Fifpre § montre la concentration de linfl trat intra-bronch que de l'ensemble des groupes un jour après le dernier challenge OVA,  The Fifpre § shows the intra-bronchial focus concentration of all the groups one day after the last OVA challenge,
Les Figures ? et S montrent les cytoiogles obtenues par les analyses de cytométrie en flux dans les poumons et le LBA de l'ensemble des groupes un jour après le dernier challenge OVA.  The figures ? and S show the cytokines obtained by the flow cytometry analyzes in the lungs and the LBA of all the groups one day after the last OVA challenge.
Les Figures § et Î montrent les résultats obtenus à 100 pM sur la dégranulation des basophiles par cytométrie en flux,, respectivement avec les marqueurs CD63 et CD203cf pour des composés selon l'invention et le composé décrit page 9? de ce document, sous la référence 8 (noté Ref, S sur tes Figures) et, le composé décrit page 137 sous la référence 359 (noté Ref,Figures Î § and show the results obtained at 100 pM on degranulation of basophils by flow cytometry, respectively with the markers CD63 and CD203c f for compounds according to the invention and the compound described on page 9? of this document, under the reference 8 (denoted by Ref, S in the Figures) and the compound described on page 137 under the reference 359 (noted Ref,
8 sur les Figures) de WO 01/98291. L S nthèse des cltalcortes 8 in the figures) of WO 01/98291. L nthesis of clalecortes
Les chalcones ont été synthétisées selon le Schéma îf cl-après dans lequel X.. n, R¾ R4 et Rg, et FV sont tels que définis pour les composés de formule (¾, par condensation aldol que entre un dérivé d'acétophénone (II) et un dérivé de benzaldéhyde (lïî), The chalcones were synthesized according to Scheme I F cl following wherein X .. n, R¾ R4 and Rg, and FV are as defined for compounds of formula (¾, by aldol condensation between that an acetophenone derivative ( II) and a benzaldehyde derivative (II),
Le protocole expérimental est le suivant : A une solution d'acétophénone (Π) dans fëthanol . ou méthane! (10 rrsL/mmol d'acétophénone} est ajoutée successivement le dérivé de benzaldéhyde (ÏH) il et une solution d'hydroxyde de potassium (KOH, 50% dans H2Q), La solution est agitée à reflux du solvant pendant 24 h, L'éthanol ou le méthanol est évaporé et de l'eau est ajoutée au résidu restant. La solution est filtrée sous pression réduite et le solde obtenu est lavé successivement à l'eau et à féther, La pureté du produit est analysée par CCM, La majorité des chalcones ont été obtenues pures à œ stade. Si la CC révèle la présence d'impuretés, une purification par colonne de chromatographie sur gel de silice éiuée par l'acétate d'éthyie/cydohexane (1/4 à 1/1, v/v) est réalisée. The experimental protocol is as follows: A solution of acetophenone (Π) in ethanol. or methane! (10 mg / mmol of acetophenone) is added successively the benzaldehyde derivative (III) it and a potassium hydroxide solution (KOH, 50% in H 2 Q), The solution was stirred at reflux of the solvent for 24 h, ethanol or methanol is evaporated and water is added to the remaining residue . The solution is filtered under reduced pressure and the balance obtained is washed successively with water and with ether. The purity of the product is analyzed by TLC. The majority of the chalcones were obtained pure at this stage. If the CC reveals the presence of impurities, purification by silica gel chromatography column eluted with ethyl acetate / cyclohexane (1/4 to 1/1, v / v) is carried out.
Le dérivé d'acétop énone requis pour Sa préparation des chalcones ont été synthétisées selon la méthode décrite dans ; Liu et al. Bioorgank à Médicinal Chemistry, 2007, 15, 7021-7034, Les dérivés de benzaidéhyde sont commerciaux.  The acetoprenone derivative required for its preparation of chalcones was synthesized according to the method described in; Liu et al. Bioorgank at Medicinal Chemistry, 2007, 15, 7021-7034, Benzahyde derivatives are commercial.
c 'hi i  it hi
dérivé de dàwë dû c sfcone  derivative of dauwe due to sfcone
m  m
Scliérua i» Schéma de synthèse des chalcones Scliérua i »Chalcone synthesis scheme
Taoleati 1, Stryctyres et caractérîsatims des chaican s et réactifs ytîlîsés» Taoleati 1, Stryctyres and characterisatims of chaican s and reagents ytîlîsés »
s) Activité sur la dêgranulatlon de basophites humains normaux CD203c et s) Activity on the degramanulatlon of normal human basophites CD203c and
Ce test consiste à analyser par cytométrie en flux impression des marqueurs mernbranaires CD203c et CD63 sur des basophlles humains normaux. Pour cela du sang provenant de donneurs sains est exposé à un anticorps dirigé contre tes Immunoglobulines E (IgE) ce qui conduit à une actlvatlon et une dêgranulatlon des basophlles, provoquant une augmentation de l'expression de CD203c et de CD63, Afin de démontrer l'effet protecteur des dérivés dlntérêfc, ceux-ci sont co-incubés avec les basophites et l'anticorps snti-IgE et les échantillons sont analysés afin de démontrer un moindre niveau d'expression de CD2ô3c et de CD63. Les composés d'Intérêt étant dissous dans du dimethylsulfoxlde (DMSO) un contrôle est également réalisé en incubant les basophiies en présence de DMSO sans principe actif. This test consists of analyzing by flow cytometry CD203c and CD63 mernbran markers on normal human basophils. For this, blood from healthy donors is exposed to an antibody against immunoglobulin E (IgE) which leads to basophll activation and degranulation, causing an increase in the expression of CD203c and CD63, in order to demonstrate As a protective effect of the derivatives of interest, they are co-incubated with the basophites and the snti-IgE antibody and the samples are analyzed to demonstrate a lower level of expression of CD2δ3c and CD63. The compounds of interest are dissolved in dimethylsulfoxide (DMSO) a control is also carried out by incubating the basophiies in the presence of DMSO without active principle.
L'activité des composés (LU), (L2) et (13) a été comparée avec des composés de l'art antérieur notamment décrits dans la demande de brevet WO2007/083060, ainsi que des composés de structure proche synthétisés par les inventeurs, mais n'ayant pas fait l'objet de publications antérieures. Les différents exemples comparatifs testés sont présentés dans le Tableau 2.  The activity of the compounds (LU), (L2) and (13) was compared with compounds of the prior art described in particular in the patent application WO2007 / 083060, as well as compounds of close structure synthesized by the inventors, but not the subject of previous publications. The different comparative examples tested are shown in Table 2.
Les résultats obtenus à 100 μΗ sur la dégranulation des basophiies par cytométrle en flux avec les marqueurs CD63 et CD203c sont présentés respectivement dans les Figyr s î et 2, L'étude réalisée montre, dans les deux cas, un effet inhibiteur des composés selon l'Invention, contrairement aux autres composés testés. Les inventeurs de la présente demande de brevet ont également reproduit le composé décrit page 97 de WO 01/98291, sous Sa référence 8 et, le composé décrit page 137 sous ia référence 359,, afin de vérifier site présentaient une activité, à 100 μΜ, sur ia dégranuiation de basophiles humains normaux CD 63 en utilisant le même protocole. Les résultats obtenus sont présentés Figures 9 (résultats sur CD63) et 2,0 (résultats sur CD203e) et montrent que ces deux composés peuvent être considérés comme inactifs, au vu des résultats obtenus, en comparaison au composé selon l'invention (1.1), The results obtained at 100 μΗ on degranulation of the basophyes by flow cytometry with the markers CD63 and CD203c are presented respectively in Figs. 1 and 2. The study carried out shows, in both cases, an inhibitory effect of the compounds according to US Pat. Invention, unlike the other compounds tested. The inventors of the present patent application have also reproduced the compound described on page 97 of WO 01/98291, with reference 8, and the compound described on page 137 under the reference 359, in order to verify the site, exhibited an activity of 100 μM. on the degranulation of normal human CD 63 basophils using the same protocol. The results obtained are shown in FIGS. 9 (results on CD63) and 2.0 (results on CD203e) and show that these two compounds can be considered as inactive, in view of the results obtained, in comparison with the compound according to the invention (1.1). ,
Une étude effet-dose a égaiement été menée avec les composés (1.1), (L2) e (1.3) sur un nombre de 4 donneurs, Les résultats avec les marqueurs CD63 et CD2ô3c sont présentés respectivement Figures 3 et 4, On observe pour ces deux marqueurs un effet dose entre 1 et 100 micromolaires de composé (1.1), (L2) ou (1.3), sans effet plateau., ni différence significative entre ces composés. L'effet est plus marqué sur CD63 (effet maximum d 80%) que sur CD203c (effet maximum de 40%), b) Effe sur la fonction respiratoire dans un modèle d'asthme chez la souris Les composés selon l'invention ont également fait l'objet de tests in vivo. Le cromoglycate a été utilisé comme composé de référence car il est actuellement le seul composé actuellement commercialisé ayant été décrit comme ayant un effet s r la dégranulation des basophiles. A dose-effect study was also conducted with the compounds (1.1), (L2) e (1.3) on a number of 4 donors. The results with the markers CD63 and CD2δ3c are presented respectively in FIGS. 3 and 4. two markers a dose effect between 1 and 100 micromolar of compound (1.1), (L2) or (1.3), without plateau effect, or significant difference between these compounds. The effect is more marked on CD63 (maximum effect of 80%) than on CD203c (maximum effect of 40%), b) Effect on respiratory function in an asthma model in mice The compounds according to the invention also is tested in vivo. Cromoglycate has been used as the reference compound because it is currently the only compound currently marketed that has been described as having effect in the degranulation of basophils.
> Le modèle utilisé est un modèle ovalbumlne (ova). Le protocole comporte  > The model used is an ovalbumine model (ova). The protocol comprises
- 4 semaines de sensibilisation avec de l'ova solubilisé dans une solution contenant de Palum et injecté en intra-péritonéal (I-P). - 4 weeks of sensitization with ova solubilized in a solution containing Palum and injected intraperitoneally (I-P).
~ 1 semaine de challenge avec 3 challenges intra-rtasals d'ova solubilisé dans du tampon phosphate PBS 3 jours de suite.  ~ 1 week of challenge with 3 intra-rtasal challenges ova solubilized in phosphate buffer PBS 3 days in a row.
> Les injections de PBS, de composé (1,1) ou, de Cromoglycate ont été réalisées tout au long de la phase de challenge et poursuivies jusqu'à la date d'analyse à raison d'une injection par jours en X-P. > Les analyses ont été réalisées 1 et 5 jours après te dernier challenge intra-nasai. > The injections of PBS, compound (1,1) or Cromoglycate were carried out throughout the challenge phase and continued until the date of analysis at the rate of one injection per day in XP. > The analyzes were performed 1 and 5 days after the last intra-nasal challenge.
* Ces analyses comprennent :  * These analyzes include:
Un jour après le dernier challenge  One day after the last challenge
- une analyse de la fonction respiratoire par plethysmographie non invasive sur 10 souris par groupes. La fonction respiratoire est analysée en réponse à une dose croissante de métachoiine (broncho-constricteur),  an analysis of the respiratory function by non-invasive plethysmography on 10 mice in groups. Respiratory function is analyzed in response to a growing dose of methacholine (bronchoconstrictor),
- récupération et analyse du lavage broncho-alvéolaire (compte du nombre de cellules, et analyse cytologique) sur 5 souris.  - recovery and analysis of bronchoalveolar lavage (count of the number of cells, and cytological analysis) on 5 mice.
- dissection des poumons pour analyses cytologiques (étude microscopique après coloration) sur tes mêmes 5 souris,  dissection of the lungs for cytological analyzes (microscopic study after staining) on the same 5 mice,
Cinq jours après 1e dernier challenge  Five days after the last challenge
~ une analyse de Sa résistance pulmonaire par la technique des oscillations forcées (méthode invasive) sur les 5 souris restantes des différents groupes. La résistance pulmonaire est analysée en réponse à une dose croissante de métachoii ne {bronchoconstneteu r) .  ~ An analysis of its pulmonary resistance by the technique of forced oscillations (invasive method) on the 5 remaining mice of the different groups. Pulmonary resistance is analyzed in response to an increasing dose of methotrex (bronchoconstneteu r).
- récupération et analyse du lavage broncho-alvéolaire (compte du nombre de cellules, et dépôt sur lame par cytospin pour analyse cytologique) sur ces 5 souris.  - Recovery and analysis of bronchoalveolar lavage (count of the number of cells, and slide on cytospin for cytological analysis) on these 5 mice.
Les souris ont été réparties en 3 groupes :  The mice were divided into 3 groups:
Un groupe composé (Ll) (n=10), un groupe i-cm (cromoglycate, n~10) et un groupe ï-PBS (n-10).  A compound group (L1) (n = 10), an i-cm group (cromoglycate, n-10) and a β-PBS group (n-10).
Mode, d'administration  Administration mode
Le composé (Ll) est dissous dans une solution de D SO. Cette solution stock est ensuite diluée dans une solution vol: vol d'éthartol.PBS avant administration inira-périonéale. Le composé (Ll) se solubilise mal ce qui peut expliquer la variabilité constatée dans certaines des expériences.  The compound (Ll) is dissolved in a solution of D SO. This stock solution is then diluted in a solution vol: vol ethartol.PBS before intra-perioneal administration. The compound (L1) solubilizes poorly which may explain the variability found in some of the experiments.
La Figure S montre la réponse en plethysmographie non invasive à des doses croissantes de métachoiine pour i'ensemble des groupes un jour après le dernier challenge OVA, Les valeurs de Penh (enhanced Pause), calculées à partir des mesures de pléitiysmographie, traduisent allongement du temps de pause expiratoire observé chez les sujets présentant une réduction du calibre bronchique et sont corrélées avec la résistance respiratoire. Une diminution des valeurs de Penh correspond donc à un effet protecteur vis-à-vis de ia bronchoconsfriction màuite par l'OVA. Figure S shows the non-invasive plethysmographic response to increasing doses of methacholine for all groups one day after the last OVA challenge. Penh (enhanced pause) values, calculated from the pleitiysmography measurements, reflect lengthening of the Expiratory pause time observed in subjects with reduced caliber bronchial and are correlated with respiratory resistance. A decrease in Penh values therefore corresponds to a protective effect vis-à-vis OVA-induced bronchoconstruction.
La Figyre 6 montre la concentration de {Infiltrât intra-bronchique de l'ensemble des groupes un jour après le dernier challenge QVA.  Figure 6 shows the concentration of intra-bronchial infiltrate of all groups one day after the last QVA challenge.
Les Figures 7 et 8 montrent les cytoiogies obtenues par les analyses de cytométrie en flux dans les poumons et le L8Â de l'ensemble des groupes un jour après 1e dernier challenge OVA.  Figures 7 and 8 show the cytokines obtained by flow cytometric analyzes in the lungs and L8 of all groups one day after the last OVA challenge.
Le groupe contrôle sensibilisé et chaliengé avec de l'OVA et injecté avec du PBS montre tous les signes d'un asthme allergique à IOVA avec une Penh élevée, et ce d'autant plus que la dose de métacholine est importante, un fort infiltrat intrabronchique et une forte éosinophilie. Ce groupe a servi de référence pour l'ensemble des résultats,  The control group sensitized and chaliengé with OVA and injected with PBS shows all the signs of allergic asthma to IOVA with a high Penh, and all the more that the dose of methacholine is important, a strong intrabronchial infiltrate and strong eosinophilia. This group served as a reference for all the results,
L'analyse de la fonction respiratoire un jour après le dernier challenge ova montre que le cromoglycate et le composé (II) conduisent à des réponses différentes. Ainsi les souris traitées par du cromoglycate présentent les mêmes augmentations de Penh, en réponse à des doses croissantes de métacholine que les souris contrôles traitées avec du PB8, En revanche, la différence est significative dès ia dose 20 si on compare avec le composé (ï.l). Si l'on compare au groupe contrôle injecté avec du PBSf la différence n'est significative que pour la dose à 40 mg/ml. The analysis of the respiratory function one day after the last challenge ova shows that cromoglycate and compound (II) lead to different responses. Thus, mice treated with cromoglycate showed the same increases in Penh in response to increasing doses of methacholine as the control mice treated with PB8. On the other hand, the difference was significant from the dose when compared with the compound .l). Comparing to the control group injected with PBS f the difference is not significant for the dose to 40 mg / ml.
Première conclusion, il semble donc qu'un jour après le dernier challenge OVA, le composé (Lî) améliore la fonction respiratoire des souris.  First conclusion, it seems that one day after the last OVA challenge, the compound (III) improves the respiratory function of the mice.
En ce qui concerne ilnflammation intra bronchique, les souris injectées avec du PBS montrent un infiltrât inflammatoire important. Le groupe cromoglycate ne montre pas de différence significative avec le groupe traité par du tampon. En revanche, le groupe traité avec du composé (ï.l) montre une diminution significative de l'infiltrat intra-bronchique comparé aux groupes PBS et cromoglycate- S! on regarde au niveau de fa composition de cet Infiltrât (Figure 7), on a une composition tout à fai en adéquation avec un modèle OVA avec une forte éosinophilie et peu d'augmentation des autres types cellulaires.  With regard to intra bronchial inflammation, the mice injected with PBS show a large inflammatory infiltrate. The cromoglycate group did not show a significant difference with the buffer group. In contrast, the group treated with compound (11) showed a significant decrease in intracranial infiltrate compared with PBS and cromoglycate-S! we look at the composition level of this infiltrate (Figure 7), we have a composition quite in line with an OVA model with strong eosinophilia and little increase of other cell types.
Plusieurs points sont intéressants ; Tout d'abord, Iinfiltrat du groupe PBS est en adéquation entre les différents paramètres regardés, L'hyperéoslnophilie corrèie bien avec l'augmentation de {Infiltrât întra bronchique et l'hyper réactivîté bronchique. En ce qui concerne ie groupe du composé (Ll),. on observe une diminution des éosinop iies et des lymphocytes T par comparaison au groupe PBS, ce qui corrèie bien avec la diminution d'hyper réactivité bronchique, Le groupe cromogiycate, quant à lui, ne montre pas de diminution significative de Iinfiltrat à éosinophiies par rapport au groupe PBS. Several points are interesting; First of all, the infiltration of the PBS group is in adequacy between the different parameters looked at. The hyperoseophilia correlates well with the increase of bronchial infiltrate and bronchial hyperreactivity. Regarding the group of the compound (L1) ,. Eosinopias and T-lymphocytes decreased compared to the PBS group, which correlates well with the decrease in bronchial hyperresponsiveness. The cromogiycate group, on the other hand, does not show a significant decrease in eosinophils compared with to the PBS group.
En conclusion, ie composé (Ll) semble jouer sur i'éoslnophilie,  In conclusion, the compound (Ll) seems to play on the eophophilia,
L'inflammation intra-puimonaire ne montre pas de grosses variations comparées à iinfiltrat întra bronchique, On a une hyperéosinophilie pour tous les groupes, mais celle-ci est beaucoup moins importante dans le groupe du composé (Ll) y compris pour Se groupe cromogiycate avec une diminution de ces éosinophiies dans le groupe du composé (Ll).  Intra-pupal inflammation does not show large variations compared to bronchial infiltrate. Eryosinophilia was observed for all groups, but it was much less important in the group of the compound (L1), including Se group cromogylate with a decrease in these eosinophils in the group of the compound (L1).
L'ensemble de ces résultats montre que le composé (1.1) induit une protection des souris vis-à-vis de la bronchoconstriction dans ce modèle d'asthme induit par l'OVA et que cette protection s'accompagne d'une réduction des signes biologiques d'Inflammation, à la fois au niveau du parenchyme pulmonaire et du liquide de lavage bronchiole-alvéolaire. De façon remarquable, le composé (1.1) réduit de façon très significative Iinfiltrat éosinophile provoqué par IOVA dans ce modèle.  All of these results show that the compound (1.1) induces protection of the mice against bronchoconstriction in this model of OVA-induced asthma and that this protection is accompanied by a reduction of the signs. Inflammation biologics, both at the level of the lung parenchyma and the bronchiole-alveolar lavage fluid. Remarkably, compound (1.1) very significantly reduces the IOVA-induced eosinophil infiltrate in this model.

Claims

1 ~ Com osés de formule (I) 1 ~ Com osés of formula (I)
dans laquelle : in which :
~ Ri, 4 et Rg, Identiques ou différents, représentent un atome d'hydrogène, chlore, brome., iode ou fluor, ou un groupe -OH ou -O-alkyle comprenant de 1 à 6 atomes de carbone ; Ri, 4 and Rg, identical or different, represent a hydrogen, chlorine, bromine, iodine or fluorine atom, or a -OH or -O-alkyl group comprising from 1 to 6 carbon atoms;
- ¾' et identiques ou différents; représentent un atome d'hydrogène, ou un groupe -OH ou -Oatkyle comprenant de 1 à 6 atomes de carbone ; étant entendu que i ' et/ou représente(nt) un groupe méthoxy ;  - ¾ 'and the same or different; represent a hydrogen atom, or a -OH or -Oalkyl group comprising from 1 to 6 carbon atoms; it being understood that i 'and / or represents (s) a methoxy group;
- n est égal à 1, 2, 3 ;  n is 1, 2, 3;
- X ~ CH2, O, S, ou (R?) ; et - X ~ CH 2 , O, S, or (R?); and
~ R? représente un atome d'hydrogène ou un groupe alky!e comprenant de 1 à 6 atomes de carbone ; ~ R ? represents a hydrogen atom or an alkyl group comprising from 1 to 6 carbon atoms;
ainsi que leurs hydrates, solvats et sels p armaceutiquement acceptables. as well as their hydrates, solvates and pharmaceutically acceptable salts.
2 - Composés selon la revendication 1, caractérisés en ce que X~N(R?). 2 - Compounds according to claim 1, characterized in that X ~ N (R ? ).
3 - Composés selon la revendication 2, caractérisés en ce que ? représente un groupe méthyie. 3 - Compounds according to claim 2, characterized in that ? represents a methyl group.
4 ~ Composés selon l'une des revendications 1 à 3, caractérisés en ce que n=2.  4 ~ Compounds according to one of claims 1 to 3, characterized in that n = 2.
5 - Composés selon l'une des revendications i à 4, caractérisés en ce que ?., R4 et Rg, identiques ou différents, représentent un atome d'hydrogène, un atome de chlore ou un groupe méthoxy. 5 - Compounds according to one of claims i to 4, characterized in that?., R 4 and Rg, identical or different, represent a hydrogen atom, a chlorine atom or a methoxy group.
i - Composés selon l'une des revendications 1 à 5, caractérisés en ce que R?/' et ¾' représentent tous deux un groupe méthoxy. Compounds according to one of claims 1 to 5, characterized in that R ' ''and''' both represent a methoxy group.
7 » Composés selon la revendication 1 choisis parmi :7 » Compounds according to claim 1, chosen from:
'-Hydroxy- ^^^'^'-pentaméthoxy-S-Ci-méthyipipéridin-^yOchalcone, composé (Ll) Hydroxy-N, N'-pentamethoxy-S-Ci-methylipiperidin-4-ylcyclone, compound (L1)
2f~Hydrox7™2i6,4'f6Hetraméthoxy~S~(l~mé^^ composé2 f ~ Hydrox7 ™ 2 i 6,4 ' f 6Hetramethoxy ~ S ~ (l ~ me ^^ compound
(12) (12)
2/ô"DichSoro-4';6,~diméthoxy^ 2 / O "DichSoro-4 '; 6, dimethoxy ~ ^
composé (1.3) compound (1.3)
ainsi que leurs hydrates, solvats et sels pharmaœutiquement acceptables. as well as their hydrates, solvates and pharmaceutically acceptable salts.
8 - Composés selon l'une des revendications l à ? pour leur utilisation en tant que médicament,  8 - Compounds according to one of claims l to? for their use as a medicine,
9 ~ Composés selon l'une des revendications î à 8 pour leur utilisation en tant que médicament anti-aliergique.  9 ~ Compounds according to one of claims 1 to 8 for their use as anti-aliegic drug.
I » Composés selon l'une des revendications i à 9 pour leur utilisation en tant que médicament pour îe traitement d'une pathologie d'origine allergique choisie parmi Ses manifestations pulmonaires, comme l'asthme allergique ; les manifestations cutanées d'allergie comme l'eczéma, l'allergie médicamenteuse, les réactions de contact à des produits de l'environnement ; les manifestations d!gestlves y compris les allergies alimentaires ; les autres manifestations muqueuses telles que les rhlnltes et les conjonctivites ; les manifestations articulaires allergiques ; les manifestations locales et systémiques résultant d'un contact avec un produit alimentaire, cosmétique, hygiénique, du milieu professionnel, médicamenteux ou toxique, le microbio e ou des parasites ; les manifestations de maladies auto-immunes ; icedème de Quincke. I "Compounds according to one of Claims i to 9 for use as a medicament for treatment of allergic IE original pathology selected from His pulmonary manifestations such as allergic asthma; cutaneous manifestations of allergy such as eczema, drug allergy, contact reactions to environmental products; events gestlves including food allergies; other mucosal manifestations such as rhinitis and conjunctivitis; allergic joint manifestations; local and systemic manifestations resulting from contact with a food product, cosmetic, hygienic, professional, drug or toxic environment, microbioe or parasites; manifestations of autoimmune diseases; icedema of Quincke.
EP14720658.5A 2013-04-05 2014-04-04 Novel chalcone derivatives having an anti-allergic activity Withdrawn EP2981521A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1353091A FR3004180B1 (en) 2013-04-05 2013-04-05 NOVEL CHALCONE DERIVATIVES WITH ANTI-ALLERGIC ACTIVITY
PCT/FR2014/050816 WO2014162106A1 (en) 2013-04-05 2014-04-04 Novel chalcone derivatives having an anti-allergic activity

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EP2981521A1 true EP2981521A1 (en) 2016-02-10

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US (1) US9896415B2 (en)
EP (1) EP2981521A1 (en)
JP (1) JP2016515605A (en)
FR (1) FR3004180B1 (en)
WO (1) WO2014162106A1 (en)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0659743A1 (en) * 1993-12-27 1995-06-28 Hoechst Aktiengesellschaft Piperidine derivatives as inhibitors of platelet aggregation and their preparation
CA2395191A1 (en) 1999-12-23 2001-06-28 Tedman Ehlers Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states
IL153565A0 (en) * 2000-06-20 2003-07-06 Atherogenics Inc 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat vcam-1 mediated disorders
FR2864956B1 (en) * 2004-01-08 2006-04-28 Genfit S A DERIVED COMPOUND OF 1,3-DIPHENYLPROP-2-EN-1-ONE, PREPARATION AND USES
FR2896245B1 (en) 2006-01-17 2010-09-17 Univ Claude Bernard Lyon NEW CHALCONE DERIVATIVES WITH ANTIMITOTIC ACTIVITY
EP2274411A4 (en) * 2008-04-11 2016-01-20 Betal Llc Xanthohumol compositions and methods for treating skin diseases or disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014162106A1 *

Also Published As

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US20160052881A1 (en) 2016-02-25
WO2014162106A1 (en) 2014-10-09
JP2016515605A (en) 2016-05-30
US9896415B2 (en) 2018-02-20
FR3004180A1 (en) 2014-10-10
FR3004180B1 (en) 2015-06-26

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