EP2307012A1 - Dérivés hétérocycliques de l'azote sous la forme de modulateurs du protéasome - Google Patents

Dérivés hétérocycliques de l'azote sous la forme de modulateurs du protéasome

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Publication number
EP2307012A1
EP2307012A1 EP09773025A EP09773025A EP2307012A1 EP 2307012 A1 EP2307012 A1 EP 2307012A1 EP 09773025 A EP09773025 A EP 09773025A EP 09773025 A EP09773025 A EP 09773025A EP 2307012 A1 EP2307012 A1 EP 2307012A1
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chosen
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German (de)
English (en)
Inventor
Bruno Villoutreix
Michèle REBOUD-RAVAUX
Nicolas Basse
Joëlle VIDAL
Matthieu Montes
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Centre National de la Recherche Scientifique CNRS
Universite de Rennes 1
Universite Pierre et Marie Curie Paris 6
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite de Rennes 1
Universite Pierre et Marie Curie Paris 6
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
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Priority to EP09773025A priority Critical patent/EP2307012A1/fr
Publication of EP2307012A1 publication Critical patent/EP2307012A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the identification and the use of nitrogen heterocycle derivatives, such as oxadiazole and triazole derivatives, as modulators of the proteasome activity. More particularly, the invention relates to the use of oxadiazole derivatives for the preparation of pharmaceutical compositions or in cosmetic compositions.
  • the present invention is also directed to a method of prevention and/or treatment of disease conditions mediated by proteasome activity, in particular cancer conditions, comprising the administration of nitrogen heterocycle derivatives, in particular triazole or oxadiazole derivatives in accordance with the invention.
  • the non-lysosomal protein degradation is mainly performed by the strictly controlled complex enzymatic machinery of the ubiquitin-proteasome pathway.
  • Proteasomes are involved in protein quality control and turnover of many critical proteins participating in a vast number of essential biological processes, such as signal transduction, cell proliferation, cell cycle control, cell differentiation and apoptosis (Coux et al., Annu Rev Biochem 1996, 65, 801; Ciechanover et al., Pr oc Natl Acad Sci USA 1998, 95:2727).
  • the 26S proteasome is formed by the 2OS catalytic core, capped at each end by a regulatory component termed the 19S complex, responsible in part for the selective degradation of a given substrate.
  • the 2OS proteasome core particle is composed of 28 subunits that are arranged into four stacked rings of seven ⁇ -type subunits or seven ⁇ -type subunits.
  • the central proteolytic chamber of this endoprotease is composed of the two ⁇ -rings.
  • Each ⁇ -ring has three different proteolytic activities associated to a N-terminal threonine hydrolase, referred to as chymotrypsin-like (CT-L), post glutamyl peptide hydro lysing or post-acid (PGPH or PA) and trypsin-like (T-L).
  • C-L chymotrypsin-like
  • PGPH or PA post glutamyl peptide hydro lysing or post-acid
  • T-L trypsin-like
  • the proteasome is a universal and broadly active cellular component, it is not surprising that it has been proposed as an interesting target in many disease indications.
  • the proteasome plays a key role in immune surveillance against virus and cancer, because it is involved in antigen processing and presentation to cytotoxic T cells, and in activation of nuclear factor-kappa B that is the central transcription factor of the immune system. It plays also a role in inflammatory responses, such as inflammatory arthritis, muscle atrophy, in several dystrophies such as limb-girdle muscular dystrophy (LGMD-IC) and Duchenne muscular dystrophy (DMD), as well as sleeping sickness.
  • LGMD-IC limb-girdle muscular dystrophy
  • DMD Duchenne muscular dystrophy
  • proteasome is also proposed as target for cancer therapy, as cancer cells are more susceptible to undergo apoptosis than normal cells after treatment with proteasome inhibitors (Adams et al., Cancer Cell, 2004, 5:417). Proteasome inhibitors sensitize cancer cells and tumours to the proapoptotic effects of conventional chemotherapeutics and radiation therapy (Yu et al., MoI Cancer Ther, 2006, 5:2378.
  • proteasome inhibitors are peptidic derivatives or natural compounds, but the large majority of these molecules is bearing a reactive group and acts as covalent inhibitors.
  • proteasome inhibitors are sorted according to their ability to interact covalently or non- covalently with the active sites of the proteasome.
  • the different classes of proteasome inhibitors are reviewed by Borissenko & Groll ⁇ Chemical Rev., 2007, 107:687) and Papapostolou & Reboud-Ravaux (J Soc Biol, 2004, 198:263).
  • Velcade ® or bortezomib which is the first proteasome inhibitor approved by the FDA, is a covalently interacting proteasome inhibitor.
  • This compound is a dipeptide boronic acid which is sensitive to oxidation (Pekol et al., Drug Metab Dispos 2005, 33:771).
  • TMC-95 is a non-covalently interacting proteasome inhibitor (Kohno et al., J Org Chem 2000, 65:990).
  • this compound presents the drawbacks of having a very complex structure, rendering complicated its synthesis, and a high molecular weight, conferring to it a weak bioavailability.
  • proteasome activators may be useful for improving, treating and/or preventing conditions mediated by accumulation of proteins or polypeptides.
  • the activation of proteasome should accelerate and improve the intracellular proteolysis favoring the removing of oxidized protein associated with aging, in particular skin aging.
  • proteasome activators would also be helpful in disease conditions associated with proteins accumulation such as Alzheimer disease or Parkinson disease.
  • Proteasome activators are, for example, described in Kisselev et al., (J. Biol. Chem. 2002, 277:22260); WiIk et al., (MoI. Biol. Rep., 1997,24:119); Ruiz de Mena et al., (Biochem. J. 1993, 296:93); Arribas et al, (J. Biol. Chem., 1990, 265: 13969); US 5,847,076 and JP 2002-029996. So far, the known proteasome modulators (inhibitors or activators) present a peptide- like structure and/or have a high molecular weight.
  • proteasome modulators that covalently interact with proteasome active sites are typically associated with numerous unwanted side effects. Their reactive group is inherently associated with lack of specifity, excessive reactivity, and instability.
  • proteasome activity modulators and in particular proteasome activity inhibitors, that are selective to the proteasome with respect to the other intracellular proteases.
  • proteasome activity modulators and in particular proteasome activity inhibitors, having a non-peptide like structure.
  • proteasome modulators and in particular proteasome activity inhibitors, that non-covalently interact with the active site of the proteasome.
  • novel proteasome activity modulators and in particular proteasome activity inhibitors, having reduced or no unwanted side effects.
  • the present invention has for object to meet those needs.
  • the instant invention relates to the use of at least one nitrogen heterocycle derivative of formula (I):
  • Het represents a triazole or an oxadiazole radical, optionally substituted with one or more linear or branched, saturated or unsaturated C 1 -C 4 alkyl group
  • Ari represents a C ⁇ -Cio aryl group, substituted with at least one R group chosen among:
  • A represents: - a covalent bond
  • R 4 and R 6 being, independently of each other chosen among H or a linear, branched or cyclic, saturated or unsaturated, C 1 -C5 alkyl group, or
  • B represents a linear, branched or cyclic, saturated or unsaturated, C 1 -C5 alkylene group, optionally substituted with one or more C 1 -C5 hydroxyalkyl group(s), or a C ⁇ -Cio arylene group,
  • R represents H or a linear, branched or cyclic, saturated or unsaturated, C1-C5 alkyl group
  • Z represents -(R 5 ) n -(Ar 2 ) m , with n and m represent, independently of each other, 0 or 1 , provided that at least one of n or m is 1 , where
  • R 5 represents, a linear, branched or cyclic, saturated or unsaturated, C 1 -C5 alkyl or alkylamido group, optionally comprising one or more heteroatom(s) chosen among O, N or S, and
  • Ar 2 represents a C ⁇ -Cio aryl group substituted with at least one R as above-defined, as proteasome activity modulator in the manufacture of a pharmaceutical composition intended to prevent and/or treat a disease condition mediated by the proteasome activity.
  • the inventors have surprisingly identified nitrogen heterocycle derivatives, and in particular oxadiazole and triazole derivatives as novel proteasome activity modulators within a compound collection known and commercially available at ChemBridge Corporation (www.chembridge.com).
  • the compounds of the invention may also be prepared according to methods well-known by the skilled artisan.
  • proteasome activity modulator or “proteasome modulator” are used interchangeably and are intended to mean a compound able to bind with at least one active site of the proteasome, i.e. a chymotrypsin-like active site, a trypsin- like active site or a post-acid (PA) active site or with a site distant from said active sites, and to, directly or allosterically, reduce or even suppress, or increase the enzymatic activity rate of at least one active site as compared with said enzymatic activity rate without said proteasome modulator.
  • active site of the proteasome i.e. a chymotrypsin-like active site, a trypsin- like active site or a post-acid (PA) active site or with a site distant from said active sites, and to, directly or allosterically, reduce or even suppress, or increase the enzymatic activity rate of at least one active site as compared with said enzymatic activity rate without said proteasome modulator
  • a proteasome modulator of the invention may exert a dual or a multiple effect, that is it may exert an effect on more than one active site.
  • a proteasome modulator may simultaneously exert a reduction, or a suppression, of the enzymatic activity rate of a first active site and an increase or a decrease of the enzymatic activity rate of a second active site.
  • the enzymatic activity rate of a third active site may be reduced or suppressed, or increased or left unchanged.
  • a proteasome modulator may be a "proteasome activity inhibitor or proteasome inhibitor".
  • a proteasome activity modulator or
  • proteasome activity inhibitor or “proteasome inhibitor” is intended to mean a proteasome modulator that reduces or suppresses the enzymatic activity rate of at least one active site of the proteasome, as compared with said enzymatic activity rate determined without said proteasome inhibitor.
  • a proteasome modulator may be a "proteasome activity activator” or “proteasome activator”.
  • a proteasome activity activator or a “proteasome activator” is intended to mean a proteasome modulator that increases the enzymatic activity rate of at least one proteasome active site, as compared with said enzymatic activity rate determined without said proteasome activator.
  • a proteasome modulator may exert only an inhibitory effect.
  • a proteasome modulator may exert only an activator effect. According to one embodiment, a proteasome modulator may exert a dual or a multiple effect.
  • a proteasome modulator may exert an effect on one, two or three active sites.
  • a proteasome modulator exerting an effect on no more than two, and in particular on no more than one active site may advantageously allow to reduce the risk of occurrence of toxic or unwanted side effects.
  • a proteasome inhibitor of the invention may inhibit no more than two active sites, and in particular no more than one active site.
  • a proteasome inhibitor may advantageously exert an inhibiting effect on the chymotrypsin-like and/or trypsin- like effect, and in particular on the chymotrypsin-like active site.
  • inhibitor or “activator” may be attributed to a compound of the invention with respect to an enzyme activity. However, it does not preclude that said compound may also exert an inhibitor and/or activator effect(s) on the other(s) enzyme activity(ies) of the proteasome.
  • pharmaceutical composition is intended to mean any substance or composition intended to be administered to an individual, human or animal, to prevent, reduce, relieve and/or cure a disease condition or a sign associated with said disease condition and/or to make a diagnostic of a disease condition.
  • prevent or "prevention” with respect to an event is intended to mean the decrease of a risk of occurrence of said event.
  • a disease condition considered in the invention may be chosen among cancers, immunological diseases, auto-immune diseases, allograft rejections, viral diseases, such as mumps, measles, Rous sarcoma or AIDS, parasitic diseases such as malaria or trypanosome, bacterial infections, such as tuberculosis, inflammatory diseases, such as polyarthritis or liver inflammation, cardiac diseases and ischemic strokes, such as myocardial, cerebral or pulmonary ischemic injuries, muscular dystrophies, muscle wasting, traumatisms, burns, disease conditions associated with aging, such as neurodegenerative diseases.
  • viral diseases such as mumps, measles, Rous sarcoma or AIDS
  • parasitic diseases such as malaria or trypanosome
  • bacterial infections such as tuberculosis
  • inflammatory diseases such as polyarthritis or liver inflammation
  • cardiac diseases and ischemic strokes such as myocardial, cerebral or pulmonary ischemic injuries, muscular dystrophies, muscle wasting,
  • the invention is directed to a use of at least one nitrogen heterocycle derivative, in particular one oxadiazole or one triazole derivative, in accordance with the invention as active agent in a cosmetic composition for the prevention and/or the treatment of skin aging.
  • the invention is directed to a kit-of-parts comprising (i) at least one nitrogen heterocycle derivative, in particular an oxadiazole or a triazole derivative, according to the invention and (ii) at least one agent useful for the prevention and/or the treatment of a cancer condition, said agent being different of said nitrogen heterocycle derivative (i).
  • the invention is directed to a method for preventing and/or treating a disease condition mediated by proteasome activity comprising at least a step of administering to an individual in need thereof at least one effective amount of at least one nitrogen heterocycle derivative, in particular an oxadiazole or a triazole derivative, according to the invention.
  • the invention is directed a nitrogen heterocycle derivative of the invention for use as a medicament.
  • novel proteasome modulators of the invention have an improved bioavailability.
  • novel proteasome modulators of the invention have an improved cellular toxicity towards tumoral cells.
  • novel proteasome modulators of the invention have a low or even have no cellular toxicity on normal healthy cells. According to another advantage, the novel proteasome modulators of the invention have reduced or no unwanted side-effects.
  • the proteasome modulators of the invention are non peptidic molecules without reactive group susceptible to lead to a lack of specificity, excessive reactivity and instability.
  • a nitrogen heterocycle derivative of the invention may be of the following formula (I):
  • Het represents a triazole or an oxadiazole radical, optionally substituted with one or more, linear or branched, saturated or unsaturated, C 1 -C 4 alkyl group,
  • Ar 1 represents a C ⁇ -Cio aryl group, substituted with at least one R group chosen among:
  • A represents:
  • R 4 and R 6 being, independently of each other, chosen among H or a linear, branched or cyclic, saturated or unsaturated, C 1 -Cs alkyl group, or - a linear, branched or cyclic, saturated or unsaturated, C 1 -Cs alkylene group,
  • B represents a linear, branched or cyclic, saturated or unsaturated, C 1 -Cs alkylene group, optionally substituted with one or more C 1 -Cs hydroxyalkyl group(s), or a C(5-Cio arylene group
  • R represents H or a linear, branched or cyclic, saturated or unsaturated, C 1 -C5 alkyl group
  • Z represents -(R 5 )n-(Ar 2 )m, with n and m representing, independently of each other, 0 or 1, provided that at least one of n or m is 1, where - R 5 represents a linear, branched or cyclic, saturated or unsaturated, C 1 -C5 alkyl or alkylamido group, optionally comprising one or more heteroatom(s) chosen among O, N or S, and
  • - Ar 2 represents a C ⁇ -Cio aryl group substituted with at least one R group as above-defined, as proteasome activity modulator in the manufacture of a pharmaceutical composition intended to prevent and/or treat a disease condition mediated by the proteasome activity.
  • the invention also relates to isoform of compounds of formula (I).
  • tautomer is intended to mean isomers, the structure of which differ by the position of one atom, typically one hydrogen atom, and one or more multiple bonds and which are able to easily and reversibly transform into each other.
  • stereoisomer is intended to mean isomers from a molecule which are identical in constitution but which differ only by one or more different arrangements of their atoms in space.
  • polymorphous form are intended to mean compounds obtained by crystallization of a compound of general formula (I) in different conditions, as for example the use of different sequences, usually used for crystallization. Crystallization at different temperature implies, for example, various mode of cooling, such as very fast to very low cooling, or warming or melting steps of compounds followed by fast or gradual cooling.
  • polymorphous forms may be identified by NMR spectroscopy, IR-spectroscopy (infrared), differential scanning calorimetry (DSC), X-ray diffraction or other similar techniques known in the art.
  • unsaturated with respect to a group from the formula (I) is intended to mean that this group may comprise one or more multiple bond(s), such as double or triple bond(s).
  • a given group from formula (I) comprises more than one unsaturated bonds, for example at least two double bonds, those unsaturated bonds may or may not be conjugated between them in said group and/or conjugated with unsaturated bond(s) of the other moieties of the formula (I).
  • unsaturated is intended to mean alkenyl or alkenyl group.
  • the term "radical” with respect to Het is intended to mean that within the compounds of general formula (I) of the invention, the triazole or the oxadiazole group is covalently bonded with B and Z, and optionally further substituted with one or more, linear or branched, saturated or unsaturated, C 1 -C 4 alkyl group.
  • Het may be substituted with one or more methyl or ethyl group, in particular with one methyl group.
  • Het may be chosen from an 1,2,4-oxadiazole, an 1,3,4-oxadiazole, an 1,2,5-oxadiazole, an 1,2,3-oxadiazole, an 1,2,3-triazole, an 1,2,4-triazole- or a 4-methyl 1,2,4-triazole radical.
  • Het may be chosen from an 1,2,4-oxadiazole, an 1,2,5- oxadiazole, an 1,2,3-oxadiazole, an 1,2,3-triazole, an 1,2,4-triazole or a 4-methyl 1,2,4-triazole radical.
  • Het may be advantageously an
  • 1,2,4-oxadiazole radical an 1,3,4-oxadiazole radical or a 4-methyl 1,2,4-triazole radical.
  • Het may be an 1,2,4-oxadiazole radical or a 4-methyl 1,2,4-triazole radical.
  • Z may represent -(R 5 ) n -(Ar2) m .
  • n and m are 1.
  • R 5 may be chosen from a linear, branched or cyclic, saturated or unsaturated, C 2 -C 4 alkyl or alkylamido group, optionally comprising one or more heteroatom chosen from N, O or S.
  • R 5 may be an alkylthioether, an N,N- aminoalkyl or an alkylether, with said alkyl group being as above-described.
  • R 5 may be D-(CH 2 )i_ 4 -C(O)N-, with D being S, O or N, and in particular R 5 may be -S-CH 2 -C(O)N-.
  • R 5 may be chosen from a methyl, an ethyl, a propyl, an iso-propyl, a butyl, a sec-, a tert- or an iso-butyl group.
  • R 5 may further comprise at its free terminus one or more heteroatom as above-indicated.
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative of formula (HA) or (HB):
  • a nitrogen heterocyle derivative of the invention is an oxadiazole derivative of formula (IIA) as above-defined.
  • Ari and Ar 2 may represent, independently of each other, a phenyl group or a napthyl group substituted with at least one R group.
  • Ari and Ar 2 may represent a phenyl group substituted with at least one R group.
  • the R group may be chosen among:
  • R may be chosen from a methyl, an ethyl, a propyl, an isopropyl, a n-butyl, a sec-, a tert- or an iso-butyl group,
  • R may be chosen from a methoxy, an ethoxy, a propoxy or an iso- propoxy group, a n-butoxy, an iso-, a sec- or a tert-butoxy group.
  • Ar 1 may be substituted with at least two R 1 groups, identical or different, said R 1 groups being as the above-defined R group.
  • R 1 may be chosen among:
  • - a methyl, an ethyl, a propyl, an iso-propyl, a n-butyl or an iso-, a sec- or a tert-butyl group, and in particular is a methyl, an ethyl or an iso-propyl group, or
  • Ar 2 may be a phenyl group substituted with at least one R group as above-defined.
  • Ar 2 may be substituted with at least two R 2 groups, identical or different, said R 2 groups being as the above-defined R group.
  • R 2 may be chosen among:
  • - a methyl, an ethyl, a propyl, an iso-propyl, a n-butyl, an iso-, a sec- or a tert- butyl group, and in particular is a methyl group, or
  • - a methoxy, an ethoxy, a propoxy or an iso-propoxy group, a n-butoxy, an iso-, a sec- or a tert-butoxy group, and in particular is a methoxy group.
  • R 3 may represent H or a linear branched or cyclic, saturated or unsaturated, C 2 -C 4 alkyl group and in particular may be chosen among a methyl, an ethyl, a propyl, an iso-propyl, a n-butyl, an iso-, a sec- or a tert-butyl, a vinyl, or an allyl group and in particular is an iso-propyl group or an allyl group.
  • A may represent a covalent bond
  • X may represent a linear or branched, saturated or unsaturated, C 2 -C 4 alkylene group or an heteroatom
  • R 4 , and R 5 independently of each other, may be chosen among H or linear or branched or cyclic, saturated or unsaturated, C2-C4 alkyl group.
  • X may be a methylene, an ethylene or a propylene group, and in particular may be a methylene group.
  • X may be a heteroatom chosen among O or N, and in particular may be O.
  • R 4 and R 6 may be, independently of each other, H or chosen among a methyl, an ethyl or a propyl group, and in particular may be a methyl group.
  • A may represent *-X-C(R 4 R 6 )-D, with *- and - ⁇ being as above-defined, X being a methylene or O, and R 4 and R 6 being, independently of each other, H or a methyl group.
  • B may represent a linear, branched or cyclic, saturated or unsaturated, C 2 -C 4 alkylene group, optionally substituted with one or more C 2 - C 4 hydroxyalkyl group(s), or a phenylene or a naphtylene group.
  • B may represent a group chosen among a methylene, an hydroxymethylmethylene, an ethylene, a propylene, an iso-propylene, a phenylene or a naphtylene group, and in particular may represent a methylene, an hydroxymethylmethylene or a phenylene group.
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative of formula (III A):
  • R 1 , R 2 , R 3 , R 4 and R 6 are as above-defined.
  • R 1 is in a position para and/or meta with respect to the group or heteroatom figured by X.
  • R 1 is in a position para with respect to X.
  • R 2 is/are in a position para and/or meta with respect to the oxadiazole radical. According to another embodiment, when R is an alkyl group as above- defined, R 2 is preferably in position meta with respect to the oxadiazole radical.
  • R 2 when R 2 is an alkoxy group as above-defined, R 2 is in position para with respect to the oxadiazole radical.
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole of formula (IIIA) as above-defined, wherein R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the following table (I):
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative advantageously selected from compounds 3, 4, 7 and 12, as above-defined.
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative of formula (IV):
  • Ri, R-3, R 4 , Re and X may be as above-defined, and
  • W may be chosen among a linear, branched or cyclic, saturated or unsaturated, C 1 -C5 alkyl or alkylamido group, optionally comprising one or more heteroatom(s) chosen among O, N or S, or a C ⁇ -Cio alkylaryl group, and preferably may be chosen among a linear or branched C 1 -C5 alkyl group or a C ⁇ -Cio alkylaryl group and in particular a benzyl group.
  • W may be chosen from a methyl, an ethyl, a propyl, an iso- propyl, a butyl, a sec-, a tert- or an iso-butyl group, or a benzyl group, and preferably may represent a methyl, an iso-propyl, a tert-butyl group or a benzyl group.
  • Ri may represent a halogen group, and in particular may be Br.
  • X may be a heteroatom chosen among O or N, and in particular may represent O.
  • R 4 and R ⁇ may be, independently of each other, H or a methyl group, and in particular may both represent H.
  • R 3 may represent H or a linear or branched
  • C 2 -C 4 alkyl group and in particular may be an iso-propyl group.
  • Ri is in a position para with respect to X.
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative of formula (IV) as above defined, wherein
  • - Ri may represent a halogen group, in particular may be Br,
  • R 3 may represent H or a linear or branched C 2 -C 4 alkyl group, and in particular may be an iso-propyl group,
  • R 4 and Re may be, independently of each other, H or a methyl group, and in particular may both represent H,
  • - X may be a heteroatom chosen among O or N, and in particular may represent O, and
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative of formula (IV) as above defined, wherein W represents a methyl, iso-propyl, tert-butyl or benzyl group; Ri is Br; X is O; R 4 and R ⁇ are both H; and R3 is an iso-propyl group.
  • Such compounds of formula (IV) may be obtained according to a method of preparation as exempl
  • 0.6 ⁇ M in particular lower or equal to 0.2 ⁇ M and more particularly lower or equal to 0.1 ⁇ M.
  • a nitrogen heterocycle derivative of the invention may be an oxadiazole derivative that exhibits an EC50 (concentration of a compound able to induce half the effect of a given pharmacological effect as compared to the maximum effect obtained with said compound) with regard to their toxicity on tumoral cells, lower or equal to 10 ⁇ M, in particular lower or equal to 8 ⁇ M, in particular lower or equal to 5 ⁇ M, in particular lower or equal to 2 ⁇ M and more particularly lower or equal to 1 ⁇ M.
  • EC50 concentration of a compound able to induce half the effect of a given pharmacological effect as compared to the maximum effect obtained with said compound
  • a nitrogen heterocycle derivative of the invention may present a low molecular weight, in particular lower than 600 g/mol, in particular lower than 550 g/mol, and more particularly lower than 500 g/mol, and have a non-peptide-like structure.
  • PHARMACEUTICAL OR COSMETIC COMPOSITIONS refers to an agent or mixture of agents that is primarily intended to treat and/or ameliorate and/or prevent a disease or a disorder or to diagnostic a disease or a disorder.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes what is acceptable for veterinary as well as human pharmaceutical use.
  • cosmetic composition is intended to have the meaning as exposed in the European Directive 76/768/CEE.
  • a "cosmetic composition” may be any substance or preparation intended to be placed in contact with the various external parts of the human body (skin, hair, nail, lips, ...), or with the teeth or mucous membranes of the oral cavity for, exclusively or mainly, cleaning them, perfuming them, changing their appearance, and/or correcting body odors, and/or protecting them or keeping them in good condition.
  • a nitrogen heterocycle derivative, and in particular an oxadiazole or triazole derivative, of the invention may be used as a cosmetic agent.
  • an “effective amount” means an amount sufficient to induce a positive modification in the condition to be regulated or treated, but low enough to avoid serious side effects.
  • An effective amount may vary with the cosmetic or pharmaceutical effect to obtain or with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated/prevented, the duration of the treatment, the nature of other treatments, the specific compound or product/composition employed, the route of administration, and like factors.
  • subject or “individual”, used interchangeably herein, means mammals and non-mammals.
  • mammals include, but are not limited to: humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.
  • non-mammals include, but are not limited to, birds, and the like.
  • the term "subject” or “individual” does not denote a particular age or sex.
  • a nitrogen heterocycle derivative, in particular an oxadiazole or a triazole derivative, of the present invention may be administered in an effective amount by any of the accepted modes of administration in the art.
  • a nitrogen heterocycle derivative of the invention in particular an oxadiazole or a triazole derivative, may be used in a composition intended to be administered by oral, nasal, sublingual, aural, ophthalmic, topical, rectal, vaginal, urethral, or parenteral injection route.
  • suitable concentration may range from 0,0001 mg/kg/d to
  • 50 mg/kg/d in particular from 0.001 mg/kg/d to 5 mg/kg/d and more particularly from 0.01 to 0.5 mg/kg/d, depending upon numerous factors such as the age and relative health of the subject, the potency of the formulation used, and the therapeutic or cosmetic indication towards which the administration is directed.
  • a pharmaceutical composition of the invention may be formulated with any known suitable pharmaceutically acceptable carrier according to the dose, the galenic form, the route of administration and the likes.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in a medicament of the invention is contemplated.
  • a pharmaceutical or a cosmetic composition of the invention may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, sprays, ointments, gels, creams, sticks, lotions, pastes, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the likes.
  • a cosmetic composition of the invention may be in particular adapted to be administered by topical route.
  • a cosmetic composition of the invention may comprise any excipient usually used in the cosmetic art, such as hydrophilic or lipophilic gelifying agent, hydrophilic or lipophilic additives, antioxidants, conservative agents, solvents, perfumes, fillers, UV screens, moisturizers, odor absorbing agents, and coloring agents.
  • excipient usually used in the cosmetic art, such as hydrophilic or lipophilic gelifying agent, hydrophilic or lipophilic additives, antioxidants, conservative agents, solvents, perfumes, fillers, UV screens, moisturizers, odor absorbing agents, and coloring agents.
  • a pharmaceutical composition of the invention may be intended to be administered separately, sequentially or simultaneously with an agent useful for the prevention and/or the treatment of a disease condition, in particular a cancer condition, said agent being different from the nitrogen heterocycle derivative of the invention.
  • a pharmaceutical composition of the invention may be intended to be administered separately, sequentially or simultaneously with a chemotherapeutic agent or a radiotherapeutic regimen.
  • the invention is also directed to a novel kit-of-parts that is suitable for use in the treatment of cancers.
  • a kit-of-part of the invention may comprise (i) a nitrogen heterocycle derivative, in particular an oxadiazole or a triazole derivative, as defined above, and (ii) at least one agent useful for the prevention and/or the treatment of a cancer condition, said agent being different of said nitrogen heterocycle derivative (i).
  • the kit-of-part of the invention may comprise (i) a nitrogen heterocycle derivative, in particular a triazole or an oxadiazole derivative, as defined above, and (ii) at least one agent as above-defined, each of (i) and (ii) being laid out to be administered separately, sequentially or simultaneously.
  • An agent useful for the prevention and/or the treatment of a cancer condition may be a chemotherapeutic agent or a radiotherapeutic agent.
  • chemotherapeutic agents chosen from alkylating agents, nitrosoureas, anti-metabolite agents, anti-tumor antibiotics, plant alkaloids, steroid hormones, monoclonal antibodies, and mixtures thereof.
  • alkylating agents that may be used in accordance with the invention, one may mention chlorambucil and cyclophosphamide.
  • nitrosoureas that may be used in accordance with the invention, one may mention carmustine and lomustine.
  • anti-metabolite agents that may be used in accordance with the invention, one may mention fludarabine, 6-mercaptopurine and 5-fluorouracil (5 FU).
  • anti-tumor antibiotics that may be used in accordance with the invention, one may mention the mitomycin-C, the bleomycin, and the anthracyclines such as the doxorubicine.
  • vincristine and vinblastine examples of plant alkaloids that may be used in accordance with the invention.
  • steroid hormones examples include tamoxiphen.
  • kits-of-parts the invention may comprise (i) at least one nitrogen heterocycle derivative, as defined above, and (ii) at least one agent useful for the prevention and/or the treatment of a cancer condition, said agent being different of said nitrogen heterocycle derivative and in particular being chosen among histone deacetylase inhibitors.
  • a histone deaceatylase inhibitor HDAC inhibitors or HDI are a class of compounds that interfere with the function of histone deacatylase.
  • hydroxamic acids such as trichostatin 1, cyclic tetrapeptides, such as trapoxin B and the depsipeptides, the benzamides, the electrophilic ketones, and the aliphatic acids compounds such as phenylbutyrate and valproic acid.
  • a HDI that may be used in accordance with the invention may be, for example, SAHA/vorinostat, belinostat/PXDlOOl, MS275, LAQ824/LBH589, CI994, or MGCD0103.
  • the additional agent useful for the prevention and/or the treatment of a cancer condition (ii) may be an agent useful for the prevention and/or the treatment of B cell lymphoma, and more particularly for the prevention and/or treatment of multiple myeloma or mantle cells lymphoma.
  • melphalan As example of such suitable agent, one may mention melphalan, vincristine, doxorubicin, cyclophosphamide, fludarabine, thalidomide, prednisone or dexamethasone, cytosine arabinoside, methotrexate or rituximab.
  • those agents may be used in combination more particularly adapted to a given disease condition such as melphalan and prednisone or thalidomide and dexamethasone, or cyclophosphamide and fludarabine or vincristine and doxorubicin and dexamethasone for multiple myeloma or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for mantle cells lymphoma.
  • a given disease condition such as melphalan and prednisone or thalidomide and dexamethasone, or cyclophosphamide and fludarabine or vincristine and doxorubicin and dexamethasone for multiple myeloma or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for mantle cells lymphoma.
  • radiotherapeutic agent that may be used in accordance with the invention, one may mention an isotope such as for example chosen from 14 C, 3 H, or 125 I, 131 1, 32 P, 89 Sr, 90 Y, administered as radio-labeled antibodies
  • the instant invention relates to a method for preventing and/or treating a disease condition comprising at least a step of administering to an individual in need thereof at least an effective amount of at least one nitrogen heterocycle derivative, in particular at least one triazole or one oxadiazole derivative, in accordance with the invention.
  • the disease condition may be chosen among cancers, immunological diseases, auto-immune diseases, allograft rejections, viral diseases, such as mumps, measles, Rous sarcoma or AIDS, parasitic diseases such as malaria or trypanosome, bacterial infections, such as tuberculosis, inflammatory diseases, such as polyarthritis or liver inflammation, cardiac diseases and ischemic strokes, such as myocardial, cerebral or pulmonary ischemic injuries, muscular dystrophies, muscle wasting, traumatisms, burns, disease conditions associated with aging, such as neurodegenerative diseases.
  • viral diseases such as mumps, measles, Rous sarcoma or AIDS
  • parasitic diseases such as malaria or trypanosome
  • bacterial infections such as tuberculosis
  • inflammatory diseases such as polyarthritis or liver inflammation
  • cardiac diseases and ischemic strokes such as myocardial, cerebral or pulmonary ischemic injuries, muscular dystrophies, muscle wasting, traumatisms
  • a disease condition may be chosen among lung and oro-pharynx cancers, colo-rectal cancers, gastro-intestinal tract cancers, breast cancers, prostate cancers, pancreas cancers, leukemias such as Hodgkin's disease, immunoprofile- rative tumors, in particular multiple myeloma, bladder cancers, kidney cancers, ovarian cancers, cervical cancers, brain cancers, head and neck cancers, skin cancers, in particular melanoma, bone cancers.
  • leukemias such as Hodgkin's disease
  • immunoprofile- rative tumors in particular multiple myeloma
  • bladder cancers in particular kidney cancers, ovarian cancers, cervical cancers, brain cancers, head and neck cancers
  • skin cancers in particular melanoma, bone cancers.
  • a disease condition may be a cancer condition, and in particular a B-cells lymphoma.
  • a disease condition may be chosen among follicular lymphoma, small non-cleaved cell lymphoma, such as endemic Burkitt's or sporadic Burkitt's or non-Burkitt's lymphoma, marginal zone lymphoma, such as mucosa- associated lymphoid tissue (MALT-oma) (extranodal), or monocytoid B-cell lymphoma (nodal) or splenic lymphoma with villous lymphocytes, mantle cell lymphoma, large cell lymphoma, such as diffused large cell, or diffused mixed cell or immune-blastic lymphoma or primary mediastinal B-cell lymphoma or angiocentric lymphoma-pulmonary B-cell, and small lymphocytic lymphoma.
  • MALT-oma mucosa- associated lymphoid tissue
  • monocytoid B-cell lymphoma nodal
  • a disease condition may be a mantle cell lymphoma. According to another embodiment, a disease condition may be a multiple myeloma.
  • a method of the invention may comprise the step of administering a nitrogen heterocycle derivative of the invention, in particular an oxadiazole or a triazole derivative, in accordance with the invention separately, sequentially or simultaneously with a chemotherapeutic agent or a radiotherapeutic regimen.
  • a chemotherapeutic agent may be as above-described.
  • a radiotherapeutic regimen may be administered by exposing an individual in need thereof to a source of ionizing radiation such as X-ray, gamma-ray or beta-ray.
  • a source of ionizing radiation such as X-ray, gamma-ray or beta-ray.
  • a source of ionizing radiation that may convene to the invention may be, for example external source such as radioactive cobalt or a digital linear accelerator producing X-rays or an administrated source under the form of an isotope such as for example 14 C, 3 H, or 125 1, 131 1, 32 P, 89 Sr, 90 Y.
  • the isotopes may be administered as radio-labeled antibodies.
  • the invention is directed to a use of at least one nitrogen heterocycle derivative of the invention, in particular an oxadiazole or triazole derivative in accordance with the invention, in a cosmetic composition for the prevention and/or the treatment of skin aging.
  • a compound of the invention that may convene may be a proteasome activator.
  • the skin aging may be from chronologic origin, and/or may be indicative of a cutaneous condition, resulting, for example, from the photoaging.
  • a cosmetic composition of the invention may be intended to prevent and/or treat a thinning of an epidermis and/or a lost of firmness, elasticity, density and/or tonicity of an epidermis and/or the formation of wrinkles.
  • the invention relates to a cosmetic method for preventing and/or treating the skin aging comprising at least the step of administering to an individual in need thereof at least one effective amount of a nitrogen heterocycle derivative of the invention, in particular an oxadiazole or triazole derivative of the invention.
  • Figure 1 Percentage of inhibition of the CT-L active site by increasing concentration of the compound 13 at pH 8 and 37°C.
  • Figure 2 Cytotoxic effect of the compound 2 on HeLa cells treated for 48 h at 37 0 C. The cell viability is determined with an XTT assay.
  • the 23 following compounds are known and commercially available from ChemBridge corporation (www.chembridge.com). The compounds were dissolved in DMSO to 10 mM stock concentrations and stored at -20 0 C. Rabbit reticulocyte 2OS proteasome was obtained from Boston Biochem,
  • the fluorogenic substrates Suc-LLVY-AMC, Boc-LRR-AMC and Z-LLE- ⁇ NA used to measure the proteasome activities CT-L, T-L and PA respectively were purchased from Bachem (France). Other reagents and solvents were purchased from commercial sources. Fluorescence was measured using a BMG Fluostar microplate reader. The 23 compounds were tested for their potential to inhibit the CT-L, T-L and
  • the buffer were (pH 8): 50 mM Tris, 150 mM NaCl, 10% (v/v) glycerol, 0.025% (w/v) SDS, and 3% (v/v) DMSO (CT-L and PA activities); 50 mM Tris, 150 mM NaCl, 10% (v/v) glycerol, and 3% (v/v) DMSO (T-L activity).
  • Compounds with inhibitor efficiency superior at 50% at 100 ⁇ M for any proteasome activity were retested with 0.1-100 ⁇ M of test compound.
  • IC50 The inhibitory activity of compounds is expressed as IC50, which corresponds to the concentration of proteasome inhibitor leading to a loss of activity of 50%.
  • Figure 1 is illustrative of an inhibition curve obtained with compound 13 with respect to the CT-L activity.
  • the inhibitors act selectively on proteasome with no inhibition at 100 ⁇ M of human calpain-I (for example, compounds 6, 11, 16) and human cathepsin B (for example, compound 13), or very poor inhibition (for example, ⁇ 30 % inhibition of calpain-I at 100 ⁇ M for compounds 8 and 9).
  • Human cells (HeLa from cervical carcinoma and HEK-293 from epithelial kidney) were obtained from Invitrogen (Cergy-Pontoise, France). The cells were grown at 37°C in DMEM supplemented with 10% fetal bovine serum (Invitrogen) in a humidified atmosphere of 5% CO 2 and 95% air. 5 x 10 3 cells in 100 ⁇ L culture medium were exposed for 48 h in 96-well plates to increasing concentrations of compounds: 5-100 ⁇ M, final concentration of DMSO is 1 % (v/v).
  • the culture medium is then replaced by 100 ⁇ L of DMEM F 12 culture medium devoid of phenol red and containing a mixture of XTT (0.3 mg/mL) and PMS (8.3 nM) (XTT: 2,3- ⁇ [2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxyanilide sodium; PMS: phenazine methosulfate, both purchased from Sigma, Saint Quentin Fallavier, France). Cells were then incubated for 3 h at 37 0 C.
  • the mitochondrial deshydrogenases of viable cells hydro lyzed the tetrazolium cycle of XTT, leading to orange formazan crystals soluble in aqueous solution.
  • the orange color was measured at 485 nm using a BMG Fluostar microplate reader.
  • cytotoxicity activity of drugs was expressed as the concentration inhibiting cell growth by 50% (EC50) calculated from the survival curves.
  • C % survival and drug concentration
  • E max the maximum drug effect
  • EC50 the concentration that produces one-half of the maximum effect
  • proteasomes are inhibited, in particular the proteasome 26S, the degradation of ubiquitinalyted proteins should be blocked, and those proteins should accumulate.
  • the concentration of proteins in the sample was determined with the BCA (Bicinchoninic Acid) protein Assay.
  • MG132 aldehyde inhibitor of the proteasome
  • proteasome inhibitors of the invention effectively cross the cell membranes and inhibit the proteasome.
  • N-[2-(4-bromophenoxy)acetyl]-7V-isopropyl glycine 4 was afforded (4.19 g, 84%).
  • N-[2-(4-bromophenoxy)acetyl]-N- isopropyl glycine 4 (0.330 g, 1.00 mol) in THF (4 mL) is added at 0 0 C, hydroxybenzotriazole (0.187 g, 1.22 mmol), EDC (0.22 mL, 1.24 mmol) and amidoxime 5a (84.7 mg, 1.14 mmol, prepared according to J. Org.
  • RMN 13 C (75 MHz, CDCl 3 ) ⁇ (75/25 mixture of rotamers): 11.5 (CH 3 ), 19.6 and 2Li (CH 3 iPr), 36Ji and 37.9 (CH 2 ), 46.6 and 4JL6 (CH), 67,4 and 68.1 (CH 2 ), 114 (C), 116.4 (CH), 132.3 (CH), 156.9 (C), 167.2 and 167.6 (C), 175.8 (C).
  • RMN 13 C (75 MHz, CDCl 3 ) ⁇ (70/30 mixture of rotamers): 19.6 and 203 (CH 3 NiPr), 2LJ . and 22.6 (CH 3 iPr), 36 ⁇ and 37.9 (CH 2 ), 46.6 and 4S£ (CH NiPr), 6M and 67.9 (CH 2 ), 113.9 (C), 116.4 (CH), 132.4 (CH), 157 (C), 167.5 (C), 175.0 (C), 175.6 (C).
  • RMN 13 C (75 MHz, CDCl 3 ) ⁇ (70/30 mixture of rotamers): 19.6 and 2U (CH 3 iPr), 22.6 (CH 3 ), 28.2 (C), 36j> and 37.9 (CH 2 ), 46.6 and 4JL5 (CH), 6L5 and 67.8 (CH 2 ), 113.9 (C), 116.4 (CH), 132.4 (CH), 156.9 and 157.0 (C), 167.5 (C), 175.4 and 176.6 (C), 177.6 (C).
  • RMN 13 C (75 MHz, CDCl 3 ) ⁇ (75/25 mixture of rotamers): 19.6 and 2U (CH 3 iPr), 32.2 (CH 2 Bn), 36j_ and 38.1 (CH 2 ), 46.6 and 4M (CH), 67,4 and 68.0 (CH 2 ), 114.0 (C), 116.4 (CH), 127.0 (CH Bn), 128.7 (CH Bn), 128.9 (CH Bn), 132.3 (CH), 135.2 (C Bn), 156.7 and 156.9 (C), 167.6 (C), 169.4 (C), 176.1 (C).

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Abstract

La présente invention porte sur l'utilisation d'au moins un dérivé hétérocyclique de l'azote de formule (I) : en tant que modulateur d'activité du protéasome dans la fabrication d'une composition pharmaceutique destinée à prévenir et/ou traiter une pathologie médiée par l'activité du protéasome.
EP09773025A 2008-07-04 2009-07-03 Dérivés hétérocycliques de l'azote sous la forme de modulateurs du protéasome Withdrawn EP2307012A1 (fr)

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