EP2244707A1 - Dérivés de tétrahydrocyclopentaýc¨acridines inhibiteurs de kinases et leurs applications biologiques - Google Patents

Dérivés de tétrahydrocyclopentaýc¨acridines inhibiteurs de kinases et leurs applications biologiques

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Publication number
EP2244707A1
EP2244707A1 EP09702789A EP09702789A EP2244707A1 EP 2244707 A1 EP2244707 A1 EP 2244707A1 EP 09702789 A EP09702789 A EP 09702789A EP 09702789 A EP09702789 A EP 09702789A EP 2244707 A1 EP2244707 A1 EP 2244707A1
Authority
EP
European Patent Office
Prior art keywords
tetrahydro
cyclopenta
hydroxy
trimethylsilanyl
defined above
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09702789A
Other languages
German (de)
English (en)
French (fr)
Inventor
Philippe Olivier Belmont
Laurent Meijer
Philip Cohen
Amaury Patin
Johann Bosson
Peter Gregory Goekjian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Original Assignee
Centre National de la Recherche Scientifique CNRS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP2244707A1 publication Critical patent/EP2244707A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the invention relates to tetrahydrocyclopenta [c] acridines derivatives as kinase inhibitors and targets their use as pharmacological tools and as medicaments.
  • the invention further relates to a process for their manufacture.
  • the inventors have a great expertise concerning acridine derivatives which led them to develop a particularly interesting synthetic route, with a reduced number of steps starting, most generally, commercial products.
  • these derivatives are particularly useful as active ingredients of drugs for the treatment of serious pathologies associated with deregulation of these kinases.
  • the invention thus aims, as kinase inhibitors, derivatives of tetrahydrocyclopenta [c] acridines.
  • the invention also relates, as products, to those of these drifts which are new.
  • the invention aims, as kinase inhibitors, of tetrahydrocydopenta [c] ac ⁇ dine derivatives corresponding to formula (I)
  • R 1 to R 4 which may be identical or different, represent H; an ether radical or polyether - (OR ') n -OR, R and R', which may be identical or different, representing a linear or branched, optionally substituted C 1 -C 12 alkyl radical; an amino group NH 2 or N (R 9 , R 10 ); NO 2 ; NH-carbamate of -NH-CO-OM type, with M representing R (or R ') as defined above or a salt; NH-CO-R, with R as defined above; N 3 and its derivatives of type 1, 2, 3-t ⁇ azole;
  • Rs is -OH; halogen; -OR with R as defined above; OH-carbamate of the type -O-CO-NHM, with M representing R (or R ') as defined above; OH-carbonate of the type -O-CO-OM, with M representing R (or R '), as defined above; NH 2 , NH-carbamate -NH-CO-OM, with M representing R (or R ') as defined above or a salt; NH-CO-R, with R as defined above; N 3 and its 1,2,3-t ⁇ azole derivatives; N (R 9 , Rio), M and R being as defined above;
  • Re represents H; the radrcal R; a group (R or R ') 3 -Si, R being as defined above; an optionally substituted aryl radical, a heteroaryl radical; halogen (iodine); or an alkynyl radical -C ⁇ CR, with R as defined above;
  • Alkyl refers to a hydrocarbon chain, linear or branched, optionally substituted, of 1 to 12 carbon atoms, preferably 1 to 5 carbon atoms;
  • Halogen represents F, Cl, Br, I as well as the group CF 3 ;
  • Aryl represents one or more aromatic rings, optionally substituted, preferably a phenyl radical.
  • Heteroaryl represents a heterocycle with N, O or S as heteroatom, where appropriate substituted, preferably a py ⁇ dyl or py ⁇ dmyle radical.
  • the invention also relates to the racemic forms of the above derivatives as well as their enantiomeric forms taken individually, more particularly the isomers in position 5, 7 and / or 8.
  • these derivatives are capable of blocking the ATP site of abnormally activated and therefore deregulated target kinases, thus preventing their phosphorylation activity.
  • these derivatives exhibit a selectivity towards these kinases during tests performed on a panel of 70 kinases.
  • kinase inhibitors make it possible to study the functions of kinases in cellular models and the effects resulting from their deregulation (overexpression or abnormal activation) in pathologies such as cancers and neurodegenerative diseases.
  • diabetes including type II diabetes, inflammatory diseases, depression and bipolar disorder or viral infections.
  • Preferred derivatives for use as kinase inhibitors correspond to selective inhibitors of CDKs and have IC 5 Q below 20 microM vis-à-vis cdkl and CDK5, in particular less than 10 .mu.M, particularly advantageous derivatives having IC50 less than 2 ⁇ M.
  • Derivatives corresponding to these characteristics are chosen from the group comprising 5-hydroxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] ac ⁇ dm-2-one, - 5-hydroxy-8 methoxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] acdin-2-one, 5-hydroxy-8,9-dimethoxy-1-trimethylsilanyl-3, 3a, 4, 5-tetrahydro-2H-cyclopenta [c] ac ⁇ dm-2-one, 5-hydroxy-9-methoxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] acdin-2-one 5-hydroxy-1-tert-butyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] ac ⁇ dm-2-one 5-hydroxy-8-methoxy-1-tert
  • 5-hydroxy-l-t ⁇ méthylsilanyl-3, 3a, 4, 5-tetrahydro-2I / - cyclopenta [c] acridin-2-one, is a particularly preferred kinase inhibitor with values of IC 5 O 0.56 at 0.74 ⁇ M against CDK1 and from 1.6 to 2.3 ⁇ M against CDK5.
  • This derivative was co-crystallized in the ATP site of CDK2-cyclin A (see FIG. 1).
  • This co-crystal constitutes a new product and as such is within the scope of the invention.
  • the representation given in FIG. 1 was carried out with the tert-butyl group R 6 instead of the group actually present trimethylsilanyl since the silicon atom (Si) is not available in the processing software used.
  • Equally advantageous derivatives of this group exhibit an IC 5 O vis-à-vis GSK-3 of less than 10 .mu.M.
  • the inhibitory activity of the derivatives defined above makes them of great interest for the treatment of pathologies related to kinase deregulation.
  • compositions are advantageously in a form suitable for a given treatment according to the state of the patient and the pathology to be treated. More particularly, galenic forms for oral, parenteral, or injectable administration.
  • the active ingredients used in therapeutically effective amounts, are mixed with the pharmaceutically acceptable carriers for the chosen mode of administration.
  • the pharmaceutical compositions are more particularly in the form of tablets, capsules, capsules, pills, dragees, drops and the like.
  • compositions may contain from 1 to 100 mg of active ingredient per unit dose, in particular from 40 to 60 mg.
  • the pharmaceutical compositions are advantageously in the form of sterile or sterilizable solutions. They contain from 10 to 50 mg of active ingredient, in particular from 20 to 30 mg.
  • compositions are particularly effective in blocking the ATP site of CDKs and thus can in particular stop the anarchic cellular division of the cancer cells.
  • these pharmaceutical compositions are also effective in treating neurodegenerative diseases, diabetes, including type II diabetes, inflammatory diseases, depression and bipolar disorders.
  • the invention relates to the derivatives of formula (I) above corresponding to new products.
  • These are derivatives in which R 1 to R 9 are as defined above with the exception of 5-hydroxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] acridine -
  • Preferred derivatives include: 5-hydroxy-8-methoxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] ac ⁇ dm-2-one, 5-hydroxy-8,9- dimethoxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2H-cyclopenta [c] acdin-2-one, 5-hydroxy-9-methoxy-1-trimethylsilanyl-3, 3a, 4, 5-Tetrahydro-2H-cyclopenta [c] acdin-2-one
  • the derivatives of the invention are advantageously obtained according to the methodology described by Patin and Belmont (1) and illustrated by the scheme given in FIG. 2. This process is also applied in principle to obtain the new derivatives of the invention. .
  • the invention thus aims at a synthesis process comprising: the reaction of a derivative of formula (II)
  • R1 to R7 are as defined above, and
  • R8 defined as above, can be dé ⁇ vatisé by cross-metathesis reaction from allyl or R8 represents H, in the presence of a catalyst such as C ⁇ 2 (CO) s (or a complex of rhodium or molybdenum), according to the Pauson-Khand (1) reaction (abbreviated PKR), under conditions making it possible to produce a derivative of formula (I)
  • the compound of formula (II) is advantageously obtained by reaction of Sonogashira or Negishi, from a 2-chloro-3-quinoline carboxaldehyde derivative (Rs' represents H or a C1-C12 alkyl radical as defined above ) of formula (III)
  • the derivative (III) is itself preferably obtained from a derivative of formula (V)
  • it is 1- (2-trimethylsilanylethynyl-quinolin-3-yl) -but-3-en-1-ol, 1- (6-methoxy-2-trimethylsilanylethynyl-quinolin-3-yl) - but-3-en-1-ol, 1- (6,7-dimethoxy-2-trimethylsilanylethynyl-quinolin-3-yl) but-3-en-1-ol, and 1- (7-methoxy-2- tetramethylsilanylethynyl-quinolin-3-yl) -but-3-en-1-ol.
  • Figures 1 and 2 show, respectively, the structure of the co-crystal of 5-hydroxy-1-trimethylsilanyl-3,3a, 4,5-tetrahydro-2f / -cyclopenta [c] ac ⁇ dm-2-one with the site ATP of CDK2 - cyclin A, and a synthetic scheme of tetrahydrocyclopenta [c] acridine derivatives.
  • the 2-ethynylquinoline-3-carbaldehyde derivative (1.00 mmol) is dissolved in 10 mL of freshly distilled THF under an argon atmosphere.
  • the reaction medium is cooled to -78 ° C.
  • the commercial solution of allyl magnesium bromide IM in Et 2 O (1.50 mL, 1.50 mmol) is added dropwise.
  • the reaction medium is stirred for 4 hours at -78 ° C.
  • the reaction medium is then poured into a saturated aqueous solution of NH 4 Cl, the aqueous phase is extracted with ethyl acetate and the organic phase thus obtained is rinsed with a saturated aqueous solution of NaCl, dried over Na 2 SO 3. 4 , filtered and evaporated.
  • the residue obtained is purified by flash chromatography.
  • IR 3367, 3077, 3003, 2959, 2929, 2851, 2159, 1621, 1497, 1244, 1213, 1008, 840cm -1 .
  • the quinoline quinene derivative of formula (II) (1.00 iranol) is dissolved in 10 ml of freshly distilled DCM under an argon atmosphere. Then the Co 2 (CO) 8 (420 mg, 1.20 mmol) is added. The reaction medium is stirred for 2 hours at room temperature and the complexation of the metal on the alkyne is monitored by TLC. Then the NMO (1171 mg, 10.00 mmol) is added portionwise and the reaction medium is stirred for 12 hours at room temperature. Then, the reaction medium is filtered through silica and then evaporated. The residue obtained is purified by flash chromatography.
  • IR 2968, 2950, 2894, 1686, 1273, 1157, 856cm -1 .
  • IR 3357, 3001, 2955, 2888, 2825, 1659, 1490, 1216, 851; 840
  • the tests are carried out as follows: The enzyme to be assayed has been purified, for example by affinity chromatography on agarose beads. Catalytic activity was measured using radiolabelled ATP at a standard final concentration. The test compounds were added at different concentrations to establish dose-response curves (activity of the enzyme as a function of concentration) and the IC 50 values were calculated from these curves and given in ⁇ M. They represent the value at which a 50% inhibition of the enzyme is observed.
  • 5-hydroxy-l-t ⁇ méthylsilanyl-3, 3a, 4, 5-tetrahydro-2.ff- cyclopenta [c] acridm-2-one has an IC 5 O 5 O with IC values of 0.54 .mu.M with respect to CDK1 and 1.6 ⁇ M vis-à-vis CDK5.
  • HT29 cells human colon adenocarcinoma, ATCC deposit HTB 38
  • the tests are performed on HT29 cells (human colon adenocarcinoma, ATCC deposit HTB 38) by operating as follows:
  • the HT29 cells are cultured in Dulbecco's MEM medium supplemented with 10% FCS.
  • the cells from a log phase culture are seeded in microwell plates (1mL-5x10 4 cells / well) and incubated for 2 days.
  • the compounds tested, in solution in DMSO (dimethylsulfoxide), are added, in a minimum volume (5 ⁇ L) in increasing concentration.
  • the control cells receive only 5 ⁇ L of DMSO alone.
  • the plates are incubated 24h, then the medium is removed and the cells washed twice with PBS (phosphate buffered saline) before before adding fresh medium without medication.
  • PBS phosphate buffered saline
  • the plates are incubated for 3 days before evaluation of cell survival using the MTT test (5) which comprises a 30 min incubation in wells, at a rate of 100 ⁇ g / well, of bromide of 3- [4,5,5].
  • MTT test (5) which comprises a 30 min incubation in wells, at a rate of 100 ⁇ g / well, of bromide of 3- [4,5,5].
  • the formazan crystals are recovered with 100 ⁇ l of DMSO and the absorbance is measured at 540 nm with a microplate reader (Model 450 Bio-Rad).
  • the survival of the cells is expressed in% of the controls treated with DMSO.
  • Table 2 Table 2
  • Example 4 MTS Tests The viability of SHSY cells is determined by measuring the reduction of MTS as described in (6).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
EP09702789A 2008-01-18 2009-01-19 Dérivés de tétrahydrocyclopentaýc¨acridines inhibiteurs de kinases et leurs applications biologiques Withdrawn EP2244707A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0800275A FR2926550B1 (fr) 2008-01-18 2008-01-18 Derives de tetrahydrocyclopenta°c!acridines inhibiteurs de kinases et leurs applications biologiques
PCT/IB2009/050179 WO2009090623A1 (fr) 2008-01-18 2009-01-19 Dérivés de tétrahydrocyclopenta[c]acridines inhibiteurs de kinases et leurs applications biologiques

Publications (1)

Publication Number Publication Date
EP2244707A1 true EP2244707A1 (fr) 2010-11-03

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EP09702789A Withdrawn EP2244707A1 (fr) 2008-01-18 2009-01-19 Dérivés de tétrahydrocyclopentaýc¨acridines inhibiteurs de kinases et leurs applications biologiques

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US (1) US8999955B2 (enExample)
EP (1) EP2244707A1 (enExample)
JP (1) JP5879036B2 (enExample)
CA (1) CA2711931A1 (enExample)
FR (1) FR2926550B1 (enExample)
WO (1) WO2009090623A1 (enExample)

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JP2018135268A (ja) * 2015-06-05 2018-08-30 大日本住友製薬株式会社 新規ヘテロアリールアミノ−３−ピラゾール誘導体およびその薬理学上許容される塩
CN105820119B (zh) * 2015-07-06 2019-04-02 盐城工学院 一种5，6-二氢苯并菲啶衍生物及其制备方法

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DK569087A (da) * 1986-10-31 1988-05-01 Sumitomo Pharma Quinolin-derivater, deres fremstilling og anvendelse

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See references of WO2009090623A1 *

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CA2711931A1 (fr) 2009-07-23
JP5879036B2 (ja) 2016-03-08
US20100285124A1 (en) 2010-11-11
FR2926550A1 (fr) 2009-07-24
FR2926550B1 (fr) 2010-09-10
WO2009090623A1 (fr) 2009-07-23
JP2011509994A (ja) 2011-03-31
US8999955B2 (en) 2015-04-07

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