EP1919873A1 - Derives de fredericamycine - Google Patents

Derives de fredericamycine

Info

Publication number
EP1919873A1
EP1919873A1 EP06791340A EP06791340A EP1919873A1 EP 1919873 A1 EP1919873 A1 EP 1919873A1 EP 06791340 A EP06791340 A EP 06791340A EP 06791340 A EP06791340 A EP 06791340A EP 1919873 A1 EP1919873 A1 EP 1919873A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
heteroaryl
independently
cycloalkyl
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Withdrawn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
EP06791340A
Other languages
German (de)
English (en)
Inventor
Werner Simon
Rajendra-Prasad Maskey
Hans-Falk Rasser
Bernd Sontag
Peter Eckard
Iris GRÜN-WOLLNY
Friedrich Hansske
Björn friedrich LINDEMANN
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.)
Bioagency AG
Discovery Partners International GmbH
Original Assignee
Bioagency AG
Discovery Partners International GmbH
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
Priority claimed from DE102005041760A external-priority patent/DE102005041760A1/de
Priority claimed from DE102006005936A external-priority patent/DE102006005936A1/de
Priority claimed from DE102006005937A external-priority patent/DE102006005937A1/de
Application filed by Bioagency AG, Discovery Partners International GmbH filed Critical Bioagency AG
Publication of EP1919873A1 publication Critical patent/EP1919873A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • 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
    • A61P33/00—Antiparasitic agents
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to novel Fredericamycin derivatives, medicaments containing these or their salts, and the use of Fredericamycin derivatives for the treatment of diseases, in particular tumors.
  • WO 2004/024696 describes an advantageous purification method of Fredericamycin.
  • Fredericamycin derivatives especially on the ring A and B acylated derivatives described.
  • US 5,166,208 also Fredericamycin derivatives are described, in particular derivatives which carry on the ring A thio or amino substituents.
  • the derivatives are produced semisythetically or completely synthetically.
  • the derivatives are produced semisythetically or completely synthetically.
  • WO 03/080582 a variety of ferdericamycin derivatives are described, which are derivatized at the rings A, B, E and / or F.
  • WO 03/087060 further derivatives of Fredericamycin are disclosed, in particular those in which the ring E is further derivatized.
  • WO 2004/004713 further derivatives of rings A and B are disclosed. There is a great need to provide further Fredericamycinderivate, in particular, have changed impact profiles (side effects, etc.).
  • Fredericamycin derivatives which are derivatized in particular on the ring A or on the rings A and E, are potent drugs. It has also been found a semisynthetic possibility to introduce residues on the ring A or on both rings A and E, which allow the effectiveness and, inter alia, to increase the water solubility of the derivatives. Further methods of derivatization known from the prior art can additionally be carried out on the derivatives according to the invention. An alternative has also been found to render water-soluble Fredericamycin derivatives in which cyclodextrin inclusion compounds are prepared.
  • the invention relates to novel Fredericamycin derivatives of general formula Ia or Ib:
  • R 1 is H, C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 4 -alkyl-cycloalkyl,
  • R21, R22 independently of one another C r Ci 4 alkyl, Ci-C 14 ⁇ alkanoyl, C r C 6 alkylhydroxy, CRCE alkylamino, CRCE-alkylamino-Ci-Ce-alkyl, C r C 6 alkylamino-di-C r C 6 - alkyl, cycloalkyl, C 1 -C 4 alkyl-cycloalkyl, heterocycloalkyl, C r C 4 alkyl heterocycloalkyl, aryl, aryloyl, C 1 -C 4 -alkyl-aryl, heteroaryl, Heteroaryloyl, C 1 -
  • R 23 independently of R 21, the same meanings as R 21 or CH 2 pyridinium salts, CH 2 -RI-CrC ⁇ -alkylammonium salts,
  • R24 independently of R21, the same meanings as R21 or H, CN, COCH 3 ,
  • R25 independently of R21, the same meanings as R21 or H, CN, COCH 3 ,
  • R24, R25 together are C 4 -C 8 cycloalkyl
  • R3 H, F, Cl, Br, I, OH, OR31, NO 2, NH 2, NHR31, NR31 R32, NHCHO,
  • R31, R32 independently of one another C r C 14 alkyl, Crd-rAlkanoyl, C r C 6 alkylhydroxy, C 6 alkylamino, CRCE-alkylamino-Ci-Ce-alkyl, CRCE-alkylamino-di-CrCe-
  • R33 independently of R31, have the same meanings as R31 or CH 2 pyridinium salts, CH 2 tri-C 1 -C 6 -alkylammonmium salts, R34 independently of R31, the same meanings as R31 or H, CN, COCH 3 ,
  • R35 independently of R31, has the same meanings as R31, or H, CN, COCH 3, COOH, COOR31, CONR31R32, NH 2, NHC0R31
  • R 34, R 35 together form C 4 -C 8 -cycloalkyl
  • R5 H C 1 -C 6 -alkyl, cycloalkyl, C r C 4 alkyl-cycloalkyl, heterocycloalkyl, C 1 -C 4 - alkyl-heterocycloalkyl, aryl, C r C 4 alkyl-aryl, heteroaryl, C r C 4- alkyl
  • R4, R6, R7 independently of one another are H, C 1 -C 6 -alkyl, CO-R41
  • X is O, S, NH, N-R8, where R8 can independently of R5 have the same meaning as R5 or R5 and R8 together with the N form a 4, 5, 6, 7 or 8-membered heterocycloalkyl ring, which may optionally be another heteroatom selected from the group N, O, S may contain
  • ZO, S, NR9, where R9 can be H or d-Ce-alkyl means their stereoisomers, tautomers and their physiologically acceptable salts or inclusion compounds.
  • the invention further relates to compounds of the formula Ia, Ib, IIa or IIb in which the radicals R except R3, have the meanings given above and R3 to R3 equal to H at least doubled the water solubility while retaining all other radicals, preferably at least fivefold, more preferably at least tenfold, more preferably at least fiftyfold, especially fifteenfold, or even fivefoldfold.
  • the increase in water solubility is e.g. on the introduction of groups that can form more hydrogen bonds and / or are polar and / or ionic.
  • Preference is given to radicals R3 having increased water solubility and the meaning given in the formulas.
  • the increase in water solubility occurs, for example, through the introduction of groups that multiply
  • a key intermediate is compounds with an aldehyde function in R2.
  • Preference is given to radicals R2 having increased water solubility and the meaning given in the formulas.
  • Particularly preferred are derivatives with increased water solubility in R2 and R3.
  • -CH N-NR21R22, NR215, O, S and R211, R212,
  • R 1 is H, C 1 -C 5 -alkyl, cycloalkyl, in particular H,
  • R2 H 1 C 1 -C 14 -A ⁇ yI 1 is C 2 -C 14 -alkenyl, aryl, C r C 4 alkyl-aryl, heteroaryl, C r C 4 alkyl heteroaryl, C 2 -C 4 alkenyl Heteroaryl, cycloalkyl, C 1 -
  • R21, R22 independently of one another -C 6 alkyl, cycloalkyl, aryl, C r C 4 alkyl-aryl, heteroaryl, -C 4 alkyl-heteroaryl
  • R 23 independently of R 21, the same meanings as R 21 or CH 2 pyridinium salts, CH 2 triCrC 6 -alkylammonmium salts,
  • R24 independently of R21, the same meanings as R21 or H, CN, COCH 3 ,
  • R25 independently of R21, the same meanings as R21 or H, CN, COCH 3 ,
  • R24.R25 together C 4 -C 8 ⁇ cycloalkyl
  • R3 H, F, Cl, Br, I, OH, OR31, NO 2, NH 2, NHR31, NR31 R32, NHCHO, NHCOR31,
  • -CH N-NHCO-CH 2 NHCOR31
  • -CH NO-CH 2 NHCOR31
  • -CH N-NHCS-R33
  • -CH CR34R35 (trans or ice)
  • -CH N-NHSO 2 -Heteroaryl, particularly preferably H, F, Cl, Br, I 1 NR31 R32, in particular Br, I 1 and / or
  • R331, R332 independently of one another C r C 4 alkyl
  • R31, R32 independently of one another C r C 4 alkyl
  • R 5 is H, C 1 -C 3 -alkyl, cycloalkyl, heterocycloalkyl,
  • R4, R6, R7 independently of one another are H, C 1 -C 5 -alkyl, CO-R41, in particular in each case H,
  • X is O, S, NH, N-R8, more preferably O, NH, N-R ⁇ , wherein R8 is the same
  • R5 can assume and with N-R8 particularly prefers R5 and R8 form together with the N a 6-membered heterocycloalkyl ring, which may optionally contain another heteroatom selected from the group N, O and in particular piperazino or morpholino, is particularly preferred O, NH, or X-R5 together equal to H,
  • Y is H, F, Cl, Br, I, N 3 , in particular Br, I
  • Z is O, S, NH, in particular O
  • R3 SCN, CN, N 3, CH 2 NR331R332 (with R331, R332, which can assume the same meaning as R33 independently of each other), CH 2 SR33,
  • -CH NOCOR31
  • -CH NOCH 2 CONR31 R32
  • -CH NOCH (CH 3)
  • CONR31R32 NOC (CH 3) 2
  • CONR31 R32, -CH N-NHCO-R33
  • -CH N-NHCS-R33
  • -CH CR34R35 (trans or ice), COOH, C00R31, C0NR31 R32,
  • -CH N-NHSO 2 aryl
  • -CH N-NHS0 2 -heteroaryl
  • Y F, Cl, Br, I 1 N 3 , CN, CH 2 NRYI RY 2 , CH 2 OH, CH 2 ORYI 1 CH 2 SRYI, SCN, aryl, hetaryl (where RY1.RY2 are each independently the same meaning R23 may have)
  • medicaments containing the above compounds of formula I or II in addition to the usual carriers and excipients.
  • These compounds according to the invention are used for the preparation of medicaments for the treatment of tumors, in particular of those which can be treated by the inhibition of the topoisomerases I and / or II.
  • Tumors which can be treated with the substances according to the invention are e.g. Leukemia, lung cancer, melanomas, prostate tumors and colon tumors.
  • the compounds of the invention are also used for the preparation of medicaments for the treatment of tumors which can be treated by the inhibition of peptidyl prolyl isomerase PIN-1.
  • Such tumors are especially prostate tumors and breast cancer.
  • the compounds according to the invention can be used for the preparation of medicaments for the treatment of atopic dermatitis, parasites and for immunosuppression.
  • alkyl by itself or as part of another substituent means a linear or branched alkyl chain radical of the length stated in each case and optionally a CH 2 - may be replaced by a carbonyl group
  • C 1-4 alkyl such as methyl.
  • Ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, d. 6 -alkyl [eg C 1-4 -alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3,3- dimethyl-butyl.
  • C 1 -C 6 -alkylhydroxy by itself or as part of another substituent, means a linear or branched alkyl chain radical of the respectively indicated length, which may be saturated or unsaturated and carries an OH group, eg hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 2 hydroxypropyl.
  • C 2-6 alkenyl eg ethenyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 2,4-butadienyl, 1 Pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 2,4-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 1, 3-hexyl, 4-methyl-1-pentenyl or 3,3-dimethyl-butenyl.
  • alkynyl by itself or as part of another substituent means a linear or branched alkyl radical having one or more carbon-carbon triple bonds of the indicated for each length, where additional double bonds may be present.
  • C 2-6 alkynyl such as ethynyl means , 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, 2-methyl-1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1, 4-pentadinyl , 1-pentyne-4-enyl, 1-hexynyl, 2-hexynyl, 1, 3-hexdiinyl, 4-methyl-1-pentynyl or 3,3-dimethylbutynyl.
  • halogen is fluorine, chlorine, bromine, iodine, preferably bromine and chlorine.
  • NR21R22 or analogous NRx1Rx2 also stands for a dialkylamino group, wherein the two alkyl groups together with the N can also form a 5- or 6-membered ring.
  • cycloalkyl alone or as part of another substituent, includes saturated, cyclic hydrocarbon groups having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethylene, cycloheptyl or cyclooctyl.
  • heterocycloalkyl by itself or as part of another substituent includes cycloalkyl groups wherein up to two CH 2 groups may be replaced by oxygen, sulfur or nitrogen atoms and another CH 2 group may be replaced by a carbonyl function, eg pyrrolidine , Piperidine, morpholine or
  • Preferred aryls are next to phenyl and 1-naphthyl and 2-naphthyl:
  • Preferred heteroaryls are:
  • 2-furyl, 3-furyl, 2-thiophenyl, 3-thiophenyl, 3-pyridinyl, 4-pyridinyl, 4-isoxazolyl, 2-N-methylpyrrolyl, and 2-pyrazinyl are preferred.
  • Very particularly preferred are these as radical R3.
  • ring system generally refers to 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, preferred are 5 and 6 membered rings, further preferred are ring systems having one or two fused rings.
  • the compounds of the formula I can be present as such or, if they have acidic or basic groups, in the form of their salts with physiologically compatible bases or acids.
  • acids are: hydrochloric, citric, trifluoroacetic, tartaric, lactic, phosphoric, methanesulfonic, acetic, formic, maleic, fumaric, succinic, succinic, sulfuric, glutaric, aspartic, pyruvic, benzoic, glucuronic, oxalic, ascorbic and acetylglycine.
  • bases are alkali metal ions, preferably Na, K, alkaline earth ions, preferably Ca, Mg, ammonium ions.
  • the compounds of the invention can be administered orally in the usual way.
  • the application can also be carried out i.V., i.m., with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the mode of administration.
  • the daily dose of active ingredient per person is between about 0.1 ⁇ g / kg and 1 g / kg when given orally. This dose may be given in 2 to 4 single doses or once a day as a slow-release form.
  • the new compounds can be used solid or liquid in the usual galenic application forms, for example as tablets, film-coated tablets, capsules, powders, granules, dragees, solutions or sprays. These are produced in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and / or propellants (see H. Sucker et al .: Pharmazeutician Technology, Thieme-Verlag, Stuttgart, 1978).
  • the thus obtained Application forms normally contain the active ingredient in an amount of from 0.1 to 99% by weight.
  • the Fredericamycin A is available by fermentation or totally synthetically by known methods.
  • the Fredericamycinderivate according to the invention can be prepared either from Fredericamycin A or from known Federicamycinderivaten by specified methods directly or by variation of the methods given.
  • the reduced forms of the formula I b and II b can be prepared by mild reducing agents from the corresponding compounds of formula I a and II a.
  • Fredericamycin (1) or Fredericamycin derivatives can be combined with halogenating agents such as N-chlorosuccinimide (NCS), bromosuccinimide (NBS), N-iodosuccinimide (NIS), fluorinating agents such as Selectfluor® or elemental Br 2 , Cl 2 , Interhalogentagen in good yields to the corresponding Halogenated Fredericamycin derivatives are reacted (Scheme 1). Amination and subsequent second halogenation leads to bishalogenated Fredericamycin derivatives with different substitution patterns. (Scheme 2).
  • halogenating agents such as N-chlorosuccinimide (NCS), bromosuccinimide (NBS), N-iodosuccinimide (NIS), fluorinating agents such as Selectfluor® or elemental Br 2 , Cl 2 , Interhalogentagen in good yields to the corresponding Halogenated Fredericamycin derivatives are reacted (Scheme 1). Amination and subsequent second
  • the Fredericamycin tetrol (2) also serves as an important intermediate for the synthesis of the Fredericamycin derivatives with increased solubility and / or profile of action mentioned in this patent.
  • the tetrol side chain can be degraded in very high yields to the Fredericamycin aldehyde (3) (see Scheme 4).
  • This aldehyde can be converted, for example, by brominating reagents such as N-bromosuccinimide, bromine or other bromine-generating reagents (or other Halogen michsreagenzien) to the nuclear-brominated compound (4) or nuclear-halogenated compounds (see Scheme 5).
  • brominating reagents such as N-bromosuccinimide, bromine or other bromine-generating reagents (or other Halogen michsreagenzien)
  • the aldehyde (3) e.g. be reacted with hydroxylamines and hydrazines to the corresponding R3 substituted oximes.
  • Amine exchange, nucleophilic substitution or C-C linkages are shown in Scheme 6.
  • Fredericamycin or Fredericamycin derivatives can be electrophilically substituted on the E ring with in situ produced dirhodane. (Scheme 9)
  • Hydroxyfredericamycin (Desmethylfredericamycin) 20.0mg (38.1 ⁇ mol) are placed under N2 in 4ml of ethanol. After the addition of 4.0 ⁇ l (40.3 ⁇ mol) piperidine and 3.2 ⁇ l (
  • Trifluoroacetic acid Vacuum and dry in vacuo.
  • Hydroxyfredericamycin (desmethylfredericamycin) 200.0 mg (381.0 ⁇ mol) are placed under N 2 in 40 ml of ethanol. After the addition of 286.0 ⁇ l (571.5 ⁇ mol) of dimethylamine (2M in
  • Example 11 1-Deoxy-5-C - [(8 R) -4] 9,9'-trihydroxy-6'-hydroxy-7'-dimethylamino-1, r, 3 ' , 5 ' , 8'-penta-oxo-1,1 ', 2,3', 5 ', 6,7,8'-octahydrospiro [cyclopenta [g] isoquinoline-8,2'-cyclopenta [b] - naphthalene] -3-yl] pentitol (Compound 20)
  • the compounds have the following structures
  • the compounds 3a and 4a are prepared by analogous procedure.
  • Hydroxyfredericamycin (desmethylfredericamycin) 10.0 mg (19.0 ⁇ mol) are dissolved under N 2 in 3 ml of dichloromethane. After addition of 3.2 .mu.l (19.0 .mu.mol) trifluoromethanesulfonic anhydride and 2.3 .mu.l (19.0 .mu.mol) of 2,6-lutidine at 0 0 C is stirred for 10 minutes after. Allow to come to room temperature and add 1.3mg (19.0 ⁇ mol)
  • the compounds 3,4 were prepared according to the analogous procedure.
  • the compounds have the following structures:
  • the water solubility of the various fredericamycin derivatives can be determined in 0.9% NaCI solution with a pH of 7.
  • Breast cancer cell line MCF7 measured.
  • the cell line is determined at 37 ° C, 95% humidity and 5% CO2 in RPMI medium (Cambrex).
  • the cells are placed in a 96 well microtiter plate (Costar) with an initial density of 2400
  • the compounds are dissolved in DMSO, prediluted with cell medium and added to the wells.
  • the cells are incubated for a further 48 hours with a concentration of the compounds between 2.4 nM and 10,000 nM at a volume of 50 ⁇ l.
  • the luminescence is measured with a microplate reader and is proportional to the
  • Number of viable cells The percentage inhibition of cell viability is calculated in comparison to (i) without cells and compound (100% inhibition) and (ii) with cells and without compound (no inhibition).
  • IC50 concentration of the half-maximal inhibition

Abstract

La présente invention concerne de nouveaux dérivés de frédéricamycine, des médicaments contenant ces composés ou des sels de ceux-ci, ainsi que l'utilisation de dérivés de frédéricamycine pour traiter des maladies, en particulier des maladies tumorales.
EP06791340A 2005-09-01 2006-09-01 Derives de fredericamycine Withdrawn EP1919873A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102005041760A DE102005041760A1 (de) 2005-09-01 2005-09-01 Fredericamycinderivate
DE102006005936A DE102006005936A1 (de) 2006-02-09 2006-02-09 Fredericamycin-Derivate
DE102006005937A DE102006005937A1 (de) 2006-02-09 2006-02-09 Fredericamycin-Derivate
PCT/DE2006/001534 WO2007025534A1 (fr) 2005-09-01 2006-09-01 Derives de fredericamycine

Publications (1)

Publication Number Publication Date
EP1919873A1 true EP1919873A1 (fr) 2008-05-14

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US (1) US20080318942A1 (fr)
EP (1) EP1919873A1 (fr)
WO (1) WO2007025534A1 (fr)

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