EP1948144A2 - Diarylharnstoff zur behandlung von diabetischer neuropathie - Google Patents

Diarylharnstoff zur behandlung von diabetischer neuropathie

Info

Publication number
EP1948144A2
EP1948144A2 EP06806712A EP06806712A EP1948144A2 EP 1948144 A2 EP1948144 A2 EP 1948144A2 EP 06806712 A EP06806712 A EP 06806712A EP 06806712 A EP06806712 A EP 06806712A EP 1948144 A2 EP1948144 A2 EP 1948144A2
Authority
EP
European Patent Office
Prior art keywords
compound
formula
diabetic neuropathy
combination
agents
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Withdrawn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
EP06806712A
Other languages
English (en)
French (fr)
Inventor
Olaf Weber
Bernd Riedl
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.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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 Bayer Healthcare AG filed Critical Bayer Healthcare AG
Priority to EP06806712A priority Critical patent/EP1948144A2/de
Publication of EP1948144A2 publication Critical patent/EP1948144A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions for treating diabetic neuropathy comprising 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy ⁇ -pyridine-2- carboxylic acid methylamide optionally combined with at least one additional therapeutic agent.
  • Diaryl urea compounds e.g. 4 ⁇ 4-[3-(4-ch!oro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy ⁇ - pyridine-2-carboxylic acid methylamide as described e.g. in US 20050038080 are potent anticancer and anti-angiogenic agents that possess various activities, including inhibitory activity on the VEGFR, PDGFR, raf, p38, and/or fIt-3 kinase signaling molecules.
  • diaryl urea compounds have been previously characterized as having various activities, including for inhibiting the Raf/MEK/ERK pathway, raf kinase, p38 kinase, VEGFR kinase, PDGFR kinase. These activities and their use in treating various diseases and conditions are disclosed in, e.g., WO 2005/009961.
  • Diabetic neuropathy also called painful diabetic neuropathy is a common diabetes related phenomenon. Pain as syndrome of neuropathy may be seen in as many as one third of all patients with diabetes. Neuropathic pain is difficult to manage and the available treatment options rarely provide total relief (CF. Corbett, The Diabetes Educator, Vol. 31, 2005, 4, 523-540). Its cause is unclear and it does not respond well to traditional pain therapies (R.A. Malik (2003) Treat. Endocrinol. 2(6), 339-400).
  • neuropathic pain Recent advancements in the diagnosis of neuropathic pain include methods that can distinguish between neuropathic and non-neuropathic pain. In the absence of treatment, nerve damage may progress while pain diminishes.
  • Symptom mangament treatment is available and includes the use of analgesics (NSAIDs), antidepressants (e.g. selective serotonin reuptake inhibitors, tricyclic antidepressants), anticonvulsants, capsicain topical cream, nexiletine, as well as physical or mechanical therapy such as electrical stimulation, acupuncture, magnet therapy or topical use of polyurethane films.
  • NSAIDs analgesics
  • antidepressants e.g. selective serotonin reuptake inhibitors, tricyclic antidepressants
  • anticonvulsants e.g. selective serotonin reuptake inhibitors, tricyclic antidepressants
  • capsicain topical cream e.g. selective serotonin reuptake inhibitors, tricyclic antide
  • NMV reduced nerve conduction velocity
  • the present invention provides pharmaceutical compositions for treating diabetic neuropathy comprising a compound of formula I and optionally at least one further therapeutic agent.
  • the present invention provides a therapeutic method which do not only reduce the neuropathic pain of patients more effectively compared to current therapies but also provides a therapeutic method for the reconstitution of nerve functions.
  • the therapeutic method according to the invention is superior to current therapies. Therefore the present invention can be used e.g. by administering a diaryl urea compound of formula I and optionally a further therapeutic agent, pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, metabolites and prodrugs.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl- sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aryl or aralkyl halides like benzyl and phenethyl bromides and others monosubstituted aralkyl halides or polysubstituted aralkyl
  • Solvates for the purposes of the invention are those forms of the compounds where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water.
  • Certain pharmacologically active agents can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing group.
  • These derivatives commonly referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects.
  • Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention that are well-tolerated, pharmaceutically acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-Cj-Cs alkyl may be used, although methyl ester is preferred.
  • esters of appropriate compounds of this invention that are well-tolerated, pharmaceutically acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-Cj-Cs alkyl may be used, although methyl ester is preferred.
  • the metabolites of the compounds of this invention include oxidized derivatives of the compounds of formula I, wherein one or more of the nitrogens are substituted with a hydroxy group; which includes derivatives where the nitrogen atom of the pyridine group is in the oxide form, referred to in the art as 1-oxo-pyridine or has a hydroxy substituent, referred to in the art as 1 -hydroxy- pyridine.
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures as described e.g. in the following published international application WO 2005/009961.
  • the compounds of formula I according to the present invention can be combined with further therapeutic agents such as analgesics, anti-depressants, anti-diabetics, glucose controlling agents, neuroprotective agents, anticonvulsants, anesthesics, anti-inflammatory agents or capsaicin.
  • analgesics include, but are not limited to, NSAID (non-steroidal antiinflammatory drugs), COX-I- or COX-2-inhibitors etc..
  • NSAID examples include, but are not limited to, e.g. aceclofenac, acetaminophen, o-acetyl- salicylic acid, alclofenac, alminprofen, amfenac, ampiroxicam, amtolmetinguacil, anirolac, antrafenin, azapropazon, benorilat, bermoprofen, bindarit, bromfenac, bucloxsaure, " bucolom, bufexamac, bumadizon, butibufen, butixirat, carbasalat calcium, carprofen, cinmetacin, cinnoxicam, clidanac, clobuzarit, deboxamet, dexibuprofen, dexketoprofen, diclofenac, diflunisal, eltenac, enfenamsaure, etersalat, etodolac, etofenamat
  • an NSAID selected from the group consisting of acetaminophen, o- acetylsalicylic acid, clidanac, diclofenac, flurbiprofen, ibuprofen, ketoprofen and sulindac. More preferably o-acetylsalicylic acid is used as NSAID.
  • anesthesics include, but are not limited to, e.g. melixetine, lidocaine and benzocaine. Preference is given to melixetine.
  • anti-depressants include, but are not limited to, e.g. selective serotonin reuptake inhibitors and tricyclic anti-depressants such as duloxetine, trazodone and venlafaxine.
  • anticonvulsants include, but are not limited to, e.g. gabapentin, lamotrigine, amitriptyline and pregabalin.
  • anti-diabetic agents include, but are not limited to, e.g. insuline, CB-I antagonists such as rimonabant or SLV-319, 5HT uptake inhibitors such as sibutramin, ilpase inhibitors such as orlistat or ALT-962, CNTF agonists such as axokine, DGAT inhibitors such as BAY 74-4113, DPP IV inhibitors such as vildagliptin, sitagliptin, saxagliptin, LAF-237, MK-0431 or BMS- 4771 18, GLP-I analogues such as exenatide, betatropin, BIM-51077, CJC-1 131 or liraglutide, PPAR ⁇ agonists such as BAY 62-9069, BAY 68-2959, tesaglitazar, muraglitazar, ONO-5129, LY-510929, LY-519818, GW-677954,
  • BAY 74-41 13 Preference is given to BAY 74-41 13, BAY 62-9069, BAY 68-2959, rimonabant, SLV-319, pioglitazone, rosiglitazone, orlistat, tesaglitazar, muraglitazar and exenatide.
  • the compounds and combinations according to the present invention can be used for manufacture of a medicament for treating diabetic neuropathy.
  • the present invention provides methods of treating diabetic neuropathy, comprising administering effective amounts of at least one compound of formula I and optionally at least one further therapeutic agent according to the invention.
  • An "effective amount" is the quantity of the compound that is useful to achieve the desired result, e.g., to treat the disease or condition.
  • Diabetic neuropathy is also known as painful diabetic neuropathy.
  • Compounds or drug combinations of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in combination with any ingredient(s), active or inactive.
  • any effective route including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in
  • Compounds or drug combinations of the present invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions.
  • formulations which may be liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions.
  • the combinations of the present invention can be administered at any time and in any effective form.
  • the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly).
  • the drugs can also be administered sequentially at different times.
  • Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.
  • the drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects.
  • reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy.
  • Compounds or drug combinations of the present invention can be further combined with any other suitable additive or pharmaceutically acceptable carrier.
  • additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker, 2002).
  • pharmaceutically acceptable carriers can be referred to herein as “pharmaceutically acceptable carriers” to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
  • compounds or drug combinations of the present invention can be administered with other active agents or other therapies that are utilized to treat any of the above-mentioned diseases and/or conditions.
  • therapies according to the invention include, but are not limited to, physical or mechanical therapy such as electrical stimulation, acupuncture, magnet therapy or topical use of polyurethane films.
  • the present invention provides also combinations of at least one compound of Formula I and at least one other therapeutic agent mentioned above useful in treating a disease or disorder.
  • “Combinations” for the purposes of the invention include:
  • compositions or dosage forms which contain at least one compound of Formula I and at least one other therapeutic agent mentioned above;
  • -kits which comprise at least one compound of Formula I and at least one other therapeutic agent mentioned above packaged separate from one another as unit dosages or as independent unit dosages, with or without instructions that they be administered concurrently or sequentially; and -separate independent dosage forms of at least one compound of Formula I and at least one other therapeutic agent mentioned above which cooperate to achieve a therapeutic effect, e.g., treatment of the same disease, when administered concurrently or sequentially.
  • each agent of the combination can be selected with reference to the other and/or the type of disease and/or the disease status in order to provide the desired therapeutic activity.
  • the active agents in the combination can be present and administered in a fixed combination.
  • "Fixed combination” is intended here to mean pharmaceutical forms in which the components are present in a fixed ratio that provides the desired efficacy. These amounts can be determined routinely for a particular patient, where various parameters are utilized to select the appropriate dosage (e.g., type of disease, age of patient, disease status, patient health, weight, etc.), or the amounts can be relatively standard.
  • the amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
  • an amount of 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]- 3-fluorophenoxy ⁇ -pyridine-2-carboxylic acid methylamide in the pharmaceutical composition from 20 to 3000 mg, preferably from 50 to 1500, more preferably from 60 to 1000 mg.
  • the compound of formula I is administered in combination with at least one further therapeutic agent in an amount that those of ordinary skill in the art can determine by their professional judgement.
  • the pharmaceutical composition according to the invention is administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route. With each administration the number of tablets or capsules taken in at the same time should not exceed two.
  • the combination can comprise effective amounts of at least one compound of Formula I and at least one other therapeutic agent mentioned above, which achieves a greater therapeutic efficacy than when either compound is used alone.
  • the combination can be useful to treat diabetic neuropathy, where the therapeutic effect is not observed when the agents are used alone, or where an enhanced effect is observed when the combination is administered.
  • the relative ratios of each compound in the combination can also be selected based on their respective mechanisms of action and the disease biology.
  • the relative ratios of each compound can vary widely and this invention includes combinations for treating diabetic neuropathy where the amounts of the formula I compound and the other therapeutic agent can be adjusted routinely such that either is present in higher amounts.
  • the release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit or when in separate independent dosage forms.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP06806712A 2005-11-10 2006-11-09 Diarylharnstoff zur behandlung von diabetischer neuropathie Withdrawn EP1948144A2 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06806712A EP1948144A2 (de) 2005-11-10 2006-11-09 Diarylharnstoff zur behandlung von diabetischer neuropathie

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP05024507 2005-11-10
EP05027448 2005-12-15
PCT/EP2006/010747 WO2007054303A2 (en) 2005-11-10 2006-11-09 Diaryl urea for treating diabetic neuropathy
EP06806712A EP1948144A2 (de) 2005-11-10 2006-11-09 Diarylharnstoff zur behandlung von diabetischer neuropathie

Publications (1)

Publication Number Publication Date
EP1948144A2 true EP1948144A2 (de) 2008-07-30

Family

ID=38023616

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06806712A Withdrawn EP1948144A2 (de) 2005-11-10 2006-11-09 Diarylharnstoff zur behandlung von diabetischer neuropathie

Country Status (5)

Country Link
EP (1) EP1948144A2 (de)
JP (1) JP2009514921A (de)
KR (1) KR20080074974A (de)
CA (1) CA2628881A1 (de)
WO (1) WO2007054303A2 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2900269B1 (de) * 2012-09-25 2018-08-01 Bayer Pharma Aktiengesellschaft Kombination von regorafenib und acetylsalicylsäure zur behandlung von kolorektalkrebs
CA3244313A1 (en) 2017-06-02 2025-06-13 Bayer Healthcare Llc Combination of regorafenib and pd-1/pd-l1(2) inhibitors for treating cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060234931A1 (en) * 2003-07-17 2006-10-19 Biggs William H Iii Treatment of diseases with kinase inhibitors
EP1663978B1 (de) * 2003-07-23 2007-11-28 Bayer Pharmaceuticals Corporation Fluorsubstituierter omega-carboxyaryldiphenylharnstoff zur behandlung und prävention von krankheiten und leiden

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007054303A2 *

Also Published As

Publication number Publication date
KR20080074974A (ko) 2008-08-13
CA2628881A1 (en) 2007-05-18
JP2009514921A (ja) 2009-04-09
WO2007054303A2 (en) 2007-05-18
WO2007054303A3 (en) 2008-03-20

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