WO2004050091A1 - ホスホジエステラーゼ10a阻害剤 - Google Patents
ホスホジエステラーゼ10a阻害剤 Download PDFInfo
- Publication number
- WO2004050091A1 WO2004050091A1 PCT/JP2003/015315 JP0315315W WO2004050091A1 WO 2004050091 A1 WO2004050091 A1 WO 2004050091A1 JP 0315315 W JP0315315 W JP 0315315W WO 2004050091 A1 WO2004050091 A1 WO 2004050091A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- disease
- pde
- phosphodiesterase
- active ingredient
- camp
- Prior art date
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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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/28—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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a phosphodiesterase 10A inhibitor comprising a pyrazo-mouth [1,5-a] pyridine derivative as an active ingredient, and Parkinson's disease, Huntington's disease, Alzheimer's disease and a combination comprising the phosphodiesterase 10A inhibitor as an active ingredient.
- the present invention relates to a drug for treating schizophrenia. Background art
- Non-Patent Document 1 Fujishige et al., J. Biol. Chem., 274: 18438-45, 1999.
- Non-Patent Document 2 Scott et al., Proc. Natl. Acad. Sci. USA, 96: 7071-6. 1999; Fujishige et al., Eur. J. Biochem., 266: 1118-27, 1999.
- Non-Patent Document 3 Fujimoto et al., J. Neuroimmunol., 95: 35-42, 1999.
- Phosphodiesterase (hereinafter sometimes abbreviated as PDE (phosphodiedterase)) is an enzyme that degrades cyclic AMP (cAMP) and cyclic GMP (cGMP), which play an important role in various intracellular reactions.
- cAMP and cGMP are generated from ATP and GTP by adenylyl cyclase and guanylyl cyclase by various extracellular stimuli, and decomposed into 5'-AMP and 5'-GMP by PDE.
- PDE decomposed into 5'-AMP and 5'-GMP by PDE.
- 1 to 11 types of PDEs have been identified, and it is determined for each type whether cAMP is specifically degraded, c GMP is specifically degraded, or both.
- There is a difference in the tissue distribution of each PDE type and it is thought that the cell response is controlled by different types of PDE depending on the organ type.
- PDE inhibitors have been developed so far, but mainly related to PDE3 (treatment for heart failure), PDE4 (treatment for asthma and C0PD) and PDE5 (treatment for male dysfunction) has been applied.
- PDE10A is involved in regulating intracellular cAMP and cGMP levels, and is mainly present in humans such as brain, testis and thyroid. In the brain, it is expressed particularly in the putamen and caudate nucleus that constitute the striatum ([Non-patent Document 1]). PDE1 OA is also highly expressed in brain and testis in mice and rats ([Non-Patent Document 2]).
- pyrazo-mouth [1,5-a] pyridine derivatives represented by the following general formula (1) are known ([Patent Document 4]).
- 3-isobutyryl-2-isopropylpyrazo mouth [l, 5-a] pyridine is known as ibudilast (generic name), and ibudilast is a cerebral circulation improving agent, a therapeutic agent for bronchial asthma, and a therapeutic agent for allergic conjunctivitis Widely used as.
- ibudilast include the effects of prosuccinyl cyclin (PGI2) on the relaxation of cerebrovascular smooth muscle, the inhibition of platelet aggregation, the suppression of airway constriction, the inhibition of leukotriene migration, the inhibition of PDE, and the memory impairment. It is also known to have an improving effect ([Patent Document 5]) and an effect on multiple sclerosis ([Non-Patent Document 3]).
- PKI2 prosuccinyl cyclin
- An object of the present invention is to find a PDE10A inhibitor that is expected to be useful for preventing or treating Parkinson's disease, Huntington's disease, Alzheimer's disease or schizophrenia.
- the present inventors have conducted extensive research to find compounds that are expected to be effective against Parkinson's disease, Huntington's disease, Alzheimer's disease, schizophrenia, and the like. Have found a compound having a PDE10A inhibitory action, and have completed the present invention. That is, the present invention provides a compound represented by the general formula (1):
- R 1 and R 2 are each independently a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
- R 3 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or 1 to 3 carbon atoms. Represents a lower alkoxy group.
- the pyrazo opening [l, 5-a] pyridine derivative represented by the general formula (1) is known.
- the common name ibudilast (Ibudilast, 3-isobutylyl-2-isopropylpyrazo [1,5-a] pyridine) is widely used as a cerebral circulation improving agent, a therapeutic agent for bronchial asthma and a therapeutic agent for allergic conjunctivitis.
- the lower alkyl group having 1 to 4 carbon atoms in the general formula (1) is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter-butyl, and preferably isopropyl.
- the lower alkoxy group having 1 to 3 carbon atoms is methoxy, ethoxy, propoxy, or isopropoxy.
- the compound of the present invention represented by the general formula (1) showed the strongest inhibitory activity against PDE10A as a result of measuring PDE inhibitory activity using cAMP or cGMP as a substrate.
- Parkinson's disease is known to be caused by a decrease in dopamine supply to the striatum. It is thought that dopamine regulates cAMP concentration in the striatum via dopamine / receptors D1 and D2 present in the striatum (putamen, caudate nucleus).
- inhibitors of PDE 10A that are specifically present at these sites can be expected as novel therapeutic agents for Parkinson's disease.
- Huntington's disease is a disease in which the striatum degenerates and atrophy, and the CAG repeat is abnormal in the gene Elongation is observed, and the mechanism by which CREB-dependent transcription reaction, which is considered essential for maintaining cell survival, is considered. Therefore, a PDE10A inhibitor that increases cAMP concentration in the striatum can be expected as a novel therapeutic agent for Huntington's disease.
- Alzheimer's disease is a degenerative disease of the brain that causes severe dementia due to amyloid deposition on nerve cells, changes in neurofibrillary tangles, loss of nerve cells, and abnormal decrease in neurotransmitters such as acetylcholine.
- cGMP is known to promote the release of neurotransmitters such as dalminic acid and acetylcholine in the brain, the promotion of neurite outgrowth, the promotion of neuronal survival, and the inhibition of beta-amyloid-induced neuronal cell death.
- an increase in cGMP in the brain may improve the progression of brain degeneration such as Alzheimer's disease. Therefore, a PDE 10A inhibitor that has the potential to increase cGMP levels in the brain is promising as a novel treatment for Alzheimer's disease.
- cGMP is known as a second messenger that promotes glutamate release in the striatum, and elevated cGMP may regulate the balance of neurotransmitter-mediated commands in the striatum. You. Therefore, a PDE10A inhibitor that has the potential to increase cGMP levels in the striatum can be expected as a novel treatment for schizophrenia.
- the pyrazo-mouth [1,5-a] pyridin derivative represented by the general formula (1) exhibits an excellent PDE10A inhibitory action, and is therefore useful for Parkinson's disease, Huntington's disease, Alzheimer's disease, or schizophrenia. It is effective for prevention and treatment of Example
- Each of the isolated cDNA fragments was introduced into insect cells Sf9 using a Gateway system (manufactured by Invitrogen) and a Bac-to_Bac (registered trademark) Baculovirus Expression system (manufactured by Invitrogen) to express each of the target PDE proteins.
- PDE1A3, PDE2A3, PDE3A, PDE4A4, PDE4B2, PDE4C2, PDE4D3, PDE5A1, PDE5A2, PDE5A3, PDE7A2, PDE8A1, PDE9A2, PDE10A1, PDE10A1, and PDE10A1 cells, from which the PDE10A1, PDE10A1, and PDE11A1 cells were expressed, were the cells with high expression of these PDE proteins. Each was purified by ion exchange chromatography.
- Recombinant PDE3B is obtained by suspending Sf9 cells overexpressing PDE3B protein in RIPA buffer [150 mM NaCl, 10 mM Tris-HCl (pH8.3), 0.13 ⁇ 4 protease inhibitor cocktai 1 (product number: P8849, manufactured by Sigma)]. , The entire suspension was used in the experiments described below.
- Ibudilast was prepared by diluting a 4 mM solution stepwise with a 15% DMS0 solution 4-fold to prepare an ibudilast solution having a concentration of 15 nM to 4 mM (the final concentration of ibudilast in the experiment was 1.5 nM to 400 M). 50 l of [ 3 H] cAMP or [] c GMP diluted with buffer [40 mM Tris-HCl ( ⁇ 7.4), 10 mM MgCl 2 ] to 10 U 1 of these ibudilast solutions to the concentrations shown in Table 1 The human unit of recombinant PDE protein 401 in the unit amount shown in 1 was added to a 96-well plate and reacted at 30 ° C for 20 minutes.
- 1 unit indicates the amount of PDE that hydrolyzes 1 M cAMP or cGMP in 1 minute under conditions of pH 7.5 and 30.
- the phosphodiesterase 10A inhibitor of the present invention is useful for prevention and treatment of Parkinson's disease, Huntington's disease, Alzheimer's disease and schizophrenia.
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/537,313 US20060106054A1 (en) | 2002-12-03 | 2003-12-01 | Phosphodiesterase 10a inhibitors |
JP2004556869A JP4589122B2 (ja) | 2002-12-03 | 2003-12-01 | ホスホジエステラーゼ10a阻害剤 |
AU2003302588A AU2003302588A1 (en) | 2002-12-03 | 2003-12-01 | Phosphodiesterase 10a inhibitors |
EP03812356A EP1570847B1 (en) | 2002-12-03 | 2003-12-01 | Phosphodiesterase 10a inhibitors for use in the treatment of parkinson's disease, huntington's disease and schizophrenia |
CA2508194A CA2508194C (en) | 2002-12-03 | 2003-12-01 | Use of ibudilast as a phosphodiesterase 10a inhibitor |
US11/980,526 US7846942B2 (en) | 2002-12-03 | 2007-10-31 | Phosphodiesterase 10A inhibitor |
US12/913,094 US8404710B2 (en) | 2002-12-03 | 2010-10-27 | Phosphodiesterase 10A inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002350804 | 2002-12-03 | ||
JP2002-350804 | 2002-12-03 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10537313 A-371-Of-International | 2003-12-01 | ||
US11/980,526 Continuation US7846942B2 (en) | 2002-12-03 | 2007-10-31 | Phosphodiesterase 10A inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004050091A1 true WO2004050091A1 (ja) | 2004-06-17 |
Family
ID=32463120
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2003/015315 WO2004050091A1 (ja) | 2002-12-03 | 2003-12-01 | ホスホジエステラーゼ10a阻害剤 |
Country Status (6)
Country | Link |
---|---|
US (3) | US20060106054A1 (ja) |
EP (1) | EP1570847B1 (ja) |
JP (2) | JP4589122B2 (ja) |
AU (1) | AU2003302588A1 (ja) |
CA (1) | CA2508194C (ja) |
WO (1) | WO2004050091A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013505911A (ja) * | 2009-09-24 | 2013-02-21 | エフ.ホフマン−ラ ロシュ アーゲー | ホスホジエステラーゼ10a阻害剤としてのイミダゾピリジンまたはイミダゾピリミジン誘導体 |
JPWO2012020821A1 (ja) * | 2010-08-12 | 2013-10-28 | 杏林製薬株式会社 | 非アルコール性脂肪肝炎の予防または治療剤 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6953774B2 (en) * | 2000-08-11 | 2005-10-11 | Applied Research Systems Ars Holding N.V. | Methods of inducing ovulation |
CA2508194C (en) * | 2002-12-03 | 2011-05-24 | Kyorin Pharmaceutical Co., Ltd. | Use of ibudilast as a phosphodiesterase 10a inhibitor |
US8338420B1 (en) | 2002-12-04 | 2012-12-25 | Mitsubishi Tanabe Pharma Corporation | Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor |
DK1928438T3 (da) * | 2005-09-26 | 2013-04-22 | Avigen Inc | Anvendelse af ibudilast til behandling af stofafhængighed |
WO2007142924A1 (en) * | 2006-05-31 | 2007-12-13 | Avigen, Inc. | Ibudilast for inhibiting macrophage migration inhibitory factor (mif) activity |
US20090028816A1 (en) * | 2007-07-27 | 2009-01-29 | Lance Sultzbaugh | Treatment of depression, psychosis, and anxiety |
WO2010005520A2 (en) * | 2008-06-30 | 2010-01-14 | Concert Pharmaceuticals, Inc. | 2-alkyl-3-acylpyrazolo[1,5-a]pyridine derivatives |
WO2015006689A1 (en) | 2013-07-12 | 2015-01-15 | University Of South Alabama | Treatment and diagnosis of cancer and precancerous conditions using pde10a inhibitors and methods to measure pde10a expression |
US10433342B2 (en) | 2016-10-19 | 2019-10-01 | Qualcomm Incorporated | Enhanced random access channel (RACH) procedure |
US11770855B2 (en) | 2016-10-19 | 2023-09-26 | Qualcomm Incorporated | Random access channel (RACH) procedure design |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11302190A (ja) * | 1998-04-24 | 1999-11-02 | Michihiro Fujiwara | 痴呆改善薬 |
WO2000009127A1 (fr) * | 1998-08-10 | 2000-02-24 | Kyorin Pharmaceutical Co., Ltd. | Traitements contre la sclerose en plaques |
JP2000224992A (ja) * | 1998-11-30 | 2000-08-15 | Tanabe Seiyaku Co Ltd | 新規ホスホジエステラーゼ及びその遺伝子 |
WO2001024781A2 (en) * | 1999-10-07 | 2001-04-12 | Novaneuron Inc. | Gene necessary for striatal function, uses thereof, and compounds for modulating same |
WO2001040226A1 (fr) * | 1999-11-30 | 2001-06-07 | Toray Industries, Inc. | Agents permettant de stimuler l'apprentissage ou la memoire |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH085790B2 (ja) * | 1988-11-11 | 1996-01-24 | 杏林製薬株式会社 | 記憶障害改善薬 |
CN1083841C (zh) * | 1996-10-04 | 2002-05-01 | 杏林制药株式会社 | 吡唑并吡啶基哒嗪酮衍生物及其制备方法 |
IL156784A0 (en) * | 2001-02-20 | 2004-02-08 | Astrazeneca Ab | 2-arylamino-pyrimidines for the treatment of gsk3-related disorders |
CA2508194C (en) | 2002-12-03 | 2011-05-24 | Kyorin Pharmaceutical Co., Ltd. | Use of ibudilast as a phosphodiesterase 10a inhibitor |
-
2003
- 2003-12-01 CA CA2508194A patent/CA2508194C/en not_active Expired - Fee Related
- 2003-12-01 AU AU2003302588A patent/AU2003302588A1/en not_active Abandoned
- 2003-12-01 WO PCT/JP2003/015315 patent/WO2004050091A1/ja active Application Filing
- 2003-12-01 US US10/537,313 patent/US20060106054A1/en not_active Abandoned
- 2003-12-01 JP JP2004556869A patent/JP4589122B2/ja not_active Expired - Fee Related
- 2003-12-01 EP EP03812356A patent/EP1570847B1/en not_active Expired - Fee Related
-
2007
- 2007-10-31 US US11/980,526 patent/US7846942B2/en not_active Expired - Fee Related
-
2010
- 2010-06-25 JP JP2010144691A patent/JP5192517B2/ja not_active Expired - Fee Related
- 2010-10-27 US US12/913,094 patent/US8404710B2/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11302190A (ja) * | 1998-04-24 | 1999-11-02 | Michihiro Fujiwara | 痴呆改善薬 |
WO2000009127A1 (fr) * | 1998-08-10 | 2000-02-24 | Kyorin Pharmaceutical Co., Ltd. | Traitements contre la sclerose en plaques |
JP2000224992A (ja) * | 1998-11-30 | 2000-08-15 | Tanabe Seiyaku Co Ltd | 新規ホスホジエステラーゼ及びその遺伝子 |
WO2001024781A2 (en) * | 1999-10-07 | 2001-04-12 | Novaneuron Inc. | Gene necessary for striatal function, uses thereof, and compounds for modulating same |
WO2001040226A1 (fr) * | 1999-11-30 | 2001-06-07 | Toray Industries, Inc. | Agents permettant de stimuler l'apprentissage ou la memoire |
Non-Patent Citations (5)
Title |
---|
HIROTOSHI KASAHARA ET AL: "Nojunkan . Taisha Kaizenyaku to Sono Tukaikata", KURINIKA, vol. 17, no. 5, 1990, pages 16 (256) - 22 (262), XP002979198 * |
KISHI, Y. ET AL: "Ibudilast Modulates Platelet-Endothelium Interaction Mainly Through Cyclic GMP-Dependent Mechanism", JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, vol. 36, no. 1, 2000, pages 65 - 70, XP002979199 * |
See also references of EP1570847A4 * |
SEIKO MURASHIMA ET AL: "Inhibitory Effect of Ibudilast (KC-404) on Cyclic Nucreotide Phosphodiesterases", BASIC PHARMACOLOGY & THERAPEUTICS, vol. 26, no. 1, 1998, pages 41 - 45, XP002927433 * |
SOUNESS, J. E.: "Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone", BRITISH JOURNAL OF PHARMACOLOGY, vol. 111, no. 4, 1994, pages 1081 - 1088, XP001018672 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013505911A (ja) * | 2009-09-24 | 2013-02-21 | エフ.ホフマン−ラ ロシュ アーゲー | ホスホジエステラーゼ10a阻害剤としてのイミダゾピリジンまたはイミダゾピリミジン誘導体 |
JPWO2012020821A1 (ja) * | 2010-08-12 | 2013-10-28 | 杏林製薬株式会社 | 非アルコール性脂肪肝炎の予防または治療剤 |
Also Published As
Publication number | Publication date |
---|---|
EP1570847B1 (en) | 2012-04-25 |
US8404710B2 (en) | 2013-03-26 |
US20080108650A1 (en) | 2008-05-08 |
CA2508194C (en) | 2011-05-24 |
JP2010248224A (ja) | 2010-11-04 |
AU2003302588A1 (en) | 2004-06-23 |
US20060106054A1 (en) | 2006-05-18 |
JP4589122B2 (ja) | 2010-12-01 |
JPWO2004050091A1 (ja) | 2006-03-30 |
CA2508194A1 (en) | 2004-06-17 |
US20110039882A1 (en) | 2011-02-17 |
JP5192517B2 (ja) | 2013-05-08 |
EP1570847A4 (en) | 2008-10-08 |
EP1570847A1 (en) | 2005-09-07 |
US7846942B2 (en) | 2010-12-07 |
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