WO2005014001A1 - Use of 2h- [1, 3] - oxazino [3, 2-a] indole derivatives for the treatment of neuropathic pain - Google Patents
Use of 2h- [1, 3] - oxazino [3, 2-a] indole derivatives for the treatment of neuropathic pain Download PDFInfo
- Publication number
- WO2005014001A1 WO2005014001A1 PCT/EP2004/007633 EP2004007633W WO2005014001A1 WO 2005014001 A1 WO2005014001 A1 WO 2005014001A1 EP 2004007633 W EP2004007633 W EP 2004007633W WO 2005014001 A1 WO2005014001 A1 WO 2005014001A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- neuropathic pain
- compound
- treatment
- pain
- use according
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
Definitions
- European patent application EP-A-0 630 376 relates to a large number of compounds of formula I:
- Compound (I) including those wherein R is H, a linear or branched alkyl chain having from 1 to 12 carbon atoms or an arylalkyl radical.
- R is H, a linear or branched alkyl chain having from 1 to 12 carbon atoms or an arylalkyl radical.
- the compound of formula (I) is active in the treatment or the prophylaxis of gastrointestinal, cardiac and central nervous system disorders.
- the compounds of formula (I) wherein R has the aforesaid meanings will for brevity be referred to as "Compound (I)". It has now surprisingly been found that Compound (I) is particularly active in neuropathic pain. It is known that on average about 10-20% of the adult population suffer from chronic pain. The chronic pain is generally associated with clinical conditions characterised by chronic and/or degenerative lesions.
- Typical examples of pathological conditions characterised by chronic pain are rheumatoid arthritis, osteoarthritis, fibromyalgia, neuropathy, and the like [Ashburn M A, Pope P S, Management of chronic pain. Lancet 1999; 353: 1865-69].
- Chronic pain, in particular neuropathic pain is often debilitating and is a cause of loss of working capacity and poor quality of life. Consequently, it also results in economic and social losses.
- the analgesic drugs currently used in the treatment of neuropathic pain include non-steroidal anti-inflammatories (NSAIDs), antidepressants, opioid analgesics, and anticonvulsants [Woolf C J,
- R is H, a linear or branched alkyl chain having from 1 to 12 carbon atoms or an arylalkyl group and of the acid addition salts thereof with pharmaceutically acceptable organic or inorganic acids
- the alkyl moiety has from 1 to 4 carbon atoms and the aryl moiety is a phenyl or naphthyl ring.
- Typical examples of pharmaceutically acceptable organic or inorganic acids are: oxalic, maleic, methanesulphonic, paratoluenesulphonic, succinic, citric, tartaric, lactic, hydrochloric, phosphoric and sulphuric.
- Typical examples of pathological conditions characterised by neuropathic pain are diabetes, cancer, immunodeficiency, traumas, ischaemia, multiple sclerosis, sciatic neuralgia, trigeminal neuralgia and post-herpetic syndromes.
- the pharmaceutical compositions of the present invention are prepared in the form of suitable dosage forms containing an effective dose of at least one Compound (I) or of an acid addition salt thereof with a pharmaceutically acceptable organic or inorganic acid and at least one pharmaceutically acceptable inert ingredient.
- suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; medicated plasters, solutions, pastes, creams and ointments for transdermal administration; suppositories for rectal administration and sterile solutions for administration by the injection or aerosol routes.
- Other suitable dosage forms are the sustained release dosage forms and the dosage forms based on liposomes for oral or injection administration.
- the dosage forms may also comprise other conventional ingredients such as: preservatives, stabilisers, surfactants, buffers, salts to regulate the osmotic pressure, emulsifiers, sweeteners, colorants, flavourings and the like. If required by particular therapies, the pharmaceutical composition of the present invention may comprise other pharmacologically active ingredients whose concomitant administration is useful.
- the amount of Compound (I) or of an acid addition salt thereof with a pharmaceutically acceptable organic or inorganic acid in the pharmaceutical composition of the present invention can vary over a wide range depending on known factors such as, for example, the type of pathology with which the neuropathic pain to be treated is associated, the severity of the disease, the patient's body weight, the dosage form, the chosen administration route, the number of administrations per day and the efficacy of the chosen compound of formula (I).
- the optimal amount can be determined in a simple and routine manner by the person skilled in the art.
- the amount of Compound (I) or of an acid addition salt thereof with a pharmaceutically acceptable organic or inorganic acid in the pharmaceutical composition of the present invention will be such as to ensure an administration level of from 0.001 to 100 mg/kg/day of Compound (I), as a base.
- the administration level will be of from 0.05 to 50 mg/kg/ day, and still more preferably of from 0.1 to 10 mg/kg/day.
- the dosage forms of the pharmaceutical composition of the present invention can be prepared by techniques well known to the pharmaceutical chemist which include mixing, granulating, compressing, dissolving, sterilizing and the like.
- the analgesic activity of Compound (I) has been proved by means of two experimental models in the rat: allodynia induced by ligature of the sciatic nerve and mechanical hyperalgesia in diabetic neuropathy induced by streptozotocin.
- the experimental model of ligature of the sciatic nerve in the rat is a neuropathy which reproduces a series of responses similar to those observed in man in many traumatic and pathological conditions associated with neuropathic pain.
- Ligature of the sciatic nerve is in fact capable of inducing a syndrome associated with the activation of specific circuits responsible for the control of the perception of pain and characterised by the appearance of allodynia, hyperalgesia and spontaneous pain.
- this model is an effective instrument for the study of drugs for use in the treatment of neuropathic pain in man and, in particular, in the control of conditions such as allodynia and hyperalgesia.
- the diabetic neuropathy induced by streptozotocin in the rat is an insulin-dependent syndrome characterised by a concomitant decrease in the conduction speed of the motor and sensory nerves and the appearance of a series of anomalies in the perception of pain.
- this model is a useful instrument for the study of drugs for use in the treatment of neuropathic pain in man.
- the model is a valid example of a large group of neuropathic pain types characterised by phenomena such as hyperalgesia and allodynia due to primary lesions or dysfunctions of the nervous system.
- Typical examples of human pathologies characterised by the dysfunctions described in the two experimental models cited above and characterised by the presence of neuropathic pain are diabetes, cancer, immunodeficiency, trauma, ischaemia, multiple sclerosis, sciatic neuralgia, trigeminal neuralgia and post-herpetic syndromes.
- TESTS 1 is a useful instrument for the study of drugs for use in the treatment of neuropathic pain in man.
- the model is a valid example of a large group of neuropathic pain types characterised by phenomena such as hyperalgesia and allodynia due to primary lesions or dysfunctions of the nervous system.
- Allodynia induced by ligature of the sciatic nerve in the rat Male CD rates of weight 200-250 g on arrival were used. The allodynia was induced by ligature under anaesthesia of the sciatic nerve of the left hind paw [Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990; 43: 205-218; Bennett G J, Xie Y K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1998; 33: 87-107].
- rats which showed a reduction of a least 50% in the response threshold recorded before the operation were selected.
- the pain threshold was measured by means of a von Frey instrument which, by applying a gradual increase in pressure on the plantar zone of the left hind paw of the rat, makes it possible to record the nocifensive response, expressed in grams, corresponding to the moment at which the animal withdraws its paw.
- the pain threshold measured in control animals was compared with that measured in animals treated with the compound under test.
- control animals were treated with same vehicle (water) as was used for administration of the compound under test (hydrochloride salt of the compound of formula (I) wherein R is n-butyl, prepared as disclosed in Example 3, Method 2, of EP-A-0 630 376).
- the results are shown in Figure 1. Similar results were obtained with the hydrochloride salt of the compound of formula (I), wherein R is cyclohexyl, prepared according to Examples 23 of EP-A-0 630 376.
- Mechanical hyperalgesia in rats with diabetes induced by streptozotocin Male CD rates of weight 240-300 g on arrival were used.
- the diabetic syndrome was induced by a single intraperitoneal (i.p.) injection of 80 mg/kg of streptozotocin dissolved in sterile physiological solution [Courteix C, Eschalier A, Lavarenne J. Streptozotocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain, 1993; 53: 81 -88; Bannon A W, Decker M W, Kim Dj, Campbell J E, Arneric S P. ABT-594, a novel cholinergic channel modulator, is efficacious in nerve ligation and diabetic neuropathy models of neuropathic pain. Brain Res. 1998; 801 : 158-63].
- rats with a glycaemia level > 300 mg/dl and a response threshold ⁇ 120 g to a mechanical nociceptive stimulus were selected.
- the glycaemia levels were measured using a reflectometer utilising reactive strips impregnated with glucose oxidase.
- the pain threshold was measured using an analgesimeter.
- the instrument by applying a gradual increase in pressure on the dorsal zone of the left hind paw of the rat, makes it possible to record the nocifensive response, expressed in grams, corresponding to the moment at which the animal withdraws its paw.
- Example 1 A tablet comprising, as the active principle, the Compound (I) of the present invention, has the following composition: Active principle 50 mg
- An ampoule comprising, as the active principle, the Compound (I) of the present invention, has the following composition: Active principle 25 mg Sorbitol q.s. for isosmotic solution
- a pharmaceutical composition in granules comprising, as the active principle, a Compound (I) of the present invention, has the following composition:
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2526852A CA2526852C (en) | 2003-07-18 | 2004-07-08 | Use of 2h- [1,3] - oxazino [3,2-a] indole derivatives for the treatment of neuropathic pain |
PL04740899T PL1646391T3 (en) | 2003-07-18 | 2004-07-08 | Use of 2h-[1,3]-oxazino[3,2-a]indole derivatives for the treatment of neuropathic pain |
US10/560,836 US20060211691A1 (en) | 2003-07-18 | 2004-07-08 | Use of 2h-[1,3]-oxazino[3,2-a] indole derivatives for the treatment of neuropathic pain |
EA200600270A EA008927B1 (en) | 2003-07-18 | 2004-07-08 | Use of 2h-[1,3]-oxazino [3,2-a] indole derivatives for the treatment of neuropathic pain |
JP2006520721A JP2006528142A (en) | 2003-07-18 | 2004-07-08 | Use of 2H- [1,3] -oxazino [3,2-A] indole derivatives for the treatment of neuropathic pain |
DE602004003252T DE602004003252T2 (en) | 2003-07-18 | 2004-07-08 | Use of 2H- [1,3] -oxazino [3,2] indole derivatives for the treatment of neuropathic pain |
DK04740899T DK1646391T3 (en) | 2003-07-18 | 2004-07-08 | Use of 2H- [1,3] -oxazino [3,2-A] indole derivatives for the treatment of neuropathic pain |
EP04740899A EP1646391B1 (en) | 2003-07-18 | 2004-07-08 | Use of 2h-[1,3]-oxazino[3,2-a]indole derivatives for the treatment of neuropathic pain |
SI200430148T SI1646391T1 (en) | 2003-07-18 | 2004-07-08 | Use of 2h-(1,3)-oxazino(3,2-a)indole derivatives for the treatment of neuropathic pain |
AU2004262876A AU2004262876B2 (en) | 2003-07-18 | 2004-07-08 | Use of 2H- [1, 3] - oxazino [3, 2-A] indole derivatives for the treatment of neuropathic pain |
UAA200600306A UA81050C2 (en) | 2003-07-18 | 2004-08-07 | Use of 2h[1,3]-oxazino[3, 2-a]indole derivatives for the treatment of neuropathic pain |
IL172156A IL172156A0 (en) | 2003-07-18 | 2005-11-24 | Use of 2h- [1,3] - oxazinono [3,2 - a] indole derivatives for the treatment of neuropathic pain |
HK06107281A HK1087027A1 (en) | 2003-07-18 | 2006-06-28 | Use of 2H-Ä1, 3Ü-oxazinoÄ3,2-AÜindole derivatives for the treatment of neuropathic pain |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT001467A ITMI20031467A1 (en) | 2003-07-18 | 2003-07-18 | ACTIVE DRUG IN NEUROPATHIC PAIN |
ITMI2003A001467 | 2003-07-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005014001A1 true WO2005014001A1 (en) | 2005-02-17 |
WO2005014001A9 WO2005014001A9 (en) | 2005-05-26 |
Family
ID=34131193
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/007633 WO2005014001A1 (en) | 2003-07-18 | 2004-07-08 | Use of 2h- [1, 3] - oxazino [3, 2-a] indole derivatives for the treatment of neuropathic pain |
Country Status (21)
Country | Link |
---|---|
US (1) | US20060211691A1 (en) |
EP (1) | EP1646391B1 (en) |
JP (1) | JP2006528142A (en) |
KR (1) | KR20060033784A (en) |
CN (1) | CN100409850C (en) |
AR (1) | AR045993A1 (en) |
AT (1) | ATE345137T1 (en) |
AU (1) | AU2004262876B2 (en) |
CA (1) | CA2526852C (en) |
DE (1) | DE602004003252T2 (en) |
DK (1) | DK1646391T3 (en) |
EA (1) | EA008927B1 (en) |
ES (1) | ES2276317T3 (en) |
GE (1) | GEP20084307B (en) |
HK (1) | HK1087027A1 (en) |
IL (1) | IL172156A0 (en) |
IT (1) | ITMI20031467A1 (en) |
PL (1) | PL1646391T3 (en) |
PT (1) | PT1646391E (en) |
UA (1) | UA81050C2 (en) |
WO (1) | WO2005014001A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE526014T1 (en) * | 2006-12-26 | 2011-10-15 | Taiho Pharmaceutical Co Ltd | THERAPEUTIC AGENT AGAINST DIABETIC NEUROPATHY |
DE102007058504A1 (en) | 2007-12-05 | 2009-07-09 | Acino Ag | Transdermal therapeutic system containing a modulator of nicotinic acetylcholine receptors (nAChR) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993006108A1 (en) * | 1991-09-27 | 1993-04-01 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolobenzoxazine derivatives as 5-ht agonists and antagonists |
US5817676A (en) * | 1995-03-16 | 1998-10-06 | Eli Lilly And Company | Indazolecarboxamides |
EP0884319A2 (en) * | 1992-03-12 | 1998-12-16 | Smithkline Beecham Plc | [1,3]oxazino[3,2-A]indole derivative |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5189041A (en) * | 1990-11-16 | 1993-02-23 | Syntex (U.S.A.) Inc. | Tricyclic 5-ht3 receptor antagonists |
JP2003506388A (en) * | 1999-08-04 | 2003-02-18 | アイカゲン インコーポレイテッド | Methods for treating or preventing pain and anxiety |
US20040038874A1 (en) * | 2002-08-22 | 2004-02-26 | Osemwota Omoigui | Method of treatment of persistent pain |
-
2003
- 2003-07-18 IT IT001467A patent/ITMI20031467A1/en unknown
-
2004
- 2004-07-08 US US10/560,836 patent/US20060211691A1/en not_active Abandoned
- 2004-07-08 PT PT04740899T patent/PT1646391E/en unknown
- 2004-07-08 CA CA2526852A patent/CA2526852C/en not_active Expired - Fee Related
- 2004-07-08 CN CNB2004800172642A patent/CN100409850C/en not_active Expired - Fee Related
- 2004-07-08 GE GEAP20049233A patent/GEP20084307B/en unknown
- 2004-07-08 KR KR1020067000490A patent/KR20060033784A/en active IP Right Grant
- 2004-07-08 EP EP04740899A patent/EP1646391B1/en not_active Expired - Lifetime
- 2004-07-08 ES ES04740899T patent/ES2276317T3/en not_active Expired - Lifetime
- 2004-07-08 AT AT04740899T patent/ATE345137T1/en active
- 2004-07-08 WO PCT/EP2004/007633 patent/WO2005014001A1/en active IP Right Grant
- 2004-07-08 AU AU2004262876A patent/AU2004262876B2/en not_active Ceased
- 2004-07-08 JP JP2006520721A patent/JP2006528142A/en active Pending
- 2004-07-08 DK DK04740899T patent/DK1646391T3/en active
- 2004-07-08 EA EA200600270A patent/EA008927B1/en not_active IP Right Cessation
- 2004-07-08 DE DE602004003252T patent/DE602004003252T2/en not_active Expired - Lifetime
- 2004-07-08 PL PL04740899T patent/PL1646391T3/en unknown
- 2004-07-15 AR ARP040102486A patent/AR045993A1/en not_active Application Discontinuation
- 2004-08-07 UA UAA200600306A patent/UA81050C2/en unknown
-
2005
- 2005-11-24 IL IL172156A patent/IL172156A0/en not_active IP Right Cessation
-
2006
- 2006-06-28 HK HK06107281A patent/HK1087027A1/en not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993006108A1 (en) * | 1991-09-27 | 1993-04-01 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolobenzoxazine derivatives as 5-ht agonists and antagonists |
EP0884319A2 (en) * | 1992-03-12 | 1998-12-16 | Smithkline Beecham Plc | [1,3]oxazino[3,2-A]indole derivative |
EP0630376B1 (en) * | 1992-03-12 | 1999-06-02 | Smithkline Beecham Plc | Condensed indole derivatives as 5-ht4-receptor antagonists |
US5817676A (en) * | 1995-03-16 | 1998-10-06 | Eli Lilly And Company | Indazolecarboxamides |
Non-Patent Citations (5)
Title |
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BEERS M. AND BERKOW R.: "The Merck Manual of Diagnosis and Therapy, Seventeenth Edition", 1999, MERCK RESEARCH LABORATORIES, WHITEHOUSE STATION, N.J., XP002279568 * |
DOAK G.J.; SAWYNOK J.: "Formalin-induced nociceptive behavior and edema: involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes", NEUROSCIENCE, vol. 80, no. 3, 1997, pages 939 - 949, XP000886556 * |
DONAHUE ET AL.: "Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats", BRAIN RESEARCH, vol. 897, no. 1-2, 2001, pages 131 - 138, XP002279567 * |
HOUGHTON L.A. ET AL: "5-HT4 receptor antagonism in irritable bowel syndrome: Effect of SB - 207266 -A on rectal sensitivity and small bowel transit.", ALIMENTARY PHARMACOLOGY AND THERAPEUTICS, 13/11 (1437-1444). REFS: 32 ISSN: 0269-2813 CODEN: APTHEN, 1999, XP008037091 * |
WEI H ET AL: "Influence of two serotonin receptor antagonists in neuropathic rats", PFLUEGERS ARCHIV EUROPEAN JOURNAL OF PHYSIOLOGY, vol. 443, no. Supplement 1, March 2002 (2002-03-01), & 81ST ANNUAL JOINT MEETING OF THE PHYSIOLOGICAL SOCIETY, THE SCANDINAVIAN PHYSIOLOGICAL SOCIETY AND T; TUEBINGEN, GERMANY; MARCH 15-19, 2002, pages S181, XP001202624, ISSN: 0031-6768 * |
Also Published As
Publication number | Publication date |
---|---|
WO2005014001A9 (en) | 2005-05-26 |
US20060211691A1 (en) | 2006-09-21 |
CN100409850C (en) | 2008-08-13 |
EP1646391A1 (en) | 2006-04-19 |
PL1646391T3 (en) | 2007-04-30 |
PT1646391E (en) | 2007-01-31 |
JP2006528142A (en) | 2006-12-14 |
CN1809361A (en) | 2006-07-26 |
AU2004262876B2 (en) | 2010-05-20 |
HK1087027A1 (en) | 2006-10-06 |
ITMI20031467A1 (en) | 2005-01-19 |
GEP20084307B (en) | 2008-02-11 |
AR045993A1 (en) | 2005-11-23 |
DK1646391T3 (en) | 2007-03-19 |
DE602004003252T2 (en) | 2007-05-03 |
UA81050C2 (en) | 2007-11-26 |
EA200600270A1 (en) | 2006-06-30 |
AU2004262876A1 (en) | 2005-02-17 |
CA2526852C (en) | 2011-08-30 |
DE602004003252D1 (en) | 2006-12-28 |
ES2276317T3 (en) | 2007-06-16 |
CA2526852A1 (en) | 2005-02-17 |
EA008927B1 (en) | 2007-08-31 |
IL172156A0 (en) | 2006-04-10 |
ATE345137T1 (en) | 2006-12-15 |
EP1646391B1 (en) | 2006-11-15 |
KR20060033784A (en) | 2006-04-19 |
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