[go: up one dir, main page]

WO2001041796A1 - Procede permettant de combattre la proliferation de cellules hyperplasiques indesirables - Google Patents

Procede permettant de combattre la proliferation de cellules hyperplasiques indesirables Download PDF

Info

Publication number
WO2001041796A1
WO2001041796A1 PCT/SE2000/002433 SE0002433W WO0141796A1 WO 2001041796 A1 WO2001041796 A1 WO 2001041796A1 SE 0002433 W SE0002433 W SE 0002433W WO 0141796 A1 WO0141796 A1 WO 0141796A1
Authority
WO
WIPO (PCT)
Prior art keywords
molecular weight
cell proliferation
low molecular
prodrug
patient
Prior art date
Application number
PCT/SE2000/002433
Other languages
English (en)
Inventor
Christer Mattsson
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU19124/01A priority Critical patent/AU1912401A/en
Publication of WO2001041796A1 publication Critical patent/WO2001041796A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a new use for low molecular weight thrombin inhibitors such as melagatran and its derivatives, and for prodrugs thereof.
  • thrombin-inhibiting compounds that is specifically disclosed in WO 94/29336 is HOOC-CH 2 -(R)-Cgl-Aze-Pab-H which is also known as melagatran (see Example 1 of WO 94/29336, and the list of abbreviations in that document).
  • melagatran HOOC-CH 2 -(R)-Cgl-Aze-Pab-H which is also known as melagatran
  • ischemic symptoms due to vessel renarrowing remains the major long-term limitation to successful treatment of coronary artery disease.
  • About 10-40% of patients undergoing any kind of revascularization procedure, such as PTCA (percutaneous transluminal coronary angioplasty), CABG (coronary artery bypass graft) or coronary or peripheral grafting will have to undergo a second procedure within 6 months due to vessel renarrowing.
  • PTCA percutaneous transluminal coronary angioplasty
  • CABG coronary artery bypass graft
  • coronary or peripheral grafting will have to undergo a second procedure within 6 months due to vessel renarrowing.
  • a variety of pharmaceutical agents have been tested in clinical trials most of them have proven ineffective at reducing the rate of vessel narrowing.
  • a low molecular weight thrombin inhibitor can inhibit hyperplastic cell proliferation and, surprisingly, that this effect is seen in cellular systems where cells are stimulated to proliferate in the absence of added thrombin.
  • a first aspect of the invention provides a method of combating undesirable hyperplastic cell proliferation in a patient the method comprising administering to the patient an effective amount of a low molecular weight thrombin inhibitor or a prodrug thereof.
  • Hyperplasia is the abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue.
  • undesirable hyperplastic cell proliferation is included any undesirable hyperplastic cell proliferation in the human body, particularly that which may lead to pathologic conditions.
  • the undesirable cell proliferation to be combated is undesirable proliferation of smooth muscle cells.
  • Undesirable proliferation of smooth muscle cells is one component in intimal hype ⁇ lasia.
  • the methods and uses of the invention may be useful in treating intimal hyperplasia.
  • the undesirable cell proliferation to be combated is the undesirable cell proliferation of vascular smooth muscle cells.
  • the proliferation of vascular smooth muscle cells is a key event in the development of intimal hyperplasia. Restenosis can be considered to be due to neointimal hype ⁇ lasia ie an abnormal increase in the number of normal cells in a normal arrangement in the newly formed inner layer of the blood vessels. Smooth muscle cells not only proliferate, but they will also migrate from their normal position in the media into the intimal layer of the vessel wall.
  • intimal hype ⁇ lasia in the context of the invention, includes restenosis (ie a new stenosis which occurs after the primary stenosis has been removed mechanically (eg by PTCA)).
  • a surgical intervention such as graft implantation, often occludes at the site of the junctions. In this case there is no primary stenosis which is responsible for the occlusion: this is also intimal hype ⁇ lasia.
  • a further aspect of the invention provides a method of preventing intimal hype ⁇ lasia in a patient, the method comprising administering to the patient an effective amount of a low molecular weight thrombin inhibitor or prodrug thereof.
  • the method of the invention is useful in preventing restenosis.
  • Further aspects of the invention provide use of a low molecular weight thrombin inhibitor or a prodrug thereof in the manufacture of a medicament for combating undesirable cell proliferation in a patient and use of a low molecular weight thrombin inhibitor or a prodrug thereof in the manufacture of a medicament for preventing intimal hype ⁇ lasia.
  • low molecular weight thrombin inhibitor will be understood by those skilled in the art.
  • the term may also by understood to include any composition of matter (eg chemical compound) which inhibits thrombin to an experimentally determinable degree in in vivo and/or in in vitro tests, and which possesses a molecular weight of below 2,000, preferably below 1 ,000.
  • Preferred low molecular weight thrombin inhibitors include low molecular weight peptide, and amino acid, based thrombin inhibitors and/or peptide analogue, based thrombin inhibitors.
  • low molecular weight thrombm inhibitors includes thrombin inhibitors with one to four peptide linkages, and/or with a molecular weight below 1000, and includes those described in the review paper by Claesson in Blood Coagul. Fibrin.
  • Preferred low molecular weight peptide-based thrombin inhibitors include those known collectively as the "gatrans". Particular gatrans which may be mentioned include HOOC-CH 2 -(R)Cha-Pic-Nag-H (known as inogatran; see International Patent Application WO 93/11152 and the list of abbreviations therein) and HOOC-CH 2 -(R)Cgl-Aze-Pab-H (known as melagatran; see International Patent Application WO 94/29336 and the list of abbreviations therein) and prodrugs thereof (see eg WO 97/23499). Particularly preferred thrombin inhibitors include melagatran.
  • Low molecular weight thrombin inhibitors include any pharmaceutically acceptable derivatives of the inhibitors described above.
  • “Pharmaceutically acceptable derivatives” includes salts (eg pharmaceutically acceptable non-toxic organic or inorganic acid addition salts) and solvates.
  • the low molecular weight thrombin inhibitors for use in the methods of the invention, including melagatran, and derivatives and prodrugs thereof, may be administered for systemic delivery to the site of undesirable cell proliferation, or may be administered for delivery directly (locally) to that site, using appropriate means of administration that are known to the skilled person. It is believed that a combination of an acute intravenous infusion during the intervention and a prolonged oral prophylaxis might be the optimal treatment.
  • the low molecular weight thrombin inhibitor such as melagatran, and derivatives and prodrugs thereof, may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, topically, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Preferred modes of delivery are systemic.
  • preferred modes of administration are parenteral, more preferably intravenous, and especially subcutaneous.
  • preferred modes of administration are oral.
  • the low molecular weight thrombin inhibitors and prodrugs thereof may be administered alone, but will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • thrombin inhibitors such as melagatran, derivatives and prodrugs thereof
  • the preparation of suitable formulations for use in administering low molecular weight thrombin inhibitors such as melagatran, derivatives and prodrugs thereof is described in the literature, for example as described in inter alia International Patent Applications WO 94/29336, WO 96/14084, WO 96/16671 , WO 97/23499, WO 97/39770, WO 97/45138 and WO 98/16252, the disclosures in which documents are hereby inco ⁇ orated by reference. Otherwise, the preparation of suitable formulations may be achieved non- inventively by the skilled person using routine techniques.
  • Suitable formulations for use in administering thrombin inhibitors are known in the art, and include those known from US Patent N° 4,346,078; International Patent Applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422 and WO 98/57932; and European Patent Applications 648 780, 468 231, 559
  • the amount of low molecular weight thrombin inhibitor or prodrug thereof, in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • a pharmaceutical formulation for use in combating undesirable cell proliferation or for use in preventing neointimal hype ⁇ lasia comprising an effective amount of a low molecular weight thrombin inhibitor or a pharmaceutically acceptable derivative or prodrug thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Low molecular weight thrombin inhibitors and prodrugs thereof may also be combined with other therapeutic agents that are useful in combating undesirable cell proliferation and/or other therapeutic agents that are useful in the treatment of a disease characterised by undesirable cell proliferation as one of its symptoms.
  • the active ingredients may be administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations.
  • Heparin, and platelet aggregation inhibitors are presently used to prevent acute vessel occlusion.
  • low molecular weight thrombin inhibitors may be “combined" with prodrugs of low molecular weight inhibitors, the inhibitor and prodrug being administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations.
  • Suitable doses of low molecular weight thrombin inhibitor such as melagatran, prodrugs and derivatives thereof, in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients are typically those which give a mean plasma concentration in the range 0.001 to 5 ⁇ mol/L.
  • the physician, or the skilled person will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the age, weight, sex and response of the particular patient.
  • concentrations are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the low molecular weight thrombin inhibitor or prodrug thereof may be administered in an appropriate dose on an "as required" basis (ie as needed or desired).
  • prodrug of a low molecular weight thrombin inhibitor includes any compound that, following oral or parenteral administration, is metabolised in vivo to form a low molecular weight thrombin inhibitor (as defined herein), in an experimentally-detectable amount, and within a predetermined time (eg within a dosing interval of between 6 and 24 hours (ie once to four times daily)), following oral or parenteral administration.
  • Prodrugs of the thrombin inhibitor melagatran include those disclosed in international patent application WO 97/23499.
  • Preferred prodrugs are those of the formula R' ⁇ 2 C-CH 2 -(R)Cgl-Aze-Pab- OH (see the list of abbreviations in WO 97/23499), wherein R 1 represents benzyl or linear or branched C 1-6 alkyl (eg Cj -4 alkyl, especially methyl, propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab.
  • R 1 represents benzyl or linear or branched C 1-6 alkyl (eg Cj -4 alkyl, especially methyl, propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab.
  • Figure 1 shows the inhibition of serum stimulated human smooth muscle cells by melagatran.
  • Figure 2 shows the inhibition of thrombin stimulated human smooth muscle cell proliferation by melagatran.
  • IC 50 concentration that inhibited cell proliferation by 50%
  • Minimal medium As above but with 0.5 % FBS instead of 10%.
  • the technique used to study cell proliferation is based on the inco ⁇ oration of a thymidine analogue (5-bromo-2'-deoxyuridine, BrdU) into the DNA of proliferating cells. After inco ⁇ oration into the DNA, BrdU is detected by immunoassay using monoclonal antibodies labelled with peroxidase (POD).
  • POD peroxidase
  • BrdU-POD was prepared by dilution in 1.1 ml redistilled water and stored in 100 ⁇ l aliquots at -20°C.
  • the anti-BrdU-POD stock solution was further diluted 1 : 100 immediately before use.
  • Example 2 Effect of melagatran on cell proliferation of thrombin- stimulated smooth muscle cells
  • Human thrombin was obtained from Haematologic Technologies Inc.
  • Minimal medium Fetal calf serum was exchanged for 0. 1 % human albumin.
  • step 2 in Example 1 above two extra steps have been introduced: 3a. Replace again with 80 ⁇ l minimal medium and add directly 10 ⁇ l of thrombin (2 units/ml) to all wells except one set with minimal medium as a control for non-proliferating cells. Add directly lO ⁇ l of the test compounds or just minimal medium to the controls and to one set measuring the thrombin effect in the absence of inhibitors. Incubate for 48 h.
  • the antiproliferative effect of melagatran on vascular smooth muscle cells was studied in male Sprague-Dawley rats. After anaesthesia, a balloon catheter was inserted into the right common carotid artery. Endothelial denudation was achieved by mechanically pulling a balloon catheter inflated at 3 atm pressure 5 times within a distance of 1 to 1.5 cm in the vessel lumen. The rats were given melagatran as an intravenous bolus dose of 4 ⁇ mol/kg immediately after denudation of the endothelium and then as a continuous intravenous infusion from a peristaltic pump placed under the skin on the neck. The infusion rate was 1.5 ⁇ mol/kg per hour and continued for 14 days.
  • Rat infused with saline served as controls. At the end of the experiment the rats were anaesthetised with foren and the abdominal part of the aorta was uncovered. A catheter was then inserted into the aorta and the vessels of the rat were perfused with saline until the perfusate was almost free of blood and the rats were dead. The vessels were then perfused with 4% formaldehyde at 110 mm Hg pressure and at a speed of 20 ml/min. The right common carotid artery was isolated and immersed in 4% formaldehyde, dehydrated and finally embedded in paraffin.
  • the artery in the paraffin block was then sliced ( ⁇ 5 ⁇ m thick) and cross-sections were mounted on glass slides and stained with hematoxylin. The area of the intimal hype ⁇ lasia (neointima) was then measured under light microscopy connected to a computer.
  • neointima area ( ⁇ m ) from all rats are summarised in the table below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé permettant de combattre la prolifération de cellules indésirables chez un patient. Ce procédé consiste à administrer au patient une quantité efficace d'un inhibiteur de thrombine à faible poids moléculaire ou un prodrogue de ce dernier. L'invention concerne également un procédé de prévention de l'hyperplasie néointimale chez un patient. Ce procédé consiste à administrer chez le patient une quantité efficace d'un inhibiteur de thrombine de faible poids moléculaire ou une prodrogue de ce dernier.
PCT/SE2000/002433 1999-12-08 2000-12-05 Procede permettant de combattre la proliferation de cellules hyperplasiques indesirables WO2001041796A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19124/01A AU1912401A (en) 1999-12-08 2000-12-05 Method of combating undesirable hyperplastic cell proliferation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9904483-6 1999-12-08
SE9904483A SE9904483D0 (sv) 1999-12-08 1999-12-08 New use

Publications (1)

Publication Number Publication Date
WO2001041796A1 true WO2001041796A1 (fr) 2001-06-14

Family

ID=20418040

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2000/002433 WO2001041796A1 (fr) 1999-12-08 2000-12-05 Procede permettant de combattre la proliferation de cellules hyperplasiques indesirables

Country Status (3)

Country Link
AU (1) AU1912401A (fr)
SE (1) SE9904483D0 (fr)
WO (1) WO2001041796A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051445A3 (fr) * 2000-12-22 2003-11-20 Abbott Gmbh & Co Kg Promédicament de faible poids moléculaire, inhibiteur de la thrombine, en formulation pharmaceutique orale et parentérale
EP1396269A1 (fr) 2002-09-09 2004-03-10 Trigen Limited Sels d'acide boronique des metaux multivalents et leur utilisation dans la préparation de médicaments pour le traitement de la thrombose
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454220A1 (fr) * 1990-04-23 1991-10-30 Akzo Nobel N.V. Dérivés d'hydrates de carbone comprenant une unité trisaccharide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454220A1 (fr) * 1990-04-23 1991-10-30 Akzo Nobel N.V. Dérivés d'hydrates de carbone comprenant une unité trisaccharide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
B. JACOTOT ET AL.: "Atherosclerosis XI", PROCEEDINGS OF THE XI-TH INTERNATIONAL SYMPOSIUM ON ATHEROSCLEROSIS, ON 5-9 OCTOBER 1997, ELSEVIER, 1998, PARIS, FRANCE, pages 623 - 629, XP002938396 *
JESSE W. CURRIER ET AL.: "Low molecular weight heparin (enoxaparin) reduces restenosis after iliac angioplasty in the hypercholesterolemic rabbit", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 17, no. 6, May 1991 (1991-05-01), pages 118B - 125B, XP002938397 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051445A3 (fr) * 2000-12-22 2003-11-20 Abbott Gmbh & Co Kg Promédicament de faible poids moléculaire, inhibiteur de la thrombine, en formulation pharmaceutique orale et parentérale
EP1396269A1 (fr) 2002-09-09 2004-03-10 Trigen Limited Sels d'acide boronique des metaux multivalents et leur utilisation dans la préparation de médicaments pour le traitement de la thrombose
EP1466917A1 (fr) 2002-09-09 2004-10-13 Trigen Limited Procédé der préparation des acides boroniques peptidiques et acides obtenus
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations

Also Published As

Publication number Publication date
SE9904483D0 (sv) 1999-12-08
AU1912401A (en) 2001-06-18

Similar Documents

Publication Publication Date Title
US5599844A (en) Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US5574059A (en) Treating disorders mediated by vascular smooth muscle cell proliferation
Edelman et al. Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.
DK174523B1 (da) Anvendelse af gamma-interferon til fremstilling af et lægemiddel til behandling af vasculær stenosis
US20080113960A1 (en) Combinations comprising a low molecular weight thrombin inhibitor and a prodrug of a low molecular weight thrombin inhibitor
EP0543653A1 (fr) Dipyridamole pour le traitement de maladies prolifératives
US11628179B2 (en) Compounds for treating and preventing extracellular histone mediated pathologies
Feuerstein et al. An inhibitory anti-factor IX antibody effectively reduces thrombus formation in a rat model of venous thrombosis
SK288707B6 (sk) Farmaceutické kombinácie obsahujúce antagonistu P2T receptora a ďalšie antitrombotické činidlá, spôsob ich prípravy a ich použitie na liečenie a prevenciu trombózy
WO2001041796A1 (fr) Procede permettant de combattre la proliferation de cellules hyperplasiques indesirables
US6562829B1 (en) Treatment of hepatic cirrhosis
Masaki et al. In vitro pharmacological inhibition of human vascular smooth muscle cell proliferation for the prevention of hemodialysis vascular access stenosis
JP2005120098A (ja) 虚血性障害の処置用医薬品の製造のためのメラガトランの使用
Wolf et al. Nitroglycerin decreases medial smooth muscle cell proliferation after arterial balloon injury
KR100983164B1 (ko) ＰＰＡＲγ 인산화 변이체를 포함하는 동맥경화 및 혈관재협착 치료 또는 예방용 조성물
CN100506230C (zh) 血管内膜增厚抑制剂
KR100987557B1 (ko) 혈관 재협착 치료 또는 예방용 조성물
JP4394882B2 (ja) 接着形成阻害方法
JPH09151137A (ja) 平滑筋細胞増殖抑制剤
US6498152B1 (en) Use of a farnesyl transferase inhibitor in the manufacture of a medicament for local administration to the vascular wall in the prevention of restenosis
WO2024023745A1 (fr) Traitement d'une lésion organique aiguë à l'aide de cd39, de cd39 recombinant
WO1993015734A1 (fr) Procede de traitement de la proliferation de tissus anormaux par l'administration d'antagoniste de l'angiotensine ii
JP2688733B2 (ja) 消化管粘膜障害の予防及び治療剤
US20070149505A1 (en) Method of Inhibiting Adhesion Formation
WO2002051445A2 (fr) Promédicament de faible poids moléculaire, inhibiteur de la thrombine, en formulation pharmaceutique orale et parentérale

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP