WO2011069944A1 - Crystalline {(3s)-3-[({1-[(2r)-2-carboxy-4-(1-naphthyl)butyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1h-1benzazepin-1-yl}acetic acid, its preparation and use - Google Patents

Crystalline {(3s)-3-[({1-[(2r)-2-carboxy-4-(1-naphthyl)butyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1h-1benzazepin-1-yl}acetic acid, its preparation and use Download PDF

Info

Publication number
WO2011069944A1
WO2011069944A1 PCT/EP2010/068932 EP2010068932W WO2011069944A1 WO 2011069944 A1 WO2011069944 A1 WO 2011069944A1 EP 2010068932 W EP2010068932 W EP 2010068932W WO 2011069944 A1 WO2011069944 A1 WO 2011069944A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
crystalline
mixture
crystalline compound
Prior art date
Application number
PCT/EP2010/068932
Other languages
English (en)
French (fr)
Inventor
Touria Elhamdaoui-Achterberg
Nicolaas Buizer
Gerrit Klein
Jeroen Van Rheenen
Eric Eibert Van Dasselaar
Guido Dirk Batema
Paulus Petrus Gerardus De Jong
Original Assignee
Abbott Healthcare Products B.V.
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 Abbott Healthcare Products B.V. filed Critical Abbott Healthcare Products B.V.
Publication of WO2011069944A1 publication Critical patent/WO2011069944A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention aims at the development of a pure form of the compound of formula (1 ) that can be dissolved and steam-sterilized without turning turbid.
  • crystals of the compound could be obtained by an unconventional process using a solvent/anti-solvent mixture. Crystallization of the compound only occurred after heating solvent/anti-solvent mixture at a temperature well above room temperature, rather than after the usual cooling. This process resulted in the desired product in a very pure form. When dissolved in physiological fluids, after steam sterilization those solutions remained clear.
  • the invention relates to a process for the preparation of crystalline compound of formula (1 ), comprising the steps of: taking up the oily compound of formula (1 ), obtainable as described in EP 0733 642, in an organic solvent miscible with water, preferably MEK or n-butyl acetate, and heating to a temperature between approximately 50°C and 80°C, preferably to around 50°C, until everything is dissolved.
  • the solution is cooled to a temperature between approximately 10°C and 30°C, preferably to around 20°C, and filtered.
  • This filtrate then is warmed to a temperature between approximately 40°C and 60°C, preferably to around 50°C, whereafter an alkane, prefably hexane(s) or heptane(s), most preferably heptane (Aldrich, distillation range 98°-99°C), is added.
  • This solution is then stirred, preferably between about 1 to 10 hours during which spontaneous crystallization occurs. Crystallization is slow: up to a certain limit prolonging the stirring results in a higher yield.
  • the mixture is then slowly cooled within about 1 to 10 hours to a temperature between approximately 10°C and 30°C, preferably to around 20°C, and stirred for an additional 1 to 5 hours at that temperature.
  • the mixture is then filtered and the residue is washed on the filter with a mixture of an organic solvent miscible with water, and an alkane, preferably a mixture of MEK and heptane, more preferably a mixture of about 70% MEK and about 30% (v/v) heptane, and subsequently washed with an alkane, preferably heptane.
  • an alkane preferably a mixture of MEK and heptane, more preferably a mixture of about 70% MEK and about 30% (v/v) heptane
  • an alkane preferably heptane.
  • the product is dried, preferably at elevated temperature and lowered pressure, yielding the compound of formula (1 ) in crystalline form.
  • the preferred drying temperature is between 20°C and 60°C.
  • the most preferred drying temperature is 50°C.
  • the preferred pressure during drying is between approximately 1 ,000 and approximately 30 mbar.
  • the most preferred pressure during drying is approximately 100 mbar.
  • the starting material oily compound of formula (1 ), obtainable as described in EP 0733 642 contains sodium or other ions
  • the crystallization can be preceded by the following washing procedure: dissolving oily compound of formula (1 ), obtained as described in EP 0733 642, in a sufficient amount of an organic solvent.
  • Suitable solvents are for instance methyl ethyl ketone (MEK) and dichloromethane. The most preferred solvent is MEK.
  • MEK methyl ethyl ketone
  • a base is added, until pH is between approximately 4 and approximately 6, preferably about 4.8.
  • the organic layer is isolated and subsequently washed with water, an acid, preferably HCI, more preferably 1 M HCI, and again water.
  • an acid preferably HCI, more preferably 1 M HCI
  • the organic layer was separated and evaporated to dryness at a temperature between about 40 and 60°C, preferably around 60°C, yielding purified compound of formula (1 ), again as oil.
  • the base used in the steps described above is selected from alkaline compounds, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, alkaline hydroxides such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, alkaline phosphates such as dipotassium hydrogen phosphate. Also mixtures of these alkaline compounds can be used.
  • alkaline compounds are sodium hydroxide, potassium hydroxide or magnesium hydroxide. Even more preferred is 20% (m/m) NaOH.
  • Crystalline compound of formula (1 ) can be used for the preparation of pharmaceutical compositions for the treatment of traumatic brain injury, acute disseminated encephalo-myelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningoencephalitis, prion diseases, poisonings with neurotoxic compounds, and radiation-induced brain damage, and of ischemic stroke.
  • compositions for treating a disorder or condition chosen from the disorders listed herein comprising a compound of the invention, and a pharmaceutically acceptable carrier;
  • compositions for treating a disorder or condition chosen from the disorders listed herein comprising a compound of the invention, a pharmaceutically acceptable carrier and additionally comprising one or more other pharmacologically active ingredients.
  • alkane denotes a univalent saturated, branched or straight, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms, indicated as C1-C1 8 .
  • alkanes group are methane, ethane, n-propane, isopropane, n-butane, isobutane, sec-butane, ie f-butane, n-pentane, isopentane, neopentane, n-hexane, isohexane, n-heptane, n-octane, n-nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, etc.
  • the heptane used in the crystallisation experiments had a distillation range of 98°-99°C (Aldrich), but also heptane with a distillation range of 94°-100°C can be used.
  • Crystal forms in general have been described by Byrn et al., (Pharmaceutical Research, 12(7), 945-954, 1995. (1995)) and Martin 'Remington: The Science and Practice of Pharmacy", Mack Publishing Company, 19 th Edition, Easton, Pa, Vol 2., Chapter 83, 1447-1462, 1995).
  • the present invention provides a pharmaceutical composition comprising the compound of formula (1 ), together with one or more pharmaceutically acceptable carriers thereof, and with or without one or more other therapeutic ingredients.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
  • this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
  • compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the term 'combination preparation' comprises both true combinations, that is a crystalline compound of formula (1 ), and other medicaments physically combined in one preparation, as well as 'kit-of-parts', comprising a crystalline compound of formula (1 ) and another medicament in separate dosage forms, together with instructions for use, with or without further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
  • the pharmacotherapy by definition is simultaneous.
  • the contents of 'kit-of-parts' can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, such as onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and may be determined by a physician.
  • total daily dose administration to a patient in single or individual doses may be in amounts, for example, from 0.001 to 20 mg/kg body weight daily, and more usually from 0.01 to 20,000 mg per day, of total active ingredients.
  • Such dosages will be administered to a patient in need of treatment from one to three times each day, or as often as needed for efficacy, and for periods of at least two months, more typically for at least six months, or chronically.
  • treatment refers to any treatment of a condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease.
  • IR spectra were recorded on a Fourier transform IR spectrometer in attenuated total reflectance (diamond crystal) with a spectral resolution of 1 cm "1 using a deuterated triglycine sulfate detector.
  • Approximately 10 mg was gently flattened on a sample holder and scanned from 3 to 50 degrees two-theta, at 0.009 degrees two-theta per step and a step time of 532 seconds using a variable angle.
  • the sample was simply placed on the sample holder.
  • the sample was rotated at 15 rpm at a voltage of 40 kV and 40 mA.
  • the sample displacement was corrected using corundum powder as internal standard.
  • DSC Differential Scanning Calorimetry
  • Solid state 13 C NMR spectra were obtained using the cross-polarisation magic-angle spinning (CP/MAS) accessory on a Bruker AM300 instrument (contact time of 4 ms, recycle delay 3 s, spectral width 30kHz, 1 H 90° pulse of 6 s, spinning rate about 8.5kHz.
  • CP/MAS cross-polarisation magic-angle spinning
  • XRPD pattern showed characteristic reflexes expressed as two-theta angle positions at about 4.20, 8.37, 10.95, 12.77, 13.50, 14.63, 16.32, 17.05, 20.38, 21 .99, 23.90, 24.60 ⁇ 0.1 degrees.
  • DSC thermogram showed a characteristic sharp endotherm of the extrapolated peak at 187 °C.
  • Solid state 13 C-NMR characteristic shifts at about: 177.0, 176.0, 174.7, 172.2, 169.7, 138.9, 136.4, 133.6, 131 .5, 130.2, 127.8, 126.5, 125.3, 124.2, 123.2, 121 .9, 55.1 , 51 .0, 41 .9, 40.8, 38.5, 37.1 , 28.4, 25.9, 23.1 , 21 .1 ⁇ 0.1 ppm.
  • the compound of formula (1 ) is formulated into pharmaceutical compositions, novel embodiments of the invention, because they contain the specific compound disclosed herein.
  • Types of pharmaceutical compositions that may be used include: tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or are apparent to a skilled person from the specification and general knowledge.
  • the compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
  • the pharmaceutical formulation contains the compound of formula (1 ) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • the total amount of active ingredients can be in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, such as from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w). In some embodiments, the amount of active ingredient can be greater than about 95% (w/w) or less than about 0.1 % (w/w).
  • the compound of the invention can be brought into forms suitable for administration by usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances such as liquid or solid, powdered ingredients, such as pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the mixture may then be processed into granules or pressed into tablets.
  • a tablet can be prepared using the ingredients below:
  • Total 230 The components are blended and compressed to form tablets each weighing 230 mg.
  • the active ingredient may be separately premixed with the other non-active ingredients, before being mixed to formulation.
  • Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
  • Hard gelatin capsules may contain granules of active ingredients.
  • Hard gelatin capsules may also contain active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. Such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
  • formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy.
  • container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • FIG. 1 XRPD pattern of amorphous compound of formula (1 ).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/EP2010/068932 2009-12-07 2010-12-06 Crystalline {(3s)-3-[({1-[(2r)-2-carboxy-4-(1-naphthyl)butyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1h-1benzazepin-1-yl}acetic acid, its preparation and use WO2011069944A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US26721009P 2009-12-07 2009-12-07
EP09178226 2009-12-07
EP09178226.8 2009-12-07
US61/267,210 2009-12-07

Publications (1)

Publication Number Publication Date
WO2011069944A1 true WO2011069944A1 (en) 2011-06-16

Family

ID=41682516

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/068932 WO2011069944A1 (en) 2009-12-07 2010-12-06 Crystalline {(3s)-3-[({1-[(2r)-2-carboxy-4-(1-naphthyl)butyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1h-1benzazepin-1-yl}acetic acid, its preparation and use

Country Status (3)

Country Link
AR (1) AR079059A1 (es)
TW (1) TW201127815A (es)
WO (1) WO2011069944A1 (es)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0733642A1 (de) 1995-03-23 1996-09-25 Kali-Chemie Pharma GmbH Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäure-derivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DE19638020A1 (de) 1996-09-18 1998-03-19 Solvay Pharm Gmbh Die gastrointestinale Durchblutung fördernde Arzneimittel
US20050153936A1 (en) 2004-01-12 2005-07-14 Solvay Pharmaceuticals B.V. Neutral endopeptidase (NEP) and human soluble endopeptidase (hSEP) inhibitors for prophylaxis and treatment of neuro-degenerative disorders
WO2006064016A1 (en) 2004-12-15 2006-06-22 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising nep-inhibitors, inhibitors of the endogenous endothelin producing system and hmg coa reductase inhibitors
EP1706121A1 (en) 2004-01-12 2006-10-04 Solvay Pharmaceuticals B.V. Neutral endopeptidase (nep) and human soluble endopeptidase (hsep) inhibitors for prophylaxis and treatment of neurodegenerative disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0733642A1 (de) 1995-03-23 1996-09-25 Kali-Chemie Pharma GmbH Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäure-derivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DE19638020A1 (de) 1996-09-18 1998-03-19 Solvay Pharm Gmbh Die gastrointestinale Durchblutung fördernde Arzneimittel
US20050153936A1 (en) 2004-01-12 2005-07-14 Solvay Pharmaceuticals B.V. Neutral endopeptidase (NEP) and human soluble endopeptidase (hSEP) inhibitors for prophylaxis and treatment of neuro-degenerative disorders
EP1706121A1 (en) 2004-01-12 2006-10-04 Solvay Pharmaceuticals B.V. Neutral endopeptidase (nep) and human soluble endopeptidase (hsep) inhibitors for prophylaxis and treatment of neurodegenerative disorders
WO2006064016A1 (en) 2004-12-15 2006-06-22 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising nep-inhibitors, inhibitors of the endogenous endothelin producing system and hmg coa reductase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BYRN ET AL., PHARMACEUTICAL RESEARCH, vol. 12, no. 7, 1995, pages 945 - 954
MARTIN: "Remington: The Science and Practice of Pharmacy", vol. 2, 1995, MACK PUBLISHING COMPANY, pages: 1447 - 1462

Also Published As

Publication number Publication date
TW201127815A (en) 2011-08-16
AR079059A1 (es) 2011-12-21

Similar Documents

Publication Publication Date Title
US20230183172A1 (en) Compositions comprising (R)-2-amino-3-phenylpropyl carbamate and uses thereof
GB2542881A (en) Crystal forms of ß-nicotinamide mononucleotide
EP1877419B1 (en) Crystalline squalamine dilactate
EA009413B1 (ru) Полиморфные формы габоксадола, агониста gaba
US20160046603A1 (en) Crystalline Forms of D-Glucitol, 1-Deoxy-1-(Methylamino)-, 1-(6-Amino-3,5-Difluoropyridine-2-Yl)-8-Chloro-6-Fluoro-1,4-Dihydro-7-(3-Hydroxyazetidin-1-Yl)-4-Oxo-3-Quinolinecarboxylate
CN112135832A (zh) 化合物的晶型和制备化合物的晶型的方法
JP6185490B2 (ja) ３−（４−ニトロ−１−オキソイソインドリン−２−イル）ピペリジン−２，６−ジオンの固体形態
KR20150130359A (ko) 오나프리스톤 다형태 및 사용 방법
RU2537847C2 (ru) Новые фумаратные соли антагониста гистаминового рецептора н3
WO2015067130A1 (zh) (s)-奥拉西坦晶型iii及其制备方法和用途
US20040063782A1 (en) Bicalutamide forms
JP5968881B2 (ja) カルシウム模倣化合物の新規多形
WO2011069944A1 (en) Crystalline {(3s)-3-[({1-[(2r)-2-carboxy-4-(1-naphthyl)butyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1h-1benzazepin-1-yl}acetic acid, its preparation and use
WO2018103027A1 (zh) 替吡法尼的晶型及其制备方法及药物组合物
HU210876A9 (en) Arginine derivatives
CN108948118A (zh) 用于骨生长的氧化固醇-他汀类化合物
WO2008110338A1 (en) Polymorph of desvenlafaxine succinate
EA045975B1 (ru) Кристаллическая l-аргининовая соль (r)-2-(7-(4-циклопентил-3-(трифторметил)бензилокси)-1,2,3,4-тетрагидроциклопента[b]индол-3-ил)уксусной кислоты (соединения 1) для применения при расстройствах, связанных с s1p1-рецептором

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10785085

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10785085

Country of ref document: EP

Kind code of ref document: A1