DE19543476A1 - Treatment of skull-brain trauma with aminomethyl-chroman compounds - Google Patents
Treatment of skull-brain trauma with aminomethyl-chroman compoundsInfo
- Publication number
- DE19543476A1 DE19543476A1 DE1995143476 DE19543476A DE19543476A1 DE 19543476 A1 DE19543476 A1 DE 19543476A1 DE 1995143476 DE1995143476 DE 1995143476 DE 19543476 A DE19543476 A DE 19543476A DE 19543476 A1 DE19543476 A1 DE 19543476A1
- Authority
- DE
- Germany
- Prior art keywords
- treatment
- skull
- aminomethyl
- traumatic brain
- brain injury
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 208000030886 Traumatic Brain injury Diseases 0.000 title claims abstract description 17
- BSRHATGBRQMDRF-UHFFFAOYSA-N 3,4-dihydro-2h-chromen-2-ylmethanamine Chemical class C1=CC=C2OC(CN)CCC2=C1 BSRHATGBRQMDRF-UHFFFAOYSA-N 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- -1 hydroxy, methoxy Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 abstract 1
- 206010061216 Infarction Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 230000007574 infarction Effects 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 210000003625 skull Anatomy 0.000 description 4
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 208000034656 Contusions Diseases 0.000 description 2
- 206010018852 Haematoma Diseases 0.000 description 2
- 208000002667 Subdural Hematoma Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 230000009519 contusion Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 210000002418 meninge Anatomy 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- CWXSZOLRFGMAHB-WKWWPMDXSA-N (2r,3r,4r,5r)-hexane-1,2,3,4,5,6-hexol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CC(O)(C(O)=O)CC(O)=O CWXSZOLRFGMAHB-WKWWPMDXSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 210000000337 motor cortex Anatomy 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung betrifft die Verwendung von substituierten Aminomethyl-chromanen zur Herstellung von Arzneimitteln zur Behandlung von Schädel-Hirn-Trauma.The invention relates to the use of substituted aminomethyl-chromanes for the manufacture of medicinal products for the treatment of traumatic brain injury.
Das Neurotrauma (Schädel-Hirn-Trauma) ist bei jungen Erwachsenen die häufigste Ursache für Tod und schwere gesundheitliche Einschränkungen. Ein Schädel-Hirn- Trauma, ist grundsätzlich die Folge einer äußeren Gewalteinwirkung auf den Schädel und/oder das Gehirn mit primären und sekundären Verletzungsfolgen.Neurotrauma (traumatic brain injury) is the most common in young adults Cause of death and severe health restrictions. A skull brain Trauma is basically the result of external violence Skull and / or brain with primary and secondary injuries.
Der Pathomechanismus der Schädel-Hirn-Trauma ist multifaktoriell bestehend aus: primären Prozessen (mechanisch/traumatische Verletzung von Hirngewebe, Kontusionen, diffuse Axonenverletzung (diffuse Axonal shearing injury) und sekundäre verzögerte Schädigungen (die Hauptursache der schlechten Prognose in mindestens 40% der Patienten) bestehend aus hypoxisch-ischämischen Schäden der Neurone und der Gliazellen, Kontusionen, intrakraniellen Blutungen, Hirn ödemen und usw.The pathomechanism of traumatic brain injury is multifactorial from: primary processes (mechanical / traumatic injury to brain tissue, Contusions, diffuse axonal shearing injury and secondary delayed damage (the main cause of the poor prognosis in at least 40% of patients) consisting of hypoxic-ischemic damage of neurons and glial cells, contusions, intracranial bleeding, brain edema and etc.
Primäre Verletzungsformen entstehen im Augenblick der Gewalteinwirkung, sind irreversibel und Ausgangspunkt für sekundäre Verletzungsfolgen. Sekundäre Ver letzungsfolgen lassen sich möglicherweise durch gezielte Therapie verringern und sind so bei rechtzeitigem und adäquatem Therapiebeginn reversibel. (In Bullock; Schweizerische Medizinische Wochenschrift 123 : 449-458 (1993).Primary forms of injury arise at the moment of violence irreversible and the starting point for secondary injuries. Secondary ver consequences of consequences can possibly be reduced by targeted therapy and are reversible if the therapy is started early and adequately. (In Bullock; Swiss Medical Weekly Journal 123: 449-458 (1993).
Es ist bekannt, daß der 5-HT1A-Rezeptoragonist 8-OH-DTAT die neuronale Dege neration/Zelltod nach cerebraler Ischämie reduzieren kann (EP 345 948).It is known that the 5-HT 1A receptor agonist 8-OH-DTAT can reduce the neuronal degeneration / cell death after cerebral ischemia (EP 345 948).
Außerdem sind substituierte Aminomethyl-chromane bereits aus EP 325 613 bekannt. Es wird beschrieben, daß diese Verbindungen eine hohe Affinität zu cere bralen 5-Hydroxy-triptamin-Rezeptoren vom 5-HT1A-Typ haben und deshalb zur Behandlung von Erkrankungen des zentralen Nervensystems geeignet sind.In addition, substituted aminomethyl chromanes are already known from EP 325 613. It is described that these compounds have a high affinity for cerebral 5-hydroxy-triptamine receptors of the 5-HT 1A type and are therefore suitable for the treatment of diseases of the central nervous system.
Es wurde nun gefunden, daß substituierte Aminomethyl-chromane der allgemeinen Formel (I)It has now been found that substituted aminomethyl-chromanes of the general Formula (I)
worin
R₁ für Wasserstoff, Hydroxy, Methoxy oder die Carbamoyl-Gruppe steht
sowie deren Salze und Isomeren
in Modellen des Schädel-Hirn-Traumas neuroprotektive Wirkung aufweisen.wherein
R₁ represents hydrogen, hydroxy, methoxy or the carbamoyl group
and their salts and isomers
have neuroprotective effects in models of traumatic brain injury.
Diese Wirkstoffe reduzieren die neuronale Degeneration und die damit verbunde nen Funktionsausfalle des Gehirnes nach Schädel-Hirn-Trauma.These agents reduce neuronal degeneration and the associated functional disorders of the brain after traumatic brain injury.
Bevorzugt eignen sich Verbindungen der allgemeinen Formel (I)
in welcher
R₁ für Wasserstoff oder Methoxy stehen,
deren Salze sowie deren Isomere
zur Behandlung von Schädel-Hirn-Trauma.Compounds of the general formula (I) are preferably suitable
in which
R₁ represents hydrogen or methoxy,
their salts and their isomers
for the treatment of traumatic brain injury.
Besonders bevorzugt werden Verbindungen der allgemeinen Formel (I)
in welcher
R₁ für Wasserstoff steht,
dessen Salz sowie dessen Isomere verwendet.Compounds of the general formula (I) are particularly preferred
in which
R₁ represents hydrogen,
its salt and its isomers used.
Ganz besonders bevorzugt ist das (-)-Enantiomere der Verbindung der Formel (I),
in welcher
R¹ für Wasserstoff steht
und dessen Salze.The (-) - enantiomer of the compound of the formula (I) in which
R1 represents hydrogen
and its salts.
Die Verbindungen der Formel (I) bewirken bei einer nach Schädel-Hirn-Trauma erfolgenden und (therapeutischen) Behandlung eine deutliche Aufhebung des Ab sterbens von Neuronen und Gliazellen im Hirngewebe.The compounds of formula (I) cause post-traumatic brain injury subsequent and (therapeutic) treatment a clear abolition of the Ab dying of neurons and glial cells in the brain tissue.
Die Wirkungsweise der Verbindungen der Formel (I) zur nachfolgenden Be handlung von Schädel-Hirn-Trauma läßt sich anhand der Methode des akuten subduralen Hämatom-Modells (SDH-Modell der Ratte als Schädel-Hirn-Trauma- Modell (SHT-Modell) und der Methode der fokalen cerebralen Ischämie bei der Ratte als cerebralem Ischämiemodell (middle Cerebral artery occlusion; MCA-O) nachweisen [Miller et al.; Neurosurgery 27 (3), 433-439 (1990) und Bederson et al.; Stroke 17 (3), 472-476 (1986)].The mode of action of the compounds of the formula (I) for the subsequent loading Action of traumatic brain injury can be done using the acute method subdural hematoma model (SDH model of the rat as a traumatic brain injury Model (SHT model) and the method of focal cerebral ischemia in the Rat as a cerebral ischemia model (middle cerebral artery occlusion; MCA-O) detect [Miller et al .; Neurosurgery 27 (3), 433-439 (1990) and Bederson et al .; Stroke 17 (3), 472-476 (1986)].
Die Behandlung von Schädel-Hirn-Trauma mit den Wirkstoffen der allgemeinen Formel (I) stellt ein neues Behandlungsprinzip dar.Treatment of traumatic brain injury with the active ingredients of the general Formula (I) represents a new treatment principle.
Die Wirkstoffe können in bekannter Art und Weise in die üblichen Formulie rungen überführt werden. The active substances can be introduced into the usual form in a known manner are transferred.
Unter Isofluran Anästhesie wird die Kopfhaut entlang der Saggitalnaht geöffnet. Über dem motorischen Cortex wird der Schädelknochen punktförmig durchbohrt, die darunterliegende Hirnhaut eröffnet und ein vorangefertigter spezieller Plastik katheter eingeführt. Dieser Katheter wird mit Gewebekleber an der Schädeldecke befestigt. Aus der Schwanzvene entnommenes Eigenblut (200 µl) wird über eine Kanüle durch den fixierten Plastikkatheter unter die Hirnhaut injiziert. Nach Ver schluß des Katheters werden die Tiere in ihren Heimkäfig zurückgesetzt.The scalp is opened along the saggital suture under isoflurane anesthesia. The skull is punctured through the motor cortex, the underlying meninges open and a pre-made special plastic catheter inserted. This catheter comes with tissue adhesive on the top of the skull attached. Own blood (200 µl) taken from the tail vein is collected using a Cannula injected under the meninges through the fixed plastic catheter. According to Ver At the end of the catheter, the animals are returned to their home cage.
Im Verlauf der folgenden Stunden entwickelt sind unterhalb des Hämatoms ein Infarkt, dessen Ausdehnung histologisch quantifiziert wird.Over the course of the next few hours are developed below the hematoma Infarction, the extent of which is histologically quantified.
Nach 7 Tagen Überlebenszeit werden die Tiere dekapitiert, das Gehirn entnommen und bei -30°C in gekühltem 2-Methylbutan eingefroren. Mit Hilfe eines Kryostat mikrotoms werden 20 µm dicke Schnitte in 500 µm Abstand im Infarktbereich hergestellt. Nach der Cresylechtviolett-Färbung der fixierten Gehirnschnitte ist das Infarktgebiet vom nicht betroffenen Gewebe deutlich durch seine blasse Farbe zu unterscheiden. Das Volumen des geschädigten cortikalen (subcortikalen) Hirnge webes (Infarkt) wird durch planimetrische Messung der Infarktoberfläche/Schnitt unter Berücksichtigung von Schnittzahl- und Abstand mit Hilfe eines compute risierten Bildanalysesystems berechnet.After 7 days of survival, the animals are decapitated and the brain removed and frozen at -30 ° C in chilled 2-methylbutane. With the help of a cryostat Microtoms are 20 µm thick sections at a distance of 500 µm in the infarct area produced. This is after the cresyle light violet staining of the fixed brain sections Infarct area of the unaffected tissue clearly due to its pale color differentiate. The volume of the damaged cortical (subcortical) brain webes (infarction) is determined by planimetric measurement of the infarct surface / section taking into account the number of cuts and the distance using a compute rized image analysis system.
Die Tiere wurden im allgemeinen direkt nach der chirugischen Induktion des Hämatoms oder zu verschiedenen Zeitpunkten danach behandelt. Der Wirkstoff wurde in Citrat-Mannit-Puffer/physiologischer Kochsalzlösung aufgenommen und in einem Volumen von 2 ml/kg als i.v. Bolus oder 4 ml/kg Stunde als i.v. Infusion über 4 Stunden infundiert. The animals were generally treated directly after the surgical induction of the Hematoma or treated at different times afterwards. The active substance was taken up in citrate-mannitol buffer / physiological saline and in a volume of 2 ml / kg as i.v. Bolus or 4 ml / kg hour as IV infusion infused over 4 hours.
Die Dosierung lag zwischen 0,001 und 0,100 mg/kg Körpergewicht.The dosage was between 0.001 and 0.100 mg / kg body weight.
In einer weiteren Serie wurde der Wirkstoff 3 Stunden nach dem chirugischen Eingriff als 4 stündige Infusion verabreicht.In another series, the active ingredient was administered 3 hours after the surgical Intervention administered as a 4 hour infusion.
Claims (4)
R₁ für Wasserstoff Hydroxy, Methoxy oder Carbamoyl steht
sowie deren Salze und Isomere
zur Behandlung von Schädel-Hirn-Trauma.1. Use of the substituted aminomethyl-chromanes of the general formula (I) in which
R₁ represents hydrogen, hydroxy, methoxy or carbamoyl
and their salts and isomers
for the treatment of traumatic brain injury.
worin
R₁ für Wasserstoff oder Methoxy steht,
deren Salze und deren Isomere
zur Behandlung von Schädel-Hirn-Trauma.2. Use of substituted aminomethyl-chromanes of the formula according to claim 1
wherein
R₁ represents hydrogen or methoxy,
their salts and their isomers
for the treatment of traumatic brain injury.
worin
R₁ für Wasserstoff steht,
deren Salze sowie deren Isomere
zur Behandlung von Schädel-Hirn-Trauma.3. Use of substituted aminomethyl-chromanes of the formula according to claim 1
wherein
R₁ represents hydrogen,
their salts and their isomers
for the treatment of traumatic brain injury.
R¹ für Wasserstoff steht,
und dessen Salze
zur Behandlung von Schädel-Hirn-Trauma.4. Use of the (-) - enantiomer of the substituted aminomethyl chroman of the formula according to claim 1, in which
R¹ represents hydrogen,
and its salts
for the treatment of traumatic brain injury.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995143476 DE19543476A1 (en) | 1995-11-22 | 1995-11-22 | Treatment of skull-brain trauma with aminomethyl-chroman compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995143476 DE19543476A1 (en) | 1995-11-22 | 1995-11-22 | Treatment of skull-brain trauma with aminomethyl-chroman compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19543476A1 true DE19543476A1 (en) | 1997-05-28 |
Family
ID=7778079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1995143476 Withdrawn DE19543476A1 (en) | 1995-11-22 | 1995-11-22 | Treatment of skull-brain trauma with aminomethyl-chroman compounds |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE19543476A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002041881A3 (en) * | 2000-11-22 | 2002-10-10 | Bayer Ag | Repinotan kit |
| WO2003029250A1 (en) * | 2001-10-01 | 2003-04-10 | Bayer Healthcare Ag | Benzisothiazolyl-substituted aminomethyl chromanes for treating diseases of the central nervous system |
-
1995
- 1995-11-22 DE DE1995143476 patent/DE19543476A1/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002041881A3 (en) * | 2000-11-22 | 2002-10-10 | Bayer Ag | Repinotan kit |
| WO2003029250A1 (en) * | 2001-10-01 | 2003-04-10 | Bayer Healthcare Ag | Benzisothiazolyl-substituted aminomethyl chromanes for treating diseases of the central nervous system |
| US6919360B2 (en) | 2001-10-01 | 2005-07-19 | Bayer Healthcare Ag | Benzisothiazolyl-substituted aminomethyl chromanes for treating diseases of the central nervous system |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8127 | New person/name/address of the applicant |
Owner name: BAYER AG, 51373 LEVERKUSEN, DE |
|
| 8110 | Request for examination paragraph 44 | ||
| 8130 | Withdrawal |