WO2002066027A1 - Agent for inhibiting tumour cells - Google Patents
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- WO2002066027A1 WO2002066027A1 PCT/DE2002/000653 DE0200653W WO02066027A1 WO 2002066027 A1 WO2002066027 A1 WO 2002066027A1 DE 0200653 W DE0200653 W DE 0200653W WO 02066027 A1 WO02066027 A1 WO 02066027A1
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- formoterol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- 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
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- 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 invention relates to agents which are able to inhibit the growth of tumor cells and to block tumor angiogenesis and metastasis.
- Formoterol and its derivatives have proven to be effective agents.
- the invention is based on the effect of formoterol and its derivatives as inhibitors of the COP9 signalosome-associated kinases.
- the invention thus relates to the use of formoterol and its derivatives for the production of agents for inhibiting cancer cells.
- ILlbeta An increase in ILlbeta is described in the lungs at high doses of formoterol (Zetterlund et al.); increased c-fos gene expression was described in the bone, which is mediated by the beta2-adrenergic effect and cAMP increase (cAMP - cyclic adenosine-3 ', 5'-monophosphate). Protein kinase inhibition, especially for the COP9 signalosome-associated kinases, has not been described according to the current state of knowledge.
- the signalosome is a protein complex that plays a central role in the signal transmission of eukaryotic cells (Seeger et al., 1998; Schwechheimer and Deng, 2000).
- the name COP9 signalosome (CSN) and a uniform nomenclature of its subunits (CSN1-CSN8) were recently introduced (Deng et al., 2000). All previous names of the particle such as Jabl signalosome or COP9 complex are summarized under COP9 signalosome.
- the complex is referred to here as the signalosome.
- the signalosome isolated from human cells is associated with kinases that phosphorylate components of cellular signaling pathways (Seeger et al., 1998).
- the signalosome-mediated phosphorylation of the tumor suppressor p53 leads to the degradation of the transcription factor (Bech-Otschir et al., 2001) and the phosphorylation of c-Jun to stabilize / activate c-Jun (Naumann et al., 1999).
- the invention has for its object to show other ways to inhibit cancer cells.
- the task was solved by scientifically analyzing the effects of formoterol and its derivatives and examining their suitability for previously unknown purposes.
- the use of formoterol and / or its derivatives according to the invention has made it possible to provide agents which lead to inhibition of tumor cells.
- the agents according to the invention for inhibiting tumor growth and blocking tumor angiogenesis and metastasis contain formoterol, its salts and / or its derivatives as effective components.
- the signalosome-associated kinases are inhibited by formoterol, as a result of which a sharp increase in the tumor suppressor p53 occurs, which leads the cancer cells into apoptosis.
- the cyclin-dependent kinase inhibitor p21 is induced by the increase in p53.
- VEGF vascular endothelial growth factor
- N-substituted, alkyl-O-substituted and aryl-O-substituted compounds are used as derivatives of formoterol, such as N-alkyl, -aryl, -acyl-substituted on the secondary amine radical, O-alkyl, -aryl, -acyl-substituted compounds on the secondary alcohol radical or O-alkyl, aryl, acyl-substituted on the aryl-O radical use and derivatives of the acid amide radical.
- Derivatives of formoterol also include the N salts in the form of their physiologically tolerable salts, which can be prepared by neutralization with suitable inorganic or organic acids, e.g.
- the essence of the invention lies in a combination of known elements - formoterol and its derivatives - and new solutions - their first use for the inhibition of tumor cells - which mutually influence one another and result in an advantage and the desired success in their new overall effect, which lies in the fact that new agents with an inhibitory effect on cancer cells are made available.
- An essential feature of the invention is that the agents according to the invention inhibit the kinases associated with the signalosome.
- formoterol or its derivatives and / or structural analogs lies in the inhibition of the signalosome-associated kinases and in that resulting triggering of apoptosis in tumor cells and in the inhibition of tumor angiogenesis and metastasis.
- a therapy similar to that in example 1 in combination with chemotherapy, radiation therapy, thermotherapy can be considered for almost all types of cancer (skin, uterine cancer), cancer types with the wild type p53 being particularly sensitive.
- cancer types with mutated p53 the activities of the mutated p53 must be considered for therapy.
- Direct drug application is possible and sensible.
- implants and dosage ampoules is recommended. The dosage must be adjusted individually.
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Mittel zur Hemmung von Tumorzellen Tumor cell inhibitor
Beschreibungdescription
Die Erfindung betrifft Mittel, die in der Lage sind, das Wachstum von Tumorzellen zu hemmen sowie Tumorangiogenese und Metastasierung zu blockieren. Als wirksame Mittel haben sich Formoterol und seine Derivate erwiesen. Die Erfindung beruht auf der Wirkung von Formoterol und seiner Derivate als Hemmstoffe der COP9 Signalosom-assoziierten Kinasen. Damit bezieht sich die Erfindung auf die Verwendung von Formoterol und seiner Derivate zur Herstellung von Mitteln zur Hemmung von Krebszellen.The invention relates to agents which are able to inhibit the growth of tumor cells and to block tumor angiogenesis and metastasis. Formoterol and its derivatives have proven to be effective agents. The invention is based on the effect of formoterol and its derivatives as inhibitors of the COP9 signalosome-associated kinases. The invention thus relates to the use of formoterol and its derivatives for the production of agents for inhibiting cancer cells.
Bisher wird Formoterol - (+/- )-2'-Hydroxy-5'-(l-hydroxy-5-(4-methoxyphenyl)-4-methyl-3- azapentyl)-formanilid - auf Grund der Hemmung des beta2-Rezeptors als Asthma- Therapeutikum und in der Behandlung entzündlicher, obstruktiver Erkrankungen der Atemwege eingesetzt (WO 93/11773). Die molekularen Unterschiede, die für die verschiedenen Wirkungen der beta-Rezeptoren verantwortlich sind, kennt man ebenso (Isogaya et al.) wie die dreidimensionale Struktur von Formoterol und seiner Salze (Kurihara et al. - Literaturverzeichnis am Ende der Beispiele). Die systemischen Wirkungen von Formoterol sind vergleichsweise gering (Guhan et al.), und umfangreiche Studien dokumentieren eine ausgezeichnete Verträglichkeit bei Kindern (Bisgaard), älteren Patienten (Thomson et al.) sowie bei extrem hohen Dosierungen (Totterman et al.). Neben der Charakterisierung zahlreicher beta-agonistischer Derivate (Damasceno et al.) spielt die Auswahl des günstigsten Isomers (Waldeck) eine Rolle bei gewebsspezifischer Wirkung und Verstoffwechselung (Zhang et al., ). Formoterol: (http: //wisda.pharmazie.uni- marburg.de/dossier.php?s_inn=Formoterol), Summenformel Cι9H 4N2O4. Neben der beta-adrenergen Hauptwirkung werden gewisse entzündungshemmende Wirkungen beschrieben (Subramantan), die überwiegend auf der Hemmung der Histamin- und Bradykinin-Wirkung beruhen (Tokuyama). Für einzelne Gewebe gibt es Beschreibungen darüber, welche Gene unter Formoterol-Einfluss verstärkt exprimiert werden. Dabei werden die Cytokine-bedingte Hemmung der Adhäsionsmoleküle ICAM und VCAM in der Lunge genannt (Spoelstra et al.), was der hier beschriebenen Wirkung zusätzlich zu Gute käme; der ebenfalls Cytokine-abhängige Einfluss auf den Tumor-Nekrose-Faktor bzw. IL6 muss innerhalb der Nieren nochmals gewebsspezifisch unterschieden werden (Nakamura et al.). In der Lunge wird bei hohen Dosen von Formoterol eine ILlbeta-Erhöhung beschrieben (Zetterlund et al.); im Knochen wurde eine erhöhte c-fos Genexpression beschrieben, die über die beta2-adrenerge Wirkung und cAMP-Erhöhung (cAMP - Cyclisches Adenosin-3',5'- monophosphat) vermittelt wird. Eine Protein-Kinase-Hemmung, insbesondere für die COP9 Signalosom-assoziierten Kinasen, ist nach derzeitigem Kenntnisstand nicht beschrieben worden.So far, formoterol - (+/-) -2'-hydroxy-5 '- (l-hydroxy-5- (4-methoxyphenyl) -4-methyl-3-azapentyl) formanilide - due to the inhibition of the beta2 receptor used as an asthma therapeutic and in the treatment of inflammatory, obstructive diseases of the respiratory tract (WO 93/11773). The molecular differences that are responsible for the different effects of the beta receptors are known (Isogaya et al.) As is the three-dimensional structure of formoterol and its salts (Kurihara et al. - bibliography at the end of the examples). The systemic effects of formoterol are comparatively low (Guhan et al.), And extensive studies document excellent tolerability in children (Bisgaard), older patients (Thomson et al.) And at extremely high doses (Totterman et al.). In addition to the characterization of numerous beta-agonistic derivatives (Damasceno et al.), The selection of the cheapest isomer (Waldeck) plays a role in tissue-specific effects and metabolism (Zhang et al.,). Formoterol: (http: //wisda.pharmazie.uni- marburg.de/dossier.php?s_inn=Formoterol), empirical formula Cι 9 H 4 N 2 O 4. In addition to the main beta-adrenergic effect, certain anti-inflammatory effects are described (Subramantan) , which are mainly based on the inhibition of histamine and bradykinin effects (Tokuyama). For individual tissues, there are descriptions of which genes are increasingly expressed under the influence of formoterol. The cytokine-related inhibition of the adhesion molecules ICAM and VCAM in the lungs are called (Spoelstra et al.), Which would additionally benefit the effect described here; the cytokine-dependent influence on the tumor necrosis factor or IL6 must also Tissue-specific distinctions can also be made within the kidneys (Nakamura et al.). An increase in ILlbeta is described in the lungs at high doses of formoterol (Zetterlund et al.); increased c-fos gene expression was described in the bone, which is mediated by the beta2-adrenergic effect and cAMP increase (cAMP - cyclic adenosine-3 ', 5'-monophosphate). Protein kinase inhibition, especially for the COP9 signalosome-associated kinases, has not been described according to the current state of knowledge.
Das Signalosom ist ein Proteinkomplex, der eine zentrale Rolle in der Signalübertragung eukaryotischer Zellen spielt (Seeger et al., 1998; Schwechheimer and Deng, 2000). Kürzlich wurde der Name COP9 Signalosom (CSN) und eine einheitliche Nomenklatur seiner Untereinheiten (CSN1-CSN8) eingeführt (Deng et al., 2000). Alle bisherigen Bezeichnungen des Partikels wie Jabl -Signalosom oder COP9 Komplex sind unter COP9 Signalosom zusammengefasst. Der Einfachheit halber wird der Komplex hier mit Signalosom bezeichnet. Das aus humanen Zellen isolierte Signalosom ist mit Kinasen assoziiert, die Komponenten zellulärer Signalwege phosphorylieren (Seeger et al., 1998). Die Signalosom-vermittelte Phosphorylierung des Tumorsuppressors p53 führt zum Abbau des Transkriptionsfaktors (Bech-Otschir et al., 2001) und die Phosphorylierung von c-Jun zur Stabilisierung/ Aktivierung von c-Jun (Naumann et al., 1999).The signalosome is a protein complex that plays a central role in the signal transmission of eukaryotic cells (Seeger et al., 1998; Schwechheimer and Deng, 2000). The name COP9 signalosome (CSN) and a uniform nomenclature of its subunits (CSN1-CSN8) were recently introduced (Deng et al., 2000). All previous names of the particle such as Jabl signalosome or COP9 complex are summarized under COP9 signalosome. For the sake of simplicity, the complex is referred to here as the signalosome. The signalosome isolated from human cells is associated with kinases that phosphorylate components of cellular signaling pathways (Seeger et al., 1998). The signalosome-mediated phosphorylation of the tumor suppressor p53 leads to the degradation of the transcription factor (Bech-Otschir et al., 2001) and the phosphorylation of c-Jun to stabilize / activate c-Jun (Naumann et al., 1999).
Der Erfindung liegt die Aufgabe zugrunde, weitere Möglichkeiten zur Hemmung von Krebszellen aufzuzeigen. Die Aufgabe wurde dadurch gelöst, dass Formoterol und seine Derivate in ihrer Wirkungsweise wissenschaftlich analysiert und auf ihre Eignung zu bisher nicht bekannten Zwecken untersucht wurden. So ist es durch die erfindungsgemäße Verwendung von Formoterol und/oder seiner Derivate gelungen, Mittel zur Verfügung zu stellen, die zu einer Hemmung von Tumorzellen führen.The invention has for its object to show other ways to inhibit cancer cells. The task was solved by scientifically analyzing the effects of formoterol and its derivatives and examining their suitability for previously unknown purposes. The use of formoterol and / or its derivatives according to the invention has made it possible to provide agents which lead to inhibition of tumor cells.
Die erfindungsgemäßen Mittel zur Hemmung des Tumorwachstums und der Blockierung der Tumorangiogenese und Metastasierung enthalten als wirksame Komponenten Formoterol, seine Salze und/oder seine Derivate. Erfindungsgemäß werden durch Formoterol die Signalosom-assoziierten Kinasen gehemmt, wodurch ein starker Anstieg des Tumorsuppressors p53 auftritt, der die Krebszellen in die Apoptose führt. Gleichzeitig wird der Cyklin-abhängige Kinase-Inhibitor p21 durch den p53- Anstieg induziert. Durch die Hemmung der Signalosom-assoziierten Kinasen mit Formoterol sinkt das endogene c-Jun der Krebszellen ab. Dadurch kommt es zu einer verminderten Produktion von VEGF (vascular endothelial growth factor), da die VEGF-Produktion in Tumorzellen hauptsächlich durch den Signalosom-abhängigen c-Jun-Signalweg reguliert wird (Pollmann et al., 2001). Dadurch kann es zu einer Hemmung der Angiogenese und somit des Tumorwachstums und der Metastasierung kommen. Die hemmende Wirkung von Formoterol und/oder seiner Derivate wird erfindungsgemäß folgendermaßen erreicht:The agents according to the invention for inhibiting tumor growth and blocking tumor angiogenesis and metastasis contain formoterol, its salts and / or its derivatives as effective components. According to the invention, the signalosome-associated kinases are inhibited by formoterol, as a result of which a sharp increase in the tumor suppressor p53 occurs, which leads the cancer cells into apoptosis. At the same time, the cyclin-dependent kinase inhibitor p21 is induced by the increase in p53. By inhibiting the signalosome-associated kinases with formoterol, the endogenous c-Jun of the cancer cells drops. This leads to a reduced Production of VEGF (vascular endothelial growth factor), since VEGF production in tumor cells is mainly regulated by the signalosome-dependent c-Jun signaling pathway (Pollmann et al., 2001). This can lead to an inhibition of angiogenesis and thus tumor growth and metastasis. The inhibitory effect of formoterol and / or its derivatives is achieved according to the invention as follows:
1. Hemmung der Signalosom-assoziierten Kinasen und dadurch der Phosphorylierung von p53 -> Anstieg des Tumorsuppressors p53 in Tumorzellen -> Apoptose1. Inhibition of the signalosome-associated kinases and thereby the phosphorylation of p53 -> increase in the tumor suppressor p53 in tumor cells -> apoptosis
2. Hemmung der Signalosom-assoziierten Kinasen und dadurch der Phosphorylierung von p53 -> p53 -abhängige Induktion von p21 -> Arrest im Zellzyklus2. Inhibition of the signalosome-associated kinases and thereby the phosphorylation of p53 -> p53 -dependent induction of p21 -> arrest in the cell cycle
3. Hemmung der Signalosom-assoziierten Kinasen und dadurch der Phosphorylierung von c- Jun -> Abfall des Transkriptionsfaktors c-Jun in Tumorzellen -> verminderte VEGF- Produktion und dadurch Unterdrückung der Tumorangiogenese.3. Inhibition of the signalosome-associated kinases and thus the phosphorylation of c-Jun -> decrease in the transcription factor c-Jun in tumor cells -> reduced VEGF production and thereby suppression of tumor angiogenesis.
Als Derivate des Formoterols finden N-substituierte, Alkyl-O-substituierte und Aryl-O- substituierte Verbindungen Verwendung, wie N-Alkyl, -Aryl, -Acyl-substituierte am sekundären Aminrest, O-Alkyl, -Aryl, -Acyl-substituierte am sekundären Alkoholrest oder O- Alkyl, -Aryl, -Acyl-substituierte am Aryl-O-Rest Verwendung sowie Derivate des Säureamidrestes. Zu den Derivaten des Formoterols gehören auch die N-Salze in Form ihrer physiologisch verträglichen Salze, die sich durch Neutralisation mit geeigneten anorganischen oder organischen Säuren herstellen lassen, z.B. mit Salzsäure, Schwefel- oder Phosphorsäure, Ameisen-, Essig-, Propion-, Glykol-, Milch-, Brenztrauben-, Malein-, Furmar-, Anthranyl-, Naphthalinsulfon-, Sulfanyl- oder Zimtsäure. Das Wesen der Erfindung liegt in einer Kombination bekannter Elemente - Formoterol und seine Derivate - und neuer Lösungswege - ihrer erstmaligen Verwendung zur Hemmung von Tumorzellen - die sich gegenseitig beeinflussen und in ihrer neuen Gesamtwirkung einen Vorteil und den erstrebten Erfolg ergeben, der darin liegt, dass neue Mittel mit einem hemmenden Effekt auf Krebszellen zur Verfugung gestellt werden. Ein wesentliches Merkmal der Erfindung besteht darin, dass mit den erfindungsgemäßen Mitteln eine Hemmung der mit dem Signalosom assoziierten Kinasen erreicht wird.N-substituted, alkyl-O-substituted and aryl-O-substituted compounds are used as derivatives of formoterol, such as N-alkyl, -aryl, -acyl-substituted on the secondary amine radical, O-alkyl, -aryl, -acyl-substituted compounds on the secondary alcohol radical or O-alkyl, aryl, acyl-substituted on the aryl-O radical use and derivatives of the acid amide radical. Derivatives of formoterol also include the N salts in the form of their physiologically tolerable salts, which can be prepared by neutralization with suitable inorganic or organic acids, e.g. with hydrochloric acid, sulfuric or phosphoric acid, formic, vinegar, propionic, glycolic, lactic, pyruvic, maleic, furmar, anthranyl, naphthalenesulfonic, sulfanyl or cinnamic acid. The essence of the invention lies in a combination of known elements - formoterol and its derivatives - and new solutions - their first use for the inhibition of tumor cells - which mutually influence one another and result in an advantage and the desired success in their new overall effect, which lies in the fact that new agents with an inhibitory effect on cancer cells are made available. An essential feature of the invention is that the agents according to the invention inhibit the kinases associated with the signalosome.
Die erfindungsgemäße Verwendung von Formoterol oder seiner Derivate und/oder Strukturanaloga liegt in der Hemmung der Signalosom-assoziierten Kinasen und in der daraus resultierenden Auslösung von Apoptose in Tumorzellen sowie in der Hemmung der Tumorangiogenese und Metastasierung.The use according to the invention of formoterol or its derivatives and / or structural analogs lies in the inhibition of the signalosome-associated kinases and in that resulting triggering of apoptosis in tumor cells and in the inhibition of tumor angiogenesis and metastasis.
Die Erfindung soll anhand von Ausführungsbeispielen näher erläutert werden, ohne auf diese Beispiele beschränkt zu sein.The invention is to be explained in more detail on the basis of exemplary embodiments, without being restricted to these examples.
Ausführungsbeispieleembodiments
Beispiel 1 :Example 1 :
Für eine Therapie von Lungenkrebs wird eine Applikation entsprechend der bereits im Einsatz befindlichen Inhalationshilfen (z.B. Turbohaler [AstraZeneca]) vorgeschlagen. Dabei wird der Wirkstoff mittels Mikropartikel in den Bronchien verteilt und - Dank seiner Membrangängigkeit - von den Zellen direkt aufgenommen. Eine hohe Dosierung ist empfehlenswert. Nach vorliegenden Studien ist eine Verzehnfachung der üblichen Dosierung bei Asthma (z.B. 120 mikrog Formoterol) gut verträglich (Tottermann et al., 1998).For a therapy of lung cancer, an application corresponding to the inhalation aids already in use (e.g. Turbuhaler [AstraZeneca]) is proposed. The active ingredient is distributed in the bronchi by means of microparticles and - thanks to its ability to pass through membranes - is directly absorbed by the cells. A high dosage is recommended. According to the available studies, a tenfold increase in the usual dosage for asthma (e.g. 120 mikrog formoterol) is well tolerated (Tottermann et al., 1998).
Beispiel 2:Example 2:
Eine ähnliche Therapie wie in Beispiel 1 in Kombination mit Chemo-, Strahlen-, Thermotherapie kommt für fast alle Krebstypen in Betracht (Haut, Gebärmutterkrebs), wobei Krebstypen mit dem Wildtyp p53 besonders empfindlich sind. Bei Krebstypen mit mutiertem p53 müssen die Aktivitäten des mutierten p53 für eine Therapie berücksichtigt werden. Eine direkte Wirkstoffapplikation ist möglich und sinnvoll. Für den gastrointestinalen Einsatz bietet sich die Verwendung von Implantaten und Dosierungsampullen an. Die Dosierung muss individuell angepasst werden.A therapy similar to that in example 1 in combination with chemotherapy, radiation therapy, thermotherapy can be considered for almost all types of cancer (skin, uterine cancer), cancer types with the wild type p53 being particularly sensitive. In cancer types with mutated p53, the activities of the mutated p53 must be considered for therapy. Direct drug application is possible and sensible. For gastrointestinal use, the use of implants and dosage ampoules is recommended. The dosage must be adjusted individually.
Bei hohen Dosen ist eine klinische Überwachung der Herz- Kreislauffunktionen erforderlich, da wegen der beta2-mimetischen Wirkung mit Tachykardien zu rechnen ist. LiteraturverzeichnisAt high doses, clinical monitoring of the cardiovascular functions is necessary because tachycardia can be expected due to the beta2-mimetic effect. bibliography
Bech-Otschir et al.; EMBO J. 20: 1630-1639, 2001.Bech-Otschir et al .; EMBO J. 20: 1630-1639, 2001.
Bisgaard; Pediatr. Pulmonol 29: 221-234. Damasceno et al.; J. Mass Spectrom. 35: 1285-1294.Bisgaard; Pediatr. Pulmonol 29: 221-234. Damasceno et al .; J. Mass Spectrom. 35: 1285-1294.
Deng et al.; Trends Genet. 16: 202-203, 2000.Deng et al .; Trends Genet. 16: 202-203, 2000.
Guhan. et al.; Thorax 55: 650-656.Guhan. et al .; Thorax 55: 650-656.
Kellenberger et al.; Bone 22: 471-478.Kellenberger et al .; Bone 22: 471-478.
Kurihara et al.; Acta Cryst.C 53: 1887-1889. Nakamura et al.; Nephrol. Dial. Transpl. 15: 1928-1934.Kurihara et al .; Acta Cryst. C 53: 1887-1889. Nakamura et al .; Nephrol. Dial. Transpl. 15: 1928-1934.
Nakamure et al.; Cytokine 11 : 759-765.Nakamure et al .; Cytokine 11: 759-765.
Naumann et al.; J. Biol. Chem. 274, 35297-35300, 1999.Naumann et al .; J. Biol. Chem. 274, 35297-35300, 1999.
Pollmann et al.; Canc. Res. 61, 8416-8421, 2001.Pollmann et al .; Canc. Res. 61, 8416-8421, 2001.
Schwechheimer and Deng; Semin. Cell Dev. Biol. 11: 495-503, 2000. Seeger et al.; FASEB J 12: 469-478, 1998.Schwechheimer and Deng; Semin. Cell Dev. Biol. 11: 495-503, 2000. Seeger et al .; FASEB J 12: 469-478, 1998.
Spoelstra et al.; Eur. Resp. J. 15: 68-74.Spoelstra et al .; Eur. Resp. J. 15: 68-74.
Subramantan; Arzneimittelforsch. 38: 502-505.Subramantan; Arzneimittelforsch. 38: 502-505.
Thomson et al.; Respir. Med. 92: 562-567.Thomson et al .; Respir. Med. 92: 562-567.
Tokuyama; Eur.J. Pharm. 193: 35-39. Totterman et al.; Eur. Respir. J. 12: 573-579, 1998.Tokuyama; Eur Pharm. 193: 35-39. Totterman et al .; Eur. Respir. J. 12: 573-579, 1998.
Waldeck; Chirality 5: 350-355.Waldeck; Chirality 5: 350-355.
Zhang et al.; Br. J. Clin. Pharm. 49: 152-157.Zhang et al .; Br. J. Clin. Pharm. 49: 152-157.
Zetterlund et al.; J.Asthma 35: 565-573. Zetterlund et al .; J. Asthma 35: 565-573.
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| Application Number | Priority Date | Filing Date | Title |
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| DE10290563T DE10290563D2 (en) | 2001-02-22 | 2002-02-21 | Tumor cell inhibitor |
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| DE10109883.9 | 2001-02-22 | ||
| DE10109883 | 2001-02-22 | ||
| DE10117266 | 2001-03-30 | ||
| DE10117266.4 | 2001-03-30 |
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|---|---|
| AU (1) | AU2002252950A1 (en) |
| DE (4) | DE10207882A1 (en) |
| WO (2) | WO2002066021A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2245612A1 (en) * | 2004-06-29 | 2006-01-01 | Universidad De Barcelona | Use of formoterol in the prophylactic and/or therapeutic treatment of muscle wasting and/or cachectic syndrome which are associated with catabolic conditions of certain diseases, such as cancer, aids, infections, diabetes and others |
| WO2024160057A1 (en) * | 2023-02-02 | 2024-08-08 | 上海市第十人民医院 | USE OF LONG-ACTING β2AR AGONIST IN PREPARATION OF DRUGS FOR TREATING CANCERS |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10147088A1 (en) * | 2001-09-25 | 2003-04-17 | Medinnova Ges Med Innovationen | Use of active substances for the prophylaxis and / or therapy of diseases which are associated with cell growth disorders and test system for finding such active substances |
| ITFI20050031A1 (en) * | 2005-02-21 | 2006-08-22 | Stefan Coccoloni | A PHARMACEUTICAL COMPOSITION TO PREVENT THE AGING AND THE RISING OF VASCULAR, NEOPLASTIC, CUTANEOUS AND PILIFEROUS DISEASES |
| GB0625270D0 (en) * | 2006-12-19 | 2007-01-31 | Univ Leicester | Angiogenesis |
| US9066974B1 (en) | 2010-11-13 | 2015-06-30 | Sirbal Ltd. | Molecular and herbal combinations for treating psoriasis |
| US9095606B1 (en) | 2010-11-13 | 2015-08-04 | Sirbal Ltd. | Molecular and herbal combinations for treating psoriasis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992005147A1 (en) * | 1990-09-26 | 1992-04-02 | Aktiebolaget Astra | New process for preparing formoterol and related compounds |
| US5135954A (en) * | 1991-05-24 | 1992-08-04 | The Regents Of The University Of California | Use of formoterol for treatment of tissue injury |
-
2002
- 2002-02-21 DE DE10207882A patent/DE10207882A1/en not_active Withdrawn
- 2002-02-21 WO PCT/DE2002/000652 patent/WO2002066021A2/en not_active Ceased
- 2002-02-21 WO PCT/DE2002/000653 patent/WO2002066027A1/en not_active Ceased
- 2002-02-21 AU AU2002252950A patent/AU2002252950A1/en not_active Abandoned
- 2002-02-21 DE DE10290563T patent/DE10290563D2/en not_active Expired - Fee Related
- 2002-02-21 DE DE10290562T patent/DE10290562D2/en not_active Expired - Fee Related
- 2002-02-21 DE DE10207881A patent/DE10207881A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992005147A1 (en) * | 1990-09-26 | 1992-04-02 | Aktiebolaget Astra | New process for preparing formoterol and related compounds |
| US5135954A (en) * | 1991-05-24 | 1992-08-04 | The Regents Of The University Of California | Use of formoterol for treatment of tissue injury |
Non-Patent Citations (1)
| Title |
|---|
| KELLENBERGER S. ET AL: "Formoterol and Isoproterenol induce C-FOS gene expression in osteoblast-like cells by activating beta2-adrenergic receptors.", BONE, vol. 22, no. 5, 1998, pages 471 - 478, XP001085125 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2245612A1 (en) * | 2004-06-29 | 2006-01-01 | Universidad De Barcelona | Use of formoterol in the prophylactic and/or therapeutic treatment of muscle wasting and/or cachectic syndrome which are associated with catabolic conditions of certain diseases, such as cancer, aids, infections, diabetes and others |
| WO2006003222A1 (en) * | 2004-06-29 | 2006-01-12 | Universidad De Barcelona | Use of formoterol in the prophylactic and/or therapeutic treatment of muscle wasting and/or cachectic syndrome which are associated with catabolic conditions of certain diseases, such as cancer, aids, infections, diabetes and others |
| ES2245612B1 (en) * | 2004-06-29 | 2007-08-16 | Universidad De Barcelona | NEW THERAPEUTIC USE OF FORMOTEROL. |
| WO2024160057A1 (en) * | 2023-02-02 | 2024-08-08 | 上海市第十人民医院 | USE OF LONG-ACTING β2AR AGONIST IN PREPARATION OF DRUGS FOR TREATING CANCERS |
Also Published As
| Publication number | Publication date |
|---|---|
| DE10207882A1 (en) | 2003-02-27 |
| DE10207881A1 (en) | 2003-02-13 |
| WO2002066021A3 (en) | 2002-10-31 |
| AU2002252950A1 (en) | 2002-09-04 |
| WO2002066021A2 (en) | 2002-08-29 |
| DE10290563D2 (en) | 2004-04-29 |
| DE10290562D2 (en) | 2004-04-29 |
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