DE102008031039A1 - Use of N-phenylquinazolin-4-amine derivatives as receptor tyrosine kinase inhibitor for accompanying treatment of organ transplantations - Google Patents

Use of N-phenylquinazolin-4-amine derivatives as receptor tyrosine kinase inhibitor for accompanying treatment of organ transplantations Download PDF

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DE102008031039A1
DE102008031039A1 DE102008031039A DE102008031039A DE102008031039A1 DE 102008031039 A1 DE102008031039 A1 DE 102008031039A1 DE 102008031039 A DE102008031039 A DE 102008031039A DE 102008031039 A DE102008031039 A DE 102008031039A DE 102008031039 A1 DE102008031039 A1 DE 102008031039A1
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phenylquinazolin
amine derivatives
kinase inhibitor
tyrosine kinase
receptor tyrosine
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Alexander Dömling
Carlos Jaime Camacho Ives
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Use of N-phenylquinazolin-4-amine derivatives for accompanying treatment of organ transplantations, is claimed. Use of N-phenylquinazolin-4-amine derivatives of formula (I) for accompanying treatment of organ transplantations, is claimed. X, R 1>-R 3>not defined. An independent claim is included for use of Tarceva(RTM: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine) (II) for the treatment of organ transplantation. [Image] ACTIVITY : Cytostatic; Immunosuppressive. MECHANISM OF ACTION : Receptor tyrosine kinase inhibitor.

Description

Die vorliegende Erfindung betrifft ein neu Anwendung des Medikaments Tarceva zur begleitenden Behandlung von Organtransplantationen. Diese Verbindung zeichnet sich durch eine hohe Wirksamkeit zur Verhinderung von Organabstossungen aus.The The present invention relates to a new application of the medicament Tarceva for the concomitant treatment of organ transplants. This compound is characterized by a high effectiveness for prevention from organ rejections.

Organtransplantationen sind häufig mit Komplikationen verbunden, wie z. B. neurologische Komplikationen, Malignome, Virus oder Bakterien bedingte Infektionen, Entzuendungen, Durchblutungsstoerungen, die zu Amputationen der Extremitäten fuehren koennen und Abstossungsreaktionen (hyperakut, akut oder chronisch) die zum Tod des Patient fuehren koennen.organ transplants are often associated with complications such. B. neurological Complications, malignancies, virus or bacterial infections, Inflammations, circulatory disturbances leading to amputations of the Extremities can lead and rejection reactions (hyperacute, acute or chronic) that can lead to the death of the patient.

Tarceva ist ein Kinaseinhibitor, der zur Behandlung spezieller Krebsarten eingesetzt wird. Der Wirkmechanismus und die Aktivität sind dabei mit der inhibitorischen Wirkung von Tarceva gegen die Rezeptortyrosinkinasen korreliert.Tarceva is a kinase inhibitor used to treat specific cancers is used. The mechanism of action and activity are there with the inhibitory effect of Tarceva against the Receptor tyrosine kinases correlated.

Aufgabe der vorliegenden Erfindung war die Erweiterung des Wirkbereiches von Kinaseinhibitor Tarceva im Bereich der Organtransplantation und damit die neuartige Anwendung von Tarceva zur begleitenden Behandlung von Organtransplantationen.task The present invention was the extension of the effective range of kinase inhibitor Tarceva in the field of organ transplantation and thus the novel use of Tarceva for concomitant treatment of organ transplants.

Es wurde gefunden, dass Wirkstoffe der allgemeinen Formel Tarceva in Kombination mit in der Transplantationsmedizin ueblichen Medikamenten eine wesentlich bessere Dosierungsbreite und Anwendungsdauer besitzt und die Zahl der Organabstossungen veringern gegenüber den herkoemmlich eingesetzten Medikamenten und Dosierungen.It has been found to contain active substances of the general formula Tarceva in Combination with common in transplantation medicine has much better dosage range and duration of use and the number of organ rejections lower the commonly used drugs and dosages.

Figure 00020001
Figure 00020001

Als Tarcevaanaloga kommen für die erfindungsgemässe Verwendung infrage: N-phenylquinazolin-4-aminderivate, wie sie in der Patentschrift:
Schnur, Rodney C.; Arnold, Lee D. Preparation of N-phenylquinazoline-4-amines as neoplasm inhibitors. PCT Int. Appl. (1996), 63 pp. WO 9630347 A1 19961003 beschrieben werden.Suitable tarceva analogs for the use according to the invention are: N-phenylquinazoline-4-amine derivatives, as described in the patent:
String, Rodney C .; Arnold, Lee D. Preparation of N-phenylquinazolines-4-amines as neoplasm inhibitors. PCT Int. Appl. (1996), 63 pp. WO 9630347 A1 19961003 are described.

Bevorzugtes N-phenylquinazolin-4-aminderivat für die erfindungsgemässe Verwendung ist Tarceva: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (Tarceva) (II)

Figure 00020002
Preferred N-phenylquinazolin-4-amine derivative for the use according to the invention is Tarceva: N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (Tarceva) (II)
Figure 00020002

Die genannten Tarcevaderivate werden in Mengen eingesetzt, die im Bereich der sonst für die Krebsbehandlung üblichen Menge liegen. Die entsprechend vorliegender Erfindung anzuwendende Menge hängt vom Umfang der durch die anderen Medikamente verursachten Nebenwirkungen ab.The Tarcevaderivate mentioned are used in quantities in the range the usual amount for cancer treatment lie. The amount applicable according to the present invention depends on the extent of the other medicines caused Side effects.

Die erfindungsgemässe Kombination wird vorzugsweise oral verabreicht, infundiert oder intramuskulär injiziert.The combination according to the invention is preferably administered orally, infused or injected intramuscularly.

Eine typische Dosis für die Anwendung am Menschen für den Tarcevaanteil dieser Erfindung ist, abhängig von der Applikationsart, 10 mg bis 100 mg (i. v.) oder 0,1 mg bis 1000 mg (p. o.), bevorzugt 1 bis 100 mg, besonders bevorzugt 0.05 bis 4 mg/kg Körpergewicht/Minute an x i. v. oder eine biologisch äquivalente Menge eines anderen N-phenylquinazolin-4-aminderivates.A typical dose for human use the Tarceva portion of this invention is dependent on the Method of administration, 10 mg to 100 mg (i.v.) or 0.1 mg to 1000 mg (p.o.), preferably 1 to 100 mg, more preferably 0.05 to 4 mg / kg body weight / minute at x i. v. or a biologically equivalent Amount of another N-phenylquinazolin-4-amine derivative.

Die vorliegende Erfindung betrifft somit die neuartige Anwendung von Tarceva zur begleitenden Behandlung von Organtransplantationen.The The present invention thus relates to the novel application of Tarceva for the concomitant treatment of organ transplants.

Beispielexample

In verscheidenen Versuchen wurden Organe (Leber, Herz, Niere) zwischen Individuen einer Tierspezies (Maus, Ratte, Hamster, Kaninchen, Hund, Schwein) implantive ausgetauscht.In Various attempts were made between organs (liver, heart, kidney) Individuals of an animal species (mouse, rat, hamster, rabbit, dog, pig) implanted exchanged.

Entsprechende Experimente sind in der Literatur beschrieben:

  • A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANT-ASSOCIATED STUDIES IN RATS1. Transplantation. 69(3): 427–430, February 15, 2000. Pratschke, J. 2 3; Wilhelm, M. J. 2; Kusaka, M. 2 4; Laskowski, I. 2; Tilney, N. L. 2 5 und
  • Krupnick AS, Kreisel D, Engels FH, Szeto WY, Plappert T, Popma SH, Flake AW, Rosengard BR. A novel small animal model of left ventricular tissue engineering. J Heart Lung Transplant. 2002 Feb; 21(2): 233–43 .
Corresponding experiments are described in the literature:
  • A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANT-ASSOCIATED STUDIES IN RATS1. Transplantation. 69 (3): 427-430, February 15, 2000. Pratschke, J. 2 3; Wilhelm, MJ 2; Kusaka, M. 2 4; Laskowski, I. 2; Tilney, NL 2 5 and
  • Krupnick AS, Kreisel D, Engels FH, Szeto WY, Plappert T, Popma SH, Flake AW, Rosengard BR. A novel small animal model of left ventricular tissue engineering. J heart lung transplant. 2002 Feb; 21 (2): 233-43 ,

Tarceva oder ein biologisch aktives Derivat und andere uebliche Transplantationsmedikamente wurden dabei vor und nach der Transplantation der Organtransplantation den Tieren in verschiedenen Dosiskombinationen verabreicht. Die durchschnittliche Uberlebensdauer der Tiere war statistisch signifikant laenger, im Vergleich zu Tarcevaunbehandelten Tieren.Tarceva or a biologically active derivative and other common transplant medicines were administered to the animals in various dose combinations before and after the transplantation of organ transplantation. The average survival time of the animals was statistically significantly longer compared to Tarcevaun treated animals.

ZITATE ENTHALTEN IN DER BESCHREIBUNGQUOTES INCLUDE IN THE DESCRIPTION

Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Zitierte PatentliteraturCited patent literature

  • - WO 9630347 A1 [0006] WO 9630347 A1 [0006]

Zitierte Nicht-PatentliteraturCited non-patent literature

  • - A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANT-ASSOCIATED STUDIES IN RATS1. Transplantation. 69(3): 427–430, February 15, 2000. Pratschke, J. 2 3; Wilhelm, M. J. 2; Kusaka, M. 2 4; Laskowski, I. 2; Tilney, N. L. 2 5 [0013] - A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANT-ASSOCIATED STUDIES IN RATS1. Transplantation. 69 (3): 427-430, February 15, 2000. Pratschke, J. 2 3; Wilhelm, MJ 2; Kusaka, M. 2 4; Laskowski, I. 2; Tilney, NL 2 5 [0013]
  • - Krupnick AS, Kreisel D, Engels FH, Szeto WY, Plappert T, Popma SH, Flake AW, Rosengard BR. A novel small animal model of left ventricular tissue engineering. J Heart Lung Transplant. 2002 Feb; 21(2): 233–43 [0013] - Krupnick AS, Kreisel D, Engels FH, Szeto WY, Plappert T, Popma SH, Flake AW, Rosengard BR. A novel small animal model of left ventricular tissue engineering. J heart lung transplant. 2002 Feb; 21 (2): 233-43 [0013]

Claims (2)

Anwendung von N-phenylquinazolin-4-aminderivaten (I),
Figure 00050001
zur begleitenden Behandlung von Organtransplantationen.Application of N-phenylquinazolin-4-amine derivatives (I),
Figure 00050001
for the concomitant treatment of organ transplants. Anwendung von Tarceva (II) zur Behandlung von Organtransplantationen.
Figure 00050002
Use of Tarceva (II) for the treatment of organ transplants.
Figure 00050002
DE102008031039A 2008-06-30 2008-06-30 Use of N-phenylquinazolin-4-amine derivatives as receptor tyrosine kinase inhibitor for accompanying treatment of organ transplantations Withdrawn DE102008031039A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010105110A1 (en) * 2009-03-11 2010-09-16 Ardea Biosciences, Inc. Pharmaceutical combinations comprising rdea119/bay 869766 for the treatment of specific cancers

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANT-ASSOCIATED STUDIES IN RATS1. Transplantation. 69(3): 427-430, February 15, 2000. Pratschke, J. 2 3; Wilhelm, M. J. 2; Kusaka, M. 2 4; Laskowski, I. 2; Tilney, N. L. 2 5
Krupnick AS, Kreisel D, Engels FH, Szeto WY, Plappert T, Popma SH, Flake AW, Rosengard BR. A novel small animal model of left ventricular tissue engineering. J Heart Lung Transplant. 2002 Feb; 21(2): 233-43

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010105110A1 (en) * 2009-03-11 2010-09-16 Ardea Biosciences, Inc. Pharmaceutical combinations comprising rdea119/bay 869766 for the treatment of specific cancers
US8673876B2 (en) 2009-03-11 2014-03-18 Ardea Biosciences Inc. Pharmaceutical combinations for treatment of specific cancers
US9220696B2 (en) 2009-03-11 2015-12-29 Ardea Biosciences, Inc. Pharmaceutical combinations for treatment of specific cancers

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