DE102008031040A1 - Use of 2-aminopyrimidine derivatives for the treatment of organ transplantation - Google Patents

Use of 2-aminopyrimidine derivatives for the treatment of organ transplantation Download PDF

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Publication number
DE102008031040A1
DE102008031040A1 DE102008031040A DE102008031040A DE102008031040A1 DE 102008031040 A1 DE102008031040 A1 DE 102008031040A1 DE 102008031040 A DE102008031040 A DE 102008031040A DE 102008031040 A DE102008031040 A DE 102008031040A DE 102008031040 A1 DE102008031040 A1 DE 102008031040A1
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Prior art keywords
treatment
organ transplantation
aminopyrimidine derivatives
iressa
organ
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DE102008031040A
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German (de)
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Alexander Priv.-Doz. Dr. 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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

Abstract

Use of 2-aminopyrimidine derivatives (I) for the treatment of organ transplantation, is claimed. Use of 2-aminopyrimidine derivatives of formula (I) for the treatment of organ transplantation, is claimed. R 1>-R 5>not defined. [Image] ACTIVITY : Immunosuppressive. MECHANISM OF ACTION : None given.

Description

Die vorliegende Erfindung betrifft ein neu Anwendung des Medikaments Iressa 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 Iressa for the concomitant treatment of organ transplants. These Compound is characterized by a high effectiveness for prevention from organ rejections.

Organtransplantationen sind haeufig mit Komplikationen verbunden, wie z. B. neurologische Komplikationen, Malignome, Virus oder Bakterien bedingte Infektionen, Entzuendungen, Durchblutungsstoerungen, die zu Amputationen der Extremitaeten 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 to and rejection reactions (hyperacute, acute or chronic) that can lead to the death of the patient.

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

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

Es wurde gefunden, dass Wirkstoffe der allgemeinen Formel (I) 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 that active ingredients of the general formula (I) in combination with transgender medicine, one 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 Iressaanaloga kommen für die erfindungsgemässe Verwendung infrage: 2-Aminopyrimidinderivate, wie sie in der Patentschrift Gibson, Keith Hopkinson. Preparation of haloanilinoquinazolines as Class I receptor tyrosine kinase inhibitors. PCI Int. Appl. (1996), 50 pp. WO 9633980 A1 19961031 beschrieben werden.As Iressaanaloga come for the inventive use in question: 2-Aminopyrimidinderivate, as described in the patent Gibson, Keith Hopkinson. Preparation of haloanilinoquinazolines as Class I receptor tyrosine kinase inhibitors. PCI Int. Appl. (1996), 50 pp. WO 9633980 A1 19961031 be described.

Bevorzugtes 2-Aminopyrimidinderivat für die erfindungsgemässe Verwendung ist Iressa:
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (Iressa)(II)

Figure 00020002
Preferred 2-aminopyrimidine derivative for the use according to the invention is Iressa:
N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (Iressa) (II)
Figure 00020002

Die genannten Iressaderivate 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 Iressaderivate are used in amounts 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 Iressaanteil 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 2-Aminopyrimidinderivates.A typical human dosage for the Isressa portion of this invention, depending on the mode of administration, is 10 mg to 100 mg (iv) or 0.1 mg to 1000 mg (po), preferably 1 to 100 mg, more preferably 0.05 to 4 mg / kg body weight / minute at x iv or a biologically equivalent amount another 2-aminopyrimidine derivative.

Die vorliegende Erfindung betrifft somit die neuartige Anwendung von Iressa zur begleitenden Behandlung von Organtransplantationen.The The present invention thus relates to the novel application of Iressa 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:Appropriate Experiments are described in the literature:

A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANTASSOCIATED STUDIES IN RATS1.A MODEL OF GRADUAL ONSET BRAIN DEATH FOR TRANSPLANTASSOCIATED 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.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 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 .
A novel small animal model of left ventricular tissue engineering.
  • J heart lung transplant. 2002 Feb; 21 (2): 233-43 ,

Iressa 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 Iressaunbehandelten Tieren.Iressa or a biologically active derivative and other common transplant medicines were doing before and after the transplantation of organ transplantation administered to the animals in different dose combinations. The average survival of the animals was statistically significant longer, compared to animals treated with Isandaun.

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 9633980 A1 [0006] WO 9633980 A1 [0006]

Zitierte Nicht-PatentliteraturCited non-patent literature

  • - 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. [0013] - Transplant. 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, roundabout D, Engels FH, Szeto WY, Plankert T, Popma SH, Flake AW, Rosengard BR. [0013]
  • - J Heart Lung Transplant. 2002 Feb; 21(2): 233–43 [0014] - J heart lung transplant. 2002 Feb; 21 (2): 233-43 [0014]

Claims (2)

Anwendung von 2-Aminopyrimidinderivaten,
Figure 00050001
zur begleitenden Behandlung von Organtransplantationen.Application of 2-aminopyrimidine derivatives,
Figure 00050001
for the concomitant treatment of organ transplants. Anwendung von Iressa (II) zur Behandlung von Organtransplantationen.
Figure 00050002
Use of Iressa (II) for the treatment of organ transplants.
Figure 00050002
DE102008031040A 2008-06-30 2008-06-30 Use of 2-aminopyrimidine derivatives for the treatment of organ transplantation Withdrawn DE102008031040A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033980A1 (en) 1995-04-27 1996-10-31 Zeneca Limited Quinazoline derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033980A1 (en) 1995-04-27 1996-10-31 Zeneca Limited Quinazoline derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J Heart Lung Transplant. 2002 Feb; 21(2): 233-43
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.

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