DE102008031038A1 - Use of 2-indolinone derivatives for the treatment of organ transplantation - Google Patents

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

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Publication number
DE102008031038A1
DE102008031038A1 DE102008031038A DE102008031038A DE102008031038A1 DE 102008031038 A1 DE102008031038 A1 DE 102008031038A1 DE 102008031038 A DE102008031038 A DE 102008031038A DE 102008031038 A DE102008031038 A DE 102008031038A DE 102008031038 A1 DE102008031038 A1 DE 102008031038A1
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Prior art keywords
treatment
organ transplantation
sutent
indolinone derivatives
transplantation
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DE102008031038A
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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-indolinone derivatives (I) for the treatment of organ transplantation, is claimed. Use of 2-indolinone 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 Sutent 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 Sutent 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.

Sutent ist ein Kinaseinhibitor, der zur Behandlung spezieller Krebsarten eingesetzt wird. Der Wirkmechanismus and die Aktivitaet sind dabei mit der inhibitorischen Wirkung von Sutent gegen Rezeptortyrosinkinasen korreliert.Sutent 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 Sutent on receptor tyrosine kinases correlated.

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

Es wurde gefunden, dass Wirkstoffe der allgemeinen Formel Sutent 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 It has been found that active ingredients of the general formula Sutent in Combination with drugs commonly used in transplantation medicine, has a 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 Sutentanaloga kommen für die erfindungsgemässe Verwendung infrage: 2-Indolinonderivate, wie sie in der Patentschrift
Tang, Peng Cho; Miller, Todd; Li, Xiaoyuan; Sun, Li; Wei, Chung Chen; Shirazian, Shahrzad; Liang, Congxin; Vojkovsky, Tomas; Nematalla, Asaad S. Preparation of pyrrole substituted 2-indolinone Protein kinase inhibitors for treatment of cancer. PCT Int. Appl. (2001), 225 pp. WO 2001060814 A2 20010823 beschrieben werden.As Sutentanaloga come for the inventive use in question: 2-indolinone derivatives, as described in the patent
Tang, Peng Cho; Miller, Todd; Li, Xiaoyuan; Sun, Li; Wei, Chung Chen; Shirazian, Shahrzad; Liang, Congxin; Vojkovsky, Tomas; Nematalla, Asaad S. Preparation of pyrrole substituted 2-indolinone protein kinase inhibitors for treatment of cancer. PCT Int. Appl. (2001), 225 pp. WO 2001060814 A2 20010823.

Bevorzugtes 2-Indolinonderivat für die erfindungsgemässe Verwendung ist Sutent: (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (Sutent)(II)

Figure 00030001
Preferred 2-indolinone derivative for the use according to the invention is sutent: (Z) -N- (2- (diethylamino) ethyl) -5 - ((5-fluoro-2-oxoindolin-3-ylidenes) methyl) -2,4-dimethyl -1H-pyrrole-3-carboxamides (Sutent) (II)
Figure 00030001

Die genannten Sutentderivate 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 said sutine derivatives are used in amounts that are in the range of otherwise for the cancer treatment usual amount. The amount to be used in accordance with the present invention depends on the extent of the side effects caused by the other drugs.

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 Sutentanteil 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-Indolinonderivates.A typical dose for human use is the Sutentanteil this invention, depending 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 2-indolinone derivative.

Die vorliegende Erfindung betrifft somit die neuartige Anwendung von Sutent zur begleitenden Behandlung von Organtransplantationen.The The present invention thus relates to the novel application of Sutent 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 ,

Sutent 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 Sutent unbehandelten Tieren.Sutent 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 Sutent untreated 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 2001060814 A2 [0006] - WO 2001060814 A2 [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 2-Indolinonderivaten,
Figure 00050001
zur begleitenden Behandlung von Organtransplantationen.Application of 2-indolinone derivatives,
Figure 00050001
for the concomitant treatment of organ transplants. Anwendung von Sutent (II) zur Behandlung von Organtransplantationen.
Figure 00050002
Use of Sutent (II) for the treatment of organ transplants.
Figure 00050002
DE102008031038A 2008-06-30 2008-06-30 Use of 2-indolinone derivatives for the treatment of organ transplantation Withdrawn DE102008031038A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060814A2 (en) 2000-02-15 2001-08-23 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060814A2 (en) 2000-02-15 2001-08-23 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors

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

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