DE102008035299A1 - Conjugate, particularly bromovinyl-deoxyuridine for manufacture medicament for inhibiting or suppressing metastasis including distant metastases in cytostatic treatment, includes heat shock protein and nucleoside - Google Patents

Conjugate, particularly bromovinyl-deoxyuridine for manufacture medicament for inhibiting or suppressing metastasis including distant metastases in cytostatic treatment, includes heat shock protein and nucleoside Download PDF

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DE102008035299A1
DE102008035299A1 DE102008035299A DE102008035299A DE102008035299A1 DE 102008035299 A1 DE102008035299 A1 DE 102008035299A1 DE 102008035299 A DE102008035299 A DE 102008035299A DE 102008035299 A DE102008035299 A DE 102008035299A DE 102008035299 A1 DE102008035299 A1 DE 102008035299A1
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Rudolf Prof. Dr. Fahrig
Jörg-Christian Dr. Heinrich
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Abstract

A conjugate includes a heat shock protein 27 (Hsp 27) and a nucleoside. The conjugate has a general formula (I), where the conjugate is made of heat shock protein 27 (Hsp 27) and nucleoside. R 1and R 2independently hydrogen, halogen, OR 8, CN, N 3, NR 6R 7and a prodrug residue; R 3hydrogen, linear or branched 1-8C alkyl or alkylene group; R 4hydrogen, halogen, OR 8, N 3or NR 6R 7; R 5hydrogen, 1-8C alkyl or aryl group; and R 6, R 7and R 8independently hydrogen, linear or branched 1-8C alkyl or acetyl group. [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : None given.

Description

Die Erfindung betrifft Konjugate aus dem Protein Hsp27 und einem Nukleosid auf Basis von Bromovinyldeoxyuridin (BVDU). Ebenso betrifft die Erfindung die Verwendung des besagten Nukleosids zusammen mit mindestens einem Zytostatikum zur Verhinderung bzw. Hemmung der Entstehung von Metastasen und/oder Rückbildung bestehender Fernmetastasen in der Zytostatikabehandlung. Der Grad der Hsp27-Expression korreliert mit dem Grad der Metastasierung. Hsp27 besitzt eine Schlüsselstellung bei der Metastasierung von Tumoren und bestimmt damit den Krankheitsverlauf. Da erhöhte Hsp27-Expression bei allen bisher untersuchten Tumorentitäten zumindest in fortgeschrittenen Entwicklungsstadien nachgewiesen worden ist, sind die Arzneimittel universell bei der Krebstherapie einsetzbar.The The invention relates to conjugates of the protein Hsp27 and a nucleoside based on bromovinyldeoxyuridine (BVDU). Likewise, the concerns Invention the use of said nucleoside together with at least a cytostatic for preventing or inhibiting the development metastases and / or regression of existing distant metastases in the cytostatic treatment. The degree of Hsp27 expression correlates with the degree of metastasis. Hsp27 has a key position in the metastasis of tumors and thus determines the course of the disease. Since increased Hsp27 expression in all tumor entities examined so far proven at least in advanced stages of development The drugs are universal in cancer therapy used.

Zwischen der Menge an „heat shock protein” (Hsp) 27 in einem Tumor und dem Grad der Metastasierung besteht ein deutlicher Zusammenhang. Hsp27 kontrolliert die Metastasierung von Tumoren und bestimmt damit den Krankheitsverlauf. Nachgewiesen wurde dieser enge Zusammenhang mit der Metastasierung u. a. beim Brustkrebs ( P. Lemieux, S. Oesterreich, J. A. Lawrence, P. S. Steeg, S. G. Hilsenbeck, J. M. Harvey, S. A. Fuqua, ”The small heat shock protein hsp27 increases invasiveness but decreases motility of breast cancer cells”, Invasion Metastasis, 1997; 17: 113–23 ), malignem Melanom ( S. Aldrian, F. Trautinger, I. Frohlich, W. Berger, M. Micksche, I. Kindas-Mugge, ”Overexpression of Hsp27 affects the metastatic phenotype of human melanoma cells in vitro”, Cell Stress Chaperones, 2002; 7: 177–85 ; F. Carta, P. P. Demuro, C. Zanini, A. Santona, D. Castiglia, S. D'Atri, P. A. Ascierto, M. Napolitano, A. Cossu, B. Tadolini, F. Turrini, A. Manca, M. C. Sini, G. Palmieri, A. C. Rozzo, Italian Melanoma Intergroup, ”Analysis of candidate genes through a proteomics-based approach in primary cell lines from malignant melanomas and their metastases”, Melanoma Res., 2005; 15: 235–44 ), Bauchspeicheldrüsenkrebs ( M. Niedergethmann, F. Alves, J. K. Neff, B. Heidrich, N. Aramin, L. Li, C. Pilarsky, R. Grutzmann, H. Allgayer, S. Post, N. Gretz, „Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model” Br. J. Cancer, 2007; 97: 1432–40 ), Leberkrebs ( H. Y. Song, Y. K. Liu, J. T. Feng, J. F. Cui, Z. Dai, L. J. Zhang, J. X. Feng, H. L. Shen, Z. Y. Tang, „Proteomic analysis an metastasis-associated proteins of human hepatocellular carcinoma tissues”, J. Cancer Res. Clin. Oncol., 2006; 132: 92–8 ), Magenkrebs ( J. Chen, T. Kahne, C. Rocken, T. Gotze, J. Yu, J. J. Sung, M. Chef, P. Hu, P. Malfertheiner, M. P. Ebert, ”Proteome analysis of gastric cancer metastasis by two-dimensional gel electrophoresis and matrix assisted laser desorption/ionization-mass spectrometry for identification of metastasis-related proteins”, J. Proteome Res., 2004; 3: 1009–16 ; K. Wang, J. Li, C. Zhen, J. Zhou, D. Xiao, J. Liu, Y. Liu, H. Jiang, C. Chef, J. Wen, „Enhanced invasive and metastatic potential induced by transforming growth factor-beta1 might be correlated with glutathione-S-transferase-pi, cofilin and heat shock protein 27 in SGC-7901 gastric cancer cells”, Acta Biochim. Biophys. Sin. (Shanghai), 2007; 39: 520–6 ), kolorektalen Tumoren ( K. Zhao, W. Wang, O. J. Rando, Y. Xue, K. Swiderek, A. Kuo, G. R. Crabtree: ”Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling”, Cell 95: 625–636, 1998 ), Prostatakrebs ( L. Xu, S. Chef, R. C. Bergan, ”MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer”, Oncogene. 2006; 25: 2987–98 ) adenosquamösem Karzinom ( L. Lo Muzio, R. Leonardi, M. A. Mariggiò, M. D. Mignogna, C. Rubini, A. Vinella, G. Pannone, L. Giannetti, R. Serpico, N. F. Testa, G. De Rosa, S. Staibano, ”HSP 27 as possible prognostic factor in patients with oral squamous cell carcinoma”, Histol. Histopathol. 2004; 19: 119–28 ) und Eierstockkrebs ( S. P. Langdon, G. J. Rabiasz, G. L. Hirst, R. J. King, R. A. Hawkins, J. F. Smyth, W. R. Miller, ”Expression of the heat shock protein HSP27 in human ovarian cancer”, Clin. Cancer Res. 1995, 12: 1603–9 ).There is a clear correlation between the amount of heat shock protein (Hsp) 27 in a tumor and the degree of metastasis. Hsp27 controls the metastasis of tumors and thus determines the course of the disease. This close connection with metastasis has been demonstrated in breast cancer, P. Lemieux, S. Oesterreich, JA Lawrence, PS Steeg, SG Hilsenbeck, JM Harvey, SA Fuqua, "The small heat shock protein hsp27 increasing invasiveness and reducing motility of breast cancer cells", Invasion Metastasis, 1997; 17: 113-23 ), malignant melanoma ( S. Aldrian, F. Trautinger, I. Frohlich, W. Berger, M. Micksche, I. Kindas-Mugge, "Overexpression of Hsp27 Affects the Metastatic Phenotype of Human Melanoma Cells in Vitro", Cell Stress Chaperones, 2002; 7: 177-85 ; F. Carta, PP Demuro, C. Zanini, A. Santona, D. Castiglia, S. D'Atri, PA Ascierto, M. Napolitano, A. Cossu, B. Tadolini, F. Turrini, A. Manca, MC Sini , G. Palmieri, AC Rozzo, Italian Melanoma Intergroup, "Analysis of candidate genes through a proteomics-based approach in primary cell lines from malignant melanomas and their metastases", Melanoma Res., 2005; 15: 235-44 ), Pancreatic cancer ( M. Niedergethmann, F. Alves, JK Neff, B. Heidrich, N. Aramin, L. Li, C. Pilarsky, R. Grutzmann, H. Allgayer, S. Post, N. Gretz, "Gene expression profiling of liver metastases and tumor invasion in pancreatic cancer using an orthotopic SCID mouse model Br. J. Cancer, 2007; 97: 1432-40 ), Liver cancer ( Yu Song, YK Liu, JT Feng, JF Cui, Z. Dai, LJ Zhang, JX Feng, HL Shen, ZY Tang, "Proteomic Analysis of Metastasis-associated proteins of human hepatocellular carcinoma tissues", J. Cancer Res. Clin. Oncol., 2006; 132: 92-8 ), Stomach cancer ( J. Chen, T. Kahne, C. Rocken, T. Gotze, J. Yu, JJ Sung, M. Chef, P. Hu, P. Malfertheiner, MP Ebert, "Proteome analysis of gastric cancer metastasis by two-dimensional gel electrophoresis and matrix assisted laser desorption / ionization mass spectrometry for identification of metastasis-related proteins ", J. Proteome Res., 2004; 3: 1009-16 ; K. Wang, J. Li, C. Zhen, J. Zhou, D. Xiao, J. Liu, Y. Liu, H. Jiang, C. Chef, J. Wen, "Enhanced invasive and metastatic potential induced by transforming growth factor-beta1 might be correlated with glutathione S-transferase-pi, cofilin and heat shock protein 27 in SGC-7901 gastric cancer cells ", Acta Biochim. Biophys. Sin. (Shanghai), 2007; 39: 520-6 ), colorectal tumors ( K. Zhao, W. Wang, OJ Rando, Y. Xue, K. Swiderek, A. Kuo, GR Crabtree: "Rapid and phosphoinositol-dependent binding of the SWI / SNF-like BAF complex to chromatin after T lymphocyte receptor signaling" , Cell 95: 625-636, 1998 ), Prostate cancer ( Chief Executive Officer, RC Bergan, "MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer", Oncogene. 2006; 25: 2987-98 ) adenosquamous carcinoma ( L. Lo Muzio, R. Leonardi, MA Mariggiò, MD Mignogna, C. Rubini, A. Vinella, G. Pannone, L. Giannetti, R. Serpico, NF Testa, G. De Rosa, S. Staibano, "HSP 27 as possible prognostic factor in patients with oral squamous cell carcinoma ", Histol. Histopathol. 2004; 19: 119-28 ) and ovarian cancer ( SP Langdon, GJ Rabiasz, GL Hirst, RJ King, RA Hawkins, JF Smyth, WR Miller, "Expression of the heat shock protein HSP27 in human ovarian cancer", Clin. Cancer Res. 1995, 12: 1603-9 ).

Ansteigende Level an Hsp27 wurden darüber hinaus in späten Stadien von Osteosarkomen, Blasenkrebs, Glialtumoren, endometrialem Krebs, Leukämien, Darmkrebs, Nierenkrebs und nicht-kleinzelligem Lungenkrebs nachgewiesen ( P. Rocchi, E. Beraldi, S. Ettinger, L. Fazli, R. L. Vessella, C. Nelson, M. Gleave, ”Increased Hsp27 after androgen ablation facilitates androgen-independent Progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis”, Cancer Res. 2005 Dec 1; 65(23): 11083–93 ; C. Garrido, M. Brunet, C. Didelot, Y. Zermati, E. Schmitt, G. Kroemer, „Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties”, Cell Cycle 2006, 5: 2592–601 ; A. P. Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, ”p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets”, HsFEBS Lett. 2007; 581: 3665–74 ).Increasing levels of Hsp27 have also been demonstrated in late stages of osteosarcoma, bladder cancer, glial tumors, endometrial cancer, leukemia, colon cancer, kidney cancer, and non-small cell lung cancer ( P. Rocchi, E. Beraldi, S. Ettinger, L. Fazli, RL Vessella, C. Nelson, M. Gleave, "Increased Hsp27 after androgen ablation androgen-independent progression in prostate cancer via signal transducers and activators of transcription. mediated suppression of apoptosis ", Cancer Res. 2005 Dec 1; 65 (23): 11083-93 ; C. Garrido, M. Brunet, C. Didelot, Y. Zermati, E. Schmitt, G. Kroemer, "Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties", Cell Cycle 2006, 5: 2592-601 ; AP Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, "p27 (HspB1) and alphaB -crystalline (HspB5) as therapeutic targets ", HsFEBS Lett. 2007; 581: 3665-74 ).

In der Literatur lässt sich im Gegensatz zu anderen „heat shock”-Proteinen nicht ein einziges Beispiel für eine positive Rolle von Hsp27 bei der Krebserkrankung finden. Dementsprechend steigt die Zahl der Arbeiten, in denen die Notwendigkeit betont wird, Hsp27-Modulatoren zu entwickeln, exponentiell an ( A. P. Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, ”p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets”, HsFEBS Lett. 2007; 581: 3665–74 ). Bisher sind Experimente mit „Anti-Sense” Oligonukleotiden oder RNAi Nukleotid-Inhibitoren, die sequenzspezifisch für Hsp27 mRNA sind, durchgeführt worden. Diese Arbeiten haben nicht zur Entwicklung wirksamer Arzneimittel geführt ( M. Kamada, A. So, M. Muramaki, P. Rocchi, E. Beraldi, und M. Gleave, ”Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells”, Molecular Cancer Therapeutics 6, 299–308, 2007 ; P. Rocchi, P. Jugpal, A. So, S. Sinneman, S. Ettinger, L. Fazli, C. Nelson, M. Gleave, ”Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro”, BJU Int. 2006, 98: 1082–9 ).In the literature, unlike other heat shock proteins, there is not a single example of a positive role for Hsp27 in cancer. Accordingly, the number of papers expounding the need to develop Hsp27 modulators is increasing exponentially ( AP Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, "p27 (HspB1) and alphaB -crystalline (HspB5) as therapeutic targets ", HsFEBS Lett. 2007; 581: 3665-74 ). So far Experiments with "anti-sense" oligonucleotides or RNAi nucleotide inhibitors that are sequence-specific for Hsp27 mRNA have been performed. This work has not led to the development of effective medicines ( M. Kamada, A. So, M. Muramaki, P. Rocchi, E. Beraldi, and M. Gleave, "Hsp27 knockdown using nucleotide-based therapy inhibit tumor growth and enhance chemotherapy in human bladder cancer cells", Molecular Cancer Therapeutics 6 , 299-308, 2007 ; P. Rocchi, P. Jugpal, A. So, S. Sinneman, S. Ettinger, L. Fazli, C. Nelson, M. Gleave, "Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro ", BJU Int. 2006, 98: 1082-9 ).

Die gezielte Entwicklung von Hsp27-Modulatoren in Form von „small molecules” ist nicht möglich, da die dreidimensionale Struktur von humanem Hsp27 nicht bekannt ist. Dies liegt daran, dass es bisher nicht möglich ist, stabile Kristalle dieser oligomeren Proteine für die Röntgen-Strukturanalyse zu erzeugen ( A. P. Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, ”p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets”, HsFEBS Lett. 2007; 581: 3665–74 ). Substanzen, die Hsp27 modulieren, lassen sich deshalb nur durch Zufall finden.The targeted development of Hsp27 modulators in the form of "small molecules" is not possible because the three-dimensional structure of human Hsp27 is unknown. This is because it has not been possible to generate stable crystals of these oligomeric proteins for X-ray structure analysis ( AP Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, "p27 (HspB1) and alphaB -crystalline (HspB5) as therapeutic targets ", HsFEBS Lett. 2007; 581: 3665-74 ). Therefore, substances that modulate Hsp27 can only be found by chance.

Ausgehend hiervon war es Aufgabe der vorliegenden Erfindung, eine Möglichkeit zur Modulation von Hsp27 zu finden.outgoing It was an object of the present invention, a possibility to find the modulation of Hsp27.

Diese Aufgabe wird durch das Konjugat mit den Merkmalen des Anspruchs 1, und die Verwendung mit den Merkmalen des Anspruchs 4 gelöst. Die weiteren abhängigen Ansprüche zeigen vorteilhafte Weiterbildungen auf.These Task is performed by the conjugate with the features of the claim 1, and the use with the features of claim 4 solved. The further dependent claims show advantageous Further education.

Erfindungsgemäß wird ein Konjugat aus mindestens einem Protein Hsp27 und mindestens einem Nukleosid bereitgestellt, wobei das Nukleosid die allgemeine Formel I

Figure 00060001
aufweist. Hierbei bedeuten:
R1 und R2 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus H, Halogen, OR8, CN, N3, NR6R7 und Prodrugresten,
R3 = H, geradkettiges oder verzweigtes C1-C8-Alkyl, geradkettiges oder verzweigtes C1-C8-Alkylen,
R4 = H, Halogen, OR8, N3, NR6R7 oder R4 gemeinsam mit R1 eine zweite Bindung zwischen den zu R1 und R4 benachbarten C-Atomen darstellen,
R5 = H, C1-C8-Alkyl oder Aryl und
R6, R7 und R8 unabhängig voneinander H, geradkettiges oder verzweigtes C1-C8-Alkyl oder Acetyl.According to the invention, a conjugate of at least one protein Hsp27 and at least one nucleoside is provided, wherein the nucleoside is the general formula I
Figure 00060001
having. Where:
R 1 and R 2 are independently selected from the group consisting of H, halogen, OR 8 , CN, N 3 , NR 6 R 7 and prodrug residues,
R 3 = H, straight-chain or branched C 1 -C 8 -alkyl, straight-chain or branched C 1 -C 8 -alkylene,
R 4 = H, halogen, OR 8 , N 3 , NR 6 R 7 or R 4 together with R 1 represent a second bond between the C atoms adjacent to R 1 and R 4 ,
R 5 = H, C 1 -C 8 alkyl or aryl and
R 6 , R 7 and R 8 independently of one another are H, straight-chain or branched C 1 -C 8 -alkyl or acetyl.

Vorzugsweise ist dabei der Prodrug-Rest ausgewählt aus der Gruppe bestehend aus

Figure 00060002
mit
R10 und R11 unabhängig voneinander geradkettiger oder verzweigter C1-C8-Alkyl, Aryl, der auch Heteroatome aufweisen kann, R12 = geradkettiger oder verzweigter C1-C8-Alkyl, Aralkylen, Aryl, der auch Heteroatome aufweisen kann, R13 = geradkettiger oder verzweigter C1-C8-Alkyl,
Figure 00070001
mit
R10 und R11 unabhängig voneinander geradkettiger oder verzweigter C1-C8-Alkyl, Aryl, der auch Heteroatome aufweisen kann, R12 = geradkettiger oder verzweigter C1-C8-Alkyl, Aralkylen, Aryl, der auch Heteroatome aufweisen kann, R13 = geradkettiger oder verzweigter C1-C8-Alkyl, R14 = O-C1-C8-Alkyl, NH-C1-C8-Alkyl, N-(C1-C8-Alkyl)2,
Figure 00070002
mit
R15 = geradkettiger er oder verzweigter C1-C8-Alkyl,
Figure 00070003
mit
R15 = geradkettiger oder verzweigter C1-C8-Alkyl,
R16 = geradkettiger oder verzweigter C1-C8-Alkyl, O-Aryl
Figure 00070004
mit
R17 = geradkettiger oder verzweigter C1-C8-Alkyl, Halogen
Figure 00080001
mit
R18 = geradkettig oder verzweigt C1-C8-Alkyl, Aryl oder Heteroaryl, R19 = Alkyl-CO-, Aryl-CO-, Aminosäure oder Peptid,
Figure 00080002
mit
R20 = geradkettig oder verzweigt C1-C8-Alkyl.Preferably, the prodrug residue is selected from the group consisting of
Figure 00060002
With
R 10 and R 11 independently of one another are straight-chain or branched C 1 -C 8 -alkyl, aryl, which may also have heteroatoms, R 12 = straight-chain or branched C 1 -C 8 -alkyl, aralkylene, aryl, which may also have heteroatoms, R 13 = straight-chain or branched C 1 -C 8 -alkyl,
Figure 00070001
With
R 10 and R 11 independently of one another are straight-chain or branched C 1 -C 8 -alkyl, aryl which may also have heteroatoms, R 12 = straight-chain or branched C 1 -C 8 -alkyl, aralkylene, aryl, which may also have heteroatoms, R 13 = straight-chain or branched C 1 -C 8 -alkyl, R 14 = OC 1 -C 8 -alkyl, NH-C 1 -C 8 -alkyl, N- (C 1 -C 8 -alkyl) 2 ,
Figure 00070002
With
R 15 = straight-chain or branched C 1 -C 8 -alkyl,
Figure 00070003
With
R 15 = straight-chain or branched C 1 -C 8 -alkyl,
R 16 = straight-chain or branched C 1 -C 8 -alkyl, O-aryl
Figure 00070004
With
R 17 = straight-chain or branched C 1 -C 8 -alkyl, halogen
Figure 00080001
With
R 18 = straight-chain or branched C 1 -C 8 -alkyl, aryl or heteroaryl, R 19 = alkyl-CO-, aryl-CO-, amino acid or peptide,
Figure 00080002
With
R 20 = straight-chain or branched C 1 -C 8 -alkyl.

Es konnte überraschend gezeigt werden, dass durch eine Cobehandlung von Bauchspeicheldrüsenkrebspatienten mit den genannten Nukleosiden die Metastasenbildung reduziert werden konnte.It could surprisingly be shown that by a co-treatment of pancreatic cancer patients with the said Nucleosides the metastasis could be reduced.

Von den Patienten, bei denen zu Beginn der Behandlung Fernmetastasen nachgewiesen wurden, die also eine durchschnittliche Lebenszeit von weniger als 6 Monaten hatten, lebten nach einem Jahr noch vier bis fünf Mal so viele Patienten im Vergleich zu der durchschnittlichen Erwartung. Die weitere Metastasierung wird somit durch die Cobehandlung mit den besagten Nukleosiden verhindert.From the patient in whom distant metastases at the beginning of treatment were proven, which is an average lifetime had less than 6 months, four more lived after one year to five times as many patients compared to the average Expectancy. The further metastasis is thus by the co-treatment prevented with the said nucleosides.

Anhand weiterer Untersuchungen, die in den Beispielen aufgeführt sind, konnte gezeigt werden, dass eine Bindung der Nukleoside an Hsp27 erfolgt.Based Further investigations, which are listed in the examples were able to be shown to bind to the nucleosides Hsp27 is done.

Erfindungsgemäß wird ebenso die Verwendung von mindestens einem der zuvor beschriebenen Nukleoside mit mindestens einem Zytostatikum zur Herstellung eines Arzneimittels zur Hemmung und/oder Unterdrückung von Fernmetastasen in der Zytostatikabehandlung bereitgestellt.According to the invention as well as the use of at least one of those previously described Nucleosides with at least one cytostatic for the preparation of a Drug for the inhibition and / or suppression of distant metastases provided in the cytostatic treatment.

Vorzugsweise erfolgt dabei die Verabreichung des Arzneimittels bei Krebspatienten im Stadium IV.Preferably In this case, the administration of the drug takes place in cancer patients in stage IV.

Das mindestens eine Nukleosid und das mindestens eine Zytostatikum können sowohl in einer einzigen Formulierung als auch in getrennten Formulierungen verwendet werden. Bei getrennten Formulierungen ist eine zeitlich versetzte Verabreichung möglich.The at least one nucleoside and the at least one cytostatic can both in a single formulation and in separate formulations be used. For separate formulations, one is temporal staggered administration possible.

Anhand der nachfolgenden Beispiele und Figuren soll der erfindungsgemäße Gegenstand näher erläutert werden, ohne diesen auf die hier gezeigten speziellen Ausführungsformen einschränken zu wollen.Based the following examples and figures, the inventive Subject to be explained in more detail, without this restrict to the specific embodiments shown here to want.

1 zeigt anhand eines Diagramms ein Vergleich der Überlebensrate von mit Chemotherapie allein behandelten Patienten und solchen, die mit BVDU und Chemotherapie behandelt wurden, 1 Fig. 1 is a graph showing a comparison of the survival rates of patients treated with chemotherapy alone and those treated with BVDU and chemotherapy;

2a zeigt anhand eines Diagramms die Überlebenswahrscheinlichkeit von mit einer Chemotherapie allein behandelten Pankreas-Krebspatienten. 2a shows the survival probability of pancreatic cancer patients treated with chemotherapy alone on the basis of a diagram.

2b zeigt anhand eines Diagramms die Überlebenswahrscheinlichkeiten von mit Chemotherapie und BVDU behandelten Pankreas-Krebspatienten, 2 B 1 shows a diagram of the survival probabilities of chemotherapy and BVDU-treated pancreatic cancer patients,

3. zeigt die Auftrennung von Actin-like protein 6a und hsp27 über Polyacrylamid-Gelelektrophorese, 3 , shows the separation of actin-like protein 6a and hsp27 via polyacrylamide gel electrophoresis,

4 zeigt ein Western-Blot mit hsp27-Antikörper, 4 shows a Western blot with hsp27 antibody,

5 zeigt anhand eines Diagramms die Ergebnisse der Testung des Invasivitäts-Assays gemäß Beispiel 5 und 5 shows a diagram of the results of testing the invasiveness assay according to Example 5 and

6 zeigt anhand eines Diagramms die Ergebnisse der Testung gemäß Beispiel 6. 6 shows a diagram of the results of the test according to Example 6.

Beispiel 1example 1

Metastasierung: Analyse von BauchspeicheldrüsenkrebspatientenMetastasis: analysis of pancreatic cancer patients

Ein Vergleich von mit Chemotherapie allein behandelten Patienten und solchen, die mit BVDU + Chemotherapie behandelt wurden, zeigte klar, dass Patienten im Stadium IV mit Fernmetastasen (Leber, Lunge etc.) besonders von der BVDU-Therapie profitieren. Hier leben fünfmal mehr Patienten ein Jahr nach Beginn der Behandlung als in der Kontrollgruppe. Patienten ohne Fernmetastasen (Stadium III) profitieren zwar auch von der Behandlung, jedoch nur in geringerem Maße. Einzelheiten der klinischen Studie können Rudolf Fahrig; Detlef Quietzsch; Jörg-Christian Heinrich; Volker Heinemann; Stefan Boeck; Roland M. Schmid; Christian Praha; Andreas Liebert; Denise Sonntag; Georg Krupitza; Mathias Hänel, BVDU improves the efficacy of chemotherapy in pancreas carcinoma cell lines arid pancreatic cancer patients. Anti-Cancer Drugs. 17(9): 1045–1056, October 2006 entnommen werden.A comparison of patients treated with chemo alone and those treated with BVDU + chemotherapy clearly showed that stage IV patients with distant metastases (liver, lungs, etc.) benefit particularly from BVDU therapy. Here five times more patients live one year after the start of treatment than in the control group. Patients without distant metastases (Stage III) benefit from the treatment, but only to a lesser extent. Details of the clinical trial can Rudolf Fahrig; Detlef Quietzsch; Jörg-Christian Heinrich; Volker Heinemann; Stefan Boeck; Roland M. Schmid; Christian Praha; Andreas Liebert; Denise Sunday; Georg Krupitza; Mathias Hänel, BVDU improves the efficacy of chemotherapy in pancreatic carcinoma cell lines arid pancreatic cancer patients. Anti-Cancer Drugs. 17 (9): 1045-1056, October 2006 be removed.

Beispiel 2Example 2

Metastasierung: Bauchspeicheldrüsenkrebspatienten mit Fernmetastasen profitieren besonders von der BehandlungMetastasis: pancreatic cancer patients with distant metastases benefit especially from the treatment

In 2a sind die Überlebens-wahrscheinlichkeiten von mit Chemotherapie allein (Gemcitabin) behandelten Pankreas-Krebspatienten dargestellt. Patienten mit Fernmetastasen in Leber, Lunge, etc. (Stadium IV) sind durch eine graue Linie gekennzeichnet, Patienten mit lokal fortgeschrittenen Tumoren (Stadium III) durch eine schwarze Linie. Jede Stufe symbolisiert das Ableben eines Patienten. Die 50%-Linie stellt das mediane Überleben dar. Demnach haben Patienten mit nur lokal fortgeschrittenen Tumoren eine doppelt so hohe Lebenserwartung wie Patienten mit Fernmetastasen.In 2a The survival probabilities of chemotherapy alone (gemcitabine) treated pancreatic cancer patients are shown. Patients with distant metastases in liver, lung, etc. (stage IV) are indicated by a gray line, patients with locally advanced tumors (stage III) by a black line. Each level symbolizes the death of a patient. The 50% line represents median survival. Thus, patients with only locally advanced tumors have twice as much life expectancy as patients with distant metastases.

In der 2b sind die Überlebens-wahrscheinlichkeiten von mit Gemcitabin + BVDU behandelten Pankreas-Krebspatienten dargestellt. Patienten mit Fernmetastasen in Leber, Lunge, etc. (Stadium IV) sind durch eine graue Linie gekennzeichnet, Patienten mit lokal fortgeschrittenen Tumoren (Stadium III) durch eine schwarze Linie. Ein x stellt einen lebenden Patienten dar. Jede Stufe symbolisiert das Ableben eines Patienten. Die 50%-Linie stellt das mediane Überleben dar. Demnach haben Patienten mit nur lokal fortgeschrittenen Tumoren keine höhere Lebenserwartung als Patienten mit Fernmetastasen. Im Gegenteil, viele Patienten mit Fernmetastasen leben auf Grund der BVDU-Kobehandlung länger als Patienten mit nur lokal fortgeschrittenen Tumoren.In the 2 B The survival probabilities of gemcitabine + BVDU-treated pancreatic cancer patients are shown. Patients with distant metastases in liver, lung, etc. (stage IV) are indicated by a gray line, patients with locally advanced tumors (stage III) by a black line. An x represents a living patient. Each level symbolizes the death of a patient. The 50% line represents median survival. Thus, patients with only locally advanced tumors have no longer life expectancy than patients with distant metastases. On the contrary, many patients with distant metastases live longer than patients with only locally advanced tumors due to BVDU coagulation.

Beispiel 3Example 3

Bindung: Identifizierung von BVDU-Zielproteinen (drug targets) unter Verwendung magnetischer Partikel.Binding: Identification of BVDU target proteins (drug targets) using magnetic particles.

Die Kopplung von BVDU an magnetische Mikro-Partikel ermöglichte die Isolierung und Identifizierung von BVDU-Bindungspartnern (drug targets) aus Zell-Lysaten.The Coupling of BVDU to magnetic micro-particles enabled the isolation and identification of BVDU binding partners (drug targets) from cell lysates.

BVDU-gekoppelte magnetische Mikro-Partikel wurden unter geeigneten Bedingungen mit Proteinen aus einem Zell-Lysat inkubiert. Nach Beendigung der Inkubationszeit wurden die Proteine, die an BVDU binden, unter Verwendung eines Magneten isoliert.BVDU-coupled Magnetic micro-particles were used under suitable conditions Proteins from a cell lysate incubated. After completion of the incubation period For example, the proteins that bind to BVDU were identified using a Magnet isolated.

Die gebundenen Proteine wurden vom Reaktionspuffer getrennt, gewaschen und eluiert. Es folgte die Auftrennung der eluierten Proteine über Polyacrylamid-Gelelektrophorese (PAGE) und anschließende Silber- oder Coomassie-Färbung (siehe 3). Spezifische Banden wurden ausgeschnitten und mittels Massenspektroskopie (nanoLC-ESI-MSMS) identifiziert.The bound proteins were separated from the reaction buffer, washed and eluted. This was followed by separation of the eluted proteins by polyacrylamide gel electrophoresis (PAGE) followed by silver or Coomassie staining (see 3 ). Specific bands were excised and identified by mass spectroscopy (nanoLC-ESI-MSMS).

Außer dem Hsp27 bindet auch das ”actin-like Protein 6A” (andere Namen: ACTIN-LIKE 6A; ACTL6A; BRG1-ASSOCIATED FACTOR, 53-KD; BAF53, BAF53A) an BVDU. Beta-Actin und ”actin-like Protein 6A” werden für eine maximale ATPase Aktivität von BRG1 und für den Komplex von BRG1 mit dem Chromatin/der nuklearen Matrix benötigt ( Zhao, K.; Wang, W.; Rando, O. J.; Xue, Y.; Swiderek, K.; Kuo, A.; Crabtree, G. R.: ”Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling”, Cell 95: 625–636, 1998 ).In addition to Hsp27, actin-like protein 6A (other names: ACTIN-LIKE 6A, ACTL6A, BRG1-ASSOCIATED FACTOR, 53-KD, BAF53, BAF53A) binds to BVDU. Beta actin and actin-like protein 6A are required for maximum ATPase activity of BRG1 and for the BRG1 complex with the chromatin / nuclear matrix ( Zhao, K .; Wang, W .; Rando, OJ; Xue, Y .; Swiderek, K .; Kuo, A .; Crabtree, GR: "Rapid and phosphoinositol-dependent binding of the SWI / SNF-like BAF complex to chromatin after T lymphocyte receptor signaling", Cell 95: 625-636, 1998 ).

Beispiel 4Example 4

Bindung: Identifizierung von BVDU-Hsp27 KonjugatBinding: Identification of BVDU-Hsp27 conjugate

BVDU-gekoppelte magnetische Mikro-Partikel wurden unter geeigneten Bedingungen mit Proteinen aus einem Zell-Lysat inkubiert. Nach Beendigung der Inkubationszeit wurden die Proteine, die an BVDU binden, unter Verwendung eines Magneten isoliert. Die gebundenen Proteine wurden vom Reaktionspuffer getrennt, gewaschen und eluiert. Es folgte die Auftrennung der eluierten Proteine über Polyacrylamid-Gelelektrophorese (PAGE) und der Transfer der Proteine auf eine PVDF-Membran (Western Blot). Die so immobilisierten Proteine wurden mit einem hsp27-Antikörper (HSP25-19, sc-51956, Santa Cruz) inkubiert und per Chemolumineszenz sichtbar gemacht (siehe 4).

  • Spur 1: Referenz beads (unbeladene magnetische Partikel), Flution bei pH 6.
  • Spur 2: BVDU-gekoppelte magnetische Partikel, Flution bei pH 6.
  • Spur 3: Referenz beads (unbeladene magnetische Partikel), Flution bei pH 5,5.
  • Spur 4: BVDU-gekoppelte magnetische Partikel, Flution bei pH 5,5.
BVDU-coupled magnetic micro-particles were incubated under suitable conditions with proteins from a cell lysate. After the incubation period, the proteins binding to BVDU were isolated using a magnet. The bound proteins were separated from the reaction buffer, washed and eluted. This was followed by separation of the eluted proteins by polyacrylamide gel electrophoresis (PAGE) and transfer of the proteins to a PVDF membrane (Western Blot). The immobilized proteins were incubated with hsp27 antibody (HSP25-19, sc-51956, Santa Cruz) and visualized by chemiluminescence (see 4 ).
  • Lane 1: Reference beads (unloaded magnetic particles), elution at pH 6.
  • Lane 2: BVDU-coupled magnetic particles, elution at pH 6.
  • Lane 3: Reference beads (unloaded magnetic particles), elution at pH 5.5.
  • Lane 4: BVDU-coupled magnetic particles, elution at pH 5.5.

Beispiel 5Example 5

Metastasierung: Invasivitäts-AssayMetastasis: Invasiveness Assay

Der Einfluss von 5-Bromovinyl-Basenanaloga auf die Invasivität der humanen Fibrosarkom-Zelllinie HT-1080 wurde mit dem ”BD BioCoat Tumor Invasion System” getestet (5).The influence of 5-bromovinyl base analogues on the invasiveness of the human fibrosarcoma cell line HT-1080 was tested with the "BD BioCoat Tumor Invasion System" ( 5 ).

Die Zellen wurden 3 Tage mit Gemcitabine +/– 5-Bromovinyl-Basenanaloga vorinkubiert und auf 24-well Matrigel-Kulturplatten ausgesät. Nach 20 bis 22 Stunden wurden Zellen, die die Matrigel-Matrix durchdrungen hatten, mit Calcein, AM angefärbt und mit einem „Tecan Genios plate reader” quantifiziert.

  • 1) Kontrolle (Invasivität gleich 100% gesetzt)
  • 2) (E)-5-(2-bromovinyl)-2'-deoxy-uridin (BVDU)
  • 3) 3',5'-Dibrom-2',3',5'-trideoxy-5-(E)-bromovinyl-uridin
  • 4) 3'-O-Acetyl-5'-cyano-2',5'-dideoxy-5-(E)-bromovinyl-uridin
Cells were preincubated with gemcitabine +/- 5-bromovinyl base analogs for 3 days and seeded on 24-well Matrigel culture plates. After 20 to 22 hours, cells that had penetrated the Matrigel matrix were stained with Calcein, AM and quantified with a Tecan Genios plate reader.
  • 1) control (invasiveness equal to 100% set)
  • 2) (E) -5- (2-bromovinyl) -2'-deoxyuridine (BVDU)
  • 3) 3 ', 5'-dibromo-2', 3 ', 5'-trideoxy-5- (E) -bromovinyl-uridine
  • 4) 3'-O-acetyl-5'-cyano-2 ', 5'-dideoxy-5- (E) -bromovinyl-uridine

Als Ergebnis kann festgehalten werden, dass 5-Bromovinyl-Basenanaloga die Invasivität der humanen Fibrosarkom-Zelllinie HT-1080 vermindern.When It can be concluded that 5-bromovinyl base analogues the invasiveness of the human fibrosarcoma cell line HT-1080 Reduce.

Beispiel 6Example 6

Hitzeschock + MMC oder Hitzeschock + MMC + 5-Bromovinyl-BasenanalogaHeat shock + MMC or heat shock + MMC + 5-bromovinyl base analogues

Ah13-Tumorzellen der Ratte wurden mit dem Zytostatikum Mitomycin C (MMC) und in Parallelansätzen zusätzlich mit 5-Bromovinyl-Basenanaloga behandelt. Nach einem und nach vier Tagen der Behandlung wurden die Zellkulturen zudem für 30 Minuten bei 45°C einem Hitzeschock ausgesetzt.

  • 1. Kontrolle (Mitomycin C, MMC) + 2 × Hitzeschock
  • 2. MMC + (E)-5-(2-bromovinyl)-2'-deoxy-uridin (BVDU) + 2 × Hitzeschock
  • 3. MMC + 3',5'-Dibrom-2',3,5'-trideoxy-5-(E)-bromovinyl-uridin + 2 × Hitzeschock
  • 4. MMC + 3'-O-Acetyl-5'-cyano-2',5'-dideoxy-5-(E)-bromovinyl-uridin + 2 × Hitzeschock
Ah13 tumor cells of the rat were treated with the cytostatic mitomycin C (MMC) and in parallel mixtures additionally with 5-bromovinyl base analogs. After one and four days of treatment, the cell cultures were also exposed to heat shock for 30 minutes at 45 ° C.
  • 1. Control (mitomycin C, MMC) + 2 × heat shock
  • 2. MMC + (E) -5- (2-bromovinyl) -2'-deoxy-uridine (BVDU) + 2 × heat shock
  • 3. MMC + 3 ', 5'-dibromo-2', 3,5'-trideoxy-5- (E) -bromovinyl-uridine + 2 × heat shock
  • 4. MMC + 3'-O-acetyl-5'-cyano-2 ', 5'-dideoxy-5- (E) -bromovinyl-uridine + 2 × heat shock

Nach 17 Tagen Behandlung von Ah13 Tumorzellen in vitro ist ein Wachstum bei der MMC-Gruppe festzustellen. 5-Bromovinyl-Basenanaloga hemmen dagegen das Wachstum. Die Ergebnisse sind in 6 dargestellt.After 17 days of treatment of Ah13 tumor cells in vitro, growth in the MMC group is noted. In contrast, 5-bromovinyl base analogs inhibit growth. The results are in 6 shown.

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.

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  • - A. P. Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, ”p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets”, HsFEBS Lett. 2007; 581: 3665–74 [0003] AP Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, "p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets ", HsFEBS Lett. 2007; 581: 3665-74 [0003]
  • - A. P. Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, ”p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets”, HsFEBS Lett. 2007; 581: 3665–74 [0004] AP Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, "p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets ", HsFEBS Lett. 2007; 581: 3665-74 [0004]
  • - M. Kamada, A. So, M. Muramaki, P. Rocchi, E. Beraldi, und M. Gleave, ”Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells”, Molecular Cancer Therapeutics 6, 299–308, 2007 [0004] M. Kamada, A. So, M. Muramaki, P. Rocchi, E. Beraldi, and M. Gleave, "Molecular Cancer Therapeutics,""Hsp27 knockdown using nucleotide-based therapy inhibit tumor growth and enhance chemotherapy in human bladder cancer cells." 6, 299-308, 2007 [0004]
  • - P. Rocchi, P. Jugpal, A. So, S. Sinneman, S. Ettinger, L. Fazli, C. Nelson, M. Gleave, ”Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro”, BJU Int. 2006, 98: 1082–9 [0004] P. Rocchi, P. Jugpal, A. So, S. Sinneman, S. Ettinger, L. Fazli, C. Nelson, M. Gleave, "Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via cas pase-3 activation in vitro ", BJU Int. 2006, 98: 1082-9 [0004]
  • - A. P. Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, ”p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets”, HsFEBS Lett. 2007; 581: 3665–74 [0005] AP Arrigo, S. Simon, B. Gibert, C. Kretz-Remy, M. Nivon, A. Czekalla, D. Guillet, M. Moulin, C. Diaz-Latoud, P. Vicart, "p27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets ", HsFEBS Lett. 2007; 581: 3665-74 [0005]
  • - Rudolf Fahrig; Detlef Quietzsch; Jörg-Christian Heinrich; Volker Heinemann; Stefan Boeck; Roland M. Schmid; Christian Praha; Andreas Liebert; Denise Sonntag; Georg Krupitza; Mathias Hänel, BVDU improves the efficacy of chemotherapy in pancreas carcinoma cell lines arid pancreatic cancer patients. Anti-Cancer Drugs. 17(9): 1045–1056, October 2006 [0024] - Rudolf Fahrig; Detlef Quietzsch; Jörg-Christian Heinrich; Volker Heinemann; Stefan Boeck; Roland M. Schmid; Christian Praha; Andreas Liebert; Denise Sunday; Georg Krupitza; Mathias Hänel, BVDU improves the efficacy of chemotherapy in pancreatic carcinoma cell lines arid pancreatic cancer patients. Anti-Cancer Drugs. 17 (9): 1045-1056, October 2006 [0024]
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Claims (9)

Konjugat aus mindestens einem Protein Hsp27 und mindestens einem Nukleosid mit der allgemeinen Formel I
Figure 00160001
mit R1 und R2 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus H, Halogen, OR8, CN, N3, NR6R7 und Prodrugresten, R3 = H, geradkettiges oder verzweigtes C1-C8-Alkyl, geradkettiges oder verzweigtes C1-C8-Alkylen, R4 = H, Halogen, OR8, N3, NR6R7 oder R4 gemeinsam mit R1 eine zweite Bindung zwischen den zu R1 und R4 benachbarten C-Atomen darstellen, R5 = H, C1-C8-Alkyl oder Aryl und R6, R7 und R8 unabhängig voneinander H, geradkettiges oder verzweigtes C1-C8-Alkyl oder Acetyl.Conjugate of at least one protein Hsp27 and at least one nucleoside of general formula I.
Figure 00160001
with R 1 and R 2 independently selected from the group consisting of H, halogen, OR 8 , CN, N 3 , NR 6 R 7 and Prodrugresten, R 3 = H, straight-chain or branched C 1 -C 8 alkyl, straight-chain or branched C 1 -C 8 -alkylene, R 4 = H, halogen, OR 8 , N 3 , NR 6 R 7 or R 4 together with R 1 represent a second bond between the C atoms adjacent to R 1 and R 4 , R 5 = H, C 1 -C 8 -alkyl or aryl and R 6 , R 7 and R 8 independently of one another are H, straight-chain or branched C 1 -C 8 -alkyl or acetyl. Konjugat nach Anspruch 1, dadurch gekennzeichnet, dass der Prodrugrest ausgewählt ist aus der Gruppe bestehend aus
Figure 00170001
mit R10 und R11 unabhängig voneinander geradkettiger oder verzweigter C1-C8-Alkyl, Aryl, der auch Heteroatome aufweisen kann, R12 = geradkettiger oder verzweigter C1-C8-Alkyl, Aralkylen, Aryl, der auch Heteroatome aufweisen kann, R13 = geradkettiger oder verzweigter C1-C8-Alkyl,
Figure 00170002
mit R10 und R11 unabhängig voneinander geradkettiger oder verzweigter C1-C8-Alkyl, Aryl, der auch Heteroatome aufweisen kann, R12 = geradkettiger oder verzweigter C1-C8-Alkyl, Aralkylen, Aryl, der auch Heteroatome aufweisen kann, R13 = geradkettiger oder verzweigter C1-C8-Alkyl, R14 = O-C1-C8-Alkyl, NH-C1-C8-Alkyl, N-(C1-C8-Alkyl)2,
Figure 00170003
mit R15 = geradkettiger oder verzweigter C1-C8-Alkyl,
Figure 00170004
mit R15 = geradkettiger oder verzweigter C1-C8-Alkyl, R16 = geradkettiger oder verzweigter C1-C8-Alkyl, O-Aryl
Figure 00180001
mit R17 = geradkettiger oder verzweigter C1-C8-Alkyl, Halogen,
Figure 00180002
mit R18 = geradkettig oder verzweigt C1-C8-Alkyl, Aryl oder Heteroaryl, R19 = Alkyl-CO-, Aryl-CO-, Aminosäure oder Peptid,
Figure 00180003
mit R20 = geradkettig oder verzweigt C1-C8-Alkyl.Conjugate according to claim 1, characterized in that the prodrug residue is selected from the group consisting of
Figure 00170001
R 10 and R 11 are each independently straight-chain or branched C 1 -C 8 -alkyl, aryl, which may also have heteroatoms, R 12 = straight-chain or branched C 1 -C 8 -alkyl, aralkylene, aryl, which may also have heteroatoms , R 13 = straight-chain or branched C 1 -C 8 -alkyl,
Figure 00170002
R 10 and R 11 are each independently straight-chain or branched C 1 -C 8 -alkyl, aryl, which may also have heteroatoms, R 12 = straight-chain or branched C 1 -C 8 -alkyl, aralkylene, aryl, which may also have heteroatoms , R 13 = straight-chain or branched C 1 -C 8 -alkyl, R 14 = OC 1 -C 8 -alkyl, NH-C 1 -C 8 -alkyl, N- (C 1 -C 8 -alkyl) 2 ,
Figure 00170003
with R 15 = straight-chain or branched C 1 -C 8 -alkyl,
Figure 00170004
with R 15 = straight-chain or branched C 1 -C 8 -alkyl, R 16 = straight-chain or branched C 1 -C 8 -alkyl, O-aryl
Figure 00180001
with R 17 = straight-chain or branched C 1 -C 8 -alkyl, halogen,
Figure 00180002
with R 18 = straight-chain or branched C 1 -C 8 -alkyl, aryl or heteroaryl, R 19 = alkyl-CO-, aryl-CO-, amino acid or peptide,
Figure 00180003
where R 20 = straight-chain or branched C 1 -C 8 -alkyl. Konjugat nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass das 5-Bromvinyl-Basenanalogon Bromovinyldeoxyuridin ist.A conjugate according to any one of claims 1 or 2, characterized in that the 5-Bromvinyl-Basenanalogon Bromovinyldeoxyuridin is. Verwendung von mindestens einem Nukleosid der allgemeinen Formel I
Figure 00190001
mit R1 und R2 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus H, Halogen, OR8, CN, N3, NR6R7 und Prodrugresten, R3 = H, geradkettiges oder verzweigtes C1-C8-Alkyl, geradkettiges oder verzweigtes C1-C8-Alkylen, R4 = H, Halogen, OR8, N3, NR6R7 oder R4 gemeinsam mit R1 eine zweite Bindung zwischen den zu R1 und R4 benachbarten C-Atomen darstellen, R5 = H, C1-C8-Alkyl oder Aryl und R6, R7 und R8 unabhängig voneinander H, geradkettiges oder verzweigtes C1-C8-Alkyl oder Acetyl mit mindestens einem Zytostatikum zur Herstellung eines Arzneimittels zur Hemmung und/oder Unterdrückung von Fernmetastasen in der Zytostatikabehandlung.Use of at least one nucleoside of the general formula I.
Figure 00190001
with R 1 and R 2 independently selected from the group consisting of H, halogen, OR 8 , CN, N 3 , NR 6 R 7 and Prodrugresten, R 3 = H, straight-chain or branched C 1 -C 8 alkyl, straight-chain or branched C 1 -C 8 -alkylene, R 4 = H, halogen, OR 8 , N 3 , NR 6 R 7 or R 4 together with R 1 is a second bond between those of R 1 and R 4 R 5 = H, C 1 -C 8 -alkyl or aryl and R 6 , R 7 and R 8 are independently H, straight-chain or branched C 1 -C 8 -alkyl or acetyl with at least one cytostatic agent Preparation of a medicament for the inhibition and / or suppression of distant metastases in the cytostatic treatment. Verwendung nach Anspruch 4, dadurch gekennzeichnet, dass der Prodrugrest ausgewählt ist aus der Gruppe bestehend aus
Figure 00190002
mit R10 und R11 unabhängig voneinander geradkettiger oder verzweigter C1-C8-Alkyl, Aryl, der auch He teroatome aufweisen kann, R12 = geradkettiger oder verzweigter C1-C8-Alkyl, Aralkylen, Aryl, der auch Heteroatome aufweisen kann, R13 = geradkettiger oder verzweigter C1-C8-Alkyl,
Figure 00200001
mit R10 und R11 unabhängig voneinander geradkettiger oder verzweigter C1-C8-Alkyl, Aryl, der auch Heteroatome aufweisen kann, R12 = geradkettiger oder verzweigter C1-C8-Alkyl, Aralkylen, Aryl, der auch Heteroatome aufweisen kann, R13 = geradkettiger oder verzweigter C1-C8-Alkyl, R14 = O-C1-C8-Alkyl, NH-C1-C8-Alkyl, N-(C1-C8-Alkyl)2,
Figure 00200002
mit R15 = geradkettiger oder verzweigter C1-C8-Alkyl,
Figure 00200003
mit R15 = geradkettiger oder verzweigter C1-C8-Alkyl, R16 = geradkettiger oder verzweigter C1-C8-Alkyl, O-Aryl
Figure 00210001
mit R17 = geradkettiger oder verzweigter C1-C8-Alkyl, Halogen,
Figure 00210002
mit R18 = geradkettig oder verzweigt C1-C8-Alkyl, Aryl oder Heteroaryl, R19 = Alkyl-CO-, Aryl-CO-, Aminosäure oder Peptid,
Figure 00210003
mit R20 = geradkettig oder verzweigt C1-C8-Alkyl.Use according to claim 4, characterized in that the prodrug residue is selected from the group consisting of
Figure 00190002
with R 10 and R 11 independently of one another straight-chain or branched C 1 -C 8 -alkyl, aryl, which may also teroatome He, R 12 = straight-chain or branched C 1 -C 8 alkyl, aralkylene, aryl, which also have heteroatoms R 13 = straight-chain or branched C 1 -C 8 -alkyl,
Figure 00200001
R 10 and R 11 are each independently straight-chain or branched C 1 -C 8 -alkyl, aryl, which may also have heteroatoms, R 12 = straight-chain or branched C 1 -C 8 -alkyl, aralkylene, aryl, which may also have heteroatoms , R 13 = straight-chain or branched C 1 -C 8 -alkyl, R 14 = OC 1 -C 8 -alkyl, NH-C 1 -C 8 -alkyl, N- (C 1 -C 8 -alkyl) 2 ,
Figure 00200002
with R 15 = straight-chain or branched C 1 -C 8 -alkyl,
Figure 00200003
with R 15 = straight-chain or branched C 1 -C 8 -alkyl, R 16 = straight-chain or branched C 1 -C 8 -alkyl, O-aryl
Figure 00210001
with R 17 = straight-chain or branched C 1 -C 8 -alkyl, halogen,
Figure 00210002
with R 18 = straight-chain or branched C 1 -C 8 -alkyl, aryl or heteroaryl, R 19 = alkyl-CO-, aryl-CO-, amino acid or peptide,
Figure 00210003
where R 20 = straight-chain or branched C 1 -C 8 -alkyl. Verwendung nach Anspruch 4 oder 5, dadurch gekennzeichnet, dass die Verabreichung des Arzneimittels bei Patienten im Stadium IV, d. h. Patienten mit Fernmetastasen, erfolgt.Use according to claim 4 or 5, characterized that the administration of the drug in patients at the stage IV, d. H. Patients with distant metastases, done. Verwendung nach einem der Ansprüche 4 bis 6, dadurch gekennzeichnet, dass das mindestens eine Nukleosid und das mindestens eine Zytostatikum in einer einzigen Formulierung verwendet werden.Use according to one of claims 4 to 6, characterized in that the at least one nucleoside and the at least one cytostatic agent in a single formulation be used. Verwendung nach einem der Ansprüche 4 bis 6, dadurch gekennzeichnet, dass das mindestens eine 5-Bromvinyl-Basenanalogon und das mindestens eine Zytostatikum in getrennten Formulierungen verwendet werden.Use according to one of claims 4 to 6, characterized in that the at least one 5-Bromvinyl-Basenanalogon and the at least one cytostatic in separate formulations be used. Verwendung nach Anspruch 8, dadurch gekennzeichnet, dass eine zeitlich versetzte Verabreichung der Formulierungen erfolgt.Use according to claim 8, characterized that a time-staggered administration of the formulations takes place.
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