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WO2004069847A1 - Analogues de nucleoside a caracteristiques induisant une apoptose, permettant de traiter des maladies causees par des cellules a haute proliferation - Google Patents

Analogues de nucleoside a caracteristiques induisant une apoptose, permettant de traiter des maladies causees par des cellules a haute proliferation Download PDF

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Publication number
WO2004069847A1
WO2004069847A1 PCT/EP2004/001212 EP2004001212W WO2004069847A1 WO 2004069847 A1 WO2004069847 A1 WO 2004069847A1 EP 2004001212 W EP2004001212 W EP 2004001212W WO 2004069847 A1 WO2004069847 A1 WO 2004069847A1
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WO
WIPO (PCT)
Prior art keywords
aryl
alkyl
acyl
geranyl
derivatives
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2004/001212
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German (de)
English (en)
Inventor
Aram Prokop
Thomas Wieder
Hans Günther SCHMALZ
Juraj Velcicki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Charite Universitaetsmedizin Berlin
Universitaet zu Koeln
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Universitaet zu Koeln
Universitatsklinikum Charite Berlin
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Priority to EP04709602A priority Critical patent/EP1592697A1/fr
Publication of WO2004069847A1 publication Critical patent/WO2004069847A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to compounds and medicaments for the treatment of diseases caused by highly proliferating cells, and to processes for the preparation of such compounds and medicaments.
  • ALL acute lymphoblastic leukemia
  • Tumor diseases such as thyroid carcinoma, very common breast cancer, difficult to access medulloblastoma or towards gliomas.
  • a benign skin condition that is also treated with such therapies is psoriasis (psoriasis). It is one of the most common skin diseases that affect two to four percent of people. The therapy for this disease is also in great need of improvement.
  • WO 2080923 AI describes nucleoside analogues that trigger apoptosis and have a cytostatic effect. These compounds have in common a ring structure which contains a diene system to which an iron tricarbonyl is preferably coordinatively bound. Because of the diene structure, the known substances are difficult to synthesize. The substances tend to undesirable side reactions due to the reactivity of the diene and are therefore relatively unstable. This is disadvantageous both for storage and preparation in connection with other pharmaceutical components, and for the specificity after administration.
  • Velcicky et al., 2002 discloses a general synthetic strategy for nucleoside analogs using targeted protecting groups. According to the authors, the synthesis should make it possible to produce a large variety of nucleoside analogues that could potentially have biological activity.
  • Nucleoside analogues have an antiviral potential.
  • EP-A-0 358 154 discloses cyclobutane derivatives and a process for their preparation.
  • FR-A-2 662 165 discloses branched nucleoside derivatives, a process for their preparation and their use in a medicament.
  • the invention is therefore based on the object of providing corresponding substances. Another task is to provide substances with alternative and new mechanisms of action in order to expand and supplement the treatment options. The invention is also based on the object of providing corresponding substances which are simple to manufacture and are relatively stable.
  • the invention does not relate to the compounds described in Velcicky et al. (2002).
  • the subject of the invention are, as far as claimed, corresponding medicaments.
  • the authors did not recognize that some of the products and intermediate products disclosed are themselves particularly suitable for the treatment of tumors.
  • the invention relates to the various stereoisomers of the compounds according to the invention, the individual enantiomers and the corresponding racemates.
  • the cis configuration in the compounds according to the invention denotes that the radicals Y and Z are on the same side of the central five-membered ring.
  • the compounds according to the invention can be used to prepare a medicament for the treatment of malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating tumors or skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, lymphomas, in particular Hodgkin's and non-Hodgkin's lymphomas, inflammatory, chronically inflammatory, bacterial and autoimmune diseases, as well as for antibacterial, antifungal, anti-protozoa, anti-plasmodia, anti-helminthic, antiviral or immunosuppressive therapy.
  • the pharmaceuticals and compounds according to the invention are unexpectedly suitable for the therapy of pathologically rapidly proliferating tissue, in particular bone marrow, but also of solid tumors, such as epithelial tumors or in particular brain tumors. Furthermore, the applicability of the substances described also extends to the treatment of benign, hyperproliferative diseases of the skin, such as, for. B. the psoriasis or the keloid.
  • the drugs and substances of the invention are characterized in that they are particularly suitable, selectively that Inhibit growth of highly proliferating cells. As a result, they initiate apoptosis of highly proliferating cells and thus destroy them, with healthy cells being affected very little.
  • the experiments carried out show that substances according to the invention trigger apoptosis unusually quickly. The experiments carried out suggest that apoptosis could be initiated using a new mechanism.
  • the substances are particularly preferably membrane-permeable, which leads to a high intracellular active substance concentration. The high effectiveness is therefore likely to be achieved through the pronounced lipophilicity of the substances.
  • the substances differ fundamentally from known nucleoside analogues used for therapy, such as cytarabine, cladribine and fludarabine 5'-dihydrogen phosphate. They are able to break existing cytostatic resistances.
  • the pharmaceuticals and compounds of the invention are particularly suitable for the treatment of tumor diseases and leukemia. They induce apoptotic cell death not only in permanent cell lines (BJAB cells) formed from tumor cells, but also in primary cells from patients with acute lymphoblastic leukemia (ALL). This allows the substances according to the invention against tumor diseases of the bone marrow, but also against tumors of another provenance, such as. B. epithelial tumors, sarcomas or malignant diseases of the skin, etc. are used.
  • the developed substances are able to cross the blood-brain barrier unhindered due to their lipophilicity. Therefore, they can be used to treat malignant brain tumors, such as, for. B. the medulloblastoma or gliomas can be used.
  • the substances according to the invention can be used to treat malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semi-malignant rapidly proliferating skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, as well as inflammatory and chronic inflammatory diseases. They are also suitable for antiviral, antibacterial, antifungal, anti-protozoa, anti-helminthic or immunosuppressive therapy.
  • the compounds and medicaments of the invention have the advantage over the known substances from WO02 / 080923 that they are easier to synthesize, handle and store, and have little tendency to undesirable side reactions in the preparation of the medicament and also in the body.
  • apoptosis shows that the cell death triggered by the novel nucleoside analogs is not undifferentiated necrosis but apoptosis.
  • the measurement of apoptosis is based on a method that demonstrates the fragmentation of DNA typical of apoptosis at the individual cell level, which distinguishes this cell death form from necrosis.
  • BJAB cells were treated for 72 h with a concentration of 20 ⁇ mol / l of different nucleoside analogs. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured the mean value given was confirmed after two independent repetitions of the experiment (deviations ⁇ 3%).
  • FIG. 3 shows apoptosis induction via the resulting DNA fragmentation on primary lymphoblasts - of children with acute lymphoblastic leukemia (ALL). After isolation of the primary lymphoblasts and dilution with cell culture medium, they were treated with 20 ⁇ M each of the nucleoside analog for 36 h.
  • ALL acute lymphoblastic leukemia
  • Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured, the mean value being confirmed after two independent repetitions of the experiment (deviations ⁇ 3%).
  • Procaspase-3, Pro-C-8 and Pro-C-9 became more specific Immunodetection in a Western blot as described by Eßmann et al. (2000).
  • the positions of the procaspases and the processed subunits in the SDS-polyacrylamide gel are indicated by dashes on the left edge of FIG. 4.
  • the addition of 20 ⁇ mol / l of the substances to the medium of BJAB cells triggers a processing of the Procaspasen-3, -8 and -9 in these cells.
  • the specific, immunochemical detection of the active subunits of caspases-3, -8 and -9 in treated cells can be seen in contrast to the corresponding control cells.
  • the nucleoside analogue (-) - 159b induces the caspase processing (FIG. 4) so quickly that even at the time of measurement after 36 h hardly any of the procaspases-3, -8 and -9 are present.
  • 5 already contains a first indication of the apoptosis signal cascade activated by the novel nucleoside analogs. 5 shows that the BJAB cells incubated with the novel nucleoside analogs over 48 h are driven into the mitchondrial apoptosis pathway. This was visualized by staining the cells with the mitochondrial specific 'ifischen dye JC-1, such as by re et al. (2001). Incubation of the cells with the new nucleoside analogues led to a significant increase in the proportion of cells with a reduced mitochondrial, membrane potential ( ⁇ m ) from 5% in the control to 80%, which indicates a strong activation of the mitochondria during the apoptotic process indicates (Fig. 5).
  • the compound racx4 (FIG. 6) shows an apoptosis of approximately 42% at a concentration of 100 ⁇ g / ml.
  • the usability of the substances according to the invention for the therapy of various malignant diseases of the hematopoietic system has been successfully tested in vitro on cells from patients with different diseases.
  • the substances of general structural formula 2 are thus effective as agents against certain tumor cells, particularly those of childish ALL, but also against other malignant diseases of different origins.
  • the medicaments according to the invention can be administered topically or intravenously.
  • the substances are administered in the concentration range between 0.1 to 100 ⁇ g / ml, based on the patient's blood volume.
  • the substances are rubbed into the diseased skin in a concentration of 0.1 to .5% by weight, based on the finished preparation.
  • racemic precursors of the rac-100 type are prepared by known methods (see WO 02/080923 and Velcicky et al., 2002).
  • To produce the optically active compounds as explained in WO 02/080923, either the chirogenic step of the synthesis (Pauson-Khand reaction) is carried out enantioselectively, or a racemate resolution is carried out at a subsequent stage.
  • the following reactions can be carried out by individual enantiomers or by the racemate.
  • a solution of lOOa-e (lmmol) and PPTS (76 mg, 300 ⁇ mol, 30 mol%) in absolute acetone (10 ml) was stirred under reflux for 3 h.
  • IR (ATR, cm “1 ): 3177 (w, NH), 3050 (w, NH), 2954 (m, CH), 2864 (m, C-
  • the compound (-) - 113b was obtained as a colorless oil (48 mg, 99% yield) according to the general experimental procedure.
  • the compound (-) - 113d-l was obtained according to the general experimental procedure as a mixture of the protected and free alcohol, which was used directly in the following reaction to remove the protective group.
  • IR (ATR, cm “1 ): 3330 (bm, OH), 3199 (m, NH), 2954 (m, CH), 2863 (m,
  • the compound (-) - 159c-1 was obtained as a light yellow liquid according to the general experimental procedure (23 mg, 79% yield).
  • Rho-GDI 2 The GDP dissociation inhibitor, D4-GDI (Rho-GDI 2), but not the homologous Rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis, Biochem. J. 346, 777-783.

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

Abstract

La présente invention concerne des médicaments et des composés pour traiter des maladies causées par des cellules à haute prolifération, telles que des cellules tumorales, notamment des blastes d'enfants atteints d'une leucémie aiguë. La présente invention concerne également la production de médicaments et de composés correspondants.
PCT/EP2004/001212 2003-02-10 2004-02-10 Analogues de nucleoside a caracteristiques induisant une apoptose, permettant de traiter des maladies causees par des cellules a haute proliferation Ceased WO2004069847A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04709602A EP1592697A1 (fr) 2003-02-10 2004-02-10 Analogues de nucleoside a caracteristiques induisant une apoptose, permettant de traiter des maladies causees par des cellules a haute proliferation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10305575 2003-02-10
DE10305575.4 2003-02-10

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WO2004069847A1 true WO2004069847A1 (fr) 2004-08-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008076778A1 (fr) * 2006-12-14 2008-06-26 Lexicon Pharmaceuticals, Inc. Composés à base de 4-amino-1h-pyrimidine-2-one, compositions les contenant et procédés d'utilisation de ceux-ci

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002080923A1 (fr) * 2001-04-07 2002-10-17 Universitätsklinikum Charitè Substances pour traiter des maladies provoquees par des cellules a haute proliferation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002080923A1 (fr) * 2001-04-07 2002-10-17 Universitätsklinikum Charitè Substances pour traiter des maladies provoquees par des cellules a haute proliferation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
J. VELCICKY ET AL.: "An efficient organometallic approach to new carbocyclic nucleoside analogues", ORG. LETT., vol. 4, 2002, pages 565 - 568, XP002284239 *
J. WACHTMEISTER ET AL.: "Synthesis of novel olefinic carbocyclic purine nucleoside analogues", NUCLEOSIDES AND NUCLEOTIDES, vol. 14, 1995, pages 405 - 408, XP002284242 *
N. HOSSAIN ET AL.: "New synthesis of 2', 3'-didehydro-3'-C-substituted thymidines", TETRAHEDRON, vol. 49, 1993, pages 10061 - 10068, XP002284241 *
P. IOANNIDIS ET AL.: "Allylic alcohol transpositions in the carbohydrate moiety of pyrimidine nuceosides", TETRAHEDRON LETTERS, vol. 34, 1993, pages 2993 - 2994, XP002284240 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008076778A1 (fr) * 2006-12-14 2008-06-26 Lexicon Pharmaceuticals, Inc. Composés à base de 4-amino-1h-pyrimidine-2-one, compositions les contenant et procédés d'utilisation de ceux-ci
US8093245B2 (en) 2006-12-14 2012-01-10 Lexicon Pharmaceuticals, Inc. 4-amino-1H-pyrimidin-2-one based compounds, compositions comprising them and methods of their use

Also Published As

Publication number Publication date
EP1592697A1 (fr) 2005-11-09

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