WO2007075094A1 - Nouveaux derives d'epirubicine, leur application medicinale et formes medicamenteuses de qualite pharmaceutique - Google Patents

Nouveaux derives d'epirubicine, leur application medicinale et formes medicamenteuses de qualite pharmaceutique Download PDF

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Publication number
WO2007075094A1
WO2007075094A1 PCT/PL2006/000080 PL2006000080W WO2007075094A1 WO 2007075094 A1 WO2007075094 A1 WO 2007075094A1 PL 2006000080 W PL2006000080 W PL 2006000080W WO 2007075094 A1 WO2007075094 A1 WO 2007075094A1
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Prior art keywords
group
epirubicin
hcv
compound
carbon atoms
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PCT/PL2006/000080
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English (en)
Inventor
Tadeusz Kulikowski
Maria Bretner
Andzelika Najda
Lucyna Cova
Christian Trepo
Ramamurthy Narayan
Andrzej Piasek
Andrzej Lipniacki
Wlodzimierz Zagorski-Ostoja
Original Assignee
Instytut Biochemii I Biofizyki
Institut National De La Sante Et De La Recherche Medicale (Inserm)
Instytut Medycyny Doswiadczalnej I Klinicznej
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Priority claimed from PCT/PL2005/000086 external-priority patent/WO2007075092A1/fr
Application filed by Instytut Biochemii I Biofizyki, Institut National De La Sante Et De La Recherche Medicale (Inserm), Instytut Medycyny Doswiadczalnej I Klinicznej filed Critical Instytut Biochemii I Biofizyki
Priority to US12/159,477 priority Critical patent/US8173610B2/en
Publication of WO2007075094A1 publication Critical patent/WO2007075094A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to novel derivatives of epirubicin, pharmaceutical compositions comprising these derivatives, and uses of epirubicin and its derivative for treating HCV.
  • HCV is of particular importance: it is highly pathogenic member of hepaciviruses of Flaviviridae superfamily, widely distributed overall the world (according to WHO report ca 300 millions infected people).
  • Chronic active hepatitis C develops in over 85% of acutely infected carriers and leads to liver cirrhosis and hepatocellular carcinoma (Hagedom and Rice, Eds., The Hepatitis C Viruses, Springer, Heidelberg 2000).
  • HCV chemotherapeutic agents HCV chemotherapeutic agents.
  • nucleoside ribavirin with interferon ⁇ 2b or ⁇ 2a and/or its pegylated derivatives were approved for the treatment of HCV infections.
  • these therapies are only partially effective (40-50% "cures") and cause a lot of undesired side effects such as: influenza-like symptoms, headache, hemolysis, nausea, anorexia, anemia, etc. Therefore there is a great need for other anti-HCV agents or methods suitable to control the chronic infection and to reduce progression to liver cirrhosis and hepatocellular carcinoma.
  • PBMC or Vero cells PBMC or Vero cells.
  • the invention further shows that these derivatives have better in vitro therapeutic index (TI) (Table 1), and lower in vivo toxicity in mice.
  • TI in vitro therapeutic index
  • epirubicin and its derivatives are effective for treating HCV infection at a very low doses, particularly at a dose associated with low or less toxicity.
  • Ri, R 2 , R 3 , and R 4 are the same or different and represent a hydrogen atom; a linear or branched alkyl group comprising from 1 to 5 carbon atoms (such as methyl, ethyl, propyl and isopropyl); a linear or branched alkenyl or alkynyl group with an alkyl chain containing 1 to 5 carbon atoms ; an alkyl carbonyl group containing 1 to 5 carbon atoms
  • Ri, R 2 , R3, and R 4 is not hydrogen; and any pharmaceutically acceptable salts thereof.
  • At least one of Ri, R 2 , R 3 , and R 4 is an hydrogen atom.
  • At least one of R 1 , R 2 , R 3 , and R 4 is an alkyl carbonyl group, more preferably an acetyl group.
  • R 3 is an acetyl group.
  • at least one of R 1 , R 2 , R 3 , and R 4 is an alkyl group, particularly a methyl group.
  • At least one of R 1 , R 2 , R 3 , and R 4 is a dialkylformamidinyl group, preferably a dimethylformamidinyl group.
  • the invention concerns a compound of Formula 1, wherein :
  • Ri, R 2 , and R 4 are hydrogen and R 3 is acetyl, or R 2 is hydrogen and Ri, R 3 and R 4 are acetyl, or - Ri, R 2/ and R 4 are hydrogen and R 3 is dimethylformamidinyl or formamidinyl, or
  • Ri and R 4 are hydrogen and R 2 and R 3 are methyl groups, or, Ri and R 2 represent an hydrogen atom and R 3 and R 4 represent acetyl groups, and pharmaceutically acceptable salts thereof.
  • Compounds of this invention may be prepared following chemical methods known per se in the art, using epirubicin as a starting material, as illustrated in the examples.
  • the present invention also concerns a pharmaceutical composition comprising at least one compound as defined above and a pharmaceutically acceptable carrier.
  • the carrier may be any solvent, saline solution, powder, stabilizer, tension-active, etc., that is used in the pharmaceutical industry.
  • the compounds may be in the form of any pharmaceutically acceptable salt, such as acid or basic addition salts, hydrochloride.
  • the present invention also relates to a compound as defined above or a salt thereof, as a medicament, particularly for treating or preventing an HCV infection in a mammalian subject, particularly a human subject.
  • the present invention also relates to pharmaceutically acceptable form of the drug containing epirubicin or above mentioned epirubicin derivatives of Formula 1, eventually in the form of hydrochloride.
  • the derivatives of the invention or epirubicin are in the form of hydrochloride.
  • the present invention concerns new biomedical application of novel derivatives of the invention, and in particular their application to the treatment of hepatitis C virus (HCV) infections.
  • HCV hepatitis C virus
  • the invention relates to the use of a compound of Formula 1:
  • Ri, R 2 , R 3 , and R 4 are the same or different and represent a hydrogen atom ; a linear or branched alkyl group comprising from 1 to 5 carbon atoms (such as methyl, ethyl, propyl and isopropyl) ; a linear or branched alkenyl or alkynyl group with an alkyl chain containing 1 to 5 carbon atoms; an alkyl carbonyl group containing 1 to 5 carbon atoms (such as an acetyl group); or a formamidinyl or dialkylformamidinyl group (with an alkyl chain containing 1 to 5 carbon atoms); and any pharmaceutically acceptable salts thereof; for the manufacture of pharmaceutical composition for treating HCV infection.
  • a linear or branched alkyl group comprising from 1 to 5 carbon atoms (such as methyl, ethyl, propyl and isopropyl)
  • novel epirubicin derivatives (Formula 1), preferably acetyl derivatives, as active substances for the treatment of HCV virus infections.
  • This invention relates also to pharmaceutically acceptable forms of the drug containing the mentioned derivatives presented in Formula 1, for the treatment of HCV infection.
  • new derivatives of 7-O-(3'-amino- 2',3',6'-trideoxy- ⁇ , ⁇ -L-arabinohexapiranosyl)-adriamycinone as presented in Formula 1, where Ri, R 2 , R 3 and R 4 are the same or different: if R 2 and R3 is hydrogen then Ri and R 4 is hydrogen, if Ri, R 2 , and R 4 is hydrogen then R 3 is acetyl, if R 2 is hydrogen, then Ri, R 3 and R 4 is acetyl, if Ri, R 2 , and R 4 is hydrogen then R 3 is dimethylformamidinyl, if R 1 , and R 4 is hydrogen then R 2 and R 3 is methyl group.
  • medical application of epirubicin derivatives as anti-HCV agents is characterized as ensuring simultaneously low toxicity against Huh7, PBMC and Vero cells, therapeutic index (TI) better than for epirubicin and lower in vivo acute toxicity.
  • the present invention concerns the use of an epirubicin derivative of the present invention or a combination thereof for preparing a medicament for treating or preventing HCV infections.
  • the present invention also concerns a method for treating or preventing HCV infection in a subject comprising administering a therapeutically effective amount of an epirubicin derivative of the present invention or a combination thereof.
  • the derivative of the present invention is used or administered in combination with an other drug, in particular a drug used against HCV infections.
  • Epirubicin hydrochloride known antitumor drug, is extremely potent anti-HCV agent at very low, nanomolar concentrations. Indeed, they evaluated anti-HCV activity of epirubicin hydrochloride in Huh7 harboring subgenomic HCV replicon and found that IC 50 of epirubicin is very low i.e 2-4 nM.
  • IC 50 of epirubicin is very low i.e 2-4 nM.
  • the direct comparison of anti-HCV activity of epirubicin hydrochloride found in vitro in cell culture system with the dose used for human antitumuor therapy is not possible, since the in vivo study of anti-HCV activity of Epirubicin hydrochloride is hampered by lack of an animal model susceptible to HCV infection, except chimpanzee which is an endangered species.
  • anti-HCV IC 5O of epirubicin hydrochloride is of 2-4 nM, i.e 7.2- 14.5 ⁇ g/m 2 of body surface (0.035-0.07 mg/m 2 ) as shown by the inventors in vitro in Huh7 cells, whereas the antitumor maximum cumulative dose of Epirubicin hydrochloride in humans is of 900-1000 mg/m 2 (Launchburry and Habboubit, Cancer Treatment Reviews 1993; 19: 197-228).
  • anti-HCV activity of Epirubicin hydrochloride demonstrated by the inventors is very low i.e 14 000-25 000 fold lower than the one use in antitumor therapy.
  • the present invention concerns a method for treating or preventing HCV infection in a subject comprising administering a drug selected in the group consisting of a epirubicin, a derivative thereof according to the invention and a pharmaceutically acceptable salt thereof, at a dose which is at least 10 times, preferably 100 times, even more preferably 1000 times lower than the anti-tumor effective dose.
  • the effective dosage is, e.g., below 100, 50, 10, 1, or 0.1 mg/m 2 of body surface.
  • the present invention also concerns the use of a drug selected in the group consisting of a epirubicin, a derivative thereof according to the invention and a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing HCV infection, the dose of the drug being lower than 100, 50, 10, 1, or 0.1 mg/m 2 .
  • the dose can be comprised between 0.001 mg/m 2 and 0.1, 1, 10, 50 or 100 mg/m 2 .
  • the dose is comprised between 0.1 or 1 nM and 5, 10, 50 or 100 nM.
  • the dose is lower than 1 mg/m 2 .
  • the dose is at least 10 000 times below that used for anti-cancer therapy.
  • the cumulative dose of the treatment is typically comprised between 0.035-0.07 mg/m 2 .
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the compounds may be administered by different routes, such as systemic, oral, local or topic routes.
  • Preferred administration route is by injection, typically by intraperitoneal, intravenous or local injection.
  • Figure 1 Antiviral activity of BN02 on HCV replicon carrying firefly luciferase gene.
  • FIG. 2 Antiviral activity of BNE06 on HCV replicon carrying firefly luciferase gene. Following BN06 treatment, cells were lysed and firefly luciferase activity was measured using Luminoskan device. Results of anti-HCV activity were expressed as dose-dependant inhibition in reference to the untreated cells taken as 100%.
  • Figure 3 Inhibition of HCV replication by epirubicin and its derivatives in chronically HCV infected human PBMC cells.
  • HCV RNA was qualitatively estimated by real-time Reverse Transcriptase Polymerase Chain Reaction using SYBR Green system.
  • Figure 4 Effect of epirubicin derivatives on HCV replication in chronically HCV-infected PBMC of PCT-4 patientGel electrophoresis analysis of a Reverse Transcriptase Polymerase Chain Reaction product in untreated cells (controls) and in cells treated with BNEOO, BNEOl and BNE02 at concentrations specified above.
  • Figure 5 Cytotoxicity of epirubicin and its derivatives in Vero cells.
  • 4'-epidoxorubicin hydrochloride (58 mg, 0.10 mmol) was dissolved in acetone (6.8 ml_) and diisopropylethylamine (18 ⁇ L) was added. The solution was cooled to 0 0 C in an ice bath and 10 ⁇ L (0.11 mmol) of acetic anhydride was added while stirring. The reaction mixture was allowed to warm to room temperature and then stirred for 2 hours. The solution was evaporated and subsequently the residue was dissolved in ca. 13 mL CHCI 3 . Furthermore the solution was washed with 0.1 M phosphate buffer pH 7.0 (3 times), and water (2 times). The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum.
  • 4'-epidoxorubicin hydrochloride (100 mg, 0.17 mmol) was dissolved in dry chloroform (10 mL) and 20 mg 4-dimethylaminopyridine was added. The solution was cooled to O 0 C in an ice bath and 400 ⁇ L (4.24 mmol) of acetic anhydride was added while stirring. The reaction mixture was allowed to warm to room temperature and then stirred. The progress of the reaction was checked by TLC (CHCI 3 :MeOH 9:1). Then the solution was washed with 0.1 M phosphate buffer pH 7.0 (3 times), and water (2 times). The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo.
  • reaction mixture was diluted with water (4 mL) and extracted with CHCI 3 (2 x 4 mL).
  • the chloroform extracts were combined, dried over anhydrous sodium sulphate and evaporated in vacuo.
  • the residue was chromatographed (silica gel PLC plates) in CHCI 3 : MeOH:H 2 O 40: 10:1); m. p. 220 0 C; MS (ES+) 572.28, (ES-) 570.22.
  • Example 4 3'-/V-(/V", ⁇ / ⁇ '-Dimethylformamidinyl)-4'-epidoxorubicin (4, BNE04)
  • 4'-epidoxorubicin hydrochloride 150 mg, 0.26 mmol, 1 equiv
  • dry methanol 7.5 mL
  • V,/V-dimethylformamide dimethyl acetal 182 ⁇ L, 1.30 mmol, 5 equiv
  • the reaction mixture was stirred for 4 hours, and then solvent was removed under reduced pressure.
  • the residue was chromatographed (column of silica gel; CHCI 3 to CHCI 3 :MeOH 9:1); m.
  • the antiviral (anti-HCV) activity of epirubicin and its derivatives was tested in vitro in cell culture model using the HCV subgenomic replicon stably transfected into Huh7 cells line (clone BM4.5) (Gao et al., J. Virol. 2001J and/or in Huh7 cells replicating selectable subgenomic HCV replicon carrying firefly luciferase gene (Vrolijk et al. J. Virol. Method. 2003).
  • the BM4.5 Huh7 cells were grown in cell culture medium in presence of varying concentrations of epirubicin hydrochloride (BNEOO) or epirubicin derivatives. The media and drug were changed everyday for 5 days.
  • RNA from the treated cells were isolated.
  • RNA was then probed with a HCV specific probe using Northern blot analysis to detect the HCV RNA.
  • the resulting blot was then exposed to phosphorimager densitometry and the viral replication quantified.
  • Huh7 cells replicating selectable subgenomic HCV replicon carrying firefly luciferase gene cells were treated with epirubicin hydrochloride (BNEOO) or epirubicin derivatives as described above for BM4,5 cells. Following the treatment, cells were lysed and firefly luciferase activity was measured using Luminoskan device (Thermolabsystem) as described (Vrolijk et al. J. Virol. Methods. 2003).
  • Results of anti-HCV activity were expressed as dose-dependant inhibition in reference to the untreated cells taken as 100%.
  • the obtained data indicate that epirubicin hydrochloride and epirubicin derivatives effectively inhibit in vitro HCV replication in HCV subgenomic replicon with IC 50 ranging from 0.002 to 0.5 ⁇ M as summarized in Table 1 and illustrated in Figures 1-2 for BNE02 and BNE06, respectively.
  • PBMC peripheral blood monocyte cells
  • HCV RNA was qualitatively estimated by real-time Reverse Transcriptase Polymerase Chain Reaction using SYBR Green system ( Figure 3). Semiquantitative estimation of HCV RNA was also performed by Reverse Transcriptase Polymerase Chain Reaction, and visualized after electrophoresis through a 1% agarose gel, using ethidium bromide staining ( Figure 4).
  • Anti-HCV activity and cytotoxicity were evaluated in Huh7 cells replicating selectable subgenomic HCV replicon carrying firefly luciferase gene as described (Vrolijk et a/. J. Virol. Methods. 2003).
  • Table 2 are presented data of cytotoxicity (CC 50 and CC 90 ), anti-HCV activity (IC 50 and IC 90 ) and of therapeutic index (TI 50 and TI 90 ) in human PBMC from chronic HCV-infected patients.

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Abstract

La présente invention concerne de nouveaux dérivés d'épirubicine, une composition pharmaceutique comprenant ces dérivés, et des applications de l'épirubicine et de ses dérivés dans le traitement d'une infection par le VHC.
PCT/PL2006/000080 2005-12-27 2006-11-14 Nouveaux derives d'epirubicine, leur application medicinale et formes medicamenteuses de qualite pharmaceutique WO2007075094A1 (fr)

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PLP378535 2005-12-27
PCT/PL2005/000086 WO2007075092A1 (fr) 2005-12-29 2005-12-29 Nouveaux derives d'epirubicine, leur application medicinale et formes medicamenteuses de qualite pharmaceutique
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090298786A1 (en) * 2007-02-07 2009-12-03 Instytut Biotechnologii I Antybiotykow Methods of treating viral infections with anthracycline antibiotics

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2757102A1 (de) * 1976-12-22 1978-07-06 Farmaceutici Italia Antitumorglycoside, verfahren zu deren herstellung und pharmazeutische mittel enthaltend diese verbindungen
DE3500029A1 (de) * 1985-01-02 1986-09-04 Farmitalia Carlo Erba S.p.A., Mailand/Milano Anthracyclinester
EP1721614A1 (fr) * 2005-05-12 2006-11-15 Institut National de la Santé et de la Recherche Médicale (INSERM) Hydrochlorure d'epirubicine pour le traitement du virus de l'hépatite C

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2757102A1 (de) * 1976-12-22 1978-07-06 Farmaceutici Italia Antitumorglycoside, verfahren zu deren herstellung und pharmazeutische mittel enthaltend diese verbindungen
DE3500029A1 (de) * 1985-01-02 1986-09-04 Farmitalia Carlo Erba S.p.A., Mailand/Milano Anthracyclinester
EP1721614A1 (fr) * 2005-05-12 2006-11-15 Institut National de la Santé et de la Recherche Médicale (INSERM) Hydrochlorure d'epirubicine pour le traitement du virus de l'hépatite C

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANTIBIOTIKI I KHIMIOTERAPIYA, vol. 34, no. 2, 1989, pages 105 - 109 *
BOROWSKI P ET AL: "NUCLEOTIDE TRIPHOSPHATASE/HELICASE OF HEPATITIS C VIRUS AS A TARGET FOR ANTIVIRAL THERAPY", ANTIVIRAL RESEARCH, ELSEVIER SCIENCE BV., AMSTERDAM, NL, vol. 55, no. 3, 2002, pages 397 - 412, XP008056992, ISSN: 0166-3542 *
DATABASE CA CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; UL'YANOVA. L.A. ET AL.: "Synthesis and antitumor properties of 3'-desamino-3'-dimethylformamidino- doxorubicin", XP002421383 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090298786A1 (en) * 2007-02-07 2009-12-03 Instytut Biotechnologii I Antybiotykow Methods of treating viral infections with anthracycline antibiotics

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