WO1999057126A1 - Nouveaux derives d'anthracycline et leur preparation - Google Patents

Nouveaux derives d'anthracycline et leur preparation Download PDF

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Publication number
WO1999057126A1
WO1999057126A1 PCT/KR1999/000220 KR9900220W WO9957126A1 WO 1999057126 A1 WO1999057126 A1 WO 1999057126A1 KR 9900220 W KR9900220 W KR 9900220W WO 9957126 A1 WO9957126 A1 WO 9957126A1
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WO
WIPO (PCT)
Prior art keywords
adriamycin
anthracycline
compounds
aspartate
pyruvate
Prior art date
Application number
PCT/KR1999/000220
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English (en)
Inventor
Sang Chul Park
Heun Soo Kang
Young S. Rho
Original Assignee
Sang Chul Park
Heun Soo Kang
Rho Young S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sang Chul Park, Heun Soo Kang, Rho Young S filed Critical Sang Chul Park
Priority to EP99919679A priority Critical patent/EP1075484A1/fr
Priority to JP2000547095A priority patent/JP2002513797A/ja
Publication of WO1999057126A1 publication Critical patent/WO1999057126A1/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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the present invention relates to novel anthracycline derivatives and a method for preparing the anthracycline derivatives. More particularly, the present invention relates to novel anthracycline derivatives which are of potent activity against various cancers with greatly reduced cardiac toxicity and to a preparing method therefor. Also, the present invention is concerned with an antitumor agent comprising the anthracycline derivatives as pharmaceutically effective ingredients.
  • Rhodomycin, daunomycin and adriamycin which all are of anthracyclines, can be obtained from the fermented broth of Actinomyces species. Since the determination of their chemical structures, much effort has been made to prepare the anthracyclines chemically because they are known to have a broad spectrum antitumor activity. Now, a variety of anthracyclines are developed, which are exemplified by daunomycin, adriamycin, carminomycin, 4'-epi-adriamycin, 4'-methoxyadriamycin, 4'- deoxyadriamycin and idarubicin. Currently, these compounds are clinically used in anticancer chemotherapy.
  • the quinone compounds with such an anthracycline chemical structure have a potent activity against a wide range of malignant tumors, including lymphocytic leukemia and malignant lymphoma, but are accompanied by serious side effects, such as cardiac problem, bone marrow depression, alopecia, etc. Especially, serious cardiac toxicity frequently appears upon their use. This cardiac toxicity runs an acute course or passes into a chronic state, causing heat contractile dysfunction, arrhythmia and hypotension. What is the worst, the patients treated with these compounds may suffer from heart failure resulting in death. They are, thus, strictly limited in clinical use.
  • anthracycline glycosides which have potent anticancer activity and are of even weaker toxic in general, and in particular significantly less cardiac toxicity than the conventional anthracycline glycoside anticancer agents, such as daunomycin, adriamycin, carminomycin and idarubicin, represented by the following structural formula I:
  • R ⁇ and R 4 which may be the same or different, each is a hydrogen atom, methoxy or hydroxy;
  • R 2 is L-aspartate or pyruvate; and R 3 is a hydrogen atom or fluorine atom.
  • This invention also provides pharmaceutically acceptable salts of the novel anthracycline derivatives.
  • antioxidants or radical scavengers in combination with the anticancer agents.
  • U.S. Pat. No. 5,646,177 reports anthracycline derivatives in which glutathione, serving as an antioxidant, is directly linked to the position 7 of the anthracycline.
  • these antioxidants and radical-scavenging enzymes are greatly limited in their use because proper conditions are not established for the enzymes included in radical removal and the antioxidants used to prevent radical damage show high reactivity.
  • novel anthracycline anticancer agents which have potent antitumor activity as well as effective antioxidant activity to reduce the side effects of oxygen radicals in addition to being highly safe, allows the invention to be realized.
  • Fig. 1 is a chemical scheme showing the preparation pathway of the novel anthracycline glycoside anticancer compounds according to the present invention.
  • the compounds represented by the structural formula I are prepared by linking L-aspartate or pyruvate via an ester bond to the position 14 of the anthracycline glycoside anticancer antibiotics represented by the following general formula II:
  • R, R 2 , R 3 and R 4 each are as defined above.
  • the well-known anthracycline glycoside anticancer compounds represented by the general formula II correspond to the starting materials la to If in the preparation scheme for the novel anthracycline glycoside anticancer compounds of the invention.
  • the preparation of the novel anthracycline glycoside compounds, represented by the general formula I is achieved by following the preparation pathway shown in Fig. 1.
  • well-known techniques Journal of Medicinal Chemistry, 17, 335, 1974 are applied.
  • the present inventors found that the compounds represented by the general formula I have similar activity against cancers to those of conventional anthracycline glycoside anticancer agents as well as show such a reduced cardiac toxicity as expected. Therefore, the compounds of the general formula I are considered as anticancer agents by virtue of their low cardiac toxicity and superb anticancer activity.
  • the compounds I of the present invention show greatly reduced cardiac toxicity as confirmed by tests.
  • Lewis lung carcinoma a solid cancer
  • physiological saline was used at a dose of 10 ml per kg of weight.
  • the tumor volumes of the experimental animals alive were measured at 16 days after cancer transplantation for Lewis lung carcinoma and at 18 days after cancer transplantation for B 16 melanoma.
  • the tumor volume was calculated as l/2ab 2 where a is the length (mm) of the longer axis and b is the shorter axis of the solid tumor mass measured by a digital caliper.
  • TGI Tumor growth inhibition
  • TGI (%) (1-Vt/Vc) x 100 wherein Vt represents an average tumor volume of a test group administered with drugs and Vc represents an average tumor volume of a control group administered with the solvent.
  • the anticancer efficacy of each of the drugs was evaluated by the ILS, which was obtained by the ratio (%) of the mean survival time in drug-treated animals to that in the control animals.
  • ILS estimated on day 61 after tumor implantation.
  • the antitumor activity of the tested drugs against the B 16 mouse melanoma transplanted into the hypodermis of BDFl mice is given in Table 1, below.
  • TGI tumor necrosis factor-1
  • all of the novel anthracycline derivatives showed efficacious effects at a dose of 25 or higher mg/kg while adriamycin was effective at a dose of 10 mg/kg only, on the basis of the measurements at 18 days after the cancer inoculation.
  • a maximal TGI was 58%) for the mouse group administered with adriamycin at a dose of 10 mg/kg.
  • the novel anthracycline derivatives showed a maximal TGI of 89% at a dose of 50 mg/kg. Therefore, the novel anthracycline derivatives all were found to be superior to adriamycin in inhibiting the growth of B16 melanoma.
  • the novel anthracycline derivatives all were effective for the groups administered at a dose of 25 mg/kg or higher and adriamycin was effective for the groups administered at a dose of 5.0 and 10.0 mg/kg, based on an ILS of 30%) or higher.
  • a maximal ILS was found at a dose of 50.0 mg/kg for the novel anthracycline derivatives and 10.0 mg/kg for adriamycin, amounting to 290-585 % and 119 %, respectively.
  • TGI tumor-free state was realized in the mice which was administered with the novel anthracycline at a dose of 50 mg/kg.
  • the novel anthracycline derivatives all were effective for the groups administered at a dose of 25 mg/kg or higher, based on an ILS of 30%) or higher.
  • a maximal ILS was found at a dose of 50.0 mg/kg for the novel anthracycline derivatives and 10.0 mg/kg for adriamycin, amounting to 245 % and 58 %, respectively.
  • Adriamycin- 14-Asp 50 81 3/6 72 +1.5 100 80 3/6 98 +0.4
  • Adriamycin- 14-Pyruv. 50 85 3/6 75 +1.2 100 80 3/6 82 +0.1 -16-
  • Idarubicin- 14-Asp 50 175 4/6 89 +1.2 100 155 3/6 97 +0.8
  • the novel anthracycline compounds of the present invention show potent activity against cancers, which would be extremely useful as antitumoral agents applicable for clinical practice, alone and in combination with other - 17 - conventional anticancer agents.
  • anthracycline compounds exhibit similar efficacy to those of parent anticancer agents because, when the novel anthracycline represented by the general formula I exert anticancer activity in vivo, they are decomposed at their ester linkage by esterase, remaining as the same forms as the parent compounds.
  • the compound No. 1 of the present invention is decomposed into adriamycin and L-aspartate by an esterase, in vivo, the former exerting anticancer effects.
  • the novel anticancer drugs were tested for cardiac toxicity as follows.
  • the animal breeding room was maintained at 22 °C under an SPF condition.
  • the rats were intraperitoneally injected with the samples once per week for 5 weeks.
  • adriamycin and daunomycin each were administered at a dose of 4 mg/kg while the aspartate derivatives and pyruvate derivatives of the anthracycline were administered at a dose of 5 mg/kg and 3.5 mg/kg, respectively, for cardiac toxicity tests.
  • the compounds of the present invention may be administered parenterally or orally in admixture with pharmaceutically acceptable carriers or diluent. Upon oral administration, the compounds may be formulated into tablets or suitable forms. Examples of the parenteral administration of the novel compounds may include abdominal injection, hypothermic injection, intravenous injection and arterial injection for animals and intravenous or arterial injection and local injection for humans.
  • the total administration amount and dose of the novel compounds of the present invention are dependent on administration routes and the patient or animal's conditions, such as age, body weight, sex, sensitivity, diet, administration time, co-administered medicines, severity, etc.
  • the compounds of the present invention are used as antitumor agents, they can be administered at a wider range of doses than can adriamycin, and are preferably used at a dose of 5.0 to 25 mg/kg of body weight per day.
  • the compounds of the general formula I exhibit antibacterial activity against gram positive bacteria and thus, can be used -22- for treating the diseases caused by gram positive bacteria, at such a dose in the administration routes as described above.
  • the novel anthracycline compounds of the present invention have antitumor activity similar to that of conventional anthracycline drugs, but are extremely lower in cardiac toxicity than the conventional drugs.
  • the novel anthracycline derivatives according to the present invention can be used as antitumor agents applicable for clinical practice.
  • the anthracycline compounds represented by the general formula I exist as salt states, they show a high solubility in water and a high chemical stability in addition to being easy to chemically handle.
  • the compounds of the present invention exhibit superb antitumor activity against cells and animal tumors, so they can be used as antitumor agents to treat malignant tumors, such as solid cancers and ascites cancers.

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

Abstract

L'invention concerne de nouveaux dérivés d'anthracycline représentés par la formule (I), (dans laquelle R1 et R4, pouvant être semblables ou différents, représentent chacun un atome d'hydrogène, méthoxy ou hydroxy; R2 représente L-aspartate ou pyruvate et R3 représente un atome d'hydrogène ou un atome de fluor),exerçant une activité antitumorale puissante contre un large spectre de tumeurs et présentant une toxicité cardiaque extrêmement limitée, ainsi que leur procédé de préparation. Ces composés peuvent compléter l'équilibre du rapport NAD/NADH in vivo afin de contrôler l'activité d'enzymes produisant des radicaux d'oxygène. La préparation de ces composés peut consister à relier L-aspartate ou pyruvate par l'intermédiaire d'une liaison ester à la position 14 de glycosides d'anthracycline classiques. Etant donné leur activité puissante et leur sûreté pharmaceutique, on peut mettre en application ces composés en tant qu'ingrédients efficaces sur le plan pharmaceutique d'agent antitumoraux.
PCT/KR1999/000220 1998-05-07 1999-05-07 Nouveaux derives d'anthracycline et leur preparation WO1999057126A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99919679A EP1075484A1 (fr) 1998-05-07 1999-05-07 Nouveaux derives d'anthracycline et leur preparation
JP2000547095A JP2002513797A (ja) 1998-05-07 1999-05-07 新規アンスラサイクリン誘導体及びその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1998/16348 1998-05-07
KR1019980016348A KR19990084528A (ko) 1998-05-07 1998-05-07 신규 안트라사이클린 유도체 및 제조방법

Publications (1)

Publication Number Publication Date
WO1999057126A1 true WO1999057126A1 (fr) 1999-11-11

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ID=19537115

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR1999/000220 WO1999057126A1 (fr) 1998-05-07 1999-05-07 Nouveaux derives d'anthracycline et leur preparation

Country Status (4)

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EP (1) EP1075484A1 (fr)
JP (1) JP2002513797A (fr)
KR (2) KR19990084528A (fr)
WO (1) WO1999057126A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011033A1 (fr) * 2002-07-24 2004-02-05 Universite Catholique De Louvain Méthode de synthèse de conjugués anthracycline-peptide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646177A (en) * 1994-05-02 1997-07-08 Board Of Regents Of The University Of Colorado Glutathione derivatives of anthracyclines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5430146A (en) * 1977-08-05 1979-03-06 Microbial Chem Res Found Novel anthracycline derivatives and their preparation
JPH0742304B2 (ja) * 1986-12-05 1995-05-10 財団法人微生物化学研究会 新規なアンスラサイクリン誘導体およびその製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646177A (en) * 1994-05-02 1997-07-08 Board Of Regents Of The University Of Colorado Glutathione derivatives of anthracyclines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011033A1 (fr) * 2002-07-24 2004-02-05 Universite Catholique De Louvain Méthode de synthèse de conjugués anthracycline-peptide

Also Published As

Publication number Publication date
KR19990084528A (ko) 1999-12-06
EP1075484A1 (fr) 2001-02-14
KR100398289B1 (ko) 2003-09-19
JP2002513797A (ja) 2002-05-14
KR20010043400A (ko) 2001-05-25

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