WO2013070988A2 - Procédé de traitement de l'ostéosarcome - Google Patents
Procédé de traitement de l'ostéosarcome Download PDFInfo
- Publication number
- WO2013070988A2 WO2013070988A2 PCT/US2012/064255 US2012064255W WO2013070988A2 WO 2013070988 A2 WO2013070988 A2 WO 2013070988A2 US 2012064255 W US2012064255 W US 2012064255W WO 2013070988 A2 WO2013070988 A2 WO 2013070988A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- indazole
- tetrachlorobis
- ruthenate
- trans
- iii
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention generally relates to pharmaceutical compositions and methods for treating cancer, and particularly to a pharmaceutical composition and method for treating osteosarcoma.
- Osteosarcoma is an aggressive malignant cancer arising from cells of mesenchymal origin, and is the most common histological form of primary bone cancer. Also, it has one of the lowest survival rates for pediatric cancer. Thus, there is urgent need for new effective therapy for osteosarcoma.
- the present invention provides methods of treating osteosarcoma.
- the present invention provides a method of treating, preventing, or delaying the onset of, osteosarcoma, comprising administering to a mammal, particularly human, having osteosarcoma a therapeutically or prophylatically effective amount of a pharmaceutically acceptable salt of trans-[tetrachlorobis(l H-indazole)mthenate(III)] (e.g., sodium trans- [tetrachlorobis(lH-indazole)ruthenate(III)] or potassium trans- [tetrachlorobis(lH- indazole)ruthenate(IIl)]).
- trans-[tetrachlorobis(l H-indazole)mthenate(III)] e.g., sodium trans- [tetrachlorobis(lH-indazole)ruthenate(III)] or potassium trans- [tetrachlorobis(lH- indazo
- a method of treating, preventing, or delaying the onset of, a refractory osteosarcoma comprising administering a therapeutically or prophylatically effective amount of a pharmaceutically acceptable salt of trans- [tetrachlorobis(lH-indazole)ruthenate(III)] (e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(III)] or potassium trans-[tetrachlorobis( l H-indazole)ruthenate(III)]) to a mammal having refractory osteosarcoma.
- a pharmaceutically acceptable salt of trans- [tetrachlorobis(lH-indazole)ruthenate(III)] e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(III)] or potassium trans-[tetrachlorobis( l H-indazole)ruthenate(III)
- trans-[tetrachlorobis(lH- indazole)ruthenate(III)] e.g., sodium trans-[tetrachlorobis(lH-indazole)ruthenate(III)] or potassium trans-[tetrachlorobis( lH-indazole)ruthenate(IH)]
- a pharmaceutically acceptable salt of trans-[tetrachlorobis(lH- indazole)ruthenate(III)] e.g., sodium trans-[tetrachlorobis(lH-indazole)ruthenate(III)] or potassium trans-[tetrachlorobis( lH-indazole)ruthenate(IH)]
- the present invention is at least in part based on the discovery that the compound sodium trans-[tetrachlorobis(lH-indazole)ruthenate(in)] is surprisingly effective in treating osteosarcoma. Accordingly, in accordance with a first aspect of the present invention, a method is provided for treating osteosarcoma including primary and metastatic osteosarcoma. The method comprises treating a mammal, including a human, having one or more osteosarcoma in need of treatment with a therapeutically effective amount of trans- [tetrachlorobis(lH-indazole)ruthenate(III)] or a pharmaceutically acceptable salt thereof.
- Examples of such a salt include an indazolium salt or alkali metal salt of trans- [tetrachlorobis(lH-indazole)ruthenate(III)] (e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(lll)] or potassium trans-[tetrachlorobis( I H-indazole)ruthenate(ni)]).
- trans- [tetrachlorobis(lH-indazole)ruthenate(III)] e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(lll)] or potassium trans-[tetrachlorobis( I H-indazole)ruthenate(ni)]
- the present invention is directed to the use of an effective amount of a trans- [tetrachlorobis( lH-indazole)nithenate(lll)] or a pharmaceutically acceptable salt thereof (e.g., indazolium or alkali metal salt) for the manufacture of medicaments for treating osteosarcoma in a mammal (human, dog, cat, etc.) identified or diagnosed as having osteosarcoma.
- a trans- [tetrachlorobis( lH-indazole)nithenate(lll)] or a pharmaceutically acceptable salt thereof (e.g., indazolium or alkali metal salt) for the manufacture of medicaments for treating osteosarcoma in a mammal (human, dog, cat, etc.) identified or diagnosed as having osteosarcoma.
- the treatment method optionally also comprises a step of diagnosing or identifying a patient as having osteosarcoma.
- the identified patient is then treated with or administered with a
- Various osteosarcoma may be diagnosed in any conventional diagnostic methods known in the art such as CT scan, endoscopy, biopsy, etc.
- another aspect of the present invention provides a method of treating refractory osteosarcoma comprising treating a mammal (human, dog, cat, etc.) identified as having a refractory osteosarcoma with a therapeutically effective amount of trans- [tetrachlorobis(lH-indazole)ruthenate(III)] or a pharmaceutically acceptable salt thereof,
- alkali metal salt thereof e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(III)] or potassium trans-[tetrachlorobis(lH-indazole)ruthenate(III)].
- refractory osteosarcoma refers to osteosarcoma that either fails to respond favorably to an anti-neoplastic treatment that does not include trans- [t.etrachlorobis(lH-indazole)ruthenate(III)] or a pharmaceutically acceptable salt thereof, or alternatively, recurs or relapses after responding favorably to an antineoplastic treatment that does not include trans-[tetrachlorobis(lH-indazole)ruthenate(III)] or a pharmaceutically acceptable salt thereof.
- osteosarcoma refractory to a treatment means osteosarcoma that fails to respond favorably to, or resistant to, the treatment, or alternatively, recurs or relapses after responding favorably to the treatment, e.g., a treatment comprising one or more drugs chosen from methotrexate, cisplatin, adriamycin, ifosfamide and etoposide.
- patients undergoing initial treatment can be carefully monitored for signs of resistance, non-responsiveness or recurring osteosarcoma. This can be accomplished by monitoring the patient's cancer's response to the initial treatment.
- the response, lack of response, or relapse of the cancer to the initial treatment can be determined by any suitable method practiced in the art. For example, this can be accomplished by the assessment of tumor size and number. An increase in tumor size or, alternatively, tumor number, indicates that the tumor is not responding to the chemotherapy, or that a relapse has occurred. The determination can be done according to the "RECIST" criteria as described in detail in Therasse et a!, J. Nail. Cancer Inst. 92:205-216 (2000).
- a method for preventing, or delaying the onset of, osteosarcoma, or preventing or delaying the recurrence of osteosarcoma which comprises treating a patient in need of the prevention or delay with a prophylatically effective amount of trans-[tetrachlorobis(lH- indazole)ruthenate(lll) I or a pharmaceutically acceptable salt thereof, preferably an alkali metal salt of trans-[tetrachlorobis(lH-indazole)ruthenate(III)] (e.g., sodium trans- [tetrachlorobis(lH-indazole)ruthenate(III)] or potassium trans-[tetrachlorobis(l H- indazole)ruthenate(III)]).
- trans-[tetrachlorobis(lH- indazole)ruthenate(lll) I or a pharmaceutically acceptable salt thereof preferably an alkali metal salt of trans-[tetrachlorobis(l
- patients with osteosarcoma who have been treated and are in remission or in a stable or progression free state may be treated with a prophylatically effective amount of an alkali metal salt of trans- [tetrachlorobis(lH-indazole)ruthenate(III)] (e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(lll)] or potassium trans-[tetrachlorobis(l H-indazole)ruthenate(III)]) to effectively prevent or delay the recurrence or relapse of osteosarcoma.
- trans- [tetrachlorobis(lH-indazole)ruthenate(III)] e.g., sodium trans-[tetrachlorobis(lH- indazole)ruthenate(lll)] or potassium trans-[tetrachlorobis(l H-indazole)ruthenate(III)]
- phrase "treating . with . . .” or a paraphrase thereof means administering a compound to the patient or causing the formation of a compound inside the body of the patient.
- osteosarcoma may be treated with a therapeutically effective amount of trans- [tetrachlorobis(lH-indazole)ruthenate(lll)] or a pharmaceutically acceptable salt thereof, preferably an alkali metal salt of trans-[tetrachlorobis( l H-indazole)ruthenate(III)], alone as a single agent, or alternatively in combination with one or more other anti-cancer agents.
- Alkali metal salts of trans-[tetrachlorobis(lH-indazole)ruthenate(III)] can be made in any methods known in the art.
- PCT Publication No. WO/2008/154553 discloses an efficient method of making sodium trans-[tetrachlorobis(l H- indazole)ruthenate(III)] .
- the pharmaceutical compounds such as sodium trans- [tetrachlorobis( 1H- indazole)ruthenate(lll)] can be administered through intravenous injection or any other suitable means at an amount of from 0.1 mg to 1000 mg per kg of body weight of the patient based on total body weight.
- the active ingredients may be administered at once, or may be divided into a number of smaller doses to be administered at predetermined intervals of time, e.g., once daily or once every two days. It should be understood that the dosage ranges set forth above are exemplary only and are not intended to limit the scope of this invention.
- the therapeutically effective amount of the active compound can vary with factors including, but not limited to, the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan.
- the amount of administration can be adjusted as the various factors change over time.
- a pharmaceutically acceptable salt e.g., an alkali metal salt preferably sodium trans-[tetrachlorobis(lH-indazole)ruthenate(III)]
- a pharmaceutically acceptable salt is administered to a patient at an amount of at least 300, 400, 500, 550, 600, 650, 700 mg/m 2 or greater based on body surface area, at each administration.
- a pharmaceutically acceptable salt e.g., an alkali metal salt preferably sodium trans-[tetrachlorobis(lH- indazole)ruthenate(Tl l)]
- the drug is administered by intravenous injection once per week, preferably on days 1 , 8, and 15 of each 28-day cycle.
- the medicament can be, e.g., in an injectable form, e.g., suitable for intravenous, intradermal, or intramuscular administration.
- injectable forms are generally known in the art, e.g., in buffered solution or suspension.
- a pharmaceutical kit comprising in a container a unit dosage form of trans- [tetrachlorobis(lH- indazole)ruthenate(III)] or a pharmaceutically acceptable salt thereof, such as an alkali metal salt of trans-[tetrachlorobis(l H-indazole)ruthenate(III)] (e.g., sodium trans- [tetrachlorobis(lH-indazole)ruthenate(III)] or potassium trans-[tetrachlorobis(l H- indazole)aithenate(III)]), and optionally instructions for using the kit in the methods in accordance with the present invention, e.g., treating, preventing, or delaying the onset of osteosarcoma, or preventing or delaying the recurrence of osteosarcoma, or treating refractory osteosarcoma.
- tetrachlorobis( lH-indazole)ruthenate(III)] or a pharmaceutically acceptable salt thereof such as an alkali metal salt of trans- [tetrachlorobis(lH-indazole)ruthenate(IH)] (e.g., sodium trans-[tetrachlorobis(l H- indazole)ruthenate(III)] or potassium trans-[tetrachloiObis(l H-indazole)ruthenate(III)])
- trans- [tetrachlorobis(lH-indazole)ruthenate(IH)] e.g., sodium trans-[tetrachlorobis(l H- indazole)ruthenate(III)] or potassium trans-[tetrachloiObis(l H-indazole)ruthenate(III)]
- ATCC's MTT Cell Proliferation Assay* was performed using the Saos-2 human osteosarcoma cell line purchased from the ATCC Stock cultures were allowed to grow to 70-80% confluence for this study.
- the anti-proliferative activity of sodium trans- [tetrachlorobis(l H-indazole)ruthenate(III)] against the indicated cell line was evaluated in vitro using the ATCC's MTT Cell Proliferation Assay (Catalog No. 30-101 OK).
- the absorbance data was analyzed as follows: Absorbance values were converted to Percent of Control and plotted against test agent concentrations for IC5 0 calculations using SoftMax ® Pro (version 5.2, Molecular Devices). The plate blank signal average was subtracted from all wells prior to calculating the Percent of Control. Percent of Control values were calculated by dividing the absorbance values for each test well by the No Drug Control average (column 1 1 values; cells + vehicle control) and multiplying by 100. Plots of Compound Concentration versus Percent of Control were analyzed using the 4-parameter equation to obtain IC5 0 values and other parameters that describe the sigmoidal dose response curve.
- the IC J O value for the test agent was estimated by curve-fitting the data using the following four parameter-logistic equation:
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
La présente invention concerne des procédés et des compositions pour traiter l'ostéosarcome.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161557427P | 2011-11-09 | 2011-11-09 | |
US61/557,427 | 2011-11-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2013070988A2 true WO2013070988A2 (fr) | 2013-05-16 |
WO2013070988A3 WO2013070988A3 (fr) | 2013-07-25 |
Family
ID=48290765
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/064255 WO2013070988A2 (fr) | 2011-11-09 | 2012-11-09 | Procédé de traitement de l'ostéosarcome |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2013070988A2 (fr) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050032801A1 (en) * | 2001-01-26 | 2005-02-10 | Faustus Forschungs Cie. Translational Cancer Research Gmbh | Compositions containing a ruthenium(III) complex and a heterocycle |
US20090318402A1 (en) * | 2006-03-07 | 2009-12-24 | The University Court Of The University Of Edinburg | Ruthenium (ii) compounds |
US20100094019A1 (en) * | 2007-06-11 | 2010-04-15 | Keppler Berhhard | Method of manufacturing a ruthenium complex |
WO2010121245A1 (fr) * | 2009-04-17 | 2010-10-21 | Niiki Pharma Inc. | Méthode de traitement du carcinome hépatocellulaire |
-
2012
- 2012-11-09 WO PCT/US2012/064255 patent/WO2013070988A2/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050032801A1 (en) * | 2001-01-26 | 2005-02-10 | Faustus Forschungs Cie. Translational Cancer Research Gmbh | Compositions containing a ruthenium(III) complex and a heterocycle |
US20090318402A1 (en) * | 2006-03-07 | 2009-12-24 | The University Court Of The University Of Edinburg | Ruthenium (ii) compounds |
US20100094019A1 (en) * | 2007-06-11 | 2010-04-15 | Keppler Berhhard | Method of manufacturing a ruthenium complex |
WO2010121245A1 (fr) * | 2009-04-17 | 2010-10-21 | Niiki Pharma Inc. | Méthode de traitement du carcinome hépatocellulaire |
Non-Patent Citations (2)
Title |
---|
HEFFETER, P. ET AL.: 'Intracellular protein binding patterns of the anticancer ruthenium drugs KP1019 and KP1339' JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY vol. 15, June 2010, pages 737 - 748, XP019854157 * |
HUDEJ, R. ET AL.: 'The Influence of Electroporation on Cytotoxicity of Anticancer Ruthenium(III) Complex KP1339 In Vitro and In Vivo' ANTICANCER RESEARCH vol. 30, June 2010, pages 2055 - 2063 * |
Also Published As
Publication number | Publication date |
---|---|
WO2013070988A3 (fr) | 2013-07-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2013543879A (ja) | 急性骨髄性白血病を治療するための単独またはシタラビンとの組合せにおけるボラセルチブ | |
JP2014513705A (ja) | 進行性固形腫瘍の治療方法 | |
AU2011323832B2 (en) | Method of treating neuroendocrine tumors | |
US20220184055A1 (en) | Chiauranib for treatment of small cell lung cancer | |
CN109419803A (zh) | 细胞自噬抑制剂与阿法替尼药物组合物及其在制备肿瘤增效制剂中的用途 | |
CA2831206A1 (fr) | Methode de traitement du cancer du pancreas | |
US20130090320A1 (en) | Method of treating prostate cancer | |
CA2821034C (fr) | Methode de traitement du cancer du pancreas | |
TWI454280B (zh) | Pharmaceutical composition or combination | |
EP2560638B1 (fr) | Composè pour i'utilisation dans le traitement d'un cancer gastrique | |
WO2013070988A2 (fr) | Procédé de traitement de l'ostéosarcome | |
WO2012068319A2 (fr) | Procédé de traitement de cancers hématologiques | |
US20130096099A1 (en) | Method of treating brain cancer | |
EP2538944B1 (fr) | Composé pour le traitement du cancer du cerveau | |
WO2012012304A2 (fr) | Procédé de traitement de cancer réfractaire | |
RU2678103C2 (ru) | Противоопухолевое средство, содержащее противоопухолевый комплекс платины, и усилитель противоопухолевого эффекта | |
WO2021143754A1 (fr) | Combinaison pour le traitement du cancer et son application | |
RU2784869C1 (ru) | Чиаураниб для лечения мелкоклеточного рака легкого | |
WO2023202563A1 (fr) | Inhibiteur d'akt en association avec un inhibiteur de kinase pim | |
JP2016210733A (ja) | ガン予防または治療用医薬組成物 | |
US20130324513A1 (en) | Method for treating esophageal cancer | |
JPS6337767B2 (fr) | ||
JP2018104291A (ja) | マグネシウム化合物を有効成分として含有することを特徴とする医薬組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
122 | Ep: pct application non-entry in european phase |
Ref document number: 12847639 Country of ref document: EP Kind code of ref document: A2 |