EP1809281A2 - Use of epothilones in the treatment of bone metastases and bone tumors or cancers - Google Patents

Use of epothilones in the treatment of bone metastases and bone tumors or cancers

Info

Publication number
EP1809281A2
EP1809281A2 EP05788787A EP05788787A EP1809281A2 EP 1809281 A2 EP1809281 A2 EP 1809281A2 EP 05788787 A EP05788787 A EP 05788787A EP 05788787 A EP05788787 A EP 05788787A EP 1809281 A2 EP1809281 A2 EP 1809281A2
Authority
EP
European Patent Office
Prior art keywords
dione
dihydroxy
methyl
ethenyl
tetramethyl
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.)
Withdrawn
Application number
EP05788787A
Other languages
German (de)
French (fr)
Inventor
Jens Hoffmann
Ulrich Klar
Hubertus Pietsch
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.)
Bayer Pharma AG
Original Assignee
Bayer Schering Pharma AG
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34928830&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1809281(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Priority to EP05788787A priority Critical patent/EP1809281A2/en
Publication of EP1809281A2 publication Critical patent/EP1809281A2/en
Withdrawn legal-status Critical Current

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
    • A61K31/33—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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • Epothilones in the Treatment of Bone Metastasis
  • the present invention relates to the use of Epothilones in the treatment of bone metastases and bone tumors or cancers, more particularly in treating, preventing or alleviating bone metastasis in a cancer patient.
  • the epothilones represent a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot., 1996, 49, 560-3; or Hoefle et al., Angew. Chem. [Applied Chem.], 1996, 108, 1671-1673). These cytotoxic antimitotic agents, block the mitotic spindle of a proliferating cell by binding to the spindle-peptide tubulin, and thus cause apoptosis (K.-H. Altmann, Curr. Opin. Chem. Biol., 2001 , 5, 424-431).
  • Epothilone A and B as well as some of their synthetic derivatives have recently found interest in connection with the treatment of cancer, and a lot of work has been done on their synthesis (K. Nicolaou et al., Angew. Chem., 1998, 110, 2120-2153) and the synthesis of modified structures.
  • WO 99/07692 disclose Epothilone derivatives, their synthesis and pharmaceutical use.
  • WO 00/66589 deals with the synthesis and pharmaceutical use of Epothilone derivatives having an alkenyl-, alkynyl-, or a cyclic ether containing substituent at the 6(1 Opposition of the macrocyclic ring.
  • WO 00/49021 discloses Epothilone derivatives with a halogen substituent in the 16(3)-position and their synthesis.
  • WO 00/71521 discloses a method for the synthesis of olefinic Epothilones.
  • WO 98/25929 deals with the manufacture of libraries of Epothilone analogs.
  • WO 99/43320 mentions, in a very general manner, the use of Epothilones for the treatment of cancer.
  • WO 03/074053 describes the use of Epothilones and Epothilone analogs in the treatment of brain diseases associated with proliferative processes.
  • WO 04/050089 describes the use of conjugates of Epothilones and Epothilone derivatives (as effectors) with suitable saccharides as saccharide derivatives (as recognition units) in the treatment of proliferative or angiogenesis-associated processes.
  • WO 2004/012735 describes the use of conjugates of Epothilones and Epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) in the treatment of proliferative or angiogenesis-associated processes.
  • WO 03/007924 describes the combination of Epothilones with a bisphosphonate, a platinum compound or a vasculostatic compound as use as combination therapy in the treatment of, inter alia, bone metastasis.
  • the present invention provides the use of an Epothilone in the manufacture of medicaments for use as an inhibitor of bone metastasis and bone tumor growth and is thus useful for the treatment of malignant diseases metastasizing to the bones.
  • the invention also provides a method of inhibiting bone metastasis and bone tumor growth in a patient in need of such treatment, which method comprises the administration to the said patient of an effective amount of an Epothilone.
  • the invention also relates to methods of treating bone metastasis by oral, parental, rectal, or local, preferably inhalational, intravenous, or intraperitoneal, most preferably intravenous administration of an Epothilone.
  • the medicament containing the Epothilone is used to treat, prevent, or alleviate bone metastasis.
  • the bone metastasis results from cancer elsewhere in the body, for example, prostate cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, colorectal cancer, ovarian cancer and brain cancer.
  • the medicament is for treating, preventing or alleviating the symptoms of bone metastasis, more particularly in the treatment of bone metastasis in patients with cancer, even more particularly in the treatment of patients with breast and prostate cancer.
  • the medicament may also be used to prevent or alleviate symptoms of pain associated with bone metastases and risk of pathological fractures and hypercalcemia.
  • the medicament containing the Epothilone is used to treat, prevent, or alleviate primary bone tumors or cancers, including benign tumors and malignant tumors such as osteosarcoma, chondrosarcoma, Ewing's tumor, Giant cell tumor of bone, and Chordoma.
  • benign tumors and malignant tumors such as osteosarcoma, chondrosarcoma, Ewing's tumor, Giant cell tumor of bone, and Chordoma.
  • an Epothilone is defined as a cyclic molecule with a 16-membered ring and variable substituents and pharmaceutical activity as a cytostatic agent that binds to tubulin (Asnes et al., Anal. Biochem. 1979, 98, 64-73; Job et al., Cellular Pharmacol. 1993, I (Suppl. I), S7-S10; Lichtner et al., PNAS 2001 , 98, 11743-11748).
  • An Epothilone also includes Epothilone conjugates such as those described in WO 04/050089 and WO 2004/012735 which are herein incorporated by reference.
  • Epothilones are that wherein the Epothilone molecule contains a lactone or a lactame moiety.
  • Preferred Epothilones for use in the present invention are compounds of the general formula:
  • R 1a , R 1b are each independently hydrogen, C- 1 -C 10 alkyl, aryl, aralkyl, or together form a -(CH 2 ) m -group where m is 2 to 5;
  • R 2a , R 2b are each independently hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together form a -(CH 2 ) n -group where n is 2 to 5, or are C 2 -C 10 alkenyl or C 2 -Ci 0 alkynyl;
  • R J is hydrogen, C- 1 -C 10 alkyl, aryl, aralkyl
  • R 4a , R 4b are each independently hydrogen, C- 1 -C 10 alkyl, aryl, aralkyl, or together form a -(CH 2 ) P - group where p is 2 to 5;
  • R 5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO 2 H, CO 2 alkyl,
  • R 6 , R 7 are each hydrogen, or together form an additional bond, or together form an epoxy function
  • G is O or CH 2 ;
  • X is O, or two groups OR 20 , or a C 2 -Ci O alkylenedioxy group (which may be straight or branched), or H and the group
  • R 8 is hydrogen, d-C-io alkyl, aryl, aralkyl, halogen, CN;
  • R 9 is hydrogen or a protecting group PG X ;
  • R 10 , R 11 are each independently hydrogen, CrC 2O alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7- membered carbocyclic ring;
  • Z is O or H and the group OR 12 ;
  • R 12 is hydrogen or a protecting group PG Z ;
  • R 20 is a Ci-C 20 alkyl group
  • R 21 is hydrogen, or CrC 10 a Ikyl
  • PG X , PG Z is C- 1 -C 20 alkyl, C 4 -C 7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, CrC 2O acyl, aroyl, CrC 20 alkylsulfonyl, arylsulfonyl, W(CrC 20 alkyl)silyl, CN(CrC 20 alkyl) arylsilyl, (CrC 20 alkyl)diarylsilyl, or tri(aralkyl)silyl;
  • terapéuticaally effective amount refers to that amount of a compound of the invention which, when administered to an individual in need thereof, is sufficient to effect treatment, as d efined below, for bone metastasis.
  • the amount which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating refers to the treatment of bone metastasis and/or bone tumors or cancers in an individual; and include: (i) preventing the disease from recurring in an individual, in particular, when such individual is in need of further medicamentous treatment after a previous surgical or medicamentous therapy;
  • alkyl refers to straight or branched alkyl groups, e. g., methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, ⁇ -pentyl, neopentyl, heptyl, or decyl.
  • Alkyl groups can be perfluorated or substituted by one to five substituents selected from the group consisting of halogen, hydroxy, d-C 4 alkoxy, or C 6 -Ci 2 aryl (which can be substituted by one to three halogen atoms).
  • alkenyl refers to a straight or branched chain monovalent or divalent radical, containing at least one double bond and having from two to ten carbon atoms, e.g., ethenyl, prop-2-en-1-yl, but-1 -enyl, pent-1-enyl, penta-1 ,4-dienyl, and the like.
  • alkynyl refers to a substituted or unsubstituted straight or branched chain monovalent or divalent radical, containing at least one triple bond and having from two to ten carbon atoms, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl, and the like.
  • Alkenyl and alkenyl groups can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO 2 H, - CO 2 Alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C 20 acyl, or C r C 20 acyloxy.
  • aryl refers to an aromatic carbocyclic or heterocyclic moiety containing five to 14 ring atoms, e.g., phenyl, naphth/l, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, chinolyl, or thiazolyl.
  • Aryl groups can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO 2 H, -CO 2 Alkyl, -NH 2 , Alkyl-NH 2 , CrC 20 alkyl-thiolanyl, -NO 2 , -N 3 , -CN, CrC 2 O alkyl.
  • the heteroatoms can be oxidized, if this does not cause a loss of aromatic character, e. g., a pyridine moiety can be oxidized to give a pyridine N- oxide.
  • aralkyl refers to a group which can contain up to 14 atoms in the aryl ring (preferred five to ten) and one to eight carbon atoms in the alkyl chain (preferred one to four), e.g., benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, or pyridylpropyl.
  • the rings can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO 2 H, -CO 2 Alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C r C 20 alkyl, CrC 20 acyl, or CrC 20 acyloxy.
  • the protecting groups PG can be alkyl- and/or aryl-substituted silyl moieties, Ci- C 20 alkyi, C 4 -C 7 cycloalkyl, which may contain an oxygen atom in the ring, aryU aralkyl, CrC 20 acyl, aroyl, alkyl- or arylsulfonyl.
  • Groups which can be easily be removed from the molecule are preferred, e.g., methoxymethyl, methoxyethyl , polyethylene glycol, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, /-butyldimethylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, as well as alkylsulfonyl or arylsulfonyl .
  • acyl groups are formyl, acetyl, propionyl, pivaloyl, butyryl, or benzoyl . which all can be substituted by one or more amino and/or hydroxy moieties.
  • R 2a , R 2b are each independently hydrogen, C 2 -Ci O alkenyl or C 2 -Ci 0 alkynyl; R 6 , R 7 form an epoxy function or together form an additional bond; W is a 2-Methyl-benzothiazol-5-yl radical or a 2-Methyl-benzoxazol-5-yl radical or a Quinoline-7-yl radical.
  • a preferred subgroup is compounds selected from the following: (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa- 5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
  • a preferred subgroup is compounds selected from the following: (4S,7R,8S ! 9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyI-7-ethyl-cyclohexadec-13-ene-2,6- dione;
  • a preferred subgroup is compounds selected from the following: (4S J 7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1- oxa- ⁇ . ⁇ .i S-tetramethyl ⁇ prop ⁇ -in-i-yO-cyclohexadec-IS-ene ⁇ . ⁇ -dione;
  • the compounds can be formulated by methods known in the art.
  • Compositions for the oral, rectal, parenteral or local application can be prepared in the form of tablets, capsules, granulates, suppositories, implantates, sterile injectable aqueous or oily solutions, suspensions or emulsions, aerosols, salves, creams, or gels, retard preparations or retard implantates.
  • the compounds may also be administered by implantable dosing systems.
  • the pharmaceutical active compound(s) can thus be mixed with adjuvants known in the art, such as gum arabic, talcum, starch, mannitol, methyl cellulose, lactose, surfactants such as tweensd ⁇ or myrj®, magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives, and flavors.
  • adjuvants known in the art, such as gum arabic, talcum, starch, mannitol, methyl cellulose, lactose, surfactants such as tweensd ⁇ or myrj®, magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives, and flavors.
  • the compounds can be used in the form of their clathrates of o, ⁇ -, or ⁇ - cyclodextrin or of substituted ⁇ -, ⁇ -, or ⁇ -cyclodextrines, or in the form of a liposomal composition, in particular a liposomal composition comprising a polyethyleneglycol(PEG)-derivatized lipid.
  • the invention also relates to pharmaceutical compositions containing one or more of the pharmaceutically active compounds listed above, and their use for the treatment and in the methods in accordance with the present invention.
  • one dose unit of these compositions contains about 0.01-100 mg of the pharmaceutically active compound(s).
  • the dosage for the use according to the invention for a human is about 0.01-100 mg per day; a preferred dosage is about 0.02-70 mg per day; a more preferred dosage is about 0.04-40 mg per day.
  • SREs skeletal-related events
  • mice Four days before tumor cells implantation, the baseline bone structure of the mice was determined by X-ray. 30 NMRI nude mice received 500,000 of MDA-
  • MB 231 breast cancer tumor cells intracardially (Day 0).
  • the tumor cells metastasized to the bones and the growth of the tumor in the bones lead to bone destruction.
  • 10 of the 29 animals were treated with the Test Compound (10 mg/kg, Lv.).
  • the size and number of bone metastases were monitored 4 days before tumor cell implantation
  • mice Preparation of the Animals (anaesthesia, fixation)
  • the mice underwent an anaesthesia with a mixture of Rompun ( Rompun 2% Bayer) diluted with sodium chloride solution( Braun) by 1 :10 and Ketavet ( Pharmacia GmbH 100mg/ ml), diluted by 1 :5 with isotonic sodium chloride solution.
  • Rompun Rompun 2% Bayer
  • Ketavet Pharmacia GmbH 100mg/ ml
  • 1 ml sterile syringes Codan Medical
  • cannula Braun Sterican, size 18
  • mice were attached to a 1 mm strong acrylic glass and additionally taped with a self-adhesive tape (sticky side facing the animal).
  • the acrylic glass served as surface on which the animals underwent the X-ray.
  • the standard setting of 35kV and 40OmAs was adjusted.
  • the setting was chosen in such a way to allow a good contrasting of the entire skeletal system and visibility of finest changes/aberrations of the bone structure and morphology.
  • the resolution of the systems lies at 0,27 ⁇ m.
  • the module "Zoomed Modus” was chosen for the detector and the ROIs 2-3 were selected in accordance with the previously selected positioning of the mouse.
  • the regulator Image High was adjusted to 2000.
  • the actual measurements were started as soon as the Offset measurings and the reference measurings had been performed.
  • the flexible table was brought into position (80 mm) and was advanced at a speed of 25,9 mm/sec.
  • the final position of the table was chosen in such a way that the entire body of the mouse could be X-rayed all at once during the examination.
  • the reference measuring was subtracted from each gained Image and was stored as a DICOM-fiie or as a BMP-file.
  • Results shown in Figure 1 show that the Test Compound inhibited bone metastasis in the in vivo model and that a prolongation of life time was observed. In fact, the size of the bone metastases were reduced after just 12 days following a single treatment and Mean Survival Time was improved.
  • treatment with the Test Compound resulted in a 5.9 mm 2 Mean Tumor Area compared to 14.0 mm 2 without treatment.
  • the overall Mean Survival Time rose from 23.4 days without treatment to 31.6 days following a single application of the Test Compound in the treatment group.
  • Figure 1 visualises the efficacy in the bone metastasis model.
  • the baseline bone structure of the mice was determined by X-ray (Animal #01 , left).
  • MDA-MB 231 breast cancer tumor cells were implanted intracardially into nude mice on Day 0 (i.e. four days after baseline). Treatment was started on Day 10 when first signs of bone metastasis were observed.
  • the same untreated animal whose survival time of 23 days is close to the mean survival time (23.4 days) of the untreated control group, has developed severe bone metastasis on Day 22 (see white arrows, middle).
  • Animal #22 represents a typical member of the treatment group whose survival time of 30 days is close to the mean survival time (31.6 days) in the treatment group. Size and amount of bone metastasis are reduced.
  • the Test Compound was given in the indicated dose. The size of the bone metastases after Day 22 with and without treatment is shown.
  • Results are shown in Table 2: The mean number of bone metastases is significantly reduced from 21.2 per animal in the untreated control group (Group 1) to 0.7 per animal in the group treated with the Test Compound (Group 2). The mean size of bone metastases is significantly reduced from 8.1 mm 2 per animal in Group 1 to 0.1 mm 2 per animal in Group 2.
  • the number of animals which developed tumors at the tumor cell injection site is reduced from 5 aminals in Group 1 to 0 animals in Group 2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to the use of Epothilones in the treatment of bone metastases and bone tumors or cancers, more particularly in treating, preventing or alleviating bone metastasis in a cancer patient.

Description

Use of Epothilones in the Treatment of Bone Metastasis
The present invention relates to the use of Epothilones in the treatment of bone metastases and bone tumors or cancers, more particularly in treating, preventing or alleviating bone metastasis in a cancer patient.
The epothilones represent a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot., 1996, 49, 560-3; or Hoefle et al., Angew. Chem. [Applied Chem.], 1996, 108, 1671-1673). These cytotoxic antimitotic agents, block the mitotic spindle of a proliferating cell by binding to the spindle-peptide tubulin, and thus cause apoptosis (K.-H. Altmann, Curr. Opin. Chem. Biol., 2001 , 5, 424-431).
The natural products Epothilone A and B as well as some of their synthetic derivatives have recently found interest in connection with the treatment of cancer, and a lot of work has been done on their synthesis (K. Nicolaou et al., Angew. Chem., 1998, 110, 2120-2153) and the synthesis of modified structures.
WO 99/07692, WO 99/02514, WO 99/67252, and WO 2004/014919 disclose Epothilone derivatives, their synthesis and pharmaceutical use.
WO 00/66589 deals with the synthesis and pharmaceutical use of Epothilone derivatives having an alkenyl-, alkynyl-, or a cyclic ether containing substituent at the 6(1 Opposition of the macrocyclic ring.
WO 00/49021 discloses Epothilone derivatives with a halogen substituent in the 16(3)-position and their synthesis.
WO 00/71521 discloses a method for the synthesis of olefinic Epothilones.
WO 98/25929 deals with the manufacture of libraries of Epothilone analogs. WO 99/43320 mentions, in a very general manner, the use of Epothilones for the treatment of cancer.
WO 03/074053 describes the use of Epothilones and Epothilone analogs in the treatment of brain diseases associated with proliferative processes.
WO 04/050089 describes the use of conjugates of Epothilones and Epothilone derivatives (as effectors) with suitable saccharides as saccharide derivatives (as recognition units) in the treatment of proliferative or angiogenesis-associated processes.
WO 2004/012735 describes the use of conjugates of Epothilones and Epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) in the treatment of proliferative or angiogenesis-associated processes.
WO 03/007924 describes the combination of Epothilones with a bisphosphonate, a platinum compound or a vasculostatic compound as use as combination therapy in the treatment of, inter alia, bone metastasis.
None of these publications, however, describe the use of Epothilones as monotherapy for the treatment of bone metastasis or bone tumors. In fact, there is no general disclosure or suggestion in the prior art that pharmaceutically effective amounts of an Epothilone directly decrease benign or malignant proliferative processes in bones. Thus the technical problem underlying the present invention is to provide compounds for the manufacture of medicaments for use in the treatment of bone metastases and bone tumors or cancers. The solution to this technical problem is achieved by using Epothilones as described below for the manufacture of said medicaments.
It has now unexpectedly been found that certain Epothilones can inhibit bone metastasis and growth of bone tumors or cancers, and thus show a beneficial effect in the treatment of malignant diseases metastasizing to the bones. Accordingly, the present invention provides the use of an Epothilone in the manufacture of medicaments for use as an inhibitor of bone metastasis and bone tumor growth and is thus useful for the treatment of malignant diseases metastasizing to the bones. The invention also provides a method of inhibiting bone metastasis and bone tumor growth in a patient in need of such treatment, which method comprises the administration to the said patient of an effective amount of an Epothilone.
The invention also relates to methods of treating bone metastasis by oral, parental, rectal, or local, preferably inhalational, intravenous, or intraperitoneal, most preferably intravenous administration of an Epothilone.
In a particular embodiment of the present invention, the medicament containing the Epothilone is used to treat, prevent, or alleviate bone metastasis. The bone metastasis results from cancer elsewhere in the body, for example, prostate cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, colorectal cancer, ovarian cancer and brain cancer. In particular, the medicament is for treating, preventing or alleviating the symptoms of bone metastasis, more particularly in the treatment of bone metastasis in patients with cancer, even more particularly in the treatment of patients with breast and prostate cancer. The medicament may also be used to prevent or alleviate symptoms of pain associated with bone metastases and risk of pathological fractures and hypercalcemia.
In another particular embodiement of the present invention, the medicament containing the Epothilone is used to treat, prevent, or alleviate primary bone tumors or cancers, including benign tumors and malignant tumors such as osteosarcoma, chondrosarcoma, Ewing's tumor, Giant cell tumor of bone, and Chordoma.
For the purposes of the present invention, an Epothilone is defined as a cyclic molecule with a 16-membered ring and variable substituents and pharmaceutical activity as a cytostatic agent that binds to tubulin (Asnes et al., Anal. Biochem. 1979, 98, 64-73; Job et al., Cellular Pharmacol. 1993, I (Suppl. I), S7-S10; Lichtner et al., PNAS 2001 , 98, 11743-11748). An Epothilone also includes Epothilone conjugates such as those described in WO 04/050089 and WO 2004/012735 which are herein incorporated by reference.
The preferred group of Epothilones is that wherein the Epothilone molecule contains a lactone or a lactame moiety.
Preferred Epothilones for use in the present invention are compounds of the general formula:
wherein:
R1a, R1b are each independently hydrogen, C-1-C10 alkyl, aryl, aralkyl, or together form a -(CH2)m-group where m is 2 to 5;
R2a, R2b are each independently hydrogen, C1-C10 alkyl, aryl, aralkyl, or together form a -(CH2)n-group where n is 2 to 5, or are C2-C10 alkenyl or C2-Ci0 alkynyl;
RJ is hydrogen, C-1-C10 alkyl, aryl, aralkyl;
R4a, R4b are each independently hydrogen, C-1-C10 alkyl, aryl, aralkyl, or together form a -(CH2)P- group where p is 2 to 5; R5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl,
CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2N(alkyl, acyl)i,2, or CH2HaI;
R6, R7 are each hydrogen, or together form an additional bond, or together form an epoxy function;
G is O or CH2;
D-E together is a group -H2C-CH2-, -HC=CH-, -C≡C-, -CH(OH)- CH(OH)-, -CH(OH)-CH2-, -CH2-CH(OH)-, -CH2-O-, -O-CH2-
(Qf-CH > whereby if G is O then D-E cannot be
CH2-O; or
D-E-G together is a group H2C-CH=CH
W is a group C(=X)R8, or is a bi- or tricyclic aromatic or heteroaromatic radical;
X is O, or two groups OR20, or a C2-CiO alkylenedioxy group (which may be straight or branched), or H and the group
OR9, or a group CR10R11;
R8 is hydrogen, d-C-io alkyl, aryl, aralkyl, halogen, CN;
R9 is hydrogen or a protecting group PGX;
R10, R11 are each independently hydrogen, CrC2O alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7- membered carbocyclic ring;
Z is O or H and the group OR12;
R12 is hydrogen or a protecting group PGZ; A-Y is a group O-C(=O), C)-CH2, CH2-C(=O), NR21-C(=O), NR21-
SO2;
R20 is a Ci-C20 alkyl group;
R21 is hydrogen, or CrC10 a Ikyl;
PGX, PGZ is C-1-C20 alkyl, C4-C7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, CrC2O acyl, aroyl, CrC20 alkylsulfonyl, arylsulfonyl, W(CrC20 alkyl)silyl, CN(CrC20 alkyl) arylsilyl, (CrC20 alkyl)diarylsilyl, or tri(aralkyl)silyl;
as a single stereoisomer or a mixture of different stereoisomers, and / or as a pharmaceutically acceptable salt thereof.
Preferred Embodiments
The term "therapeutically effective amount" as used herein refers to that amount of a compound of the invention which, when administered to an individual in need thereof, is sufficient to effect treatment, as d efined below, for bone metastasis. The amount which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
"Treating" or "treatment" as used herein refers to the treatment of bone metastasis and/or bone tumors or cancers in an individual; and include: (i) preventing the disease from recurring in an individual, in particular, when such individual is in need of further medicamentous treatment after a previous surgical or medicamentous therapy;
(ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. The term "alkyl" as used herein refers to straight or branched alkyl groups, e. g., methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, π-pentyl, neopentyl, heptyl, or decyl. Alkyl groups can be perfluorated or substituted by one to five substituents selected from the group consisting of halogen, hydroxy, d-C4 alkoxy, or C6-Ci2 aryl (which can be substituted by one to three halogen atoms).
The term "alkenyl" as used herein refers to a straight or branched chain monovalent or divalent radical, containing at least one double bond and having from two to ten carbon atoms, e.g., ethenyl, prop-2-en-1-yl, but-1 -enyl, pent-1-enyl, penta-1 ,4-dienyl, and the like.
The term "alkynyl" as used herein refers to a substituted or unsubstituted straight or branched chain monovalent or divalent radical, containing at least one triple bond and having from two to ten carbon atoms, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl, and the like.
Alkenyl and alkenyl groups can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO2H, - CO2Alkyl, -NH2, -NO2, -N3, -CN, C1-C20 acyl, or CrC20 acyloxy.
The term "aryl" as used herein refers to an aromatic carbocyclic or heterocyclic moiety containing five to 14 ring atoms, e.g., phenyl, naphth/l, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, chinolyl, or thiazolyl. Aryl groups can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO2H, -CO2Alkyl, -NH2, Alkyl-NH2, CrC20 alkyl-thiolanyl, -NO2, -N3, -CN, CrC2O alkyl. C1-C20 acyl, or C1- C20 acyloxy. The heteroatoms can be oxidized, if this does not cause a loss of aromatic character, e. g., a pyridine moiety can be oxidized to give a pyridine N- oxide.
The term "aralkyl" as used herein refers to a group which can contain up to 14 atoms in the aryl ring (preferred five to ten) and one to eight carbon atoms in the alkyl chain (preferred one to four), e.g., benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, or pyridylpropyl. The rings can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO2H, -CO2Alkyl, -NH2, -NO2, -N3, -CN, CrC20 alkyl, CrC20 acyl, or CrC20 acyloxy.
The protecting groups PG can be alkyl- and/or aryl-substituted silyl moieties, Ci- C20 alkyi, C4-C7 cycloalkyl, which may contain an oxygen atom in the ring, aryU aralkyl, CrC20 acyl, aroyl, alkyl- or arylsulfonyl. Groups which can be easily be removed from the molecule are preferred, e.g., methoxymethyl, methoxyethyl , polyethylene glycol, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, /-butyldimethylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, as well as alkylsulfonyl or arylsulfonyl .
Preferred acyl groups are formyl, acetyl, propionyl, pivaloyl, butyryl, or benzoyl . which all can be substituted by one or more amino and/or hydroxy moieties.
A preferred group is compounds of the general formula as given above, wherein A-Y is O-C(=O); D-E is H2C-CH2; G is CH2; Z is O; R1a, R1b are both CrC10 alkyl or form together a -(CH2)P- group where p is 2 to 3; R2a, R2b are each independently hydrogen, CrCi0 alkyl, C2-Ci0 alkenyl, or C2-Ci0 alkynyl; R3 is hydrogen; R4a, R4b are each independently hydrogen or CrCi0 alkyl; R5 is Q- Cio alkyl.
Another preferred group is compounds of the general formula as given above , wherein R2a, R2b are each independently hydrogen, C2-CiO alkenyl or C2-Ci0 alkynyl; R6, R7 form an epoxy function or together form an additional bond; W is a 2-Methyl-benzothiazol-5-yl radical or a 2-Methyl-benzoxazol-5-yl radical or a Quinoline-7-yl radical.
Of this group, a preferred subgroup is compounds selected from the following: (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa- 5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2- methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione; (48,7R1SS1QS, 13E/Z.16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1 -oxa- 5,5,9, 13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2- methyl-benzothiazol-5-yl)-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa- 9,13-dimethyl-5,5-(1 ,3-trimethylen)-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6- dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2- methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1 ,3-trimethylen)-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa- 5,5,9, 13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2- methyl-benzothiazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(chinolin-7-yl)-1-oxa-5,5,9,13- tetramethyl-7-(prop-2-en-1 -yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3- (chinolin-7-yl)-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo[14.1.0]heptadecane-5,9- dione;
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10- (prop^-en-i-yl^δ.δ.^JΘ-tetramethyl^.^-dioxabicyclot^.i .OJheptadθcanθ- 5,9-dione; (4S,7R,8S,9S,13E/Z,16S)-4!8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza- 5,5,9, 13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione; and
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2- methyl-benzothiazol-δ-yO-δ.δ.^.iβ-tetramethyl-^aza-U-oxabicyclotM.I .O] heptadecane-5,9-dione.
Another preferred group of compounds has the general formula as given above, wherein R2a, R2b are each independently hydrogen, or Ci~Cio alkyl; R6, R7 form an epoxy function, or form an additional bond; W is a group C(=X)R8; X is a group CR10R11; R8 is hydrogen, halogen, CrCi0 alkyl; R10, R11 are hydrogen/2- methyl-thiazol-4-yl, hydrogen/2-pyridyl, hydrogen/2-methylamine-thiazol-4-yl, or hydrogen/2-methylsulfanyl-thiazol-4-yl .
Of this group, a preferred subgroup is compounds selected from the following: (4S,7R,8S!9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyI-7-ethyl-cyclohexadec-13-ene-2,6- dione;
(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2- methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyc!o[14.1.0]heptadecane-5,9-dione;
(4S>7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5-(1 ,3-trimethylen)-9,13-dimethyl-7-ethyl- cyclohexadec-13-ene-2,6-dione;
(1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2- methyl-4-thiazolyl)ethenyl)-8,8-(1 ,3-trimethylen)-12,16-dimethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyOethenyO-i-oxa-δ.δ.θ.iS-tetramethyl^-propyl-cyclohexadec-IS-enθ^.β- dione; (IS/R^SCEJJS.IOR.H R.^S.IβR/SK.H-dihydroxy-IO-propyl-S-CI-methyl^- (2-methyl-4-thiazolyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/ZI16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyOethenylJ-i-oxa-δ^J^JS-pentamethyl-cyclohexadec-IS-ene^.β-dione;
(1 S/R,3S(Z),7S, 10R, 11 S, 12S116R/S)-7, 11 -dihydroxy-3-(1 -fluor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/ZJ16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6- dione;
(15/R1SS(Z)JS1IOR111S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8, 12, 16-tetra methyl- 10-ethyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S)7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)θthenyl)-1-oxa-5,5-(1 ,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13- ene-2,6-dione;
(IS/R.SSCZJJS.IOR.I IS.^S.IβR/SK.H-dihydroxy-S^I-fluor^^-methyl^- thiazoIyl)θthenyl)-8,8-(1.S-trimethylenJ-IO.^je-trimethyM.17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5-(1 ,3-trimethylen)-9,13-dimethyl-7-ethyl- cyclohexadec-13-ene-2,6-dione;
(1S/R,3S(Z),7S)10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8-(1 ,3-trimethylen)-12,16-dimethyl-10-ethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione;
(18/R1SS(Z)1ZS1IOR111S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-8Λ10,12,16iDentamethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R)8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5, 5,9,1 S-tetramethyl-y-ethyl-cycIohexadec-IS-ene^.θ- dione;
(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazoIyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6- dione;
(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8, 12,16-tetramethyl-10-propyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1- oxa-δ.δ^.iS-tetramethyl^-propyl-cyclohexadec-IS-ene^.θ-dione;
(1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2- (2-pyridyl)ethenyl)-8,8,12>16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane- 5,9-dione;
(4S,7R,8Sf9S,13t=/Z,16S(E))-4I8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1- oxa-5,5-(1 ,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione; (1S/R,3S(E),7S,10R,11 R,12S>16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2- pyridyI)ethenyl)-8,8-(1 ,3-trimethylen)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S, 13E/Z.16S(E))-4,8-dihydroxy-16-(1 -methyl-2-(2-pyridyl)ethenyl)-1 ■ oxa-5,5-(1 ,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-3-(1-methyl-2-(2- pyridyl)ethenyl)-8,8-(1 ,3-trimethylen)-10,12,16-trimethyl-4, 17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8SI9S>13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1- oxa-5,5,9,13-tθtramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione; (1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2- (2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane- 5,9-dione;
(4SJR1SS^S1I 3E/Z.16S(Z))-4,8-dihydroxy-16-(1 -fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5-(1 ,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13- ene-2,6-dione;
(1 S/R,3S(Z),7S, 10R, 11 S, 12S, 16R/S)-7, 11 -dihydroxy-3-(1 -fluor-2-(2-methyl-4- thiazolyOethenyO-δ.δ-CI .S-trimethylen^iO.^.ie-dimethyl^,^- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z)16S(Z))-4l8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6- dione;
(1S/R,3S(Z),7S,10R,11S,12S)16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8, 12, 16-tetramethyl-10-ethyI-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione; (4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl) ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione; and
(1S/R,3S(Z),7S,10R,11SI12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-8,8, 12,16-tetramethyl-10-ethyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione.
Another preferred group is compounds of the general formula as given above, wherein R2a, R2b are each independently hydrogen, C2-Ci0 alkenyl or C2-C10 alkynyl; R6, R7 form an epoxy function or together form an additional bond; W is a group C(=X)R8; X is a group CR10R11; R8 is hydrogen, halogen, CrCi0 alkyl; R10, R11 are hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl.
Of this group, a preferred subgroup is compounds selected from the following: (4SJ7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1- oxa-δ^.θ.i S-tetramethyl^prop^-in-i-yO-cyclohexadec-IS-ene^.δ-dione;
(1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2- pyridyI)ethenyl)-8,8, 12,16-tetramethyl-4,17-dioxabicyclo[14.1. OJheptadecane- 5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1- oxa-5, 5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(IS/R.SSCEJJS.IOR.H R.^S.ieR/SK.H-dihydroxy-IO-Cprop^-en-i-yO-S-CI- methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z.16S(E))-4,8-dihydroxy-16-(1 -methyl-2-(2-pyridyl)ethenyl)-1 - oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione; (18/R1SS(E)JS1IOR, 11 R, 12S116R/S)-7, 11 -dihydroxy-10-(but-3-in-1 -yl)-3-(1 - methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(I SZR1SS(E)JS1IOR, 11 R,12S,16RZS)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1- methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(1S/R,3S(E)JS,10R, 11 R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3~(2-(2- pyridyl)ethenyl)-8,8,1 2,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane- 5,9-dione;
(4SJR,8S,9S,13EZZ, 16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methylthiazol-4- yl)θthenyl)-1 -oxa-5,5 , 9, 13-tetramethyl-7-(prop-2-in-1 -yl)-cyclohexadec-13-ene- 2,6-dione;
(1SZR,3S(Z)JS,10R, 11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1- fluor-2-(2-methylthiaz:ol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S JR,8S,9S,13EZZ.16S(Z))-4,8-dihydroxy-16-(1 -fluor-2-(2-methylthiazol-4- yl)ethenyl)-1 -oxa-5,5 ,9,13-tetramethyl-7~(prop-2-en-1 -yl)-cyclohexadec-13-ene- 2,6-dione; and
(1 SZR,3S(Z) JS.1 OR, 11 R.12S.16RZS)-7, 11 -dihydroxy-10-(prop-2-en-1 -yl)-3-(1 - fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione.
Also preferred are the natural compound Epothilone B and compounds of the general formula as g iven above wherein A-Y is NR21-C=O.
The synthesis of the compounds listed above is described in the international patent applications VVO 99/07692, WO 00/49021 , WO 03/041068, WO 03/041063, WO 00/66589, WO 04/050089 and WO 2004/012735 which are incorporated herein by reference.
For the use according to the invention, the compounds can be formulated by methods known in the art. Compositions for the oral, rectal, parenteral or local application can be prepared in the form of tablets, capsules, granulates, suppositories, implantates, sterile injectable aqueous or oily solutions, suspensions or emulsions, aerosols, salves, creams, or gels, retard preparations or retard implantates. The compounds may also be administered by implantable dosing systems.
The pharmaceutical active compound(s) can thus be mixed with adjuvants known in the art, such as gum arabic, talcum, starch, mannitol, methyl cellulose, lactose, surfactants such as tweensdϋ or myrj®, magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives, and flavors.
The compounds can be used in the form of their clathrates of o, β-, or γ- cyclodextrin or of substituted α-, β-, or γ-cyclodextrines, or in the form of a liposomal composition, in particular a liposomal composition comprising a polyethyleneglycol(PEG)-derivatized lipid.
The invention also relates to pharmaceutical compositions containing one or more of the pharmaceutically active compounds listed above, and their use for the treatment and in the methods in accordance with the present invention. Preferably, one dose unit of these compositions contains about 0.01-100 mg of the pharmaceutically active compound(s). The dosage for the use according to the invention for a human is about 0.01-100 mg per day; a preferred dosage is about 0.02-70 mg per day; a more preferred dosage is about 0.04-40 mg per day.
Compounds of the present invention have demonstrated positive results in bone metastasis animal models. The compounds of the present invention can be tested for utility through clinical trials, wherein the compounds are administered to human bone metastasis patients and the endpoint determines whether the compounds have any effect on bone metastasis. The beneficial effects of Epothilones to reduce skeletal-related events (SREs) in cancer patients with a history of metastatic bone disease, can also be determined directly through the results of these studies or by changes in the study design known to a person skilled in the art. SREs are defined as pathological bone fracture events, spinal cord compression events, surgery to bone, radiation therapy to bone and a change of antineoplastic therapy to treat bone pain.
The present invention will be further illustrated in the following Examp
Example 1 - Inhibition of Bone Metastasis Using an Epothilone (Bone Metastasis Model)
Model:
Human breast cancer MDA MB 231 , injected to NMRI nude mice intracardially
Test Compound:
7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,1 2,16- tetramethyM.I Z-dioxabicyclotM.I .OJheptadecane-δ.θ-dione
Experimental Design:
Four days before tumor cells implantation, the baseline bone structure of the mice was determined by X-ray. 30 NMRI nude mice received 500,000 of MDA-
MB 231 breast cancer tumor cells intracardially (Day 0). The tumor cells metastasized to the bones and the growth of the tumor in the bones lead to bone destruction. After the period of 10 days (Day 10), 10 of the 29 animals were treated with the Test Compound (10 mg/kg, Lv.). The size and number of bone metastases were monitored 4 days before tumor cell implantation
(baseline) and on Day 22 in each animal using the X-ray technology described below.
Investigation of Bone Metastasis on Mice with Mammomat 3000 (Siemens) (X- Ray Technology):
Preparation of the Animals (anaesthesia, fixation) The mice underwent an anaesthesia with a mixture of Rompun ( Rompun 2% Bayer) diluted with sodium chloride solution( Braun) by 1 :10 and Ketavet ( Pharmacia GmbH 100mg/ ml), diluted by 1 :5 with isotonic sodium chloride solution. For application of the narcotics, 1 ml sterile syringes (Codan Medical) and cannula (Braun Sterican, size 18) were used.
Once the tolerance stage was reached, the mice were attached to a 1 mm strong acrylic glass and additionally taped with a self-adhesive tape (sticky side facing the animal). The acrylic glass served as surface on which the animals underwent the X-ray.
Instrumental Equipment / Mammomat for Monochromatic X-Ray
At the console of the Mammomat (run by the software "Detector" (Ifg) on Windows NT platform), the standard setting of 35kV and 40OmAs was adjusted. The setting was chosen in such a way to allow a good contrasting of the entire skeletal system and visibility of finest changes/aberrations of the bone structure and morphology. The resolution of the systems lies at 0,27 μm.
After initializing the Software the module "Zoomed Modus" was chosen for the detector and the ROIs 2-3 were selected in accordance with the previously selected positioning of the mouse. The regulator Image High was adjusted to 2000.
The actual measurements were started as soon as the Offset measurings and the reference measurings had been performed. The flexible table was brought into position (80 mm) and was advanced at a speed of 25,9 mm/sec. The final position of the table was chosen in such a way that the entire body of the mouse could be X-rayed all at once during the examination. The reference measuring was subtracted from each gained Image and was stored as a DICOM-fiie or as a BMP-file. Results
Analysis of the treatment was performed on Day 22 by evaluating twice the constructed exposures of the mice and searching for destructive processes of the skeletal system (focussing mainly on the long bones, spine and pelvis). The extend/area of the destructive processes/bone metastasis were determined with a special DICOM-Software (based on Microsoft Excel).
Results shown in Figure 1 show that the Test Compound inhibited bone metastasis in the in vivo model and that a prolongation of life time was observed. In fact, the size of the bone metastases were reduced after just 12 days following a single treatment and Mean Survival Time was improved. As can be seen in Table 1, treatment with the Test Compound resulted in a 5.9 mm2 Mean Tumor Area compared to 14.0 mm2 without treatment. The overall Mean Survival Time rose from 23.4 days without treatment to 31.6 days following a single application of the Test Compound in the treatment group.
Table 1
Description of the Figures
Figure 1 visualises the efficacy in the bone metastasis model. The baseline bone structure of the mice was determined by X-ray (Animal #01 , left). MDA-MB 231 breast cancer tumor cells were implanted intracardially into nude mice on Day 0 (i.e. four days after baseline). Treatment was started on Day 10 when first signs of bone metastasis were observed. The same untreated animal, whose survival time of 23 days is close to the mean survival time (23.4 days) of the untreated control group, has developed severe bone metastasis on Day 22 (see white arrows, middle). Animal #22 represents a typical member of the treatment group whose survival time of 30 days is close to the mean survival time (31.6 days) in the treatment group. Size and amount of bone metastasis are reduced. The Test Compound was given in the indicated dose. The size of the bone metastases after Day 22 with and without treatment is shown.
Example 2 - Inhibition of Bone Metastasis Using an Epothilone (Bone Metastasis Model)
Model:
Human breast cancer MDA MB 231 , injected to NMRI nude mice intracardially
Test Compound:
7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16- tetramethyl-^I T-dioxabicyclotM.I .Olheptadecane-δ.θ-dione
Experimental Design:
30 NMRI nude mice received 500,000 of MDA-MB 231 breast cancer tumor cells intracardially (Day 0). The tumor cells metastasized to the bones and the growth of the tumor in the bones lead to bone destruction. In addition, the development of tumors near the tumor cell injection site is observed. After 5 days (Day 5), 15 of the 30 animals were treated with the Test Compound (10 mg/kg, i.v.). On Day 20 the experiment was terminated and the size and number of bone metastases were measured in each animal using the X-ray technology described in example 1. In addition, the numer of animals which developed tumors at the tumor cell injection site was determined.
Results
Results are shown in Table 2: The mean number of bone metastases is significantly reduced from 21.2 per animal in the untreated control group (Group 1) to 0.7 per animal in the group treated with the Test Compound (Group 2). The mean size of bone metastases is significantly reduced from 8.1 mm2 per animal in Group 1 to 0.1 mm2 per animal in Group 2.
The number of animals which developed tumors at the tumor cell injection site is reduced from 5 aminals in Group 1 to 0 animals in Group 2.
Table 2

Claims

What is claimed is:
1. Use of an Epothilone for the preparation of a medicament for use as an inhibitor of bone metastasis or bone tumor growth.
2. Use according to claim 1 wherein the medicament is for treating, preventing or alleviating bone metastasis.
3. Use according to claim 1 wherein the medicament is for treating, preventing or alleviating bone tumor growth.
4. Use according to claim 3 wherein the medicament is used to treat, prevent, or alleviate primary bone tumors or cancers including benign tumors and malignant tumors such as osteosarcoma, chondrosarcoma, Ewing's tumor, Giant cell tumor of bone, and Chordoma.
5. Use according to claim 2 wherein the medicament is for treating, preventing or alleviating bone metastasis in a cancer patient.
6. Use of any one of claims 1-5, wherein the Epothilone contains a lactone or a iactame moiety.
7. Use of any one of claims 1-5 wherein the Epothilone is a compound of the general formula:
wherein
R1a, R1b are each independently hydrogen, C-i-C-io alkyl, aryl, aralkyl, or together form a where m is 2 to 5;
R2a, R2b are each independently hydrogen, C1-C10 alkyl, aryl, aralkyl, or together form a -(CH2)n-group where n is 2 to 5, or are C2-Ci0 alkenyl or C2-C-Io alkynyl;
R3 is hydrogen, C1-Ci0 alkyl, aryl, aralkyl;
R4a, R4b are each independently hydrogen, CrCi0 alkyl, aryl, aralkyl, or together form a -(CH2)P- group where p is 2 to 5;
R5 is hydrogen, CrC10 alkyl, aryl, aralkyl, CO2H, CO2alkyl,
CH2OH, CH2OaIlCyI, CH2OaCyI, CN, CH2NH2, CH2N(alkyl, acyl)i,2, Or CH2HaI;
R6, R7 are each hydrogen, or together form an additional bond, or together form an epoxy function;
G is O or CH2;
D-E together is a group -H2C-CH2-, -HC=CH-, -C≡C-, -CH(OH)- CH(OH)-, -CH(OH)-CH2-, -CH2-CH(OH)-, -CH2-O-, -0-CH2-
(Q£-CH . whereby if G is O then D-E cannot be
CH2-O; or
D-E-G together is a group H2C-CH=CH;
W is a group C(=X)R8, or is a bi- or tricyclic aromatic or heteroaromatic radical;
X is O, or two groups OR20, or a C2-C10 alkylenedioxy group (which may be straight or branched), or H and the group OR9, or a group CR10R11;
R is hydrogen, C1-C10 alkyl, aryl, aralkyl, halogen, CN;
R9 is hydrogen or a protecting group PGX;
R10, R11 are each independently hydrogen, C-1-C20 alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7- membered carbocyclic ring;
Z is O or H and the group OR12;
R12 is hydrogen or a protecting group PGZ;
A-Y is a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O), or
NR21-SO2;
R is a C1-C2O alkyl group;
R21 is hydrogen, or CrC10 alkyl;
PGX, PGZ is C1-C20 alkyl, C4-C7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, C1-C20 acyl, aroyl, C1-C20 alkylsulfonyl, arylsulfonyl, W(C1-C20 alkyl)silyl, di(CrC20 alkyl) arylsilyl, (C1-C20 alkyl) diarylsilyl, or tri(aralkyl)silyl;
as a single stereoisomer or a mixture of different stereoisomers, and/or as a pharmaceutically acceptable salt thereof.
8. The use of claim 7, wherein
A-Y is O-C(=O); D-E is H2C-CH2;
G is CH2;
Z is O;
R1a, R1b are both CrCi0 alkyl or together form a — (CH2)m- group where m is 2 or 3;
R2a, R2b are each independently hydrogen, GrCi0 alkyl, C2-Ci0 alkenyl, or C2-Ci0 alkynyl;
R3 is hydrogen;
R4a, R4b are each independently hydrogen or CrCi0 alkyl;
Rϋ is CrCi0 alkyl.
9. The use of any one of claims 7 or 8, wherein
R2a, R2b are each independently hydrogen, C2-C-I 0 alkenyl or C2-Ci0 alkynyl;
R6, R7 together form an epoxy function or an additional bond; and
W is a 2-Methyl-benzothiazol-5-yl radical, a 2-MethyI- benzoxazol-5-yl radical, or a Quinoline-7r-yl radical.
10. The use of claim 7, wherein the compound is selected from the group consisting of:
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1- oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6- dione; (1S/RJ3S(E)l7S,10R,11 RJ12S,16R/S)-7!11-dihydroxy-10-(prop-2-en-1-yl)- 3-(2-methyl-benzoxazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9SI13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothia-zol-5-yl)- i-oxa-δ.δ.θ.iS-tetramethyl-Z^prop^-en-i-yO-cyclohexadec-IS-ene^.β- dione;
(18/R1SSJS1IOR111 R1^S1IeRZSH, 11 -dihydroxy-10-(prop-2-en-1-yl)-3- (2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)- 1-oxa-9,13-dimethyl-5,5-(1 ,3-trimethylen)-7-(prop-2-en-1-yl)- cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-
(2-methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1 ,3-trinnethylen>4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothia-zol-5-yl)- 1 -oxa-5,5,9, 13-tetramethyl-7-(prop-2-in-1 -yl)-cyclohexadec-13-ene-2,6- dione;
(1S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-
(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(chinolin-7-yl)-1-oxa- 5,5,9,13-tθtramethyl-7-(prop-2-en-1 -yl)-cyclohexadec-13-ene-2,6-dione;
(1 SZR1SSJS1I OR1I I R1^S1I eRZSH1H -dihydroxy-10-(prop-2-en-1-yl)-3- (chinolin-2-yl)-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo[14.1.0] heptadecane-5,9-dione; (1S,3S,7SI10R,11S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol- 5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyI-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)- 1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6- dione; and
(18/R1SSJS1IOR111 R,12S,16R/S)-7,11-dihydrOxy-10-(prop-2-en-1-yl)-3-
(2-methyl-benzothiazol-5-yl)-8,8, 12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecane-5,9-dione.
11. The use of any one of claims 7 or 8, wherein
R2a, R2b are each independently hydrogen, or CrCi0 alkyl;
R6, R7 together form an epoxy function or an additional bond;
W is a group C(=X)R8;
X is a group CR10R11;
R8 is hydrogen, halogen, or C1-C10 alkyl; and
R10, R11 are hydrogen/2-methyl-thiazol-4-yl, hydrogen/2-pyridyl, hydrogen/2-methylamine-thiazol-4-yl, or hydrogen/2- methylsulfanyl-thiazol-4-yl .
12. The use of claim 7, wherein the compound is selected from the group consisting of: (4SJR1SS^S113E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5, 5,9,1 S-tetramethyU-ethyl-cyclohexadec-i 3- ene-2,6-dione;
(18/R1SS(E)1ZS1IOR1I I R.iaS.iβR/SJ-y.H-dihydroxy-IO-ethyl-^i- methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5-(1 ,3-trimethylen)-9,13-dimethyl-7-ethyl- cyclohexadec-13-ene-2,6-dione;
(1 SZR1SS(E)JS110R,11 R,12S,16R/S)-7,11 -dihydroxy-10-ethyl-3-(1 - methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1 ,3-trimethylen)-12,16- dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13EZZ,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5, 5,9,1 S-tetramethyU-propyl-cyclohexadec-i 3- ene-2,6-dione;
(1 SZR1SS(E)JS110R,1 1 R,12S,16RZS)-7,1 1 -dihydroxy-10-propyl-3-(1- methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4SJR,8S,9S,13EZZ,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methy[-4- thiazolyOethenyO-i-oxa-δ.δJ.ΘJ S-pentamethyl-cyclohexadec-IS-ene-
2,6-dione;
(1 SZR,3S(Z)JS,10R,11 S,12S,16RZS)-7,1 1-dihydroxy-3-(1-fluor-2-(2- methyl-4-thiazoIyl)θthenyl)-8,8,10,12,16-pentamethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4SJR,8S,9S,13EZZ,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5, 5,9,13-tetramethyl-7-ethyl-cyclohexadec-13- ene-2,6-dione; (18/R1SS(Z)JS1IOR111 S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5-(1 ,3-trimethylen)-7,9,13-trimethyl- cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S(Z),7S,10R,1 1 S,12S,16R/S)-7,1 1-dihydroxy-3-(1-fluor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8-(1 ,3-trimethylen)-10, 12, 16-trimethyl-4, 17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5-(1 ,3-trimethylen)-9,13-dimethyl-7-ethyl- cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-fIuor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8-(1 ,3-trimethylen)-12,16-dimethyl-10-ethyl- 4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5,7,9,13-pentamethyl-cyclohexadec-i 3-ene- 2,6-dione;
(1 S/R,3S(Z),7S,10R,1 1S,12S)16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-ethyl-cyclohexadec-13- ene-2,6-dione; (1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8, 12,16-tetramethyl-10-ethyl-4, 17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S>7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-propyl-cyclohexadec-13- ene~2,6-dione;
(IS/R.SSCZ^S.IOR.HS.^S.ieR/SK.H-dihydroxy-S-CI-chlor^^- methyI-4-thiazolyl)ethenyl)-8,8, 12,16-tetramethyI-10-propyl-4, 17- dioxabicyclo[14.1.0] heptadecane~5,9-dione;
(4SJR1SS^S113EZZ.16S(E))-4,8-dihydroxy-16-(1 -methyl-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13- ene-2,6-dione;
(I SZR1SS(E)JS1I OR1I 1 R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1- methyl-2-(2-pyridyl)ethenyl)-8l8,12l16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4SJR1SS^S113E/Z,16S(E))-4,8-dihydroxy-16-(1 -methyl-2-(2- pyridyl)ethenyl)-1-oxa-5l5-(1 ,3-trimethyIen)-9,13-dimethyl-7-ethyl- cyclohexadec-13-ene-2,6-dione;
(1 SZR1SS(E)JS1I OR1H R1^S116R/S)-7,11 -dihydroxy-10-ethyl-3-(1 - methyl^^-pyridyOethenyO-δ^^i .S-trimethylenV^.i e-dimethyl^,^- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4SJR1SS^S113EZZ,16S(E))-4,8-dihydroxy-16-(1 -methyl-2-(2- pyridylJethenyO-i-oxa-δ.δ^i .S-trimethylen^^.i S-trimethyl- cyclohexadec-13-ene-2,6-dione; (18/R1SS(E)1TS1IOR111 R,12S,16R/S)-7,11-clihycliOxy-3-(1-methyl-2-(2- pyridyl)ethenyl)-8,8-(1 ,3-trimethylen)-10,12,16-trimethyl-4, 17- dioxabicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S,13E/Z,16S(E))-4I8-dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13- ene-2,6-dione;
(1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1- methyl^a-pyridyOethenyO-δ.δ.^Jβ-tetramethyM,^- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S>7R,8S,9SI13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5-(1 ,3-trimethylen)-7,9,13-trimethyl- cyclohexadθc-13-ene-2,6-dione;
(1S/R,3S(Z),7SI10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8-(1 ,3-trimethylen)-10,12,16-dimethyl-4,17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S, 13E/Z, 16S(Z))-4,8-dihydroxy-16-(1 -chlor-2-(2-methyl-4- thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13- ene-2,6-dione;
(1 S/RI3S(Z),7S,10R,1 1 S,12S,16R/S)-7,1 1-dihydroxy-3-(1-chlor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8, 12,16-tetramethyl-10-ethyl-4, 17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z)H,8-dihydroxy-16-(1-fluor-2-(2-methyl-4- thiazolyl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-ethyl-cyclohexadec-13- ene-2,6-dione; and
(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7I11-dihydroxy-3-(1-fluor-2-(2- methyl-4-thiazolyl)ethenyl)-8,8, 12, 16-tetramethyl-10-ethyl-4, 17- dioxabicyclo[14.1.0] heptadecane-5,9-dione.
13. The use of any one of claims 7 or 8, wherein
R2a, R2b are each independently hydrogen, C2-Ci0 alkenyl or C2-C10 alkynyl;
R6, R7 together form an epoxy function or an additional bond;
W is a group C(=X)R8;
X is a group CR10R11;
R is hydrogen, halogen, or C1-Ci0 alkyl; and
R10, R11 are hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl.
14. The use of claim 7, wherein the compound is selected from the group consisting of:
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-oxa-5, 5,9,13-tetramethyl-7-(prop-2-in-1 -yl)- cyclohexadec-13-ene-2,6-dione;
(1S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-
3-(2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S, 13E/Z,16S(E))-4,8-dihydroxy-16-(1 -methyl-2-(2- pyridyl)ethenyI)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)- cyclohexadec-13-ene-2,6-dione; (1 S/R,3S(E),7S,10R,1 1 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)- 3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1 .0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4!8-dihydroxy-16-(1-methyl-2-(2- pyrϊdyl)ethenyl)-1 -oxa-5,5,9,13-tetramethyl-7-(but-3-in-1 -yl)- cyclohexadec-13-ene-2,6-dione;
(I S/R.SSCEJJSJ OR.H R.^Sj eR/S^.H-dihydroxy-I O-Cbut-S-in-i-yO-S-
(i-methyl^^-pyridyOethenyO-δ.δ.^.iβ-tetramethyM, - dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(13/R1SS(E)JS1I OR111 R,12S,16R/S)-7,1 1-dihydroxy-10-(but-3-en-1-yl)- 3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1 .0] heptadecane-5,9-dione;
(1S/R,3S(E),7S,10R,1 1 R,12S,16R/S)-7I11-dihydroxy-10-(but-3-en-1-yl)- 3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S, 13E/Z, 16S(Z))-4,8-dihydroxy-16-(1 -fluor-2-(2-methylthiazol- 4-yl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-(prop-2-in-1 -yl)-cyclohexadec- 13-ene-2,6-dione;
(1S/R)3S(Z),7S,10R,1 1 R)12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)- 3-(1 -f luor-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methylthiazol-
4-yl)ethenyl)-1 -oxa-5,5,9, IS-tθtramethyl^prop^-en-i-yO-cyclohexadec- 13-ene-2,6-dione; and (13/R1SS(Z)JS1IOR111 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)- 3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicycio[14.1.0] heptadecane-5,9-dione.
15. The use of claim 7, wherein:
A-Y is NR21-C(=O)
16. The use of any one of claims 1 to 6 wherein the Epothilone is Epothilone B.
17. A method of treating bone metastasis or tumors comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 6 to 16.
18. A method according to claim 17 of treating, preventing or alleviating bone metastasis.
19. A method according to claim 17 of treating, preventing or alleviating bone tumor growth.
20. A method according to claim 18 of treating, preventing or alleviating bone metastasis in a cancer patient.
21. The use or the method according to any one of claims 1 to 20, wherein the medicament or the Epothilone is to be administered orally, parenterally, rectally, or locally.
22. The use or method according to claim 21 wherein the medicament or the Epothilone is administered intravenously.
EP05788787A 2004-09-24 2005-09-22 Use of epothilones in the treatment of bone metastases and bone tumors or cancers Withdrawn EP1809281A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05788787A EP1809281A2 (en) 2004-09-24 2005-09-22 Use of epothilones in the treatment of bone metastases and bone tumors or cancers

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP04090377A EP1640004A1 (en) 2004-09-24 2004-09-24 Use of epothilones in the treatment of bone metastases and bone tumors or cancers
EP05788787A EP1809281A2 (en) 2004-09-24 2005-09-22 Use of epothilones in the treatment of bone metastases and bone tumors or cancers
PCT/EP2005/010400 WO2006032537A2 (en) 2004-09-24 2005-09-22 Use of epothilones in the treatment of bone metastases and bone tumors or cancers

Publications (1)

Publication Number Publication Date
EP1809281A2 true EP1809281A2 (en) 2007-07-25

Family

ID=34928830

Family Applications (2)

Application Number Title Priority Date Filing Date
EP04090377A Withdrawn EP1640004A1 (en) 2004-09-24 2004-09-24 Use of epothilones in the treatment of bone metastases and bone tumors or cancers
EP05788787A Withdrawn EP1809281A2 (en) 2004-09-24 2005-09-22 Use of epothilones in the treatment of bone metastases and bone tumors or cancers

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP04090377A Withdrawn EP1640004A1 (en) 2004-09-24 2004-09-24 Use of epothilones in the treatment of bone metastases and bone tumors or cancers

Country Status (21)

Country Link
EP (2) EP1640004A1 (en)
JP (1) JP2008514569A (en)
KR (1) KR20070054214A (en)
CN (1) CN101065126A (en)
AR (1) AR051035A1 (en)
AU (1) AU2005287477A1 (en)
BR (1) BRPI0516080A (en)
CA (1) CA2580215A1 (en)
CR (1) CR9064A (en)
EC (1) ECSP077390A (en)
GT (1) GT200500267A (en)
IL (1) IL181785A0 (en)
MX (1) MX2007003503A (en)
NO (1) NO20072099L (en)
PA (1) PA8646201A1 (en)
PE (1) PE20060695A1 (en)
RU (1) RU2007115162A (en)
TW (1) TW200626150A (en)
UY (1) UY29136A1 (en)
WO (1) WO2006032537A2 (en)
ZA (1) ZA200703306B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1930004A1 (en) * 2006-12-08 2008-06-11 Bayer Schering Pharma Aktiengesellschaft Use of epothilones in the treatment of osteoporosis and related diseases

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6605599B1 (en) * 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
FR2775187B1 (en) * 1998-02-25 2003-02-21 Novartis Ag USE OF EPOTHILONE B FOR THE MANUFACTURE OF AN ANTIPROLIFERATIVE PHARMACEUTICAL PREPARATION AND A COMPOSITION COMPRISING EPOTHILONE B AS AN IN VIVO ANTIPROLIFERATIVE AGENT
PT1140944E (en) * 1998-12-22 2004-01-30 Novartis Pharma Gmbh EPOTILONE DERIVATIVES AND THEIR USE AS ANTITUMATIC AGENTS
PE20010116A1 (en) * 1999-04-30 2001-02-15 Schering Ag 6-ALKENYL-, 6-ALKINYL- AND 6-EPOXY-EPOTILONE DERIVATIVES, PROCEDURES FOR THEIR PREPARATION
AU775373B2 (en) * 1999-10-01 2004-07-29 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
JP2004508810A (en) * 2000-04-28 2004-03-25 コーサン　バイオサイエンシーズ，　インコーポレイテッド Polyketide formation
UA75365C2 (en) * 2000-08-16 2006-04-17 Bristol Myers Squibb Co Epothilone analog polymorph modifications, a method for obtaining thereof (variants), a pharmaceutical composition based thereon
WO2002080846A2 (en) * 2001-04-03 2002-10-17 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
TWI315982B (en) * 2001-07-19 2009-10-21 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
AU2003218107A1 (en) * 2002-03-12 2003-09-29 Bristol-Myers Squibb Company C12-cyano epothilone derivatives
EP1503756B1 (en) * 2002-05-01 2009-08-12 Novartis AG Epothilone derivative for the treatment of hepatoma and other cancer diseases
JP2006510626A (en) * 2002-12-05 2006-03-30 シエーリング アクチエンゲゼルシャフト Epothilone analogs for site-specific delivery in the treatment of proliferative diseases
GB0305928D0 (en) * 2003-03-14 2003-04-23 Novartis Ag Organic compounds
EP1475105A1 (en) * 2003-05-09 2004-11-10 Schering AG Bone localising radiopharmaceutical and tubulin-interacting compound combinatorial radiotherapy
BRPI0412000A (en) * 2003-06-27 2006-08-15 Novartis Ag epothilone cancer treatment
AU2004268377B2 (en) * 2003-09-02 2008-06-26 Novartis Ag Cancer treatment with epothilones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006032537A2 *

Also Published As

Publication number Publication date
AR051035A1 (en) 2006-12-13
KR20070054214A (en) 2007-05-28
IL181785A0 (en) 2007-07-04
WO2006032537A2 (en) 2006-03-30
MX2007003503A (en) 2007-08-17
CN101065126A (en) 2007-10-31
BRPI0516080A (en) 2008-08-19
ECSP077390A (en) 2007-05-30
AU2005287477A1 (en) 2006-03-30
TW200626150A (en) 2006-08-01
ZA200703306B (en) 2010-06-30
CA2580215A1 (en) 2006-03-30
PE20060695A1 (en) 2006-08-03
EP1640004A1 (en) 2006-03-29
WO2006032537A3 (en) 2006-05-04
JP2008514569A (en) 2008-05-08
GT200500267A (en) 2006-06-06
RU2007115162A (en) 2008-11-20
NO20072099L (en) 2007-04-23
PA8646201A1 (en) 2006-11-09
UY29136A1 (en) 2006-04-28
CR9064A (en) 2007-10-01

Similar Documents

Publication Publication Date Title
RU2351330C2 (en) Application of epothilones in treatment of brain diseases associated with proliferative processes
ES3053660T3 (en) Pharmaceutical combination comprising ponesimod and its use in the treatment of multiple sclerosis
JP2002504511A5 (en)
JP2003531821A5 (en)
AU2010308306A1 (en) Combination cancer therapy with HSP90 inhibitory compounds
CA2193751A1 (en) Treatment and prophylaxis of osteoporosis
JP2005527576A (en) Oral administration of epothilone compounds
JPH08509486A (en) Use of thiazolidinediones for the treatment of atherosclerosis and dietary disorders
JP2005528414A (en) Epothilone derivatives for the treatment of liver cancer and other cancer diseases
CN105263501A (en) Sugar-analog phosphorus-containing heterocycles having an anti-metastatic activity
EP1809281A2 (en) Use of epothilones in the treatment of bone metastases and bone tumors or cancers
US20060069136A1 (en) Use of Epothilones in the treatment of bone metastasis
WO2008068043A1 (en) Use of epothilones in the treatment of osteoporosis and related diseases
US20140024687A1 (en) Combinations of Vascular Disrupting Agents with Inhibitor of Apoptosis Proteins Antagonists
JP2004525168A (en) Thiazolidinedione alone or in combination with other therapeutic agents to suppress or reduce tumor growth
JP2007530567A (en) Combination therapy with epothilone and carboplatin
JPH11335298A (en) Therapeutic agent for leukemia
MXPA06010921A (en) Combination therapies with epothilones and carboplatin
ZA200607806B (en) Combination therapies with epothilones and carboplatin
JP2001213783A (en) Medocal treatment agent for animals

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070312

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

17Q First examination report despatched

Effective date: 20090609

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090922