WO2014180882A2 - Traitement des métastases cérébrales d'un cancer - Google Patents

Traitement des métastases cérébrales d'un cancer Download PDF

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Publication number
WO2014180882A2
WO2014180882A2 PCT/EP2014/059303 EP2014059303W WO2014180882A2 WO 2014180882 A2 WO2014180882 A2 WO 2014180882A2 EP 2014059303 W EP2014059303 W EP 2014059303W WO 2014180882 A2 WO2014180882 A2 WO 2014180882A2
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WO
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Prior art keywords
compound
cancer
brain metastasis
pharmaceutically acceptable
treatment
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PCT/EP2014/059303
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English (en)
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WO2014180882A3 (fr
Inventor
Angels SIERRA JIMÉNEZ
Baldomero Oliva Miguel
Laia MUIXÍ
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Universitat De Barcelona
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Publication of WO2014180882A2 publication Critical patent/WO2014180882A2/fr
Publication of WO2014180882A3 publication Critical patent/WO2014180882A3/fr

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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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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

  • a brain metastasis is a secondary tumor induced by cancer cells that has migrated to the brain from another location in the body. Many tumor or cancer types can spread to the brain, being lung cancer and breast cancer among the most common sources of brain metastases. Metastatic brain tumors occur in about 25% of all cancers that spread through the body and are much more common than primary brain tumors.
  • R 1 is independently selected from halogen, Ci-C 6 alkyl, CrC 6 haloalkyl and NR'R", wherein R' and R" are independently selected from H, and CrC 6 alkyl;
  • the invention is directed to a GRP94 inhibitor compound for use in the prevention or treatment of brain metastasis from cancer.
  • Another aspect refers to a HDAC inhibitor compound for use in the prevention or treatment of brain metastasis from cancer.
  • the invention refers to a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt, isomer or solvate thereof, and a GRP94 inhibitor, for simultaneous, separate or sequential use in the prevention or treatment of brain metastasis from cancer.
  • the invention refers to the use of a GRP94 inhibitor compound in the preparation of a medicament for the prevention or treatment of brain metastasis from cancer.
  • the invention is directed to a method of preventing or treating brain metastasis from cancer in a patient, said method comprising the simultaneous, separate or sequential administration of an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, isomer or solvate thereof, and a GRP94 inhibitor compound.
  • Figure 2 shows A) Western-blot showing GRP94 expression of 435/P, 435/Br1 and two more brain metastatic cells, Br1V5 and Br1 V5CA1 , derived from in vivo/in vitro successive rounds to obtain high brain metastatic cells; and B) Survival assay using Br1V5 to assess the IC50 of the NVP, which exerted a cytotoxic effect with a IC50 at 50 nM.
  • Figure 3 is a time-course diagram showing the mean growth ratio of the tumors (volume/mm 3 ) after administration of vehicle (control), 17-AAG (AAG17), NVP-AUY922 (NVP), docetaxel (TXT - comparative) and lenalidomide (LND).
  • Figure 5 is a time-course diagram showing the mean growth ratio of the tumors (volume/mm 3 ) after administration of vehicle (control), NVP-AUY922 (NVP), docetaxel (TXT - comparative), lenalidomide (LND), the combination of lenalidomide and docetaxel (LND+TXT) and the combination of lenalidomide and NVP-AUY922 (LND+NVP).
  • the invention is directed to a compound (I) as defined above, or a pharmaceutically acceptable salt, isomer or solvate thereof, for use in the prevention or treatment of brain metastasis from cancer, preferably brain metastasis from lung cancer or brain metastasis from breast cancer.
  • R 1 is NR'R", wherein R' and R" are independently selected from H, and Ci-C 6 alkyl. More preferably, R' and R" are independently selected from H, and C1-C3 alkyl.
  • n is selected from 0, 1 and 2.
  • n is selected from 0 and 1.
  • R 2 is selected from H and Ci-C 3 alkyl.
  • R 2 is H.
  • R 1 is NH 2
  • R 2 is H
  • n is selected from 0 and 1.
  • the compound of formula (I) is selected from thalidomide, lenalidomide and pomalidomide, or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the compound of formula (I) is lenalidomide or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the compound of formula (I) is pomalidomide or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the compounds of formula (I) are for use in the treatment or prevention of brain metastasis from cancer, preferably brain metastasis from lung cancer or breast cancer, in patients overexpressing the Fn14 protein.
  • the invention is directed to a GRP94 inhibitor compound for use in the prevention or treatment of brain metastasis from cancer, preferably brain metastasis from lung cancer or brain metastasis from breast cancer.
  • HSP90 heat shock protein 90
  • the GRP94 inhibitor is selected from 17-AAG and NVP-AUY922, or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the GRP94 inhibitor is 17-AAG or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the GRP94 inhibitor is NVP-AUY922 or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • HDAC inhibitors include compounds of the following classes: hydroxamic acids (e.g., trichostatin A, vorinostat or suberoylanilide hydroxamic acid, belinostat, panobinostat, abexinostat, pracinostat, givinostat and quisinostat), cyclic tetrapeptides (e.g. trapoxin, apicidin and depsipeptide), benzamides (e.g. entinostat, CI-994 and mocetinostat), electrophilic ketones (e.g. trifluoromethyl o ketones and oketoamides) and aliphatic acids (e.g.
  • hydroxamic acids e.g., trichostatin A, vorinostat or suberoylanilide hydroxamic acid, belinostat, panobinostat, abexinostat, pracinostat, givinostat and quisinostat
  • the primary tumor responsible for brain metastasis is selected from lung cancer, breast cancer, bladder cancer, prostate cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, sarcoma and lymphoma.
  • lung cancer is selected from breast cancer and lung cancer.
  • the invention is directed to a compound (I) as defined above, or a pharmaceutically acceptable salt, isomer or solvate thereof, for use in the prevention or treatment of brain metastasis from breast cancer.
  • the invention is directed to a HDAC inhibitor compound as defined above for use in the prevention or treatment of brain metastasis from breast cancer.
  • the breast cancer is ER-negative breast cancer. In an embodiment, the breast cancer is PR-negative breast cancer. In an embodiment, the breast cancer is HER2-negative breast cancer. In an embodiment, the breast cancer is ER-negative, HER2-negative and PR-negative (triple negative breast cancer).
  • the breast cancer is positive for at least one of: estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2).
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 human epidermal growth factor receptor 2
  • the breast cancer is ER-positive breast cancer.
  • the breast cancer is PR-positive breast cancer.
  • the breast cancer is HER2-positive breast cancer.
  • breast cancer is both ER-positive and PR-positive.
  • breast cancer is selected from HER2-positive breast cancer and ER-negative, HER2-negative and PR-negative breast cancer.
  • breast cancer is HER2-positive breast.
  • breast cancer is ER-negative, HER2-negative and PR-negative breast cancer.
  • HER2-negative refers to specific subtype of breast cancer that does not express the genes for HER2, estrogen receptor (ER) or progesterone receptor (PR), respectively.
  • HER2-positive means characterized by overexpression of HER2, ER and PR protein, respectively.
  • overexpression can be determined by methods well known in the art, such as immunohistochemistry, fluorescence in situ hybridization or ligand binding assays.
  • the invention is directed to a compound (I) as defined above, or a pharmaceutically acceptable salt, isomer or solvate thereof, for use in the prevention or treatment of brain metastasis from lung cancer, including non-small cell lung cancer and small cell lung cancer.
  • the invention is directed to a GRP94 inhibitor compound as defined above for use in the prevention or treatment of brain metastasis from lung cancer, including non-small cell lung cancer and small cell lung cancer.
  • the invention is directed to a HDAC inhibitor compound as defined above for use in the prevention or treatment of brain metastasis from lung cancer, including non-small cell lung cancer and small cell lung cancer.
  • salts can be synthesized from the parent compound by conventional methods.
  • such salts can be prepared by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid in water, in an organic solvent or in a mixture of the two.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
  • the compounds of the invention can be in free form or in solvate form (for example, hydrates, alcoholates, etc.), both forms being included within the scope of the present invention. Solvation methods are generally well known in the state of the art.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, isomer or solvate thereof, a GRP94 inhibitor and a pharmaceutically acceptable carrier.
  • the compound of formula (I) is selected from thalidomide, lenalidomide and pomalidomide, or a pharmaceutically acceptable salt, isomer or solvate thereof, and the GRP94 inhibitor is selected from 17-AAG and NVP- AUY922, or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the compound of formula (I) is lenalidomide or a pharmaceutically acceptable salt, isomer or solvate thereof, and the GRP94 inhibitor is NVP-AUY922, or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • FIG. 1 Further aspects of the invention refer to the use of a pharmaceutical composition as defined above in the preparation of a medicament and to the use of a pharmaceutical composition as defined above in the preparation of a medicament for the prevention or treatment of brain metastasis from cancer, preferably brain metastasis from breast cancer or brain metastasis from lung cancer.
  • compositions according to the present invention refers to pharmaceutically acceptable solvents, suspending agents or vehicles for delivering a compound of the present invention and which are acceptable from a toxicological viewpoint.
  • pharmaceutically acceptable carriers depend on the desired administration form. Suitable pharmaceutical carriers are known by the person skilled in the art, and they and the methods of formulating the compositions can be found in standard references (e.g. "Remington: The Science and Practice of Pharmacy", 20th edition (2003) Genaro A.R., ed., Lippincott Williams & Wilkins, Philadelphia, US).
  • treatment refers to both therapeutic measures and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • prevention or “preventing” as used herein mean that the compounds are useful when administered to a patient who has not been diagnosed as possibly having the disorder or disease at the time of administration, but who would normally be expected to develop the disorder or disease or be at increased risk for the disorder or disease.
  • the compounds of the invention will slow the development of the disorder or disease symptoms, delay the onset of the disorder or disease, or prevent the individual from developing the disorder or disease at all.
  • the expression “effective amount” refers to the sufficient amount of the compound to provide the desired effect and will generally be determined by, among other causes, the characteristics of the compound itself and the therapeutic effect to be achieved. It will also depend on the subject to be treated, the severity of the disease suffered by said subject, the chosen dosage form, administration route, etc.
  • the doses mentioned in this invention must be considered only as guides for the person skilled in the art, and he must adjust the doses depending on the aforementioned variables.
  • the compound of the invention can be administered one or more times a day, for example, 1 , 2, 3 or 4 times a day in a typical total daily amount comprised between 0.1 and 30 mg/kg of body mass/day, preferably between 1 and 10 mg/kg of body mass/day.
  • the effective amount produces at least one therapeutic effect selected from the group consisting of reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathological complete response.
  • the compounds and compositions described herein may be administered by any suitable administration route, such as, but not limited to, parenteral, oral, topical, nasal, rectal route.
  • parenteral route e.g. by intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, intrathecal or epidural administration. In a further embodiment, it is administered intravenously.
  • Illustrative examples of dosage forms for administration by the oral route include tablets, capsules, granulate, solutions, suspensions, etc., and can contain the conventional excipients, such as binders, diluents, disintegrants, lubricants, wetting agents, etc., and can be prepared by conventional methods.
  • the pharmaceutical compositions can also be adapted for their parenteral administration, in the form of, for example, solutions, suspensions, emulsions or lyophilized products, etc and can include the suitable excipients, such as buffers, surfactants, anti-oxidants, etc. In any case, the excipients will be chosen according to the selected pharmaceutical dosage form.
  • the compounds of the invention will be given in the range of 0.1 to 30 mg/kg of body mass per day, preferably in the range of 1 to 10 mg/kg of body mass per day.
  • the term "patient” means any mammal, preferably a human.
  • the method and uses provided herein may further comprise another anti-cancer therapy including, but not limited to, surgery, radiation therapy, chemotherapy, or a combination thereof.
  • the compound of the invention is administered simultaneously, separately or sequentially with at least one other chemotherapeutic agent.
  • said other chemotherapeutic agent is selected from the group consisting of taxanes, antimetabolites, platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkaloids, topoisomerase I or II inhibitors, proteasome inhibitors and macrolides.
  • a compound of formula (I), or a pharmaceutically acceptable salt, isomer or solvate thereof, as defined herein is administered simultaneously, separately or sequentially with a GRP94 inhibitor, for use in the prevention or treatment of brain metastasis from cancer, preferably brain metastasis from breast cancer or brain metastasis from lung cancer.
  • compound of formula (I) and the GRP94 inhibitor are as defined herein.
  • compound of formula (I) is selected from a compound wherein R 1 is NH 2 , R 2 is H, and n is selected from 0 and 1 , and the GRP94 inhibitor is selected from 17-AAG and NVP-AUY922, or a pharmaceutically acceptable salt, isomer or solvate thereof.
  • the above mentioned combinations of the compound of formula (I) and another chemotherapeutic agent may provide a synergetic effect in the prevention or treatment of brain metastasis from cancer, preferably brain metastasis from breast cancer or brain metastasis from lung cancer, in particular, the combination of lenalidomide or a pharmaceutically acceptable salt, isomer or solvate thereof and docetaxel.
  • the additional anti-cancer therapy is radiotherapy.
  • kits for administration of a compound of formula (I), or a pharmaceutically acceptable salt, isomer or solvate thereof, as defined herein and a GRP94 inhibitor may further comprise packaging and/or printed instructions for use of the combination.
  • V1 cells The 435-Br1 obtained from the brain when mice were injected for the first time in the left ventricle are named V1 cells, and those obtained after the fifth injection are named V5 cells.
  • V5 cells were injected in the internal carotid artery and a new variant V5CA1 was obtained (Martinez et al., Development of a preclinical therapeutic model of human brain metastasis with chemotherapy. IJMS Manuscript ID: ijms-25852 in press).
  • brain metastasis variants from human breast cancer provided through the METABRE consortium: MDA-MB 361 (Laboratoire d'Oncogenetique, Centre Rene Huguenin, Saint-Cloud, France) were also used.
  • Example 2 In vivo/in vitro characterization of NVP action on MDA-MB 435 parental breast cancer cells (435/P) and the brains metastatic variant 435/Br1
  • PVDF polyvinylidene fluoride
  • Cytotoxic assay To check NVP cytotoxicity we treated 6x10 3 Br1V5 cells/well with 5- 50 nM of NVP in DMSO 100% during 72 h. MTT survival assay was performed with 1 %DMSO to assess the IC50 of the NVP, which exerted a cytotoxic effect with a IC50 at 50 nM. Results are shown in Figure 2B.
  • Example 3 In vivo treatment of subcutaneous xenograft of brain metastasis from lung carcinoma- Experimental models.- Athymic Nude-Foxn1 nu mice of 22-28 gr weight (Charles-River Laboratories (Wilmington, MA) were used. Small pieces of 2 mm 3 from brain metastases biopsies were implanted subcutaneously on the back or intra mammary fat path, respectively. After 10 days when the engraftment was growing we started the treatment with the drug or with the vehicle. Daily control of weight and tumor volume was used to follow the treatment. Tumors were explored in paraffin sections by hematoxylin-eosin stain and specific antibodies.
  • Drugs used and protocols of treatment were treated with: Docetaxel (TXT - comparative assay) 15 mg/Kg/day, every 4 days, for two weeks; with Lenalidomide (LND) 50 mg/Kg/day, 5 days a week for two weeks; GRP94 inhibitors (NVP-AUY922 ) 30mg/Kg/day, 3 doses per week, for two weeks and 17AAG 40 mg/Kg/d in 20% Cremophor, i.p. 5 days a week for two weeks; Valproic Acid 100mg/Kg/day5 days a week for two weeks. All of them were administered intra peritoneal ⁇ i.p.). Controls were treated with the vehicle: physiologic serum 50% DMSO. In the case of combinations, the treatments were administered at the same doses. No secondary effects were detected.

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

Abstract

La présente invention concerne l'utilisation de composés de formule (I), d'inhibiteurs de GRP94 et d'inhibiteurs d'HDAC dans le traitement d'une métastase cérébrale d'un cancer, de préférence une métastase cérébrale d'un cancer du sein ou une métastase cérébrale d'un cancer du poumon.
PCT/EP2014/059303 2013-05-07 2014-05-07 Traitement des métastases cérébrales d'un cancer WO2014180882A2 (fr)

Applications Claiming Priority (4)

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US201361820444P 2013-05-07 2013-05-07
EP13382168 2013-05-07
EP13382168.6 2013-05-07
US61/820,444 2013-05-07

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WO2014180882A2 true WO2014180882A2 (fr) 2014-11-13
WO2014180882A3 WO2014180882A3 (fr) 2015-01-08

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Cited By (2)

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US10017492B2 (en) 2014-10-30 2018-07-10 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
US10844039B2 (en) 2018-11-13 2020-11-24 Biotheryx, Inc. Substituted isoindolinones

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OA13284A (en) * 2003-11-06 2007-01-31 Corporation Celgene Methods and compositions using thalidomide for thetreatment and management of cancers and other dis eases.

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FERNANDEZ, Y.; ESPANA, L.; MANAS, S.; FABRA, A.; SIERRA, A., CELL DEATH DIFFER., vol. 7, no. 4, 2000, pages 350 - 359
MARTINEZ-ARANDA A; HERNANDEZ V; PICON C; MODOLELL I; SIERRA A.: "Development of a preclinical therapeutic model of human brain metastasis with chemoradiotherapy", INT J MOL SCI., vol. 14, no. 4, 16 April 2013 (2013-04-16), pages 8306 - 27
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10017492B2 (en) 2014-10-30 2018-07-10 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
US10844039B2 (en) 2018-11-13 2020-11-24 Biotheryx, Inc. Substituted isoindolinones
US11352338B2 (en) 2018-11-13 2022-06-07 Biotheryx, Inc. Substituted isoindolinones

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