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WO2009138779A1 - Combinaison comprenant de la 4-(3-chloro-2-fluoroanilino)-7-méthoxy-6-{[1-(n-méthylcarbamoylméthyl)pipéridin-4-yl]oxy}quinazoline - Google Patents

Combinaison comprenant de la 4-(3-chloro-2-fluoroanilino)-7-méthoxy-6-{[1-(n-méthylcarbamoylméthyl)pipéridin-4-yl]oxy}quinazoline Download PDF

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Publication number
WO2009138779A1
WO2009138779A1 PCT/GB2009/050494 GB2009050494W WO2009138779A1 WO 2009138779 A1 WO2009138779 A1 WO 2009138779A1 GB 2009050494 W GB2009050494 W GB 2009050494W WO 2009138779 A1 WO2009138779 A1 WO 2009138779A1
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Prior art keywords
combination
cancer
treatment
compound
breast cancer
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English (en)
Inventor
Lisa Renee Bailey Iacona
Ian Smith
Mary Stuart
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a combination comprising 4-(3-chloro-2- fluoroanilino)-7-methoxy-6- ⁇ [ 1 -(N-methylcarbamoylmethyl)piperidin-4-yl ]oxy ⁇ quinazoline, or a pharmaceutically acceptable salt thereof, hereafter "Compound (I)", 5 and an endocrine agent suitable for use in the treatment of breast cancer.
  • the combination is expected to be useful for the treatment or prophylaxis of cancer.
  • the invention also relates to a pharmaceutical composition comprising such combinations and to the use thereof in the manufacture of a medicament for use in the treatment or prophylaxis of cancer, such as breast cancer.
  • the erbB family of receptor tyrosine kinases which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells and as such the erbB family of receptors is implicated in a number of epithelial cancers (reviewed in Olayioye et al., EMBO J., 2000, Jj ) , 3159), including for example breast cancer (Sainsbury et al., Brit. J. Cancer. 1988, 58, 458; Guerin et al., Oncogene Res.. 1988, is 3. 21; Slamon et al.. Science. 1989. 244. 707; Klijn et al..
  • NSCLCs non-small cell lung cancers
  • adenocarcinomas Cerny et al., Brit. J. Cancer. 1986, 54, 265; Reubi et al., Int. J. Cancer. 1990, 45, 269; Rusch et al., Cancer Research. 1993, 53, 2379; Brabender et al, Clin. Cancer Res.. 2001, 7, 1850
  • an inhibitor of erbB receptor tyrosine kinases should be of value as a selective inhibitor of the growth of certain carcinomas.
  • a number of erbB tyrosine kinase inhibitors have demonstrated clinical benefit and a number of erbB tyrosine kinase inhibitors have been approved for use in the treatment of cancer.
  • the EGFR tyrosine kinase inhibitors gef ⁇ tinib and erlotinib for the treatment of advanced non-small cell lung cancer and lapatinib, which has erbB2 tyrosine kinase inhibitory activity, for use in metastatic breast cancer.
  • Several other EGFR and erbB2 tyrosine kinase inhibitors are currently in development.
  • endocrine agents are well known in the treatment of certain hormone sensitive human cancers.
  • Numerous endocrine agents are suitable for use in the treatment of breast cancer, for example, anti-estrogen agents, selective estrogen receptor modulators (SERMs), aromatase inhibitors, estrogen-receptor down-regulator (ERDs), gonadontropin releasing hormone agonists (GnRH or LHRH analogues), an estrogen (to restore sensitivity following aquired resistance to endocrine therapy), progestogens or progesterone receptor antagonists and combinations thereof.
  • SERMs selective estrogen receptor modulators
  • EGDs estrogen-receptor down-regulator
  • GnRH or LHRH analogues gonadontropin releasing hormone agonists
  • progestogens or progesterone receptor antagonists and combinations thereof.
  • Anti-estrogen agents include SERMs that are agents which selectively block the action of estrogen at the estrogen receptor and include for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene.
  • SERMs that are agents which selectively block the action of estrogen at the estrogen receptor and include for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene.
  • tamoxifen was the anti-hormonal treatment of choice for the treatment of hormone sensitive breast cancer.
  • aromatase inhibitors are more effective than tamoxifen in postmenopausal women with hormone sensitive breast cancer.
  • Aromatase inhibitor is an agent that inhibits the enzyme aromatase and by that means lowers the level of the estrogen estradiol.
  • Aromatase is an enzyme of the cytochrome P-450 superfamily and the product of the CYP19 gene, and is highly expressed in the placenta and in the granulosa cells of ovarian follicles, where its expression depends on cyclical gonadotropin stimulation.
  • Aromatase catalyses the conversion of testosterone (an androgen) to estradiol (an estrogen) in many tissues including the adrenal glands, ovaries, placenta, testicles, adipose tissue and brain. Estrogen is produced directly by the ovaries and is also made by the body using aromatase. Aromatase inhibitors interfere with the body's use of aromatase.
  • Aromatase inhibitors may therefore be used to treat estrogen-dependent tumours after the menopause. Aromatase inhibitors are used mostly in women who have reached menopause, when the ovaries are no longer producing estrogen. Examples of aromatase inhibitors include anastrozole, letrozole, vorazole and exemestane.
  • the only approved estrogen-receptor down-regulator (ERD) is Faslodex (chemical name: fulvestrant).
  • Fulvestrant is an option for post-menopausal women with advanced (metastatic) breast cancer that is hormone-receptor-positive and has stopped responding to other anti-estrogen therapy. Fulvestrant offers a benefit to post-menopausal women with metastatic (advanced) hormone-receptor-positive breast cancer whose cancer has progressed on either tamoxifen or aromatase inhibitors or who cannot take other hormonal medications (possibly because of other medical conditions).
  • Fulvestrant is a competitive inhibitor of estrogen action by binding to the estrogen receptor (ER) and preventing access to estrogen and as such has anti-estrogen properties.
  • ER estrogen receptor
  • the binding of fulvestrant to the ER results in a reduction in ER protein levels leading to a rapid degredation of the ER in the target tissue resulting in insufficient ER for binding to estrogen.
  • the net effect is that estrogen cannot exert its biological effect due to the ER being "down-regulated” and inactivated.
  • Luteinizing hormone-releasing hormone agonists LHRH agonists
  • LHRH agonists have been used in the treatment of premenopausal breast cancer to suppress ovarian function by reducing the production of estrogen-stimulating hormones from the pituitary gland.
  • Luteinizing hormone-releasing hormone agonists such as goserelin have proven to be as effective as surgical oophorectomy in premenopausal advanced breast cancer.
  • Progestogens such as medroxyprogesterone acetate have been shown to be effective in the treatment of breast cancer in post-menopausal women.
  • Progesterone receptor antagonists act to block the action of progesterone at the progesterone receptor.
  • Such agents for example ZK232011 are expected to be useful in the treatment or hormone sensistive breast cancer.
  • Estrogens such as ethinyl estradiol have been used in the treatment of advanced breast cancer in patients that have become resistant to endocrine therapies such as tamoxifen and aromatase inhibitors such as anastrozole. The estrogen appears to restore sensitivity to endocrine agents in these patients.
  • TM kinase such as gefitinib (Iressa ) with an anti-estrogen.
  • Iressa gefitinib
  • BJC BJC
  • WO2005/028469 then goes on to describe examples of such conjoint treatment including surgery, radiotherapy and many different types of chemotherapeutic agent. Nowhere in WO2005/028469 is the specific combination of Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer suggested.
  • Compound (I) is an erbB receptor tyrosine kinase inhibitor, in particular Compound (I) is a potent inhibitor of EGFR and erbB2 receptor tyrosine kinases.
  • erbB3 does not have an intrinsic tyrosine kinase activity, activation of the erbB3 receptor is achieved only through the formation of heterodimeric receptor complexes with other kinase-active receptors including particularly EGFR and erbB2 .
  • EGFR and erbB2 heterodimers formed with erbB3 are thought to drive tumour growth in tumours where these receptors are expressed.
  • Compound (I) also inhibits erbB3 mediated signalling through the inhibition of phosphorylation of erbB3 following ligand stimulated EGFR/erbB3 and/or erbB2/erbB3 heterodimerisation.
  • Compound (I) exhibits a unique erbB tyrosine kinase inhibitory effect compared to other erbB tyrosine kinase inhibitors such as gef ⁇ tinib or erlotinib that act primarily as EGFR tyrosine kinase inhibitors.
  • erbB tyrosine kinase inhibitors such as gef ⁇ tinib or erlotinib that act primarily as EGFR tyrosine kinase inhibitors.
  • Compound (I) exhibits improved anti-tumour effects compared to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib. Without wishing to be bound by theory, it is thought that the improved properties may result from the inhibition of the erbB3 mediated signalling by Compound (I).
  • a combination comprising Compound (I), and an endocrine agent suitable for use in the treatment of breast cancer.
  • a combination comprising Compound (I), and an endocrine agent selected from a selective estrogen receptor modulator, an aromatase inhibitor and a selective estrogen receptor down regulator.
  • a combination comprising Compound (I), and an endocrine agent selected from a selective estrogen receptor modulator and an aromatase inhibitor.
  • a combination comprising Compound (I), and an anti-estrogen agent.
  • a combination comprising Compound (I), and a selective estrogen receptor modulator.
  • a combination comprising Compound (I), and an aromatase inhibitor.
  • a combination comprising Compound (I), and an estrogen receptor down-regulator.
  • a combination comprising Compound (I), and a progesterone receptor antagonist.
  • a combination comprising Compound (I), and luteinizing hormone-releasing hormone agonist.
  • a combination comprising Compound (I), and a progestrogen.
  • a combination comprising Compound (I), an estrogen and an endocrine agent suitable for use in the treatment of breast cancer.
  • a combination comprising Compound (I), an estrogen and an selective aromatase inhibitor.
  • a combination comprising Compound (I), an estrogen and selective estrogen receptor modulator.
  • endocrine agent suitable for use in the treatment of breast cancer refers to any endocrine agent that exhibits anti-cancer activity against breast cancer cells or tumours. Such activity includes in-vitro and/or in-vivo activity.
  • endocrine agents include for example, an endocrine agent selected from an anti-estrogen agent, a selective estrogen receptor modulator, an aromatase inhibitor, a selective estrogen receptor down regulator, an LHRH agonist, a progesterone receptor antagonist and a progestogen.
  • anti-estrogen means any agent that acts to block or modulate the binding of estrogen to the estrogen receptor, for example by competitively binding to the estrogen receptor, by interacting with estrogen to inhibit binding to the receptor, by inhibiting estrogen levels or by modulating the expression or function of the estrogen receptor.
  • selective estrogen receptor modulator refers to an agent that binds to the estrogen receptor and thereby modifies estrogen binding to the receptor, for example by acting as a receptor antagonist in breast cancer.
  • aromatase inhibitor refers to any agent, which inhibits the enzyme aromatase and by that means lowers the level of the estrogen estradiol.
  • estogen receptor down-regulator is an agent, which binds to the estrogen receptor leading to a reduction in ER protein levels and degredation of the estrogen receptor in the target tissue and by those means prevents estogen from exerting its biological actions.
  • a “progesterone receptor antagonist” is an agent that acts at the progesterone receptor as an agtagonist to inhibit binding of progesterone to the receptor.
  • LHRH agonist refers to any chemical compound, or a pharmaceutically acceptable salt thereof, including small molecules and peptides, which acts as an agonist at the LHRH receptor, whether by an interaction with the LHRH binding site or by an allosteric mechanism, i.e. acts at a position on the LHRH receptor different to the LHRH binding site.
  • References herein to "Compound (I)” unless stated otherwise include Compound
  • a compound or a pharmaceutically acceptable salt thereof is referred to this refers to the compound only. In another aspect this refers to a pharmaceutically acceptable salt of the compound.
  • cancer refers to oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing's tumour, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, brain cancer, renal cancer, lymphoma and leukaemia.
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • gastric cancer gastric cancer
  • head and neck cancer brain cancer
  • renal cancer lymphoma and leukaemia
  • breast cancer for example hormone receptor- positive breast cancer.
  • cancer refers to SCLC, NSCLC, colorectal cancer, ovarian cancer and / or breast cancer.
  • cancer refers to SCLC. In addition, it refers to NSCLC. In addition, it refers to colorectal cancer. In addition, it refers to ovarian cancer. In addition, more particularly it refers to breast cancer. In addition, more particularly it refers to hormone receptor positive breast cancer, especially to hormone receptor positive breast cancer in post-menopausal women. In one embodiment it refers to early stage non-metastatic hormone receptor positive breast cancer, for example early stage non-metastatic hormone receptor positive breast cancer in post- menopausal women. Still furthermore it refers to early stage non-metastatic estrogen and/or progesterone receptor positive breast cancer, especially to early stage non- metastatic estrogen and/or progesterone receptor positive breast cancer in post-menopausal women.
  • metastatic hormone receptor positive breast cancer especially to metastatic hormone receptor positive breast cancer in post- menopausal women.
  • metastatic estrogen and/or progesterone receptor positive breast cancer especially to metastatic estrogen and/or progesterone receptor positive breast cancer in post-menopausal women.
  • bladder cancer oesophageal cancer, gastric cancer, melanoma, cervical cancer and / or renal cancer.
  • the cancer is in a non- metastatic state.
  • particularly the cancer is in a metastatic state.
  • the cancer is in a metastatic state, and more particularly the cancer produces skin metastases.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces lymphatic metastases.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces brain metastases.
  • the treatment of cancer is referred to particularly this is the treatment of cancerous tumours expressing one or more of the erbB family of receptors, for example EFGR, erbB2 and/or erbB3 receptors.
  • the anti-cancer effect of the combination according to the invention may be measured in terms of one or more of the anti-tumour effect, the extent of the response (for example reduced tumour volume or reduced tumour burden), the response rate, the clinical benefit rate (the sum of complete response, partial response and stable disease) the time to disease progression, progression- free survival and the overall survival rate.
  • the anti-tumour effects of the combination according to the invention may be for example one or more of inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment or slowing of disease progression.
  • Compound (I) may also have a beneficial effect in preventing the onset of cancer in warm-blooded animals, such as man.
  • Compounds, or pharmaceutically acceptable salts thereof that are selective estrogen receptor modulators include, for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene. Fulvestrant also exhibits anti-estrogen effects and as such may be considered to be a selective estrogen receptor modulator.
  • the selective estrogen receptor modulator is tamoxifen.
  • Compounds, or pharmaceutically acceptable salts thereof possessing aromatase inhibitor activity include, for example, anastrozole, exemestane, letrozole, aminoglutethimide, formestane, fadrozole, rogletimide or vorozole.
  • the aromatase inhibitor is selected from anastrozole.
  • the aromatase inhibitor is selected from exemestane.
  • the aromatase inhibitor is selected from letrozole.
  • the aromatase inhibitor is selected from aminoglutethimide.
  • the aromatase inhibitor is selected from formestane.
  • the aromatase inhibitor is selected from fadrozole.
  • the aromatase inhibitor is selected from rogletimide.
  • the aromatase inhibitor is selected from vorozole.
  • a particular estrogen receptor down-regulator for use in the present invention is fulvestrant.
  • a further particular estrogen receptor down-regulator for use in the present invention is AZD4992.
  • a further particular estrogen receptor down-regulator for use in the present invention is CH-4893237.
  • a further particular estrogen receptor down-regulator for use in the present invention is one of the compounds from US 7,018,994, the specific examples of which are incorporated herein by reference.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl ⁇ -17 ⁇ - methylestra-l,3,5(10)-triene-3, 17- ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(8,8,9,9, 10,10,10-heptafiuorodecyl)amino]pentyl ⁇ - 17 ⁇ -methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is (RS)-11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9,l 0,10,10-nonafluorodecyl)amino]- pentyl ⁇ -17 ⁇ -methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl ⁇ -17 ⁇ - methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(9,9, 10,10,10-pentafiuorodecyl)amino]pentyl- 1 Ia- methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl ⁇ -17 ⁇ - methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9, 10,10,10- nonafluorodecyl)amino]pentyl ⁇ - 17 ⁇ -methylestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl ⁇ -17 ⁇ - methylestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 17 ⁇ -ethinyl-l l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8, 8,9,9, 10, 10,10-nonafluorodecyl)- amino]pentyl ⁇ -estra- 1 ,3 ,5(10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 17 ⁇ -ethinyl-l l ⁇ -fluoro-3-(2-tetrahydropyranoyloxy)-7 ⁇ - ⁇ 5- [methyl(7,7,8,8,9,9,10,10,10-nonafiuorodecyl)amino[pentyl ⁇ -estra-l,3,5(10)-trien-17 ⁇ -ol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -fluoro-3-(2-tetrahydrophyranyloxy)-7 ⁇ - ⁇ 5-methyl(7,7,8,8,9,9, 10,10,10- nonafluorodecyl)amino]pentyl ⁇ - 17 ⁇ -methylestra- 1,3,5(10)-trien- 17 ⁇ -ol.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9, 10, 10,10- nonafluorodecyl)amino]pentyl ⁇ - 17 ⁇ -trifluoromethylestra- 1 ,3 ,5(10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(6, 6,7, 7,8,8, 8-heptafluorooctyl)amino[pentyl ⁇ -17 ⁇ - methylestra-l,3,5(5-triene-3, 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(8,8,9,9, 10,10,10-heptafiuorodecyl)amino[pentyl ⁇ - 17 ⁇ -methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(6,6,7,7,8,8,9,9,10,10,10-undecafluorodecyl)amino]- pentyl ⁇ - 17 ⁇ -methylestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorooctyl)aminopentyl ⁇ - 17 ⁇ -methylestra-l,3,5(10)-triene-3, 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(9,9, 10,10,11,11,11- heptafluoroundecyl)amino[pentyl ⁇ - 17 ⁇ -methylestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -7 ⁇ - ⁇ 5-[methyl(9,9, 10,10,10-pentafiuorodecyl)amino]pentyl ⁇ - 17 ⁇ - methylestra- 1 ,3 ,5( 10)-triene-3 , 17 ⁇ -diol.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9-heptaflorononyl)amino]pentyl ⁇ -17 ⁇ - methylestra-l,3,5(10)-triene-3,17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ - ⁇ 5-(methyl ⁇ 3-[(2,3,4,5,6-pentafluorophenyl)sulfanyl]propyl ⁇ - amino ⁇ pentyl]estra-l,3,5(10)-triene-3, 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ -[5-(methyl ⁇ 3-[(4,4,5,5,5- pentafluoropentyl)sulfanyl]propyl ⁇ amino)-pentyl]estra-l,3,5(10)-triene-3, 17 ⁇ -diol N- oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ -[5-(methyl ⁇ 3-[(4,4,5,5,5- pentafluoropentyl)sulf ⁇ nyl]propyl ⁇ amino)-pentyl]estra-l,3,5(10)-triene-3, 17 ⁇ -diol N- oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9, 10, 10,10- nonafluorodecyl)amino]pentyl ⁇ estra- 1,3,5 (10)-triene-3 , 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is (S)-I l ⁇ -fiuoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9, 10,10,10- nonafluorodecyl)amino]pentyl ⁇ - 17 ⁇ -mehylestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is (R)-11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(7,7,8,8,9,9,l 0,10,10- nonafluorodecyl)amino]pentyl ⁇ - 17 ⁇ -mehylestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 11 ⁇ -fluoro-7 ⁇ - ⁇ 5-[methyl(9,9, 10,10,10-pentylfiuorodecyl)amino]pentyl ⁇ estra- l,3,5(10)-triene-3,17 ⁇ -diol N-oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ -[5-(methyl ⁇ 3-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]propyl ⁇ amino)-pentyl]estra- 1,3,5(10)-trien-3-ol- 17-one N- oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is 1 l ⁇ -fluoro-7 ⁇ -[5-(methyl ⁇ 3-[(4,4,5,5,5- pentafluoropentyl)sulfanyl]propyl ⁇ amino)-pentyl] estra- 1,3,5(10)-trien-3 -ol- 17-one N- oxide.
  • a further particular estrogen receptor down-regulator for use in the present invention is l l ⁇ -fluoro-7 ⁇ - ⁇ 5[methyl(7,7,8,8,9,9,10,10,10- nonafluorodecyl)amino]pentyl ⁇ estra- 1,3,5(10)-trien-3-ol- 17one N-oxide.
  • LHRH agonists that may be used in the present invention include small molecule LHRH agonists as well as peptides or peptide derivatives.
  • Peptide and peptide derivatives include for example: i) buserelin (US Patent 4 024 248) (py ⁇ Glu-His-Trp-Ser-Tyr-D-Se ⁇ Bu ⁇ -Leu-Arg-Pro-NHCHjCH, ii) triptorelin (US Patent 4 010 125)
  • the LHRH agonist is selected from leuprorelin, buserelin, triptorelin and goserelin, or a pharmaceutically acceptable salt thereof. In another embodiment the LHRH agonist is goserelin or a pharmaceutically acceptable salt thereof.
  • a particular progesterone receptor antagonist is for example ZK232011 or a pharmaceutically acceptable salt thereof.
  • a particular progestrogen is for example medroxyprogesterone acetate.
  • Estrogens may be used to restore hormone sensitivity to tumours which have become resistant to endocrine therapy. Accordingly, combinations comprising Compound (I), an endocrine agent suitable for use in the treatment of breast cancer and an estrogen form a further aspect of the present invention. Estrogens include for example stilbestrol or ethinylestradiol.
  • Particular combinations of the present invention include: • Compound (I) and tamoxifen, or a pharmaceutically acceptable salt thereof;
  • Suitable pharmaceutically-acceptable salts include, for example, salts with alkali metal (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine.
  • suitable pharmaceutically-acceptable salts include, pharmaceutically-acceptable acid-addition salts with hydrogen halides, sulphuric acid, phosphoric acid and with organic acids such as citric acid, maleic acid, methanesulphonic acid and p-toluenesulphonic acid.
  • the compounds may exist in zwitterionic form.
  • a particular pharmaceutically acceptable salt of Compound (I) is a di-fumarate salt, still more particularly Compound (I) di-fumarate salt Form A, as described in the Examples.
  • a combination comprising Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer, for use as a medicament.
  • a combination comprising Compound (I) and a selective estrogen receptor modulator for use as a medicament. Therefore according to the present invention, there is provided a combination, comprising Compound (I) and an aromatase inhibitor for use as a medicament.
  • a combination comprising Compound (I) and an estrogen receptor down-regulator for use as a medicament.
  • a combination comprising Compound (I) and a progesterone receptor antagonist for use as a medicament.
  • a combination comprising Compound (I) and an LHRH agonist for use as a medicament.
  • a combination comprising Compound (I) and an endocrine agent suitable for use in treatment of breast cancer, for use in the treatment of estrogen receptor positive breast cancer.
  • a combination comprising Compound (I) and a selective estrogen receptor modulator for use in the treatment of estrogen receptor positive breast cancer.
  • a combination comprising Compound (I) and an aromatase inhibitor for use in the treatment of estrogen receptor positive breast cancer. Therefore according to the present invention, there is provided a combination, comprising Compound (I) and an estrogen receptor down-regulator for use in the treatment of estrogen receptor positive breast cancer.
  • a combination comprising Compound (I) and a progesterone receptor antagonist for use in the treatment of estrogen receptor positive breast cancer.
  • a combination comprising Compound (I) and an LHRH agonist for use in the treatment of estrogen receptor positive breast cancer.
  • a pharmaceutical composition which comprises Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I) and a selective estrogen receptor modulator in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I) and an aromatase inhibitor in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I) and an estrogen receptor down-regulator in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I) and a progesterone receptor antagonist in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an endocrine agent suitable for use in the treatment of breast cancer in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises a selective estrogen receptor modulator in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an aromatase inhibitor in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an estrogen receptor down-regulator in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises a progesterone receptor antagonist in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an LHRH agonist in association with a pharmaceutically acceptable diluent or carrier.
  • a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an endocrine agent suitable for use in the treatment of breast cancer.
  • a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an endocrine agent selected from a selective estrogen receptor modulator, an aromatase inhibitor, a selective estrogen receptor down- regulator, a progesterone receptor antagonist and an LHRH agonist.
  • an endocrine agent selected from a selective estrogen receptor modulator, an aromatase inhibitor, a selective estrogen receptor down- regulator, a progesterone receptor antagonist and an LHRH agonist.
  • a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a selective estrogen receptor modulator.
  • a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an aromatase inhibitor. Therefore according to the present invention, there is provided a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an estrogen receptor down-regulator.
  • a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a progesterone receptor antagonist. Therefore according to the present invention, there is provided a method of treating cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an LHRH agonist.
  • the treatment of cancer also refers to the prevention of metastases and the treatment of metastases, i.e. cancer spread. Therefore the combination of the present invention could be used to treat a patient who has no metastases to stop them occurring, or to lengthen the time period before they occur, and to a patient who already has metastases to treat the metastases themselves.
  • the treatment of cancer also refers to treatment of an established primary tumour or tumours and developing primary tumour or tumours.
  • the treatment of cancer relates to the prevention of metastases.
  • the treatment of cancer relates to the treatment of metastases.
  • the treatment of cancer relates to treatment of an established primary tumour or tumours or developing primary tumour or tumours.
  • the treatment of cancer relates to an adjuvant treatment.
  • the treatment of cancer refers to the neo-adjuvant treatment of cancer.
  • the combination according to the invention is used as an adjuvant treatment of hormone sensitive breast cancer, particularly as an adjuvant treatment of estrogen receptor positive breast cancer in post-menopausal women.
  • the combination according to the invention is used as a neo-adjuvant treatment of hormone sensitive breast cancer, particularly as a neoadjuvant treatment of estrogen receptor positive breast cancer in post-menopausal women.
  • the combination is used to treat advanced (metastatic) hormone sensitive breast cancer, particularly advanced estrogen receptor positive cancer in post- menopausal women.
  • the combination is used to treat cancer patients that have not received any prior endocrine therapy before being treated with a combination according to the present invention.
  • Such patients may benefit further from the anti-cancer effects of a combination according to the present invention in for example, an improved time to progression compared to treatment using an endocrine therapy such as an aromatase inhibitor alone.
  • the combination may be used to treat breast cancer patients who have not received any prior endocrine therapy.
  • Such prior endocrine therapy may be for example, a selective estrogen receptor modulator tamoxifen or an aromatase inhibitor such as anastrozole, more particularly tamoxifen.
  • the combination may be used to treat hormone sensitive breast cancer in a patient that has not received prior endocrine therapy.
  • the combination according to the invention may be used to treat women (particularly post-menopausal women) with hormone sensitive advanced (metastatic) breast cancer who have not received prior endocrine therapy (such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant). More particularly, the combination according to the invention may be used to treat postmenopausal women with estrogen sensitive advanced (metastatic) breast cancer who have not received prior endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • hormone sensitive advanced (metastatic) breast cancer who have not received prior endocrine therapy
  • a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvest
  • the combination according to the invention may be used to treat women (particularly treat post-menopausal women) with hormone sensitive early stage (non-metastatic) breast cancer who have not received prior endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • hormone sensitive early stage breast cancer such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • the combination according to the invention may be used as an adjuvant therapy in the treatment of hormone sensitive breast cancer in patients, where such patients have not received prior endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • a selective estrogen receptor modulator such as tamoxifen
  • an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator
  • fulvestrant a selective estrogen receptor modulator
  • a selective estrogen receptor modulator such as tamoxifen
  • an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • the combination according to the invention is not used as a neo-adjuvant treatment.
  • the above methods of treatment and uses require as a step in the treatment or use the pre-selection of a patient or patients that have not received prior endocrine therapy. Following identification of such a patient or patients, the combination described herein is administered to the selected patient(s).
  • adjuvant therapy refers to a treatment given following removal of the primary tumour.
  • removal of the primary tumour may be effected by, for example, surgery (for example lumpectomy or mastectomy) and/or radiotherapy.
  • cancer refers to a treatment given prior to removal of the primary tumour by surgery or radiotherapy.
  • the treatment of cancer also refers to the prevention of cancer per se.
  • a method for the treatment of advanced (metastatic) estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an aromatase inhibitor such as anastrozole, wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • a combination comprising Compound (I) and an aromatase inhibitor, for use in the treatment of advanced (metastatic) estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • Compound (I) and an aromatase inhibitor in the manufacture of a medicament for the treatment of advanced (metastatic) estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • a method for the treatment of non-metastatic estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of an aromatase inhibitor such as anastrozole, wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • the combination is suitably administered as an adjuvant treatment.
  • a combination comprising Compound (I) and an aromatase inhibitor, for use in the treatment of non-metastatic estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • a combination comprising Compound (I) and an aromatase inhibitor, in the manufacture of a medicament for the treatment of non-metastatic estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • a method for the treatment of non-metastatic estrogen and/or progesterone positive breast cancer in a warm-blooded animal, such as man, in need of such treatment which comprises
  • a warm-blooded animal such as man, that has non-metastatic estrogen and/or progesterone positive breast cancer and wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant; and
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant; and
  • a combination comprising Compound (I) and an aromatase inhibitor, for use in the treatment of a warm-blooded animal, such as man, which has been diagnosed with non-metastatic estrogen and/or progesterone positive breast cancer and wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • a combination comprising Compound (I) and an aromatase inhibitor, in the manufacture of a medicament for the treatment of a warm-blooded animal, such as man, which has been diagnosed with non- metastatic estrogen and/or progesterone positive breast cancer and wherein said animal has not previously been treated with an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • an endocrine therapy such as for example, a selective estrogen receptor modulator such as tamoxifen, an aromatase inhibitor such as anastrozole or an estrogen receptor down-regulator such as fulvestrant.
  • the warm-blooded animal is suitably a post-menopausal woman.
  • post-menopausal includes women that are naturally post-menopausal and women where the menopause has been induced, by for example, treatment with an LHRH agonist such as goserelin.
  • a patient has not previously been treated with an endocrine therapy” or has “not received prior endocrine therapy”
  • the treatment of a patient with an LHRH agonist to induce early menopause in the patient is not considered to be "prior endocrine therapy”.
  • patients that have been treated with an LHRH agonist to induce early menopause are not excluded from those embodiments that are described herein as not having received "prior endocrine therapy” or "not received prior endocrine therapy”.
  • the patients have not been treated with a selective estrogen receptor modulator such as tamoxifen or an aromatase inhibitor such as anastrozole or exemestane prior to being treated with the combination according to the present invention.
  • a method of treating breast cancer that has become resistant to endocrine therapy, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a combination comprising an estrogen, Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer.
  • Endocrine agents suitable for use in the treatment of breast cancer for use in this aspect of the invention are any of the endocrine agents described hereinbefore.
  • the presence of the estrogen may restore endocrine sensitivity in the tumour and thereby overcome resistance to endocrine therapy.
  • the effect of a method of treatment of the present invention is expected to be at least equivalent to the addition of the effects of each of the components of said treatment used alone, that is, of each of Compound (I) and the endocrine agent used alone.
  • the effect of a method of treatment of the present invention is expected to be greater than the addition of the effects of each of the components of said treatment used alone, that is, of each of Compound (I) and the endocrine agent used alone.
  • the effect of a method of treatment of the present invention is expected to be a synergistic effect.
  • a combination treatment is defined as affording a synergistic effect if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose.
  • the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with Compound (I) or the endocrine agent alone.
  • the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to Compound (I) or the endocrine agent alone.
  • the effect of the combination treatment is defined as affording a synergistic effect if one of the components is dosed at its conventional dose and the other component(s) is/are dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to that achievable on dosing conventional amounts of the components of the combination treatment.
  • synergy is deemed to be present if the conventional dose of Compound (I) or the endocrine agent may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with fewer and/or less troublesome side-effects than those that occur when conventional doses of each component are used.
  • a kit comprising Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer; optionally with instructions for use.
  • kits comprising Compound (I) and selective estrogen receptor modulator; optionally with instructions for use.
  • kits comprising Compound (I) and an aromatase inhibitor; optionally with instructions for use.
  • kits comprising Compound (I), and an estrogen receptor down-regulator; optionally with instructions for use.
  • kits comprising: a) Compound (I), in a first unit dosage form; b) an endocrine agent suitable for use in the treatment of breast cancer; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), in a first unit dosage form; b) a selective estrogen receptor modulator; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), in a first unit dosage form; b) an aromatase inhibitor; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), in a first unit dosage form; b) an estrogen receptor down-regulator; in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) an endocrine agent suitable for use in the treatment of breast cancer, in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a selective estrogen receptor modulator, in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) an aromatase inhibitor, in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) an estrogen receptor down-regulator, in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • An example of a unit dosage form for Compound (I) might be a tablet for oral administration, for example that described herein below.
  • An example of a unit dosage form for a selective estrogen receptor modulators might be tablet for oral administration.
  • An example of a unit dosage form for an aromatase inhibitor might be a tablet for oral formulation, see that described herein below.
  • An example of a unit dosage from for an estrogen receptor down-regulator might be a formulation for intramuscular administration, see that described herein below.
  • a pharmaceutical composition which comprises Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I) and a selective estrogen receptor modulator in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • composition which comprises Compound (I) and an aromatase inhibitor in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • composition which comprises Compound (I) and an estrogen receptor down-regulator in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I) and a progesterone receptor antagonist in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I) and an LHRH agonist in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an endocrine agent suitable for use in the treatment of breast cancer in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises a selective estrogen receptor modulator in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, for use in combination with a pharmaceutical composition which comprises an aromatase inhibitor in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an estrogen receptor down-regulator in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises a progesterone receptor antagonist in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises an LHRH agonist in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • compositions of compound (I) and the endocrine agents suitable for use in the treatment of breast cancer described herein may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution, suspension or emulsion for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • Compound (I) is suitably formulated as a tablet using the following excipients: Tablet Core:
  • Compound (I) lactose; microcrystalline cellulose; crospovidone; polyvidone (PVP); and magnesium stearate
  • the tablet core may be coated with a conventional film-coating such as an HPMC based film coating which optionally contains one or more colorants and/or light protective agents.
  • Compound (I) is used in the tablet as the Compound (I) difumarate salt, more specifically the Compound (I) difumarate salt.
  • the Compound (I) may be milled prior to formulation into the tablet to provide a uniform particle size distribution of the Compound (I) in the tablet.
  • Compound (I) difumarate may be milled to provide an average particle size of about 5 ⁇ m. Suitable milling methods are well known.
  • the tablets may be prepared using conventional methods and as illustrated in the Examples.
  • the fulvestrant may be formulated as a composition suitable for intra-muscular administration, for example a composition comprising fulvestrant in a ricinoleate vehicle, a pharmaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable alcohol.
  • a composition suitable for intra-muscular administration for example a composition comprising fulvestrant in a ricinoleate vehicle, a pharmaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable alcohol.
  • Particular fulvestrant compositions are those described in US 6,774,122.
  • a kit comprising Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer; optionally with instructions for use; for use in the treatment of cancer.
  • Suitable endocrine agent for use in the treatment of breast cancer are any of the endocrine agents described herein.
  • Compound (I) in combination with an endocrine agent suitable for use in the treatment of breast cancer, in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with a selective estrogen receptor modulator in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with an aromatase inhibitor in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with an estrogen receptor down-regulator in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with a progesterone receptor antagonist in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with an endocrine agent suitable for use in the treatment of breast cancer, in the treatment of cancer (for example hormone sensitive breast cancer), in a warm-blooded animal, such as man.
  • Suitable endocrine agents for use in this aspect of the invention include any of the endocrine agents described herein.
  • a combination comprising Compound (I) and an endocrine agent suitable for use in the treatment of breast cancer, for use in the treatment of cancer (for example hormone sensitive breast cancer).
  • Suitable endocrine agents for use in this aspect of the invention include any of the endocrine agents described herein.
  • a combination treatment comprising the administration of an effective amount of Compound (I), optionally together with a pharmaceutically acceptable diluent or carrier, in combination with an effective amount of an endocrine agent suitable for use in the treatment of breast cancer optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment, for use in the treatment of cancer (for example hormone sensitive breast cancer).
  • Suitable endocrine agents for use in this aspect of the invention include any of the endocrine agents described herein.
  • Compound (I) or a pharmaceutically acceptable salt thereof, administered would be that sufficient to provide the desired pharmaceutical effect.
  • Compound (I) could be administered to a warm-blooded animal orally, at a unit dose less than Ig daily but more than lmg.
  • Particularly Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 250 mg per day.
  • Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 160 mg per day.
  • Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 50 mg per day.
  • the dose of Compound (I) may be administered as a single daily dose or as multiple fractions of the total daily dose.
  • the total daily dose of Compound (I) may be administered as two doses, which may be the same or different. Suitably however, each fraction of the total daily dose would be approximately equal.
  • compound (I) may be administered as a one or more tablets containing, for example 1, 2.5, 10, 40 or lOOmg of Compound (I).
  • Compound (I) of 40, 80, 100, 160, 200 or 240mg of Compound (I) is administered twice a day.
  • the Compound (I) is suitably administered as the Compound (I) difumarate salt in an amount sufficient to give the required dose of the Compound (I) free base.
  • a dose of Compound (I) difumarate equivalent to 160 mg of Compound (I) as the free base is administered twice a day.
  • a dose of Compound (I) difumarate equivalent to 200 mg of Compound (I) as the free base is administered twice a day.
  • a dose of Compound (I) difumarate equivalent to 240 mg of Compound (I) as the free base is administered twice a day.
  • Selective estrogen receptor modulators and aromatase inhibitors would normally be administered to a warm-blooded animal at a unit dose, of an amount known to the skilled practitioner as a therapeutically effective dose.
  • the active ingredients may be compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about lmg to 40mg, particularly about 1 mg to about 20 mg, more particularly lmg to 5 mg of each active ingredient.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the estrogen receptor down-regulator will normally be administered to a warm-blooded animal at a unit dose, of an amount known to the skilled practitioner as a therapeutically effective dose.
  • the active ingredients may be compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 20-500 mg, particularly 250 mg, of each active ingredient.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the dosage of each of the drugs and their proportions have to be composed so that the best possible treatment effects, as defined by national and international guidelines (which are periodically reviewed and re-defined), will be met.
  • Compound (I) may be prepared as described in Example 1 of WO2005/028469. Alternatively Compound (I) may be prepared as described in the Examples.
  • Figure 1 shows the marked improvement in time to progression of patients treated with anastrozole plus gefitinib compared to patients treated with anastrozole plus placebo in a phase II clinical trial on postmenopausal women with hormone receptor positive metastatic breast cancer.
  • Figure 2 illustrates the objective response rate and the clinical benefit rate of the anastrozole plus gefitinib treated patients compared to the patients treated with anastrozole plus placebo in the same clinical trial.
  • CR refers to complete response
  • PR refers to partial response
  • SD refers to stable disease
  • TTP refers to time to progression.
  • Figure 3 shows the probability of progression free survival over time in postmenopausal ER/PR positive metastatic breast cancer patients that had received endocrine therapy before being administered either gefitinib + anastrozole or gefitinib + placebo.
  • Figure 4 shows the probability of progression free survival over time in post- menopausal ER/PR positive metastatic breast cancer patients that had not received endocrine therapy before being administered either gefitinib + anastrozole or gefitinib + placebo.
  • the x-axis shows time in months and the y-axis the probability of progression- free survival.
  • the reference to "at risk” shows the number of patients over time in each of the treatment arms of the trial.
  • Figure 5 shows an X-ray powder diffraction pattern (XRPD) for Compound (I) difumarate Form A.
  • the x-axis shows the 2-theta value and the y-axis the counts.
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 500 MHz using perdeuterio dimethyl sulfoxide (DMSO-d ⁇ ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
  • 6-Acetoxy-7-methoxyquinazolin-4-one (International Patent Application WO 96/15118, Example 39 thereof; 21.4 kg, 89.3 mol) was suspended in toluene (150 kg). To this was added N-ethyldiisopropylamine (13.3 kg, 103 mol). The brown suspension was heated to 70 0 C then phosphorus oxychloride (36.0 kg, 228 mol) was charged. The reaction mixture was stirred at 70 0 C for 5 hours. Further toluene (84.0 kg) was added followed by 3-chloro-2-fluoroaniline (14.88 kg, 102 mol). The reaction mixture was stirred at 70 0 C for 2 hours during which time a solid precipitated.
  • Step 2 4-(3-Chloro-2-fluoroanilino)-6-hvdroxy-7-methoxyquinazoline 6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (33.5 kg, 69.6mol) was suspended in methanol (198 kg). To the stirred suspension at 25°C was added water (86 kg) and sodium hydroxide (31.5 kg, 32%). The resulting solution was stirred at 60 0 C for 4.5 hours and then cooled to 25°C. Acetic acid (approximately 16.0 kg) was added until a pH of 5.5-6.0 was achieved at which point the product precipitates from solution.
  • the mixture was then cooled to 80 0 C and quenched by the addition of water (216.6 kg).
  • the batch was stirred at 80 0 C for a further 60 minutes then cooled to 20 0 C over 2 hours, during which time the product crystallized.
  • the product was isolated by filtration.
  • the product was dissolved in hot (reflux) methanol (200 L). To this mixture was added water (20 L), which induced crystallization. The suspension was cooled to 0 0 C and filtered.
  • Step 4 4-f3-chloro-2-fluoroanilino)-7-methoxy-6-[fpiperidin-4-yl)oxyl ⁇ uinazoline dihydrochloride 6- ⁇ [(l-tert-Butoxycarbonyl)piperidin-4-yl]oxy ⁇ -4-(3-chloro-2-fluoroanilino)-7- methoxyquinazoline from step 3 (18.80 kg, 37.38 mol) was suspended in isopropanol (139.8 kg), and heated to 40 0 C with stirring. Hydrochloric acid (15.40 kg, -156.3 mol) was charged to the vessel over 50 minutes, allowing an exotherm of approximately 9°C to occur.
  • the batch was stirred at 65 0 C for a further 2 hours to establish crystallisation.
  • the slurry was cooled to 20 0 C over 6 hours.
  • the product was isolated by filtration.
  • the filter cake was slurried with aqueous ethanol (ethanol 117 ml, water 58 ml) and then displacement washed with aqueous ethanol (ethanol 117 ml, water 58 ml).
  • the filter cake was then slurried with water (175 ml) and then displacement washed with water (175 ml).
  • Step 2 4-f3-chloro-2-fluoroanilino)-7-methoxy-6-[fpiperidin-4-yl)oxyl ⁇ uinazoline dihydrochloride
  • Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 0 0 C over 8 hours and held for 1 hour before isolation by filtration.
  • Example F Preparation of Compound (D Difumarate Form A: 2-[4-( ⁇ 4-r(3-Chloro-2- fluorophenvDaminol -7-methoxyq uinazolin-6-yl ⁇ oxy)piperidin- 1-yll -N- methylacetamide di-[(2E)-but-2-enedioatel Form A
  • the filter used to clarify the fumaric acid solution was then washed with isopropanol (37 ml). After holding for 1 hour at 40 0 C the reaction was cooled to 20 0 C over 1 hour. The reaction mixture was held for 13.5 hours before isolating the product by filtration.
  • Compound (I) difumarate Form A is a free flowing powder.
  • X-ray powder diffraction of Compound (I) difumarate ( Figure 5) indicates that the material is crystalline.
  • the X-Ray Powder Diffraction analysis was carried out using a Siemens D5000 powder X- ray diffractometer fitted with a scintillation detector; the X-Ray source was Cu IQ x , giving a wavelength of 1.54A; data were collected over the range 2-theta 2 - 40°, in increments of 2-theta 0.02°, with 1 second per increment and was categorised into the categories identified in the table below:
  • the relative intensities are derived from diffractograms measured with fixed slits.
  • Compound (I) tablets may be manufactured using conventional wet granulation, compression and film coating processes as illustrated in the example below in which Compound (I) difumarate was used.
  • the powdered ingredients are charged to a mixer and mixed to produce a uniform distribution of drug substance.
  • a binder solution is prepared and added to the powders with further mixing until a suitable wet mass is formed.
  • the wet mass is passed through a screen and the resultant granules dried to an appropriate moisture content.
  • the dried granules are passed through an appropriately sized screen and blended with magnesium stearate before compressing into tablet cores using conventional tablettin ⁇ equipment.
  • the compressed cores are coated with an aqueous suspension of film coating components using a conventional perforated drum coater.
  • Hypromellose 3 15.0 15.0 15.0 15.0 15.0
  • Titanium dioxide 3 5.0 5.0 5.3 5.0
  • Tablet strengths refer to the equivalent amount of Compound (I) free base present in the tablet.
  • the Compound (I) difumarate was micronised prior to formulation to give an average particle size of less than about 5 ⁇ m.
  • the hypromellose, macrogol 300 and titanium dioxide are included as Opadry White
  • Purified water is used as the solvent/carrier fluid during film-coating and is removed during the coating process.
  • a suitable manufacturing process is outlined below:
  • Compound (I) (for example difumarate) Lactose STAGE Ir DRY MIX Microcrystalline cellulose
  • Binder solution Polyvidone STAGE 2: WET MIX Purified water i
  • Hypromellose Macrogol 300 STAGE 8 i COATING Titanium dioxide Purified water
  • the target patient population for this trial was female postmenopausal patients aged 18 years or older with newly diagnosed metastatic ER and/or PgR positive breast cancer. Patients with recurrent disease during or after adjuvant tamoxifen or patients who are hormone therapy naive are eligible for this trial.
  • Primary objective
  • the primary objective of this study was to compare the time to progression (TTP) between the two treatment arms (anastrozole/placebo and anastrozole/ZD1839) in postmenopausal patients with newly diagnosed metastatic breast cancer. Secondary objectives
  • ORR objective response rate
  • CR complete response
  • PR partial response
  • RECIST Response Evaluation Criteria
  • CBR clinical benefit rate
  • FSH serum follicle stimulating hormone
  • LH luteinizing hormone
  • Adequate bone marrow function granulocytes > 1500/mm 3 and platelets > 100 000/mm 3
  • Bilirubin ⁇ 1.5 times upper limit of normal ULN, alanine amino transferase (ALT) or aspartate amino transferase (AST) ⁇ 2.5 times the ULN if no demonstrable liver metastasis, or ⁇ 5 times the ULN in the presence of liver metastasis 8. Patients must have a life expectancy > 3 months. 9. All patients must give signed written informed consent. Method Used in Actual Trial:
  • a total of 94 women with newly diagnosed hormone receptor positive metastatic breast cancer were randomized (1 : 1) (one woman died prior to treatment) to receive anastrozole 1 mg/day and either gefitinib 250 mg/day or placebo (50 to anastrozole + placebo; 43 to anastrozole + gefitinib).
  • PFS progression-free survival
  • Anastrozole plus gefitinib was well tolerated and associated with a marked advantage in time to progression compared to anastrozole plus placebo in postmenopausal women with newly diagnosed hormone receptor positive metastatic breast cancer.
  • the endocrine therapy naive patient subgroup of this trial received clinical benefit when gefitinib was combined with anastrozole. These patients showed an unexpected improvement in progression free survival.
  • a tissue block from either the metastatic or primary tumor site is required.
  • Bilirubin >1.5 times upper limit of normal ULN, alanine amino transferase (ALT) or aspartate amino transferase (AST) >2.5 times the ULN if no demonstrable liver metastases, or >5 times the ULN in the presence of liver metastases
  • PFS progression-free survival
  • Compound (I) was compared to that of gefitinib to assess their ability to: a) inhibit the activation (phosphorylation) of EGFR, ErbB2 and ErbB3 in ligand- stimulated cells; and b) inhibit the basal and ligand-stimulated proliferation of MCF-7 cells. a) Comparison of Compound (I) With Gefitinib in Ligand Driven Assays Methods:
  • KB cells and MCF-7 cells were obtained from the American Type Culture Collection (ATCC) and routinely cultured in RPMI 1640 (Phenol red free) + 10% Foetal Bovine Serum + 2mM L-Glutamine.
  • KB cells were seeded at 5000cells/well and MCF-7 cells at 4000cells/well in 96 well plates in RPMI 1640 media containing 10% FBS. Cells were incubated for 72 hours before replacing the media with serum-free RPMI 1640 media for 24 hrs. Cells were then treated with Compound (I) or gefitinib for 90 mins at concentrations ranging from 0- lO ⁇ M. Immediately before cell lysis, MCF-7 and KB cells were incubated for 5 minutes with ligand (heregulin (“HRG”) for the MCF-7 cells and epidermal growth factor (" EGF”) for the KB cells) at concentrations required to increase receptor phosphorylation to 90% of max (ED 90 ) to allow inter-assay comparison.
  • HRG ligand
  • EGF epidermal growth factor
  • the p-EGFR status of KB cells was measured using the Human phospho-EGFR Duoset ELISA kit (R&D systems, DYC 1095).
  • the p-ErbB2 and p-ErbB3 content of MCF- 7 cells were measured using the Human phospho-ErbB2 Duoset ELISA kit (R&D systems, DYC 1768) and Human phospho-ErbB3 Duoset ELISA kit (R&D systems, DYC 1769) respectively.
  • the kits measured whole cell tyrosine phosphorylation of EGFR, ErbB2 or ErbB3. Assays were performed according to the manufacturers instructions, with 50 ⁇ l lysate added per well. Results:
  • Table 1 Compound activity against p-EGFR (in KB cells) and p-ErbB2 and p-
  • Table 1 shows that Compound (I) is a statistically significantly more potent inhibitor of phospho-EGFR, phospho-ErbB2 and phospho-ErbB3 in these cells than gefitinib. b) Compound (I) compared to gefitinib in basal or HRG-stimulated MCF-7 cell proliferation assay
  • MCF-7 cells were routinely cultured in DMEM (Phenol red free) + 10% Foetal Bovine Serum + 2mM L-Glutamine.
  • Cells were seeded at 4000 cells per well in 96 well plates in DMEM media containing 1% charcoal/dextran-treated FBS and 2mM glutamine and allowed to settle for 4 hours prior to treatment with Compound (I) or gefitinib at concentrations ranging from 0- 3 ⁇ M and 0-10 ⁇ g/ml respectively. Two hours following treatment, cells were incubated with 10ng/ml HRG, a concentration required to increase MCF-7 cell proliferation to 90% of max (ED90). Basal wells were unstimulated with ligand.
  • MCF-7 basal assays represent a situation where there no increased stimulation or activation of erbB2/erbB3 heterodimerisation.
  • Table 3 shows that even in such conditions Compound (I) is a more potent inhibitor of MCF-7 proliferation than gef ⁇ tinib.
  • Compound (I) is a superior erbB tyrosine kinase inhibitor compared to gefitinib and would therefore be expected to provide a beneficial anti-cancer effect when used in combination with an endocrine agent suitable for use in the treatment of breast cancer (for example an aromatase inhibitor such as anastrozole, letrozole or exemestane) in the treatment of cancer, particularly hormone sensitive breast cancer such as estrogen receptor positive breast cancer.
  • an endocrine agent suitable for use in the treatment of breast cancer
  • an aromatase inhibitor such as anastrozole, letrozole or exemestane
  • hormone sensitive breast cancer such as estrogen receptor positive breast cancer.

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Abstract

L'invention porte sur une combinaison comprenant de la 4-(3-chloro-2-fluoroanilino)-7-méthoxy-6-{[1-(N-méthylcarbamoylméthyl)pipéridin-4-yl]oxy}quinazoline, ou sur un sel pharmaceutiquement acceptable de celle-ci, et sur un agent endocrinien approprié pour une utilisation dans le traitement du cancer du sein. L'invention porte également sur l'utilisation de la combinaison dans le traitement du cancer.
PCT/GB2009/050494 2008-05-13 2009-05-11 Combinaison comprenant de la 4-(3-chloro-2-fluoroanilino)-7-méthoxy-6-{[1-(n-méthylcarbamoylméthyl)pipéridin-4-yl]oxy}quinazoline Ceased WO2009138779A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US5270608P 2008-05-13 2008-05-13
US61/052,706 2008-05-13
US11066408P 2008-11-03 2008-11-03
US61/110,664 2008-11-03
US12058308P 2008-12-08 2008-12-08
US61/120,583 2008-12-08

Publications (1)

Publication Number Publication Date
WO2009138779A1 true WO2009138779A1 (fr) 2009-11-19

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Country Status (1)

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WO (1) WO2009138779A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010122340A3 (fr) * 2009-04-23 2011-09-09 Astrazeneca Ab Procédé 738

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082831A1 (fr) * 2002-03-28 2003-10-09 Astrazeneca Ab Derives de 4-anilino quinazoline utilises en tant qu'agents antiproliferatifs
WO2005028469A1 (fr) * 2003-09-19 2005-03-31 Astrazeneca Ab Derives de quinazoline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082831A1 (fr) * 2002-03-28 2003-10-09 Astrazeneca Ab Derives de 4-anilino quinazoline utilises en tant qu'agents antiproliferatifs
WO2005028469A1 (fr) * 2003-09-19 2005-03-31 Astrazeneca Ab Derives de quinazoline

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010122340A3 (fr) * 2009-04-23 2011-09-09 Astrazeneca Ab Procédé 738
JP2012524769A (ja) * 2009-04-23 2012-10-18 アストラゼネカ アクチボラグ ４−（３−クロロ−２−フルオロアニリノ）−７−メトキシ−６−｛［１−（ｎ−メチルカルバモイルメチル）ピペリジン−４−イル］オキシ｝キナゾリンの製造方法
US8450482B2 (en) 2009-04-23 2013-05-28 Astrazeneca Ab Process for the preparation of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-([1-(N-methylcarbamoymethyl)piperidin-4-yl]oxy)quinazoline

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