WO2011129837A1 - Emploi d'un promédicament de type 4-hydroxytorémifène dans le traitement du cancer du sein - Google Patents

Emploi d'un promédicament de type 4-hydroxytorémifène dans le traitement du cancer du sein Download PDF

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Publication number
WO2011129837A1
WO2011129837A1 PCT/US2010/031447 US2010031447W WO2011129837A1 WO 2011129837 A1 WO2011129837 A1 WO 2011129837A1 US 2010031447 W US2010031447 W US 2010031447W WO 2011129837 A1 WO2011129837 A1 WO 2011129837A1
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Prior art keywords
breast cancer
mixture
compound
cancer
compounds
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PCT/US2010/031447
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English (en)
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Peter Kushner
Cyrus Harmon
David Myles
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Olema Pharmaceuticals, Inc.
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Priority to PCT/US2010/031447 priority Critical patent/WO2011129837A1/fr
Publication of WO2011129837A1 publication Critical patent/WO2011129837A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • the present invention is directed to compounds, compositions thereof, and the use of the compounds and compositions for the treatment and prevention of breast cancer.
  • the present invention relates to the use of a prodrug of 4-hydroxytoremifene or a related compound for the treatment of breast cancer in mono-therapy or in combination therapy, or for a reduction in the recurrence rate of previously-treated breast cancer.
  • intermediates are presented for the synthesis of compounds and compositions for the treatment and prevention of breast cancer.
  • Estrogen Receptor (ER)-positive breast cancer is treated with agents designed to block the pro-proliferative action of the estrogen receptor.
  • One such agent is the antiestrogen tamoxifen.
  • Other agents have been reported, including endoxifen, 4-hydroxytoremifene, and 4-iodotamoxifen. See for example, U.S. Patent 4,839,155, herein incorporated by reference.
  • Tamoxifen itself binds very poorly to the ER. However, when activated by metabolic action, tamoxifen gives rise to derivatives that bind very tightly to the ER and put it in an inactive state that prevents it from modulating transcription of pro-proliferative genes.
  • the tamoxifen is activated to inhibit ER action by metabolizing enzymes that convert the tamoxifen to 4-hydroxy tamoxifen (4-OHT) or to 4-hydroxy N-desmethyl tamoxifen (also known as endoxifen). These later compounds bind with high affinity to the ER, with binding constants roughly equal to that of estradiol. See Jordan, V.C., "New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer," Steroids, vol. 72, issue 13, pp. 829-842, November 2007.
  • SSRIs selective serotonin reuptake inhibitors
  • PAXIL® selective serotonin reuptake inhibitors
  • the present invention is directed to a prodrug of 4-hydroxytoremifene or related compounds with improved clinical outcome.
  • Compounds according to the invention may result in improved outcomes for patients non-responsive to tamoxifen therapy due to the cytochrome p450 enzyme Cyp2D6.
  • Compounds according to the invention may have improved bioavailability in that they are no longer substrates for UGTs in the gut, or may be more readily absorbed than tamoxifen or endoxifen.
  • Prodrugs according to the invention may include, for example, 4-hydroxytoremifene phosphate in which the hydroxyl moiety is modified to a phosphate, where the phosphate may lead to more efficient absorption when it is converted to active metabolite at high concentration at the apical cell surface.
  • the present invention is directed to compounds, compositions thereof, and the use of the compounds and compositions for the treatment and prevention of breast cancer.
  • Compounds according to the invention may be considered prodrugs of endoxifen or 4-hydroxytoremifene and related compounds.
  • the compounds may be used for the treatment of breast cancer, or for a reduction in the recurrence rate or severity of previously-treated breast cancer.
  • intermediate compounds according to the invention are used for the synthesis of an anti-cancer agent.
  • the compounds according to the invention are compounds of the following formula I:
  • Ri may be H, lower alkyl, cyclic alkyl (by replacing the methyl group on the nitrogen or by creating a quaternary ammonium), or a prodrug moiety
  • R 2 may be H or a prodrug moiety, with the understanding that at least one of Ri and R 2 is a prodrug moiety.
  • Known compounds 4-hydroxy-tamoxifen and endoxifen are not encompassed within compounds according to the invention. While the compound of Formula I is drawn with a specific orientation around the double bond, both E and Z configurations around the double bond are encompassed by the invention, for example, as represented b Formula la:
  • the compounds according to the invention are compounds of the following formula:
  • Ri may be H or CH 3 .
  • the wavy bond indicates unspecified stereochemistry for the ethyl and phenyl substituents, such that the structure has either an E or Z configuration around the double bond.
  • Such compounds may be referred to as O-Pro-Endoxifens, when Ri is H.
  • the compound according to the invention has the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • the compound according to the invention has the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • R 2 is an H
  • the wavy bond indicates unspecified stereochemistry for the ethyl and phenyl substituents, such that the structure has either an E or Z configuration around the double bond.
  • Such compounds may be referred to as N-Pro-Endoxifens.
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • Such compounds may be referred to as N,0-di-Pro-Endoxifens.
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula II:
  • Ri may be H, lower alkyl, cyclic alkyl (by replacing the methyl group on the nitrogen or by creating a quaternary ammonium), or a prodrug moiety
  • R 2 may be H or a prodrug moiety, with the understanding that at least one of Ri and R 2 is a prodrug moiety. While the compound of Formula II is drawn with a specific orientation around the double bond, both E and Z configurations around the double bond are encompassed by the invention for example, as represented by Formula Ila:
  • the compound according to the invention is a compound of the following formula:
  • the compounds according to the invention are compounds of the following formula III:
  • Ri may be H, lower alkyl, cyclic alkyl (by replacing the methyl group on the nitrogen or by creating a quaternary ammonium), or a prodrug moiety, and where Z is selected from fluoro or chloro, and the wavy line indicates that the configuration around the double bond may be either E or Z.
  • the compounds according to the invention are compounds of the following formula:
  • Ri is H.
  • the compounds according to the invention are compounds of the following formula:
  • Ri is H.
  • compounds according to the above formulas are capable of being metabolized in vivo to endoxifen or 4-hydroxytoremifene in one or more steps.
  • Those compounds which are metabolized in vivo to endoxifen or 4- hydroxytoremifene may be referred to as prodrugs.
  • the compounds may be metabolized through a pathway that does not involve liver enzymes, or does not specifically involve Cyp2D6, such as hydrolysis in the stomach.
  • the compounds are resistant to glucuronidation at either the O- or N-position.
  • the compounds according to the invention may have improved bioavailability by virtue of improved oral adsorption compared to endoxifen or 4- hydroxytoremifene or related compounds.
  • the compounds according to the invention may be more resistant to metabolic breakdown compared to endoxifen.
  • the invention encompasses methods of making compounds according to the above formulas.
  • the invention includes compositions comprising a pharmaceutically acceptable carrier and a compound according to the above formula. Such compositions may be pharmaceutical formulations themselves, or may be formulated with additional ingredients at a later time prior to administration to yield the actual pharmaceutical formulation.
  • compositions comprising mixtures of E/Z isomers are also envisioned. Such mixtures may be equimolar or enriched in either the E or the Z isomer.
  • Compositions according to the invention may have a physical form of the compound selected from the group consisting of an anhydrous form, a single crystalline form, a mixture of polymorphic forms, a hydrated form, and mixtures thereof.
  • the invention may have a physical form of the compound selected from the group consisting of an anhydrous form, a single crystalline form, a mixture of polymorphic forms, a hydrated form, and mixtures thereof.
  • compositions comprising or consisting essentially of the compounds described herein, as well as kits comprising the compositions and combinations thereof.
  • the invention encompasses methods of treating breast cancer, or of reducing the rate or severity of recurrence of breast cancer in previously-treated breast cancer patients. Treating includes management of, amelioration of symptoms of, and slowing the progression of the condition.
  • Methods according to the invention comprise administering to a patient in need thereof a therapeutically effective amount of the compound as an active agent.
  • the breast cancer is estrogen receptor (ER) positive.
  • Treatment may be directed to those patients that will benefit the most from a compound according to the invention as an alternative to tamoxifen.
  • treatment may be directed at human females who are resistant or non-responsive to tamoxifen treatment. Non- responsiveness may be found empirically through dosage with tamoxifen, or it may be inferred through genetic, enzymatic, or other assay of samples from the patient.
  • non-responsiveness to tamoxifen may be a transient or induced condition.
  • non-responsiveness to tamoxifen may be due to
  • Non-responsiveness to tamoxifen may be due to inability to convert tamoxifen to endoxifen in vivo, or may be due to resistance by overexpression of HER2/neu by the cancer cells, or due to some other mechanism.
  • the subject has previously undergone treatment, and in some cases, the previous therapy has failed.
  • the subject is in remission.
  • the subject is post-menopausal.
  • the subject is at risk for breast cancer.
  • Subjects are mammalian, and preferably are human, and more preferably are human females.
  • treatment is for patients that are non-responsive to tamoxifen, wherein non-responsiveness may be determined by a method selected from the group consisting of liver enzyme assay, genotyping Cyp2D6 for one or more copies of a partly or completely defective allele, for example the * 10 allele, detecting the presence, absence, or levels of endoxifen in biological fluids, determining if the patient is taking drugs that interfere with tamoxifen metabolism, and combinations thereof.
  • the breast cancer to be treated is ER positive. In some embodiments, the breast cancer is tamoxifen resistant or overexpresses
  • the breast cancer is recurring. In some embodiments, the breast cancer is recurring.
  • the breast cancer progression rate from ductal carcinoma in situ (DCIS) or atypical hyperplasia is reduced or delayed.
  • the compounds may be used for the treatment of breast cancer, or for a reduction in the recurrence rate or severity of previously-treated breast cancer.
  • the compound is administered as mono-therapy, where the compound according to the invention is the only agent active against breast cancer.
  • the monotherapeutically effective amount of compound according to the invention is bioequivalent to oral tamoxifen of 5-80 mg per day.
  • the invention encompasses methods of treating breast cancer using a combination of two or more drugs.
  • each drug may be active individually against the breast cancer, or one or more drugs may be active against the breast cancer, and one or more additional drugs may serve to improve the efficacy of the active drug(s) by reducing side effects, increasing potency of the active drug(s), or some other mechanism.
  • the two or more compounds e.g., two, three, four, five, or more compounds
  • may be administered in combination e.g., in the same formulation, or may be administered in separate formulations at the same or at different times.
  • Pharmaceutical formulations of all combinations listed herein are also contemplated.
  • compounds according to the invention are used in combination therapy with HDAC inhibitors such as valproic acid, trichostatin A, or SAHA; and/or IGF receptor inhibitors such as EGCG; and/or mTOR inhibitors such as rapamycin and/or sulforaphane; an EGFR inhibitor; and/or tamoxifen and related compounds; other chemotherapeutic agent, biologic, radiation therapy, or other agents and procedures useful in the treatment of cancer; and combinations thereof.
  • HDAC inhibitors such as valproic acid, trichostatin A, or SAHA
  • IGF receptor inhibitors such as EGCG
  • mTOR inhibitors such as rapamycin and/or sulforaphane
  • an EGFR inhibitor such as a EGFR inhibitor
  • tamoxifen and related compounds other chemotherapeutic agent, biologic, radiation therapy, or other agents and procedures useful in the treatment of cancer
  • formula I, a HDAC inhibitor, and an IGF receptor inhibitor are administered.
  • the IGF-1R inhibitor can be any one of the embodiments.
  • picropodophyllin see, e.g., Girnita, A. et al, Cancer Res., 2004. 64(1): 236-242
  • the green tea polyphenol, EGCG see, e.g., Shimizu, M. et al, Biochem. Biophys. Res. Commun., 2005. 334(3): 947-953; Li, M. et al, Cancer Epidemiol. Biomarkers Prev., 2007. 16(3): 598-605.
  • An EGFR inhibitor may be gefitinib, and the mTOR inhibitor may be rapamycin or rapamycin derivatives (see, e.g., Johnston, S.R., Clin. Cancer Res., 2006. 12(3 Pt. 2): 1061-1069s).
  • the skilled practitioner will be able to use a variety of IGF-1R, EGFR, and mTOR inhibitors in the invention, to provide therapeutically effective combinations.
  • Embodiments of the above combinations include administering formulas I or II, EGCG, and sulforaphane; formulas I or II, rapamycin, and sulforaphane; and formulas I or II, EGCG, rapamycin, and sulforaphane.
  • Sulforaphane may be administered at 01. -10 micromolar, 0.5-5 micromolar, 0.5-2 micromolar, or about 1 micromolar amounts. Additional embodiments include administering formulas I or II and valproic acid; formulas I or II, valproic acid, and EGCG; formulas I or II, valproic acid, and rapamycin; and formulas I or II, valproic acid, EGCG, and rapamycin.
  • Embodiments of the above combinations include administering formulas I or II and trichostatin A; formulas I or II, trichostatin A, and EGCG; formulas I or II, trichostatin A, and rapamycin; and formulas I or II, trichostatin A, EGCG, and rapamycin.
  • Embodiments of the above combinations include administering formulas I or II and EGCG; formulas I or II and rapamycin; and formulas I or II, EGCG, and rapamycin.
  • the daily dose of valproic acid is from about 15/mg/kg to about 60 mg/kg. In one embodiment, the daily dose of valproic acid is sufficient to achieve about 300 to about 867 micromolar in patient serum. In another embodiment, the daily dose of valproic acid is sufficient to achieve about 300 to about 1000 micromolar in patient serum, and in another embodiment, the daily dose of valproic acid is sufficient to achieve about 500 to about 1000 micromolar in patient serum. In some embodiments, the dose of SAHA is from about 200 mg/day to about 600 mg/day. In another embodiment, the dose of SAHA is about 400 mg/day.
  • the dose of EGCG is from about 300 mg/day to about 800 mg/day. In one embodiment, the dose of rapamycin is from about 0.125 mg/day to about 1 mg/day. In one embodiment, the dose of gefitinib is from about 200 mg/day to about 300 mg/day. In another embodiment, the dose of gefitinib is about 250 mg/day. In one embodiment, the dose of erlotinib is from about 100 mg/day to about 150 mg/day. In some embodiments, compounds are administered in combination, with ratios of those compounds which preserve the recommended daily doses of the compounds. In some embodiments, compounds are administered in combination, with ratios of those compounds which preserve the ranges of doses as described herein.
  • the invention provides a method of treating, reducing the recurrence rate, or reducing the severity of recurrence of breast cancer, the method comprising the step of administering a therapeutically effective amount of a compound according to the invention and a compound selected from the group consisting of a HDAC inhibitor or an IGF receptor inhibitor.
  • the invention provides a method of treating, reducing the recurrence rate, or reducing the severity of recurrence of breast cancer, the method comprising the step of
  • the invention provides a method of treating, reducing the recurrence rate, or reducing the severity of recurrence of breast cancer, the method comprising the step of administering a therapeutically effective amount of a compound according to the invention and sulforaphane.
  • the invention provides a method of treating, reducing the recurrence rate, or reducing the severity of recurrence of breast cancer, without attendant increase in risk of uterine cancer, the method comprising the step of administering a therapeutically effective amount of compound according to the invention with an HDAC inhibitor.
  • the HDAC inhibitor is VP A, TSA, sulforaphane, or SAHA.
  • the invention provides a method of treating, reducing the recurrence rate, or reducing the severity of recurrence of breast cancer, without attendant increase in risk of uterine cancer, the method comprising the step of administering a therapeutically effective amount of compound according to the invention with an HDAC inhibitor, wherein the compound according to the invention has an estrogen-like effect on the uterus.
  • Attendant risk of uterine cancer refers to reducing or eliminating the risk of uterine cancer that typically exists with anti- estrogen therapy alone. In some embodiments, this risk is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or it is virtually or wholly eliminated. Prevention of breast cancer is also envisioned.
  • the compound according to the invention is administered as part of a hormonal therapy.
  • hormonal therapy may be an antiestrogen therapy or aromatase inhibitor therapy.
  • the hormonal therapy can also be estrogen ablation therapy, including an aromatase inhibitor.
  • the aromatase inhibitor can be, but is not limited to, exemestane, letrozole, or anastrozole.
  • the dose of letrozole is from about 1 mg/day to about 5 mg/day.
  • the dose of letrozole is about 2.5 mg/day.
  • the dose of exemestane is from about 10 mg/day to about 40 mg/day.
  • the dose of exemestane is about 25 mg/day.
  • the dose of anastrozole is from about 0.5 mg/day to about 3 mg/day.
  • the dose of anastrozole is about 1 mg/day.
  • the compound according to the invention is administered in combination with 4-hydroxytamoxifen or a prodrug of 4- hydroxytamoxifen.
  • combinations of the compound according to the invention and 4-hydroxytamoxifen (or prodrug thereof) are administered to those patients that are non-responsive to tamoxifen, and the administered ratio of compound according to the invention and 4-hydroxytamoxifen or 4-hydroxytamoxifen prodrug (which may also be a compound according to the invention) results in in vivo levels of endoxifen or 4-hydroxytoremifene and 4-hydroxytamoxifen that mimic the levels of endoxifen and 4-hydroxytamoxifen following administration of tamoxifen to responsive patients.
  • the in vivo levels may correlate with serum levels or may be measured at the site of action, or by other manner, such as by plural effusion.
  • the ratio of compound according to the invention to 4-hydroxytamoxifen or prodrug thereof is the bioequivalent of from about 0.5 to about 10 times endoxifen to 4-hydroxytamoxifen.
  • levels of endoxifen are about 4 times the level of 4-hydroxytamoxifen up to endoxifen levels of about 6 times the level of 4- hydroxytamoxifen.
  • Bioequivalence may be determined by assay of serum levels, or by levels in plural effusion, among other methods of determining bioequivalence. Prevention of breasts cancer is also envisioned.
  • the present invention encompasses methods and compositions for reducing the incidence of breast cancer or delaying the progression of pre-cancerous conditions, including in subjects who are at risk for breast cancer that is greater than the average risk for breast cancer.
  • Risk factors considered in preventing breast cancer in subjects include family history of breast cancer (relatives with breast cancer), genetic markers for breast cancer such as BRCA1 and BRCA2, age at menarche, age at first live birth, the number of breast biopsies, presence of atypical hyperplasia on breast biopsy, population rates of breast cancer and death from other causes.
  • the present invention also provides methods and compositions for reducing the rate of progression of breast cancer to a later stage for those who already have breast cancer or precancerous indicators, as well as reducing the rate and/or severity of the recurrence of breast cancer for those in remission from breast cancer.
  • the invention contemplates methods of delaying the progression of DCIS to breast cancer, and methods of delaying the progression of atypical hyperplasia to breast cancer.
  • the invention encompasses treating estrogen receptor positive breast cancer.
  • the present invention encompasses treating DCIS and, in another embodiment, the present invention encompasses treating atypical hyperplasia.
  • the present invention further contemplates that the combination therapies as described herein can also reduce or eliminate other side effects of treatment, at least in part because lower doses of compounds can be used in treatment or prevention protocols.
  • breast cancer that is tamoxifen resistant, as well as to treat breast cancer that overexpresses Her2/Neu.
  • the invention also contemplates treating subjects with breast cancer for whom previous therapy has failed, or for whom the cancer is recurring. In some
  • the invention is to treat subjects with breast cancer who are post-menopausal, and in some embodiments, the invention contemplates treating subjects who are genetically predisposed to breast cancer or otherwise at increased risk.
  • the invention also encompasses methods of treating subjects to prevent progression of breast cancer, and in some embodiments, the invention encompasses treating or preventing breast cancer in patients with pre-cancerous growths or benign tumors. It is within the scope of the invention to treat subjects that are in remission from breast cancer, and to treat subjects with breast cancer that have previously undergone treatment.
  • intermediates are presented for the synthesis of compounds and compositions for the treatment and prevention of breast cancer.
  • the intermediates may be immediate precursors of the compounds to be administered to the patient, or the intermediates may require two or more synthetic steps to be converted into a compound to be administered to a patient.
  • FIG. 1 shows the chemical structures for tamoxifen, 4-hydroxy- tamoxifen, endoxifen, and 4-hydroxytoremifene.
  • FIG. 2 shows a proposed synthetic scheme for endoxifen phosphate.
  • FIG. 3 shows additional synthetic options for access to O-Pro- endoxifens.
  • FIG. 4 shows a direct activation of the phenol-OH.
  • FIG. 5 shows a route to O-Pro-endoxifen via a protected amine.
  • FIG. 6 shows additional options for access to O-Pro-endoxifens.
  • FIG. 7 shows additional classes of phenol prodrugs.
  • FIG. 8 shows proposed synthetic options for access to N-Pro- endoxifens.
  • FIG. 9 shows a synthetic scheme for 4-hydroxytoremifene via an aldehyde precursor.
  • the -OR groups form an acetal, and may be, for example, -OMe or -OEt.
  • FIG. 10 shows a synthetic scheme of a pivalate ester and a phosphate prodrug via a common precursor.
  • the -OR groups form an acetal, and may be, for example, -OMe or -OEt.
  • FIG. 11 shows a synthetic scheme of a pivalate ester and a phosphate prodrug via a common precursor.
  • the -OR groups form an acetal, and may be, for example, -OMe or -OEt.
  • a phosphate group is attached at the 4-hydroxy position of endoxifen or 4-hydroxytoremifene. While not wishing to be bound by theory, it is believed that this modification and other modifications can lead to improved clinical outcomes for breast cancer patients.
  • prodrug means a compound with a temporary modification of a functional group of a drug in order to improve the pharmaceutical utility of the drug.
  • Prodrug may refer to the entire compound, or it may refer to the chemical modification, in the context of a prodrug moiety being the chemical modification.
  • the functional group of the drug is a handle for the introduction of a moiety that confers on the new entity some desirable characteristic.
  • the prodrug moiety is intimately connected with the pharmaceutical deficiency of the parent drug, and the presence of the prodrug moiety directly addresses the deficiency.
  • prodrugs rely on in vivo enzymatic activation for conversion to active form of the drug for example by cleavage of the prodrug moiety by an enzyme. In other embodiments, prodrugs rely on physiological chemical conditions for release of the drug, for example through a change in pH.
  • the benefits of a prodrug are not limited to improved in vivo benefits compared to the parent drug, but may also include improved processing or storage characteristics or economic considerations prior to administration to the patient.
  • cancer refers to a disease involving cells that have the potential to metastasize to distal sites and exhibit phenotypic traits that differ from those of non-cancer cells. Cancer cells acquire a characteristic set of functional capabilities during their development, albeit through various mechanisms. Such capabilities include evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion/metastasis, limitless replicative potential, and sustained angiogenesis.
  • cancer cell is meant to encompass both pre-malignant and malignant cancer cells.
  • Estrogen receptor positive breast cancer refers to breast cancers that are in the positive or intermediate range for the estrogen receptor protein. For example, when estrogen receptor protein can be measured as femtomoles per milligram of cytosol protein. In this assay, values above 10 are positive, values from 3 to 10 are intermediate, and values less than 3 are negative. Other assays known in the art can be used to determined if the breast cancer is estrogen receptor positive, in particular assays based on antibodies to estrogen receptors alpha and beta and their use in biochemical or histological assays.
  • histone deacetylase inhibitor and “inhibitor of histone deacetylase” mean a compound which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity, abbreviated as HDAC inhibitors.
  • “Inhibiting histone deacetylase enzymatic activity” means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. (see, e.g., Minucci et al, Nature 6:38-51 (2006). In some preferred embodiments, such reduction of histone deacetylase activity is at least about 50%, more preferably at least about 75%, and still more preferably at least about 90%.
  • histone deacetylase activity is reduced by at least 95% and more preferably by at least 99%.
  • Assays for determining inhibition are described in Phiel, C.J., et al., J Biol Chem., 2001. 276(39): p. 36734-41 and Gottlich, M., et al, Embo J., 2001. 20(24): p. 6969- 78.
  • the histone deacetylase inhibitor reduces the ability of a histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect.
  • the concentration of the inhibitor required for histone deacetylase inhibitory activity is at least 2-fold lower, more preferably at least 5-fold lower, even more preferably at least 10-fold lower, and most preferably at least 20-fold lower than the concentration required to produce an unrelated biological effect.
  • active ingredient includes having a therapeutic or prophylactic effect on breast cancer in the combinations. This does not include inactive ingredients such as pharmaceutical carriers, excipients, and the like.
  • rapamycin protein inhibitor or "mTOR inhibitor” includes drugs such as rapamycin, temsirolimus, and everolimus that selectively inhibit the mammalian target of rapamycin (mTOR).
  • mTOR inhibitor refers to drugs such as picropodophyllin and podophyllotoxin that selectively inhibit the IGF-1 receptor.
  • EGF receptor inhibitor of "EGFR inhibitor” refers to drugs such as gefitinib and erlotinib that selectively inhibit the EGF receptor.
  • Insufficient to fully prevent production of estrogen refers to the inability of an aromatase inhibitor to fully prevent a tumor cell from converting an estrogen precursor into a functional estrogen that can stimulate tumor proliferation.
  • Less than estrogen receptor-saturating amounts refers to amounts of fulvestrant less than 100 fold molar excess to the amounts of estradiol or less than 10 nanomolar in patient circulation.
  • “Hormonal therapy” refers to drugs or treatments that block the effect of, or reduce the levels of hormones, and in particular which block the effect of estrogen or lower estrogen levels, including anti-estrogen therapy and estrogen ablation therapy.
  • the terms "prevent,” “preventing” and “prevention” refer to the prevention of the recurrence, worsening, or spread of a disease in a subject resulting from the administration of a prophylactic or therapeutic agent.
  • overexpress refers to a protein or nucleic acid (RNA) that is translated or transcribed at a detectably greater level, usually in a cancer cell, in comparison to a normal cell.
  • RNA nucleic acid
  • RNA and protein stability as compared to a normal cell.
  • Overexpression can be detected using conventional techniques for detecting mRNA (i.e., RT-PCR, PCR, hybridization, microarray) or proteins (i.e., ELISA, immunohistochemical techniques).
  • Overexpression can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a normal cell. In certain instances, overexpression is 1-fold, 2-fold, 3- fold, 4-fold or more higher levels of transcription or translation in comparison to a normal cell.
  • the term “in combination” refers to the use of more than one prophylactic and/or therapeutic agents.
  • the use of the term “in combination” does not restrict the order in which prophylactic and/or therapeutic agents are administered to a subject with cancer, especially breast cancer.
  • a first prophylactic or therapeutic agent can be administered prior to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second prophylactic or therapeutic agent to a subject which had, has, or is susceptible to cancer, especially breast cancer.
  • the prophylactic or therapeutic agents are administered to a subject in a sequence and within a time interval such that the agent of the invention can act together with the other agent to provide an increased benefit than if they were administered otherwise. Any additional prophylactic or therapeutic agent can be administered in any order with the other additional prophylactic or therapeutic agents.
  • the term “combine effectively” refers to a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) which is more effective than any single agent administered alone. Combining effectively may also refer to combinations of therapies that are not less effective than any single agent or even less effective than any single agent, but which also eliminate or reduce the adverse effects of one or more of the agents, such as eliminating or reducing the risk of uterine cancer associated with one or more of the agents.
  • the term "synergistic” refers to a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) which is more effective than the additive effects of any two or more single agents.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies (e.g., agents) to a subject with a disease or disorder, in particular, cancer, or a condition or symptom associated therewith.
  • a synergistic effect can result in improved efficacy of therapies in the prevention, management, or treatment of a disease or disorder, in particular, cancer or a condition or symptom associated therewith.
  • the synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of any single therapy.
  • side effects encompasses unwanted and adverse effects of a prophylactic or therapeutic agent. Adverse effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a prophylactic or therapeutic agent might be harmful or uncomfortable or risky. Side effects can refer specifically to an increase in uterine cell proliferation, as well as to an increase in the frequency of uterine cancer and an increase in the risk of developing uterine cancer.
  • Side effects from chemotherapy include, but are not limited to, gastrointestinal toxicity such as, but not limited to, early and late-forming diarrhea and flatulence, nausea, vomiting, anorexia, leukopenia, anemia, neutropenia, asthenia, abdominal cramping, fever, pain, loss of body weight, dehydration, alopecia, dyspnea, insomnia, dizziness, mucositis, xerostomia, and kidney failure, as well as constipation, nerve and muscle effects, temporary or permanent damage to kidneys and bladder, flu-like symptoms, fluid retention, and temporary or permanent infertility.
  • Side effects from radiation therapy include but are not limited to fatigue, dry mouth, and loss of appetite.
  • Side effects from biological bowel infections include but are not limited to chronic respiratory infections, nausea, vomiting, anorexia, leukopenia, anemia, neutropenia, asthenia, abdominal cramping, fever, pain, loss of body weight, dehydration, alopecia, dyspnea, insomnia, dizziness,
  • therapies/immunotherapies include but are not limited to rashes or swellings at the site of administration, flu-like symptoms such as fever, chills and fatigue, digestive tract problems and allergic reactions.
  • Side effects from hormonal therapies include but are not limited to nausea, fertility problems, depression, loss of appetite, eye problems, headache, and weight fluctuation. Additional undesired effects typically experienced by patients are numerous and known in the art. Many are described in the Physicians' Desk Reference (56 th ed., 2002).
  • therapeutically effective amount or dose or “therapeutically sufficient amount or dose” or “effective or sufficient amount or dose” herein is meant a dose that produces therapeutic effects for which it is administered, in the context of the combination therapy in which it is administered. Often, the therapeutically effective or sufficient amount or dose of the compounds comprising the
  • compositions of the invention will be lower when administered in the specific combinations, than the doses that would be therapeutically effective or sufficient when the compounds are administered separately.
  • the exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g. , Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington. The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to destroy, modify, control or remove primary, regional or metastatic cancer tissue.
  • a therapeutically effective amount may refer to the amount of therapeutic agent sufficient to delay or minimize the spread of cancer.
  • a therapeutically effective amount may also refer to the amount of the therapeutic agent that provides a therapeutic benefit in the treatment or management of cancer.
  • a therapeutically effective amount with respect to a therapeutic agent of the invention means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of cancer. In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.
  • a therapeutically effective amount refers to the amount of a therapeutic agent that, e.g., reduces the proliferation of cancer cells, increases the death of cancer cells or, reduces the size of a tumor or spread of a tumor in a subject.
  • a therapeutically effective amount of a therapeutic agent reduces the size of a tumor or the spread of a tumor in a subject by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, ate least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% relative to a control such as PBS.
  • a therapeutically effective amount refers to the amount of a therapeutic agent that increases survival by 1 month, 2 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more. In some embodiments, a therapeutically effective amount refers to the amount of a therapeutic agent that prevents the progression from DCIS or atypical hyperplasia to breast cancer.
  • carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in
  • compositions will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions are sterile and in suitable form for administration to a subject, preferably an animal subject, more preferably a mammalian subject, and most preferably a human subject.
  • the term “intermediates” encompasses compounds used in the synthesis of prodrug compounds according to the invention.
  • intermediates may have activity in their own right, or may be biologically inactive.
  • compositions of the present invention are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g. , Remington 's Pharmaceutical Sciences, 20 th ed., 2003).
  • compositions of the invention may be administered locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion, by injection, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • an implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • care must be taken to use materials to which the prophylactic or therapeutic agents do not absorb.
  • the invention can be delivered in a vesicle, in particular a liposome
  • composition can be delivered in a controlled release or sustained release system.
  • a pump may be used to achieve controlled or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al, 1980, Surgery 88:507; Saudek et al, 1989, N. Engl. J. Med.
  • polymeric materials can be used to achieve controlled or sustained release of the antibodies of the invention or fragments thereof (see e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y. (1984); Ranger and Peppas, 1983, J., Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al, 1985, Science 228: 190; During et al, 1989, Ann. Neurol. 25:351; Howard et al, 1989, J.
  • polymers used in sustained release formulations include, but are not limited to, poly(2 -hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolides (PLG), polyanhydrides, poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides) (PLGA), and polyorthoesters.
  • the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable.
  • a controlled or sustained release system can be placed in proximity of the therapeutic target, i.e., the lungs, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • suitable routes of administration include, but are not limited to, ingestion, parenteral (e.g., intravenous, intramuscular, intradermal, intra-tumoral, intra-synovial, and subcutaneous), oral (e.g., inhalation, ingestion), intranasal, transdermal (topical), transmucosal, intra- tumoral, intra-synovial, vaginal, and rectal administration.
  • parenteral e.g., intravenous, intramuscular, intradermal, intra-tumoral, intra-synovial, and subcutaneous
  • oral e.g., inhalation, ingestion
  • intranasal e.g., intranasal
  • transdermal e.g., topical
  • transmucosal e.g., transmucosal, intra- tumoral, intra-synovial, vaginal
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • compositions of the invention are to be administered topically, the compositions can be formulated in the form of, e.g., a toothpaste, ointment, cream, transdermal patch, lotion, gel, oral gel, shampoo, spray, aerosol, solution, emulsion, or other form well-known to one of skill in the art. See, e.g., Remington's
  • viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed.
  • Suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
  • auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts
  • Other suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as Freon), or in a squeeze bottle.
  • a pressurized volatile e.g., a gaseous propellant, such as Freon
  • Moisturizers or humectants can also be
  • compositions of the invention are to be administered intranasally, the compositions can be formulated in an aerosol form, spray, mist or in the form of drops.
  • prophylactic or therapeutic agents for use according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing
  • compositions of the invention are to be administered orally
  • the compositions can be formulated orally in the form of, e.g., gum, tablets, capsules, cachets, gelcaps, solutions, suspensions and the like.
  • Tablets or capsules can be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or
  • hydroxypropyl methylcellulose hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium starch glycolate
  • wetting agents e.g., sodium lauryl sulphate
  • the tablets may be coated by methods well-known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
  • preservatives e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salt
  • Preparations for oral administration may be suitably formulated for slow release, controlled release or sustained release of a prophylactic or therapeutic agent(s).
  • compositions of the invention may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • compositions of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • compositions of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compositions may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions of the invention are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the invention provides a pharmaceutical pack or kit comprising one or more containers filled with individual components (in pharmaceutical formulations) of the combination therapies described herein; for example, contained filled with an HDAC inhibitor and one or more hormonal therapy agents, and/or one or more therapeutic or prophylactic agents such as an IGF-1R inhibitor, an EGFR inhibitor, an mTOR inhibitor, or another active ingredient.
  • Containers may also be filled with an HDAC inhibitor, and one or more therapeutic or prophylactic agents such as an IGF- 1R inhibitor, an EGFR inhibitor, an mTOR inhibitor, and/or another active ingredient.
  • the pharmaceutical pack or kit may further comprises one or more other prophylactic or therapeutic agents useful for the treatment of a disease or disorder.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the present invention provides pharmaceutical packs or kits that can be used in the above methods.
  • the kit may further comprises one or more other prophylactic or therapeutic agents, or active ingredients useful for the treatment of cancer in one or more containers.
  • the kit may comprise at least one compound according to the invention, at least one HDAC inhibitor, and one or more of at least one or more of an IGF-1R inhibitor, an EGFR inhibitor or mTOR inhibitor. Examples of such agents and compounds are disclosed above.
  • the present invention also encompasses a finished packaged and labeled pharmaceutical product.
  • This article of manufacture includes the appropriate unit dosage form in an appropriate vessel or container such as a glass vial or other container that is hermetically sealed.
  • the active ingredient is sterile and suitable for administration as a particulate free solution.
  • the invention encompasses both parenteral solutions and lyophilized powders, each being sterile, and the latter being suitable for reconstitution prior to injection.
  • the unit dosage form may be a solid suitable for oral, transdermal, intratumoral, intra-synovial, topical or mucosal delivery.
  • the unit dosage form is suitable for intravenous, intramuscular, intratumoral, intra-synovial, or subcutaneous delivery.
  • the invention encompasses solutions, preferably sterile, suitable for each delivery route.
  • the packaging material and container are designed to protect the stability of the product during storage and shipment.
  • the products of the invention include instructions for use or other informational material that advise the physician, technician or patient on how to appropriately prevent or treat the disease or disorder in question.
  • the article of manufacture includes instruction means indicating or suggesting a dosing regimen including, but not limited to, actual doses, monitoring procedures (such as methods for monitoring mean absolute lymphocyte counts, tumor cell counts, calcium concentration, and tumor size) and other monitoring information.
  • the invention provides an article of manufacture comprising packaging material, such as a box, bottle, tube, vial, container, sprayer, insufflator, intravenous (i.v.) bag, envelope and the like; and at least one unit dosage form of a pharmaceutical agent contained within said packaging material.
  • packaging material such as a box, bottle, tube, vial, container, sprayer, insufflator, intravenous (i.v.) bag, envelope and the like
  • a unit dosage form of a pharmaceutical agent contained within said packaging material such as a box, bottle, tube, vial, container, sprayer, insufflator, intravenous (i.v.) bag, envelope and the like.
  • an article of manufacture comprises packaging material and a pharmaceutical agent and instructions contained within said packaging material, and a pharmaceutically acceptable carrier, and said instructions indicate a dosing regimen for preventing, treating or managing a subject with cancer.
  • an article of manufacture comprises packaging material and a pharmaceutical agent and instructions contained within said packaging material, and said instructions indicate a dosing regimen for preventing, treating or managing a subject with a cancer.
  • the compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. For example, dosages can be empirically determined considering the type and stage of cancer diagnosed in a particular patient.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. Doses can be given daily, or on alternate days, as determined by the treating physician.
  • Toxicity and efficacy of the prophylactic and/or therapeutic treatments and protocols of the instant invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Prophylactic and/or therapeutic agents that exhibit large therapeutic indices are preferred. While prophylactic and/or therapeutic agents that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage of the prophylactic and/or therapeutic agents for use in humans.
  • the dosage of such agents lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma
  • concentration range that includes the IC 50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • any of the assays described herein, as well as those known in the art are also encompassed by the invention to determine therapeutic or prophylactic utility.
  • any relevant cancer and more specifically, breast cancer animal models.
  • pending safety and efficacy are clinical trials to assess the compounds and methods of the present invention.
  • the present invention is directed to compounds, compositions thereof, and the use of the compounds and compositions for the treatment and prevention of breast cancer.
  • Compounds according to the invention may be considered prodrugs of endoxifen or 4-hydroxytoremifene and related compounds.
  • the compounds may be used for the treatment of breast cancer, or for a reduction in the recurrence rate or severity of previously-treated breast cancer.
  • the compounds according to the invention are compounds of the following formula I:
  • Ri may be H, lower alkyl, cyclic alkyl (by replacing the methyl group on the nitrogen or by creating a quaternary ammonium), or a prodrug moiety, and where R 2 may be H or a prodrug moiety, with the understanding that at least one of Ri and R 2 is a prodrug moiety.
  • Known compounds 4-hydroxy-tamoxifen and endoxifen are not encompassed within compounds according to the invention.
  • Ri when Ri is CH 3 , XR 2 is not OP0 3 H 2 . While the compound of Formula I is drawn with a specific orientation around the double bond, both E and Z configurations around the double bond are encompassed by the invention, for example, as represented by Formula la: la
  • the compounds according to the invention are compounds of the following formula:
  • the compound according to the invention has the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula II:
  • Ri may be H, lower alkyl, cyclic alkyl (by replacing the methyl group on the nitrogen or by creating a quaternary ammonium), or a prodrug moiety
  • R 2 may be H or a prodrug moiety, with the understanding that at least one of Ri and R 2 is a prodrug moiety. While the compound of Formula II is drawn with a specific orientation around the double bond, both E and Z configurations around the double bond are encompassed by the invention, for example, as represented by Formula Ila:
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula: and pharmaceutically-acceptable salts thereof.
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula III:
  • Ri may be H, lower alkyl, cyclic alkyl (by replacing the methyl group on the nitrogen or by creating a quaternary ammonium), or a prodrug moiety
  • R 2 may be H or CI
  • Z is selected from fluoro or chloro, and the wavy line indicates that the configuration around the double bond may be either E or Z.
  • the compounds according to the invention are compounds of the following formula:
  • the compounds according to the invention are compounds of the following formula:
  • Ri is H.
  • Ri and R 2 are each independently selected from the following groups:
  • Alkyl groups preferably having from 1 to 12 carbon atoms.
  • a preferred class of alkyl groups has 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.
  • Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention.
  • the term alkyl unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.
  • Lower alkyl groups refers may refer to alkyl groups with 1 to 6 carbon atoms.
  • Alkyl groups may form part of an ester, such as a pivalate group.
  • alkenyl and alkynyl groups having one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 2, 3 or 4 carbon atoms.
  • alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.
  • Alkylidene groups branched or unbranched, and preferably having from 1 to 12 carbon atoms.
  • One more preferred class of alkylidene groups has from 1 to about 8 carbon atoms, yet more preferably from 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.
  • Methylidene, ethylidene and propylidene including isopropylidene are particularly preferred alkylidene groups in the compounds of the present invention.
  • SO sulfoxide
  • Aminoalkyl groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms.
  • Secondary and tertiary amine groups are generally more preferred than primary amine moieties.
  • heterocyclic groups including heteroaromatic and heteroalicyclic groups.
  • Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol.
  • Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl groups.
  • Aryl groups including single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
  • Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms.
  • Specifically preferred aryl groups include substituted or unsubstituted phenyl, naphthyl, biphenyl, phenanthryl, and anthracyl.
  • references herein to substituted groups in the compounds of the present invention refer to the specified moiety, typically alkyl or alkenyl, that may be substituted at one or more available positions by one or more suitable groups, e.g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido;
  • alkyl groups including those groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkylsulfmyl groups including those moieties having one or more sulfmyl linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1
  • Preferred R groups include alkyl, alkenyl and alkynyl that may be substituted at one or more available positions by one or more suitable groups, e.g., halogen such as fluoro, chloro, bromo and iodo, especially co-chloro or perfluoro; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; aryl having 6 or more carbons, particularly phenyl; aralkyl such as benzyl; heterocyclic groups including heteroalicyclic and heteroaromatic groups, especially with 5 to 10 ring atoms of which 1 to 4 are heteroatoms, more preferably heterocyclic groups with 5 or 6 ring atoms and 1 or 2 heteroatoms or with 10 ring atoms and 1 to 3 heteroatoms, the heterocyclic groups optionally being substituted with one or more of the substituents, especially amino such as dimethylamino or with keto
  • prodrugs are known in the art. For example, see Simplicio et al, "Prodrugs for Amines," Molecules, vol. 13, iss. 3, pp. 519-547, March 2008, available from the internet at «http://www.mdpi.org»; see also Larsen, C.S., et al, "Chapter 14: Design and application of prodrugs” from Textbook of Drug Design and Discovery, Third Edition, edited by Krogsgaard-Larsen, P. et al, pages 410-458, 2002. The contents of each publication are incorporated by reference.
  • the prodrug moiety may be selected from Table
  • R groups in a figure may be the same or different:
  • the prodrug moiety may be selected from Table
  • R groups in a figure may be the same or different:
  • a prodrug moiety may be adapted from
  • prodrugs may include R groups (including R ls R 2 , etc.) as defined above for Formulas I and II.
  • the synthesis of prodrugs according to the invention may be adapted from Examples 1-7 below, from Figures 2-8, and from standard transformations available to the practitioner in the art. For example, see Simplicio et al, "Prodrugs for Amines," Molecules, vol. 13, iss. 3, pp. 519-547, March 2008, available from the internet at
  • prodrug means a compound with a temporary modification of a functional group of a drug in order to improve the pharmaceutical utility of the drug.
  • Prodrug may refer to the entire compound, or it may refer to the chemical modification, in the context of a prodrug moiety being the chemical modification.
  • the functional group of the drug is a handle for the introduction of a moiety that confers on the new entity some desirable characteristic.
  • the prodrug moiety is intimately connected with the pharmaceutical deficiency of the parent drug, and the presence of the prodrug moiety directly addresses the deficiency.
  • prodrugs rely on in vivo enzymatic activation for conversion to active form of the drug for example by cleavage of the prodrug moiety by an enzyme. In other embodiments, prodrugs rely on physiological chemical conditions for release of the drug, for example through a change in pH.
  • the benefits of a prodrug are not limited to improved in vivo benefits compared to the parent drug, but may also include improved processing or storage characteristics or economic considerations prior to administration to the patient.
  • the advantages of the prodrug moiety may be selected from the group consisting of improved biomembrane passage and bioavailability (including improved oral absorption, dermal absorption, ocular absorption, gastro-intestinal absorption, and/or reduced first-pass metabolism), site-directed drug delivery, site-specific bioactivation, improvement of drug formulation, and combinations thereof.
  • the compounds of the invention can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • Non-toxic salts may include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine,
  • salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, p-toluenesulfonic,
  • Salts of the invention include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the invention also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p- toluenesulfonic acid, acetic acid, and the like. Additional salt-forming excipients which are contemplated for use in the practice of the present invention are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S.
  • Any therapy e.g., chemotherapies, radiation therapies, hormonal therapies, and/or biological therapies/immunotherapies
  • chemotherapies e.g., radiation therapies, hormonal therapies, and/or biological therapies/immunotherapies
  • Any therapy e.g., radiation therapies, hormonal therapies, and/or biological therapies/immunotherapies
  • the anti-cancer agents contemplated in the methods and compositions of the present invention, which can be administered in combination with the compositions of the present invention include, but are not limited to doxorubicin, epirubicin, the combination of doxorubicin and
  • cyclophosphamide AC
  • CAF doxorubicin and 5- fluorouracil
  • CEF epirubicin and 5- fluorouracil
  • herceptin tamoxifen
  • tamoxifen the combination of tamoxifen and cytotoxic chemotherapy
  • taxanes such as docetaxel and paclitaxel.
  • the combinations of the invention can be administered with taxanes plus standard doxorubicin and cyclophosphamide for adjuvant treatment of node-positive, localized breast cancer.
  • the dose of doxorubicin hydrochloride is 60-
  • the dose of epirubicin is 100-120 mg/m 2 on day 1 of each cycle or divided equally and given on days 1-8 of the treatment cycle.
  • the dose of docetaxel is 60-100 mg/m 2 over 1 hour.
  • the dose of paclitaxel is 175 mg/m 2 over 3 hours.
  • the present invention can be used to treat a patient with any type of breast cancer.
  • Breast cancers may include carcinoma in situ, infiltrating (or invasive) ductal carcinoma, infiltrating (or invasive) lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, and inflammatory carcinoma.
  • stages 0-IV In addition to the different types of breast cancer, there are also different stages of breast cancer, referred to as stages 0-IV.
  • the system most often used to describe the growth and spread of breast cancer is the TNM staging system, also known as the American Joint Committee on Cancer (AJCC) system.
  • TNM staging information about the tumor, nearby lymph nodes, and distant organ metastases is combined and a stage is assigned to specific TNM groupings. The grouped stages are described using Roman numerals from I to IV.
  • the clinical stage is determined by results from physical examination and tests.
  • the pathologic stage includes the findings of the pathologist after surgery. Most of the time, pathologic stage is the most important stage because usually the cancer isn't known to have spread to lymph nodes until the pathologist examines them under the microscope.
  • T stands for the size of the cancer (measured in centimeters; 2.54 centimeters 1 inch); N stands for spread to lymph nodes in the area of the breast, and M is for metastasis (spread to distant organs of the body).
  • the T category describes the original (primary) tumor.
  • Tis Tis is used only for carcinoma in situ or noninvasive breast cancer such as ductal carcinoma in situ, (DCIS) or lobular carcinoma in situ (LCIS).
  • Tl The cancer is 2 cm in diameter (about 3/4 inch) or smaller.
  • T2 The cancer is more than 2 cm but not more than 5 cm in diameter.
  • T3 The cancer is more than 5 cm in diameter.
  • T4 The cancer is any size and has spread to the chest wall, the skin, or lymphatics.
  • the N category is based on which of the lymph nodes near the breast, if any, are affected by the cancer.
  • NO The cancer has not spread to lymph nodes.
  • Nl The cancer has spread to lymph nodes under the arm on the same side as the breast cancer. Lymph nodes have not yet attached to one another or to the surrounding tissue.
  • N2 The cancer has spread to lymph nodes under the arm on the same side as the breast cancer and are attached to one another or to the surrounding tissue or enlarged. Or, the cancer can be seen to have spread to the internal mammary lymph nodes (next to the sternum), but not to the lymph nodes under the arm.
  • the cancer has spread to lymph nodes above or just below the collarbone on the same side as the cancer, and may or may not have spread to lymph nodes under the arm. Or, the cancer has spread to internal mammary lymph nodes and lymph nodes under the arm, both on the same side as the cancer.
  • M categories The M category depends on whether the cancer has spread to any distant tissues and organs. M0: No distant cancer spread. Ml : Cancer has spread to distant organs.
  • Clinical staging estimates how much cancer there is based on the results of the physical exam, imaging tests (x-rays, CT scans, etc.) and sometimes biopsies of affected areas. For certain cancers the results of other tests, such as blood tests, are also used in staging.
  • Pathologic staging can only be done on patients who have had surgery to remove or explore the extent of the cancer. It combines the results of clinical staging (physical exam, imaging tests, etc.) with the results from the surgery. In some cases, the pathologic stage may be different from the clinical stage (for example, if the surgery shows the cancer is more extensive than it was previously thought to be). Restaging is sometimes used to determine the extent of the disease if a cancer recurs (comes back) after treatment.
  • the methods and compositions of the present invention are used to treat patients with stage I breast cancer. In one embodiment, the methods and compositions of the present invention are used to treat patients with stage II breast cancer. In one embodiment, the methods and compositions of the present invention are used to treat patients with stage III breast cancer. In one embodiment, the methods and compositions of the present invention are used to treat patients with stage IV breast cancer, i.e. patients with metastatic cancer.
  • the patient having breast cancer has already failed other treatment regimens such as chemotherapy.
  • the methods and pharmaceutical compositions of the present invention may be used to prevent the development of a cancer, particularly in an individual at higher risk than average to develop such cancer than other individuals, or to treat a patient afflicted with breast cancer.
  • any means of risk assessment is contemplated by the present invention as determining which subjects are at risk for breast cancer and can undergo treatment via the methods and compositions of the present invention.
  • the invention contemplates treatment for individuals with a higher than average lifetime risk for breast cancer, the average being about one in eight women in the U.S.
  • the invention provides methods treating asymptomatic patients who have a likelihood of benefiting from therapeutic treatment of breast cancer.
  • the asymptomatic patients can comprise patients in any of the many high risk groups for breast cancer.
  • the high risk groups can include e.g. patients with a family history of breast cancer, patients of increasing age (e.g., patients 40 years of age or older), menopausal patients, patients having at least one high risk parity factor (e.g. early start of menses, late onset of menopause, no pregnancies, or late-age pregnancy), patients having high risk gene status (e.g.
  • risk factors are continually being defined and can include such considerations, as geographic location (e.g. where women living in a particular region have been found to have a higher incidence of breast cancer). Diet is also thought to play a role in breast cancer risk; specifically women who include more fat in their diet may be more likely to develop breast cancer (see Kniget et al. Cancer Epidemiol Biomarkers Prev 8(2): 123-8, 1999).
  • the Gail model is a common means of determining risk for breast cancer, and was developed based on the Breast Cancer Detection Demonstration Project (see Gail, M. et al, J Natl Cancer Inst., 1989. 81 : p. 1879-86).
  • the risk factors used in the Gail model are age, age at menarche, age at first live birth, number of previous breast biopsies, number of first-degree relatives with breast cancer. These risk factors are broadly consistent with those selected from other large population- based studies.
  • a revised Gail model also incorporates race, presence of atypical hyperplasia on breast biopsy, and 1987 population rates of breast cancer and death from other causes.
  • Claus model Another commonly used prediction model is the Claus model, based on the Cancer and Steroid Hormone Study (see Claus E. et al, Cancer, 1994. 73: 643- 51) and incorporates more extensive information about family history.
  • the Claus model provides individual estimates of breast-cancer risk according to decade from 29-79 years of age. It takes into account factors such as the number of first-degree and number of second-degree relatives with breast cancer, as well as different combinations of different degree relatives with breast cancer.
  • the invention also contemplates treatment for early stages of cancer, for recurrent cancer, and for those in remission from cancer.
  • the present invention also encompasses treatment for subjects with markers for breast cancer, including, but not limited to having mutations or other alterations in the genes, BRCA1, BRCA2, P53, P65, ATM, or pS2, or a changed ratio of the expression of the genes HOXB13 and ILl 7BR, amplification of the AIBl/pCIP coactivator gene, overproduction of HER2 protein and/or gene, and alterations in levels of hormones, such as estrogen and progesterone, or their receptors.
  • markers for breast cancer including, but not limited to having mutations or other alterations in the genes, BRCA1, BRCA2, P53, P65, ATM, or pS2, or a changed ratio of the expression of the genes HOXB13 and ILl 7BR, amplification of the AIBl/pCIP coactivator gene, overproduction of HER2 protein and/or gene, and alterations in levels of hormones, such as estrogen and progesterone, or their receptors.
  • Markers can also include neoplastic ductal epithelial cells,
  • transforming growth factor- ⁇ carcinoma embryonic antigen (CEA), prostate specific antigen (PSA), Erb B2 antigen, gross cystic disease fluid protein- 15 (GCDFP-15), lactose dehydrogenase (LDH), measured in the ductal epithelial cells.
  • the marker is neoplastic ductal epithelial cells
  • the cells can be at a stage including hyperplasia, atypical hyperplasia, low grade ductal carcinoma in situ (LG-DCIS), high grade ductal carcinoma in situ (HG-DCIS) or invasive carcinoma.
  • the present invention encompasses providing the pharmaceutical compositions described herein to treat subjects with any of the described markers, and also to prevent the progression from DCIS and from atypical hyperplasia to breast cancer.
  • compositions of the invention may be administered either prior to or following surgical removal of primary tumors and/or treatment such as
  • Treatments for breast cancer are well known in the art and continue to be developed. Treatments include but are not limited to surgery, including axillary dissection, sentinel lymph node biopsy, reconstructive surgery, surgery to relieve symptoms of advanced cancer, lumpectomy (also called breast conservation therapy), partial (segmental) mastectomy, simple or total mastectomy, modified radical mastectomy, and radical mastectomy; immunotherapy, e.g.
  • HerceptinTM an anti-HER2 humanized monoclonal antibody developed to block the HER2 receptor
  • bone marrow transplantation peripheral blood stem cell therapy
  • bisphosphonates additional chemotherapy agents
  • radiation therapy acupressure
  • acupuncture any combination of therapies may be used in conjunction with the present invention.
  • the methods and compositions comprising the combination therapies described herein may also be used to reduce the proliferation of cancer cells, increase the death of cancer cells or, reduces the size of a tumor or spread of a tumor in a subject. It is contemplated by the present invention that the combination therapies described herein may reduce the size of a tumor or the spread of a tumor in a subject by at least 5%, preferably at least 10%, at least 15%, at least 20%>, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% relative to a control such as PBS.
  • the combination therapies described herein may increase survival by 1 month, 2 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more, it may render the subject disease-free, or it may prevent the progression from DCIS or atypical hyperplasia to breast cancer.
  • Example 1 (Z)-Endoxifen phosphate ethyl carbamate ((Z)-ethyl methyl(2-(4-(2 -phenyl- 1 -(4-(phosphonooxy)phenyl)but- 1 - enyl)phenoxy)ethyl)carbamate)
  • 4-Hydroxy -tamoxifen is dissolved in toluene or other suitable organic solvent. To this mixture is added an alkylating agent such as 4-nitrobenzyl iodide. This mixture may be heated. After starting material is completely consumed, volatile organics are removed to afford among other products the separable E and Z isomers of N-(4-nitrobenzyl)-4-hydroxy-tamoxifen iodide.
  • an alkylating agent such as 4-nitrobenzyl iodide
  • Example 6 Endoxifen-(6-N,N-dimethylamino)-l-hexyl carbonate t- butyl carbamate ((Z)-tert-butyl 2-(4-(l-(4-((6- (dimethylamino)hexyloxy)carbonyloxy)phenyl)-2-phenylbut- 1 - enyl)phenoxy)ethyl(methyl)carbamate)
  • the mixture is then extracted with ethyl acetate or other suitable organic solvent.
  • the combined organic extracts are then dried over a suitable desiccant (e.g. magnesium sulfate anh.).
  • the mixture is then filtered and the organic solvent removed to furnish among other things N-Boc-endoxifen (6-N,N- dimethylamino)- 1 -hexyl carbonate.
  • Example 8 Endoxifen phosphate ethyl carbamate ((E)-ethyl methyl(2-
  • Example 10 Endoxifen valine ester t-butyl carbamate ((S,E)-4-(l -(4-
  • Endoxifen is dissolved in dichloromethane or other suitable organic solvent. To this solution is added triethyl amine or other suitable base. This solution may be cooled. To this solution is added Boc-O-Boc. The mixture is stirred for 1-12 h, at which time the reaction is quenched by addition of aqueous sodium bicarbonate or other quenching reagent. The mixture is then washed with dilute HC1 (aq.). The mixture is then extracted with ethyl acetate or other suitable organic solvent. The combined organic extracts are then dried over a suitable desiccant (e.g. magnesium sulfate anh.). The mixture is then filtered and the organic solvent removed to furnish among other things N-Boc-endoxifen.
  • aqueous sodium bicarbonate or other quenching reagent The mixture is then washed with dilute HC1 (aq.).
  • the mixture is then extracted with ethyl acetate or other suitable organic solvent.
  • [00171] B The product of the previous step is dissolved in dichloromethane or other suitable organic solvent. To this solution is added triethyl amine or other suitable base. This solution may be cooled. To this solution is added an activated form of N-Boc-valine (e.g. O-t-butyloxycarbonyl valine). The mixture is stirred for 1-12 h, at which time the reaction is quenched by addition of aqueous sodium bicarbonate or other quenching reagent. The mixture is then washed with dilute HC1 (aq.) The mixture is then extracted with ethyl acetate or other suitable organic solvent. The combined organic extracts are then dried over a suitable desiccant (e.g.
  • Example 13 Endoxifen-(6-N,N-dimethylamino)-l-hexyl carbonate t- butyl carbamate ((E)-tert-butyl 2-(4-(l-(4-((6- (dimethylamino)hexyloxy)carbonyloxy)phenyl)-2-phenylbut- 1 - enyl)phenoxy)ethyl(methyl)carbamate)
  • 6-(N,N-dimethylamino)-l-hexanol is dissolved in dichloromethane or other suitable organic solvent. To this solution may be added triethyl amine or other suitable base. This solution may be cooled. To this solution is added carbonyl diimidazole or other suitable phosgene equivalent or phosgene. The mixture is stirred for 1-12 h, at which time N-Boc-endoxifen (product of example 10, step A). The mixture is then stirred for 1-12 h. The reaction is quenched by addition of aqueous sodium bicarbonate or other quenching reagent. The mixture is then washed with dilute HC1 (aq.).
  • the mixture is then extracted with ethyl acetate or other suitable organic solvent.
  • the combined organic extracts are then dried over a suitable desiccant (e.g. magnesium sulfate anh.).
  • the mixture is then filtered and the organic solvent removed to furnish among other things N-Boc-endoxifen (6-N,N- dimethylamino)- 1 -hexyl carbonate.
  • Phenol 1 (0.041 moles) is dissolved in dry DMF (40 ml) at room temperature under N 2 .
  • Imidazole (0.083 moles) is added followed by tert- butyldimethylsilyl chloride (0.0458 moles).
  • the reaction is stirred for 2 hours, added to saturated sodium chloride solution (200 ml) and extracted with ethyl acetate (250 ml).
  • the ethyl acetate layer can be separated, washed 3 times with NaCl solution (100 ml), separated, dried over sodium sulfate, filtered through a small pad of silica gel with the aid of ethyl acetate, and concentrated to give ketone 2 among other products.
  • a TLC system of ethyl acetate/hexanes (3:7) can be used to follow the progress of the reaction.
  • Ketone 2 (7.76 mmoles) is dissolved in dry THF (20 ml) at room temperature under N 2 .
  • Anhydrous CeCl 3 (2.3g, 9.33 mmoles) is added and the suspension is stirred for 5 hours.
  • 4-Bromophenol-p-methoxybenzyl ether (2.73g, 9.32 mmoles) is dissolved in dry THF (35 ml) in a separate flask and cooled to -78°C (forming a paste at this temperature) under N 2 .
  • Adduct 3 (4.05 mmoles) is dissolved in ethanol (25 ml) at rt.
  • PPTS PPTS
  • Phenol 5 (3.87 mmoles) is dissolved in dry DMF (14 ml). The solution was cooled to 0°C under N 2 and NaH (0.193g, 4.82 mmoles) is added. After 30 minutes, bromoacetaldehyde diethyl acetal (0.80g, 4.06 mmoles) is added and the reaction mixture heated at 55°C for 20 hours. The reaction is cooled, added to saturated NaCl solution (50 ml), and extracted with ethyl acetate (75 ml). The organic layer is separated, washed 3 times with saturated NaCl solution (50 ml), dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography using ethyl acetate/hexanes gives ether 6 containing E and Z isomers among other products.
  • Phenol 7 (4.18 mmoles) is dissolved in THF (18 ml) at room temperature. 3M HC1 (18 ml) is added. The reaction is heated at 50°C for 17 hours. After cooling, the reaction mixture is added to ethyl acetate (50 ml), the organic layer separated, dried over sodium sulfate, filtered and concentrated to give crude aldehyde 8 containing E and Z isomers among other products.
  • Phenol 7 (1.02 mmoles) and dimethylaminopyridine (1.85 mmoles) are dissolved in dry dichloromethane (10 ml) and the solution is cooled to 0°C under N 2 .
  • Pivaloyl chloride (0.2 lg, 1.73 mmoles) is added dropwise via syringe and the reaction is then allowed to warm to room temperature. After 6 hours, IN aqueous HCl is added and additional dichloromethane (50 ml) is added. The organic layer is separated, dried over Na 2 S0 4 , filtered, and concentrated. Purification by flash chromatography using ethyl acetate/hexanes gives ester 10 containing E and Z isomers among other products.
  • Dimethyl acetal 10 (0.63 mmoles) is dissolved in 10 ml of THF at room temperature. 6 ml of 3N HC1 is added and the reaction mixture heated at 45- 50°C for 15 hours. After cooling, the mixture is added to water and ethyl acetate (1 : 1, 50 ml). The organic layer is separated, dried over Na 2 S0 4 , filtered, and concentrated to give crude aldehyde 11 containing E and Z isomers among other products.
  • Aldehyde 11 (0.52 mmoles) is dissolved in dry THF (10 ml) at rt.
  • Carbamate 13 (0.13 mmoles) is dissolved in 4 ml of dry THF. The solution is cooled to 0°C under N 2 . L1AIH 4 (0.026g, 0.70 mmoles) is added. The reaction mixture is stirred for 30 minutes and then water (39 ⁇ ) added. The mixture is filtered through celite with the aid of THF (15 ml) and ethyl acetate (15 ml). The filtrate is dried over MgS0 4 , filtered, and concentrated to give 14.
  • Phenol 14 is dried prior to reaction by treatment with 3 x 10 ml of dry acetonitrile followed by rotary evaporation.
  • the phenol 14 (0.087 mmoles) is then dissolved in dry acetonitrile (1.5 ml) and is then cooled to -10°C under N 2 .
  • CC1 4 (0.068g, 0.44 mmoles) is added and the suspension stirred for 10 minutes.
  • Hunig's base 0.024g, 0.18 mmoles
  • ⁇ , ⁇ -dimethylaminopyridine (1 mg
  • dibenzyl phosphate (0.034g, 0.12 mmoles) is added.
  • Phosphate 15 (0.052 mmoles) is dissolved in 20 ml of ethanol. Pd on carbon (10%, 30 mg) is added. The mixture is hydrogenated at rt and 40 psi for 5 hours. The catalyst is removed by filtration through celite and the filtrate concentrated to give 16.
  • Aldehyde 11 (0.52 mmoles) is dissolved in dry THF (10 ml) at rt.
  • Compound 9 (from Example 21 or from Example 30 or from any other source) is dried prior to reaction by treatment with 3 x 10 ml of dry acetonitrile followed by rotary evaporation.
  • the phenol 9 (0.087 mmoles) is then dissolved in dry acetonitrile (1.5 ml) and is then cooled to -10°C under N 2 .
  • CC1 4 (0.068g, 0.44 mmoles) is added and the suspension stirred for 10 minutes.
  • Hunig's base 0.024g, 0.18 mmoles
  • N,N-dimethylaminopyridine (1 mg) are added.
  • dibenzyl phosphate (0.034g, 0.12 mmoles) is added.
  • Example 32 Compound 20.
  • Phosphate 19 (0.052 mmoles) is dissolved in 20 ml of ethanol. Pd on carbon (10%, 30 mg) is added. The mixture is hydrogenated at rt and 40 psi for 5 hours. The catalyst is removed by filtration through celite and the filtrate concentrated to give 20.
  • 6-(N,N-dimethylamino)-l-hexanol is dissolved in dichloromethane or other suitable organic solvent. To this solution may be added triethyl amine or other suitable base. This solution may be cooled. To this solution is added carbonyl diimidazole or other suitable phosgene equivalent or phosgene. The mixture is stirred for 1-12 h, at which time N-Boc-N-desmethyl-4-hydroxytoremifene is added. The mixture is then stirred for 1-12 h. The reaction is quenched by addition of aqueous sodium bicarbonate or other quenching reagent. The mixture is then washed with dilute HC1 (aq.).
  • the mixture is then extracted with ethyl acetate or other suitable organic solvent.
  • the combined organic extracts are then dried over a suitable desiccant (e.g. magnesium sulfate anh.).
  • the mixture is then filtered and the organic solvent removed to furnish among other things compound 27.
  • 6-(N,N-dimethylamino)-l-hexanol is dissolved in dichloromethane or other suitable organic solvent. To this solution may be added triethyl amine or other suitable base. This solution may be cooled. To this solution is added carbonyl diimidazole or other suitable phosgene equivalent or phosgene. The mixture is stirred for 1-12 h, at which time 4-hydroxytoremifene is added. The mixture is then stirred for 1-12 h. The reaction is quenched by addition of aqueous sodium bicarbonate or other quenching reagent. The mixture is then washed with dilute HC1 (aq.).
  • the mixture is then extracted with ethyl acetate or other suitable organic solvent.
  • the combined organic extracts are then dried over a suitable desiccant (e.g. magnesium sulfate anh.).
  • the mixture is then filtered and the organic solvent removed to furnish among other things compound 29.

Abstract

La présente invention concerne des composés, des compositions les incluant et l'emploi desdits composés et compositions dans le traitement prophylactique et thérapeutique du cancer du sein. Dans l'un des modes d'application, la présente invention concerne l'emploi d'un promédicament d'endoxifène ou de 4-hydroxytorémifène ou d'un composé apparenté dans le traitement du cancer du sein en monothérapie ou en thérapie combinatoire, ou pour réduire le taux de récurrence d'un cancer du sein précédemment traité.
PCT/US2010/031447 2010-04-16 2010-04-16 Emploi d'un promédicament de type 4-hydroxytorémifène dans le traitement du cancer du sein WO2011129837A1 (fr)

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JP2016522179A (ja) * 2013-04-24 2016-07-28 ノイジル、ジリ 腫瘍性疾患であって特に高ｈｅｒ２タンパク質レベルの腫瘍性疾患を治療するためのタモキシフェン誘導体
WO2016196342A1 (fr) * 2015-05-29 2016-12-08 Eisai R&D Management Co., Ltd. Composés alcéniques tétrasubstitués et leur utilisation
US9796683B2 (en) 2015-05-29 2017-10-24 Eisai R&D Management Co., Ltd. Tetrasubstituted alkene compounds and their use
CN107674051A (zh) * 2017-09-20 2018-02-09 南京医科大学 4‑羟基他莫昔酚环状衍生物乏氧活化前药及其药物用途
CN110267940A (zh) * 2016-11-24 2019-09-20 卫材 R&D 管理有限公司 四取代的烯烃化合物和它们的用途
US10640483B2 (en) 2016-11-28 2020-05-05 Eisai R&D Management Co., Ltd. Salts of indazole derivative and crystals thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090176305A1 (en) * 2003-09-18 2009-07-09 City Of Hope Compounds and methods for treating breast cancer and other diseases
WO2009120999A2 (fr) * 2008-03-28 2009-10-01 Olema Pharmaceuticals, Inc. Utilisation d’un promédicament d’endoxifène dans le traitement du cancer de la poitrine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090176305A1 (en) * 2003-09-18 2009-07-09 City Of Hope Compounds and methods for treating breast cancer and other diseases
WO2009120999A2 (fr) * 2008-03-28 2009-10-01 Olema Pharmaceuticals, Inc. Utilisation d’un promédicament d’endoxifène dans le traitement du cancer de la poitrine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016522179A (ja) * 2013-04-24 2016-07-28 ノイジル、ジリ 腫瘍性疾患であって特に高ｈｅｒ２タンパク質レベルの腫瘍性疾患を治療するためのタモキシフェン誘導体
WO2016196342A1 (fr) * 2015-05-29 2016-12-08 Eisai R&D Management Co., Ltd. Composés alcéniques tétrasubstitués et leur utilisation
US9796683B2 (en) 2015-05-29 2017-10-24 Eisai R&D Management Co., Ltd. Tetrasubstituted alkene compounds and their use
US10851065B2 (en) 2015-05-29 2020-12-01 Eisai R&D Management Co., Ltd. Tetrasubstituted alkene compounds and their use
CN110267940A (zh) * 2016-11-24 2019-09-20 卫材 R&D 管理有限公司 四取代的烯烃化合物和它们的用途
US10640483B2 (en) 2016-11-28 2020-05-05 Eisai R&D Management Co., Ltd. Salts of indazole derivative and crystals thereof
CN107674051A (zh) * 2017-09-20 2018-02-09 南京医科大学 4‑羟基他莫昔酚环状衍生物乏氧活化前药及其药物用途

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