Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens

Definitions

• This invention is in the field of pharmaceuticals, and in particular, this invention is related to the treatment of cancers mediated by the estrogen receptor by administering a specific benzopyran (in the form of a mixture of S-C2 and R-C2 diastereomers or its pure S-diastereomer) as described in US 2013/0178445 and WO 2013/090921 in combination with particular agents, active agents, anti-cancer agents or chemotherapeutic agents.
• a specific benzopyran in the form of a mixture of S-C2 and R-C2 diastereomers or its pure S-diastereomer
• Estrogen receptor modulators are a class of compounds that act on the estrogen receptor. These compounds can be pure agonists (mimicking estrogen), pure antagonists, or mixed agonist-antagonists (sometimes referred to as Selective Estrogen Receptor Modulators (SERMs)). For example, estradiol (A) is a pure agonist, fulvestrant (B) is a complete antagonist, and tamoxifen (C) and raloxifene (D) are SERMs.
• ER estrogen receptors
• Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
• fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
• fulvestrant is substantially superior to the aromatase inhibitor anastrozole in treating metastatic breast cancer (Robertson et al. J Clin Oncol (2009) 27(27):4530-5).
• Estradiol is a naturally-occuring female estrogenic hormone.
• Raloxifene was disclosed by Eli Lilly in 1981 (U.S. Patent No. 4,418,068; 5,478,847; 5,393,763; and 5,457,117) for prevention of breast cancer and treatment of osteoporosis. Fulvestrant was disclosed by Imperial Chemical Industries (ICI) in 1983 (U.S. Patent No. 4,659,516, expired in 2007 with a patent term extension; U.S. Patent Nos. 6,774, 122 and 7,456, 160). Tamoxifen was also disclosed by ICI in the '516 patent. Tamoxifen was developed for the treatment of breast cancer on the basis of strong antagonism of estrogen action in mammary tissue (Jordan, J. Cell. Biochem. 51 (1995)).
• ovariectomized rodents to test doses of the compound both in the absence (agonist mode) and presence (antagonist mode) of estrogen.
• Tamoxifen and other partial anti-estrogens stimulate uterine weight gain in the agonist mode and only partly block estrogen-driven uterine weight gain in the antagonist mode.
• Fulvestrant and other complete anti-estrogens do not stimulate uterine weight gain in the agonist mode and completely block estrogen-driven weight gain in the antagonist mode.
• the induction of estrogen-regulated alkaline phosphatase expression in human uterine cancer cell growth in culture can be used to distinguish partial and complete anti-estrogenicity and correlates well with the rodent weight gain assay.
• Tamoxifen and fulvestrant both inhibit cultured human breast cancer cell proliferation provoked by estrogen.
• fulvestrant more fully inhibits the proliferation when provoked with growth factors, especially of the insulin/insulin-like growth factor family.
• growth-factor driven breast cancer cell proliferation and the effect on uterine weight provide two assays which can distinguish between complete and partial anti- estrogens.
• Tamoxifen binding stabilizes the estrogen receptor whereas fulvestrant and chemically related antiestrogens, such as ICI-164384 and RU-58668, cause degradation of the estrogen receptor.
• fulvestrant and chemically related antiestrogens such as ICI-164384 and RU-58668, cause degradation of the estrogen receptor.
• some compounds like GW-5638 (Wu et al, Mol Cell.,18,413 (2005), and OP1075, described below, degrade the receptor but are partial estrogens- that is, not complete anti-estrogens.
• the ability to degrade the estrogen receptor does not ensure complete antiestrogenicity.
• the ability to induce degradation of the receptor is nonetheless a factor that differentiates the behavior of tamoxifen and fulvestrant and may be desirable in a drug to treat breast cancer.
• Fulvestrant which degrades the estrogen receptor, incorporates a core of 17-beta estradiol. It has a long flexible aliphatic side chain that blocks oral absorption. The estradiol core blocks oral absorption and the long flexible aliphatic side chain makes the drug very insoluble which worsens the problem. Fulvestrant must be injected because of the poor oral bioavailability. Two 5 ml intramuscular depot injections, one into each buttock, must be administered monthly by a health professional. Furthermore, it is unclear whether these two injections provide sufficient drug exposure for optimal action. The drug does not seem to work in pre-menopausal women.
• Patent No. 5,395,842 (see claim 29) which taught that EM-343 (H), showed superior binding to the estrogen receptor with no loss of anti-estrogen action.
• EM-343 differed from the Saeed compounds by including the hydroxyl at the 4'-position of a 4-methyl, 7-hydroxyl benzopyran.
• Labrie et al. filed a continuation-in-part patent application, which issued in 2000 as U.S. Patent No. 6,060,503, disclosing prodrugs and optically active species of EM- 343.
• Labrie et al. disclosed a pure isomer of EM-343, EM-652, referred to as acolbifene (I), which is (S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-(2-(piperidin-l- yl)ethoxy)phenyl)-2H-chromen-7-ol.
• D is -OCH 2 CH 2 N(R 3 )R4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound together being a ring structure selected from the group consisting of pyrrolidino, dimethyl- 1-pyrrolidino, methyl-l-purrolidinyl, piperidino, hexamethyleneimino and morpholino); and
• Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl and a moiety converted in vivo in to hydroxyl, and
• Ri and R 2 are independently selected from the group consisting of hydroxyl and a moiety converted in vivo in to hydroxyl;
• R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen-containing cyclic moiety, nitrogen-containing polycyclic moiety, and RaRb (Ra and Rb being independently hydrogen, straight or branched Ci-C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight of branched C 2 -C 6 alkynyl.
• Acolbifene binds to the estrogen receptor alpha with three times the affinity of 17- beta estradiol, the native ligand (Katzenellenbogen (2011) J Med Chem 54(15):5271-82). Since anti-estrogens must compete with estradiol for binding to the estrogen receptor, high affinity binding is an important drug virtue.
• EM-800, a pivalate prodrug of EM-652, and HC1 salts of EM-652 were also described in the '503 patent.
• Acolbifene was initially thought to be a complete anti-estrogen.
• careful studies with the rodent uterine assay and human uterine cell alkaline phosphatase assays revealed that it retained some estrogen-like action, about 12% that of estradiol (Labrie et al. "The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?" Endocrinology. 2003 144(11):4700-6). This contrasts with fulvestrant where the residual estrogen-like action is almost unmeasurable.
• Acolbifene is orally bioavailable and is currently being positioned for Phase III clinical trials for the treatment of breast cancer by the Canadian company Endoceutics (Founded by Dr. Labrie).
• a daily oral dose of 40 mg of acolbifene or EM800 in women produces mean drug exposures of 8.3 and 15 ng/ml of circulating acolbifene, respectively.
• the Merck chromane core differs from the acolbifene core by the absence of a double bond in the oxane ring. These structures also had a hydroxyl at position 6 (not 7) of the fused benzene ring.
• a chromane core with a 2-m ethyl pyrrolidine (but not a 3 -methyl) with a methyl on the linker created a nearly complete anti-estrogen, (see compound 12 of the Blizzard et al. paper).
• Blizzard et al. commented on the differences among anti-estrogenic activities of variously substituted cores, and noted that the size and stereogenic placement of substituents is crucial for receptor potency and selectivity.
• Blizzard et al. again studied the dihydrobenzoxathiin core and reported that their studies have resulted in the discovery that addition of a methyl group to the side chain at the appropriate position and with the right stereochemistry, either on the pyrrolidine ring or on the linker substantially increased estrogen antagonist activity in uterine tissue. Blizzard et al. also reported that the best estrogen antagonist activity in this dihydrobenzoxathiin series was determined to have a methyl group on the pyrrolidine and a methyl group on the linker, with the hydroxyl in the 6-position of the fused benzene ring. Blizzard et al.
• SRMs Selective Estrogen Receptor Modulators
• Kushner et al. (US 2013/0178445 and WO 2013/090921, both filed Dec. 17, 2012 and both assigned to Olema Pharmaceuticals) describe OP-1038 (3-(4-hydroxyphenyl)-4-methyl- 2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol) and OP-1074 ((2S)-3- (4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H- chromen-7-ol), as well as pharmaceutical compositions and methods of use.
• Bazedoxifene is a SERM, under development for prevention and treatment of postmenopausal osteoporosis (Biskobing, D. M. (2007) Clinical interventions in aging 2 (3): 299-303).
• Lasofoxifene is another SERM under development for the treatment of
• U.S. Patent 5,254,568 discloses benzopyrans as anti-estrogenic agents.
• WO2010/145010 discloses a combination of SERM and sex steroid precursor for treating hot flashes and other symptoms.
• WO2004/091488 discloses benzopyrans as estrogen receptor modulators.
• U.S. Patent 5,840,735 discloses benzopyrans as sex steroid activity inhibitors.
• U.S. Patent 6,262,270 discloses a method for the enantiomeric synthesis of acolbifene derivatives.
• Embodiments described herein relate to a method of treating a disorder modulated, mediated or affected by the estrogen receptor in a subject comprising administering to the subject a compound, which is
• Ri and R 2 are independently either:
• R can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring;
• an agent selected from the group consisting of an mTOR inhibitor, a CDK 4/6 inhibitor, a PI3 Kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.
• the compound is in the form of a pharmaceutically acceptable salt.
• either or both of Rl or R2 is an ester, amide, carbonate or phosphate.
• compound is in the form of a prodrug, further wherein the prodrug is
• the compound is (2S)-3-(4- hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy ⁇ phenyl)-2H-chromen- 7-ol, which has the chemical structure:
• Embodiments described herein relate to a method of treating a disorder modulated, mediated or affected by the estrogen receptor in a subject comprising administering to the subject a compound, which is (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3- methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol, which has the chemical structure:
• the compound is administered in alternation with an agent selected from the group consisting of an mTOR inhibitor, a CDK 4/6 inhibitor, a PI3 Kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.
• Embodiments described herein relate to a combination of a compound, which is
• Ri and R 2 are independently either:
• R 9 is independently selected from H, halogen (CI, Br, I or F), natural or non- naturally occurring amino acid (bound through either the OC(O)- or C(0)0- (an ester) or the amino (through either -C(0)-N- or -N-C(O)- (an amide linkage)), R 10 , -OR 10 , or -SR 1(
• R can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring;
• the compound is in the form of a pharmaceutically acceptable salt.
• the compound is (2S)-3-(4- hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy ⁇ phenyl)-2H-chromen- 7-ol, which has the chemical structure:
• Embodiments described herein relate to a combination of (2S)-3-(4- hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy ⁇ phenyl)-2H- 7-ol, which has the chemical structure:
• the disorder is mediated by the estrogen receptor.
• the disorder is breast cancer.
• the breast cancer is local, advanced or metastatic estrogen or progesterone receptor positive advanced breast cancer.
• the breast cancer is estrogen or progesterone receptor positive advanced breast cancer.
• the breast cancer is estrogen or progesterone receptor negative breast cancer.
• the disorder is selected from the group consisting of ovarian cancer, endometrial cancer, vaginal cancer, endometriosis, lung cancer, and bronchial cancer.
• the disorder is selected from the group consisting of ovarian, endometrial, and vaginal cancer and
• the disorder is retinoblastoma positive breast cancer.
• the disorder is selected from the group consisting of retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers.
• the disorder is lung cancer or bronchial cancer.
• the subject is a patient.
• the agent is a
• the CDK 4/6 inhibitor is PD-0332991, LY2835219, or LEE011.
• the CDK 4/6 inhibitor is PD-0332991, or a pharmaceutically acceptable salt thereof.
• the CDK 4/6 inhibitor is PD-0332991.
• the agent is an mTOR inhibitor.
• the mTOR inhibitor is rapamycin, everolimus, temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, or Ppl21.
• the mTOR inhibitor is everolimus.
• the agent is a
• the PI3 Kinase inhibitor is BKM-120, XL-147, RG-7321, CH-5132799 and BAY-80-6946.
• the PI3 Kinase inhibitor is BKM-120.
• the agent is a taxane.
• the taxane is paclitaxel or docetaxel.
• the agent is an antimetabolite.
• the antimetabolite is 5- fluorouracil.
• the agent is an antitumor antiobiotic.
• the antitumor antibiotic is doxorubicin.
• Embodiments described herein relate to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically effective amount of a compound, which is
• Ri and R 2 are independently either:
• R C1 can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring;
• an agent selected from the group consisting of an mTOR inhibitor, a CDK 4/6 inhibitor, a PI3 Kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic, and a pharmaceutically acceptable carrier.
• the compound is in the form of a pharmaceutically acceptable salt.
• Ri or ester, amide, carbonate or phosphate is in embodiments of the pharmaceutical composition of the invention.
• the compound is in the form o
• the compound is (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol, which has the chemical structure:
• Embodiments described herein relate to a pharmaceutical composition of the invention relates to a compound, which is (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3- methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol, which has the chemical structure:
• an agent selected from the group consisting of an mTOR inhibitor, a CDK 4/6 inhibitor, a PI3 Kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic, and a pharmaceutically acceptable carrier.
• the agent is a
• the CDK 4/6 inhibitor is PD-0332991, LY2835219, or LEE011.
• the CDK 4/6 inhibitor is PD-0332991, or a pharmaceutically acceptable salt thereof.
• the CDK 4/6 inhibitor is PD-0332991.
• the agent is an mTOR inhibitor.
• the mTOR inhibitor is rapamycin, everolimus, temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, or Ppl21.
• the mTOR inhibitor is everolimus.
• the agent is a
• the PI3 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• Kinase inhibitor is BKM-120, XL-147, RG-7321, CH-5132799 and BAY-80-6946.
• the PI3 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• Kinase inhibitor is BKM-120.
• the agent is a taxane.
• the taxane is paclitaxel or docetaxel.
• the agent is an antimetabolite.
• the antimetabolite is 5-fluorouracil.
• the agent is an antitumor antiobiotic.
• the antitumor antibiotic is doxorubicin.
• the present invention relates to the treatment of tumors, including cancers, mediated by the estrogen receptor with the combination of a specific benzopyran (in the form of a mixture of S-C2 and R-C2 diastereomers and also its pure S-diastereomer) as described in US 2013/0178445 and WO 2013/090921 in combination or alternation with specific agents, active agents, anti-cancer agents or chemotherapeutic agents, and in some embodiments, in certain improved dosages or formulations.
• Benefits that can result include increased efficacy and/or lower doses when the specified combinations are used.
• Tumors, including cancers which benefit from such combinations or alternations are those that are mediated by the estrogen receptor and will also respond to the second agent.
• agents, active agents, anti-cancer agents or chemotherapeutic agents that can be combined with compounds described in US 2013/0178445 and WO 2013/090921 include an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or an antimetabolite such as 5-fluorouracil, or an antitumor antibiotic such as doxorubicin.
• the combination therapy includes the described anti-estrogenic compounds combined with PD-0332991 for treatment of retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers.
• 2013/0178445 and WO 2013/090921 with an agent, active agent, anti-cancer agent or
• chemotherapeutic agent wherein the concerted use can be either (i) a pharmaceutically acceptable formulation that includes both active agents; or (ii) separate pharmaceutical formulations that independently provide each active and are either administered at the same time or at different times but in a concerted synchronized fashion in a manner that optimizes the benefit of the combination therapy (i.e., alternation therapy).
• a pharmaceutically acceptable formulation that includes both active agents
• separate pharmaceutical formulations that independently provide each active and are either administered at the same time or at different times but in a concerted synchronized fashion in a manner that optimizes the benefit of the combination therapy (i.e., alternation therapy).
• certain actives will normally be administered orally, such as in a tablet, pill or liquid, and others might be normally administered via intravenous injection or other systemic, topical, parenteral, transdermal or other route.
• OP-1038 3 -(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2- [(3R)-3 -methylpyrrolidin- 1 -yl] ethoxy ⁇ phenyl)-2H- chromen-7-ol.
• OP-1074 is (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2- [(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol.
• the active compound to be combined or alternated with an agent, active agent, anti-cancer agent or chemotherapeutic agent can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or R 1 and/or R 2 - substituted derivative optionally in a pharmaceutically acceptable composition to treat a tumor that is modulated or affected by an estrogen receptor, including those treatable with an antiestrogenic compound optimally with virtually no estrogenic effect.
• OP-1038 and OP-1074 have two chiral carbons and thus there are four possible diastereomers.
• the chiral carbon at the C2 position is in the S-configuration in OP-1074 (the same configuration in EM-652, acolbifene) and is a mixture of R and S in OP-1038.
• OP-1038, OP-1074 and their prodrugs are especially useful to treat locally advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer) and are also responsive to the specific agent, active agent, anti-cancer agent or chemotherapeutic agent.
• the combinations are used to treat estrogen or progesterone receptor negative breast cancer. The combinations can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer.
• active agents that can be combined with compounds described in US 2013/0178445 and WO 2013/090921 include an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or
• the combination therapy includes the compounds described in US 2013/0178445 and WO 2013/090921 combined with PD-0332991 for treatment of retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers.
• the combinations described in the present invention are also useful as adjuvant therapy after surgery to prevent recurrance. Such adjuvant use is often administered for several years, for instance 5 years, or even up to 10 years after surgery and associated chemotherapy and radiotherapy have been concluded.
• the adjuvant combination therapy includes the compounds described in US 2013/0178445 and WO 2013/090921 combined with PD-0332991 for treatment of retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers.
• the combinations described in the present invention are also useful for the prevention of breast cancer in women at high risk for breast cancer and can be taken for any desired time period, including indefinitely.
• a patient typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRCAl or BRCA2 gene or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention.
• the combinations described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence.
• these combinations are also useful to treat other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis.
• the combinations are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
• the combination of the compound described in US 2013/0178445 and WO 2013/090921 with PD-0332991 is beneficial.
• Fig. 1 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in combination with increasing amounts of PD-0332991.
• IB plots the effects on MCF-7 cell proliferation of vehicle or lOOnM PD-0332991 in combination with increasing amounts of OP- 1074.
• Fig. 1C plots the effects on MCF-7 cell proliferation of vehicle or 3nM OP- 1074, tamoxifen, or fulvestrant in combination with increasing amounts of PD-0332991. Proliferation was measured using Cyquant fluorescent DNA-binding dye (Invitrogen, Grand Island, NY). Results were from a single representative experiment and reported as the mean percent induction relative to E2 from triplicate treatments, with error bars representing SEM.
• FIG. 1 plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or lOOnM OP-1074 in combination with increasing amounts of everolimus.
• Fig. 1 plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or lOOnM OP-1074 in combination with increasing amounts of everolimus.
• FIG. 2B plots the effects on MCF-7 cell proliferation of vehicle, InM or ⁇ everolimus in combination with increasing amounts of OP-1074.
• Fig. 2C plots the effects on MCF-7 cell proliferation of vehicle or 3nM OP-1074, tamoxifen, or fulvestrant in combination with increasing amounts of everolimus. Proliferation was measured as in Figure 1 and results were from a single representative experiment and reported as the mean percent induction relative to E2 from triplicate treatments, with error bars representing SEM.
• FIG. 3 OP-1074 increases the potency of the pan PI3K inhibitor BKM-120 in inhibiting E2-stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP-1074 enhances the efficacy and potency of the PI3K inhibitor BKM-120 in inhibiting E2-stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and BKM-120 in hormone-depleted medium for 7 days in the presence of 100 pM 17P-estradiol (E2).
• Fig. 3 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or lOOnM OP-1074 in combination with increasing amounts of BKM-120.
• Fig. 3B plots the effects on MCF-7 cell proliferation of vehicle, 32nM or lOOnM BKM-120 in combination with increasing amounts of OP-1074. Proliferation was measured as in Figure 1 and results were from a single
• FIG. 4 OP-1074 increases the potency of 5-Fluorouracil in inhibiting E2- stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP-1074 enhances the efficacy and potency of the thymidylate synthase inhibitor 5-Fluorouracil in inhibiting E2-stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and 5- fluorouracil in hormone-depleted medium for 6 days in the presence of 100 pM 17P-estradiol (E2). The effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in
• MCF-7 breast cell proliferation The antiestrogen OP-1074 enhances the efficacy and potency of paclitaxel and docetaxel in inhibiting E2-stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and taxane in hormone-depleted medium for 6 days in the presence of 100 pM 17P-estradiol (E2).
• Fig. 5 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in combination with increasing amounts of paclitaxel.
• Fig. 5B plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP- 1074 in combination with increasing amounts of docetaxel. Proliferation was measured as in Figure 1 and results were from a single representative experiment and reported as the mean percent induction relative to E2 from triplicate treatments, with error bars representing SEM.
• OP-1074 increases the potency of the anthracycline doxorubicin in inhibiting E2-stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP-1074 enhances the efficacy and potency of the anthracycline doxorubicin in inhibiting E2-stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and doxorubicin in hormone-depleted medium for 7 days in the presence of 100 pM 17P-estradiol (E2). The effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in
• the present invention relates to the treatment of tumors, including cancers, mediated by the estrogen receptor with the combination of a specific benzopyran (in the form of a mixture of S-C2 and R-C2 diastereomers and also its pure S-diastereomer) as described in US 2013/0178445 and WO 2013/090921 in combination or alternation with specific agents, active agents, anti-cancer agents or chemotherapeutic agents, and in some embodiments, in certain improved dosages or formulations.
• Benefits that can result include increased efficacy and/or lower doses when the specified combinations are used. Cancers which benefit from such combinations or alternations are those that are mediated by the estrogen receptor and will also respond to the second agent.
• agents, active agents, anti-cancer agents or chemotherapeutic agents that can be combined with compounds described in US 2013/0178445 and5 and WO 2013/090921 include an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or an antimetabolite such as 5-fluorouracil, or an antitumor antibiotic such as doxorubicin.
• an mTOR inhibitor such as everolimus
• a CDK 4/6 inhibitor such as PD-0332991
• a PI3 Kinase Inhibitor such as BKM-120
• an antimetabolite such as 5-fluorouracil
• an antitumor antibiotic such as doxorubicin.
• the combination therapy includes the described anti-estrogenic compounds combined with PD-0332991 for treatment of retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers.
• the compound to be provided in combination or alternation with particular agents, active agents, anti-cancer agents or chemotherapeutic agents can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or Ri and/or R 2 -substituted derivative or a pharmaceutically acceptable composition thereof to treat a disorder that is mediated, modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic compound with virtually no estrogenic effect.
• Ri and R 2 are independently either:
• R can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring.
• Ri or R 2 is an ester, amide, carbonate or phosphate.
• prodrugs of the described compounds that can be combined or alternated with the particular agents, active agents, anti-cancer agents or chemotherapeutic agents are:
• Examples of useful metabolically cleavable prodrug groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups.
• Combinations of OP-1038, OP-1074 and their prodrugs are especially useful to treat locally advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer).
• the combinations are used to treat estrogen or progesterone receptor negative breast cancer.
• active agents include an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as PD-0332991, or a PI3 Kinase Inhibitor such as BKM-120, or a taxane, or an antimetabolite such as 5-fluorouracil, or an antitumor antibiotic such as doxorubicin.
• an mTOR inhibitor such as everolimus
• a CDK 4/6 inhibitor such as PD-0332991
• a PI3 Kinase Inhibitor such as BKM-120
• a taxane or an antimetabolite such as 5-fluorouracil
• an antitumor antibiotic such as doxorubicin.
• 2013/090921 can be combined with a CDK 4/6 inhibitor, for example PD-0332991.
• OP-1074 is combined with PD-0332991.
• 2013/090921 can be combined with an mTOR inhibitor, for example everolimus.
• OP-1074 is combined with everolimus.
• 2013/090921 can be combined with a PI3 Kinase Inhibitor, for example BKM-120.
• OP-1074 is combined with BKM-120.
• 2013/090921 can be combined with a taxane, for example paclitaxel or docetaxel.
• OP-1074 is combined with paclitaxel or docetaxel.
• 2013/090921 can be combined with antimetabolites, for example 5-fluorouracil.
• OP-1074 is combined with 5-fluorouracil.
• 2013/090921 can be combined with antitumor antibiotics, for example doxorubicin.
• OP-1074 is combined with doxorubicin.
• compositions are described of combinations of the compounds as described in US 2013/0178445 and WO 2013/090921 combined or alternated with particular agents, active agents, anti-cancer agents or chemotherapeutic agents.
• the compositions can be administered in a pharmaceutical composition suitable for oral delivery to the patient, typically a human.
• the compounds can be delivered in a carrier suitable for topical, transdermal (including by patch), intravenous, parenteral, intraortal, subcutaneous or other desired delivery route, including any method of controlled delivery, for example, using degradable polymers, or with nano or microparticles, liposomes, layered tablets or other structural frameworks which slow delivery.
• compositions can be in the form of salts of the actives. They can be administered as a pharmaceutically acceptable salt, for example, a pharmaceutically acceptable acid addition salt, including a hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.
• a pharmaceutically acceptable salt for example, a pharmaceutically acceptable acid addition salt, including a hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.
• the compositions are used to treat or prevent a disorder modulated by the estrogen receptor in an animal, typically a mammal,
• the combinations can also be used as adjunctive therapy.
• a therapeutically effective amount of the compound can be used in combination with another anticancer agent, especially for estrogen receptor positive breast cancer, but in some embodiments, for estrogen receptor negative breast cancer.
• a method of treating a patient with combinations of a once-a-day, orally administered, treatment regimen including selecting one of the plurality of treatment regimens and titrating the dosages supplied to the patient after weekly, monthly or quarterly periods of time.
• Some embodiments of the present invention facilitate the selection of a combination treatment regimen and/or the change in dosages or titration of dosages of a treatment regimen over time.
• the combination of the compounds of the present invention with other actives, in particular other agents, active agents, anti-cancer agents or chemotherapeutic actives, can be done in a single fixed dose combination pill such as a multi-pill, combopill or polypill.
• a polypill is a medication that is a drug product in pill form (i.e., tablet or capsule) that combines multiple active pharmaceutical ingredients. In one embodiment it is manufactured as a fixed-dose combination (FDC) drug product targeting treatment or prevention of a disease.
• FDC fixed-dose combination
• Polypills can reduce the number of tablets or capsules (generally orally administered) that need to be taken, which in turn may facilitate handling and administration of pharmaceuticals as well as alleviate patient pill-burden.
• the multiple drugs in a given polypill might all be aimed at a single underlying condition (or, group of related conditions), for whom a given combination of drugs/dosages might be appropriate (particularly in the case of mass-produced polypills, i.e. FDCs).
• polypills can also be custom-made for specific patients through a process called pharmacy compounding.
• the present invention also relates to protocols enabling the physician or other healthcare provider to deliver the medications in a plurality of treatment regimens in a combination or alternation dose packaging (once-a-day, more than once a day, alternate days, every third day, twice a week, once a week, once every other week, once a month and so on) to increase compliance with medical therapy.
• a combination or alternation dose packaging once-a-day, more than once a day, alternate days, every third day, twice a week, once a week, once every other week, once a month and so on
• the present invention provides protocols for a plurality of pills into a combination dose packaging or polypill corresponding to the combination treatments mentioned above used in treating a patient for cancer, and in particular breast cancer, as well as other estrogen mediated diseases that would benefit from the compounds of the present invention, and related health issues over a weekly, monthly, quarterly, or longer period of time.
• the present invention can further greatly improve patient compliance by providing the combination doses over a period of time (e.g. week, month, quarter, or longer) and having the physician titrate the dosages (adjust the dosages of each effective therapeutic ingredient) over the period of time based upon the condition of the patient.
• the combination treatment pack may provide alternative dosages for treatment at more than one time per day.
• an agent, active agent, anti-cancer agent or chemotherapeutic agent wherein the concerted use can be either (i) a pharmaceutically acceptable formulation that includes both active agents; or (ii) separate pharmaceutical formulations that independently provide each active and are either administered at the same time or at different times but in a concerted synchronized fashion in a manner that optimizes the benefit of the combination therapy (i.e., alternation therapy).
• a pharmaceutically acceptable formulation that includes both active agents
• separate pharmaceutical formulations that independently provide each active and are either administered at the same time or at different times but in a concerted synchronized fashion in a manner that optimizes the benefit of the combination therapy (i.e., alternation therapy).
• certain actives will normally be administered orally, such as in a tablet, pill or liquid, and others might be normally administered via intravenous injection or other systemic, topical, parenteral, transdermal or other route.
• a “pharmaceutical composition” can thus contain either one of the active agents or a combination of agents, based on how the active agents are best administered according to compatibility with the carrier, dosage, dosage scheduling, possibility of drug holidays and other general differences in physical properties, convenience, efficacy, toxicity and dosage regimes.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically effective amount of a compound as described in US 2013/0178445 and WO 2013/090921 in combination with a particular agent, active agent, anti-cancer agent or chemotherapeutic agent, and a pharmaceutically acceptable carrier.
• the amount of the composition administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• compositions provided herein can be administered by a variety of routes including oral, topical, parenteral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal with a pharmaceutical carrier suitable for such administration.
• the compound is administered in a controlled release formulation.
• compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders.
• the compositions are presented in unit dosage forms to facilitate accurate dosing.
• unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
• Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
• the compound is usually a minor component (as a nonlimiting example, from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
• a minor component as a nonlimiting example, from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
• compositions can be used for treating a patient with combinations of a once- a-day, orally administered, treatment regimen, including selecting one of the plurality of treatment regimens and titrating the dosages supplied to the patient after weekly, monthly or quarterly periods of time.
• Some embodiments of the present invention facilitate the selection of a combination treatment regimen and/or the change in dosages or titration of dosages of a treatment regimen over time.
• the combination of the compounds of the present invention with other actives, in particular other chemotherapeutic actives can be done in a single fixed dose combination pill such as a multi-pill, combopill or polypill.
• a polypill is a medication that is a drug product in pill form (i.e., tablet or capsule) that combines multiple active pharmaceutical ingredients. In one embodiment it is manufactured as a fixed-dose combination (FDC) drug product targeting treatment or prevention of a disease.
• FDC fixed-dose combination
• Polypills can reduce the number of tablets or capsules (generally orally administered) that need to be taken, which in turn may facilitate handling and administration of pharmaceuticals as well as alleviate patient pill-burden.
• the multiple drugs in a given polypill might all be aimed at a single underlying condition (or, group of related conditions), for whom a given combination of drugs/dosages might be appropriate (particularly in the case of mass-produced polypills, i.e. FDCs).
• polypills can also be custom-made for specific patients through a process called pharmacy compounding.
• the present invention also relates to protocols enabling the physician or other healthcare provider to deliver the medications in a plurality of treatment regimens in a combination protocol (once-a-day, more than once a day, alternate days, every third day, twice a week, once a week, once every other week, once a month and so on) to increase compliance with medical therapy.
• the present invention provides protocols for a plurality of pills into a combination protocol or polypill corresponding to the combination treatments mentioned above used in treating a patient for cancer, and in particular breast cancer, as well as other estrogen mediated diseases that would benefit from the compounds of the present invention, over a weekly, monthly, quarterly, or longer period of time.
• the present invention can further greatly improve patient compliance by providing the combination doses over a period of time (e.g. week, month, quarter, or longer) and having the physician titrate the dosages (adjust the dosages of each effective therapeutic ingredient) over the period of time based upon the condition of the patient. If necessary, the combination treatment may provide alternative dosages for treatment at more than one time per day.
• a period of time e.g. week, month, quarter, or longer
• the combination treatment may provide alternative dosages for treatment at more than one time per day.
• Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
• Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
• Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), for example in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10%) by weight, and more preferably from about 0.5 to about 15%> by weight.
• the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a suitable delivery polymeric composition, or a paraffinic or a water-miscible ointment base.
• the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
• Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
• compositions provided herein can be administered by a transdermal device.
• Transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
• compositions of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
• sustained release materials can be found in Remington 's Pharmaceutical Sciences.
• the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. In certain embodiments, the formulation comprises hexapropyl-P-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-P-cyclodextrin (10-50%) in water).
• the present invention also includes pharmaceutically acceptable acid addition salts of compounds of the compositions of the invention.
• the acids which are used to prepare the pharmaceutically acceptable salts are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
• Combinations of OP-1038, OP-1074 and their prodrugs are useful to treat disorders modulated, mediated or affected by the estrogen receptor.
• the combinations of the present invention can be used to treat local, advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer).
• the combinations are used to treat estrogen or progesterone receptor negative breast cancer.
• the combinations can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer, in combination with one or more other anti-cancer agents described below or otherwise known to those skilled in the art.
• a targeted therapy such as an mTOR inhibitor such as everolimus or a CDK 4/6 inhibitor such as PD-0332991.
• the combinations of the invention are also useful as adjunctive therapy after or instead of chemotherapy, radiation or surgery. Such adjuvant use is often used for several years, perhaps 5 years, after chemotherapy or other therapies have been concluded, but may optimally be continued for additional years.
• the combinations of the invention are also useful for the prevention of breast cancer in women at high risk and can be taken for any desired time period, including indefinitely.
• a patient typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRCA1 or BRCA2 gene or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention.
• the combinations described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence.
• these combinations are useful in treating other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis. Besides these reproductive tissues the combinations are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
• the present combinations are used as therapeutic or prophylactic agents for the treatment of conditions in mammals, particularly humans whose conditions are modulated by estrogen receptors.
• Combinations described herein are useful for treating locally advanced or metastatic breast cancer, preventing recurrence or early breast cancer after surgery, and preventing breast cancer in women at high risk. Such combinations are useful for treating all estrogen-dependent cancers of the reproductive tract including endometrial and ovarian cancers. Such combinations have potential uses in the treatment of lung and bronchial cancers that express estrogen receptors.
• active agents that can be combined with compounds as described in US 2013/0178445 and WO 2013/090921 include an mTOR inhibitor such as everolimus, or a CDK 4/6 inhibitor such as palbociclib (PD-0332991), or a PI3 Kinase Inhibitor such as BKM-120, or taxanes, or antimetabolites such as 5-fluorouracil, or antitumor antibiotics such as doxorubicin.
• mTOR inhibitor such as everolimus
• CDK 4/6 inhibitor such as palbociclib (PD-0332991)
• a PI3 Kinase Inhibitor such as BKM-120
• taxanes or antimetabolites
• antimetabolites such as 5-fluorouracil, or antitumor antibiotics such as doxorubicin.
• CDK 4/6 inhibitors for the treatment of cancer are presently in the clinic.
• CDK 4/6 normal function in cell cycle regulation is through phosphorylation of retinoblastoma protein at Serine 780 and 795. Cancers which are Retinoblastoma positive are targets for CDK 4/6 inhibitors.
• PD-0332991 (palbociclib, Pfizer), 6-acetyl-8-cyclopentyl-5-methyl-2-(5- piperazin-l-yl-pyridin-2-ylamino)-8H-pyrido[2,3- ⁇ i]pyrimidin-7-one or 6-acetyl-8-cyclopentyl-5- methyl-2- ⁇ [5-(l-piperazinyl)-2-pyridinyl]amino ⁇ pyrido[2,3-d]pyrimidin-7(8H)-one was first described and synthesized in Barvian et al. (WO 2003/062236).
• PD-0332991 is currently being evaluated in numerous tumor types including late- line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, multiple myeloma and mantle cell lymphoma.
• Such cancers are generally categorized as retinoblastoma positive as CDK 4/6 normal function in cell cycle regulation is through phosphorylation of retinoblastoma protein at Serine 780 and 795.
• PD-0332991 is dosed at 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment.
• PD-0332991 is being evaluated in combination with the aromatase inhibitor letrozole in a comparison trial with letrozole plus placebo for 1st line metastatic breast cancer. Preliminary results reported in December 2012 suggest the combination is substantially superior to letrozole alone in progression-free survival.
• Cancers that would benefit from the combination of compounds of the present invention, including OP- 1038 and OP- 1074 include include advanced or metastatic breast cancer, preventing recurrence or early breast cancer after surgery, and preventing breast cancer in women at high risk.
• Other cancers include retinoblastoma positive estrogen-dependent cancers of the reproductive tract including endometrial and ovarian cancers as well as retinoblastoma positive lung and bronchial cancers that express estrogen receptors.
• the amount of PD-0332991 administered as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 250 mg; suitably, the amount will be selected from about 2 mg to about 150 mg; suitably, the amount will be selected from about 2.5 mg to about 125 mg. Accordingly, the amount of PD-0332991 administered as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 250 mg.
• the amount of PD-0332991 administered as part of the combination according to the present invention can be a lower dose than that currently administered alone, such as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or 125 mg.
• the selected amount of PD-0332991 is administered once a day.
• the selected amount of PD-0332991 is administered twice a day.
• PD-0332991 administered as part of the combination according to the present invention orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment.
• PD-0332991 may be administered with less days off treatment as part of every 28 day cycle, for instance daily on Day 1 to Day 22 of every 28-day cycle followed by 6 days off treatment, daily on Day 1 to Day 23 of every 28-day cycle followed by 5 days off treatment, daily on Day 1 to Day 24 of every 28-day cycle followed by 4 days off treatment, daily on Day 1 to Day 25 of every 28-day cycle followed by 3 days off treatment, daily on Day 1 to Day 26 of every 28-day cycle followed by 2 days off treatment, daily on Day 1 to Day 27 of every 28-day cycle followed by 1 days off treatment, or daily for the entire 28 -day cycle with no days of off treatment.
• the term mTOR inhibitor, mTOR and derivatives thereof, unless otherwise defined, include but are not limited to rapamycin and its analogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Ppl21.
• the mTOR inhibitor is selected form rapamycin, everolimus (Afinitor) and temsirolimus.
• the mTOR inhibitor is selected from rapamycin and everolimus (Afinitor).
• the mTOR inhibitor is everolimus.
• the amount of everolimus administered as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 20 mg; suitably, the amount will be selected from about 2 mg to about 15 mg; suitably, the amount will be selected from about 2.5 mg to about 10 mg. Accordingly, the amount of everolimus administered as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 20 mg. For example, the amount of everolimus
• administered as part of the combination according to the present invention can be 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg.
• the selected amount of everolimus is administered twice a day.
• the selected amount of everolimus is administered once a day.
• the administration of everolimus will begin as a loading dose.
• the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times.
• the loading does will be administered from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
• the amount of temsirolimus administered as part of the combination according to the present invention will be an amount infused over a 30 to 60 minute period, where the amount is selected from about 5 mg to about 50 mg; suitably, the amount will be selected from about 10 mg to about 40 mg; suitably, the amount will be selected from about 15 mg to about 35 mg. Accordingly, the amount of temsirolimus administered as part of the combination according to the present invention will be an amount selected from about 5 mg to about 50 mg.
• the amount of temsirolimus administered as part of the combination according to the present invention can be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg.
• the selected amount of temsirolimus is administered twice a day.
• the selected amount of temsirolimus is administered once a day.
• the administration of temsirolimus will begin as a loading dose.
• the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times.
• the loading does will be administered from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
• PI3K inhibitors may include, without being limited to, BKM-120, XL- 147, RG-
• Phosphoinositides which are phosphorylated derivatives of
• phosphatidylinositol are essential in eukaryotic cells, regulating nuclear processes, cytoskeletal dynamics, signaling and membrane trafficking.
• PI3 -kinases PI3K
• PI3-kinases phosphorylate phosphatidylinositols or Pis at the 3-position of the inositol ring.
• the 3- phosphorylated phospholipids generated by PI3K activity bind to the pleckstrin homology (PH) domain of protein kinase B (PKB or AKT), causing translocation of PKB to the cell membrane and subsequent phosphorylation of PKB.
• Phosphorylated PKB inhibits apoptosis-inducing proteins such as FKHR, Bad, and caspases, and is thought to play an important role in cancer progression.
• the PDKs are divided into classes I-III, and class I is further subclassified into classes la and lb. Among these isoforms, class la enzymes are thought to play the most important role in cell proliferation in response to growth factor-tyrosine kinase pathway activation
• PI3-kinases are attractive targets for the treatment of proliferative diseases.
• PI3 -kinase inhibitors including wortmannin and
• wortmannin is a potent PI3K inhibitor with a low nanomolar IC 50 value, it has low in vivo anti-tumor activity.
• a group of morpholine substituted quinazoline, pyridopyrimidine and thienopyrimidine compounds have been reported to be effective in inhibiting PI3 kinase pi 10. alpha.. (Hayakawa, 6847-6858).
• Oral dosage of a morpholine substituted thienopyrimidine compound has shown tumor suppression in glioblastoma xenografts in vivo.
• the following publications disclose a series of thienopyrimidine, pyridopyrimidine and quinazoline based PI3-Kinase inhibitors: WO 2008/073785; WO 2008/070740; WO 2007/127183; U.S. Patent Publication 20080242665.
• Phosphatidylinositol-3 -kinase (PI3-kinase) inhibitors include, but are not limited to, e.g., celecoxib and analogs thereof, such as OSU-03012 and OSU-03013 (e.g., Zhu et al., Cancer Res., 64(12): 4309-18, 2004); 3-deoxy-D-myo-inositol analogs (e.g., U.S. Application No. 20040192770; Meuillet et al., Oncol.
• quinazoline-4-one derivatives such as IC486068 (e.g., U.S. Application No. 20020161014; Geng et al., Cancer Res., 64:4893-99, 2004); 3-(hetero)aryloxy substituted benzo(b)thiophene derivatives (e.g., WO 04 108715; also WO 04 108713); viridins, including semi -synthetic viridins such as such as PX-866 (acetic acid ( 1 S,4E, 1 OR, 11R, 13 S, 14R)-[4-diallylaminomethylene-6-hydroxy- 1 -methoxymethy- 1-10,13- dimethyl-3,7, 17-trioxo-l,3,4,7, 10,l l, 12,13, 14,15, 16,17-dodecahydro- -2-oxa- cyclopenta[a]phenanthren-l
• IC486068 e.g., U.S. Application No
• the PI3K inhibitor is 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4- (trifluoromethyl)-2-pyridinamine (BKM-120).
• BKM-120 is currently being tested in Phase III clinical trials at a daily dose of 100 mg via oral capsules.
• the amount of BKM-120 administered as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 250 mg; suitably, the amount will be selected from about 2 mg to about 150 mg; suitably, the amount will be selected from about 2.5 mg to about 100 mg.
• the amount of BKM-120 administered as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 250 mg.
• administered as part of the combination according to the present invention can be a lower dose than that currently administered alone, such as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg.
• the selected amount ofBKM-120 is administered once a day.
• the selected amount of BKM-120 is administered twice a day.
• Efudex is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase.
• 5-FU is an intravenously (IV) administered fluorinated pyrimidine cytotoxic agent that inhibits the function of thymidylate synthase, an enzyme necessary for the production of the thymidine nucleotides required for DNA synthesis.
• 5-FU has activity in the therapy of a number of tumor types but is most commonly given in the treatment of colorectal cancer, upper gastrointestinal malignancies, and breast cancer.
• 5-FU is currently administered in various protocols such as 500 mg/m 2 IV on
• a method that has been used to overcome the poor oral bioavailability of 5-FU involves the administration of a prodrug that has good bioavailability and is ultimately converted to 5-FU.
• Capecitabine penentyl [l-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo- lH-pyrimidin-4-yl]carbamate, Xeloda) is such a novel oral fluoropyrimidine carbamate. It is readily absorbed from the gastrointestinal tract and is preferentially converted to 5-FU in tumor tissue.
• capecitabine After oral administration, capecitabine passes intact from the gastrointestinal tract to the liver, where it is converted by carboxylesterases to 5'-deoxy-5-flourocytidine (5'-DFCR), then by cytidine deaminase in liver and tumor tissue to 5'-deoxy-5-flourouridine (5'-DFUR), and finally by thymidine phosphorylase (dThdPase) in tumor tissue to 5-FU.
• the usual starting dose is 2,500 mg/m2/day in two divided doses, 12 hours apart.
• One cycle includes two weeks of treatment followed by one week without treatment. Cycles can be repeated every three weeks.
• the dosage of 5-FU may be, for example, 10-1000 mg/ m 2 /day, preferably 50-1000 mg/ m 2 /day and more preferably 100-600 mg/ m 2 /day.
• the dosage Capecitabine may be, for example, 100-10000 mg/ m 2 /day, preferably 500-5000 mg/ m 2 /day and more preferably 1000-5000 mg/ m 2 /day.
• Doxorubicin also known as Adriamycin, is one of the more common cytotoxic agents used for the treatment of breast cancer.
• the term doxorubicin includes doxorubicin as well as the pharmaceutically acceptable salts of doxorubicin.
• Doxorubicin or hydroxyldaunorubicin is an antineoplastic drug widely used in chemotherapy (Hortobagyi, Drugs, 54 (Supplement 4): 1-7 (1997)). It is an anthracycline antibiotic and structurally closely related to daunomycin (Minotti et al., Pharmacologiy. Rev., 56; 185-229 (2004).
• Doxorubicin is commonly used in the treatment of a wide range of cancers, including cancers of the blood, lymph system, bladder, breast, stomach, lung, ovaries, thyroid, nerves, kidneys, bones, soft tissues, including muscles and tendons, multiple myeloma, and others.
• the hydrochloride salt of doxorubicin is one of the most common forms.
• doxorubicin hydrochloride 14- hydroxydaunorubicin hydrochloride; 3-hydroxyacetyldaunorubicin hydrochloride; and 5, 12- naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranosyl)oxy]-7,8,9, 10-te- trahydro-6,8,1 l-trihydroxy-8-(hydroxyacetyl)-l-methoxy-, hydrochloride, (8S-cis)-(9Cl).
• Doxorubicin hydrochloride has the molecular formula C 2 7H 2 9NC)ii.HCl, a molecular weight (MW) of 580.0, and CAS number 25316-40-9.
• the dosage amount of doxorubicin is preferably in the range from 30 to 100 mg/m 2 /day, more preferably 40 to 80 mg/m 2 /day, more preferably a dose of about 50 mg/m 2 /day or about 60 mg/m 2 /day.
• Infusion times for doxorubicin are generally up to 6 hours, more preferable 1-3 hours, with 1 hour most preferred.
• the dosage may be, for example, 10-100 mg/ m 2 /day, preferably 30-100 mg/ m 2 /day and more preferably 30-60 mg/ m 2 /day.
• Taxane Combination Therapy examples include paclitaxel (trade name: Taxol) and docetaxel (trade name: Taxotere). Poliglumex paclitaxel (trade name: Opaxio) is also included in taxanes. Such taxanes have been approved and developed for application to breast cancer, non-small-cell lung cancer, gastric cancer, head and neck cancer, ovarian cancer, esophageal cancer, gastric cancer, uterine body cancer or the like. In addition, combination therapy for various cancers has also been approved or developed by combining taxane with various drugs, for example, with bevacizumab for breast cancer and with carboplatin for ovarian cancer and non-small-cell lung cancer.
• Taxane may be administered according to known clinical practice.
• the dosage and dosing schedule may be altered according to a specific symptom or all symptoms of the patient's disease.
• the dosage may appropriately be reduced according to age, symptoms or incidence of side effects.
• taxane may usually, but without limitation, be administered for 0.01-10000 mg/m 2 /day, preferably 0.1- 1000 mg/m 2 /day and more preferably 1-500 mg/m 2 /day for an adult, which may be administered usually once to three times a day.
• the dosage needs to be reduced if undue toxicity occurs in the patient.
• the dosage and dosing schedule may be altered when one or more additional agents, active agents, anti-cancer agents or chemotherapeutic agents are used in addition to the combination therapy of the invention.
• the dosing schedule may be determined by the physician in charge of the treatment of the specific patient.
• the dosage paclitaxel may be 0.01-10000 mg/m 2 /day, preferably 0.1-1000 mg/m 2 /day and more preferably 1-500 mg/m 2 /day.
• the dosage of docetaxel may be 0.01-10000 mg/m 2 /day, preferably 0.1-1000 mg/m 2 /day and more preferably 1-500 mg/m 2 /day.
• the dosage of poliglumex paclitaxel may be 0.01-10000 mg/m 2 /day, preferably 0.1- 1000 mg/m 2 /day and more preferably 1-500 mg/m 2 /day.
• the combinations of the present invention are provided for use in medical therapy, including for any of the conditions described herein.
• the use of the present compositions in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases is also provided.
• Injection dose levels range are provided in any desired dosage of the active agents, for example, from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
• a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
• the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
• any dose of the active agents, as combined, is appropriate that achieved the desired goals.
• suitable daily dosages of active agents of the present invention are between about 0.1-4000 mg, more typically between 5 mg and 1 gram, more typically between 10 mg and 500 mg, and administered orally once-daily, twice-daily or three times-daily, continuous (every day) or intermittently (e.g., 3-5 days a week).
• the dose of the compounds of this invention usually ranges between about 0.1 mg, more usually 10, 50, 100, 200.250, 1000 or up to about 2000 mg per day.
• the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative substituted benzopyrans that have been listed herein.
• the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
• the diastereomerically or enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate or mixture of diastereomers by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer or diastereomer. See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H.
• a diastereomerically pure compound may be obtained by reaction of the racemate or mix of diastereomers with a suitable optically active acid or base.
• suitable acids or bases include those described in Bighley et al.., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, the contents of which are hereby incorporated by reference in their entireties.
• Enantiomerically or diastereomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer or diastereomer used.
• the identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art.
• the diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer or diastereomer regenerated by treatment with an appropriate base or acid.
• the other enantiomer or diasteromer may be obtained from the racemate or mix of diastereomers in a similar manner or worked up from the liquors of the first separation.
• enantiomerically or diastereomerically pure compound can be separated from racemic compound or a mixture of diastereomers by chiral
• chiral columns and eluents for use in the separation of the enantiomers or diastereomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art.
• Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to
• CHIRALPACK® IC CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
• Step 1 Reaction to produce l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone
• the solid was transferred to a 2 L Erlenmeyer flask. Isopropyl alcohol (IPA) was used to rinse the flask. The solid was recrystallized from IPA (1.4 L). The suspension was cooled in an ice bath for 30 minutes and the solid collected by vacuum filtration. The solid was rinsed with ice cold IPA until the filtrate was colorless and dried in a vacuum oven to give a white powder (162.24 g). The mother liquor and washes were combined and concentrated to orange oil (38.09 g).
• IPA isopropyl alcohol
• the oil bath was cooled to 90 °C and 380 mL of isopropyl alcohol was added in one portion.
• the reaction mixture became a cloudy white suspension and redissolved to give a solution in less than a minute at 90 °C.
• the heating to the bath was set to 50 °C and the flask was allowed to gradually cool to 50 °C.
• a precipitate started to form at 60 °C and gave a suspension at 50 °C.
• a thick oily mass falls out of solution ⁇ 55-53 °C.
• Vigorous agitation with overhead stirrer 300 rpm was required to prevent the oily mass from solidifying into one solid as seen with small scale reactions equipped with stir bar. The reaction was left to stir until the mixture cooled to room temperature.
• the mother liquor was decanted and fresh isopropanol (100 mL) was added to the flask to rinse the solid.
• the liquid was decanted and combined with the mother liquor.
• the mother liquor was concentrated to a dark red oil (27.13 g) and DCM (150 mL) was added to the flask to give a red solution.
• Silica gel 55 g was added to solution and concentrated to dryness.
• the silica gel mixture was poured into a 600 mL sintered glass funnel filled with silica gel (50 g). The solids were washed with ethyl acetate (1.2 L) and the filtrate concentrated to an orange oil (137.61 g crude).
• the oil was dissolved into boiling 80 % IP A/water (1.2 L) and the solution allowed to cool to room temperature and stand overnight to give a cake.
• the cake was filtered and washed with cold IPA (100 mL).
• the mother liquor was partially concentrated on a rotovap to give a tan powder. This process was repeated until an oil could not be washed away from the powder.
• the product was pooled and dried in a vacuum oven to give an impure tan powder (118.25 g, 85.6 %).
• the red oil was dissolved into ethyl acetate (500 mL) and washed with saturated sodium bicarbonate solution (3 x 1 L). The organic layers was washed with brine (1 L), filtered and concentrated to give a red oil (109.32 g, crude). The oil was loaded onto 100 g of silica gel and chromatographed in 40 g portions on silica gel (100 g cartridge, 5-30 % EA/Hex). Fractions containing spots with Rf 0.55 (33 % EA/Hex) were pooled and concentrated to a light red glass (53.37 g). The glass was mixed with DCM (200 mL) and sonicated to give a pink suspension.
• the solid was filtered through a sintered glass funnel washed with a 20 % DCM in Hexanes solution (250 mL) and dried in a vacuum oven overnight (32.41 g). The mother liquor was concentrated to a glass and the process repeated a second time to give a pink solid (4.2784 g).
• the impure mixed fractions were pooled and concentrated to a glass (16.71 g).
• the glass was dissolved into DCM (75 mL) and pink crystals formed on standing (7.0862 g). This process was repeated to give a second crop of pink crystals (2.3643).
• the mother liquors from both the pure and impure fractions were combined and chromatographed with the same method (2 x 100 g cartridges). The fractions with Rf 0.55 were pooled and concentrated to give a red oil (17.388 g) which did not solidify. The oil was not combined with previous batches but reprotected in a separate reaction.
• the reaction was diluted with DCM (200 mL), washed with saturated NaHC03 (200 mL), water (200 mL), brine (200 mL), dried over Na2S04, filtered and concentrated to give a red viscous residue.
• the residue adsorbed onto silica gel (75 g) was purified on a silica gel column (4 x 100 g, 0 - 20 % EA/Hex) to give a white solid which was triturated with methanol and dried in a vacuum oven at 40° C for 16 h to afford the titled compound as a white powder (51.67 g 90.2 %).
• the reaction mixture was heated in an oil bath at 120 °C. After 91 h of heating the reaction was cooled to room temperature and the mixture filtered through a pad of Celite (3 cm) which was successively washed with DCM (200 mL), EA (200 mL) and MeOH (200 mL). The filtrate was collected and concentrated. The residue was adsorbed onto silica gel (25 g) purified with silica gel (100 g cartridge, 0 - 30% MeOH/DCM) [TLC: 5 % MeOH/DCM, 4 major spots, Rf (SM:0.95), 0.9, 0.83, (prod. 0.43)]. The fractions containing product were pooled and concentrated to give a brown foam (13.64 g, 81.0 %).
• OP- 1038 was separated into its diastereomers (2S)-3-(4-hydroxyphenyl)-4- methyl-2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol (OP-1074) and (2R)-3-(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H- chromen-7-ol (OP-1075) using a Diacel, Chiralpak IC column at room temperature in isocratic mode with 80 % hexanes, 20 % 2-propanol with 0.1 % dimethylethylamine or 0.1% diethyl amine as a modifier. This method was used at analytical and preparative scale. Step 9:
• (R)-3-methylpyrrolidine hydrochloride (20.000 g, 164.5 mmol, 1.0 equiv.) was added to a round bottom flask and dissolved into anhydrous DCM (45 mL). Freshly distilled Diisopropylethylamine (60.157 ml, 345.4 mmol, 2.1 equiv.) and freshly activated 4 A molecular sieves (- 21 g) was added to the solution and stirred for 10 minutes.
• the mixture was filtered through a pad of Celite (4 cm). The solids were washed with DCM (5 x 500 mL). The filtrate was poured into a separatory funnel and the layers separated (-200 mL aqueous layer recovered). The aqueous layer was extracted with DCM (3 x 100 mL). The organic layers were combined and washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a yellow liquid (33.43 g).
• This liquid was loaded onto silica gel (25 g) and chromatographed through silica gel (2 x 100 g cartridge) with 50-100 % ethyl acetate in hexanes followed by 10-40 % methanol in dichloromethane to give a yellow oil (29.17 g, quant).
• the oil was taken up in methanol (50 mL) and 25 % sodium methoxide in methanol (9.9 mL, 45.5 mmol, 1 equiv) was added to the methanolic solution to give a white suspension.
• the mixture was concentrated to dryness and taken up into anhydrous DCM (35 mL).
• the suspension was centrifuged at 3K rpm for 5 minutes.
• the clear solution was collected and the solid resuspended into DCM (35 mL). This process was repeated a total of 4 times.
• the combined solution was concentrated to a yellow liquid (5.6341 g, 95.6 %).
• OP-1083 was prepared by air oxidation on OP-1074, followed by
• OP-1083 and OP-1074 chromatographic separation of OP-1083 and OP-1074.
• the mixture of OP-1074 and OP-1083 (560 mg) was dissolved in methanol (15 mL) and mixed with silica gel (3 g). The mixture was dried to give a dark red powder. This powder was loaded into a cartridge and chromatographed on silica gel (4 g cartridge) with 0-25 % methanol in dichlorom ethane to give OP-1074 as an orange solid (0.261 g, 46.6 %) and OP-1083 as an orange solid (41.1 mg, 15 %)
• Method 0 % MeOH for 4 min, gradient to 5 % MeOH/DCM over 5 minutes, hold at 5 % for 6 minutes, gradient to 10 % MeOH/DCM over 2 minutes, hold at 10 % MeOH/DCM for 8 minutes, gradient to 25 % MeOH/DCM over 0 minutes, hold at 25 % for 5 minutes.
• TLC (5 % MeOH/DCM): 4 spots, 0.84, 0.42, 0.26 (Product), 0.16 (Mono carbonate).
• Gradient method 0 % MeOH/DCM hold for 2 minutes, gradient to 5 % MeOH/DCM over 5 minutes, hold at 5 % MeOH/DCM for 3 minutes, gradient to 15 % MeOH/DCM over 3 minutes, hold at 15 % MeOH/DCM for 2 minutes.
• the reaction stirred at this temperature for 1.5 h. The solution became slurry after -45 minutes. The reaction was allowed to reach room temperature over 45 min and stirred at room temperature for 2 h. A sample was quenched with water and analysis showed the mass of the desired product.
• the reaction mixture was concentrated to dryness.
• the crude mixture was suspended into 2 N HC1 (5 mL). The suspension was sonicated and centrifuged at 5000 rpm for 6 minutes. The supernatant was decanted and the solid resuspended into 5 mL of 2 N HC1 and the process was repeated. The solid was dried under vacuum to give 129 mg of the crude product.
• MCF-7 Proliferation in MCF-7 was measured using a fluorescent DNA binding dye 6-8 days after treatment in triplicate with anti-estrogens in the presence of 100 pM E2. Specifically, MCF-7 cells were treated with anti-estrogens alone or in combination with other
• chemotherapeutics in hormone-depleted medium for 6-8 days in the presence of 100 pM E2. Proliferation was measured using Cyquant fluorescent DNA-binding dye (Invitrogen, Grand Island, NY). Results were from a single representative experiment and reported as the mean percent induction relative to E2 from triplicate treatments, with error bars representing SEM.
• Fig. 1 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in combination with increasing amounts of PD-0332991.
• IB plots the effects on MCF-7 cell proliferation of vehicle or ⁇ PD-0332991 in combination with increasing amounts of OP-1074.
• Fig. 1C plots the effects on MCF-7 cell proliferation of vehicle or 3nM OP-1074, tamoxifen, or fulvestrant in combination with increasing amounts of PD- 0332991.
• the combination of OP-1074 with PD- 0332991 at several concentrations leads to a lower percentage of proliferation of MCF-7 breast cells than either agent by themselves.
• OP-1074 increases the potency of the mTOR inhibitor everolimus in inhibiting E2-stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP- 1074 enhances the efficacy and potency of the mTOR inhibitor everolimus in inhibiting E2- stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and everolimus in hormone-depleted medium for 6 days in the presence of 100 pM 17P-estradiol (E2).
• Fig. 2 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in combination with increasing amounts of everolimus.
• FIG. 2B plots the effects on MCF-7 cell proliferation of vehicle, InM or lOnM everolimus in combination with increasing amounts of OP-1074.
• FIG. 2C plots the effects on MCF-7 cell proliferation of vehicle or 3nM OP- 1074, tamoxifen, or fulvestrant in combination with increasing amounts of everolimus.
• OP-1074 with everolimus at several concentrations leads to a lower percentage of proliferation of MCF-7 breast cells than either agent by themselves.
• OP-1074 increases the potency of the pan PI3K inhibitor
• Fig. 3 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in combination with increasing amounts of BKM-120.
• Fig. 3B plots the effects on MCF-7 cell proliferation of vehicle, 32nM or ⁇ BKM-120 in combination with increasing amounts of OP-1074.
• OP-1074 increases the potency of 5-fluorouracil in inhibiting E2-stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP-1074 enhances the efficacy and potency of the thymidylate synthase inhibitor 5-fluorouracil in inhibiting E2- stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and 5-fluorouracil in hormone-depleted medium for 6 days in the presence of 100 pM 17p-estradiol (E2).
• E2 100 pM 17p-estradiol
• OP-1074 increases the potency of taxanes in inhibiting El- stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP-1074 enhances the efficacy and potency of paclitaxel and docetaxel in inhibiting E2-stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and taxane in hormone-depleted medium for 6 days in the presence of 100 pM 17P-estradiol (E2).
• Fig. 5 A plots the effects on MCF-7 cell proliferation of vehicle, 1, 10 or ⁇ OP-1074 in combination with increasing amounts of paclitaxel.
• OP-1074 increases the potency of the anthracycline doxorubicin in inhibiting E2-stimulated MCF-7 breast cell proliferation.
• the antiestrogen OP- 1074 enhances the efficacy and potency of the anthracycline doxorubicin in inhibiting El- stimulated breast cell proliferation in vitro.
• MCF-7 cells were treated with the indicated amount of OP-1074 and Doxorubicin in hormone-depleted medium for 7 days in the presence of 100 pM 17p-estradiol (E2).
• E2 100 pM 17p-estradiol
• Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
• HPLC high pressure liquid chromatography
• analogue means one analogue or more than one analogue.
• “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
• such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
• pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkyl ammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66(1): 1-79 (Jan.'77).
• “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
• “Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule indicated herein.
• Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions a compound of the invention that are pharmaceutically active in vivo.
• Solvate refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
• solvents include water, ethanol, acetic acid and the like.
• the compounds of the invention may be prepared e.g. in crystalline or liquid form and may be solvated or hydrated.
• Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
• a "subject" to which administration is contemplated includes, but is not limited to, humans ⁇ i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
• the subject is a human.
• the subject is a non-human animal.
• the terms "human", “patient” and “subject” are used interchangeably herein.
• the term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight.
• the term may refer to more than 96% by weight, more than 97% by weight, more than 98%) by weight, more than 98.5%> by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
• the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
• the term “enantiomerically pure R- compound” refers to at least 95% by weight R-compound and at most about 5% by weight S- compound. In alternative embodiments, when specified, the term can refer to at least about 99% by weight R-compound and at most about 1% by weight S-compound or at least about 99.9% by weight R-compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
• the term “enantiomerically pure S- compound” or “S-compound” refers to at least about 95% by weight S-compound and at most about 5% by weight R-compound. In alternative embodiments, when specified, the term can refer to at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Molecular Biology (AREA)
• Diabetes (AREA)
• Gynecology & Obstetrics (AREA)
• Pregnancy & Childbirth (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=51022942

Family Applications (1)

Country Status (4)

Cited By (28)

Families Citing this family (2)

Citations (36)

• 2014
  • 2014-06-12 WO PCT/IB2014/062176 patent/WO2014203129A1/en active Application Filing
  • 2014-06-16 TW TW103120702A patent/TW201511755A/zh unknown
  • 2014-06-17 JP JP2014124014A patent/JP2015003909A/ja active Pending
  • 2014-06-18 AR ARP140102308A patent/AR096645A1/es unknown

Patent Citations (49)

Non-Patent Citations (48)

Also Published As

Similar Documents

Legal Events