JP2015003909A - Combinations of benzopyran compounds, compositions and uses thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a combination and a pharmaceutical composition for treating a medical disorder modulated, mediated or affected by an estrogen receptor such as breast cancer.SOLUTION: This invention provides a method of administering, to a subject, a benzopyran derivative represented by the following compound in combination 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.

Description

  The present invention is in the field of medicine, and in particular, the present invention relates to a mixture of S-C2 and R-C2 diastereoisomers as described in US 2013/0178445 and WO 2013/090921 or its pure S-diastereo It relates to the treatment of estrogen receptor mediated cancer by administering certain benzopyrans (in isomeric form) in combination with certain drugs, active drugs, anticancer drugs, or chemotherapeutic drugs.

  Estrogen receptor modulators are a class of compounds that act on estrogen receptors. Such compounds can be pure agonists (mimetic 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 full antagonist, tamoxifen (C) and raloxifene (D) are SERMs.

  Most breast cancers express the estrogen receptor (ER) and its growth is driven by the action of estrogen at that receptor, primarily ERα. This type of cancer is treated with estrogen antagonists, but estrogen antagonists compete with estrogen for binding to the receptor, but do not activate the receptor and are driven by estrogen. Disturb. Partial antiestrogens such as raloxifene and tamoxifen have some estrogenic effects, including estrogenic stimulation of uterine growth and, in some cases, actual tumor growth, including estrogenic effects during breast cancer progression. Keep the effect. In contrast, fulvestrant, a complete antiestrogen, has no estrogenic effects on the uterus and is effective in tamoxifen-resistant tumors. Recent studies also suggest that fulvestrant is substantially superior to the aromatase inhibitor anastrozole in the treatment of metastatic breast cancer (Robertson et al., J Clin Oncol (2009) 27 (27). : 4530-5).

  Estradiol is a naturally occurring female estrogen hormone. Raloxifene was disclosed by Eli Lilly in 1981 for prevention of breast cancer and treatment of osteoporosis (US Pat. Nos. 4,418,068, 5,478,847, 5,393,763, and No. 5,457,117). Fulvestrant was disclosed by Imperial Chemical Industries (ICI) in 1983 (U.S. Pat. No. 4,659,516 expired in 2007 and extended in patent term; U.S. Pat. No. 6,774). 122, and 7,456,160). Tamoxifen is also disclosed by ICI in the '516 patent. Tamoxifen has been developed for the treatment of breast cancer based on a strong antagonism of estrogen action in breast tissue (Jordan, J. Cell. Biochem. 51 (1995)).

  The degree of antiestrogenicity often results in immature (preferably ovariectomized) rodents in females, both in the absence (agonist mode) and presence (antagonist mode) of estrogen, Assayed by placing under the action of a test dose of compound. Tamoxifen and other partial antiestrogen drugs stimulate uterine weight gain in agonist mode and only partially block estrogen driven uterine weight gain in antagonist mode. Fulvestrant and other fully antiestrogens do not stimulate uterine weight gain in the agonist mode and completely block the weight gain driven by estrogen in the antagonist mode. Induction of estrogen-regulated alkaline phosphatase expression in human uterine cancer cell growth in culture can be used to differentiate between partial and complete antiestrogens and correlates well with rodent weight gain assays To do.

  Both tamoxifen and fulvestrant inhibit the growth of cultured human breast cancer cells caused by estrogens. However, fulvestrant inhibits proliferation more completely when triggered by growth factors, particularly the growth factors of the insulin / insulin-like growth factor family. Thus, from the inhibition of breast cancer cell proliferation driven by growth factors and the effect on uterine weight, two assays can be obtained that can distinguish between full and partial antiestrogens.

  Binding by tamoxifen stabilizes the estrogen receptor, whereas fulvestrant and chemically similar antiestrogens such as ICI-164384 and RU-58668 cause degradation of the estrogen receptor (Dodge et al. J. Bone Miner. Res., 8 (Extra. 1, S278 (1993); Waking, Breast Cancer Res. Treat. 25, 1 (1993); Baer et al., Calcified Tissue Int., 55, 338 (1994)). However, some compounds such as GW-5638 (Wu et al., Mol Cell., 18, 413 (2005)) and OP1075 described below are receptor estrogen, although they degrade the receptor-i.e., complete Antiestrogens Therefore, the ability to degrade estrogen receptors does not guarantee full anti-estrogenicity, yet the ability to induce receptor degradation is a factor that distinguishes the behavior of tamoxifen and fulvestrant, It may be desirable for drugs to treat breast cancer.

  Fulvestrant that degrades the estrogen receptor contains a 17-β estradiol nucleus. Fulvestrant has flexible long aliphatic side chains that block oral absorption. Oral absorption is blocked by the estradiol nucleus, and the flexible long aliphatic side chain makes the drug very insoluble, which exacerbates the problem. Fulvestrant has to be injected because of its low oral bioavailability. Two 5 ml intramuscular depot injections, one for each buttocks, must be administered monthly by a medical professional. Furthermore, it is uncertain whether these two injections will provide sufficient drug exposure for optimal action. This drug does not appear to work in premenopausal women.

  In 1990, oral anti-estrogen drug development took an important step with the discovery of a family of high-affinity benzopyran antiestrogen drugs by Kapil and colleagues (Sharma et al. (1990) J Med Chem, 33 (12 ): 3222-9; Sharma et al. (1990) J Med Chem, 33 (12): 3216-22). The numbering system for benzopyran is usually as follows.

Sharma et al. Have shown that the combination of the 7-hydroxyl group and the 4′-hydroxyl group confer high affinity binding to the estrogen receptor by the benzopyran nucleus (Compound G, Sharma et al. (1990) J Med). Chem, 33 (12): 3222-9, see compound 25. R ¹ and R ² are OH).

さらに、Ｓｈａｒｍａらは、ベンゾピラン核の４位にあるメチル基の存在によって、４’位のヒドロキシル基なしで、受容体結合親和性が高められたことを報告している。

Furthermore, Sharma et al. Reported that the presence of a methyl group at the 4-position of the benzopyran nucleus increased receptor binding affinity without the hydroxyl group at the 4'-position.

  In 1991, Labrie and colleagues filed a patent application issued as US Pat. No. 5,395,842 (see claim 29), where EM-343 (H) is an anti-estrogen. It teaches that it has shown excellent binding to the estrogen receptor without loss of action. EM-343 differed from the Saeded compound by containing a hydroxyl at the 4 'position of 4-methyl, 7-hydroxylbenzopyran.

  In 1995, Labrie et al. Filed a continuation-in-part patent application issued in 2000 as US Pat. No. 6,060,503, disclosing prodrugs and optically active species of EM-343. Specifically, Labrie et al. (S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2H-chromene-7 Discloses EM-652, a pure isomer of EM-343, called acolbifen (I), which is an ol.

  Labrie et al., In WO 01/54699 (see FIGS. 4a and 4b), ring systems in which the side chain is variously substituted, including pyrrolidinyl, piperidinyl, methyl-1-pyrrolidinyl, and dimethyl-1-pyrrolidinyl. Several broad generic Markush-type benzopyran-containing compounds are also presented, including the acolbifene analogs ending in

  Labrie U.S. Pat. Nos. 7,005,428 and 6,465,445, claiming priority from the June 1998 application, have the following general formula for use as anti-estrogenic compounds:

［式中、Ｄは、−ＯＣＨ_２ＣＨ_２Ｎ（Ｒ_３）Ｒ_４（Ｒ_３およびＲ_４は、Ｃ_１〜Ｃ_４アルキルからなる群から独立に選択され、またはＲ_３、Ｒ_４、およびこれらが結合している窒素原子が、一緒になって、ピロリジノ、ジメチル−１−ピロリジノ、メチル−１−プロリジニル、ピペリジノ、ヘキサメチレンイミノ、およびモルホリノからなる群から選択される環構造である）であり、
Ｒ_１およびＲ_２は、水素、ヒドロキシル、およびｉｎ ｖｉｖｏでヒドロキシルに変換された部分からなる群から独立に選択される］、および

Wherein D is —OCH ₂ CH ₂ N (R ₃ ) R _{4, wherein} R ₃ and R ₄ are 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 bonded together is a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-prolidinyl, piperidino, hexamethyleneimino, and morpholino) Yes,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, and a moiety that is converted to hydroxyl in vivo], and

［式中、Ｒ_１およびＲ_２は、ヒドロキシル、およびｉｎ ｖｉｖｏでヒドロキシルに変換された部分からなる群から独立に選択され、
Ｒ_３は、飽和、不飽和、または置換ピロリジニル、飽和、不飽和、または置換ピペリジノ、飽和、不飽和、または置換ピペリジニル、飽和、不飽和、または置換モルホリノ、窒素含有環式部分、窒素含有多環式部分、およびＮＲａＲｂ（ＲａおよびＲｂは、独立に、水素、直鎖状または分枝状Ｃ_１〜Ｃ_６アルキル、直鎖状または分枝状Ｃ_２〜Ｃ_６アルケニル、および直鎖状または分枝状Ｃ_２〜Ｃ_６アルキニルである）からなる群から選択される種である］を記載している。

[Wherein R ₁ and R ₂ are independently selected from the group consisting of hydroxyl and a moiety that is converted in vivo to hydroxyl;
R ₃ is 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 polycycle wherein moiety, and NRaRb (Ra and Rb are independently hydrogen, linear or branched _C 1 -C ₆ alkyl, linear or branched _C 2 -C ₆ alkenyl, and straight or branched Is a species selected from the group consisting of branched C ₂ -C ₆ alkynyl).

Acolbifen binds to the estrogen receptor α with a three times higher affinity than the natural ligand 17-β estradiol (Katzenellenbogen (2011) J Med Chem 54 (15): 5271-82). High affinity binding is an important medicinal effect because antiestrogens must compete with estradiol for binding to the estrogen receptor. Both the Labrie '842 patent and the Labrie' 503 patent disclose benzopyran compounds that may contain an unsubstituted pyrrolidine at the “tail” or R ³ position shown in Compound F. EM-800, the pivalic acid prodrug of EM-652, and the HCl salt of EM-652 are also described in the '503 patent.

  Acolbifen was initially thought to be a complete antiestrogen. However, careful studies using the rodent uterus assay and the human uterine cell alkaline phosphatase assay revealed that acorbifen retained some estrogenic action of approximately 12% 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 is in contrast to fulvestrant, where the remaining estrogenic effects are almost unmeasurable. Furthermore, fulvestrant binding induces significant degradation of the estrogen receptor, whereas acorbifen induces no or less receptor degradation. Raloxifene and bazedoxifene do not degrade the receptor, but the degree of stabilization of the receptor is much weaker than tamoxifen.

  Acolbifen has oral bioavailability and is currently in the phase III clinical trial of breast cancer treatment by Canadian company Endocetics (founded by Dr. Labrie). If a woman is orally dosed with 40 mg of acolbifen or EM800 daily, the average drug exposure is 8.3 ng / ml and 15 ng / ml of circulating acorbifen, respectively. In preclinical studies, both forms of drug are effective against tamoxifen-resistant human breast cancer xenografts growing in immunocompromised mice. In clinical studies, a 40 mg dose of EM800 was numerically as effective as anastrozole in preventing the progression of metastatic estrogen receptor positive breast cancer.

  Merck's Blizzard and colleagues have published a series of papers on estrogen receptor ligands since 2005. They first focused on using a dihydrobenzoxanthine nucleus (J) with an alkyl substituted pyrrolidine side chain and linker as a SERAM (Selective Estrogen Receptor α Modulator) (Blizzard et al. (2005) Bioorg. Med Chem Lett. 15 (1): 107-13).

  This group attempted to maximize the estrogen receptor α / β selectivity ratio and minimize uterine activity (eg, maximize antagonism against uterine activity). They have an unbranched linker with 3-methylpyrrolidinyl and 3,4-methylpyrrolidinyl, and an α-methyl (ie methyl on ethylene α-position) linker with an unsubstituted pyrrolidinyl side chain. It reports that it was noteworthy. Blizzard et al. Conclude that minor changes in side chains or linkers have had a significant impact on biological activity, particularly in uterine tissue.

  Blizzard et al. Also studied the chroman nucleus (Blizzard et al. (2005) Bioorg Med Chem Lett. 15 (6): 1675-81) (compound K).

  Merck chroman nuclei differ from acorbiphene nuclei by the absence of double bonds in the oxane ring. These structures also had a hydroxyl at the 6-position (not 7) of the fused benzene ring. A chroman nucleus with 2-methylpyrrolidine (rather than 3-methyl) and methyl on the linker resulted in an almost complete anti-estrogen drug (see compound 12 in Blizzard et al.). Blizzard et al. Describe the differences in the anti-estrogenic activity of variously substituted nuclei and point out that the size and configuration of substituents is very important for receptor potency and selectivity.

  In the third publication of this series (Blizzard et al. (2005) Bioorg Med Chem Lett. 15 (17): 3912-6), Blizzard et al. Re-studied the dihydrobenzoxanthine nucleus, We reported that the addition of a methyl group to the side chain, either on the ring or on the linker, with the proper position and proper stereochemistry, led to the discovery that estrogen antagonist activity in uterine tissue was substantially increased. ing. Blizzard et al. Also noted that the best estrogen antagonist activity in this dihydrobenzoxathiin series is that it has a methyl group on the pyrrolidine, a methyl group on the linker, and a hydroxyl exists at the 6-position of the fused benzene ring. It has also been reported. Blizzard et al. Also know that their optimized side chain with two methyl groups is a SERM / SERD (selective estrogen) that only changes the structure of existing SERMs to a relatively small scale. It was pointed out that this was the first example to be converted into a receptor alpha modulator and a down-regulator.

  The Merck team then investigated whether the optimized side chain changes reported for the dihydrobenzoxanthine nucleus were “portable” and could confer strong antiestrogenicity when attached to different nuclei (Blizzard). (2005) Bioorg Med Chem Lett. 15 (23): 5214-8). Merck found that none of the three nuclei tested (raloxifene, bazedoxifene, or lasofoxifene) became higher anti-estrogenic by changing either 3-methylpyrrolidine or the chiral side chain. It has been demonstrated. Blizzard et al., “The fact that side chains A and B are incorporated has no dramatic effect on the uterine profile is that the structure-activity relationship of the side chain of dihydrobenzoxatiin SERAM is not transferable to other platforms. Is clearly shown. "

  In yet another 2005 presentation, Gauthier, Labrie, and colleagues reported the synthesis and structure-activity relationships of analogs of acolbifen (Gauthier et al. (2005) J Enzyme Inhibi Med Chem, 20 (2). : 165-77). They sought to improve the anti-estrogenic properties of acorbifen by making analogs in which the terminal piperidine was replaced with pyrrolidine or in various ways. All of these analogs were found to be more estrogenic than acorbifen, as revealed by the rodent uterus assay. This experience suggests that improving the anti-estrogenic properties of acorbifen is a challenge and that changes can produce unpredictable results.

Blizzard reviewed Merck's work on antiestrogens in 2008 (Curr Top Med Chem. 8 (9): 792-812). He points out:
“Selective estrogen receptor modulators (SERMs) have been the subject of numerous medicinal chemistry efforts at several pharmaceutical companies, including Merck. Chemists and biologists have been involved and have worked for several years to discover a new class of SERMs with a range of selectivity .... There are still no drugs on the market as a result of this effort. "

  In fact, Merck's efforts began in the early 1990s and continued well into the 2000s, reflecting impressive scientific research but lacking commercial products. Merck's most promising compounds, which contain a side chain in which the piperidine ring is replaced by a mono- or di-substituted pyrrolidine ring attached to the benzoxanthine nucleus, particularly the 3-R methylpyrrolidine terminus, are shown in rodent uterine assays. Although not as complete as fulvestrant, it showed antiestrogenic properties. Anti-estrogenicity also improved with chiral methyl on atom 2 of the flexible linker. The coexistence of two features in the doubly substituted side chain imparted antiestrogenic properties similar to fulvestrant. Unfortunately, Merck's nucleus was accompanied by problematic reactive metabolites when investigated in primates, which ceased clinical development.

  Aragon Pharmaceuticals is a PCT / US2011 / 035669 (2011 as WO2011 / 156518) claiming priority from US Provisional Application No. 61 / 353,531, filed June 2010 entitled “Estrogen Receptor Modulators and Uses thereof”. Issued on Dec. 15, 2000). Aragon discloses a wide variety of benzopyran derivatives and at least 71 acorbifen analogs intended for the treatment of tamoxifen-resistant breast cancer. Aragon appears to have utilized Merck's prior art teachings on how to optimize the dihydrobenzoxanthine nucleus and applied it to the acorbiphene benzopyran nucleus. Aragon is looking to advance the drug to the clinic for end-stage progressive metastatic disease.

  Kusner et al. (US 2013/0178445 and WO 2013/090921, both filed on Dec. 17, 2012 and both assigned to Olema Pharmaceuticals) are described in OP-1038 (3- (4-hydroxyphenyl) -4- Methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol) and OP-1074 ((2S) -3- (4 -Hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol), and pharmaceutical compositions and How to use is described.

  Bazedoxifene is a SERM being developed for the prevention and treatment of postmenopausal osteoporosis (Biscobing, DM (2007) Clinical interventions in aging 2 (3): 299-303). Lasofoxifene is another SERM that is being developed for the treatment of postmenopausal osteoporosis and vaginal atrophy (Gennari et al. (2006), Expert Opin Investig Drugs 15 (9): 1091-103).

  US Pat. No. 5,254,568 discloses benzopyran as an anti-estrogen agent.

  WO 2010/145010 discloses a combination of SERM and sex steroid precursors for treating hot flashes and other symptoms.

  WO 2004/091488 discloses benzopyran as an estrogen receptor modulator.

  US Pat. No. 5,840,735 discloses benzopyran as a sex steroid activity inhibitor.

  US Pat. No. 6,262,270 discloses a method for the enantiomeric synthesis of acorbiphene derivatives.

US2013 / 0178445 WO2013 / 090921 U.S. Pat. No. 4,418,068 US Pat. No. 5,478,847 US Pat. No. 5,393,763 US Pat. No. 5,457,117 US Pat. No. 4,659,516 US Pat. No. 6,774,122 US Pat. No. 7,456,160 US Pat. No. 5,395,842 US Pat. No. 6,060,503 WO01 / 54699 US Pat. No. 7,005,428 US Pat. No. 6,465,445 PCT / US2011 / 039669 (WO2011 / 156518) US Provisional Application No. 61 / 353,531 US Pat. No. 5,254,568 WO2010 / 145010 WO2004 / 091488 US Pat. No. 5,840,735 US Pat. No. 6,262,270 WO2003 / 062236 WO2005 / 005426 WO2008 / 032157 US 6,936,612 US7,208,489 US7,456,168 US 7,863,278 US7,345,171 US 7,781,583 WO2008 / 073785 WO2008 / 070740 WO2007 / 127183 US Patent Publication No. 20080242665 US Patent Application No. 20040192770 US Pat. No. 6,608,056 US Pat. No. 6,403,588 US Pat. No. 6,653,320 US Patent Application No. 20020161014 WO04108715 WO04108713 US Patent Application No. 20020037276 US Pat. No. 5,726,167 US Pat. No. 5,504,103 US Pat. No. 5,480,906 US Pat. No. 5,468,773 US Pat. No. 5,441,947 US Pat. No. 5,378,725 U.S. Pat. No. 3,668,222

Robertson et al., J Clin Oncol (2009) 27 (27): 4530-5. Jordan, J.M. Cell. Biochem. 51 (1995) Dodge et al. Bone Miner. Res. , 8 (Special Issue 1, S278 (1993) Wakeling, Breast Cancer Res. Treat. 25, 1 (1993) Baer et al., Calcified Tissue Int. 55, 338 (1994) Wu et al., Mol Cell. 18, 413 (2005) Sharma et al. (1990) J Med Chem, 33 (12): 3222-9. Sharma et al. (1990) J Med Chem, 33 (12): 3216-22. Katzenellenbogen, (2011) J Med Chem 54 (15): 5271-82. 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 Blizzard et al. (2005) Bioorg Med Chem Lett. 15 (1): 107-13 Blizzard et al. (2005) Bioorg Med Chem Lett. 15 (6): 1675-81 Blizzard et al. (2005) Bioorg Med Chem Lett. 15 (17): 3912-6 Blizzard et al. (2005) Bioorg Med Chem Lett. 15 (23): 5214-8 Gauthier et al., (2005) J Enzyme Inhibi Med Med, 20 (2): 165-77. Curr Top Med Chem. 8 (9): 792-812 Biskobing, D.B. M.M. (2007) Clinical interventions in aging 2 (3): 299-303 Gennari et al. (2006), Expert Opin Investig Drugs 15 (9): 1091-103. Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania Lindmo et al., Journal of Cell Science 119, 605-614, 2006. Hayagawa et al., Bioorganic & Medicinal Chemistry 14 6847-6858, 2006. Stephens et al., Current Opinion in Pharmacology, 5 (4) 357-365, 2005. Hayagawa et al., Bioorg Med Chem 14 (20), 6847-6858 (2006). Folkes et al., Journal of Medicinal Chemistry, 51, 5522-5532, 2008. Zhu et al., Cancer Res. 64 (12): 4309-18, 2004. Meillet et al., Oncol. Res. 14: 513-27, 2004. Tabellini et al., Br. J. et al. Haematol. 126 (4): 574-82, 2004. Vlahos et al. Biol. Chem. 269 (7) 5241-5248, 1994 Geng et al., Cancer Res. 64: 4893-99, 2004. Ihle et al., Mol Cancer Ther. 3 (7): 763-72, 2004 Hortobagyi, Drugs, 54 (Special Issue 4): 1-7 (1997) Minotti et al., Pharmacology. Rev. 56: 185-229 (2004) T. T. et al. W. Greene and P.M. G. M.M. Wuts, Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 J. et al. Jacques, A.M. Collet, and S.M. H. "Enantiomers, Racemates and Resolutions" by Wilen, (Wiley-Interscience, New York, 1981) S. H. Wilen, A.M. Collet, and J.M. Jacques, Tetrahedron 33, 2725 (1977) E. L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) S. H. Wilen, Tables of Resolving Agents and Optical Resolutions, 268 pages (E.L. Eliel, Univ. Of Notre Name Press, Notre Name, IN, 1972) Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. et al. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.) Stereoselective Synthesis A Practical Approach, Mihary Nogradi (1995 VCH Publishers, Inc., NY, NY) Bigley et al., 1995, Salt Forms of Drugs and Adsorption, Source: Encyclopedia of Pharmaceutical Technology, Vol. 13, edited by Swarbrick and Boykland, Marky D. ten Hoeve and H.W. Wynberg, 1985, Journal of Organic Chemistry 50: 4508-4514. Dale and Mosher, 1973, J. MoI. Am. Chem. Soc. 95: 512 CRC Handbook of Optical Resolution via Diatomeric Salt Formation Berge et al. Pharm. Sci. 66 (1): 1-79 (January 1977)

  Accordingly, there is a need for new combinations and pharmaceutical compositions for treating medical disorders mediated or affected by estrogen receptors.

  Each of the embodiments described below can be combined with any other embodiment described herein that is not in conflict with the combined embodiments. The expression “or a pharmaceutically acceptable salt thereof” is potentially included in the description of all compounds described herein, but in one aspect of any of the embodiments herein, the compound is , In the form of the free base.

  Embodiments described herein are methods of treating a disorder modulated, mediated, or affected by an estrogen receptor in a subject comprising:

［式中、Ｒ_１およびＲ_２は、独立に、ＯＨまたはＯＲ^９であり、
Ｒ^９は、Ｈ、ハロゲン（Ｃｌ、Ｂｒ、ＩまたはＦ）、天然もしくは天然に存在しないアミノ酸（ＯＣ（Ｏ）−もしくはＣ（Ｏ）Ｏ−（エステル）またはアミノ（−Ｃ（Ｏ）−Ｎ−または−Ｎ−Ｃ（Ｏ）−（アミド結合）を介する）のいずれかを介して結合したもの）、Ｒ^１０、−ＯＲ^１０、または−ＳＲ^１０から独立に選択され、
Ｒ^１０は、−Ｃ（＝Ｏ）Ｒ^Ｃ１、−Ｃ（＝Ｏ）ＯＲ^Ｃ１、−Ｃ（＝Ｏ）ＳＲ^Ｃ１、−Ｃ（＝Ｏ）Ｎ（Ｒ^Ｃ１）_２、または
ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリール、
−Ｓ（＝Ｏ）_２Ｒ^Ｃ１、−Ｓ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｓ（＝Ｏ）Ｒ^Ｃ１、−Ｓ（＝Ｏ）ＯＲ^Ｃ１、−Ｐ（＝Ｏ）_２Ｒ^Ｃ１、−Ｐ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｐ（＝Ｏ）（ＯＲ^Ｃ１）_２、−Ｐ（＝Ｏ）（Ｒ^Ｃ１）_２、もしくは−Ｐ（Ｒ^Ｃ１）（ＯＲ^Ｃ１）、または
酸素保護基に結合している酸素（投与されるとＯＨを生じる）、硫黄保護基に結合している硫黄（投与されるとＳＨまたはジスルフィドを生じる）、もしくは窒素保護基に結合している窒素（投与されると−ＮＨ−を生じる）であり、
Ｒ^Ｃ１は、水素、ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールから独立に選択することができ、または２つのＲ^Ｃ１基が合わさって、置換もしくは非置換ヘテロ環を形成している］
である化合物または薬学的に許容できるその塩、溶媒和物、水和物、プロドラッグ、立体異性体、互変異性体、もしくはＮ−オキシドを、
ｍＴＯＲ阻害薬、ＣＤＫ４／６阻害薬、ＰＩ３キナーゼ阻害薬、タキサン、代謝拮抗薬、および抗腫瘍抗生物質からなる群から選択される薬剤と組み合わせて対象に投与することを含む方法に関する。

[Wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle]
Or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide thereof,
It relates to a method comprising administering to a subject in combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.

  In an embodiment of the method of the present invention, the compound is in the form of a pharmaceutically acceptable salt.

In an embodiment of the method of the present invention, either or both R ₁ or R ₂ is an ester, amide, carbonate, or phosphate.

  In an embodiment of the methods of the invention, the compound is in the form of a prodrug, and further the prodrug is

である。

It is.

  In an embodiment of the method of the invention, the compound has the chemical structure:

を有する、（２Ｓ）−３−（４−ヒドロキシフェニル）−４−メチル−２−（４−｛２−［（３Ｒ）−３−メチルピロリジン−１−イル］エトキシ｝フェニル）−２Ｈ−クロメン−７−オールまたは薬学的に許容できるその塩、溶媒和物、水和物、もしくはＮ−オキシドである。

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene -7-ol or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof.

  Embodiments described herein are methods of treating a disorder modulated, mediated, or affected by an estrogen receptor in a subject, the chemical structure:

を有する、（２Ｓ）−３−（４−ヒドロキシフェニル）−４−メチル−２−（４−｛２−［（３Ｒ）−３−メチルピロリジン−１−イル］エトキシ｝フェニル）−２Ｈ−クロメン−７−オールである化合物または薬学的に許容できるその塩を、
ｍＴＯＲ阻害薬、ＣＤＫ４／６阻害薬、ＰＩ３キナーゼ阻害薬、タキサン、代謝拮抗薬、および抗腫瘍抗生物質からなる群から選択される薬剤と組み合わせて対象に投与することを含む方法に関する。

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene A compound that is -7-ol or a pharmaceutically acceptable salt thereof,
It relates to a method comprising administering to a subject in combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.

  In an embodiment of the methods of the invention, the compound is administered alternately with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic. To do.

  Embodiments described herein are for treating disorders that are modulated, mediated, or affected by estrogen receptors.

である化合物
［式中、Ｒ_１およびＲ_２は、独立に、ＯＨまたはＯＲ^９であり、
Ｒ^９は、Ｈ、ハロゲン（Ｃｌ、Ｂｒ、ＩまたはＦ）、天然もしくは天然に存在しないアミノ酸（ＯＣ（Ｏ）−もしくはＣ（Ｏ）Ｏ−（エステル）またはアミノ（−Ｃ（Ｏ）−Ｎ−または−Ｎ−Ｃ（Ｏ）−（アミド結合）を介する）のいずれかを介して結合したもの）、Ｒ^１０、−ＯＲ^１０、または−ＳＲ^１０から独立に選択され、
Ｒ^１０は、−Ｃ（＝Ｏ）Ｒ^Ｃ１、−Ｃ（＝Ｏ）ＯＲ^Ｃ１、−Ｃ（＝Ｏ）ＳＲ^Ｃ１、−Ｃ（＝Ｏ）Ｎ（Ｒ^Ｃ１）_２、または
ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリール、
−Ｓ（＝Ｏ）_２Ｒ^Ｃ１、−Ｓ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｓ（＝Ｏ）Ｒ^Ｃ１、−Ｓ（＝Ｏ）ＯＲ^Ｃ１、−Ｐ（＝Ｏ）_２Ｒ^Ｃ１、−Ｐ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｐ（＝Ｏ）（ＯＲ^Ｃ１）_２、−Ｐ（＝Ｏ）（Ｒ^Ｃ１）_２、もしくは−Ｐ（Ｒ^Ｃ１）（ＯＲ^Ｃ１）、または
酸素保護基に結合している酸素（投与されるとＯＨを生じる）、硫黄保護基に結合している硫黄（投与されるとＳＨまたはジスルフィドを生じる）、もしくは窒素保護基に結合している窒素（投与されると−ＮＨ−を生じる）であり、
Ｒ^Ｃ１は、水素、ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールから独立に選択することができ、または２つのＲ^Ｃ１基が合わさって、置換もしくは非置換ヘテロ環を形成している］
または薬学的に許容できるその塩、溶媒和物、水和物、プロドラッグ、立体異性体、互変異性体、もしくはＮ−オキシドと、
ｍＴＯＲ阻害薬、ＣＤＫ４／６阻害薬、ＰＩ３キナーゼ阻害薬、タキサン、代謝拮抗薬、および抗腫瘍抗生物質からなる群から選択される薬剤と
の組合せに関する。

A compound wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle]
Or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide thereof,
It relates to a combination with a drug selected from the group consisting of mTOR inhibitors, CDK4 / 6 inhibitors, PI3 kinase inhibitors, taxanes, antimetabolites, and antitumor antibiotics.

  In an embodiment of the combination of the present invention, the compound is in the form of a pharmaceutically acceptable salt.

  In an embodiment of the combination of the present invention, the compound has the chemical structure:

を有する、（２Ｓ）−３−（４−ヒドロキシフェニル）−４−メチル−２−（４−｛２−［（３Ｒ）−３−メチルピロリジン−１−イル］エトキシ｝フェニル）−２Ｈ−クロメン−７−オールまたは薬学的に許容できるその塩、溶媒和物、水和物、もしくはＮ−オキシドである。

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene -7-ol or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof.

  Embodiments described herein include chemical structures for treating disorders that are modulated, mediated, or affected by estrogen receptors:

を有する、（２Ｓ）−３−（４−ヒドロキシフェニル）−４−メチル−２−（４−｛２−［（３Ｒ）−３−メチルピロリジン−１−イル］エトキシ｝フェニル）−２Ｈ−クロメン−７−オールまたは薬学的に許容できるその塩と、
ｍＴＯＲ阻害薬、ＣＤＫ４／６阻害薬、ＰＩ３キナーゼ阻害薬、タキサン、代謝拮抗薬、および抗腫瘍抗生物質からなる群から選択される薬剤と
の組合せに関する。

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene -7-ol or a pharmaceutically acceptable salt thereof,
It relates to a combination with a drug selected from the group consisting of mTOR inhibitors, CDK4 / 6 inhibitors, PI3 kinase inhibitors, taxanes, antimetabolites, and antitumor antibiotics.

  In embodiments of the methods and combinations of the invention, the disorder is mediated by an estrogen receptor.

  In embodiments of the methods and combinations of the present invention, the disorder is breast cancer.

  In embodiments of the methods and combinations of the invention, the breast cancer is a local, advanced, or metastatic estrogen or progesterone receptor positive advanced breast cancer.

  In embodiments of the methods and combinations of the invention, the breast cancer is estrogen or progesterone receptor positive advanced breast cancer.

  In embodiments of the methods and combinations of the invention, the breast cancer is estrogen or progesterone receptor negative breast cancer.

  In embodiments of the methods and combinations of the present invention, the disorder is selected from the group consisting of ovarian cancer, endometrial cancer, vaginal cancer, endometriosis, lung cancer, and bronchial cancer.

  In embodiments of the methods and combinations of the present invention, the disorder is selected from the group consisting of ovarian cancer, endometrial cancer, vaginal cancer, and endometriosis.

  In embodiments of the methods and combinations of the invention, the disorder is retinoblastoma positive breast cancer.

  In embodiments of the methods and combinations of the invention, the disorder is selected from the group consisting of retinoblastoma positive endometrial cancer, vaginal cancer, and ovarian cancer, lung cancer and bronchial cancer.

  In embodiments of the methods and combinations of the present invention, the disorder is lung cancer or bronchial cancer.

  In embodiments of the methods and combinations of the present invention, the subject is a patient.

  In embodiments of the methods and combinations of the invention, the agent is a CDK4 / 6 inhibitor.

  In embodiments of the methods and combinations of the invention, the CDK4 / 6 inhibitor is PD-0332991, LY2835219, or LEE011.

  In an embodiment of the methods and combinations of the invention, the CDK4 / 6 inhibitor is PD-0332991 or a pharmaceutically acceptable salt thereof.

  In an embodiment of the methods and combinations of the invention, the CDK4 / 6 inhibitor is PD-0332991.

  In embodiments of the methods and combinations of the invention, the agent is an mTOR inhibitor.

  In embodiments of the methods and combinations of the invention, the mTOR inhibitor is rapamycin, everolimus, temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, or Pp121.

  In embodiments of the methods and combinations of the invention, the mTOR inhibitor is everolimus.

  In embodiments of the methods and combinations of the invention, the agent is a PI3 kinase inhibitor.

  In embodiments of the methods and combinations of the invention, the PI3 kinase inhibitor is BKM-120, XL-147, RG-7321, CH-5132799, and BAY-80-6946.

  In embodiments of the methods and combinations of the invention, the PI3 kinase inhibitor is BKM-120.

  In embodiments of the methods and combinations of the invention, the agent is a taxane.

  In embodiments of the methods and combinations of the present invention, the taxane is paclitaxel or docetaxel.

  In embodiments of the methods and combinations of the invention, the agent is an antimetabolite.

  In an embodiment of the method of the invention, the antimetabolite is 5-fluorouracil.

  In embodiments of the methods and combinations of the invention, the agent is an antitumor antibiotic.

  In embodiments of the methods and combinations of the invention, the anti-tumor antibiotic is doxorubicin.

  The embodiments described herein are:

［式中、Ｒ_１およびＲ_２は、独立に、ＯＨまたはＯＲ^９であり、
Ｒ^９は、Ｈ、ハロゲン（Ｃｌ、Ｂｒ、ＩまたはＦ）、天然もしくは天然に存在しないアミノ酸（ＯＣ（Ｏ）−もしくはＣ（Ｏ）Ｏ−（エステル）またはアミノ（−Ｃ（Ｏ）−Ｎ−または−Ｎ−Ｃ（Ｏ）−（アミド結合）を介する）のいずれかを介して結合したもの）、Ｒ^１０、−ＯＲ^１０、または−ＳＲ^１０から独立に選択され、
Ｒ^１０は、−Ｃ（＝Ｏ）Ｒ^Ｃ１、−Ｃ（＝Ｏ）ＯＲ^Ｃ１、−Ｃ（＝Ｏ）ＳＲ^Ｃ１、−Ｃ（＝Ｏ）Ｎ（Ｒ^Ｃ１）_２、または
ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリール、
−Ｓ（＝Ｏ）_２Ｒ^Ｃ１、−Ｓ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｓ（＝Ｏ）Ｒ^Ｃ１、−Ｓ（＝Ｏ）ＯＲ^Ｃ１、−Ｐ（＝Ｏ）_２Ｒ^Ｃ１、−Ｐ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｐ（＝Ｏ）（ＯＲ^Ｃ１）_２、−Ｐ（＝Ｏ）（Ｒ^Ｃ１）_２、もしくは−Ｐ（Ｒ^Ｃ１）（ＯＲ^Ｃ１）、または
酸素保護基に結合している酸素（投与されるとＯＨを生じる）、硫黄保護基に結合している硫黄（投与されるとＳＨまたはジスルフィドを生じる）、もしくは窒素保護基に結合している窒素（投与されると−ＮＨ−を生じる）であり、
Ｒ^Ｃ１は、水素、ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールから独立に選択することができ、または２つのＲ^Ｃ１基が合わさって、置換もしくは非置換ヘテロ環を形成している］
である薬学的有効量の化合物または薬学的に許容できるその塩、溶媒和物、水和物、プロドラッグ、立体異性体、互変異性体、もしくはＮ−オキシドを、
ｍＴＯＲ阻害薬、ＣＤＫ４／６阻害薬、ＰＩ３キナーゼ阻害薬、タキサン、代謝拮抗薬、および抗腫瘍抗生物質からなる群から選択される薬剤と組み合わせたものと、
薬学的に許容できる担体とを含む医薬組成物に関する。

[Wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle]
A pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide thereof,
in combination with a drug selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic;
It relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

  In an embodiment of the pharmaceutical composition of the present invention, the compound is in the form of a pharmaceutically acceptable salt.

In an embodiment of the pharmaceutical composition of the present invention, R ₁ or R ₂ is an ester, amide, carbonate, or phosphate.

  In an embodiment of the pharmaceutical composition of the present invention, the compound is in the form of a prodrug, and the prodrug further comprises

である。

It is.

  In an embodiment of the pharmaceutical composition of the invention, the compound has the chemical structure:

を有する、（２Ｓ）−３−（４−ヒドロキシフェニル）−４−メチル−２−（４−｛２−［（３Ｒ）−３−メチルピロリジン−１−イル］エトキシ｝フェニル）−２Ｈ−クロメン−７−オールまたは薬学的に許容できるその塩、溶媒和物、水和物、もしくはＮ−オキシドである。

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene -7-ol or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof.

  Embodiments described herein include chemical structures:

を有する、（２Ｓ）−３−（４−ヒドロキシフェニル）−４−メチル−２−（４−｛２−［（３Ｒ）−３−メチルピロリジン−１−イル］エトキシ｝フェニル）−２Ｈ−クロメン−７−オールである化合物または薬学的に許容できるその塩を、
ｍＴＯＲ阻害薬、ＣＤＫ４／６阻害薬、ＰＩ３キナーゼ阻害薬、タキサン、代謝拮抗薬、および抗腫瘍抗生物質からなる群から選択される薬剤と組み合わせたものと、薬学的に許容できる担体とを含む本発明の医薬組成物に関する。

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene A compound that is -7-ol or a pharmaceutically acceptable salt thereof,
A book comprising a combination of a drug selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic, and a pharmaceutically acceptable carrier It relates to the pharmaceutical composition of the invention.

  In an embodiment of the pharmaceutical composition of the present invention, the drug is a CDK4 / 6 inhibitor.

  In an embodiment of the pharmaceutical composition of the invention, the CDK4 / 6 inhibitor is PD-0332991, LY2835219, or LEE011.

  In an embodiment of the pharmaceutical composition of the present invention, the CDK4 / 6 inhibitor is PD-0332991 or a pharmaceutically acceptable salt thereof.

  In an embodiment of the pharmaceutical composition of the present invention, the CDK4 / 6 inhibitor is PD-0332991.

  In an embodiment of the pharmaceutical composition of the present invention, the drug is an mTOR inhibitor.

  In an embodiment of the pharmaceutical composition of the invention, the mTOR inhibitor is rapamycin, everolimus, temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, or Pp121.

  In an embodiment of the pharmaceutical composition of the invention, the mTOR inhibitor is everolimus.

  In an embodiment of the pharmaceutical composition of the present invention, the drug is a PI3 kinase inhibitor.

  In embodiments of the pharmaceutical composition of the invention, the PI3 kinase inhibitor is BKM-120, XL-147, RG-7321, CH-5132799, and BAY-80-6946.

  In an embodiment of the pharmaceutical composition of the present invention, the PI3 kinase inhibitor is BKM-120.

  In an embodiment of the pharmaceutical composition of the present invention, the drug is a taxane.

  In an embodiment of the pharmaceutical composition of the present invention, the taxane is paclitaxel or docetaxel.

  In an embodiment of the pharmaceutical composition of the present invention, the drug is an antimetabolite.

  In an embodiment of the pharmaceutical composition of the present invention, the antimetabolite is 5-fluorouracil.

  In an embodiment of the pharmaceutical composition of the present invention, the drug is an antitumor antibiotic.

  In an embodiment of the pharmaceutical composition of the present invention, the antitumor antibiotic is doxorubicin.

  The present invention relates to a specific benzopyran described in US 2013/0178445 and WO 2013/090921 (mixture of S-C2 and R-C2 diastereoisomers and also in the form of its pure S-diastereoisomer) Mediated by estrogen receptors, in combination with drugs, active agents, anticancer drugs, or chemotherapeutic drugs, or in alternating combinations, and in some embodiments, in certain improved dosages or formulations It relates to the treatment of tumors including cancer. Benefits that can be obtained include increased efficacy and / or lower doses when using a specified combination. Tumors, including cancer, that benefit from such a combination or alternation are tumors that are mediated by estrogen receptors and also respond to a second agent. Specific examples of agents, active agents, anticancer agents, or chemotherapeutic agents that can be combined with the compounds described in US 2013/0178445 and WO 2013/090921 include mTOR inhibitors such as everolimus, or CDK4 such as PD-0332991 / 6 inhibitors, or PI3 kinase inhibitors such as BKM-120, or taxanes, or antimetabolites such as 5-fluorouracil, or antitumor antibiotics such as doxorubicin. In one embodiment, the combination therapy is described to treat retinoblastoma positive breast cancer and retinoblastoma positive endometrial cancer, vaginal cancer, and ovarian cancer, lung cancer and bronchial cancer. Of an anti-estrogen compound in combination with PD-0332991.

  As used herein, the term “combination of the invention” or the like (eg, “in combination with”) refers to one or more of the compounds described in US 2013/0178445 and WO 2013/090921, as a drug, an active agent, It refers to the concerted use with anti-cancer drugs or chemotherapeutic drugs, where concerted use is either (i) a pharmaceutically acceptable formulation containing both active agents, or (ii) each active agent separately Even in separate pharmaceutical formulations that are administered either simultaneously or at different times, but in either a concerted and concurrent fashion (ie, alternation therapy) in a manner that optimizes the benefits of combination therapy Good. For example, certain active agents are usually administered orally, such as in tablets, pills, or liquids, and other active agents are intravenously injected or other systemic, topical, parenteral, transdermal routes, Or it may be normally administered by another route.

  Compounds that can be combined or alternated with drugs, active agents, anti-cancer drugs, or chemotherapeutic agents are described in US 2013/0178445 and WO 2013/090921, and are hereinafter referred to as OP-1038 and OP-1074 Show. The chemical name of OP-1038 is 3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H- Chromen-7-ol. The chemical name of OP-1074 is (2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl ) -2H-chromen-7-ol.

Active compounds in combination or alternating with drugs, active drugs, anti-cancer drugs, or chemotherapeutic drugs are optimally estrogen-receptive, including tumors that can be treated with anti-estrogen compounds that are substantially free of estrogenic effects To treat a tumor that is modulated or affected by the body, a pharmaceutically acceptable salt, solvate, hydrate, prodrug, steric, optionally in a pharmaceutically acceptable composition, if desired. It can be provided as an isomer, tautomer, N-oxide, or derivative substituted with R ₁ and / or R ₂ .

  OP-1038 and OP-1074 have two chiral carbons and therefore have four diastereoisomers. The chiral carbon at the C2 position is in the S configuration (EM-652, i.e. the same configuration in acorbifen) in OP-1074, and is a mixture of R and S in OP-1038.

  OP-1038, OP-1074, and prodrugs thereof (including esters, carbonates, and phosphates), derivatives, and salts thereof in combination with certain drugs, active drugs, anticancer drugs, or chemotherapeutic drugs Sometimes locally advanced or metastatic breast cancer that is positive for the expression of estrogen receptor, progesterone receptor, or both, and is also responsive to certain drugs, active drugs, anticancer drugs, or chemotherapeutic drugs It is particularly useful for the treatment of (receptor positive advanced breast cancer). In an alternative embodiment, the combination is used to treat estrogen or progesterone receptor negative breast cancer. The combination can be used as an initial treatment for advanced breast cancer in patients who have not previously received hormonal therapy for advanced breast cancer. Specific examples of active agents that can be combined with the compounds described in US2013 / 0178445 and WO2013 / 090921 include mTOR inhibitors such as everolimus, or CDK4 / 6 inhibitors such as PD-0332991, or PI3 such as BKM-120. Kinase inhibitors, or taxanes, or antimetabolites such as 5-fluorouracil, or antitumor antibiotics such as doxorubicin. In one embodiment, the combination therapy is US 2013 to treat retinoblastoma positive breast cancer and retinoblastoma positive endometrial cancer, vagina cancer, and ovarian cancer, lung cancer and bronchial cancer. / 0178445 and WO2013 / 090921 in combination with PD-0332991.

  The combinations described in the present invention are also useful as adjuvant therapy after surgery to prevent recurrence. In such ancillary use, administration is often done for several years after the surgery and associated chemotherapy and radiation therapy are completed, for example, for 5 years or even at most 10 years. In one embodiment, the adjuvant combination therapy is for treating retinoblastoma positive breast cancer and retinoblastoma positive endometrial cancer, vagina cancer, and ovarian cancer, lung cancer and bronchial cancer. US2013 / 0178445 and WO2013 / 090921 in combination with PD-0332991.

  The combinations described in the present invention are also useful for preventing breast cancer in women at high risk of breast cancer, and can be taken for any desired period, including indefinite periods. For example, a patient, usually a woman who has a family history of breast cancer or who has been determined to have a mutation in the BRCA1 or BRCA2 gene or other genes that make the patient susceptible to breast cancer, The use of such prophylactic treatment can be selected instead of therapeutic intervention. The combinations described herein are also useful as neoadjuvants that allow large tumors to shrink prior to surgical resection to allow for conservative breast surgery and reduce the risk of recurrence. In addition to breast cancer, these combinations are also used to treat other cancers of the female reproductive system and other overgrowth diseases, including ovarian cancer, endometrial cancer, vaginal cancer, and endometriosis. Useful. In addition to these reproductive tissues, the combination is useful in the treatment of lung cancer that is positive for estrogen or progesterone receptors. When such cancers are retinoblastoma positive, the combination of compounds described in US 2013/0178445 and WO 2013/090921 with PD-0332991 is beneficial.

  Other objects and advantages will become apparent to those skilled in the art upon consideration of the detailed description that follows. All variations and modifications of the disclosed invention are considered to be within the scope of the invention.

FIG. 5 is a graph showing that OP-1074 increases the potency and efficacy of the CDK4 / 6 inhibitor PD-0332991 in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The antiestrogen drug OP-1074 enhances the efficacy and efficacy of PD-0332991 in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of antiestrogens and PD-0332991 in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium for 6-7 days. FIG. 1A plots the effect of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of PD-0332991 on MCF-7 cell proliferation. FIG. 1B plots the effect of medium combined with increasing amounts of OP-1074 or 100 nM PD-0332991 on MCF-7 cell proliferation. FIG. 1C plots the effect of increasing amounts of PD-0332991 in combination with 3 nM OP-1074, Tamoxifen, or fulvestrant on MCF-7 cell proliferation. Proliferation was measured using a Cyquant fluorescent DNA binding dye (Invitrogen, Grand Island, NY). Results are from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars represent SEM. FIG. 7 is a graph showing that OP-1074 increases the efficacy of the mTOR inhibitor everolimus in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The anti-estrogen drug OP-1074 enhances the efficacy and efficacy of the mTOR inhibitor everolimus in the inhibition of breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and everolimus for 6 days in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium. FIG. 2A plots the effect of vehicle, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of everolimus on MCF-7 cell proliferation. FIG. 2B plots the effect of 1 nM or 10 nM everolimus on MCF-7 cell proliferation in combination with increasing amounts of OP-1074. FIG. 2C plots the effect of media combined with increasing amounts of everolimus, or 3 nM OP-1074, Tamoxifen, or fulvestrant on MCF-7 cell proliferation. Proliferation was measured as in FIG. 1 and results were from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars indicate SEM. Represent. FIG. 5 is a graph showing that OP-1074 increases the potency of the universal PI3K inhibitor BKM-120 in inhibiting MCF-7 breast cell proliferation stimulated by E2. The anti-estrogen drug OP-1074 enhances the efficacy and potency of the PI3K inhibitor BKM-120 in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and BKM-120 in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium for 7 days. FIG. 3A plots the effect of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of BKM-120 on MCF-7 cell proliferation. FIG. 3B plots the effect of 32 nM or 100 nM BKM-120 on increasing MCF-7 cell proliferation in combination with increasing amounts of OP-1074. Proliferation was measured as in FIG. 1 and results were from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars indicate SEM. Represent. FIG. 5 is a graph showing that OP-1074 increases the efficacy of 5-fluorouracil in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The anti-estrogen drug OP-1074 enhances the efficacy and efficacy of the thymidylate synthase inhibitor 5-fluorouracil in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and 5-fluorouracil for 6 days in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium. The effects of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of 5-fluorouracil on MCF-7 cell proliferation are plotted. Proliferation was measured as in FIG. 1 and results were from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars indicate SEM. Represent. FIG. 5 is a graph showing that OP-1074 increases the efficacy of taxanes in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The antiestrogen agent OP-1074 enhances the efficacy and efficacy of paclitaxel and docetaxel in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and taxane in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium for 6 days. FIG. 5A plots the effect of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of paclitaxel on MCF-7 cell proliferation. FIG. 5B plots the effect of vehicle, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of docetaxel on MCF-7 cell proliferation. Proliferation was measured as in FIG. 1 and results were from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars indicate SEM. Represent. FIG. 5 is a graph showing that OP-1074 increases the efficacy of anthracycline xorubicin in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The antiestrogen OP-1074 enhances the efficacy and efficacy of anthracycline xorubicin in inhibiting in vitro breast cell proliferation stimulated by E2. MCF-7 cells were treated with the indicated amounts of OP-1074 and doxorubicin for 7 days in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium. The effects of vehicle, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of doxorubicin on MCF-7 cell proliferation are plotted. Proliferation was measured as in FIG. 1 and results were from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars indicate SEM. Represent.

  The present invention relates to a specific benzopyran described in US 2013/0178445 and WO 2013/090921 (mixture of S-C2 and R-C2 diastereoisomers and also in the form of its pure S-diastereoisomer) Mediated by estrogen receptors, in combination with drugs, active agents, anticancer drugs, or chemotherapeutic drugs, or in alternating combinations, and in some embodiments, in certain improved dosages or formulations It relates to the treatment of tumors including cancer. Benefits that can be obtained include increased efficacy and / or lower doses when using a specified combination. Cancers that benefit from such a combination or alternation are cancers that are mediated by the estrogen receptor and also respond to a second agent. Specific examples of agents, active agents, anticancer agents, or chemotherapeutic agents that can be combined with the compounds described in US 2013/0178445 and WO 2013/090921 include mTOR inhibitors such as everolimus, or CDK4 such as PD-0332991 / 6 inhibitors, or PI3 kinase inhibitors such as BKM-120, or taxanes, or antimetabolites such as 5-fluorouracil, or antitumor antibiotics such as doxorubicin. In one embodiment, the combination therapy is described to treat retinoblastoma positive breast cancer and retinoblastoma positive endometrial cancer, vaginal cancer, and ovarian cancer, lung cancer and bronchial cancer. Of an anti-estrogen compound in combination with PD-0332991.

Compounds provided in combination or alternation with certain drugs, active drugs, anti-cancer drugs, or chemotherapeutic drugs are estrogen, including disorders treatable with anti-estrogen compounds with substantially no estrogenic effect A pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomerism, if desired, to treat a receptor mediated, modulated, or affected disorder. Body, N-oxide, or a derivative substituted with R ₁ and / or R ₂ , or a pharmaceutically acceptable composition.

［式中、Ｒ_１およびＲ_２は、独立に、ＯＨまたはＯＲ^９であり、
Ｒ^９は、Ｈ、ハロゲン（Ｃｌ、Ｂｒ、ＩまたはＦ）、天然もしくは天然に存在しないアミノ酸（ＯＣ（Ｏ）−もしくはＣ（Ｏ）Ｏ−（エステル）またはアミノ（−Ｃ（Ｏ）−Ｎ−または−Ｎ−Ｃ（Ｏ）−（アミド結合）を介する）のいずれかを介して結合したもの）、Ｒ^１０、−ＯＲ^１０、または−ＳＲ^１０から独立に選択され、
Ｒ^１０は、−Ｃ（＝Ｏ）Ｒ^Ｃ１、−Ｃ（＝Ｏ）ＯＲ^Ｃ１、−Ｃ（＝Ｏ）ＳＲ^Ｃ１、−Ｃ（＝Ｏ）Ｎ（Ｒ^Ｃ１）_２、または
ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリール、
−Ｓ（＝Ｏ）_２Ｒ^Ｃ１、−Ｓ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｓ（＝Ｏ）Ｒ^Ｃ１、−Ｓ（＝Ｏ）ＯＲ^Ｃ１、−Ｐ（＝Ｏ）_２Ｒ^Ｃ１、−Ｐ（＝Ｏ）_２ＯＲ^Ｃ１、−Ｐ（＝Ｏ）（ＯＲ^Ｃ１）_２、−Ｐ（＝Ｏ）（Ｒ^Ｃ１）_２、もしくは−Ｐ（Ｒ^Ｃ１）（ＯＲ^Ｃ１）、または
酸素保護基に結合している酸素（投与されるとＯＨを生じる）、硫黄保護基に結合している硫黄（投与されるとＳＨまたはジスルフィドを生じる）、もしくは窒素保護基に結合している窒素（投与されると−ＮＨ−を生じる）であり、
Ｒ^Ｃ１は、水素、ポリエチレングリコール、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールから独立に選択することができ、または２つのＲ^Ｃ１基が合わさって、置換もしくは非置換ヘテロ環を形成している］。

[Wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Can be independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle].

In certain embodiments, either R ₁ or R ₂ or both are esters, amides, carbonates, or phosphates.

  Specific examples of prodrugs of the described compounds that can be combined or alternated with certain drugs, active drugs, anticancer drugs, or chemotherapeutic drugs are as follows:

  Examples of useful prodrug groups that are cleaved by metabolism include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

  OP-1038, OP-1074, and prodrugs (including esters, carbonates, and phosphates), derivatives, and combinations of these salts described in US 2013/0178445 and WO 2013/090921 are specific drugs, active drugs, Particularly useful in the treatment of locally advanced or metastatic breast cancer (receptor positive advanced breast cancer) that is positive for the expression of estrogen receptor, progesterone receptor, or both when combined with anticancer drugs or chemotherapeutic drugs . In an alternative embodiment, this combination is used to treat estrogen or progesterone receptor negative breast cancer. Specific examples of active agents that can be combined with the compounds of the present invention include mTOR inhibitors such as everolimus, or CDK4 / 6 inhibitors such as PD-0332991, or PI3 kinase inhibitors such as BKM-120, or taxanes, Or an antimetabolite such as 5-fluorouracil, or an antitumor antibiotic such as doxorubicin.

  In one embodiment, the compounds described in US2013 / 0178445 and WO2013 / 090921 can be combined with a CDK4 / 6 inhibitor, such as PD-0332991. In another embodiment, OP-1074 is combined with PD-0332991.

  In one embodiment, the compounds described in US2013 / 0178445 and WO2013 / 090921 can be combined with mTOR inhibitors, such as everolimus. In another embodiment, OP-1074 is combined with everolimus.

  In one embodiment, the compounds described in US2013 / 0178445 and WO2013 / 090921 can be combined with a PI3 kinase inhibitor, such as BKM-120. In another embodiment, OP-1074 is combined with BKM-120.

  In one embodiment, the compounds described in US 2013/0178445 and WO 2013/090921 can be combined with a taxane, such as paclitaxel or docetaxel. In another embodiment, OP-1074 is combined with paclitaxel or docetaxel.

  In one embodiment, the compounds described in US 2013/0178445 and WO 2013/090921 can be combined with an antimetabolite, such as 5-fluorouracil. In another embodiment, OP-1074 is combined with 5-fluorouracil.

  In one embodiment, the compounds described in US 2013/0178445 and WO 2013/090921 can be combined with antitumor antibiotics, such as doxorubicin. In another embodiment, OP-1074 is combined with doxorubicin.

  A composition is described in which the compounds described in US2013 / 0178445 and WO2013 / 090921 are combined or alternated in combination with certain drugs, active agents, anticancer drugs, or chemotherapeutic agents. The composition can be administered as a pharmaceutical composition suitable for oral delivery to a patient, usually a human. Alternatively, the compounds include, for example, any controlled delivery method using degradable polymers or using nano- or microparticles, liposomes, layered tablets, or other structural frameworks that slow delivery. It can also be delivered in a carrier suitable for the topical, transdermal (including by patch), intravenous, parenteral, buccal, subcutaneous, or other desired delivery route.

  The composition can be in the form of a salt of the active agent. The composition is a pharmaceutically acceptable salt such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, hydrogensulfate, phosphate, acetate, lactate, citrate , Tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like, and can be administered as a pharmaceutically acceptable acid addition salt.

  The composition is used to treat or prevent disorders modulated by estrogen receptors in animals, usually mammals, most typically humans.

  The combination can also be used as an adjunct therapy. For example, a therapeutically effective amount of a compound can be used in combination with another anticancer drug, particularly for estrogen receptor positive breast cancer, and in some embodiments, for estrogen receptor negative breast cancer.

  In another aspect of embodiments of the present invention, selecting one of a plurality of treatment plans and setting a dosage to be delivered to the patient after a weekly, monthly or quarterly period has elapsed. A method for treating a patient with a combination of treatment plans that are administered orally once a day. Some embodiments of the present invention facilitate selection of a combination treatment plan and / or change of dosage or setting of dosage over time of a treatment plan. Combinations of compounds of the present invention with other active agents, particularly other agents, active agents, anticancer agents, or chemotherapeutic agents, are single fixed dose combinations such as multipills, combopills, or polypills Can be done as a pill. Polypills are pharmaceutical products that are drug products in pill form (ie, tablets or capsules) that combine multiple active pharmaceutical ingredients. In one embodiment, the polypill is manufactured as a fixed dose combination (FDC) drug product for the treatment or prevention of disease. Polypills can reduce the number of tablets or capsules that need to be taken (generally administered orally), which can facilitate the handling and administration of the medication and reduce the patient's pill burden. The Sometimes (especially in the case of mass-produced polypills, or FDCs), all of the drugs in a given polypill are all a single basis for which a given drug / dosage combination may be appropriate It may be aimed at a state (or a collection of related states). In addition to the fixed dose polypills noted, polypills can also be tailored for specific patients via a process called dispensing.

  In an alternative embodiment, the present invention also allows physicians or other health care providers to combine or alternate dose packaging (in multiple treatment plans), rather than integrating specialized combinations of pharmaceuticals into a single treatment plan. Deliver medicines once a day, more than once a day, every other day, every third day, twice a week, once a week, once a week, every other month, etc.) to increase compliance with medical therapy It relates to a protocol that can

  The present invention is useful for treating multiple pills in cancer patients, particularly breast cancer, as well as other estrogen-mediated diseases and related health problems that would benefit the compounds of the present invention. Providing a protocol incorporated into a combination dose package or polypill corresponding to the above-described combination therapies used for unit, monthly, quarterly or longer periods.

  The present invention provides a combined dose over a period of time (eg, week, month, quarter, or longer), over which period the physician sets the dosage based on the patient's condition (the dosage of each active therapeutic ingredient) The patient's compliance can be further increased. If necessary, the combination treatment pack may provide alternative dosages for treatment more than once a day.

  Additional embodiments within the scope provided herein are described in a non-limiting manner elsewhere in the specification and in the examples. It should be understood that such examples are for illustrative purposes only and are not to be construed as limiting in any way.

Pharmaceutical composition As used herein, the term “a combination of the present invention” and the like refers to one or more of the compounds described in US2013 / 0178445 and WO2013 / 090921, as a drug, active drug, anticancer drug, or chemical. It refers to concerted use with therapeutic agents, where concerted use is either (i) a pharmaceutically acceptable formulation comprising both active agents, or (ii) providing each active agent separately, simultaneously, or It may be a separate pharmaceutical formulation that is administered at any one time, but in any of the concerted and concurrent forms (ie, alternation therapy) in a manner that optimizes the benefits of the combination therapy. For example, certain active agents are usually administered orally, such as in tablets, pills, or liquids, and other active agents are intravenously injected or other systemic, topical, parenteral, transdermal routes, Or it may be normally administered by another route. Thus, a “pharmaceutical composition” is compatible with the carrier, dosage, dosing schedule, drug holiday potential, and other general differences in physical properties, convenience, efficacy, toxicity, and dosing schedule Depending on sex, it may contain either one of the active agents or a combination of agents, based on how best the active agent is administered.

  In one aspect, the invention provides a pharmaceutically effective amount of a compound described in US 2013/0178445 and WO 2013/090921 in combination with a particular drug, active agent, anticancer drug, or chemotherapeutic agent, And an acceptable carrier. The dosage of the composition is usually determined by a physician in the context of the condition being 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.

  The pharmaceutical compositions provided herein are suitable pharmaceutical carriers for such administration by a variety of routes including oral, topical, parenteral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Can be administered. In one embodiment, 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. Usually the composition is in unit dosage form to facilitate accurate dosing. The term “unit dosage form” is calculated such that each unit, in combination with an appropriate pharmaceutical excipient, produces the desired therapeutic effect, suitable as a unit dosage for human subjects and other mammals. Refers to a physically separate unit containing a predetermined amount of active material. Typical unit dosage forms include pre-filled and pre-metered ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, and the like. In such compositions, the compound is usually a minor component (as a non-limiting 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 media or carriers, and processing aids that help to achieve the desired dosage form.

  The composition includes selecting one of a plurality of treatment plans and setting a dosage to be delivered to the patient after a weekly, monthly, or quarterly period of time. It can be used to treat patients with a combination of treatment regimens that are administered once orally. Some embodiments of the present invention facilitate selection of a combination treatment plan and / or change of dosage or setting of dosage over time of a treatment plan. The combination of the compounds of the present invention with other active agents, particularly other chemotherapeutic agents, can be done in a single fixed dose combination pill such as multipill, combopill, or polypill. Polypills are pharmaceutical products that are drug products in pill form (ie, tablets or capsules) that combine multiple active pharmaceutical ingredients. In one embodiment, the polypill is manufactured as a fixed dose combination (FDC) drug product for the treatment or prevention of disease. Polypills can reduce the number of tablets or capsules that need to be taken (generally administered orally), which can facilitate the handling and administration of the medication and reduce the patient's pill burden. The Sometimes (especially in the case of mass-produced polypills, or FDCs), all of the drugs in a given polypill are all a single basis for which a given drug / dosage combination may be appropriate It may be aimed at a state (or a collection of related states). In addition to the fixed dose polypills noted, polypills can also be tailored for specific patients via a process called dispensing.

  In addition, the present invention also allows a physician or other health care provider to combine a combination protocol (once daily) in multiple treatment plans, rather than integrating specialized combinations of pharmaceuticals into a single treatment plan. More than once a day, every other day, every third day, twice a week, once a week, once every week, every other month, etc.) for protocols that can increase compliance with medical therapy .

  The present invention provides multiple pills, weekly, monthly, in treating a patient's cancer, particularly breast cancer, as well as other estrogens-mediated diseases that would benefit from the compounds of the invention. Provide a combination protocol or a protocol incorporated into a polypill corresponding to the combination therapy described above, used quarterly or over a longer period of time.

  The present invention provides a combined dose over a period of time (eg, week, month, quarter, or longer), over which period the physician sets the dosage based on the patient's condition (the dosage of each active therapeutic ingredient) The patient's compliance can be further increased. If necessary, the combination treatment may provide an alternative dosage for treatment more than once a day.

  Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous media with buffering agents, suspending and dispensing agents, coloring agents, flavoring agents and the like. Solid forms include, for example, the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch and lactose; disintegrants such as alginic acid, Primogel, or corn starch; magnesium stearate, and the like A glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, methyl salicylate, or orange, or a compound of similar nature. Good.

  Injectable compositions are typically based on injectable sterile saline or phosphate buffered solutions or other injectable carriers known in the art.

  Transdermal compositions typically contain the active ingredient (s), for example, 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 Formulated as a topical ointment or cream containing 10% by weight, more preferably in an amount ranging from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is usually combined with either a suitable delivery polymer composition or a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can 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 comprise an active ingredient or additional ingredients to increase the stability skin penetration of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

  The compositions provided herein can be administered by a transdermal device. Transdermal administration can be achieved using patches of either reservoir or porous membrane type or various solid matrices.

  The above-mentioned components of compositions that can be administered orally, by injection or topically are only representative. Other materials, processing techniques, etc. are described in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, incorporated herein by reference.

  The compositions of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found at Remington's Pharmaceutical Sciences.

  In certain embodiments, the formulation includes water. In another embodiment, the formulation comprises a cyclodextrin derivative. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more detailed embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

  The invention also encompasses pharmaceutically acceptable acid addition salts of the compounds of the compositions of the invention. Acids used in the preparation of pharmaceutically acceptable salts are non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrogen bromide. Acid salt, nitrate, sulfate, hydrogen sulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonic acid It is an acid that forms salts and the like.

Use of Compounds in Medical Therapy Certain of OP-1038, OP-1074, and prodrugs (including esters, carbonates and phosphates), derivatives, and salts thereof as described in US2013 / 0178445 and WO2013 / 090921 Combinations with drugs, active agents, anticancer drugs, or chemotherapeutic agents are useful for the treatment of disorders that are modulated, mediated, or affected by estrogen receptors.

  In one embodiment, the combinations of the invention can be used to treat local, advanced, or metastatic breast cancer (receptor positive advanced breast cancer) that is positive for expression of estrogen receptor, progesterone receptor, or both. In an alternative embodiment, the combination is used to treat estrogen or progesterone receptor negative breast cancer. The combination was combined with one or more other anti-cancer drugs described below or otherwise known to one of skill in the art in patients who have not previously received hormonal therapy for advanced breast cancer In form, it can be used as an initial treatment for advanced breast cancer. The compound has failed previous hormone therapy alone or in combination with another anticancer drug, for example, a targeted therapy such as an mTOR inhibitor such as everolimus or a CDK4 / 6 inhibitor such as PD-0332991 It is also useful for second line treatment for later treatment.

  The combinations of the present invention are also useful as chemotherapy, radiation, or adjuvant therapy after or instead of surgery. Such supplemental use often results in use for several years, perhaps five years after the end of chemotherapy or other therapy, but may continue for several more years for optimal use.

  The combination of the present invention is also useful for preventing breast cancer in high-risk women and can be taken for any desired period, including indefinite period. For example, a patient, usually a woman who has a family history of breast cancer or who has been determined to have a mutation in the BRCA1 or BRCA2 gene or other genes that make the patient susceptible to breast cancer, The use of such prophylactic treatment can be selected instead of therapeutic intervention. The combinations described herein are also useful as neoadjuvants that allow large tumors to shrink prior to surgical resection to allow for conservative breast surgery and reduce the risk of recurrence. In addition to breast cancer, these combinations are also used to treat other cancers of the female reproductive system and other overgrowth diseases, including ovarian cancer, endometrial cancer, vaginal cancer, and endometriosis. Useful. In addition to these reproductive tissues, the combination is useful in the treatment of lung cancer that is positive for estrogen or progesterone receptors.

  The combination is used as a therapeutic or prophylactic agent for treating a condition in a mammal, particularly a human, whose condition is modulated by an estrogen receptor.

  The combinations described herein are useful for the treatment of locally advanced or metastatic breast cancer, the prevention of recurrence or early breast cancer after surgery, and the prevention of breast cancer in high-risk women. Such combinations are useful for the treatment of all estrogen-dependent cancers of the reproductive system, including endometrial cancer and ovarian cancer. Such combinations have potential use in the treatment of lung and bronchial cancers that express estrogen receptors.

  Specific examples of active agents that can be combined with the compounds described in US2013 / 0178445 and WO2013 / 090921 include mTOR inhibitors such as everolimus, or CDK4 / 6 inhibitors such as palviciclib (PD-0332991), or PI3 kinase inhibitors such as BKM-120, or anti-tumor antibiotics such as taxanes, or antimetabolites such as 5-fluorouracil, or doxorubicin. These combinations are described in more detail below.

CDK4 / 6 combination therapy CDK4 / 6 inhibitors for the treatment of cancer are currently in the clinic. Examples include PD-0332991 (Parvocyclib, Pfizer), LY2835219 (Lilly), and LEE011 (Novartis). The normal function of CDK4 / 6 in cell cycle regulation is through phosphorylation at the retinoblastoma protein serines 780 and 795. Cancers that are positive for retinoblastoma are targets for CDK4 / 6 inhibitors.

  PD-0332991 (Parvocyclib, Pfizer), ie 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] Pyrimidin-7-one or 6-acetyl-8-cyclopentyl-5-methyl-2-{[5- (1-piperazinyl) -2-pyridinyl] amino} pyrido [2,3-d] pyrimidine-7 (8H ) -One was first described and synthesized in Barvian et al. (WO2003 / 062236). Further disclosures of its use, specific salts, and synthetic methods can be found, for example, in WO2005 / 005426, WO2008 / 032157, US6,936,612, US7,208,489, US7,456,168, US7,863,278. , US 7,345,171 and US 7,781,583.

  PD-0332991 currently includes late metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumor, multiple myeloma, and mantle cell lymphoma Many tumor types have been evaluated. Such cancers are generally classified as positive for retinoblastoma because the normal function of CDK4 / 6 in cell cycle regulation is through phosphorylation of serine 780 and 795 of the retinoblastoma protein. Currently, PD-0332991 is taken orally at 125 mg once daily on days 1 to 21 of a 28-day cycle, followed by 7 days of treatment cessation.

  PD-0332991 has been evaluated in combination with the aromatase inhibitor letrozole in a comparative study with letrozole plus placebo for stage 1 metastatic breast cancer. Preliminary results reported in December 2012 suggest that the combination is substantially better than letrozole alone in progression-free survival.

  Cancers that benefit from the combination of compounds of the invention, including OP-1038 and OP-1074, include advanced or metastatic breast cancer, prevention of recurrence or early breast cancer after surgery, and breast cancer in high-risk women. Prevention included. Other cancers include genital retinoblastoma-positive estrogen-dependent cancers, including endometrial and ovarian cancer, and retinoblastoma-positive lung cancers that express estrogen receptors and Examples include bronchial cancer.

  Where appropriate, the dose of PD-0332991 as part of the combination according to the invention will be an amount selected from about 1.25 mg to about 250 mg, where appropriate the amount is selected from about 2 mg to about 150 mg, Where appropriate, the amount is selected from about 2.5 mg to about 125 mg. Accordingly, the dose of PD-0332991 as part of the combination according to the invention will be an amount selected from about 1.25 mg to about 250 mg. For example, the dose of PD-0332991 as part of a combination according to the present invention is a dose lower than that currently administered alone, eg, 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, It can be 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. Where appropriate, a selected amount of PD-0332991 is administered once daily. Where appropriate, a selected amount of PD-0332991 is administered twice daily.

  PD-0332991 administered as part of a combination according to the present invention is taken orally once a day on days 1 to 21 of a 28 day cycle, followed by 7 days of treatment cessation. Alternatively, PD-0332991 has fewer treatment cessation days as part of every 28-day cycle, for example, daily on days 1 to 22 of every 28-day cycle, followed by 6 days of treatment. Pause, daily on days 1 to 23 of every 28 day cycle, followed by 5 days of treatment, daily on days 1 to 24 of every 28 day cycle, followed by 4 days of treatment pauses, every 28 days Daily from day 1 to day 25 of the circadian cycle, followed by 3 days of treatment interruption, daily from day 1 to day 26 of every 28 day cycle, followed by 2 days of treatment interruption, 1 in every 28 day cycle It may be administered daily from day 27 to day, followed by one day of treatment cessation, or daily for a total 28 day cycle, without treatment cessation days.

mTOR inhibitor combination therapy For use herein, the terms mTOR inhibitor, mTOR, and derivatives thereof, unless otherwise defined, include, but are not limited to, rapamycin and analogs thereof, RAD001 or Everimus, CCI-779. Or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, and Pp121. Suitably the mTOR inhibitor is selected from rapamycin, everolimus (Afinitor), and temsirolimus. Suitably, the mTOR inhibitor is selected from rapamycin and everolimus (Afinitor). Suitably the mTOR inhibitor is everolimus.

  Where appropriate, the dosage of everolimus as part of the combination according to the invention will be an amount selected from about 1.25 mg to about 20 mg, where appropriate the amount is selected from about 2 mg to about 15 mg, If so, the amount is selected from about 2.5 mg to about 10 mg. Thus, the dosage of everolimus 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 dosage of everolimus as part of the combination according to the invention is 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, It can be 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. Where appropriate, a selected amount of everolimus is administered twice daily. Where appropriate, a selected amount of everolimus is administered once daily. The administration of everolimus is suitably started as the initial dose. Where appropriate, the initial dose is 2 to 100 times the maintenance amount, 2 to 10 times when appropriate, 2 to 5 times when appropriate, 2 times when appropriate, 3 times when appropriate, appropriate In some cases, the amount is 4 times, and in appropriate cases, the amount is 5 times. If appropriate, the initial dose is 1-7 days, 1-5 days if appropriate, 1-3 days if appropriate, 1 day if appropriate, 2 days if appropriate, 3 days if appropriate Administration is followed by maintenance administration protocol.

  Where appropriate, the dosage of temsirolimus as part of a combination according to the present invention will be the amount that is infused over a period of 30-60 minutes, the amount being selected from about 5 mg to about 50 mg, where appropriate, the amount is Selected from about 10 mg to about 40 mg, and where appropriate, the amount is selected from about 15 mg to about 35 mg. Accordingly, the dosage of temsirolimus as part of the combination according to the invention will be an amount selected from about 5 mg to about 50 mg. For example, the dosage of temsirolimus as part of a combination according to the invention can be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg. Where appropriate, a selected amount of temsirolimus is administered twice daily. Where appropriate, a selected amount of temsirolimus is administered once daily. The administration of temsirolimus is suitably started as the initial dose. Where appropriate, the initial dose is 2 to 100 times the maintenance amount, 2 to 10 times when appropriate, 2 to 5 times when appropriate, 2 times when appropriate, 3 times when appropriate, appropriate In some cases, the amount is 4 times, and in appropriate cases, the amount is 5 times. If appropriate, the initial dose is 1-7 days, 1-5 days if appropriate, 1-3 days if appropriate, 1 day if appropriate, 2 days if appropriate, 3 days if appropriate Administration is followed by maintenance administration protocol.

PI3 Kinase Inhibitor Combination Therapy PI3K inhibitors can include, but are not limited to, BKM-120, XL-147, RG-7321 (GDC-0941), CH-5132799, and BAY-80-6946.

  Phosphoinositide (PI), a phosphorylated derivative of phosphatidylinositol, regulates nuclear processes, cytoskeletal dynamics, signal transduction, and membrane trafficking and is essential in eukaryotic cells. Among the enzymes involved in PI metabolism, PI3 kinase (PI3K) is of particular interest due to its carcinogenic potential and potential as a drug target. PI3 kinase phosphorylates phosphatidylinositol or PI at the 3-position of the inositol ring (Lindmo et al., Journal of Cell Science 119, 605-614, 2006). Phospholipids phosphorylated at position 3 produced by PI3K activity bind to the pleckstrin homology (PH) domain of protein kinase B (PKB or AKT), translocate PKB to the cell membrane, and subsequently phosphorylate PKB. Oxidize. Phosphorylated PKB inhibits apoptosis-inducing proteins such as FKHR, Bad, and caspases and is thought to play an important role in cancer progression. PI3K is divided into classes I-III, and class I is further reclassified into classes Ia and Ib. Among these isoforms, class Ia enzymes are thought to play the most important role in cell proliferation in response to growth factor-tyrosine kinase pathway activation (Hayakawa et al., Bioorganic & Medicinal Chemistry 14 6847-6858, 2006). . Three frequent mutations in cancer constitutively activate PI3Kα and when expressed in cells are cancerous, and molecules such as PKB, S6K, and 4E bp1 that are common in cancer cells Promotes chronic activation of downstream signaling by (Stephens et al., Current Opinion in Pharmacology, 5 (4) 357-365, 2005). Therefore, PI3 kinase is an attractive target for the treatment of proliferative diseases.

Several PI3 kinase inhibitors are known, including wortmannin and LY294002. While wortmannin is a potent PI3K inhibitor with low nanomolar IC ₅₀ values, it has low in vivo anti-tumor activity (Hayakawa et al., Bioorg Med Chem 14 (20), 6847-6858 (2006)). Recently, a group of morpholine-substituted quinazolines, pyridopyrimidine, and thienopyrimidine compounds have been reported to be effective in inhibiting PI3 kinase p110α (Hayakawa, 6847-6858). An oral dosage of a morpholine-substituted thienopyrimidine compound (GDC-0941) has demonstrated tumor suppression of glioblastoma xenografts in vivo (Folkes et al., Journal of Medicinal Chemistry, 51, 5522-5532, 2008). The following publications disclose a series of PI3 kinase inhibitors based on thienopyrimidine, pyridopyrimidine, and quinazoline: WO2008 / 073785, WO2008 / 07740, WO2007 / 127183, US Patent Publication No. 20080226665.

  Examples of phosphatidylinositol-3-kinase (PI3 kinase) inhibitors include, but are not limited to, for example, celecoxib and its analogs, such as OSU-03012 and OSU-03013 (see, for example, Zhu et al., Cancer Res., 64 (12): 4309-18, 2004); 3-deoxy-D-myo-inositol analogues (e.g., U.S. Patent Application No. 20040192770; Meuillet et al., Oncol. Res., 14: 513-27, 2004), e.g. PX-316; 2′-substituted 3′-deoxy-phosphatidyl-myo-inositol analogues (eg, Tabellini et al., Br. J. Haematol., 126 (4): 574-82, 2004); fused heteroaryl derivatives (USA No. 6,608,056); 3- (imidazo [1,2-a] pyridin-3-yl) derivatives (eg, US Pat. Nos. 6,403,588 and 6,653,320); Ly294002 (eg, Vlahos et al., J. Biol., Chem., 269 (7) 5241-5248, 1994); quinazolin-4-one derivatives, eg, IC486068 (eg, US Patent Application No. 20020161014; Res., 64: 4893-99, 2004); 3- (hetero) aryloxy-substituted benzo (b) thiophene derivatives (eg, WO04108715, also WO04108713); viridine, semi-synthetic pyridines, eg, PX-866 ( Acetic acid (1S, 4E, 10R, 1 R, 13S, 14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12 , 13, 14, 15, 16, 17-dodecahydro-2-oxa-cyclopenta [a] phenanthren-11-yl ester) (eg, Ihle et al., Mol Cancer Ther., 3 (7): 763-72, 2004, US Patent Application No. 20020037276, US Pat. No. 5,726,167); and wortmannin and its derivatives (eg, US Pat. Nos. 5,504,103, 5,480,906, 5,468). 773, No. 5,441,947, No. 5,378,725, No. 3,668,222).In certain embodiments, 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 a daily dose of 100 mg by oral capsules in Phase III clinical trials. Where appropriate, the dosage of BKM-120 as part of a combination according to the invention will be an amount selected from about 1.25 mg to about 250 mg, where appropriate the amount is selected from about 2 mg to about 150 mg; Where appropriate, the amount is selected from about 2.5 mg to about 100 mg. Accordingly, the dose of BKM-120 as part of the combination according to the present invention will be an amount selected from about 1.25 mg to about 250 mg. For example, the dose of BKM-120 as part of a combination according to the present invention is a dose lower than that currently administered alone, eg, 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, It can be 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. Where appropriate, a selected amount of BKM-120 is administered once daily. Where appropriate, a selected amount of BKM-120 is administered twice daily.

5-Fluorouracil Combination Therapy Fluorouracil or 5-FU (5-Fluoro-1H, 3H-pyrimidine-2,4-dione, branded Efudex) is a pyrimidine analog used in cancer treatment It is a drug. This drug is a suicide inhibitor and works by irreversibly inhibiting thymidylate synthase. 5-FU is a fluoropyrimidine cytotoxic drug administered intravenously (IV) that inhibits the function of thymidylate synthase, an enzyme required for the production of thymidine nucleotides required for DNA synthesis. 5-FU is active in the therapy of several tumor types, but is most often administered in the treatment of colorectal cancer, upper gastrointestinal malignancies, and breast cancer.

5-FU is currently the like 1-5 day 500 mg / ^{m 2} intravenously, or weekly 450~600mg / ^{m 2} intravenously, daily or 200 to 400 mg / ^{m 2} intravenous continuous infusion, generally 800 mg / day It is administered with various protocols not exceeding.

  A method that has been used to overcome the low oral bioavailability of 5-FU is to administer a prodrug that has good bioavailability and is ultimately converted to 5-FU. It is. Capecitabine (pentyl [1- (3,4-dihydroxy-5-methyltetrahydrofuran-2-yl) -5-fluoro-2-oxo-1H-pyrimidin-4-yl] carbamate, Xeloda) Oral fluoropyrimidine carbamate. Capecitabine is readily absorbed from the gastrointestinal tract and is preferentially converted to 5-FU in tumor tissue. After oral administration, capecitabine proceeds intact from the gastrointestinal tract to the liver where it is converted to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase and then to liver and tumor tissue by cytidine deaminase. 5′-deoxy-5-fluorouridine (5′-DFUR) is finally converted to 5-FU in tumor tissue by thymidine phosphorylase (dThdPase). The usual starting dose is 2,500 mg / m2 / day, with the dose divided into two at 12 hour intervals. One cycle includes 2 weeks of treatment followed by 1 week of no treatment. The cycle can be repeated every 3 weeks.

More particularly, when a compound of the invention is combined with 5-FU, the dosage of 5-FU is, for example, 10 to 1000 mg / m ² / day, preferably 50 to 1000 mg / m ² / day, more preferably 100-600 mg / m < ² > / day may be sufficient.

More particularly, when the compound of the present invention is combined with capecitabine, the dosage of capecitabine is, for example, 100-10000 mg / m ² / day, preferably 500-5000 mg / m ² / day, more preferably 1000-5000 mg / day. m ² / day may be sufficient.

Doxorubicin combination therapy Doxorubicin, also known as adriamycin, is one of the more common cytotoxic drugs used to treat breast cancer. The term doxorubicin encompasses pharmaceutically acceptable salts of doxorubicin in addition to doxorubicin. Doxorubicin or hydroxyl daunorubicin is an antineoplastic drug widely used in chemotherapy (Hortobagyi, Drugs, 54 (extra number 4): 1-7 (1997)). Doxorubicin is an anthracycline antibiotic and is structurally closely related to daunomycin (Minotti et al., Pharmalogy. Rev., 56: 185-229 (2004)). Doxorubicin (DOX) includes cancers of soft tissues including blood, lymphatic system, bladder, breast, stomach, lung, ovary, thyroid, nerves, kidneys, bones, muscles and tendons, multiple myeloma, etc. Commonly used in the treatment of a wide range of cancers. Doxorubicin hydrochloride is one of the most common forms. The hydrochloride salts include doxorubicin hydrochloride, 14-hydroxydaunorubicin hydrochloride, 3-hydroxyacetyldaunorubicin hydrochloride, and 5,12-naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α. -L-lyxo-hexopyranosyl) oxy] -7,8,9,10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-, hydrochloride, (8S-cis)- It is called by various names such as (9Cl). Doxorubicin hydrochloride has a molecular formula of C ₂ 7H ₂₉ NO ₁₁ . HCl, molecular weight (MW) is 580.0, CAS number is 25316-40-9.

The dosage of doxorubicin, 30-100 mg / ^{m 2} / day, more preferably from 40-80 mg / ^{m 2} / day, more preferably about 50 mg / ^{m 2} / day or a dose of about 60 mg / ^{m 2} / day It is preferable to do. The doxorubicin injection time is generally up to 6 hours, more preferably 1-3 hours, and most preferably 1 hour.

More specifically, when the compound of the present invention is combined with doxorubicin, the dosage is, for example, 10-100 mg / m ² / day, preferably 30-100 mg / m ² / day, more preferably 30-60 mg / m ^2. / Day is fine.

Taxane combination therapy Examples of taxanes include paclitaxel (trade name: Taxol) and docetaxel (trade name: Taxotere). Paclitaxel poly gourmet (trade name: Opaxio) is also included in the taxane. Such taxanes have been approved and developed for use in breast cancer, non-small cell lung cancer, stomach cancer, head and neck cancer, ovarian cancer, esophageal cancer, stomach cancer, endometrial cancer and the like. In addition, combination therapies for various cancers have been approved or developed by combining taxanes with various drugs such as bevacizumab for breast cancer, ovarian cancer and carboplatin for non-small cell lung cancer. Yes.

Taxanes can be administered according to known clinical practice. The dosage and dosing schedule can also be varied depending on the specific symptoms or all symptoms of the patient's disease. The dosage can also be reduced as appropriate according to age, symptoms, or incidence of side effects. When using the pharmaceutical compositions and / or kits of the present invention, the taxane typically, but not limited to, adults 0.01~10000mg / ^{m 2} / day, preferably 0.1 to 1000 mg / ^{m 2} / day, more Preferably, it can be administered at 1 to 500 mg / m ² / day, and this can be usually administered once to 3 times a day. The dosage should be reduced if excessive toxicity occurs in the patient. Dosages and dosing schedules can be altered when using one or more additional agents, active agents, anticancer agents, or chemotherapeutic agents in addition to the combination therapy of the present invention. The medication schedule may be determined by a physician in charge of treating a particular patient.

More particularly, when the compound of the invention is combined with paclitaxel, the dosage of paclitaxel is 0.01-10000 mg / m ² / day, preferably 0.1-1000 mg / m ² / day, more preferably 1- 500 mg / m ² / day may be sufficient.

Furthermore, when the compound of the present invention is combined with docetaxel, the dosage of docetaxel is 0.01 to 10000 mg / m ² / day, preferably 0.1 to 1000 mg / m ² / day, more preferably 1 to 500 mg / m. ² / day is sufficient.

In addition, when the compound of the present invention is combined with paclitaxel polygourax, the dosage of paclitaxel polygourax is 0.01-10000 mg / m ² / day, preferably 0.1-1000 mg / m ² / day, more preferably It may be 1 to 500 mg / m ² / day.

  In another embodiment, the combinations of the present invention are provided for use in medical therapy, including for any of the conditions described herein. Also provided is the use of this combination in the manufacture of a medicament for treating or preventing one of the aforementioned conditions and diseases.

  The range of injectable dose levels is any desired dosage of active agent, for example from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all from about 1 to about 120 hours, especially 24 to 96 hours. Provided in. In one embodiment, a pre-dose bolus of about 0.1 mg / kg to about 10 mg / kg or more can be administered to achieve a reasonable steady state level. For a 40-80 kg human patient, it is unlikely that the maximum total dose will exceed about 2 g / day.

  For oral dosing, any dose of active agent combined that achieves the desired goal is reasonable. In one example, a suitable daily dosage of an active agent of the present invention is between about 0.1 to 4000 mg, more typically between 5 mg to 1 gram, more typically between 10 mg to 500 mg. Orally once daily, twice daily, or three times daily, continuously (daily) or intermittently (eg, 3-5 days a week). For example, when used in the treatment of any of the disorders described herein, the dosage of a compound of the invention is usually about 0.1 mg per day, more usually 10, 50, 100, 200, 250, The range is up to 1000, or about 2000 mg.

General Synthetic Procedures The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. For example, see the synthesis scheme below. In indicating typical or preferred process conditions (ie reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) it will be understood that other process conditions may be used unless otherwise stated. . Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

  In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for specific functional groups and conditions suitable for protection and deprotection is well known in the art. For example, for several protecting groups and their introduction and removal, see T.W. W. Greene and P.M. G. M.M. Wuts, Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991, and references cited therein.

  The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, or HPLC. In the following scheme, details on the preparation of representative substituted benzopyrans listed herein are presented. The compounds provided herein can be prepared from starting materials and reagents known or commercially available by those skilled in the art of organic synthesis.

  The compounds provided herein that are pure with respect to diastereoisomers or enantiomers can be prepared according to any technique known to those of skill in the art. For example, such compounds can also be prepared by chiral synthesis or asymmetric synthesis from appropriate optically pure precursors, or from racemic or diastereomeric mixtures by any conventional technique, For example, it can also be obtained by chiral column, chromatographic resolution using TLC, or by preparing diastereoisomers, separating them and regenerating the desired enantiomers or diastereoisomers. For example, J.A. Jacques, A.M. Collet, and S.M. H. “Enantiomers, Racemates and Resolutions” by Wilen (Wiley-Interscience, New York, 1981); H. Wilen, A.M. Collet, and J.M. Jacques, Tetrahedron, 2725 (1977); L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); H. Wilen, Tables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel, Univ. Of Notre Name Press, Notre Dam, IN, 1972); Eliel, Samuel H. et al. Wilen, and Lewis N. See Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihary Nogradi (1995 VCH Publishers, Inc., NY, NY).

  In certain embodiments, a pure compound with respect to a diastereoisomer can be obtained by reacting a racemic or diastereomeric mixture with a suitable optically active acid or base. Suitable acids or bases include Bigley et al., 1995, Salts of Drugs and Adsorption, the entire contents of which are incorporated herein by reference, Encyclopedia of Pharmaceutical Sciences, Volumes 13 and 13; , Marcel Dekker, New York; ten Hoeve and H .; Wynberg, 1985, Journal of Organic Chemistry 50: 4508-4514; Dale and Mosher, 1973, J. MoI. Am. Chem. Soc. 95: 512; as well as those described in CRC Handbook of Optical Resolution via Diatometic Salt Formation.

  Compounds that are pure with respect to enantiomers or diastereoisomers are crystallized diastereoisomers or mother liquors depending on the particular acid resolving agent used and the solubility of the particular acid enantiomer or diastereoisomer used. It can also be recovered from either of these. The identity and optical purity of the particular compound so recovered can be revealed by optical rotation analysis or other analytical methods known in the art. The diastereoisomers can then be separated by, for example, chromatography or fractional crystallization and the desired enantiomer or diastereoisomer can be regenerated by treatment with the appropriate acid or base. The other enantiomer or diastereoisomer can be obtained analogously from the racemate or mixture of diastereoisomers or worked up from the first separated liquid.

  In certain embodiments, compounds that are pure with respect to enantiomers or diastereoisomers can be separated from the racemate or mixture of diastereoisomers by chiral chromatography. Various chiral columns and eluents are available for use in the separation of enantiomers or diastereoisomers, and conditions suitable for the separation can be determined experimentally by methods known to those skilled in the art. Exemplary chiral columns that can be used in the separation of enantiomers provided herein include, but are not limited to, CHIRALPACK® IC, CHIRALCEL® OB, CHIRALCEL® OB— H, CHIRALCEL (R) OD, CHIRALCEL (R) OD-H, CHIRALCEL (R) OF, CHIRALCEL (R) OG, CHIRALCEL (R) OJ, and CHIRALCEL (R) OK.

  General steps for preparing the compounds of the invention are provided as further embodiments of the invention and are illustrated in the following schemes.

3- (4-Hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol (OP- 1038) and separation and purification of stereoisomers (OP-1074 and OP-1075)

ステップ１：
１−（２，４−ジヒドロキシフェニル）−２−（４−ヒドロキシフェニル）エタノンを生成する反応
パドル、等圧添加漏斗、温度計、およびマントルヒーターを取り付けた２Ｌの三口丸底フラスコに、レソルシノール（１，３−ジヒドロキシベンゼン）（６２．０００ｇ、５６３．１ｍｍｏｌ、１．０当量）および４−ヒドロキシフェニル酢酸（９４．２３７ｇ、６１９．４ｍｍｏｌ、１．１当量）を加えた。フラスコにトルエン（３５０ｍＬ）を加えて懸濁液を得た。反応液を窒素パージし、カニューレを用いて添加漏斗を三フッ化ホウ素エーテレート（１９８．２０１ｍｌ、１５７８．０ｍｍｏｌ、２．８当量）で満たした。反応液を１５０ｒｐｍで撹拌し、三フッ化ホウ素エーテレートを３〜４ｍＬずつ加え、反応液を加熱した。加える間、内部温度が１００℃に上昇した。反応液は、黄色から濃赤色へと様々に色が変化した。三フッ化ホウ素エーテレートを全部加えた後、添加漏斗を外し、冷却器と取り替えた。反応液を内部温度１０８℃で１．５時間撹拌した。サンプルを採取し、ＨＰＬＣ分析により、反応が完了したことが示された。反応液を冷却し、撹拌を止めて、二相性の溶液を得た。反応液に酢酸ナトリウムの１２％水溶液（４１ｇ、３３６ｍＬ）を撹拌しながらゆっくりと加えた。反応液を１６時間撹拌した。一晩かけて沈殿が生成し、焼結ガラス漏斗に収集した。固体を真空オーブンで１６時間乾燥させて、生成物を白色の粉末（１１９．６７ｇ、８７．０％）として得た。

Step 1:
Reaction to produce 1- (2,4-dihydroxyphenyl) -2- (4-hydroxyphenyl) ethanone A 2 L three-necked round bottom flask equipped with a paddle, isobaric addition funnel, thermometer, and mantle heater was charged with resorcinol ( 1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 eq) and 4-hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 eq) were added. Toluene (350 mL) was added to the flask to obtain a suspension. The reaction was purged with nitrogen and the addition funnel was filled with boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) Using a cannula. The reaction solution was stirred at 150 rpm, 3 to 4 mL of boron trifluoride etherate was added, and the reaction solution was heated. During the addition, the internal temperature rose to 100 ° C. The reaction solution varied in color from yellow to dark red. After all the boron trifluoride etherate was added, the addition funnel was removed and replaced with a condenser. The reaction was stirred at an internal temperature of 108 ° C. for 1.5 hours. A sample was taken and HPLC analysis indicated that the reaction was complete. The reaction was cooled and agitated to give a biphasic solution. A 12% aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction mixture with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried in a vacuum oven for 16 hours to give the product as a white powder (119.67 g, 87.0%).

Step 2:
1- (2-hydroxy-4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) -2- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) ethanone is produced To a 2 L 3-neck round bottom flask equipped with a stir bar, thermometer, condenser, and nitrogen inlet was added 1- (2,4-dihydroxyphenyl) -2- (4-hydroxyphenyl) ethanone (119.000 g). 487.2 mmol, 1.0 eq.) And ethyl acetate (400 mL). The flask was flushed with nitrogen for 2 minutes and 3,4-dihydro-2H-pyran (222.252 ml, 2436.1 mmol, 5.0 equiv) was added from a graduated cylinder. The suspension was flushed with nitrogen for 2 minutes and p-toluenesulfonic acid (0.378 g, 2.2 mmol, 0.0 equiv) was added to the reaction. An exothermic reaction occurred and the temperature rose from 20 ° C. to 33 ° C. over 5 minutes. Within 1 minute of adding PTSA, the yellow suspension turned into a red solution. The reaction was stirred at room temperature for 66 hours. The reaction was monitored by HPLC at 4, 5, and 6 hours. The chromatogram showed that the reactions were 74%, 90%, and 100% complete, respectively, at the indicated time points. TEA (5 mL) was added to the cream colored slurry to stop the reaction. The slurry was transferred to a round bottom flask (2 L) and the three neck flask was rinsed with ethyl acetate. The slurry was concentrated with a rotary evaporator to obtain a cream-colored powdery solid. 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 was 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 washings were combined and concentrated to an orange oil (38.09 g).

Step 3:
2- (4-Iodophenyl) -7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) chroman-4 Reaction to produce -one In a 1 L three-necked round bottom flask was added 1- (2-hydroxy-4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) -2- (4-((tetrahydro-2H -Pyran-2-yl) oxy) phenyl) ethanone (16.228 g, 39.34 mmol) was added. To the flask was added 2-butanol (380 mL, 0.197 M) and 4-iodobenzaldehyde (51.700 g, 222.8 mmol, 1.0 equiv) to give a suspension. To the suspension was added piperidine (7.300 ml, 73.9 mmol, 0.3 eq) and 1,8-diazabicyclo [5.4.0] undec-7-ene (11.300 ml, 75.6 mmol, 0.3 eq). Equivalent) was added. The flask was equipped with a Dean-Stark apparatus and a condenser, a thermometer and a stirring shaft and heated in an oil bath at 130 ° C. to obtain an orange solution (it became a solution when the internal temperature was 80 ° C.). Half of the solvent (190 mL) was collected over 1.5 hours. The Dean-Stark trap was removed, a condenser was placed on the flask, and the reaction was heated for an additional hour. The solution gradually thickened and became orange. The oil bath was cooled to 90 ° C. and 380 mL of isopropyl alcohol was added in one portion. The reaction mixture became a white cloudy suspension and redissolved at 90 ° C. to give a solution in less than 1 minute. Heating the bath was set to 50 ° C and the flask was gradually cooled to 50 ° C. A precipitate began to form at 60 ° C. and a suspension was obtained at 50 ° C. A thick oily mass settles out of solution at about 55-53 ° C. Vigorous stirring (300 rpm) with an overhead stirrer was required to prevent the oily mass from solidifying into a single solid as seen in small scale reactions with a stir bar. The reaction was left stirring until the mixture cooled to room temperature. Even with vigorous stirring, the oily mass solidified into a cake. 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 the 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 solid was washed with ethyl acetate (1.2 L) and the filtrate was concentrated to an orange oil (unpurified 137.61 g). The oil was dissolved in boiling 80% IPA / water (1.2 L) and the solution was cooled to room temperature and allowed to stand overnight to obtain a cake. The cake was filtered and washed with cold IPA (100 mL). The mother liquor was partially concentrated on a rotary evaporator to give a tan powder. This process was repeated until no oil could be washed out of the powder. The product was pooled and dried in a vacuum oven to give an impure tan powder (118.25 g, 85.6%).

Step 4a:
2- (4-Iodophenyl) -4-methyl-7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl ) Reaction to produce chroman-4-ol 90.0% 2- (4-iodophenyl) -7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4-((tetrahydro-2H To a solution of -pyran-2-yl) oxy) phenyl) chroman-4-one (104.891 g, 150.7 mmol, 1.0 eq) in THF (1.2 L) was added methylmagnesium chloride 3 0.0 M THF solution (160.000 ml, 480.0 mmol, 3.2 eq) was added via addition funnel over 30 minutes. During the addition, the temperature did not rise to about 8 ° C. The reaction solution was removed from the ice bath, stirred at room temperature, and further stirred for 1 hour. TLC (20% ethyl acetate in hexane) showed that the reaction was free of starting material. The solution was cooled in an ice bath and carefully quenched with saturated ammonium chloride (35 mL). To the reaction mixture was added ethyl acetate (1.2 L) and water (1.2 L) and the layers were separated. The aqueous layer was extracted with EA (1 L). The combined organic layers were washed with brine (1 L), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a pale yellow foam (crude 111.26 g). This material was used without further purification.

Step 4b:
Reaction to produce 3- (4-hydroxyphenyl) -2- (4-iodophenyl) -4-methyl-2H-chromen-7-ol To a 2 L round bottom flask was added 2- (4-iodophenyl) -4 -Methyl-7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) chroman-4-ol (96.820 g 150.7 mmol, 1.0 equiv) and 80% acetic acid H ₂ O solution (686 mL). The suspension was degassed, flushed with nitrogen and heated at 90 ° C. for 1.5 hours. TLC analysis of the reaction (1: 2 EA / Hex) showed no starting material present. The solvent was removed to give a red oil. The red oil was dissolved in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate solution (3 × 1 L). The organic layer was washed with brine (1 L), filtered and concentrated to give a red oil (109.32 g, crude). The oil was loaded on 100 g of silica gel and a 40 g portion was chromatographed on silica gel (100 g cartridge, 5-30% EA / Hex). Fractions containing spots with an Rf of 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 a pink suspension. The solid was filtered using a sintered glass funnel, washed with 20% DCM in hexane (250 mL) and dried in a vacuum oven overnight (32.41 g). The mother liquor was concentrated to glass and this process was repeated a second time to give a pink solid (4.2784 g). Impure mixed fractions were pooled and concentrated to a glass (16.71 g). The glass was dissolved in DCM (75 mL) and allowed to stand to produce pink crystals (7.0862 g). This process was repeated to obtain a pink crystal (2.3643) for the second time. Mother liquors from both pure and impure fractions were combined and chromatographed in the same way (2 × 100 g cartridge). Fractions with Rf of 0.55 were pooled and concentrated to give a red oil (17.388 g) that did not solidify. This oil did not match the previous minute and was reprotected in another reaction.

  Gradient method: (5-30% EA / Hex) Hold at 5% EA for 2 minutes, ramp to 15% over 3 minutes, hold at 15% EA / Hex for 7 minutes, ramp to 30% over 7 minutes And hold for 17 minutes at 30% EA / Hex. Fractions with an Rf of 0.55 (33% EA / Hex) were pooled and concentrated to a light pink oil that was triturated with DCM.

Step 5:
2- (4-Iodophenyl) -4-methyl-7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl ) Reaction to produce -2H-chromene 3- (4-hydroxyphenyl) -2- (4-iodophenyl) -4-methyl-2H-chromen-7-ol (41.860 g, 91.7 mmol, 1.0 Eq.) And para-toluenesulfonic acid pyridinium (4.822 g, 19.3 mmol, 0.2 eq) in a solution of DCM (200 mL) in 3,4-dihydro-2H-pyran (49.226 ml, 539. 6 mmol, 5.9 equivalents) was added. The reaction was stirred at room temperature overnight (17 hours). TLC showed most to be the desired product. The reaction is diluted with DCM (200 mL), washed with saturated NaHCO3 (200 mL), water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated to give a viscous red residue. It was. The residue adsorbed on silica gel (75 g) was purified on a silica gel column (4 × 100 g, 0-20% EA / Hex) to give a white solid, which was triturated with methanol in a 40 ° C. vacuum oven. Drying for 16 hours gave the title compound as a white powder (51.67 g, 90.2%).
1H NMR (300 MHz,
CDCl3): δ 7.53 (d, J = 5.4 Hz, 2H)), 7.18 (d, J = 8.7
Hz, 1H), 7.06 (apparent t, J = 7.8 Hz, 4H), 6.71 (s, 1H),
6.59 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 5.15 (s, 2H), 4.59 (s, 2H),
4.63 (d, J = 5.7 Hz, 2H), 3.98 (s, 3H), 3.84 (s, 3H).

Step 6:
-(3R) -3-methyl-1- (2- (4- (4-methyl-7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4-((tetrahydro-2H- Reaction to produce pyran-2-yl) oxy) phenyl) -2H-chromen-2-yl) phenoxy) ethyl) pyrrolidine 2- (4-iodophenyl) -4-methyl-7-((tetrahydro-2H-pyran) -2-yl) oxy) -3- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) -2H-chromene (16.800 g, 26.9 mmol, 1.0 equiv), (R ) -2- (3-Methylpyrrolidin-1-yl) ethanol (10.416 g, 80.6 mmol, 3.0 eq), 1,10-phenanthroline (0.970 g, 5.4 mmol, 0.2 eq) , And a mixture of cesium carbonate (17.530 g, 53.8 mmol, 2.0 eq) in butyronitrile (84 mL) was charged to a 250 mL round bottom flask evacuated and refilled with argon (3 times). To the suspension was added copper (I) iodide (5.123 g, 26.9 mmol, 1.0 equiv), evacuated and refilled with argon (3 times). The reaction mixture was heated in a 120 ° C. oil bath. After 91 hours of heating, the reaction was cooled to room temperature, the mixture was filtered through a Celite pad (3 cm), and the pad was washed sequentially 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) and purified on silica gel (100 g cartridge, 0-30% MeOH / DCM) [TLC: 5% MeOH / DCM, major 4 spots, Rf (SM: 0.95), 0 .9, 0.83, (product 0.43)]. Fractions containing product were pooled and concentrated to give a brown foam (13.64 g, 81.0%).

  Gradient method 0% MeOH for 4 minutes, 1% MeOH / DCM gradient over 3 minutes, 1% MeOH / DCM held for 10 minutes, 5% MeOH / DCM over 3 minutes gradient, 5% MeOH / Hold at DCM for 12 minutes, gradient over 25 minutes to 25% MeOH / DCM, hold at 25% MeOH / DCM for 15 minutes. Many fractions contained a mixture of starting material and product. All fractions were pooled, concentrated, rechromatographed on silica gel (15 g and 100 g cartridges) and this gradient method (4 min with 0% MeOH, gradient over 3 min to 1% MeOH / DCM). Gradient elution with 1% MeOH / DCM for 20 minutes, 5% MeOH / DCM gradient over 5 minutes, 5% MeOH / DCM for 20 minutes). Fractions 74-126 were pooled and concentrated to a brown oil that solidified into a foam (13.64 g, 81%) (late from the first column containing a spot corresponding to amino alcohol). Elution fraction). These fractions were pooled and concentrated to give a red-black liquid (6.38 g).

Step 7:
3- (4-Hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol (OP- (3R) -3-methyl-1- (2- (4- (4-methyl-7-((tetrahydro-2H-pyran-2-yl) oxy) -3- (4- ( (Tetrahydro-2H-pyran-2-yl) oxy) phenyl) -2H-chromen-2-yl) phenoxy) ethyl) pyrrolidine (15.130 g, 24.2 mmol, 1.0 equiv) was added to 80% acetic acid / Dissolved in water (150 mL). The solution was heated in a 90 ° C. oil bath for 1 hour. HPLC analysis of the reaction mixture indicated that the reaction was complete. The dark red solution was concentrated to a dark red oil. The oil was suspended in ethyl acetate (600 mL) and washed with saturated NaHCO 3 (3 × 300 mL). The aqueous layers were combined and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give a red oil (14.03 g, crude). The oil was adsorbed onto silica gel (30 g) and chromatographed on silica gel (2 × 100 g cartridge) using 0-10% MeOH in DCM. Product containing fractions were pooled and concentrated to give a red foam (6.68 g). The impure fraction was concentrated and purified again under the same conditions to give an additional 0.9496 g of red foam which was combined with the previous foam. Total yield 7.6296 g, 69.0%.

  Gradient method 0% MeOH / DCM for 5 min, gradient over 10 min to 10% MeOH / DCM, 10 min with 10% MeOH / DCM. TLC conditions (UV and I2): 10% MeOH / DCM 5 spots 0.64, 0.48, (product) 0.31, 0.21, 0.07. HPLC: 100% purity (0-90% acetonitrile / water). LC_MS: [M + 1] + = 458.3.

Step 8:
Using a Diacel, Chiralpak IC column in isocratic mode with 80% hexane, 20% 2-propanol with 0.1% dimethylethylamine or 0.1% diethylamine as modifier at room temperature , OP-1038 as its diastereoisomer, (2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidine-1- Yl] ethoxy} phenyl) -2H-chromen-7-ol (OP-1074) and (2R) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R)- 3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol (OP-1075). This method was used on analytical and preparative scales.

Step 9:
Reaction to produce (R) -2- (benzyloxy) -1- (3-methylpyrrolidin-1-yl) ethanone In a round bottom flask, (R) -3-methylpyrrolidine hydrochloride (20.000 g, 164.5 mmol) , 1.0 eq.) And dissolved in anhydrous DCM (45 mL). To the solution was added freshly distilled diisopropylethylamine (60.157 ml, 345.4 mmol, 2.1 eq) and freshly activated quadrumolecular sieve (about 21 g) and stirred for 10 minutes. Using a room temperature water bath for cooling, the reaction solution was charged with 2- (benzyloxy) acetyl chloride (31.881 g, 172.7 mmol, 1.1 eq) dissolved in DCM (50 mL) at room temperature with a syringe. It was added dropwise over a period of minutes. After all was added, the reaction was stirred for 17 hours. TLC analysis (1: 1, EA / Hex, Rf: 0.83, 0.33, 0.05) showed no acid chloride present. The reaction was poured into a separatory funnel and the organic layer was washed successively with 1M HCl (2 × 200 mL), saturated sodium bicarbonate (200 mL), and brine (200 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to an orange oil (42.40 g). The oil was applied to silica gel (30 g) and the mixture was divided into approximately 18 g portions and chromatographed on silica gel (4 × 100 g cartridge) using a 10-80% EA / Hex gradient method. The spot fractions with Rf 0.33 were pooled and concentrated to give a yellow oil (34.02 g, 88.7%).

  Gradient method: 10% EA / Hex held for 5 minutes, gradient to 80% EA / Hex over 15 minutes, 80% EA / Hex held for 10 minutes. Fractions with Rf of 0.33 were pooled and concentrated.

Step 10:
Reaction to produce (R) -1- (2- (benzyloxy) ethyl) -3-methylpyrrolidine Aluminum trichloride (54.513 g, 408.8 mmol, 3.0 eq) was dissolved in anhydrous THF (750 mL). Cooled in an ice bath. To the above suspension, lithium aluminum hydride (35.688 g, 940.3 mmol, 6.9 equivalents) was added in small portions over 35 minutes with a powder addition funnel, and the mixture was further stirred for 10 minutes. The suspension was cooled to −78 ° C. for 15 minutes, and (R) -2- (benzyloxy) -1- (3-methylpyrrolidin-1-yl) ethanone (33.980 g, 136. 3 mmol, 1.0 equivalent) in anhydrous THF (150 mL) was added dropwise over 20 minutes with an isobaric addition funnel. The reaction solution was kept at −78 ° C. for 1 hour and stirred at room temperature for 1 hour. The reaction was carefully quenched with 6N HCl solution (100 mL) and stirred for 17 hours to give a gray suspension. 6N NaOH solution (216 mL) was added to the mixture and a white suspension was obtained after stirring for 30 min. The mixture was filtered through a Celite pad (4 cm). The solid was washed with DCM (5 × 500 mL). The filtrate was poured into a separatory funnel and the layers were separated (approximately 200 mL of aqueous layer was recovered). The aqueous layer was extracted with DCM (3 × 100 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a yellow liquid (33.43 g). This liquid was applied to silica gel (25 g) and chromatographed on silica gel (2 × 100 g cartridge) using 50-100% ethyl acetate in hexane followed by 10-40% methanol in dichloromethane to give a yellow oil ( 29.17 g, quantitative) was obtained.

  Gradient method: 50% EA / Hex for 4 minutes, gradient to 100% EA over 6 minutes, hold at 100% EA for 5 minutes, change solvent to 10% MeOH in DCM and hold for 0 minutes, 40% MeOH Gradient to DCM solution over 1 minute, hold with 40% MeOH DCM solution for 8 minutes. Fractions were pooled and concentrated to a yellow oil (29.17 g, quantitative).

Step 11:
In a 400 mL Parr flask, (R) -1- (2- (benzyloxy) ethyl) -3-methylpyrrolidine (10.000 g, 45.6 mmol, 1.0 eq) (0.4822 g, 0.7137 g) was added. In addition, methanol (60 mL) was added and the solution was cooled in an ice bath for 10 minutes. To the cooled solution was added 20% Pd (OH) 2 carbon, 50% H 2 O (6.403 g, 45.6 mmol, 1.0 eq) and flushed with nitrogen. To the mixture was added hydrochloric acid (6M, 7.6 mL). The flask was pressurized to 30 psi with hydrogen and shaken for 1 minute to release hydrogen. This was repeated two more times and pressurized with hydrogen to 100 psi. This suspension was shaken for 16 hours. A sample was taken and TLC (10% MeOH in DCM) showed that the reaction was not complete and additional catalyst (2.0 g) was added to the mixture. The reaction was treated in the same manner as described above and shaken for an additional 30 hours on the hydrogenator. Celite (5 g) was added to the Parr flask and the mixture was filtered through a Celite pad (2 cm). The solid was washed with methanol (2 × 250 mL). The filtrate was concentrated and dried with a rotary evaporator to obtain a red oil (7.81 g). The oil was dissolved in methanol (50 mL), and 25% sodium methoxide methanol solution (9.9 mL, 45.5 mmol, 1 equivalent) was added to the methanol solution to give a white suspension. The mixture was concentrated to dryness and dissolved in anhydrous DCM (35 mL). The suspension was centrifuged at 3K rpm for 5 minutes. The clear solution was collected and the solid was suspended in DCM (35 mL). This process was repeated a total of 4 times. The solutions were combined and concentrated to a yellow liquid (5.6341 g, 95.6%).

  OP-1046 and OP-1047 were synthesized according to the above general procedure and using appropriate reagents and starting materials.

Synthesis of HCl salts of OP-1038 and OP-1074 3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl ) -2H-chromen-7-ol (OP-1038, 0.020 g, 0.0 mmol, 1.0 eq) or (2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-Methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol (OP-1074, 0.020 g, 0.0 mmol, 1.0 eq) (Compound 33 ) Was placed in a 1-dram vial and dissolved in methanol (0.2 mL). To the solution was added 4M HCl methanol solution (200 μL) and stirred for 15 minutes. The yellow solution was concentrated to a yellow-orange solid (0.022 g and 0.0206 g, respectively).

Synthesis of OP-1083 OP-1083 was prepared by air-oxidizing OP-1074 followed by chromatographic separation of OP-1083 and OP-1074. A 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 deep red powder. This powder was applied to a cartridge and chromatographed on silica gel (4 g cartridge) using 0-25% methanol in dichloromethane to give OP-1074 as an orange solid (0.261 g, 46.6%), OP-1083. Was obtained as an orange solid (41.1 mg, 15%).

  Method: 0% MeOH for 4 minutes, gradient to 5% MeOH / DCM over 5 minutes, 5% hold for 6 minutes, gradient over 2 minutes to 10% MeOH / DCM with 10% MeOH / DCM Hold for 8 minutes, gradient over 25 minutes to 25% MeOH / DCM, hold at 25% for 5 minutes.

Synthesis of OP-1084 In a 30 mL vial, (2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy } Phenyl) -2H-chromen-7-ol (0.020 g, 0.0 mmol, 1.0 eq) was added and suspended in anhydrous ethyl acetate (20 mL). To the suspension was added diisopropylethylamine (19 ul, 0.1 mmol, 2.5 eq) and the solution was cooled in an ice bath for 5 minutes. Ethyl chloroformate (10 ul, 0.1 mmol, 2.3 equivalents) was added to the reaction solution with an airtight syringe. The reaction immediately became a white cloudy suspension. The reaction solution was removed from the ice bath and stirred at room temperature for 16 hours. The reaction was concentrated to dryness, dissolved in a minimum amount of DCM and applied to a 4 g silica gel cartridge. The crude material was eluted with 0-15% MeOH / DCM to give the desired product as a pale yellow film (0.0068 g, 27%).

  TLC (5% MeOH / DCM): 4 spots, 0.84, 0.42, 0.26 (product), 0.16 (monocarbonate). Gradient method: 0% MeOH / DCM held for 2 minutes, 5% MeOH / DCM over 5 minutes, 5% MeOH / DCM over 3 minutes, 15% MeOH / DCM over 3 minutes Hold for 15 minutes with 15% MeOH / DCM. Fractions 16-19 were pooled: 6.8 mg. LCMS (m / z): 602; HPLC (254 nm): 95.65%.

Synthesis of OP-1085 To a dry 1-dram vial equipped with a stir bar, in a stream of N2, (2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R ) -3-Methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol (0.035 g, 0.1 mmol, 1.0 equiv) was added. The vial was sealed with a septum and freshly distilled pyridine (400 ul, 5.0 mmol, 113.6 equiv) was added to the vial with a syringe to give a dark pink solution. The vial was cooled in a 0 ° C. ice / water bath for 10 minutes and to the solution trimethylacetyl chloride (100 ul, 0.8 mmol, 10.6 equiv) was added in one portion with a GC syringe. The solution immediately became pale yellow and was stirred at 0 ° C. for 30 minutes. The reaction was allowed to reach room temperature over 30 minutes and stirred at room temperature for 1 hour. Analysis of the sample by LCMS indicated the presence of a mixture of monoester and diester. The reaction mixture was concentrated to dryness, dissolved in a minimum amount of DCM and chromatographed on silica gel (4 g cartridge) using 0-25 MeOH / DCM. Product containing fractions were pooled and concentrated to give a pale yellow film (9.2 mg, 33%).

  Gradient: 0% MeOH / DCM for 2 minutes, gradient over 2.5 minutes to 2.5% MeOH / DCM, hold for 5 minutes with 2.5% MeOH / DCM over 1 minute to 10% MeOH / DCM Gradient for 10 min with 10% MeOH / DCM, gradient over 2 min to 25% MeOH / DCM, 7 min at 25%. Fractions 11-17 and 19-28 were pooled. LCMS (m / z): M + 1, 626; HPLC (254 nm): 98.0%.

Synthesis of OP-1086 and OP-1088 To a dry 1-dram vial equipped with a stir bar was added pyridine (2000 ul, 24.8 mmol, 113.6 equiv). The vial was cooled with a −15 ° C. dry ice methanol / water bath. To the solution, phosphorus oxychloride (71 ul, 0.8 mmol, 3.5 eq) was added in one portion with a GC syringe. The solution was stirred for 5 minutes and then solid 3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] in N 2 stream. ] Ethoxy} phenyl) -2H-chromen-7-ol (OP-1038, 0.100 g, 0.2 mmol, 1.0 equiv) or (2S) -3- (4-hydroxyphenyl) -4-methyl-2 -(4- {2-[(3R) -3-Methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromen-7-ol (OP-1074, 0.100 g, 0.2 mmol, 1.0 equiv. ) Was added at once. The reaction was stirred at this temperature for 1.5 hours. After about 45 minutes, the solution became a slurry. The reaction was allowed to reach room temperature over 45 minutes and stirred at room temperature for 2 hours. The sample was quenched with water and analysis showed it to be the desired product mass. The reaction mixture was concentrated to dryness. The crude mixture was suspended in 2N HCl (5 mL). The suspension was sonicated and centrifuged at 5000 rpm for 6 minutes. The supernatant was decanted and the solid was resuspended in 5 mL of 2N HCl and the process was repeated. The solid was dried in vacuo to give 129 mg of crude product. The solid was suspended in water (2 mL) and 6N sodium hydroxide solution (174 μL, 1 mmol, 5 eq) was added to give an orange solution. This was purified by preparative LC using acetonitrile and water to give the product as a tan solid.

Synthesis of OP-1087 In a 30 mL vial, (2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} Phenyl) -2H-chromen-7-ol (0.020 g, 0.0 mmol, 1.0 eq) was added and suspended in anhydrous ethyl acetate (20 mL). To the suspension was added diisopropylethylamine (19 ul, 0.1 mmol, 2.5 eq) and the solution was cooled in an ice bath for 5 minutes. To the reaction solution, methyl chloroformate (7 ul, 0.1 mmol, 2.2 eq) was added with an airtight syringe. The reaction immediately became a white cloudy suspension. The reaction solution was removed from the ice bath and stirred at room temperature for 16 hours. The reaction was concentrated to dryness, dissolved in a minimum amount of DCM and applied to a 4 g silica gel cartridge. The crude material was eluted with 0-15% MeOH / DCM to give the desired product as a pale yellow film (0.0096 g, 40%).

  TLC (5% MeOH / DCM): 4 spots, 0.95, 0.55, 0.38 (product), 0.25 (monocarbonate).

  Gradient method: 0% MeOH / DCM held for 2 minutes, 5% MeOH / DCM over 5 minutes, 5% MeOH / DCM over 3 minutes, 15% MeOH / DCM over 3 minutes Hold for 15 minutes with 15% MeOH / DCM. Fractions 11-15 were pooled: 9.6 mg. LCMS (m / z): 574; HPLC (254 nm): 95.08%.

Assays The compounds provided herein can be evaluated using various in vitro and in vivo assays, examples of which are described below.

  The following biological examples are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting the scope thereof.

Demonstration of the superiority of OP-1074 in combination with chemotherapy using a sensitive in vitro proliferation assay. Growth on MCF-7 was treated in triplicate with an anti-estrogen drug in the presence of 100 pM E2. 6-8 days after measurement using a fluorescent DNA binding dye. Specifically, MCF-7 cells were treated with anti-estrogens alone or in combination with other chemotherapeutic drugs for 6-8 days in the presence of 100 pM E2 in hormone removal medium. Proliferation was measured using a Cyquant fluorescent DNA binding dye (Invitrogen, Grand Island, NY). Results are from a representative single experiment and are reported as mean percentage induced for E2 of triplicate treatments, error bars represent SEM.

  As shown in FIG. 1, OP-1074 increases the potency and efficacy of the CDK4 / 6 inhibitor PD-0332991 in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The antiestrogen drug OP-1074 enhances the efficacy and efficacy of PD-0332991 in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of antiestrogens and PD-0332991 in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium for 6-7 days. FIG. 1A plots the effect of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of PD-0332991 on MCF-7 cell proliferation. FIG. 1B plots the effect of medium combined with increasing amounts of OP-1074 or 100 nM PD-0332991 on MCF-7 cell proliferation. FIG. 1C plots the effect of increasing amounts of PD-0332991 in combination with 3 nM OP-1074, Tamoxifen, or fulvestrant on MCF-7 cell proliferation. As can be seen from these experiments, when OP-1074 is combined with PD-0332991 at several concentrations, the percentage of MCF-7 breast cell proliferation is lower than either drug alone.

  As shown in FIG. 2, OP-1074 increases the efficacy of the mTOR inhibitor everolimus in inhibiting MCF-7 breast cell proliferation stimulated by E2. The anti-estrogen drug OP-1074 enhances the efficacy and efficacy of the mTOR inhibitor everolimus in the inhibition of breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and everolimus for 6 days in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium. FIG. 2A plots the effect of vehicle, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of everolimus on MCF-7 cell proliferation. FIG. 2B plots the effect of 1 nM or 10 nM everolimus on MCF-7 cell proliferation in combination with increasing amounts of OP-1074. FIG. 2C plots the effect of media combined with increasing amounts of everolimus, or 3 nM OP-1074, Tamoxifen, or fulvestrant on MCF-7 cell proliferation. As can be seen from these experiments, when OP-1074 is combined with everolimus at several concentrations, the percentage of MCF-7 breast cell proliferation is lower than either drug alone.

  As shown in FIG. 3, OP-1074 increases the efficacy of the universal PI3K inhibitor BKM-120 in inhibiting MCF-7 breast cell proliferation stimulated by E2. The anti-estrogen drug OP-1074 enhances the efficacy and potency of the PI3K inhibitor BKM-120 in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and BKM-120 in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium for 7 days. FIG. 3A plots the effect of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of BKM-120 on MCF-7 cell proliferation. FIG. 3B plots the effect of 32 nM or 100 nM BKM-120 on increasing MCF-7 cell proliferation in combination with increasing amounts of OP-1074. As can be seen from these experiments, when OP-1074 is combined with BKM-120 at several concentrations, the percentage of MCF-7 breast cell proliferation is lower than either drug alone.

  As shown in FIG. 4, OP-1074 increases the efficacy of 5-fluorouracil in inhibiting MCF-7 breast cell proliferation stimulated by E2. The anti-estrogen drug OP-1074 enhances the efficacy and efficacy of the thymidylate synthase inhibitor 5-fluorouracil in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and 5-fluorouracil for 6 days in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium. The effects of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of 5-fluorouracil on MCF-7 cell proliferation are plotted. As can be seen from these experiments, when OP-1074 is combined with 5-fluorouracil at several concentrations, the percentage of MCF-7 breast cell proliferation is lower than either drug alone.

  As shown in FIG. 5, OP-1074 increases the efficacy of taxanes in inhibiting MCF-7 breast cell proliferation stimulated by E2. The antiestrogen agent OP-1074 enhances the efficacy and efficacy of paclitaxel and docetaxel in inhibiting breast cell proliferation stimulated by E2 in vitro. MCF-7 cells were treated with the indicated amounts of OP-1074 and taxane in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium for 6 days. FIG. 5A plots the effect of medium, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of paclitaxel on MCF-7 cell proliferation. FIG. 5B plots the effect of vehicle, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of docetaxel on MCF-7 cell proliferation. As can be seen from these experiments, when OP-1074 is combined with paclitaxel or docetaxel at several concentrations, the percentage of MCF-7 breast cell proliferation is lower than either drug alone.

  As shown in FIG. 6, OP-1074 increases the efficacy of anthracycline xorubicin in inhibiting ECF-stimulated MCF-7 breast cell proliferation. The antiestrogen OP-1074 enhances the efficacy and efficacy of anthracycline xorubicin in inhibiting in vitro breast cell proliferation stimulated by E2. MCF-7 cells were treated with the indicated amounts of OP-1074 and doxorubicin for 7 days in the presence of 100 pM 17β-estradiol (E2) in hormone removal medium. The effects of vehicle, 1, 10 or 100 nM OP-1074 in combination with increasing amounts of doxorubicin on MCF-7 cell proliferation are plotted. As can be seen from these experiments, when OP-1074 is combined with doxorubicin at several concentrations, the percentage of MCF-7 breast cell proliferation is lower than either drug alone.

Definitions The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, eg, enantiomers and / or diastereoisomers. . For example, the compounds described herein may be in the form of individual enantiomers, diastereoisomers, or geometric isomers, or are enriched in racemic mixtures, and one or more stereoisomers. In some cases, the mixture may be in the form of a mixture of stereoisomers. Isomers can also be isolated from mixtures by methods known to those skilled in the art including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization, or preferred isomers by asymmetric synthesis. Can also be prepared. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33: 2725 (1977); Eliel, Stereochemistry b See Tables of Resolving Agents and Optical Resolutions, page 268 (edited by EL Eliel, Univ. Of Notre Name Press, Notre Dam, IN, 1972). Unless stated otherwise, the invention includes the compounds described herein as individual isomers substantially free of other isomers, while as mixtures of various isomers.

  The articles “a” and “an” are used herein to refer to one or more (ie, at least one) grammatical objects of an article. Can do. By way of example, “an analog” means one analog or more than one analog.

  “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be addition salts of inorganic or organic acids or base addition salts. Specifically, such salts include (1) formed against inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, propionic acid, hexanoic acid, cyclopentanepropion. 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, camphorsulfonic acid 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropyl Acid addition salts formed with organic acids such as pionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, or (2) parent When acidic protons present in the compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine And salts formed when it coordinates. The salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functional group, a salt of a non-toxic organic or inorganic acid, such as , Hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. (eg Berge et al., J. Pharm. Sci. 66 (1): 1-79 ('77 1 Month)).

  “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

  A “group that is cleaved by pharmaceutically acceptable metabolism” refers to a group that is cleaved in vivo to yield the parent molecule shown herein.

  A “prodrug” includes a derivative of a compound of the invention, including a derivative of the compound of the invention, having a group that is cleaved and having pharmacological activity in vivo by solvolysis or under physiological conditions. Is a compound.

  “Solvate” refers to a form of a compound that is associated with a solvent or water (also referred to as a “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention can be prepared, for example, in crystalline or liquid form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include stoichiometric solvates and non-stoichiometric solvates. In certain examples, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystalline lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

  “Subjects” for which administration is intended include, but are not limited to, humans (ie, men or women of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young) Middle-aged or elderly adults)), and / or non-human animals, such as primates (eg, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs Mammals such as In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. As used herein, the terms “human”, “patient”, and “subject” are used interchangeably.

  As used herein, the term “pure with respect to enantiomer” or “pure enantiomer” means that the compound comprises more than 95% by weight. In an alternative embodiment, when specified, the term indicates that the enantiomer is greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, greater than 98.5 wt%, greater than 99 wt%, Greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% by weight. Sometimes it points. Weight is based on the total weight of all enantiomers or stereoisomers of the compound.

  As used herein and unless otherwise indicated, the term “enantiomerically pure R-compound” means at least 95% by weight of R-compound and at most about 5% by weight of S-compound. Refers to that. In an alternative embodiment, when specified, the term includes at least about 99 wt.% R-compound, at most about 1 wt.% S-compound, or at least about 99.9 wt.% R-compound, S-compound. May be at most about 0.1% by weight. In certain embodiments, the weight is based on the total weight of the compound.

  As used herein and unless otherwise indicated, the term “enantiomerically pure S-compound” or “S-compound” means that the S-compound is at least about 95% by weight and the R-compound is high. Both indicate about 5% by weight. In alternative embodiments, when specified, the term includes at least about 99% by weight of the S-compound, at most about 1% by weight of the R-compound, or at least about 99.9% by weight of the S-compound. May be at most about 0.1% by weight. In certain embodiments, the weight is based on the total weight of the compound.

  These and other exemplary substituents are described in greater detail in the Detailed Description, the Examples, and the Claims. The present invention is not limited in any way by the above list of exemplary substituents.

Claims (37)

A method of treating a disorder modulated, mediated, or affected by an estrogen receptor in a subject comprising:

[Wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Can be independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle)]
Or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide thereof,
A method comprising administering to a subject in combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.   2. The method of claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt. Compound has chemical structure:

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene The method of claim 1, which is -7-ol or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof. A method of treating a disorder modulated, mediated, or affected by an estrogen receptor in a subject comprising a chemical structure:

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene A compound that is -7-ol or a pharmaceutically acceptable salt thereof,
A method comprising administering to a subject in combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.   5. A method according to claim 1 or 4, wherein the disorder is mediated by an estrogen receptor.   The method according to claim 1 or 4, wherein the disorder is breast cancer.   7. The method of claim 6, wherein the breast cancer is a local, advanced, or metastatic estrogen or progesterone receptor positive advanced breast cancer.   The method according to claim 6, wherein the breast cancer is estrogen or progesterone receptor positive advanced breast cancer.   7. The method of claim 6, wherein the breast cancer is estrogen or progesterone receptor negative breast cancer.   5. The method according to claim 1 or 4, wherein the disorder is selected from the group consisting of ovarian cancer, endometrial cancer, vaginal cancer, and endometriosis.   The method according to claim 1 or 4, wherein the disorder is retinoblastoma positive breast cancer.   The method according to claim 1 or 4, wherein the disorder is selected from the group consisting of retinoblastoma-positive endometrial cancer, vaginal cancer, and ovarian cancer, lung cancer and bronchial cancer.   The method according to claim 1 or 4, wherein the disorder is lung cancer or bronchial cancer.   The method of claim 1 or 4, wherein the agent is a CDK4 / 6 inhibitor.   15. The method of claim 14, wherein the CDK4 / 6 inhibitor is PD-0332991, LY2835219, or LEE011.   15. The method of claim 14, wherein the CDK4 / 6 inhibitor is PD-0332991 or a pharmaceutically acceptable salt thereof.   15. The method of claim 14, wherein the CDK4 / 6 inhibitor is PD-0332991.   5. The method according to claim 1 or 4, wherein the agent is an mTOR inhibitor.   19. The method of claim 18, wherein the mTOR inhibitor is everolimus.   19. The method of claim 18, wherein the mTOR inhibitor is rapamycin, everolimus, temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, or Pp121.   5. The method of claim 1 or 4, wherein the agent is a PI3 kinase inhibitor.   The method of claim 21, wherein the PI3 kinase inhibitor is BKM-120, XL-147, RG-7321, CH-5132799, and BAY-80-6946.   24. The method of claim 21, wherein the PI3 kinase inhibitor is BKM-120.   The method of claim 1 or 4, wherein the agent is a taxane.   25. The method of claim 24, wherein the taxane is paclitaxel or docetaxel.   The method of claim 1 or 4, wherein the drug is an antimetabolite.   27. The method of claim 26, wherein the antimetabolite is 5-fluorouracil.   The method according to claim 1 or 4, wherein the drug is an antitumor antibiotic.   30. The method of claim 28, wherein the antitumor antibiotic is doxorubicin.

[Wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Can be independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle)]
A pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide thereof,
in combination with a drug selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic;
A pharmaceutical composition comprising a pharmaceutically acceptable carrier.   32. The pharmaceutical composition according to claim 30, wherein the compound is in the form of a pharmaceutically acceptable salt. Compound has chemical structure:

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene 32. The pharmaceutical composition according to claim 31, which is -7-ol or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof. Chemical structure:

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene A pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, which is -7-ol,
A pharmaceutical comprising a combination of a drug selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic, and a pharmaceutically acceptable carrier Composition. For treating disorders modulated, mediated or affected by estrogen receptors,

A compound wherein R ₁ and R ₂ are independently OH or OR ⁹ ;
R ⁹ is H, halogen (Cl, Br, I or F), a natural or non-naturally occurring amino acid (OC (O)-or C (O) O- (ester) or amino (-C (O) -N - or -N-C (O) - (amide bond) via a) of those attached via ^any), R 10, is selected from ^{-OR 10} or ^{-SR 10,} independently,
R ¹⁰ is —C (═O) R ^C1 , —C (═O) OR ^C1 , —C (═O) SR ^C1 , —C (═O) N (R ^C1 ) ₂ , or 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,
^{_{-S (= O) 2 R C1}} , -S (= O) 2 OR C1, -S (= O) R C1, -S (= O) OR C1, -P (= O) 2 R C1, -P (═O) ₂ OR ^C1 , —P (═O) (OR ^C1 ) ₂ , —P (═O) (R ^C1 ) ₂ , or —P (R ^C1 ) (OR ^C1 ), or an oxygen protecting group Oxygen (when it is administered yields OH), sulfur bound to a sulfur protecting group (when administered it produces SH or disulfide), or nitrogen bound to a nitrogen protecting group (when administered) -NH-)
R ^C1 is 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 Independently selected from heteroaryl, or two R ^C1 groups together form a substituted or unsubstituted heterocycle]
Or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or N-oxide thereof,
A combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.   35. A combination according to claim 34, wherein the compound is in the form of a pharmaceutically acceptable salt. Compound has chemical structure:

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene 35. The combination of claim 34, which is -7-ol or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof. Chemical structures for treating disorders that are modulated, mediated, or affected by estrogen receptors:

(2S) -3- (4-hydroxyphenyl) -4-methyl-2- (4- {2-[(3R) -3-methylpyrrolidin-1-yl] ethoxy} phenyl) -2H-chromene -7-ol or a pharmaceutically acceptable salt thereof,
A combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.

Images