WO2022020605A1 - Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé - Google Patents

Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé Download PDF

Info

Publication number
WO2022020605A1
WO2022020605A1 PCT/US2021/042796 US2021042796W WO2022020605A1 WO 2022020605 A1 WO2022020605 A1 WO 2022020605A1 US 2021042796 W US2021042796 W US 2021042796W WO 2022020605 A1 WO2022020605 A1 WO 2022020605A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
cancer
erso
erd
Prior art date
Application number
PCT/US2021/042796
Other languages
English (en)
Inventor
Paul J. Hergenrother
David J. Shapiro
Matthew Boudreau
Original Assignee
The Board Of Trustees Of The University Of Illinois
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Board Of Trustees Of The University Of Illinois filed Critical The Board Of Trustees Of The University Of Illinois
Publication of WO2022020605A1 publication Critical patent/WO2022020605A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • Endocrine (hormonal) therapies for these tumors include aromatase inhibitors that block estrogen production.
  • Examples of endocrine therapies include tamoxifen, which competes with estrogens for binding to ERD, and fulvestrant/Faslodex/ICI 182,780, which both competes with estrogens and promotes ERD degradation.
  • tamoxifen which competes with estrogens for binding to ERD
  • fulvestrant/Faslodex/ICI 182,780 which both competes with estrogens and promotes ERD degradation.
  • MDR1 Multidrug Resistance Protein 1
  • This disclosure provides small molecule therapeutic compounds with greatly increased therapeutic potential compared to known therapeutic compounds for cancer that metastasized to the brain.
  • the compounds display an improved ability to actually kill cancer cells, including therapy-resistant cancer cells.
  • the therapy-resistant cancer cells that metastasized to the brain can include breast cancer cells, ovarian cancer cells, and endometrial cancer cells. To prevent cancer recurrence, it is critical to destroy the entire population of growing and dormant therapy- resistant cancer cells.
  • this disclosure provides therapeutic compounds that, compared to BHPI and to endocrine therapies such as tamoxifen and fulvestrant, possess significantly increased ability to kill cancer cells, and thus, dramatically increased therapeutic potential.
  • endocrine therapies such as tamoxifen and fulvestrant
  • ErSO and ErSO(OH) which can cross the blood-brain barrier have greatly increased ability to kill breast cancer cells metastasized to the brain and therefore shows dramatically increased therapeutic potential.
  • this disclosure provides a method for treating an alpha estrogen receptor (ERD ⁇ positive cancer that metastasized to the brain comprising administering to a subject having an ERD positive cancer that metastasized to the brain a therapeutically effective amount of a compound of Formula I: or a salt thereof; wherein X is O, S, or NR D ; Z is O, S, or NR D ; R 1 is trifluoromethyl, trifluoromethoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -OR A , -SR A , or -N(R A ) 2 ; R 2 , R 3 , and R 4 are each independently H, halo, -OR A , -SR A , -N(R A ) 2 , alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A 1 , A 2 , and A 3 are each independently H, OH, halo
  • alkyl is substituted with three halo groups provides a trihaloalkyl such as a trifluoromethyl.
  • any alkyl group of Formula I can be a trifluoromethyl group.
  • Compounds of the formulas described herein can bind to the alpha estrogen receptor (ERD) and kill or inhibit the growth of cancer cells by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum.
  • the compound of Formula I is cytotoxic. Accordingly, this disclosure provides a method of treating a cancer that metastasized to the brain comprising administering to an ERD positive cancer subject in need thereof a therapeutically effective amount of a compound described herein, thereby treating the cancer in the subject.
  • the cancer that metastasized to the brain can be from, for example, breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, endometrial cancer, lung cancer, pancreatic cancer, prostate cancer, or colon cancer.
  • BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention.
  • mice (CD-1) were treated with the indicated doses and times, then sacrificed and their serum and brains collected. Concentrations were determined via LC/MS/MS analysis. The average blood per mouse was approximated as 58.5 mL/kg.
  • FIG. 1 Mouse model of ERD+ metastasis to the brain. Percent change comprising of Day 0 and Day 14 for MYSluc for the brain metastases model. Representative image showing ErSO induces regression in a brain tumor. Images are 3D-DLIT renders. Figure 4. ErSO induces profound regression of breast cancer in brain. 40 mg/kg ErSO injected subcutaneously daily for 14 days. Figure 5. ErSO induces profound regression of breast cancer in brain.
  • MYS-Luc MYS-Luc (MCF7-ER ⁇ Y537S-Luc cells); Tumor Model: Direct injection of MYS-Luc cells into the Brain; Tumor Outgrowth: 14 days showing Day 0 of treatment; Treatment: 40 mg/kg ErSO daily for 14 Days, injected subcutaneously in abdomen; Tumor Visualization: 3D tumor imaging with CAT scan of skeleton; Quantitation: Using a sensitive 2D imaging, this tumor regressed 96%.
  • Figure 6. Ex-vivo imaging of vehicle control and ErSO-treated breast cancer in the brain. In general, vehicle tumors formed diffuse metastases throughout the brain hemisphere into which the breast cancer cells were injected but did not spread into the other brain hemisphere.
  • DETAILED DESCRIPTION Cancer cells can remain quiescent for extended periods of time and then reactivate. It is therefore desirable to kill the tumor cells, not merely to prevent them from proliferating.
  • This disclosure provides therapeutic compounds, including cytotoxic compounds, and assays for testing compounds for the ability to kill cancer cells, including therapy-resistant breast cancer cells that metastasized to the brain.
  • new compounds that are more effective than BHPI in killing breast cancer cells expressing both wild type estrogen receptor D (ERD) and ERD mutations that are common in metastatic breast cancer. These mutations are associated with resistance to current breast cancer therapies.
  • ERD estrogen receptor D
  • Also provided herein are compounds active against ovarian cancer cells, uterine cancer cells, and other cancer cells that are ERD positive.
  • the compound BHPI illustrated above, is a known anticancer drug.
  • the compounds described herein share an oxindole core with BHPI but were surprisingly discovered to have vastly different therapeutic properties.
  • Various endocrine therapies such as BHPI, the 7- trifluormethyl BHPI derivative 01-15, fulvestrant, and tamoxifen merely slow cancer cell growth, i.e., they are cytostatic.
  • ErSO and ErSO(OH) are cytotoxic. Both ErSO and ErSO(OH) were identified by their distinct cytotoxicity profile and ability to quantitatively kill cancer cells, and therefore will be an effective therapy for treating tumors.
  • one or more substituents on a phenyl ring refers to one to five substituents on the ring.
  • all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about.” These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value without the modifier "about” also forms a further aspect.
  • any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • all language such as “up to”, “at least”, “greater than”, “less than”, “more than”, “or more”, and the like include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above.
  • all ratios recited herein also include all sub-ratios falling within the broader ratio.
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.
  • endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “number1” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10 means 1, 2, 3, 4, 5, ... 9, 10.
  • variable disclosed is a number less than “number10”, it implies a continuous range that includes whole numbers and fractional numbers less than number10, as discussed above. Similarly, if the variable disclosed is a number greater than “number10”, it implies a continuous range that includes whole numbers and fractional numbers greater than number10. These ranges can be modified by the term “about”, whose meaning has been described above.
  • contacting refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.
  • An "effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
  • an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art.
  • an “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
  • an “effective amount” generally means an amount that provides the desired effect.
  • the terms "effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).
  • treating include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
  • the terms “treat”, “treatment”, and “treating” can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated.
  • treatment can include medical, therapeutic, and/or prophylactic administration, as appropriate.
  • subject or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy.
  • a patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein.
  • patient may include either adults or juveniles (e.g., children).
  • patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of a compound of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site.
  • the compound can be administered by any appropriate route that results in delivery to a desired location in the subject.
  • the compounds and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs.
  • the terms “inhibit”, “inhibiting”, and “inhibition” refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells.
  • the inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.
  • the term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified.
  • the term could refer to a numerical value that may not be 100% the full numerical value.
  • the full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%.
  • halo or halide refers to fluoro, chloro, bromo, or iodo.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • alkyl refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below.
  • Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (iso-propyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3- dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like.
  • the alkyl can be unsubstituted or substituted, for example, with a substituent described below or otherwise described herein.
  • the alkyl can also be optionally partially or fully unsaturated.
  • the recitation of an alkyl group can include an alkenyl group or an alkynyl group.
  • the alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene).
  • An alkylene is an alkyl group having two free valences at carbon or two different carbon atoms of a carbon chain.
  • alkenylene and alkynylene are respectively an alkene and an alkyne having two free valences at two different carbon atoms.
  • cycloalkyl refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted.
  • the cycloalkyl group can be monovalent or divalent and can be optionally substituted as described for alkyl groups.
  • the cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like.
  • heterocycloalkyl or “heterocyclyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring.
  • Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyl substituents examples include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4- oxazepane, and 1,4-oxathiapane.
  • the group may be a terminal group or a bridging group.
  • aromatic refers to either an aryl or heteroaryl group or substituent described herein. Additionally, an aromatic moiety may be a bisaromatic moiety, a trisaromatic moiety, and so on.
  • a bisaromatic moiety has a single bond between two aromatic moieties such as, but not limited to, biphenyl, or bipyridine. Similarly, a trisaromatic moiety has a single bond between each aromatic moiety.
  • aryl refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • the radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system.
  • the aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms.
  • the aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl).
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • the aryl can be unsubstituted or optionally substituted with a substituent described below.
  • heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring.
  • the heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of "substituted”.
  • Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms, wherein the ring skeleton comprises a 5-membered ring, a 6-membered ring, two 5-membered rings, two 6-membered rings, or a 5-membered ring fused to a 6-membered ring.
  • heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H- quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, E-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
  • heteroaryl denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non- peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (C 1 -C 6 )alkylaryl.
  • heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • substituted or “substituent” is intended to indicate that one or more (for example, in various embodiments, 1-10; in other embodiments, 1-6; in some embodiments 1, 2, 3, 4, or 5; in certain embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a selection from the indicated group(s), or with a suitable group known to those of skill in the art, provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • Suitable indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkylthio, alkylsulfinyl, and alkylsulfonyl.
  • Substituents of the indicated groups can be those recited in a specific list of substituents described herein, or as one of skill in the art would recognize, can be one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, and cyano.
  • Suitable substituents of indicated groups can be bonded to a substituted carbon atom include F, Cl, Br, I, OR', OC(O)N(R') 2 , CN, CF 3 , OCF 3 , R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R') 2 , SR', SOR', SO 2 R', SO 2 N(R') 2 , SO 3 R', C(O)R', C(O)C(O)R', C(O)CH 2 C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R') 2 , OC(O)N(R') 2 , C(S)N(R') 2 , (CH 2 ) 0- 2 NHC(O)R', N(R')N(R')C(O)R', N(R')N(R')
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, which form part of the present invention.
  • Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s).
  • d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate (defined below), which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • enantiomerically enriched (“ee”) as used herein refers to mixtures that have one enantiomer present to a greater extent than another. Reactions that provide one enantiomer present to a greater extent than another would therefore be “enantioselective” (or demonstrate “enantioselectivity”).
  • the term “enantiomerically enriched” refers to a mixture having at least about 2% ee; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 5% ee; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 20%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 50%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 80%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 90%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 95%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 98%; in another embodiment of
  • enantiomerically enriched includes enantiomerically pure mixtures which are mixtures that are substantially free of the species of the opposite optical activity or one enantiomer is present in very low quantities, for example, 0.01%, 0.001% or 0.0001%.
  • IC 50 is generally defined as the concentration required to kill 50% of the cells in 24 hours.
  • ErSO(OH) refers to the active compound (S)-ErSO(OH), whereas the inactive compound is specifically referred to as (R)-ErSO(OH) and the racemic mixture is specifically referred to as (R/S)-ErSO(OH).
  • ErSO refers to the more active compound (R)-ErSO where (S)-ErSO is the less active compound.
  • Embodiments of the Invention provides a method for treating an alpha estrogen receptor (ERD ⁇ positive cancer that metastasized to the brain comprising administering to a subject having an ERD positive cancer that metastasized to the brain a therapeutically effective amount of a compound of Formula I: or a salt thereof; wherein X is O, S, or NR D ; Z is O, S, or NR D ; R 1 is trifluoromethyl, trifluoromethoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -OR A , -SR A , or -N(R A ) 2 ; R 2 , R 3 , and R 4 are each independently H, halo, -OR A , -SR A , -N(R A ) 2 , alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A 1 , A 2 , and A 3 are each independently H,
  • effective treatment results in complete elimination of a cancer in the brain (e.g., a cancerous brain tumor).
  • an effective 2-week treatment results in reducing a cancer in the brain by more than 90% of the initial volume of the cancer in the brain.
  • a 2-week treatment reduces the volume of the cancer in the brain by about 80%, about 70%, about 60%, or about 50%.
  • G 1 and G 2 are not both OH.
  • G 1 , G 2 , or G 3 is -OR B , -OR C , or -OR W , respectively, R B , R C , and R W each independently can be an oxygen protecting group.
  • alkyl when a variable, such as any one of R 1 -R 4 , A 1 -A 3 , G 1 - G 3 , R A , R B , R C , R D , or R W , is alkyl, the alkyl is optionally substituted with one or more substituents, such as one or more of the substituents described in the definition of substituents herein.
  • Alkyl optionally substituted with one or more substituents can be, for example, alkyl substituted with one to six substituents, one to five substituents, one to four substituents, one to three substituents, one or two substituents, or one substituent.
  • Alkyl optionally substituted with one or more substituents includes, for example, halo-substituted alkyl groups such as CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CF 2 CH 3 , or CF 2 CF 3 .
  • R 1 is CF 3 .
  • G 1 is CF 3 .
  • G 1 is OCF 3 .
  • G 2 is CF 3 .
  • G 2 is OCF3.
  • G 3 is CF3.
  • G 3 is OCF3.
  • G 1 is OR B .
  • R B is H or -(C1-C6)alkyl.
  • R B is -(C1)alkyl optionally substituted with one to three substituents. In various embodiments, R B is -(C 1 )alkyl substituted with one to three halo substituents. In one specific embodiment, G 1 is OH. In another specific embodiment, G 1 is methyl or trifluoromethyl. In some embodiments R B and R C are each independently –(C 1 -C 6 )CCR X wherein R X is H or –(C 1 -C 6 )alkyl. In various embodiments, alkyl or –(C 1 -C 6 )alkyl is saturated, or unsaturated wherein the unsaturated moiety comprises double bonds, triple bonds, or a combination thereof.
  • G 2 is OR C .
  • R C is H or -(C1-C6)alkyl.
  • R C is -(C1)alkyl optionally substituted with one to three substituents.
  • R C is -(C 1 )alkyl substituted with one to three halo substituents.
  • G 2 is OH.
  • G 2 is methyl or trifluoromethyl.
  • G 3 is OR W .
  • R W is H or -(C1-C6)alkyl.
  • R W is -(C1)alkyl optionally substituted with one to three substituents.
  • R W is -(C1)alkyl substituted with one to three halo substituents.
  • G 3 is OH.
  • G 3 is methyl or trifluoromethyl.
  • R A , R B , R C and R D are each independently H or -(C 1 -C 6 )alkyl.
  • R 1 , R 2 , R 3 and R 4 are each independently H, halo, or -(C 1 -C 6 )alkyl.
  • a 1 , A 2 , and A 3 are each independently H or halo, and G 1 is -OR B , and G 2 is -OR C .
  • X is NR D and Z is O.
  • R D is H.
  • R A , R B , R C , R D , R W , R 1 , R 2 , R 3 and R 4 are each independently -(C1-C6)alkyl, -(C2-C6)alkyl, -(C3-C6)alkyl, or -(C3-C6)cycloalkyl.
  • At least one -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkyl, -(C 3 -C 6 )alkyl, or -(C 3 - C 6 )cycloalkyl is substituted with one or more halo.
  • -(C 1 - C 6 )alkyl is trifluoromethyl.
  • R 1 is CH 3 , CH 2 CH 3 , CF 3 , CHF 2 , CH 2 CF 3 , CF 2 CH 3 , or CF 2 CF 3 .
  • G 1 is OH
  • G 2 is -OR C
  • R C is H, CH3, CH 2 CH3, CF3, CHF2, CH 2 CF3, CF2CH3, or CF2CF3.
  • R 1 is CH3 or CF3,
  • R 2 is H, F, or Cl
  • R 3 and R 4 are H
  • X is NH
  • Z is O
  • a 1 -A 3 are H
  • G 1 is OH
  • G 2 is OCF3
  • G 3 is OH.
  • the compound of Formula I is the (S)-enantiomer.
  • the compound of Formula I is the (R)-enantiomer.
  • the compound of Formula I is a compound of Formula II: wherein R 1 is –(C 1 -C 6 )alkyl; R 2 is H, halo, –(C1-C6)alkyl, or -OR A ; G 2 is -OR C , –(C1-C6)alkyl; and G 3 is H, halo, -OR W ; wherein –(C1-C6)alkyl is optionally substituted with one or more halo.
  • R 1 is CF 3
  • R 2 is H
  • G 1 is OH
  • G 2 is OCF 3
  • G 3 is OH.
  • At least one of G 1 , G 2 , and G 3 is OP wherein P is an oxygen protecting group selected from allyl, benzyl, thiobenzyl, acetyl, chloroacetyl, trifluoroacetyl, phenacyl, methyl methoxy, PEG (-(OCH 2 CH 2 ) n OH or (-(OCH 2 CH 2 ) n O-alkyl wherein n is 2 to about 1,000), an amino acid, and a silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), or t-butyl-diphenylsilyl (TBDPS)), or each of G 1 and G 3 is OP and their OP groups taken together form a benzylidene group.
  • P is an oxygen protecting group selected from allyl, benzyl, thiobenzyl, acetyl, chloroacetyl, tri
  • one or more hydrogen atoms is deuterium or tritium, one or more carbon atoms is a carbon isotope, or a combination thereof.
  • the compound is ErSO: (ErSO).
  • the compound is ErSO(OH): (ErSO(OH)).
  • the compound is levorotatory.
  • the compound is dextrorotatory.
  • the compound is (S)-ErSO(OH).
  • the compound is (R)-ErSO.
  • the compound is (S)-3-(3,4-dihydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one. In another embodiments, the compound is (R)-3-(3,4-dihydroxyphenyl)-3-(4- (trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one. In one other embodiment, the compound is (R)-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7- (trifluoromethyl)indolin-2-one.
  • the compound is (S)-3-(4- hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one.
  • the compound inhibits (or has a binding affinity for) ERD and has an anticancer cellular IC 50 that is less than about 200 nM.
  • the compound is metabolized by the subject to form an active metabolite that inhibits (or has a binding affinity for) ERD and has an anticancer cellular IC 50 that is less than about 200 nM.
  • the compound of Formula I or II, or the metabolized compound (of one enantiomer or racemate) inhibits or has a binding affinity for the alpha estrogen receptor (ERD) wherein the anticancer cellular IC 50 is less than about 500 nM.
  • the IC 50 for ERD is about 1 pM to about 1000 nM, about 0.1 nM to about 750 nM, about 1 nM to about 250 nM, about 5 nM to about 500 nM, about 10 nM to about 5000 nM, about 10 nM to about 80 nM, or about 20 nM to about 45 nM.
  • the compound can kill or inhibit the growth of cancer cells by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum.
  • the cancer cells can be ERD positive cancer cells.
  • the compounds are cytotoxic.
  • the cancer cells are breast cancer cells, ovarian cancer cells, or endometrial cancer cells.
  • This disclosure also provides a composition comprising the compound disclosed herein and a second drug.
  • the disclosure further provides a pharmaceutical composition comprising an enantiopure or enantioenriched compound disclosed herein in combination with a pharmaceutically acceptable diluent, carrier, excipient, or buffer.
  • the compound is a racemic or scalemic mixture of (R)-ErSO(OH) and (S)-ErSO(OH), or (R)-ErSO and (S)-ErSO.
  • the mixture is a mixture of enantiomers wherein the mixture of enantiomers has a ratio of about 50:50, about 45:55, about 40:60, about 30:70, about 20:80, about 10:90, or about 5:95.
  • the compound is (S)-ErSO(OH), (R)-ErSO, (R)-ErSO(OH), or (S)-ErSO.
  • the disclosure additionally provides a method of treating a cancer comprising administering to an ERD positive cancer subject in need thereof a therapeutically effective amount of a compound disclosed herein, thereby treating the cancer in the subject.
  • the compound kills or inhibits growth of ERD positive cancer that metastasized to the brain by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum.
  • the ERD positive cancer is a breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, or endometrial cancer.
  • the disclosure additionally provides a use of the compound for the treatment of an ERD positive cancer that metastasized to the brain.
  • the ERD positive cancer that metastasized to the brain can be a cancer metathesized from breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, endometrial cancer, or high-grade glioma.
  • the compound can be administered orally, by injection, subcutaneously, sublingually, rectally, by infusion, intravenously, or by dermal absorption.
  • the therapeutically effective amount of the compound is administered orally, intravenously, subcutaneously, transdermally, or intramuscularly.
  • the compound crosses the blood-brain barrier to enter the subject’s brain in an amount sufficient to effectively treat the subject having ERD positive cancer that metastasized to the brain.
  • the sufficient amount of compound in the subject’s brain is at least 10 mol% of the therapeutically effective amount of the compound administered orally, intravenously, subcutaneously, transdermally, or intramuscularly. In other embodiments, at least 10 mol% of the compound administered crosses the blood-brain barrier.
  • the amount of compound that crosses the blood-brain barrier is about 10 mol% to about 20 mol%, about 20 mol% to about 30 mol%, about 30 mol% to about 40 mol%, about 40 mol% to about 50 mol%, about 50 mol% to about 60 mol%, about 60 mol% to about 70 mol%, about 70 mol% to about 80 mol%, about 80 mol% to about 90 mol%, or about 90 mol% to about 100 mol%.
  • the recited mol% is weight%.
  • the therapeutically effective amount of the compound administered to a human in a single dose is about 75 mg/kg or less.
  • the single dose is about 60 mg/kg, about 50 mg/kg, about 40 mg/kg, about 30 mg/kg, about 20 mg/kg, about 10 mg/kg, or about 5 mg/kg.
  • the therapeutically effective amount of the compound administered is at least 1 mg/kg/day in a human, or about 200 mg/kg/day or less.
  • the therapeutically effective amount of the compound administered is about 5 mg/kg/day to about 150 mg/kg/day, about 10 mg/kg/day, about 20 mg/kg/day, about 30 mg/kg/day, about 40 mg/kg/day, about 50 mg/kg/day, about 60 mg/kg/day, about 70 mg/kg/day, about 80 mg/kg/day, about 90 mg/kg/day, about 100 mg/kg/day, about 110 mg/kg/day, about 120 mg/kg/day, about 130 mg/kg/day, about 140 mg/kg/day, about 160 mg/kg/day, about 170 mg/kg/day, about 180 mg/kg/day, about 190 mg/kg/day, or about 200 mg/kg/day to about 400 mg/kg/day.
  • the compound is administered in combination with a pharmaceutically acceptable carrier.
  • the method further comprises administering a second active agent.
  • the second active agent is ErSO.
  • the second active agent is ErSO(OH).
  • the second active agent is tamoxifen, fulvestrant (Faslodex/ICI 182,780), an aromatase inhibitor (e.g. anastrozole), or a combination thereof.
  • ErSO and/or ErSO(OH) is combined with endocrine therapy.
  • the second active agent and the compound are administered sequentially or simultaneously (in a combined mixture or separately).
  • the compound is administered before (or after) the second active agent.
  • this disclosure provides a method for treating an alpha estrogen receptor (ERD ⁇ positive breast cancer that metastasized to the brain comprising administering to a human having an ERD positive breast cancer that metastasized to the brain a therapeutically effective amount of ErSO or ErSO(OH): wherein the therapeutically effective amount of the compound is about 200 mg/kg/day or less and the compound is administered orally, intravenously, subcutaneously, transdermally, or intramuscularly, wherein the cancer is thereby treated.
  • the therapeutically effective amount of the compound administered is about 1 mg/kg/day to about 150 mg/kg/day.
  • Metastatic estrogen receptor D (ERD) positive breast cancer is presently incurable, and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ERD to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. To target metastatic ERD positive breast cancer, we exploited our finding that estrogen-ERD activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO.
  • UTR anticipatory unfolded protein response
  • ErSO kills cancer cells by acting non-competitively through ERD to induce lethal hyperactivation of the anticipatory UPR, triggering rapid necrotic cell death.
  • luciferase to image primary tumors and metastases containing lethal ERDD538G and ERDY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity.
  • oral and injected ErSO induced complete regression (>115,000 fold mean regression) in about 45% of mice (18/39). Although durable response without treatment for 4-6 months was common, tumors that did recur remained fully sensitive to ErSO re-treatment.
  • ErSO medium from breast cancer cells killed by ErSO contained high levels of the established immune cell activators, HMGB1 and ATP, robustly activated mouse and human macrophage and increased macrophage migration.
  • use of ErSO is not limited to breast cancer. ErSO rapidly kills ERD positive ovarian and endometrial cancer cells that do not require estrogen for growth. ErSO’s potent activity against advanced primary and metastatic ER ⁇ -positive breast cancers represents a paradigm shift in leveraging ER ⁇ for anticancer efficacy.
  • the CRISPR/Cas9 gene editing system was used to replace wild type ERD in T47D human breast cancer cells with the two most common ERD mutations seen in metastatic breast cancer, ERDY537S and ERDD538G.
  • the resulting cell lines TYS-4 (also called TYS) and TDG-1 (also called TDG) exhibit significant resistance to tamoxifen (the active form of tamoxifen is z-4-hydroxytamoxifen; z-OHT) and to fulvestrant/ICI 182,780.
  • TDG-4 also called TYS
  • TDG-1 also called TDG
  • tamoxifen the active form of tamoxifen is z-4-hydroxytamoxifen; z-OHT
  • fulvestrant/ICI 182,780 To allow visualization of tumors harboring these mutations in live animal, clonal lines of TYS and TDG cells stably expressing firefly luciferase were isolated. Orthotopic mouse tumors containing these TYS-Luc and TYDG-Luc cells are visualized in live animals by bioluminescent imaging (BLI).
  • IVIS In Vivo Imaging System
  • BHPI is a potent first-in-class non-competitive small molecule ERD biomodulator that kills therapy-resistant ERD positive breast and endometrial cancer cells and blocks growth of ovarian cancer cells.
  • BHPI binds at a different site on ERD than tamoxifen and fulvestrant and has a different mechanism of action. It was demonstrated that BHPI works through ERD to induce persistent lethal hyperactivation of the anticipatory pathway of activation of the unfolded protein response (UPR).
  • URR unfolded protein response
  • BHPI selectively blocks growth of cancer cells.
  • BHPI blocked proliferation of the TYS and TDG cells expressing ERD mutations identified in metastatic breast cancer.
  • Trypan Blue uptake is universally accepted as a measure of cell death, it has not been used by others to test potential anticancer drugs. Additional assays used to evaluate cell death include fluorescence activated cell sorting (FACS) and assays based on inhibition of proliferation and determination of cell number, sometimes in conjunction with raptinal, a compound known to induce 100% cell death.
  • FACS fluorescence activated cell sorting
  • novel compounds that are superior to BHPI in their ability to kill breast cancer cells were identified. This led to the discovery of ErSO, a small molecule with potent anticancer efficacy with significant cancer cell selectivity even at concentrations more than 10 times higher than those needed to eradicate ER ⁇ positive breast cancer cells.
  • mice Female Mice, compounds were formulated in 5% DMSO, 10% Tween-20, 85% PBS and solutions filtered prior to tail-vein injection; 3 mice were treated with each (R)-ErSO dose, 2-3 mice per (S)-ErSO dose level, and 2 mice per (S)-ErSO(OH) dose.
  • the results in Table 3 indicates that decreasing clogP and clogBB is a viable strategy to reduce toxicity.
  • Mechanism of Action of ErSO(OH) include, but are not limited to, inducing lethal hyperactivation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR).
  • Endoplasmic reticulum (EnR) stress sensor of the unfolded protein response (UPR) balances the synthesis of new proteins with the availability of chaperones and other proteins that help fold and transport proteins within cells.
  • the anticipatory UPR pathway is activated in the absence of unfolded proteins and anticipates future needs for new protein folding capacity.
  • ErSO(OH) binds to ERD in cancer cells. This leads to activation of phospholipase C J (PLCJ).
  • PLCJ phospholipase C J
  • Activated PLCJ enzymatically produces inositol triphosphate (IP3).
  • IP3 binds to and opens endoplasmic reticulum IP3 receptor calcium channels in the EnR.
  • IP3R calcium channels results in very rapid efflux of calcium stored in the lumen (interior) of the endoplasmic reticulum into the cell body. This hyperactivates the UPR.
  • one arm of the UPR the PERK arm, inhibits protein synthesis.
  • Activation of another arm of the UPR, IRE1D induces formation of the active spliced from of the mRNA encoding the transcription factor XBP-1 (spXBP-1).
  • SERCA pumps in the membrane of the endoplasmic reticulum carry out ATP dependent pumping of calcium from the cell body into the interior of the EnR.
  • UPR markers and inhibitors Formation of spXBP-1 mRNA is used as a marker for UPR activation.
  • the widely used small molecule 2-APB locks the IP 3 Rs closed and prevents the calcium efflux and UPR hyperactivation.
  • the small molecule thapsigargin (THG) potently inhibits the SERCA pumps and prevents the cell from using up its ATP stores.
  • the compounds and compositions can be prepared by any of the applicable techniques of organic synthesis, for example, the techniques described herein (see Scheme 1). Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol.2, Ian T. Harrison and Shuyen Harrison, 1974; Vol.3, Louis S. Hegedus and Leroy Wade, 1977; Vol.4, Leroy G. Wade, Jr., 1980; Vol.5, Leroy G. Wade, Jr., 1984; and Vol.6, Michael B. Smith; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Ed.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • the temperatures will be -100 °C to 200 °C
  • solvents will be aprotic or protic depending on the conditions required
  • reaction times will be 1 minute to 2 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water / organic layer system (extraction) and separation of the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 °C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 °C. Heating can also be used when appropriate.
  • Solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 °C to -100 °C) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • Protecting Groups refers to any group which, when bound to a hydroxy or other heteroatom prevents undesired reactions from occurring at this group and which can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl group.
  • removable protecting group employed is not always critical and preferred removable hydroxyl blocking groups include conventional substituents such as, for example, allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidene, phenacyl, methyl methoxy, silyl ethers (e.g., trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), or t-butyldimethylsilyl (TBS)) and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • silyl ethers e.g., trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), or t-butyldimethylsilyl (TBS)
  • TMS trimethylsilyl
  • TDPS t-butyl-
  • Suitable hydroxyl protecting groups are known to those skilled in the art and disclosed in more detail in T.W. Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981 (“Greene”) and the references cited therein, and Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), both of which are incorporated herein by reference.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds by the methods of the invention.
  • Live cells maintain a reducing environment.
  • the non-fluorescent cell permeable ingredient of Alamar Blue ⁇ (resazurin) is taken up by cells. In living cells, it is reduced to the fluorescent compound resorufin.
  • raptinal 100 ⁇ M kills 100% of cells.
  • the vehicle in which the test compound is dissolved is not toxic (1% DMSO).
  • the fluorescence reading for vehicle corresponds to 100% viable cells and the signal for raptinal corresponds to 0% viable cells.
  • 6000 cells were seeded per well in a 96-well plate and allowed to adhere overnight before DMSO solutions of compounds were added to each well. Final concentration of DMSO in each well is 1%, final volume: 100 ⁇ L.
  • media was aspirated and new media (100 ⁇ L) was added.
  • compositions for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier.
  • the compounds may be added to a carrier in the form of a salt or solvate.
  • a pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and E- glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.
  • the compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms.
  • the forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes.
  • the compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • compounds can be enclosed in hard or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet.
  • Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • compositions and preparations typically contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate.
  • a sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil.
  • preparations may contain a preservative to prevent the growth of microorganisms.
  • Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • a polyol for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like
  • vegetable oils nontoxic glyceryl esters, and suitable mixtures thereof.
  • suitable mixtures thereof can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers, or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and/or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization.
  • methods of preparation can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution.
  • compounds may be applied in pure form, e.g., when they are liquids.
  • a dermatologically acceptable carrier which may be a solid, a liquid, a gel, or the like.
  • a dermatologically acceptable carrier which may be a solid, a liquid, a gel, or the like.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like.
  • Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of dermatological compositions for delivering active agents to the skin are known to the art; for example, see U.S.
  • Patent Nos.4,992,478 Gaeria
  • 4,820,508 Wortzman
  • 4,608,392 Jacquet et al.
  • 4,559,157 Smith et al.
  • Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No.4,938,949 (Borch et al.).
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
  • the compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg/m 2 , conveniently 10 to 750 mg/m 2 , most conveniently, 50 to 500 mg/m 2 of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the compounds described herein can be effective anti-tumor agents and have higher potency and/or reduced toxicity as compared to BHPI.
  • compounds of the invention are more potent and less toxic than BHPI, and/or avoid a potential site of catabolic metabolism encountered with BHPI, i.e., have a different metabolic profile than BHPI.
  • the compounds described herein cause less severe ataxia than BHPI and other known compounds.
  • the invention provides therapeutic methods of treating cancer in a vertebrate such as a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein.
  • a mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like.
  • Cancer refers to any of the various type of malignant neoplasm, which are in general characterized by an undesirable cellular proliferation, e.g., unregulated growth, lack of differentiation, local tissue invasion, and metastasis.
  • Cancers that can be treated by a compound described herein include, for example, cancer that has metastasized to the brain from breast cancer, cervical carcinoma, colon cancer, endometrial cancer, leukemia, lung cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, or uterine cancer, and in particular, any cancer that is ERD positive.
  • the ability of a compound of the invention to treat cancer may be determined by using assays well known to the art.
  • mice were sacrificed and blood collected. Residual circulatory volume was removed via perfusion. Blood samples were centrifuged at 13,000 RCF for five minutes and the supernatant was collected and stored at -80°C prior to analysis. Brains were harvested from the cranial vault, weighed, and flash frozen. Thawed brains were then homogenized in 1000 ⁇ L of cold methanol using a handheld tissue homogenizer. The resultant slurry was centrifuged twice at 13,000 RCF for 10 minutes per run and the supernatant was collected and frozen at -80°C prior to analysis. Samples were then analyzed by LC-MS/MS (Metabolomics Laboratory of the Roy J Carver Biotechnology Center UIUC) to determine ErSO concentration in both serum and brain.
  • LC-MS/MS Methodabolomics Laboratory of the Roy J Carver Biotechnology Center UIUC
  • MYS Brain Model 50,000 MYS-Luc cells are suspended in an injected volume of 0.5 microliters of sterile Hanks balanced salt solution. A 5 mm incision is made in the skin on the head. Stereotaxic coordinates are +0.5 mm anterior to bregma, 2.25 - 2.5 mm to the right of midline, -3.5 to -3.3 mm ventral to the skull surface. A small hole is punctured in the skull using a 27 g needle mounted on the stereotaxic holder. A 0.5 ul Hamilton syringe with a 33 g needle is used for the injection.
  • mice The needle is lowered into the brain, then the cells are injected over a period of 1 min. Tumors were allowed to grow for 3-weeks. Mice were then randomized into either Vehicle IP (DMSO) treated, 40 mg/kg ErSO Oral, or 40 mg/kg ErSO IP consisting of 5 mice each for ErSO groups and 4 for the vehicle group. Mice received daily treatments of either IP DMSO, 40 mg/kg ErSO oral, or 40 mg/kg ErSO IP for 21 days. BLI imaging of the mice occurred on days 0, 3, 7, and 14 ( Figures 2-3). Mouse weights were taken a minimum of once per week throughout the treatment arm of the study. Following the treatment regimen, all mice were euthanized. Brain Tumor Xenograft Method Steps.
  • DMSO Vehicle IP
  • 40 mg/kg ErSO Oral 40 mg/kg ErSO IP consisting of 5 mice each for ErSO groups and 4 for the vehicle group.
  • Mice received daily treatments of either IP DMSO, 40 mg/kg ErSO oral, or 40 mg/kg ErSO
  • MYS-Luc MYS-Luc cells
  • MYS-Luc cells are our most aggressive and most metastatic tumor model. Patients whose metastatic tumors harbor the ER ⁇ Y537S mutation have 12 months shorter median survival than patients whose tumors contain wild type ER ⁇ .).
  • the grafted mice were imaged via IVIS one (1) week post graft.
  • Two weeks after the initial injection tumors exhibited sufficient light output and treatment began.
  • Mice were randomly assigned into 3 groups (Vehicle: 4 mice/group; ErSO treated: 5 mice/group). Vehicle was administered daily for 14 days. ErSO (40 mg/kg) was injected i.p. daily for 14 days.
  • the resultant mixture was stirred at -78 qC for 1 hour, warmed to r.t., and then stirred for 1 hour.
  • the reaction was quenched with water (10 mL).
  • the solution was extracted with ethyl acetate (3x) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • a new round bottom flask was charged with crude tertiary alcohol and catechol (6.95 mmol) and dissolved in dichloromethane (7.7 mL).
  • the reaction mixture was then placed in an ice bath and triflic acid (TfOH, 0.7 mL) was then added dropwise.
  • the reaction vessel was removed from the ice bath and stirred at room temperature for 1 hour.
  • the reaction was kept at reflux for 40 minutes, then cooled to reflux and the aqueous solution was extracted with ethyl acetate (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Concentrated sulfuric acid (3 mL) was then added to the resultant residue. This solution was heated to 80 qC for 20 minutes, then poured onto ice. The resulting aqueous mixture was extracted with ethyl acetate (3x), and the combined organic layers dried over sodium sulfate, filtered, and concentrated in vacuo. The red-brown solid obtained after concentration proved to be poorly soluble in most organic solvents.
  • 'Compound X' a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof
  • 'Compound X' a pharmaceutically acceptable salt or solvate thereof
  • Topical Ointment wt.% 'Compound X' 5% Propylene glycol 1% Anhydrous ointment base 40% Polysorbate 80 2% Methyl paraben 0.2% Purified water q.s. to 100g (x) Topical Cream 1 wt.% 'Compound X' 5% White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s.
  • Topical Cream 2 wt.% 'Compound X' 5% Stearic acid 10% Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5% Isopropyl palmitate 2 % Methyl Paraben 0.2%
  • Purified water q.s. to 100g may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes.

Abstract

L'invention concerne une méthode de traitement comprenant un biomodulateur ERα à petites molécules qui élimine le cancer ERα résistant à la thérapie qui s'est métastasé dans le cerveau. Dans une forme de réalisation, le biomodulateur à petites molécules présente un potentiel thérapeutique accru du fait d'une capacité accrue à éliminer les cellules cancéreuses du sein résistantes à la thérapie qui se sont métastasées dans le cerveau comparativement à BHPI et d'autres thérapies classiques (thérapies endocrines, tamoxifène et fulvestrant/ICI). Les biomodulateurs à petites cellules n'inhibent pas seulement la prolifération des cellules cancéreuses mais les éliminent également, empêchant ainsi la réactivation des tumeurs des années plus tard.
PCT/US2021/042796 2020-07-23 2021-07-22 Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé WO2022020605A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063055583P 2020-07-23 2020-07-23
US63/055,583 2020-07-23

Publications (1)

Publication Number Publication Date
WO2022020605A1 true WO2022020605A1 (fr) 2022-01-27

Family

ID=79728345

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/042796 WO2022020605A1 (fr) 2020-07-23 2021-07-22 Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé

Country Status (1)

Country Link
WO (1) WO2022020605A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200009084A1 (en) * 2014-03-28 2020-01-09 Duke University Method of treating cancer using selective estrogen receptor modulators
WO2020028593A1 (fr) * 2018-07-31 2020-02-06 Oncternal Therapeutics, Inc. Méthode de traitement de cancers du sein exprimant un mutant er avec des modulateurs sélectifs du récepteur des androgènes (sarm)
US20200190029A1 (en) * 2018-07-03 2020-06-18 The Board Of Trustees Of The University Of Illinois Activators of the unfolded protein response

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200009084A1 (en) * 2014-03-28 2020-01-09 Duke University Method of treating cancer using selective estrogen receptor modulators
US20200190029A1 (en) * 2018-07-03 2020-06-18 The Board Of Trustees Of The University Of Illinois Activators of the unfolded protein response
WO2020028593A1 (fr) * 2018-07-31 2020-02-06 Oncternal Therapeutics, Inc. Méthode de traitement de cancers du sein exprimant un mutant er avec des modulateurs sélectifs du récepteur des androgènes (sarm)

Similar Documents

Publication Publication Date Title
US11046647B2 (en) Activators of the unfolded protein response
JP6113751B2 (ja) ポリヒドロキシベンゾピランケトン化合物の合成およびその抗腫瘍効果
JP2016530285A (ja) 癌の撮像及び治療のためのハロゲン化化合物、及びその使用方法
JP5649652B2 (ja) 置換ヒドラジド類化合物及びその応用
US20220089602A1 (en) Compounds that induce ferroptic cell death
JP2017507175A (ja) 官能化ベンゾピラン化合物およびその使用
TW201609094A (zh) 治療癌症之新穎方法
RU2664327C2 (ru) Ацил-гидразоновые и оксадиазоловые соединения, фармацевтические композиции, содержащие их, и их применение
WO2022020605A1 (fr) Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé
WO2021222738A1 (fr) Composés pour cancers positifs au récepteur des oestrogènes
WO2021113605A1 (fr) Procédés,composés et compositions pour le traitement du cancer par inhibition de la maturation de notch-1
US11731947B2 (en) Deuterated antimicrobial compounds
US20230391721A1 (en) Anticancer compounds selective for er-positive cancers
WO2004039797A1 (fr) Composes d'indole de type special, leur preparation et leur utilisation pour le traitement et la prevention de maladies telles que le cancer
WO2023070071A2 (fr) Activateurs à petites molécules du système immunitaire
CN117447480A (zh) E20在化疗致卵巢损伤保护中的应用
JP2016098200A (ja) 新規な親油性のｎ−置換ノルカンタリミド誘導体、及びその使用
TWI573589B (zh) 新穎親脂性之ｎ－取代去甲基斑蝥素衍生物及其用途
CN114026098A (zh) 苯并吡喃基化合物、方法及其用途
KR20100047495A (ko) 신규 갈바닉산 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 다약제내성 억제용 약학적 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21846718

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21846718

Country of ref document: EP

Kind code of ref document: A1