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WO2025171226A1 - Compositions et méthodes pour induire la ferroptose - Google Patents

Compositions et méthodes pour induire la ferroptose

Info

Publication number
WO2025171226A1
WO2025171226A1 PCT/US2025/014958 US2025014958W WO2025171226A1 WO 2025171226 A1 WO2025171226 A1 WO 2025171226A1 US 2025014958 W US2025014958 W US 2025014958W WO 2025171226 A1 WO2025171226 A1 WO 2025171226A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
patient
cancer
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/US2025/014958
Other languages
English (en)
Inventor
Laura FURST
Lu Yan
Horst Hemmerle
JR. John Kitridge EATON
JR. John HYNES
Ramesh Kumar SISTLA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kojin Therapeutics Inc
Original Assignee
Kojin Therapeutics Inc
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Filing date
Publication date
Application filed by Kojin Therapeutics Inc filed Critical Kojin Therapeutics Inc
Publication of WO2025171226A1 publication Critical patent/WO2025171226A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms

Definitions

  • X is NR 4 or O;
  • R 2 is selected from the group consisting of -N(R N2 ) 2 , -CH 2 (R N2 ) 2 , and -OH;
  • R N1 is selected from the group consisting of hydrogen and Ci-Csalkyl
  • R N2 is selected from the group consisting of hydrogen, Ci-Cealkyl, -C(O)Ci-Cealkyl, and -C(O)OCi-C 6 alkyl;
  • R 12 is selected from the group consisting of hydrogen and Ci-Csalkyl
  • R 12 and R 13 together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl which may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NR a R b , Ci-Cealkyl, and Ci-Cealkoxy;
  • R 14 is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, -NR a R b , Ci-Csalkyl, and Ci-Csalkoxy;
  • L is selected from the group consisting of -C(O)-O-Ci-C3alkylene-, -Ci-Csalkylene- O-C(O)-, -O-Ci-Csalkylene-, and -Ci-Csalkylene-O-; wherein Ci-Csalkylene may be interrupted in the alkylene chain by -C(O)NR a - or -NR a C(O)-; and wherein Ci-Csalkylene may optionally be substituted with one or two substituents each independently selected from - CF 3 and -NR a R b ;
  • R 3 is Cs-C27alkyl optionally substituted with one or more halogens
  • R 4 is selected from the group consisting of hydrogen and Ci-Csalkyl
  • R a and R b are each independently selected for each occurrence from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci-Cealkoxy; or
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci-4alkyl, and Ci-3alkyl, respectively.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as Ci-Csalkenyl, C2-Cealkenyl, and C3-C4alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • heterocyclyl refers to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.
  • heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen.
  • heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc.
  • heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononany
  • the heterocycle is a spiro heterocycle.
  • the heterocycle is a bridged heterocycle.
  • Spiro heterocyclyl or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) m (wherein m is an integer of 0 to 2) as ring atoms.
  • hydroxy and “hydroxyl” as used herein refers to the radical -OH.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and/or partial agonism.
  • the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulf
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol — denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carboncarbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • Certain isotopically labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2- i2)alkylcarbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxy carbonyloxy)ethyl having
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxym ethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, 1 -methyl- l-((Ci-6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci- 6)alkoxycarbonylaminomethyl, succinoyl, (Ci-e)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, arylalkylcarbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a- aminoalkylcarbonyl, where each a -aminoalkylcarbonyl group is independently selected from the naturally occurring L-a group
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine.
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. “About” can be understood as within plus or minus: 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.” Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value.
  • anti-cancer agent or “chemotherapeutic agent” and its grammatical equivalents as used herein refer to an agent that is capable of killing cells that divide rapidly (e.g., cancer cells), preventing the cells that divide rapidly from further dividing, of slowing the division of rapidly dividing cells.
  • exemplary anti-cancer agents provided herein can include ferroptosis inducing agents, can be used be used in combination with one or more additional ferroptosis inducing agents, can be used in combination with an iron-dependent cell death inducing agent, and/or can be used in combination with a second therapeutic agent or second active agent.
  • the second therapeutic agent or second active agent can be in the form of a prodrug.
  • the second therapeutic agent or second active agent can be an antitumor antibiotic, for example, a doxorubicin, a mitoxantrone, or a bleomycin.
  • the second therapeutic or the second active agent can be, for example, mechlorethamine, leucovorin, methotrexate, mercaptopurine, busulfan, chlorambucil, cyclophosphamide, vincristine, dactinomycin, vinblastine, thioguanine, procarbazine, floxuridine, fluorouracil, mitotane, bleomycin, doxorubicin, dacarbazine, lomustine, carmustine, cisplatin, asparaginase, streptozocin etoposide, ifosfamide, carboplatin, altretamine, fludarabine, pentostatin, paclitaxel, melphalan, teniposide, cladribine, vin
  • the disease or condition can be a cancer, for example in a tissue of the subject.
  • the cancer can be comprised in a mammal, or contained in a tissue of a mammal, which can be a human, which can be male, female.
  • the disease or condition can be an inflammatory disease, or a fibrosis.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the cancer is a carcinoma, a sarcoma, or a melanoma.
  • the carcinoma is a liver carcinoma.
  • the cancer is a clear cell renal carcinoma or non-clear cell renal carcinoma.
  • the cancer is an SWI/SNF deficient-complex cancer.
  • a method of modulating e.g., inducing, ferroptosis in a cell or tissue, which can be in a patient in need thereof, comprising contacting, for example directly or indirectly, optionally in a sustained manner, the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a method of modulating e.g., inducing, ferroptosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a method of modulating, inhibiting, or partially inhibiting a target comprising glutamate-cysteine ligase (GCL) in a cell or tissue comprising contacting, for example directly or indirectly, optionally in a sustained manner, the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a method of modulating, inhibiting, or partially inhibiting a target comprising glutamate-cysteine ligase (GCL) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the solid tumor is a carcinoma, a melanoma, or a sarcoma.
  • the melanoma is a dedifferentiated melanoma or amelanotic melanoma.
  • the patient has a melanoma with a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation.
  • BRAF serine/threonine kinase
  • the patient has a sarcoma with a Kirsten rat sarcoma (KRAS) mutation.
  • the sarcoma is a soft tissue sarcoma.
  • the sarcoma is leiomyosarcoma.
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • leiomyosarcoma LMS
  • mastocytosis e.g., systemic mastocytosis
  • muscle cancer myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), angiogenic myeloid metaplasia (AMM) a.k.a.
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CIVIL), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors); penile cancer (e.g.
  • the patient has, is suspected of having, or is at risk of developing a hyperproliferative disease or condition.
  • methods provided herein further comprise a step of obtaining a biopsy of the tissue for histological analysis.
  • the tissue comprises a histological abnormality, wherein the histological abnormality is hyperplasia or fibrosis.
  • the patient is suffering from one or more conditions selected from the group consisting of, for example, obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).
  • one or more conditions selected from the group consisting of, for example, obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (
  • a compound disclosed herein or a pharmaceutical composition thereof.
  • Also disclosed herein is a method of inducing, regulating, or modulating weight loss, body composition, or fat loss or fat reduction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • Also disclosed herein is a method of treating, inducing, regulating, modulating, or diminishing cholesterol metabolism or a disease associated with cholesterol metabolism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the disclosure provides a method of treating the medical indications contemplated herein comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.
  • the compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein.
  • contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic.
  • a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.
  • a disclosed compound and one additional therapeutic agent is administered.
  • a disclosed compound as defined herein and two additional therapeutic agents are administered.
  • a disclosed compound as defined herein and three additional therapeutic agents are administered.
  • Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately.
  • a disclosed compound and an additional therapeutic agent can be formulated and administered separately.
  • Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents.
  • a disclosed compound and an additional therapeutic agent can be administered in a single formulation.
  • Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y- X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
  • the methods provided herein comprise administering at least one additional treatment to a subject.
  • the additional treatment is surgery.
  • the additional treatment is radiation therapy.
  • the additional treatment is radioligand therapy.
  • the additional treatment is a dietary supplement.
  • Non-limiting examples of dietary supplements include: probiotics, selenium, iron, vitamins (e.g., vitamin A, vitamin C, vitamin E), curcumin, fish oils, beta carotene, hydrogen sulfides, fatty acids, methionine, cysteine, homocysteine, taurine, cystine or di-cysteine.
  • the dietary supplement is a high-selenium nutritional supplement.
  • the methods described herein further comprises administering to the patient one or more additional therapeutic agents that treats a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.
  • the methods provided herein comprise administering an additional agent in combination with a ferroptosis-inducing agent (e.g., a compound disclosed herein), an iron-dependent cell death inducing agent, and/or a priming agent provided herein.
  • a ferroptosis-inducing agent e.g., a compound disclosed herein
  • an iron-dependent cell death inducing agent e.g., an iron-dependent cell death inducing agent
  • a priming agent provided herein.
  • the additional agent is a cell-death inducing agent.
  • the additional agent is an anti-cancer agent.
  • the anti-cancer agent is a chemotherapeutic agent.
  • a chemotherapeutic agent or compound is any agent or compound useful in the treatment of cancer.
  • chemotherapeutic cancer agents that can be used in combination with ferroptosis-inducing agents or iron-dependent cell death agents provided herein which include, but are not limited to, mitotic inhibitors (vinca alkaloids). These include, for example, vincristine, vinblastine, vindesine and NavelbineTM (vinorelbine, 5’-noranhydroblastine).
  • chemotherapeutic cancer agents include topoisomerase I inhibitors, such as camptothecin compounds.
  • camptothecin compounds include CamptosarTM (irinotecan HCL), HycamtinTM (topotecan HCL) and other compounds derived from camptothecin and its analogues.
  • chemotherapeutic cancer agents that can be used in the methods and compositions disclosed herein are podophyllotoxin derivatives, such as etoposide, teniposide and mitopodozide.
  • the present disclosure further encompasses other chemotherapeutic cancer agents known as alkylating agents, which alkylate the genetic material in tumor cells. These include without limitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacarbazine.
  • alkylating agents which alkylate the genetic material in tumor cells.
  • alkylating agents which alkylate the genetic material in tumor cells.
  • alkylating agents which alkylate the genetic material in tumor cells. These include without limitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chloram
  • an additional category of therapeutic agents e.g., chemotherapeutic cancer agents, that may be used in the methods and compositions disclosed herein include, for example, aldehyde dehydrogenase inhibitors.
  • aldehyde dehydrogenase inhibitors include, but are not limited to, e.g., 4- amino-4-methyl-2-pentyne-l-al (AMP AL), N-acetyl-N-acetoxy-4- chlorobenzenesulfonamide, 2-allyl-6-(((l-propyl-lH-benzo[d]imidazol-2- yl)amino)methyl)phenol, 5-(l,3-benzodioxol-5-yl)-2-phenyl-pyrazolo[l,5-a]pyrimidine-7- carboxylic acid methyl ester, A-(l,3-benzodioxol-5-ylmethyl)-2,6-d
  • an aldehyde dehydrogenase inhibitor contemplated herein may be selected from those disclosed in W02020/230701 Al, which is incorporated herein by reference in its entirety.
  • the aldehyde dehydrogenase inhibitor is, for example, oxyfedrine.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an aldehyde dehydrogenase inhibitor, for example, oxyfedrine.
  • a pharmaceutical composition comprising: a compound disclosed herein, or a pharmaceutically acceptable salt thereof; an aldehyde dehydrogenase inhibitor, for example, oxyfedrine; and a pharmaceutically acceptable excipient.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising: a compound disclosed herein, or a pharmaceutically acceptable salt thereof; an aldehyde dehydrogenase inhibitor, for example, oxyfedrine; and a pharmaceutically acceptable excipient.
  • chemotherapeutic cancer agents that may be used in the methods and compositions disclosed herein include antibiotics. Examples include without limitation doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. The present disclosure further encompasses other chemotherapeutic cancer agents including without limitation anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, ifosfamide and mitoxantrone.
  • the disclosed agents provided herein can be administered in combination with other anti-tumor agents, including cytotoxic/antineoplastic agents and anti-angiogenic agents.
  • Cytotoxic/anti -neoplastic agents can be defined as agents who attack and kill cancer cells.
  • Some cytotoxic/anti-neoplastic agents can be alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine.
  • cytotoxic/anti-neoplastic agents can be antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine.
  • Other cytotoxic/anti-neoplastic agents can be antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
  • doxorubicin e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
  • mitotic inhibitors (vinca alkaloids).
  • Miscellaneous cytotoxic/anti-neoplastic agents include, for example, taxol and its derivatives, L- asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.
  • Anti-angiogenic agents can also be used. Suitable anti -angiogenic agents for use in the disclosed methods and compositions include, for example, anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other inhibitors of angiogenesis include, for example, angiostatin, endostatin, interferons, interleukin 1 (including a and P) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti -angiogenic activity, can also be used.
  • anti-cancer agents that can be used in combination with the ferroptosis- inducing agents provided herein can include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; avastin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bevacizumab; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbe
  • anti-cancer agents include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara- CDP-DL-
  • any of the aforementioned chemotherapeutics can be administered at a clinically effective dose.
  • a chemotherapeutic can also be administered from about day: -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, - 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or up to about day 14 after administration of an agent provided herein.
  • a subject can have a refractory cancer that is unresponsive to a chemotherapeutic.
  • the methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition.
  • a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition.
  • the method further comprises administering to the patient an additional therapeutic agent that treats a cancer, or that treats a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.
  • administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and/or preventing cancer, or in treating, ameliorating, and/or preventing a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.
  • the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.
  • a compound disclosed herein can be comprised as a ligand in a proteolysis-targeting chimera (PROTAC) protein degrader.
  • a bifunctional PROTAC molecule can comprise the ligand of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3).
  • the POI can be any protein herein.
  • the POI can be cysteine-glutamate antiporter (system Xc), a glutathione peroxidase 4 (GPX4), a p53, a cargo receptor NCOA4, a glutathione synthetase (GSH), or a glutamate-cysteine ligase (GCL).
  • system Xc glutathione peroxidase 4
  • GSH glutathione synthetase
  • GCL glutamate-cysteine ligase
  • the inactivation or inhibition of some of these molecules, for example, system Xc, GPX4, or glutathione synthetase PROTAC protein degraders can work by recruiting a chosen E3 ligase into close proximity with a specific disease-causing protein so that it can be tagged with ubiquitin and sent off for degradation by the proteasome. After the protein is degraded, the PROTAC can be released to continue to elicit further degradation.
  • a compound described herein can be part of an antibodydrug conjugate (ADC) where the compound is optionally linked to the antibody by a linker.
  • ADC antibodydrug conjugate
  • a typical human dose of compound provided herein may be from about 10 pg/kg body weight/day to 10,000 mg/kg/day.
  • the dose of an agent provided herein is from about 0.1 mg/kg to about 1000 mg/kg, from 1 mg/kg to 1000 mg/kg, 1 mg/kg to 800 mg/kg, from about 1 mg/kg to about 700 mg/kg, from about 2 mg/kg to about 500 mg/kg, from about 3 mg/kg to about 400 mg/kg, 4 mg/kg to about 300 mg/kg, or from about 5 mg/kg to about 200 mg/kg.
  • the suitable dosages of the agent can be about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, 2,000 mg/kg, 3,000 mg/kg, 4,000 mg/kg, 5,000 mg/kg, 6,000 mg/kg, 7,000/mg/kg, 8,000 mg/kg, 9,000 mg/kg, up to 9,600 mg/kg.
  • the dose of compound provided herein is from about 100 mg/kg/day to about 6,400 mg/kg/day four times per day. In some embodiments, the dose of a compound provided herein is from about 50 mg/kg/day to about 25 mg/kg/day. In some embodiments, the dose of a compound provided herein is from about 400 mg/kg/day to about 800 mg/kg/day. In certain embodiments, the dose of the compound can be administered once per day or divided into subdoses and administered in multiple doses, e.g., twice, three times, or four times per day.
  • compounds provided herein are administered in an amount of at least about 10 nanograms (ng) or more, about 20 ng or more, about 30 ng or more, about 40 ng or more, about 50 ng or more, about 60 ng or more, about 70 ng or more, about 80 ng or more, about 90 ng or more, up to 100 ng.
  • ng nanograms
  • compounds provided herein are administered in an amount of at least about 10 nanograms (ng) or more, about 20 ng or more, about 30 ng or more, about 40 ng or more, about 50 ng or more, about 60 ng or more, about 70 ng or more, about 80 ng or more, about 90 ng or more, up to 100 ng.
  • the compound is administered in an amount of at least about 1 microgram (pg) or more, about 5 pg or more, about 10 pg or more, about 20 pg or more, about 30 pg or more, about 40 pg or more, about 50 pg or more, about 60 pg or more, about 70 pg or more, about 80 pg or more, about 90 pg or more, up to 100 pg.
  • pg microgram
  • compounds provided herein are administered at a concentration of at least about 0.1 micromolar (pM) or more, about 1 pM or more, about 2 pM or more, about 3 pM or more, about 4 pM or more, about 5 pM or more, about 6 pM or more, about 7 pM or more, about 8 pM or more, about 9 pM or more, about 10 pM or more, about 15 pM or more, about 20 pM or more, about 25 pM or more, about 30 pM or more, about 35 pM or more, about 40 pM or more, about 45 pM or more, about 50 pM or more, about 55 pM or more, about 60 pM or more, about 65 pM or more, about 70 pM or more, about 75 pM or more, about 80 pM or more, about 85 pM or more, about 90 pM or more, about 95 pM or more, about 100 pM
  • compounds provided herein are administered at a concentration of at least about 0.1 pM up to about 500 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 1 pM up to 500 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 0.1 pM up to 10 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 1 pM up to 10 pM.
  • ferroptosis-inducing agents provided herein are administered intravenously.
  • compounds provided herein are administered intravenously at a concentration of at least about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, about 1000 mg/kg, about 1100 mg/kg, about 1200 mg/kg, about 1300 mg/kg, about 1400 mg/kg, about 1500 mg/kg, about 2000 mg/kg, about 2200 mg/kg, about 2400 mg/kg, up to about 2500 mg/kg.
  • compounds provided herein are administered intravenously at a concentration of about 25 mg/kg once per day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 25 mg/kg twice per day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 450 mg/kg/day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 650 mg/kg/day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 650 mg/kg/day for 3 continuous days. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 1300 mg/kg/day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 2400 mg/kg/day.
  • compounds provided herein are administered orally. In some embodiments, compounds provided herein are administered orally at a concentration of at least about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, about 1000 mg/kg, about 1100 mg/kg, about 1200 mg/kg, about 1300 mg/kg, about 1400 mg/kg, about 1500 mg/kg, about 2000 mg/kg, about 2200 mg/kg, about 2400 mg/kg, up to about 2500 mg/kg.
  • compounds provided herein are administered orally at a concentration of about 25 mg/kg once per day. In some embodiments, compounds provided herein are administered orally at a concentration of about 25 mg/kg twice per day. In some embodiments, compounds provided herein are administered orally at a concentration of about 1300 mg/kg/day. In some embodiments, compounds provided herein are administered orally at a concentration of about 2400 mg/kg/day.
  • the methods provided herein can be characterized by or further comprise measuring the distribution of an agent in a target tissue.
  • Distribution of a compound provided herein can be determined by the amount or concentration of the agent within a square millimeter (mm 2 ) or cubic millimeter (mm 3 ) of tissue.
  • the tissue may be from about 6 to 7 mm in diameter, 36 to 42 mm 2 , or 216 to 294 mm 3 .
  • the data obtained from animal studies may be used in formulating a range of drug distribution in a mammalian tissue.
  • Methods of determining tissue distribution of a compound include, for example, mass spectrometry, chromatography, imaging techniques, and immunoassays.
  • the distribution of a compound provided herein can be determined using a system provided herein.
  • the tissue is administered a therapeutic amount of a compound disclosed herein, wherein administration of comprises providing to a tissue the compound in an amount sufficient to achieve a desired drug distribution.
  • the compound may achieve a distribution within a tissue of at least about 1 ng/mm 2 or more, about 5 ng/mm 2 or more, about 10 ng/mm 2 or more, about 15 ng/mm 2 or more, about 20 ng/mm 2 or more, about 25 ng/mm 2 or more, about 30 ng/mm 2 or more, about 35 ng/mm 2 or more, about 40 ng/mm 2 or more, about 45 ng/mm 2 or more, about 50 ng/mm 2 or more, about 55 ng/mm 2 or more, about 60 ng/mm 2 or more, about 65 ng/mm 2 or more, about 70 ng/mm 2 or more, about 75 ng/mm 2 or more, about 80 ng/mm 2 or more, about 85 ng/mm 2 or more, about 90 ng/mm 2
  • the compound may achieve a distribution within a tissue of at least about 1 ng/mm 3 or more, about 5 ng/mm 3 or more, about 10 ng/mm 3 or more, about 15 ng/mm 3 or more, about 20 ng/mm 3 or more, about 25 ng/mm 3 or more, about 30 ng/mm 3 or more, about 35 ng/mm 3 or more, about 40 ng/mm 3 or more, about 45 ng/mm 3 or more, about 50 ng/mm 3 or more, about 55 ng/mm 3 or more, about 60 ng/mm 3 or more, about 65 ng/mm 3 or more, about 70 ng/mm 3 or more, about 75 ng/mm 3 or more, about 80 ng/mm 3 or more, about 85 ng/mm 3 or more, about 90 ng/mm 3 or more, about 95 ng/mm 3 or more, about 100 ng/mm 3 or more, about 110 ng/mm 3 or more, about 120 ng/mm 3 or more, about 130 ng/mm
  • a compound disclosed herein may be administered at least about once per day, twice per day, three times per day, four times per day, or five times per day. In some embodiments of any of the aspects, compounds are administered at least about every week, at least about every 2 weeks, or at least about every 3 weeks.
  • the amount of compound administered depends on the size of the tissue, the type of disease being treated, and the type of administration (e.g., local administration to a tissue in vivo using a system provided herein). Effective doses will vary, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments.
  • administering comprises, for example, intratumoral injection, oral administration, transdermal injection, inhalation, nasal administration, topical administration, vaginal administration, ophthalmic administration, intracerebral administration, rectal administration, intravenous administration, intra-arterial administration, intramuscular administration, or subcutaneous administration.
  • compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier.
  • pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stea
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • non-ionic surfactants Teweens, Pluronics, or polyethylene glycol
  • innocuous proteins like serum albumin
  • sorbitan esters oleic acid
  • lecithin amino acids
  • amino acids such as glycine
  • buffers buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein.
  • kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like).
  • Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • the compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure.
  • Step 2 (2S)-2-(tert-butoxycarbonylamino)-4-[N-tert-butoxycarbonyl-S-[(3R)-4,4,4- trifluoro-3-octanoyloxy-butyl sulfonimidoyl butanoic acid) : [00131] A solution of (S)-4-((R,3R)-N-(tert-butoxycarbonyl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid (0.3 g, 609 pmol, 1 eq), pyridine(241 mg, 3.05 mmol, 246 pL, 5 eq) in DCM (3 mL) was degassed with N2 for 3 times, and then compound 2 (119 mg, 731 pmol, 125 pL, 1.2 eq) in DCM (0.3 m
  • Step 3 (2S)-2-amino-4-[[(3R)-4,4,4-trifluoro-3-octanoyloxy-butyl]sulfonimidoyl]butanoic acid:
  • Step 1 dodecanoyl chloride: [00133] A solution of dodecanoic acid (75 mg, 374.41 pmol, 1 eq) in SOCh (1 mL) was stirred at 78 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown oil.
  • Step 2 (2S)-2-(tert-butoxycarbonylamino)-4-[N-tert-butoxycarbonyl-S-[(3R)-3- dodecanoyloxy-4, 4, 4-trifluoro-butyl ] sulfonimidoyl Jbutanoic acid:
  • the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 50%-80% B over 12.0 min) to afford the title compound (30 mg, 39.57 pmol, 14.07% yield, 89% purity) as a white solid.
  • Step 3 (2S)-2-amino-4-[[(3R)-3-dodecanoyloxy-4, 4, 4-trifluoro- butyl J sulfonimidoyl butanoic acid:
  • Step 2 (S)-4-( (R, 3R)-N-( tert-butoxycarbonyl)-4, 4, 4-trifluoro-3-(palmitoyloxy) butylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid:
  • the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 50%-80% B over 12.0 min) to afford the title compound (70 mg, 95.77 pmol, 31.45% yield) as a colorless oil.
  • Step 3 (S)-2-amino-4-( (R, 3R)-4, 4, 4-trifluoro-3-(palmitoyloxy)butylsulfonimidoyl)butanoic acid:
  • Step 2 (S)-4-( (R, 3R)-N-( ter tdmtoxy carbonyl) -4, 4, 4-trifluoro-3-( t) 6, 6, 6- trijluorohexanoyl)oxy) butylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid:
  • Step 3 (S)-2-amino-4-( (R, 3R)-4, 4, 4-trifluoro-3-( ( 6, 6, 6-trifluorohexanoyl)oxy) butylsulfonimidoyl) butanoic acid:
  • the GCL enzyme assay was run in 50 mM HEPES, pH 7.5, containing 150 mM NaCl, 30 mM MgCh, 0.5 mM EDTA, 1 mM DTT, 0.1 mg/mL BSA, and 0.2% F-127 in a total assay volume of 10 pL.
  • Compound in pure DMSO was stamped in assay plates (Greiner black 384-well) using a D300e digital dispenser (TEC AN) and the final DMSO concentration was normalized to 1%.
  • the GCL enzyme reaction was initiated by addition of a 5 pL mixture of mono sodium glutamate (final concentration: 1 mM) and a- aminobutyrate (final concentration: 1.2 mM).
  • the reaction was stopped after 2 h by addition of 5 pL ADP GLO Reagent (Promega).
  • the resulting solution was incubated for 2 h at room temperature. This was then followed by the addition of 5 pL ADP GLO Detection.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

L'invention concerne des composés, p. ex. des composés de formule I, et leur utilisation dans le traitement de maladies ou de troubles médicaux, tels que le cancer. Les composés sont envisagés pour être des modulateurs, p. ex. des inducteurs, de la ferroptose.
PCT/US2025/014958 2024-02-07 2025-02-07 Compositions et méthodes pour induire la ferroptose Pending WO2025171226A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140121277A1 (en) * 2010-08-09 2014-05-01 William Brusilow Use of methionine sulfoximine to treat acute liver failure and other diseases caused by an inflammatory cytokine response
WO2020230701A1 (fr) 2019-05-14 2020-11-19 学校法人 慶應義塾 Agent antitumoral et agent de formulation
WO2023085367A1 (fr) * 2021-11-11 2023-05-19 小野薬品工業株式会社 Inhibiteur de gcl
WO2024030960A2 (fr) * 2022-08-03 2024-02-08 Kojin Therapeutics, Inc. Compositions et méthodes pour induire la ferroptose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140121277A1 (en) * 2010-08-09 2014-05-01 William Brusilow Use of methionine sulfoximine to treat acute liver failure and other diseases caused by an inflammatory cytokine response
WO2020230701A1 (fr) 2019-05-14 2020-11-19 学校法人 慶應義塾 Agent antitumoral et agent de formulation
WO2023085367A1 (fr) * 2021-11-11 2023-05-19 小野薬品工業株式会社 Inhibiteur de gcl
WO2024030960A2 (fr) * 2022-08-03 2024-02-08 Kojin Therapeutics, Inc. Compositions et méthodes pour induire la ferroptose

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GREENEWUTS: "Protective Groups in Organic Synthesis", 1999
KRISTY L. HENTCHEL: "In Salmonella enterica, the Gcn5-Related Acetyltransferase MddA (Formerly YncA) Acetylates Methionine Sulfoximine and Methionine Sulfone, Blocking Their Toxic Effects", JOURNAL OF BACTERIOLOGY, vol. 197, no. 2, 3 November 2014 (2014-11-03), US, pages 314 - 325, XP093166576, ISSN: 0021-9193, DOI: 10.1128/JB.02311-14 *
RAUTIOKUMPULAINEN ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 7, 2008, pages 255
SIMPLICIO ET AL., MOLECULES, vol. 13, 2008, pages 519
YIN LINZHOU ET AL: "Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications", vol. 244, 1 December 2022 (2022-12-01), AMSTERDAM, NL, pages 114861, XP093272637, ISSN: 0223-5234, Retrieved from the Internet <URL:https://pdf.sciencedirectassets.com/271932/1-s2.0-S0223523422X00160/1-s2.0-S0223523422007632/main.pdf?hash=5200f4fdbac26a5e120609a0ec04e59505c7cf4a6512b2a6e9f82f7e373b627d&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0223523422007632&tid=spdf-52c25362-910c-4b8b-9aeb-d23> DOI: 10.1016/j.ejmech.2022.114861 *

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