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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • 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
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• compositions comprising an oxidative phosphorylation inhibitor and a glycolytic inhibitor.
• the composition further comprises a pharmaceutically acceptable excipient.
• the composition comprises a liquid vehicle(s) to provide a physiologically acceptable formulation for parenteral administration.
• combination therapies comprising administration of an oxidative phosphorylation inhibitor and a glycolytic inhibitor to an individual in need thereof.
• the oxidative phosphorylation inhibitor is a mitochondrial oxygenase inhibitor.
• the oxidative phosphorylation inhibitor is a benzopyran derivative.
• the combination therapy comprises administration of a benzopyran derivative and a glycolytic inhibitor.
• the benzopyran derivative is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:
• Ri is hydroxy, alkoxy, haloalkyl, or halo
• R 2 is hydroxy or alkoxy
• R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
• R 7 is alkyl or hydrogen
• R 9 is hydroxy or alkoxy.
• Some embodiments provided herein describe a method of treating a disease or disorder associated with dysregulation of cell proliferation, comprising administering to a subject in need thereof an effective amount of:
• Ri is hydroxy, alkoxy, haloalkyl, or halo
• R 2 is hydroxy or alkoxy
• R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
• R 7 is alkyl or hydrogen
• R 9 is hydroxy or alkoxy.
• Ri is hydroxy or alkoxy.
• R 2 is hydroxy.
• R 3 , R 4 , R 5 , and 5 are independently hydrogen or alkyl. In other words,
• R 3 , R 4 , R 5 , and R 6 are independently hydrogen.
• R7 is methyl or hydrogen.
• Ri is hydroxy or alkoxy; R 2 is hydroxy or alkoxy; R 3 , R 4 , R 5 , and 5 are independently hydrogen, hydroxy, alkoxy, or alkyl; R 7 is alkyl or hydrogen; and R 9 is hydroxy or alkoxy.
• Ri is hydroxy or alkoxy; R 2 is hydroxy or alkoxy; R 3 , R 4 , R 5 , and R 6 are independently hydrogen; R 7 is alkyl or hydrogen; and R 9 is hydroxy.
• Ri is hydroxy or methoxy; R 2 is hydroxy or methoxy; R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, methoxy, methyl; R 7 is methyl or hydrogen; and R 9 is hydroxy or methoxy.
• Ri is hydroxy or methoxy; R 2 is hydroxy or methoxy; R 3 , R4, R5, and R 6 are independently hydrogen; R 7 is methyl or hydrogen; and R9 is hydroxy.
• the glycolytic inhibitor is a hexokinase inhibitor.
• the hexokinase inhibitor is 2-deoxyglucose, 2-fluorodeoxyglucose, or 3- bromopyruvate.
• the glycolytic inhibitor is a glucose-6-phosphate dehydrogenase inhibitor.
• the glucose-6-phosphate dehydrogenase inhibitor is red algal bromophenols.
• the glycolytic inhibitor is an angiogenesis inhibitor.
• the angiogenesis inhibitor is nintedanib (BIBF 1120), bevacizumab (Avastin), everolimus (Afinitor), temsirolimus (Torisel), lenalidomide (Revlimid), pazopanib (Votrient), ramucirumab (Cyramza), sorafenib (Nexavar), sunitinib (Sutent), thalidomide (Thalomid), vandetanib (Caprelsa), cediranib (Recentin), axitinib (Inlyta), motesanib, vatalanib, dovitinib, brivanib, linifanib, tivozanib, lenvatinib, regorafenib (Stivarga), foretinib, telatinib, cabozantinib (BIBF 1120), bevacizuma
• the angiogenesis inhibitor is nintedanib (BIBF 1120), bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), thalidomide (Thalomid), or imatinib (Gleevec). In certain embodiments, the angiogenesis inhibitor is nintedanib (BIBF 1120).
• the disease or disorder to be treated is cancer.
• the disease or disorder is breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemia, lymphoma, ovarian cancers, neuroblastoma, glioblastoma, kidney cancer, bladder cancer, gastrointestinal stromal tumors, liver cancer, head and neck cancer, lung cancer, melanoma, or a hematological malignancy.
• the disease or disorder is breast cancer.
• the cancer is refractory, non-responsive, or resistant to chemotherapy and/or haploidentical stem cell transplantation.
• the cancer is non-responsive or resistant to the glycolytic inhibitor.
• the glycolytic inhibitor and compound of formula (II) are administered simultaneously or sequentially.
• Ri is hydroxy, alkoxy, haloalkyl, or halo
• R 2 is hydroxy or alkoxy
• R 3 , R4, R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
• R7 is alkyl or hydrogen
• R9 is hydroxy or alkoxy.
• the chemoresistant cancer is breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemia, lymphoma, ovarian cancers, neuroblastoma, glioblastoma, kidney cancer, bladder cancer, gastrointestinal stromal tumors, liver cancer, head and neck cancer, lung cancer, melanoma, or a hematological malignancy.
• the cancer is resistant to the glycolytic inhibitor.
• the glycolytic inhibitor is nintedanib (BIBF 1120).
• cancer cells include cancer cells that create ATP for energy anaerobically and cancer cells that aerobically generate ATP, the method comprising administering to a subject in need thereof an effective amount of:
• Ri is hydroxy, alkoxy, haloalkyl, or halo
• R 2 is hydroxy or alkoxy
• R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
• R 7 is alkyl or hydrogen
• R9 is hydroxy or alkoxy.
• kits comprising one or more containers filled with a glycolytic inhibitor and one or more containers filled with a compound of Formula (II) or a harmaceutically acceptable salt thereof:
• Ri is hydroxy, alkoxy, haloalkyl, or halo
• R 2 is hydroxy or alkoxy
• R 3 , R 4 , R5, and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
• R 7 is alkyl or hydrogen
• R 9 is hydroxy or alkoxy.
• Figure 1 depicts tumor growth in a mouse model of breast cancer with sequential treatment of nintedanib (BIBF) and compound 5 (ME).
• BIBF nintedanib
• ME compound 5
• Figure 2 depicts inhibition of tumor growth in a mouse model of breast cancer following treatment with vehicle, single agent treatment with nintedanib (BIBF), single agent treatment with compound 5 (ME), and combination treatment of nintedanib (BIBF) and compound 5 (ME).
• BIBF single agent treatment with nintedanib
• ME single agent treatment with compound 5
• ME combination treatment of nintedanib
• ME compound 5
• Figure 3 depicts tumor growth in a mouse model of breast cancer following treatment with vehicle (VEH), single agent treatment with dovitinib (Dovi), single agent treatment with compound 5 (ME), and combination treatment of dovitinib (Dovi) and compound 5 (ME).
• Figure 4 depicts tumor growth in a mouse model of breast cancer following treatment with vehicle (VEH), single agent treatment of regorafenib (Rego), single agent treatment with compound 5 (ME), and combination treatment of regorafenib (Rego) and compound 5 (ME).
• Figure 5 depicts non-small cell lung cancer growth inhibition in a mouse xenograft model (PULM024) following treatment with Vehicle, single agent treatment with nintedanib (BIBF), single agent treatment with compound 5 (ME), and combination treatment of nintedanib (BIBF) and compound 5 (ME).
• PULM024 mouse xenograft model
• Figure 6 depicts squamous cell lung cancer growth inhibition in a mouse xenograft model (ECB1) following treatment with vehicle (VEH), single agent treatment with nintedanib (BIBF), single agent treatment with compound 5 (ME), and combination treatment of nintedanib (BIBF) and compound 5 (ME).
• VH vehicle
• BIBF single agent treatment with nintedanib
• ME single agent treatment with compound 5
• ME compound 5
• compositions and therapies described herein comprise a benzopyran derivative (e.g., substituted diaryl chroman derivatives and super-benzopyrans, such as
• TrilexiumTM and Trx-1 and glycolytic inhibitors. Also provided herein are methods to induce apoptosis in a cancer cell, methods to treat cancer in individuals in need of cancer therapy, and methods to increase sensitivity of a cancer cell to a chemotherapeutic agent and/or radiation therapy (or to sensitize an individual to a particular chemotherapy).
• alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms.
• Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l- propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl- 1-propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer
• a numerical range such as "Ci-C 6 alkyl” or "Ci -6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
• Ci-C3-alkyl and “Ci-C6-alkyl” as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom.
• Examples of Ci-C 3 -alkyl radicals include methyl, ethyl, propyl and isopropyl.
• Ci-C 6 -alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.
• cycloalkyl refers to a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.
• C 3 -C 6 cycloalkyl denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• the alkyl group or cycloalkyl group may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, Ci -4 alkoxycarbonyl, Ci -4 alkylaminocarbonyl, di-( Ci -4 alkyl)-aminocarbonyl, hydroxyl, Ci -4 alkoxy, formyloxy, Ci -4 alkylcarbonyloxy, Ci -4 alkylthio, C 3-6 cycloalkyl or phenyl.
• alkoxy refers to an alkyl ether radical, -O-alkyl, including the groups -O-aliphatic and -O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein.
• alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
• Ci-C 3 -alkoxy refers to the Ci-C 3 -alkyl group and Ci-C 6 -alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
• Ci-C 6 -alkoxy radicals include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
• halo and "halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
• haloalkyl includes “alkyl” wherein one or more such as 1, 2, 3, 4, or 5 of the hydrogens have been replaced by a halo atom.
• the haloalkyl may be straight chain or branched chain "alkyl" unit.
• Non-limiting examples include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 2 F, -CF 2 CHF 2 , -CF 2 CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 Br, - CHBr 2 , and -CBr 3 .
• fluoroalkyl includes “alkyl” wherein one or more such as 1, 2, 3, 4, or 5 of the hydrogens have been replaced by fluoro.
• the fluoroalkyl may be straight chain or branched chain “alkyl” unit.
• Preferred fluoroalkyl groups include trifluoromethyl and pentafluoroethyl.
• pharmaceutically acceptable refers to a material, including but not limited, to a salt, carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose.
• the salts are prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base function with a suitable organic acid.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
• a reference to a salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
• Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
• cyclodextrin refers to cyclic carbohydrates consisting of at least six to eight sugar molecules in a ring formation.
• the outer part of the ring contains water soluble groups; at the center of the ring is a relatively nonpolar cavity able to accommodate small molecules.
• administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
• co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
• the term "effective amount,” as used herein, refers to a sufficient amount of an agent or a compound 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 appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
• pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• fixed combination means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• non-fixed combination means that the active ingredients, e.g.
• a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
• cocktail therapy e.g. the administration of three or more active ingredients.
• the term "patient”, “subject” or “individual” are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non- mammals. None of the terms require that the individual be under the care and/or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to 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. Examples of non-mammals include, but are not limited to, birds, fish and the like.
• the individual is a mammal. In preferred embodiments, the individual is a human.
• treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
• the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
• compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
• preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
• carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
• a dosage of an oxidative phosphorylation inhibitor or a glycolytic inhibitor may be expressed in absolute or relative terms.
• phosphorylation inhibitor or a glycolytic inhibitor may be expressed as a certain number of milligrams (mg) of an oxidative phosphorylation inhibitor or a glycolytic inhibitor, or a pharmaceutically acceptable salt thereof, administered to a patient.
• a dosage of an oxidative phosphorylation inhibitor or a glycolytic inhibitor herein may be expressed as "mg/kg,” which expresses the number of milligrams the oxidative phosphorylation inhibitor or glycolytic inhibitor, or pharmaceutically acceptable salt thereof, administered to a patient per kg of the patient's body weight. Dosage may also be expressed in terms of mg/m 2 , indicating the mass of active ingredient administered per square meter of the patient's estimated surface area.
• the benzopyran derivative is a substituted diaryl chroman derivative, super- benzopyrans, or a combination thereof.
• the benzopyran derivative has the structure of Formula (I):
• Ri is hydrogen, hydroxy, halo, R 14 R 15 , C 3 - 6 cycloalkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, COOR i2 , COR13, (0) n Ci -4 alkyleneNRi4Ri5 or Ci -6 alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or R 14 R 15 groups;
• R 2 , R 3 , R 4 , R 5 , R5, R 9 , and Rio are independently hydrogen, hydroxy, halo, R 14 R 15 , C 3 - 6 cycloalkyl, Ci -6 alkoxy, Ci- 6 haloalkyl, C 2-6 alkenyl, COORi 2 , COR 13 , or Ci. 6alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or R14R15 groups;
• R 7 is hydrogen, hydroxy, halo, R 14 R 15 , C 3-6 cycloalkyl, Ci -6 alkoxy, C 2-6 alkenyl, Ci.
• Ci -6 alkyl optionally substituted by one or more hydroxy, chloro, bromo, iodo or Ri 4 Ri 5 groups;
• R 2 together represent a double bond or the drawing represents a single bond and Rn is hydrogen, hydroxy, NR 14 R 15 , Ci.
• Rn and R i2 are independently hydrogen, Ci -6 alkyl, C 3-6 cycloalkyl, or trialkyl silyl;
• Ri 3 is hydrogen, C 3 - 6 cycloalkyl or R 14 R 15 ;
• n 0 or 1 ;
• Ri 4 and R 15 independently represent hydrogen or or R 14 R 15 when taken together represents a 5 or 6 membered heteroaromatic or heterocyclic, or a pharmaceutically acceptable salt thereof.
• Ri is hydroxy, alkoxy, haloalkyl, or halo
• R 2 is hydroxy or alkoxy
• R 3 , R4, R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl and
• R 7 is alkyl or hydrogen
• R9 is hydroxy or alkoxy
• Ri is hydroxy or alkoxy. In some embodiments, Ri is hydroxy. In other embodiments, Ri is Ci-C 6 alkoxy. In further or additional embodiments, Ri is Ci- C 3 alkoxy. In other embodiments, Ri is Ci-C 2 alkoxy. In specific embodiments, Ri is methoxy. In specific embodiments, Ri is ethoxy. In specific embodiments, Ri is propoxy. In specific embodiments, Ri is iso-propoxy. In specific embodiments, Ri is butoxy. In specific
• Ri is iso-butoxy. In specific embodiments, Ri is sec-butoxy. In specific embodiments, Ri is tert-butoxy. In specific embodiments, Ri is pentyloxy. In specific embodiments, Ri is hexyloxy. In further or alternative embodiments, Ri is fluoro. In other embodiments, Ri is chloro. In other embodiments, Ri is iodo. In other embodiments, Ri is bromo. In other embodiments, Ri is haloalkyl. In other embodiments, Ri is haloCi- 6 alkyl. In other embodiments, Ri is haloCi -3 alkyl. In other embodiments, Ri is haloCi -2 alkyl. In specific embodiments, Ri is monofluorom ethyl. In specific embodiments, Ri is difluoromethyl. In specific embodiments, Ri is trifluorom ethyl.
• R 2 is hydroxy. In some embodiments, R 2 is Ci-C 6 alkoxy. In further or additional embodiments, R 2 is Ci-C 3 alkoxy. In further or additional embodiments, R 2 is Ci-C 2 alkoxy. In specific embodiments, R 2 is methoxy. In specific embodiments, R 2 is ethoxy. In specific embodiments, R 2 is propoxy. In specific embodiments, R 2 is iso-propoxy. In specific embodiments, R 2 is butoxy. In specific embodiments, R 2 is iso-butoxy. In specific embodiments, R 2 is sec-butoxy. In specific embodiments, R 2 is tert-butoxy. In specific embodiments, R 2 is pentyloxy.
• R 2 is hexyloxy.
• R 3 , R 4 , R 5 , and 5 are independently hydrogen, alkoxy, or alkyl. In some embodiments, R 3 , R 4 , R 5 , and 5 are independently hydrogen or alkyl. In other embodiments, R 3 , R 4 , R 5 , and R 6 are independently hydrogen.
• R 3 is hydrogen. In some embodiments, R 3 is Ci-C 6 alkyl. In other embodiments, R 3 is Ci-C 3 alkyl. In other embodiments, R 3 is Ci-C 2 alkyl. In specific
• R 3 is methyl. In specific embodiments, R 3 is ethyl. In specific embodiments, R 3 is propyl. In specific embodiments, R 3 is iso-propyl. In specific embodiments, R 3 is butyl. In specific embodiments, R 3 is iso-butyl. In specific embodiments, R 3 is sec-butyl. In specific embodiments, R 3 is tert-butyl. In specific embodiments, R 3 is pentyl. In specific embodiments, R 3 is hexyl. In some embodiments, R 3 is Ci-C 6 alkoxy. In further or additional embodiments, R 3 is Ci-C 3 alkoxy. In further or additional embodiments, R 3 is Ci-C 2 alkoxy. In specific
• R 3 is methoxy. In specific embodiments, R 3 is ethoxy. In specific embodiments, R 3 is propoxy. In further or alternative embodiments, R 3 is fluoro. In other embodiments, R 3 is chloro. In other embodiments, R 3 is iodo. In other embodiments, R 3 is bromo. In other embodiments, R 3 is haloalkyl. In other embodiments, R 3 is haloCi -6 alkyl. In other embodiments, R 3 is haloCi -3 alkyl. In other embodiments, R 3 is haloCi -2 alkyl. In specific embodiments, R 3 is monofluorom ethyl. In specific embodiments, R 3 is difluorom ethyl. In specific embodiments, R 3 is trifluoromethyl.
• R 4 is hydrogen. In some embodiments, R 4 is Ci-C 6 alkyl. In other embodiments, R 4 is Ci-C 3 alkyl. In other embodiments, R 4 is Ci-C 2 alkyl. In specific
• R 4 is methyl. In specific embodiments, R 4 is ethyl. In specific embodiments, R 4 is propyl. In specific embodiments, R 4 is iso-propyl. In specific embodiments, R 4 is butyl. In specific embodiments, R 4 is iso-butyl. In specific embodiments, R 4 is sec-butyl. In specific embodiments, R 4 is tert-butyl. In specific embodiments, R 4 is pentyl. In specific embodiments, R 4 is hexyl. In some embodiments, R 4 is Ci-C 6 alkoxy. In further or additional embodiments, R 4 is Ci-C 3 alkoxy. In further or additional embodiments, R 4 is Ci-C 2 alkoxy. In specific
• R 4 is methoxy. In specific embodiments, R 4 is ethoxy. In specific embodiments, R 4 is propoxy. In further or alternative embodiments, R 4 is fluoro. In other embodiments, R 4 is chloro. In other embodiments, R 4 is iodo. In other embodiments, R 4 is bromo. In other embodiments, R 4 is haloalkyl. In other embodiments, R 4 is haloCi- 6 alkyl. In other embodiments, R 4 is haloCi -3 alkyl. In other embodiments, R 4 is haloCi -2 alkyl. In specific embodiments, R 4 is monofluorom ethyl. In specific embodiments, R 4 is difluorom ethyl. In specific embodiments, R 4 is trifluoromethyl.
• R 5 is hydrogen. In some embodiments, R 5 is Ci-C 6 alkyl. In other embodiments, R 5 is Ci-C 3 alkyl. In other embodiments, R 5 is Ci-C 2 alkyl. In specific embodiments, R 5 is methyl. In specific embodiments, R 5 is ethyl. In specific embodiments, R 5 is propyl. In specific embodiments, R 5 is iso-propyl. In specific embodiments, R 5 is butyl. In specific embodiments, R 5 is iso-butyl. In specific embodiments, R 5 is sec-butyl. In specific embodiments, R 5 is tert-butyl. In specific embodiments, R 5 is pentyl.
• R 5 is hexyl. In some embodiments, R 5 is Ci-C 6 alkoxy. In further or additional embodiments, R 5 is Ci-C 3 alkoxy. In further or additional embodiments, R 5 is Ci-C 2 alkoxy. In specific
• R 5 is methoxy. In specific embodiments, R 5 is ethoxy. In specific embodiments, R 5 is propoxy. In further or alternative embodiments, R5 is fluoro. In other embodiments, R5 is chloro. In other embodiments, R5 is iodo. In other embodiments, R5 is bromo. In other embodiments, R 5 is haloalkyl. In other embodiments, R 5 is haloCi -6 alkyl. In other embodiments, R 5 is haloCi -3 alkyl. In other embodiments, R5 is haloCi -2 alkyl. In specific embodiments, R5 is monofluorom ethyl. In specific embodiments, R5 is difluorom ethyl. In specific embodiments, R5 is trifluoromethyl.
• R 6 is hydrogen. In some embodiments, R 6 is Ci-C 6 alkyl. In other embodiments, R 6 is Ci-C 3 alkyl. In other embodiments, 5 is Ci-C 2 alkyl. In specific
• R 6 is methyl. In specific embodiments, R 6 is ethyl. In specific embodiments, R 6 is propyl. In specific embodiments, R 6 is iso-propyl. In specific embodiments, R 6 is butyl. In specific embodiments, R 6 is iso-butyl. In specific embodiments, R 6 is sec-butyl. In specific embodiments, R 6 is tert-butyl. In specific embodiments, 5 is pentyl. In specific embodiments, R 6 is hexyl. In some embodiments, R 6 is Ci-C 6 alkoxy. In further or additional embodiments, R 6 is Ci-C 3 alkoxy. In further or additional embodiments, R 6 is Ci-C 2 alkoxy. In specific
• R 6 is methoxy. In specific embodiments, R 6 is ethoxy. In specific embodiments, R 6 is propoxy. In further or alternative embodiments, R 6 is fluoro. In other embodiments, R 6 is chloro. In other embodiments, R 6 is iodo. In other embodiments, R 6 is bromo. In other embodiments, R 6 is haloalkyl. In other embodiments, R 6 is haloCi- 6 alkyl. In other embodiments, R 6 is haloCi -3 alkyl. In other embodiments, R 6 is haloCi -2 alkyl. In specific embodiments, R 6 is monofluorom ethyl. In specific embodiments, R 6 is difluorom ethyl. In specific embodiments, R 6 is trifluoromethyl.
• R 7 is Ci-C 6 alkyl. In other embodiments, R 7 is Ci-C 3 alkyl. In other embodiments, R 7 is Ci-C 2 alkyl. In specific embodiments, R 7 is methyl. In specific embodiments, R 7 is ethyl. In specific embodiments, R 7 is propyl. In specific embodiments, R 7 is isopropyl. In alternative embodiments, R 7 is hydrogen. In some embodiments, R 7 is methyl or hydrogen.
• R 9 is hydroxy. In some embodiments, R 9 is Ci-C 6 alkoxy. In further or additional embodiments, R 9 is Ci-C 3 alkoxy. In further or additional embodiments, R 9 is Ci-C 2 alkoxy. In specific embodiments, R 9 is methoxy. In specific embodiments, R 9 is ethoxy. In specific embodiments, R is propoxy. In specific embodiments, R 9 is iso-propoxy. In specific embodiments, R 9 is butoxy. In specific embodiments, R 9 is iso-butoxy. In specific embodiments, R 9 is sec-butoxy. In specific embodiments, R 9 is tert-butoxy. In specific embodiments, R 9 is pentyloxy. In specific embodiments, R 9 is hexyloxy.
• Ri is hydroxy or alkoxy
• R 2 is hydroxy or alkoxy
• R 3 , R 4 , R 5 , and 5 are independently hydrogen, hydroxy, alkoxy, or alkyl
• R 7 is alkyl or hydrogen
• R 9 is hydroxy or alkoxy.
• Ri is hydroxy or alkoxy
• R 2 is hydroxy or alkoxy
• R 3 , R 4 , R5, and 5 are independently hydrogen
• R 7 is alkyl or hydrogen
• R 9 is hydroxy.
• Ri is hydroxy or methoxy
• R 2 is hydroxy or methoxy
• R 3 , R 4 , R 5 , and 5 are independently hydrogen, hydroxy, methoxy, methyl
• R 7 is methyl or hydrogen
• R 9 is hydroxy or methoxy.
• Ri is hydroxy or methoxy
• R 2 is hydroxy or methoxy
• R 3 , R 4 , R 5 , and 5 are independently hydrogen
• R 7 is methyl or hydrogen
• R 9 is hydroxy.
• compounds of the general Formula (II) have the substituents Ri, R 3 , and R 4 distributed as shown below:
• compounds of the general Formula (II) have the substituents R 2 , R 5 , and 5 distributed as shown below:
• compounds of the general Formula (IV) have the substituents R 3
• substituents are selected from among a subset of the listed alternatives.
• Exemplary compounds include the following compounds:
• Exemplary compounds include the following compounds:
• the aryl substituents on the heterocyclic ring can be cis or trans relative to each other. In certain embodiments of the invention, these substituents will be cis.
• the compounds according to some embodiments of this invention include two chiral centers.
• the present invention includes all the enantiomers and diastereomers as well as mixtures thereof in any proportions.
• the invention also extends to isolated enantiomers or pairs of enantiomers.
• Some of the compounds herein including, but not limited to benzopyran derivatives and reagents for producing the aforementioned compounds) have asymmetric carbon atoms and can therefore exist as enantiomers or diastereomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as chromatography and/or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof are considered as part of the compositions described herein.
• an appropriate optically active compound e.g., alcohol
• any compound described herein is in the optically pure form (e.g., optically active (+) and (-), (R)- and (S)-, d- and /-, or (D)- and (L)-isomers).
• a compound of Formulas (I), (II), (III), or (IV) is the ⁇ i-isomer. Accordingly, provided herein, in some embodiments, is the optically active ⁇ i-isomer having a structure of Formulas (I), (II), (III), or (IV) in enantiomeric excess.
• the ⁇ i-isomer of a compound of Formulas (I), (II), (III), or (IV) is provided in at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 95%, or 99.9% enantiomeric excess.
• the ⁇ i-isomer of a compound of Formulas (I), (II), (III), or (IV) is provided in greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess.
• of a compound of Formulas (I), (II), (III), or (IV) has greater than 95%
• Specific optically active compounds i.e., enantiomers of Formulas (I), (II), (III), or (IV) include:
• a compound of Formulas (I), (II), (III), or (IV) is d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)chroman-7-ol.
• a compound of Formulas (I), (II), (III), or (IV) is i/-cz ' s-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol .
• a compound of Formulas (I), (II), (III), or (IV) is the ⁇ i-isomer. Accordingly, provided herein, in some embodiments, is the optically active ⁇ i-isomer having a structure of Formulas (I), (II), (III), or (IV) in enantiomeric excess.
• the d- isomer is provided in at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 95.5%, or 99.9% enantiomeric excess.
• the ⁇ i-isomer is provided in greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess.
• a compound of Formulas (I), (II), (III), or (IV) has greater than 95% enantiomeric excess.
• a compound of Formulas (I), (II), (III), or (IV) has greater than 98% enantiomeric excess.
• a compound of Formulas (I), (II), (III), or (IV) has greater than 99% enantiomeric excess. In specific embodiments, a compound of Formulas (I), (II), (III), or (IV) has greater than 99.9% enantiomeric excess.
• the benzopyran derivative is a super-benzopyran. In some embodiments, the benzopyran derivative is TrilexiumTM (TRXE-009), CantrixilTM (TRXE-002, Trx-1), or combinations thereof. In some embodiments, the benzopyran derivative is
• TrilexiumTM In some embodiments, the benzopyran derivative is CantrixilTM.
• the compounds described herein are used in the form of pro-drugs. In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
• any compound described herein may be synthesized according to the exemplary synthesis shown in Schemes 1 and 2.
• compounds 6 and 7 are synthesized from 4'- bis-tert-butyldimethylsilyoxy-8-methyldihydrodaidzein.
• 4'-bis-tert-butyldimethylsilyoxy-8- methyldihydrodaidzein is treated with 4-methoxy-3-methylphenylmagnesium bromide in anhydrous THF.
• the reaction mixture is treated with wet ether (50:50 H 2 0/Et 2 0).
• the resultant mixture is extracted with Et 2 0.
• the organic layer is washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo.
• the resultant residue is treated with pTsOH and ethanol.
• the reaction mixture is heated to reflux for 3 hours.
• the reaction mixture is concentrated in vacuo then poured into water (0 °C).
• the mixture is extracted with EtOAc, then the organic layer is washed with water (3 x), brine, dried (MgSC ⁇ ), filtered and concentrated in vacuo to provide the 3-alkene intermediate.
• the intermediate is treated with Pd catalyst and ethanol.
• the reaction mixture is hydrogenated at low pressure for 3 h.
• the reaction is filtered through Celite and the filtrate is concentrated to a volume of 15 mL.
• the resultant solution is added to water.
• the mixture is extracted with Et 2 0 (3 x), the organic layers are combined and washed with water, brine, dried (MgSC ⁇ ), filtered and concentrated in vacuo.
• the resultant residue is purified by recrystallization to provide compound 7.
• compounds described herein are prepared as prodrugs.
• a "prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
• An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the "prodrug") but then is metabolically hydrolyzed to provide the active entity.
• a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
• a prodrug upon in vivo administration, is chemically converted to the biologically,
• a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
• Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al, Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
• a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
• a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
• a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
• compounds described herein are prepared as alkyl ester prodrugs.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds are prodrugs for another derivative or active compound.
• the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
• a "metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
• active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
• metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
• Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
• glycolytic inhibitors that are capable of inhibiting at least one step of the glycolytic pathway in a cell.
• the glycolytic inhibitor is a hexokinase inhibitor.
• the hexokinase inhibitor is 2-deoxyglucose, 6-fluoroglucose, 6-thioglucose, 2-fluorodeoxyglucose, 3-bromopyruvate, or a pharmaceutically acceptable salt thereof.
• the hexokinase inhibitor is 2- deoxyglucose, 2-fluorodeoxyglucose, 3-bromopyruvate, or a pharmaceutically acceptable salt thereof.
• the glycolytic inhibitor is a homolog, analog and/or derivative of 2-deoxy-D-glucose.
• 2-deoxyglucose derivatives include 2-deoxy- D-glucose, 2-deoxy-L-glucose; 2-bromo-D-glucose, 2-fluoro-D-glucose, 2-iodo-D-glucose, 6- fluoro-D-glucose, 6-thio-D-glucose, 7-glucosyl fluoride, 3-fluoro-D-glucose, 4-fluoro-D-glucose, 1-O-propyl ester of 2-deoxy-D-glucose, 1-O-tridecyl ester of 2-deoxy-D-glucose, 1-0- pentadecyl ester of 2-deoxy-D-glucose, 3-O-propyl ester of 2-deoxy-D-glucose, 3-O-tridecy
• the glycolytic inhibitor is a lactic dehydrogenase inhibitor.
• the lactic dehydrogenase inhibitor is oxamate or a pharmaceutically acceptable salt thereof.
• the glycolytic inhibitor is a glyceraldehyde 3- phosphate dehydrogenase (e.g., iodoacetate or a pharmaceutically acceptable salt thereof).
• the glycolytic inhibitor is a glucose-6-phosphate dehydrogenase inhibitor.
• the glucose-6-phosphate dehydrogenase inhibitor is red algal bromophenols.
• the glycolytic inhibitor is an angiogenesis inhibitor.
• the angiogenesis inhibitor is a multi-tyrosine kinase inhibitor.
• angiogenesis inhibitors include agents targeting (e.g. inhibiting) endothelial- specific receptor tyrosine kinase (Tie-2), epidermal growth factor (receptor) (EGF(R)), insulinlike growth factor (receptor) (IGF-(R)), fibroblast growth factor (receptor) (FGF(R)), platelet- derived growth factor (receptor) (PDGF(R)), hepatocyte growth factor (receptor) (HGF(R)), or vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR); as well as
• thrombospondin analogs thrombospondin analogs, matrix metalloprotease (e.g. MMP-2 or MMP-9) inhibitors,
• thalidomide or thalidomide analogs include integrins, angiostatin, endostatin, vascular disrupting agents, protein kinase C(PKC) inhibitors, and the like.
• angiogenesis inhibitors are agents targeting (e.g. inhibiting) vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR).
• Agents targeting (e.g. inhibiting) VEGF/VEGFR relate to compounds which target (e.g. inhibit) one or more members of the VEGF or VEGFR family (VEGFR 1, VEGFR2, VEGFR3) and include inhibitors of any vascular endothelial growth factor (VEGF) ligand (such as e.g. ligand antibodies or soluble receptors) as well as inhibitors of any VEGF receptor (VEGFR) (such as e.g.
• VEGFR tyrosin kinase inhibitors VEGFR antagonists or receptor antibodies.
• small molecule VEGFR inhibitors include, without being limited to, sorafenib (Nexavar, also an inhibitor of Raf, PDGFR, Flt3, Kit and RETR), sunitinib (Sutent, also inhibitor of Kit, Flt3 and PDGFR), pazopanib (GW-786034, also inhibitor of Kit and PDGFR), cediranib (Recentin, AZD-2171), axitinib (AG-013736, also inhibitor of PDGFR and Kit), vandetanib (Zactima, ZD-6474, also inhibitor of EGFR and Ret), vatalanib (also inhibitor of PDGFR and Kit), motesanib (AMG-706, also inhibitor of PDGFR and Kit), brivanib (also FGFR inhibitor), linifanib (ABT-869, also inhibitor of PDGFR, Flt3 and Kit), tivozani
• VEGF(R) examples include, without being limited to, anti- VEGF ligand antibodies such as bevacizumab (Avastin); soluble receptors such as aflibercept (VEGF-Trap); anti-VEGF receptor antibodies such as ramucirumab (FMC-1121b) or FMC-18F1; VEGFR antagonists such as CT-322 or CDP-791.
• anti- VEGF ligand antibodies such as bevacizumab (Avastin); soluble receptors such as aflibercept (VEGF-Trap); anti-VEGF receptor antibodies such as ramucirumab (FMC-1121b) or FMC-18F1; VEGFR antagonists such as CT-322 or CDP-791.
• Agents targeting (e.g. inhibiting) PDGFR relate to compounds which target (e.g. inhibit) one or more members of the PDGFR family and include inhibitors of a platelet-derived growth factor receptor (PDGFR) family tyrosin kinase (either as single kinase inhibitor or as
• PDGFR platelet-derived growth factor receptor
• small molecule PDGFR inhibitors include, without being limited to, nintedanib (also inhibitor of VEGFR and FGFR), axitinib (also inhibitor of VEGFR and Kit), dovitinib (also inhibitor of VEGFR, Flt3, Kit and FGFR), sunitinib (also inhibitor of VEGFR, Flt3 and Kit), motesanib (also inhibitor of VEGFR and Kit), pazopanib (also inhibitor of VEGFR and Kit), nilotinib (also inhibitor of Abl and Kit), tandutinib (also inhibitor of Flt3 and Kit), vatalanib (also inhibitor of VEGFR and Kit), tivozanib (KRN-951, also inhibitor of VEGFR, Kit, and MAP), AC -220 (also inhibitor of Flt3 and Kit), TSU-68 (also inhibitor of FGFR and VEGFR), KRN-633 (also inhibitor of VEGFR, Kit
• Agents targeting FGFR relate to compounds which target one or more members of the FGFR family and include inhibitors of a fibroblast growth factor receptor family tyrosin kinase (either as single kinase inhibitor or as multikinase inhibitor).
• small molecule FGFR inhibitors include, without being limited to, nintedanib (also inhibitor of VEGFR and PDGFR), dovitinib (also inhibitor of VEGFR, Flt3, Kit and PDGFR), KW-2449 (also inhibitor of Flt3 and Abl), brivanib (also VEGFR inhibitor), TSU-68 (also inhibitor of PDGFR and VEGFR).
• Agents targeting (e.g. inhibiting) EGFR relate to compounds which target (e.g. inhibit) one or more members of the epidermal growth factor receptor family (erbB l, erbB2, erbB3, erbB4) and include inhibitors of one or more members of the epidermal growth factor receptor (EGFR) family kinases (either as single kinase inhibitor or as multikinase inhibitor) as well as antibodies binding to one or more members of the epidermal growth factor receptor (EGFR) family.
• EGFR epidermal growth factor receptor family
• small molecule epidermal growth factor receptor (EGFR) inhibitors include, without being limited to, erlotinib (Tarceva), gefitinib (Iressa), afatinib, lapatinib (Tykerb), vandetanib (Zactima, also inhibitor of VEGFR and RETR), BMS-690514 (also an inhibitor of VEGFR), neratinib (HKI-272), varlitinib, AZD-8931, AC-480, AEE-788 (also inhibitor of VEGFR).
• Examples of antibodies against the epidermal growth factor receptor include the anti -ErbBl antibodies cetuximab, panitumumab or nimotuzumab, the anti-ErbB2 antibodies trastuzumab (Herceptin), pertuzumab (Omnitarg) or ertumaxomab, and the anti-EGFR antibody zalutumumab.
• EGFR epidermal growth factor receptor
• IGF(R) inhibitors are agents that target one or more members of the insulin-like growth factor (IGF) family (e.g. IGF1 and/or IGF2), particularly of the IGFR family of tyrosine kinases, e.g. IGF1 and/or IGF2
• IGF insulin-like growth factor
• IGF1 and/or IGF2 members of the insulin-like growth factor family
• IGF2 insulin-like growth factor 2
• IGFR family of tyrosine kinases e.g.
• IGFR-1 (either as single kinase inhibitor or as multikinase inhibitor), and/or of insulin receptor pathways, and may include, without being limited to, the IGFR tyrosin kinase inhibitors OSI-906 (linsitinib) and l- ⁇ 4-[(5-cyclopropyl-lH-pyrazol-3-yl)amino]pyrrolo[2, l- f][l,2,4]triazin-2-yl ⁇ -N-(6-fluoro-3-pyridinyl)-2-methyl-L-prolinamide (BMS-754807), as well as the anti-IGF(R) antibodies figitumumab, cixutumumab, dalotuzumab, ganitumab and robatumumab.
• OSI-906 lainsitinib
• HGF(R) inhibitors are agents that target one or more members of the hepatocyte growth factor (HGF) family, particularly of the HGFR family of tyrosine kinases (either as single kinase inhibitor or as multikinase inhibitor), and may include, without being limited to, the HGFR tyrosin kinase inhibitors cabozantinib (XL-184, also inhibitor of VEGFR, Flt3, Ret, Tek and Kit), crizotinib (also inhibitor of Alk), foretinib (also inhibitor of Flt3, Kit and VEGFR) and tivantinib, as well as the anti-HGF(R) antibodies ficlatuzumab and onartuzumab.
• HGF hepatocyte growth factor
• vascular disrupting agents include, without being limited to, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, vadimezan), combretastatin A4 phosphate (Zybrestat) or combretastatin A4 analogues, such as ombrabulin (AVE-8062).
• DMXAA 5,6-dimethylxanthenone-4-acetic acid
• Zybrestat combretastatin A4 phosphate
• combretastatin A4 analogues such as ombrabulin (AVE-8062).
• the angiogenesis inhibitor is nintedanib (BIBF 1120, Vargatef), bevacizumab (Avastin), everolimus (Afinitor), temsirolimus (Torisel), lenalidomide (Revlimid), pazopanib (Votrient), ramucirumab (Cyramza), sorafenib (Nexavar), sunitinib (Sutent), thalidomide (Thalomid), vandetanib (Caprelsa), cediranib (Recentin), axitinib (Inlyta), motesanib, vatalanib, dovitinib, brivanib, linifanib, tivozanib, lenvatinib, regorafenib (Stivarga), foretinib, telatinib, cabozantinib (Cometriq), nilotinib (Tasigna
• the angiogenesis inhibitor is nintedanib (BIBF 1120), everolimus (Afinitor), temsirolimus (Torisel), pazopanib (Votrient), axitinib (Inlyta), bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), thalidomide (Thalomid), dovitinib, regorafenib (Stivarga), or imatinib (Gleevec).
• the angiogenesis inhibitor is nintedanib (BIBF 1120), everolimus (Afinitor), temsirolimus (Torisel), pazopanib (Votrient), axitinib (Inlyta), bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), thalidomide (Thalomid), dovit
• angiogenesis inhibitor is dovitinib, regorafenib (Stivarga), or nintedanib (BIBF 1120). In certain embodiments, the angiogenesis inhibitor is dovitinib or nintedanib (BIBF 1 120). In certain embodiments, the angiogenesis inhibitor is dovitinib. In certain embodiments, the angiogenesis inhibitor is nintedanib (BIBF 1120).
• Some embodiments provided herein describe a method of inducing apoptosis in a cancer cell. Also described herein, in other embodiments, is a method of treating cancer in an individual in need of cancer therapy. In specific embodiments, the methods comprise contacting the cancer or cancer cell with an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor. In certain embodiments, the cancer or cancer cell is present in an individual. In specific embodiments, the individual is in need of cancer therapy.
• an oxidative phosphorylation inhibitor e.g., a benzopyran derivative
• provided herein is a method of treating a disease or disorder associated with dysregulation of cell proliferation.
• the disease or disorder is cancer.
• provided herein is a method of increasing, inducing, or restoring sensitivity to a cancer therapy in an individual.
• Some embodiments provided herein describe a method of treating a chemoresistant cancer.
• the methods comprise contacting the cancer or cancer cell with an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor.
• the cancer or cancer cell is present in an individual. In specific embodiments, the individual is in need of cancer therapy.
• the cancer or cancer cell has lost sensitivity to a chemotherapeutic agent, anti -cancer agent or radiation therapy.
• the combination of an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor has an enhanced effect.
• the combination of an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative), a glycolytic inhibitor, and an additional anti -cancer agent has an enhanced effect.
• the combination therapies and/or compositions described herein chemosensitize cancer cells, wherein the combination therapies and/or compositions lower the amount of anti-cancer agent that is required to kill the cancer cell.
• the combination therapies and/or compositions described herein chemosensitize cancer cells, wherein the combination therapies and/or compositions convert cancer cells from a state of chemo-resistant to chemo-sensitive.
• the combination therapies and/or compositions described herein radiosensitize cancer cells, wherein the combination therapies and/or compositions lower the amount of gamma-irradiation that is required to kill the cancer cell.
• the combination therapies and/or compositions described herein radiosensitize cancer cells, wherein the combination therapies and/or compositions convert cancer cells from a state of radio-resistant to radio-sensitive.
• the cancer is drug -resistant or chemoresistant. In some embodiments, the cancer is multi-drug resistant. As used herein, a "drug-resistant cancer" is a cancer that is resistant to conventional commonly known cancer therapies.
• Examples of conventional cancer therapies include treatment of the cancer with agents such as methotrexate, doxorubicin, 5-fluorouracil, vincristine, vinblastine, pamidronate disodium, anastrozole, exemestane, cyclophosphamide, epirubicin, toremifene, letrozole, trastuzumab, megestrol, tamoxifen, paclitaxel, docetaxel, capecitabine, goserelin acetate, etc.
• the cancer is resistant to nintedanib.
• a "multi-drug resistant cancer” is a cancer that resists more than one type or class of cancer agents, i.e., the cancer is able to resist a first drug having a first mechanism of action, and a second drug having a second mechanism of action.
• a method to treat cancer in an individual comprising administering to the individual an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative) and a glycolytic inhibitor, wherein the side-effects associated with chemotherapy, radiotherapy, or cancer therapy is reduced or minimized.
• an oxidative phosphorylation inhibitor e.g., a benzopyran derivative
• a glycolytic inhibitor e.g., a glycolytic inhibitor
• the combination therapies and/or compositions described herein provide chemo- protective and/or radio-protective properties to non-cancerous cells.
• the lower amount of oxidative phosphorylation inhibitor e.g., a benzopyran derivative
• a glycolytic inhibitor e.g., a glycolytic inhibitor
• additional anti -cancer agent reduces or minimizes any undesired side-effects associated with chemotherapy.
• side-effects associated with chemotherapy, radiotherapy or cancer therapy include fatigue, anemia, appetite changes, bleeding problems, diarrhea, constipation, hair loss, nausea, vomiting, pain, peripheral neuropathy, swelling, skin and nail changes, urinary and bladder changes, and trouble swallowing.
• cancer cells include cancer cells that create ATP for energy anaerobically and cancer cells that aerobically generate ATP, the method comprising
• an oxidative phosphorylation inhibitor e.g., a benzopyran derivative
• a glycolytic inhibitor e.g., a benzopyran derivative
• cancer cells e.g., at the inner core of a tumor, are poorly oxygenated and consequently rely on anaerobic metabolism for survival.
• cancer cells use steps of the glycolytic pathway to create ATP for energy anaerobically.
• these tumor cells divide more slowly than outer growing aerobic cells and
• the anaerobic tumor cells are resistant to chemotherapeutic agents that target aerobic metabolism (e.g., oxidative phosphorylation).
• chemotherapeutic agents that target aerobic metabolism e.g., oxidative phosphorylation
• cells growing anaerobically exhibit a form of multidrug resistance (MDR).
• MDR multidrug resistance
• cancer cells metabolize glucose at high rates to synthesize high levels of ATP, exhibiting increased glycloysis. In some instances where the glycolytic pathway is inhibited, cancer cells develop an escape mechanism and switch to mitochondrial oxidative phosphorylation to synthesize ATP. In some instances, the cancer cells shift to reliance on mitochondrial metabolism as the primary energy source.
• the combination therapies and/or compositions are used to treat anaerobic tumor cells and aerobic tumor cells (with inhibitors of oxidative
• the combination therapies and/or compositions provide synergistic antitumor activity.
• inhibiting oxidative phosphorylation to convert aerobic tumor cells to anaerobic cells hypersensitizes the cancer cells to glycolytic inhibitors.
• inhibiting glycolysis to convert anaerobic tumor cells to aerobic cells hypersensitizes the cancer cells to oxidative phosphorylation inhibitors (e.g., benzopyran derivatives).
• the administration time of the oxidative phosphorylation inhibitors (e.g., benzopyran derivatives) and the glycolytic inhibitors is not restricted.
• the oxidative phosphorylation inhibitors (e.g., benzopyran derivatives) and the glycolytic inhibitors are administered to an individual simultaneously.
• the oxidative phosphorylation inhibitors (e.g., benzopyran derivatives) and the glycolytic inhibitors are administered at staggered times.
• the individual is first treated with a glycolytic inhibitor, followed by an oxidative phosphorylation inhibitor.
• the individual is first treated with an oxidative phosphorylation inhibitor, followed by a glycolytic inhibitor.
• Some embodiments provided herein describe a method of treating cancer or a tumor in a subject, the method comprising i) treating the subject with a glycolytic inhibitor; ii) administering to the subject a positron emission tomography (PET) scan (or other imaging procedure suitable to assess efficacy of anti-cancer or anti-tumor treatment with the glycolytic inhibitor); and iii) if the result of the PET scan (or other imaging) testing procedure in step ii is positive (i.e., if the cancer or tumor is responsive), treating the subject with the glycolytic inhibitor and an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative).
• PET positron emission tomography
• step ii if the result of the PET scan (or other imaging procedure) in step ii is negative (i.e., the tumor or cancer is unresponsive to the glycolytic inhibitor), treatment with the glycolytic inhibitor is continued and the PET scan (or other imaging procedure) in step ii is re-administered in 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, at which point, if the result of the PET scan (or other imaging) testing procedure in step ii is positive (i.e., if the cancer or tumor is responsive), treating the subject with the glycolytic inhibitor and an oxidative phosphorylation inhibitor (e.g., a benzopyran derivative).
• an oxidative phosphorylation inhibitor e.g., a benzopyran derivative
• the cancer is selected from the group consisting of bladder cancer, breast cancer, metastatic breast cancer, metastatic HER2 -negative breast cancer, colon cancer, rectal cancer, metastatic colorectal cancer, endometrial cancer, cervical cancer, uterine cancer, ovarian cancer, kidney cancer, liver cancer, leukemia, lung cancer (both small cell and non-small cell), squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, melanoma, Lewis lung carcinoma, non-Hodgkin lymphoma, pancreatic cancer, testicular cancer, prostate cancer, thyroid cancer, sarcoma (including osteosarcoma), esophageal cancer, gastric cancer, head and neck cancer, lung cancer melanoma, myeloma, neuroblastoma, glioblastoma, and cancers of the brain.
• the cancer is selected from, by way of non- limiting example, human breast, prostate, ovarian, pan
• a tumor cell in a subject or individual may be part of any type of cancer.
• cancer include, but are not limited to, biliary tract cancer; bladder cancer; brain cancer including glioblastomas and medulloblastomas; breast cancer; cervical cancer;
• choriocarcinoma colon cancer; endometrial cancer; esophageal cancer; gastric cancer;
• hematological neoplasms including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS-associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer; lung cancer; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cell carcinoma; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer including melanoma, Kaposi's sarcoma, basocellular cancer, and squamous cell cancer; testicular cancer including germinal tumor
• the methods described herein are useful in treating various cancers including but not limited to bone cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including acoustic neuroma,
• endocrine cancers including adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasma, gastrointestinal cancers including stomach cancer, esophageal cancer, small intestine cancer, liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer, gynaecological cancers including cervical cancer, ovarian cancer, vaginal cancer, uterus/endometrium cancer, vulva cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma
• Hodgkin's disease non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS related Lymphoma, B-cell lymphoma, Burkitt's lymphoma, eye cancers including retinoblastoma, intraocular melanoma, skin cancers including melanoma, non- melanoma skin cancer, squamous cell carcinoma, merkel cell cancer, soft tissue sarcomas such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers including kidney cancer, Wilms tumour, bladder cancer, urethral cancer, and transitional cell cancer.
• the cancer is a hematological malignancy.
• the hematological malignancy is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, thrombolytic leukemia, a myelodysplasia syndrome (MDS), a myeloproliferative disorder, refractory anemia, a preleukemia syndrome, a lymphoid leukemia, lymphoma, non-Hodgkin's lymphoma, or an undifferentiated leukemia.
• AML acute myeloid leukemia
• CML chronic myeloid leukemia
• MDS myelodysplasia syndrome
• a myeloproliferative disorder refractory anemia, a preleukemia syndrome, a lymphoid leukemia, lymphoma, non-Hodgkin's lymphoma, or an undifferentiated leukemia.
• the cancer is myelodysplasia syndrome (MDS) or acute myeloid leukemia (AML).
• MDS myelodysplasia syndrome
• AML acute myeloid leukemia
• Non-limiting examples of non-Hodgkin's lymphoma include diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL).
• DLBCL diffuse large B-cell lymphoma
• MCL mantle cell lymphoma
• CLL chronic lymphocytic leukemia
• exemplary cancers that may be treated by the methods described herein include but are not limited to leukemias such as erythroleukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute lymophocytic leukemia, acute T-cell leukemia and lymphoma such as B-cell lymphoma (e.g. Burkitt's lymphoma), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma.
• leukemias such as erythroleukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute lymophocytic leukemia, acute T-cell leukemia and lymphoma
• B-cell lymphoma e.g. Burkitt's lymphoma
• CTCL cutaneous T-cell lymphoma
• peripheral T-cell lymphoma peripheral T-cell lymphoma
• cancer therapy is, by way of non-limiting example, at least one anti-cancer agent (e.g., one anti-cancer agent),
• the administration time of the combination therapy/composition and a concomitant anti -cancer agent is not restricted.
• the combination therapy/composition and a concomitant anti-cancer agent are administered to an individual simultaneously.
• the combination therapy/composition and a concomitant anti-cancer agent are administered at staggered times.
• An anti -cancer agent includes but is not limited to a chemotherapeutic agent, immunotherapeutic agent, a pharmaceutical agent that inhibits the action of cell growth factor and a receptor thereof and the like.
• chemotherapeutic agents that are optionally employed, by way of non-limiting example, are cisplatin, carboplatin, paclitaxel, gemcitabine or doxorubicin.
• chemotherapeutic agents include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.
• Alkylating agents include but are not limited to nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin sti
• Antimetabolites include but are not limited to mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,
• 5-FU drugs e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,
• gallocitabine emitefur, and the like
• aminopterine leucovorin calcium
• tabloid butocine
• folinate calcium levofolinate calcium
• cladribine emitefur
• fludarabine gemcitabine
• hydroxy carbamide pentostatin
• piritrexim idoxuridine
• mitoguazone mitoguazone
• thiazophrine hydroxy carbamide
• Anticancer antibiotics include but are not limited to actinomycin-D, actinomycin-
• Plant-derived anticancer agents include but are not limited to etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and the like.
• Immunotherapeutic agents include but are not limited to picibanil, krestin, sizofuran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine,
• Non-limiting examples of a cell growth factor in pharmaceutical agents that inhibit the action of cell growth factors or cell growth factor receptors include any substances that promote cell proliferation, which are normally peptides having a molecular weight of not more than 20,000 that are capable of exhibiting their activity at low concentrations by binding to a receptor, including (1) EGF (epidermal growth factor) or substances possessing substantially the same activity as it [e.g., EGF, heregulin, and the like], (2) insulin or substances possessing substantially the same activity as it [e.g., insulin, IGF (insulin-like growth factor)- 1, IGF -2, and the like], (3) FGF (fibroblast growth factor) or substances possessing substantially the same activity as it [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF- 10, and the like], (4) other cell growth factors [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF
• Cell growth factor receptors include but are not limited to any receptors capable of binding to the aforementioned cell growth factors, including EGF receptor, heregulin receptor (HER2), insulin receptor, IGF receptor, FGF receptor- 1 or FGF receptor-2, and the like.
• Pharmaceutical agents that inhibit the action of cell growth factor include but are not limited to HER2 antibody (e.g., trastuzumab), imatinib mesylate, ZD1839 or EGFR antibody (e.g., cetuximab), antibody to VEGF (e.g., bevacizumab), VEGFR antibody, VEGFR inhibitor, and EGFR inhibitor (e.g., erlotinib).
• HER2 antibody e.g., trastuzumab
• imatinib mesylate ZD1839 or EGFR antibody
• VEGF e.g., bevacizumab
• VEGFR antibody e.g., bevacizumab
• VEGFR inhibitor e.g., erlotinib
• anti-cancer agents include but are not limited to L-asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, and the like), topoisomerase II inhibitors (e.g., sobuzoxane, and the like),
• differentiation inducers e.g., retinoid, vitamin D, and the like
• a-blockers e.g., tamsulosin hydrochloride, naftopidil, urapidil, alfuzosin, terazosin, prazosin, silodosin, and the like
• serine/threonine kinase inhibitor endothelin receptor antagonist (e.g., atrasentan, and the like)
• proteasome inhibitor e.g., bortezomib, and the like
• Hsp 90 inhibitor e.g., 17-AAG, and the like
• spironolactone minoxidil, 1 la-hydroxyprogesterone
• bone resorption inhibiting/metastasis suppressing agent e.g., zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid
• Non-limiting examples of hormonal therapeutic agents include fosfestrol, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestrol, Tadenan, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti- estrogens (e.g., tamoxifen citrate, toremifene citrate, and the like), ER down-regulator (e.g., fulvestrant and the like), human menopausal gonadotrophin, follicle stimulating hormone, pill preparations, mepitiostane, testrolactone, aminoglutethimide, LH-RH agonists (e.g., gosereli
• the non-drug therapy is exemplified by surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization, and the like, and any combinations thereof.
• compositions wherein the composition further comprises one or more pharmaceutical carriers, excipients, auxiliaries, binders and/or diluents.
• Pharmaceutical compositions are formulated in a
• composition described herein optionally comprises minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
• the composition further comprises one or more of lactose, dextrose, mannitol, pH buffering agents, antioxidant agents, preservative agents, tonicity adjusters or a combination thereof.
• Examples of pharmaceutically acceptable carriers that are optionally used include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other
• the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by
• the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
• Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dio
• methylbenzoate monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate and xylenesulfonate.
• the compounds described herein are prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic
• those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
• a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
• Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Cl-4alkyl)4, and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
• the compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
• Base addition salts are be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
• organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like
• inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
• the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
• the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
• Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
• enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
• parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
• compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
• topical application such as creams or ointments, injection, catheter, or implant.
• the administration can also be by direct injection at the site of a diseased tissue or organ.
• compositions suitable for oral are provided.
• administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient is presented as a bolus, electuary or paste.
• compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
• inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
• granulating and disintegrating agents such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or
• the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
• sterile liquid carrier for example, saline or sterile pyrogen-free water
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
• Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
• compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
• compositions may be administered topically, that is by non- systemic administration.
• systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
• compositions suitable for topical administration include liquid or semi -liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
• compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
• Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
• the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
• Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbito
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• preservatives for example ethyl, or n-propyl p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
• flavoring agents such as sucrose, saccharin or aspartame.
• sweetening agents such as sucrose, saccharin or aspartame.
• Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
• the pharmaceutical composition contains additional ingredients such as flavorings, binders, excipients and the like.
• excipients such as citric acid
• disintegrants such as starch, alginic acid and certain complex silicates
• binding agents such as sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
• solid compositions of a similar type are employed in soft and hard filled gelatin capsules.
• Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
• the active compound therein is combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
• oily suspensions are formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
• the oily suspensions contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
• sweetening agents such as those set forth above, and flavoring agents are added to provide a palatable oral preparation.
• these compositions are preserved by the addition of an anti -oxidant such as butylated hydroxyanisol or alpha-tocopherol.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. In some embodiments, additional excipients, for example sweetening, flavoring and coloring agents, are also present. In further or additional embodiments, these compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
• compositions are in the form of oil-in- water emulsions.
• the oily phase is a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents include but are not limited to naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions contain sweetening agents, flavoring agents, preservatives and antioxidants.
• compositions described herein are in the form of a sterile injectable aqueous solution.
• Acceptable vehicles and solvents include but are not limited to water, Ringer's solution, phosphate buffered saline solution, U.S.P. and isotonic sodium chloride solution, ethanol, and 1,3-butanediol.
• sterile, fixed oils are optionally employed as a solvent or suspending medium.
• any bland fixed oil is optionally employed including synthetic mono- or diglycerides.
• Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes or other microparticulate systems may be used to target the agent to blood components or one or more organs.
• the sterile injectable preparation is a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
• the active ingredient is first dissolved in a mixture of soybean oil and lecithin.
• the oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
• the injectable solutions or microemulsions are introduced into an individual's blood-stream by local bolus injection.
• a continuous intravenous delivery device are utilized.
• An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
• the pharmaceutical composition is in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
• this suspension is formulated using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil is optionally employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• compositions are administered in the form of suppositories for rectal administration of the drug.
• These compositions are prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
• the compounds or compositions described herein are delivered in a vesicle, such as a liposome.
• the compounds and pharmaceutical compositions described herein are delivered in a controlled release system, or a controlled release system can be placed in proximity of the therapeutic target.
• a pump is used.
• creams, ointments, jellies, solutions or suspensions, etc., containing an active agent is used.
• topical application includes mouth washes and gargles.
• compositions are administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using transdermal skin patches.
• suitable intranasal vehicles and delivery devices or via transdermal routes, using transdermal skin patches.
• the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
• the pharmaceutical composition described herein further comprises a cyclodextrin.
• the cyclodextrin has a concentration (w/v) ranging from about 0.001% to about 50%. In other embodiments, the cyclodextrin has a concentration (w/v) ranging from about 2% to about 48%>. In other embodiments, the
• cyclodextrin has a concentration (w/v) ranging from about 4% to about 45%. In other embodiments, the cyclodextrin has a concentration (w/v) ranging from about 10%> to about 43%. In other embodiments, the cyclodextrin has a concentration (w/v) ranging from about 15% to about 40%). In other embodiments, the cyclodextrin has a concentration (w/v) ranging from about 20% to about 38%. In other embodiments, the cyclodextrin has a concentration (w/v) ranging from about 22% to about 37%. In other embodiments, the cyclodextrin has a
• concentration (w/v) ranging from about 25% to about 35%.
• the cyclodextrin has a concentration (w/v) ranging from about 28% to about 32%.
• compositions further comprising cyclodextrin, wherein the cyclodextrin has a concentration (w/v) of about 15%, 18%, 20%, 22%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, or 38% when cyclodextrin derivative is SBE7-P-CD (Captisol®).
• the cyclodextrin has a concentration (w/v) of about 30% when cyclodextrin derivative is SBE7-P-CD (Captisol®).
• the solubility enhancer has a concentration (w/v) of about 29.4% when the cyclodextrin derivative is SBE7-P-CD (Captisol®).
• Suitable cyclodextrins and derivatives useful in certain embodiments of the compositions, methods and kits described herein include, for example, those described in Challa et al., AAPS PharmSciTech 6(2): E329-E357 (2005), U.S. Patent Nos. 5, 134,127, 5,376,645, 5,874,418, each of which is incorporated by reference herein for such disclosure.
• suitable cyclodextrins or cyclodextrin derivatives for use in certain embodiments of the compositions, methods and kits described herein include, but are not limited to, a- cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, SAE-CD derivatives (e.g., SBE-a-CD, SBE- ⁇ - CD, SBEl-p-CD, SBE4-P-CD, SBE7-p-CD (Captisol®), and SBE-y-CD) (Cydex, Inc.
• SAE-CD derivatives e.g., SBE-a-CD, SBE- ⁇ - CD, SBEl-p-CD, SBE4-P-CD, SBE7-p-CD (Captisol®), and SBE-y-CD
• KS Lenexa, KS
• hydroxy ethyl, hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl -hydroxy ethyl and ethyl- hydroxypropyl ethers of ⁇ -, ⁇ - and ⁇ - cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of ⁇ -, ⁇ - and ⁇ - cyclodextrin, which may contain one or more sugar residues, e. g.
• Specific cyclodextrin derivatives for use herein include hydroxypropyl - ⁇ -cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, hy droxy ethyl - ⁇ - cyclodextrin, dihydroxypropyl-P-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl- ⁇ - cyclodextrin, maltotriosyl-
• cyclodextrins suitable for use in certain embodiments of the compositions, methods and kits described herein include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 by ORGANON (AKZO-NOBEL),
• hydroxybutenyl ether derivatives by EASTMAN sulfoalkyl-hydroxyalkyl ether derivatives, sulfoalkyl-alkyl ether derivatives, and other derivatives, for example as described in U.S. Patent Application Nos. 2002/0128468, 2004/0106575, 2004/0109888, and 2004/0063663, or U.S. Patents Nos. 6,610,671, 6,479,467, 6,660,804, or 6,509,323, each of which is specifically incorporated by reference herein for such disclosure.
• Hydroxypropyl-P-cyclodextrin can be obtained from Research Diagnostics Inc.
• hydroxypropyl-P-cyclodextrin products include Encapsin® (degree of substitution ⁇ 4) and Molecusol® (degree of substitution ⁇ 8); however, embodiments including other degrees of substitution are also available and are within the scope of the present invention.
• Dimethyl cyclodextrins are available from FLUKA Chemie (Buchs, CH) or
• Suitable derivatized cyclodextrins suitable for use in the invention include water soluble derivatized cyclodextrins.
• Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-P-cyclodextrins, e. g., succinyl- ⁇ - cyclodextrin (SCD). All of these materials can be made according to methods known in the art and/or are available commercially. Suitable derivatized cyclodextrins are disclosed in Modified
• Cyclodextrins Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed. Anthony Duchene, Editions de Sante, Paris, France, 1991).
• compositions described herein are used in the preparation of medicaments for the treatment of diseases or conditions.
• Methods for treating any of the diseases or conditions described herein in an individual in need of such treatment involves administration of pharmaceutical compositions described herein to said individual.
• compositions described herein are administered for prophylactic and/or therapeutic treatments.
• the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
• prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
• prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
• the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
• the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
• the length of the drug holiday is between 1 day and 1 year, including by way of example only, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
• the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
• a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• the daily dosages appropriate for the active agents are from about 0.1 mg to about 3000 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form.
• Suitable unit dosage forms for oral administration include from about 0.1 to 1000 mg active ingredient, from about 0.1 to 500 mg active ingredient, from about 1 to 250 mg of active ingredient, from about 1 to about 100 mg active ingredient, from about 1 to about 75 mg active ingredient, from about 1 to about 50 mg active ingredient, from about 1 to about 30 mg active ingredient, from about 1 to about 20 mg active ingredient, or from about 1 to about 10 mg active ingredient.
• Such dosages are optionally altered depending on a number of variables, not limited to the activity of the compound used, the mode of
• the desired dose is
• the dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
• the dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
• the unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
• the dosage of the oxidative phosphorylation inhibitor is reduced to a level at which the oxidative phosphorylation inhibitor is efficacious in combination with the glycolytic inhibitor.
• the reduced dosage is about 0.5 mg/kg to about 10 mg/kg, e.g., about: 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, or 1 mg/kg.
• the reduced dosage is about 5 mg/kg.
• the frequency of administration of the oxidative phosphorylation inhibitor is reduced, either independently of, or in conjunction with, reduction in the dosage of the oxidative
• the dosage of sorafenib is 400 mg twice a day.
• the dosage of sunitinib is 50 mg daily for 4 weeks, followed by 2 weeks off.
• the dosage of pazopanib is 800 mg daily.
• the dosage of axitinib is 5 mg twice daily. In some instances, the maintenance dosage of axitinib is 2 to 10 mg twice daily. In some embodiments, the dosage of regorafenib is 160 mg once daily for 21 days for each 28 day cycle. In some embodiments, the dosage of cabozantinib is 140 mg once daily. In some embodiments, the dosage of temsirolimus is 25 mg IV infusion over a 30 to 60 minute period once a week. In some embodiments, the dosage of everolimus is 10 mg daily. In some embodiments, the dosage of erlotinib is 150 mg daily. In some embodiments, the dosage of nintedanib is 150 mg.
• the dosage of nintedanib is 150 mg twice daily. In some embodiments, the dosage of dovitinib is about 500 mg/kg 5 days on and 2 days off in 28 day cycles. In some embodiments, the dosage of dovitinib is about 250 mg/kg 5 days on and 2 days off in 28 day cycles. In some embodiments, the dosage of dovitinib is about 400 mg/kg 5 days on and 2 days off in 28 day cycles.
• any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the individual; and/or (b) administered orally to the individual; and/or (c) intravenously administered to the individual; and/or (d) administered by injection to the individual; and/or (e) administered topically to the individual; and/or (f) administered non-systemically or locally to the individual.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further
• the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
• the length of the drug holiday varies from 1 day to 1 year.
• the oxidative phosphorylation inhibitor e.g., benzopyran derivative
• the glycolytic inhibitor is administered to the subject 5 days per week (e.g., Monday through Friday).
• the pharmaceutical compositions described herein are in unit dosage forms suitable for single administration of precise dosages.
• the formulation is divided into unit doses containing appropriate quantities of one or more active ingredient.
• the unit dosage is in the form of a package containing discrete quantities of the formulation.
• Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
• aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
• formulations for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or in multi dose containers, with an added preservative.
• Some embodiments described herein provide a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV), or an enantiomer thereof, as described herein, for use in combination with a pharmaceutical composition comprising a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• Some embodiments described herein provide a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV), or an enantiomer thereof, as described herein, and a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• Some embodiments provide a pharmaceutical composition comprising a glycolytic inhibitor for use in combination with a pharmaceutical composition comprising a compound of (I), (II), (III), or (IV), or an enantiomer thereof, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• Some preferred embodiments include a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV) for use in combination with a pharmaceutical composition comprising a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• a pharmaceutical composition comprising d-cis-3-(4- hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol for use in combination with a pharmaceutical composition comprising a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder assocated with dysregulation of cell proliferation, as described herein.
• the glycolytic inhibitor is a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein.
• Some preferred embodiments include a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV) and a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• the pharmaceutical composition comprises ⁇ i- c/5-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol and a glycolytic inhibitor, as described herein.
• the glycolytic inhibitor is a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein.
• the angiogenesis inhibitor is nintedanib (BIBF 1120).
• Some preferred embodiments include a pharmaceutical composition comprising a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein, for use in combination with a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV), as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• a pharmaceutical composition comprising a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein, for use in combination with a pharmaceutical composition comprising i/-cz ' s-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• a pharmaceutical composition comprising i/-cz ' s-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)- 8-methylchroman-7-ol for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• compositions comprising a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor in combination with a pharmaceutical composition comprising a ⁇ i-isomer of a compound of formula (I), (II), (III), or (IV), as described herein, in at least, or greater than, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess for treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• a pharmaceutical composition comprising a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein, for combination with a pharmaceutical composition comprising i/-cz ' s-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8- methylchroman-7-ol in at least, or greater than, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess for treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• the glycolytic inhibitor is nintedanib (BIBF 1120).
• Some embodiments described herein provide use of a compound of formula (I), (II), (III), or (IV), or an enantiomer thereof, as described herein, for the manufacture of a medicament for use in combination with a pharmaceutical composition comprising a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• the angiogenesis inhibitor is nintedanib (BIBF 1120).
• Some embodiments described herein provide use of a compound of formula (I), (II), (III), or (IV), or an enantiomer thereof, as described herein, and a glycolytic inhibitor, for the manufacture of a medicament for use in the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• Some embodiments described herein provide use of a glycolytic inhibitor for the manufacture of a medicament for use in combination with a pharmaceutical composition comprising a compound of (I), (II), (III), or (IV), or an enantiomer thereof, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• Some preferred embodiments include use of a a compound of formula (I), (II), (III), or (IV) for manufacture of a medicament for use in combination with a pharmaceutical composition comprising a glycolytic inhibitor, as described herein, for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• the medicament comprises i/-c/5-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.
• the glycolytic inhibitor is a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein.
• the angiogenesis inhibitor is nintedanib (BIBF 1120).
• Some preferred embodiments include use of a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein, in the manufacture of a medicament for use in combination with a
• the medicament is for use in combination with a pharmaceutical composition comprising i/-cz ' s-3-(4-hydroxyphenyl)-4-(4- hydroxyphenyl)-8-methylchroman-7-ol for the treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• the medicament comprises a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor for use in combination with a pharmaceutical composition comprising a ⁇ i-isomer of a compound of formula (I), (II), (III), or (IV), as described herein, in at least, or greater than, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% enantiomeric excess for treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• a pharmaceutical composition comprising a ⁇ i-isomer of a compound of formula (I), (II), (III), or (IV), as described herein, in at least, or greater than, 50%, 55%, 60%, 65%, 70%, 75%, 80%
• the medicament comprising a hexokinase, a lactic dehydrogenase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor or an angiogenesis inhibitor, as described herein, is for use in combination with a pharmaceutical composition comprising d-cis- 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol in at least, or greater than, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%), 98%), 99%), 99.5%), or 99.9% enantiomeric excess for treatment of a disease or disorder associated with dysregulation of cell proliferation, as described herein.
• the angiogenesis inhibitor is nintedanib (BIBF 1120).
• mice were obtained from W. Muller (McMaster University, Ontario, Canada). C57BL/6J01aHsd were obtained from the CNIO Animal House (Madrid, Spain). Four- to 6-week-old female athymic nude mice (Hsd: Athymic Nude- Foxnlnu) were purchased from Charles River Laboratories (Spain). Pulm24 PDX was kindly provided by Dr. Manuel Hidalgo. Tumors were implanted subcutaneously in the lower back of Athymic Nude-Foxnlnu, and mouse-mouse passages were performed to obtain the experimental animal cohorts.
• Nintedanib (BIBF) and regorafenib (Rego) were administered at 85 and 10 mg/kg/d, respectively, by oral gavage Monday through Friday.
• Compound 5 (ME) was administered at 50 mg/kg intraperitoneally three times per week.
• Dovitinib (Dovi) was freshly prepared in pH 2.5 water and administered by oral gavage at 40 mg/kg/d Monday through Friday.
• TGI [1 - (7F/70)A/(7F/70)V] x 100, where 7F is the time point analyzed, 70 is the initial time, A is the corresponding drug, and V is the vehicle.
• FVB-PyMT mice used as a genetically engineered mouse model of breast cancer, were treated at the first appearance of tumor cell growth with nintedanib (Figure 1). Upon reaching almost sacrifice size (10 weeks), the animal cohort was split in two; one cohort received nintedanib plus compound 5 (BIBF-BIBF+ME) and the other was treated with continued nintedanib (BIBF-BIBF) alone. Chronic exposure to nintedanib led to tumor cell resistance despite an initial delay in tumor growth, suggesting that the acquired resistance was characterized by a switch from a mainly glycolytic metabolism to a mostly mitochondrial metabolism. The animals treated with nintedanib + compound 5 experienced sustained tumor regression.
• FVB-PyMT mice were treated at the first appearance of tumor cell growth with vehicle, nintedanib (BIBF1120), compound 5 (ME) or the combination nintedanib + compound
• Example 3 Breast Cancer Mouse Model (dovitinib + compound 5)
• FVB-PyMT mice (model for breast cancer) were treated at the first appearance of tumor cell growth with vehicle, dovitinib (Dovi), compound 5 (ME) or the combination dovitinib + compound 5 (Dovi + ME). The animals treated with the combination of dovitinib + compound 5 experienced sustained tumor growth inhibition ( Figure 3).
• FVB-PyMT mice (model for breast cancer) were treated at the first appearance of tumor cell growth with vehicle, regorafenib (Rego), compound 5 (ME) or the combination regorafenib + compound 5 (Rego + ME).
• Regorafenib as a monotherapy lacked efficacy.
• the animals treated with the combination of regorafenib + compound 5 experienced sustained tumor growth inhibition ( Figure 4).
• Pulm024 is a lung cancer patient-derived xenograft (PDX). This PDX is an
• nintedanib alone was able to delay tumor growth, but the combination of nintedanib (BIBF) plus compound 5 (ME) completely abrogated tumor growth (Figure 5).
• a mouse xenograft model (ECB1) was used as a squamous cell lung cancer model. Tumor growth inhibition analysis was completed following single agent treatment of vehicle, nintedanib, and compound 5, and combination treatment of nintedanib and compound 5. Tumor growth inhibition analysis demonstrated that combination treatment of nintedanib and compound 5 significantly delayed tumor growth (Figure 6).
• Study Design This study will be a Phase I, single-center, open-label,
• Patients should not have had exposure to compound 5 prior to the study entry. Patients must not have received treatment for their cancer within 2 weeks of beginning the trial. Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
• Phase I Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Doses of compound 5 may be held or modified for toxicity based on assessments as outlined below. Patients receive nintedanib (150 mg) orally (PO) twice daily (BID) on days 1- 28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of compound 5 and nintedanib until the maximum tolerated dose (MTD) for compound 5 and nintedanib is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Dose limiting toxicities are determined according to the definitions and standards set by the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 3.0 (March 9, 2006).
• NCI National Cancer Institute
• CCAE Common Terminology for Adverse Events
• Phase II Patients receive compound 5 and nintedanib as in phase I at the MTD determined in phase I. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• randomized dose escalation study followed by a Phase II study in small cell lung cancer patients Patients should not have had exposure to compound 5 prior to the study entry. Patients must not have received treatment for their cancer within 2 weeks of beginning the trial, with the exception of nintedanib. Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
• Phase I Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Doses of compound 5 may be held or modified for toxicity based on assessments as outlined below. Patients receive nintedanib (150 mg) orally (PO) twice daily (BID) on days 1- 28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of compound 5 and nintedanib until the maximum tolerated dose (MTD) for compound 5 and nintedanib is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Dose limiting toxicities are determined according to the definitions and standards set by the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 3.0 (March 9, 2006).
• NCI National Cancer Institute
• CCAE Common Terminology for Adverse Events
• Phase II Patients receive compound 5 and nintedanib as in phase I at the MTD determined in phase I. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
• Phase II Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Patients receive nintedanib (150 mg) orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Blood Sampling Serial blood is drawn by direct vein puncture before and after administration of compound 5. Venous blood samples (5 mL) for determination of serum concentrations are obtained at about 10 minutes prior to dosing and at approximately the following times after dosing: days 1, 8, 15, and 22. Each serum sample is divided into two aliquots. All serum samples are stored at -20°C. Serum samples are shipped on dry ice.
• Pharmacokinetic parameters are calculated by model independent methods on a Digital
• the following pharmacokinetics parameters are determined: peak serum concentration (Cmax); time to peak serum concentration (t ma x); area under the concentration-time curve (AUC) from time zero to the last blood sampling time (AUCo-72) calculated with the use of the linear trapezoidal rule; and terminal elimination half-life (ti /2 ), computed from the elimination rate constant.
• the elimination rate constant is estimated by linear regression of consecutive data points in the terminal linear region of the log-linear concentration-time plot.
• the mean, standard deviation (SD), and coefficient of variation (CV) of the pharmacokinetic parameters are calculated for each treatment.
• the ratio of the parameter means preerved formulation/non- preserved formulation) is calculated.
• Patient response is assessed via imaging with X-ray, CT scans, MRI, and imaging is performed prior to beginning the study and at the end of the first cycle, with additional imaging performed every four weeks or at the end of subsequent cycles. Imaging modalities are chosen based upon the cancer type and
• TrilexiumTM and nintedanib TrilexiumTM and nintedanib.
• randomized dose escalation study followed by a Phase II study in small cell lung cancer patients Patients should not have had exposure to TrilexiumTM prior to the study entry. Patients must not have received treatment for their cancer within 2 weeks of beginning the trial, with the exception of nintedanib. Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
• Phase I Patients receive TrilexiumTM on days 1, 8, and 15 of each 28-day cycle injected intraperitoneally in their abdominal cavity. Doses of TrilexiumTM may be held or modified for toxicity based on assessments as outlined below. Patients receive nintedanib (150 mg) orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of TrilexiumTM and nintedanib until the maximum tolerated dose (MTD) for TrilexiumTM and nintedanib is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Dose limiting toxicities are determined according to the definitions and standards set by the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 3.0 (March 9, 2006).
• NCI National Cancer Institute
• CCAE Common Terminology for Adverse Events
• Phase II Patients receive TrilexiumTM and nintedanib as in phase I at the MTD determined in phase I. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Study Design This study will be a Phase II study in renal cell carcinoma patients. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for
• Phase II Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Patients receive 400 mg sorafenib (two 200 mg tablets) orally (PO) twice daily (BID) either one hour before or two hours after meals on days 1-28. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Phase II Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Patients receive 400 mg sorafenib (two 200 mg tablets) orally (PO) twice daily (BID) either one hour before or two hours after meals on days 1-28. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Study Design This study will be a Phase I, single-center, open-label, randomized dose escalation study followed by a Phase II study in ovarian cancer patients.
• Patients should not have had exposure to compound 5 prior to the study entry. Patients must not have received treatment for their cancer within 2 weeks of beginning the trial. Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
• Phase I Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Doses of compound 5 may be held or modified for toxicity based on assessments as outlined below. Patients receive dovitinib (500 mg/kg) orally (PO) 5 days on and 2 days off in 28 day cycles. Courses repeat every 28 days in the absence of disease progression or
• Phase II Patients receive compound 5 and dovitinib as in phase I at the MTD determined in phase I. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies. Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment. All subjects are evaluated for safety and all blood collections for pharmacokinetic analysis are collected as scheduled. All studies are performed with institutional ethics committee approval and patient consent.
• Phase II Patients receive i.v. compound 5 (10 mg/kg) on days 1, 8, and 15 of each 28-day cycle. Patients receive dovitinib (500 mg/kg) orally (PO) 5 days on and 2 days off in 28 day cycles. Treatment repeats every 4 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria.
• Blood Sampling Serial blood is drawn by direct vein puncture before and after administration of compound 5. Venous blood samples (5 mL) for determination of serum concentrations are obtained at about 10 minutes prior to dosing and at approximately the following times after dosing: days 1, 8, 15, and 22. Each serum sample is divided into two aliquots. All serum samples are stored at -20°C. Serum samples are shipped on dry ice.
• Pharmacokinetic parameters are calculated by model independent methods on a Digital
• the following pharmacokinetics parameters are determined: peak serum concentration (Cmax); time to peak serum concentration (t ma x); area under the concentration-time curve (AUC) from time zero to the last blood sampling time (AUCo-72) calculated with the use of the linear trapezoidal rule; and terminal elimination half-life (ti /2 ), computed from the elimination rate constant.
• the elimination rate constant is estimated by linear regression of consecutive data points in the terminal linear region of the log-linear concentration-time plot.
• the mean, standard deviation (SD), and coefficient of variation (CV) of the pharmacokinetic parameters are calculated for each treatment.
• the ratio of the parameter means preerved formulation/non- preserved formulation) is calculated.
• Patient response is assessed via imaging with X-ray, CT scans, MRI, and imaging is performed prior to beginning the study and at the end of the first cycle, with additional imaging performed every four weeks or at the end of subsequent cycles. Imaging modalities are chosen based upon the cancer type and

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