Nothing Special   »   [go: up one dir, main page]

WO2022051503A1 - Methods of administering glutaminase inhibitors - Google Patents

Methods of administering glutaminase inhibitors Download PDF

Info

Publication number
WO2022051503A1
WO2022051503A1 PCT/US2021/048877 US2021048877W WO2022051503A1 WO 2022051503 A1 WO2022051503 A1 WO 2022051503A1 US 2021048877 W US2021048877 W US 2021048877W WO 2022051503 A1 WO2022051503 A1 WO 2022051503A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
cancer
formula
pharmaceutically acceptable
treatment
Prior art date
Application number
PCT/US2021/048877
Other languages
French (fr)
Inventor
Mai Le
Evan Lewis
Christopher Molineaux
Matthew I. Gross
Original Assignee
Calithera Biosciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Calithera Biosciences, Inc. filed Critical Calithera Biosciences, Inc.
Publication of WO2022051503A1 publication Critical patent/WO2022051503A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/4261,3-Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/50Pyridazines; Hydrogenated pyridazines
    • A61K31/501Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • glutaminolysis is a major source of energy in the form of NADPH.
  • the first step in glutaminolysis is the deamination of glutamine to form glutamate and ammonia, which is catalyzed by the glutaminase enzyme.
  • deamination via glutaminase is a control point for glutamine metabolism.
  • glutaminase has been theorized to be a potential therapeutic target tor the treatment of diseases characterized by actively proliferating cells, such as cancer. Therefore, compositions and methods for administering glutaminase inhibitors to prevent or treat disease are desirable.
  • the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease, comprising orally administering a compound of formula I, formula II, and/or formula III, wherein the compound is administered while acting to increase stomach acidity when the compound is ingested.
  • acting to increase stomach acidity e.g. ingesting an acidic beverage
  • acting to increase stomach acidity is performed concurrently while ingesting the compound.
  • acting to increase stomach acidity e.g. discontinuing treatment with a proton pump inhibitor (PPI) and/or beginning treatment with an H 2 blocker
  • PPI proton pump inhibitor
  • the invention relates to a method of administering a compound of formula I, formula II, and/or formula III, to a patient, comprising: determining whether the patient is receiving treatment with a proton pump inhibitor; and, if the patient is receiving treatment with a proton pump inhibitor, instructing the patient to act to increase stomach acidity while ingesting the compound.
  • acting to increase stomach acidity comprises ingesting the compound with an acidic beverage.
  • acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound, e.g., at least 24 hours before commencing oral administration of the compound.
  • the method may further comprise beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor.
  • the H 2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
  • the invention relates to a method of ingesting a compound of formula I, formula II, and/or formula III, while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity' while ingesting the compound.
  • acting to increase stomach acidity comprises ingesting an acidic beverage while ingesting the compound of formula I.
  • tire invention relates to a method for improving the effectiveness of a compound of formula I, formula II, and/or formula III, in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound, e.g., at least 24 hours before commencing oral administration of the compound.
  • the method may further comprise beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor.
  • the H 2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
  • the invention relates to a method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with a compound of formula I, formula II, and/or formula III, comprising (i) determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and (ii) if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H2 blocker.
  • the Hr blocker is nizatidine, famotidine, ranitidine, or cimetidine.
  • Figures 1A-1F show PPI effects on telaglenastat exposure on cycle 1 day 1 .
  • Figures 1A-1C show that AUC0-8hr, Cmax, and AUCiast of telaglenastat in 600 mg BID patients are separated into two groups: with or without concomitant administration of a PPI (patients taking histamine H2 -receptor antagonists (HERA) were excluded from this analysis).
  • Figures ID- IF show that AUC0-8hr, Cmax, and AUCiast of telaglenastat in 800 mg BID patients are separated into two groups: with or without concomitant administration of a PPI.
  • the dashed line corresponds to the median; the solid line to the arithmetic mean.
  • Tire ends of the “box” are the 25th and 75th percentiles, also referred to as the first and third quartiles.
  • the whiskers show the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still wdthin 1.5 IQR of the upper quartile, where IQR is the interquartile range (the difference between the third and first quartiles, the middle 50%). Data values that do not fall between the whiskers are plotted as outliers (markers outside of the whiskers).
  • Figures 2A-2F show' PPI effects on telaglenastat exposure on cycle 1 day 15.
  • Figures 2A-2C show' that AUC0-8hr, Cmax, and AUClast of telaglenastat in 600 mg BID patients are separated into two groups: with or without concomitant administration of a PPI (patients taking histamine H2-receptor antagonists were excluded from this analysis).
  • Figures 2D-2F show' that AUC0-8hr, Cmax, and AUCiast of telaglenastat in 800 mg BID patients are separated into two groups: with or without concomitant administration of a PPI.
  • the dashed line corresponds to the median; tire solid line to the arithmetic mean.
  • the ends of the “box” are the 25th and 75 th percentiles, also referred to as the first and third quartiles.
  • the whiskers show' the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile, where IQR is the interquartile range (the difference between the third and first quartiles, the middle 50%). Data values that do not fall between the whiskers are plotted as outliers (markers outside of the whiskers).
  • Figure 3 show's the H2RA effects on telaglenastat exposure on C1D1 and C1D15.
  • AUC0-8hr of telaglenastat was assessed for patients dosed with 400 - 800 mg BID telaglenastat.
  • Patients were separated into patients without concomitant administration of H2RAs (left column of each graph) and patients with concomitant administration of an H2RA (right column of each graph). Patients were assessed on Cycle 1, Day 1 (C1D1) and Cycle 1, Day 15 (C1D15). Patients taking PPIs were excluded from this analysis.
  • Patients without concomitant administration of H2RAs included 111 on Day 1 and 89 on Day
  • Patients with concomitant administration of H2RAs included 89 patients on Day 1 and 13 patients on Day 15. The number above the scatter plot of each group denotes the geometric mean of the group.
  • a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each earner must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of formulas I-III).
  • a common method for malting a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids
  • some or all of the compounds of formulas I-III in a formulation can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
  • terapéuticaally effective amount relates to the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the patient. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher ei al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • treating includes prophylactic and/or therapeutic treatments.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g. , disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unw anted condition), whereas if it is administered after manifestation of the unw anted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the terms “with food”, “with a meal”, “with meals”, “during a meal”, “after a meal” refers to the administration of a compound in temporal proximity to (e.g., before, during, or after) the ingestion of food (e.g., a meal), and more particularly refers to the administration of a compound within 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 minu tes before ingesting food, during a meal, or within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 45, 60, or 90 minutes after ingesting food.
  • the terms “with food” and “with a meal” refer to the administration of a compound with a meal, before the meal (e.g., 30 minutes before ingesting the food or meal), and after the meal (e.g., 90 minutes after ingesting the food or meal).
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula bydrocarbyiC(O)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl ,
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below', except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • an “’alkyl” group or “’alkane” is a straight chained or branched non-arornatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.
  • Ci-Cs straight chained or branched alkyl group is also referred to as a "lower alkyl” group.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “un substituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen such as
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CM and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
  • Cx-yalkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C2- y alkenyl and C2- yalkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-,
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
  • substituents include all those contemplated for alkyl groups, as discussed above, except where stability’ is prohibitive.
  • substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group wherein each R 10 independently represent a hydrogen or hydrocarbyl group, or two R 10 are taken together with the N atom to which they are atached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R 10 independently represents a hydrogen or a hydrocarbyl group, or two R 10 ' are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a. 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • carbamate is art-recognized and refers to a group wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R 9 and R 10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycie includes bicyclic molecules in w hich one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycie in which each of the rings shares two adjacent atoms with the oilier ring.
  • Each ring of a fused carbocycie may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • carbocyclic Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5- cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1 ,0]hept-3 ⁇ ene.
  • “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • a “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherw ise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings,
  • a “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-R 10 , wherein R 10 represents a hydrocarbyl group.
  • esters refers to a group -C(O)OR 10 wherein R 10 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycie and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalky 1 and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole. furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocycly Is.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • Hydrocarbyl groups include, but are not limited to ary 1, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substi tuent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sil refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substitu ted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxy carbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy 1, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety
  • sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl, such as alkyl, or R 9 and R 10 taken together with the intervening atorn(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group ⁇ S(O) ⁇ R 10 , wherein R 10 represents a hydrocarbyl .
  • sulfonate is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • sulfone is art-recognized and refers to the group -S(O)2-R 10 , wherein R 10 represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 10 or -SC(O)R 10 wherein R 10 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 9 taken together with R 10 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • protecting group refers to a group of atoms that, when atached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethyIsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, all yloxy carbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (estenfied) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • the present invention relates to methods of orally administering a compound of formula I, or a. pharmaceutically acceptable salt thereof, wherein:
  • L represents CH 2 CH 2 ;
  • R1 and R2. each represent H;
  • R3 independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl; to a patient, comprising: determining whether the patient is receiving treatment with a proton pump inhibitor; and, if the patient is receiving treatment with a proton pump inhibitor, instracting the patient to act to increase stomach acidity' while ingesting the compound of formula I, or a pharmaceu tically acceptable salt thereof.
  • the present invention further relates to methods of ingesting a compound of formula I, or a pharmaceutically acceptable salt thereof, while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity while ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein:
  • L represents CH 2 CH 2 ;
  • R2 each represent H; and R3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl.
  • the present invention further relates methods for improving the effectiveness of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof, wherein:
  • L represents CH 2 CH 2 ;
  • R1 and R2 each represent H
  • R3 independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl.
  • the present invention further relates to a method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • L represents CH 2 CH 2 ;
  • R1 and R2 each represent H
  • R.3 independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl; comprising: determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and, if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H 2 blocker.
  • a pharmaceutically acceptable salt as includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-suIfonic, oxalic, mandelic and other acids.
  • Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1: 1.
  • contemplated salts of the invention are hydrochloride (HC1) salts.
  • acylaminoalkyl such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaiyl, heteroarylaikyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoaikoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(O)CFs)), carbonylalkyl (such as carboxyalkyl, alkoxy carbonylalkyl, formylalkyl, or
  • acting to increase stomach acidity comprises ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof, with an acidic beverage.
  • acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the proton pump inhibitor may be discontinued for at least 24 hours, preferably 1 to 14 days, before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • acting to increase stomach acidity further comprises beginning treatment with an H2 blocker concurrently w ith or after discontinuing the treatment with the proton pump inhibitor.
  • Non-linnted examples of the H2 blocker are nizatidine, famotidine, ranitidine, and cimetidine.
  • Hr blockers may also be referred to herein as a histamine H2 receptor antagonist or H2RA.
  • each occurrence of R3 is not identical (e.g., the compound of formula I is not symmetrical).
  • each R3 is independently substituted or unsubstituted arylalkyl or heteroarylaikyl.
  • the compound of formula I has the structure of formula II, or a pharmaceutically acceptable salt thereof, wherein: R3 represents substituted or unsubstituted arylalkyl or heteroarylalkyl; R11 represents arylalkyl or heteroarylalkyl, wherein the aryl or heteroaryl ring is substituted with either -OCHF2 or -OCF3 and is optionally further substituted.
  • R11 represents arylalkyl, such as benzyl, wherein the aryl group is substituted with -OCF3, such as meta-substituted with -OCF3. In certain such embodiments, the and ring is not further substituted. In certain embodiments, R11 represents trifluoromethoxy benzyl, such as
  • R3 and R11 are not identical.
  • R3 represents heteroarylalkyl, such as pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl (e.g., pyridylalkyl).
  • L represents CH 2 CH 2
  • Y represents H
  • X represents S
  • Z represents R3(CO)
  • R1 and R2 each represent H
  • R3 represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, such as heteroarylalkyl (e.g., pyridylalkyl)
  • R11 represents arylalkyl, such trifluoromethoxy benzyl (e.g,
  • Z represents R3(CO) and R3 represents pyridylmethyl, such as wherein Z represents
  • the compound used in the methods of the invention is a compound having the structure of Formula (III): or a pharmaceutically acceptable salt thereof.
  • the compound having the structure of Formula (III) is also referred to herein as CB-839 or telaglenastat.
  • the names CB-839 and telaglenastat refer to the compound free base.
  • the studies described in the examples section utilized the hydrochloride salt of the compound of Formula (III) (i.e., telaglenastat HC1 or CB-839 HC1).
  • compounds of the invention may be prodrugs of the compounds of formulas I-III, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, or carboxylic acid).
  • compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, compounds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • the present invention relates to methods of treatment with a compound of formulas I-III, or a pharmaceutically acceptable salt thereof.
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formulas I-III).
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g, in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g, in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formulas I-III).
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the present invention provides a pharmaceutical preparation suitable for oral administration to a human patient, comprising any of the compounds shown above (e.g., a glutaminase inhibitor, such as a compound of formulas I-III), and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical preparation suitable for oral administration to a human patient comprising any of the compounds shown above (e.g., a glutaminase inhibitor, such as a compound of formulas I-III), and one or more pharmaceutically acceptable excipients.
  • Glutamine plays an important role as a carrier of nitrogen, carbon, and energy. It is used for hepatic urea synthesis, for renal ammoniagenesis, for gluconeogenesis, and as respiratory' fuel for many cells.
  • the conversion of glutamine into glutamate is inflated by tlie mitochondrial enzyme, glutaminase (“GLS”).
  • GLS glutaminase
  • K-type and L ⁇ type are distinguished by their Km values for glutamine and response to glutamate, wherein the Km value, or Michaelis constant, is the concentration of substrate required to reach half the maximal velocity.
  • the L-type also known as “liver- type” or GLS2, has a high Km for glutamine and is glutamate resistant.
  • the K-type also known as “kidney -type or GLS1
  • GLS1 has a low Km for glutamine and is inhibited by glutamate.
  • GAC glutmainase C
  • GAC glutmainase C
  • the compounds may selectively' inhibit GLS1, GLS2 and GAC.
  • the compounds selectively' inhibit GLS1 and GAC.
  • amino acids have been shown to contribute to many processes critical for growing and dividing cells, and this is particularly true for cancer cells. Nearly all definitions of cancer include reference to dysregulated proliferation.
  • the invention provides methods for treating or preventing cancer, a myeloproliferative disease, an immunological disease, or a neurological diseasecomprising orally administering a glutaminase inhibitor (e.g. , a compound of any of formulas I -III, or a pharmaceutically acceptable salt thereof), preferably wherein the compound is administered while acting to increase stomach acidity.
  • a glutaminase inhibitor e.g. , a compound of any of formulas I -III, or a pharmaceutically acceptable salt thereof
  • the cancer may be one or a variant of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS- Related Cancers (Kaposi Sarcoma and Lymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepitbelioma, Pineal
  • oncogenic mutations promote glutamine metabolism.
  • Cells expressing oncogenic K-Ras exhibit increased utilization of glutamine.
  • the cancer cells have a mutated K-Ras gene.
  • the cancer is associated with tissue of the bladder, bone marrow, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, skin or thyroid.
  • Tire c-Myc gene is known to be altered in numerous cancers. Increased Myc protein expression has been correlated with increased expression of glutaminase, leading to up-regulation of glutamine metabolism.
  • the cancer cells have an oncogenic c-Myc gene or elevated Myc protein expression.
  • the cancer is associated with tissue of the bladder, bone, bowel, breast, central nervous system (like brain), colon, gastric system (such as stomach and intestine), liver, lung, ovary, prostate, muscle, and skin.
  • VHL- deficient cell lines have been shown to have an increased requirement for glutamine due to a loss of ability to make fatty acids from glucose (Metallo et al. Nature 2013). This dependency on glutamine makes the cells susceptible to glutaminase inhibitors (Gameiro et al., Cell Metab. 2013). Certain embodiments of the invention relate to the use of the compounds described herein for the treatment of VHL-deficient carcinomas.
  • the cancer is RCC.
  • the cancer is ccRCC.
  • EGFR Epidermal growth factor receptor
  • EGF epidermal growth factor
  • Mutations associated with EGFR overexpression have been associated with certain cancers, including lung cancers. Approximately 10% of non-small cell lung cancer patients in the United States, and approximately 35% of nsclc patients in East Asia have tumors associated with an EGFR mutation. Typically the EGFR mutation occurs in a region of the gene that encodes a portion of the EGFR kinase domain. Usually, such mutations result tn gene amplification, increased kinase activity of EGFR, and hyperactivation of downstream pro- survival signaling pathways. See A.
  • Glutaminase inhibition may also be effective in certain rare cancers that have mutations or deletions of the TCA cycle enzymes including fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase (IDH). Glutamate feeds into the TCA cycle upstream of where these mutations or deletions occur.
  • FH fumarate hydratase
  • SDH succinate dehydrogenase
  • IDH isocitrate dehydrogenase
  • inhibitors of glutaminase may block the effect of these mutations or deletions by limiting the availability of upstream starting materials.
  • Rare mutations in FH lead to the development of hereditary leiomyomatosis and renal cell cancer (HLRCC), where patients can develop tumors of the skin, uterus and kidneys.
  • Some gastrointestinal stromal tumors (GIST) arise from the lack of expression of SDH, and are often hereditary.
  • Other SDH-loss-of-function mutations are found in patients exhibiting a rare head and neck cancer known as paraganglioma, and a rare adrenal or extra-adrenal cancer known as pheochromocytoma, and a rare subset clear cell RCC.
  • compounds described herein can be used for the treatment of disease identified with a FH, SDH or IDH (1 and 2) mutation .
  • the disease is an isocitrate dehydrogenase (IDH)-rnutant solid tumor.
  • IDH isocitrate dehydrogenase
  • the disease is hereditary leiomyomatosis or renal cell cancer (HLRCC).
  • HRCC renal cell cancer
  • the disease is GIST (e.g., SDH-deficient GIST), paraganglioma, pheochromocytoma, or clear cell RCC.
  • the disease is glioma, chondrosarcoma, cholangiocarcinoma, acute myeloid leukemia (AML), or myelodysplasia/myeloproliferative disorder.
  • the disease is mesothelioma. In certain embodiments, the disease is multiple myeloma.
  • the cancer is a non-small cell lung cancer having a KRAS or EGFR mutation.
  • gene expression analysis of breast cancers has identified five intrinsic subtypes (luminal A, luminal B, basal, HER2+, and normal-like).
  • glutamine deprivation has an impact on cell growth and viability, basal-like cells appear to be more sensitive to the reduction of exogenous glutamine. This supports the concept that glutamine is a very important energy source in basal-like breast cancer cell lines, and suggests that inhibition of the glutaminase enzyme would be beneficial in the treatment of breast cancers comprised of basal-like cells.
  • TNBC Triple- negative breast cancer
  • an embodiment of the invention is the use of the compounds described herein for the treatment of TNBC, basal- type breast cancers, or claudin-low breast cancers.
  • the invention provides methods for treating colorectal cancer.
  • the invention provides methods for treating endocrine cancer, such as adrenal cortex adenoma, adrenal cortex carcinoma, adrenal gland pheochromocytoma, and parathyroid gland adenoma.
  • the cancer is melanoma.
  • Cachexia the massive loss of muscle mass, is often associated with poor performance status and high mortality rate of cancer patients.
  • a theory behind this process is that tumors require more glutamine than is normally supplied by diet, so muscle, a major source of glutamine, starts to breakdown in order to supply enough nutrient to the tumor.
  • inhibition of glutaminase may reduce the need to breakdown muscle.
  • An embodiment of the invention is the use of the present compounds to prevent, inhibit or reduce cachexia.
  • the most common neurotransmiter is glutamate, derived from the enzymatic conversion of glutamine via glutaminase. High levels of glutamate have been shown to be neurotoxic. Following traumatic insult to neuronal cells, there occurs a rise in neurotransmiter release, particularly glutamate.
  • mice bred to have reduced glutaminase levels sensitivity to psychotic-stimulating drugs, such as amphetamines, was dramatically reduced, thus suggesting that glutaminase inhibition may be beneficial in the treatment of schizophrenia.
  • Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. This disease is treated with mood stabilizers such as lithium and valproate; however, chronic use of these drugs appears to increase the abundance of glutamate receptors, which may lead to a decrease in the drug’s effectiveness overtime.
  • an alternative treatment may be to reduce the amount of glutamate by inhibiting glutaminase. This may or may not be in conjunction with the mood stabilizers.
  • Memantine a partial antagonist of N-methyl-D-aspartate receptor (NMD AR), is an approved therapeutic in the treatment of Alzheimer’s disease.
  • NMD AR N-methyl-D-aspartate receptor
  • memantine has been shown to partially block the NMDA glutamate receptor also, it is not unreasonable to speculate that decreasing glutamate levels by inhibiting glutaminase could also treat Alzheimer’s disease, vascular dementia and Parkinson’s disease.
  • Alzheimer’s disease, bipolar disorder, HIV-associated dementia, Huntington’s disease, ischemic insult, Parkinson’s disease, schizophrenia, stroke, traumatic insult and vascular dementia are but. a few' of the neurological diseases that have been correlated to increased levels of glutamate.
  • the compounds may be used for the treatment or prevention of neurological diseases.
  • Activation of T lymphocytes induces ceil growth, proliferation, and cytokine production, thereby placing energetic and biosynthetic demands on the cell.
  • Glutamine serves as an amine group donor for nucleotide synthesis, and glutamate, the first component in glutamine metabolism, plays a direct role in amino acid and glutathione synthesis, as well as being abie to enter the Krebs cycle for energy production.
  • Mitogen-induced T cell proliferation and cytokine production require high levels of glutamine metabolism, thus inhibiting glutaminase may serve as a means of immune modulation.
  • the activated microglia exhibit up-regulated glutaminase and release increased levels of extracellular glutamate.
  • Glutamine levels are lowered by sepsis, injury, burns, surgery and endurance exercise. These situations put the individual at risk of immunosuppression.
  • glutaminase gene expression and enzyme activity are both increased during T cell activity. Patients given glutamine following bone marrow transplantation resulted in a lower level of infection and reduced graft versus host disease.
  • T cell proliferation and activation is involved in many immunological diseases, such as inflammatory bowel disease, Crohn’s disease, sepsis, psoriasis, arthritis (including rheumatoid arthritis), multiple sclerosis, graft versus host disease (GVHD), infections, lupus, diabetes, ankylosing spondylitis, erythema nodosum leprosum (ENL), HIV-associated wasting syndrome, lupus erythematosus, post- polycythemia, psoriasis, psoriatic arthritis, recurrent aphthous ulcers, severe recurrent aphthous stomatitis, and systemic sclerosis.
  • the compounds described herein can be used to treat or prevent immunological diseases.
  • Hepatic encephalopathy represents a series of transient and reversible neurologic and psychiatric dysfunction in patients with liver disease or portosystemic shunting.
  • HE is not a single clinical entity and may reflect reversible metabolic encephalopathy, brain atrophy, brain edema, or a combination of these factors; however, the current hypothesis is that the accumulation of ammonia, mostly derived from the intestine, plays a key role in the pathophysiology. The deamination of glutamine in small intestine, renal and muscle synthesis all contribute to ammonia production. Impaired hepatic clearance caused by hepatocellular clearance or portosystemic shunting causes increased accumulation of ammonia.
  • Ammonia toxicity affects astrocytes in the brain via glutamine synthetase, which metabolizes the ammonia to produce increased glutamine.
  • Glutamine in turn, attracts water into the astrocytes, leading to swelling and oxidative dysfunction of the mitochondria.
  • the resulting cerebral edema is thought to contribute to neurologic dysfunction seen m HE.
  • the compounds described herein can be used to treat or prevent HE.
  • the pain can be neuropathic pain, chemotherapy -induced pain or inflammatory pain.
  • glutaminase inhibitors which cause increased glutamine levels and decrease glu tamate levels, would decrease the incidence of diabetes mellitus and cardiovascular disease.
  • the liver and small intestine are major sites of glutamine utilization in diabetic animals, and glutaminase activity is higher than normal in these organs in streptozotocin-induced diabetic rats.
  • the compounds described herein can be used to treat diabetes.
  • the present compounds can be used to reduce high blood pressure.
  • the method of treating or preventing cancer, a myeloproliferative disease, an immunological disease, or a neurological disease may comprise orally administering a compound of the invention, e.g., a compound of any of formulas I-Ill, or a pharmaceutically acceptable salt thereof, e.g., while acting to increase stomach acidity, conjointly with one or more additional therapeutic agents.
  • the compounds of the invention may be conjointly administered with an anticancer agent selected from an enzyme inhibitor (such as a kinase inhibitor), a mitotic inhibitor, a DNA-modifying agent, an immune-checkpoint inhibitor, and a cytidine analog.
  • anticancer agents with which the compounds of the invention may be administered in a combination therapy include microtubule assembly inhibitors, DNA crosslinking agents, antimetabolites, AKT inhibitors, ALK inhibitors, BRAF inhibitors, mTOR inhibitors, CDK4/6 inhibitors, MEK inhibitors, RTK inhibitors, ATM inhibitors, ATR inhibitors, PI3K inhibitors, EGFR inhibitors, VEGFR inhibitors, B-Raf inhibitors, C- kit inhibitors, DNA cross-linking agents, DNA intercalating agents, anti-PD-1 inhibitors, anti-PDL-1 inhibitors, CTLA-4 inhibitors, PARI’ inhibitors, KRAS inhibitors, aromatase inhibitors, estrogen-receptor modulators, and cytidine analogs.
  • the anticancer agent is nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, bevacizumab, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, ienvatinib, regorafemb, ponatmib, vandetanib, ramucirumab, everolimus, temsiroiimus, osimertinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, necitumumab, dacomitinib, cetuximab , panitumumab, alectinib, brigatinib, lorlotinib, ceritinib, vemurafenib,
  • a compound of the invention may be conjointly administered (e.g., orally administered, while acting to increase stomach acidity) with non- chemical methods of cancer treatment.
  • a compound of the invention may be conjointly administered with radiation therapy.
  • a compound of the invention may be conjointly administered wi th surgery', with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these.
  • the compounds of the invention may be conjointly administered with another GVHD therapeutic agent selected from ibrutinib, ruxolitinib, belomosudil, and steroids such as prednisone.
  • another GVHD therapeutic agent selected from ibrutinib, ruxolitinib, belomosudil, and steroids such as prednisone.
  • different compounds of the invention may be conjointly administered with one or more other compounds of the invention.
  • such combinations may be conjointly administered with other therapeutic agents, such as oilier agents suitable for the treatment of cancer, immunological or neurological diseases, such as the agents identified above.
  • Gastrointestinal absorption of the glutaminase inhibitors disclosed herein is reduced, and efficacy negatively affected, in patients taking proton primp inhibitors.
  • Proton pump inhibitors or (PPIs) are a group of drugs that reduce gastric acid production.
  • Proton pump inhibitors act by blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H7K’ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells.
  • proton pump inhibitors include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole. Accordingly, patients who take a proton pump inhibitor and who might benefit from taking a glutaminase inhibitor as disclosed herein may benefit from one or more strategies that reduce the effect of the proton pump inhibitor on the effect of the glutaminase inhibitor, e.g., for treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease.
  • the patient may be instructed to act to increase stomach acidity while administering a compound of formula I, formula II, and/or formula III, e.g., by drinking an acidic beverage when ingesting the glutaminase inhibitor, or discontinuing use of the proton pump inhibitor at least 24 hours before commencing oral administration of the glutaminase inhibitor.
  • a compound of formula I, formula II, and/or formula III e.g., by drinking an acidic beverage when ingesting the glutaminase inhibitor, or discontinuing use of the proton pump inhibitor at least 24 hours before commencing oral administration of the glutaminase inhibitor.
  • Acidi c beverages are beverages or drinks with low pH, e.g., below 5.0, preferably in the range of 1 .0 to 4.0.
  • Suitable acidic beverages include lime juice, lemon juice, cranberry juice, vinegar, cider vinegar, lemonade, tropical fruit juice, cola, soda, tonic water, seltzer, strawberry -grape juice, strawberry juice, grape juice, orange juice, grape soda, coffee, grapefruit juice, iced tea, pineapple juice, wine, apple juice, plurn nectar, vegetable juice, prune juice, root beer, pear nectar, tomato juice, and buttermilk.
  • taking or ingesting a glutaminase inihibitor ‘ with an acidic beverage” includes drinking the acidic beverage before or after the glutaminase inhibitor in this way .
  • H 2 blockers are a class of drugs that block the action of histamine at the histamine Hz receptors of the parietal cells in the stomach. This decreases the production of stomach acid.
  • Representative H 2 blockers include cimetidine, ranitidine, famotidine, and nizatidine.
  • the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease while receiving treatment with a proton pump inhibitor by acting to increase stomach acidity while ingesting compound of formula I, formula II, and/or formula III,.
  • acting to increase stomach acidity e.g., ingesting an acidic beverage
  • acting to increase stomach acidity is performed concurrently while administering the compound.
  • acting to increase stomach acidity e.g., discontinuing treatment with a proton pump inhibitor and/or beginning treatment with an H 2 blocker
  • the invention relates to a method of administering a compound of formula I, formula II, and/or formula III to a patient, comprising: (1) determining whether the patient is receiving treatment with a proton pump inhibitor; and, (2) if the patient is receiving treatment with a proton pump inhibitor, instructing the patient to act to increase stomach acidity while ingesting the compound.
  • acting to increase stomach acidity comprises ingesting the compound with an acidic beverage.
  • acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor before commencing oral administration of tire compound.
  • acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound.
  • acting to increase stomach acidity comprises discontinuing treatment with tire proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound; and beginning treatment with an H 2 blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor.
  • the H 2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
  • the invention relates to a method of ingesting a compound of formula I, formula II, and/or formula III while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity while ingesting the compound.
  • acting to increase stomach acidity? comprise ingesting an acidic beverage while ingesting the compound.
  • the invention relates to a method for improving tire effectiveness of a compound of formula I, formula II, and/or formula III in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound.
  • the invention relates to a method for improving the effectiveness of the compound in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound.
  • the invention relates to a method for improving the effectiveness of the compound in a subject recei ving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound; and beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor.
  • the Hr blocker is nizatidine, famotidine, ranitidine, or cimetidine.
  • the present invention further relates to a method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with a compound of formula I, formula II, and/or formula III, comprising (i) determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and, (ii) if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H 2 blocker.
  • the H 2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
  • the condition is gastroesophageal reflux disease (GERD) or peptic ulcer disease.
  • the method further comprises instructing the patient to avoid taking a proton pump inhibitor.
  • proton pump inhibitors omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.
  • the present invention provides a kit comprising: a) one or more single dosage forms of a compound of the invention: b) one or more single dosage forms of a chemotherapeutic agent as mentioned above; and c) instructions for the administration of the compound of the invention and the chemotherapeutic agent.
  • the instructions may state that the compound be taken while acting to increase stomach acidity.
  • the instructions may state that the compound should be taken with an acidic beverage.
  • Tire instructions may state that the compound should be taken once, twice, or three times a day, e.g., while acting to increase stomach acidity.
  • the instructions may state that tire compound should be taken after discontinuing treatment with a proton pump inhibitor.
  • the instructions may state that the compound should be taken after discontinuing treatment with a proton purnp inhibitor, and beginning treatment with an Hi. blocker.
  • the present invention provides a kit comprising: a) a pharmaceutical formulation (e.g., one or more single dosage forms) comprising a compound of the invention; and b) instructions for the administration of the pharmace utical formulation, e.g. , for treating or preventing any of the conditions discussed above, wherein the instructions state that the compound should be taken while acting to increase stomach acidity.
  • a pharmaceutical formulation e.g., one or more single dosage forms
  • instructions for the administration of the pharmace utical formulation e.g. , for treating or preventing any of the conditions discussed above, wherein the instructions state that the compound should be taken while acting to increase stomach acidity.
  • the kit further comprises instructions for the administration of the pharmaceutical formulation comprising a compound of the invention conjointly with a chemotherapeutic agent as mentioned above.
  • the kit further comprises a second pharmaceutical formulation (e.g., as one or more single dosage forms) comprising a chemotherapeutic agent as mentioned above.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable earners are well known in the art and include, for example, aqueous solutions such as water or physiological! ⁇ ' buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or organic esters.
  • the excipients can be chosen, for example, to effect delayed release of an agent.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, or tire like.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorp tion of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • a pharmaceutical composition may be administered to a patient orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes).
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,1 10,973, 5,763,493, 5,731,000, 5,541,231 , 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein (hereby incorporated by reference).
  • Tire amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the in vention, with the carrier and, optionally, one or more accessor ⁇ - 7 ingredients.
  • an active compound such as a compound of the in vention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixi r or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and tlie like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary' or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (tor example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or con trolled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active mgredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve tlie desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drags, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase tire dosage until the desired effect is achieved.
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • compositions and methods of the present invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention.
  • pharmaceutically acceptable salt includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphtlialene-2-sulfonic, oxalic, mandelic and other acids.
  • contemplated salt forms can include forms wherein the ratio of molecules comprising the salt is not 1: 1.
  • contemplated salts of the invention are hydrochloride (HC1) salts.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyllmorpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium. triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), le
  • the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease, comprising orally administering a compound of formula I, formula II, and/or formula III, wherein the compound is administered while acting to increase stomach acidity .
  • the subject is a mammal. In certain preferred embodiments, the subject is a human.
  • the compound is administered orally between 30 minutes prior to the subject (e.g., a human) ingesting food to 6 hours after ingesting food, such as between 30 minutes prior to ingesting food to 5 hours after ingesting food, between 30 minutes prior to ingesting food to 4 hours after ingesting food, between 30 minutes prior to ingesting food to 3 hours after ingesting food, between 30 minutes prior to ingesting food to 2 hours after ingesting food, or between 30 minutes prior to ingesting food to 1 hours after ingesting food.
  • the subject e.g., a human
  • the compound is administered between 30 minutes prior to the subject ingesting food to 90 minutes after ingesting food, such as between 20 minutes prior to ingesting food to 90 minutes after ingesting food, between 20 minutes prior to ingesting food to 60 minutes after ingesting food, between 10 minutes prior to ingesting food to 60 minutes after ingesting food, between 5 minutes prior to ingesting food to 60 minutes after ingesting food, or between 5 minutes prior to ingesting food to 30 minutes after ingesting food.
  • the method comprises orally administering a glutaminase inhibitor (e.g., preferably a compound of formula III) to a subject (e.g., a human), preferably while acting to increase stomach acidity, wherein between 100 mg and 10 g of the compound is administered orally per day.
  • a glutaminase inhibitor e.g., preferably a compound of formula III
  • the daily oral dose of the compound may be from 100 mg to 5000 mg, e.g., 200 mg to 4000 mg, 300 mg to 3000 mg, 600 mg to 2400 mg, 800 mg to 2200 mg, 1000 mg to 2000 mg, or 1200 mg to 1800 mg, or about 1600 mg.
  • the method comprises orally administering the compound of formula III, and 100 mg to 10 g of the compound is administered orally per day.
  • 100 mg to 5000 mg of the compound may be administered orally per day, such as 200 mg to 4000 mg, 300 mg to 3000 mg, 600 mg to 2400 mg, 800 mg to 2200 mg, 1000 mg to 2000 mg, 1200 mg to 1800 mg, or about 1600 mg.
  • an aggregate dose equivalent to between 100 mg and 10 g of the compound of formula III is administered orally per day.
  • the term “aggregate dose” refers to the total amount of the compound administered, e.g., per day. For example, if a 600 mg dose of the compound is administered two times per day, then the aggregate dose is 1200 mg per day.
  • the term “equivalent to an amount of the compound of formula III” refers to the administration of an amount of a compound that has the same efficacy as an amount of the compound of formula III.
  • a first compound such as a compound of formula I or II
  • an equivalent of the first compound is equal to the same amount of the compound of formula III, e.g., 600 mg of the first compound is equivalent to 600 mg of the compound of formula III.
  • a second compound has, for example, twice the efficacy of the compound of formula III
  • an equivalent of the second compound is equal to half the amount of the compound of formula III, e.g., 300 mg of the second compound is equivalent to 600 mg of the compound of formula III.
  • the glutaminase inhibitor is administered to the subject while acting to increase stomach acidity.
  • an aggregate dose equivalent to between about 100 mg and about 5000 mg of a glutaminase inhibitor (e.g., preferably a compound of formula III) is administered to a subject (e.g., a human) orally per day.
  • an aggregate dose is equivalent to between about 200 mg and about 4000 mg, about 300 mg and about 3000 mg, about 400 mg and about 2800 mg, about 600 mg and about 2400 mg, about 800 mg and about 2200 mg, about 1000 mg and about 2000 mg, about 1000 mg and about 1800 mg, about 1200 mg and about 1800 mg, about 1200 mg and about 1600 mg.
  • a compound of formula III is delivered orally to a human subject twice daily for an aggregate dose of 1600 mg.
  • the human subject is acting to increase stomach acidity.
  • the compound is administered while acting to increase stomach acidity.
  • an aggregate dose equivalent to between about 100 mg and about 5000 mg of the compound of formula III is administered to a subject (e.g., a human) orally per day.
  • an aggregate dose is equivalent to between about 200 mg and about 4000 mg, about 300 mg and about 3000 mg, about 400 mg and about 2800 mg, about 600 mg and about 2400 mg, about 800 mg and about 2200 mg, about 1000 mg and about 2000 mg, about 1000 mg and about 1800 mg, about 1200 mg and about 1800 mg, about 1200 mg and about 1600 mg.
  • a compound of formula III is delivered orally to a human subject twice daily for an aggregate dose of 1600 mg.
  • the human subject acting to increase stomach acidity e.g., the compound is administered while acting to increase stomach acidity.
  • between 100 mg and 10 g of the compound is administered daily.
  • 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, or 10,000 mg may be administered daily.
  • 1200 mg of the compound is administered per day, e.g., with two doses of 600 mg each.
  • 1800 mg of the compound is administered per day, e.g. , with three doses of 600 mg each .
  • 1600 mg of the compound is administered to a subject (e.g., a human) per day, e.g. , with two doses of 800 mg each.
  • each administration is performed while acting to increase stomach acidity.
  • the compound is administered once per day, two times per day, three times per day, or four times per day. In preferred embodiments, the compound is administered two times per day or three times per day, e.g, while acting to increase stomach acidity. In more preferred embodiments, the compound is administered two times per day, e.g., while acting to increase stomach acidity.
  • Example 1 Telaglenastat: glutaminase inhibitor for the treatment of solid and hematological malignancies
  • telaglenastat requires low pH conditions for optimal solubilization. Concomitant treatment with proton pump inhibitors (PPIs) results in reduced exposure to telaglenastat. If possible, concomitant administration of telaglenastat with PPIs should be avoided.
  • PPIs proton pump inhibitors
  • telaglenastat patients may be switched to shorter acting agents such as histamine H2 receptor antagonists (H2RA) and as-needed antacid buffering agents (e.g., calcium carbonate, magnesium hydroxide and aluminum hy droxide) since, based on limited clinical data, they do not appear to result in a significant reduction of telaglenastat exposure. It is recommended that telaglenastat be dosed at least 2 hr before antacid therapy.
  • H2RA histamine H2 receptor antagonists
  • antacid buffering agents e.g., calcium carbonate, magnesium hydroxide and aluminum hy droxide

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

In some aspects, the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease, comprising orally administering a compound of formula I, formula IΙ, or formula III, wherein the compound is administered while acting to increase stomach acidity (e.g., ingesting the compound with an acidic beverage as defined herein or discontinuing treatment with a proton pump inhibitor).

Description

METHODS OF ADMINISTERING GLUTAMINASE INHIBITORS
Related Application
This application claims the benefit of priority to U.S. Provisional Patent Application
No. 63/074,687, filed September 4, 2.020, which application is hereby incorporated by reference in its entirety.
Background
Glutamine supports cell survival, growth and proliferation through metabolic and non-metabolic mechanisms. In actively proliferating cells, the metabolism of glutamine to lactate, also referred to as "glutaminolysis" is a major source of energy in the form of NADPH. The first step in glutaminolysis is the deamination of glutamine to form glutamate and ammonia, which is catalyzed by the glutaminase enzyme. Thus, deamination via glutaminase is a control point for glutamine metabolism.
Ever since the observation that ascites tumor cells exhibited high rates of glucose consumption and lactate secretion in the presence of oxygen, researchers have been exploring how cancer cells utilize metabolic pathways to be able to continue actively proliferating. Subsequent research has demonstrated how glutamine metabolism supports macromolecular synthesis necessary' for cells to replicate.
Thus, glutaminase has been theorized to be a potential therapeutic target tor the treatment of diseases characterized by actively proliferating cells, such as cancer. Therefore, compositions and methods for administering glutaminase inhibitors to prevent or treat disease are desirable.
Summary
In some aspects, the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease, comprising orally administering a compound of formula I, formula II, and/or formula III, wherein the compound is administered while acting to increase stomach acidity when the compound is ingested. In some embodiments, acting to increase stomach acidity (e.g. ingesting an acidic beverage) is achieved concurrently while ingesting the compound. In other embodiments, acting to increase stomach acidity (e.g. discontinuing treatment with a proton pump inhibitor (PPI) and/or beginning treatment with an H2 blocker) is performed to increase acidity' at a later time when the compound will be ingested. In some aspects, the invention relates to a method of administering a compound of formula I, formula II, and/or formula III, to a patient, comprising: determining whether the patient is receiving treatment with a proton pump inhibitor; and, if the patient is receiving treatment with a proton pump inhibitor, instructing the patient to act to increase stomach acidity while ingesting the compound. In some embodiments, acting to increase stomach acidity comprises ingesting the compound with an acidic beverage. In some embodiments, acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound, e.g., at least 24 hours before commencing oral administration of the compound. The method may further comprise beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor. In some embodiments, the H2 blocker is nizatidine, famotidine, ranitidine, or cimetidine. In some aspects, the invention relates to a method of ingesting a compound of formula I, formula II, and/or formula III, while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity' while ingesting the compound. In some embodiments, acting to increase stomach acidity comprises ingesting an acidic beverage while ingesting the compound of formula I.
In some aspects, tire invention relates to a method for improving the effectiveness of a compound of formula I, formula II, and/or formula III, in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound, e.g., at least 24 hours before commencing oral administration of the compound. In some such embodiments, the method may further comprise beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor. In some embodiments, the H2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
In some aspects, the invention relates to a method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with a compound of formula I, formula II, and/or formula III, comprising (i) determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and (ii) if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H2 blocker. In some embodiments, the Hr blocker is nizatidine, famotidine, ranitidine, or cimetidine. Brief Description of the Drawings
Figures 1A-1F show PPI effects on telaglenastat exposure on cycle 1 day 1 . Figures 1A-1C show that AUC0-8hr, Cmax, and AUCiast of telaglenastat in 600 mg BID patients are separated into two groups: with or without concomitant administration of a PPI (patients taking histamine H2 -receptor antagonists (HERA) were excluded from this analysis). Figures ID- IF show that AUC0-8hr, Cmax, and AUCiast of telaglenastat in 800 mg BID patients are separated into two groups: with or without concomitant administration of a PPI. The dashed line corresponds to the median; the solid line to the arithmetic mean. Tire ends of the “box” are the 25th and 75th percentiles, also referred to as the first and third quartiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still wdthin 1.5 IQR of the upper quartile, where IQR is the interquartile range (the difference between the third and first quartiles, the middle 50%). Data values that do not fall between the whiskers are plotted as outliers (markers outside of the whiskers).
Figures 2A-2F show' PPI effects on telaglenastat exposure on cycle 1 day 15. Figures 2A-2C show' that AUC0-8hr, Cmax, and AUClast of telaglenastat in 600 mg BID patients are separated into two groups: with or without concomitant administration of a PPI (patients taking histamine H2-receptor antagonists were excluded from this analysis). Figures 2D-2F show' that AUC0-8hr, Cmax, and AUCiast of telaglenastat in 800 mg BID patients are separated into two groups: with or without concomitant administration of a PPI. The dashed line corresponds to the median; tire solid line to the arithmetic mean. The ends of the “box” are the 25th and 75 th percentiles, also referred to as the first and third quartiles. The whiskers show' the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile, where IQR is the interquartile range (the difference between the third and first quartiles, the middle 50%). Data values that do not fall between the whiskers are plotted as outliers (markers outside of the whiskers).
Figure 3 show's the H2RA effects on telaglenastat exposure on C1D1 and C1D15. AUC0-8hr of telaglenastat was assessed for patients dosed with 400 - 800 mg BID telaglenastat. Patients were separated into patients without concomitant administration of H2RAs (left column of each graph) and patients with concomitant administration of an H2RA (right column of each graph). Patients were assessed on Cycle 1, Day 1 (C1D1) and Cycle 1, Day 15 (C1D15). Patients taking PPIs were excluded from this analysis. Patients without concomitant administration of H2RAs included 111 on Day 1 and 89 on Day
15. Patients with concomitant administration of H2RAs included 89 patients on Day 1 and 13 patients on Day 15. The number above the scatter plot of each group denotes the geometric mean of the group.
Detailed Description
Definitions
As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each earner must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of formulas I-III). A common method for malting a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formulas I-III in a formulation can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
The term “therapeutically effective amount” relates to the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the patient. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher ei al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
The term “treating” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g. , disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unw anted condition), whereas if it is administered after manifestation of the unw anted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
The terms “with food”, “with a meal”, “with meals”, “during a meal”, “after a meal” refers to the administration of a compound in temporal proximity to (e.g., before, during, or after) the ingestion of food (e.g., a meal), and more particularly refers to the administration of a compound within 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 minu tes before ingesting food, during a meal, or within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 45, 60, or 90 minutes after ingesting food. In preferred embodiments, the terms “with food” and “with a meal” refer to the administration of a compound with a meal, before the meal (e.g., 30 minutes before ingesting the food or meal), and after the meal (e.g., 90 minutes after ingesting the food or meal).
Definitions of I^unclional Groups
The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula bydrocarbyiC(O)NH-.
The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl ,
The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below', except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
An “’alkyl” group or “’alkane” is a straight chained or branched non-arornatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A Ci-Cs straight chained or branched alkyl group is also referred to as a "lower alkyl" group. Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "un substituted alkyls" and "substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CM and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
The term ''C, T when used hr conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-yalkenyl” and “C2- yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.
The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-, The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability’ is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
The term “amide”, as used herein, refers to a group
Figure imgf000009_0001
wherein each R10 independently represent a hydrogen or hydrocarbyl group, or two R10 are taken together with the N atom to which they are atached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
Figure imgf000009_0002
wherein each R10 independently represents a hydrogen or a hydrocarbyl group, or two R10' are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.
The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. lire term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a. 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
The term " carbamate” is art-recognized and refers to a group
Figure imgf000010_0001
wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycie includes bicyclic molecules in w hich one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycie in which each of the rings shares two adjacent atoms with the oilier ring. Each ring of a fused carbocycie may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5- cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1 ,0]hept-3~ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherw ise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings, A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.
The term “carbonate” is art-recognized and refers to a group -OCO2-R10, wherein R10 represents a hydrocarbyl group.
The term “carboxy”, as used herein, refers to a group represented by the formula -CO2II.
The term “ester”, as used herein, refers to a group -C(O)OR10 wherein R10 represents a hydrocarbyl group.
The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycie and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
The terms “hetaralky 1” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
Tire term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole. furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocycly Is. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.
The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to ary 1, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.
The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substi tuent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. lire term “silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substitu ted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxy carbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy 1, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae
Figure imgf000014_0001
wherein R9 and R10 independently represents hydrogen or hydrocarbyl, such as alkyl, or R9 and R10 taken together with the intervening atorn(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term “sulfoxide” is art-recognized and refers to the group ~S(O)~R10, wherein R10 represents a hydrocarbyl .
The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
The term “sulfone” is art-recognized and refers to the group -S(O)2-R10, wherein R10 represents a hydrocarbyl.
The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.
The term “thioester”, as used herein, refers to a group -C(O)SR10 or -SC(O)R10 wherein R10 represents a hydrocarbyl.
The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
The term “urea” is art-recognized and may be represented by the general formula
Figure imgf000014_0002
wherein R9 and R10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R9 taken together with R10 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term “protecting group” refers to a group of atoms that, when atached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethyIsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, all yloxy carbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (estenfied) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
I. COMPOUNDS
The present invention relates to methods of orally administering a compound of formula I,
Figure imgf000015_0001
or a. pharmaceutically acceptable salt thereof, wherein:
L represents CH2CH2;
X, independently for each occurrence, represents S or CH=CH; each Y represents H;
Z represents R3(CO);
R1 and R2. each represent H; and
R3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl; to a patient, comprising: determining whether the patient is receiving treatment with a proton pump inhibitor; and, if the patient is receiving treatment with a proton pump inhibitor, instracting the patient to act to increase stomach acidity' while ingesting the compound of formula I, or a pharmaceu tically acceptable salt thereof.
The present invention further relates to methods of ingesting a compound of formula I, or a pharmaceutically acceptable salt thereof, while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity while ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein:
L represents CH2CH2;
X, independently for each occurrence, represents S or CH = C H ; each Y represents H;
Z represents R3(CO);
Rs and R2 each represent H; and R3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl.
The present invention further relates methods for improving the effectiveness of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof;
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof, wherein:
L represents CH2CH2;
X, independently for each occurrence, represents S or CH=CH; each Y represents H;
Z represents R3(CO);
R1 and R2 each represent H; and
R3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl.
The present invention further relates to a method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with of Formula I,
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein:
L represents CH2CH2;
X, independently tor each occurrence, represents S or CH=CH; each Y represents H;
Z represents R3(CO);
R1 and R2 each represent H; and
R.3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl; comprising: determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and, if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H2 blocker.
A pharmaceutically acceptable salt as includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-suIfonic, oxalic, mandelic and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1: 1. In some preferred embodiments, contemplated salts of the invention are hydrochloride (HC1) salts.
In certain embodiments wherein alkyl, hydroxyalkyl, ammo, acylamino, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl are substituted, they are substituted with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, ary l, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino. acylaminoalkyl, such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaiyl, heteroarylaikyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoaikoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(O)CFs)), carbonylalkyl (such as carboxyalkyl, alkoxy carbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(O)CFs)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate.
In certain embodiments, acting to increase stomach acidity comprises ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof, with an acidic beverage. Alternatively, acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof. The proton pump inhibitor may be discontinued for at least 24 hours, preferably 1 to 14 days, before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, acting to increase stomach acidity further comprises beginning treatment with an H2 blocker concurrently w ith or after discontinuing the treatment with the proton pump inhibitor. Non-linnted examples of the H2 blocker are nizatidine, famotidine, ranitidine, and cimetidine. Hr blockers may also be referred to herein as a histamine H2 receptor antagonist or H2RA.
In certain embodiments, one X represents S and the other X represents CH=CH.
In certain embodiments, each occurrence of R3 is not identical (e.g., the compound of formula I is not symmetrical).
In certain embodiments, each R3 is independently substituted or unsubstituted arylalkyl or heteroarylaikyl.
In certain embodiments, the compound of formula I has the structure of formula II,
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein: R3 represents substituted or unsubstituted arylalkyl or heteroarylalkyl; R11 represents arylalkyl or heteroarylalkyl, wherein the aryl or heteroaryl ring is substituted with either -OCHF2 or -OCF3 and is optionally further substituted.
In certain embodiments, R11 represents arylalkyl, such as benzyl, wherein the aryl group is substituted with -OCF3, such as meta-substituted with -OCF3. In certain such embodiments, the and ring is not further substituted. In certain embodiments, R11 represents trifluoromethoxy benzyl, such as
Figure imgf000019_0002
In certain embodiments, R3 and R11 are not identical.
In certain embodiments, R3 represents heteroarylalkyl, such as pyridylalkyl (e.g.,
" pyridylmethyl). In certain such embodiments, Z represents
Figure imgf000019_0003
In certain embodiments, L represents CH2CH2, Y represents H, X represents S, Z represents R3(CO), R1 and R2 each represent H, R3 represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, such as heteroarylalkyl (e.g., pyridylalkyl), and R11 represents arylalkyl, such trifluoromethoxy benzyl (e.g, In certain such embodiments, Z represents R3(CO) and R3 represents
Figure imgf000019_0004
pyridylmethyl, such as wherein Z represents
Figure imgf000019_0005
Exemplary’ compounds of Formulae (I) and (II) are found in PCT Application Publication Nos. WO 2013/078123 and WO 2014/078645, which are hereby incorporated by reference, particularly for the formulas and structures of glutaminase inhibitors disclosed therein. In certain embodiments of the methods described herein, the compound used in the methods of the invention is a compound having the structure of Formula (III):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof. The compound having the structure of Formula (III) is also referred to herein as CB-839 or telaglenastat. The names CB-839 and telaglenastat refer to the compound free base. As described below, the studies described in the examples section utilized the hydrochloride salt of the compound of Formula (III) (i.e., telaglenastat HC1 or CB-839 HC1).
Compounds of any of Formulae (I), (II), or (III) are alternatively referred to herein as “glutaminase inhibitors.”
In certain embodiments, compounds of the invention may be prodrugs of the compounds of formulas I-III, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, or carboxylic acid).
In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, compounds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
In certain embodiments, the present invention relates to methods of treatment with a compound of formulas I-III, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formulas I-III). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g, in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formulas I-III). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
In certain embodiments, the present invention provides a pharmaceutical preparation suitable for oral administration to a human patient, comprising any of the compounds shown above (e.g., a glutaminase inhibitor, such as a compound of formulas I-III), and one or more pharmaceutically acceptable excipients.
Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein.
II. USE OF COMPOUNDS
Glutamine plays an important role as a carrier of nitrogen, carbon, and energy. It is used for hepatic urea synthesis, for renal ammoniagenesis, for gluconeogenesis, and as respiratory' fuel for many cells. The conversion of glutamine into glutamate is inflated by tlie mitochondrial enzyme, glutaminase (“GLS”). There are two major forms of the enzyme, K-type and L~type, which are distinguished by their Km values for glutamine and response to glutamate, wherein the Km value, or Michaelis constant, is the concentration of substrate required to reach half the maximal velocity. The L-type, also known as “liver- type” or GLS2, has a high Km for glutamine and is glutamate resistant. The K-type, also known as “kidney -type or GLS1, has a low Km for glutamine and is inhibited by glutamate. An alternative splice form of GLS1, referred to as glutmainase C or “GAC”, has been identified recently and has similar activity characteristics of GLS1. In certain embodiments, the compounds may selectively' inhibit GLS1, GLS2 and GAC. In certain preferred embodiments, the compounds selectively' inhibit GLS1 and GAC. In addition to serving as the basic building blocks of protein synthesis, amino acids have been shown to contribute to many processes critical for growing and dividing cells, and this is particularly true for cancer cells. Nearly all definitions of cancer include reference to dysregulated proliferation. Numerous studies on glutamine metabolism in cancer indicate that many tumors are avid glutamine consumers. Accordingly, in certain embodiments, the invention provides methods for treating or preventing cancer, a myeloproliferative disease, an immunological disease, or a neurological diseasecomprising orally administering a glutaminase inhibitor (e.g. , a compound of any of formulas I -III, or a pharmaceutically acceptable salt thereof), preferably wherein the compound is administered while acting to increase stomach acidity.
In certain embodiments, the cancer may be one or a variant of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS- Related Cancers (Kaposi Sarcoma and Lymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepitbelioma, Pineal Parenchymal Tumors of Intermediate Differentiation, Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma), Breast Cancer , Bronchial Tumors, Burkitt Lymphoma, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System (such as Atypical Teratoid/Rhabdoid Tumor, Embryonal Tumors and Lymphoma), Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sezary Syndrome), Duct, Bile (Extrahepatic), Ductal Carcinoma In Situ (DCIS), Embryonal Tumors (Central Nervous System), Endometrial Cancer, Ependymoblastoma, Ependy moma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (like Intraocular Melanoma, Retinoblastoma), Fibrous Histiocytoma of Bone (including Malignant and Osteosarcoma) Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal, Ovarian), Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi Sarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell), Lip and Oral Cavity' Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (Non- Small Cell and Small Cell), Lymphoma (AIDS-Related, Burkitt, Cutaneous T-Cell (Mycosis Fungoides and Sezary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancer with Occult Primary', Midline Tract Carcinoma Invol ving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), myelodysplastic syndromes (MDS), Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor, and Low Malignant Potential Tumor), Pancreatic Cancer (including Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary' Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (like Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue, Uterine), Sezary Syndrome, Skin Cancer (such as Melanoma, Merkel Ceil Carcinoma, Nonmelanoma), Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach (Gastric) Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma(Cutaneous, Mycosis Fungoides and Sezary Syndrome), Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Unknown Primary, Unusual Cancers of Childhood, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Waldenstrom Macroglobulmemia and Wilms Tumor.
In some instances, oncogenic mutations promote glutamine metabolism. Cells expressing oncogenic K-Ras exhibit increased utilization of glutamine. In certain embodiments, the cancer cells have a mutated K-Ras gene. In certain embodiments, the cancer is associated with tissue of the bladder, bone marrow, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, skin or thyroid. Tire c-Myc gene is known to be altered in numerous cancers. Increased Myc protein expression has been correlated with increased expression of glutaminase, leading to up-regulation of glutamine metabolism. In certain embodiments, the cancer cells have an oncogenic c-Myc gene or elevated Myc protein expression. In some embodiments, the cancer is associated with tissue of the bladder, bone, bowel, breast, central nervous system (like brain), colon, gastric system (such as stomach and intestine), liver, lung, ovary, prostate, muscle, and skin.
For example, the most common type of renal cell carcinoma (RCC), clear cell type (ccRCC), is closely associated with von Hippel-Lindau (VHL) gene mutations. VHL- deficient cell lines have been shown to have an increased requirement for glutamine due to a loss of ability to make fatty acids from glucose (Metallo et al. Nature 2013). This dependency on glutamine makes the cells susceptible to glutaminase inhibitors (Gameiro et al., Cell Metab. 2013). Certain embodiments of the invention relate to the use of the compounds described herein for the treatment of VHL-deficient carcinomas. In certain embodiments the cancer is RCC. In certain embodiments the cancer is ccRCC.
EGFR (Epide tmal growth factor receptor) is the cell -surface receptor for members of the epidermal growth factor (EGF) family of extracellular protein ligands. Mutations associated with EGFR overexpression have been associated with certain cancers, including lung cancers. Approximately 10% of non-small cell lung cancer patients in the United States, and approximately 35% of nsclc patients in East Asia have tumors associated with an EGFR mutation. Typically the EGFR mutation occurs in a region of the gene that encodes a portion of the EGFR kinase domain. Usually, such mutations result tn gene amplification, increased kinase activity of EGFR, and hyperactivation of downstream pro- survival signaling pathways. See A. Kuykendall, et al. (‘"Advanced EGFR Mutation- Positive Non-Small Cell Lung Cancer: Case Report, Literature Review, and Treatment Recommendations” Cancer Control, 2014, V. 21, No. 1, 67-73) for a review about NSCLC and EGFR mutations.
Glutaminase inhibition may also be effective in certain rare cancers that have mutations or deletions of the TCA cycle enzymes including fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase (IDH). Glutamate feeds into the TCA cycle upstream of where these mutations or deletions occur. Published studies indicate that glutamine metabolism is important in the synthesis of fumarate and succinate. In addition to FH and SDH, there is evidence that glutamine contributes to the production of 2-hydroxyglutatrate, another driver of tumor formation that accumulates in patients with tumors harboring mutations in the enzyme isocitrate dehydrogenase. Thus, inhibitors of glutaminase may block the effect of these mutations or deletions by limiting the availability of upstream starting materials. Rare mutations in FH lead to the development of hereditary leiomyomatosis and renal cell cancer (HLRCC), where patients can develop tumors of the skin, uterus and kidneys. Some gastrointestinal stromal tumors (GIST), arise from the lack of expression of SDH, and are often hereditary. Other SDH-loss-of-function mutations are found in patients exhibiting a rare head and neck cancer known as paraganglioma, and a rare adrenal or extra-adrenal cancer known as pheochromocytoma, and a rare subset clear cell RCC. Some patients with glioma, a form of brain cancer, chondrosarcoma, a rare bone cancer, cholangiocarcinoma, a rare bile duct tumor, AML, or high risk myeldysplasia/myeioproliferative disorders, a group of blood disorders, have IDH1 or IDH2 driver mutations.
In certain embodiments of the invention, compounds described herein can be used for the treatment of disease identified with a FH, SDH or IDH (1 and 2) mutation . For example, in certain embodiments, the disease is an isocitrate dehydrogenase (IDH)-rnutant solid tumor. In certain embodiments the disease is hereditary leiomyomatosis or renal cell cancer (HLRCC). In certain embodiments the disease is GIST (e.g., SDH-deficient GIST), paraganglioma, pheochromocytoma, or clear cell RCC. In certain embodiments, the disease is glioma, chondrosarcoma, cholangiocarcinoma, acute myeloid leukemia (AML), or myelodysplasia/myeloproliferative disorder. In certain embodiments, the disease is mesothelioma. In certain embodiments, the disease is multiple myeloma.
In certain embodiments, the cancer is a non-small cell lung cancer having a KRAS or EGFR mutation.
While many cancer cells depend on exogenous glutamine for survival, the degree of glutamine dependence among tumor cell subtypes may make a population of cells more susceptible to the reduction of glutamine. As an example, gene expression analysis of breast cancers has identified five intrinsic subtypes (luminal A, luminal B, basal, HER2+, and normal-like). Although glutamine deprivation has an impact on cell growth and viability, basal-like cells appear to be more sensitive to the reduction of exogenous glutamine. This supports the concept that glutamine is a very important energy source in basal-like breast cancer cell lines, and suggests that inhibition of the glutaminase enzyme would be beneficial in the treatment of breast cancers comprised of basal-like cells. Triple- negative breast cancer (TNBC) is characterized by a lack of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. It has a higher rate of relapse following chemotherapy, and a poorer prognosis than with the other breast cancer subtypes. Interestingly, there appears to be significant similarities in metabolic profiling between TNBC cells and basal-like breast cancer cells. Therefore, an embodiment of the invention is the use of the compounds described herein for the treatment of TNBC, basal- type breast cancers, or claudin-low breast cancers.
In certain embodiments, the invention provides methods for treating colorectal cancer. In certain embodiments, the invention provides methods for treating endocrine cancer, such as adrenal cortex adenoma, adrenal cortex carcinoma, adrenal gland pheochromocytoma, and parathyroid gland adenoma.
In certain embodiments, the cancer is melanoma.
Cachexia, the massive loss of muscle mass, is often associated with poor performance status and high mortality rate of cancer patients. A theory behind this process is that tumors require more glutamine than is normally supplied by diet, so muscle, a major source of glutamine, starts to breakdown in order to supply enough nutrient to the tumor. Thus, inhibition of glutaminase may reduce the need to breakdown muscle. An embodiment of the invention is the use of the present compounds to prevent, inhibit or reduce cachexia. The most common neurotransmiter is glutamate, derived from the enzymatic conversion of glutamine via glutaminase. High levels of glutamate have been shown to be neurotoxic. Following traumatic insult to neuronal cells, there occurs a rise in neurotransmiter release, particularly glutamate. Accordingly, inhibition of glutaminase has been hypothesized as a means of treatment following an ischemic insult, such as stroke (PCT Publication No. WO 99/09825). Huntington’s disease is a progressive, fatal neurological condition. In genetic mouse models of Huntington’s disease, it was observed that the early manifestation of the disease correlated with dysregulated glutamate release. In HIV-associated dementia, HIV infected macrophages exhibit upregulated glutaminase activity and increased glutamate release, leading to neuronal damage. Similarly, in another neurological disease, the activated microglia in Rett Syndrome release glutamate causing neuronal damage. The release of excess glutamate has been associated with the up- regulation of glutaminase. In mice bred to have reduced glutaminase levels, sensitivity to psychotic-stimulating drugs, such as amphetamines, was dramatically reduced, thus suggesting that glutaminase inhibition may be beneficial in the treatment of schizophrenia. Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. This disease is treated with mood stabilizers such as lithium and valproate; however, chronic use of these drugs appears to increase the abundance of glutamate receptors, which may lead to a decrease in the drug’s effectiveness overtime. Thus, an alternative treatment may be to reduce the amount of glutamate by inhibiting glutaminase. This may or may not be in conjunction with the mood stabilizers. Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMD AR), is an approved therapeutic in the treatment of Alzheimer’s disease. Currently, research is being conducted looking at memantine as a means of treating vascular dementia and Parkinson's disease. Since memantine has been shown to partially block the NMDA glutamate receptor also, it is not unreasonable to speculate that decreasing glutamate levels by inhibiting glutaminase could also treat Alzheimer’s disease, vascular dementia and Parkinson’s disease. Alzheimer’s disease, bipolar disorder, HIV-associated dementia, Huntington’s disease, ischemic insult, Parkinson’s disease, schizophrenia, stroke, traumatic insult and vascular dementia are but. a few' of the neurological diseases that have been correlated to increased levels of glutamate. Thus, inhibiting glutaminase with a compound described herein can reduce or prevent neurological diseases. Therefore, in certain embodiments, the compounds may be used for the treatment or prevention of neurological diseases. Activation of T lymphocytes induces ceil growth, proliferation, and cytokine production, thereby placing energetic and biosynthetic demands on the cell. Glutamine serves as an amine group donor for nucleotide synthesis, and glutamate, the first component in glutamine metabolism, plays a direct role in amino acid and glutathione synthesis, as well as being abie to enter the Krebs cycle for energy production. Mitogen-induced T cell proliferation and cytokine production require high levels of glutamine metabolism, thus inhibiting glutaminase may serve as a means of immune modulation. In multiple sclerosis, an inflammatory autoimmune disease, the activated microglia exhibit up-regulated glutaminase and release increased levels of extracellular glutamate. Glutamine levels are lowered by sepsis, injury, burns, surgery and endurance exercise. These situations put the individual at risk of immunosuppression. In fact, in general, glutaminase gene expression and enzyme activity are both increased during T cell activity. Patients given glutamine following bone marrow transplantation resulted in a lower level of infection and reduced graft versus host disease. T cell proliferation and activation is involved in many immunological diseases, such as inflammatory bowel disease, Crohn’s disease, sepsis, psoriasis, arthritis (including rheumatoid arthritis), multiple sclerosis, graft versus host disease (GVHD), infections, lupus, diabetes, ankylosing spondylitis, erythema nodosum leprosum (ENL), HIV-associated wasting syndrome, lupus erythematosus, post- polycythemia, psoriasis, psoriatic arthritis, recurrent aphthous ulcers, severe recurrent aphthous stomatitis, and systemic sclerosis. In an embodiment of the invention, the compounds described herein can be used to treat or prevent immunological diseases.
Hepatic encephalopathy (HE) represents a series of transient and reversible neurologic and psychiatric dysfunction in patients with liver disease or portosystemic shunting. HE is not a single clinical entity and may reflect reversible metabolic encephalopathy, brain atrophy, brain edema, or a combination of these factors; however, the current hypothesis is that the accumulation of ammonia, mostly derived from the intestine, plays a key role in the pathophysiology. The deamination of glutamine in small intestine, renal and muscle synthesis all contribute to ammonia production. Impaired hepatic clearance caused by hepatocellular clearance or portosystemic shunting causes increased accumulation of ammonia. Ammonia toxicity affects astrocytes in the brain via glutamine synthetase, which metabolizes the ammonia to produce increased glutamine. Glutamine, in turn, attracts water into the astrocytes, leading to swelling and oxidative dysfunction of the mitochondria. The resulting cerebral edema is thought to contribute to neurologic dysfunction seen m HE. In an embodiment of the invention, the compounds described herein can be used to treat or prevent HE.
Primary sensory neurons in the dorsal root ganglion have been shown to elevate their glutaminase enzyme activity following inflammation. It is believed that the resulting increased glutamate production contributes to both central and peripheral sensitization, identified as pain. An aspect of the invention is the use of the present compounds herein for the treatment or diminishment of pain. In certain embodiments, the pain can be neuropathic pain, chemotherapy -induced pain or inflammatory pain.
High blood glucose levels, high insulin levels, and insulin resistance are risk factors for developing diabetes mellitus. Similarly, high blood pressure is a risk factor for developing cardiovascular disease. In a recent report from a large human cohort study, these four risk factors were inversely correlated with glutamine-to-glutamate ratios in the blood stream. Furthermore, plasma glutamine-to-glutamate ratios were inversely correlated with the eventual incidence of diabetes mellitus over 12 years. Experiments with animal models were consistent with these findings. Mice fed glutamine-rich diets exhibited lower blood glucose levels in a glucose tolerance test after 6 hours of fasting, and intraperitoneal injection of glutamine into mice rapidly decreased their blood pressure. Therefore, it is plausible that glutaminase inhibitors, which cause increased glutamine levels and decrease glu tamate levels, would decrease the incidence of diabetes mellitus and cardiovascular disease. In particular, the liver and small intestine are major sites of glutamine utilization in diabetic animals, and glutaminase activity is higher than normal in these organs in streptozotocin-induced diabetic rats. In an embodiment of the invention, the compounds described herein can be used to treat diabetes. In another embodiment of the invention, the present compounds can be used to reduce high blood pressure.
In certain embodiments, the method of treating or preventing cancer, a myeloproliferative disease, an immunological disease, or a neurological disease may comprise orally administering a compound of the invention, e.g., a compound of any of formulas I-Ill, or a pharmaceutically acceptable salt thereof, e.g., while acting to increase stomach acidity, conjointly with one or more additional therapeutic agents. In certain embodiments, the compounds of the invention may be conjointly administered with an anticancer agent selected from an enzyme inhibitor (such as a kinase inhibitor), a mitotic inhibitor, a DNA-modifying agent, an immune-checkpoint inhibitor, and a cytidine analog. Examples of anticancer agents with which the compounds of the invention may be administered in a combination therapy include microtubule assembly inhibitors, DNA crosslinking agents, antimetabolites, AKT inhibitors, ALK inhibitors, BRAF inhibitors, mTOR inhibitors, CDK4/6 inhibitors, MEK inhibitors, RTK inhibitors, ATM inhibitors, ATR inhibitors, PI3K inhibitors, EGFR inhibitors, VEGFR inhibitors, B-Raf inhibitors, C- kit inhibitors, DNA cross-linking agents, DNA intercalating agents, anti-PD-1 inhibitors, anti-PDL-1 inhibitors, CTLA-4 inhibitors, PARI’ inhibitors, KRAS inhibitors, aromatase inhibitors, estrogen-receptor modulators, and cytidine analogs. In certain embodiments, the anticancer agent is nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, bevacizumab, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, ienvatinib, regorafemb, ponatmib, vandetanib, ramucirumab, everolimus, temsiroiimus, osimertinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, necitumumab, dacomitinib, cetuximab , panitumumab, alectinib, brigatinib, lorlotinib, ceritinib, vemurafenib, dabrafenib, encorafenib, trametimb, cobimetinib, binimetmib, palbociclib, nbociclib, abemaciclib, olaparib, niraparib, rucaparib, talazaparib, cisplatin, carboplatin, oxaliplatin, pemetrexed, 5-fluorouracil, capecitabine, gemcitabine, fludarabine, floxuridine, docetaxel, paclitaxel, AMG510, MRTX849, anastrozole, letrozole, exemestane, fulvestrant, and tamoxifen.
In certain embodiments, a compound of the invention may be conjointly administered (e.g., orally administered, while acting to increase stomach acidity) with non- chemical methods of cancer treatment. In certain embodiments, a compound of the invention may be conjointly administered with radiation therapy. In certain embodiments, a compound of the invention may be conjointly administered wi th surgery', with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these.
In certain embodiments, the compounds of the invention may be conjointly administered with another GVHD therapeutic agent selected from ibrutinib, ruxolitinib, belomosudil, and steroids such as prednisone.
In certain embodiments, different compounds of the invention may be conjointly administered with one or more other compounds of the invention. Moreover, such combinations may be conjointly administered with other therapeutic agents, such as oilier agents suitable for the treatment of cancer, immunological or neurological diseases, such as the agents identified above. Gastrointestinal absorption of the glutaminase inhibitors disclosed herein is reduced, and efficacy negatively affected, in patients taking proton primp inhibitors. Proton pump inhibitors or (PPIs) are a group of drugs that reduce gastric acid production. Proton pump inhibitors act by blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H7K’ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells. Representative proton pump inhibitors include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole. Accordingly, patients who take a proton pump inhibitor and who might benefit from taking a glutaminase inhibitor as disclosed herein may benefit from one or more strategies that reduce the effect of the proton pump inhibitor on the effect of the glutaminase inhibitor, e.g., for treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease. Specifically, the patient may be instructed to act to increase stomach acidity while administering a compound of formula I, formula II, and/or formula III, e.g., by drinking an acidic beverage when ingesting the glutaminase inhibitor, or discontinuing use of the proton pump inhibitor at least 24 hours before commencing oral administration of the glutaminase inhibitor.
For example, ingesting an acidic beverage will temporarily reduce gastric pH and improve absorption and efficacy of the glutaminase inhibitor. Acidi c beverages are beverages or drinks with low pH, e.g., below 5.0, preferably in the range of 1 .0 to 4.0. Suitable acidic beverages include lime juice, lemon juice, cranberry juice, vinegar, cider vinegar, lemonade, tropical fruit juice, cola, soda, tonic water, seltzer, strawberry -grape juice, strawberry juice, grape juice, orange juice, grape soda, coffee, grapefruit juice, iced tea, pineapple juice, wine, apple juice, plurn nectar, vegetable juice, prune juice, root beer, pear nectar, tomato juice, and buttermilk. While it is perhaps simplest to use an acidic beverage to assist swallowing the glutaminase inhibitor, similar effects may be achieved by drinking the acidic beverage shortly before or after (e.g., within about 60 min., preferably within about 30 min. or even within 15 min.) ingesting the glutaminase inhibitor. For the purpose of this invention taking or ingesting a glutaminase inihibitor ‘ with an acidic beverage” includes drinking the acidic beverage before or after the glutaminase inhibitor in this way .
While discontinuing treatment with a proton pump inhibitor is effective to increase stomach acidity, some patients may still require medication to reduce stomach acidity. Since proton pump inhibitors are typically more effective at reducing stomach acidity than H2 blockers, some patients may switch from taking a proton pump inhibitor to taking an H2 blocker during treatment with the glutaminase inhibitor, e.g., beginning treatment with an H2 blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor. H2 blockers (or " H2 antagonists” or “H2RAs” or “histamine H2 receptor antagonists”) are a class of drugs that block the action of histamine at the histamine Hz receptors of the parietal cells in the stomach. This decreases the production of stomach acid. Representative H2 blockers include cimetidine, ranitidine, famotidine, and nizatidine.
Thus, in one aspect, the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease while receiving treatment with a proton pump inhibitor by acting to increase stomach acidity while ingesting compound of formula I, formula II, and/or formula III,. In certain embodiments, acting to increase stomach acidity (e.g., ingesting an acidic beverage) is achieved concurrently while administering the compound. In other aspects, acting to increase stomach acidity (e.g., discontinuing treatment with a proton pump inhibitor and/or beginning treatment with an H2 blocker) is performed to increase acidity at a later time when the compound will be administered.
In some aspects, the invention relates to a method of administering a compound of formula I, formula II, and/or formula III to a patient, comprising: (1) determining whether the patient is receiving treatment with a proton pump inhibitor; and, (2) if the patient is receiving treatment with a proton pump inhibitor, instructing the patient to act to increase stomach acidity while ingesting the compound. In some embodiments, acting to increase stomach acidity comprises ingesting the compound with an acidic beverage. In some embodiments, acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor before commencing oral administration of tire compound. In some embodiments, acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound. In some embodiments, acting to increase stomach acidity comprises discontinuing treatment with tire proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound; and beginning treatment with an H2 blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor. In some embodiments, the H2 blocker is nizatidine, famotidine, ranitidine, or cimetidine. In some aspects, the invention relates to a method of ingesting a compound of formula I, formula II, and/or formula III while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity while ingesting the compound. In some embodiments, acting to increase stomach acidity? comprise ingesting an acidic beverage while ingesting the compound.
In some aspects, the invention relates to a method for improving tire effectiveness of a compound of formula I, formula II, and/or formula III in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor before commencing oral administration of the compound. In some aspects, the invention relates to a method for improving the effectiveness of the compound in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound. In some embodiments, the invention relates to a method for improving the effectiveness of the compound in a subject recei ving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound; and beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor. In some embodiments, the Hr blocker is nizatidine, famotidine, ranitidine, or cimetidine.
In further embodiments, the present invention further relates to a method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with a compound of formula I, formula II, and/or formula III, comprising (i) determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and, (ii) if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H2 blocker.
In some embodiments, the H2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
In further embodiments, the condition is gastroesophageal reflux disease (GERD) or peptic ulcer disease.
In further embodiments, the method further comprises instructing the patient to avoid taking a proton pump inhibitor. Exemplary' proton pump inhibitors omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole. III. KITS
In certain embodiments, the present invention provides a kit comprising: a) one or more single dosage forms of a compound of the invention: b) one or more single dosage forms of a chemotherapeutic agent as mentioned above; and c) instructions for the administration of the compound of the invention and the chemotherapeutic agent. The instructions may state that the compound be taken while acting to increase stomach acidity. For example, the instructions may state that the compound should be taken with an acidic beverage. Tire instructions may state that the compound should be taken once, twice, or three times a day, e.g., while acting to increase stomach acidity. For example, the instructions may state that tire compound should be taken after discontinuing treatment with a proton pump inhibitor. Furthermore, the instructions may state that the compound should be taken after discontinuing treatment with a proton purnp inhibitor, and beginning treatment with an Hi. blocker.
The present invention provides a kit comprising: a) a pharmaceutical formulation (e.g., one or more single dosage forms) comprising a compound of the invention; and b) instructions for the administration of the pharmace utical formulation, e.g. , for treating or preventing any of the conditions discussed above, wherein the instructions state that the compound should be taken while acting to increase stomach acidity.
In certain embodiments, the kit further comprises instructions for the administration of the pharmaceutical formulation comprising a compound of the invention conjointly with a chemotherapeutic agent as mentioned above. In certain embodiments, the kit further comprises a second pharmaceutical formulation (e.g., as one or more single dosage forms) comprising a chemotherapeutic agent as mentioned above.
IV. PHARMACEUTICAL COMPOSITIONS
The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable earners are well known in the art and include, for example, aqueous solutions such as water or physiological!}' buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or organic esters. The excipients can be chosen, for example, to effect delayed release of an agent. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, or tire like.
A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorp tion of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
A pharmaceutical composition (preparation) may be administered to a patient orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes). In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,1 10,973, 5,763,493, 5,731,000, 5,541,231 , 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein (hereby incorporated by reference).
The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Tire amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the in vention, with the carrier and, optionally, one or more accessor}-7 ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixi r or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and tlie like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary' or paste.
To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (tor example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsides (including sprinkle capsules and gelatin capsides), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or con trolled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active mgredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve tlie desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drags, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase tire dosage until the desired effect is achieved.
In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphtlialene-2-sulfonic, oxalic, mandelic and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1: 1. In some preferred embodiments, contemplated salts of the invention are hydrochloride (HC1) salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyllmorpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium. triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
V. METHODS
In some aspects, the invention relates to a method of treating cancer, a myeloproliferative disease, an immunological disease, or a neurological disease, comprising orally administering a compound of formula I, formula II, and/or formula III, wherein the compound is administered while acting to increase stomach acidity .
In certain embodiments, the subject is a mammal. In certain preferred embodiments, the subject is a human.
In some embodiments, the compound is administered orally between 30 minutes prior to the subject (e.g., a human) ingesting food to 6 hours after ingesting food, such as between 30 minutes prior to ingesting food to 5 hours after ingesting food, between 30 minutes prior to ingesting food to 4 hours after ingesting food, between 30 minutes prior to ingesting food to 3 hours after ingesting food, between 30 minutes prior to ingesting food to 2 hours after ingesting food, or between 30 minutes prior to ingesting food to 1 hours after ingesting food. Preferably, the compound is administered between 30 minutes prior to the subject ingesting food to 90 minutes after ingesting food, such as between 20 minutes prior to ingesting food to 90 minutes after ingesting food, between 20 minutes prior to ingesting food to 60 minutes after ingesting food, between 10 minutes prior to ingesting food to 60 minutes after ingesting food, between 5 minutes prior to ingesting food to 60 minutes after ingesting food, or between 5 minutes prior to ingesting food to 30 minutes after ingesting food.
In some embodiments, the method comprises orally administering a glutaminase inhibitor (e.g., preferably a compound of formula III) to a subject (e.g., a human), preferably while acting to increase stomach acidity, wherein between 100 mg and 10 g of the compound is administered orally per day. For example, the daily oral dose of the compound may be from 100 mg to 5000 mg, e.g., 200 mg to 4000 mg, 300 mg to 3000 mg, 600 mg to 2400 mg, 800 mg to 2200 mg, 1000 mg to 2000 mg, or 1200 mg to 1800 mg, or about 1600 mg.
In some embodiments, the method comprises orally administering the compound of formula III, and 100 mg to 10 g of the compound is administered orally per day. For example, 100 mg to 5000 mg of the compound may be administered orally per day, such as 200 mg to 4000 mg, 300 mg to 3000 mg, 600 mg to 2400 mg, 800 mg to 2200 mg, 1000 mg to 2000 mg, 1200 mg to 1800 mg, or about 1600 mg.
In some embodiments, an aggregate dose equivalent to between 100 mg and 10 g of the compound of formula III is administered orally per day. The term “aggregate dose” refers to the total amount of the compound administered, e.g., per day. For example, if a 600 mg dose of the compound is administered two times per day, then the aggregate dose is 1200 mg per day. The term “equivalent to an amount of the compound of formula III” refers to the administration of an amount of a compound that has the same efficacy as an amount of the compound of formula III. For example, if a first compound, such as a compound of formula I or II, has the same efficacy as the compound of formula III, then an equivalent of the first compound is equal to the same amount of the compound of formula III, e.g., 600 mg of the first compound is equivalent to 600 mg of the compound of formula III. Similarly, if a second compound has, for example, twice the efficacy of the compound of formula III, then an equivalent of the second compound is equal to half the amount of the compound of formula III, e.g., 300 mg of the second compound is equivalent to 600 mg of the compound of formula III. Preferably, the glutaminase inhibitor is administered to the subject while acting to increase stomach acidity.
In some embodiments, an aggregate dose equivalent to between about 100 mg and about 5000 mg of a glutaminase inhibitor (e.g., preferably a compound of formula III) is administered to a subject (e.g., a human) orally per day. In exemplary embodiments, an aggregate dose is equivalent to between about 200 mg and about 4000 mg, about 300 mg and about 3000 mg, about 400 mg and about 2800 mg, about 600 mg and about 2400 mg, about 800 mg and about 2200 mg, about 1000 mg and about 2000 mg, about 1000 mg and about 1800 mg, about 1200 mg and about 1800 mg, about 1200 mg and about 1600 mg. In certain preferred embodiments, a compound of formula III is delivered orally to a human subject twice daily for an aggregate dose of 1600 mg. Preferably, the human subject is acting to increase stomach acidity. In certain preferred embodiments, the compound is administered while acting to increase stomach acidity.
In some embodiments, an aggregate dose equivalent to between about 100 mg and about 5000 mg of the compound of formula III is administered to a subject (e.g., a human) orally per day. In exemplary embodiments, an aggregate dose is equivalent to between about 200 mg and about 4000 mg, about 300 mg and about 3000 mg, about 400 mg and about 2800 mg, about 600 mg and about 2400 mg, about 800 mg and about 2200 mg, about 1000 mg and about 2000 mg, about 1000 mg and about 1800 mg, about 1200 mg and about 1800 mg, about 1200 mg and about 1600 mg. In certain preferred embodiments, a compound of formula III is delivered orally to a human subject twice daily for an aggregate dose of 1600 mg. Preferably, the human subject acting to increase stomach acidity, e.g., the compound is administered while acting to increase stomach acidity.
In some embodiments, between 100 mg and 10 g of the compound is administered daily. For example, 100 mg, 150 mg, 200 mg, 2.50 mg, 300 mg, 350 mg, mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1350 mg, 1400 mg, 1500 mg, 1600 mg, 1650 mg,
1700 mg, 1800 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2200 mg, 2250 mg, 2300 mg,
2400 mg, 2500 mg, 2550 mg, 2600 mg, 2700 mg, 2800 mg, 2850 mg, 2900 mg, 3000 mg,
4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, or 10,000 mg may be administered daily. In certain preferred embodiments, 1200 mg of the compound is administered per day, e.g., with two doses of 600 mg each. In some embodiments, 1800 mg of the compound is administered per day, e.g. , with three doses of 600 mg each . In other preferred embodiments, 1600 mg of the compound is administered to a subject (e.g., a human) per day, e.g. , with two doses of 800 mg each. Preferably, each administration is performed while acting to increase stomach acidity.
In some embodiments, the compound is administered once per day, two times per day, three times per day, or four times per day. In preferred embodiments, the compound is administered two times per day or three times per day, e.g, while acting to increase stomach acidity. In more preferred embodiments, the compound is administered two times per day, e.g., while acting to increase stomach acidity. Examples
Example 1 : Telaglenastat: glutaminase inhibitor for the treatment of solid and hematological malignancies
A comparison between subjects in the presence or absence of proton pump inhibitors (PPI) was performed for the 600 and 800 mg BID dose levels under fed conditions. Box plots are presented in Figure 1 and Figure 2.
On cycle 1 day 1 (C1D1), subjects receiving 600 mg BID who were administered PPIs (N = 12) showed a 44%, 45% and 45% decrease, respectively, in the mean AUC0-8, AUCiast, and Cmax of CB-839 compared with subjects who did not receive PPIs (N = 35) (Figures 1A-1C). Subjects receiving 800 rng BID who were administered PPIs (N = 3) showed a 20%, 19% and 27% decrease, respectively, compared with subjects who did not receive PPIs (N = 14) (Figures ID-1F).
On cycle 1 day 1 (C1D15), subjects receiving 600 mg BID who were administered PPIs (N = 11) showed a 42%, 42% and 39% decrease in mean AUC0-8, AUCiast, and Cmas of CB-839, respectively, compared with subjects who did not receive PPIs (N = 30) (Figures 2A-2C). Subjects receiving 800 mg BID who were administered PPIs (N ~ 2) showed a
31%, 31% and 41% decrease, respectively, compared with subjects who did not receive PPIs (N = 8) (Figures 2D-2F). These data indicate that telaglenastat requires low pH conditions for optimal solubilization. Concomitant treatment with proton pump inhibitors (PPIs) results in reduced exposure to telaglenastat. If possible, concomitant administration of telaglenastat with PPIs should be avoided. Example 2: Impact of a Histamine H2 Receptor Antagonist (H2RA) on the Pharmacokinetics of Telaglenastat in Patients
A comparison between subjects dosed with 400 - 800 mg BID telaglenastat in the presence or absence of famotidine, a histamine H2 receptor antagonist, was performed under fed conditions. Results are shown in Figure 3.
The effect of an H2RA treatment on the PK of telaglenastat was estimated in patients during Phase 1 studies by comparing PK in patients who took H2RAs during the treatment to that of patients who did not take any H2.RA (Figure 3). A decrease of 34.3% in the AUC0-8 hr following a single dose of telaglenastat on Day 1 was observed in pahents receiving an H2RA. By the time steady state levels were achieved, there was no effect of H2RAs on exposure.
Patients may be switched to shorter acting agents such as histamine H2 receptor antagonists (H2RA) and as-needed antacid buffering agents (e.g., calcium carbonate, magnesium hydroxide and aluminum hy droxide) since, based on limited clinical data, they do not appear to result in a significant reduction of telaglenastat exposure. It is recommended that telaglenastat be dosed at least 2 hr before antacid therapy.
Incorporation by Reference
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control .
In particular, suitable compounds for practicing the invention, and methods for synthesizing said compounds, are described in U.S. Patent No. 8,604,016, U.S. Patent Application Publication No. 2014/0194421, and U.S. Application Publication Nos. 2015/0004134, 2014/0142081, and 2014/0142146, which are hereby incorporated by reference in their entirety.
Equivalents
While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review' of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

Claims:
1. A method of orally administering a compound of formula I
Figure imgf000046_0001
or a pharmaceutically acceptable salt thereof, wherein: L represents CH2CH2;
X, independently for each occurrence, represents S or CH=CH; each Y represents H;
Z represents R3(CO); R1 and R2 each represent H; and R3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl; to a patient, comprising: determining whether the patient is receiving treatment with a proton pump inhibitor; and, if the patient is receiving treatment with a proton pump inhibitor, instructing the patient to act to increase stomach acidity while ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein acting to increase stomach acidity comprises ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof, with an acidic beverage.
3. The method of claim 1, wherein acting to increase stomach acidity comprises discontinuing treatment with the proton pump inhibitor, e.g., at least 24 hours before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof.
4. The method of claim 3, wherein treatment with the proton pump inhibitor is discontinued 1 to 14 days before commencing oral administration of tire compound of formula 1, or a pharmaceutically acceptable salt thereof.
5. The method of claim 3 or claim 4, wherein acting to increase stomach acidity- further comprises beginning treatment with an H2 blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor.
6. The method of claim 5, wherein the H2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
7. The method of any one of claims 1-6, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
8. A method of ingesting a compound of formula I, or a pharmaceutically acceptable salt thereof, while receiving treatment with a proton pump inhibitor, comprising acting to increase stomach acidity while ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof;
Figure imgf000047_0001
wherein:
L represents CH2CH2;
X, independently for each occurrence, represents S or CH=CH; each Y represents H;
Z represents R3(CO); R1 and R2 each represent H; and
R3, independently for each occurrence, represents substituted or unsubstituted aryialkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl.
9. The method of claim 8, wherein acting to increase stomach acidity comprises ingesting the compound of formula I, or a pharmaceutically acceptable salt thereof, with an acidic beverage.
10. The method of any one of claims 8-9, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
11, A method for improving the effectiveness of a compound of formula I, or a pharmaceutically acceptable salt thereof in a subject receiving treatment with a proton pump inhibitor, comprising discontinuing treatment with the proton pump inhibitor, e.g., at least 2.4 hours before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof;
Figure imgf000048_0001
wherein:
L represents CH2CH2;
X, independently for each occurrence, represents S or CH=CH; each Y represents H;
Z represents R3(CO); R1 and Rr each represent H; and R3, independently for each occurrence, represents substituted or unsubstituted aryialkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl.
12. The method of claim 11 , wherein treatment with the proton pump inhibitor is discontinued 1 to 14 days before commencing oral administration of the compound of formula I, or a pharmaceutically acceptable salt thereof.
13. The method of claim 11 or claim 12, further comprising beginning treatment with an Hr blocker concurrently with or after discontinuing the treatment with the proton pump inhibitor.
14. The method of claim 13, wherein the Hr blocker is nizatidine, famotidine, ranitidine, or cimetidine.
15. The method of any one of claims 11-14, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
16. A method of treating a condition that would benefit from treatment with a proton pump inhibitor in a patient undergoing treatment with a compound of Formula I,
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof, wherein:
L represents CH2CH2;
X, independently tor each occurrence, represents S or CH=CH; each Y represents H; Z represents R3(CO);
Ri and R2 each represent H; and
R3, independently for each occurrence, represents substituted or unsubstituted arylalkyl, cycloalkyl, heterocycloalkyl, or heteroarylalkyl: comprising: determining whether the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor; and, if the patient is suffering from a condition that would benefit from treatment with a proton pump inhibitor, instructing the patient to take an H2 blocker.
17. The method of claim 16, wherein the H2 blocker is nizatidine, famotidine, ranitidine, or cimetidine.
18. The method of claim 16 or 17, wherein the condition is gastroesophageal reflux disease (GERD) or peptic ulcer disease.
19. The method of any one of claims 16-18, further compri sing instracting the patient to avoid taking a proton pump inhibitor.
20. Tire method of claim 19, wherein the proton pump inhibitor is selected from omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.
21. The method of any one of claims 16-20, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
22. The method of any one of the preceding claims, wherein one X represents S and the other X represents
23. The method of any one of the preceding claims, wherein each occurrence of R3 is not identical.
24. The method of any one of the preceding claims, wherein each R3 is independently substituted or unsubstituted arylalkyl or heteroarylalkyl.
25. The method of any one of the preceding claims, wherein the compound of formula I has the structure of formula II,
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof, wherein: R3 represents substituted or unsubstituted arylalkyl or heteroarylalkyl; R11 represents arylalkyl or heteroarylalkyl, wherein the aryl or heteroaryl ring is substituted with either -OCHF2 or --OCF3 and is optionally further substituted.
26. The method of claim 25, wherein R11 represents arylalkyl, wherein the aryl ring is substituted with -OCF3.
27, The method of claim 2.6, wherein R11 represents trifluoromethoxybenzyl.
28. The method of claim 27, wherein R11 represents
Figure imgf000050_0002
29. The method of any one of claims 25-28, wherein R3 represen ts substituted or unsubstituted heteroarylalkyl .
30. Tire method of claim 29, wherein R3 represents substituted or unsubstituted pyridylalkyl.
31 , The method of any one of claims 19-30, wherein Z represents
Figure imgf000051_0001
.
32. The method of any preceding claim, wherein the compound of formula (I) has the structure of the compound of formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000051_0002
33. The method of any one of the preceding claims, for treating cancer, wherein the cancer is selected from acute myeloid leukemia (AML), brain malignancy, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin’s lymphoma, Kaposi’s sarcoma, MALT lymphoma, mantle cell lymphoma (MCL), multiple myeloma (MM), myelodysplastic syndromes (MDS), non- Hodgkin lymphoma (NHL), and Waldenstrom macrogloulinemia (WM).
34. The method of claim 33, wherein the cancer is multiple myeloma.
35. The method of any one of claims 1 to 32, for treating cancer, wherein the cancer is selected from breast cancer (such as breast cancer that comprises basal-type breast cancer cells, triple-negative breast cancer cells or claudin-low breast cancer cells), colorectal cancer, endocrine cancer (such as adrenal cortex adenoma, adrenal cortex carcicnoma, adrenal gland pheochromocytoma, or parathyroid gland adenoma), lung cancer, melanoma, mesothelioma, renal cancer, pancreatic cancer, hepatocellular carcinoma, malignant peripheral nerve sheath tumor, head and neck cancer, gliomas, esophageal cancer, and B cell malignancies (such as multiple myeloma, leukemia, or lymphoma).
36. The method of claim 35, wherein the cancer is lung cancer.
37. The method of claim 36, wherein the lung cancer is squamous cell lung carcinoma.
38. The method of claim 36, wherein the lung cancer is lung adenocarcinoma.
39. The method of claim 36, wherein the lung cancer is lung cancer having a KRAS mutation.
40. The method of claim 36, wherein the lung cancer is lung cancer having a Keapl/Nrf2 pathway mutation,
41 . The method of claim 35, wherein the cancer is colorectal cancer.
42. The method of claim 35, wherein the cancer is endocrine cancer.
43. The method of claim 36, wherein the endocrine cancer is selected from adrenal cortex adenoma, adrenal cortex carcicnoma, adrenal gland pheochromocytoma, and parathyroid gland adenoma,
44. The method of claim 35, wherein the cancer is melanoma.
45. The method of claim 35, wherein the cancer is renal cancer.
46. The method of claim 35, wherein the cancer is a B cell malignancy.
47. The method of claim 46, wherein the B cell malignancy is selected from multiple myeloma, leukemia, and lymphoma.
48. The method of claim 46, wherein the B cell malignancy is multiple myeloma.
49. The method of claim 46, wherein the B cell malignancy is leukemia.
50. The method of claim 49, wherein the leukemia is selected from acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.
51 . The method of claim 47, wherein the B cell malignancy is lymphoma.
52. The method of claim 51, wherein the lymphoma is selected from Burkitt’s lymphoma. Diffuse large B cell lymphoma, follicular lymphoma, and Hodgkin’s lymphoma.
53. The method of any one of claims 1 to 32, tor treating a myeloproliferative disease, wherein the myeloproliferative disease is selected from chronic eosinophilic leukemia, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, and myelofibrosis.
54. The method of any one of claims 1 to 32, tor treating or preven ting an immune- related disease, wherein the immune-related disease is selected from inflammatory bowel disease, sepsis, multiple sclerosis, diabetes, ankylosing spondylitis, Crohn's disease, erythema nodosum leprosum (ENL), graft versus host disease (GVHD), HIV -associated wasting syndrome, lupus erythematosus, post-polycythemia, psoriasis, psoriatic arthritis, recurrent aphthous ulcers, rheumatoid arthritis (RA), severe recurrent aphthous stomatitis, and systemic sclerosis.
55. The method of any one of the preceding claims, wherein the compound is the compound of formula III and 300 mg to 3000 mg of the compound is administered per day.
56. The method of claim 55, wherein 600 mg to 2400 mg of the compound is administered per day.
57. The method of claim 56, wherein 1000 mg to 2000 mg of the compound is administered per day.
58. The method of claim 57, wherein 1200 mg or 1800 mg of the compound is administered per day.
59. The method of any one of claims 1 to 55, wherein an aggregate dose equivalent to between 300 mg and 3000 mg of the compound of formula III is administered per day.
60. The method of claim 59, wherein an aggregate dose equivalent to between 600 mg to 2400 mg of the compound of formula III is administered per day.
61. The method of claim 60, wherein an aggregate dose equivalent to between 1000 rng to 2000 mg of the compound of formula III is administered per day.
62, The method of claim 61 , wherein an aggregate dose equivalent to 1200 mg or 1800 mg of the compound of formula III is administered per day.
63. The method of claim 62, wherein a dose equivalent to 600 nig of the compound of formula III is administered twice a day.
64. The method of claim 62, wherein a dose equivalent to 600 mg of the compound of formula III is administered three times a day.
65. The method of claim 61, wherein an aggregate dose equivalent to 1600 mg of the compound of formula III is administered per day.
66. The method of claim 65, wherein a dose equivalent to 800 mg of the compound of formula III is administered twice a day.
67. The method of any one of the preceding claims, wherein the compound is administered two times per day.
68. The method of any one of claims 1 to 59, wherein the compound is administered three times per day.
69. The method of any preceding claim, wherein compound is administered to a human.
PCT/US2021/048877 2020-09-04 2021-09-02 Methods of administering glutaminase inhibitors WO2022051503A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063074687P 2020-09-04 2020-09-04
US63/074,687 2020-09-04

Publications (1)

Publication Number Publication Date
WO2022051503A1 true WO2022051503A1 (en) 2022-03-10

Family

ID=80491546

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/048877 WO2022051503A1 (en) 2020-09-04 2021-09-02 Methods of administering glutaminase inhibitors

Country Status (1)

Country Link
WO (1) WO2022051503A1 (en)

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "A Study of Telaglenastat (CB-839) in Combination With Palbociclib in Patients With Solid Tumors", CLINICALTRIALS.GOV IDENTIFIER: NCT03965845, 29 May 2019 (2019-05-29), pages 1 - 10, XP055914514 *
ANONYMOUS: "CB-839 With Cabozantinib vs. Cabozantinib With Placebo in Patients With Metastatic Renal Cell Carcinoma (CANTATA", CLINICALTRIALS.GOV IDENTIFIER: NCT03428217, 9 February 2018 (2018-02-09), pages 1 - 7, XP055914524 *
ANONYMOUS: "U. S. National Library of Medicine . A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC (KEAPSAKE", CLINICALTRIALS.GOV IDENTIFIER: NCT04265534, 11 February 2020 (2020-02-11), pages 1 - 12, XP055914509 *
HUANG JIA-QING, HUNT RICHARD H.: "Pharmacological and pharmacodynamic essentials of H2-receptor antagonists and proton pump inhibitors for the practising physician . Best practice & research", BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY, vol. 15, no. 3, 1 June 2001 (2001-06-01), pages 355 - 370, XP055914536, Retrieved from the Internet <URL:http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.550.4027&rep=repl&type=pdf> *
KATZ PO ET AL.: "Gastric acidity and acid breakthrough with twice-daily omeprazole or lansoprazole", ALIMENTARY PHARMACOLOGY & THERAPEUTICS, vol. 14, no. 6, 1 June 2000 (2000-06-01), pages 709 - 714, XP055914532 *
TABE YOKO, LORENZI PHILIP L., KONOPLEVA MARINA: "Amino acid metabolism in hematologic malignancies and the era of targeted therapy", BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY, vol. 134, no. 13, 26 September 2019 (2019-09-26), pages 1014 - 23, XP055914534, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S000649712070786X> *

Similar Documents

Publication Publication Date Title
EP3277276B1 (en) Methods of administering glutaminase inhibitors
AU2002210993B2 (en) Medicinal compositions for concominant use as anticancer agents
CN111225911B (en) Compounds and compositions for treating hematological disorders
KR20170012562A (en) Combination therapy with glutaminase inhibitors
JPWO2006088193A1 (en) Antitumor agent
BRPI0616202A2 (en) Dosage forms and use of a tyrosine kinase inhibitor
CN115297862A (en) Triple pharmaceutical combination comprising dabrafenib, an ERK inhibitor and an SHP2 inhibitor
US20070203153A1 (en) Compositions and methods for treating thrombocytopenia
KR20190040302A (en) Combination therapy with glutaminase inhibitor
TW201006823A (en) Use of pyrimidylaminobenzamide derivatives for the treatment of fibrosis
US20240277722A1 (en) Cancer therapy using a combination of cdk7 inhibitor with an anti-cancer agent
EP3429582A1 (en) Combination therapy for proliferative diseases
WO2022084930A2 (en) Cancer therapy using a combination of cdk7 inhibitor with an anti-microtubule agent
WO2022051503A1 (en) Methods of administering glutaminase inhibitors
MX2008001971A (en) Combination of organic compounds.
WO2023244639A1 (en) Methods of predicting cns cancer response to treatment with egfr inhibitors
KR20160038895A (en) Agent for alleviating side effects in cancer chemotherapy
KR102714321B1 (en) Anticancer composition comprising cancer metabolism regulator
JP7565132B2 (en) Medicines for the treatment or prevention of cancer
JP4362457B2 (en) Neuropathic pain treatment
JP4227121B2 (en) Neuropathic pain treatment
WO2023224961A1 (en) Cancer therapy using a combination of a cdk7 inhibitor with an oral serd
JP2007063205A (en) Therapeutic agent for neuropathic pain
WO2006085686A1 (en) Remedy for neurogenic pain

Legal Events

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

Ref document number: 21865115

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21865115

Country of ref document: EP

Kind code of ref document: A1