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WO2025019622A2 - Procédé d'absorption améliorée d'inhibiteurs du récepteur tyrosine-kinase de type iii de quinoxaline - Google Patents

Procédé d'absorption améliorée d'inhibiteurs du récepteur tyrosine-kinase de type iii de quinoxaline Download PDF

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Publication number
WO2025019622A2
WO2025019622A2 PCT/US2024/038448 US2024038448W WO2025019622A2 WO 2025019622 A2 WO2025019622 A2 WO 2025019622A2 US 2024038448 W US2024038448 W US 2024038448W WO 2025019622 A2 WO2025019622 A2 WO 2025019622A2
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methoxy
carbonitrile
amino
quinoxaline
phenyl
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WO2025019622A3 (fr
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Hung-Kai Chen
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Elixiron Immunotherapeutics Inc
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Elixiron Immunotherapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to a method to deliver quinoxaline compounds which can function as type III receptor tyrosine kinase inhibitors into animals and/or human.
  • Receptor tyrosine kinases are a sub-family of protein kinases Type Ill RTKs, including Colony-stimulating factor- 1 receptor (CSF-1R), Platelet-derived growth factor receptor a (PDGFRa), PDGFR[3, Fms-like tyrosine kinase 3 (FLT3) and c-KIT, are implicated in various proliferative, inflammatory, and autoimmune diseases. Small molecule inhibitors of type III RTKs provide a rational approach to treatments of these diseases.
  • CSF-1R Colony-stimulating factor- 1 receptor
  • PDGFRa Platelet-derived growth factor receptor a
  • FLT3 Fms-like tyrosine kinase 3
  • c-KIT c-KIT
  • CSF-1R also known as macrophage colony-stimulating factor receptor (M-CSFR)
  • M-CSFR macrophage colony-stimulating factor receptor
  • Binding of M- CSF to its receptor activates signal transduction pathways, including PI3K/Akt and MAPK pathways, resulting in proliferation, survival, motility, and differentiation of cells of the monocyte/macrophage lineage, include the microglia. Elevated expression or activation of CSF-IR and/or its ligand have been found in a variety of cancers and elevated levels of M-CSF is associated with poor prognosis in certain cancers.
  • M-CSF is one of several cytokines implicated in the recruitment of tumor-associated macrophages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis.
  • TAMs tumor-associated macrophages
  • Activation of CSF-IR also leads to proliferation and differentiation of osteoclast precursors, thereby mediating the process of bone resorption.
  • Inhibition of CSF-IR therefore provides treatments of cancers, especially cancer invasion, angiogenesis, metastasis, immunotolerance, and bone metastases. Because of its role in osteoclast biology, CSF-IR is also an important therapeutic target for osteoporosis, inflammatory arthritis, and other inflammatory bone erosion.
  • Receptor tyrosine kinase of the Platelet growth factor receptor (PDGFR) kinases are implicated in various proliferative disorders, such as gliomas, sarcomas, chronic myelo- monocytic leukemia (CML), and gastrointestinal, making them potential targets for anti-tumor therapy.
  • PDGFR Platelet growth factor receptor
  • FLT3 plays an important role in the proliferation and differentiation of hematopoietic stem cells. More than a dozen FLT3 inhibitors are being developed, some of which have shown promising clinical effects against acute myeloid leukemia (AML). FLT3 receptor is also expressed in dendritic cell progenitors and inhibition of FLT3 down-regulates dendritic cell (DC)-mediated inflammatory and autoimmune responses.
  • DC dendritic cell
  • c-KIT stem cell growth factor receptor (SCFR)
  • SCFR stem cell growth factor receptor
  • the present invention relates to methods of delivery of quinoxaline compounds as activity inhibitors of kinases, such as CSF-IR, PDGFR, FLT-3 and/or c-KIT, into animals and/or human for treating diseases mediated by such kinases, such as cancers, autoimmune diseases, bone resorptive diseases, and neurodegenerative diseases.
  • kinases such as CSF-IR, PDGFR, FLT-3 and/or c-KIT
  • the present invention provides a method of improving pharmacokinetics of a compound of formula (I), including administering a medicament including the compound of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof to a subject in need thereof in a non-fasting state,
  • the compound of formula (I) is administered orally.
  • the improving pharmacokinetics includes increasing the maximum plasma concentration (Cmax) and/or bioavailability (AUC).
  • the medicament further includes a carrier, diluent or excipient.
  • the excipient includes a surfactant, a binder, a disintegrant and/or a lubricant.
  • Efficient delivery of drug compounds into the animal and/or the human body is critical to the therapeutic applications of the compounds. The better the delivery, the more therapeutic effects are expected from the drug compounds in the therapeutic treatments for the targeted diseases.
  • Embodiments of the invention are based on unexpected findings that delivery of said quinoxaline compounds that have low solubility in water but have high solubility in acidic buffers can be delivered more efficiently into biological bodies after/with food ingestion.
  • FIG. 1 illustrates pH changes in stomach before/after a meal in the prior art.
  • FIG. 2 illustrates DCBCO1701-DS concentrations time course in blood samples of study 2 in accordance with an embodiment of the present invention.
  • FIGs. 3 A and 3B illustrate pharmacokinetics of EI-1071 tablet in Beagle dogs about Cmax and AUC, respectively, in accordance with an embodiment of the present invention.
  • non-fasting or “postprandial” as used herein means that the animals, such as dogs, receive a nutritionally balanced daily ration during the pre-test period and the whole test period.
  • AUC means “Area Under the Curve” and is used in its normal meaning, i.e. as the area under the plasma concentration-time curve from 0 to 24 hours, where the dosage form has been administered orally to animals, such as rats and dogs (beagle), under fasting or non-fasting conditions in the embodiments.
  • the AUC has units of concentration times time. Once the experimental concentration-time points have been determined, the AUC may conveniently be calculated, e.g., by a computer program or by the trapezoidal method.
  • improved pharmacokinetics refers to improved Cmax (the maximum plasma level), T ina x (time to maximum plasma level), AUC or plasma half-life of the drug, or improved level of the drug in blood, liver or another tissue.
  • the amount of the compound of formula (I) in the tablet is sufficient to boost the in vivo pharmacokinetics of the co-formulated drug(s).
  • alkyl refers to a straight or branched monovalent saturated hydrocarbon containing, unless otherwise stated, 1-20 carbon atoms.
  • the numerical ranges in this description are intended to include any number(s) in the defined range, as if the individual numbers have been separately disclosed.
  • an alkyl group of 1-20 carbons would include Ci, C2, ...C20, as well as C1-C20, C1-C15, C1-C10, C 1 -C 6 , C1-C4, etc.
  • alkyl include methyl, ethyl, n-propyl, z-propyl, zz-butyl, z-butyl, and /-butyl.
  • alkenyl refers to a straight or branched monovalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more double bonds. Examples of alkenyl include ethenyl, propenyl, allyl, and 1 ,4-butadienyl.
  • alkynyl refers to a straight or branched monovalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more triple bonds.
  • alkynyl include ethynyl, 1 -propynyl, 1 - and 2-butynyl, and l-methyl-2-butynyl.
  • alkoxy refers to an -O-alkyl radical, wherein the alkyl portion is as defined above.
  • alkoxy include methoxy, ethoxy, n-propoxy, z-propoxy, z?-butoxy, i- butoxy, x-butoxy, and /-butoxy.
  • acyloxy refers to an -O-C(O)-R radical in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl as defined herein.
  • amino refers to NH2.
  • alkylamino refers to an -N(R)-alkyl radical, in which “alkyl” is as defined above and R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
  • cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C6 or C3-C12).
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantanyl.
  • cycloalkenyl refers to a monovalent non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C 3 C 6 or C3-C12) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • heterocycloalkyl refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • heterocycloalkyl groups include piperazinyl, pyrrolidinyl, piperidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.
  • heterocycloalkenyl refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds.
  • aryl refers to a monovalent 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system. Examples of aryl groups include phenyl, naphthyl, and anthracenyl.
  • aryloxyl refers to an -O-aryl, wherein “aryl” is as defined above.
  • arylamino refers to an -N(R)-aryl, wherein “aryl” is as defined above and R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
  • heteroaryl refers to a monovalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, pyrrolyl, isoquinolinyl, purinyl, oxazolyl, pyrazolyl, and carbazolyl.
  • aryl portion is as defined above.
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, amino, alkylamino, arylamino, alkoxy, aryloxy, aryl, and heteroaryl may be substituted or unsubstituted moieties.
  • alkyl, alkenyl, or alkynyl include all of the above-recited substituents except C1-C10 alkyl.
  • Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other.
  • Embodiments of the invention relate to a method of improving pharmacokinetics of a compound of formula (T), comprising administering a medicament comprising the compound of formula (I) to a subject in need thereof in a non-fasting state, wherein the compound of formula (I) has a structure of:
  • X is selected from the group consisting of CR 4 R 5 , NR 6 , O and S; Z is selected from the group consisting of -NR 7 - and-O-;
  • U is N or CR 8 ;
  • G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycle, alkene and alkyne;
  • R 1 selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, Ci- Ce alkylamino, C 1 -C 6 dialkylamino, C3-C6 cycloalkylamino, C 1 -C 6 alkoxy, C3-C6 cycloalkoxy, aryl, a 3-to-6 membered heterocyclyl, and a 5-to-6 membered heteroaryl, wherein the alkylamino, dialkylamino, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylamino, cycloalkoxy, heterocyclyl, aryl and heteroaryl are optionally substituted with halogen, amino,
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxy, carboxylic acid, C 1 -C 6 alkyl carbonyl, C2-C6 alkenyl carbonyl, C 1 -C 6 alkoxy carbonyl, amino carbonyl, C 1 -C 6 alkylamino carbonyl and C 1 -C 6 dialkylamino carbonyl;
  • R 3 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, Ci-G> alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino and C 1 -C 6 dialkylamino;
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and aryl;
  • R s is selected from the group consisting of hydrogen, deuterium, Ci-G, alkyl and C 1 -C 6 haloalkyl;
  • R 6 is selected from the group consisting of hydrogen, Ci-G> alkyl and Ci-G> haloalkyl
  • R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl
  • R 8 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, trifluoromethyl, G-Galkyl, C1-C6 alkoxy, C1-C6 alkylamino and C1-C6 dialkylamino.
  • G in a compound of Formula 1 may be selected from: wherein
  • R 9 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylaminoC1-C6 alkyl, C1-C6 dialkylaminoC1-C6 alkyl, C1-C6 alkylamino, C1-C6- alkoxy C1-C6 alkyl, C1-C6 dialkylamino, C1-C6alkoxy, carboxylic acid, carbonyl C1-C6 alkoxy, carbonyl C1-C6 alkylamino, and carbonyl C1-C6 dialkylamino;
  • R 10 is selected from the group consisting of hydrogen, G-G> alkyl and G-G, haloalkyl; and each n is individually and independently 0, 1, 2, or 3.
  • G in a compound of Formula 1 may be selected from:
  • R 11 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci- Ce alkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, carboxylic acid, carbonyl C 1 -C 6 alkoxy, carbonyl C 1 -C 6 alkylamino and carbonyl C 1 -C 6 dialkylamino;
  • R 12 is selected from the group consisting of hydrogen, C -Ce alkyl and Ci -G> haloalkyl; and each n is individually and independently 0, 1, 2, or 3.
  • G in a compound of Formula 1 may be selected from: wherein
  • R 13 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxy, carboxylic acid, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylaminocarbonyl and C 1 -C 6 dialkylaminocarbonyl; and each n is individually and independently 0, 1, 2, or 3.
  • G in a compound of Formula 1 may be selected from: wherein
  • R 14 is selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, Ci-G, dialkylamino, C 1 -C 6 alkoxy, carboxylic acid, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylaminocarbonyl and C 1 -C 6 dialkylaminocarbonyl;
  • Q is selected from NR 15 , O, and S, wherein R 15 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; and each n is individually and independently 0, 1, 2, or 3.
  • G in a compound of Formula 1 may be selected from: wherein R 16 is selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, Ci-
  • a protein tyrosine kinase such as CSF-1R, PDGFR, FLT-3 and/or c-KIT.
  • the compound of formula (I) described above is administered orally.
  • the medicament is in a form of tablet with 150 mg of the compound of formula (I).
  • the compound of formula (i) shows a dose-adjusted AUC of the compound of formula (I) plasma concentration in dogs, under non-fasting conditions, of at least 170 kg*ng*hr/mL/mg.
  • the compound of formula (I) shows a dose-adjusted Cmax in dogs, under non-fasting conditions, of at least 20 kg*ng/mL/mg.
  • the improving pharmacokinetics includes increasing the maximum plasma concentration (Cmax) and/or bioavailahility (AUC).
  • the medicament further includes a carrier, diluent or excipient.
  • the excipient may include a surfactant, a binder, a disintegrant and/or a lubricant.
  • the surfactant includes but are not limited to: betain, quaternary ammonium salts, polysorbates, sorbitan erters, a poloxamer and povidone® K-90. In one embodiment, the surfactant is povidone K-90.
  • the binder includes but are not limited to: starches, e.g., potato, wheat or corn starch; microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hypromellose, and polyvinylpyrrolidone (e.g., Povidone® K- 90).
  • polyvinylpyrrolidone e.g., Povidone® K- 90.
  • polyvinylpyrrolidone is used, preferably Povidone® K-90.
  • the disintegrant includes but are not limited to: maize starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, and sodium starch glycolate e.g., sodium starch glycolate type A).
  • PVP polyvinylpyrrolidone
  • alginic acid sodium alginate
  • sodium starch glycolate e.g., sodium starch glycolate type A
  • sodium starch glycolate e.g., sodium starch glycolate type A is used.
  • the lubricant includes but are not limited to: magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, behenate glyceryl esters, hydrogenated vegetable oils.
  • magnesium stearate is used.
  • the compound of formula (I) is formed as amorphous solid dispersions (ASDs) with but are not limited to: povidone®, polymethaacrylate derivatives, hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate derivatives.
  • ASDs amorphous solid dispersions
  • HPMC hydroxypropyl methyl cellulose
  • HPMC hydroxypropyl methylcellulose acetate succinate derivatives.
  • the compound of formula (I) is formed as ASDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS) (named as “DCBCO1701-SP01” hereinafter).
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • the compound of formula (I) is used to manufacture a medicament tablet with HPMCAS, povidone K-90, sodium starch glycolate type A and/or magnesium stearate (named as “El- 1071 tablet” hereinafter).
  • Certain drugs that exhibit higher solubility in low pH environments may experience reduced maximum concentration (Cmax) and area under the curve (AUC) following a meal. This phenomenon occurs because, under fasted conditions, the stomach environment in healthy individuals typically is around pH 1. However, after food consumption, gastric pH transiently increases a higher pH ranging from pH 4.5 to pH 4.98, and remaining elevated for up to 4.5 hours. As illustrated in FIG. 1 [1] , the pH changes in stomach before and after a meal is illustrated. At baseline, median gastric pH was about pH 1, increased to pH 4.5 or higher with ingestion of a meal, and then returned to approximately pH 1 about 3-4 hours after the start of the meal.
  • Cmax maximum concentration
  • AUC area under the curve
  • solubility of drugs with higher solubility in acidic environment may decrease if they are administered post-food consumption, therefore leading to reduced absorption of the drugs.
  • concomitant oral drug administration after food ingestion can severely impact systemic bioavailability due to changes in gastrointestinal physiology, which affect the drug’s transit time, luminal dissolution, and permeability.
  • Repaglinide it exhibits higher solubility under low pH conditions. When administered with food, the mean T max remains unchanged, while the mean Cmax and AUC decrease by 20% and 12.4%, respectively.
  • Telmisartan it exhibits higher solubility under low pH conditions. When administered in a non- fasted state, both mean Cmax and AUC decrease.
  • the compound of formula (I) is administered to the subject in need in the non-fasting state.
  • Non-fasting state or fed state
  • active agents are administered together with or after food intake, e.g., a meal, such as breakfast, lunch and/or dinner, more particularly together with or after breakfast and/or dinner.
  • the compound of formula (I) (and optionally an orally available) is administered within 5 hours, more particularly within 4 hours, even more particularly within 3 hours, yet even more particularly within 2.5 hours, yet even more particularly within 2 hours, yet even more particularly within 60 minutes, yet even more particularly within 30 minutes after food intake, particularly a meal, more particularly a light meal, in particular a light breakfast and/or dinner.
  • a recommendation by the physician for a light meal could be a small to medium portion of 1 or 2 of the following: fruit, yogurt, cereal, toast, croissant, bread, cold meat, cheese, or salad, with coffee, tea, juice, or milk or similar amounts of food, which typically amounts to around 150-300 kcal, while however the numbers and amounts may vary to some extent in the actual treatment setting, taking into account that the patients are typically treated ambulatory and thus for the most part determine their diet themselves.
  • the first administration may be within the time frames in relation to a breakfast or light breakfast as detailed above and particularly within 30 minutes after said breakfast or light breakfast; and the second administration may be within the time frames in relation to a dinner or light dinner as detailed above and particularly within 30 minutes after said dinner or light dinner.
  • food intake, meal, etc. logically refer to food intake, meal, etc. of the patient receiving the administration of the aforementioned agents.
  • a yellow powder contains DCBCO1701-DS, 20-40% w/w, and hydroxypropyl methylcellulose acetate succinate (HPMCAS), 60-80% w/w.
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • Each EI-1071 tablet contains DCBCO1701-SP01 (60-70% w/w), povidone K-90 (4-8% w/w), sodium starch glycolate type A (25-30% w/w), and magnesium stearate (0.2-1% w/w).
  • DCBCO1701-DS As shown in Table 2, the solubility of DCBCO1701-DS was determined in pure water and buffers of various pH conditions: pH 1.2, pH 4.0, pH 6.8, and pH 7.4. DCBCO1701-DS is barely soluble in pure water and was determined as ⁇ 1 pg/mL. However, the solubility thereof was measured 493.33 ⁇ 125.70 pg /mL in pH 1.2 buffer and dropped significantly to become barely detectable 1.86 ⁇ 0.1 1 pg/mL in pH 4.0 and ⁇ 1 pg/mL in pH 6.8 and pH 7.4. The solubility is significantly higher in an acidic buffer of pH 1.2.
  • DCBCO1701-SP01 As shown in Table 3, the solubility of DCBCO1701-SP01 was determined in pure water and buffers of various pH conditions: pH 1.2, pH 4.0, and pH 6.8. Solubility of DCBC01701-SP01 was barely soluble in pure water and was determined as 4.38 + 0.05 pg/mL. The solubility of DCBCO1701-SP01 was measured 441.46 + 76.06 pg /mL in pH 1.2, which was similar to that of DCBCO1701-DS in pH 1.2.
  • solubility dropped significantly to barely detectable levels of 2.08 ⁇ 0.70 pg/mL in pH 4.5 and 7.52 ⁇ 2.08 pg/mL in pH 6.8, which was similar to that of pure water and was also similar to that of DCBCO1701-DS in similar pH conditions.
  • HPMCAS-based ASDs have become well established in commercially available products and are widely utilized as a solubility enhancer to improve the solubility of poorly soluble drugs or as a precipitation inhibitor or stabilizer to achieve supersaturation and inhibit crystallization of drugs in the gastrointestinal tract.
  • solubility enhancer to improve the solubility of poorly soluble drugs or as a precipitation inhibitor or stabilizer to achieve supersaturation and inhibit crystallization of drugs in the gastrointestinal tract.
  • the solubility of DCBCO1701-DS in pure water and in various pH conditions is not significantly affected by other ingredients, HPMCAS, in DCBC01701-SP01.
  • PK Pharmacokinetics
  • DCBCO1701-DS and DCBCO1701-SP01, of which each was suspended in 0.5% methylcellulose (0.5% MC) and was administered orally, also often mentioned as per os (PO), to rats which had been fasted for at least 10 hours, at a dose level, or at an equivalent dose level in case of DCBCO1701-SP01, of 10 mg/kg of DCBCO1701-DS once via jugular gavage.
  • Blood samples were collected selected time points post dosing: pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 hours.
  • the concentration of DCBCO1701-DS in each blood sample was determined by liquid chromatography-tandem spectrometry (LC-MS/MS). Parameters of PK, including Cmax and AUC were calculated as illustrated in Table 4.
  • AUC(o-oo) area under the concentration-time curve from time 0 to the last measurable concentration
  • DCBCO1701 is highly soluble in low pH but barely soluble in other pH conditions, it may, like other drugs with similar physical properties, experience reduced Cmax and AUC following a meal.
  • two PK studies, study 2 and study 3 were conducted in Beagle dogs. The results are summarized in Table 5 (study 2) and Tables 6 and 7 (study 3) below.
  • All AUC data herein were dose adjusted to the 1 mg dose level. For the purposes herein, the AUC is determined within a dose range where the AUC increases proportionally with dose.
  • AUC Area under the concentration-time curve
  • the present invention provides unexpected findings that delivery of the quinoxaline compounds in the present invention that have low solubility in water but have high solubility in acidic buffers can be delivered more efficiently into biological bodies after/with food ingestion to improve the treatment of diseases mediated by such kinases, such as cancers, autoimmune diseases, bone resorptive diseases, and neurodegenerative diseases.
  • diseases mediated by such kinases such as cancers, autoimmune diseases, bone resorptive diseases, and neurodegenerative diseases.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé d'amélioration de la pharmacocinétique d'un composé de formule (I), consistant à administrer un médicament comprenant le composé de formule (I) à un sujet en ayant besoin dans un état non à jeun, le composé de formule (I) présentant une structure de formule (I) ou un stéréoisomère, un tautomère, un promédicament ou un sel pharmaceutiquement acceptable correspondant. Le composé de formule (I) peut être utilisé dans les traitements de maladies ou d'affections médiées par des kinases CSF-1R, PDGFR, FLT3 ou c-KIT. De telles maladies ou affections peuvent comprendre des cancers, des maladies auto-immunes et des maladies de résorption osseuse.
PCT/US2024/038448 2023-07-18 2024-07-18 Procédé d'absorption améliorée d'inhibiteurs du récepteur tyrosine-kinase de type iii de quinoxaline Pending WO2025019622A2 (fr)

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US202363514214P 2023-07-18 2023-07-18
US63/514,214 2023-07-18

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WO2025019622A2 true WO2025019622A2 (fr) 2025-01-23
WO2025019622A3 WO2025019622A3 (fr) 2025-03-27

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PCT/US2024/038448 Pending WO2025019622A2 (fr) 2023-07-18 2024-07-18 Procédé d'absorption améliorée d'inhibiteurs du récepteur tyrosine-kinase de type iii de quinoxaline

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101257158B1 (ko) * 2008-05-23 2013-04-23 노파르티스 아게 단백질 티로신 키나제 억제제로서의 퀴놀린 및 퀴녹살린의 유도체
GB201118654D0 (en) * 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
EP3523285A4 (fr) * 2016-10-10 2020-04-22 Development Center for Biotechnology Composés de quinoxaline en tant qu'inhibiteurs de tyrosine kinase du récepteur de type iii

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