WO2023202651A1 - Formes polymorphes d'un antagoniste de la glutamine et leurs utilisations - Google Patents

Formes polymorphes d'un antagoniste de la glutamine et leurs utilisations Download PDF

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WO2023202651A1
WO2023202651A1 PCT/CN2023/089396 CN2023089396W WO2023202651A1 WO 2023202651 A1 WO2023202651 A1 WO 2023202651A1 CN 2023089396 W CN2023089396 W CN 2023089396W WO 2023202651 A1 WO2023202651 A1 WO 2023202651A1
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polymorph form
cancer
solvent
pharmaceutical composition
heptane
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PCT/CN2023/089396
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English (en)
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Runze LI
Wei LONG
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Jacobio Pharmaceuticals Co., Ltd.
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Publication of WO2023202651A1 publication Critical patent/WO2023202651A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C245/18—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to new polymorphic forms of the Glutamine antagonist, processes for preparing these new polymorphic forms, pharmaceutical compositions thereof, and use of new polymorphic forms and pharmaceutical compositions for the treatment of a Glutamine mediated disease, such as various cancers.
  • Glutamine antagonist such as 6-diazo-5-oxo-L-norleucine (DON) have been shown to exhibit anti-cancer activities.
  • severe toxicity e.g., dose limiting GI toxicities, such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain
  • dose limiting GI toxicities such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain
  • Many pharmaceutically active organic compounds can crystallize in more than one type of three-dimensional crystal structure. That is, the compounds may crystallize in different crystalline forms. This phenomenon (identical chemical structure but different crystalline structure) is referred to as polymorphism, and the species having different molecular structures are referred to as polymorphs.
  • Polymorphs of a particular organic pharmaceutical compound may have different physical properties, such as solubility, stability, and hygroscopicity due to their distinct three-dimensional crystal structures. However, it is generally not possible to predict whether a particular organic compound will form different crystalline forms, let alone predict the structure and properties of the crystalline forms themselves.
  • the discovery of a new crystalline or polymorph form of a pharmaceutically useful compound may provide a new opportunity for improving the overall characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing. It may be advantageous when this repertoire is enlarged by the discovery of new polymorphs of a useful compound.
  • the presently disclosed invention is directed to the compound of Formula I, named isopropyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate, approximately pure polymorph forms thereof, and pharmaceutical acceptable salts thereof.
  • the polymorph forms have great solubility, chemical stability, and making them preferable for application.
  • the compound of Formula I of the present invention exists in one or more polymorph forms.
  • the polymorph form is selected from the group consisting of polymorph form I and polymorph form II.
  • the compound of Formula I may be anhydrous, or may contain varying amounts of water or one or more solvents.
  • Each polymorph form may be characterized by analytical method well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to X-ray powder diffraction (XRPD) , differential scanning calorimetry analysis (DSC) , thermogravimetric analysis (TGA) , dynamic vapor sorption (DVS) , fourier transform infrared spectrometer (FT-IR) , and high performance liquid chromatography (HPLC) .
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry analysis
  • TGA thermogravimetric analysis
  • DVS dynamic vapor sorption
  • FT-IR fourier transform infrared spectrometer
  • HPLC high performance liquid chromatography
  • the present invention provides polymorph form I of the compound of Formula I.
  • polymorph form I is anhydrous.
  • polymorph form I when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of at least one of 9.5° ⁇ 0.2°, 12.9° ⁇ 0.2° and 25.9° ⁇ 0.2°.
  • polymorph form I when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 9.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, 15.8° ⁇ 0.2°, 17.3° ⁇ 0.2° and 25.9° ⁇ 0.2°.
  • polymorph form I when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 4.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.9° ⁇ 0.2°, 15.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.4° ⁇ 0.2°, 24.7° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
  • polymorph form I when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 4.8° ⁇ 0.2°, 9.5° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 12.9° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.9° ⁇ 0.2°, and 28.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of polymorph form I is substantially shown as in Figure 1.
  • the polymorph form I exhibits an endothermic peak with a peak temperature of about 63°C ⁇ 2°C as measured by differential scanning calorimetry (DSC) .
  • DSC differential scanning calorimetry
  • the DSC analysis spectrum of the polymorph form I has a characteristic absorption peak at 62.8°C.
  • the DSC analysis spectrum of the polymorph form I is substantially characterized as in Figure 2.
  • the hygroscopicity of polymorph form I is ⁇ 0.5%, more preferably ⁇ 0.3%, most preferably ⁇ 0.2%.
  • polymorph form I was characterized by showing a weight gain of at most 0.13 weight-%based on the weight of the crystalline form, as determined by dynamic vapor sorption (DVS) in the range of from 0 to 80%relative humidity at a temperature of (25.0 ⁇ 0.2) °C.
  • DFS dynamic vapor sorption
  • the polymorph form I is no hygroscopicity.
  • the present invention provides polymorph form II of the compound of Formula I.
  • polymorph form II is anhydrous.
  • polymorph form II when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 9.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 13.8° ⁇ 0.2°.
  • polymorph form II when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 9.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 18.3° ⁇ 0.2° and 21.0° ⁇ 0.2°.
  • polymorph form II when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 9.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 18.3° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.3° ⁇ 0.2°and 22.9° ⁇ 0.2°.
  • polymorph form II when characterized by X-ray powder diffraction, has an X-Ray diffraction pattern with peaks at diffraction angles 2 ⁇ of 9.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.9° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.3° ⁇ 0.2° and 27.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of polymorph form II is substantially shown as in Figure 3.
  • the polymorph form II exhibits an endothermic peak with a peak temperature of 61°C ⁇ 2°C as measured by differential scanning calorimetry (DSC) .
  • DSC differential scanning calorimetry
  • the DSC analysis spectrum of the polymorph form II has a characteristic absorption peak at 61.28°C.
  • the DSC analysis spectrum of the polymorph form II is substantially characterized as in Figure 4.
  • the hygroscopicity of polymorph form II is ⁇ 0.3%, more preferably ⁇ 0.2%, most preferably ⁇ 0.1%.
  • polymorph form I was characterized by showing a weight gain of at most 0.10 weight-%based on the weight of the crystalline form, as determined by dynamic vapor sorption (DVS) in the range of from 0 to 80%relative humidity at a temperature of (25.0 ⁇ 0.2) °C.
  • DFS dynamic vapor sorption
  • the polymorph form II is no hygroscopicity.
  • Polymorph Form I or II disclosed herein can have a purity of ⁇ 85%, ⁇ 95%, ⁇ 99%, or even ⁇ 99.5%.
  • the polymorph Form I and the polymorphs Form II described herein exhibits advantageous stability.
  • the polymorph Form I and Form II are therefore advantageous during the process of preparation, transportation, storage and preservation.
  • the invention provides a process for the preparation of the compound of formula I, as follows:
  • the present invention provides processes for preparing a polymorph form of the compound of Formula I according to the above aspect of the invention is provided.
  • the process for preparing a polymorph form of the compound of Formula I comprises at least one step choose from evaporation crystallization, slurry crystallization, cooling crystallization, anti-solvent crystallization, reverse anti-solvent crystallization, or vapor diffusion.
  • Polymorph form I of the compound of Formula I is prepared as follows:
  • the compound of Formula I was dissolved in a solvent.
  • the solution was filtered and the filtrate was evaporated at RT to obtain the polymorph form I.
  • the solvent is isopropyl ether or 1, 4-Dioxane/acetone; or
  • the compound of Formula I was added in a corresponding solvent to obtain a suspension.
  • the suspension was stirred for 3 days and then centrifuged.
  • the obtained solid was dried overnight under vacuum at RT to obtain the polymorph form I.
  • the solvent is selected from n-Heptane, n-Hexane, cyclohexane, methylcyclohexane, or isooctane.
  • the solvent is selected from n-Heptane/ethyl acetate, n-Heptane/isopropanol, methylcyclohexane/butanone, methylcyclohexane/iosopropyl acetate, n-Hexane/n-Propanol, n-Hexane/MTBE, n-Hexane/1, 4-Dioxane, n-Hexane/chloroform, isooctane/2-Butanol, isooctane/toluene, isooctane/methylcyclohexane, cyclohexane/n-Butanol, cyclohexane/MTBE, cyclohexane/THF, n-Heptane/acetone, n-Heptane/iosopropyl acetate, methylcyclohexane/THF, methylcyclohex
  • first solvent/second solvent is selected from butanone/n-Heptane, isopropyl acetate/n-Heptane, ethyl acetate/methylcyclohexane, isopropanol/n-Hexane, MTBE/n-Hexane, THF/n-Hexane, MTBE/isooctane, or toluene/cyclohexane; or
  • first solvent/second solvent is selected from butanone/n-Heptane, ethyl ether/n-Heptane, acetone/methylcyclohexane, ethyl acetate/n-Hexane, 1, 4-Dioxane/isooctane, DCM/isooctane, or butyl acetate/cyclohexane; or
  • the solvent is selected form isopropyl ether or n-Heptane.
  • the solvent is selected form ethanol/n-Heptane, butanone/n-Heptane, ethyl acetate/n-Heptane, MTBE/n-Heptane, THF/methylcyclohexane, or toluene/methylcyclohexane.
  • the solution is prepared at a temperature of about 40°C to 80°C, preferably at 45°C to 65°C, more preferably at about 45°C or 65°C; or
  • the compound of Formula I was added in a first solvent to obtain a clear solution in a centrifuge tube.
  • the solution was kept in the atmosphere of solvent 2 at RT. After precipitation occurred, the solution was centrifuged and the obtained solid was dried overnight under vacuum at RT to obtain the polymorph form I.
  • the first solvent /second solvent is selected from MTBE/methyclcyclohexane or isopropyl acetate/n-Hexane.
  • Polymorph form II of the compound of Formula I is prepared as follows:
  • the polymorph form I was dissolved in a corresponding solvent.
  • the solution was filtered and the filtrate was evaporated at the corresponding temperature to obtain the polymorph form II.
  • the solvent is methanol, ethanol, isopropanol, acetone, THF, DCM, TFE, 1, 4-Dioxane, ACN, or water.
  • the solvent is selected from methanol/water, THF/water, acetone/water, methanol/DCM, isopropyl ether/THF, MTBE/ACN, butanone/1, 4-Dioxane, DCM/MTBE, TFE/water, butanone/ethyl acetate, TFE/toluene, or isopropyl acetate/chloroform.
  • the evaporation temperature is carried out at about 5 to 50°C, preferably at about 10°C to 40°C, most preferably at room temperature or 40°C; or
  • the polymorph form I was added in a solvent of 1, 4-Dioxane/methylcyclohexane. It was heated to the corresponding temperature to dissolve. The solution was filtered and the filtrate was stirred for 30 minutes in an ice-salt bath. The obtained solid was centrifuged and dried overnight under vacuum at RT to obtain the polymorph form II.
  • the solution is prepared at a temperature about 65°C.
  • the volume radio between 1, 4-Dioxane and methylcyclohexane is 1: 10; or
  • the polymorph form I was added in THF to obtain a clear solution in a centrifuge tube.
  • the solution was kept in the atmosphere of iscooctane at RT. After precipitation occurred, the solution was centrifuged and the obtained solid was dried overnight under vacuum at RT to obtain the polymorph form II; or
  • the polymorph form I was dissolved in chloroform or DCM. The solution was concentrated to dryness under reduced pressure at 40°C to obtain the polymorph form II.
  • Suitable solvents for the crystallization to achieve separation of a polymorph can be chosen from, but are not limited to, low carbon alcohols, ketones, ethers, esters, halogenated hydrocarbons, alkanes, halogenated benzene, aliphatic nitrile, and other aromatic solvents, or any combination thereof.
  • the solvent for the crystallization of the compound of Formula I can be chosen from methol, EtOH, TFE, n-Propanol, isopropanol, 2-Butanol, IPAc, 1, 4-dioxane, acetone, butanone, chloroform, ethyl acetate, butyl acetate, THF, MTBE, ethyl ether, nitromethane, water, N, N-dimethylformamide, n-hexane, n-heptane, isooctane, cyclohexane, methylcyclohexane, DCM, mEtOH, ACN, n-propanol, toluene, or any combination thereof.
  • crystallization of the polymorph forms of the present invention can be conducted by any conventional techniques well-known in the art.
  • Such crystallization techniques may include, without limitation, one or more of the following: precipitation, evaporation, slurrying, cooling, diffusion, milling, addition of anti-solvents and polymer template, or any combination thereof.
  • crystallization may be done with or without seed crystals.
  • the individual crystalline forms disclosed herein can develop under specific conditions dependent on the particular thermodynamic and equilibrium properties of the crystallization process. Therefore, any persons of ordinary skill in the art of polymorphism in this area know that the formed crystals are a consequence of the kinetic and thermodynamic properties of the crystallization process. Under certain conditions (e.g., solvent, temperature, pressure, and concentration of the compound of this invention) , a particular crystalline form may be more stable than another crystalline form (or in fact more stable than any other crystalline forms) . However, the relatively low thermodynamic stability of particular crystals may have advantageous kinetics. Additional factors other than kinetics, such as time, impurity distribution, stirring, and the presence or absence of seed crystals, etc., may also affect the crystalline form.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one polymorph form of the compound of Formula I disclosed herein and at least one pharmaceutically acceptable carrier.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
  • the "therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • the "therapeutically effective amount” refers to the total amount of the combined active ingredient for the effective treatment of a disease, a disorder or a condition.
  • the pharmaceutical composition comprises 0.01 wt%-99 wt%of at least one of the crystalline polymorphs disclosed herein.
  • the pharmaceutical composition comprises 0.1 wt%-70 wt%of at least one of the crystalline polymorphs disclosed herein.
  • the pharmaceutical composition comprises 1 wt%-70 wt%of at least one of the crystalline polymorphs disclosed herein.
  • the pharmaceutical composition comprises 1 wt%-50 wt%of at least one of the crystalline polymorphs disclosed herein.
  • the pharmaceutical composition comprises 10 wt%-30 wt%of at least one of the crystalline polymorphs disclosed herein.
  • the "pharmaceutically acceptable carrier” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc.; a filler such as starch, sucrose, etc.; a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammoniums; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc.
  • a diluent a vehicle such as water, various organic solvents, etc.
  • a filler such as starch, sucrose, etc.
  • a binder such as cellulose derivatives, alginates
  • the pharmaceutical composition further comprises at least one other pharmaceutically acceptable excipient such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a diffusion enhancer, a polymer, a fragrance, a sweetener, and a dye.
  • the excipient is suitable for desired formulation and administration type.
  • suitable pharmaceutical carriers are chosen from water, various organic solvents and various inert diluents or fillers.
  • the pharmaceutical compositions may further comprise one or more additives such as spices, adhesives and excipients.
  • tablets can contain at least one excipient chosen, for example, from citric acid, a variety of disintegrant agents such as starch, alginic acid, and some silicates, and a variety of adhesives such as sucrose, gelatin and Arabic gum.
  • lubricants including magnesium stearate and talc fillers may, for example, be used in the production of tablets. These components can also, for example, be used to formulate soft and hard gelatin capsules.
  • the active compound When an aqueous suspension is needed for oral administration, the active compound may be mixed with at least one component chosen, for example, from a variety of sweeteners and flavoring agents, pigments, and dye combinations. If necessary, a variety of emulsifiers may be employed or suspensions generated; diluents such as water, EtOH, propylene glycol, glycerin, or their combination may also be utilized.
  • at least one component chosen, for example, from a variety of sweeteners and flavoring agents, pigments, and dye combinations.
  • emulsifiers may be employed or suspensions generated; diluents such as water, EtOH, propylene glycol, glycerin, or their combination may also be utilized.
  • the pharmaceutical composition further comprises at least one additional active ingredient other than a polymorph form of the compound of Formula I.
  • the pharmaceutical composition comprising the polymorph (s) of the present invention can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject who needs treatment.
  • the pharmaceutical composition may be a regular solid formulation such as tablets, pills, coated tablets, powders, granules, capsules and the like, a liquid preparation such as water or oil suspension or other liquid preparation such as syrup, solution, suspension or the like.
  • the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like.
  • the formulation of the pharmaceutical composition disclosed herein is selected from tablet, coated tablet, capsule, suppository, nasal spray, and injection. In some embodiments, the formulation of the pharmaceutical composition disclosed herein is chosen from tablets and capsules.
  • the pharmaceutical composition may be suitable for oral administration. In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered intramuscularly. In some embodiments, the pharmaceutical composition is administered intrathecally. In some embodiments, the pharmaceutical composition is administered subcutaneously.
  • the pharmaceutical compositions disclosed herein may be administered orally in forms such as tablets, capsules, pills, powders, sustained release forms, solutions and/or suspensions; by non-intestinal injection in such form as a sterile solution, suspension or emulsion; through a local treatment form such as paste, cream, or ointment; or via a rectal form such as suppositories.
  • the pharmaceutical compositions disclosed herein may be in a unit dosage form that is suitable for precise dosing applications.
  • the pharmaceutical composition is in the form of tablets or capsules.
  • the pharmaceutical composition preferably contains 0.05-5000mg at least one polymorph form of the compound of Formula I disclosed herein.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
  • the pharmaceutical composition of the present invention can be produced by known conventional methods in the pharmaceutical field. For example, one can mix the active ingredient with one or more excipients, and make the mixture into the target formulation.
  • a method for treating a disease or a condition comprising administering to a subject in need of treatment of, at least one polymorph form of the compound of Formula I disclosed herein and/or the pharmaceutical composition thereof, in an amount effective for treating the disease or condition.
  • the presently disclosed subject matter provides the use of at least one polymorph form of the compound of Formula I disclosed herein and/or the pharmaceutical composition thereof, in treating the disease or condition.
  • the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, cognitive deficit, and a neurodegenerative or neurological disease.
  • the disease or condition is selected from the group consisting of acute respiratory distress syndrome, allograft rejection during cell, tissue, or organ transplantation, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, lupus, Parkinson's disease, and pulmonary fibrosis.
  • the disease or condition is selected from cancer.
  • the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, cognitive deficit, and a neurodegenerative or neurological disease.
  • the medicament is used for the treatment or prevention a cancer.
  • the cancer is selected from hepatocellular cancer, brain cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
  • the medicament is used as a glutamine antagonist.
  • glutamine antagonist refers to a glutamine analog that interfers with a glutamine metabolic pathway, e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds.
  • glutamine metabolic pathway e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds.
  • Examples of such metabolic pathways are well known (see, e.g., Hensley et al, "Glutamine and cancer: cell biology, physiology, and clinical opportunities” J Clin Invest. 2013; 123 (9) : 3678-3684; DeBerardinis et al, "Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer” Oncogene.
  • glutamine antagonist also includes glutamine analogs that inhibit glutamine uptake by cells, thereby reducing its biological activity. Diseases or conditions wherein excess and/or aberrant glutamine.
  • provided here is at least one polymorph form of the compound of Formula I disclosed herein, and/or the pharmaceutical composition of the present invention for use in therapy.
  • the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, cognitive deficit, and a neurodegenerative or neurological disease.
  • the cancer is selected from hepatocellular cancer, brain cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
  • a "cancer” in a patient refers to the presence of cells possessing characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers.
  • cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells.
  • a “tumor, " as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.
  • a "solid tumor, " as used herein, is an abnormal mass of tissue that generally does not contain cysts or liquid areas.
  • a solid tumor may be in the brain, colon, breasts, prostate, liver, kidneys, lungs, esophagus, head and neck, ovaries, cervix, stomach, colon, rectum, bladder, uterus, testes, and pancreas, as non-limiting examples.
  • the solid tumor regresses or its growth is slowed or arrested after the solid tumor is treated with the presently disclosed methods.
  • the solid tumor is malignant.
  • the cancer comprises Stage 0 cancer.
  • the cancer comprises Stage I cancer.
  • the cancer comprises Stage II cancer.
  • the cancer comprises Stage III cancer. In some embodiments, the cancer comprises Stage IV cancer. In some embodiments, the cancer is refractory and/or metastatic. For example, the cancer may be refractory to treatment with radiotherapy, chemotherapy or monotreatment with immunotherapy.
  • Cancer as used herein includes newly diagnosed or recurrent cancers, including without limitation, acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, breast carcinoma, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, colorectal carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung carcinoma, Lewis lung carcinoma, lymphoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premen
  • a “cognitive deficit” refers to a disease, disorder, or condition that is characterized by impairment of the mental processes of perception, learning, memory, judgment, and/or reasoning.
  • the cognitive deficit is selected from the group consisting of dementia, and mild to moderate cognitive decline (the latter resulting in gradual incapacitation of daily activities) .
  • the term “dementia” refers to a terminal disease or disorder that involves inability to think, learn, and remember such that a person's daily functioning is affected among other disabilities such as seizures and motor detects.
  • the term “cognitive decline” refers to a gradual decrease in a person's mental processes of perception, learning, memory, judgment, and reasoning.
  • a “mild cognitive decline” refers to a decrease in a person's mental processes of perception, memory, judgment, and reasoning that is less than a 40%decrease, less than a 30%decrease, less than a 20%decrease, or less than a 10%decrease as compared to the person's cognitive ability before the cognitive decline occurred.
  • the cognitive deficit is due to a viral infection. In some embodiments, the cognitive deficit is due to the human immunodeficiency virus (HIV) infection. In some embodiments, the subject is infected with HIV that is latent in T lymphocytes, other viruses that may be latent (e.g., JCV, Herpes) and the subject shows few or no symptoms of the infection except cognitive deficits. In such embodiments, the methods of treating and/or preventing may include administering to the subject an effective amount of an anti-viral agent.
  • HIV human immunodeficiency virus
  • a method of treating a subject having a cancer comprising administering to the subject a therapeutically effective amount of at least one polymorph form of the compound of Formula I disclosed herein and/or the pharmaceutical composition of the present invention.
  • the cancer is selected from hepatocellular cancer, brain cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
  • treating as in “treating a disease” in this description means to cause recovery in or to alleviate or suppress a “disease” or one or more “diseases” .
  • the methods set forth above may be applied in combination with any chemical therapy, biological therapy, and/or radiation therapy.
  • At least 85 %of the compound of Formula I present in the pharmaceutical composition is in a crystalline form.
  • at least 85%of the compound of Formula I present in the pharmaceutical composition is at least one chosen from the polymorphs of the compound of Formula I disclosed herein.
  • At least 95 %of the compound of Formula I present in the pharmaceutical composition is in a crystalline form.
  • at least 95%of the compound of Formula I present in the pharmaceutical composition is at least one chosen from the polymorphs of the compound of Formula I disclosed herein.
  • At least 99 %of the compound of Formula I present in the pharmaceutical composition is in a crystalline form.
  • at least 99%of the compound of Formula I present in the pharmaceutical composition is at least one chosen from the polymorphs of the compound of Formula I disclosed herein.
  • New polymorphic, hydrate or solvate forms can provide various advantages, including improved physical characteristics such as stability or solubility.
  • the polymorph forms disclosed herein are purer and more efficacious.
  • the X-ray powder diffraction pattern shown as in Figure 1 refers to the X-ray powder diffraction pattern that show major peaks as in Figure 1, wherein major peaks refer to those with the relative intensity greater than 10%, preferably greater than 30%, relative to the highest peak (with its relative intensity designated to be 100%) in Figure 1.
  • the X-ray powder diffraction pattern shown as in Figure 3 refers to the X-ray powder diffraction pattern that show major peaks as in Figure 3, wherein major peaks refer to those with the relative intensity greater than 10%, preferably greater than 30%, relative to the highest peak (with its relative intensity designated to be 100%) in Figure 3.
  • no hygroscopicity refers to compounds showing a weight gain of less than 0.2weight-%based on the weight of the compound when measured in the range of from 0%RH to 80%RH at 25 ⁇ 0.1°C.
  • the term “about” means 10%above or below the value recited. With respect to temperature, unless otherwise defined, the term “about” means the value recited plus or minus 5 degrees.
  • amorphous refers to a disordered solid state, which may appear during manufacture of the drug substance (crystallization step, drying, and milling) or the drug product (granulation, compression) .
  • the X-ray powder diffraction pattern of an amorphous solid exhibits no sharp peaks.
  • solvate means having on a surface, in a lattice or on a surface and in a lattice, a stoichiometric or non-stoichiometric amount of a solvent such as water, acetic acid, mEtOH, etc., or mixtures thereof, bound by non-covalent intermolecular forces.
  • a solvent such as water, acetic acid, mEtOH, etc., or mixtures thereof.
  • hydrate may be used specifically to describe a solvate comprising water.
  • anhydrous as used herein, means a crystalline form containing less than about 1 % (w/w) of adsorbed moisture as determined by standard methods, such as a Karl Fisher analysis.
  • Figure 1 shows the X-ray powder diffraction pattern of polymorph form I.
  • Figure 2 shows the DSC analysis spectrum of polymorph form I.
  • Figure 3 shows the X-ray powder diffraction pattern of polymorph form II.
  • Figure 4 shows the DSC analysis spectrum of polymorph form II.
  • the X-ray powder diffraction (XRPD) patterns for the samples were generated on a Bruker D8 Advance X-ray powder diffraction instrument with the Lynxeye detector by Bragg-Brentano method (X-ray source: 40 Kv, 40mA, Wavelength: (CuK alpha) ) .
  • the Scanning range was from 3°-40° 2 ⁇ with the scanning step of 0.02.
  • DSC Differential scanning calorimetry
  • T 3 P 1, 3, 5, 2, 4, 6-Trioxatriphosphorinane, 2, 4, 6-tripropyl-, 2, 4, 6-trioxide
  • Step 1 Isopropyl (S) -2- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -6-diazo-5-oxohexanoate
  • Step 2 Isopropyl (S) -6-diazo-2- ( (S) -2-methoxypropanamido) -5-oxohexanoate
  • Example 1 About 30 mg of compound of Formula I obtained from Example 1 was dissolved in Isopropyl ether (2.0ml) or 1, 4-Dioxane/acetone (0.4mL/0.4mL) by heating with sonication to obtain a clear solution. The solution was filtered, and the filtrate was evaporated at RT to obtain the Polymorph Form I of the compound of Formula I.
  • Example 1 About 50 mg of compound of Formula I obtained from Example 1 was dissolved in a single solvent to obtain a suspension. The suspension was stirred at a corresponding temperature for 3 days. The suspension was centrifuged to separate. The obtained solid was dried overnight under vacuum at RT and identified as polymorph form I.
  • the specific preparation parameters are shown in Table 1.
  • Example 5 50mg compound of Formula I obtained from Example 1 was dissolved in a single solvent at the corresponding temperature to obtain a clear solution. The solution was filtered and the filtrate was stirred for 30mins in an ice-salt bath. The obtained solid was centrifuged, dried overnight under vacuum at RT, and identified as polymorph form I. The specific preparation parameters are shown in Table 5.
  • Example 7 About 30 mg of compound of Formula I obtained from Example 1 was taken into an uncapped centrifuge tube and exposed in a solvent atmosphere for diffusion for a period of time. The solid was analyzed by XRPD, and determined to be polymorph form I. The specific preparation parameters are shown in Table 7.
  • the XRPD of polymorph form I is substantially characterized in Figure 1 and a summary of XRPD angles and relative intensities are given in Table 9.
  • Polymorph Form I obtained from Example 2 was dissolved in 1, 4-Dioxane (0.1mL) and Methylcyclohexane (1.0mL) at 65 ⁇ 5°C to obtain a clear solution. The solution was filtered and the filtrate was stirred for 30mins in an ice-salt bath. The obtained solid was centrifuged and dried overnight under vacuum at RT to obtain the Polymorph Form II of the compound of Formula I.
  • Polymorph Form I obtained from Example 2 was taken into an uncapped centrifuge tube and THF (0.1mL) was added to obtain a clear solution. The solution was kept in the atmosphere of isooctane at RT. After precipitation occurred, the solution was centrifuged. The obtained solid was dried overnight under vacuum at RT and identified as polymorph form II.
  • Polymorph Form I obtained from Example 2 was dissolved in 4 mL chloroform. The solution was concentrated to dryness under reduced pressure at 40°C to obtain the polymorph form II.
  • the XRPD of the polymorph form II is substantially characterized in Figure 3 and a summary of XRPD angles and relative intensities are given in Table 12.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouvelles formes polymorphes du composé de formule (I), une composition pharmaceutique de celui-ci, et des procédés de préparation et d'utilisation de celles-ci.
PCT/CN2023/089396 2022-04-21 2023-04-20 Formes polymorphes d'un antagoniste de la glutamine et leurs utilisations WO2023202651A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108290827A (zh) * 2015-07-31 2018-07-17 约翰霍普金斯大学 谷氨酰胺类似物的前药
CN111566083A (zh) * 2017-10-06 2020-08-21 约翰·霍普金斯大学 新的谷氨酰胺拮抗剂及其用途
CN113461563A (zh) * 2021-07-27 2021-10-01 中国药科大学 Nqo1激活型6-重氮基-5-氧代-l-正亮氨酸前药及其制备方法和应用
CN113677338A (zh) * 2019-02-11 2021-11-19 羿尊生物医药股份有限公司 由l-焦谷氨酸制备don前药的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108290827A (zh) * 2015-07-31 2018-07-17 约翰霍普金斯大学 谷氨酰胺类似物的前药
CN111566083A (zh) * 2017-10-06 2020-08-21 约翰·霍普金斯大学 新的谷氨酰胺拮抗剂及其用途
CN113677338A (zh) * 2019-02-11 2021-11-19 羿尊生物医药股份有限公司 由l-焦谷氨酸制备don前药的方法
CN113461563A (zh) * 2021-07-27 2021-10-01 中国药科大学 Nqo1激活型6-重氮基-5-氧代-l-正亮氨酸前药及其制备方法和应用

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