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WO2024179548A1 - Forme solide de composé - Google Patents

Forme solide de composé Download PDF

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Publication number
WO2024179548A1
WO2024179548A1 PCT/CN2024/079374 CN2024079374W WO2024179548A1 WO 2024179548 A1 WO2024179548 A1 WO 2024179548A1 CN 2024079374 W CN2024079374 W CN 2024079374W WO 2024179548 A1 WO2024179548 A1 WO 2024179548A1
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Prior art keywords
cancer
solid form
pharmaceutical composition
xrpd
thymoma
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Pending
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English (en)
Chinese (zh)
Inventor
王在琪
刘学彬
高晶
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Inxmed Nanjing Co Ltd
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Inxmed Nanjing Co Ltd
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Publication of WO2024179548A1 publication Critical patent/WO2024179548A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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 belongs to the field of medicinal chemistry. Specifically, the present invention relates to a solid form of 2-fluoro-5-methoxy-4-((4-((2-methyl-3-oxoisoindolin-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide hydrochloride.
  • FAK also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of the focal adhesion complex. FAK plays an important role in mediating integrin and growth factor signals to regulate the invasion, proliferation and survival of tumor cells. FAK is widely expressed and evolutionarily conserved. Studies over the past two decades have shown that FAK is overexpressed in a variety of solid tumors, and the expression level is negatively correlated with tumor prognosis. Recent studies have also shown that FAK plays an important role in regulating the tumor microenvironment, suggesting that FAK plays an important role in adaptive resistance to immunotherapy and anti-tumor therapy.
  • PTK2 protein tyrosine kinase 2
  • 2-Fluoro-5-methoxy-4-((4-((2-methyl-3-oxoisoindolin-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide is a FAK inhibitor having a structure shown in formula (I).
  • the compound of formula (I) exhibits anti-tumor activity in CDX (human tumor cell line transplanted mice) models of multiple tumor types.
  • CDX human tumor cell line transplanted mice
  • the present invention provides a solid form which is a hydrochloride salt of a compound of formula (I):
  • it is in crystalline form.
  • Form II it is Form II, having one or more of the following properties:
  • XRPD X-ray powder diffraction
  • the present invention provides a pharmaceutical composition comprising any one of the above-mentioned solid forms.
  • the present invention provides the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation, which is used as a medicine.
  • the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation is used to treat FAK-mediated diseases.
  • the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation is used to treat tumors, especially selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma
  • the present invention provides use of the above solid form or pharmaceutical composition or pharmaceutical preparation in the preparation of a medicament for treating a FAK-mediated disease.
  • the present invention provides use of the above solid form or pharmaceutical composition or pharmaceutical preparation in preparing a drug for treating tumors.
  • the tumor is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; in particular,
  • the present invention provides a method for treating a FAK-mediated disease, comprising administering a therapeutically effective amount of the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation to a subject in need of treatment.
  • the present invention provides a method for treating tumors, comprising administering a therapeutically effective amount of the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation to a subject in need of treatment.
  • the tumor is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer
  • FIG1 is an X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form II of the compound of formula (I).
  • FIG2 shows the thermogravimetric analysis (TGA) of the hydrochloride form II of the compound of formula (I).
  • FIG3 shows the differential scanning calorimetry (DSC) analysis results of the hydrochloride crystal form II of the compound of formula (I).
  • FIG4 shows the 1 H NMR (DMSO-d 6 ) chart of the hydrochloride crystal form II of the compound of formula (I).
  • FIG5 shows a dynamic vapor sorption (DVS) isotherm diagram of the hydrochloride form II of the compound of formula (I).
  • FIG6 is a stability analysis of the hydrochloride crystal form II of the compound of formula (I).
  • the term "about” or “approximately” when used in combination with a numerical value or a numerical range means that the numerical value or numerical range may deviate from a range that is considered reasonable by a person of ordinary skill in the art, such as within experimental variation (or within statistical experimental error), so the numerical value or numerical range may vary, for example, between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, and between 0.5% and 1% of the numerical value or numerical range.
  • "about” used in conjunction with the diffraction angle (2 ⁇ ) refers to ⁇ 0.2 degrees in a certain embodiment, and to ⁇ 0.1 degrees in another embodiment.
  • a wavy line i.e., " ⁇ " before a numerical value or numerical range means “about” or “approximately”.
  • the word “about” before the first number also applies to the numbers that follow.
  • the phrase “peaks at about 8.38, 18.2, 21.6, and 22.44 degrees 2 ⁇ ” means “peaks at about 8.38, about 18.2, about 21.6, and about 22.44 degrees 2 ⁇ ”.
  • subject refers to mammals and non-mammals. Mammals refer to any member of the class mammals, including but not limited to: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, and pigs; livestock, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like.
  • the term "subject” does not limit a particular age or sex. In some embodiments, the subject is a human.
  • the term "treat” refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic, including partial or substantial achievement of one or more of the following results: partial or total alleviation of the extent of a disease, disorder or syndrome; improvement of clinical symptoms or indicators associated with the disease; or delay, inhibition or reduction of the likelihood of progression of a disease, disorder or syndrome.
  • the term "effective amount" as used herein refers to a solid form of the hydrochloride of the compound of formula (I) that is sufficient to reduce or improve the severity, duration, progression or onset of a disease or condition, delay or prevent the progression of a disease or condition, cause regression of a disease or condition or delay the recurrence or progression of symptoms, or enhance or improve the therapeutic effect of another therapy.
  • the exact amount given to the subject will depend on various factors, such as a given drug or compound, a pharmaceutical formulation, a route of administration, a type of disease, a condition, the identity of the subject or host being treated, etc., but can still be routinely determined by a person skilled in the art. For example, determining the effective amount also depends on the degree, severity and type of cell proliferation.
  • a technician will be able to determine a suitable dose based on these and other factors.
  • the "effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable doses are known for approved therapeutic agents and can be determined by a technician based on the subject's condition, the type of condition being treated, and the hydrochloride of the compound of formula (I)
  • the effective dosage of the solid form of the hydrochloride of the compound of formula (I) may be 10 ⁇ g-2000 mg (calculated as free base). This example is non-limiting.
  • the pharmaceutical preparation prepared from the solid form of the hydrochloride salt of the compound of formula (I) can be administered by any suitable administration method. Suitable methods include oral, intravenous, intramuscular or subcutaneous administration to a subject.
  • the term "pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” includes solvents, dispersion media, coatings, antimicrobial agents, isotonic agents, absorption delaying agents, and the like.
  • solvents dispersion media, coatings, antimicrobial agents, isotonic agents, absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known to those skilled in the art. Unless any conventional media or agents are incompatible with the active ingredient, it is contemplated that they may be used in the pharmaceutical formulations herein. Supplementary active ingredients may also be added to the pharmaceutical formulations.
  • the solid form of the compound of formula (I) hydrochloride can be orally administered with a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier. They can be encapsulated in hard or soft shell gelatin capsules, can be compressed into tablets, or can be directly mixed with the patient's food.
  • a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier.
  • the solid form can be combined with one or more excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups or wafers. These preparations contain an effective amount of the compound of formula (I) hydrochloride.
  • Tablets, lozenges, pills, capsules, etc. may further include: a binder, such as gum tragacanth, gum arabic, corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrant, such as corn starch, potato starch, alginic acid, etc.; a lubricant, such as magnesium stearate; or a sweetener, such as sucrose, fructose, lactose or aspartame; or a flavoring agent.
  • a binder such as gum tragacanth, gum arabic, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrant such as corn starch, potato starch, alginic acid, etc.
  • a lubricant such as magnesium stearate
  • a sweetener such as sucrose, fructose, lactose or aspartame
  • a flavoring agent such as sucrose, fructose, lac
  • compositions prepared from the solid forms of the hydrochloride salt of the compound of formula (I) can also be administered intravenously or intraperitoneally by infusion or injection.
  • Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions.
  • the final dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the amount of the solid form of the compound of formula (I) hydrochloride for the treatment of required can be with route of administration, the nature of the disease being treated and the age and condition of the patient change, and can finally be determined by the attending physician or clinician.
  • the dosage of the solid form of the compound of formula (I) hydrochloride can be in the range of about 0.1 to about 50 mg/kg body weight every day (in terms of free alkali).
  • the desired dose may conveniently be presented in a single dose or in divided doses administered at appropriate intervals.
  • solid form refers to a physical form that is not predominantly liquid or gaseous.
  • the solid form may be crystalline, non-crystalline, or a mixture thereof.
  • crystalline form refers to a crystalline form. It includes single-component crystalline forms and multi-component crystalline forms, and includes, but is not limited to, polymorphs, solvates, and other molecular complexes, as well as salts thereof, solvates of salts, other molecular complexes of salts, and polymorphs.
  • the crystalline form of a substance may be substantially free of amorphous and/or other crystalline forms.
  • the crystalline form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 9
  • the crystalline forms described herein are substantially pure, i.e., substantially free of other crystalline forms and/or other compounds, and contain less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% by weight of one or more other crystalline forms and/or other compounds.
  • Crystal forms can show different physical characteristic data, which are unique to specific crystal forms such as the crystal forms described herein. These characteristic data can be obtained by various techniques known to those skilled in the art, including, for example, x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and nuclear magnetic resonance spectroscopy (NMR). The data provided by these techniques can be used to identify a specific crystal form. Those skilled in the art can determine whether a crystal form is "consistent” with the reference data provided herein that are identified as being unique to a specific crystal form. Characteristic data that are "consistent" with the data of a reference crystal form are understood by those skilled in the art to be equivalent to the same crystal form as the reference crystal form. In the analysis of whether the data is "consistent”, those skilled in the art will understand that, due to, for example, experimental error and routine sample-to-sample analysis, specific characteristic data points may vary to a reasonable degree and still describe a given crystal form.
  • amorphous or “amorphous form” and related terms refer to a substance, component or product that is substantially not crystalline as determined by x-ray powder diffraction.
  • amorphous describes a disordered solid form, i.e., a solid form that lacks long-range crystalline order.
  • an amorphous form of a substance may be substantially free of other amorphous and/or crystalline forms.
  • an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of one or more other amorphous and/or crystalline forms.
  • an amorphous form of a substance may be physically and/or chemically pure.
  • an amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or chemically pure.
  • the present invention provides a solid form comprising a hydrochloride salt of a compound of formula (I):
  • the solid form comprising the hydrochloride of the compound of formula (I) can be a crystalline form, a partially crystalline form, or a mixture of a crystalline form and an amorphous form.
  • the solid form can include a crystalline form of the hydrochloride of the compound of formula (I), or a solvate thereof, or a mixture thereof.
  • the solid form further includes a co-former.
  • a co-crystal comprising a solid form of the hydrochloride of the compound of formula (I) and a co-former.
  • the solid form is an amorphous form. In some embodiments, the solid form is substantially pure.
  • the solid form includes the solid form of the compound of formula (I) hydrochloride or its solvate. In some embodiments, the solid form includes the solid form of the compound of formula (I) hydrochloride. In some embodiments, the solid form includes the solid form of the solvate of the compound of formula (I) hydrochloride.
  • the compound of formula (I) hydrochloride or its solvate or its mixture can exist in a variety of solid forms. Such solid forms include crystalline forms, amorphous solids or a mixture of crystalline forms and amorphous forms. In some embodiments, the solid form is substantially crystalline. In some embodiments, the solid form is crystalline.
  • the molar ratio of the hydrochloride of the compound of formula (I) in the solid form to the solvent/water ranges from about 10:1 to about 1:10. In some embodiments, the molar ratio of the hydrochloride of the compound of formula (I) in the solid form to the solvent/water ranges from about 5:1 to about 1:5. The molar ratio of the hydrochloride of the compound of formula (I) in the solid form to the solvent/water ranges from about 3:1 to about 1:3. The molar ratio of the hydrochloride of the compound of formula (I) in the solid form to the solvent/water ranges from about 2:1 to about 1:2. In some embodiments, the molar ratio is about 1:2 (i.e., a disolvate). In some embodiments, the molar ratio is about 1:1 (i.e., a monosolvate). In some embodiments, the molar ratio is about 2:1 (i.e., a hemisolvate).
  • the solid form is a crystalline form II of the hydrochloride salt of the compound of formula (I).
  • the crystalline form II is substantially free of amorphous form.
  • the crystalline form II is substantially free of other crystalline forms.
  • the crystalline form II is substantially pure crystalline form II.
  • Form II has an x-ray powder diffraction (XRPD) pattern comprising peaks at 8.38, 18.20, 21.60, and 22.44 degrees 2 ⁇ .
  • XRPD x-ray powder diffraction
  • Form II has an x-ray powder diffraction (XRPD) pattern comprising peaks at approximately 8.38, 17.039, 18.20, 20.739, 21.60, and 22.44 degrees 2 ⁇ .
  • XRPD x-ray powder diffraction
  • Form II has an x-ray powder diffraction (XRPD) pattern comprising peaks at approximately 8.38, 11.198, 11.978, 15.381, 17.039, 18.20, 18.719, 20.739, 21.60, 22.44, 23.259, and 27.319 degrees 2 ⁇ .
  • XRPD x-ray powder diffraction
  • Form II has an x-ray powder diffraction (XRPD) pattern comprising peaks at approximately 8.38, 9.72, 10.60, 11.198, 11.978, 13.48, 15.381, 15.901, 17.039, 18.20, 18.719, 19.96, 20.739, 21.60, 22.44, 23.259, 23.86, 25.039, 26.199, 27.319, 28.681, 30.061, and 30.639 degrees 2 ⁇ .
  • XRPD x-ray powder diffraction
  • Form II has an X-ray powder diffraction (XRPD) pattern comprising chromatographic positions at about 4.259, 8.38, 8.779, 9.72, 10.60, 11.198, 11.978, 12.56, 13.48, 14.178, 15.381, 15.901, 17.039, 18.20, 18.719, 19.96, 20.739, 21.60, 22.44, 23.259 , 23.86, 25.039, 25.719, 26.199, 26.642, 27.319, 28.681, 29.30, 30.061, 30.639, 31.68, 32.479, 33.32, 33.80, 34.90, 36.08, 36.719, 38.198, 40.179, 41.278, 42.42, 43.598, and 43.98 degrees 2 ⁇ .
  • XRPD X-ray powder diffraction
  • Form II has an XRPD pattern substantially as shown in Figure 1.
  • Form II exhibits a weight loss of about 0.8001% when heated from about 25° C. to about 140° C.
  • Form II has a TGA spectrum substantially as shown in Figure 2. From TGA analysis, it can be seen that the Form II is a non-solvate.
  • the Form II exhibits an endothermic event as characterized by DSC, having an onset temperature at about 275.87° C. and/or a peak temperature at about 280.70° C. In some embodiments, the Form II has a DSC spectrum substantially as shown in FIG. 3 .
  • the Form II exhibits a weight gain of about 1.22% when subjected to an increase in relative humidity from about 40% to about 80% relative humidity. In some embodiments, it has a DVS spectrum substantially as shown in FIG. 5 .
  • the present invention provides a pharmaceutical composition comprising any one of the above-mentioned solid forms.
  • the present invention provides a pharmaceutical preparation comprising any one of the above-mentioned solid forms and a pharmaceutically acceptable carrier, in particular, a therapeutically effective amount of the solid form.
  • the present invention provides the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation, which is used as a medicine.
  • the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation is used to treat FAK-mediated diseases.
  • the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation is used to treat tumors, especially selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma
  • the present invention provides use of the above solid form or pharmaceutical composition or pharmaceutical preparation in the preparation of a medicament for treating a FAK-mediated disease.
  • the present invention provides use of the above solid form or pharmaceutical composition or pharmaceutical preparation in preparing a drug for treating tumors.
  • the tumor is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; in particular,
  • the present invention provides a method for treating a FAK-mediated disease, comprising administering a therapeutically effective amount of the above-mentioned solid form or pharmaceutical composition or pharmaceutical preparation to a subject in need of treatment.
  • the present invention provides a method for treating a tumor, comprising administering a therapeutically effective amount of the solid form or pharmaceutical composition or pharmaceutical preparation described above to a subject in need of treatment.
  • the tumor is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, Liver cancer, bile duct cancer, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, stomach cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oroph
  • I, II, III or IV in the above table are all different crystalline forms of the corresponding acid after salt formation.
  • the solvent is ethyl acetate
  • the precipitated crystalline form III is the crystalline form III of the hydrochloride salt.
  • NA means that no sample was obtained.
  • a certain mass of the compound of formula (I) or the hydrochloride crystal form II of the compound of formula (I) was weighed into a 5 mL sample bottle, and 2 mL of deionized water, pH 2.0 glycine-hydrochloric acid buffer, pH 4.5 Na 2 HPO 4 -citric acid buffer or pH 6.8 Na 2 HPO 4 -citric acid buffer was added respectively, and the mixture was shaken on a shaker at 25° C. for 24 hours and then filtered. The solubility of the filtrate was determined by HPLC; the solid was detected by XRPD to determine whether the crystal form had changed.
  • phase B is acetonitrile
  • A:B 10:90
  • solubility test results show that compared with the free base amorphous form, the solubility of hydrochloride form II in deionized water and buffered saline solutions of different pH values is greater than 10 mg/ml.
  • High humidity test Place the powder with its opening in a constant temperature and humidity chamber at 25°C and 90% ⁇ 5%RH for 10 days, and take samples on the 5th and 10th days to test the solid XRPD to examine its hygroscopic and deliquescent properties.
  • Strong light irradiation test Place the powder opening in a light stabilization box equipped with a fluorescent lamp and place it at an illumination of 4500 ⁇ 500lx for 10 days. Samples are taken on the 5th and 10th days for solid XRPD testing.
  • Accelerated test Place the powder opening in a constant temperature and humidity chamber at 40°C and 75% ⁇ 5%RH for 10 days. Samples were taken on the first and 10th day and tested by solid XRPD.
  • Dynamic water sorption instrument (DVS) was used to investigate the adsorption and desorption experiments of hydrochloride crystal form II at 25°C and 0-95% relative humidity to determine the moisture absorption properties of various crystal forms (see Figure 5 for details). The results showed that within the humidity range of 40-80% RH, the moisture absorption of crystal form II was 1.22%.

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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne un chlorhydrate d'un composé de formule (I) et une forme solide de celui-ci, ainsi qu'une composition pharmaceutique, une préparation pharmaceutique et une utilisation thérapeutique associée.
PCT/CN2024/079374 2023-03-02 2024-02-29 Forme solide de composé Pending WO2024179548A1 (fr)

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CN202310195326.3 2023-03-02
CN202310195326.3A CN118580221A (zh) 2023-03-02 2023-03-02 化合物的固体形式

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WO2024179548A1 true WO2024179548A1 (fr) 2024-09-06

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CN (1) CN118580221A (fr)
WO (1) WO2024179548A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102292322A (zh) * 2008-11-24 2011-12-21 贝林格尔.英格海姆国际有限公司 用于治疗例如癌症的疾病的取代的嘧啶
WO2022028367A1 (fr) * 2020-08-03 2022-02-10 应世生物科技(南京)有限公司 Forme solide de composé
CN115052603A (zh) * 2020-02-05 2022-09-13 应世生物科技(南京)有限公司 Bi853520与化疗药物的联用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102292322A (zh) * 2008-11-24 2011-12-21 贝林格尔.英格海姆国际有限公司 用于治疗例如癌症的疾病的取代的嘧啶
CN115052603A (zh) * 2020-02-05 2022-09-13 应世生物科技(南京)有限公司 Bi853520与化疗药物的联用
WO2022028367A1 (fr) * 2020-08-03 2022-02-10 应世生物科技(南京)有限公司 Forme solide de composé

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