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WO2022199669A1 - Forme cristalline, type sel, et utilisation d'un composé de pyridinone condensé - Google Patents

Forme cristalline, type sel, et utilisation d'un composé de pyridinone condensé Download PDF

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Publication number
WO2022199669A1
WO2022199669A1 PCT/CN2022/082855 CN2022082855W WO2022199669A1 WO 2022199669 A1 WO2022199669 A1 WO 2022199669A1 CN 2022082855 W CN2022082855 W CN 2022082855W WO 2022199669 A1 WO2022199669 A1 WO 2022199669A1
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Prior art keywords
crystal form
ray powder
powder diffraction
diffraction pattern
formula
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Chinese (zh)
Inventor
张勇
李雪健
曹程
吴迎春
程宏明
彭建彪
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Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
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Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
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Priority to CN202280020397.3A priority Critical patent/CN116964056A/zh
Publication of WO2022199669A1 publication Critical patent/WO2022199669A1/fr
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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • the present invention relates to the salt form, crystal form and pharmaceutical composition of the compound represented by formula (I), and its application as a KRAS inhibitor.
  • Cancer has been ranked first among the top ten causes of death in China for 31 consecutive years, among which lung cancer is one of the tumors with the highest incidence, and non-small cell lung cancer accounts for more than 80%.
  • lung cancer is one of the tumors with the highest incidence
  • non-small cell lung cancer accounts for more than 80%.
  • the research and development of innovative drugs for cancer treatment is very necessary for the company's long-term development, and has important economic and social significance.
  • pancreatic, colorectal, and lung The three cancers with the highest mortality rates in the United States (pancreatic, colorectal, and lung) also happen to be the three cancers with the most common RAS mutations, accounting for 95%, 52%, and 31%, respectively, of patients with these three cancers.
  • KRAS mutations account for the absolute majority, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder cancer and head and neck cancer.
  • KRAS-mutant tumors are the most potentially targeted molecular subtype of non-small cell lung cancer (NSCLC), with a mutation rate of approximately 15%-25% in non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • KRAS mutations mainly occur at codons 12 and 13.
  • KRAS small molecule drugs including 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase regulators and 2 KRAS gene regulators; there is 1 such drug currently under clinical research.
  • Android Health the first KRAS inhibitor developed by a Taiwanese company, has entered the US FDA Phase II clinical trial, and AstraZeneca's inhibitor of KRAS downstream MEK, selumetinib, is also undergoing Phase II clinical trials. KRAS mutation is the most important tumor driver gene.
  • the present invention provides the sulfate salt of the compound represented by formula (I)
  • the above-mentioned sulfate salt contains sulfuric acid in an amount of 0.5 to 3.0 molar equivalents relative to compound (I).
  • the above-mentioned sulfate salt contains sulfuric acid in an amount of 0.5 to 2.5 molar equivalents relative to compound (I).
  • the above-mentioned sulfate contains 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.7, 2.9 or 3.0 molar equivalents of sulfuric acid.
  • the present invention provides the crystalline form A of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 16.80 ⁇ 0.2°, 17.75 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.54 ⁇ 0.2 °, 16.80 ⁇ 0.2°, 17.75 ⁇ 0.2°, 19.09 ⁇ 0.2°, 20.91 ⁇ 0.2°, 21.71 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the above-mentioned crystal form A contains 0.5-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A contains 1.0-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A contains 1.0-1.1 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I). These crystal forms A with different molar equivalents have the same characteristic peaks, for example, as shown in Figures 13-16.
  • the above crystal form A contains 1.024, 1.063, 1.075, 1.082, 1.087 or 1.108 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 5%-15%. In some embodiments of the present invention, the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 5.87%-13.23%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 6.6%-10.4%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4% or 10.5%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4% or 10.5%, these crystal forms A with different moisture contents have the same characteristic peaks, as shown in Figures 1 and 12.
  • the above-mentioned common characteristic peaks are selected from diffraction angles (2 ⁇ ): 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 16.80 ⁇ 0.2°, 17.75 ⁇ 0.2° at least 3 peaks in .
  • the above-mentioned common characteristic peaks are selected from diffraction angles (2 ⁇ ): 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.54 ⁇ 0.2°, 16.80 ⁇ 0.2° , at least 3 peaks in 17.75 ⁇ 0.2°, 19.09 ⁇ 0.2°, 20.91 ⁇ 0.2°, 21.71 ⁇ 0.2°.
  • the present invention provides the crystalline form B of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.67 ⁇ 0.2°, 8.78 ⁇ 0.2°, 10.28 ⁇ 0.2°, 11.02 ⁇ 0.2°, 12.19 ⁇ 0.2°, 15.51 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.67 ⁇ 0.2°, 8.78 ⁇ 0.2°, 10.28 ⁇ 0.2°, 11.02 ⁇ 0.2°, 12.19 ⁇ 0.2 °, 12.60 ⁇ 0.2°, 13.14 ⁇ 0.2°, 15.51 ⁇ 0.2°, 15.99 ⁇ 0.2°, 19.56 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .
  • the above-mentioned crystal form B contains 0.8-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form B contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I).
  • the present invention provides the crystalline form C of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 5.51 ⁇ 0.2°, 7.71 ⁇ 0.2°, 11.90 ⁇ 0.2°, 13.67 ⁇ 0.2°, 15.69 ⁇ 0.2°, 20.15 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • the above-mentioned crystal form C contains 2.0-3.0 molar equivalents of sulfuric acid relative to compound (I).
  • the above crystal form C contains 2.3, 2.4, 2.5, 2.6 or 2.7 molar equivalents of sulfuric acid relative to compound (I).
  • the above crystal form C is tetrahydrofuran and ethyl acetate solvate
  • the content of tetrahydrofuran in the tetrahydrofuran and ethyl acetate solvate is 0-10wt%
  • the content of ethyl acetate is 0-12wt% %.
  • crystal form C can be a single solvate of ethyl acetate, that is, when the content of tetrahydrofuran is 0wt%; or crystal form C can be a single solvate of tetrahydrofuran, that is, when the content of ethyl acetate is 0wt%; Or the crystal form C is a mixed solvate of tetrahydrofuran and ethyl acetate, that is, the content of tetrahydrofuran and ethyl acetate is not 0 wt%.
  • the above crystal form C is tetrahydrofuran and ethyl acetate solvate
  • the content of tetrahydrofuran in the tetrahydrofuran and ethyl acetate solvate is 4.1wt%, 4.2wt%, 4.3wt%, 4.4wt% %, 4.5wt%, 4.6wt%, 4.7wt%, 4.8wt%, 4.9wt%, 5.0wt%, 5.1wt%, 5.2wt%, 5.3wt%, 5.4wt%, 5.5wt%, 5.6wt%, 5.7wt%, 5.8wt%, 5.9wt%, 6.0wt%
  • the content of ethyl acetate is 0.1wt%.
  • the present invention provides the crystalline form D of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 6.85 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.78 ⁇ 0.2°, 16.36 ⁇ 0.2°, 19.84 ⁇ 0.2°, 20.66 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form D are shown in Table 4 below.
  • the above-mentioned crystal form D contains 0.2-0.8 molar equivalent of sulfuric acid relative to compound (I).
  • the above crystal form D contains 0.3, 0.4, 0.5 or 0.6 molar equivalent of sulfuric acid relative to compound (I).
  • the present invention provides the crystalline form E of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.52 ⁇ 0.2°, 8.93 ⁇ 0.2°, 11.04 ⁇ 0.2°, 12.16 ⁇ 0.2°, 12.82 ⁇ 0.2°, 22.67 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.52 ⁇ 0.2°, 8.52 ⁇ 0.2°, 8.93 ⁇ 0.2°, 11.04 ⁇ 0.2°, 12.16 ⁇ 0.2 °, 12.82 ⁇ 0.2°, 14.63 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.88 ⁇ 0.2°, 22.67 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form E are shown in Table 5 below.
  • the above-mentioned crystal form E contains 0.8-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystalline form E contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form E is an ethanol solvate, and the content of ethanol in the ethanol solvate is 5%-22%.
  • the above-mentioned crystal form E is an ethanol solvate, and the content of ethanol in the ethanol solvate is 17%, 18%, 19%, 20%, 21% or 22%.
  • the present invention provides the crystalline form F of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 5.40 ⁇ 0.2°, 13.01 ⁇ 0.2°, 18.09 ⁇ 0.2°, 21.65 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form F has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form F are shown in Table 6 below.
  • the above-mentioned crystal form F contains 1.0-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form F contains 1.1, 1.2, 1.3 or 1.4 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form F is methyl isobutyl ketone and dimethyl sulfoxide solvate, and methyl isobutyl ketone and dimethyl sulfoxide solvate are among the methyl isobutyl ketone and dimethyl sulfoxide solvate.
  • the content of the base ketone is 0-12 wt %, and the content of dimethyl sulfoxide is 0-17 wt %.
  • the crystal form F can be a single solvate of methyl isobutyl ketone, that is, when the content of dimethyl sulfoxide is 0 wt%; or the crystal form F can be a single solvate of dimethyl sulfoxide, That is, when the content of methyl isobutyl ketone is 0wt%; or crystal form F is a mixed solvate of methyl isobutyl ketone and dimethyl sulfoxide, that is, the mixture of methyl isobutyl ketone and dimethyl sulfoxide. The content is not 0 wt%.
  • the above-mentioned crystal form F is methyl isobutyl ketone and dimethyl sulfoxide solvate
  • methyl isobutyl ketone and dimethyl sulfoxide solvate are among the methyl isobutyl ketone and dimethyl sulfoxide solvate.
  • the content of the base ketone is 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1.0wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt% or 1.5wt%, two
  • the content of methyl sulfoxide is 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 14.6wt%, 14.7wt%, 14.8wt%, 14.9wt% or 15.0wt% .
  • the present invention provides the crystalline form G of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 5.88 ⁇ 0.2°, 7.05 ⁇ 0.2°, 9.39 ⁇ 0.2°, 10.87 ⁇ 0.2°, 12.00 ⁇ 0.2°, 16.15 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form G are shown in Table 7 below.
  • the present invention provides the crystalline form H of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 6.11 ⁇ 0.2°, 11.59 ⁇ 0.2°, 12.19 ⁇ 0.2°, 15.66 ⁇ 0.2°, 18.34 ⁇ 0.2°, 13.82 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 8 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form H are shown in Table 8 below.
  • the above crystal form H contains 0.5-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above crystal form H contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form H is an anhydrous crystal form.
  • the present invention provides a benzenesulfonate salt of a compound represented by formula (I).
  • the above-mentioned benzenesulfonic acid salt contains 0.5-3.0 molar equivalent of benzenesulfonic acid relative to compound (I).
  • the above-mentioned benzenesulfonic acid salt contains 1.0-2.5 molar equivalents of benzenesulfonic acid relative to compound (I).
  • the above-mentioned benzenesulfonate contains 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.7, 2.9 or 3.0 molar equivalents of benzenesulfonic acid.
  • the present invention provides the crystal form I of the benzenesulfonate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 7.63 ⁇ 0.2°, 12.05 ⁇ 0.2°, 13.78 ⁇ 0.2°, 15.09 ⁇ 0.2°, 16.04 ⁇ 0.2°, 18.35 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 7.63 ⁇ 0.2°, 11.35 ⁇ 0.2°, 12.05 ⁇ 0.2°, 13.78 ⁇ 0.2°, 15.09 ⁇ 0.2 °, 16.04 ⁇ 0.2°, 16.65 ⁇ 0.2°, 18.35 ⁇ 0.2°, 18.87 ⁇ 0.2°, 23.53 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form I are shown in Table 9 below.
  • the above-mentioned crystal form I contains 1.5-2.5 molar equivalents of benzenesulfonic acid relative to compound (I).
  • the above-mentioned Form I contains 1.6, 1.7, 1.8, 1.9, 2.0 or 2.1 molar equivalents of sulfuric acid relative to compound (I).
  • the present invention also provides a pharmaceutical composition
  • the pharmaceutical composition contains the sulfate salt of the compound represented by the formula (I) and the benzenesulfonic acid of the compound represented by the formula (I) as described above Salt or crystal forms A to I.
  • the present invention also proposes the sulfate salt of the compound represented by the formula (I), the benzenesulfonate salt of the compound represented by the formula (I), or the crystal forms A to I or the aforementioned compound represented by the formula (I).
  • the above-mentioned KRAS-G12C-related diseases are selected from non-small cell lung cancer, colon cancer and pancreatic cancer.
  • Crystalline refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts. Crystalline forms of materials can be obtained by a number of methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding in the presence of additives such as co-crystallizing anti-molecules, among others.
  • Amorphous or “amorphous form” refers to a substance formed when its particles (molecules, atoms, ions) are arranged aperiodically in three-dimensional space, characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural features suggest that it is inextricably linked with crystalline matter. Amorphous forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran
  • Antisolvent refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent.
  • the antisolvent may comprise a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
  • Solidvate means that the crystal has a solvent on the surface, or in the lattice, or both on the surface and in the lattice, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloride Carbon, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N- Dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene and mixtures thereof and
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the lattice, or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, or in the lattice, or both on the surface and in the lattice.
  • Crystalline or amorphous form can be identified by various techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry dissolution calorimetry
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form.
  • the peak positions of the XRPD patterns depend primarily on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • DSC Differential Scanning Calorimetry
  • an inert reference commonly ⁇ -Al 2 O 3
  • the melting peak heights of DSC curves depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors, and the peak positions and peaks of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the apparatus used in the experiments of the present invention, there is an error tolerance of ⁇ 3°C for the melting peak.
  • the glass transition refers to the transition of an amorphous substance between a highly elastic state and a glass state, which is an inherent property of the substance; its corresponding transition temperature is the glass transition temperature (Tg), which is an important part of the amorphous substance. physical properties. Glass transition is a phenomenon related to molecular motion, therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details and the like.
  • the amorphous glass transition temperature (Tg) of the present invention is determined by differential scanning calorimetry (DSC) and is characterized by having a glass transition temperature of 107.44°C. Depending on the condition of the instrumentation used in the experiments of the present invention, there is a tolerance of ⁇ 3°C for the glass transition temperature.
  • DSC Differential scanning calorimetry
  • Crystal transformation Due to the transformation of the crystal form, the mechanical, electrical, magnetic and other properties of the crystal will undergo great changes.
  • DSC differential scanning calorimetry
  • the transformation process can be observed on a differential scanning calorimetry (DSC) pattern, which is characterized in that the DSC pattern has an exothermic peak reflecting the transformation process, and There are two or more endothermic peaks at the same time, which are the characteristic endothermic peaks of different crystal forms before and after transformation.
  • DSC differential scanning calorimetry
  • Thermogravimetric analysis is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent. Case.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and between different samples.
  • the calcium salt crystal form A of the present invention loses about 5.1% in weight at a temperature of about 150°C. There is an error tolerance of ⁇ 0.3% for mass variation depending on the condition of the instrumentation used for the experiments of the present invention.
  • the 2 ⁇ values in an X-ray powder diffraction pattern are all in degrees (°).
  • the content unit “wt%” and the content unit “%” can be used interchangeably, and refer to the mass ratio (g/g), for example, in the hydrate, the moisture content of the crystal form A is 10.02%, which is It means that the ratio (g/g) of the mass of water in the crystal form A to the mass of the crystal form A is 10.02; for another example, in the solvate, the content of tetrahydrofuran in the crystal form C is 5.1wt%, which means that the crystal form The ratio (g/g) of the mass of tetrahydrofuran in Form C to the mass of the crystal form C (g/g) was 5.1.
  • a peak refers to a feature that would be recognized by those skilled in the art that would not be attributed to background noise.
  • substantially pure means that a crystalline form is substantially free of one or more other crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 93% pure, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, said The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • Relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the first intense peak when the intensity of the first intense peak is 100% among all diffraction peaks in an X-ray powder diffraction pattern (XRPD).
  • Fig. 1 is the X-ray powder diffraction (XRPD) pattern of crystal form A;
  • Fig. 2 is the X-ray powder diffraction (XRPD) pattern of crystal form B;
  • Fig. 3 is the X-ray powder diffraction (XRPD) pattern of crystal form C;
  • Fig. 4 is the X-ray powder diffraction (XRPD) pattern of crystal form D;
  • Fig. 5 is the X-ray powder diffraction (XRPD) pattern of crystal form E;
  • Fig. 7 is the X-ray powder diffraction (XRPD) pattern of crystal form G;
  • Figure 10 is a graph showing the relationship between the days of NCI-H358 cell inoculation and body weight change after administration of the compound of formula (I);
  • Figure 11 is a graph showing the relationship between the days of inoculation of NCI-H358 cells and tumor volume after administration of the compound of formula (I);
  • Figure 12 is the X-ray powder diffraction (XRPD) pattern of crystal form A with different water contents
  • Figure 13 is an X-ray powder diffraction (XRPD) pattern of sample X-1;
  • Figure 14 is the X-ray powder diffraction (XRPD) pattern of sample X-2;
  • Figure 15 is the X-ray powder diffraction (XRPD) pattern of sample X-3;
  • Figure 16 is an X-ray powder diffraction (XRPD) pattern of sample X-4.
  • the XRPD patterns were acquired on an X-ray powder diffraction analyzer produced by PANalytacal, and the scan parameters are shown in Table 10 below.
  • TGA and DSC graphs were collected on a TA Q5000/Discovery 5500 thermogravimetric analyzer and a TA Q2000/Discovery 2500 differential scanning calorimeter, respectively, and the test parameters are listed in Table 11.
  • Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 ) 2 and KCl. DVS test parameters are listed in Table 12.
  • the liquid nuclear magnetic spectrum of the present invention is collected on a Bruker 400M nuclear magnetic resonance apparatus, and DMSO-d 6 is used as a solvent.
  • the PLM image of the present invention was photographed by an Olympus SZX7 stereo microscope.
  • the dissociation constant of the compound of the present invention is obtained by the Sirius pKa log P/D tester (model: T3Dt).
  • the purity test, dynamic solubility and stability test are tested by Agilent 1260 high performance liquid chromatograph, and the salt molar ratio test of ions is tested by ion chromatography.
  • the analysis conditions are shown in Table 13 and Table 14.
  • Moisture test method (KF method): the present invention adopts the volumetric method to measure the moisture in the sample.
  • the parameters are shown in Table 15 below.
  • the moisture measurement based on the Karl Fischer method may produce an error within the range of ⁇ 0.3%, so it is necessary to calculate the moisture content of the sample.
  • the value is understood to include the numerical value within the range of about ⁇ 0.3%.
  • the embodiments of the present invention disclose salt forms and crystal forms of the compound of formula (I) and their preparation methods. Those skilled in the art can learn from the content of the present invention and appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications will be apparent to those skilled in the art, and they are deemed to be included in the present invention.
  • the method of the present invention has been described through preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention .
  • the raw material 8-1 (10 g, 52.351 mmol) was dissolved in thionyl chloride (30 mL), and the system was heated to 85° C. for 16 h. The system was concentrated, the residue was dissolved in 1,4 dioxane (30 mL), the solution was slowly added to stirring methanol at 0 °C, and the system was heated to 70 °C for reaction for 2 h. The system was concentrated to obtain compound 8-2.
  • the diastereomeric compound 29 was purified by SFC (ChiralPak AD, 250 ⁇ 30 mm ID, 10 ⁇ m; mobile phase: [CO 2 -ethanol (0.1% ammonia)]; % ethanol: 25%; flow rate: 60 mL/min; column temperature: 38°C). After concentration, the compound of formula (I) is obtained.
  • chromatographic column Waters XBridge 4.6*100mm, 3.5um; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min. SFC 100%ee. Retention time 4.349min.
  • the water content in the crystal form A was determined by KF test. The results are shown in Table 17. The water content in the sample is 10.0% (the theoretical crystal water content in the pentahydrate is about 10.3%).
  • Reference substance stock solution (0.5mg/ml): Precisely weigh about 50mg potassium sulfate into a 100ml measuring bottle, dissolve with diluent and make up to the mark, and mix well.
  • Reference substance solution (0.05mg/ml): Precisely pipette 1ml of reference substance stock solution into a 10ml volumetric flask, dilute to volume with diluent, and mix well.
  • Control solution the same as the preparation method of the reference solution.
  • Test solution (0.2mg/ml): Precisely weigh about 20mg of the test product into a 100ml volumetric flask, dilute to the mark with diluent, and mix well. Make 2 servings.
  • Blank interference The blank solution should have no interference (if there is interference, it should not exceed 0.2% of the main peak area of the first reference solution)
  • the reference solution is injected continuously for 5 needles, and the RSD of the main peak area should be less than or equal to 5%.
  • Recovery rate The recovery rate of the main peak area in the reference solution and the control solution should be between 95% and 105%.
  • the recovery rate of the main peak area in the returned reference solution should be 95% to 105%.
  • n molecular weight of sulfate (96)
  • the relative deviation of the two results should not exceed 2.0%.
  • the molar mass of free base is 688.20g/moL, and the molar mass of sulfuric acid is 98.07g/moL.
  • the sulfate crystal form B was obtained by suspending and stirring the sulfate crystal form A in a MeOH solvent system at room temperature for about 8 days, and drying the solid sample at room temperature for about one day.
  • the sulfuric acid (4M) and the initial free state sample (the compound of formula I) were charged in a molar ratio of 0.5:1, and the solid sample was centrifuged after stirring at room temperature in THF for about 4 days, and the XRPD was tested after being vacuum-dried at room temperature for about 8 hours to obtain Amorphous samples.
  • the amorphous sample was then suspended and stirred in ACN:H 2 O (19:1, v:v) at room temperature for about 2 days to obtain Form D.
  • Form E was obtained by slowly volatilizing a sample of sulfate crystal form A in EtOH/DCM (4:1, v/v) system.
  • Form F was obtained by suspending and stirring a sample of sulfate crystal form A in a DMSO:MIBK (1:19, v:v) solvent system at room temperature for about 5 days.
  • a sample of sulfate crystal form G was obtained by antisolvent addition of the initial free state sample (compound of formula I) in the EtOH/n-Heptane system.
  • the starting sample (compound of formula I) and benzenesulfonic acid in the free state were charged at 1:2 (molar ratio), and were suspended and stirred at room temperature for about 2 days in the EtOAc solvent system.
  • the solid sample was centrifuged and vacuum-dried at room temperature for 17 hours. It was cyclically heated and suspended in EtOAc solvent system for about 4 days, and the isolated solid was obtained after vacuum drying at room temperature for about 20 hours.
  • Phosphorylated ERK levels were detected using an enzyme-linked immunosorbent (ELISA) method.
  • Phosphorylated ERK antibody (Cell Signal Technology cat. no. 4370) was diluted 1:400 in 1X blocking solution containing 0.05% Tween 20, added to a 96-well plate and incubated overnight at 4°C. Plates were washed 5 times with PBS containing 0.05% Tween 20.
  • the HRP-conjugated secondary antibody (Thermo cat# 31460) was diluted 1:10,000 in 1X blocking solution containing 0.05% Tween 20, added to a 96-well plate and incubated for 2 hours at room temperature.
  • the total number of cells in each well was detected using Gena Green staining. After the phosphorylated ERK level was detected, the 96-well plate was washed with PBS until colorless, and 0.1% kena green (Abcam catalog number ab111622) was added and incubated for 10 minutes. After washing with double-distilled water, 0.1 mol/L HCl was added and incubated for 10 minutes with shaking. OD values were read at a wavelength of 595 nm using EnVision (PerkinElmer).
  • the signal of pERK(Thr202/Tyr204) was normalized using the signal value of Gena Green and the percent inhibition after drug treatment relative to the DMSO reference was calculated. Percentage values were fitted by a four-parameter dose-response curve and IC50 values were generated. The experimental results are shown in Table 24.
  • the compounds of the present invention exhibit an excellent ability to inhibit RAS-mediated signaling.
  • the growth inhibitory ability of the compounds of the present invention on KRAS-G12C expressing cells was evaluated by measuring the cell viability and calculating the GI50 value.
  • the tumor cell line NCI-H358 (ATCC catalog number CRL-5807) expressing KRAS-G12C was cultured in RPMI medium supplemented with 10% fetal bovine serum and penicillin/streptomycin
  • the tumor cell line MIA PaCa2 (ATCC CRL-1420) expressing KRAS-G12C was supplemented with 10% fetal bovine serum (fetal bovine serum), 2.5% horse serum (horse serum) and penicillin/streptomycin double antibody (penicillin/ streptomycin) in DMEM medium.
  • Cells NCI-H358, MIA-Paca2 were seeded in black clear bottom 384-well plates (PerkinElmer cat# 6007460) at 1000 and 800 cell densities, respectively, and cells were allowed to adhere overnight (8-12 hours).
  • the experimental group was added with the compound of the invention diluted 5 times the concentration of the working solution (the final concentration contained 0.1% dimethyl sulfoxide, namely DMSO); the control group was added with the same dilution as the experimental group (final concentration with 0.1% DMSO).
  • the amount of cell proliferation was determined by measuring ATP content using Cell Titer Glo reagent (Promega Cat. No. G7572) according to the manufacturer's method.
  • the brief operation steps are: take out the cell plate and place it at room temperature to equilibrate for 30 minutes; add the same volume of Cell Titer Glo reagent as the culture; place the plate on a shaker for 2 minutes, and let the plate stand at room temperature for 10 minutes ; Use a microplate reader EnVision (PerkinElmer) to read the light signal value.
  • mice Male ICR mice were given a single dose of the test compound 1 mg/Kg (intravenous injection, solvent 5% DMSO+15% Solutol+80% saline) and 5 mg/Kg (gavage administration, solvent 1%) Tween80/2%HPMC/97%water), blood was collected via orbital vein at 5, 15, 30 min, 1, 2, 4, 6, 8, 24hr after administration, each sample was collected about 0.20mL, heparin sodium anticoagulation, collected Place on ice and centrifuge within 1 hour to separate plasma for testing. The plasma concentration of the drug was detected by liquid tandem mass spectrometry (LC/MS/MS), and the measured concentration was used to calculate the pharmacokinetic parameters. The results are shown in Table 26 and Table 27 below.
  • Cell line xenograft experiments were performed to grow NCI-H358 tumors in mice. Once tumor size reached 300 mm3 , animals were randomized and treated with vehicle control (1% Tween80 + 1% HPMC) or compound (dose: 10 mg/kg/day, 30 mg/kg/day, 100 mg/kg/day, respectively) day, orally) treatment. Tumor volume was calculated using the formula) 0.5 ⁇ length ⁇ width ⁇ width. At the end of the experiment, animals were sacrificed, tumors were collected, weighed, and stored for additional analysis.

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Abstract

L'invention concerne une forme cristalline, type sel, et l'utilisation d'un composé de pyridinone condensé. Plus spécifiquement, l'invention concerne une forme cristalline, type sel, et l'utilisation d'un composé représenté par la formule (I).
PCT/CN2022/082855 2021-03-25 2022-03-24 Forme cristalline, type sel, et utilisation d'un composé de pyridinone condensé Ceased WO2022199669A1 (fr)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
WO2019110751A1 (fr) * 2017-12-08 2019-06-13 Astrazeneca Ab Composés tétracycliques en tant qu'inhibiteurs de la protéine ras mutante g12c, destinés à être utilisés en tant qu'agents anticancéreux
WO2020239123A1 (fr) * 2019-05-31 2020-12-03 上海翰森生物医药科技有限公司 Modulateur de dérivé hétérocyclique aromatique et son procédé de préparation et son utilisation
CN112300194A (zh) * 2019-07-30 2021-02-02 上海凌达生物医药有限公司 一类稠环吡啶酮类化合物、制备方法和用途
WO2021052499A1 (fr) * 2019-09-20 2021-03-25 上海济煜医药科技有限公司 Composé de pyridone fusionnée, son procédé de préparation et son utilisation
WO2021083167A1 (fr) * 2019-10-30 2021-05-06 劲方医药科技(上海)有限公司 Composé cyclique condensé hétérocyclique substitué, son procédé de préparation et son utilisation pharmaceutique
WO2022037630A1 (fr) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 Dérivé tétracylique, procédé de préparation de celui-ci et son utilisation en médecine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019110751A1 (fr) * 2017-12-08 2019-06-13 Astrazeneca Ab Composés tétracycliques en tant qu'inhibiteurs de la protéine ras mutante g12c, destinés à être utilisés en tant qu'agents anticancéreux
WO2020239123A1 (fr) * 2019-05-31 2020-12-03 上海翰森生物医药科技有限公司 Modulateur de dérivé hétérocyclique aromatique et son procédé de préparation et son utilisation
CN112300194A (zh) * 2019-07-30 2021-02-02 上海凌达生物医药有限公司 一类稠环吡啶酮类化合物、制备方法和用途
WO2021052499A1 (fr) * 2019-09-20 2021-03-25 上海济煜医药科技有限公司 Composé de pyridone fusionnée, son procédé de préparation et son utilisation
WO2021083167A1 (fr) * 2019-10-30 2021-05-06 劲方医药科技(上海)有限公司 Composé cyclique condensé hétérocyclique substitué, son procédé de préparation et son utilisation pharmaceutique
WO2022037630A1 (fr) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 Dérivé tétracylique, procédé de préparation de celui-ci et son utilisation en médecine

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