WO2023030492A1 - 一种ep4拮抗剂化合物及其盐、多晶型和用途 - Google Patents

一种ep4拮抗剂化合物及其盐、多晶型和用途 Download PDF

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WO2023030492A1
WO2023030492A1 PCT/CN2022/116768 CN2022116768W WO2023030492A1 WO 2023030492 A1 WO2023030492 A1 WO 2023030492A1 CN 2022116768 W CN2022116768 W CN 2022116768W WO 2023030492 A1 WO2023030492 A1 WO 2023030492A1
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crystal form
compound
formula
free acid
salt
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张学军
乐洋
臧杨
雷四军
夏庆丰
李园
刘哲
杨俊�
李莉娥
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Priority to KR1020247007045A priority Critical patent/KR102959367B1/ko
Priority to JP2024513882A priority patent/JP7819298B2/ja
Priority to US18/687,190 priority patent/US20240368088A1/en
Priority to EP22863626.2A priority patent/EP4397654A4/en
Priority to CA3230557A priority patent/CA3230557A1/en
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Definitions

  • the invention belongs to the field of medicine, and relates to an EP4 antagonist compound, its salt, polymorph, and its preparation method and application.
  • Prostaglandin E 2 is an endogenous bioactive lipid, and PGE 2 induces a wide range of upstream and downstream dependent biological responses by activating prostaglandin receptors (Legler, DF et al, hit. J Biochem .Cell Biol.2010,42,p.198-201), involved in the regulation of many physiological and pathological processes including inflammation, pain, renal function, cardiovascular system, lung function and cancer. It has been reported that PGE 2 is highly expressed in cancerous tissues of various cancers, and it has been confirmed that PGE 2 is associated with the initiation, growth and progression of cancer and disease conditions in patients. It is generally believed that PGE 2 is associated with the activation of cell proliferation and cell death (apoptosis), and plays an important role in the process of cancer cell proliferation, disease progression and cancer metastasis.
  • EP4 receptor antagonists are promising as anti-inflammatory and/or analgesic drugs to treat diseases related to PGE 2 -EP4 pathway, such as inflammatory diseases, diseases accompanied by various pains, and the like.
  • EP4 is a major receptor involved in arthritic pain in rodent models of rheumatoid arthritis and osteoarthritis (see e.g. J. Pharmacol. Exp. Ther., 325, 425 (2008)), which upon activation leads to intracellular Accumulation of the signaling molecule cAMP.
  • Expression of EP4 receptors has been detected on peripheral nerve endings of nociceptors, macrophages, and neutrophils, and these cell types have been shown to be extremely important for endometriosis.
  • EP4 antagonists are useful in the treatment of arthritis, including arthritis pain, as well as endometriosis, diabetic nephropathy, and overactive bladder.
  • the existing therapeutic drugs for arthritis are mainly traditional NSAIDs (non-steroidal anti-inflammatory drugs) or selective COX-2 inhibitors, which may cause cardiovascular and/or gastrointestinal side effects.
  • selective EP4 antagonists are less likely to produce cardiovascular side effects.
  • PGE 2 persistently activates EP receptors in the tumor microenvironment (produced in large quantities by tumor cells) (Ochs et al, J Neurochem. 2016, 136, p.1142-1154; Zelenay, S. et al, Cell 2015,162,p.1257-1270), which can promote the accumulation and enhance the activity of various immunosuppressive cells, including type 2 tumor-associated macrophages (TAMS), Treg cells and myeloid-derived suppressor cells (MDSCs) .
  • TAMS type 2 tumor-associated macrophages
  • MDSCs myeloid-derived suppressor cells
  • One of the main features of the immunosuppressive tumor microenvironment is the presence of a large number of MDSCs and TAMs, which in turn are associated with gastric cancer, ovarian cancer, breast cancer, bladder cancer, hepatocellular carcinoma (HCC), head and neck cancer, and other types of cancer patients. It is closely related to poor overall survival. Furthermore, PGE 2 has been reported to induce immune tolerance by inhibiting the accumulation of antigen-presenting dendritic cells (DCs) in tumors and inhibiting the activation of tumor-infiltrating DCs (Wang et al, Trends in Molecular Medicine 2016, 22, p .1-3). All these PGE 2 -mediated effects will collectively help tumor cells escape immune surveillance.
  • DCs antigen-presenting dendritic cells
  • PGE 2 plays a very important role in promoting the occurrence and development of tumors.
  • Increased expression levels of PGE 2 and its related receptors EP2 and EP4 have been found in various malignant tumors including colon cancer, lung cancer, breast cancer, and head and neck cancer, and are often closely related to poor prognosis (Bhooshan, N.et al. Lung Cancer 101, 88-91). Therefore, selectively blocking EP2 and EP4 signaling pathways can inhibit tumor development by changing the tumor microenvironment and regulating tumor immune cells.
  • the EP4 antagonist E7046 developed by Eisai also launched a phase I clinical study in 2015, and a phase Ib clinical trial in combination with radiotherapy or radiotherapy and chemotherapy for rectal cancer in 2017.
  • ONO-4578 developed by Ono Pharmaceutical launched a Phase I clinical trial for advanced or metastatic solid tumors in 2017, and a Phase I/II clinical trial for the treatment of advanced solid tumors as a single drug or in combination with nivolumab in 2018.
  • the compound of the formula I can effectively antagonize the activity of the EP4 receptor, and has broad application prospects in the preparation of drugs for the treatment of EP4-related diseases. Therefore, further research on the compound of the formula I and its salt form and crystal form is of great importance for the development of effective therapeutic drugs. significance.
  • the present invention provides a crystal form of a compound of formula I, wherein the structure of formula I is as follows:
  • the present invention provides the free acid crystal form A of the compound of formula I, the X-ray powder diffraction spectrum of the free acid crystal form A represented by 2 ⁇ 0.2° diffraction angle is at 7.88, 11.00, 12.13 , 16.10, 19.75, 20.65, 21.04, 22.92, 23.53, 26.69 have diffraction peaks; or the X-ray powder diffraction spectrum of the free acid crystal form A expressed at 2 ⁇ 0.2° diffraction angle is at 7.88, 8.08, 11.00, There are diffraction peaks at 12.13, 16.10, 19.75, 20.65, and 23.53; further, the X-ray powder diffraction spectrum of the free acid crystal form A expressed at 2 ⁇ 0.2° diffraction angle is at 7.88, 8.08, 11.00, 12.13, 13.59 , 15.50, 16.10, 19.44, 19.75, 20.65, 21.04, 22.92, 23.53, 25.32, 26.44, 26.69, 27.
  • the free acid crystalline form A has one, two or three of the following characteristics:
  • the TGA curve of the free acid crystal form A has a weight loss of about 0-2% at 150.0 ⁇ 3°C, preferably about 0-1% (for example, 0.84%);
  • the DSC curve of the free acid crystal form A has an endothermic peak at 136.8 ⁇ 3°C.
  • the free acid crystalline form A has one, two or three of the following characteristics:
  • the DSC curve of the free acid crystal form A has an endothermic peak at 136.8 ⁇ 3°C.
  • the TGA chart of the free acid crystal form A is shown in Figure 2; the DSC chart of the free acid crystal form A is shown in Figure 3; the 1 H NMR chart of the free acid crystal form A As shown in Figure 4.
  • the present invention provides the free acid crystal form B of the compound of formula I, the X-ray powder diffraction spectrum of the free acid crystal form B represented by 2 ⁇ 0.2° diffraction angle is at 7.38, 8.91, 11.07 . , 12.01, 17.85, 18.52, 19.38, 23.05, 26.01, and 26.76 have diffraction peaks; further, the X-ray powder diffraction spectrum of the free acid crystal form B expressed at 2 ⁇ ⁇ 0.2° diffraction angle is at 5.56, 6.00 , 7.38, 8.91, 11.07, 11.58, 12.01, 13.58, 14.16, 14.78, 17.85, 18.52, 19.38, 22.33, 23.05, 24.64, 26.01, 26.76 have diffraction peaks; still further, the free acid crystal form B is The X-ray powder diffraction spectrum represented by 2 ⁇ 0.2° diffraction angle is at 5.56, 6.00, 7.38, 8.27, 8.91, 11.07, 11.58,
  • the present invention provides a pharmaceutically acceptable salt of the compound of formula I, which can be selected from the compound of formula I and alkali metal salt (such as sodium salt or potassium salt), alkaline earth metal salt (such as calcium salt or magnesium salt) , ammonium salts, or salts formed with organic bases providing physiologically acceptable cations, such as salts formed with the following bases: sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, betaine, Monoethanolamine, caffeine, urea, niacinamide, isonicotine, dimethylglucosamine, ethylglucosamine, glucosamine, meglumine, lysine, arginine, choline, ammonia, di Cyclohexylamine, 1,6-hexanediamine, ethanolamine, diethanolamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, tromethamine, diethy
  • the pharmaceutically acceptable salt of the compound of formula I is tromethamine salt, diethylamine salt and lysine salt of the compound of formula I.
  • the molar ratio of the compound of formula I to the base can be 5:1 to 1:5, such as 3:1 , 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3.
  • the molar ratio of the compound of formula I to the base is 1:1.
  • the present invention provides a crystalline form of a pharmaceutically acceptable salt of the compound of formula I.
  • the present invention provides the tromethamine salt crystal form A of the compound of formula I, and the tromethamine salt crystal form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2 ⁇ 0.2° There are diffraction peaks at 6.03, 9.01, 13.50, 15.06, 18.09, and 24.27; further, the X-ray powder diffraction spectrum of the tromethamine salt crystal form A expressed at 2 ⁇ 0.2° diffraction angle is at 6.03, 9.01 , 13.50, 15.06, 16.03, 18.09, 24.27, 27.28, 30.39, and 36.72 have diffraction peaks; further, the tromethamine salt crystal form A has an XRPD spectrum basically as shown in FIG. 6 .
  • the tromethamine salt form A has one, two or three of the following characteristics:
  • the TGA curve of tromethamine salt crystal form A loses about 1.0-3.5% of the weight at 120.0 ⁇ 3°C, preferably about 2.0-3.0% (for example, 2.41%);
  • the DSC curve of the free acid crystal form A has an endothermic peak at 139.2 ⁇ 3°C.
  • the tromethamine salt form A has one, two or three of the following characteristics:
  • the DSC curve of the free acid crystal form A has an endothermic peak at 139.2 ⁇ 3°C.
  • the TGA chart of the tromethamine salt crystal form A is shown in Figure 7; the DSC chart of the tromethamine salt crystal form A is shown in Figure 8; the tromethamine The 1 H NMR chart of salt crystal form A is shown in FIG. 9 .
  • the present invention provides the diethylamine salt crystal form A of the compound of formula I, and the diethylamine salt crystal form A has an X-ray powder diffraction spectrum represented by 2 ⁇ 0.2° diffraction angle at 5.29 , 9.79, 10.53, 18.30, 19.61, 19.99, 21.10, 25.33, and 26.45 have diffraction peaks; further, the X-ray powder diffraction spectrum of the diethylamine salt crystal form A represented by 2 ⁇ 0.2° diffraction angle is in 5.29 ⁇ 9.79 ⁇ 10.53 ⁇ 11.20 ⁇ 12.52 ⁇ 14.85 ⁇ 15.20 ⁇ 16.22 ⁇ 16.86 ⁇ 18.30 ⁇ 19.61 ⁇ 19.99 ⁇ 21.10 ⁇ 22.12 ⁇ 22.47 ⁇ 24.57 ⁇ 24.85 ⁇ 25.33 ⁇ 26.45 ⁇ 27.39 ⁇ 28.01 ⁇ 29.61 ⁇ 32.13 ⁇ 35.00 ⁇ 37.44 ⁇ There are diffraction peaks; further, the diethylamine salt crystal form A has an X-ray powder
  • the diethylamine salt crystal form A has one or both of the following characteristics:
  • the TGA curve of diethylamine salt crystal form A has a weight loss of about 0.50-3.00% at 100.0 ⁇ 3°C, preferably about 1.00-2.50% (for example, 1.80%); a weight loss of about 2.00% at 210.0 ⁇ 3°C -5.00%, preferably about 3.00-4.50 (eg 3.99%);
  • the DSC curve of diethylamine salt form A has two endothermic peaks at 104.3 ⁇ 10°C and 121.5 ⁇ 10°C; in particular, the DSC curve of diethylamine salt form A is at 104.3 ⁇ 5°C and There are two endothermic peaks at 121.5 ⁇ 5°C.
  • the diethylamine salt crystal form A has one or both of the following characteristics:
  • the TGA curve of diethylamine salt crystal form A has a weight loss of about 1.80% at 100.0 ⁇ 3°C, and a weight loss of about 3.99% at 210.0 ⁇ 3°C;
  • the DSC curve of diethylamine salt form A has two endothermic peaks at 104.3 ⁇ 10°C and 121.5 ⁇ 10°C; in particular, the DSC curve of diethylamine salt form A is at 104.3 ⁇ 5°C and There are two endothermic peaks at 121.5 ⁇ 5°C.
  • the TGA chart of the diethylamine salt crystal form A is shown in Figure 11; the DSC chart of the diethylamine salt crystal form A is shown in Figure 12; the diethylamine salt crystal form The 1 H NMR chart of A is shown in FIG. 13 .
  • the present invention provides the lysine salt crystal form A of the compound of formula I, and the X-ray powder diffraction spectrum represented by the 2 ⁇ 0.2° diffraction angle of the lysine salt crystal form A is at 5.12 , 10.44, 15.56, 18.07, 19.61, and 21.10 have diffraction peaks; further, the X-ray powder diffraction spectrum of the lysine salt crystal form A represented by 2 ⁇ 0.2° diffraction angle is at 5.12, 10.44, 15.56, There are diffraction peaks at 18.07, 19.61, 21.10, 24.22, and 32.97; furthermore, the lysine salt crystal form A has an XRPD spectrum basically as shown in FIG. 14 .
  • the present invention provides a method for preparing the free acid crystal form A of the compound of formula I, which includes the following methods.
  • Method 1 Add the compound of formula I into organic solvent I and volatilize at room temperature; the organic solvent I can be selected from one or more of ethyl acetate, dichloromethane, methyl tert-butyl ether, isopropanol, and water kind of mix.
  • Method 2 Add anti-solvent crystallization to the compound of formula I in organic solvent II; if stirring without precipitation, add anti-solvent to the system;
  • the organic solvent II can be selected from methanol, methyl ethyl ketone, isoacetic acid Propyl ester, tetrahydrofuran, methyl tert-butyl ether, one or more mixtures of dimethylacetamide;
  • the anti-solvent can be selected from water, isopropyl ether, toluene, m-xylene, 4-methylisopropyl One or more mixtures of phenyl, n-pentane, n-heptane, cyclohexane, and methylcyclohexane.
  • Method 3 suspending and stirring the compound of formula I in an organic solvent III at room temperature for crystallization;
  • the organic solvent III may be selected from n-pentane, toluene, m-xylene, isopropyl ether, n-hexane, cyclohexane, methylcyclohexane Alkanes, water, methanol, N,N-dimethylformamide, 2-methyltetrahydrofuran, acetone, methyl acetate, dichloromethane, acetonitrile or a mixture of one or more;
  • Method 4 Suspend and stir the compound of formula I in an organic solvent IV at 40-60°C (for example, 50°C) to crystallize;
  • the organic solvent IV can be selected from methylcyclohexane, cumene, water, 1, 4-dioxane, dimethylacetamide, tetrahydrofuran, n-hexane, 2-methyltetrahydrofuran, n-pentane, methyl ethyl ketone, isopropyl acetate, toluene, isobutanol, chloroform, meta One or more mixtures of xylenes;
  • Method 5 Wet grinding and crystallizing the compound of formula I in an organic solvent V; the organic solvent V can be selected from ethanol, dichloromethane, ethyl acetate, and tetrahydrofuran in combination.
  • the present invention provides a method for preparing the free acid crystal form B of the compound of formula I, which comprises the following steps: dissolving the free acid crystal form A of the compound of formula I in an organic solvent B1 and then placing it in an atmosphere of an organic solvent B2 Obtained by gas-liquid diffusion;
  • the organic solvent B1 is selected from ketones, such as methyl ethyl ketone, methyl isopropyl ketone, acetone, diethyl ketone, dipropyl ketone, diisopropyl ketone, dibutyl Ketone, diisobutyl ketone;
  • the organic solvent B2 is selected from alkane organic compounds, preferably C1-C7 alkane organic compounds, such as selected from n-pentane, n-heptane, cyclohexane; in some embodiments,
  • the free acid crystal form A of the compound of formula I is dissolved in MIBK (methyl isobutyl ketone) and then diffused in
  • the present invention also provides a preparation method of a pharmaceutically acceptable salt of the compound of formula I, which comprises the following steps: mixing the compound of formula I with a salt-forming reagent (such as a corresponding base) in a suitable solvent.
  • a salt-forming reagent such as a corresponding base
  • the solvent is selected from one or a combination of ethanol, heptane, ethyl acetate, MTBE, acetonitrile, water, and acetone.
  • the present invention provides a pharmaceutical composition, which comprises the free acid crystal form of the compound of formula I (such as free acid crystal form A, free acid crystal form B), the compound of formula I pharmaceutically available One or more of the accepted salts, including crystalline forms thereof.
  • the present invention provides the free acid crystal form of the compound of formula I (such as free acid crystal form A, free acid crystal form B), the pharmaceutically acceptable salt of the compound of formula I (including its crystal form) or the
  • the application of the above-mentioned pharmaceutical composition in the preparation of medicine, the medicine is used for treating or preventing EP4-related diseases.
  • the EP4-related diseases include at least one selected from the following: inflammatory diseases, pain, cancer, metabolic diseases, urinary system diseases; the inflammatory diseases include at least one selected from the following: Arthritis, rheumatoid arthritis; the pain includes osteoarthritis pain, pain caused by endometriosis.
  • the free acid crystal form of the compound of formula I (such as free acid crystal form A, free acid crystal form B), the pharmaceutically acceptable salt of the compound of formula I (including its crystal form) or the
  • the pharmaceutical composition of can be administered in combination with radiation therapy and/or antibody therapy, wherein the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.
  • the cancer comprises solid cancer.
  • the cancer comprises breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer cancer, prostate cancer, skin cancer and urinary tract cancer.
  • the metabolic disease comprises diabetes and the urinary system disease comprises overactive bladder.
  • the free acid crystal form (such as free acid crystal form A, free acid crystal form B) of the compound of formula I described in the present invention, the pharmaceutically acceptable salt of the compound of formula I (including its crystal form) Or the pharmaceutical composition can provide better and more effective clinical treatment drugs or programs for patients in need.
  • the present invention also relates to a method for treating diseases related to EP4, the method comprising administering to the patient a therapeutically effective dose of the free acid crystalline form (such as free acid crystalline form A, free acid crystalline form B) of the compound of formula I, formula I A pharmaceutically acceptable salt of the compound (including its crystalline form) or a pharmaceutical formulation of the pharmaceutical composition.
  • a therapeutically effective dose of the free acid crystalline form such as free acid crystalline form A, free acid crystalline form B
  • the compound of formula I formula I
  • formula I A pharmaceutically acceptable salt of the compound (including its crystalline form) or a pharmaceutical formulation of the pharmaceutical composition.
  • the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein.
  • two or more kinds represent 2, 3, 4, 5, 6, 7, 8, 9, 10 or more kinds.
  • numbers it should be understood to recite both endpoints of the range, each integer within the range, and each decimal within the range.
  • “the number from 0 to 10” should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual, or human, and includes any of the following or more of: (1) preventing a disease: e.g., preventing a disease, disorder, or condition in an individual susceptible to the disease, disorder, or condition but not yet experiencing or developing disease pathology or symptoms; (2) inhibiting the disease: e.g., while experiencing or developing Suppressing a disease, disorder, or condition (i.e., arresting the further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition; Amelioration of a disease, disorder or condition (ie, reversal of pathology and/or symptoms) in an individual with symptoms or symptoms.
  • preventing a disease e.g., preventing a disease, disorder, or condition in an individual susceptible to the disease, disorder
  • pharmaceutically acceptable means that the formulation ingredients or active ingredients do not have an undue adverse effect on health for the general purpose of treatment.
  • pharmaceutically acceptable excipient or carrier means one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
  • Cosmetic herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier, wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive oil
  • the present invention provides the crystal form of the compound of formula I, which has good medicinal properties.
  • the free acid crystal form A has low hygroscopicity and good physical and chemical stability, which is beneficial to the storage, quality stability and further formulation of drugs.
  • the present invention obtains the pharmaceutically acceptable salt of the compound of formula I through optimization test screening, and further obtains the crystal form product of the salt, such as tromethamine salt crystal form A, diethylamine salt crystal form A, lysine salt Crystal form A, wherein, tromethamine crystal form A has low hygroscopicity and good physical and chemical stability, has higher solubility in biological solvents, and has better pharmaceutical value.
  • Fig. 1 is the XRPD spectrum of formula 1 compound free acid crystalline form A
  • Fig. 2 is the TGA figure of formula 1 compound free acid crystalline form A
  • Fig. 3 is the DSC figure of formula 1 compound free acid crystalline form A
  • Fig. 4 is the 1 H NMR figure of the free acid crystal form A of the compound of formula 1
  • Figure 5 is the XRPD spectrum of the free acid crystal form B of the compound of formula 1
  • Fig. 6 is the XRPD spectrum of formula 1 compound tromethamine salt crystal form A
  • Figure 7 is the TGA figure of formula 1 compound tromethamine salt crystal form A
  • Fig. 8 is the DSC figure of formula 1 compound tromethamine salt crystal form A
  • Figure 9 is the 1 H NMR figure of formula 1 compound tromethamine salt crystal form A
  • Figure 10 is the XRPD pattern of formula 1 compound diethylamine salt crystal form A
  • Figure 11 is the TGA figure of formula 1 compound diethylamine salt crystal form A
  • Figure 12 is the DSC figure of formula 1 compound diethylamine salt crystal form A
  • Fig. 13 is the 1 H NMR figure of formula 1 compound diethylamine salt crystal form A
  • Figure 14 is the XRPD spectrum of formula 1 compound lysine salt crystal form A
  • Figure 15 is a dynamic solubility curve at 37°C
  • Figure 16 is the XRPD overlay of the solubility sample of free acid crystal form A in H 2 O
  • Figure 17 is the XRPD overlay of the solubility sample of free acid crystal form A in SGF
  • Figure 18 is the XRPD overlay of the solubility sample of free acid crystal form A in FaSSIF
  • Figure 19 is the XRPD overlay of the solubility sample of free acid crystal form A in FeSSIF
  • Figure 20 is the XRPD overlay of the solubility sample of tromethamine salt form A in SGF
  • Figure 21 is the XRPD overlay of the solubility sample of tromethamine salt form A in FeSSIF
  • Figure 22 is the DVS diagram of free acid crystal form A
  • Figure 23 is the XRPD overlay of free acid crystal form A DVS before and after testing
  • Figure 24 is the DVS diagram of tromethamine salt crystal form A
  • Figure 25 is the XRPD overlay of tromethamine salt crystal form ADVS before and after testing
  • Figure 26 is the XRPD overlay of the free acid crystal Form A stability evaluation sample
  • Figure 27 is the XRPD overlay of the stability evaluation sample of tromethamine salt crystal form A
  • the instrument and detection method adopted in the present invention are as follows:
  • the XRPD pattern was collected on an X-ray powder diffraction analyzer produced by PANalytacal, and the scanning parameters are shown in Table A-1 below.
  • TGA Thermogravimetric Analysis
  • DSC Differential Scanning Calorimetry
  • TGA and DSC charts were collected on TA Q5000/5500 thermogravimetric analyzer and TA Q2000/2500 differential scanning calorimeter respectively, and the test parameters are listed in Table A-2 below.
  • Dynamic moisture sorption (DVS) curves were collected on 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. The DVS test parameters are listed in Table A-3 below.
  • the compound of formula I prepared according to the method of Example 2 was dissolved in a mixed solvent of dichloromethane and n-hexane (1:10, v/v), and concentrated to obtain the free acid crystal form A of the compound of formula I.
  • the XRPD of the obtained free acid crystal form A of the compound of formula I is shown in FIG. 1 .
  • TGA/DSC results show that the sample has a weight loss of 0.84% when heated to 150°C, and there is an endothermic peak at 136.8 ⁇ 3°C.
  • the 1 H NMR results of the free acid crystal form A are shown in FIG. 4 . In view of the low TGA weight loss of the free acid form A and only a single melting endotherm signal by DSC, it was presumed to be an anhydrous form.
  • the crystal form A of the free acid was dissolved in MIBK (methyl isobutyl ketone) and obtained by gas-liquid diffusion in n-pentane atmosphere (its XRPD pattern is shown in Figure 5).
  • Free acid crystal form B is transformed into free acid crystal form A after drying at room temperature.
  • Free acid crystal form A and equimolar amount of trometamol were slurried in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum-dried at room temperature to obtain formula I compound tromethamine salt crystal form A.
  • the XRPD pattern of tromethamine salt crystal form A sample is shown in FIG. 6 .
  • the TGA/DSC results are shown in Figures 7-8. TGA results showed that the sample had a weight loss of 2.41% when heated to 120°C; DSC results showed that the sample had an endothermic peak at 139.2°C (peak temperature). 1 H NMR was measured in CD 3 OD, and the results are shown in Fig. 9 . The results showed that the molar ratio of tromethamine to free acid in the tromethamine salt crystal form A was 1:1, and no MTBE solvent residue was observed.
  • Peak ID 2 ⁇ [°] Relative Strength[%] 1 6.0250 37.14 2 9.0145 100.00 3 13.5026 2.69 4 15.0624 5.41 5 16.0258 1.18 6 18.0940 14.19 7 24.2684 23.15 8 27.2793 1.85 9 30.3859 1.27 10 36.7231 1.30
  • the XRPD pattern of the diethylamine salt crystal form A sample is shown in FIG. 10 . See Figure 11-12 for TGA/DSC results.
  • the TGA results showed that the sample had a weight loss of 1.80% when heated to 100.0°C, and a weight loss of 3.99% when heated from 100.0°C to 210.0°C; the DSC results showed that the sample had two endothermic peaks at 104.3°C and 121.5°C (peak temperature).
  • 1 H NMR was measured in CD 3 OD, and the results are shown in Fig. 13 .
  • the results showed that the molar ratio of diethylamine to free acid in the diethylamine salt crystal form A was 1:1, and no MTBE solvent residue was observed.
  • the hygroscopicity of free acid crystal form A and tromethamine salt crystal form A was evaluated by dynamic moisture sorption instrument (DVS). Starting from 0% RH, the test collected the mass change percentage of the sample when the humidity changed (0% RH-95% RH-0% RH) under the constant temperature condition of 25°C. DVS test results and XRPD results before and after DVS test are shown in Figure 22-25. The results show that the moisture adsorption of the free acid crystal form A sample at 25°C/80%RH is 0.07%, indicating that it has almost no hygroscopicity; the weight of the tromethamine salt crystal form A sample at 25°C/80%RH is 0.6%, indicating that it is slightly hygroscopic. Free acid crystalline form A and tromethamine salt crystalline form A did not change after the DVS test.
  • Embodiment 11 solid state stability
  • Embodiment 12 Different preparation processes of the free acid crystal form A of the compound of formula I
  • the compound of formula I was prepared according to the process of Example 2, and the free acid crystal form A (identified by XRPD) could be prepared according to the following method.
  • the anti-solvent adopts water; when the dissolving solvent adopts methyl ethyl ketone, the anti-solvent adopts 4-isopropyltoluene or n-heptane; when the dissolving solvent adopts isopropyl acetate, the anti-solvent adopts water;
  • the solvent adopts cyclohexane or m-xylene; when the dissolving solvent is selected from tetrahydrofuran, the anti-solvent adopts water or toluene; when the dissolving solvent is selected from methyl tert-butyl ether, the anti-solvent is selected from methylcyclohexane; the dissolving solvent is selected from In the case of dimethylacetamide, the anti-solvent is selected from water.
  • the anti-solvent is n-heptane; when the dissolving solvent is one of acetone, tert-butyl acetate or chloroform
  • the anti-solvent is toluene; when the dissolving solvent is acetonitrile, the anti-solvent is water.
  • the solvent is selected from n-pentane, m-xylene, isopropyl ether, cyclohexane, water, methanol/water (1:5), N,N-dimethylformamide/water (1:4), 2 -Methyltetrahydrofuran/n-hexane (1:5), acetone/n-heptane (1:4), anisole/n-heptane (1:4), methyl acetate/cyclohexane (1:4), One of methanol/4-isopropyltoluene (1:4), dichloromethane/methyl-n-hexane (1:5), acetonitrile/toluene (1:4).
  • the solvent is selected from methylcyclohexane, cumene, water, 1,4-dioxane/water (1:9), dimethylacetamide/water (1:9), tetrahydrofuran/n-hexane Alkane (1:9), 2-methyltetrahydrofuran/cyclohexane (1:4), cyclopentyl methyl ether/n-pentane (1:4), methyl ethyl ketone/cumene (1:7 ), one of isopropyl acetate/toluene (1:9), isobutanol/4-isopropyltoluene (1:4), and chloroform/m-xylene (1:4).
  • the solvent is selected from toluene, n-heptane, 4-isopropyltoluene, ethanol/water (1:4), ethyl acetate/methylcyclohexane (1:9), cyclopentyl methyl ether/n-hexane (1:3), one of chloroform/n-heptane (1:7), methyl ethyl ketone/m-xylene (1:9).
  • the solvent is selected from one of ethanol, dichloromethane, ethyl acetate and tetrahydrofuran.

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KR1020247007045A KR102959367B1 (ko) 2021-09-03 2022-09-02 Ep4 길항제 화합물, 이의 염, 다형체 및 용도
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US18/687,190 US20240368088A1 (en) 2021-09-03 2022-09-02 Ep4 antagonist compound as well as salt, polymorph and use thereof
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