WO2019057104A1 - Sel d'un inhibiteur de dioxygénase, son procédé de préparation et son utilisation - Google Patents

Sel d'un inhibiteur de dioxygénase, son procédé de préparation et son utilisation Download PDF

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WO2019057104A1
WO2019057104A1 PCT/CN2018/106652 CN2018106652W WO2019057104A1 WO 2019057104 A1 WO2019057104 A1 WO 2019057104A1 CN 2018106652 W CN2018106652 W CN 2018106652W WO 2019057104 A1 WO2019057104 A1 WO 2019057104A1
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acid
cancer
salt
compound
formula
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Chinese (zh)
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呙临松
刘福萍
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles

Definitions

  • the invention belongs to the field of medicine and relates to (Z)-N-(3-bromo-4-fluoro-phenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfinyl) Salt of imino)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine, preparation method and application thereof, the invention discloses as an IDO inhibitor for treatment A disease having an IDO-mediated pathological feature of a tryptophan metabolism pathway, including cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder, and AIDS.
  • Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries.
  • the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%.
  • Ageing, urbanization, industrialization and lifestyle changes In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy.
  • the host's natural defense mechanisms such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
  • the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
  • Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • other cytokines they can activate IDO under certain conditions.
  • IDO In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels.
  • IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells;
  • IDO catalyzes the main product produced by the metabolism of tryptophan.
  • Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
  • Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
  • the present invention relates to a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof,
  • M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1- Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxynonanoic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-amino Benzoic acid, citric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid,
  • y is an integer of 1, 2 or 3.
  • a preferred embodiment of the invention is characterized by a salt of the compound shown, a stereoisomer thereof or a mixture thereof, characterized in that it is selected from the group consisting of the salts of the compounds of formula (II):
  • a preferred embodiment of the invention is characterized by the salt of the compound shown, its stereoisomer or a mixture thereof, characterized in that it is selected from the salt of the compound of formula (II-1):
  • a preferred embodiment of the invention is characterized in that the salt of the compound of the formula (I), its stereoisomer or a mixture thereof is characterized by its free base crystalline form, characterized by having a ratio of 15.9, 17.2 , 17.9, 19.7, 20.5, 21.1, 22.8, 27.0, 27.5, 28.1, 30.5, 33.6 and 35.5 ⁇ 0.2° diffraction angle 2 ⁇ ( ⁇ 0.2°) shows the XRPD of the peak with a melting peak of 176.4 ⁇ 0.5 ° C on the DSC .
  • a preferred embodiment of the invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, wherein M is selected from the group consisting of phosphoric acid, maleic acid and adipic acid , benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, fumaric acid and L-malic acid.
  • a preferred embodiment of the present invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, wherein M is selected from adipic acid, benzenesulfonic acid, and para Benzobenzenesulfonic acid, tartaric acid and fumaric acid; preferably benzenesulfonic acid and p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.
  • a preferred embodiment of the invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, wherein y is 1.
  • a preferred embodiment of the present invention is characterized by the salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, characterized in that when M is p-toluenesulfonic acid, it is a pair Methylbenzenesulfonate characterized by having diffraction angles 2 ⁇ ( ⁇ 0.2°) at 6.1, 9.6, 10.4, 14.8, 16.0, 17.1, 18.6, 19.4, 20.8, 22.1, 23.3, 24.6, 26.0 and 28.5 ⁇ 0.2°.
  • the XRPD of the peak is shown to have a melting peak of 162.7 ⁇ 0.5 ° C on the DSC;
  • M is benzenesulfonic acid, i.e., besylate
  • M is benzenesulfonic acid, i.e., besylate
  • it is characterized by having 5.2, 6.1, 7.6, 9.5, 10.4, 10.4, 11.2, 14.1, 15.7, 16.0, 17.0, 18.2, 18.7, 19.4, 21.3, 22.2. , 22.6, 23.0, 23.6, 24.5, 24.9, 26.1, 26.5, 26.9, 28.7, 29.3, 30.6, 33.3, 34.5, 35.6, 36.5 and 41.0 ⁇ 0.2° diffraction angle 2 ⁇ ( ⁇ 0.2°) shows the XRPD of the peak, The DSC has a melting peak of 152.3 ⁇ 0.5 °C.
  • the invention further relates to a preparation scheme for the preparation of a salt of the compound of the formula (I), comprising the steps of:
  • Preparation of stock solution take the free compound of the general formula, add organic solvent to dissolve, to obtain a clear stock solution, the solution concentration is: 20 ⁇ 30mg / mL; the organic solvent is preferably ethyl acetate, the solution concentration is preferably 25mg / mL;
  • the organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butyl Ketone, 3-pentanone, heptane, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethyl acetate, ethanol ;
  • the counter ion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid
  • the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid and 1-hydroxy-2-naphthoic acid.
  • the invention further relates to a preparation scheme for the preparation of a salt of the compound of the formula (I), comprising the steps of:
  • the benign solvent is preferably ethyl acetate
  • the poor solvent is preferably heptane and dichloromethane
  • the benign solvent is selected from the group consisting of acetone, 2-butanone, tetrahydrofuran, 1,4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate or acetonitrile; preferably ethyl acetate, ethanol, 2 - Butanone, 1,4-dioxane and acetone.
  • the organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butyl Ketone, 3-pentanone, heptane, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethyl acetate, ethanol
  • the above-mentioned benign solvent and organic solution need to be mutually soluble when used;
  • the poor solvent is selected from the group consisting of heptane, dichloromethane, water, methyl tert-butyl ether, toluene, diisopropyl ether or ethanol; preferably heptane and dichloromethane;
  • the counter ion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid
  • the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid and 1-hydroxy-2-naphthoic acid.
  • the invention further relates to a preparation scheme, wherein the solvent is ethyl acetate or ethanol.
  • the invention further relates to a preparation scheme, wherein the counter ion acid is benzenesulfonic acid and p-toluenesulfonic acid.
  • a solution of a composition of the invention a pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.
  • the salt of the compound of the formula (I), the stereoisomer thereof or a mixture thereof, or the composition thereof is prepared for prevention and/or treatment with IDO-mediated
  • the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease , depression, anxiety, cataract, psychological disorder and AIDS;
  • the cancer is preferably selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor , head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer.
  • the present invention also relates to a method of treating a disease preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  • viruses such as
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the method exhibits outstanding efficacy and less side effects, wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor Head and neck tumors, leukemias, lymphomas, myelomas and non-small cell lung cancers, preferably fallopian tube tumors, peritoneal tumors, stage IV melanoma, myeloma and breast cancer, more preferably breast cancer.
  • the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer
  • Figure 1 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of free base.
  • Figure 2 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of phosphate.
  • Figure 3 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of maleate salt.
  • Figure 4 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of adipate salt.
  • Figure 5 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of besylate.
  • Figure 6 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of p-toluenesulfonate.
  • Figure 7 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of citrate.
  • Figure 8 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of malonate.
  • Figure 9 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of L-malate.
  • Figure 10 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of tartrate.
  • Figure 11 is a graphical representation of the fumarate DSC-TGA (differential heat-thermogravimetric analysis).
  • Figure 12 is a graphical representation of the results of physical stability experiments for p-toluenesulfonic acid.
  • Figure 13 is a graphical representation of the results of the physical stability test of besylate.
  • Figure 14 is a graphical representation of the results of a polycrystalline screening experiment for p-toluenesulfonate.
  • Figure 15 is a graphical representation of the results of polystyrene screening experiments for besylate.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • TGA Thermogravimetric Analysis
  • Differential Scanning Calorimetry refers to differential scanning calorimetry (DSC) experiments.
  • Mobile phase A: water (0.1% trifluoroacetic acid);
  • Example 1 Preparation by natural evaporation method
  • the solution was sonicated to obtain a clear solution at a solution concentration of 25 mg/mL.
  • a salt solution of 2 was added to 1 mL of the stock solution 1, and it was naturally evaporated, and dried under vacuum at 60 ° C to obtain a salt of the corresponding compound.
  • Figure 1 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of free base
  • Figure 2 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of phosphate
  • Figure 3 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of maleate
  • Figure 4 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of adipate salt
  • Figure 5 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of besylate
  • Figure 6 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of p-toluenesulfonate;
  • FIG. 7 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of citrate
  • Figure 8 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of malonate
  • Figure 9 Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of L-malate.
  • the benign solvent is selected to dissolve the compound, and the compound is crystallized out with a poor solvent.
  • Benign solvent acetone, 2-butanone (MEK), tetrahydrofuran (THF), 1,4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile;
  • Counterionic acid methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, L-malic acid.
  • 2 benign solvents are: acetone, THF, 1,4-dioxane; anti-solvent: heptane, dichloromethane;
  • 3 benign solvents are: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: ethanol, isopropanol;
  • 4 benign solvents are: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: methyl tert-butyl ether, isopropyl ether;
  • the benign solvents are: 2-butanone, 1,4-dioxane and ethyl acetate; the anti-solvent is: dichloromethane, n-heptane;
  • Counterion acid solution solvent ethanol.
  • the former indicates the amount of the anti-solvent added, expressed by volume or weight, and the latter indicates the phenomenon exhibited by the salt solution after the addition of the anti-solvent to the volume or weight.
  • the benign solvent is ethyl acetate and the antisolvent is heptane, phosphate, maleate, adipate, benzenesulfonate, p-toluenesulfonate, citrate, C Diacid salts, tartrate salts, fumarate salts and L-malate salts are all present in large amounts.
  • the molar ratio of the counter ion was changed to 0.6 and 2.2 (the molar ratio is the ratio of the number of counterions to the number of moles of free base).
  • the same crystallization process was used to investigate the feasibility of the salt crystallization process and the salt reaction ratio.
  • the mass percentage of free base in the crystalline product was determined by HPLC and external standard method, and compared with the mass percentage of the theoretical reaction ratio.
  • sample name Free base was measured in the crystal Theoretical free base in salt
  • solids By changing the amount of counterion of the feed, solids can be crystallized out; the solids which are crystallized are subjected to free base quantification, and most of the precipitated crystals are free bases, and a salt having a molar ratio of 1:1 is not formed.
  • the molar ratio of the counter ion charge is in the range of 1 to 1.2, p-toluenesulfonic acid and benzenesulfonate having a stoichiometric ratio of 1:1 can be formed.
  • Example 4 Simulating the solubility test in artificial gastrointestinal
  • Approximately 2 mg of the compound was suspended in 1 mL of artificial simulated gastric juice (SGF), fasted artificial simulated intestinal fluid (Fa), non-fasted artificial simulated intestinal fluid (Fe), and pure water for 16 hours, and the compound was determined by HPLC and external standard method. Thermodynamic solubility.
  • SGF artificial simulated gastric juice
  • Fe fasted artificial simulated intestinal fluid
  • Fe non-fasted artificial simulated intestinal fluid
  • pure water pure water
  • the physicochemical stability of the candidate compound salt under accelerated conditions or influencing factors was investigated to provide a basis for salt screening and compound salt storage.
  • the compound p-toluenesulfonate was extremely unstable at 50 ° C & RH 75%. After 5 days of storage, the impurity increased by more than 40%. After being placed at 30 ° C & RH 65% for 5 days, the related substances increased by 0.63%, and the RH was 75%. After being placed at room temperature for 5 days and 10 days, the increase of related substances was not obvious, and the impurity increased by 0.22% in 10 days; the compound p-toluenesulfonate was stable under high temperature (70 ° C) for 10 days, and the impurity only increased by 0.06%; Under light conditions, the compound p-toluenesulfonate was slightly degraded for 5 days and 10 days. Therefore, the compound p-toluenesulfonate should be protected from moisture and light.
  • the compound benzenesulfonate did not increase significantly, but the content decreased significantly.
  • the compound besylate was stable under high temperature (70 °C) for 5 days, and the impurity increased suddenly for 10 days. More than %; under light conditions, the compound p-toluenesulfonate was degraded for 5 days and 10 days.
  • the hygroscopicity of the compounds under different relative humidity conditions was investigated to provide a basis for screening and storage of the compound salts.
  • the compound salt is placed in saturated water vapor of different relative humidity to achieve a dynamic equilibrium between the compound and the water vapor, and the percentage of moisture absorption and weight gain of the compound after equilibrium is calculated.
  • the p-toluenesulfonate was not wetted under RH 75% conditions (Chinese Pharmacopoeia 2015 edition), and the besylate salt had hygroscopicity under RH 75% conditions. And the p-methylbenzenesulfonate is hygroscopically and desorbed four times under the condition of 0-95% relative humidity, and the XRPD mode is not changed, that is, there is no crystal transformation; the besylate salt crystallizes under the same treatment conditions. Type change.
  • p-toluenesulfonate is superior to besylate.
  • the compound p-toluenesulfonate can be converted into a free base by beating in water, and besed in other solvents EtOH, DCM, 88% acetone and ethyl acetate.
  • EtOH, DCM, 88% acetone and ethyl acetate The compound is stable to the methylbenzenesulfonate crystal form and is not converted into other Stable crystal form.
  • the compound besylate is not converted to a free form in water except for beating in ethyl acetate, and is converted to a free base in water, and crystal transformation occurs in other solvents.
  • the p-toluenesulfonate of the compound significantly increases the exposure of the compound in rats.

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Abstract

La présente invention concerne un sel d'un inhibiteur de dioxygénase, son procédé de préparation et son utilisation, en particulier un sel de (Z)-N-(3-bromo-4-fluoro-phényl)-4-((2-(N-(cyclopropylsulfonyl)-S-méthylsulfinylimine)éthyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine ayant la structure de formule générale (I), son procédé de préparation et son utilisation, ainsi qu'une composition pharmaceutique comprenant une quantité efficace sur le plan thérapeutique du sel. Le sel peut être largement utilisé dans le traitement ou la prévention de cancers ou de tumeurs, d'infections virales, de la dépression, une maladie neurodégénérative, un traumatisme, la cataracte liée à l'âge, le rejet de greffe d'organe ou des maladies auto-immunes, et est supposé être développé en une nouvelle génération d'immunosuppresseurs, la définition de chaque substituant dans la formule générale (I) étant la même que celle définie dans la description.
PCT/CN2018/106652 2017-09-20 2018-09-20 Sel d'un inhibiteur de dioxygénase, son procédé de préparation et son utilisation Ceased WO2019057104A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005958A2 (fr) * 2008-07-08 2010-01-14 Incyte Corporation 1,2,5-oxadiazoles constituant des inhibiteurs de l'indoleamine 2,3-dioxygénase
WO2016041489A1 (fr) * 2014-09-15 2016-03-24 中国科学院上海有机化学研究所 Inhibiteur de l'indoleamine-2,3-dioxygénase et son procédé de préparation
WO2017181849A1 (fr) * 2016-04-20 2017-10-26 江苏豪森药业集团有限公司 Inhibiteur de l'indoléamine 2,3-dioxygénase, procédé pour sa préparation et application

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016155545A1 (fr) * 2015-03-31 2016-10-06 江苏恒瑞医药股份有限公司 Dérivé de 1,2,5-oxadiazole contenant un groupe sulfamyle, son procédé de préparation et son utilisation dans des produits pharmaceutiques
CN107304191B (zh) * 2016-04-20 2023-09-29 上海翰森生物医药科技有限公司 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005958A2 (fr) * 2008-07-08 2010-01-14 Incyte Corporation 1,2,5-oxadiazoles constituant des inhibiteurs de l'indoleamine 2,3-dioxygénase
WO2016041489A1 (fr) * 2014-09-15 2016-03-24 中国科学院上海有机化学研究所 Inhibiteur de l'indoleamine-2,3-dioxygénase et son procédé de préparation
WO2017181849A1 (fr) * 2016-04-20 2017-10-26 江苏豪森药业集团有限公司 Inhibiteur de l'indoléamine 2,3-dioxygénase, procédé pour sa préparation et application

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