WO2019057104A1 - Salt of dioxygenase inhibitor and preparation method therefor and use thereof - Google Patents
Salt of dioxygenase inhibitor and preparation method therefor and use thereof Download PDFInfo
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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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
The present invention relates to a salt of a dioxygenase inhibitor and a preparation method therefor and the use thereof, in particular relates to a salt of (Z)-N-(3-bromo-4-fluoro-phenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfinylimine)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine having the structure of general formula (I), a preparation method therefor and the use thereof, and a pharmaceutical composition comprising a therapeutic effective amount of the salt. The salt can be widely used to treat or prevent cancers or tumours, virus infections, depression, neurodegenerative disease, trauma, age-related cataract, organ-graft refection or autoimmune diseases, and is expected to be developed into a new generation of immunosuppressors, wherein the definition of each substituent in the general formula (I) is the same as defined in the description.
Description
本发明属于医药领域,涉及(Z)-N-(3-溴-4-氟-苯基)-4-((2-(N-(环丙基磺酰基)-S-甲基亚磺酰亚胺)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-甲脒的盐、制备方法及其应用,本发明公开了其作为IDO抑制剂,用于治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病,所述的疾病包括癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。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.
肿瘤是严重危害人类生命的重大疾病之一,一半以上发生在发展中国家。我国恶性肿瘤发病率总体呈上升趋势,发病率以年均3%~5%的速度递增,预计到2020年,我国将有400万人发生癌症,300万人死于癌症,其主要原因是:老龄化、城镇化、工业化及生活习惯改变。在中国医院用药市场,抗肿瘤药物的销售规模近几年来一直稳步增长,2012年达到了664.2亿元,同比增长了13.07%,预计到2017年,抗肿瘤药物的市场规模将达到1055.7亿元,同比增长7.57%。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%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die of cancer. The main reasons are: 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%.
由于恶性肿瘤的无限制生长与浸润、转移,现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞,因此常出现肿瘤转移或复发。肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法,因其安全、有效、不良反应低等特点,成为继手术、放疗、化疗之后肿瘤治疗的第四种模式,其通过调动宿主的天然防御机制(比如抑制IDO介导的肿瘤免疫逃逸机制)或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. 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.
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase,IDO)是一种含铁血红素单体蛋白,由403个氨基酸残基组成,包括两个折叠的α-螺旋结构域,大结构域包含催化口袋,底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶,广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中,是肝脏以外唯一可催化色氨酸分解代谢的限速酶,而色氨酸是细胞维持活化和增殖所必需的氨基酸,也是构成蛋白质不可缺少的重要成分。IDO与干扰素(interferon,IFN)、白细胞介素(interleukin,IL)、肿瘤坏死因子等多种细胞因子关系密切,它们在一定条件下可激活IDO。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点,一方面,IDO使局部色氨酸耗竭,致使T-细胞停滞于G1期中期,从而抑制了T细胞的增殖;另一方面,IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡,这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白血病细胞中较高表达,使局部T细胞增殖受抑,抑制T-细胞介导的免疫反应,使T-细胞活化信号转导受阻,从而介导肿瘤细胞逃逸免疫系统的攻击。已经发现 大多数人类肿瘤组成性地表达IDO。因此,IDO是一个具潜力的癌症免疫治疗的靶标。Indoleamine-pyrrole-2,3-dioxygenase (IDO) 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 is closely related to interferon (IFN), interleukin (IL), tumor necrosis factor and other cytokines, and they can activate IDO under certain conditions. In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels. On the one hand, IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells; On the other hand, 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. A large number of studies have shown that 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.
PCT专利(申请号:PCT/CN2017/079585)中公开了(Z)-N-(3-溴-4-氟-苯基)-4-((2-(N-(环丙基磺酰基)-S-甲基亚磺酰亚胺)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-甲脒的结构,在后续的研发中,为了产物易于处理、过滤和干燥,寻求适合的便于储存、产品长期稳定等特点,本发明对上述物质的盐进行了全面的研究,致力于得到最适合的盐型。(Z)-N-(3-Bromo-4-fluoro-phenyl)-4-((2-(N-(cyclopropylsulfonyl)) is disclosed in PCT Patent Application No. PCT/CN2017/079585 -S-methylsulfinimide)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazol-3-carboxamidine, in the subsequent development, for easy handling of the product, Filtration and drying, seeking suitable storage, long-term stability of the product, etc., the present invention has carried out a comprehensive study on the salt of the above substances, and is committed to obtaining the most suitable salt type.
发明内容Summary of the invention
本发明涉及一种通式(I)所示的化合物的盐、其立体异构体或其混合物形式,The present invention relates to a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof,
其中:among them:
M为无机酸或有机酸,其中所述无机酸选自盐酸、硫酸、氢溴酸、氢氟酸、氢碘酸或磷酸,所述有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸;且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, glutamic acid, isoascorbic acid , lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, Galactose, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid , malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicin , 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; And
y为1、2或3的整数。y is an integer of 1, 2 or 3.
本发明的一个优选方案,特征在于所示化合物的盐、其立体异构体或其混合物形式,其特征在于,选自式(II)化合物的盐: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):
其中:M和y的定义如通式(I)所述。Wherein: M and y are as defined in the general formula (I).
本发明的一个优选方案,特征在于所示化合物的盐、其立体异构体或其混合物形式,其特征在于,选自式(II-1)化合物的盐: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):
其中:M和y的定义如通式(I)所述。Wherein: M and y are as defined in the general formula (I).
本发明的一个优选方案,特征在于所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其自由碱结晶形式,特征在于具有在15.9,17.2,17.9,19.7,20.5,21.1,22.8,27.0,27.5,28.1,30.5,33.6与35.5±0.2°的衍射角2θ(±0.2°)显示峰的XRPD,在于DSC上具有176.4±0.5℃的熔融峰。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 2θ (±0.2°) shows the XRPD of the peak with a melting peak of 176.4 ± 0.5 ° C on the DSC .
本发明的一个优选方案,特征在于所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其中M选自磷酸、马来酸、己二酸、苯磺酸、对甲基苯磺酸、柠檬酸、酒石酸、富马酸和L-苹果酸。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.
本发明的一个优选方案,特征在于所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其中M选自己二酸、苯磺酸、对甲基苯磺酸、酒石酸和富马酸;优选苯磺酸和对甲基苯磺酸;更优选对甲基苯磺酸。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.
本发明的一个优选方案,特征在于所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其中y为1。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.
本发明的一个优选方案,特征在于所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,当M为对甲基苯磺酸,即为对甲基苯磺酸盐,特征在于具有在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与28.5±0.2°的衍射角2θ(±0.2°)显示峰的XRPD,在于DSC上具有162.7±0.5℃的熔融峰;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 2θ (±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;
当M为苯磺酸,即为苯磺酸盐时,特征在于具有在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与41.0±0.2°的衍射角2θ(±0.2°)显示峰的XRPD,在于DSC上具有152.3±0.5℃的熔融峰。When 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 2θ (±0.2°) shows the XRPD of the peak, The DSC has a melting peak of 152.3 ± 0.5 °C.
本发明的还涉及一种制备方案,制备所述的通式(I)所示化合物的盐的方法,包括如下步骤: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:
1)储备液制备:取通式化合物自由碱,加入有机溶剂溶解,得到澄清储备液溶液,溶液浓度为:20~30mg/mL;有机溶剂优选乙酸乙酯,溶液浓度优选25mg/mL;1) 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;
2)反离子酸溶液制备:把反离子酸加入有机溶剂中,得到澄清的反离子酸溶液;有机溶剂优选为乙醇,浓度优选为0.25~2摩尔/升;2) Preparation of a counter-ion acid solution: adding a counter-acid to an organic solvent to obtain a clear counter-acid solution; the organic solvent is preferably ethanol, and the concentration is preferably 0.25 to 2 mol/liter;
3)化合物盐制备:储备液加入反离子酸溶液,得澄清盐溶液,自然挥干,真空干燥后得到通式(I)所示化合物的盐;真空温度优选60℃,反离子酸的量优选1~1.2当量;3) Preparation of compound salt: the stock solution is added to the counterion acid solution to obtain a clear salt solution, which is naturally evaporated, and dried under vacuum to obtain a salt of the compound of the formula (I); the vacuum temperature is preferably 60 ° C, and the amount of the counter ion acid is preferably 1 to 1.2 equivalents;
其中:among them:
所述的有机溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、丙酮、正己烷、石油醚、苯、甲苯、氯仿、乙腈、四氯化碳、二氯乙烷、四氢呋喃、2-丁酮、3-戊酮、庚烷、甲基叔丁基醚、异丙醚、1,4-二氧六环、叔丁醇或N,N-二甲基甲酰胺;优选乙酸乙酯、乙醇;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 ;
所述的反离子酸选自盐酸、硫酸、氢溴酸、氢氟酸、氢碘酸或磷酸,所述有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸;优选甲磺酸、硫酸、磷酸、苯磺酸、马来酸、己二酸、对甲基苯磺酸、柠檬酸、丙二酸或L-苹果酸;最优选苯磺酸和对甲基苯磺酸。The counter ion 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 and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin Acid, bismuth Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.
本发明的还涉及一种制备方案,制备所述的通式(I)所示化合物的盐的方法,包括如下步骤: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:
1)称取适量的自由碱,用良性溶剂溶解;良性溶剂优选乙酸乙酯;1) Weigh an appropriate amount of free base and dissolve it with a benign solvent; the benign solvent is preferably ethyl acetate;
2)称取1~3当量反离子酸,用有机溶剂溶解;有机溶剂优选乙醇;反离子酸的量优选1.2当量;2) weigh 1-3 equivalents of counterion acid, dissolved in an organic solvent; organic solvent is preferably ethanol; the amount of counterion acid is preferably 1.2 equivalents;
3)把上述两种溶液合并,并滴加不良溶剂直至出现浑浊,或搅拌过夜;不良溶剂优选庚烷和二氯甲烷;3) Combine the above two solutions, and add a poor solvent until turbidity occurs, or stir overnight; the poor solvent is preferably heptane and dichloromethane;
4)静置或吹干得通式(I)所示化合物的盐;4) standing or blow drying to obtain a salt of the compound of the formula (I);
其中:among them:
所述的良性溶剂选自丙酮、2-丁酮、四氢呋喃、1,4-二氧六环、3-戊酮、2-甲基四氢呋喃、乙酸乙酯或乙腈;优选乙酸乙酯、乙醇、2-丁酮、1,4-二氧六环和丙酮。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.
所述的有机溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、丙酮、正己烷、石油醚、苯、甲苯、氯仿、乙腈、四氯化碳、二氯乙烷、四氢呋喃、2-丁酮、3-戊酮、庚烷、甲基叔丁基醚、异丙醚、1,4-二氧六环、叔丁醇或N,N-二甲基甲酰胺;优选乙酸乙酯、乙醇;上述良性溶剂和有机溶液使用时需互溶;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;
所述的不良溶剂选自庚烷、二氯甲烷、水、甲基叔丁基醚、甲苯、异丙醚或乙醇;优选庚烷和二氯甲烷;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;
所述的反离子酸选自盐酸、硫酸、氢溴酸、氢氟酸、氢碘酸或磷酸,所述有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸;优选甲磺酸、硫酸、磷酸、苯磺酸、马来酸、己二酸、对甲基苯磺酸、柠檬酸、丙二酸或L-苹果酸;最优选苯磺酸和对甲基苯磺酸。The counter ion 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 and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin Acid, bismuth Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.
本发明的还涉及一种制备方案,所述的制备方法,其中所述的溶剂为乙酸乙酯或乙醇。The invention further relates to a preparation scheme, wherein the solvent is ethyl acetate or ethanol.
本发明的还涉及一种制备方案,所述的制备方法,其中所述的反离子酸为苯磺酸和对甲基苯磺酸。The invention further relates to a preparation scheme, wherein the counter ion acid is benzenesulfonic acid and p-toluenesulfonic acid.
本发明的一个组合物的方案,一种药物组合物,其含有治疗有效量的所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。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.
本发明的一个优选方案,所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,或所述的组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。According to a preferred embodiment of the present invention, 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 use of the pathological features of the tryptophan metabolic pathway for the use of drugs in disease.
本发明的一个优选方案,所述的用途,其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病;所述的癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。A preferred embodiment of the invention, wherein 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.
本发明还涉及一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的方法,其包括向患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物。这些疾病包括诸如AIDS等病毒的感染,诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病,其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。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. These 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.
本发明另一方面涉及一种治疗癌症的方法,该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐。该方法显示出突出的疗效和较少的副作用,其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌,优选为输卵管肿瘤、腹膜肿瘤、IV期黑色素瘤、骨髓瘤和乳腺癌,更优选为乳腺癌。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.
图1为自由碱的DSC-TGA(差热—热重分析)图示。Figure 1 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of free base.
图2为磷酸盐的DSC-TGA(差热—热重分析)图示。Figure 2 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of phosphate.
图3为马来酸盐的DSC-TGA(差热—热重分析)图示。Figure 3 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of maleate salt.
图4为己二酸盐的DSC-TGA(差热—热重分析)图示。Figure 4 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of adipate salt.
图5为苯磺酸盐的DSC-TGA(差热—热重分析)图示。Figure 5 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of besylate.
图6为对甲基苯磺酸盐的DSC-TGA(差热—热重分析)图示。Figure 6 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of p-toluenesulfonate.
图7为柠檬酸盐的DSC-TGA(差热—热重分析)图示。Figure 7 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of citrate.
图8为丙二酸盐的DSC-TGA(差热—热重分析)图示。Figure 8 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of malonate.
图9为L-苹果酸盐的DSC-TGA(差热—热重分析)图示。Figure 9 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of L-malate.
图10为酒石酸盐的DSC-TGA(差热—热重分析)图示。Figure 10 is a graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of tartrate.
图11为富马酸盐DSC-TGA(差热—热重分析)图示。Figure 11 is a graphical representation of the fumarate DSC-TGA (differential heat-thermogravimetric analysis).
图12为对甲基苯磺酸物理稳定性实验结果图示。Figure 12 is a graphical representation of the results of physical stability experiments for p-toluenesulfonic acid.
图13为苯磺酸盐物理稳定性实验结果图示。Figure 13 is a graphical representation of the results of the physical stability test of besylate.
图14为对甲基苯磺酸盐多晶筛选实验结果图示。Figure 14 is a graphical representation of the results of a polycrystalline screening experiment for p-toluenesulfonate.
图15为苯磺酸盐多晶筛选实验结果图示。Figure 15 is a graphical representation of the results of polystyrene screening experiments for besylate.
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义,即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。"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.
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。"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.
“热重分析(TGA)”是指热重分析(TGA)实验。Thermogravimetric Analysis (TGA) refers to a thermogravimetric analysis (TGA) experiment.
“差示扫描量热法(DSC)”是指差示扫描量热法(DSC)实验。"Differential Scanning Calorimetry (DSC)" refers to differential scanning calorimetry (DSC) experiments.
以下结合实施例进一步描述本发明,但这些实施例并非限制着本发明的范围。The invention is further described in the following examples, which are not intended to limit the scope of the invention.
1.1实验仪器1.1 Experimental equipment
1.1.1物理化学检测仪器的一些参数1.1.1 Some parameters of physical and chemical detection instruments
1.2液相分析条件1.2 liquid phase analysis conditions
1.2.1仪器与设备1.2.1 Instruments and equipment
仪器名称equipment name | 型号model |
分析天平Analytical Balances | Sartorius BSA224S-CWSartorius BSA224S-CW |
纯水机Pure water machine | Milli-Q Plus,MilliporeMilli-Q Plus, Millipore |
高效液相色谱仪High performance liquid chromatography | Agilent1260Agilent1260 |
泵Pump | Agilent G1311BAgilent G1311B |
进样器Sampler | G1329BG1329B |
柱温箱Column thermostat | G1316AG1316A |
检测器Detector | G1315DG1315D |
1.2.2色谱条件1.2.2 Chromatographic conditions
色谱柱:Waters X-Bridge(C18,3.5μm,4.6*100mm)Column: Waters X-Bridge (C18, 3.5μm, 4.6*100mm)
流速:1.0mL/minFlow rate: 1.0mL/min
柱温:40℃Column temperature: 40 ° C
检测波长:287nmDetection wavelength: 287nm
进样体积:5μLInjection volume: 5μL
运行时间:15minRunning time: 15min
稀释剂:乙腈-水(v/v,1:1)Thinner: acetonitrile-water (v/v, 1:1)
流动相:A:水(0.1%三氟乙酸);Mobile phase: A: water (0.1% trifluoroacetic acid);
B:乙腈(0.1%三氟乙酸)B: acetonitrile (0.1% trifluoroacetic acid)
T(min)T(min) | B(%)B (%) |
00 | 1010 |
1212 | 9090 |
12.112.1 | 1010 |
1515 | 9090 |
实施例一:自然挥干法制备Example 1: Preparation by natural evaporation method
1.1实验目的:1.1 Experimental purpose:
选择不同的反离子酸,采用自然挥干法,检测哪些反离子酸可以形成化合物盐。Different counterion acids are selected and natural counter-drying methods are used to detect which counter-acids can form compound salts.
1.2实验步骤:1.2 Experimental steps:
1)仪器和设备1) Instruments and equipment
名称name | 型号model | 来源source |
分析天平Analytical Balances | BSA224S-CWBSA224S-CW | SartoriusSartorius |
超声波清洗仪Ultrasonic cleaner | SK5200LHCSK5200LHC | 上海科导超声仪器Shanghai Science and Technology Ultrasonic Instrument |
移液枪Pipette | Eppendorf(50mL,1000μL)Eppendorf (50mL, 1000μL) | EppendorfEppendorf |
2)操作程序2) Operating procedures
①储备液制备1 stock preparation
取通式化合物自由碱288.8mg,加入乙酸乙酯3×3.85mL(使用5mL移液器),Take the formula compound free base 288.8mg, add ethyl acetate 3 × 3.85mL (using a 5mL pipette),
超声溶解,得到澄清溶液,溶液浓度为:25mg/mL。The solution was sonicated to obtain a clear solution at a solution concentration of 25 mg/mL.
②盐溶液制备(反离子酸加入量为1.2当量的自由碱)2 salt solution preparation (reverse ion acid addition amount of 1.2 equivalents of free base)
在1mL储备液①中加入②的盐溶液,自然挥干后,60℃真空干燥后得到相应化合物的盐。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.
1.2.3DSC-TGA测试1.2.3DSC-TGA test
图1:自由碱的DSC-TGA(差热—热重分析)图示;Figure 1: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of free base;
图2:磷酸盐的DSC-TGA(差热—热重分析)图示;Figure 2: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of phosphate;
图3:马来酸盐的DSC-TGA(差热—热重分析)图示;Figure 3: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of maleate;
图4:己二酸盐的DSC-TGA(差热—热重分析)图示;Figure 4: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of adipate salt;
图5:苯磺酸盐的DSC-TGA(差热—热重分析)图示;Figure 5: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of besylate;
图6:对甲基苯磺酸盐的DSC-TGA(差热—热重分析)图示;Figure 6: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of p-toluenesulfonate;
图7:柠檬酸盐的DSC-TGA(差热—热重分析)图示;Figure 7: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of citrate;
图8:丙二酸盐的DSC-TGA(差热—热重分析)图示;Figure 8: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of malonate;
图9:L-苹果酸盐的DSC-TGA(差热—热重分析)图示。Figure 9: Graphical representation of DSC-TGA (differential heat-thermogravimetric analysis) of L-malate.
1.3实验结论1.3 Experimental conclusions
通过DSC-TGA(差热—热重分析)数据分析,并与自由碱的数据进行对比,表明以上所有反离子酸均能形成化合物盐。Data analysis by DSC-TGA (differential heat-thermogravimetric analysis) and comparison with the data of free base showed that all of the above counterionic acids were able to form compound salts.
实施例二:反溶剂法制备Example 2: Preparation by anti-solvent method
2.1实验目的:2.1 Experimental purpose:
选择良性溶剂溶解化合物,用不良溶剂将化合物结晶出来。The benign solvent is selected to dissolve the compound, and the compound is crystallized out with a poor solvent.
良性溶剂:丙酮、2-丁酮(MEK)、四氢呋喃(THF)、1,4-二氧六环、3-戊酮、2-甲基四氢呋喃、乙酸乙酯、乙腈;Benign solvent: acetone, 2-butanone (MEK), tetrahydrofuran (THF), 1,4-dioxane, 3-pentanone, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile;
不良溶剂:庚烷、二氯甲烷、水、甲基叔丁基醚、甲苯、异丙醚、乙醇;Poor solvent: heptane, dichloromethane, water, methyl tert-butyl ether, toluene, diisopropyl ether, ethanol;
反离子酸:甲磺酸、硫酸、磷酸、苯磺酸、马来酸、己二酸、对甲基苯磺酸、柠檬酸、丙二酸、L-苹果酸。Counterionic acid: methanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, L-malic acid.
2.2实验步骤2.2 Experimental steps
1)仪器和设备1) Instruments and equipment
名称name | 型号model | 来源source | |
分析天平Analytical Balances | BSA224S-CWBSA224S-CW | SartoriusSartorius | |
超声波清洗仪Ultrasonic cleaner | SK5200LHCSK5200LHC | 上海科导超声仪器Shanghai Science and Technology Ultrasonic Instrument | |
循环式水泵Circulating water pump | SHB-IIISHB-III | 郑州长城科工贸易有限公司Zhengzhou Great Wall Science and Trade Co., Ltd. |
2)操作程序2) Operating procedures
方案一:自由碱结晶良溶剂与反溶剂选择Scheme 1: Free base crystallization good solvent and anti-solvent selection
①良性溶剂为:丙酮、THF、1,4-二氧六环、乙腈;反溶剂:水;1 benign solvent: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: water;
②良性溶剂为:丙酮、THF、1,4-二氧六环;反溶剂:庚烷、二氯甲烷;2 benign solvents are: acetone, THF, 1,4-dioxane; anti-solvent: heptane, dichloromethane;
③良性溶剂为:丙酮、THF、1,4-二氧六环、乙腈;反溶剂:乙醇、异丙醇;3 benign solvents are: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: ethanol, isopropanol;
④良性溶剂为:丙酮、THF、1,4-二氧六环、乙腈;反溶剂:甲基叔丁基醚、异丙醚;4 benign solvents are: acetone, THF, 1,4-dioxane, acetonitrile; anti-solvent: methyl tert-butyl ether, isopropyl ether;
自由碱反溶剂选择的具体实施方法:Specific implementation of free base anti-solvent selection:
称取50mg自由碱,加入2mL良性溶剂溶解后,在搅拌条件下滴加反溶剂,出现白色沉淀时,停止滴加,静置后,收集沉淀,真空干燥,检测XRPD。50 mg of free base was weighed, dissolved in 2 mL of benign solvent, and the anti-solvent was added dropwise under stirring. When a white precipitate appeared, the dropwise addition was stopped. After standing, the precipitate was collected, dried under vacuum, and XRPD was detected.
不同良性溶剂和不良溶剂的筛选情况如下表:The screening of different benign solvents and poor solvents is as follows:
由以上实验可知:上述良性溶剂和不良溶剂构成的体系,乙醇、异丙醇、甲基叔丁基醚、异丙醚不是理想反溶剂。From the above experiments, it is known that ethanol, isopropanol, methyl tert-butyl ether, and isopropyl ether are not ideal anti-solvents in the system composed of the above-mentioned benign solvent and poor solvent.
方案二:化合物盐结晶良溶剂与反溶剂选择Scheme 2: Compound salt crystallization good solvent and anti-solvent selection
良性溶剂为:2-丁酮、1,4-二氧六环和乙酸乙酯;反溶剂为:二氯甲烷、正庚烷;The benign solvents are: 2-butanone, 1,4-dioxane and ethyl acetate; the anti-solvent is: dichloromethane, n-heptane;
反离子酸溶液溶剂:乙醇。Counterion acid solution solvent: ethanol.
盐制备良溶剂与反溶剂选择的具体实施方法:Specific implementation methods for salt preparation of good solvent and anti-solvent:
1)称取自由碱150mg,用6mL良性溶剂溶解;1) Weigh 150 mg of free base and dissolve it with 6 mL of benign solvent;
2)称取1.2当量反离子酸,用乙醇溶解;2) Weigh 1.2 equivalents of counterion acid and dissolve it with ethanol;
3)自由碱溶液和反离子酸溶液互溶;3) the free base solution and the counter ion acid solution are mutually soluble;
4)滴加不良溶剂直至出现浑浊,搅拌过夜;4) adding a poor solvent until turbidity occurs, stirring overnight;
5)静置或吹干得固体盐。5) Allow to stand or blow dry to obtain a solid salt.
自由碱和反离子酸的溶液配比如下表:The solution of free base and counterion acid is as follows:
不同良性溶剂和不良溶剂的筛选情况如下表:The screening of different benign solvents and poor solvents is as follows:
#:前者表示加入反溶剂的量,用体积或重量表示,后者表示加入到该体积或重量的反溶剂后,盐溶液所呈的现象。#: 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.
通过以上实验可知:Through the above experiments, we can know:
1)在良性溶剂为乙酸乙酯,反溶剂为庚烷的体系下,磷酸盐,马来酸盐,己二酸盐,苯磺酸盐,对甲基苯磺酸盐,柠檬酸盐,丙二酸盐,酒石酸盐,富马酸盐和L-苹果酸盐都有大量固体存在。1) In a system where 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.
2)在良性溶剂为1,4-二氧六环,反溶剂为二氯甲烷的体系下,己二酸、马来酸、柠檬酸、L-苹果酸稍浑浊,其他为澄清溶液。2) Under a system in which the benign solvent is 1,4-dioxane and the anti-solvent is dichloromethane, adipic acid, maleic acid, citric acid, and L-malic acid are slightly turbid, and the others are clear solutions.
3)在氢溴酸盐、硫酸盐和硝酸盐中有黑色沉淀物形成。3) There is a black precipitate formed in hydrobromide, sulfate and nitrate.
自由碱与各种盐的XRPD射线衍射数据XRPD ray diffraction data of free base and various salts
1、己二酸盐的XRPD射线衍射数据:1. XRPD ray diffraction data of adipate:
2、D-酒石酸盐的XRPD射线衍射数据:2. XRPD ray diffraction data of D-tartrate:
3、富马酸盐的XRPD射线衍射数据:3. XRPD ray diffraction data of fumarate:
4、对甲基苯磺酸盐的XRPD射线衍射数据:4. XRPD ray diffraction data of p-toluenesulfonate:
5、苯磺酸盐的XRPD射线衍射数据:5. XRPD ray diffraction data of besylate:
6、自由碱的XRPD射线衍射数据:6. XRPD ray diffraction data of free base:
实施例三:盐的反应摩尔比实验Example 3: Reaction molar ratio experiment of salt
3.1实验目的:3.1 Experimental purpose:
加入不同摩尔反应比的反离子,考察在既定的结晶工艺条件下,生成对甲基苯磺酸盐与苯磺酸盐计量比的稳定性。The counterions of different molar ratios were added to investigate the stability of the stoichiometric ratio of p-toluenesulfonate to besylate under the established crystallization conditions.
3.2实验方案:3.2 Experimental plan:
将反离子的投料量摩尔比更改为0.6与2.2(摩尔比是反离子摩尔数与自由碱摩尔数的比值),采用相同的结晶工艺,考察盐结晶工艺的可行性与盐反应计量比。采用HPLC,外标法测定结晶产品中自由碱的质量百分含量,并与理论反应计量比的质量百分含量进行比较。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.
3.3实验结果:3.3 Experimental results:
样品名称sample name | 测得自由碱在结晶物中Free base was measured in the crystal | 理论自由碱在盐中Theoretical free base in salt |
含量%content% | (1:1摩尔比)含量%(1:1 molar ratio) content% | |
对甲基苯磺酸盐-0.6P-toluenesulfonate-0.6 | 98.298.2 | 76.276.2 |
对甲基苯磺酸盐-2.2P-toluenesulfonate-2.2 | 94.794.7 | 76.276.2 |
苯磺酸盐-0.6Benzenesulfonate-0.6 | 92.092.0 | 77.777.7 |
苯磺酸盐-2.2Benzenesulfonate-2.2 | 89.089.0 | 77.777.7 |
改变投料的反离子量,均能有固体被结晶出来;对结晶出来的固体进行自由碱定量,析出来的晶体大部分是自由碱,并不能形成1:1反应摩尔比的盐。在反离子投料量摩尔比在1~1.2范围内时,可以形成计量比为1:1的对甲基苯磺酸与苯磺酸盐。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. When 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.
实施例四:模拟人工肠胃中溶解度实验Example 4: Simulating the solubility test in artificial gastrointestinal
4.1实验目的:4.1 Experimental purpose:
比较化合物不同盐在模拟人工胃肠液中溶解度大小,为盐可成药性评估提供依据。Comparing the solubility of different salts of compounds in simulated artificial gastrointestinal fluids, it provides a basis for the evaluation of salt drug availability.
4.2实验方案:4.2 Experimental plan:
将约2mg化合物混悬到1mL人工模拟胃液(SGF)、禁食人工模拟肠液(Fa)、非禁食人工模拟肠液(Fe)以及纯水中16小时,用HPLC,外标法测定化合物室温下的热力学溶解度。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.
4.3实验结果:4.3 Experimental results:
从化合物及其盐在模拟小肠液中溶解度结果,化合物的苯磺酸盐与对甲基苯磺酸盐较之自由碱,增溶效果比较明显,为首要筛选的盐。From the solubility of the compound and its salt in the simulated intestinal fluid, the solubilization effect of the compound besylate and p-toluenesulfonate compared with the free base is obvious, and it is the primary screening salt.
实施例五:固体稳定性实验Example 5: Solid Stability Experiment
5.1实验目的:5.1 Experimental purposes:
考察候选化合物盐在加速条件或影响因素条件下,化合物的物理化学稳定性,为盐筛选与化合物盐贮存提供依据。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.
5.2实验方案:5.2 Experimental protocol:
1)对甲基苯磺酸盐:1) p-toluenesulfonate:
取对甲基苯磺酸盐约10mg,密闭置70℃烘箱、光照箱(5000lx±500lx)中,敞口置40℃&RH75%(饱和NaCl水溶液)、RH75%(室温)与30℃RH65%条件 下(饱和铬酸钾溶液)考察5天与10天,用HPLC,外标法测定盐的含量,并采用色谱峰面积归一化法计算盐有关物质的变化。Take about 10mg of p-toluenesulfonate, sealed in 70 ° C oven, light box (5000lx ± 500lx), open 40 ° C & RH75% (saturated NaCl aqueous solution), RH75% (room temperature) and 30 ° CRH 65% conditions The lower (saturated potassium chromate solution) was examined for 5 days and 10 days, and the salt content was determined by HPLC and external standard method, and the change of the salt-related substance was calculated by the chromatographic peak area normalization method.
2)苯磺酸盐:2) Benzene sulfonate:
取苯磺酸盐约10mg,密闭置70℃烘箱、光照箱(5000lx±500lx)中,敞口置30℃&RH75%(饱和NaCl水溶液)环境下考察5天与10天,用HPLC,外标法测定盐的含量,并采用色谱峰面积归一化法计算盐有关物质的变化。Take about 10mg of benzenesulfonate, seal it in a 70°C oven, light box (5000lx±500lx), open it in 30°C & RH75% (saturated NaCl aqueous solution) for 5 days and 10 days, using HPLC, external standard method. The salt content was determined, and the change in the salt-related substance was calculated by the chromatographic peak area normalization method.
3)物理稳定测定:3) Physical stability measurement:
考察10天的两个盐样品,测定其XRPD,并与0天的XRPD进行比较。Two salt samples from 10 days were examined and their XRPD was determined and compared to X-day XRPD.
5.3实验结果:5.3 Experimental results:
1)对甲基苯磺酸盐物理化学稳定性结果:1) Physicochemical stability results of p-toluenesulfonate:
对甲基苯磺酸盐化学稳定性结果:The chemical stability results of p-toluenesulfonate:
样品名称sample name | 含量%content% | 总杂质%Total impurity % | 杂质增加%Increase in impurities |
对甲基苯磺酸盐-0天P-toluenesulfonate - 0 days | // | 0.440.44 | // |
对甲基苯磺酸盐-50℃&RH75%-5天P-toluenesulfonate -50 ° C & RH 75% - 5 days | 36.0536.05 | 49.6049.60 | 49.1649.16 |
对甲基苯磺酸盐-50℃&RH75%-10天P-toluenesulfonate -50 ° C & RH 75% - 10 days | 20.4820.48 | 67.8767.87 | 67.4367.43 |
对甲基苯磺酸盐-70℃-5天P-toluenesulfonate -70 ° C - 5 days | 100.76100.76 | 0.470.47 | 0.030.03 |
对甲基苯磺酸盐-70℃-10天P-toluenesulfonate -70 ° C - 10 days | 103.21103.21 | 0.500.50 | 0.060.06 |
对甲基苯磺酸盐-光照-5天P-toluenesulfonate - light -5 days | 97.9797.97 | 1.841.84 | 1.401.40 |
对甲基苯磺酸盐-光照-10天P-toluenesulfonate - light -10 days | 95.6295.62 | 2.752.75 | 2.312.31 |
对甲基苯磺酸盐-30℃&RH65%-5天P-toluenesulfonate -30 ° C & RH 65% - 5 days | 99.3599.35 | 1.071.07 | 0.630.63 |
对甲基苯磺酸盐-30℃&RH65%-10天P-toluenesulfonate -30 ° C & RH 65% - 10 days | 94.0894.08 | 2.092.09 | 1.651.65 |
对甲基苯磺酸盐-RH75%-5天p-toluenesulfonate-RH75%-5 days | 98.6698.66 | 0.560.56 | 0.120.12 |
对甲基苯磺酸盐-RH75%-10天p-toluenesulfonate-RH75%-10 days | 97.8097.80 | 0.660.66 | 0.220.22 |
化合物对甲基苯磺酸盐在50℃&RH75%条件下极不稳定,放置5天后杂质增加40%以上,在30℃&RH65%条件下放置5天,有关物质增加了0.63%,在RH75%条件下室温放置5天、10天,有关物质增加并不明显,10天杂质增加0.22%;化合物对甲基苯磺酸盐在高温(70℃)条件下放置10天稳定,杂质仅增加0.06%;光照条件下,化合物对甲基苯磺酸盐放置5天、10天均有少许降解。所以化合物对甲基苯磺酸盐应防潮避光包装。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.
对甲基苯磺酸物理稳定性结果:Physical stability results of p-toluenesulfonic acid:
测试结果如图10所示The test results are shown in Figure 10.
XRPD结果表明,对甲基苯磺酸盐在30℃&RH65%、RH75%(室温)、光照与高温条件下考察10天,其晶型与0天样品比较,晶型没有发生转变。XRPD results showed that p-toluenesulfonate was investigated at 30 ° C & RH 65%, RH 75% (room temperature), light and high temperature for 10 days, and the crystal form did not change compared with the 0 day sample.
1)苯磺酸盐物理化学稳定性结果:1) Physicochemical stability results of besylate:
苯磺酸盐化学稳定性结果:The chemical stability results of besylate:
样品名称sample name | 含量%content% | 总杂质%Total impurity % | 杂质增加%Increase in impurities |
苯磺酸盐-0天Benzene sulfonate - 0 days | // | 1.091.09 | // |
苯磺酸盐-30℃&RH65%-5天Benzene sulfonate -30 ° C & RH 65% - 5 days | 96.1996.19 | 1.031.03 | -0.06-0.06 |
苯磺酸盐-30℃&RH65%-10天Benzene sulfonate -30 ° C & RH 65% - 10 days | 94.4094.40 | 1.581.58 | 0.490.49 |
苯磺酸盐-70℃-5天Benzene sulfonate -70 ° C - 5 days | 99.6799.67 | 0.960.96 | -0.13-0.13 |
苯磺酸盐-70℃-10天Benzene sulfonate -70 ° C - 10 days | 92.9492.94 | 13.4613.46 | 12.3712.37 |
苯磺酸盐-光照-5天Benzene sulfonate - light -5 days | 79.1879.18 | // | // |
苯磺酸盐-光照-10天Benzene sulfonate - light -10 days | 77.1877.18 | 22.8822.88 | 21.7921.79 |
化合物苯磺酸盐在30℃&RH65%条件下,有关物质没有明显增加,但含量下降比较明显;化合物苯磺酸盐在高温(70℃)条件下放置5天稳定,放置10天杂质突然增加12%以上;光照条件下,化合物对甲基苯磺酸盐放置5天、10天均有大量降解。Under the condition of 30 °C & RH65%, 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.
苯磺酸盐物理稳定性结果:Physical stability results of besylate:
测试结果如图11所示。The test results are shown in Figure 11.
XRPD结果表明,化合物苯磺酸盐在30℃&RH65%条件下放置10天,晶型发生了改变;化合物苯磺酸盐在光照与高温条件下考察10天,其晶型与0天样品比较,晶型没有发生转变。XRPD results showed that the compound besylate was allowed to stand at 30 ° C & RH 65% for 10 days, and the crystal form changed. The compound besylate was observed under light and high temperature for 10 days, and its crystal form was compared with the 0 day sample. The crystal form did not change.
5.4总结:化合物对甲基苯磺酸盐与苯磺酸盐固定稳定性结果表明,对甲基苯磺酸盐在满足防潮避光包装条件下,较之苯磺酸更具有优越性。5.4 Summary: The stability of the compound p-toluenesulfonate and benzenesulfonate stability shows that p-toluenesulfonate is superior to benzenesulfonic acid in the condition of moisture-proof and light-proof packaging.
实施例六:引湿性实验Example 6: Humidity test
6.1实验目的6.1 Experimental purpose
考察化合物在不同相对湿度条件下的引湿性,为化合物盐筛选与贮存提供依据。The hygroscopicity of the compounds under different relative humidity conditions was investigated to provide a basis for screening and storage of the compound salts.
6.2实验方案:6.2 Experimental protocol:
将化合物盐置不同相对湿度的饱和水蒸气中,使化合物与水蒸气达到动态平衡,并计算平衡后化合物吸湿增重的百分数。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.
6.3实验结果:6.3 Experimental results:
对甲基苯磺酸盐在RH75%条件下不引湿(中国药典2015版),苯磺酸盐在RH75%条件下具有引湿性。并且对甲基苯磺酸盐经0-95%相对湿度条件下吸湿与解吸湿循环四次,XRPD模式并未改变,即没有晶型转变;苯磺酸盐在相同处理条件下,会发生晶型的转变。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.
从引湿性角度,对甲基苯磺酸盐优于苯磺酸盐。From the viewpoint of wettability, p-toluenesulfonate is superior to besylate.
实施例七:多晶筛选实验Example 7: Polycrystalline screening experiment
7.1实验目的:通过多晶筛选,找到比较稳定的化合物盐的晶型。7.1 Experimental purpose: Through the polycrystalline screening, the crystal form of the relatively stable compound salt was found.
7.2实验方案:选择有一定溶解度的有机溶剂、水,将化合物悬浮于溶剂体系 中,室温搅拌打浆1周后,离心,弃掉上清液,固体在40℃条件真空干燥(-0.1Mpa)过夜后,测定固体的XRPD,并与化合物盐的XRPD比较。7.2 Experimental protocol: Select an organic solvent and water with a certain solubility, suspend the compound in a solvent system, stir and beat at room temperature for 1 week, centrifuge, discard the supernatant, and dry the solid at 40 ° C overnight (-0.1 Mpa) overnight. Thereafter, the solid XRPD was determined and compared to the XRPD of the compound salt.
7.3实验结果:7.3 Experimental results:
1)对甲基苯磺酸盐结果:1) p-toluenesulfonate results:
多晶筛选实验结果如图12所示。The results of the polycrystal screening experiment are shown in FIG.
化合物对甲基苯磺酸盐在水中打浆可以转换成自由碱,在其它溶剂EtOH、DCM、88%丙酮与乙酸乙酯中打浆,化合物对甲基苯磺酸盐晶型稳定,未转变成其它稳定晶型。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. The compound is stable to the methylbenzenesulfonate crystal form and is not converted into other Stable crystal form.
2)苯磺酸盐结果:2) Benzene sulfonate results:
多晶筛选实验结果图13所示。The results of the polycrystal screening experiment are shown in FIG.
化合物苯磺酸盐除在乙酸乙酯中打浆未发生晶型转变外,在水中会转换成自由碱,在其它溶剂中都发生了晶型转变。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.
从多晶筛选的结果,对甲基苯磺酸盐比苯磺酸盐晶型更稳定。From the results of polycrystalline screening, p-toluenesulfonate is more stable than the benzsulfonate crystal form.
实施例八:动物PK研究Example 8: Animal PK Study
8.1实验目的:通过动物PK研究,比较化合物盐与自由碱在动物体内的暴露量差异。8.1 Experimental Objective: To compare the difference in exposure between compound salt and free base in animals by animal PK study.
8.2实验方案:将化合物的自由碱、对甲基苯磺酸盐与苯磺酸盐,用含0.1%Tween80的CMC-Na(0.5%)水溶液混悬均匀后,灌胃,大鼠给药,平行两只大鼠,给药剂量为100mg/kg,化合物的量全部折算成相同自由碱的量。8.2 Experimental protocol: The free base, p-toluenesulfonate and besylate of the compound were suspended in a CMC-Na (0.5%) aqueous solution containing 0.1% Tween 80, and then administered orally, and the rats were administered. Two rats in parallel were administered at a dose of 100 mg/kg, and the amounts of the compounds were all converted into the same amount of free base.
8.3实验结果:8.3 Experimental results:
自由碱Free base | 苯磺酸盐Benzene sulfonate | 对甲基苯磺酸盐P-toluenesulfonate | |
T max(h) T max (h) | 22 | 11 | 44 |
C max(ng/mL) C max (ng/mL) | 592.5592.5 | 545.0545.0 | 705.0705.0 |
AUC 0-t(ng/mL*h) AUC 0-t (ng/mL*h) | 2908.52908.5 | 2419.12419.1 | 4432.44432.4 |
AUC 0-∞(ng/mL*h) AUC 0-∞ (ng/mL*h) | 3730.13730.1 | 2584.52584.5 | 5914.95914.9 |
t 1/2(h) t 1/2 (h) | 3.453.45 | 1.701.70 | 3.343.34 |
MRT 0-∞(h) MRT 0-∞ (h) | 5.535.53 | 3.493.49 | 6.116.11 |
化合物的对甲基苯磺酸盐能显著提高化合物在大鼠体内的暴露量。The p-toluenesulfonate of the compound significantly increases the exposure of the compound in rats.
Claims (14)
- 一种通式(I)所示化合物的盐、其立体异构体或其混合物形式,a salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof,其中:among them:M为无机酸或有机酸,其中所述无机酸选自盐酸、硫酸、氢溴酸、氢氟酸、氢碘酸或磷酸,所述有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸;且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, glutamic acid, isoascorbic acid , lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, Galactose, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid , malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicin , 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; Andy为1、2或3的整数。y is an integer of 1, 2 or 3.
- 根据权利要求1所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,选自式(II)化合物的盐:A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof, according to claim 1, characterized in that it is a salt selected from the compound of the formula (II):其中:among them:M和y的定义如通式(I)所述。M and y are as defined in the general formula (I).
- 根据权利要求1或2所述的通式(I)所示化合物,其自由碱结晶形式,特征在于具有在15.9,17.2,17.9,19.7,20.5,21.1,22.8,27.0,27.5,28.1,30.5,33.6与35.5±0.2°的衍射角2θ(±0.2°)显示峰的XRPD,在于DSC上具有176.4±0.5℃的熔融峰。The compound of the formula (I) according to claim 1 or 2, which is in the form of a free base crystal, characterized by having 15.9, 17.2, 17.9, 19.7, 20.5, 21.1, 22.8, 27.0, 27.5, 28.1, 30.5, The diffraction angle 2θ (±0.2°) of 33.6 and 35.5 ± 0.2° shows the XRPD of the peak with a melting peak of 176.4 ± 0.5 ° C on the DSC.
- 根据权利要求1或2所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其中M选自磷酸、马来酸、己二酸、苯磺酸、对甲基苯磺酸、柠檬酸、丙二酸、酒石酸、富马酸和L-苹果酸。A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to claim 1 or 2, wherein M is selected from the group consisting of phosphoric acid, maleic acid, adipic acid, and benzenesulfonate. Acid, p-toluenesulfonic acid, citric acid, malonic acid, tartaric acid, fumaric acid and L-malic acid.
- 根据权利要求1-4中任一项所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其中M选自己二酸、苯磺酸、对甲基苯磺酸、酒石酸和富马酸;优选苯磺酸和对甲基苯磺酸;更优选对甲基苯磺酸。A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to any one of claims 1 to 4, wherein M is selected from adipic acid, benzenesulfonic acid, or the like. Methylbenzenesulfonic acid, tartaric acid and fumaric acid; preferably benzenesulfonic acid and p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.
- 根据权利要求1-5中任一项所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,其特征在于,其中y为1。A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to any one of claims 1 to 5, wherein y is 1.
- 根据权利要求1-6中任一项所述的通式(I)所示化合物:A compound of the formula (I) according to any one of claims 1 to 6:当M为对甲基苯磺酸,即为对甲基苯磺酸盐,特征在于具有在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与28.5±0.2°的衍射角2θ(±0.2°)显示峰的XRPD,在于DSC上具有162.7±0.5℃的熔融峰;When M is p-toluenesulfonic acid, ie p-toluenesulfonate, characterized by having 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 with The diffraction angle 2θ (±0.2°) of 28.5±0.2° shows the XRPD of the peak, which has a melting peak of 162.7±0.5° C. on the DSC;当M为苯磺酸,即为苯磺酸盐时,特征在于具有在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与41.0±0.2°的衍射角2θ(±0.2°)显示峰的XRPD,在于DSC上具有152.3±0.5℃的熔融峰。When 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 2θ (±0.2°) shows the XRPD of the peak, The DSC has a melting peak of 152.3 ± 0.5 °C.
- 一种制备根据权利要求1-6中任一项所述的通式(I)所示化合物的盐的方法,包括如下步骤:A process for the preparation of a salt of a compound of the formula (I) according to any one of claims 1 to 6, comprising the steps of:1)储备液制备:取通式化合物自由碱,加入有机溶剂溶解,得到澄清储备液溶液,溶液浓度为:20~30mg/mL;有机溶剂优选乙酸乙酯,溶液浓度优选25mg/mL;1) 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;2)反离子酸溶液制备:把反离子酸加入有机溶剂中,得到澄清的反离子酸溶液;有机溶剂优选为乙醇,浓度优选为0.25~2摩尔/升;2) Preparation of a counter-ion acid solution: adding a counter-acid to an organic solvent to obtain a clear counter-acid solution; the organic solvent is preferably ethanol, and the concentration is preferably 0.25 to 2 mol/liter;3)化合物盐制备:储备液加入反离子酸溶液,得澄清盐溶液,自然挥干,真空干燥后得到通式(I)所示化合物的盐;真空温度优选60℃,反离子酸的量优选1~1.2当量;3) Preparation of compound salt: the stock solution is added to the counterion acid solution to obtain a clear salt solution, which is naturally evaporated, and dried under vacuum to obtain a salt of the compound of the formula (I); the vacuum temperature is preferably 60 ° C, and the amount of the counter ion acid is preferably 1 to 1.2 equivalents;其中:among them:所述的有机溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、丙酮、正己烷、石油 醚、苯、甲苯、氯仿、乙腈、四氯化碳、二氯乙烷、四氢呋喃、2-丁酮、3-戊酮、庚烷、甲基叔丁基醚、异丙醚、1,4-二氧六环、叔丁醇或N,N-二甲基甲酰胺;优选乙酸乙酯、乙醇;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 ;所述的反离子酸选自盐酸、硫酸、氢溴酸、氢氟酸、氢碘酸或磷酸,所述有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸;优选甲磺酸、硫酸、磷酸、苯磺酸、马来酸、己二酸、对甲基苯磺酸、柠檬酸、丙二酸或L-苹果酸;最优选苯磺酸和对甲基苯磺酸。The counter ion 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 and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin Acid, bismuth Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.
- 一种制备根据权利要求1-7中任一项所述的通式(I)所示化合物的盐的方法,包括如下步骤:A process for the preparation of a salt of a compound of the formula (I) according to any one of claims 1 to 7, comprising the steps of:1)称取适量的自由碱,用良性溶剂溶解;良性溶剂优选乙酸乙酯;1) Weigh an appropriate amount of free base and dissolve it with a benign solvent; the benign solvent is preferably ethyl acetate;2)称取1~3当量反离子酸,用有机溶剂溶解;有机溶剂优选乙醇;反离子酸的量优选1.2当量;2) weigh 1-3 equivalents of counterion acid, dissolved in an organic solvent; organic solvent is preferably ethanol; the amount of counterion acid is preferably 1.2 equivalents;3)把上述两种溶液合并,并滴加不良溶剂直至出现浑浊,或搅拌过夜;不良溶剂优选庚烷和二氯甲烷;3) Combine the above two solutions, and add a poor solvent until turbidity occurs, or stir overnight; the poor solvent is preferably heptane and dichloromethane;4)静置或吹干得通式(I)所示化合物的盐;4) standing or blow drying to obtain a salt of the compound of the formula (I);其中:among them:所述的良性溶剂选自丙酮、2-丁酮、四氢呋喃、1,4-二氧六环、3-戊酮、2-甲基四氢呋喃、乙酸乙酯或乙腈;优选乙酸乙酯、乙醇、2-丁酮、1,4-二氧六环和丙酮;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;所述的有机溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、丙酮、正己烷、石油醚、苯、甲苯、氯仿、乙腈、四氯化碳、二氯乙烷、四氢呋喃、2-丁酮、3-戊酮、庚烷、甲基叔丁基醚、异丙醚、1,4-二氧六环、叔丁醇或N,N-二甲基甲酰胺;优选乙酸乙酯、乙醇;上述良性溶剂和有机溶液使用时需互溶;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;所述的不良溶剂选自庚烷、二氯甲烷、水、甲基叔丁基醚、甲苯、异丙醚或乙醇;优选庚烷和二氯甲烷;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;所述的反离子酸选自盐酸、硫酸、氢溴酸、氢氟酸、氢碘酸或磷酸,所述有 机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸;优选甲磺酸、硫酸、磷酸、苯磺酸、马来酸、己二酸、对甲基苯磺酸、柠檬酸、丙二酸或L-苹果酸;最优选苯磺酸和对甲基苯磺酸。The counter ion 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 and 1-hydroxy-2-naphthoic acid. Acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, citric acid, Acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, almond Acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid , glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methylsulfonate Acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosaponin acid, Diacid, stearic acid, succinic acid, thiocyanate, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably methanesulfonic acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid or L-malic acid; most preferred are benzenesulfonic acid and p-toluenesulfonic acid.
- 根据权利要求8所述的制备方法,其中所述的有机溶剂为乙酸乙酯或乙醇。The production method according to claim 8, wherein the organic solvent is ethyl acetate or ethanol.
- 根据权利要求8或9所述的制备方法,其中所述的反离子酸为苯磺酸和对甲基苯磺酸。The production method according to claim 8 or 9, wherein the counterionic acid is benzenesulfonic acid and p-toluenesulfonic acid.
- 一种药物组合物,其含有治疗有效量的根据权利要求1-7中任一项所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of the formula (I) according to any one of claims 1 to 7, a stereoisomer thereof or a mixture thereof, and one or A wide variety of pharmaceutically acceptable carriers, diluents or excipients.
- 根据权利要求1-7中任一项所述的通式(I)所示化合物的盐、其立体异构体或其混合物形式,或根据权利要求12所述的组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。A salt of the compound of the formula (I), a stereoisomer thereof or a mixture thereof according to any one of claims 1 to 7, or a composition according to claim 12, which is prepared for prevention and / Use in the treatment of a disease having a pathological feature of the IDO-mediated tryptophan metabolism pathway.
- 根据权利要求13所述的用途,其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病;所述的癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。The use according to claim 13, wherein 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 Tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.
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