WO2021047528A1 - 一个烟醇醚衍生物的马来酸盐及其晶型和应用 - Google Patents

一个烟醇醚衍生物的马来酸盐及其晶型和应用 Download PDF

Info

Publication number
WO2021047528A1
WO2021047528A1 PCT/CN2020/114137 CN2020114137W WO2021047528A1 WO 2021047528 A1 WO2021047528 A1 WO 2021047528A1 CN 2020114137 W CN2020114137 W CN 2020114137W WO 2021047528 A1 WO2021047528 A1 WO 2021047528A1
Authority
WO
WIPO (PCT)
Prior art keywords
bromo
pyridine
chlorobenzyl
phenylbenzyloxy
methoxy
Prior art date
Application number
PCT/CN2020/114137
Other languages
English (en)
French (fr)
Inventor
冯志强
陈晓光
马辰
杨阳
来芳芳
王雨辰
季鸣
郭凯静
Original Assignee
中国医学科学院药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医学科学院药物研究所 filed Critical 中国医学科学院药物研究所
Priority to JP2022515664A priority Critical patent/JP2022547208A/ja
Priority to EP20863682.9A priority patent/EP4029863A4/en
Priority to CN202080063645.3A priority patent/CN114450278A/zh
Priority to KR1020227011675A priority patent/KR20220061184A/ko
Publication of WO2021047528A1 publication Critical patent/WO2021047528A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the technical field of medicine, and discloses a maleate of nicotinol ether derivative and its crystal form and application, namely (S)-N-(2-(pyridine-3-methoxy)-4-( 2-Bromo-3-phenylbenzyloxy)-5-chlorobenzyl)serine isopropyl maleate, its preparation method, crystal form, pharmaceutical composition and use.
  • the ability of tumor cells to evade the immune system is achieved by the programmed death ligand (PD-L1) produced on its surface that binds to the PD-1 protein of T cells.
  • the tumor microenvironment in the body will induce the infiltrating T cells to highly express PD-1 molecules, and the tumor cells will highly express PD-1 ligands PD-L1 and PD-L2, leading to continuous activation of the PD-1 pathway in the tumor microenvironment.
  • the function of T cells is suppressed and the tumor cannot be detected so that the immune system cannot send the treatment that needs to attack the tumor and kill the tumor cells.
  • PD-1 antibody is an antibody protein against PD-1 or PD-L1, which prevents the first two proteins from binding, blocks this pathway, and partially restores the function of T cells, so that these cells can continue to kill tumor cells.
  • FDA Food and Drug Administration
  • Opdivo Its anti-cancer immunotherapy drug nivolumab was launched under the trade name of Opdivo It is used to treat patients with unresectable or metastatic melanoma who do not respond to other drugs. It is the second PD-1 inhibitor to be marketed in the United States after Merck’s Keytruda.
  • monoclonal antibody treatment drugs have their own shortcomings: they are easily decomposed by proteases, so they are unstable in the body and cannot be taken orally; easy to produce immune cross-reactions; product quality is not easy to control, and the production technology requirements are high; mass preparation and purification are difficult, and production High cost; inconvenient to use, only injection or intravenous drip. Therefore, small molecule inhibitors of PDl/PD-Ll interaction are a better choice for tumor immunotherapy.
  • Example 1 of the present invention is the hydrochloride salt prepared completely according to the preparation method in the international patent application PCT/CN2017/085418, as a comparative example.
  • the technical problem solved by the present invention is to provide a (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3) with structural formula I that inhibits the interaction of PD1/PD-L1 -Phenylbenzyloxy)-5-chlorobenzyl)serine isopropyl ester maleate, and its stereoisomers, its preparation method, pharmaceutical composition and its preparation for prevention or treatment and PDl/PD-Ll Signal pathways are related to the use of disease drugs.
  • the present invention provides the following technical solutions:
  • the first aspect of the technical scheme of the present invention is to provide (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy) as shown in formula I -5-chlorobenzyl) serine isopropyl maleate and its stereoisomers,
  • the second aspect of the technical scheme of the present invention provides a (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-chloro
  • the crystalline type A solid substance of benzyl)serine isopropyl maleate, characterized in that, when the experimental conditions of Cu target radiation are used for powder X-ray diffraction analysis, the diffraction peak position: 2-Theta value (°) or d value
  • the relative intensity (%) of the diffraction peak has the following characteristics:
  • the crystal type A solid substance is characterized in that when infrared spectroscopy is used for analysis, it is in 3059, 2984, 2841, 2761, 2519, 2170, 1988, 1968, 1807, 1741, 1716, 1623, 1602, 1580, 1505, 1505, 3059, 2984, 2841, 2761, 2519, 2170, 1988, 1968, 1807, 1741, 1716, 1623, 1602, 1580, 1505, 1481, 1460, 1446, 1425, 1401, 1389, 1368, 1309, 1262, 1242, 1205, 1171, 1111, 1095, 1069, 1040, 1004, 972, 953, 924, 884, 870, 864, 854, 824,
  • the absorption peaks of 788, 761, 721, 703, 662 cm -1 ⁇ 2 cm -1 are the characteristic peak positions of the infrared spectrum presented by the crystal A solid material.
  • the said crystal A type solid substance is characterized in that, when analyzed by differential scanning calorimetry technique, it shows that when the heating rate is 10°C per minute, the DSC spectrum contains an endothermic peak at 175°C ⁇ 3°C. .
  • the second aspect of the technical scheme of the present invention also provides a (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-
  • the mixed crystal solid substance of chlorobenzyl)serine isopropyl maleate characterized in that it contains any non-zero proportion of the (S)-N-(2-(pyridine-3-methoxy)- 4-(2-Bromo-3-phenylbenzyloxy)-5-chlorobenzyl)serine isopropyl ester maleate is a crystal type A solid substance.
  • the preparation method of the compound of formula I is: (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-chlorobenzyl (S)-N-(2-(pyridine-3-methoxy) is reacted with maleic acid in a solvent to form a salt, the best solvent is isopropanol, or tetrahydrofuran, or acetone; Base)-4-(2-bromo-3-phenylbenzyloxy)-5-chlorobenzyl)serine isopropyl ester maleate is crystallized in a mixed solvent of acetone and water.
  • the ratio of acetone and water is in the range of Between 200:1 and 1:1, the preferred ratio is between 50:1 and 5:1, and the best ratio is between 25:1 and 10:1.
  • polymorphism may occur under different crystallization conditions.
  • the fourth aspect of the technical solution of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient the (S)-N-(2-(pyridine-3- Methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-chlorobenzyl)serine isopropyl maleate and its stereoisomers or the second aspect of the crystal form
  • Solid substances and pharmaceutically acceptable carriers or excipients are examples of the following compounds listed above.
  • the present invention also relates to a pharmaceutical composition using the compound of the present invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods known in the art.
  • the compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to prepare any dosage form suitable for human or animal use.
  • the content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops
  • the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the compound of the present invention can be made into ordinary preparations, and can also be made into slow-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.
  • the diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the humectant can be water, ethanol, iso Propanol, etc.
  • the binder can be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia syrup, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • the disintegrant can be dry starch, microcrystalline cellulose
  • the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • the active ingredient of the compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule.
  • the compound of the present invention as an active ingredient can be prepared into granules or pellets with diluents, binders, and disintegrants, and then placed in hard or soft capsules.
  • the various diluents, binders, wetting agents, disintegrants and glidants used in the preparation of the compound tablets of the present invention can also be used to prepare the capsules of the compound of the present invention.
  • solubilizing agent or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH adjusting agent can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure adjusting agent can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents can also be added to the pharmaceutical preparations.
  • the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
  • the dosage of the compound pharmaceutical composition of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form.
  • the appropriate daily dose range of the compound of the present invention is 0.001-150 mg/Kg body weight, preferably 0.01-100 mg/Kg body weight.
  • the above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other treatment means.
  • the compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.
  • the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
  • the fifth aspect of the technical scheme of the present invention is to provide (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-chlorobenzyl (Base) serine isopropyl ester maleate and its stereoisomers or the crystal type
  • Base serine isopropyl ester maleate and its stereoisomers or the crystal type
  • a solid substance described in the second aspect is used in the preparation of drugs for the prevention and/or treatment of diseases related to the PD-1/PD-L1 signaling pathway Applications.
  • the diseases related to the PD-1/PD-L1 signaling pathway are selected from cancer, infectious diseases, and autoimmune diseases.
  • the cancer is selected from skin cancer, lung cancer, urinary system tumor, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer.
  • the infectious diseases are selected from bacterial infections and viral infections.
  • the autoimmune disease is selected from organ-specific autoimmune diseases, systemic autoimmune diseases, wherein the organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, Myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhage nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosis, acute idiopathic polyneuritis, the described system Autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia.
  • organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, Myasthenia gravis, ulcerative colitis, pernicious anemia with chronic
  • the compound of the present invention (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-chlorobenzyl) serine isopropyl ester maleate Compared with hydrochloride salt, its crystal form is stable, and it has good stability to light irradiation, high humidity and high temperature environment. It can be used in mouse subcutaneous transplantation tumor model or in NSG tumor-bearing mouse model of human immune system reconstruction. It has high tumor inhibition rate for many types of tumors.
  • Measuring instrument Bruker AVANCE III 500 high-resolution superconducting nuclear magnetic resonance spectrometer for nuclear magnetic resonance spectroscopy.
  • QSTAR Elite LC/MS/MS System is used for mass spectrometry.
  • Elemental analysis uses FLASH1112 trace element analyzer and MX-5 one millionth balance.
  • Shimadzu UV-2700 UV-Vis spectrophotometer is used for UV analysis.
  • the specific rotation uses the American PE Model 343 polarimeter.
  • D8-Advance X-ray diffractometer was used for powder X-ray diffraction analysis.
  • Differential scanning calorimetry/thermogravimetric analysis (DSC/TG) uses Swiss Mettler Mettler TGA/DSC3 + thermal analyzer.
  • Example 1 (S)-N-[2-(pyridine-3-methyleneoxy)-4-(2-bromo-3-(phenyl)benzyloxy)-5-chlorobenzyl]serine Isopropyl ester hydrochloride (this example serves as a comparative example and is a known compound, and its preparation method is exactly the same as that of Example 6 of International Application PCT/CN2017/085418)
  • Test method determination of carbon, hydrogen, and nitrogen, two parallel determinations.
  • Test equipment QSTAR Elite LC/MS/MS System
  • Test instrument Shimadzu UV-2700 ultraviolet-visible spectrophotometer
  • Test method Prepare the sample into a certain concentration solution, and use the same batch of solvent as a blank control, and use a 1cm absorption cell to measure in the range of 190-400nm.
  • Solvent water-methanol (1:1), 0.1mol/L hydrochloric acid-methanol (1:1), 0.1mol/L sodium hydroxide-methanol (1:1)
  • Test solution concentration 20 ⁇ l/ml.
  • Test instrument British PE (Spectrum400) infrared spectrometer
  • Test instrument Bruker AVANCE III 500 high-resolution superconducting nuclear magnetic resonance spectrometer
  • Test instrument American PE Model 343 polarimeter.
  • Test instrument D8-Advance X-ray diffractometer
  • Test conditions working voltage 40kV, working current 40mA, Cu target.
  • the scanning speed is 0.02 degrees/step, and the dwell time is 0.1 seconds/step.
  • Test instrument Mettler Mettler TGA/DSC3 + thermal analyzer from Switzerland
  • TGA The weight loss starts at about 170°C, and the weight loss is obvious at 175°C.
  • DSC shows an endothermic peak at 174.68°C, which should be caused by the melting and absorption of heat by the compound of Example 2.
  • TGA shows that the thermogravimetric curve is basically unchanged before 160°C, and there is no weight loss, indicating that the compound of Example 2 does not contain a crystallization solvent.
  • the weight loss is obvious, which is the weight loss caused by the melting and decomposition of the sample.
  • the DSC endothermic peak is the decomposition point of the compound of Example 2.
  • Example 1 The compound of Example 1 was placed at a high temperature of 60°C for 5 days, and there was no obvious change in appearance, melting point, and impurity content, and it was stable under high temperature conditions; placed at high humidity RH 92.5% for 5 days. Severe moisture absorption, the appearance is colorless viscous liquid, the related substances have not changed; the appearance is transparent and lumpy under light conditions, the impurities increase to 4.0%, and it is unstable under light conditions.
  • the compound of Example 2 is stable under light, high temperature and high humidity conditions.
  • mice The experiment was divided into solvent control group, cyclophosphamide 80 mg/kg group (CTX), compound of Example 1 and compound of Example 2 were 5 mg/kg group and 10 mg/kg group, respectively.
  • CTX cyclophosphamide 80 mg/kg group
  • compound of Example 1 and compound of Example 2 were 5 mg/kg group and 10 mg/kg group, respectively.
  • TGI tumor growth inhibition rate
  • the anti-tumor efficacy of the compound of Example 1 and the compound of Example 2 of PD-L1 inhibitor on mouse colon cancer MC38 in vivo was evaluated on a mouse subcutaneous xenograft tumor model.
  • mice The experiment was divided into a solvent control group, a cyclophosphamide 80 mg/kg group (CTX), a compound of Example 1 and a compound of Example 2 at 5 mg/kg and 10 mg/kg, respectively.
  • CTX cyclophosphamide 80 mg/kg group
  • TGI tumor growth inhibition rate
  • the in vivo anti-tumor efficacy of the compound of Example 1 and the compound of Example 2 of the PD-L1 inhibitor was evaluated on the human lung cancer NCI-H460 model of NSG tumor-bearing mice with reconstructed human immune system.
  • mice The experiment was divided into a solvent control group, a cyclophosphamide 80 mg/kg group (CTX), a compound of Example 1 and a compound of Example 2 at 5 mg/kg and 10 mg/kg, respectively.
  • CTX cyclophosphamide 80 mg/kg group
  • mice After separating fresh human leukocytes to obtain PBMCs, they were inoculated into NSG mice through the tail vein, 1 ⁇ 10 7 cells per mouse, and NCI-H460 tumor cells were inoculated under the armpits of the mice on the third day, 1 ⁇ each was inoculated. 10 6 pcs. After the tumors grow to 100-300 mm 3, they are administered in groups. The solvent control group is given 0.5% CMC orally every day; cyclophosphamide is given intraperitoneally; the test compound is given orally once a day. The animals were weighed during processing and the animals were sacrificed. The tumor tissue was stripped, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the intensity of the anti-tumor effect.
  • TGI tumor growth inhibition rate
  • the compound of Example 2 orally administered daily at 5 mg/kg and 10 mg/kg doses has tumor inhibition rates of 40% and 55%, respectively, while the compound of Example 1
  • the tumor inhibition rates at the same dose were 11% and 13%, respectively.
  • the compound of Example 2 orally administered daily at 5mg/kg and 10mg/kg doses has 75% and 57% tumor inhibition rates, respectively, while the compound of Example 1 is at the same dose.
  • the tumor inhibition rates were 18% and 27%, respectively.
  • the compound of Example 2 has a better tumor inhibition rate than the compound of Example 1 at a dose of 15 mg/kg administered orally per day (tumor inhibition rate 30.6% vs 24.7 %).

Abstract

本发明涉及医药技术领域，公开了一个烟醇醚衍生物的马来酸盐及其晶型和应用，即(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体、晶型及其制法和药物组合物与用途。具体而言，涉及式I所示的S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐以及其晶型，其立体异构体及其制备方法，含有该化合物或其晶型的组合物，和该化合物或其晶型在制备治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病的药物中的用途.

Description

一个烟醇醚衍生物的马来酸盐及其晶型和应用 技术领域
本发明属于医药技术领域，公开了一个烟醇醚衍生物的马来酸盐及其晶型和应用,即(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐、及其制法、晶型和药物组合物与用途。具体而言，涉及式I所示的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐，其立体异构体及其制备方法和晶型，含有该化合物或其晶型的组合物，和该化合物在制备预防或治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病等药物中的用途。
背景技术
随着对肿瘤免疫研究的深入，人们发现肿瘤微环境可以保护肿瘤细胞不被机体免疫系统识别和杀伤，肿瘤细胞的免疫逃逸在肿瘤发生、发展中扮演了非常重要的角色。2013年Science杂志将肿瘤免疫治疗列为十大突破之首，再次让免疫治疗成为肿瘤治疗领域的“焦点”。机体免疫细胞的激活或抑制是通过正性信号和负性信号来调节，其中程序性死亡分子1(programmed death 1，PD-1)/PD-1配体(PD-1 ligand，PD-L1)便是负性免疫调节信号，抑制了肿瘤特异性CD8+T细胞的免疫活性，介导了免疫逃逸。
肿瘤细胞所具有的逃避免疫系统的能力，是通过在其表面产生的程序性死亡配体(PD-L1)结合到T细胞的PD-1蛋白上实现的。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子，肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2，导致肿瘤微环境中PD-1通路持续激活，T细胞功能被抑制而不能发现肿瘤以至于不能向免疫系统发出需要攻击肿瘤和杀伤肿瘤细胞的治疗。PD-1抗体是针对PD-1或者PD-L1的一种抗体蛋白，使得前两种蛋白不能发生结合，阻断这一通路，部分恢复T细胞的功能，使这些细胞能够继续杀伤肿瘤细胞。
最近，一系列令人惊喜的研究结果证实PDl/PD-Ll抑制性抗体对多种肿瘤具有强大的抗瘤活性，格外引人注目。2014年9月4日美国默克的
Figure PCTCN2020114137-appb-000001
(pembrolizumab)成为FDA批准的首例PD-1单抗用于治疗对其它药物治疗无效的晚期或无法切除的黑色素瘤患者。目前，默沙东正在30多种不同类型的癌症中试验Keytruda的潜力，包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。2014年12月22日，制药巨头百时美施贵宝公司不负重望，率先发力，获得美国食品药品监督管理局(FDA)加速批准，其研发的抗癌免疫疗法药物nivolumab以Opdivo的商品名上市，用于治疗对其它药物没有应答的不可切除的或转移性黑色素瘤患者，是继默沙东Keytruda之后第二个在美国上市的PD-1抑制剂。FDA于2015年3月4日批准了nivolumab用于治疗在经铂为基础化疗期间或化疗后发生疾病进展的转移性鳞性非小细胞肺癌。根据默沙东公布的Keytruda(pembrolizumab)治疗实体瘤的一项Ib期KEYNOTE-028研究数据，Keytruda治疗在25例胸膜间皮瘤(pleuralmesothelioma，PM)患者中取得了28％的总缓 解率(ORR)，并有48％的患者病情稳定，疾病控制率达到了76％。对当前任何已获批药物均无治疗反应的晚期霍奇金淋巴瘤(HL)患者，接受默沙东Keytruda和百时美Opdvio治疗后，能够达到完全缓解。在2015AACR年会上，约翰霍普金斯基梅尔癌症中心(Kimmel Cancer Center)的肿瘤内科学副教授Leisha A.Emens,MD,PhD做出的报道指出，罗氏的MPDL3280A这一具有抗PD-L1作用的单克隆抗体，在晚期三阴性乳腺癌中表现出了持久的疗效。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的革命。但是，单抗治疗药物有其本身的缺陷：易被蛋白酶分解，因而在体内不稳定，不能口服；易产生免疫交叉反应；产品质量不易控制，制作技术要求高；大量制备和纯化比较困难，生产成本高；使用不方便，只能注射或点滴。所以，PDl/PD-Ll相互作用小分子抑制剂是肿瘤免疫治疗的更佳选择。
本发明人在国际申请PCT/CN2017/085418中公开了(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯盐酸盐以及其在制备预防或治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病等药物中的用途。发明人在后期研究中发现该化合物的马来酸盐相比其盐酸盐在稳定性和药效上均强于后者。本发明的实施例1为完全按照国际专利申请PCT/CN2017/085418中的制备方法制备的其盐酸盐，作为对比例。
发明内容
本发明解决的技术问题是提供一种具有抑制PDl/PD-Ll相互作用的结构式I的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐，以及其立体异构体，其制备方法、药物组合物和其在制备预防或治疗与PDl/PD-Ll信号通路有关疾病药物中的用途。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供如式I所示的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体，
Figure PCTCN2020114137-appb-000002
本发明技术方案的第二方面提供了一种(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的晶A型固体物质，其特征在于，当使用粉末X射线衍射分析采用Cu靶辐射实验条件时，衍射峰位置：2-Theta值(°)或d值
Figure PCTCN2020114137-appb-000003
和衍射峰相对强度(％)具有如下特征：
Figure PCTCN2020114137-appb-000004
Figure PCTCN2020114137-appb-000005
所述的晶A型固体物质，其特征在于，使用红外光谱进行分析时在3059、2984、2841、2761、2519、2170、1988、1968、1807、1741、1716、1623、1602、1580、1505、1481、1460、1446、1425、1401、1389、1368、1309、1262、1242、1205、1171、1111、1095、1069、1040、1004、972、953、924、884、870、864、854、824、788、761、721、703、662cm -1±2cm -1的吸收峰为所述晶A型固体物质所呈现的红外光谱特征峰位置。
所述的晶A型固体物质，其特征在于，使用差示扫描量热技术分析时，表现为当升温速率为每分钟10℃的DSC图谱中在175℃±3℃处含有1个吸热峰。
本发明技术方案的第二方面还提供了一种(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的混晶固体物质，其特征在于，含有任意非零比例的所述的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的晶A型固体物质。
本发明技术方案的第三方面是提供了第一方面所述化合物和第二方面所述晶A型固体物质的制备方法：
Figure PCTCN2020114137-appb-000006
式I所述化合物的制备方法为：将(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯和马来酸在溶剂中反应成盐，最佳溶剂为异丙醇、或四氢呋喃、或丙酮；将获得的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐在丙酮和水的混合溶剂中结晶，丙酮和水的比例范围为200:1至1:1间,较佳比例范围在50:1 至5:1间，最佳比例范围在25:1至10:1间。在所述的式I化合物及其溶剂化物和其盐的制备过程中，不同结晶条件可能出现多晶。
本发明技术方案的第四方面是提供了一种药物组合物，所述的药物组合物包含作为有效成分的本发明第一方面所述的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体或第二方面所述晶A型固体物质以及药学上可接受的载体或赋形剂。
本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩 解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.01-100mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明技术方案的第五方面是提供了(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体或第二方面所述的晶A型固体物质在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。
所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。所述的感染性疾病选自细菌感染、病毒感染。所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病，其中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
有益技术效果：
本发明化合物(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐与盐酸盐相比，其晶型稳定，对光照射、高湿、高温环境的稳定性好，在小鼠皮下移植瘤模型上或在人免疫系统重建的NSG荷瘤小鼠模型上对多种类型肿瘤具有较高的抑瘤率。
附图说明
图1、实施例1化合物的差示扫描量热分析/热重分析图谱
图2、实施例2化合物的差示扫描量热分析/热重分析图谱
图3、实施例2化合物的粉末X-射线衍射图谱
具体实施方式：
以下将结合实施例对发明作进一步说明，但并不限制本发明的范围。
测定仪器：核磁共振光谱用Bruker AVANCE III 500型高分辨超导核磁共振谱仪。质谱用QSTAR Elite LC/MS/MS System。元素分析用FLASH1112微量元素分析仪及MX-5百万分之一天平。紫外分析用岛津UV-2700紫外可见分光光度仪。比旋光度用美国PE Model 343旋光仪。粉末X-射线衍射分析用D8-Advance型X-射线衍射仪。差示扫描量热分析/热重分析(DSC/TG)用瑞士Mettler Mettler TGA/DSC3 +热分析仪。
1、盐的制备：
实施例1：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯盐酸盐(该实施例作为对比例，为已知化合物，其制备方法和国际申请PCT/CN2017/085418的实施例6完全相同)
Figure PCTCN2020114137-appb-000007
将598毫克(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸和60毫升无水异丙醇置于100毫升圆底烧瓶中，冰水浴搅拌下加入6毫升二氯亚砜，2滴DMF，室温搅拌2小时后加热回流至反应完全，减压除去溶剂得到(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯盐酸盐白色固体。 1H NMR(400MHz,DMSO-d 6)δ9.62(s,1H,-HCl),9.40(s,1H,-HCl),9.10(s,1H,-ArH),8.86(d,1H,-ArH),8.59(d,J＝7.6Hz,1H,-ArH),8.01–7.91(m,1H,-ArH),7.73–7.64(m,2H,-ArH),7.57–7.46(m,3H,-ArH),7.46–7.37(m,4H,-ArH),7.16(s,1H,-ArH),5.47(s,2H,-CH 2-),5.36(s,2H,-CH 2-),4.92(m1H,-CH-),4.30–4.15(m,2H,-CH 2-),4.05(s,1H,-CH-),3.97(dd,J＝12.0,3.0Hz,1H,-CH 2-),3.84(dd,J＝12.0,3.8Hz,1H,-CH 2-),1.20(d,J＝6.4Hz,3H,-CH 3),1.18(d,J＝6.4Hz,3H,-CH 3).MS(FAB):640(M)。
实施例2：(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐(IMMH-010)
室温下，将(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯(2.6g)，异丙醇9mL加入到50mL反应瓶中，升温至40℃，搅拌0.5h，滴加马来酸(0.594g)-异丙醇(4mL)溶液，控温35～45℃，有固体析出，保温搅拌0.5h，自然降至室温，搅拌过 夜。次日，抽滤，滤饼依次用异丙醇0.5mL，丙酮0.5mL淋洗，得淡黄色固体，即为(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐粗品。室温下，将粗品，丙酮26mL加入到50mL反应瓶中，升温至回流，滴加纯化水1.4mL，体系全溶，热过滤，滤毕，转移到50mL反应瓶中，自然降至室温，搅拌析晶过夜。次日，降温至5～15℃，搅拌2h，抽滤，滤饼用丙酮0.5mL淋洗，45℃鼓风干燥至恒重，得白色固体0.73g精品。
2、实施例2化合物的结构确证：
1)元素分析：
(1)测试仪器：微量元素分析仪FLASH1112及百万分之一天平MX-5。
(2)测试方法：碳、氢、氮测定，平行测定两次。
(3)测得结果：
实施例2化合物的元素分析数据表
Figure PCTCN2020114137-appb-000008
2)高分辨质谱：
(1)测试仪器：QSTAR Elite LC/MS/MS System
(2)测试条件：ESI源
(3)测得数据：
实施例2化合物的高分辨质谱数据
[M+H] +测定值(m/z) 639.1259
[M+H] +理论值(m/z) 639.1256
误差(×10 -6) 0.49
分子离子峰分子组成 C 32H 33N 2O 5ClBr
分子式 C 32H 32N 2O 5ClBr
3)紫外吸收光谱：
(1)测试仪器：岛津UV-2700紫外可见分光光度仪
(2)测试方法：将样品配制成一定浓度溶液，并用同批溶剂作为空白对照，采用1cm吸收池在190～400nm范围内测定。
溶剂：水-甲醇(1:1)、0.1mol/L盐酸-甲醇(1:1)、0.1mol/L氢氧化钠-甲醇(1:1)
试液浓度：20μl/ml。
(3)测得数据：
实施例2化合物的UV数据表
Figure PCTCN2020114137-appb-000009
4)红外吸收光谱：
(1)测试仪器：英国PE(Spectrum400)红外光谱仪
(2)测试条件：衰减全反射(ATR)红外光谱法，粉末直接进样方式
实施例2化合物的IR数据表
Figure PCTCN2020114137-appb-000010
5)核磁共振氢谱及碳谱：
(1)测试仪器：Bruker AVANCE III 500型高分辨超导核磁共振谱仪
(2)测试条件：溶剂为DMSO-d 6，内标为TMS
实施例2化合物的 1H-NMR数据
Figure PCTCN2020114137-appb-000011
Figure PCTCN2020114137-appb-000012
实施例2化合物的 13C-NMR数据
Figure PCTCN2020114137-appb-000013
Figure PCTCN2020114137-appb-000014
6)比旋光度：
(1)测试仪器：美国PE Model 343旋光仪。
(2)测定方法：取本品，精密称定，加DMSO溶解并定量稀释制成每1ml中约含50mg的溶液，测定比旋度。
(3)测定温度：20℃
(4)结果
以DMSO为溶剂，测定浓度50mg/ml，实施例2化合物的比旋度为+5.5°。[α] 20 589＝+5.5°(C＝5,DMSO)
3、实施例2化合物的晶型分析：
1)粉末X-射线衍射分析：
(1)测试仪器：D8-Advance型X-射线衍射仪
(2)测试条件：工作电压40kV，工作电流40mA，Cu靶。扫描速度0.02度/步，停留时间0.1秒/步。
(3)测试结果(见图3)：
实施例2化合物的粉末X-射线衍射数据表
Figure PCTCN2020114137-appb-000015
Figure PCTCN2020114137-appb-000016
(4)解析：粉末X-射线衍射分析显示，实施例2化合物为晶态物质。
2)差示扫描量热分析/热重分析(DSC/TG)：
(1)测试仪器：瑞士Mettler Mettler TGA/DSC3 +热分析仪
(2)参数设置：起始温度35℃；终止温度250℃；升温速率10℃/min。
(3)测得数据：DSC：峰顶温度：174.68℃(吸热)。
TGA：约170℃开始失重，175℃失重明显。
(4)解析：DSC显示174.68℃处有一吸热峰，应为实施例2化合物熔融吸收热量导致。TGA显示在160℃之前热重曲线基本不变，没有失重，表明实施例2化合物不含结晶溶剂。温度升高至DSC吸热峰顶(约175℃)失重明显，为样品熔融分解导致的失重，DSC吸热峰为实施例2化合物的分解点。
4、实施例1化合物和实施例2化合物的稳定性比较
1)实施例1化合物的稳定性
(1)理化性质
外观：类白色粉末
熔点：119.36℃(DSC法)(见附图1)
纯度：99.5％(HPLC归一化法)
log P＝2.4
(2)影响因素试验
Figure PCTCN2020114137-appb-000017
实施例1化合物在高温60℃放置5天，外观、熔点、杂质含量均无明显变化，高温条件下稳定；高湿RH92.5％放置5天。严重吸湿，外观呈无色粘稠液体，有关物质未发生变化；光照条件下外观呈透明块状，杂质增加至4.0％，光照条件下不稳定。
2)实施例2化合物的稳定性
(1)理化性质
外观：白色固体
熔点：174.68℃(DSC法)(见附图2)
纯度：98.7％(HPLC归一化法)
log P＝3.2
(2)影响因素试验
Figure PCTCN2020114137-appb-000018
实施例2化合物光照、高温、高湿条件下稳定。
5、实施例1化合物和实施例2化合物对小鼠黑色素瘤B16F10的体内抗肿瘤药效比较
实验目的：
在小鼠皮下移植瘤模型上评价PD-L1抑制剂实施例1化合物和实施例2化合物对小鼠黑色素瘤B16F10的体内抗肿瘤药效。
实验方案：
动物分组：实验分为溶剂对照组、环磷酰胺80mg/kg组(CTX)、实施例1化合物和实施例2化合物分别为5mg/kg组、10mg/kg组。
实验步骤：将传代的B16F10瘤株用匀浆器研匀后，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为9×10 6个/ml肿瘤细胞悬液，将0.2ml细胞混悬液接种到C57BL/6J小鼠右侧腋下，记为第0天。接种后次日动物随机分组，称重后给药。溶剂对照组每天口服给予0.5％CMC；环磷酰胺腹腔给药；待测化合物每天口服给药1次。处理时称量体重，处死动物。剥取肿瘤组织，称重并进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
计算统计方法：肿瘤增殖抑制率TGI(％)：TGI＝(1‐T/C)×100。(T：治疗组肿瘤重量；C：阴性对照组肿瘤重量)。
统计方法：利用Graphpad进行数据统计分析，采用One-way ANOVA检验，*p<0.05、**p<0.01、***p<0.001。
实验结果：
给药后处理动物称取肿瘤重量，实施例1化合物和实施例2化合物对小鼠黑色素瘤B16F10抗肿瘤作用详见下表。
实施例2化合物对小鼠B16F10的体内抗肿瘤作用
Figure PCTCN2020114137-appb-000019
注：与溶剂对照组比较,*p<0.05、**p<0.01、***p<0.001,One-way ANOVA NA:不适用
实施例1化合物对小鼠B16F10的体内抗肿瘤作用
Figure PCTCN2020114137-appb-000020
注：与溶剂对照组比较,*p<0.05、**p<0.01、***p<0.001,One-way ANOVA NA:不适用
6、实施例1化合物和实施例2化合物对小鼠结肠癌MC38的体内抗肿瘤药效比较
实验目的：
在小鼠皮下移植瘤模型上评价PD-L1抑制剂实施例1化合物和实施例2化合物对小鼠结肠癌MC38的体内抗肿瘤药效。
实验方案：
动物分组：实验分为溶剂对照组、环磷酰胺80mg/kg组(CTX)、实施例1化合物和实施例2化合物分别5mg/kg组、10mg/kg组。
实验步骤：将传代的MC38瘤株用匀浆器研匀后，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为9×10 6个/ml肿瘤细胞悬液，将0.2ml细胞混悬液接种到C57BL/6J小鼠右侧腋下，记为第0天。接种后次日动物随机分组，称重后给药。溶剂对照组每天口服给予0.5％CMC；环磷酰胺腹腔给药；待测化合物每天口服给药1次。处理时称量体重，处死动物。剥取肿瘤组织，称重并进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
计算统计方法：肿瘤增殖抑制率TGI(％)：TGI＝(1‐T/C)×100。(T：治疗组肿瘤重量；C：阴性对照组肿瘤重量)。
统计方法：利用Graphpad进行数据统计分析，采用One-way ANOVA检验，*p<0.05、** p<0.01、***p<0.001。
实验结果：
给药后处理动物称取肿瘤重量，实施例1化合物和实施例2化合物对小鼠结肠癌MC38抗肿瘤作用详见下表。
实施例2化合物对小鼠结肠癌MC38抗肿瘤作用
Figure PCTCN2020114137-appb-000021
注：与溶剂对照组比较,*p<0.05、**p<0.01、***p<0.001,One-way ANOVA NA:不适用
实施例1化合物对小鼠结肠癌MC38抗肿瘤作用
Figure PCTCN2020114137-appb-000022
注：与溶剂对照组比较,*p<0.05、**p<0.01、***p<0.001,One-way ANOVA NA:不适用
7、实施例1化合物和实施例2化合物在人肺癌NCI-H460模型上抗肿瘤药效比较
实验目的：
在人免疫系统重建的NSG荷瘤小鼠人肺癌NCI-H460模型上评价PD-L1抑制剂实施例1化合物和实施例2化合物的体内抗肿瘤药效。
实验方案：
动物分组：实验分为溶剂对照组、环磷酰胺80mg/kg组(CTX)、实施例1化合物和实施例2化合物分别5mg/kg组、10mg/kg组。
实验步骤：将新鲜的人白细胞分离获得PBMC后，尾静脉接种至NSG小鼠，每只接种1×10 7个，第3天在小鼠腋下接种NCI-H460肿瘤细胞，每只接种1×10 6个。带肿瘤生长至100～300mm 3后分组给药，溶剂对照组每天口服给予0.5％CMC；环磷酰胺腹腔给药；待测化合物每天口服给药1次。处理时称量体重，处死动物。剥取肿瘤组织，称重并进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
计算统计方法：肿瘤增殖抑制率TGI(％)：TGI＝(1‐T/C)×100。(T：治疗组肿瘤重量；C：阴性对照组肿瘤重量)。
统计方法：利用Graphpad进行数据统计分析，采用One-way ANOVA检验，*p<0.05、**p<0.01、***p<0.001。
实验结果：
给药后处理动物称取肿瘤重量，实施例1化合物和实施例2化合物对NCI-H460抗肿瘤作用详见下表。
实施例1化合物和实施例2化合物对NCI-H460抗肿瘤作用
Figure PCTCN2020114137-appb-000023
与溶剂对照组比较,*p<0.05、**p<0.01、***p<0.001,One-way ANOVA NA:不适用
综上实验结果显示：
在小鼠黑色素瘤高转移株B16F10皮下移植瘤模型中，实施例2化合物每天口服给药在5mg/kg和10mg/kg剂量下的抑瘤率分别为40％和55％，而实施例1化合物在同等剂量下的抑瘤率分别为11％和13％。
在小鼠结肠癌MC38皮下移植瘤模型中，实施例2化合物每天口服给药在5mg/kg和10mg/kg剂量下的抑瘤率分别为75％和57％，而实施例1化合物在同等剂量下的抑瘤率分别为18％和27％。
在人免疫系统重建的NSG荷瘤小鼠(NCI-H460)上，实施例2化合物每天口服给药在15mg/kg剂量下的抑瘤率优于实施例1化合物(抑瘤率30.6％vs 24.7％)。
肿瘤模型 同剂量抑瘤率比较
B16F10 实施例2化合物(马来酸盐)>实施例1化合物(盐酸盐)
MC38 实施例2化合物(马来酸盐)>实施例1化合物(盐酸盐)
NSG NCI-H460 实施例2化合物(马来酸盐)>实施例1化合物(盐酸盐)

Claims (10)

  1. 如式I所示的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体，
    Figure PCTCN2020114137-appb-100001
  2. 一种(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的晶A型固体物质，其特征在于，当使用粉末X射线衍射分析采用Cu靶辐射实验条件时，衍射峰位置：2-Theta值(°)或d值
    Figure PCTCN2020114137-appb-100002
    和衍射峰相对强度(％)具有如下特征：
    Figure PCTCN2020114137-appb-100003
  3. 根据权利要求2的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的晶A型固体物质，其特征在于，使用红外光谱进行分析时在3059、2984、2841、2761、2519、2170、1988、1968、1807、1741、1716、1623、1602、1580、1505、1481、1460、1446、1425、1401、1389、1368、1309、1262、1242、1205、1171、1111、1095、1069、1040、1004、972、953、924、884、870、864、854、824、788、761、721、703、662cm-1±2cm-1的吸收峰为所述晶A型固体物质所呈现的红外光谱特征峰位置。
  4. 根据权利要求2的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的晶A型固体物质，其特征在于，使用差示扫描量热技术分析时，表现为当升温速率为每分钟10℃的DSC图谱中在175℃±3℃处含有1个吸热峰。
  5. 一种(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的混晶固体物质，其特征在于，含有任意非零比例的权利要求2中所述的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐的晶A型固体物质。
  6. 权利要求1所述的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐或权利要求2所述的晶A型固体物质的制备方法，其特征在于，所述的制备方法为：将(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯和马来酸在溶剂中反应成盐，优选的溶剂为异丙醇、或四氢呋喃、或丙酮；将获得的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐在丙酮和水的混合溶剂中结晶，丙酮和水的比例范围为200:1至1:1间,优选的比例范围在50:1至5:1间，更优选的比例范围在25:1至10:1间。
  7. 一种药物组合物，其特征在于，所述的药物组合物包含作为有效成分的权利要求1所述的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体或权利要求2-4任一项所述的晶A型固体物质或权利要求5所述的混晶固体物质以及其药学上可接受的载体或赋形剂。
  8. 权利要求1所述的(S)-N-(2-(吡啶-3-甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基)丝氨酸异丙酯马来酸盐及其立体异构体或权利要求2-4任一项所述的晶A型固体物质或权利要求5所述的混晶固体物质在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。
  9. 根据权利要求8的应用，其特征在于，所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。
  10. 根据权利要求9的应用，其特征在于，所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌；所述的感染性疾病选自细菌感染、病毒感染；所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病，其中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
PCT/CN2020/114137 2019-09-09 2020-09-09 一个烟醇醚衍生物的马来酸盐及其晶型和应用 WO2021047528A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2022515664A JP2022547208A (ja) 2019-09-09 2020-09-09 ニコチニルアルコールエーテル誘導体のマレイン酸塩、その結晶形、及びその使用
EP20863682.9A EP4029863A4 (en) 2019-09-09 2020-09-09 MALEATE OF NICOTINYL ALCOHOL ETHER DERIVATIVES, CRYSTAL FORM THEREOF AND APPLICATION THEREOF
CN202080063645.3A CN114450278A (zh) 2019-09-09 2020-09-09 一个烟醇醚衍生物的马来酸盐及其晶型和应用
KR1020227011675A KR20220061184A (ko) 2019-09-09 2020-09-09 니코티닐 알코올 에테르 유도체의 말레에이트, 이의 결정형, 및 이의 응용

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910864721 2019-09-09
CN201910864721.X 2019-09-09

Publications (1)

Publication Number Publication Date
WO2021047528A1 true WO2021047528A1 (zh) 2021-03-18

Family

ID=73309271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/114137 WO2021047528A1 (zh) 2019-09-09 2020-09-09 一个烟醇醚衍生物的马来酸盐及其晶型和应用

Country Status (5)

Country Link
EP (1) EP4029863A4 (zh)
JP (1) JP2022547208A (zh)
KR (1) KR20220061184A (zh)
CN (2) CN114450278A (zh)
WO (1) WO2021047528A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114450278A (zh) * 2019-09-09 2022-05-06 中国医学科学院药物研究所 一个烟醇醚衍生物的马来酸盐及其晶型和应用
WO2023050104A1 (zh) * 2021-09-28 2023-04-06 中国医学科学院药物研究所 二氢吲哚衍生物、及其制法和药物组合物与用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126428A1 (en) * 2012-02-21 2013-08-29 Allergan, Inc. Phenoxy derivatives as sphingosine 1-phosphate (s1p) receptor modulators
CN103787902A (zh) * 2014-02-17 2014-05-14 华东理工大学 苄基取代的苯胺类化合物及其应用
WO2015160641A2 (en) * 2014-04-14 2015-10-22 Bristol-Myers Squibb Company Compounds useful as immunomodulators
CN109153670A (zh) * 2016-05-23 2019-01-04 中国医学科学院药物研究所 烟醇醚类衍生物、及其制法和药物组合物与用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114450278A (zh) * 2019-09-09 2022-05-06 中国医学科学院药物研究所 一个烟醇醚衍生物的马来酸盐及其晶型和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126428A1 (en) * 2012-02-21 2013-08-29 Allergan, Inc. Phenoxy derivatives as sphingosine 1-phosphate (s1p) receptor modulators
CN103787902A (zh) * 2014-02-17 2014-05-14 华东理工大学 苄基取代的苯胺类化合物及其应用
WO2015160641A2 (en) * 2014-04-14 2015-10-22 Bristol-Myers Squibb Company Compounds useful as immunomodulators
CN109153670A (zh) * 2016-05-23 2019-01-04 中国医学科学院药物研究所 烟醇醚类衍生物、及其制法和药物组合物与用途

Also Published As

Publication number Publication date
JP2022547208A (ja) 2022-11-10
CN111925318A (zh) 2020-11-13
EP4029863A4 (en) 2023-10-25
CN114450278A (zh) 2022-05-06
KR20220061184A (ko) 2022-05-12
EP4029863A1 (en) 2022-07-20
CN111925318B (zh) 2023-02-28

Similar Documents

Publication Publication Date Title
US20060199773A1 (en) Crystalline forms of (1R,2S)-N-[(1,1-dimethylethoxy)carbonyl]-3-methyl-L-valyl-(4R)-4-[(6-methoxy-1-isoquinolinyl)oxy]-L-prolyl-1-amino-N-(cyclopropylsulfonyl)-2-ethenyl-cyclopropanecarboxamide, monopotassium salt
CN110054624B (zh) 盐酸小檗碱与咖啡酸共晶物及制备方法和其组合物与用途
CN112010839B (zh) 靶向丝/苏氨酸激酶抑制剂的晶型
WO2021047528A1 (zh) 一个烟醇醚衍生物的马来酸盐及其晶型和应用
TW201831191A (zh) 一種新的硼酸衍生物及其藥物組合物
US10323044B2 (en) Crystal of imidazo-oxazine, pharmaceutical composition containing said crystal, and method for producing said crystal
KR102531772B1 (ko) Cdk4/6 키나아제 억제제를 타겟팅하는 결정형
US20210094961A1 (en) Form of ponatinib
RU2816099C1 (ru) Малеат эфирного производного никотинилового спирта, его кристаллическая форма и его применение
CN113214207A (zh) 橙皮素与甜菜碱共晶物a及制备方法和其组合物与用途
TWI814468B (zh) 藥用組合物、其製備方法及用途
JP7282787B2 (ja) ピラゾロ［３，４－ｄ］ピリミジンの結晶
KR20190090729A (ko) 토파시티닙의 신규 염, 이의 제조방법 및 이를 포함하는 약학 조성물
CN103304556B (zh) 含有苯并吡喃的希夫碱类化合物、其制备方法和用途
TWI769395B (zh) 以吡唑并[3,4-d]嘧啶化合物為有效成分之治療劑
US20220162214A1 (en) Polymorphs of a Kinase Inhibitor, Pharmaceutical Compositions Containing Such a Compound, Preparation Methods, and Applications
CN110248931B (zh) 一种双加氧酶抑制剂的盐及其制备方法和用途
US20240140950A1 (en) NITROGEN-CONTAINING POLYCYCLIC AROMATIC COMPOUND, and PREPARATION METHOD AND APPLICATION THEREOF
CN115477647A (zh) 小檗碱富马酸盐晶型及其制备方法和其组合物与应用
CN115572292A (zh) 小檗碱丁二酸盐晶型及其制备方法和其组合物与应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20863682

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022515664

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20227011675

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020863682

Country of ref document: EP

Effective date: 20220411