WO2019120199A1 - Dérivés de quinoline et leurs utilisations - Google Patents

Dérivés de quinoline et leurs utilisations Download PDF

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WO2019120199A1
WO2019120199A1 PCT/CN2018/121870 CN2018121870W WO2019120199A1 WO 2019120199 A1 WO2019120199 A1 WO 2019120199A1 CN 2018121870 W CN2018121870 W CN 2018121870W WO 2019120199 A1 WO2019120199 A1 WO 2019120199A1
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cancer
alkyl
disease
group
pharmaceutically acceptable
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PCT/CN2018/121870
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张磊
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成都华健未来科技有限公司
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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to a class of quinolin-4-ylcyclohexane compounds, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof, and processes for their preparation and combinations thereof, alone or in combination with other drugs
  • a disease is used in the treatment of pathological features of the IDO-mediated tryptophan metabolism pathway.
  • Tryptophan is an essential amino acid in the human body. Part of the tryptophan obtained from the diet is used to synthesize proteins and the neurotransmitter serotonin, and the rest is mainly metabolized by the kynurenine pathway.
  • Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway. When the expression level of IDO1 is high in tissue cells, a large amount of tryptophan is metabolized by the kynurenine metabolic pathway, and the tryptophan content is decreased, which directly inhibits the activation and proliferation of effector T cells.
  • the metabolites produced by the kynurenine pathway have certain effects on immunity, reproduction and central nervous system. In addition to directly inhibiting the survival of effector T cells, they also inhibit effector T cells by promoting the differentiation of regulatory T cells. Studies have shown that the total uric acid metabolic pathway of tryptophan is an important cause of immune escape in tumor cells.
  • IDO-mediated kynurenine metabolism is also associated with other diseases.
  • diseases such as the kynurenine pathway and myelodysplastic syndrome (Leuk Res. 2013; 37 (5): 573-9); neurodegenerative diseases, schizophrenia and depression (Nat Rev Neurosci. 2012; 13 (7): 465 -77); Alzheimer's disease (J Neural Transm (Vienna). 2000; 107(3): 343-53); cataract (Curr Eye Res. 2009; 34(4): 274-81); inflammation and sepsis (Nat. Med 2010; 16 (3): 279-85); AIDS (PLoS One. 2013; 8 (9): e74551);
  • IDO inhibitors have therapeutic and preventive effects in various diseases such as tumors, and have good application prospects, but existing IDO inhibitors have shown insufficient effectiveness or dose-limiting toxicity in clinical trials, which is required in the art. Development of new IDO inhibitors.
  • R 1 is -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl;
  • X is selected from O or S
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , —NO 2 , wherein the alkyl, alkenyl and alkynyl groups may be substituted by a substituent selected from halogen, —C 1-4 alkyl;
  • R 3 and R 4 are each independently hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl; or
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may be substituted by a -C 1-4 alkyl group.
  • the invention provides a compound of formula (II),
  • R 1 is -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl;
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -CHF 2 , -OCF 3 , - NH 2 , -NO 2 .
  • the invention provides a compound of formula (II), a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
  • R 1 is selected from the following structures:
  • R 3 is selected from fluorine.
  • ⁇ refers herein to -D.
  • halogen refers to -F, -Cl, -Br and -I.
  • alkyl refers to an alkyl group that does not contain a hetero atom.
  • the term includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like.
  • the term also includes branched chain isomers of branched alkyl groups, including but not limited to, the following groups: -CH (CH 3) 2, -CH (CH 3) (CH 2 CH 3), - CH (CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )-CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH
  • alkenyl refers to at least one point of unsaturation in which two adjacent carbon atoms are bonded to the alkyl group defined above by a double bond, wherein the alkyl group is as defined herein.
  • alkynyl refers to an alkyl group wherein two adjacent carbon atoms are joined by a triple bond, wherein the alkyl group is as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic radical containing only carbon and hydrogen, and is optionally saturated, partially unsaturated or fully unsaturated. Depending on the structure, the cycloalkyl group is mono- or di-radical (for example, a cycloalkylene group).
  • heterocycloalkyl refers to at least one heteroatom selected from O, N and S and optionally contains one or more double or triple bond non-aromatic cycloalkyl groups.
  • the heterocycloalkyl group as a whole may have 3 to 14 ring atoms and contain 1 to 5 hetero atoms (for example, 3 to 6 ring atoms in the case of a monocyclic heterocycloalkyl group, in the case of a polycyclic heterocycloalkyl group) Has 7-14 ring atoms).
  • Heterocycloalkyl groups can be covalently attached to a defined chemical structure at any hetero atom or carbon atom that results in a stable structure.
  • heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl groups may also contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl , pyridine-2(1H)-keto group and the like.
  • heterocycloalkyl groups also include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrroline Base, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, piperidinyl, azetidine, piperazinyl and the like.
  • substituents of the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention encompasses subgroups of each of the members or members of such groups and ranges.
  • the term "C 1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • compound of the invention refers herein to compounds of formula (I)-(II) and all their pure and mixed stereoisomers, geometric isomers, tautomers. , solvates, hydrates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts.
  • the solvate of the compound of the present invention means a compound or a salt thereof, such as a hydrate, an ethanolate, a methanolate or the like, in combination with a stoichiometric and non-stoichiometric solvent.
  • the compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal to which it is treated.
  • stereoisomer refers to a chiralally different compound having one or more stereocenters, including the corresponding isomers and diastereomers.
  • the compound of the present invention can be used in the form of a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including chlorides, bromides and iodines of methyl, ethyl, propyl and butyl groups.
  • a dialkyl sulfate including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long chain halides, including sulfhydryl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
  • the invention also includes isotopically-labeled compounds of the invention, i.e., identical to those disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons.
  • isotopes incorporating compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I, etc.
  • the compounds of the present invention are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention such as those labeled with 3 H or 14 C, can be used in drug tissue distribution assays, and therefore, these 3 H or 14 C isotopes are particularly preferred for their ease of preparation and detection.
  • certain compounds of the invention that are replaced by heavier isotopes such as 2 H have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses, etc., therefore, 2 H is in some It is also preferred in some cases.
  • Isotopically labeled compounds of the formula (I) according to the invention and their presuppositions can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopic labels when carrying out the processes disclosed in the following schemes and/or examples and preparations. Reagents.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)-(II), or a pharmaceutically acceptable carrier, diluent or excipient thereof.
  • the invention further relates to a compound of the formula (I)-(II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for use in the prevention and/or treatment of IDO-mediated tryptophan metabolism
  • a pathway for the pathology of a drug in a disease The use of a pathway for the pathology of a drug in a disease.
  • the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorder, nerve Lesions and pain, cataracts, AIDS and pneumonia, wherein the cancer is preferably selected from prostate cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, and skin.
  • Cancer including melanoma and basal cell carcinoma
  • oral cancer including melanoma and basal cell carcinoma
  • bone cancer ovarian cancer
  • brain cancer head and neck cancer
  • mesothelioma leukemia, lymphoma, esophageal cancer
  • kidney cancer thyroid cancer
  • myeloma choriocarcinoma
  • testicular cancer glioma
  • maternal glioma fallopian tube tumor.
  • the present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, autoimmune Disease, Alzheimer's disease, depression, schizophrenia, anxiety, psychological disorders, neuropathy and pain, cataracts, AIDS and pneumonia.
  • the present invention also relates to a method of treating a disease preventing and/or treating a disease having an IDO-mediated pathology of a tryptophan metabolism pathway comprising administering to a patient a therapeutically effective amount of the formula (I)-(II) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is selected from the group consisting of prostate cancer , breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, liver cancer, bladder cancer, pancreatic cancer, rectal cancer, skin cancer (including melanoma and basal cell carcinoma), oral cancer, bone cancer, ovarian cancer , brain cancer, head and neck cancer, mesothelioma, leukemia, lymphoma, esophageal cancer, kidney cancer, thyroid cancer, myeloma, choriocarcinoma, test
  • the compounds provided herein can be prepared by standard synthetic methods well known in the art, and the present specification provides general methods for preparing the compounds of the invention.
  • Starting materials are usually commercially available, for example by Alfa TCI, Suiyuan Chemical, An Naiji Chemical, Ester (Chengdu) Biopharmaceutical, Chengdu Best Reagent, Chengdu Huana Chemical Preparation Co., Ltd., Aiqi Kang Pharmaceutical Technology (Shanghai) Co., Ltd., Shanghai Yuxiang Biotechnology Co., Ltd. It is commercially available from companies such as Shanghai WuXi PharmaTech Development Co., Ltd. or by methods well known to those skilled in the art.
  • reaction temperature e.g., reaction temperature, time, molar ratio of reactants, reaction solvent, and pressure, etc.
  • Optimum reaction conditions may vary depending on the particular reaction substrate or solvent employed, but such conditions can be determined by one of ordinary skill in the art by routine optimization.
  • reaction starting materials, intermediates, and example compounds can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (e.g., column chromatography, TLC separation, etc.).
  • TLC was extracted from Yantai Huanghai HSGF254 thin-layer chromatography silica gel plate (0.2 ⁇ 0.03 mm) by TLC.
  • the Yantai Yellow Sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm) was purchased from Qingdao Ocean Chemical Plant.
  • reaction temperature reaction temperature
  • reaction solvent reactant molar ratio or/and reaction duration
  • the purification conditions of the compound may also vary.
  • the appropriate column chromatography eluent is selected according to the Rf value of TLC, or the corresponding compound is isolated and purified by preparative TLC.
  • the compound of the formula (I) of the present invention can be produced according to the following Scheme 1.
  • the condensation of A and B gives the compound of formula (I), which typically employs a condensing agent such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP, and the like.
  • a condensing agent such as CDI, EDCI, DIC, DCC, HATU, HBTU, PyBOP, and the like.
  • the compound of the formula (I) of the present invention can be produced according to the following Scheme 2.
  • Reaction of A with thionyl chloride in a suitable solvent such as dichloromethane affords intermediate C.
  • Intermediates C and B in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, DBU, etc. in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, In the hexacyclic or the like, the reaction gives a compound of the formula (I).
  • a base such as pyridine, triethylamine, diisopropylethylamine, DBU, etc.
  • dichloromethane tetrahydrofuran
  • N,N-dimethylformamide N,N-dimethylformamide
  • HeLa cells were purchased from ATCC and cultured in DMEM containing L-glutamine (2 mM), non-essential amino acids (84 mg/L) and fetal bovine serum (10% FBS) at 95% humidity, 5% CO 2 , 37 ° C. Incubator. One day before the test, the cells were continuously passaged and grown well. More than 90% of the fused Hela cells were digested with EDTA/trypsin, resuspended in DMEM complete medium, and seeded in 96-well culture plates at a density of 5000/well. Cultivate overnight.
  • 96-well plate cell culture medium was replaced, and 200 ⁇ l of IFN- ⁇ (final concentration 50 ng/mL, purchased from R&D) and serial dilutions of the compound medium were added to each well. The highest concentration of the compound was 1000 nM, and 7 concentration gradients were diluted 5 times.
  • 150 ⁇ l of the supernatant/well was transferred to a new 96-well plate, 7.5 ⁇ l of trichloroacetic acid was added to each well, and the mixture was incubated at 50 ° C for 30 min to produce N.
  • - Formyl kynurenine is hydrolyzed to kynurenine.
  • the precipitate was then removed by centrifugation at 12000 rpm for 10 minutes.
  • the supernatant was analyzed by liquid/triple quadrupole mass spectrometry (LC/MS/MS, LC-20AD high performance liquid chromatography system, Shimadzu, Japan; API4000 triple quadrupole mass spectrometer, Applied Biosystem, USA) for analysis of L-kynurenine concentration.
  • a standard curve was established with a concentration gradient of 2-5000 ng/ml L-kynurenine; the concentration of L-kynurenine in the cell culture supernatant was measured to calculate the activity of each compound to inhibit IDO by fitting with original 7.5.
  • IC 50 of uridine
  • test results indicate that the compound of the present invention has a significantly better inhibitory effect on IDO1 in Hela cells than BMS-986205.

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Abstract

L'invention concerne un composé de quinoline-4-base cyclohexane, son sel pharmaceutiquement acceptable, son hydrate, son solvate ou son stéréo-isomère, ainsi que son procédé de préparation. Ledit composé seul ou combiné avec d'autres médicaments sert à traiter les manifestations pathologiques du syndrome métabolique du tryptophane induit par l'IDO.
PCT/CN2018/121870 2017-12-18 2018-12-18 Dérivés de quinoline et leurs utilisations WO2019120199A1 (fr)

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CN201711359879.9A CN109928924A (zh) 2017-12-18 2017-12-18 一类作为ido抑制剂
CN201711359879.9 2017-12-18

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WO2017192813A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192840A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192815A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192844A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂
WO2017192813A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192840A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192815A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192844A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation

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