WO2013107164A1 - Nouvel inhibiteur de l'indoléamine-2,3-dioxygénase, son procédé de fabrication et ses utilisations - Google Patents

Nouvel inhibiteur de l'indoléamine-2,3-dioxygénase, son procédé de fabrication et ses utilisations Download PDF

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WO2013107164A1
WO2013107164A1 PCT/CN2012/078617 CN2012078617W WO2013107164A1 WO 2013107164 A1 WO2013107164 A1 WO 2013107164A1 CN 2012078617 W CN2012078617 W CN 2012078617W WO 2013107164 A1 WO2013107164 A1 WO 2013107164A1
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匡春香
王勇
王淑君
陈斌
关玉晶
刘莹
田宁
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辽宁思百得医药科技有限公司
天津南开允公医药科技有限公司
西藏林芝百盛药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/22—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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a tryptophan guanamine- 2,3-dioxygenase inhibitor containing a 1,2,3-triazole structure, a preparation method thereof and use thereof. Background technique
  • Indole-2,3-dioxygenase (IDO; MW 48,000; EC 1.13.11.42) is a heme-containing enzyme that is the first enzyme in the mammalian tryptophan metabolism pathway and is Rate limiting enzyme.
  • IDO catalyzes the oxidation of the essential amino acid monotryptophan by the conversion of hydrogen to N-nonanoyl kynurenine and is responsible for the cleaning of tryptophan in the human body.
  • IDO causes a microenvironment in which tryptophan is absent in the body, which in turn leads to the development of diseases such as cancer, cataracts, and neurological disorders that are closely related to the loss of tryptophan.
  • Interferon Y is one of several potential IDO expression inducers. During sustained activation of high levels of interferon gamma stimulation, IDO reduces the availability of free serum tryptophan and thus reduces the production of serotonin. These changes, combined with the accumulation of neuroactive kynurenine metabolites such as quinolinic acid (also induced by IDO), promote the development of neuropathy/psychiatric disorders and are a cause of multiple psychological disorders, as well as IDO activation and Tryptophan degradation is a cause of symptoms associated with chronic diseases such as Acquired Immunodeficiency Syndrome (AIDS), Alzheimer's disease, various types of depression and cancer (Wirleitner, Curr. Med. Chem. 2003, 10, 1581).
  • AIDS Acquired Immunodeficiency Syndrome
  • Alzheimer's disease various types of depression and cancer
  • IDO activity also involves the development of age-related nuclear cataracts.
  • IDO is the first enzyme in the biosynthesis of UV filters in the lens and is the rate-limiting enzyme.
  • Ultraviolet filter compounds derived from tryptophan degradation (kynurenine and 3-hydroxykynurenine glucoside) modify the proteins present in the human lens. The amount of these ultraviolet filter compounds increases with age (Takikawa et al. Adv. Exp. Med. Biol. 1999, 241, 467) and it has been reported that these ultraviolet filter compounds cause the lens to become cloudy, which leads to the so-called Age-related nuclear cataract.
  • IDO inhibitors block this natural process (Takikawa et al. Exp. Eye Res. 2001, 72, 271).
  • IDO expression also involves inhibition of the immune response by preventing local T-lymphocyte proliferation.
  • T-lymphocytes are very sensitive to the lack of tryptophan and in the absence of tryptophan, T-lymphocytes are arrested in the G1 phase of the cell cycle.
  • This T cell-mediated inhibition of immune response is a factor that causes many diseases, including autoimmune diseases, allogeneic rejection, neurodegenerative disorders, depression, bacterial or viral infections (eg, human immunodeficiency virus HIV). And cancer (Swanson et al. Am. J. Respir. Cell Mol. Biol. 2003 30, 311).
  • IDO inhibitors can be used to modulate T cell mediated immune responses.
  • IDO inhibitors Uyttenhove et al. Nat. Med. 2003, 9, 1269.
  • Pathological features of the tryptophan metabolism pathway including infections of viruses such as AIDS, bacterial infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (eg Alzheimer's disease, Huntington's disease and Paar) Jinsen disease), depression, cancer (including T-cell leukemia and colon cancer), eye diseases (such as cataracts and age-related yellowing), and autoimmune diseases.
  • in vitro assays can be used to screen (eg, high throughput screening), test reaction reference or IDO inhibitors of extracts obtained from natural sources. Activity, or determine its IDO inhibition kinetics constant.
  • IDO is closely related to a variety of disease pathogenesis. It has been proven to be a target for major diseases such as cancer, Alzheimer's disease, depression, cataract, etc. IDO inhibitors have broad application prospects as drugs, but so far there is no suitable IDO inhibitors can be marketed as drugs, so it is of great theoretical and practical value to find new and effective IDO inhibitors.
  • IDO inhibitor 1-MT 1-mercaptotryptophan
  • 1-MT was included in the RAID (rapid access to intervention development) program by the National Cancer Institute, and entered the Phase I clinical trial in the fall of 2007. However, it is regrettable that most of the existing IDO inhibitors have low inhibitory efficacy.
  • 1-MT is a commonly used IDO inhibitor in various in vitro and in vivo experiments, and its inhibition constant Ki is only 34 ⁇ . Therefore, it has been found that new and highly effective IDO inhibitors have significant application value.
  • the tryptamine is an quinazoline alkaloid whose chemical name is ⁇ [ 2,1-b ]quinazoline-6,12-dione. Tryptophan is a yellow needle crystal which is mainly found in blue plants such as horse blue, indigo, and indigo (Honda G, et al. Planta Medica, 1980, 38(3): 275-276.). Alternatively, it can be extracted from the fermentation broth of the cockroach (Hosoe T, et al. Mycopathologia, 1999, 144(1): 9-12. ).
  • the main method of synthesizing tryptamine is the reaction of hydrazine with isatoic anhydride. This method has a high yield and mild reaction conditions.
  • functionalized groups can be introduced on both the ruthenium and isatoic anhydride precursors to synthesize various functional tryptamines.
  • the most important method for synthesizing hydrazine is to use hydration of trichloroacetaldehyde, hydroxylamine and aniline in an aqueous solution of hydrochloric acid to form a hydrazine compound, and then ring closure to obtain hydrazine under concentrated sulfuric acid.
  • the present invention has been structurally modified to improve the solubility and pharmacological activity of tryptamine, with the aim of obtaining an active compound having application value.
  • the research and pharmacological tests of the present invention show that the tryptophan derivative formed by introducing a triazole group into the tryptamine molecule can be used as a more efficient IDO inhibitor, which has antibacterial, anti-inflammatory, anti-tumor and the like.
  • Pharmacological activity has broad application prospects.
  • the synthesis method of the present invention has the advantages of an operation unit, a mild condition, a high yield, and the like, and is easier to industrially produce than the conventional method for synthesizing a tryptophan derivative.
  • the present invention relates to the compound, its tautomeric form, its structural analog or a pharmaceutically acceptable salt thereof, and a composition containing at least one of the compound, its structural analog or a pharmaceutically acceptable salt thereof.
  • diseases include, but are not limited to, tumors, cancer, eye diseases, autoimmune diseases, mental disorders, depression, and anxiety disorders.
  • uses include in vivo and in vitro applications, as well as in the preparation of pharmaceuticals, IDO inhibitors, and pharmaceutical compositions.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or exosome thereof
  • R 1 or R 2 is independently selected from the group consisting of hydrogen, CC 5 alkyl, a substituent of the formula II, and one of R 1 and R 2 is a substituent of the formula II,
  • the invention also provides a process for the preparation of the above compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, the process comprising the steps of: in the presence of a base, formula XIII a compound of the formula XIV I,
  • the above preparation method comprises the following steps:
  • a compound of formula III is reacted with NaN 3 in disulfoxide to form a compound of formula IV.
  • R 1 is selected from the group consisting of hydrogen, CC 5 alkyl, and halogen, and R 2 is a substituent of Formula II;
  • R 1 is a substituent of the formula II, and R 2 is selected from the group consisting of hydrogen, C r C 5 alkyl and halogen.
  • the above preparation method comprises the following steps:
  • R 1 is selected from the group consisting of hydrogen, C r C 5 alkyl, and halogen, and R 2 is a substituent of Formula II;
  • the compound of formula VIII is in glacial acetic acid and acetic anhydride in the presence of chromium trioxide After reacting at 80-90 ° C for 3 hours, after the reaction is completed, the reaction product is cooled to room temperature, water is added, suction filtration, and the solid is washed with water, and filtered to obtain a compound of the formula XI;
  • R 1 is a substituent of the formula II, and R 2 is selected from the group consisting of hydrogen, C r C 5 alkyl and halogen.
  • the molar ratio of the compound of the formula III to NaN 3 is 1:1.2; preferably, in the step (2), The molar ratio of the compound of the formula IV to the sodium ascorbate, cuprous iodide and phenylacetylene is 1:
  • the molar ratio between the compound represented by the formula VI and the reduced iron powder is 1:8; preferably, in the step (4)
  • the molar ratio of the compound of the formula VII to the hydrated trichloroacetaldehyde, anhydrous sodium sulfate, and hydroxylamine hydrochloride is 1: 1: 1: 3; preferably, in the step (6)
  • the molar ratio of the compound of the formula IX to the compound of the formula XII and the triethylamine is 1: 1:5; preferably, in the step (7), the chromium trioxide
  • the molar ratio between the compound represented by the formula VIII is 1: 1.1-1.2, and the molar ratio between the glacial acetic acid and acetic anhydride is 1:1; preferably, in the step (7),
  • the molar ratio of the compound of the formula XI to the compound of the formula XII and triethylamine is 1:
  • the invention provides the use of a compound of the above, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, in the manufacture of an IDO inhibitor.
  • the present invention provides a compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof for the preparation of a prophylactic and/or therapeutic treatment with indole-2,3-bis Oxygenase-mediated application of drugs for diseases associated with tryptophan metabolism disorders.
  • the disease associated with a guanamine-2,3-dioxygenase-mediated disorder of tryptophan metabolism is selected from the group consisting of a tumor, a cancer, an Alzheimer's disease, an autoimmune disease, a cataract, a mental disorder. , one or more of depression and anxiety.
  • the present invention provides a pharmaceutical composition for a guanamine-2,3-dioxygenase inhibitor, which comprises the above compound or a pharmaceutically acceptable salt, solvate thereof, Polymorphs, enantiomers or racemic mixtures, and pharmaceutically acceptable carriers and/or excipients.
  • the present invention provides a method for treating, preventing or delaying a disease associated with a guanamine-2,3-dioxygenase-mediated disorder of tryptophan metabolism, the method comprising administering A therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, solvate in a patient in need of treatment , a polymorph, an enantiomer or a racemic mixture or a pharmaceutical composition as described above,
  • the disease associated with a guanamine-2,3-dioxygenase-mediated disorder of tryptophan metabolism is selected from the group consisting of a tumor, a cancer, an Alzheimer's disease, an autoimmune disease, a cataract, a mental disorder. , one or more of depression and anxiety.
  • the present invention provides an 8-amino-1,2,3-triazole-containing tryptamine IDO which inhibits the structure of the IDO inhibitor as follows:
  • R is hydrogen or halogen
  • the 8-position tryptophan IDO inhibitor having a 1,2,3-triazole structure
  • the preparation method includes the following steps:
  • the 1-azidoindolyl-4-nitrobenzene, sodium ascorbate, cuprous iodide, acetonitrile, water and phenylacetylene prepared in the step (1) are sequentially added to the reaction flask, protected by nitrogen, and stirred at room temperature. After overnight, the TLC test showed that the reaction was completed, the reaction mixture was poured into water, extracted with ethyl acetate, and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. That is, wherein, the molar ratio of 1-azidoindol-4-nitrobenzene, sodium ascorbate, cuprous iodide to phenylacetylene is 1: 04: 0.2: 2;
  • the filter cake is washed with 10% by weight aqueous hydrochloric acid solution, washed with water and dried under vacuum to obtain 4-(4-phenyl-1H-1,2,3-triazol-1-yl group.
  • the molar ratio of mercaptoaniline to hydrated trichloroacetaldehyde, anhydrous sodium sulfate, hydroxylamine hydrochloride is 1: 1: 1: 3;
  • the concentrated sulfuric acid is added to the reaction flask, and the product obtained in the step (4) is added in portions under vigorous stirring, until all is dissolved in concentrated sulfuric acid, and then the temperature is raised to 65 ° C, and the reaction is carried out for 4-5 hours.
  • the TLC detection shows the reaction of the raw materials. After completion, the reaction solution is poured into cold water, that is, a yellow solid is precipitated, which is suction filtered, and the filter cake is washed with water and dried in vacuo;
  • R is hydrogen or halogen
  • the present invention provides a 2-position tryptamine-containing IDO having a 1,2 azole structure as follows:
  • R is hydrogen or halogen
  • the above formula for the tryptophan IDO inhibitor having a 1,2,3-triazole structure at the 2-position is as follows:
  • the preparation method includes the following steps:
  • the compound represented by the following formula, the isocyanuric acid anhydride-containing phthalic anhydride, the terpene benzene, and the triethylamine prepared in the step (1) are sequentially added to the reaction flask, and then the temperature is raised to 110 ° C for 3 hours, and the reaction is completed. After that, the triethylamine and the terpene are first removed, and then recrystallized by adding ethanol to obtain a dark green solid.
  • R is hydrogen or halogen
  • IDO has been shown to be closely related to a variety of human major diseases such as Alzheimer's disease, cataract, cancer, etc.
  • the 1,2,3-triazole-containing tryptophan derivatives of the present invention have been Known IDO inhibitors have more potent IDO inhibition and can be used to treat diseases with IDO-mediated pathological features of the tryptophan metabolism pathway, and have antibacterial, anti-inflammatory, anti-tumor, autoimmune and other Pharmacological activity, therefore, the novel IDO inhibitor obtained by the invention can be used as a novel drug and has broad application prospects. At the same time, it can be used as a further modified pharmaceutical intermediate with potential application value for the development of other new drugs.
  • the method for preparing the above-mentioned tryptophan IDO inhibitor containing 1,2,3-triazole structure has the advantages of convenient operation, mild reaction conditions, solvent saving, pollution reduction and the like, and is convenient for industrial production.
  • the preparation method of the present invention uses p-nitrobenzyl chloride as a raw material, reacts with sodium azide to form 1-azidoindol-4-nitrobenzene, and then 1,3-dipolar cycloaddition with phenylacetylene. The reaction is formed to form a triazole compound.
  • the compound is reacted with an amino group in an ammonium chloride solution in the presence of a reduced iron powder; then, the amino compound reacts with hydrated trichloroacetaldehyde or hydroxylamine hydrochloride to form a triazole-containing hydrazine. Then, in the presence of concentrated acid, the ruthenium ring is closed to form a triazole-containing eosin derivative.
  • the isoxazole derivative-containing isatin derivative is reacted with isatoic anhydride or a derivative thereof under alkaline conditions in a solvent of toluene to synthesize a series of tryptamine derivatives containing a triazole structure.
  • the isoflavone derivative (304 mg, lmmol) containing the 1,2,3-triazole structure prepared in the step (5) and the isatoic anhydride (purchased from Aladdin Reagent Co., Ltd.) (163 mg, lmmol) were added to the reaction.
  • triethylamine and terpene were added, and the temperature was raised to 110 ° C.
  • the reaction was stirred under reflux for 3-4 h. After TLC detection showed that the reaction was completed, triethylamine and toluene were removed by vacuum rotary evaporation, and recrystallized from anhydrous ethanol. Finally, a yellow-green solid 284 mg was obtained with a yield of 70%.
  • Example 2 2-Fluoro-8-(4-phenyl-lH-1,2,3-triazol-1-ylindenyl)tryptamine
  • the isoflavone derivative containing the 1,2,3-triazole structure prepared in the step (5) of Example 1 (304 mg, lmmol) and 5-fluoroindigonic anhydride (purchased from Yancheng City Medico chemical production limited ( 181mg, lmmol ) was added to the reaction flask, then added triethylamine, toluene, and the temperature was raised to 110 ° C, and the reaction was stirred for 4 hours under reflux. After TLC detection showed that the reaction was completed, triethylamine and toluene were removed by vacuum rotary evaporation. It was recrystallized by adding absolute ethanol, and finally a dark yellow-green solid 275 mg was obtained in a yield of 65%.
  • the construction of the plasmid containing the human IDO gene, expression, extraction and purification in E. coli were carried out according to the method of Littlejohn et al. (Takikawa 0, Kuroiwa T, Yamazaki F, et al. J. Biol. Chem. 1988, 263, 2041-2048).
  • the inhibitory activities of the isolated components and monomeric compounds against IDO were examined by the methods described below.
  • Reaction conditions In a 500 ⁇ reaction system, first add 50 mM potassium phosphate buffer (pH 6.5), 40 mM vitamin C, 400 g/ml catalase, 20 ⁇ M ruthenium blue, 300 mM substrate L-color ammonia.
  • the reaction was carried out at 37 ° C for 30 minutes, 30% (w / v) trichloroacetic acid 200 ⁇ 1 was added to terminate the reaction, and the reaction system was heated in a water bath at 65 ° C for 15 minutes to complete the chymolyserine To the conversion of kynurenine, then centrifuge at 12000 rpm for 10 minutes, take the supernatant and mix with an equal volume of 2% (w/v) acetic acid solution of diammonium aminobenzaldehyde, and measure the wavelength of 490nm with a microplate reader. reading.
  • the reaction was carried out at 37 ° C for 30 minutes, 30% (w / v) trichloroacetic acid 200 ⁇ l was added to terminate the reaction, and the reaction system was heated at 65 ° C for 15 minutes to complete the reaction from decanoyl kynurenine to guanine ammonia. Acid conversion, then rotate at 12000 rpm for 10 minutes, take 200 ⁇ 1 supernatant and mix with an equal volume of 2% (w/v) of di-aminobenzaldehyde in acetic acid solution. The yellow color produced by the reaction of kynurenine can be used.
  • the microplate reader was tested at 490 nm and the results were obtained using IC 5 . Calculation software calculation (see Table 1 for results).
  • the measurement mechanism is as follows:
  • Plasmid pcDNA3.1-MDO was transiently transfected into HEK 293 cells using liposome Lipofectamin 2000.
  • HEK293 cell culture medium was high glucose DMEM containing 50 U/mL penicillin, 50 U/mL streptomycin, 10% FBS, 37 °C, 5% CO 2 culture. After the cells were transfected into the plasmid for 24 h, the drug to be tested was added. After incubation for a period of time, the supernatant was taken.
  • mice 6-8 weeks old DBA/2 mice, inbred lines, SPF grade, 50, male and female, body mass (22.0 ⁇ 1.6) g, purchased from Shanghai Slack Laboratory Animal Co., Ltd. All mice were housed in the Barrier Environmental Animal Laboratory of the Experimental Animal Center of Shenyang Pharmaceutical University.
  • P388 leukemia cells in logarithmic growth phase cultured in vitro were washed twice with physiological saline, and then intraperitoneally inoculated into 2 DBA/2 mice for about 1 ⁇ 10 6 cells, and sterilized on the 8th day after sacrifice.
  • the milky white translucent Under the ascites, the milky white translucent, set the density of the cells in a sterile container with physiological saline to 5 x l0 6 / mL, take a little suspension for trypan blue staining, count under light microscope, the number of viable cells should be more than 95%, then the above tumor cell suspension was intraperitoneally injected (ip) 0.2 mL (about 1 x 10 6 cells) into each mouse under sterile conditions, and a total of 50 cells were inoculated.
  • ip intraperitoneally injected
  • mice Prepared in 20% DMSO, diluted to a suitable concentration of working solution according to the body weight of the mice according to the weight of the mice, the maximum concentration of DMSO is not more than 10%.
  • 50 successfully vaccinated mice were randomly divided into 5 groups, namely blank control group, solvent control group and tryptamine derivative group (Examples 1, 2, 3, each group). 35mg/kg), 10 in each group, half male and half female. The administration started on the next day of inoculation.
  • each mouse ip corresponds to a drug of 35 mg/kg, and the final volume is 0.2 mL.
  • Life extension rate (average survival of the experimental group - average survival of the control group) / average survival time of the control group X 100%
  • mice After the administration of the mice in each of the drug-administered groups, the abdomen gradually swelled. In the three groups, abdominal augmentation was observed around 12 days. After the death, a large amount of bloody ascites was also observed in the abdominal cavity, and the tumor mass was less.
  • the tryptophan derivatives of the present invention can significantly prolong the survival of P388 leukemia mice, indicating that they have a good anti-tumor effect in P388 leukemia mice.
  • Example 10 Effect on learning and memory ability of Alzheimer's rats
  • Quinolinic acid supplied by Sigma. Kit (Tunnel): Provided by Wuhan Boster Bioengineering Co., Ltd., product number MK1020. Brain stereo locator NARISHIGE SN-2 type. Morris Water Maze: Manufactured by the Department of Pharmacology, China Medical University.
  • rats were randomly divided into 5 groups, namely, the sham injury group, the model group, and the tryptamine derivative group (Examples 1, 2, and 3, 50 mg/kg each), 10 rats in each group, and the weight of the rats between the groups. There was no statistical difference.
  • the experimental animals were anesthetized with 3% pentobarbital sodium 1 ml/kg ip; fixed on the brain stereotaxic instrument, the cranial cranial midline incision, reference to the rat brain stereotactic map (AP 0.2 mm, ML 2.5mm, DV 4.5mm), after stereotactic positioning of the bilateral hippocampal CA1 area, drill the skull, use a 2 ⁇ 1 micro-injector to vertically insert the needle, and dissolve QA 2 ⁇ 1 (containing 150nmol QA) with 0.01mol/L (pH 7.4) PBS buffer.
  • the dummy injury group was injected with 0.01mol/L (pH7.4) PBS 2 ⁇ 1, the injection time per side was 5min, the needle was kept for 5min, the skull was sealed with dental mud after needle extraction, and the skin was partially disinfected after disinfection. Intramuscular injection of penicillin for 3 days to prevent infection. One week after operation, each group was dosed. The sham injury group and the model group were given distilled water 2 ml/supply for 2 weeks.
  • each rat's head and neck hair was blacked out with a common hair dye.
  • the laboratory temperature was 24 ⁇ 25 °C during the test, and 1 kg of milk powder was added to the water maze, and it was washed with hot water.
  • the pool is marked with four water inlets from east to west and north and south.
  • the pool is divided into four quadrants, SW, NW, SE, NE.
  • the safety platform is located in the SW quadrant, 23cm from the center of the circle. After the safety platform is fixed, it is separated from the four quadrants.
  • the rats were placed in the water pool, and the time (latency, SPL) and number of inductions of the rats from the water inlet point were recorded. If the animal could not find a safety platform within 2 minutes, the experimenter put them back to safety. Platforms, movement paths and other indicators, as a positioning of academic achievement.
  • SPL time (latency, SPL) and number of inductions of the rats from the water inlet point were recorded. If the animal could not find a safety platform within 2 minutes, the experimenter put them back to safety. Platforms, movement paths and other indicators, as a positioning of academic achievement.
  • the rats were allowed to swim freely for 5 min to familiarize themselves with the environment. The next day, the first day, each training session was 4 times, for 3 consecutive days, and the fifth day was carried out for space exploration experiments (ie, removing the safety platform and observing the mouse within 2 minutes) The ratio of swimming distance to total distance in the quadrant) to detect spatial memory in rats. Each group of 5 groups was performed in parallel.
  • Wistar rats were randomly divided into 5 groups: control group, model group, and tryptamine derivative group (Examples 1, 2, and 3, 50 mg/kg each), 20 in each group. Feed with breast milk and ordinary pellets, and drink freely.
  • the rats were injected subcutaneously with a small dose (3.46 mg/kg body weight) of sodium selenite, once every other day for 3 times. Rats in the control group did not receive any treatment.
  • the lens changes were observed with a slit lamp microscope on the third day after the last administration, and the lens opacity was successfully modeled.
  • Each administration group was administered at a dose of 1 time/day for 2 weeks; the rats in the control group and the model group were given no drugs and were given free drinking water.
  • lens homogenate Weigh the double-lens lens into a 5ml homogenized cup, add 8.6g/L ice physiological saline according to a certain ratio, and use a high-speed tissue masher to control the mash at 10000r/min. Min, 3.5% lens homogenate was prepared, then centrifuged at 2000 r/min for 8 min at low speed, and the supernatant was separated for MDA content and SOD activity.
  • Table 5 Comparison of MDA content and SOD activity in rat serum and lens (X s) group lens (pair) MDA (nmol/mgprot) SOD (U/mgprot) control group 10 1.06 ⁇ 0.26 27.26 ⁇ 3.28 model group 10 1.51 ⁇ 0.27 16.64 ⁇ 3.96
  • the detection of MDA content showed that the MDA in the lens of the first, second and third groups was significantly lower than that of the model group, and the difference was significant (P ⁇ 0.05).
  • the detection of SOD activity showed that the SOD activity in the lens of the first, second and third groups was significantly higher than that of the model group, and the difference was significant (P ⁇ 0.05).
  • the tryptophan derivatives of the present invention can alleviate the degree of lens opacity, which may be related to increasing SOD in the lens and lowering the MDA content, thereby counteracting and alleviating peroxidative damage.
  • Example 12 Antidepressant effect on a mouse depression model
  • mice Male SPF Kunming mice, individual quality 20 ⁇ 25g, purchased from China Medical University Center of things.
  • mice were subjected to neurobehavioral testing and screening before the experimental grouping.
  • the mice with different differences were screened out, and 40 mice were randomly selected and randomly divided into 4 groups, namely blank group. , tryptamine derivatives (Examples 1, 2, 3, 60 mg/kg per group), 10 per group.
  • TST Tail Suspension Test
  • mice in the 4 groups were acclimated to the environment for 1 week. The animals were kept in single cages 24 hours before the experiment, and fasting could not be stopped. On the day of the test, each group was intragastrically administered according to the dosage requirements. After lh administration, the tail of the mouse was glued to the tail-tailed balance scaffold at a distance of 2 cm from the tip of the tail, so that the tail of the mouse was not twisted and folded, and the head was turned to the head. The lower suspension is inverted, the head is 15cm away from the tabletop, each mouse is hovering for 6min, the first 2min is adapted, and the cumulative immobility time within 4min after the recording is 3 ⁇ 4. All the limbs are not moved except for breathing. .
  • mice in the 4 groups were acclimated to the environment for 1 week.
  • the animals were trained to swim for 15 minutes before the experiment, and they were kept in a single cage.
  • the mice in each group were dosed for 1 h, and placed in a circular container with a diameter of about 18 cm, a water depth of 18 cm, and a water temperature of (25 ⁇ 1) °C.
  • Accumulated immobility time floating state, only the nostrils are exposed to keep breathing, and the limbs are occasionally swiped to keep the body from sinking).
  • mice in Kunming Forty male mice in Kunming, with an individual mass (20 ⁇ 2 ) g, were purchased from the Experimental Animal Center of China Medical University. After 1 week of adaptive feeding, the mice were randomly divided into 4 groups, namely, the blank group and the tryptamine derivative group (Examples 1, 2, and 3, each group of 60 mg/kg), and the mice started joint operation after lh administration. Behavior detection.
  • mice were placed in the middle of the joint opening experiment box containing a 40 cm 40 cm 16-hole plate while timing was started.
  • Infrared emitters and camera devices are placed in the joint opening experimental box, which can effectively record various spontaneous activity and caving behavior of mice.
  • the depth of the hole is 2.2 cm, and infrared rays are placed at a depth of 1 cm.
  • the instrument will automatically record the behavior of the cavity and accumulate the number of holes.
  • Each mouse was recorded continuously for 6 minutes. The environment was kept quiet during the operation. The excretion in the box was cleaned before each time the mouse was placed, and the objectivity of each batch was ensured as much as possible.
  • Liquid paraffin produced by Tianjin Chemical Reagent Factory
  • medicinal lanolin produced by Shanghai Huaheng Lanolin Factory
  • BCG for intradermal injection produced by Shanghai Institute of Biological Products.
  • 1/lOOmm electronic digital caliper produced by Tianjin Measuring Tool Factory.
  • mice After 50 days of adaptive feeding, 50 rats were randomly divided into 5 groups, namely blank group, model group and tryptophan derivative group (Examples 1, 2, 3, 50 mg/kg), 10 in each group. Animals in each group were intragastrically administered at 1 h before the onset of inflammation, and administered once a day after modeling for 3 days.
  • Freund's complete adjuvant (0.05 mL/only) was injected intradermally into the right hind paw of the rat.
  • the normal control group was injected with an equal volume of normal saline.
  • Swelling degree of the paws on the injection side (primary lesions): The thickness of the paws was measured by the caliper method before and after the inflammation, 18, 36, and 72 hours after the inflammation, and the degree of swelling was calculated.
  • the tryptamine derivative group (Examples 1, 2, and 3) can significantly inhibit the paw swelling of the model side arthritis model rats after 36 hours of administration (PO). .05 or P ⁇ 0.01).
  • the results of the present experiment indicate that the intragastric administration of the tryptophan derivative of the present invention has a significant therapeutic effect on the primary lesion of the adjuvant arthritis model rat, and can suppress the immunological inflammation.

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Abstract

La présente invention concerne un nouvel inhibiteur de l'indoléamine-2,3-dioxygénase (IDO), un procédé de fabrication de ce dernier et ses utilisations. L'inhibiteur est un composé tel que représenté par la formule (I) ou un sel, un solvate, un polymorphe, un énantiomère ou un mélange racémique pharmaceutiquement acceptable de ce dernier. R1 ou R2 sont indépendamment choisis parmi un hydrogène, un groupe alkyle en C1 à C5, un halogène, et un groupe substituant tel que représenté par la formule (II), et un des groupes R1 et R2 est un groupe substituant tel que représenté par la formule (II). R3 est choisi parmi un groupe aryle, et n = 0, 1, 2, ou 3. Par comparaison avec un inhibiteur de l'IDO connu, le nouvel inhibiteur a un effet inhibiteur de l'IDO plus puissant, et peut être utilisé pour soigner des maladies caractérisées par une pathologie du métabolisme du tryptophane médié par l'IDO, par exemple des tumeurs, des cancers, la maladie d'Alzheimer, des maladies auto-immunes, la cataracte, des troubles mentaux, la dépression, et/ou des troubles de l'anxiété. Les avantages du procédé de préparation sont une opération facile et une condition de réaction douce, et le procédé économise du solvant et réduit la pollution, ce qui permet ainsi de faciliter la production industrielle.
PCT/CN2012/078617 2012-01-20 2012-07-13 Nouvel inhibiteur de l'indoléamine-2,3-dioxygénase, son procédé de fabrication et ses utilisations WO2013107164A1 (fr)

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WO2015070766A1 (fr) * 2013-11-12 2015-05-21 复旦大学 Dérivé de n-benzyltryptanthrine, et son procédé de préparation et son application
US9675571B2 (en) 2013-03-15 2017-06-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase (IDO)
WO2017140272A1 (fr) * 2016-02-19 2017-08-24 正大天晴药业集团股份有限公司 Composé tricyclique servant d'immunomodulateur
CN107531693A (zh) * 2015-04-10 2018-01-02 百济神州有限公司 作为吲哚胺2，3‑二加氧酶和/或色氨酸2，3‑二加氧酶抑制剂的新颖的5或8‑取代的咪唑并[1，5‑a]吡啶
WO2018054365A1 (fr) 2016-09-24 2018-03-29 Beigene, Ltd. Nouvelles imidazo[1,5-a]pyridines substituées en position 5 ou 8 en tant qu'indoleamine et/ou tryptophane 2,3-dioxygénases
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
US11472788B2 (en) 2017-11-25 2022-10-18 Beigene, Ltd. Benzoimidazoles as selective inhibitors of indoleamine 2,3-dioxygenases

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CN107260743B (zh) * 2016-04-05 2020-01-31 北京大学 氮杂色胺酮衍生物作为ido1和/或tdo抑制剂的用途
US11103511B2 (en) 2017-06-05 2021-08-31 Fudan University Substituted indolo[2,1-b]quinazolines as inhibitors of tryptophan dioxygenase and indoleamine 2,3-dioxygenase 1
CN110734423B (zh) * 2018-07-18 2022-07-08 复旦大学 一类吲哚醌类吲哚胺-2,3-双加氧酶抑制剂及其药用用途
CN110183454B (zh) * 2019-06-20 2022-01-07 同济大学 一种含1,2,3-三氮唑的色胺酮及其制备方法和应用
CN110283192B (zh) * 2019-07-18 2021-08-06 同济大学 一种含硼酸的色胺酮衍生物的制备方法及应用
CN112724147B (zh) * 2020-12-23 2022-03-15 合肥工业大学 4(3h)-喹唑啉酮类化合物的制备方法
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9675571B2 (en) 2013-03-15 2017-06-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase (IDO)
WO2015070766A1 (fr) * 2013-11-12 2015-05-21 复旦大学 Dérivé de n-benzyltryptanthrine, et son procédé de préparation et son application
US20160297822A1 (en) * 2013-11-12 2016-10-13 Fudan University N-benzyl tryptanthrin derivative, and preparation method and application thereof
US10059712B2 (en) 2013-11-12 2018-08-28 Fudan University N-benzyl tryptanthrin derivative, and preparation method and application thereof
AU2014350729B2 (en) * 2013-11-12 2019-01-03 Fudan University N-benzyl tryptanthrin derivative, and preparation method and application thereof
CN107531693A (zh) * 2015-04-10 2018-01-02 百济神州有限公司 作为吲哚胺2，3‑二加氧酶和/或色氨酸2，3‑二加氧酶抑制剂的新颖的5或8‑取代的咪唑并[1，5‑a]吡啶
CN107531693B (zh) * 2015-04-10 2021-07-06 百济神州有限公司 作为吲哚胺、色氨酸二加氧酶抑制剂的5或8-取代的咪唑并[1，5-a]吡啶
WO2017140272A1 (fr) * 2016-02-19 2017-08-24 正大天晴药业集团股份有限公司 Composé tricyclique servant d'immunomodulateur
WO2018054365A1 (fr) 2016-09-24 2018-03-29 Beigene, Ltd. Nouvelles imidazo[1,5-a]pyridines substituées en position 5 ou 8 en tant qu'indoleamine et/ou tryptophane 2,3-dioxygénases
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
US11472788B2 (en) 2017-11-25 2022-10-18 Beigene, Ltd. Benzoimidazoles as selective inhibitors of indoleamine 2,3-dioxygenases
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase

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