WO2020106059A1 - Nouveau composé tricyclique en tant qu'inhibiteur d'irak4 - Google Patents

Nouveau composé tricyclique en tant qu'inhibiteur d'irak4

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WO2020106059A1
WO2020106059A1 PCT/KR2019/015948 KR2019015948W WO2020106059A1 WO 2020106059 A1 WO2020106059 A1 WO 2020106059A1 KR 2019015948 W KR2019015948 W KR 2019015948W WO 2020106059 A1 WO2020106059 A1 WO 2020106059A1
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compound
mmol
nmr
mhz
dmso
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PCT/KR2019/015948
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English (en)
Korean (ko)
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조희영
임희종
박우규
정대영
김현영
윤새봄
이정옥
이흥경
홍빅터석봉
최지혜
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한국화학연구원
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Priority claimed from KR1020190148566A external-priority patent/KR102329235B1/ko
Application filed by 한국화학연구원 filed Critical 한국화학연구원
Priority to JP2021528390A priority Critical patent/JP7233130B2/ja
Priority to CN201980076657.7A priority patent/CN113227095B/zh
Priority to US17/294,705 priority patent/US20220009933A1/en
Priority to EP19887212.9A priority patent/EP3885348A4/fr
Priority to AU2019383845A priority patent/AU2019383845B2/en
Publication of WO2020106059A1 publication Critical patent/WO2020106059A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

Definitions

  • the present invention is an IRAK4 inhibitor, a novel tricyclic compound, a pharmaceutical composition for the prevention or treatment of autoimmune diseases or tumors containing the tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient, and the tricyclic compound It relates to a health food composition for the prevention or improvement of autoimmune diseases or tumors containing as an active ingredient.
  • IRAK4 Interleukin-1 receptor (IL-1R) associated kinase 4
  • TLR toll-like receptor
  • IL-1R interleukin-1 receptor
  • SLE systemic lupus erythematosus
  • lymph cancer which are rare immune diseases
  • Lupus is an autoimmune disease with unclear causes, fever, joint pain, arthritis, edema, fatigue, facial erythema, photosensitization, anemia, myocarditis, pleurisy, and neurological disorders. , Laboratory tests and immunological tests are comprehensively diagnosed.
  • the drug for lupus is hydroxychloroquine, which was approved in 1955, and steroids, non-steroidal anti-inflammatory drugs (NSAIDs) and plaquenil (Plaquenil) are used as symptomatic drugs.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Paquenil plaquenil
  • the first lupus drug, Benlysta (belimumab, GSK, 2010), is an antibody injection that inhibits B-cell receptor binding of BlyS (BAFF), thereby inhibiting abnormal B lymphocytes, but it is not only expensive, but also greatly improves disease There is a problem that can not be.
  • MYD88 L265P mutations are found in about 30% of diffuse large B-cell lymphomas (DLBCL), especially activated B-cell subtypes (ABC-DLBCL), and in these mutant cancers, NF- ⁇ B is excessively activated, resulting in high concentrations of inflammatory cytokines. Secreted and is associated with a poor prognosis of the tumor (J. Exp. Med. 2015: 212, 2189-2201).
  • IRAK4 is a member of the IRAK family of 460 amino acids (IRAK family member) that is activated by the toll-receptor 7/9 (TLR7 / 9) by a ligand containing DNA / RNA, secreting interferon (IFN) and inflammatory cytokines. It is regulated to be, and is most frequently expressed in white blood cells, followed by high expression in the order of immune organ cells such as the adrenal cortex, lymph nodes, and thyroid (PLos ONE. 2012. 7. e49771).
  • IRAK4 mediates the secretion of inflammatory cytokines such as interferon- ⁇ (IFN- ⁇ ) from plasmacytoid dendritic cells (pDCs), so IRAK4 inhibition of interferon- ⁇ , a biomarker of lupus disease It was observed that mice capable of inhibiting secretion, and in which IRAK4, IRAK1 expression was suppressed, did not develop lupus, and an oligonucleotide inhibitor of TLR7 / 9 improved lupus in an animal model (J Immunol 2011; 186: 1279 -1288). Therefore, IRAK4 inhibitors are highly likely to treat or improve autoimmune diseases and tumors.
  • IFN- ⁇ interferon- ⁇
  • pDCs plasmacytoid dendritic cells
  • IRAK4 inhibitors have been studied continuously over the past decade.
  • a quinazoline derivative that strongly inhibits IRAK4 has also been reported, and the reported compound No. 23 is 30% or more (30 mg / kg), 90% or more (100 mg / kg) of IL-6 induced by R848 in animal experiments. It was shown to inhibit (Bioorg. Med. Chem. Lett. 2017: 27, 2721-2726).
  • WO2017-033093A1 discloses a bicyclic-fused heteroaryl or aryl compound as an IRAK4 modulator, and inhibitors of IRAK4 kinase activity are potential for various diseases including autoimmune, tumor, inflammation, cardiovascular disease, cancer and metabolic diseases It was confirmed again as a therapeutic agent.
  • Pfizer an American pharmaceutical company, is conducting Phase 2 clinical trials of the compound that inhibits IRAK4, PF-06650833, as a therapeutic agent for rheumatoid arthritis.
  • the present applicant strongly inhibits IRAK4 and develops a novel structure inhibitor with excellent kinase selectivity, pharmacological evaluation of IRAK4 enzyme, inflammatory cytokine secretion, and inflammatory promoter by TLR4 / 7/9 signaling
  • the activity change was evaluated and the activity was confirmed in the systemic animal model and xenograft lymph cancer animal model to find the optimized IRAK4 inhibitory structure.
  • An object of the present invention is to provide a tricyclic compound having a novel structure that strongly inhibits IRAK4 and has excellent kinase selectivity.
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of autoimmune diseases or tumors containing the tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a health food composition for preventing or improving autoimmune diseases or tumors containing the tricyclic compound as an active ingredient.
  • the present invention provides a tricyclic compound represented by Formula 1 below.
  • [A 1 and A 2 are each independently N or CH,
  • a 3 is N or CR 1 ,
  • R 1 is hydrogen, halogen, -COOR 5 or (C3-C12) heteroaryl,
  • R 2 is hydrogen, an amino group, -COOR 6 , (C1-C12) heteroaryl, (C1-C12) heteroaryl, (C6-C12) aryl fused with (C3-C12) cycloalkyl, or nitrogen, oxygen and sulfur 5 to 7 membered heterocyclic amino containing at least one heteroatom selected from,
  • R 3 is hydrogen or (C6-C12) aryl
  • R 4 is -L 1 -L 2 -R 7 ,
  • the amino group (-NH 2 ), (C1-C12) heteroaryl or (C6-C12) aryl of R 2 is (C1-C4) alkyl, (C1-C4) alkyl substituted with halogen, (C1-C4) thioalkyl , Amino group (-NH 2 ), methylamino group (-NHCH 3 ), dimethylamino group (-N (CH 3 ) 2 ), -CH 2 OH, (C1-C4) alkoxy, hydroxy group (-OH), halogen, methanesulfo Niyl group (-SO 2 CH 3 ), -SO 2 N (CH 3 ) 2 , nitro group (-NO 2 ), cyano group (-CN), , , , , , , , And It may be optionally substituted with at least one group selected from the group consisting of,
  • (C6-C12) aryl of R 3 may be optionally substituted with a nitro group (-NO 2 ),
  • L 1 is -N (R 8 )-or -O-
  • L 2 is-(CH 2 ) m- , , or Is, m is an integer from 2 to 5,
  • R 7 is -N (R 9 ) 2 , -OR 10 , -SO 2 CH 3 , -SO 2 N (CH 3 ) 2 , or from 5 to 5 containing at least one heteroatom selected from nitrogen, oxygen and sulfur 7-membered heterocyclic amino,
  • R 5 is (C1-C4) alkyl
  • R 6 is (C1-C4) alkyl
  • R 8 is hydrogen or (C1-C4) alkyl
  • R 9 is (C1-C4) alkyl
  • R 10 is (C1-C4) alkyl
  • Heterocyclic amino of R 7 is -SO 2 CH 3 And -COOC (CH 3 ) 3 (-Boc) may be optionally substituted with at least one group selected from the group consisting of,
  • a 3 teeth CR 1 and R 1 is halogen, -COOR 5 Or (C3-C12) heteroaryl, L 2 is not-(CH 2 ) m- ,
  • Boc is t-butyloxycarbonyl (-COOC (CH 3 ) 3 ).
  • R 1 phosphorus (C3-C12) heteroaryl is preferably , , or to be.
  • R 2 phosphorus (C1-C12) heteroaryl, (C3-C12) cycloalkyl fused with (C1-C12) heteroaryl, or substituted (C1-C12) heteroaryl is preferably It is either chosen:
  • R 2 phosphorus (C6-C12) aryl or substituted (C6-C12) aryl is preferably any one selected from:
  • R 3 phosphorus (C6-C12) aryl or substituted (C6-C12) aryl is preferably or to be.
  • R 4 is preferably any one selected from the following:
  • the tricyclic compound represented by Formula 1 of the present invention may be preferably prepared by the following [Scheme 1-1], [Scheme 1-2], [Scheme 2], [Scheme 3] or [Scheme 4] .
  • R 1 , R 2 , R 3 and R 4 are as defined in Chemical Formula 1.
  • a 1 in Formula 1 is CH
  • a 2 is N
  • a 3 is CR 1 corresponds to manufacturing for the case, and includes the following four-step process:
  • R 1 , R 2 , R 3 and R 4 are as defined in Chemical Formula 1, and X represents halogen.
  • a 1 in Formula 1 is CH
  • a 2 is N
  • a 3 is CR 1 corresponds to manufacturing for the case, and includes the following five steps:
  • R 1 , R 2 , R 3 and R 4 are as defined in Chemical Formula 1, and Z represents PMB (p-Methoxybenzyl, p-methoxybenzyl).
  • a 1 in Formula 1 is CH
  • a 2 is N
  • a 3 is CR 1 corresponds to manufacturing for the case, and includes the following four-step process:
  • R 1 , R 2 , R 3 and R 4 are as defined in Chemical Formula 1.
  • a 1 and A 2 in Formula 1 are CH
  • a 3 CR 1 corresponds to manufacturing for the case, and includes the following five steps:
  • R 1 , R 2 , R 3 and R 4 are as defined in Chemical Formula 1.
  • a 1 and A 2 in Formula 1 are N and A 3 CR 1 corresponds to manufacturing for the case, and includes the following five steps:
  • the tricyclic compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt.
  • the salt acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid , Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, etc.
  • Suitable inorganic acids include hydrochloric acid, sulfuric acid or phosphoric acid. Can be used.
  • the tricyclic compound represented by Formula 1 of the present invention can be used in the form of not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by conventional methods.
  • the tricyclic compound represented by Formula 1 of the present invention has an effect of inhibiting IRAK4, and thus is effective in the prevention, treatment and improvement of autoimmune diseases and tumors.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of autoimmune diseases or tumors containing the tricyclic compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition of the present invention may contain one or more active ingredients exhibiting the same or similar function in addition to the tricyclic compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the tricyclic compound of Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like.
  • Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, etc. These solid preparations are starch in the tricyclic compound of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof, It may be prepared by mixing at least one excipient selected from calcium carbonate, sucrose, lactose, and gelatin. In addition, lubricants such as magnesium stearate, talc, etc. may be used in addition to simple excipients.
  • Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions or syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. are included. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized preparations, and suppositories.
  • non-aqueous solvents and suspensions propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • injectable esters such as ethyl oleate
  • a base for suppositories witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
  • the dosage of the tricyclic compound of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the patient's age, body weight, sex, dosage form, health status, and degree of disease. Based on an adult patient weighing 70 kg, it is generally 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, and once to several times a day at regular time intervals according to the judgment of a doctor or pharmacist It can also be administered in divided circuits.
  • the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of autoimmune diseases or tumors.
  • the present invention provides a health food composition for preventing or improving autoimmune diseases or tumors containing the triple ring compound represented by Formula 1 as an active ingredient.
  • the derivative when used as a food additive, the derivative may be added as it is or used with other food or food ingredients, and may be suitably used according to a conventional method. .
  • the content of the active ingredient may be appropriately determined according to the purpose of use (improvement, improvement of health or therapeutic treatment, etc.).
  • the tricyclic compound of Formula 1 is added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less based on the raw material.
  • the content of the active ingredient may be in the above range, but if there is no problem in terms of safety, the content of the active ingredient may be more than the above range.
  • the autoimmune disease is preferably multiple sclerosis, psoriasis, systemic inflammatory disease, small intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and multiple arthritis, local and systemic Scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, skin lupus, dermatomyositis, multiple myositis, Sjogren's syndrome, nodular epithelial arthritis, autoimmune bowel disease, atopic dermatitis or proliferative glomerulonephritis.
  • the tumor is preferably acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia or chronic myelogenous leukemia.
  • the tricyclic compound represented by Formula 1 of the present invention has excellent inhibitory activity against IRAK4, it is effective for preventing, treating, or improving various diseases related thereto, and preventing autoimmune diseases or tumors known to be related to IRAK4 inhibitory activity. , It can be useful for treatment or improvement.
  • Figure 2 shows the inhibitory effect of the tricyclic compound of the present invention against systemic inflammatory disease.
  • Figure 4 shows the anti-tumor effect of the tricyclic compound of the present invention.
  • Compound 4b was prepared in three steps from Compound 1b in the same manner as in Production Example 1.
  • Compound 4c was prepared in three steps from Compound 1c in the same manner as in Production Example 1.
  • Compound 4d was prepared in three steps from Compound 1d in the same manner as in Production Example 1.
  • N-dimethylaminoethyl alcohol 22 ⁇ L, 0.22 mmol
  • DMSO 2 mL
  • NaH 3.5 mg, 2.0 equivalents
  • the compound 6aaf 50 mg, 1.0 eq
  • water (10 mL) was added, followed by extraction with ethyl acetate (10 mL).
  • Water (10 mL) was extracted with ethyl acetate (5 mL), and then ethyl acetate (15 mL) was washed with water (5 X 3 mL).
  • Example 6 and the compound in the same manner 6aa (30 mg, 0.06 mmol) and tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxa-beam Lorraine - 2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate ( tert -butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate) (22 mg, 0.06 mmol) was reacted, and after the reaction, the residue was subjected to silica gel tube chromatography (dichloromethane: ethyl acetate). : Methanol 1: 8: 1 ⁇ 1: 5: 1) to give 119 mg of white solid (65%).
  • PMB represents p-methoxybenzyl (p-Methoxybenzyl).
  • a white solid 753 mg was prepared by reacting compound 27a (805 mg, 1.80 mmol) in a similar manner to step 4 of Example 46 (92%).
  • the white solid compound was added to 2 mL of trifluoroacetic acid, and 0.2 mL of methanesulfonic acid was added, followed by stirring at 60 ° C for 14 hours.
  • 60a 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ 1.34-1.37 (m, 2H), 1.59-1.65 (m, 2H), 1.91-1.93 (m, 4H), 2.25 (m, 1H), 2.75 (s, 3H), 3.25 (s, 3H), 3.57 (m, 4H), 4.28 (m, 1H), 6.85 (d, 1H), 7.72 (d, 1H), 7.74 (d, 1H), 7.86 (m, 2H), 7.98 (d, 1H), 8.36 (s, 1H), 8.60 (s, 1H), 12.04 (s, 1H).
  • the starting material 73a (trans-ene-bac-1,4-cyclohexenediamine hydrochloride) and potassium carbonate (K 2 CO 3 ) were dissolved in dimethylformamide and stirred for 2-3 minutes.
  • Potassium iodide (KI) and compound 72b bis (2-chloroethyl) sulfan) were added to the reaction mixture, followed by stirring at room temperature for 15 hours.
  • dilute in ethyl acetate filter with a pad of celite, wash with water, remove moisture with sodium sulfate (Na 2 SO 4 ) and concentrate under reduced pressure.
  • the residue is purified by silica gel column chromatography to obtain the target compound as a pale yellow solid.
  • the starting material 4a, compound 73c and triethylamine were dissolved in dimethyl sulfoxide and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was washed with water, dried with sodium sulfate (Na 2 SO 4 ), and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a pale yellow solid as the target compound.
  • the tricyclic compound of the present invention exhibits an IC 50 of about 1 to 1,000 nM in an inhibition experiment for the IRAK4 enzyme, and thus exhibits excellent inhibitory activity against IRAK4. Therefore, the tricyclic compound of the present invention can be useful for the prevention or treatment of diseases related to the induction activity of IRAK4.
  • PBMCs peripheral blood monocytes isolated from whole blood were distributed in 96-well plates.
  • TNF- ⁇ was dispensed at a density of 1 x 10 5 cells / well
  • IFN- ⁇ was dispensed at a density of 2 x 10 5 cells / well
  • the compound diluted to 4 times the final concentration was treated to pre-incubate for 30 minutes.
  • TNF- ⁇ was treated with 100 ng / ml lipopolysaccharide (LPS)
  • IFN- ⁇ was treated with 500 nM ODN2216 (CpG TLR9 stimulator), and further cultured for 24 hours and 72 hours, respectively.
  • Enzyme-linked immunosorbent assay was performed using TNF- ⁇ using BD Biosciences ELISA kit and IFN- ⁇ using PBL Assay Science ELISA kit. Cell supernatant and standard drug were added to the ELISA plate and reacted for 2 hours. The plate was washed, and the antibody to be measured and streptavidin-HRP were sequentially added. After washing the plate, TMB substrate was added and reacted in a dark place. The reaction was stopped by adding a stop solution, and absorbance at 450 nm and 570 nm was measured using an absorber (OPTIMax Tunable Microplate Reader, Molecular Devices). Table 2 shows the experimental results.
  • the tricyclic compound of the present invention has an excellent effect of inhibiting TNF- ⁇ and IFN- ⁇ at a concentration of micromolar level.
  • NF- ⁇ B inhibition experiment using THP1-Lucia TM NF- ⁇ B cell line Invivogen
  • ISG inhibition experiment THP1-Lucia TM ISG cell lines were used.
  • NF- ⁇ B inhibition experiment cells were planted in a 96 well-plate at a density of 1 x 10 4 cells / well, and for an ISG inhibition experiment, cells were planted in a 96 well-plate at a density of 2 x 10 4 cells / well. .
  • the compound diluted to 4 times the final concentration was treated and pre-incubated for 30 minutes.
  • NF- ⁇ B was treated with 100 ng / ml lipopolysaccharide (LPS), and ISG was treated with a 1 ⁇ g / ml Poly (dA: dT) / LyoVec stimulator and incubated for 24 hours. 10 ⁇ l of cell supernatant was taken and transferred to a 96-well plate. Using an automatic dispenser of a measuring instrument (Envision Multilabel Plate Reader, Perkin Elmer), a 50 ⁇ l Quanti-luc solution was dispensed and a luminescence signal was measured.
  • Example 1 89 48 78 37 5bb (Example 2) 92 58 73 43 5da (Example 4) 30 5 20
  • One 6aaa (Example 6) 71 23 55 17 6aab (Example 7) 61 8 54 11 6aac (Example 8) 64 17 45 7 6aad (Example 9) 78 33 79 37 6aae (Example 10) 40 ⁇ 1 29 4 6aaf (Example 11) 82 43 83 24 6aag (Example 12) 37 12 52 20 6aah (Example 13) 63 19 47 10 6aai (Example 14) 36 6 41 9 6aaj (Example 15) 33 ⁇ 1 20 14 6aak (Example 16) 37 ⁇ 1 30 ⁇ 1 6aal (Example 17) 15
  • mice 8-week-old C57BL / 6 (20-23 g) mice were supplied from Orient Bio (Seongnam, Gyeonggi-do) and used. The mice were adapted for 2 weeks or more in an animal room of the Korea Research Institute of Chemical Technology where the temperature (22 ⁇ 1 ° C) and humidity (50 ⁇ 10%) were automatically controlled, and were used for the experiment. This animal experiment was conducted with the approval of the Experimental Animal Committee of the Korea Research Institute of Chemical Technology.
  • LPS lipopolysaccharide, lipopolysaccharide, Sigma L2880
  • the test drug was suspended in a 10% cremophor solution and administered orally 2 hours before the LPS injection, and an hour after the LPS administration, the mouse was anesthetized with isoflurane and blood was drawn from the heart. The collected blood was centrifuged at 13,000 rpm for 15 minutes to obtain serum, stored at -20 ° C, taken out if necessary, and the cytokine (TNF- ⁇ ) content in the serum was measured using an ELISA kit from BD Biosciences.
  • LPS lipopolysaccharide, lipopolysaccharide, Sigma L2880
  • PF-06650833 As a positive control drug, PF-06650833 (AstraTech) was purchased and used. Statistical significance for the systemic inflammation inhibitory effect of the test drug was tested using the Student's T-test or Dunnett's T-test (SigmaStat, Jandel Scientific) program. . The test results are shown in FIGS. 1 and 2.
  • a skid (severe complex immunodeficiency) mouse (CB-17 / IcrCrj-scid , female) was purchased from Charles River, Japan, and used. The mice were used in the experiment after acclimatization for 2 weeks or more in an animal room in which temperature (22 ⁇ 1 ° C) and humidity (50 ⁇ 10%) were automatically controlled, and water and feed were freely consumed.
  • This animal experiment was conducted with the approval of the Korea Research Institute of Chemical Technology.
  • Tumors of skid mice were induced by transplanting 9 x 10 6 cells per mouse under the right flank of TMD-8 cells, and drug administration was started when the size of the transplanted tumor reached about 200 mm 3 (test period) : 1 day).
  • the test drug was suspended in 20% PEG 400 and 3% Tween 80 solutions and administered orally once a day for 14 days.
  • the diameter of the tumor i.e., the long diameter (a) and the short diameter (b)
  • PF-06650833 Sigma
  • Ibrutinib Medicalhem Express
  • Student's T-test SigmaStat, Jandel Scientific
  • the compound 6aaf of the present invention did not show a significant effect difference when compared with PF-06650833, but exhibited a slightly superior tendency, and exhibited excellent effect when administered in combination with Ibrutinib. . There was little change in the weight of the experimental animals during the test period.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter des maladies auto-immunes ou des tumeurs, contenant, en tant que principe actif, un composé tricyclique représenté par la formule 1 suivante ou un sel pharmaceutiquement acceptable de celui-ci, et une composition d'aliments naturels pour prévenir ou soulager des maladies auto-immunes ou des tumeurs, contenant le composé tricyclique en tant que principe actif. [Formule chimique 1] Un composé tricyclique représenté par la formule chimique 1 de la présente invention présente une excellente activité inhibitrice contre IRAK4 et peut ainsi être efficacement utilisé dans la prévention, le traitement ou le soulagement de maladies auto-immunes ou de tumeurs.
PCT/KR2019/015948 2018-11-21 2019-11-20 Nouveau composé tricyclique en tant qu'inhibiteur d'irak4 WO2020106059A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2021528390A JP7233130B2 (ja) 2018-11-21 2019-11-20 Ｉｒａｋ４阻害剤としての新規な三環式化合物
CN201980076657.7A CN113227095B (zh) 2018-11-21 2019-11-20 作为irak4抑制剂的新三环化合物
US17/294,705 US20220009933A1 (en) 2018-11-21 2019-11-20 Novel tricyclic compound as irak4 inhibitor
EP19887212.9A EP3885348A4 (fr) 2018-11-21 2019-11-20 Nouveau composé tricyclique en tant qu'inhibiteur d'irak4
AU2019383845A AU2019383845B2 (en) 2018-11-21 2019-11-20 Novel tricyclic compound as IRAK4 inhibitor

Applications Claiming Priority (4)

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KR10-2018-0144188 2018-11-21
KR20180144188 2018-11-21
KR1020190148566A KR102329235B1 (ko) 2018-11-21 2019-11-19 Irak4 저해제로서 신규의 삼중고리 화합물
KR10-2019-0148566 2019-11-19

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