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WO2018128407A1 - Nouveau dérivé de quinolinone et composition pharmaceutique pour prévenir ou traiter une maladie allergique telle que l'asthme ou l'atopie comprenant celui-ci en tant que principe actif - Google Patents

Nouveau dérivé de quinolinone et composition pharmaceutique pour prévenir ou traiter une maladie allergique telle que l'asthme ou l'atopie comprenant celui-ci en tant que principe actif Download PDF

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Publication number
WO2018128407A1
WO2018128407A1 PCT/KR2018/000165 KR2018000165W WO2018128407A1 WO 2018128407 A1 WO2018128407 A1 WO 2018128407A1 KR 2018000165 W KR2018000165 W KR 2018000165W WO 2018128407 A1 WO2018128407 A1 WO 2018128407A1
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mhz
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Korean (ko)
Inventor
변영주
전영호
이기호
이기용
정용우
손상현
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Korea University Research and Business Foundation
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Korea University Research and Business Foundation
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Priority to CN201880005933.6A priority Critical patent/CN110177796B/zh
Priority to EP18736592.9A priority patent/EP3567044A4/fr
Priority to US16/473,362 priority patent/US11168094B2/en
Priority claimed from KR1020180001019A external-priority patent/KR102009756B1/ko
Publication of WO2018128407A1 publication Critical patent/WO2018128407A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a novel quinoline derivative, and more particularly, 4-substituted 2- that exhibits efficacy in preventing or treating allergic diseases such as asthma or atopy by controlling intracellular signal transduction by TSLP and IL-33.
  • It relates to a pharmaceutical composition for the prevention and treatment of allergic diseases such as asthma or atopic dermatitis.
  • Bronchodilators or anti-inflammatory drugs used in the treatment of allergic inflammatory diseases are performed mainly for symptomatic therapy, which may temporarily reduce the symptoms. However, they do not have fundamental control over allergic diseases. .
  • Th2 cells are well known to play a pivotal role in inducing allergic reactions.
  • CD4 T cells When CD4 T cells are stimulated by antigens in lymphocytes, they can be differentiated into several Th cells according to cytokines that are recognized at the same time, and the recognized cytokines are thymic stromal lymphoprotein (TSLP). Or in the case of type 2 cytokines such as IL-4, these cells differentiate into Th2 to induce an allergic reaction.
  • TSLP thymic stromal lymphoprotein
  • Interleukin-33 is a congenital cytokine produced mainly by various external stimuli in mucosal epithelial cells, and is known to play an important role in regulating the immune response of Th2 cell mediated allergic reactions such as asthma.
  • the IL-33 receptor complex for IL-33 mediated signaling consists of the ligand IL-33, the ligand conjugate ST2 (IL-1R4), and the signal receptor IL-1 receptor accessory protein (IL-1RAcP; IL-1R3). It is. Stimulation of IL-33 produces Th2 inflammatory cytokines and chemokines including IL-4, IL-5, IL-6, IL-13 and IL-8.
  • the IL-33 receptor complex is passed through sub-signals such as NF-kB and AP-1 via IL-1 receptor-associated kinase (IRAK), TNF receptor associated factor 6 (TRAF6) and / or MAPKs. Activate the molecules of the system.
  • sub-signals such as NF-kB and AP-1 via IL-1 receptor-associated kinase (IRAK), TNF receptor associated factor 6 (TRAF6) and / or MAPKs.
  • TSLP and IL-33 are cytokines that play an important role in the differentiation of Th2 cells and are expected to be able to treat allergic diseases by controlling them.
  • Non-Patent Document 2 S. Kamijo, H. Takeda, T. Tokura, M. Suzuki, K. Inui, M. Hara, H. Matsuda, A. Matsuda, K. Oboki, T. Ohno, H. Saito, S Nakae, K. Sudo, H. Suto, S. Ichikawa, H. Ogawa, K. Okumura, T. Takai, IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation , J Immunol, 190 (2013) 4489-4499.
  • the present invention is to provide a novel quinolinone derivative exhibiting efficacy in the prevention or treatment of allergic diseases such as asthma or atopy by controlling intracellular signal transduction by TSLP and IL-33.
  • compositions for the prevention or treatment of allergic diseases such as asthma or atopy containing the novel quinolinone derivatives as an active ingredient, and a pharmaceutically acceptable carrier.
  • the present invention provides a quinolinone derivative represented by the following [formula 1a] or [formula 1b] to solve the above problems.
  • the present invention contains a quinolinone derivative represented by the above [Formula 1a] or [Formula 1b] as an active ingredient, prevention or treatment of allergic diseases such as asthma or atopy, including a pharmaceutically acceptable carrier It provides a pharmaceutical composition.
  • the quinolinone derivative compound according to the present invention is capable of effectively inhibiting the formation of an inflammatory response of an allergic disease such as asthma or atopic dermatitis, and fundamentally prevents various allergic diseases such as asthma or atopy using a pharmaceutical composition comprising the same. It can be prevented or treated.
  • FIG. 1 is a graph showing the evaluation of TSLP-TSLPR interaction inhibition of the compound [Formula 2] according to the present invention using an ELISA.
  • Figure 2 is a graph showing the evaluation of TSLP-TSLPR interaction inhibition of the compound [Formula 7] according to the present invention using an ELISA.
  • Figure 3 is a graph showing the inhibition of IL-6 secretion by the IL-33 inhibition of the formula [10] according to the present invention.
  • Figure 6 is a graph showing the chemical shift perturbation of Thr 120 residues of IL-33 protein by the compound according to the present invention.
  • Figure 7 is a graph showing the chemical shift perturbation of the Glu 121 residue of the IL-33 protein by the compound according to the present invention.
  • the quinolinone derivatives represented by the following [Formula 1a] and [Formula 1b] is a key cytokine TSLP and IL-33, which is a key cytokine to induce allergic diseases such as asthma or atopy, between such cytokines and receptors It was confirmed that effectively inhibits the binding of the present invention was completed based on this.
  • One aspect of the present invention relates to a quinolinone derivative represented by the following [Formula 1a] or [Formula 1b], and controls the intracellular signal transduction by TSLP and IL-33, and the cytokine TSLP (thymic stromal lymphopoietin) It is characterized by inhibiting the binding between the TSLP receptor or the binding between the cytokine IL-33 and ST-2.
  • TSLP thymic stromal lymphopoietin
  • R 1 and R 2 is the same as or different from each other, and each independently an alkyl group having 1 to 4 carbon atoms, an alkylene group having 1 to 4 carbon atoms, and any one selected from the following [Formula 1].
  • Z is a hetero atom selected from O, S or N, or-(CH 2 ) m- (m is an integer of 0 to 5).
  • X and Y are each independently hydrogen (H), halogen group (fluor (F), chlorine (Cl), bromine (Br), iodine (I)), hydroxy group (OH), amino group (NH 2 ), nitro group ( NO 2 ), cyano group (CN), trifluoromethyl group (CF 3 ), CO-R ', NHR', NR'R ', NHCOR' and COOR '(any R' is 1 to 4 carbon atoms) Alkyl group).
  • p is an integer of 0-4
  • q is an integer of 0-5, and when said p and q are multiple, some X and some Y are each the same or different.
  • the quinolinone derivative represented by the above [Formula 1a] or [Formula 1b] is not limited by this, but may be specifically any one selected from the following [Formula 2] to [Formula 15].
  • the quinolinone derivatives according to the present invention can be prepared through a Sandmeyer reaction, a Suzuki-bond and a Heck reaction under a palladium-catalyst, a nitro group reduction reaction, a cyclization reaction and a substitution reaction under basic conditions, for example starting materials.
  • ethyl 2-aminooxazole-4-carboxylate as a starting material, various 2-aryloxazole-4-carboxylate derivatives can be synthesized using arylboronic acid substituted in ethyl 2-chlorooxazole-4-carboxylate obtained through Sandmeyer reaction.
  • 2-aryl-5-aryloxazole-4-carboxylate derivatives having various substituents introduced therein may be prepared using 2-iodo-1-nitrobenzene substituted in the Heck reaction. After the reduction of the nitro group through a hydrogenation reaction, it is possible to synthesize a quinolinone derivative through the intramolecular reaction of the amine group and the ester group under basic conditions.
  • Various basic quinolinone derivatives represented by the above [Formula 1a] or [Formula 1b] may be prepared by a substitution reaction with dialkylethyl bromide under basic conditions.
  • the compounds of [Formula 2] to [Formula 13] may be prepared through the synthesis process as follows, and the following [1] is quinolinone represented by [Formula 1a] or [Formula 1b] according to the present invention.
  • [2] and [3] are flow charts schematically showing the synthesis process of a compound wherein R 1 and R 2 are ethyl groups. .
  • Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating allergic diseases, such as asthma or atopy, containing a quinolinone derivative represented by the above [Formula 1a] or [Formula 1b] as an active ingredient, TSLP And control intracellular signal transduction by IL-33, inhibit the binding between the cytokine thymic stromal lymphopoietin (TSLP) and the TSLP receptor or inhibit the binding between the cytokine IL-33 and ST-2.
  • allergic diseases such as asthma or atopy
  • a quinolinone derivative represented by the above [Formula 1a] or [Formula 1b] as an active ingredient
  • TSLP thymic stromal lymphopoietin
  • the pharmaceutical composition according to the present invention can be used for the prevention and treatment of a wide range of allergic diseases such as asthma or atopic dermatitis, but the allergic disease is atopic dermatitis, urticaria rhinitis, allergic rhinitis or asthma May be a disease.
  • composition according to the present invention may be administered in the form of a complex preparation together with other drugs known for the prophylaxis or treatment of allergic diseases such as asthma or atopy, or other components such as carriers, diluents, adjuvants and stabilizers, It may also include.
  • the form of the composition according to the present invention may be variously selected depending on the mode to be administered, but is not limited thereto, for example, solid phases such as tablets, pills, powders, capsules, gels, ointments, fluids or suspensions, and the like. It may be in the form of a semi-solid or liquid dosage form, may be administered in a unit dosage form suitable for the precise administration of the dosage alone, orally or parenterally, and in the case of parenteral administration, intravenous, subcutaneous, It can be administered by intramuscular injection.
  • solid phases such as tablets, pills, powders, capsules, gels, ointments, fluids or suspensions, and the like.
  • It may be in the form of a semi-solid or liquid dosage form, may be administered in a unit dosage form suitable for the precise administration of the dosage alone, orally or parenterally, and in the case of parenteral administration, intravenous, subcutaneous, It can be administered by intramuscular injection.
  • compositions may include, depending on the desired formulation, a pharmaceutically acceptable carrier, diluent, adjuvant, stabilizer, defined as an aqueous-based carrier commonly used in formulating pharmaceutical compositions for human administration.
  • Carrier means a substance that facilitates the addition of the compound into a cell or tissue, and is commonly used in the preparation, for example, carbohydrate compounds (eg lactose, amylose, dextrose, water) Cross, sorbitol, mannitol, starch, cellulose, etc.), acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, salt solution, alcohol, arabian Rubber, vegetable oils (e.g.
  • Diluent is defined as a substance that not only stabilizes the biologically active form of a compound of interest, but also is diluted in water to dissolve the compound.
  • examples of diluents include distilled water, physiological saline, Ringer's solution, glucose solution, and Hank's solution and the like.
  • Stabilizers can be selected from the group consisting of proteins, sugars, buffers and mixtures thereof.
  • lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives and the like but also not limited thereto.
  • an effective amount of other components such as carriers, diluents, adjuvants and stabilizers and the like is an amount effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc. of the component.
  • prevention has not been diagnosed as having a disease or a disease, but means inhibiting the occurrence of such a disease or a disease
  • treatment refers to the inhibition of the development of the disease or a disease, disease or disease It is meant to include the alleviation and elimination of diseases or diseases.
  • "contains as an active ingredient” means that the ingredient is included in an amount necessary or sufficient to realize a desired biological effect.
  • the determination of the amount to be included as an active ingredient is an amount for treating a subject disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition being treated, the form of the composition to be administered, It may vary depending on various factors such as the size of the subject or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of an individual composition without undue experimentation.
  • pharmaceutically acceptable means a property that does not impair the biological activity and physical properties of the compound.
  • reaction mixture was reflected for 1 hour with stirring, cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and 2M sodium hydroxide solution, and the aqueous layer was washed twice more with ethyl acetate. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated in vacuo.
  • the product was purified by silica gel column chromatography (hexane / Et 2 O, 5: 1 to 3: 1, v / v) to give product 22b as a white solid (250 mg, 73%) in the shape of fluffy.
  • a palladium catalyst was added to a solution of compound 23b (192 mg, 0.54 mmol) and MeOH (15 mL), and stirred for 1 hour in a hydrogen (50 psi) atmosphere. After the reaction mixture was filtered through a celite bed, the volatiles were reduced to remove and 4a (145 mg, 82%) was obtained as a yellow solid.
  • ELISA was used to measure the response by HRP using FLAG-TSLP protein and TSLPR-His protein.
  • the TSLP-TSLPR interaction assay was used to evaluate the inhibitory activity.
  • ELISA analysis was performed on Ni-NTA HisSorb plates (Qiagen, Germany). Dispense 100 ⁇ L of the TSLPR solution with hexahistidine (His) tag at the C-terminus to each well of the plate and incubate for 2 hours at room temperature, then wash each well twice with 200 ⁇ L of PBS, 0.05% Tween-20. Then 100 ⁇ L of the compound solution (sample) according to the invention and 100 ⁇ L of TSLP with N-terminal FLAG tag were dispensed. After incubation overnight at 4 ° C., each well was washed twice and treated with 100 ⁇ L of blocking buffer (PBS-0.05% Tween 20 and 1% skim milk).
  • blocking buffer PBS-0.05% Tween 20 and 1% skim milk
  • the plates were washed twice and then coated with 100 ⁇ L of monoclonal anti-FLAG horseradish peroxidase antibody (Sigma-Aldrich Co., USA) for 2 hours, incubated at room temperature, and then each well was washed five times. Each well was treated with 200 ⁇ L of o-phenylenediaminedihydrochloride (Sigma-Aldrich Co., USA) solution and incubated for 30 minutes. After incubation, 1N HCl was added to each well.
  • Optical densities (ODs) were measured at 450 nm of a microplate spectrophotometer, and the TSLP-TSLPR interaction inhibitory effect was calculated using the following formula, and the results are shown in the following [Table 1].
  • Inhibition (inhibition) (%) (1-sample OD / control OD) ⁇ 100
  • HMC-1 a human mast cell line
  • IL-33 and the compound according to the present invention at a predetermined concentration were mixed with the cells, incubated at 37 ° C. for 24 hours, and then the supernatant was obtained by centrifugation before IL-6.
  • the secretion of IL-6 was analyzed by ELISA kit (Biolegend, USA), and the results are shown in the following [Table 2].
  • the quinolinone derivatives according to the present invention are the cytokines TSLP and TSLP receptors or the binding of IL-33 and ST-2, which play a key role in inducing allergic diseases such as asthma or atopy.
  • Splenocytes were isolated from DO11.10 mice and approximately 1 ⁇ 10 6 CD4 T cells were transferred intravenously to pure BALB / c mice.
  • CSPs Chemical shift perturbations
  • IL-33 was cloned by the expression vector pPROEX, an N-terminal His-tag fusion protein in E. coli BL21 (DE3), and cells were cultured at 0.5 mM IPTG (isopropyl-bD-) when the cell density (OD 600 ) reached 0.6. thiogalactoside) and further growth at 20 ° C. overnight.
  • IPTG isopropyl-bD-
  • thiogalactoside cell density
  • lysis buffer 0.1 M Tris pH 7.4, 0.3 M NaCl, 1 mM ⁇ -mercaptoethanol, 0.1% TritonX100, and 0.1 mM phenylmethylsulfonyl fluoride.
  • Cell lysis was sonicated in an ice bath, and cell lysates were centrifuged at 10000 ⁇ g, 4 ° C. for 25 minutes. The pellet was discarded and the supernatant was eluted on 5 mL of HisPur cobalt resin column Thermo Scientific Inc.
  • TEV protease was used to cleave the fusion protein overnight in dialysis buffer (Tris 20 mM (pH 7.4), sodium chloride 300 mM) and 4 ° C.
  • the IL-33 containing mixture was placed in a HisPur cobalt resin column and washed with Tris 0.1 M (pH 7.4), 0.3 M sodium chloride and 1 mM ⁇ -mercaptoethanol, and the bound protein was then tris 0.1 M (pH 7.4), sodium chloride 0.3 M and Elution with 1 mM (20 mL) ⁇ -mercaptoethanol.
  • the protein was loaded on a Superdex S75 gel filtration column (16/60 GE Healthcare) at 20 mM sodium phosphate (pH 6.8), sodium chloride 100 mM, BME 5 mM to obtain pure IL-33 protein.
  • the quinolinone derivative compound according to the present invention is capable of effectively inhibiting the formation of an inflammatory response of an allergic disease such as asthma or atopic dermatitis, and fundamentally prevents various allergic diseases such as asthma or atopy using a pharmaceutical composition comprising the same. It can be prevented or treated.

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Abstract

La présente invention concerne un nouveau composé dérivé de quinolinone qui est efficace pour prévenir ou traiter une maladie allergique telle que l'asthme ou l'atopie par la régulation de la signalisation intracellulaire par l'intermédiaire de SLP et d'IL-33. Le composé dérivé de quinolinone selon la présente invention est capable d'inhiber efficacement l'apparition d'une réaction inflammatoire d'une maladie allergique telle que l'asthme ou l'atopie, et la composition pharmaceutique le comprenant peut être utilisée pour prévenir ou traiter essentiellement diverses maladies allergiques et asthmatiques.
PCT/KR2018/000165 2017-01-06 2018-01-04 Nouveau dérivé de quinolinone et composition pharmaceutique pour prévenir ou traiter une maladie allergique telle que l'asthme ou l'atopie comprenant celui-ci en tant que principe actif Ceased WO2018128407A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201880005933.6A CN110177796B (zh) 2017-01-06 2018-01-04 喹啉酮衍生物及其用于预防或治疗变应性疾病的药物组合物
EP18736592.9A EP3567044A4 (fr) 2017-01-06 2018-01-04 Nouveau dérivé de quinolinone et composition pharmaceutique pour prévenir ou traiter une maladie allergique telle que l'asthme ou l'atopie comprenant celui-ci en tant que principe actif
US16/473,362 US11168094B2 (en) 2017-01-06 2018-01-04 Quinolinone derivative and pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopic dermatitis including the quinolinone derivative as active ingredient

Applications Claiming Priority (4)

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KR10-2017-0002326 2017-01-06
KR20170002326 2017-01-06
KR10-2018-0001019 2018-01-04
KR1020180001019A KR102009756B1 (ko) 2017-01-06 2018-01-04 신규한 퀴놀리논 유도체 및 이를 유효성분으로 포함하는 천식 또는 아토피 등의 알러지성 질환의 예방 또는 치료용 약학 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020009374A1 (fr) * 2018-07-04 2020-01-09 고려대학교 세종산학협력단 Nouveaux dérivés d'oxazoloquinolinone substitués en position 4, sel pharmaceutiquement acceptable de ceux-ci et composition pharmaceutique pour la prévention ou le traitement de maladies allergiques notamment l'asthme ou la dermatite atopique les comprenant

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WO2000009506A1 (fr) * 1998-08-12 2000-02-24 Hokuriku Seiyaku Co., Ltd. Derives de 1h-imidazopyridine
JP2010143829A (ja) * 2008-12-16 2010-07-01 Dainippon Sumitomo Pharma Co Ltd 新規なイミダゾキノリン誘導体

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WO2000009506A1 (fr) * 1998-08-12 2000-02-24 Hokuriku Seiyaku Co., Ltd. Derives de 1h-imidazopyridine
JP2010143829A (ja) * 2008-12-16 2010-07-01 Dainippon Sumitomo Pharma Co Ltd 新規なイミダゾキノリン誘導体

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KI M, Y. K. ET AL.: "Discovery of an Interleukin 33 Inhibitor by Molecular Docking Simulation and NMR Analysis", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 37, no. 2, 28 January 2016 (2016-01-28), pages 117 - 118, XP055512044 *
NOHA, S. M. ET AL.: "Discovery of Novel, Non-acidic mPGES-1 Inhibitors by Virtual Screening with a Multistep Protocol", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 23, no. 15, 1 August 2015 (2015-08-01), pages 4839 - 4845, XP055512043 *
S. KAMIJOH. TAKEDAT. TOKURAM. SUZUKIK. INUIM. HARAH. MATSUDAA. MATSUDAK. OBOKIT. OHNO: "IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation", J IMMUNOL, vol. 190, 2013, pages 4489 - 4499
SHIRO, T. ET AL.: "7-Phenyl-imidazoquinolin-4(5H)-one Derivatives as Selective and Orally Available mPGES-1 Inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 21, no. 11, 6 April 2013 (2013-04-06), pages 2868 - 2878, XP028535205 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020009374A1 (fr) * 2018-07-04 2020-01-09 고려대학교 세종산학협력단 Nouveaux dérivés d'oxazoloquinolinone substitués en position 4, sel pharmaceutiquement acceptable de ceux-ci et composition pharmaceutique pour la prévention ou le traitement de maladies allergiques notamment l'asthme ou la dermatite atopique les comprenant

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