WO2020009374A1 - 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 - Google Patents

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 Download PDF

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WO2020009374A1
WO2020009374A1 PCT/KR2019/007822 KR2019007822W WO2020009374A1 WO 2020009374 A1 WO2020009374 A1 WO 2020009374A1 KR 2019007822 W KR2019007822 W KR 2019007822W WO 2020009374 A1 WO2020009374 A1 WO 2020009374A1
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formula
substituted
group
unsubstituted
derivative
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PCT/KR2019/007822
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English (en)
Korean (ko)
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변영주
전영호
이기호
이기용
정용우
손상현
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고려대학교 세종산학협력단
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Priority claimed from KR1020190076612A external-priority patent/KR20200004752A/ko
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Publication of WO2020009374A1 publication Critical patent/WO2020009374A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • 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

Definitions

  • the present invention relates to a novel 4-substituted oxazoloquinolinone derivative compound, and more particularly, to control intracellular signal transduction by IL-33 and TSLP to prevent or treat allergic diseases such as asthma or atopy.
  • the present invention relates to a 4-substituted oxazoloquinolinone derivative compound exhibiting efficacy, a salt thereof, and a pharmaceutical composition for preventing and treating allergic diseases such as asthma or atopy containing the same as an active ingredient.
  • 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.
  • allergic diseases cannot be treated because they cannot be fundamentally controlled. .
  • 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.
  • IL-33 and TSLP are cytokines that play an important role in the differentiation of Th2 cells and are expected to be able to fundamentally treat allergic diseases by controlling them.
  • the present invention provides novel 4-substituted oxazoloquinolinone derivative compounds and pharmaceuticals that are effective in the prevention or treatment of allergic diseases such as asthma or atopy by controlling intracellular signal transduction by IL-33 and TSLP. It is intended to provide a compound that is a salt of the above-mentioned derivative.
  • the present invention provides a 4-substituted oxazoloquinazoline derivative represented by the following [Formula 1] and a salt of the derivative in order to solve the above problems.
  • the present invention is an allergic property such as asthma or atopy containing a 4-substituted oxazoloquinazoline derivative represented by the above [Formula 1] and a compound which is a salt of the derivative as an active ingredient, and includes a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating a disease is provided.
  • the 4-substituted oxazoloquinolinone derivatives and salts thereof according to the present invention can effectively inhibit the formation of an inflammatory response in allergic diseases such as asthma or atopy, and various asthma or atopy using the pharmaceutical composition comprising the same. Allergic diseases such as can be prevented or treated fundamentally.
  • FIG. 1 is a graph showing the inhibition of IL-6 secretion by the inhibition of IL-33 of [Formula 2], [Formula 8], [Formula 3] and [Formula 9] according to the present invention (1, 10 ⁇ M) .
  • Figure 3 is a graph showing the inhibition of IL-6 secretion by IL-33 inhibition of the compound of formula 12 (1, 10, 100 nM) according to the present invention.
  • Figure 4 is an animal test results of HDM (house dust mite) -induced allergic airway inflammation mouse model for the compound according to the present invention (Formula 9, KB-1529).
  • FIG. 5 is an animal test result of a house dust mite-induced allergic airway inflammation mouse model of a compound according to the present invention (Formula 12, KB-1540).
  • TSLP which is a core cytokine that induces allergic diseases such as asthma or atopy
  • TSLP is a 4-substituted oxazoloquinolinone derivative represented by the following [Formula 1] and a compound which is a salt of the pharmaceutically acceptable derivative.
  • IL-33 it was confirmed that effectively inhibits the binding between the cytokine and the receptor, based on this has been completed the present invention.
  • One aspect of the present invention relates to a 4-substituted oxazoloquinolinone derivative represented by the following [Formula 1] and a compound thereof, which controls intracellular signal transduction by IL-33 and TSLP, and cytokine IL-33. And ST-2 or inhibit the binding between the cytokine thymic stromal lymphopoietin (TSLP) and the TSLP receptor.
  • TSLP thymic stromal lymphopoietin
  • X is selected from hydrogen, a halogen group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylamine group, a substituted or unsubstituted alkylthiol group and a substituted or unsubstituted heterocycloalkyl group, more specifically May be a halogen group or any one selected from -OR 1 , -SR 2 , -NHR 3, and -NR 4 R 5 structure.
  • R 1 to R 5 are the same as or different from each other, and each independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkylamine group, a substituted or unsubstituted alkylthiol group, a substituted or Unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted heteroarylalkyl group, substituted or unsubstituted arylalkylamine group And a substituted or unsubstituted heteroarylalkylamine group, wherein R 4 and R 5 may be linked to each other to form a ring, and the ring may include a heteroatom.
  • Y and Z may each independently be any one selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, halogenated alkyl, CO-R, NHR, NRR, NHCOR and COOR (wherein R ' Is an alkyl group), p is an integer of 1 to 4, q is an integer of 1 to 5, when p and q are each a plurality of X and a plurality of Y may be the same or different from each other.
  • the substituted or unsubstituted may be substituted with one or more substituents, and the one or more substituents may be an amine group, a halogen group, a hydroxy group, Of sulfonyl group, ester group, carboxyl group, alkyl group, cycloalkyl group, alkylamine group, alkylthiol group, aryl group, heteroaryl group, heterocycloalkyl group, arylalkyl group, heteroarylalkyl group, arylalkylamine group, heteroarylalkylamine group Can be selected.
  • the alkyl group may be linear or branched, carbon number is not particularly limited, but is preferably 1 to 10, specific examples are methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert -Butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl and the like, but are not limited thereto.
  • the cycloalkyl group is also not particularly limited, but is preferably 3 to 20 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl , 4-methylcyclohexyl, and the like, and the like, and the heterocycloalkyl group is a form in which a carbon is substituted with a hetero atom in a ring in a cycloalkyl group.
  • the amine group may be selected from -NH 2 , alkylamine group, N-alkylarylamine group, arylamine group, N-arylheteroarylamine group, N-alkylheteroarylamine group, heteroarylamine group, heterocycloalkylamine group and the like.
  • N-alkylarylamine group means an amine group substituted with an alkyl group and an aryl group in N of the amine group
  • N-arylheteroarylamine group means an amine group substituted with an aryl group and heteroaryl group in N of the amine group
  • N-alkylheteroarylamine group means an amine group in which an alkyl group and a heteroarylamine group are substituted for N of the amine group.
  • the aryl group is not particularly limited, but preferably has 6 to 30 carbon atoms, and the aryl group may be monocyclic or polycyclic, and specifically, may be a phenyl group, a biphenyl group, a terphenyl group, but is not limited thereto.
  • the aryl group includes one or more atoms other than carbon and heteroatoms, and specifically, the heteroatoms may include one or more atoms selected from the group consisting of O, N, Se, and S, and the like. Although carbon number is not specifically limited, It is preferable that it is C2-C30.
  • the 4-substituted oxazoloquinolinone derivatives according to the present invention can be prepared through Sandmeyer reaction, Suzuki-bonding and Heck reaction under palladium-catalyst, nitro group reduction reaction, cyclization reaction and substitution reaction under basic conditions. Through the synthesis process as described below it can be synthesized a variety of derivatives implemented in [Formula 1], including [Formula 2] to [Formula 17].
  • Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating allergic diseases, such as asthma or atopy, containing the 4-substituted oxazoloquinolinone derivative represented by the above [Formula 1] as an active ingredient, IL Controls intracellular signal transduction by -33 and TSLP, inhibits binding between cytokines IL-33 and ST-2, or inhibits binding between cytokine thymic stromal lymphopoietin (TSLP) and TSLP receptors.
  • allergic diseases such as asthma or atopy
  • IL Controls intracellular signal transduction by -33 and TSLP inhibits binding between cytokines IL-33 and ST-2, or inhibits binding between cytokine thymic stromal lymphopoietin (TSLP) and TSLP receptors.
  • TSLP cytokine 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, etc. 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 a disease or a disease, a disease or a 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.
  • Ethyl 2-aminooxazole-4-carboxylate (468 mg, 3 mmol) was added to t-butylnitrite (540 ⁇ l, 0.45 mmol), copper chloride (600 mg, 4.5 mmol) and acetonitrile (22 ml). Add at 60 ° C. and heat the mixture at 80 ° C. for 1 h. After cooling the mixture was partitioned in dichloromethane, ice, hydrochloric acid, the aqueous layer was further extracted with dichloromethane and the organics were washed with brine, dried (MgSO 4 ) and evaporated.
  • the product was purified by silica gel column chromatography (hexane / Et2O, 5: 1 to 3: 1, v / v) to give the product intermediate B as a fluffy white solid (250 mg, 73%).
  • intermediate D 95 mg, 0.27 mmol
  • DME 7 mL
  • 2 M potassium carbonate solution 0.5 mL, 1.0 mmol
  • Dioxane and alcohol (1.5 equiv.) Solution was added to a suspension of NaH (60% mineral oil, 1.5-3.0 equiv., 1 mL dioxane) at 0 ° C. under argon for 3 minutes. After stirring for 1 hour at room temperature, dioxane (1 mL) and 2-chloroquinoline (1 equiv.) Solutions were added to the reaction mixture for 1 minute at room temperature. The mixture was refluxed under argon for 4 hours, cooled before NH 4 Cl was added and the mixture was extracted with EtOAc. After drying over MgSO 4 , drying the organic phase and concentrating, the residue was purified by silica gel column chromatography.
  • HMC-1 a human mast cell line
  • HMC-1 a human mast cell line
  • oxazoloquinolinone derivatives according to the present invention is a binding between the cytokine IL-33 and ST-2 which plays a key role in causing allergic diseases such as asthma or atopic dermatitis Or inhibit the binding between the cytokine thymic stromal lymphopoietin (TSLP) and the TSLP receptor, and according to the present invention, therefore, by inhibiting signal transduction mediated by TSLP or IL-33, allergic reactions such as asthma or atopy The fundamental prevention and treatment of the disease is possible.
  • TSLP thymic stromal lymphopoietin
  • Splenocytes were isolated from DO11.10 mice and approximately 1 ⁇ 10 6 CD4 T cells were transferred intravenously to pure BALB / c mice.
  • the compounds according to the invention 143 nM
  • PBS control mice
  • the total number of cells and the number of eosinophils in the airways of the mice treated with the formulas 9 (KB-1529) and 12 (KB-1540) according to the present invention are not treated with the compounds according to the present invention. It can be seen that significantly reduced compared to the case. Therefore, by using the 4-substituted oxazoloquinolinone derivatives according to the present invention, it is possible to fundamentally prevent and treat allergic diseases such as asthma or atopy.
  • TSLP-TSLPR using ELISA to measure the response by HRP using FLAG-TSLP protein and TSLPR-His protein produced in-house to confirm whether the compound according to the present invention directly inhibits the binding between TSLP and TSLP receptor.
  • the interaction assay was established to evaluate the inhibitory activity, and the results are shown in the following [Table 1].
  • 4-substituted oxazoloquinolinone derivatives and salts thereof according to the present invention can effectively inhibit the formation of inflammatory reactions of allergic diseases such as asthma or atopy, and various asthma or atopy using the pharmaceutical composition comprising the same Allergic diseases such as can be prevented or treated fundamentally.

Abstract

La présente invention concerne un dérivé d'oxazoloquinolinone substitué en position 4, et un composé, qui est un sel du dérivé, présentant des effets de prévention et de traitement de maladies allergiques, telles que l'asthme ou la dermatite atopique, par la régulation de la transduction du signal intracellulaire due à l'IL-33. Le dérivé et le composé selon la présente invention peuvent supprimer de manière efficace la formation de réactions inflammatoires de maladies allergiques, telles que l'asthme ou la dermatite atopique, et ainsi, une composition pharmaceutique comprenant le dérivé et le composé peut être utilisée pour prévenir ou traiter fondamentalement diverses allergies et maladies asthmatiques.
PCT/KR2019/007822 2018-07-04 2019-06-27 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 WO2020009374A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2018-0077593 2018-07-04
KR20180077593 2018-07-04
KR10-2019-0076612 2019-06-26
KR1020190076612A KR20200004752A (ko) 2018-07-04 2019-06-26 4-치환 옥사졸로퀴놀리논 유도체, 약학적으로 허용되는 이의 염인 화합물 및 이를 유효성분으로 포함하는 천식 또는 아토피 등의 알러지성 질환의 예방 또는 치료용 약학 조성물

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182290A (en) * 1991-08-27 1993-01-26 Neurogen Corporation Certain oxazoloquinolinones; a new class of GABA brain receptor ligands
KR100919147B1 (ko) * 2001-11-16 2009-09-25 닛뽕 케미파 가부시키가이샤 크산틴 옥시다제 저해제
WO2016136727A1 (fr) * 2015-02-24 2016-09-01 国立大学法人鳥取大学 Médicament pour prévenir et/ou traiter la démence
KR101839721B1 (ko) * 2017-01-06 2018-03-16 고려대학교 세종산학협력단 바이칼레인을 유효성분으로 포함하는 천식 또는 아토피 등의 알러지성 질환의 예방 또는 치료용 약학 조성물
WO2018128407A1 (fr) * 2017-01-06 2018-07-12 고려대학교 세종산학협력단 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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182290A (en) * 1991-08-27 1993-01-26 Neurogen Corporation Certain oxazoloquinolinones; a new class of GABA brain receptor ligands
KR100919147B1 (ko) * 2001-11-16 2009-09-25 닛뽕 케미파 가부시키가이샤 크산틴 옥시다제 저해제
WO2016136727A1 (fr) * 2015-02-24 2016-09-01 国立大学法人鳥取大学 Médicament pour prévenir et/ou traiter la démence
KR101839721B1 (ko) * 2017-01-06 2018-03-16 고려대학교 세종산학협력단 바이칼레인을 유효성분으로 포함하는 천식 또는 아토피 등의 알러지성 질환의 예방 또는 치료용 약학 조성물
WO2018128407A1 (fr) * 2017-01-06 2018-07-12 고려대학교 세종산학협력단 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

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