WO2022071777A1 - Composition et procédé pour la prévention ou le traitement d'une maladie respiratoire - Google Patents

Composition et procédé pour la prévention ou le traitement d'une maladie respiratoire Download PDF

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WO2022071777A1
WO2022071777A1 PCT/KR2021/013401 KR2021013401W WO2022071777A1 WO 2022071777 A1 WO2022071777 A1 WO 2022071777A1 KR 2021013401 W KR2021013401 W KR 2021013401W WO 2022071777 A1 WO2022071777 A1 WO 2022071777A1
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alkyl
aryl
heteroaryl
cycloalkyl
alkenyl
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최재영
한균희
남궁완
박성하
박무석
유태현
송두나
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연세대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical compounds and compositions useful for the prevention or treatment of fendrine-associated respiratory diseases, and more particularly to compounds, compositions and methods for modulating downregulation of fendrine.
  • Pendrine is encoded by the SLC26A4 gene, which is an anion exchanger and a member of the SLC26 gene family, and exchanges Cl ⁇ for anions such as HCO 3 ⁇ , I ⁇ , OH ⁇ and SCN ⁇ .
  • Pendrine is a cell membrane protein expressed in the luminal membrane of airway epithelial cells. However, pendrine expression is not associated with inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, pertussis infection, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and the common cold caused by rhinovirus.
  • COPD chronic obstructive pulmonary disease
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • pendrine knockout ameliorated airway inflammation in all mouse models for COPD, allergic rhinitis, asthma, pertussis infection and rhinovirus infection.
  • the pathophysiological role of pendrine in airway inflammation has not been clearly elucidated.
  • new evidence indicates that pendrine is involved in airway surface fluid (ASL) volume conservation and regulation of mucus production in inflammatory airway disease.
  • ASL airway surface fluid
  • ASL volume increase in primary mouse tracheal epithelial cell cultures by IL-13 was significantly higher in pendrine KO mice compared with WT mouse controls.
  • IL-13-induced ASL volume increase in primary human nasal epithelial (HNE) cell cultures of deaf patients carrying the pendrine mutant (DFNB4) was significantly higher than that of normal controls.
  • inhibition of fendrine by pendrine inhibitors significantly increased IL-13-induced ASL volume in primary cultures of human bronchial epithelial cells.
  • US Patent Publication No. US 2019/0054071 discloses a small molecule inhibitor of phendrine ion exchange of a compound represented by the following formula (I) and its medicinal use as a therapeutic agent for respiratory diseases or a diuretic.
  • the present invention is based on the discovery that certain compounds can act as pendrine inhibitors and thus can be used as diuretics or therapeutic agents for related diseases through inhibition of pendrine activity.
  • the present invention provides that some compounds discovered through cell-based HTS screening for the identification of small molecule pendrine inhibitors or novel newly designed compounds can be used for asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic
  • respiratory diseases inflammatory airway disease
  • fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD) based on the discovery that it can be done.
  • the present invention is based on the finding that some small molecules can show that fendrine down-regulation reduced IL-13-induced up-regulation of MUC5AC gene expression in HNE cells differentiated from normal subjects.
  • some molecules have been used as pendrine inhibitors to ameliorate airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic asthma.
  • OVA ovalbumin
  • an object of the present invention is to provide a compound represented by the following Chemical Formula 1 or 2, a composition for preventing, improving or treating respiratory diseases through its pendrine inhibitory activity, and a composition for diuresis.
  • the present invention provides a compound represented by the following formula (1), its E- or Z- isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or two types thereof A mixture of isomers is provided:
  • V 1 and V 2 are each independently Aryl, heteroaryl, C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazine, C 2 to C 10 alkynyl, S(O) i (C 1 to C 6 alkyl), OS(O) i (aryl), S(O) i NR 3 R 4 , C(O)R 3 , OR 3 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C(O)R 4 , C(O)NR 3 R 4 , or NR 3 R 4 , said aryl, heteroaryl, C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazin
  • aryl optionally substituted, said aryl, C 1 to C 10 alkylaryl, C 3 to C 7 cycloalkyl, heteroaryl, heterocycloalkyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), S(O) i NR 3 (C 1 to C 6 alkyl), C(O)OR 3 , C one of (O)R 3 , OR 3 , OCR 3 F 2 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C(O)R 4 , C(O)NR 3 R 4 and NR 3 R 4 .
  • sulfanyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, arylalkyl, C 3 to C 7 cycloalkyl, hetero aryl, heterocycloalkyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl) , S(O) i (aryl), S(O) i (heteroaryl), S(O) i NR 3 (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , with one or more groups independently selected from OR 3 , OCR 3 F 2 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C
  • i and j are each independently 0, 1 or 2
  • R 1 and R 2 are hydrogen, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , independently selected from the group consisting of C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 , said aryl, heteroaryl, heterocyclyl , C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl),
  • R 3 and R 4 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, hetero Aryl, Heteroaryl(C 1 ⁇ C 10 Alkyl), C 1 ⁇ C 10 Alkylheteroaryl, C 1 ⁇ C 10 Alkyl, C 2 ⁇ C 6 Alkenyl, C 2 ⁇ C 6 Alkynyl, C 3 ⁇ C 6 independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, heteroaryl, heteroaryl (C 1 to one of C 10 alkyl), C 1 to C 10 alkylheteroaryl, C 1 to C 10 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 al
  • R 3 and R 4 may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , optionally substituted with one or more groups independently selected from OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 ,
  • a 1 is It is represented by a structure selected from the group consisting of,
  • X 1 and X 2 are each independently selected from the group consisting of O, S, CHR 4 and NR 4 ,
  • J is N or CH
  • R 5 , R 6 and R 7 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C independently selected from the group consisting of 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 3 to C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl and trifluoromethyl, wherein one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C 1 to C 10 alkylaryl and heteroaryl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, tri Fluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C 1 to C
  • R 5 and A 1 may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is Oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 optionally substituted with one or more groups independently selected from , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 .
  • one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is
  • the present invention provides a compound represented by the following formula (2), its E- or Z- isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or a mixture of two isomers thereof to provide:
  • V 3 and V 4 are each independently aryl, heteroaryl, C 3 ⁇ C 7 cycloalkyl, heterocycloalkyl, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 heteroalkyl, C 2 ⁇ C 10 alkenyl, C 0 to C 3 methylenehydrazine, C 2 to C 10 alkynyl, S(O) i (C 1 to C 6 alkyl), OS(O) i (aryl), S(O) i NR 3 R 4 , C( O)R 3 , OR 3 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C(O)R 4 , C(O)NR 3 R 4 , or NR 3 R 4 , said aryl, heteroaryl , C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3
  • i is each independently 0, 1 or 2
  • R 3 and R 4 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, hetero Aryl, Heteroaryl(C 1 ⁇ C 10 Alkyl), C 1 ⁇ C 10 Alkylheteroaryl, C 1 ⁇ C 10 Alkyl, C 2 ⁇ C 6 Alkenyl, C 2 ⁇ C 6 Alkynyl, C 3 ⁇ C 6 independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, heteroaryl, heteroaryl (C 1 to one of C 10 alkyl), C 1 to C 10 alkylheteroaryl, C 1 to C 10 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 al
  • R 3 and R 4 may be cyclized together to cyclize (form a ring) to a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, said carbocyclic, heterocyclic,
  • One of the aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 optionally substituted with one or more groups independently selected from , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 ,
  • X 3 is hydrogen, OR 3 , aryl, heteroaryl, C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazine, C 2 to C 10 alkynyl, S(O) i (C 1 to C 6 alkyl), S(O) i NR 3 , C(O)R 3 , OC(O)R 3 , (O)COR 3 , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 and NR 3 R 4 , wherein OR 3 , aryl, heteroaryl , C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazin
  • i 0, 1 or 2
  • X 4 is O, S, NR 5 , NSO 2 R 5 , C 1 to C 6 alkyl, C 1 to C 6 alkoxy, aryl, arylalkyl, C 1 to C 10 alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR 5 , NSO 2 R 5 , C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, aryl, arylalkyl, C 1 ⁇ C 10 alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cyclo
  • R 5 to R 8 are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), S(O) i (aryl ), S(O) i (heteroaryl), S(O) i NR 3 R 4 , C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C( O) independently selected from the group consisting of NR 3 R 4 and NR 3 R 4 , said aryl, C 1 to C 10 alkylaryl, arylalkyl, cycloalkyl, heteroaryl, hetero
  • R 5 and A 2 may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , optionally substituted with one or more groups independently selected from OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 ,
  • I 0, 1 or 2.
  • the compound of Formula 2 is,
  • V 3 is C 1 to C 6 alkyl
  • V 4 is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl includes 1 to 3 heteroatoms selected from the group consisting of N, O and S;
  • X 3 is OR 3 ,
  • R 3 is H
  • R 8 may be H.
  • the compound of Formula 2 is,
  • V 3 is C 1 to C 4 alkyl
  • V 4 is pyrrole
  • X 3 is OH
  • R 8 may be H.
  • the invention in another aspect, relates to at least one of said compounds, at least one E- or Z-isomer thereof, at least one optical isomer thereof, at least one mixture of two isomers thereof, at least one precursor thereof, at least one thereof It provides a pharmaceutical composition for the prevention or treatment of respiratory diseases (inflammatory airway diseases) comprising a pharmaceutically acceptable salt or at least one solvate thereof as an active ingredient.
  • respiratory diseases inflammatory airway diseases
  • the composition can inhibit, prevent, ameliorate or treat a respiratory disease (inflammatory airway disease).
  • the present invention provides a composition comprising a compound represented by Formula 1 or 2 or a mixture thereof, and a composition comprising the compound represented by Formula 1 or 2 or a mixture thereof together with a pharmaceutically acceptable carrier .
  • the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof as a pendrine inhibitor.
  • the present invention provides a compound represented by Formula 1 or 2, and a pharmaceutical composition thereof, which specifically modulates a chloride channel.
  • the present invention provides a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which preserves the volume of airway surface liquid (ASL) and reduces the separation of mucin.
  • ASL airway surface liquid
  • the invention relates to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD).
  • asthma acute or chronic bronchitis
  • allergic rhinitis acute respiratory infection
  • acute upper respiratory tract infection acute upper respiratory tract infection
  • cystic fibrosis idiopathic pulmonary fibrosis
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • COPD chronic obstructive pulmonary disease
  • the present invention provides a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof for diuresis.
  • the present invention provides a compound represented by Formula 1 or 2, a mixture thereof, and the use of the pharmaceutical composition for prevention or improvement of diuresis as an active ingredient in a pharmaceutical composition.
  • the present invention provides a compound and the use of the dietary supplement as a pendrine inhibitor for the prevention or improvement of respiratory diseases (inflammatory airway disease) as an active ingredient in a dietary supplement.
  • the present invention provides a compound represented by Formula 1 or 2 and a health functional food, which specifically modulates chloride channels for the prevention or improvement of respiratory diseases (inflammatory airway disease) as an active ingredient in health functional foods to provide.
  • respiratory diseases inflammatory airway disease
  • the present invention relates to Formula 1, which preserves the volume of airway surface liquid (ASL) and reduces the separation of mucin for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in dietary supplements
  • Or 2 provides a compound and its health functional food.
  • the present invention provides a use for preventing or improving a respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food, wherein the respiratory disease (inflammatory airway disease) is asthma, acute or chronic bronchitis, allergic rhinitis , acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD).
  • a respiratory disease inflammatory airway disease
  • the respiratory disease is asthma, acute or chronic bronchitis, allergic rhinitis , acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD).
  • the present invention provides a compound represented by Formula 1 or 2, a mixture thereof, and the use of the health functional food for diuresis as an active ingredient in a health functional food.
  • the present invention provides a compound and its use as a fendrine inhibitor for diuresis as an active ingredient in nutraceuticals and nutraceuticals.
  • the present invention provides a method for preventing, improving or treating a respiratory disease by administering a compound represented by Formula 1 or 2 or a pharmaceutical composition thereof, a method for diuresis, or prevention of dysuria related diseases or hypertension and related diseases , improving or treating methods is provided.
  • the compound represented by Formula 1 or 2 according to the present invention is a pendrine inhibitor It is useful for the prevention, improvement or treatment of respiratory diseases, for example, inflammatory airway diseases, particularly asthma or acute lung injury, and can also be utilized as a diuretic.
  • respiratory diseases for example, inflammatory airway diseases, particularly asthma or acute lung injury, and can also be utilized as a diuretic.
  • 1 is a diagram showing the principle of cell-based high-throughput screening and the results of finding a pendrine inhibitor.
  • FIG. 2 is a graph confirming that the compounds F56, G23, G24 and G25 according to the present invention exhibit a dose-dependent Cl - /I - exchange inhibitory activity in WT-pendrin and CHO-K1 cells overexpressing iodide-sensitive YFP. am.
  • Figure 3 shows that the compounds F56, G23, G24 and G25 according to the present invention are high concentrations of Cl ⁇
  • Application of Cl ⁇ induces a decrease in intracellular pH through phendrine mediated Cl ⁇ /HCO 3 ⁇ exchange and results in a decrease in YFP fluorescence, resulting in a dose
  • FIG. 4 is a graph showing that compounds F56 and G23 according to the present invention dose-dependently inhibit phendrine-mediated Cl ⁇ /I ⁇ and Cl ⁇ /HCO 3 ⁇ exchange activity.
  • Figure 5 shows pendrine-mediated Cl - /I - , Cl - /SCN - , Cl-/HCO 3 - and Cl - /OH - exchange activity by F56 measured in CHO-K1-YFP cells expressing pendrine. It is a graph confirming the inhibitory effect.
  • FIG. 6 is a diagram showing the activity of inhibiting Cl-/HCO 3 -exchange by F56 in SLC26 isoform - transformed cells.
  • FIG. 7 shows that F56 dose-dependently inhibits mouse PDS (mPDS) mediated Cl ⁇ /I ⁇ exchange activity but does not alter CFTR and ANO1/TMEM16A Cl ⁇ channel activity.
  • mPDS mouse PDS
  • B As a result of measuring the effect of F56 on CFTR chloride channel activity in FRT cells expressing human wild-type CFTR, it is a graph showing that CFTR current was activated by 20 ⁇ M forskolin and inhibited by 10 ⁇ M CFTRinh-172.
  • Figure 8 shows the inhibition of endogenous phendrine-mediated Cl ⁇ /HCO 3 ⁇ exchange activity by F56 in primary culture of human nasal epithelial (HNE) cells.
  • HNE human nasal epithelial
  • FIG. 9 is a diagram showing the effect of F56-induced fendrine inhibition on airway hyper-responsiveness in an OVA-induced mouse model of allergic asthma.
  • FIG. 10 is a diagram showing the improvement of allergic airway inflammation by F56 in a mouse model of asthma.
  • C Photographs showing representative histological results of airways stained with hematoxylin and eosin. Scale bar: 100 ⁇ m.
  • FIG. 11 is a diagram showing the association of pendrine on mucin expression in airway epithelium.
  • A Goblet cell proliferation of IL-4 (10ng/ml)-treated HNE cells in the absence or presence of F56 (30 ⁇ M) was confirmed by periodic acid-Schiff (PAS) staining.
  • B A diagram showing the results of PAS staining of airway sections of vehicle-treated, OVA-sensitized/challenged and F56 (10 mg/kg)-treated OVA-sensitized/challenged mice.
  • 12 is a dosing schedule designed to confirm the protective effect of G7 before and after treatment in an LPS-induced acute lung injury model.
  • FIG. 13 is an LPS-induced acute lung injury model confirming the effect of suppressing the acute lung injury phenotype according to the treatment before and after G7
  • FIG. 13a is the average body weight of the mouse
  • FIG. 13b is the total number of BALF cells
  • FIG. 13c is the BALF cytospin staining result. is shown.
  • the term “about” is to be understood within the general tolerance of the art, eg, within two standard deviations of the mean, unless specifically stated or clear from context.
  • a drug may be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. there is. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • active agent refers to a desired pharmacological effect (eg, reduction of inflammation) when administered to a subject by any means described herein (eg, any animal, including a human or non-human animal). used interchangeably herein to refer to a chemical substance or compound that induces a decrease (such as reduction).
  • an excipient may be an excipient (eg, one or more excipients), an antioxidant (eg, one or more antioxidants), a stabilizer (eg, one or more stabilizing agents), preservatives (eg, one or more preservatives), pH adjusting and/or buffering agents (eg, one or more pH adjusting and/or buffering agents), tonicity adjusting agents (eg, one or more isotonicity adjusting agents), thickening agents (eg, one or more thickening agents), suspending agents (eg, one or more suspending agents), binders (eg, one or more binders), viscosity increasing agents (eg, one or more viscosity increasing agents), and the like.
  • an excipient may be an excipient (eg, one or more excipients), an antioxidant (eg, one or more antioxidants), a stabilizer (eg, one or more stabilizing agents), preservatives (eg, one or more preservatives), pH adjusting and/or
  • additives include calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, treatment and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as low melting waxes, ion exchange resins, and the like.
  • suitable pharmaceutically acceptable excipients may be appropriately selected from excipients well known in the art.
  • administration refers to administration to a subject as oral administration, suppository, topical contact intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, intravitreal or subcutaneous administration, or sustained release device. , for example, the implantation of a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (eg, oral, nasal, pulmonary, rectal, buccal, vaginal, ocular, and transdermal routes).
  • parenteral and transmucosal eg, oral, nasal, pulmonary, rectal, buccal, vaginal, ocular, and transdermal routes.
  • a derivative may differ from the parent compound in, for example, one or more substituents present on the core, which may include one or more atoms, functional groups or substructures.
  • the derivative may differ from the parent compound in the order of bonding between atoms in the core.
  • derivatives can be predicted to be formed from the parent compound, at least theoretically, through chemical and/or physical processes.
  • antioxidant may refer to an artificial or natural substance capable of preventing or delaying some types of cell damage and/or oxidation. Antioxidants are found in many foods, including fruits and vegetables. Also, they can be used as a dietary supplement. Exemplary antioxidants may include ⁇ -carotene, lutein, lycopene, selenium, vitamin A, vitamin C, and vitamin E. In addition, other antioxidants known to those skilled in the art may be used. The antioxidants described herein may be used in any suitable amount.
  • Co-administration means that a compound or composition described herein is administered simultaneously immediately before or immediately after administration of an additional treatment or active agent or excipient described herein.
  • a compound or composition of the present disclosure may be administered alone or co-administered to a patient.
  • Co-administration is construed to include the simultaneous or sequential administration of the compounds individually or in combination (one or more compounds or agents). If desired, the preparations may also be combined with other active substances.
  • “simultaneous administration” includes, at least in part, overlapping durations. For example, when two agents (eg, any agent or class of agents described herein having bioactivity) are administered simultaneously, their administration occurs within a certain desired time period. Administration of the formulation may start and end on the same day. In addition, administration of one agent may precede administration of a second agent as long as the two agents are taken at least once on the same day. Similarly, administration of one agent may be extended beyond administration of a second agent as long as both agents are taken at least once on the same day. The bioactive agent/agent need not be taken at the same time each day to include simultaneous administration.
  • an “effective amount” or “therapeutically effective amount” is an amount sufficient to effect a desired biological effect, such as beneficial outcome, including clinical outcome.
  • an “effective amount” depends on the circumstances in which it is applied.
  • An effective amount may vary depending on factors known in the art, such as the disease state, age, sex and weight of the individual being treated. Several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the urgency of the therapeutic situation.
  • the compositions/agents of the present disclosure may be administered as often as necessary to achieve a therapeutic amount.
  • gel may refer to a material that is not readily flowable liquid and is not a solid, ie, semi-solid. Gels can be formed from natural or synthetic materials. The gel is not aligned but slightly aligned, showing birefringence and liquid crystal properties. The gel may be administered topically.
  • the term "respiratory disease” has its conventional medical meaning and includes asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory tract infections, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD), and closely related diseases and disorders of the respiratory system.
  • asthma acute or chronic bronchitis
  • allergic rhinitis acute respiratory infections
  • acute upper respiratory tract infections cystic fibrosis
  • cystic fibrosis idiopathic pulmonary fibrosis
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • COPD chronic obstructive pulmonary disease
  • the term “inhibit” means to prevent, reduce, slow down or stop. In one embodiment, if the amount or rate of a process or reaction that occurs in the presence of the compound or composition is reduced by at least about 10%, compared to the amount or rate in the absence of the compound or composition, the composition or compound comprises at least one It is considered to inhibit the viability of proteins (eg, pendrins). In other embodiments, a composition or compound is a process or reaction if the amount or rate of a process or reaction that occurs in the presence of the compound or composition decreases by at least about 20%, as compared to the amount or rate in the absence of the compound or composition.
  • the amount or rate of inhibition that occurs in the presence of the compound or composition is at least about 25%, about 30%, about 40%, about 50%, about
  • a compound or composition is considered to inhibit one or more proteins (eg, pendrine) when reduced by 60%, about 70%, about 75%, or about 80%.
  • the compound or composition is considered to inhibit the viability of one or more proteins, ie, arrest their development.
  • intermittent dosing refers to a period of time during which an agent is administered (this may be considered a “first dosing period”) followed by a period during which no agent is ingested or at a lower dose (this is referred to as an "off-period”). may be considered), followed by a period during which the agent is re-administered, which may be referred to as a “second dosing period.”
  • the dosage level of the agent is adjusted for the first dosing period. It is consistent with that administered during the period, but may be increased or decreased as medically necessary.
  • a “jelly” according to the present disclosure is composed of a gel, which is a semi-solid system composed of a suspension consisting of either small inorganic particles or large organic molecules impregnated by a liquid containing a high fraction of a structurally cohesive matrix, usually water.
  • liquid is a dosage form consisting of a composition in a liquid state. Liquids can be spilled; It flows and behaves in a container at room temperature. Liquids exhibit Newtonian or pseudoplastic flow behavior.
  • “semi-liquid,” as used herein, can have the properties of both liquids and other formulations (ie, suspensions, emulsions, solutions, creams, gels, jellies, etc.). .
  • the term “ointment” may refer to a highly viscous liquid or semi-liquid formulation that may be used in the therapeutic treatment of a disease, syndrome or condition.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible.
  • the type of carrier can be selected based on the intended route of administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile topical solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • compositions for eg, a derivative or analog of Formula 1, a derivative or analog of Formula 1 described herein, or a pharmaceutically acceptable salt, solvent, hydrate or polymorph thereof.
  • any conventional medium or agent is incompatible with the composition (eg, a derivative or analog of Formula 1, a derivative or analog of Formula 1 described herein, or a pharmaceutically acceptable salt, solvent, hydrate or polymorph thereof), the present disclosure Its use in compositions for
  • pharmaceutical carrier may further comprise a pharmaceutically acceptable carrier, excipient or stabilizer that is not toxic to cells or mammals at the dosages and concentrations employed.
  • Physiologically acceptable carriers are often aqueous pH buffered solutions.
  • physiologically acceptable carriers include buffers such as phosphate, citrate and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween TM , polyethylene glycol (PEG) and Pluronics TM .
  • buffers such as phosphate, citrate and other organic acids
  • antioxidants including ascorbic acid
  • low molecular weight (less than about 10 residues) polypeptides proteins such as serum albumin,
  • 'pharmaceutically acceptable means a federal or state regulatory agency or may be approved or may be approved by such agency in a country other than the United States, or may be used in animals, and more particularly in humans, in the United States Pharmacopoeia or other generally means listed in a recognized pharmacopeia.
  • salt or complex refers to a salt or complex of a compound represented by Formula 1 specified below.
  • examples of such salts are organic or inorganic such as hydroxides, carbonates or bicarbonates of metal cations such as those selected from the group consisting of alkali metals (eg sodium, potassium or lithium) and alkaline earth metals (eg calcium or magnesium).
  • salt or “salt form” or “pharmaceutically acceptable salt” refers to an inorganic base such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxide and, for example, base addition salts (formed with free carboxyl or other anionic groups) derived from organic bases such as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like.
  • salts are formed as acid addition salts with any free cationic group, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with, for example, acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid , is generally formed with organic acids such as organic acids such as mandelic acid and the like.
  • Salts of the present disclosure may include amine salts formed by protonation of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the present disclosure also include amine salts formed by protonation of an amino group with a suitable organic acid such as p-toluenesulfonic acid, acetic acid, and the like.
  • pH agent may refer to a compound or buffer useful as a pH adjusting agent. These may include, but are not limited to, glycerol buffers, citrate buffers, borate buffers, acetate buffers, gluconate buffers, phosphate buffers or citric acid-phosphate buffers. A pH agent or buffer may be used in any suitable amount.
  • preservative may refer to a substance or chemical that prevents undesirable chemical changes in a compound or composition or formula as described herein. Suitable preservatives are, for example, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium sorbic acid, Onamer M polyquat, cetyl bromide, cetyl pyridinium chloride, benzyl Bromide, EDTA, phenylmercury nitrate, phenylmercuric acetate, thimerosal, merthiolate, acetate and phenylmercuric borate, polymyxin B sulfate, methyl and propyl parabens, quaternary ammonium chloride, sodium benzoate, sodium propionate and sodium perborate, and other agents known to those skilled in the art, or combinations thereof.
  • the terms “prevent,” “preventing,” or “prevention,” and other grammatical equivalents are intended to reduce the incidence of a syndrome, as well as prevent the development, occurrence, disturbance or avoidance of a disease or condition syndrome.
  • Prevention can be complete (ie, no detectable symptoms) or partial, so that fewer symptoms can be observed than in the absence of treatment.
  • the term further includes prophylactic benefit.
  • the composition may be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological syndromes of the disease, although not being diagnosed with the disease.
  • Ranges provided herein are understood to be shorthand for all values within the range.
  • a range from 1 to 10 includes all intermediate decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and 1.9, as well as 1, 2, 3 , 4, 5, 6, 7, 8, 9 or 10 is understood to include any number, combination of numbers, or subranges.
  • “nested subranges” extending from one of the endpoints of the range are particularly contemplated.
  • overlapping subranges of an example range of 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 50 in the other direction.
  • Ranges may be expressed herein as “about” one particular value and/or “about” another particular value. When such ranges are expressed, other aspects include the one particular value and/or the other particular value. Similarly, when values are expressed as approximations using the antecedent "about,” it is understood that the particular value forms another aspect. It is further understood that the endpoints of each range are important with respect to and independently of the other endpoints. Also, it is understood that there are a number of values disclosed herein, and that each value is also disclosed herein as “about” that particular value in addition to the value itself. Also, throughout applications, it is understood that data is presented in a number of different formats, and that such data represents endpoints and starting points and ranges for any combination of data points.
  • Additional excipients contemplated for use in the practice of the present disclosure may include, without limitation, known excipients available to those skilled in the art.
  • a “semi-solid gel” according to the present disclosure is a semi-solid.
  • the apparent viscosity of a semi-solid formulation may increase with concentration.
  • sequential administration means that administration of two agents (eg, a compound or composition described herein) occurs separately on the same day or does not occur on the same day (eg, occurs on consecutive days) ) is included.
  • a “solution” according to the present disclosure may be a clear, homogeneous liquid dosage form containing one or more chemical substances dissolved in a solvent or mixture of solvents that are miscible with one another.
  • Solutions are liquid formulations containing one or more dissolved chemicals in a suitable solvent or mixture of solvents that are miscible with one another. Because the molecules of the drug substance in solution are uniformly dispersed, the use of the solution as a dosage form generally provides assurance of a uniform dosage upon administration and good accuracy when the solution is diluted or otherwise mixed.
  • solvent refers to a liquid solvent that is aqueous or non-aqueous.
  • Aqueous solvents may consist solely of water, or they may consist of water and one or more miscible solvents, and may contain dissolved solutes such as sugars, buffers, salts or other excipients.
  • More commonly used non-aqueous solvents are short-chain organic alcohols such as methanol, ethanol, propanol, short-chain ketones such as acetone, and polyalcohols such as glycerol.
  • Subject or “patient” means a human or non-human animal, such as a mammal.
  • a “subject” may include any animal, including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish and birds.
  • a human subject may refer to a patient.
  • a “suspension” is a liquid dosage form containing solid particles dispersed in a liquid vehicle.
  • viscosity refers to the flow resistance of a fluid. Viscous agents can be used herein, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, known to those skilled in the art. other agents, or combinations thereof.
  • weight percentage refers to the percentage of a component in a solution calculated based on the weight of the component and solvent. For example, a 1% (w/w) solution of a component would have 1 g of component dissolved in 100 g of solvent.
  • volume percentage refers to the percentage of a component in a solution calculated based on the volume of the component and solvent. For example, a 1% (v/v) solution of a component will have 1 ml of the component dissolved in 100 ml of solvent.
  • weight/volume percentage refers to the percentage of a component in a solution calculated based on the weight of the component and the volume of solvent. For example, a 1.0% (w/v) solution of a component would have 1 g of component dissolved in 100 ml of solvent.
  • the term “syndrome” refers to a condition characterized by a group or series of related symptoms that occur continuously together.
  • a syndrome eg, acute respiratory distress syndrome
  • a disease may be a health condition with a clearly defined reason behind it.
  • the syndrome from the Greek meaning 'to run together'
  • the terms “treat,” “treating,” or “treatment,” and other grammatical equivalents refer to alleviation, alleviation, amelioration, or prevention of a disease, condition (eg, acute respiratory distress syndrome) or symptom, or treatment of an additional symptom.
  • prevention, amelioration or prophylaxis of the underlying metabolic cause of a symptom, inhibition of a disease or condition such as arresting the development of the disease or condition, alleviation of the disease or condition, regression of the disease or condition, alleviation of the condition caused by the disease or condition; or cessation of symptoms of a disease or condition, and is intended to include prevention.
  • the term further includes achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Further, since a therapeutic benefit is achieved in eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disorder.
  • bitterraceuticals refers to foods or food supplements manufactured or processed with raw materials, functional ingredients, active pharmaceutical ingredients or additives useful for improving and/or nutrition and/or preservation of physiological functions of the human body.
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • airway surface liquid refers to a thin layer of fluid that coats the apical surface of the airway epithelium at the air interface.
  • ASL plays a pivotal role in maintaining airway homeostasis.
  • ASL volume, pH and ionic balance are directly involved in the regulation of antimicrobial activity, ciliary function and mucosal clearance.
  • inflammatory airway disease refers to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI). ), chronic obstructive pulmonary disease (COPD), and other inflammatory airway disorders.
  • IPF idiopathic pulmonary fibrosis
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • COPD chronic obstructive pulmonary disease
  • inhibitor as used in the context of the present invention is defined as a molecule, two or more molecules or a pharmaceutical composition that completely or partially inhibits the activity of a target or two or more targets that induce a desired biological effect.
  • targets include enzymes, receptors, ion-channels or transporters (eg, pendrins), and the like.
  • An “inhibitor” is capable of reversibly or irreversibly inhibiting a target, and reversible inhibition includes competitive inhibition, uncompetitive inhibition, non-competitive inhibition, and mixed inhibition.
  • alkyl includes straight-chain or branched C 1 -C 20 alkyl, when used alone or in combination with other terms, refers to a monovalent alkyl group having from 1 to 20 carbon atoms. These terms include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethyl propyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydroger
  • they include C 1 -C 9 alkyl, more preferably C 1 -C 6 alkyl, particularly preferably C 1 -C 4 alkyl, which likewise include monovalent alkyl groups having 1 to 9 carbon atoms; a monovalent alkyl group having 1 to 6 carbon atoms and a monovalent alkyl group having 1 to 4 carbon atoms, respectively.
  • alkenyl when used alone or in combination with other terms, includes straight-chain or branched C 2 -C 20 alkenyl. It can have any available number of double bonds at any available position, and the configuration of the double bond can be either the (E) or (Z) configuration.
  • they include C 2 -C 8 alkenyl, more preferably C 2 -C 6 alkenyl.
  • alkynyl when used alone or in combination with other terms, includes straight-chain or branched C 2 -C 20 alkynyl. It may have any available number of triple bonds in any available position. This term includes 2 to 20 carbon atoms and any It is exemplified by the group such as alkynyl group which may have double bond or triple bond.In particular, they include C 2 -C 8 alkynyl, more preferably C 2 -C 6 alkynyl etc. Preferably 2 to 6 carbons C 2 -C 6 alkynyl, which has an atom and refers to a group having alkynyl unsaturation in at least one or two positions.
  • heteroalkyl refers to C 1 -C 12 -alkyl, preferably C 1 -C 6 -alkyl, wherein at least one carbon is a hetero selected from O, N or S, including 2-methoxyethyl and the like. replaced by atoms.
  • aryl refers to a single ring (eg, phenyl) or multiple condensed rings (eg, indenyl, naphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthyl). refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having Aryl includes phenyl, naphthyl, anthryl, phenanthrenyl and the like.
  • C 1 -C 6 alkyl aryl refers to aryl groups having C 1 -C 6 alkyl substituents including methyl phenyl, ethyl phenyl, t-butyl phenyl, and the like.
  • aryl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an aryl substituent including 3-phenylpropanyl, benzyl, and the like.
  • heteroaryl refers to a monocyclic heteroaromatic, or bicyclic or tricyclic fused-ring heteroaromatic group. Specific examples of heteroaromatic groups are optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1H-pyrazolyl , 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzo Triazolyl
  • C 1 -C 6 alkyl heteroaryl refers to heteroaryl groups having C 1 -C 6 alkyl substituents including methyl furyl, t-butyl furyl, and the like.
  • heteroaryl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having a heteroaryl substituent including furyl methyl and the like.
  • C 2 -C 6 alkenyl aryl refers to an aryl group having a C 2 -C 6 alkenyl substituent, including vinyl phenyl and the like.
  • aryl C 2 -C 6 alkenyl refers to a C 2 -C 6 alkenyl group having an aryl substituent including phenyl vinyl and the like.
  • C 2 -C 6 alkenyl heteroaryl refers to a heteroaryl group having a C 2 -C 6 alkenyl substituent, including vinyl pyridinyl and the like.
  • heteroaryl C 2 -C 6 alkenyl refers to a C 1 -C 6 alkenyl group having a heteroaryl substituent including pyridinyl vinyl and the like.
  • C 3 -C 8 -cycloalkyl refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (eg cyclohexyl) or multiple condensed rings (eg norbornyl).
  • C 3 -C 8 -cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl refers to C 3 -C 8 -cycloalkyl according to the definition above, wherein up to 3 carbon atoms are replaced with a heteroatom selected from the group consisting of O, S and NR (wherein R is defined as hydrogen or methyl) or Refers to multiple condensed rings.
  • Heterocycloalkyl includes lactams or lactones.
  • Non-limiting examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, decahydroisoquinolinyl, octahydro-1H-pyrano[3,4-c]pyridinyl, 4-methylene-5(4H)-one, pyrrolidin-2-one, and the like.
  • C 1 -C 6 alkyl C 3 -C 8 cycloalkyl refers to a C 3 -C 8 cycloalkyl group having a C 1 -C 6 alkyl substituent including methyl cyclopentyl and the like.
  • C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having C 3 -C 8 -cycloalkyl substituents including 3-cyclopentyl propyl and the like.
  • C 1 -C 6 alkyl heterocycloalkyl refers to a heterocycloalkyl group having a C 1 -C 6 alkyl substituent including 4-methylpiperidinyl and the like.
  • heterocycloalkyl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having a heterocycloalkyl substituent including (1-methylpiperidin-4-yl)methyl and the like.
  • carboxy C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having a carboxy substituent including 2-carboxyethyl and the like.
  • acyl refers to the group —C(O)R, including acetyl and the like, where R is H, “alkyl” preferably “C 1 -C 6 alkyl” “aryl” “heteroaryl” “C 3 —C 8 cycloalkyl” “heterocycloalkyl” “aryl C 1 -C 6 alkyl” “heteroaryl C 1 -C 6 alkyl” “C 3 -C 8 cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl C 1 -C 6 alkyl”.
  • acyl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an acyl substituent including 2-acetylethyl and the like.
  • acyl aryl refers to an aryl group having an acyl substituent including 2-acetylphenyl and the like.
  • acyloxy refers to the group -OC(O)R, including acetyloxy and the like, wherein R is H, "C 1 -C 6 alkyl”, “C 2 -C 6 alkenyl”"C 2 - C 6 alkynyl” “C 3 -C 8 -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “C 3 -C 8 -cycloalkyl C 1 —C 6 alkyl” or “heterocycloalkyl C 1 -C 6 alkyl”.
  • acyloxy C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an acyloxy substituent including 2-(ethylcarbonyloxy)ethyl and the like.
  • alkoxy refers to the group —OR, wherein R is “C 1 -C 6 alkyl”, “aryl”, “heteroaryl”, “aryl C 1 -C 6 alkyl” or “heteroaryl C 1 -C 6 alkyl”.
  • Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, and the like.
  • alkoxy C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an alkoxy substituent, including methoxyethyl and the like.
  • alkoxycarbonyl refers to the group —C(O)OR, wherein R is “C 1 -C 6 alkyl”, “aryl”, “heteroaryl”, “aryl C 1 -C 6 alkyl”, “ heteroaryl C 1 -C 6 alkyl” or “heteroalkyl”.
  • alkoxycarbonyl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an alkoxycarbonyl substituent including 2-(benzyloxycarbonyl)ethyl and the like.
  • aminocarbonyl refers to the group —C(O)NRR′, including N-phenyl carbonyl and the like, wherein R and R′ are independently H, C 1 -C 6 alkyl, aryl, heteroaryl, “aryl C 1 -C 6 alkyl” or “heteroaryl C 1 -C 6 alkyl”.
  • aminocarbonyl C 1 -C 6 alkyl has aminocarbonyl substituents including 2-(dimethylaminocarbonyl)ethyl, N-ethyl acetamidyl, N,N-diethyl-acetamidyl, and the like. refers to an alkyl group.
  • acylamino refers to the group —NRC(O)R′, including acetylamino and the like, wherein R and R′ are independently H, “C 1 -C 6 alkyl” “C 2 -C 6 alkenyl.
  • acylamino C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an acylamino substituent including 2-(propionylamino)ethyl and the like.
  • ureido refers to the group -NRC(O)NR'R'', wherein R, R' and R'' are independently H, "C 1 -C 6 alkyl”"alkenyl” “alkynyl” “C 3 -C 8 cycloalkyl” “heterocycloalkyl” “C 1 -C 6 aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “Aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl C 1 -C 6 alkyl” wherein R′ and R′′ together with the nitrogen atom to which they are attached may optional
  • ureido C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having a ureido substituent including 2-(N′-methylureido)ethyl and the like.
  • carbamate refers to the group —NRC(O)OR′, wherein R and R′ are independently “C 1 -C 6 alkyl” “C 2 -C 6 alkenyl” “C 2 -C 6 alkyl” nyl” “C 3 -C 8 -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “C 1 -C 6 alkyl aryl”, “heteroaryl C 1 -C 6 alkyl” “aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “cycloalkyl C 1 -C 6 alkyl” or “heterocyclo alkyl C 1 -C 6 alkyl”, and R may be hydrogen.
  • amino refers to the group -NRR', wherein R and R' are independently H, "C 1 -C 6 alkyl", “aryl”, “heteroaryl”, “C 1 -C 6 alkyl aryl” , “C 1 -C 6 alkyl heteroaryl”"cycloalkyl” or “heterocycloalkyl”, wherein R and R' together with the nitrogen atom to which they are attached, optionally form a 3-8 membered heterocycloalkyl ring can be formed
  • amino alkyl refers to an alkyl group having an amino substituent including 2-(1-pyrrolidinyl)ethyl and the like.
  • ammonium refers to the positively charged group -N + RR'R'', wherein R, R' and R'' are independently "C 1 -C 6 alkyl", “C 1 -C 6 alkyl. aryl”, “C 1 -C 6 alkyl heteroaryl” “cycloalkyl” or “heterocycloalkyl”, wherein R and R′ together with the nitrogen atom to which they are attached, are a 3-8 membered heterocycloalkyl ring can be formed arbitrarily.
  • ammonium alkyl refers to an alkyl group having an ammonium substituent including 1-ethylpyrrolidinium and the like.
  • halogen refers to fluoro, chloro, bromo and iodine atoms.
  • sulfonyloxy refers to the group —OSO 2 R, where R is a “C 1 -C 6 alkyl” substituted with a “C 1 -C 6 alkyl” halogen, such as the group —OSO 2 CF 3 , “ C 2 -C 6 alkenyl” “alkynyl” “C 3 -C 8 cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl alkyl”.
  • sulfonyloxy C 1 -C 6 alkyl refers to an alkyl group having a sulfonyloxy substituent including 2-(methylsulfonyloxy)ethyl and the like.
  • sulfonyl refers to the group “—SO 2 R”, wherein R is “C 1 -C 6 alkyl” substituted with “aryl” “heteroaryl” “C 1 -C 6 alkyl” halogen, such as, —SO 2 CF 3 group, “C 2 -C 6 alkenyl” “C 2 -C 6 alkynyl” “C 3 -C 8 cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl", "heteroaryl C 1 -C 6 alkyl”"aryl C 2 -C 6 alkenyl""heteroaryl C 2 -C 6 alkenyl""aryl C 2 -C 6 alkynyl”"heteroaryl C 2 -C 6 alkynyl” “cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl C
  • sulfonyl C 1 -C 6 alkyl refers to an alkyl group having a sulfonyl substituent including 2-(methylsulfonyl)ethyl and the like.
  • sulfinyl refers to the group “—S(O)R”, where R is “alkyl” substituted with an “alkyl” halogen, such as a —SOCF 3 group, “C 2 -C 6 al kenyl” “C 2 -C 6 alkynyl” “C 3 -C 8 cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl C 1 -C 6 alkyl”.
  • sulfinyl alkyl refers to an alkyl group having a sulfinyl substituent including 2-(methylsulfinyl)ethyl and the like.
  • sulfanyl refers to the group -SR, wherein R is H, "C 1 -C 6 alkyl", “C 1 -C 6 alkyl” substituted by halogen, eg, -SCF 3 group, “C 2 -C 6 alkenyl” “C 2 -C 6 alkynyl” “C 3 -C 8 -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “alkynylheteroaryl” “cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl C 1 -C 6 alkyl.”
  • R is H, "C 1
  • sulfanyl C 1 -C 6 alkyl refers to a C 1 -C 5 -alkyl group having a sulfanyl substituent including 2-(ethylsulfanyl)ethyl and the like.
  • sulfonylamino refers to the group —NRSO 2 R′, wherein R and R′ are independently “C 1 -C 6 alkyl” “C 2 -C 6 alkenyl” “C 2 -C 6 alkynyl.
  • C 3 -C 8 -cycloalkyl “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “aryl C 2 -C 6 alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “C 3 -C 8 cycloalkyl C 1 -C 6 alkyl” or “heterocycloalkyl C 1 -C 6 alkyl.”
  • sulfonylamino C 1 -C 6 alkyl refers to an alkyl group having a sulfonylamino substituent including 2-(ethylsulfonylamino)ethyl and the like.
  • aminosulfonyl refers to the group -SO 2 NRR', wherein R and R' are independently H, "C 1 -C 6 alkyl”"C 2 -C 6 alkenyl""C 2 -C 6 alkynyl” “C 3 -C 8 -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C 1 -C 6 alkyl”, “heteroaryl C 1 -C 6 alkyl” “aryl alkenyl” “heteroaryl C 2 -C 6 alkenyl” “aryl C 2 -C 6 alkynyl” “heteroaryl C 2 -C 6 alkynyl” “C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl” or “ heterocycloalkyl C 1 -C 6 alkyl", wherein R and R' together with the nitrogen atom to which they are attached may optionally
  • aminosulfonyl C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl group having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like.
  • substituted means “C 1 -C 6 alkyl”, “C 2 -C 6 alkenyl”, “C 2 -C 6 alkynyl”, “C 3 -C 8 cycloalkyl”, “heterocycloalkyl”, “C 1 -C 6 alkyl aryl”, “C 1 -C 6 alkyl heteroaryl”, “C 1 -C 6 alkyl cycloalkyl”, “C 1 -C 6 alkyl heterocycloalkyl”, “amino”, “aminosulfonyl”, “ammonium”, “acyl amino”, “amino carbonyl”, “aryl”, “heteroaryl”, “sulfinyl”, “sulfonyl” 1 to 5 selected from the group consisting of , “alkoxy”, “alkoxy carbonyl”, “carbamate”, “sulfanyl”, “halogen”, trihalomethyl, cyano,
  • One aspect of the present invention provides a compound represented by the following formula (1) or (2), its E- or Z- isomer, its optical isomer, its two isomer mixture, its precursor, its pharmaceutically acceptable salt or its solvate do:
  • One aspect of the present invention provides a compound represented by the following formula (1), its E- or Z- isomer, its optical isomer, a mixture of two isomers, a precursor thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
  • V 1 and V 2 are each independently Aryl, heteroaryl, C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazine, C 2 to C 10 alkynyl, S(O) i (C 1 to C 6 alkyl), OS(O) i (aryl), S(O) i NR 3 R 4 , C(O)R 3 , OR 3 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C(O)R 4 , C(O)NR 3 R 4 , or NR 3 R 4 , said aryl, heteroaryl, C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazin
  • aryl optionally substituted, said aryl, C 1 to C 10 alkylaryl, C 3 to C 7 cycloalkyl, heteroaryl, heterocycloalkyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), S(O) i NR 3 (C 1 to C 6 alkyl), C(O)OR 3 , C one of (O)R 3 , OR 3 , OCR 3 F 2 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C(O)R 4 , C(O)NR 3 R 4 and NR 3 R 4 .
  • sulfanyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, arylalkyl, C 3 to C 7 cycloalkyl, hetero aryl, heterocycloalkyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl) , S(O) i (aryl), S(O) i (heteroaryl), S(O) i NR 3 (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , with one or more groups independently selected from OR 3 , OCR 3 F 2 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C
  • i and j are each independently 0, 1 or 2
  • R 1 and R 2 are hydrogen, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , independently selected from the group consisting of C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 , said aryl, heteroaryl, heterocyclyl , C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl),
  • R 3 and R 4 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, hetero Aryl, Heteroaryl(C 1 ⁇ C 10 Alkyl), C 1 ⁇ C 10 Alkylheteroaryl, C 1 ⁇ C 10 Alkyl, C 2 ⁇ C 6 Alkenyl, C 2 ⁇ C 6 Alkynyl, C 3 ⁇ C 6 independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, heteroaryl, heteroaryl (C 1 to one of C 10 alkyl), C 1 to C 10 alkylheteroaryl, C 1 to C 10 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 al
  • R 3 and R 4 may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , optionally substituted with one or more groups independently selected from OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 ,
  • a 1 is It is represented by a structure selected from the group consisting of,
  • X 1 and X 2 are each independently selected from the group consisting of O, S, CHR 4 and NR 4 ,
  • J is N or CH
  • R 5 , R 6 and R 7 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C independently selected from the group consisting of 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 3 to C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl and trifluoromethyl, wherein one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C 1 to C 10 alkylaryl and heteroaryl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, tri Fluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C 1 to C
  • R 5 and A 1 may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is Oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 optionally substituted with one or more groups independently selected from , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 .
  • one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is
  • V 3 and V 4 are each independently aryl, heteroaryl, C 3 ⁇ C 7 cycloalkyl, heterocycloalkyl, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 heteroalkyl, C 2 ⁇ C 10 alkenyl, C 0 to C 3 methylenehydrazine, C 2 to C 10 alkynyl, S(O) i (C 1 to C 6 alkyl), OS(O) i (aryl), S(O) i NR 3 R 4 , C( O)R 3 , OR 3 , OCOR 3 , NR 3 C(O)OR 4 , NR 3 C(O)R 4 , C(O)NR 3 R 4 , or NR 3 R 4 , said aryl, heteroaryl , C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3
  • i is each independently 0, 1 or 2
  • R 3 and R 4 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, hetero Aryl, Heteroaryl(C 1 ⁇ C 10 Alkyl), C 1 ⁇ C 10 Alkylheteroaryl, C 1 ⁇ C 10 Alkyl, C 2 ⁇ C 6 Alkenyl, C 2 ⁇ C 6 Alkynyl, C 3 ⁇ C 6 independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, heteroaryl, heteroaryl (C 1 to one of C 10 alkyl), C 1 to C 10 alkylheteroaryl, C 1 to C 10 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 al
  • R 3 and R 4 together may form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo , halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , optionally substituted with one or more groups independently selected from NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 ,
  • X 3 is hydrogen, OR 3 , aryl, heteroaryl, C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazine, C 2 to C 10 alkynyl, S(O) i (C 1 to C 6 alkyl), S(O) i NR 3 , C(O)R 3 , OC(O)R 3 , (O)COR 3 , NR 3 C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 and NR 3 R 4 , wherein OR 3 , aryl, heteroaryl , C 3 to C 7 cycloalkyl, heterocycloalkyl, C 1 to C 6 alkyl, C 1 to C 6 heteroalkyl, C 2 to C 10 alkenyl, C 0 to C 3 methylenehydrazin
  • i 0, 1 or 2
  • X 4 is O, S, NR 5 , NSO 2 R 5 , C 1 to C 6 alkyl, C 1 to C 6 alkoxy, aryl, arylalkyl, C 1 to C 10 alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR 5 , NSO 2 R 5 , C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, aryl, arylalkyl, C 1 ⁇ C 10 alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cyclo
  • R 5 to R 8 are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), S(O) i (aryl ), S(O) i (heteroaryl), S(O) i NR 3 R 4 , C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C( O) independently selected from the group consisting of NR 3 R 4 and NR 3 R 4 , said aryl, C 1 to C 10 alkylaryl, arylalkyl, cycloalkyl, heteroaryl, hetero
  • R 5 and A 2 may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C 1 to C 10 alkylaryl, heteroaryl, heterocyclyl, C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, C 3 to C 6 cycloalkyl, S(O) i (C 1 to C 6 alkyl), C(O)OR 3 , C(O)R 3 , optionally substituted with one or more groups independently selected from OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 ,
  • I 0, 1 or 2.
  • Non-limiting examples of the compound according to Formula 1 or 2 include the following compounds shown in Tables 1 and 2.
  • the term 'compound of the present invention' and equivalent expressions include compounds represented by Formula 1 or 2 described above, and these expressions include its E- or Z-isomer, its optical isomer, and a mixture of two isomers thereof. , a precursor thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, and is newly synthesized.
  • the compounds represented by Formula 1 or 2 are any one selected from the group consisting of the following compounds:
  • the compound of Formula 1 or 2 according to the present invention may be each of the following specific compounds.
  • Another aspect of the present invention provides a method for preparing a compound represented by Formula 1 or 2.
  • the synthesis method is well described in the detailed examples set out herein.
  • a base may be an organic or inorganic base.
  • organic bases include pyridine, trimethylamine, N,N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo[5.4.0]unde-7-ene (DBU).
  • DIPEA N,N-diisopropylethylamine
  • DBU 1,8-diazabicyclo[5.4.0]unde-7-ene
  • inorganic bases include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. They may be used alone or in combination in stoichiometric or excess.
  • Non-limiting examples of solvents that may be used include ethers (such as tetrahydrofuran (THF), diethyl ether and 1,2-dimethoxyethane), alcohols (such as methanol, ethanol, propanol and butanol), dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, and acetone. These solvents may be used alone or in combination.
  • ethers such as tetrahydrofuran (THF), diethyl ether and 1,2-dimethoxyethane
  • alcohols such as methanol, ethanol, propanol and butanol
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • DCM dichloromethane
  • dichloroethane water
  • acetone acetone
  • the present invention includes pharmaceutical compositions comprising a compound as described herein and a formulation suitable for administration of a compound as described herein.
  • Formulations of pharmaceutical compositions suitable for administration by any medically acceptable means are encompassed by the present invention.
  • the pharmaceutical formulation may contain a pharmaceutically acceptable excipient or carrier suitable for the means of administration and a pharmaceutically acceptable compound (composition).
  • the compounds described herein can be used as excipients (eg, one or more excipients), antioxidants (eg, one or more antioxidants), stabilizers (eg, one or more stabilizers), preservatives (eg, one or more preservatives), pH control and/or Buffers (eg, one or more pH adjusting and/or buffering agents), tonicity adjusting agents (eg one or more tonicity adjusting agents), thickening agents (eg one or more thickening agents), suspending agents (eg, one or more suspending agents), binders (such as , one or more binders), viscosity increasing agents (eg, one or more viscosity increasing agents), etc., provided as additional ingredients that are pharmaceutically acceptable for the particular condition being treated.
  • excipients eg, one or more excipients
  • antioxidants eg, one or more antioxidants
  • stabilizers eg, one or more stabilizers
  • preservatives eg, one or more preserv
  • the formulation may include a combination of additional ingredients as described herein (eg, 2, 3, 4, 5, 6, 7, 8 or more additional ingredients).
  • the additive is, for example, calcium phosphate, magnesium stearate, talc, monosaccharide, disaccharide, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-beta-cyclo treatment and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as dextrins, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like.
  • compositions described herein may include inhalation, nasal spray, intravenous, intramuscular injection, intravitreal injection, as an ointment or solution; It may be suitable for oral administration which may consist of suspensions, semi-liquids, semi-solids, gels, semi-solid gels, jellies, emulsions, ointments, tablets, liquids and creams.
  • Tablet forms include lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid and other excipients, colorants, fillers, binders, diluents , buffers, humectants, preservatives, flavoring agents, dyes, disintegrants and pharmaceutically suitable carriers.
  • the capsule may contain suitable excipients with the compound or the compound may be used alone in the shell. All of these formulated compounds may be administered alone, co-administered, intermittently, sequentially or simultaneously.
  • compositions of the present invention include those that can be administered in any manner of oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, via inhalation, buccal or intranasal administration, or combinations thereof, not limited
  • Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intraarterial.
  • the compositions of the present invention may be administered as an implant, which allows for slow, controlled intravenous administration as well as slow release of the composition.
  • the dose administered to an individual in single or multiple doses will depend on a variety of factors, including pharmacokinetic characteristics, patient condition and characteristics (sex, age, weight, health, size), severity of symptoms, concurrent treatment, frequency of treatment, and desired effect. so it will vary.
  • the compound according to the present invention and a pharmaceutical formulation thereof may be administered alone or together with an adjuvant useful for the treatment of respiratory disorders or diseases.
  • the compound according to the present invention and a pharmaceutical formulation thereof may be administered together with radiation therapy.
  • the present invention includes administration of a compound according to the present invention or a pharmaceutical formulation thereof, wherein the compound according to the present invention or a pharmaceutical formulation thereof is administered in a therapeutically effective amount to another therapeutic regimen or adjuvant useful for the treatment of cancer (e.g., multiple drug therapy), either simultaneously or sequentially, to the subject.
  • a compound according to the present invention or a pharmaceutical formulation thereof administered simultaneously with the adjuvant may be administered in the same or different composition(s) and by the same or different route(s) of administration.
  • the patient according to the present invention has bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary viral infection (influenza), pulmonary hypertension, idiopathic pulmonary fibrosis and chronic Patients suffering from a respiratory disorder or disease such as obstructive pulmonary disease (COPD) and the like.
  • a respiratory disorder or disease such as obstructive pulmonary disease (COPD) and the like.
  • COPD obstructive pulmonary disease
  • the compound according to the present invention and a pharmaceutical formulation thereof may be administered alone or in combination with one or more other diuretics.
  • the diuretic is furosemide, torasemide (torasemide), bumetanide (bumetanide), etacrynic acid (etacrynic acid), azosemide (azosemide), muzolimine (muzolimine), pyretanide (piretanide), Tripamide, bendroflumethazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methychlothiazide , polythiazide, trichlormethiazide, chlorthialidone, indapamide, metolazone, quinethazone, etozolin , triamteren (triamteren), amiloride (amiloride) and may be selected from the group consisting of pharmaceutically acceptable derivatives thereof, but is not limited thereto.
  • the compound according to the present invention or a pharmaceutical formulation thereof is administered together with furosemide, and may be administered at an appropriate ratio in consideration of the toxicity of each drug.
  • the compound or a pharmaceutical formulation thereof and furosemide may be administered in a weight ratio of about 1:10, but is not limited thereto.
  • the present invention provides the use of a compound represented by Formula 1 or 2, a mixture of compounds, or a pharmaceutical composition thereof for the prevention, improvement or treatment of a respiratory disease (inflammatory airway disease).
  • a respiratory disease inflammatory airway disease
  • the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof as a pendrine inhibitor.
  • the present invention relates to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD) and the like.
  • asthma acute or chronic bronchitis
  • allergic rhinitis acute respiratory infection
  • acute upper respiratory tract infection cystic fibrosis
  • cystic fibrosis idiopathic pulmonary fibrosis
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • COPD chronic obstructive pulmonary disease
  • the present invention provides the use of a compound, a mixture of compounds, or a pharmaceutical composition thereof for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in a health functional food.
  • respiratory diseases inflammatory airway diseases
  • the present invention provides the use of the compound represented by Formula 1 and a pharmaceutical composition thereof as a pendrine inhibitor for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in health functional foods.
  • respiratory diseases inflammatory airway diseases
  • the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which as an active ingredient in a health functional food, a chloride channel for the prevention or improvement of respiratory diseases (inflammatory airway diseases) specifically regulated.
  • a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which as an active ingredient in a health functional food, a chloride channel for the prevention or improvement of respiratory diseases (inflammatory airway diseases) specifically regulated.
  • the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which is an airway surface liquid for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in a health functional food (ASL) preserves the volume and reduces the secretion of mucin.
  • respiratory diseases inflammatory airway diseases
  • ASL health functional food
  • the present invention provides a use for the prevention or improvement of a respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food, wherein the respiratory disease (inflammatory airway disease) is asthma, acute or chronic bronchitis, allergy one or more from the group consisting of rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or chronic obstructive pulmonary disease (COPD). is chosen
  • Another aspect of the present invention provides the use of a compound represented by Formula 1 or Formula 2, a mixture of compounds, or a pharmaceutical composition thereof, which exhibits a diuretic effect.
  • the present invention provides the use of a compound represented by Formula 1 or Formula 2, a mixture of compounds, or a health functional food composition thereof, which exhibits a diuretic effect as an active ingredient in a health functional food.
  • the compound according to the present invention includes a compound represented by Formula 1, a tautomer thereof, a geometric isomer (eg, e, z isomer) thereof, an optically active form as an optical isomer, a diisomer and a racemic form thereof, as well as , and a pharmaceutically acceptable salt thereof.
  • Derivatives exemplified herein can be prepared from readily available starting materials using the following general methods and procedures. Given typical or preferred experimental conditions (ie, reaction temperature, time, moles of reagent, solvent, etc.), it will be understood that other experimental conditions may be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvents employed, but such conditions can be determined by one of ordinary skill in the art using routine optimization procedures.
  • compound 'F1' is (E)-4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5 (4H)-one, (Z )-4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one or a mixture of two isomers. This phenomenon is well documented by the study of Graziano et al (Tetrahedron 62 ( 2006 ) 1165-1170).
  • step 3 2-(4-(tert-butyl)benzamido)acetic acid (200mg, 0.85mmol) and 1-ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (179.25mg, 0.935mmol) were stirred under stirring. It was added sequentially to methylene chloride (8.5 ml) at room temperature.
  • tert-Butyl 3-formyl-1H-indole-1-carboxylate (208 mg, 0.085 mmol) and triethylamine (0.208 ml, 2.550 mmol) were added sequentially to this mixture at room temperature under stirring and the whole mixture was stirred at 12 stirred for hours at room temperature.
  • the solvent was removed under reduced pressure and the resulting solid was obtained by passing it through a filter funnel.
  • the obtained solid was washed with methanol and the desired product (tert-butyl 3-((2-(4-(tert-butyl)phenyl)-5-oxooxazol-4(5H)-ylden)methyl)-1H -indole-1-carboxylate, F4 ).
  • Example 1.10 4-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F10 )
  • Example 1.11 4- (benzo [b] thiophen-2-ylmethylene) -2- (4- (tert-butyl) phenyl) oxazol-5 (4H) -one ( F11 )
  • Example 1.12 4-((1H-pyrrol-2-yl)methylene)-2-(4-isopropylphenyl)oxazol-5(4H)-one ( F12 )
  • Example 1.17 4-((1H-pyrrol-2-yl)methylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F17 )
  • Example 1.20 4-((1H-pyrrol-2-yl)methylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F20 )
  • Example 1.25 4-((1H-pyrrol-2-yl)methylene)-2-([1,1'-biphenyl]-4-ylmethyl)oxazol-5(4H)-one ( F25 )
  • Example 1.30 4-((1H-pyrrol-2-yl)methylene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F30 )
  • Example 1.60 4-((2-(4-methoxyphenyl)-5-oxooxazol-4(5H)-ylden)methyl)benzoic acid ( F60 )
  • Example 1.68 4-((Z)-1-(3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-ylden)butan-2-ylden)-2-phenyl Oxazol-5(4H)-one ( F68 )
  • Example 1.69 4-((2-(4-acetamidophenyl)-5-oxoxazol-4(5H)-ylden)methyl)-2-ethoxyphenylthiophene-2-carboxylate ( F69 )
  • Example 1.70 4-((6-ethoxy-2-(phenylthio)quinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F70 )
  • Example 1.72 4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-bromophenyl)oxazol-5(4H)-one ( F72 )
  • Example 1.81 4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F81 )
  • Example 1.82 4-((1-acetyl-3-phenyl-1H-pyrazol-4-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F82 )
  • Example 1.83 4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-2-(p-tolyl)oxazol-5(4H)-one ( F83 )
  • Example 1.84 4-((6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F84 )
  • Example 1.90 4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl acetate ( F90 )
  • Example 1.100 2-(benzo[d][1,3]dioxoyl-5-yl)-4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)oxa Zol-5(4H)-one ( F100 )
  • Example 1.105 4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F105 )
  • Example 1.114 4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F114 )

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Abstract

La présente invention porte sur une utilisation médicale de composés ayant une activité inhibitrice contre la pendrine, et concerne un composé représenté par la formule chimique 1 ou 2, ci-dessous, un isomère E ou Z, un isomère optique, un précurseur, un sel pharmaceutiquement acceptable, un solvate de celui-ci, ou un mélange d'au moins deux isomères de celui-ci, et une composition pour la prévention, le soulagement ou le traitement de maladies respiratoires, ou une composition diurétique, chaque composition utilisant l'activité inhibitrice du composé contre la pendrine. [Formule chimique 1] [Formule chimique 2]
PCT/KR2021/013401 2020-09-29 2021-09-29 Composition et procédé pour la prévention ou le traitement d'une maladie respiratoire WO2022071777A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3111520A (en) * 1960-12-05 1963-11-19 Smith Kline French Lab Alkylidene derivatives of 6-pteridine-hydrazides and amidrazones
US4985444A (en) * 1989-01-23 1991-01-15 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine compound and processes for preparation thereof
JP2006096708A (ja) * 2004-09-29 2006-04-13 Mochida Pharmaceut Co Ltd Ｐｓ−ｐｌａ１阻害剤
KR20190114299A (ko) * 2018-03-29 2019-10-10 김미희 RhoA 억제제 및 이의 용도
WO2020077459A1 (fr) * 2018-10-18 2020-04-23 3R Valo, S.E.C. Dérivés d'acide aminobenzoïque destinés à être utilisés en tant qu'agents anti-inflammatoires, agents anti-métastatiques et/ou agents anticancéreux
WO2020204602A1 (fr) * 2019-04-02 2020-10-08 연세대학교 산학협력단 Nouveau composé et composition pour la prévention ou le traitement de maladies respiratoires comprenant celui-ci comme principe actif

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3111520A (en) * 1960-12-05 1963-11-19 Smith Kline French Lab Alkylidene derivatives of 6-pteridine-hydrazides and amidrazones
US4985444A (en) * 1989-01-23 1991-01-15 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine compound and processes for preparation thereof
JP2006096708A (ja) * 2004-09-29 2006-04-13 Mochida Pharmaceut Co Ltd Ｐｓ−ｐｌａ１阻害剤
KR20190114299A (ko) * 2018-03-29 2019-10-10 김미희 RhoA 억제제 및 이의 용도
WO2020077459A1 (fr) * 2018-10-18 2020-04-23 3R Valo, S.E.C. Dérivés d'acide aminobenzoïque destinés à être utilisés en tant qu'agents anti-inflammatoires, agents anti-métastatiques et/ou agents anticancéreux
WO2020204602A1 (fr) * 2019-04-02 2020-10-08 연세대학교 산학협력단 Nouveau composé et composition pour la prévention ou le traitement de maladies respiratoires comprenant celui-ci comme principe actif

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