WO2020204602A1 - 신규 화합물 및 이를 유효성분으로 포함하는 호흡기 질환의 예방 또는 치료용 조성물 - Google Patents
신규 화합물 및 이를 유효성분으로 포함하는 호흡기 질환의 예방 또는 치료용 조성물 Download PDFInfo
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- WO2020204602A1 WO2020204602A1 PCT/KR2020/004464 KR2020004464W WO2020204602A1 WO 2020204602 A1 WO2020204602 A1 WO 2020204602A1 KR 2020004464 W KR2020004464 W KR 2020004464W WO 2020204602 A1 WO2020204602 A1 WO 2020204602A1
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- 0 CC(*)=C(C*)N=C(C)* Chemical compound CC(*)=C(C*)N=C(C)* 0.000 description 8
- SLJPTZJWRPDCEH-XNTDXEJSSA-N CC(C)(C)c(cc1)ccc1C(N/C(/C(O)=O)=C/c1c[s]cc1)=O Chemical compound CC(C)(C)c(cc1)ccc1C(N/C(/C(O)=O)=C/c1c[s]cc1)=O SLJPTZJWRPDCEH-XNTDXEJSSA-N 0.000 description 1
- RZIWCIKYWZQIAW-WJDWOHSUSA-N CC(C)(C)c(cc1)ccc1C(OC1=O)=N/C1=C\c1ccc(C)[s]1 Chemical compound CC(C)(C)c(cc1)ccc1C(OC1=O)=N/C1=C\c1ccc(C)[s]1 RZIWCIKYWZQIAW-WJDWOHSUSA-N 0.000 description 1
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- IAVRGEHUYMOIEK-SSDVNMTOSA-N O=C1OC(c2cc3ccccc3cc2)=N/C1=C/c1c[n](Cc(cccc2)c2Cl)nc1 Chemical compound O=C1OC(c2cc3ccccc3cc2)=N/C1=C/c1c[n](Cc(cccc2)c2Cl)nc1 IAVRGEHUYMOIEK-SSDVNMTOSA-N 0.000 description 1
- RXCIWLWWSQOFFL-GZTJUZNOSA-N O=C1OC(c2cccc3c2cccc3)=N/C1=C/Cc1ccc[nH]1 Chemical compound O=C1OC(c2cccc3c2cccc3)=N/C1=C/Cc1ccc[nH]1 RXCIWLWWSQOFFL-GZTJUZNOSA-N 0.000 description 1
- RSBHOLGAOUTXMM-UHFFFAOYSA-N O=C1OC(c2ccccc2)=NC1=C1C=C(c2ccccc2)SC(c2ccccc2)=C1 Chemical compound O=C1OC(c2ccccc2)=NC1=C1C=C(c2ccccc2)SC(c2ccccc2)=C1 RSBHOLGAOUTXMM-UHFFFAOYSA-N 0.000 description 1
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- FAJKDYPLEQZBJE-GHXNOFRVSA-N [O-][NH+](c(cc1)cc(Cl)c1C(OC1=O)=N/C1=C\C1=CCCS1)O Chemical compound [O-][NH+](c(cc1)cc(Cl)c1C(OC1=O)=N/C1=C\C1=CCCS1)O FAJKDYPLEQZBJE-GHXNOFRVSA-N 0.000 description 1
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- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
- C07D413/10—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 aromatic rings
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- 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
- C07D413/12—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 chain containing hetero atoms as chain links
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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
- C07D413/14—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
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- 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
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- 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 a novel compound and a composition for preventing or treating respiratory diseases comprising the same as an active ingredient.
- Gave pen is encrypted by the SLC26A4 gene is a member of the SLC26 anion exchanger, and gene family, Cl - for HCO 3 -, I -, OH - , and SCN - anion is exchanged for the same.
- Pendrin is a cell membrane protein expressed on the lumen of airway epithelial cells.
- pendrin expression is associated with chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, pertussis infection, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and inflammatory airway diseases such as the common cold caused by rhinovirus Is strongly upregulated in, and upregulation of pendrin is observed when they are incubated with IL-4, IL-13 and IL-17A in primary airway epithelial cells.
- COPD chronic obstructive pulmonary disease
- ALI acute lung injury
- ARDS acute respiratory distress syndrome
- inflammatory airway diseases such as the common cold caused by rhinovirus Is strongly upregulated in, and upregulation of pendrin is observed when they are incubated with IL-4, IL-13 and IL-17A in primary airway epithelial cells.
- pendrin knockout (KO) improves airway inflammation in all mouse models for COPD, allergic rhinitis, asthma, pertussis infection and rhinovirus infection.
- the pathophysiological role of fendrin in airway inflammation
- the increase in ASL volume in primary mouse organ epithelial cell culture with IL-13 was significantly higher in Fendrin KO mice compared to the WT mouse control.
- the IL-13 induced ASL volume increase in primary human nasal epithelial (HNE) cell cultures of deaf patients carrying the pendrin mutant (DFNB4) was significantly higher than that of the normal control.
- inhibition of pendrin by a pendrin inhibitor significantly increased the volume of IL-13 induced ASL in the primary culture of human bronchial epithelial cells.
- the present invention is based on the discovery that certain compounds can act as pendrin inhibitors with the potential to treat respiratory diseases.
- some compounds discovered through cell-based HTS screening for the identification of small molecule pendrin inhibitors or novel newly designed compounds include asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory infections, cystic
- respiratory diseases inflammatory airway diseases
- ARDS acute respiratory distress syndrome
- ALI acute lung injury
- COPD chronic obstructive pulmonary disease
- the present invention is based on the discovery that some small molecules can show that pendrin downregulation reduced IL-13 induced upregulation of MUC5AC gene expression in HNE cells differentiated from normal subjects.
- some molecules have been used as pendrin inhibitors to improve airway inflammation in a mouse model of ovalbumin (OVA) induced allergic asthma.
- OVA ovalbumin
- the present invention provides a compound represented by the following formula (1), its E- or Z-isomer, its optical isomer, a mixture of the two isomers, its precursor, its pharmaceutically acceptable salt, or its solvate. :
- V 1 and V 2 are 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 ⁇ C 10 alkynyl, S(O) i (C 1 ⁇ 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 , NR 3 R 4 , and the aryl, heteroaryl, C 3 ⁇ 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 methylenehydra
- i and j are 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 ⁇ C 10 alkyl, C 2 ⁇ C 10 alkenyl, C 2 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i (C 1 ⁇ C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 And NR 3 R 4 It is independently selected from the group consisting of, the aryl, heteroaryl, heterocyclyl , C 1 ⁇ C 10 alkyl, C 2 ⁇ C 10 alkenyl, C 2 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i
- 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 It is independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, and the aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, heteroaryl, heteroaryl (C 1 to 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 alky
- R 3 and R 4 may be cyclized into a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, and 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 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i (C 1 ⁇ C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 are optionally substituted with one or more groups independently selected,
- a 1 is or Is represented by
- X 1 and X 2 are independently selected from the group consisting of O, S, CHR 4 and NR 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 ⁇ C 3 methylenehydrazine, C 2 ⁇ C 10 alkynyl, S(O) i (C 1 ⁇ 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 , and the 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 methylene
- R 5 and R 6 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, heteroaryl, 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, heterocyclyl, aryl, heteroaryl and trifluoromethyl are independently selected from the group consisting of, the Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C 1 ⁇ C 10 alkylaryl, one of the heteroaryl moieties is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, Trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C 1 to
- R 5 and A 1 may be cyclized with a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, and 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 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i (C 1 ⁇ C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 are optionally substituted with one or more groups independently selected from.
- the present invention provides at least one of the compounds, at least one of its E- or Z-isomers, at least one of its optical isomers, a mixture of at least one of its two isomers, at least one of its precursors, at least one of its 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 respiratory diseases (inflammatory airway diseases).
- the present invention provides a composition comprising a compound represented by Formula 1 or a mixture thereof, and a composition comprising a compound represented by Formula 1 or a mixture thereof together with a pharmaceutically acceptable carrier.
- the present invention provides a use of a compound represented by Formula 1 and a pharmaceutical composition thereof as a pendrin inhibitor.
- the present invention provides a compound represented by Formula 1 and a pharmaceutical composition thereof, which specifically modulates a chloride channel.
- the present invention provides a compound represented by Formula 1 and a pharmaceutical composition thereof, which preserves the volume of airway surface liquid (ASL) and reduces the separation of mucins.
- ASL airway surface liquid
- the present invention relates to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory infections, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD).
- respiratory diseases inflammatory airway diseases selected from the group consisting of.
- the present invention provides a use of a compound represented by Formula 1, a mixture thereof, and 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 a compound and a pharmaceutical composition thereof as a pendrin inhibitor for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in a dietary supplement.
- respiratory diseases inflammatory airway diseases
- the present invention provides a compound represented by Formula 1 and a pharmaceutical composition thereof, which specifically modulates chloride channels 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 preserves the volume of airway surface liquid (ASL) and reduces the separation of mucin for the prevention or improvement of respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food, Formula 1 It provides a compound represented by and a pharmaceutical composition thereof.
- ASL airway surface liquid
- the present invention provides a use for preventing or improving respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food
- respiratory disease inflammatory airway disease
- the respiratory disease is asthma, acute or chronic bronchitis, allergic rhinitis , Acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD).
- the novel compound can act as a pendrin inhibitor, and as a result, it can be usefully used as a composition for preventing, treating, or improving respiratory diseases (inflammatory airway diseases, in particular, asthma or acute lung injury).
- respiratory diseases inflammatory airway diseases, in particular, asthma or acute lung injury.
- Shows the inhibitory activity of the exchange - Figure 3 is a pen gave by F56-mediated Cl - / HCO 3. High density Cl - application of the pen gave-induced intracellular pH decreased through the exchange and result in a decrease in YFP fluorescence-mediated Cl - / HCO 3. The indicated concentration of the pendrin inhibitor was pretreated for 10 minutes.
- FIG. 5(a) shows that F56 , a novel pendrin inhibitor, blocks pendrin-mediated cellular responses in IL-4-stimulated HNE cells.
- A Chemical structure of F56 .
- D Representative protein expression results of pendrin (PDS) in untreated and IL-4-treated HNE cells.
- PDS mRNA expression level was determined at 120 hours after F10 treatment by real-time quantitative PCR in IL-4 treated HNE cells.
- Figure 6(a) shows the pendrin-mediated Cl ⁇ /base exchange activity in CHO-K1 cells expressing human pendrin.
- B, C Representative trace of intracellular pH. Cl-free application of the solution gave a pen-induced intracellular alkalizing through exchange activity-mediated Cl - / HCO 3 - and Cl - / OH. The indicated concentration of F56 was pretreated for 10 minutes.
- (DF) gave pen-mediated Cl - / I - was measured exchange activity in CHO-K1 cells expressing the human pen gave.
- FIG. 6(b) shows the effect of F10 on cell viability in NIH3T3 and CHO-K1 cells.
- Cells were treated with F10 for 24 hours.
- FIG. 7(a) shows the characteristics of F56 .
- B (hPDS) gave the human pen-mediated (closed circles, Fig. 5 (a), C) and mPDS- parameters (open circles) Cl - / I - F56 capacity for inhibition of the exchange activity-summary of the reaction.
- CF Representative traces of the intracellular pH of CHO-K1 cells expressing SLC26A3, SLC26A6, SLC26A7 and SLC26A9 were shown.
- Cl - free solution is the application of Cl - induced intracellular alkalizing through exchange - / HCO 3.
- the indicated concentration of F56 was pretreated for 10 minutes.
- G The effect of F56 (100 ⁇ M) on CFTR chloride channel activity was measured in FRT cells expressing human CFTR. CFTR current was activated by 20 ⁇ M forskolin and inhibited by 10 ⁇ M CFTR inh -172.
- H The effect of F56 (100 ⁇ M) on ANO1 chloride channel activity was measured in FRT cells expressing human ANO1. F56 was added 10 minutes prior to ANO1 activation with 100 ⁇ M ATP.
- Figure 7(b) shows the effect of F10 on the channel activity of CFTR, ANO1 and hERG.
- A The effect of F10 (30 ⁇ M) on the CFTR channel was measured in FRT cells expressing human CFTR and variant YFP. CFTR was activated by 20 ⁇ M forskolin and inhibited by 10 ⁇ M CFTR inh -172.
- B The effect of F10 (30 ⁇ M) on ANO1 channel activity was measured in human and FRT cells expressing variant YFP. ANO1 was activated by 100 ⁇ M ATP and inhibited by 10 ⁇ M T16A inh- A01.
- Figure 8(a) shows the effect of F56 on pendrin and other ion channels in HNE cells.
- A Representative trace of intracellular pH of untreated (grey line) and IL-4 (10 ng/ml) treated HNE cells. Fendrin was inhibited by F56 (50 mM).
- C Cl - / HCO 3 - was measured exchange activity in IL-4- processed HBE cells. F56 was pretreated for 5 minutes.
- D, E Short circuit current recording of HNE cells.
- Figure 8(b) shows the effect of F10 on the mRNA expression level of ANO1, CFTR and ENaC.
- ANO1, CFTR and ENaC mRNA expression levels were determined at 120 hours after F10 treatment by real-time quantitative PCR in IL-4 treated HNE cells.
- Figure 9 (a) is the F56 OVA- the allergenicity in a mouse model gave pen / SCN of asthma inducing shows Sikkim improve airway inflammation via inhibition of / NF-kB path.
- A Airway resistance of animals sensitized and challenged with OVA.
- D Protein expression level results for HNE cells treated with IL-4 in the presence or absence of F56 .
- Figure 9(b) shows the effect of F10 on airway resistance in animals sensitized and challenged with OVA.
- FIG. 10 shows the improvement of allergic airway inflammation by F56 in the mouse model of asthma.
- A Protocol of induction and time course of resolving allergic airway inflammation after allergen challenge in wild-type mice.
- C Representative histology of airways stained with hematoxylin and eosin. Size bar, 100 ⁇ m.
- (E) Summary of inflammation scores (mean ⁇ SE, n 4).
- (F) OVA-specific IgE levels in serum (mean ⁇ SE, n 4).
- FIG. 11 shows the improvement of allergic asthma by F56 in an established model of allergic asthma.
- A Induction and time-lapse protocol of allergic airway inflammation after allergen antigen challenge in wild-type mice. F56 (10 mg/kg 3 times/day) was applied after the 3rd OVA challenge.
- C Representative PAS staining of airway tissue. Size bar, 100 ⁇ m.
- FIG. 12(a) shows the effect of F56 on mucosal production and ASL volume control in IL-4-treated HNE cells.
- B Periodic acid-Schief (PAS) staining showing goblet cell hyperplasia of HNE cells treated with IL-4 and IL-13 (10 ng/ml) in the absence or presence of F56 (30 M) on day 7.
- C Measurement of the total volume of ASL and fluid meniscus in HNE cells expressing wild-type (wt) or mutant (mt) PDS.
- D Representative images of transwell inserts with normal HNE cells. Arrows indicate fluid meniscus of HNE cells treated with IL-4 (10 ng/ml, 48 hours) with or without 30 mM F56 .
- E Results of representative protein expression levels of pendrin in IL-4 and IL-13-treated HNE cells.
- MUC5AC mRNA expression level was determined at 120 hours after F10 treatment by real-time quantitative PCR in IL-4 treated HNE cells.
- FIG. 13 shows the effect of F56 on auditory threshold and plasma thyroid hormone levels.
- A Representative examples of ABR waveforms from control and F56 (10 mg/kg/day for 7 days) treated mice.
- D Representative force trace showing airway smooth muscle (ASM) contraction response in rat tracheal rings.
- F56 (30 mM) was applied after induction of ASM contraction by carbacol (CCh) at submaximal concentration (300 nM). ASM relaxation was induced by forskolin and IBMX.
- Pendrin inhibitors can reduce NF-kB activation by blocking SCN - transport in the airway epithelium and enhance mucosal clearance by inhibiting upregulated pendrin-mediated ASL deficiency in airway inflammation.
- FIG. 15 shows that pendrin deficiency attenuates LPS-induced lung damage in mice.
- Wild-type (WT) and pendrin-null (Pds -/- ) mice were administered LPS (10 mg/kg) or vehicle (PBS) intranasally.
- LPS 10 mg/kg
- PBS vehicle
- A Total bronchoalveolar lavage (BAL) cell number and BAL protein concentration were analyzed 48 hours after LPS or PBS administration in WT mice.
- B Representative image of H&E staining of lung tissue 48 hours after LPS or PBS administration (x400), size bar: 50 ⁇ m.
- C Total BAL cell number and BAL protein concentration were analyzed 48 hours after LPS or PBS administration in pendrin-null mice.
- Figure 16 shows that the novel pendrin inhibitor ( F56 ) blocked pendrin activity in human alveolar epithelial cells.
- A Chemical structure of the pendrin inhibitor F56 .
- B Representative protein expression results of pendrin (PDS) in human alveolar epithelial cells (hAEC).
- Light Summary of dose-response.
- FIG. 17 shows that F56 suppressed the LPS-induced acute lung injury phenotype in mice.
- A F56 (10 mg/kg) was injected intraperitoneally 1 hour before LPS treatment.
- B BALF total cell count.
- C BALF protein concentration.
- D Representative image of H&E lung tissue staining ( ⁇ 400), size bar: 50 ⁇ m.
- E Lung damage score.
- F F56 (10 mg/kg) was injected intraperitoneally at 6 hours and 12 hours after LPS inhalation.
- G BALF total cell count.
- H BALF protein concentration.
- FIG. 18 shows SCN - triggered LPS-induced lung injury in the presence of F56 or Pendrin null mice.
- A BALF total cell count. LPS (10 mg/kg, in), F56 (10 mg/kg, ip), NaOH (100 mM, in), NaHCO 3 (100 mM, in) and NaSCN (100 mM, in) were treated in WT mice. .
- B BALF protein concentration.
- C Lung damage score.
- D BALF protein concentration in pendrin-null mice. NaSCN (100 mM, in) was applied to LPS-treated pendrin-null mice.
- FIG. 19 shows that F56 blocked the NF- ⁇ pathway and reduced the level of pro-inflammatory cytokines in LPS-induced acute lung injury.
- A Representative images of lungs of NF- ⁇ /SPC-Cre mice exposed to LPS (10 mg/kg) and treated with F56 (10 mg/kg) or vehicle. IVIS image fluorescence is expressed as radiation efficiency.
- C Representative protein expression results in lung lysates.
- D Relative protein levels were determined by densitometry for pendrin and phospho-I ⁇ .
- Figure 20 shows the level of pendrin in human BALF.
- Patients with ARDS due to pneumonia showed increased levels of pendrin compared to control patients (not infected).
- FIG 21 shows a schematic diagram of the role of pendrin and its inhibitors in LPS-induced lung injury.
- SCN - is actively transported from the apical surface of the alveolar epithelium to the lung lumen via fendrin.
- SCN - is catalyzed to OSCN - by peroxidase with H 2 O 2 .
- the resulting OSCN - activates NF- ⁇ and causes inflammatory cytokine release, neutrophil infiltration and subsequent lung damage.
- the pendrin inhibitor F56 blocks transport through the epithelium of OSCN - the SCN - which inhibits induced NF- ⁇ activation and subsequent onset of ALI.
- active agent refers to the desired pharmacological effect (eg, of inflammation) when administered to a subject by any means described herein (eg, any animal, including human or non-human animals). (Such as reduction) is used interchangeably herein to refer to a chemical substance or compound that induces.
- additive may refer to any additional ingredients that may be added to the compositions and formulas described herein.
- the additives may be excipients (e.g., one or more excipients), antioxidants (e.g., one or more antioxidants), stabilizers (e.g., one or more), while providing additional ingredients are pharmaceutically acceptable for the particular condition being treated.
- preservatives e.g., one or more preservatives
- pH adjusting and/or buffering agents e.g., one or more pH adjusting and/or buffering agents
- tonicity adjusting agents e.g., one or more isotonicity adjusting agents
- thickening agents e.g., One or more thickeners
- suspending agents e.g, one or more suspending agents
- binders eg, one or more binders
- viscosity increasing agents eg, one or more viscosity increasing agents
- additives include calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, Treatment agents and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as low melting point waxes, ion exchange resins, and the like.
- suitable pharmaceutically acceptable excipients are described in “Remington's Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), and “Remington: The Science and Practice of Pharmacy”, Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005).
- the additives described herein can be used with any suitable drug.
- administration refers to oral administration, suppository, topical contact intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, intravitreal or subcutaneous administration to a subject, or sustained-release devices.
- a small-sized osmotic pump is administered by any route including parenteral and transmucosal (eg, oral, nasal, pulmonary, rectal, buccal, vaginal, ocular and transdermal routes).
- “Analog” and “derivative” are used interchangeably herein and have the same core as the parent compound, but in the absence or presence of one or more atoms and/or groups of atoms, and combinations thereof, different from the parent compound in the order of bonding.
- Derivatives may differ from the parent compound, for example in one or more substituents present on the core, which may contain one or more atoms, functional groups or substructures. Further, 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 cellular damage and/or oxidation. Antioxidants are found in many foods, including fruits and vegetables. Also, they can be used as dietary supplements. 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 can be used. The antioxidants described herein can 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 the additional treatment or active agent or additive described herein.
- the compounds or compositions of the present disclosure may be administered alone or co-administered to a patient. Co-administration is construed to include administering the compounds individually or in combination (one or more compounds or agents) simultaneously or sequentially. If desired, the formulation can 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 a bioactive activity) are administered simultaneously, their administration occurs within a certain desired time. Administration of the formulation can begin and end on the same day. Further, administration of one agent may precede administration of the 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 the second agent as long as the two agents are taken at least once on the same day. It is not necessary to take the bioactive agent/agent at the same time each day to include simultaneous administration.
- two agents eg, any agent or class of agents described herein having a bioactive activity
- an “effective amount” or “therapeutically effective amount” is an amount sufficient to affect a desired biological effect, such as an advantageous outcome, including a clinical outcome.
- the "effective amount” depends on the circumstances in which it is applied.
- the effective amount may vary depending on factors known in the art such as 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 treatment situation.
- the compositions/formulations of the present disclosure may be administered as often as necessary to achieve a therapeutic amount.
- gel can readily refer to a material that is not a flowable liquid, but is a solid, ie, a semi-solid. Gels can be formed from natural or synthetic materials. The gel is not aligned but is slightly aligned and exhibits birefringence and liquid crystal properties. The gel can be administered topically.
- respiratory disease as used herein has its usual medical meaning and has asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory infections, cystic fibrosis, 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.
- ARDS acute respiratory distress syndrome
- ALI acute lung injury
- COPD chronic obstructive pulmonary disease
- the term “inhibition” means prevention, reduction, slowing or arrest.
- the composition or compound when the amount or rate of a process or reaction occurring in the presence of the compound or composition is reduced by at least about 10% when compared to the amount or rate in the absence of the compound or composition, the composition or compound is at least one It is considered to inhibit the viability of a protein (eg, pendrin).
- the amount or rate of a process or reaction occurring in the presence of the compound or composition is reduced by at least about 20% when compared to the amount or rate in the absence of the compound or composition, the composition or compound is Is considered to suppress.
- the amount or rate of inhibition occurring in the presence of the compound or composition is about 25% or greater, about 30%, about 40%, about 50%, about the amount or rate of inhibition when compared to the amount or rate in the absence of the compound or composition.
- the compound or composition is considered to inhibit one or more proteins (eg, pendrin).
- the compound or composition is considered to inhibit the viability of one or more proteins, i.e., inhibit their development.
- “intermittent administration” refers to the period of administration of the agent (which may be considered the “first administration period”), followed by the period of not taking the agent or taking it at a lower dose (this is the “off-period”). May be considered), followed by a period of re-administration of the agent (which may be considered a “second period of administration.”
- the dosage level of the agent is the period of the first administration. It is consistent with that administered during, but can be increased or decreased as medically necessary.
- “Jelly” is composed of a gel, which is a semi-solid system composed of a suspension of one of small inorganic particles or large organic molecules infiltrated by a liquid with a high structural cohesive matrix, usually a liquid containing water.
- liquid is a dosage form consisting of a composition in a liquid state. Liquid can be poured; It flows and behaves in a container at room temperature. Liquids exhibit Newtonian or pseudoplastic flow behavior.
- “semi-liquid” as used herein may have the properties of both liquids and other formulations (ie, suspensions, emulsions, solutions, creams, gels, jellies, etc.). .
- the term “ointment” may refer to a high viscosity liquid or semi-liquid formulation that can be used in the therapeutic treatment of a disease, syndrome or condition.
- “pharmaceutically acceptable carrier” includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. 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.
- composition e.g., a derivative or analog of Formula 1, Formula 1 described herein, or a pharmaceutically acceptable salt, solvent, hydrate or polymorph thereof
- any conventional medium or agent e.g., a derivative or analog of Formula 1, Formula 1 described herein, or a pharmaceutically acceptable salt, solvent, hydrate or polymorph thereof
- the present disclosure Its use in the composition for is contemplated.
- a “pharmaceutical carrier” or “carrier” may further include a pharmaceutically acceptable carrier, excipient or stabilizer that is not toxic to cells or mammals at the dosages and concentrations employed.
- the physiologically acceptable carrier is often an aqueous pH buffered solution.
- physiologically acceptable carriers include buffering agents 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 dextrin; Chelating agents such as EDTA; Sugar alcohols such as mannitol or sorbitol; Salt-forming counter ions such as sodium; And/or nonionic surfactants such as Tween TM , polyethylene glycol (PEG) and Pluronics TM .
- buffering agents such as phosphate, citrate and other organic acids
- Antioxidants including ascorbic acid
- Low molecular weight (less than about 10 residues) polypeptides
- 'pharmaceutically acceptable may be approved or approved by a federal or state regulatory agency or an agency outside the United States, or for use in animals, and more particularly in humans, by the U.S. Pharmacopoeia or other generally Means listed in an accepted pharmacopoeia.
- 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 (e.g. sodium, potassium or lithium) and alkaline earth metals (e.g. calcium or magnesium). It includes, but is not limited to, a base addition salt formed by reaction of a compound represented by Formula 1 having a base or having a primary, secondary, or tertiary alkyl amine.
- salt or “salt form” or “a weakly 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 by free carboxyl or other anionic groups) derived from organic bases such as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like.
- Such salts are formed as acid addition salts having any free cationic group, for example inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or for example acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid. And organic acids such as mandelic acid, and the like.
- the salt of the present disclosure may include an amine salt formed by protonation of an amino group having an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like.
- the salts of the present disclosure include amine salts formed by protonation of an amino group having 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 modifier. These may include, but are not limited to, a glycerol buffer, a citrate buffer, a borate buffer, an acetate buffer, a gluconate buffer, a phosphate buffer or a citric acid-phosphate buffer.
- the pH agent or buffer can be used in any suitable amount.
- preservative may refer to a substance or chemical substance that prevents undesirable chemical changes in the compounds or compositions or formulas 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, phenylmercury acetate, thimerosal, merthiolate, acetate and phenylmercury borate, polymyxin B sulfate, methyl and propyl paraben, quaternary ammonium chloride, sodium benzoate, sodium propionate And sodium perborate, and other agents known to those skilled in the art, or combinations thereof.
- the preservative are, for
- the terms “prevent”, “preventing” or “prevention” and other grammatical equivalents are intended to reduce the incidence of the syndrome, as well as to prevent the development, occurrence, obstruction or avoidance of a disease or condition syndrome. Includes one for. Prevention can be complete (ie, no detectable symptoms) or partial, so that fewer symptoms can be observed than without treatment. The term further includes prophylactic benefits.
- the composition may be administered to a patient at risk of developing a particular disease or to a patient who may not be a diagnosis of such a disease but reports one or more physiological syndromes of the disease.
- the ranges provided herein are shorthand for all values within the range.
- the range of 1 to 10 is all intermediate decimal values between the aforementioned integers, such as 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. It is understood to include any number, combination of numbers, or subranges from the group consisting of. With regard to subranges, “nested subranges" extending from one of the end points of the range are particularly contemplated.
- the overlapping subranges of the exemplary 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 the other direction.
- Ranges may be expressed herein as “about” one specific value and/or “about” another specific value. When this range is expressed, the other aspect includes one particular value and/or another particular value. Similarly, when a value is expressed as an approximation using the preceding “about”, it is understood that a particular value forms another aspect. It is further understood that the endpoints of each range are important in relation to the other endpoints and independently of the other endpoints. In addition, there are a number of values disclosed herein, and it is understood that each value is also disclosed herein as "about” for that particular value in addition to the value itself.
- data is provided in a number of different formats, such data representing endpoints and starting points and ranges for any combination of data points. For example, when a specific data point "10" and a specific data point "15" are disclosed, it is considered that between 10 and 15, as well as greater than, greater than, less than, less than, less than, and equal to 10 and 15 are disclosed. It is also understood that each unit between two specific units is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13 and 14 are also disclosed.
- a “semi-solid gel” according to the present disclosure is a semi-solid.
- the apparent viscosity of a semi-solid formulation can increase with concentration.
- sequential administration means that the administration of two agents (e.g., a compound or composition described herein) occurs separately on the same day or does not occur on the same day (e.g., occurs on consecutive days). It includes).
- a “solution” according to the present disclosure may be a transparent, homogeneous liquid dosage form containing one or more chemical substances dissolved in a solvent or a mixture of solvents compatible with each other.
- Solutions are liquid formulations containing one or more dissolved chemicals in a suitable solvent or mixture of solvents compatible with each other. Since the molecules of the drug substance in the solution are uniformly dispersed, the use of a solution as a dosage form generally provides a guarantee 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 may consist of water and one or more miscible solvents, and may contain dissolved solutes such as sugars, buffers, salts or other excipients.
- non-aqueous solvents are short chain organic alcohols such as methanol, ethanol, and 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. “Subject” may include any animal including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cows, fish and birds. Human subjects can point to patients.
- suspension is a liquid dosage form containing solid particles dispersed in a liquid vehicle.
- viscosity refers to the flow resistance of a fluid. Viscosifiers 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 the ingredients will have 1 g of the ingredients 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 the ingredients will have 1 ml of the ingredients 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 the solvent. For example, a 1.0% (w/v) solution of the ingredients will have 1 g of the ingredients dissolved in 100 ml of solvent.
- the term “syndrome” refers to a condition characterized by a group of symptoms or a series of related symptoms that occur continuously together.
- Syndromes eg, acute respiratory distress syndrome
- a disease can be a health condition with clearly defined reasons behind it.
- the syndrome from the Greek word meaning'run together' can cause a number of symptoms without any identifiable cause. They can imply the likelihood of an underlying disease or the likelihood of a disease occurring.
- the terms “treat”, “treating” or “treatment”, and other grammatical equivalents refer to alleviation, attenuation, amelioration or prevention of a disease, condition (eg, acute respiratory distress syndrome) or symptom, of an additional symptom.
- Prevention, improvement or prevention of underlying metabolic causes of symptoms, suppression of a disease or condition, e.g., arrest of 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 encompasses achieving a therapeutic benefit and/or a prophylactic benefit.
- Therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated.
- the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder achieves therapeutic benefit, an improvement is observed in the patient, although the patient may still suffer from the underlying disorder.
- health functional food refers to a food or food supplement prepared or processed from raw materials, functional ingredients, active pharmaceutical ingredients or additives useful for improving and/or nutritional and/or preserving the physiological function of the human body.
- ARDS acute respiratory distress syndrome
- ARDS is a medical condition that occurs in severely ill patients with extensive inflammation in the lungs.
- ARDS is a clinical phenotype that can result from a variety of pathologies such as pneumonia and sepsis.
- Extensive damage to cells forming the alveolar barrier, surfactant dysfunction, abnormal coagulation and activation of the innate immune response are hallmarks of ARDS.
- 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 infections, acute upper respiratory infections, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease ( COPD) and the like.
- inhibitor as used in the context of the present invention is defined as a molecule, two or more molecules or pharmaceutical compositions that completely or partially inhibit the activity of a target or two or more targets that elicit a desired biological effect.
- targets include enzymes, receptors, ion-channels or transporters (eg, pendrine), and the like.
- “Inhibitor” can reversibly or irreversibly inhibit a target, and reversible inhibition includes competition 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, indicating a monovalent alkyl group having 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, tetrahydrogerany
- C 1 -C 9 alkyl Preferably, they comprise C 1 -C 9 alkyl, more preferably C 1 -C 6 alkyl, particularly preferably C 1 -C 4 alkyl, which likewise comprises monovalent alkyl groups having 1 to 9 carbon atoms, It represents 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 bonds can be of the (E) or (Z) configuration.
- they comprise 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 can have any available number of triple bonds at any available position. These terms include 2 to 20 carbon atoms, such as ethynyl (-C ⁇ 1-propynyl, 2-propynyl (propagyl: -CH 2 C ⁇ 2-butynyl, 2-penten-4-ynyl, etc.) and any Exemplified by groups such as alkynyl groups which may have double bonds or triple bonds, in particular, they include C 2 -C 8 alkynyl, more preferably C 2 -C 6 alkynyl, etc. Preferably 2 to 6 carbon C 2 -C 6 alkynyl, which refers to a group having an atom and having an alkynyl unsaturation of 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, etc. 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) It refers to an unsaturated aromatic carbocyclic group having 6 to 14 carbon atoms.
- Aryl includes phenyl, naphthyl, anthryl, phenanthrenyl, and the like.
- C 1 -C 6 alkyl aryl refers to an aryl group having a C 1 -C 6 alkyl substituent 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 aryl substituents 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 a heteroaryl group having a C 1 -C 6 alkyl substituent 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 heteroaryl substituents 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 aryl substituents 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 heteroaryl substituents 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 above definition, wherein at most 3 carbon atoms are replaced with a heteroatom selected from the group consisting of O, S and NR (R is defined as hydrogen or methyl) or It 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 a C 3 -C 8 -cycloalkyl substituent 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 carboxy substituents including 2-carboxyethyl and the like.
- acyl refers to a group -C(O)R including acetyl, etc., wherein 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 a group -OC(O)R including acetyloxy, etc., 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 a group -C(O)NRR', including N-phenyl carbonyl, etc., 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 refers to aminocarbonyl substituents including 2-(dimethylaminocarbonyl)ethyl, N-ethyl acetamidyl, N,N-diethyl-acetamidyl, etc. Refers to an alkyl group.
- acylamino refers to a group -NRC(O)R' including acetylamino, etc., 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 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”.
- 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 attached to them, may optionally form
- 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 alky 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 attached to them, optionally 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 a 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 attached to them, 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 is a group -OSO 2 R a point, wherein, R is "C 1 -C 6 alkyl” substituted by halogen "C 1 -C 6 alkyl", for example, -OSO 2 CF 3 group, " 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 group is pointing to the "-SO 2 R", wherein, R is "aryl", “heteroaryl”, “C 1 -C 6 alkyl” substituted by halogen "C 1 -C 6 alkyl", for example, -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
- 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”, wherein R is “alkyl” substituted with “alkyl” halogen, such as -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 denotes the group -SR, wherein, R is H, "C 1 -C 6 alkyl", substituted by halogen "C 1 -C 6 alkyl", 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 C 1 -C 6 alky
- 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 attached to them 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 refers to “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” , "Alkoxy”, “alkoxy carbonyl”, “carbamate”, “sulfanyl”, “halogen”, trihalomethyl, cyano, hydroxy, mecapto,
- 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 the two isomers, its precursor, its pharmaceutically acceptable salt, or its solvate:
- V 1 and V 2 are 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 ⁇ C 10 alkynyl, S(O) i (C 1 ⁇ 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 , NR 3 R 4 , and the aryl, heteroaryl, C 3 ⁇ 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 methylenehydra
- i and j are 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 ⁇ C 10 alkyl, C 2 ⁇ C 10 alkenyl, C 2 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i (C 1 ⁇ C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 And NR 3 R 4 It is independently selected from the group consisting of, the aryl, heteroaryl, heterocyclyl , C 1 ⁇ C 10 alkyl, C 2 ⁇ C 10 alkenyl, C 2 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i
- 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 It is independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, and the aryl, aryl (C 1 to C 10 alkyl), C 1 to C 10 alkylaryl, heteroaryl, heteroaryl (C 1 to 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 alky
- R 3 and R 4 may be cyclized into a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, and 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 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i (C 1 ⁇ C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 are optionally substituted with one or more groups independently selected,
- a 1 is or Is represented by
- X 1 and X 2 are independently selected from the group consisting of O, S, CHR 4 and NR 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 ⁇ C 3 methylenehydrazine, C 2 ⁇ C 10 alkynyl, S(O) i (C 1 ⁇ 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 , and the 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 methylene
- R 5 and R 6 are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C 1 to C 10 alkylaryl, heteroaryl, 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, heterocyclyl, aryl, heteroaryl and trifluoromethyl are independently selected from the group consisting of, the Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C 1 ⁇ C 10 alkylaryl, one of the heteroaryl moieties is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, Trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C 1 to
- R 5 and A 1 may be cyclized with a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, and 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 ⁇ C 10 alkynyl, C 3 ⁇ C 6 cycloalkyl, S(O) i (C 1 ⁇ C 6 alkyl), C(O)OR 3 , C(O)R 3 , OR 3 , NR 3 C(O)OR 4 , C(O)NR 3 R 4 and NR 3 R 4 are optionally substituted with one or more groups independently selected from.
- Non-limiting examples of the above compounds include the following compounds listed in Tables 1 and 2.
- the term'compound of the present invention' and equivalent expressions include compounds represented by Formula 1 described above, and such expressions include the E- or Z-isomer, the optical isomer, the mixture of the two isomers, and It includes a precursor, a pharmaceutically acceptable salt or solvate thereof, and is newly synthesized.
- Another aspect of the present invention provides a method of preparing a compound represented by Chemical Formula 1.
- the synthetic method is well described in the detailed examples described herein.
- a base may be an organic or inorganic base.
- organic bases include pyridine, trimethylamine, N, N-diisopropylethylamine (DIPEA) and 1,8-diazabi cyclo[5.4.0]unde-7-ene (DBU).
- DIPEA N, N-diisopropylethylamine
- DBU 1,8-diazabi cyclo[5.4.0]unde-7-ene
- the inorganic base include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. These may be used alone or in combination stoichiometrically or in excess.
- Non-limiting examples of solvents that can 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 described herein and formulations suitable for administration of the compounds described herein.
- Formulations of pharmaceutical compositions suitable for administration by any medically acceptable means are included in the present invention.
- the pharmaceutical formulation may contain a pharmaceutically acceptable additive or carrier suitable for the means of administration and a pharmaceutically acceptable compound (composition).
- excipients e.g., one or more excipients
- antioxidants e.g., one or more antioxidants
- stabilizers e.g., one or more stabilizers
- preservatives e.g., one or more preservatives
- pH control and/or Buffers e.g., one or more pH adjusting and/or buffering agents
- isotonicity adjusting agents e.g., one or more isotonicity adjusting agents
- thickening agents e.g., one or more thickening agents
- suspending agents e.g., one or more suspending agents
- binding agents e.g.
- One or more binders may be formulations (including pharmaceutical compositions), and are provided as additional pharmaceutically acceptable ingredients for the particular condition being treated.
- the formulation may comprise a combination of additional ingredients (eg, 2, 3, 4, 5, 6, 7, 8 or more additional ingredients) as described herein.
- the additive is, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-beta-cyclo Treatment agents and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as dextrin, polyvinylpyrrolidone, low melting point wax, ion exchange resin, and the like.
- Formulations of the compositions described herein may be inhaled, nasal spray, intravenous, intramuscular injection, intravitreal injection, as an ointment or as a solution, suspension, semi-liquid, semi-solid, gel, semi-solid gel, jelly, emulsion, ointment, tablet, liquid And may be suitable for oral administration which may consist of a cream.
- Tablet form is 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.
- Capsules may contain suitable excipients together with the compound or the compound may be used alone in the shell. All of these formulated compounds can be administered alone, co-administered, intermittently administered, sequentially or simultaneously.
- composition of the present invention includes those that can be administered orally, parenterally, sublingually, transdermally, rectal, transmucosal, topical, through inhalation, through buccal or intranasal administration, or any combination thereof.
- Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intraarterial.
- the compositions of the present invention can be administered as an implant, which allows for slow controlled intravenous administration as well as slow release of the composition.
- Doses administered as single or multiple doses to an individual 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. It will change in various ways.
- the compounds according to the present invention and pharmaceutical formulations 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 its pharmaceutical formulation can be administered together with radiation therapy.
- the present invention includes administration of a compound according to the present invention or a pharmaceutical formulation thereof, and the compound or pharmaceutical formulation thereof according to the present invention is a therapeutically effective amount, and other therapeutic regimens or adjuvants useful for the treatment of cancer (e.g., Multiple drug therapy) to the subject simultaneously or sequentially.
- the 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 is bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, cystic fibrosis, pulmonary viral infection (influenza), pulmonary hypertension, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD), etc.
- the present invention provides the use of a compound represented by Formula 1, a mixture of compounds, or a pharmaceutical composition thereof for the prevention, improvement or treatment of respiratory diseases (inflammatory airway diseases).
- the present invention provides a use of a compound represented by Formula 1 and a pharmaceutical composition thereof as a pendrin inhibitor.
- the present invention relates to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease. (COPD) and the like in one or more selected from the group consisting of respiratory diseases (inflammatory airway diseases) to provide use.
- respiratory diseases inflammatory airway diseases
- the present invention provides the use of a compound represented by Formula 1, 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 a compound represented by Formula 1 and a pharmaceutical composition thereof as a pendrin inhibitor for preventing or improving respiratory diseases (inflammatory airway diseases) as an active ingredient in a health functional food.
- the present invention provides the use of a compound represented by Formula 1 and a pharmaceutical composition thereof, which is an active ingredient in a health functional food, and a chloride channel is specific for the prevention or improvement of respiratory diseases (inflammatory airway diseases).
- a compound represented by Formula 1 and a pharmaceutical composition thereof, which is an active ingredient in a health functional food, and a chloride channel is specific for the prevention or improvement of respiratory diseases (inflammatory airway diseases).
- the present invention provides a use of a compound represented by Formula 1 and a pharmaceutical composition thereof, which is an active ingredient in a health functional food for the prevention or improvement of respiratory diseases (inflammatory airway diseases). ) To preserve the volume and reduce the secretion of mucin.
- the present invention provides a use for preventing or improving respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food
- respiratory disease inflammatory airway disease
- the respiratory disease is asthma, acute or chronic bronchitis, allergy Rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD).
- the name of the compound was generated by ChemDraw Professional V.15.1.
- the compounds according to the present invention include compounds represented by Formula 1, their tautomers, their geometrical isomers (e.g., e, z isomers), optically active forms as their optical isomers, their diaisomers and their racemic forms, as well as , And its pharmaceutically acceptable salts.
- the derivatives exemplified in the present invention can be prepared from readily available starting materials using the following general methods and procedures. Given typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvent, etc.), it will be appreciated that other experimental conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by one of skill in the art using routine optimization procedures.
- the 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).
- Such 2-(4-(trifluoromethyl)benzamido)acetic acid (529 mg, 2.14 mmol) and 1-ethyl-3- (3-dimethylamino) propyl carbodiimide hydrochloride (410 mg, 2.14 mmol) was added sequentially to methylene chloride (21 ml) at room temperature under stirring. ml). Then, 1H-pyrrole-2-carbaldehyde (200 mg, 1.783 mmol) and triethylamine (0.497 ml, 3.567 mmol) were added under stirring at room temperature and stirred at this temperature for 12 hours. The solvent was evaporated under reduced pressure.
- 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 sequentially added to this mixture at room temperature under stirring and the entire mixture was added to 12 Stir for hours at room temperature.
- the solvent was removed under reduced pressure and the resulting solid was obtained by passing 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)-ylidene)methyl)-1H -Indole-1-carboxylate, F4 ) was provided.
- Example 1.10 4-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F10 )
- 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 1.18 4-(thiophen-3-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F18 )
- 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 1.48 4-(furan-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F48 )
- Example 1.60 4-((2-(4-methoxyphenyl)-5-oxooxazole-4(5H)-ylidene)methyl)benzoic acid ( F60 )
- Example 1.62 4-(4-isopropylbenzylidene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F62 )
- Example 1.68 4-((Z)-1-(3-ethyl-5-methoxybenzo[d]thiazole-2(3H)-ylidene)butan-2-ylidene)-2-phenyl Oxazole-5(4H)-one ( F68 )
- Example 1.69 4-((2-(4-acetamidophenyl)-5-oxoxazole-4(5H)-ylidene)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 1.74 4-((7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F74 )
- 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 1.100 2-(benzo[d][1,3]dioxoyl-5-yl)-4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)oxa Zol-5(4H) -on ( 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 )
- Example 1.118 4-((5-bromothiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F118 )
- Example 1.120 4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F120 )
- Example 1.121 4-((5-bromothiophen-2-yl)methylene)-2-(2-(difluoromethoxy)phenyl)oxazol-5(4H)-one ( F121 )
- Example 1.123 4-((1-(2-chlorobenzyl)-1H-pyrazol-4-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F123 )
- Example 1.127 N,N-diethyl-4-(4-(1-methylpyridin-2(1H)-ylidene)-5-oxo-4,5-dihydrooxazol-2-yl)benzene Sulfonamide ( F127 ),
- Example 1.130 4-((1-benzyl-1H-pyrazol-4-yl)methylene)-2-(4-isopropoxyphenyl)oxazol-5(4H)-one ( F130 )
- Example 1.132 4-(4-(1H-1,2,4-thiazol-1-yl)benzylidene)-2-(2-iodophenyl)oxazol-5(4H)-one ( F132 )
- Example 1.136 4-((1-(tert-butyl)-1H-pyrazol-4-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F136 )
- Example 1.137 4-((4-methylthiazol-5-yl)methylene)-2-(4-propylphenyl)oxazol-5(4H)-one ( F137 )
- Example 1.138 4-((1H-pyrrol-2-yl)methylene)-2-(4-butoxyphenyl)oxazol-5(4H)-one ( F138 )
- Example 1.140 4-((1H-indol-2-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F140 )
- Example 1.141 4-(furan-2-ylmethylene)-2-(4-pentylphenyl)oxazol-5(4H)-one ( F141 )
- Example 1.143 4-((1H-pyrrol-2-yl)methylene)-2-(4-propylphenyl)oxazol-5(4H)-one ( F143 )
- Example 1.147 4-((1H-pyrrol-2-yl)methylene)-2-(4-hexylphenyl)oxazol-5(4H)-one ( F147 )
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Abstract
Description
Claims (10)
- 하기 화학식 1로 표시되는 화합물, 그 E- 또는 Z- 이성질체, 그 광학 이성질체, 그 이성질체 2개 혼합물, 그 전구체, 그 약학적으로 허용가능한 염 또는 그 용매화물:[화학식 1]상기 화학식 1에서,V1 및 V2는 아릴, 헤테로아릴, C3 ~ C7 사이클로알킬, 헤테로사이클로알킬, C1 ~ C6 알킬, C1 ~ C6 헤테로알킬, C2 ~ C10 알케닐, C0 ~ C3 메틸렌하이드라진, C2 ~ C10 알키닐, S(O)i(C1 ~ C6 알킬), OS(O)i(아릴), S(O)iNR3R4, C(O)R3, OR3, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4, NR3R4이고, 상기 아릴, 헤테로아릴, C3 ~ C7 사이클로알킬, 헤테로사이클로알킬, C1 ~ C6 알킬, C1 ~ C6 헤테로알킬, C2 ~ C10 알케닐, C0 ~ C3 메틸렌하이드라진, C2 ~ C10 알키닐, S(O)i(C1 ~ C6 알킬), OS(O)i(아릴), S(O)iNR3R4, C(O)R3, OR3, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4 및 NR3R4 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 설파닐, 아릴, C1 ~ C10 알킬아릴, C3 ~ C7 사이클로알킬, 헤테로아릴, 헤테로사이클로알킬, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)iNR3(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, OCR3F2, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4, NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 치환되며, 상기 아릴, C1 ~ C10 알킬아릴, C3 ~ C7 사이클로알킬, 헤테로아릴, 헤테로사이클로알킬, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)iNR3(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, OCR3F2, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4 및 NR3R4 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, C1 ~ C10 알킬아릴, 아릴알킬, C3 ~ C7 사이클로알킬, 헤테로아릴, 헤테로사이클로알킬, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)i(아릴), S(O)i(헤테로아릴), S(O)iNR3(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, OCR3F2, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 치환되고,i 및 j는 독립적으로 0, 1 또는 2이고,R1 및 R2 는 수소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 설파닐, 아릴, C1 ~ C10 알킬아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로 이루어진 군으로부터 독립적으로 선택되고, 상기 아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4 중 하나는 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 치환되고,R3 및 R4는 수소, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 설파닐, 아릴, 아릴(C1 ~ C10 알킬), C1 ~ C10 알킬아릴, 헤테로아릴, 헤테로아릴(C1 ~ C10 알킬), C1 ~ C10 알킬헤테로아릴, C1 ~ C10 알킬, C2 ~ C6 알케닐, C2 ~ C6 알키닐, C3 ~ C6 사이클로알킬, 헤테로사이클일 및 트리플루오로메틸로 이루어진 군으로부터 독립적으로 선택되고, 상기 아릴, 아릴(C1 ~ C10 알킬), C1 ~ C10 알킬아릴, 헤테로아릴, 헤테로아릴(C1 ~ C10 알킬), C1 ~ C10 알킬헤테로아릴, C1 ~ C10 알킬, C2 ~ C6 알케닐, C2 ~ C6 알키닐, C3 ~ C6 사이클로알킬 및 헤테로사이클일 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 치환되고, 또는,R3 및 R4는 4 내지 10원 카보사이클릭, 헤테로사이클릭, 방향족 또는 헤테로방향족 고리로 사이클화될 수 있고, 상기 카보사이클릭, 헤테로사이클릭, 방향족 또는 헤테로방향족 고리 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, C1 ~ C10 알킬아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 치환되고,X1 및 X2 는 O, S, CHR4 및 NR4로 이루어진 군으로부터 독립적으로 선택되고,X3는 수소, OR3, 아릴, 헤테로아릴, C3 ~ C7 사이클로알킬, 헤테로사이클로알킬, C1 ~ C6 알킬, C1 ~ C6 헤테로알킬, C2 ~ C10 알케닐, C0 ~ C3 메틸렌하이드라진, C2 ~ C10 알키닐, S(O)i(C1 ~ C6 알킬), S(O)iNR3, C(O)R3, OC(O)R3, (O)COR3, NR3C(O)OR3, NR3C(O)R3, C(O)NR3 및 NR3R4로 이루어진 군으로부터 선택되고, 상기 OR3, 아릴, 헤테로아릴, C3 ~ C7 사이클로알킬, 헤테로사이클로알킬, C1 ~ C6 알킬, C1 ~ C6 헤테로알킬, C2 ~ C10 알케닐, C0 ~ C3 메틸렌하이드라진, C2 ~ C10 알키닐, S(O)i(C1 ~ C6 알킬), S(O)iNR3, C(O)R3, OC(O)R3, (O)COR3, NR3C(O)OR3, NR3C(O)R3, C(O)NR3 및 NR3R4 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 설파닐, 아릴, C1 ~ C10 알킬아릴, C3 ~ C7 사이클로알킬, 헤테로아릴, 헤테로사이클로알킬, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)iNR3(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, OCR3F2, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4 및 NR3R4 로부터 독립적으로 선택된 하나 이상의 군으로 임의로 선택되고, 상기 아릴, C1 ~ C10 알킬아릴, C3 ~ C7 사이클로알킬, 헤테로아릴, 헤테로사이클로알킬, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)iNR3(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, OCR3F2, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4 및 NR3R4 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 설파닐, 아릴, C1 ~ C10 알킬아릴, 아릴알킬, C3 ~ C7 사이클로알킬, 헤테로아릴, 헤테로사이클로알킬, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)i(아릴), S(O)i(헤테로아릴), S(O)iNR3(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, OCR3F2, OCOR3, NR3C(O)OR4, NR3C(O)R4, C(O)NR3R4 및 NR3R4,로 독립적으로 선택된 하나 이상의 군으로 임의로 치환되고,R5 및 R6은 수소, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 설파닐, 아릴, C1 ~ C10 알킬아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C6 알킬, C2 ~ C6 알케닐, C2 ~ C6 알키닐, C3 ~ C6 사이클로알킬, 헤테로사이클일, 아릴, 헤테로아릴 및 트리플루오로메틸로 이루어진 군으로부터 독립적으로 선택되고, 상기 알킬, 알케닐, 알키닐, 사이클로알킬, 헤테로사이클일, 아릴, C1 ~ C10 알킬아릴, 헤테로아릴 부위 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)i(아릴), S(O)i(헤테로아릴), S(O)iNR3R4, C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 선택되고, 상기 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)i(아릴), S(O)i(헤테로아릴), S(O)iNR3R4, C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4 중 하나는 수소, 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), S(O)i(아릴), S(O)i(헤테로아릴), S(O)iNR3R4, C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 선택되고, 또는,R5 및 A1은 4 내지 10원 카보사이클릭, 헤테로사이클릭, 방향족 또는 헤테로방향족 고리로 사이클화될 수 있고, 상기 카보사이클릭, 헤테로사이클릭, 방향족 또는 헤테로방향족 고리 중 하나는 옥소, 할로겐, 시아노, 아자이도, 니트로, 트리플루오로메틸, 트리플루오로메톡시, 아릴, C1 ~ C10 알킬아릴, 헤테로아릴, 헤테로사이클일, C1 ~ C10 알킬, C2 ~ C10 알케닐, C2 ~ C10 알키닐, C3 ~ C6 사이클로알킬, S(O)i(C1 ~ C6 알킬), C(O)OR3, C(O)R3, OR3, NR3C(O)OR4, C(O)NR3R4 및 NR3R4로부터 독립적으로 선택된 하나 이상의 군으로 임의로 치환된다.
- 제1항에 따른 화합물, 그 E- 또는 Z- 이성질체, 그 광학 이성질체, 그 이성질체 2개 혼합물, 그 전구체, 그 약학적으로 허용가능한 염 또는 그 용매화물을 유효성분으로 포함하는, 호흡기 질환의 예방 또는 치료용 약학 조성물.
- 제2항에 있어서,상기 호흡기 질환은 염증성 기도 질환인, 약학 조성물.
- 제3항에 있어서,상기 염증성 기도 질환은 천식, 급성 또는 만성 기관지염, 알레르기 비염, 급성 호흡기 감염, 급성 상부 호흡기 감염, 낭성 섬유증, 급성 호흡 곤란 증후군(ARDS), 급성 폐 손상(ALI) 및 만성 폐쇄성 폐 질환(COPD)으로 이루어진 군으로부터 선택된 하나 이상인, 약학 조성물.
- 제2항에 있어서,상기 유효성분은 펜드린 억제제로서 작용하는, 약학 조성물.
- 제2항에 있어서,상기 유효성분은 호흡기 질환과 연관된 채널을 특이적으로 제어하는, 약학 조성물.
- 제2항에 있어서,상기 유효성분은 기도 표면 액체(ASL)의 부피를 보존하고 뮤신(mucin)의 분리를 감소시키는, 약학 조성물.
- 제2항에 있어서,약학적으로 허용가능한 담체를 추가로 포함하는, 약학 조성물.
- 제2항에 있어서,다른 약학 성분을 추가로 포함하는, 약학 조성물.
- 제1항에 따른 화합물, 그 E- 또는 Z- 이성질체, 그 광학 이성질체, 그 이성질체 2개 혼합물, 그 전구체, 그 약학적으로 허용가능한 염 또는 그 용매화물을 유효 성분으로 포함하는, 호흡기 질환의 예방 또는 개선용 건강기능식품.
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JP2021559016A JP2022527980A (ja) | 2019-04-02 | 2020-04-01 | 新規化合物およびこれを有効成分として含む呼吸器疾患の予防または治療用組成物 |
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KR102459858B1 (ko) | 2022-10-27 |
CA3135943A1 (en) | 2020-10-08 |
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AU2020253853A1 (en) | 2021-11-11 |
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