JP6377152B2 - RORγtのフェニル結合キノリニルモジュレータ - Google Patents
RORγtのフェニル結合キノリニルモジュレータ Download PDFInfo
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- JP6377152B2 JP6377152B2 JP2016523292A JP2016523292A JP6377152B2 JP 6377152 B2 JP6377152 B2 JP 6377152B2 JP 2016523292 A JP2016523292 A JP 2016523292A JP 2016523292 A JP2016523292 A JP 2016523292A JP 6377152 B2 JP6377152 B2 JP 6377152B2
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- methyl
- mmol
- imidazol
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
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- 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
- 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
- C07D417/14—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 three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
R1はアゼチジニル、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、チアゾリル、ピリジル、ピリジルN−オキシド、ピラジニル、ピリミジニル、ピリダジル(pyridazyl)、ピペリジニル、テトラヒドロピラニル、フェニル、オキサゾリル、イソキサゾリル、チオフェニル、ベンゾオキサゾリル、又はキノリニルであり、前記ピペリジニル、ピリジル、ピリジルN−オキシド、イミダゾリル、フェニル、チオフェニル、ベンゾオキサゾリル、及びピラゾリルは、SO2CH3、C(O)CH3、C(O)NH2、CH3、CH2CH3、CF3、Cl、F、−CN、OCH3、N(CH3)2、−(CH2)3OCH3、SCH3、OH、CO2H、CO2C(CH3)3、又はOCH2OCH3で置換されていてもよく、かつ、Cl、OCH3、及びCH3からなる群から独立して選択される最大2つの更なる置換基により置換されていてもよく、前記トリアゾリル、オキサゾリル、イソキサゾリル、及びチアゾリルは1つ又は2つのCH3基により置換されていてもよく、前記アゼチジニルはCO2C(CH3)3、C(O)NH2、CH3、SO2CH3、又はC(O)CH3により置換されていてもよく、
R2は1−メチル−1,2,3−トリアゾリル、ピリジル、ピリジル−N−オキシド、1−メチルピラゾール−4−イル、ピリミジン−5−イル、ピリダジル、ピラジン−2−イル、オキサゾリル、イソキサゾリル、N−アセチル−アゼチジン−3−イル、N−メチルスルホニル−アゼチジン−3−イル、N−Boc−アゼチジン−3−イル、N−メチル−アゼチジン−3−イル、N−アセトアミジル−アゼチジン−3−イル、N−アセチルピペリジニル、1−H−ピペリジニル、N−Boc−ピペリジニル、N−C(1〜2)アルキル−ピペリジニル(N−メチルピペリジン−4−イルを含む)、チアゾール−5−イル、1−メチルイミダゾール−2−イル、1−(3−メトキシプロピル)−イミダゾール−5−イル、又は1−C(1〜2)アルキルイミダゾール−5−イルであり、前記1−C(1〜2)アルキルイミダゾール−5−イルは、最大2つの更なるCH3基、又はSCH3、及びClからなる群から選択される1つの置換基により置換されていてもよく、前記ピリジル、及びピリジル−N−オキシドは、C(O)NH2、−CN、OCH3、CF3、Cl、及びCH3からなる群から独立して選択される最大2つの置換基により置換されていてもよく、前記チアゾール−5−イル、オキサゾリル、及びイソキサゾリルは最大2つのCH3基により置換されていてもよく、前記1−メチルピラゾール−4−イルは最大2つの更なるCH3基により置換されていてもよく、
R3はH、OH、OCH3、NHCH3、N(CH3)2、又はNH2であり、
R4はH又はFであり、
R5はH、Cl、−CN、CF3、SCH3、OC(1〜3)アルキル、OH、C(1〜4)アルキル、N(CH3)OCH3、NH(C(1〜2)アルキル)、N(C(1〜2)アルキル)2、NH−シクロプロピル、OCHF2、4−ヒドロキシ−ピペリジニル、アゼチジン−1−イル、又はフル−2−イルであり、
R6は2−クロロ−チオフェン−5−イル、1−メチル−ピラゾール−4−イル、ピリジル若しくはフェニル、ピリミジニル、又はピリジルであり、前記フェニル、ピリミジニル、及びピリジルはSO2CH3、NHSO2CH3、CF3、F、Cl、−CN、OCH3、又はOCF3により置換されていてもよく、
R7はH、Cl、−CN、C(1〜4)アルキル、OCH2CF3、OCH2CH2OCH3、CF3、SCH3、SO2CH3、OCHF2、NA1A2、C(O)NHCH3、N(CH3)CH2CH2NA1A2、OCH2CH2NA1A2、OCH2CH2NH2、OC(1〜3)アルキル、OCH2−(1−メチル)−イミダゾール−2−イル、イミダゾール−2−イル、フル−2−イル、ピラゾール−4−イル、ピリド−3−イル、若しくはピリミジン−5−イル;チオフェン−3−イル、1−メチル−インダゾール−5−イル、1−メチル−インダゾール−6−イル、フェニル、又は
A1はH若しくはC(1〜4)アルキル(CH3を含む)であり、
A2はC(1〜4)アルキル(CH3を含む)、シクロプロピル、C(1〜4)アルキルOC(1〜4)アルキル、C(1〜4)アルキルOH、C(O)C(1〜2)アルキル、若しくはOCH3であるか、又はA1及びA2は、結合した窒素と共に、
RaはH、F、OCH3、又はOHであり、
RbはCH3、又はフェニルであり、
R8はH、CH3、OCH3、又はFであり、
R9はH又はFである。)
の化合物及びその医薬的に許容される塩を含む
(ただし、(4−クロロ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−3−イル)メタンアミン、(4−クロロフェニル)(2,4−ジクロロ−3−(2−クロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、(4−クロロ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−4−イル)メタンアミン、(4−クロロフェニル)(3−(2,6−ジクロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)メタノール、(4−クロロ−3−フェニルキノリン−6−イル)(2−(ジメチルアミノ)ピリジン−4−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、4−(2−((4−クロロ−6−((4−クロロフェニル)(ヒドロキシ)(1−メチル−1H−イミダゾール−5−イル)メチル)−3−フェニルキノリン−2−イル)オキシ)エチル)チオモルホリン1,1−ジオキシド、1−(2−((4−クロロ−6−((4−クロロフェニル)(ヒドロキシ)(1−メチル−1H−イミダゾール−5−イル)メチル)−3−フェニルキノリン−2−イル)オキシ)エチル)ピロリジン−2−オン、(2−クロロ−4−(ジメチルアミノ)−3−フェニルキノリン−6−イル)(ピリジン−2−イル)(ピリジン−4−イル)メタノール、(4−クロロ−3−フェニルキノリン−6−イル)(2−フルオロピリジン−4−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、(4−クロロ−2−(1−メチル−1H−ピラゾール−4−イル)−3−フェニルキノリン−6−イル)(4−クロロフェニル)(ピリジン−3−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)ジ(ピリジン−2−イル)メタノール、6−((3−クロロフェニル)(ヒドロキシ)(2−(トリフルオロメチル)ピリジン−4−イル)メチル)−3−フェニルキノリン−2−カルボニトリル、(2,4−ジクロロ−8−メチル−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−4−イル)(6−メチルピリジン−3−イル)メタノール、(4−クロロフェニル)(2,4−ジクロロ−3−(2−クロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)(フェニル)(ピリジン−2−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)(オキサゾール−2−イル)(フェニル)メタノール、(4−メトキシ−3−フェニル−2−(トリフルオロメチル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−2−イル)メタノールの第2の溶出エナンチオマー、及び(4−クロロ−2−メトキシ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)ピリミジン−2−イルメタノールの第2の溶出エナンチオマー(chiralcel ODカラムで精製した場合)は実施形態から除く)。
R1はアゼチジニル、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、チアゾリル、ピリジル、ピリジルN−オキシド、ピラジニル、ピリミジニル、ピリダジル、ピペリジニル、テトラヒドロピラニル、フェニル、オキサゾリル、イソキサゾリル、チオフェニル、ベンゾオキサゾリル、又はキノリニルであり、前記ピペリジニル、ピリジル、ピリジルN−オキシド、イミダゾリル、フェニル、チオフェニル、ベンゾオキサゾリル、及びピラゾリルは、SO2CH3、C(O)CH3、C(O)NH2、CH3、CH2CH3、CF3、Cl、F、−CN、OCH3、N(CH3)2、−(CH2)3OCH3、SCH3、OH、CO2H、CO2C(CH3)3、又はOCH2OCH3で置換されていてもよく、かつ、Cl、OCH3、及びCH3からなる群から独立して選択される最大2つの更なる置換基により置換されていてもよく、前記トリアゾリル、オキサゾリル、イソキサゾリル、及びチアゾリルは1つ又は2つのCH3基により置換されていてもよく、前記アゼチジニルはCO2C(CH3)3、C(O)NH2、CH3、SO2CH3、又はC(O)CH3により置換されていてもよく、
R2は1−メチル−1,2,3−トリアゾリル、ピリジル、ピリジル−N−オキシド、1−メチルピラゾール−4−イル、ピリミジン−5−イル、ピリダジル、ピラジン−2−イル、オキサゾリル、イソキサゾリル、N−アセチル−アゼチジン−3−イル、N−メチルスルホニル−アゼチジン−3−イル、N−Boc−アゼチジン−3−イル、N−メチル−アゼチジン−3−イル、N−アセトアミジル−アゼチジン−3−イル、N−アセチルピペリジニル、1−H−ピペリジニル、N−Boc−ピペリジニル、N−C(1〜2)アルキル−ピペリジニル(N−メチルピペリジン−4−イルを含む)、チアゾール−5−イル、1−メチルイミダゾール−2−イル、1−(3−メトキシプロピル)−イミダゾール−5−イル、又は1−C(1〜2)アルキルイミダゾール−5−イルであり、前記1−C(1〜2)アルキルイミダゾール−5−イルは、最大2つの更なるCH3基、又はSCH3、及びClからなる群から選択される1つの置換基により置換されていてもよく、前記ピリジル、及びピリジル−N−オキシドは、C(O)NH2、−CN、OCH3、CF3、Cl、及びCH3からなる群から独立して選択される最大2つの置換基により置換されていてもよく、前記チアゾール−5−イル、オキサゾリル、及びイソキサゾリルは最大2つのCH3基により置換されていてもよく、前記1−メチルピラゾール−4−イルは最大2つの更なるCH3基により置換されていてもよく、
R3はH、OH、OCH3、NHCH3、N(CH3)2、又はNH2であり、
R4はH又はFであり、
R5はH、Cl、−CN、CF3、SCH3、OC(1〜3)アルキル、OH、C(1〜4)アルキル、N(CH3)OCH3、NH(C(1〜2)アルキル)、N(C(1〜2)アルキル)2、NH−シクロプロピル、OCHF2、4−ヒドロキシ−ピペリジニル、アゼチジン−1−イル、又はフル−2−イルであり、
R6は2−クロロ−チオフェン−5−イル、1−メチル−ピラゾール−4−イル、ピリジル若しくはフェニル、ピリミジニル、又はピリジルであり、前記フェニル、ピリミジニル、及びピリジルはSO2CH3、NHSO2CH3、CF3、F、Cl、−CN、OCH3、又はOCF3により置換されていてもよく、
R7はH、Cl、−CN、C(1〜4)アルキル、OCH2CF3、OCH2CH2OCH3、CF3、SCH3、SO2CH3、OCHF2、NA1A2、C(O)NHCH3、N(CH3)CH2CH2NA1A2、OCH2CH2NA1A2、OCH2CH2NH2、OC(1〜3)アルキル、OCH2−(1−メチル)−イミダゾール−2−イル、イミダゾール−2−イル、フル−2−イル、ピラゾール−4−イル、ピリド−3−イル、若しくはピリミジン−5−イル;チオフェン−3−イル、1−メチル−インダゾール−5−イル、1−メチル−インダゾール−6−イル、フェニル、又は
A1はH若しくはC(1〜4)アルキル(CH3を含む)であり、
A2はC(1〜4)アルキル(CH3を含む)、シクロプロピル、C(1〜4)アルキルOC(1〜4)アルキル、C(1〜4)アルキルOH、C(O)C(1〜2)アルキル、若しくはOCH3であるか、又はA1及びA2は、結合した窒素と共に、
RaはH、F、OCH3、又はOHであり、
RbはCH3、又はフェニルであり、
R8はH、CH3、OCH3、又はFであり、
R9はH又はFである。)
の化合物及びその医薬的に許容される塩を含む
(ただし、(4−クロロ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−3−イル)メタンアミン、(4−クロロフェニル)(2,4−ジクロロ−3−(2−クロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、(4−クロロ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−4−イル)メタンアミン、(4−クロロフェニル)(3−(2,6−ジクロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)メタノール、(4−クロロ−3−フェニルキノリン−6−イル)(2−(ジメチルアミノ)ピリジン−4−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、4−(2−((4−クロロ−6−((4−クロロフェニル)(ヒドロキシ)(1−メチル−1H−イミダゾール−5−イル)メチル)−3−フェニルキノリン−2−イル)オキシ)エチル)チオモルホリン1,1−ジオキシド、1−(2−((4−クロロ−6−((4−クロロフェニル)(ヒドロキシ)(1−メチル−1H−イミダゾール−5−イル)メチル)−3−フェニルキノリン−2−イル)オキシ)エチル)ピロリジン−2−オン、(2−クロロ−4−(ジメチルアミノ)−3−フェニルキノリン−6−イル)(ピリジン−2−イル)(ピリジン−4−イル)メタノール、(4−クロロ−3−フェニルキノリン−6−イル)(2−フルオロピリジン−4−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、(4−クロロ−2−(1−メチル−1H−ピラゾール−4−イル)−3−フェニルキノリン−6−イル)(4−クロロフェニル)(ピリジン−3−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)ジ(ピリジン−2−イル)メタノール、6−((3−クロロフェニル)(ヒドロキシ)(2−(トリフルオロメチル)ピリジン−4−イル)メチル)−3−フェニルキノリン−2−カルボニトリル、(2,4−ジクロロ−8−メチル−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−4−イル)(6−メチルピリジン−3−イル)メタノール、(4−クロロフェニル)(2,4−ジクロロ−3−(2−クロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)(フェニル)(ピリジン−2−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)(オキサゾール−2−イル)(フェニル)メタノール、(4−メトキシ−3−フェニル−2−(トリフルオロメチル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−2−イル)メタノールの第2の溶出エナンチオマー、及び(4−クロロ−2−メトキシ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)ピリミジン−2−イルメタノールの第2の溶出エナンチオマー(chiralcel ODカラムで精製した場合)は実施形態から除く)。
R1はイミダゾリル、チアゾリル、ピリジル、ピリミジニル、又はフェニルであり、前記ピリジル、及び前記フェニルは−CN、CF3、F、又はClにより置換されていてもよく、前記イミダゾリル、及び前記チアゾリルは1つ又は2つのCH3基により置換されていてもよく、
R2は1−メチル−1,2,3−トリアゾール−5−イル、N−アセチルピペリジン−4−イル、N−Boc−ピペリジン−4−イル、N−メチルピペリジン−4−イル、1−H−ピペリジン−4−イル、オキサゾール−2−イル、2,4−ジメチルチアゾール−5−イル、1−メチルイミダゾール−2−イル、1−メチル−イミダゾール−5−イル、又はピリジルであり、前記ピリジルはCF3により置換されていてもよく、
R3はH、OHであり、
R4はHであり、
R5はH、Cl、−CN、C(1〜4)アルキル、OC(1〜2)アルキル、SCH3、N(CH3)2又はN(CH3)OCH3であり、
R6は2−クロロ−チオフェン−5−イル、1−メチル−ピラゾール−4−イル、フェニル、ピリミジニル、又はピリジルであり、前記フェニル、ピリミジニル、及びピリジルはSO2CH3、NHSO2CH3、CF3、Cl、−CN、OCF3又はOCH3により置換されていてもよく、
R7は、Cl、−CN、CF3、SCH3、OCH2CF3、NA1A2、N(CH3)CH2CH2NA1A2、OC(1〜3)アルキル、OCH2CH2OCH3、OCH2CH2NA1A2又はOCH2CH2NH2であり、
A1はH若しくはCH3であり、
A2はOCH3、CH3、CH2CH2OH、C(O)C(1〜2)アルキル、若しくはCH2CH2OCH3であるか、又はA1及びA2は、結合した窒素と共に、
R8はH又はCH3であり、
R9はHであり、
その医薬的に許容される塩を含む
(ただし、(4−クロロフェニル)(2,4−ジクロロ−3−(2−クロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)メタノール、6−((3−クロロフェニル)(ヒドロキシ)(2−(トリフルオロメチル)ピリジン−4−イル)メチル)−3−フェニルキノリン−2−カルボニトリル、(2,4−ジクロロ−3−フェニルキノリン−6−イル)ジ(ピリジン−2−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)(フェニル)(ピリジン−2−イル)メタノール、(2−クロロ−4−(ジメチルアミノ)−3−フェニルキノリン−6−イル)(ピリジン−2−イル)(ピリジン−4−イル)メタノール、(4−クロロフェニル)(2,4−ジクロロ−3−(2−クロロフェニル)キノリン−6−イル)(1−メチル−1H−イミダゾール−2−イル)メタノール、(2,4−ジクロロ−3−フェニルキノリン−6−イル)(オキサゾール−2−イル)(フェニル)メタノール、(4−メトキシ−3−フェニル−2−(トリフルオロメチル)キノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−2−イル)メタノールの第2の溶出エナンチオマー、及び(4−クロロ−2−メトキシ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)ピリミジン−2−イルメタノールの第2の溶出エナンチオマー(chiralcel ODカラムで精製した場合)は実施形態から除く)。
及びその医薬的に許容される塩である。
本発明の方法に関し、用語「投与する」とは、式Iの化合物、又はその形成物、組成物若しくは薬剤を使用することによる、本明細書に記載した症候群、障害又は病気の治療的若しくは予防的な予防、治療又は緩和方法を意味する。かかる方法は、有効量の上記化合物、化合物形成物、組成物又は薬剤を、一連の治療の異なる時点で又は組み合わせ形式で同時に投与することを含む。本発明の方法は、既知の治療学的処置レジメンを全て包含するものとして理解されなければならない。
医薬的に許容される酸性/陰イオンの塩としては、酢酸塩、ベンゼンスルホン酸塩、安息香酸塩、重炭酸塩、酒石酸水素塩、臭化物、エデト酸カルシウム、カンシル酸塩、炭酸塩、塩化物、クエン酸塩、二塩酸塩、エデト酸塩、エジシル酸塩、エストル酸塩、エシル酸塩、フマル酸塩、グルセプト酸塩、グルコン酸塩、グルタミン酸塩、グリコリルアルサニル酸塩、ヘキシルレソルシン酸塩、ヒドラバミン、臭化水素酸塩、塩酸塩、ヒドロキシナフトエ酸塩、ヨウ化物、イセチオン酸塩、乳酸塩、ラクトビオン酸塩、リンゴ酸塩、マレイン酸塩、マンデル酸塩、メシル酸塩、メチル臭化物、メチル硝酸塩、メチル硫酸塩、ムコ酸塩、ナプシル酸塩、硝酸塩、パモ酸塩、パントテン酸塩、リン酸塩/二リン酸塩、ポリガラクツロン酸塩、サリチル酸塩、ステアリン酸塩、塩基性酢酸塩、コハク酸塩、硫酸塩、タンニン酸塩、酒石酸塩、テオクル酸塩、トシル酸塩及びトリエチオジドが挙げられるが、これらに限定されない。有機又は無機酸としてはまた、ヨウ化水素酸、過塩素酸、硫酸、リン酸、プロピオン酸、グリコール酸、メタンスルホン酸、ヒドロキシエタンスルホン酸、シュウ酸、2−ナフタレンスルホン酸、p−トルエンスルホン酸、シクロヘキサンスルファミン酸、サッカリン酸、又はトリフルオロ酢酸も挙げられるが、これらに限定されない。
本発明は、予防、治療又は緩和を必要とする対象に、有効量の式Iの化合物、又はその形成物、組成物若しくは薬剤を投与することを含む、RORγtが媒介する炎症性症候群、障害又は病気の予防、治療又は緩和方法に関する。
更に、本発明の化合物は、1種類若しくは2種類以上の多形体又は非晶質結晶性形態を有してよく、これらの形態も本発明の範囲に含まれるものとする。加えて、化合物は、例えば水(すなわち、水和物)又は一般的な有機溶媒と共に溶媒和物を形成してよい。本明細書で使用するとき、用語「溶媒和物」は、本発明の化合物と1種類若しくは2種類以上の溶媒分子との物理的会合を意味する。この物理的会合は、水素結合を含む、イオン結合及び共有結合の度合いが変化することを伴う。特定の場合、例えば、1つ若しくは2つ以上の溶媒分子が結晶固形物の結晶格子内に組み込まれている場合には、溶媒和物を単離することができる。用語「溶媒和物」は、溶液相及び分離可能な溶媒和物の両方を包含することを意図する。好適な溶媒和物の非限定例としては、エタノレート、メタノレート等が挙げられる。
本明細書において、及び本願を通して、以下の略語を使用することができる。
本発明における式Iの化合物を、当業者に既知の一般的な合成方法に従い合成することができる。以下の反応スキームは、本発明の代表的な実施例であるということのみを意味し、すなわち本発明の限定であることは全く意味しない。
tert−ブチル4−(ヒドロキシ(1−メチル−1H−イミダゾール−5−イル)メチル)ピペリジン−1−カルボキシレート
tert−ブチル4−(1−メチル−1H−イミダゾール−5−カルボニル)ピペリジン−1−カルボキシレート
1−(4−(1−メチル−1H−イミダゾール−5−カルボニル)ピペリジン−1−イル)エタノン
6−(トリフルオロメチル)ニコチノイルクロリド
N−メトキシ−N−メチル−6−(トリフルオロメチル)ニコチンアミド
(1−メチル−1H−イミダゾール−5−イル)(6−(トリフルオロメチル)ピリジン−3−イル)メタノン
6−ブロモ−2,4−ジクロロ−8−メチル−3−フェニルキノリン
1−(4−ベンゾイルピペリジン−1−イル)エタノン
2−(3−(トリフルオロメチル)フェニル)アセチルクロリド
メチル5−ブロモ−2−(2−(3−(トリフルオロメチル)フェニル)アセトアミド)ベンゾエート
6−ブロモ−4−ヒドロキシ−3−(3−(トリフルオロメチル)フェニル)キノリン−2(1H)−オン
6−ブロモ−2,4−ジクロロ−3−(3−(トリフルオロメチル)フェニル)キノリン
6−ブロモ−4−クロロ−2−メトキシ−3−(3−(トリフルオロメチル)フェニル)キノリン
(1−メチル−1H−1,2,3−トリアゾール−5−イル)(1−メチル−1H−イミダゾール−5−イル)メタノール
(1−メチル−1H−1,2,3−トリアゾール−5−イル)(1−メチル−1H−イミダゾール−5−イル)メタノン
メチル5−ブロモ−2−(2−フェニルアセトアミド)ベンゾエート
6−ブロモ−4−ヒドロキシ−3−フェニルキノリン−2(1H)−オン
6−ブロモ−2,4−ジクロロ−3−フェニルキノリン
4−クロロ−N−メトキシ−N−メチルベンズアミド
(4−クロロフェニル)(1−メチル−1H−イミダゾール−5−イル)メタノン
メチル5−ブロモ−2−(2−(ピリジン−2−イル)アセトアミド)ベンゾエート
6−ブロモ−3−(ピリジン−2−イル)キノリン−2,4(1H、3H)−ジオン
6−ブロモ−2,4−ジクロロ−3−(ピリジン−2−イル)キノリン
メチル5−ブロモ−2−(2−(ピリジン−3−イル)アセトアミド)ベンゾエート
6−ブロモ−3−(ピリジン−3−イル)キノリン−2,4(1H、3H)−ジオン
6−ブロモ−2,4−ジクロロ−3−(ピリジン−3−イル)キノリン
メチル2−(2−(ベンジルオキシ)アセトアミド)−5−ブロモベンゾエート
3−(ベンジルオキシ)−6−ブロモ−4−ヒドロキシキノリン−2(1H)−オン
3−(ベンジルオキシ)−6−ブロモ−2,4−ジクロロキノリン
(3−(ベンジルオキシ)−2,4−ジクロロキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(6−(トリフルオロメチル)ピリジン−3−イル)メタノール
(3−(ベンジルオキシ)−4−クロロ−2−メトキシキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(6−(トリフルオロメチル)ピリジン−3−イル)メタノール
4−クロロ−6−(ヒドロキシ(1−メチル−1H−イミダゾール−5−イル)(6−(トリフルオロメチル)ピリジン−3−イル)メチル)−2−メトキシキノリン−3−オール
4−クロロ−6−(ヒドロキシ(1−メチル−1H−イミダゾール−5−イル)(6−(トリフルオロメチル)ピリジン−3−イル)メチル)−2−メトキシキノリン−3−イルトリフルオロメタンスルホネート
(1−メチル−1H−イミダゾール−5−イル)(ピリジン−2−イル)メタノール
(1−メチル−1H−イミダゾール−5−イル)(ピリジン−2−イル)メタノン
ジエチル2−(4−(トリフルオロメトキシ)フェニル)マロネート
2−(4−(トリフルオロメトキシ)フェニル)マロン酸
6−ブロモ−2,4−ジクロロ−8−メチル−3−(4−(トリフルオロメトキシ)フェニル)キノリン
6−ブロモ−4−クロロ−2−メトキシ−8−メチル−3−(4−(トリフルオロメトキシ)フェニル)キノリン
tert−ブチル4−(ヒドロキシ(6−(トリフルオロメチル)ピリジン−3−イル)メチル)ピペリジン−1−カルボキシレート
tert−ブチル4−(6−(トリフルオロメチル)ニコチノイル)ピペリジン−1−カルボキシレート
ピペリジン−4−イル(6−(トリフルオロメチル)ピリジン−3−イル)メタノン
1−(4−(6−(トリフルオロメチル)ニコチノイル)ピペリジン−1−イル)エタノン
N−メトキシ−N−メチルピリミジン−2−カルボキサミド
(1−メチル−1H−イミダゾール−5−イル)(ピリミジン−2−イル)メタノン
(2,4−ジメチルチアゾール−5−イル)(1−メチル−1H−1,2,3−トリアゾール−5−イル)メタノール
(2,4−ジメチルチアゾール−5−イル)(1−メチル−1H−1,2,3−トリアゾール−5−イル)メタノン
N−メトキシ−N,2,4−トリメチルチアゾール−5−カルボキサミド
(2,4−ジメチルチアゾール−5−イル)(1−メチル−1H−イミダゾール−5−イル)メタノン
(2,4−ジクロロ−3−フェニルキノリン−6−イル)(1,2−ジメチル−1H−イミダゾール−5−イル)メタノール
(2,4−ジクロロ−3−フェニルキノリン−6−イル)(1,2−ジメチル−1H−イミダゾール−5−イル)メタノン
6−ブロモ−3−フェニル−2−(トリフルオロメチル)キノリン−4−オール
6−ブロモ−4−クロロ−3−フェニル−2−(トリフルオロメチル)キノリン
6−ヨード−3−フェニル−2−(トリフルオロメチル)キノリン−4−オール
4−クロロ−6−ヨード−3−フェニル−2−(トリフルオロメチル)キノリン
tert−ブチル4−ニコチノイルピペリジン−1−カルボキシレート
(3−クロロフェニル)(6−(トリフルオロメチル)ピリジン−3−イル)メタノン
(3−クロロフェニル)(2,4−ジクロロ−3−フェニルキノリン−6−イル)(6−(トリフルオロメチル)ピリジン−3−イル)メタノール
N−メトキシ−N−メチル−2−(トリフルオロメチル)イソニコチンアミド
(3−クロロフェニル)(2−(トリフルオロメチル)ピリジン−4−イル)メタノン
(3−クロロフェニル)(2,4−ジクロロ−3−フェニルキノリン−6−イル)(ピリジン−3−イル)メタノール
N−メトキシ−N−メチルイソニコチンアミド
(1−メチル−1H−イミダゾール−5−イル)(ピリジン−4−イル)メタノン
(2,4−ジクロロ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−4−イル)メタノール・TFA
(4−ブチル−2−クロロ−3−フェニルキノリン−6−イル)(1−メチル−1H−イミダゾール−5−イル)(ピリジン−4−イル)メタノール・TFA
(2,4−ジクロロ−3−フェニルキノリン−6−イル)(ピリジン−2−イル)(ピリジン−4−イル)メタノール・TFA
2−フルオロ−N−メトキシ−N−メチルイソニコチンアミド
(2−フルオロピリジン−4−イル)(1−メチル−1H−イミダゾール−2−イル)メタノン
tert−ブチル4−((2,4−ジクロロ−3−フェニルキノリン−6−イル)(ヒドロキシ)(ピリジン−3−イル)メチル)ピペリジン−1−カルボキシレート
(4−クロロフェニル)(2,4−ジメチルチアゾール−5−イル)メタノン
N−(4−ブロモフェニル)−2−フェニルアセトアミド
6−ブロモ−2−クロロ−3−フェニルキノリン
メチル5−ブロモ−2−(2−(2−クロロフェニル)アセトアミド)ベンゾエート
6−ブロモ−3−(2−クロロフェニル)−4−ヒドロキシキノリン−2(1H)−オン
6−ブロモ−2,4−ジクロロ−3−(2−クロロフェニル)キノリン
ThermoFluor(登録商標)アッセイ
ThermoFluor(登録商標)は、タンパク質の熱安定性におけるリガンドの効果を測定することによりリガンドの結合親和性を推定する、蛍光ベースアッセイである(Pantoliano,M.W.,Petrella,E.C.,Kwasnoski,J.D.,Lobanov,V.S.,Myslik,J.,Graf,E.,Carver,T.,Asel,E.,Springer,B.A.,Lane,P.,and Salemme,F.R.(2001)High−density miniaturized thermal shift assays as a general strategy for drug discovery.J Biomol Screen 6,429〜40,and Matulis,D.,Kranz,J.K.,Salemme,F.R.,and Todd,M.J.(2005)Thermodynamic stability of carbonic anhydrase:measurements of binding affinity and stoichiometry using ThermoFluor.Biochemistry 44,5258〜66)。本手法は多種多様の系に適用可能であり、平衡結合定数(KD)の定量化による理論解釈において正確である。
ThermoFluor(登録商標)アッセイで使用したRORγt構築物に関し、ヌクレオチド配列のナンバリングは、ヒトRORγtに対する参照配列である、転写変異体2、NCBIアクセッション:NM_001001523.1(配列番号1)に基づいている。野生型ヒトRORγtリガンド結合領域(RORγt LBD)をコードするヌクレオチド850〜1635(配列番号2)を、改変型pET大腸菌発現ベクターであるpHIS1ベクター(Accelagen、San Diego)内にクローニングした。このベクターは、クローニングした挿入配列の上流に、インフレームのN末端Hisタグ及びTurboTEVプロテアーゼ切断部位(ENLYFQG、配列番号3)を含有する。Thermofluorアッセイで使用したRORγt構築物に対するアミノ酸配列を、配列番号4として示す。
RORγt 0.065mg/mL
1,8−ANS 60μm
Hepes 100mM、pH7.0
NaCl 10mM
GSH 2.5mM
Tween−20 0.002%
基準RORγt Tm;47.8℃
ΔH(Tm)=115kcal/mol
ΔCp(Tm)=3kcal/mol
細胞ベースの生物学的データ
RORγtレポーターアッセイ
Th17分化に望ましい条件下でCD4 T細胞により産生されるIL−17に対するRORγtモジュレータ化合物の効果を、ヒトTh17アッセイにより試験する。製造元の使用説明書(Miltenyi Biotec)に従って、CD4+T細胞単離キットIIを使用し、健康なドナーの末梢血単核細胞(PBMC)から、全ての(total)CD4+T細胞を単離した。10%ウシ胎児血清、ペニシリン、ストレプトマイシン、グルタミン酸、及びβ−メルカプトエタノールを含むRPMI−1640培地に細胞を再懸濁し、各ウェル毎に100μL当たり1.5×105個で96ウェルプレートに加えた。DMSOで滴定した濃度にて、50μLの化合物を、最終的なDMSO濃度0.2%にて各ウェルに加えた。細胞を1時間インキュベートし、次に50μLのTh17細胞分化培地を各ウェルに加えた。分化培地中での抗体及びサイトカイン(R&D Systems)の最終濃度は、3×106個/mLの抗CD3/CD28ビーズ(ヒトT細胞活性化/増殖キット(Miltenyi Biotec)を使用して調製)、10μg/mLの抗IL4、10μg/mLの抗IFNγ、10ng/mLのIL1β、10ng/mLのIL23、50ng/mLのIL6、3ng/mLのTGFβ及び20U/mLのIL2であった。細胞は37℃及び5% CO2で3日間培養した。上清を回収し、MULTI−SPOT(登録商標)サイトカインプレートを使用して、製造元の使用説明書(Meso Scale Discovery)に従い、培養物中に蓄積されたIL−17を測定した。Sector Imager 6000を使用してプレートを読み取り、検量線からIL−17濃度を外挿した。IC50はGraphPadにより決定した。
Claims (18)
-
- 請求項1に記載の化合物と、医薬的に許容される担体とを含む、医薬組成物。
- 請求項1に記載の化合物と、医薬的に許容される担体とを混合することにより製造される、医薬組成物。
- 請求項1に記載の化合物と、医薬的に許容される担体とを混合することを含む、医薬組成物の製造プロセス。
- RORγtが媒介する炎症性症候群、障害若しくは病気の治療又は緩和するためのものである、請求項2又は3に記載の医薬組成物。
- 前記病気は、炎症性腸疾患、関節リウマチ、乾癬、慢性閉塞性肺疾患、乾癬性関節炎、強直性脊椎炎、好中球性ぜんそく、ステロイド抵抗性ぜんそく、多発性硬化症、及び全身性エリテマトーデスからなる群から選択される、請求項5に記載の医薬組成物。
- 前記病気は乾癬である、請求項5に記載の医薬組成物。
- 前記病気は関節リウマチである、請求項5に記載の医薬組成物。
- 前記炎症性腸疾患は潰瘍性大腸炎である、請求項6に記載の医薬組成物。
- 前記炎症性腸疾患はクローン病である、請求項6に記載の医薬組成物。
- 前記病気は多発性硬化症である、請求項5に記載の医薬組成物。
- 前記病気は好中球性ぜんそくである、請求項5に記載の医薬組成物。
- 前記病気はステロイド抵抗性ぜんそくである、請求項5に記載の医薬組成物。
- 前記病気は乾癬性関節炎である、請求項5に記載の医薬組成物。
- 前記病気は強直性脊椎炎である、請求項5に記載の医薬組成物。
- 前記病気は全身性エリテマトーデスである、請求5に記載の医薬組成物。
- 前記病気は慢性閉塞性肺疾患である、請求5に記載の医薬組成物。
- 1種類若しくは2種類以上の抗炎症剤、又は免疫抑制剤と組み合わせてなる、請求項2、3及び5〜17のいずれか1項に記載の医薬組成物。
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