JP2022551087A - 新規化合物およびその自己免疫疾患の治療用途 - Google Patents
新規化合物およびその自己免疫疾患の治療用途 Download PDFInfo
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- indol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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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
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
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- 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
- C07D417/12—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 chain containing hetero atoms as chain links
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Abstract
Description
AはC5~C12の単環または二環基であり、
前記環基の各環は1~3個のヘテロ原子で置換されていてもよく、
前記環基はハロゲン、C1~C5のアルキルまたはC1~C5のアルコキシで置換されていてもよい。)
(式中、Q1~Q15はそれぞれ独立してC、NまたはSであり、R7~R30はそれぞれ独立して水素、ハロゲン、C1~C3のアルキルまたはC1~C3のアルコキシであり、Q4がNであると、R11はない。)
(式中、R7~R30はそれぞれ独立して水素、ハロゲン、C1~C3のアルキルまたはC1~C3のアルコキシである。)
(式中、R7~R24はそれぞれ独立して水素、ハロゲン、C1~C3のアルキルまたはC1~C3のアルコキシである。)
(式中、R9~R16はそれぞれ独立して水素、ハロゲン、C1~C3のアルキルまたはC1~C3のアルコキシである。)
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミド;
2-(1H-インドール-3-イル)-N-(3,4,5-トリメトキシフェニル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(3,4,5-トリメトキシフェニル)アセトアミド;
N-(3,5-ジクロロフェニル)-2-(1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(3,5-ジクロロフェニル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(ピリジン-4-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-N-メチル-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)-N-メチルアセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチル-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチルアセトアミド;
2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(6-クロロ-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(チアゾール-2-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(キノリン-2-イル)アセトアミド;および、
2-(5-クロロ-1H-インドール-3-イル)-N-(4,5,6,7-テトラヒドロベンゾ[ジ]チアゾール-2-イル)アセトアミド
(式中、R9~R16はそれぞれ独立して水素、ハロゲン、C1~C3のアルキルまたはC1~C3のアルコキシである。)
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミド;
2-(1H-インドール-3-イル)-N-(3,4,5-トリメトキシフェニル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(3,4,5-トリメトキシフェニル)アセトアミド;
N-(3,5-ジクロロフェニル)-2-(1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(3,5-ジクロロフェニル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(ピリジン-4-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-N-メチル-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)-N-メチルアセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチル-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチルアセトアミド;
2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(6-クロロ-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(チアゾール-2-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(キノリン-2-イル)アセトアミド;および、
2-(5-クロロ-1H-インドール-3-イル)-N-(4,5,6,7-テトラヒドロベンゾ[ジ]チアゾール-2-イル)アセトアミド
室温でN-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)アセトアミド(70.0mg,0.228mmol)のDMF(1mL)溶液をアルゴン雰囲気下で撹拌しながらt-BuOK(74.0mg,0.456mmol)を滴加し、5分間撹拌した。混合物にMeI(28.4μL,0.456mmol)を滴加し、30分間撹拌した。混合物に蒸留水(1mL)を加えて反応を終了した。層を分離し、有機層を蒸留水で洗浄し、無水MgSO4で乾燥し、ろ過した。ろ液を減圧濃縮した後、濃縮液をカラムクロマトグラフィー(SiO2,ヘキサン:EtOAc=4:1)で精製し、白色の標題化合物(39.0mg,51%)を得た。
(1)ステップ1:2-(1H-インドール-3-イル)アセチルクロリドの合成
0℃でインドール-3-酢酸(39.3mg,0.224mmol)のCH2Cl2(1.5mL)溶液をアルゴン雰囲気下で撹拌しながら、オキサリルクロリド(oxalyl chloride)(96.0μL,1.12mmol)およびDMF(1drop)を順次滴加した。反応混合物を1時間撹拌した。混合物を減圧濃縮および真空乾燥し、さらなる精製なしに次の反応に使用した。
0℃で5-クロロ-6-フルオロ-N-メチルピリジン-2-アミン(30.0mg,0.187mmol)のTHF(1mL)溶液をアルゴン雰囲気下で撹拌しながら、n-BuLi(116μL,0.187mmol)を一滴ずつ滴加した。反応混合物を1時間撹拌した。混合物にステップ1で調製した2-(1H-インドール-3-イル)アセチルクロリドのCH2Cl2(0.5mL)溶液を滴加した。混合物を5分間撹拌した後、蒸留水(1mL)を加えて反応を終了した。層を分離し、有機層を蒸留水で洗浄し、無水MgSO4で乾燥し、ろ過した。ろ液を減圧濃縮した後、濃縮液をカラムクロマトグラフィー(SiO2,ヘキサン:EtOAc:CH2Cl2=3:3:1)で精製し、茶色の標題化合物(19.0mg,27%)を得た。
前記製造例6において、酢酸を2-(5-クロロ-1H-インドール-3-イル)酢酸に変更した以外は同様な実験方法を実施し、茶色の標題化合物(11.6mg,15%)を得た。
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミドを用いて、前記製造例5と同様の実験方法で白色の標題化合物(26.4mg,54%)を得た。
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミドを用いて、前記製造例5と同様の実験方法で黄色の標題化合物(7.2mg,54%)を得た。
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミドを用いて、前記製造例5と同様の実験方法で黄色の標題化合物(17.7mg,56%)を得た。
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミドを用いて、前記製造例5と同様の実験方法で白色の標題化合物(8.20mg,27%)を得た。
1.化合物の探索および調製
調製した化合物の標的特異性(target specificity)を確認するために、以下の方法で評価を行った。
本発明による化合物のマクロファージIL-6の産生抑制効果を評価するために、以下の実験を行った。
本発明による化合物の免疫寛容(immune tolerance)誘導効果を調べるために、以下のようにインビトロ(in vitro)調節T細胞(Foxp3+Treg)の産生実験を行った。
本発明による化合物の炎症性腸疾患の治療効果を調べるために、以下のようにC57BL/6マウスに炎症性腸疾患を誘導し、化合物(8、43、40、26、44、54、60)を投与してその効果を評価した(図6~7)。
本発明による化合物の炎症誘導大腸癌の予防効果を調べるために、以下のようにC57BL/6マウスのAOM/DSS誘導大腸癌マウスモデルに化合物40および26を投与し、その効果を評価した(図11)。発癌物質であるAOM(azoxymethane)はマウスへの単独投与によっては大腸癌を発生させないが、DSSで炎症を追加すると大腸癌が発生する。
本発明による化合物の多発性硬化症の治療効果を調べるために、以下のようにC57BL/6マウスに自己免疫脳脊髄炎(EAE)を誘導し、化合物(8、43、40、26)を投与してその効果を評価した(図12~14)。
マウスIL-17A順方向、5’-TTT AAC TCC CTT GGC GCA AAA-3''(配列番号21)と逆方向、5’-CTT TCC CTC CGC ATT GAC AC-3''(配列番号22)。
マウスIL-1β順方向、5’-CTC GTG CTG TCG GAC CCA TAT-3''(配列番号23)と逆方向、5’-TTG AAG ACA AAC CGC TTT TCC A-3''(配列番号24)。
マウスGAPDH順方向、5’-TTC ACC ACC ATG GAG AAG GC-3''(配列番号25)と逆方向、5’-GGC ATG GAC TGT GGT CAT GA-3''(配列番号26)。
マウスIL-10順方向、5’-CAA GGC AGT GGA GCA GGT GAA-3'(配列番号27)と逆方向、5’-CGG AGA GAG GTA CAA ACG AGG TT-3''(配列番号28)。
マウスFoxp3順方向、5’-CCC ATC CCC AGG AGT CTT G-3''(配列番号29)と逆方向、5’-ACC ATG ACT AGG GGC ACT GTA-3''(配列番号30)。
本発明による化合物の移植片対宿主疾患(Graft versus host disease,GVHD)の抑制効果を調べるために、以下のようにC57BL/6マウスに同種骨髄移植で急性移植片対宿主疾患を誘導し、化合物(40、26)を投与してその効果を評価した(図15~16)。
マウスIL-6順方向、5’-CAT GTT CTC TGC GAA ATC GTG G-3’(配列番号33)と逆方向、5’-AAC GCA CTA GGT TTG CCG AGT A-3’(配列番号34)。
マウスIL-10順方向、5’-CAA GGC AGT GGA GCA GGT GAA-3’(配列番号35)と逆方向、5’-CGG AGA GAG GTA CAA ACG AGG TT-3’(配列番号36)。
マウスGAPDH順方向、5’-TTC ACC ACC ATG GAG AAG GC-3’(配列番号37)と逆方向、5’-GGC ATG GAC TGT GGT CAT GA-3’(配列番号38)。
Claims (18)
- R2及びR3がそれぞれ独立してF、ClまたはBrである、請求項1に記載の化合物、その立体異性体またはその薬学的に許容される塩。
- 以下の化合物からなる群より選択される、請求項1に記載の化合物、その立体異性体またはその薬学的に許容される塩。
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)アセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミド;
2-(1H-インドール-3-イル)-N-(3,4,5-トリメトキシフェニル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(3,4,5-トリメトキシフェニル)アセトアミド;
N-(3,5-ジクロロフェニル)-2-(1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(3,5-ジクロロフェニル)アセトアミド;
N-(5-ブロモ-6-メチルピリジン-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(ピリジン-4-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-N-メチル-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1H-インドール-3-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-2-(1H-インドール-3-イル)-N-メチルアセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチル-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)-N-メチルアセトアミド;
2-(5-クロロ-1-メチル-1H-インドール-3-イル)-N-(5-クロロ-6-フルオロピリジン-2-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)-N-メチルアセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-クロロ-1-メチル-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(5-フルオロ-1H-インドール-3-イル)アセトアミド;
N-(ベンゾ[ジ]チアゾール-2-イル)-2-(6-クロロ-1H-インドール-3-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(チアゾール-2-イル)アセトアミド;
2-(5-クロロ-1H-インドール-3-イル)-N-(キノリン-2-イル)アセトアミド;および、
2-(5-クロロ-1H-インドール-3-イル)-N-(4,5,6,7-テトラヒドロベンゾ[ジ]チアゾール-2-イル)アセトアミド - 請求項1~7のいずれか一項に記載の化合物、その立体異性体またはその薬学的に許容される塩を含む薬学組成物。
- 自己免疫疾患の治療または予防用である、請求項8に記載の薬学組成物。
- 多発性硬化症、炎症性腸疾患、移植片対宿主疾患、喘息、アトピー、乾癬、関節リウマチ、全身紅斑ループスおよび1型糖尿病からなる群より選択されるいずれかの自己免疫疾患の治療または予防用である、請求項8に記載の薬学組成物。
- 癌の治療または予防用である、請求項8に記載の薬学組成物。
- 前記癌は、黒色腫、大腸癌、肝癌、膠細胞腫、卵巣癌、大腸癌、頭頸部癌、膀胱癌、腎細胞癌、胃癌、乳癌、転移癌、前立腺癌、胆嚢癌、膵臓癌、血液癌、皮膚癌および肺癌からなる群より選択される、請求項11に記載の癌の治療または予防用薬学組成物。
- 請求項1~7のいずれか一項に記載の化合物、その立体異性体またはその薬学的に許容される塩を、それを必要とする対象に投与するステップを含む自己免疫疾患の治療方法。
- 前記自己免疫疾患は、多発性硬化症、炎症性腸疾患、移植片対宿主疾患、喘息、アトピー、乾癬、関節リウマチ、全身紅斑ループスおよび1型糖尿病からなる群より選択される、請求項13に記載の自己免疫疾患の治療方法。
- 請求項1~7のいずれか一項に記載の化合物、その立体異性体、またはその薬学的に許容される塩を投与するステップを含む、AHRの活性誘導方法。
- 請求項1~7のいずれか1項に記載の化合物、その立体異性体、またはその薬学的に許容される塩を投与するステップを含む、IL-6の産生抑制方法。
- 請求項1~7のいずれか一項に記載の化合物、その立体異性体、またはその薬学的に許容される塩を、それを必要とする対象に投与するステップを含む、癌の治療方法。
- 前記癌は、黒色腫、大腸癌、肝癌、膠細胞腫、卵巣癌、大腸癌、頭頸部癌、膀胱癌、腎細胞癌、胃癌、乳癌、転移癌、前立腺癌、胆嚢癌、膵臓癌、血液癌、皮膚癌および肺癌からなる群より選択される、請求項17に記載の癌の治療方法。
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