JP2018519244A - ピロリジンカルボキサミド誘導体ならびにその調製および使用方法 - Google Patents
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Abstract
Description
[式1]
式中:nは0、1または2であり;Aは-a1-であり、これは、アラニン、(Ala,A)、アルギニン(Arg,R)、アスパラギン(Asn,N)、アスパラギン酸(Asp,D)、システイン(Cys,C)、グルタミン酸(Glu,E)、グルタミン(Gln,Q)、グリシン(Gly,G)、ヒスチジン(His,H)、イソロイシン(Ile,I)、ロイシン(Leu,L)、リシン(Lys,K)、メチオニン(Met,M)、フェニルアラニン(Phe,F)、プロリン(Pro,P)、セリン(Ser,S)、トレオニン(Thr,T)、トリプトファン(Trp,W)、チロシン(Tyr,Y)およびバリン(Val,V)からなる群より独立して選択されるアミノ酸であり、該アミノ酸の両末端はカルボニル基またはアミン基にアミド結合によって連結され;R1は、直鎖もしくは分枝鎖のC1〜36アルキル、少なくとも1つの二重結合を含む直鎖もしくは分枝鎖のC2〜36アルケニル、または少なくとも1つの三重結合を含む直鎖もしくは分枝鎖のC2〜36アルキニルである。
特記しない限りは、本明細書で用いる科学技術用語はすべて、本開示が属する技術分野の当業者に一般的に理解されている意味を有する。以下の参考文献(これらは引用により本明細書に組み込まれる)は当業者に、本明細書で用いている用語の多くの一般的な定義を示すものである:The Cambridge Dictionary of Science and Technology(Walker編, 1988);The Glossary of Genetics,5版, R.Rieger et.al.(編),Springer Verlag(1991);およびHale & Marham,The Harper Collins Dictionary of Biology(1991)。本明細書で用いる場合、以下の用語は、特に指定のない限り、以下にその用語に対して示した意味を有する。
上記に論考したように、本発明の一態様により、下記の式1で表される化合物、その光学異性体、またはその医薬上許容される塩を提供する。
[式1]
式中:nは0、1または2であり;Aは-a1-であり、これは、アラニン、(Ala,A)、アルギニン(Arg,R)、アスパラギン(Asn,N)、アスパラギン酸(Asp,D)、システイン(Cys,C)、グルタミン酸(Glu,E)、グルタミン(Gln,Q)、グリシン(Gly,G)、ヒスチジン(His,H)、イソロイシン(Ile,I)、ロイシン(Leu,L)、リシン(Lys,K)、メチオニン(Met,M)、フェニルアラニン(Phe,F)、プロリン(Pro,P)、セリン(Ser,S)、トレオニン(Thr,T)、トリプトファン(Trp,W)、チロシン(Tyr,Y)およびバリン(Val,V)からなる群より独立して選択されるアミノ酸であり、該アミノ酸の両末端はカルボニル基またはアミン基にアミド結合によって連結され;R1は、直鎖もしくは分枝鎖のC1〜36アルキル、少なくとも1つの二重結合を含む直鎖もしくは分枝鎖のC2〜36アルケニル、または少なくとも1つの三重結合を含む直鎖もしくは分枝鎖のC2〜36アルキニルである。
[式A]
本発明のもう一つの態様により、式1で表される化合物を調製するための方法を提供する。方法は、以下に示す反応図式1に例示したように:化合物2を化合物3と反応させて化合物4を調製すること(工程1);化合物4を塩基の存在下で加水分解させて化合物5を調製すること(工程2);化合物5を化合物6と反応させて化合物7を調製すること(工程3);化合物7を塩基の存在下で加水分解させて化合物8を調製すること(工程4);化合物8を化合物9と反応させて化合物10を調製すること(工程5);化合物10を塩基の存在下で加水分解させて式Iの化合物を調製すること(工程6)を含むものである。
[反応図式1]
ここで、A、R1およびnは請求項1に規定したものと同じであり、R2は直鎖または分枝鎖のC1〜5アルキルである。
反応図式1の出発物質である下記の式2で表される化合物2の例は、例えば、以下に示す調製方法Aによって調製され得る。
[式2]
以下に示す式aで表される化合物は、アラニン、(Ala,A)、アルギニン(Arg,R)、アスパラギン(Asn,N)、アスパラギン酸(Asp,D)、システイン(Cys,C)、グルタミン酸(Glu,E)、グルタミン(Gln,Q)、グリシン(Gly,G)、ヒスチジン(His,H)、イソロイシン(Ile,I)、ロイシン(Leu,L)、リシン(Lys,K)、メチオニン(Met,M)、フェニルアラニン(Phe,F)、プロリン(Pro,P)、セリン(Ser,S)、トレオニン(Thr,T)、トリプトファン(Trp,W)、チロシン(Tyr,Y)およびバリン(Val,V)よりなる群から選択されるアミノ酸と、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、ヒドロキシベンゾトリアゾールおよび塩基の存在下で連結されてアミド結合を形成し、それにより化合物2が調製される。
[式a]
本発明のさらにもう一つの態様により、種々の疾患(例えば、炎症性の適応症、がん、および眼科系の適応症)を予防、改善および処置するための組成物であって、活性成分として少なくとも1種類の該化合物、少なくとも1種類の該光学異性体または少なくとも1種類の該塩を含む組成物を提供する。
本発明のさらなる一態様により、必要とするる被験体に該組成物(または本明細書に記載の化合物もしくは製剤)を投与することを含む、種々の疾患(例えば、炎症性の適応症、がん、および眼科系の適応症)を予防、改善または処置するための方法を提供する。
実施例1.1:(S)-3-(4-ヒドロキシフェニル)-2-(2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(Pal-PPGY-OH)
実施例1.2の工程2で調製した(S)-1-パルミトイルピロリジン-2-カルボン酸(10.0 g,28.3 mmol)、EDCI(5.96 g,31.1 mmol)、HOBt(4.20 g,31.1 mmol)およびトリエチルアミン(11.8 mL,84.9 mmol)をジクロロメタン中で混合することにより混合物溶液を作製した。プロリンメチルエステル塩酸塩(5.15 g,31.1 mmol)を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、減圧濃縮し、重炭酸ナトリウム水溶液で希釈し、酢酸エチルで3回抽出した。有機層をすべて生理食塩水溶液で洗浄し、1N HClで3回洗浄した。得られたものを生理食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧濃縮し、1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボン酸(S)-メチル(11.4 g,収率87%)を得た。
1H-NMR(300 MHz,CDCl3)δ 4.69-4.65(m,1 H),4.54-4.58(m,1 H),3.83-3.93(m,1 H),3.58-3.72(m,5H),3.45-3.53(m,1 H),1.89-2.31(m,10 H),1.60-1.64(m,2 H),1.25(m,24 H),0.88(t,J = 6.87Hz,3 H).
MS(ESI),C27H48N2O4の計算値 464.4,実測値 m/z465.2(M + H+).
工程1で調製した1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボン酸(S)-メチル(15.0 g,32.3 mmol)をテトラヒドロフランと混合した。水酸化ナトリウム(2.58 g,64.6 mmol)水溶液を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、濃縮した。1N HClを添加してpHを1.0に調整した。その水層を酢酸エチルで3回抽出した。有機層をすべて無水硫酸マグネシウムで乾燥させ、濃縮し、(S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボン酸(13.2 g,収率91%)を白色固形物として得た。
MS(ESI),C26H46N2O4の計算値 450.3,実測値 m/z451.1(M + H+).
工程2で調製した(S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボン酸(12 g,26.6 mmol)をジクロロメタンと混合した。グリシンエチルエステル塩酸塩(4.09 g,29.3 mmol)、EDCI(5.62 g,29.3 mmol)、HOBt(3.96 g,29.3 mmol)およびトリエチルアミン(triethyamine)(11.1 mL,79.8 mmol)を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、減圧濃縮し、炭酸ナトリウム水溶液で希釈し、酢酸エチルで3回抽出した。有機層をすべて生理食塩水溶液で洗浄し、1N HClで3回洗浄した。有機層を生理食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濃縮し、2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキシアミド)酢酸エチル(11.1 g,収率78%)を得た。
MS(ESI),C30H53N3O5の計算値 535.4,実測値 m/z536.5(M + H+).
工程3で調製した2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキシアミド)酢酸エチル(12 g,22.4 mmol)をテトラヒドロフランと混合した。水酸化ナトリウム(1.79 g,44.8 mmol)水溶液を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、濃縮した。1N HClを添加してpHを1.0に調整した。水層を酢酸エチルで3回抽出した。有機層をすべて無水硫酸マグネシウムで乾燥させ、濃縮し、2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキサミド)酢酸(9.5 g,収率84%)を得た。
MS(ESI),C28H49N3O5の計算値 507.4,実測値 m/z508.2(M + H+).
工程4で調製した2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキサミド)酢酸(10 g,19.7 mmol)をジクロロメタンと混合した。チロシンメチルエステル(4.23 g,21.7 mmol)、EDCI(4.16 g,21.7 mmol)、HOBt(21.7 g,21.7 mmol)およびトリエチルアミン(8.19 mL,59.1 mmol)を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、減圧濃縮し、重炭酸ナトリウム水溶液で希釈し、酢酸エチルで3回抽出した。有機層をすべて生理食塩水溶液で洗浄し、1N HClで3回洗浄した。有機層を生理食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濃縮し、MPLCで精製し、3-(4-ヒドロキシフェニル)-2-(2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(S)-メチル(8.4 g,収率62%)を得た。
MS(ESI),C37H60N4O7の計算値 684.4,実測値 m/z685.2(M + H+).
工程5で調製した3-(4-ヒドロキシフェニル)-2-(2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(S)-メチル(4.9 g,7.16 mmol)をテトラヒドロフランと混合した。水酸化ナトリウム(0.86 g,21.5 mmol)水溶液を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、濃縮した。1N HClを添加してpHを1.0に調整した。水層を酢酸エチルで3回抽出した。有機層をすべて無水硫酸マグネシウムで乾燥させ、濃縮し、(S)-3-(4-ヒドロキシフェニル)-2-(2-((S)-1-((S)-1-パルミトイルピロリジン-2-カルボニル)ピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(4.5 g,収率93%)を得た。
1H-NMR(300 MHz,MeOD)δ 7.04(d,J = 8.31 Hz,2 H)6.70(d,J = 8.37 Hz,2 H),4.38-4.68(m,3 H),3.44-4.04(m,6 H),2.91-3.13(m,2 H),1.81-2.38(m,10 H),1.54-1.60(m,2 H),1.30(m,24 H),0.88(t,J = 6.63 Hz,3 H).
MS(ESI),C37H58N4O7の計算値 670.4,実測値 m/z671.3(M + H+).
パルミチン酸(7 g,27.3 mmol)、EDCI(5.78 g,30.0 mmol)、HOBt(4.05 g,30.0 mmol)およびトリエチルアミン(11.4 mL,81.9 mmol)をジクロロメタンと混合した。プロリンメチルエステル塩酸塩(4.97 g,30.0 mmol)を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、減圧濃縮し、炭酸ナトリウム水溶液で希釈し、酢酸エチルで3回抽出した。有機層をすべて生理食塩水溶液で洗浄し、1N HClで3回洗浄した。有機層を生理食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧濃縮し、1-パルミトイルピロリジン-2-カルボン酸(S)-メチル(9.6 g,収率96%)を粘性の液状物として得た。
1H-NMR(300 MHz,CDCl3)δ 4.46-4.50(m,1 H),3.47-3.75(m,5 H),1.90-2.36(m,6 H),1.59-1.69(m,2 H),1.25(m,24 H),0.88(t,J = 6.84 Hz,3H)
MS(ESI),C22H41NO3の計算値 367.3,実測値 m/z368(M + H+).
工程1で調製した1-パルミトイルピロリジン-2-カルボン酸(S)-メチル(10.0 g,27.2 mmol)をテトラヒドロフランと混合した。水酸化ナトリウム(3.26 g,81.6 mmol)水溶液を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、濃縮した。1N HClを添加してpHを1.0に調整した。水層を酢酸エチルで3回抽出した。有機層をすべて無水硫酸マグネシウムで乾燥させ、濃縮し、(S)-1-パルミトイルピロリジン-2-カルボン酸(8.6 g,収率89%)を白色固形物として得た。
1H-NMR(300 MHz,CDCl3)δ 4.59-62(m,1 H),3.42-3.59(m,2H),2.46-2.53(m,1 H),2.33-2.38(m,2 H),1.93-2.01(m,3 H),1.62-1.69(m,2 H),1.25(m,24 H),0.88(t,J = 6.90 Hz,3 H)
MS(ESI),C21H39NO3の計算値 353.3,実測値 m/z354.2(M + H+).
工程2で調製した(S)-1-パルミトイルピロリジン-2-カルボン酸(10 g,28.3 mmol)、グリシンエチルエステル塩酸塩(4.34 g,31.1 mmol)、EDCI(5.76 g,31.1 mmol)、HOBt(4.20 g,31.1 mmol)およびトリエチルアミン(1,5.7 mL,113 mmol)をジクロロメタンと混合した。得られた混合物を室温で一晩撹拌し、減圧濃縮し、炭酸ナトリウム水溶液で希釈し、酢酸エチルで3回抽出した。有機層をすべて生理食塩水溶液で洗浄し、1N HClで3回洗浄した。有機層を生理食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濃縮し、2-(1-パルミトイルピロリジン-2-カルボキサミド)酢酸(S)-エチル(10.7 g,収率86%)を得た。
MS(ESI),C25H46N2O4の計算値 438.3,実測値 m/z439.1(M + H+).
工程3で調製した2-(1-パルミトイルピロリジン-2-カルボキサミド)酢酸(S)-エチル(12 g,27.4 mmol)をテトラヒドロフランと混合した。水酸化ナトリウム(2.20 g,54.7 mmol)水溶液を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、濃縮した。1N HClを添加してpHを1.0に調整した。水層を酢酸エチルで3回抽出した。有機層をすべて無水硫酸マグネシウムで乾燥させ、濃縮し、(S)-2-(1-パルミトイルピロリジン-2-カルボキサミド)酢酸(10.2 g,収率91%)を白色固形物として得た。
MS(ESI),C23H42N2O4の計算値 410.3,実測値 m/z 411.3(M + H+).
工程4で調製した(S)-2-(1-パルミトイルピロリジン-2-カルボキサミド)酢酸(7 g,27.3 mmol)をジクロロメタンと混合した。チロシンメチルエステル(5.86 g,30.0 mmol)、EDCI(5.78 g,30.0 mmol)、HOBt(4.05 g,30.0 mmol)およびトリエチルアミン(11.4 mL,81.9 mmol)を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、減圧濃縮し、重炭酸ナトリウム水溶液で希釈し、酢酸エチルで3回抽出した。有機層をすべて生理食塩水溶液で洗浄し、1N HClで3回洗浄した。有機層を生理食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濃縮し、MPLCで精製し、3-(4-ヒドロキシフェニル)-2-(2-((S)-1-パルミトイルピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(S)-メチル(9.8 g,収率61%)を得た。
1H-NMR(300 MHz,CDCl3)δ 7.25-7.50(m,3 H),6.93(d,J = 8.34 Hz,2 H)6.70(d,J = 8.34 Hz,2 H),4.70-4.77(m,1 H),4.39-4.43(m,1 H),3.95-4.21(m,1 H),3.41-3.72(m,5 H),2.92-3.12(m,2 H),1.91-2.35(m,7 H),1.57-1.61(m,2 H),1.25(m,24 H),0.88(t,J = 6.87 Hz,3 H)
MS(ESI),C33H53N3O6の計算値 587.4,実測値 m/z588.1(M + H+).
工程5で調製した3-(4-ヒドロキシフェニル)-2-(2-((S)-1-パルミトイルピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(S)-メチル(2.85 g,4.85 mmol)をテトラヒドロフランと混合した。水酸化ナトリウム(0.58 g,14.6 mmol)水溶液を混合物溶液に添加した。得られた混合物を室温で一晩撹拌し、濃縮した。1N HClを添加してpHを1.0に調整した。水層を酢酸エチルで3回抽出した。有機層をすべて無水硫酸マグネシウムで乾燥させ、濃縮し、(S)-3-(4-ヒドロキシフェニル)-2-(2-((S)-1-パルミトイルピロリジン-2-カルボキサミド)アセトアミド)プロパン酸(2.2 g,収率79%)を白色固形物として得た。
1H-NMR(300 MHz,MeOD)δ 7.03(d,J = 8.40 Hz,2 H)6.70(d,J = 8.40 Hz,2 H),4.58-4.61(m,1 H),4.33-4.56(m,1 H),3.58-4.37(m,4 H),2.96-3.15(m,2 H),1.92-2.39(m,6 H),1.55-1.62(m,2 H),1.29(m,24 H),0.91(t,J = 6.87 Hz,3 H)
MS(ESI),C32H51N3O6の計算値 573.4,実測値 m/z574.2(M + H+).
LC-MS(ESI):C14H24N2O5の計算値 300.2,実測値 m/z 301.2(M + H+).
LC-MS(ESI):C12H20N2O5の計算値 272.1,実測値 m/z 273.1(M + H+).
LC-MS(ESI):C22H31N3O7の計算値 449.2,実測値 m/z 450.2(M + H+).
LC-MS(ESI):C17H23N3O5の計算値 349.2,実測値 m/z 350.2(M + H+).
LC-MS(ESI):C25H36N4O8の計算値 520.3,実測値 m/z 520.7(M + H+).
LC-MS(ESI):C20H28N4O6の計算値 420.2,実測値 m/z 420.6(M + H+).
LC-MS(ESI):C36H58N4O7の計算値 658.4,実測値 m/z 659.1(M + H+)
1H NMR(500 MHz,CD3OD)δ 7.05(d,J = 8.50 Hz,2 H),6.70(d,J = 8.50 Hz,2 H),4.59-4.65(m,2 H),4.39-4.41(m,1 H),3.96-3.99(m,1 H),3.84-3.89(m,1 H),3.65-3.76(m,2 H),3.10-3.14(m,1 H),2.97-3.01(m,1 H),2.20-2.24(m,3 H),2.09-2.14(m,1 H),1.96-2.03(m,2 H),1.58-1.60(m,3 H),1.31-1.36(m,30 H),0.92(t,J = 7.15 Hz,3 H).LC-MS(ESI):C35H56N4O7の計算値 644.4,実測値 m/z 644.6(M + H+).
実施例2.1:IL-6の発現の抑制
本発明の化合物によるIL-6の発現の抑制を評価するため、以下の実験を行なった。
LPSによって誘導したNF-κBシグナルが本発明の化合物によって特異的に抑制されるかどうかを評価するため、以下の実験を行なった。
本発明による化合物1.1のシグナル伝達経路の選択性を評価するため、以下の実験を行なった。以下の実験を、個々の誘導因子によって誘導したシグナル伝達経路を化合物1.1が特異的に抑制するかどうかを試験するために行なった。
本発明の化合物が、MyD88および/またはRIP1によって媒介される炎症シグナル伝達経路タンパク質複合体、例えば、Toll様受容体(TLR)シグナル伝達経路タンパク質複合体の形成を崩壊させ得るかどうかを試験するため、免疫沈降実験を行なった。同時に、以下の実験を、本発明の化合物によるIκB分解をIκB濃度の変化を測定しながら測定するために行なった。
デキストラン硫酸ナトリウム(DSS)によって誘導した慢性大腸炎を有する動物モデルにおける本発明の化合物の疾患活動性指標を評価するため、以下の実験を行なった。
誘導性急性大腸炎(これはDSSによって誘導する)を有する動物モデルにおける本発明の化合物の抑制活性を評価するため、以下の実験を行なった。
1)体重減少(0ポイント:体重減少なし;1ポイント:1〜5%の体重減少、2ポイント:6〜10%の体重減少、3ポイント:11〜20%の体重減少;4ポイント:20%以上の体重減少);
2)下痢(0ポイント:正常な便通;2ポイント:軟便;4ポイント:下痢);および
3)血便(0ポイント:正常な便;2ポイント:便に少量の血;4ポイント:便にかなりの血)
本発明の化合物1.1によるDDS誘導性慢性大腸炎の処置効果を確認するため、無処置群、DDS誘導性慢性大腸炎モデル群および化合物1.1で処置した群の大腸絨毛を写真撮影した(図12〜16)。
静脈内投与および経口投与した本発明の化合物1.1の血中(血流)濃度の変化を評価するため、以下の実験を行なった。
本発明による化合物1.1の組織分布を評価するため、以下の実験を行なった。
本発明の化合物1.1および化合物1.2がMAPK/ERKシグナル伝達経路を抑制するかどうかを試験するため、ウエスタンブロット解析を行なった(図20)。
実施例2.3に記載のように、5×NF-κB-LucレポータープラスミドでRAW 246.7マクロファージ細胞をトランスフェクトした。24時間後、NF-κB-Lucレポータープラスミドでトランスフェクトした細胞を化合物1.1(100 nM)、インターロイキン-1-受容体関連キナーゼ-1/4阻害薬(IRAK1/4)阻害薬(25μM,CAS 509093-47-4)およびsmaducin-6(100 nM)で30分間前処理し、次いで、LPS(100 ng/ml)で2時間さらに処理した。続いて、細胞内のルシフェラーゼ活性を測定した。
化合物1.1は、血管新生関連因子または抑制因子に影響を及ぼした。
ストレプトゾトシン(STZ)を50mg/kgの用量でマウスに毎日、5日間投与し、糖尿病性網膜症が誘導されたマウスモデルを得た。実験群のマウスモデルに化合物1.1を、0.2μgの量でマウスの一方の目に、投与から20日目から24日目まで、2日間の間隔で3回注射した。50日間の投与後、化合物1.1で処理しなかったDR試料と化合物1.1で処理したDR試料を収集した。
多発性硬化症に対する化合物1.1の効果を確認するため、マウス(10週齢,雌)をMOG35-55/CFUおよびPTXで感作し、実験的自己免疫性脳脊髄炎マウスモデルを得た。実験方法は、Oncotarget,Vol.7(2016),No.13,15382-15393に記載されたものであり、これは引用により本明細書に組み込まれる。
敗血症に対する化合物1.1の効果を確認するため、各群10匹のマウス(7週齢,雄性)に麻酔し、その後、腹部の切開によって虫垂を露出させた。露出させた虫垂の回盲弁の下側部分を結び、22ゲージシリンジ用針を使用することによって1個の孔を開けた。処置した虫垂を腹腔内に再挿入し、糸を用いて生着させ、敗血症誘導性マウスモデル(盲腸結紮穿孔(pucture)モデル,CLPモデル)を得た。実験方法は、EMBO Mol Med.(2015)Mar 12;7(5):577-92に記載のとおりにし、これは引用により本明細書に組み込まれる。
式1の化合物 2g
ラクトース 1g
この顆粒剤は当該技術分野で知られた方法に従って調製した。
式1の化合物 100mg
コーンスターチ 100mg
ラクトース 100mg
ステアリン酸マグネシウム 2mg
この錠剤は当該技術分野で知られた方法に従って調製した。
式1の化合物 100mg
コーンスターチ 100mg
ラクトース 100mg
ステアリン酸マグネシウム 2mg
このカプセル剤は当該技術分野で知られた方法に従って調製した。
式1の化合物 100mg
マンニトール 180mg
Na2HPO4・2H2O 26mg
留水 2974mg
この注射剤は当該技術分野で知られた方法に従って調製した。
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Claims (20)
- 下記の式1
[式1]
(式中:
nは0、1または2であり;
Aは-a1-であり、アラニン、(Ala,A)、アルギニン(Arg,R)、アスパラギン(Asn,N)、アスパラギン酸(Asp,D)、システイン(Cys,C)、グルタミン酸(Glu,E)、グルタミン(Gln,Q)、グリシン(Gly,G)、ヒスチジン(His,H)、イソロイシン(Ile,I)、ロイシン(Leu,L)、リシン(Lys,K)、メチオニン(Met,M)、フェニルアラニン(Phe,F)、プロリン(Pro,P)、セリン(Ser,S)、トレオニン(Thr,T)、トリプトファン(Trp,W)、チロシン(Tyr,Y)およびバリン(Val,V)からなる群より独立して選択されるアミノ酸であり、該アミノ酸の両末端はカルボニル基またはアミン基にアミド結合によって連結され;
R1は、直鎖もしくは分枝鎖のC1〜36アルキル、少なくとも1つの二重結合を含む直鎖もしくは分枝鎖のC2〜36アルケニル、または少なくとも1つの三重結合を含む直鎖もしくは分枝鎖のC2〜36アルキニルである)
で表される化合物、その光学異性体、またはその医薬上許容される塩。 - 下記の反応図式1で表される:
化合物2を化合物3と反応させて化合物4を調製すること;
該化合物4を塩基の存在下で加水分解させて化合物5を調製すること;
該化合物5を化合物6と反応させて化合物7を調製すること;
該化合物7を塩基の存在下で加水分解させて化合物8を調製すること;
該化合物8を化合物9と反応させて化合物10を調製すること;
該化合物10を塩基の存在下で該加水分解させて請求項1に記載の化合物を調製すること
[反応図式1]
を含む、式1で表される請求項1に記載の化合物の調製方法。 - 活性成分として請求項1に記載の化合物、その光学異性体または塩を含む、炎症性腸疾患を予防、改善または処置するための組成物。
- MyD88によって媒介される炎症シグナル伝達複合体の形成を阻害する、ペリノ-1によって媒介される炎症シグナル伝達複合体の形成を阻害する、Rip1によって媒介される炎症シグナル伝達複合体の形成を阻害する、G-CSF、IL-2、SCF、VEGF、CX3CL1、IGFBP5、IGFBP6、IL-1α、IL-1β、IL-6、IL-9、MCP-1、MIP-3α、IL12p40/70、MIG、TNF-αおよびVCAM-1よりなる群から選択される少なくとも1種類のタンパク質の発現を抑制する、またはNF-κBの活性を抑制する、請求項5に記載の組成物。
- 炎症性腸疾患として潰瘍性大腸炎、ベーチェット病およびクローン病が包含される、請求項5に記載の組成物。
- 疾患または症候群を予防、改善または処置する方法における使用のための、有効量の請求項1に記載の化合物、その光学異性体または塩を含む組成物。
- 疾患または症候群が炎症性腸疾患である、請求項8に記載の使用のための組成物。
- 炎症性腸疾患として潰瘍性大腸炎、ベーチェット病およびクローン病が包含される、請求項9に記載の使用のための組成物。
- 疾患または症候群には、多発性硬化症、乾癬、敗血症、地図状萎縮、滲出型加齢性黄斑疾患、萎縮型加齢性黄斑疾患、糖尿病性網膜症、感染性肺疾患、細菌性肺炎、ウイルス性肺炎、びまん性大細胞型B細胞性リンパ腫、ウイルス感染、自己免疫疾患、リンパ腫を含めた血液がん、および内臓の腫瘍が包含される、請求項8に記載の使用のための組成物。
- 活性成分として請求項1に記載の化合物、その光学異性体または塩を含む、疾患または症候群を予防、改善または処置するための組成物であって、該疾患または症候群には、地図状萎縮、滲出型加齢性黄斑疾患、萎縮型加齢性黄斑疾患および糖尿病性網膜症が包含される組成物。
- 請求項1に記載の化合物、その光学異性体または塩が網膜色素上皮細胞に対して医薬品的効果を有する、請求項12に記載の組成物。
- 請求項1に記載の化合物、その光学異性体または塩が、網膜色素上皮細胞において、Nox-4、VEGF、VEGFR1、VEGFR2、Ang2、EPOおよびEPORよりなる群から選択される少なくとも1種類のタンパク質の発現を阻害するものである、請求項12に記載の組成物。
- 請求項1に記載の化合物、その光学異性体または塩が網膜色素上皮細胞においてAng 1、Tie2または双方の発現を増大させるものである、請求項12に記載の組成物。
- 活性成分として請求項1に記載の化合物、その光学異性体または塩を含む、疾患または症候群を予防、改善または処置するための組成物であって、該疾患または症候群には敗血症および多発性硬化症が包含される組成物。
- 活性成分として請求項1に記載の化合物、その光学異性体または塩を含む、脱毛症を予防、改善または処置するための組成物であって、該活性成分が頭皮および毛嚢においてIL-6の発現を阻害するものである組成物。
- 活性成分として請求項1に記載の化合物、その光学異性体または塩を含む、疾患または症候群を予防、改善または処置するための組成物であって、該疾患または症候群が、MyD88、RIP1または双方を含むペリノ-1誘導性炎症シグナル伝達複合体の形成を伴うものである組成物。
- 疾患または症候群に、多発性硬化症、乾癬、敗血症、地図状萎縮、滲出型加齢性黄斑疾患、萎縮型加齢性黄斑疾患、糖尿病性網膜症、感染性肺疾患、細菌性肺炎、ウイルス性肺炎、びまん性大細胞型B細胞性リンパ腫、ウイルス感染、自己免疫疾患、リンパ腫を含めた血液がん、および内臓の腫瘍が包含される、請求項18に記載の組成物。
- 疾患または症候群が、MyD88、RIP1または双方を含むペリノ-1誘導性炎症シグナル伝達複合体の形成を伴うものである、請求項8に記載の使用のための組成物。
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