JP2007308501A - カスパーゼ阻害剤およびそれらの用途 - Google Patents
カスパーゼ阻害剤およびそれらの用途 Download PDFInfo
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- JP2007308501A JP2007308501A JP2007139751A JP2007139751A JP2007308501A JP 2007308501 A JP2007308501 A JP 2007308501A JP 2007139751 A JP2007139751 A JP 2007139751A JP 2007139751 A JP2007139751 A JP 2007139751A JP 2007308501 A JP2007308501 A JP 2007308501A
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- Prior art keywords
- aliphatic
- oxo
- pyridin
- aryl
- heteroaryl
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Classifications
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Abstract
【解決手段】式I
(式中、R1は、R6C(O)−、HC(O)−、R6SO2−、R6OC(O)−、(R6)2NC(O)−、(R6)(H)NC(O)−、R6C(O)C(O)−、R6−、(R6)2NC(O)C(O)−、R6(H)NC(O)C(O)−またはR6OC(O)C(O)−であり;R2は、水素、−CF3、−ハロ、−OR7、−NO2、−OCF3、−CNまたはR8であり;R3は、水素または(C1〜C4)−脂肪族−であり;R4は、−COOHまたは−COOR8であり;R5は、−CH2Fまたは−CH2O−2,3,5,6−テトラフルオロフェニルである。)で表されるカスパーゼ阻害剤。
【選択図】なし
Description
本発明は、医薬品化学の分野であり、細胞アポトーシスおよび炎症を媒介するカスパーゼを阻害する化合物およびそれらの薬学的組成物に関する。本発明はまた、これらの化合物を調製する方法に関する。本発明は、さらに、本発明の化合物および薬学的組成物を使用してカスパーゼ活性が関係した疾患を治療する方法に関する。
アポトーシス、すなわち、プログラム化細胞死は、生物体が不要な細胞を排除する主な機構である。アポトーシスの調節解除は、過剰なアポトーシスまたはそれを受けることの減退のいずれであれ、多くの疾患(例えば、癌、急性炎症性および自己免疫性障害、虚血性疾患および特定の神経変性障害)に関係している(一般に、Science,1998,281,1283〜1312;Ellisら、Ann.Rev.Cell.Biol.,1991,7,663を参照)。
(項目1)
式Iの化合物であって:
ここで:
R 1 は、R 6 C(O)−、HC(O)−、R 6 SO 2 −、(R 6 ) 2 NC(O)−、(R 6 )(H)NC(O)−、R 6 C(O)C(O)−、R 6 −、(R 6 ) 2 NC(O)C(O)−、(R 6 )(H)NC(O)C(O)−またはR 6 OC(O)C(O)−であり;
R 2 は、水素、−CF 3 、−ハロ、−OR 7 、−NO 2 、−OCF 3 、−CNまたはR 8 であり;
R 3 は、水素または(C1〜C4)−脂肪族−であり;
R 4 は、−COOHまたは−COOR 8 であり;
R 5 は、−CH 2 Fまたは−CH 2 O−2,3,5,6−テトラフルオロフェニルであり;
R 6 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR 6 基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;そしてここで、R 6 は、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;
2個のR 7 基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、その環は、3個までのヘテロ原子を有し、そのヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO 2 から選択され、ここで、その環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、そしてここで、任意の環は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択されるか;または
各R 7 は、独立して、以下から選択され:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R 7 は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択され;そして
J 2 は、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=N(R 7 )、=NO(R 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−CN、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;そして
R 8 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;そしてここで、R 8 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択される、
化合物。
(項目2)
式Iの化合物であって:
ここで:
R 1 は、R 6 C(O)−、R 6 SO 2 −、R 6 OC(O)−、(R 6 ) 2 NC(O)−、R 6 C(O)C(O)−、R 6 −、(R 6 ) 2 NC(O)C(O)−またはR 6 OC(O)C(O)−であり;
R 2 は、水素、−CF 3 、−ハロ、−OR 7 、−NO 2 、−OCF 3 、−CNまたはR 8 であり;
R 3 は、水素または(C1〜C4)−脂肪族−であり;
R 4 は、−COOHまたは−COOR 8 であり;
R 5 は、−CH 2 Fまたは−CH 2 O−2,3,5,6−テトラフルオロフェニルであり;
R 6 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR 6 基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;そしてここで、R 6 は、6個までの置換基で置換され、その置換基は、独立して、Rから選択される;
Rは、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;
2個のR 7 基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、その環は、3個までのヘテロ原子を有し、そのヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO 2 から選択され、ここで、その環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、そしてここで、任意の環は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択されるか;または
各R 7 は、独立して、以下から選択され:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R 7 は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択され;そして
J 2 は、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−CN、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;そして
R 8 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得る、
化合物。
(項目3)
R 5 が、−CH 2 O−2,3,5,6−テトラフルオロフェニルである、項目1または2に記載の化合物。
(項目4)
R 5 が、−CH 2 Fである、項目1または2に記載の化合物。
(項目5)
R 1 が、R 6 C(O)−である、項目1〜4のいずれか1項に記載の化合物。
(項目6)
R 1 が、R 6 SO 2 −である、項目1〜4のいずれか1項に記載の化合物。
(項目7)
R 1 が、R 6 −である、項目1〜4のいずれか1項に記載の化合物。
(項目8)
R 1 が、(R 6 ) 2 NC(O)−である、項目1〜4のいずれか1項に記載の化合物。
(項目9)
R 1 が、(R 6 )(H)NC(O)−である、項目1〜4のいずれか1項に記載の化合物。
(項目10)
R 1 が、(R 6 )OC(O)−である、項目1〜4のいずれか1項に記載の化合物。
(項目11)
R 6 が、(C1〜C4)−脂肪族−、(C3〜C10)−環状脂肪族、(C3〜C10)−ヘテロシクリル、(C5〜C10)−ヘテロアリール、(C6〜C10)−アリール−または(C6〜C10)−アリール−(C1〜C12)−であり;ここで、3個までの脂肪族炭素原子が、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 6 が、必要に応じて、置換されている、項目1〜10のいずれか1項に記載の化合物。
(項目12)
R 6 が、(C1〜C4)−脂肪族−、(C5〜C10)−ヘテロアリール−または(C6〜C10)−アリール−であり、ここで、そのヘテロアリールまたはアリールが、必要に応じて、置換されているか、またはここで、各R 6 が、N−原子と一緒になって、(C3−C7)−環状脂肪族基である、項目1〜10のいずれか1項に記載の化合物。
(項目13)
R 6 が、(C1〜C4)−脂肪族−または(C6〜C10)−アリール−であり、ここで、そのアリールが、必要に応じて、置換されているか、またはここで、各R 6 が、N−原子と一緒になって、(C3−C7)−環状脂肪族基である、項目1〜10のいずれか1項に記載の化合物。
(項目14)
上記脂肪族が、(C1〜C4)−アルキル−である、項目1〜13のいずれか1項に記載の化合物。
(項目15)
R 2 が、水素、CF 3 またはCH 3 である、項目1〜14のいずれか1項に記載の化合物。
(項目16)
R 2 が、水素またはCF 3 である、項目1〜15のいずれか1項に記載の化合物。
(項目17)
R 3 が、(C1〜C4)−アルキル−である、項目1〜16のいずれか1項に記載の化合物。
(項目18)
R 3 が、エチルである、項目1〜17のいずれか1項に記載の化合物。
(項目19)
表1から選択される、化合物。
(項目20)
以下:
a)項目1〜19のいずれか1項に記載の化合物;および
b)薬学的に受容可能なキャリア、アジュバントまたはビヒクル
を含有する、薬学的組成物。
(項目21)
患者のIL−1媒介疾患、アポトーシス媒介疾患、炎症性疾患、自己免疫性疾患、破壊性骨障害、増殖性障害、感染症疾患、変性疾患、細胞死に関連した疾患、ウイルス媒介疾患または肝疾患を治療する方法であって、その患者に、治療有効量の、項目1〜19のいずれか1項に記載の化合物、または項目20に記載の薬学的組成物を投与する工程を包含する、方法。
(項目22)
患者の関節リウマチ、骨関節炎、骨粗鬆症、全身性エリテマトーデス、強皮症、慢性甲状腺炎、グレーブス病、重症筋無力症、自己免疫性好中球減少、自己免疫性溶血性貧血、血小板減少症、若年性関節リウマチ、痛風、ベーチェット症候群、スチル症候群、マクロファージ活性化症候群、サルコイドーシス、Muckle−Wells症候群、家族性寒冷蕁麻疹、慢性乳児性神経学的皮膚反応および関節症候群、家族性地中海熱、TNFR1関連周期性症候群(TRAPS)、Hyper−IgD周期性発熱症候群(HIDS)、ブラウ症候群、乾癬、アトピー性皮膚炎、瘢痕、脱毛症、尋常性座瘡、天疱瘡、喘息、成人呼吸困難症候群、嚢胞性線維症、肺気腫、慢性気管支炎、慢性閉塞性肺疾患、特発性肺線維症、炎症性腹膜炎、炎症性腸疾患、クローン病、潰瘍性大腸炎、自己免疫性胃炎、ピロリ菌関連胃および十二指腸潰瘍病、糖尿病、膵炎、糸球体腎炎、慢性活動性肝炎、過剰な食用アルコール摂取疾患、腎疾患、多発性嚢胞腎、火傷、火傷後臓器アポトーシス、出血性ショック、臓器不全、子宮内膜症、移植片対宿主病、臓器移植拒絶、白血病、脊髄形成異常症候群、多発性骨髄腫関連骨障害、急性骨髄性白血病、慢性骨髄性白血病、転移性黒色腫、カポジ肉腫、多発性骨髄腫、慢性心疾患、急性心疾患、心筋梗塞、心筋虚血、鬱血性心不全、アテローム性動脈硬化症、冠動脈バイパス移植片(CABG)、冠動脈バイパス移植片に関連した合併症、急性冠血管症候群、アルツハイマー病、パーキンソン病、ハンチントン病、ケネディ病、プリオン病、脳虚血、癲癇、脊髄筋肉萎縮症、筋萎縮性側索硬化症、多発性硬化症、HIV関連脳炎、外傷性脳損傷、脊椎損傷、脳卒中が原因の神経損傷、糖尿病性神経障害、急性および慢性疼痛、ブドウ膜炎、網膜障害、糖尿病性網膜症、緑内障、角膜炎、ウイルス媒介病、敗血症、感染性ショック、細菌性赤痢、B型肝炎、C型肝炎、G型肝炎、黄熱病、デング熱、日本脳炎、HIV感染、結核、髄膜炎、シュードモナス感染、アシネトバクター感染または加齢を治療する方法であって、その患者に、治療有効量の、項目1〜19のいずれか1項に記載の化合物または項目20に記載の薬学的組成物を投与する工程を包含する、方法。
(項目23)
上記疾患が、骨関節炎、膵炎、喘息、成人呼吸困難症候群、糸球体腎炎、関節リウマチ、全身性エリテマトーデス、強皮症、慢性甲状腺炎、グレーブス病、自己免疫性胃炎、インシュリン依存性糖尿病(I型)、自己免疫性溶血性貧血、自己免疫性好中球減少、血小板減少症、慢性活動性肝炎、重症筋無力症、炎症性腸疾患、クローン病、乾癬、移植片対宿主病、骨粗鬆症、多発性骨髄腫関連骨障害、急性骨髄性白血病、慢性骨髄性白血病、転移性黒色腫、カポジ肉腫、多発性骨髄腫、敗血症、感染性ショック、細菌性赤痢、脳虚血、心筋虚血、脊髄筋肉萎縮症、または脳卒中が原因の神経損傷である、項目22に記載の方法。
(項目24)
上記疾患が、冠状動脈バイパス移植に関連した合併症である、項目22に記載の方法。
(項目25)
患者におけるカスパーゼ媒介機能を阻害する方法であって、その患者に、治療有効量の、項目1〜19のいずれか1項に記載の化合物または項目20に記載の薬学的組成物を投与する工程を包含する、方法。
(項目26)
患者におけるIGIF産生またはIFN−γ産生を減少させるための方法であって、治療有効量の、項目1〜19のいずれか1項に記載の化合物または項目20に記載の薬学的組成物を投与する工程を包含する、方法。
(項目27)
細胞を保存する方法であって、その方法は、その細胞を、項目1〜19のいずれか1項に記載の化合物の溶液に浸す工程を包含する、方法。
(項目28)
上記細胞が、以下:
a)移植のために意図された臓器;または
b)血液製剤、
に存在している、項目27に記載の方法。
(項目29)
免疫療法を使用して癌を治療する方法であって、ここで、その免疫療法は、その成分として、項目1〜19のいずれか1項に記載の化合物を含む、方法。
(項目30)
上記方法が、追加治療薬を投与する工程を包含する、項目20〜29のいずれか1項に記載の方法。
(項目31)
式Iの化合物:
を調製する方法であって、
ここで:
R 1 は、R 6 C(O)−、HC(O)−、R 6 SO 2 −、R 6 OC(O)−、(R 6 ) 2 NC(O)−、(R 6 )(H)NC(O)−、R 6 C(O)C(O)−、R 6 −、(R 6 ) 2 NC(O)C(O)−、(R 6 )(H)NC(O)C(O)−またはR 6 OC(O)C(O)−であり;
R 2 は、水素、−CF 3 、−ハロ、−OR 7 、−NO 2 、−OCF 3 、−CNまたはR 8 であり;
R 3 は、水素または(C1〜C4)−脂肪族−であり;
R 4 は、−COOHまたは−COOR 8 であり;
R 5 は、−CH 2 Fまたは−CH 2 O−2,3,5,6−テトラフルオロフェニルであり;
R 6 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR 6 基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 6 は、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;
2個のR 7 基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、その環は、3個までのヘテロ原子を有し、そのヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO 2 から選択され、ここで、その環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、ここで、任意の環は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択されるか;あるいは
各R 7 は、独立して、以下から選択され:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R 7 は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択され;そして
J 2 は、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−CN、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;そして
R 8 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 8 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
その方法は:
(a)カップリング条件および溶媒の存在下にて、式(III):
の化合物と式(IV):
の化合物とを反応させる工程を包含し、
式(III)において:
R 9 は、−NO 2 、−C(O)OR 10 、−CN、R 6 C(O)N(H)−、R 6 SO 2 N(H)−、R 6 OC(O)N(H)−、(R 6 ) 2 NC(O)N(H)−、R 6 C(O)C(O)N(H)−、R 6 N(H)−、(R 6 ) 2 NC(O)C(O)N(H)−またはR 6 OC(O)C(O)N(H)−であり;
R 10 は、独立して、水素、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N(H)、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 10 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;そして
R、R 2 、R 3 およびR 6 は、上で定義したとおりであり;
式(IV)において、
Yは、カルボニル基またはOH基のいずれかであり;そして
R 4 およびR 5 は、上で定義したとおりであり;
但し、YがOH基である場合、その方法は、さらに、(b)そのOH基を酸化して、式(I)の化合物を提供する工程を包含し;そして
但し、R 9 が、−NO 2 、−C(O)OR 10 または−CNである場合、その方法は、さらに、その−NO 2 、−C(O)OR 10 または−CNを、R 6 C(O)N(H)−、R 6 SO 2 N(H)−、R 6 OC(O)N(H)−、(R 6 ) 2 NC(O)N(H)−、R 6 C(O)C(O)N(H)−、R 6 N(H)−、(R 6 ) 2 NC(O)C(O)N(H)−またはR 6 OC(O)C(O)N(H)−に変換する工程を包含する、
方法。
(項目32)
式(III):
の上記化合物が、以下の方法により調製される、項目31に記載の方法であって、
式(III)において、
R 2 は、水素、−CF 3 、−ハロ、−OR 7 、−NO 2 、−OCF 3 、−CNまたはR 8 であり;
R 3 は、水素または(C1〜C4)−脂肪族−であり;
R 9 は、−NO 2 、−C(O)OR 10 、−CN、R 6 C(O)N(H)−、R 6 SO 2 N(H)−、R 6 OC(O)N(H)−、(R 6 ) 2 NC(O)N(H)−、R 6 C(O)C(O)N(H)−、R 6 N(H)−、(R 6 ) 2 NC(O)C(O)N(H)−またはR 6 OC(O)C(O)N(H)−であり;
R 6 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR 6 基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 6 は、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;
2個のR 7 基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、その環は、3個までのヘテロ原子を有し、そのヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO 2 から選択され、ここで、その環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、ここで、任意の環は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択されるか;あるいは
各R 7 は、独立して、以下から選択され:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R 7 は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択され;そして
J 2 は、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−CN、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;そして
R 8 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 8 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
その方法は、溶媒中で、脱保護条件の存在下にて、(c)式(V):
の化合物を反応させる工程を包含し、
式(V)において:
R 10 は、独立して、水素、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N(H)、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;そして
R、R 2 、R 3 およびR 9 は、上で定義したとおりである、
方法。
(項目33)
式(V):
の上記化合物が、以下の方法により調製される、項目32に記載の方法であって、
式(V)において、R 2 、R 3 、R 9 およびR 10 は、項目32で定義したとおりであり;
その方法は、(d)溶媒および塩基の存在下にて、式(VI):
の化合物と式(VII):
の化合物とを反応させる工程を包含し、
式(VI)において、R 2 およびR 9 は、項目32で定義したとおりであり;
式(VII)において、Xは、適当な脱離基であり;そして
R 3 およびR 10 は、上で定義したとおりである、
方法。
(項目34)
式(VIII):
の化合物を調製するための方法であって、
式(VIII)において:
R 2 は、−CF 3 、−Cl、−OR 7 、−NO 2 、−OCF 3 、−CNまたはR 8 であり;
R 3 は、水素または(C1〜C4)−脂肪族−であり;
R 9 は、−NO 2 、−C(O)OR 10 、−CN、R 6 C(O)N(H)−、R 6 SO 2 N(H)−、R 6 OC(O)N(H)−、(R 6 ) 2 NC(O)N(H)−、R 6 C(O)C(O)N(H)−、R 6 N(H)−、(R 6 ) 2 NC(O)C(O)N(H)−またはR 6 OC(O)C(O)N(H)−であり;
R 10 は、独立して、水素、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N(H)、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 10 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
R 6 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR 6 基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 6 は、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;
2個のR 7 基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、その環は、3個までのヘテロ原子を有し、そのヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO 2 から選択され、ここで、その環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、ここで、任意の環は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択されるか;あるいは
各R 7 は、独立して、以下から選択され:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R 7 は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択され;そして
J 2 は、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−CN、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;そして
R 8 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 8 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
その方法は、溶媒および塩基の存在下にて、(e)式(IX):
の化合物と式(VII):
の化合物とを反応させる工程を包含し、
式(IX)において、R 2 およびR 9 は、上で定義したとおりであり;
式(VII)において、R 3 およびR 10 は、上で定義したとおりであり;そしてXは、適当な脱離基である、
方法。
(項目35)
式(I):
の化合物を調製するための方法であって、
式(I)において:
R 1 は、R 6 C(O)−、R 6 SO 2 −、R 6 OC(O)−、(R 6 ) 2 NC(O)−、(R 6 )(H)NC(O)−、R 6 C(O)C(O)−、R 6 −、(R 6 ) 2 NC(O)C(O)−、(R 6 )(H)NC(O)C(O)−またはR 6 OC(O)C(O)−であり;
R 2 は、水素、−CF 3 、−ハロ、−OR 7 、−NO 2 、−OCF 3 、−CNまたはR 8 であり;
R 3 は、水素または(C1〜C4)−脂肪族−であり;
R 4 は、−COOHまたは−COOR 8 であり;
R 5 は、−CH 2 Fまたは−CH 2 O−2,3,5,6−テトラフルオロフェニルであり;
R 6 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR 6 基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 6 は、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;
2個のR 7 基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、その環は、3個までのヘテロ原子を有し、そのヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO 2 から選択され、ここで、その環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、ここで、任意の環は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択されるか;あるいは
各R 7 は、独立して、以下から選択され:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R 7 は、3個までの置換基を有し、その置換基は、独立して、J 2 から選択され;そして
J 2 は、ハロゲン、−OR 7 、−OC(O)N(R 7 ) 2 、−NO 2 、−CN、−CF 3 、−OCF 3 、−R 7 、オキソ、チオキソ、=NR 7 、=N(OR 7 )、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R 7 ) 2 、−SR 7 、−SOR 7 、−SO 2 R 7 、−SO 2 N(R 7 ) 2 、−SO 3 R 7 、−C(O)R 7 、−C(O)C(O)R 7 、−C(O)C(O)OR 7 、−C(O)C(O)N(R 7 ) 2 、−C(O)CH 2 C(O)R 7 、−C(S)R 7 、−C(S)OR 7 、−C(O)OR 7 、−OC(O)R 7 、−C(O)N(R 7 ) 2 、−OC(O)N(R 7 ) 2 、−C(S)N(R 7 ) 2 、−(CH 2 ) 0〜2 NHC(O)R 7 、−N(R 7 )N(R 7 )COR 7 、−N(R 7 )N(R 7 )C(O)OR 7 、−N(R 7 )N(R 7 )CON(R 7 ) 2 、−N(R 7 )SO 2 R 7 、−N(R 7 )SO 2 N(R 7 ) 2 、−N(R 7 )C(O)OR 7 、−N(R 7 )C(O)R 7 、−N(R 7 )C(S)R 7 、−N(R 7 )C(O)N(R 7 ) 2 、−N(R 7 )C(S)N(R 7 ) 2 、−N(COR 7 )COR 7 、−N(OR 7 )R 7 、−CN、−C(=NH)N(R 7 ) 2 、−C(O)N(OR 7 )R 7 、−C(=NOR 7 )R 7 、−OP(O)(OR 7 ) 2 、−P(O)(R 7 ) 2 、−P(O)(OR 7 ) 2 または−P(O)(H)(OR 7 )であり;そして
R 8 は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO 2 から選択される基で置き換えられ得;ここで、R 8 は、必要に応じて、6個までの置換基で置換され、その置換基は、独立して、Rから選択され;
その方法は、(a)カップリング条件および溶媒の存在下にて、式(III):
の化合物と式(X):
の化合物とを反応させる工程を包含し、
式(III)において:
R 9 は、−NO 2 、−C(O)OR 10 、−CN、R 6 C(O)N(H)−、R 6 SO 2 N(H)−、R 6 OC(O)N(H)−、(R 6 ) 2 NC(O)N(H)−、R 6 C(O)C(O)N(H)−、R 6 N(H)−、(R 6 ) 2 NC(O)C(O)N(H)−またはR 6 OC(O)C(O)N(H)−であり;そして
R 2 、R 10 およびR 6 は、上で定義したとおりであり;
式(X)において、Yは、カルボニル基またはOH基のいずれかであり;そしてR 3 、R 4 およびR 5 は、上で定義したとおりであり;
但し、YがOH基である場合、その方法は、さらに、(b)そのOH基を酸化して、式(I)の化合物を提供する工程を包含し;そして
但し、R 9 が、−NO 2 、−C(O)OR 10 または−CNである場合、その方法は、さらに、その−NO 2 、−C(O)OR 10 または−CNを、R 6 C(O)N(H)−、R 6 SO 2 N(H)−、R 6 OC(O)N(H)−、(R 6 ) 2 NC(O)N(H)−、R 6 C(O)C(O)N(H)−、R 6 N(H)−、(R 6 ) 2 NC(O)C(O)N(H)−またはR 6 OC(O)C(O)N(H)−に変換する工程を包含する、
方法。
本発明は、式Iの化合物を提供する:
本発明は、式Iの化合物を提供する:
R1は、R6C(O)−、HC(O)−、R6SO2−、SO2(O)−、(R6)2NC(O)−、(R6)(H)NC(O)−、R6C(O)C(O)−、R6−、(R6)2NC(O)C(O)−、(R6)(H)NC(O)C(O)−またはR6OC(O)C(O)−であり;
R2は、水素、−CF3、−ハロ、−OR7、−NO2、−OCF3、−CNまたはR8であり;
R3は、水素または(C1〜C4)−脂肪族−であり;
R4は、−COOHまたは−COOR8であり;
R5は、−CH2Fまたは−CH2O−2,3,5,6−テトラフルオロフェニルであり;
R6は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR6基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO2から選択される基で置き換えられ得;ここで、R6は、6個までの置換基で置換され、該置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR7、−OC(O)N(R7)2、−NO2、−CN、−CF3、−OCF3、−R7、オキソ、チオキソ、=NR7、=N(OR7)、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R7)2、−SR7、−SOR7、−SO2R7、−SO2N(R7)2、−SO3R7、−C(O)R7、−C(O)C(O)R7、−C(O)C(O)OR7、−C(O)C(O)N(R7)2、−C(O)CH2C(O)R7、−C(S)R7、−C(S)OR7、−C(O)OR7、−OC(O)R7、−C(O)N(R7)2、−OC(O)N(R7)2、−C(S)N(R7)2、−(CH2)0〜2NHC(O)R7、−N(R7)N(R7)COR7、−N(R7)N(R7)C(O)OR7、−N(R7)N(R7)CON(R7)2、−N(R7)SO2R7、−N(R7)SO2N(R7)2、−N(R7)C(O)OR7、−N(R7)C(O)R7、−N(R7)C(S)R7、−N(R7)C(O)N(R7)2、−N(R7)C(S)N(R7)2、−N(COR7)COR7、−N(OR7)R7、−C(=NH)N(R7)2、−C(O)N(OR7)R7、−C(=NOR7)R7、−OP(O)(OR7)2、−P(O)(R7)2、−P(O)(OR7)2または−P(O)(H)(OR7)であり;
2個のR7基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、該環は、3個までのヘテロ原子を有し、該ヘテロ原子は、独立して、N、N(R)、O、S、SOまたはSO2から選択され、ここで、該環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、ここで、任意の環は、3個までの置換基を有し、該置換基は、独立して、J2から選択され;または
各R7は、独立して、以下から選択される:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R7は、3個までの置換基を有し、該置換基は、独立して、J2から選択され;そして
J2は、ハロゲン、−OR7、−OC(O)N(R7)2、−NO2、−CN、−CF3、−OCF3、−R7、オキソ、チオキソ、=NR7、=N(OR7)、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R7)2、−SR7、−SOR7、−SO2R7、−SO2N(R7)2、−SO3R7、−C(O)R7、−C(O)C(O)R7、−C(O)C(O)OR7、−C(O)C(O)N(R7)2、−C(O)CH2C(O)R7、−C(S)R7、−C(S)OR7、−C(O)OR7、−OC(O)R7、−C(O)N(R7)2、−OC(O)N(R7)2、−C(S)N(R7)2、−(CH2)0〜2NHC(O)R7、−N(R7)N(R7)COR7、−N(R7)N(R7)C(O)OR7、−N(R7)N(R7)CON(R7)2、−N(R7)SO2R7、−N(R7)SO2N(R7)2、−N(R7)C(O)OR7、−N(R7)C(O)R7、−N(R7)C(S)R7、−N(R7)C(O)N(R7)2、−N(R7)C(S)N(R7)2、−N(COR7)COR7、−N(OR7)R7、−CN、−C(=NH)N(R7)2、−C(O)N(OR7)R7、−C(=NOR7)R7、−OP(O)(OR7)2、−P(O)(R7)2、−P(O)(OR7)2または−P(O)(H)(OR7)であり;そして
R8は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N、N(R)、S、SOおよびSO2から選択される基で置き換えられ得;ここで、R8は、必要に応じて、6個までの置換基で置換され、該置換基は、独立して、Rから選択される。
R1は、R6C(O)−、R6SO2−、R6OC(O)−、(R6)2NC(O)−、R6C(O)C(O)−、R6−、(R6)2NC(O)C(O)−またはR6OC(O)C(O)−であり;
R2は、水素、−CF3、−ハロ、−OR7、−NO2、−OCF3、−CNまたはR8であり;
R3は、水素または(C1〜C4)−脂肪族−であり;
R4は、−COOHまたは−COOR8であり;
R5は、−CH2Fまたは−CH2O−2,3,5,6−テトラフルオロフェニルであり;
R6は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であるか、または同じ原子に結合された2個のR6基は、その原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し;ここで、任意の環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され;ここで、3個までの脂肪族炭素原子は、O、N(H)、N(R)、S、SOおよびSO2から選択される基で置き換えられ得;ここで、R6は、6個までの置換基で置換され、該置換基は、独立して、Rから選択され;
Rは、ハロゲン、−OR7、−OC(O)N(R7)2、−NO2、−CN、−CF3、−OCF3、−R7、オキソ、チオキソ、=NR7、=N(OR7)、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R7)2、−SR7、−SOR7、−SO2R7、−SO2N(R7)2、−SO3R7、−C(O)R7、−C(O)C(O)R7、−C(O)C(O)OR7、−C(O)C(O)N(R7)2、−C(O)CH2C(O)R7、−C(S)R7、−C(S)OR7、−C(O)OR7、−OC(O)R7、−C(O)N(R7)2、−OC(O)N(R7)2、−C(S)N(R7)2、−(CH2)0〜2NHC(O)R7、−N(R7)N(R7)COR7、−N(R7)N(R7)C(O)OR7、−N(R7)N(R7)CON(R7)2、−N(R7)SO2R7、−N(R7)SO2N(R7)2、−N(R7)C(O)OR7、−N(R7)C(O)R7、−N(R7)C(S)R7、−N(R7)C(O)N(R7)2、−N(R7)C(S)N(R7)2、−N(COR7)COR7、−N(OR7)R7、−C(=NH)N(R7)2、−C(O)N(OR7)R7、−C(=NOR7)R7、−OP(O)(OR7)2、−P(O)(R7)2、−P(O)(OR7)2または−P(O)(H)(OR7)であり;
2個のR7基は、それらが結合する原子と一緒になって、3員〜10員の芳香環または非芳香環を形成し、該環は、3個までのヘテロ原子を有し、該ヘテロ原子は、独立して、N(H)、N(R)、O、S、SOまたはSO2から選択され、ここで、該環は、必要に応じて、(C6〜C10)アリール、(C5〜C10)ヘテロアリール、(C3〜C10)シクロアルキルまたは(C3〜C10)ヘテロシクリルに縮合され、ここで、任意の環は、3個までの置換基を有し、該置換基は、独立して、J2から選択され;または
各R7は、独立して、以下から選択される:
水素−、
(C1〜C12)−脂肪族−、
(C3〜C10)−環状脂肪族−、
(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、
(C6〜C10)−アリール−、
(C6〜C10)−アリール−(C1〜C12)脂肪族−、
(C3〜C10)−ヘテロシクリル−、
(C6〜C10)−ヘテロシクリル−(C1〜C12)脂肪族−、
(C5〜C10)−ヘテロアリール−、または
(C5〜C10)−ヘテロアリール−(C1〜C12)−脂肪族−;
ここで、R7は、3個までの置換基を有し、該置換基は、独立して、J2から選択され;そして
J2は、ハロゲン、−OR7、−OC(O)N(R7)2、−NO2、−CN、−CF3、−OCF3、−R7、オキソ、チオキソ、=NR7、=N(OR7)、1,2−メチレンジオキシ、1,2−エチレンジオキシ、−N(R7)2、−SR7、−SOR7、−SO2R7、−SO2N(R7)2、−SO3R7、−C(O)R7、−C(O)C(O)R7、−C(O)C(O)OR7、−C(O)C(O)N(R7)2、−C(O)CH2C(O)R7、−C(S)R7、−C(S)OR7、−C(O)OR7、−OC(O)R7、−C(O)N(R7)2、−OC(O)N(R7)2、−C(S)N(R7)2、−(CH2)0〜2NHC(O)R7、−N(R7)N(R7)COR7、−N(R7)N(R7)C(O)OR7、−N(R7)N(R7)CON(R7)2、−N(R7)SO2R7、−N(R7)SO2N(R7)2、−N(R7)C(O)OR7、−N(R7)C(O)R7、−N(R7)C(S)R7、−N(R7)C(O)N(R7)2、−N(R7)C(S)N(R7)2、−N(COR7)COR7、−N(OR7)R7、−CN、−C(=NH)N(R7)2、−C(O)N(OR7)R7、−C(=NOR7)R7、−OP(O)(OR7)2、−P(O)(R7)2、−P(O)(OR7)2または−P(O)(H)(OR7)であり;そして
R8は、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−または(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N(H)、N(R)、S、SOおよびSO2から選択される基で置き換えられ得る。
a)本明細書中で規定した式Iの化合物またはそれらの薬学的に受容可能な塩;および
b)薬学的に受容可能なキャリア、アジュバントまたはビヒクル。
P.G.M Wutz、「Protective Groups in Organic Synthesis」、3rd Edition,John Wiley & Sons,Inc.(1999)およびこの本の前の版を参照)。保護しなければならない典型的な官能基は、アミンである。任意のアミンおよび他の官能基は、当該技術分野で公知の方法に従って、保護され得る。アミンを含めた化合物は、その反応混合物から単離してまたは単離せずに、使用され得る。
R9は、−NO2、−C(O)OR10、R6C(O)N(H)−、R6SO2N(H)−、R6OC(O)N(H)−、(R6)2NC(O)N(H)−、R6C(O)C(O)N(H)−、R6N(H)−、(R6)2NC(O)C(O)N(H)−またはR6OC(O)C(O)N(H)−であり;
R10は、独立して、水素、(C1〜C12)−脂肪族−(C3〜C10)−環状脂肪族−、(C6〜C10)−アリール−、(C3〜C10)−ヘテロシクリル−、(C5〜C10)−ヘテロアリール−、(C3〜C10)−環状脂肪族−(C1〜C12)−脂肪族−、(C6〜C10)−アリール−(C1〜C12)−脂肪族−、(C3〜C10)−ヘテロシクリル−(C1〜C12)−脂肪族−、(C5〜C10)−ヘテロアリール(C1〜C12)−脂肪族−であり、ここで、3個までの脂肪族炭素原子は、O、N(H)、N(R)、S、SOおよびSO2から選択される基で置き換えられ得;ここで、R10は、必要に応じて、6個までの置換基で置換され、該置換基は、独立して、Rから選択され;そして
R、R2、R3およびR6は、本明細書中の式(I)の実施態様のいずれかで定義したとおりであり;
R4およびR5は、本明細書中の式(I)の実施態様のいずれかで定義したとおりであり;
但し、もし、YがOH基であるなら、該方法は、さらに、(b)該OH基を酸化して、式(I)の化合物を提供する工程を包含し;
但し、もし、R9が、−NO2、−C(O)OR10または−CNであるなら、該方法は、さらに、該−NO2、−C(O)OR10または−CNを、R6C(O)N(H)−、R6SO2N(H)−、R6OC(O)N(H)−、(R6)2NC(O)N(H)−、R6C(O)C(O)N(H)−、R6N(H)−、(R6)2NC(O)C(O)N(H)−またはR6OC(O)C(O)N(H)−に変換する工程を包含する。
R2は、−CF3、−Cl、−OR7、−NO2、−OCF3、−CNまたはR8であり;そして
R3、R8、R9およびR10は、本明細書中で定義したとおりであり;
該方法は、溶媒および塩基の存在下にて、(e)式(IX)の化合物と式(VII)の化合物とを反応させる工程を包含する:
R9は、−NO2、−C(O)OR10、−CN、R6C(O)N(H)−、R6SO2N(H)−、R6OC(O)N(H)−、(R6)2NC(O)N(H)−、R6C(O)C(O)N(H)−、R6N(H)−、(R6)2NC(O)C(O)N(H)−またはR6OC(O)C(O)N(H)−であり;そして
R2、R3およびR6は、本明細書中で定義したとおりであり;
但し、もし、YがOH基であるなら、該方法は、さらに、(b)該OH基を酸化して、式(I)の化合物を提供する工程を包含し;
但し、もし、R9が、−NO2、−C(O)OR10または−CNであるなら、該方法は、さらに、該−NO2、−C(O)OR10または−CNを、R6C(O)N(H)−、R6SO2N(H)−、R6OC(O)N(H)−、(R6)2NC(O)N(H)−、R6C(O)C(O)N(H)−、R6N(H)−、(R6)2NC(O)C(O)N(H)−またはR6OC(O)C(O)N(H)−に変換する工程を包含する。
((S,S)−3−[2−(3−アセチルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
方法E:
(S,S)−3−[2−(3−アセチルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−ヒドロキシ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸、第三級ブチルエステル
方法F:
(S,S)−3−[2−(3−アセチルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸第三級ブチルエステル
((S,S)−4−オキソ−3−[2−(2−オキソ−3−プロピオニルアミノ−2H−ピリジン−1−イル)−ブチリルアミノ]−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−ブチリルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−{2−[3−(シクロプロパンカルボニル−アミノ)−2−オキソ−2H−ピリジン−1−イル]−ブチリルアミノ}−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−イソブチリルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
(実施例6)
((S,S)−3−{2−[3−(2−メトキシ−アセチルアミノ)−2−オキソ−2H−ピリジン−1−イル]−ブチリルアミノ}−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−(2−{3−[(フラン−2−カルボニル)−アミノ]−2−オキソ−2H−ピリジン−1−イル}−ブチリルアミノ)−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−(2−{3−[(フラン−3−カルボニル)−アミノ]−2−オキソ−2H−ピリジン−1−イル}−ブチリルアミノ)−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−4−オキソ−3−(2−(2−オキソ−3−[(ピリジン−3−カルボニル)−アミノ]−2H−ピリジン−1−イル}−ブチリルアミノ)−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−(2−{3−[(イソチアゾール−3−カルボニル)−アミノ]−2−オキソ−2H−ピリジン−1−イル}−ブチリルアミノ)−4−オキソ−5−(2,3,5,6−テトラフルオロフェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−ベンゾイルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−4−オキソ−3−[2−(2−オキソ−3−フェニルアセチルアミノ−2H−ピリジン−1−イル)−ブチリルアミノ]−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−アセチルアミノ−2−オキソ−5−トリフルオロメチル−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−{2−[3−(3−エチル−ウレイド)−2−オキソ−2H−ピリジン−1−イル]−ブチリルアミノ}−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−{2−[3−(3,3−ジエチル−ウレイド)−2−オキソ−2H−ピリジン−1−イル]−ブチリルアミノ}−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
方法H:
(S)−2−(3−アミノ−2−オキソ−2H−ピリジン−1−イル)−酪酸第三級ブチルエステル(400mg、1.59mmol)のジクロロエタン(3mL)冷却(0℃)溶液に、トリエチルアミン(0.254mL、1.82mmol)を加えた。この溶液を、0℃で、10分間にわたって、ジホスゲン(0.11mL、0.91mmol)のジクロロエタン(7mL)溶液に滴下した。その反応混合物を、室温で、90分間攪拌し、次いで、EtOAcと1M HCl水溶液との間で分配した。その有機層をブラインで洗浄し、乾燥し(MgSO4)、濾過し、そして蒸発させて、褐色オイルとして、そのイソシアネートを得た。
((S,S)−4−オキソ−3−(2−{2−オキソ−3−[(ピロリジン−1−カルボニル)−アミノ]−2H−ピリジン−1−イル}−ブチリルアミノ)−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−メトキシカルボニルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−エタンスルホニルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−4−オキソ−3−{2−[2−オキソ−3−(プロパン−1−スルホニルアミノ)−2H−ピリジン−1−イル]−ブチリルアミノ}−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−4−オキソ−3−{2−[2−オキソ−3−(プロパン−2−スルホニルアミノ)−2H−ピリジン−1−イル]−ブチリルアミノ}−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−ベンゼンスルホニルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−エタンスルホニルアミノ−2−オキソ−5−トリフルオロメチル−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[3−メチル−2−(2−オキソ−3−フェニルアセチルアミノ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−3−[2−(3−エタンスルホニルアミノ−2−オキソ−2H−ピリジン−1−イル)−3−メチル−ブチリルアミノ]−4−オキソ−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S)−5−フルオロ−4−オキソ−3−[2−(2−オキソ−3−プロピオニルアミノ−2H−ピリジン−1−イル)−プロピオニルアミノ]−ペンタン酸)
((S)−3−[2−(3−ベンゾイルアミノ−2−オキソ−2H−ピリジン−1−イル)−プロピオニルアミノ]−5−フルオロ−4−オキソ−ペンタン酸)
((S)−3−{2−[3−(2,6−ジクロロ−ベンゾイルアミノ)−2−オキソ−2H−ピリジン−1−イル]−プロピオニルアミノ}−5−フルオロ−4−オキソ−ペンタン酸)
((S)−5−フルオロ−4−オキソ−3−[2−(2−オキソ−3−フェニルアセチルアミノ−2H−ピリジン−1−イル)−プロピオニルアミノ]−ペンタン酸)
((S)−5−フルオロ−4−オキソ−3−[2−(2−オキソ−3−プロピオニルアミノ−2H−ピリジン−1−イル)−ブチリルアミノ]−ペンタン酸)
((S)−3−[2−(3−ベンゾイルアミノ−2−オキソ−2H−ピリジン−1−イル)−ブチリルアミノ]−5−フルオロ−4−オキソ−ペンタン酸)
((S)−3−{2−[3−(2、6−ジクロロ−ベンゾイルアミノ)−2−オキソ−2H−ピリジン−1−イル]−ブチリルアミノ}−5−フルオロ−4−オキソ−ペンタン酸)
((S)−5−フルオロ−4−オキソ−3−(2−{2−オキソ−3−[(ピリジン−2−カルボニル)−アミノ]−2H−ピリジン−1−イル}−ブチリルアミノ)−ペンタン酸)
((S)−5−フルオロ−4−オキソ−3−{2−[2−オキソ−3−(2−m−トリル−アセチルアミノ)−2H−ピリジン−1−イル]−ブチリルアミノ}−ペンタン酸)
((S)−5−フルオロ−4−オキソ−3−[2−(2−オキソ−3−プロピオニルアミノ−2H−ピリジン−1−イル)−ペンタノイルアミノ]−ペンタン酸)
((S)−5−フルオロ−3−[4−メチル−2−(2−オキソ−3−プロピオニルアミノ−2H−ピリジン−1−イル)−ペンタノイルアミノ]−4−オキソ−ペンタン酸)
((S)−5−フルオロ−3−[2−(5−メチル−2−オキソ−3−フェニルアセチルアミノ−2H−ピリジン−1−イル)−ブチリルアミノ]−4−オキソ−ペンタン酸)
((S,S)−4−オキソ−3−{2−[2−オキソ−3−(チアゾール−2−イルアミノ)−2H−ピリジン−1−イル]−ブチリルアミノ}−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
((S,S)−4−オキソ−3−[2−(2−オキソ−3−プロピルアミノ−2H−ピリジン−1−イル)−ブチリルアミノ]−5−(2,3,5,6−テトラフルオロ−フェノキシ)−ペンタン酸)
(酵素アッセイ)
カスパーゼ阻害アッセイは、精製した組換えヒトカスパーゼ−1、−3または−8による蛍光発生基質の開裂に基づいている。これらのアッセイは、各酵素に特異的な基質を使用して、Garcia−Calvoら(J.Biol.Chem.273(1998),32608〜32613)が報告した様式とほぼ同じ様式で、実行される。カスパーゼ−1用の基質は、アセチル−Tyr−Val−Ala−Asp−アミノ−4−メチルクマリンである。カスパーゼ−3および−8用の基質は、アセチル−Asp−Glu−Val−Asp−アミノ−4−メチルクマリンである。両方の基質は、当該技術分野で公知である。
(全血からのIL−1β分泌の阻害)
ヒト血液を、健常なドナーから新たに採血し、PBSで1:2希釈する。500μlの希釈血液に、予めRPMI培地に希釈した試験化合物50mlおよびLPS 10ml(プレート上での最終濃度5ng/ml)を添加する(LPS,Serotype 0111:B4,Sigma L3012)。18時間刺激した後、上清を収集し、適切なELISAキット(R&D systems)を用いてIL−1βレベルをアッセイした。
(ラット皮質ニューロンの低酸素誘導アポトーシス)
皮質神経を、Rogersら、1997、Brain Res.Bulletin,44:131の改良手順により、Wistarラットの胚(E17)から切除する。簡単に言うと、15〜20個のWistarラットの胚から大脳皮質を無菌的に隔離する。大脳皮質を刻み、パパイン消化することによって、細胞懸濁物を調製する。細胞を、オボムコイド酵素インヒビターおよびDNaseIで洗浄し、そして10%熱不活性化ウシ胎仔血清、L−グルタミン、ペニシリン、およびストレプトマイシンを含有する高グルコースDMEM中の、ポリ−Dリジンコートプレート上にプレーティングする。ニューロンの収率は、10×7/胚であり、トリパンブルー除去法により評価した場合、それらは80〜90%生存率である。
(抗−Fas誘発アポトーシスアッセイ)
細胞アポトーシスは、Fas配位子(FasL)をそのレセプタであるCD95(Fas)に結合することにより、誘発され得る。CD95は、1系統の関連レセプタ(これは、デスレセプタとして知られている)の1つであり、これは、このカスパーゼ酵素カスケードの活性化によって、細胞でのアポトーシスを誘発できる。この過程は、アダプタ分子であるFADD/MORT−1がCD−95レセプタ配位子錯体の細胞質ドメインに結合することにより、開始される。カスパーゼ−8は、次いで、FADDを結合し、そして活性化して、下流カスパーゼの活性化および引き続く細胞アポトーシスを含む事象のカスケードを開始する。アポトーシスはまた、抗体を使用して、FasLよりもむしろ、CD95、例えば、Jurkat E6.1 T細胞のリンパ腫細胞系を発現して、細胞表面CD95を架橋することにより、誘発できる。抗−Fas誘発アポトーシスはまた、カスパーゼ−8の活性化により、誘発される。これにより、カスパーゼ−8媒介アポトーシス経路の阻害用のスクリーン化合物に対する細胞ベースアッセイの基礎が得られる。
Jurkat E6.1細胞を、完全培地(これは、RPMI−1640(Sigma No)+10%ウシ胎児血清(Gibco BRL No.10099−141)+2mM L−グルタミン(Sigma No.G−7513)からなる)中で培養する。これらの細胞を、対数期の成長で収集する。100mlの細胞を、5〜8×105個の細胞/mlで、無菌50ml Falcon遠心管に移動して、室温で、100×gで、5分間遠心分離する。その上澄み液を除去し、合わせた細胞ペレットを、完全培地25ml中で懸濁させる。これらの細胞を数え、その密度を、完全培地を使って、2×106個の細胞/mlに調節する。
本発明は、式Iの化合物を提供し:
Claims (1)
- 明細書に記載の、カスパーゼ阻害剤。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US10143267B1 (en) | 2013-12-31 | 2018-12-04 | Dynasty Footwear, Ltd. | Shoe bottom surface having attached particles |
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