JP4603268B2 - 新規化合物 - Google Patents
新規化合物 Download PDFInfo
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- JP4603268B2 JP4603268B2 JP2003585724A JP2003585724A JP4603268B2 JP 4603268 B2 JP4603268 B2 JP 4603268B2 JP 2003585724 A JP2003585724 A JP 2003585724A JP 2003585724 A JP2003585724 A JP 2003585724A JP 4603268 B2 JP4603268 B2 JP 4603268B2
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- 150000001875 compounds Chemical class 0.000 title claims description 164
- -1 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds Chemical class 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims description 28
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- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- UMNPZIKRPVBEDR-UHFFFAOYSA-N 4-(2,4-difluorophenyl)-2-(1,3-dihydroxypropan-2-ylamino)-8-(2,4,6-trifluorophenyl)pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C=CC(=O)N(C=3C(=CC(F)=CC=3F)F)C2=NC(NC(CO)CO)=NC=1C1=CC=C(F)C=C1F UMNPZIKRPVBEDR-UHFFFAOYSA-N 0.000 claims description 5
- WJLJTZCRKSSROJ-UHFFFAOYSA-N 4-(2-chloro-4-fluorophenyl)-8-(2,4-difluorophenyl)-2-(1,3-dihydroxypropan-2-ylamino)pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C=CC(=O)N(C=3C(=CC(F)=CC=3)F)C2=NC(NC(CO)CO)=NC=1C1=CC=C(F)C=C1Cl WJLJTZCRKSSROJ-UHFFFAOYSA-N 0.000 claims description 5
- LPAWYEYFSNWBHC-UHFFFAOYSA-N 2-(1,3-dihydroxypropan-2-ylamino)-4-(2-fluorophenyl)-8-(2,4,6-trifluorophenyl)pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C=CC(=O)N(C=3C(=CC(F)=CC=3F)F)C2=NC(NC(CO)CO)=NC=1C1=CC=CC=C1F LPAWYEYFSNWBHC-UHFFFAOYSA-N 0.000 claims description 4
- QWSRSVMAHMEJSH-UHFFFAOYSA-N 4,8-bis(2,4-difluorophenyl)-2-(1,3-dihydroxypropan-2-ylamino)pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C=CC(=O)N(C=3C(=CC(F)=CC=3)F)C2=NC(NC(CO)CO)=NC=1C1=CC=C(F)C=C1F QWSRSVMAHMEJSH-UHFFFAOYSA-N 0.000 claims description 4
- JCLDTGONWQOHTP-UHFFFAOYSA-N 4-(2,4-difluoroanilino)-6-(2,4-difluorophenyl)-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound O=CC=1C(C=2C(=CC(F)=CC=2)F)=NC(SC)=NC=1NC1=CC=C(F)C=C1F JCLDTGONWQOHTP-UHFFFAOYSA-N 0.000 claims description 4
- XIDKYJHGKBVRDL-LBPRGKRZSA-N 8-(2,4-difluorophenyl)-4-(2-fluorophenyl)-2-[[(2s)-1-hydroxypropan-2-yl]amino]pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C=CC(=O)N(C=3C(=CC(F)=CC=3)F)C2=NC(N[C@H](CO)C)=NC=1C1=CC=CC=C1F XIDKYJHGKBVRDL-LBPRGKRZSA-N 0.000 claims description 4
- BHLGLVOFWRMAQD-UHFFFAOYSA-N 2-(1,3-dihydroxypropan-2-ylamino)-4-(4-fluorophenyl)-8-(2,4,6-trifluorophenyl)pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C=CC(=O)N(C=3C(=CC(F)=CC=3F)F)C2=NC(NC(CO)CO)=NC=1C1=CC=C(F)C=C1 BHLGLVOFWRMAQD-UHFFFAOYSA-N 0.000 claims description 3
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- Endocrinology (AREA)
Description
本発明は、新規2,4,8−三置換−8H−ピリド[2,3−d]ピリミジン−7−オン化合物類、その製造方法、CSBP/p38キナーゼ媒介疾患の治療におけるその使用、およびかかる治療において使用するための医薬組成物に関する。
細胞内シグナル伝達は、細胞が細胞外刺激に応答する手段である。細胞表面受容体(例えば、タンパク質チロシンキナーゼまたは7回膜貫通G−タンパク質結合受容体)の特性に関係なく、プロテインキナーゼおよびホスファターゼはホスホリパーゼと共に、シグナルがさらに細胞内部に伝達される必須の機構である[Marshall, J.C. Cell, 80, 179-278 (1995)]。プロテインキナーゼは、該酵素がその基質を特定のチロシン残基またはセリン/スレオニン残基のいずれにおいてリン酸化するかに応じてチロシンキナーゼおよびセリン/スレオニンキナーゼの2つの主要なクラスを含む5つのクラスに分類することができる[Hunter, T., Methods in Enzymology (Protein Kinase Classification) p.3, Hunter, T.; Sefton, B.M.; eds. vol.200, Academic Press; San Diego, 1991]。
医薬活性、殺虫活性および除草活性を有する他のピリド[2,3−d]ピリミジン含有ファルマコフォアは、WO 98/33798;WO 98/23613;WO 95/19774、現在の米国特許第6,265,410号;WO 00/23444;WO 01/19828(本願の出願日後に公開された);米国特許第5,532,370号;米国特許第5,597,776号;日本特許出願公開2000−38350;WO 00/43374;WO 98/08846;およびWO 01/55147(本願の出願日後に公開された)におけるように当該技術分野において見ることができる。
図1は、p38キナーゼカスケードを示す。
本発明は、式(I)および(Ia)、および式(II)および(IIa)で示される新規化合物、ならびに式(I)および式(Ia)、および式(II)および(IIa)で示される化合物および医薬上許容される希釈剤または担体を含む医薬組成物に関する。
R1は、置換されていてもよいアリールまたは置換されていてもよいヘテロアリール環であり;
R2は、水素、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であるか(ここで、該部分は全て置換されていてもよい)、または、R2は、X1(CR10R20)qC(A1)(A2)(A3)部分またはC(A1)(A2)(A3)部分であり;
A1は、置換されていてもよいC1-10アルキルであり;
A2は、置換されていてもよいC1-10アルキルであり;
A3は、水素であるか、または置換されていてもよいC1-10アルキルであり;
R3は、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルC1-4アルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);
R4およびR14は、各々、独立して、水素、置換されていてもよいC1-4アルキル、置換されていてもよいC3-7シクロアルキル、C3-7シクロアルキルC1-4アルキル、置換されていてもよいアリール、または置換されていてもよいアリール−C1-4アルキルから選択されるか、または、R4およびR14は、それらが結合している窒素と一緒になって、置換されていてもよい4〜7員ヘテロサイクリック環を形成し(ここで、該環は、酸素、硫黄またはNR9から選択される付加的ヘテロ原子を含有していてもよい);
R6は、水素、C1-10アルキル、C3-7シクロアルキル、ヘテロサイクリル、ヘテロサイクリルC1-10アルキル、アリール、アリールC1-10アルキル、ヘテロアリールまたはヘテロアリールC1-10アルキルであり(ここで、これらの部分の各々は置換されていてもよい);
R9は、水素、C(Z)R6または置換されていてもよいC1-10アルキル、置換されていてもよいアリールまたは置換されていてもよいアリール−C1-4アルキルであり;
R10およびR20は、独立して、水素またはC1-4アルキルから選択され;
Xは、R2、OR2、S(O)mR2、(CH2)nN(R10)S(O)mR2、(CH2)nN(R10)C(O)R2、(CH2)nNR4R14、または(CH2)nN(R2)2であり;
X1は、N(R10)、O、S(O)m、またはCR10R20であり;
nは、0、または1〜10の値を有する整数であり;
mは、0、または1もしくは2の値を有する整数であり;
qは、0、または1〜10の値を有する整数であり;
Zは、酸素または硫黄である]
で示される化合物またはその医薬上許容される塩を提供する。
本発明の別の態様は、式(II)および(IIa):
R1は、YRa部分であり;
R2は、水素、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であるか(ここで、該部分は、全て、置換されていてもよい)、または、R2は、X1(CR10R20)qC(A1)(A2)(A3)部分、またはC(A1)(A2)(A3)部分であり;
A1は、置換されていてもよいC1-10アルキルであり;
A2は、置換されていてもよいC1-10アルキルであり;
A3は、水素であるか、または置換されていてもよいC1-10アルキルであり;
R3は、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルC1-4アルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);
R4およびR14は、各々独立して、水素、置換されていてもよいC1-4アルキル、置換されていてもよいC3-7シクロアルキル、C3-7シクロアルキルC1-4アルキル、置換されていてもよいアリール、または置換されていてもよいアリール−C1-4アルキルから選択されるか、またはR4およびR14は、それらが結合している窒素と一緒になって、置換されていてもよい4〜7員ヘテロサイクリック環を形成し(ここで、該環は、酸素、硫黄またはNR9から選択される付加的ヘテロ原子を含有していてもよい);
R6は、水素、C1-10アルキル、C3-7シクロアルキル、ヘテロサイクリル、ヘテロサイクリルC1-10アルキル、アリール、アリールC1-10アルキル、ヘテロアリールまたはヘテロアリールC1-10アルキルであり(ここで、これらの部分の各々は置換されていてもよい);
R9は、水素、C(Z)R6または置換されていてもよいC1-10アルキル、置換されていてもよいアリールまたは置換されていてもよいアリール−C1-4アルキルであり;
R10およびR20は、独立して、水素またはC1-4アルキルから選択され;
Yは、C(Rb)(Rd)、C(O)、N(Rd)、N(Rd)C(Rc)(Rd)、酸素、OC(Rc)(Rd)、S(O)m、またはS(O)mC(Rc)(Rd)であり;
Raは、アリールまたはヘテロアリール環であり(ここで、該環は置換されていてもよい);
Rbは、水素、C1-2アルキル、NRc、ヒドロキシ、チオ、C1-2アルコキシ、S(O)mC1-2アルキルであり;
Rcは、水素またはC1-2アルキルであり;
Rdは、水素またはC1-2アルキルであり;
Xは、R2、OR2、S(O)mR2、(CH2)nN(R10)S(O)mR2、(CH2)nN(R10)C(O)R2、(CH2)nNR4R14、または(CH2)nN(R2)2であり;
X1は、N(R10)、O、S(O)m、またはCR10R20であり;
nは、0、または1〜10の値を有する整数であり;
mは、0、または1もしくは2の値を有する整数であり;
qは、0、または1〜10の値を有する整数であり;
Zは、酸素または硫黄である]
で示される化合物または医薬上許容される塩を提供する。
適当には、Zは酸素または硫黄である。
適当には、Ra'は、C1-4アルキル、ハロ置換C1-4アルキル、C2-4アルケニル、C2-4アルキニル、C3-7シクロアルキル、C5-7シクロアルケニル、アリール、アリールC1-4アルキル、ヘテロアリール、ヘテロアリールC1-4アルキル、ヘテロサイクリル、ヘテロサイクリルC1-4アルキル、(CR10R20)vOR7、(CR10R20)vS(O)mR7、(CR10R20)vNR10S(O)2R7、または(CR10R20)vNR4R14であり;ここで、該アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキルは置換されていてもよい。
適当には、YはC(Rb)(Rd)、C(O)、N(Rd)、N(Rd)C(Rc)(Rd)、酸素、OC(Rc)(Rd)、S(O)m、またはS(O)mC(Rc)(Rd)である。
適当には、Rbは、水素、C1-2アルキル、NRc、ヒドロキシ、チオ、C1-2アルコキシ、S(O)mC1-2アルキルである。
適当には、Rcは水素またはC1-2アルキルである。
適当には、mは0、または1もしくは2の値を有する整数である。
適当には、Raは、置換されていてもよいアリール環または置換されていてもよいヘテロアリール環である。これらの環の任意の置換基は、上記した式(I)および(Ia)のR1のアリールおよびヘテロアリール環についてと同じである。
適当には、R9は、水素、C(Z)R6、置換されていてもよいC1-10アルキル、置換されていてもよいアリールまたは置換されていてもよいアリール−C1-4アルキルである。
適当には、R10およびR20は、独立して、水素またはC1-4アルキルから選択される。
適当には、mは0、または1もしくは2の値を有する整数である。
適当には、Xは、R2、OR2、S(O)mR2、(CH2)nN(R10)S(O)mR2、(CH2)nN(R10)C(O)R2、(CH2)nNR4R14、または(CH2)nN(R2)2である。好ましくは、Xは、R2、OR2、(CH2)nNR4R14、または(CH2)nN(R2)2である。好ましくは、XがR2である場合、R2は、X1(CR10R20)qC(A1)(A2)(A3)部分またはC(A1)(A2)(A3)部分である。
適当には、qは、0、または1〜10の値を有する整数である。
適当には、A1は、置換されていてもよいC1-10アルキルである。
適当には、A2は、置換されていてもよいC1-10アルキルである。
適当には、A3は、水素であるか、または置換されていてもよいC1-10アルキルである。
好ましいC(A1)(A2)(A3)基は、CH(CH2OH)2、またはC(CH3)(CH2OH)2、X1(CR10R20)qCH(CH2OH)2、またはX1(CR10R20)qC(CH3)(CH2OH)2である。X1は、好ましくは、酸素または窒素である。
式(I)、(Ia)、(II)および(IIa)で示される化合物は、本明細書に記載する合成法を適用することにより得ることができる。提供される合成法は、適当に保護される任意の置換基を使用して反応させて本明細書に概略記載される反応に適合させる、種々の異なったR1、R2、Y、X、およびR3基を有する式(I)、(Ia)、(II)および(IIa)で示される化合物の製造に適用可能である。これらの場合、次いで、次なる脱保護により一般に記載されている性質を有する化合物を得る。本明細書には特定の置換基を有する特定の式を示しているが、該合成法は本明細書における全ての式および全ての置換基に適用可能である。
R1は、アリールまたはヘテロアリール環であり(ここで、該環は置換されていてもよい);
R3は、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);
R12は、C1-10アルキル、アリール、ヘテロアリール、またはアリールアルキルであり;
mは、0、または1もしくは2の値を有する整数であり;
RgはC1-4アルキルである]
で示される新規中間体である。
好ましくは、mは0、または1もしくは2の値を有する整数である。より好ましくは、mは0または2である。
好ましくは、R1はアリール部分であり、より好ましくは、フェニル環であり、ハロゲン、C1-4アルキル、またはハロ置換C1-4アルキルによって1回またはそれ以上置換されていてもよい。より好ましくは、フェニル環は、2−フルオロ、4−フルオロ、2,4−ジフルオロ、2,4,6−トリフルオロまたは2−メチル−4−フルオロのように、2位、4位もしくは6位で独立して置換されているか、または2,4位で二置換されている。より好ましくは、フェニル環は、例えばフッ素または塩素により、独立して、3位で置換されているか、2,3−置換されているか、または3,4−置換されている。
R1は、YRa部分であり;
Yは、C(Rb)(Rd)、C(O)、N(Rd)、N(Rd)C(Rc)(Rd)、酸素、OC(Rc)(Rd)、S(O)m、またはS(O)mC(Rc)(Rd)であり;
Raは、アリールまたはヘテロアリール環であり(ここで、該環は置換されていてもよい);
Rbは、水素、C1-2アルキル、NRc、ヒドロキシ、チオ、C1-2アルコキシ、S(O)mC1-2アルキルであり;
Rcは、水素またはC1-2アルキルであり;
Rdは、水素またはC1-2アルキルであり;
mは、0、または1もしくは2の値を有する整数であり;
R3は、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);
R12は、C1-10アルキル、アリール、ヘテロアリール、またはアリールアルキルであり;
mは、0、または1もしくは2の値を有する整数であり;
Rgは、C1-4アルキルである]
で示される新規中間体である。
R1は、ハロゲン、置換されていてもよいアリールまたは置換されていてもよいヘテロアリール環であり;
R3は、水素、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);(ただし、R3が水素である場合、R1は塩素以外である);
mは、0、または1もしくは2の値を有する整数であり;
Rgは、C1-4アルキルである]
で示される新規中間体である。
4−(2,4−ジフルオロ−フェニルアミノ)−6−(2,4,6−トリフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2,4−ジフルオロ−フェニル)−6−(2,4−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2−フルオロフェニル)−6−(2,4,6−トリフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(4−フルオロフェニル)−6−(2,4,6−トリフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2−フルオロフェニル)−6−(2,4−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2,4−ジフルオロ−フェニル)−6−(4−フルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2,4−ジフルオロ−フェニル)− 6−(2,4−ジフルオロフェニルアミノ)−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2−クロロ−4−フルオロフェニル)−6−(2,4−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;または
4−(2,4−ジフルオロフェニル)−6−(2,3−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド。
R1は、YRaであり;
Yは、C(Rb)(Rd)、C(O)、N(Rd)、N(Rd)C(Rc)(Rd)、酸素、OC(Rc)(Rd)、S(O)m、またはS(O)mC(Rc)(Rd)であり;
Raは、アリールまたはヘテロアリール環であり(ここで、該環は置換されていてもよい);
Rbは、水素、C1-2アルキル、NRc、ヒドロキシ、チオ、C1-2アルコキシ、S(O)mC1-2アルキルであり;
Rcは、水素またはC1-2アルキルであり;
Rdは、水素またはC1-2アルキルであり;
mは、0、または1もしくは2の値を有する整数であり;
R3は、水素、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);
mは、0、または1もしくは2の値を有する整数であり;
Rgは、C1-4アルキルである]
で示される新規中間体である。
R1は、式(I)で示される化合物についての上記定義と同じであり、R3、Rg、およびmは、式(III)で示される化合物についての定義と同じであり、置換されていてもよいアリールまたはヘテロアリール部分である]
で示される新規中間体である。
R1は、式(II)で示される化合物についての上記定義と同じであり、R3、Rg、およびmは、式(IIIa)で示される化合物についての定義と同じであり、置換されていてもよいアリールまたはヘテロアリール部分である]
で示される新規中間体である。
R1は、ハロゲンであり;
R3は、水素、C1-10アルキル、C3-7シクロアルキル、C3-7シクロアルキルアルキル、アリール、アリールC1-10アルキル、ヘテロアリール、ヘテロアリールC1-10アルキル、ヘテロサイクリック、またはヘテロサイクリルC1-10アルキル部分であり(ここで、該部分は置換されていてもよい);(ただし、R3が水素である場合、R1は塩素以外である);
mは、0、または1もしくは2の値を有する整数であり;
Rgは、C1-4アルキルである]
で示される新規中間体である。
適当には、R3置換基は、本明細書における式(I)および(II)で示される化合物についてのものと同じである。
8−(2,4,6−トリフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;
4,8−ビス−(2,4−ジフルオロ−フェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
8−(2,4,6−トリフルオロフェニル)−4−(2−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;
8−(2,4,6−トリフルオロフェニル)−4−(4−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;
4−(2−フルオロ−フェニル)−8−(2,4−ジフルオロ−フェニル)−2−((S)−2−ヒドロキシ−1−メチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
4−(2,4−ジフルオロ−フェニル)−8−(4−フルオロ−フェニル)−2−((S)−2−ヒドロキシ−1−メチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
4,8−ビス−(2,4−ジフルオロ−フェニル)−2−(2−ヒドロキシ−1−メチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
8−(2,4−ジフルオロフェニル)−4−(2−クロロ−4−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;もしくは
8−(2,3−ジフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチル−エチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;または
その医薬上許容される塩である。
式(I)および(Ia)で示される化合物またはその医薬上許容される塩は、ヒトまたは他の哺乳動物における、単球および/またはマクロファージ(これらに限定されるものではない)のようなかかる哺乳動物の細胞による過剰または未制御のサイトカイン産生により悪化するかまたは引き起こされるいずれもの病態を予防的または治療的に処置するための薬物の製造において使用することができる。
a)単球またはマクロファージを包含するがこれらに限定されるものではない全ての細胞によるサイトカイン(IL−1、IL−6、IL−8またはTNF)のインビボ放出を阻害することによりヒトにおける該サイトカインの過剰なインビボレベルを正常レベルまたは正常下レベルに減少させること;
b)ゲノムレベルで、ヒトにおけるサイトカイン(IL−1、IL−6、IL−8またはTNF)の過剰なインビボレベルを正常レベルまたは正常下レベルにダウンレギュレートすること;
c)翻訳後事象としてのサイトカイン(IL−1、IL−6、IL−8またはTNF)の直接合成を阻害することによりダウンレギュレートすること;または
d)翻訳レベルで、ヒトにおけるサイトカイン(IL−1、IL−6、IL−8またはTNF)の過剰なインビボレベルを正常レベルまたは正常下レベルにダウンレギュレートすること
を意味する。
本発明の化合物のサイトカイン阻害効果を以下のインビトロアッセイによって決定することができる:インターロイキン−1(IL−1)、インターロイキン−8(IL−8)、および腫瘍壊死因子(TNF)についてのアッセイは、当該技術分野においてよく知られており、数多くの刊行物および特許において見ることができる。本明細書において使用するための代表的な適当なアッセイは、Adams et al.の米国特許第5,593,992号(記載内容は全体として出典明示により本明細書の記載とする)に記載されている。
Colotta et al., J Immunol, 132, 936 (1984)の方法に従って、ボランティアドナーからの新鮮な血液製剤または血液銀行バフィーコートからヒト末梢血単球を単離し精製する。これらの単球(1×106)を24ウェルプレート中にてウェル1個につき1〜2×106/mlの濃度でプレーティングする。該細胞を2時間付着させ、その後、穏やかに洗浄することにより付着していない細胞を除去する。次いで、該細胞に試験化合物を添加してから1時間後にリポ多糖(50ng/ml)を添加し、培養液を37℃でさらに24時間インキュベートする。この期間の最後に、培養上清を取り出し、細胞および全ての残骸を浄化する。次いですぐに、Simon et al., J. Immunol. Methods, 84, 85, (1985)の方法(IL−1の、A23187イオノフォアと協力してインターロイキン2産生性細胞系(EL−4)を刺激してIL−2を分泌する能力に基づく)またはLee et al., J. ImmunoTherapy, 6(1), 1-12 (1990) の方法(ELISAアッセイ)のいずれかによってIL−1生物学的活性について培養上清をアッセイする。
(1)Griswold et al., Drugs Under Exp. and Clinical Res., XIX(6), 243-248 (1993);または
(2)Boehm, et al., Journal Of Medicinal Chemistry 39, 3929-3937 (1996)
(記載内容は全体として出典明示により本明細書の記載とする)
齧歯動物におけるLPS誘発TNFα産生のインビボ阻害を評価するために、マウスおよびラットの両方にLPSを注射する。
チャールス・リバー・ラボラトリーズ(Charles River Laboratories)からの雄性のBalb/cマウスを化合物またはビヒクルで予備処理(30分)する。30分間の予備処理時間の後、このマウスに、マウス1匹につき、リン酸緩衝生理食塩水(pH7.0)25μl中のLPS(ミズリー州セントルイスのシグマ・ケミカル・カンパニー(Sigma Chemical Co.)、エシェリヒア・コリ血清型055−85由来のリポ多糖)25μgを腹腔内投与する。2時間後、マウスをCO2吸入により屠殺し、ヘパリン処理した血液採集管への全血採取により血液試料を採集し、氷上で貯蔵する。血液試料を遠心分離に付し、血漿を集め、ELISAによりTNFαについてアッセイするまで−20℃で貯蔵する。
チャールス・リバー・ラボラトリーズからの雄性のルイス(Lewis)ラットを化合物またはビヒクルで様々な時点で予め処理する。所定の予備処理時間の後、該ラットにLPS(ミズリー州セントルイスのシグマ・ケミカル・カンパニー、エシェリヒア・コリ血清型055−85由来のリポ多糖)3.0mg/kgを腹腔内投与する。LPS注射の90分後、ラットをCO2吸入により屠殺し、心臓を穿刺して各ラットからヘパリン処理した全血を採集する。血液試料を遠心分離に付し、TNFαレベルについてのELISAによる分析のために血漿を回収する。
Olivera et al., Circ. Shock, 37, 301-306 (1992)(記載内容は全体として出典明示により本明細書の記載とする)に記載されているように、捕獲抗体としてハムスターモノクローナル抗ネズミTNFα(マサチューセッツ州ボストンのジェンザイム(Genzyme))および第2抗体としてポリクローナルウサギ抗ネズミTNFα(ジェンザイム)を用いて、サンドイッチELISA法を用いてTNFαレベルを測定した。検出のため、ペルオキシダーゼ複合ヤギ抗ウサギ抗体(イリノイ州ロックホードのピアース(Pierce))を添加し、次いで、ペルオキシダーゼニ対する基質(過酸化尿素1%を含む1mg/mlのオルトフェニレンジアミン)を添加した。各動物からの血漿試料中のTNFαレベルを、組換えネズミTNFα(ジェンザイム)を用いて作成した標準曲線より算出した。
アッセイ:10X濃度の試験化合物濃縮物を調製し、LPSを1ug/mI(最終濃度50ng/ml LPS)で調製し、体積50uLを1.5mLのエッペンドルフ管に添加した。ヘパリン処理したヒト全血を健康なボランティアから採取し、化合物およびLPSを含有するエッペンドルフ管中に体積0.4mLずつ分配し、該管を37℃でインキュベートした。4時間インキュベートした後、該管をTOMY微量遠心管中にて5000rpmで5分間遠心分離し、血漿を取り除いて−80℃で冷凍した。
サイトカイン測定:標準的なELISA法を用いてIL−Iおよび/またはTNFを定量化した。インハウスELISAキットを使用してヒトIL−1およびTNFを検出した。適当なサイトカインの標準曲線からIL−1またはTNFの濃度を決定し、直線回帰分析により試験化合物についてのIC50値(LPS刺激サイトカイン産生の50%を阻害して濃度)を算出した。
このアッセイは、32Pの、[a−32P]ATPから、以下の配列:
試験した式(I)および(Ia)で示される代表的な最終化合物である実施例1〜3の化合物は全て、この結合アッセイにてIC50が<10μMである正の阻害活性を示した。
このアッセイは、ラットにおける実験的に誘発させた側方液体打撃外傷性脳損傷(TBI)の結果として起こる特定の脳領域における腫瘍壊死因子mRNAの発現の実験を行う。TNF−αは、神経増殖因子(NGF)を誘発することができ、他のサイトカインの活性アストロサイトからの放出を刺激することができるので、TNF−αの遺伝子発現のこの外傷後変化は、CNS外傷に対する急性応答および修復性応答の両方において重要な役割を果たす。適当なアッセイは、WO 97/35856において見ることができる(記載内容は出典明示により本明細書の記載とする)。
このアッセイは、ラットにおける実験的側方流体打撃外傷性脳損傷(TBI)の結果として起こる特定の脳領域におけるインターロイキン−1β(IL−1β)mRNAの領域的発現を特徴とする。これらのアッセイからの結果は、TBI後、IL−1β mRNAの側頭部の発現が特定の脳領域において局所的に刺激されることを示している。IL−1βのようなサイトカインにおけるこれらの領域的変化は、脳損傷の外傷後病理的または修復性続発症において役割を果たす。適当なアッセイは、WO 97/35856において見ることができる(記載内容は出典明示により本明細書の記載とする)。
WO 97/32583(記載内容は出典明示により本明細書の記載とする)には、サイトカイン阻害によって血管の過剰または不適当な増殖の組織破壊が停止されることを示すのに使用できる炎症性血管形成の測定についてのアッセイが開示されている。
ライノウイルス血清型39およびインフルエンザウイルスA/PR/8/34の細胞系をアメリカン・タイプ・カルチャー・コレクション(ATCC)から購入した。クローンティクス・コーポレーション(Clonetics Corp.)から購入したBEGM(気管支上皮成長培地)を使用して、ATCCにより提供された使用説明書に従ってBEAS−2B細胞を培養した。ウイルスの検出および力価決定のために使用するHELA細胞培養物を、10%ウシ胎仔血清、2mM l−グルタミンおよび10mM HEPES緩衝液(MEM)を含有するイーグル最少必須培地中に維持した。
試験化合物の不在下にて蛍光リガンドが有意に(>50%)酵素結合し、十分な濃度(>10×Ki)の有効阻害剤の存在下にて未結合蛍光リガンドの異方性が該結合値とは測定可能に異なるような条件下にて、CSBPキナーゼ酵素、蛍光リガンドおよび種々の濃度の試験化合物を一緒にインキュベートして熱力学的平衡に到達させる。
キナーゼ酵素の濃度は、好ましくは、≧1×Kfである。必要な蛍光リガンドの濃度は、使用する計測手段、ならびに蛍光特性および物理化学的特性に依存する。使用濃度は、キナーゼ酵素の濃度よりも低くなければならず、好ましくは、キナーゼ酵素濃度の半分未満である。
全ての成分を最終組成物62.5mM HEPES、pH7.5、1.25mM CHAPS、1.25mM DTT、12.5mM MgCl2 3.3%DMSOのバッファーに溶解する。
p38酵素濃度:12nM
蛍光リガンド濃度:5nM
試験化合物濃度:0.1nM〜100uM
平衡に達するまで(5〜30分間)、NUNC 384ウェルブラックマイクロタイタープレート中にて最終容量30ulで成分をインキュベートする。
蛍光異方性をLJL Acquestにて読み取る。
定義:Ki = 阻害剤結合についての解離定数
Kf = 蛍光リガンド結合についての解離定数
蛍光リガンドは、5−[2−(4−アミノメチルフェニル)−5−ピリジン−4−イル−1H−イミダゾール−4−イル]−2−クロロフェノールおよびローダミングリーンから誘導される以下の化合物である:
ここで、単に例示するものであって本発明の範囲を限定しようとするものではない以下の実施例を引用して本発明を記載する。全ての温度は、摂氏で示し、全ての溶媒は入手可能な最高純度のものであり、全ての反応は、無水条件下にて、必要な場合にはアルゴン(Ar)雰囲気中にて行われる。
satd=飽和;aq=水溶液;NMP=1−メチル−2−ピロリジノン;soln=溶液;他の略語はACS Style Guide(American Chemical Society, Washington, DC, 1986)に記載されているとおりである。
8−(2,4,6−トリフルオロフェニル)−4−(4−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチル−エチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン
8−(2,4−ジフルオロフェニル)−4−(2−フルオロフェニル)−2−((S)−2−ヒドロキシ−1−メチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン
8−(4−フルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−((S)−2−ヒドロキシ−1−メチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン
8−(2,4−ジフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−((S)−2−ヒドロキシ−1−メチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン
8−(2,3−ジフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチル−エチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン
好ましい実施態様を包含する上記記載事項は本発明を十分に開示する。本明細書に具体的に開示した実施態様の変更および改良は特許請求の範囲の範囲内に含まれる。さらに詳述せずとも、当業者は上記記載事項を用いて本発明を最大限に利用することができると考えられる。したがって、本明細書における実施例は単に例示的であって、如何なる場合も本発明の範囲を制限するものではないと考えられる。排他的所有権または特権を主張する本発明の実施態様は特許請求の範囲に定義するとおりである。
Claims (7)
- 8−(2,4,6−トリフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;
4,8−ビス−(2,4−ジフルオロ−フェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
8−(2,4,6−トリフルオロフェニル)−4−(2−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;
8−(2,4,6−トリフルオロフェニル)−4−(4−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;
4−(2−フルオロ−フェニル)−8−(2,4−ジフルオロ−フェニル)−2−((S)−2−ヒドロキシ−1−メチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
4−(2,4−ジフルオロ−フェニル)−8−(4−フルオロ−フェニル)−2−((S)−2−ヒドロキシ−1−メチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
4,8−ビス−(2,4−ジフルオロ−フェニル)−2−(2−ヒドロキシ−1−メチル−エチルアミノ)−8H−ピリド−[2,3−d]−ピリミジン−7−オン;
8−(2,4−ジフルオロフェニル)−4−(2−クロロ−4−フルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン;または
8−(2,3−ジフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチル−エチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン
である化合物;またはその医薬上許容される塩。 - 請求項1記載の化合物の有効量および医薬上許容される担体または希釈剤を含む医薬組成物。
- 4−(2,4−ジフルオロ−フェニルアミノ)−6−(2,4,6−トリフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2,4−ジフルオロ−フェニル)−6−(2,4−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2−フルオロフェニル)−6−(2,4,6−トリフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(4−フルオロフェニル)−6−(2,4,6−トリフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2−フルオロフェニル)−6−(2,4−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2,4−ジフルオロ−フェニル)−6−(4−フルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2,4−ジフルオロ−フェニル)−6−(2,4−ジフルオロフェニルアミノ)−メチルスルファニル−ピリミジン−5−カルバルデヒド;
4−(2−クロロ−4−フルオロフェニル)−6−(2,4−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド;または
4−(2,4−ジフルオロフェニル)−6−(2,3−ジフルオロフェニルアミノ)−2−メチルスルファニル−ピリミジン−5−カルバルデヒド
である化合物。 - 8−(2,4,6−トリフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オンである化合物またはその医薬上許容される塩。
- 請求項4記載の化合物の有効量および医薬上許容される担体または希釈剤を含む医薬組成物。
- 8−(2,4,6−トリフルオロフェニル)−4−(2,4−ジフルオロフェニル)−2−(2−ヒドロキシ−1−ヒドロキシメチルエチルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オンである化合物。
- 請求項6記載の化合物の有効量および医薬上許容される担体または希釈剤を含む医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US37421902P | 2002-04-19 | 2002-04-19 | |
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JP (1) | JP4603268B2 (ja) |
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CN (1) | CN1646131A (ja) |
AT (1) | ATE370952T1 (ja) |
AU (1) | AU2003225072A1 (ja) |
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CA (1) | CA2482022A1 (ja) |
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US7629350B2 (en) | 2009-12-08 |
CN1646131A (zh) | 2005-07-27 |
IL164606A0 (en) | 2005-12-18 |
NO20045025L (no) | 2004-11-18 |
JP2005529877A (ja) | 2005-10-06 |
DE60315826D1 (de) | 2007-10-04 |
WO2003088972A1 (en) | 2003-10-30 |
KR20040103972A (ko) | 2004-12-09 |
EP1499320B1 (en) | 2007-08-22 |
EP1499320A4 (en) | 2006-05-17 |
MXPA04010267A (es) | 2005-02-03 |
PL373339A1 (en) | 2005-08-22 |
RU2004133811A (ru) | 2005-04-20 |
BR0309053A (pt) | 2005-02-22 |
DE60315826T2 (de) | 2008-05-21 |
US20060293348A1 (en) | 2006-12-28 |
ATE370952T1 (de) | 2007-09-15 |
EP1499320A1 (en) | 2005-01-26 |
ES2291630T3 (es) | 2008-03-01 |
AU2003225072A1 (en) | 2003-11-03 |
IS7507A (is) | 2004-10-15 |
CA2482022A1 (en) | 2003-10-30 |
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