JP4636486B2 - 脈管形成阻害活性を有するアリール尿素 - Google Patents
脈管形成阻害活性を有するアリール尿素 Download PDFInfo
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- JP4636486B2 JP4636486B2 JP2003567410A JP2003567410A JP4636486B2 JP 4636486 B2 JP4636486 B2 JP 4636486B2 JP 2003567410 A JP2003567410 A JP 2003567410A JP 2003567410 A JP2003567410 A JP 2003567410A JP 4636486 B2 JP4636486 B2 JP 4636486B2
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- JP
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- Prior art keywords
- phenyl
- amino
- carboxamide
- butyl
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/16—Amides, e.g. hydroxamic acids
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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Description
(i)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されたフェニル;
(ii)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されたナフチル;
(iii)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を持っている5および6員単環ヘテロアリール基;および
(iv) 8ないし10員の2環ヘテロアリール基であって、第1の環は式IのNHへ結合し、そしてO,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を含み、第2の環は3ないし4個の炭素原子を使用して第1の環へ縮合している2環ヘテロアリールである。この2環ヘテロアリール基は任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されている。
(i)任意に−L−M,C1 −C5 直鎖もしくは分岐アルキル、C1 −C5 直鎖もしくは分岐ハロアルキル、C1 −C3 アルコキシ、ヒドロキシ、アミノ、C1 −C3 アルキルアミノ、C1 −C6 ジアルキルアミノ、ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されたフェニル;
(ii) 任意に−L−M,C1 −C5 直鎖もしくは分岐アルキル、C1 −C5 直鎖もしくは分岐ハロアルキル、C1 −C3 アルコキシ、ヒドロキシ、アミノ、C1 −C3 アルキルアミノ、C1 −C6 ジアルキルアミノ、ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されたナフチル;
(iii)任意に−L−M,C1 −C5 直鎖もしくは分岐アルキル、C1 −C5 直鎖もしくは分岐ハロアルキル、C1 −C3 アルコキシ、ヒドロキシ、アミノ、C1 −C3 アルキルアミノ、C1 −C6 ジアルキルアミノ、ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を有する5および6員単環ヘテロアリール基;
(iv) 任意に−L−M,C1 −C5 直鎖もしくは分岐アルキル、C1 −C5 直鎖もしくは分岐ハロアルキル、C1 −C3 アルコキシ、ヒドロキシ、アミノ、C1 −C3 アルキルアミノ、C1 −C6 ジアルキルアミノ、ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を有する8ないし10員の2環ヘテロアリール基。
(a)−(CH2 )m −O−(CH2 )1 −、
(b)−(CH2 )m −(CH2 )1 −、
(c)−(CH2 )m −C(O)−(CH2 )1 −、
(d)−(CH2 )m −NR3 −(CH2 )1 −、
(e)−(CH2 )m −NR3 C(O)−(CH2 )1 −、
(f)−(CH2 )m −S−(CH2 )1 −、
(g)−(CH2 )m −C(O)NR3 −(CH2 )1 −、
(h)−(CH2 )m −CF2 −(CH2 )1 −、
(i)−(CH2 )m −CCl2 −(CH2 )1 −、
(j)−(CH2 )m −CHF−(CH2 )1 −、
(k)−(CH2 )m −CH(OH)−(CH2 )1 −、
(l)−(CH2 )m −C≡C−(CH2 )1 −、
(m)−(CH2 )m −C=C−(CH2 )1 −、 (n)mおよびlが0の場合の単結合、
(o)−(CH2 )m −CR4 R5 −(CH2 )1 −、 よりなる群から選ばれ、ここで変数mおよび1は独立に0〜4から選ばれた整数である。
(i)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されたフェニル;
(ii) 任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されたナフチル、
(iii)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノ、ニトロおよびオキサイド(例えば=O,−O- または−OH)よりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を持っている5および6員単環ヘテロアリール基;
(iv) 任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノ、ニトロおよびオキサイド(例えば=O,−O- または−OH)よりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を持っている8ないし10員2環ヘテロアリール基;
(v)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノ、ニトロおよびオキサイド(例えば=O,−O- または−OH)よりなる群から独立に選ばれた1〜3の置換基で置換された、飽和および部分的飽和C3 −C6 単環炭素環基;
(vi) 任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換された飽和および部分的飽和C8 −C102環炭素環基;
(vii)任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノ、ニトロおよびオキサイド(例えば=O,−O- または−OH)よりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を持っている飽和および部分的飽和5および6員単環複素環基;
(viii) 任意にR1 ,OR1 ,NR1 R2 ,S(O)q R1 ,SO2 NR1 R2 ,NR1 SO2 R2 ,C(O)R1 ,C(O)OR1 ,C(O)NR1 R2 ,NR1 C(O)R2 ,NR1 C(O)OR2 ,ハロゲン、シアノ、ニトロおよびオキサイド(例えば=O,−O- または−OH)よりなる群から独立に選ばれた1〜3の置換基で置換された、O,NおよびSよりなる群から独立に選ばれた1〜3のヘテロ原子を持っている飽和および部分的飽和8ないし10員2環複素環基。
(a)水素、
(b)C1 −C6 アルキル、好ましくはC1 −C5 直鎖、分岐または環状アルキル(該アルキルは任意にペルハロまでハロゲンで置換されている)、
(c)フェニル、
(d)O,NおよびSよりなる群から選ばれた1〜4のヘテロ原子を有する5〜6員の単環ヘテロアリールまたはO,NおよびSよりなる群から選ばれた1〜4のヘテロ原子を有する8〜10員2環ヘテロアリール、
(e)C1 −C3 アルキル−フェニル(アルキル部分は任意にペルハロまでハロゲンで置換されている)、および
(f)O,NおよびSよりなる群から選ばれた1〜4のヘテロ原子を有するアルキル−ヘテロアリール(該ヘテロアリール基は5〜6員単環ヘテロアリールまたは8〜10員2環ヘテロアリールであり、アルキル部分は任意にペルハロまでハロゲンで置換されている)、よりなる群から独立に選ばれ;
各R1 〜R5 は、水素でない時、任意にC1 −C5 直鎖、分岐もしくは環状アルキル(該アルキルは任意にペルハロまでハロゲンで置換されている)、C1 −C3 アルコキシ(該アルコキシはペルハロまで任意にハロゲンで置換されている)、ヒドロキシ、アミノ、C1 −C3 アルキルアミノ、C2 −C6 ジアルキルアミノ、ハロゲン、シアノおよびニトロよりなる群から独立に選ばれた1〜3の置換基で置換されており;
各変数qは0,1または2から独立に選ばれる。
ベンゾフラニル、ベンゾチエニル、ベンズイミダゾリル、ベンゾピラゾリル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイソオキサゾリル、ベンズ−1,3−オキサジアゾリル、キノリニル、イソキノリニル、キナゾリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、ジヒドロベンゾフラニル、ピラゾロ〔3,4−b〕ピリミジニル、プリニル、ベンゾジアジン、プラリジニル、ピロロ〔2,3−b〕ピリジニル、ピラゾロ〔3,4−b〕ピリジニル、オキサゾ〔4,5−b〕ピリジニル、イミダゾ〔4,5−b〕ピリジニル、ヘクロペンテノピリジン、シクロヘキサノピリジン、シクロペンタノピリミジン、シクロヘキサノピリミジン、シクロペンタノピラジン、シクロヘキサノピラジン、シクロペンタノピリダジン、シクロヘキサノピリダジン、シクロペンタノイミダゾール、シクロヘキサノイミダゾール、シクロペンタノチオフエンおよびシクロキサノチオフエン。
フェニル、ピリジニル、ピリミジニル、クロロフェニル、ジクロロフェニル、ブロモフェニル、ジブロモフェニル、クロロピリジニル, ブロモピリジニル、ジクロロピリジニル、ジブロモピリジニル、メチルフェニル、メチルピリジニル、キノリニル、イソキノリニル、イソインドリニル、ピラジニル、ピリダジニル、ピロリニル、イミダゾリニル、チエニル、フリル、イソオキサゾリニル、イソチアゾリニル、ベンゾピリジニル、ベンゾチアゾリル、
C1 −C5 アシル;
アミノフェニルのようなNH(C1 −C5 アルキル、フェニルまたはピリジニル);
ジエチルアミノおよびジメチルアミノのようなN(C1 −C5 アルキル)(C1 −C5 アルキル、フェニルまたはピリジニル);
メタンスルホニルのようなS(O)q (C1 −C5 アルキル;S(O)q H;
SO2 NH2 ;
SO2 NH(C1 −C5 アルキル);
SO2 N(C1 −C5 アルキル)(C1 −C5 アルキル);
NHSO2 (C1 −C5 アルキル);
N(C1 −C5 アルキル)SO2 (C1 −C5 アルキル);
C(O)(C1 −C6 アルキルまたはフェニル);
C(O)H;
C(O)OCH3 ,C(O)OCH2 CH3 のようなC(O)O(C1 −C6 アルキルまたはフェニル);
C(O)OCH2 CH2 CH3 ;
C(O)OH;
C(O)NH2 (カルバモイル);
N−メチルエチルカルバモイル、N−メチルカルバモイル、N−エチルカルバモイル、またはN−ジメチルアミノエチルカルバモイルのようなC(O)NH(C1 −C6 アルキルまたはフェニル);
N−ジメチルカルバモイルのようなC(O)NH(C1 −C6 アルキルまたはフェニル)(C1 −C6 アルキルまたはフェニルまたはピリジニル);
ジメチルカルバモイル;
C(N(C1 −C5 アルキル)(C1 −C5 アルキル);
NHC(O)(C1 −C6 アルキルまたはフェニル);および
N(C1 −C5 アルキル)C(O)(C1 −C5 アルキル);
を含む。上の置換基の各自は、ジフルオロメチルスルホニルのように任意に部分的または完全にハロゲン化される。
A=フェニル、B=ピリジニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=フェニル、B=ナフチル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=ピリジニル、B=フェニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=ピリジニル、B=ピリジニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=ピリジニル、B=ナフチル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=イソキノリニル、B=フェニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=イソキノリニル、B=ピリジニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=イソキノリニル、B=ナフチル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=キノリニル、B=フェニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=キノリニル、B=ピリジニル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない;
A=キノリニル、B=ナフチル、M=フェニル、ピリジニル、キノリニル、イソキノリニル、または存在しない。
複素環アミノは既知の方法(Katrizky et al.Comprehensive Hetrocyclic Chemistry;Permagon Press:Oxford,UK(1984).March,Advanced Organic Chemistry,3rd Ed.;John Weley:New York(1985)を利用して合成することができる。例えば、スキームIに示すように、N−1位においてアリールまたはヘテロアリールで置換れさた5−アミノピラゾールは、α−シアノケトン(2)と適当なアリールまたはヘテロアリールヒドラジン(3,R2 =アリールまたはヘテロアリール)との反応によって合成することができる。シアノケトン2は、アセタミデートイオンと、適当なアシル誘導体、例えばエステル、酸ハライドまたは酸無水物との反応によって入手し得る。R2 基が好適なアニオン安定化を提供する場合は、2−アリールおよび2−ヘテロアリールフランは、シアノケトン2とアルコール5の実延反応、続いてフリールアミン7を与えるエノールエーテル6の塩基触媒使用環化によって合成することができる。
08/996,344、1997年12月22日出願
08/996,343、1997年12月22日出願
08/996,181、1997年12月22日出願
08/995,749、1997年12月22日出願
08/995,750、1997年12月22日出願
08/995,751、1997年12月22日出願
09/083,399、1998年5月22日出願
09/425,228、1999年10月22日出願
09/777,920、2001年2月7日出願
09/722,418、2000年11月28日出願
09/838,285、2001年4月20日出願
09/838,286、2001年4月20日出願
09/458,548、2001年1月12日出願
09/948,915、2001年9月10日出願
代理人整理番号:BAYER 34 V1,2001年12月3日出願
AcOH 酢酸
anh 無水
BOC t−ブトキシカルボニル
conc 濃縮
dec 分解
DMPU 1,3−ジメチルー3,4,5,6−テトラヒドロ−2(1H) ピリミジン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
DPPA ジフェニルフォスフォリルアシド
EtOAc 酢酸エチル
EtOH エタノール(100%)
Et2 O ジエチルエーテル
Et3 N トリエチルアミン
m−CPBA 3−クロロペルオキシ安息香酸
MeOH メタノール
pet.ether 石油エーテル(沸騰範囲30〜60℃)
THF テトラヒドロフラン
TFA トリフロロ酢酸
Tf トリフロロメタンスルホニル
N−〔4−クロロ−3−(トリフロロメチル)フェニル〕−N’−{4−〔2−カルバモイルー(4−ピリジル)〕フェニル}尿素:
ステップ1:4−クロロ−2−ピリジンカルボキサマイドの製造
KDR(VEGFR2)アッセイ:
KDRキナーゼのサイトゾルキナーゼドメインはSf9昆虫細胞内に6His融合タンパクとして発現される。このKDRキナーゼドメイン融合タンパクをNi++キレーティングカラム上で精製した。96ウエルELISAプレートを100μl HEPESバッファー(20mM HEPES,0.1%BSA,pH7.5,150mM NaCl,0.02%チメロサール)中のHEPESバッファー(20mMポリ(Glu4;Tyr1)(Sigma Chemical Co.,St.Louis,MO)で4℃で一夜コートした。使用前、プレートはHEPES,NaClバッファーで洗い、そしてプレートを1%BSA,HEPES中の1%Tween20,NaClバッファーでブロックした。
エントリーNo. 化合物名
73 N−〔5−(t−ブチル)−2−(3−チエニル)フェニル〕〔4−( 4−ピリジルオキシ)フェニルアミノ〕カルボキサマイド
96 {〔4−(4−メトキシフェノキシ)フェニル〕アミノ−N−〔2−メ トキシ−5−(トリフロロメチル)フェニル〕}カルボキサマイド
99 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔3−(4 −ピリジルチオ)フェニル)アミノ〕カルボキサマイド
100 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔3−(4 −ピリジルチオ)フェニル)アミノ〕カルボキサマイド
101 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔4−(4 −ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
エントリーNo. 化合物名
11 N−〔5−(t−ブチル)−2−メトキシフェニル〕〔3−(4−ピリ ジルチオ)フェニル)アミノ〕カルボキサマイド
12 N−〔5−(t−ブチル)−2−(3−チエニル)フェニル〕〔4−( 4−ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
17 N−〔3−(t−ブチル)フェニル〕〔4−(4−ピリジルオキシ)フ ェニル)アミノ〕カルボキサマイド
23 {〔3−(t−ブチル)フェニル〕アミノ}−N−(4−(3−ピリジ ル)フェニル)カルボキサマイド
33 {〔4−(4−メトキシフェノキシ)フェニル〕アミノ}−N−〔2− メトキシ−5−(トリフロロメチル)フェニル〕カルボキサマイド
36 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔(3−( 4−ピリジルチオ)フェニル)アミノ〕カルボキサマイド
37 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔(3−( 4−ピリジルチオ)フェニル)アミノ〕カルボキサマイド
38 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔(4−( 4−ピリジルチオ)フェニル)アミノ〕カルボキサマイド
56 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕{〔3−( 2−メチル(4−ピリジルオキシ)フェニル〕アミノ}カルボキサマイ ド
70 〔(3−クロロ−4−(6−キノリルオキシ)フェニル)アミノ〕−N −〔2−メトキシ−5−(トリフロロメチル)フェニル〕カルボキサマ イド
81 〔(4−ピリジルオキシ)フェニル)アミノ〕−N−〔3−(トリフロ ロメチル)フェニル〕カルボキサマイド
82 N−〔2−クロロ−5−(トリフロロメチル)フェニル〕〔4−(4− ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
83 N−〔2−フロロ−5−(トリフロロメチル)フェニル〕〔(4−(4 −ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
91 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N− (2−メチル−4−(3−ピリジルオキシ)フェニル)カルボキサマイ ド
102 N−〔4−クロロ−3−(トリフロロメチル)フェニル〕〔4−(4− ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
103 N−〔4−クロロ−3−(トリフロロメチル)フェニル〕{〔4−(4 −メトキシフェノキシ)フェニル〕アミノ}カルボキサマイド
105 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N− 〔3−(4−ピリジルカルボニル)フェニル〕カルボキサマイド
106 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N− (3−(2−メチル−4−ピリジルオキシ)フェニル〕アミノ}−N− 〔3−(4−ピリジルカルボニル)フェニル〕カルボキサマイド
119 N−〔4−フロロ−3−(トリフロロメチル)フェニル〕〔4−(4− ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
132 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル 〕〔(4−(4−ピリジルオキシ)フェニル)アミノ〕カルボキサマイ ド
133 N−〔5−メトキシ−3−(トリフロロメチル)フェニル〕〔(4−( 4−ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
135 〔3−ブロモ−4−クロロフェニル)アミノ〕−N−(4−(4−ピリ ジルオキシ)フェニル)カルボキサマイド
141 N−〔3,5−ビス(トリフロロメチル)フェニル〕〔4−(4−ピリ ジルオキシ)フェニル)アミノ〕カルボキサマイド
エントリーNo. 化合物名
18 N−〔5−(t−ブチル)イソオキサゾール−3−イル〕〔(4−(4 −ピリジルチオ)フェニル)アミノ〕カルボキサマイド
32 {〔5−(t−ブチル)イソオキサゾール−3−イル〕アミノ}−N− (3−(4−ピリジルチオ)フェニル)カルボキサマイド
53 N−〔5−(t−ブチル)イソオキサゾール−3−イル〕〔(4−(4 −ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
59 N−〔5−(t−ブチル)イソオキサゾール−3−イル〕〔(4−(4 (3−ピリジルオキシ)フェニル)アミノ〕カルボキサマイド
67 {3−〔4−({〔5−(t−ブチル)イソオキサゾール−3−イル〕 アミノ}カルボニルアミノ)フェノキシ〕フェニル}−N−メチルカル ボキサマイド
85 {〔5−(t−ブチル)イソオキサゾール−3−イル〕アミノ}−N− 〔3−(2−メチル(4−ピリジルオキシ)フェニル〕カルボキサマイ ド
86 {〔5−(t−ブチル)イソオキサゾール−3−イル〕{〔4−(2− メチル(4−ピリジルオキシ)フェニル〕アミノ}カルボキサマイド
103 4−〔4−({〔5−(t−ブチル)イソオキサゾール−3−イル〕ア ミノ}カルボニルアミノ)フェノキシ〕ピリジン−2−カルボキサマイ ド
104 {〔5−(t−ブチル)イソオキサゾール−3−イル〕アミノ}−N− {3−〔2−(N−メチルカルバモイル}アミノフエノキシ〕ピリジン −2−カルボキサマイド
105 4−〔3−({N−〔5−(t−ブチル)イソオキサゾール−3−イル 〕カルバモイル}アミノ)フェノキシ〕ピリジン−2−カルボキサマイ ド
106 3−[4−({[5−(t−ブチル)イソオキサゾールー3−イル]ア ミノ}カルボニルアミノ)フェノキシ]ベンズアミド
143 N−[3−(メチルエチル)イソオキサゾールー5−イル][4−(ピ リジルオキシ)フェニル)アミノ]カルボキサマイド
146 N−(3−シクロブチルイソオキサゾールー5−イル)[4−(4−ピ リジルオキシ)フェニル)アミノ]カルボキサマイド
147 N−(3−シクロブチルイソオキサゾールー5−イル)[4−(6−キ ノリルオキシ)フェニル)アミノ]カルボキサマイド
162 {[−3−(t−ブチル)イソオキサゾールー5−イル]アミノ}−N −(3−(4−ピリジルオキシ)フェニル)カルボキサマイド
163 N−[3−(t−ブチル)イソオキサゾールー5−イル][(4−(4 −ピリジルオキシ)フェニル)アミノ]カルボキサマイド
164 N−[3−(t−ブチル)イソオキサゾールー5−イル]{[(4−メ トキシフェノキシ)フェニル]アミノ}カルボキサマイド
188 N−[3−(1,1−ジメチルプロピル)イソオキサゾールー5−イル ][3−(4−ピリジルチオ)フェニル)アミノ]カルボキサマイド
195 N−[3−(1,1−ジメチルプロピル)イソオキサゾールー5−イル ][(4−(4−ピリジルオキシ)フェニル)アミノ]カルボキサマイ ド
220 {[3−(t−ブチル)ピラゾールー5−イル]アミノーN−(3−( 4−ピリジルチオ)フェニル)カルボキサマイド
221 N−[3−(t−ブチル)ピラゾールー5−イル][(4−(4−ピリ ジルチオ)フェニル)アミノ]カルボキサマイド
222 {3−[4−({3−(t−ブチル)ピラゾールー5−イル]アミノ} カルボニルアミノ)フェノキシ]フェニル}−N−メチルカルボキサマ イド、2、2、2−トリフロロ酢酸
225 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル][(3 −(4−ピリジルチオ)フェニル)アミノ]カルボキサマイド
251 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル][(4 −(4−ピリジルオキシ)フェニル)アミノ]カルボキサマイド
261 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル]{[4 (4−ピリジルメチル)フェニル]アミノ}カルボキサマイド
266 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル]{[4 −(4−ピリジルメトキシ)フェニル]アミノ}カルボキサマイド
277 t−ブチル 3−(t−ブチル)−5−[({4−[3−(N−メチル カルバモイル)フェノキシ]フェニル}アミノ)ピラゾールカルボキシ レート
280 N−[5−(t−ブチル)(1、3、4−チアジアゾールー2−イル) ][(4−(4−ピリジルオキシ)フェニル)アミノ]カルボキサマイ ド
281 {[5−(t−ブチル)(1、3、4−チアジアゾールー2−イル)] アミノ}−N−(3−(4−ピリジルオキシ)フェニル)アミノカルボ キサマイド
284 N−[5−(t−ブチル)(3−チエニル)][(4−(3−ピリジル オキシ)フェニル)アミノ]カルボキサマイド
293 N−[5−(t−ブチル)(3−チエニル)][4−(4−ピリジルオ キシ)フェニル)アミノ]カルボキサマイド
299 N−(6−クロロ(1Hーインダゾールー3−イル))[(4−(4− ピリジルオキシ)フェニル)アミノ]カルボキサマイド
302 ({4−[2−(N−メチルカルバモイル)(4−ピリジルオキシ)] フェニル}アミノ)ーN−(1−メチルー3−フェニルピラゾールー5 ーイル)カルボキサマイド
エントリーNo. 化合物
21 N−[5−(t−ブチル)イソオキサゾールー3−イル][(4−(4 −ピリジルチオ)フェニル)アミノ]カルボキサマイド
42 {[5−(t−ブチル)イソオキサゾールー3−イル]アミノ}−N− (3−(4−ピリジルチオ)フェニル)カルボキサマイド
59 N−[5−(t−ブチル)イソオキサゾールー3−イル][(4−(4 −ピリジルオキシ)フェニル)アミノ]カルボキサマイド
64 N−[5−(t−ブチル)イソオキサゾールー3−イル][(4−(3 ピリジルオキシ)フェニル)アミノ]カルボキサマイド
69 {3−[4−(5−(t−ブチル)イソオキサゾールー3−イル]アミ ノ}カルボニルアミノ)フェノキシ]フェニル}−N−メチルカルボキ サマイド
81 {[5−(t−ブチル)イソオキサゾールー3−イル]アミノ}−N− [3−(2−メチル(4−ピリジルオキシ)フェニル]カルボキサマイ ド
82 N−[5−(t−ブチル)イソオキサゾールー3−イル]{[4−(2 −メチル(4−ピリジルオキシ)フェニル]アミノ}カルボキサマイド
101 {4−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)フェノキシ](2−ピリジル)}−N−メ チルカルボキサマイド
103 4−[4−({[5−(t−ブチル)イソオキサゾールー3−イル]ア ミノ}カルボニルアミノ)フェノキシ]ピリジンー2−カルボキサマイ ド
104 4−[3−({N−[5−(t−ブチル)イソオキサゾールー3−イル ]カルバモイル}アミノ)フェノキシ]ピリジンー2−カルボキサマイ ド
105 {[5−(t−ブチル)イソオキサゾールー3−イル]アミノ}−N− {3−[2−(N−メチルカルバモイル)(4−ピリジルオキシ)]フ ェニル}カルボキサマイド
106 3−[4−({[5−(t−ブチル)イソオキサゾールー3−イル]ア ミノ}カルボニルアミノ)フェノキシ]ベンズアミド
118 {4−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)−3−クロロフェノキシ](2−ピリジル )}−N−メチルカルボキサマイド
124 {3−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)フェノキシ]フェニル}−N−(2−モル ホリンー4−イルエチル)カルボキサマイド
125 {4−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)フェノキシ](2−ピリジル)}−N−エ チルカルボキサマイド
126 {4−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)ー2−クロロフェノキシ](2−ピリジル ーN−メチルカルボキサマイド
127 {[5−(t−ブチル)イソオキサゾールー3−イル]アミノ}−N− {2−メチルー4−[2−(N−メチルカルバモイル)(4−ピリジル オキシ)フェニル}カルボキサマイド
128 {[5−(t−ブチル)イソオキサゾールー3−イル]アミノ}−N− {3−[2−(N−メチルカルバモイル)(4−ピリジルチオ)フェニ ル}カルボキサマイド
130 {3−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)フェノキシ]フェニル}−N−(3−ピリ ジル)カルボキサマイド
140 {4−[4−({[5−(t−ブチル)イソオキサゾールー3−イル] アミノ}カルボニルアミノ)フェニルチオ](2−ピリジル)}−N− メチルカルボキサマイド
182 N−メチル{4−[4−({[3−(メチルエチル)イソオキサゾール ー5−イル]アミノ}カルボニルアミノ)フェノキシ](2−ピリジル )}カルボキサマイド
186 N−メチル{4−[3−({[3−(メチルエチル)イソオキサゾール ー5−イル]アミノ}カルボニルアミノ)フェノキシ](2−ピリジル )}カルボキサマイド
187 N−(3−シクロブチルイソオキサゾールー5−イル)[(4−(6− キノリルオキシ)フェニル)アミノ]カルボキサマイド
188 N−(3−シクロブチルイソオキサゾールー5−イル)[4−(4−ピ リジルオキシ)フェニル)アミノ]カルボキサマイド
194 N−[3−(t−ブチル)イソオキサゾールー5−イル][4−(4− ピリジルオキシ)フェニル)アミノ]カルボキサマイド
195 N−[3−(t−ブチル)イソオキサゾールー5−イル]{[4−(4 −メトキシフェノキシ)フェニル]アミノ}カルボキサマイド
206 {[3−(t−ブチル)イソオキサゾールー5−イル]アミノ}−N− (3−(4−ピリジルチオ)フェニル)カルボキサマイド
212 N−[3−(tーブチル)イソオキサゾールー5−イル]{[4−(1 ,3−ジオキソイソインドリンー5−イルオキシ)フェニル]アミノ} カルボキサマイド
213 {[3−(t−ブチル)イソオキサゾールー5−イル]アミノ}−N− [4−(1−オキソインドリンー5−イルオキシ)フェニル]カルボキ サマイド
214 {4−[4−({[3−(t−ブチル)イソオキサゾールー5−イル] アミノ}カルボニルアミノ)フェノキシ](2−ピリジル)}−N−エ チルカルボキサマイド
215 {4−[4−({[3−(t−ブチル)イソオキサゾールー5−イル] アミノ}カルボニルアミノ)ー2−クロロフェノキシ](2−ピリジル )}−N−メチルカルボキサマイド
216 {[3−(t−ブチル)イソオキサゾールー5−イル]アミノ}−N− {3−[2−N−メチルカルバモイル)(4−ピリジルチオ)]フェニ ル}カルボキサマイド
217 {4−[4−({[3−(t−ブチル)イソオキサゾールー5−イル] アミノ}カルボニルアミノ)フェニルチオ](2−ピリジル)−N−メ チルカルボキサマイド
218 {4−[4−({[3−(t−ブチル)イソオキサゾールー5−イル] アミノ}カルボニルアミノ)フェノキシ](2−ピリジル)}−N−メ チルカルボキサマイド
228 {[3−(t−ブチル)イソオキサゾールー5−イル]アミノ}−N− [3−(6−メチル(3−ピリジルオキシ))フェニル]カルボキサマ イド
240 N−[3−(t−ブチル)イソオキサゾールー5−イル][6−(4ー ピリジルチオ)(3−ピリジル))アミノ]カルボキサマイド
247 {[3−(t−ブチル)イソオキサゾールー5−イル]アミノ}−N− {3−[2−N−メチルカルバモイル)(4−ピリジルオキシ]フェニ ル}カルボキサマイド
253 N−[3−(1,1−ジメチルプロピル)イソオキサゾールー5−イル ][3−(4−ピリジルチオ)フェニル)アミノカルボキサマイド
255 N−[3−(1,1−ジメチルプロピル)イソオキサゾールー5−イル ][(4−(4−ピリジオキシ)フェニル)アミノカルボキサマイド
261 N−[3−(1,1−ジメチルプロピル)イソオキサゾールー5−イル ]({4−[2−(N−メチルカルバモイル)(4−ピリジルオキシ) ]フェニル}アミノカルボキサマイド
263 N−[3−(1,1−ジメチルプロピル)イソオキサゾールー5−イル ]{[4−(2−メチル(4−ピリジルチオ)フェニル]アミノ}カル ボキサマイド
292 N−[3−(t−ブチル)ピラゾールー5−イル]{[4−(6−メチ ル(3−ピリジルオキシ)フェニル]アミノ}カルボキサマイド
298 {[3−(t−ブチル)ピラゾールー5−イル]アミノ}−N−(3− (4−ピリジルチオ)フェニル)カルボキサマイド
299 N−[3−(t−ブチル)ピラゾールー5−イル][(4−(4−ピリ ジルチオ)フェニル)アミノ]カルボキサマイド
300 {3−[4−({[3−(t−ブチル)ピラゾールー5−イル]アミノ }カルボニルアミノ)フェノキシ]フェニル}−N−メチルピリジルメ トキシ)フェニル]アミノ}カルボキサマイド
304 N−[3−(t−ブチル)ピラゾールー5−イル]{[4−(4−ピリ ジルメトキシ)フェニル]アミノ}カルボキサマイド
305 {5−[4−({[3−(t−ブチル)ピラゾールー5−イル]アミノ }カルボニルアミノ)フェノキシ]−2−メトキシフェニル}−N−メ チルカルボキサマイド
309 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル][(3 −(4−ピリジルチオ)フェニル)アミノ]カルボキサマイド
321 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル][(4 −(4−ピリジルオキシ)フェニル]アミノ}カルボキサマイド
326 N−[3−(t−ブチル)−1−メチルピラゾールー5−イル][(4 ーピリジルメチル)フェニル]アミノ}カルボキサマイド
339 t−ブチル 3−(t−ブチル)−5−[({4−[3−(N−メチル カルバモイル)フェノキシ)フェニル}アミノ)カルボニルアミノ]ピ ラゾールカルボキシレート
341 N−[5−(t−ブチル)(1、3、4−チアジアゾールー2−イル] [(4−(4−ピリジルオキシ)フェニル]アミノ}カルボキサマイド
342 {[5−(t−ブチル)(1、3、4−チアジアゾールー2−イル]ア ミノ}−N−(3−(4−ピリジルチオ)フェニル)カルボキサマイド
356 N−[5−(t−ブチル)(1、3、4−チアジアゾールー2−イル) ]{[6−(6−メチル(3−ピリジルオキシ)(3−ピリジル)]ア ミノ}カルボキサマイド
366 N−[5−(1,1−ジメチルプロピル)(1、3、4−チアジアゾー ルー2−イル)][4−(4−ピリジルオキシ)フェニル)アミノ]カ ルボキサマイド
367 N−[5−(1,1−ジメチルプロピル)(1、3、4−チアジカゾー ルー2−イル)][3−(4−ピリジルチオ)フェニル)アミノ]カル ボキサマイド
376 N−[5−(t−ブチル)(3−チエニル)][4−(3−ピリジルオ キシ)フェニル)アミノ]カルボキサマイド
388 {3−[4−({[5−(t−ブチル)(1、3、4−オキサジアゾー ルー2−イル)]アミノ}カルボニルアミノ)フェノキシ]フェニル} −N−エチルカルボキサマイド
389 {3−[4−({[5−(t−ブチル)(1、3、4−オキサジアゾー ルー2−イル)]アミノ}カルボニルアミノ)フェノキシ]フェニル} −N−(メチルエチル)カルボキサマイド
390 {3−[4−({[5−(t−ブチル)(1、3、4−オキサジアゾー ルー2−イル)]アミノ}カルボニルアミノ)フェノキシ]フェニル} −N−メチルカルボキサマイド
392 N−(3−シクロプロピルー1−メチルピラゾールー5−イル)[(4 −(6−キノリルオキシ)フェニル)アミノ]カルボキサマイド
393 ({4−[2−(N−メチルカルバモイル)(4−ピリジルオキシ)] フェニル}アミノ)ーN−(1−メチルー3−フェニルピラゾールー5 イル)カルボキサマイド
395 N−[2−(t−ブチル)(1、3−チアゾールー5−イル)]{[4 −(6−メチル(3−ピリジルオキシ)フェニル]アミノ}カルボキサ マイド
エントリーNo. 化合物名
1 [(2,3−ジクロロフェニル)アミノ]−N−[3−(t−ブチル) ー1−フェニルピラゾールー5−イル]カルボキサマイド
2 N−[1−(4−アミノフェニル)−3−(t−ブチル)ピラゾールー 5−イル][(2,3−ジクロロフェニル)アミノ]カルボキサマイド
11 N−[1−(3−アミノフェニル)−3−(t−ブチル)ピラゾールー 5−イル][(2,3−ジクロロフェニル)アミノ]カルボキサマイド
18 N−{3−(3−t−ブチル)−5−{[4−フェノキシフェニル)ア ミノ]カルボニルアミノ}ピラゾリール)フェニル]アセタミド
23 N−[1−(2,6−ジクロロフェニル)−3−(t−ブチル)ピラゾ ールー5−イル]{[4−(4−ピリジルメチル)フェニル]アミノ} カルボキサマイド
24 N−[3−(t−ブチル)−1−(4−クロロフェニル)ピラゾールー 5−イル]{[4−(4−ピリジルメチル)フェニル]アミノ}カルボ キサマイド
25 N−[3−(t−ブチル)−1−(2−メチルフェニル)ピラゾールー 5−イル]{[4−(4−ピリジルメチル)フェニル]アミノ}カルボ キサマイド
26 N−[3−(t−ブチル)−1−(3−クロロフェニル)ピラゾールー 5−イル]{[4−(4−ピリジルメチル)フェニル]アミノ}カルボ キサマイド
27 N−[3−(t−ブチル)−1−[4−(メチルスルホニル)フェニル ]ピラゾールー5−イル}{[4−(4−ピリジルメチル)フェニル] アミノ}カルボキサマイド
28 N−[3−(t−ブチル)−1−(4−ニトロフェニル)ピラゾール− 5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カルボ キサマイド
29 N−[3−(t−ブチル)−1−(3−メトキシフェニル)ピラゾール −5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カル ボキサマイド
30 N−〔1−(アミノフェニル)−3−(t−ブチル)ピラゾール−5− イル〕{〔4−(4−ピリジルメチル)フェニル)フェニル〕アミノ} カルボキサマイド
32 N−〔1−(アミノフェニル)−3−(t−ブチル)ピラゾール−5− イル〕{4−(4−ピリジルチオ)フェニル)アミノ}カルボキサマイ ド
34 N−〔3−(t−ブチル)−1−(3−フロロフェニル)ピラゾール− 5−イル〕〔(3−(4−ピリジルオキシ)フェニル)アミノ〕カルボ キサマイド
35 N−〔3−(t−ブチル)−1−(4−フロロフェニル)ピラゾール− 5−イル〕〔(3−(4−ピリジルオキシ)フェニル)アミノ〕カルボ キサマイド
36 N−〔3−(t−ブチル)−1−(3−フロロフェニル)ピラゾール− 5−イル〕〔(4−(4−ピリジルオキシ)フェニル)アミノ〕カルボ キサマイド
37 N−〔3−(t−ブチル)−1−(4−フロロフェニル)ピラゾール− 5−イル〕〔(4−(4−ピリジルオキシ)フェニル)アミノ〕カルボ キサマイド
エントリーNo. 化合物名
1 〔(2,3−ジクロフェニル)アミノ−N−〔3−(t−ブチル)−1 −フェニルピラゾール−5−イル〕カルボキサマイド
2 N−〔1−(4−アミノフェニル)−3−(t−ブチル)ピラゾール− 5−イル〕〔(2,3−ジクロロフェニル)アミノ〕カルボキサマイド
14 N−〔1−(3−アミノフェニル)−3−(t−ブチル)ピラゾール− 5−イル〕〔(2,3−ジクロロフェニル)アミノ〕カルボキサマイド
22 N−〔3−(3−(t−ブチル)−5−{〔(4−フェノキシフェニル )アミノ〕カルボニルアミノ}ピラゾリール)フェニル〕アセタミド
27 N−〔1−(2,6−ジクロロフェニル)−3−(t−ブチル)ピラゾ ール−5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ} カルボキサマイド
28 N−〔3−(t−ブチル)−1−(4−フロロフェニル)ピラゾール− 5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カルボ キサマイド
29 N−〔3−(t−ブチル)−1−(2−メチルフェニル)ピラゾール− 5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カルボ キサマイド
30 N−〔3−(t−ブチル)−1−(3−フロロフェニル)ピラゾール− 5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カルボ キサマイド
31 N−{3−(t−ブチル)−1−〔4−(メチルスルホニル)フェニル 〕ピラゾール−5−イル}{〔4−(4−ピリジルメチル)フェニル〕 アミノ}カルボキサマイド
32 N−〔3−(t−ブチル)−1−(4−ニトロフェニル)ピラゾール− 5−イル〕{〔4−(ピリジルメチル)フェニル〕アミノ}カルボキサ マイド
33 N−〔3−(t−ブチル)−1−(3−メトキシフェニル)ピラゾール −5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カル ボキサマイド
34 N−〔1−(3−アミノフェニル)−3−(t−ブチル)ピラゾール− 5−イル〕{〔4−(4−ピリジルメチル)フェニル〕アミノ}カルボ キサマイド
36 N−〔1−(3−アミノフェニル)−3−(t−ブチル)ピラゾール− 5−イル〕〔4−(4−ピリジルチオ)フェニル)アミノ〕カルボキサ マイド
エントリーNo. 化合物名
1 {3−〔4−({〔3−(t−ブチル)フェニル〕アミノ}カルボニル
アミノ)フェノキシ〕フェニル}−N−メチルカルボキサマイド
11 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({3−〔
2−(N−メチルカルバモイル)(4−ピリジルオキシ)〕フェニル}
アミノ)カルボキサマイド
12 4−〔3−({N−〔2−メトキシ−5−(トリフロロメチル)フェニ
ル〕カルバモイル}アミノ)フェノキシ〕ピリジン−2−カルボキサマ
イド
13 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔
2−(N−メチルカルバモイル)(4−ピリジルオキシ)〕フェニル}
アミノ)カルボキサマイド
14 4−〔4−({N−〔2−メトキシ−5−(トリフロロメチル)フェニ
ル〕カルバモイル}アミノ)フェノキシ〕ピリジン−2−カルボキサマ
イド
16 {4−〔4−({N−〔2−メトキシ−5−(トリフロロメチル)フェ
ニル〕カルバモイル}アミノ)−3−メチルフェノキシ〕(2−ピリジ
ル)}−N−メチルカルボキサマイド
17 ({2−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリジ
ルオキシ)〕フェニル}アミノ)−N−〔2−メトキシ−5−(トリフ
ロロメチル)フェニル〕カルボキサマイド
19 ({4−〔2−N−エチルカルバモイル)(4−ピリジルオキシ)〕フ
ェニル}アミノ)−N−〔2−メトキシ−5−(トリフロロメチル)フ
ェニル〕カルボキサマイド
20 ({3−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリジ
ルオキシ)〕フェニル}アミノ)−N−〔2−メトキシ−5−(トリフ
ロロメチル)フェニル〕カルボキサマイド
22 3−〔4−({N−〔2−メトキシ−5−(トリフロロメチル)フェニ
ル〕カルバモイル}アミノ)フェノキシ〕ベンズアミド
24 ({4−〔2−(N,N−ジメチルカルバモイル)(4−ピリジルオキ
シ〕フェニル}アミノ)−N−〔2−メトキシ−5−(トリフロロメチ
ル)フェニル〕カルボキサマイド
27 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔
2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェニル}ア
ミノ)カルボキサマイド
29 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({3−〔
2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェニル}ア
ミノ)カルボキサマイド
31 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔(4−{
5−〔N−2−モルホリン−4−イルエチル)カルバモイル〕(3−ピ
リジルオキシ)}フェニル)アミノ〕カルボキサマイド
32 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔(4−{
5−〔N−メチルカルバモイル)(3−ピリジルオキシ)〕フェニル}
アミノ)カルボキサマイド
34 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔
3−(3−ピリジル)カルバモイル)フェノキシ〕フェニル}アミノ)
カルボキサマイド
42 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕
アミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−メ
チルカルボキサマイド
43 4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕ア
ミノ}カルボニルアミノ)フェノキシ〕ピリジン−2−カルボキサマイ
ド
44 4−〔3−({〔4−クロロ−3−(トリフロロメチル)フェニル〕ア
ミノ}カルボニルアミノ)フェノキシ〕ピリジン−2−カルボキサマイ
ド
45 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N−
{3−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ)フェ
ニル}カルボキサマイド
47 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N−
{2−メチル−4−〔2−(N−メチルカルバモイル)(4−ピリジル
オキシ)フェニル}カルボキサマイド
49 {4−〔3−クロロ−4−({〔4−クロロ−3−(トリフロロメチル
)フェニル〕アミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル
)}−N−メチルカルボキサマイド
51 N−〔4−クロロ−3−(トリフロロメチル)フェニル〕({4−〔2
−(N−エチルカルバモイル)(4−ピリジルオキシ)〕フェニル}ア
ミノ)カルボキサマイド
61 {3−〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}カ
ルボニルアミノ)フェノキシ〕フェニル}−N−(2−モルホリン−4
−イルエチル)カルボキサマイド
62 {3−〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}カ
ルボニルアミノ)フェノキシ〕フェニル}−N−(2−ピペリジルエチ
ル)カルボキサマイド
65 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕
アミノ}カルボニルアミノ)フェニルチオ〕(2−ピリジル)}−N−
メチルカルボキサマイド
69 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N−
{3−〔2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェ
ニル}カルボキサマイド
70 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕
アミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−
(2−モルホリン−4−イルエチル)カルボキサマイド
72 {5−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕
アミノ}カルボニルアミノ)フェノキシ〕(3−ピリジル)}−N−メ
チルカルボキサマイド
75 N−〔4−クロロ−3−(トリフロロメチル)フェニル〕({4−〔3
−(N−(3−ピリジルカルバモイル)フェノキシ〕フェニル}アミノ
)カルボキサマイド
84 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル}
アミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−(
2−ヒドロキシエチル)カルボキサマイド
87 {4−〔4−({〔4−ブロモ−3−(トリフロロメチル)フェニル〕
アミノ}カルボニルアミノ)−2ークロロフェノキシ〕(2−ピリジル
)}−N−メチルカルボキサマイド
88 N−〔4−ブロモ−3−(トリフロロメチル)フェニル〕({4−〔2
−(N−エチルカルバモイル)(4−ピリジルオキシ)〕フェニル}ア
ミノ)カルボキサマイド
89 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕アミノ}−N−
{3−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ)〕フ
ェニル}カルボキサマイド
90 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕アミノ}−N−
{4−メチル−3−〔2−(N−メチルカルバモイル)(4−ピリジル
オキシ)フェニル}カルボキサマイド
93 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕アミノ}−N−
{3−〔2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェ
ニル}カルボキサマイド
94 {4−〔4−({〔4−ブロモ−3−(トリフロロメチル)フェニル〕
アミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−(
2−モルホリン−4−イルエチル)カルボキサマイド
95 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル
〕({4−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ)
〕フェニル}アミノ)カルボキサマイド
96 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル
〕({2−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリ
ジルオキシ)〕フェニル}アミノ)カルボキサマイド
97 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル
〕({3−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリ
ジルオキシ)フェニル}アミノ)カルボキサマイド
98 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル
〕({3−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ)
〕フェニル}アミノ)カルボキサマイド
99 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル
〕({4−〔2−(N−エチルカルバモイル)(4−ピリジルオキシ)
〕フェニル}アミノ)カルボキサマイド
エントリーNo. 化合物名
1 {3−〔4− ({3−(t−ブチル)フェニル〕アミノ}カルボニルア ミノ)フェノキシ〕フェニル}−N−メチルカルボキマイド
11 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({3−〔 2−(N−メチルカルバモイル)(4−ピリジルオキシ)〕フェニル} アミノ)カルボキサマイド
12 4−〔3−({N−〔2−メトキシ−5−(トリフロロメチル)フェニ ル〕カルバモイル}アミノ)フェノキシ)ピリジン−2−カルボキサマ イド
13 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔 2−(N−メチルカルバモイル)(4−ピリジルオキシ)〕フェニル} アミノ)カルボキサマイド
14 4−〔4−({N−〔2−メトキシ−5−(トリフロロメチル)フェニ ル〕カルバモイル}アミノ)フェノキシ〕ピリジン−2−カルボキサマ イド
16 {4−〔4−({N−〔2−メトキシ−5−(トリフロロメチル)フェ ニル〕カルバモイル}アミノ)−3−メチルフェノキシ〕(2−ピリジ ル)}−N−メチルカルボキサマイド
17 ({2−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリジ ルオキシ)〕フェニル}アミノ)−N−〔2−メトキシ−5−(トリフ ロロメチル)フェニル〕カルボキサマイド
19 ({4−〔2−(N−エチルカルバモイル)(4−ピリジルオキシ)〕 フェニル}アミノ)−N−〔2−メトキシ−5−(トリフロロメチル) フェニル〕カルボキサマイド
20 ({3−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリジ ルオキシ)〕フェニル}アミノ)−N−〔2−メトキシ−5−(トリフ ロロメチル)フェニル〕カルボキサマイド
22 3−〔4−({N−〔2−メトキシ−5−(トリフロロメチル)フェニ ル〕カルバモイル}アミノ)フェノキシ〕ベンズアミド
24 ({4−〔2−(N,N−ジメチルカルバモイル)(4−ピリジルオキ シ)〕フェニル}アミノ)−N−〔2−メトキシ−5−(トリフロロメ チル)フェニル〕カルボキサマイド
27 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔 2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェニル}ア ミノ)カルボキサマイド
29 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({3−〔 2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェニル}ア ミノ)エルボキサマイド
31 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕〔(4−{ 5−〔N−(2−モルホリン−4−イルエチル)カルバモイル〕(3− ピリジルオキシ)}フェニル)アミノ〕カルボキサマイド
32 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔 5−(N−メチルカルバモイル)(3−ピリジルオキシ)〕フェニル} アミノ)カルボキサマイド
34 N−〔2−メトキシ−5−(トリフロロメチル)フェニル〕({4−〔 3−(N−(3−ピリジル)カルバモイル)フェノキシ〕フェニル}ア ミノ)カルボキサマイド
42 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕 アミノ}カルボニルアミノ)フェのキシ〕(2−ピリジル)}−N−メ チルカルボキサマイド
43 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕 アミノ}カルボニルアミノ)フェノキシ〕ピリジン−2−カルボキサマ イド
44 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕 アミノ}カルボニルアミノ)フェノキシ〕ピリジン−2−カルボキサマ イド
45 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N− {3−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ)〕フ ェニル}カルボキサマイド
47 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N− {2−メチル−4−〔2−(N−メチルカルバモイル)(4−ピリジル オキシ)〕フェニル}カルボキサマイド
49 {4−〔3−クロロ−4−({〔4−クロロ−3−トリフロロメチル) フェニル〕アミノ}カルボニルアミノ)フェノキシ)(2−ピリジル) −N−メチルカルボキサマイド
51 N−〔4−クロロ−3−(トリフロロメチル)フェニル〕({4−〔2 −(N−エチルカルバモイル)(4−ピリジルオキシ)〕フェニル}ア ミノ)カルボキサマイド
61 {3−〔4−({〔4−クロロ−3−トリフロロメチル)フェニル〕ア ミノ〕カルボニルアミノ)フェノキシ〕フェニル}−N−(2−モルホ リン−4−イルエチル)カルボキサマイド
62 {3−〔4−({〔4−クロロ−3−トリフロロメチル)フェニル〕ア ミノ〕カルボニルアミノ)フェニルチオ〕フェニル}−N−(2−ピペ リジルエチル)カルボキサマイド
65 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕 アミノ}カルボニルアミノ)フェニチオ〕(2−ピリジル)}−N−メ チルカルボキサマイド
69 {〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}−N− {3−〔2−N−メチルカルバモイル)(4−ピリジルチオ)〕フェニ ル}カルボキサマイド
70 {4−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕 アミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−( 2−モルホリン−4−イルエチル)カルボキサマイド
72 {5−〔4−({〔4−クロロ−3−(トリフロロメチル)フェニル〕 アミノ}カルボニルアミノ)フェノキシ〕(3−ピリジル)}−N−メ チルカルボキサマイド
75 N−〔4−クロロ−3−(トリフロロメチル)フェニル〕({4−〔3 −(N−(3−ピリジル)カルバモイル)フェノキシ〕フェニル}アミ ノ)カルボキサマイド
84 {4−〔4−クロロ−3−(トリフロロメチル)フェニル〕アミノ}カ ルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−(2−ヒドロ キシエチル)カルボキサマイド
87 {4−〔ブロモ−3−(トリフロロメチル)フェニル〕アミノ}カルボ ニルアミノ)−2−クロロフェノキシ〕(2−ピリジル)}−N−メチ ルカルボキサマイド
88 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕({4−〔2− (N−エチルカルバモイル)(4−ピリジルオキシ)〕フェニル}アミ ノ)カルボキサマイド
89 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕アミノ}−N− {3−〔2−(N−メチルカルボニル)(4−ピリジルオキシ)〕フェ ニル}カルボキサマイド
90 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕アミノ}−N− {4−メチル−3−〔2−(N−メチルカルバモイル)(4−ピリジル チオ)〕フェニル}カルボキサマイド
93 {〔4−ブロモ−3−(トリフロロメチル)フェニル〕アミノ}−N− 3−〔2−(N−メチルカルバモイル)(4−ピリジルチオ)〕フェニ ル}カルボキサマイド
94 {4−〔4−{〔4−ブロモ−3−(トリフロロメチル)フェニル〕ア ミノ}カルボニルアミノ)フェノキシ〕(2−ピリジル)}−N−(2 −モルホリン−4−イルエチル)カルボキサマイド
95 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル 〕({4−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ) 〕フェニル}アミノ)カルボキサマイド
96 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル 〕({2−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリ ジルオキシ)〕フェニル}アミノ)カルボキサマイド
97 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル 〕({3−クロロ−4−〔2−(N−メチルカルバモイル)(4−ピリ ジルオキシ)〕フェニル}アミノ)カルボキサイド
98 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル 〕({3−〔2−(N−メチルカルバモイル)(4−ピリジルオキシ) 〕フェニル}アミノ)カルボキサマイド
99 N−〔4−クロロ−2−メトキシ−5−(トリフロロメチル)フェニル 〕({4−〔2−(N−エチルエルバモイル)(4−ピリジルオキシ) 〕フェニル}アミノ)カルバキサマイド
エントリーNo. 化合物名
16 〔(4−フロロフェニル)アミノ〕−N−(3−イソキノリル)カルボ キサマイド
25 N−(2−メトキシ(3−キノリル))〔(4−(4−ピリジルオキシ )フェニル)アミノ〕カルボキサマイド
27 N−(2−メトキシ(3−キノリル))〔3−(4−ピリジルチオ)フ ェニル)アミノ〕カルボキサマイド
28 N−〔1−(4−メチルピペラジニル)(3−イソキノリル)〕〔(4 −(4−ピリジルオキシ)フェニル)アミノカルボキサマイド
エントリーNo. 化合物名
25 N−(2−メトキシ(3−キノリル)〔(4−(4−ピリジルオキシ) フェニル)アミノ〕カルボキサマイド
27 N−(2−メトキシ(3−キノリル)〔(3−(4−ピリジルチオ)フ ェニル)アミノ〕カルボキサマイド
28 N−〔1−(4−メチルピヘラジニル)(3−イソキノリル)〕〔(4 −(4−ビリジルオキシ)フェニル)アミノ〕カルボキサマイド
KDRレセプターの全長を発現するNIH3T3を10%新生ウシ血清、低グルコース、25mM/Lピルジン酸ナトリウム、塩酸ピリドキシンおよび0.2mg/mlのG418(Life Technologies Inc.,Grand Island,NY)で補足したDMEM(Life Technologies Inc.,Grand Island,NY)中で生育させる。細胞はコラーゲン−IをコートしたT75フラスコ(Becton Dockinson Labware,Bedford,MA)中で加湿した5%CO2 雰囲気中37℃で維持する。
細胞15,000個はDMEM生育媒地中のコラーゲンIをコートした96ウエルプレートの各ウエル中へプレートされる。6時間後、細胞を洗い、そして培地を血清なしのDMEMで交換する。細胞を静止させるため一夜培養した後、培地は0.1%ウシアルブミン(Sigma Chemical Co.,St.Louis,MO)を加えたDulbecco リン酸緩衝化食塩水(Life Technologies Inc.,Grand Island,NY)により交換する。種々の濃度(0−300mM)のデスト化合物をDMSOの1%最終濃度において細胞へ加えた後、細胞を室温で30分インキュベートする。VEGF刺激の後、バッファーを除去し、細胞は抽出バッファー(10%グリセロール,50mM BGP,2mM EDTA,10mM NaF,0.5mM NaVO4 ,0.3% TX−100を補足した90mM トリス,pH7.8)の150μlの添加により、4℃で30分溶解する。
レセプターホスフォリール化を評価するため、各細胞溶解液の100μlを抗体C20(Santa Cruz Biotechnology,Inc.,Santa Cruz,CA)300ngでプレコートしたELISAプレートのウエルへ加える。60分間のインキュベーション後、プレートを洗い、結合KDRを抗ホスホチロシンmAbクローン4G10(Upstate Biotechnology,Lake Placid,NY)を用いてホスフォチロシンについてプローブする。ウエルを洗い、そして抗マウスIgG/HRP接合体(Amersham International ple,Buckinghamshere,England)と60分間インキュベートする。ウエルを洗浄し、そしてホスフォチロシンを100μl/ウエルの3,3’,5,5’−テトラメチルベンジジン(Kirkegaard and Perry,TMB 1コンポーネント停止溶液)の添加によって定量する。
光学密度(OD)を450nmにおいて96ウエルリーダー(SpectraMax250,Molecular Device)中で分光測光法的に決定する。バックグラウンドOD(VEGF 添加なし)はすべてのODから差引かれ、そして%阻害が下記式に従って計算される。
Matrigelプラグの調製およびインビボフェーズ:
MatrigelTM(Collaborative Biomedical Products,Bedord,MA)は、主としてラミニン、コラーゲンIVおよびヘパランサルフェートプロテオグリカンより構成されるネズミ腫瘍からの基底膜抽出物である。それは4℃において無菌液として提供されるが、しかし37℃において固体ゲルを容易に生成する。
4℃のMatrigelを、選別できるマーカーを有するネズミVEGF遺伝子を含むプラスミドで形質転換したSK−MEL2 ヒト腫瘍細胞と混合する。腫瘍細胞は選別下インビトロで生育され、そして細胞は2×106 /0.5mlの比で冷Matrigel液と混合される。25ゲージ針を用いて1/2mlを腹中央線近くに皮下移植する。テスト化合物は、移植日から出発して1日1回30,100および300mg/kgPOにおいてエタノール/Ceremaphor EL/食塩水(12.5%:12.5%:75%)中の溶液として投与される。移植後12日にマウスを安楽死させ、そしてMatrigelペレットをヘモグロビン含量の分析のために収穫する。
ヘモグロビンアッセイ:
Matrigelペレットは、4℃の溶解バッファー(20mMトリスpH7.5,1mM EGTA,1mM EDTA,1% Triton X−100(EM Science,Gibbstown,NJ)、および完全EDTA フリープロテアーゼ阻害剤カクテル(Mannheim,Germany))の4容積中に入れ、4℃でホモジネートされる。ホモジネートは氷の上で振とうしながら30分間インキュベートされ、4℃で30分14K×gにおいて遠心される。上清は冷たいマイクロ遠心チューブに移され、そしてヘモグロビンアッセイのために4℃で貯蔵される。
マウスヘモグロビン(Sigma Chemical Co.,St.Louis,MO)はオートクレーブ滅菌水(Bio Whittaker,Inc,Walkersvill,MD)に5mg/mlに懸濁する。標準曲線は溶解バッファー(上述)中で500μg/mlから30μg/mlまで作成される。標準曲線および溶解物サンプルはポリスチレン96ウエルプレートへ5μl/ウエルにおいて二重に加えられる。Sigma血漿ヘモグロビンキット(Sigma Chemical Co.,St.Louis,MO)を用い、TMS基質を室温酢酸溶液50ml中に復元する。基質100μlを各ウエルへ加え、次に室温で過酸化水素溶液100μl/ウエルを加える。
光学密度は600nmにおいて96ウエルリーダー(SpectraMax250マイクロプレート分光光度計システム、Molecnlar Devices,Sunnyvale,CA)を用いて分光測光法で決定される。バックグラウンド溶解物バッファーの読みはすべてウエルから差引かれる。
総サンプルヘモグロビン含量は以下の式に従って計算される。
Claims (1)
- N−〔4−クロロ−3−(トリフロロメチル)フェニル〕−N’−{4−〔2−カルバモイル−(4−ピリジルオキシ)〕フェニル}尿素、またはN−〔4−クロロ−3−(トリフロロメチル)フェニル〕−N’−{4−〔2−(N−メチルカルバモイル)−4−(ピリジルオキシ)〕フェニル}尿素、またはそれらの薬学的に許容し得る塩を含む、VEGF誘発信号形質導入によって仲介されるヒトまたは他の哺乳類の網膜症または未熟児網膜症を処置するための医薬。
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US7838541B2 (en) | 2010-11-23 |
WO2003068228A1 (en) | 2003-08-21 |
US8242147B2 (en) | 2012-08-14 |
JP4685068B2 (ja) | 2011-05-18 |
AU2003209116A1 (en) | 2003-09-04 |
DK1478358T3 (da) | 2013-10-07 |
US20080227828A1 (en) | 2008-09-18 |
JP2005522448A (ja) | 2005-07-28 |
EP1478358A1 (en) | 2004-11-24 |
MXPA04007832A (es) | 2005-09-08 |
PT1478358E (pt) | 2013-09-11 |
ES2425739T3 (es) | 2013-10-17 |
CA2475703A1 (en) | 2003-08-21 |
US20110015195A1 (en) | 2011-01-20 |
CA2475703C (en) | 2016-12-20 |
US20120289552A1 (en) | 2012-11-15 |
SI1478358T1 (sl) | 2013-09-30 |
US20030207870A1 (en) | 2003-11-06 |
EP2324825A1 (en) | 2011-05-25 |
US8618141B2 (en) | 2013-12-31 |
EP1478358B1 (en) | 2013-07-03 |
JP2007302687A (ja) | 2007-11-22 |
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