JP2007504160A - c−Kit調節因子および使用方法 - Google Patents
c−Kit調節因子および使用方法 Download PDFInfo
- Publication number
- JP2007504160A JP2007504160A JP2006524905A JP2006524905A JP2007504160A JP 2007504160 A JP2007504160 A JP 2007504160A JP 2006524905 A JP2006524905 A JP 2006524905A JP 2006524905 A JP2006524905 A JP 2006524905A JP 2007504160 A JP2007504160 A JP 2007504160A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- oxy
- tetrazol
- acetamide
- optionally substituted
- 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.)
- Granted
Links
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title claims abstract description 58
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 189
- 230000000694 effects Effects 0.000 claims abstract description 64
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 40
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
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- -1 cyclic sulphonamides Chemical class 0.000 claims description 509
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 420
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 285
- 125000000217 alkyl group Chemical group 0.000 claims description 116
- 125000000623 heterocyclic group Chemical group 0.000 claims description 81
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 50
- 108091000080 Phosphotransferase Proteins 0.000 claims description 38
- 102000020233 phosphotransferase Human genes 0.000 claims description 38
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 29
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- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 150000003254 radicals Chemical class 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
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- 125000005842 heteroatom Chemical group 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000006413 ring segment Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 10
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- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
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- 238000012216 screening Methods 0.000 claims description 9
- VMNKQTURBLGWFS-UHFFFAOYSA-N 3-[[2-[3-(tetrazol-1-yl)phenoxy]acetyl]amino]benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)COC=2C=C(C=CC=2)N2N=NN=C2)=C1 VMNKQTURBLGWFS-UHFFFAOYSA-N 0.000 claims description 8
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- 125000001401 1,2,4-triazol-4-yl group Chemical group N=1N=C([H])N([*])C=1[H] 0.000 claims description 6
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- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims description 3
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
Description
本願は、発明者としてチェン,ウェイらが示された、「c−Kit調節因子および使用方法」の表題で、2003年8月29日に出願された、米国仮特許出願第60/499,224号の優先権を主張する;これは、すべての目的において、その全体が参考として本明細書に援用される。
(発明の分野)
本発明は、増殖、分化、プログラム細胞死、遊走および化学侵襲(chemoinvasion)のような、細胞活性を調節するためのプロテインキナーゼ酵素活性を調節するための化合物に関する。さらにより具体的には、本発明は、上述の細胞活性における変化に関するキナーゼレセプターシグナル伝達経路を阻害、制御および/または調節する化合物、これら化合物を含む組成物、ならびにキナーゼ依存性の疾患および状態を処置するためにこれらを使用する方法に関する。
癌を処置するために使用される因子の特異性の改良は、これら因子の投与に関連する副作用が軽減され得る場合に実現される治療上の利益に起因して、かなり重要なことである。伝統的に、癌の処置における劇的な改良は、新規機構を介して作用する治療因子の同定と関連する。
1つの局面において、本発明は、c−Kitキナーゼ活性を調節するための化合物、およびこの化合物を利用して、c−Kit活性によって媒介される疾患を処置する方法、およびこの化合物の薬学的組成物を提供する。c−Kit活性によって媒介される疾患としては、侵襲性細胞増殖に関連する遊走、侵襲、増殖および他の生物学的活性によって部分的に特徴付けられる疾患が挙げられるが、これらに限定されない。
本発明の組成物は、異常な細胞活性およびまたは制御されない細胞活性と関連する疾患を処置するために使用される。本明細書中に提供される方法および組成物によって処置され得る疾患状態としては、以下が挙げられるが、これらに限定されない:癌(以下にさらに考察される)、免疫障害(例えば、慢性関節炎リューマチ、移植片−宿主疾患、多発性硬化症、乾鮮;心臓血管疾患(例えば、アテローム硬化症、心筋梗塞、虚血、発作および再狭窄);他の炎症性疾患および変性疾患(例えば、腸内疾患、骨関節炎、黄斑変性、糖尿病性網膜症)。
各々のR1は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つの隣接したR1は、それらが結合する環原子と一緒になって、5員環〜6員環を形成し得、この環は、2つまでのヘテロ原子を含み、そして必要に応じて3つまでのR10で置換され;
L1は、単結合、必要に応じて置換されたC1−2アルキレン、−O−、−CH2O−、−N(R7)−、−C(=O)N(R7)−、−SO2N(R7)−、−CH2N(R7)−、および−S(O)0−2−から選択され;
環Bは、5員〜10員のアリールまたは5員〜10員のヘテロシクリルであり;
各々のR2は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つの隣接するR2は、それらが結合する環原子と一緒になって、5員環〜6員環を形成し得、この環は、2つまでのヘテロ原子を含み、そして必要に応じて3つまでのR15で置換され;
L2は、C4アルキレン、C4アルキリデン、C4アルキリジン、−X(CH2)2O−、−X(CH2)2N(R7)−、−XCH2SO2N(R7)−、−XN(R7)C(=O)N(R7)−、−XCH2C(=O)N(R7)−、−(CH2)3X−、−XN(R7)SO2N(R7)−、−XCH2N(R7)SO2−、−CH2X(CH2)2−、−CH=CHC(=O)N(R7)−、−CH=CHSO2N(R7)−、−XCH2N(R7)C(=O)−、−M−M−、−CH2N(R7)C(=O)O−、および−CH2OC(=O)N(R7)−から選択され;ここで、Xは−CH2−、−O−、−N(R7)−、−C(=O)−および−S(O)0−2−から選択され;Mは−C(=O)N(R7)−および−SO2N(R7)−から選択され;そしてL2のうち任意のC−Hは必要に応じてC−R20であり;
環Cは、5員〜10員のアリールまたは5員〜10員のヘテロアリールであり;
各々のR3は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;但し、R3は、環状スルホンアミドの窒素を介して環Cに結合した環状スルホンアミドではない;
2つの隣接したR3は、それらが結合する環原子と一緒になって、5員環〜6員環を形成し得、この環は、2つまでのヘテロ原子を含み、そして必要に応じて3つまでのR25で置換され;
R4は、−H、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つのR4は、それらが結合する共通の窒素原子と一緒になって、必要に応じて置換された5員〜7員のヘテロシクリルを形成し得、この必要に応じて置換された5員環〜7員環ヘテロシクリルは、必要に応じて、N、O、SおよびPから選択される少なくとも1つのさらなるヘテロ原子を含み;
R5は、−H、−CN、−NO2、−OR4、−S(O)0−2R4、−CO2R4、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたC1−6アルケニル、および必要に応じて置換されたC1−6アルキニルから選択され;
R7は、−H、必要に応じて置換されたC1−6アルキル、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;そして
各々のR10、各々のR15、各々のR20、および各々のR25は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
但し;
1)環Bおよび環Cの両方がフェニルである場合:
a)かつ本化合物が環B−CH2N(H)C(=O)N(H)−環Cを含む場合、L1は単結合でなければならず;R3は、L2に対してオルト位である、式−O(CH2)2−4−N−ピペラジンの基を含み得ず;そして環Aは5−メチル−[1,2,4]−オキサジアゾール−3−イルラジカルでも4H−[1,2,4]−オキサジアゾール−5−オン−3−イルラジカルでも4’−[2,2’;6’,2”]テルピリジニルラジカルでもあり得ず;
b)かつL1が単結合以外である場合、L2は−N(H)C(=O)C(=O)N(H)−も−N(H)C(=Q)C(H)CNC(=O)−も含み得ず(ここで、QはSまたはOである);
c)かつL1が単結合以外である場合、Aはキノリン−2−イル−L1でもキノリン−3−イル−L1でもキノリン−4−イル−L1でもあり得ず;
2)環Aが縮合アリール系である場合、L1は単結合でなければならず;
3)環Bがフェニルである場合、環CはC6−16炭素環であり、L1は単結合であり、そしてこの化合物が−環B−OCH2C(=O)N(H)−を含む場合、環Aは2,5−ジメチル−1H−ピロール−1−イルラジカルであり得ず;
4)L1が−N(H)−でありかつ環Bがフェニルである場合、環Aはピリミジン−2−イルラジカルであり得ず;
5)本化合物が以下の式
6)この化合物は、以下のうちの1つではない:N−ナフタレン−1−イル−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(フェニルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2、4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−(2,4,6−トリメチルフェニル)アセトアミド、N−(2−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジエチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[3−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2,4−ビス(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(ジメチルアミノ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジクロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−クロロ−3−メチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−ブロモフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[2−(トリフルオロメチル)フェニル]アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[3−(トリフルオロメチル)フェニル]アセトアミド、メチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、エチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、3−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]安息香酸、N−[3−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−クロロ−5−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(4H−1,2,4−トリアゾール−4−イル)フェニル]オキシ}アセトアミド、N−(4−クロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−アミノフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、およびN−(4−アセチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド。
各々のYは独立して=C(H)−または=N−のどちらかであり;
Zは、−O−、−S(O)0−2−および−N(R7)−から選択され;
EおよびGは、各々独立して、−O−、−S(O)0−2−、−C(R31)(R32)−および−N(R33)−から選択され;
J1およびJ2はそれぞれ独立して=C(H)−または=N−であり;
各々のR26およびR30は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR40、−N(R40)R40、−S(O)0−2R40、−SO2N(R40)R40、−CO2R40、−C(=O)N(R40)R40、−C(=NR50)N(R40)R40、−C(=NR50)R40、−N(R40)SO2R40、−N(R40)C(O)R40、−NCO2R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つの隣接したR26および2つの隣接したR30は、それらが結合する環原子と一緒になって、5員〜6員環を形成し得、この環は2つまでのヘテロ原子および必要に応じて置換された3つまでのR35を含み;
R31およびR32は、各々独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR40、−N(R40)R40、−S(O)0−2R40、−SO2N(R40)R40、−CO2R40、−C(=O)N(R40)R40、−C(=NR50)N(R40)R40、−C(=NR50)R40、−N(R40)SO2R40、−N(R40)C(O)R40、−NCO2R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
R33は、−H、必要に応じて置換された低級アルキル、−SO2N(R40)R40、−CO2R40、−C(=O)N(R40)R40、−C(=NR50)N(R40)R40、−C(=NR50)R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
R40は、−H、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つのR40は、それらが結合する共通の窒素原子と一緒になる場合、必要に応じて置換された5員〜7員のヘテロシクリルを形成し、この必要に応じて置換された5員〜7員のヘテロシクリルは、N、O、SおよびPから選択される少なくとも1つのさらなるヘテロ原子を必要に応じて含み;
R50は、−H、−CN、−NO2、−OR40、−S(O)0−2R40、−CO2R40、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたC1−6アルケニル、および必要に応じて置換されたC1−6アルキニルから選択され;
R55は、−H、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;そして
2つのR55は、それらが結合する共通の窒素原子と一緒になる場合、必要に応じて置換された5員〜7員のヘテロシクリルを形成し、この必要に応じて置換された5員〜7員のヘテロシクリルは、N、O、SおよびPから選択される少なくとも1つのさらなるヘテロ原子を必要に応じて含む。
本明細書中で使用される場合、以下の語句は、それら語句が使用される文脈がそれ以外のことを示す範囲またはそれら語句が異なる何かを意味することが明確に定義される範囲を除き、一般的に以下に記載するとおりの意味を有するよう意図される。
本発明の化合物またはそれらの薬学的に受容可能な塩の、純粋な状態でかまたは適切な薬学的組成物での投与は、任意の受容される投与形式または類似の有用性を提供するための薬剤を介して実行され得る。従って、投与は、固体形態、半固体形態、凍結乾燥粉末形態、または液体投薬形態(例えば、錠剤、坐剤、丸剤、軟弾性カプセルおよび硬ゼラチンカプセル、散剤、溶剤、懸濁剤、またはエアゾールなど)で、好ましくは、正確な投薬の1回の投与に適切な単位投薬形態で、例えば経口、鼻腔内、非経口(静脈内、筋肉内、または皮下)、局所的、経皮的、膣内、膀胱内、槽内、または直腸的であり得る。
例えばc−Kitレセプターキナーゼに結合する候補因子についてのスクリーニングの方法において本発明の化合物を使用するため、タンパク質は支持体に結合され、そして本発明の化合物がアッセイに添加される。あるいは、本発明の化合物が支持体に結合され、そしてタンパク質が添加される。新規の結合性因子が求められ得るものの中での候補因子の分類は、特定の抗体、化学ライブラリーのスクリーニングにおいて同定された非天然の結合因子、ペプチドアナログなどを含むことが求められ得る。ヒト細胞に低毒性を有する候補因子についてのスクリーニングアッセイは、特に有益である。広範なアッセイがこの目的に使用され得、このようなアッセイとしては、インビトロでの標識されたタンパク質−タンパク質結合アッセイ、電気泳動移動度シフトアッセイ、タンパク質結合についての免疫アッセイ、機能アッセイ(リン酸化アッセイなど)などが挙げられる。
以下の略号および用語が、全体にわたって示された意味を有する:
スキーム1〜3は、本発明の化合物の一般的合成経路を記し、そして限定されることを意図しない。特定の例はこの一般的な合成の記載に続いて記載される。一般的経路およびこの後の特定の例の記載を用いて、当業者は、記載のように本発明の化合物を作製し得る。
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{(3−(1H−テトラゾール−1−イル)−フェニル]オキシ}アセトアミド 4の合成)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(1H−1,2,3−トリアゾール−1−イル)フェニル]オキシ}アセトアミド 8の合成)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−[3−(1H−テトラゾール−1−イル)フェニル]ヒドラジンカルボキサミド13の合成)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)−フェニル]オキシ}アセトアミド 15の合成)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(5−メチル−1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド 17の合成)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル)−2−{[3−1H−テトラゾール−1−イル)フェニル]チオ}アセトアミド 20の合成)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−[(4−アリール−フェニル−オキシ]アセトアミド 23についての一般的な手順)
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[4−(1H−1,2,4−トリアゾール−4−イル)フェニル]オキシアセトアミド 25の合成}
(N−[4−クロロ−3−(トリフルオロメチル)フェニル]−N’−{[3−(1H−テトラゾール−1−イル)フェニル]メチル}ウレア 28の合成)
固定したミエリン塩基性タンパク質(MBP)へのγ−33P ATPの取り込みの測定により、キナーゼアッセイを実施した。Tris緩衝化生理食塩水(TBS;50mM Tris pH8.0、138mM NaCl、2.7mM KCl)中の20μg/mlのMBP(Sigma #M−1891)をウェルあたり60μl、24時間4℃でインキュベーションすることにより、高結合性の白色384ウェルプレート(Greiner)をMBPでコーティングした。プレートを100μlのPBSで3回洗浄した。キナーゼ反応を、キナーゼ緩衝液(5mM Hepes pH7.6、15mM NaCl、0.01% ウシγグロブリン(Sigma #I−5506)、10mM MgCl2、1mM DTT、0.02% TritonX−100)中で総量34μlで実行した。化合物の希釈をDMSO中で実施し、そしてDMSO終濃度1%までアッセイウェルに添加した。各々のデータ点を二連で測定し、そして各々の化合物の決定のため少なくとも2つの二連アッセイを実施した。酵素を、例えば終濃度10nMまたは20nMまで添加した。未標識ATPおよびγ−33P ATPの混合物を添加して反応を開始した(代表的には、ウェルあたり2×106cpmのγ−33P ATP(3000Ci/mmole)および10μMまたは30μMのいずれかの未標識ATP)。この反応を、振盪しながら室温で1時間実施した。プレートをTBSで7回洗浄し、続いてウェルあたり50μlのシンチレーション液(Wallac)を添加した。プレートをWallac Triluxカウンターを使用して読み取った。このことは、単なる1つの例示的なアッセイである:当業者に公知なように、種々の形式が可能である。
キナーゼ活性および化合物の阻害は、以下に記載される3つのアッセイ様式のうち1つ以上を使用して調べられる。各々のアッセイについてのATP濃度は、各々別個のキナーゼについて、ほぼMichaelis−Menten定数(KM)に近くなるように選択される。用量応答実験を、384ウェルプレートの様式で10個の異なるインヒビター濃度で実施する。これらのデータを以下の4パラメーターの式(2)に当てはめる;ここで、Yは観察されたシグナルであり、Xはインヒビター濃度であり、Minは酵素の非存在下(0%の酵素活性)でのバックグラウンドシグナルであり、Maxはインヒビター非存在下(100%の酵素活性)でのシグナルであり、IC50は50%酵素阻害でのインヒビター濃度であり、そしてHは協同作用を測定するための経験的なHillの傾きを示す。代表的に、Hは1に近い。
c−Kitの生化学的反応を、上記のAlphaScreenTM(Perkin Elmer)技術を使用して評価した。試験化合物、ATP、ビオチン化ポリ(Glu、Tyr)およびc−Kitキナーゼを、384ウェルの結合が中間の白色マイクロタイタープレート(Greiner)において容量20μLで併せた。反応混合物を周囲温度で1時間インキュベーションした。75mM Hepes、pH7.4、300mM NaCl、120mM EDTA、0.3% BSAおよび0.03% Tween−20を含む15〜30mg/mLのAlphaScreenビーズ懸濁物を10μL添加することにより反応をクエンチした。周囲温度で16時間のインキュベーション後、プレートを、AlphaQuestリーダー(Perkin Elmer)を使用して読み取った。
表3は、選択された本発明の化合物についての構造−活性の相関データを示す。阻害は、以下のキーを用いてIC50として示される:A=50nM未満のIC50、B=50nMを超えるが500nM未満のIC50、C=500nMを超えるが5000nM未満のIC50、およびD=5,000nM以上のIC50。
Claims (35)
- 式I
環Aは5員〜14員のヘテロアリールであり;
各々のR1は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つの隣接したR1は、それらが結合する環原子と一緒になって、5員環〜6員環を形成し得、該環は、2つまでのヘテロ原子を含み、そして必要に応じて3つまでのR10で置換され;
L1は、単結合、必要に応じて置換されたC1−2アルキレン、−O−、−CH2O−、−N(R7)−、−C(=O)N(R7)−、−SO2N(R7)−、−CH2N(R7)−、および−S(O)0−2−から選択され;
環Bは、5員〜10員のアリールまたは5員〜10員のヘテロシクリルであり;
各々のR2は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つの隣接するR2は、それらが結合する環原子と一緒になって、5員〜6員環を形成し得、該環は、2つまでのヘテロ原子を含み、そして必要に応じて3つまでのR15で置換され;
L2は、C4アルキレン、C4アルキリデン、C4アルキリジン、−X(CH2)2O−、−X(CH2)2N(R7)−、−XCH2SO2N(R7)−、−XN(R7)C(=O)N(R7)−、−XCH2C(=O)N(R7)−、−(CH2)3X−、−XN(R7)SO2N(R7)−、−XCH2N(R7)SO2−、−CH2X(CH2)2−、−CH=CHC(=O)N(R7)−、−CH=CHSO2N(R7)−、−XCH2N(R7)C(=O)−、−M−M−、−CH2N(R7)C(=O)O−、および−CH2OC(=O)N(R7)−から選択され;ここで、Xは−CH2−、−O−、−N(R7)−、−C(=O)−および−S(O)0−2−から選択され;Mは−C(=O)N(R7)−および−SO2N(R7)−から選択され;そしてL2のうち任意のC−Hは必要に応じてC−R20であり;
環Cは、5員〜10員のアリールまたは5員〜10員のヘテロアリールのどちらかであり;
各々のR3は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;但し、R3は、環状スルホンアミドの窒素を介して環Cに結合した環状スルホンアミドではなく;
2つの隣接したR3は、それらが結合する環原子と一緒になって5員環〜6員環を形成し得、該環は、2つまでのヘテロ原子を含み必要に応じて3つまでのR25で置換され;
R4は、−H、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つのR4は、それらが結合する共通の窒素原子と一緒になったとき、必要に応じて置換された5員〜7員のヘテロシクリルを形成し得、該必要に応じて置換された5員環〜7員環ヘテロシクリルは、必要に応じて、N、O、SおよびPから選択される少なくとも1つのさらなるヘテロ原子を含み;
R5は、−H、−CN、−NO2、−OR4、−S(O)0−2R4、−CO2R4、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたC1−6アルケニル、および必要に応じて置換されたC1−6アルキニルから選択され;
R7は、−H、必要に応じて置換されたC1−6アルキル、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;そして
各々のR10、各々のR15、各々のR20、および各々のR25は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR4、−N(R4)R4、−S(O)0−2R4、−SO2N(R4)R4、−CO2R4、−C(=O)N(R4)R4、−C(=NR5)N(R4)R4、−C(=NR5)R4、−N(R4)SO2R4、−N(R4)C(O)R4、−NCO2R4、−C(=O)R4、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
但し;
1)環Bおよび環Cの両方がフェニルである場合:
a)かつ該化合物が環B−CH2N(H)C(=O)N(H)−環Cを含む場合、L1は単結合でなければならず;R3は、L2に対してオルト位である、式−O(CH2)2−4−N−ピペラジンの基を含み得ず;そして環Aは5−メチル−[1,2,4]−オキサジアゾール−3−イルラジカルでも4H−[1,2,4]−オキサジアゾール−5−オン−3−イルラジカルでも4’−[2,2’;6’,2”]テルピリジニルラジカルでもあり得ず;
b)かつL1が単結合以外である場合、L2は−N(H)C(=O)C(=O)N(H)−も−N(H)C(=Q)C(H)CNC(=O)−も含み得ず(ここで、QはSまたはOである);
c)かつL1が単結合以外である場合、Aはキノリン−2−イル−L1でもキノリン−3−イル−L1でもキノリン−4−イル−L1でもあり得ず;
2)環Aが縮合アリール系である場合、L1は単結合でなければならず;
3)環Bがフェニルである場合、環CはC6−16炭素環式であり、L1は単結合であり、そして該化合物が−環B−OCH2C(=O)N(H)−を含む場合、環Aは2,5−ジメチル−1H−ピロール−1−イルラジカルであり得ず;
4)L1が−N(H)−でありかつ環Bがフェニルである場合、環Aはピリミジン−2−イルラジカルであり得ず;
5)該化合物が以下の式
6)該化合物は:
N−ナフタレン−1−イル−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(フェニルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−(2,4,6−トリメチルフェニル)アセトアミド、N−(2−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジエチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[3−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2,4−ビス(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(ジメチルアミノ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジクロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−クロロ−3−メチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−ブロモフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[2−(トリフルオロメチル)フェニル]アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[3−(トリフルオロメチル)フェニル]アセトアミド、メチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、エチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、3−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]安息香酸、N−[3−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−クロロ−5−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(4H−1,2,4−トリアゾール−4−イル)フェニル]オキシ}アセトアミド、N−(4−クロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−アミノフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、およびN−(4−アセチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド
のうちの1つではない、
化合物または該化合物の薬学的に受容可能な塩、水和物もしくはプロドラッグ。 - L1が単結合である、請求項1に記載の化合物。
- 環Aが1〜4の間の環窒素を含む、請求項2に記載の化合物。
- 環Bがフェニレンまたはピリジレンである、請求項4に記載の化合物。
- L1およびL2が結合する環Bの環原子が隣接しない、請求項5に記載の化合物。
- 請求項6に記載の化合物であって、ここでL2は、−X(CH2)2O−、−X(CH2)2N(R7)−、−CH2XC(=O)N(R7)−、−XCH2SO2N(R7)−、−XN(R7)C(=O)N(R7)−および−XCH2C(=O)N(R7)−から選択され;ここで、Xは、−CH2−、−O−、−S(O)0−2−および−N(R7)−から選択され;そしてL2の任意のC−Hは必要に応じてC−R20である、化合物。
- 請求項7に記載の化合物であって、ここでL2は、−N(H)N(H)C(=O)N(H)−、−CH2N(H)C(=O)N(H)−、−CH2OC(=O)N(H)−、および−XCH2C(=O)N(H)−から選択され;ここで、Xは、−O−、−S(O)0−2−および−N(R7)−から選択され;そしてL2の任意のC−Hは必要に応じてC−R20である、化合物。
- 環Cがフェニレンまたはピリジルである、請求項9に記載の化合物。
- ハロゲンであるR3が少なくとも1つ存在する、請求項10に記載の化合物。
- トリハロメチルであるR3が少なくとも1つ存在する、請求項10に記載の化合物。
- トリフルオロメチルであるR3が少なくとも1つ存在する、請求項10に記載の化合物。
- 環Cが、L2に対してメタ位にトリフルオロメチルラジカルを含むフェニルである、請求項13に記載の化合物。
- 各々のR3が、−H、ハロゲン、トリハロメチル、−OR4、−CO2R4、−C(=O)R4および必要に応じて置換されたC1−6アルキルから独立して選択される、請求項10に記載の化合物。
- 以下の式II
Wは以下
各々のR27は、独立して、ハロゲン、トリハロメチル、−CN、−NO2、−OR55、−N(R55)R55、−S(O)0−2R55、−SO2N(R55)R55、−CO2R55、−C(=O)N(R55)R55、−C(=NR50)N(R55)R55、−C(=NR50)R55、−N(R55)SO2R55、−N(R55)C(O)R55、−NCO2R55、−C(=O)R55、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
各々のYは独立して=C(H)−または=N−のどちらかであり;
Zは、−O−、−S(O)0−2−および−N(R7)−から選択され;
EおよびGは、各々独立して、−O−、−S(O)0−2−、−C(R31)(R32)−および−N(R33)−から選択され;
J1およびJ2はそれぞれ独立して=C(H)−または=N−であり;
各々のR26およびR30は、独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR40、−N(R40)R40、−S(O)0−2R40、−SO2N(R40)R40、−CO2R40、−C(=O)N(R40)R40、−C(=NR50)N(R40)R40、−C(=NR50)R40、−N(R40)SO2R40、−N(R40)C(O)R40、−NCO2R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つの隣接したR26および2つの隣接したR30は、それらが結合する環原子と一緒になって、5員〜6員環を形成し得、該環は2つまでのヘテロ原子および必要に応じて置換された3つまでのR35を含み;
R31およびR32は、各々独立して、−H、ハロゲン、トリハロメチル、−CN、−NO2、−OR40、−N(R40)R40、−S(O)0−2R40、−SO2N(R40)R40、−CO2R40、−C(=O)N(R40)R40、−C(=NR50)N(R40)R40、−C(=NR50)R40、−N(R40)SO2R40、−N(R40)C(O)R40、−NCO2R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
R33は、−H、必要に応じて置換された低級アルキル、−SO2N(R40)R40、−CO2R40、−C(=O)N(R40)R40、−C(=NR50)N(R40)R40、−C(=NR50)R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
R40は、−H、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;
2つのR40は、それらが結合する共通の窒素原子と一緒になる場合、必要に応じて置換された5員〜7員のヘテロシクリルを形成し、該必要に応じて置換された5員〜7員のヘテロシクリルは、N、O、SおよびPから選択される少なくとも1つのさらなるヘテロ原子を必要に応じて含み;
R50は、−H、−CN、−NO2、−OR40、−S(O)0−2R40、−CO2R40、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたC1−6アルケニル、および必要に応じて置換されたC1−6アルキニルから選択され;
R55は、−H、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択され;そして
2つのR55は、それらが結合する共通の窒素原子と一緒になる場合、必要に応じて置換された5員〜7員のヘテロシクリルを形成し、該必要に応じて置換された5〜7員環ヘテロシクリルは、N、O、SおよびPから選択される少なくとも1つのさらなるヘテロ原子を必要に応じて含む、
化合物。 - WおよびEが結合する環Bの環炭素が隣接しない、請求項16に記載の化合物。
- 請求項17に記載の化合物であって、R30は、−H、ハロゲン、トリハロメチル、−OR40、−N(R40)R40、−CO2R40、−C(=O)R40、必要に応じて置換されたアルコキシ、必要に応じて置換されたC1−6アルキル、必要に応じて置換されたアリール、必要に応じて置換されたアリールC1−6アルキル、必要に応じて置換されたヘテロシクリル、および必要に応じて置換されたヘテロシクリルC1−6アルキルから選択される、化合物。
- トリハロメチルであるR30が少なくとも1つ存在する、請求項18に記載の化合物。
- トリフルオロメチルであるR30が少なくとも1つ存在する、請求項18に記載の化合物。
- Eは−O−、−S(O)0−2−および−NH−から選択され;そしてGは−CH2−である、請求項22に記載の化合物。
- Eは−CH2−または−NH−のいずれかであり;そしてGは−O−、−S−および−NH−から選択される、請求項22に記載の化合物。
- 請求項23または請求項24のいずれかに記載される化合物であって、ここで各々のR3は、独立して、−H、ハロゲン、トリハロメチル、−OR4、−CO2R4、−C(=O)R4、および必要に応じて置換されたC1−6アルキルから選択される、化合物。
- R30のうち少なくとも1つは、−E−G−C(=O)N(H)−に対してメタ位のトリフルオロメチルラジカルである、請求項25に記載の化合物。
- 請求項1〜27のいずれか1つに記載の化合物および薬学的に受容可能なキャリアを含む、薬学的組成物。
- 請求項1〜28のいずれか1つに記載の化合物または薬学的組成物の、代謝産物。
- キナーゼのインビボ活性を調節するための方法であって、該方法は、請求項1〜27のいずれか1つに記載の化合物またはN−ナフタレン−1−イル−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(フェニルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−(2,4,6−トリメチルフェニル)アセトアミド、N−(2−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジエチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[3−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2,4−ビス(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(ジメチルアミノ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジクロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−クロロ−3−メチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−ブロモフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[2−(トリフルオロメチル)フェニル]アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[3−(トリフルオロメチル)フェニル]アセトアミド、メチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、エチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、3−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]安息香酸、N−[3−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−クロロ−5−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(4H−1,2,4−トリアゾール−4−イル)フェニル]オキシ}アセトアミド、N−(4−クロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−アミノフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、およびN−(4−アセチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミドから選択される化合物の有効量を被験体に投与する工程を含む、方法。
- 前記キナーゼがc−Kitである、請求項30に記載の方法。
- c−Kitのインビボ活性を調節する工程がc−Kitの阻害を含む、請求項31に記載の方法。
- 制御されない細胞活性、異常な細胞活性および/または所望されない細胞活性に関係する疾患または障害を処置する方法であって、該方法は、該処置を必要とする哺乳動物に対して、請求項1〜請求項28のうちのいずれか1つに記載される化合物もしくは薬学的組成物の治療有効量、またはN−ナフタレン−1−イル−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(フェニルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,5−ジメチル−フェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−(2,4,6−トリメチルフェニル)アセトアミド、N−(2−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジエチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[3−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2,4−ビス(メチル−オキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(ジメチルアミノ)−フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジクロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−クロロ−3−メチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−ブロモフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[2−(トリフルオロメチル)フェニル]アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[3−(トリフルオロ−メチル)フェニル]アセトアミド、メチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、エチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、3−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]安息香酸、N−[3−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−クロロ−5−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(4H−1,2,4−トリアゾール−4−イル)フェニル]オキシ}アセトアミド、N−(4−クロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−アミノフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、およびN−(4−アセチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミドから選択される化合物もしくは該化合物を含む薬学的組成物の治療有効量を投与する工程を含む、方法。
- c−Kitの調節因子についてスクリーニングする方法であって、該方法は、請求項1〜請求項27のうちのいずれか1つに記載の化合物またはN−ナフタレン−1−イル−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(フェニルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−(2,4,6−トリメチルフェニル)アセトアミド、N−(2−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジエチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[3−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2,4−ビス(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(ジメチルアミノ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジクロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−クロロ−3−メチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−ブロモフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[2−(トリフルオロメチル)フェニル]アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[3−(トリフルオロメチル)フェニル]アセトアミド、メチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、エチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、3−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]安息香酸、N−[3−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−クロロ−5−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(4H−1,2,4−トリアゾール−4−イル)フェニル]オキシ}アセトアミド、N−(4−クロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−アミノフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、およびN−(4−アセチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミドから選択される化合物と、少なくとも該候補因子とを組み合わせる工程、ならびにc−Kit活性に対する該候補因子の効果を決定する工程を含む、方法。
- 細胞における増殖活性を阻害する方法であって、該方法は、請求項1〜27のいずれか1つに記載の化合物、またはN−ナフタレン−1−イル−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(フェニルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,4−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(3,5−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジメチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−(2,4,6−トリメチルフェニル)アセトアミド、N−(2−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−エチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,6−ジエチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[3−(エチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2,4−ビス(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(ジメチルアミノ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2,3−ジクロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−クロロ−3−メチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−ブロモフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(2−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−フルオロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[2−(トリフルオロメチル)フェニル]アセトアミド、2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}−N−[3−(トリフルオロメチル)フェニル]アセトアミド、メチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、エチル4−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]ベンゾエート、3−[({[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセチル)アミノ]安息香酸、N−[3−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−(メチルオキシ)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[2−クロロ−5−(トリフルオロメチル)フェニル]−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−[4−クロロ−3−(トリフルオロメチル)フェニル]−2−{[3−(4H−1,2,4−トリアゾール−4−イル)フェニル]オキシ}アセトアミド、N−(4−クロロフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、N−(4−アミノフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミド、およびN−(4−アセチルフェニル)−2−{[3−(1H−テトラゾール−1−イル)フェニル]オキシ}アセトアミドから選択される化合物を含む有効量の組成物を、1細胞または複数の細胞に投与する工程を含む、方法。
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US8362017B2 (en) | 2013-01-29 |
AU2004268621C1 (en) | 2011-08-18 |
JP5010917B2 (ja) | 2012-08-29 |
WO2005020921A3 (en) | 2005-10-06 |
EP1663204A4 (en) | 2008-08-13 |
JP2011190284A (ja) | 2011-09-29 |
AU2004268621B2 (en) | 2010-12-16 |
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