JP4709759B2 - アンドロゲン受容体モジュレーター化合物としての6−シクロアミノ−2−キノリノン誘導体 - Google Patents
アンドロゲン受容体モジュレーター化合物としての6−シクロアミノ−2−キノリノン誘導体 Download PDFInfo
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- JP4709759B2 JP4709759B2 JP2006524121A JP2006524121A JP4709759B2 JP 4709759 B2 JP4709759 B2 JP 4709759B2 JP 2006524121 A JP2006524121 A JP 2006524121A JP 2006524121 A JP2006524121 A JP 2006524121A JP 4709759 B2 JP4709759 B2 JP 4709759B2
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- Prior art keywords
- compound
- trifluoromethyl
- quinolinone
- methyl
- pyrrolidinyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 418
- 239000000849 selective androgen receptor modulator Substances 0.000 title description 18
- -1 (R)-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl) -5 (R) -methyl-1-pyrrolidinyl Chemical group 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
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- QPASXJGWXPFYCA-YVILZHTOSA-N 4-chloro-1-(difluoromethyl)-6-[(2r,5r)-2-methyl-5-[(1s)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl]quinolin-2-one Chemical compound C[C@@H]1CC[C@H]([C@H](O)C(F)(F)F)N1C1=CC=C(N(C(F)F)C(=O)C=C2Cl)C2=C1 QPASXJGWXPFYCA-YVILZHTOSA-N 0.000 claims description 6
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- 229940035363 muscle relaxants Drugs 0.000 description 1
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
本出願は、2003年8月22日出願の米国仮出願60/497,125の優先権を主張し、その記載の全体を本明細書に引用して包含する。
本発明は、アンドロゲン受容体のモジュレーター(すなわち、アゴニスト、部分アゴニストおよびアンタゴニスト)である非ステロイド化合物、およびそのような化合物の製造法および使用法に関する。
構造的に関連した遺伝子レギュレーターのクラスを作る細胞内受容体(IR)を、科学者は“リガンド依存性転写因子”と名付けている(R. M. Evans, Science, 240: 889, 1988)。ステロイド受容体はIRの認識されたサブセットであり、アンドロゲン受容体、プロゲステロン受容体(PR)、エストロゲン受容体(ER)、グルココルチコイド受容体(GR)、および鉱質コルチコイド受容体(MR)を含む。このような因子による遺伝子の制御は、IR自体ならびにそのIRに遺伝子転写に作用する方法で選択的に結合する能力を有する対応するリガンドを必要とする。
本発明はアンドロゲン受容体が介在する過程を調節するための、化合物、医薬組成物、および方法に関する。本発明のある化合物は、下記の通り示され得る:
R1は水素、F、Cl、またはC1−C3アルキルであり;
R2は、水素、F、Cl、Br、C1−C4アルキル、C1−C4ハロアルキル、およびC1−C4ヘテロアルキルからなる群から選択され;
R3およびR4は、各々独立して水素、C1−C4アルキル、C1−C4ハロアルキル、C1−C4ヘテロアルキル、所望により置換されているアリールおよびヘテロアリールからなる群から選択され;
R5およびR6は、各々独立して水素、F、Cl、OR10、C1−C4アルキル、C1−C4ハロアルキル、およびC1−C4ヘテロアルキルからなる群から選択され;
R7およびR8は、各々独立して水素、F、Cl、C1−C4アルキル、C1−C4ハロアルキル、およびC1−C4ヘテロアルキルからなる群から選択されるか;または
R7およびR8は、一体となってカルボニル基を形成し;
R9は、ハロゲン、OR10、SR10、NR10R11、C1−C4ハロアルキル、C1−C4ヘテロアルキル、およびC1−C4ヘテロハロアルキルからなる群から選択され;
R10およびR11は、各々独立して水素、C1−C4アルキル、フェニル、およびベンジルからなる群から選択され;そして
N=0または1である。〕。
前記の一般的な記載および下記の詳細な記載の両方とも例であり、かつ例示のみであり、請求している本発明を限定するものではないことは理解すべきである。本発明での使用において、単数形は特記されない限り、複数形も包含する。本明細書での使用において、“または”は特記されない限り“および/または”を意味する。さらに、“含む”ならびに“含み”および“包含”のような用語の使用は、限定的ではない。
具体的な定義が提供されていない限り、分析化学、合成有機化学、医化学および薬化学と関連して、ならびにこれらの研究法および技術において使用する命名法は、当分野で既知のものである。標準的な化学記号をこのような記号により表される完全な名前と交換可能に使用する。故に、例えば、“水素”および“H”なる用語は同じ意味を有すると理解すべきである。標準的技術を、化学合成、化学分析、医薬調製物、製剤、送達および患者の処置において使用し得る。標準技術を組み換えDNA法、オリゴヌクレオチド合成、組織培養および形質転換(例えば、エレクトロポレーション、リポフェクション)のために使用し得る。反応および精製法は、当分野で一般的に達成されるようにまたは本明細書に記載のように、例えば、製造者に指示に従ってキットを使用して、行い得る。前記の技術および方法は、一般に、当分野で既知の慣用法に従い、かつ、本明細書を通して引用し、記載する様々な一般的またはより具体的な引用文献に記載の通り、行い得る。例えば、全ての目的のために引用して本明細書に包含するSambrook et al. Molecular Cloning: A Laboratory Manual(2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989))参照。
アンドロゲン受容体と結合するおよび/またはこのような受容体の活性を調節するある種の化合物は、健康に役割を担う(例えば、正常な増殖、発育、および/または疾患の不在)。ある態様において、選択的アンドロゲン受容体モジュレーターおよび/または結合化合物は、様々な疾患または状態の何れかの処置に有用である。
(R)−6−(2−(2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物101);
(R)−6−(2−フェニルチオメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物102);
(R)−6−(2−(2,2,2−トリフルオロエチル)−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物103);
(R)−6−(2−ベンジルオキシメチル)−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物104);
(R)−6−(2−ジエチルアミノメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物105);
6−(2(R)−ヒドロキシメチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物106);
6−(2(R)−フルオロメチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物107);
6−(2(R)−フルオロメチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物108);
6−(2(R)−ジフルオロメチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物109);
6−(2(R)−フルオロメチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物110);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物111);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物112);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物113);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物114);
6−(2(R)−(2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物115);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−ヒドロキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物116);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−ヒドロキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物117);
6−(2(R)−(1(S)−フルオロ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物118);
6−(2(R)−(1(R)−フルオロ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物119);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物120);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物121);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物122);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物123);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物124);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物125);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物126);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物127);
4−クロロ−6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−2(1H)−キノリノン(化合物128);
4−クロロ−6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−2(1H)−キノリノン(化合物129);
4−クロロ−6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−2(1H)−キノリノン(化合物130);
4−クロロ−6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−2(1H)−キノリノン(化合物131);
6−(2(R)−(1(R)−ヒドロキシ−1−メチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物132);
6−(2(R)−(1(S)−ヒドロキシ−1−メチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物133);
6−(2(R)−(1−ヒドロキシ−1−トリフルオロメチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物134);
6−(2(R)−(1(R)−エトキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物135);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−プロピル−2(1H)−キノリノン(化合物136);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−プロピル−2(1H)−キノリノン(化合物137);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−エチル−2(1H)−キノリノン(化合物138);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−エチル−2(1H)−キノリノン(化合物139);
6−(2(R)−クロロメチル−5−(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物140);
6−(2(R)−クロロメチル−5−(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物141);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物142);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物143);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物144);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物145);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物146);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物147);
6−(2(R)−(1(R),2−ジヒドロキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物148);
6−(2(R)−(1(S),2−ジヒドロキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物149);
6−(2(R)−(1(R)−ヒドロキシベンジル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物150);
6−(2(R)−(1(S)−ヒドロキシベンジル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物151);
6−(2(R)−(1(R)−ヒドロキシベンジル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物152);
6−(2(R)−((2−1,3−ジチアニル)−1(R)−ヒドロキシメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物153);
6−(2(R)−((2−1,3−ジチアニル)−1(59−ヒドロキシメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物154);
6−(2(R)−ジフルオロメチル−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物155);
6−(2(R)−フルオロメチル−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物156);
6−(2(R)−ヒドロキシメチル−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物157);
6−(2(R)−ヒドロキシメチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物158);
6−(2(R)−(1(S)−ヒドロキシエチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物159);
6−(2(R)−(1(R)−ヒドロキシエチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物160);
6−(2(R)−トリフルオロアセチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物161);
6−(2(R)−(1(S)−ヒドロキシペンチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物162);
6−(2(R)−(1(R)−ヒドロキシペンチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物163):
6−(2(R)−(1(R)−ヒドロキシエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物164);
6−(2(R)−(1−ヒドロキシ−1−メチルエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物165);
6−(2(R)−(1(S)−ヒドロキシ−1−シクロプロピルメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物166);
6−(2(R)−(1(R)−ヒドロキシ−1−シクロプロピルメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物167);
6−(2(R)−(1(S)−ヒドロキシプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物168);
6−(2(R)−(1(R)−ヒドロキシプロピル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物169);
6−(2(R)−(1(R)−ヒドロキシプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物170);
6−(2(R)−(1(S)−ヒドロキシプロピル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物171);
6−(2(R)−(1(R)−ヒドロキシ−2−メチルプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物172);
6−(2(R)−(1(R)−ヒドロキシ−2−アセトキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物173);
6−(2(R)−(1(R)−ヒドロキシ−2−クロロエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物174);
6−(2(R)−(2−ヒドロキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物175);
6−(R)−(2−オキソエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物176);
6−(2(R)−アセチルオキシメチル−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物177);
6−(2(R)−(1(R)−クロロ−2−ヒドロキシメチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物178);
6−(2(R)−ヒドロキシメチル−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物179);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物180);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物181);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物182);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物183);
6−(2(R)−(2(S)−ヒドロキシ−3,3,3−トリフルオロプロピル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物184);
6−(2(R)−(2(R)−ヒドロキシ−3,3,3−トリフルオロプロピル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物185);
6−(2(R)−アセチルオキシメチル−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−(2(1H)−キノリノン(化合物186);
6−(2(R)−ヒドロキシエチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物187);
6−(2(R)−ヒドロキシエチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物188);
6−(2(R)−アセチルオキシエチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物189);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物190);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物191);
およびこれらの化合物の何れかの薬学的に許容される塩、エステル、アミドおよび/またはプロドラッグ。
ある合成スキームをここで提供する。この合成スキームは、本発明の化合物を製造する可能性のある方法を説明するためのみに提供し、本発明をいかなる方法でも限定しない。当業者は、本発明の化合が、種々の異なる出発物質を使用して、種々のスキームのいずれかを介して合成できることを認識しよう。スキームIにおいて、R基(例えば、R1、R2など)は、実施例に記した特異的置換パターンに対応する。しかしながら、当業者には、式Iの化合物の示される位置においてここで記載される他の官能基も、スキームI内の構造の同様の1つの可能性のある置換基を構成することは認識されよう。
ある態様において、本発明の化合物は、以前に記載されている“同時トランスフェクション”アッセイ(“cis−trans”アッセイとも呼ばれる)において、アンドロゲン受容体の活性を、調節できる。例えば、Evans et al, Science, 240:889-95(1988);米国特許4,981,784および5,071,773;Pathirana et al., Mol. Pharm. 47:630-35(1995))参照。同時トランスフェクションアッセイにおける調節活性は、インビボ調節活性と相関することが示されている。故に、ある態様において、同時トランスフェクションアッセイは、インビボ活性の予測となる。例えば、Berger et al., J. Steroid Biochem. Molec. Biol. 41:773(1992)参照。
ある態様において、少なくとも1個の選択的アンドロゲン受容体モジュレーター、またはそれらの薬学的に許容される塩、エステル、アミドおよび/またはプロドラッグを、単独で、または1個またはそれ以上の薬学的に許容される担体と組み合わせて、医薬組成物を形成する。本発明の化合物の製剤および投与の技術は、例えば、“Remington's Pharmaceutical Sciences” Mack Publishing Co. , Easton, PA,18th edition, 1990に見ることができる。
ある態様において、1個またはそれ以上の本発明の薬剤を、1個またはそれ以上の他の薬剤と併用投与する。ある態様において、このような1個またはそれ以上の他の薬剤を、本発明の1個またはそれ以上の薬剤と同じ疾患または状態を処置するために設計する。ある態様において、このような1個またはそれ以上の他の薬剤は、本発明の1個またはそれ以上の薬剤と異なる疾患または状態を処置するために設計する。ある態様において、このような1個またはそれ以上の他の薬剤を、本発明の1個またはそれ以上の薬剤の望ましくない作用を処置するために設計する。ある態様において、1個またはそれ以上の本発明の薬剤を、他の薬剤の望ましくない作用を処置するために、他の薬剤と併用投与する。ある態様において、1個またはそれ以上の本発明の薬剤および1個またはそれ以上の他の薬剤を同時に投与する。ある態様において、1個またはそれ以上の本発明の薬剤および1個またはそれ以上の他の薬剤を異なる時点で投与する。ある態様において、1個またはそれ以上の本発明の薬剤および1個またはそれ以上の他の薬剤を共に一つの製剤として製造する。ある態様において、1個またはそれ以上の本発明の薬剤および1個またはそれ以上の他の薬剤を別々に製造する。
ある態様において、本発明は、1個またはそれ以上の本発明の化合物を投与することを含む、患者の処置法を提供する。ある態様において、このような患者はアンドロゲン受容体介在状態に罹患している。ある態様において、患者を、状態の発生を減少または低下するために予防的に処置する。
下記実施例は、実験および得られた結果を含み、説明のためのみに提供するものであり、本発明を限定するものと解釈してはならない。
(R)−6−(2−(2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物101、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =R 9 =トリフルオロメチル、n=0)。
(R)−6−(2−フェニルチオメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物102、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7= R 8= H、R 2 =トリフルオロメチル、R 9 =フェニルチオ、n=0)。
(R)−6−(2−(2,2,2−トリフルオロエチル)−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物103、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5= R 6 =R 7 =R 8= H、R 2 =R 9 =トリフルオロメチル、n=1)
(R)−6−(2−ベンジルオキシメチル)−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物104、スキームIの構造式10、ここで、R 1 =R 3 =R 4= R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =ベンジルオキシ、n=1)。
(R)−6−(2−ジエチルアミノメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物105、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =ジエチルアミノ、n=0)。
6−(2(R)−ヒドロキシメチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物106、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =ヒドロキシル、n=0)。
6−(2(R)−フルオロメチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物107、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 9 =フッ素、n=0)および6−(2(R)−フルオロメチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物108、スキームIの構造式10、ここで、R 1= R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =フッ素、n=0)。
6−(2(R)−ジフルオロmethvl−5(R)−メチル−1−ピロリジン)−4−トリフルオロメチル−2(1H)−キノリノン(化合物109、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 8 =R 9 =フッ素、n=0)および6−(2(R)−フルオロメチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物110、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =R 9 =フッ素、n=0)。
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物111、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 7 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)、6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物112、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 8 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)、6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物113、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =トリフルオロメチル、R 9 =ヒドロキシル、n=0)、および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物114、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 7 =トリフルオロメチル、R 9 =ヒドロキシル、n=0)。
化合物113:1H NMR(500 MHz, CDCl3)11.59(br, 1H), 7.35(d, 1H, J =9.0), 7.28(dd, 1H, J=9.5, 3.0), 7.25(m, 1H), 7.08(s, 1H), 4.04(t, 1H, J= 7.5), 3.79(m, 1H), 3.71(m, 1H), 3.45(s, 1H), 2.32(m, 1H), 2.05(m, 1H), 1.91(m, 1H), 1.72(m, 1H), 1.40(d, 3H, J=6.0);
化合物114:1H NMR(500 MHz, CDCl3)12.20(br, 1H), 7.33(d, 1H, J=9.5), 7.08(dd, 1H, J=9.5および2.5), 6.98(s, 1H), 6.84(m, 1H), 4.39(m, 1H), 4.09(m, 1H), 3.82(m, 1H), 3.42(br, 1H), 2.49(m, 1H), 2.01-2.09(m, 2H), 1.78(m, 1H), 1.32(d, 3H, J=6.5)。
6−(2(R)−(2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物115、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =R 9 =トリフルオロメチル、R 3 =メチル、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−ヒドロキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物116、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 6 =R 7 =H、R 5 =R 9 =ヒドロキシ、R 2 =R 8 =トリフルオロメチル、n=0)および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−ヒドロキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物117、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 6 =R 8 =H、R 5 =R 9 =ヒドロキシ、R 2 =R 7 =トリフルオロメチル、n=0)。
化合物116:1H NMR(CDCl3, 500 MHz)10.70(br, 1H), 7.26-7.30(m, 1H), 7.21(d, 1H, J=9.0), 7.03(m, 1H), 6.99(s, 1H), 5.56(t, 1H, J=5.0), 4.28(m, 2H), 3.80(br, 1H), 3.70(d, 1H, J=12.0), 3.57(dd, 1H, J=12.0および5.5), 2.35(m, 1H), 2.25(d, J=15.0);
6−(2(R)−(1(S)−フルオロ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物118、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 7 =H、R 6 =R 9 =フッ素、R 2 =R 8 =トリフルオロメチル、n=0)および6−(2(R)−(1(R)−フルオロ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物119、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 8 =H、R 6 =R 9 =フッ素、R 2 =R 7 =トリフルオロメチル、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物120、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 6 =R 7 =H、R 5 =メチル、R 9 =ヒドロキシ、R 2 =R 8 =トリフルオロメチル、n=0)、6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物121、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 6 =R 8 =H、R 5 =メチル、R 9 =ヒドロキシ、R 2 =R 7 =トリフルオロメチル、n=0)、6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物122、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 7 =H、R 6 =メチル、R 9 =ヒドロキシ、R 2 =R 8 =トリフルオロメチル、n=0)、および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物123、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 8 =H、R 6 =メチル、R 9 =ヒドロキシ、R 2 =R 7 =トリフルオロメチル、n=0)。
化合物121:1H NMR(500 MHz, CDCl3)12.45(bs, 1H), 7.32(d, 1H, J=9.0), 6.92(dd, 1H, J=2.5, 9.0), 6.87(bs, 1H), 6.69(bs, 1H), 4.54(m, 1H), 4.43(bs, 1H), 4.20(m, 1H), 3.40(m, 1H), 2.93(m, 1H), 2.21(m, 1H), 2.10(m, 1H), 1.80(m, 1H), 1.07(d, 3H, J=6.0);
6−(2(R)−(1(S)−ヒドロyx−2,2,2−トリフルオロエチル)−4(R)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物124、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 6 =R 7 =H、R 5 =メトキシ、R 9 =ヒドロキシ、R 2 =R 8 =トリフルオロメチル、n=0)、6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(R)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物125、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 6 =R 8 =H、R 5 =メトキシ、R 9 =ヒドロキシ、R 2 =R 7 =トリフルオロメチル、n=0)、6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物126、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 8 =H、R 6 =メトキシ、R 9 =ヒドロキシ、R 2 =R 7 =トリフルオロメチル、n=0)および6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−メトキシ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物127、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 7 =H、R 6 =メトキシ、R 9 =ヒドロキシ、R 2 =R 8 =トリフルオロメチル、n=0)。
4−クロロ−6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−2(1H)−キノリノン(化合物128、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 3 =メチル、R 9 =ヒドロキシ、R 2 =塩素、R 8 =トリフルオロメチル、n=0)および4−クロロ−6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−2(1H)−キノリノン(化合物129、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 3 =メチル、R 9 =ヒドロキシ、R 2 =塩素、R 7 =トリフルオロメチル、n=0)。
4−クロロ−6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−2(1H)−キノリノン(化合物130、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 9= ヒドロキシ、R 2 =塩素、R 8 =トリフルオロメチル、n=0)および4−クロロ−6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−2−(1H)−キノリノン(化合物131、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 9 =ヒドロキシ、R 2 =塩素、R 7 =トリフルオロメチル、n=0)。
6−(2(R)−(1(R)−ヒドロキシ−1−メチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物132、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =H、R 3 =R 8 =メチル、R 9 =ヒドロキシ、R 2 =R 7 =トリフルオロメチル、n=0)および6−(2(R)−(1(S)−ヒドロキシ−1−メチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物133、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =H、R 3 =R 7 =メチル、R 9 =ヒドロキシ、R 2 =R 8 =トリフルオロメチル、n=0)。
6−(2(R)−(1−ヒドロキシ−1−トリフルオロメチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物134、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =H、R 3 =メチル、R 9 =ヒドロキシ、R 2 =R 7 =R 8 =トリフルオロメチル、n=0)。
6−(2(R)−1(R)−エトキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物135、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 9 =エトキシ、R 2 =R 7 =トリフルオロメチル、n=0)。
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロメチル)−1−ピロリジニル)−4−プロピル−2(1H)−キノリノン(化合物136、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 9 =ヒドロキシ、R 2 =プロピル、R 7 =トリフルオロメチル、n=0)および6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−プロピル−2(1H)−キノリノン(化合物137、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 9 =ヒドロキシ、R 2 =プロピル、R 8 =トリフルオロメチル、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−エチル−2(1H)−キノリノン(化合物138、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 9 =ヒドロキシ、R 2= エチル、R 8 =トリフルオロメチル、n=0)および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−1−ピロリジニル)−4−エチル−2(1H)−キノリノン(化合物139、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 9 =ヒドロキシ、R 2 =エチル、R 7 =トリフルオロメチル、n=0)。
6−(2(R)−クロロメチル−5−(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物140、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 3 =メチル、R 9 =塩素、R 2 =トリフルオロメチル、n=0)および6−(2(R)−クロロメチル−5−(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物141、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =R 8 =H、R 4 =メチル、R 9 =塩素、R 2 =トリフルオロメチル、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物142、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =フェニル、R 8 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物143、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =フェニル、R 7 =トリフルオロメチル、R 9 =ヒドロキシル、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物144、スキームIの構造式10、ここで、R 1 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =R 4 =メチル、R 8 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物145、スキームIの構造式10、ここで、R 1 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =R 4 =メチル、R 7 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物146、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =フェニル、R 8 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−フェニル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物147、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 7 =トリフルオロメチル、R 9 =ヒドロキシル、n=0。
6−(2(R)−(1(R),2−ジヒドロキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物148、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 8 =ヒドロキシメチル、R 9 =ヒドロキシ、n=0)および6−(2(R)−(1(S),2−ジヒドロキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物149、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 9 =H、R 2 =トリフルオロメチル、R 8 =ヒドロキシメチル、R 7 −ヒドロキシ、n=0)。
6−(2(R)−(1(R)−ヒドロキシベンジル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物150、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 8 =フェニル、R 9 =ヒドロキシ、n=0)、6−(2(R)−(1(S)−ヒドロキシベンジル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物151、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 9 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =フェニル、R 7= ヒドロキシ、n=0)、および6−(2(R)−(1(R)−ヒドロキシベンジル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物152、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =フェニル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−((2−1,3−ジチアニル)−1(R)−ヒドロキシメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物153、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =2−1,3−ジチアン、R 9 =ヒドロキシ、n=0)および6−(2(R)−((2−1、3−ジチアニル)−1(S)−ヒドロキシメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物154、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 9 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =2−1,3−ジチアン、R 7 =ヒドロキシ、n=0)。
6−(2(R)−ジフルオロメチル−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物155、スキームIの構造式10、ここで、R 1 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =R 4 =メチル、R 8 =R 9 =フッ素、n=0)。
6−(2(R)−フルオロメチル−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物156、スキームIの構造式10、ここで、R 1 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =R 4 =メチル、R 9 =フッ素、n=0)。
6−(2(R)−ヒドロキシメチル−5,5−ジメチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物157、スキームIの構造式10、ここで、R 1 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =R 4 =メチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−ヒドロキシメチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物158、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =ヒドロキシ、n=1)。
6−(2(R)−(1(S)−ヒドロキシエチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物159、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 7 =メチル、R 9 =ヒドロキシ、n=1)および6−(2(R)−(1(R)−ヒドロキシエチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物160、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 8 =メチル、R 9 =ヒドロキシ、n=1)。
6−(2(R)−トリフルオロアセチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物161、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =H、R 2 =トリフルオロメチル、R 7 、R 8 =カルボニル、R 9 =トリフルオロメチル、n=1)。
6−(2(R)−(1(S)−ヒドロキシペンチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物162、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 7 =n−ブチル、R 9 =ヒドロキシ、n=1)および6−(2(R)−(1(R)−ヒドロキシペンチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物163、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 8 =n−ブチル、R 9 =ヒドロキシ、n=1)。
6−(2(R)−(1(R)−ヒドロキシエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物164、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =R 8 =メチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1−ヒドロキシ−1−メチルエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物165、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =H、R 2 =トリフルオロメチル、R 3 =R 7 =R 8 =メチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−1−シクロプロピルメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物166、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 7 =シクロプロピル、R 7 =ヒドロキシル、n=0)および6−(2(R)−(1(R)−ヒドロキシ−1−シクロプロピルメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物167、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =シクロプロピル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1(S)−ヒドロキシプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物168、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 7 =エチル、R 9 =ヒドロキシ、n=0)、6−(2(R)−(1(R)−ヒドロキシプロピル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物169、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 8 =エチル、R 9 =ヒドロキシ、n=0)、6−(2(R)−(1(R)−ヒドロキシプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物170、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =エチル、R 9 =ヒドロキシ、n=0)、および6−(2(R)−(1(S)−ヒドロキシプロピル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物171、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 4 =メチル、R 7 =エチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1(R)−ヒドロキシ−2−メチルプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物172、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 8 =イソプロピル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1(R)−ヒドロキシ−2−アセトキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物173、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 8 =アセトキシメチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(1(R)−ヒドロキシ−2−クロロエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物174、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =H、R 2 =トリフルオロメチル、R 8 =クロロメチル、R 9 =ヒドロキシ、n=0)。
6−(2(R)−(2−ヒドロキシエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物175、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =ヒドロキシメチル、n=0)。
6−(2(R)−(2−オキソエチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物176、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =ホルミル、n=0)。
6−(2(R)−アセチルオキシメチル−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物177、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =アセチルオキシ、n=1)。
6−(2(R)−(1(R)−クロロ−2−ヒドロキシメチル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物178、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 7 =ヒドロキシメチル、R 9 =クロロ、n=0)。
6−(2(R)−ヒドロキシメチル−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物179、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =ヒドロキシ、n=1)。
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物180、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 7 =トリフルオロメチル、R 9 =ヒドロキシ、n=1)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物181、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =H、R 2 =クロロジフルオロメチル、R 3 =メチル、R 8 =トリフルオロメチル、R 9 =クロロ、n=0)、6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物182、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 8 =H、R 2 =クロロジフルオロメチル、R 3 =メチル、R 7 =トリフルオロメチル、R 9 =クロロ、n=0)、および6−(2−(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物183、スキームIの構造式10、ここで、R 1 =R 3 =R 5 =R 6 =R 7 =H、R 2 =クロロジフルオロメチル、R 4 =メチル、R 8 =トリフルオロメチル、R 9 =クロロ、n=0)。
6−(2(R)−(2(S)−ヒドロキシ−3,3,3−トリフルオロプロピル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物184、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =1(S)−ヒドロキシ−2,2,2−トリフルオロエチル、n=0)および6−(2(R)−(2(R)−ヒドロキシ−3,3,3−トリフルオロプロピル)−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物185、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 9 =1(R)−ヒドロキシ−2,2,2−トリフルオロエチル、n=0)。
6−(2(R)−アセチルオキシメチル−6(R)−メチル−1−ピペリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物186、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =アセチルオキシメチル、n=1)。
6−(2(R)−ヒドロキシエチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物187、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =ヒドロキシメチル、n=0)および6−(2(R)−ヒドロキシエチル−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物188、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =ヒドロキシメチル、n=0)。
6−(2(R)−アセチルオキシエチル−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物189、スキームIの構造式10、ここで、R 1 =R 4 =R 5 =R 6 =R 7 =R 8 =H、R 2 =トリフルオロメチル、R 3 =メチル、R 9 =アセチルオキシメチル、n=0)。
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物190、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 7 =H、R 2 =トリフルオロメチル、R 6 =フルオロ、R 8 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)および6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−4(S)−フルオロ−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物191、スキームIの構造式10、ここで、R 1 =R 3 =R 4 =R 5 =R 8 =H、R 2 =トリフルオロメチル、R 6 =フルオロ、R 7 =トリフルオロメチル、R 9 =ヒドロキシ、n=0)。
同時トランスフェクションアッセイ
CV−1細胞(アフリカミドリザル腎臓繊維芽細胞)を、10%チャコール樹脂精製(charcoal resin-stripped)ウシ胎児血清添加ダルベッコ改良イーグル培地(DMEM)の存在下で培養し、96ウェルマイクロタイタープレートにトランスフェクションの前日に移した。
LUC応答/β−Gal速度
(式中、β−Gal速度=β−Gal・1×10−5/β−Galインキュベーション時間)。
AR結合:全細胞結合アッセイのために、DMEM−10%FBS含有96ウェルマイクロタイタープレート中のCOS−1細胞を、上記のように、下記のプラスミドDNAでトランスフェクトした:pRShAR(2ng/ウェル)、pRS−β−Gal(50ng/ウェル)およびpGEM(48ng/ウェル)。トランスフェクション6時間後、培地を除去し、細胞をPBSで洗浄し、新鮮な培地を添加した。翌日、培地を無血清DMEMに変え、細胞中の受容体と結合するはずである何らかの内因性リガンドを除いた。
IC 50
Ki=(1+[3H−DHT])/3H−DHTのKd
である。
錠剤を下記の成分を使用して製造する:
各々60mgの活性成分を含む錠剤を、下記の通り製造する:
Claims (6)
- 式I:
R1は、水素であり;
R2は、F、Cl、Br、CH 3 、C 2 H 5 、CH 2 F、CHF 2 、CF 3 、C 2 F 5 またはCF 2 Clであり;
R3は、C1−C4 アルキルであり;
R4は、水素であり;
R5およびR6は、水素であり;
R7 は、C 1 −C 2 アルキルまたはC 1 −C 2 ハロアルキルであり、そしてR8は、水素、C1−C 2 アルキルまたはC1−C 2 ハロアルキルであるか;または
R 7 は水素、C 1 −C 2 アルキルまたはC 1 −C 2 ハロアルキルであり、そしてR 8 は、C 1 −C 2 アルキルまたはC 1 −C 2 ハロアルキルであり;
R9は、OR10 であり;
R10は、水素であり;そして
n=0である。〕
の化合物。 - R2が、Cl、CH2F、CHF2、CF3、C2F5およびCF2Clからなる群から選択され;
R3が、Cl−C2アルキルであり;
R 7 が、CH3、CF3、C2F5 またはCF2Clであり、そしてR 8 が、水素、CH 3 、CF 3 、C 2 F 5 またはCF 2 Clであるか;または
R 7 が、水素、CH 3 、CF 3 、C 2 F 5 またはCF 2 Clであり、そしてR 8 が、CH 3 、CF 3 、C 2 F 5 またはCF 2 Clである、
請求項1記載の化合物。 - R2が、Cl、CH2F、CHF2、CF3またはCF2Clであり;
R3が、CH3であり;そして
R 7 が、CH3、CF3またはCF2Clであり、そしてR 8 が、水素、CH 3 、CF 3 またはCF 2 Clであるか;または
R 7 が、水素、CH 3 、CF 3 またはCF 2 Clであり、そしてR 8 が、CH 3 、CF 3 またはCF 2 Clである、
請求項2記載の化合物。 - R2が、Cl、CH2F、CHF2、またはCF3であり;そして
R 7 が、CH3またはCF3であり、そしてR 8 が、水素、CH 3 またはCF 3 であるか;または
R 7 が、水素、CH 3 またはCF 3 であり、そしてR 8 が、CH 3 またはCF 3 である、
請求項3記載の化合物。 - 化合物が:
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物111);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物112);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物113);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物114);
4−クロロ−6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−2(1H)−キノリノン(化合物128);
4−クロロ−6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−2(1H)−キノリノン(化合物129);
6−(2(R)−(1(R)−ヒドロキシ−1−メチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物132);
6−(2(R)−(1(S)−ヒドロキシ−1−メチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物133);
6−(2(R)−(1−ヒドロキシ−1−トリフルオロメチル−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物134);
6−(2(R)−(1(R)−ヒドロキシエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物164);
6−(2(R)−(1−ヒドロキシ−1−メチルエチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物165);
6−(2(R)−(1(S)−ヒドロキシ−1−シクロプロピルメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物166);
6−(2(R)−(1(R)−ヒドロキシ−1−シクロプロピルメチル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物167);
6−(2(R)−(1(S)−ヒドロキシプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物168);
6−(2(R)−(1(R)−ヒドロキシプロピル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物169);
6−(2(R)−(1(R)−ヒドロキシプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物170);
6−(2(R)−(1(S)−ヒドロキシプロピル)−5(S)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物171);
6−(2(R)−(1(R)−ヒドロキシ−2−メチルプロピル)−5(R)−メチル−1−ピロリジニル)−4−トリフルオロメチル−2(1H)−キノリノン(化合物172);
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物181);
6−(2(R)−(1(R)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(R)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物182);および
6−(2(R)−(1(S)−ヒドロキシ−2,2,2−トリフルオロエチル)−5(S)−メチル−1−ピロリジニル)−4−クロロジフルオロメチル−2(1H)−キノリノン(化合物183);
から選択される、請求項1記載の化合物。 - 医薬として使用するための、請求項1ないし5のいずれか一項記載の化合物。
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EP (1) | EP1656142A4 (ja) |
JP (2) | JP4709759B2 (ja) |
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- 2004-08-23 BR BRPI0413820-1A patent/BRPI0413820A/pt not_active Application Discontinuation
- 2004-08-23 JP JP2006524121A patent/JP4709759B2/ja not_active Expired - Fee Related
- 2004-08-23 WO PCT/US2004/027483 patent/WO2005018573A2/en active Application Filing
- 2004-08-23 MX MXPA06001751A patent/MXPA06001751A/es not_active Application Discontinuation
- 2004-08-23 EP EP04782052A patent/EP1656142A4/en not_active Withdrawn
- 2004-08-23 CN CNA2004800241252A patent/CN1838956A/zh active Pending
- 2004-08-23 US US10/566,569 patent/US7816372B2/en not_active Expired - Fee Related
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BRPI0413820A (pt) | 2006-10-24 |
CA2536349A1 (en) | 2005-03-03 |
WO2005018573A2 (en) | 2005-03-03 |
JP2007503398A (ja) | 2007-02-22 |
AU2004266160A1 (en) | 2005-03-03 |
MXPA06001751A (es) | 2006-05-12 |
CN1838956A (zh) | 2006-09-27 |
US7816372B2 (en) | 2010-10-19 |
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