JP6114815B2 - 肝臓xレセプターモジュレーター - Google Patents
肝臓xレセプターモジュレーター Download PDFInfo
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- JP6114815B2 JP6114815B2 JP2015500603A JP2015500603A JP6114815B2 JP 6114815 B2 JP6114815 B2 JP 6114815B2 JP 2015500603 A JP2015500603 A JP 2015500603A JP 2015500603 A JP2015500603 A JP 2015500603A JP 6114815 B2 JP6114815 B2 JP 6114815B2
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- Prior art keywords
- isopropyl
- methylsulfonyl
- mmol
- mixture
- trifluoromethyl
- Prior art date
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- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Description
本出願は、2012年3月16日に出願された米国特許仮出願第61/612,063号の出願日の利益を主張し、その内容全体を参照により本明細書に組み込む。
対象においてコレステロール逆輸送を促進し且つ肝臓脂質生成を抑制するための、並びにアテローム性動脈硬化症及び脂質異常症を含めた疾患又は障害を予防、回復又は治療するための治療薬として有用であるLXRモジュレーターが開示される。開示されるLXRモジュレーターは、LXRαサブタイプよりもLXRβサブタイプに対して選択的である(例えば、実施例6、アイソマー1;実施例7、アイソマー1;及び実施例13、アイソマー1を参照されたい)。
XはN又はCRcである。
R1はアルキル又は−NRaRbである。
Ra及びRbは独立にH、アルキルであり、又はRa及びRbは、それらが結合している窒素と一緒になって、単環式非芳香族複素環を形成することができる。
本発明の別の態様は、本発明の化合物及び医薬的に許容される担体又は希釈剤を含む医薬組成物である。
XはN又はCRcである。
R10はアルキル又は−NRaRbである。
Ra及びRbは独立にH、アルキルであり、又はRa及びRbは、それらが結合している窒素と一緒になって、単環式非芳香族複素環を形成することができる。
本明細書で提供する本発明の化合物(複数可)(又はその調製で使用する中間体(複数可))は、中性型及び医薬的に許容されるその塩の両方を含む。
R3はアルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、シクロアルキル又はフェニルであり、R3によって表されるフェニル基は、アルキル、ハロゲン、ハロアルキル、アルコキシ、ハロアルコキシ、ニトロ及び−CNから選択される1つ又は複数の基で置換されていてもよい。
R6はH、ハロゲン、−CN、−OR、−SR、−N(R)2、−C(O)R、−C(O)OR、−OC(O)O(アルキル)、−C(O)O(ハロアルキル)、−OC(O)R、−C(O)N(R)2、−OC(O)N(R)2、−NRC(O)R、−NRC(O)O(アルキル)、−S(O)R、−SO2R、−SO2N(R)2、−NRS(O)R、−NRSO2R、−NRC(O)N(R)2、−NRSO2N(R)2、ハロアルキル、ハロアルコキシ、シクロアルコキシ、シクロアルキル又はアルキルであり、R6によって表されるアルキル基は、−CN、−OR、−SR、−N(R)2、=O、−C(O)R、−C(O)OR、−C(O)O(ハロアルキル)、−OC(O)R、−OC(O)O(アルキル)、−C(O)N(R)2、−OC(O)N(R)2、−NRC(O)R、−NRC(O)O(アルキル)、−S(O)R、−SO2R、−SO2N(R)2、−NRS(O)R、−NRSO2R、−NRC(O)N(R)2及び−NRSO2N(R)2から選択される1つ又は複数の基で置換されていてもよい。
R1はメチル又は−NH2である。
残りの変数についての値は、式Iについて又は第1の代替実施形態について定義した通りである。
式VIIIからXの中間化合物の第2の代替実施形態では、R20は−CH2OH、−CH2O(保護基)、−COOH又は−C(O)O(アルキル)である。残りの変数についての値は、式Iaについて、又は式VIIIからXについての第1の代替実施形態で定義した通りである。
式VIIIからXの中間化合物の第6の代替実施形態では、中間化合物は、
B.定義
別段の指定がない限り、本明細書で使用する以下の用語は次のように定義される。
「アルキル」は、鎖中に1から15個の炭素原子を有する直鎖状又は分枝状の炭化水素基を意味する。一実施形態では、アルキル基は、鎖中に1から12個の炭素原子を有する。別の実施形態では、アルキル基は、1から6個の炭素原子を有する。例示的なアルキル基としては、これらに限定されないが、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、tert−ブチル、sec−ブチル、n−ペンチル、3−ペンチル、ヘプチル、オクチル、ノニル、デシル及びドデシルが挙げられる。
「アルコキシアルキル」は、アルキルリンカーを介して別の部分に結合しているアルコキシ基である。「ヒドロキシアルキル」又は「ジヒドロキシアルキル」は、アルキルリンカーを介して別の部分に結合している、それぞれ1又は2個のヒドロキシ基である。代表的な、「ヒドロキシアルキル」又は「ジヒドロキシアルキル」としては、−CH2OH、−CH(OH)(CH2)(OH)、−C(OH)(CH3)2、−CH(OH)(CH3)、−CH(OH)(CH2)(CH3)、−CH(OH)(CH2)2(CH3)、−C(CH3)2(OH)などが挙げられる。
「単環式非芳香族複素環」は、単一の飽和複素環を意味し、典型的には3から10員、より典型的には3から7員を環に有し、環の中の少なくとも1つの原子はヘテロ原子、例えば、窒素、酸素、硫黄(スルホキシド及びスルホンを含む)などである。3から4員の単環式非芳香族複素環は2個までのヘテロ原子を含むことができ、5から6員の単環式複素環は、3個までのヘテロ原子を含むことができ、7から10員の単環式非芳香族複素環は、4個までのヘテロ原子を含むことができる。単環式非芳香族複素環は、単環式非芳香族複素環の任意のヘテロ原子又は炭素原子を介して別の基に結合していてもよい。代表的な単環式非芳香族複素環としては、モルホリニル、チオモルホリニル、ピロリジノニル、ピロリジニル、ピペリジニル、ピペラジニル、イミダゾリジニル、ピラゾリジニル、オキサゾリジニル、イソチアゾリジニル、ヒダントイニル、バレロラクタミル、オキシラニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、テトラヒドロピリンジニル、テトラヒドロピリミジニル、テトラヒドロチオフェニル、テトラヒドロチオピラニルなどが挙げられる。一実施形態では、単環式非芳香族複素環は、4、5、6又は7員の複素環である。
一実施形態では、本発明の化合物及び医薬的に許容される担体又は希釈剤を含む医薬組成物を本明細書で提供する。
経鼻投与については、本発明の化合物は、エアゾール剤、滴剤、ゲル剤及び粉末剤として製剤化することができる。エアゾール剤は、生理学的に許容される水性又は非水性溶媒中に、活性物質の溶液又は微細懸濁液を典型的には含み、密閉容器中に滅菌した形態で、単回又は多回用量で通常提供され、噴霧装置と共に使用するためにカートリッジ又はリフィルの形態をとってもよい。あるいは密閉容器は、例えば、使用後に処分することが企図された定量バルブが装着された単回用量の鼻吸入器又はエアゾールディスペンサーなどの単位分配装置(unitary dispensing device)でもよい。剤形がエアゾールディスペンサーを含む場合は、それは噴霧剤を含み、噴霧剤は圧縮空気などの圧縮ガス又はフルオロクロロ炭化水素などの有機噴霧剤でもよい。エアゾール剤形は、ポンプ噴霧器の形態をとってもよい。
本発明の化合物の局所及び/又は局部投与は、種々の方法で達成することができ、その方法には、これらに限定されないが、軟膏剤、ローション剤、ペースト剤、クリーム剤、ゲル剤、粉末剤、滴剤、スプレー剤、液剤、吸入剤、パッチ剤、坐剤、停留浣腸、咀しゃく又は舐めることが可能な錠剤又はペレット剤及びエアゾール剤が含まれる。局所及び/又は局部投与は、経皮パッチ又はイオン導入装置(iontophoresis device)などの経皮投与の使用を含んでもよい。局所及び/又は局部投与については、本発明の化合物は、軟膏剤、クリーム剤、乳剤、膏薬、粉末剤、含浸パッド、合成洗剤、液剤、ゲル剤、スプレー剤、フォーム剤、懸濁剤、ローション剤、スティック剤、洗髪剤又は洗浄基剤として製剤化することができる。本発明の化合物は、制御放出のために、脂質小胞若しくはポリマー小胞又はナノスフェア若しくはマイクロスフェア又はポリマーパッチの懸濁剤及びハイドロゲルの形で投与してもよい。
LXRのモジュレーションによって治療可能な疾患又は障害を有する対象の治療方法を本明細書で提供する。一実施形態では、LXRは、LXR活性をアップレギュレートすることによってモジュレートされる。この方法は、有効量の本発明の化合物を投与することを含む。さらに、その医薬を必要とする対象におけるLXR活性をアップレギュレートすることによって治療可能な疾患又は障害を有する対象を治療するための医薬の製造のための本発明の化合物の使用を、本明細書で提供する。
本発明の化合物は、異常なコレステロール輸送、コレステロール逆輸送、脂肪酸代謝、コレステロール吸収、コレステロール再吸収、コレステロール分泌、コレステロール排出又はコレステロール代謝に付随する疾患又は障害の治療又は予防に有用である。代表的な疾患又は障害としては、これらに限定されないが、脂質障害;癌、特に卵巣癌、乳癌及び前立腺癌を含めたホルモン依存性癌;ざ瘡様皮膚状態;皮膚炎症性疾患;免疫障害;表皮性バリア機能の撹乱に特徴付けられる状態;表皮若しくは粘膜の分化が乱れた状態又は表皮若しくは粘膜の過剰増殖状態;心血管疾患;生殖器系障害;視神経及び網膜の病態;疾患において起こる変性神経障害;自己免疫疾患;中枢神経系若しくは末梢神経系への外傷性損傷;又は神経変性疾患;老化による変性過程;腎臓の疾患若しくは障害;及び骨粗鬆症並びに関連疾患が挙げられる。
本発明はまた、高密度リポタンパク質(HDL)コレステロールレベルを増大させる必要性に関係がある疾患又は障害を治療する方法であって、有効量の本発明の化合物を、それらを必要とする哺乳動物(特にヒト)に投与することを含む方法を提供する。
合成方法の概要
本発明の化合物は、容易に利用可能な出発材料、試薬及び従来の合成方法を使用して、以下の反応スキーム及び実施例又はそれらの改変に従って、容易に調製することができる。反応の多くは、マイクロ波条件下で、又は従来の加熱を使用して、又は固相試薬/スカベンジャー若しくはフローケミストリーなどの他の技術を利用して行うこともできる。こうした反応では、それ自身当業者に知られている変異型を使用することも可能であるが、さらに詳細には言及しない。さらに、本発明の化合物を調製するための他の方法は、以下の反応スキーム及び実施例を考慮すれば、当業者に容易に明らかになるであろう。合成の中間体及び最終生成物が所望の反応を妨げる可能性がある潜在的に反応性の官能基、例えば、アミノ基、ヒドロキシ基、チオール基及びカルボン酸基を含む場合は、中間体の保護形態を用いるのが有利であり得る。保護基の選択、導入、及び引き続く除去の方法は当業者に周知である。以下の議論では、X、R1、R2、R3、R4、R5及びR6は、別段指示がない限り、上で示された意味を有する。これらの実験の詳細で使用される略称は以下に列挙され、さらなる略称は合成分野の当業者に知られているはずである。さらに、以下の参考文献、March、Advanced Organic Chemistry、第3版、John Wiley&Sons、1985、Greene及びWuts、Protective Groups in Organic Synthesis、第2版、John Wiley&Sons、1991、並びにRichard Larock、Comprehensive Organic Transformations、第4版、VCH publishers Inc.、1989に記載されているような適切な合成方法について参照することができる。
方法1(10〜80、2分)
HPLCシステム:Waters ACQUITY;カラム:Waters ACQUITY CSH(商標)C18 1.7μM Guardカラム:Waters Assy.Frit、0.2μM、2.1mm;カラム温度:40℃。
時間(分) B%、
0 10
0.8 90
1.20 90
1.21 10
質量分析計のパラメーター
質量分析計:Waters SQD;イオン化:ポジティブエレクトロスプレーイオン化(ESI);モードスキャン(0.2秒毎に100〜1400m/z);ESキャピラリー電圧:3.5kv;ESコーン電圧:25vソース温度:120℃;脱溶媒和(Disolvation)温度:500℃;脱溶媒和ガス流:窒素設定650(L/hr);コーンガス流:窒素設定50(L/hr)。
方法A:
機器:Thar SFC80;カラム:AD 250mm*30mm、5μm;移動相:A:超臨界CO2、B:IPA(0.05%DEA)、60ml/minでA:B=80:20;カラム温度:38℃;ノズル圧力:100バール;ノズル温度:60℃;蒸発器温度:20℃;トリマー温度:25℃;波長:220nm。
機器:SFC MG2;カラム:OJ 250mm*30mm、5μm;移動相:A:超臨界CO2、B:MeOH(0.05%DEA)、70ml/minでA:B=90:10;カラム温度:38℃;ノズル圧力:100バール ノズル温度:60℃;蒸発器温度:20℃;トリマー温度:25℃;波長:220nm。
分析的キラルHPLC
本発明の化合物のキラル純度は、分析的キラルHPLCによって決定し、これは、Chiralcel(登録商標)カラム又はChiralpak(登録商標)カラムを使用して、溶出液としての、0.05%DEAを含有する5%から40%のメタノール、エタノール又はイソプロパノールと共に、CO2を使用して行った。
X=Nの場合は、式2の中間体は、式3aの中間体を環化し、それに続いて、G2が水素でない場合にG2を除去することによって、調製することができる。G2はアミン保護基、例えばBoc、Cbz及びトリフルオロアセタミドなどである。
調製1
Tert−ブチル1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−カルボキシレート
ステップ3:
ステップ4:
ステップ5:
調製2
(R)−2−tert−ブチル8−メチル1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2,8(1H)−ジカルボキシレート
ステップ2:
ステップ3:
ステップ4:
ステップ5:
ステップ6:
ステップ8:
ステップ9:
調製3
1−イソプロピル−7−(メチルチオ)−1,2,3,4−テトラヒドロピラジノ[1,2−a]インドール
ステップ2:
LC-MS MS (ESI) m/z 304.0 [M + H]+.1H NMR (CDCl3 400MHz): δ 7.93-7.75 (m, 3H), 7.58-7.41 (m, 5H), 7.17 (dd, J1 = 8.0Hz, J2 = 1.6Hz, 1H), 6.63-6.60 (m, 1H), 2.53 (s, 3H).
ステップ3:
ステップ4:
ステップ5:
調製4
8−(((tert−ブチルジフェニルシリル)オキシ)メチル)−(1−イソプロピル−7−(メチルスルホニル)−2−(4−(トリフルオロメチル)ピリミジン−2−イル)−1,2,3,4−テトラヒドロピラジノ[1,2−a]インドール
ステップ2:
ステップ4:
ステップ5:
ステップ6:
ステップ7:
ステップ8:
調製5
1−(2−クロロ−4−(トリフルオロメチル)ピリミジン−5−イル)エタノン
方法1:
方法2:
化合物(E)−1−(2−アセチル−4,4,4−トリフルオロ−3−オキソブタ−1−エン−1−イル)尿素(55g、0.25mol)及びPOCl3(240.7g、1.57mol)の混合物を、100℃で3時間撹拌した。この混合物を水(1.5L)に室温で滴下し、EtOAc(3×500mL)で抽出した。合わせた有機層をブラインで洗浄し(500mL)、無水Na2SO4で脱水し、濾過し、濃縮した。残留物を、PE/EtOAc3/1で溶出するカラムクロマトグラフィーによって精製して、淡黄色の油として、化合物1−(2−クロロ−4−(トリフルオロメチル)ピリミジン−5−イル)エタノン(23.5g、収率42.7%)を得た。1H NMR (CDCl3 300MHz):δ8.80 (s, 1H), 2.58 (s, 3H).
19F NMR (920-083-1A CDCl3 400MHz):δ-65.5 ppm. 13C NMR (903-158-1A CDCl3400MHz):δ195.9, 162.3, 160.1, 153.8 (dd, J=50Hz), 130.9, 119.5 (dd, J=366Hz), 30.7.
1−(2−クロロ−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−1−オン及び1−(2−クロロ−4−(トリフルオロメチル)ピリミジン−5−イル)ブタン−1−オン
調製6
5−ブロモ−2−クロロ−4−(トリフルオロメチル)ピリミジン
標記化合物は、Ondi,L.ら、Eur.J.Org.Chem.2004、3714に基づく改変方法を使用して調製した。
アイソマー1は、以下の方法に従って、塩酸塩として再結晶化することができる。
LC-MS m/z 528 [M+H]+. 1H NMR (400MHz, CD3OD):δ8.95 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 6.28 (d, J=8.0Hz, 1H), 5.43 (dd, J1=14.4Hz, J2=4.8Hz, 1H), 5.15 (s, 2H), 4.70 (dd, J1=12.8Hz, J2=3.6Hz, 1H), 4.34 (td, J1=12.0Hz, J2=4.8Hz, 1H), 3.92 (dddd, J1=14.4Hz, J2=12.8Hz, J3=4.8Hz, 1H), 3.26 (s, 3H), 2.70-2.62 (m, 1H), 1.60 (s, 6H), 1.31 (d, J=6.8Hz, 3H), 1.13 (d, J=6.8Hz, 3H).
アイソマー2:(S)−2−(2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−2−オール。分析的キラルHPLC:15分のクロマトグラフィーでtR=6.680分(方法:OD−H_3_5_40_2.35ML)。LC-MS MS (ESI) m/z 528.2 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.87 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.03 (d, J=8.0Hz, 1H), 5.31 (dd, J=4.4及び14.0Hz, 1H), 5.09 (s, 2H), 4.51-4.47 (m, 1H), 4.23-4.16 (m, 1H), 3.91-3.83 (m, 1H), 3.25 (s, 3H), 2.60-2.51 (m, 1H), 1.59 (s, 6H), 1.26 (d, J=6.8Hz, 3H), 1.05 (d, J=6.8Hz, 3H).
あるいは、2−(2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−2−オールのラセミ混合物(mxture)を以下の方法によって調製した。
LC-MS MS (ESI) m/z 556.0 [M+H]+. 1H NMR (CD3OD, 400MHz):δ8.88 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 6.05 (d, J=8.0Hz, 1H), 5.32 (dd, J=4.8及び14.0Hz, 1H), 4.53 (dd, J=3.2及び12Hz, 1H), 4.27-4.20 (m, 1H), 3.95 (s, 3H), 3.90-3.83 (m, 1H), 3.41 (s, 3H), 2.61-2.52 (m, 1H), 1.59 (s, 6H), 1.27 (d, J=6.8Hz, 3H), 1.06 (d, J=6.8Hz, 3H).
(R)−メチル−2−(5−(2−ヒドロキシプロパン−2−イル)−4−(トリフルオロメチル)ピリミジン−2−イル)−1−イソプロピル−7−(メチルスルホニル)−1,2,3,4−テトラヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−8−カルボキシレート(109mg、0.196mmol)をDCM(4mL)に入れた溶液に、DIBAL−HをDCM(0.98mLの1.0M溶液、0.98mmol)に入れた溶液を−78℃で滴下した。反応を約1時間かけてゆっくりと−10℃まで温め、その時点で1mLのMeOHを加えて、過剰なDIBAL−Hをクエンチした。飽和ロッシェル塩(酒石酸カリウムナトリウム(KNaC4H4O6))水溶液(5mL)及びDCM(5mL)を加え、この混合物を勢いよく15分間撹拌した。DCM層を分離し、水性層をDCM(2×5mL)で抽出した。DCM層を混合し、Na2SO4を使用して乾燥させ、蒸発させて、粗生成物を得た。70%EtOAcのヘキサンで溶出するISCO FCCを使用して精製して、71mgの2−(2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−2−オールをラセミ混合物(69%)として得た。LC-MS MS (ESI) m/z 528.25 [M+H]+. 1H NMR (CDCl3, 400MHz):δ8.72 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 6.01 (d, J=7.6Hz, 1H), 5.27 (d, J=4.4及び14.0Hz, 1H), 5.00-4.86 (m, 2H), 4.26-4.08 (m, 2H), 3.74-3.67 (m, 1H), 3.15(s, 3H), 3.15-3.10 (m, 1H), 2.47-2.40 (m, 1H), 1.96 (b, 1H), 1.59 (s, 6H), 1.23 (d, J=6.8Hz, 3H), 1.10 (d, J=6.8Hz, 3H).
2−(2−クロロ−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−2−オールは、以下のように調製した。
分析的キラルHPLC:15分のクロマトグラフィーでtR=8.397分(方法:OD−H_5_5_40_2.35ML)。LC-MS MS (ESI) m/z 514.1 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.89 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 6.03 (d, J=8.0Hz, 1H), 5.32 (dd, J=4.4及び14.4Hz, 1H), 5.11-5.08 (m, 3H), 4.50-4.46 (m, 1H), 4.28-4.16 (m, 1H), 3.90-3.83 (m, 1H), 3.24 (s, 3H), 2.72-2.39 (m, 1H), 1.42 (d, J=6.4Hz, 3H), 1.26 (d, J=6.8Hz, 3H), 1.04 (d, J=6.8Hz, 3H).
アイソマー2
分析的キラルHPLC:15分のクロマトグラフィーでtR=6.700分(方法:AS−H_5_5_40_2.35ML)。LC-MS MS (ESI) m/z 514.1 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.89 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.03 (d, J=8.0Hz, 1H), 5.32 (dd, J=4.4及び14.4Hz, 1H), 5.11-5.08 (m, 3H), 4.50-4.46 (m, 1H), 4.23-4.16 (m, 1H), 3.95-3.79 (m, 1H), 3.25 (s, 3H), 2.59-2.51 (m, 1H), 1.42 (d, J=6.0Hz, 3H), 1.26 (d, J=6.4Hz, 3H), 1.04 (d, J=6.4Hz, 3H).
アイソマー3
分析的キラルHPLC:15分のクロマトグラフィーでtR=7.666分(方法:AS−H_5_5_40_2.35ML)。LC-MS MS (ESI) m/z 514.2 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.89 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.03 (d, J=8.0Hz, 1H), 5.32 (dd, J=4.0及び14.0Hz, 1H), 5.11-5.08 (m, 3H), 4.51-4.47 (m, 1H), 4.24-4.15 (m, 1H), 3.91-3.84 (m, 1H), 3.25 (s, 3H), 2.61-2.43 (m, 1H), 1.42 (d, J=6.0Hz, 3H), 1.26 (d, J=6.8Hz, 3H), 1.05 (d, J=6.8Hz, 3H).
アイソマー4
分析的キラルHPLC:15分のクロマトグラフィーでtR=9.621分(方法:OD−H_5_5_40_2.35ML)。LC-MS MS (ESI) m/z 514.1 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.89 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.03 (d, J=8.0Hz, 1H), 5.32 (dd, J=4.0及び14.0Hz, 1H), 5.11-5.08 (m, 3H), 4.50-4.23 (m, 1H), 4.23-4.15 (m, 1H), 3.91-3.80 (m, 1H), 3.25 (s, 3H), 2.59-2.51 (m, 1H), 1.42 (d, J=6.4Hz, 3H), 1.26 (d, J=6.8Hz, 3H), 1.05 (d, J=6.8Hz, 3H).
アイソマー2:(S)−1−(2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−1−オン。分析的キラルHPLC:15分のクロマトグラフィーでtR=8.40分(方法:OJ−H_3_5_40_2.5ML)。LC-MS m/z 526.1 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.93 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.15-6.01 (m, 1H), 5.47-5.31 (m, 1H), 5.09 (s, 2H), 4.53 (dd, J=4.0及び12.0Hz, 1H), 4.24 (dt, J=4.8及び12.0Hz, 1H), 3.97-3.90 (m, 1H), 3.24 (s, 3H), 2.92 (q, J=6.8Hz, 2H), 2.60-2.55 (m, 1H), 1.28 (d, J=6.8Hz, 3H), 1.14 (t, J=7.2Hz, 3H), 1.07 (d, J=6.8Hz, 3H).
アイソマー2:白色固体。分析的キラルHPLC:15分のクロマトグラフィーでtR=7.502分(方法:OD−H_3_5_40_2.35ML)。LC-MS m/z 528.2 [M+H]+. 1H NMR (CDCl3 400MHz):δ8.82 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 6.10 (d, J=7.6Hz, 1H), 5.39-5.34 (m, 1H), 5.05-5.02 (m, 2H), 4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.16 (m, 1H), 3.82-3.74 (m, 1H), 3.22 (s, 3H), 3.10 (t, J=6.8Hz, 1H), 2.52-2.49 (m, 1H), 2.01-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.30 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8Hz, 3H), 0.99 (t, J=7.2Hz, 3H).
アイソマー3:白色固体。分析的キラルHPLC:15分のクロマトグラフィーでtR=5.173分(方法:OJ−H_3_5_40_2.35ML)。LC-MS m/z 528.2 [M+H]+. 1H NMR (CDCl3400MHz):δ8.81 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 6.10 (d, J=7.6Hz, 1H), 5.38-5.34 (m, 1H), 5.05-5.02 (m, 2H), 4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.17 (m, 1H), 3.82-3.76 (m, 1H), 3.23 (s, 3H), 3.07 (t, J=6.8Hz, 1H), 2.52-2.50 (m, 1H), 1.94-1.93 (m, 1H), 1.80-1.75 (m, 2H), 1.31 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8Hz, 3H), 0.99 (t, J=7.2Hz, 3H).
アイソマー4:白色固体。分析的キラルHPLC:15分のクロマトグラフィーでtR=5.817分(方法:OJ−H_3_5_40_2.35ML)。LC-MS m/z 528.2 [M+H]+. 1H NMR (CDCl3400MHz):δ8.81 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 6.10 (d, J=8.0Hz, 1H), 5.38-5.35 (m, 1H), 5.05-5.04 (m, 2H), 4.98-4.90 (m, 1H), 4.34-4.30 (m, 1H), 4.21-4.18 (m, 1H), 3.81-3.76 (m, 1H), 3.23 (s, 3H), 3.06 (t, J=6.4Hz, 1H), 2.52-2.50 (m, 1H), 1.94-1.93 (m, 1H), 1.81-1.75 (m, 2H), 1.31 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8Hz, 3H), 0.99 (t, J=7.2Hz, 3H).
アイソマー2:分析的キラルHPLC:15分のクロマトグラフィーでtR=10.264分(方法:OD−H_3_5_40_2.35ML)。LC-MS MS (ESI) m/z 542.1 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.87 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 6.06 (d, J=8.0Hz, 1H), 5.36-5.33 (m, 1H), 5.14 (s, 2H), 4.54-4.51 (m, 1H), 4.27-4.20 (m, 1H), 3.94-3.86 (m, 1H), 3.29 (s, 3H), 2.60-2.52 (m, 1H), 1.78-1.71 (m, 1H), 1.60-1.49 (m, 2H), 1.43-1.26 (m, 5H), 1.08 (d, J=6.8Hz, 3H), 0.96 (t, J=6.8Hz, 3H).
アイソマー2:(S)−(2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)メタノール。分析的キラルHPLC:15分のクロマトグラフィーでtR=8.340分(方法:AD−H_5_5_40_2.35ML)。LC-MS MS (ESI) m/z 500.1 [M+H]+. 1H NMR (CD3OD 400MHz):δ8.73 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.04 (d, J=8.4Hz, 1H), 5.33 (dd, J=4.8及び14.4Hz, 1H), 5.09 (s, 2H), 4.63 (s, 2H), 4.52-4.45 (m, 1H), 4.24-4.17 (m, 1H), 3.91-3.84 (m, 1H), 3.25 (s, 3H), 2.68-2.46 (m, 1H), 1.26 (d, J=6.8Hz, 3H), 1.05 (d, J=6.8Hz, 3H).
アイソマー2:(S)−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−カルボン酸。分析的キラルHPLC:15分のクロマトグラフィーでtR=8.468分(方法:OJ−H_3_5_40_2.35ML)。LC-MS MS (ESI) m/z 514.0 [M+H]+. 1H NMR (CD3OD 400MHz):δ9.02 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 6.20-6.15 (m, 1H), 5.50-5.35 (m, 1H), 5.12 (s, 2H), 4.60-4.50 (m, 1H), 4.35-4.20 (m, 1H), 4.03-3.89 (m, 1H), 3.28 (s, 3H), 2.70-2.50 (m, 1H), 1.30 (d, J=6.8Hz, 3H), 1.08 (d, J=6.8Hz, 3H).
アイソマー2:(S)−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−カルボキサミド。
アイソマー1:(R)−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−N−メチル−4−(トリフルオロメチル)ピリミジン−5−カルボキサミド。分析的キラルHPLC:15分のクロマトグラフィーでtR=6.355分(方法:AS−H_3_5_40_2.35ML)。LC-MS MS (ESI) m/z 548.9 [M+Na]+. 1H NMR (CD3OD 400MHz):δ8.68 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 6.14-6.00 (m, 1H), 5.45-5.30 (m, 1H), 5.13 (s, 2H), 4.60-4.50 (m, 1H), 4.30-4.18 (m, 1H), 4.00-3.86 (m, 1H), 3.30 (s, 3H), 2.90 (s, 3H), 2.66-2.51 (m, 1H), 1.31 (d, J=6.8Hz, 3H), 1.15 (d, J=6.8Hz, 3H).
アイソマー2:(S)−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−N−メチル−4−(トリフルオロメチル)ピリミジン−5−カルボキサミド。分析的キラルHPLC:15分のクロマトグラフィーでtR=6.486分(方法:AS−H_3_5_40_2.35ML)。LC-MS MS (ESI) m/z 549.0 [M+Na]+. 1H NMR (CD3OD 400MHz):δ8.68 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 6.14-6.00 (m, 1H), 5.45-5.30 (m, 1H), 5.13 (s, 2H), 4.62-4.52 (m, 1H), 4.32-4.20 (m, 1H), 4.02-3.87 (m, 1H), 3.30 (s, 3H), 2.91 (s, 3H), 2.67-2.51 (m, 1H), 1.31 (d, J=6.8Hz, 3H), 1.11 (d, J=6.8Hz, 3H).
アイソマー1:(R)−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−N,N−ジメチル−4−(トリフルオロメチル)ピリミジン−5−カルボキサミド。分析的キラルHPLC:8分のクロマトグラフィーでtR=3.649分(方法:AS−H_S_3_5_40_3ML)。LC-MS MS (ESI) m/z 563.1 [M+Na]+. 1H NMR (CD3OD 400MHz):δ8.62 (s, 1H), 8.23 (d, J=6.4Hz, 1H), 7.95 (d, J=5.2Hz, 1H), 6.09-5.98 (m, 1H), 5.50-5.26 (m, 1H), 5.10 (d, J=4.4Hz, 2H), 4.59-4.50 (m, 1H), 4.32-4.20 (m, 1H), 4.03-3.87 (m, 1H), 3.30-3.25 (m, 3H), 3.11 (s, 3H), 2.95 (s, 3H), 2.67-2.51 (m, 1H), 1.31 (d, J=6.8Hz, 3H), 1.09 (d, J=6.8Hz, 3H).
アイソマー2:(S)−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)−N,N−ジメチル−4−(トリフルオロメチル)ピリミジン−5−カルボキサミド。分析的キラルHPLC:8分のクロマトグラフィーでtR=4.502分(方法:AS−H_S_3_5_40_3ML)。LC-MS MS (ESI) m/z 563.1 [M+Na]+.
1H NMR (CD3OD 400MHz):δ8.62 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 6.09-5.98 (m, 1H), 5.49-5.28 (m, 1H), 5.13 (s, 2H), 4.59-4.50 (m, 1H), 4.33-4.20 (m, 1H), 4.05-3.90 (m, 1H), 3.30 (s, 3H), 3.12 (s, 3H), 2.95 (s, 3H), 2.68-2.52 (m, 1H), 1.32 (d, J=6.8Hz, 3H), 1.10 (d, J=6.8Hz, 3H).
アイソマー2:(S)−(4−シクロプロピル−2−(8−(ヒドロキシメチル)−1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロベンゾ[4,5]イミダゾ[1,2−a]ピラジン−2(1H)−イル)ピリミジン−5−イル)メタノール。分析的キラルHPLC:15分のクロマトグラフィーでtR=10.770分(方法:OD−H_3_5_40_2.35ML)。LC-MS MS (ESI) m/z 472.2 [M+H]+. 1H NMR (G000237343 901-086-P1 CD3OD 400MHz):δ8.23 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 6.02 (d, J=8.0Hz, 1H), 5.27-5.22 (m, 1H), 5.13 (s, 2H), 4.64 (s, 2H), 4.47-4.40 (m, 1H), 4.23-4.11 (m, 1H), 3.85-3.74 (m, 1H), 3.28 (s, 3H), 2.57-2.44 (m, 1H), 2.32-2.20 (m, 1H), 1.27 (d, J=6.8Hz, 3H), 1.21-1.09 (m, 4H), 1.05 (d, J=6.8Hz, 3H).
1−(2−(1−イソプロピル−7−(メチルチオ)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)エタノン(110mg、0.23mmol)をメタノール(3mL)に入れた溶液に、NaMoO4−2H2O(107.61mg、0.49mmol)を0℃で加えた。この反応混合物を0℃で10分間撹拌した。次いで、H2O2(5mL、30%wt)を、形成した混合物に加えた。この混合物を室温で1時間撹拌した。この混合物を、ジクロロメタン(30mL)/i−PrOH(10mL)の混合溶媒で3回抽出した。合わせた有機層を濃縮し、PE/EtOAc1:1で溶出するシリカゲルによる分取TLCによって精製し、SFC分離で精製して、無色の油として、(R)−1−(2−(1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)エタノン(26.90mg、収率22.38%、アイソマー1)を、及び無色の油として、(S)−1−(2−(1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)エタノン(23.80mg、収率20.20%、アイソマー2)を得た。
アイソマー2:(R)−1−(2−(1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)エタノン。分析的キラルHPLC:15分のクロマトグラフィーでtR=11.077分(方法:AD−H_5_5_40_2.35ML)。LC-MS MS (ESI) m/z 481.1 [M+H]+, 503.1 [M+Na]+. 1H NMR (CDCl3400MHz):δ8.75-8.73 (m, 1H), 7.95 (s, 1H), 7.73-7.70 (m, 1H), 7.65 (d, J1=8.4Hz, J2=1.6Hz, 1H), 6.51-6.48 (m, 1H), 5.94-5.92 (m, 1H), 5.25-5.22 (m, 1H), 4.41-4.36 (m, 1H), 4.15-4.10 (m, 1H), 3.88-3.84 (m, 1H), 3.08 (s, 3H), 2.54 (s, 3H), 2.34-2.27 (m, 1H), 1.21-1.18 (m, 3H), 1.07-1.05 (m, 3H).
(S)−2−(2−(1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)プロパン−2−オール(アイソマー2)は、(S)−1−(2−(1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)エタノンから、同様の方法で調製した。分析的キラルHPLC:15分のクロマトグラフィーでtR=7.631分(方法:AS−H_3_5_40_2.35ML)。LC-MS m/z 497.2 [M+H]+. 1H NMR (CDCl3400MHz):δ8.75 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=8.4Hz, 1H), 7.62 (d, J1=8.4Hz, J2=1.6Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8Hz, 1H), 5.16-5.12 (m, 1H), 4.32-4.28 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.92 (s, 1H), 1.68 (s, 6H), 1.18 (d, J=7.2Hz, 3H), 1.06 (d, J=7.2Hz, 3H).
アイソマー2:分析的キラルHPLC:15分のクロマトグラフィーでtR=4.04分(方法:AD−H_3_30%、_2.35ML)。LC-MS m/z 483.0 [M+H]+. 1H NMR (CDCl3400MHz):δ8.83 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2Hz, 1H), 7.52 (d, J=7.2Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8Hz, 1H), 5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m, 1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8Hz, 3H).
アイソマー3:分析的キラルHPLC:15分のクロマトグラフィーでtR=6.08分(方法:AD−H_3_30%、_2.35ML)。LC-MS m/z 483.0 [M+H]+. 1H NMR (CDCl3400MHz):δ8.83 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2Hz, 1H), 7.61 (d, J=7.2Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8Hz, 1H), 5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m, 1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8Hz, 3H).
アイソマー4:分析的キラルHPLC:15分のクロマトグラフィーでtR=10.21分(方法:AD−H_3_30%、_2.35ML)。LC-MS m/z 483.0 [M+H]+. 1H NMR (CDCl3400MHz):δ8.84 (s, 1H), 7.93 (s, 1H), 7.68 (d, J=7.2Hz, 1H), 7.61 (d, J=7.2Hz, 1H), 6.47 (s, 1H), 5.89 (d, J=8.8Hz, 1H), 5.24-5.14 (m, 2H), 4.33-4.31 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.81 (m, 1H), 3.08 (s, 3H), 2.36-2.29 (m, 1H), 1.53-1.51 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 1.07 (d, J=6.8Hz, 3H).
アイソマー2:(S)−(2−(1−イソプロピル−7−(メチルスルホニル)−3,4−ジヒドロピラジノ[1,2−a]インドール−2(1H)−イル)−4−(トリフルオロメチル)ピリミジン−5−イル)メタノール。分析的キラルHPLC:15分のクロマトグラフィーでtR=11.33分(方法:OD−3_5_5_40_2.5ML)。LC-MS m/z 469.1 [M+H]+. 1H NMR (CDCl3400MHz):δ8.63 (s, 1H), 7.94 (s, 1H), 7.70 (d, J=8.4Hz, 1H), 7.63 (d, J1=8.4Hz, J2=1.6Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8Hz, 1H), 5.19-5.14 (m, 1H), 4.71 (s, 2H), 3.86-3.82 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.82-1.78 (m, 1H), 1.18 (d, J=7.2Hz, 3H), 1.04 (d, J=7.2Hz, 3H).
アイソマー2:分析的キラルHPLC:15分のクロマトグラフィーでtR=8.65分(方法:OD−H_5_5_40_2.35ML)。LC-MS m/z 527 [M+H]+. 1H NMR (400MHz, CD3OD):δ8.83 (s, 1H), 8.08 (s, 1H), 7.77 (s, 1H), 6.50 (s, 1H), 5.87 (d, J=8.4Hz, 1H), 5.10 (m, 1H), 5.06 (s, 2H), 4.44-4.40 (m, 1H), 4.09-4.02 (m, 1H), 3.91-3.84 (m, 1H), 3.26 (s, 3H), 2.36-2.29 (m, 1H), 1.59 (s, 6H), 1.16 (d, J=6.8Hz, 3H),3 1.02 (d, J=6.8Hz, 3H).
アイソマー2:分析的キラルHPLC:8分のクロマトグラフィーでtR=4.91分(方法:AS−H_S_3_40_3ML)。LC-MS m/z 494 [M+H-18]+, 512 [M+H]+. 1H NMR (400MHz, CD3OD):δ8.68 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.54 (s, 1H), 6. 00-5.87 (m, 1H), 5.20-5.08 (m, 1H), 5.07 (s, 2H), 4.50-4.46 (m, 1H), 4.14-4.08 (m, 1H), 3.98-3.90 (m, 1H), 3.27 (s, 3H), 2.39-2.32 (m, 1H), 1.29 (s, 2H), 1.18 (d, J=6.8Hz, 3H), 1.04 (d, J=6.8Hz, 3H).
本発明の化合物を競合結合アッセイで評価し、様々な濃度の化合物を、放射標識されたLXRリガンドの[3H]TO901317の存在下で、LXRリガンド結合ドメイン(LBD)と共にインキュベートした。[3H]T0901317と複合体形成したLXR−LBDの量を、ポリリジンでコーティングしたケイ酸イットリウムビーズへのLXR−LBDの非特異的結合を用いるシンチレーション近接アッセイ(SPA)によって測定した。部分精製したLXRα又はβのLBDタンパク質(15〜45nM)を、96ウェルプレート中において、2.5%DMSO、1%グリセロール、2mM EDTA、2mM CHAPS及び5mM DTTを含む80μLのリン酸緩衝食塩水(PBS)緩衝液中で、15nM[3H]TO901317(25〜40Ci/mmol)及び様々な濃度の試験化合物と共に、室温で30分間インキュベートした。ポリリジンSPAビーズ(50μg)を各ウェルに加え、総容積を120μLに調整した。プレートを旋回シェーカー上で20分間振盪し、次いで、あと10分間室温で沈降させてから、2,000rpmで1分間、短時間の遠心分離を行った。SPAのシグナルを、MicroBeta(登録商標)液体シンチレーションカウンター(Perkin Elmer、Waltham、MA)で測定し、その結果を使用して、全結合(DMSOコントロール)及び非特異的結合(5μMの非標識TO901317)コントロールに基づいてIC50値を計算した。Ki値は、方程式1に従って計算し、[RL]は、アッセイにおける[3H]TO901317の終濃度であり、LXRα及びLXRβのLBDに対する、20nM及び10nMのTO901317のKd値はそれぞれ、これらのタンパク質を用いた放射性リガンドの直接滴定によって決定した。
LXRルシフェラーゼ転写レポーター遺伝子アッセイは、LXRリガンドが、LXRのリガンド結合ドメイン(LBD)を介して転写活性化を促進する能力を測定する。HEK293細胞を、10%FBS(Gibco(登録商標)、#11995−065)及び1xPenStrep(Gibco(登録商標)、#15140)を含むDMEM培地中で、5%CO2雰囲気で37℃で増殖させた。150mmシャーレ由来の90%集密状態の細胞を、6つの100mmシャーレに播種した。この細胞を、LXRα又はLXRβのLBDのいずれかに融合したGal4DNA結合ドメインを含む発現プラスミド、及びホタルルシフェラーゼ遺伝子(luc+)の上流にGal4応答エレメントを有するルシフェラーゼレポータープラスミド、pG5−Luc(Promega、Madison、WI)でバッチトランスフェクトした。トランスフェクションは、製造業者が示したプロトコールに従ってLipofectamine(商標)2000(Gibco(登録商標))を用いて達成した。トランスフェクションしてから5時間後に、DMEMに入れた10%活性炭処理したFBS(Hyclone、#SH30070.03)を15mL、トランスフェクション培地を取り除くことなしにトランスフェクトしたシャーレに加え、次いで、細胞を37℃で一晩インキュベートする。翌日、トランスフェクトしたシャーレ由来の細胞をトリプシン処理し、PBSで洗浄し、10%活性炭処理したDMEM培地に再懸濁し、ウェルあたり60,000細胞/100μLで、96ウェルプレートに播いた。この細胞を37℃で約4時間インキュベートしてから、様々な濃度(最終的なDMSO濃度は0.2%)で、100μLの試験化合物又はコントロールリガンドを加えた。物質と共に細胞を16時間インキュベートした後、培養培地を捨て、Bright−Glo(商標)ルシフェラーゼ試薬(Promega、Cat.#E2610)を加えて、細胞を溶解し、ルシフェラーゼ反応を惹起した。ルシフェラーゼ活性の測定として、プレートリーダー(Victor2、PE−Wallac)中で発光を検出した。試験物質の存在下での転写活性化を、その物質の非存在下でインキュベートした細胞のものと比較して、発光のフォールドチェンジとして表した。EC50値は、XLfit(商標)プログラム(IDBS、Guilford、UK)を使用し計算した。
Claims (10)
- 以下の構造式:
によって表される化合物、又は医薬的に許容されるその塩(式中、
XはN又はCRcであり;
R1はメチルであり;
R2はH又は−CH 2 OHであり;
R3はイソプロピルであり;
R4 はメチル、ハロゲン化メチル、シクロプロピル、−OCHF 2 又は−OCH 3 であり;
R5はメチル、−CH 2 OH、−C(OH)(CH 3 ) 2 、−CH(OH)(CH 3 )、−CH(OH)(CH 2 )(CH 3 )、−CH(OH)(CH 2 ) 2 (CH 3 )、−C(O)NH 2 、−C(O)N(CH 3 ) 2 、−C(O)OH、−C(O)NH(CH 3 )、−C(O)CH 3 、−C(O)CH 2 CH 3 、−C(O)O(CH 2 )(CH 3 )、又は−OCH 3 であり;
R6はHであり;
RcはHである)。 - R4がCF3である、請求項1〜3のいずれか一項に記載の化合物。
- R5が−C(OH)(CH3)2である、請求項1〜4のいずれか一項に記載の化合物。
- 医薬担体又は希釈剤及び請求項1から7のいずれか一項に記載の化合物を含む、医薬組成物。
- 請求項1から7のいずれか一項に記載の化合物を含む、高脂質血症、高コレステロール血症、高リポタンパク質血症、高トリグリセリド血症、脂肪ジストロフィ、脂肪肝、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪性肝疾患(NAFLD)、高血糖症、インスリン抵抗性、真性糖尿病、脂質異常症、心血管疾患、アテローム性動脈硬化症、胆石症、尋常性ざ瘡、皮膚炎、乾癬、接触性皮膚炎、アトピー性皮膚炎、湿疹、皮膚創傷、皮膚老化、光老化、しわ、糖尿病、ニーマン・ピック病C型、パーキンソン病、アルツハイマー病、炎症、黄色腫、肥満症、代謝症候群、X症候群、脳卒中、末梢性閉塞性疾患、記憶喪失、糖尿病性神経障害、タンパク尿症、糸球体症、糖尿病性腎障害、高血圧性腎障害、IGA腎障害、巣状分節性糸球体硬化症、高リン酸血症、高リン酸血症の心血管系の合併症、癌又は多発性硬化症から選択される疾患又は障害の治療のための医薬組成物。
- 疾患又は障害がアテローム性動脈硬化症、アルツハイマー病、心血管疾患、高リン酸血症の心血管系の合併症、又は皮膚炎である、請求項9に記載の医薬組成物。
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