JP6691044B2 - 置換n−アセチル−l−システイン誘導体及び関連化合物 - Google Patents
置換n−アセチル−l−システイン誘導体及び関連化合物 Download PDFInfo
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- JP6691044B2 JP6691044B2 JP2016528225A JP2016528225A JP6691044B2 JP 6691044 B2 JP6691044 B2 JP 6691044B2 JP 2016528225 A JP2016528225 A JP 2016528225A JP 2016528225 A JP2016528225 A JP 2016528225A JP 6691044 B2 JP6691044 B2 JP 6691044B2
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N c(cc1)cc2c1nn[nH]2 Chemical compound c(cc1)cc2c1nn[nH]2 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N CC(N[C@@H](CS)C(O)=O)=O Chemical compound CC(N[C@@H](CS)C(O)=O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- WSPBIYTZXPCLCG-ZDUSSCGKSA-N CCOC([C@H](CSC(c1ccc(C)cc1)=O)NC(C)=O)=O Chemical compound CCOC([C@H](CSC(c1ccc(C)cc1)=O)NC(C)=O)=O WSPBIYTZXPCLCG-ZDUSSCGKSA-N 0.000 description 1
- SDCYUYGPHDDHDC-VIFPVBQESA-N C[C@@H](CSC(c1ccc(C)cc1)=O)C(O)=O Chemical compound C[C@@H](CSC(c1ccc(C)cc1)=O)C(O)=O SDCYUYGPHDDHDC-VIFPVBQESA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N Cc(cc1)ccc1C(Cl)=O Chemical compound Cc(cc1)ccc1C(Cl)=O NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
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Description
R3は
R3は
一般的方法
使用した溶媒はすべて市販されており、更に精製することなく使用した。典型的には、反応物を窒素の不活性雰囲気下で無水溶媒を用いて流した。化合物はケムドロー7、リアクシス、または市販されているならばカタログ名で指定した。
aq. 水性;
DMSO ジメチルスルホキシド;
EtOAc 酢酸エチル;
HOAc 酢酸;
MeOH メタノール;
NMM 4−メチルモルホリン;
ON 一晩;
r.t. 室温;
TFA トリフルオロ酢酸;及び
THF テトラヒドロフラン。
1H−ベンゾトリアゾール(19.4g,163mmol)をTHF(180mL)中に含む溶液にチオニルクロリド(2.96mL,40.8mmol)を添加した。溶液を氷浴で冷却し、0.5時間後(4R)−2−オキソ−チアゾリジン−4−カルボン酸(OTZ、6.00g,40.8mmol)を添加した。溶液を1時間かけて周囲温度までゆっくり加温した。室温で1.25時間後、生じた固体を真空濾過により除去した。固体及びフラスコを洗浄するためにTHF(60mL)を用いて、濾液を(2R)−2−アセチルアミノ−3−メルカプト−プロピオン酸(NAC,6.00g,36.7mmol)及びNMM(4.04mL,36.7mmol)をTHF(30mL)中に含む氷***液に移した。氷浴を外した。30分後、反応は1HNMRにより完了したと見られた。混合物にTFAを添加し、生じた溶液を2つに分け、酢酸エチルで予め洗浄した2つの330gのシリカゲルイスコカラムに適用した。2つのカラムのバイオタージクロマトグラフィー(EtOAc−20% メタノール(0.5% AcOH))により、EtOAcと摩砕し、真空中で乾燥した後、2.36g(HPLC純度:97.35%)の標記化合物が生じた。速く流れるUV活性画分を濃縮し、EtOAcと摩砕することにより更に化合物を得た。次いで、固体を水中に溶解し、濾過し、凍結乾燥させると、標記化合物が白色凍結乾燥物として生じた。この物質をEtOAc母液からのバッチと合わせ、〜1:1 EtOAc−MeOHを用いて25gのシリカゲルに吸着させた。バイオタージ精製(330gのイスコ,EtOAc−20% メタノール(0.5% AcOH)、カラムをEtOAcで予め湿らす)すると、水中に溶解し、濾過し、凍結乾燥させた後、0.84g(淡黄色凍結乾燥物,HPLC純度:94.70%)及び3.74g(白色凍結乾燥物,HPLC純度:96.88%)が生じた。収量:6.94g(65%)。1H NMR(400MHz,DMSO−d6) δ 13.01(br.s,1H),8.95(d,J=2.0Hz,1H),8.33(d,J=8.2Hz,1H),4.61−4.57(m,1H),4.39−4.33(m,1H),3.81(dd,J=11.7,9.0Hz,1H),3.43(dd,J=11.7,2.3Hz,1H),3.39(dd,J=13.3,4.7Hz,1H),3.08(dd,J=13.7,8.6Hz,1H),1.84(s,3H);13C NMR(100.6MHz,DMSO−d6) 200.9,173.5,171.6,169.4,61.7,51.2,32.7,30.0,22.3ppm;MS(ES) m/z:293(M+H)+;HPLC:96.88%(マックスプロット220〜400nm);元素分析(C9H12N2O5S2):計算値:C,36.98%;H,4.14%;N,9.58% 実測値:C,36.80%;H,4.24%;N,9.63%;[α]D 25 −71.58(c 1.0,水)。
1H−ベンゾトリアゾール(7.68g,64.4mmol)をTHF(60mL)中に含む溶液に2−メトキシ−ベンゾイルクロリド(4.36mL,29.3mmol)を添加した。15分後、生じた溶液は曇り、混合物を1.75時間以上撹拌した。生じた固体を真空濾過により除去し、15mLのTHFで洗浄した。15mLのTHFを含む生じた濾液を(2R)−2−アセチルアミノ−3−メルカプト−プロピオン酸(NAC、3.83g,23.4mmol)及びNMM(2.57mL,23.4mmol)をTHF(30mL)中に含む予***液に添加した。氷浴を外した。一晩室温に置いたが、反応は1H NMRにより完了していなかった。さらにNMM(2.57mL,23.4mmol)を添加し、混合物を55℃に一晩加熱した。混合物にTFA(4mL)を添加し、溶液を真空中で濃縮した。残渣をMeOH及びEtOAc中に溶解し、〜80gのシリカゲルに吸着させた。バイオタージシリカゲルクロマトグラフィー(330gのイスコカラム,120mLの1:2 EtOAc−ヘキサン、次いで120mLの1:1 EtOAc−20% MeOH(1% AcOH)勾配)にかけて精製した後、温MeCN/水 1:1混合物(100mL)中に溶解し,真空中でMeCNを除去し、周囲温度で一晩放置した後、沈殿を吸引濾過し、水で洗浄することにより精製した。標記化合物を白色固体として単離した。収量:2.29g(33%)。Mp 179〜181℃;1H NMR(399.7MHz,DMSO−d6) δ 12.89(br.s,1H),8.31(d,J=8.2Hz,1H),7.65(dd,J=7.8,1.6Hz,1H),7.59−7.54(m,1H),7.18(d,J=8.6Hz,1H),7.06−7.02(m,1H),4.42−4.36(m,1H),3.85(s,3H),3.47(dd,J=13.7,5.1Hz,1H),3.11(dd,J=13.7,9.0Hz,1H),1.82(s,3H);13C NMR(100.5MHz,DMSO−d6) 189.4,171.8,169.3,157.4,134.3,129.0,125.9,120.4,113.8,55.9,51.4,30.3,22.3ppm;MS(ES) m/z:298(M+H)+;HPLC:97.72%(マックスプロット220〜400nm);元素分析(C13H15NO5S):計算値:C,52.51%;H,5.09%;N,4.71%;S,10.78% 実測値:C,52.58%;H,5.07%;N,4.82%;S,10.55%;[α]D 25 −21.49(c 1.014,DMSO)。
1H−ベンゾトリアゾール(9.91g,83.2mmol)をTHF(80mL)中に含む溶液に4−メチル−ベンゾイルクロリド(5.00mL,37.8mmol)を添加した。2時間後、生じた固体を真空濾過により除去し、25mLのTHFで洗浄した。25mLのTHF洗浄液を含む生じた濾液を(2R)−2−アセチルアミノ−3−メルカプト−プロピオン酸(NAC,5.55g,34.0mmol)及びNMM(3.74mL,34.0mmol)をTHF(50mL)中に含む予***液に添加した。氷浴を外した。一晩室温に置いたが、反応は1H NMRにより完了していなかった。混合物を55℃に1時間加熱した。混合物にTFA(3.6mL)及び水(100mL)を添加した。溶液を真空中で濃縮して、THFの殆どを除去した。さらに水(80mL)及びジクロロメタン(180mL)を添加し、層を分離した。水性層をジクロロメタンで抽出した。有機層を合わせ、Na2SO4で乾燥し、酢酸エチル(100mL)を添加し、真空中で濃縮してジクロロメタンを除去した。結晶化を開始するために残存する酢酸エチル溶液を冷凍庫中に短時間置いた後、周囲温度で一晩放置した。得られた固体を真空濾過により集め、乾燥後3.28gが生じた。添加した若干のメタノールを含む濾液を85gのシリカゲルに吸着させた。バイオタージカラムクロマトグラフィー(330gのイスコ,ヘキサン−酢酸エチル 1:1(0.5CV)、次いでEtOAc−20% MeOH(1%AcOH)勾配)にかけると、2.62gの物質が生じた。EtOAc沈殿由来の固体及びカラムからの物質を合わせ、温MeCN/水 1:1混合物中に溶解した。MeCNを真空中で除去し、周囲温度で一晩放置した後に形成された沈殿を吸引濾過により集めた。標記化合物を白色固体として単離した。収量:4.81g(50%)。Mp 182〜184℃;1H NMR(399.7MHz,DMSO−d6) 12.98(br.s,1H),8.38(d,J=7.8Hz,1H),7.82(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),4.47−4.42(m,1H),3.55(dd,J=13.7,5.1Hz,1H),3.23(dd,J=13.7,8.6Hz,1H),2.89(s,3H),1.84(s,3H);13C NMR(100.5MHz,DMSO−d6) 189.9,171.7,169.3,144.6,133.6,129.6,127.0,51.4,29.9,22.3,21.2ppm;MS(ES) m/z:282(M+H)+;HPLC:94.77%(マックスプロット220〜400nm);元素分析(C13H15NO4S):計算値:C,55.50%;H,5.37%;N,4.98%;S,11.40% 実測値:C,55.46%;H,5.33%;N,5.08%;S,11.66%;[α]D 25 −23.74(c 1.0,DMSO)。
(2R)−2−アセチルアミノ−3−メルカプト−プロピオン酸(NAC、4.02g,24.6mmol)を水(30mL)中に含む溶液に炭酸ナトリウム(2.64g,24.9mmol)、次いでTHF(30mL)を添加した。次いで、クロロギ酸ベンジル(7.73mL,54.1mmol)を添加した。1時間後、pHを〜8に調節するためにさらに炭酸ナトリウムを添加した。更に0.5時間後、真空中で部分的に濃縮した。水性層をEtOAc(3×)で抽出した後、水性層を2N HClを用いてpH〜3に酸性化した。エーテルを添加し、層を分離した。水性層をEtOAc(2×)で抽出し、有機層を合わせ、Na2SO4で乾燥し、濾過し、真空中で濃縮した。バイオタージカラムクロマトグラフィー(330gのイスコ,1:1 hex/EtOAc(120mL)、次いでEtOAc−20% MeOH(1% AcOH)勾配,サンプルを若干のヘキサンを含むEtOAc中に充填)により精製して、標記化合物を白色固体として得た。収量:2.18g(30%)。Mp 146〜148℃;1H NMR(399.7MHz,DMSO−d6) δ 12.98(br.s,1H),8.33(d,J=8.2Hz,1H),7.40−7.32(m,5H),5.27−5.20(m,2H),4.44−4.38(m,1H),3.35−3.30(dd,H2Oにより部分的に隠れている,1H),3.05(dd,J=14.0,8.6Hz,1H),1.81(s,3H);13C NMR(100.5MHz,DMSO−d6) 171.6,169.6,169.4,135.2,128.54,128.47,128.38,68.9,51.5,32.1,22.3ppm;MS(ES) m/z:298(M+H)+;HPLC:98.22%(マックスプロット220〜400nm);元素分析(C13H15NO5S):計算値:C,52.51%;H,5.09%;N,4.71%;S,10.78% 実測値:C,ペンディング%;H,ペンディング%;N,ペンディング%;S,ペンディング%;[α]D 25 ペンディング(c,)。
1H−NMRスペクトルはバリアン・マーキュリー300MHz NMRで獲得した。純度(%)は210〜400nmの2996ダイオードアレイ検出器を備えているウォーターズ・アライアンス2695 HPLC(ウォーターズ・シンメトリーC18,4.6×75mm,3.5μm)を用いて測定した。
本発明の化合物による 14 C摂取
これらの実験の目的は、14C−シスチン摂取を調べることであった。
本アッセイも上記した脳星状膠細胞腫由来のヒトグリア細胞(1321N1)の細胞培養系を用いる。初めに、細胞をHBBSSで洗浄し、3H−グルタメートを添加する(パーキンエルマー:1mCi/mLストック溶液を希釈し(30μL+500μL HBBSS)、各ウェルに10μLの希釈した放射標識を添加する)。細胞に標識したグルタメートを充填するために1時間インキュベートした後、細胞を再びHBBSSで洗浄し、薬物を添加する。30、90及び180分目に、各ウェルから50μLの細胞外培地をサンプリングし、ベックマンLS 6500シンチレーションカウンターを用いて測定する。
どのようなプロセスで14C−シスチン摂取の抑制が生ずるかを更に解明するために、細胞内システインレベルを測定する。
プレパルス抑制実験
本実験の目的は、統合失調症の予測動物モデルにおいて試験化合物の有効性を立証することであった。
本実験の目的は、試験化合物がCNSに浸透する能力を立証することであった。
本実験の目的は、C57BL/6マウスの脳における試験化合物の薬物動態特性を立証することであった。
Claims (18)
- 請求項1に記載の化合物及び、医薬的に許容され得る担体を含む、医薬組成物。
- 治療有効量の請求項1に記載の化合物及び、医薬的に許容され得る担体を含む、医薬組成物。
- 請求項4に記載の化合物及び、医薬的に許容され得る担体を含む、医薬組成物。
- 治療有効量の請求項4に記載の化合物及び、医薬的に許容され得る担体を含む、医薬組成物。
- 治療有効量の請求項1又は4に記載の化合物を含む、トリコチロマニア、統合失調症、薬物中毒、遺伝性ミトコンドリア病、副腎白質ジストロフィー、ハンチントン病、HIV関連神経認知障害、及び低酸素性虚血性脳症からなる群から選択される、中枢神経系(CNS)の疾患又は状態を治療するための医薬組成物。
- CNSの疾患又は状態が、トリコチロマニアである、請求項7に記載の医薬組成物。
- CNSの疾患又は状態が、統合失調症である、請求項7に記載の医薬組成物。
- CNSの疾患又は状態が、薬物中毒である、請求項7に記載の医薬組成物。
- CNSの疾患又は状態が、遺伝性ミトコンドリア病である、請求項7に記載の医薬組成物。
- 遺伝性ミトコンドリア病が、(a)リー症候群、(b)アルパース病又は(c)ミトコンドリア脳筋症、乳酸アシドーシス及び脳卒中様症状(MELAS)である、請求項11に記載の医薬組成物。
- CNSの疾患又は状態が、副腎白質ジストロフィー、ハンチントン病、HIV関連神経認知障害、又は低酸素性虚血性脳症である、請求項7に記載の医薬組成物。
- 治療有効量の請求項1又は4に記載の化合物を含む、対象における酸化ストレスを低減するための医薬組成物。
- 治療有効量の請求項1又は4に記載の化合物を含む、対象におけるグルタメートシグナリングを改善させるための医薬組成物。
- 治療有効量の請求項1又は4に記載の化合物を含む、対象におけるグルタチオンレベルを上昇させるための医薬組成物。
- 治療有効量の請求項1又は4に記載の化合物を含む、対象におけるシスチングルタメートアンチポーター活性を改善するための医薬組成物。
- 治療有効量の請求項1又は4に記載の化合物を含む、酸化的不均衡又はグルタミン酸作動性の機能障害に関連する中枢神経系(CNS)の疾患又は状態を治療するための医薬組成物。
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