JP2018530593A - 統合失調症、双極性障害、認知障害及び大うつ病性障害の治療のための非定型的抗精神病薬ならびにnmda調節剤の医薬品の組み合わせ - Google Patents
統合失調症、双極性障害、認知障害及び大うつ病性障害の治療のための非定型的抗精神病薬ならびにnmda調節剤の医薬品の組み合わせ Download PDFInfo
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Abstract
【選択図】なし
Description
本出願は2015年10月16日出願の米国特許出願第62/242,633号に対する優先権を主張し、そのすべての内容は本明細書に参照により組み込まれる。
が挙げられ、それは分子量413.47及び化学式C18H31N5O6を有する。rapastinelは、向知性、神経保護及び抗侵害受容性活性を示し、in vivo学習、記憶及び認知を強化する。
本開示は部分的には、1つ以上の非定型的抗精神病薬、及び本明細書で開示するrapastinel及び他のNMDA調整剤(そのそれぞれは本明細書で「成分」と称される場合がある)などのNMDA調整剤を含む、組み合わせを特徴とする。このような組み合わせの有益な効果は、rapastinel及び非定型的抗精神病薬(例えばルラシドン)の投与(例えば、亜急性用量)が、NMDARアンタゴニスト誘発性認知障害(例えばNMDARアンタゴニストの繰り返し投与により誘発される、例えば新奇物体認識でのNMDARアンタゴニスト誘発性障害)を回復させる及び/または予防することができるという発見に、部分的には基づく。開示した組み合わせは、1つ以上の他の生物活性成分(例えば、1つ以上の他の抗うつ化合物)及び/または1つ以上の薬学的に許容される賦形剤及び/または担体を更に含むことができる。前記組み合わせの成分(本明細書で、化学物質または化合物とも称される場合がある)は、逐次的(各成分が異なる時間に投与される)にまたは実質的に同時に患者に投与されることができる。前記成分が、同じ薬学的に許容される担体中に存在してもよく、したがって同時に投与されてもよいことは、理解されるであろう。あるいは各成分が、同時にまたは逐次的に投与されることができる、従来の経口投与形態または非経口形態などの別個の薬学的担体中に存在することができる(または一成分が経口で、他が非経口でもよい)。したがって一態様では、NMDARアンタゴニストを急性的に投与した患者の認知障害を実質的に回復させる、または予防する方法を提供し、それは、rapastinelなどの開示されたNMDA調節剤及び非定型的抗精神病薬(例えばルラシドン)を投与することを含む。例えば、必要とする患者の統合失調症または双極性障害を治療する方法が、本明細書に提供され、非定型的抗精神病薬;及びrapastinel、(S)−N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシプロパノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシ−プロパノイル)−ピロリジン−2−カルボニル)−ピロリジン−2−カルボキサミド、及びN−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミドからなる群から選択されるNMDA調節剤を投与することを含む。特定の想到される方法で、NMDA調整剤及び非定型的抗精神病薬は、単独で投与される場合、亜有効用量でそれぞれ投与される。
rapastinelは、本明細書に参照により取り込まれる、米国特許第5,763,393号及び同第4,086,196号に開示されているような周知の組換え法または合成法によって得てもよい。rapastinelの多形体、水和物、同族体、溶媒和物、遊離塩基、及び/またはこれに限定されないが酢酸塩などの好適な塩形態も想到される。ペプチドは、米国特許第5,763,393号に更に開示されるように、環化されても、非環化でもよい。いくつかの実施形態で、rapastinelの類似体は、Thr群またはPro群のうちの1つ以上での、CH3、OHもしくはNH2の部位の欠失など一部の挿入または欠失を含んでいてもよい。他の実施形態で、rapastinelは、1つ以上のハロゲン、C1〜C3アルキル(ハロゲンもしくはアミノと任意に置換される)、ヒドロキシル及び/またはアミノと任意に置換されていてもよい。本明細書の使用に想到される他の化合物としては、米国特許第5,763,393号、同第6,107,271号、及びWood et al.,Neuro.Report,19,1059−1061,2008に開示される、NMDARのグリシン部位部分アゴニストを含み、その全内容は参照により本明細書に取り込まれる。
一態様で、非定型的抗精神病薬(例えば、ルラシドン、クエチアピン、オランザピン、アセナピン、リスペリドン、ジプラシドン、クロザピン、メルペロン、カリプラジン、アリピプラゾール、ピマバンセリン、ITI−007、RP506及びレモキシプリドからなる群から選択されるもの)、及び本明細書に記載のものなどのNMDA調節剤(例えば、rapastinel)を投与することを含む、患者の認知障害疾患を実質的に回復させる、または予防する方法が、提供される。
を有する薬学的活性化合物またはその薬学的に許容される塩の60mg/mL〜約200mg/mL(例えば、約125mg/mL〜約175mg/mL、例えば、約150mg/mLまたは約75mg/mL)、(ii)水(例えば、注射用水);及び(iii)酸を含むことができ、安定な水性組成物は、25℃で約3.9〜約5.5(例えば、約4.0〜約5.0、約4.2〜約5.0、約4.1〜約4.7、約4.2〜約4.8、約4.0、約4.5)のpHを有する。特定の実施形態で、このような組成物を、化合物の量を少なくとも1回の単回用量として抽出可能である容器(例えば、プレフィルドシリンジまたはバイアル)内に配分することができる。特定の実施形態で、単回用量は、約1mL〜約4mL(例えば、3mL)の体積を有することができる。
雄のC57BL/6Jマウス(月齢2−1/2−3、Jackson(MA、USA))(N=40、45及び48)の3つのコホートを、それぞれ実施例1、2、3で使用した。21±2℃及び相対湿度50±15%、14:10時間の明暗期間(点灯:午前5時00分)で保持した制御された環境下で、マウスはグループ収容された(5匹/ケージ)。すべての実験は、明周期中に行われた。食物及び水は、自由に摂取させた。マウスは到着1週間でコロニーに慣れ、その間、取り扱われなかった。すべての実験は、Northwestern University(Chicago)動物実験委員会に従って行われた。
物体探索の有意な効果は、グループのいずれの獲得試行中でも見いだせなかった(F3,31=0.90、P=0.96、データは示さず)。保持試行で、薬物処理と物体探索時間の間に有意な相互作用があった(F3,31=24.76、***P<0.001、データは示さず)。更に事後分析で、sal及びsal+rapastinel(1.0mg/kg)を与えた野生型マウスは、熟知した物体と比べて新規の物体にはっきりした好みを示し、すなわち新規の物体対熟知した物体を探索するのに著しく長い時間を費やしたことが明らかとなった(P<0.001)。この効果は、急性ケタミン(30mg/kg)で処理したマウスでは消失した−すなわち、これらのマウスは両方の物体を探索するのに同程度の時間を費やした。更に、急性ケタミン(30mg/kg)の前にrapastinel(1.0mg/kg)を与えたマウスは、熟知した物体と比較して新規の物体にはっきりした好みを示した(P<0.01)。
物体探索の有意な効果は、グループのいずれの獲得試行中でも見いだせなかった(F4,47=0.76、P=0.23、データは示さず)。保持試行で、薬物処理と物体探索時間の間に有意な相互作用があった(F4,47=10.45、***P<0.001、データは示さず)。更に事後分析で、salを与えた野生型マウスは、熟知した物体と比べて新規の物体にはっきりした好みを示した(P<0.001)。この効果は、亜慢性ケタミンで処理したマウス、または亜慢性PCP処理した動物で消失した。急性rapastinel(1.0mg/kg)処理した動物は、熟知した物体と比較して新規の物体を著しく長く探索し、それによって亜慢性PCPまたは亜慢性ケタミンによって誘発される障害を回復させる(P<0.001、データは示さず)。DIにおいて、グループ間に有意な相互作用があった(F4,47=9.30、***P<0.001、図2)。亜慢性PCP及び亜慢性ケタミン処理したマウスのDIは、sal+sal処理した対照マウスと比較して著しく低下した(*P<0.05及び**P<0.01、図2)。1.0mg/kgのrapastinelを与えた、亜慢性PCP及び亜慢性ケタミン処理した動物のDIは著しく増加し、それによって亜慢性PCP及び亜慢性ケタミンの両方の処理によって生じるNOR障害の回復を著しく示す(###P<0.001、図2)。
物体探索の有意な効果は、グループのいずれの獲得試行中でも見いだせなかった(F4,43=0.92、P=0.13、データは示さず)。保持試行で、薬物処理と物体探索時間の間に有意な相互作用があった(F4,43=12.45、***P<0.001、データは示さず)。更に事後分析で、salを与えた野生型マウスは、熟知した物体と比べて新規の物体にはっきりした好みを示した(P<0.001)。scケタミン処理したマウス、ならびにscケタミン+亜有効用量のrapastinel(0.3mg/kg)及びscケタミン+亜有効用量のルラシドン(0.1mg/kg)を与えた動物で、この効果は消失した。しかしscケタミンを、亜有効用量のルラシドン+亜有効用量のrapastinelに与えるとき、動物は熟知した物体と比較して新規の物体を著しく長く探索した(P<0.001、示されないデータ)。DIは、グループ間の有意な相互作用を示した(F4,43=10.04、***P<0.001、図3)。scケタミン+sal、scケタミン+rapastinel(0.3mg/kg)、及びscケタミン+ルラシドン(0.1mg/kg)処理したマウスは、生理食塩水対照と比較してDIの著しい低下を示した(***P<0.001)。亜有効用量のrapastinel及びルラシドンの組み合わせの効果は、単独で与えられたどちらの薬の有効量の効果とも有意差はなかった。
以下の反応順序は、(S)−N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシプロパノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミドを合成するために用いた(スキームA)。
1H−NMR:(500MHz,DMSO−d6):δ7.38−7.31(m,5H),7.26(s,1H),7.10−7.03(m,2H),6.65(br s,1H),5.04−5.01(m,2H),4.98−4.84(m,1H),4.76−4.75(m,1H),4.61(s,1H),4.38−4.31(m,2H),4.02−4.00(m,2H),3.77−3.74(m,1H),3.67−3.56(m,3H),3.44−3.37(m,2H),2.14−1.86(m,8H),1.01−1.00(m,3H).
質量m/z:550[M++1].
1H−NMR:(500MHz,DMSO−d6)(回転異性体):δ7.39(d,J=8.0Hz,1H),7.08−7.03(m,2H),6.65(br s,1H),4.89−4.85(m,1H),1.61−1.59(m,1H),4.39−4.38(m,1H),4.02−4.00(m,2H),3.68−3.52(m,4H),3.43−3.36(m,2H),3.22−3.10(m,2H),2.19−2.13(m,1H),2.07−1.98(m,1H),1.93−1.81(m,5H),1.75(s,2H),1.01−1.00(m,3H).
LCMS m/z:400.2[M++1].
HPLC純度:99.27%。
質量m/z:250.0[M++1].
化合物8(5.0g、20.08mmol)をCH2Cl2(50mL)中に溶解させて、NMM(2.43mL、22.08mmol)及びIBCF(2.74mL、23.09mmol)を加え、不活性雰囲気下にて−15℃で30分間撹拌した。DMF(15mL)中の(2S,3R)−メチル2−アミノ−3−ヒドロキシブタノエート(2.93g、22.08mmol)及びNMM(2.43mL、22.08mmol)の混合物を、−15℃で滴下した。得られた反応混合物を、室温で3時間撹拌した。それはDCM(200mL)で希釈され、有機層は水(50mL)、食塩水(50mL)で洗浄され、無水Na2SO4上で乾燥して、減圧下で濃縮した。得られた粗生成物は、30%のEtOAc/ヘキサンで溶出するシリカゲルカラムクロマトグラフィーによって精製されて、化合物9(3.1g、42%)を得た。
1H−NMR:(500MHz,DMSO−d6)(回転異性体):δ7.98−7.94(m,1H),7.35−7.27(m,5H),5.09−4.94(m,3H),4.44(dd,J=5.5,8.5Hz,1H),4.29−4.27(m,1H),4.12(s,1H),3.62(s,3H),3.44−3.30(m,2H),2.20−2.08(m,1H),1.87−1.78(m,3H),1.08−0.94(2d,3H).
質量m/z:365.0[M++1].
以下の反応順序は、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミドを合成するために用いた(スキームB):
1H−NMR:(500MHz,DMSO−d6):δ12.49(br s,1H),4.08−4.03(m,1H),3.36−3.24(m,2H),2.22−2.11(m,1H),1.87−1.76(m,3H),1.39(s,9H).
質量m/z:216.0[M++1].
質量m/z:317.0[M++1].
(S)−Tert−ブチル−2−((S)−3−ヒドロキシ−1−メトキシ−1−オキソプロパン−2−イルカルバモイル)−ピロリジン−1−カルボキシレート(3)(500mg、1.58mmol)を、1,4−ジオキサン(3mL)中に溶解させ、ジオキサン(3.16mL、3.16mmol)中のHCl溶液を加えて、室温にて4時間撹拌した。揮発物を減圧下で蒸発させ、化合物4(280mg)を固体として得た。
1H−NMR:(200MHz,DMSO−d6):δ9.99(br s,1H),9.12−9.08(m,1H),8.53(br s,1H),5.48(br s,2H),4.43−4.22(m,2H),3.82−3.67(m,4H),3.56(s,3H),2.36−2.27(m,1H),1.93−1.86(m,3H).
質量m/z:217.0[M++1].
1H−NMR:(500MHz,DMSO−d6):δ8.13(d,J=8.0Hz,1H),7.74(d,J=7.5Hz,1H),7.38−7.31(m,5H),5.08−4.96(m,3H),4.85−4.82(m,1H),4.56(d,J=8.0Hz,1H),4.44−4.42(m,2H),4.27(d,J=7.0Hz,1H),4.10(d,J=10.5Hz,2H),3.81−3.78(m,1H),3.72−3.70(m,1H),3.61−3.59(m,3H),3.54−3.50(m,2H),2.16−2.14(m,1H),2.05−2.01(m,1H),1.90(s,3H),1.87−1.86(m,3H),1.85−1.84(m,3H),1.21−1.20(d,J=6.0Hz,3H).
質量m/z:591.0[M++1].
1H−NMR:(500MHz,DMSO−d6):δ7.60(d,J=7.5Hz,1H),7.35−7.30(m,5H),7.18(d,J=7.0Hz,1H),7.11−7.06(m,2H),5.05−4.97(m,2H),4.82−4.81(m,1H),4.60−4.59(m,2H),4.33−4.31(m,1H),4.15−4.08(m,2H),3.81−3.79(m,1H),3.72−3.64(m,2H),3.59−3.53(m,4H),2.14(s,1H),2.03(d,J=9.0Hz,1H),1.95−1.85(m,5H),1.75(s,1H),1.10(d,J=6.5Hz,3H).
質量m/z:550.0[M++1].
1H−NMR:(500MHz,DMSO−d6):δ7.65−7.60(m,1H),7.12−7.03(m,2H),4.81(br s,1H),4.58−4.57(m,1H),4.49(m,1H),4.38−4.19(m,1H),4.10−4.06(m,1H),3.69−3.62(m,2H),3.59−3.56(m,4H),3.49−3.45(m,2H),3.37−3.26(m,2H),2.19−2.15(m,1H),2.09−1.99(m,1H),1.95−1.84(m,5H),1.75(s,1H),1.06(d,J=13.0Hz,3H).
LCMS m/z:400.8[M++1].
HPLC純度:97.71%。
以下の反応順序は、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシ−プロパノイル)−ピロリジン−2−カルボニル)−ピロリジン−2−カルボキサミドを合成するために用いた(スキームC)。
1H−NMR:(500MHz,DMSO−d6):δ12.49(br s,1H),4.08−4.03(m,1H),3.36−3.24(m,2H),2.22−2.11(m,1H),1.87−1.76(m,3H),1.39(s,9H).
質量m/z:216.0[M++1].
質量m/z:317.0[M++1].
1H−NMR:(200MHz,DMSO−d6):δ9.99(br s,1H),9.12−9.08(m,1H),8.53(br s,1H),5.48(br s,2H),4.43−4.22(m,2H),3.82−3.67(m,4H),3.56(s,3H),2.36−2.27(m,1H),1.93−1.86(m,3H).
質量m/z:217.0[M++1].
質量m/z:535.0[M++1].
1H−NMR:(500MHz,DMSO−d6):δ7.60(d,J=7.5Hz,1H),7.36−7.31(m,6H),7.11−7.06(m,2H),5.04−4.98(m,2H),4.82−4.74(m,2H),4.61−4.59(m,1H),4.36−4.30(m,2H),4.10−4.07(m,1H),3.67−3.65(m,2H),3.59−3.55(m,6H),3.44−3.40(m,2H),1.95−1.92(m,6H).
質量m/z:520.0[M++1].
ベンジル−(S)−1−((S)−2−((S)−2−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イルカルバモイル)ピロリジン−1−カルボニル)ピロリジン−1−イル)−3−ヒドロキシ−1−オキソプロパン−2−イルカルバメート7(300mg、0.57mmol)をメタノール(8mL)中に溶解させて、10%のPd/C(50mg)を加えて、反応混合物を水素雰囲気下で2時間撹拌した。反応混合物を濾過し、濾液を減圧下で濃縮して、化合物C(150mg、68%)を得た。
1H−NMR:(500MHz,DMSO−d6)(回転異性体):δ7.62(d,J=8.0Hz,1H),7.24(br s,1H),7.14−7.07(m,2H),4.87−4.82(m,2H),4.59−4.57(m,1H),4.37−4.31(m,2H),4.11−4.07(m,2H),3.70−3.39(m,8H),2.17−2.01(m,2H),1.95−1.79(m,6H).
LCMS m/z:386.4[M++1].
HPLC純度:98.45%。
以下の反応順序は、N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミド(化合物D及びE)を合成するために用いた(スキームD)。
スキームD.化合物D及びEの合成.
1−ベンジル2−エチル2−ベンジルピロリジン−1,2−ジカルボキシレート(2)の合成:及び
1H−NMR:(200MHz,DMSO−d6):δ7.47−7.32(m,5H),7.27−7.16(m,3H),7.07−7.04(m,2H),5.29−5.06(m,2H),4.16−3.89(m,2H),3.57−3.33(m,2H),3.02−2.78(m,2H),2.13−1.89(m,2H),1.56−1.51(m,1H),1.21−1.04(m,3H),0.93−0.79(m,1H).
質量m/z:368.2[M++1].
CH3OH(20mL)中の化合物2(8.0g、21.79mmol)の撹拌溶液に、2NのKOH水溶液(20mL)を加え、100℃まで加熱して、16時間撹拌した。揮発物を減圧下で蒸発させた。得られた残留物を氷冷水(50mL)で希釈して、エーテル(50mL)で洗浄した。水性層は、HCl溶液を使用してpH約2まで酸性化し、EtOAc(2×100mL)で抽出した。混合有機層を、無水Na2SO4上で乾燥して、減圧下で濃縮し、化合物3(6g、81%)をオフホワイトの固体として得た。
1H−NMR:(200MHz,DMSO−d6):δ12.71(br s,1H),7.40−7.30(m,5H),7.25−7.19(m,3H),7.07−7.00(m,2H),5.27−5.02(m,2H),3.59−3.32(m,2H),3.02−2.83(m,2H),2.13−1.91(m,2H),1.58−1.49(m,1H),0.90−0.77(m,1H).
質量m/z:340.1[M++1].
1H−NMR:(200MHz,DMSO−d6):δ7.62−7.59(m,1H),7.44−7.31(m,5H),7.21−7.18(m,3H),7.06−6.99(m,2H),5.25−5.24(m,1H),5.12−4.94(m,2H),4.30(s,1H),4.15−4.08(m,1H),3.66−3.64(m,3H),3.63−3.49(m,2H),3.14(s,1H),2.89(s,1H),2.09−2.02(m,2H),1.56−1.51(m,1H),1.09−0.98(m,4H).
質量m/z:455.1[M++1],477.3[M+Na].
1H−NMR:(500MHz,DMSO−d6)(回転異性体):δ8.15−7.71(m,1H),7.42−7.04(m,10H),5.30−5.19(m,2H),5.11−5.09(m,1H),4.99−4.93(m,1H),4.67−4.62(m,1H),3.66−3.64(m,3H),3.55−3.46(m,2H),3.38−3.35(m,1H),2.88−2.69(m,1H),2.17−2.00(m,2H),1.98−1.92(m,3H),1.56−1.46(m,1H),1.23−1.17(m,3H),1.02−0.86(m,1H).
LCMS m/z:497.4[M++1].
1H−NMR:(500MHz,DMSO−d6)(回転異性体):δ8.22−8.17(m,1H),7.24−7.16(m,5H),5.17(t,J=11.5Hz,1H),4.48−4.42(m,1H),3.60−3.54(s,3H),3.20(t,J=13.5Hz,1H),3.06−2.97(m,1H),2.82−2.68(m,3H),2.08−2.02(m,1H),1.89(s,3H),1.72−1.51(m,3H),1.10(2d,3H).
LCMS m/z:363[M++1],385[M+Na].
1H−NMR:(500MHz,DMSO−d6)(回転異性体):δ7.36−7.23(m,8H),7.15−7.12(m,3H),5.21−5.15(m,2H),5.04−4.92(m,1H),4.57−4.50(m,2H),3.88(d,J=14.5Hz,1H),3.65(s,3H),3.54−3.46(m,3H),3.21−3.13(m,1H),3.02−2.90(m,2H),2.19−2.02(m,4H),1.97(s,3H),1.89(s,1H),1.77−1.65(m,1H),1.17(s,2H),1.06(s,2H).
質量m/z:594.1[M++1].
1H−NMR:(500MHz,CDCl3)(回転異性体):δ7.88−7.87(d,1H,J=8.5),7.30−7.26(m,2H),7.24−7.21(m,1H),7.13−7.12(d,2H,J=7),5.44−5.43(m,1H),4.76−4.74(m,1H),3.94−3.92(m,1H),3.84−3.81(m,1H),3.75(s,3H),3.50(m,1H),3.26−3.12(m,3H),2.90−2.88(m,1H),2.23−2.15(m,4H),2.04(s,3H),1.87−1.77(m,5H),1.27−1.24(m,3H).
質量m/z:460(M+1).
1H−NMR:(500MHz,DMSO−d6):δ7.37−7.30(m,5H),6.60(d,J=8.5Hz,1H),5.18−5.08(m,2H),4.76(d,J=7Hz,1H),4.08−4.00(m,2H),1.38(s,9H),1.09(d,J=6.0Hz,3H).
質量m/z:310.0[M++1],210[M+−De Boc].
1H−NMR:(500MHz,DMSO−d6):δ7.35−7.34(m,5H),7.27−7.25(d,J=8.5Hz,1H),5.18−5.06(m,3H),4.34−4.32(m,1H),1.90(s,3H),1.39(s,9H),1.16(d,J=3Hz,3H).
質量m/z:252[M++1−De Boc].
1H−NMR:(500MHz,DMSO−d6):δ12.78(br s,1H),6.94(d,J=9.5Hz,1H),5.16−5.14(m,1H),4.17−4.15(m,1H),1.95(s,3H),1.39(s,9H),1.10(d,J=6.0Hz,3H).
質量m/z:260.0[M−1].
1H−NMR:(500MHz,CD3OD)(回転異性体):δ7.30−7.24(m,3H),7.15−7.13(m,2H),4.62−4.55(m,2H),4.29−3.97(m,1H),3.98−3.79(m,4H),3.75(s,3H),3.62−3.22(m,2H),3.23(d,J=13.5Hz,1H),3.00−2.95(q,1H),2.37−2.31(m,1H),2.23−2.10(m,2H),2.02−1.88(m,3H),1.46−1.28(m,2H),0.97(d,J=7.0Hz,6H).
1H−NMR:(500MHz,CD3OD)(回転異性体):δ7.33−7.26(m,3H),7.16(s,2H),4.55−4.54(m,1H),4.39(s,1H),4.14(s,1H),4.01−3.98(m,1H),3.91−3.71(m,3H),3.59(s,2H),3.25−3.16(m,1H),3.04−3.00(m,1H),2.33−2.10(m,3H),2.01−1.91(m,2H),1.86−1.80(m,1H),1.46−1.44(m,1H),1.34−1.29(m,1H),1.25−1.19(m,3H),0.99−0.97(d,J=14.0Hz,3H).
質量m/z:503[M+];HPLC純度:98.1%.
当業者は、日常的な実験のみを用いて、本明細書に記載される本発明の特定の実施形態に対する多くの等価物を認識する、または確認することができるだろう。そのような等価物は、以下の特許請求の範囲によって網羅されることが意図される。
本明細書に引用したすべての特許、公開された特許出願、ウェブサイト及び他の引用文献は、参照によりそれらの全体を本明細書に明示的に組み込まれる。
Claims (23)
- 治療を必要とする患者の統合失調症を治療する方法であって、前記患者へ
非定型的抗精神病薬、ならびに
rapastinel、(S)−N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシプロパノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシ−プロパノイル)−ピロリジン−2−カルボニル)−ピロリジン−2−カルボキサミド、及びN−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミドからなる群から選択されるNMDA調節剤を投与することを含む、前記方法。 - 治療を必要とする患者の双極性障害を治療する方法であって、前記患者へ
非定型的抗精神病薬、ならびに
rapastinel、(S)−N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシプロパノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシ−プロパノイル)−ピロリジン−2−カルボニル)−ピロリジン−2−カルボキサミド、及びN−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミドからなる群から選択されるNMDA調節剤を投与することを含む、前記方法。 - 治療を必要とする患者の認知障害疾患を治療する方法であって、前記患者に非定型的抗精神病薬、ならびにrapastinel、(S)−N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシプロパノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシ−プロパノイル)−ピロリジン−2−カルボニル)−ピロリジン−2−カルボキサミド、及びN−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミドからなる群から選択されるNMDA調節剤を投与することを含む、前記方法。
- 前記認知障害疾患が、認知能力の障害、先天性欠陥、環境因子(複数可)または薬物誘発のうちの1つ以上が原因である、請求項3に記載の方法。
- 前記認知障害疾患が、学習障害、自閉症及び/または失読症である、請求項4に記載の方法。
- 治療を必要とする患者の大うつ病性障害を治療する方法であって、前記患者へ
非定型的抗精神病薬、ならびに
rapastinel、(S)−N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシプロパノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)ピロリジン−2−カルボニル)ピロリジン−2−カルボキサミド、(S)−N−((S)−1−アミノ−3−ヒドロキシ−1−オキソプロパン−2−イル)−1−((S)−1−((S)−2−アミノ−3−ヒドロキシ−プロパノイル)−ピロリジン−2−カルボニル)−ピロリジン−2−カルボキサミド、及びN−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミドからなる群からのNMDA調節剤を投与することを含む、前記方法。 - 前記大うつ病性障害が難治性である、請求項6に記載の方法。
- 前記非定型的抗精神病薬がルラシドン、クエチアピン、オランザピン、アセナピン、リスペリドン、ジプラシドン、クロザピン、メルペロン、カリプラジン、アリピプラゾール、ピマバンセリン、ITI−007、RP506及びレモキシプリドを含む、請求項1〜7のいずれか一項に記載の方法。
- 前記非定型的抗精神病薬がルラシドンである、請求項1〜8のいずれか一項に記載の方法。
- 前記NMDA調整剤及び前記非定型的抗精神病薬が、単独で投与される場合、亜有効用量でそれぞれ投与される、請求項1〜9のいずれか一項に記載の方法。
- 前記NMDA調節剤を投与することが、前記非定型的抗精神病薬を投与することと実質的に同時に生じる、請求項1〜10のいずれか一項に記載の方法。
- 前記NMDA調節剤及び前記非定型的抗精神病薬が連続的に投与される、請求項1〜10のいずれか一項に記載の方法。
- 前記NMDA調節剤が、前記非定型的抗精神病薬の前に投与される、請求項12に記載の方法。
- 前記NMDA調節剤が、前記非定型的抗精神病薬の後に投与される、請求項12に記載の方法。
- NMDARアンタゴニストを亜慢性的に投与された患者の認知障害を実質的に回復または予防する方法であって、前記患者に亜有効用量のNMDA調節剤及び亜有効用量の非定型的抗精神病薬を投与することを含む、前記方法。
- 前記NMDARアンタゴニストがケタミンである、請求項15に記載の方法。
- 前記NMDA調節剤がrapastinelである、請求項1〜16のいずれか一項に記載の方法。
- 前記NMDA調節剤が、N−((2S,3R)−1−アミノ−3−ヒドロキシ−1−オキソブタン−2−イル)−1−((S)−1−((2S,3R)−2−アミノ−3−ヒドロキシブタノイル)−ピロリジン−2−カルボニル)−2−ベンジルピロリジン−2−カルボキサミドである、請求項1〜16のいずれか一項に記載の方法。
- NMDA調整剤及び非定型的抗精神病薬を含む、薬学的に許容される組成物。
- NMDARアンタゴニストを更に含む、請求項19に記載の薬学的に許容される組成物。
- 前記NMDARアンタゴニストがケタミンである、請求項20に記載の薬学的に許容される組成物。
- 前記非定型的抗精神病薬がルラシドンである、請求項19〜21のいずれか一項に記載の薬学的に許容される組成物。
- 前記NMDA調節剤がrapastinelである、請求項19〜22のいずれか一項に記載の薬学的に許容される組成物。
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