JP2022159322A - Nmdar調節化合物の組合せ - Google Patents
Nmdar調節化合物の組合せ Download PDFInfo
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- JP2022159322A JP2022159322A JP2022116942A JP2022116942A JP2022159322A JP 2022159322 A JP2022159322 A JP 2022159322A JP 2022116942 A JP2022116942 A JP 2022116942A JP 2022116942 A JP2022116942 A JP 2022116942A JP 2022159322 A JP2022159322 A JP 2022159322A
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- JP
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- Prior art keywords
- nmdar antagonist
- glyx
- nmdar
- antagonist
- alkyl
- 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.)
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Abstract
Description
本出願は、その全体が参照によって本明細書に組み込まれる、2014年5月6日出願の米国特許仮出願第61/989,183号の利益を請求する。
本開示は、1種または複数種のNMDARアンタゴニスト及びGLYX-13を含む組み合わせを特色とする(これらはそれぞれ、本明細書において時に、「構成要素」と称される)。上記組み合わせの有益効果は、部分的に、GLYX-13の投与(例えば、単回投与)が、NMDARアンタゴニスト誘発性認知障害(例えば、新規物体認識におけるNMDARアンタゴニスト誘発性障害;例えば、NMDARアンタゴニストの繰り返し投与によって誘発)を反転及び/または予防し得るという発見に基づく。上記組み合わせは、1種もしくは複数種の他の生物学的活性成分(例えば、1種または複数種の他の抗うつ化合物)ならびに/または1種もしくは複数種の薬学的に許容される添加剤及び/もしくは担体をさらに含み得る。上記組合せの構成要素(本明細書において時に、化学成分または化学化合物とも称される)は、患者に、連続的に(各構成要素を、異なる時間に投与する)、または実質的に同時に投与することができる。構成要素が、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分かるであろう。別法では、構成要素はそれぞれ、従来の経口剤形もしくは非経口形態(または一方の構成要素は経口であってよく、他方は非経口であってよい)など、同時に、または順に投与することができる別々の医薬担体中に存在することができる。一部の実施形態では、GLYX-13での事前処置(すなわち、1種または複数種のNMDARアンタゴニストを投与する前に投与)が、特に有利であり得る。
GLYX-13は、参照によって本明細書に組み込まれる米国特許第5,763,393号及び同第4,086,196号において記載されているものなどの周知の組換えまたは合成方法によって得てもよい。GLYX 13の多形体、水和物、同族体、溶媒和物、遊離塩基、及び/またはこれらだけに限定されないが、酢酸塩などの適切な塩形態も企図されている。ペプチドは、米国特許第5,763,393号においてさらに記載されているとおりの環化または非環化形態であってもよい。一部の実施形態では、GLYX-13類似体は、CH2、OH、またはNH2部分の欠失など、1個または複数個のThrまたはPro基上の部分の挿入または欠失を含んでよい。他の実施形態では、GLYX-13は、1個または複数個のハロゲン、C1~C3アルキル(ハロゲンまたはアミノで置換されていてもよい)、ヒドロキシル、及び/またはアミノで置換されていてもよい。本明細書において使用するために企図される他の化合物には、それらの内容全体が参照によって本明細書に組み込まれる米国特許第5,763,393号、米国特許第6,107,271号、及びWoodら、Neuro. Report、19、1059~1061、2008において開示されているNMDARのグリシン部位部分アゴニストが含まれる。
[式中、
R1は、ハロ;-OH;NRaRb(ここで、Ra及びRbはそれぞれ、H及びC1~C3アルキルから独立に選択される);C1~C3アルキル;及びC1~C3アルコキシからなる群から独立に選択される1~3個の置換基でそれぞれ置換されていてもよいフェニル、チエニル、またはベンゾチエニルであり;
R2は、Rc及びRdがそれぞれ、H、及び-OHまたはC1~C3アルコキシで置換されていてもよいC1~C6アルキルから独立に選択されるか;またはRc及びRdが、それぞれが結合している窒素原子と一緒に、1~2個の独立に選択されるC1~C3アルキルで置換されていてもよい5~7員環を形成している-NRcRdであり;
R3は、H、オキソ、またはC1~C3アルキルである;
またはその薬学的に許容される塩もしくはプロドラッグ]。
R1は、ハロ;-OH;NRaRb(ここで、Ra及びRbはそれぞれ独立に、H及びC1~C3アルキルから選択される);C1~C3アルキル;及びC1~C3アルコキシからなる群から独立に選択される1~3個の置換基で置換されていてもよいフェニルであり(例えば、R1は、フェニル、3-ヒドロキシフェニル、3-メトキシフェニル、3-アミノフェニル、3-メチルフェニル、4-フルオロフェニル、4-ヒドロキシフェニル、3-メトキシフェニル、または2-クロロフェニルである);
R2は、Rc及びRdがそれぞれ独立に、H、及び-OHまたはC1~C3アルコキシで置換されていてもよいC1~C6アルキル;例えば、H及びC1~C6アルキル、例えば、H及びC1~C3アルキルから選択され;例えば、Rc及びRdの一方が、Hであり、他方が、C1~C3アルキルである-NRcRdであり;例えば、R2は、-NH(C1~C3アルキル)、例えば、-NH(CH3)であり得;
R3は、Hまたはオキソ(例えば、オキソ)である。
R1は、ハロ;-OH;NRaRb(ここで、Ra及びRbはそれぞれ独立に、H及びC1~C3アルキルから選択される);C1~C3アルキル;及びC1~C3アルコキシからなる群から独立に選択される1~3個の置換基で置換されていてもよいフェニルであり(例えば、R1は、フェニル、3-ヒドロキシフェニル、3-メトキシフェニル、3-アミノフェニル、3-メチルフェニル、4-フルオロフェニル、4-ヒドロキシフェニル、3-メトキシフェニル、または2-クロロフェニルである);
R2は、Rc及びRdが、それぞれが結合している窒素と一緒に、1~2個の独立に選択されるC1~C3アルキルで置換されていてもよい5~7員環を形成している-NRcRd、例えば、ピペリジニルであり;
R3は、Hまたはオキソ(例えば、H)である。
一態様では、NMDARアンタゴニストを急性投与される患者において認知障害を実質的に反転または予防する方法であって、有効量のGLYX-13を投与することを含む方法を提供する。
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。ある種の実施形態では、そのような組成物を、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。ある種の実施形態では、単回用量は、約1mL~約4mL(例えば、3mL)の体積を有し得る。
なお、本発明としては、以下の態様も好ましい。
〔1〕 有効量のGLYX-13を投与することを含む、NMDARアンタゴニストを急性投与される患者において認知障害を実質的に反転または予防する方法。
〔2〕 前記NMDARアンタゴニストを急性投与する前に、有効量のGLYX-13の前記投与を行う、〔1〕に記載の方法。
〔3〕 前記NMDARアンタゴニストを急性投与した後に、有効量のGLYX-13の前記投与を行う、〔1〕に記載の方法。
〔4〕 前記NMDARアンタゴニストの急性投与と実質的に同時に、有効量のGLYX-13の前記投与を行う、〔1〕に記載の方法。
〔5〕 GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者において認知欠陥障害を処置する方法。
〔6〕 前記認知欠陥障害が、認知能力の不足、先天性欠陥、環境因子(複数可)、または薬物誘発の1つまたは複数のためである、〔5〕に記載の方法。
〔7〕 前記認知欠陥障害が、学習障害及び/または失読症である、〔5〕に記載の方法。
〔8〕 GLYX-13及びNMDARアンタゴニストを投与することを含む、神経学的障害または他の障害を処置する方法。
〔9〕 前記障害が、卒中、精神病性障害、疼痛(神経障害性疼痛)、うつ病(大うつ病)、パーキンソン病、及びアルツハイマー病からなる群から選択される、〔8〕に記載の方法。
〔10〕 GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者において中枢神経系疾患を処置するための方法。
〔11〕 前記中枢神経系疾患が、神経変性疾患、卒中、外傷性脳損傷、及び脊髄損傷からなる群から選択される、〔10〕に記載の方法。
〔12〕 GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者において統合失調症を処置する方法。
〔13〕 GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者においてうつ病を処置する方法。
〔14〕 前記うつ病が難治性うつ病である、〔13〕に記載の方法。
〔15〕 前記GLYX-13及び前記NMDARアンタゴニストを実質的に同時に投与する、〔5〕から〔14〕のいずれか一項に記載の方法。
〔16〕 前記GLYX-13及び前記NMDARアンタゴニストを順に投与する、〔5〕から〔14〕のいずれか一項に記載の方法。
〔17〕 前記NMDARアンタゴニストの前に、前記GLYX-13を投与する、〔16〕に記載の方法。
〔18〕 前記NMDARアンタゴニストの後に、前記GLYX-13を投与する、〔16〕に記載の方法。
〔19〕 GLYX-13及びNMDARアンタゴニストを含む、薬学的に許容される組成物。
〔20〕 前記NMDARアンタゴニストが、式(I):
[式中、
R 1 は、ハロ;-OH;NR a R b (ここで、R a 及びR b はそれぞれ、H及びC 1 ~C 3 アルキルから独立に選択される);C 1 ~C 3 アルキル;及びC 1 ~C 3 アルコキシからなる群から独立に選択される1~3個の置換基でそれぞれ置換されていてもよいフェニル、チエニル、またはベンゾチエニルであり;
R 2 は、R c 及びR d がそれぞれ、H、及び-OHまたはC 1 ~C 3 アルコキシで置換されていてもよいC 1 ~C 6 アルキルから独立に選択されるか;またはR c 及びR d が、それぞれが結合している窒素原子と一緒に、1~2個の独立に選択されるC 1 ~C 3 アルキルで置換されていてもよい5~7員環を形成している-NR c R d であり;
R 3 は、H、オキソ、またはC 1 ~C 3 アルキルである;
またはその薬学的に許容される塩もしくはプロドラッグ]を有する、〔1〕から〔18〕のいずれか一項に記載の方法、または〔19〕に記載の医薬組成物。
〔21〕 R 1 が、ハロ;-OH;NR a R b (ここで、R a 及びR b はそれぞれ独立に、H及びC 1 ~C 3 アルキルから選択される);C 1 ~C 3 アルキル;及びC 1 ~C 3 アルコキシからなる群から独立に選択される1~3個の置換基で置換されていてもよいフェニルである、〔20〕に記載の方法。
〔22〕 R 1 が、フェニル、3-ヒドロキシフェニル、3-メトキシフェニル、3-アミノフェニル、3-メチルフェニル、4-フルオロフェニル、4-ヒドロキシフェニル、3-メトキシフェニル、または2-クロロフェニルである、〔21〕に記載の方法。
〔23〕 R 2 が、-NH(C 1 ~C 3 アルキル)またはピペリジニルである、〔20〕に記載の方法。
〔24〕 R 3 が、Hまたはオキソである、〔20〕に記載の方法。
〔25〕 R 1 がフェニルであり、R 2 がピペリジニルであり、R 3 がHである、〔20〕に記載の方法。
〔26〕 R 1 が2-クロロフェニルであり、R 2 が-NH(CH 3 )であり、R 3 がオキソである、〔20〕に記載の方法。
〔27〕 前記NMDARアンタゴニストが、ケタミン、メマンチン、ラニセミン(AZD6765)、CERC-301、デキストロメトルファン、デキストロルファン、フェンシクリジン、ジゾシルピン(MK-801)、アマンタジン、イフェンプロジル、AV-101、AZD6423、及びリルゾール、またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔1〕から〔18〕のいずれか一項に記載の方法、または〔19〕に記載の医薬組成物。
〔28〕 前記NMDARアンタゴニストがケタミンである、〔27〕に記載の方法。
〔29〕 前記NMDARアンタゴニストが(S)-ケタミンである、〔28〕に記載の方法。
〔30〕 前記NMDARアンタゴニストがフェンシクリジンである、〔27〕に記載の方法。
〔31〕 前記NMDARアンタゴニストが、メマンチンまたはアマンタジンである、〔27〕に記載の方法。
〔32〕 前記NMDARアンタゴニストがジゾシルピン(MK-801)である、〔27〕に記載の方法。
〔33〕 前記NMDARアンタゴニストが、デキストロメトルファンまたはデキストロルファンである、〔27〕に記載の方法。
〔34〕 前記NMDARアンタゴニストが、ラニセミン(AZD6765)、CERC-301、AV-101、AZD6423、またはイフェンプロジルである、〔27〕に記載の方法。
〔35〕 前記NMDARアンタゴニストが、亜酸化窒素、アトモキセチン、デキストラロルファン、ジフェニジン、エチシクリジン、ガシクリジン、イボガイン、メトキセタミン、ニトロメマンチン、ロリシクリジン、テノシクリジン、メトキシジン、チレタミン、ネラメキサン、エリプロジル、エトキサドロール、デキソキサドロール、メタドン、WMS-2539、NEFA、レマセミド、デルセミン、8A-PDHQ、アプチガネル(Cerestat、CNS-1102)、HU-211、レマセミド、リンコフィリン、TK-40、トラキソプロジル(CP-101,606)、1-アミノシクロプロパンカルボン酸(ACPC)、キヌレン酸もしくはその誘導体、2-カルボキシテトラヒドロキノリンもしくはその誘導体、2-カルボキシインドールもしくはその誘導体、4-ヒドロキシ-2-キノリンもしくはその誘導体、4-ヒドロキシキノリンもしくはその誘導体、キノキサリン-2,3-ジオンもしくはその誘導体、三環式アンタゴニスト、ラコサミド、L-フェニルアラニン、ミダフォテル、及びアプチガネル、またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔1〕から〔18〕のいずれか一項に記載の方法、または〔19〕に記載の医薬組成物。
〔36〕 前記NMDARアンタゴニストが、2-カルボキシテトラヒドロキノリンまたはその誘導体である、〔35〕に記載の方法。
〔37〕 前記NMDARアンタゴニストが、
またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔36〕に記載の方法。
〔38〕 前記NMDARアンタゴニストが、2-カルボキシインドールまたはその誘導体である、〔35〕に記載の方法。
〔39〕 前記NMDARアンタゴニストが、
またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔38〕に記載の方法。
〔40〕 前記NMDARアンタゴニストが、キヌレン酸またはその誘導体である、〔35〕に記載の方法。
〔41〕 前記NMDARアンタゴニストが、
またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔40〕に記載の方法。
〔42〕 前記NMDARアンタゴニストが、4-ヒドロキシキノリンまたはその誘導体である、〔35〕に記載の方法。
〔43〕 前記NMDARアンタゴニストが、
またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔42〕に記載の方法。
〔44〕 前記NMDARアンタゴニストが、キノキサリン-2,3-ジオンまたはその誘導体である、〔35〕に記載の方法。
〔45〕 前記NMDARアンタゴニストが、
またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔44〕に記載の方法。
〔46〕 前記NMDARアンタゴニストが、三環式アンタゴニストである、〔35〕に記載の方法。
〔47〕 前記NMDARアンタゴニストが、
またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、〔46〕に記載の方法。
Claims (47)
- 有効量のGLYX-13を投与することを含む、NMDARアンタゴニストを急性投与される患者において認知障害を実質的に反転または予防する方法。
- 前記NMDARアンタゴニストを急性投与する前に、有効量のGLYX-13の前記投与を行う、請求項1に記載の方法。
- 前記NMDARアンタゴニストを急性投与した後に、有効量のGLYX-13の前記投与を行う、請求項1に記載の方法。
- 前記NMDARアンタゴニストの急性投与と実質的に同時に、有効量のGLYX-13の前記投与を行う、請求項1に記載の方法。
- GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者において認知欠陥障害を処置する方法。
- 前記認知欠陥障害が、認知能力の不足、先天性欠陥、環境因子(複数可)、または薬物誘発の1つまたは複数のためである、請求項5に記載の方法。
- 前記認知欠陥障害が、学習障害及び/または失読症である、請求項5に記載の方法。
- GLYX-13及びNMDARアンタゴニストを投与することを含む、神経学的障害または他の障害を処置する方法。
- 前記障害が、卒中、精神病性障害、疼痛(神経障害性疼痛)、うつ病(大うつ病)、パーキンソン病、及びアルツハイマー病からなる群から選択される、請求項8に記載の方法。
- GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者において中枢神経系疾患を処置するための方法。
- 前記中枢神経系疾患が、神経変性疾患、卒中、外傷性脳損傷、及び脊髄損傷からなる群から選択される、請求項10に記載の方法。
- GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者において統合失調症を処置する方法。
- GLYX-13及びNMDARアンタゴニストを投与することを含む、それを必要とする患者においてうつ病を処置する方法。
- 前記うつ病が難治性うつ病である、請求項13に記載の方法。
- 前記GLYX-13及び前記NMDARアンタゴニストを実質的に同時に投与する、請求項5から14のいずれか一項に記載の方法。
- 前記GLYX-13及び前記NMDARアンタゴニストを順に投与する、請求項5から14のいずれか一項に記載の方法。
- 前記NMDARアンタゴニストの前に、前記GLYX-13を投与する、請求項16に記載の方法。
- 前記NMDARアンタゴニストの後に、前記GLYX-13を投与する、請求項16に記載の方法。
- GLYX-13及びNMDARアンタゴニストを含む、薬学的に許容される組成物。
- 前記NMDARアンタゴニストが、式(I):
[式中、
R1は、ハロ;-OH;NRaRb(ここで、Ra及びRbはそれぞれ、H及びC1~C3アルキルから独立に選択される);C1~C3アルキル;及びC1~C3アルコキシからなる群から独立に選択される1~3個の置換基でそれぞれ置換されていてもよいフェニル、チエニル、またはベンゾチエニルであり;
R2は、Rc及びRdがそれぞれ、H、及び-OHまたはC1~C3アルコキシで置換されていてもよいC1~C6アルキルから独立に選択されるか;またはRc及びRdが、それぞれが結合している窒素原子と一緒に、1~2個の独立に選択されるC1~C3アルキルで置換されていてもよい5~7員環を形成している-NRcRdであり;
R3は、H、オキソ、またはC1~C3アルキルである;
またはその薬学的に許容される塩もしくはプロドラッグ]を有する、請求項1から18のいずれか一項に記載の方法、または請求項19に記載の医薬組成物。 - R1が、ハロ;-OH;NRaRb(ここで、Ra及びRbはそれぞれ独立に、H及びC1~C3アルキルから選択される);C1~C3アルキル;及びC1~C3アルコキシからなる群から独立に選択される1~3個の置換基で置換されていてもよいフェニルである、請求項20に記載の方法。
- R1が、フェニル、3-ヒドロキシフェニル、3-メトキシフェニル、3-アミノフェニル、3-メチルフェニル、4-フルオロフェニル、4-ヒドロキシフェニル、3-メトキシフェニル、または2-クロロフェニルである、請求項21に記載の方法。
- R2が、-NH(C1~C3アルキル)またはピペリジニルである、請求項20に記載の方法。
- R3が、Hまたはオキソである、請求項20に記載の方法。
- R1がフェニルであり、R2がピペリジニルであり、R3がHである、請求項20に記載の方法。
- R1が2-クロロフェニルであり、R2が-NH(CH3)であり、R3がオキソである、請求項20に記載の方法。
- 前記NMDARアンタゴニストが、ケタミン、メマンチン、ラニセミン(AZD6765)、CERC-301、デキストロメトルファン、デキストロルファン、フェンシクリジン、ジゾシルピン(MK-801)、アマンタジン、イフェンプロジル、AV-101、AZD6423、及びリルゾール、またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、請求項1から18のいずれか一項に記載の方法、または請求項19に記載の医薬組成物。
- 前記NMDARアンタゴニストがケタミンである、請求項27に記載の方法。
- 前記NMDARアンタゴニストが(S)-ケタミンである、請求項28に記載の方法。
- 前記NMDARアンタゴニストがフェンシクリジンである、請求項27に記載の方法。
- 前記NMDARアンタゴニストが、メマンチンまたはアマンタジンである、請求項27に記載の方法。
- 前記NMDARアンタゴニストがジゾシルピン(MK-801)である、請求項27に記載の方法。
- 前記NMDARアンタゴニストが、デキストロメトルファンまたはデキストロルファンである、請求項27に記載の方法。
- 前記NMDARアンタゴニストが、ラニセミン(AZD6765)、CERC-301、AV-101、AZD6423、またはイフェンプロジルである、請求項27に記載の方法。
- 前記NMDARアンタゴニストが、亜酸化窒素、アトモキセチン、デキストラロルファン、ジフェニジン、エチシクリジン、ガシクリジン、イボガイン、メトキセタミン、ニトロメマンチン、ロリシクリジン、テノシクリジン、メトキシジン、チレタミン、ネラメキサン、エリプロジル、エトキサドロール、デキソキサドロール、メタドン、WMS-2539、NEFA、レマセミド、デルセミン、8A-PDHQ、アプチガネル(Cerestat、CNS-1102)、HU-211、レマセミド、リンコフィリン、TK-40、トラキソプロジル(CP-101,606)、1-アミノシクロプロパンカルボン酸(ACPC)、キヌレン酸もしくはその誘導体、2-カルボキシテトラヒドロキノリンもしくはその誘導体、2-カルボキシインドールもしくはその誘導体、4-ヒドロキシ-2-キノリンもしくはその誘導体、4-ヒドロキシキノリンもしくはその誘導体、キノキサリン-2,3-ジオンもしくはその誘導体、三環式アンタゴニスト、ラコサミド、L-フェニルアラニン、ミダフォテル、及びアプチガネル、またはそれらの薬学的に許容される塩もしくはプロドラッグからなる群から選択される、請求項1から18のいずれか一項に記載の方法、または請求項19に記載の医薬組成物。
- 前記NMDARアンタゴニストが、2-カルボキシテトラヒドロキノリンまたはその誘導体である、請求項35に記載の方法。
- 前記NMDARアンタゴニストが、2-カルボキシインドールまたはその誘導体である、請求項35に記載の方法。
- 前記NMDARアンタゴニストが、キヌレン酸またはその誘導体である、請求項35に記載の方法。
- 前記NMDARアンタゴニストが、4-ヒドロキシキノリンまたはその誘導体である、請求項35に記載の方法。
- 前記NMDARアンタゴニストが、キノキサリン-2,3-ジオンまたはその誘導体である、請求項35に記載の方法。
- 前記NMDARアンタゴニストが、三環式アンタゴニストである、請求項35に記載の方法。
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US10221182B2 (en) | 2015-02-04 | 2019-03-05 | Rugen Holdings (Cayman) Limited | 3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists |
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KR20230056971A (ko) * | 2021-10-21 | 2023-04-28 | 삼육대학교산학협력단 | 신규 케타민 유도체를 포함하는 우울증 예방 또는 치료용 약학적 조성물 |
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---|---|---|---|---|
US5597809A (en) * | 1994-06-23 | 1997-01-28 | Massachusetts Eye & Ear Infirmary | Treatment of optic neuritis |
AU2004251636B2 (en) * | 2003-05-27 | 2006-11-09 | Merz Pharma Gmbh & Co. Kgaa | Combination of an NMDA receptor antagonist and a selective serotonin reuptake inhibitor for the treatment of depression and other mood disorders |
GB0523998D0 (en) * | 2005-11-25 | 2006-01-04 | Merck Sharp & Dohme | Therapeutic agents |
US20090275597A1 (en) * | 2008-05-02 | 2009-11-05 | Forest Laboratories Holdings Limited | Methods of treating cns disorders |
UY31956A (es) * | 2008-07-03 | 2010-01-29 | Amira Pharmaceuticals Inc | Antagonistas de heteroalquilo de receptores de prostaglandina d2 |
WO2010078348A1 (en) * | 2008-12-29 | 2010-07-08 | Vanderbilt University | 3.1.0 bicyclic glyt1 inhibitors and methods of making and using same |
US8951968B2 (en) * | 2009-10-05 | 2015-02-10 | Northwestern University | Methods of treating depression and other related diseases |
US8846765B2 (en) * | 2010-06-15 | 2014-09-30 | Gruenenthal Gmbh | Pharmaceutical combination |
US9737531B2 (en) * | 2012-07-12 | 2017-08-22 | Glytech, Llc | Composition and method for treatment of depression and psychosis in humans |
MX2014010939A (es) * | 2012-03-12 | 2014-11-13 | Janssen Pharmaceutica Nv | Esketamina para el tratamiento de la depresion refractaria al tratamiento o resistente al tratamiento. |
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- 2015-05-06 CN CN201580031430.2A patent/CN106659762A/zh active Pending
- 2015-05-06 KR KR1020167034031A patent/KR20170013890A/ko not_active Application Discontinuation
- 2015-05-06 KR KR1020227022906A patent/KR20220102662A/ko not_active Application Discontinuation
- 2015-05-06 MX MX2016014581A patent/MX2016014581A/es unknown
- 2015-05-06 RU RU2016146714A patent/RU2721948C2/ru active
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- 2015-05-06 BR BR112016025910A patent/BR112016025910A8/pt not_active Application Discontinuation
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AU2015256075A1 (en) | 2016-11-24 |
BR112016025910A8 (pt) | 2021-07-13 |
CA2947976A1 (en) | 2015-11-12 |
RU2016146714A3 (ja) | 2018-10-08 |
CN106659762A (zh) | 2017-05-10 |
EP3139943A4 (en) | 2018-07-18 |
JP2020138973A (ja) | 2020-09-03 |
EP3139943A1 (en) | 2017-03-15 |
BR112016025910A2 (pt) | 2017-08-15 |
AU2015256075B2 (en) | 2021-02-25 |
RU2721948C2 (ru) | 2020-05-25 |
US20170072005A1 (en) | 2017-03-16 |
KR20220102662A (ko) | 2022-07-20 |
JP2017514871A (ja) | 2017-06-08 |
RU2016146714A (ru) | 2018-06-06 |
MX2016014581A (es) | 2018-02-16 |
KR20170013890A (ko) | 2017-02-07 |
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