JP2017518323A - オキシステロールおよびその使用方法 - Google Patents
オキシステロールおよびその使用方法 Download PDFInfo
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- JP2017518323A JP2017518323A JP2016572739A JP2016572739A JP2017518323A JP 2017518323 A JP2017518323 A JP 2017518323A JP 2016572739 A JP2016572739 A JP 2016572739A JP 2016572739 A JP2016572739 A JP 2016572739A JP 2017518323 A JP2017518323 A JP 2017518323A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
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Abstract
Description
本願は、米国仮出願第62/014,014号(2014年6月18日出願)、および米国仮出願第62/107,236号(2015年1月23日出願)に対する優先権を主張する。これらの全内容は、本明細書中に参考として援用される。
NMDAレセプターは、NR1、NR2、および/またはNR3サブユニットを含むヘテロメリック複合体であり、外因性リガンドおよび内因性リガンドのための異なる認識部位を有する。これらの認識部位は、グリシンのための結合部位ならびにグルタミン酸アゴニストおよびモジュレーターを含む。NMDAレセプターは、末梢組織およびCNSにおいて発現され、ここで興奮性シナプス伝達に関与する。これらのレセプターを活性化すると、状況によってはシナプス可塑性に寄与し、他の場合には興奮毒性に寄与する。これらのレセプターは、グルタメートとグリシンとの結合後にCa2+を受け入れるリガンド依存性イオンチャネルであり、そして興奮性神経伝達および正常なCNS機能にとって基本的である。正のモジュレーターは、認知増強剤として、およびグルタミン酸作動性伝達が低下または欠損している精神障害の治療において潜在的な臨床用途を有する治療剤として有用であり得る(例えば、Horak et al.,J.of Neuroscience,2004,24(46),10318−10325を参照のこと)。対照的に、負のモジュレーターは、グルタミン酸作動性伝達が病理学的に増加している精神医学的障害(例えば、治療抵抗性うつ病)の治療において潜在的な臨床用途を有する治療薬として有用であり得る。
オキシステロールは、コレステロールに由来し、NMDAレセプター機能を強力かつ選択的に調節することが示されている。NMDAの発現および機能に関連する状態の予防および治療のためにNMDAレセプターを調節する新規および改善されたオキシステロールが必要である。本明細書に記載の化合物、組成物および方法は、この目的に向けられている。
本明細書中で、広範な障害(NMDAにより媒介される障害が挙げられるが、これに限定されない)を予防および/または処置するために有用な、置換オキシステロールが提供される。これらの化合物は、他のステロールと比較される場合に、改善されたインビボ効力、薬物動態学(PK)特性、経口バイオアベイラビリディ、製剤化性、安定性、および/または安全性を示すと予測される。さらに、本発明の化合物を含有する薬学的組成物、ならびにこれらの使用および処置の方法が提供される。
1つの局面において、本明細書中で、式(I):
定義
化学的定義
または炭素原子上の2つのジェミナル水素は、=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbbもしくは=NORcc基で置き換えられ;
Raaの各存在は、独立して、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリールおよび5〜14員ヘテロアリールから選択されるか、または2つのRaa基が連結して、3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、ここで、各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0個、1個、2個、3個、4個または5個のRdd基で置換され;
Rbbの各存在は、独立して、水素、−OH、−ORaa、−N(Rcc)2、−CN、−C(=O)Raa、−C(=O)N(Rcc)2、−CO2Raa、−SO2Raa、−C(=NRcc)ORaa、−C(=NRcc)N(Rcc)2、−SO2N(Rcc)2、−SO2Rcc、−SO2ORcc、−SORaa、−C(=S)N(Rcc)2、−C(=O)SRcc、−C(=S)SRcc、−P(=O)2Raa、−P(=O)(Raa)2、−P(=O)2N(Rcc)2、−P(=O)(NRcc)2、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリールおよび5〜14員ヘテロアリールから選択されるか、または2つのRbb基が連結して、3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、ここで、各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0個、1個、2個、3個、4個または5個のRdd基で置換され;
Rccの各存在は、独立して、水素、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリールおよび5〜14員ヘテロアリールから選択されるか、または2つのRcc基が連結して、3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、ここで、各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0個、1個、2個、3個、4個または5個のRdd基で置換され;
Rddの各存在は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−ORee、−ON(Rff)2、−N(Rff)2、−N(Rff)3 +X−、−N(ORee)Rff、−SH、−SRee、−SSRee、−C(=O)Ree、−CO2H、−CO2Ree、−OC(=O)Ree、−OCO2Ree、−C(=O)N(Rff)2、−OC(=O)N(Rff)2、−NRffC(=O)Ree、−NRffCO2Ree、−NRffC(=O)N(Rff)2、−C(=NRff)ORee、−OC(=NRff)Ree、−OC(=NRff)ORee、−C(=NRff)N(Rff)2、−OC(=NRff)N(Rff)2、−NRffC(=NRff)N(Rff)2、−NRffSO2Ree、−SO2N(Rff)2、−SO2Ree、−SO2ORee、−OSO2Ree、−S(=O)Ree、−Si(Ree)3、−OSi(Ree)3、−C(=S)N(Rff)2、−C(=O)SRee、−C(=S)SRee、−SC(=S)SRee、−P(=O)2Ree、−P(=O)(Ree)2、−OP(=O)(Ree)2、−OP(=O)(ORee)2、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、3〜10員ヘテロシクリル、C6〜10アリール、5〜10員ヘテロアリールから選択され、ここで、各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0個、1個、2個、3個、4個もしくは5個のRgg基で置換されるか、または2つのジェミナルRdd置換基が連結して、=Oもしくは=Sを形成し得;
Reeの各存在は、独立して、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、C6〜10アリール、3〜10員ヘテロシクリルおよび3〜10員ヘテロアリールから選択され、ここで、各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0個、1個、2個、3個、4個または5個のRgg基で置換され;
Rffの各存在は、独立して、水素、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、3〜10員ヘテロシクリル、C6〜10アリールおよび5〜10員ヘテロアリールから選択されるか、または2つのRff基が連結して、3〜14員ヘテロシクリルもしくは5〜14員ヘテロアリール環を形成し、ここで、各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0個、1個、2個、3個、4個または5個のRgg基で置換され;
Rggの各存在は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−OC1〜6アルキル、−ON(C1〜6アルキル)2、−N(C1〜6アルキル)2、−N(C1〜6アルキル)3 +X−、−NH(C1〜6アルキル)2 +X−、−NH2(C1〜6アルキル)+X−、−NH3 +X−、−N(OC1〜6アルキル)(C1〜6アルキル)、−N(OH)(C1〜6アルキル)、−NH(OH)、−SH、−SC1〜6アルキル、−SS(C1〜6アルキル)、−C(=O)(C1〜6アルキル)、−CO2H、−CO2(C1〜6アルキル)、−OC(=O)(C1〜6アルキル)、−OCO2(C1〜6アルキル)、−C(=O)NH2、−C(=O)N(C1〜6アルキル)2、−OC(=O)NH(C1〜6アルキル)、−NHC(=O)(C1〜6アルキル)、−N(C1〜6アルキル)C(=O)(C1〜6アルキル)、−NHCO2(C1〜6アルキル)、−NHC(=O)N(C1〜6アルキル)2、−NHC(=O)NH(C1〜6アルキル)、−NHC(=O)NH2、−C(=NH)O(C1〜6アルキル)、−OC(=NH)(C1〜6アルキル)、−OC(=NH)OC1〜6アルキル、−C(=NH)N(C1〜6アルキル)2、−C(=NH)NH(C1〜6アルキル)、−C(=NH)NH2、−OC(=NH)N(C1〜6アルキル)2、−OC(NH)NH(C1〜6アルキル)、−OC(NH)NH2、−NHC(NH)N(C1〜6アルキル)2、−NHC(=NH)NH2、−NHSO2(C1〜6アルキル)、−SO2N(C1〜6アルキル)2、−SO2NH(C1〜6アルキル)、−SO2NH2、−SO2C1〜6アルキル、−SO2OC1〜6アルキル、−OSO2C1〜6アルキル、−SOC1〜6アルキル、−Si(C1〜6アルキル)3、−OSi(C1〜6アルキル)3 −C(=S)N(C1〜6アルキル)2、C(=S)NH(C1〜6アルキル)、C(=S)NH2、−C(=O)S(C1〜6アルキル)、−C(=S)SC1〜6アルキル、−SC(=S)SC1〜6アルキル、−P(=O)2(C1〜6アルキル)、−P(=O)(C1〜6アルキル)2、−OP(=O)(C1〜6アルキル)2、−OP(=O)(OC1〜6アルキル)2、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、C6〜10アリール、3〜10員ヘテロシクリル、5〜10員ヘテロアリールであるか;または2つのジェミナルRgg置換基が連結して、=Oもしくは=Sを形成し得;ここで、X−は、対イオンである。
他の定義
本明細書中で使用される場合、他に特定されない限り、化合物の「予防有効量」とは、疾患、障害もしくは状態、またはその疾患、障害もしくは状態に関連する1つもしくはより多くの症状を予防するため、あるいはその再発を予防するために充分な量である。化合物の予防有効量とは、その疾患、障害または状態の予防において予防上の利点を提供する、単独でかまたは他の剤と組み合わせての、治療剤の量を意味する。用語「予防有効量」は、予防全体を改善させる量、または別の予防剤の予防効力を増強する量を包含し得る。
[1] 上に一般的に記載されたように、本発明は、広範な障害(NMDAにより媒介される障害が挙げられるが、これに限定されない)を予防および/または処置するために有用な、19−置換オキシステロールを提供する。これらの化合物は、他のステロールと比較される場合に、改善されたインビボ効力、薬物動態学(PK)特性、経口バイオアベイラビリディ、製剤化性、安定性、および/または安全性を示すと予測される。
化合物
薬学的組成物
処置の方法および使用
なお別の局面において、本発明の化合物と別の薬理学的に活性な剤との組み合わせ物が提供される。本明細書中に提供される化合物は、単一の活性剤として投与され得るか、または他の剤と組み合わせて投与され得る。組み合わせでの投与は、当業者に明らかである任意の技術(例えば、別々の投与、逐次投与、同時投与、および交互投与)によって進行し得る。
化合物A3の合成。A2(60g,148mmol)の乾燥ピリジン(400ml)中の溶液に、4−トルエンスルホニルクロリド(62g,325mmol)の乾燥ピリジン(200ml)中の溶液を添加した。室温で2日間撹拌した後に、氷片をこの混合物にゆっくりと添加した。沈殿した固体を濾過し、次いで10%のHClおよび水で洗浄して、粗製生成物A3(100g,95%)を白色固体として得た。1H NMR (400 MHz, CDCl3), δ 7.80−7.78 (d, 2H), 7.74−7.72 (d, 2H), 7.35 (t, 4H), 4.81 (m, 1H), 4.32 (m, 1H), 2.47 (s, 6H), 0.90−0.88 (d, 3H), 0.81 (s, 3H), 0.60 (s, 3H)。
化合物A4の合成。A3(6.72g,9.4mmol)および酢酸カリウム(720mg,7.2mmol)の、水(6mL)およびDMF(40mL)中の溶液を一晩加熱還流させた。この反応混合物を氷水に注ぎ、そしてEtOAc(100ml×3)で抽出した。合わせた有機層をブライン(80mL×2)で洗浄し、Na2SO4で乾燥させ、濾過し、そして濃縮した。その粗製生成物をカラムクロマトグラフィー(シリカゲル,EA/PE=5:1)により精製して、A4(1.60g,43%)を白色固体として得た。1H NMR (400 MHz, CDCl3), δ 5.36 (t, 1H), 3.67 (s, 3H), 3.53 (m, 1H), 1.00 (s, 3H), 0.93−0.92 (d, 3H), 0.68 (s, 3H)。
化合物A5の合成。A4(1.60g,4.1mmol)の無水酢酸(40mL)中の溶液を90℃まで一晩加熱した。その溶媒を減圧により除去し、その残渣を飽和NaHCO3(50mL)で希釈し、そして2時間撹拌した。この混合物をEtOAc(50mL×3)で抽出し、そして合わせた有機層をブライン(60mL)で洗浄し、Na2SO4で乾燥させ、濾過し、そして濃縮した。その粗製生成物をカラムクロマトグラフィー(シリカゲル,EA/PE=1:6)により精製して、A5(1590mg,90%)を白色固体として得た。1H NMR (400 MHz, CDCl3), δ 5.39−5.38 (d, 1H), 4.60 (m, 1H), 3.66 (s, 3H), 2.03 (s, 3H), 1.01 (s, 3H), 0.93−0.92 (d, 3H), 0.68 (s, 3H)。
化合物A6の合成。A5(200mg,0.46mmol)の1,4−ジオキサン(10mL)中の溶液に、水(1mL)および過塩素酸(0.2mL,0.78mmol)を添加した。得られた混合物を光から保護し、そして−10℃まで冷却した。N−ブロモスクシンイミド(125mg,0.70mmol)を一度に添加した。−10℃で30分間撹拌した後に、さらなるN−ブロモスクシンイミド(42mg,0.24mmol)を添加した。この反応混合物を、TLCがSMを示さなくなるまで撹拌した。この反応混合物を0.1MのNa2S2O5溶液(40mL)でクエンチし、そしてEtOAc(40mL×3)で抽出した。合わせた有機層をNa2SO4で乾燥させ、濾過し、そして濃縮した。その残渣をカラムクロマトグラフィー(PE:EA 10:1,5:1)により精製して、A6(100mg,42%)およびA6−a(50mg,21%)を白色固体として得た。A6 1H NMR (400 MHz, CDCl3), δ 5.09 (m, 1H), 3.98 (s, 1H), 3.67 (s, 3H), 2.06 (s, 3H), 1.36 (s, 3H), 0.94−0.92 (d, 3H), 0.72 (s, 3H); A6−a 1H NMR (400 MHz, CDCl3), δ 5.49 (m, 1H), 4.2 (s, 1H), 2.04 (s, 3H), 1.33 (s, 3H), 0.93−0.91 (d, 3H), 0.68 (s, 3H)。
化合物A7の合成。Pd(OAc)4(1.14g,3.32mmol)およびI2(170mg,0.67mmol)のシクロヘキサン(60mL)中の溶液を10分間加熱還流させた。次いで、化合物A6(700mg,1.33mmol)およびAIBN(10mg,0.08mmol)を添加し、そして得られた混合物を一晩還流させた。この反応混合物を室温まで放冷し、セライトのプラグで濾過し、そしてEtOAc(100mL)で洗浄した。その有機層を10%のメタ重亜硫酸ナトリウムの溶液(40mL×2)で洗浄し、Na2SO4で乾燥させ、濾過し、そして濃縮した。その残渣をカラムクロマトグラフィー(シリカゲル,EA/PE=1:5)により精製して、A7(500mg,83%)を白色固体として得た。1H NMR (400 MHz, CDCl3), δ 5.21 (m, 1H), 4.07−4.06 (d, 1H), 3.94−3.92 (d, 1H), 3.76−3.74 (d, 1H), 3.67 (s, 3H), 2.04 (s, 3H), 0.92−0.91 (d, 3H), 0.70 (s, 3H)。
化合物A8の合成。A7(500mg,0.95mmol)のEtOH(40mL)中の溶液に、Zn(620mg,9.5mmol)を添加し、得られた溶液を4時間加熱還流させた。この反応混合物を室温まで放冷し、セライトのプラグで濾過し、EtOAcで洗浄し、そして濃縮した。その残渣をカラムクロマトグラフィー(シリカゲル,EA/PE=5:1)により精製して、A8(310mg,72%)を白色固体として、そしてA8−a(80mg,17%)を白色固体として得た。A8 1H NMR (400 MHz, CDCl3), δ 5.78 (t, 1H), 4.66 (m, 1H), 3.86−3.83 (d, 1H), 3.67 (s, 3H), 3.64−3.61 (d, 1H), 2.05 (s, 3H), 0.94−0.93 (d, 3H), 0.74 (s, 3H)。A8−a 1H NMR (400 MHz, CDCl3), δ 5.75 (m, 1H), 3.84−3.81 (d, 1H), 3.67 (s, 3H), 3.62−3.60 (d, 1H), 0.94−0.92 (d, 3H), 0.74 (s, 3H)。
化合物1の合成。A8−a(70mg,0.17mmol)のTHF(5mL)中の溶液に、MeMgBr(2mL,THF中1M)を滴下により添加した。室温で一晩撹拌した後に、この混合物を水(20mL)でクエンチし、そしてEtOAc(15mL×3)で抽出した。合わせた有機層をブラインで洗浄し、Na2SO4で乾燥させ、濾過し、そして濃縮した。その残渣をカラムクロマトグラフィー(シリカゲル,EA:PE=1:1)により精製して、1(20mg,30%)を白色固体として得た。1H NMR (400 MHz, CD3OD), δ 5.62−5.61 (d, 1H), 3.85−3.82 (d, 1H), 3.59−3.56 (d, 1H), 1.17 (s, 3H), 3.45 (m, 1H), 1.16 (s, 3H), 0.97−0.96 (d, 3H), 0.78 (s, 3H)。
化合物2の合成。B2(140mg,0.336mmol)の乾燥THF(5mL)中の溶液に、N2下0℃でEtMgBr(ジエチルエーテル中3M,0.56mL,1.67mmol)を滴下により添加した。この混合物を25℃まで温め、そして16時間撹拌した。LCMSは、出発物質が完全に消費されたことを示した。この反応混合物を水性NH4Cl(10mL)でクエンチし、EtOAc(10mL×3)で抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、そして濃縮した。その残渣をprep.HPLCにより精製して、2(3mg,2%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ=5.57 (d, J=5.02 Hz, 1 H), 3.59 (d, J=10.04 Hz, 1 H), 3.26−3.32 (m, 4 H), 2.47 (d, J=13.05 Hz, 1 H), 1.61−2.08 (m, 10 H), 1.24−1.49 (m, 9 H), 1.05−1.17 (m, 10 H), 0.74−1.03 (m, 11 H), 0.71 (s, 3 H)。LCMS 2分間のクロマトグラフィーでRt=1.239min、30〜90AB、純度100%、MS ESI calcd. for C29H51O3 [M+H]+ 447, found 411 ([M+H−36]+)。
化合物D3の合成。D2(24.8g,113mmol)のトルエン(100mL)中の撹拌溶液に、Me3Al(トルエン中2M,28.3mL,56.6mmol)をN2下0℃で滴下により添加した。得られた溶液を25℃で1時間撹拌した。これをドライアイス/アセトン浴で−70℃まで冷却し、そして(8R,9S,10S,13S,14S)−10−(メトキシメチル)−13−メチル−7,8,9,10,11,12,13,14,15,16−デカヒドロ−1H−シクロペンタ[a]フェナントレン−3,17(2H,4H)−ジオン(6g,18.9mmol)のトルエン(150mL)中のスラリーを添加し、次いで−50〜−60℃で1時間撹拌した。次いで、ジエチルエーテル中のMeMgBr(3M,18.8mL,56.6mmol)を滴下により添加し、この間、この添加中の温度を−50〜−40℃に維持した。次いで、この反応混合物を−50〜−60℃で3時間撹拌した。この混合物を10%の水性クエン酸(200mL)でクエンチし、EtOAc(200mL×3)で抽出した。合わせた有機層をブライン(400mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、そして濃縮した。その残渣を、シリカゲルでのカラムクロマトグラフィー(PE:EA=8:1)により精製して、D3(4.5g,71.6%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ=5.61 (d, J=5.0 Hz, 1H), 3.65 (d, J=10.0 Hz, 1H), 3.33−3.26 (m, 4H), 2.54−2.39 (m, 2H), 2.17−2.02 (m, 4H), 1.98−1.81 (m, 3H), 1.72−1.61 (m, 3H), 1.57−1.47 (m, 3H), 1.29−1.17 (m, 2H), 1.16 (s, 3H), 1.12−1.04 (m, 1H), 0.99−0.88 (m, 4H)。LCMS 7分間のクロマトグラフィーでRt=1.412min、30〜90AB、純度100%、MS ESI calcd. for C21H33O3 [M+H]+ 333, found 315 ([M+H−18]+)。
化合物D4の合成。ブロモ(エチル)トリフェニルホスホラン(18.3g,49.5mmol)のTHF(100mL)中の溶液に、N2下で、t−BuOK(5.55g,49.5mmol)のTHF(60mL)中の溶液を添加した。この混合物は橙色になった。1時間撹拌した。D3(3.3g,9.92mmol)のTHF(40mL)中の溶液をこの混合物に添加し、そして得られた混合物を60℃でさらに16時間撹拌した。この反応混合物を水性NH4Cl(200mL)でクエンチし、EtOAc(100mL×2)で抽出した。合わせた有機層をブライン(200mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、そして濃縮した。その残渣を、シリカゲルでのカラムクロマトグラフィー(PE:EA=10:1)により精製して、D4(2.5g,73.3%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ=5.62−5.54 (m, 1H), 5.16−5.10 (m, 1H), 3.61 (d, J=10.0 Hz, 1H), 3.36−3.26 (m, 4H), 2.53−2.27 (m, 3H), 2.23−1.94 (m, 4H), 1.90−1.81 (m, 1H), 1.69−1.64 (m, 3H), 1.63−1.45 (m, 8H), 1.28−1.19 (m, 1H), 1.16 (s, 3H), 1.11−1.01 (m, 2H), 0.97−0.83 (m, 4H)。LCMS 2分間のクロマトグラフィーでRt=1.506min、10〜80AB、純度100%、MS ESI calcd. for C23H37O2 [M+H]+ 345, found 327 ([M+H−18]+)。
化合物D5の合成。D4(1.2g,3.48mmol)およびプロピオール酸メチル(874mg,10.4mmol)のジクロロメタン(15mL)中の溶液に、N2下0℃でジエチルアルミニウムクロリド(トルエン中0.9M,15.4mL,13.9mmol)を滴下により添加した。得られた混合物を25℃で16時間撹拌した。TLC(PE:EA=3:1)は、出発物質が消費されたことを示した。この反応混合物を、水性クエン酸(100mL)で0℃で注意深くクエンチした。この混合物をジクロロメタン(100mL×3)で抽出し、そして合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、そして濃縮した。その残渣を、他のバッチ(SAGE−LGY−041)と一緒に、シリカゲルでのカラムクロマトグラフィー(PE:EA=10:1)により精製して、D5(3.5g,76.4%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ=6.98−6.88 (m, 1H), 5.90−5.72 (m, 1H), 5.57 (d, J=4.0 Hz, 1H), 5.45−5.32 (m, 1H), 3.77−3.69 (m, 3H), 3.61 (d, J=10.0 Hz, 1H), 3.36−3.25 (m, 4H), 3.02 (t, J=6.4 Hz, 1H), 2.47 (d, J=12.4 Hz, 1H), 2.10−1.92 (m, 5H), 1.90−1.59 (m, 2H), 1.23−1.14 (m, 7H), 1.10−0.92 (m, 3H), 0.90−0.81 (m, 5H)。LCMS 2分間のクロマトグラフィーでRt=1.176min、30〜90AB、純度100%、MS ESI calcd. for C27H41O4 [M+H]+ 429, found 451 ([M+Na]+)。
化合物D6の合成。D5(2g,4.66mmol)のEtOAc(50mL)中の溶液に、Pd/C(5%炭素担持,0.5g)を添加した。この混合物を脱気してH2でパージすることを3回行い、そしてH2バルーン下25℃で2時間撹拌した。LCMSは、出発物質が完全に消費されたことを示した。この混合物をセライトのパッドで濾過し、そしてその濾液を濃縮して、D6(2g,99.5%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ=5.56 (d, J=5.0 Hz, 1H), 3.66 (s, 3H), 3.59 (d, J=10.0 Hz, 1H), 3.32−3.26 (m, 4H), 2.46 (d, J=12.5 Hz, 1H), 2.40−2.30 (m, 1H), 2.26−2.17 (m, 1H), 2.08−1.92 (m, 4H), 1.89−1.73 (m, 3H), 1.68−1.59 (m, 2H), 1.54−1.23 (m, 7H), 1.15 (s, 3H), 1.13−0.99 (m, 4H), 0.95−0.83 (m, 5H), 0.70 (s, 3H)。LCMS 2分間のクロマトグラフィーでRt=1.210min、30〜90AB、純度100%、MS ESI calcd. for C27H45O4 [M+H]+ 433, found 415 ([M+H−18]+)。
化合物5の合成。D6(100mg,0.231mmol)の乾燥THF(10mL)中の溶液に、0℃でLiAlH4(87.2mg,2.30mmol)を少しずつ注意深く添加した。得られたスラリーを0℃で2時間撹拌した。TLC(PE:EA=3:1)は、出発物質が消費されたことを示した。この反応混合物を水性NH4Cl(20mL)で0℃で滴下により注意深くクエンチし、セライトのパッドで濾過し、そしてその濾液をEtOAc(10mL×3)で抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥させ、そして濃縮した。その残渣をprep.HPLCにより精製して、5(32mg,34.2%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ=5.56 (d, J=4.4 Hz, 1H), 3.65−3.56 (m, 3H), 3.34−3.25 (m, 4H), 2.47 (d, J=12.4 Hz, 1H), 2.08−1.94 (m, 4H), 1.87−1.73 (m, 2H), 1.68−1.56 (m, 4H), 1.50−1.21 (m, 9H), 1.17−1.00 (m, 8H), 0.97−0.84 (m, 5H), 0.71 (s, 3H)。LCMS 2分間のクロマトグラフィーでRt=1.074min、30〜90AB、純度100%、MS ESI calcd. for C26H45O3 [M+H]+ 405, found 427 ([M+Na]+)。
化合物7の合成。E2(100mg,0.247mmol)およびトリメチル(トリフルオロメチル)シラン(174mg,1.23mmol)のTHF(5mL)中の溶液に、CsF(3.75mg,24.7μmol)を添加した。この混合物を25℃で1時間撹拌した。TLC(PE:EA=3:1)は、出発物質が消費されたことを示した。TBAFの溶液(THF中1M,1.23mL,1.23mmol)をこの混合物に添加し、そして得られた混合物を25℃で16時間撹拌した。この反応混合物を濃縮し、そしてその残渣を、シリカゲルでのカラムクロマトグラフィー(PE:EA=10:1)により精製して、7(8mg,6.83%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ= 3.92−3.79 (m, 1H), 3.52−3.43 (m, 2H), 3.30 (s, 3H), 2.21−1.91 (m, 4H), 1.89−1.60 (m, 7H), 1.52−1.40 (m, 3H), 1.39−1.18 (m, 9H), 1.16−0.97 (m, 5H), 0.97−0.75 (m, 5H), 0.73−0.62 (m, 4H)。LCMS 2分間のクロマトグラフィーでRt=1.204min、30〜90AB、純度100%、MS ESI calcd. for C27H46F3O3 [M+H]+ 475, found 457 ([M+H−18]+)。
化合物9の合成。D7(200mg,0.496mmol)の乾燥THF(5mL)中の溶液に、0℃でMeMgBr(ジメチルエーテル中3M,0.83mL,2.48mmol)を添加した。この混合物を25℃で2時間撹拌した。TLC(PE:EA=3:1)は、出発物質が消費されたことを示した。この反応混合物を飽和水性塩化アンモニウム(5mL)でクエンチし、EtOAc(5mL×3)で抽出し、硫酸ナトリウムで乾燥させ、濾過し、そして濃縮して、9(190mg,91.7%)を白色固体として得た。1つのバッチ(140mg)を次の工程で直接使用し、そして他方のバッチ(50mg)をprep.HPLCにより精製して、所望の化合物(3mg)を得た。1H NMR (400 MHz, CDCl3) δ=5.56 (d, J=5.0 Hz, 1H), 3.77−3.71 (m, 1H), 3.59 (d, J=10.0 Hz, 1H), 3.33 − 3.25 (m, 4H), 2.47 (d, J=13.1 Hz, 1H), 2.10 − 1.92 (m, 5H), 1.87 − 1.73 (m, 3H), 1.69 − 1.58 (m, 3H), 1.49 − 1.23 (m, 10H), 1.20 − 1.00 (m, 11H), 0.96 − 0.81 (m, 6H), 0.71 (s, 3H)。LCMS 2分間のクロマトグラフィーでRt=1.126min、30〜90AB、純度100%、MS ESI calcd. for C27H47O3 [M+H]+ 419, found 401 ([M+H−18]+)。
材料および方法
アッセイ方法
NMDA相乗作用
哺乳動物細胞のホールセルパッチクランプ
哺乳動物細胞のホールセルパッチクランプ(IWB)
ホールセルパッチクランプ技術を使用して、哺乳動物細胞において発現されるNR1/NR2Aグルタメートレセプターに対する効果を調査した。その結果を表2に示す。
試験物品の効果を、8点濃度応答フォーマット(4連のウェル/濃度)で評価した。全ての試験溶液およびコントロール溶液が、0.3%のDMSOおよび0.01%のKolliphor(登録商標)EL(C5135,Sigma)を含んだ。試験物品の処方物を、384ウェルの化合物プレートに、自動液体ハンドリングシステム(SciClone ALH3000,Caliper LifeScienses)を使用して装填した。測定を、Ion Works Barracudaプラットフォームを使用して、この手順に従って行った:
電気生理学的手順:
a)細胞内溶液(mM):50mMのCsCl、90mMのCsF、2mMのMgCl2、5mMのEGTA、10mMのHEPES。CsOHでpH7.2に調整。
b)細胞外溶液、HB−PS(mMでの組成):NaCl,137;KCl,1.0;CaCl2,5;HEPES,10;グルコース,10;pHをNaOHで7.4に調整(使用まで冷蔵)。
c)保持電位:−70mV、アゴニスト/PAM増幅中の電位:−40mV。
記録手順:
a)細胞外バッファは、PPCプレートウェルに装填される(1ウェルあたり11μL)。細胞懸濁物は、PPC平面電極のウェルにピペットで入れられる(1ウェルあたり9μL)。
b)ホールセル記録構成は、パッチ穿孔により確立され、膜電流は、オンボードパッチクランプ増幅器によって記録される。
c)2回の記録(走査)が行われる。1回目は、PAM単独の増幅前の間(増幅前の持続時間−5分間)であり、そして2回目は、試験物品およびアゴニスト(EC20 L−グルタメートおよび30μMのグリシン)の同時適用中であり、試験物品の正の調節効果を検出する。
試験物品の投与:1回目の予備適用は、20μLの、2倍に濃縮した試験物品溶液の添加からなり、そして2回目は、20μLの1倍濃度の試験物品およびアゴニストの10μL/sでの添加からなる(2秒間の全適用時間)。
他の実施形態
Claims (44)
- 式(I):
式(I)において:
R1は、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、カルボシクリル、またはヘテロシクリルであり;
R2aおよびR2bの各々は独立して、水素、C1〜C6アルキル、ハロ、シアノ、−ORA、または−NRBRCであるか、あるいは
R2aとR2bとは、これらが結合している炭素原子と一緒になって、環(例えば、3員〜7員の環、例えば、5員〜7員の環;少なくとも1個のヘテロ原子、例えば窒素原子、酸素原子、または硫黄原子を含む環)を形成し;
R4aおよびR4bの各々は独立して、存在しないか、または水素、C1〜C6アルキル、もしくはハロであり;
Xは、−C(RX)2−または−O−であり、ここでRXは独立して、水素、ハロであるか、または1個のRX基とR5bとは一緒になって、二重結合を形成し;
Yは、−ORYであり、ここでRYは、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、−C(O)RA、−C(O)ORA、−C(O)NRBRC、または−S(O)2RDであり;
R5aおよびR5bの各々の例は独立して、水素、ハロ、またはC1〜C6アルキルであり;
R6aおよびR6bの各々は独立して、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、カルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであるか、あるいは
R6aとR6bとは、これらが結合している炭素原子と一緒になって、環(例えば、3員〜6員の環、例えば、1個のヘテロ原子を含む4員〜6員の環)を形成するか;あるいは
R5aとR6aとは、これらが結合している炭素原子と一緒になって、環(例えば、3員〜6員の環、例えば、1個のヘテロ原子を含む4員〜6員の環)を形成し;そして
R7は存在しないか、またはα配置の水素であり;
R8は、水素、ハロ、C1〜6アルキル、カルボシクリル、または−ORAであり;
ここで−CR7と−CR4aR4bとの間の
該
RAは、水素、C1〜C6アルキル、カルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;
RBおよびRCの各々は独立して、水素、C1〜C6アルキル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリールであるか、あるいはこれらが結合している原子と一緒になって、環(例えば、3員〜7員の環、例えば、5員〜7員の環;少なくとも1個のヘテロ原子、例えば窒素原子、酸素原子、または硫黄原子を含む環)を形成し;そして
RDは、水素、C1〜C6アルキル、カルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールである、
化合物またはその薬学的に受容可能な塩。 - R1は、非置換C1〜3アルキルである、請求項1に記載の化合物。
- R1は、−CH3、−CH2CH3、または−CH2CH2CH3である、請求項2に記載の化合物。
- R1は、置換C1〜3アルキルである、請求項1に記載の化合物。
- R1は、ハロアルキル(例えば、−CF3)または−CH2OCH3である、請求項1に記載の化合物。
- R2aまたはR2aは水素である、請求項1に記載の化合物。
- R2aおよびR2aは水素である、請求項1に記載の化合物。
- R4aは水素である、請求項1に記載の化合物。
- Xは−CH2−である、請求項1に記載の化合物。
- R8は、置換または非置換のC1〜3アルキルである、請求項1に記載の化合物。
- R8は−CH3である、請求項10に記載の化合物。
- R5aまたはR5bは水素である、請求項1に記載の化合物。
- R5aとR5bとの両方が水素である、請求項1に記載の化合物。
- R6aは、置換または非置換のC1〜3アルキルである、請求項1に記載の化合物。
- R6aは、−CH3または−CH2CH3である、請求項17に記載の化合物。
- R6aは、置換または非置換のC2〜4アルキル、置換または非置換のC2〜3アルケニル、置換または非置換のC2〜3アルキニル、あるいは置換または非置換のカルボシクリルである、請求項1に記載の化合物。
- R6bは、置換または非置換のC1〜3アルキルである、請求項1に記載の化合物。
- R6bは、−CH3または−CH2CH3である、請求項20に記載の化合物。
- R6bは水素である、請求項1に記載の化合物。
- R6bは、−CH3または−CF3である、請求項20に記載の化合物。
- R6aとR6bとの両方が−CH3である、請求項1に記載の化合物。
- R6aとR6bとは、これらが結合している原子と一緒になって、環を形成する、請求項1に記載の化合物。
- 前記環は3員環である、請求項25に記載の化合物。
- R1は、水素またはC1〜3アルキルであり、R6aは、置換または非置換のC1〜3アルキル、置換または非置換のC2〜3アルケニル、置換または非置換のC2〜3アルキニル、あるいは置換または非置換のカルボシクリルであり、そしてR6bは−CH3である、請求項1に記載の化合物。
- R6aは、置換または非置換のC1〜3アルキル、非置換C2〜3アルケニル、非置換C2〜3アルキニル、あるいは非置換カルボシクリルからなる群より選択される、請求項27に記載の化合物。
- R6aは、置換または非置換のC1〜3アルキルから選択される、請求項27に記載の化合物。
- R1は、−CH3または−CH2CH3であり、そしてR6bは、−CH3または−CF3である、請求項1に記載の化合物。
- RYは、置換または非置換のC1〜3アルキルである、請求項1に記載の化合物。
- RYは、置換または非置換のヘテロシクリルである、請求項1に記載の化合物。
- RYは−CH3である、請求項31に記載の化合物。
- RYは−CF3である、請求項31に記載の化合物。
- 請求項1に記載の化合物、またはその薬学的に受容可能な塩、および薬学的に受容可能なキャリアを含有する、薬学的組成物。
- 鎮静または麻酔を誘導する方法であって、被験体に、有効量の請求項1に記載の化合物、またはその薬学的に受容可能な塩、あるいはその薬学的組成物を投与する工程を包含する、方法。
- 本明細書中に記載される障害を処置または予防するための方法であって、その必要がある被験体に、有効量の請求項1に記載の化合物、またはその薬学的に受容可能な塩、あるいはその薬学的組成物を投与する工程を包含する、方法。
- 前記障害は、胃腸(GI)障害であり、例えば、便秘症、過敏性腸症候群(IBS)、炎症性腸疾患(IBD)(例えば、潰瘍性大腸炎、クローン病)、GIに影響を与える構造障害、肛門の障害(例えば、痔核、内痔核、外痔核、肛門裂傷、肛門周囲膿瘍、肛門フィステル)、結腸ポリープ、がん、大腸炎である、請求項38に記載の方法。
- 前記障害は炎症性腸疾患である、請求項38に記載の方法。
- 前記障害は、がん、糖尿病、またはステロール合成障害である、請求項38に記載の方法。
- CNS関連状態を処置または予防するための方法であって、その必要がある被験体に、有効量の請求項1に記載の化合物、またはその薬学的に受容可能な塩、あるいはその薬学的組成物を投与する工程を包含する、方法。
- 前記CNS関連状態は、適応障害、不安障害(強迫性障害、心的外傷後ストレス障害、および社会恐怖が挙げられる)、認知障害(アルツハイマー病および他の形態の痴呆が挙げられる)、解離性障害、摂食障害、気分障害(うつ病(例えば、産後うつ)、双極性障害、気分変調性障害、自殺傾向が挙げられる)、統合失調症または他の精神病性障害(分裂情動精神病が挙げられる)、睡眠障害(不眠症が挙げられる)、物質関連障害、人格障害(強迫性人格障害が挙げられる)、自閉症スペクトラム障害(Shank群のタンパク質(例えば、Shank3)に対する変異を含むものが挙げられる)、神経発達障害(レット症候群、結節性脳硬化症複合体が挙げられる)、多発性硬化症、ステロール合成障害、疼痛(急性疼痛および慢性疼痛が挙げられる)、ある医学的状態に対して二次的な脳障害(肝性脳障害および抗NMDAレセプター脳炎が挙げられる)、発作性障害(てんかん重積持続状態および単一遺伝子形態のてんかん、例えばドラベ病が挙げられる)、脳卒中、外傷性脳損傷、運動障害(ハンティングトン病およびパーキンソン病が挙げられる)、視覚障害、聴覚障害、ならびに耳鳴である、請求項42に記載の方法。
- 前記障害はステロール合成障害である、請求項42に記載の方法。
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---|---|---|---|---|
CN107936076B (zh) | 2011-09-08 | 2021-10-15 | 萨奇治疗股份有限公司 | 神经活性类固醇、组合物、及其用途 |
JP6255082B2 (ja) | 2013-03-13 | 2017-12-27 | セージ セラピューティクス, インコーポレイテッド | 神経刺激性ステロイドおよびその使用方法 |
EP3157528B1 (en) | 2014-06-18 | 2023-09-13 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
KR20170065637A (ko) * | 2014-10-07 | 2017-06-13 | 세이지 테라퓨틱스, 인크. | 신경활성 화합물 및 그의 사용 방법 |
KR20180026742A (ko) | 2015-07-06 | 2018-03-13 | 세이지 테라퓨틱스, 인크. | 옥시스테롤 및 그의 사용 방법 |
JP2018519351A (ja) | 2015-07-06 | 2018-07-19 | セージ セラピューティクス, インコーポレイテッド | オキシステロールおよびそれらの使用の方法 |
AU2016289965B2 (en) | 2015-07-06 | 2021-09-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
BR112018070123A2 (pt) * | 2016-04-01 | 2019-02-05 | Sage Therapeutics Inc | oxiesterós e métodos de uso dos mesmos |
WO2017193046A1 (en) | 2016-05-06 | 2017-11-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
LT3481846T (lt) | 2016-07-07 | 2021-08-25 | Sage Therapeutics, Inc. | 11-pakeistieji 24-hidroksisteroliai, skirti naudoti gydant su nmda susijusias būkles |
MA46351A (fr) | 2016-09-30 | 2021-06-02 | Sage Therapeutics Inc | Oxystérols substitués en c7 et procédés en tant que modulateurs nmda |
KR20230051723A (ko) | 2016-10-18 | 2023-04-18 | 세이지 테라퓨틱스, 인크. | 옥시스테롤 및 그의 사용 방법 |
CN115181153A (zh) | 2016-10-18 | 2022-10-14 | 萨奇治疗股份有限公司 | 氧甾醇及其使用方法 |
US10857163B1 (en) | 2019-09-30 | 2020-12-08 | Athenen Therapeutics, Inc. | Compositions that preferentially potentiate subtypes of GABAA receptors and methods of use thereof |
WO2022261510A1 (en) | 2021-06-11 | 2022-12-15 | Sage Therapeutics, Inc. | Neuroactive steroid for the treatment of alzheimer's disease |
WO2023114224A1 (en) | 2021-12-13 | 2023-06-22 | Sage Therapeutics, Inc. | Combination of muscarinic receptor positive modulators and nmda positive allosteric modulators |
CN116514893A (zh) * | 2022-01-28 | 2023-08-01 | 珂阑(上海)医药科技有限公司 | 甾类化合物、其制备方法和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013036835A1 (en) * | 2011-09-08 | 2013-03-14 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
Family Cites Families (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2594323A (en) | 1948-07-22 | 1952-04-29 | Upjohn Co | 24-substituted delta 5-cholene-3, 24-diols |
US3079385A (en) | 1961-01-24 | 1963-02-26 | Roussel Uclaf | Novel process of preparation of polyhydroxylated pregnanes |
US3206459A (en) * | 1962-10-19 | 1965-09-14 | Syntex Corp | 10alpha-pregnan-19-ol derivatives |
US4071625A (en) | 1974-05-13 | 1978-01-31 | Richardson-Merrell Inc. | 19-Oxygenated-5α-androstanes for the enhancement of libido |
US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
DE69435286D1 (de) | 1993-05-24 | 2010-05-20 | Purdue Pharma Ltd | Verfahren und zusammensetzungen zum hervorrufen von schlaf |
IL110309A0 (en) | 1993-07-15 | 1994-10-21 | Univ Kentucky Res Found | A method of protecting against neuron loss |
JP4066272B2 (ja) | 1994-02-14 | 2008-03-26 | ユーロ‐セルティック エス. ア. | Gaba受容体のアロステリックな調節のためのアンドロスタン及びプレグナン類 |
US5595996A (en) | 1994-10-25 | 1997-01-21 | Merck & Co., Inc. | 7-substituted 4-aza cholanic acid derivatives and their use |
JPH08268917A (ja) | 1995-03-31 | 1996-10-15 | D D S Kenkyusho:Kk | 癌組織への移行性の高い制癌剤 |
UA57706C2 (uk) | 1995-06-06 | 2003-07-15 | Косенсіз, Інк | Нейроактивні стероїди ряду андростанів та прегнанів, фармацевтична композиція і спосіб лікування (варіанти) |
HUP9900454A3 (en) | 1995-06-23 | 1999-11-29 | Novo Nordisk As | Meiosis regulating compounds and their use |
US6645953B2 (en) | 1995-06-23 | 2003-11-11 | Novo Nordisk A/S | Meiosis regulating compounds |
US5888996A (en) | 1995-07-26 | 1999-03-30 | Trustees Of Boston University | Inhibition of NMDA receptor activity and modulation of glutamate-mediated synaptic activity |
US6122371A (en) | 1997-07-22 | 2000-09-19 | Atwell; Ronald C. | Apparatus for protecting coin-operated telephones from vandalism and larceny |
KR20010043558A (ko) | 1998-05-13 | 2001-05-25 | 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느 | 감수분열 조절 화합물 |
US8541600B2 (en) | 1998-11-24 | 2013-09-24 | Harbor Therapeutics, Inc. | 11-aza, 11-thia and 11-oxa sterol compounds and compositions |
GB9910934D0 (en) | 1999-05-11 | 1999-07-14 | Res Inst Medicine Chem | Chemical compounds |
GB0000228D0 (en) | 2000-01-06 | 2000-03-01 | Phytopharm Plc | Fluoro substituted sapogenins and their use |
GB0019290D0 (en) | 2000-08-04 | 2000-09-27 | Symphar Sa | Methods for inducing apolipoprotein E secretion |
GR1003861B (el) | 2000-12-29 | 2002-04-11 | Νεα νευροστεροειδη που αλληλεπιδρουν με τον υποδοχεα gabaa. | |
GB0107822D0 (en) | 2001-03-28 | 2001-05-23 | Phytopharm Plc | Sapogenin derivatives their synthesis and use methods based upon their use |
US20070197484A1 (en) | 2001-05-03 | 2007-08-23 | Ching Song | Method of treating disorder related to high cholesterol concentration |
EP1450816A4 (en) | 2001-11-08 | 2008-02-13 | Univ Chicago | METHOD FOR TREATING DISORDER IN CONNECTION WITH INCREASED CHOLESTERITE CONCENTRATION |
US20030162758A1 (en) | 2001-12-07 | 2003-08-28 | Schwartz Daniel M. | Treatment for age-related macular degeneration (AMD) |
ATE424211T1 (de) | 2002-03-27 | 2009-03-15 | Phytopharm Plc | Therapeutische verwendung von sapogeninen |
CN102727501A (zh) | 2002-03-27 | 2012-10-17 | 菲特法姆股份有限公司 | 皂角苷配基及其衍生物的用途 |
WO2004055201A2 (en) | 2002-12-13 | 2004-07-01 | Bayer Healthcare Ag | Cholesterol 24-hydroxylase (cyp46) as therapeutic target for the treatment of alzheimer's disease |
FR2850023B1 (fr) | 2003-01-17 | 2007-04-06 | Mapreg | Medicaments pour le systeme nerveux |
GB0403889D0 (en) | 2004-02-21 | 2004-03-24 | Univ Edinburgh | Uses of er-beta modulators |
WO2006037016A2 (en) | 2004-09-27 | 2006-04-06 | The Regents Of The University Of California | Novel therapy for treatment of chronic degenerative brain diseases and nervous system injury |
AU2007217366A1 (en) | 2006-02-27 | 2007-08-30 | The Regents Of The University Of California | Oxysterol compounds and the hedgehog pathway |
WO2008057468A1 (en) | 2006-11-02 | 2008-05-15 | Curis, Inc. | Small organic molecule regulators of cell proliferation |
NZ599643A (en) | 2007-06-20 | 2013-11-29 | Auspex Pharmaceuticals Inc | Substituted N-aryl pyridinones as fibrotic inhibitors |
CA2703497A1 (en) | 2007-11-06 | 2009-05-14 | N.V. Organon | A method of hormone suppression in humans |
WO2009090063A1 (en) | 2008-01-16 | 2009-07-23 | Jado Technologies Gmbh | Steroid sapogenin, androstane and triterpenoid sapogenin derivatives for the treatment and prevention of infectious diseases |
EP2296658A4 (en) | 2008-05-09 | 2014-01-15 | Univ Emory | ANTAGONISTS OF NMDA RECEPTORS USEFUL FOR THE TREATMENT OF NEUROPSYCHIATRIC DISORDERS |
WO2010065709A2 (en) | 2008-12-03 | 2010-06-10 | Amin Khan | Hydroxamic acid derivatives, preparation and therapeutic uses thereof |
US20120040916A1 (en) | 2008-12-22 | 2012-02-16 | Massachusetts Institute Of Technology | Molecular inhibitors of the wnt/beta-catenin pathway |
US20110319416A1 (en) | 2009-01-28 | 2011-12-29 | Emory University | Subunit Selective NMDA Receptor Antagonists For The Treatment Of Neurological Conditions |
US8829213B2 (en) | 2009-07-29 | 2014-09-09 | The University Of Chicago | Liver X receptor agonists |
WO2011028794A2 (en) | 2009-09-01 | 2011-03-10 | Lazarus Therapeutics, Inc. | Treatment of huntington's disease with cycloserine and an nmda receptor antagonist |
FR2953138B1 (fr) | 2009-12-02 | 2015-10-16 | Assist Publ Hopitaux Marseille | Composes aminosteroidiens pour une application topique locale pour la decolonisation cutaneo-muqueuse de staphylococcus aureus |
KR101692275B1 (ko) | 2010-02-11 | 2017-01-04 | 노오쓰웨스턴 유니버시티 | 2차 구조 안정화된 nmda 수용체 조절제 및 그의 용도 |
US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
US20120035156A1 (en) | 2010-08-09 | 2012-02-09 | Daniela Alberati | Combination of glyt1 compound with antipsychotics |
US8969525B2 (en) | 2010-11-09 | 2015-03-03 | Enzo Life Sciences, Inc. | Hydroxycholesterol immunoassay |
WO2012142039A1 (en) | 2011-04-15 | 2012-10-18 | University Of North Dakota | Combination of liver x receptor modulator and estrogen receptor modulator for the treatment of age-related diseases |
US20140335050A1 (en) | 2011-05-27 | 2014-11-13 | The General Hospital Corporation | Methods, compositions, and kits for the treatment of cancer |
EP2736919A4 (en) | 2011-07-29 | 2015-01-14 | Univ California | NEW 17-BETA-HETEROARYL-SUBSTITUTED STEROIDS AS MODULATORS OF GABAA RECEPTORS |
US20150291654A1 (en) | 2011-10-14 | 2015-10-15 | Sage Therapeutics, Inc. | 3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof |
US20150119327A1 (en) | 2012-04-25 | 2015-04-30 | The Regents Of The University Of California | Drug screening platform for rett syndrome |
WO2014028942A2 (en) | 2012-08-17 | 2014-02-20 | Trueex Group Llc | Interoffice bank offered rate financial product and implementation |
SI2935307T1 (en) | 2012-12-18 | 2018-08-31 | Washington University | Non-reactive 19-alkoxy-17-substituted steroids useful in therapeutic procedures |
CN112552364A (zh) | 2013-01-23 | 2021-03-26 | 司菲埃拉制药私人有限公司 | 用于线粒体生物发生和与线粒体功能障碍或耗竭相关的疾病的新颖11β-羟基类固醇化合物 |
SG11201505934XA (en) | 2013-01-29 | 2015-09-29 | Naurex Inc | Spiro-lactam nmda receptor modulators and uses thereof |
BR112015022934A8 (pt) | 2013-03-13 | 2019-11-26 | Sage Therapeutics Inc | esteróides neuroativos, composições e usos destes |
JP6255082B2 (ja) | 2013-03-13 | 2017-12-27 | セージ セラピューティクス, インコーポレイテッド | 神経刺激性ステロイドおよびその使用方法 |
EP3157528B1 (en) | 2014-06-18 | 2023-09-13 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US10238664B2 (en) | 2014-07-09 | 2019-03-26 | Duke University | Compositions and methods for the repair of myelin |
KR20170065637A (ko) | 2014-10-07 | 2017-06-13 | 세이지 테라퓨틱스, 인크. | 신경활성 화합물 및 그의 사용 방법 |
JP2018519351A (ja) | 2015-07-06 | 2018-07-19 | セージ セラピューティクス, インコーポレイテッド | オキシステロールおよびそれらの使用の方法 |
KR20180026742A (ko) | 2015-07-06 | 2018-03-13 | 세이지 테라퓨틱스, 인크. | 옥시스테롤 및 그의 사용 방법 |
AU2016289965B2 (en) | 2015-07-06 | 2021-09-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
GB2557875A (en) | 2015-09-02 | 2018-07-04 | Univ Swansea | Diagnostic methods and kits |
US11969506B2 (en) | 2017-03-15 | 2024-04-30 | Modernatx, Inc. | Lipid nanoparticle formulation |
AU2018288883B2 (en) | 2017-06-23 | 2022-06-02 | Intercept Pharmaceuticals, Inc. | Methods and intermediates for the preparation of bile acid derivatives |
KR20200085837A (ko) | 2017-11-10 | 2020-07-15 | 마리누스 파마슈티컬스 인코포레이티드 | 유전적 간질 질환 치료에 사용하기 위한 가낙솔론의 용도 |
-
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- 2015-06-18 US US15/319,504 patent/US10259840B2/en active Active
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-
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013036835A1 (en) * | 2011-09-08 | 2013-03-14 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
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