JP2005514381A - Mglur5アンタゴニスト活性を有するアセチレン誘導体 - Google Patents
Mglur5アンタゴニスト活性を有するアセチレン誘導体 Download PDFInfo
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Abstract
Description
mは、0または1であり、
nは、0または1であり、そして
Aは、ヒドロキシであり、
Xは、水素であり、そして
Yは、水素であるか、または
Aは、XまたはYと一重結合を形成し;
R0は、水素、(C1−4)アルキル、(C1−4)アルコキシ、トリフルオロメチル、ハロゲン、シアノ、ニトロ、−COOR1[式中、R1は(C1−4)アルキルである。]または−COR2[式中、R2は水素もしくは(C1−4)アルキルである。]であり、そして
Rは、−COR3、−COOR3、−CONR4R5または−SO2R6であり、ここで、R3は、(C1−4)アルキル、(C3−7)シクロアルキルまたは所望により置換されていてもよいフェニル、2−ピリジルまたは2−チエニルであり、R4およびR5は、独立して、水素または(C1−4)アルキルであり、そしてR6は、(C1−4)アルキル、(C3−7)シクロアルキルまたは所望により置換されていてもよいフェニルであり、
R'は、水素または(C1−4)アルキルであり、そして
R''は、水素または(C1−4)アルキルであるか、あるいは
R'およびR''は、一体となって−CH2−(CH2)p−を形成し、
ここで、pは、0、1または2であり、この場合においてnおよびpの一方は0ではなく、
ただし、mが1であり、nが0であり、Aはヒドロキシであり、XおよびYはともに水素であり、RはCOOEtであり、そしてR'およびR''は一体となって−(CH2)2−を形成する場合、R0は水素、トリフルオロメチルおよびメトキシでないものとする。〕
で示される化合物を提供する。
a)Aがヒドロキシである式Iの化合物の製造のために、式II
で示される化合物を、式III
で示される化合物と反応させる工程、あるいは
b)AがXまたはYとともに一重結合を形成する式Iの化合物の製造のために、Aがヒドロキシである式Iの化合物を脱水する工程、
ならびに、得られる式Iの化合物を遊離塩基または酸付加塩の形態で回収する工程
を含んでなる方法を提供する。
50mlのTBMEおよび30g(34.8mmol)のビニル酢酸中の11.76g(47.16mmol)の(3aRS,4SR,7aRS)−4−ヒドロキシ−オクタヒドロ−インドール−1−カルボン酸 tert−ブチルエステルに、0.5gのCandida antarctica(Novozyme 435)由来の固定化リパーゼを添加し、そして混合物を室温にて24時間撹拌する。混合物の濾過後に、溶媒を除去し、そして得られる油性残渣をフラッシュクロマトグラフィーにより精製する。当該アセテート (3aS,4R,7aS)−4−アセトキシ−オクタヒドロ−インドール−1−カルボン酸 tert−ブチルエステルは、99%を超える光学純度、47%の収率で単離される(GC、[α]D 20=+54.6° c=1、MeOH)。回収されたアルコール (3aR,4S,7aR)−4−ヒドロキシ−オクタヒドロ−インドール−1−カルボン酸 tert−ブチルエステルは、51%収率かつ>95%eeで単離される(GC、[α]D 20=−41.3° c=1、MeOH)。MPLCでのさらなる精製により、99.5%純度かつ99.5%eeで該アルコールが得られる。
融点=118〜121℃。
融点=195.5〜196.5℃。
1H NMR (400MHz; CDCl3): 1.27 (t, 3H), 1.60-1.80 (m, 4H), 1.88-2.11 (m, 5H), 2.27 (m, 1H), 3.38(m, 1H), 3.54 (m, 1H), 4.10 (m, 2H), 7.22-7.31 (m, 3H), 7.40 (m, 1H)。
HPLC−MS:354(M+Na)。
ES−MS(+):356(M+1)。
ES−MS(+):356(M+1)。
1H NMR (400MHz; CHCl3): 7.39 (s, 1H), 7.25 (m, 3H), 5.27 (m, 1H), 4.10-3.85 (m, 5H), 3.55 (m, 1H), 3.4 (m, 1H), 2.7 (m, 1H), 2.3 (s, 1H), 2.2-1.9 (m, 6H), 1.8-1.6 (m, 3H), 1.07 (m, 1H)。
ES−MS(+):328.2 [M+1]、融点=123〜124℃。
ES−MS(+):332.2、融点=115〜116℃。
NMR (CDCl3): 7.41 (s, 1H), 7.30 (m, 3H), 3.93 (m, 1H), 3.57 (m, 1H), 3.35 (m, 1H), 2.85 (s, 3H), 2.69 (m, 1H), 2.35 (bs, 1H), 2.14 (m, 1H), 2.0 (m, 1H), 1.90 (m, 1H), 1.82-1.65 (m, 4H), 1.35 (m, 1H)。HPLC:1ピーク、99%。
ES−MS(+):320.3(M+1)、Rf=0.62(TLC シリカゲル、ヘキサン/酢酸エチル 2:1)。
ES−MS(+):310.2(M+1)、Rf=0.55(TLC シリカゲル、ヘキサン/酢酸エチル 2:1)。
ES−MS(+):310.2(M+1)、Rf=0.59(TLC シリカゲル、ヘキサン/酢酸エチル 2:1)。
ES−MS(+):330.2(M+1)、Rf=0.56(TLC シリカゲル、ヘキサン/酢酸エチル 2:1)。
ES−MS(+):314.2(M+1)、Rf=0.42(TLC シリカゲル、ヘキサン/酢酸エチル 2:1)。
ES−MS(+):314.2(M+1)。
ES−MS(+):336.2(M+Na)。
ES−MS(+):348.2(M+Na)。
ES−MS(+):348.2(M+Na)。
ES−MS(+):328(M+1)、RP−HPLC:単一のピーク。
HPLC−MS:単一のピーク、350(M+Na)。
HPLC−MS:単一のピーク、361(M+Na)。
ES−MS(+):344(M+1)、HPLC:単一のピーク。
ES−MS(+):332(M+1)、HPLC:単一のピーク。
ES−MS(+):356(M+1)、RP−HPLC:単一のピーク。
HPLC−MS:372(M+Na)。
HPLC−MS:346(M+Na)。
HPLC−MS:361(M+1)、383(M+Na)。
HPLC−MS:444.2(M+Na)+。
HPLC−MS:444.2(M+Na)+。
HPLC−MS:368.2(M+Na)+。
HPLC−MS:352.2(M+Na)+。
HPLC−MS:356.2(M+Na)+。
HPLC−MS:328.2(M+Na)+。
HPLC−MS:328.2(M+Na)+。
HPLC−MS:340.2(M+Na)+。
HPLC−MS:340.2(M+Na)+。
Rf=0.31(TLC シリカゲル、ヘキサン/酢酸エチル 1:1)。
Rf=0.22(TLC シリカゲル、ヘキサン/酢酸エチル 1:1)。
HPLC−MS:294.2(M+Na)。
融点 152〜155℃。
HPLC−MS:324.2(M+Na)。
融点 106〜107℃。
HPLC−MS:328.2(M+Na)。
融点 121〜123℃。
HPLC−MS:340.2(M+Na)。
HPLC−MS:276.2(M+1)、298.2(M+Na)。
HPLC−MS:340.2(M+Na)。
HPLC−MS:288.2(M+1)、310.2(M+Na)。
HPLC−MS:288.2(M+1)、310.2(M+Na)。
HPLC−MS:368.2(M+Na)。
HPLC−MS:368.2(M+Na)。
HPLC−MS:352.2(M+Na)。
HPLC−MS:352.1(M+Na)。
HPLC−MS:356.2(M+Na)。
HPLC−MS:356.2(M+Na)。
HPLC−MS:314.2(M+Na)。
HPLC−MS:314.2(M+Na)。
ラセミ体2:1H-NMR (400 MHz): デルタ = 7.40 (m, 2H); 7.30 (m, 3H); 6.19 (s, 1H); 4.68 (broad s, 1H); 4.10 (q, 2H); 3.92 (broad s, 1H); 2.61 (d, 1H); 2.28 (broad s, 2H); 2.12, 1.85, 1.59 (3m, 3H); 1.23 (t, 3H)。
1H-NMR (400 MHz): デルタ = 7.40 (m, 2H); 7.30 (m, 3H); 6.18 (s, 1H); 4.22 (broad m, 1H); 4.15 (q, 2H); 2.8 (broad s, 3H); 2.35 (broad s, 4H); 1.80-1.60 (m, 1H); 1.15 (t, 3H)。
NMR (DMSO-D6, 500MHz): 7.84 (s, 1H), 7.45 (m, 4H), 6.95 (d, 1H), 6.63 (d, 1H), 5.51 (s, 1H), 4.03 (m, 1H), 3.94 (m, 1H), 3.32 (m, 1H), 2.06 (m, 1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.94 (m, 1H), 1.85 (m, 1H), 1.74 (m, 2H), 1.71 (m, 1H), 1.60 (m, 1H), 1.50 (m, 1H), 1.41 (m, 1H)。
NMR (DMSO-D6, 500MHz): 7.83 (s, 1H), 7.43 (m, 4H), 6.95 (d, 1H), 6.62 (m, 1H), 5.77 (s, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 3.31 (m, 1H), 2.12 (m, 1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H), 1.83 (m, 1H), 1.77 (m, 1H), 1.66 (m, 1H), 1.59 (m, 2H), 1.46 (m, 1H), 1.22 (m, 1H)。
NMR (CDCl3): 7.42 (d,J=1.1Hz, 1H), 7.32 (m, 3H), 3.55 (m, 1H), 3.48 (m, 1H), 3.10 (m, 1H), 2.08 (m, 3H), 1.90 (m, 1H), 1.8-1.6 (m, 7H), 1.46 (s, 9H), 1.38 (m, 1H)。
LC−MS、M+1=403.1
LC−MS、M+1=416.2
1H NMR (400MHz; CDCl3): 1.25 (t, 3H), 1.39-1.56 (m, 2H), 1.56-1.98 (m, 8H), 1.98-2.23 (m, 2H), 2.35 (s, 3H), 3.15 (m, 1H), 3.55-3.79 (m, 2H), 4.04-4.20 (m, 2H), 7.10 (m, 1H), 7.15-7.25 (m, 3H)。
1H NMR (400MHz; CDCl3): 1.25 (t, 3H), 1.30-1.50 (m, 2H), 1.56-2.20 (m, 8H), 2.20-2.44 (m, 3H), 2.85-3.19 (m, 1H), 3.54-3.63 (m, 1H), 3.69-3.84 (m, 1H), 4.07-4.19 (m, 2H), 7.05-7.27 (m, 4H)。
Claims (10)
- 遊離塩基または酸付加塩の形態の式I
mは、0または1であり、
nは、0または1であり、そして
Aは、ヒドロキシであり、
Xは、水素であり、そして
Yは、水素であるか、または
Aは、XまたはYと一重結合を形成し;
R0は、水素、(C1−4)アルキル、(C1−4)アルコキシ、トリフルオロメチル、ハロゲン、シアノ、ニトロ、−COOR1[式中、R1は(C1−4)アルキルである。]または−COR2[式中、R2は水素もしくは(C1−4)アルキルである。]であり、そして
Rは、−COR3、−COOR3、−CONR4R5または−SO2R6であり、ここで、R3は、(C1−4)アルキル、(C3−7)シクロアルキルまたは所望により置換されていてもよいフェニル、2−ピリジルまたは2−チエニルであり、R4およびR5は、独立して、水素または(C1−4)アルキルであり、そしてR6は、(C1−4)アルキル、(C3−7)シクロアルキルまたは所望により置換されていてもよいフェニルであり、
R'は、水素または(C1−4)アルキルであり、そして
R''は、水素または(C1−4)アルキルであるか、あるいは
R'およびR''は、一体となって−CH2−(CH2)p−を形成し、
ここで、pは、0、1または2であり、この場合においてnおよびpの一方は0ではなく、
ただし、mが1であり、nが0であり、Aはヒドロキシであり、XおよびYはともに水素であり、RはCOOEtであり、そしてR'およびR''は一体となって−(CH2)2−を形成する場合、R0は水素、トリフルオロメチルおよびメトキシでないものとする。〕
で示される化合物。 - 遊離塩基または酸付加塩の形態の(−)−(3aR,4S,7aR)−4−ヒドロキシ−4−m−トリルエチニル−オクタヒドロインドール−1−カルボン酸メチルエステルである、請求項1に記載の化合物。
- 医薬として使用するための、遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物。
- グルタミン酸作動性シグナル伝達の異常に関連する障害、およびmGluR5により全体的にまたは部分的に介在される神経系障害の処置における使用のための、遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物。
- 医薬担体または希釈剤とともに、遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物を含んでなる医薬組成物。
- グルタミン酸作動性シグナル伝達の異常に関連する障害、およびmGluR5により全体的にまたは部分的に介在される神経系障害の処置における、遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物の使用。
- グルタミン酸作動性シグナル伝達の異常に関連する障害、およびmGluR5により全体的にまたは部分的に介在される神経系障害の処置のために設計される医薬組成物の製造のための、遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物の使用。
- グルタミン酸作動性シグナル伝達の異常に関連する障害、およびmGluR5により全体的にまたは部分的に介在される神経系障害の処置方法であって、かかる処置を必要とする対象に、治療上有効量の遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物を投与することを含んでなる方法。
- 同時的または逐次的投与のための、治療上有効量の遊離塩基または医薬上許容される酸付加塩の形態の請求項1に記載の化合物および第二医薬物質を含んでなる組合せ剤。
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- 2005-02-28 HK HK05101701A patent/HK1071510A1/xx not_active IP Right Cessation
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2006
- 2006-08-03 CY CY20061101091T patent/CY1105460T1/el unknown
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2008
- 2008-02-29 US US12/040,081 patent/US20080146647A1/en not_active Abandoned
- 2008-07-09 JP JP2008179005A patent/JP5036648B2/ja not_active Expired - Lifetime
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2011
- 2011-09-22 US US13/239,467 patent/US8536229B2/en not_active Expired - Lifetime
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2012
- 2012-11-20 AR ARP120104356A patent/AR088921A2/es not_active Application Discontinuation
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2013
- 2013-08-15 US US13/967,719 patent/US20130331568A1/en not_active Abandoned
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2010502664A (ja) * | 2006-09-11 | 2010-01-28 | ノバルティス アクチエンゲゼルシャフト | 代謝型グルタミン酸受容体の調節剤としてのニコチン酸誘導体 |
JP2014088404A (ja) * | 2006-09-11 | 2014-05-15 | Novartis Ag | 代謝型グルタミン酸受容体の調節剤としてのニコチン酸誘導体 |
JP2011500529A (ja) * | 2007-10-12 | 2011-01-06 | ノバルティス アーゲー | パーキンソン病処置用代謝型グルタミン酸受容体モジュレーター |
JP2014240425A (ja) * | 2007-10-12 | 2014-12-25 | ノバルティス アーゲー | パーキンソン病処置用代謝型グルタミン酸受容体モジュレーター |
JP2011526596A (ja) * | 2008-06-30 | 2011-10-13 | ノバルティス アーゲー | 組み合わせ製品 |
JP2011530566A (ja) * | 2008-08-12 | 2011-12-22 | ノバルティス アーゲー | 4−オキソ−オクタヒドロ−インドール−1−カルボサイリックアシッドメチルエステルとその誘導体の調製方法 |
JP2013524840A (ja) * | 2010-04-30 | 2013-06-20 | ノバルティス アーゲー | 脆弱x症候群(fxs)の治療において有用な予測マーカー |
JP2016520663A (ja) * | 2013-06-12 | 2016-07-14 | ノバルティス アーゲー | 調節放出製剤 |
US11878001B2 (en) | 2017-07-31 | 2024-01-23 | Novartis Ag | Use of mavoglurant in the reduction of ***e use or in preventing relapse into ***e use |
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