JP2008303226A - 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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Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0128996D0 (en) * | 2001-12-04 | 2002-01-23 | Novartis Ag | Organic compounds |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
GB0325956D0 (en) * | 2003-11-06 | 2003-12-10 | Addex Pharmaceuticals Sa | Novel compounds |
US20080125403A1 (en) | 2004-04-02 | 2008-05-29 | Merck & Co., Inc. | Method of Treating Men with Metabolic and Anthropometric Disorders |
GB0503646D0 (en) * | 2005-02-22 | 2005-03-30 | Novartis Ag | Organic compounds |
GB0508318D0 (en) * | 2005-04-25 | 2005-06-01 | Novartis Ag | Organic compounds |
GB0508314D0 (en) * | 2005-04-25 | 2005-06-01 | Novartis Ag | Organic compounds |
GB0508319D0 (en) | 2005-04-25 | 2005-06-01 | Novartis Ag | Organic compounds |
GB0514296D0 (en) * | 2005-07-12 | 2005-08-17 | Novartis Ag | Organic compounds |
EP2069305A2 (en) * | 2006-09-11 | 2009-06-17 | Novartis AG | Nicotinic acid derivatives as modulators of metabotropic glutamate receptors |
EA020466B1 (ru) | 2007-06-04 | 2014-11-28 | Синерджи Фармасьютикалз Инк. | Агонисты гуанилатциклазы, пригодные для лечения желудочно-кишечных нарушений, воспаления, рака и других заболеваний |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
RU2508107C2 (ru) * | 2007-10-12 | 2014-02-27 | Новартис Аг | Модуляторы метаботропного глутаматного рецептора для лечения болезни паркинсона |
AU2012254934B2 (en) * | 2007-10-12 | 2013-10-17 | Novartis Ag | Metabotropic glutamate receptor modulators for the treatment of Parkinson's disease |
CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
CA2729595C (en) * | 2008-06-30 | 2017-01-03 | Novartis Ag | Combinations comprising mglur modulators for the treatment of parkinson's disease |
ES2547269T3 (es) | 2008-08-12 | 2015-10-05 | Novartis Ag | Procedimientos para la preparación de éster metílico de ácido 4-oxo-octahidro-indol-1-carboxílico y derivados del mismo |
US8334287B2 (en) | 2009-07-17 | 2012-12-18 | Hoffmann-La Roche Inc. | Imidazoles |
CN102573842A (zh) | 2009-07-23 | 2012-07-11 | 诺瓦提斯公司 | 氮杂双环烷基衍生物或吡咯烷-2-酮衍生物的用途 |
TWI558398B (zh) | 2009-09-22 | 2016-11-21 | 諾華公司 | 菸鹼乙醯膽鹼受體α7活化劑之用途 |
EP2490691A1 (en) | 2009-10-20 | 2012-08-29 | Novartis AG | Use of 1h-quinazoline-2,4-diones |
WO2011137206A1 (en) * | 2010-04-30 | 2011-11-03 | Novartis Ag | Predictive markers useful in the treatment of fragile x syndrome (fxs) |
US20130096145A1 (en) | 2010-06-24 | 2013-04-18 | Novartis Ag | Use of 1H-quinazoline-2,4-diones |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
US20130274294A1 (en) * | 2010-12-20 | 2013-10-17 | David Carcache | 4-(Hetero)Aryl-Ethynyl-Octahydro-Indole-1-Esters |
EP2668159A1 (en) | 2011-01-24 | 2013-12-04 | Novartis AG | 4-tolyl-ethynyl-octahydro-indole-1-ester derivatives |
MX2013008704A (es) | 2011-01-27 | 2013-08-21 | Novartis Ag | Uso de activadores del receptor de acetil-colina nicotinico alfa-7. |
MX2013010698A (es) | 2011-03-18 | 2014-02-17 | Novartis Ag | Combinaciones de activadores del receptor de acetil-colina nicotinico alfa-7 y antagonistas del receptor de glutamato metabotropico 5 (mglur5) para usarse en la discinesia inducida por dopamina en la enfermedad de parkinson. |
EP2753331A1 (en) | 2011-09-07 | 2014-07-16 | Novartis AG | Use of 1h-quinazoline- 2, 4 -diones for use in the prevention or treatment photosensitive epilepsy |
WO2013131981A1 (en) | 2012-03-08 | 2013-09-12 | Novartis Ag | Predictive markers useful in the diagnosis and treatment of fragile x syndrome (fxs) |
GB201215033D0 (en) | 2012-08-23 | 2012-10-10 | Novartis Ag | Diazepinone derivatives |
JP6137336B2 (ja) | 2013-01-15 | 2017-05-31 | ノバルティス アーゲー | ナルコレプシーの処置のためのアルファ7ニコチン性受容体アゴニストの使用 |
KR101879919B1 (ko) | 2013-01-15 | 2018-07-18 | 노파르티스 아게 | 알파 7 니코틴성 아세틸콜린 수용체 작용물질의 용도 |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
CN113388007A (zh) | 2013-06-05 | 2021-09-14 | 博士医疗爱尔兰有限公司 | 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法 |
JP6444996B2 (ja) * | 2013-06-12 | 2018-12-26 | ノバルティス アーゲー | 調節放出製剤 |
CN105669686B (zh) * | 2014-11-19 | 2018-08-03 | 上海合全药业股份有限公司 | 一种6-(叔丁氧羰基)八氢呋喃[2,3-c]吡啶-4-羧酸的合成方法 |
CA3066711A1 (en) | 2017-07-31 | 2019-02-07 | Novartis Ag | Use of mavoglurant in the reduction of cocaine use or in preventing relapse into cocaine use |
EP3661501A1 (en) | 2017-07-31 | 2020-06-10 | Novartis AG | Use of mavoglurant in the reduction of alcohol use or in preventing relapse into alcohol use |
CA3124931A1 (en) | 2019-01-29 | 2020-08-06 | Novartis Ag | The use of an mglur5 antagonist for treating opioid analgesic tolerance |
US20230270720A1 (en) | 2020-07-17 | 2023-08-31 | Novartis Ag | Mavoglurant, a mglur5 antagonist, for use in the treatment in the reduction of opioid use |
IL303248A (en) | 2020-12-11 | 2023-07-01 | Novartis Ag | Use of MGLUR5 antagonists to treat amphetamine addiction |
AU2021404023A1 (en) | 2020-12-14 | 2023-06-29 | Novartis Ag | Use of mglur5 antagonists for treating gambling disorder |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5340766A (en) * | 1976-09-22 | 1978-04-13 | Sandoz Ag | Improvement in organic compound |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2802833A1 (de) | 1978-01-23 | 1979-07-26 | Sandoz Ag | 4-styryl-4-indolinol-derivate, ihre verwendung und herstellung |
US5264456A (en) | 1989-12-29 | 1993-11-23 | Allergan, Inc. | Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity |
US5284957A (en) | 1992-09-03 | 1994-02-08 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
US5593994A (en) | 1994-09-29 | 1997-01-14 | The Dupont Merck Pharmaceutical Company | Prostaglandin synthase inhibitors |
DE69634822T2 (de) | 1995-08-22 | 2006-04-27 | Japan Tobacco Inc. | Amid-verbindungen und ihre anwendung |
WO1997048697A1 (en) | 1996-06-19 | 1997-12-24 | Rhone-Poulenc Rorer Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
TW544448B (en) * | 1997-07-11 | 2003-08-01 | Novartis Ag | Pyridine derivatives |
US6313071B1 (en) | 1998-06-04 | 2001-11-06 | Kumiai Chemical Industry Co., Ltd. | Phenylacetylene derivatives and agricultural/horticultural fungicides |
IL142047A0 (en) | 1998-10-02 | 2002-03-10 | Sibia Neurosciences Inc | Mglur5 antagonists for the treatment of pain and anxiety |
EA004290B1 (ru) | 1999-07-06 | 2004-02-26 | Эли Лилли Энд Компани | СЕЛЕКТИВНЫЕ АНТАГОНИСТЫ РЕЦЕПТОРА iGluR5 ДЛЯ ЛЕЧЕНИЯ МИГРЕНИ |
GB0007108D0 (en) | 2000-03-23 | 2000-05-17 | Novartis Ag | Organic compounds |
AU1339302A (en) | 2000-10-20 | 2002-05-06 | Biocryst Pharm Inc | Biaryl compounds as serine protease inhibitors |
CN1257894C (zh) | 2000-12-04 | 2006-05-31 | 弗·哈夫曼-拉罗切有限公司 | 作为谷氨酸受体拮抗剂的苯基乙烯基或苯基乙炔基衍生物 |
GB0103045D0 (en) | 2001-02-07 | 2001-03-21 | Novartis Ag | Organic Compounds |
US7138404B2 (en) | 2001-05-23 | 2006-11-21 | Hoffmann-La Roche Inc. | 4-aminopyrimidine derivatives |
WO2003048123A1 (en) | 2001-12-04 | 2003-06-12 | F. Hoffmann-La Roche Ag | Substituted 2-amino-cycloalkanecarboxamides and their use as cysteine protease inhibitors |
GB0128996D0 (en) * | 2001-12-04 | 2002-01-23 | Novartis Ag | Organic compounds |
TW200303309A (en) | 2001-12-04 | 2003-09-01 | Bristol Myers Squibb Co | Novel n-[4-(1h-imidazol-1-yl)-2-fluorophenyl]-3-trifluoromethyl)-1h-pyrazole-5-carboxamides as factor Xa inhibitors |
-
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-
2013
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5340766A (en) * | 1976-09-22 | 1978-04-13 | Sandoz Ag | Improvement in organic compound |
US4129658A (en) * | 1976-09-22 | 1978-12-12 | Sandoz Ltd. | 4-Styryl-hexahydro-4-indolinols |
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