ES2582367T3 - Inhibidores heterocíclicos de la aspartil proteasa - Google Patents

Inhibidores heterocíclicos de la aspartil proteasa

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Publication number
ES2582367T3
ES2582367T3 ES08714220.4T ES08714220T ES2582367T3 ES 2582367 T3 ES2582367 T3 ES 2582367T3 ES 08714220 T ES08714220 T ES 08714220T ES 2582367 T3 ES2582367 T3 ES 2582367T3
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Spain
Prior art keywords
compound
solution
mmol
tautomer
ch2ch
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ES08714220.4T
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Inventor
Zhaoning Zhu
Brian Mckittrick
Zhong-Yue Sun
Yuanzan C. Ye
Johannes H. Voigt
Corey Strickland
Elizabeth M. Smith
Andrew Stamford
William J. Greenlee
Jr. Robert D. Mazzola
John Caldwell
Jared N. Cumming
Lingyan Wang
Yusheng Wu
Ulrich Iserloh
Xiaoxiang Liu
Ying Huang
Guoqing Li
Jianping Pan
Jeffrey A. Misiaszek
Tao Guo
Thuy X. H. Le
Kurt W. Saionz
Suresh D. Babu
Rachael C. Hunter
Michelle L. Morris
Huizhong Gu
Gang Qian
Dawit Tadesse
Gaifa Lai
Jingqi Duo
Chuanxing Qu
Yuefei Shao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Pharmacopeia LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
Pharmacopeia LLC
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Application filed by Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC, Pharmacopeia LLC filed Critical Merck Sharp and Dohme Ltd
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Abstract

Un compuesto, o un tautomero del mismo, o una sal farmaceuticamente aceptable de dicho compuesto o dicho tautomero, en donde dicho compuesto se selecciona entre el grupo que consiste en:**Tabla**

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
imagen10
imagen11
imagen12
imagen13
imagen14
imagen15
Método A
imagen16
5 Método A, Etapa 1:
A una solución de A1 (R3 = CH3 y R4 = CH2CH(CH3)2) (10 mmol, 1 equiv.) en 30 ml de CH2Cl2 anhíd. se le añadió tiocarbonil dipiridona (1,2 equiv.). Después de agitar durante una noche la solución se diluyó con CH2Cl2, se lavó con HCl 1N, H2O (2 x) y una solución acuosa saturada de NaCl (2 x). La solución orgánica se secó sobre Na2SO4, se
10 filtró y se concentró. El material en bruto se purificó por cromatografía ultrarrápida para proporcionar A2 (R3 = CH3 y R4 = CH2CH(CH3)2).
Método A, Etapa 2:
15 Una solución de 3,5-difluorobencil amina (0,15 mmol, 1,5 equiv.) en THF (0,15 ml) se añadió a una solución de A2 (R3 = CH3 y R4 = CH2CH(CH3)2) (0,1 mmol, 1 equiv.) en CH2Cl2 anhidro (1 ml). La mezcla de reacción se calentó a reflujo durante una noche. La solución de reacción se añadió a una resina de MP-TsOH (2-3 equiv.) y se diluyó con CH3CN. La suspensión se agitó durante una noche. La mezcla se filtró y el filtrado se concentró para proporcionar A3 (R1 = 3,5-difluorobencilo, R3 = CH3,y R4 = CH2CH(CH3)2).
20
Método A, Etapa 3:
A una solución de A3 (R1 = 3,5-difluorobencilo, R3 = CH3,y R4 = CH2CH(CH3)2) (10 mg) en CH3OH (1ml) se le añadieron NH4OH (0,44 ml) y peróxido de hidrógeno de tbutilo (0,1 ml) y la mezcla de reacción se agitó durante 2 d. 25 La solución se concentró, el residuo resultante se disolvió en CH3OH (1,2 ml) y se trató con resina de ácido sulfónico. La suspensión se agitó durante una noche y la resina se lavó con CH3OH (4 x 10 min) antes de tratarse con NH3 2N en CH3OH durante 1 h. La suspensión se filtró y el filtrado se concentró para dar el material en bruto que se purificó por HPLC preparativa/LCMS eluyendo con un gradiente de CH3CN/H2O para proporcionar A4 (R1 = 3,5-difluorobencilo, R2 = H, R3 = CH3,y R4 = CH2CH(CH3)2). RMN (CD3OD): δ 6,9, m, 3H; δ 4,8-4,9, m; δ 1,75, d, 2H;
30 δ1,5, m, 1 H; δ 1,42, s, 3H; δ 0,85, d, 3H; δ 0,65, d, 3H. ES-LCMS (m/e) 296,1.
Los siguientes compuestos se sintetizaron usando métodos similares:
N.º Estructura PM m/e Obs. N.º Estructura PM m/e Obs.
1
imagen17223 224 94
imagen18363 364
2
223 224 95
imagen19363 364
17
imagen20
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
282 283 133
415 416
imagen28
282 283 134
415 416
imagen29
282 283 135
415 416
imagen30
283 284 136
417 418
imagen31
285 286 137
419 420
imagen32
287 288 138
421 422
24
imagen33
imagen34
imagen35
imagen36
imagen37
imagen38
328 329 163
481 482
imagen39
330 331 164
481 482
imagen40
331 332 165
487 488
imagen41
331 332 166
488 489
imagen42
335 336 167
499 500
29
imagen43
imagen44
imagen45
imagen46
Método B, Etapa 3:
El compuesto B4 (R2 = H, R3 = CH3,R4 = CH2CH(CH3)2,y R1 = 3-Clorofenetilo) se preparó a partir de B3 (R3 = CH3, R4 = CH2CH(CH3)2,yR1 = 3-Clorofenetilo) siguiendo un procedimiento similar al Método A, Etapa 3. RMN (CD3OD): δ 8,1, a, 1 H; δ 7,35, s, 1 H; δ 7,25, m, 3H; δ 3,6, m, 1 H; δ 3,4, m, 1 H; δ 3,0, m, 1H; δ 2,8, m, 1 H; δ 1,75, m, 1H; δ 1,6, m, 1H; δ 1,35, m, 1H; δ 1,2 s, 3H; δ 0,8, m, 6H. ES-LCMS (m/e): 308,1 Los siguientes compuestos se prepararon usando métodos similares:
34
imagen47
imagen48
imagen49
imagen50
imagen51
Método E
imagen52
Método E, Etapa 1:
10 Se añadió gota a gota cloruro de tionilo (0,47, 6,38 mmol) a una solución de E1 (R3 = CH2CH2C6H5) (2 g, 6,38 mmol) y benzaldehído dimetil acetal (0,96 ml, 6,38 mmol) en THF anhidro a 0 ºC en una atmósfera de N2. Después de 5 min, se añadió ZnCl2 (0,87 g, 6,38 mmol) y la mezcla de reacción se agitó a 0 ºC. Después de 3 h, se añadió una cantidad adicional de ZnCl2 (0,18 g, 1,28 mmol) y cloruro de tionilo (0,1 ml, 1,28 mmol) y se agitó durante 1 h a 0 ºC.
15 La mezcla de reacción se vertió en una suspensión agitada de hielo/H2O. La mezcla se agitó ocasionalmente hasta que el hielo se fundió. La solución acuosa se extrajo con éter (3 x). Los extractos orgánicos combinados se lavaron con H2O (3 x), una solución acuosa sat. de NaHCO3 (1 x) y H2O (2 x). La solución orgánica se secó sobre Na2SO4, se filtró y se concentró. El material en bruto se purificó por cromatografía ultrarrápida eluyendo con acetato de etilo en hexano para producir el compuesto E2 (R3 = CH2CH2C6H5).
20
Método E, Etapa 2:
Se añadió gota a gota una solución de hexametildisilazida de litio en hexano (1,0 M, 1,65 ml, 1,64 mmol) a una solución de E2 (R3 = CH2CH2C6H5) (600 mg, 1,49 mmol) y HMPA (0,85 ml) en THF (6,5 ml) enfriado a -78 ºC en una
25 atmósfera de N2. Después de 15 min, se añadió gota a gota yoduro de isobutilo (0,52 ml, 4,48 mmol) y la mezcla de reacción se agitó a -78 ºC durante 3 h. La reacción se calentó a -65 ºC, se agitó durante 2 h y se calentó a ta durante una noche. La solución de reacción se vertió en una mezcla de NaHCO3 sat. (ac.)/éter/hielo. La capa acuosa se extrajo con éter (3 x). Los extractos orgánicos se combinaron y se lavaron con salmuera (2 x). La solución orgánica se secó sobre Na2SO4, se filtró y se concentró. El material en bruto se purificó por cromatografía ultrarrápida
30 eluyendo con acetato de etilo en hexano para producir el compuesto E3 (R3 = CH2CH2C6H5,R4 = CH2CH(CH3)2).
39
imagen53
imagen54
imagen55
imagen56
680
imagen57398 399 693
imagen58511 512
406 407
Método H
imagen59
imagen60
5
Método H, Etapa 1:
A una solución de H1 (R3 = CH3) (5 g, 39 mmol) en una mezcla 1:1 de NaHCO3 0,5 M:CH3CH2OH se le añadió R1-NCS (R1 = 3-clorobencilo) (11,5 ml, 78 mmol). La mezcla de reacción se calentó a 50 ºC durante una noche. La
10 reacción se enfrió y se diluyó con agua. La fase acuosa se extrajo con acetato de etilo (5 x). Los extractos orgánicos se combinaron, se lavaron con agua (2 x) y se secaron sobre Na2SO4. La solución se filtró y el disolvente se retiró para dar un pequeño volumen de solución. Se añadió hexano y la suspensión resultante se filtró para producir 6,8 g de un sólido H2 (R3 = CH3,R1 = CH2(3-ClC6H4)) (61 %).
15 Método H, Etapa 2:
El compuesto H3 (R3 = CH3,R1 = CH2(3-ClC6H4)) se sintetizó a partir de H2 (R3 = CH3,R1 = CH2(3-ClC6H4)) siguiendo un procedimiento similar al Método A, Etapa 3.
44
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Método K, Etapa 1:
Se añadió una solución de R15SO2Cl (R15 = Propilo) (1,5 equiv.) a una suspensión de resina de poliestireno
10 diisopropiletilamina (18 mg, 3,45 mmol/g, 3 equiv.) y la base libre de K1 preparada usando el método H (R1 = CH2(3-ClC6H4) y R3 = CH3) (0,021 mmol) en 1:1 de CH3CN:THF. La suspensión se agitó durante una noche. Se añadieron resina de isocianato de poliestireno (45 mg, 3 equiv.), resina de poliestireno trisamina (40 mg, 6 equiv.) y una mezcla
1:1 de CH3CN:THF (0,5 ml). La mezcla se agitó durante 6 h. La suspensión se filtró y el filtrado se concentró para
proporcionar K2 (R1 = CH2(3-ClC6H4), R3 = CH3,y R15 =CH2CH2CH3). 15
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Método M
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5
(En el esquema, -Z-NH-C(O)-NHR15 - es equivalente a R1 sustituido por R21,oR1 sustituido por alquil-R22, en la que R21
y R22 son -N(R16)-C(O)-NHR15 y R16 es H, y en la que Z es alquileno-arileno, alquileno-arileno-alquileno, alquileno-heteroarileno, alquileno-heteroarileno-alquileno, alquileno-cicloalquileno, alquileno-cicloalquileno-alquileno, alquileno-heterocicloalquileno, alquileno-heterocicloalquileno-alquileno, arileno, heteroarileno, cicloalquileno o
10 heterocicloalquileno opcionalmente sustituidos).
Método M, Etapa 1:
El compuesto M2 (R3 = CH3,R4 = CH2CH(CH3)2, Z = para-(CH2)C6H4(CH2)-, R15 = 3,4-difluorofenilo) se preparó a
15 partir de M1 (R3 = CH3,R4 = CH2CH(CH3)2, Z = para-(CH2)C6H4(CH2)-) siguiendo el procedimiento descrito en el Método J, Etapa 1.
Método M, Etapa 2:
20 El compuesto M3 (R3 = CH3,R4 = CH2CH(CH3)2, Z = para-(CH2)C6H4(CH2)-, R15 = 3,4-difluorofenilo) se preparó a partir de M2 (R3 = CH3,R4 = CH2CH(CH3)2, Z = para-(CH2)C6H4(CH2)-, R15 = 3,4-difluorofenilo) siguiendo el procedimiento descrito en el Método A, Etapa 3. RMN (CD3OD) δ 7,45, m, 1 H; δ 7,26, m, 4H; 7,24, m, 1 H; δ 6,96, m, 1 H; δ 4,8, m; δ 4,3, s, 2H; δ 1,69, m, 2H; δ 1,44, m, 1 H; δ 1,37, s, 3H; δ 0,8, m, 3H; δ 0,63, m, 3H. ES-LCMS (m/e) 430,27
25 Los siguientes compuestos se prepararon usando un método similar.
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Claims (4)

  1. imagen1
    imagen2
    imagen3
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    imagen5
    imagen6
  2. 9.
    Un compuesto de acuerdo con la reivindicación 1, o un tautómero del mismo, o una sal farmacéuticamente aceptable de dicho compuesto o dicho tautómero, en donde dicho compuesto es:
  3. 10.
    Un compuesto de acuerdo con la reivindicación 1, o un tautómero del mismo, o una sal farmacéuticamente aceptable de dicho compuesto o dicho tautómero, en donde dicho compuesto es:
    Est. n.º
    Estructura
    3783
    Est. n.º
    Estructura
    3963
  4. 11. Un compuesto de acuerdo con la reivindicación 1, o un tautómero del mismo, o una sal farmacéuticamente 10 aceptable de dicho compuesto o dicho tautómero, en donde dicho compuesto es:
    Est. n.º
    Estructura
    3986
    418
    imagen7
    imagen8
    imagen9
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Families Citing this family (116)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3259012B2 (ja) 1995-08-02 2002-02-18 ミヤチテクノス株式会社 インバータ式抵抗溶接制御装置
JP3259013B2 (ja) 1995-08-10 2002-02-18 ミヤチテクノス株式会社 インバータ式抵抗溶接電源装置
US7592348B2 (en) * 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7700603B2 (en) * 2003-12-15 2010-04-20 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
ATE489370T1 (de) * 2005-06-14 2010-12-15 Schering Corp Herstellung und verwendung von verbindungen als aspartylproteasehemmer
AU2006259675A1 (en) * 2005-06-14 2006-12-28 Schering Corporation Aspartyl protease inhibitors
WO2006138265A2 (en) 2005-06-14 2006-12-28 Schering Corporation Heterocyclic aspartyl protease inhibitors, preparation and use thereof
PE20070135A1 (es) 2005-06-14 2007-03-09 Schering Corp Compuestos heterociclicos como inhibidores de aspartil proteasas
CA2628074C (en) 2005-10-25 2014-01-14 Shionogi & Co., Ltd. Aminodihydrothiazine derivative
AU2006333049A1 (en) * 2005-12-19 2007-07-12 Wyeth 2-amino-5-piperidinylimidazolone compounds and use thereof for beta-secretase modulation
PE20080155A1 (es) * 2006-06-12 2008-03-10 Schering Corp Compuestos heterociclicos como inhibidores de aspartil-proteasa
US20100016341A1 (en) * 2006-12-12 2010-01-21 Zhaoning Zhu Aspartyl protease inhibitors containing a tricyclic ring system
JP2010512389A (ja) 2006-12-12 2010-04-22 シェーリング コーポレイション アスパルチルプロテアーゼ阻害剤
US8653067B2 (en) * 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
JP5383484B2 (ja) 2007-04-24 2014-01-08 塩野義製薬株式会社 環式基で置換されたアミノジヒドロチアジン誘導体
CA2723222C (en) 2008-04-22 2013-04-02 Schering Corporation Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as bace-1 inhibitors, compositions, and their use
KR101324426B1 (ko) * 2008-06-13 2013-10-31 시오노기세야쿠 가부시키가이샤 β 세크레타제 저해 작용을 갖는 황 함유 복소환 유도체
EP2583556B1 (de) * 2008-07-17 2016-01-20 Bayer CropScience AG Heterocyclische Verbindungen als Schädlingsbekämpfungsmittel
WO2010021680A2 (en) 2008-08-19 2010-02-25 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
MY148558A (en) * 2008-09-11 2013-04-30 Amgen Inc Spiro-tetracyclic ring compounds as betasecretase modulators and methods of use
CN102186841A (zh) * 2008-10-22 2011-09-14 盐野义制药株式会社 具有bace1抑制活性的2-氨基嘧啶-4-酮及2-氨基吡啶衍生物
DE102008063992A1 (de) * 2008-12-19 2010-09-02 Lerner, Zinoviy, Dipl.-Ing. Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung
EP2375899B1 (en) * 2009-01-12 2015-02-25 Array Biopharma Inc. Piperidine-containing compounds and use thereof in the treatment of diabetes
MX2011009571A (es) 2009-03-13 2011-10-19 Boehringer Ingelheim Int Inhibidores de beta-secretasa.
PT3061821T (pt) 2009-07-22 2019-09-05 PureTech Health LLC Composições para tratamento de distúrbios melhorados por ativação de recetores muscarínicos
US10265311B2 (en) 2009-07-22 2019-04-23 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
GB0912778D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydro-oxazine derivatives
GB0912777D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydropyrimidone derivatives
WO2011044187A1 (en) 2009-10-08 2011-04-14 Schering Corporation Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
EP2485590B1 (en) 2009-10-08 2015-01-07 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use
UA108363C2 (uk) * 2009-10-08 2015-04-27 Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування
EP2485920B1 (en) * 2009-10-08 2016-04-27 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use
MX2012006491A (es) 2009-12-11 2012-07-03 Shionogi & Co Derivados de oxazina.
JP5828848B2 (ja) 2010-02-24 2015-12-09 ヴァイティー ファーマシューティカルズ，インコーポレイテッド ベータセクレターゼインヒビター
EP2547685A1 (en) 2010-03-15 2013-01-23 Amgen Inc. Spiro-tetracyclic ring compounds as beta - secretase modulators
US8497264B2 (en) 2010-03-15 2013-07-30 Amgen Inc. Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
US8921363B2 (en) 2010-08-05 2014-12-30 Amgen Inc. Derivatives of 1 H-isoindol-3-amine, 1 H-iso-aza-indol-3amine, 3,4-dihydroisoquinolin-1-amine, and 1,4-dihydroisoquinolin-3-amine as beta-secretase inhibitors
JP5816630B2 (ja) 2010-10-29 2015-11-18 塩野義製薬株式会社 ナフチリジン誘導体
EP2634188A4 (en) 2010-10-29 2014-05-07 Shionogi & Co FUSIONED AMINODIHYDROPYRIMIDINE DERIVATIVE
US8957083B2 (en) 2010-11-23 2015-02-17 Amgen Inc. Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
GB201100181D0 (en) 2011-01-06 2011-02-23 Eisai Ltd Fused aminodihydrothiazine derivatives
GB201101140D0 (en) 2011-01-21 2011-03-09 Eisai Ltd Fused aminodihydrothiazine derivatives
GB201101139D0 (en) 2011-01-21 2011-03-09 Eisai Ltd Fused aminodihydrothiazine derivatives
US9346827B2 (en) 2011-02-07 2016-05-24 Amgen Inc. 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use
EP2675810A1 (en) 2011-02-15 2013-12-25 Amgen Inc. Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
EP2694521B1 (en) 2011-04-07 2015-11-25 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use
EP2694489B1 (en) 2011-04-07 2017-09-06 Merck Sharp & Dohme Corp. C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use
BR112013026341A2 (pt) 2011-04-13 2019-09-24 Merck Sharp & Dohe Corp composto, composição farmacêutica, e, método para tratar, prevenir e/ou atrasar o início de uma doença ou patologia
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
CN103874496A (zh) 2011-08-22 2014-06-18 默沙东公司 作为bace抑制剂的2-螺-取代的亚氨基噻嗪类及其单和二氧化物、组合物及其用途
WO2013044092A1 (en) 2011-09-21 2013-03-28 Amgen Inc. Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
TWI557112B (zh) 2012-03-05 2016-11-11 百靈佳殷格翰國際股份有限公司 β－分泌酶抑制劑
CN104270945B (zh) 2012-03-19 2017-03-29 巴克老龄化研究所 App特异性bace抑制剂(asbi)及其用途
WO2013142396A1 (en) * 2012-03-23 2013-09-26 Merck Sharp & Dohme Corp. N3-substituted iminopyrimidinones as renin inhibitors, compositions, and their use
EP2669286A1 (en) * 2012-05-31 2013-12-04 Ares Trading S.A. Spiro tetrahydro-benzothiophen derivatives useful for the treatment of neurodegenerative diseases
TW201422592A (zh) 2012-08-27 2014-06-16 Boehringer Ingelheim Int β－分泌酶抑制劑
JP2015532282A (ja) 2012-09-28 2015-11-09 ヴァイティー ファーマシューティカルズ，インコーポレイテッド β−セクレターゼの阻害剤
US9422277B2 (en) 2012-10-17 2016-08-23 Merck Sharp & Dohme Corp. Tricyclic substituted thiadiazine dioxide compounds as BACE inhibitors, compositions and their use
EP2908824B1 (en) 2012-10-17 2018-05-02 Merck Sharp & Dohme Corp. Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use
EP2912035A4 (en) 2012-10-24 2016-06-15 Shionogi & Co DERIVATIVES OF DIHYDROOXAZINE OR OXAZEPINE HAVING BACE1 INHIBITING ACTIVITY
US9353072B2 (en) * 2012-10-31 2016-05-31 Purdue Research Foundation Antimicrobial substituted thiazoles and methods of use
WO2014078314A1 (en) 2012-11-15 2014-05-22 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
WO2014093190A1 (en) * 2012-12-14 2014-06-19 Merck Sharp & Dohme Corp. Bace inhibitors of iminothiadiazine dioxides
US9489013B2 (en) 2012-12-20 2016-11-08 Merck Sharp & Dohme Corp. C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use
EP2934539B1 (en) 2012-12-20 2019-03-27 Merck Sharp & Dohme Corp. C5, c6 oxacyclic-fused iminothiazine dioxide compounds as bace inhibitors
WO2014099788A1 (en) 2012-12-21 2014-06-26 Merck Sharp & Dohme Corp. C5-spiro iminothiadiazine dioxides as bace inhibitors
CA2899938C (en) 2013-02-12 2021-10-19 Buck Institute For Research On Aging Hydantoins that modulate bace-mediated app processing
JP6321685B2 (ja) 2013-02-25 2018-05-09 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ ２−アミノ−３，４−ジヒドロ−キナゾリン誘導体、およびそのカテプシンｄ阻害剤としての使用
WO2014134341A1 (en) 2013-03-01 2014-09-04 Amgen Inc. Perfluorinated 5,6-dihydro-4h-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
MX374512B (es) 2013-03-08 2025-03-06 Amgen Inc Compuestos de 1,3-oxazin-2-amina fusionados con ciclopropilo perfluorado como inhibidores de beta-secretasa y métodos de uso.
WO2014160775A1 (en) * 2013-03-26 2014-10-02 Saint Louis University Compositions and methods for the treatment of malaria
WO2015038446A1 (en) 2013-09-13 2015-03-19 Merck Sharp & Dohme Corp. C5-spiro iminothiazine dioxides as bace inhibitors, compositions, and their use
WO2015094930A1 (en) 2013-12-18 2015-06-25 Merck Sharp & Dohme Corp. C-6 spirocarbocyclic iminothiadiazine dioxides as bace inhibitors, compositions, and their use
WO2015095104A1 (en) 2013-12-18 2015-06-25 Merck Sharp & Dohme Corp. Iminothiadiazepane dioxide compounds as bace inhibitors, compositions, and their use
TW201623295A (zh) 2014-04-11 2016-07-01 塩野義製藥股份有限公司 具有ｂａｃｅ１抑制活性之二氫噻及二氫衍生物
CN106795147B (zh) 2014-08-08 2020-09-22 美国安进公司 作为β-分泌酶抑制剂的环丙基稠合噻嗪-2-胺化合物和使用方法
US9957269B2 (en) 2014-09-12 2018-05-01 Merck Sharp & Dohme Corp. S-imino-S-oxo iminothiazine compounds as bace inhibitors, compositions, and their use
US9868738B2 (en) 2014-09-19 2018-01-16 Merck Sharp & Dohme Corp. Diazine-fused amidines as BACE inhibitors, compositions, and their use
WO2016085780A1 (en) 2014-11-25 2016-06-02 Merck Sharp & Dohme Corp. C5-c6-oxacyclic fused iminopyrimidinone compounds as bace inhibitors, compositions, and their use
WO2016118404A1 (en) 2015-01-20 2016-07-28 Merck Sharp & Dohme Corp. Iminothiadiazine dioxides bearing an amine-linked substituent as bace inhibitors, compositions, and their use
ES2942308T3 (es) 2015-04-21 2023-05-31 Allgenesis Biotherapeutics Inc Compuestos y su uso como inhibidores de BACE1
WO2017061534A1 (en) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dihydrothiazine derivatives
CN108290860B (zh) * 2015-11-25 2021-08-10 Ucb生物制药有限责任公司 作为plasmepsin v抑制剂的亚氨基四氢嘧啶酮衍生物
WO2017095759A1 (en) 2015-12-04 2017-06-08 Merck Sharp & Dohme Corp. C5-c6-carbocyclic fused iminothiadiazine dioxides as bace inhibitors, compositions, and their use
EP3413895B1 (en) 2016-02-11 2021-07-21 Merck Sharp & Dohme Corp. C5-c6-oxacylic fused iminothiadiazine dioxide compounds bearing an ether linker as bace inhibitors, compositions, and their use
EP3414253B1 (en) 2016-02-11 2021-07-21 Merck Sharp & Dohme Corp. C5-c6-oxacylic fused iminothiazine dioxide compounds bearing an ether linker as bace inhibitors, compositions, and their use
WO2017142821A1 (en) * 2016-02-18 2017-08-24 Merck Sharp & Dohme Corp. Compounds for the treatment of malaria
US11766435B2 (en) 2016-02-18 2023-09-26 Merck Sharp & Dohme Llc N3-substituted iminopyrimidinones as antimalarial agents
GB201603104D0 (en) * 2016-02-23 2016-04-06 Ucb Biopharma Sprl Therapeutic agents
JP6860551B2 (ja) * 2016-03-11 2021-04-14 武田薬品工業株式会社 芳香環化合物
US11352328B2 (en) 2016-07-12 2022-06-07 Arisan Therapeutics Inc. Heterocyclic compounds for the treatment of arenavirus
MX2019001918A (es) 2016-08-15 2019-09-06 Bayer Cropscience Ag Derivados del heterociclo biciclico condensado como agentes de control de plagas.
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
US10696639B2 (en) 2016-12-06 2020-06-30 Merck Sharp & Dohme Corp. Heterocyclic compounds as HIV protease inhibitors
US20200261421A1 (en) * 2016-12-22 2020-08-20 Merck Sharp & Dohme Corp. Heterocyclic compounds as hiv protease inhibitors
WO2018118829A1 (en) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Heterocyclic compounds as hiv protease inhibitors
CN106810458B (zh) * 2016-12-31 2019-05-03 武汉工程大学 一种拆分dl-2-氨基丙醇制备l-2-氨基丙醇的方法
JOP20180092A1 (ar) * 2017-10-13 2019-04-13 Gilead Sciences Inc مثبطات hiv بروتياز
GB201805816D0 (en) 2018-04-06 2018-05-23 Ucb Biopharma Sprl Therapeutic agents
AU2019258575A1 (en) 2018-04-27 2020-10-29 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity
US10844044B2 (en) * 2018-06-14 2020-11-24 Vanderbilt University WDR5 inhibitors and modulators
KR102408292B1 (ko) 2018-09-28 2022-06-10 카루나 세러퓨틱스 인코포레이티드 무스카린성 수용체 활성화에 의해 개선된 장애의 치료를 위한 조성물 및 방법
US12419865B2 (en) 2018-12-06 2025-09-23 Arisan Therapeutics Inc. Compounds for the treatment of arenavirus infection
TW202104210A (zh) 2019-04-17 2021-02-01 美商基利科學股份有限公司 Hiv蛋白酶抑制劑
GB201906804D0 (en) 2019-05-14 2019-06-26 Ucb Biopharma Sprl Therapeutic agents
CN110066221B (zh) * 2019-05-16 2022-03-08 海门瑞一医药科技有限公司 一种环丙基甲胺的制备方法
CN110256285B (zh) * 2019-07-09 2022-03-18 上海出入境检验检疫局动植物与食品检验检疫技术中心 一种稳定同位素标记拟除虫菊酯的合成方法
WO2021026884A1 (en) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Antimalarial agents
JP7592069B2 (ja) 2019-08-19 2024-11-29 ユーシービー バイオファルマ エスアールエル 抗マラリア性ヘキサヒドロピリミジン類似体
WO2021097676A1 (en) 2019-11-19 2021-05-27 Merck Sharp & Dohme Corp. Antimalarial agents
WO2021155612A1 (en) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Antimalarial agents
GB202010606D0 (en) 2020-07-10 2020-08-26 Ucb Biopharma Sprl Therapeutic agents
WO2023102747A1 (en) * 2021-12-07 2023-06-15 Merck Sharp & Dohme Llc Antimalarial agents
WO2022206742A1 (zh) * 2021-03-30 2022-10-06 苏州开拓药业股份有限公司 一种一步法合成乙内酰硫脲衍生物的方法
WO2023152042A1 (en) 2022-02-08 2023-08-17 UCB Biopharma SRL Antimalarial hexahydropyrimidine analogues

Family Cites Families (274)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3200123A (en) 1962-01-26 1965-08-10 Richardson Merreil Inc Imidazoquinolines
US3197476A (en) 1962-12-06 1965-07-27 Air Prod & Chem Method of synthesis of 1-acyl imidazoles
US3632814A (en) 1968-11-25 1972-01-04 Velsicol Chemical Corp Phosphoramidate esters
ZA87563B (en) 1986-02-03 1987-09-30 Squibb & Sons Inc N-heterocyclic alcohol renin inhibitors
DE3643890A1 (de) 1986-12-22 1988-06-30 Basf Ag Neue polyalkylpiperidinderivate mit alkylenbruecken, ihre verwendung als stabilisator und zwischenprodukte
JPH03500772A (ja) 1987-10-21 1991-02-21 ジ・アップジョン・カンパニー （１‐アミノ‐２‐ヒドロキシ‐２‐ヘテロサイクリック）エチル基を含有するレニン抑制物質類
EP0361341A3 (en) 1988-09-28 1991-07-03 Miles Inc. Therapeutics for aids based on inhibitors of hiv protease
IL92011A0 (en) 1988-10-19 1990-07-12 Abbott Lab Heterocyclic peptide renin inhibitors
US5534520A (en) * 1990-04-10 1996-07-09 Fisher; Abraham Spiro compounds containing five-membered rings
US5852029A (en) * 1990-04-10 1998-12-22 Israel Institute For Biological Research Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity
GB9109972D0 (en) 1991-05-09 1991-07-03 Ici Plc Therapeutic compounds
US5731431A (en) * 1991-12-26 1998-03-24 Nippon Soda Co., Ltd. Process for preparing 4-substituted azetidinone derivatives
WO1993013064A1 (fr) 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4
US5536727A (en) 1992-05-20 1996-07-16 Merck & Co., Inc. 17-Ethers and thioethers of 4-aza-steroids
JPH07508039A (ja) 1992-05-20 1995-09-07 メルク　エンド　カンパニー　インコーポレーテッド ４−アザステロイドのエステル誘導体
DE4233715A1 (de) * 1992-10-07 1994-04-14 Bayer Ag Substituierte Carbamoylpyrazoline
US5338740A (en) * 1993-07-13 1994-08-16 Pfizer Inc. Angiotensin II receptor antagonists
US5502222A (en) 1994-06-01 1996-03-26 Schering Corporation Process for preparing delta 9,11 and 21-chloro corticosteroids
US5889006A (en) * 1995-02-23 1999-03-30 Schering Corporation Muscarinic antagonists
IL117149A0 (en) * 1995-02-23 1996-06-18 Schering Corp Muscarinic antagonists
US5691372A (en) * 1995-04-19 1997-11-25 Vertex Pharmaceuticals Incorporated Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
JPH11509846A (ja) 1995-07-31 1999-08-31 ノボ ノルディスク アクティーゼルスカブ ヘテロ環式化合物、それらの調製及び使用
FR2741342B1 (fr) * 1995-11-22 1998-02-06 Roussel Uclaf Nouvelles phenylimidazolidines fluorees ou hydroxylees, procede, intermediaires de preparation, application comme medicaments, nouvelle utilisation et compositions pharmaceutiques
GB9611046D0 (en) 1996-05-25 1996-07-31 Wivenhoe Techn Ltd Pharmacological compounds
US5935958A (en) * 1996-07-01 1999-08-10 Schering Corporation Muscarinic antagonists
US5952349A (en) * 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
GB9615831D0 (en) 1996-07-27 1996-09-11 Agrevo Uk Ltd Fungicides
US5977138A (en) * 1996-08-15 1999-11-02 Schering Corporation Ether muscarinic antagonists
US5981556A (en) 1997-07-22 1999-11-09 G.D. Searle & Co. 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors
JPH11335518A (ja) 1998-03-25 1999-12-07 Polyplastics Co ポリアセタ―ル樹脂組成物およびその製造方法
US6066636A (en) * 1998-06-30 2000-05-23 Schering Corporation Muscarinic antagonists
US6638937B2 (en) 1998-07-06 2003-10-28 Bristol-Myers Squibb Co. Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
US6413725B1 (en) * 1998-08-07 2002-07-02 California Institute Of Technology Biochemical assay to monitor the ubiquitin ligase activities of cullins
US6864240B1 (en) 1999-06-15 2005-03-08 Elan Pharmaceuticals, Inc. Dipeptide inhibitors of β-secretase
CA2374610A1 (en) * 1999-06-28 2001-01-04 Jordan J. N. Tang Catalytically active recombinant memapsin and methods of use thereof
US6492408B1 (en) 1999-07-21 2002-12-10 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
US6294554B1 (en) * 1999-09-22 2001-09-25 Schering Corporation Muscarinic antagonists
ATE339417T1 (de) 1999-12-15 2006-10-15 Bristol Myers Squibb Co Biphenyl - sulfonamide als duale angiotensin - endothelin - rezeptor - antagonisten
DE60124080T2 (de) * 2000-03-23 2007-03-01 Elan Pharmaceuticals, Inc., San Francisco Verbindungen und verfahren zur behandlung der alzheimerschen krankheit
CN1436175A (zh) 2000-04-03 2003-08-13 布里斯托尔-迈尔斯斯奎布药品公司 作为Aβ－蛋白生产抑制剂的环状内酰胺
WO2001077086A1 (en) 2000-04-11 2001-10-18 Dupont Pharmaceuticals Company SUBSTITUTED LACTAMS AS INHIBITORS OF Aβ PROTEIN PRODUCTION
US6713276B2 (en) * 2000-06-28 2004-03-30 Scios, Inc. Modulation of Aβ levels by β-secretase BACE2
JP2004502664A (ja) 2000-06-30 2004-01-29 イーラン　ファーマスーティカルズ、インコーポレイテッド アルツハイマー病処置用化合物
PE20020276A1 (es) 2000-06-30 2002-04-06 Elan Pharm Inc COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER
US6846813B2 (en) 2000-06-30 2005-01-25 Pharmacia & Upjohn Company Compounds to treat alzheimer's disease
WO2002007419A2 (en) 2000-07-14 2002-01-24 Vigilant Networks Llc Tdr lan cables attenuation measurement
US6344473B1 (en) * 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
WO2002012243A2 (en) 2000-08-09 2002-02-14 Boehringer Ingelheim Pharmaceuticals, Inc. SYNTHESIS OF (R)-3-(4-BROMOBENZYL)-1-(3,5-DICHLOROPHENYL)-5-IODO-3-METHYL-1-H-IMIDAZO[1,2-a]IMIDAZOL-2-ONE
ATE439344T1 (de) * 2000-12-22 2009-08-15 Schering Corp Muscarin-antagonisten
WO2002062803A1 (en) 2001-02-08 2002-08-15 Yamanouchi Pharmaceutical Co., Ltd. Thienopyrimidine derivative
WO2002074719A2 (en) 2001-03-15 2002-09-26 The Johns Hopkins University Inhibitors of plasmepsins
EP1389194A2 (en) 2001-04-27 2004-02-18 Vertex Pharmaceuticals Incorporated Inhibitors of bace
US7384773B1 (en) * 2001-05-10 2008-06-10 Pfizer Inc Crystal of HIV protease-cleaved human beta secretase and method for crystallization thereof
MXPA03011046A (es) 2001-06-01 2004-06-25 Elan Pharm Inc Hidroxialquilaminas.
US20070213407A1 (en) * 2001-06-29 2007-09-13 Elan Pharmaceuticals And Pharmacia & Upjohn Company Llc Compounds to treat Alzheimer's disease
EP1432674A2 (en) 2001-10-04 2004-06-30 Elan Pharmaceuticals, Inc. Hydroxypropylamines
JP2005506339A (ja) 2001-10-10 2005-03-03 シェーリング　コーポレイション ムスカリン性アンタゴニストとしてのピペリジン化合物
US6673821B2 (en) 2001-10-22 2004-01-06 Enanta Pharmaceuticals, Inc. Nitrogen heterocycle inhibitors of aspartyl protease
JP4547152B2 (ja) 2001-10-23 2010-09-22 オクラホマ メディカル リサーチ ファウンデーション β−セクレターゼ阻害剤および使用方法
AU2002359376B2 (en) * 2001-11-08 2008-01-10 Elan Pharmaceuticals, Inc. N, N'-substituted-1,3-diamino-2-hydroxypropane derivatives
BR0214295A (pt) 2001-11-19 2004-11-09 Elan Pharm Inc Composto, método para tratar um paciente que tem ou prevenir um paciente de adquirir uma doença ou condição, e, método para produzir um composto
AU2002360508A1 (en) 2001-12-06 2003-06-23 Elan Pharmaceuticals, Inc. Substituted hydroxyethylamines
CA2471099C (en) 2001-12-20 2011-04-12 Bristol-Myers Squibb Company .alpha.-(n-sulphonamido)acetamide derivatives as .beta.-amyloid inhibitors
US7273743B2 (en) 2002-02-21 2007-09-25 Elan Pharmaceuticals, Inc. Modified BACE
WO2003106405A1 (en) 2002-06-01 2003-12-24 Sunesis Pharmaceuticals, Inc. Aspartyl protease inhibitors
US7459476B2 (en) 2002-06-27 2008-12-02 Elan Pharmaceuticals, Inc. Methods for treating Alzheimer's disease using hydroxyethylene compounds containing a heterocyclic amide bond isostere
CA2497979A1 (en) * 2002-09-06 2004-03-18 Elan Pharmaceuticals, Inc. 1, 3-diamino-2-hydroxypropane prodrug derivatives
UY27967A1 (es) 2002-09-10 2004-05-31 Pfizer Acetil 2-hindroxi-1,3-diaminoalcanos
MXPA05003432A (es) 2002-10-09 2005-07-05 Pfizer Prod Inc Compuestos pirazoles para el tratamiento de trastornos neurodegenerativos.
US7537914B1 (en) 2002-11-04 2009-05-26 Florida State University Research Foundation, Inc. Nucleic acid and allergenic polypeptides encoded thereby in cashew nuts (Anacardium occidentale)
ATE443043T1 (de) 2002-11-12 2009-10-15 Merck & Co Inc Phenylcarboxamide als beta-sekretase-hemmer zur behandlung von alzheimer
CA2507484A1 (en) 2002-11-27 2004-06-17 Elan Pharmaceuticals, Inc. Substituted ureas and carbamates
GB0228410D0 (en) 2002-12-05 2003-01-08 Glaxo Group Ltd Novel Compounds
WO2004058727A1 (en) 2002-12-20 2004-07-15 Bayer Pharmaceuticals Corporation Substituted 3,5-dihydro-4h-imidazol-4-ones for the treatment of obesity
US7354933B2 (en) * 2003-01-31 2008-04-08 Aventis Pharma Sa Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
FR2850652B1 (fr) 2003-01-31 2008-05-30 Aventis Pharma Sa Nouveaux derives d'uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases
WO2004076478A1 (ja) 2003-02-28 2004-09-10 Yoshiaki Kiso βセクレターゼ阻害活性を有するペプチド誘導体
TW200512195A (en) 2003-04-21 2005-04-01 Elan Pharm Inc Benzamide 2-hydroxy-3-diaminoalkanes
GB0309221D0 (en) 2003-04-23 2003-06-04 Glaxo Group Ltd Novel compounds
MXPA05012196A (es) 2003-05-12 2006-02-08 Pfizer Prod Inc Compuestos de isoxazol e isotiazol para el tratamiento de trastornos neurodegenerativos.
GB0314302D0 (en) 2003-06-19 2003-07-23 Glaxo Group Ltd Novel compounds
JP2007516207A (ja) 2003-06-30 2007-06-21 メルク　エンド　カムパニー　インコーポレーテッド アルツハイマー病の治療のためのＮ−アルキルフェニルカルボキサミドβ−セクレターゼ阻害剤
DE10336035A1 (de) 2003-08-01 2005-03-24 Endress + Hauser Wetzer Gmbh + Co Kg Verfahren zur automatischen Anpassung eines busfähigen Feldgerätes der Prozessautomatisierungstechnik an das auf dem Feldbus verwendete Busprotokoll
WO2005016876A2 (en) 2003-08-08 2005-02-24 Schering Corporation Cyclic amine bace-1 inhibitors having a benzamide substituent
AR045219A1 (es) 2003-08-08 2005-10-19 Pharmacopeia Inc Aminas ciclicas inhibidoras de base - 1 que poseen un sustiuyente heterociclico
EP1658072A4 (en) 2003-08-21 2009-03-25 Pfizer Prod Inc Compounds for the Treatment of Neurodegenerative Diseases
CA2543756A1 (en) * 2003-10-30 2005-05-12 Elan Pharmaceuticals, Inc. Hydroxypropyl amides for the treatment of alzheimer's disease
US20050171112A1 (en) * 2003-11-03 2005-08-04 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
US20060034848A1 (en) * 2003-11-07 2006-02-16 Ayae Kinoshita Methods and compositions for treating Alzheimer's disease
AU2004294182C1 (en) * 2003-11-21 2014-01-16 Visual Physics, Llc Micro-optic security and image presentation system
EP2335701B1 (en) 2003-12-15 2012-07-11 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7700603B2 (en) * 2003-12-15 2010-04-20 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7592348B2 (en) * 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
US7550481B2 (en) 2003-12-19 2009-06-23 Merck & Co., Inc. Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease
US7205370B2 (en) * 2004-01-12 2007-04-17 Bridgestone Corporation Polymeric nano-particles of flower-like structure and applications
WO2005070407A1 (en) 2004-01-21 2005-08-04 Elan Pharmaceuticals, Inc. Methods of treatment of amyloidosis using aspartyl-protease inihibitors
JP2007528404A (ja) 2004-03-09 2007-10-11 エラン ファーマシューティカルズ，インコーポレイテッド 置換された尿素およびカルバメート、フェナシル−２−ヒドロキシ−３−ジアミノアルカン、ならびにベンズアミド−２−ヒドロキシ−３−ジアミノアルカン系のアスパラギン酸プロテアーゼ阻害薬
JP2007530696A (ja) 2004-03-30 2007-11-01 メルク　エンド　カムパニー　インコーポレーテッド アスパラギン酸プロテアーゼ阻害剤として有用な２−アミノチアゾール化合物
US7232820B2 (en) 2004-04-01 2007-06-19 Pfizer Inc Thiadiazole-amine compounds for the treatment of neurodegenerative disorders
US7244757B2 (en) 2004-04-01 2007-07-17 Pfizer Inc Pyrazole-amine compounds for the treatment of neurodegenerative disorders
JP2007533743A (ja) 2004-04-20 2007-11-22 メルク　エンド　カムパニー　インコーポレーテッド アルツハイマー病治療のためのβ−セクレターゼ阻害薬として有用な１，３，５−置換フェニル誘導体化合物
CA2563639A1 (en) 2004-04-20 2005-11-03 Merck & Co., Inc. 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
US7585885B2 (en) 2004-04-22 2009-09-08 Eli Lilly And Company Pyrrolidine derivatives useful as BACE inhibitors
US7618978B2 (en) 2004-04-22 2009-11-17 Eli Lilly And Company Amides as BACE inhibitors
EP1756040A4 (en) 2004-05-13 2008-04-30 Merck & Co Inc ALS-SEKRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER DISEASE, PHENYL ACETIC ACID AMID COMPOUNDS SUITABLE
WO2005113582A1 (en) 2004-05-22 2005-12-01 Boehringer Ingelheim International Gmbh Substituted ethane-1,2-diamines for the treatment of alzheimer's disease
US7714021B2 (en) 2004-06-15 2010-05-11 Merck & Co., Inc. Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease
PE20060526A1 (es) 2004-06-15 2006-07-13 Schering Corp Compuestos triciclicos como antagonistas de mglur1
BRPI0512213A (pt) * 2004-06-16 2008-02-19 Wyeth Corp método para tratamento, prevenção ou melhora de uma doença ou distúrbio; composição farmacêutica; processo para a preparação de um composto; e uso de um composto
RU2006144075A (ru) 2004-06-16 2008-07-27 Вайет (Us) ДИФЕНИЛИМИДАЗОПИРИМИДИН И -ИМИДАЗОЛАМИНЫ КАК ИНГИБИТОРЫ β-СЕКРЕТАЗЫ
WO2006010095A2 (en) * 2004-07-09 2006-01-26 Elan Pharmaceuticals Inc. Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors
CA2574218A1 (en) * 2004-07-22 2006-02-09 Schering Corporation Substituted amide beta secretase inhibitors
CA2575340A1 (en) 2004-07-28 2006-02-09 Schering Corporation Macrocyclic beta-secretase inhibitors
US8436006B2 (en) 2004-08-06 2013-05-07 Jansssen Pharmaceutica N.V. 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE)
EP1776350B1 (en) 2004-08-06 2013-01-23 Janssen Pharmaceutica NV NOVEL 2-AMINO-QUINAZOLINE DERIVATIVES USEFUL AS INHIBITORS OF ß-SECRETASE ( BACE )
DE602005023887D1 (de) 2004-08-06 2010-11-11 Janssen Pharmaceutica Nv Als b-sekretase (bace)-hemmer nützliche 2-amino-chinazolinderivate
WO2006018287A1 (en) 2004-08-17 2006-02-23 Novartis Ag Three-dimensional strcture of the human aspartyl protease beta-site amyloid precursor-protein-cleaving enzyme 2 (bace2), methods and use thereof
US7388007B2 (en) * 2004-08-26 2008-06-17 Bristol-Myers Squibb Company Gamma-lactams as beta-secretase inhibitors
JP2008511643A (ja) * 2004-08-27 2008-04-17 エラン ファーマシューティカルズ，インコーポレイテッド 置換エタノール環式アミンアスパラギン酸プロテアーゼ阻害剤を用いて、アミロイドーシスを治療する方法
WO2006029850A1 (en) 2004-09-14 2006-03-23 The Genetics Company, Inc. Hydrazone derivatives and their use as beta secretase inhibitors
AU2005286844A1 (en) 2004-09-17 2006-03-30 Comentis, Inc Bicyclic compounds which inhibit beta-secretase activity and methods of use thereof
SV2006002232A (es) 2004-09-21 2006-05-25 Lilly Co Eli Inhibidores bace ref. x-16940
GB0422755D0 (en) 2004-10-13 2004-11-17 Glaxo Group Ltd Novel compounds
US8114887B2 (en) 2004-10-13 2012-02-14 Merck, Sharp & Dohme Corp. Spiropiperidine compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
GB0422765D0 (en) 2004-10-13 2004-11-17 Glaxo Group Ltd Novel compounds
GB0422766D0 (en) 2004-10-13 2004-11-17 Glaxo Group Ltd Novel compounds
EP1802588A4 (en) 2004-10-15 2010-02-17 Astrazeneca Ab SUBSTITUTED AMINOPYRIMIDONE AND APPLICATIONS THEREOF
JP2008516945A (ja) 2004-10-15 2008-05-22 アストラゼネカ・アクチエボラーグ 置換されたアミノ化合物およびそれらの使用
WO2006060109A1 (en) 2004-10-29 2006-06-08 Merck & Co., Inc. 2-aminopyridine compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
WO2006050862A1 (en) 2004-11-10 2006-05-18 Boehringer Ingelheim International Gmbh Statine derivatives for the treatment of alzheimer's disease
US7951949B2 (en) 2004-11-23 2011-05-31 Merck, Sharp & Dohme, Corp. Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of Alzheimer's disease
ES2259891B1 (es) 2004-11-30 2007-11-01 Laboratorios Almirall S.A. Nuevos derivados de piridotienopirimidina.
EP1831207B1 (en) * 2004-12-17 2012-11-14 Amgen Inc. Aminopyrimidine compounds as plk inhibitors
GB0500683D0 (en) * 2005-01-13 2005-02-23 Novartis Ag Organic compounds
CA2593515A1 (en) * 2005-01-14 2006-07-20 Wyeth Amino-imidazolones for the inhibition of beta-secretase
CA2594946A1 (en) 2005-01-19 2006-07-27 Merck & Co., Inc Tertiary carbinamines having substituted heterocycles, which are active as inhibitors of beta-secretase, for the treatment of alzheimer's disease
EP1855679B1 (en) 2005-01-19 2016-06-29 Merck Sharp & Dohme Corp. Aminomethyl beta-secretase inhibitors for the treatment of alzheimer's disease
WO2006081072A1 (en) 2005-01-24 2006-08-03 Abbott Laboratories Antagonists of the mglu receptor and uses thereof
US20070299093A1 (en) 2005-01-27 2007-12-27 Alma Mater Studiorum-Universitá Di Bologna Organic Compounds Useful for the Treatment of Alzheimer's Disease, Their Use and Method of Preparation
CA2595994A1 (en) 2005-01-27 2006-08-03 Alma Mater Studiorum - Universita' Di Bologna Organic compounds useful for the treatment of alzheimer's disease, their use and method of preparation
CN101111489A (zh) * 2005-02-01 2008-01-23 惠氏公司 作为β-分泌酶的抑制剂的氨基-吡啶
WO2006088694A1 (en) 2005-02-14 2006-08-24 Wyeth SUBSTITUTED THIENYL AND FURYL ACYLGUANIDINES AS β-SECRETASE MODULATORS
BRPI0606902A2 (pt) * 2005-02-14 2009-07-28 Wyeth Corp composto; método para o tratamento de uma doença ou distúrbio associado a atividade excessiva de bace em um paciente que dele necessite; método para modular a atividade de bace; composição farmacêutica
WO2006088705A1 (en) * 2005-02-14 2006-08-24 Wyeth Terphenyl guanidines as [beta symbol] -secretase inhibitors
US7745470B2 (en) 2005-03-10 2010-06-29 Bristol-Myers Squibb Company Isophthalates as beta-secretase inhibitors
NZ562314A (en) 2005-04-08 2010-02-26 Comentis Inc Compounds which inhibit beta-secretase activity and methods of use thereof
WO2006133588A1 (en) 2005-06-13 2006-12-21 Oncalis Ag ARYL UREA COMPOUNDS AS β-SECRETASE INHIBITORS
ATE489370T1 (de) 2005-06-14 2010-12-15 Schering Corp Herstellung und verwendung von verbindungen als aspartylproteasehemmer
AR053902A1 (es) * 2005-06-14 2007-05-23 Schering Corp Inhibidores de aspartil proteasa heterociclicos macrociclicos
PE20070135A1 (es) 2005-06-14 2007-03-09 Schering Corp Compuestos heterociclicos como inhibidores de aspartil proteasas
WO2006138265A2 (en) 2005-06-14 2006-12-28 Schering Corporation Heterocyclic aspartyl protease inhibitors, preparation and use thereof
KR20080025079A (ko) * 2005-06-14 2008-03-19 쉐링 코포레이션 아스파르틸 프로테아제 억제제
EP1896406A2 (en) 2005-06-14 2008-03-12 Shering Corporation The preparation and use of compounds as protease inhibitors
AU2006259675A1 (en) * 2005-06-14 2006-12-28 Schering Corporation Aspartyl protease inhibitors
US7273882B2 (en) 2005-06-21 2007-09-25 Bristol-Myers Squibb Company Aminoacetamide acyl guanidines as β-secretase inhibitors
WO2007002214A2 (en) 2005-06-21 2007-01-04 Bristol-Myers Squibb Company Acyl guanidines as beta-secretase inhibitors
EP1917352A4 (en) 2005-06-21 2009-03-25 Medimmune Vaccines Inc METHODS AND COMPOSITIONS FOR EXPRESSING HETEROLOGOUS PROTEASE
TW200738683A (en) 2005-06-30 2007-10-16 Wyeth Corp Amino-5-(5-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation
AU2006266167A1 (en) * 2005-06-30 2007-01-11 Wyeth Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation
JP2009502786A (ja) 2005-07-18 2009-01-29 メルク エンド カムパニー インコーポレーテッド アルツハイマー病を治療するためのスピロピペリジンβ−セクレターゼ阻害剤
TW200730523A (en) 2005-07-29 2007-08-16 Wyeth Corp Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation
EP1915339A1 (de) 2005-08-11 2008-04-30 Boehringer Ingelheim International GmbH Inhibitoren der beta-sekretase zur behandlung der alzheimer- erkrankung
US20090042867A1 (en) * 2005-08-11 2009-02-12 Klaus Fuchs Compounds for the treatment of alzheimer's disease
US20100168070A1 (en) 2005-08-11 2010-07-01 Niklas Heine Compounds for the treatment of alzheimer's disease
US20100144681A1 (en) 2005-08-11 2010-06-10 Klaus Fuchs Compounds for the treatment of alzheimer's disease
WO2007021793A1 (en) * 2005-08-12 2007-02-22 Bristol-Myers Squibb Company Macrocyclic diaminopropanes as beta-secretase inhibitors
US7601751B2 (en) * 2005-09-01 2009-10-13 Bristol-Myers Squibb Company Indole acetic acid acyl guanidines as β-secretase inhibitors
JP2009509957A (ja) * 2005-09-26 2009-03-12 ワイス β−セクレターゼ阻害剤としてのアミノ−５−［４−（ジフルオロメトキシ）フェニル］−５−フェニルイミダゾロン化合物
EP1937638A1 (en) 2005-10-12 2008-07-02 Elan Pharmaceuticals Inc. Methods of treating amyloidosis using aryl-cyclopropyl derivative aspartyl protease inhibitors
WO2007047305A1 (en) 2005-10-12 2007-04-26 Elan Pharmaceuticals, Inc. Methods of treating amyloidosis using cyclopropyl derivative aspartyl protease inhibitors
EP1966198B1 (en) 2005-10-25 2011-03-16 Janssen Pharmaceutica NV 2-amino-3,4-dihydro-pyrido[3,4-d]pyrimidine derivatives useful as inhibitors of beta-secretase (bace)
CA2628074C (en) 2005-10-25 2014-01-14 Shionogi & Co., Ltd. Aminodihydrothiazine derivative
ATE478070T1 (de) * 2005-10-27 2010-09-15 Schering Corp Heterozyklische aspartyl-proteasehemmer
JP2009513670A (ja) * 2005-10-31 2009-04-02 シェーリング コーポレイション アスパルチルプロテアーゼインヒビター
WO2007051333A1 (en) 2005-11-02 2007-05-10 Oncalis Ag Triazine beta-secretase inhibitors
JP2009515950A (ja) 2005-11-15 2009-04-16 アストラゼネカ・アクチエボラーグ 新規な２−アミノピリミジン誘導体およびその使用
EP1951680A4 (en) 2005-11-15 2011-08-10 Astrazeneca Ab NOVEL 2-AMINOPYRIMIDINONE DERIVATIVES AND THEIR USE
TW200804290A (en) 2005-11-15 2008-01-16 Astrazeneca Ab Compounds and uses thereof
CN101360721A (zh) 2005-11-15 2009-02-04 阿斯利康(瑞典)有限公司 新颖的2-氨基嘧啶酮衍生物或2-氨基吡啶酮衍生物及其用途
US7872009B2 (en) 2005-11-21 2011-01-18 Amgen Inc. Beta-Secretase modulators and methods of use
US7745484B2 (en) 2005-11-21 2010-06-29 Amgen Inc. Beta-secretase modulators and methods of use
WO2007061670A1 (en) 2005-11-21 2007-05-31 Amgen Inc. Beta-secretase modulators and methods of use
TW200734311A (en) 2005-11-21 2007-09-16 Astrazeneca Ab New compounds
US7838676B2 (en) 2005-11-21 2010-11-23 Amgen Inc. Beta-secretase modulators and methods of use
WO2007058601A1 (en) 2005-11-21 2007-05-24 Astrazeneca Ab Novel 2-amino-imidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, alzheimer’s disease, neurodegeneration and dementia
US20090069287A1 (en) 2005-11-22 2009-03-12 Pfizer Inc Substituted azacycloalkanes useful for treating cns conditions
AR057579A1 (es) 2005-11-23 2007-12-05 Merck & Co Inc Compuestos espirociclicos como inhibidores de histona de acetilasa (hdac)
AU2006333049A1 (en) 2005-12-19 2007-07-12 Wyeth 2-amino-5-piperidinylimidazolone compounds and use thereof for beta-secretase modulation
AR058381A1 (es) 2005-12-19 2008-01-30 Astrazeneca Ab Compuestos derivados de 2-aminopiridin-4-onas y una composicion farmaceutica
GB0526614D0 (en) * 2005-12-30 2006-02-08 Novartis Ag Organic compounds
EP1816122A3 (en) * 2006-01-19 2007-09-19 Speedel Experimenta AG 3,4,5-substituted piperidines as therapeutic compounds
US7932261B2 (en) 2006-02-06 2011-04-26 Janssen Pharmaceutica Nv Macrocycle derivatives useful as inhibitors of β-secretase (BACE)
US7776882B2 (en) 2006-02-06 2010-08-17 Baxter Ellen W 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of β-secretase (BACE)
US7868022B2 (en) 2006-02-06 2011-01-11 Janssen Pharmaceutica Nv 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE)
GB0602951D0 (en) 2006-02-14 2006-03-29 Novartis Ag Organic Compounds
WO2007100536A1 (en) * 2006-02-24 2007-09-07 Wyeth DIHYDROSPIRO[DIBENZO[A,D][7]ANNULENE-5,4'-IMIDAZOL] COMPOUNDS FOR THE INHIBITION OF β-SECRETASE
US7390925B2 (en) * 2006-04-03 2008-06-24 Bristol-Myers Squibb Company Oxime-containing acyl guanidines as beta-secretase inhibitors
US20070232624A1 (en) * 2006-04-03 2007-10-04 Palumbo Joseph M Use of paliperidone for the treatment of sleep disturbances and/or excessive daytime sleepiness in psychiatric patients
US7408071B2 (en) * 2006-04-03 2008-08-05 Bristol-Myers Squibb Company N-aryl pyrrolidine derivatives as beta-secretase inhibitors
CN101460480A (zh) 2006-04-05 2009-06-17 阿斯利康(瑞典)有限公司 2-氨基嘧啶-4-酮类化合物及其用于治疗或预防Aβ相关病理的用途
TW200808751A (en) 2006-04-13 2008-02-16 Astrazeneca Ab New compounds
CN101472877A (zh) 2006-04-21 2009-07-01 惠氏公司 制备手性纯氨基醇中间体、其衍生物及其用途
PE20080155A1 (es) * 2006-06-12 2008-03-10 Schering Corp Compuestos heterociclicos como inhibidores de aspartil-proteasa
TW200815447A (en) * 2006-06-14 2008-04-01 Astrazeneca Ab Novel compounds IV
TW200815449A (en) * 2006-06-14 2008-04-01 Astrazeneca Ab Novel compounds II
US20080051420A1 (en) * 2006-06-14 2008-02-28 Astrazeneca Ab New Compounds 317
TW200808796A (en) 2006-06-14 2008-02-16 Astrazeneca Ab New compounds III
TW200815443A (en) 2006-06-14 2008-04-01 Astrazeneca Ab Novel compounds I
TW200815349A (en) 2006-06-22 2008-04-01 Astrazeneca Ab New compounds
BRPI0715437A2 (pt) 2006-07-20 2013-04-16 Novartis Ag lactamas macrocÍclicas
TW200817406A (en) 2006-08-17 2008-04-16 Wyeth Corp Imidazole amines as inhibitors of β-secretase
US7700606B2 (en) * 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
WO2008036196A2 (en) * 2006-09-21 2008-03-27 Wyeth Indolylalkylpyridin-2-amines for the inhibition of beta-secretase
ATE549923T1 (de) 2006-10-06 2012-04-15 Merck Sharp & Dohme Makrozyklische spiropiperidin-beta-sekretase- hemmer zur behandlung von morbus alzheimer
WO2008063114A1 (en) 2006-11-20 2008-05-29 Astrazeneca Ab Amino- imidazolones and their use as medicament for treating cognitive impairment alzheimer disease, neurodegeneration and dementia
JP2010512389A (ja) * 2006-12-12 2010-04-22 シェーリング コーポレイション アスパルチルプロテアーゼ阻害剤
US20100016341A1 (en) * 2006-12-12 2010-01-21 Zhaoning Zhu Aspartyl protease inhibitors containing a tricyclic ring system
US7902218B2 (en) * 2006-12-12 2011-03-08 Bristol-Myers Squibb Company Substituted tetrahydroisoquinolines as β-secretase inhibitors
WO2008076044A1 (en) 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino-5, 5-diaryl-imidazol-4-ones
TW200831091A (en) 2006-12-20 2008-08-01 Astrazeneca Ab New compounds
TW200831484A (en) * 2006-12-20 2008-08-01 Astrazeneca Ab New compounds
CN101209976B (zh) 2006-12-29 2012-01-11 中国人民解放军军事医学科学院毒物药物研究所 取代的酒石酸衍生物及其用于制备β-分泌酶抑制剂的用途
CA2673888A1 (en) 2007-01-04 2008-07-17 Merck And Co., Inc. Bicyclic spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease
CN101600700B (zh) 2007-02-02 2013-08-21 弗·哈夫曼-拉罗切有限公司 作为taar1配体用于cns病症的新的2-氨基噁唑啉
CL2008000784A1 (es) 2007-03-20 2008-05-30 Wyeth Corp Compuestos amino-5-[-4-(diflourometoxi) fenil sustituido]-5-fenilmidazolona, inhibidores de b-secretasa; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar alzheimer, deterioro cognitivo, sindrome de down, disminucion co
CL2008000791A1 (es) 2007-03-23 2008-05-30 Wyeth Corp Compuestos derivados de 2-amino-5-(4-difluorometoxi-fenil)-5-fenil-imidazolidin-4-ona; composicion farmaceutica que comprende a dichos compuestos; y su uso en el tratamiento de una enfermedad asociada con la actividad bace excesiva, tales como enferm
WO2008128231A1 (en) 2007-04-16 2008-10-23 Hutchison Medipharma Enterprises Limited Pyrimidine derivatives
JP5383484B2 (ja) 2007-04-24 2014-01-08 塩野義製薬株式会社 環式基で置換されたアミノジヒドロチアジン誘導体
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
TW200902499A (en) 2007-05-15 2009-01-16 Astrazeneca Ab New compounds
TW200902503A (en) 2007-05-15 2009-01-16 Astrazeneca Ab New compounds
WO2009005471A1 (en) 2007-07-05 2009-01-08 Astrazeneca Ab Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors
WO2009005470A1 (en) 2007-07-05 2009-01-08 Astrazeneca Ab Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors
US8222264B2 (en) 2007-07-06 2012-07-17 Boehringer Ingelheim International Gmbh Substituted amino-quinazolinones, medicaments comprising said compound, their use and their method of manufacture
WO2009013293A1 (en) 2007-07-24 2009-01-29 Novartis Ag Substituted cyclohexanecarboxamides useful as bace inhibitors
PL2233474T3 (pl) 2008-01-18 2015-12-31 Eisai R&D Man Co Ltd Skondensowana pochodna aminodihydrotiazyny
WO2009092566A1 (en) 2008-01-22 2009-07-30 Boehringer Ingelheim International Gmbh Substituted amino-benzimidazoles, medicaments comprising said compound, their use and their method of manufacture
WO2009097278A1 (en) 2008-01-28 2009-08-06 Janssen Pharmaceutica N.V. 6-SUBSTITUTED-THIO-2-AMINO-QUINOLINE DERIVATIVES USEFUL AS INHIBITORS OF β-SECRETASE (BACE)
EP2240472B1 (en) 2008-01-29 2012-11-21 Janssen Pharmaceutica NV 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (bace)
EP2245019B1 (en) * 2008-02-18 2012-11-14 F. Hoffmann-La Roche AG 4, 5-dihydro-oxazol-2-yl amine derivatives
AU2009217518A1 (en) 2008-02-28 2009-09-03 Merck Sharp & Dohme Corp. 2-aminoimidazole beta-secretase inhibitors for the treatment of Alzheimer's disease
CA2723222C (en) * 2008-04-22 2013-04-02 Schering Corporation Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as bace-1 inhibitors, compositions, and their use
TWI431004B (zh) 2008-05-02 2014-03-21 Lilly Co Eli Ｂａｃｅ抑制劑
JP2011519913A (ja) 2008-05-05 2011-07-14 ファイザー・インク 神経変性疾患治療のための新規なクラスのスピロピペリジン
KR101324426B1 (ko) 2008-06-13 2013-10-31 시오노기세야쿠 가부시키가이샤 β 세크레타제 저해 작용을 갖는 황 함유 복소환 유도체
WO2010013302A1 (ja) 2008-07-28 2010-02-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 スピロアミノジヒドロチアジン誘導体
CN102105475B (zh) 2008-07-28 2014-04-09 卫材R&D管理有限公司 螺氨基二氢噻嗪衍生物
MY148558A (en) 2008-09-11 2013-04-30 Amgen Inc Spiro-tetracyclic ring compounds as betasecretase modulators and methods of use
JP5666304B2 (ja) 2008-09-30 2015-02-12 エーザイ・アール・アンド・ディー・マネジメント株式会社 新規な縮合アミノジヒドロチアジン誘導体
WO2010042030A1 (en) 2008-10-07 2010-04-15 Medivir Ab Aspartyl protease inhibitors
EP2349244A4 (en) 2008-10-10 2012-09-19 Comentis Inc BICYCLIC COMPOUNDS FOR INHIBITING BETA SEKRETASE ACTIVITY AND METHOD OF USE THEREOF
CN102186841A (zh) 2008-10-22 2011-09-14 盐野义制药株式会社 具有bace1抑制活性的2-氨基嘧啶-4-酮及2-氨基吡啶衍生物
US20100125081A1 (en) 2008-11-14 2010-05-20 Astrazeneca Ab New compounds 574
US8394807B2 (en) 2008-11-20 2013-03-12 Purdue Research Foundation Quinazoline inhibitors of BACE 1 and methods of using
AU2010241929A1 (en) 2009-04-27 2011-10-06 High Point Pharmaceuticals, Llc Substituted imidazo[1,2-a]pyridine derivatives, pharmaceutical compositions, and methods of use as beta-secretase inhibitors
JP2012525389A (ja) 2009-04-27 2012-10-22 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー 置換イソキノリン誘導体、医薬組成物、及びβ−セクレターゼ阻害剤としての使用方法
AR077277A1 (es) 2009-07-09 2011-08-17 Lilly Co Eli Compuestos de biciclo (1,3)tiazin-2-amina formulacion farmaceutica que lo comprende y su uso para la manufactura de un medicamento util para el tratamiento de la enfermedad de alzheimer
GB0912777D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydropyrimidone derivatives
GB0912778D0 (en) 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydro-oxazine derivatives
UY32799A (es) 2009-07-24 2011-02-28 Novartis Ag Derivados de oxazina y su uso en el tratamiento de trastornos neurológicos
US8188079B2 (en) * 2009-08-19 2012-05-29 Hoffman-La Roche Inc. 3-amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines
WO2011044057A1 (en) 2009-10-05 2011-04-14 Comentis, Inc. Sulfonamido pyrrolidine compounds which inhibit beta-secretase activity and methods of use thereof
EP2485920B1 (en) 2009-10-08 2016-04-27 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use
WO2011044187A1 (en) 2009-10-08 2011-04-14 Schering Corporation Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
UA108363C2 (uk) 2009-10-08 2015-04-27 Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування
EP2485590B1 (en) 2009-10-08 2015-01-07 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use
WO2011063233A1 (en) 2009-11-23 2011-05-26 Amgen Inc. Amino heteroaryl compounds as beta-secretase modulators and methods of use
EP2504330A1 (en) 2009-11-23 2012-10-03 Amgen Inc. Amino heteroaryl compounds as beta-secretase modulators and methods of use
JPWO2011071109A1 (ja) 2009-12-11 2013-04-22 塩野義製薬株式会社 アミノ基を有する縮合ヘテロ環化合物
MX2012006491A (es) 2009-12-11 2012-07-03 Shionogi & Co Derivados de oxazina.
WO2011077726A1 (ja) 2009-12-24 2011-06-30 塩野義製薬株式会社 ４－アミノ－１，３－チアジンまたはオキサジン誘導体
US8497264B2 (en) 2010-03-15 2013-07-30 Amgen Inc. Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
EP2547685A1 (en) 2010-03-15 2013-01-23 Amgen Inc. Spiro-tetracyclic ring compounds as beta - secretase modulators

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JP2013014628A (ja) 2013-01-24
EP2097387B1 (en) 2016-05-04
TWI355937B (en) 2012-01-11
PT2097387T (pt) 2016-07-20
CA2678958A1 (en) 2008-08-28
CL2008000531A1 (es) 2008-09-22
IL200561A (en) 2015-03-31
AR065421A1 (es) 2009-06-03

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