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
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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
    imagen4
    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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BRPI0807547A2 (pt) 2014-06-17
TWI355937B (en) 2012-01-11
SI2097387T1 (sl) 2016-09-30
US20120276118A1 (en) 2012-11-01
US8691831B2 (en) 2014-04-08
HRP20160876T1 (hr) 2016-09-23
MY149183A (en) 2013-07-31
RU2009135277A (ru) 2011-03-27
HUE029867T2 (en) 2017-04-28
MX2009009063A (es) 2010-01-29

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