ES2594156T3 - Cicloalquilaminas como inhibidores de la recaptación de monoaminas - Google Patents
Cicloalquilaminas como inhibidores de la recaptación de monoaminas Download PDFInfo
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- ES2594156T3 ES2594156T3 ES07716419.2T ES07716419T ES2594156T3 ES 2594156 T3 ES2594156 T3 ES 2594156T3 ES 07716419 T ES07716419 T ES 07716419T ES 2594156 T3 ES2594156 T3 ES 2594156T3
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Abstract
Un compuesto que tiene una estructura de acuerdo con la Fórmula (II):**Fórmula** en donde m es un entero de 0 a 12, que no es mayor que 10 Ar es**Fórmula** en donde Y y Z son cada uno independientemente halógeno; o Ar es**Fórmula** en donde Y1, Z1, Y2, Z2 y son miembros seleccionados independientemente del grupo que consiste de: H, halógeno, CN, CF3, OMe, OEt y OCF3; cada X es un miembro seleccionado independientemente del grupo que consiste de H, halógeno, CN, CF3, OR5, SR5, acilo, C(O)OR5, C(O)NR6R7, S(O)2R5, S(O)2NR6R7, NR6R7, NR6S(O)2R5, NR6C(O)R5, alquilo sustituido o no sustituido, heteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, heteroarilo sustituido o no sustituido y heterocicloalquilo sustituido o no sustituido, en donde cada R5, R6 y R7 es un miembro seleccionado independientemente del grupo que consiste de H, acilo, alquilo sustituido o no sustituido, heteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido y heteroarilo sustituido o no sustituido, en donde dos de R5, R6 y R7, junto con los átomos a los que están unidos, se unen opcionalmente para formar un anillo de 3 a 7 miembros; cada R1 y R2 es un miembro seleccionado independientemente del grupo que consiste de H y (C1-C4) alquilo sustituido o no sustituido; R3 y R4 son miembros seleccionados independientemente del grupo que consiste de H, alquilo sustituido o no sustituido y heteroalquilo sustituido o no sustituido; con la condición de que el compuesto no es:**Fórmula** y cualquier sal, enantiómero, diastereómero, mezcla racémica, mezcla enantioméricamente enriquecida, y forma enantioméricamente pura farmacéuticamente aceptable de la misma; en donde los sustituyentes para los radicales alquilo, heteroalquilo y heterocicloalquilo se seleccionan del grupo que consiste de: alquilo no sustituido, heteroalquilo no sustituido, arilo no sustituido, heteroarilo no sustituido, heterocicloalquilo no sustituido-OR', >=O, >=NR' >=N-OR', -NR'R",-SR', -halógeno, -SiR'R"R"', -OC(O)R', -C(O)R', - CO2R', -CONR'R", -OC(O)NR'R",-NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')>=NR"", - NRC(NR'R")>=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN y -NO2 en un número que varía de cero a (2m'+1), donde m' es el número total de átomos de carbono en tal radical; R', R", R'" y R"" se refieren cada uno independientemente a hidrógeno, heteroalquilo no sustituido, arilo no sustituido, alquilo no sustituido, alcoxi o grupos tioalcoxi, o grupos arilalquilo; y en donde los sustituyentes para los grupos arilo y heteroarilo se seleccionan del grupo que consiste de: alquilo no sustituido, heteroalquilo no sustituido, arilo no sustituido, heteroarilo no sustituido, heterocicloalquilo no sustituido, -- OR', >=O, >=NR' >=N-OR', -NR'R", -SR', -halógeno,-SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", - OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')>=NR"", -NR-C(NR'R")>=NR"', - S(O)R',-S(O)2R', -S(O)2NR'R", -NRSO2R', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alcoxi, y fluoro(C1- C4)alquilo, en un número que va de cero al número total de valencias abiertas en el sistema de anillo aromático; y donde R', R", R'" y R"" se seleccionan cada uno independientemente de hidrógeno, alquilo no sustituido, heteroalquilo no sustituido, arilo no sustituido y heteroarilo no sustituido.
Description
Alternativamente, la cetona Y puede ser tratada con borohidruro de sodio para producir DD como una mezcla de diastereómeros cis y trans (Esquema 12). En una realización de ejemplo, en la que Ar es 3,4–diclorofenilo, el cis– diastereómero de DD se formó principalmente. La reducción del nitrilo y protección de BOC del grupo amino resultante produjo la amina EE. Los estereoisómeros se pueden separar por cromatografía quiral para dar dos pares de enantiómeros derivados de cis EE y trans EE.
Además, el grupo hidroxilo de cualquiera de los análogos anteriores (por ejemplo, compuesto DD) puede ser funcionalizado o reemplazado para generar nuevos análogos de ciclohexil amina 3–sustituidos. Por ejemplo, alcation
10 del grupo hidroxilo de DD con yoduro de metilo dio el metoxi nitrilo FF tal como se describe en el Esquema 13, a continuación. Los estereoisómeros de FF se pueden aislar a través de cromatografía quiral. El nitrilo se procesa adicionalmente para generar una amina. Por ejemplo, el grupo nitrilo se reduce (por ejemplo, reducción de borano) para producir la amina correspondiente, que puede ser entonces convertida en la correspondiente alquilamina (por ejemplo, metilamina o dimetilamina) como se describe más arriba.
17
HPLC Rt = 8.63 min; 1H RMN (400 MHz, CD3OD) 7.50 (d, J = 9.16 Hz, 2H), 7.28 (d, J = 8.80 Hz, 2H), 3.02 (s, 2H),
1–(1–(naftalen–1–il)ciclohexil)etanamina (16) 3 CH3 I
Columna SFC w/AS y 30% MeOH/0.1% DEA, 280 nm. 16 E1: HPLC Rt = 2.23 min; LC–MS 7.56 min, (M+1)+254 @
7.78 min 16 E2: LC–MS 7.59 min, (M+1)+254 @ 7.9 min.
1–(1–(3,4–diclorofenil)ciclohexil)propan–1–amina (17) 3 CH2CH3 I
Columna SFC w/AS y 20% MeOH/0.1% DEA, 280 nm. 17 E1: HPLC Rt = 1.58 min; 1H RMN (400 MHz, CDCl3) 7.50
15 (d, J = 1.47 Hz, 1H), 7.44 (d, J = 8.43 Hz, 1H), 7.29–7.27 (m, 1H), 3.01–2.97 (m, 1H), 2.44 (d, J = 13.2 Hz, 1H), 2.21 (d, J = 13.2 Hz, 1H), 1.98–1.92 (m, 1H), 1.79–1.25 (m, 8H), 1.09–1.03 (m, 4H); LC–MS 8.89 min, (M+1)+286 @ 9.01 min. 17 E2: LC–MS 8.89 min, (M+1)+288 @ 8.91 min.
(±) 1–(1–(4–clorofenil)ciclohexil)propan–1–amina (18) 3 CH2CH3 I
HPLC Rt = 8.68 min; LC–MS 7.91 min, (M+1)+252 @ 8.04 min.
1–(1–(4–(trifluorometoxi)fenil)ciclohexil)etanamina (19) 3 CH3 I
30 HPLC Quiral con columna AD y 100% MeOH/0.1% DEA, 280 nm 19 E1: HPLC Rt = 1.52 min; LC–MS (método del minuto 15) 8.18 min, (M+1)+ 288 @ 8.35 min. 19 E2: LC–MS (método del minuto 15) 8.24 min, (M+1)+ 288 @ 8.27 min.
1–(1–(4–(furan–3–il)fenil)ciclohexil)etanamina (20) 35 3 CH3I
36
Columna SFC w/AD y 35% de MeOH/10% IPA/0.1% DEA, temp. de columna 25°C, flujo total 10 ml/min, 280 nm para dar el enantiómero de movimiento rápido E1 y el enantiómero de movimiento lento E2. 20 E1: 1H RMN (400 MHz, CDCl3) 7.73 (s, 1H), 7.48–7.46 (m, 3H), 7.32 (d, J = 8.43 Hz, 2H), 6.70 (d, J = 0.7 Hz, 1H), 2.77–2.72 (m, 1H), 2.37 (d, J = 13.2 Hz, 1H), 2.30 (d, J = 13.2 Hz, 1H), 1.58–1.42 (m, 5H), 1.32–1.22 (m, 3H), 0.87 (d, J = 6.60 Hz, 3H); LC–MS 7.94 min, (M+1)+270 @ 8.06 min 20 E2: LC–MS 7.97 min, (M+1)+270 @ 8.12 min
1–(1–(4–clorofenil)ciclohexil)–3–metilbutan–1–amina (21) 3 iso–butilo I
SFC w/columna AS y 15% IPA/0.1% DEA, temperatura de columna 25°C,flujo total 10 ml/min, 280 nm para dar el enantiómero de movimiento rápido E1 y el enantiómero de movimiento lento E2. 21 E1: HPLC Rt = 9.26 min; 1H RMN (400 MHz, CDCl3); 7.31–7.23 (m, 4H), 2.57–2.54 (m, 1H), 2.32–2.23 (m, 2H), 1.65–1.43 (m, 6H), 1.24–1.13 (m, 4H), 0.93–0.78 (m, 7H), 0.70–0.63 (m, 1H); LC–MS 9.01 min, (M+1)+280 @ 9.19
15 min 21 E2: LC–MS 9.01 min, (M+1)+280 @ 9.19 min
1–(1–(4–(furan–2–il)fenil)ciclohexil)etanamina (22) 3 CH3 I
SFC w/ Columna OD y 12% MeOH/0.1% DEA, temperatura de columna 40°C, flujo total 10 ml/min, 280 nm para dar el enantiómero de movimiento rápido E1 y el enantiómero de movimiento lento E2. 22 E1: HPLC Rt = 8.76 Hz, 2H), 7.45 (d, J = 1.71 Hz, 1H), 6.45 (dd, J = 1H), 2.30 (d, J = 11.7 Hz, 6.35 Hz, 3H); LC–
25 MS 8.09 min; Hz, 1H), , 3.42 1H), min, 1H RMN {400 7.34 (d, Hz, 1H), 1.56–1.45 (M+1)+270 400 MHz, CDCl3) 7.66 (d, J = 8.54 J = 8.54 Hz, 2H), 6.63 (d, J = 3.42 2.83 (bs, 1H), 2.39 (d, J = 12.7 Hz, m, 5H), 1.26 (bs, 3H), 0.90 (d, J = 270 @ 8.24 min. 22 E2: LC–MS 8.09 min, (M+1)+280 @ 8.24 min.
30 (1–(3’,5’–difluorobifenil–4–il)ciclohexil)metanamina (23) 3 HE
35 HPLC Rt = 9.24 min; 1H RMN (400mHz, CD3OD) 7.68–7.64 (m, 2H), 7.51 (dd, J=1.95, 8.96, 2H), 7.26–7.19 (m, 2H), 6.90–6.84 (m, 1H), 3.03 (s, 2H), 2.28–2.24 (m, 2H), 1.67–1.36 (m, 8H).
(±) 1–(1–(4–(tiazol–2–il)fenil)ciclohexil)etanamina (24) 3 CH3 I
HPLC Rt = 1.50 min; LC–MS (método del minuto 15) 7.51 min, (M+1)+ 287 @ 7.72 min; 1H RMN (400 MHz, CDCl3)
7.95 (d, J=8.43Hz, 2H), 7.85 (d, J=3.30Hz, 1H), 7.44 (d, J=8.43Hz, 2H), 7.32 (d, J=3.30Hz, 1H), 3.13 (d, J=6.23Hz, 45 1H), 2.50 (d, J=11.36Hz, 1H), 2.33 (d, J=12.10Hz, 1H), 1.60–1.57 (m, 2H), 1.33–1.20 (m, 6H), 0.97–0.83 (m, 3H).
(±) 1–(1–(3,4–diclorofenil)ciclohexil)pentan–1–amina (25) 3 n–butilo I
HPLC Rt = 1.68 min; LC–MS (método del minuto 15) 9.92 min, (M+1)+ 316 @ 10.04 min; 1H RMN (400MHz, CDCl3) 7.47–7.42 (m, 2H), 7.26–7.23 (m, 1H), 2.95 (d, J=9.16Hz, 1H), 2.38 (d, J=12.10Hz, 1H), 2.23 (d, J=12.83Hz, 1H),
37
El compuesto del título se sintetizó a partir de 1–(4–clorofenil)–ciclohexanocarbonitrilo. La sal de HCl cruda se recristalizó a partir de CH3CN (3 mL) para dar clorhidrato de (1–(4–clorofenil)ciclohexil)metanamina puro como agujas blancuzcas/hay. HPLC Rt = 8.22 min; 1H RMN (400 mHz, MeOH–d4) 7.38 (s, 4H), 2.97 (s, 2H), 2.19–2.14 (m, 2H), 1.63–1.30 (m, 8H); LC–MS 7.83 min, (M+1)+224 a 8.1 min.
Clorhidrato de (1–(3,4–difluorofenil)ciclohexil)metanamina (30)
El compuesto del título se sintetizó a partir de 1–(3,4–difluorofenil)–ciclohexanocarbonitrilo. La sal de HCl cruda se
10 recristalizó a partir de CH3CN (6 mL) para dar clorhidrato de (1–(3,4–difluorofenil)ciclohexil)metanamina puro (38 mg, 17%) como agujas blancuzcas/hay HPLC Rt = 8.06 min; 1H RMN (400 mHz, MeOH–d4) 7.34–7.20 (m, 3H), 2.99 (m, 2H), 2.15–2.12 (m, 2H), 1.64–1.31 (m, 8H); LC–MS 7.01 min, (M+1)+226 @ 7.16 min.
Clorhidrato de (1–fenilciclohexil)metanoamina (31)
El compuesto del título se sintetizó a partir de 1–fenilciclohexano–carbonitrilo. La sal de HCl cruda se recristalizó a partir de CH3CN para dar clorhidrato de (1–fenilciclohexil)metanoamina como agujas de color blancuzco. HPLC Rt =
7.59 min; 1H RMN (400 mHz, MeOH–d4) 7.40–7.36 (m, 4H), 7.27–7.25 (m, 1H), 2.98 (s, 2H), 2.22–2.20 (m, 2H), 1.62–1.32 (m, 8H); LC–MS 6.16 min, (M+1)+ 190 @ 6.36 min.
20 (1–(3–cloro–4–fluorofenil)ciclohexil)–metanamina (32)
El compuesto del título se preparó a partir de 1–(3–cloro–4–fluorofenil)ciclohexanocarbonitrilo. Una solución de del producto crudo en MTBE se basificó a 0°C con KOH, se extrajo con MTBE y se evaporó. El residuo se diluyó en
25 DCM, se filtró a través de una columna de aminopropilo y se evaoró para dar la amina primaria (64.1mg, 25%) como un aciete. LCMS Rt = 7.62 min, m/z = 242 (M+1). 1H RMN (CDCl3, δ) 7.34 (dd, J = 2.4, 7.1Hz, 1H), 7.19 (ddd, J = 2.4, 4.6, 8.7Hz, 1H), 7.11 (t, J = 8.7Hz, 1H), 2.68 (s, 2H), 2.1 (m, 2H), 1.6–1.2 (m, 8H), 0.79 (bs, 2H). 13C RMN (CDCl3, δ, mult): 157.4(0), 154.9(0), 142.2(0), 129.5(0), 127.0(0), 126.9(1), 120.8(1), 120.6(1), 116.3(1), 116.1(1), 54.5(2), 43.3(0), 33.7(2), 26.5(2), 22.0(2).
39
(1–(naftalen–2–il)ciclohexil)metanamina (33)
El compuesto del título se sintetizó en 37% de rendimiento a partir de 1–(naftalen–2–il)ciclohexano–carbonitrilo. HPLC Rt (5–100–8) = 8.44 min. LCMS Rt = 8.22 min, m/z = 240 (M+1). 1H RMN (CDCl3, δ): 7.9–7.2 (m, 7H), 2.78 (s, 2H), 2.3 (m, 2H), 1.7–1.3 (m, 8H), 0.9 (bs, 2H). 13C RMN (CDCl3, δ, mult): 133.4(0), 131.7(0), 128.0(1), 127.8(1), 127.3(1), 126.4(1), 125.8(1), 125.4(1), 125.2(1), 54.6(2), 43.7(0), 33.8(2), 26.7(2), 22.2(2).
(1–(4–(trifluorometil)fenil)–ciclohexil)metanamina (34)
El compuesto del título se preparó a partir de 1–(4–(trifluorometil)fenil)–ciclohexanocarbonitrilo (127 mg, 0.50 mmol). El producto crudo se purificó por cromatografía de columna en sílica gel (MeOH/CH2Cl2, MeOH de 0% a 10%) para dar (1–(4–(trifluorometil)fenil)ciclohexil)metanamina (62 mg, 48%) como un aceite transparente. 1H RMN (CDCl3): δ 1.26–1.52 (m 4H), 1.54–1.61 (m, 2H), 1.66–1.73 (m, 2H), 2.13–2.18 (m, 2H), 2.28 (s, 3H), 2.63 (s, 2H), 7.49 (d, J=
15 8.0 Hz, 2H), 7.59 (d, J= 8.0 Hz, 2H). 13C RMN (CDCl3) δ 22.3, 26.7, 34.8, 42.9, 54.4, 125.5, 125.6, 127.9, 129.9,
149.1. ESI MS m/z 258.
(1–(benzo[d][1,3]dioxol–5–il)ciclohexil)metanamina (35)
20 El compuesto del título se preparó a partir de 1–(benzo[d][1,3]dioxol–5–il)ciclohexanocarbonitrilo (115 mg, 0.50 mmol). El producto crudo se purificó por cromatografía (SiO2, MeOH/CH2Cl2, MeOH de 0% a 10%) para dar (±) (1– (benzo[d][1,3]dioxol–5–il)ciclohexil)metanamina (58 mg, 50%) como un aceite transparente. 1H RMN (CDCl3) 1.34–
1.39 (m, 3H), 1.46–1.54 (m, 7H), 2.01–2.06 (m, 2H), 2.64 (s, 2H), 5.93 (s, 2H), 6.78 (s, 2H), 6.84 (s, 1H). 13C RMN (CDCl3) 22.3, 26.9, 34.3, 43.5, 54.9, 101.1, 107.9, 108.2, 120.6, 138.7, 145.6, 148.2. ESI MS m/z 234.
25 (1–(3–(trifluorometil)fenil)–ciclohexil)metanamina (36)
El compuesto del título se preparó a partir de 1–(3–(trifluorometil)fenil)–ciclohexanocarbonitrilo (127 mg, 0.50 mmol). El producto crudo se purificó por cromatografía (SiO2, MeOH/CH2Cl2, MeOH de 0% a 10%) para dar (±) (1–(3–
30 (trifluorometil)fenil)–ciclohexil)metanamina (26 mg, 20%) como un aceite transparente. 1H RMN (CDCl3): 1.26–1.41 (m, 5H), 1.50–1.63 (m, 5H), 2.12–2.16 (m, 2H), 2.73 (s, 2H), 7.47–7.49 (m, 2H), 7.52–7.5 (m, 1H), 7.58 (s, 1H). 13C RMN (CDCl3) 22.3, 26.7, 33.8, 43.9, 54.6, 122.9, 124.1, 124.2, 129.1, 130.8, 130.9, 146.3. ESI MS m/z 257.
(1–(3–fluorofenil)ciclohexil)metanamina (37)
40
El compuesto del título se preparó a partir de 1–(3–fluorofenil)ciclohexanocarbonitrilo (102 mg, 0.50 mmol). El producto crudo se purificó por cromatografía (SiO2, MeOH/CH2Cl2, MeOH de 0% a 10%) para dar (±) (1–(3–
5 fluorofenil) ciclohexil)metanamina (32 mg, 31%) como un aceite transparente. 1H RMN (CDCl3): 1.26–1.39 (m, 5H), 1.51–1.58 (m, 5H), 2.07–2.10 (m, 2H), 2.69 (s, 2H), 6.88–6.93 (m, 1H), 7.04 (d, J= 8.0 Hz, 1H), 7.11 (d, J= 8.0 Hz, 1H), 7.27–7.34 (m, 1H). 13C RMN (CDCl3) 22.3, 26.8, 33.8, 43.9, 54.8, 112.7, 113.0, 114.5, 114.7, 123.0, 123.1, 129.9, 130.0, 162.3, 164.7. ESI MS m/z 208.
(1–(2,4–diclorofenil)ciclohexil)metanamina (38)
10
1H RMN (400 MHz, CD3Cl) δ 7.35 (d, J=2.4 Hz, 1 H), 7.32 (d, J=8.4 Hz, 1 H), 7.19 (dd, J=2.4, 8.4 Hz, 1 H), 3.08 (s, 2 H), 2.25 (m, 2 H), 1.45 (m, 2 H), 1.31 (m, 2 H), 1.28–1.18 (m, 4 H); 13C RMN (100 MHz, CD3Cl) δ 139.91, 134.39, 133.70, 132.89, 132.23 48.61, 45.83, 33.70, 26.77, 26.66, 22.56; ESI MS m/z 258.1.
15 (1–(6–fluoronaftalen–2–il)ciclohexil)metanamina (39)
El compuesto del título se sintetizó de acuerdo con el Esquema 25, más adelante.
20 A una solución de ácido 6–fluoro–naftalen–2–carboxílico (3.0 g, 15.8 mmol) se añadió BH3.THF (31.6 mL, 31.6 mmol). La mezcla de reacción se agitó durante la noche antes de ser concentrada. Al residuo se añadió dietil éter (100 mL) y solución de NaOH (10 mL). La capa orgánica se separó, se secó y concentró. El residuo resultante se purificó por cromatografía de columna en sílica gel (acetato de etilo/hexano 1:7) para producir (6–fluoro–naftalen–2– il)–metanol (2.28 g, 82%).
25 A una solución de (6–fluoro–naftalen–2–il)–metanol (2.0 g, 11.3 mmol) en CH2Cl2 (30 mL) se añadió PBR3 (1.0 M en CH2Cl2, 22.6 mmol). La mezcla de reacción se agitó durante 3 h a temperatura ambiente antes de ser detenida mediante NH4Cl (30 mL). La capa orgánica se separó, se secó y concentró. El residuo resultante se purificó por
41 5
10
15
20
25
30
35
cromatografía de columna en sílica gel (acetato de etilo/hexano= 1:10) para producir 2–bromometil–6–fluoro– naftaleno (2.23 g, 74%).
A una mezcla de 2–bromometil–6–fluoro–naftaleno (1.5 g, 5.9 mmoL) en CH3CN (30 mL) se añadió KCN (1.16 g,
17.8 mmoL). La mezcla de reacción se calentó a reflujo durante 6 h antes de ser concentrada. Al residuo se añadió dietil éter (100 mL) y H2O (15 mL). La capa orgánica se separó, se secó y concentró. El residuo resultante se purificó por cromatografía de columna en sílica gel (acetato de etilo/hexano= 1:10) para producir el (6–fluoro–naftalen– 2–il)– acetonitrilo (0.88 g, 70%).
El compuesto del título se sintetizó a partir de (6–fluoro–naftalen–2–il)–acetonitrilo (1.0 g, 5.48 mmoL) de acuerdo con el Procedimiento General J para formar el intermediario nitrilo (0.98 g, 71%), que se purificó por cromatografía de columna en sílica gel (acetato de etilo/hexano 1:7), seguido por el Procedimiento General E.
El producto crudo se disolvió en MeOH (4 mL) y se sometió a cromatografía de columna en fase reversa (CH3CN/H2O/0.1% ácido fórmico=5% a 100%) para dar el compuesto del título (0.53 g, 75%). 1H RMN (400 MHz, CD3Cl) δ 8.29 (m, 1 H), 8.18 (m, 1 H), 7.83 (m, 1 H), 7.50 (dd, J=3.6, 6.8 Hz, 1 H), 7.41 (dd, J=6.0 Hz, 8.8 Hz, 1 H0,
7.06 (dd, J=8.8, 8.8 Hz, 1 H), 3.37 (s, 2 H), 2.34 (m, 2 H), 1.89 (m, 2 H), 1.58 (m, 2 H), 1.45 (m, 2 H); 13C RMN (100 MHz, CD3Cl) δ 168.08, 159.85, 157.34, 132.96, 132.93, 128.58, 128.50, 126.04, 125.69, 125.67, 125.63, 125.47, 125.35, 125.32, 122.44, 122.37, 108.63, 108.44, 47.62, 43.53, 35.59, 26.43, 22.47, 22.31; ESI MS m/z 258.1.
(1–(4–fluoronaftalen–1–il)ciclohexil)metanamina (40)
El compuesto del título se sintetizó a partir de ácido 4–fluoro–naftalen–1–carboxílico (2.0 g, 10.3 mmol) de acuerdo con los procedimientos sintéticos descritos más arriba para la síntesis de 39 (Esquema 25). El producto crudo se disolvió en MeOH (4 mL) y se sometió a cromatografía de columna en fase reversa (CH3CN/H2O/0.1% ácido fórmico=5% a 100%) para dar 40 (0.51 g). 1H RMN (400 MHz, CD3OD) δ 8.48(d, J=8.4 Hz, 1 H), 8.20 (d, J=8.4 Hz, 1 H), 7.6 (m, 3 H), 7.21 (dd, J=8.4, 8.4 Hz, 1 H), 3.67 (s, 2 H), 2.52 (m, 2 H), 2.04 (m, 2 H), 1.68 (m, 2 H), 1.50 (m, 4 H);13C RMN (100 MHz, CD3OD), δ 160.04, 157.54, 133.03, 132.99, 131.91, 160.04, 157.54, 133.03, 132.99, 131.01, 128.74, 128.64, 126.64, 125.67, 125.65, 125.51, 125.24, 125.22, 121.80, 121.73, 108.33, 108.14, 47.00, 42.50, 35.12, 26.03, 21.89; ESI MS m/z 258.2.
1.3. Síntesis de aminas secundarias y terciarias
Los compuestos en la Tabla 2, más adelante, se sintetizaron a partir de la amina primaria indicada de acuerdo con el Procedimiento General indicado y se convirtieron opcionalmente en la forma de sal de HCl correspondiente
Tabla 2: Resumen de aminas secundarias y terciarias de ejemplo
R1 R3 R4
Ar n Procedimiento General Preparado a partir de
1–(1–(3,4–diclorofenil)ciclobutil)–N,N–dimetilmetanamina (41) 1 H CH3CH3 c 1
42
LC–MS 7.03 min, (M+1)+286 @ 7.58 min.
1–(1–(bifenil–4–il)ciclohexil)–N–metilmetanamina (49) 3 HHCH3 A 8
HPLC Rt = 9.06 min; 1H RMN (400 MHz, CD3OD) 7.66 (d, J = 8.06 Hz, 2H), 7.59 (d, J = 8.43 Hz, 2H), 7.50 (d, J =
8.06 Hz, 2H), 7.40 (d, J = 7.70 Hz, 2H), 7.31–7.29 (m, 1H), 3.14 (s, 2H), 2.54 (s, 3H), 2.29–2.27 (m, 2H), 1.69–1.52 (m, 5H), 1.43–1.37 (m, 3H); LC–MS 7.05 min, (M+1)+ 280 @ 7.52 min.
(±) 1–(1–(4–clorofenil)ciclohexil)–N–metiletanamina (50)
3 CH3H CH3 A 11
HPLC Rt = 8.59 min; 1H RMN (400 MHz, CD3OD) 7.43–7.34 (m, 4H), 3.14–3.08 (m, 1H), 2.59 (d, J = 0.73 Hz, 3H), 15 2.52–2.48 (d, J = 12.2 Hz, 1H), 2.33–2.29 (d, J = 13.4 Hz, 1H), 1.59–1.47 (m, 5H), 1.31–1.13 (m, 3H), 1.09 (d, J =
(±) N–metil–1–(1–(tiofen–2–il)ciclohexil)etanamina (51) 3 CH3H CH3 A 6
HPLC Rt = 7.92 min; 1H RMN (400 MHz, CD3OD) 7.42–7.40 (m, 1H), 7.07–7.04 (m, 1H), 7.01–6.99 (m, 1H), 3.17–
3.10 (m, 1H), 2.61 (s, 3H), 2.42–2.38 (m, 1H); 2.14–2.10 (m, 1H), 1.64–1.26 (m, 8H), 1.19 (d, J = 6.59 Hz, 3H); LC– MS 5.80 min, (M+1)+ 224 @ 6.19 min.
25 N,N–dimetil–1–(1–(4–(metiltio)fenil)ciclohexil)metanamina (52) 3 H CH3CH3 c 10
HPLC Rt = 8.54 min; 1H RMN (400 MHz, CD3OD) 7.39 (d, J = 8.07 Hz, 2H), 7.30–7.28 (m, 2H), 3.34 (s, 2H), 2.52 (s, 6H), 2.43 (s, 3H), 2.26–2.23 (d, J = 11.7 Hz, 2H), 1.66–1.52 (m, 5H), 1.38–1.37 (m, 3H); LC–MS 6.97 min, (M+1)+ 264 30 @ 7.16 min.
45
N,N–dimetil–1–(1–(naftalen–1–il)ciclohexil)metanamina (53) 3 H CH3CH3 F 12
HPLC Rt = 8.96 min; 1H RMN (400 MHz, CD3OD) 8.00–7.86 (m, 4H), 7.65 (dd, J = 2.2, 8.8 Hz, 1H), 7.54–7.51 (m, 2H), 3.52 (s, 2H), 2.54 (s, 6H), 2.46–2.44 (d, J = 8.43 Hz, 2H), 1.84–1.50 (m, 9H); LC–MS 8.28 min, (M+1)+ 268 @
8.39 min.
(±) 1–(1–(4–clorofenil)ciclohexil)–N,2–dimetilpropan–1–amina (54) 3 iso–propilo H CH3 F 14
HPLC Rt = 9.09 min; 1H RMN (400 MHz, CD3OD) 7.40 (s, 4H), 2.99 (s, 1H), 2.67 (s, 3H), 2.45–2.38 (m, 2H), 2.17– 2.14(m, 1H), 1.61–1.53 (m, 5H), 1.31–1.16 (m, 3H), 0.98 (d, J = 7.33 Hz, 3H), 0.65 (d, J = 6.97 Hz, 3H); LC–MS 9.26 min, (M+1)+280 @ 9.29 min.
15 (±) N,N–dimetil–1–(1–(naftalen–2–il)ciclohexil)etanamina (55) 3 CH3 CH3 CH3 F 13
HPLC Rt = 9.04 min; 1H RMN (400 MHz, CDCl3) 7.82–7.76 (m, 4H), 7.58–7.56 (m, 1H), 7.45–7.39 (m, 2H), 2.78 (d, J = 12.5 Hz, 1H), 2.53–2.48 (m, 1H), 2.30 (d, J = 13.6 Hz, 1H), 1.94–1.18 (m, 8H), 0.76 (d, J = 6.96 Hz, 3H); LC–MS
20 8.04 min, (M+1)+282 @ 8.16 min.
N,N–dimetil–1–(1–(naftalen–2–il)ciclohexil)etanamina (56 E1) 3 CH3 CH3 CH3 F 13 E1
25 HPLC Rt = 9.12 min; 1H RMN (400 MHz, CD3OD) 8.03 (d, J = 1.1 Hz, 1H), 7.99 (d, J = 8.80 Hz, 1H), 7.96–7.93 (m, 1H), 7.90–7.88 (m, 1H), 7.65 (dd, J = 1.83, 8.80 Hz, 1H), 7.56–7.51 (m, 2H), 3.59 (q, J = 6.97, 13.9 Hz, 1H), 2.95–
2.92 (m, 1H), 2.87 (s, 3H), 2.59–2.56 (m, 1H), 2.0 (s, 3H), 1.76–1.19 (m, 11H); LC–MS 7.37 min, (M+1)+282 @ 7.60 min.
30 N,N–dimetil–1–(1–(naftalen–2–il)ciclohexil)etanamina (56 E2) 3 CH3 CH3 CH3 F 13 E2
46
LC–MS 8.42 min, (M+1)+282 @ 8.57 min.
N–metil–1–(1–(naftalen–1–il)ciclohexil)metanamina (57) 3 H HCH3 A 12
HPLC Rt = 8.65 min; 1H RMN (400 MHz, CD3OD) 8.67 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 1.47 Hz, 1H), 7.96 (d, J = 1.83 Hz, 1H), 7.89 (d, J = 8.43 Hz, 1H), 7.67–7.50 (m, 3H), 3.80 (bs, 2H), 2.63–2.58 (s, 2H), 2.55 (s, 3H), 2.05–2.01 (bs, 2H), 1.69 (bs, 2H), 1.55 (bs, 3H); LC–MS 7.36 min, (M+1)+254 @ 7.50 min.
10 N–metil–1–(1–(naftalen–2–il)ciclohexil)etanamina (58 E1) 3C H3 H CH3 A 13E1
HPLC Rt = 8.93 min; 1H RMN (400 MHz, CD3OD) 7.98–7.87 (m, 4H), 7.60–7.57 (m, 1H), 7.55–7.50 (m, 2H), 3.30 (1H, oculto), 2.76–2.72 (m, 1H), 2.64 (s, 3H), 2.59–2.55 (m, 1H), 1.69–1.60 (m, 6H), 1.41–1.30 (m, 3H), 1.21 (d, J =
15 6.96 Hz, 3H); LC–MS 7.92 min, (M+1)+268 @ 8.06 min.
N–metil–1–(1–(naftalen–2–il)ciclohexil)etanamina (58 E2) 3 CH3 H CH3 A 13E2
20 LC–MS 7.88 min, (M+1)+268 @ 8.00 min.
N–metil–1–(1–(naftalen–1–il)ciclohexil)etanamina (59 E1)
3 CH3 H CH3 A 16E1
HPLC Rt=1.56 min; LC–MS (método del minuto 5) 2.75 min, (M+1)+ 268 @ 2.84 min.; 1H RMN (300 MHz, CD3OD)
8.43 (s, 1H), 8.33 (d, J=8.80Hz, 1H), 7.85 (t, 1H), 7.78 (d, J=8.07Hz, 1H), 7.56 (d, J=7.70Hz, 1H), 7.45–7–38 (m, 2H),
4.05 (m, 1H), 2.52 (bs, 5H), 1.82–1.78 (m, 2H), 1.75–1.48 (m, 4H), 1.32–1.06 (m, 5H).
30 N–metil–1–(1–(naftalen–1–il)ciclohexil)etanamina (59 E2) 3 CH3 H CH3 A 16E2
47
3 CH3 H CH3 A 19E2
LC–MS (método del minuto 15) 7.91 min, (M+1)+ 302 @ 8.20 min.
5
Los siguientes compuestos se sintetizaron a partir de la correspondiente amina primaria de acuerdo con el Procedimiento General F. El producto crudo se purificó por cromatografía de columna en sílica gel para dar los respectivos productos mono– y dimetilados
1–(1–(2,4–diclorofenil)ciclohexil)–N–metilmetanamina (65)
10
El compuesto del título se sintetizó a partir de 38. 1H RMN (400 MHz, CD3Cl) δ 7.35 (d, J=8.4 Hz, 1 H), 7.34 (d, J=2.4 Hz, 1 H), 7.19 (dd, J=8.4, 2.4 Hz, 1H), 3.00 (s, 2 H), 2.31 (s, 3 H), 2.31–2.28 (m, 2 H), 1.83 (m, 2 H), 1.56 (m, 2 H), 1.48–1.29 (m, 4 H); 13C RMN (400 MHz, CD3Cl) δ 140.61, 134.31, 132.63, 132.53, 132.08, 126.99, 58.24, 44.40,
15 37.68, 34.44, 26.67, 22.58; ESI MS m/z 272.07.
1–(1–(2,4–diclorofenil)ciclohexil)–N,N–dimetilmetanamina (66)
El compuesto del título se sintetizó a partir de 38. 1H RMN (400 MHz, CD3Cl) δ 7.42 (d, J=8.8 Hz, 1 H), 7.32 (d, J=2.0 20 Hz, 1 H), 7.20 (dd, J=8.8, 2.0 Hz, 1 H), 3.04 (s, 2 H), 2.40 (m, 2 H), 2.18 (s, 6 H), 1.80 (m, 2 H), 1.54 (m, 2 H), 1.48–
1.32 (m, 4H); 13C RMN (100 MHz, CD3Cl) δ 139.8, 134.27, 133.03, 132.99, 132.07, 127.29, 65.40, 47.26, 44.12, 34.37, 26.37, 22.34; ESI MS m/z 286.1.
1–(1–(6–fluoronaftalen–2–il)ciclohexil)–N–metilmetanamina (67)
25
El compuesto del título se sintetizó a partir de 39. 1H RMN (400 MHz, CD3Cl) δ 8.55 (m, 1 H), 8.19 (m, 1 H), 7.56–
7.40 (m, 2 H), 7.30 (m, 1 H), 3.22 (s, 2 H), 2.32 (m, 1H), 2.25 (s, 3 H), 2.26 (m, 1 H), 1.62 (m, 1 H), 1.54–1.35 (m, 5 H); 13C RMN (400 MHz, CD3Cl) 167.08, 159.65, 156.34, 132.86, 132.83,127.56, 127.49, 126.06, 125.92, 125.85, 125.83, 125.72, 125.32, 125.29, 122.11, 122.03, 108.64, 108.45, 60.17, 44.42, 37.61, 36.73, 35.90, 26.89, 26.82,
30 22.68, 22.73; ESI MS m/z 272.1.
50
1–(1–(6–fluoronaftalen–2–il)ciclohexil)–N,N–dimetilmetanamina (68)
El compuesto del título se sintetizó a partir de 39. 1H RMN (400 MHz, CD3Cl) δ 8.47 (m, 1 H), 8.17 (m, 1 H), 7.50–
5 7.44 (m, 2 H), 7.08 (dd, J=10.0, 8.4 Hz, 1 H), 2.95 (m, 2 H), 2.39 (m, 2 H), 2.14 (m, 2 H), 1.97 (s, 6 H), 1.59 (m, 2 H),
1.44 (m, 2 H); 13C RMN (100 MHz, CD3Cl) 167.07, 158.95, 158.31, 133.87, 132.73, 127.32, 127.23, 126.74, 126.72, 125.32, 125.00, 124.99, 121.96, 121.90, 108.61, 108.41, 68.39, 48.40, 45.03, 37.61, 36.62, 26.91, 22.74; ESI MS m/z 286.3.
1–(1–(4–fluoronaftalen–1–il)ciclohexil)–N–metilmetanamina (69)
10
El compuesto del título se sintetizó a partir de 40. 1H RMN (400 MHz, CD3OD) δ 8.5 (m, 1 H) 8.19 (m, 1 H), 7.5 (m, 3H), 7.10 (dd, J=8.4, 9.0 Hz, 1 H), 3.22 (s, 2 H), 2.31 (m, 2 H), 2.25 (s, 3 H), 2.04 (m, 2 H), 1.61 (m, 2 H), 1.44 (m, 4 H); 13C RMN (100 MHz, CD3OD) δ 159.26, 156.78, 136.59, 133.32, 133.29, 159.26, 156.78, 136.59, 133.32, 133.29,
15 127.56, 127.48, 125.85, 125.85, 125.31, 125.29, 122.11, 122.03, 108.64, 108.46, 60.13, 44.41, 37.59, 36.72, 29.94, 26.89, 26.82, 22.72; ESI MS m/z 272.2.
1–(1–(4–fluoronaftalen–1–il)ciclohexil)–N,N–dimetilmetanamina (70)
20 El compuesto del título se sintetizó a partir de 40. 1H RMN (400 MHz, CD3OD) δ 8.44 (m, 1 H), 8.18 (m, 1 H), 7.50 (m, 3 H), 7.09 (dd, J=8.8, 8.8 Hz, 1 H), 2.95 (s, 2 H), 2.38 (m, 2 H), 2.20 (m, 2 H), 1.96 (s, 6 H), 1.60 (m, 4 H), 1.44 (m, 2 H); 13C RMN (100 MHz, CD3OD), δ 159.06, 156.57, 133.53, 127.22, 126.76, 126.73, 125.32, 125.00, 124.99, 121.96, 121.89, 108.00, 108.43, 68.40, 48.42, 45.03, 36.63, 29.94, 26.92, 22.74; ESI MS m/z 286.2.
1–(1–(3,4–diclorofenil)ciclohex–3–enil)–N,N–dimetilmetanamina (72)
25 El compuesto del título se sintetizó de acuerdo con el Esquema 26, más adelante.
51
(a) La amina primaria 71 se sintetizó a partir de 1–(3,4–diclorofenil)–4–oxociclohexanocarbonitrilo de acuerdo con los Procedimientos Generales Q, U, y E1. 1H RMN (400 MHz, CDCl3) δ 7.45 (d, J=8.4 Hz, 1 H), 7.39(s, 1 H), 7.17 (d, J=8.4 Hz, 1 H), 5.75 (m, 1 H), 5.64 (m, 1 H), 3.16 (d, J=12.8 Hz, 1 H), 3.03 (d, J=12.8 Hz, 1 H), 2.5 (d, J=16.8 Hz, 1
5 H), 2.23 (d, J=16.8 Hz, 1 H), 2.06 (m, 1 H), 1.95 (m, 1 H), 1.84 (m, 1 H), 1.74 (m, 1 H); 13C RMN (100 MHz, CDCl3) δ 140.55, 133.33, 131.96, 131.33, 129.30, 127.53, 126.59, 123.44, 50.25, 39.35, 32.24, 30.58, 22.03; ESI MS m/z
256.1.
El compuesto del título se sintetizó a partir de 71 de acuerdo con el Procedimiento General D. 1H RMN (400 MHz, CDCl3) δ 8.35 (ancho, 1 H), 7.41(s, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 7.20 (d, J=8.4 Hz, 1 H), 5.75 (m, 1 H), 5.62 (m, 1
10 H), 3.02 (s, 2 H), 2.64 (d, J=15.6 Hz, 1 H), 2.45 (d, J=18.8 Hz, 1 H), 2.36 (s, 6 H), 1.98 (m, 1 H), 1.88 (m, 2 H), 1.58 (m, 1 H); 13C RMN (100 MHz, CDCl3), δ 144.16, 138.66, 132.99, 131.14, 130.70, 129.04, 127.36, 126.53, 124.13, 69.27, 47.54, 46.45, 40.38, 33.04, 32.93, 21.99; ESI MS m/z 284.0.
N–((1–(3,4–diclorofenil)ciclohexil)metil)–N–etiletanamina (clorhidrato) (73)
15
(a) Síntesis de 1–(3,4–diclorofenil)–N,N–dietilciclohexano–carboxamida
La amida se sintetizó a partir de ácido 1–(3,4–diclorofenil)–ciclohexanocarboxílico (232 mg, 0.85 mmol) y dietil amina usando el Procedimiento General G y se aisló con un rendimiento del 13% como un sólido de color blanco. HPLC Rt = 12.0 min; 1H RMN (400 mHz, CDCl3) 7.38–7.26 (m, 2H), 7.08 (dd, J = 2.2, 8.4 Hz, 1H), 3.29 (bs, 2H), 2.84 (bs, 2H),
20 2.26 (d, J = 12.1 Hz, 2H), 1.73–1.54 (m, 7H), 1.29–1.24 (m, 2H), 1.08 (bs, 3H), 0.82 (bs, 3H); 13C RMN (100 mHz, CDCl3) 172.9, 147.2, 133.0, 130.8, 130.4, 127.5, 125.2, 51.2, 42.0, 40.9, 37.3, 26.0, 23.7, 13.4, 12.4; GC–MS (SCOUT) 13.2 min, M+ 327.
(b) Síntesis de N–((1–(3,4–diclorofenil)ciclohexil)metil)–N–etiletanamina (clorhidrato)
El compuesto del título se sintetizó a partir de 1–(3,4–diclorofenil)–N,N–dietilciclohexanocarboxamida (19 mg, 0.058
25 mmol) usando el Procedimiento General E seguido por formación de sal de HCl. La sal de HCl cruda se recristalizó a partir de EtOAc (1.5 mL) para dar clorhidrato de [1–(3,4–Dicloro–fenil)–ciclohexilmetil]–dietil–amina puro como un sólido blancuzco HPLC Rt = 9.07 min; 1H RMN (MeOH–d4) 7.65 (d, J = 2.20 Hz, 1H), 7.55 (d, J = 8.55 Hz, 1H), 7.43 (dd, J = 2.2, 8.55 Hz, 1H), 3.24 (s, 2H), 2.90–2.83 (m, 4H), 2.30–2.25 (m, 2H), 1.68–1.53 (m, 5H), 1.35–1.24 (m, 3H),
1.10 (a, 6H); LCMS 10.8 min, (M + 1)+ 314 @ 11.0 min.
52
(a) Síntesis de 1–(3,4–diclorofenil)–N–ciclopropilciclo–hexanocarboxamida
El compuesto del título se sintetizó a partir de ácido 1–(3,4–diclorofenil)–ciclohexanocarboxílico (372 mg, 1.37 mmol) y ciclopropilamina usando el Procedimiento General G y se aisló con un rendimiento del 25% como un sólido de 5 color blanco. HPLC Rt = 10.6 min; 1H RMN (400 mHz, CDCl3) 7.45 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.43 Hz, 1H), 7.23–7.21 (m, 1H), 5.49 (bs, 1H), 2.62–2.59 (m, 1H), 2.25–2.20 (m, 2H), 1.84–1.78 (m, 2H), 1.59–1.55 (m, 5H), 1.38–
1.33 (m, 1H), 0.73–0.68 (m, 2H), 0.37–0.33 (m, 2H); 13C RMN (100 mHz, CDCl3) 176.0, 144.8, 133.0, 131.0, 130.8, 128.6, 126.2, 50.4, 34.9, 25.7, 23.1, 6.91; GC–MS (SCOUT) 13.5 min, M+ 311.
(b) Síntesis de clorhidrato de N–((1–(3,4–diclorofenil)ciclohexil)metil)–ciclopropanamina
10 El compuesto del título se sintetizó a partir de 1–(3,4–diclorofenil)–N–ciclopropilciclohexano carboxamida (108 mg,
0.35 mmol) usando el Procedimiento General E seguido por formación de HCl. La sal de HCl cruda se recristalizó a partir de 3:1 EtOAc:CH3CN (4 mL) y 1:1 EtOAc:CH3CN (3 mL) para dar clorhidrato de N–((1–(3,4– diclorofenil)ciclohexil)–metil)ciclopropanamina puro como cristales blancos. HPLC Rt = 9.02 min; 1H RMN (400 mHz, MeOH–d4) 7.57–7.52 (m, 2H), 7.35 (dd, J= 1.83, 8.43 Hz, 1H), 3.29 (s, 2H), 2.56–2.54 (m, 1H), 2.16–2.13 (m, 2H),
15 1.67–1.30 (m, 8H), 0.78–0.74 (m, 4H); LC–MS 10.6 min, (M+1)+ 298 @ 10.8 min.
Síntesis de clorhidrato de (1–(3–clorofenil)ciclohexil)–N–metilmetanamina (79)
Procedimiento General H: Una solución de 1–(3–clorofenil)ciclohexano–carbaldehído (119 mg, 0.53 mmol), metil
20 amina (291 µL, 0.58 mmol, 2.0 M en THF) y cianoborohidruro de sodio (100 mg, 1.59 mmol) en 1:1 MeOH:Trietilortoformiato (4 mL) se agitó a temperatura ambiente durante la noche. La solución se vertió en K2CO3 saturado acuoso y se lavó con EtOAc (2 X 20 mL). Las fases orgánicas combinadas lavadas se secaron (Na2SO4), se filtraron y concentraron. El material crudo se disolvió en Et2O y se agregó HCl (1.5 mL, 2.0 M en Et2O). La reacción se concentró y la sal de HCl se recristalizó a partir de CH3CN (4.5 mL) para dar clorhidrato de (1–(3–
25 clorofenil)ciclohexil)–N–metilmetanamina puro como cristales incoloros HPLC Rt = 8.25 min; 1H RMN (400 mHz, MeOH–d4) 7.43–7.28 (m, 4H), 3.12 (s, 2H), 2.54 (s, 3H), 2.19–2.16 (m, 2H), 1.67–1.30 (m, 8H); LC–MS 7.29 min, (M+1)+ 238 @ 7.50 min.
N–metil(1–fenilciclohexil)metanamina (clorhidrato) (80)
El compuesto del título se sintetizó a partir de 1–fenilciclohexano–carbaldehído (126 mg, 0.67 mmol) y metil amina (370 µL, 0.73 mmol, 2.0 M en THF) de acuerdo con el Procedimiento General H, seguido por formación de sal de HCl. La sal de HCl se recristalizó a partir de CH3CN para dar el clorhidrato de N–metil(1–fenilciclohexil)metanamina puro (8 mg, 6%) como cristales incoloros. HPLC Rt = 7.76 min; 1H RMN (400 mHz, MeOH–d4) 7.43–7.38 (m, 4H),
55
7.28–7.25 (m, 1H), 3.11 (s, 2H), 2.50 (s, 3H), 2.25–2.22 (m, 2H), 1.67–1.23 (m, 8H); LC–MS 6.37 min, (M+1)+ 204 @
Clorhidrato de (1–(3,4–difluorofenil)ciclohexil)–N–metilmetanamina (81)
5
El compuesto del título se sintetizó a partir de 1–(3,4–difluorofenil)–ciclohexanocarbaldehído (131 mg, 0.58 mmol) y metil amina (320 µL, 0.64 mmol, 2.0 M en THF) de acuerdo con el Procedimiento General H, seguido por formación de sal de HCl. La sal de HCl se recristalizó a partir de CH3CN para dar el clorhidrato de (1–(3,4– difluorofenil)ciclohexil)–N–metilmetanamina puro como cristales incoloros. HPLC Rt = 8.15 min; 1H RMN (400 mHz, 10 MeOH–d4) 7.36–7.21 (m, 3H), 3.11 (s, 2H), 2.55 (d, J = 3.67 Hz, 3H), 2.15–2.12 (m, 2H), 1.67–1.31 (m, 8H); LC–MS
7.04 min, (M+1)+ 240 @ 7.19 min.
Clorhidrato de (1–(3–clorofenil)ciclohexil)–N,N–dimetilmetanamina (82)
15 El compuesto del título se sintetizó a partir de 1–(3–clorofenil)–N,N–dimetilciclohexanocarboxamida (191 mg, 0.72 mmol) usando el Procedimiento General E, seguido por formación de sal de HCl. La sal de HCl cruda se recristalizó a partir de 2:1 CH3CN:EtOAc (4.5 mL) para dar el clorhidrato de (1–(3–clorofenil)ciclohexil)–N,N–dimetilmetanamina puro como un sólido blancuzco (21 mg, 12%). HPLC Rt = 8.41 min; 1H RMN (400 mHz, MeOH–d4) 7.51–7.30 (m, 4H), 3.26–3.24 (m, 2H), 2.54 (s, 6H), 2.24–2.20 (m, 2H), 1.72–1.33 (m, 8h); LC–MS 8.16 min, (M+1)+ 252 @ 8.27
20 min.
Clorhidrato de (1–(3,4–difluorofenil)ciclohexil)–N,N–dimetilmetanamina (83)
El compuesto del título se sintetizó a partir de 1–(3,4–difluorofenil)–N,N–dimetilciclohexanocarboxamida (195 mg,
25 0.73 mmol) usando el Procedimiento General E (la amida se preparó a partir del correspondiente ácido carboxílico de acuerdo con el Procedimiento General G), seguido por formación de sal de HCl. La sal de HCl cruda se recristalizó a partir de 1:1 CH3CN:EtOAc (3.0 mL) para dar el clorhidrato de (1–(3,4–difluorofenil)ciclohexil)–N,N– dimetilmetanamina puro como un sólido blancuzco (16 mg, 8%). HPLC Rt = 8.24 min; 1H RMN (400 mHz, MeOH–d4) 7.51–7.46 (m, 1H), 7.37–7.34 (m, 2H), 3.31–3.30 (m, 2H), 2.62 (s, 6H), 2.26–2.23 (m, 2H), 1.78–1.38 (m, 8H); LC–
30 MS 7.69 min, (M+1)+254 @ 7.91 min.
Clorhidrato de (1–(4–clorofenil)ciclohexil)–N–metilmetanamina (84)
56
El compuesto del título se sintetizó a partir de 1–(4–clorofenil)–N–metilciclohexanocarboxamida (278 mg, 1.11 mmol) usando el Procedimiento General E, seguido por formación de sal de HCl para dar el clorhidrato de (1–(4– clorofenil)ciclohexil)–N–metilmetanamina puro como un sólido blancuzco (185 mg, 70%). HPLC Rt = 8.38 min; 1H RMN (400 mHz, MeOH–d4) 7.39 (s, 4H), 3.10 (s, 2H), 2.52 (s, 3H), 2.19–2.16 (m, 2H), 1.65–1.49 (m, 6H), 1.37–1.30 (m, 4H); LC–MS 7.49 min, (M+1)+238 @ 7.63 min.
(1–(4–clorofenil)ciclohexil)–N,N–dimetilmetanamina (85)
10 El compuesto del título se preparó a partir de 1–(4–clorofenil)–N,N–dimetilciclohexanocarboxamida (241 mg, 0.91 mmol) de acuerdo con el Procedimiento General E. El producto en bruto se purificó por TLC preparativa con 10% de Me– OH/CH2Cl2 (Rf= 0.74) para dar base libre de (1–(4–clorofenil)ciclohexil)–N,N–dimetilmetanamina (11 mg, 5%) como un aceite transparente. HPLC Rt = 8.55 min; 1H RMN (400 mHz, MeOH–d4) 7.30 (q, 4H), 2.30 (s, 2H), 2.09–
2.06 (m, 2H), 1.97 (s, 6H), 1.60–1.25 (m, 10H); LC–MS 8.09 min, (M+1)+252 @ 8.15 min.
15 Clorhidrato de N,N–dimetil(1–fenilciclohexil)metanamina (86)
El compuesto del título se sintetizó a partir de N,N–dimetil–1–fenilciclohexanocarboxamida (200 mg, 0.87 mmol) usando el Procedimiento General E, seguido por formación de sal de HCl. La sal de HCl crudas se recristalizó a
20 partir de 2:1 EtOAc:CH3CN para dar el clorhidrato de N,N–dimetil(1–fenilciclohexil)metanamina como un sólido blancuzco analíticamente puro (8 mg, 4%). HPLC Rt = 8.55 min; 1H RMN (400 mHz, MeOH–d4) 7.30 (q, 4H), 2.30 (s, 2H), 2.09–2.06 (m, 2H), 1.97 (s, 6H), 1.60–1.25 (m, 10H); LC–MS 8.09 min, (M+1)+252 @ 8.15 min. HPLC Rt = 8.03 min; 1H RMN (400 mHz, MeOH–d4) 7.48–7.39 (m, 4H), 7.29–7.28 (m, 1H), 3.34 (d, J = 2.57 Hz, 2H), 2.46 (d, J = 3.30 Hz, 6H), 2.29–2.26 (m, 2H), 1.67–1.39 (m, 8H); LCMS 6.62 min, (M+1)+218 @ 6.80 min.
25 (1–(3,4–diclorofenil)ciclopentil)metanamina (87)
Procedimiento General G1 – Amidación con cloruro de oxalilo: A una solución de ácido 1–(3,4– diclorofenil)ciclopentanocarboxílico (200mg, 0.7718 mmol) en DCM (1mL) y DMF (1mL) se agregó cloruro de oxalilo 30 (1.54mL, 1M en DCM) gota a gota. Después de cinco minutos, los volátiles se eliminaron en vacuo y el aceite
57
El compuesto del título se sintetizó a partir de ácido 1–(naftalen–2–il)ciclohexano–carboxílico y dimetil amina usando el Procedimiento General G, seguido por el Procedimiento General E y se obtuvo en 11% de rendimiento como un aceite transparente. LCMS Rt = 6.47 min, m/z = 268 (M+1). 1H RMN (CDCl3, δ): 7.80 (m, 4H), 7.55 (dd, J = 1.7, 8.6Hz, 1H), 7.45 (m, 2H), 2.2 (m, 2H), 1.97 (s, 6H), 1.8–1.3 (m, 8H). 13C RMN (CDCl3, δ, mult): 133.4, 131.6, 127.9, 127.4, 127.2, 126.2, 126.1, 125.8, 125.5, 125.1, 72.6, 56.6, 48.4, 34.3, 26.6, 22.3.
(1–(4–cloro–3–fluorofenil)ciclohexil)–N–metilmetanamina (95)
10 Procedimiento General H1 – Aminación reductiva: A una solución de 1–(4–cloro–3– fluorofenil)ciclohexanocarbaldehído (100mg, 0.4154 mmol) en metilamina (2.1mL, 2M en THF, 10eq) se agregó ácido acético (104ul, 5% de volumen), y se añadió metanol hasta que la solución se volvió transparente. La solución se agitó durante dos horas. Se añadió a la solución borohidruro de sodio (40 mg, 3 eq) y la agitación se continuó durante 30 minutos. La reacción se detuvo con carbonato de potasio acuoso y se extrajo con MTBE. La fase
15 orgánica se separó y el solvente se eliminó en vacuo. El residuo se redisolvió en MTBE y se extrajo con HCl 3M. La fase acuosa se separó, se enfrió en hielo, y se basificó con KOH. Luego, la fase acuosa se extrajo con MTBE y el solvente se eliminó en vacuo. El el residuo se diluyó en DCM, se filtró a través de cartucho de aminopropilo. se eliminó de nuevo para dar la amina secundaria (75.1mg, 71%) como un aceite transparente. LCMS Rt = 7.39 min, m/z = 256 (M+1). 1H RMN (CDCl3, δ): 7.34 (t, J = 8.2Hz, 1H), 7.15 (dd, J = 2.2, 11.4Hz, 1H), 7.09 (dd, J = 1.9, 8.4Hz,
20 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.0 (m, 2H), 1.7–1.3 (m, 8H). 13C RMN (CDCl3, δ, mult): 159.4(0), 156.9(0), 147.2(0), 147.1(0), 130.2(1), 123.5(1), 123.5(1), 118.0(0), 117.8(0), 115.6(1), 115.4(1), 64.2(2), 42.3(0), 37.3(3), 34.5(2), 26.4(2), 22.1(2).
(1–(3–cloro–4–fluorofenil)ciclohexil)–N–metilmetanamina (96)
25
El compuesto del título se sintetizó a partir de 1–(3–cloro–4–fluorofenil)–ciclohexanocarbaldehído y metil amina usando el Procedimiento General H1 y se obtuvo 55% de rendimiento. LCMS Rt = 7.73 min, m/z = 256 (M+1). 1H RMN (CDCl3, δ): 7.37 (dd, J = 2.4, 7.1Hz, 1H), 7.22 (ddd, J = 2.4, 4.6, 8.7Hz, 1H), 7.09 (t, J = 8.7Hz, 1H), 2.58 (s, 2H), 2.29 (s, 3H), 2.0 (m, 2H), 1.7–1.2 (m, 8H). 13C RMN (CDCl3, δ, mult): 157.4(0), 154.9(0), 142.9(0), 129.2(1),
30 126.8(1), 126.7(1), 120.8(0), 120.6(0), 116.3(1), 116.1(1), 64.2(2), 42.1(0), 37.3(3), 34.6(2), 26.4(2), 22.1(2).
(1–(3–cloro–4–fluorofenil)ciclohexil)–N,N–dimetilmetanamina (97)
60
El compuesto del título se sintetizó a partir de 1–(3–cloro–4–fluorofenil)ciclohexanocarbaldehído y dimetil amina usando el Procedimiento General H1 y se obtuvo con 88% de rendimiento como un sólido oleoso. El compuesto del título también se sintetizó a partir de 1–(1–(3–cloro–4–fluorofenil)–ciclohexil)–N–metilmetanamina de acuerdo con el
5 Procedimiento General C.
LCMS Rt = 8.81 min, m/z = 270 (M+1). 1H RMN (CDCl3, δ): 7.38 (dd, J = 2.4, 7.2Hz, 1H), 7.22 (ddd, J = 2.4, 4.6, 8.7Hz, 1H), 7.07 (t, J = 8.8Hz, 1H), 2.29 (s, 2H), 2.0 (m, 2H), 1.99 (s, 6H), 1.7–1.2 (m, 8H). 13C RMN (CDCl3, δ, mult): 157.2(0), 154.7(0), 143.4(0), 129.6(1), 127.1(1), 127.1(1), 120.3(0), 120.1(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.0(0), 34.1(2), 26.4(2), 22.0(2).
10 (1–(4–cloro–3–fluorofenil)ciclohexil)–metanamina (98)
El compuesto del título se sintetizó a partir de 1–(4–cloro–3–fluorofenil)–ciclohexanocarbonitrilo usando el Procedimiento General E y se obtuvo en 19% de rendimiento como un aceite transparente. HPLC Rt = 8.28 min.
15 LCMS Rt = 8.13 min, m/z = 242 (M+1). Sal de HCl – 1H RMN (DMSO–d6, δ): 7.35 (t, J = 8.1Hz, 1H), 7.17 (d, J = 11.3Hz, 1H), 7.10 (d, J = 8.4Hz, 1H), 2.82 (s, 2H), 2.1 (m, 2H), 1.7–1.1 (m, 8H). 13C RMN (DMSO–d6, δ, mult): 159.2(0), 156.7(0), 143.1(0), 143.0(0), 130.6(1), 124.1(1), 124.1(1), 118.5(0), 118.3(0), 116.2(1), 116.0(1), 50.2(2), 40.6(0), 33.3(2), 25.5(2), 21.4(2).
(1–(4–cloro–3–fluorofenil)ciclohexil)–N,N–dimetilmetanamina (99)
20 El compuesto del título se sintetizó a partir de 1–(4–cloro–3–fluorofenil)ciclohexanocarbaldehído y dimetil amina usando el Procedimiento General H1 y se obtuvo en 97% de rendimiento. LCMS Rt = 9.07 min, m/z = 270 (M+1). 1H RMN (CDCl3, δ): 7.31 (t, J = 8.2Hz, 1H), 7.17 (dd, J = 2.1, 11.7Hz, 1H), 7.09 (dd, J = 1.8, 8.5Hz, 1H), 2.30 (s, 2H),
25 2.0 (m, 2H), 1.99 (s, 3H), 1.7–1.3 (m, 8H). 13C RMN (CDCl3, δ, mult): 159.2(0), 156.7(0), 147.8(0), 129.7(1), 123.9(1), 123.8(1), 117.5(0), 117.3(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.3(0), 34.1(2), 26.4(2), 22.1(2).
N–metil–1–(1–(4–(trifluorometil)fenil)–ciclohexil)metanamina (100)
61
- (a)
- Preparación de 1–(4–(trifluorometil)fenil)ciclohexanocarbonitrilo
El compuesto del título se sintetizó a partir de 2–(4–(trifluorometil)fenil)–acetonitrilo (4.11 g, 22.2 mmol) y 1,5– dibromopentano (3.324 ml, 24.4 mmol) de acuerdo con el Procedimiento General J y se obtuvo como un aceite transparente (4.98 g, 89%). 1H RMN (CDCl3) δ 1.23–1.39 (m, 1H), 1.76–1.92 (m, 7H), 2.17 (d, J = 11.2 Hz, 2H), 7.63 (s, 4H). 13C RMN (CDCl3) δ 23.7, 25.0, 37.4, 44.7, 122.2, 126.0, 126.7, 130.2, 145.6, GC–MS m/z 253.
- (b)
- Preparación de 1–(4–(trifluorometil)fenil)ciclohexanocarbaldehído
10 Procedimiento General M: A una solución de 1–(4–(trifluorometil)fenil)–ciclohexanocarbonitrilo (4.80 g, 18.95 mmol) en tolueno (60 ml) a –70ºC se agregó gota a gota DIBAL 1 M en hexano (38 ml, 38 mmol) durante 30 min. La mezcla se agitó a –70ºC durante 30 min y durante otras 4h a temperatura ambiente, después de lo cual se añadió formiato de etilo (3 ml). La mezcla se agitó a temperatura ambiente durante 1 hora y luego se vertió en solución saturada de NH4Cl (70 ml). Después de 30 min, se añadió H2SO4 acuoso 2M (100 ml) y el producto se extrajo con hexanos (3 X
15 100 ml). Las fases orgánicas combinadas se secaron sobre MgSO4 y y se evaporaron en vacuo. El residuo se purificó por cromatografía de columna en sílica gel (EtOAc/hexanos, EtOAc de 0% a 25%) para dar 1–(4– (trifluorometil)fenil)–ciclohexanocarbaldehído (3.0 g, 65%) como aceite transparente. 1H RMN (CDCl3): δ 1.29–1.37 (m, 1H), 1.46–1.55 (m, 2H), 1.59–1.69 (m, 3H), 1.83–1.90 (m, 2H), 2.29–2.34 (m, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 9.40 (s, 1H). 13C RMN (CDCl3) δ 22.9, 25.6, 31.5, 54.7, 125.9, 126.0, 127.8, 129.5, 144.2, 202.0.
20 (c) Preparación de N–metil(1–(4–(trifluorometil)fenil)ciclohexil)–metanamina
Procedimiento General H2 – Aminación reductiva: Una mezcla de 1–(4–(trifluorometil)fenil)ciclohexanocarbaldehído (256 mg, 1.0 mmol) y metilamina (2.0 M en THF, 3 ml, 6.0 mmol) en 1,2–dicloroetano se agitó a temperatura ambiente durante 30 min y y entonces se trató con triacetoxiborohidruro de sodio (297 mg, 1.4 mmol). La mezcla de reacción se agitó a temperatura ambiente durante la noche y luego se detuvo con solución acuosa saturada de 25 NaHCO3 (10 ml). El producto se extrajo con EtOAc (3 X 10 ml). Las capas orgánicas combinadas se secaron sobre MgSO4 y y se evaporaron en vacuo. El residuo se purificó por cromatografía de columna en sílica gel (MeOH/CH2Cl2, MeOH de 0% a 20%) para dar N–metil–1–(1–(4–(trifluorometil)fenil)ciclohexil)metanamina (178 mg, 66%). 1H RMN (CDCl3): δ 1.26–1.52 (m 4H), 1.54–1.61 (m, 2H), 1.66–1.73 (m, 2H), 2.13–2.18 (m, 2H), 2.28 (s, 3H),
2.63 (s, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H). 13C RMN (CDCl3) δ 22.3, 26.7, 34.7, 37.5, 42.9, 64.5, 30 125.4, 125.9, 127.6, 128.3, 150.2. ESI MS m/z 271.
N,N–dimetil–1–(1–(4–(trifluorometil)fenil)–ciclohexil)metanamina (101)
62
13C RMN (CDCl3) δ 22.3, 26.7, 34.6, 37.4, 42.6, 64.2, 123.0, 123.9, 127.9, 129.1, 130.8, 131.1, 146.7. ESI MS m/z
271. N,N–dimetil–1–(1–(3–(trifluorometil)–fenil)ciclohexil)–metanamina (105)
El compuesto del título se preparó a partir de 1–(3–(trifluorometil)fenil)ciclohexano–carbaldehído (128 mg, 0.50 mmol) y dimetilamina (2.0 M en THF, 2.5 ml, 5.0 mmol) de acuerdo con el Procedimiento General H2. El producto crudo se purificó por cromatografía de columna en sílica gel (MeOH/CH2Cl2, MeOH de 0% a 15%) para dar N,N– dimetil–1–(1–(3–(trifluorometil) fenil)ciclohexil)metanamina (74 mg, 52%) como un aceite transparente. 1H RMN
10 (CDCl3): δ 1.29–1.38 (m 3H), 1.48–1.57 (m, 3H), 1.63–1.70 (m, 2H), 1.97 (s, 6H), 2.11–2.15 (m, 2H), 2.34 (s, 2H), 7.41–7.43 (m, 2H), 7.56–7.59 (m, 1H), 7.63 (s, 1H). 13C RMN (CDCl3) δ 22.4, 26.7, 34.3, 43.9, 48.6, 72.7, 122.4, 124.3, 128.6, 126.0, 131.1, 147.6, 150.8. ESI MS m/z 286.
1–(1–(3–fluorofenil)ciclohexil)–N–metilmetanamina (106)
(a) Preparación de 1–(3–fluorofenil)ciclohexanocarbonitrilo
El compuesto del título se preparó a partir de 2–(3–fluorofenil)acetonitrilo (2.58 ml, 22.2 mmol) y 1,5– dibromopentano (3.324 ml, 24.4 mmol) de acuerdo con el Procedimiento General J para producir 1–(3– fluorofenil)ciclohexanocarbonitrilo (4.43 g, 97%) como un aceite transparente. 1H RMN (CDCl3) δ 1.26–1.39 (m, 1H),
20 1.76–1.88 (m, 7H), 2.17 (d, J = 11.2 Hz, 2H), 6.93–6.98 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.30–7.35 (m, 1H). 13C RMN (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.
(b) Preparación de 1–(3–fluorofenil)ciclohexanocarbaldehído
25 El compuesto del título se preparó a partir de 1–(3–fluorofenil)ciclohexanocarbonitrilo (3.52 g, 17.32 mmol) de acuerdo con el Procedimiento General M. El producto crudo se purificó por cromatografía de columna en sílica gel (EtOAc/hexanos, EtOAc de 0% a 25%) para dar 1–(3–fluorofenil)ciclohexanocarbaldehído (2.01 g, 56%) como un aceite transparente. 1H RMN (CDCl3): δ 1.29–1.37 (m, 1H), 1.44–1.53 (m, 2H), 1.58–1.67 (m, 3H), 1.79–1.85 (m, 2H), 2.26–2.31 (m, 2H), 6.93–6.98 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.30–7.35 (m, 1H), 9.36 (s,
30 1H). 13C RMN (CDCl3) δ 22.9, 25.7, 31.5, 54.5, 114.4, 123.0, 130.5, 142.8, 162.2, 164.7, 202.0.
(c) Síntesis de 1–(1–(3–fluorofenil)ciclohexil)–N–metilmetanamina
65
El compuesto del título se preparó a partir del 1–(3–fluorofenil)ciclohexano–carbaldehído anterior (103 mg, 0.5 mmol) y metilamina (2.0 M en THF, 2.5 ml, 5.0 mmol) de acuerdo con el Procedimiento General H2. El producto crudo se purificó por cromatografía de columna en sílica gel (MeOH/CH2Cl2, MeOH de 0% a 15%) para dar 1–(1–(3– fluorofenil)ciclohexil)– N–metilmetanamina (50 mg, 45%). 1H RMN (CDCl3): 1.28–1.52 (m 4H), 1.54–1.60 (m, 2H), 1.69–1.76 (m, 2H), 2.12–2.18 (m, 2H), 2.28 (s, 3H), 2.61 (s, 2H), 7.45–7.48 (m, 2H), 6.87–6.92 (m, 1H), 7.08 (d, J =
8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.27–7.32 (m, 1H). 13C RMN (CDCl3) h 22.4, 26.8, 34.9, 37.5, 42.6, 64.6, 112.7, 112.9, 114.2, 114.4, 122.8, 129.9, 130.0, 162.2, 164.7. ESI MS m/z 222.
1–(1–(3–fluorofenil)ciclohexil)–N,N–dimetilmetanamina (107)
El compuesto del título se preparó a partir de 1–(3–fluorofenil)ciclohexano–carbaldehído (103 mg, 0.50 mmol) y dimetilamina (2.0 M en THF, 2.5 ml, 5.0 mmol) de acuerdo con el Procedimiento General H2. El producto crudo se purificó por cromatografía de columna (SiO2, MeOH/CH2Cl2, MeOH de 0% a 15%) para dar 1–(1–(3– fluorofenil)ciclohexil)–N,N–dimetilmetanamina (46 mg, 39%) como un aceite transparente. 1H RMN (CDCl3): δ 1.32–
15 1.38 (m 3H), 1.49–1.56 (m, 3H), 1.59–1.66 (m, 2H), 1.99 (s, 6H), 2.05–2.09 (m, 2H), 2.33 (s, 2H), 6.83–6.88 (m, 1H),
7.08 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.23–7.29 (m, 1H). 13C RMN (CDCl3) δ 22.4, 26.8, 34.4, 43.6, 48.6, 72.9, 112.2, 112.4, 114.6, 114.8, 123.2, 129.4, 129.5, 162.0, 164.5. ESI MS m/z 236.
(±) 1–(1–(3,4–diclorofenil)ciclohexil)–N–metiletanamina (108)
(a) Síntesis de 1–(1–(3,4–diclorofenil)ciclohexil)etanol
A una solución de 1–(3,4–diclorofenil)ciclohexanocarbaldehído (440 mg, 1.71 mmol) en THF anhidro (17 mL) a 0°C
25 se agregó lentamente metil–litio (1.6 M en Et2O, 3.21 mL, 5.14 mmol). La solución se dejó calentar hasta temperatura ambiente y se agitó durante 16h. It luego se detuvo con MeOH (5 mL). La mezcla de reacción cruda se vertió en HCl 2M (15 mL) y se lavó con EtOAc (3 X 20 mL). Las capas orgánicas combinadas se secaron (Na2SO4), se filtraron y concentraron para dar 1–(1–(3,4–diclorofenil)ciclohexil)etanol. HPLC Rt = 11.28 min; 1H RMN (400 mHz, CDCl3) 7.44–7.41 (m, 2H), 7.20 (dd, J = 2.2, 8.4 Hz, 1H), 3.63–3.58 (m, 1H), 2.39–2.35 (m, 1H), 2.14–2.10 (m, 1H),
30 1.67–1.48 (m, 5H), 1.31–1.16 (m, 3H), 0.92 (d, J = 6.6 Hz, 3H).
(b) Síntesis de 1–(1–(3,4–diclorofenil)ciclohexil)etanona
66 5
10
15
20
25
30
35
A una solución de 1–(1–(3,4–diclorofenil)ciclohexil)etanol crudo (494 mg, 1.81 mmol) en CH2Cl2 t = 11.61 min; 1H RMN (400 mHz, CDCl3) 7.42–7.40 (m, 2H), 7.15 (dd, J = 2.2, 8.4 Hz, 1H), 2.32–2.29 (m, 2H), 1.92 (s, 3H), 1.80–1.74 (m, 2H), 1.65–1.43 (m, 5H), 1.35–1.30 (m, 1H); 13C RMN (100 mHz, CDCl3) 209.5, 143.3, 133.2, 131.3, 130.9, 128.9, 126.3, 56.2, 33.7, 25.8 (2 picos superpuestos), 23.2.
(c) Síntesis de (±) clorhidrato de 1–(1–(3,4–diclorofenil)ciclohexil)–N–metiletanamina
Una mezcla de 1–(1–(3,4–diclorofenil)ciclohexil)etanona (247 mg, 0.91 mmol) y metil amina (455 µL, 2.0 M en THF,
- 0.91
- mmol) se agitó a temperatura ambiente durante 2 min. Se agregó entonces isopróxido de titanio (IV) (336 µL,
- 1.14
- mmol). La solución de color verde amarilla se agitó a temperatura ambiente durante 3h. La solución de NaBH3CN (640 mL, 1.0 M en MeOH, 0.64 mmol) y la solución turbia se agitó a temperatura ambiente durante 16 h. La solución se detuvo con solución saturada de NaCl (3 mL), se filtró, y se lavó con MeOH (50 mL). Se agregó HCl 6M (20 mL) y la fase acuosa se lavó con Et2O (2 X 20 mL). El pH de la fase acuosa se ajustó hasta pH = 12 con NaOH 3M y se lavó con EtOAc (3 X 30 mL). Las fases orgánicas combinadas se secaron (Na2SO4), se filtraron y concentraron. A una solución de la amina cruda en Et2O (3 mL) se añadió HCl (3 mL, 2.0 M en Et2O). La sal de HCl cruda se recristalizó a partir de CH3CN (6 mL) a 110°c para dar 1–(1–(3,4–diclorofenil)ciclohexil)–N–metiletanamina (8 mg) como cristales blancos. HPLC Rt = 8.90 min; 1H RMN (400 mHz, CD3OD) 7.57–7.53 (m, 2H), 7.33–7.31 (m, 1H), 3.15–3.13 (m, 2H), 2.61 (s, 3H), 2.45 (ancho d, J = 11.73 Hz, 1H), 2.30 (ancho d, J = 12.46, 1H), 1.59–1.51 (m, 5H), 1.31–1.08 (m, 6H); LC–MS 7.87 min, (M+1)+ 286 @ 8.10min.
Síntesis de 1–(1–(3,4–diclorofenil)ciclohexil)propan–1–ona
(a) 1–(1–(3,4–diclorofenil)ciclohexil)propan–1–ol
Se disolvió 1–(3,4–diclorofenil)ciclohexanocarbaldehído (519 mg, 2.01 mmol) en THF anhidro (17 mL) y se enfrió hasta 0°C. Se agregó lentamente cloruro de etil magnesio (2.0 M en THF, 3.03 mL, 6.06 mmol). La solución se dejó calentar hasta temperatura ambiente y se agitó durante 16h, luego se detuvo con MeOH (5 mL). La mezcla de reacción cruda se vertió en HCl 2M (15 mL) y se lavó con EtOAc (3 X 20 mL). Las fases orgánicas combinadas lavadas se secaron (Na2SO4), se filtraron y concentraron para dar el alcohol secundario (443 mg, 77% durante 2 etapas) como un sólido de color blanco. HPLC Rt = 11.65 min; 1H RMN (400 mHz, CDCl3) 7.43–7.41 (m, 2H), 7.19 (dd, J = 2.2, 8.4 Hz, 1H), 3.27–3.23 (m, 1H), 2.37–2.33 (m, 1H), 2.17–2.14 (m, 1H), 1.57–1.46 (m, 6H), 1.29–1.17 (m, 4H), 0.90–0.77 (m, 4H); 13C RMN (125 mHz, CDCl3) 143.0, 132.4, 130.9, 130.1, 130.0, 128.3, 81.7, 47.1, 32.6 (doblete), 26.7, 24.4, 22.2, 11.4.
(b) 1–(1–(3,4–diclorofenil)ciclohexil)propan–1–ona
67
(±) 1–((1–(3,4–diclorofenil)ciclohexil)metil)–2–metilpirrolidina (115)
HPLC Rt = 9.25 min; 1H RMN (400 MHz, CD3OD) 7.64 (s, 1H), 7.55 (dd, J = 3.67, 8.43 Hz, 1H), 7.42 (d, J = 7.33 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H), 3.25 (s, 2H), 3.00–2.98 (m, 1H), 2.69–2.65 (m, 1H), 2.37–2.34 (m, 1H), 2.11 (bs, 2H), 1.91–1.23 (m, 14H); LC–MS 10.1 min, (M+1)+ 326 @ 10.1 min.
(±) 2–((1–(3,4–diclorofenil)ciclohexil)metilamino)ciclopentanol (116)
HPLC Rt = 8.86 min; 1H RMN (400 MHz, CD3OD) 7.58 (d, J = 2.57 Hz, 1H), 7.53 (d, J = 8.43 Hz, 1H), 7.39–7.36 (m, 10 1H), 4.03–3.98 (m, 1H), 3.40 (d, J = 13.2 Hz, 1H), 3.17–3.10 (m, 2H), 2.17–2.04 (m, 3H), 1.95–1.89 (m, 1H), 1.71–
1.32 (m, 12H); LC–MS 9.31 min, (M+1)+ 342 @ 9.42 min.
(±) 2–((1–(3,4–diclorofenil)ciclohexil)metilamino)ciclohexanol (117)
15 HPLC Rt = 9.1 min; 1H RMN (400 MHz, CD3OD) 7.60 (d, J = 2.20 Hz, 1H), 7.60–7.52 (m, 1H), 7.41–7.37 (m, 1H), 3.48–3.43 (m, 1H), 3.15–3.11 (m, 1H), 2.75–2.69 (m, 1H), 2.21–2.11 (m, 2H), 1.98–1.15 (m, 16H); LC–MS 9.50 min, (M+1)+ 356 @ 9.6 min.
Ejemplo 2 20 Síntesis de cicloalquilaminas 2–sustituidas
2.1. Síntesis de cicloalquilaminas 2–Hidroxi–sustituidas
El compuesto descrito a continuación de la invención se sintetizó a partir de los análogos bromometilo correspondientes de acuerdo con los Procedimientos Generales O y P (descritos a continuación).
25 cis–2–(aminometil)–2–(3,4–diclorofenil)ciclohexanol (cis 121)
70
Tabla 8: Resumen de resultados – Ensayos de captación de Monoamina
- Comp. No.
- hSERT Humano IC50 (nM) hNET hDAT rSERT Rata IC50 (nM) rNET rDAT
- 73
- 2240 6 1 710 15 6
- 74
- 19 4 1 30 6 10
- 27
- 201 273 150 500 150 95
- 75
- 169 85 21 110 20 58
- 76
- 156 9 1
- 77
- 158 19 4
- 170 E1
- 1030 189 1190
- 170 E2
- 673 26 427
- 78
- 651 36 2
- 172 E1
- 51 4 66
- 172 E2
- 89 127 762
- 174
- 246 2495 2781
- 175
- 55 15 125
- 176
- 533 612 775
- 177
- 3220 84 322
- 28
- 4560 1840 707
- 29
- 5240 1480 195
- 30
- 4520 >10,000 5870
- 31
- >10,000 >10,000 >10,000
- 80
- 9170 >10,000 >10,000
- 79
- 768 270 884
- 101
- 96 529 268
- 102
- 195 586 420
- 100
- 1500 6630 3410
- 103
- 3540 5090 7740
- 81
- 2720 2190 3640
- 88
- 829 171 93
- 89
- 278 63 9
- 32
- 949 902 424
- 87
- 1470 334 139
- 82
- 55 9990 42
- 83
- 57 61 57
- 33
- 305 232 83
- 98
- >10,000 782 419
- 105
- 1530 28 625
- 107
- 224 146 546
- 104
- 9490 516 5160
- 106
- 8330 816 1770
148 149 150 151 152 153 154 155
- 34
- >10,000 6690 5320
- 35
- >10,000 2970 4710
- 36
- 6550 1630 >10,000
- 37
- >10,000 5760 >10,000
- 84
- 1870 326 395
- 85
- 102 51 26
- 96
- 688 137 170
- 97
- 31 10 11
- 95
- 480 160 324
- 91
- >10,000 8550 1830
- 90
- 839 1850 3360
- 92
- 33 206 125
- 93
- 34 295 90
- 94
- 3 7 3
- 99
- 145 26 17
- 86
- 249 346 384
- 133 E1
- 969 217 355
- 133 E2
- 342 374 886
- 134 E1
- 260 179 598
- 134 E2
- 1260 132 149
- 173
- 1550 277 412
- 1
- 1290 175 103
- 41
- 898 22 82
- 165 E1
- 1580 183 66
- 165 E2
- 661 620 978
- 166 E1
- 176 310 245
- 166 E2
- 90 32 99
- 173 E1
- 1660 1350 388
- 173 E2
- 406 174 280
- 2
- 543 316 69
- 169 E2
- 332 22 87
- 169 E1
- 1100 242 778
- 152 E1
- 405 32 18
- 152 E2
- 77 157 585
- 153 E1
- 17 19 85
- 153 E2
- 64 135 25
- 42
- 935 280 761
- cis 121 E1
- >10,000 2060 3390
- cis 121 E2
- 3160 6580 >10,000
- trans 121 E1
- 247 303 687
- trans 121 E2
- 8150 392 665
- 2 E1
- 406 167 180
- 2E2
- 821 1040 770
- 108
- 65 36 85
- 43
- 15 7 64
- 3
- 331 888 <1
- 109
- 9674 114 12
- 4
- 637 2783 75
- 110
- 7932 790 2
- 111
- 8571 232 1.7
- 112
- 299 39 <1
- 298
- >10,000 6730 76
- 184 E1
- >10,000 2977 213
- 184 E2
- >10,000 3385 789
- 187 E1
- 1896 1095 209
- 187 E2
- 376 928 17
- 116
- 2060 633 3
- 117
- 7903 405 33
- 115
- >10,000 41 <1
- 114
- >10,000 1813 16
- 113
- 2574 2217 285
- 185 E1
- >10,000 >10,000 421
- 185 E2
- >10,000 >10,000 121
- 190 E1
- 2962 442 24
- 190 E2
- 44 17 3 120 340 45
- 191 E1
- 2532 747 42
- 191 E2
- 426 74 2
- 45
- 5936 964 9
- 46
- >10,000 >10,000 349
- 188 E1
- 4479 10000 426
- 188 E2
- >10,000 5287 66
- 44 E1
- 12 10 36 14 2.2 150
- cis 167
- >10,000 >10,000 2217
- trans 167
- 4912 1092 145
- 168
- 1465 732 108
- 253
- 906 949 37
- 254
- 294 19 <1 190 2.4 100
- 71
- 1298 1342 123
- 72
- 136 63 1.7
- 299
- 3873 2377 720
- 44 E2
- 239 570 219 210 44 1800
- 5
- 7115 5004 1522
- 287
- 1037 335 192
- 255
- 1421 2472 170
- 256
- 69 39 157 280 130 990
- 288
- 84 18 22 67 11 370
- 47
- 364 2894 5171
- 48 E2
- 149 441 297 230 74 550
- 48 E1
- 81 57 30 54 5.1 170
- 257
- 2075 6546 1999
- 259
- 5892 1179 665
- 6
- >10,000 >10,000 1000
- 7
- 255 3987 527
- 260
- 2146 1772 306
- 261
- 30 62 7
- 262
- >10,000 >10,000 4283
- 263
- 674 187 498
- 8
- 855 8733 996
- 9
- >10,000 9987 >10,000
- 49
- 286 9217 739
- 10
- 1905 7446 2928
- 264
- 1052 194 17
- 11
- 7549 2811 532
- 265
- 109 3464 1454
- 266
- 168 2811 859
- 12
- 1517 5761 6043 1100 480 1900
- 57
- 1079 3177 1777 2200 740 2300
- 51
- 2948 >10,000 >10,000
- 50
- 1069 950 499
- cis 124
- 6857 5934 5313
- trans 124 E1
- 2489 842 1475
- trans 124 E2
- 227 288 187
- 14
- 2953 257 46
- 267
- 1290 3256 147
- 268
- 704 241 27
- 269
- 787 36 <1
- 300
- >10,000 7625 1733
- 301
- >10,000 >10,000 8785
- cis 125
- 684 399 871
- trans 125 E1
- 6 158 1408
- trans 125 E2
- 32 783 1113
- 52
- 44 1063 176
- 13
- 377 324 122
- 194
- 330 1832 2369
- 196
- 1445 732 911
- 197
- 227 67 450
- 192
- >10,000 > 10,000 1957
- 200
- 2051 3742 1100
- 201
- 261 518 88
- 204
- 2253 3457 296
- 205 E1
- 4208 999 800
- 205 E2
- 1714 326 12
- cis 132i
- 708 5555 153
- trans 132i
- 28 353 140
- 15
- 1398 >10,000 >10,000
- 206 E1
- 72 121 59
- 206 E2
- 306 7 <1
- 147 E1
- 94 5764 1391 18 370 1200
- 147 E2
- 2500 9706 1344 1700 1200 1500
- 148 E1
- 97 538 464 36 81 250
- 148 E2
- 229 1136 289 330 4900 680
- 53
- <1 20 1 6.5 2.9 6.1
- 54
- 2387 857 85
- 55
- <1 61 72
- 163 E1
- 43 2793 413 260 4200 1100
- 163 E2
- 139 2650 309 1900 3200 1500
- 164 E1
- 2 152 36 9.6 500 230
- 164 E2
- 13 194 40 45 720 140
- 195 E2
- 45 > 10,000 5320
- 270
- 469 515 376
- 271
- 79 42 197
- 289
- 469 1467 282
- 290
- 992 > 10,000 1388
- 17
- 657 119 29
- 16
- 1764 4034 4085
- 13 E1
- 187 528 66
- 18
- 3892 794 184
- 19
- 107 3177 2316
- 13 E2
- 60 779 108
- 56 E1
- <1 21 28 2.9 2.3 24
- 56 E2
- 63 468 145 120 79 100
- 272
- >10,000 9572 2601
- 273
- 830 474 528
- 274
- 809 321 251
- 275
- 1187 943 518
- 276
- 210 55 71 360 17 190
- 277
- 34 13 41 42 2.7 43
- 58 E1
- 6 23 63 9.5 3.6 22
- 58 E2
- 118 341 176 100 33 160
- 140 E1
- 2688 >10,000 8819
- 140 E2
- >10,000 >10,000 5667
- 139 E1
- >10,000 >10,000 >10,000
- 139 E2
- >10,000 >10,000 >10,000
- 20
- 24 5847 275
- 20 E1
- 40 6439 369
- 20 E2
- 60 >10,000 437
- 21
- 2095 7192 43
- 207
- 142 3602 1025
- 209
- 1158 >10,000 4758
- 222
- 609 5347 2090
- 225
- 7 23 167
- 223
- 73 145 874
- 22
- 296 3727 141
- 155 E1
- 2986 >10,000 >10,000
- 155 E2
- 6281 >10,000 >10,000
- 136 E1
- >10,000 6497 2871
- 136 E2
- >10,000 >10,000 3375
- 138 E1
- >10,000 1341 918
- 138 E2
- 6996 3946 2539
- 21 E1
- 9661 7606 234
- 21 E2
- 1235 6041 64
- 193 E2
- 957 >10,000 3163
- 193 E1
- 416 897 266
- 198
- 2324 >10,000 1940
- 202
- 868 1625 58
- 199
- 2188 2585 462
- 203
- 56 166 1.4
- 156 E1
- 76 >10,000 1310
- 156 E2
- 653 >10,000 3996
- 226
- 44 737 278
- 23
- 62 7678 682
- 22 E1
- 63 2624 136
- 22 E2
- 101 5566 112
- 208
- 1987 >10,000 7667
- 227
- 742 4103 5778
- 228
- 96 387 1565
- 229
- 11 33 40
- 224
- 69 665 993
- 154 E1
- 2170 3679 795
- 154 E2
- 439 981 888
- 16 E1
- 1755 1291 1286
- 16 E2
- 7296 1910 9248
- 211
- 55 1274 195
- 230
- 30 104 11
- 231 E1
- 1276 136 460
- 231 E2
- 63 19 83
- 291
- 185 784 72
- 212
- 91 948 75
- 213
- 283 2031 337
- 17 E1
- 355 66 71
- 17 E2
- 709 93 5
- 60 E1
- 184 86 748
- 60 E2
- 4632 3304 6740
- 61 E1
- 5947 1504 959
- 59 E2
- 4396 2197 3875
- 59 E1
- 1589 486 1754
- 61 E2
- 9442 1555 116
- 293
- 42 33 4
- 232
- 744 904 25
- 233
- 37 64 3
- 62 E1
- 3176 414 39
- 62 E2
- 4241 121 4
- 19 E1
- 1514 1901 696
- 19 E2
- 398 4027 735
- 234 E1
- 3382 820 346
- 234 E2
- 18 33 21
- 63 E2
- 2 1110 1818
- 64 E1
- 58 2797 >10,000
- 64 E2
- 32 2647 3640
- 63 E1
- 194 5946 6537
- 235
- 9 256 92
- 292
- 360 903 89
- 236
- 38 718 444
- 38
- 472 >10,000 9647
- 65
- 1618 3644 1936
- 66
- 221 587 355
- 278
- 5143 >10,000 3193
- 279
- 383 2477 1449
- 280
- 7 371 242
- 25
- 78 1029 90
- 26
- 740 2102 238
- 214
- >10,000 10000 >10,000
- 237
- 7296 > 10000 9129
- 238
- 1178 3533 5715
- 215
- 4192 >10000 6243
- 239
- 8661 7372 9451
- 240
- 1812 3694 9029
- 39
- 295 6644 2237
- 67
- 230 3149 1761
- 68
- 19 603 343
- 294
- >10,000 >10,000 >10,000
- 281
- 256 788 384
- 282
- 296 289 186
- 283
- 20 41 37
- 216
- >10,000 >10,000 >10,000
- 241
- >10,000 >10,000 >10,000
- 242
- 7656 >10,000 >10,000
- 295
- >10,000 >10,000 >10,000
- 217
- 47 1838 1975
- 243
- 26 293 851
- 244
- 14 59 334
- 24
- 364 6380 1370
- 141 E1
- 3687 2229 1252
- 141 E2
- 2771 10000 3665
- 142 E1
- 1898 >10,000 5247
- 142 E2
- 2315 >10,000 7852
- 218
- 480 >10,000 5587
- 245
- 538 10000 2274
- 246
- 43 984 282
- 40
- 753 7668 2324
- 69
- 930 2290 605
- 70
- 29 261 214
- 157 E1
- 1303 3725 575
- 157 E2
- 290 3446 849
- 158 E1
- 8439 7497 945
- 158 E2
- 2991 >10,000 5023
- 145 E1
- 75 10000 4726
- 145 E2
- 220 >10,000 6520
- 146 E1
- 4545 >10,000 >10,000
- 146 E2
- 2284 >10,000 >10,000
- 219
- 269 >10,000 >10,000
- 247
- 707 9690 10000
- 248
- 159 5689 7252
- 220
- 6150 10000 >10,000
- 249
- 405 >10,000 >10,000
- 250
- 47 1669 10000
- 284
- 7896 6662 2462
- 285
- 1139 4038 1897
- 286
- 46 182 198
- 162 E2
- 247 >10,000 >10,000
- 162 E1
- 495 >10,000 >10,000
- 161 E2
- 1.1 4395 4609
- 161 E1
- 9 8626 9950
- 221
- 61 5825 182
- 251
- 199 2131 107
- 252
- 11 108 6
- 252
- 12 134 5
- 143 E1
- 8611 >10,000 8787
- 143 E2
- 7172 >10,000 8630
- 144 E1
- 5626 >10,000 10000
- 144 E2
- 8748 >10,000 9858
- 159 E1
- 1255 >10,000 3801
- 159 E2
- 42 10000 2310
- 160 E1
- 7193 >10,000 9725
- 160 E2
- 5091 >10,000 >10,000
- 296
- 73 87 27
- 297
- 40 57 13
En la Tabla 8, los números de los compuestos corresponden a los utilizados en los Ejemplos anteriores. Además, las siguientes abreviaturas se han utilizado en la Tabla I: SERT (transportador de serotonina), NET (transportador de norepinefrina) y DAT (transportador de dopamina).
156
Se generó un valor para el enlazamiento específico (dpm) restando la media de enlazamiento no específico (dpm) de la media de enlazamiento total (dpm) para cada animal. Los datos se presentan como media de enlazamiento específico (dpm) y como un porcentaje del control tratado con vehículo tomado como 100%.
7.4. Resumen de los resultados
Los datos de ocupación de enlazamiento/receptor de SERT, NET y DAT Ex vivo se generaron para los compuestos seleccionados de la invención. Los resultados se resumen en la Tabla 9, a continuación. Los resultados mostraron que los compuestos exhiben relaciones variables de inhibición de SERT, NET y DAT.
Tabla 9: Perfil de enlazamiento ex vivo en ratones.
- Dosis de Tratamiento (mg/kg, PO)
- Media de enlazamiento específica (dpm) ± S.E.M. (Los valores entre paréntesis denotan el % de ocupación del transportador)
- NET
- SERT DAT
- 225
- 0 1 3 1570 ± 31 1170 ± 68 (25)* 813 ± 64 (48)* 4639 ± 294 3842 ± 152 (17)* 2118 ± 139 (54)* 20453 ± 2500 19787 ± 3338 (3) 21666 ± 3698 (–6)
- 10 30
- 393 ± 21 (75)* 230 ± 33 (85)* 904 ± 35 (81)* 414 ± 37 (91)* 18872 ± 2775 (8) 14618 ± 1209 (29)
- 48 E1
- 0 2405 ± 150 4345 ± 123 20378 ± 1315
- 1
- 2111 ± 119 (12) 4398 ± 39 (–1) 20656 ± 1531 (–1)
- 3
- 1911 ± 144 (21)* 3957 ± 224 (9) 18039 ± 1265 (11)
- 10
- 954 ± 115 (60)* 2796 ± 100 (36)* 9792 ± 977 (52)*
- 30
- 346 ± 55 (86)* 1003 ± 104 (77)* 3173 ± 541 (84)*
- 276
- 0 1541 ± 87 4269 ± 299 15011 ± 2450
- 1
- 1602 ± 51 (–4) 3743 ± 199 (12) 18155 ± 2275 (–21)
- 3
- 1631 ± 92 (–6) 3685 ± 292 (14) 16312 ± 2396 (–9)
- 10
- 1553 ± 27 (–1) 3092 ± 207 (28)* 15879 ± 2265 (–6)
- 30
- 1138 ± 59 (26)* 1558 ± 169 (64)* 10397 ± 931 (31)
- 58 E1
- 0 1763 ± 45 3410 ± 200 16873 ± 1162
- 1
- 1705 ± 71 (3) 3245 ± 107 (5) 15732 ± 1360 (7)
- 3
- 1748 ± 56 (1) 3021 ± 182 (11) 14938 ± 2613 (11)
- 10
- 1262 ± 79 (28)* 1799 ± 115 (47)* 17215 ± 2151 (–2)
- 30
- 502 ± 36 (71)* 469 643 (86)* 12876 ± 2152 (24)
- 153 E2
- 0 1915 ± 57 3223 ± 109 20775 ± 1607
- 1
- 1804 ± 79 (6) 3271 ± 199 (–1) 22774 ± 916 (–10)
- 3
- 1726 ± 44 (10) 2968 ± 100 (8) 24159 ± 1313 (–16)
- 10
- 1734 ± 62 (9) 2327 ± 150 (28)* 22015 ± 1912 (–6)
- 30
- 1140 ± 53 (40)* 1359 ± 89 (58)* 16194 ± 1293 (22)
- 164 E1
- 0 1040 ± 76 3504 ± 223 21321 ± 1994
- 1
- 1122 ± 58 (–8) 2796 ± 133 (20)* 23574 ± 1313 (–11)
- 3
- 1046 ± 23 (–1) 2273 ± 74 (35)* 18002 ± 1516 (16)
- 10
- 903 ± 48 (13) 783 ± 61 (78)* 17727 ± 2871 (17)
- 30
- 610 ± 59 (41) 271 ± 50 (92)* 15630 ± 1085 (27)
- 56 E1
- 0 767 ± 34 3326 ± 78 43705 ± 2192
- 1
- 616 ± 50 (20)* 2625 ± 138 (19)* 41561 ± 1611 (5)
- 3
- 368 ± 17 (52)* 1346 ± 109 (58)* 42127 ± 2130 (4)
- 10
- 106 ± 20 (86)* 278 ± 42 (91)* 33478 ± 1779 (23)*
- 30
- 19 ± 2 (98)* 151 ± 60 (95)* 14637 ± 1567 (67)*
158
Los datos fueron analizados por análisis de varianza de una sola vía (ANOVA) seguido de comparaciones post–hoc en su caso. Un efecto se consideró significativo si p <0.05. Los datos se representan como la media y el error estándar de la media (s.e.m.).
5 Los compuestos seleccionados de la invención se evaluaron en la prueba de actividad locomotora y de suspensión por la cola del ratón (Tabla 10). Los resultados mostraron que todos los compuestos probados mostraron un perfil antidepresivo (es decir, disminuyó significativamente el tiempo de inmovilidad) con MED en el rango de 3–30 mg/kg, PO. A dosis activas en la prueba de suspensión por la cola, no se observó cambio o disminución de la actividad motora de línea de base indicando que la actividad de tipo antidepresivo no se debía a un efecto general
10 estimulante.
Los compuestos seleccionados de la invención también se evaluaron en las pruebas de nado forzado de la rata y actividad locomotora (Tabla 11). Todos los compuestos probados mostraron efectos de tipo antidepresivo con MED en el rango de 10–30 mg/kg, PO. La disminución en la inmovilidad producida por estos compuestos parecía ser debido a los incrementos en el comportamiento de la natación y la escalada indicativos de la actividad de transporte
15 mixto (esto es, perfiles de IRSN). En conclusión, los compuestos probados de la invención exhibieron un perfil antidepresivo en al menos tres modelos animales, la prueba de suspensión por la cola de ratón y la prueba de actividad locomotora de la rata, así como la prueba de natación forzada de la rata.
Tabla 10: Resultados de suspensión por la cola del ratón y actividad locomotora
- Dosis de tratamiento (mg/kg, PO)
- Suspensión por la cola del ratón Actividad locomotora del ratón
- Tiempo medio de inmovilidad ± S.E.M.
- Distancia Total recorrida ± S.E.M.
- 153 E2
- 0 3 10 30 200.1 ± 5.8 195.4 ± 7.7 170.2 ± 6.3 * 154.5 ± 8.4 * 537.2 ± 67.2 625.5 ± 88.8 519.5 ± 88.4 573.7 ± 63.6
- 44 E1
- 0 3 10 30 198.3 ± 7.6 188.9 ± 7.3 174.5 ± 8.1 120.4 ± 9.0 * 660.0 ± 51.6 576.5 ± 66.9 721.1 ± 36.5 402.3 ± 71.0 *
- 93
- 0 3 10 30 204.6 ± 5.6 203.5 ± 8.0 185.4 ± 7.9 162.0 ± 8.1 * 494.0 ± 64.1 644.0 ± 55.7 606.9 ± 72.4 737.6 ± 89.5
- 48 E1
- 0 3 10 30 199.9 ± 6.7 189.8 ± 7.2 174.1 ± 5.8 * 134.5 ± 9.6 * 647.7 ± 42.6 622.5 ± 101.6 620.0 ± 79.4 468.6 ± 114.2
- 134 E2
- 0 3 10 30 200.0 ± 6.7 191.4 ± 6.2 170.8 ± 6.0 * 137.2 ± 7.2 * 782.8 ± 94.2 862.7 ± 100.4 671.6 ± 63.3 728.2 ± 107.7
- 75
- 0 3 10 30 194.2 ± 6.0 187.8 ± 9.6 177.7 ± 5.8 143.5 ± 5.8 * 659.4 ± 63.1 653.5 ± 48.4 608.8 ± 83.4 655.3 ± 117.7
- 148 E1
- 0 3 10 30 207.6 ± 7.8 193.7 ± 6.0 189.3 ± 5.9 174.5 ± 5.0 * 445.7 ± 71.5 584.8 ± 65.7 486.3 ± 74.3 559.6 ± 88.2
- 225
- 0 195.1 ± 4.1 735.2 ± 54.5
160 161
- 0.3 1 3
- 188.1 ± 8.0 186.5 ± 5.2 158.5 ± 4.9 * 519.5 ± 56.4 * 423.4 ± 62.3 * 415.9 ± 61.6 *
- 225
- 0 192.5 ± 6.3 336.6 ± 77.5
- 3
- 155.2 ± 6.0 * 341.8 ± 78.3
- 10
- 137.8 ± 5.2 * 234.2 ± 49.4
- 30
- 136.3 ± 2.5 * 177.4 ± 47.8
- 164 E1
- 0 197.3 ± 7.0 509.4 ± 92.7
- 3
- 183.8 ± 6.5 377.8 ± 67.6
- 10
- 162.1 ± 4.6 * 210.3 ± 40.4 *
- 30
- 155.3 ± 7.8 * 494.0 ± 84.9
- 56 E1
- 0 203.6 ± 4.5 439.6 ± 63.5
- 3
- 184.0 ± 4.8 410.2 ± 89.3
- 10
- 174.8 ± 6.1 * 440.2 ± 62.6
- 30
- 141.9 ± 7.4 * 252.2 ± 55.8
- 277
- 0 199.8 ± 6.1 378.9 ± 45.2
- 3
- 182.3 ± 8.1 418.8 ± 80.6
- 10
- 164.4 ± 6.8 * 411.8 ± 87.8
- 30
- 147.1 ± 3.1 * 327.7 ± 67.1
- 276
- 0 202.7 ± 6.3 565.9 ± 104.3
- 3
- 182.0 ± 4.2 625.9 ± 47.5
- 10
- 164.1 ± 5.7 * 382.4 ± 63.4
- 30
- 160.2 ± 7.2 * 607.8 ± 57.8
- 164 E2
- 0 184.6 ± 10.1 520.4 ± 103.8
- 3
- 181.8 ± 6.3 518.2 ± 106.1
- 10
- 179.1 ± 4.5 464.5 ± 86.2
- 30
- 141.8 ± 6.0 * 669.9 ± 75.6
- 17 E1
- 0 197.3 ± 5.6 463.0 ± 73.4
- 3
- 184.7 ± 9.0 649.3 ± 78.4
- 10
- 182.6 ± 4.1 478.3 ± 88.5
- 30
- 150.9 ± 7.8 * 428.3 ± 120.6
- * p<0.05, vs. vehículo (0); ANOVA de una vía
Tabla 11: Resultados de natación forzada de la rata y actividad locomotora
- Dosis de tratamiento (mg/kg,
- Natación forzada de la rata (Media ± S.E.M.) Actividad Locomotora de la rata
- PO)
- Inmovilidad Nado Escalada Distancia Total recorrida ± S.E.M.
- 48 E1
- 0 3 10 30 48.0 ± 2.1 49.6 ± 1.5 35.6 ± 3.5* 26.9 ± 4.4* 4.8 ± 1.2 3.7 ± 1.0 6.5 ± 1.6 9.7 ± 1.7* 7.0 ± 1.5 7.1 ± 0.6 17.9 ± 2.5* 20.6 ± 2.9 * 1480.0 ± 67.4 1869.9 ± 188.4 1825.3 ± 109.3 1840.6 ± 56.6
- 153 E2
- 0 3 10 30 50.8 ± 1.8 49.9 ± 1.7 44.0 ± 2.1 31.3 ± 6.7* 1.0 ± 0.3 1.9 ± 0.8 4.3 ± 1.1* 4.6 ± 1.3* 8.2 ± 1.8 8.8 ± 1.5 11.7 ± 1.8 22.2 ± 5.2* 1685.1 ± 106.8 1577.8 ± 80.1 1994.2 ± 263.9 2033.7 ± 215.4
- 93
- 0 3 10 30 48.5 ± 1.4 44.5 ± 2.5 41.4 ± 2.8 25.8 ± 5.4* 3.7 ± 0.7 6.5 ± 1.6 6.9 ± 1.3 12.0 ± 2.1* 7.8 ± 1.1 9.0 ± 1.3 12.8 ± 2.2 22.2 ± 3.5* 1682.2 ± 66.8 1802.6 ± 150.6 1641.0 ± 144.5 2095.6 ± 147.2
- 277
- 0 3 10 30 46.5 ± 2.9 50.4 ± 1.1 42.5 ± 2.6 14.6 ± 3.5* 1.2 ± 0.6 0.8 ± 0.3 3.7 ± 0.9* 6.1 ± 1.4* 12.1 ± 2.7 9.0 ± 1.2 13.8 ± 2.3 35.6 ± 5.2* 1586.0 ± 191.3 1406.2 ± 84.9 1861.4 ± 187.8 2612.4 ± 210.8*
- 225
- 0 3 52.4 ± 1.8 50.8 ± 1.8 0.8 ± 0.4 .0.8 ± 0.3 6.8 ± 1.8 8.4 ± 1.7 1610.3 ± 101.1 1783.4 ± 182.7
- 10 30
- 47.6 ± 3.0 33.4 ± 4.8* 1.2 ± 0.6 1.1 ± 0.5 11.1 ± 2.7 25.0 ± 4.6* 1628.5 ± 159.2 2182.8 ± 151.2*
- 56 E1
- 0 3 10 30 53.8 ± 0.6 52.2 ± 1.6 50.7 ± 1.0 40.4 ± 2.7* 0.4 ± 0.2 0.3 ± 0.2 0.8 ± 0.3 1.0 ± 0.4 5.8 ± 0.7 7.1 ± 1.6 8.6 ± 0.9 17.9 ± 2.4* 1272.6 ± 113.2 1227.9 ± 84.4 1230.8 ± 64.8 1359.8 ± 132.7
- * p<0.05, vs. vehículo (0); ANOVA de una vía
La presente invención no está limitada en el alcance por las realizaciones específicas divulgadas en los ejemplos los cuales se pretenden como ilustraciones de unos pocos aspectos de la invención y cualesquier realizaciones que son funcionalmente equivalentes están dentro del alcance de esta invención. De hecho, diversas modificaciones de la invención además de las mostradas y descritas aquí serán evidentes para los expertos en la técnica y se pretende que caigan dentro del alcance de las reivindicaciones adjuntas.
162
Claims (5)
-
imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 imagen8 imagen9 imagen10 o forma enantioméricamente pura farmacéuticamente aceptable del mismo. - 19. El compuesto de la reivindicación 1, en donde el compuesto es: o una sal, enantiómero, diastereómero, mezcla racémica, mezcla enriquecida enantioméricamente
imagen11 o forma enantioméricamente pura farmacéuticamente aceptable del mismo. - 20. El compuesto de la reivindicación 1, en donde el compuesto es: o una sal, enantiómero, diastereómero, mezcla racémica, mezcla enriquecida enantioméricamente
imagen12 o forma enantioméricamente pura farmacéuticamente aceptable del mismo. - 21. El compuesto de la reivindicación 1, en donde el compuesto es: o una sal, enantiómero, diastereómero, mezcla racémica, mezcla enriquecida enantioméricamente
imagen13 15 o forma enantioméricamente pura farmacéuticamente aceptable del mismo. - 22. El compuesto de la reivindicación 1, en donde el compuesto es: o una sal, enantiómero, diastereómero, mezcla racémica, mezcla enriquecida enantioméricamente172
imagen14 imagen15
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Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7488747B2 (en) | 2003-12-29 | 2009-02-10 | Sepracor Inc. | Pyrrole and pyrazole DAAO inhibitors |
MX2008000250A (es) | 2005-07-06 | 2008-03-19 | Sepracor Inc | Combinaciones de eszopiclona y trans-4-(3,4-diclorofenil)-1,2,3,4- tetrahidro-n-metil-1-naftalenamina o trans 4-(3,4-diclorofenil)-1, 2,3,4-tetrahidro-1-naftalenamina y metodos de tratamiento de menopausia y trastornos del estado de animo, ansiedad y |
CN101426372A (zh) * | 2006-01-06 | 2009-05-06 | 塞普拉柯公司 | 基于四氢萘酮的单胺再摄取抑制剂 |
CN101394847B (zh) | 2006-01-06 | 2017-05-24 | 塞普拉柯公司 | 作为单胺重摄取抑制剂的环烷基胺类 |
CA2648121C (en) | 2006-03-31 | 2013-08-06 | Sepracor Inc. | Preparation of chiral amides and amines |
AU2007236115A1 (en) | 2006-04-11 | 2007-10-18 | Novartis Ag | Organic compounds |
US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
US7579370B2 (en) * | 2006-06-30 | 2009-08-25 | Sepracor Inc. | Fused heterocycles |
AU2007296074B2 (en) | 2006-09-15 | 2012-07-12 | Reviva Pharmaceuticals, Inc. | Synthesis, methods of using, and compositions of cycloalkylmethylamines |
US20080082066A1 (en) * | 2006-10-02 | 2008-04-03 | Weyerhaeuser Co. | Crosslinked carboxyalkyl cellulose fibers having non-permanent and temporary crosslinks |
EP2124913A1 (en) * | 2006-12-22 | 2009-12-02 | Novartis AG | 1-aminomethyl- l- phenyl- cyclohexane derivatives as ddp-iv inhibitors |
MX2009007410A (es) * | 2007-01-18 | 2009-09-09 | Sepracor Inc | Inhibidores de d-aminoacido oxidasa. |
US7902252B2 (en) * | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
CN101686672A (zh) | 2007-05-31 | 2010-03-31 | 塞普拉柯公司 | 苯基取代的环烷胺作为一元胺再摄取抑制剂 |
US20100120740A1 (en) * | 2008-08-07 | 2010-05-13 | Sepracor Inc. | Prodrugs of fused heterocyclic inhibitors of d-amino acid oxidase |
US8389559B2 (en) * | 2009-02-09 | 2013-03-05 | Sunovion Pharmaceuticals Inc. | Pyrrolidine triple reuptake inhibitors |
US20110021928A1 (en) * | 2009-07-23 | 2011-01-27 | The Boards Of Trustees Of The Leland Stanford Junior University | Methods and system of determining cardio-respiratory parameters |
US20110034434A1 (en) * | 2009-08-07 | 2011-02-10 | Sepracor Inc. | Prodrugs of fused heterocyclic inhibitors of d-amino acid oxidase |
SG186885A1 (en) | 2010-06-04 | 2013-02-28 | Albany Molecular Res Inc | Glycine transporter-1 inhibitors, methods of making them, and uses thereof |
WO2012003501A2 (en) | 2010-07-02 | 2012-01-05 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using cycloalkylmethylamine derivatives |
WO2012142067A2 (en) * | 2011-04-13 | 2012-10-18 | Sunovion Pharmaceuticals Inc. | Formulations, salts, and solid forms of substituted cyclohexylmethanamines, processes for preparation, and uses thereof |
MX352874B (es) | 2011-12-30 | 2017-12-13 | Reviva Pharmaceuticals Inc | Composiciones, sintesis, y metodos para usar derivados de fenilcicloalquilmetilamina. |
UY35338A (es) | 2013-02-21 | 2014-08-29 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Compuestos bicíclicos moduladores de la actividad de s1p1 y composiciones farmacéuticas que los contienen |
WO2014141110A2 (en) * | 2013-03-14 | 2014-09-18 | Curadev Pharma Pvt. Ltd. | Aminonitriles as kynurenine pathway inhibitors |
US20150057443A1 (en) * | 2013-08-21 | 2015-02-26 | Prexa Pharmaceuticals, Inc. | Cycloalkyl Amine Compounds |
US9840482B2 (en) * | 2014-04-19 | 2017-12-12 | Sunshine Lake Pharma Co., Ltd. | Sulfonamide derivatives and pharmaceutical applications thereof |
TWI689487B (zh) | 2014-08-20 | 2020-04-01 | 美商必治妥美雅史谷比公司 | 經取代雙環化合物 |
CN104387279B (zh) * | 2014-10-29 | 2016-04-06 | 河南师范大学 | 一种简便合成3,3-二氟环己基甲胺的方法 |
RU2637928C2 (ru) * | 2016-02-08 | 2017-12-08 | Закрытое Акционерное Общество "Вертекс" | Производные арилциклоалкиламинов, нейропротектор (варианты), вещество, обладающее сочетанным нейропротекторным, анальгетическим и антидепрессивным действием, фармацевтические композиции на его основе |
CN110343050B (zh) * | 2018-04-04 | 2021-09-24 | 上海键合医药科技有限公司 | 芳香类化合物及其制备方法和用途 |
EP3950664A4 (en) * | 2019-10-29 | 2022-05-11 | API Corporation | HIGH PURITY 2-NAPHTYLACETONITRILE AND METHOD FOR PRODUCING IT |
WO2023069455A1 (en) * | 2021-10-19 | 2023-04-27 | Kirkland Justin | Mesembrine derivatives |
Family Cites Families (148)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE112485C (es) | ||||
BE616646A (es) | ||||
US1124485A (en) * | 1913-07-08 | 1915-01-12 | Standard Knitting Mills Company | Undergarment. |
DE1124485B (de) * | 1960-02-12 | 1962-03-01 | Hoechst Ag | Verfahren zur Herstellung von analeptisch wirksamen Phenylcycloalkylmethylaminen |
DE1518545A1 (de) * | 1965-04-01 | 1970-01-15 | Boehringer Mannheim Gmbh | Verfahren zur Herstellung neuer Phenylcyclohexylalkylamine und ihrer Salze |
SE7600674L (sv) | 1975-02-05 | 1976-08-06 | Rohm & Haas | Fungicider |
US4105762A (en) | 1975-02-05 | 1978-08-08 | Rohm And Haas Company | Metal salt complexes of 1-substituted aralkyl imidazoles, and methods and compositions for controlling phytopathogenic fungi using them |
US4065573A (en) * | 1976-06-03 | 1977-12-27 | The Upjohn Company | 4-Amino-4-phenylcyclohexanone ketal compositions and process of use |
JPS6033106B2 (ja) | 1977-10-07 | 1985-08-01 | 住友化学工業株式会社 | カルボン酸エステル、その製造法およびそれを有効成分とする殺虫、殺ダニ剤 |
US4369184A (en) * | 1980-01-24 | 1983-01-18 | Janssen Pharmaceutica N.V. | 1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives |
ZA817261B (en) | 1980-10-23 | 1982-09-29 | Schering Corp | Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them |
US4540690A (en) | 1982-02-09 | 1985-09-10 | The Upjohn Company | 2-(Phenylmethylene)cycloalkylamines and -azetidines |
JPS58177915A (ja) | 1982-04-12 | 1983-10-18 | Green Cross Corp:The | 抗血栓剤 |
EP0100426A1 (en) * | 1982-07-28 | 1984-02-15 | American Cyanamid Company | 3a-(substituted-phenyl)-hexaloctahydro-4,7-alkanoisoindoles |
WO1986000896A1 (en) | 1984-07-30 | 1986-02-13 | Schering Corporation | NOVEL PROCESS FOR THE PREPARATION OF CIS, ENDOOCTAHYDROCYCLOPENTA ADb BDPYRROLE-2-CARBOXYLATE |
DE3431541A1 (de) | 1984-08-28 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | Cis,endo-2-azabicycloalkan-3-carbonsaeure-derivate, verfahren zu deren herstellung, deren verwendung sowie zwischenprodukte bei deren herstellung |
US4738709A (en) | 1985-01-10 | 1988-04-19 | Ppg Industries, Inc. | Herbicidally active substituted benzisoxazoles |
US5015644A (en) * | 1987-06-02 | 1991-05-14 | Warner-Lambert Company | Antihyperlipidemic and antiatherosclerotic urea and carbamate compounds |
JPS6416786A (en) | 1987-07-09 | 1989-01-20 | Sumitomo Chemical Co | Thienopyrrolopyrroles and preparation thereof |
US4751231A (en) | 1987-09-16 | 1988-06-14 | Merck & Co., Inc. | Substituted thieno[2,3-b]pyrrole-5-sulfonamides as antiglaucoma agents |
JPH01172388A (ja) | 1987-12-25 | 1989-07-07 | Sumitomo Chem Co Ltd | チエノ〔3,2−b〕ピロロ〔2,3−d〕ピロール類およびその製法 |
ES2051927T3 (es) * | 1988-06-14 | 1994-07-01 | Searle & Co | 1,2-diariletilaminas para el tratamiento de daños neurotoxicos. |
US4981870A (en) | 1989-03-07 | 1991-01-01 | Pfizer Inc. | Use of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives in the treatment of psychosis, inflammation and as immunosuppressants |
PT93943A (pt) | 1989-05-05 | 1991-02-08 | Searle & Co | Processo para a preparacao de composicoes contendo compostos indole-2-carboxilato para tratamento de perturbacoes do snc |
WO1990015047A1 (en) | 1989-05-31 | 1990-12-13 | The Upjohn Company | Therapeutically useful 2-aminotetralin derivatives |
JPH0477476A (ja) | 1990-07-19 | 1992-03-11 | Sankyo Co Ltd | 抗潰瘍剤 |
US5086054A (en) | 1990-07-31 | 1992-02-04 | Sri International | Novel arylcycloalkanepolyalkylamines |
SK279958B6 (sk) * | 1992-04-02 | 1999-06-11 | Smithkline Beecham Corporation | Zlúčeniny s protialergickým a protizápalovým účink |
GB9208492D0 (en) | 1992-04-16 | 1992-06-03 | Glaxo Spa | Heterocyclic compounds |
WO1994010158A1 (en) | 1992-10-28 | 1994-05-11 | Toyama Chemical Co., Ltd. | Novel 1,2-benzisoxazole derivative or salt thereof, and brain protective agent comprising the same |
GB9304500D0 (en) | 1993-03-05 | 1993-04-21 | Glaxo Spa | Heterocyclic compounds |
ES2081747B1 (es) | 1993-09-07 | 1997-01-16 | Esteve Labor Dr | Amidas derivadas de tienopirroles, su preparacion y su aplicacion como medicamentos. |
GB9321221D0 (en) | 1993-10-14 | 1993-12-01 | Glaxo Spa | Heterocyclic compounds |
GB9326284D0 (en) | 1993-12-23 | 1994-02-23 | Erba Carlo Spa | Pyrrolydenemethyl-derivatives and process for their preparation |
CN1047384C (zh) | 1994-07-28 | 1999-12-15 | 北京大学 | 雷米普利的合成方法 |
KR970705549A (ko) | 1994-08-30 | 1997-10-09 | 가와무라 요시부미 | 이속사졸류(isoxazoles) |
US5484763A (en) | 1995-02-10 | 1996-01-16 | American Cyanamid Company | Substituted benzisoxazole and benzisothiazole herbicidal agents |
US5620997A (en) | 1995-05-31 | 1997-04-15 | Warner-Lambert Company | Isothiazolones |
US5859042A (en) | 1995-09-27 | 1999-01-12 | Ono Pharmaceutical Co., Ltd. | Five membered heterocyclic compounds |
BR9711342A (pt) * | 1996-08-22 | 1999-08-17 | Warner Lambert Co | Antagonistas de receptor de bombesina nÆo-pept¡do |
GB9619757D0 (en) | 1996-09-21 | 1996-11-06 | Knoll Ag | Chemical process |
GB9705428D0 (en) * | 1997-03-15 | 1997-04-30 | Knoll Ag | Therapeutic agents |
DE19711785A1 (de) | 1997-03-21 | 1998-09-24 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
EP0884640A1 (en) * | 1997-06-13 | 1998-12-16 | Eastman Kodak Company | Processing of photographic elements using N,N-dialkylhydroxylamine antioxidants in photographic color developers |
US6080760A (en) * | 1997-06-18 | 2000-06-27 | Merck & Co., Inc. | Alpha 1A adrenergic receptor antagonists |
GB9717804D0 (en) | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
AU9275498A (en) | 1997-10-03 | 1999-04-27 | Chirotech Technology Limited | Chiral amines |
GB9803226D0 (en) | 1998-02-17 | 1998-04-08 | Zeneca Ltd | Chemical compounds |
GB9803228D0 (en) | 1998-02-17 | 1998-04-08 | Zeneca Ltd | Chemical compounds |
WO1999048868A2 (en) | 1998-03-26 | 1999-09-30 | Sugen, Inc. | Heterocyclic classes of compounds for the modulating tyrosine protein kinase |
US6476078B2 (en) * | 1999-08-11 | 2002-11-05 | Sepracor, Inc. | Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction |
US6632836B1 (en) * | 1998-10-30 | 2003-10-14 | Merck & Co., Inc. | Carbocyclic potassium channel inhibitors |
US6828460B2 (en) | 1999-03-22 | 2004-12-07 | Pfizer Inc. | Resorcinol derivatives |
US20020058606A1 (en) * | 1999-05-10 | 2002-05-16 | Gonzalez Maria Isabel | Treatment of sexual dysfunction |
FR2795733B1 (fr) | 1999-06-30 | 2001-09-07 | Aventis Pharma Sa | Derives de streptogramines, leur preparation et les compositions qui les contiennent |
ATE257480T1 (de) | 1999-09-30 | 2004-01-15 | Pfizer Prod Inc | Bicyclische pyrrolylamide als glycogenphosphorylase-inhibitoren |
EP1391460A1 (en) | 1999-09-30 | 2004-02-25 | Pfizer Products Inc. | Tricyclic pyrrolyl amides as glycogen phosphorylase inhibitors |
CA2387016C (en) | 1999-10-08 | 2010-09-28 | William H. Miller | Acrylamide derivatives as fab i inhibitors |
DE19960917A1 (de) | 1999-12-17 | 2001-06-21 | Bayer Ag | Neue 3-Oxo-2,1-benzisoxazol-1(3H)-carboxamide zur Behandlung von ZNS-Erkrankungen |
JP2001247462A (ja) | 2000-03-07 | 2001-09-11 | Otsuka Pharmaceut Co Ltd | ウレアーゼ阻害剤 |
US6632417B2 (en) * | 2000-03-07 | 2003-10-14 | Chevron U.S.A. Inc. | Process for preparing zeolites |
EP1136071A3 (en) | 2000-03-22 | 2003-03-26 | Pfizer Products Inc. | Use of glycogen phosphorylase inhibitors |
US6632948B2 (en) | 2000-04-19 | 2003-10-14 | Kaneka Corporation | Azetidine derivative and process for preparation thereof |
GB0012214D0 (en) | 2000-05-19 | 2000-07-12 | Merck Sharp & Dohme | Therapeutic agents |
CN100491253C (zh) * | 2000-05-31 | 2009-05-27 | 切夫里昂美国公司 | Ssz-53沸石 |
US6395762B1 (en) * | 2000-07-17 | 2002-05-28 | American Home Products Corporation | Phenyl amino squarate and thiadiazole dioxide beta-3 adrenergic receptor agonists |
RU2272030C2 (ru) * | 2000-08-01 | 2006-03-20 | Оно Фармасьютикал Ко., Лтд. | Производные 3,4-дигидроизохинолина и фармацевтический агент, включающий его в качестве активного ингредиента |
JP2004505982A (ja) | 2000-08-04 | 2004-02-26 | イーライ・リリー・アンド・カンパニー | 新規なsPLA2インヒビター |
GB0021831D0 (en) | 2000-09-06 | 2000-10-18 | Astrazeneca Ab | Chemical compounds |
EP1318988A2 (en) * | 2000-09-11 | 2003-06-18 | Sepracor, Inc. | Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission) |
FR2814073B1 (fr) | 2000-09-21 | 2005-06-24 | Yang Ji Chemical Company Ltd | Composition pharmaceutique antifongique et/ou antiparasitaire et nouveaux derives de l'indole a titre de principes actifs d'une telle composition |
EP1330515A4 (en) | 2000-10-06 | 2005-12-07 | Affinium Pharm Inc | METHOD FOR AGONIZATION AND ANTAGONIZATION OF FABK |
TWI283575B (en) | 2000-10-31 | 2007-07-11 | Eisai Co Ltd | Medicinal compositions for concomitant use as anticancer agent |
IL155703A0 (en) * | 2000-11-17 | 2003-11-23 | Warner Lambert Co | Treatment of sexual dysfunction with non peptide bombesin receptor antagonists |
DE10063992A1 (de) | 2000-12-21 | 2002-07-04 | Max Planck Gesellschaft | Tryptophan-Analoga in Proteinen, Peptiden und peptidischen Leitstrukturen |
US6372919B1 (en) | 2001-01-11 | 2002-04-16 | Dov Pharmaceutical, Inc. | (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as an anti-depressant agent |
US20020123490A1 (en) | 2001-03-01 | 2002-09-05 | Pfizer Inc. | Combination treatment for anxiety, depression, obsessive compulsive disorder and psychosis |
DE10110051C2 (de) * | 2001-03-02 | 2003-07-03 | Clariant Gmbh | Verfahren zur Herstellung von Boron- und Borinsäuren |
WO2003000657A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
NZ529973A (en) * | 2001-06-27 | 2006-01-27 | Smithkline Beecham Corp | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
US6603000B2 (en) | 2001-07-11 | 2003-08-05 | Boehringer Ingelheim Pharmaceuticals, Inc. | Synthesis for heteroarylamine compounds |
US6464956B1 (en) | 2001-07-13 | 2002-10-15 | Chevron U.S.A. Inc. | Zeolite SSZ-59 composition of matter and synthesis thereof |
EP1415992B1 (en) | 2001-08-09 | 2012-05-02 | Daiichi Sankyo Company, Limited | Diamine derivatives |
US7045543B2 (en) | 2001-11-05 | 2006-05-16 | Enzrel Inc. | Covalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites |
US20030162825A1 (en) | 2001-11-09 | 2003-08-28 | Sepracor Inc. | D-amino acid oxidase inhibitors for learning and memory |
WO2003048113A1 (en) | 2001-11-30 | 2003-06-12 | Sepracor Inc. | Tramadol analogs and uses thereof |
TW200307539A (en) | 2002-02-01 | 2003-12-16 | Bristol Myers Squibb Co | Cycloalkyl inhibitors of potassium channel function |
DE10303638B4 (de) * | 2002-02-28 | 2018-10-04 | Merck Patent Gmbh | Axial substituiertes Cyclohexylenderivat und flüssigkristallines Medium |
GB0205170D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205165D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
US6995144B2 (en) | 2002-03-14 | 2006-02-07 | Eisai Co., Ltd. | Nitrogen containing heterocyclic compounds and medicines containing the same |
WO2003091213A1 (fr) | 2002-04-25 | 2003-11-06 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'amide ou sels de ces derives |
JP2005538047A (ja) * | 2002-05-03 | 2005-12-15 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | ボンベシンアンタゴニスト |
US7576204B2 (en) | 2002-07-31 | 2009-08-18 | Mercian Corporation | Heterocyclic macrolide pharmaceutical agent, a method of producing the same and use of the same |
PT1543011E (pt) | 2002-09-06 | 2006-08-31 | Janssen Pharmaceutica Nv | Composto de tienopirrolilo e furanopirrolilo e sua utilizacao como ligandos do receptor h4 da histamina |
AU2003272461A1 (en) | 2002-09-16 | 2004-04-30 | Sepracor Inc. | TREATMENT OF CNS DISORDERS WITH trans 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-N-METHYL-1-NAPTHALENAMINE |
MXPA05002700A (es) | 2002-09-16 | 2005-09-08 | Sepracor Inc | Tratamiento de trastornos del sistema nervioso central con trans 4-(3,4-diclorofenil)-1,2,3,4-tetrahidro-1-naftalenamina y su formamida. |
AU2003284005B2 (en) | 2002-10-03 | 2009-12-17 | Forest Laboratories Holdings Limited | Dosage escalation and divided daily dose of anti-depressants to treat neurological disorders |
GB0222909D0 (en) | 2002-10-03 | 2002-11-13 | Astrazeneca Ab | Novel process and intermediates |
GB0222912D0 (en) | 2002-10-03 | 2002-11-13 | Astrazeneca Ab | Novel process and intermediates |
US20040097554A1 (en) | 2002-10-30 | 2004-05-20 | Pfizer Inc | Heteroaryl-hexanoic acid amide derivatives as immonomodulatory agents |
WO2004041780A2 (en) | 2002-11-07 | 2004-05-21 | Pfizer Products Inc. | N-(indole-2-carbonyl) amides as anti-diabetic agents |
DE60323133D1 (de) * | 2002-12-13 | 2008-10-02 | Smithkline Beecham Corp | Cyclohexylverbindungen als ccr5-antagonisten |
WO2004067509A1 (ja) | 2003-01-31 | 2004-08-12 | Sanwa Kagaku Kenkyusho Co., Ltd. | ジペプチジルペプチダーゼivを阻害する化合物 |
JP2006522746A (ja) | 2003-04-11 | 2006-10-05 | ノボ ノルディスク アクティーゼルスカブ | 置換されたアミドの薬学的使用 |
CA2521962A1 (en) | 2003-04-30 | 2004-11-11 | Pfizer Products Inc. | Anti-diabetic agents |
WO2004113345A1 (ja) | 2003-06-20 | 2004-12-29 | Japan Tobacco Inc. | 縮合ピロール化合物及びその医薬用途 |
ES2286393T3 (es) | 2003-06-30 | 2007-12-01 | Les Laboratoires Servier | Nuevo procedimiento de sintesis de perindopril y de sus sales farmaceuticamente aceptables. |
KR20060033780A (ko) | 2003-07-07 | 2006-04-19 | 시바 스페셜티 케미칼스 홀딩 인크. | 푸로피롤의 제조방법 |
JP2005060375A (ja) * | 2003-07-28 | 2005-03-10 | Kyowa Hakko Kogyo Co Ltd | 含酸素複素環化合物 |
CA2534342C (en) | 2003-07-29 | 2016-05-10 | V. Ravi Chandran | Amino acid prodrugs |
GB0318463D0 (en) | 2003-08-07 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
GB0319759D0 (en) | 2003-08-22 | 2003-09-24 | Astrazeneca Ab | Chemical compounds |
WO2005020986A1 (en) | 2003-08-29 | 2005-03-10 | Astrazeneca Ab | Heterocyclic amide derivatives which posses glycogen phosphorylase inhibitory activity |
GB0320422D0 (en) | 2003-08-30 | 2003-10-01 | Astrazeneca Ab | Chemical compounds |
CN1886393A (zh) * | 2003-10-08 | 2006-12-27 | 沃泰克斯药物股份有限公司 | 含有环烷基或吡喃基基团的atp-结合弹夹转运蛋白的调控剂 |
US7396940B2 (en) | 2003-10-23 | 2008-07-08 | Hoffmann-La Roche Inc. | Combinatorial library of 3-aryl-1H-indole-2-carboxylic acid |
ES2282586T3 (es) | 2003-11-19 | 2007-10-16 | Les Laboratoires Servier | Procedimiento de sintesis de perindopril y de sus sales farmaceuticamente aceptables. |
PL380766A1 (pl) | 2003-12-29 | 2007-03-19 | Sepracor Inc. | Benzo[d]izooksazol-3- olowe inhibitory DAAO |
US7488747B2 (en) | 2003-12-29 | 2009-02-10 | Sepracor Inc. | Pyrrole and pyrazole DAAO inhibitors |
AU2005206437B2 (en) * | 2004-01-23 | 2010-08-12 | Mitsui Chemicals Agro, Inc. | 3-(dihydro(tetrahydro)isoquinolin-1-yl)quinolines |
JP2007529468A (ja) | 2004-03-16 | 2007-10-25 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ベンズイソオキサゾール |
JPWO2005097738A1 (ja) * | 2004-04-06 | 2008-02-28 | 大日本住友製薬株式会社 | 新規スルホンアミド誘導体 |
US7772232B2 (en) | 2004-04-15 | 2010-08-10 | Bristol-Myers Squibb Company | Quinazolinyl compounds as inhibitors of potassium channel function |
CN1950351B (zh) * | 2004-05-07 | 2012-01-18 | 沃尼尔·朗伯有限责任公司 | 适用作h3配体的3-或4-单取代酚及苯硫酚衍生物 |
US20050261327A1 (en) * | 2004-05-20 | 2005-11-24 | Bock Mark G | 2-(Bicyclo)alkylamino-derivatives as mediatores of chronic pain and inflammation |
US20100234409A1 (en) | 2004-05-21 | 2010-09-16 | Lihu Yang | Amino cyclopentyl heterocyclic and carbocyclic modulators of chemokine receptor activity |
EP1757591A4 (en) | 2004-05-26 | 2010-05-05 | Eisai R&D Man Co Ltd | ZIMTSÄUREAMIDVERBINDUNG |
WO2005123677A1 (en) | 2004-06-16 | 2005-12-29 | Actelion Pharmaceuticals Ltd | 4-carbonyl substituted 1,1,2-trimethyl-1a,4,5,5a-tetrahydro-1h-4-aza-cyclopropa'a!pentalene derivatives as agonists for the g-protein-coupled receptor s1p1/edg1 and immunosuppressive agents |
US7932250B2 (en) | 2004-07-01 | 2011-04-26 | Daiichi Sankyo Company, Limited | Thienopyrazole derivative having PDE7 inhibitory activity |
US7276631B2 (en) | 2004-07-20 | 2007-10-02 | Bristol-Myers Squibb Company | Cyclopentylamine and cyclohexylamine derivatives as NK-1/SSRI antagonists |
JO2629B1 (en) | 2004-08-19 | 2012-06-24 | افينتيس فارما سوتيكالز انك | Branched carboxylic acid amides containing thienobirol, carboxylic acid amides containing pyrolithiazole, and the like as kinase inhibitors casein epsilon |
US20090069384A1 (en) | 2005-01-19 | 2009-03-12 | Biolipox Ab | Thienopyrroles useful in the treatment of inflammation |
CN100391945C (zh) | 2005-05-31 | 2008-06-04 | 浙江大学 | 一种s-(-)-吲哚啉-2-羧酸的合成方法 |
EP1942885A1 (en) | 2005-10-06 | 2008-07-16 | Merck Sharp & Dohme Ltd. | Use of fused pyrrole carboxylic acids for the treatment of neurodegenerative and psychiatric diseases as d-amino acid oxidase inhibitors |
UA95788C2 (en) | 2005-12-15 | 2011-09-12 | Ф. Хоффманн-Ля Рош Аг | Fused pyrrole derivatives |
CN101426372A (zh) | 2006-01-06 | 2009-05-06 | 塞普拉柯公司 | 基于四氢萘酮的单胺再摄取抑制剂 |
CN101394847B (zh) | 2006-01-06 | 2017-05-24 | 塞普拉柯公司 | 作为单胺重摄取抑制剂的环烷基胺类 |
CA2648121C (en) | 2006-03-31 | 2013-08-06 | Sepracor Inc. | Preparation of chiral amides and amines |
US20080058395A1 (en) | 2006-06-30 | 2008-03-06 | Sepracor Inc. | Fused heterocyclic inhibitors of D-amino acid oxidase |
US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
EP2057162A2 (en) | 2006-06-30 | 2009-05-13 | Sepracor Inc. | Fused heterocyclic inhibitors of d-amino acid oxidase |
US7579370B2 (en) | 2006-06-30 | 2009-08-25 | Sepracor Inc. | Fused heterocycles |
CN1962656A (zh) | 2006-11-29 | 2007-05-16 | 沈阳药科大学 | 吲哚美辛5-氟尿嘧啶甲酯药用化合物及其制剂和制备方法 |
MX2009007410A (es) | 2007-01-18 | 2009-09-09 | Sepracor Inc | Inhibidores de d-aminoacido oxidasa. |
US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
CN101686672A (zh) | 2007-05-31 | 2010-03-31 | 塞普拉柯公司 | 苯基取代的环烷胺作为一元胺再摄取抑制剂 |
US20100120740A1 (en) | 2008-08-07 | 2010-05-13 | Sepracor Inc. | Prodrugs of fused heterocyclic inhibitors of d-amino acid oxidase |
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US20070203111A1 (en) | 2007-08-30 |
BRPI0706365A2 (pt) | 2011-03-22 |
ZA200806145B (en) | 2010-02-24 |
US20150126511A1 (en) | 2015-05-07 |
RU2430913C2 (ru) | 2011-10-10 |
US10562878B2 (en) | 2020-02-18 |
AU2007205114B2 (en) | 2012-11-08 |
WO2007081857A2 (en) | 2007-07-19 |
US9868718B2 (en) | 2018-01-16 |
CN101394847B (zh) | 2017-05-24 |
KR20080083201A (ko) | 2008-09-16 |
EP1976513A2 (en) | 2008-10-08 |
RU2011119990A (ru) | 2012-11-27 |
KR101294014B1 (ko) | 2013-08-09 |
NZ569630A (en) | 2011-09-30 |
EP1976513A4 (en) | 2012-04-18 |
AU2007205114A1 (en) | 2007-07-19 |
JP2009531277A (ja) | 2009-09-03 |
US20180230120A1 (en) | 2018-08-16 |
IL192613A0 (en) | 2009-09-22 |
CN101394847A (zh) | 2009-03-25 |
RU2008132320A (ru) | 2010-02-20 |
US8877975B2 (en) | 2014-11-04 |
JP2013209390A (ja) | 2013-10-10 |
US20100190861A1 (en) | 2010-07-29 |
IL192613A (en) | 2015-11-30 |
CA2636324A1 (en) | 2007-07-19 |
WO2007081857A3 (en) | 2007-11-08 |
EP1976513B1 (en) | 2016-08-24 |
JP5432526B2 (ja) | 2014-03-05 |
CA2636324C (en) | 2012-03-20 |
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