ES2594156T3 - Cicloalquilaminas como inhibidores de la recaptación de monoaminas - Google Patents

Cicloalquilaminas como inhibidores de la recaptación de monoaminas Download PDF

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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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unsubstituted
nmr
substituted
cyclohexyl
mhz
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Liming Shao
Fengjiang Wang
Scott Christopher Malcolm
Michael Charles Hewitt
Larry R. Bush
Jianguo Ma
Mark A. Varney
Una Campbell
Sharon Rae Engel
Larry Wendell Hardy
Patrick Koch
John E. Campbell
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Sunovion Pharmaceuticals Inc
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Sunovion Pharmaceuticals Inc
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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

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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.
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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
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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),
2.19 (d, J = 12.8 Hz, 2H), 1.67–1.31 (m, 8H); LC–MS 7.93 min, (M+1)+274 @ 8.18 min.
1–(1–(naftalen–1–il)ciclohexil)etanamina (16) 3 CH3 I
imagen37
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
imagen38
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
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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
imagen56
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
imagen57
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)
imagen58
El compuesto del título se sintetizó de acuerdo con el Esquema 25, más adelante.
imagen59
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)
imagen60
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
imagen61
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
imagen62
imagen63
imagen46
LC–MS 7.03 min, (M+1)+286 @ 7.58 min.
1–(1–(bifenil–4–il)ciclohexil)–N–metilmetanamina (49) 3 HHCH3 A 8
imagen64
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
imagen65
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 =
6.84 Hz, 3H); LC–MS 7.10 min, (M+1)+252 @ 7.32 min.
(±) N–metil–1–(1–(tiofen–2–il)ciclohexil)etanamina (51) 3 CH3H CH3 A 6
imagen46
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
imagen66
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
imagen46
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
imagen67
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
imagen68
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
imagen69
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
imagen70
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
imagen71
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
imagen72
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
imagen73
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
imagen46
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
imagen74
imagen75
3 CH3 H CH3 A 19E2
imagen76
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
imagen77
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)
imagen78
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)
imagen79
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)
imagen80
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
imagen81
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)
imagen82
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
imagen83
(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)
imagen84
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
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imagen86
imagen87
(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)
imagen88
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)
imagen89
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 @
6.62 min.
Clorhidrato de (1–(3,4–difluorofenil)ciclohexil)–N–metilmetanamina (81)
imagen90
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)
imagen91
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)
imagen92
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
imagen93
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)
imagen94
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)
imagen95
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)
imagen96
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
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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)
imagen100
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)
imagen101
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
imagen102
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)
imagen103
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),
imagen104
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
imagen105
(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
imagen106
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)
imagen107
62
imagen108
imagen109
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)
imagen110
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)
imagen111
(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
imagen112
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)
imagen113
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)
imagen114
(a) Síntesis de 1–(1–(3,4–diclorofenil)ciclohexil)etanol
imagen115
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
imagen116
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
imagen117
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
imagen118
imagen119
(±) 1–((1–(3,4–diclorofenil)ciclohexil)metil)–2–metilpirrolidina (115)
imagen120
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)
imagen121
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)
imagen122
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).
imagen123
25 cis–2–(aminometil)–2–(3,4–diclorofenil)ciclohexanol (cis 121)
70
imagen124
imagen125
imagen126
imagen127
imagen128
imagen129
imagen130
imagen131
imagen132
imagen133
imagen134
imagen135
imagen136
imagen137
imagen138
imagen139
imagen140
imagen141
imagen142
imagen143
imagen144
imagen145
imagen146
imagen147
imagen148
imagen149
imagen150
imagen151
imagen152
imagen153
imagen154
imagen155
imagen156
imagen157
imagen158
imagen159
imagen160
imagen161
imagen162
imagen163
imagen164
imagen165
imagen166
imagen167
imagen168
imagen169
imagen170
imagen171
imagen172
imagen173
imagen174
imagen175
imagen176
imagen177
imagen178
imagen179
imagen180
imagen181
imagen182
imagen183
imagen184
imagen185
imagen186
imagen187
imagen188
imagen189
imagen190
imagen191
imagen192
imagen193
imagen194
imagen195
imagen196
imagen197
imagen198
imagen199
imagen200
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
imagen201
7.3. Análisis de datos
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
imagen202
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.).
8.4. Resumen del resultado
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)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    imagen6
    imagen7
    imagen8
    imagen9
    imagen10
    o forma enantioméricamente pura farmacéuticamente aceptable del mismo.
  2. 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.
  3. 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.
  4. 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.
  5. 22. El compuesto de la reivindicación 1, en donde el compuesto es: o una sal, enantiómero, diastereómero, mezcla racémica, mezcla enriquecida enantioméricamente
    172
    imagen14
    imagen15
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