ES2592819T3 - Compuestos de acrilamida como ligandos del receptor H3 de la histamina - Google Patents
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- ES2592819T3 ES2592819T3 ES12844650.7T ES12844650T ES2592819T3 ES 2592819 T3 ES2592819 T3 ES 2592819T3 ES 12844650 T ES12844650 T ES 12844650T ES 2592819 T3 ES2592819 T3 ES 2592819T3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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Abstract
Un compuesto de la Fórmula general (I):**Fórmula** en donde, R1 se selecciona independientemente de hidrógeno, halógeno, alquilo o alcoxi; "A" es un alquilo, cicloalquilo o cicloalquilalquilo; "X" es CH o N; "Y" es CH2, O o sulfona o sus sales farmacéuticamente aceptables.
Description
Compuestos de acrilamida como ligandos del receptor H3 de la histamina Campo de la invención La presente invención se refiere a nuevos compuestos de acrilamida de la Fórmula (I) y sus sales farmacéuticamente
aceptables, para el tratamiento de diversos trastornos que se relacionan con los receptores H3 de la histamina.
10
15
Antecedentes de la invención
El receptor H3 de la histamina es un receptor acoplado a la proteína G (GPCR) y es uno de los cuatro receptores de la
20 familia de la histamina. El receptor H3 de la histamina se identificó en 1983 y su clonación y caracterización se realizaron en el 1999. El receptor H3 de la histamina se expresa en gran medida en el sistema nervioso central, y en menor medida en el sistema nervioso periférico.
Evidencias de la literatura sugieren que los ligandos del receptor H3 de la histamina pueden usarse en el tratamiento de
25 los trastornos cognitivos (British Journal of Pharmacology, 2008, 154(6), 1166-1181), la demencia (Drug News Perspective, 2010, 23(2), 99-103), los trastornos por déficit de atención e hiperactividad, la obesidad (Indian Journal of Pharmacology, 2001, 33, 17-28), la esquizofrenia (Biochemical Pharmacology, 2007, 73(8), 1215-1224) y el dolor (Journal of Pharmacology and Experimental Therapeutics, 2011,336(1), 30-37).
30 Las publicaciones de patentes núms. WO 2007/137955, US 2009/0170869, US 2010/0029608, US 2010/0048580, WO 2009/100120, WO 2009/121812y WO 2009/135842 describen una serie de compuestos como ligandos del receptor H3 de la histamina. Aunque se han descrito algunos ligandos del receptor H3 de la histamina, en esta área de la investigación hasta la fecha ninguno de estos compuestos se encuentra en el mercado y existe aún la necesidad y la posibilidad de descubrir fármacos con estructuras químicas novedosas para el tratamiento de los trastornos que
35 involucran el receptor H3 de la histamina.
Breve descripción de la invención
La presente invención se refiere a nuevos compuestos de acrilamida como ligandos del receptor H3 de la histamina de 40 la Fórmula (I),
en donde,
50 en cada aparición, R1 se selecciona independientemente de hidrógeno, halógeno, alquilo o alcoxi; "A" es un alquilo, cicloalquilo o cicloalquilalquilo; "X" es C o N;
55 "Y" es C, O o
La presente invención se refiere al uso de una cantidad con eficacia terapéutica del compuesto de la Fórmula (I), para fabricar un medicamento para el tratamiento de diversos trastornos que se relacionan con el receptor H3 de la histamina.
60 Específicamente, los compuestos de esta invención son útiles en el tratamiento de diversos trastornos tales como déficits cognitivos en esquizofrenia, narcolepsia, obesidad, trastorno por déficit de atención e hiperactividad, dolor o enfermedad de Alzheimer.
65 En otro aspecto, la invención se refiere a composiciones farmacéuticas que contienen una cantidad con eficacia
2
A una solución en agitación de 3-[4-(1-ciclobutil piperidin-4-iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1-ona (23.52 g, 0.063 moles) en metanol (300 ml) se le adicionó una solución de ácido fumárico (7.32 g, 0.063 moles) en 30 ml de metanol. La masa clara, que se obtuvo de esa manera, se agitó adicionalmente durante 2-3 horas a temperatura ambiente. El solvente se evaporó para proporcionar una masa sólida. La masa sólida se trituró con dietiléter (3 x 100 ml) y se secó
5 bajo condiciones de presión reducida para obtener el compuesto del título (29.54 g).
Rendimiento: 95 %.
1 H -NMR (δ ppm): 1.60 -1.65 (2H, m), 1.73 -1.77 (2H, m), 2.01 -2.09 (6H, m), 2.49 -2.52 (2H, m), 2.81 -2.89 (2H, m),
10 3.14 -3.19 (1H, m), 3.50 -3.70 (8H, m), 4.50 -4.60 (1H, m), 6.56 (2H, s), 6.97 -6.99 (2H, d, J = 8.45 Hz), 7.07 -7.10 (1H, d, J = 15.32 Hz), 7.43 -7.47 (1H, d, J = 15.27 Hz), 7.63 -7.65 (2H, d, J = 8.45 Hz); Masa (m/z): 371.3 (M+H)+.
Ejemplos 2-28:
15 Los compuestos de los Ejemplos 2-28 se prepararon siguiendo los procedimientos como se describieron en el Ejemplo 1, con algunas variaciones no críticas
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60
- 2.
- Sal hidrocloruro de 3-[4-(1-ciclobutil 1H -NMR (δ ppm): 1.60 -1.74 (8H, m), 1.82 -1.87 (2H, m), 1.95
- piperidin-4-iloxi) fenil]-1-(piperidin-1-il)
- 2.08 (6H, m), 2.29 (2H, bs), 2.64 (2H, bs), 2.78 -2.82 (1H, m), 3.62
- imagen9
- prop-2-en-1-ona -3.65 (4H, m), 4.39 (1H, m), 6.75 -6.79 (1H, d, J = 15.3 Hz), 6.87 6.89 (2H, d, J = 8.63 Hz), 7.44 -7.46 (2H, d, J = 8.63 Hz), 7.58 7.62 (1H, d, J = 15.3 Hz); Masa (m/z): 369.3 (M+H)+ .
- 3.
- Sal hidrocloruro de 3-[4-(1-ciclobutil 1H -NMR (δ ppm): 1.66 -1.97 (6H, m), 2.07 (5H, s), 2.25 (2H, bs),
- piperidin-4-iloxi) fenil]-1-(1,1-dioxo
- 2.63 (2H, bs), 2.76 -2.80 (1H, m), 2.86 -2.89 (1H, m), 3.10 (4H,
- imagen10
- tiomorfolin-4-il) prop-2-en-1-ona m), 4.17 (4H, m), 4.40 (1H, bs), 6.69 -6.73 (1H, d, J = 15.2 Hz), 6.89 -6.91 (2H, d, J = 8.65 Hz), 7.46 -7.48 (2H, d, J = 8.66 Hz), 7.69 -7.73 (1H, d, J = 15.2 Hz); Masa (m/z): 419.2 (M+H)+ .
- 4.
- Sal L(+)-tartrato de 3-[2-(1-ciclobutil 1H -NMR (δ ppm): 1.66 -1.72 (8H, m), 1.80 -1.85 (2H, m), 1.95
- piperidin-4-iloxi) piridin-5-il]-I-(piperidin
- 2.03 (6H, m), 2.32 (2H, bs), 2.63 (2H, bs), 2.80 -2.82 (1H, m), 2.88
- imagen11
- 1-il) prop-2-en-1-ona (2H, s) 3.60 -3.63 (4H, m), 3.82 (1H, m), 5.30-5.32 (1H, d, J = 8.36 Hz), 5.55 -5.59 (1H, d, J = 15.6 Hz), 5.94 -5.98 (1H, d, J = 15.6 Hz), 6.52 -6.54 (1H, d, J = 8.32 Hz), 6.75 (1H, s); Masa (m/z): 370.4 (M+H)+ .
- 5.
- Sal L(+)-tartrato de 3-[2-(1-ciclobutil 1H -NMR (δ ppm): 1.68 -1.75 (2H, m), 1.80 -1.95 (4H, m), 1.99
- piperidin-4-iloxi) piridin-5-il]-1-(morfolin
- 2.06 (4H, m), 2.19 -2.24 (2H, m), 2.55 -2.62 (2H, m), 2.70 -2.79
- imagen12
- 4-il) prop-2-en-1-ona (1H, m), 2.87 (2H, s), 3.60 -3.88 (8H, m), 5.42 (1H, m), 6.93 -6.99 (1H, m), 7.09 -7.13 (1H, m), 7.55 -7.58 (1H, m), 8.08 -8.10 (1H, m), 8.32 (1H, s); ) Masa (m/z): 372.4 (M+H)+ .
- 6.
- Sal L(+)-tartrato de 3-[2-fluoro-4-(1 1H -NMR (δ ppm): 1.16 -1.18 (2H, m), 1.20 -1.27 (1H, m), 1.38
- isopropil piperidin-4-iloxi) fenil]-1
- 1.41 (6H, m), 1.90 -2.34 (4H, m), 3.30 -3.69 (4H, m), 3.71 -3.80
- imagen13
- (morfolin-4-il) prop-2-en-1-ona (7H, m), 4.53 (2H, m), 6.80 -6.89 (2H, m), 7.06 -7.10 (1H, m), 7.67 -7.71 (2H, m); Masa (m/z): 377.3 (M+H)+ .
- 7.
- Sal L(+)-tartrato de 3-[2-fluoro-4-(1 1H -NMR (δ ppm): 1.60 -1.70 (4H, m), 1.80 -1.90 (2H, m), 1.99
- ciclobutil piperidin-4-iloxi) fenil]-1
- 2.09 (3H, m), 2.14 -2.20 (2H, m), 2.40 -2.51 (4H, m), 2.70 -2.76
- imagen14
- (morfolin-4-il) prop-2-en-1-ona (2H, m), 3.00 -3.09 (1H, m), 3.48 (2H, s), 3.60 -3.80 (6H, m), 4.53 (2H, m), 6.61 -6.70 (2H, m), 6.85 -6.89 (1H, d, J = 15.56 Hz), 7.39 -7.43 (1H, m), 7.65 -7.69 (1H, d, J = 15.56 Hz); Masa (m/z): 389.4 (M+H)+ .
- 8.
- Sal L(+)-tartrato de 3-[4-(1-ciclobutil 1H -NMR (δ ppm): 1.81 -1.91 (3H, m), 2.11 -2.33 (9H, m), 2.41
- piperidin-4-iloxi)-2-metil fenil]-1
- (3H, s), 3.14 -3.20 (4H, m), 3.71 (8H, s), 4.43 (2H, s), 6.85 -6.93
- imagen15
- (morfolin-4-il) prop-2-en-1-ona (3H, m), 7.67 -7.69 (1H, d, J = 8.3 Hz), 7.85 -7.89 (1H, d, J = 15. Hz); Masa (m/z): 385.4 (M+H)+ .
- 9.
- Sal L(+)-tartrato de 3-[4-(1-isopropil 1H -NMR (δ ppm): 1.38 -1.40 (6H, d), 1.91 -1.98 (1H, m), 2.16
- piperidin-4-iloxi)-2-metil fenil]-1
- 2.30 (4H, m), 2.42 (3H, s), 3.34 -3.57 (3H, m), 3.71 (8H, s), 4.41
- imagen16
- (morfolin-4-il) prop-2-en-1-ona (2H, s), 4.75 (2H, m), 6.86 -6.95 (3H, m), 7.69 -7.71 (1H, d, J = 8.45 Hz), 7.86 -7.90 (1H, d, J = 15.28 Hz) Masa (m/z): 373.4 (M+H)+ .
8
5
10
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50
55
60
- 10.
- Sal L(+)-tartrato de 3-[4-(1-ciclobutil 1H -NMR (δ ppm): 1.60 -1.65 (2H, m), 1.73 -1.77 (2H, m), 2.01
- piperidin-4-iloxi) fenil]-1-(morfolin-4-il)
- 2.09 (6H, m), 2.49 -2.52 (2H, m), 2.81 -2.89 (2H, m), 3.14 -3.19
- imagen17
- prop-2-en-1-ona (1H, m), 3.50 -3.70 (8H, m), 4.46 (2H, s), 4.50-4.60 (1H, m), 6.97 6.99 (2H, d, J = 8.45 Hz), 7.07 -7.10 (1H, d, J = 15.32 Hz), 7.43 7.47 (1H, d, J = 15.27 Hz), 7.63 -7.65 (2H, d, J = 8.45 Hz); Masa (m/z): 371.3 (M+H)+ .
- 11.
- Sal L(+)-tartrato de 3-[4-(1-ciclobutil 1H -NMR (δ ppm): 1.86 -1.93 (3H, m), 2.14 -2.38 (9H, m), 3.15
- piperidin-4-iloxi)-3-metoxi fenil]-1
- 3.25 (3H, m), 3.72 (8H, s), 3.92 (3H, s), 4.46 (2H, s), 4.71 -4.77
- imagen18
- (morfolin-4-il) prop-2-en-1-ona (1H, m), 7.06 -7.10 (2H, m), 7.19 -7.21 (1H, d, J = 7.7 Hz), 7.35 (1H, s), 7.54 -7.58 (1H, d, J = 15.37 Hz); Masa (m/z): 401.3 (M+H)+ .
- 12.
- Sal L(+)-tartrato de 3-[4-(1 1H -NMR (δ ppm): 0.46 -0.48 (2H, m), 0.78 -0.83 (2H, m), 1.15 -
- Ciclopropilmetil piperidin-4-iloxi)-3
- 1.19 (1H, m), 1.33 -1.39 (2H, m), 2.17 -2.26 (4H, m) 3.07 -3.10
- metoxi fenil]-1-(morfolin-4-il) prop-2-en
- (2H, m), 3.41 -3.52 (2H, m) 3.72 (8H, s), 3.92 (3H, s), 4.46 (2H, s),
- imagen19
- 1-ona 4.69 (1H, m), 7.05 -7.09 (2H, m), 7.20 -7.22 (1H, d, J = 8.2 Hz), 7.35 (1H, s), 7.54 -7.58 (1H, d, J = 15.37 Hz); Masa (m/z): 401.4 (M+H)+ .
- 13.
- Sal L(+)-tartrato de 3-[4-(1-Isobutil 1H -NMR (δ ppm): 1.03 -1.05 (6H, d), 2.13 -2.15 (5H, m), 2.96
- piperidin-4-iloxi)-3-metoxi fenil]-1
- 2.98 (2H, m), 3.39 -3.45 (4H, m), 3.68 -3.81 (8H, m), 3.88 (3H, s),
- (morfolin-4-il) prop-2-en-1-ona
- 4.39 (2H, s), 4.65 (1H, m), 7.05 -7.09 (2H, m), 7.15-7.17 (1H, d, J
- = 8.28 Hz), 7.31 (1H, s), 7.50 -7.54 (1H, d, J = 15.36 Hz); Masa
- imagen20
-
imagen21 (m/z): 403.4 (M+H)+.
- 14.
- Sal L(+)-tartrato de 3-[4-(1-isopropil 1H -NMR (δ ppm): 1.40 -1.42 (6H, d), 1.92 -1.96 (1H, m), 2.14
- piperidin-4-iloxi)-3-metoxi fenil]-1
- 2.31 (4H, m), 3.48 -3.49 (4H, m), 3.72 -3.93 (8H, s), 3.93 (3H, s),
- (morfolin-4-il) prop-2-en-1-ona
- 4.44 (2H, s), 4.80 -4.82 (1H, m), 7.06 -7.10 (2H, m), 7.20 -7.22
- (1H, d, J = 7.76 Hz), 7.35 (1H, s) 7.54 -7.58 (1H, d, J = 15.37 Hz);
- imagen22
-
imagen23 Masa (m/z): 389.4 (M+H)+.
- 15.
- Sal L(+)-tartrato de 3-[4-(1-isopropil 1H -NMR (δ ppm): 1.36 -1.38 (6H, d), 1.60 -1.62 (4H, m), 1.69
- piperidin-4-iloxi)-3-metoxi fenil]-1
- 1.70 (2H, m), 2.14 (4H, bs), 3.44 -3.46 (4H, m), 3.53-3.56 (1H, m),
- (piperidin-1-il) prop-2-en-1-ona
- 3.63 -3.75 (4H, m), 3.89 (3H, s), 4.39 (2H, s), 4.64 -4.66 (1H, m),
- 7.03 -7.07 (2H, m), 7.14 -7.16 (1H, d, J = 8.21 Hz), 7.29 (1H, s),
- imagen24
-
imagen25 7.45 -7.49 (1H, d, J = 15.53 Hz); Masa (m/z): 387.4 (M+H)+.
- 16.
- Sal L(+)-tartrato de 3-[4-(1-ciclobutil 1H -NMR (δ ppm): 0.46 -0.48 (2H, m), 0.81 -0.83 (2H, m), 1.18
- piperidin-4-iloxi)-3-metoxi fenil]-1
- 1.21 (2H, m), 1.34 -1.30 (2H, d, J = 6.56 Hz), 1.62 -1.64 (4H, m),
- imagen26
- (piperidin-1-il) prop-2-en-1-ona 1.73 -1.75 (2H, m), 2.18 (4H, bs), 3.08 -3.10 (2H, m), 3.39 -3.50 (1H, m), 3.67 -3.73 (4H, m), 3.93 (3H, s), 4.45 (2H, s), 4.70 -4.76 (1H, m), 7.07 -7.11 (2H, m), 7.18-7.20 (1H, d, J = 8.23 Hz), 7.34 (1H, s), 7.49 -7.53 (1H, d, J = 15.38 Hz); Masa (m/z): 399.5 (M+H)+.
- 17.
- 3-[4-(1-Ciclopropilmetil piperidin-4-iloxi) 1H -NMR (δ ppm): 0.09 -0.12 (2H, d), 0.50 -0.54 (2H, d), 0.85
- fenil]-1-(morfolin-4-il) prop-2-en-1-ona
- 0.89 (1H, m), 1.81 -1.90 (2H, m), 2.01 -2.05 (2H, m), 2.27 -2.28
- (2H, d), 2.38 -2.41 (2H, m), 2.83 -2.89 (2H, m), 3.62 -3.72 (8H,
- m), 4.35 -4.37 (1H, m), 6.68 -6.72 (1H, d, J = 15.30 Hz), 6.88
- 6.90 (2H, m, J = 8.64 Hz), 7.44 -7.46 (2H, m, J = 8.63 Hz), 7.63
- imagen27
-
imagen28 7.67 (1H, d, J = 15.33 Hz); Masa (m/z): 371.2 (M+H)+.
- 18.
- 3-[4-(1-Isobutil piperidin-4-iloxi) fenil]-l 1H -NMR (δ ppm): 0.89 -0.90 (6H, d), 1.73 -1.84 (3H, m), 1.97
- (morfolin-4-il) prop-2-en-1-ona
- 2.00 (2H, m), 2.08 -2.10 (2H, d), 2.18 -2.23 (2H, m), 2.68 -2.70
- (2H, m), 3.62 -3.72 (8H, m), 4.31 -4.35 (1H, m), 6.68 -6.71 (1H,
- d, J = 15.38 Hz), 6.87 -6.89 (2H, m, J = 8.62 Hz), 7.44 -7.46 (2H,
- m, J = 8.65 Hz), 7.63 -7.67 (1H, d, J = 15.30 Hz); Masa (m/z):
- imagen29
-
imagen30 373.4 (M+H)+.
- 19.
- 3-[3-Bromo-4-(1-isopropil piperidin-4 1H -NMR (δ ppm): 1.25 -1.27 (6H, d), 2.01 -2.06 (1H, m), 2.11
- iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1
- 2.14 (2H, m), 2.61 -2.68 (2H, m), 3.11 -3.18 (2H, m), 3.23 -3.27
- ona
- (2H, m), 3.66 -3.73 (8H, m), 4.79 -4.80 (1H, m), 6.71 -6.75 (1H,
- d, J = 15.32 Hz), 6.90 -6.92 (1H, d, J = 8.50 Hz), 7.42 -7.44 (1H,
- dd, J = 8.49 Hz), 7.56 -7.60 (1H, d, J = 15.33 Hz) 7.74 (1H, d, J =
- imagen31
-
imagen32 1.56 Hz); Masa (m/z): 437.3, 439.2 (M+H)+.
9
5
10
15
20
25
30
35
40
45
50
55
60
- 20.
- 3-[3-Bromo-4-(1-ciclobutil piperidin-4iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1ona 1H -NMR (δ ppm): 1.37 -1.42 (2H, m), 1.57 -1.61 (2H, m), 1.68 1.75 (2H, m), 1.84 (1H, m), 2.01 -2.04 (2H, m), 2.13 -2.15 (2H, m), 2.31 -2.32 (2H, m), 2.75 -2.80 (2H, m), 3.66-3.72 (8H, m), 4.66 -4.70 (1H, m), 6.69 -6.73 (1H, d, J = 15.37 Hz), 6.88 -6.90 (1H, d, J = 8.57 Hz), 7.38 -7.41 (1H, dd, J = 8.34, 1.44 Hz), 7.56 7.60 (1H, d, J = 15.33 Hz) 7.74 (1H, d, J = 1.77 Hz); Masa (m/z): 449.3, 451.2 (M+H)+ .
- 21.
- 3-[3-Bromo-4-(1-isobutil piperidin-4iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1ona 1H -NMR (δ ppm): 1.25 -1.27 (6H, d), 1.62 -1.71 (4H, m), 1.94 1.99 (2H, m), 2.01 -2.06 (1H, m), 2.21 -2.39 (2H, m), 2.76 -2.80 (2H, m), 3.67 -3.72 (8H, m), 4.50 -4.53 (1H, m), 6.69 -6.72 (1H, d, J = 15.36 Hz), 6.87 -6.90 (1H, d, J = 8.55 Hz), 7.36 -7.38 (1H, d, J = 8.39 Hz), 7.56 -7.60 (1H, d, J = 15.35 Hz), 7.75 (1H, d, J = 1.86 Hz); Masa (m/z): 451.2, 453.3 (M+H)+ .
- 22.
- 3-[3-Bromo-4-(1-ciclopropilmetil 1H -NMR (δ ppm): 0.29 -0.31 (2H, d), 0.66 -0.68 (2H, d), 1.11
- piperidin-4-iloxi) fenil]-1-(morfolin-4-il)
- 1.15 (1H, m), 2.05 -2.08 (2H, m), 2.38 -2.42 (2H, m), 2.62 -2.70
- imagen33
- prop-2-en-1-ona (2H, m), 3.03 -3.10 (4H, m), 3.66 -3.72 (8H, m), 4.68 -4.71 (1H, m), 6.70 -6.73 (1H, d, J = 15.33 Hz), 6.89 -6.91 (1H, d, J = 8.55 Hz), 7.39 -7.41 (1H, d, J = 8.46 Hz), 7.56 -7.60 (1H, d, J = 15.31 Hz) 7.74 -7.75 (1H, d, J = 1.60 Hz); Masa (m/z): 449.3,451.2 (M+H)+ .
- 23.
- Sal L(+)-tartrato de 3-[6-(ciclopropilmetil piperidin-4-iloxi) piridin3-il]-1-(morfolin-4-il) prop-2-en-1-ona 1H -NMR (δ ppm): 0.44 -0.47 (2H, m), 0.76 -0.81 (2H, m), 1.16 1.19 (1H, m), 1.28 -1.30 (1H, m), 2.19 -2.30 (4H, m), 3.06 -3.08 (2H, d), 3.35 -3.49 (3H, bs), 3.72 -3.76 (8H, m), 4.42 (2H, s), 5.39 (1H, bs), 6.88 -6.90 (1H, d, J = 8.64 Hz), 7.10 -7.14 (1H, d, J = 15.46 Hz), 7.56 -7.60 (1H, d, J = 15.46 Hz), 8.09 -8.11 (1H, dd, J = 8.61, 2.21 Hz), 8.34 -8.35 (1H, d, J = 2 Hz); Masa(m/z): 372.4 (M+H)+.
- 24.
- Sal L(+)-tartrato de 3-[6-(1-isobutil 1H -NMR (δ ppm): 1.08 -1.09 (6H, d), 1.28 -1.30 (1H, m), 1.39
- piperidin-4-iloxi) piridin-3-il]-1-(morfolin
- 1.42 (1H, m), 2.18 -2.31 (4H, m), 3.03 -3.05 (2H, d), 3.35 -3.49
- 4-il) prop-2-en-1-ona
- (3H, m), 3.72 -3.76 (8H, m), 4.47 (2H, s), 5.40 (1H, bs), 6.88 -6.90
- (1H, d, J = 8.59 Hz), 7.11 -7.15 (1H, d, J = 15.46 Hz), 7.56 -7.60
- (1H, d, J = 15.46 Hz), 8.09 -8.12 (1H, dd, J = 8.52, 1.86 Hz), 8.34
- imagen34
-
imagen35 8.35 (1H, d, J = 1.86 Hz); Masa (m/z): 374.4 (M+H)+.
- 25.
- 3-[2-Cloro-4-(1-ciclobutil piperidin-4 1H -NMR (δ ppm): 1.69 -1.76 (4H, d), 1.82 -1.94 (3H, m), 2.00
- iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1
- 2.09 (3H, m), 2.21 -2.25 (2H, m), 2.59 -2.63 (2H, m), 2.73 -2.79
- ona
- (1H, m), 3.70 -3.76 (8H, m), 4.11-4.16 (1H, bs), 6.74 -6.78 (1H,
- d, J = 15.41 Hz), 6.82 -6.85 (1H, dd, J = 8.71, 2.2 Hz), 6.97 -6.98
- (1H, d, J = 2.23 Hz), 7.53 -7.55 (1H, dd, J = 8.71 Hz), 7.99 -8.03
- imagen36
-
imagen37 (1H, d, J = 15.42 Hz); Masa (m/z): 405.3, 407.4 (M+H)+.
- 26.
- 3-[2-Cloro-4-(1-isopropil piperidin-4iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1ona 1H -NMR (δ ppm): 1.05 -1.06 (6H, d), 1.78 -1.85 (2H, m), 1.99 2.09 (2H, m), 2.38 -2.43 (2H, t), 2.72 -2.78 (3H, m), 3.66 -3.72 (8H, s), 4.30 -4.33 (1H, m), 6.71 -6.74 (1H, d, J = 15.33 Hz), 6.79 -6.81 (1H, dd, J = 8.71, 2.07 Hz), 6.94 -6.95 (1H, d, J = 2.4 Hz), 7.49 -7.52 (1H, d, J = 8.73 Hz), 7.96 -7.99 (1H, d, J = 15.39 Hz); Masa (m/z): 393.2, 395.2 (M+H)+.
- 27.
- 3-[2-Cloro-4-(1-ciclopropilmetil 1H -NMR (δ ppm): 0.13 -0.19 (2H, m), 0.54 -0.59 (2H, m), 0.90
- piperidin-4-iloxi) fenil]-1-(morfolin-4-il)
- 0.91 (1H, m), 1.87 -1.93 (2H, m), 2.04 -2.09 (2H, m), 2.31 -2.32
- prop-2-en-1-ona
- (2H, d), 2.43 (2H, m), 2.86 (2H, m), 3.69 -3.76 (8H, m), 4.37 -4.38
- (1H, m), 6.74 -6.78 (1H, d, J = 15.41 Hz), 6.83 -6.86 (1H, dd, J =
- 8.72, 2.22 Hz), 6.98 -6.99 (1H, d, J = 2.41 Hz), 7.54 -7.56 (1H, d,
- J = 8.71 Hz), 8.00 -8.03 (1H, d, J = 15.46 Hz); Masa(m/z): 405.3,
- imagen38
-
imagen39 407.4 (M+H)+.
- 28.
- 3-[2-Cloro-4-(1-isobutil piperidin-4-iloxi) fenil]-1-(morfolin-4-il) prop-2-en-1-ona 1H -NMR (δ ppm): 0.93 -0.94 (6H, d), 1.77 -1.87 (3H, m), 2.00 2.04 (2H, m), 2.12 -2.14 (2H,d), 2.23 -2.28 (2H, t), 2.72 (2H, m), 3.70 -3.76 (8H, s), 4.32 -4.36 (1H, m), 6.74 -6.78 (1H, d, J = 15.45 Hz), 6.82 -6.85 (1H, dd, J = 8.72, 2.35 Hz), 6.97 -6.98 (1H, d, J = 2.24 Hz), 7.53 -7.55 (1H, d, J = 8.76 Hz), 8.00 -8.03 (1H, d, J = 15.41 Hz); Masa (m/z): 407.3, 409.2 (M+H)+.
10
Claims (1)
-
imagen1 imagen2
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