ES2592819T3 - Compuestos de acrilamida como ligandos del receptor H3 de la histamina - Google Patents

Compuestos de acrilamida como ligandos del receptor H3 de la histamina Download PDF

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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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piperidin
mass
prop
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Ramakrishna Nirogi
Anil Karbhari Shinde
Adi Reddy Dwarampudi
Venkateswarlu Jasti
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Suven Life Sciences Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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

DESCRIPCIÓN
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
imagen1
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),
imagen2
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
imagen3o sus sales farmacéuticamente aceptables.
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
imagen4
imagen5
imagen6
imagen7
imagen8
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
20
25
30
35
40
45
50
55
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
15
20
25
30
35
40
45
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
imagen40
imagen41
imagen42
imagen43

Claims (1)

  1. imagen1
    imagen2
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