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ES2613399T3 - Compuesto de pirazincarboxamida - Google Patents

Compuesto de pirazincarboxamida Download PDF

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Publication number
ES2613399T3
ES2613399T3 ES13738947.4T ES13738947T ES2613399T3 ES 2613399 T3 ES2613399 T3 ES 2613399T3 ES 13738947 T ES13738947 T ES 13738947T ES 2613399 T3 ES2613399 T3 ES 2613399T3
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esi
estr
apci
data
ejp
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Inventor
Takahiro Matsuya
Yutaka Kondoh
Itsuro Shimada
Shigetoshi KIKUCHI
Maiko IIDA
Kenichi Onda
Hiroki Fukudome
Yukihiro TAKEMOTO
Nobuaki Shindou
Hideki SAKAGAMI
Hisao Hamaguchi
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Astellas Pharma Inc
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Astellas Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Un compuesto de fórmula (I) o una de sus sales:**Fórmula** (en donde R1 representa piperazinilo que está sustituido con alquilo C1-C6, piperidinilo que está sustituido con alquilo C1-C6, o piperidinilo sustituido con piperazinilo que puede estar sustituido con alquilo C1-C6, el Anillo A representa benceno que puede estar sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halógeno, alquilo C1-C6 que puede estar sustituido con uno o más átomos de halógeno, y -O-alquilo C1-C6, pirazol que puede estar sustituido con alquilo C1-C6, imidazol que puede estar sustituido con alquilo C1-C6 o pirimidina que puede estar sustituida con alquilo C1-C6, L1 representa NH-, R2 representa H o alquilo C1-C6, L2 representa-O- o un enlace, Y representa el Anillo X, el anillo X representa un heterociclo aromático, un heterociclo no aromático, cicloalcano, o benceno que puede estar sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halógeno, -O alquilo C1-C6, -CN, cicloalquilo, arilo, grupo heterocíclico aromático, grupo heterocíclico no aromático que puede estar sustituido con alquilo C1-C6, oxo, y alquilo C1-C6 que puede estar sustituido con uno o más átomos de halógeno, L3 representa -NH-, -N(alquil C1-C6)- o un enlace, M representa -C(O), R3 representa H, R4 representa H).

Description

imagen1
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[Tabla 1]
Ej
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)
1
1,3 42 1,2 69 1,3
C3
1,4 43 1,4 73 1,2
15
1,2 54 1,7 79 1,3
22
1,5 56 1,3 80 1,2
24
1,1 63 1,8 82 1,5
26
1,1 64 1,7 imagen18
Ejemplo de Ensayo 2: Ensayo de evaluación de la actividad inhibidora sobre la proliferación celular dependiente de la quinasa con mutación T790M/L858R en EGFR y la quinasa con mutación T790M/del19 en EGFR
5 El presente ensayo se realizó utilizando células Ba/F3 que habían expresado una quinasa con mutación T790M/L858R en EGFR y una quinasa con mutación T790M/del19 en EGFR.
En una placa de 96 pocillos (Iwaki), se sembraron células Ba/F3 a 500 células por pocillo en un medio RPMI1640
10 (Invitrogen) que contenía suero bovino fetal al 10%, seguido de la adición del compuesto de ensayo (concentraciones finales que oscilaban de 1 µm a 0,1 nM) y DMSO que era un disolvente del compuesto de ensayo como control negativo. En presencia de 5% de CO2, las células se cultivaron a 37°C durante 2 días. A esto se le añadió un reactivo de recuento de células (Cell Titer-Glo; Promega) y la intensidad de emisión de luz se midió utilizando un luminómetro (Envison o ARVO; PerkinElmer Inc.). Se supuso que los valores medidos en el medio solo
15 y el control negativo eran 100% de inhibición y 0% de inhibición, respectivamente. Se calculó la tasa de inhibición del compuesto de ensayo y se determinó la concentración que causaba una inhibición de 50% (valor CI50) mediante un método de regresión logística.
Los valores de CI50 de varios compuestos de la fórmula (I) se muestran en la Tabla 2. Ej indica el Núm. de Ejemplo 20
imagen19
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imagen28
imagen29
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imagen31
imagen32
imagen33
imagen34
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imagen37
imagen38
imagen39
imagen40
imagen41
imagen42
imagen43
imagen44
imagen45
imagen46
EjP
pSyn Estr Datos
1
1
imagen47 ESI +: 323 325
2
2
imagen48 ESI +: 478
3
3
imagen49 ESI +: 561
4
4
imagen50 ESI +: 480
5
5
imagen51 ESI +: 479
6
6
imagen52 ESI +: 492
EjP
pSyn Estr Datos
7
7
imagen53 ESI +: 448
8
8
imagen54 ESI +: 447
9
9
imagen55 APCI/ESI +: 462
10
10
imagen56 ESI +: 462
11
11
imagen57 ESI +: 449
12
12
imagen58 ESI +: 478
EjP
pSyn Estr Datos
13
13
imagen59 ESI +: 466
14
14
imagen60 APCI/ESI +: 490
15
15
imagen61 ESI +: 479
16
16
imagen62 ESI +: 508
17
17
imagen63 ESI +: 614 616
18
18
imagen64 ESI +: 570 572
EjP
pSyn Estr Datos
19
19
imagen65 ESI +: 514 516
20
20
imagen66 ESI +: 446
21
21
imagen67 ESI +: 528 530
22
22
imagen68 ESI +: 461
23
23
imagen69 ESI +: 527
24
24
imagen70 ESI +: 475
EjP
pSyn Estr Datos
25
25
imagen71 ESI +: 529 531
26
26
imagen72 ESI +: 546
27
27
imagen73 ESI +: 389 391
28
28
imagen74 ESI +: 467
29
29
imagen75 ESI +: 371 373
30
30
imagen76 ESI +: 526
EjP
pSyn Estr Datos
31
31
imagen77 APCI/ESI +: 609
32
32
imagen78 ESI +: 621
33
33
imagen79 APCI/ESI +: 623
34
34
imagen80 ESI +: 426
35
35
imagen81 ESI +: 623
EjP
pSyn Estr Datos
36
36
imagen82 ESI +: 619
37
37
imagen83 ESI +: 519
38
38
imagen84 ESI +: 521
39
39
imagen85 ESI +: 339 341
40
40
imagen86 ESI +:237
41
41
imagen87 ESI +:207
EjP
pSyn Estr Datos
42
42
imagen88 ESI +:260
43
43
imagen89 ESI +:276
44
44
imagen90 ESI +:290
45
45
imagen91 ESI +:271
46
46
imagen92 ESI +:193
47
47
imagen93 ESI +:195
48
1 imagen94 ESI +: 323 325
49
1 imagen95 ESI +: 323 325
EjP
pSyn Estr Datos
50
1 imagen96 ESI +: 337 339
51
1 imagen97 ESI +: 337 339
52
1 imagen98 ESI +: 337 339
53
1 imagen99 ESI +: 353 355
54
1 imagen100 ESI +:295 297
55
1 imagen101 ESI +: 391 393
56
1 imagen102 ESI +: 393 395
EjP
pSyn Estr Datos
57
2 imagen103 ESI +: 508
58
3 imagen104 ESI +: 478
59
3 imagen105 ESI +: 478
60
3 imagen106 ESI +: 492
61
3 imagen107 ESI+: 492
62
3 imagen108 ESI+: 492
EjP
PSyn Estr Datos
63
3 imagen109 ESI+: 508
64
3 imagen110 ESI+: 492
65
3 imagen111 ESI+: 546
66
3 imagen112 ESI+: 496
67
3 imagen113 ESI+: 575
68
3 imagen114 ESI+: 450
EjP
PSyn Estr Datos
69
3 imagen115 ESI+: 546
70
3 imagen116 ESI+: 591
71
3 imagen117 ESI+: 591
72
3 imagen118 ESI+: 509
73
3 imagen119 ESI+: 493
74
3 imagen120 ESI+: 467
EjP
PSyn Estr Datos
75
3 imagen121 ESI+: 477
76
3 imagen122 ESI+: 478
77
4 imagen123 ESI+: 508
78
4 imagen124 ESI+: 492
79
5 imagen125 ESI+: 499, 501
80
5 imagen126 ESI+: 479
EjP
PSyn Estr Datos
81
5 imagen127 ESI+: 483
82
5 imagen128 ESI+: 536
83
5 imagen129 ESI+: 535
84
5 imagen130 ESI+: 451
85
5 imagen131 ESI+: 449
86
5 imagen132 ESI+: 477
EjP
PSyn Estr Datos
87
5 imagen133 ESI+: 410
88
5 imagen134 ESI+: 507
89
5 imagen135 ESI+: 492
90
5 imagen136 ESI+: 492
91
5 imagen137 ESI+: 480
92
5 imagen138 ESI+: 467
EjP
PSyn Estr Datos
93
5 imagen139 ESI+: 546
94
5 imagen140 ESI+: 481
95
5 imagen141 ESI+: 494
96
5 imagen142 ESI+: 532
97
5 imagen143 ESI+: 546
98
6 imagen144 ESI+: 465
EjP
PSyn Estr Datos
99
7 imagen145 ESI+: 448
100
7 imagen146 ESI+: 448
101
7 imagen147 ESI+: 531
102
7 imagen148 ESI+: 561
103
7 imagen149 ESI+: 561
EjP
PSyn Estr Datos
104
7 imagen150 ESI+: 462
105
7 imagen151 ESI+: 462
106
7 imagen152 ESI+: 462
107
7 imagen153 ESI+: 478
108
7 imagen154 ESI+: 462
109
7 imagen155 ESI+: 516
EjP
PSyn Estr Datos
110
7 imagen156 ESI+: 466
111
7 imagen157 ESI+: 545
112
7 imagen158 ESI+: 420
113
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114
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115
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EjP
PSyn Estr Datos
116
7 imagen162 ESI+: 437
117
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118
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119
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120
7 imagen166 ESI+: 454,456
121
7 imagen167 ESI+: 498,500
EjP
PSyn Estr Datos
122
7 imagen168 ESI+: 421
123
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124
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125
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126
7 imagen172 ESI+: 464
127
7 imagen173 ESI+: 497
EjP
PSyn Estr Datos
128
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129
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130
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131
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132
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133
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EjP
PSyn Estr Datos
134
7 imagen180 ESI+: 451
135
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136
8 imagen182 ESI+: 448
137
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138
9 imagen184 ESI+: 451
139
9 imagen185 ESI+: 465
EjP
PSyn Estr Datos
140
9 imagen186 ESI+: 477
141
10 imagen187 ESI+: 435
142
10 imagen188 ESI+: 469,471
143
11 imagen189 ESI+: 449
144
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145
11 imagen191 ESI+: 505
EjP
PSyn Estr Datos
146
11 imagen192 ESI+: 477
147
11 imagen193 ESI+: 516
148
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149
13 imagen195 ESI+: 482,484
150
13 imagen196 ESI+: 462
151
13 imagen197 ESI+: 466
EjP
PSyn Estr Datos
152
13 imagen198 ESI+: 466
153
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154
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155
13 imagen201 ESI+: 437
156
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157
13 imagen203 ESI+: 462
EjP
PSyn Estr Datos
158
13 imagen204 ESI+: 462
159
13 imagen205 ESI+: 562
160
15 imagen206 ESI+: 493
161
15 imagen207 ESI+: 505
162
19 imagen208 ESI+: 470,472
163
21 imagen209 ESI+: 484,486
EjP
PSyn Estr Datos
164
23 imagen210 ESI+: 526
165
27 imagen211 ESI+: 364,366
166
27 imagen212 ESI+: 389,391
167
27 imagen213 ESI+: 489,491
168
29 imagen214 ESI+: 371
169
29 imagen215 ESI+: 371
170
29 imagen216 ESI+: 385
EjP
PSyn Estr Datos
171
29 imagen217 ESI+: 401
172
30 imagen218 APCI/ESI +: 526
173
30 imagen219 APCI/ESI +: 526
174
31 imagen220 ESI+: 623
175
31 imagen221 ESI+: 637
176
32 imagen222 ESI+: 635
EjP
PSyn Estr Datos
177
34 imagen223 APCI/ESI +: 509
178
34 imagen224 APCI/ESI +: 523
179
34 imagen225 APCI/ESI +: 426
180
34 imagen226 APCI/ESI +: 426
181
34 imagen227 ESI+: 523
EjP
PSyn Estr Datos
182
34 imagen228 ESI+: 537
183
34 imagen229 ESI+: 523
184
34 imagen230 ESI+: 537
185
35 imagen231 ESI+: 637
186
36 imagen232 APCI/ESI +: 605
EjP
PSyn Estr Datos
187
36 imagen233 APCI/ESI +: 522
188
37 imagen234 APCI/ESI +: 505
189
37 imagen235 ESI+: 422
190
38 imagen236 APCI/ESI +: 507
191
42 imagen237 ESI+:246
192
43 imagen238 ESI+:262
EjP
PSyn Estr Datos
193
44 imagen239 ESI+:276
194
E1 imagen240 ESI+: 588
195
E1 imagen241 ESI+: 616
196
198 imagen242 ESI+: 496
197
197
imagen243 ESI+: 447
198
198
imagen244 ESI+: 510
EjP
PSyn Estr Datos
199
197 imagen245 ESI+: 544
200
200
imagen246 ESI+: 522
201
200 imagen247 ESI+: 522
202
200 imagen248 ESI+: 508
EjP
PSyn Estr Datos
203
203
imagen249 ESI+: 554
204
204
imagen250 ESI+: 529
205
200 imagen251 ESI+: 425
206
198 imagen252 APCI/ESI +: 508
EjP
PSyn Estr Datos
207
198 imagen253 APCI/ESI +: 455
208
198 imagen254 APCI/ESI +: 538
209
198 imagen255 ESI+: 536
210
210
imagen256 APCI/ESI +: 390,392
EjP
PSyn Estr Datos
211
198 imagen257 APCI/ESI +: 425
212
198 imagen258 APCI/ESI +: 439
213
198 imagen259 APCI/ESI +: 443
214
198 imagen260 APCI/ESI +: 440
215
198 imagen261 APCI/ESI +: 425
EjP
PSyn Estr Datos
216
210 imagen262 APCI/ESI +: 472
217
198 imagen263 APCI/ESI +:412
218
198 imagen264 APCI/ESI +: 424
219
198 imagen265 APCI/ESI +: 522
220
210 imagen266 APCI/ESI +:389
EjP
PSyn Estr Datos
221
221
imagen267 APCI/ESI +:292
222
198 imagen268 APCI/ESI +: 439
223
223
imagen269 APCI/ESI +:262
224
210 imagen270 APCI/ESI +: 458
225
210 imagen271 APCI/ESI +: 445
226
226
imagen272 ESI+: 588
EjP
PSyn Estr Datos
227
198 imagen273 ESI+: 508
228
198 imagen274 APCI/ESI +: 495
229
229
imagen275 ESI+: 444,446
230
198 imagen276 APCI/ESI +: 511
231
231
imagen277 ESI+: 544
EjP
PSyn Estr Datos
232
232
imagen278 ESI+: 628,630
233
34 imagen279 ESI+: 528,530
234
203 imagen280 APCI/ESI +: 608
235
203 imagen281 APCI/ESI +: 594
EjP
PSyn Estr Datos
236
203 imagen282 APCI/ESI +: 594
237
203 imagen283 APCI/ESI +: 608
238
238
imagen284 ESI+: 376,378
239
238 imagen285 ESI+: 376,378
240
203 imagen286 ESI+: 526
EjP
PSyn Estr Datos
241
318 imagen287 APCI/ESI +: 608
242
318 imagen288 APCI/ESI +: 608
243
318 imagen289 APCI/ESI +: 622
244
318 imagen290 APCI/ESI +: 622
245
34 imagen291 ESI+: 426
EjP
PSyn Estr Datos
246
203 imagen292 ESI+: 526
247
34 imagen293 APCI/ESI +: 508
248
34 imagen294 APCI/ESI +: 522
249
34 imagen295 APCI/ESI +: 508
250
34 imagen296 APCI/ESI +: 522
EjP
PSyn Estr Datos
251
318 imagen297 APCI/ESI +: 622
252
318 imagen298 APCI/ESI +: 636
253
318 imagen299 ESI+: 622
254
318 imagen300 ESI+: 636
EjP
PSyn Estr Datos
255
34 imagen301 APCI/ESI +: 426
256
256
imagen302 ESI+: 380,382
257
34 imagen303 APCI/ESI +: 522
258
34 imagen304 APCI/ESI +: 536
259
34 imagen305 APCI/ESI +: 522
EjP
PSyn Estr Datos
260
34 imagen306 APCI/ESI +: 536
261
203 imagen307 ESI+: 530
262
318 imagen308 ESI+: 622
263
318 imagen309 APCI/ESI +: 636
EjP
PSyn Estr Datos
264
318 imagen310 APCI/ESI +: 622
265
318 imagen311 APCI/ESI +: 636
266
34 imagen312 ESI+: 430
267
198 imagen313 ESI+: 522
EjP
PSyn Estr Datos
268
34 imagen314 APCI/ESI +: 522
269
34 imagen315 APCI/ESI +: 536
270
34 imagen316 APCI/ESI +: 522
271
34 imagen317 APCI/ESI +: 536
EjP
PSyn Estr Datos
272
318 imagen318 APCI/ESI +: 622
273
318 imagen319 APCI/ESI +: 636
274
318 imagen320 APCI/ESI +: 622
275
318 imagen321 APCI/ESI +: 636
EjP
PSyn Estr Datos
276
34 imagen322 APCI/ESI +: 522
277
34 imagen323 APCI/ESI +: 522
278
34 imagen324 APCI/ESI +: 536
279
318 imagen325 APCI/ESI +: 622
EjP
PSyn Estr Datos
280
318 imagen326 APCI/ESI +: 636
281
34 imagen327 APCI/ESI +: 522
282
34 imagen328 APCI/ESI +: 536
283
203 imagen329 APCI/ESI +: 626
EjP
PSyn Estr Datos
284
318 imagen330 ESI+: 636
285
318 imagen331 ESI+: 622
286
198 imagen332 APCI/ESI +: 522
287
198 imagen333 APCI/ESI +: 536
EjP
PSyn Estr Datos
288
198 imagen334 APCI/ESI +: 550
289
34 imagen335 APCI/ESI +: 522
290
34 imagen336 APCI/ESI +: 536
291
291
imagen337 APCI/ESI +: 536
EjP
PSyn Estr Datos
292
318 imagen338 ESI+: 540
293
226 imagen339 ESI+: 574,576
294
294
imagen340 ESI+: 618,620
295
4 imagen341 ESI+: 536
296
17 imagen342 ESI+: 614,616
EjP
PSyn Estr Datos
297
229 imagen343 ESI+: 430,432
298
231 imagen344 ESI+: 530
299
232 imagen345 ESI+: 614,616
300
34 imagen346 ESI+: 514,516
301
318 imagen347 APCI/ESI +: 636
EjP
PSyn Estr Datos
302
318 imagen348 APCI/ESI +: 650
303
229 imagen349 ESI+: 474,476
304
231 imagen350 ESI+: 574
305
232 imagen351 ESI+: 658,660
306
306
imagen352 ESI+: 558,560
EjP
PSyn Estr Datos
307
34 imagen353 APCI/ESI +: 536
308
34 imagen354 APCI/ESI +: 550
309
309
imagen355 APCI/ESI +: 536
310
309 imagen356 APCI/ESI +: 522
EjP
PSyn Estr Datos
311
309 imagen357 APCI/ESI +: 536
312
312
imagen358 ESI+: 657
313
306 imagen359 ESI+: 557
314
314
imagen360 ESI+: 556
EjP
PSyn Estr Datos
316
34 imagen361 ESI+: 523
317a
317 imagen362 ESI+: 605
317b
317 imagen363 ESI+: 623
318
318
imagen364 APCI/ESI +: 636
EjP
PSyn Estr Datos
319
318 imagen365 APCI/ESI +: 650
320
318 imagen366 APCI/ESI +: 650
321
34 imagen367 ESI+: 505
322
318 imagen368 ESI+: 636
EjP
PSyn Estr Datos
323
318 imagen369 ESI+: 650
324
34 imagen370 APCI/ESI +: 536
325
34 imagen371 APCI/ESI +: 550
326
34 imagen372 APCI/ESI +: 550
EjP
PSyn Estr Datos
327
34 imagen373 APCI/ESI +: 536
328
34 imagen374 APCI/ESI +: 550
329
380 imagen375 ESI+: 562
330
306 imagen376 ESI+: 462
331
19 imagen377 ESI+: 514,516
EjP
PSyn Estr Datos
332
21 imagen378 ESI+: 528,530
333
7 imagen379 ESI+: 498,500
334
318 imagen380 ESI+: 637
335
34 imagen381 ESI+: 537
336
318 imagen382 ESI+: 680
EjP
PSyn Estr Datos
337
318 imagen383 ESI+: 622
338
27 imagen384 ESI+: 364,366
339
13 imagen385 ESI+: 512,514
340
340
imagen386 ESI+: 622
341
318 imagen387 ESI+: 652
EjP
PSyn Estr Datos
342
318 imagen388 ESI+: 666
343
343
imagen389 ESI+: 613
344
13 imagen390 ESI+: 484
345
13 imagen391 ESI+: 455
346
34 imagen392 ESI+: 552
EjP
PSyn Estr Datos
347
34 imagen393 ESI+: 566
348
34 imagen394 ESI+: 580
349
306 imagen395 ESI+: 522
350
34 imagen396 ESI+: 522
351
351
imagen397 ESI+: 449
EjP
PSyn Estr Datos
352
352
imagen398 ESI+: 357
353
13 imagen399 ESI+: 482,484
354
13 imagen400 ESI+: 516,518
355
31 imagen401 ESI+: 595
356
31 imagen402 ESI+: 609
EjP
PSyn Estr Datos
357
340 imagen403 ESI+: 608
358
358
imagen404 ESI+:252
359
34 imagen405 ESI+: 508
360
34 imagen406 ESI+: 495
361
34 imagen407 ESI+: 509
EjP
PSyn Estr Datos
362
32 imagen408 ESI+: 651
363
13 imagen409 ESI+: 478
364
364
imagen410 ESI+:222
365
35 imagen411 ESI+: 653
366
13 imagen412 ESI+: 473
EjP
PSyn Estr Datos
367
27 imagen413 ESI+: 405,407
368
13 imagen414 ESI+: 478
369
13 imagen415 ESI+: 478
370
13 imagen416 ESI+: 478
371
34 imagen417 ESI+: 553
EjP
PSyn Estr Datos
372
372
imagen418 RMN H1(CD C13):1.07-1.18(4H,m), 2.422.50(1H,m), 8.30 (1H,s)
373
27 imagen419 ESI+:281,283
374
27 imagen420 ESI+:281,283
375
27 imagen421 ESI+: 389,391
376
13 imagen422 ESI+: 466
377
13 imagen423 ESI+: 372
EjP
PSyn Estr Datos
378
13 imagen424 ESI+: 372
379
13 imagen425 ESI+: 462
380
380
imagen426 ESI+: 556,558
381
381
imagen427 ESI+: 586
382
27 imagen428 ESI+: 450,452
EjP
PSyn Estr Datos
383
383
imagen429 ESI-:231
384
384
imagen430 ESI+: 613
385
384 imagen431 ESI+: 613
386
386
imagen432 EI+:231,233
EjP
PSyn Estr Datos
387
387
imagen433 ESI+: 523
388
387 imagen434 ESI+: 523
389
389
imagen435 ESI+: 350,352
390
27 imagen436 ESI+: 470,472
391
391
imagen437 ESI+: 503
EjP
PSyn Estr Datos
392
392
imagen438 ESI+: 432,434
393
384 imagen439 ESI+: 663
394
392 imagen440 ESI+: 414,416
395
395
imagen441 ESI+: 408,410
396
13 imagen442 ESI+: 523
EjP
PSyn Estr Datos
397
13 imagen443 ESI+: 541
398
13 imagen444 ESI+: 505
399
13 imagen445 ESI+: 523
400
13 imagen446 ESI+: 499
401
13 imagen447 ESI+: 517
402
7 imagen448 ESI+: 473
EjP
PSyn Estr Datos
403
403
imagen449 ESI+: 621
404
34 imagen450 ESI+: 521
405
405
imagen451 ESI+: 483
406
406
imagen452 ESI+:245
407
407
imagen453 ESI+:145
EjP
PSyn Estr Datos
408
358 imagen454 ESI+:252
409
358 imagen455 ESI+:266
410
410
imagen456 ESI+:291
411
42 imagen457 ESI+:222
412
42 imagen458 ESI+:236
413
27 imagen459 ESI+: 405,407
EjP
PSyn Estr Datos
414
27 imagen460 ESI+: 419,421
415
415
imagen461 ESI+: 347
416
384 imagen462 ESI+: 649
417
34 imagen463 ESI+: 549
418
42 imagen464 ESI+: 317
EjP
PSyn Estr Datos
419
27 imagen465 ESI+: 500,502
420
13 imagen466 ESI+: 478
421
13 imagen467 ESI+: 492
422
422
imagen468 ESI+: 547
423
427 imagen469 ESI+: 449
EjP
PSyn Estr Datos
424
384 imagen470 ESI+: 651
425
34 imagen471 ESI+: 551
426
13 imagen472 ESI+: 473
427
427
imagen473 ESI+: 449
428
428
imagen474 ESI+: 341,343
EjP
PSyn Estr Datos
429
384 imagen475 ESI+: 653
430
13 imagen476 ESI+: 473
431
384 imagen477 ESI+: 653
432
432
imagen478 ESI+: 523
EjP
PSyn Estr Datos
433
198 imagen479 ESI+: 536
434
32 imagen480 ESI+: 474
435
435
imagen481 ESI+: 473
436
35 imagen482 ESI+: 476
437
35 imagen483 ESI+: 475
EjP
PSyn Estr Datos
438
438
imagen484 ESI+: 432
439
384 imagen485 ESI+: 609
440
432 imagen486 ESI+: 523
441
441
imagen487 ESI+: 414
442
442
imagen488 APCI/ESI +:229
EjP
PSyn Estr Datos
443
34 imagen489 ESI+: 376
444
34 imagen490 ESI+: 375
445
35 imagen491 ESI+: 416
446
34 imagen492 ESI+: 509
447
27 imagen493 ESI+: 377,379
EjP
PSyn Estr Datos
448
318 imagen494 APCI/ESI +: 650
449
13 imagen495 ESI+: 468
450
34 imagen496 ESI+: 550
451
451
imagen497 APCI/ESI +: 550
452
452
imagen498 ESI+:206
EjP
PSyn Estr Datos
453
384 imagen499 ESI+: 627
454
387 imagen500 ESI+: 537
455
27 imagen501 ESI+: 430,432
456
456
imagen502 ESI+: 711
EjP
PSyn Estr Datos
457
34 imagen503 ESI+: 611
458
384 imagen504 ESI+: 675
459
384 imagen505 ESI+: 635
460
460
imagen506 ESI+: 545
EjP
PSyn Estr Datos
461
27 imagen507 ESI+: 417,419
462
34 imagen508 ESI+: 535
463
403 imagen509 ESI+: 581
464
384 imagen510 ESI+: 635
EjP
PSyn Estr Datos
465
34 imagen511 ESI+: 535
466
34 imagen512 ESI+: 481
467
403 imagen513 ESI+: 568
468
34 imagen514 ESI+: 468
EjP
PSyn Estr Datos
469
34 imagen515 APCI/ESI +: 536
470
407 imagen516 ESI+:131
471
471
imagen517 ESI+: 472,474
Ej
Estr
1
imagen518
C2
imagen519
C3
imagen520
C4
imagen521
C5
imagen522
6
imagen523
Ej
Estr
C7
imagen524
8
imagen525
9
imagen526
10
imagen527
11
imagen528
Ej
Estr
12
imagen529
13
imagen530
14
imagen531
15
imagen532
16
imagen533
17
imagen534
Ej
Estr
18
imagen535
19
imagen536
20
imagen537
21
imagen538
22
imagen539
Ej
Estr
23
imagen540
24
imagen541
25
imagen542
26
imagen543
27
imagen544
Ej
Estr
28
imagen545
C29
imagen546
C30
imagen547
C31
imagen548
C32
imagen549
C33
imagen550
Ej
Estr
C34
imagen551
C35
imagen552
36
imagen553
C37
imagen554
C38
imagen555
39
imagen556
Ej
Estr
40
imagen557
C41
imagen558
42
imagen559
43
imagen560
C44
imagen561
C45
imagen562
Ej
Estr
C46
imagen563
C47
imagen564
C48
imagen565
C49
imagen566
C50
imagen567
C51
imagen568
Ej
Estr
C52
imagen569
C53
imagen570
54
imagen571
55
imagen572
56
imagen573
57
imagen574
Ej
Estr
58
imagen575
C59
imagen576
C60
imagen577
61
imagen578
C62
imagen579
63
imagen580
Ej
Estr
64
imagen581
C65
imagen582
66
imagen583
C67
imagen584
C68
imagen585
Ej
Estr
69
imagen586
C70
imagen587
C71
imagen588
72
imagen589
73
imagen590
Ej
Estr
74
imagen591
75
imagen592
76
imagen593
77
imagen594
78
imagen595
Ej
Estr
79
imagen596
80
imagen597
81
imagen598
82
imagen599
83
imagen600
Ej
Estr
84
imagen601
85
imagen602
C86
imagen603
87
imagen604
C88
imagen605
89
imagen606
Ej
Estr
90
imagen607
91
imagen608
92
imagen609
93
imagen610
C94
imagen611
Ej
Estr
C95
imagen612
C96
imagen613
C97
imagen614
C98
imagen615
C99
imagen616
Ej
Estr
C100
imagen617
C101
imagen618
C102
imagen619
103
imagen620
Ej
Estr
104
imagen621
105
imagen622
106
imagen623
107
imagen624
Ej
Estr
108
imagen625
109
imagen626
110
imagen627
111
imagen628
Ej
Estr
C112
imagen629
C113
imagen630
114
imagen631
115
imagen632
Ej
Estr
116
imagen633
C117
imagen634
118
imagen635
C119
imagen636
Ej
Estr
C120
imagen637
C121
imagen638
C122
imagen639
123
imagen640
Ej
Estr
124
imagen641
125
imagen642
126
imagen643
127
imagen644
Ej
Estr
128
imagen645
C129
imagen646
C130
imagen647
131
imagen648
Ej
Estr
132
imagen649
133
imagen650
134
imagen651
C135
imagen652
Ej
Estr
136
imagen653
137
imagen654
138
imagen655
139
imagen656
Ej
Estr
140
imagen657
C141
imagen658
142
imagen659
143
imagen660
Ej
Estr
C144
imagen661
C145
imagen662
C146
imagen663
C147
imagen664
Ej
Estr
148
imagen665
C149
imagen666
C150
imagen667
C151
imagen668
Ej
Estr
C152
imagen669
C153
imagen670
C154
imagen671
C155
imagen672
Ej
Estr
C156
imagen673
C157
imagen674
C158
imagen675
C159
imagen676
Ej
Estr
C160
imagen677
C161
imagen678
C162
imagen679
C163
imagen680
Ej
Estr
C164
imagen681
C165
imagen682
C166
imagen683
C167
imagen684
Ej
Estr
C168
imagen685
C169
imagen686
170
imagen687
171
imagen688
C172
imagen689
Ej
Estr
C173
imagen690
C174
imagen691
C175
imagen692
C176
imagen693
Ej
Estr
177
imagen694
178
imagen695
179
imagen696
C180
imagen697
181
imagen698
Ej
Estr
182
imagen699
183
imagen700
184
imagen701
185
imagen702
186
imagen703
Ej
Estr
187
imagen704
188
imagen705
C189
imagen706
C190
imagen707
C191
imagen708
Ej
Estr
C192
imagen709
C193
imagen710
C194
imagen711
C195
imagen712
C196
imagen713
C197
imagen714
Ej
Estr
C198
imagen715
C199
imagen716
C200
imagen717
201
imagen718
C202
imagen719
Ej
Estr
C203
imagen720
204
imagen721
C205
imagen722
C206
imagen723
207
imagen724
Ej
Estr
C208
imagen725
209
imagen726
C210
imagen727
211
imagen728
212
imagen729
Ej
Estr
213
imagen730
C214
imagen731
C215
imagen732
C216
imagen733
C217
imagen734
Ej
Estr
218
imagen735
219
imagen736
C220
imagen737
C221
imagen738
Ej
Estr
222
imagen739
C223
imagen740
224
imagen741
C225
imagen742
Ej
Estr
226
imagen743
227
imagen744
C228
imagen745
C229
imagen746
Ej
Estr
C230
imagen747
C231
imagen748
C232
imagen749
C233
imagen750
Ej
Estr
C234
imagen751
C235
imagen752
C236
imagen753
237
imagen754
Ej
Estr
C238
imagen755
C239
imagen756
240
imagen757
Ej
Estr
241
imagen758
C242
imagen759
243
imagen760
Ej
Estr
C244
imagen761
C245
imagen762
C246
imagen763
C247
imagen764
Ej
Estr
C248
imagen765
C249
imagen766
C250
imagen767
C251
imagen768
Ej
Estr
252
imagen769
253
imagen770
C266
imagen771
Ej
Syn Datos
1
E1 ESI+:502 RMN H1(DMSO-d6):1,32(3H,t,J=7,5Hz),2,22(3H,s),2,38-2,47(4H,m),2,84(2H,q,J=7,5Hz),2,923,00(4H,m),5,77(1H,dd,J=2,0,10,0Hz),6,26(1H,dd,J=2,0,16,9Hz),6, 43(H,dd,J=10,0,16,9Hz),6,57(2H,d,J=9,1Hz),6,94-6,99(1H,m),7,08(2H,d,J=9,1Hz),7,42-7,49(1H,m),7,637,69(3H,m),7,93-7,97(1H,m),10,34(1H,s),10,93(1H,s)
C2
E2 ESI+: 564,566
C3
E3 ESI+: 559 RMN H1(DMSO-d6):1,32(3H,t,J=7,5Hz),2,16(6H,s),2,21(3H,s),2,382,43(4H,m),2,84(2H,q,J=7,5Hz),2,92-2,98(4H,m),3,02-3,07(2H,m),6,236,30(1H,m),6,57(2H,d,J=9,1Hz),6,69-6,78(1H,m),6,916,96(1H,m),7,07(2H,d,J=9,1Hz),7,43(1H,t,J=8,1Hz),7,59-7,69(3H,m),7,927,96(1H,m),10,25(1H,s),10,92(1H,s)
C4
E4 ESI+: 615
C5
E5 ESI+: 586
6
E6 ESI+: 532
C7
E7 ESI+: 532
8
E8 ESI+: 516
9
E1 ESI+: 585
10
E1 ESI+: 615
11
E1 ESI+: 615
12
E1 ESI+: 502
13
E1 ESI+: 502
14
E1 ESI+: 516
15
E1 ESI+: 516 RMN H1(DMSO-d6):1,34(3H,t,J=7,5Hz),2,01(3H,s),2,20(3H,s),2,372,45(4H,m),2,88(2H,q,J=7,5Hz),2,93-3,02(4H,m),5,72-5,82(1H,m),6,27(1H,dd,J=2,1,17,0Hz),6,536,66(3H,m),6,96(2H,d,J=9,1Hz),7,03(1H,d,J=7,7Hz),7,32(1H,t,J=8, 1Hz),7,62-7,72(2H,m),7,917,97(1H,m),9,60(1H,s),10,95(1H,s)
16
E1 ESI+: 516
17
E1 ESI+: 532
18
E1 ESI+: 516
19
E1 ESI+: 570
20
E1 ESI+: 520
21
E1 ESI+: 599
Ej
Syn Datos
22
E1 ESI+: 516 RMN H1(DMSO-d6):1,33(6H,d,J=6,9Hz),2,21(3H,s),2,38-2,44(4H,m),2,92-2,99(4H,m),3,313,41(1H,m),5,755,79(1H,m),6,26(1H,dd,J=2,0,17,0Hz),6,43(1H,dd,J=10,0,17,0Hz),6,57(2H,d,J=9,1Hz),6,9 4-6,98(1H,m),7,07(2H,d,J=9,1Hz),7,42-7,49(1H,m),7,62-7,72(3H, m),7,887,92(1H,m),10,34(1H,s),10,91(1H,s)
23
E1 ESI+: 573
24
E1 ESI+:575 RMN H1(DMSO-d6):1,25(3H,t,J=7,5Hz),1,48-1,88(8H,m),2,17(3 H,s),2,18(3H,s),2,20-2,60(11H,m),2,76-2,86(3H,m),2,97-3,06(2H, m),3,20-3,32(2H,m),4,15-4,24(1H,m),4,524,61(1H,m),5,69(1H,dd, J=2,5,10,4Hz),6,12(1H,dd,J=2,5,16,7Hz),6,86(1H,dd,J=10,4,16,7H z),6,92(1H,d,J=8,6Hz),7,30(1H,dd,J=2,5,8,6Hz),7,58(1H,d,J=2,5Hz),7,81-7,85(1H,m),8,108,14(1H,m),10,85(1H,s)
25
E1 ESI+: 570
26
E1 ESI+: 474 RMN H1(DMSO-d6):2,21(3H,s),2,36-2,46(4H,m),2,913,04(4H,m),5,78(H,dd,J=2,0,10,1Hz),6,26(H,dd,J=2,0,17,0Hz),6,44(H,dd, J=10,1,17,0Hz),6,62(2H,d,J=9,1Hz),6,94-7,01(1H,m),7,15(2H,d,J= 9,1Hz),7,41-7,49(1H,m),7,60-7,73(3H,m),7,78(1H,s),8,07-8,15(1H, m),10,35(1H,s),11,17(1H,s)
27
E1 ESI+: 501
28
E1 ESI+: 502
C29
E1 ESI+: 516
C30
E1 ESI+: 489
C31
E1 ESI+: 533
C32
E1 ESI+: 503
C33
E1 ESI+: 503
C34
E1 ESI+: 523,525
C35
E1 ESI+: 517
36
E1 ESI+: 491
C37
E4 ESI+: 599
C38
E1 ESI+: 507
39
E1 ESI+: 504
40
E1 ESI+: 480
C41
E3 ESI+: 573
Ej
Sy n Datos
42
E1 ESI+:532 RMN H1(DMSO-d6):1,30(3H,t,J=7,5Hz),2,17(3H,s),2,30-2,40(4H, m),2,69-2,77(4H,m),2,83(2H,q,J=7,5Hz),3,66(3H,s),5,76(1H,dd,J= 2,0,10,1Hz),6,25(1H,dd,J=2,0,17,0Hz),6,43(1H,dd,J=10,1,17,0Hz), 6,51(1H,d,J=8,9Hz),6,70(1H,d,J=2,6Hz),6,86(1H,dd,J=2,5,8,8Hz), 6,93(1H,ddd,J=0,8,2,3,8,1Hz),7,40(1H,t,J=8,1Hz),7,54-7,58(1H,m),7,63(1H,t,J=2,1Hz),7,697,72(1H,m),7,97-8,00(1H,m),10,29(1H,s),11,00(1H,s)
43
E1 ESI+: 516 RMN H1(DMSO-d6):1,03(3H,t,J=7,2Hz),1,32(3H,t,J=7,5Hz),2,35(2H,q,J=7,2Hz),2,42-2,48(4H,m),2,84(2H,q,J=7,5Hz),2,93-2,98(4H, m),5,77(1H,dd,J=2,0,10,1Hz),6,26(1H,dd,J=2,0,17,0Hz),6,43(1H,d d,J=10,1,17,0Hz),6,57(2H,d,J=9,1Hz),6,96(1H,ddd,J=1,0,2,2,8,1Hz),7,07(2H,d,J=9,1Hz),7,45(1H,t,J=8,4H z),7,62-7,69(3H,m),7,91-7,9 7(1H,m),10,33(1H,s),10,92(1H,s)
C4 4
E1 ESI+: 559
C4 5
E4 ESI+: 587
C4 6
E4 ESI+: 613
C4 7
E1 ESI+: 515
C4 8
E1 ESI+: 475
C4 9
E1 ESI+: 473
C5 0
E1 ESI+: 501
C5 1
E1 ESI+: 434
C5 2
E1 ESI+: 531
C5 3
E1 ESI+: 518
54
E1 ESI+:563 RMN H1(DMSO-d6):1,16(3H,t,J=7,5Hz),1,42-1,58(2H,m), 1,78-1, 89(2H,m),2,072,71(18H,m),3,20-3,99(6H,m),5,46-5,57(1H,m),5,6 2-5,72(1H,m),6,10-6,19(1H,m),6,49-6,68(1H,m),6,906,96(2H,m), 7,40-7,47(2H,m),7,54-7,58(1H,m),7,81-7,85(1H,m),10,94-11,00(1 H,m)
55
E1 ESI+: 577
56
E1 ESI+:505 RMN H1(DMSO-d6):1,32(6H,d,J=6,9Hz),1,58-1,75(4H,m),1,93-2, 02(2H,m),2,20(3H,s),2,742,83(2H,m),3,31-3,41(1H,m),3,55-3,65(1H,m),5,77(1H,dd,J=2,0,10,1Hz),6,25(1H,dd,J=2,0,17,0Hz),6,42(1 H,dd,J=10,1,17,0Hz),6,96-7,01(1H,m),7,09-7,12(1H,m),7,29-7,31(1H,m),7,46-7,52(1H,m),7,627,71(3H,m),7,84-7,90(1H,m),10,34(1 H,s),10,69(1H,s)
Ej
Syn Datos
57
E1 ESI+: 508,510
58
E1 ESI+: 552,554
C59
E1 ESI+: 551
C60
E1 ESI+: 550
61
E1 ESI+: 519
C62
E1 ESI+: 531
63
E1 ESI+: 516 RMN H1(DMSO-d6):1,03(3H,d,J=6,1Hz), 1,32(3H,t,J=7,5Hz),2,04-2,13(1H,m),2,162,26(5H,m),2,54-2,63(1H,m),2,73-2,79(1H,m),2, 84(2H,q,J=7,5Hz),3,253,35(2H,m),5,77(1H,dd,J=2,0,10,0Hz),6,26 (1H,dd,J=2,0,17,0Hz),6,44(1H,dd,J=10,0,17,0Hz),6,57(2H,d,J=9,1 Hz),6,96(1H,ddd,J=0,9,2,3,8,1Hz),7,07(2H,d,J=9,1Hz),7,45(1H,t,J =8,1Hz),7,61-7,71(3H,m),7,917,97(1H,m),10,33(1H,s),10,92(1H,s)
64
E1 ESI+: 516 RMN H1(DMSO-d6):1,03(3H,d,J=6,1Hz),1,32(3H,t,J=7,5Hz),2,04-2,13(1H,m),2,162,26(5H,m),2,54-2,63(1H,m),2,73-2,79(1H,m),2, 84(2H,q,J=7,5Hz),3,253,35(2H,m),5,77(1H,dd,J=2,0,10,0Hz),6,26 (1H,dd,J=2,0,17,0Hz),6,44(1H,dd,J=10,0,17,0Hz),6,57(2H,d,J=9,1 Hz),6,96(1H,ddd,J=0,9,2,3,8,1Hz),7,07(2H,d,J=9,1Hz),7,45(1H,t,J =8,1Hz),7,61-7,71(3H,m),7,917,97(1H,m),10,33(1H,s),10,92(1H,s)
C65
E1 ESI+: 499
66
E1 ESI+: 559
C67
E1 ESI+: 504
C68
E1 ESI+: 491
69
E1 ESI+: 561 RMN H1(DMSO-d6):1,25(3H,t,J=7,6Hz),1,42-1,89(8H,m),2,14(3 H,s),2,20-2,38(5H,m),2,43-3,03(9H,m),3,18-3,67(4H,m),4,12-4,23(1H,m),4,51-4,60(1H,m),5,68(1H,dd,J=2,5Hz,10,4Hz),6,12(1H,dd,J =2,5Hz,16,6Hz),6,82-6,93(3H,m),7,46(2H,d,J=9,1Hz),7,78-7,81(1 H,m),8,07-8,12(1H,m),10,78(1H,s)
C70
E1 ESI+: 500
C71
E1 ESI+: 570
72
E1 ESI+: 480
73
E1 ESI+: 480 RMN H1(DMSO-d6):1,16(3H,t,J=7,5Hz),2,14-2,37(5H,m),2,42-2, 69(6H,m),3,043,12(4H,m),3,40-3,99(4H,m),5,47-5,57(1H,m),5,62-5,72(1H,m),6,10-6,19(1H,m),6,496,68(1H,m),6,94(2H,d,J=9,0Hz),7,41-7,49(2H,m),7,54-7,59(1H,m),7,81-7,86(1H,m),10,95-11,02(1 H,m)
Ej
Syn Datos
74
E1 ESI+: 505
75
E75 ESI+: 476
76
E1 ESI+: 520
77
E1 ESI+: 536,538
78
E1 ESI+: 516
79
E1 ESI+: 577
RMN H1(DMSO-d6):1,13(3H,t,J=7,4Hz),1,42-2,08(8H,m),2,14(3 H,s),2,20-2,70(3H,m),3,014,14(6H,m),5,02-5,11(1H,m),5,45-5,7 2(1H,m),5,97-6,12(1H,m),6,47-6,95(3H,m),7,35-7,44(2H,m),7,517,57(H,m),7,78-7,85(H,m),10,92-10,99(1H,m)
80
E1 ESI+: 591
RMN H1(DMSO-d6):1,13(3H,t,J=7,4Hz),1,47-2,07(8H,m),2,14(3 H,s),2,19-2,69(16H,m),2,984,23(6H,m),5,06-5,13(1H,m),5,43-5,7 2(1H,m),5,95-6,11(1H,m),6,48-6,92(1H,m),6,97(1H,d,J=8,6Hz),7,2 8-7,35(1H,m),7,38-7,42(1H,m),7,55-7,60(1H,m),7,82-7,86(1H,m),1 1,04-11,08(1H,m)
81
E1 ESI+: 520
82
E1 ESI+: 520
RMN H1(DMSO-d6):1,32(3H,t,J=7,5Hz),2,21(3H,s),2,38-2,45(4H, m),2,86(2H,q,J=7,5Hz),2,93-3,01(4H,m),5,78(1H,dd,J=2,1,10,0Hz),6,26(H,dd,J=2,1,17,0Hz),6,41(1H,dd,J=10,0,17,0Hz),6,59(2H,d,J =9,1Hz),7,02(2H,d,J=9,1Hz),7,45(1H,dd,J=9,1,10,1Hz),7,62-7,67(1H,m),7,697,73(1H,m),7,78(1H,dd,J=2,5,7,2Hz),7,95-8,01(1H,m), 10,36(1H,s),10,93(H,s)
83
E1 ESI+: 503
84
E1 ESI+: 536,538
85
E1 ESI+: 491
C86
E1 ESI+: 570
87
E1 ESI+: 491
C88
E1 ESI+: 556
89
E1 ESI+: 577
90
E1 ESI+: 591
91
E8 ESI+: 488
92
E1 ESI+: 516
93
E1 ESI+: 516
C94
E1 ESI+: 550
C95
E1 ESI+: 501
C96
E3 ESI+: 558
C97
E1 ESI+: 564
Ej
Syn Datos
C98
E1 ESI+: 598
C99
E1 ESI+: 576
C100
E1 ESI+: 576
C101
E1 ESI+: 562
C102
E1 ESI+: 479
103
E1 ESI+: 583
104
E1 ESI+: 562
105
E1 ESI+: 509
106
E1 ESI+: 592
107
E1 ESI+: 590
108
E1 ESI+: 479
109
E1 ESI+: 493
110
E1 ESI+: 479
111
E1 ESI+: 497
C112
E1 ESI+: 494
C113
E1 ESI+: 466
114
E1 ESI+: 478
115
E1 ESI+: 576
116
E1 ESI+: 493
C117
E1 ESI+: 549
118
E1 ESI+: 562
C119
E1 ESI+: 565
C120
E1 ESI+: 582,584
C121
E122 ESI+: 562
C122
E122 ESI+: 548
123
E122 ESI+: 548
124
E122 ESI+: 562
125
E1 ESI+: 562
126
E1 ESI+: 576
127
E1 ESI+: 562
128
E1 ESI+: 576
C129
E1 ESI+: 480
C130
E1 ESI+: 480
131
E1 ESI+: 576
132
E1 ESI+: 590
133
E1 ESI+: 576
134
E1 ESI+: 590
Ej
Syn Datos
C135
E1 ESI+: 484
136
E1 ESI+: 576
137
E1 ESI+: 576
138
E1 ESI+: 590
139
E1 ESI+: 576
140
E1 ESI+: 590
C141
E1 ESI+: 576
142
E1 ESI+: 576
143
E1 ESI+: 590
C144
E1 ESI+: 576
C145
E1 ESI+: 590
C146
E1 ESI+: 576
C147
E1 ESI+: 590
148
E1 ESI+: 576
C149
E1 ESI+: 590
C150
E1 ESI+: 604
C151
E1 ESI+: 590
C152
E1 ESI+: 568,570
C153
E1 ESI+: 612,614
C154
E1 ESI+: 590
C155
E1 ESI+: 604
C156
E1 ESI+: 611
C157
E1 ESI+: 590
C158
E1 ESI+: 576
C159
E1 ESI+: 590
C160
E1 ESI+: 610
C161
E1 ESI+: 577
C162
E1 ESI+: 559
C163
E1 ESI+: 590
C164
E1 ESI+: 604
C165
E1 ESI+: 604
C166
E1 ESI+: 590
C167
E1 ESI+: 604
C168
E1 ESI+: 516
C169
E1 ESI+: 591
170
E1 ESI+: 538
171
E1 ESI+: 509
C172
E1 ESI+: 576
Ej
Syn Datos
C173
E1 ESI+: 606
C174
E1 ESI+: 620
C175
E1 ESI+: 634
C176
E1 ESI+: 576
177
E1 ESI+: 503
178
E1 ESI+: 536,538
179
E1 ESI+: 570,572
C180
E1 ESI+: 562
181
E1 ESI+: 532
182
E1 ESI+: 549
183
E1 ESI+: 563
184
E1 ESI+: 527
185
E1 ESI+: 532
186
E1 ESI+: 532
187
E1 ESI+: 607
188
E1 ESI+: 520
C189
E1 ESI+: 426
C190
E1 ESI+: 426
C191
E1 ESI+: 516
C192
E192 ESI+: 532
C193
E1 ESI+: 577
C194
E1 ESI+: 595
C195
E1 ESI+: 559
C196
E1 ESI+: 577
C197
E1 ESI+: 553
C198
E1 ESI+: 571
C199
E1 ESI+: 577
C200
E1 ESI+: 577
201
E1 ESI+: 527
C202
E1 ESI+: 575
C203
E1 ESI+: 537
204
E1 ESI+: 603
C205
E205 ESI+: 532
C206
E1 ESI+: 546
207
E1 ESI+: 503
C208
E1 ESI+: 605
209
E1 ESI+: 527
C210
E1 ESI+: 601
Ej
Syn Datos
211
E1 ESI+: 527
212
E1 ESI+: 577
213
E1 ESI+: 577
C214
E214 ESI+: 430
C215
E214 ESI+: 429
C216
E1 ESI+: 590
C217
E214 ESI+: 470
218
E1 ESI+: 503
219
E1 ESI+: 522
C220
E1 ESI+: 604
C221
E1 ESI+: 604
222
E1 ESI+: 591
C223
E1 ESI+: 563
224
E1 ESI+: 589
C225
E1 ESI+: 599
226
E1 ESI+: 589
227
E1 ESI+: 535
C228
E1 ESI+: 522
C229
E1 ESI+: 665
C230
E1 ESI+: 590
C231
E231 ESI+: 550
C232
E231 ESI+: 576
C233
E231 ESI+: 592
C234
E231 ESI+: 626
C235
E231 ESI+: 578
C236
E253 ESI+: 576
237
E253 ESI+: 638
C238
E253 ESI+: 652
C239
E253 ESI+: 682
240
E253 ESI+: 618
241
E253 ESI+: 590
C242
E253 ESI+: 652
243
E253 ESI+: 574
C244
E231 ESI+: 564
C245
E231 ESI+: 626
C246
E231 ESI+: 576
C247
E231 ESI+: 576
C248
E231 ESI+: 590
Ej
Syn Datos
C249
E231 ESI+: 590
C250
E231 ESI+: 592
C251
E231 ESI+: 592
252
E253 ESI+: 590
253
E253 ESI+: 602
C266
E231 ESI+: 576
[Tabla 161]
Núm.
Estr
CA1
imagen772
A2
imagen773
A3
imagen774
5
Aplicabilidad industrial
El compuesto de fórmula (I) o una de sus sales tiene una acción inhibidora sobre la quinasa con una mutación T790M en EGFR y una acción inhibidora sobre la proliferación celular dependiente de proteínas con mutación
10 T790M en EGFR, y se puede utilizar para el tratamiento o similar de cáncer positivo para la mutación T790M en EGFR, por ejemplo cáncer de pulmón positivo para la mutación T790M en EGFR, cáncer de pulmón de células no pequeñas positivo para la mutación T790M en EGFR, cáncer positivo para proteínas con mutación T790M en EGFR, y cáncer de pulmón positivo para proteínas con mutación T790M en EGFR, y similares.
15 Puesto que el cáncer positivo para mutación T790M en EGFR exhibe resistencia a los inhibidores de tirosina quinasa de EGFR existentes tales como gefitinib y erlotinib, el compuesto de fórmula (I) o una de sus sales se puede utilizar para el tratamiento o similar del cáncer resistente a inhibidores de tirosina quinasa de EGFR, por ejemplo cáncer de pulmón resistente a inhibidores de tirosina quinasa de EGFR, cáncer de pulmón de células no pequeñas resistente a inhibidores de tirosina quinasa de EGFR, y similares.
20

Claims (1)

  1. imagen1
    imagen2
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