ES2494294T3 - Antagonistas del receptor de glucagón - Google Patents

Antagonistas del receptor de glucagón Download PDF

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Publication number
ES2494294T3
ES2494294T3 ES08729528.3T ES08729528T ES2494294T3 ES 2494294 T3 ES2494294 T3 ES 2494294T3 ES 08729528 T ES08729528 T ES 08729528T ES 2494294 T3 ES2494294 T3 ES 2494294T3
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cf3co2h
tfa
aryl
nahco3
optionally substituted
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Jorge E. Gomez-Galeno
Raja K. Reddy
Paul D. Van Poelje
Robert Huerta Lemus
Thanh Huu Nguyen
Matthew P. Grote
Qun Dang
Scott J. Hecker
Venkat Reddy Mali
Mingwei Chen
Zhili Sun
Serge Henri Boyer
Haiqing Li
William Craigo
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Metabasis Therapeutics Inc
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Metabasis Therapeutics Inc
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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Abstract

Compuesto de fórmula ó en la que: R44 es H, CH3 o CH3CH2, R45 es alquilo C1-C6, alquenilo, alcoxilo, cicloalquilo C3-6, arilo, fenilo o cicloalquenilo C4-8, pudiendo estar cualquiera de ellos opcionalmente sustituido con uno o más sustituyentes, L es fenilo, indenilo, benzofuran-2-ilo o benzoxazol-2-ilo, opcionalmente sustituido con uno o más sustituyentes, y R46 es H, F, Cl, CH3, CF3, OCF3 o CN; o enantiómero individual, diastereómero, sal farmacéuticamente aceptable, co-cristal, anhidrato, hidrato o solvato de los mismos; y en los que "arilo" se refiere a grupos aromáticos que tienen 5-17 átomos de anillo y al menos un anillo que tiene un sistema de electrones pi conjugados e incluye arilo carbocíclico, arilo heterocíclico, arilo monocíclico, arilo bicíclico y grupos biarilo, pudiendo estar todos ellos opcionalmente sustituidos.

Description

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E08729528
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través de un tapón de Celite, se lavó con acetato de etilo (2x50 ml) y se concentró a presión reducida. Se secó el compuesto resultante a vacío para proporcionar ácido 4-[2-(4-benzofuran-2-il-fenilcarbamoil)-2-(4-ciclohexil-fenil)etil]-benzoico (9) (0,21 g, 92%). 1H-RMN (300 MHz, CD3OD): 7,85 (d, J = 8,1 Hz, 2 H), 7,70 (d, J = 8,7 Hz, 2 H), 7,50 (d, J = 9,0 Hz, 2 H), 7,16 - 7,45 (m, 8 H), 7,07 (s, 1 H), 3,95 (dd, J = 6,0, 9,3 Hz, 1 H), 3,51 (dd, J = 9,3, 12,0 Hz, 1 H), 3,06 (dd, J = 5,7, 10,8 Hz, 1 H), 2,42 - 2,48 (m, 1 H), 1,72 - 1,90 (m, 5 H), 1,35 - 1,46 (m, 5 H); LC-MS m/z = 543 [C37H36NO3+H]+
Etapa B:
imagen44
10
A una mezcla de ácido 4-[2-(4-benzofuran-2-il-fenilcarbamoil)-2-(4-ciclohexil-fenil)-etil]-benzoico (9) (0,21 g, 0,38 mmol), EDCI (148 g, 1,11 mmol), HOBt (118 mg, 0,77 mmol) y N,N-diisopropiletilamina (0,2 g, 1,54 mmol) en DMF (15 ml) se le añadió taurina (97 mg, 0,77 mmol). Tras agitar durante 14 h, se eliminó el disolvente a presión 15 reducida. Se trató el residuo con un exceso de hidróxido de sodio y se cargó sobre una columna de fase inversa C18. Se eluyó con H2O/acetonitrilo al 40% para proporcionar sal de sodio del ácido 4-[2-(4-benzofuran-2-ilfenilcarbamoil)-2-(4-ciclohexil-fenil)-etil]-benzoilamino-etanosulfónico (10) (124 mg, 50%), como un sólido blanco. 1H-RMN (300 MHz, DMSO-d6): 10,25 (s, 1 H), 8,42 (t, J = 4,8 Hz, 1 H), 7,81 (d, J = 8,7 Hz, 2 H), 7,55 - 7,70 (m, 6 H), 7,18 - 7,40 (m, 9 H), 4,0 (dd, J = 6,0, 13,5 Hz, 1 H), 3,45 - 3,55 (m, 3 H), 3,01 (dd, J = 7,8, 14,1 Hz, 1 H), 2,63 (t, J =
20 6,9 Hz, 2 H), 2,30 - 2,46 (m. 1 H), 1,65 - 1,80 (m, 5 H), 1,24 - 1,45 (m, 5 H); LC-MS m/z = 673 [C38H37N2O6SNa+H]+; condiciones de HPLC: Atlantis C-18 OBD 4,6x150 mm de Waters; fase móvil = ACN/(H2O:0,1TFA) velocidad de flujo = 1,0 ml/min; detección = UV a 254, 220 nm, tiempo de retención en min: 19,42; anal. calc.: (MF:C38H37N2O6SNa+1,9H2O) calc.: C: 64,07, H: 5,86, N: 3,93 Hallado: C: 63,87, H: 5,78, N: 3,94.
25 Se prepararon los siguientes compuestos mediante los métodos descritos anteriormente con modificaciones evidentes para un experto individual en la técnica: (los compuestos marcados con * no son según la invención).
Ejemplo
Estructura Espect. de masas (modo) Fórmula CHN (calc.) CHN (hallado)
1.005 *
imagen45 579,3 (+) C32H38N2O6S + 0,8H2O C: 61,58 H: 6,40 N: 4,49 C: 61,87 H: 7,03 N: 4,80
1.006 *
imagen46 567,3 (+) C31H38N2O6S + 1,5H2O C: 62,71 H: 6,96 N: 4,72 C: 62,89 H: 6,88 N: 5,14
1.007 *
imagen47 571,5 (-) C33H36N2O6S + 1H2O + 0,2TFA C: 65,39 H: 6,28 N: 4,57 C: 65,21 H: 6,43 N: 4,81
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1.008 *
imagen48 633,3 (-) C36H46N2O6S + 2,25H2O C: 64,02 H: 7,54 N: 4,15 C: 64,29 H: 8,04 N: 4,31
1.009 *
imagen49 619,5 (-) C35H44N2O6S + 3H2O C: 62,29 H: 7,47 N: 4,15 C: 64,64 H: 7,85 N: 4,15
1.010 *
imagen50 633,0 (-) C28H31IN2O5S + 2H2O C: 50,15 H: 5,26 N: 4,18 C: 50,28 H: 5,53 N: 5,49
1.011 *
imagen51 597,3 (-) C35H38N2O6S + 2,75H2O C: 64,84 H: 6,76 N: 4,32 C: 64,85 H: 6,86 N: 4,31
1.012 *
imagen52 666,5 (-) C39H45N3O6S + 1,75H2O C: 66,98 H: 6,99 N: 6,01 C: 67,10 H: 7,31 N: 5,98
1.013 *
imagen53 565,5 (+) C32H40N2O5S + 2,75H2O C: 62,57 H: 7,47 N: 4,56 C: 62,57 H: 7,62 N: 5,80
1.014 *
imagen54 565,5 (+) C32H40N2O5S + 2,75H2O C: 62,57 H: 7,47 N: 4,56 C: 62,59 H: 7,30 N: 5,21
1.015 *
imagen55 567,9 (+) C32H42N2O5S + 2,75H2O C: 62,36 H: 7,77 N: 4,55 C: 62,01 H: 7,56 N: 5,41
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1.016 *
imagen56 579,3 (-) C33H44N2O5S + 2,75H2O C: 62,88 H: 7,92 N: 4,44 C: 62,57 H: 7,73 N: 5,06
1.017 *
imagen57 515,3 (-) C28H40N2O5S + 2,25H2O C: 60,35 H: 8,05 N: 5,03 C: 60,01 H: 8,09 N: 6,13
1.018 *
imagen58 544 C28H31N2O5ClS+3H2O 56,32 6,25 4,69 56,17 5,10 4,77
1.019 *
imagen59 588 C28H31N2O5BrS + 3,7H2O 51,41 5,92 4,28 51,04 5,53 4,38
1.020 *
imagen60 545 C28H30N2O5F2S+3,6H2O 55,09 6,31 4,59 54,75 5,36 4,80
1.021 *
imagen61 578 C28H30N2O5Cl2S +1,5H2O + 0,3Taurina 53,50 5,51 5,02 53,45 5,23 5,33
1.022 *
imagen62 642,6 (+) C37H43N3O5S + 1,0H2O + 0,5TFA 63,67 6,40 5,86 63,51 6,69 5,93
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1.023 *
imagen63 557,3 (+) C29H33ClN2O5S +2 1H2O 58,55 6,30 4,71 58,15 6,15 5,10
1.024 *
imagen64 573,3 (+) C29H33ClN2O6S +3H2O 55,54 6,27 4,47 55,39 6,05 4,84.
1.025 *
imagen65 533,5 (+) C29H32N2O7S +3,3H2O 56,91 6,36 4,58. 56,66 5,41 4,49.
1.026 *
imagen66 577,3 (+) C28H30Cl2N2O5S +3,8H2O 52,06 5,87 4,34 52,07 4,87 3,97.
1.027 *
imagen67 577,3 (+) C29H31F3N2O5S +3H2O 55,23 5,91 4,44. 54,75 5,37 4,50
1.028 *
imagen68 534,3 (+) C29H31N3O5S +3H2O 59,27 6,35 7,15 59,26 5,30 6,81.
1.029 *
imagen69 621,3 (-) C34H42N2O7S +3H2O 60,34 7,05 4,14 60,11 7,20;4,54
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1.030 *
imagen70 673,6 (+) C40H36N2O6S + 2,2H2O + 0,6TFA C: 63,37, H: 5,29, N: 3,59 C: 63,70, H: 5,68, N: 3,96
1.031 *
imagen71 673,6 (+) C40H36N2O6S + 1,5H2O C: 68,65, H: 5,62, N: 4,00 C: 69,03, H: 6,09, N: 4,18
1.032
imagen72 637,9 (+) C37H38N2O6S + 2,0H2O + 0,2CF3CO2H C: 64,39, H: 6,10, N: 4,02 C: 64,39, H: 6,00, N: 4,01
1.033
imagen73 687,6 (-) C34H32N2O5Cl3SNa + 0,6H2O 56,65 4,64 3,89 56,30 4,40 3,91
1.034
imagen74 657,4 C36H35N2O6ClS + 2,5H2O + 0,3CF3COOH 59,53 5,50 3,79 59,26 5,87 4,02
1.035
imagen75 687,6 (-) C34H33N2O5Cl3S + 1H2O + 0,6CF3COOH 54,59 4,63 3,62 54,31 4,42 3,50
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1.036
imagen76 657,4 (-) C36H35N2O6ClS + 1H2O + 0,4CF3COOH 61,15 5,22 3,88 61,13 4,92 3,82
1.037
imagen77 613,4 (-) C35H38N2O6S + 2H2O +0,5CF3COOH 61,09 6,05 3,96 60,78 6,23 4,24
1.038
imagen78 701,4 (-) C35H34N2O6F3ClS + 3H2O 55,52 5,32 3,70 55,82 5,29 3,57
1.039
imagen79 687,6 (-) C34H32N2O5F2Cl2S + 0,8CF3COOH 54,76 4,23 3,59 54,72 4,23 3,63
1.040
imagen80 659,6 (-) C36H34N2O6F2S + 0,1H2O + 0,6CF3COOH 61,13 4,80 3,83 60,78 4,99 4,19
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1.041
imagen81 701,4 (-) C35H34N2O6F3ClS + 0,7CF3COOH 55,84 4,47 3,58 56,11 4,08 3,44
1.042
imagen82 603,4 (-) C32H27N2O6ClS + H2O C: 61,88 H: 4,71 N: 4,51 C: 61,55 H: 4,60 N: 4,82
1.043
imagen83 603,9 (-) C30H25N2O5Cl3S + 0,4H2O C: 56,37 H: 4,07 N: 4,38 C: 56,61 H: 4,15 N: 4,36
* 1.044
imagen84 661,6 (-) C33H29N2O6BrS + 2H2O C: 56,82 H: 4,77 N: 4,02 C: 56,79 H: 4,76 N: 4,07
1.045
imagen85 649 (+) C35H31N2O6SN+1,2H2O C: 64,35, H: 5,31, N: 4,29 C: 64,10, H: 4,77, N: 4,46
1.046
imagen86 609 (+) C35H31N2O6SNa +1,2H2O C: 64,35, H: 5,31, N: 4,29 C: 64,10, H: 4,77, N: 4,46
* 1.047
imagen87 577 (+) C32H36N2O6SNa +0,4CH2Cl2 C: 61,41, H: 5,85, N: 4,42 C: 61,15 H: 5,57, N: 4,19
* 1.048
imagen88 605 (+) C30H34N2O6SNa +0,8NaCl C: 61,41, H: 5,85, N: 4,42: C: 55,26 H: 5,07, N: 3,99
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1.049
imagen89 635 (+) C37H33N2O6SNa +4,0H2O C: 60,89, H: 5,80, N: 3,84 C: 60,50, H: 5,45, N: 4,08 (C37H33N2O6SNa+4,0H2 O)
1.050
imagen90 569 (+) C32H28N2O6S +2,5H2O +0,1CH3CN C: 62,70, H: 5,28, N: 4,77 C: 62,70, H: 5,50, N: 4,99
1.051
imagen91 632 (+) C35H31N2O6SNa +2,0H2O C: 62,96, H: 5,43, N: 4,20 C: 62,97, H: 5,63, N: 4,53 (C35H31N2O6SNa+2,0H2 O)
1.052
imagen92 651 (+) C38H37N2O6SNa +2,0H2O C: 64,39, H: 5,83, N: 3,95 C: 64,28, H: 5,86, N: 4,12
* 1.053
imagen93 626,6 (+) C35H34N3O6SNa + 6,0H2O C: 55,62, H: 6,13, N: 5,56; C: 55,32, H: 5,71, N: 5,36.
* 1.054
imagen94 626,6 (+) C35H34N3O6SNa + 2,5H2O C: 60,68, H: 5,67, N: 6,07; C: 60,79, H: 5,40, N: 6,02
* 1.055
imagen95 539,4 (+) C29H32N4O5S + 0,2TFA C: 61,79, H: 5,68, N: 9,80; C: 61,56, H: 5,41, N: 9,84
* 1.056
imagen96 633,6 (+) C30H30F3N4O6SNa + 3,6H2O C: 50,08, H: 5,21, N: 7,79; C: 49,95, H: 4,88, N: 7,40.
* 1.057
imagen97 563,4 (+) C30H33N4O5SNa + 4,2H2O C: 54,57, H: 6,32, N: 8,48; C: 54,58, H: 5,59, N: 8,41.
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* 1.058
imagen98 583,1 (+) C20H30ClN4O5SNa + 1,8H2O C: 54,64, H: 5,31, N: 8,79; C: 54,59, H: 5,28, N: 8,68.
* 1.059
imagen99 633,6 (-) C28H30N2O5SINa + (0,5)H2O C: 50,53, H: 4,69, N: 4,21 C: 50,64, H: 4,64, N: 4,33
* 1.060
imagen100 623,6 (-) C36H36N2O6S + (19)H2O C: 65,62, H: 6,09, N: 4,25 C: 65,31, H: 5,68, N: 4,15
* 1.061
imagen101 623 9 (+) C37H39N2O5P C: 71,37, H: 6,31; N: 4,50 C: 64,86; H: 5,75; N: 4,04
* 1.062
imagen102 593,6 (+) C29H31F3N2O6S 58,77 5,27 4,73 57,66 6,54 6,00
* 1.063
imagen103 586,3 (+) C35H35N3O5S+1,5H2O+1 .1CF3CO2H C: 57,27; H: 5,34; N: 5,69 C: 57,07; H: 5,52; N: 5,78
* 1.064
imagen104 584,6 (-) C33H34N3O5SNa+2,5H2O C: 60,72; H: 6,02; N: 6,44 C: 60,56; H: 5,73; N: 6,41
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1.065
imagen105 639,6 (+) C37H37N2O6SNa C: 67,26 H: 5,64; N: 4,24 No medido
* 1.066
imagen106 611,6 (+) C35H33N2O6S + 0,5Na + 0,5HTEA + 1H2O 66,12 6,28 5,07 65,75 6,51 5,27
1.067
imagen107 625,3 (+) C36H35N2O6S + 0,8H2O + C6H16N 68,14 7,16 5,68 68,00 7,30 5,81
1.068
imagen108 585,3 (+) C34H36N2O5S+3H2O C: 63,93; H: 6,63; N: 4,39 C: 63,63; H: 6,17; N: 4,49
* 1.069
imagen109 631,2 (+) C36H36N2O4Cl2 C: 68,46 H; 5,75 N: 4,44 C: 68,59 H: 5,87 N: 4,32
* 1.070
imagen110 625,3 (-) C35H50N206S + 1,2H2O C: 64,83 H: 8,14 N: 4,32 C: 64,73 H: 7,89 N: 4,74
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* 1.071
imagen111 625,3 (-) C35H50N206S + 3H2O C: 61,74 H: 8,29 N: 4,11 C: 61,97 H: 8,56 N: 4,39
* 1.072
imagen112 611,3 (+) C30H36N2O5S + 2 5H2O + 0,16DMF C 61,69; H: 7,15; N: 5,10 C: 61,41; H: 7,43; N: 5,49
1.073
imagen113 631 4 (-) C30H25Cl3N2O5S + 1,7H2O C: 5438, H: 4,32, N: 4,23 C: 54 04, H: 4 07, N: 4 34
1.074
imagen114 637,3 (+) C33H27N2O6F3S + 2,6H2O + 0,1TFA C: 57,39, H: 4,69, N: 4,03 C: 5767, H: 520, N: 4,20
1.075
imagen115 665,2 (+) C31H25N2O5F3Cl2S + 1,4H2O + 0,1TFA C: 53,37, H: 4,01, N: 3,99 C: 53,15, H: 4,53, N: 4,39
1.076
imagen116 653,6 (+) C33H27F3N2O7S +0,8H2O +0,1TFA C: 58,77, H: 4,26, N: 4,13 C: 58,37, H: 4,16, N: 4,55
1.077
imagen117 601,6 (-) C32H27ClN2O6S + 1,3H2O C: 61,35, H: 4,76, N: 4,47 C: 61,07, H: 4,79, N: 4,68
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1.078
imagen118 645,4 (+) C38H32N2O6S + 2,6H2O + 0,3DMF C: 65,48, H: 5,55, N: 4,52 C: 65,88, H:5,98, N: 4,22
1.079
imagen119 673,4 (+) C36H30N2O5 Cl2S + 2,6H2O + 0,6DMF C: 59,40, H: 5,20, N: 4,76 C: 59,29, H: 5,55, N: 4,78
1.080
imagen120 681,4 (+) C31H25Cl2F3N2O6S + 1H2O + 0,1TFA C: 52,55, H: 3,84, N: 3,94 C: 52,33, H: 4,21, N: 3,95
1.081
imagen121 665,6 (+) C32H26N2O5F6S + 2,7H2O + 0,3TFA C: 52,38, H:4,27, N: 3,75 C: 52,21, H: 4,58, N: 4,10
1.082
imagen122 651,6 (-) C35H35F3N2O5S + 2,1H2O C: 60,88, H: 5,72, N: 4,06 C: 61,26, H: 6,20, N: 4,37
1.083
imagen123 601,6 (-) C34H35FN2O5S + 1,9H2O C: 64,11, H: 6,14, N: 4,40 C: 64,27, H: 5,94, N: 4,60
1.084
imagen124 681,4 (+) C32H26N2O6F6S + 1,2H2O + 0,2TFA C: 53,67, H: 3,98, N: 3,86 C: 53,64, H: 4,02, N: 4,11
1.085
imagen125 617,4 (-) C34H35ClN2O5S + 1,7H20 + 0,1TFA C: 62,12, H: 5,87, N: 4,24 C: 61,84, H: 6,20, N: 4,14
1.086
imagen126 667,4 (-) C35H35F3N2O6S 2,0H2O C 59,65, H: 5,58, N: 3,97 C 59,38, H: 4,94, N: 3,96
20-08-2014 E08729528
* 1.087
imagen127 699 1 (+) C31H25Cl2F3N2O5S + 1,8H2O C: 51,00, H: 3,95, N: 3,84 C: 50,89, H: 3,57, N:3,75
* 1.088
imagen128 547,6 (-) C31H36N2O5S + 2,3H2O C: 63,09, H: 6,93, N: 4,57 C: 62,93, H: 7,19, N: 4,77
* 1.089
imagen129 669,4 (+) C33H27F3N2O6S2 + 1,5H2O C: 56,97, H: 4,35, N: 4,03 C: 56,81, H: 3,99, N: 4,25
1.090
imagen130 615,4 (+) C31H26N2O5F4S + 0,9H2O + 0,3TFA C: 57,07, H: 4,26, N: 4,21 C: 56,76, H: 3,83, N: 4,64
1.091
imagen131 631,6 (+) C31H26N2O5F3ClS + 2,6H2O + 0,1TFA C: 54,36, H: 4,58, N: 4,06 C: 54,53, H: 4,88, N: 4,43
1.092
imagen132 619,4 (-) C34H34F2N2O5S + 1,6H2O C: 62,87, H: 5,77, N: 4,31 C: 62,60, H: 5,62, N: 4,50
* 1.093
imagen133 587,4 (-) C34H40N2O5S + 2,5H2O C: 64,43, H: 7,16, N: 4,42 C: 64,10, H: 6,43, N: 4,34
* 1.094
imagen134 639,6 (-) C36H36N2O5S2 + 1,8H2O C: 64,23, H: 5,93, N: 4,16 C: 64,06, H: 5,73, N: 4,14
20-08-2014
* 1.095
imagen135 573,7 (-) C32H34N2O6S + 3H2O C: 61,13 H: 6,41 N: 4,46 C: 53,75 H: 4,41 N: 6,91
1.096
imagen136 651,19 (-) C35H34N2O5SF3Na+ (2,2)H2O C: 58,85, H: 5,42, N: 3,92 C: 58,52, H: 5,01, N: 4,03
* 1.097
imagen137 537,3 (+) C30H36N2O5S + 2,5H2O + 0,16DMF C: 61,69, H: 7,15, N: 5,10 C: 61,41, H: 7,43, N: 5,49

EJEMPLO 1.098: (no según la invención) PRECURSOR 1:
imagen138
Se calentó una mezcla de 2,372 g de la N-(2-bromoetil)ftalimida disponible comercialmente y 5,00 g de dietilmetilfosfonita a 140ºC durante un periodo de 21 h. Se eliminaron los compuestos volátiles a presión reducida y
10 se purificó el residuo mediante cromatografía sobre gel de sílice (gradiente de metanol-diclorometano). Se obtuvo el producto como un aceite amarillo. H-RMN (300MHz, DMSO-d6): 7,8 (4H, m), 3,83 (6H, m), 2,10 (2H, m), 1,46 (3H, d, J = 13,9 Hz), 1,10(3H, t, J = 7,0 Hz).
Se trató el aceite obtenido en la etapa anterior (2,454 g) en 7 ml de etanol con 2,12 ml de hidrato de hidrazina. Se
15 calentó la mezcla resultante a reflujo durante un periodo de 2 h y se permitió que se enfriase hasta temperatura ambiente. Se retiró el precipitado blanco formado mediante filtración y se concentró la disolución a presión reducida para proporcionar el precursor 1 como un aceite amarillo. H-RMN (300MHz, DMSO-d6): 3,90 (4H, m), 2,75 (2H, m), 2,60 (2H, ancho), 1,80 (2H, m), 1,38 (3H, d, J = 13,8 Hz), 1,20 (3H, t, J = 7,0 Hz)
20 Etapa A:
imagen139
Se preparó ácido 4-[1-(4-benzofuran-2-il-fenilcarbamoil)-heptiloxi]-benzoico tal como se describe en Bioorganic &
25 Medicinal Chemistry Letters 14 (2004) 2047 -2050. A una disolución de 200 mg del ácido carboxílico de partida (preparado tal como se describe en Bioorganic & Medicinal Chemistry Letters 2004, 14, 2047-2050) en THF se le añadió carbonildiimidazol (85 mg) y se agitó la disolución a temperatura ambiente durante 1 h. Se añadió el precursor 1 (77 mg) en una porción y se agitó la mezcla de reacción durante un periodo adicional de 1 h. Entonces se diluyó la mezcla con acetato de etilo y se lavó con agua. Tras secado sobre sulfato de magnesio y concentración,
30 se sometió el producto bruto a cromatografía sobre gel de sílice usando un gradiente de acetato de etilo-hexanos.
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
N.º de ej.
Estructura CL-EM (modo) Fórmula CHN (calc.) CHN (hallado)
1.142 *
imagen178 652,9 (+) C37H37N3O6S + 1,5 H2O + 0,2 CF3CO2H 64,03 5,78 5,99 64,09 5,75 5,87
1.143
imagen179 656,6 (+) C36H37N3O7S + 0,1 H2O + 0,1 CF3CO2H 64,99 5,62 6,28 64,99 5,79 6,50
1.144
imagen180 797,9 (+) C38H35N2O6F6ClS + 0,8 H2O + 0,3 CF3CO2H 54,81 4,40 3,31 54,79 4,17 3,20
1.145
imagen181 682,9 (+) C38H39N3O7S + 1,7 H2O + 0,3 CF3CO2H 62,09 5,76 5,63 61,90 5,65 5,57
1.146
imagen182 666,6 (+) C38H39N3O6S + 0,9 H2O + 0,1 CF3CO2H 66,17 5,95 6,06 66,19 5,90 6,03
1.147
imagen183 666,6 (+) C38H39N3O6S + 0,9 H2O + 0,3 CF3CO2H 64,73 5,78 5,87 64,73 5,49 5,73
1.148
imagen184 666,6 (+) C38H39N3O6S + 1,5 H2O + 0,3 CF3CO2H 63,77 5,86 5,78 63,74 5,85 5,67
1.149 *
imagen185 650,9 (+) C38H39N3O5S + 2,1 H2O + 0,1 CF3CO2H 65,64 6,24 6,01 65,95 6,58 5,80
1.150
imagen186 686,6 (+) C37H36N3O6ClS + 2,0 H2O 61,53 5,58 5,82 61,55 5,40 5,84
1.151 *
imagen187 681,6 (+) C38H40N4O6S + 1,9 H2O + 0,1 CF3CO2H 62,51 6,01 7,59 62,47 6,07 7,44
1.152 *
imagen188 685,9 (+) C37H37N4O5ClS + 1,5 H2O + 0,1 CF3CO2H 61,74 5,59 7,74 61,85 5,65 7,76
1.153 *
imagen189 668,4 (+) C37H37N3O5S2 + 0,8 H2O + 0,1(CH3)2C(O) 65,05 5,75 6,12 65,09 5,85 6,24
1.154
imagen190 652,6 (+) C37H37N3O6S + 0,3 H2O + 0,1(CH3)2C(O) 67,51 5,82 6,35 67,68 5,93 6,38
1.155
imagen191 687,6 (+) C33H26N2O7F3ClS +1,6 H2O + 0,1 CF3CO2H 54,83 4,06 3,85 55,11 4,44 3,84
1.156
imagen192 638,6 (+) C32H26N3O6F3S + 3,0 H2O + 0,4 CF3CO2H 53,43 4,43 5,70 53,46 4,46 5,75
1.157 *
imagen193 642,4 (+) C35H35N3O5S2 + 0,2 H2O 65,13 5,53 6,51 65,16 5,35 6,51
1.158
imagen194 655,6 (+) C33H26N2O6F4S + 1,7 H2O + 0,3 CF3CO2H 56,09 4,16 3,89 56,15 3,96 3,76
1.159
imagen195 671,4 (+) C33H26N2O7F4S + 1,8 H2O + 0,2 CF3CO2H 55,27 4,14 3,86 55,38 4,05 3,75
1.160
imagen196 683,4 (+) C31H24N2O5F4Cl2S + 1,2 H2O +0,1 CF3CO2H 52,30 3,73 3,91 52,13 3,98 3,74
1.161
imagen197 671,4 (+) C33H26N2O6F3ClS + 1,6 H2O + 0,1 CF3CO2H 56,06 4,15 3,94 56,14 4,09 3,82
1.162
imagen198 699,4 (+) C31H24N2O5F3Cl3S + 1,7 H2O + 0,1 CF3CO2H 50,51 3,74 3,78 50,78 4,04 3,73
1.163 *
imagen199 638,6 (+) C32H26N3O6F3S + 1,3 CH3OH + 0,3 CF3CO2H 57,07 4,45 5,89 57,43 4,87 5,53
1.164
imagen200 625,6 (+) C36H36N2O6S + 2,6H2O + 0,05 CF3CO2H 64,02 6,14 4,14 64,33 6,52 4,42
1.165 *
imagen201 610,6 (+) C33H27N3O7S + 2,9H2O 59,88 4,99 6,35 59,84 4,88 6,32
1.166
imagen202 653,6 (+) C35H35N2O5F3S + 1,5 H2O + 0,3 CF3CO2H 59,89 5,41 3,92 59,78 5,73 3,95
1.167 *
imagen203 615,6 (+) C39H38N2O5 + 1,0 CH3OH 74,28 6,55 4,33 74,35 6,96 4,54
1.168 *
imagen204 667,4 (+) C34H29N2O5F3S2 + 2,5 H2O 57,37 4,81 3,94 57,40 4,63 3,96
1.169
imagen205 642,4 (-) C35H34N3O5ClS + 2,3H2O + 0,4CF3COOH 58,80 5,38 5,75 58,76 5,07 5,58
1.170
imagen206 662,9 (-) C34H31N3O5 Cl2S + 0,8CF3COOH 56,57 4,24 5,56 56,53 4,16 5,64
1.171
imagen207 648,6 (-) C38H39N3O5S + 2H2O + 0,2CF3COOH 65,09 6,14 5,93 65,28 6,06 5,86
1.172
imagen208 645,6 (-) C37H34N2O5F3Cl2SNa + 2,3H2O 54,79 4,80 3,45 54,62 4,41 3,51
1.173
imagen209 725,6 (-) C38H38N2O5F3ClS + 3H2O 58,42 5,68 3,59 58,44 5,84 3,19
1.174
imagen210 668,4 (-) C37H36N3O5ClS + 2,5H2O + 0,4CF3COOH 59,67 5,48 5,52 59,81 5,64 5,65
1.175
imagen211 671,6 (-) C38H40N2O5ClS Na + 2,5H2O 61,65 6,13 3,78 61,25 5,70 3,88
1.176
imagen212 671,4 (-) C38H40N2O5ClSNa + 2,5H2O 61,65 6,13 3,78 61,59 5,83 3,81
1.177
imagen213 725,6 (-) C38H38N2O5ClS + 2H2O + 0,2CF3COOH 58,67 5,41 3,55 58,67 5,32 3,55
1.178
imagen214 745,6 (-) C37H34N2O5F3Cl2SNa + 2H2O 55,16 4,75 3,48 55,35 4,51 3,51
1.179
imagen215 725,6 (-) C38H37N2O5F3ClSNa + 2H2O + 0,3CF3COOH 56,58 5,08 3,42 56,76 5,04 3,48
1.180
imagen216 759,9 (-) C39H38N2O5F6S + 1,8H2O 59,05 5,29 3,53 59,05 5,37 3,70
1.181
imagen217 725,6 (-) C38H40N2O5ClSNa + 2H2O + 0,2CF3COOH 61,16 5,91 3,71 61,2 6,27 3,83
1.182
imagen218 675,6 (-) C37H38N2O5FClS + 2H2O + 0,3CF3COOH 60,42 5,70 3,75 60,66 5,51 3,57
1.183
imagen219 691,6 (-) C37H38N2O5Cl2S 64,06 5,52 4,04 No sometido a prueba.
1.184
imagen220 699,4 (-) C36H36N2O5F3ClS + 2,2H2O + CF3COOH 53,39 4,88 3,28 53,13 5,01 3,11
1.185
imagen221 649,6 (-) C35H36N2O5FClS 64,56 5,57 4,30 No sometido a prueba.
1.186 *
imagen222 627,9 (-) C37H44N2O5S + 2H2O + 0,8CF3COOH 61,32 6,51 3,71 61,03 6,25 3,34
1.187 *
imagen223 647,6 (-) C36H41N2O5ClS + 2,5H2O 55,49 5,72 3,37 55,25 5,75 3,52
1.188
imagen224 631,6 (-) C35H37N2O5ClS + 2H2O + 0,3CF3COOH 60,79 5,92 3,98 60,91 6,25 3,72
1.189
imagen225 665,6 (-) C35H35N2O5Cl2SNa + 2,2H2O + 0,2CF3COOH 56,54 5,31 3,72 56,62 5,70 4,02
1.190
imagen226 649,6 (-) C35H35N2O5FClSNa + 2 2H2O + 0,3CF3COOH 57,24 5,36 3,75 57,06 5,44 3,88
1.192
imagen227 649,6 (-) C35H36N2O5FClS 64,56 5,57 4,30 No sometido a prueba.
1.193
imagen228 631,6 (-) C35H37N2O5ClS + 2H2O + 0,4CF3COOH 60,15 5,84 3,92 60,34 5,98 3,99
1.194
imagen229 665,6 (-) C35H35N2O5Cl2SNa + 1,5H2O 58,66 5,34 3,91 58,53 5,35 3,98
1.195
imagen230 649,6 (-) C35H36N2O5FClS + 2H2O + 0,3CF3COOH 59,27 5,63 3,88 59,08 5,75 3,85
1.196
imagen231 637,6 (-) C37H37N2O6SNa + 3H2O 62,17 6,06 3,92 62,02 6,35 4,13
1.197
imagen232 649,6 (-) C35H35N2O5FClSNa + 2H2O 59,18 5,54 3,95 59,19 5,94 4,07
1.198
imagen233 645,4 (-) C36H39ClN2O5S 66,81 6,07 4,33 No sometido a prueba.
1.199
imagen234 651,6 (-) C34H34N2O5Cl2S + 1,5H2O + 0,2CF3COOH 58,74 5,33 3,98 58,89 5,03 3,88
1.200
imagen235 669,4 (-) C34H33N2O5FCl2S + 2H2O + 0,5CF3COOH 54,98 4,94 3,66 54,85 4,65 3,52
1.201
imagen236 703,6 (-) C39H45N2O6ClS 66,41 6,43 3,97 No sometido a prueba.
1.202
imagen237 687,9 (-) C39H45N2O5ClS 67,96 6,58 4,06 No sometido a prueba
1.203
imagen238 669,4 (-) C34H33N2O5FCl2S + 1,8H2O + 0,1CF3COOH 57,42 5,17 3,92 57,43 4,88 3,53
1.204
imagen239 669,4 (-) C34H33N2O5FCl2S + 2H2O + 0,4CF3COOH 55,49 5,00 3,72 55,66 5,01 3,47
1.205 *
imagen240 623,6 (-) C34H41N2O5ClS + 0,6H2O + 0,1CF3COOH 63,45 6,59 4,33 63,14 6,24 4,24
1.206
imagen241 653,6 (-) C39H46N2O5S+3H2O 66,08 7,39 3,95 66,17 7,07 3,64
1.207
imagen242 635,9 (-) C34H34N2O5FClS + 2H2O + 0,2CF3COOH 59,36 5,53 4,02 59,53 5,93 3,67
1.208
imagen243 622,6 (-) C36H37N3O5S 69,32 5,98 6,74 No sometido a prueba.
1.209 *
imagen244 589,6 (-) C34H42N2O5S + 3H2O 63,33 7,50 4,34 63,19 7,27 3,99
1.210
imagen245 703,6 (-) C34H26N2O6F6S + 2H2O + 0,1CF3COOH 54,62 4,03 3,72 54,88 4,32 3,46
1.211
imagen246 613,4 (-) C34H32N2O7S + 2,5H2O + 0,3DMF 61,66 5,80 4,74 61,86 5,74 4,90
1.212
imagen247 647,6 (+) C34H31N2O7ClS + 0 6H2O 62,07 4,93 4,26 61,90 4,82 4,15
1.213
imagen248 629,6 (-) C34H31N2O7FS + 2,6H2O 60,27 5,39 4,13 60,11 5,24 4,07
1.214
imagen249 631,4 (-) C33H29N2O7ClS + 2H2O + 0,4CF3COOH 56,80 4,71 3,92 56,96 4,88 3,94
1.215
imagen250 643,4 (-) C35H33N2O6ClS + H2O 63,39 5,32 4,22 63,36 5,16 4,17
1.216 *
imagen251 665,6 (-) C37H31N2O7FS + 3H2O 61,67 5,17 3,89 61,73 5,45 3,66
1.217 *
imagen252 681,6 (-) C37H31N2O7ClS + 3H2O 60,28 5,06 3,80 60,21 4,87 3,67
1.218
imagen253 691,9 (-) C35H39N2O5F3ClSNa + 1H2O 57,33 5,64 3,82 57,07 5,83 3,90
1.219
imagen254 691,9 (-) C35H39N2O5F3ClSNa + 1H2O 57,33 5,64 3,82 57,11 5,74 4,06
1.220
imagen255 673,6 (-) C38H39N2O5F2SNa + 1,4H2O 63,21 5,84 3,88 63,11 5,70 4,14
1.221
imagen256 727,6 (-) C38H36N2O5F5SNa + 1,5H2O 58,68 5,05 3,60 58,60 4,90 3,87
1.222
imagen257 693,6 (-) C37H36N2O5F2ClSNa + 2,5 H2O 58,30 5,42 3,68 57,94 5,22 4,04
1.223
imagen258 747,6 (-) C37H34N2O5F5ClSNa + 1 H2O 56,31 4,47 3,55 56,39 4,65 3,69
1.224
imagen259 713,6 (-) C36H33N2O5F2Cl2SNa + 1,5H2O 56,55 4,75 3,66 56,62 4,56 3,69
1.225 *
imagen260 723,6 (-) C41H40N2O6ClSNa + 2,5 H2O + 0,5 NaHCO3 59,74 5,50 3,36 59,74 5,16 3,27
1.226 *
imagen261 745,9 (-) C38H35N2O5F6SNa + 3 H2O + 0,5 NaHCO3 53,47 4,84 3,24 53,18 4,63 3,06
1.227 *
imagen262 779,6 (-) C38H34N2O5F6ClSNa + 3 H2O + 0,5 NaHCO3 51,42 4,54 3,12 51,54 4,21 2,99
1.228 *
imagen263 661,9 (-) C36H36N2O5FClSNa + 2 H2O 59,87 5,58 3,88 59,69 5,39 3,71
1.229 *
imagen264 649,6 (-) C36H42N2O5ClSNa + 0,1 NaHCO3 + 3 H2O 58,94 6,59 3,81 58,79 6,26 3,65
1.230 *
imagen265 679,6 (-) C36H34N2O5F2ClSNa + 1,5 H2O 59,22 5,11 3,84 59,06 5,06 3,73
1.231 *
imagen266 647,4 (-) C30H31N2O5ClBrSNa + 1,4 H2O 51,83 4,90 4,03 51,84 4,87 3,97
1.232 *
imagen267 651,6 (-) C31H31N2O6F3ClSNa + 1,5 H2O 53,03 4,88 3,99 53,06 4,58 3,93
1.233 *
imagen268 666,6 (-) C37H36N3O5S2Na + 2 H2O 61,22 5,55 5,79 61,03 5,43 5,69
1.234 *
imagen269 687,6 (-) C34H32N2O5Cl3SNa + 2,5 H2O 54,08 4,94 3,71 54,01 4,68 3,49
1.236 *
imagen270 655,6 (-) C34H33N2O5Cl2SNa + 2,5 H2O 56,67 5,31 3,89 56,55 4,94 3,71
1.237 *
imagen271 653,6 (+) C34H33N2O5ClSNa + 3H2O 55,97 5,39 3,84 55,88 5,24 3,74
1.238 *
imagen272 625,6 (+) C34H40N2O5ClSNa + 1,8 H2O 60,09 6,47 4,12 60,04 6,31 3,95
1.239 *
imagen273 703,6 (+) C35H33N2O6F3ClSNa + 2,5 H2O 54,58 4,97 3,64 54,40 4,79 3,42
1.240 *
imagen274 648,6 (+) C35H40N3O5S2Na + 4H2O + 0,2 NaHCO3 55,72 6,40 5,54 55,60 6,71 5,36
1.241 *
imagen275 633,6 (+) C29H35N2O6F3ClSNa + 1,8 H2O + 0,3 NaHCO3 49,38 5,50 3,93 48,53 5,92 3,75
1.242 *
imagen276 633,6 (+) C29H35N2O6F3ClSNa + 1,8 H2O + 0,1 NaHCO3 50,22 5,60 4,03 49,98 5,23 3,79
1.243 *
imagen277 679,6 (+) C36H35N2O5Cl2Na + 3 H2O + 0,4 NaHCO3 55,39 5,29 3,55 55,07 4,89 3,43
1.244 *
imagen278 726,6 (+) C37H35N2O6F3ClSNa + 3 H2O + 0,2 NaHCO3 54,35 5,03 3,41 54,17 4,77 3,49
1.245
imagen279 659,6 (+) C34H39N2O5Cl2SNa + 1,9 H2O 57,04 6,03 3,91 56,71 5,82 3,64
1.246
imagen280 629,6 (-) C36H41N2O6SNa + 2,5 H2O + 0,2 NaHCO3 60,84 6,52 3,92 60,82 6,25 3,90
1.247
imagen281 673,4 (+) C35H41N2Cl2SNa + 3 H2O 56,07 6,32 3,74 56,41 5,10 3,74
1.248
imagen282 645,4 (+) C37H43N2O6SNa + 4 H2O 60,15 6,96 3,79 59,85 6,82 3,68
1.249 *
imagen283 627,6 (+) C34H29N2O8SNa + 2,7 H2O 58,56 4,97 4,02 58,32 4,62 4,04
1.250
imagen284 609,9 (+) C34H40N2O5FSNa + 1,5 H2O + 0,1 NaHCO3 61,48 6,52 4,21 61,24 6,22 4,18
1.251 *
imagen285 753,4 (-) C39H31N2O5F6SNa + 2,2 H2O 57,38 4,37 3,43 57,45 4,17 3,33
1.252
imagen286 725,6 (-) C37H36Cl3N2O5SNa + 1,8H2 56,79 5,10 3,58 56,54 4,81 3,35
1.253
imagen287 701,6 (-) C40H43F2N2O5SNa + 2H2O 63,14 6,23 3,68 63,25 6,08 3,68
1.254
imagen288 732,1 (-) C41H45F2N2O6SNa + 1,6H2O 62,84 6,20 3,57 62,97 5,97 3,45
1.255
imagen289 781,6 (-) C38H33F8N2O5Na + 0,6H2O + 0,4Na2CO3 53,76 4,02 3,27 53,59 3,62 2,95
1.256
imagen290 664,1 (-) C36H34F3N2O5SNa + 1,7H2O 60,28 5,26 3,91 60,15 5,10 3,75
1.257
imagen291 673,6 (-) C38H39F2N2O5SNa + 2H2O 62,28 5,91 3,82 62,23 5,52 3,60
1.258
imagen292 727,6 (-) C38H36F5N2O5SNa + 1,2H2O + 0,15Na2CO3 58,13 4,91 3,55 58,52 4,50 3,14
1.259
imagen293 713,6 (-) C36H33Cl2F2N2O5SNa + 2,5H2O 55,25 4,89 3,58 55,19 4,81 3,40
1.260
imagen294 743,9 (-) C38H36ClF4N2O5SNa + 2,4H2O 56,32 5,07 3,46 56,32 4,85 3,30
1.261
imagen295 747,6 (-) C37H33ClF5N2O5SNa + 2,6H2O 54,33 4,71 3,42 54,30 4,38 3,09
1.262
imagen296 729,6 (-) C37H34ClF4N2O5SNa + 2H2O 56,31 4,85 3,55 56,36 4,68 3,42
1.263
imagen297 679,6 (-) C36H34ClF2N2O5SNa + 3,2H2O 56,83 5,35 3,68 57,15 4,96 3,15
1.264
imagen298 569,6(-) C30H31F2N2O5SNa + 2,9H2O 55,88 5,75 4,34 55,63 5,36 4,25
1.265
imagen299 693,6 (-) C37H36ClF2N2O5SNa + 2,2H2O 58,72 5,38 3,70 58,57 5,26 3,56
1.266
imagen300 649,6 (-) C30H30BrF2N2O5SNa + 1,9H2O 51,06 4,83 3,97 51,08 4,54 4,02
1.267
imagen301 715,9 (-) C40H41ClFN2O5SNa + 2H2O + 0,1Na2CO3 61,28 5,77 3,56 60,96 5,44 3,44
1.268
imagen302 731,9 (-) C40H41Cl2N2O5SNa + 1,6H2O 61,24 5,68 3,57 61,21 5,71 3,32
1.269
imagen303 711,6 (-) C41H44ClN2O5SNa +2H2O 63,84 6,27 3,63 63,82 6,23 3,34
1.270
imagen304 765,6 (-) C41H41ClF3N2O5SNa + 2,9H2O + 0,1Na2CO3 57,93 5,54 3,29 57,56 5,17 3,12
1.271 *
imagen305 675,6 (-) C37H37ClFN2O5SNa + 3H2O 59,00 5,75 3,72 58,88 5,62 3,53
1.272 *
imagen306 665,6 (-) C34H38BrN2O5SNa + 2,8H2O 55,18 5,94 3,79 55,45 6,68 3,76
1.273 *
imagen307 551,6 (-) C30H32FN2O5SNa + 2,5H2O + 0,1Na2CO3 57,36 5,92 4,44 57,35 5,61 4,31
1.274 *
imagen308 631,4 (-) C30H31 BrFN2O5SNa + 2H2O 52,25 5,12 4,05 51,96 4,95 3,96
1.275 *
imagen309 567,6 (-) C30H32ClN2O5SNa + 1,7H2O + 0,25Na2CO3 56,05 5,50 4,32 55,74 5,13 4,07
1.276 *
imagen310 677,6 (-) C36H35Cl2N2O5SNa + 3,2H2O + 0,2Na2CO3 55,71 5,35 3,59 55,33 4,95 3,38
1.277 *
imagen311 711,4 (-) C36H34Cl3N2O5SNa + 2,2H2O 55,74 4,99 3,61 54,49 4,68 3,43
1.278
imagen312 711,4 (-) C36H34Cl3N2O5SNa + 2H2O 56,00 4,96 3,63 55,83 4,94 3,61
1.279 *
imagen313 647,4 (-) C30H31BrClN2O5SNa + 2H2O + 0,1Na2CO3 50,45 4,92 3,91 50,21 4,57 4,10
1.280
imagen314 727,4 (-) C37H35ClF3N2O6SNa + 1,8H2O + 0,2Na2CO3 55,52 4,83 3,48 55,21 4,45 3,56
1.281 *
imagen315 569,6 (-) C30H31F2N2O5SNa + 2,3H2O + 0,1Na2CO3 56,08 5,57 4,35 55,83 5,27 4,26
1.282
imagen316 677,6 (-) C36H35Cl2N2O5SNa + 2,3H2O 58,19 5,37 3,77 57,87 4,98 3,54
1.283 *
imagen317 601,69 (-) C31H32F3N2O5SNa + 2,9H2O + 0,15Na2CO3 54,00 5,50 4,04 53,66 5,13 3,87
1.284 *
imagen318 693,4 (-) C30H31ClIN2O5SNa+3H2O 46,73 4,84 3,63 46,68 4,65 3,67
1.285 *
imagen319 601,6 (-) C30H31Cl2N2O3SNa + 2,5H2O 53,73 5,41 4,18 54,10 5,74 4,27
1.286 *
imagen320 589,6 (-) C34H41N2O5SNa + 2,9H2O 61,41 7,09 4,21 61,13 6,57 3,94
1.287 *
imagen321 609,9 (-) C35H33N2NaO6S + 3H2O 61,21 5,72 4,08 61,12 5,57 3,82
1.288 *
imagen322 561,4 (-) C31H33N2O6SNa + 4,7H2O 55,63 6,38 4,19 55,25 5,44 4,00
1.289 *
imagen323 533,1 (-) C29H29N2O6SNa + 4,1H2O 55,25 5,95 4,44 54,96 5,57 4,28
1.290 *
imagen324 605,6 (-) C35H29N2O6SMa + 3H2O 61,57 5,17 4,10 61,38 4,92 4,05
1.291 *
imagen325 589,4 (-) C29H29Cl2N2O5SNa + 2H2O 53,79 5,14 4,33 53,51 4,42 4,26
1.292 *
imagen326 559,4 (-) C31H31N2O6SNa + 3,2H2O 58,15 5,89 4,38 57,83 5,57 4,26
1.293 *
imagen327 623,9 (-) C34H41ClN2O5S + 2,5H2O 60,93 6,92 4,18 60,69 6,55 4,44
1.294 *
imagen328 529,6 (-) C29H26N2O6S + 2,3H2O 60,89 5,39 4,90 60,78 5,23 5,05
1.295 *
imagen329 589,6 (-) C34H42N2O5S + 1,8H2O 65,53 7,38 4,50 65,30 6,90 4,49
1.296
imagen330 651 (+) C38H37N2O6SNa+ 2,5 H2O 63,58, 5,90, 3,90 63,49, 5,90, 3,71
1.297
imagen331 693(+) C38H38N2O5F3SNa+ 0,65H2O 62,82, 5,45, 3,86 62,82, 5,37, =3,80
1.298
imagen332 711(-) C37H35N2O5F3ClSNa+ 1,2H2O 58,72, 4,98, 3,70 58,77, 4,75, 3,60
1.299
imagen333 661(+) C37H38N2O5ClSNa+ 0,7H2O 64,05, 5,72, 4,04 64,09, 5,47, 4,04
1.300
imagen334 681(+) C36H35N2O5Cl2SNa+ 0,7H2O 60,54, 5,14, 3,92 60,54, 4,99, 3,88
1.301
imagen335 661 (+) C37H38N2O5ClSNa+ 0,8H2O 63,88, 5,74, 4,03 63,85, 5,85, 3,76
1.302
imagen336 675(+) C38H40N2O5ClSNa+1 2H2O 63,67, 5,96, 3,91 63,71, 5,87, 3,86
1.303
imagen337 705(M+) C39H40N2O5F3SNa+ 1,1H2O 62,57, 5,68, 3,74 62,58, 5,87, 3,69
1.304
imagen338 711 (+) C38H40N2O6F3SNa+ 1,2H2O 60,50, 5,66, 3,71 60,43, 5,65, 3,97
1.305
imagen339 733(+) C37H37N2O6F3ClSNa+ 2,3H2O 55,92, 5,28, 3,53 55,89, 4,94, 3,74
1.306
imagen340 677(M+) C37H40N2O6ClSNa+ 1,3H2O 61,50, 5,94, 3,88 61,47, 5,94, 3,73
1.307
imagen341 699(+) C36H37N2O6Cl2SNa+1,5H2O 57,91, 5,40, 3,75 57,91, 5,51, 3,70
1.308
imagen342 679(+) C37H40N2O6SClNa+ 2,2 H2O 60,15, 6,06, 3,79 59,96, 5,65, 3,65
1.309
imagen343 719(+) C36H35N2O6SF3ClNa+ 2,0 H2O 55,78, 5,07, 3,61 55,71, 4,82, 3,52
1.310
imagen344 716(+) C37H35N2O5F3ClSNa+ 0,8 H2O 59,28, 4,92, 3,74 59,33, 5,15, 3,63
1.311
imagen345 709(-) C38H40N2O6F3SN 0,8 H2O 61,08, 5,61, 3,75 61,09, 5,24, 3,59
1.312
imagen346 732(+) 57,62, 5,10, 3,63 57,61, 4,66, 3,42 (C37H37N2O6F3SClNa+ 1,0 H2O)
1.313
imagen347 697(-) C37H38N2O6F3SClNa+ 1,1 H2O 60,17, 5,49, 3,79 60,17, 5,61, 3,70
1.314
imagen348 717(M+) C36H35N2O6SF3ClNa+ 1,0 H2O 57,10, 4,93, 3,70 57,04, 4,56, 3,44
1.315
imagen349 709(+) C38H39N2O5Cl2SNa+ 1,3H2O 60,60. 5,57, 3,72 60,50, 5,41, 3,67
1.316
imagen350 677 (M+) C40H41N2O6SNa+ 2,2 H2O 64,88, 6,18, 3,78 64,81, 6,06, 3,7
1.317
imagen351 745 (M+) 58,28, 4,71, 3,58 58,26, 4,89, 3,69 (C38H35N2O5F6SNa+0,8 H2O)
1.318
imagen352 697(+) C37H35N2O5F4SNa+ 0,6 H2O 60,91, 5,00, 3,87 60,92, 4,95, 3,88
1.319
imagen353 728(+) C38H37N2O5F3ClSNa+1,1 H2O 59,35, 5,14, 3,64 59,23, 5,14, 3,75
1.320
imagen354 693(+) C38H38N2O5F3SN 0,8 H2O 62,59, 5,47, 3,84 62,64, 5,36, 3,83
1.321
imagen355 647(-) C39H39N2O5SNa+ 1,6 H2O 66,95, 6,08, 4,00 66,95, 5,93, 3,98
1.322
imagen356 637(-) C38H42N2OS+ 1,8 H2O 67,99, 6,85, 4,17 67,80, 7,12, 4,35
1.323 *
imagen357 643 (M+) C38H47N2O5SNa+ 1,8 H2O 65,27, 7,29, 4,01 65,22, 7,68, 3,90
1.324 *
imagen358 638(+) C37H38N3O5SNa+ 2,6 H2O 62,89, 6,16, 5,95 62,97, 6,30, 6,30
1.325
imagen359 713(+) C36H32N2O5Cl3SNa+ 1,0H2O + 0,1 CH3CN 57,50, 4,57, 3,89 57,34, 4,50, 4,20
1.326
imagen360 665(+) C39H39N2O6SNa+2,0 H2O 64,80, 6,00, 3,88 64,75, 6,11, 3,71
1.327
imagen361 683 (+) C35H33N2O6Cl2S+1,6 H2O 57,39, 4,98, 3,82 57,35, 4,66, 3,52
1.328
imagen362 653(+) C36H35N2O7SNa+1,1 H2O 63,98, 5,40, 4,03 63,86, 4,93, 3,71
1.329
imagen363 670(+) C35H35N2O6FSClNa+ 3,7 H2O 55,62, 5,65, 3,71 55,44, 5,21, 3,71
1.330
imagen364 651(+) C38H37N2O6SNa+ 3,7 H2O 61,73, 6,05, 3,79 61,52, 5,74, 3,74
1.331
imagen365 705(+) C42H43N2O6SNa+ 2,1 H2O 65,97, 6,22, 3,66 65,91, 6,29, 3,57
1.332 *
imagen366 652(+) C37H36N3O6SNa+ 4,0 H2O 59,59, 5,95, 5,63 59,50, 5,67, 5,36
1.333
imagen367 639(+) C36H33N2O7SNa+ 1,6 H2O 62,71, 5,29, 4,06 62,72, 5,26, 3,81
1.334 *
imagen368 623(+) C36H33N2O6SNa+ 2,9 H2O 62,04, 5,61, 4,02 61,77, 5,15, 4,15
1.335 *
imagen369 665(-) C38H38N2O7SNa + 1,2 H2O + 0,2 CH3CN 64,09, 5,74, 4,28 64,10, 5,90, 4,54
1.336
imagen370 677(+) C40H39N2O6SNa+ 2 0 H2O 65,38, 5,90, 3,81 65,34, 5,72, 4,01
1.337
imagen371 679(+) C40H41 N2O6SNa+ 1,8 H2O 65,52, 6,13, 3,82 65,55, 6,20, 3,74
1.338
imagen372 653(+) C38H39N2O6SNa+ 1,5 H2O+0,4 4 CH3CN 64,88, 6,06, 4,68 64,61, 5,63, 5,12
1.339 *
imagen373 649(+) C38H35N2O6SNa + 3,2 H2O 62,66, 5,73, 3,85 62,55, 5,66, 3,86
1.340 *
imagen374 671,4 (-) C35H39F3N2O6S + 2,25H2O 58,94 6,15 3,93 59,02 6,25 3,74
1.341 *
imagen375 655,6 657,6 (-) C34H38Cl2N2O5S + 3H2O + 0,1CF3CO2H 56,81 6,15 3,87 56,57 5,99 3,71
1.342 *
imagen376 643,6 (-) C38H48N2O5S + 3H2O + 0,2CF3CO2H 63,91 7,57 3,88 63,83 7,23 3,82
1.343
imagen377 765,4 767,4 (-) C40H40Cl3N2O5SN + 3H2O 56,91 5,49 3,32 56,75 5,08 3,32
1.344
imagen378 695,4 697,4 (-) C36H34Cl2FN2O5SNa + 1,75H2O 57,56 5,03 3,73 57,50 4,90 3,57
1.345
imagen379 731,6 733,6 (-) C36N33Cl3FN2O5SNa + 2,25H2O 54,42 4,76 3,53 54,30 4,43 3,47
1.346
imagen380 743,9 (-) C38H37ClF4N2O5S + 3H2O + 0,2CF3CO2H 56,10 5,30 3,41 55,93 5,41 3,30
1.347
imagen381 709,6 711,6 (-) C37H37Cl2FN2O5S + 2,25H2O + 0,2CF3CO2H 57,96 5,42 3,61 57,81 5,44 3,60
1.348
imagen382 709,6 711,6 (-) C37H37Cl2FN2O5S +2,25H2O + 0,1CF3CO2H 58,51 5,49 3,67 58,52 5,59 3,55
1.349
imagen383 689 9 (-) C38H40ClFN2O5S + 3H2O 61,24 6,22 3,76 61,22 6,36 3,75
1.350
imagen384 675 6 (-) C37H38ClFN2O5S + 2 25H2O + 0,1CF3CO2H 61,28 5,89 3,84 61,09 6,13 4,15
1.351 *
imagen385 695,1 6974 (-) C31H32BrF3N2O6S + 3H2O 49,54 5,10 3,73 49,49 4,72 3,71
1 352 *
imagen386 741 6 (-) C38H38ClF3N2O6S + 2,5H2O + 0,2CF3CO2H 56,86 5,37 3,45 56,91 5,50 3,82
1.353
imagen387 687,6 (-) C38H41ClN2O6S + 3H2O + 0,3CF3CO2H 59,63 6,13 3,60 59,85 6,00 3,59
1.354
imagen388 741,6 (-) C38H38ClF3N2O6S + 3H2O + 0,1CF3CO2H 56,74 5,50 3,46 56,67 5,74 3,18
1.355 *
imagen389 695,4 697,6 (-) C36H35Cl2FN2O5S + 2,75H2O +0,5CF3CO2H 55,26 5,14 3,48 55,24 4,23 3,38
1.356 *
imagen390 675,6 (-) C37H38ClFN2O5S + 2,75H2O + 0,2CF3CO2H 59,93 5,88 3,74 60,11 5,96 3,49
1.357 *
imagen391 695,6 697,4 (-) C36H35Cl2FN2O5S + 2,75 H2O + 0,1 CF3CO2H 57,32 5,39 3,69 57,33 5,53 3,57
1.358 *
imagen392 675,6 (-) C37H38ClFN2O5S + 2,75H2O + 0,2CF3CO2H 59,93 5,88 3,74 60,01 5,82 3,75
1.359
imagen393 691,6 693,4 (-) C37H38Cl2N2O5S + 3H2O + 0,2CF3CO2H 58,30 5,78 3,64 58,37 5,71 3,66
1.360 *
imagen394 647,6 (-) C36N39ClN2O5S + 3H2O 61,48 6,74 3,98 61,66 6,89 4,08
1.361
imagen395 684,6 (-) C37H36ClN3O6S + 2,75H2O + 0,2CF3CO2H 59,22 5,54 5,54 59,13 5,10 5,54
1.362 *
imagen396 631,6 (-) C35H40N2O7S + 3,25 H2O 60,81 6,78 4,05 60,65 6,77 4,16
1.363 *
imagen397 657,6 (-) C34H37F3N2O6S + 3,5H2O 56,58 6,14 3,88 56,40 6,16 3,59
1.364 *
imagen398 617,4 (-) C31H33F3N2O6S + 3H2O + 0,1CF3CO2H 54,78 5,76 4,09 54,52 5,41 4,32
1.365 *
imagen399 633,6 (-) C34H35ClN2O6S + 3H2O + 0,3CF3CO2H 57,45 5,75 3,87 57,44 5,49 3,80
1.366 *
imagen400 627,4 629,4 (-) C32H34Cl2N2O5S + 2,25H2O 57,35 5,79 4,18 57,58 5,88 4,10
1.367 *
imagen401 557,6 (-) C32H34N2O5S + 3,5H2O 62,27 6,61 4,54 62,23 6,71 4,84
1.368 *
imagen402 658,6, 660,6 (-) C35H34ClN3O6S + 3,5H2O 58,12 5,71 5,81 58,37 6,37 5,73
1.369 *
imagen403 585,4, 587,1 (-) C29H28Cl2N2O5S + 1,75H2O 56,27 5,13 4,53 56,52 5,54 4,61
1.370 *
imagen404 689,9 (-) C42H42N2O6S + 3H2O + 0,4CF3CO2H 63,51 6,17 3,54 63,17 6,25 3,67
1.371 *
imagen405 687,9 689,9 (-) C31H29ClN2O6S + 1,5H2O 60,04 5,20 4,52 59,71 5,47 5,10
1.372 *
imagen406 569,6 (-) C30H31F2N2O5SNa + 1,75H2O 57,73 5,57 4,49 57,93 5,50 4,87
1.373 *
imagen407 607,6 (-) C32H32ClN2O6Na + 2,25 H2O 57,22 5,48 4,17 57,29 5,59 4,44
1.374 *
imagen408 591,4 (-) C32H32FN2O6SNa + 1,7H2O 59,96 5,53 4,34 59,75 6,10 5,70
1.375 *
imagen409 637,6 (-) C37H37N2O6SNa + 4,5H2O 59,91 6,25 3,78 59,92 6,02 3,60
1.376 *
imagen410 655,6 (-) C37H37FN2O6S + 1H2O 65,86 5,83 4,15 65,98 5,98 3,09
1.377 *
imagen411 663,9 (-) C39H40N2O6S + 2,5H2O 65,99 6,39 3,95 65,69 6,40 3,76
1.378 *
imagen412 725,4 (-) C40H33F3N2O65 + 2,5H2O 62,25 4,9 3,63 62,37 4,89 3,40
1.379 *
imagen413 667,4 (-) C34H28F4N2O6S + 3H2O +0,3CF3CO2H 54,90 4,57 3,70 54,81 4,49 3,65
1.380 *
imagen414 649,6 (-) C34H29F3N2O6S + 0,5 H2O + 0,4 CF3CO2H 59,26 4,34 3,97 58,84 4,04 4,46
1.381 *
imagen415 675,6 (-) C39H33FN2O6S + 3H2O 64,10 5,38 3,83 63,91 5,13 3,80
1.382 *
imagen416 571,5 (-) C32H32N2O6S + 2H2O + 0,3CF3CO2H 60,90 5,69 4,36 60,57 5,57 4,59
1.383 *
imagen417 575,6 (-) C32H36N2O6S + 0,5 H2O +0,3 CF3CO2H 63,16 6,06 4,52 63,27 5,74 3,70
1.384 *
imagen418 603,6 (-) C30H34Cl2N2O5S +1H2O + 0,2 CF3CO2H 56,49 5,64 4,33 56,13 5,47 4,57
1.385
imagen419 759,6 (+) C38H32Cl3N2O5SNa + 1 H2O + 0,2 Na2CO3 57,55 4,30 3,51 57,25 3,91 3,26
1.386
imagen420 803,4 (+) C40H32ClF6N2O5SNa + 0 5 Na2CO3 55,39 3,67 3,19 55,49 3,39 3,26
1.387
imagen421 745,9 (+) C42H42ClN2O5SNa + 0,8 H2O 61,77 5,38 3,43 61,73 5,50 3,59
1.388 *
imagen422 693,4 (+) C24H2OBrIClN2O5SNa 37,40 2,62 3,63 37,30 2,51 3,54
1.389
imagen423 717,6 (+) C40H38ClN2O5SNa + 2,2 H2O 63,48 5,65 3,70 63,08 5,25 3,77
1.390 *
imagen424 653,6 (+) C35H34N2O5F3SNa + 1 H2O 60,69 5,24 4,04 60,37 5,39 4,05
1.391
imagen425 833,6 (+) C43H39N2O5F6SNa + 1 H2O 60,70 4,86 3,29 60,87 5,19 3,57
1.392
imagen426 779,6 (+) C41H35N2O5Cl3SNa + 1,3 H2O 59,79 4,97 3,40 59,76 5,14 3,67
1.393
imagen427 777,6 (+) C42H39N2O5F3ClSNa + 3,1 H2O 58,99 5,33 3,28 58,73 5,00 3,10
1.394
imagen428 779,6 (+) C43H42N2O5F3SNa + 2,7 H2O 62,41 5,77 3,39 62,67 5,60 3,14
1.395
imagen429 732,1 (+) C45H49N2O5SNa + 1,2 H2O 69,78 6,69 3,62 69,40 7,02 3,83
1.396
imagen430 837,6 (+) C41H32N2O5F9SNa + 1 H2O + 0,2 Na2CO3 55,39 3,84 3,14 55,21 3,44 3,07
1.397 *
imagen431 599,9 (+) C35H37N2O5SNa + (0,4)NaO3SCH2CH2NH2 63,27 5,84 4,95 63,07 6,07 5,25
1.398
imagen432 710,4 (+) C41H40N2O5CISNa + 1,7 H2O 64,63 5,74 3,68 64,56 5,70 3,56
1.399
imagen433 779,6 (+) C42H39N2O5F3ClSNa + 1 H2O 61,72 5,06 3,43 61,50 5,33 3,32
1.400
imagen434 745,6 (+) C41H39Cl2N2O5SNa + 3,7 H2O 59,16 5,62 3,37 59,17 5,46 3,54
1.401
imagen435 757,6 (+) C43H42F3N2O5SNa + 3 H2O 62,01 5,81 3,36 61,86 5,65 3,52
1.402
imagen436 769,6 (+) C39H32Cl2F3N2O5SNa + 3 H2O 55,39 4,53 3,31 55,39 4,17 3,57
1.403
imagen437 729,6 (+) C41H35N2O5F3SNa + 0,6 H2O + 0,3 Na2CO3 63,07 5,02 3,56 62,74 4,71 3,42
1.404 *
imagen438 679,4 (+) C25H20N2O5F3Br2SNa + 1,5 H2O 41,28 3,19 3,85 41,16 2,97 3,96
1.405
imagen439 703,6 (+) C43H45N2O5SNa + 2,5 H2O + 0,1 Na2CO3 66,52 6,48 3,60 66,47 6,11 3,73
1.406
imagen440 752,6 (+) C40H37N2O5Cl2SNa + 1,7 H2O 61,41 5,21 3,58 61,07 4,82 3,42
1.407
imagen441 703,6 (+) C43H45N2O5SNa + 2,6 H2O 66,92 6,56 3,63 66,83 6,32 3,43
1.408 *
imagen442 585,6 (+) C34H35N2O5SNa + 2,4 H2O 62,83 6,17 4,31 62,66 6,23 4,51
1.409
imagen443 787,4 (+) C41H37ClF3N2O5SNa + 1,5 H2O 60,63 4,96 3,45 60,89 5,25 3,31
1.410
imagen444 709,6 (+) C41H40N2OClSNa + 1,8 H2O 64,48 5,75 3,67 64,27 5,43 3,61
1.411
imagen445 689,6 (+) C42H43N2O5SNa + 2,9 H2O 66,11 6,45 3,67 66,13 6,13 3,54
1.412
imagen446 743,6 (+) C42H41F3N2O5SNa+ 1,8 H2O 63,27 5,51 3,51 63,26 5,55 3,64
1.413
imagen447 799,4 (+) C37H26N2O5Cl2SNa + 2,5 H2O 52,62 3,70 3,32 52,69 3,53 3,29
1.414
imagen448 645,1 (+) C36H36N2ClSNa + 2,1 H2O 61,33 5,75 3,97 61,38 5,83 4,13
1.415
imagen449 807,6 (+) C45H46N2O5F3SNa + 2,5 H2O + 0,4 MeOH 63,06 6,13 3,24 63,43 5,90 2,84
1.416
imagen450 717,9 (+) C44H47N2O5SNa + 3,2 H2O 66,34 6,76 3,52 66,05 6,47 3,49
1.417
imagen451 685,6 (+) C38H35N2O7SNa + 4 H2O 60,15 5,71 3,69 60,12 5,38 3,44
1.418
imagen452 811 6 (+) C38H27N2O5F6Cl2SNa + 2,3 H2O 52,28 3,65 3,21 52,13 3,50 3,25
1.419
imagen453 633,4 (+) C38H35N2O5SNa + 3 H2O 64,39 5,83 3,95 64,66 5,72 4,04
1.420
imagen454 661,6 (+) C40H39N2O5SNa + 2,3 H2O 66,34 6,07 3,87 66,33 6,05 3,88
1.421
imagen455 703,6 (+) C38H33N2O5Cl2SNa + 1,8 H2O 60,37 4,88 3,71 60,27 4,67 3,71
1.422
imagen456 7359,9 (+) C36H25N2O5F6SNa + 1,5 H2O +0,1 Na2CO3 56,15 3,65 3,63 56,11 3,32 3,80
1.423
imagen457 675,4 (+) C36H29N2O5Cl2SNa + 3 H2O 57,68 4,71 3,74 57,86 4,67 3,81
1.424 *
imagen458 613,6 (+) C36H39N2O5SNa + 2,5 H2O 63,61 6,52 4,12 63,47 6,46 4,04
1.425 *
imagen459 611,1 (+) C24H21N2O5Br2SNa + 4,1 H2O 40,82 4,17 3,97 40,48 3,78 3,82
1.426
imagen460 688,9 (+) C36H34N2O5F3SNa + 2,5 H2O + 0,3 Na2CO3 57,10 5,15 3,67 56,85 4,85 3,84
1.427
imagen461 809,4 (+) C38H27N2O5F6Cl2SNa + 2,9 H2O 51,64 3,74 3,17 51,33 3,66 3,17
1.428
imagen462 810,4 (+) C38H27N2O5F6Cl2SNa + 2,5 H2O 52,06 3,68 3,20 51,71 3,54 3,20
1.429
imagen463 743,6 (+) C36H28N2O5Cl4S + 0,5 H2O 57,54 3,89 3,73 57,63 3,99 3,71
1.430
imagen464 699,4 (+) C36H27N2O5F4SNa +3,5 H2O 56,77 4,50 3,68 56,60 4,18 3,63
1.431 *
imagen465 687,6 (+) C38H39N4O5SNa + 3H2O +1 MEOH 60,32 6,47 7,16 60,64 6,16 6,77
1.432 *
imagen466 693,4 (+) C34H42N2O8SPNa + 2H2O 56,04 6,36 3,84 55,86 6,40 3,96
1.433
imagen467 655,10 (+) C37H37N2O7SNa + 5,5 H2O 57,28 6,24 3,61 57,26 5,97 3,78
1.434 *
imagen468 690,1 (+) C40H51N2O6SNa+(1,5)H2O+(0,3)C9H20N3O 64,61 7,62 5,12 64,94 7,96 5,28
1.435 *
imagen469 707,6 (+) C37H35N2O6Cl2SNa + (4,0)H2O + (0 5) C9H20N3O 55,70 5,97 5,48 55,48 6,11 5,79
1.436 *
imagen470 689,9 (+) C40H51N2O6SNa + (1,5)H2O + (0 35) C9H20N3O 64,53 7,66 5,32 64,24 7,65 5,38
1.437 *
imagen471 697,4 (+) C36H35Cl2N2O6SNa + 3,5 H2O 55,46 5,30 3,59 55,41 4,95 3,54
1.438
imagen472 713,6 (+) C37H35N2O5F3ClSNa + 3 6 H2O 55,55 5,32 3,50 55,17 5,29 3,72
1.439
imagen473 681 6 (+) C38H29N2O6F2SNa + 2,7 H2O 60,75 4,61 3,73 60,44 4,21 3,56
1.440
imagen474 733 1 (+) C41H38N3O8SNa + 2,5 H2O 61,49 5,41 5,25 61,26 5,55 5,37
1.441
imagen475 745,6 (+) C39H33N2O8S2Na + 2,5 H2O 59,31 4,88 3,93 59,12 4,68 3,55
1.442
imagen476 657,6 (+) C35H29N4O6SNa + 3,5 H2O 58,41 5,04 7,78 58,18 4,86 7,73
1.443
imagen477 702,6 (+) C37H29N3O6ClSNa + 5,8 H2O 55,09 5,07 5,21 54,72 4,67 5,34
1.444
imagen478 668,4 (+) C37H30N3O6SNa + 4,2 H2O 59,78 5,21 5,65 59,50 4,87 5,86
1.445
imagen479 665,4 (+) C37H32N2O6S2 + 0,5 H2O 65,95 4,94 4,16 65,73 4,83 4,20
1.446
imagen480 673,4 (+) C36H29N2O6S2Na + 3,5 H2O 58,76 4,93 3,81 58,92 4,56 4,00
1.447
imagen481 673,1 (+) C36H29N2O6S2Na + 3,5 H2O 58,76 4,93 3,81 58,39 4,68 3,96
1.448
imagen482 657,4 (+) C36H29N2O7SNa + 3 H2O 60,84 4,96 3,94 60,51 4,58 4,12
1.449
imagen483 597,4 (+) C30H26Cl2N2O5S + 3,8 H2O + 0,4 TFA 51,99 4,80 3,94 51,67 4,50 4,44
1.450
imagen484 665,6 (+) C38H39N3O6S + H2O + 0,7 TFA 61,97 5,50 5,50 62,00 5,20 5,34
1.451
imagen485 769,9 (+) C41H44ClF3N2O5S + 2 H2O + TFA 56,18 5,37 3,05 55,86 5,48 3,21
1.452
imagen486 715,6 (+) C37H35F5N2O5S + 1,2 H2O +0,2 TFA 59,17 4,99 3,69 59,04 5,26 3,30
1.453
imagen487 696,6 (+) C37H36F4N2O5S + 0,5 H2O + 0,1 TFA 62,30 5,21 3,91 62,24 5,25 2,65
1.454
imagen488 653,6 (+) C38H40N2O6S + 2 H2O + 0,2 TFA 64,81 6,21 3,94 64,51 5,99 3,82
1.455
imagen489 713,6 (+) C37H36ClF3N2O5S + 0,8 H2O + 0,1 TFA 60,46 5,14 3,79 60,75 6,39 4,68
1.456 *
imagen490 701,6 (+) C42H40N2O6 + H2O + 0,4 TFA 67,24 5,59 3,66 67,13 5,89 3,39
1.457
imagen491 719,6 (+) C39H37F3N2O6S + H2O + 0,2 TFA 62,30 5,19 3,90 62,54 5,16 3,71
1.458 *
imagen492 733,6 (+) C34H33BrCl2N2O5S + H2O + 0,5 TFA 52,06 4,43 3,47 51,86 4,21 3,25
1.459 *
imagen493 705,6 (+) C36H35BrN2O6S + 3 H2O +0,3 TFA 55,51 5,26 3,54 55,12 5,03 3,77
1.460
imagen494 693,6 (-) C37H35F3N2O6S + 3 H2O + 0,1 TFA + 0,1 DMF 58,84 5,50 3,84 58,93 5,55 4,24
1.461
imagen495 661,6 (+) C36H34F2N2O6S + 1,4 H2O + 0,1 TFA 62,35 5,33 4,02 62,55 5,64 3,67
1.462
imagen496 659,6 (+) C36H35ClN2O6S + 2 H2O + 0,2 TFA 60,89 5,50 3,90 60,59 5,25 4,27
1.463
imagen497 709,6 (+) C37H35F3N2O7S + 0,5 TFA 59,60 4,67 3,66 59,29 4,58 3,51
1.464
imagen498 653,6 (+) C37H36N2O7S + 2 H2O + 0,1 TFA 63,81 5,57 4,00 63,69 5,48 3,91
1.465
imagen499 655,6 (+) C37H38N2O7S + 3 H2O + 0,4 TFA 60,18 5,93 3,71 59,98 5,78 3,55
1.466
imagen500 650,9 (+) C37H35N3O6S + 3,4 H2O 63,14 5,87 5,97 62,13 5,99 6,91
1.467
imagen501 653,1 (+) C37H37N3O6S + 2,5 H2O 63,78 6,08 6,03 64,09 6,48 7,31
1.468 *
imagen502 574,5 (+) C31H31N3O6S + 0,5 TFA 60,94 5,03 6,66 60,60 4,74 6,79
1.469 *
imagen503 602,7 (+) C31H31N3O6S + 0,5 TFA 60,94 5,03 6,66 60,60 4,74 6,79
1.470
imagen504 656,6 (+) C36H37N3O7S + (0,1) H2O + (0,1) TFA C: 64,99 H: 5,62 N: 6,28 C: 64,99 H: 5,79 N: 6,50
1.471 *
imagen505 652,9 (+) C37H37N3O6S + (1,5) H2O + (0,2) TFA C: 64,03 H: 5,78 N: 5,99 C: 64,09 H: 5,75 N: 5,87
1.472
imagen506 747,6 (-) C36H33N2O5Cl4SNa + (1) H2O C: 54,83 H: 4,47 N: 3,55 C: 54,68 H: 4,47 N: 3,52
1.473
imagen507 727,4 (-) C37H36N2OCl3SNa + (1 5) H2O C: 57,18 H: 5,06 N: 3,60 C: 57,20 H: 4,90 N: 3,59
1.474
imagen508 741 9 (+) C39H40ClF3N2O5S + (0,9) EtOH C: 62,61 H: 5,85 N: 3,58 C: 62,84 H: 5,46 N: 4,02
1.475
imagen509 705,9 (-) C39H41F3N2O5S C: 66,27 H: 5,85 N: 3,96 No sometido a prueba
1.476
imagen510 725,6 (-) C38H38ClF3N2O5S C: 62,76 H: 5,27 N: 3,85 No sometido a prueba
1.477
imagen511 705,9 (-) C38H39Cl2N2O5SNa + (1 7) H2O C: 60,03 H: 5,62 N: 3,68 C: 59,82 H: 5,40 N: 3,61
1.478
imagen512 705,9 (-) C38H39Cl2N2O5SNa + (0,5) H2O + (0,2) NaHCO3 C: 60,73 H: 5,36 N: 3,71 C: 60,65 H: 4,88 N: 3,57
1.479
imagen513 733,9 (-) C40H43Cl2N2O5SNa + (1,5) H2O + (0,2) NaHCO3 C: 60,24 H: 5,81 N: 3,49 C: 60,59 H: 5,47 N: 3,22
1.480 *
imagen514 620,6 (+) C34H41N3O6S + (2,0) H2O + (0,3) TFA C: 60,23 H: 6,62 N: 6,09 C: 60,04 H: 6,43 N: 5,96
1.481
imagen515 765,6 (+) C37H35N2O6F3Cl2S + (1,5) H2O + (0,1) TFA C: 55,71 H:4,79 N: 3,49 C: 55,45 H: 4,87 N: 3,44
1.482 *
imagen516 707,6 (-) C31H33ClIN2O5SNa + (1,7) H2O C: 48,89 H: 4,82 N: 3,68 C: 48,70 H: 4,63 N: 3,50
1.483
imagen517 685,9 (-) C39H42ClN2O5SNa + (1,5) H2O C: 63,62 H: 6,16 N: 3,80 C: 63,63 H: 6,01 N: 3,70
1.484
imagen518 691 9 (-) C37H37Cl2N2O5SNa + (1,6) H2O C: 59,69 H: 5,44 N: 3,76 C: 59,57 H: 5,10 N: 3,66
1.485
imagen519 759,9 (-) C38H36Cl2F3N2O5SNa + (2,3) H2O C: 55,32 H: 4,96 N: 3,40 C: 55,67 H: 4,70 N: 3,30
1.486
imagen520 739 9 (-) C39H39ClF3N2O5SNa + (2,0) H2O C: 58,61 H: 5,42 N: 3,50 C: 58,67 H: 5,27 N: 3,34
1.487
imagen521 761 9 (+) C38H36Cl2F3N2O5SNa + (2,3) H2O C: 55,32 H: 4,96 N: 3,40 C: 55,09 H: 4,70 N: 3,29
1.488
imagen522 763,9 (+) C41H37ClF3N2O5SNa + (2,2) H2O C: 59,70 H: 5,06 N: 3,40 C: 59,67 H: 4,96 N: 3,24
1.489
imagen523 750,6 (+) C40H35ClF3N2O5SNa + (2,1) H2O C: 59,38 H: 4,88 N: 3,46 C: 59,04 H: 4,52 N: 3,39
1.490 *
imagen524 653,6 (+) C36H36N4O6S + (1,5) H2O + (0,2) TFA C: 62,23 H: 5,63 N: 7,97 C: 62,26 H: 5,63 N: 7,67
1.491 *
imagen525 733,6 (+) C35H33N2O5F3BrSNa + (1,0) H2O C: 54,48 H: 4,57 N: 3,63 C: 54,48 H: 4,28 N: 3,42
1.492
imagen526 677,9 (-) C37H36F3N2O5SNa + (1,5) H2O C: 61,06 H: 5,40 N: 3,85 C: 61,06 H: 5,31 N: 3,74
1.493
imagen527 701,9 (-) C43H45N2O5SNa + (2,8) H2O C: 66,61 H: 6,58 N: 3,61 C: 66,54 H: 6,15 N: 3,60
1.494
imagen528 735,9 (-) C39H37N2O5F3ClSNa + (0,8) H2O C: 60,39 H: 5,02 N: 3,61 C: 60,38 H: 4,76 N: 3,59
1.495
imagen529 671,6 (-) C41H41N2O5Na + (1,0) H2O + (0,2) NaHCO3 C: 65,35 H: 5,67 N: 3,66 C: 65,36 H: 5,49 N: 3,58
1.496
imagen530 672,6 (-) C37H39N3O5ClSNa + (2,8) H2O + (0,3) NaCO3 C: 57,55 H: 5,77 N: 5,40 C: 57,49 H: 5,54 N: 5,28
Se generaron anilinas que contenían benzoxazol requeridas para la síntesis de compuestos tales como el del ejemplo 1.146 usando métodos conocidos tal como se muestra a continuación:
imagen531
A una suspensión de ácido 4-acetilamino-2-metil-benzoico (2,0 g, 10,3 mmol) en PPA (85 g) se le añadió aminofenol (1,2 g, 10,8 mmol). Se calentó la reacción hasta 200ºC durante 2 h, entonces se extinguió cuidadosamente en carbonato de sodio acuoso (saturado al 50%) a temperatura ambiente. Se añadió acetato de
10 etilo, y se lavó la fase orgánica con agua y salmuera y se secó sobre sulfato de sodio. Se obtuvo el producto bruto como un aceite naranja y se purificó posteriormente mediante cromatografía en columna ultrarrápida sobre gel de sílice eluyendo con acetato de etilo en hexanos para proporcionar el producto deseado, 4-benzooxazol-2-il-3-metilfenilamina como un sólido incoloro, 290 mg (13%). 1H-RMN (300 MHz, DMSO-d6):  7,84-7,81 (m, 1 H), 7,64-7,62 (m, 2 H), 7,32-7,27 (m, 2H), 6,51 (d, J = 9,0 Hz, 2 H), 5,83 (s, 2 H), 2,61 (s, 3H). CL-EM m/z = 225 [C14H12N2O+ H]+.
15 EJEMPLO 1.497 (no según la invención)
imagen532
imagen533
imagen534
imagen535
imagen536
imagen537
imagen538
2.003
imagen539 531,4 (-) C30H31N2O5SNa + 2H2O 61,00 5,97 4,74 60,66 5,86 4,58
2.005
imagen540 643,6 (-) C36H33N2o5F2SNa+ 2,2H2O 61,22 5,34 3,97 60,91 4,93 4,21
2.007
imagen541 675,6 (-) C37H34N2O5F3SNa+ 1,1H2O ‘61,85 5,08 3,90 61,50 5,16 3,87
2008
imagen542 641,4, 643 6 (-) C36H34N2O5ClSNa + 0,2NaOH + 1,4 H2O 61,91 5,34 4,01 61,56 4,97 4,09
2.009
imagen543 641 4, 643 6 (-) C36H34N2O5ClSNa + 1,5H2O ‘62,47 5,39 4,05 62,29 5,25 4,09
2.010
imagen544 609,6 (-) C30H30N2O5BrSNa+ 1,2 H2O 55,00 4,98 4,28 54,67 4,97 4,43
2.011
imagen545 675,6 (-) C36H33N2O5Cl2SNa+ 2,5H2O 58,07 5,14 3,76 58,47 5,58 4,02
2.012
imagen546 643,3 (-) C36H33N2O5F2SNa+ 1H2O ‘63,15 5,15 4,09 62,95 5,29 4,14
2.013
imagen547 675,6 (-) C37H34N2O5F3SNa + 2H2O 60,48 5,21 3,81 60,23 4,87 3,77
2.014
imagen548 607,3 (+) C37H35ClN2O4 +(1,0)H2O C: 71,09; H: 5,97 N: 4,48 C:71,33; H: 6,11; N: 4,60
2.015
imagen549 675,0 (-) C37H35F3N2O5S + 2H2O C: 62,35; H: 5,51; N:3,93 C: 62,18; H: 5,60; N: 3,89
2.016
imagen550 621,3 (-) C37H38N2O5S + 1H2O + 0,2 TFA C: 67,69 H: 6,11 N: 4,22 C: 67,96 H: 6,37 N: 4,17
2.017
imagen551 675,0 (-) C37H35F3N2O5S + 1,5 H2O + 0,25CF3CO2H C: 61,51 H: 5,26 N: 3,83 C: 61,66 H: 5,55 N: 3,78
2.018
imagen552 C36H35ClN2O5S + 2 H2O + 0,1 TFA C: 62,96 H: 5,71 N: 4,06 C: 63,03 H: 5,91 N: 3,87
2.019
imagen553 668,66 C32H30F6N2O5S 55,83 4,80 4,39 56,21 5,17 4,22
2.020
imagen554 644,81 C35H32ClF3N2O6S2 + 2 H2O + 0,5 CF3CO2H 54,44 4,63 3,53 54,30 4,96 3,56
2.021
imagen555 590,30 (+) C34H33ClN2O6S +2H2O C: 61,02; H: 5,57; N: 4,19 C: 60,74; H: 5,67; N: 4,14
2.022
imagen556 625,6 (-) C36H34N2O5FSNa+1,2 H2O C: 64,50; H: 5,47; N: 4,18 C: 64,12; H: 5,10; N: 4,12
2.023
imagen557 643,2 (-) C36H34F2N2O5S + 2,2H2O C:63,18; H: 5,66; N: 4,09 C: 62,95; H: 5,73; N: 4,21
2.024
imagen558 701,16 C35H32ClF3N2O6S2 + 2 H2O + 0,5 CF3CO2H 54,44 4,63 3,53 54,30 4,96 3,56
2.025
imagen559 685,6(-) C37H37N2O7S2Na +1,8H2O C: 59,95; H: 5,52; N: 3,78 C: 60,06; H: 5,55; N: 3,97
2.026
imagen560 685,6 (-) C37H37N2O7S2Na +1,9H2O C: 59,81; H: 5,53; N: 3,77 C: 59,57; H: 5,13; N: 3,43
2.027
imagen561 692,76 C37H35F3N2O6S + CF3CO2H + 0,5 H2O C: 57,42; H: 4,57; N: 3,43 C: 57,13; H: 4,73; N: 3,55
2.028
imagen562 643,2 (-) C36H34F2N2O5S + 2,2H2O C: 63,18; H: 5,66; N: 4,09 C: 62,95; H: 5,73; N: 4,21
2.029
imagen563 71,4,6 (-) C38H40N3O7S2Na + 1,2H2O 60,10 5,63 5,53 59,96 5,53 5,50
2.030
imagen564 768,6 (-) C39H40N3O6SNa +1H2O 65,07 5,88 5,84 64,71 5,99 5,72
2.031
imagen565 700,4 (-) C37H38N3O7SNa + 2H2O 58,48 5,57 5,53 58,24 5,67 5,69
2.032
imagen566 632,6 (-) C37H34N3O5SNa + 0,8H2O 66,31 5,35 6,27 66,26 5,36 5,96
2.033
imagen567 650,6 (-) C36H34N2O6SClNa + 2,5H2O + 0,2 CH3CN 59,53 5,43 4,20 59,32 5,51 4,59
2.034
imagen568 650,6 (-) C37H33N3O5FSNa + 1H2O 64,24 5,10 6,07 64,08 5,15 5,96
2.035
imagen569 691,6 (-) C36H33N2O6Cl2SNa + 1,5H2O 58,22 4,89 3,77 58,55 4,67 3,42
2.036
imagen570 691,6 (-) C36H33N2O6Cl2SNa + 1H2O 58,94 4,81 3,82 59,13 4,61 3,45
2.037
imagen571 647,4 (-) C38H35N2O6SNa +H2O 66,27 5,41 4,07 65,95 5,41 4,02
2.038
imagen572 657,2 (-) C36H34N2O6ClSNa + 3H2O + 0,1 CH3CN 58,81 5,49 3,98 59,04 5,22 4,33
2.039
imagen573 643,2 (-) C36H35N2O6FS + 2,5 H2O 62,87 5,86 4,07 62,70 5,73 4,02
2.040
imagen574 733 (+) C43H41N2O6FS + (0,9) H2O +(0,2) CF3CO2H C:67,53 H:5,61 N: 3,63 C:67,57 H:5,83 N: 3,67
2.041
imagen575 661,6 (+) C36H34N2O5FClS + (0,5) H2O + (0,2) TFA C:63,09 H:5,12 N:4,04 C:63,09 H:5,23 N:3,79
2.042
imagen576 617,4 (+) C31H31N2O6F3S + (1,5) H2O +(0,6) TFA C:54,31 H:4,90 N:3,93 C:54,29 H:5,00 N:3,93
2.043
imagen577 633,6 (+) C31H31N2O5S2 + (1,0) H2O C:57,22 H:5,11 N:4,30 C:57,22 H:5,45 N:4,04
2.044
imagen578 649,6 (+) C34H33N2O5ClS2 + (1,5) H2O C:60,39 H:5,37 N:4,14 C:60,49 H:5,75 N:4,10
2.045
imagen579 643,6 (+) C36H35N2O6FS + (1,2) H2O + (0,8) TFA C:59,77 H:5,10 N:3,71 C:59,69 H:5,38 N:3,58
2.046
imagen580 745,6 (+) C38H34N2O5F6S + (1,2) TFA C:55,04 H:4,02 N:3,18 C:55,18 H:3,93 N:2,84
2.047
imagen581 695,4 (+) C37H34N2O5F4S + (1,5) TFA C:55,49 H:4,13 N:3,24 C:55,28 H:3,97 N:2,89
2.048
imagen582 661,6 (+) C36H34N2O5FClS + (1,1) H2O + (0,1) TFA C:62,79 H:5,28 N:4,05 C:62,78 H:5,59 N:4,20
2.049
imagen583 715,9 (+) C43H42N2O6S + (2,2) H2O + (0,1) TFA C:67,75 H:6,12 N:3,66 C:67,60 H:6,30 N:3,71
2.050
imagen584 657,2 (+) C37H37N2O6FS +(1,8) H2O + (0,1) TFA C:63,77 H:5,86 N:4,00 C:63,79 H:6,22 N:4,39
2.051
imagen585 633,3 (+) C34H33N2O6ClS + (2 2) H2O + (0,1) TFA C 60,04 H:5 52 N:4 09 C:60 01 H.5 86 N:4 23
2.052
imagen586 655,6 (+) C33H26ClF3N2O5S + (0,3) H2O + (0,1) TFA C:59,35 H:4,01 N:4,17 C:59,40 H:3,68 N:3,98
2.053
imagen587 581,6 (+) C32H31N2O5F3 + (0,1) DMF + (0 5) H2O C:64,99 H:5,52 N:4,93 C:65,36 H:5,99 N:4,88
2.054
imagen588 618,4 (+) C28H29BrN2O5S2 + H2O + (0,6) TFA C: 49,82 H: 4,52 N: 3,98 Hallado C = 49,86 H = 4,59 N=4,03
2.055
imagen589 639,6 (+) C37H38N2O6S + (3,0) H2O C: 64,14 H: 6,40 N: 4,04 C: 64,12 H: 6,03 N: 4,06
2.056
imagen590 625,6 (+) C36H36N2O6S + 5H2O C: 60,19 H:6,51 N: 3,90 C: 60,02 H:6,15 N: 3,95
2.057
imagen591 650,6 (+) C34H33ClN2O5S2 + (0,6) TFA C: 57,19 H: 4,54 N: 3,73 C: 57,19 H: 4,59 N: 3,69
2.058
imagen592 650,6 (+) C35H32F4N2O5S2 + (1,1) DMF + (0,2) H2O C: 58,62 H: 5,15 N: 5,53 C: 59,02 H: 5,55 N: 5,28
2.059
imagen593 709 (-) C37H34ClF3N2O5S + (0,3) TFA + (1,2) H2O C: 58,88, H: 4,82, N: 3,65 C: 58,86, H: 4,95, N: 3,57
2.060
imagen594 727,729 (-) C37H33ClF4N2O5S + (0,7) TFA + (0,3) H2O C: 56,63, H: 4,25, N: 3,44 C: 56,20, H: 4,47, N: 3,64
2.061
imagen595 639 (-) C37H37FN2O5S + (0,1) TFA + (1,1) H2O C: 66,49, H: 5,89, N: 4,17 C: 66,33, H: 5,89, N: 4,0
2.062
imagen596 683 (-) C39H41FN2O6S + (0,2) TFA + (1,7) H2O C: 64,10, H: 6,09, N: 3,79 C: 64,02, H:5,92, N: 3,7
2.063
imagen597 655 (-) C37H37FN2O6S + (0,7) TFA + (1,7) H2O C: 60,12, H: 5,40, N: 3,65 C: 60,19, H:5,26, N: 3,50
2.064
imagen598 659,6 (-) C36H34ClFN2O5S + 0,6 H2O C: 64,34 H: 5,28 N: 4,17 C: 64,27 H: 5,48 N: 4,1
2.065
imagen599 695,4 (+) C37H34N2O5F4S + 1,6 H2O C: 61,42; H:5,18; N: 3,87 C: 61,63; H: 5,53; N: 3,79
2.066
imagen600 645,4 (-)? C36H34N2O5S + 0,7 H2O + 1,2 CF3CO2H C: 60,99 H: 4,88 N: 3,70 C: 61,08 H: 4,55 N: 3,84
2.067
imagen601 695,4 (+) C37H34N2O5F4S + 1,5H2O C: 61,57 H: 5,17 N: 3,88 C: 61,94 H: 5,54 N: 3,72
2.068
imagen602 729,6 (+) C37H33N2O5F4ClS + 0,6 H2O + 0,2 CF3CO2H C: 58,89 H: 4,55 N: 3,67 C: 58,88 H: 4,28 N: 3,65
2.069
imagen603 729,6 (+) C37H33N2O5FClS + 1 H2O + 0,4 CF3CO2H C: 57,21 H: 4,50 N: 3,53 C: 57,25 H: 4,34 N: 3,43
2.070
imagen604 661,9 (+) C36H34N2O5FClS + 0,9 CF3CO2H C: 59,76 H: 4,93 N: 3,76 C: 59,50 H: 4,44 N: 3,66
2.071
imagen605 645,4 (+) C36H34N2O5 F2S + 0,5 H2O C: 66,14 H: 5,40 N: 4,29 C: 66,17 H: 5,46 N: 4,09
2.072
imagen606 661,2 (+) C36H34N2O5FClS + 1 H2O C: 63,66 H: 5,34 N: 4,12 C: 63,36 H: 5,48 N: 4,07
2.073
imagen607 693,0 (-) C37H34N2O5F4SNa + 2H2O C: 58,96 H: 5,08 N: 3,72 C: 58,79 H: 5,05 N: 3,76
2.074
imagen608 725 (-) C37H33ClF3N2O6S Na + 3H2O C: 55,33 H: 4,89 N: 3,49 C: 55,42 H: 5,03 N: 3,24
2.075
imagen609 659,6 (-) C36H34N2O5FClS + 1,2 H2O C: 63,33 H: 5,37 N: 4,10 C: 63,25 H: 5,14 N: 4,13
2.076
imagen610 645,4 (+) C36H34N2O5F2S + 1,3 H2O C: 64,71 H: 5,52 N: 4,19 C: 64,71 H: 5,29 N: 4,20
2.077
imagen611 692,8 (-) C37H35N2O6F3S + 0,6 H2O C: 63,17 H: 5,19 N: 3,98 C: 63,22 H: 5,47 N: 4,14
2.078
imagen612 633,9 (+) C39H36N2O4ClNa+ (1,3)H2O C: 69,03 H:5,73 N: 4,13 C: 69,05 H:5,48 N: 4,07
2.079
imagen613 669,6 (+) C38H36N2O5ClSNa+ (0,6)H2O C: 65,01 H: 5,34 N: 3,99 C: 64,94 H: 5,51 N: 3,87
2.080
imagen614 677 (-) C36H33F3N2O6S +1,5H2O C 61,27, H: 5,14, N: 3,97 C 61,04, H: 5,02, N: 3,88
2.081
imagen615 647 (-) C35H33ClN2O6S+1,5 H2O C: 62,54, H: 5,40, N: 4,17 C: 62,27, H: 5,20, N: 4,09
2.082
imagen616 7,27,4 (-) C37H33N2O5SClF4 + (0,7) CF3CO2H C: 57,01; H 4,20; N: 346 C: 56,93; H 4,47; N: 3,40
2.083
imagen617 681 (-) C35H32Cl2N2O6S +2,0 H2O +0 6CH2Cl2 C:55,78, H: 4,89, N: 3,65 C:55,68, H: 4,73, N: 3,32
2.084
imagen618 630 (-) C35H33FN2O6S +2 0 H2O +01CH3CN C6321, H: 5 62, N 4 40 C6319, H:5,02, N: 471
2.085
imagen619 664 (-) C35H32ClFN2O6S+1,5 H2O+0,1CH3CN C:60,89, H: 5,12, N: 4,24 C:60,75, H: 5,00, N: 4,35
2.086
imagen620 641 (-) C36H35FN2O6S +2,5 H2O C:62,87, H: 5,86, N: 4,07 C:62,89, H: 5,82, N: 4,02
2.087
imagen621 613 (+) C29H29BrN2O6S +1,5 H2O C:54,38, H: 5,04, N: 4,37 C:54,21, H: 4,74, N: 4,49
2.088
imagen622 645 (-) C35H32F2N2O6 +2,7 H2O +0,2CH3CN C:60,43, H: 5,44, N: 4,38 C:60,16, H: 5,00, N: 4,62
2.089
imagen623 657,0 (+) C36H35N2O5ClS + (1,4) H2O + (1,0) LiCl C: 61,31, H: 5,53, N: 3,86 C: 61,27, H: 5,63, N: 3,94
2.090
imagen624 601,9 (+) C35H31N6O2Cl + (1,2)HCl +(0,1)CH3CO2H C: 64,87, H:5,03, N: 12,93 C: 65,15, H: 4,65, N: 12,53
2.091
imagen625 623,6 (+) C37H35N2O5Cl + (1,4) H2O + (0,4) CF3CO2H C: 65,42, H: 5,55, N: 4,04 C: 65,16, H: 5,24, N: 4,37
2.092
imagen626 622,3 (+) C37H36N3O4Cl + (1,2) C6H6 + (0,4) CF3CO2H C: 70,98, H: 5,77, N: 5,52 C: 71,36, H: 5,69, N: 5,16
2.093.
imagen627 643,2 (+) C36H36N2O5ClP + (0,8) H2O C: 65,76, H: 5,76, N: 4,26 C: 65,81, H: 5,70, N: 4,27
2.094
imagen628 641,3 (+) C37H38N2O4CIP +(2,1) H2O + (1,2) CH3OH C: 63,95, H: 6,60, N: 3,90 C: 64,21, H: 7,00, N: 3,84
2.095
imagen629 671,3 (+) C38H39N2O5ClPNa + (1,7) H2O + (0,2) CH3OH C: 62,84, H: 5,96, N: 3,84 C: 62,90, H: 5,73, N: 3,77
2.096
imagen630 601,2 (+) C30H30N2O5Cl2SNa + (1,5) H2O C: 55,30, H: 5,10, N: 4,30 C: 55,25, H: 4,93, N: 4,25
2.097
imagen631 675,677 (-) C36H34Cl2N2O5S + 0,25 CF3CO2H C: 61,61, H:4,94, N: 3,94 C: 61,38, H: 5,31, N: 3,88
2.098
imagen632 659,6 (-) C36H34ClFN2O5S + 0,5 CF3CO2H + 0,5 H2O C: 61,11, H: 4,92, N: 3,85 C: 61,18, H:4,57, N: 3,96
2.099
imagen633 565 (-) C30H31ClN2O5S + 0,1 CF3CO2H + 1,5 H2O Esperado C 59 90, H 5,68, N: 4 63 Hallado C: 6022, H:566, N:456
2.100
imagen634 710 (-) C37H36F2N2O6S + 0,1 CF3CO2H - 1,7 H2O C: 63,76, H: 5,68, N: 4,00 C: 63,53, H: 5,64, N: 3,88
2.101
imagen635 673 (-) C37H36F2N2O6S + 0 1 CF3CO2H + 1,7 H2O Esperado C.63 76, H 5,68, N: 4,00 Hallado C: 63,53, H: 5,64, N: 3,88
2.102
imagen636 C33H35ClN2O5S + 0,2 CF3CO2H + 1,5 H2O C: 61,06, H: 5,86, N: 4,26 C: 60,92, H: 6,13, N: 4,58
2.103
imagen637 571 (-) C33H35ClN2O5S + 0,2 CF3CO2H + 1,5 H2O C: 61,06, H: 5,86, N: 4,26 C: 60,92, H: 6,13, N: 4,58
2.104
imagen638 605,607 (-) C33H35ClN2O5S + 0,2 CF3CO2H + 1,5 H2O C: 61,06, H: 5,86, N: 4,26 C: 60,92, H: 6,13, N: 4,58
2.105
imagen639 675,4 (-) C36H34Cl2N2O5S + 1,2 H2O C: 61,84, H: 5,25, N:4,01 C: 61,71, H:4,99, N:4,18
2.106
imagen640 709,6 (-) C37H34ClF3N2O5S + 1H2O 60,94 4,98 3,84 60,91 4,63 3,67
2.107
imagen641 725,4 (-) C37H34ClF3N2O6S + 1,8H2O C: 58,50, H:4,99, N:3,69 C: 58,18, H: 4,33, N:3,64
2.108
imagen642 677,6 (-) C36H34ClN2O5S + 1,2H2O + 0,1 CH2Cl2 C:61,62, H:5,21, N:3,96 C: 60,93, H: 4,61, N:3,90
2.109
imagen643 659,6 (-) C36H34ClFN2O5S + 1,0H2O + 1,0TFA C: 57,54, H:4,70, N:3,53 C: 57,35, H:4,53, N:3,44
2.110
imagen644 645,0 (-) C30H30BrClN2O5S + 0,5TFA C: 52,96, H:4,37, N:3,98 C: 52,64, H:4,69, N:3,81
2.111
imagen645 739,6 (+) C36H35ClN2O4S + 0,5 CF3CO2H C: 64,95, H:5,23, N:4,09 C: 64,91, H:4,97, N:4,19
2.112
imagen646 711,4 (-) C36H33Cl3N2O5S + 1,2H2O C: 58,93, H: 4,86, N:3,82 C: 58,66, H:5,16, N:4,16
2.113
imagen647 743,6 (-) C37H33Cl3F3N2O5S + 1,3H2O C: 57,79, H: 4,67, N: 3,64 C: 57,83, H: 4,43, N:3,77
2.114
imagen648 709,2 (-) C37H34ClF3N2O5S + 1,3H2O C:60,49, H:5,02, N:3,81 C:60,18, H:4,95, N:4,14
2.115
imagen649 759,2 (-) C38H34F6N2O6S + 1,3H2O C: 58,20, H:4,70, N:3,57 C: 57,94, H:4,67, N:3,73
2.116
imagen650 693,0 (-) C37H34F4N2O5S + 15H2O C: 61,57, H:5,17, N:3,88 C:61,26, H:4,86, N:4,10
2.117
imagen651 705,6 (-) C38H37F3N2O6S + 1,5H2O C: 62,20, H: 549, N:3,82 C: 61,99, H:5,54, N:4,22
2.118
imagen652 709,6 (-) C37H34ClF3N2O5S + 1,3H2O C: 60,49, H:5,02, N:3,81 C: 60,20, H: 4,83, N:4,43
2.119
imagen653 675,0 (-) C37H35F3N2O5S + 2 H2O C: 62,35, H: 5,51, N: 3,93 C: 62,18, H: 5,60, N: 3,89
Se sintetizaron compuestos enriquecidos enantioméricamente de esta clase tal como se describe a continuación: (no según la invención):
Éster metílico del ácido 4-[3-(4-bencil-2-oxo-oxazolidin-3-il)-[2-(4-terc-butil-fenil)-3-oxo-propil]-benzoico
imagen654
Etapa 1:
10 A una disolución de éster metílico del ácido (4-terc-butil-fenil)-2-carboxi-etil]-benzoico (2,5 g, 5,20 mmol, preparado tal como se notifica en Bioorg. Med. Chem Lett. 2004, 14, 2047-2050) en CH2Cl2 (50 ml) a temperatura ambiente se le añadió cloruro de oxalilo (0,98 g, 7,81 mmol). Se agitó la mezcla de reacción a temperatura ambiente durante la noche y se eliminó el disolvente a presión reducida. Se secó el residuo a vacío durante 3-4 h. Se usó el cloruro de ácido bruto en la siguiente etapa.
15
imagen655
imagen656
imagen657
bien sonda nasogástrica oral. Los modelos animales usados en esta evaluación [por ejemplo el ratón db/db, la rata ZF, la rata ZDF, el perro expuesto a glucagón (0,3-5 g/kg), la rata o el ratón tratado con aloxano o estreptozotocina, el ratón NOD o la rata BB] o bien se alimentan libremente o bien están en ayunas desde 3 hasta 24 horas antes de la administración del compuesto. En algunos casos, los animales pueden someterse a una prueba de tolerancia a la 5 glucosa tras la administración del compuesto mediante administración intravenosa u oral de hasta 2 g/kg de glucosa. Se evalúan los niveles de glucemia en muestras de sangre obtenidas mediante extracción de sangre de la cola o mediante toma de muestras en un vaso sanguíneo apropiado por medio de una jeringuilla o catéter. Se mide la glucosa usando un glucómetro portátil tales como los glucómetros OneTouch o HemoCue a intervalos de tiempo regulares durante hasta 24 horas. Se determina el grado de disminución de glucemia provocado por los compuestos
10 de la invención mediante la comparación con las de animales control a los que sólo se les administra el vehículo. Se calcula el porcentaje de disminución de glucemia logrado en relación con los niveles de glucemia en animales control no diabéticos tratados con vehículo o no expuestos a glucagón.
EJEMPLO D - Disminución de glucosa en ratones db/db.
15 Objetivo: Evaluar los efectos de los compuestos de la invención sobre los niveles de glucemia en el ratón db/db, un modelo animal de la diabetes tipo 2.
Métodos: Se disolvieron los compuestos en polietilenglicol-400 y se administraron mediante sonda nasogástrica oral
20 a ratones db/db en el estado alimentado libremente a dosis de 30 y/o 100 mg/kg. Se evaluaron los niveles de glucemia en muestras de sangre obtenidas mediante extracción de sangre de la cola en el nivel inicial (antes de la administración del fármaco) y a intervalos de tiempo regulares a lo largo de 24 horas usando un glucómetro portátil tal como los glucómetros OneTouch o HemoCue. Se determinó la magnitud de disminución de glucemia provocada por los compuestos de la invención mediante la comparación con las de ratones db/db a los que sólo se les
25 administra el vehículo. Se calculó el porcentaje de disminución de glucosa factorizando los niveles de glucemia de ratones db/+ magros tratados con vehículo (heterocigotos), representando el 100% la normalización de los niveles de glucemia desde el estado hiperglucémico (ratones db/db tratados con vehículo) hasta el estado normoglucémico (ratones db/+ tratados con vehículo).
30 Resultados: Tal como se muestra en la tabla a continuación, los compuestos de la invención disminuyeron la glucemia de los ratones db/db en estado alimentado libremente en de 19 a 172 mg/dl. El porcentaje de disminución de glucemia logrado osciló entre el 6 y el 68% en relación con los animales control magros.
Ejemplo n.º
DOSIS (mg/kg) Disminución de glucosa (mg/dl) % de disminución de glucosa
1.052
30 147 61
1.155
30 108 49
1.321
30 161 68
1.135
100 131 41
1.137
30 159 53
1.136
30 47 16
1.320
30 121 39
1.270
30 63 24
1.138
30 19 6
1.315
30 172 57
1.311
30 109 36
1.359
100 150 48
1.179
30 102 34
1.314
30 95 40
1.173
30 172 50
1.269
30 124 42
1.133
30 157 57
35 Conclusión: Los compuestos de la invención tienen actividad antihiperglucémica pronunciada en modelos animales de diabetes tipo 2 y por tanto pueden tener utilidad para el tratamiento de la diabetes tipo 2.
imagen658

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