ES2582585T3 - Compuestos inhibidores de 11-beta-hidroxiesteroide deshidrogenasa de tipo 1 - Google Patents

Compuestos inhibidores de 11-beta-hidroxiesteroide deshidrogenasa de tipo 1 Download PDF

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ES2582585T3
ES2582585T3 ES10783009.3T ES10783009T ES2582585T3 ES 2582585 T3 ES2582585 T3 ES 2582585T3 ES 10783009 T ES10783009 T ES 10783009T ES 2582585 T3 ES2582585 T3 ES 2582585T3
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octahydroquinolin
amide
acid
oxopentanoic acid
octahydroisoquinolin
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Juan Lorenzo Catena Ruiz
Carme Serra Comas
Óscar Rey Puiggros
Albert Antolín Hernández
Ester Monlleo Mas
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Laboratorios Salvat SA
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Abstract

Los compuestos de fórmula (I) son derivados de perhidroquinolina y perhidroisoquinolina y son útiles como principios activos farmacéuticos para Ia profilaxis o tratamiento de enfermedades causadas por trastornos asociados con Ia enzima 11 beta-hidroxiesteroide deshidrogenasa de tipo 1 (11 beta- HSD1), tales como glaucoma, presión ocular elevada, trastornos metabólicos, obesidad, síndrome metabólico, dislipidemia, hipertensión, diabetes, aterosclerosis, síndrome de Cushing, psoriasis, artritis reumatoide, alteraciones de Ia cognición, enfermedad de Alzheimer o neurodegeneración.

Description

imagen1
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El esquema 6 muestra un procedimiento de preparación de los compuestos de la presente invención de tipo amido-S-tiocarbamato y amido-ditiocarbamato. Tras la formación de la amida intermedia (IVp) por procedimientos previamente descritos y su posterior reacción con isocianato, tiocianato, cloruro de carbamoílo o cloruro de tiocarbamoílo proporciona el S-tiocarbamato o ditiocarbamato (Ip).
Esquema 7
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El esquema 7 muestra un procedimiento de preparación de la sulfonamida (Im) en el que se hace reaccionar decahidroquinolina con el cloruro de éster sulfonílico (IIm). El tratamiento de desprotección y acoplamiento
10 previamente descrito en el esquema 1 proporciona las sulfonamidas (Im). Los siguientes ejemplos sirven para una mejor ilustración de la invención, pero no deben ser considerados como limitantes de ella.
La nomenclatura utilizada en el presente documento se basa en el programa informático del instituto Beilstein denominado AUTONOM (Automatic Nomenclature), que usa la nomenclatura sistemática de la IUPAC 15 Abreviaturas: AcOEt acetato de etilo Salmuera solución saturada de NaCI DCM diclorometano DMF dimetilformamida 20 DMSO dimetilsulfóxido EDC 1-(3-dimetilaminopropil)-3-etilcarbodiimida EtsN trietilamina EtOH etanol HOBT 1-hidroxibenzotriazol 25 HPLC cromatografia Iíquida de alta resolución MeOH metanol EM espectrometría de masas m/z proporción masa/carga ta temperatura ambiente 30 THF tetrahidrofurano
9 5
10
15
20
25
30
35
TLC
cromatografia en capa fina
tr
tiempo de retención
UV
ultravioleta
Datos generales:
Los productos se analizaron usando un equipo de HPLC-UV-EM de Agilent provisto de un detector UV de longitud de onda variable y de un espectrómetro de masas modelo 1100 VL. La longitud de onda empleada para la detección UV fue 210 nm, mientras que el detector de EM se ha operado en modo de ionización por electropulverización positiva y ha realizado un barrido de m/z 100 a 700. En cuanto a la separación cromatográfica, la columna empleada ha sido una Kromasil 100 C18, 40 x 4,0 mm, 3,5 µm y se han inyectado 5 µl. Para la elución se ha seguido uno de los dos gradientes de solventes que se describen a continuación:
Procedimiento A: B al 5-90 %, 0-8 min; B al 90 %, 8-11 min; B al 5 %, 9-11 min. El caudal de la fase móvil es de 0,7 ml/min.
Procedimiento B: B al 5-90 %, 0-4,5 min; B al 90 %, 4,5-6 min; B, al 5 %, 6-7 min. El caudal de la fase móvil es de 1,4 ml/min.
En ambos casos, el solvente A consiste en ácido fórmico al 0,2 % en agua, mientras que B es ácido fórmico al 0,2 % en acetonitrilo.
Alternativamente, se lleva a cabo el análisis por medio de equipo de HPLC-UV-EM de Waters provisto con un detector que tiene diodos en serie y un espectrómetro de masas modelo EMD1000. La longitud de onda usada para detectar UV fue 210 nm, mientras que el detector de EM descrito se ha operado en un modo de ionización por electropulverizacióin positiva y se ha realizado un escaneo de 100 a 700 m/z. En cuanto a la separación cromatográfica, la columna usada fue una Kromasil C18 de 2,1 x 50 mm, se inyectaron 3,5 µm y 2 µl. Para la elución, se siguió el siguiente gradiente:
Procedimiento C: B al 5-100 %, 0-5 min; B al 100 %, 5-6,5 min; B al 5 %, 6,5-8 min. El caudal de la fase móvil es 0,5 ml/min.
Intermedio llla.1: 3-(octahidroquinolin-1-il)-3-oxopropionato de etilo.
imagen10
A una solución de 1,5 ml (10 mmol) de decahidroquinolina en 100 ml de AcOEt se añaden 3,38 ml de Et3N y 1,44 ml (11 mmol) de 3-cloro-3-oxopropionato de etilo. La solución resultante se mantiene con agitación a reflujo durante 10 h. A continuación se añade agua y se separa la fase orgánica, la fase acuosa se extrae una vez más con AcOEt. Se juntan las fases orgánicas y se lavan primero con solución al 5 % de NaHCO3 y posteriormente con salmuera, se secan sobre Na2SO4 anhidro, se filtran y se evapora el disolvente a presión reducida. Se obtienen 2,0 g de un aceite amarillo. Es identificado como el intermedio llla.1. Procedimiento A: tr: 6,75 min; m/z: 268.
Intermedio llla.2: éster metílico del ácido 6-(octahidroisoquinolin-2-il)-6-oxohexanoico
imagen11
A una mezcla formada por 1,1 ml (8,32 mmol) de decahidroisoquinolina, 1,5 ml (10 mmol) de adipato de monometilo, 2 g (15 mmol) de HOBT y 2,9 g (15 mmol) de EDC se añaden 80 ml de AcOEt y a continuación, 3 ml (22 mmol) de Et3N. La solución formada se mantiene con agitación durante 18 h. A continuación, se trata con agua y AcOEt, se separa la fase orgánica y la fase acuosa se extrae una vez más con AcOEt. Se juntan las fases orgánicas y se lavan sucesivamente con solución de NaHCO3 saturada, HCl 1N y salmuera. A continuación se secan sobre Na2SO4
10
anhidro, se filtran y se evapora el disolvente a presión reducida. Se obtienen 1,5 g de un aceite identificado como el intermedio llla.2. Procedimiento B: tr: 3,66 min/ 3,78; m/z: 282/282. Los siguientes intermedios se prepararon de manera similar a los intermedios llla.1 o llla.2:
imagen12
Intermedio lllb.1: Ester metílico del ácido 3-[(octahidroquinolin-1-carbonil)amino]propiónico.
11
imagen13
Etapa 1:
imagen14
2-Clorocarboniloctahidroisoquinolina: Se preparó de manera análoga a la descrita para la etapa 1 del intermedio Illb.1. 5 IR: 1737.
Etapa 2:
A una solución, a 0 ºC de 0,55 ml (5 mmol) del éster metílico del ácido 3-mercaptopropiónico en 10 ml de piridina se añade 1 g (5 mmol) de 2-clorocarboniloctahidroisoquinolina. Una vez añadido, se deja con agitación a ta durante 18 h. Acontinuación a la mezcla de reacción se le añade AcOEt y se lava secuencialmente con una solución al 5 % de
10 NaHCO3, HCI 1N y salmuera. La fase orgánica se seca sobre Na2SO4 anhidro, se filtra y se evapora el disolvente a presión reducida purificándose mediante cromatografía en columna de gel de sílice, utilizando como eluyente una mezcla (1:1) de hexano:AcOEt, proporcionando 1,17 g de un residuo identificado como el intermedio lllb.5 y 210 mg de un sólido identificado como la bis-(octahidroisoquinolin-2-il)metanona (Vb.1).
imagen15
15 Procedimiento B: para lllb.5 tr: 4,35 min; m/z: 286.
Para Vb.1: tr: 5,34 min8; m/z: 305.
Los siguientes intermedios se prepararon de forma similar al intermedio lllb.5:
imagen16
Intermedio lllm.1: éster metílico del ácido 3-(octahidroquinolin-1-sulfonil)propiónico
13
imagen17
Etapa 1
A una solución formada por 2,47 ml (22,4 mmol) de 3-mercaptopropionato de metilo y 5,64 g (55,9 mmol) de nitrato potásico enfriada a 0 °C se añaden gota a gota 4,48 ml (55,9 mmol) de cloruro de sulfurilo. Una vez añadidos se deja
5 alcanzar la ta manteniendo la agitación durante 10 h. Se añade solución saturada de NaHCO3 y se separa la fase orgánica, que posteriormente se vuelve a lavar de nuevo con NaHCO3 y posteriormente con salmuera. La fase orgánica se seca sobre Na2SO4 anhidro, se filtra y se evapora el disolvente a presión reducida proporcionando 2,6 g de un aceite identificado como el éster metílico del ácido 3-clorosulfonilpropionico. Procedimiento B: tr: 2,05 min; m/z: no ionizable.
10 Etapa 2
A una solución formada por 1,1 ml (7,6 mmol) de decahidroquinolina en 70 ml de AcOEt se añaden 2,1 ml de Et3N (15,3 mmol) y posteriormente, gota a gota, 1,3 g (7 mmol) del éster metílico del ácido 3-clorosulfonilpropiónico. La mezcla se calienta a 70 °C y se mantiene a esa temperatura durante 12 h. A continuación se deja enfriar y se le añade agua, se separa la fase orgánica y se lava secuencialmente con solución al 5 % de bicarbonato sódico, HCI 2 N y
15 salmuera. La fase orgánica se seca sobre Na2SO4 anhidro, se filtra y se evapora el disolvente a presión reducida proporcionando 1,32 g de un aceite rojizo identificado como el intermedio lllm.1.
Procedimiento B: tr: 3,36 min; m/z: 290
Los siguientes intermedios se prepararon de forma similar al intermedio lllm.1:
imagen18
Intermedio lVb.1: ácido 4-[(octahidroisoquinolin-2-carbonil)amino]-butírico
imagen19
14
imagen20
imagen21
16
imagen22
imagen23
imagen24
imagen25
Intermedio lc.1: 2-[4-(octahidroquinolin-1-il)-4-oxobutil]isoindol-1.3-diona
20
imagen26
imagen27
imagen28
imagen29
Intermedio IVj.1: 5-hidroxil-1-(octahidroisoquinolin-2-il)pentan-1-ona
imagen30
A una solución de 1,25 g (4,93 mmol) del intermedio IVa.8 y 0,6 ml de N-metilmorfolina (5,4 mmol) en 50 ml de THF
5 anhidro y enfriada a 0 ºC, se le añaden gota a gota 0,63 ml (4,93 mmol) de cloroformiato de isobutilo. La solución resultante se deja agitar 30 minutos a esa temperatura y posteriormente se le añaden 370 mg (9,86 mmol) de borohidruro sódico. Acabada la adición se le deja alcanzar ta y se agita durante 2 h. Posteriormente se fracciona con AcOEt y agua. La fase acuosa se extrae dos veces con AcOEt, se reúnen las fases orgánicas, se secan sobre Na2SO4 anhidro, se filtran y evaporan a sequedad, obteniéndose 1 g de un aceite amarillo, que se utilizó sin posterior
10 purificación.
Procedimiento B: tr: 2,94 min/3,06 min; m/z: 240/240.
Intermedio lVj.2: 5-hidroxil-1-(octahidroquinolin-1-il)pentan-1-ona
imagen31
Se prepara de manera análoga a la descrita para el intermedio IVj.1. Procedimiento B: tr: 2,94 min; m/z: 240 15 Intermedio IVp.1: 3-mercapto-1-(octahidroquinolin-1-il)propan-1-ona
imagen32
A una solución formada por 3 g (28,2 mmol) de ácido 3-mercaptopropiónico en 45 ml de DMF y enfriada a 0 °C se le añaden 8,5 ml de Et3N, 6,5 g de EDC (mmol) y 5,7 g de HOBT (mmol) y se deja 15 minutos con agitación a esa temperatura. Se añaden 4,2 g (28,3 mmol) de decahidroquinolina a continuación y se deja agitar a ta durante 18 h. A
20 continuación, se trata con agua y AcOEt, se separa la fase orgánica y la fase acuosa se extrae una vez más con AcOEt. Se juntan las fases orgánicas y se lavan sucesivamente con solución saturada de NaHCO3, HCl 1 N y salmuera. A continuación se seca sobre Na2SO4 anhidro, se filtra y se evapora el disolvente a presión reducida. El residuo resultante se purifica mediante cromatografía en columna de gel de sílice, utilizando como eluyente una mezcla (50:1) de DCM:MeOH, proporcionando 600 mg del tiol intermedio IVp.1.
25 Intermedio IVp.2: 3-mercapto-1-(octahidroisoquinolin-2-il)propan-1-ona
24
imagen33
imagen34
imagen35
imagen36
imagen37
imagen38
imagen39
imagen40
imagen41
imagen42
imagen43
imagen44
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imagen47
imagen48
imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
imagen55
imagen56
imagen57
imagen58
imagen59
imagen60
imagen61
imagen62
imagen63
imagen64
imagen65
imagen66
imagen67
imagen68
imagen69
imagen70
Im.21*
1-(3,5-dimetilpiperidin-1-il)-4(octashidroisoquinolin-2sulfonil)butan-1-ona B 4,37 4,45 385 385
Im.22*
4-(octahidroisoquinolin-2-sulfonil)-1-(perhidrooxazocin-1ilbutan-1-ona B 423 4,30 385 385
Im23*
1-((R)-3-hidroxipiperidin-1-il)-4-(octahidroisoquinolin-2sulfonil)butan-2-ona B 3,15 3,22 373 373
Im.24*
1-(4-metilpiperidin-1-il)-4-(octahidroisoquinolin-2-sulfonil) butan-2-ona B 4,12 4,19 371 371
Im.25*
1-(3-metilpiperidin-1-il)-4-(octahidroisoquinolin-2-sulfonil) butan-2-ona B 4,11 4,18 371 371
Im.26*
N-ciclohexil-N-metil-4-(octahidroisoquinolin)-2-sulfonil) butiramida B 4,31 4,37 385 385
Im.27*
1-(3,3-difluiropioeridin-1-il)-4-(octahidroisoquinolin-2-sulfonil)butan-1-ona B 3,87 3,93 393 393
Im.28*
1-(4,4-difluoropiperidin-1-il)-4-(octahidroisoquinolin-2-sulfonil)butan-1-ona B 3,87 3,94 393 393
Im.29
imagen71 4-(octahidroisoquinolin-1-sulfonil)-1-(octahidroquinolin-1il)butan-1-ona B 4,51 411
Im.30
4-(octahidroisoquinolin-2-sulfonil)-1-(octahidroquinolin-2il)butan-1-ona B 4,63 4,70 411 411
Ia.168
4-(octahidroisoquinolin-2-il)-4-(6-octahidroindol-1-il)butan -1-ona B 4,33 4,41 361 361
Ia.169
4-(octahidroisoquinolin-2-il)-5-(6-octahidroindol-1-il)pentan-1,5-diona B 4,38 4,48 375 375
63
imagen72
imagen73
Ia.179
N-(2-metoxifenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,74 387
Ia.180
N-(2-clorofenil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,88 391
Ia.181
N-(4-sulfamoilfenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 2,97 436
Ia.182
N-(2-fenoxietil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,67 373
Ia.183
N-(3-metoxifenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,65 387
Ia.184
N-(3-clorofenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,92 391
Ia.185
N-[2-benzo[d][1,3]dioxol-5-il)etil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,56 401
Ia.186
N-[(1-fenilciclopropil)metil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,92 383
Ia.187
N-[2-naftalen-2-iletil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,05 407
Ia.188
imagen74 N-[(R)-2-fenil-2-hidroxietil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,19 373
Ia.189
imagen75 N-[(1R,2S)-1-2-fenil-1-hidroxipropan-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,37 387
Ia.190
imagen76 N-(2,3-dihidro-1H-inden-2-il)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,77 369
Ia.191
Éster metílico del ácido (2S)-3-(4-hidroxifenil)-2-[5-(octahidroquinolin-1-il)5-oxipentanamida]propanoico B 3,21 431
Ia.192
N-[2-(tiofen-2-il)etil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,58 363
66 67 68 69 70 71
Ia.193
N-(4-clorofenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,93 391
Ia.194
N-(2,2-difenilpropil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,39 447
Ia.195
N-(2,2-difeniletil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,16 443
Ia.196
N-(4-metilfenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,88 371
Ia.197
N-(4-metilfenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,61 387
Ia.198
N-(3-fluorofenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,72 375
Ia.199
N-(4-hidroxifenetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,10 373
Ia.200
N-(1-hidroxi-1-(4-hidroxifenil)propan-2-il)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 2,88 403
Ia.201
N-(1-hidroxil-1-(3-hidroxifenil)propn-2-il)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,00 403
Ia.202
N-[2-(5-hidroxil-1H-indol-3-iletil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,04 412
Ia.203
imagen77 N-[(R)-1-amino-3-fenil-1-oxopropan-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,19 400
Ia.204
imagen78 N-((4-feniltetrahidro-2H-piran-4-il)metil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,89 441
Ia.205
N-[2-fenilpropil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,02 395
Ia.206
N-[2-(naftalen-1-il)etil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,06 407
Ia.207
N-[(4-feniltetrahidro-2H-piran-4-il)metil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,06 427
Ia.208
N-[(S)-3-fenil-1-oxo-1-[pirrolidin-1-il)propan-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,65 454
Ia.209
N-[(S)-1-(ciclohexilamino)-3-fenilpropan-1-oxo-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,06 482
Ia.210
N-[(S)-1-amino-3-fenil-1-oxopropan-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,19 400
Ia.211
N-fenetilamida del ácido N-(2-amino-2-oxoetil)-5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,41 414
Ia.212
N-[(S)-1-amino-3-(1H-indol-3-il)-1-oxopropan-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,15 439
Ia.213
1-(2-fenil-4-metilpiperazin-1-il)-5-(octahidroquinolin-1-il)pentano-1,5-diona del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 2,58 412
Ia.214
N-bencil-N-etilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,06 371
Ia.215
N-(4-metoxibencil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,50 373
Ia.216
N-(4-(trifluorometil)bencil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,97 411
Ia.217
N-[(R)-1-fenilatil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,70 357
Ia.218
N,N-dibencilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,53 433
Ia.219
N-(9H-fluoren-9-il)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,19 417
Ia.220
Éster etílico del ácido 2-(N-bencil-5-(octahidroquinolin-1-il)-5oxopentanamida)acético B 4,12 429
Ia.221
N-[ciano(fenil)metil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,68 368
Ia.222
N-bencidrilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,15 419
Ia.223
Éster metílico del ácido (2R)-2-[5-(octahidroquinolin-1-il)-5-oxopentanamido)-2fenilacético B 3,67 401
Ia.224
N-(1,2,3,4-tetrahidronaftalen-1-il)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,96 383
Ia.225
N-(venzo[d][1,3]dioxol-5-ilmetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,46 387
Ia.226
N-bencil-N-butilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoic B 4,51 399
Ia.227
N-bencil-N-[2-(dimetilamino)etil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoic B 2,83 414
Ia.228
N-bencil-N-[isopropilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoic B 4,22 385
Ia.229
Éster etílico del ácido 2-[N-[3-(1H-imodazol-1-il)propil]-5-(octahidroquinolin-1-il)-5oxopentanamido]acético B 2,67 447
Ia.230
Éster etílico del ácido 2-[5-(octahidroquinolin-1-il)-5-oxo-N-(4sulfamoilfenetil)pentanamido]acético B 3,43 522
Ia.231
Éster etílico del ácido 2-[N-[2-(5-metoxi-1H-3-il)etil]-5-(octahidroquinolin-1-il)5-oxo-N-[2-(piridin-2-il)etil]pe3ntanamido]acético B 3,92 512
Ia.232
Éster etílico del ácido 2-[5-(octahidroquimolin-1-il)-5-oxo-N-[2(piridin-2-il)etil]pentanamido]acético B 2,79 444
Ia.233
N-(2-amino-2-oxoetil)-N-bencilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,29 400
Ia.234
Éster etílico del ácido 3-[N-bencil-5-(octahidroquinolinb-1-il)-5-oxopentqnamido]propanoico B 4,15 443
Ia.235
N-bencil-N-(2-hidroxietil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,47 387
Ia.236
N-(1,2-difeniletil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,21 433
Ia.237
N-bencidril-N-metilamida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,53 433
Ia.238
N-(4-clorobencil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,82 377
Ia.239
N-(4-(trifluorometoxi)bencil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,06 437
Ia.240
N-[3-(trifluorometoxi)bencil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,06 427
Ia.241
N-fenetil-N-[2-(fenetilamino)-2-oxoetil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,97 411
Ia.242
N-fenetil-N-[2-(fenetilamino)-2-oxoetil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,25 518
Ia.243*
N-[2-oxo-2-([2-(tiofen-2-il)etil]amino)etil]-N-[2-(tiofen-2iletil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,11 530
Ia.244
N-[(S)-3-fenil-1-hidroxipropan-2-il]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,31 387
Ia.245
N-[(S)-1-feniletil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,70 357
Ia.246
Éster etílico del ácido 2-[N-(4-hidrofenetil)-5-(octahidroquinolin1-il)-3-oxopentanamido]acético B 3,59 459
Ia.247
Éster etílico del ácido 2-(N-(3,4-dimetoxifenetil)-5-(octahidroquinolin-1-il)-5-oxopentanamido]acético B 3,91 503
Ia.248
Éster etílico del ácido 2-[N-[2-(1H-indol-3-il)etil]-5-((octahidroquinolin-1-il)-5oxopentanamido)acético B 4,04 492
Ia.249
Éster etílico del ácido 2-[N-[2-(1H-hidroxi-1H-indol-3-il)etil]-5(octahidroquinolin-1-il)-5-oxopentanamido]acético B 3,47 498
Ia.250
Éster metílico del ácido 2-[N-(4-nitrofenenetil)-5-(octahidroquinolin-1-il)-5-oxo-pentanamido)acético B 4,10 488
Ia.251
Éster etílico del ácido 2-[N-(2,4-diclorofenetil)-3-octahidroquinolin-1-il)-5-oxopentanamido]acético B 4,73 511
Ia.252
Éster etílico del ácido 2-[N-(4-clorofenetil)-5-(octahidroquinolin-1-il)-5-oxopentanamido]acético B 4,45 477
Ia.253
Éster etílico del ácido 2-[N-(4-metoxifenetil)-5-(octahidroquinolin-1-il)-5-oxopentanamido]acético B 4,14 473
Ia.254
Éster metílico del ácido 2-[5-octahidroquinolinil-1-il)-5-oxo-N-[2(trifluorometil)bencil]pentanamido]acético B 4,27 483
Ia.255
N-(2-amino-2-oxoetil)-N-[2-(1H-indol-3-il)etil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 3,34 453
Ia.256
N-(2,4-diclorofenetil)-N-[2-[(2,4-diclorofenetil)amino]-2-oxoetil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 5,13 654, 656
Ia.257
Éster metílico del ácido 2-[N-4-(benciloxi)bencil]-5-(octahidroquinolin-1-il)-5-oxopentanamido]acético B 4,48 521
Ia.258
Éster etílico del ácido 2-[5-octahidroquinolinil-1-il)-5-oxo-N-[fenoxi-bencil)pentanamido]acético B 4,65 521
Ia.259
Éster etílico del ácido 2-[5-octahidroquinolinil-1-il)-5-oxo-N-[4-fenil-butil)pentanamido]acético B 4,34 471
Ia.260
Éster metílico del ácido 3-(N-[4-(bencil]-5-(octahidroquinolinil-1-il)-5-oxopentanamido)propanoico B 4,48 535
Ia.261
N-metil-N-(naftalen-1-ilmetil)amida del ácido 6-(octahidroisoquinolin-2-il)-6-oxohexanoico B 4,31 4,40 421 421
Ia.262
imagen79 1-(octahidroisoquinolin-2-il)-6-(4-oxooctahidroquinolin-1-il)hexano-1,5-diona B 3,72 3,81 403 403
Ia.263
(3-metil-10,11-dihidro-5H-dibenzo[a,d]ciclohepten-5-il)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico C 5,01 459
Ia.264
(3-etil-10,11-dihidro-5H-dibenzo[a,d]ciclohepten-5-il)amida C 5,20 473
Ia.265
5-[(R)-1-fenil-3,4-dihidro-1H-isoquinolin-2-il]-1-(octahidroQuinolinil-1-il)-pentano-1,5-diona C 5,02 445
Ia.266
(1-fenil-ciclobutilmetil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico C 4,64 397
Ia.267
(2-ciclohexil-2-fenil-etil)amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico C 5,19 439
* Ejemplos comparativos
Ej. Ie.1: 1-[5-(octahidroquinolin-1-il)-5-oxopentil]-3-triciclo[3.3.1.1.3]-1decan-1-ilurea
imagen80
Se disuelven 35 mg (0,15 mmol) del intermedio Vc.4 en 2 ml de THF anhidro y 23 µl (0,25 mmol) de Et3N. Una vez disueltos se añaden lentamente 17,3 mg (0,1 mmol) de isocianato de 1-adamantilo y se lleva a reflujo durante 2 días. Posteriormente se añade AcOEt y la solución resultante se lava secuencialmente con agua, HCl 1N y salmuera. La fase orgánica se seca sobre Na2SO4 anhidro, se filtra y se evapora el disolvente a presión reducida proporcionando 47,5 mg de un aceite amarillento identificado como el ejemplo le.1. Procedimiento B: tr: 4,27 min; m/z: 416.
Los siguientes ejemplos se prepararon de manera similar al ejemplo le.1.
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imagen82
imagen83
imagen84
imagen85
imagen86
imagen87
imagen88
imagen89
imagen90
imagen91
imagen92
imagen93
Ie.70
1-[4-(octahidroquinolin-1-il)-4-oxobutil]-3-[4oxobutil]-3-[4-(tiofen-2-il)tetrahidropiran-4-il]urea B 3,43 434
Ie.71
N-[3-(octahidroquinolin-1-il)-3-oxopropil]amida del ácido octahidroquinolin-1-il)-3-oxopropil]amida B 4,09 376
Ie.72
1-[(3s,5s,7s)-adamantan-1-il]-3-[3-(octahidroisoquinolin2-il)-3-oxopropil]urea B 4,17 4,26 388 388
Ie.73
1-isopropil-3-[5-(octahidroisoquinolin-2-il)-5-oxopentil]urea B 4,60 4,68 324 324
Ie.74
1-[(3s,5s,7s)-adamantan-1-il]-3-[5-octahidroisoquinolin-2il)-5-oxopentil]urea B 4,27 4,35 416 416
Ie.75
1-t-butil-3-[2-(octahidroisoquinolin-2-il)-2-oxoetil)urea B 3,47 296
Ie.76
1-[2-(octahidroisoquinolin-2-il)-2-oxoetil]-3-(tiofen-2-il)urea B 3,50 322
Ie.77
1-[(3s,5s,7s)-adamantan-1-il]-3-[4-(octahidroisoquinolin-1il)-4-oxobutil]tiourea B 4,68 418
Ie.78
imagen94 1-[2-(ciclohex-1-en-1l)etil]-3-[4-(-(octahidroisoquinolin-1il)-4-oxobutil]tiourea B 4,44 392
Ie.79
imagen95 1-[(3s,5s,7s)-adamantan-1-il]-3-[5-(octahidroisoquinolin2-il)-5-oxopentil)tiourea B 4,57 4,74 432 432
Ie.80
1-ciclopentil-3-[5-(octahidroisoquinolin-2-il)-5-oxopentil]tiourea B 3,88 3,98 366 366
Ie.81
3-fenil-1-[5-(octahidroisoquinolin-2-il)-5-oxopentil]-tiourea B 3,81 3,87 374 374
86
Ie.82
1-(ciclohexilmetil)-3-[5-(octahidroisoquinolin-2-il)-5oxopentil]tiourea B 4,32 4,40 394 394
Ie.83
1-t-butil-3-[5-(octahidroisoquinolin-2-il)-5-oxopentil]tiourea B 3,89 3,99 354 354
Ie.84
1-(ciclohexil-3-[5-(octahidroisoquinolin-2-il)-5-oxopentil]tiourea B 4,09 4,18 380 380
Ie.85
1-bencidril-3-[5-(octahidroisoquinolin-2-il)-5-oxopentil]tiourea B 4,49 4,56 464 464
Ie.86
imagen96 1-[2-(ciclohex-1-en-1-il)etil]-3-[5-(octahidroisoquinolin-2il)-5-oxopentil]tiourea B 4,41 4,49 406 406
Ig.36
N-[3-(3-etilureido)propil]amida del ácido octahidroisoquinolin-1-carboxílico B 2,91 311
Ig.37
N-[3-(3-isopropilureido)propil]amida del ácido octahidroisoquinolin-1-carboxílico B 3,13 325
Ig.38
N-[3-[3-(6-fluoro-4H-benzo[d][1,3]dioxin-8-il)ureido]propil]amida del ácido octahidroisoquinolin-1-carboxílico B 3,69 435
Ig.39
N-[3-[3-tiofenil-2-il)ureido]propil]amida del ácido octahidroquinolin-1-carboxílico B 3,34 365
Ig.40
N-[3-(3-etilureido)propil]amida del ácido octahidroquinolin-2-carboxílico B 3,02 311
Ig.41
imagen97 N-[3-(3-isopropilureido)propil]amida del ácido octahidroquinolin-2-carboxílico B 3,23 325
Ig.42
imagen98 N-[3-[3-(tiofen-2-il)ureido]propil]amida del ácido octahidroquinolin-2-carboxílico B 3,51 365
Ig.43
N-[3-[3-[(3s,5s,7s)-adamantan-1-il]tioureido]propil]amida del ácido 5-(octahidroquinolin-1-il)-5-oxopentanoico B 4,67 433
Ejemplo ld.1: N-[3-(octahidroquinolin-1-il)-3-oxopropil]-2-tiofen-2-ilacetamida
imagen99
A una solución de 21,3 mg (0,15 mmol) de ácido 2-tienilacetico en 2 ml de AcOEt se añaden 46 µl de Et3N, 30,4 mg (15 mmol) de HOBT y 43,1 mg (15 mmol) de EDC; se le añaden 35 mg (0,17 mmol) de la amina intermedia Vc.3. La suspensión formada se mantiene con agitación durante 18 h. A continuación se trata con agua y se añade más AcOEt, se separa la fase orgánica y la fase acuosa se extrae una vez más con más AcOEt. Se juntan las fases orgánicas y se
87
imagen100
imagen101
imagen102
imagen103
imagen104
imagen105
imagen106
imagen107
imagen108
Ej.
estructura nombre Proced. tr (min) m/z
Ip.2
S-[4-octahidroquinolin-1-il)-4-oxobutil]éster del ácido ciclohexiltiocarbámico B 4,34 367
Ip.3
S-[4-octahidroquinolin-1-il)-4-oxobutil]éster del ácido feniltiocarbámico B 4,14 341
Ip.4
S-[4-octahidroquinolin-1-il)-4-oxobutil]éster del ácido (4-fluorofenil)tiocarbámico B 4,19 379
Ip.5
4-(octahidroquinolin-1-il)-4-oxobutil]éster del ácido benciltiocarbámico B 4,08 375
Ip.6
4-(octahidroquinolin-1-il)-4-oxobutil]éster del ácido (2-ciclohex-1-eniletil)ditiocarbámico B 5,19 409
Ip.7
S-[4-octahidroquinolin-1-il)-4-oxobutil]éster del ácido (furan-2-ilmetil)carbámico B 3,82 365
Ip.8
S-[4-octahidroquinolin-1-il)-4-oxobutil]éster del ácido cicloheptiltiocarbámico B 4,54 381
Ip.9
S-[3-octahidroquinolin-1-il)-3-oxopropil]éster del ácido octahidroquinolin-1-tiocarbámico B 4,94 393
Ip.10
4-(octahidroquinolin-1-il)-4-oxobutil]éster del ácido bencilditiocarbámico B 4,54 391
Ip.11
4-(octahidroquinolin-1-il)-4-oxobutil]éster del ácido [2-(ciclihex-1-en-1-il)etil]ditiocarbámico B 5,13 409
Ip.12
4-(octahidroquinolin-1-il)-4-oxobutil]éster del ácido ciclohexilditiocarbámico B 4,82 393
97
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Claims (1)

  1. imagen1
    imagen2
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US8822452B2 (en) 2014-09-02
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