ES2560612T3 - Derivados bencilamina como inhibidores de la calicreina plasmática - Google Patents
Derivados bencilamina como inhibidores de la calicreina plasmática Download PDFInfo
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- ES2560612T3 ES2560612T3 ES12735610.3T ES12735610T ES2560612T3 ES 2560612 T3 ES2560612 T3 ES 2560612T3 ES 12735610 T ES12735610 T ES 12735610T ES 2560612 T3 ES2560612 T3 ES 2560612T3
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- phenyl
- aminomethyl
- benzylcarbamoyl
- ethyl
- ethoxy
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- C07—ORGANIC CHEMISTRY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K31/18—Sulfonamides
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
Compuesto de fórmula I**Fórmula** en el que: R1 está seleccionado de entre H, alquilo, -COalquilo, -COarilo, -COheteroarilo, -CO2alquilo, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alquilo, -SO2arilo, -SO2(CH2)hR13, -CO(CH2)iR14, -COcicloalquilo, -COCH>=CHR15, -CO(CH2)jNHCO(CH2)kR16 y -CONR17R18; R2 está seleccionado de entre H y alquilo; R3 está seleccionado de entre H, alquilo, -(CH2)darilo, -(CH2)eheteroarilo, -(CH2)fcicloalquilo, -(CH2)gheterocicloalquilo, -CH(cicloalquilo)2, -CH(heterocicloalquilo)2 y -(CH2)larilo-O-(CH2)m-arilo; R4 y R6 están seleccionados independientemente de entre H y alquilo; R5 está seleccionado de entre H, alquilo, alcoxi y OH; o R4 y R5, junto con los átomos a los que están fijados, pueden unirse para formar un estructura azacicloalquilo de 5 ó 6 miembros; R7 y R8 están seleccionados independientemente de entre H, alquilo, alcoxi, CN, halo y CF3; R9 es arilo o heteroarilo; R10 es H o alquilo; a, b, c, d, e, f, g, h, i, j, l y m son independientemente 1, 2 ó 3; k es 0, 1, 2 ó 3; *1 y *2 indican centros quirales; el alquilo es un hidrocarburo saturado lineal que tiene hasta 10 átomos de carbono (C1-C10) o un hidrocarburo saturado ramificado de entre 3 y 10 átomos de carbono (C3-C10); el alquilo puede estar opcionalmente sustituido con 1 ó 2 sustituyentes seleccionados independientemente de entre cicloalquilo(C3-C10), alcoxi(C1-C6), OH, CN, CF3, COOR11, fluoro y NR11R12; el cicloalquilo es un hidrocarburo saturado monocíclico o bicíclico de entre 3 y 10 átomos de carbono; el cicloalquilo puede estar opcionalmente condensado con un grupo arilo; o el cicloalquilo es adamantilo; el heterocicloalquilo es un anillo monocíclico o bicíclico saturado de 3 a 10 miembros unido a través del C o del N, en el que dicho anillo heterocicloalquilo contiene, cuando sea posible, 1, 2 ó 3 heteroátomos seleccionados independientemente de entre N, NR11 y O; el alcoxi es un hidrocarburo lineal unido a través del O de entre 1 y 6 átomos de carbono (C1-C6) o un hidrocarburo ramificado unido a través del O de entre 3 y 6 átomos de carbono (C3-C6); el alcoxi puede estar opcionalmente sustituido con 1 ó 2 sustituyentes seleccionados independientemente de entre cicloalquilo(C3-C10), OH, CN, CF3, COOR11, fluoro y NR11R12; el arilo es fenilo, bifenilo o naftilo; el arilo puede estar opcionalmente sustituido con hasta 5 sustituyentes seleccionados independientemente de entre alquilo, alcoxi, OH, halo, CN, COOR11, CF3 y NR11R12; el heteroarilo es un anillo aromático monocíclico o bicíclico de 5, 6, 9 ó 10 miembros, que contiene, cuando sea posible, 1, 2 ó 3 miembros del anillo seleccionados independientemente de entre N, NR11, S y O; el heteroarilo puede estar opcionalmente sustituido con 1, 2 ó 3 sustituyentes seleccionados independientemente de entre alquilo, alcoxi, OH, halo, CN, COOR11, CF3, NR11R12 y NHR19; R11 y R12 están seleccionados independientemente de entre H y alquilo; R13 es arilo o heteroarilo; R14 es arilo, heteroarilo, cicloalquilo o heterocicloalquilo; R15 es H, alquilo, arilo, heteroarilo, cicloalquilo o heterocicloalquilo; R16 es H, arilo o heteroarilo; R17 es H, alquilo, arilo, heteroarilo o heterocicloalquilo; R18 es -(CH2)mR21, en el que m es 0, 1, 2 ó 3 y R21 es H, arilo o heteroarilo; R19 es -COalquilo, -COarilo o -COheteroarilo; y tautómeros, estereoisómeros (incluidos enantiómeros, diastereoisómeros y mezclas racémicas y no racémicas del mismo), sales y solvatos farmacéuticamente aceptables del mismo.
Description
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[(R)-1-[(S)-]1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-2carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido ciclohexanocarboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido isoxazol-5carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido benzo[b]tiofeno-2-carboxílico; (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(4-cloro-bencenosulfonilamino)-3-(4-etoxi-fenil)propionamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3-cloro-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-cloro-benzamida N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3-trifluorometilbenzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metilbenzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,4-dicloro-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metoxi-benzamida; (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(2-fenilacetilamino-acetilamino)-propionilamino]-3-fenilpropionamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-fluoro-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-6-metil-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metil-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,6-dicloro-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-5,6-dicloro-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,3,6-trifluoroisonicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,3,3-trifluoropropionamida; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2,4-dimetiltiazol-5-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2-metiltiazol-5-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-clorotiofeno-2-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 4-metiltiazol-5-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido furan-2carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metiltiofeno-2-carboxílico; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metoxi-isonicotinamida; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-1Hpirrol-2-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-aminotiofeno-2-carboxílico; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-propoxifenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-cloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-metoxi-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-3-il-etilcarbamoil-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-3-cloro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2-carboxílico; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metoxibenzamida;
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citratos, lactatos, tartratos, mesilatos, succinatos, oxalatos, fosfatos, esilatos, tosilatos, bencenosulfonatos, naftalenodisulfonatos, maleatos, adipatos, fumaratos, hipuratos, canforatos, xinafoatos, p-acetamidobenzoatos, dihidroxibenzoatos, hidroxinaftoatos, succinatos, ascorbatos, oleatos, bisulfatos, y similares.
También pueden formarse hemisales de ácidos y bases, por ejemplo, sales de hemisulfato y hemicalcio.
Para una revisión de las sales adecuadas, véase "Handbook of Pharmaceutical Salts: Properties, Selection and Use" de Stahl y Wermuth (Wiley-VCH, Weinheim, Alemania, 2002).
"Profármaco" se refiere a un compuesto que puede convertirse in vivo mediante medios metabólicos (por ejemplo, mediante hidrólisis, reducción u oxidación) en un compuesto de la invención. Los grupos adecuados para formar profármacos se describen en "The Practice of Medicinal Chemistry, 2ª ed. págs. 561-585 (2003) y en F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.
Los compuestos de la invención pueden existir en formas tanto solvatadas como no solvatadas. El término “solvato” se utiliza en el presente documento para describir un complejo molecular que comprende el compuesto de la invención y una cantidad estequiométrica de una o más moléculas de disolvente farmacéuticamente aceptables, por ejemplo, etanol. El término "hidrato" se emplea cuando el disolvente es agua.
Cuando los compuestos de la invención existan en una o más formas geométricas, ópticas, enantioméricas, diastereoméricas y tautoméricas, incluidas pero no limitadas a las formas cis y trans, las formas E y Z, las formas R, S y meso, las formas ceto y enol. A menos que se indique otra cosa, una referencia a un compuesto concreto incluye todas esas formas isoméricas, incluidas las racémica y otras mezclas de las mismas. Cuando proceda, tales isómeros pueden separarse de sus mezclas aplicando o adaptando métodos conocidos (por ejemplo, técnicas cromatográficas y técnicas de recristalización). Cuando proceda, tales isómeros pueden prepararse aplicando o adaptando métodos conocidos (por ejemplo, síntesis asimétrica).
En el contexto de la presente invención, las referencias en el presente documento a "tratamiento" incluyen referencias al tratamiento curativo, paliativo y profiláctico.
Métodos generales
Los compuestos de fórmula (I) deben evaluarse para determinar sus propiedades biofarmacéuticas, tales como la solubilidad y la estabilidad de la solución (a través del pH), la permeabilidad, etc., con el fin de seleccionar la forma farmacéutica y vía de administración más apropiadas para el tratamiento de la indicación propuesta. Pueden administrarse solos o en combinación con uno o más de otros compuestos de la invención o en combinación con uno o más de otros fármacos (o como cualquier combinación de los mismos). Generalmente, se administrarán como una formulación en asociación con uno o más excipientes farmacéuticamente aceptables. El término "excipiente" se utiliza en el presente documento para describir cualquier ingrediente distinto del compuesto o compuestos de la invención que puede conferir a las formulaciones una característica funcional (es decir, el control de la velocidad de liberación del fármaco) y/o una no funcional (es decir, aditivo de procesamiento o diluyente). La elección del excipiente dependerá en gran medida de factores tales como el modo concreto de administración, el efecto del excipiente sobre la solubilidad y la estabilidad, y la naturaleza de la forma farmacéutica.
Los compuestos de la invención destinados a uso farmacéutico pueden administrarse como sólido o líquido, tal como un comprimido, una cápsula o una solución. Las composiciones farmacéuticas adecuadas para la administración de los compuestos de la presente invención y los métodos para su preparación resultarán evidentes para los expertos en la materia. Tales composiciones y métodos para su preparación pueden encontrarse, por ejemplo, en Remington’s Pharmaceutical Sciences, 19a edición (Mack Publishing Company, 1995).
Por consiguiente, la presente invención proporciona una composición farmacéutica que comprende un compuesto de fórmula (I) y un vehículo, diluyente o excipiente farmacéuticamente aceptable.
Para el tratamiento de afecciones tales como la permeabilidad vascular retiniana asociada con la retinopatía diabética y el edema macular diabético, los compuestos de la invención pueden administrarse en una forma adecuada para la inyección en la región ocular de un paciente, en particular, en una forma adecuada para la inyección intravítrea. Se prevé que las formulaciones adecuadas para tal uso adopten la forma de soluciones estériles de un compuesto de la invención en un vehículo acuoso adecuado. Las composiciones pueden administrarse al paciente bajo la supervisión del médico a cargo.
Los compuestos de la invención también pueden administrarse directamente en el torrente sanguíneo, en el tejido subcutáneo, en el músculo o en un órgano interno. Los medios adecuados para la administración parenteral incluyen la intravenosa, intraarterial, intraperitoneal, intratecal, intraventricular, intrauretral, intraesternal, intracraneal, intramuscular, intrasinovial y subcutánea. Los dispositivos adecuados para la administración parenteral incluyen inyectores de aguja (incluidos inyectores de microaguja), inyectores sin aguja y técnicas de infusión.
puede conseguirse en una sola etapa, ya sea por reducción directa del nitrilo mediante hidrogenación en un disolvente adecuado tal como metanol en presencia de un catalizador adecuado tal como paladio sobre carbón en presencia de un ácido tal como ácido clorhídrico o por reducción con un borohidruro adecuado en presencia de un metal de transición adecuado tal como cloruro de níquel o cobalto en un disolvente adecuado tal como metanol a
5 temperatura ambiente. Como alternativa, puede aislarse la amina protegida con terc-butoxicarbonilo (Boc) 9 (utilizando, por ejemplo, el método que se describe en S. Caddick et al., Tetrahedron Lett., 2000, 41, 3513) y desprotegerse posteriormente mediante los métodos convencionales descritos anteriormente para dar la amina 10.
Breve descripción de los dibujos
La Figura 1 muestra el efecto inhibidor del Ejemplo 3 y CH-3457 (control positivo; inhibidor de calicreína plasmática) sobre la PVR estimulada con CA-I en ratas Sprague Dawley. La Figura 2 muestra las concentraciones del Ejemplo 3 en los tejidos oculares después de la administración IVT de 4,2 µg/ml (210 ng/ojo).
Ejemplos
La invención se ilustra mediante los siguientes ejemplos no limitativos en los que se utilizan las siguientes abreviaturas y definiciones:
15
25
- DMF
- N,N-dimetilformamida
- DMSO
- Dimetilsulfóxido
- Et
- Etilo
- EtOAc
- Acetato de etilo
- hrs
- Horas
- HOBt
- Hidroxibenzotriazol
- LCMS
- Cromatografía de líquidos -espectrometría de masas
- Me
- Metilo
- MeCN
- Acetonitrilo
- MeOH
- Metanol
- min
- Minutos
- MS
- Espectro de masas
- m/z
- Relación entre masa y carga (del ion precursor, MH+, a menos que se indique otra cosa)
- RMN
- Espectro de resonancia magnética nuclear -los espectros de RMN se registraron a una frecuencia de 400 MHz a menos que se indique otra cosa
- Éter de pet.
- Fracción de éter de petróleo en ebullición a 60°C-80°C
- Ph
- Fenilo
- Phe
- Fenilalanina
- n-Pr
- n-propilo
- THF
- Tetrahidrofurano
- TFA
- Ácido trifluoroacético
Todas las reacciones se llevaron a cabo en atmósfera de nitrógeno a menos que se especifique otra cosa.
Los espectros de 1H RMN se registraron en un espectrómetro Brucker Avance III (400 MHz) con respecto a un
disolvente de deuterio y a temperatura ambiente.
Los iones moleculares se obtuvieron utilizando LCMS que se llevó a cabo utilizando una columna Chromolith
35 SpeedROD RP-18e, 50 x 4,6 mm, con un gradiente lineal del 10% al 90%, HCO2H al 0,1%/MeCN en HCO2H al 0,1%/H2O, durante 11 minutos, caudal 1,5 ml/min. Los datos se recogieron utilizando un espectrómetro de masas Thermofinnigan Surveyor MSQ con ionización por electronebulización junto con un sistema Thermofinnigan Surveyor LC. Los nombres químicos se generaron utilizando el software Autonom proporcionado como parte del paquete ISIS/Draw de MDL Information Systems. Cuando los productos se purificaron mediante cromatografía ultrarrápida, "sílice" se refiere a gel de sílice para cromatografía, de 0,035 mm a 0,070 mm (de malla 220 a 440) (por ejemplo, Merck Silica Gel 60), y una elución en columna acelerada a presión de nitrógeno aplicada de hasta 10 p.s.i . Las purificaciones de HPLC preparativa de fase inversa se llevaron a cabo utilizando un sistema de bombeo de gradiente binario Waters 2525 a caudales de por
45 lo general 20 ml/minutos utilizando un detector de matriz de fotodiodos Waters 2996. Todos los disolventes y reactivos comerciales se utilizaron tal como se recibieron.
EJEMPLO 1
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenil-propionamida
65 A. Éster metílico del ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenilpropiónico
5
15
25
35
45
55
65
Se disolvió H-Phe-OMe.HCl (2,3 g, 10,7 mmol) en CH2Cl2 (100 ml) y DMF (10 ml). Esta solución se enfrió a 0°C. Se añadió ácido (R)-2-butoxiloxicarbonilamino-3-(4-etoxi-fenil)-propiónico (3,0 g, 9,7 mmol) seguido de HOBt (1,57 g, 11,6 mmol) y trietilamina (2,9 g, 29,0 mmol). A continuación, se añadió carbodiimida hidrosoluble (2,04 g, 10,6 mmol). Después de 18 horas a una temperatura de 0°C a temperatura ambiente, la mezcla de reacción se diluyó con cloroformo (100 ml) y se lavó con NaHCO3 (1x30 ml), agua (1x30 ml), salmuera (1x30 ml), se secó (Na2SO4) y se evaporó a vacío, lo que dio un aceite amarillo. El residuo se purificó mediante cromatografía ultrarrápida (sílice), eluyente éter de pet. al 20% (60°C-80°C), EtOAc al 80%, las fracciones se combinaron y evaporaron a vacío para dar un aceite incoloro identificado como éster metílico del ácido (S)-2-[(R)-2-tercbutoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenil-propiónico (4,25 g, 9,03 mmol, 93%). [M+H]+ = 471,27.
B. Ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenil-propiónico
Se disolvió éster metílico del ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3fenilpropiónico (2,5 g, 5,3 mmol) en THF (100 ml). Se añadió hidróxido de litio monohidrato (668 mg, 15,9 mmol) en agua (10 ml). La mezcla de reacción se agitó a temperatura ambiente durante 18 horas, después de lo cual la mezcla de reacción se diluyó con EtOAc (150 ml). Esta solución se lavó con KHSO4 0,3 M (1x50 ml), agua (1x30 ml), salmuera (1x30 ml), se secó (Na2SO4) y se evaporó a vacío para dar un sólido blanco identificado como ácido (S)-2[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenil-propiónico (2,095 g, 4,58 mmol, 86%). [M+H]+ = 457,25.
C. Éster terc-butílico del ácido [(R)-1-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etil]-carbámico
Se disolvió clorhidrato de 4-(aminometil)benzonitrilo (303 mg, 1,80 mmol) en CH2Cl2 (50 ml) y DMF (5 ml). Esta solución se enfrió a 0°C. Se añadió ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]3-fenil-propiónico (745 mg, 1,63 mmol) seguido de HOBt (265 mg, 1,96 mmol) y trietilamina (495 mg, 4,9 mmol). A continuación, se añadió carbodiimida hidrosoluble (344 mg, 1,8 mmol). Después de 18 horas a una temperatura de 0°C a temperatura ambiente, la mezcla de reacción se diluyó con cloroformo (100 ml) y se lavó con NaHCO3 (1x30 ml), agua (1x30 ml), salmuera (1x30 ml), se secó (Na2SO4) y se evaporó a vacío, lo que dio un aceite amarillo. El residuo se purificó mediante cromatografía ultrarrápida (sílice), eluyente éter de pet. al 20% (60°C-80°C), EtOAc al 80%, las fracciones se combinaron y evaporaron a vacío para dar un aceite incoloro identificado como éster tercbutílico del ácido [(R)-1-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-carbámico (493 mg, 0,86 mmol, 53%). [M+H]+ = 571,29
D. Clorhidrato de (R)-2-amino-N-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-propionamida
Se trató éster terc-butílico del ácido [(R)-1-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxifenil)-etil]-carbámico (225 mg, 0,39 mmol) con HCl/dioxano 4M (50 ml). Después de una hora a temperatura ambiente, se eliminó el disolvente para dar un sólido blanco identificado como clorhidrato de (R)-2-amino-N-[(S)-1-(4ciano-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-propionamida (200 mg, 0,39 mmol, 100%).
- [M+H]+ = 471,26
- E.
- (S)-N-(4-ciano bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenil
- propionamida
- Se
- disolvió clorhidrato de (R)-2-amino-N-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)
propionamida (200 mg, 0,37 mol) en diclorometano (50 ml), esta solución se enfrió a 0°C. Se añadió trietilamina (111 g, 1,1 mmol) seguido de cloruro de propionilo (39 mg, 0,40 mmol). Después de 18 horas a una temperatura de 0°C a temperatura ambiente, la mezcla de reacción se diluyó con CHCl3 (50 ml), esta solución se lavó con una solución saturada de NaHCO3 (1x20 ml), agua (1x20 ml), salmuera (1x20 ml), se secó (Na2SO4) y se evaporó a vacío. El residuo se purificó mediante cromatografía ultrarrápida (sílice), eluyente MeOH al 2%, CHCl3 al 98%, las fracciones se combinaron y evaporaron a vacío para dar un aceite incoloro identificado como (S)-N-(4-ciano-bencil)2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenil-propionamida (189 mg, 0,36 mmol, 98%). [M+H]+ = 527,27
F. Éster terc-butílico del ácido [4-({(S)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenilpropionilamino}-metil)-bencil]-carbámico
Se disolvió (S)-N-(4-ciano-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenilpropionamida (100 mg, 0,19 mmol) en metanol (50 ml). Esta solución se enfrió a 0°C. Se añadieron cloruro de níquel
(II) hexahidrato (4,5 mg, 0,0192 mmol) y dicarbonato de di-terc-butilo (83 mg, 0,38 mmol) seguido de borohidruro sódico (50 mg, 1,33 mmol) en porciones. La mezcla de reacción se agitó a una temperatura de 0°C a temperatura ambiente durante 18 horas. El metanol se eliminó por evaporación. El residuo se disolvió en CHCl3 (70 ml), se lavó
Tabla 2
5
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25
- Nº de ejemplo
- * & R1 R2 R4 R5 m/z
- 60
- separado pero no confirmado R H H H OH 491,2
- 61
- R H H H OH 491,2
- 62
- separado pero no confirmado R CH3CH2CO H H OH 547,2
- 63
- R CH3CH2CO H H OH 547,3
- 64
- separado pero no confirmado R CH3CH2CO H CH3CH2 H 559,3
- 65
- R CH3CH2CO H CH3CH2 H 559,3
- 66
- S S CH3CH2CO CH3 H H 545,3
Tabla 3
5
15
25
35
45
55
- 15
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-bencenosulfonilamino-3-(4-etoxi-fenil)propionamida
- 16
- (S)-N-(4-aminometil-bencil)-3-(3,4-dicloro-fenil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilaminopropionilamino]-propionamida
- 17
- Ácido [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etilamino]-acético
- 18
- (R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-(4-trifluorometilfenil)-propionamida
- 19
- ((R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-2-propionilamino-3-(4trifluorometil-fenil)-propionamida
- 20
- (R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-ciclohexilpropionamida
- 21
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-ciclohexil-2-propionilaminopropionamida
- 22
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-etil}-benzamida
- 23
- (S)-N-(4-aminometil-3-cloro-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3fenil-propionamida
- 24
- (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-N-metil-3fenil-propionamida
- 25
- (R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-N-metilpropionamida
- 26
- (S)-N-(4-aminometil-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-metilamino}-3fenil-propionamida
- 27
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-metilaminopropionamida
- 28
- Ácido {(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-3-metilbutilamino}-acético
- 29
- Ácido ({(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-ciclohexil-etil}-metilamino)-acético
- 30
- Ácido ((R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2-ciclohexiletilamino)-acético
- 31
- (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(metil-propionilamino)-propionilamino]-3fenil-propionamida
- 32
- (S)-N-(4-aminometil-3-fluoro-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-metilamino}-3-fenil-propionamida
- 33
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-metilamino-propionamida
- 34
- Ácido ((R)-1-{[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2ciclohexil-etilamino)-acético
- 35
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-N-metil-2-propilaminopropionamida
- 36
- Ácido ((R)-1-{(S)-1-[(4-aminometil-bencil)-metil-carbamoil]-2-fenil-etilcarbamoil}-2-ciclohexiletilamino)-acético
- 37
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-propilamino-propionamida
- 38
- N-[(R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2-(4-etoxi-fenil)-etil]benzamida
- 39
- (R)-2-acetilamino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-N-metilpropionamida
- 40
- (R)-N-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-metilaminopropionamida
- 41
- (R)-N-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-ciclohexil-2metilamino-propionamida
- 42
- Ácido ({(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-ciclohexil-etil}metil-amino)-acético
- 43
- Ácido ({(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-(3,4-diclorofenil)-etilcarbamoil]-2ciclohexil-etil}-metil-amino)-acético
- 44
- N-[(R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2-(4-etoxi-fenil)-etil]isobutiramida
- 45
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-(metil-propilamino)propionamida
- 46
- Éster metílico del ácido {(R)-1-[(S)-1-(-4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2ciclohexil-etilamino}-acético
15
25
35
45
55
- 47
- Éster metílico del ácido {(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2ciclohexil-etilamino}-acético
- 48
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(carbamoilmetil-metilamino)-3ciclohexil-propionamida
- 49
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-[(2-hidroxietil)-metil-amino]propionamida
- 50
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(carbamoilmetil-amino)-3-ciclohexilpropionamida
- 51
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-(2-hidroxietilamino)propionamida
- 52
- (R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3,3-diciclohexil-propionamida
- 53
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-dipropilamino-propionamida
- 54
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido naftaleno-1-carboxílico
- 55
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-clorobenzamida
- 56
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4trifluorometil-benzamida
- 57
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido bifenil-4-carboxílico
- 58
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil)-2-(4-etoxi-fenil)-etil]-2,4dicloro-benzamida
- 59
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,4difluoro-benzamida
- 60
- (R)-2-amino-N-[(1R,2S)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etil]-3-(4-etoxi-fenil)propionamida
- 61
- (R)-2-amino-N-[(1S,2S)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etil]-3-(4-etoxi-fenil)propionamida
- 62
- (2R,3S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3hidroxi-3-fenil-propionamida
- 63
- (2S,3S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3hidroxi-3-fenil-propionamida
- 64
- (R)-N-(4-aminometil-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-etilamino}-3-fenilpropionamida
- 65
- (S)-N-(4-aminometil-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-etilamino}-3-fenilpropionamida
- 66
- (S)-N-(4-aminometil-bencil)-2-[(S)-3-(4-etoxi-fenil)-2-(metil-propionilamino)-propionilamino]-3fenil-propionamida
- 67
- 4-aminometil-bencilamida del ácido (2S,3R)-1-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-3fenil-pirrolidina-2-carboxílico
- 68
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(3-bencil-ureido)-3-(4-etoxi-fenil)propionamida
- 69
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-(3-fenil-ureido)propionamida
- 70
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]nicotinamida
- 71
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]isonicotinamida
- 72
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-3-carboxílico
- 73
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-2-carboxílico
- 74
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido ciclopropanocarboxílico
- 75
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido ciclohexanocarboxílico
- 76
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido hexanoico
- 77
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-(3-isopropil-ureido)propionamida
- 78
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-(3-hexil-ureido)propionamida
15
25
35
45
55
- 79
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido isoxazol-5-carboxílico
- 80
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4trifluorometoxi-benzamida
- 81
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2-carboxílico
- 82
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil] -2-(4-etoxi-fenil)-etil]-amida del ácido 2,5-dimetil-2H-pirazol-3-carboxílico
- 83
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido benzo[b]tiofeno-2-carboxílico
- 84
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(4-clorobencenosulfonilamino)-3-(4etoxi-fenil)-propionamida
- 85
- (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-fenilacetilamino-propionilamino]-3-fenilpropionamida
- 86
- (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(3-fenilpropionilamino)-propionilamino]-3fenil-propionamida
- 87
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-fenilbutiramida
- 88
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3-clorobenzamida
- 89
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-clorobenzamida
- 90
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3trifluorometil-benzamida
- 91
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido adamantano-1-carboxílico
- 92
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metilbenzamida
- 93
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,4dicloro-benzamida
- 94
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoi]-2-(4-etoxi-fenil)-etil]-3,5dicloro-benzamida
- 95
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metoxibenzamida
- 96
- (E)-N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3fenil-acrilamida
- 97
- (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(2-fenilacetilamino-acetilamino)propionilamino]-3-fenil-propionamida
- 98
- N-{[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etilcarbamoil]-metil}-benzamida
- 99
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-fluorobenzamida
- 100
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2fenilmetanosulfonilamino-propionamida
- 101
- (S)-N-(4-aminometil-bencil)-2-{(R)-3-(4-etoxi-fenil)-2-[2-(tolueno-4-sulfonilamino)-acetilamino]propionilamino}-3-fenil-propionamida
- 102
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-[3-(4-cloro-fenil)-ureido]-3-(4-etoxifenil)-propionamida
- 103
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(3-bencil-3-etil-ureido)-3-(4-etoxi-fenil)propionamida
- 104
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-6-metilnicotinamida
- 105
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metilnicotinamida
- 106
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,6dicloro-nicotinamida
- 107
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-5,6dicloro-nicotinamida
- 108
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,3,6trifluoro-isonicotinamida
- 109
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,3,3trifluoro-propionamida
5
15
25
35
45
55
- 110
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-cloro6-metil-isonicotinamida
- 111
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2,4-dimetil-tiazol-5-carboxílico
- 112
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2-metil-tiazol-5-carboxílico
- 113
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2,5-dimetil-oxazol-4-carboxílico
- 114
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2-metil-quinolina-6-carboxílico
- 115
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 7-cloro-quinolina-3-carboxílico
- 116
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
- 117
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 4-metil-tiazol-5-carboxílico
- 118
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido furan-2-carboxílico
- 119
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-tiofeno-2-carboxílico
- 120
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 6-metoxi-piridina-2-carboxílico
- 121
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-5-metoxinicotinamida
- 122
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metoxi-tiofeno-2-carboxílico
- 123
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metoxiisonicotinamida
- 124
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-1H-pirrol-2-carboxílico
- 125
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
- 126
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-ciclohexil-etil}-benzamida
- 127
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-cloro-fenil)-etil]benzamida
- 128
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(4-cloro-benciloxi)-fenil]etil}-benzamida
- 129
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-hidroxifenil)-etil]benzamida
- 130
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(4-fluoro-benciloxi)-fenil]etil}-benzamida
- 131
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-propoxi-fenil)-etil]benzamida
- 132
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-benciloxi-fenil)-etil]benzamida
- 133
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-3-metil-butil}-benzamida
- 134
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(2,6-dicloro-benciloxi)fenil]-etil}-benzamida
- 135
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-p-tolil-etil}-benzamida
- 136
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(3-fluoro-benciloxi)-fenil]etil}-benzamida
- 137
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(6-metoxi-piridin-3-il)-etil]benzamida
- 138
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-metoxi-fenil)-etil]benzamida
- 139
- N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-fenil-etil}-benzamida
- 140
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 141
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 142
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-cloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
15
25
35
45
55
- 143
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 144
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3-trifluorometil-fenil)-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
- 145
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 146
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-metoxi-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 147
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 148
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-trifluorometil-fenil)-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
- 149
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 150
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 151
- N-[(R)-1-[(S)-l-(4-aminometil-bencilcarbamoil)-2-tiofen-3-il-etilcarbamoil-2-(4-etoxi-fenil)-etil]benzamida
- 152
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 153
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 154
- N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 155
- N-[(R)-1-[(S)-1-(4-aminometil-3-cloro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 156
- N-[(R)-1-[(S)-1-(4-aminometil-3-trifluorometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
- 157
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2-carboxílico
- 158
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metoxi-benzamida
- 159
- [(R)-1-[(S)-1-(4-aminometil-3-cloro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]amida del ácido piridina-2-carboxílico
- 160
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metoxi-benzamida
- 161
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-difluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-isonicotinamida
- 162
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-2-carboxílico
- 163
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4cloro-benzamida
- 164
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metil-benzamida
- 165
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-diclorofenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido piridina-2-carboxílico
- 166
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etil]-3-(4-etoxi-fenil)-2-propionilaminopropionamida
- 167
- N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]isonicotinamida
- 168
- [(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]amida del ácido piridina-2-carboxílico
- 169
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-diclorofenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido tiofeno-2-carboxílico
- 170
- (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etil]-3-(4-etoxi-fenil)-2-propionilaminopropionamida
- 171
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-isonicotinamida
- 172
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-3,3,3-trifluoro-propionamida
- 173
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4cloro-benzamida
5
15
25
35
45
55
- 174
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido isoxazol-5-carboxílico
- 175
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
- 176
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(1H-indol-3-il)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 177
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(1H-imidazol-4-il)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 178
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-isonicotinamida
- 179
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-acetilamino-tiofeno-2-carboxílico
- 180
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(2-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 181
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-tiofeno-2-carboxílico
- 182
- N-[(R)-1-[(S)-1-(4-aminometil-3-metil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
- 183
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
- 184
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
- 185
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metil-benzamida
- 186
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-metil-1H-pirrol-2-carboxílico
- 187
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
- 188
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-acetilamino-tiofeno-2-carboxílico
- 189
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3metil-benzamida
- 190
- N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2metil-benzamida
- 191
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3,5-dimetil-1H-pirrol-2-carboxílico
- 192
- N-[(R)-1-[(S)-1-(4-aminometil-3-metil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
- 193
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-acetilamino-tiofeno-2-carboxílico
- 194
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
- 195
- [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido3-acetilamino-tiofeno-2-carboxílico
- 196
- [(R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil]-2-(4-etoxi-fenil)-etil]amida del ácido3-cloro-tiofeno-2-carboxílico
- 197
- N-[(R)-1-[(1S,2R)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
- 198
- [(R)-1-[(1S,2R)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
15
25
35
45
55
- 6
- CD3OD δ1,42 (3H, t, J=7,0Hz), 2,80-2,89 (2H, m), 2,95-3,00 (1H, m), 3,08-3,13 (1H, m), 4,03-4,13 (3H, m), 4,21 (2H, s), 4,32-4,38 (1H, m), 4,46-4,51 (1H, m), 4,65-4,69 (1H, m), 6,88 (2H, d, J=8,6Hz), 7,03 (2H, d, J= 8,6Hz), 7,05-7,09 (2H, m), 7,267,37 (5H, m), 7,41-7,47 (1H, m), 8,78-8,80 (1H, m).
- 7
- CD3OD δ 1,02 (3H, t, J=7,7Hz), 1,42 (3H, t, J=7,0Hz), 2,13-2,21 (2H, m), 2,71-2,77 (1H, m), 2,81-2,92 (3H, m), 3,12-3,16 (1H, m), 4,05 (2H, q, J=6,9Hz), 4,13 (2H, s), 4,374,50 (3H, m), 4,57-4,69 (1H, m), 6,82 (2H, d, J=8,6Hz), 7,05 (2H, d, J= 8,6Hz), 7,17-7,27 (4H, m), 7,30-7,35 (3H, m), 7,46-7,49 (1H, m).
- 8
- CD3OD δ 0,82-0,94 (2H, m), 1,19-1,28 (4H, m), 1,42-1,48 (2H, m), 1,64-1,71 (5H, m), 2,922,98 (1H, m), 3,23-3,28 (1H, m), 3,88 (1H, q, J=7,6Hz), 4,15 (2H, s), 4,39 (1H, d, J=15,3Hz), 4,52 (1H, d, J=15,3Hz), 4,76-4,79 (1H, m), 7,33-7,37 (7H, m), 7,44 (2H, d, J= 8,1Hz).
- 9
- CD3OD δ 0,84-1,03 (4H, m), 1,13-1,23 (2H, m), 1,52-1,77 (7H, m), 2,93 (6H, s), 2,96-3,02 (1H, m), 3,20-3,30 (1H, m), 3,81 (1H, q, J=3,9Hz), 4,15 (2H, s), 4,47 (2H, q, J=15,4Hz), 4,76 (1H, dd, J=5,3, 10,5Hz), 7,29-7,40 (7H, m), 7,45 (2H, d, J= 8,2Hz).
- 10
- CD3OD δ 0,84-0,92 (2H, m), 1,03 (3H, t, J=7,7Hz), 1,11-1,20 (4H, m), 1,35-1,39 (2H, m), 1,64-1,67 (5H, m), 2,15-2,26 (2H, m), 2,87-2,93 (1H, m), 3,39-3,42 (1H, m), 4,14 (2H, s), 4,21-4,26 (1H, m), 4,41-4,42 (1H, m), 4,44-4,57 (1H, m), 4,69-4,75 (1H, m), 7,27-7,44 (9H, m), 8,08(1H, d, J=5,8Hz), 8,49 (1H, d, J= 8,3Hz), 8,63-8,70 (1H, m).
- 11
- CD3OD δ 0,85-0,95 (2H, m), 1,21-1,40 (6H, m), 1,70-1,79 (5H, m), 2,85 (3H, s), 2,95 (1H, dd, J=10,0, 14,0Hz), 3,29 (1H, dd, J=5,5, 14,0Hz), 3,98 (1H, dd, J= 5,6, 8,8Hz), 4,14 (2H, s), 4,43 (2H, s), 4,71 (1H, dd, J=5,4, 10,0Hz), 7,27-7,35 (7H, m), 7,42 (2H, d, J= 8,1Hz).
- 12
- CD3OD δ 1,04 (3H, t, J=7,5Hz), 1,40 (3H, t, J=7,0Hz), 2,15-2,23 (2H, m), 2,74-2,90 (3H, m), 2,97-3,21(2H, m), 3,98-4,13 (2H, m), 4,14 (2H, s), 4,35-4,58 (3H, m), 4,61-4,68 (1H, m), 6,82 (2H, d, J=8,6Hz), 7,04-7,08 (1H, m), 7,12-7,42 (9H, m), 7,55 (1H, d, J= 1,6Hz).
- 13
- CD3OD δ 1,42 (3H, t, J=7,0Hz), 2,61-2,66 (1H, m), 2,83-2,88 (1H, m), 3,00 (6H, s), 3,023,08 (1H, m), 3,29 (1H, dd, J= 12,9, 4,9Hz), 3,98-4,06 (3H, m), 4,14 (2H, s), 4,194,21 (1H, m), 4,33-4,45 (2H, m), 6,87 (2H, d, J=8,6Hz), 6,89-7,05 (2H, m), 7,12 (2H, d, J= 8,6Hz), 7,22-7,27 (5H, m), 7,40 (2H, d, J= 8,2Hz), 8,61-8,64 (1H, m).
- 14
- CD3OD δ 1,42 (3H, t, J=7,0Hz), 2,82-2,92 (2H, m), 3,03-3,09 (2H, m), 4,04-4,13 (3H, m), 4,15 (2H, s), 4,30-4,35 (1H, m), 4,48-4,53 (1H, m), 4,65-4,69 (1H, m), 6,87-6,91 (2H, m), 7,02-7,06 (2H, m), 7,15 (1H, dd, J=8,3, 2,0Hz), 7,29 (2H, d, J= 8,1Hz), 7,43-7,46 (4H, m), 8,74 (1H, t, J= 5,8Hz).
- 15
- CD3OD δ 1,42 (3H, t, J=7,0Hz), 2,54-2,60 (1H, m), 2,67-2,72 (1H, m), 2,78-2,83 (1H, m), 3,06-3,11 (1H, m), 3,91-3,95 (1H, m), 3,98-4,04 (2H, m), 4,14 (2H, s), 4,36-4,49 (2H, m), 4,54-4,58 (1H, m), 6,69-6,72 (2H, m), 6,91 (2H, d, J= 8,6Hz), 7,19-7,21 (2H, m), 7,24-7,32 (5H, m), 7,41-7,45 (4H, m), 7,55-7,59 (1H, m), 7,64-7,66 (2H, m).
- 16
- CD3OD δ 1,03 (3H, t, J=7,6Hz), 1,42 (3H, t, J=7,0Hz), 2,14-2,24 (2H, m), 2,75-2,94 (3H, m), 3,07-3,12 (1H, m), 4,04 (2H, q, J=7,0Hz), 4,14 (2H, s), 4,36-4,51 (3H, m), 4,614,65 (1H, m), 6,81-6,84 (2H, m), 7,03-7,09 (3H, m), 7,33 (2H, d, J= 8,1Hz), 7,387,43 (4H, m).
- 17
- CD3OD δ 1,17 (3H, t, J=7,0Hz), 2,49-2,54 (1H, m), 2,74-2,83 (3H, m), 3,32 (2H, s), 3,81 (2H, q, J=7,0Hz), 3,88 (2H, s), 3,90-3,94 (1H, m), 4,08-4,21 (2H, m), 4,30-4,34 (1H, m), 6,60-6,65 (2H, m), 6,77-6,82 (2H, m), 6,94-6,96 (2H, m), 7,01-7,11 (5H, m), 7,17 (2H, d, J= 8,2Hz), 8,43 (1H, t, J= 6,0Hz).
- 18
- CD3OD δ 2,82-2,88 (1H, m), 3,02-3,09 (2H, m), 3,20-3,26 (1H, m), 4,15 (2H, s), 4,21-4,34 (2H, m), 4,49-4,54 (1H, m), 4,68-4,72 (1H, m), 7,19 (1H, dd, J=8,2, 2,0Hz), 7,29 (2H, d, J=8,1Hz), 7,34 (2H, d, J=8,0Hz), 7,43-7,48 (4H, m), 7,68 (2H, d, J=8,2Hz), 8,76 (1H, t, J=5,8Hz).
- 19
- CD3OD δ 1,02 (3H, t, J=7,6Hz), 2,19 (2H, q, J=7,6Hz), 2,86-2,94 (2H, m), 3,06-3,16 (2H, m), 4,14 (2H, s), 4,37-4,50 (2H, m), 4,61-4,70 (2H, m), 7,13 (1H, dd, J= 8,3, 2,0Hz), 7,32-7,37 (4H, m), 7,42-7,45 (4H, m), 7,60 (2H, d, J=8,2Hz).
- 20
- CD3OD δ 0,82-0,99 (2H, m), 1,15-1,30 (4H, m), 1,44-1,54 (2H, m), 1,62-1,73 (5H, m), 2,912,97 (1H, m), 3,22-3,27 (1H, m), 3,90 (1H, t, J=7,1Hz), 4,16 (2H, s), 4,38-4,55 (2H, m), 4,77-4,81 (1H, m), 7,26 (1H, dd, J=8,2, 2,0Hz), 7,37 (2H, d, J=8,1Hz), 7,437,52 (4H, m).
- 21
- CD3OD δ 0,85-0,94 (2H, m), 1,02-1,22 (7H, m), 1,34-1,42 (2H, m), 1,62-1,69 (5H, m), 2,162,27 (2H, m), 2,85-2,92 (1H, m), 3,39-3,44 (1H, m), 4,14 (2H, s), 4,18-4,24 (1H, m), 4,40-4,45 (1H, m), 4,53-4,58 (1H, m), 4,73-4,79 (1H, m), 7,24 (1H, dd, J=8,2, 2,0Hz), 7,38-7,51 (6H, m), 8,11 (1H, d, J=5,6Hz), 8,59 (1H, d, J=8,5Hz), 8,69 (1H, t, J=6,0Hz).
15
25
35
45
55
- 22
- CD3OD δ 1,30 (3H, d, J=7,1 Hz), 2,92-2,98 (1 H, m), 3,40 (1H, d, J=4,9Hz), 4,09 (2H, s), 4,41-4,48 (2H, m), 4,54-4,60 (1H, m), 4,68-4,74 (1H, m), 7,24-7,34 (5H, m), 7,38 (4H, s), 7,43-7,49 (2H, m), 7,56-7,60 (1H, m), 7,80-7,82 (2H, m), 8,51 (1H, d, J=8,2Hz), 8,56 (1H, d, J=5,3Hz), 8,66 (1H, t, J=6,0Hz).
- 23
- CD3OD δ 1,03 (3H, t, J=7,6Hz), 1,42 (3H, t, J=7,0Hz), 2,16-2,22 (2H, m), 2,73-2,93 (3H, m), 3,11-3,16 (1H, m), 4,05 (2H, q, J=6,9Hz),), 4,28 (2H, s), 4,37-4,48 (3H, m), 4,60-4,64 (1H, m), 6,82 (2H, d, J=8,6Hz), 7,05 (2H, d, J= 8,7Hz), 7,17 (2H, t, J=6,6Hz), 7,297,33 (4H, m), 7,46 (2H, dd, J=9,6,1,4Hz).
- 24
- CD3OD δ 1,08 (3H, t, J=7,7Hz), 1,38-1,42 (3H, m), 2,18-2,25 (2H, m), 2,71-3,07 (7H, m), 4,00-4,07 (2H, m), 4,14 (2H, s), 4,54-4,58 (2H, m), 4,62-4,66 (1H, m), 5,09-5,15 (1H, m), 6,83-6,88 (2H, m), 7,08-7,21 (4H, m), 7,26-7,38 (4H, m), 7,42 (2H, d, J= 8,1Hz), 8,29 (1H, d, J=7,8Hz), 8,35 (1H, d, J= 8,3Hz).
- 25
- CD3OD δ 1,41 (3H, t, J= 7,0Hz), 2,56-2,68 (2H, m), 2,94-2,98 (1H, m), 3,01 (3H, s), 3,39-3,41 (1H, m), 4,05 (2H, q, J= 7,0Hz), 4,14 (2H, s), 4,33-4,38 (1H, m), 4,49-4,55 (2H, m), 5,52-5,56 (1H, m), 6,86-6,89 (2H, m), 7,02 (2H, d, J= 8,6Hz), 7,28-7,39 (7H, m), 7,43 (2H, d, J=8,1Hz), 8,53 (1H, t, J= 5,8Hz).
- 26
- CD3OD δ 1,05 (3H, t, J= 7,6Hz), 1,39 (3H, t, J= 7,0Hz), 2,15-2,23 (2H, m), 2,51-2,63 (2H, m), 2,83-2,90 (1H, m), 2,96 (3H, s), 3,39-3,41 (1H, m), 4,01 (2H, q, J= 7,0Hz), 4,13 (2H, s), 4,38-4,50 (2H, m), 4,83-4,87 (1H, m), 5,47-5,51 (1H, m), 6,78-6,82 (2H, m), 7,01 (2H, d, J= 8,6Hz), 7,22-7,40 (7H, m), 7,43 (2H, d, J= 8,1 Hz), 8,19 (1H, d, J= 6,8Hz), 8,34 (1H, t, J= 6,0Hz).
- 27
- CD3OD δ 1,42 (3H, t, J= 7,0Hz), 2,66 (3H, s), 2,78-2,90 (1H, m), 3,01-3,15 (3H, m), 4,02-4,10 (3H, m), 4,14 (2H, s), 4,34-4,47 (2H, m), 4,59-4,70 (1H, m), 6,83-6,88 (2H, m), 6,977,02 (2H, m), 7,20-7,22 (2H, m), 7,26-7,34 (5H, m), 7,42 (2H, d, J= 8,1Hz), 8,69 (1H, t, J= 5,8Hz).
- 28
- CD3OD δ 0,81-0,83 (6H, m), 1,10-1,18 (1H, m), 1,48-1,55 (1H, m), 1,58-1,65 (1H, m), 2,922,98 (1H, m), 3,25-3,30 (1H, m), 3,75 (2H, s), 3,92-3,96 (1H, m), 4,15 (2H, s), 4,484,53 (2H, m), 4,75-4,79 (1H, m), 7,27-7,40 (7H, m), 7,46 (2H, d, J= 8,2Hz), 8,83 (1H, t, J= 5,9Hz).
- 29
- CD3OD δ 0,70-1,03 (6H, m), 1,37-1,69 (7H, m), 2,81-2,87 (4H, m), 3,06-3,11 (1H, m), 3,723,96 (3H, m), 3,99 (2H, s), 4,26-4,37 (2H, m), 4,58-4,62 (1H, m), 7,13-7,24 (7H, m), 7,30 (2H, d, J= 8,1Hz), 8,72 (1H, t, J= 5,9Hz).
- 30
- CD3OD δ 0,75-0,93 (3H, m), 1,20-1,31 (5H, m), 1,54-1,81 (5H, m), 3,02 (3H, s), 3,08-3,17 (1H, m), 3,43-3,48 (1H, m), 3,81 (2H, s), 4,15 (2H, s), 4,45-4,53 (3H, m), 5,65-5,71 (1H, m), 7,27-7,39 (5H, m), 7,41 (2H, d, J= 8,1Hz), 7,48 (2H, d, J= 8,2Hz), 8,67 (1H, t, J= 5,9Hz).
- 31
- CD3OD δ 0,67-0,71 y 0,77-0,80 (3H, m), 1,19-1,24 (3H, m), 1,99-2,11 (2H, m), 2,65-2,83 (5H, m), 2,91-3,09 (2H, m), 3,81-3,88 (2H, m), 3,95 (2H, s), 4,17-4,32 (2H, m), 4,43-4,54 (1H, m), 4,77-4,82 (1H, m), 6,62-6,69 (2H, m), 6,90-6,94 (2H, m), 6,98-7,20 (7H, m), 7,21-7,26 (2H, m), 7,69 (1H, d, J= 7,9Hz), 8,26-8,29 y 8,40-8,43 (1H, m).
- 32
- CD3OD δ 1,02-1,10 (3H, m), 1,40 (3H, t, J= 7,0Hz), 2,11-2,24 (2H, m), 2,51-2,63 (2H, m), 2,82-2,90 (1H, m), 2,95 (3H, s), 3,36-3,41 (1H, m), 3,98-4,03 (2H, m), 4,20 (2H, s), 4,38-4,51 (2H, m), 4,85 (1H, t, J= 7,3Hz), 5,46-5,50 (1H, m), 6,77-6,85 (2H, m), 7,007,08 (2H, m), 7,11-7,18 (2H, m), 7,21-7,36 (5H, m), 7,42-7,48 (1H, m), 8,43 (1H, t, J= 6,1Hz).
- 33
- CD3OD δ 0,63-0,80 (2H, m), 0,87-1,08 (4H, m), 1,32-1,54 (7H, m), 2,50 (3H, s), 2,79-2,85 (1H, m), 3,08-3,13 (1H, m), 3,66-3,70 (1H, m), 3,99 (2H, s), 4,27-4,36 (2H, m), 4,594,65 (1H, m), 7,13-7,24 (7H, m), 7,30 (2H, d, J= 8,2Hz), 8,71 (1H, t, J= 5,9Hz), 8,80 (1H, d, J= 7,6Hz).
- 34
- CD3OD δ 0,75-0,91 (3H, m), 1,20-1,33 (5H, m), 1,55 (1H, d, J= 12,3Hz), 1,62-1,71 (3H, m), 1,80 (1H, d, J= 12,5Hz), 3,02 (3H, s), 3,08-3,18 (1H, m), 3,45-3,50 (1H, m), 3,83-3,87 (2H, m), 4,23 (2H, s), 4,46-4,52 (3H, m), 5,66-5,72 (1H, m), 7,21-7,41 (7H, m), 7,52 (1H, t, J=7,8Hz), 8,77 (1H, t, J= 6,0Hz).
- 35
- CD3OD δ 0,83 (3H, t, J= 7,4Hz), 1,24-1,30 (3H, m), 1,51-1,62 (2H, m), 2,64 (3H, s), 2,65-2,89 (5H, m), 3,09-3,14 (1H, m), 3,85-3,96 (2H, m), 3,98 (2H, s), 4,16-4,22 (1H, m), 4,284,37 (1H, m), 4,47-4,50 (1H, m), 5,29 (1H, t, J= 8,1Hz), 6,67-6,75 (2H, m), 6,87-6,90 (2H, m), 7,09 (2H, d, J= 8,2Hz), 7,15-7,29 (7H, m), 8,42 (1H, t, J= 6,0Hz).
- 36
- CD3OD δ 1,15-1,30 (6H, m), 1,52-1,76 (7H, m), 2,89-3,02 (4H, m), 3,10-3,19 (1H, m), 3,733,80 (2H, m), 3,99-4,05 (1H, m), 4,12-4,14 (2H, m), 4,48-4,59 (1H, m), 4,71-4,80 (1H, m), 5,08-5,16 (1H, m), 7,19-7,49 (9H, m).
- 38
- CD3OD δ 1,39 (3H, t, J= 7,0Hz), 2,66-2,71 (1H, m), 2,79-2,94 (2H, m), 3,01 (3H, s), 3,38-3,43 (1H, m), 3,97-4,03 (2H, m), 4,07-4,14 (2H, m), 4,40-4,50 (2H, m), 5,03-5,09 (1H, m), 5,52-5,56 (1H, m), 6,78-6,86 (2H, m), 7,05-7,18 (2H, m), 7,20-7,71 (12H, m), 7,737,81 (2H, m), 8,37 (1H, t, J= 6,0Hz), 8,58 (1H, d, J= 6,7Hz).
5
15
25
35
45
55
- 39
- CD3OD δ 1,39 (3H, t, J= 7,0Hz), 1,93 (3H, s), 2,50-2,63 (2H, m), 2,81-2,90 (1H, m), 2,95 (3H, s), 3,34-3,41 (1H, m), 3,95-4,05 (2H, m), 4,13 (2H, s), 4,33-4,51 (2H, m), 4,824,89( 1H, m), 5,46-5,50 (1H, m), 6,78-6,85 (2H, m), 7,00-7,05 (2H, m), 7,09-7,36 (7H, m), 7,39-7,43 (2H, m), 8,29 (1H, t, J= 6,0Hz).
- 40
- CD3OD δ 0,61-0,81 (2H, m), 0,88-1,05 (4H, m), 1,34-1,54 (7H, m), 2,51 (3H, s), 2,80-2,86 (1H, m), 3,08-3,13 (1H, m), 3,67-3,70 (1H, m), 4,07 (2H, s), 4,27-4,37 (2H, m), 4,59-4,63 (1H, m), 6,99-7,04 (2H, m), 7,13-7,24 (5H, m), 7,34 (1H, t, J= 7,9Hz), 8,73 (1H, t, J= 6,0Hz).
- 41
- CD3OD δ 0,73-1,25 (6H, m), 1,50-1,69 (7H, m), 2,67 (3H, s), 2,94-3,00 (1H, m), 3,24-3,29 (1H, m), 3,81-3,85 (1H, m), 4,23 (2H, s), 4,44-4,54 (2H, m), 4,76-4,80 (1H, m), 7,18-7,23 (2H, m), 7,31 (1H, dd, J= 8,3, 2,0 Hz), 7,45-7,56 (3H, m), 8,91 (1H, t, J= 5,9Hz), 8,97 (1H, d, J= 7,7Hz).
- 42
- CD3OD δ 0,83-1,19 (6H, m), 1,53-1,85 (7H, m), 2,94-3,08 (4H, m), 3,21-3,26 (1H, m), 3,874,08 (3H, m), 4,22 (2H, s), 4,38-4,55 (2H, m), 4,72-4,76 (1H, m), 7,18-7,22 (2H, m), 7,28-7,39 (5H, m), 7,47-7,51 (1H, m), 8,93 (1H, t, J= 6,0Hz), 9,05 (1H, d, J= 7,2Hz).
- 43
- CD3OD δ 0,78-0,97 (4H, m), 1,03-1,20 (2H, m), 1,47-1,50 (1H, m), 1,54-1,63 (5H, m), 1,751,82 (1H, m), 2,92-2,95 (1H, m), 2,98 (3H, s), 3,19-3,24 (1H, m), 3,98-4,13 (3H, m), 4,19 (2H, s), 4,38-4,52 (2H, m), 4,70-4,74 (1H, m), 7,17-7,20 (2H, m), 7,27 (1H, dd, J= 8,3, 2,0 Hz), 7,37-7,52 (3H, m), 8,92 (1H, t, J= 5,9Hz), 9,08 (1H, d, J= 7,3Hz).
- 44
- CD3OD δ 1,01-1,05 (6H, m), 1,40 (3H, t, J=7,0Hz), 2,36-2,62 (3H, m), 2,85-2,91 (1H, m), 2,96 (3H, s), 3,37-3,42 (1H, ,m), 3,98-4,04 (2H, m), 4,13 (2H, s), 4,39-4,50 (2H, m), 4,82-4,86 (1H, ,m), 5,48-5,52 (1H, m), 6,77-6,85 (2H, m), 6,99-7,04 (2H, m), 7,227,36 (7H, m), 7,39-7,44 (2H, m), 8,37 (1H, t, J= 6,0Hz).
- 45
- CD3OD δ 0,71-1,03 (9H, m), 1,36-1,63 (9H, m), 2,75 (3H, s), 2,81-3,11 (4H, m), 3,71-3,74 (1H, m), 4,00 (2H, s), 4,31-4,33 (2H, m), 4,59-4,63 (1H, m), 7,14-7,24 (7H, m), 7,30 (2H, d, J=8,2Hz), 8,71 (1H, t, J= 5,8Hz).
- 46
- CD3OD δ 0,78-0,97 (2H, m), 1,09-1,25 (4H, m), 1,54-1,69 (7H, m), 2,93-2,99 (1H, m), 3,243,29 (1H, m), 3,87 (3H, s), 3,94 (2H, d, J= 2,5Hz), 3,99-4,04 (1H, m), 4,15 (2H, s), 4,43-4,53 (2H, m), 4,73-4,77 (1H, m), 7,25-7,38 (7H, m), 7,46 (2H, d, J= 8,1Hz), 8,83 (1H, t, J= 5,9Hz).
- 47
- CD3OD δ 0,72-1,14 (6H, m), 1,40-1,73 (7H, m), 2,85-2,91 (4H, m), 3,11-3,16 (1H, m), 3,77 (3H, s), 3,93-3,96 (1H, m), 4,04 (2H, s), 4,07-4,18 (2H, m), 4,36 (2H, s), 4,63-4,67 (1H, m), 7,17-7,27 (7H, m), 7,35 (2H, d, J= 8,1Hz), 8,73 (1H, t, J= 5,9Hz), 8,92 (1H, d, J=7,3Hz).
- 48
- CD3OD δ 0,87-1,17 (6H, m), 1,54-1,79 (7H, m), 2,89 (3H, s), 2,95-3,02 (1H, m), 3,21-3,27 (1H, m), 3,79-3,99 (3H, m), 4,15 (2H, s), 4,47 (2H, s), 4,74-4,78 (1H, m), 7,29-7,39 (7H, m), 7,46 (2H, d, J= 8,1Hz), 8,84 (1H, t, J= 5,8Hz).
- 49
- CD3OD δ 0,75-1,08 (6H, m), 1,41-1,76 (7H, m), 2,85-2,91 (4H, m), 3,11-3,36 (3H, m), 3,783,90 (3H, m), 4,04 (2H, s), 4,31-4,41 (2H, m), 4,63-4,67 (1H, m), 7,18-7,29 (7H, m), 7,35 (2H, d, J= 8,2Hz), 8,76(1H, t, J= 5,9Hz).
- 52
- CD3OD δ, 0,74-0,88 (4H 0,78-2,10 (23H, m), 2,92-3,08 (1H, m), 3,12-3,30 (1H, m), 4,07 (1H, d, 4,2Hz), 4,15 (2H, s), 4,42 (1H, dd, J=15,3, 5,5Hz), 4,52 (1H, dd, J=15,3, 6,0Hz), 4,66 (1H, dd, J=10,2, 5,2Hz), 7,20-7,48 (9H, m), 8,87 (1H, t, J=6,0Hz).
- 53
- CD3OD δ 0,83-1,19 (12H, m), 1,50 (1H, d, J=12,2 Hz), 1,60-1,79 (10H, m), 2,98 (1H, dd, J=10,6, 14,2 Hz), 3,14-3,28 (5H, m), 3,91 (1H, dd, J=3,4, 11,7 Hz), 4,15 (2H, s), 4,47-4,49 (2H, m), 4,77 (1H, dd, J=5,2, 10,5 Hz), H, s7,36-7,41(6H (7H, m), 7,45 (2H, d, J=8,1 Hz), 8,89-8,92 (1H, m).
- 54
- CD3OD δ 1,44 (3H, t, J= 7,0 Hz), 2,81-2,87 (1H, m), 2,95-3,02 (2H, m), 3,19-3,24 (1H, m), 4,03-4,09 (4H, m), 4,46 (2H, d, J = 6,0 Hz), 4,84-4,89 (1H, m), 6,88 (2H, d, J = 8,5 Hz), 7,04 (2H, d, J = 8,5 Hz), 7,17-7,51 (13H, m), 7,85 (1H, d, J= 8,5 Hz), 7,93 (1H, d, J= 8,5 Hz), 7,90 y 8,00 (1H total, cada uno dd, J= cada uno 7,2 Hz), 8,43 (1H, d, J= 8,1 Hz), 8,63 (1H, t, J= 5,9 Hz), 8,75 (1H, t, J= 7,0 Hz).
- 55
- CD3OD δ 1,25 (3H, t, J= 7,0 Hz), 2,77-2,83 (H3H, m), 2,96-3,02 (1H, m), 3,85-3,97 (4H, m), 4,22-4,26 (1H, m), 4,27-4,39 (1H, m), 4,48-4,54 (2H, m), 6,66-6,68 (2H, m), 6,94 (2H, d, J = 8,6 Hz), 7,01-7,03 (2H, m), 7,11-7,29 (9H, m), 7,31 (1H, d, J= 1,8 Hz), 7,53 (1H,d, J=8,6 Hz), 8,22 (1H, d, J= 8,0 Hz), 8,36-8,44 (2H, m).
- 56
- CD3OD δ 1,25 (3H, t, J= 7,0 Hz), 2,75-2,83 (4H, m), 2,87-2,99 (1H, m), 3,85-3,89 (2H, m), 3,97 (2H, s), 4,22-4,39 (2H, m), 4,53-4,57 (H1H, m), 6,67 (2H, d, J = 8,5 Hz), 6,95 (2H, d, J =8,5 Hz), 7,02-7,04 (2H, m), 7,11-7,22 (7H, m), 7,60 (2H, d, J= 8,3 Hz), 7,71 (2H, d, J= 8,2 Hz), 8,25 (1H, d, J= 8,0 Hz), 8,42 (1H, t, J= 5,8 Hz).
15
25
35
45
55
- 57
- CD3OD δ 1,41 (3H, t, J= 7,0 Hz), 2,91-3,04 (4H, m), 3,15-3,20 (1H, m), 4,01-4,07 (4H, m), 4,40 (1H, d, J= 15,4 Hz), 4,53 (1H, d, J= 15,4 Hz), 4,67-4,71 (2H, m), 6,84 (2H, d, J = 8,7 Hz), 7,11 (2H, d, J = 8,6 Hz), 7,19-7,24 (2H, m), 7,27-7,37 (9H, m), 7,44-7,54 (2H, m), 7,70-7,73 (4H, m), 7,80-7,82 (1H, m).
- 58
- CD3OD δ 1,42 (3H, t, J= 7,0 Hz), 2,80-2,98 (4H, m), 3,02-3,06 (1H, m), 4,05 (2H, d, J = 7,0 Hz), 4,12 (2H, s), 4,39-4,46 (2H, m), 4,68-4,76 (2H, m), 6,85 (2H, d, J = 8,6 Hz), 7,12 (2H, d, J = 8,6 Hz), 7,20-7,22 (2H, m), 7,26-7,32 (6H, m), 7,39-7,41 (3H, m), 7,54 (1H, d, J = 1,9 Hz), 8,54 (1H, t, J = 5,9 Hz).
- 59
- CD3OD δ 1,25 (3H, t, J= 7,0 Hz), 2,77-2,81 (4H, m), 2,97-3,02 (1H, m), 3,87 (2H, q, J = 7,0 Hz), 3,93 (2H, s), 4,26-4,30 (1H, m), 4,35-4,40 (1H, m), 4,48-4,55 (2H, m), 6,68 (2H, d, J = 8,6 Hz), 6,94 (2H, d, J = 8,6 Hz), 7,01-7,03 (2H, m), 7,09-7,22 (8H, m), 7,42-7,45 (2H, m), 8,22 (1H, d, J= 8,1 Hz), 8,41 (1H, t, J= 5,8 Hz).
- 60
- CD3OD δ 1,23 (3H, t, J= 7,0Hz), 2,81-2,87 (1H, m), 3,01-3,06 (1H, m), 3,85-3,91 (2H, m), 3,94 (2H, s), 3,96-4,04 (2H, m), 4,18-4,24 (1H, m), 4,53 (1H, d, J= 7,0Hz), 4,84 (1H, d, J=7,1Hz), 6,70-6,74 (2H, m), 6,88 (2H, d, J= 8,0Hz), 7,01-7,04 (2H, m), 7,13-7,23 (5H, m), 7,27-7,31 (2H, m).
- 61
- CD3OD δ 1,43 (3H, t, J= 7,0Hz), 2,68-2,74 (1H, m), 2,98-3,03 (1H, m), 4,06 (2H, q, J= 7,0Hz), 4,14 (2H, s), 4,21-4,24 (1H, m), 4,42-4,50 (2H, m), 4,75 (1H, d, J= 4,4Hz), 5,28 (1H, d, J=4,4Hz), 6,85-6,89 (2H, m), 6,97-7,00 (2H, m), 7,30-7,35 (4H, m), 7,38-7,43 (3H, m), 7,5 (2H, d, J= 7,3Hz).
- 62
- CD3OD δ 0,93 (3H, t, J= 7,7Hz), 1,25 (3H, t, J= 7,0Hz), 2,01-2,11 (2H, m), 2,60-2,66 (1H, m), 2,79-2,84 (1H, m), 3,86 (2H, q, J= 7,0Hz), 3,99 (2H, s), 4,22-4,32 (2H, m), 4,41-4,43 (1H, m), 4,46 (1H, d, J= 4,0Hz), 5,13 (1H, d, J= 4,0Hz), 6,64-6,67 (2H, m), 6,91-6,95 (2H, m), 7,14-7,33 (9H, m).
- 63
- CD3OD δ 1,00 (3H, t, J= 7,6Hz), 1,43 (3H, t, J= 7,0Hz), 2,13-2,19 (2H, ,m), 2,61-2,66 (1H, m), 2,78-2,83 (1H, m), 4,04 (2H, q, J=7,0Hz), 4,14 (2H, s), 4,45-4,65 (4H, m), 5,37 (1H, d, J=3,0Hz), 6,77-6,81 (2H, m), 7,01 (2H, d, J= 8,6Hz), 7,28-7,45 (9H, ,m), 8,00 (1H, d, J=6,9Hz), 8,23 (1H, d, J= 8,4Hz), 8,51 (1H, t, J= 6,0Hz).
- 64
- CD3OD δ 0,98 (3H, t, J= 7,2Hz), 1,06-1,13 (3H, m), 1,40 (3H, t, J= 7,0Hz), 2,19-2,24 (2H, m), 2,71-2,82 (2H, ,m), 2,98-3,05 (1H, m), 3,14-3,22 (1H, m), 3,29-3,35 (1H, ,m), 3,51-3,60 (1H, m), 3,98-4,04 (2H, m), 4,13 (2H, s), 4,35-4,48 (2H, m), 4,78-4,89 (1H, m), 5,125,21 (1H, m), 6,79-6,83 (2H, m), 7,07-7,16 (2H, m), 7,26-7,38 (7H, m), 7,41 (2H, d, J= 8,1Hz), 8,21 (1H, t, J= 6,1 Hz).
- 65
- CD3OD δ 0,96-1,10 (6H, m), 1,33-1,44 (3H, m), 2,10-2,27 y 2,41-2,46 (3H total, m), 2,74-2,97 (2H, m), 3,12-3,23 (1H, m), 3,28-3,34 (1H, m), 3,41-3,50 (1H, m), 3,92-4,08 (2H, m), 4,12 (2H, s), 4,34-4,50 (2H, m), 4,60-4,64 y 4,78-4,82 (1H, m), 4,94-4,98 y 5,08-5,12(1H total, m), 6,80-6,89 (2H, m), 7,09-7,42 (11H, m), 8,11 (1H, t, J=6,0 Hz), 8,20 (1H, d, J=6,5 Hz), 8,45 (1H, d, J=7,2 Hz), 8,77 (1H, t, J=5,8 Hz).
- 66
- CD3OD δ 0,82-0,86 y 0,96-1,00 (3H total, m), 1,38-1,43 (3H, m), 2,18-2,30 (2H, m), 2,63 (3H, s), 2,84-3,02 (2H, m), 3,11-3,28 (2H, m), 3,99-4,06 (2H, m), 4,15 (2H, s), 4,39-4,51 (2H, m), 4,64-4,79 (1H, m), 5,22-5,26 (1H, m), 6,81-6,87 (2H, m), 7,09-7,13 (2H, m), 7,22-7,37 (7H, m), 7,42-7,46 (2H, m), 7,76 (1H, d, J= 7,9Hz), 8,45-8,47 y 8,59-8,62 (1H total, m).
- 67
- CD3OD δ 1,00 (3H, t, J=7,7Hz), 1,44 (3H, t, J=7,0Hz), 1,64-1,72 (1H, m), 2,08-2,31 (3H, m), 2,98-3,09 (2H, m), 3,30-3,36 (1H, m), 3,39-3,44 (1H, m), 3,91-3,97 (1H, m), 4,03-4,07 (2H, m), 4,14 (2H, s), 4,10-4,16 (1H, m), 4,31-4,34 (1H, m), 4,37 (1H, d, J=4,9Hz), 4,51-4,57 (1H, m), 4,82-4,86 (1H, m), H, s6,91-6,97 (4H, m), 7,25-7,36 (7H, m), 7,42 (2H, d, J=8,2Hz), 8,35-8,50 (1H, m).
- 68
- d6-DMSO δ: 1,29 (3H, t, J = 7,0Hz), 2,43 (1H, dd, J = 13,7, 8,0Hz), 2,63 (1H, dd, J = 13,8, 4,7Hz), 2,77 (1H, dd, J = 13,6, 10,4Hz), 3,06 (1H, dd, J = 13,7, 4,4Hz), 3,91-3,96 (4H, m), 4,07 (1H, dd, J = 15,4, 5,8Hz), 4,15 (1H, dd, J = 15,4, 6,0Hz), 4,23-4,26 (2H, m), 4,32-4,37 (1H, m), 4,44-4,50 (1H, m), 6,09 (1H, d, J = 7,7Hz), 6,58 (1H, t, J = 6,0Hz)), 6,67 (2H, d, J =8,7Hz), 6,76 (2H, d, J = 8,6Hz), 7,08-7,38 (11H, m), 7,45 (2H, d, J = 7,5Hz), 8,28 (3H, br s), 8,48 (1H, d, J = 8,5Hz), 8,62 (1H, t, J = 6,0Hz).
- 69
- d6-DMSO δ: 1,28 (3H, t, J = 7,0Hz), 2,47-2,50 (1H, m), 2,67 (1H, dd, J = 13,9, 4,6Hz), 2,79 (1H, dd, J = 13,6, 10,5Hz), 3,07 (1H, dd, J = 13,7, 4,3Hz), 3,90-3,97 (4H, m), 4,23-4,33 (2H, m), 4,43-4,53 (2H, m), 6,24 (1H, d, J = 7,7Hz), 6,66 (2H, d, J = 8,7Hz), 6,72 (2H, d, J = 8,7Hz), 6,86 (1H, t, J = 7,4Hz), 7,13-7,32 (11H, m), 7,36 (2H, d, J = 8,1Hz), 8,23 (2H, br s), 8,58-8,63 (2H, m), 8,77 (1H, s),
- 70
- d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,66 (1H, dd, J = 13,5, 10,6Hz), 2,73 (1H, dd, J = 13,8, 4,0Hz), 2,82 (1H, dd, J = 13,5, 10,2Hz), 3,05 (1H, dd, J = 13,6, 4,9Hz), 3,89-4,01 (4H, m), 4,27 (1H, dd, J = 15,4, 5,8Hz), 4,34 (1H, dd, J = 15,4, 6,1Hz), 4,55-4,68 (2H, m), 6,75 (2H, d, J = 8,6Hz), 7,07-7,32 (8H, m), 7,39 (2H, d, J = 8,1Hz), 7,73 (1H, dd, J = 7,9, 5,2Hz), 8,13-8,59 (4H, m), 8,63 (2H, m), 8,81 (1H, dd, J = 5,1, 1,3Hz), 8,99-9,01 (2H, m).
- 71
- d6-DMSO δ: 1,26 (3H, t, J = 6,9Hz), 2,64 (1H, dd, J = 13,5, 10,8Hz), 2,72 (1H, dd, J = 13,6, 3,8Hz), 2,82 (1H, dd, J = 13,5, 10,2Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,80-4,01 (4H, m), 4,27 (1H, dd, J = 15,4, 5,8Hz), 4,34 (1H, dd, J = 15,4, 6,0Hz), 4,58-4,68 (2H, m), 6,75 (2H, d, J = 8,6Hz), 7,14 (2H, d, J = 8,7Hz), 7,17-7,27 (6H, m), 7,38 (2H, d, J = 8,1Hz), 7,85 (2H, d, J = 5,9Hz), 8,14-8,50 (3H, m), 8,64 (1H, d, J = 6,2Hz), 8,67 (1H, d, J = 8,6Hz), 8,80 (2H, d, J = 6,0Hz), 9,03 (1H, d, J = 8,3Hz).
- 72
- d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,62-2,64 (2H, m), 2,81 (1H, dd, J = 13,6, 10,0Hz), 3,03 (1H, dd, J = 13,4, 4,5Hz), 3,92 (2H, q, J = 7,0Hz), 3,96 (2H, s), 4,25-4,35 (2H, m), 4,54-4,61 (2H, m), 6,74 (2H, d, J = 8,6Hz), 7,13 (2H, d, J = 8,7Hz), 7,16-7,25 (7H, m), 7,35 (2H, d, J = 8,1Hz), 7,43 (1H, dd, J = 5,0, 1,3Hz), 7,53 (1H, dd, J = 5,0, 3,0Hz), 8,11 (1H, dd, J =2,8, 1,0), 8,20 (2H, br s), 8,33 (1H, d, J = 8,2Hz), 8,54 (1H, d, J = 8,7Hz), 8,60 (1H, t, J =6,0Hz).
- 73
- d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,48-2,68 (2H, m), 2,81 (1H, dd, J = 13,6, 10,1Hz), 3,03 (1H, dd, J = 13,6, 4,7Hz), 3,89-3,96 (4H, m), 4,24-4,34 (2H, m), 4,53-4,62 (2H, m), 6,74 (2H, d, J = 8,6Hz), 7,10-7,27 (9H, m), 7,37 (2H, d, J = 8,1Hz)), 7,71 (1H, dd, J = 4,9, 0,9Hz), 7,82 (1H, dd, J = 3,6, 2,8Hz),8,20 (3H, br s), 8,56 (2H, dd, J = 10,5, 9,1Hz), 8,62 (1H, t, J = 6,0Hz).
- 74
- d6-DMSO δ: 0,48-0,57(4H,m), 1,29(3H,t,J= 7,0Hz), 1,56-1,62(1H,m), 2,43-2,49(1H,m), 2,542,59(1H,m), 2,73-2,79(1H,m), 3,00-3,05(1H,m), 3,92-3,97(4H,m), 4,20-4,33(2H,m), 4,38-4,43(1H,m), 4,47-4,53(1H,m), 6,73(2H,d,J= 8,6Hz), 6,98(2H,d,J= 8,6Hz), 7,16-7,26(7H,m), 7,38(2H,d,J= 8,1Hz), 8,23(1H,d,J= 7,7Hz), 8,28(2H,s), 8,48(1H,d,J=8,6Hz), 8,54(1H,t,J =6,0Hz).
- 75
- d6-DMSO δ: 0,96-1,15(5H,m), 1,20(3H,t,J= 7,0Hz), 1,36-1,55(5H,m), 1,96-2,01(1H,m), 2,342,41(1H,m), 2,51-2,56(1H,m), 2,67-2,73(1H,m), 2,92-2,97(1H,m), 3,86(2H,q,J=7,0Hz), 3,90(2H,s), 4,15-4,24(2H,m), 4,27-4,32(1H,m), 4,414,47(1H,m), 6,64(2H,d,J=8,6Hz), 6,88(2H,d,J= 8,6Hz), 7,08-7,18(7H,m), 7,30(2H,d,J= 8,1Hz), 7,66(1H,d,J= 8,0Hz), 8,17(2H,s), 8,29(1H,d,J= 8,5Hz), 8,51(1H,t,J =6,0Hz).
- 76
- d6-DMSO δ: 0,78(3H,t,J= 7,3Hz), 0,99-1,05(2H,m), 1,12-1,21(2H,m), 1,26-1,36(5H,m), 1,912,03(2H,m), 2,38-2,44(1H,m), 2,56-2,61(1H,m), 2,74-2,80(1H,m), 2,99-3,04(1H,m), 3,93(2H,q,J= 7,0Hz), 3,97(2H,s), 4,23-4,33(2H,m), 4,39-4,44(1H,m), 4,504,56(1H,m), 6,72(2H,d,J= 8,6Hz), 6,98(2H,d,J= 8,6Hz), 7,15-7,26(7H,m), 7,38(2H,d,J= 8,1Hz), 7,88(1H,d,J= 8,0Hz), 8,22(2H,s), 8,42(1H,d,J= 8,6Hz), 8,58(1H,t,J =6,0Hz).
- 77
- d6-DMSO δ: 0,93 (3H, d, J = 4,2Hz), 0,95 (3H, d, J = 4,1Hz), 1,28 (3H, t, J = 7,0Hz), 2,41 (1H, dd, J = 13,7, 8,0Hz), 2,58 (1H, dd, J = 13,8, 4,7Hz), 2,77 (1H, dd, J = 13,6, 10,5Hz)), 3,06 (1H, dd, J = 13,7, 4,2Hz), 3,50-3,58 (1H, m), 3,70-4,01 (4H, m), 4,25-4,30 (3H, m), 4,41-4,47 (1H, m), 5,82 (1H, d, J = 7,6Hz), 5,99 (1H, d, J = 7,6Hz), 6,67 (2H, d, J = 8,6Hz), 6,76 (2H, d, J = 8,6Hz), 7,16-7,26 (7H, m), 7,39 (2H, d, J = 8,1 Hz), 8,37 (2H, br s), 8,46 (1H, d, J = 8,5Hz), 8,65 (1H, t, J = 6,0Hz).
- 78
- d6-DMSO δ: 0,83 (3H, t, J = 7,0Hz), 1,16-1,30 (11H, m), 2,41 (1H, dd, J = 13,8, 8,0Hz), 2,59 (1H, dd, J = 13,6, 4,6Hz), 2,77 (1H, dd, J = 13,7, 10,5Hz), 2,83-2,90 (2H, m), 3,05 (1H, dd, J = 13,7, 4,2Hz), 3,93 (2H, q, J = 7,0Hz), 3,95 (2H, m), 4,26-4,32 (3H, m), 4,42-4,46 (1H, m), 5,91 (1H, d, J = 7,6Hz), 6,09 (1H, t, J = 5,6Hz), 6,67 (2H, d, J = 8,7Hz), 6,76 (2H, d, J = 8,6Hz), 7,16-7,26 (7H, m), 7,39 (2H, d, J = 8,1Hz), 8,35 (2H, br s), 8,45 (1H, d, J =8,5Hz), 8,65 (1H, t, J = 6,0Hz).
- 79
- d6-DMSO δ: 1,34(3H,t,J= 7,0Hz), 2,65-2,79(2H,m), 2,85-2,91 (1H,m), 3,09-3,13(1H,m), 3,99(2H,q,J= 7,0Hz), 4,04(2H,s), 4,32-4,42(2H,m), 4,65-4,73(2H,m), 6,80(2H,d,J= 8,6Hz), 7,15(2H,d,J= 1,9Hz)), 7,16(1H,s), 7,22-7,34(7H,m), 7,44(2H,d,J= 8,1Hz), 8,29(2H,s), 8,68-8,72(2H,m), 8,77(1H,d,J= 1,8Hz), 8,96(1H,d,J = 8,6Hz).
- 80
- d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,61-2,72(2H,m), 2,79-2,84(1H,m), 3,02-3,07(1H,m), 3,92(2H,q,J=7,0Hz), 3,96(2H,s), 4,25-4,37(2H,m), 4,56-4,63(2H,m), 6,75(2H,d,J= 8,6Hz), 7,14(2H,d,J=8,6Hz), 7,16-7,25(7H,m), 7,37(2H,d,J= 8,1Hz), 7,42(2H,d,J= 8,2Hz), 7,85-7,88(2H,m), 8,21(2H,s), 8,56-8,64(3H,m).
- 81
- d6-DMSO δ: 1,25 (3H, t, J = 7,0Hz), 2,68 (1H, m), 2,78-2,85 (2H, m), 3,06 (1H, dd, J = 13,6, 4,4Hz), 3,86-4,01 (4H, m), 4,28 (2H, d, J = 6,0Hz), 4,50-4,56 (1H, m), 4,74-4,79 (1H, m), 6,59 (2H, d, J = 8,7Hz), 6,65 (2H, d, J = 8,8Hz), 7,17-7,38 (8H, m), 7,597,61 (1H, m), 7,96-7,99 (2H, m), 8,33 (3H, br s), 8,48 (1H, d, J = 8,2Hz), 8,61 (1H, dt, J = 4,7, 1,2Hz), 8,66 (1H, t, J = 6,0Hz), 8,71 (1H, d, J = 8,5Hz).
- 82
- d6-DMSO δ: 1,27 (3H, t, J = 6,9Hz), 2,13 (3H, s), 2,57-2,69 (2H, m), 2,82 (1H, dd, J = 13,6, 10,0Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,78 (3H, s), 3,91 (2H, q, J = 7,0Hz), 3,923,99 (2H, m), 4,25-4,36 (2H, m), 4,50-4,62 (2H, m), 6,63 (1H, s), 6,74 (2H, d, J = 8,6Hz), 7,11 (2H, d, J = 8,7Hz), 7,17-7,25 (7H, m), 7,37 (2H, d, J = 8,2Hz), 8,25 (2H, br s), 8,35 (1H, d, J =8,4Hz), 8,55 (1H, d, J = 8,6Hz), 8,60 (1H, t, J = 6,0Hz).
- 83
- d6-DMSO δ: 1,25 (3H, t, J = 7,0Hz), 2,61-2,70 (2H, m), 2,82 (1H, dd, J = 13,5, 10,1Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,91 (2H, q, J = 7,0Hz), 3,94 (2H, s), 4,25-4,35 (2H, m), 4,58-4,64 (2H, m), 6,75 (2H, d, J = 8,6Hz), 7,14-7,25 (9H, m), 7,38 (2H, d, J = 8,2Hz), 7,42-7,45 (2H, m), 7,93-7,99 (2H, m), 8,18 (1H, s), 8,27 (2H, br s), 8,63-8,67 (2H, m), 8,84 (1H, d, J =8,4Hz).
- 84
- d6-DMSO δ: 1,31(3H,t,J= 7,0Hz), 2,21-2,27(1H,m), 2,35-2,39(1H,m), 2,67-2,72(1H,m), 2,902,95(1H,m), 3,94(2H,q,J= 7,0Hz), 3,99(3H,s), 4,22-4,27(1H,m), 4,38-4,44(1H,m), 4,49-4,55(1H,m), 6,63(2H,d,J= 8,6Hz), 6,93(2H,d,J= 8,6Hz), 7,13-7,25(7H,m), 7,317,34(2H,m), 7,38-7,42(4H,m), 8,10(1H,s), 8,20(2H,s), 8,48(1H,d,J= 8,8Hz), 8,56(1H,t,J = 6,0Hz).
- 85
- d6-DMSO δ: 1,30 (3H, t, J= 6,96Hz), 2,38-2,42 (1H, m), 2,58-2,62 (1H, m), 2,73-2,79 (1H,m), 2,99-3,03 (1H,m), 3,91-3,95 (4H, m), 4,24-4,25 (2H, m), 4,41-4,46 (1H,m), 4,51-4,57 (1H,m), 6,67 (2H, d, J= 8,69Hz), 6,89 (2H, d, J= 8,64Hz), 7,07 (2H, d, J= 1,8Hz), 7,17-7,25 (10H,m), 7,37 (2H, t, J= 8,08Hz), 8,14 (1H, t, J= 8,12Hz), 8,26 (3H,s, br), 8,49 (1H, d, J =8,57Hz), 8,56-8,59 (1H, m).
- 86
- d6-DMSO δ: 1,28 (3H, t, J= 6,92Hz), 2,26-2,35 (2H, m), 2,39-2,45 (1H, m), 2,49 (2H, s), 2,562,65 (2H,m), 2,74-2,80 (1H, m), 3,00-3,05 (1H, m), 3,93-3,96 (3H, m), 4,25-4,32 (2H, m), 4,41-4,46 (1H,m), 4,49-4,55 (1H, m), 6,70 (2H, d, J= 8,48Hz), 6,92 (2H, d, J= 8,48Hz), 7,08 (2H, d, J= 7,16Hz), 7,18-7,24 (10H, m), 7,38 (2H, t, J= 8,0Hz), 8,00 (1H, d, J= 8,00Hz), 8,28 (3H,s, br), 8,46 (1H, d, J = 8,48Hz), 8,57 (1H, t, J= 5,92Hz).
- 87
- d6-DMSO δ: 1,28 (3H, t, J= 6,92Hz), 1,51-1,58 (2H, m), 1,73-1,86 (2H, m), 2,39-2,45 (2H, m), 2,49 (2H, s), 2,56-2,65 (2H, m), 2,95-3,03 (1H, m), 3,86-3,97 (4H, m), 4,29-4,34 (3H, m), 4,47-4,53 (1H, m), 6,66 (2H, d, J= 8,21Hz), 6,96 (2H, d, J= 8,17Hz), 7,17-7,34 (10H, m), 7,36-7,40 (2H, m), 8,02-8,11 (1H, m), 8,26 (3H,s, br), 8,34-8,56 (2H, m).
- 88
- d6-DMSO δ: 1,33 (3H,t,J= 6,93Hz), 2,71-2,75 (2H, m), 2,86-2,92 (1H, m), 3,09-3,14 (1H,m), 3,98-4,03 (4H, m), 4,32-4,43 (2H, m), 4,63-4,69 (2H,m), 6,82 (2H, d, J= 8,52Hz), 7,21 (2H, d, J=8,68Hz), 7,27-7,31 (7H,m), 7,44 (2H, d, J = 8,07Hz), 7,51-7,54 (1H,m), 7,63-7,65 (1H,m), 7,77 (1H, d, J= 7,84Hz), 7,86 (1H, d, J= 1,68Hz), 8,35 (3H,s, br), 8,63-8,74 (3H, m).
- 89
- d6-DMSO δ: 1,29 (3H, t, J= 6,88Hz), 2,52-2,58 (1H, m), 2,71-2,79 (1H, m), 2,81-2,84 (1H, m), 3,02-3,07 (1H,m), 3,95-3,98 (4H, m), 4,24-4,36 (2H, m), 4,58-4,63 (2H,m), 6,76 (2H, d, J=8,56Hz), 7,08 (2H, d, J= 8,56Hz), 7,14-7,25 (9H, m), 7,33-7,43 (4H,m), 8,285 (3H,s, br), 8,47 (2H, t, J= 7,84Hz), 8,62 (1H, t, J= 5,764Hz).
- 90
- d6-DMSO δ: 1,26 (3H,t,J= 6,89Hz), 2,61-2,74 (2H, m), 2,79-2,85 (1H, m), 3,02-3,07 (1H, m), 3,91-3,96 (4H, m), 4,25-4,36 (2H, m), 4,58-4,67 (2H,m), 6,74 (2H, d, J= 8,56Hz), 7,15-7,24 (9H, m), 7,37 (2H, d, J= 8,12Hz), 7,68 (1H, t, J= 7,80Hz), 7,87 (1H, d, J= 7,89Hz), 8,03 (1H, d, J=7,89Hz), 8,09 (1H, s) 8,28 (3H,s, br), 8,48=8,65 (2H, m), 8,82 (1H, d, J= 8,28Hz).
- 91
- d6-DMSO δ: 1,27 (3H, t, J= 6,88Hz), 1,55-1,61 (11H, m), 1,89 (2H, s), 2,49 (2H, s), 2,62-2,72 (2H, m), 2,79-2,84 (1H, m), 3,01-3,05 (1H,m), 3,91-3,96 (4H, m), 4,23-4,39 (3H, m), 4,49-4,54 (1H,m), 6,69 (2H, d, J= 8,36Hz), 6,88 (2H, d, J= 8,37Hz), 7,19-7,25 (8H, m), 7,39 (2H, d, J = 7,84Hz), 8,32-8,38 (3H,m), 8,65-8,68 (1H, m).
- 92
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,32 (3H, s), 2,67 (2H,d, J = 7,20Hz), 2,78-2,84 (1H,m), 3,02-3,07 (1H,m), 3,91-3,97 (4H, m), 4,27-4,36 (2H, m), 4,57-4,60 (2H,m), 6,73 (2H, d, J= 8,57Hz), 7,12 (2H, d, J= 8,57Hz), 7,21-7,24 (9H,m), 7,36 (2H, t, J= 8,08Hz), 7,65 (2H, t, J= 8,17Hz), 8,25 (3H,s, br), 8,37 (1H, d, J = 8,08Hz), 8,54 (1H, d, J= 8,60Hz), 8,59-8,62 (1H, m).
- 93
- d6-DMSO δ: 1,33 (3H,t,J= 6,97Hz), 2,67-2,79 (2H,m), 2,86-2,91 (1H,m), 3,093-3,14 (1H, m), 3,98-4,04 (4H, m), 4,32-4,44 (2H, m), 4,63-4,70 (2H, m), 6,81 (2H, d, J= 8,57Hz), 7,21 (2H, d, J= 8,60Hz), 7,27-7,32 (8H,m), 7,44 (2H, t, J= 8,08Hz), 7,79 (2H, s), 8,06 (1H, s), 8,38 (3H,s, br), 8,63-8,70 (1H, m), 8,83 (1H, d, J= 8,28Hz).
- 94
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,61-2,71 (2H, m), 2,71-2,84 (1H, m), 3,02-3,06 (1H, m), 3,92-3,96 (4H, m), 4,25-4,35 (2H, m), 4,57-4,64 (2H, m), 6,75 (2H, d, J= 8,64Hz), 7,14 (2H, d, J= 8,56Hz), 7,21-7,25 (8H,m), 7,36 (2H, d, J = 8,08Hz), 7,76-7,79 (3H,m), 8,24 (3H,s, br), 8,59 (1H, t, J = 6,32Hz), 8,78 (1H, d, J= 8,24Hz).
- 95
- d6-DMSO δ: 1,26 (3H, t, J= 6,97Hz), 2,65-2,69 (2H, m), 2,79-2,84 (1H, m), 3,03-3,07 (1H, m), 3,797 (3H, s), 3,91-3,95 (4H, m), 4,25-4,34 (2H, m), 4,53-4,59 (2H,m), 6,73 (2H, d, J= 8,57Hz), 6,95 (2H, d, J= 8,88Hz), 7,13 (2H, d, J= 8,64Hz), 7,18-7,24 (7H,m), 7,37 (2H, d, J= 8,12H), 7,74 (2H, t, J= 8,85Hz), 8,29 (3H,s, br), 8,34 (1H, d, J = 8,60Hz), 8,54 (1H, d, J= 8,60Hz), 8,61 (1H, t, J= 5,96Hz).
- 96
- d6-DMSO δ: 1,27 (3H, t, J= 6,92Hz), 2,61-2,66 (2H, m), 2,76-2,82 (1H, m), 3,01-3,06 (1H, m), 3,90-3,95 (4H, m), 4,28-4,31 (2H, m), 4,52-4,62 (2H, m), 6,67-6,73 (3H, m), 6,97 (2H, d, J= 8,53Hz), 7,18-7,27 (10H, m), 7,35-7,41 (3H, m), 7,50 (2H, d, J= 6,73Hz), 8,21 (4H, d, J= 8,00Hz), 8,59 (2H, t, J = 7,24Hz).
- 97
- d6-DMSO δ: 1,28 (3H, t, J= 6,88Hz), 2,40-2,46 (1H, m), 2,59-2,64 (1H, m), 2,73-2,79 (1H,m), 2,98-3,03 (1H,m), 3,43 (2H, s), 3,51-3,57 (1H,m), 3,67-3,73 (1H, m), 3,92-3,97 (4H, m), 4,24-4,33 (2H, m), 4,43-4,54 (2H,m), 6,68 (2H, d, J= 8,56Hz), 6,88 (2H, d, J= 8,57Hz), 7,20-7,26 (12H, m), 7,37 (2H, d, J = 8,08Hz), 7,96 (1H, d, J= 8,21Hz), 8,20-8,27 (4H, m), 8,47 (1H, d, J = 8,50Hz), 8,57 (1H, t, J= 5,97Hz).
- 98
- d6-DMSO δ: 1,27 (3H, t, J= 6,93Hz), 2,47-2,49 (1H, m), 2,62-2,66 (1H, m), 2,76-2,82 (1H, m), 3,01-3,06 (1H, m), 3,72-3,77 (1H, m), 3,85-3,91 (3H, m), 3,94-3,98 (2H, m), 4,264,30 (2H, m), 4,44-4,54 (2H,m), 6,61 (2H, d, J= 8,64Hz), 6,83 (2H, d, J= 8,60Hz), 7,18 (2H, d, J=8,05Hz), 7,26-7,27 (5H,m), 7,36 (2H, d, J= 8,12Hz), 7,46 (2H, d, J= 7,68Hz), 7,51-7,55 (1H,m), 7,84 (2H, t, J= 7,126Hz), 7,92 (1H, d, J= 8,08Hz), 8,30 (3H,s, br), 8,50 (1H, d, J = 8,53Hz), 8,57 (1H, t, J= 5,93Hz), 8,73 (1H, t, J = 5,84),
- 99
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,65-2,67 (2H, m), 2,78-2,84 (1H, m), 3,03-3,07 (1H, m), 3,91-3,96 (4H, m), 4,25-4,36 (2H, m), 4,55-4,61 (2H, m), 6,74 (2H, d, J= 8,60Hz), 7,14 (2H, d, J= 8,64Hz), 7,21-7,28 (9H,m), 7,36 (2H, d, J = 8,12Hz), 7,80-7,83 (2H, m), 8,23 (3H,s, br), 8,53-8,583 (3H, m).
- 100
- d6-DMSO δ: 1,36(3H,t,J= 7,0Hz), 2,50-2,56(1H,m), 2,59-2,63(1H,m), 2,82-2,88(1H,m), 3,023,07(1H,m), 3,79-3,85(1H,m), 3,97(2H,s), 4,03(2H,q,J= 7,0Hz), 4,16-4,21(2H,m), 4,32(2H,d,J= 5,8Hz), 4,63-4,69(1H,m), 6,87(2H,d,J= 8,6Hz), 7,15(2H,d,J= 8,6Hz), 7,20-7,35(14H,m), 7,47-7,57(1H,m), 7,73-7,81(2H,m), 8,61-8,66(2H,m).
- 101
- d6-DMSO δ: 1,28 (3H, t, J= 6,92Hz), 2,36 (3H, s), 2,38-2,42 (1H, m), 2,56-2,60 (1H, m), 2,732,78 (1H, m), 2,98-3,03 (1H, m), 3,23-3,28 (1H, m), 3,92-3,98 (4H, m), 4,27-4,32 (2H, m), 4,41-4,46 (1H, m), 4,49-4,55 (1H, m), 6,66 (2H, d, J= 8,61 Hz), 6,79 (2H, d, J= 8,60Hz), 7,20 (2H, d, J= 6,21 Hz), 7,26-7,29 (6H,m), 7,32-7,40 (4H,m), 7,62 (2H, d, J= 8,28Hz), 7,80-7,88 (2H, m), 8,29 (3H,s, br), 8,52 (1H, d, J = 8,52Hz), 8,59-8,62 (1H, m).
- 102
- d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,42-2,47(1H,m), 2,64-2,69(1H,m), 2,75-2,81(1H,m), 3,043,08(1H,m), 3,92(2H,q,J= 7,0Hz), 3,96(2H,s), 4,28(2H,d,J= 5,8Hz), 4,434,53(2H,m), 6,23(1H,d,J= 7,7Hz), 6,65(4H,s), 7,17-7,23(5H,m), 7,26-7,36(8H,m), 8,19(2H,s), 8,63-8,65(2H,m), 8,91(1H,s),
- 103
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 1,31-1,43 (7H, m), 2,68 (2H, d, J= 7,47Hz), 2,79-2,84 (1H, m), 3,02-3,07 (1H, m), 3,90-3,95 (2H, m), 4,06 (2H, d, J= 6,40Hz), 4,25-4,32 (2H, m), 4,56-4,63 (2H,m), 6,75 (2H, d, J= 8,52Hz), 7,13-7,22 (12H, m), 7,32-7,35 (1H, m), 7,40-7,43 (2H, m), 7,59-7,63 (1H, m), 7,74 (2H, d, J = 7,90Hz), 8,45-8,52 (3H, m).
- 104
- d6-DMSO δ:1,26 (3H,t,J= 6,93Hz), 2,65-2,75 (2H, m + 3H, s), 2,82-2,86 (1H, m), 3,04-3,08 (1H,m), 3,91-3,96 (4H, m), 4,24-4,36 (2H, m), 4,57-4,69 (2H,m), 6,73 (2H, d, J= 8,52Hz), 7,14 (2H, d, J= 8,68Hz), 7,17-7,24 (6H,m), 7,39 (2H, d, J = 8,07Hz), 7,79 (1H, d, J= 7,84Hz), 8,44 (3H,s, br), 8,49-8,52 (1H, m), 8,65-8,69 (2H, m), 9,00 (1H, d, J= 1,68Hz), 9,14 (1H, d, J=1,68Hz).
- 105
- d6-DMSO δ: 1,29 (3H,t,J= 6,93Hz), 2,42 (3H, s), 2,75-2,86 (3H, m), 3,05-3,09 (1H,m), 3,953,97 (4H, m), 4,25-4,37 (2H, m), 4,61-4,74 (2H,m), 6,78 (2H, d, J= 8,52Hz), 7,09 (2H, d, J= 8,68Hz), 7,21-7,27 (6H,m), 7,40 (2H, d, J = 8,07Hz), 7,76-7,80 (1H, m), 8,07-8,13 (1H, m), 8,42 (3H,s, br), 8,67-8,73 (3H, m), 8,94 (1H, d, J= 1,68Hz).
- 106
- d6-DMSO δ: 1,13 (3H,t,J= 6,93Hz), 2,70-2,84 (3H, m), 3,01-3,06 (1H,m), 3,95-3,98 (4H, m), 4,24-4,36 (2H, m), 4,59-4,69 (2H,m), 6,76 (2H, d, J= 8,52Hz), 7,04 (2H, d, J= 8,68Hz), 7,16-7,26 (6H,m), 7,38 (2H, d, J = 8,07Hz), 7,61 (2H, s), 8,33 (3H,s, br), 8,58-8,60 (1H, m), 8,64-8,67 (1H, m), 8,78 (1H, d, J= 1,68Hz).
- 107
- d6-DMSO δ: 1,24 (3H,t,J= 6,93Hz), 2,56-2,62 (1H, m), 2,69-2,73 (1H, m), 2,78-2,84 (1H, m), 3,02-3,07 (1H,m), 3,89-3,95 (4H, m), 4,24-4,37 (2H, m), 4,58-4,67 (2H,m), 6,75 (2H, d, J= 8,52Hz), 7,13 (2H, d, J= 8,68Hz), 7,16-7,25 (8H, m), 7,36 (2H, d, J = 8,07Hz), 8,26 (3H,s, br), 8,59-8,64 (1H, m), 8,65 (1H, d, J= 1,68Hz), 8,94 (1H, d, J= 1,68Hz).
- 108
- d6-DMSO δ: 1,28 (3H,t,J= 6,93Hz), 2,69-2,82 (2H, m), 3,02-3,09 (2H,m), 3,92-3,98 (4H, m), 4,26-4,33 (2H, m), 4,59-4,62 (2H,m), 6,74 (2H, d, J= 8,52Hz), 6,98 (2H, d, J= 8,68Hz), 7,23-7,29 (7H, m), 7,37-7,40 (2H, m), 8,05 (1H,s, br), 8,23 (3H,s, br), 8,658,69 (1H, m), 8,85 (1H,d,J=1,68Hz).
- 109
- d6-DMSO δ: 1,28 (3H,t,J= 6,93Hz), 2,36-2,40 (1H, m), 2,59-2,63 (1H, m), 2,73-2,79 (1H, m), 3,00-3,03 (1H, m), 3,19-3,27 (1H, m), 3,91-3,97 (4H, m), 4,28-4,36 (2H, m), 4,524,54 (2H,m), 6,68 (2H, d, J= 8,52Hz), 6,84 (2H, d, J= 8,68Hz), 7,19-7,24 (7H,m), 7,38 (2H, d, J = 8,07Hz), 8,35 (3H,s, br), 8,59-8,63 (2H, m).
- 110
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,47 (3H, s), 2,49-2,50 (1H, m), 2,59-2,63 (1H, m), 2,692,74 (1H, m), 3,02-3 ,07 (1H,m), 3,91-3,95 (4H, m), 4,28-4,37 (2H, m), 4,57-4,66 (2H,m), 4,79-4,80 (2H,m), 6,74 (2H, d, J= 8,52Hz), 7,14 (2H, d, J= 8,68Hz), 7,167,23 (6H, m), 7,38 (2H, d, J = 8,07Hz), 7,55 (2H, d, J= 7,84Hz), 8,40 (2H,s, br), 8,638,67 (1H, m), 8,91 (1H, d, J= 1,68Hz).
- 111
- d6-DMSO δ: 1,27 (3H, t, J= 6,93Hz), 2,30 (3H, s), 2,59 (3H, s), 2,61-2,72 (2H, m), 2,79-2,84 (1H, m), 3,04-3,09 (1H,m), 3,91-3,96 (4H, m), 4,29-4,35 (2H, m), 4,50-4,60 (2H, m), 6,73 (2H, d, J= 8,52Hz), 7,03 (2H, d, J= 8,68Hz), 7,15-7,27 (7H, m), 7,39 (2H, d, J = 8,07Hz), 8,07 (1H, d, J= 7,84Hz), 8,42 (2H,s, br), 8,62-8,66 (2H, m).
- 112
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,66 (3H, s), 2,77-2,84 (3H, m), 3,03-3,08 (1H, m), 3,873,97 (4H, m), 4,28 (2H, d), 4,49-4,55 (1H, m), 4,70-4,75 (1H, m), 6,61 (2H, d, J= 8,52Hz), 6,67 (2H, d, J= 8,68Hz), 7,19-7,30 (7H, m), 7,38 (2H, d, J = 8,07Hz), 7,89 (1H, d, J= 7,84Hz), 8,06 (1H, s), 8,41 (2H,s, br), 8,65-8,70 (2H, m).
- 113
- d6-DMSO δ: 1,27 (3H, t, J= 6,93Hz), 2,36 (3H, s), 2,45 (3H, s), 2,63-2,68 (1H, m), 2,75-2,84 (2H, m), 3,04-3,08 (1H,m), 3,88-3,96 (4H, m), 4,29 (2H, d), 4,48-4,54 (1H, m), 4,644,69 (1H, m), 6,62 (2H, d, J= 8,52Hz), 6,65 (2H, d, J= 8,68Hz), 7,17-7,24 (6H, m), 7,39 (2H, d, J =8,07Hz), 7,54 (1H, d, J= 7,84Hz), 8,40 (3H,s, br), 8,64-8,66 (2H, m).
- 114
- d6-DMSO δ: 1,26 (3H, t, J= 7,07Hz), 2,09 (3H, s), 2,67-2,77 (2H, m), 2,78-2,88 (1H, m), 3,053,09 (1H, m), 3,92-3,97 (4H, m), 4,31-4,40 (2H, m), 4,59-4,63 (1H, m), 4,64-4,74 (1H, m), 6,77 (2H, d, J= 8,34Hz), 7,17-7,29 (10H, m), 7,39 (2H, d, J = 8,36Hz), 7,87 (1H, d, J= 8,55Hz), 8,26-8,36 (4H, m), 8,62 (1H, s), 8,68-8,71 (2H, m), 8,88-8,95 (1H, m).
- 115
- d6-DMSO δ: 1,26 (3H, t, J= 6,36Hz), 2,66-2,87 (3H, m), 3,05-3,10 (1H,m), 3,92-3,97 (4H, m), 4,31-4,38 (2H, m), 4,38-4,40 (2H, m), 4,59-4,63 (1H,m), 4,69-4,75 (1H,m), 6,77 (2H, d, J=7,95Hz), 7,14 (2H, d, J= 7,95Hz), 7,16-7,23 (6H, m), 7,38 (2H, d, J = 7,82Hz), 7,55 (2H, d, J= 7,95Hz), 7,74 (1H, d, J= 11,13Hz), 8,40 (3H,s, br), 8,63-8,67 (1H, m), 8,91 (1H, d, J= 2,69Hz), 9,05 (1H, J = 8,68Hz), 9,20 (1H, d, J = 2,2Hz).
- 116
- d6-DMSO δ: 1,28(3H, t, J= 6,57Hz), 2,61-2,67 (1H, m), 2,79-2,85 (2H, m), 3,08-3,12 (1H,m), 3,92-3,98 (4H, m), 4,31 (2H, d, J = 6,57Hz), 4,53-4,58 (1H,m), 4,67-4,71 (1H, m), 6,66 (2H, d, J=8,09Hz), 6,74 (2H, d, J= 8,23Hz), 7,14 (1H, d, J= 5,47Hz), 7,22-7,25 (2H, m), 7,30-7,35 (4H, m),7,39 (2H, d, J = 8,09Hz), 7,82 (1H, d, J= 7,66Hz), 7,86 (1H, d, J= 5,47Hz), 8,35 (3H,s, br), 8,69(1H, t, J = 6,57Hz), 8,76 (1H, d, J= 8,21 Hz).
- 117
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,38 (3H, s), 2,62 (1H, d, J = 10,3 Hz), 2,70 (1H, dd, J = 14,3 Hz, 4,2 Hz), 2,82 (1H, dd, J = 13,5 Hz, 10,1 Hz), 3,07 (1H, dd, J = 13,6 Hz, 4,5 Hz), 3,95 (2H, q, J = 7,0 Hz), 3,98 (2H, d, J = 4,8 Hz), 4,26 -4,37 (2H, m), 4,52 -4,62 (2H, m), 6,75 (2H, d, J = 8,7 Hz), 7,07 (2H, d, J = 8,6 Hz), 7,18 -7,12 (1H, m), 7,23 7,28 (6H, m), 7,38 (2H, d, J = 8,1 Hz), 8,21 (1H, d, J = 8,3 Hz), 8,26 (2H, br,s), 8,62 (2H, d, J = 7,6 Hz), 9,01 (1H, s)
- 118
- d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,64 -2,67 (2H, m), 2,81 (1H, dd, J = 13,5 Hz, 10,1 Hz), 3,04 (1H, dd, J = 13,5, 4,6 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,97 (2H, d, J = 5,4 Hz), 4,30 (2H, dd, J = 5,5 Hz, 3,5 Hz), 4,54 -4,63 (2H, m), 6,60 (1H, dd, J = 3,5 Hz, 1,9 Hz), 6,7 (2H, d, J =8,6 Hz), 7,01 (2H, d, J = 8,6 Hz), 7,11 (1H, d, J = 3,5 Hz), 7,16 7,28 (7H, m), 7,38 (2H, d, J = 8,1 Hz), 7,81 (1H, d, J = 1,1 Hz), 8,18 (1H, d, J = 8,4 Hz), 8,28 (2H, br,s), 8,60 (1H, d, J = 8,6 Hz), 8,64 (1H, t, J = 6,0 Hz).
- 119
- d6-DMSO δ: 1,28 (3H, t, J = 6,9 Hz), 2,22 (3H, s), 2,65 (1H, dd, J = 13,6 Hz, 9,3 Hz), 2,72 (1H, dd, J = 13,8 Hz, 4,2 Hz), 2,82 (1H, dd, J = 13,5 Hz, 10,2 Hz), 3,08 (1H, dd, J = 13,5 Hz, 4,5 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 (2H, br,s), 4,31 (2H, d, J = 5,8 Hz), 4,52 4,59 (2H, m), 6,73 (2H, d, J = 8,6 Hz), 6,91 (1H, d, J = 5,0 Hz), 6,98 (2H, d, J = 8,6 Hz), 7,18 -7,21 (1H, m), 7,23 -7,30 (6H, m), 7,38 (2H, d, J = 7,9 Hz), 7,55 (1H, d, J = 5,0 Hz), 7,72 (1H, d, J = 7,8 Hz), 8,23 (2H, br,s), 8,62 (2H, d, J = 9,6 Hz).
- 120
- d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,70-2,75(1H,m), 2,80-2,86(2H,m), 3,07-3,11(1H,m), 3,88(3H,s), 3,92(2H,q,J= 6,9Hz), 3,97(2H,q,J= 5,7Hz), 4,31(2H,d,J= 6,1Hz), 4,524,58(1H,m), 4,67-4,72(1H,m), 6,65(2H,d,J= 8,6Hz), 6,76(2H,d,J= 8,4Hz), 7,027,04(1H,m), 7,21-7,34(7H,m), 7,37(2H,d,J= 8,1Hz), 7,53-7,55(1H,m), 7,857,88(1H,m), 8,23(2H,s), 8,27(1H,d,J= 8,1Hz), 8,67(1H,t,J= 5,9Hz), 8,71(1H,d,J= 8,4Hz).
- 121
- d6-DMSO δ: 1,28(3H,t,J= 6,9Hz), 2,66-2,75(2H,m), 2,80-2,86(1H,m), 3,03-3,08(1H,m), 3,87(3H,s), 3,91-4,00(4H,m), 4,30-4,38(2H,m), 4,59-4,68(2H,m), 6,77(2H,d,J= 8,6Hz), 7,16(1H,s), 7,18-7,21(2H,m), 7,23-7,27(6H,m), 7,38(2H,d,J= 8,2Hz), 7,70(1H,t,J= 4,2Hz), 8,24(2H,s), 8,44(1H,d,J= 2,9Hz), 8,51(1H,d,J= 1,6Hz), 8,628,64(2H,m), 8,79(1H,d,J=8,4Hz).
- 122
- d6-DMSO δ: 1,29(3H,t,J= 7,0Hz), 2,56-2,62(1H,m), 2,73-2,84(2H,m), 3,07-3,11(1H,m), 3,89(3H,s), 3,94(2H,q,J= 7,0Hz), 3,98(2H,s), 4,30(2H,d,J= 6,0Hz), 4,494,55(1H,m), 4,65-4,70(1H,m), 6,67(4H,s), 7,11(1H,d,J= 5,4Hz), 7,20-7,25(3H,m), 7,29-7,35(4H,m), 7,37(2H,d,J= 8,1Hz), 7,47(1H,d,J= 7,4Hz), 7,72(1H,d,J= 5,5Hz), 8,18(2H,s), 8,63(1H,t,J=6,0Hz), 8,67(1H,d,J= 8,5Hz).
- 123
- d6-DMSO δ: 1,28(3H,t,J= 7,0Hz), 2,58-2,70(2H,m), 2,79-2,85(1H,m), 3,03-3,08(1H,m), 3,87(3H,s), 3,93(2H,q,J= 7,0Hz), 3,99(2H,q,J= 5,5Hz), 4,26-4,38(2H,m), 4,594,65(2H,m), 6,76(2H,d,J= 8,6Hz), 7,08(1H,s), 7,15(2H,d,J= 8,3Hz), 7,187,27(8H,m), 7,36(2H,d,J=8,0Hz), 8,19(2H,s), 8,25(1H,d,J= 5,2Hz), 8,598,62(2H,m), 8,72(1H,d,J= 8,1Hz).
- 124
- d6-DMSO δ: 1,28(3H, t, J= 6,84Hz), 2,13 (3H, s), 2,56-2,59 (1H, m), 2,69-2,74 (1H, m), 2,782,84 (1H, m), 3,05-3,10 (1H,m), 3,91-4,00 (4H, m), 4,30 (2H, d, J = 5,82Hz), 4,524,64 (2H,m), 5,91 (1H, s) 6,71 (2H, d, J= 8,66Hz), 6,77 (1H, t, J= 2,36Hz), 6,92 (2H, d, J= 7,78Hz), 7,18-7,28 (8H, m), 7,34 (2H, d, J = 8,49Hz), 8,09 (3H,s, br), 8,60-8,64(2H, m).
- 125
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,67 -2,69 (2H, m), 2,82 (1H, dd, J = 13,5 Hz, 10,0 Hz), 3,05 (1H, dd, J = 13,6 Hz, 6,4 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,97 (2H, d, J = 5,6 Hz), 4,31 (2H, d, J = 5,8 Hz), 4,47 -4,57 (2H, m), 6,57 (1H, d, J = 5,4 Hz), 6,71 (2H, d, J = 8,6 Hz), 6,97 (2H, d, J = 8,6 Hz), 7,18 -7,27 (10H m), 7,38 (2H, d, J = 6,0 Hz), 7,40 (1H, d, J = 3,1 Hz), 8,28 (2H, br,s), 8,51 (1H, d, J = 8,5 Hz), 8,61 (1H, t, J = 6,0 Hz).
- 126
- d6-DMSO δ: 0,80-0,85(2H,m), 1,02-1,12(4H,m), 1,22-1,32(1H,m), 1,41-1,48(1H,m), 1,531,62(5H,m), 2,76-2,82(1H,m), 3,09-3,13(1H,m), 3,95(2H,s), 4,28-4,35(2H,m), 4,374,43(1H,m), 4,46-4,52(1H,m), 7,15-7,27(7H,m), 7,34-7,37(2H,m), 7,39-7,46(2H,m), 7,48-7,54(1H,m), 7,80-7,83(2H,m), 8,21(2H,s), 8,51(2H,d,J= 7,8Hz), 8,59(1H,t,J= 6,1 Hz).
- 127
- d6-DMSO δ: 2,62-2,69 (2H, m), 2,71-2,77 (1H, m), 2,96-3,01(1H, m), 3,87 (2H, d, J= 4,56Hz), 4,22-4,25 (2H, m), 4,49-4,61 (2H,m), 7,10-7,22 (10H, m), 7,30-7,36 (4H, m), 7,407,48 (1H, m), 7,67 (2H, d, J = 6,61Hz), 8,30 (3H,s, br), 8,47 (1H, d, J= 8,82Hz), 8,56-8,62 (2H, m).
- 128
- d6-DMSO δ: 2,70 (2H, d, J = 7,21Hz), 2,78-2,85 (1H, m), 3,03-3,07 (1H, m), 3,95 (2H, d, J= 8,78Hz), 4,27-4,36 (2H, m), 4,55-4,63 (2H,m), 6,84 (2H, d, J=8,52Hz), 7,05-7,29 (12H, m), 7,37-7,44 (6H, m), 7,74 (2H, d, J= 7,52Hz), 8,34 (3H,s, br), 8,50 (1H, d, J= 7,57Hz), 8,58 (1H, d, J=8,77Hz), 8,63-8,66 (2H, m).
- 129
- d6-DMSO δ: 2,61-2,63 (2H, m), 2,70-2,77 (1H, m), 2,95-3,00 (1H, m), 3,88 (2H, d, J= 6,26Hz), 4,18-4,29 (2H, m), 4,47-4,54 (2H,m), 4,91 (1H, s), 6,76 (2H, d, J= 8,18Hz), 7,07-7,18 (9H, m), 7,26-7,36 (4H, m), 7,66-7,68 (2H, m), 8,24 (3H,s, br), 8,42 (1H, d, J= 8,17Hz), 8,50 (1H, d, J= 8,02Hz), 8,53-8,58 (1H, m).
- 130
- d6-DMSO δ: 2,65 (2H, d, J = 5,97Hz), 2,79-2,85 (1H, m), 3,03-3,06 (1H, m), 3,95 (2H, s), 4,31 (2H, s), 4,55 (2H, s, br), 6,58 (2H, d, J= 7,55Hz), 7,01 (2H, d, J= 7,12Hz), 7,18-7,24 (10H, m), 7,37-7,50 (7H, m), 7,74 (2H, d, J= 7,10Hz), 8,32 (3H,s, br), 8,46 (1H, d, J= 9,60Hz), 8,53 (1H, d, J= 9,60Hz), 8,61 (1H, s),
- 131
- d6-DMSO δ: 1,43 (3H, t, J= 6,97Hz), 2,88 (2H, d, J= 6,67Hz), 2,95-3,06 (2H, m), 3,14-3,23 (2H, m), 4,06-4,12 (2H, m), 4,39-4,49 (2H, m), 4,75-4,78 (2H, m), 6,91 (2H, d, J= 8,95Hz), 7,31 (2H, m), 7,37-7,46 (9H, m), 7,54-7,67 (5H, m), 7,89-7,98 (2H, m), 8,46 (2H, s, br), 8,65-8,81 (3H, m).
- 132
- d6-DMSO δ: 2,68 (2H, d, J = 7,36Hz), 2,79-2,98 (1H, m), 3,03-3,06 (1H, m), 3,96 (2H, s), 4,21-4,32 (2H, m), 4,59-4,61 (2H,m), 5,00 (2H, s), 6,84 (2H, d, J= 8,15Hz), 7,147,24 (12H, m), 7,35-7,40 (5H, m), 7,67-7,76 (2H, m), 7,82-7,88 (2H, m), 8,24(1H,s, br), 8,47-8,64 (4H, m).
- 133
- d6-DMSO δ: 0,81(3H,d,J= 6,3Hz), 0,87(3H,d,J= 6,3Hz), 1,27-1,39(2H,m), 1,45-1,52(1H,m), 2,81-2,87(1H,m), 3,20-3,24(1H,m), 4,02(2H,s), 4,35-4,44(3H,m), 4,52-4,58(1H,m), 7,22-7,35(7H,m), 7,43(2H,d,J= 8,1Hz), 7,48-7,52(2H,m), 7,58-7,64(1H,m), 7,877,89(2H,m), 8,30(2H,s), 8,59-8,69(3H,m).
- 134
- d6-DMSO δ: 2,70 (2H, d, J = 7,36Hz), 2,78-2,84 (1H, m), 3,03-3,06 (1H, m), 3,97 (2H, s), 4,11-4,34 (2H, m), 4,59-4,63 (2H,m), 5:14 (2H, s), 6,90 (2H, d, J= 8,21Hz), 7,117,30 (11H, m), 7,36-7,54 (5H, m), 7,67-7,75 (2H, m), 7,80-7,88 (2H, m), 8,47-8,58 (4H, m).
- 135
- d6-DMSO δ: 2,20 (3H, s), 2,71 (2H, d, J = 7,81Hz), 2,79-2,85 (1H, m), 3,03-3,07(1H,m), 3,933,96 (2H, m), 4,25-4,36 (2H, m), 4,55-4,65 (2H,m), 7,00 (2H, d, J= 9,01Hz), 7,12 (2H, d, J=7,78Hz), 7,18 (2H, d, J= 7,79Hz), 7,22-7,24 (4H, m), 7,38 (2H, d, J= 6,49Hz), 7,42 (2H, d, J= 7,79Hz), 7,48-7,50 (1H, m), 7,74-7,76 (2H,m), 8,33 (3H,s, br), 8,51 (1H, d, J= 7,79Hz), 8,58 (1H, d, J= 7,79Hz), 8,62-8,65 (1H, m).
- 136
- d6-DMSO δ: 2,70 (2H, d, J = 7,28Hz), 2,74-2,85 (1H, m), 3,04-3,08 (1H, m), 3,95 (2H, s), 4,274,36 (2H, m), 4,58-4,62 (2H,m), 5,03 (2H, s), 6,85 (2H, d, J= 8,21Hz), 7,15-7,24 (11H, m), 7,37-7,52 (5H, m), 7,56-7,61 (1H, m), 7,75 (2H, d, J = 8,22Hz), 8,34 (3H, s, br), 8,50(1H, d, J= 7,02Hz), 8,58(1H, d, J= 9,38Hz), 8,62-8,65 (1H, m).
- 137
- d6-DMSO δ: 2,66-2,69 (2H, m), 2,81 (1H, dd, J = 13,5, 10,0Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,69 (2H, s), 3,77 (3H, s), 4,23-4,33 (2H, m), 4,58-4,67 (2H, m), 6,68 (1H, d, J = 8,5Hz), 7,07-7,25 (11H, m), 7,43 (2H, t, J = 7,3Hz), 7,49-7,55 (2H, m), 7,75 (2H, d, J = 7,2Hz), 8,00 (1H, d, J = 1,8Hz),8,49-8,57 (3H, m).
- 138
- d6-DMSO δ: 2,69-2,71 (1H, m), 2,79-2,85 (1H, m), 3,03-3,07(1H,m), 3,67 (3H, s), 3,96 (2H, s), 4,26-4,32 (2H, m), 4,55-4,63 (2H,m), 6,76 (2H, d, J= 8,52Hz), 7,14-7,25 (9H, m), 7,36-7,44 (4H, m), 7,48-7,52 (1H,m), 7,74-7,76 (2H,m), 8,29 (3H,s, br), 8,56 (1H, d, J= 1,68Hz), 8,613-8,64 (2H, m).
- 139
- d6-DMSO δ: 2,82-2,85 (3H, m), 3,03-3,08 (1H,m), 3,93-3,98 (2H, m), 4,26-4,31 (2H, m), 4,564,69 (2H,m), 7,11-7,26 (12H, m), 7,37-7,43 (4H, m), 7,48-7,51 (1H,m), 7,73-7,75 (2H,m), 8,32 (3H,s, br), 8,53-8,65 (2H, m).
- 140
- d6-DMSO δ: 1,09 (3H, t, J = 7,0Hz), 2,50-2,66 (2H, m), 3,05 (1H, dd, J = 13,4, 10,4Hz), 3,263,32 (1H, m), 3,45-3,54 (2H, m), 3,74 (2H, q, J = 7,0Hz), 4,09-4,15 (2H, m), 4,334,38 (1H, m), 4,65-4,71 (1H, m), 6,57 (2H, d, J = 8,6Hz), 7,00 (2H, d, J = 8,5Hz), 7,09 (2H, d, J = 8,0Hz), 7,16-7,35 (5H, m), 7,53-7,58 (4H, m), 7,95-8,20 (3H, br m), 8,48-8,56 (3H, m), 8,64 (1H, d, J = 8,5Hz).
- 141
- d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,65-2,84(3H,m), 3,03-3,08(1H,m), 3,92(2H,q,J= 7,0Hz), 3,96(2H,s), 4,27-4,35(2H,m), 4,57-4,63(2H,m), 6,75(2H,d,J= 8,7Hz), 7,16(2H,d,J= 8,6Hz), 7,23(1H,dd,J= 8,3,1,7Hz), 7,27(2H,d,J= 8,1Hz), 7,37-7,51(6H,m), 7,55(1H,d,J=1,8Hz), 7,73-7,75(2H,m), 8,24(2H,s), 8,50(1H,d,J= 8,1Hz), 8,67-8,71 (2H,m).
- 142
- d6-DMSO δ: 1,26(3H,t,J= 6,9Hz), 2,67-2,83(3H,m), 3,01-3,05(1H,m), 3,89-3,95(4H,m), 4,274,35(2H,m), 4,53-4,63(2H,m), 6,75(2H,d,J= 8,5Hz), 7,14(2H,d,J= 8,5Hz), 7,207,26(5H,m), 7,37-7,44(4H,m), 7,50(1H,t,J= 7,3Hz), 7,66-7,72(1H,m), 7,75(2H,d,J=7,4Hz), 8,31(2H,s), 8,53(1H,d,J= 8,1Hz), 8,62(1H,d,J= 8,7Hz), 8,69(1H,t,J= 5,9Hz).
- 143
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,70 (2H, d, J= 7,52Hz), 2,89-2,95 (1H, m), 3,12-3,17 (1H, m), 3,89-3,94 (2H, m), 3,95 (2H, s), 4,31 (2H, d, , J= 5,38Hz), 4,56-4,66 (2H,m), 6,74 (2H, d, J= 8,52Hz), 7,12 (2H, d, J= 6,93Hz), 7,26 (2H, d, J= 9,72Hz), 7,38-7,44 (5H, m), 7,50-7,54 (3H, m), 7,75 (2H, d, J = 8,31Hz), 8,34 (3H, s, br), 8,51 (1H, d, J= 8,32Hz), 8,62 (1H, d, J= 8,32Hz), 8,68-8,71 (1H, m).
- 144
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,65 (2H, d, J= 6,98Hz), 2,89-2,95 (1H, m), 3,16-3,21 (1H, m), 3,91-3,96 (2H, m), 4,32 (2H, J= 5,82Hz), 4,57-4,66 (2H, m), 6,73 (2H, d, J= 8,54Hz), 7,13 (2H, d, J= 9,08Hz), 7,27 (2H, d, J= 8,01Hz), 7,39-7,44 (8H, m), 7,507,57 (1H, m), 7,68-7,71 (1H, m), 7,73-7,75 (2H, m), 8,44-8,50 (4H, m), 8,72-8,76 (2H, m).
- 145
- d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,64 (2H, d, J = 7,2Hz), 2,82 (1H, dd, J = 13,5, 10,3Hz), 3,07 (1H, dd, J = 13,6, 4,2Hz), 3,81 (2H, s), 3,92 (2H, q, J = 7,0Hz), 4,26-4,35 (2H, m), 4,55-4,65 (2H, m), 5,70-6,60 (2H, br s), 6,75 (2H, d, J = 8,6Hz), 7,14-7,34 (7H, m), 7,39-7,51 (3H, m), 7,62 (1H, d, J = 7,7Hz), 7,73 (2H, d, J = 7,2Hz), 8,39 (1H, dd, J = 4,8, 1,4Hz), 8,46 (1H, d, J = 1,6Hz), 8,52 (1H, d, J = 8,0Hz), 8,62 (1H, t, J = 6,0Hz), 8,68 (1H, d, J = 8,8Hz).
- 146
- d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,69-2,77(3H,m), 2,94-2,99(1H,m), 3,65(3H,s), 3,92(2H,q,J=7,0Hz), 3,96(2H,s), 4,25-4,35(2H,m), 4,49-4,54(1H,m), 4,57-4,63(1H,m), 6,75(4H,dd,J=8,6,1,7Hz), 7,13-7,18(4H,m), 7,25(2H,d,J= 8,1Hz), 7,36(2H,d,J= 8,1Hz), 7,40-7,44(2H,m),7,48-7,52(1H,m), 7,72-7,75(2H,m), 8,19(2H,s), 8,488,53(2H,m), 8,62(1H,t,J= 6,0Hz).
- 147
- d6-DMSO δ: 1,26 (3H, t, J = 7,0 Hz), 2,69 (2H, d, J = 7,2 Hz), 2,83 (1H, dd J = 13,6, 10,0 Hz), 3,06 (1H, dd, J = 13,7,4,5 Hz), 3,87 (2H,s), 3,92 (2H, q, J = 7,0 Hz), 4,26-4,31(2H, m), 4,55-4,60 (1H, m), 4,62-4,67 (1H, m), 6,51-6,79 (1H, m), 6,75 (2H, d, J = 8,6Hz), 7,13-7,19 (3H, m), 7,20-7,22 (4H, m), 7,31 (1H, d, J = 8,1Hz), 7,40-7,44 (3H, m), 7,45-7,52 (1H, m), 7,71-7,75 (2H, m), 8,36-8,39 (2H, m), 8,50-8,61 (3H, m).
- 148
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,70 (2H, d, J= 7,09Hz), 2,89-2,95 (1H, m), 3,12-3,17 (1H, m), 3,89-3,94 (2H, m), 3,95 (2H, s), 4,31-4,32 (2H, m), 4,56-4,66 (2H,m), 6,74 (2H, d, J=7,19Hz), 7,12 (2H, d, J= 8,40Hz), 7,26 (2H, d, J= 8,40Hz), 7,38-7,44 (5H, m), 7,50-7,54 (3H, m), 7,74-7,76 (2H, m), 8,35 (3H, s, br), 8,51 (1H, d, J= 7,2Hz), 8,62 (1H, d, J= 8,40Hz), 8,68-8,71 (1H, m).
- 149
- d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,67-2,69 (2H, m), 2,81-2,87 (1H, m), 3,06-3,10 (1H,m), 3,59 (2H, s, br), 3,89-3,98 (4H, m), 4,22-4,33 (2H, m), 4,57-4,62 (2H,m), 6,74 (2H, d, J= 8,52Hz), 7,13-7,16 (7H, m), 7,22-7,27 (2H,m), 7,35-7,41 (3H,m), 7,43-7,51 (1H, m), 7,72-7,81 (2H,m), 8,29-8,32 (1H,m), 8,48-8,53 (1H, m), 8,54-8,64 (1H, m).
- 150
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,80 -2,87 (2H, m), 3,07 (1H, dd, J = 14,7, 9,4 Hz), 3,27 (2H, dd, J = 14,8, 4,3 Hz), 3,32 (2H, br,s), 3,69 (1H, s), 3,94 (2H, q, J = 6,9 Hz), 4,27 -4,30 (2H, m), 4,53 -4,58 (1H, m), 4,60 -4,66 (1H, m), 6,78 (2H, d, J = 8,6 Hz), 6,86 -6,90 (2H, m), 7,12 -7,24 (6H, m), 7,31 (1H, d, J = 5,0 Hz), 7,42 (2H, t, J = 7,4 Hz), 7,50 (1H, q, J =7,3 Hz), 7,73 (2H, d, J = 7,1 Hz), 8,51 (1H, t, J = 5,5 Hz), 8,57 (2H, m).
- 151
- d6-DMSO δ: 1,28 (3H, t, J = 6,9 Hz), 2,77 (2H, br,s), 2,89 (1H, dd, J = 14,1, 9,8 Hz), 3,07 (1H, dd, J = 14,1, 4,4 Hz), 3,33 (3H, br,s), 3,65 (1H, br,s), 3,94 (2H, q, J = 6,9 Hz), 4,28 (2H, t, J =5,8 Hz), 4,52 -4,58 (1H, m), 4,60 -4,65 (1H, m), 6,78 (2H, d, J = 8,5 Hz), 6,98 (1H, d, J = 4,6 Hz), 7,15 (3H, br,s), 7,18 -7,23 (4H, m), 7,38 -7,41 (1H, m), 7,44 (2H, d, J = 7,6 Hz), 7,51 (1H, t, J = 7,2 Hz), 7,75 (2H, d, J = 7,2 Hz), 8,50 (1H, br,s), 8,57 (2H, d, J = 6,2 Hz).
- 152
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,67 (1H, t, J = 1,6 Hz), 2,77 (1H, d, J = 7,3 Hz), 3,06 (1H, dd, J = 14,5 Hz, 9,7 Hz), 3,23 (1H, dd, J = 14,6 Hz, 4,7 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,96 -3,99 (2H, m), 4,31 (2H, t, J = 5,7 Hz), 4,58 (1H, q, J = 7,5 Hz), 4,70 (1H, td, J = 9,1 Hz, 4,6 Hz), 6,77 (2H, d, J = 8,6 Hz), 7,16 (2H, d, J = 8,6 Hz), 7,23 (2H, d, J = 8,1 Hz), 7,26 (1H, d, J = 1,5 Hz), 7,33 (2H, d, J = 8,2 Hz), 7,43 (2H, t, J = 7,5 Hz), 7,52 (1H, t, J = 7,4 Hz), 7,42 (2H, d, J = 7,1 Hz), 8,05 (2H, br,s), 8,55 (2H, d, J = 7,6 Hz), 8,59 (1H, d, J = 8,6 Hz), 8,95 (1H, d, J = 1,8 Hz).
- 153
- d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,66 -2,72 (3H, m), 3,10 (1H, dd, J = 14,4 Hz, 9,8 Hz), 3,91 (2H, q, J = 7,0 Hz), 3,98 (2H, d, J = 5,2 Hz), 4,33 (2H, qd, J = 14,5 Hz, 6,0 Hz), 4,61 (1H, td, J = 8,7 Hz, 4,9 Hz), 4,72 (1H, td, J = 9,1 Hz, 4,7 Hz), 6,71 (2H, d, J = 8,6 Hz), 7,12 (2H, d, J = 8,6 Hz), 7,26 (2H, d, J = 8,2 Hz), 7,35 (3H, d, J = 7,7 Hz), 7,38 -7,40 (2H, m), 7,42 (2H, d, J = 7,8 Hz), 7,49 (1H, d, J = 7,4 Hz), 7,73 (2H, d, J = 7,2 Hz), 7,97 (2H, d, J = 8,0 Hz), 8,06 (2H, br,s), 8,45 (1H, d, J = 7,8 Hz), 8,66 -8,72 (2H, m).
- 154
- d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,70(2H,d,J= 7,3Hz), 2,79-2,85(1H,m), 3,03-3,08(1H,m), 3,94(2H,q,J= 7,0Hz), 4,00(2H,s), 4,27-4,39(2H,m), 4,54-4,62(2H,m), 6,75(2H,d,J= 8,6Hz), 7,07-7,25(9H,m), 7,41-7,52(4H,m), 7,70-7,74(2H,m), 8,26(2H,s), 8,49(1H,d,J= 8,1Hz), 8,58(1H,d,J= 8,6Hz), 8,66(1H,t,J=6,0Hz).
- 155
- d6-DMSO δ: 1,26(3H,t,J= 6,9Hz), 2,72(2H,d,J= 7,2Hz), 2,80-2,86(1H,m), 3,03-3,08(1H,m), 3,92(2H,q,J= 6,9Hz), 4,06(2H,s), 4,26-4,37(2H,m), 4,53-4,62(2H,m), 6,74(2H,d,J= 8,5Hz), 7,13(2H,d,J= 8,5Hz), 7,15-7,23(6H,m), 7,38-7,43(3H,m), 7,48-7,53(2H,m), 7,75(2H,d,J=7,3Hz), 8,49(2H,s), 8,52(1H,d,J= 8,2Hz), 8,59(1H,d,J= 8,5Hz), 8,71 (1H,t,J= 5,9Hz).
- 156
- d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,70(2H,d,J= 7,2Hz), 2,79-2,85(1H,m), 3,03-3,07(1H,m), 3,92(2H,q,J= 7,0Hz), 4,11(2H,s), 4,33-4,46(2H,m), 4,54-4,62(2H,m), 6,74(2H,d,J= 8,6Hz), 7,12(2H,d,J= 8,6Hz), 7,16-7,25(7H,m), 7,39-7,43(2H,m), 7,47-7,56(2H,m), 7,67-7,74(4H,m), 8,48(1H,d,J= 8,0Hz), 8,59(1H,d,J= 8,5Hz), 8,75(1H,t,J= 6,0Hz).
- 157
- d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,81-2,86(1H,m), 2,93-2,97(1H,m), 3,06-3,12(1H,m), 3,243,29(1H,m), 3,90-3,99(4H,m), 4,30(2H,d,J= 5,8Hz), 4,50-4,56(2H,m), 4,784,83(2H,m), 6,69(2H,d,J= 8,6Hz), 6,86(2H,d,J= 8,6Hz), 6,91-6,94(2H,m), 7,23(2H,d,J= 8,1Hz), 7,35-7,38(3H,m), 7,60-7,63(1H,m), 7,96-8,00(2H,m), 8,20(2H,s), 8,56(1H,d,J= 8,3Hz), 8,63(1H,d,J= 4,8Hz), 8,67(1 H,d,J= 6,0Hz), 8,74(1H,d,J= 8,3Hz).
- 158
- d6-DMSO δ: 1,28 (3H, t, J = 6,9 Hz), 2,74 (2H, d, J = 7,2 Hz), 3,02 (2H, dd, J = 13,9 Hz, 9,4 Hz), 3,18 (1H, d, J = 13,9 Hz, 4,6 Hz), 3,66 (1H, s), 3,80 (3H, s), 3,93 (2H, q, J = 6,9 Hz), 4,27 (2H, d, J = 6,0 Hz), 4,52 (1H, q, J = 7,4 Hz), 4,73 -4,79 (1H, m), 6,74 (2H, d, J = 8,6 Hz), 6,96 (2H, d, J = 8,8 Hz), 7,09 (2H, d, J = 8,2 Hz), 7,13 (2H, d, J =8,6 Hz), 7,17 -7,21 (3H, m), 7,34 (1H, d, J = 7,8 Hz), 7,63 (1H, td, J = 7,6 Hz, 1,7 Hz), 7,7 (2H, d, J = 8,8 Hz), 8:36 (1H, d, J = 4,0 Hz), 8,41 (2H, d, J = 6,6 Hz), 8,60(1H,d,J=8,4Hz).
- 159
- d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,68-2,74(1H,m), 2,82-2,88(2H,m), 3,05-3,10(1H,m), 3,90(2H,q,J=7,0Hz), 4,06(2H,q,J= 5,7Hz), 4,31(2H,d,J= 5,9Hz), 4,50-4,55(1H,m), 4,76-4,81(1H,m), 6,59-6,65(4H,m), 7,19-7,23(2H,m), 7,28(2H,t,J= 7,4Hz), 7,33(2H,d,J= 7,2Hz), 7,37(1H,d,J= 1,0Hz), 7,50(1H,d,J= 8,0Hz), 7,59-7,63(1H,m), 7,98-8,02(2H,m), 8,38(2H,s), 8,51(1H,d,J= 8,2Hz), 8,61(1H,d,J= 4,7Hz), 8,718,74(2H,m).
- 160
- d6-DMSO δ: 1,28 (3H, t, J = 7,66Hz), 2,70 (2H, d, J = 7,60Hz), 2,94-3,00 (1H, m), 3,21-3,24 (1H, m), 3,80 (3H, s), 3,92-4,00 (4H, m), 4,33 (2H, d, J= 6,69Hz), 4,52 (1H, q, J = 7,45Hz), 4,66-4,69 (2H, m), 6,75 (2H, d, J = 7,79Hz), 6,96 (2H, d, J = 8,68Hz), 7,17 (2H, d, J = 8,45Hz), 7,27 (2H, d, J = 7,82Hz), 7,38 (2H, d, J = 7,82Hz), 7,67 (1H, s, br), 7,74 (1H, d, J = 9,03Hz), 8,11 (1H, s, br), 8,22 (2H, s, br), 8,45 (1H, d, J = 8,34Hz), 8,68-8,69 (4H, m).
- 161
- d6-DMSO δ: 1,28 (3H, t, J= 6,94Hz), 2,62-2,84 (3H, m), 2,96-3,07 (1H, m), 3,90-4,02 (4H, m), 4,32 (2H, d, J= 5,8Hz), 4,60-4,67 (2H, m), 6,77(2H, d, J = 8,88Hz), 7,16 -7,22 (1H, m), 7,26 (2H, d, J= 8,32Hz), 7,29-7,35(5H, m), 7,36 (2H, d, J= 8,32Hz), 7,64 (1H, d, J= 6,53Hz), 8,08 (3H,s, br), 8,58-8,71(3H, m), 8,82 (1H, d, J= 7,71Hz).
- 162
- d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,61 (2H, dd, J = 14,0 Hz, 4,3 Hz), 2,86 (1H, dd, J = 13,7 Hz, 10,3 Hz), 3,10 (1H, dd, J = 13,7 Hz, 4,5 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,98 -4,00 (2H, m), 4,3 (2H, d, J = 5,8 Hz), 4,56 (1H, td, J = 9,0 Hz, 5,0 Hz), 4,66 (1H, td, J = 9,0 Hz, 4,8 Hz), 6,75 (2H, d, J = 8,6 Hz), 7,12 (1H, dd J = 4,9, 3,7 Hz), 7,16 (2H, d, J = 8,6 Hz), 7,26 (2H, d, J = 8,3 Hz), 7,36 (3H, d, J = 8,1 Hz), 7,72 (1H, dd, J = 5,0 Hz, 0,7 Hz), 7,76 (1H, br,s), 7,81 (1H, d, J = 3,2 Hz), 8,07 (2H, br,s), 8,47 -8,55 (3H, m), 8,64 (2H, t, J = 9,0 Hz).
- 163
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,67 -2,75 (2H, m), 3,03 (2H, dd, J = 13,8 Hz, 9,5 Hz), 3,21 (2H, dd, J = 14,0 Hz, 4,7 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,99 (2H, q, J = 5,8 Hz), 4,20 -4,40 (3H, m), 4,53 -4,58 (1H, m), 4,77 -4,83 (1H, m), 6,75 (2H, d, J = 8,6 Hz), 7,14 (2H, d, J = 8,6 Hz), 7,23 (2H, d, J = 8,1Hz), 7,34 (2H, d, J = 8,2 Hz), 7,52 (2H, d, J =8,6 Hz), 7,76 (2H, d, J = 8,6 Hz), 8,07 (2H, br,s), 8,44 (1H, d, J = 4,5 Hz), 8,53 (1H, br,s), 8,66 (2H, d, J = 7,6 Hz).
- 164
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,34 (3H, s), 2,74 (2H, d, J = 8,2 Hz), 3,05 (1H, dd, J = 13,9, 9,5 Hz), 3,23 (1H, dd, J = 14,0, 4,7 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,99 (2H, q, J = 5,8 Hz), 4,26 -4,36 (2H, m), 4,54 (1H, dd, J = 14,5, 7,7 Hz), 4,79 (1H, td, J = 8,9 Hz, 4,8 Hz), 6,75 (2H, d, J = 8,6 Hz), 7,13 (2H, d, J = 8,6 Hz), 7,24 (4H, d, J = 8,0 Hz), 7,30 (1H, br,s), 7,34 (3H, d, J = 8,0 Hz), 7,66 (2H, d, J = 8,1 Hz), 7,76 (1H, br,s), 8,09 (2H, br,s), 8,45 (2H, t, J = 6,0 Hz), 8,54 (1H, t, J = 6,0 Hz), 8,64 (1H, d, J = 8,3 Hz).
- 165
- d6-DMSO δ: 1,28(3H,t,J= 6,9Hz), 2,71-2,92(3H,m), 3,06-3,10(1H,m), 3,92(2H,q,J= 6,9Hz), 3,96-4,01 (2H,m), 4,31(2H,d,J= 5,8Hz), 4,53-4,59(1H,m), 4,75-4,80(1H,m), 6,576,72(4H,m), 7,27(2H,d,J= 8,0Hz), 7,30-7,33(1H,m), 7,37(2H,d,J= 8,0Hz), 7,55(1H,d,J= 8,2Hz), 7,59-7,63(1H,m), 7,64(1H,s), 7,98-8,01(2H,m), 8,13(2H,s), 8,47(1H,d,J= 8,2Hz), 8,62(1H,d,J=4,7Hz), 8,65-8,67(1H,m), 8,77(1H,d,J= 8,2Hz).
- 166
- d6-DMSO δ: 0,85 (3H, t, J = 7,6 Hz), 1,30 (3H, t, J = 7,0 Hz), 2,02 (2H, q, J = 7,6 Hz), 2,63 2,68 (1H, m), 2,99 (2H, dd, J = 14,0 Hz, 9,6 Hz), 3,20 (1H, dd, J = 13,9, 4,8 Hz), 3,95 (2H, q, J = 7,0 Hz), 4,00 (2H, q, J = 6,0 Hz), 4,28 (2H, t, J = 7,2 Hz), 4,32 -4,35 (1H, m), 4,74 (1H, td, J = 8,9 Hz, 4,8 Hz), 6,73 (2H, d, J = 8,6 Hz), 7,00 (2H, d, J = 8,6 Hz), 7,23 (2H, d, J = 8,1 Hz), 7,29 (2H, d, J = 7,24 Hz), 7,36 (2H, d, J = 8,12 Hz), 7,74 (1H, br,s), 7,97 (1H, d, J = 5,2 Hz), 8,08 (2H, br,s), 8,51 (3H, d, J = 4,2 Hz).
- 167
- d6-DMSO δ: 1,27(3H,t,J= 6,9Hz), 2,65-2,89(3H,m), 3,05-3,10(1H,m), 3,93(2H,q,J= 6,9Hz), 4,00(2H,q,J= 5,4Hz), 4,27-4,40(2H,m), 4,58-4,70(2H,m), 6,76(2H,d,J= 8,5Hz), 7,08(1H,s), 7,11(1H,d,J= 2,8Hz), 7,16-7,29(7H,m), 7,51(1H,t,J= 8,0Hz), 7,95(2H,s), 8,47(2H,s), 8,72-8,78(2H,m), 8,87(2H,s), 9,19(1H,d,J= 7,7Hz).
- 168
- d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,69-2,74(1H,m), 2,82-2,93(2H,m), 3,05-3,10(1H,m), 3,90(2H,q,J=7,0Hz), 4,01(2H,q,J= 5,7Hz), 4,32(2H,d,J= 6,0Hz), 4,51-4,56(1H,m), 4,76-4,79(1H,m), 6,60-6,67(3H,m), 7,06-7,09(2H,m), 7,18-7,22(2H,m), 7,28(2H,t,J= 7,4Hz), 7,33(2H,d,J=3,8Hz), 7,46(1H,t,J= 7,8Hz), 7,59-7,63(1H,m), 7,96-7,99(2H,m), 8,31(2H,s), 8,50(1H,d,J=8,2Hz), 8,60-8,62(1H,m), 8,71-8,74(2H,m).
- 169
- d6-DMSO δ: 1,26-1,30(3H,m), 2,60-2,84(3H,m), 3,03-3,07(1H,m), 3,93(2H,q,J= 7,0Hz), 4,00(2H,q,J= 5,4Hz), 4,32(2H,d,J= 5,8Hz), 4,56-4,66(2H,m), 6,76(2H,d,J= 8,6Hz), 7,11-7,13(1H,m), 7,16(2H,d,J= 8,5Hz), 7,23(1H,dd,J= 8,3,1,8Hz), 7,28(2H,d,J= 8,0Hz), 7,38(2H,d,J= 8,0Hz), 7,48(1H,d,J= 8,2Hz) 7,55(1H,d,J=1,7Hz), 7,73(1H,dd,J= 5,0,0,7Hz), 7,81(1H,d,J= 3,2Hz), 8,17(2H,s), 8,53(1H,d,J= 8,3Hz), 8,63-8,66(2H,m).
- 170
- d6-DMSO δ: 0,84 (3H, t, J = 7,6 Hz), 1,30 (3H, t, J = 7,0 Hz), 2,00 (2H, q, J = 7,6 Hz), 2,43 2,47 (1H, m), 2,61 (1H, dd, J = 13,7 Hz, 4,8 Hz), 2,94 (1H, dd, J = 13,6 Hz, 10,2 Hz), 3,20 (1H, dd, J = 13,8 Hz, 4,4 Hz), 3,97 (2H, q, J = 7,0 Hz), 3,99 (2H, q, J = 5,5 Hz), 4,30 (2H, d, J = 5,6 Hz), 4,35 (1H, td, J = 8,4, 5,2 Hz), 4,62 (1H, td, J = 9,3, 4,6 Hz), 6,73 (2H, d, J = 8,6 Hz), 7,02 (2H, d, J = 8,6 Hz), 7,26 (2H, d, J = 8,0 Hz), 7,40 (2H, d, J = 8,1 Hz), 7,71 (1H, br,s), 8,00 (1H, d, J = 7,6 Hz), 8,12 (1H, d, J = 6,4 Hz), 8,27 (2H, br,s), 8,58 (1H, d, J =8,4 Hz), 8,65 (1H, br,s), 8,66 (2H, br,s).
- 171
- d6-DMSO δ: 1,28(3H,t,J= 7,0Hz), 2,62-2,68(1H,m), 2,75-2,85(2H,m), 3,03-3,08(1H,m), 3,94(2H,q,J=7,0Hz), 3,97-4,02(2H,m), 4,28-4,38(2H,m), 4,63-4,67(2H,m), 6,77(2H,d,J= 8,6Hz), 7,17(2H,d,J= 8,5Hz), 7,22-7,25(1H,m), 7,28(2H,d,J= 8,1Hz), 7,38(2H,d,J= 8,0Hz), 7,50(1H,d,J= 8,2Hz), 7,55(1H,d,J= 1,4Hz)), 7,65(2H,d,J= 5,8Hz), 7,71-7,78(1H,m), 8,12(2H,s), 8,62-8,73(3H,m), 8,81(1H,d,J= 8,4Hz).
- 173
- d6-DMSO δ: 1,28 (3H, t, J = 6,82Hz), 2,61-2,71 (2H, m), 2,85-2,91 (1H, m), 3,02-3,14 (1H, m), 3,93-4,01 (4H, m), 4,32-4,34 (2H, m), 4,56-4,69 (2H, m), 6,76 (2H, d, J = 8,67Hz), 7,16 (2H, d, J = 8,67Hz), 7,26 (2H, d, J = 8,67Hz), 7,36 (2H, d, J = 7,51Hz), 7,40-7,47 (1H, m), 7,51 (2H, d, J = 8,48Hz), 7,56 (1H, d, J = 7,51Hz), 7,76 (2H, d, J = 8,09Hz), 8,12 (2H, s, br), 8,48-8,58 (2H, m), 8,62-8,68(3H, m).
- 174
- d6-DMSO δ: 1,28(3H, t, J= 7,05Hz), 2,65-2,71 (1H, m), 2,79-2,82 (1H, m), 3,04-3,07 (1H, m), 3,28-3,31 (1H,m), 3,91-3,99 (4H, m), 4,31 (2H, s), 4,58-4,60 (1H,m), 4,74-4,75 (1H,m), 6,75 (2H, d, J= 8,13Hz), 7,14 (2H, d, J= 9,73Hz), 7,27 (2H, d, J= 8,41Hz), 7,41 (2H, d, J = 8,41Hz), 7,85-7,88 (1H, m),8,34-8,42 (4H, m), 8,72-8,83 (5H, m), 9,08 (1H, d, J= 8,41Hz).
- 175
- d6-DMSO δ: 1,29 (3H, t, J = 6,75 Hz), 2,61-2,64 (1H, m), 2,78-2,83 (1H, m), 2,87-2,93 (1H, m), 3,14-3,19 (1H, m), 3,92-4,00 (4H, m), 4,32 (2H, d, J = 5,78Hz), 4,60-4,65 (2H, m), 6,71 (2H, d, J = 8,18 Hz), 6,87 (2H, d J = 8,56 Hz), 7,14 (1H, d, J = 5,45 Hz), 7,26 (2H, d, J =8,56 Hz), 7,37 (2H, d, J = 7,78 Hz), 7,49-7,52 (1H, m), 7,83-7,90 (2H, m), 8,10 (3H, s, br), 8,54 (1H, d, J = 4,69Hz), 8,60 -8,66 (2H, m), 8,77 (1H, d, J = 8,63 Hz).
- 176
- d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,66 -2,77 (2H, m), 2,98 (1H, dd, J = 14,5 Hz, 9,6 Hz), 3,19 (1H, dd, J = 14,5 Hz, 4,6 Hz), 3,91 (2H, q, J = 7,0 Hz), 3,98 (2H, q, J = 5,7 Hz), 4,32 (2H, d, J = 5,9 Hz), 4,62 (2H, qd, J = 9,3 Hz, 4,6 Hz), 6,69 (2H, d, J = 8,6 Hz), 6,99 (1H, t, J =6,9 Hz), 7,08 (3H, d, J = 8,7 Hz), 7,16 (1H, d, J = 2,1 Hz), 7,26 (2H, d, J = 8,0 Hz), 7,33 (3H, dd, J = 8,0 Hz, 6,1 Hz), 7,42 (2H, t, J = 7,5 Hz), 7,51 (1H, t, J = 7,4 Hz), 7,66 (1H, d, J = 7,8 Hz), 7,73 (2H, d, J = 7,2 Hz), 8,06 (2H, br,s), 8,39 (1H, d, J = 7,8 Hz), 8,52 (1H, d, J = 6,5 Hz), 8,61 (1H, t, J = 4,9 Hz), 10,82 (1H, br,s).
- 177
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,32 -2,34 (1H, m), 2,66 (2H, t, J = 1,7 Hz), 2,85 (1H, d, J =7,44 Hz), 2,91 -3,03 (1H, m), 3,17 (1H, dd, J = 15,2 Hz, 5,0 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 -4,00 (1H, br,m), 4,20 (1H, d, J = 6,2 Hz), 4,55 (1H, q, J = 7,4 Hz), 4,62 -4,68 (1H, m), 6,78 (2H, d, J = 8,5 Hz), 7,19 (2H, d, J = 8,5 Hz), 7,28 (2H, d, J = 8,4 Hz), 7,34-7,38 (2H, m), 7,44 (2H, q, J = 8,0 Hz), 7,51 -7,56 (1H, m), 7,72 7,78 (2H, m), 8,08 (2H, br,s), 8,52 (1H, t, J = 6,6 Hz), 8,59 -8,66 (2H, m), 8,97 (1H, br,s), 14,02 (1H, br,s), 14,18 (1H, br,s).
- 178
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,66 (1H, d, J = 11,0 Hz), 2,73 (1H, dd, J = 13,5, 3,6 Hz), 3,10 (1H, dd, J = 14,4, 9,8 Hz), 3,29 (1H, d, J = 4,9 Hz), 3,66 (2H, s), 3,92 (2H, q, J = 7,0 Hz), 4,30 (2H, qd, J = 15,2, 5,7 Hz), 4,66 (1H, td, J = 9,1, 4,4 Hz), 4,75 (1H, td, J = 9,0, 5,0 Hz), 6,73 (2H, d, J = 8,6 Hz), 7,14 (5H, dd, J = 8,3, 5,1 Hz), 7,22 (2H, d, J = 8,1 Hz), 7,35 -7,44 (4H, m), 7,61 (2H, dd, J = 4,5, 1,5 Hz), 7,97 (2H, t, J = 9,4 Hz), 8,62 (1H, br, s), 8,67 (2H, dd, J = 4,5, 1,5 Hz), 8,71 (1H, br,s), 8,80 (1H, br,s).
- 179
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,02 (3H, s), 2,68 -2,74 (2H, m), 2,83 (1H, dd, J = 13,6, 10,0 Hz), 3,05 (1H, dd, J = 13,5, 4,6 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,98 (2H, d, J = 5,8 Hz), 4,32 (2H, qd, J = 15,3, 6,0 Hz), 4,55-4,64 (2H, m), 6,73 (2H, d, J = 8,5 Hz), 7,06 (2H, d, J = 8,5 Hz), 7,19-7,27 (7H, m), 7,38 (2H, d, J = 8,1 Hz), 7,69 (1H, d, J = 5,4 Hz), 7,85 (1H, d, J =5,4 Hz), 8,11 (1H, d, J = 8,1 Hz), 8,22 (2H, br,s), 8,58 (1H, d, J = 8,5 Hz), 8,65 (1H, t, J =5,7 Hz), 10,70 (1H, s)
- 180
- d6-DMSO δ: 1,27 (3H, t, J= 7,09Hz), 2,72-2,74 (2H, m), 2,84-2,90 (1H, m), 3,09-3,16 (1H,m), 3,59 (2H, s, br), 3,91-3,98 (4H, m), 4,29-4,33 (2H, m), 4,57-4,67 (2H,m), 6,76 (2H, d, J= 8,79Hz), 7,01-7,16 (7H, m), 7,22-7,27 (2H,m), 7,35-7,41 (3H,m), 7,43-7,51 (1H, m), 7,76 (2H, d, J = 7,19Hz), 8,37 (3H, s, br), 8,57 (1H, d, J = 7,97Hz), 8,648,69 (1H, m).
- 181
- d6-DMSO δ: 1,30 (3H, t, J = 7,21 Hz), 2,22 (3H, s), 2,56-2,78 (2H, m), 2,96-3,08 (1H, m), 3,233,28 (1H, m), 3,95-4,00 (4H, m), 4,32 (2H, d, J = 5,60Hz), 4,49-4,54 (1H, m), 4,664,72 (1H, m), 6,76 (2H, d, J = 8,32 Hz), 6,91 (1H, d J = 5,14 Hz), 7,05 (2H, d, J = 8,69Hz), 7,27 (2H, d, J = 7,90 Hz), 7,39 (2H, d, J = 8,30 Hz), 7,56 (1H, d, J = 5,14Hz), 7,72 (1H, s, br), 7,88 (1H, d, J = 7,61?Hz), 8,16 (1H, d, J = 7,61Hz), 8,27 (3H, s, br), 8,67 -8,74 (3H, m).
- 182
- d6-DMSO δ: 1,28(3H,t,J= 7,0Hz), 2,29(3H,s), 2,69(2H,d,J= 7,2Hz), 2,80-2,86(1H,m), 3,043,09(1H,m), 3,91-3,97(4H,m), 4,24-4,34(2H,m), 4,56-4,63(2H,m), 6,76(2H,d,J=8,7Hz), 7,08-7,31(10H,m), 7,41-7,45(2H,m), 7,50-7,53(1H,m), 7,747,76(2H,m), 8,15(2H,s), 8,48(1H,d,J= 8,0Hz), 8,57-8,61(2H,m).
- 183
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,76 (2H, d, J = 5,8 Hz), 3,06 (2H, dd, J = 14,5, 9,5 Hz), 3,22 (1H, dd, J = 14,5, 4,5 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 (1H, d, J = 5,7 Hz), 4,29 (2H, d, J = 6,0 Hz), 4,44 -4,50 (1H, m), 4,65 (1H, td, J = 8,8, 4,9 Hz), 6,33 (2H, br,s), 6,55 (1H, d, J = 5,3 Hz), 6,74 (2H, d, J = 8,6 Hz), 7,04 (2H, d, J = 8,5 Hz), 7,22 (2H, d, J = 8,0 Hz), 7,27 (1H, d, J = 1,4 Hz), 7,29 (1H, s), 7,34 (2H, d, J = 8,0 Hz), 7,39 (1H, d, J = 5,4 Hz), 8,07 (2H, br,s), 8,52 (1H, s), 8,53 (1H, s), 8,97 (1H, d, J = 1,8 Hz).
- 184
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 1,35 (1H, s), 1,89 (3H, s), 2,72 (1H, dd, J = 14,7, 7,9 Hz), 2,86 (1H, dd, J = 13,7, 4,7 Hz), 3,05 (1H, dd, J = 14,4, 9,8 Hz), 3,24 (1H, dd, J = 14,7, 4,6 Hz), 3,67 (2H, s), 3,94 (2H, q, J = 7,0 Hz), 4,25 (2H, d, J = 5,2 Hz), 4,654,70 (2H, m), 6,72 (2H, d, J = 8,6 Hz), 6,88 (2H, d, J = 8,7 Hz), 7,11 (2H, d, J = 7,9 Hz), 7,14 (1H, d, J = 5,2 Hz), 7,22 (2H, d, J = 7,8 Hz), 7,34 (1H, d, J = 1,7 Hz), 7,85 (1H, d, J = 5,2 Hz), 7,89 (2H, d, J = 7,5 Hz), 8,51 (1H, t, J = 6,0 Hz), 8,68 (1H, d, J = 8,6 Hz), 9,04 (1H, d, J = 1,9 Hz).
- 185
- d6-DMSO δ:1,28(3H,t,J= 6,9Hz), 2,34(3H,s), 2,77(2H,d,J= 7,3Hz), 3,05(1H,dd,J=14,6,9,6Hz), 3,22(1H,dd,J=14,6,4,7Hz), 3,93(2H,q,J=7,0Hz), 3,97(2H,m), 4,3(2H,dd,J=5,0,4,9Hz), 4,56(1H,dd,J=14,8,7,6), 4,66-4,71(1H,m), 6,76(2H,d,J= 8,7Hz), 7,15(2H,d,J=8,6Hz), 7,22-7,26(4H,m), 7,34(2H,d,J=8,2Hz), 7,66(2H,d,J=8,2Hz), 8,08(3H,br s), 8,47(1H,d,J=7,8Hz), 8,54(1H,d,J=6,0), 8,58(1H,d,J= 8,3Hz), 8,95(1H,d,J=2,0Hz).
- 186
- d6-DMSO δ: 1,26 (3H, t, J = 7,0 Hz), 2,12 (3H, s), 2,26-2,67 (1H, m), 2,74 (1H, dd, J = 13,7, 4,7 Hz), 3,09 (1H, dd, J = 14,5, 10,1 Hz), 3,35 (1H, d, J = 5,6 Hz), 3,65 (2H, s), 3,89 (2H, q, J =7,0 Hz), 4,27 (2H, d, J = 6,0 Hz), 4,64 (2H, dd, J = 7,5, 4,7 Hz), 5,90 (1H, br,s), 6,59 (2H, d, J = 8,6 Hz), 6,76 (1H, t, J = 2,5 Hz), 6,86 (2H, d, J = 8,5 Hz), 7,13 (2H, d, J = 7,3 Hz), 7,20 (2H, d, J = 8,1 Hz), 7,24 (1H, br,s), 7,36-7,45 (3H, m), 7,97 (2H, d, J = 8,2 Hz), 8,64 (1H, br,s), 8,68 (1H, d, J = 7,2 Hz), 11,12 (1H, br,s).
- 187
- d6-DMSO δ: 1,29 (3H, t, J = 7,0 Hz), 2,14 (3H, s), 2,66 (1H, dd, J = 13,1, 9,0 Hz), 2,78 (1H, dd, J =13,7, 4,5 Hz), 2,86 (1H, dd, J = 14,2, 10,0 Hz), 3,07 (1H, dd, J = 14,2, 4,4 Hz), 3,66 (2H, s), 3,95 (2H, q, J = 7,0 Hz), 4,26 (2H, d, J = 4,6 Hz), 4,51 (1H, td, J = 9,0, 4,8 Hz), 4,61-4,67 (1H, m), 5,91 (1H, s), 6,75 (2H, d, J = 8,6 Hz), 6,77 (1H, d, J = 2,7 Hz), 7,02 (3H, d, J =8,5 Hz), 7,12 (2H, d, J = 7,6 Hz), 7,15 (2H, br,s), 7,21 (2H, d, J = 8,3 Hz), 7,29 (1H, d, J = 7,4 Hz), 7,42 (1H, dd, J = 4,8, 2,9 Hz), 8,32 (1H, s), 8,49 (1H, br,s), 8,57 (1H, d, J = 7,0 Hz), 11,11 (1H, s)
- 188
- d6-DMSO δ: 1,26 (3H, t, J = 7,0 Hz), 2,01 (3H, s), 2,08 (1H, s), 2,66-2,72 (1H, m), 2,76-2,80 (1H, m), 3,12 (1H, dd, J = 14,4, 9,6), 3,67 (1H, s), 3,90 (2H, q, J = 7,0 Hz), 4,10 (1H, dd, J =17,3, 6,1 Hz), 4,28-4,31 (2H, m), 4,35 (1H, dd, J = 13,5, 6,8 Hz), 4,59 (1H, br,s), 4,71-4,76 (1H, m), 6,66 (2H, d, J = 8,6 Hz), 7,02 (2H, d, J = 8,5 Hz), 7,14 (3H, d, J = 7,6 Hz), 7,22 (1H, d, J = 8,2 Hz), 7,31-7,42 (4H, m), 7,67 (1H, d, J = 5,2 Hz), 7,84 (1H, d, J = 5,4 Hz), 7,97 (2H, dd, J = 12,2, 8,0 Hz), 8,05 (br,s, 1H), 8,60 (2H, br,d, J = 7,1 Hz), 10,66 (1H, br,s).
- 189
- d6-DMSO δ: 1,28 (3H, t, J = 6,70Hz), 2,33 (3H, s), 2,69 (2H, d, J = 7,51Hz), 2,91-2,99 (1H, m), 3,13-3,18 (1H, m), 3,92-4,00 (4H, m), 4,33 (2H, d, J = 5,94Hz), 4,52-4,61 (1H, m), 4,63-4,69 (1H, m), 6,76 (2H, d, J = 8,67Hz), 7,15 (2H, d, J = 7,86Hz), 7,27 (2H, d, J = 8,096Hz), 7,31 (2H, d, J= 6,36Hz), 7,36 (2H, d, J = 7,51Hz), 7,47-7,53 (1H, m), 7,56 (1H, d, J = 7,51Hz), 7,87 (1H, d, J = 7,341Hz), 8,11 (3H, s, br), 8,45 (1H, d, J = 7,86Hz), 8,53 (2H, d, J =4,72Hz), 8,57-8,65(2H, m).
- 190
- d6-DMSO δ: 1,31 (3H, t, J = 6,88Hz), 2,08 (3H, s), 2,70-2,71 (1H, m), 2,74-2,75 (1H, m), 2,882,94 (1H, m), 3,13-3,18 (1H, m), 3,90-4,01 (4H, m), 4,33 (2H, d, J = 6,21?Hz), 4,574,62 (1H, m), 4,66-4,71 (1H, m), 6,80 (2H, d, J = 8,06Hz), 7,09-7,11 (5H, m), 7,147,31 (2H, m), 7,36 (2H, d, J = 8,056Hz), 7,45-7,48 (1H, m), 7,84 (1H, d, J = 7,051Hz), 8,11 (3H, s, br), 8,34 (1H, d, J = 8,06Hz), 8,52-8,53(1H, m), 8,56 (1H, d, J = 5,021Hz), 8,63-8,65(2H, m).
- 191
- d6-DMSO δ: 1,29 (3H, t, J= 6,84Hz), 2,07 (3H, s), 2,14 (3H, s), 2,53-2,59 (1H, m), 2,69-2,74 (1H, m), 2,77-2,83 (1H, m), 3,05-3,09 (1H,m), 3,91-4,01 (4H, m), 4,30 (2H, d, J = 5,98Hz), 4,51-4,65 (2H, m), 5,63 (1H, d, J = 1,50Hz) 6,71 (2H, d, J= 8,88Hz), 6,90 (2H, t, J= 8,88Hz), 7,04 (1H, d, J= 8,17Hz), 7,18-7,28 (8H, m), 7,34 (2H, d, J = 7,35Hz), 8,10 (2H, s, br), 8,57-8,64(2H, m).
- 192
- d6-DMSO δ: 1,28 (3H, t, J= 6,82Hz), 2,30 (3H,s), 2,71-2,74 (2H, m), 2,80-2,86(1H,m), 3,043,09(1H,m), 3,91-3,95 (4H,m), 4,25-4,30 (2H,m), 4,54-4,59(1H,m), 4,69-4,74 (1H,m), 6,76 (2H, d, J= 7,887Hz), 7,08-7,31(10H, m), 7,41-7,45(2H,m), 7,50-7,53(1H,m), 7,74-7,76(2H,m), 8,31-8,39 (3H, m), 8,63(1H, d, J= 7,88Hz), 8,75-8,78 (3H,m).
- 193
- d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,01 (3H, s), 2,32-2,34 (1H, m), 2,67 (1H, t, J = 1,7 Hz), 2,76-2,78 (2H, m), 2,88 (2H, dd, J = 14,1, 9,6 Hz), 3,04 (2H, dd, J = 14,2, 4,6 Hz), 3,67 (1H, s), 3,93 (2H, q, J = 7,0 Hz), 4,28 (2H, t, J = 6,4 Hz), 4,56-4,62 (2H, m), 6,75 (2H, d, J = 8,6 Hz), 6,99 (1H, d, J = 5,8 Hz), 7,12 (3H, t, J = 8,3Hz), 7,15 (1H, d, J = 3,5 Hz), 7,22 (2H, d, J =8,0 Hz), 7,39 (1H, dd, J = 4,8, 3,0 Hz), 7,69 (1H, d, J = 5,4 Hz), 7,85 (1H, d, J = 5,4 Hz), 8,15 (1H, d, J = 8,3 Hz), 8,50 (2H, t, J = 8,0 Hz), 10,69 (1H, br,s).
- 194
- d6-DMSO (DMSO) δ: 1,27 (3H, t, J = 7,0 Hz), 7,00 (2H, d, J = 7,0 Hz), 3,10 (2H, dd, J = 14,5, 10,0 Hz), 3,90 (2H, q, J= 7,0 Hz), 4,00 (2H, q, J = 5,5 Hz), 4,33 (2H, d, J = 6,1 Hz), 4,52 (1H, q, J = 6,6 Hz), 4,67 (1H, td, J = 9,6 Hz, 4,1 Hz), 6,35 (1H, br,s), 6,56 (1H, d, J = 5,4 Hz), 6,61 (2H, d, J = 8,6 Hz), 6,91 (2H, d, J = 8,6 Hz), 7,14 (1H, d, J = 7,7 Hz), 7,26 (2H, d, J = 7,5 Hz), 7,36 (2H, d, J = 8,1 Hz), 7,38 (2H, d, J = 5,3 Hz), 7,467,41 (3H, m), 7,98 (2H, d, J = 8,8 Hz), 8,06 (2H, br,s), 8,60 (1H, d, J = 8,12 Hz), 8,70 (1H, br,s).
- 195
- d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,76 (2H, d, J = 5,8 Hz), 3,06 (2H, dd, J = 14,5, 9,5 Hz), 3,22 (1H, dd, J = 14,5, 4,5 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 (1H, d, J = 5,7 Hz), 4,29 (2H, d, J = 6,0 Hz), 4,44 -4,50 (1H, m), 4,65 (1H, td, J = 8,8, 4,9 Hz), 6,33 (2H, br,s), 6,55 (1H, d, J = 5,3 Hz), 6,74 (2H, d, J = 8,6 Hz), 7,04 (2H, d, J = 8,5 Hz), 7,22 (2H, d, J = 8,0 Hz), 7,27 (1H, d, J = 1,4 Hz), 7,29 (1H, s), 7,34 (2H, d, J = 8,0 Hz), 7,39 (1H, d, J = 5,4 Hz), 8,07 (2H, br,s), 8,52 (1H, s), 8,53 (1H, s), 8,97 (1H,d,J=1,8Hz).
- 196
- d6-DMSO δ: 1,29(3H, t, J= 6,91 Hz), 2,42-2,46 (1H, m), 2,76-3,00 (3H, m), 3,05 (3H, s), 3,273,31 (1H,m), 3,93-4,00 (4H, m), 4,29 (2H, d, J = 6,28Hz), 4,89-4,99 (1H, m), 5,345,38 (1H, m), 6,67 (2H, d, J= 8,78Hz), 6,74 (2H, d, J= 8,21Hz), 6,98-7,01 (1H, m), 7,14 (1H, d, J= 5,67Hz), 7,19-7,38 (7H, m), 7,86 (1H, d, J= 5,67Hz), 7,88 (1H, d, J= 7,09Hz), 8,09 (3H,s, br), 8,41-8,48 (1H, m).
- 197
- d6-DMSO δ: 1,28 (3H, t, J= 7,15Hz), 2,72-2,74 (2H, m), 3,92-3,99 (4H, m), 4,36 (2H, d, J = 6,40Hz), 4,47-4,50 (1 H, m), 4,67-4,73 (1H, m), 5,22 (1H, s, br), 5,83 (1H, s, br), 6,76 (2H, d, J=8,51Hz), 7,17-7,30 (6H, m), 7,37-7,45 (5H, m), 7,52-7,53 (1H, m), 8,30 (4H,s, br), 8,38-8,44 (2H, m), 8,60 (1H, d, J = 7,64Hz).
- 198
- d6-DMSO δ: 1,28(3H, t, J= 6,70Hz), 2,61-2,64 (1H, m), 2,79-2,83 (1H, m), , 3,91-4,00 (4H, m), 4,34-4,36 (2H, m), 4,45-4,48 (1H, m), 4,82-4,85 (1H, m), 5,26-5,28 (1H, m), 5,855,86 (1H, m), 6,54 (1H,s, br), 6,65 (2H, d, J= 8,21Hz), 6,71 (2H, d, J= 8,213Hz), 7,13 (1H, d, J=5,47Hz), 7,23-7,36 (4H, m), 7,49 (2H, d, J = 7,11Hz), 7,82-7,86 (3H, m), 8,07 (3H,s, br), 8,36(1H, t, J = 5,81Hz), 8,53 (1H, d, J= 8,92Hz).
EJEMPLO 199
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metilbenzamida
Tabla 9
- Nº de ejemplo
- Solubilidad en tampón PO4 (µ/ml)
- 3
- 10
- 38
- 14,55
- 54
- 0,8
- 55
- 1,5
- 56
- 0,9
- 58
- 4,1
- 59
- 7,7
- 70
- 11,53
- 71
- 22,1
- 72
- 6,9
- 73
- 5,1
- 75
- 1,06
- 79
- 2,4
- 81
- 1,3
- 84
- 0,5
- 88
- 0,2
- 92
- 0,2
- 93
- 0,01
- 95
- 2,05
- 99
- 2,88
- 116
- 1,39
- 119
- 1,61
- 124
- 64,45
- 125
- 43,60
- 131
- 0,56
- 140
- 79,63
- 141
- 0,15
- 143
- 2,86
- 145
- 68,91
- 150
- 0,12
- 151
- 4,31
- 152
- 122,19
- 153
- 0,19
- 154
- 3,14
- 155
- 0,44
- 157
- 4,77
- 158
- 70,56
- 159
- 1,15
- 160
- 20,4
- 162
- 69,69
- 173
- 2,38
- 174
- 232,69
- 175
- 23,4
- 176
- 2,28
- 178
- 1,54
- 179
- 17,72
- 181
- 61,65
- 199
- 15,88
- 200
- 0,22
Métodos biológicos
La capacidad de los compuestos de fórmula (I) para inhibir la calicreína plasmática puede determinarse utilizando el siguiente ensayo biológico: Determinación de la CI50 para la calicreína plasmática
La actividad inhibidora de calicreína plasmática in vitro se determinó utilizando métodos convencionales publicados (véase, por ejemplo, Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Se incubó calicreína plasmática humana (Protogen) a 37°C con el sustrato fluorogénico H-DPro-Phe-Arg-AFC y diversas concentraciones del compuesto de ensayo. La actividad enzimática residual (velocidad de reacción inicial) se determinó midiendo el cambio en la absorbancia óptica a 410 nm y se determinó el valor de CI50 para el compuesto de ensayo.
Los datos obtenidos a partir de este ensayo se muestran en las siguientes Tablas 10 y 11:
Tabla 10
- Nº de ejemplo
- CI50 (PKal humana) µM Nº de ejemplo CI50 (PKal humana) µM Nº de ejemplo CI50 (PKal humana) µM
- 1
- 0,089 24 0,45 47 2,1
- 2
- 0,82 25 0,34 48 4,7
- 3
- 0,022 26 0,081 49 2,2
- 4
- 0,23 27 1,3 50 4,3
- 5
- 0,46 28 8,9 51 1,0
- 6
- 1,0 29 0,30 52 0,86
- 7
- 0,074 30 0,58 53 0,65
- 8
- 0,74 31 4,3 54 0,083
- 9
- 2,0 32 0,20 55 0,031
- 10
- 7,2 33 1,1 56 0,50
- 11
- 1,7 34 1,4 57 10
- 12
- 0,29 35 2,0 58 0,17
- 13
- 10 36 8,2 59 0,078
- 14
- 0,40 37 0,91 60 10
- 15
- 0,47 38 0,047 61 0,22
- 16
- 0,053 39 0,31 62 10
- 17
- 5,8 40 1,8 63 0,052
- 18
- 8,8 41 1,3 64 3,4
- 19
- 10 42 0,53 65 10
- 20
- 0,73 43 1,3 66 10
- 21
- 5,1 44 0,18 67 1,6
- 22
- 10 45 0,79
- 23
- 0,031 46 1,2
Tabla 11
- Nº de ejemplo
- CI50 (PKal humana) (µM)
- 68
- 0,861
- 69
- 0,621
- 70
- 0,126
- 71
- 0,077
- 72
- 0,046
- 73
- 0,025
- 74
- 0,545
- 75
- 0,270
- 76
- 0,452
- 77
- 1,959
- 78
- 10,000
- 79
- 0,038
- 80
- 0,398
- 81
- 0,040
- 82
- 0,539
- 83
- 0,254
- 84
- 0,219
- 85
- 0,485
- 86
- 0,423
- 87
- 0,755
- 88
- 0,090
- 89
- 0,099
- 90
- 0,276
- 91
- 2,083
- 92
- 0,032
- 93
- 0,175
- 94
- 1,080
- 95
- 0,046
- 96
- 0,764
- 97
- 0,241
- 98
- 0,576
- 99
- 0,095
- 100
- 0,474
- 101
- 1,113
- 102
- 10,000
- 103
- 10,000
- 104
- 0,159
- 105
- 0,185
- 106
- 0,256
- 107
- 0,133
- 108
- 0,232
- 109
- 0,155
- 110
- 0,598
- 111
- 0,058
- 112
- 0,298
- 113
- 0,455
- 114
- 0,427
- 115
- 0,417
- 116
- 0,018
- 117
- 0,048
- 118
- 0,061
- 119
- 0,015
- 120
- 0,540
- 121
- 0,310
- 122
- 0,519
- 123
- 0,214
- 124
- 0,020
- 125
- 0,010
- 126
- 4,013
- 127
- 0,521
- 128
- 2,009
- 129
- 10,000
- 130
- 2,491
- 131
- 0,040
- 132
- 1,209
- 133
- 10,000
- 134
- 10,000
- 135
- 0,424
- 136
- 1,017
- 137
- 7,540
- 138
- 0,310
- 139
- 1,141
- 140
- 0,045
- 141
- 0,055
- 142
- 0,096
- 143
- 0,083
- 144
- 0,340
- 145
- 0,025
- 146
- 0,232
- 147
- 0,284
- 148
- 0,934
- 149
- 0,091
- 150
- 0,051
- 101
- >10
- 102
- 9,0
- 103
- >10
- 104
- >10
- 105
- >10
- 106
- 8,4
- 107
- 7,5
- 108
- >10
- 109
- >10
- 110
- >10
- 111
- >10
- 112
- >10
- 113
- >10
- 114
- >10
- 115
- 9,0
- 116
- 6,3
- 117
- 6,1
- 118
- >10
- 119
- 6,1
- 120
- >10
- 121
- >10
- 122
- 4,8
- 123
- >10
- 124
- 8,4
- 125
- 7,0
- 126
- >10
- 127
- >10
- 128
- >10
- 129
- >10
- 130
- >10
- 131
- 9,5
- 132
- >10
- 133
- >10
- 134
- >10
- 135
- >10
- 136
- >10
- 137
- >10
- 138
- >10
- 139
- >10
- 140
- >10
- 141
- >10
- 142
- >10
- 143
- >10
- 144
- >10
- 145
- >10
- 146
- >10
- 147
- >10
- 148
- >10
- 149
- >10
- 150
- >10
- 151
- >10
- 152
- >10
- 153
- >10
- 154
- >10
- 155
- >10
- 156
- >10
- 157
- >10
- 158
- >10
- 159
- >10
- 160
- >10
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US8598206B2 (en) * | 2010-01-28 | 2013-12-03 | The Medicines Company (Leipzig) Gmbh | Trypsin-like serine protease inhibitors, and their preparation and use |
JP2013121919A (ja) | 2010-03-25 | 2013-06-20 | Astellas Pharma Inc | 血漿カリクレイン阻害剤 |
US8921319B2 (en) | 2010-07-07 | 2014-12-30 | The Medicines Company (Leipzig) Gmbh | Serine protease inhibitors |
US9290485B2 (en) | 2010-08-04 | 2016-03-22 | Novartis Ag | N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides |
EP2697196A1 (en) | 2011-04-13 | 2014-02-19 | Activesite Pharmaceuticals, Inc. | Prodrugs of inhibitors of plasma kallikrein |
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2011
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2012
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