RESUMEN
To develop a novel and effective anticoagulant with potent and selective factor Xa (FXa) inhibitory activity, a new series of cinnamyl derivatives with enhanced lipophilicity and prodrug forms were synthesized and their biological activities were evaluated. As a result, we found that cinnamyl derivative (N-[4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl]-N-[(Z)-3-(3-amidinophenyl)-2-fluoro-2-propenyl]sulfamoyl)acetic acid dihydrochloride (26d, R-142086) with a fluorine atom on the double bond exhibited potent anticoagulant activity and no mutagenic potential. Moreover, orally administered R-142086 exhibited potent anti-FXa activity and anticoagulant activity in dogs.
Asunto(s)
Amidinas , Anticoagulantes , Antitrombina III , Cinamatos/química , Inhibidores del Factor Xa , Sulfonamidas , Administración Oral , Amidinas/síntesis química , Amidinas/química , Amidinas/farmacología , Animales , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/farmacología , Antitrombina III/síntesis química , Antitrombina III/química , Antitrombina III/farmacología , Cricetinae , Perros , Humanos , Masculino , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
To develop a potent and oral anticoagulant, a series of compounds with cinnamyl moiety was synthesized and their factor Xa (FXa) inhibitory activities were examined. As a result, some cinnamyl derivatives showed potent FXa inhibitory activities in vitro. Among them, compounds with substituent at the 3-position on the central benzene ring represented by (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-chlorophenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45b) and (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45j) exhibited potent FXa inhibitory activities with IC(50) values of less than 10 nM in vitro. These compounds also showed potent anticoagulant activities both in vitro and ex vivo. Furthermore, these compounds exhibited no lethal toxicity (30 mg/kg, i.v.).
Asunto(s)
Cinamatos/síntesis química , Cinamatos/farmacología , Inhibidores del Factor Xa , Animales , Coagulación Sanguínea/efectos de los fármacos , Cricetinae , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Inhibidores de Tripsina/farmacologíaRESUMEN
General homogeneous conditions for the palladium-catalyzed synthesis of carbonyl compounds with tertiary carbon stereocenters at the alpha-position are reported. The highly reactive catalyst tolerates a variety of substrate substitution and functionality, and generates enantioenriched cyclic ketones from racemic allyl beta-ketoester starting materials.
Asunto(s)
Ácidos Carboxílicos/química , Paladio/química , Catálisis , Espectroscopía de Resonancia Magnética , Protones , EstereoisomerismoRESUMEN
A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety exhibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant activities in vitro.
Asunto(s)
Anticoagulantes/farmacología , Cinamatos/farmacología , Inhibidores del Factor Xa , Indoles/farmacología , Anticoagulantes/síntesis química , Cinamatos/síntesis química , Cinamatos/química , Humanos , Indoles/síntesis química , Indoles/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Relación Estructura-Actividad , Tripsina/metabolismoRESUMEN
Factor Xa (FXa) is well known to play a pivotal role in blood coagulation, so FXa inhibitor is a promising drug candidate for prophylaxis and treatment of thromboembolic diseases. In the course of our research, we have found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) showed potent FXa inhibitory activity in vitro. However, single oral administation (RS)-1 showed high toxicity in mice. Among newly synthesized compounds, ({(RS)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((RS)-11d) showed more potent FXa inhibitory activity and higher safety than (RS)-1. The R-isoform of compound 11d ((R)-11d) exhibited potent in vitro anticoagulant activity in human and hamster plasma. Orally administered (R)-11d also showed dose-dependent potent anticoagulant activity in hamsters, marmosets and cynomolgus monkeys. Compound (R)-11d with potent anticoagulant activity and high safety is therefore favorable as a novel oral FXa inhibitor.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Inhibidores del Factor Xa , Indoles/síntesis química , Indoles/farmacología , Animales , Callithrix , Cricetinae , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Ratones , Estructura MolecularRESUMEN
We report a highly enantioselective, general catalytic system for the facile synthesis of tertiary stereocenters by protonation adjacent to cyclic ketones. The method relies on catalytic decarboxylative protonation of readily accessible racemic quaternary beta-ketoesters. A range of substituted cycloalkanone compounds can be accessed through this process with high levels of enantioselectivity.
Asunto(s)
Cetonas , Protones , Catálisis , Descarboxilación , Cetonas/síntesis química , Cetonas/química , Estructura Molecular , Paladio/química , Solventes/química , EstereoisomerismoRESUMEN
A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.
Asunto(s)
Inhibidores del Factor Xa , Indoles/síntesis química , Indoles/farmacología , Adulto , Animales , Coagulación Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química Física , Cricetinae , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Much interest has been shown in Amaryllidaceae alkaloids as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from members of the Amaryllidaceae family; most of them can be classified into eight skeletally homogeneous groups. We have succeeded in the first asymmetric total syntheses of the crinane-type alkaloids (+)-crinamine (1), (-)-haemanthidine (2), and (+)-pretazettine (3). The starting cyclohexenylamine 14 was obtained from allyl phosphonate 11c by palladium-catalyzed asymmetric amination in 82% yield and with 74% ee. The product was recrystallized from MeOH. Interestingly, (-)-14 with 99% ee was obtained from the mother liquor (74% recovery). Intramolecular carbonyl-ene reaction of (-)-10 proceeds in a highly stereoselective manner to give hexahydroindole derivative 9 as the sole product. In the Lewis-acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product, 20, was isolated in high yield. From 9, (+)-crinamine was synthesized. Thus, the asymmetric total synthesis of (+)-crinamine was achieved in 10 steps from 11c, and the overall yield is 19%. The total synthesis of (-)-haemanthidine was also achieved from 9 by a short sequence of steps.