RESUMO
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.
Assuntos
Amidinas , Anticoagulantes , Antitrombina III , Cinamatos/química , Inibidores do Fator Xa , Sulfonamidas , Administração Oral , Amidinas/síntese química , Amidinas/química , Amidinas/farmacologia , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombina III/síntese química , Antitrombina III/química , Antitrombina III/farmacologia , Cricetinae , Cães , Humanos , Masculino , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
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.).
Assuntos
Cinamatos/síntese química , Cinamatos/farmacologia , Inibidores do Fator Xa , Animais , Coagulação Sanguínea/efeitos dos fármacos , Cricetinae , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Inibidores da Tripsina/farmacologiaRESUMO
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.
Assuntos
Ácidos Carboxílicos/química , Paládio/química , Catálise , Espectroscopia de Ressonância Magnética , Prótons , EstereoisomerismoRESUMO
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.
Assuntos
Anticoagulantes/farmacologia , Cinamatos/farmacologia , Inibidores do Fator Xa , Indóis/farmacologia , Anticoagulantes/síntese química , Cinamatos/síntese química , Cinamatos/química , Humanos , Indóis/síntese química , Indóis/química , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Químicos , Relação Estrutura-Atividade , Tripsina/metabolismoRESUMO
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.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Inibidores do Fator Xa , Indóis/síntese química , Indóis/farmacologia , Animais , Callithrix , Cricetinae , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Camundongos , Estrutura MolecularRESUMO
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.
Assuntos
Cetonas , Prótons , Catálise , Descarboxilação , Cetonas/síntese química , Cetonas/química , Estrutura Molecular , Paládio/química , Solventes/química , EstereoisomerismoRESUMO
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.
Assuntos
Inibidores do Fator Xa , Indóis/síntese química , Indóis/farmacologia , Adulto , Animais , Coagulação Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Cricetinae , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
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.