RESUMO
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.
Assuntos
Analgésicos/farmacologia , Descoberta de Drogas , Morfinanos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Conformação Molecular , Morfinanos/síntese química , Morfinanos/química , Dor/induzido quimicamente , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor are attractive targets in the development of drugs for pain and pruritus. We previously reported the synthesis of 10α-hydroxy TRK-820 (1). In this study, we elucidated the biological properties of 1 and optimized its 6-acyl unit by modifying our synthetic route. Among the 10α-hydroxy TRK-820 derivatives prepared, 26 showed the most potent κ-opioid agonist activity (EC50=0.00466nM) and excellent selectivity and 22 was the most κ-selective agonist.
Assuntos
Analgésicos/farmacologia , Descoberta de Drogas , Morfinanos/farmacologia , Neuralgia/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Morfinanos/administração & dosagem , Morfinanos/química , Ratos , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Relação Estrutura-Atividade , Substância P/administração & dosagem , Substância P/farmacologiaRESUMO
The full details of the asymmetric epoxidation of alpha,beta-unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium-biphenyldiol catalyst, generated from Y(OiPr)3-biphenyldiol ligand-triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various alpha,beta-unsaturated esters. With this catalyst, beta-aryl alpha,beta-unsaturated esters gave high enantioselectivities and good yields (< or = 99% ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5-2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For beta-alkyl alpha,beta-unsaturated esters, an yttrium-binol catalyst, generated from Y(OiPr)3-binol ligand-triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (< or = 97% ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (-)-ragaglitazar, a potential antidiabetes agent.
Assuntos
Compostos de Epóxi/síntese química , Oxazinas/síntese química , Fenilpropionatos/síntese química , Catálise , Ésteres/química , Estereoisomerismo , ÍtrioRESUMO
Direct catalytic enantioselective cross aldol-type reaction of an acetate surrogate was developed using Cu alkoxide-chiral phosphine complexes as catalysts. Chemoselective activation and deprotonation of the donor substrate (acetonitrile) by the soft metal alkoxide in a strongly donating solvent (HMPA) are key to success in this reaction. Useful chemical yields and promising enantioselectivities are produced using either DTBM-SEGPHOS or a tuned BIPHEP as a chiral ligand. [reaction: see text]
RESUMO
We succeeded in a catalytic asymmetric epoxidation reaction of alpha,beta-unsaturated esters via a conjugate addition of an oxidant using 2-10 mol % of the yttirium-chiral biphenyldiol catalyst. A variety of substrates with beta-aryl and beta-alkyl substituents were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy esters in up to 97% yield and 99% ee.
Assuntos
Compostos de Epóxi/síntese química , Ésteres/síntese química , Compostos Organometálicos/química , Fenóis/química , Ítrio/química , Catálise , Compostos de Epóxi/química , Ésteres/química , Conformação MolecularRESUMO
[reaction: see text] A new entry in catalytic alkynylation of carbonyl compounds was developed in which dual activation of both soft nucleophiles (terminal alkynes) and hard electrophiles (aldehydes and ketones) is achieved using an indium(III) catalyst. Preliminary mechanistic studies using in situ IR and NMR spectroscopic analysis are also discussed.
RESUMO
The characteristic property of the lanthanide complex, which easily undergoes a dynamic ligand exchange and alters its structure and function in situ, is described. After the completion of the catalytic asymmetric epoxidation of various alpha,beta-unsaturated amides 2 in the presence of the Sm-(S)-BINOL-Ph3As=O (1:1:1) complex 1 (2-10 mol %), the addition of Me3SiN3 directly to the reaction mixture led to smooth epoxide-opening at room temperature, affording the corresponding anti-beta-azido-alpha-hydroxyamide 4 in excellent overall yield (up to 99%) with complete regioselectivity and excellent enantiomeric excess (up to >99%). The key to the success of the sequential process was the in situ generation of the highly reactive samarium azide complex through dynamic ligand exchange. In situ IR spectroscopy and other experiments provided strong evidence that the samarium azide complex was generated. In addition, the relatively high Lewis basicity of the amide moiety had a key role in the high reactivity of both the epoxidation and the epoxide-opening reactions. Examinations of other nucleophiles such as sulfur or carbon nucleophiles as well as transformations of epoxide-opened products are also described.