Synthesis and biological evaluation of new 2-(4,5-dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine derivatives

Frédérique Touzeau; Axelle Arrault; Gérald Guillaumet; Elizabeth Scalbert; Bruno Pfeiffer; Marie-Claire Rettori; Pierre Renard; Jean-Yves Mérour

doi:10.1021/jm021050c

Synthesis and biological evaluation of new 2-(4,5-dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine derivatives

J Med Chem. 2003 May 8;46(10):1962-79. doi: 10.1021/jm021050c.

Authors

Frédérique Touzeau¹, Axelle Arrault, Gérald Guillaumet, Elizabeth Scalbert, Bruno Pfeiffer, Marie-Claire Rettori, Pierre Renard, Jean-Yves Mérour

Affiliation

¹ Institut de Chimie Organique et Analytique, UMR-CNRS 6005, BP 6759, Université d'Orléans, 45067 Orléans Cedex 2, France.

PMID: 12723959
DOI: 10.1021/jm021050c

Abstract

2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine derivatives and tricyclic analogues with a fused additional ring on the nitrogen atom of the benzoxazine moiety have been prepared and evaluated for their cardiovascular effects as potential antihypertensive agents. The imidazoline ring was generated by reaction of the corresponding ethyl ester with ethylenediamine. Affinities for imidazoline binding sites (IBS) I(1) and I(2) and alpha(1) and alpha(2) adrenergic receptors were evaluated as well as the effects on mean arterial blood pressure (MAP) and heart rate (HR) of spontaneously hypertensive rats. With few exceptions the most active compounds on MAP were those with high affinities for IBS and alpha(2) receptor. Among these, compound 4h was the most interesting and is now, together with its enantiomers, under complementary pharmacological evaluation.

MeSH terms

Adrenal Medulla / metabolism
Animals
Antihypertensive Agents / chemical synthesis*
Antihypertensive Agents / chemistry
Antihypertensive Agents / pharmacology
Binding Sites
Blood Pressure / drug effects
Cattle
Frontal Lobe / drug effects
Frontal Lobe / metabolism
Heart Rate / drug effects
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
Imidazoline Receptors
In Vitro Techniques
Kidney / drug effects
Kidney / metabolism
Oxazines / chemical synthesis*
Oxazines / chemistry
Oxazines / pharmacology
Rabbits
Radioligand Assay
Rats
Rats, Inbred SHR
Rats, Wistar
Receptors, Adrenergic, alpha-1 / drug effects
Receptors, Adrenergic, alpha-1 / metabolism
Receptors, Adrenergic, alpha-2 / drug effects
Receptors, Adrenergic, alpha-2 / metabolism
Receptors, Drug / drug effects
Receptors, Drug / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

6-fluoro-2-(4,5-dihydro-1H-imidazol-2-yl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine
Antihypertensive Agents
Imidazoles
Imidazoline Receptors
Oxazines
Receptors, Adrenergic, alpha-1
Receptors, Adrenergic, alpha-2
Receptors, Drug
imidazoline I1 receptors