Fluorescent Angiotensin AT₁ Receptor Antagonists
Fluorescent selective angiotensin AT₁ receptor antagonists (sartans) that contain naphthalene (6, 7, 10, and 11), anthracene (12 and 14), acenaphthene (13 and 15), and coumarin (8 and 9) substituents have been prepared and their preliminary pharmacology evaluated in Chinese hamster ovary (CHO) cell based assays. Compounds 6-15 proved to be effective sartans with pKB estimates in the range of 6.7-10.5; their potential as cellular imaging agents is also discussed.
Novel paramagnetic AT₁ receptor antagonists
Novel paramagnetic selective angiotensin AT₁ receptor antagonists (sartans) bearing nitroxides (3, 4) have been prepared and their pharmacology evaluated in vitro as well as in vivo. Compounds 3, 4 proved to be effective sartans with pKB estimates in the range 6.2-9.1. In addition, the sodium salt (11) of 4 (R = Bu) is able to protect against vascular injury in hypertensive rats as determined by its ability to attenuate the development of intimal thickening caused by balloon injury of the carotid artery.
Stereoselective Cyclopropanation of (-)-Levoglucosenone Derivatives Using Sulfonium and Sulfoxonium Ylides
The synthesis of tri- and tetrasubstituted cyclopropanes from 3-aryl-substituted levoglucosenones (LGO) has been developed. In contrast to the unstabilised ylide dimethylsulfonium methylide which gives epoxides from LGO via 1,2-addition, we have found that the soft nucleophile dimethylsulfoxonium methylide affords cyclopropanes in moderate yields from LGO and in excellent yields and stereoselectivity with 3-aryl LGO derivatives. The use of 1,1,3,3-tetramethylguanidine as base in DMSO to generate the ylide provided the best yields and shortest reaction times. Ester stabilised sulfonium ylides could also be used to generate tetrasubstituted cyclopropane derivatives. One of the products was converted into a cyclopropyl lactone via Baeyer-Villiger oxidation to demonstrate the utility of applying cyclopropanation chemistry to LGO.
N,N'-Bis(2-methoxybenzylidene) adducts of ethane-1,2-diamine, propane-1,3-diamine and butane-1,4-diamine.
We have isolated and crystallographically characterized the three homologous compounds N,N'-bis(2-methoxybenzylidene) ethane-1,2-diamine (MeSalen), C₁₈H₂₀N₂O₂, N,N'-bis-(2-methoxybenzylidene)propane-1,3-diamine (MeSalpr), C₁₉-H₂₂N₂O₂, and N,N'-bis(2-methoxybenzylidene)butane-1,4-diamine (MeSalbu), C₂₀H₂₄N₂O₂. In contrast with MeSalpr, the molecules of MeSalen and MeSalbu, which have an even number of methylene units, have crystallographic '1' symmetry. Comparing these methoxy-substituted species with their hydroxy equivalents shows that the aryl rings rotate upon removal of the O-H···N hydrogen bonds. The packing of MeSalen and MeSalpr is controlled by C-H···π interactions, whereas that of MeSalbu has only van der Waals contacts.
Tandem free-radical addition/substitution chemistry and its application to the preparation of novel AT₁ receptor antagonists
Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT1 receptor antagonist properties. While the sulfur-containing systems were prepared following existing methodology, the selenium-containing analogues required the development of novel, tandem free-radical chemistry involving addition of aryl radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All four compounds prepared proved to be excellent AT₁ receptor antagonists, with pKв estimates of 7.2-9.5.