Design, synthesis, and structure-activity Relationships of a new series of .alpha.-adrenergic agonists: spiro[(1,3-diazacycylpent-1-ent)-5,2'-(1',2',3',4'-tetrahydronaphthalene)]

Abstract

The contractions induced by a partial alpha 1-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial alpha 1-adrenoceptor agonist increases when the temperature is raised, a response that contrasts to that noted with full alpha 1- and alpha 2-adrenoceptor agonists. This observation may be of importance for the treatment of the symptoms of venous insuffiency, favored during warm summer days. A new series of full and partial alpha-adrenergic agonists was designed and synthesized, the spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)] 7a-kk or spiro-imidazolines. Using in vitro (femoral artery and saphenous vein) and in vivo (pithed rat) biological evaluations, structure-activity relationships could be defined which allowed the discovery of a full alpha 2-agonist (34b), a full alpha 1-agonist (7s), and a nonselective partial alpha 1/alpha 2-agonist (7aa) endowed with an outstanding veinotonic selectivity as compared to its effect on mean arterial pressure. The latter compound is presently undergoing extensive pharmacological and toxicological evaluations, as a clinical candidate.

Lanthanum‐Catalyzed Enantioselective Trifluoromethylation by Using an Electrophilic Hypervalent Iodine Reagent

“…Then, a broad range of cyclic β‐keto esters 1 was examined using the optimized pre‐catalyst combination and reaction conditions (Scheme ). Keto esters 1 were prepared as previously described (see Supporting Information). First, we noticed that the size of the ester group had a strong influence on the enantiocontrol.…”

“…Keto esters 1 were prepared as previously described [28][29][30] (see Supporting Information). Keto esters 1 were prepared as previously described [28][29][30] (see Supporting Information).…”

Recording of the saphenous vein compliance by an ultrasonic echo‐tracking device in the dog: effects of S 18149

“…S 18149, (5S)-spiro[(1,3-diazacyclopent-1-ene)-5:2'-(7'-methyl-1',2',3',4'-tetra-hydro-naphthalene)] fumarate, has been selected in a screening programme aimed at ®nding substances that possess partial agonist activity at a 1 -adrenoceptors (Cordi et al, 1995). S 18149 is a potent but partial agonist at both a 1 -and a 2 -adrenoceptors in vitro and in the pithed rat; the compound induces concentration-dependent constrictions in dog isolated saphenous veins at concentrations which do not contract dog isolated femoral arteries .…”

A Practical and Cost-Effective Synthesis of 6,7-Dimethoxy-2-tetralone

“…There have been several syntheses reported for this compound, the most widely employed perhaps being the reaction of 3,4-dimethoxyphenylacetyl chloride with ethylene gas in the presence of aluminum chloride as a catalyst. 6,13,14 This method suffers from difficulty in optimizing reaction parameters (e.g. ethylene gas flow), a very tedious workup, and despite numerous reactions in our laboratory where we attempted to optimize each variable, always afforded yields of less than 30%.…”

“…ethylene gas flow), a very tedious workup, and despite numerous reactions in our laboratory where we attempted to optimize each variable, always afforded yields of less than 30%. Ketone transposition [13][14][15][16] of the corresponding 1-tetralone has found limited success, but it is a multi-step synthesis that requires the preparation of the 1-tetralone starting material. Other reported methods employ silylenol ethers, 17 rhodium catalyzed cyclization of diazoketones, 18 or Pummerer rearrangement of a β-keto sulfoxide.…”