John P. Dusza

Steroid conjugates IV. The preparation of steroid sulfates with triethylamine-sulfur trioxide

A lengthy series of steroid sulfate triethylammonium salts has been prepared using triethylamine-sulfur trioxide in pyridine as the sulfating agent. In addition to the expected sulfating capacity of the reagent, selective sulfation was observed in those cases where rate factors greatly differentiated between the reaction of various hydroxyl groups. Modifications of the general reaction conditions have allowed the sulfation of hindered hydroxyl groups, and the preparation of several disulfate salts. A simple procedure for the conversion of triethylammonium salts to the corresponding ammonium salts has been outlined.

VPA-985, a nonpeptide orally active and selective vasopressin V2 receptor antagonist.

The introduction of the thiazides as orally-active diuretics about forty years ago (1), and other more effective low-ceiling diuretics thereafter, revolutionized the treatment of edema, ascites, hypertension and related diseases. Later, the addition of potent high-ceiling (loop) and potassium-sparing diuretics provided clinicians with a wide choice of diuretics to eliminate retained sodium and water (2). However, it was soon evident that many patients became refractory to these saluretic agents and some developed hyponatremia (serum sodium < 130 mEq/L) (3, 4, 5). Hyponatremia also occurs in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in patients with congestive heart failure (CHF), liver cirrhosis with ascites, renal failure, and many other disorders where the plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic (water diuretic), not a conventional diuretic, would be the drug of choice to promote the excretion of the retained body water and to normalize plasma osmolality and sodium concentration (6, 7, 8). As vasopressin (AVP, antidiuretic hormone (ADH)) acting at V2 receptors in the collecting ducts controls water re-absorption (7, 8), considerable effort has been spent over many years to develop vasopressin Vz receptor antagonists or agents that could inhibit the release of vasopressin from the posterior pituitary (8,9). Many peptide vasopressin analogs have been developed as vasopressin V2 receptor antagonists, and two of them, SK&F 101926 and SK&F 105494, showed excellent V2 antagonistic activity in many animal models, including nonhuman primates. Unfortunately, in humans, both compounds behaved as vasopressin V2 agonists (9). Recently, three nonpeptidic and orally active vasopressin receptor antagonists have been described in the literature. The first two, OPC-31260 (10), and SR 121463A (11), are V2 selective, while the third compound, YM087 (12), is a dual V1a/V2 receptor antagonist.

Steroid conjugates I. The use of sulfamic acid for the preparation of steroid sulfates

Abstract The utility of sulfamic acid for the preparation of diverse steroid sulfates has been investigated. Sulfates of the following steroids were prepared and characterized: testosterone, choleseterol, pregnenolone, dehydroisoandrosterone, estrone, 2-methyoxyestrone, ethynylestradiol and ethynylesteradiol-3-methyl ether.

The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines.

Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.

Structure–activity study of novel tricyclic benzazepine arginine vasopressin antagonists

Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.

The preparation of estradiol-17β sulfates with triethylamine-sulfur trioxide

Abstract Reaction of estradiol-17β with triethylamine-sulfur trioxide in pyridine gives exclusively monosulfation at the C17-hydroxyl group with the preparation of 17β-sulfooxyestra-1,3,5(10)-trien-3-ol triethylammonium salt (V). The structural assignment suggested by spectroscopic measurements was confirmed by synthetic studies. A synthesis of 3-sulfooxyestra-1,3,5(10)-trien-17β-ol triethylammonium salt (II) has been accomplished based on the preparation of 17β-formyloxyestra-1,3,5(10)-trien-3-ol (XIII). Fusion of the 3-sulfate triethylammonium salt II gives rise to the 17-sulfate triethylamine salt V. The preparation of estradiol-17β disulfate has also been achieved.

Synthesis of substituted 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-ones, a new class of agents for the improvement of cognition.

Abstract The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests. The synthesis and biological activity of the title compounds is described.

A fusion method for the preparation of steroid sulfates

A method for the preparation of steroid triethylammonium sulfates is outlined which involves the fusion of triethylamine-sulfur trioxide and steroids. Experimental details are presented which define the process as a thermal equilibrium resulting in the preferential sulfation of aliphatic hydroxyl groups. Sulfation of an aromatic hydroxyl group can be achieved in the absence of an aliphatic hydroxyl group. With excess reagent both types of hydroxyl groups in the same molecule can be sulfated.

C16-methyl derivatives of progesterone and 17α-acetoxyprogesterone: Preparation and biological activities

Mehrere Derivate des 16α-Methyl-progesteron wurden synthetisiert und biologisch geprüft. Die Einführung einer C16α-Methylgruppe ergab keine gesteigerte Progesteronaktivität in den getesteten Verbindungen.