Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones.

Several A- and D-ring substituted steroidal 7 alpha-alkoxycarbonyl spirolactones were synthesized with the purpose of increasing the aldosterone antagonistic potency and reducing the endocrinological side effects relative to the standard drug spironolactone. It was found that the 15 beta,16 beta-methylene derivative 17 exhibited a 2-fold higher aldosterone antagonistic activity compared to either spironolactone or the 15,16-unsubstituted derivative 29 while showing remarkably reduced antiandrogenicity.

Aldosterone antagonists. 2. New 7 alpha-(acetylthio)-15,16-methylene spirolactones.

Some 15,16-methylene derivatives of the aldosterone antagonist spironolactone were synthesized with the purpose of increasing the antialdosterone potency and reducing the endocrinological effects of this standard compound. By introduction of a 1,2-double bond and a 15 beta,16 beta-methylene ring in the spironolactone molecule both goals were achieved. In animal studies mespirenone exhibited a threefold-greater antialdosterone potency and less than 10% of the antiandrogenic activity of spironolactone.

Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones.

Several steroidal 6,6-ethylene-15,16-methylene 17-spirolactones were synthesized to find new progestogens that exhibit both progestational and antimineralocorticoidal activities. The influence of substituents in the 10- and 13-position of the steroidal framework on both properties was investigated. It was found that only compound 12, carrying methyl groups at the 10- and 13-positions, possesses high progestational and antimineralocorticoidal activity.

Aldosterone antagonists. 1. Synthesis and activities of 6 beta,7 beta:15 beta,16 beta-dimethylene steroidal spirolactones.

Several derivatives of the highly active aldosterone antagonists dihydrospirorenone (2) and spirorenone (3) were synthesized. The purpose of these efforts was to prepare compounds exhibiting reduced endocrinological properties with the same or better aldosterone antagonistic activity than that of spirorenone. The 1 alpha,2 alpha-methylene derivative 20 has a similar aldosterone antagonistic potency compared to that of spirorenone but does not show decreased endocrinological side effects. Other substituents as in compounds 4-11, 15-19, and 21 sharply decreased the aldosterone antagonistic activity of 2 or 3, respectively.

Diamond-blackfan anemia in pregnancy.

BACKGROUND: Diamond-Blackfan anemia is a rare form of congenital red-cell aplasia. Approximately 90% of the patients are diagnosed by 1 year of age. This report presents two pregnancies with good outcomes in a patient over a period of 1.5 years. CASE: The patient, a 20-year-old woman, was diagnosed with Diamond-Blackfan anemia at age 3.5 months. Treatments consisted of red blood cell transfusions and oral corticosteroids. She conceived at age 18 years and delivered prematurely at 34 weeks' gestation. Her second pregnancy was diagnosed 4 months after delivery of the first child, and she delivered spontaneously at 38 weeks and 6 days' gestation. She received multiple blood transfusions during both of the pregnancies. The infants were average for gestational age and had normal examination at birth. CONCLUSION: Based on this case and a review of the literature, it appears that pregnancy and birth control pills may contribute to the relapse of anemia in patients diagnosed with Diamond-Blackfan syndrome. This may require an increase in the frequency of blood transfusions. Pregnancies are usually tolerated well and can be managed with supportive therapy.

Comparative evaluation of the dissociation rate between the vaginotrophic and uterotrphic activities of 1-hydroxy-1, 3, 5 (10)-estratriene derivatives with natural and unnatural configuration at C8 using ovariectomized mice.

Influences on estrogenic.activities of 1-hydroxylation and C8-isomerization in the molecules of naturally occurring estrogens have been studied. All compounds tested behaved qualitatively in the same manner as estradiol, as far as the decrease in the vaginal and uterine sialic acid levels and the increase in the organ weights of the vagina and uterus of castrated mice are concerned. They were, however, different not only in the relative ptoencies of the estrogenic effects, but also in the dissociation rate between the vaginotrphic and uterotrophic activities. Of the compounds tested, 1-hydroxy-8alpha-estrone, 1-hydroxy-8alpha-estradiol and their acetates had a higher value of the dissociation index than that of estriol. These compounds seemed to exert a predominant effect on the vagina rather than on the uterus. Following structural factors seem to be of significance for the dissociation of estrogenic effects: the 1- or 16alpha- hydroxy group and 8alpha-configuration decrease the uterotrophic activity more intensely than the vaginotrophic activity, and the 17alpha-ethinyl group selectively increases the uterotrophic activity.

New steroids with antiprogestational and antiglucocorticoid activities.

A number of 11-substituted 19-norsteroids with inverse configuration at C-13 were synthesized. 11 beta-Aryl compounds in this series were found to possess antiprogestational and antiglucocorticoid activities.

Synthesis of ent-17-(prop-1-ynyl-17 beta-hydroxy-11 beta-(4-(N,N-dimethylamino)-phenyl)-4,9-estradien-3-one, the antipode of RU-38 486.

The title compound was synthesized and tested for its biological activities. It showed neither antiprogesterone nor antiglucocorticoid properties.

Synthesis and biological activity of 17-chloro-16(17) unsaturated D-homo antiprogestins.

An efficient approach to 17-chloro-16(17) unsaturated D-homo antiprogestins is described. The key steps of the synthesis are a ring-expansion via dichlorocarbene addition to a 17-silyl enol ether and a palladium catalyzed coupling of an 11 beta-(4-aryltriflate) with tributyl(1-ethoxyethenyl)stannane or diethyl(3-pyridinyl)-borane. The new progesterone antagonists were tested for their biological activities and compared to those of known antiprogestins.

Synthesis and biological testing of 4'-(dimethylamino)-17 beta-hydroxy-17 alpha-(1-propynyl)benzo[12,12a]-11 alpha,18-cyclo-12a,12b-dihomo-13 alpha-estr-4-en-3-one: an interesting RU 38 486 analog.

A partial synthesis of the title compound, 4'-(dimethylamino)-17 beta-hydroxy-17 alpha-(1-propynyl)benzo[12,12a]-11 alpha,18-cyclo-12a,12b- dihomo-13 alpha-estr-4-en-3-one 1, is reported. The key step in this synthesis represents an intramolecular alkenylaryl radical cyclization. Treatment of 18-[bromo-5-(dimethylamino)phenyl]gona-5,9(11)-diene-3,17-dione-3, 17- bis[cyclic 1,2-ethanediyl acetal] 5 with tributyl tin hydride and a radical initiator introduces the desired 11 beta,18-bridge. The reduced progesterone receptor affinity of this RU 38 486 analog contributes valuable information to the empirical characterization of the steroid binding site of the receptor protein and explains the observed lack of in vivo antigestational activity.

Synthesis of antiprogestational steroids.

The discovery of the first competitive progesterone antagonist RU 38,486 has initiated an intense search for more potent and more selective anti-progestins. Among several hundreds of compounds under preliminary investigation, biological characterization is most advanced for derivatives RU 38,486, ZK 98,734 and ZK 98,299. These compounds do not only differ in relative potency, but are clearly distinguished by their different behaviour in various animal models. Emphasis is laid on the synthetic problems associated with chemical operations in a sterically crowded environment as represented by structures RU 38,486 and ZK 98,299.

[Synthesis of Butyl 6alpha-Fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (Fluocortin Butylester) (author's transl)]. / Synthese von 6alpha-Fluor-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-säure-butylester (Fluocortin-butylester).

Among the metabolites of fluocortolone (1) there was found the alpha-keto acid 4a. This acid, as well as the esters 4b--4k were synthesized and the butyl ester 4c was chosen for local anti-inflammatory therapy.

[Synthesis of gestodene]. / Synthesen von Gestoden.

The synthesis of the new progestogen, 17 alpha-ethinyl-17 beta-hydroxy-18-methyl-4,15-estradien-3-one (gestodene, 6), starting from 18-methyl-4-estren-3,17-dione (1) can be accomplished by several methods. The oral progestational activity of gestodene is greater than that of levonorgestrel. Gestodene, in combination with ethinylestradiol, is contained in a recently developed oral contraceptive.