Alexander Kasal

Epalons: 6-Substituted Derivatives of 7-Norepiallopregnanolone

Abstract The target compounds (3α-hydroxy-5,6-epoxy-7-nor-5α-pregnan-20-one, 3α-hydroxy-5,6β-epoxy-7-nor-5β-pregnan-20-one and 3α-hydroxy-7-nor-5α-pregnane-6,20-dione) were prepared from 5,6β-dihydroxy-20-oxo-5α-pregnan-3β-yl acetate via the corresponding 5,6-seco acid and 3β-acetoxy-20-oxo-7-nor-5β,6α-pregnane-6,5-carbolactone-actone. Intermediate 3β-hydroxy-7-norpregn-5-en-20-one was converted into the corresponding 5α,6α and 5β,6β epoxides. The latter was isomerized into 3β-hydroxy-7-nor-5α-pregnane-6,20-dione. The configuration of the 3β-hydroxy group in these compounds was inverted by Mitsunobu reactions.

Suppressing aggressive behavior with analogs of allopregnanolone (epalon)

3alpha-Hydroxy-20-oxo-5alpha-pregnan-21-yl hemisuccinate (8) was produced by partial acylation of 3alpha,21-dihydroxy-5alpha-pregnan-20-one (14). 3alpha-Fluoro-5alpha-pregnan-20-one (9) was prepared by treatment of 3beta-hydroxy-5alpha-pregnan-20-one (11) with DAST and by solvolysis of tosylate 12 with tetrabutylammonium fluoride. A behavioral test on mice was performed using 3alpha-hydroxy-5alpha-pregnan-20-one (1) and compounds 8 and 9. Compound 8 was found to be inactive, while the fluoro derivative 9 selectively reduced aggressive behavior in mice more than the corresponding 3alpha-hydroxy compound 1; locomotion and other behavioral features were not affected.

Synthesis and GABAA receptor activity of A-homo analogues of neuroactive steroids.

A procedure is described for the preparation of A-homo-5-pregnenes via an acid catalyzed rearrangement of cyclopropylcarbinols assisted by microwave irradiation. 3alpha-Hydroxy and 4alpha-hydroxy-A-homo-5-pregnen-20-one, analogues of the neuroactive steroid allopregnanolone, were obtained by means of a regioselective epoxidation of a double bond in the expanded A-ring, using a fructose-derived chiral ketone as catalyst and oxone as oxidant. Although both these compounds were marginally active in inhibiting TBPS binding to GABA(A) receptors, 3beta-hydroxy-A-homo-5-pregnen-20-one was almost as active as allopregnanolone. Reduction of the double bond of the latter compound resulted in a ten fold loss of activity.

Allopregnanolone and pregnanolone analogues modified in the C ring: synthesis and activity.

(25R)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α-pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABAA receptor. Their biological activity was measured by in vitro test with [(3)H]flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABAA receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic-hydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor.

Trans hydrindanes by dimide reduction: Synthesis of dihydro-B-nortestosterone and its 17α-methyl derivative

Abstract Reductive hydroboration of Δ 5 -B-norsteroids (e.g., 1 ) affords 5α-dihydro products (e.g., 3 ) in a low yield. Better yields, however, were obtained by reduction with diimide. The method was employed in the synthesis of potential antiandrogens - 17β-hydroxy-B-nor-5α-androstan-3-one ( 8 ) and its 17α-methyl derivative ( 9 ).

Analogues of androgen hormones with inverted configuration at carbons 5, 9, and 10

On catalytic hydrogenation of Delta(9)-steroids (e.g. 3beta-hydroxy-5-methyl-19-nor-5beta-androst-9-en-17-one), four isomers were formed: 9alpha,10alpha-, 9alpha,10beta-, 9beta,10alpha- and 9beta,10beta-adducts. The product distribution was affected by the nature of the C-3 substituent. A chair conformation of A, B, and C rings was found in all of the products with the exception of the 9alpha,10alpha-adduct whose B ring adopts a twist boat conformation. The products were utilized for the synthesis of dihydrotestosterone analogues.

An expedient synthesis of [16,16,17-2H3)-epitestosterone via a one pot deuteration and reduction of the 17-ketone followed by epimerization of a deuterated alcohol

The 17-Oxo group in androstane derivatives was reduced by sodium in deuterium oxide to [17-2H]-17β-alcohol. The 17β-tosyloxy group of 4 was found to be stable under the conditions of the i-steroid rearrangement The SN2 reaction of 17β tosylate 6 with potassium nitrite yielded the 17α alcohol 7 without the loss of deuterium.