Oxido-bridged neurosteroid analogues. Synthesis of 2,19-oxido-allopregnanolone

Abstract

3α-Hydroxy-2,19-oxido-5αH-pregnan-20-one was synthesized in 6 steps from the easily available 19-hydroxypregnenolone 3-acetate. The 2,19-oxido bridge was formed in a single step upon spontaneous cyclization and desilylation of a TBDMS protected 19-hydroxy-2α,3α-epoxypregnane. The 4,19-oxido analogue was obtained as a byproduct upon cyclization of the isomeric 3α,4α-epoxide.

Activity of B-Nor Analogues of Neurosteroids on the GABAA Receptor in Primary Neuronal Cultures

“…New types of neuroactive steroids have been widely sought, and structure modification of allopregnanolone has been examined in light of the vast family of GABA receptor subtypes within the brain. ,− Additional metabolic arguments 12 are also worthy of consideration because the application of natural neurosteroids is affected by very fast metabolism; the half-time of allopregnanolone in man is about 16 min. , The enzymatic system for the reduction of progesterone into allopregnanolone ( 1 ) is present in the body and could convert allopregnanolone back into progestins; if a long-term treatment were required, this metabolism could cause complications in the patient's overall hormone equilibrium. This is the reason why we produced B-nor analogues of allopregnanolone ( 5 ) and pregnanolone ( 6 ): their eventual oxidation would lead to dihydro-B-norprogesterone or B-norprogesterone, which do not exert any significant gestagenic activity …”

Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors

“…The stereospecific a-epoxidation of the alkene takes place because the b face of the A ring is sterically hindered due to the presence of the 19-acetate. 20 Deacetylation of 16 with sodium methoxide in methanol resulted in the intramolecular attack of the 19-alcoxide on C-2 to give the 2b,19-epoxy bridge. Hydrolysis of the methyl ester 17 with lithium hydroxide in methanol gave the 2,19-epoxy acid, that was transformed to the corresponding cholanamide 5 as above.…”

“…The resulting acid was converted to the amide 5 following the general procedure described above. The crude material was crystallized from chloroform/n-hexane to give 5 (20 5.1.17. N,N-Dimethyl-3b-hydroxy-2b,19-epoxy-5aH-cholanamide (6) Compound 5 (13 mg, 0.031 mmol) in anhydrous dichloromethane (1.0 mL) was treated with a suspension of pyridinium chlorochromate (13 mg, 0.060 mmol), barium carbonate (12 mg, 0.019 mmol) and 3 Å molecular sieves (19 mg) in anhydrous dichloromethane (1.5 mL) as previously described for 9.…”

Synthesis of 6-azaprogesterone and 19-hydroxy-6-azasteroids

“…For example, the 1,2-dehydrogenation of 19-hydroxysteroids is a highly efficient method for the preparation of estrogens [12]. In previous publications we have reported the synthesis of C(11)-C(19) [13], and C(2)-C(19) [14] oxygen bridged pregnanes and C(6)-C(19) sulfur bridged pregnanes, [15] from the corresponding 19-hydroxy precursors using an intramolecular remote functionalization and some of them have been shown to possess interesting activities. Moreover, the presence of the hydroxyl group at C-19 is by itself a starting point to prepare a wide variety of 19-functionalized steroids by simple chemical transformations as oxidations, substitutions or additions.…”