Azasteroidal mimics
View Patent ↗An azasteroid mimic or an intermediate for the preparation of an azasteroid and azasteroid mimic is formed via an oxocycloalkenyl isoxazolium anhydrobase and its dimer. The dimer can be used to form mono- and dihydrazones, which can be an azasteroid mimic or an intermediate for the preparation of an azasteroid and azasteroid mimic. A method of preparation of the dimer and the azasteroid mimic or an intermediate for the preparation of an azasteroid and azasteroid mimic occurs with hydrazonation and, optionally, a subsequent dehydrazonation. The dimer can be converted by inserting a nitrogen atom into the six membered ring of to a C-17 position cyclohexenone moiety of the dimer to yield a reduced tetrazolo[1,5-a]azepin-8-yl group. A subsequent hydrozone formation at a benzylic ketone can be carried out to generate an azasteroid mimic with a (triazol-4-yl)imino substituent. Monohydrazones can be converted to their thione equivalents.
1. An azasteroid mimic or intermediate for the preparation of an azasteroid and azasteroid mimic, consisting of an oxocycloalkenyl isoxazolium anhydrobase, or any salt thereof, where the oxocycloalkenyl isoxazolium anhydrobase
is a modified dimer of
having the structure:
where independently,
X═O,
wherein at least one X is not O; or a ring-expanded dimer of the structure:
wherein X is O or
2. The azasteroid mimic or intermediate for the preparation of an azasteroid or azasteroid mimic according to claim 1 , wherein the azasteroid mimic is a monohydrazone of the structure:
3. The azasteroid mimic or intermediate for the preparation of an azasteroid or azasteroid mimic according to claim 1 , wherein the modified dimer is a monohydrazone of the structure:
4. The azasteroid mimic or intermediate for the preparation of an azasteroid or azasteroid mimic according to claim 1 , wherein the modified dimer is a dihydrazone of the structure:
5. The azasteroid mimic or intermediate for the preparation of an azasteroid and azasteroid mimic, according to claim 1 , wherein the structure is:
6. The azasteroid mimic or intermediate for the preparation of an azasteroid and azasteroid mimic, according to claim 1 , wherein the structure is:
7. The azasteroid mimic or intermediate for the preparation of an azasteroid and azasteroid mimic, according to claim 1 , wherein the structure is:
8. The azasteroid mimic or intermediate for the preparation of an azasteroid and azasteroid mimic, according to claim 1 , wherein the structure is:
9. A method of preparing an azasteroid mimic or intermediate for the preparation of an azasteroid or azasteroid mimic according to claim 1 , comprising:
providing an oxocycloalkenyl isoxazolium anhydrobase of the structure:
dimerizing the oxocycloalkenyl isoxazolium anhydrobase to a dimer of the structure:
optionally, selectively ring-expanding the cycloheneyl ketone with trimethylsilyl azide and trimethylsilyl triflates to form a dimer of the structure:
reacting the dimer with one or two equivalents of 4-amino-4H-1,2,4-tirazole to a first monohydrazone, a dihydrazone, or mixture thereof optionally, in the presence of a ketone activating catalyst;
optionally, transforming the ketone of the first monohydrazone to a thione of the structure:
optionally, dehydrazonating the dihydrazone to a second monohydrazone;
and
isolating the azasteroid mimic or intermediate for the preparation of an azasteroid or azasteroid mimic.
10. The method of claim 9 , wherein the ketone activating catalyst is titanium isopropoxide, cerium (III) chloride or scandium triflates.
11. The method of claim 9 , wherein the ketone activating catalyst is scandium triflates.
12. The method of claim 9 , wherein the 4-amino-4H-1,2,4-tirazole is added in a first addition and the ketone activating catalyst is added after formation of the monohydrazone to convert at least a portion of the monohydrazone to a dihydrazone.
13. The method of claim 9 , wherein the dehydrazonating is catalyzed by cupric chloride.
14. The method of claim 9 , wherein the transforming to a thione is reacting with Lawesson's reagent.