Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.

Discovery and Metabolic Stabilization of Potent and Selective 2-Amino-N-(adamant-2-yl) Acetamide 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Evaluation of the effect of strain upon reactivity

Published data on the synthesis of adamantane derivatives bearing various functional groups (halogen, hydroxy, nitrato, amino, carboxy and others) are systematised and generalised. The bibliography includes 236 references.

https://iopscience.iop.org/article/10.1070/RC1999v068n12ABEH000495/pdf

Reactions of adamantanes in electrophilic media

Bei der Hydrierung 1,1-disubstituierter Cyclopropanderivate 1 bewirken elektronenabgebende Reste (R = Alkyl, CH2OH, OR) die Hydrogenolyse der C-2C-3-Bindung zu 2, elektronenanziehende Substituenten (R = CO2R, COR, CN) dagegen die Offnung der C-1C-2-Bindung unter Bildung der Produkte 3. 1,1-Bis(trifluormethyl)cyclopropan lies sich nicht hydrieren.

Hydrogenolyse kleiner Kohlenstoffringe, VII. Die selektive Hydrierung 1,1‐disubstituierter Cyclopropanderivate

The effect of remote oxygens on the ring-opening reactions of oxabicyclic compounds with organolithium reagents. Synthesis of the C21–C27 segment of rifamycin S

Synthesis of 1,3-Disubstituted Adamantanes.



A series of new 1-substituted 3-bromoadamantanes has been prepared. An improved method for the formation of cyclopropanes from olefins with diazomethane and copper salts is described.

Die Synthese von 1,3‐disubstituierten Adamantanen

When heated with sodium ethoxide in ethanol 7-methylidenebicyclo[3.3.1]nonan-3-endo-ol (endo-1) is converted into 1-methyl-2-oxa-adamantane (3). This reaction involves nucleophilic addition of a hydroxy group to an unactivated olefinic bond. Formation of the cyclic ether 3 also takes place when endo-1 is heated in aqueous ethanol. This electrophilic addition is strongly catalysed by weak acids and suppressed by weak bases. These unusual reactions proceed more slowly with 7-methylbicyclo[3.3.1]non-6-en-3-endo-ol (endo-2) and can be ascribed to a proximity effect. This follows from the IR. and NMR. spectra of endo-1 and endo-2 which show strong intramolecular hydrogen (OH-π) bonding. The unsaturated endo- and exo-alcohols 1 and 2, respectively, undergo only exo-complexation with silver ion.

Hajime Katayama

Papers

Die Synthese von 1,3‐disubstituierten Adamantanen

Proximity Effects in Acid and Base‐Catalysed Ether Formation

The synthesis of 1,3-disubstituted adamantanes

Inductive, CC-hyperconjugative and frangomeric effects in the solvolysis of 1-substituted 3-bromoadamantanes