Convergent and enantioselective syntheses of cytosolic phospholipase A₂α inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates

Abstract

Cytosolic phospholipase A2α (cPLA2α) is an important enzyme of the inflammation cascade. Therefore, inhibitors of cPLA2α are assumed to be promising drug candidates for the treatment of inflammatory disorders. Recently we have found that indole-5-carboxylic acid with a 3-(4-octylphenoxy)-2-(phenoxycarbonylamino)propyl substituent in position 1 is an inhibitor of cPLA2α. We have now synthesized a corresponding derivative with the indole heterocycle replaced by an indazole (4) employing an analogous reaction sequence as for the synthesis of the indole derivative. Besides, a more convergent synthesis for 4 was established using an aziridine as central intermediate. Furthermore, a chiral-pool based enantioselective synthesis was developed for the synthesis of (R)- and (S)-4. Starting compound for both enantiomers was the (R)-serine derived oxazolidine (R)-25. Compound 4 proved to be a moderate inhibitor of cPLA2α, with the S-enantiomer being twice as active as the R-enantiomer. The racemate 4 and the enantiomers (R)- and (S)-4 showed a high in vitro metabolic stability in rat liver S9 fractions.

Convenient Synthesis of N-Heterocycle-Fused Tetrahydro-1,4-diazepinones

“…Subsequently, alkylation reaction conditions were investigated in the presence of solvent. To our satisfaction, both Cs 2 CO 3 (Entry 5) [52] and NaH (Entry 6) in DMF [53] provided desired isomer 2a as the major product in high regioselectivity. An attempt to perform reaction in refluxing ACN using Cs 2 CO 3 as a base [54] gave similar results (Entry 7).…”

PIDA‐Mediated Intramolecular N‐N Bond Formation to Access 2‐Aminoindazoles and 2,2′‐Biindazoles**

“…[4] They are also used as an efficient bioisosteric replacement for other heterocyclic assemblies such as benzimidazole and indoles. [5] The indazoles continue to play a vital role in biological activities such as antitumor, [6] anticancer, [7] antidepressant, [8] HIV-protease inhibition, [9] antitubercular, [10] anti-angiogenic agents, [11] antimicrobial, [12] antidiabetic, [13] anti-inflammatory, [14] antichagasic and trichomonacidal activity, [15], etc. It is also present in various FDA-approved drugs e. g. granisetron, lonidamine, and Niraparib (Figure 1).…”

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

“…In order to get inhibitors, which are not inactivated in organism so quickly, we substituted the scissile ketone function with phenoxy-carbamate moieties, which in principle, can also act as serine traps. These variations resulted in substances with higher metabolic in vitro stability but significantly lower inhibitory potency 18,19 . In the present study, we describe the effect of the replacement of the activated electrophilic ketone by further serine traps such as a-ketoheterocycle, cyanamide, and nitrile 20,21 on enzyme inhibition and metabolic stability.…”