Synthesis and evaluation of antiinflammatory activities of a series of corticosteroid 17.alpha.-esters containing a functional group

Abstract

A series of 21-desoxy-21-chlorocorticosteroids that contain a functionalized ester group at 17 alpha has been prepared and examined to separate their systemic activity from topical antiinflammatory activity. Introduction of the functionalized ester group at 17 alpha was carried out by an acid-catalyzed formation of cyclic ortho esters with 17 alpha,21-hydroxyl groups of corticosteroids and subsequent acid-catalyzed hydrolysis. As for the functional group, chloro, methoxy, acetoxy, cyano, cyclopropyl, or alkoxycarbonyl group was introduced at the terminal carbon atom of the 17 alpha-alkanoate group. The topical antiinflammatory activity and systemic activity of these compounds were examined and found to be significantly dependent on the functionalities in the 17 alpha-esters. Among these derivatives, a series of 17 alpha-(alkoxycarbonyl)alkanoates (17 alpha-OCO(CH2)nCOOR) showed an excellent separation of the systemic activity from topical activity. The effects of the number of methylene groups (n) and of the alkyl groups of the ester (R) on either topical or systemic activity of the corticosteroid derivatives were also investigated.

A Novel Rearrangement of Cyclic Glutamine Derivatives: Ring Contraction in 3,6‐Diamino‐2,3,4,5‐tetrahydropyridin‐2‐ones to Yield 5‐Iminoproline Amides

“…A literature search indicated that l-glutamine should easily be transformable into tetrahydropyridinone derivative 2 with the same configuration at the stereogenic center as in the biologically most potent A-diastereomer of TAN-1057. Indeed, cyclic amidines with one acylated nitrogen incorporated into a five-or six-membered ring are easily available from ethyl 3-cyanopropionate or 4-cyanobutyrate, respectively, by a three-step procedure starting with the transformation of the nitrile into an imino ester [4] followed by aminolysis and spontaneous cyclization of the resulting amidine to yield 2-amino-1-pyrrolin-5-one or 6-amino-2,3,4,5-tetrahydropyridin-2-one. [5] Tetrahydropyridinone derivative 2 should thus be accessible by performing an analogous transformation with Z-protected ethyl 2-amino-4-cyanobutyrate (5, Z = PhCH 2 OCO).…”

“…To keep the Z protecting group intact, this reaction was carried out at -5 to -10°C. When run at the temperature of an ice bath, [4] benzyl chloride, formed by cleavage of the Z protective group, could be extracted with diethyl ether from salt 7 to the extent of ca. 10 mol-%.…”

Retrometabolism‐Based Drug Design and Targeting

“…Other Corticosteroid Designs Other groups also made attempts to separate local and systemic effects by integrating moieties susceptible to rapid, nonhepatic metabolism within the corticosteroid structure. One of the more successful attempts explored 17a-(alkoxycarbonyl)alkanoates analogs (54) of clobetasol propionate [221]. Again, this can be considered as a hypothetical inactive metabolite-based approach, and a corresponding metabolite (54, n ¼ 2, R ¼ H) has indeed been shown to be inactive.…”

Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

“…One of the more successful attempts explored 17α-(alkoxycarbonyl)alkanoates analogues (15) of clobetasol propionate [124]. Again, this can be considered as a hypothetical inactive metabolite-based approach, and a corresponding metabolite (15, n = 2, R = H) has indeed been shown to be inactive.…”