Cortisone potency

The natural compounds cortisol [50-23-7], cortisone [53-06-5], and corticosterone [50-22-6] vary only slightly in stmctures and pharmacologic properties (see Steroids). The synthetic analogues inmore modem practice, prednisolone [52438-85-4], dexamethasone [50-02-2], triamcinolone [124-94-7], and betamethasone have greater antiinflammatory potency, and their effects on sodium retention tend to be less severe. 

The increase in potency observed in the progestin series by incorporation of additional unsamration in the A ring (see delmadinone, (5-4) obtains in the corticoid series as well the majority of commercial steroid anti-inflamatories in fact include this feamre. The double bond at the 1 position may be formed by fermentation with an organism such as Corynebacterium simplex [11] or by reaction with selenium dioxide. Hydrocortisone acetate (13-4) yields the widely used corticoid prednisolone acetate (14-1) in the same vein, cortisone acetate (13-5) goes to prednisone acetate (14-2). Mild saponification of either of these products yields the free alcohols prednisolone and prednisone, respectively. 

Fluorine at the equatorial 6a position also results in an increase in potency. One scheme for the production of such a compound relies on the shift of the double bond from the 4,5 to the 5,6 position, which follows the formation of an acetal at position 3. The scheme starts with the selective reduction of the 11 ketone in the cortisone intermediate (13-2). Epoxidation of the product (18-1) with a peracid takes place selectively at the unconjugated double bond to give the 5a,6a oxirane (18-2). Treatment of that with hydrogen fluoride in tetrahydrofuran leads to fluorohydrin (18-3). (There is evidence to indicate that the reagent involves an HF THF acid base complex since the omission of THF in at least some cases leads to a complex mixture of rearrangement products [15].) The side chain in fluorohydrin (18-3) is then converted... 

The 9,11 olefin in the intermediate (25-4) is next converted to the 9a-fluoro-11(3-hydroxy derivative (26-1) by the customary scheme. The additional unsaturation in ring A is then introduced by means of selenium dioxide to afford triamcinolone (26-2). Reaction of that compound with acetone converts the 16,17 diol to an acetal to afford triamcinolone acetonide (26-3) [21]. The latter is approximately 50 times more potent than cortisone in animal models the free glycol interestingly shows only a 2.5-fold increase in potency over the cortisone in the same model. 

As in the case of the less highly substituted compounds, the acetonide of a 16a hydroxyl corticoid shows about the same potency as its 16a methyl counterpart. Thus, fluodnonide (28-2), obtained by an analogous set of transformations starting with a 6 fluorinated 16 dehydro intermediate (28-1) [23], is 440 times as potent as cortisone in the standard assay. 

The approximate potency of various mineralocorticoids relative to cortisone is shown in Table 1. 

On the hypothesis that the side chain could perhaps be stabilized against such metabolic inactivation by an appropriately placed but otherwise chemically inert substituent, some analogues of cortisone containing a 16a-methyl group were synthesized by Arth et al. [20] in the expectation that the 16a-methyl substituent would enhance potency by protecting the 20-ketone from metabolism. Ultimately, these authors prepared 9-fluoro-16a-methylprednisolone which was the first derivative of fluorocortisol with markedly increased anti-inflammatory activity that was devoid of mineralocorticoid activity. This latter fact supports the concept that it is the presence of 16a-substituents that prevents binding to the mineralocorticoid receptor. Dexamethasone has become Merck s principal marketed anti-inflammatory steroid. 

Table 1 Approximate potency of various mineraiocorticoids reiative to cortisone...

The presence of a hydroxyl group at Cig has an enhancing effect on potency similar to that of a methyl group at the same position. Cortisone (5-7) constitutes the starting material for the synthesis of one of those 16)8,17)8-diols. Dehydration of cortisone occurs in ring D to afford the corresponding 16,17-dehydro derivative 18-1 (Scheme 7.18). The carbonyl... 

Hydrocortisone is an adrenocorticoid with both glucocorticoid and mineralocorticoid properties. It is a weak antiinflammatory agent but a potent mineralocorticoid, having potency similar to that of cortisone and twice that of prednisone. Hydrocortisone (or cortisone) is usually the drug of choice for replacement therapy in patients with adrenal insufficiency. It is usually not used for immunosuppressant... 

Beclomethasone possesses roughly 5000 times the potency of cortisone. 

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