9-fluoro-hydrocortisone

In 1953, Fried and Sabo announced the synthesis of the highly potent steroid analogue fludrocortisone (9-fluoro-hydrocortisone), formally accenting the beginning of the analogue era [10-13]. 

This earliest of the important enhancement discoveries was in itself not of therapeutic value, due to salt retention, yet it became a component in nearly all of the ultrapotent corticoids to be marketed. Indeed, it is why the discovery of the potent 9-fluoro-hydrocortisone was an event that had far-reaching significance. 

Introduction of the 16a-hydroxyl group into 9-fluoro-hydrocortisone and 9-fluoro-prednisolone has been shown by Bernstein et al. [16] to result in complete suppression of the salt-retaining properties of these steroids, without appreciably impairing their glucocorticoid activity. Moreover, studies in man have demonstrated the anti-arthritic activity of 9-fluoro-16a-hydroxy-prednisolone and have confirmed its lack of salt-retaining activity. Subsequently, Lederle reported that the anti-inflammatory potency was lowered, but salt retention was eliminated. 

Since triamcinolone does not produce chromogens when reacted with a sulfuric acid, fructose, cysteine mixture this method can be used to determine small amounts of non-16a-hydrox-ylated steroids such as 9a-fluoro-hydrocortisone in the presence of triamcinolone . 

It was the pioneering work of Fried on preparation of 9oc-fluoro-hydrocortisone acetate (1) (40) that led to the first significant successful application of selective fluorination for the puipose of modifying biological activity. This publication marked the beginning of a new era when medicinal chemists and biochemists routinely introduced fluorine as a substituent to modify biological activity. 

One of the first indications that the antiinflammatory potency of the corticoids could be increased was the observation that incorporation of a 9a-fluoro group in hydrocortisone resulted in a tenfold increase in activity. Treatment of hydrocortisone acetate (170a) with phosphorus oxychloride in pyridine yields the corresponding olefin, 172. This, on being subjected to the reaction sequence depicted in the transformation of 104 to 108 (addition of HOBr, closure to the epoxide and ring opening with HF),... 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A <" -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

A mixture of 1.2 grams of 6o -fluoro-16a-hydroxy-hydrocortisone, 4 cc of acetic anhydride and 8 cc of pyridine was heated at 60°C for 2 hours and then kept at room temperature for 2 hours. Ice and water were added and the solid was collected, washed with water, dried and recrystallized from methylene chloride-methanol, thus giving 1.05 grams of the... 

A mixture of 1.38 grams of the above compound and 15 cc of dioxane was treated with 1.9 cc of a 0.5 N aqueous solution of perchloric acid and 600 mg of N-bromoacetamide, adding the latter in the dark, in three portions, in the course of half an hour and under continuous stirring. It was then stirred for a further 1% hours in the dark, then the excess of reagent was decomposed by the addition of aqueous sodium bisulfite solution and ice water was added the product was extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, thus giving a yellow oil consisting of the 16,21-diacetate of 6a-fluoro-9a-bromo-16o-hydroxy-hydrocortisone which was used for the next step without further purification. 

The adrenal glands secrete over 50 different steroids, the most important of which are aldosterone and hydrocortisone. Aldosterone causes salt retention in the body. It is not commercially available. Hydrocortisone is useful for its anti-inflammatory and antiallergic activity. Cortisone and its derivatives have similar activity and it is reduced in vivo to hydrocortisone. The two substances are used to treat rheumatoid arthritis. The 11-P-hydroxyl of hydrocortisone is believed to be of major importance in binding to the receptors of enzymes. Anti-inflammatory activity is significantly Increased by various substituents 6a-fluoro, 9a-fluoro, 21-hydroxy, 2a-methyl, 9a-chloro, and a double bond at C-1. 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al,... 

HYDROCORTISONE see AQX500 FLUOROLON 4 see TAI250 FLUOROMAR see TKB250 FLUOROMETHANE see FJKOOO A -9-a-FLUORO-16-a-METHYLCORTISOL see SOWOOO... 

FI. Faivre, G., Gilgenkrantz, J.-M., Barrucand, M., and Gilles, D., Syndrome pseudo-myopathique apparu au cours d un traitement par la 9a-fluoro-16a-hydro3qf-A-hydrocortisone (triamcinolone). Bull. Soc. Med, Hop. Paris 76, 731 (1960). 

Treatment consists in prescribing a cream containing steroid anti-inflammatories. The sooner treatment is started, the more effective it is with low-dose products. If treatment is delayed, higher doses of fluoro-corticosteroids have to be used, and the results are less satisfactory. A (2.5%) hydrocortisone cream or a topical clobetasone... 

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