Steroids acetonides

Stearic anhydride, 1117 Stearolic acid, 603,946,1021,1036 Stearyl alcohol, 225 Stearyl bromid 657 Stephan reaction, 1116 Sterculic add, 1021-1022 Steroid acetonides, 801-802 Steroid diosphenols, 159-160 Stigmastadienone, 775-776, 889 Stigmasterol, 775-776, 889 CM-Stilbene, 156,967-968,975,1234 epoxide, 610,1192... 

Acetonides are quite stable to base, and to oxidation, dehydration and acylation reactions carried out in pyridine. They are cleaved by acid hydrolysis. The 17,21-acetonides of 17a,21-dihydroxy-20-keto steroids and related acetals are split by very mild acid conditions. ... 

Steroidal cis vicinal diols at the 1,2-, ° 2,3-, ° 5,6- or 11,12- " positions can be selectively protected as acetonides, prepared by reaction with acetone at room temperature or at higher temperatures in the presence of hydrochloric, perchloric or -toluenesulfonic acids. Cis nonvicinal-diols can be similarly protected. 

The synthesis of halcinonide is summarized in Figure 1, starting with 16a-hydroxy-9a-fluorohydrocortisone (A1 -pregnene-9a-fluoro-llg,16a,17a,21-tetrol-3,20-dione dihydrotriamcinolone, I), which is available commercially.10-13 This tetrahydroxy steroid is slurried in acetone, and then 70% perchloric acid is added slowly. The acetonide, II (9a-fluoro-llg, 16a, 17, 21-tetrahydroxypregn-4-ene-3, 20-dione, cyclic 16,17-acetal with acetone dihydrotriamcinolone-acetonide) precipitates spontaneously from solution. Mesyl chloride is added to the acetonide in pyridine to give the 21-mesylate derivative (dihydrotriamcinolone acetonide-21-mesylate, III). Compound III is dissolved in dimethylformamide, lithium chloride is added and the mixture is refluxed to produce halcinonide (IV), which is recrystallized from a solution of ft-propanol in water. 

Halcinonide was partitioned between hexanes and methanol, and between hexanes and aqueous acetonitrile at apparent pH values of 2,4,6(unadjusted), and 10. After one hour of mixing, the steroid content was determined by ultraviolet spectrometry of both phases. In all cases, absorbance at the peak maximum of 239 nm was detected only in the acetonitrile-water or methanol layer. The aqueous acetonitrile (pH 6) result was verified- using 14C-halcinonide labeled at the 2- carbon of the acetonide moiety. Thus, the halcinonide is completely retained in either the acetonitrile-water or methanol layers, indicating the utility of these solvent systems for extracting the steroid from formulations. 

In Figure 3, the active steroid (triamcinolone acetonide) and preservative (benzyl alcohol) are determined from a steroid cream. The higher molecular weight components of the cream base are well separated from the analytes. The ability to elute all the components of a cream or ointment in a SMGPC analysis gives an important sample preparation advantage over competing separation techniques. 

Figure 3. Determination of triamcinolone acetonide and benzyl alcohol from a steroid cream.

Examples of group I, i.e. weak or low efficacy topical steroids, are hydrocortisone acetate in various concentrations, methylprednisolone 1.0% and prednisolone 0.5%. Group II, the moderately potent steroids, includes alclometasone dipropionate 0.05%, hydrocortisone butyrate 0.1%, triamcinolone acetonide 0.025% and fluocinolone ace-tonide 0.01%. Group III, the potent steroids, contains among others betamethasone valerate 0.1%, betamethasone dipropionate 0.05%, budesonide 0.025%, desoximetasone 0.05%, fluticasone propionate 0.05%, amcinonide 0.1%, fluocinonide 0.05% and mometasone furoate 0.1%. Group IV comprises the very potent agents such as clobetasol propionate 0.05% and halobetasol propionate 0.05%. 

This reagent is quite specific for corticosteroids producing blue spots on a white background. The tetrazolium spray is used in a test for related foreign steroids in fluclorolone acetonide. 

Topical preparations usually contain relatively insoluble steroids, such as clobetasol propionate, triamcinolone acetonide, or triamcinolone diacetate. Side effects of this mode of drug application are usually milder and more transient than those seen after systemically administered steroids. However, potent topical corticosteroids, such as clobetasol propionate (Temovate), can suppress adrenal function when used in large amounts for a long time, especially when the skin surface is denuded or when occlusive dressings are employed. Since the high potency topical preparations carry a higher risk of local side effects, their use should be held in reserve. 

Acetonides [383,384] and siliconides [385,386] are prepared by the reactions of neighbouring hydroxyl groups, e.g., in positions 16,17 and 17,21, with acetone or dimethylchlorosilane. The reaction with acetone proceeds under acid catalysis with hydrogen chloride or TMCS, as follows. Steroids are dissolved in 10 ml of freshly distilled acetone and 100 n 1 of TMCS are added. The mixture is agitated at room temperature for 2 h, 1 ml of 1 N sodium hydroxide solution is added and the solvent is evaporated at... 

Research teams at Glaxo then undertook the synthesis of derivatives of betamethasone that might afford superior local anti-inflammatory and anti-allergic effectiveness. Using McKenzie and Stoughton s [21] new human-based pharmacologic test that could identify with ease the relative topical potency of steroid inflammatory compounds, a series of 17-esters of betamethasone prepared by Elks [22] was evaluated. This resulted in compounds with new standards of topical potency such as triamcinolone acetonide and fluocinolone acetonide. It was then discovered, that potency peaked with betamethasone-17-valerate and betamethasone-17,21-dipropionate, which were between four- and ten-fold more potent than the standard. 

Fluocinolone acetonide is a steroid acetal used to treat skin conditions such as eczema and psoriasis. The acetal group decreases the water solubility of the parent steroid, enhancing its potency and allowing for a longer duration of action. 

Some of the most important physiological steroids are the adrenocortical hormones, synthesized by the adrenal cortex. Most of these hormones have either a carbonyl group or a hydroxyl group at Cl 1 of the steroid skeleton. The principal adrenocortical hormone is cortisol, used for the treatment of inflammatory diseases of the skin (psoriasis), the joints (rheumatoid arthritis), and the lungs (asthma). Figure 25-10 compares the structure of natural cortisol with two synthetic corticoids fluocinolone acetonide, a fluori-nated synthetic hormone that is more potent than cortisol for treating skin inflammation and beclomethasone, a chlorinated synthetic hormone that is more potent than cortisol for treating asthma. 

FIGURE 5-41. Determination of triamcinolone acetonide (peak A) and benzyl alcohol (peak B) from a steroid cream. Column 500 A Ultrastyragel 7.8 mm ID x 30 cm. Mobile phase THF. Flow rate 1 mL/min. Detection UV, 254 nm, 0.2 AUFS. (Reprinted from reference 13 with permission.)... 

Acid-catalysed rearrangement/hydrolysis of the 3a,20a-disulphate (168) gave the 17/3-methyl-18-nor-compound (169). Rearrangement of the 17a-hydroxy-3-oxo-A -triene (170) to the c-ring aromatic compound (171) occurred in formic acid as did the rearrangement of 17a-ethynyloestradiol to the chrysene derivative (172). The 9,ll-epoxy-17-hydroxy-steroids (173) and (174) were converted with BF3-Et20 into the C-ring aromatic compounds (175) and (176) respectively. " Normal acetonide formation in the reaction of... 

Intralesional injection of steroid can lead to adrenal suppression. Infents and small children are especially susceptible, because a given amoimt of steroid is distributed in a smaller volume of fluid and tissue compartments. Infents injected with mixtiu es of triamcinolone acetonide and betamethasone or dexamethasone fiar periocular hemangiomas exhibited depressed serum cortisol and adrenocorticotropic hormone levels. The adrenal suppression can last up to 5 months and can result in weight loss and growth retardation. It is not known whether other corticosteroid preparations would produce similar effects or which other fectors might influence these results. In general, topical and periocular use of steroids produces minimal systemic effects. Withdrawal of topical or periocular steroids does not generally cause adrenal crisis. 

A new cortisone derivative, 3,20-dioxo-lljS,17a,21-trihydroxypregna-l,4,7-triene (298), has been prepared from the intermediate (297) by a classical combination of chemical and microbiological reactions.The chemistry of 17,20-and 20,21-acetonides, epimeric at C(20), has been described. A deprotection of masked steroidal alcohols by hydride transfer has been reported.Several benzyl ethers and bismethylenedioxy-steroids have been prepared and treated with trityl fluoroborate. The results demonstrated that the benzyl hydrogen atoms are sufficiently basic to give a benzyloxonium ion, as shown in the conversion of the 17,20 20,21-bismethylenedioxy-corticoid (299) into its free analogue (302) (see Part II, Chapter 1, refs. 120 and 323). 

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