Steroid 17-carboxylates

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

If a hapten does not contain free carboxyl, such group(s) may often be introduced. Alkylation of oxygen or nitrogen substituents with halo-esters, followed by hydrolysis of the ester, is frequently used for this purpose (Kabakoff, 1980). For steroids, carboxyl groups may be introduced to the hydroxyl or keton groups, through the formation of hemisuccinate esters or (carboxymethyl)oximes, respectively. 

Barbier-Wieland degradation of steroid carboxylic acids Ethylene derivatives from carboxylic acids... 

Bile adds components of bile which serve as emuldfying agents. They are steroid carboxylic adds linked to taurine or glycine by a peptide bond. According to the constituent amino add, they are called glycocholic or taurocholic acids. Ihe former predominate in human and bovine bile, the latter in canine bile. B. a. are characteristic of mammals in lower vertebrates the same function is performed by Bile alcohols (see). In mammals, the pattern of B.a. is often spedfic for the spedes. 

Lithocholic acid 3a-hydroxy-5P-cholanoic add, or 3a-hydroxy-5p-cholan-24 c acid, M, 376.58, m.p. 185 C, [a]D + 32 ° (ethanol). L. a. is a monohydroxyla-ted steroid carboxylic add, and one of the bile acids. It has been isolated from the bile of man, cow, rabbit, sheep and goat, and is normally prepared from bovine bile. L.a. is formed from chenodeoxycholate by intestinal bacteria. It is absorbed and returned to the liver for secretion. It is not readily conjugated, and it is relatively toxic to the liver. L.a. may be important in the pathogenesis of liver damage following biliary sta-... 

Ursodsoxycholic acid 3a,7p-dihydroxy-5p-cho-lan-24-oic acid, a dihydroxylated steroid carboxylic acid, one of the bile acids M, 392.58, m.p. 203 °C, [o]d -( 57° (ethanol). U. is a characteristic component of bear bile, and is also present in human bile. 

XI. Bile Acids and Conjugates, Steroid Carboxylic Acids and Steroid Conjugates... 

Organomanganese compounds react with acid chlorides to afford ketones in high yields as shown in eq. (14.28). Thus reactions are able to proceed in many solvents. These reactions have a high selectivity to the functional groups, and are often available for a ketone synthesis [72—75]. For example, a steroid carboxylic acid reacts with SOCI2 to afford an acid chloride, then organomanganese compounds react with the acid chloride to give a ketone by condensation reaction as... 

Diene carboxylates can be prepared by the reaction of alkenyl halides with acrylates[34]. For example, pellitorine (30) is prepared by the reaction of I-heptenyl iodide (29) with an acrylate[35]. Enol triflates are reactive pseudo-halides derived from carbonyl compounds, and are utilized extensively for novel transformations. The 3,5-dien-3-ol triflate 31 derived from a 4,5-unsaturated 3-keto steroid is converted into the triene 32 by the reaction of methyl acrylate[36]. 

Methyl group (Section 2 7) The group —CH3 Mevalonic acid (Section 26 10) An intermediate in the biosyn thesis of steroids from acetyl coenzyme A Micelle (Section 19 5) A sphencal aggregate of species such as carboxylate salts of fatty acids that contain a lipophilic end and a hydrophilic end Micelles containing 50-100 car boxylate salts of fatty acids are soaps Michael addition (Sections 18 13 and 21 9) The conjugate ad dition of a carbanion (usually an enolate) to an a 3 unsatu rated carbonyl compound... 

Bde salts, cholesterol, phosphoHpids, and other minor components are secreted by the Hver. Bile salts serve three significant physiological functions. The hydrophilic carboxylate group, which is attached via an alkyl chain to the hydrophobic steroid skeleton, allows the bile salts to form water-soluble micelles with cholesterol and phosphoHpids in the bile. These micelles assist in the solvation of cholesterol. By solvating cholesterol, bile salts contribute to the homeostatic regulation of the amount of cholesterol in the whole body. Bile salts are also necessary for the intestinal absorption of dietary fats and fat-soluble vitamins (24—26). 

If a molecule contains several asymmetric C atoms, then the diastereomers show diastereotopic shifts. Clionasterol (28a) and sitosterol (28b) for example, are two steroids that differ only in the absolute configuration at one carbon atom, C-24 Differing shifts of C nuclei close to this asymmetric C atom in 28a and b identify the two diastereomers including the absolute configuration of C-24 in both. The absolute configurations of carboxylic acids in pyrrolizidine ester alkaloids are also reflected in diastereotopic H and C shifts which is used in solving problem 54. 

Carboxylic esters are usually decomposed by heating the fused steroid at 300 to 500°, often under vacuum. Benzoates decompose at lower temperatures than acetates, and some selectivity of elimination can be achieved from steroids carrying both functionalities. " The high temperatures necessary for these eliminations preclude their use with sensitive compounds, and successful applications have usually been with naked steroids, in which case yields may be quite good. °° ... 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

Pentafluorobenzyl bromide has been used in the derivatization of mercaptans [55] and phenols [36], m the analysis of prostaglandins [37], and in quantitative GC-MS [5S] 1,3 Dichlorotetrafluoroacetone is used for the derivatization of amino acids to the corresponding cyclic oxazolidinones and allows the rapid analysis of all 20 protein ammo acids [d] Pentafluorophenyldialkylchlorosilane derivatives have facilitated the gas chromatographic analysis of a wide range of functionally substituted organic compounds, including steroids, alcohols, phenols, amines, carboxylic acids, and chlorohydrms [4]... 

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