15. Anti-inflammatory esters of steroidal carboxylic acids

Bain, B.M.; May, Paul J.; Phillipps, G. H.; Woollett, E. A.

doi:10.1016/0022-4731(74)90160-5

Cited by 7 publications

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“…6a 9a °1H NMR and infrared spectra were obtained for all compounds, and data are in the Experimental Section for selected compounds. 6 Persistent solvation was confirmed spectroscopically.c Decomposition. C-17 resonances (92.1 and 91.1 ppm) were structurally characteristic, and the 1H NMR confirmed that the ethyl groups in each isomer were no longer part of an ester function; the configurations of the two isomers were not established.…”

Section: Chemistrymentioning

confidence: 89%

“…NMR (90 MHz) 0.99 (13-CH3 s) 1.07 (propionate CH3, t,J = 7 Hz), 1.29 = 6 Hz), 2.39 (propionate CH2, q, J = 7 Hz), 2.99, 3.04 ( ß2, singlets), 7.32 (1-H, d, J = 10 Hz).…”

Section: Methodsmentioning

confidence: 99%

“…NMR (90 MHz) 0.98 (13-CHs, s), 1.06 (propionate CH3, t, =7 = 7 Hz), d,=7=7 Hz), 1.53 (10-CH3, s), 2.38 (propionate CH2, q, =7 = 7 Hz), 4.28 (lla-H, broad m), 5.11 (CH2C1, s), 6.05 (4-H, m), 6.27 (2-H, broad d, J = 10 Hz), 7.29 (1-H, d, =7 = 10 Hz). A similar result was obtained with ICH2C1 in place of BrCH2Cl.…”

Section: Methodsmentioning

confidence: 99%

“…The carbothioic acid 6i (0.104 g, 0.230 mmol) in DMSO (1 mL) was stirred and heated at 85 °C for 1.5 h. The solution was diluted with EtOAc (100 mL), washed with 5% NaHCOs and water, dried, and evaporated in vacuo to a solid (0.108 g). PLC and two crystallizations from acetone gave the title disulfide (0.068 g, 65.6%): NMR (90 MHz) 0.99 (13-CH3, s), 1.06 (propionate CHs, t, J = 7 Hz), d, J = 6 Hz), 1.52 (10-CHs, s), 2.42 (propionate CH2, q, J = 7 Hz), 4.33 (11a-H, m), 5.72 (11/S-OH, m), 6.08 (4-H, s), 6.29 Test Methods. Human Vasoconstrictor Activity.…”

Section: S-fluoromethylmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationships in a Series of Antiinflammatory Corticosteroid Analogs, Halomethyl Androstane-17.beta.-carbothioates and -17.beta.-carboselenoates

Phillipps¹,

Bailey²,

Bain³

et al. 1994

J. Med. Chem.

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The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)- 11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alpha-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17 beta-carboselenoate analogues. Anti-inflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 alpha-propionyloxy group. S-Fluoromethyl 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha- (propionyloxy)androsta-1,4-diene-17 beta-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.

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Section: Chemistrymentioning

confidence: 89%

“…NMR (90 MHz) 0.99 (13-CH3 s) 1.07 (propionate CH3, t,J = 7 Hz), 1.29 = 6 Hz), 2.39 (propionate CH2, q, J = 7 Hz), 2.99, 3.04 ( ß2, singlets), 7.32 (1-H, d, J = 10 Hz).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: S-fluoromethylmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationships in a Series of Antiinflammatory Corticosteroid Analogs, Halomethyl Androstane-17.beta.-carbothioates and -17.beta.-carboselenoates

Phillipps¹,

Bailey²,

Bain³

et al. 1994

J. Med. Chem.

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Hormones, Adrenal‐Cortical

Avery

Woolfrey

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Adrenal‐cortical hormones, following the introduction of cortisone and hydrocortisone nearly a half‐century ago, have continued to be the drug of choice in treatment of afflictions ranging from skin rash to severe acute inflammatory disorders and are now included in many other therapeutic regimes. The adrenal cortex releases both mineralocorticoids and glucocorticoids; the latter influence carbohydrate and protein metabolism, and the former regulate sodium reabsorption in the kidney. Moreover, corticosteroids and their metabolites were early noted to possess powerful antiinflammatory and immunomodulatory properties, leading to a massive increase in research in the area of steroid synthesis and physiology, imparting great impetus to the development of synthetic steroids. These exhibited activities far greater than those of the natural hormones, thereby opening the way to development of many more active antiinflammatory agents. Corticosteroids are commonly used as topicals for the suppression of symptoms, including inflammation. Though they are rarely considered curative, many diseases respond well symptomatically to treatment with them, eg, liver disease, acute spinal cord injury, organ transplants, GI diseases, and dermatologic diseases, among others. Mineralocorticoid therapy is less common. Progesterone is the key intermediate in both mineralocorticoid and glucocorticoid biosynthesis. Cortisol and aldosterone are results of oxidations of progesterone. The major metabolic transformations of the adrenal cortical hormones generally follow the metabolism of cortisol. The effects of adrenal‐cortical steroids are thought to result from their interaction with intracellular receptors; these are the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The primary structure of the GR has been identified as a 795 residue protein; a significant amount of 3‐D structure elucidation of the GR has been made. The process by which adrenocortical steroids impart their action is based on the action of the steroid on a receptor (GR or MR). The use of glucocorticoids leads to antiinflammatory effects by first controlling gene expression, which subsequently leads to the synthesis and/or suppression of inflammation regulatory proteins. Microorganisms are available which transform progesterone and cortisone into steroids. These steroids surpass their parent hormones in antirheumatic and antillergic activity and produce lower levels of side effects. When tested in patients with rheumatoid arthritis, fludrocortisone acetate proved to be 10 times more potent than hydrocortisone acetate. Triamcinolone possesses high glucocorticoid and antiinflammatory activity and is almost entirely devoid of salt‐retaining activity. 2α‐Methyl‐9α‐fluorocortisol has been reported to show enhanced glucocorticoid activity and greatly enhanced mineralocorticoid activity, surpassing aldosterone in sodium‐retaining and potassium‐excreting potency. Hyperaldosteronism is accompanied by elevation of blood pressure and can be treated with an aldosterone antagonist, eg, spironolactone. Antagonists of glucocorticoid and mineralocorticoid activity have found increased use in the treatment of hypertension. The most clinically useful GR antagonist is RU‐486.

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Optimisation of Drug Delivery: 7. Bioreversible Chemical Modifications of Drugs

Prankerd¹

1998

The Australian Journal of Hospital Pharmacy

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This article reviews the appplication of bioreversible chemical modification to overcome drug delivery or drug utilisation problems. This involves the use of prodrugs, ‘soft’ drugs and chemical delivery systems. Mechanisms are outlined for some specific examples. Drug products available in Australia which are based on these approaches are listed. As this area of drug delivery optimisation is still developing, examples which indicate future directions have been selected for review.

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15. Anti-inflammatory esters of steroidal carboxylic acids

Cited by 7 publications

References 0 publications

Synthesis and Structure-Activity Relationships in a Series of Antiinflammatory Corticosteroid Analogs, Halomethyl Androstane-17.beta.-carbothioates and -17.beta.-carboselenoates

Synthesis and Structure-Activity Relationships in a Series of Antiinflammatory Corticosteroid Analogs, Halomethyl Androstane-17.beta.-carbothioates and -17.beta.-carboselenoates

Hormones, Adrenal‐Cortical

Optimisation of Drug Delivery: 7. Bioreversible Chemical Modifications of Drugs

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