- Evidence for a new biologic pathway of androstenedione synthesis from 11-deoxycortisol
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17-Hydroxyprogesterone is a well-known precursor of androstenedione in adrenal biosynthesis.This study using sheep adrenal incubations demonstrates that 11-deoxycortisol, the precursor of cortisol synthesis, also can be a precursor of androstenedione.Indeed, our data shown that androstenedione synthesis is negatively correlated to the synthesis of cortisol and cortisone.This fact allowed us to infer that this new pathway is closely related to the activity of the 11β-hydroxylase that is responsible for the synthesis of cortisol.Indeed, when the activity of this enzyme is impaired, 11-deoxycortisol follows the pathway that leads to androstenedione synthesis in the adrenals.This pathway could explain, at least in part, the marked increase of androstenedione observed in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.
- Auzeby, Andre,Bogdan, Andre,Touitou, Yvan
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Read Online
- ADRENAL 11-HYDROXYLASE ACTIVITY IN A HYPERCORTISOLEMIC NEW WORLD PRIMATE: ADAPTIVE INTRA-ADRENAL CHANGES
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The squirrel monkey, a representative New World primate, has high plasma cortisol and aldosterone concentrations when compared to Old World primates.We measured adrenal mitochondrial 11-hydroxylase (11-OHase) activity in squirrel monkeys and in two representative Old World species (cynomolgus and rhesus macaques) in an effort to explain these elevated plasma glucocorticoid and mineralocorticoid levels.The activity of 11-OHase was 5-fold higher in the squirrel monkey than in the Old World species tested.Calculated 11-OHase Vmax was different in the squirrel monkey and the cynomolgus.However, the Km values were similar in the New World primate when compared to cynomolgus.The ability of metyrapone to block 11-OHase was less in the former than in the latter.The data are consistent with the hypothesis that the squirrel monkey adrenal cortex possesses an increased number of 11-hydroxylase enzyme units compared to that of Old World primate species, and is therefore more efficient in producing cortisol.This difference in 11-OHase activity in the squirrel monkey, in addition to other previously reported adrenal steroidogenic enzyme alterations, may be adaptive in nature, favoring increased cortisol and aldosterone production in this and possibly other New World primate species.
- Albertson, Barry D.,Brandon, David D.,Chrousos, George P.,Loriaux, D. Lynn
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Read Online
- Preparation method of high-purity hydrocortisone
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The invention discloses a preparation method of high-purity hydrocortisone, and belongs to the technical field of preparation and processing of medicines. According to the method, 17alpha-hydroxypregna-4, 9 (11)-diene-3, 20-diketone-21-acetate is used as a starting material, and the high-purity hydrocortisone is prepared through three steps of bromo-hydroxyl, debromination and hydrolysis. According to the preparation method of the high-purity hydrocortisone disclosed by the invention, the reaction process can be effectively shortened by improving the defects of a traditional process, the generation of impurities during the reaction process is controlled, the use of iodine with characteristics of high toxicity and environmental unfriendliness is avoided, the environmental pollution is reduced, and the method has characteristics of high overall conversion rate, simple operation and wide market prospect, and is suitable for industrial production.
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- Hydrocortisone compound with 1/10 water
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The invention discloses a hydrocortisone compound with 1/10 water and a preparation method of the hydrocortisone compound. According to powder X-ray diffraction measurement of the compound, characteristic diffraction peaks are shown at positions with 2theta+/-0.2 degree diffraction angles of 5.6 degrees, 14.1 degrees, 16.0 degrees, 17.2 degrees and 18.5 degrees. The prepared hydrocortisone compound with 1/10 water has the advantages of good photostability and high purity, and the preparation method is simple in process, high in yield and high in repeatability, and is suitable for industrial production.
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Paragraph 0035; 0037-0038; 0039; 0041-0042; 0043; 0045-0046
(2020/01/14)
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- Dehalogenation methodof 9-halogenated steroid compound and application
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The invention provides a dehalogenation method of a 9-halogenated steroid compound and application, and relates to the technical field of chemical synthesis. The dehalogenation method of the 9-halogenated steroid compound comprises the following steps: reacting a compound I with a hydrogen donor and an azo radical initiator to obtain a 9-dehalogenated product compound II of the 9-halogenated steroid compound. According to the dehalogenation method of the 9-halogenated steroid compound, a hydrogen donor adopts one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene, and an initiator adopts an azo free radical initiator. Reagents such as chromium, divalent chromium salt, trivalent chromium salt or tributyltin hydride which are high in toxicity and cause serious pollution to the environment are not used in the reaction, the method is green and environmentally friendly, the synthesis process is simple, convenient and easy to implement, and the production applicability is improved.
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Paragraph 0161-0163
(2021/01/11)
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- A biocatalytic hydroxylation-enabled unified approach to C19-hydroxylated steroids
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Steroidal C19-hydroxylation is pivotal to the synthesis of naturally occurring bioactive C19-OH steroids and 19-norsteroidal pharmaceuticals. However, realizing this transformation is proved to be challenging through either chemical or biological synthesis. Herein, we report a highly efficient method to synthesize 19-OH-cortexolone in 80% efficiency at the multi-gram scale. The obtained C19-OH-cortexolone can be readily transformed to various synthetically useful intermediates including the industrially valuable 19-OH-androstenedione, which can serve as a basis for synthesis of C19-functionalized steroids as well as 19-nor steroidal drugs. Using this biocatalytic C19-hydroxylation method, the unified synthesis of six C19-hydroxylated pregnanes is achieved in just 4 to 9 steps. In addition, the structure of sclerosteroid B is revised on the basis of our synthesis.
- Wang, Junlin,Zhang, Yanan,Liu, Huanhuan,Shang, Yong,Zhou, Linjun,Wei, Penglin,Yin, Wen-Bing,Deng, Zixin,Qu, Xudong,Zhou, Qianghui
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- Preparation method of hydrocortisone
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The invention relates to a preparation method of a steroidal compound, in particular to a preparation method of hydrocortisone. The preparation method includes: sequentially subjecting chloride serving as the initiator to 9, 11-bromine hydroxyl preparation, 9, 11-reduction, 21-site esterification and 21-site hydrolysis to obtain the hydrocortisone. The preparation method has the advantages that the new preparation method has an industrialization value and can effectively control side reaction and increase reaction yield and quality; the design of the preparation does not involve with high-riskreaction, and industrialization can be achieved easily; the preparation method does not have high-pollution reaction, and environmental protection treatment pressure is relieved.
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- (Poly)cationic λ3-Iodane-Mediated Oxidative Ring Expansion of Secondary Alcohols
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Herein, a simplified approach to the synthesis of medium-ring ethers through the electrophilic activation of secondary alcohols with (poly)cationic λ3-iodanes (N-HVIs) is reported. Excellent levels of selectivity are achieved for C–O bond migration over established α-elimination pathways, enabled by the unique reactivity of a novel 2-OMe-pyridine-ligated N-HVI. The resulting hexafluoroisopropanol (HFIP) acetals are readily derivatized with a range of nucleophiles, providing a versatile functional handle for subsequent manipulations. The utility of this methodology for late-stage natural product derivatization was also demonstrated, providing a new tool for diversity-oriented synthesis and complexity-to-diversity (CTD) efforts. Preliminary mechanistic investigations reveal a strong effect of alcohol conformation on the reactive pathway, thus providing a predictive power in the application of this approach to complex molecule synthesis.
- Walters, Jennifer C.,Tierno, Anthony F.,Dubin, Aimee H.,Wengryniuk, Sarah E.
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supporting information
p. 1460 - 1464
(2018/04/06)
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- Facile synthesis of corticosteroids prodrugs from isolated hydrocortisone acetate and their quantum chemical calculations
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In the present research paper corticosteroids prodrugs of hydrocortisone acetate (1) have been synthesized, which was isolated from the flowers of Allamanda Violacea. The hydrocortisone acetate (1) was hydrolyzed to hydrocortisone (2) which was subsequently converted to prednisolone (3). Both the hydrocortisone (1) and prednisolone (2) underwent Steglich esterification with naproxen and Ibuprofen yielding compounds 11, 17 dihydroxy-21-(2-(6-methoxynaphthalene-2yl) propionoxy)-pregn-4-ene-3, 20-dione (4), 11, 17-dihydroxy-21-(2-(4-isobutylphenyl) propionoxy)-pregn-4-ene-3, 20-dione (5), 21-(2-(6-methoxynaphthalene-2-yl) propionoxy) 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene (6) and 11,17-di-hydroxy-3,20-diketo-pregn-1,4-diene-21-yl-2-(4-isobutylphenyl) propanoate (7). The synthesized compounds have been characterized with the help of spectroscopic techniques like 1H, 13C NMR, FT-IR spectroscopy and mass spectrometry. Density functional theory (DFT) with B3LYP functional and 6-31G (d, p) basis set has been used for the Quantum chemical calculations. The electronic properties such as frontier orbitals and band gap energies were calculated by TD-DFT approach. Intramolecular interactions have been identified by AIM (Atoms in Molecule) approach and vibrational wavenumbers have been calculated using DFT method. The reactivity and reactive site within the synthesized prodrugs have been examined with the help of reactivity descriptors. Dipole moment, polarizability and first static hyperpolarizability have been calculated to get a better insight of the properties of synthesized prodrugs. The molecular electrostatic potential (MEP) surface analysis has also been carried out.
- Sethi, Arun,Singh, Ranvijay Pratap,Prakash, Rohit,Amandeep
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p. 860 - 866
(2016/12/18)
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- A from the butyric acid of hydrocortisone in the mother liquor recovery of hydrocortisone method
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The invention discloses a method for recycling hydrocortisone in hydrocortisone butyrate mother liquor. The method comprises the steps of adding refined hydrocortisone butyrate mother liquor into methyl alcohol to obtain a mixture, concentrating the mixture until the mixture is sticky, adding a mixed solvent for stirring and dissolving, and performing cooling; under the protection of inert gas, dropping alkaline liquid, performing heat preservation reaction after the alkaline liquid is added; performing neutralization, concentration, freezing filtration and drying to obtain hydrocortisone. By a reaction mode combining inert gas protection and the mixed solvent, the phenomenon that materials cannot be recycled because of decomposition of compounds due to breakage of the D-ring structure of steroid nucleus is effectively avoided. The method disclosed by the invention is easy to operate, short in treatment time, low in production cost and high in production safety and material stability, and the environment cannot be polluted; the recycling rate is high, so that the purity of recycled hydrocortisone is high; after being dried, hydrocortisone can be directly used as a raw material for producing hydrocortisone butyrate.
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Paragraph 0027; 0028; 0029; 0030; 0031; 0032
(2017/08/25)
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- Method for preparing hydrocortisone
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The invention relates to a method for preparing hydrocortisone. The method includes: subjecting a cortisone acetate raw material to sites No. 3,20-keto protective reaction, site No.11-keto reduction reaction, site No.21-hydroxy esterification reaction, sites No. 3,20-ketone deprotection reaction, and site No. 21-acetate hydrolysis to obtain hydrocortisone. The method provides a new synthetic route containing esterification and deprotection in order, greatly improves the reaction selectivity, easily separates deprotection reaction products and avoids the posttreatment of tedious several times of extraction of a large amount of solvents in the traditional deprotection reaction process, and also avoids the side reaction caused by quenching reaction in the posttreatment of the traditional process; and the ester hydrolysis reaction is carried out under protection of inert gases in a mixed solvent, so as to avoid by-products produced in the hydrolysis reaction. The process route of the invention is novel, simple for operation, low in production cost, and applicable to industrial scale production.
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Paragraph 0022
(2016/10/17)
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- Selective acceptorless dehydrogenation and hydrogenation by iridium catalysts enabling facile interconversion of glucocorticoids
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An iridium(III) pentamethylcyclopentadienyl catalyst supported by 6,6'-dihydroxy-2,2'-bipyridine displays exquisite selectivity in acceptorless alcohol dehydrogenation of cyclic α,β-unsaturated alcohols over benzylic and aliphatic alcohols under mild aqueous reaction conditions. Hydrogenation of aldehydes and ketones occurs indiscriminately using the same catalyst under hydrogen, although chemoselectivity could be achieved when other potentially reactive carbonyl groups present are sterically inaccessible. This chemistry was demonstrated in the reversible hydrogenation and dehydrogenation of the A ring of glucocorticoids, despite the presence of other alcohol/or carbonyl functionalities in rings C and D. NMR studies suggest that an iridium(III) hydride species is a key intermediate in both hydrogenation and dehydrogenation processes.
- Ngo, Anh H.,Adams, Michael J.,Do, Loi H.
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supporting information
p. 6742 - 6745
(2015/02/19)
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- Carbonyl reduction of triadimefon by human and rodent 11β- hydroxysteroid dehydrogenase 1
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11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the conversion of inactive 11-oxo glucocorticoids (endogenous cortisone, 11-dehydrocorticosterone and synthetic prednisone) to their potent 11β-hydroxyl forms (cortisol, corticosterone and prednisolone). Besides, 11β-HSD1 accepts several other substrates. Using rodent liver microsomes and the unspecific inhibitor glycyrrhetinic acid, it has been proposed earlier that 11β-HSD1 catalyzes the reversible conversion of the fungicide triadimefon to triadimenol. In the present study, recombinant human, rat and mouse enzymes together with a highly selective 11β-HSD1 inhibitor were applied to assess the role of 11β-HSD1 in the reduction of triadimefon and to uncover species-specific differences. To further demonstrate the role of 11β-HSD1 in the carbonyl reduction of triadimefon, microsomes from liver-specific 11β-HSD1-deficient mice were employed. Molecular docking was applied to investigate substrate binding. The results revealed important species differences and demonstrated the irreversible 11β-HSD1-dependent reduction of triadimefon. Human liver microsomes showed 4 and 8 times higher activity than rat and mouse liver microsomes. The apparent Vmax/ Km of recombinant human 11β-HSD1 was 5 and 15 times higher than that of mouse and rat 11β-HSD1, respectively, indicating isoform-specific differences and different expression levels for the three species. Experiments using inhibitors and microsomes from 11β-HSD1-deficient mice indicated that 11β-HSD1 is the major if not only enzyme responsible for triadimenol formation. The IC50 values of triadimefon and triadimenol for cortisone reduction suggested that exposure to these xenobiotica unlikely impairs the 11β-HSD1-dependent glucocorticoid activation. However, elevated glucocorticoids during stress or upon pharmacological administration likely inhibit 11β-HSD1-dependent metabolism of triadimefon in humans.
- Meyer, Arne,Vuorinen, Anna,Zielinska, Agnieszka E.,Da Cunha, Thierry,Strajhar, Petra,Lavery, Gareth G.,Schuster, Daniela,Odermatt, Alex
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p. 1370 - 1378
(2013/08/25)
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- Design, synthesis, and pharmacological effects of a cyclization-activated steroid prodrug for colon targeting in inflammatory bowel disease
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Glucocorticoids are used in the treatment of inflammatory bowel disease. A limitation to their use is that they undergo absorption from the GIT before reaching the colon causing severe systemic side effects. We report here on a novel prodrug approach to targeting corticosteroids to the colon. The design involves attaching a 21-ester group that suppresses absorption during transit to the colon. The prodrug is designed to be primed by colonic microflora liberating an amino ester that cyclizes releasing the steroid. One of the prodrugs 5b was as efficacious as prednisolone in the murine DSS model but did not cause thymic atrophy, a marker for systemic steroid effects.
- Márquez Ruiz, Juan F.,Radics, Gabor,Windle, Henry,Serra, Hugo O.,Simplício, Ana Luísa,Kedziora, Kinga,Fallon, Padraic G.,Kelleher, Dermot P.,Gilmer, John F.
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supporting information; experimental part
p. 3205 - 3211
(2010/03/24)
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- Discovery of novel dual functional agent as PPARγ agonist and 11β-HSD1 inhibitor for the treatment of diabetes
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PPARγ and 11β-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARγ agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11β-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of α-aryloxy-α-methylhydrocinnamic acids as dual functional agents which activate PPARγ and inhibit 11β-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARγ (EC50 = 6.76 μM) and 11β-HSD1 (IC50 = 0.76 μM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.
- Ye, Yang-liang,Zhou, Zhou,Zou, Han-jun,Shen, Yu,Xu, Ti-fei,Tang, Jing,Yin, Hua-zhong,Chen, Min-li,Leng, Ying,Shen, Jian-hua
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scheme or table
p. 5722 - 5732
(2009/12/28)
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- PHENYLSULFONAMIDE DERIVATIVES FOR USE AS 11-BETA-HYDROXYSTEROID DEHYDROGENASE INHIBITORS
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A compound having Formula (I): R1-SO2NR3-L-R2; wherein R1 is an optionally substituted phenyl ring; R2 is a heterocyclic ring; R3 is H or a hydrocarbyl group; and L is an optional acyclic linker wherein when R2 is a five--membered aromatic heterocyclic ring, L is present. These compounds are useful as 11β-hydroxysteroid dehydrogenase inhibitors.
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(2008/06/13)
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- Chemical enhancer and method
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The present invention relates to compositions containing at least one salicylic acid derivative and at least one cosmetic, dermatologic, pharmaceutical, etc. active agent, where the salicylic acid derivative increases, enhances, etc., the efficacy of the active agent, as well as to methods of making and using such compositions. The invention further relates to a method for enhancing the efficacy of active agents with these salicylic acid derivatives.
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- Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
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Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
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- Pharmaceutical formulation
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PCT No. PCT/SE96/00123 Sec. 371 Date Mar. 8, 1996 Sec. 102(e) Date Mar. 8, 1996 PCT Filed Feb. 2, 1996 PCT Pub. No. WO96/24359 PCT Pub. Date Aug. 15, 1996The invention relates to a pharmaceutical composition for topical administration comprising a combination of foscarnet and an antiinflammatory glucocorticoid, in admixture with a carrier based on galactolipids and a polar solvent. The pharmaceutical composition can be used in a prophylactic and/or curative treatment of herpesvirus infections in mammals including man. The invention also relates to the use of said pharmaceutical composition in the manufacture of a medicament for said prophylactic or curative treatment.
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- Application of Curvularia sp to the hydrolysis of steroid pivalates
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As glucocorticoids have alkali - sensitive hydroxyacetylic side chain, conventional methods of removing of 21 - pivalates groups are risky. In this paper we described the hydrolysis of pivalates of some glucocorticoids by fungi imperfecti: Curvularia lunata, Curvularia tuberculata, Cylindrocladium simplex Meyer and Cunninghamella elegans. The highest yield of hydrolysis was found in the case of hydrocortisone and prednisolone pivalates with Curvularia lunata and Curvularia tuberculata. The other two tested enzymes gave in all studied cases null or extremely poor results.
- Kruszewska,Chmielowiec,Uszycka-Horawa
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p. 809 - 810
(2007/10/03)
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- 9α-dehalogenation process
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The present invention involves improved processes for the dehalogenation of 9α-halosteroids (I) STR1 to produce the corresponding 11β-hydroxy steroids (II) STR2 which are known to be useful as pharmaceutical, where the improvements comprise (1) adding the 9α-halo steroid (I) to the chromium and (2) using catalytic amounts of chromium in the presence of a means of converting chromium (II) to chromium (III).
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- Process for steroid preparation
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A process for the preparation of a compound of the formula STR1 wherein R1 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms optionally substituted by halogen or a nitrogen or oxygen function and alkenyl and alkynyl of 2 to 4 carbon atoms, R2 is alkyl of 1 to 4 carbon atoms and the A, B, C and D rings are optionally substituted by at least one member of the group consisting of optionally protected --OH or =0, halogen, alkyl and alkoxy of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms comprising reacting a compound of the formula STR2 wherein R1 and R2 and the A, B, C and D rings are defined as above with an oxidizing agent in the presence of water and an at least partially water-miscible solvent to obtain a compound of the formula STR3 wherein R1 and R2 and the A, B, C and D rings are defined as above, subjecting the latter to a solvolysis in a basic or acidic media and optionally subjecting the product to a deprotection reaction of any protected --OH or =0 groups to obtain the compound of formula I and novel intermediates.
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- Gastric preparation with sustained release
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A gastric preparation developed in order to solve the technical problems of conventional preparations, which is prepared by the bilayer packing technique and comprises 5 to 60%, desirably 10 to 40% of a rapid release portion which can establish the therapeutic level of a drug shortly after the administration and 95 to 40%, desirably 90 to 60% of a sustained release portion which has a specific gravity or 1 or less and can maintain a satisfactory release rate.
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- Process for the preparation of hydrocortisone
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An improved process for the preparation of hydrocortisone and novel intermediates which avoids an 11-hydroxylation step and results in improved yields.
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- Inhibition of angiogenesis
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Angiogenesis in mammals is inhibited by administration of the active agents (1) heparin or a heparin fragment which is a hexasaccharide or larger or analogous compounds and (2) a steroid having 17α- and 21-hydroxy groups, 3- and 20-one groups, and in the 16-position hydrogen hydroxy or a methyl group, and non-toxic physiologically acceptable carboxylates, acetals, ketals and phosphates thereof.
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- BIOSYNTHESIS OF ANDROGENS BY PHEOCHROMOCYTOMAS
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Homogenates from four adrenal pheochromocytomas converted 4-14C-labeled pregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone into androstenedione and testosterone.In addition to these androgens, labeled pregnane substrates were also transformed into corticosteroids, as previously reported, and this conversion occurred in even higher yield.The formation of labeled metabolites of either pathway was greater in homogenates from intraadrenal pheochromocytomas than in those derived from an extraadrenal tumor, but less than in preparations of hyperplastic adrenal cortex.Incubations of subcellular fractions isolated from an adrenal pheochromocytoma showed that the enzyme activities involved in androgen formation from the radioactive substrates studied were associated with the microsomes and required exogenous cofactors.In contrast to adrenocortical tissue, chromaffin cell preparations uniformly failed to convert substrate cholesterol into either androgens or corticosteroids.The data available demonstrate the presence in chromaffin tissue of all of the enzyme activities required for the biosynthesis of androgens and corticosteroids except for those involved in the side-chain scission of cholesterol.
- Carballeira, Andres,Brown, John W.,Fishman, Lawrence M.
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p. 647 - 660
(2007/10/02)
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- High molecular weight prodrug derivatives of antiinflammatory drugs
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Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
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- Partial Purification and Characterization of Two β-Glucoronidases from Alcaligenes NG-11
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A strain of Alcaligenes isolated from soil was a good producer of β-glucuronidase, and the enzyme was purified from the cell-free extract by sequential column chromatography on DEAE-Toyopearl, Toyopearl HW-55F, and Phenyl-Sepharose CL-4B.By these procedures, two β-glucuronidases designated as β-glucuronidases I and II were purified 240- and 508-fold, respectively. β-Glucuronidase I, with a molecular weight of 75,000, had an optimum pH at 7.5 and the enzyme II, with a molecular weight of 300,000, and maximum activity at pH 6.0.Both enzymes were strongly inhibited by saccharo-1,4-lactone, glucaro-δ-lactam, p-chloromercuribenzoate, Hg2+, and N-bromosuccinimide. β-Glucuronidase I was active toward estrogen-3-β-glucuronides and inert toward β-glucuronide conjugates of menthol, estrogen-17β-, estrogen-16α-, androsterone-3α-, testosterone-17β-, cortisol-17α-. β-Glucuronidase II hydrolyzed all of these substrates. β-Glucuronidase I was inhhibited by phenolphthalein and its glucuronide.
- Ogushi, Susumu,Koga, Satoshi,Ito, Kiyoshi,Makino, Yasutaka,Ando, Makoto,Tsuru, Daisuke
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p. 3093 - 3100
(2007/10/02)
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- Process and intermediates for the preparation of 17 alphahydroxyprogesterones and corticoids from an enol steroid
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This invention discloses an improved process for the production of corticoids from 17α-hydroxy steroids utilizing peroxymonosulfate.
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- Solution kinetics of a water-soluble hydrocortisone prodrug: Hydrocortisone-21-lysinate
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Hydrocortisone-21-lysinate was synthesized as an amino acid prodrug of hydrocortisone to serve as a substrate for brush border aminopeptidases. This strategy was developed to demonstrate that an improvement in oral absorption could be obtained through reconversion in vivo. The aqueous stability of hydrocortisone-21-lysinate was studied over the pH range 3-8 at 25 °C. Reversible acyl migration of the lysine group between the 21- and 17-position hydroxyl groups was observed as well as hydrolysis. The observed half-life for direct hydrolysis of hydrocortisone-21-lysinate is 40 d at pH 3 and 30 min at pH 7. The relative instability at pH 7 is probably due to electrostatic stabilization of the negatively charged tetrahedral intermediate by the protonated amino groups.
- Johnson,Amidon,Pogany
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- Sulfonate containing ester prodrugs of corticosteroids
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Novel solution stable ester prodrugs of corticosteroids of the formula STR1 and their salts.
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- Radiolytic degradation scheme for 60Co-irradiated corticosteroids
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The cobalt 60 radiolytic degradation products have been identified in the following corticosteroids: cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone sodium succinate, isoflupredone acetate, methylprednisolone, methylprednisolone acetate, prednisolone, prednisolone acetate, and prednisone. Two major types of degradation processes have been identified: loss of the corticoid side chain the D-ring to produce the C-17 ketone and conversion of the C-11 alcohol, if present, to the C-11 ketone. Minor degradation products derived from other changes affecting the side chain are also identified in several corticosteroids. These compounds are frequently associated in corticosteroids as process impurities or degradation compounds. No new radiolytic compounds unique to 60Co-irradiation have been found. The majority of corticosteroids have been shown to be stable to 60Co-irradiation. The rates of radiolytic degradation ranged from 0.2 to 1.4%/Mrad.
- Kane,Tsuji
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- Differences between adrenal adenoma causing primary aldosteronism and other adrenal tissues in the incorporation of labeled steroid precursors into their products
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The incorporation and conversion of several labeled steroid precursors into their products were examined in slices of adrenal tissue from two patients with primary aldosteronism and compared with that in 'normal' adrenal tissue and adrenal tissues from a patient with Cushing's syndrome. The products of the incorporation were separated by Sephadex LH-20 column chromatography. The major products of conversion in the adenomatous tissue of primary aldosteronism were 18-hydroxycorticosterone and lesser amounts of aldosterone. Smaller amounts of 18-hydroxycorticosterone were isolated from all other adrenal tissues studied. No aldosterone could be recovered after incubating any of the adrenal tissue studied with labeled 18-hydroxy-11-deoxycorticosterone or 18-hydroxycorticosterone as precursor steroid. These in vitro results seem to suggest that there is increased 18-hydroxylation in the adenoma of primary aldosteronism compared with other tissues and that relatively more 18-hydroxycorticosterone is produced in such tissue than aldosterone.
- Usa,Ganguly,Weinberger
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p. 531 - 545
(2007/10/02)
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- Novel 17-substituted 11 β-hydroxy steroids of the pregnane series, their manufacture, preparation and use
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Corticoids of the formula STR1 wherein represents a single bond or a double bond; X is hydrogen, fluorine, chlorine or methyl; Y is hydrogen and Z is hydrogen, fluorine or chlorine, or Y and Z together are a carbon-to-carbon bond; V is β-hydroxymethylene, β-chloromethylene or carbonyl; W is methylene, ethylidene or vinylidene; Q is oxygen or sulfur; R1 is alkyl of 1-8 carbon atoms, alkyl of 2-8 carbon atoms with an oxygen atom between two of the carbon atoms or benzyl, and R2 is hydrogen or alkyl of 1-4 carbon atoms, or R1 and R2 collectively are trimethylene or tetramethylene; and R3 is hydrogen, fluorine, chlorine, hydroxy, or hydroxy esterified by a C1-16 hydrocarbon carboxylic acid have valuable pharmacological properties, e.g., anti-inflammatory activity.
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- Novel steroids of the pregnane series, substituted in the 17-position, their manufacture and their use
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Steroids of the formula STR1 wherein represents a single or double bond, X is hydrogen, fluorine or methyl; Y is hydrogen, hydroxy or alkanoyloxy of 1-6 carbon atoms; Z is hydrogen or methyl; V is methylene, ethylidene, hydroxymethylene or vinylidene; and R1 is alkyl of 1-6 carbon atoms or alkyl of 2-6 carbon atoms with an oxygen atom between two of the carbon atoms; R2 is hydrogen or alkyl of 1-6 carbon atoms, or R1 and R2 together form a tri- or tetramethylene group provided that Y is hydroxy or alkanoyloxy; have pharmacological activity and are useful as intermediates for preparing other pharmacologically active steroids.
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- Selenium-75 steroids
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Novel dimeric and monomeric selenium-75 derivatives of steroids are made by reacting a keto steroid with selenium-75 dioxide or selenious acid-Se75. The resulting diselenide dimers can be converted into monomeric compounds by the use of a cleaving reagent followed by an alkylating agent. The compounds are useful in saturation analyses such as radioimmunoassays.
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- Novel N-nitroso compounds, compositions containing such compounds, processes for their preparation and methods of treatment therewith, and novel intermediates
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This invention relates to novel N-halogenoalkyl-N-nitroso carbamates and N 4 halogenalkyl-N 4 -nitroso allophanates of steroid compounds, having an anti-tumor activity, and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and methods of treatment therewith.
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