- Characterization of new recombinant 3-ketosteroid-Δ1-dehydrogenases for the biotransformation of steroids
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3-Ketosteroid-Δ1-dehydrogenases (KstDs [EC 1.3.99.4]) catalyze the Δ1-dehydrogenation of steroids and are a class of important enzymes for steroid biotransformations. In this study, we cloned 12 putative KstD-encoding (kstd) genes from both fungal and Gram-positive microorganisms and attempted to overproduce the recombinant proteins in E. coli BL21(DE3). Five successful recombinant enzymes catalyzed the Δ1-desaturation of a variety of steroidal compounds such as 4-androstene-3,17-dione (AD), 9α-hydroxy-4-androstene-3,17-dione (9-OH-AD), hydrocortisone, cortisone, and cortexolone. However, the substrate specificity and catalytic efficiency of the enzymes differ depending on their sources. The purified KstD from Mycobacterium smegmatis mc2155 (MsKstD1) displayed high catalytic efficiency toward hydrocortisone, progesterone, and 9-OH-AD, where it had the highest affinity (Km 36.9?±?4.6?μM) toward 9-OH-AD. On the other hand, the KstD from Rhodococcus erythropolis WY 1406 (ReKstD) exhibited high catalytic efficiency toward androst-4,9(11)-diene-3,17-dione (Diene), 21-acetoxy-pregna-4,9(11),16-triene-3,20-dione (Triene), and cortexolone, where in all three cases the Km values (12.3 to 17.8?μM) were 2.5–4-fold lower than that toward hydrocortisone (46.3?μM). For both enzymes, AD was a good substrate although ReKstD had a 3-fold higher affinity than MsKstD1. Reaction conditions were optimized for the biotransformation of AD or hydrocortisone in terms of pH, temperature, and effects of hydrogen peroxide, solvent, and electron acceptor. For the biotransformation of hydrocortisone with 20?g/L wet resting E. coli cells harboring MsKstD1 enzyme, the yield of prednisolone was about 90% within 3?h at the substrate concentration of 6?g/L, demonstrating the application potential of the newly cloned KstDs.
- Wang, Xiaojun,Feng, Jinhui,Zhang, Dalong,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
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Read Online
- Microbial transformation of topical corticosteroid: Prednicarbate
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In the present research, the steroidal antiinflammatory topically used drug prednicarbate (1) was subjected to microbial biotransformation by Cunninghamella elegans. Prednicarbate (1) was transformed into various metabolites. One new and two known metabolites were purified named as prednisolone 17-ethylcarbonate (2) Prednisolone (3) and 4-(4-hydroxybenzyl)-2-(3-methylbut-2-enyl)phenyl methyl carbonate (4). The compound (4) was separated as a new compound and was not reported in literature. Its structure did not show resemblance with prednicarbate so possibly derived from fungal mass. Their structures were elucidated by using modern spectroscopic techniques e.g. 13C NMR, 1H NMR, HMQC, HMQC, COSY, NOESY and mass spectrometry e.g. EI-MS.
- Ahmad, Saeed,Mukhtar, Muhammad Fahad,Khaliq, Farhan Hameed,Irshad, Sajid,Iqbal, Javed
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Read Online
- Preparation method of prednisolone acetate
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The invention relates to prednisolone acetate and a preparation method of prednisolone acetate, which are characterized in that the prednisolone acetate is prepared by sequentially carrying out a biological fermentation, an esterification reaction, a bromination reaction and a debromination reaction on the raw material, the prednisolone acetate is subjected to a hydrolysis reaction to obtain prednisolone, the overall yield is up to 81.75%, and the HPLC area normalization content of prednisolone is up to 99.5%. The preparation method is short in synthetic route and low in cost, is suitable forindustrial production, and has a very high industrial value.
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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 0149-0151
(2021/01/11)
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- Δ1-dehydrogenation and C20 reduction of cortisone and hydrocortisone catalyzed by rhodococcus strains
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Prednisone and prednisolone are steroids widely used as anti-inflammatory drugs. Development of the pharmaceutical industry is currently aimed at introducing biotechnological processes and replacing multiple-stage chemical syntheses. In this work we evaluated the ability of bacteria belonging to the Rhodococcus genus to biotransform substrates, such as cortisone and hydrocortisone, to obtain prednisone and prednisolone, respectively. These products are of great interest from a pharmaceutical point of view as they have higher anti-inflammatory activity than the starting substrates. After an initial lab-scale screening of 13 Rhodococcus strains, to select the highest producers of prednisone and prednisolone, we reported the 200 ml-batch scale-up to test the process efficiency and productivity of the most promising Rhodococcus strains. R. ruber, R. globerulus and R. coprophilus gave the Δ1-dehydrogenation products of cortisone and hydrocortisone (prednisone and prednisolone) in variable amounts. In these biotransformations, the formation of products with the reduced carbonyl group in position C20 of the lateral chain of the steroid nucleus was also observed (i.e., 20β-hydroxy-prednisone and 20β-hydroxy-prednisolone). The yields, the absence of collateral products, and in some cases the absence of starting products allow us to say that cortisone and hydrocortisone are partly degraded.
- Costa, Stefania,Fantin, Giancarlo,Semeraro, Bruno,Summa, Daniela,Zappaterra, Federico
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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 process for the preparation of prednisolone
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The application relates to a method for synthetizing prednisolone. Double bond bromination, reductive debromination, bromination and hydrolysis reaction are carried out on a compound with a structure of formula I so as to generate the prednisolone. The method is high in yield, is easy to operate, and is applicable to industrial production.
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Paragraph 0031
(2016/10/07)
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- A process for the preparation of prednisolone (by machine translation)
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The invention relates to a process for the preparation of prednisolone, including: to ACOH predinisone as raw materials, sequentially through the 3,20-keto-protection reaction and 11-keto-reduction reaction, 21-position hydroxy esterification reaction, 3,20- position alkone remove protection reaction, 21-bit b ester hydrolysis reaction is prednisolone. The present invention provides a first esterification, then deprotected of the new synthetic route, the deprotected process the nitrosation quenching reaction and resin hydrolysis reaction; an ester reaction in the mixed solvent and to complete the protection of inert gas, to avoid the hydrolysis reaction produces by-products. Process route of this invention is novel, the operation process is simple, the production cost is low, is suitable for industrial scale production. (by machine translation)
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Paragraph 0020
(2016/12/16)
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- A nitrophenyl-based prodrug type for colorectal targeting of prednisolone, budesonide and celecoxib
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Celecoxib is a COX-2 inhibitor drug that can be used to reduce the risk of colorectal adenocarcinoma. Glucocorticoids are used in the treatment of inflammatory bowel disease. A limitation to the use of both drug types is that they undergo absorption from the intestinal tract with serious side effects. The prodrug systems introduced here involve forming a nitro-substituted acylsulfonamide group in the case of celecoxib and a nitro-substituted 21-ester for the glucocorticoids. Drug release is triggered by the nitro reductase action of the colonic microflora, liberating a cyclization competent species. The release of the active parent drugs was evaluated in vitro using Clostridium perfringens and epithelial transport through Caco-2 monolayer evaluation was carried out to estimate the absorption properties of the prodrugs compared to the parental drugs.
- Marquez Ruiz, Juan F.,Kedziora, Kinga,Pigott, Maria,Keogh, Brian,Windle, Henry,Gavin, Jason,Kelleher, Dermot P.,Gilmer, John F.
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p. 1693 - 1698
(2013/04/10)
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- FLUOROQUINOLONE DERIVATIVES FOR OPHTHALMIC APPLICATIONS
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The present invention relates to fluoroquinolone derivatives having enhanced ocular penetration characteristics and/or antimicrobial activity, and to compositions comprising such derivatives. The derivatives and compositions are particularly well suited for treating ophthalmic bacterial infections. The present invention more particularly relates to the discovery that a 2-methyl substitution on a diazabicyclo group attached to a fluoroquinolone ring system produces improved permeability characteristics, and that a 5-amino substitution on a fluoroquinolone ring system results in improved anti-microbial activity.
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- TARGETING DIAZO PRODRUGS FOR THE TREATMENT OF GASTROINTESTINAL DISEASES
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Provided herein are compounds, compositions and methods for decreasing NFkB DNA-binding activity in a patient comprising administering of a therapeutically effective amount of a compound or composition of the application to the patient to reduce, alleviate or treat various gastrointestinal diseases, such as inflammatory bowel disease (IBD).
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Page/Page column 10; 44-45; 3/11 - 5/11
(2009/03/07)
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- Mild and selective deprotection method of acetylated steroids and diterpenes by dibutyltin oxide
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Dibutyltin oxide (DBTO) was first utilized for the deacetylation of steroid and diterpene esters. The results showed the deprotection of acetylated steroids and diterpenes separately with moderate catalysis dibutyltin oxide in methanol selectively removed part acetyl groups of these substrates, whereas several functional groups of the steroids and diterpenes were retained and neither isomerization nor degradation of these substrates was observed. It seems that the acetyl groups with lower steric hindrance or near carbonyl, alkoxy, or hydroxyl groups can be cleaved by the reaction, whereas the acetyl groups with higher steric hindrance or without carbonyl, alkoxy, or hydroxyl groups neighboring were retained under the same conditions. One of the interesting results obtained was the selective hydrolysis of the 3β-O-acetyl group in the presence of the 6β group in 3β,6β-Di-O-acetyl-5α-hydroxypregn-16-en-20-one. This allows for subsequent introduction of one unit at C-3 and the other unit at C-6. This procedure is useful for the synthesis of a series of closely related isomers of 3β,5α,6β-trihydroxypregn-16-en-20-one and other widespread polyhydroxysteroids in marine organisms and some terrestrial species.
- Wang, Shao-Min,Zhang, Yan-Bing,Liu, Hong-Min,Yu, Guo-Bin,Wang, Ke-Rang
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- Effective high-pressure cleavage of sterically hindered steroid esters
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A simple and effective method to deprotect of sterically hindered steroid esters is described. Deprotection was carried out in MeOH in the presence of a catalytic amount of Et3N under high-pressure conditions. Enzymatic, anionite, and high-pressure methods are compared.
- Kroszczynski, Wojciech,Olszewska, Ewa,Salanski, Piotr,Jurczak, Janusz
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p. 1488 - 1492
(2007/10/03)
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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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- Hydrolysis behavior of prednisolone 21-hemisuccinate/β-cyclodextrin amide conjugate: Involvement of intramolecular catalysis of amide group in drug release
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Prednisolone 21-hemisuccinate/β-cyclodextrin (β-CyD) amide conjugate was prepared by binding prednisolone 21-hemisuccinate covalently to the amino group of mono(6-deoxy-6-amino)-β-CyD through amide linkage. Prednisolone 21-hemisuccinate was intramolecularly transformed to prednisolone 17-hemisuccinate, and the parent drug, prednisolone, was slowly released from the 21-hemisuccinate with a half life of 69 h in pH 7.0 at 37°C; the drug release at 25°C was less than 10% for 48 h. In sharp contrast, the hydrolysis of prednisolone 21-hemisuccinate/β-CyD amide conjugate was significantly faster (half life of 6.50 min at 25°C) and gave prednisolone and mono(6-deoxy-6-succimino)-β-CyD as products. The hydrolysis of the β-CyD amide conjugate was subject to a specific-base catalysis in the alkaline region. The rapid hydrolysis of the conjugate can be ascribed to the involvement of an intramolecular nucleophilic catalysis of the amide group in the reaction. The succinic acid, bound to a drug through ester linkage at one carboxylic group and bound to a pro-moiety through amide linkage at another carboxylic group, may be useful as a spacer for construction of the immediate release type prodrugs of CyDs.
- Yano,Hirayama,Arima,Uekama
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p. 1125 - 1128
(2007/10/03)
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- A mild method of deprotection of corticosteroidal esters
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The effect of microwave radiation and ultrasounds on the reaction of transesterification of corticosteroidal esters were investigated.
- Kroszczynski, Wojciech,Olszewska, Ewa
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p. 331 - 332
(2007/10/03)
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- Pharmaceutical preparations for oral administration that are adapted to release the drug at appropriate sites in the intestines
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The improved pharmaceutical preparation for oral administration which is adapted to release the drug at appropriate sites in the intestines comprises: a core that comprises an active ingredient and a pharmaceutically acceptable excipient, a first layer that covers the core and which comprises an enteric or water-soluble ingredient and an optional insoluble ingredient, a second layer that covers the first layer and which comprises a non-enteric ingredient that dissolves upon reacting with at least one ingredient in the core, and a third layer that covers the second layer and which comprises an enteric ingredient. This preparation is characterized in that it will not release the active ingredient until after it reaches a desired site in the intestines and that, in addition, it is capable of controlling the rate at which the active ingredient is released after it has reached the desired site. Therefore, this preparation is particularly effective in administering active ingredients having absorption specificity at specific sites in the intestines or for treating diseases at specific sites in the intestines.
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- Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity
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Mucosal adhesive devices are provided for use in the oral cavity for therapy against infections. The devices are dosage units which comprise a combination of antimicrobial agents such as antifungal agents and anti-inflammatory agents, optionally also a local anesthetic. The dosage units yield a gradual and relatively constant release of the pharmaceuticals over at least a 12-hour period.
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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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- 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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- 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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- 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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- Prednisolone derivatives
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Novel prednisolone derivatives modified at C-17,C-20 and/or C-21 positions. Many of the compounds are anti-inflammatory agents which do not significantly suppress the pituitary-adrenal axis.
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- Water-soluble steroid compounds
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Beta-cyclodextrin forms a water-soluble complex or inclusion compound with steroid compounds having a molecular structure smaller than the interior cavity in the doughnut-shaped molecular structure of beta-cyclodextrin. The resulting inclusion compounds can be used for a variety of applications including aqueous topical ophthalmic preparations and topical dermatological ointments.
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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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