- Novel phosphorus-containing 17β-side chain mifepristone analogues as progesterone receptor antagonists
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A novel series of steroidal compounds were designed and synthesized with various phosphorus-containing groups on the 17β-side chain as progesterone receptor antagonists. The structure-activity relationships of these compounds are discussed. Selected compo
- Jiang, Weiqin,Allan, George,Chen, Xin,Fiordeliso, James J.,Linton, Olivia,Tannenbaum, Pamela,Xu, Jun,Zhu, Peifang,Gunnet, Joseph,Demarest, Keith,Lundeen, Scott,Sui, Zhihua
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Read Online
- Synthesis of Norgestomet and its 17β-isomer and evaluation of their agonistic activities against progesterone receptor
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Norgestomet is a synthetic progesterone derivative applied in veterinary medicine to control estrus and ovulation in cattle. Norgestomet has been widely used in the livestock industry to promote the synchronization of estrus in cattle and increase pregnancy rates. However, highly reproducible synthetic methods for Norgestomet have been rarely reported. Here, we described a method for the synthesis of Norgestomet and performed quantitative NMR analysis to determine the purity of the products. Moreover, the agonistic activity of the synthesized compounds against progesterone receptors (PRs) was evaluated using an alkaline phosphatase assay. We synthesized Norgestomet with 97.9% purity that exhibited agonistic activity against PR with EC50 values of 4.5 nM. We also synthesized the 17β-isomer of Norgestomet with 92.7% purity that did not exhibit any PR agonistic activity. The proposed synthetic route of Norgestomet can facilitate the assessment of residual Norgestomet in foods.
- Kurohara, Takashi,Ito, Takahito,Tsuji, Genichiro,Misawa, Takashi,Yokoo, Hidetomo,Yanase, Yuta,Shoda, Takuji,Sakai, Takatoshi,Hosoe, Junko,Uchiyama, Nahoko,Akiyama, Hiroshi,Demizu, Yosuke
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supporting information
(2021/10/04)
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- SOLID FORMS AND FORMULATIONS COMPRISING A GLUCOCORTICOID RECEPTOR ANTAGONIST AND USES THEREOF
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The present invention relates generally to formulations and methods for treating cancer. Provided herein are formulations comprising substituted steroidal derivatives. The subject formulations are useful for the treatment of cancer.
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Paragraph 00232
(2019/11/04)
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- Design and synthesis of fluorescently labeled steroidal antiestrogens
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A set of derivatives of 11β-(4-oxyphenyl)estradiol were prepared as potential fluorescent imaging agents for the evaluation of the estrogen receptor. The compounds were designed based on the established affinity and selectivity of 11β-[4-(dimethylethoxy)p
- Hanson, Robert N.,Gajadeera, Nisal
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- First synthesis and characterization for the stereoisomers of Ulipristal acetate
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The three stereoisomers, 11α,17α-isomer I, 11α,17β-isomer II and 11β,17β-isomer III are related substances of the selective progesterone receptor modulator Ulipristal acetate. Herein, we presented an efficient and practical synthesis approach to deliver t
- Zhao, Yi,Li, Xiaolong,Liu, Hong,Yu, Yongguo,Hai, Li,Guo, Li,Wu, Yong
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- Synthesis and biological evaluation of 11′ imidazolyl antiprogestins and mesoprogestins
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Antiprogestins with a 4′ para imidazolylphenyl moiety were synthesized and their biochemical interactions with the progesterone and glucocorticoid receptor were investigated. Depending on the substitution pattern at the 17 position partial progesterone re
- Nickisch, Klaus,Elger, Walter,Santhamma, Bindu,Garfield, Robert,Killeen, Zachary,Amelkina, Olga,Schneider, Birgitt,Meister, Reinhard
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- IMIDAZOLYL PROGESTERONE ANTAGONISTS
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Described herein are imidazolyl compounds which either act as pure antiprogestins and methods of using such pure antagonists for gynecological indications and breast cancer.
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Paragraph 0132
(2015/01/06)
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- Synthesis and preliminary evaluation steroidal antiestrogen-geldanamycin conjugates
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Three novel steroidal antiestrogen-geldanamycin conjugates were prepared using a convergent strategy. The antiestrogenic component utilized the 11β-(4-functionalized-oxyphenyl) estradiol scaffold, while the geldanamycin component was derived by replacement of the 17-methoxy group with an appropriately functionalized amine. Ligation was achieved in high yield using azide alkyne cyclization reactions. Evaluation of the products against two breast cancer cell lines indicated that the conjugates retained significant antiproliferative activity.
- Adam Hendricks,Hanson, Robert N.,Amolins, Michael,Mihelcic, John M.,Blagg, Brian S.
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supporting information
p. 3635 - 3639
(2013/07/19)
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- A simple and convenient synthetic route to Ulipristal acetate
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We set out to describe a new and efficient route for preparing Ulipristal acetate with a good yield. The selected epoxidization conditions gave out 80% of 5α,10α-epoxide 2a in the two diastereoisomers which greatly improved the yield of 11β-substituted isomer 4a. And phenyl-sulfinyl compound 6 was synthesized from ketone 5 directly treated with phenylsulfenyl chloride in the presence of triethylamine. These synthetic procedures is only 8 steps, less than currently reported in the literature, but more suitable for industrial process.
- Yu, Yongguo,He, Yun,Zhao, Yi,Hai, Li,Wu, Yong
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p. 1293 - 1297
(2013/11/06)
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- Synthesis and antihormonal properties of novel 11β-benzoxazole- substituted steroids
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Early studies led to the identification of 11β-aryl-4×,5 times;-dihydrospiro[estra-4,9-diene-17β,4 times;-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present
- Jin, Chunyang,Fix, Scott E.,Kepler, John A.,Cook, C. Edgar
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scheme or table
p. 1705 - 1708
(2012/04/04)
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- Design, synthesis, and initial biological evaluation of a steroidal anti-estrogen - Doxorubicin bioconjugate for targeting estrogen receptor-positive breast cancer cells
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As part of our program to develop breast cancer specific therapeutic agents, we have synthesized a conjugate agent that is a conjugate of the steroidal anti-estrogen and the potent cytotoxin doxorubicin. In this effort, we employed a modular assembly appr
- Dao, Kinh-Luan,Sawant, Rupa R.,Hendricks, J. Adam,Ronga, Victoria,Torchilin, Vladimir P.,Hanson, Robert N.
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experimental part
p. 785 - 795
(2012/07/28)
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- Synthesis of a spin-labeled anti-estrogen as a dynamic motion probe for the estrogen receptor ligand binding domain
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The preparation and characterization of a novel nitroxide spin probe based on a steroidal anti-estrogen is described. The probe 5 demonstrated very high binding affinity for both the alpha and beta isoforms of the estrogen receptor-ligand binding domain. EPR spectrometric studies demonstrate conformational constraints for the ligand, consistent with the nitroxyl moiety occupying a position just beyond the receptor-solvent interface.
- Hendricks, J. Adam,Gullà, Stefano V.,Budil, David E.,Hanson, Robert N.
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supporting information; experimental part
p. 1743 - 1746
(2012/04/10)
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- INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11beta-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS
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The present invention relates to a process for the synthesis of the known 17-acetoxy-11-β-[4-(dimethyl amino)-phenyl]-21-methoxy-19-norpregna-4,9-dien-3,20-dione (further on CDB-4124) of formula (I) from 3,3-[1,2-ethandiyl-bis(oxy)]-oestr-5(10),9(11)-dien
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Page/Page column 10
(2010/06/16)
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- Copper-catalyzed cyclization of steroidal acylaminoacetylenes: Syntheses of novel 11β-Aryl-17,17-spiro[(4′H,5′-methylene)oxazol]- substituted steroids
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A variety of novel 11β-aryl-17,17-spiro[(4′H,5′-methylene) oxazol]-substituted steroids have been synthesized in moderate to good yields via copper-catalyzed cyclization of acylaminoacetylenes. The best result was obtained with a catalytic amount of Cul i
- Chunyang, Jin,Burgess, Jason P.,Kepler, John A.,Cook, C. Edgar
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p. 1887 - 1890
(2008/02/05)
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- Synthesis and identification of novel 11β-aryl-4′,5′-dihydrospiro[estra-4,9-diene-17β, 4′-oxazole] analogs with dissociated antiprogesterone activities
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A series of novel 11β-aryl-4′,5′-dihydrospiro[estra-4,9-diene-17β, 4′-oxazole] analogs have been evaluated for their antagonist hormonal properties using the T47D cell-based alkaline phosphatase assay and the A549 cell-based functional assay. Some of the
- Jin, Chunyang,Manikumar,Kepler, John A.,Edgar Cook,Allan, George F.,Kiddoe, Margaret,Bhattacharjee, Sheela,Linton, Olivia,Lundeen, Scott G.,Sui, Zhihua
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p. 5754 - 5757
(2008/03/13)
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- 17-PHOSPHOROUS STEROID DERIVATIVES USEFUL AS PROGESTERONE RECEPTOR MODULATORS
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The present invention is directed to novel 17-phosphorous steroid derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by a progesterone or glucocorticoid receptor.
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Page/Page column 18-19; 19
(2010/11/28)
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- 11-PHOSPHOROUS STEROID DERIVATIVES USEFUL AS PROGESTERONE RECEPTOR MODULATORS
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The present invention is directed to novel 11-phosphorous steroid derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by a progesterone or glucocorticoid receptor.
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Page/Page column 18; 19
(2010/11/28)
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- Method for preparing oestrogen derivatives
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A process for the preparation of compounds of formula (I) in which R1, R2, R3 and n are defined as indicated in the description, use of said compounds as intermediates for the preparation of estrogen derivatives as well as the intermediates of this process.
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Page/Page column 6-7
(2010/02/08)
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- Novel method and intermediates for preparing 19-norsteroid compounds
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The subject of the invention is a method for preparing compounds of general formula (I): in which A, Z, R3 are as defined in the description, and the intermediate compounds for carrying out this method.
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- Recent developments in the synthesis of 11β-aryl-estrone derivatives
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An industrial synthesis of 11β-aryl-estrone derivatives is described, based on the 1,4-addition of the aryl side-chain, as a cuprate, on to a mixture of allylic 5(10) alpha and beta epoxides, followed by hydrolysis and subsequent aromatization.
- Prat, Denis,Benedetti, Fran?oise,Bouda, Lahlou Nait,Girard, Gilles Franc
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p. 765 - 768
(2007/10/03)
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- Industrial synthesis of 4-chloro, 11β-arylestradiol: How to circumvent a poor diastereoselectivity
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An industrial synthesis of 11β-arylestrone derivatives is described, based on the conjugate opening of a mixture of allylic 5(10)-α and -β epoxides by an aryl cuprate generated catalytically, followed by hydrolysis and subsequent aromatisation of the isomeric mixture of arylation products. An original method for selective 4-chlorination of estrone derivatives is also described.
- Prat, Denis,Benedetti, Francoise,Girard, Gilles Franc,Bouda, Lahlou Nait,Larkin, John,Wehrey, Christian,Lenay, Jacques
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p. 219 - 228
(2013/09/04)
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- GLUCOCORTICOID RECEPTOR LIGANDS FOR THE TREATMENT OF METABOLIC DISORDERS
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This invention relates to novel compounds that are liver selective glucocorticoid receptor antagonists, to methods of preparing such compounds, and to methods for using such compounds in the regulation of metabolism, especially lowering serum glucose levels, insulin levels, or lipid levels, and/or decreasing body weight.
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- The synthesis of 17α-Methyl-11β-arylestradiol: Large-scale application of the cerium (III)-mediated alkylation of a ketone
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17α-Methyl-11lβ-arylestradiol (17α-methyl-11β-(4-(2-(1-piperidinyl)ethoxy)phenyl)estra-1,3,5 (10)-triene-3,17β-diol) is a new molecule developed by Aventis Pharma for the treatment of osteoporosis. It was produced on the pilot plant scale from the norster
- Larkin, John Patrick,Wehrey, Christian,Boffelli, Philippe,Lagraulet, Henri,Lemaitre, Guy,Nedelec, Alban,Prat, Denis
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- Effect of a 17α-(3-hydroxypropyl)-17β-acetyl substituent pattern on the glucocorticoid and progestin receptor binding of 11β-arylestra-4,9-dien-3-ones
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(matrix presented) Replacing the 17α-acetoxy substituent in an antiprogestational 17β-acetyl-11β-arylestra-4,9-dien-3-one by 3-hydroxypropyl significantly diminished glucocorticoid receptor binding with little effect on progestin receptor binding.
- Cook, C. Edgar,Raje, Prasad,Lee, David Y.-W.,Kepler, John A.
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p. 1013 - 1016
(2007/10/03)
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- New 11β-aryl-substituted steroids exhibit both progestational and antiprogestational activity
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The syntheses of three 11β-aryl-19-norpregna-4,9-dien-3-one derivatives with 17-spirolactone and 17β-hydroxy-17α-cyanoethyl substitutions are described. The progesterone agonist/antagonist activities of the new compounds are investigated using a recently
- Rao, Pemmaraju N.,Wang, Zhiqiang,Cessac, James W.,Rosenberg, Rachel S.,Jenkins, David J. A.,Diamandis, Eleftherios P.
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p. 523 - 530
(2007/10/03)
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- Synthesis and characterization of tritium-labelled RU486
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[3H]RU38486 (RU486) was synthesized from its penultimate precursor, desmethyl RU486, by substitution of the secondary amine with tritiated methyl iodide; specific activity 85 Ci/mmol. Ligand binding studies confirm that RU486 binds with high affinity to human progesterone receptor type A (PR-A) and progesterone receptor type B (PR-B).
- Mais,Chen,Wagoner,Scott Hayes,Wang
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p. 1199 - 1203
(2007/10/03)
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