2-methoxyestradiol derivatives and medical uses thereof
Inventors
SEO, Haeng Ran • CHOI, Inhee • Choi, Junghwan • Kim, Young Mi • SONG, Yeonhwa • Kim, A-Ram • Lee, Yoon Jin • Lee, Hae-June • NAM, Jae-kyung • KIM, Jihee • LEE, Su-Yeon
Assignees
Institut Pasteur Korea • Korea Institute of Radiological and Medical Sciences
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Publication Number
US-12570685-B2
Publication Date
2026-03-10
Expiration Date
Abstract
The present invention relates to novel 2-Methoxyestradiol derivatives and their medical use. In particular, the novel derivatives of the present invention are useful for the treatment or prevention of liver or lung fibrosis. Accordingly, the present invention also provides medical uses of the 2-Methoxyestradiol derivatives of the present invention. The present invention also provides a method of treating or preventing liver or lung fibrosis comprising administering an effective amount of the 2-Methoxyestradiol derivatives of the present invention.
Core Innovation
The invention relates to a compound or pharmaceutically acceptable salt having a defined (13S,17S) stereochemistry and a decahydro-6H-cyclopenta[a]phenanthrene core. The core is substituted with specified sulfonate and sulfonate-derivative groups, including benzenesulfonate, dibenzenesulfonate, bis(sulfonate) forms, fluorinated and substituted arylsulfonate groups, naphthalene sulfonates, and sulfonyl-oxy acetate variants.
The compounds are exemplified as (13S,17S)-17-hydroxy-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthren-3-yl derivatives and related 2-methoxy decahydro-6H-cyclopenta[a]phenanthrene compounds carrying benzenesulfonate, dibenzenesulfonate, 4-fluorobenzenesulfonate, 4-nitrobenzenesulfonate, 4-methoxybenzenesulfonate, naphthalene-1-sulfonate, and naphthalene-2-sulfonate groups.
A further aspect of the disclosure relates to pharmaceutical compositions and methods that use the compound or its pharmaceutically acceptable salt. The document states pharmaceutical composition use with a pharmaceutically acceptable carrier and describes treating or preventing fibrosis by administering the compound or salt to a subject in need thereof, including liver fibrosis and pulmonary fibrosis.
Claims Coverage
The independent claim set covers specific (13S,17S) decahydro-6H-cyclopenta[a]phenanthrene sulfonate/sulfonate-derivative compounds and pharmaceutically acceptable salts, and extends to pharmaceutical compositions and methods of treating or preventing fibrosis. Across the items, there are 4 main inventive features: defined stereospecific compound structures, a pharmaceutical composition with a pharmaceutically acceptable carrier, a fibrosis treatment method, and indication narrowing to liver fibrosis or pulmonary fibrosis with specified liver fibrosis causes.
Stereospecific sulfonate compound
A compound or pharmaceutically acceptable salt thereof, wherein the compound is a (13S,17S)-17-hydroxy-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate; a (13S,17S)-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyldibenzenesulfonate; a (13S,17S)-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(4-fluorobenzenesulfonate); a (13S,17S)-2-methoxy-13-methyl-3-((phenylsulfonyl)oxy) decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate; a (13S,17S)-2-methoxy-13-methyl-17-((methylsulfonyl)oxy) decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate; a (13S,17S)-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(3,4-difluorobenzenesulfonate); a (13S,17S)-17-hydroxy-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-nitrobenzenesulfonate; a (13S,17S)-17-hydroxy-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-methoxybenzenesulfonate; a (13S,17S)-17-hydroxy-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthren-3-yl naphthalene-2-sulfonate; a (13S,17S)-17-hydroxy-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthren-3-yl naphthalene-1-sulfonate; a (13S,17S)-2-methoxy-13-methyl decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(naphthalene-2-sulfonate); a (13S,17S)-2-methoxy-13-methyl-3-((naphthalen-2-ylsulfonyl)oxy) decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate; a (13S,17S)-2-methoxy-13-methyl-3-(((4-nitrophenyl)sulfonyl)oxy) decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate; or a (13S,17S)-2-methoxy-3-(((4-methoxyphenyl)sulfonyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate.
Pharmaceutical composition including a pharmaceutically acceptable carrier
A pharmaceutical composition that includes the compound or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
Method of treating or preventing fibrosis by administering the compound
A method of treating or preventing fibrosis by administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof.
Fibrosis treatment covering liver fibrosis or pulmonary fibrosis
The method is used for liver fibrosis or pulmonary fibrosis.
Overall, the claims cover specific (13S,17S) decahydro-6H-cyclopenta[a]phenanthrene sulfonate/sulfonate-derivative compounds and salts, pharmaceutical compositions including a pharmaceutically acceptable carrier, and therapeutic methods using administration for treating or preventing fibrosis, including liver fibrosis or pulmonary fibrosis.
Stated Advantages
Reduces radiation-induced pulmonary fibrosis (RIPF).
Alters stress fiber/F-actin and α-SMA expression in the context of radiation-induced pulmonary fibrosis (RIPF).
Treating or preventing fibrosis.
Anti-fibrotic activity in radiation-induced and liver fibrosis settings is demonstrated in disclosed evaluations.
Documented Applications
Reduction of radiation-induced pulmonary fibrosis (RIPF) using 2-methoxyestradiol (2-ME) derivative compounds, with evaluation context including stress fibers/F-actin and α-SMA expression.
Liver fibrosis evaluation using multicellular hepatic spheroids (MCHSs) model and in vivo models.
Treating or preventing liver fibrosis.
Treating or preventing pulmonary or lung fibrosis.
Treating or preventing liver fibrosis caused by chronic hepatitis virus infection.
Treating or preventing liver fibrosis caused by alcohol abuse.
Treating or preventing liver fibrosis caused by drug-induced liver injury (DILI).
Treating or preventing liver fibrosis caused by cholestasis.
Treating or preventing liver fibrosis caused by NASH.
Treating or preventing idiopathic pulmonary fibrosis.
A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
A method of treating or preventing fibrosis by administering the compound or pharmaceutically acceptable salt to a subject in need thereof.
The fibrosis method is specified for liver fibrosis or pulmonary fibrosis.
For liver fibrosis, causes are specified as chronic hepatitis virus infection, alcohol abuse, drug-induced liver injury (DILI), cholestasis, or NASH.
Regulators of radiation-induced EndMT evaluated using a high-content screening readout under radiation.
Radiation-induced pulmonary fibrosis model with lung fibrosis scoring and histology staining described for in vivo evaluation of 2-methoxyestradiol (2-ME) derivatives.
Liver fibrosis evaluation using multicellular hepatic spheroids (MCHSs), with assessment of many 2-ME derivative structures listed in a table of derivative structures.
Additional in vitro and mouse models for liver fibrosis, including spheroid fibrosis assays and CCl4-induced liver fibrosis with lung/liver fibrosis scoring and histological assessment.
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