2-methoxyestradiol derivatives and medical uses thereof

Patent metadata

Field	Value
Publication number	US-2023295217-A1
Application number	US-202017768936-A
Country	US
Kind code	A1
Filing date	Oct 14, 2020
Priority date	Oct 15, 2019
Publication date	Sep 21, 2023
Grant 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.

First claim

1 . A compound of Chemical Formula 1:

or a pharmaceutically acceptable salt thereof,
in Chemical Formula 1,
n is 0, 1, 2, or 3
A is a moiety selected from the group consisting of: phenyl, naphthyl, pyridyl, and pyrimidyl, wherein A is not substituted or optionally substituted with at least one substituent selected from the group consisting of halogen, NO 2 , —O—C 1-4 alkyl, OH, CN, NH 2 , COOH, —C 1-4 alkyl, -halo-C 1-4 alkyl, —C 1-4 haloalkoxy, phenyl, pyrrolyl, and pyrrolidinyl,
B is H, —S(O) 2 —R 1 , —C(O)—R 1 , or —OC(O)—R 1 , and
R 1 is phenyl, —C 1-4 alkyl, naphthyl, NH 2 , OH, or CN, wherein the phenyl, alkyl, and naphthyl of R 1 is not substituted or optionally substituted with at least one substituent selected from the group consisting of halogen, NO 2 , —O—C 1-4 alkyl, OH, CN, NH 2 , COOH, phenyl, —C 1-4 alkyl, -halo-C 1-4 alkyl, and —C 1-4 haloalkoxy.

2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein
n is 0, 1, or 2, A is a moiety selected from the group consisting of: phenyl, naphthyl, and pyridyl, wherein A is not substituted or optionally substituted with at least one substituent selected from the group consisting of halogen, NO 2 , —O—C 1-4 alkyl, OH, CN, NH 2 , COOH, —C 1-4 alkyl, -halo-C 1-4 alkyl, phenyl, pyrrolyl, and pyrrolidinyl, B is H, —S(O) 2 —R 1 , or —C(O)—R 1 , and R 1 is phenyl, —C 1-4 alkyl, naphthyl, NH 2 , OH, or CN, wherein the phenyl, alkyl, and naphthyl of R 1 is not substituted or optionally substituted with at least one substituent selected from the group consisting of halogen, NO 2 , —O-C 1-4 alkyl, OH, CN, NH 2 , COOH, —C 1-4 alkyl, and -halo-C 1-4 alkyl.

3 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is (13S, 17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate,
(13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyldibenzenesulfonate, 13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(4-fluorobenzenesulfonate), (13S,17S)-2-methoxy-13-methyl-3-((phenylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate, (13S,17S)-2-methoxy-13-methyl-17-((methylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(3,4-difluorobenzenesulfonate), (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl4-nitrobenzenesulfonate, (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl4-methoxybenzenesulfonate, (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl naphthalene-2-sulfonate, (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl naphthalene-1-sulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(naphthalene-2-sulfonate), (13S,17S)-2-methoxy-13-methyl-3-((naphthalen-2-ylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(4-fluorobenzenesulfonate), (13S,17S)-2-methoxy-13-methyl-3-(((4-nitrophenyl)sulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate, or (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.

4 . The compound or pharmaceutically acceptable salt of claim 3 , wherein the compound is (13S, 17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate,
(13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyldibenzenesulfonate, (13S, 17S)-2-methoxy-13-methyl-17-((methylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate, or (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(naphthalene-2-sulfonate).

5 . A composition comprising a compound or pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.

6 . A method for treating or preventing fibrosis, comprising:
administering to a subject in need of treatment or prevention of fibrosis a compound or pharmaceutically acceptable salt of claim 1 .

7 . The method of claim 6 , wherein the fibrosis is liver fibrosis or pulmonary fibrosis.

8 . The method of claim 7 , wherein the liver fibrosis is a fibrosis caused by chronic hepatitis virus infection, alcohol abuse, drug-induced liver injury (DILI), cholestasis, or NASH (Non-Alcoholic Steath Hepatitis).

9 . The method of claim 6 , wherein the compound is
(13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ylbenzenesulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyldibenzenesulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(4-fluorobenzenesulfonate), (13S,17S)-2-methoxy-13-methyl-3-((phenylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate, (13S,17S)-2-methoxy-13-methyl-17-((methylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzenesulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(3,4-difluorobenzenesulfonate), (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl4-nitrobenzenesulfonate, (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl4-methoxybenzenesulfonate, (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ylnaphthalene-2-sulfonate, (13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ylnaphthalene-1-sulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(naphthalene-2-sulfonate), (13S,17S)-2-methoxy-13-methyl-3-((naphthalen-2-ylsulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ylacetate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl bis(4-fluorobenzenesulfonate), (13S,17S)-2-methoxy-13-methyl-3-(((4-nitrophenyl)sulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ylacetate, or (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-ylacetate.

10 . The method of claim 9 , wherein the compound is
(13S,17S)-17-hydroxy-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ylbenzenesulfonate, (13S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyldibenzenesulfonate, (13S, 17S)-2-methoxy-13-methyl-17-((methylsulfonyl)oxy)

Assignees

• Pasteur Institut Korea
• Korea Inst Radiological & Medical Sciences

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

Classifications

• A61P1/16 Primary

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07J1/007 Primary

  the substituent being an OH group free esterified or etherified · CPC title

• C07J1/0074 Primary

  Esters · CPC title

• C07J31/006

  not covered by C07J31/003 · CPC title

• C07J41/0072

  the A ring of the steroid being aromatic · CPC title