Vitamin d3 derivatives and pharmaceutical use thereof

Patent metadata

Field	Value
Publication number	US-2023278955-A1
Application number	US-202318117358-A
Country	US
Kind code	A1
Filing date	Mar 3, 2023
Priority date	Dec 24, 2014
Publication date	Sep 7, 2023
Grant date	—

Abstract

The present invention relates to vitamin D 3 derivatives of the following formula, wherein each symbol has the same meaning as defined herein, and pharmaceutical or medical use thereof for treating metabolic disease, liver disease, obesity, diabetes, cardiovascular disease, or cancer in a patient in need thereof.

First claim

14 . A compound of the following general formula (I):

wherein one of R A and R B is hydroxyl and the other is NR 1 R 2 ; R 1 and R 2 are each independently selected from hydrogen; C 1-4 alkyl; C 1-4 alkylcarbonyl optionally substituted with at least one halogen which are the same of different; C 1-4 alkylsulfonyl; benzyloxycarbonyl; 3 to 6-membered cycloalkyl-C 1-4 alkyl; C 6-10 arylcarbonyl optionally substituted with at least one group independently selected from the group consisting of halogen, halo-C 1-4 alkyl, -S-halo-C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, nitro, cyano, C 1-4 alkoxycarbonyl and C 6-10 aryl; C 6-10 arylsulfonyl optionally substituted with at least one group independently selected from the group consisting of C 1-4 alkyl, nitro, and di-(C 1-4 alkyl)amino; 5 to 6-membered saturated heterocyclyl-C 1-4 alkyl optionally substituted with at least one group independently selected from the group consisting of halogen and hydroxyl; 5 to 6-membered heteroaryl; and a group of the following formula:

or
R 1 and R 2 may optionally combine together with the nitrogen atom to which they attach to form phthalimidyl or a nitrogen-containing oxo-substituted saturated 5 to 6-membered heterocyclic ring which may be optionally fused with a C 6-10 aryl ring; and
R 3 is hydrogen or ═CH 2 ; or
a pharmaceutically acceptable salt thereof;
provided that R 1 and R 2 are not concurrently hydrogen.

15 . The compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 , wherein R 3 is ═CH 2 .

16 . The compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 , wherein R 3 is hydrogen.

17 . The compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 , wherein the compound has a structure selected from the group consisting of the following formulae:

18 . The compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 , wherein R 2 is hydrogen.

19 . The compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 , wherein the compound has a structure selected from the group consisting of the following formulae:

20 . A method for treating metabolic disease, liver disease, obesity, diabetes, cardiovascular disease, or cancer in a subject in need thereof, comprising:
administering to the subject in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 .

21 . The method of claim 20 , wherein the disease is obesity, non-alcoholic steatohepatitis (NASH), fatty liver, or cancer.

22 . The method of claim 20 , wherein the compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of the following formulas:

23 . The method of claim 20 , wherein the compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of the following formulas:

24 . A pharmaceutical composition, comprising:
as the active ingredient the compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 , and a pharmaceutically acceptable carrier.

25 . The pharmaceutical composition of claim 24 , wherein the compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of the following formulas:

26 . The pharmaceutical composition of claim 24 , wherein the compound or the pharmaceutically acceptable salt thereof is selected from the group consisting of the following formulas:

27 . A method for treating metabolic disease, liver disease, obesity, diabetes, cardiovascular disease, or cancer in a subject in need thereof, comprising:
administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 24 .

28 . The method of claim 27 , wherein the disease is obesity, non-alcoholic steatohepatitis (NASH), fatty liver, or cancer.

29 . The method of claim 28 , wherein the compound or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from the group consisting of the following formulas:

30 . The method of claim 28 , wherein the compound or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from the group consisting of the following formulas:

31 . A method of inhibiting an SREBP in a subject in need thereof, comprising administering to the subject in need thereof the compound or the pharmaceutically acceptable salt thereof in accordance with claim 14 .

Assignees

• Univ Kyoto
• National Univ Corporation Tokyo Univ Of Agriculture And Technology

Inventors

• Watanabe Mizuki
• Asano Risa
• Nagasawa Kazuo
• Uesugi Motonari

Classifications

• C07C401/00 Primary

  Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D209/48

  with oxygen atoms in positions 1 and 3, e.g. phthalimide · CPC title

• C07D211/46

  having a hydrogen atom as the second substituent in position 4 · CPC title

• A61K31/593

  9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3 · CPC title