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US-20260124170-A1 - PHARMACEUTICAL COMPOSITION COMPRISING METABOLITE OF ENAVOGLIFLOZIN, AND USE THEREOF

US20260124170A1US 20260124170 A1US20260124170 A1US 20260124170A1US-20260124170-A1

Abstract

The present invention relates to a pharmaceutical composition comprising a metabolite of enavogliflozin, and a use thereof. An enavogliflozin M1 metabolite of chemical formula 1 is a SGLT1/SGLT2 dual inhibitor and exhibits a different pharmacological mechanism from enavogliflozin which is a SGLT2 selective inhibitor. A pharmaceutical composition comprising, as an active ingredient, the enavogliflozin M1 metabolite that is a SGLT1/SGLT2 dual inhibitor can be useful in the prevention or treatment of diabetes or heart failure.

Inventors

  • Sun Hwa Park
  • Hye Young JI
  • Ji Soo CHOI
  • A Hye Youn
  • Mi Jie Park
  • Joon Seok Park

Assignees

  • DAEWOONG PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260507
Application Date
20230908
Priority Date
20220908

Claims (7)

  1. 1 . A method of preventing or treating diabetes or heart failure, which comprises administering a pharmaceutical composition comprising an effective amount of an enavogliflozin M1 metabolite represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof to a subject in need thereof
  2. 2 . The method of claim 1 , wherein the diabetes is type 1 diabetes.
  3. 3 . The method of claim 1 , wherein the diabetes is type 2 diabetes.
  4. 4 . The method of claim 1 , wherein the pharmaceutical composition is for oral or parenteral administration.
  5. 5 . The method of claim 1 , wherein a once-daily dose of the enavogliflozin M1 metabolite of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is 0.1 to 0.5 mg.
  6. 6 . The method of claim 1 , wherein the pharmaceutical composition is administered once a day.
  7. 7 . A sodium glucose cotransporter 1 (SGLT1)/sodium glucose cotransporter 2 (SGLT2) dual inhibitor comprising an enavogliflozin M1 metabolite represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising a metabolite of enavogliflozin and a use thereof. BACKGROUND ART Sodium glucose cotransporter 2 (SGLT2) is a transporter that is responsible for glucose reabsorption in the kidneys together with sodium glucose cotransporter 1 (SGLT1), and SGLT2 plays most of the role. Therefore, when an SGLT2 inhibitor inhibits the SGLT2 transporter, the glucose excreted into the urine increases, which ultimately lowers blood sugar levels and furthermore, the calories contained in blood sugar are excreted, resulting in the effect of losing weight. One of the drugs developed as an SGLT2 inhibitor that can be effectively used as a therapeutic for type 2 diabetes due to such effects is enavogliflozin, which is represented by the following structural formula (Chemical Formula A) and disclosed in Korean Patent Publication No. 2014-0022086 (Patent Document 1). Compound Name: (2S,3R,4R,5S,6R)-2-(7-chloro-6 (4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol Enavogliflozin is a drug that treats type 2 diabetes by selectively inhibiting SGLT2 and exhibits the same or better efficacy with only 0.3 mg, which is less than 1/30th of the amount of existing SGLT2 inhibitors. Through phase 3 clinical trials conducted on patients with type 2 diabetes, it was proven that enavogliflozin has superior glycated hemoglobin (HbA1c) and fasting blood sugar lowering effects and safety compared to existing commercially available drugs, and thus enavogliflozin was approved for marketing. According to Non-Patent Document 1, enavogliflozin was confirmed to produce a total of five metabolites in human hepatocytes: M1, M2, M3, U1, and U2. The formation of M1 and M2 from enavogliflozin was catalyzed by CYP3A4 and CYP2C19. M3 was produced by hydroxylation of M1, which was catalyzed by CYP3A4. The formation of U1 was catalyzed by UGT2B7, whereas the formation of U2 was catalyzed by UGTIA4, UGT1A9, and UGT2B7. Non-Patent Document 1 is a paper on the elucidation of the drug metabolism of enavogliflozin in the liver and the metabolites and metabolic enzymes of enavogliflozin, but it does not reveal anything about the activity exhibited by the metabolites of enavogliflozin. RELATED ART DOCUMENT Patent Document Korean Patent Publication No. 2014-0022086 Non-Patent Document Ju-Hyun Kim et al., Pharmaceutics. 2020 Sep. 11; 12(9):865. doi: 10.3390/pharmaceutics 12090865. DISCLOSURE Technical Problem The present invention aims to provide a pharmaceutical use of a metabolite of enavogliflozin. Technical Solution In the process of studying the metabolites of enavogliflozin, the present inventors confirmed that the enavogliflozin M1 metabolite represented by Chemical Formula 1 is a sodium glucose cotransporter 1 (SGLT1)/sodium glucose cotransporter 2 (SGLT2) dual inhibitor and exhibits a pharmacological mechanism that is different from that of enavogliflozin, which is an SGLT2 selective inhibitor, and thereby completed the present invention. (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2-hydroxy-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol SGLT2 inhibitors target SGLT2, which is responsible for reabsorption of more than 90% of glucose filtered by the kidneys, and SGLT1 inhibitors target SGLT1, which is responsible for reabsorption of the remaining 10% of glucose in the small intestinal epithelial cells. Most of the SGLT2 inhibitors developed previously were drugs with high selective binding affinity for SGLT2, and enavogliflozin, developed by the applicant of the present invention, is also a drug with very high selectivity for SGLT2 compared to SGLT1, and was recently approved as a therapeutic for type 2 diabetes. As an SGLT1/SGLT2 dual inhibitor, Lexicon Pharmaceuticals' sotagliflozin was approved for type 1 diabetes in the EU and for heart failure (HF) by the US Food and Drug Administration (FDA). The present invention provides a use of the enavogliflozin M1 metabolite as an SGLT1/SGLT2 dual inhibitor. Hereinafter, the present invention is described more specifically. The present invention provides a use of the enavogliflozin M1 metabolite or a pharmaceutically acceptable salt thereof as an SGLT1/SGLT2 dual inhibitor, a pharmaceutical composition for use in preventing or treating diabetes or heart failure, comprising the enavogliflozin M1 metabolite or a pharmaceutically acceptable salt thereof as an active ingredient, and a method of preventing or treating diabetes or heart failure, comprising administering an effective amount of enavogliflozin M1 metabolite or a pharmaceutically acceptable salt thereof to a subject in need thereof. The present invention provides a pharmaceutical composition for use in preventing or treating diabetes or heart failure, comprising the enavogliflozin M1 metabolite represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredie