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WO2024147408A1 - Isomère (r,rp)-isomère de promédicament de monophosphate d'adénosine carbocyclique de 2'-fluoro-6'-méthylène et son utilisation - Google Patents

Isomère (r,rp)-isomère de promédicament de monophosphate d'adénosine carbocyclique de 2'-fluoro-6'-méthylène et son utilisation Download PDF

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Publication number
WO2024147408A1
WO2024147408A1 PCT/KR2023/003627 KR2023003627W WO2024147408A1 WO 2024147408 A1 WO2024147408 A1 WO 2024147408A1 KR 2023003627 W KR2023003627 W KR 2023003627W WO 2024147408 A1 WO2024147408 A1 WO 2024147408A1
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WO
WIPO (PCT)
Prior art keywords
compound
isomer
mmol
cdcl
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2023/003627
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English (en)
Inventor
Do-Hyun Nam
Jaeyeon LEE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Immunodesigners Co Ltd
Original Assignee
Immunodesigners Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Immunodesigners Co Ltd filed Critical Immunodesigners Co Ltd
Publication of WO2024147408A1 publication Critical patent/WO2024147408A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2416—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of cycloaliphatic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides

Definitions

  • Hepatitis B is an acute or chronic liver disease caused by a viral infection and highly prevalent worldwide. According to an estimate by the WHO, there are approximately 296 million chronically infected people as of 2019, and 1.5 million new infections occur each year. As of 2019, an estimated 820,000 people died from hepatitis B virus infection, which has been a very serious disease worldwide.
  • Therapeutic agents for Hepatitis B are broadly classified into two types: one is interferon injections which have immunomodulatory effects, and the other is nucleoside-based oral antiviral agents.
  • alanine ester In order for protides to be activated in cells, alanine ester should be hydrolyzed first, converted into a nucleoside monophosphate, and reacted successively with kinases to become an activated nucleoside triphosphate.
  • hydrolases such as esterases, peptidases, etc.
  • hydrolases stereoselectively react in vivo so as to sensitively response to the stereoisomeric structure of protides. Therefore, the antiviral effects may vary depending on the chirality of the phosphate group.
  • KR Patent No. 2002886 reported that 2'-fluoro-6'-methylene-carbocyclic adenosine (FMCA) and its monophosphate prodrug (a phosphoramidate of FMCA, "FMCAP") have excellent antiviral activity against HBV, in particular, drug-resistant HBV types, in more particular, against HBV which is resistant to Lamivudine and/or Adefovir anti-HBV preparations.
  • the FMCAP presented in the "886" patent have four diastereomers in stereo structure because alanine group and phosphoryl group each having a chiral center are linked to each other.
  • the present invention is to solve the above-described technical problem, and the means for solving the problem are as follows:
  • R is a C 1-6 alkyl
  • a pharmaceutical composition for treating a disease associated with hepatitis B virus infection comprising the compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate or tautomer thereof.
  • a diastereomer in which alanine is in D-(R)-configuration and phosphate group is also in R-configuration has significantly low cytotoxicity with excellent pharmacokinetics and hepatocyte selectivity compared with remaining three isomers (Compounds 7, 8 and 11) while exhibiting antiviral activity equivalent to a diastereomer mixture in which alanine is in L-(S)-configuration and phosphate group is in racemic.
  • reaction solution was extracted with ethyl acetate, and organic layer was dried over anhydrous sodium sulfate and then filtered. Filtrate was concentrated under reduced pressure. Residue was purified by column chromatography under the conditions of dichloromethane:methanol (30:1 to 15:1) to obtain Compound 7.
  • Step 3 Frozen tissue (liver) is take out from storage, broken into small pieces, and quickly put into a conical tube weighed in advance, and then the weight of the tube is measured and recorded.
  • Step 4 The homogenizing solution (5X) is added to the weighed tissue (for example: when the tissue weight is 0.5 g, 2.5 mL of the homogenizing solution is added). The tissue is homogenized under low temperature conditions (dry ice-ethanol) by a homogenizer (3 times or more, 10 seconds for each until being homogenized).
  • the lower limit of quantification (LLOQ) for the triphosphate of Compound 5 is 5 ng/mL in the mouse liver homogenate sample (or 30 ng/g in mouse liver tissue), and the upper limit of quantification (ULOQ) is 5000 ng/mL in the mouse liver homogenate sample (or 30,000 ng/g in mouse liver tissue).
  • the average blood or liver concentration data for all test substances were determined with Phoenix WinNonlin ⁇ software (version 6.3, Pharsight, Mountain View, CA). Nominal doses were used for calculating pharmacokinetic parameters.
  • Maximum blood concentration (Cmax) and time to reach maximum concentration (Tmax) were taken directly from the blood concentration versus time profile for the PO group.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)

Abstract

La présente invention concerne un composé représenté par la formule 1 suivante, ou un sel, un hydrate, un solvate ou un tautomère pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci pour traiter des maladies associées à une infection par le virus de l'hépatite B, R étant un alkyle en C1-6.
PCT/KR2023/003627 2023-01-03 2023-03-17 Isomère (r,rp)-isomère de promédicament de monophosphate d'adénosine carbocyclique de 2'-fluoro-6'-méthylène et son utilisation Ceased WO2024147408A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2023-0000861 2023-01-03
KR1020230000861A KR20240109108A (ko) 2023-01-03 2023-01-03 2'-플루오로-6'-메틸렌-탄소환 아데노신 일인산 전구약물의 (R, Rp)-이성질체 및 이의 용도

Publications (1)

Publication Number Publication Date
WO2024147408A1 true WO2024147408A1 (fr) 2024-07-11

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2023/003627 Ceased WO2024147408A1 (fr) 2023-01-03 2023-03-17 Isomère (r,rp)-isomère de promédicament de monophosphate d'adénosine carbocyclique de 2'-fluoro-6'-méthylène et son utilisation

Country Status (2)

Country Link
KR (1) KR20240109108A (fr)
WO (1) WO2024147408A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015077360A2 (fr) * 2013-11-20 2015-05-28 Idenix Pharmaceuticals, Inc. Analogues nucléosidiques renfermant un cyclopentane ou un cyclopentène pour le traitement de l'hépatite c
US20190100523A1 (en) * 2016-04-07 2019-04-04 University Of Georgia Research Foundation, Ionc. Synthesis of 2'-fluoro-6'-methylene-carbocyclic adenosine (fmca) and 2'-fluoro-6'-methylene-carbocyclic guanosine (fmcg)
KR102002886B1 (ko) * 2011-05-13 2019-07-23 유니버시티 오브 조지아 리서치 파운데이션, 인코포레이티드 2’-플루오로-6’-메틸렌 탄소환 뉴클레오시드 및 바이러스 감염을 치료하는 방법

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102002886B1 (ko) * 2011-05-13 2019-07-23 유니버시티 오브 조지아 리서치 파운데이션, 인코포레이티드 2’-플루오로-6’-메틸렌 탄소환 뉴클레오시드 및 바이러스 감염을 치료하는 방법
WO2015077360A2 (fr) * 2013-11-20 2015-05-28 Idenix Pharmaceuticals, Inc. Analogues nucléosidiques renfermant un cyclopentane ou un cyclopentène pour le traitement de l'hépatite c
US20190100523A1 (en) * 2016-04-07 2019-04-04 University Of Georgia Research Foundation, Ionc. Synthesis of 2'-fluoro-6'-methylene-carbocyclic adenosine (fmca) and 2'-fluoro-6'-methylene-carbocyclic guanosine (fmcg)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RAWAL, R. K. ET AL.: "2’-Fluoro-6’-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: In vitro anti-HBV activity against the lamivudine–entecavir resistant triple mutant and its mechanism of action", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, 2013, pages 503, XP055168738, DOI: 10.1016/j.bmcl.2012.11.027 *
UMA S. SINGH, MULAMOOTTIL VARUGHESE A., CHU CHUNG K.: "Synthesis of an Anti-hepatitis B Agent, 2′-Fluoro-6′-methylene-carbocyclic Adenosine (FMCA) and Its Phosphoramidate (FMCAP)", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, UNITED STATES, vol. 84, no. 2, 18 January 2019 (2019-01-18), United States, pages 752 - 759, XP055667625, ISSN: 0022-3263, DOI: 10.1021/acs.joc.8b02599 *

Also Published As

Publication number Publication date
KR20240109108A (ko) 2024-07-10

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