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ANTI-HUMAN NOROVIRUS AGENT

Foreign code F200010208
File No. (S2019-0175-N0)
Posted date Jul 31, 2020
Country WIPO
International application number 2019JP051496
International publication number WO 2020138447
Date of international filing Dec 27, 2019
Date of international publication Jul 2, 2020
Priority data
  • P2018-244213 (Dec 27, 2018) JP
Title ANTI-HUMAN NOROVIRUS AGENT
Abstract The present invention addresses the problem of providing an anti-human norovirus agent capable of suppressing infection and growth of human norovirus. The present inventers have discovered that said problem can be solved by providing an anti-human norovirus agent that contains, as an active ingredient, a fucose analog having an activity of inhibiting glycosylation by fucose transferase (FUT). The active ingredient is, for example, a fucose analog represented by formula (III) or (IV), or a salt thereof (wherein, formula (III) or (IV) respectively represent an α- or β-anomer, R1, R3, and R4 each represent–OH or –OAc, R2 represents a halogen atom, -OH, or –OAc, R5 represents -CH3, -C≡CH, -C≡CCH3, or -CH2C≡CH).
Outline of related art and contending technology BACKGROUND ART
Norovirus (Norovirus) is 1 of 4 viruses belonging to the caliciviridae family, and Norwalk virus (Norwalk virus) is only the virus species currently.
Human norovirus is infected mainly through food (fish and shellfish or water), and can be infected even with a small amount of about 100-1000 virus particles in the food, and has very strong infective power. Food poisoning by human norovirus occupies 90 % or more of viral food poisoning.
The major symptoms of human norovirus infection are nausea, vomiting, diarrhea, and fever. Vomiting and diarrhea are more than 10 times when they are several times a day, and eels may be mixed with bile and intestinal substances, which are considered to be severe pain.
In North American data, about 2000 million persons suffer from human norovirus infection for, years, about 200 million persons were consulted at hospitals, 40 million persons were first carried, million persons were hospitalized, and 7000 persons were dead for, years.
Vomiting diarrhea caused by human norovirus infection in Japan has been increasing to 100-300 million people over several tens of years by the estimation of National Institute of infection. As a result, there is a high demand for antiviral drugs and vaccines against human noroviruses from Japan, and the order of development priority is located at the 4 th position in administrative administration. In Japan, there are few cases where human norovirus infection is a direct cause of death, but in the case of other diseases and elderly people, there is a high risk of prolongation and severity. In addition, even if the symptoms described above are settled, excretion of human norovirus having a very strong infectious power into feces lasts for 7-14 days or for 2 months or longer in the case of a long period of time, and it is impossible to return to schools or workplaces during that period. In addition, insensible infected persons of human norovirus are always detected at a rate of several percent of the total population. Since an insensible infected person of human norovirus is not aware of viral infection by the infected person itself, it has been reported that, for example, the insensible infected person acts as a food worker to cause large-scale food poisoning.
As described above, human norovirus is a food-toxic virus which has a high frequency of morbidity and is accompanied by pain of a patient, and is a virus which has a strong infectivity and is recognized to be insensible infection, but there is no special effect drug at present. Through hydration by oral or drip infusion or the like, progress observation is basic while preventing dehydration, and other measures such as administration of an antiemetic agent and an enteric agent are performed. In this paper, we propose a new method for the prevention of virus infection in the intestinal tract.
In 2002 years, the French group reported that the virus-like hollow particle (VLP) of human norovirus binds to human tissue blood group antigen (HBGA), and it was suggested that this molecule may be a receptor of human norovirus.
Subsequently, verification by human volunteers proceeds, and it was clarified that HBGA non-secretory individuals (non-secretor individual) are less susceptible to human norovirus and HBGA secretory individuals (secretor individual) are susceptible to human norovirus.
However, at present, HBGA itself is not a receptor responsible for the invasion of human norovirus into cells. This is due to the following reasons.
That is, whether or not HBGA is secreted into saliva and mucous membrane is considered to be related to the genetic polymorphism of 2 position) among FUT2 (fucosyltransferase positions 2 and 1-8. However, even if the FUT2 gene is introduced into a cell in which HBGA is not expressed on the cell surface to secrete HBGA and express HBGA on the cell surface, infection with human norovirus to the cell is not established. Therefore, HBGA itself is not said to be a receptor responsible for invasion of human norovirus into cells, and the causal relationship (directly and indirectly between FUT2 gene polymorphism and human norovirus infection susceptibility has not yet been elucidated.
Patent Document 1 is a prior art document in which applications of anticancer agents are disclosed mainly for the active ingredient of the anti-norovirus agent of the present invention described below. In Patent Document 1, a general description of use in treating infectious diseases is recognized, but examples are not disclosed. In addition, noroviruses and related diarrhea viruses are not disclosed among the viruses listed in Patent Document 1, and the mechanism of action in paired infections described in Patent Document 1 is the enhancement of immune response, which is completely different from the anti-norovirus agent of the present invention.
Patent Document 2 describes 2 D set used in the examples.
Scope of claims (In Japanese)[請求項1]
 フコーストランスフェラーゼ(FUT)による糖鎖修飾を阻害するフコースアナログ又はそれらの塩を有効成分とする、抗ヒトノロウイルス剤。

[請求項2]
 フコースアナログにより糖鎖修飾を阻害されるフコーストランスフェラーゼは、FUT2を含んでいる、請求項1に記載の抗ヒトノロウイルス剤。

[請求項3]
 下記式(III)又は(IV)のフコースアナログあるいはそれらの塩を有効成分とする、抗ヒトノロウイルス剤。
[化1]
(省略)
 [式中、式(III)又は(IV)のそれぞれは、α若しくはβアノマーであり、
  R 1、R 3及びR 4のそれぞれは、-OH、又は-OAcであり、
  R 2は、F(フッ素原子)若しくはCl(塩素原子)であるハロゲン原子、-OH、又は-OAcであり、
  R 5は、-CH 3、-C≡CH、-C≡CCH 3、又は-CH 2C≡CHである。]

[請求項4]
 前記抗ヒトノロウイルス剤において、R 2が前記ハロゲン原子の場合、R 1、R 3及びR 4のうち少なくとも1つが-OAcであり;
 R 5が-C≡CH、-C≡CCH 3、又は-CH 2C≡CHの場合、R 1、R 2、R 3及びR 4のうち少なくとも1つが-OAcである、請求項3に記載の抗ヒトノロウイルス剤。

[請求項5]
 前記抗ヒトノロウイルス剤において、R 2が前記ハロゲン原子の場合、R 5は-CH 3であり;R 5が、-C≡CH、-C≡CCH 3、又は-CH 2C≡CHの場合、R 2は、-OH、若しくは-OAcである、請求項3又は4に記載の抗ヒトノロウイルス剤。

[請求項6]
 前記抗ヒトノロウイルス剤において、R 2が前記ハロゲン原子の場合、R 1、R 3及びR 4の全てが-OAcであり;
 R 5が-C≡CH、-C≡CCH 3、又は-CH 2C≡CHの場合、R 1、R 2、R 3及びR 4の全てが-OAcである、請求項3-5のいずれか1項に記載の抗ヒトノロウイルス剤。

[請求項7]
 前記抗ヒトノロウイルス剤において、R 2はF(フッ素原子)である、請求項3-6のいずれか1項に記載の抗ヒトノロウイルス剤。

[請求項8]
 前記抗ヒトノロウイルス剤において、R 5は-C≡CHである、請求項3-7いずれか1項に記載の抗ヒトノロウイルス剤。

[請求項9]
 有効成分であるフコースアナログあるいはそれらの塩は、式(III)のフコースアナログあるいはその塩である、請求項3-8のいずれか1項に記載の抗ヒトノロウイルス剤。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • KEIO UNIVERSITY
  • THE KITASATO INSTITUTE
  • Inventor
  • KATAYAMA Kazuhiko
  • FUJIMOTO Akira
  • HAGA Kei
  • TODAKA Reiko
  • SATO Toshiro
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG

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