Triterpene derivative and its anti-influenza use

Patent metadata

Field	Value
Publication number	US-9920088-B2
Application number	US-201314437611-A
Country	US
Kind code	B2
Filing date	Oct 18, 2013
Priority date	Oct 22, 2012
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

The present invention relates to the use of triterpenoid derivatives for the preparation of a medicament for preventing or treating influenza diseases, in which the substituents are as defined in the specification. The triterpenoid derivatives of the present invention have obvious inhibition effect on influenza virus, and are capable of obviously preventing influenza virus from entering cells, and can be used for preventing or treating influenza.

First claim

The invention claimed is:

1. A method for treating influenza comprising administering to a subject in need thereof a compound of the following structural formula:

or a stereoisomer, an epimer, a configurational isomer, a pharmaceutically acceptable salt, or a hydrate thereof;
wherein:
the dotted line represents a single or double bond;
R 1 is XR 1 ′, wherein X is NH;
R 1 ′ is hydrogen, or
a monosaccharide, oligosaccharide, polysaccharide, a substituted monosaccharide, a substituted oligosaccharide, or a substituted polysaccharide,
wherein the substituted monosaccharide, oligosaccharide, or polysaccharide has one, two, three or four hydroxyl groups each independently replaced with a substituent group selected from acetoxy, C1-C6 alkanoyloxy, C1-C6 alkoxy, benzoyloxy, benzyloxy, hydrogen, methoxy, an amino group, and an acetylamino group; or

vitamin C, sialic acid, an amino sugar having one, two or three monosaccharide units, or Oseltamivir or a prodrug thereof;
R 2 and R 7 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, nitro, mercapto, carbonyl, C1-C6 thioalkyl, C1-C6 alkyl group unsubstituted or substituted by a hydroxyl group, an amino group or a carboxyl group, amino, and NR 11 ′R 12 ′, wherein R 11 ′ and R 12 ′ are each independently selected from C1-C6 alkyl group unsubstituted or substituted by a hydroxyl group, an amino group or a carboxyl group;
R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of H, C1-C6 alkyl group unsubstituted or substituted by a hydroxyl group, an amino group or a carboxyl group;
R 9 is selected from the group consisting of H, halogen, hydroxy, cyano, nitro, mercapto, C1-C6 thioalkyl group, a carbonyl group, an oxime group, C1-C6 alkyl group unsubstituted or substituted by a hydroxyl group, an amino group or a carboxyl group;
R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of H, OH, NHR 9 ′, mercapto, C1-C6 thioalkyl, C1-C3 alkyl unsubstituted or substituted by hydroxyl, amino or carboxyl; and
R 9 ′ is H, C1-C3 alkyl unsubstituted or substituted by hydroxyl, amino or carboxyl group, provided that when R 7 is hydroxyl, R 2 and R 1 ′ are not hydrogen.

2. The method according to claim 1 , wherein R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of H, hydroxy, amino, unsubstituted C1-C3 alkyl group; or R 10 , R 11 , R 12 , R 13 , and R 14 are each independently methyl or C1-C3 alkyl group substituted by hydroxy, amino or carboxyl group; or R 10 , R 11 , R 12 , R 13 , and R 14 are each independently methyl; or R 11 and R 12 are each independently selected from H or methyl, R 10 is H, and/or R 13 and R 14 are each independently selected from H, OH or NH 2 .

3. The method according to claim 1 , wherein the compound is administered by oral, rectal, nasal, aerosol or particulate inhalation, or administered topically by buccal and sublingual, transdermal, vaginal, intravesical, intralesional and parenteral route; or administered as a spray for oral or nasal administration, or indoor or topical environment sterilization and disinfection.

4. The method according to claim 1 , wherein the monosaccharide is independently selected from the group consisting of glucose, mannose, fructose, xylose, arabinose, galactose, ribose and deoxyribose, wherein the oligosaccharide is maltose, sucrose or lactose.

5. The method according to claim 1 , wherein:
X is NH;
R 1 ′ is a monosaccharide or disaccharide, or an acetylated derivative, wherein a hydroxyl group of the monosaccharide or disaccharide is replaced with an acetoxy group.

6. The method according to claim 1 , wherein R 2 is H, OH, carbonyl, SH or NH 2 , or wherein R 2 is H, OH or carbonyl.

7. The method according to claim 1 , wherein R 3 , R 4 , R 5 , R 6 and R 8 are each methyl.

8. The method according to claim 1 , wherein R 7 is independently selected from the group consisting of H, OH, carbonyl, NH 2 or SH, or wherein R 7 is OH or carbonyl.

9. The method according to claim 1 , wherein the compound is:
any one of compounds Y1-Y16,
3β,16α-dihydroxy-olean-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-galactoside),
3β,16α-dihydroxy-olean-12-en-28-oic acid-28-N-(β-D-galactoside),
3,16-dione-olean-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-galactoside),
3,16-dione-olean-12-en-28-oic acid-28-N-(β-D-galactoside),
3β-hydroxy-olean-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-galactoside),
3β-hydroxy-olean-12-en-28-oic acid-28-N-(β-D-galactoside),
3β-hydroxy-olean-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-mannoside),
3β-hydroxy-olean-12-en-28-oic acid-28-N-(β-D-galactoside),
3-carbonyl-olean-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-galactoside),
3-carbonyl-olean-12-en-28-oic acid-28-N-(Jβ-D-galactoside),
3β,16α-dihydroxy-olean-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-mannoside),
3β,16α-dihydroxy-olean-12-en-28-oic acid-28-N-β-D-galactoside),
3β-hydroxy-urs-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-β-D-galactoside),
3β-hydroxy-urs-12-en-28-oic acid-28-N-(β-D-galactoside),
3β-hydroxy-urs-12-en-28-oic acid-28-N-(2,3,4,6-tetra-O-acetyl-(β-D-mannoside), and
3β-hydroxy-urs-12-en-28-oic acid-28-N-(β-D-mannoside).

10. The method according to claim 1 , wherein the benzene ring of the benzoyloxy or benzyloxy group of the substituted monosaccharide, oligosaccharide, or polysaccharide is unsubstituted or substituted with one or more groups selected from halogen, nitro, amino and C1-C6 alkyl.

11. The method according to claim 1 , wherein the compound inhibits influenza virus infection.

12. The method according to claim 1 , wherein:
X is NH;
R 1 ′ is an acetylated galactose derivative in which a hydroxy group is replaced with an acetoxy group.

13. The method of claim 1 , wherein the compound is

or a stereoisomer, an epimer, a configurational isomer, a pharmaceutically acceptable salt, or a hydrate thereof.

Assignees

• Univ Beijing
• Univ Macau
• Univ Of Macao

Inventors

• Zhou Demin
• Yu Maorong
• Xiao Sulong
• Yu Fei
• Peng Yiyun
• Qiu Yunyan
• Zhang Lihe
• Wang Yitao

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07H15/256 Primary

  Polyterpene radicals · CPC title

• A61K31/56

  Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids · CPC title

• C07H13/08

  having the esterifying carboxyl radicals directly attached to carbocyclic rings · CPC title

• C07J63/008

  Expansion of ring D by one atom, e.g. D homo steroids · CPC title