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EP-4737486-A1 - HYALURONIC ACID DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF

EP4737486A1EP 4737486 A1EP4737486 A1EP 4737486A1EP-4737486-A1

Abstract

The present invention relates to a hyaluronic acid derivative as shown in formula I, and a preparation method thereof and the use thereof in the preparation of an anti-infection drug. The structure of the compound or the pharmaceutically acceptable salt thereof of the present invention is significantly different from that of commercially available hyaluronic acid substances such as TCIsHA and R&D HA, and the compound or the pharmaceutically acceptable salt thereof can form a molecular structure recognized by HepSS-1. The molecule with the new structure can achieve an anti-infection effect by means of inhibiting the binding of SARS-Cov-2 spike protein to ACE2 of a host cell, and is less likely to cause serious adverse reactions clinically, such as bleeding and thrombocytopenia, as compared with heparin.

Inventors

  • ASARI, AKIRA
  • ZHANG, LIBO

Assignees

  • Five Hertz Innovation (Xiamen) Medical Technology Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240423

Claims (12)

  1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein a structure of formula I is shown as follows: wherein in formula I, R is identical or different and is each independently selected from H and SO 3 H; M is selected from a proton and a monovalent cation; n is selected from 3-9; in formula I, a degree of sulfation is less than or equal to 4.2 and greater than 3.65; and the structure of formula I can be recognized by HepSS-1.
  2. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein in formula I, NHCOCH 3 is not sulfated; preferably, n is selected from 3, 4, 5, 6, 7, 8, and 9; and preferably, the monovalent cation is selected from Na + and K + .
  3. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein in formula I, the degree of sulfation is less than or equal to 4.2 and greater than or equal to 3.75.
  4. A preparation method for the compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-3, comprising the following steps: (1) mixing water with hyaluronic acid or a water-soluble salt thereof; (2) adding a sulfating agent and reacting; (3) adding ethanol, mixing, and centrifuging; (4) removing supernatant and adding water, adding ethanol, mixing, and centrifuging; (5) removing supernatant and allowing to stand for 4-24 hours; and (6) adding water, filtering, and lyophilizing to obtain a product.
  5. The method according to claim 4, wherein the sulfating agent is selected from pyridine coordination complexes of sulfur trioxide.
  6. The method according to claim 4, wherein: in step (1), 0.5-3 g of hyaluronic acid or a water-soluble salt thereof is mixed with each 1 mL of water.
  7. The method according to any one of claims 4-6, wherein: in step (2), the reaction is performed at a temperature of 0-20 °C, and the reaction is performed for 24-100 hours; the sulfating agent and the hyaluronic acid or the water-soluble salt thereof are in a mass ratio of 0.5-6:100; in step (3), an addition amount of ethanol is: 10-50 mL of ethanol per 1 g of hyaluronic acid or the water-soluble salt thereof; and in step (4), an addition amount of water is: 0.5-2 mL of water per 1 g of hyaluronic acid or the water-soluble salt thereof.
  8. A composition, comprising the compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-3.
  9. The composition according to claim 8, further comprising a pharmaceutically acceptable carrier.
  10. Use of the compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-3 or the composition according to claim 8 for the manufacturing of a medicament for treating an infection.
  11. The use according to claim 10, wherein the infection is selected from an infection caused by coronavirus (COVID-19).
  12. A method for treating an infection, the method comprising administering to a patient a therapeutically effective amount of the compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-3 or the composition according to claim 8.

Description

The present application claims priority to the prior application with the patent application No. 202310778756.8 entitled "HYALURONIC ACID DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF" and filed to the China National Intellectual Property Administration on June 29, 2023, which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present disclosure relates to the field of pharmaceutical chemistry, and particularly, to a hyaluronic acid derivative, a preparation method therefor, and use thereof. BACKGROUND Hyaluronic acid (HA) is a glycosaminoglycan composed of D-glucuronic acid and N-acetylglucosamine linked alternately by β-1,4-glycosidic bonds and β-1,3-glycosidic bonds, and is an important component in the natural extracellular matrix. Hyaluronic acid substances may have different pharmacological activity depending on molecular weight and modified groups, such that they can be widely applied to the fields of cosmetics, food, and pharmaceuticals. The high water absorption capacity and high viscoelasticity of hyaluronic acid confer unique properties in biomaterials, making it suitable for various medical and pharmaceutical applications. Various hyaluronic acid products can be found in daily life. For example, since hyaluronic acid can retain water, it is used in some cosmetics to maintain youthful and fresh skin. Although hyaluronic acid is abundant in the skin, the water-retaining capacity of hyaluronic acid in the skin decreases with age due to depolymerization. Therefore, retaining abundant hyaluronic acid in the skin can help maintain a youthful appearance. In fields other than cosmetics, researchers have proposed many concepts for applying hyaluronic acid. However, there are few practical applications of hyaluronic acid in medicine, mainly in the treatment of osteoarthritis and in ophthalmic medical devices. Heparin is also a glycosaminoglycan composed of hexuronic acid and N-acetylglucosamine linked alternately by 1,4-glycosidic bonds, and has been widely used as an anticoagulant drug in clinical practice. Some modified hyaluronic acids exhibit an anticoagulant effect similar to that of heparin. However, due to the anticoagulant activity of heparin and analogs thereof, serious adverse reactions such as bleeding and thrombocytopenia are easily caused. SUMMARY To ameliorate the technical problems existing in the prior art, in a first aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the structure of formula I is shown as follows: wherein in formula I, R is identical or different and is each independently selected from H and SO3H;M is selected from a proton and a monovalent cation;n is selected from 3-9. According to an embodiment of the present disclosure, n is selected from 3, 4, 5, 6, 7, 8, and 9. According to an embodiment of the present disclosure, the monovalent cation is selected from Na+ and K+. According to an embodiment of the present disclosure, the weight-average molecular weight of formula I is less than 10000. In some embodiments, the weight-average molecular weight of formula I is 2480-6590. According to an embodiment of the present disclosure, in formula I, at least part of R is selected from SO3H (that is, R is not all H). In some embodiments, in formula I, the degree of sulfation is less than or equal to 4.2; in some embodiments, in formula I, the degree of sulfation is greater than 3.65, and preferably, the degree of sulfation is greater than or equal to 3.75; in some embodiments, in formula I, the degree of sulfation is less than or equal to 4.2 and greater than 3.65; in some embodiments, in formula I, the degree of sulfation is less than or equal to 4.2 and greater than or equal to 3.75; in some embodiments, in formula I, the degree of sulfation is less than or equal to 4.0 and greater than or equal to 3.75; for example, the degree of sulfation is selected from 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.05, 4.10, 4.15, and 4.20. According to an embodiment of the present disclosure, in formula I, NHCOCH3 is not sulfated. According to an embodiment of the present disclosure, the structure of formula I can be recognized by HepSS-1. In a second aspect, the present disclosure provides a preparation method for the compound of formula I or the pharmaceutically acceptable salt thereof, comprising the following steps: (1) mixing water with hyaluronic acid or a water-soluble salt thereof;(2) adding a sulfating agent and reacting;(3) adding ethanol, mixing, and centrifuging;(4) removing supernatant and adding water, adding ethanol, mixing, and centrifuging;(5) removing supernatant and allowing to stand for 4-24 hours; and(6) adding water, filtering, and lyophilizing to obtain a product. According to an embodiment of the present disclosure, the sulfating agent is selected from coordination complexes of sulfur trioxide, preferably pyridine coordination complexes of sulfur trioxide.