Low molecular weight glycosaminoglycan derivative, pharmaceutical composition thereof, preparation method therefor and use thereof

1. A low-molecular-weight glycosaminoglycan derivative or a pharmaceutically acceptable salt thereof, wherein:

monosaccharide components of the low-molecular-weight glycosaminoglycan derivative comprise hexuronic acid, hexosamine, deoxyhexamethylose and the sulfate forms of those monosaccharides; wherein, the hexuronic acid is D-glucuronic acid and Δ 4,5 -hexuronic acid (4-deoxy-threo-hex-4-enepyranosyluronic acid), the hexosamine is acetylgalactosamine (2-N-acetylamino-2-deoxy-D-galactose) or a terminal reduction product thereof, the deoxyhexamethylose is L-fucose;

based on molar ratio, the ratio of each monosaccharide and —OSO 3 − in the low-molecular-weight glycosaminoglycan derivative is hexuronic acid: hexosamine: deoxyhexamethylose: sulfate group=1: (1±0.3): (1±0.3): (3.0±1.0); in the hexuronic acid, based on molar ratio, the percentage of Δ 4,5 -hexuronic acid is not less than 2.5% of the total hexuronic acid;

the low-molecular-weight glycosaminoglycan derivative has a weight average molecular weight (Mw) of 3 kD-20 kD;

the low-molecular-weight glycosaminoglycan derivative has a polydispersity index of between 1.0 and 1.8; and

the low-molecular-weight glycosaminoglycan derivative is a mixture of the homologous glycosaminoglycan derivatives having a structure of Formula (I),

(I)

in Formula (I):

n is an integer with average value of 2-20;

-D-GlcUA-β1- is -D-glucuronic acid-β1-yl;

-D-GalNAc-β1- is -2-deoxy-2-N-acetylamino-D-galactose-β1-yl;

L-Fuc-α1- is -L-fucose-α1-yl;

ΔUA-1- is Δ 4,5 -hexuronic acid-1-yl (4-deoxy-threo-hex-4-enepyranosyluronic acid-1-yl);

R is —OH or —OSO 3 − ;

R′ is —OH, C1-C6 alkoxy, or C7-C10 aryloxy;

R 1 is a group shown in Formula (II) or (III), and in said mixture, based on molar ratio, the ratio of the compounds that R 1 is Formula (II) to the compounds that R 1 is Formula (III) is not less than 2:1;

wherein, R and R′ are defined as above;

R 2 is a group shown in Formula (IV) or (V),

wherein, R and R′ are defined as above;

R 3 is carbonyl, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C6-C12 aryl, substituted or non-substituted five or six membered nitrogen-containing heterocyclic group, or —NHR 4 ; wherein R 4 in —NHR 4 is substituted or non-substituted straight or branched chain C1-C6 alkyl, substituted or non-substituted C7-C12 aryl, substituted or non-substituted heteroatom-containing heterocyclic aryl.

2. The low-molecular-weight glycosaminoglycan derivative or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the low-molecular-weight glycosaminoglycan derivative has a weight average molecular weight of 5 kD-12 kD; the low-molecular-weight glycosaminoglycan derivative has a polydispersity index of between 1.1 and 1.5.

3. The low-molecular-weight glycosaminoglycan derivative or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the low-molecular-weight glycosaminoglycan derivative is a β-elimination depolymerization product of fucosylated glycosaminoglycan from body wall and/or viscera of an echinoderm of the class Holothuroidea, or a derivative obtained by reduction of the reducing terminal of the depolymerized product.

4. The low-molecular-weight glycosaminoglycan derivative or a pharmaceutically acceptable salt thereof according to claim 3 , wherein the echinoderm of the class Holothuroidea includes:

Apostichopusjaponicus;

Actinopygamauritiana;

Actinopygamiliaris;

Acaudinamolpadioides;

Bohadschiaargus;

Holothuriaedulis;

Holothurianobilis;

Holothurialeucospilota;

Holothuriasinica;

Holothuriavagabunda;

Isostichopusbadionotus;

Ludwigothureagrisea;

Stichopuschloronotus;

Thelenotaananas;

Thelenotaanax.

5. The low-molecular-weight glycosaminoglycan derivative or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the pharmaceutically acceptable salt is an alkali metal salt, an alkaline-earth metal salt and an organic ammonium salt of the low-molecular-weight glycosaminoglycan derivative.

6. The low-molecular-weight glycosaminoglycan derivative or a pharmaceutically acceptable salt thereof according to claim 5 , wherein the pharmaceutically acceptable salt is sodium salt, potassium salt or calcium salt of the low-molecular-weight glycosaminoglycan derivative.

7. A pharmaceutical composition comprising an anticoagulant effective amount of the low-molecular-weight glycosaminoglycan or a pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutical excipient.

8. The pharmaceutical composition according to claim 7 , wherein a dosage form of said pharmaceutical composition is water solution for injection or lyophilized powder for injection.