Derivative of hyaluronic acid modified with amino-carboxylic acid

1. A hyaluronic acid derivative comprising disaccharide units represented by Formula (I):

wherein

R 1 , R 2 , R 3 , and R 4 are each independently selected from a hydrogen atom, C 1-6 alkyl, formyl and C 1-6 alkylcarbonyl;

R 8 is a hydrogen atom, formyl or C 1-6 alkylcarbonyl;

X is a group represented by —NHCH 3 , —NH(CH 2 ) 2 CH 3 , —NR x -A-B—COOR y or —NR x —CHR c —CONR ya R yb ;

R x and R y are each independently selected from a hydrogen atom and C 1-6 alkyl;

A is selected from —CR a R b —, C 3-8 cycloalkylene, 2-cyclohexylethane-1,1-diyl, 2-(2-naphthyl)ethane-1,1-diyl, 3-phenylpropane-1,1-diyl, cyclohexylmethane-1,1-diyl, and 4-hydroxyphenylmethane-1,1-diyl, and B is a direct bond; or

A is —CH 2 — or —CH 2 —CH 2 —, and B is selected from phenylene (wherein the phenylene may be substituted by one or more groups selected from hydroxy and halogen atoms), C 3-8 cycloalkylene and phenylmethane-1,1-diyl;

R a is selected from a hydrogen atom and C 1-6 alkyl;

R b is selected from a hydrogen atom and C 1-6 alkyl (wherein the C 1-6 alkyl may be substituted by one or more groups selected from hydroxy, carboxy and carbamoyl);

R c represents C 1-3 -alkyl which may be substituted by carbamoyl;

R ya and R yb are each independently selected from a hydrogen atom, C 1-6 alkyl, formyl and C 1-6 alkylcarbonyl,

wherein, when X in Formula (I) is —NHCH 3 , —NH(CH 2 ) 2 CH 3 , or —NR x —CHR c —CONR ya R yb , or when A in Formula (I) is —CR a R b — or C 3-8 cycloalkylene, the proportion of the disaccharide units of Formula (I) with respect to disaccharide units present is at least 70%.

2. The hyaluronic acid derivative according to claim 1 , wherein X is —NHCH 3 , —NH(CH 2 ) 2 CH 3 or —NR x —CHR c —CONR ya R yb , or A is —CR a R b — or C 3-8 cycloalkylene.

3. The hyaluronic acid derivative according to claim 1 , wherein

A is C 3-8 cycloalkylene, and B is a direct bond;

A is —CH 2 — or —CH 2 —CH 2 —, and B is selected from phenylene (wherein the phenylene may be substituted by one or more groups selected from hydroxy and halogen atoms), C 3-8 cycloalkylene and phenylmethane-1,1-diyl; or

A is selected from 2-cyclohexylethane-1,1-diyl, 2-(2-naphthyl)ethane-1,1-diyl, 3-phenylpropane-1,1-diyl, cyclohexylmethane-1,1-diyl and 4-hydroxyphenylmethane-1,1-diyl, and B is a direct bond.

4. The hyaluronic acid derivative according to claim 1 , wherein

A is —CH 2 —, and B is selected from cyclohexane-1,1-diyl, benzene-1,4-diyl, benzene-1,3-diyl, 2-chlorobenzene-1,4-diyl and phenylmethane-1,1-diyl;

A is —CH 2 CH 2 —, and B is benzene-1,4-diyl; or

A is selected from 2-cyclohexylethane-1,1-diyl, 2-(2-naphthyl)ethane-1,1-diyl, and 3-phenylpropane-1,1-diyl; and B is a direct bond.

5. The hyaluronic acid derivative according to claim 1 , further comprising disaccharide units represented by Formula (II):

wherein

R 1a , R 2a , R 3a , and R 4a are each independently selected from a hydrogen atom, C 1-6 alkyl, formyl and C 1-6 alkylcarbonyl;

R 8a is a hydrogen atom, formyl or C 1-6 alkylcarbonyl;

X a is selected from hydroxy and —O − Q + wherein Q + represents a countercation.

6. The hyaluronic acid derivative according to claim 1 , further comprising disaccharide units represented by Formula (III):

wherein

R 1b , R 2b , R 3b , and R 4b are each independently selected from a hydrogen atom, C 1-6 alkyl, formyl and C 1-6 alkylcarbonyl;

R 8b is a hydrogen atom, formyl or C 1-6 alkylcarbonyl;

X b is a group represented by —NR e —Y b —R d ; wherein

R e is a hydrogen atom or C 1-6 alkyl;

R d is a hydrogen atom, C 1-6 alkyl, —CO—C(R 7 )═CH 2 , or —CO-G 4 -X e ;

R 7 is a hydrogen atom or methyl;

G 4 is selected from phenylene, C 3-8 cycloalkylene, and -G 5 -(C 1-10 alkylene)-G 6 -, wherein the C 1-10 alkylene moiety may have one to three phenylenes or C 3-8 cycloalkylenes inserted therein;

G 5 and G 6 are each independently selected from a direct bond, phenylene, or C 3-8 cycloalkylene;

X c is mercapto, a halogen atom or a group represented by the formula:

Y b is —CH 2 —(CHR 5 ) l-2 —CH 2 —NH—, —CH 2 —(CHR 6 ) p-2 —CH 2 —O˜, —(CH 2 ) j —S—, or —(CH 2 ) a —(Y 1 —(CH 2 ) b ) c -G-;

l, p, and j are each independently an integer selected from 2 to 10, R 5 and R 6 are each independently a hydrogen atom or hydroxy;

a is an integer selected from 2 to 10;

each b is independently an integer selected from 2 to 10;

c is an integer selected from 1 to 200;

Y 1 is an oxygen atom or —NR n —;

G is an oxygen atom, a sulfur atom or —NH—;

R n is a hydrogen atom, C 1-6 alkyl, —CO—(CH 2 ) d —R o , —(CH 2 ) e —R p or —(CH 2 ) f —(Y 2 —(CH 2 ) g ) h —R q ;

each g is independently an integer selected from 2 to 10;

d, e, f and h are each independently an integer selected from 2 to 10;

R o , R p and R q are each independently a hydrogen atom, hydroxy, carboxy or —NHR r ;

Y 2 is an oxygen atom or —NH—;

R r is a hydrogen atom, formyl or C 1-6 alkylcarbonyl.

7. The hyaluronic acid derivative according to claim 1 , which is prepared using hyaluronic acid composed exclusively of the disaccharide units each represented by Formula (II):

wherein, when R 1a , R 2a , R 3a , and R 4a are all hydrogen atoms, R 8a is acetyl, and X a is —O − Na + , the weight-average molecular weight is in the range of 20-120 kilodaltons.

8. The hyaluronic acid derivative according to claim 1 , wherein an underivatized hyaluronic acid corresponding to the hyaluronic acid derivative in terms of backbone structure has a weight-average molecular weight of 20-120 kilodaltons, wherein the underivatized hyaluronic acid is hyaluronic acid composed exclusively of disaccharide units of Formula (II):

wherein R 1a , R 2a , R 3a , and R 4a are hydrogen atoms, R 8a is acetyl, and X a is —O − Na + .

9. A pharmaceutical composition comprising the hyaluronic acid derivative according to claim 1 , as a carrier.

10. A hyaluronic acid derivative/drug conjugate wherein one or more drugs are conjugated to the hyaluronic acid derivative according to claim 1 .

11. A biodegradable drug carrier comprising the hyaluronic acid derivative according to claim 1 .