Cinnamic acid derivative

• US 6,107,410 A
• Filed: 12/22/1998
• Issued: 08/22/2000
• Est. Priority Date: 11/17/1994
• Status: Expired due to Term

• Current Assignee: Seikagaku Corporation
• Original Assignee: Seikagaku Corporation
• Inventors: Miyamoto, Kenji, Waki, Michinori, Motani, Yoshihiro
• Primary Examiner(s): Zitomer, Fred
• Application Number:
  US09/217,902
• Time in Patent Office: 609 Days
• Field of Search: 525/293, 525/298, 525/302
• US Class Current: 525/293
• CPC Class Codes: C07C 217/08 the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 219/10 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
• CPC Class Codes: C07C 229/22 the carbon skeleton being further substituted by oxygen atoms
• CPC Class Codes: C07C 233/51 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 237/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 237/12 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C08B 37/003 Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The invention provides a cinnamic acid derivative having a novel spacer introduced into cinnamic acid which is photodimerizable, a cinnamic acid-polysaccharide derivative photocurable with high sensitivity and efficiency obtainable by introducing the above cinnamic acid derivative into a host polysaccharide such as a glycosaminoglycan, and a photocrosslinked cinnamic acid-polysaccharide derivative obtainable by exposing the same cinnamic acid-polysaccharide derivative to ultraviolet light irradiation.

Claims

1. A crosslinked cinnamic acid-polysaccharide derivative wherein a cinnamic acid-polysaccharide derivative represented by any of the following formulas (13)-(15) is crosslinked by containing a cyclobutane ring produced by photodimerization of R¹ and R¹, R² and R², or R¹ and R² in the cinnamic acid-polysaccharide derivative represented by formula (13), (14) or (15) or in a mixture thereof:

space="preserve" listing-type="equation">R.sup.1 --A--P.sup.1 (

     13)

space="preserve" listing-type="equation">R.sup.1 --B--P.sup.2 (

     14)

space="preserve" listing-type="equation">R.sup.2 --C--P.sup.1 (

     15)

wherein R¹ represents a group of the formula (4);

##STR24## wherein R³ and R⁴ independently represent a hydrogen atom, a nitro group, an amino group, a hydroxyl group or a C_1-4 alkoxy group;

R² represents a group of the formula (5);

##STR25## wherein R³ and R⁴ are as defined above;

R⁵ represents a lower alkyl group;

A-- represents an amino- and hydroxy-containing compound residue represented by any of the formulas (6'"'"')-(9);

space="preserve" listing-type="equation">--O--(CH.sub.2).sub.n --NH (6'"'"')

wherein n represents a whole number of 3-18,

space="preserve" listing-type="equation">--(O--CH.sub.2 CH.sub.2).sub.m --NH (7'"'"')

wherein m represents a whole number of 2-10,

space="preserve" listing-type="equation">--O--CHR.sup.6 CH(COOR.sup.7)--NH (8'"'"')

wherein R⁶ represents a hydrogen atom or a lower alkyl group;

R⁷ represents a lower alkyl group.

space="preserve" listing-type="equation">--O--(CH.sub.2).sub.l --NHCO--CHR.sup.8 --NH (9'"'"')

wherein l represents a whole number of 2-18;

R⁸ represents the side chain of an α

-amino acid residue;

B-represents an amino acid residue of the formula (10'"'"');

space="preserve" listing-type="equation">--NH--(CH.sub.2).sub.k --CO (10'"'"')

wherein k represents a whole number of 1-18;

C-- represents an amino acid residue of the formula (11'"'"') or (12'"'"');

space="preserve" listing-type="equation">--CO--(CH.sub.2).sub.k --NH (11'"'"')

wherein k is as defined above,

space="preserve" listing-type="equation">--(COCHR.sup.8 NH).sub.i ( 12'"'"')

wherein i represents a whole number of 1-6;

R⁸ is as defined above;

P¹ represents a carboxy-containing polysaccharide residue;

P² represents an amino- or hydroxy-containing polysaccharide residue;

the A--P¹ linkage is the amide bond formed between the terminal amino group of the formula (6'"'"'), (7'"'"'), (8'"'"') or (9'"'"') and the carboxyl group of P¹ ;

the B--P² linkage is the amide bond formed between the terminal carboxyl group of the formula (10'"'"') and the amino group of P² or the ester bond formed between the terminal carboxyl group of the formula (10'"'"') and the hydroxyl group of P² ; and

the C--P¹ linkage is the amide bond formed between the terminal amino group of the formula (11'"'"') or (12'"'"') and the carboxyl group of P¹ ;

with the proviso that, when the polysaccharide is a hyaluronic acid, the photodimerizable-crosslinkable group is introduced into the cinnamic acid-polysaccharide derivative at a degree of substitution of 0.05-5.0% to a repeating constituent saccharide unit of the hyaluronic acid.

2. The crosslinked cinnamic acid-polysaccharide derivative of claim 1 wherein the cinnamic acid-polysaccharide derivative is crosslinked by containing a cyclobutane ring produced by photodimerization of R¹ and R¹ in the cinnamic acid-polysaccharide derivative represented by the formula (13).

3. The crosslinked cinnamic acid-polysaccharide derivative of claim 1 wherein the cinnamic acid-polysaccharide derivative is crosslinked by containing a cyclobutane ring produced by photodimerization of R¹ and R¹ in the cinnamic acid-polysaccharide derivative represented by the formula (14).

4. The crosslinked cinnamic acid-polysaccharide derivative of claim 1 wherein the cinnamic acid-polysaccharide derivative is crosslinked by containing a cyclobutane ring produced by photodimerization of R² and R² in the cinnamic acid-polysaccharide derivative represented by the formula (15).

5. The crosslinked cinnamic acid-polysaccharide derivative of claim 1 wherein the cinnamic acid-polysaccharide derivative contains the cyclobutane ring produced by photodimerization of R¹ and R¹, R² and R², or R¹ and R² and a geometrically isomerized R¹ or R² produced by photoisomerization, each by irradiating the cinnamic acid-polysaccharide derivative represented by the formula (13), (14) or (15) with ultraviolet light.

6. The croselinked cinnamic acid-polysuaccharide derivative of claim 1 wherein the photodimerizable-crosslinkable group is introduced into the cinnamic acid-polysaccharide derivative represented by the formulas (13) and/or (15) at a degree of substitution of 0.05-5.0% to a repeating constituent saccharide unit of the polysaccharide.

7. The crosslinked cinnamic acid-polysaccharide derivative of claim 1, which is a water-insoluble crosslinked hyaluronic acid derivative in the form of film, gel or powder.

8. The crosslinked cinnamic acid-polysaccharide derivative of claim 1 wherein the polysaccharide is a glycosaminoglycan or a polyaminosaccharide.

9. The crosslinked cinnamic acid-polysaccharide derivative of claim 8 wherein the glycosaminoglycan, is a member selected from the group consisting of hyaluronic acid, chondroitin sulfate, dermatan sulfate, chondroitin, heparin, heparan sulfate and keratan sulfate.

10. The crosslinked cinnamic acid-polysaccharide derivative of claim 8 wherein the glycosaminoglycan is a hyaluronic acid.

11. The crosslinked cinnamic acid-polysaccharide derivative of claim 10 wherein the hyaluronic acid has a number average molecular weight of 100,000-5,000,000.

12. The crosslinked cinnamic acid-polysaccharide derivative of claim 8 wherein the polyaminosaccharide is a chitin or chitosan.