Polyethylene glycol derivatives, their modified peptides, methods for producing them and use of the modified peptides

• US 5,183,660 A
• Filed: 08/15/1991
• Issued: 02/02/1993
• Est. Priority Date: 08/28/1990
• Status: Expired due to Fees

• Current Assignee: Sumitomo Pharmaceuticals Company Limited (Sumitomo Chemical Company Limited)
• Original Assignee: Sumitomo Pharmaceuticals Company Limited (Sumitomo Chemical Company Limited)
• Inventors: Ikeda, Yoshiharu, Ono, Keiichi, Kai, Yoshiyuki
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US07/745,496
• Time in Patent Office: 537 Days
• Field of Search: 530/345, 530/389, 530/406, 530/410, 530/307, 530/399, 530/391.1, 568/629, 568/630, 568/648, 562/465, 562/473, 562/493, 562/496, 528/425, 514/2, 514/12, 424/94.4, 424/94.64, 424/94.3, 435/177, 435/188
• US Class Current: 424/94.3
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C08G 65/3317 phenolic
• CPC Class Codes: C08G 65/3326 aromatic

Abstract

Polyethylene glycol derivatives of the formula ##STR1## wherein R₁ and R₂ are the same or different and each represents a lower alkyl, m and n are the same or different and each represents a positive integer and p is 0 or a positive integer, peptides modified by the polyethylene glycol derivatives, methods for producing them and use of the modified peptides. The peptides modified by the polyethylene glycol derivatives (I) of the invention, as compared with the corresponding non-modified peptides, show decreased antigenicity, are considerably delayed in biological clearance, and exhibit their physiological activities effectively over a long period, rendering them very effective as pharmaceuticals as well as drugs for animals.

Claims

1. A polyethylene glycol derivative of the formula ##STR16## wherein R₁ and R₂ are the same or different and each represents a lower alkyl, m and n are the same or different and each represents a positive integer of 10 to 400, and p is 0 or a positive integer.

2. A polyethylene glycol derivative as claimed in claim 1 wherein p is 0 or a positive integer of 1 to 10.

3. A polyethylene glycol derivative as claimed in claim 1 which is selected from the group consisting of 3,5-bis-methoxypolyethylene glycol dihydrocinnamic acid.

4. A modified peptide wherein amino groups in the peptide are modified by a polyethylene glycol derivative as claimed in claim 1.

5. A modified peptide as claimed in claim 4 wherein the peptide has 2 or more amino acids bound by peptide bonds and at least one of the constituent amino acids has a free amino group.

6. A modified peptide as claimed in claim 4 wherein the peptide is selected from the group consisting of superoxide dismutase, insulin-like growth factor-I, insulin-like growth factor-II, calcitonin gene related peptide, elastase and growth hormone-releasing factor.

7. A modified peptide as claimed in claim 4 which is selected from the group consisting of superoxide dismutase modified by 3,5-bis-methoxypolyethylene glycol benzoic acid, insulin-like growth factor-I modified by 3,5-bis-methoxypolyethylene glycol benzoic acid, insulin-like growth factor-II modified by 3,5-bis-methoxypolyethylene glycol benzoic acid, calcitonin gene related peptide modified by 3,5-bis-methoxypolyethylene glycol benzoic acid, elastase modified by 3,5-bis-methoxypolyethylene glycol benzoic acid, superoxide dismutase modified by 3,4-bis-methoxypolyethylene glycol dihydrocinnamic acid, insulin-like growth factor-I modified by 3,4-bis-methoxypolyethylene glycol dihydrocinnamic acid, calcitonin gene related peptide modified by 3,4-bis-methoxypolyethylene glycol dihydrocinnamic acid, elastase modified by 3,4-bis-methoxypolyethylene glycol dihydrocinnamic acid and growth hormone-releasing factor modified by 3,4-bis-methoxypolyethylene glycol dihydrocinnamic acid.

8. A method for producing a polyethylene glycol derivative as claimed in claim 1 comprising reacting a compound of the formula (III) of (III'"'"') ##STR17## wherein X₁ and X₂ are the same or different and each represents an alkylsulfonyloxy, an aromatic sulfonyloxy or a halogen, and R₁, R₂, m and n are as defined in claim 1, with a compound of the formula (IV) ##STR18## wherein p is as defined in claim 1.

9. A pharmaceutical composition comprising a modified peptide as claimed in claim 4 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a modified peptide as claimed in claim 5 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a modified peptide as claimed in claim 6 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a modified peptide as claimed in claim 7 and a pharmaceutically acceptable carrier.

13. A method for producing a modified peptide comprising reacting a carboxyl group-activated compound of a polyethylene glycol derivative of the formula ##STR19## wherein R₁ and R₂ are the same or different and each represents a lower alkyl, m and n are the same or different and each represents a positive integer and p is 0 or a positive integer, with a peptide having at least one free amino group.

14. A method as claimed in claim 13 wherein m and n are respectively a positive integer of 10 to 400.