Branched polyalkylene glycols

• US 20050063936A1
• Filed: 01/30/2002
• Published: 03/24/2005
• Est. Priority Date: 01/30/2001
• Status: Active Grant

• Current Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited)
• Original Assignee: Kyowa Hakko Kogyo Company Limited (Kirin Holdings Company Limited)
• Inventors: Makai, Mayumi, Yamasaki, Motoo, Kuwabara, Takashi, Murakami, Tatsuya, Sakurai, Noriko, Suzawa, Toshiyuki, Yamashita, Kinya
• Granted Patent: US 7,291,713 B2
• Time in Patent Office: Days
• US Class Current: 424/78.270
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/641 Branched, dendritic or hypercomb peptides
• CPC Class Codes: A61K 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3311 containing a hydroxy group
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

The present invention provides a branched polyalkylene glycol wherein three or more single-chain polyalkylene glycols and a group having reactivity with an amino acid side chain, the N-terminal amino group or the C-terminal carboxyl group in a polypeptide or a group convertible into the group having reactivity are bound; and a physiologically active polypeptide modified with the branched polyalkylene glycol.

Claims

1. A branched polyalkylene glycol wherein three or more single-chain polyalkylene glycols and a group having reactivity with an amino acid side chain, the N-terminal amino group or the C-terminal carboxyl group in a polypeptide or a group convertible into the group having reactivity are bound.

2. A branched polyalkylene glycol represented by formula (1):

(R¹—

M_n—

X¹)_mL(X²—

X³—

R²)_q 

 

(I)

{wherein L represents a group capable of having four or more branches;

M represents OCH₂CH₂, OCH₂CH₂CH₂, OCH(CH₃)CH₂, (OCH²CH²)_r—

(OCH₂CH₂CH₂)_s (in which r and s, which may be the same or different, each represent an arbitrary positive integer) or (OCH²CH²)_ra—

[OCH(CH₃)CH₂]_sa (in which ra and sa have the same meanings as the above r and s, respectively);

n represents an arbitrary positive integer;

m represents an integer of 3 or more;

q represents an integer of 1 to 3;

R¹ represents a hydrogen atom, lower alkyl or lower alkanoyl;

R² represents a group having reactivity with an amino acid side chain, the N-terminal amino group or the C-terminal carboxyl group in a polypeptide or a group convertible into the group having reactivity;

X¹ represents a bond, O, S, alkylene, O(CH₂)_ta (in which ta represents an integer of 1 to

     8), (CH₂)_tbO (in which tb has the same meaning as the above ta), NR³ (in which R³ represents a hydrogen atom or lower alkyl), R⁴—

NH—

C(═

O)—

R⁵ [in which R⁴ represents a bond, alkylene or O(CH₂)_tc (in which tc has the same meaning as the above ta) and R⁵ represents a bond, alkylene or OR^5a (in which R^5a represents a bond or alkylene)], R⁶—

C(═

O)—

NH—

R⁷ [in which R⁶ represents a bond, alkylene or R^6aO (in which R^6a has the same meaning as the above R^5a) and R⁷ represents a bond, alkylene or (CH₂)_tdO (in which td has the same meaning as the above ta)], R⁸—

C(═

O)—

O (in which R⁸ has the same meaning as the above R^5a) or O—

C(═

O)—

R⁹ (in which R⁹ has the same meaning as the above R^5a);

X² represents a bond, O or (CH₂)_teO (in which te has the same meaning as the above ta);

X³ represents a bond or alkylene; and

three or more R¹—

M_n—

X¹ '"'"'s may be the same or different, and when two or three X²—

X³-R²'"'"'s are present (when q is 2 or

     3), they may be the same or different}.

3. The branched polyalkylene glycol according to claim 2, wherein q is 1.

4. The branched polyalkylene glycol according to claim 2, wherein m is 3 or 4.

5. The branched polyalkylene glycol according to any of claims 2 to 4, wherein n is 10 to 100,000, and r and s, and ra and sa, which may be the same or different, each represent 1 to 100,000.

6. The branched polyalkylene glycol according to claim 5, wherein R² is a hydroxyl group, carboxy, formyl, amino, vinylsulfonyl, mercapto, cyano, carbamoyl, halogenated carbonyl, halogenated lower alkyl, isocyanato, isothiocyanato, oxiranyl, lower alkanoyloxy, maleimido, succinimidooxycarbonyl, substituted or unsubstituted aryloxycarbonyl, benzotriazolyloxycarbonyl, phthalim idooxycarbonyl, imidazolylcarbonyl, substituted or unsubstituted lower alkoxycarbonyloxy, substituted or unsubstituted aryloxycarbonyloxy, tresyl, lower alkanoyloxycarbonyl, substituted or unsubstituted aroyloxycarbonyl, substituted or unsubstituted aryldisulfido, or azido.

7. The branched polyalkylene glycol according to claim 6, which has a molecular weight of 500 to 1,000,000.

8. The branched polyalkylene glycol according to claim 7, wherein L is a group selected from the group consisting of a group formed by removing four or more hydrogen atoms from tricine, a group formed by removing four or more hydrogen atoms from shikimic acid, a group formed by removing four or more hydrogen atoms from quinic acid, a group formed by removing four or more hydrogen atoms from erythritol, a group formed by removing four or more hydrogen atoms from pentaerythritol, and a group formed by removing four or more hydrogen atoms from glucose.

9. A chemically modified polypeptide wherein a physiologically active polypeptide or its derivative is modified with at least one branched polyalkylene glycol according to claim 8 directly or through a spacer.

10. The chemically modified polypeptide according to claim 9, wherein the physiologically active polypeptide is an enzyme, a cytokine or a hormone.

11. A pharmaceutical composition comprising the chemically modified polypeptide according to claim 10 and a pharmaceutically acceptable courier.