Multi-substituted insulins

Patent metadata

Field	Value
Publication number	US-9260503-B2
Application number	US-201214126215-A
Country	US
Kind code	B2
Filing date	Jun 14, 2012
Priority date	Jun 15, 2011
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

The present invention regards an insulin derivative comprising at least 2 albumin binding moieties, wherein said albumin binding moieties comprise fatty diacid substitutions and a method for preparing such an insulin derivative by acylation and/or reductive alkylation. The present invention also concern a pharmaceutical comprising such an insulin derivative.

First claim

The invention claimed is:

1. A soluble insulin derivative or pharmaceutically acceptable salt thereof selected from the group consisting of
A1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-aminomethyl-benzyl B1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl A14E B25H desB27 desB30 human insulin,
A1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-aminomethyl-benzyl B1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl A14E B25H desB30 human insulin,
A1N α -hexadecandioyl-γ-L-glutamyl-OEG-OEG-aminomethyl-benzyl B1N α -hexadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl A14E B25H desB27 desB30 human insulin,
A1N α -tetradecandioyl-γ-L-glutamyl-OEG-OEG-aminomethyl-benzyl B1N α -tetradecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl A14E B25H desB27 desB30 human insulin,
A1N α -hexadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl B1N α -hexadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl A14E B25H desB30 human insulin,
B1N-octadecandioyl-γ-L-glutamyl-OEG-OEG-aminomethyl-benzyl B29N ε -octadecandioyl-γ-L-glutamyl-OEG-OEG A14E B25H desB30 human insulin,
A1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl B1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl B29N ε -octadecandioyl-γ-L-glutamyl-OEG-OEG A14E B25H desB30 human insulin,
B1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl B29N ε -octadecandioyl-γ-L-glutamyl-OEG-OEG A14E B16H B25H desB30human insulin,
B1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-4-aminomethyl-benzyl A14E B25H B29N ε -octadecandioyl-γ-L-glutamyl-OEG-OEG desB30human insulin, and
B1N α -octadecandioyl-γ-L-glutamyl-OEG-OEG-aminomethyl-benzyl B29N ε -octadecandioyl-γ-L-glutamyl-OEG-OEG A14E B25H desB27 desB30 human insulin,
wherein OEG is *—NH—(CH 2 ) 2 O—(CH 2 ) 2 O—CH 2 CO—*.

2. A soluble insulin derivative or a pharmaceutically acceptable salt thereof of general formula
XZ n -Ins-Z 1 m X 1 ,
wherein
Ins represents an insulin comprising a B29 lysine or B29 arginine residue and/or a A22 lysine residue, X is a fatty diacid substitution, X 1 is a fatty diacid substitution, Z is a linker between X and Ins, Z 1 is a linker between Ins and X 1 , n is zero or 1, and m is zero or 1, and wherein at least one of Z and Z 1 comprises OEG-OEG-aminomethyl-benzyl, wherein OEG is *—NH—(CH 2 ) 2 O—(CH 2 ) 2 O—CH 2 CO—*.

3. The soluble insulin derivative or a pharmaceutically acceptable salt thereof according to claim 2 , wherein Ins represents an insulin comprising a B29 lysine or B29 arginine residue and a A22 lysine residue, and X is located at said A22 lysine residue.

4. The soluble insulin derivative or a pharmaceutically acceptable salt thereof according to claim 3 , wherein said fatty diacid substitutions each comprise 14-20 carbon atoms.

5. The soluble insulin derivative or a pharmaceutically acceptable salt thereof according to claim 4 , wherein X 1 is located at a position selected from the group consisting of B29 lysine, N-terminus of the A chain, and N-terminus of the B chain.

6. The soluble insulin derivative or a pharmaceutically acceptable salt thereof according to claim 4 , wherein X 1 is located at a position selected from the group consisting of N-terminus of the A chain, and N-terminus of the B chain.

7. The soluble insulin derivative or a pharmaceutically acceptable salt thereof according to claim 4 , wherein X 1 is located at a position selected from the group consisting of B29lysine and N-terminus of the B chain.

8. The soluble insulin derivative or pharmaceutically acceptable salt thereof according to claim 3 , wherein said fatty acid substitutions are each selected from a group of protracting moieties selected from Chem. 3 and Chem. 4, wherein
Chem 3 is HOOC—(CH 2 ) x —CO—*, and

Chem 4 is HOOC—C 6 H4-O—(CH 2 ) y —CO—*,

wherein x is an integer from 10 to 20 and y is an integer from 6 to 14.

9. The soluble insulin derivative or pharmaceutically acceptable salt thereof according to claim 8 , wherein x is 14, 16 or 18 and y is 8, 10 or 12.

10. The soluble insulin derivative or pharmaceutically acceptable salt thereof according to claim 5 , wherein said fatty acid substitutions are each selected from a group of protracting moieties selected from Chem. 3 and Chem. 4, wherein
Chem 3 is HOOC—(CH 2 )x-CO—*, and

Chem 4 is HOOC—C 6 H4-O—(CH 2 )y-CO—*,

wherein x is 14, 16 or 18 and y is 8, 10 or 12.

11. The soluble insulin derivative or pharmaceutically acceptable salt thereof according to claim 10 , wherein Z and Z 1 comprise one or more linker elements selected from the group consisting of selected from the group consisting of: alpha-L-Glu, alpha-D-Glu, gamma-L-Glu, gamma-D-Glu, alpha-L-Asp, alpha-D-Asp, beta-L-Asp, beta-D-Asp, CPH, IDA and OEG, wherein CPH is *—CH 2 PhCH 2 NH—*, IDA is *—N((CH 2 ) n COOH)(CH 2 ) m CO—*, wherein n is 1 or 2 and m is 1 or 2, and OEG is *—NH—(CH 2 ) 2 O—(CH 2 ) 2 O—CH 2 CO—*, wherein at least one of Z and Z 1 comprises OEG-OEG-aminomethyl-benzyl.

12. A pharmaceutical composition comprising a soluble insulin derivative or a pharmaceutically acceptable salt thereof of claim 2 and a pharmaceutically suitable excipient.

13. A pharmaceutical composition comprising a soluble insulin derivative or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically suitable excipient.

14. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, or type 1 diabetes in a subject in need of said treatment, said method comprising administering to a said subject a therapeutically effective amount of a pharmaceutical composition of claim 12 .

15. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, or type 1 diabetes in a subject in need of said treatment, said method comprising administering to a said subject a therapeutically effective amount of a pharmaceutical composition of claim 13 .

Assignees

• Hoeg-Jensen Thomas
• Madsen Peter
• Spetzler Jane
• Tagmose Tina Moeller
• Novo Nordisk As

Inventors

• Hoeg-Jensen Thomas
• Madsen Peter
• Spetzler Jane
• Tagmose Tina Moeller

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• C07K14/622 Primary

  at least 1 amino acid in D-form · CPC title