Insulin Analogues with an Acyl and Alkylene Glycol Moiety

• US 20110098440A1
• Filed: 08/15/2008
• Published: 04/28/2011
• Est. Priority Date: 08/15/2007
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Moller, Tagmose Tina, Borglum, Kjeldsen Thomas, Thomas, Hoeg-Jensen, Tibor, Kodra János, Xenia, Gram Dorte, Palle, Jakobsen, William, Garbay Patrick, Madsen, Peter
• Granted Patent: US 9,150,633 B2
• Time in Patent Office: Days
• US Class Current: 530/303
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

An acylated insulin analogue wherein the insulin analogue comprises a lysine residue connected C-terminally to the A21 amino acid residue or a peptide residue of up to 4 amino acid residues comprising a lysine residue which peptide residue is connected C-terminally to the A21 amino acid residue, characterized in that an acyl moiety comprising an alkylene glycol moiety is attached to the lysine residue in the A22 position or attached to a lysine residue present in the peptide residue that is attached to the C terminal end of the A21 amino acid residue and wherein there is only one lysine (K, Lys) in the insulin analogue, can conveniently be administered pulmonary.

Claims

1. An acylated insulin analogue wherein the insulin analogue comprises a lysine residue connected C-terminally to the A21 amino acid residue or a peptide residue of up to 4 amino acid residues comprising a lysine residue which peptide residue is connected C-terminally to the A21 amino acid residue, characterized in that an acyl moiety comprising an alkylene glycol moiety is attached to the lysine residue in the A22 position or attached to a lysine residue present in the peptide residue that is attached to the C terminal end of the A21 amino acid residue and wherein there is only one lysine (K, Lys) in the insulin analogue.

2. An acylated insulin analogue, according to claim 1, wherein the acyl moiety has the general formula I:

Acy-AA1_n-AA2_m-AA3_p- 

 

(I),

wherein

n is 0 or an integer in the range 1-3,

m is 0 or an integer in the range 1-6,

p is 1, 2 or 3,

Acy is a fatty acid or a fatty diacid comprising about 8-24 carbon atoms from which, formally, a hydroxy group has been removed from the carboxy group of the fatty acid or from one of the carboxy groups of the fatty diacid,

AA1 is a neutral cyclic amino acid from which, formally, a hydrogen atom has been removed from the amino group and a hydroxy group has been removed from the carboxy group,

AA2 is an acidic amino acid from which, formally, a hydrogen atom has been removed from the amino group and a hydroxy group has been removed from the carboxy group,

AA3 is a neutral, alkyleneglycol-containing amino acid from which, formally, a hydrogen atom has been removed from the amino group and a hydroxy group has been removed from the carboxy group,

the order by which AA1, AA2 and AA3 appears in the formula can be interchanged independently,

the connections between Acy, AA1, AA2 and/or AA3 are amide (peptide) bonds, and

attachment to the parent insulin can be from the C-terminal end of a AA1, AA2, or AA3 residue in the acyl moiety of the formula (I) or from one of the side-chain(s) of an AA2 residue present in the moiety of formula (I).

3. An acylated insulin analogue, according to any one of the preceding, possible claims, wherein AA1 is selected from:

4. An acylated insulin analogue, according to the preceding claim, wherein AA1 is

5. An acylated insulin analogue, according to any one of the preceding, possible claims, wherein AA2 is selected from γ

Glu, β

Asp or any of the following compounds;

6. An acylated insulin analogue, according to any one of the preceding, possible claims which is any of the following comoiunds:

A22K(N^ε

-hexadecandioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γ

Glu), B29R, desB30 human insulin;

A22K(N^ε

-hexadecandioyl-(2-aminoethyl-PEG2000-yl-acetyl)), B29R desB30 human insulin;

A22K(N^ε

-3-(3-{4-[3-(5-carboxypentanoylamino)propoxy]butoxy}propylcarbamoyl)propionyl-γ

Glu), B29R, desB30 human insulin;

A22K(N^ε

-[2(2-[2-(2-[2-(octadecandioyl-γ

Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]), B29R, desB30 human insulin;

A22K(N^ε

-3-(3-{4-[3-(13-carboxytridecanoylamino)propoxy]butoxy}propylcarbamoyl)propionyl-γ

Glu), B29R, desB30 human insulin;

A22K(N^ε

-[2-(2-[2-(2-[2-(eicosanedioyl-γ

Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]), B29R, desB30 human insulin;

A14E, A22K(N^ε

-[2-(2-[2-(2-[2-(octadecandioyl-γ

Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]), B25H, B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), desB29, desB30 human insulin;

A14E, A22K(N^ε

-eicosanedioyl-γ

Glu-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl)), B25H, B29R, desB30 human insulin;

A18L, A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl-γ

Glu), B29R, desB30 human insulin;

A22K(N^ε

-eicosanedioyl-γ

Glu-(3-{2-[2-(2-{2-[2-(2-amino-ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}propionyl)), B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-γ

Glu-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl)), B29R, desB30 human insulin;

A14E, A22K(N^ε

-octadecandioyl-γ

Glu-(3-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl)), B25H, B29R, desB30 human insulin;

A14E, A22K(N^ε

-eicosanedioyl-γ

Glu-γ

Glu-(3-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl)), B25H, B29R, desB30 human insulin;

A14E, A22K(N^ε

-octadecandioyl-γ

Glu-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl)-γ

Glu), B25H, B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B28E, B29R, desB30 human insulin;

22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A14E, A22K(N^ε

-[2-(2-[2-(2-[2-(eicosanedioyl-γ

Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]), B25H, B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γ

Glu), B29R, desB30 human insulin;

A22K(N^ε

-eicosanedioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γ

Glu), B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-(2-aminoethyl-PEG2000-ylacetyl)), B29R desB30 human insulin;

A22K(N^ε

-eicosanedioyl-(2-aminoethyl-PEG2000-yl-acetyl)), B29R desB30 human insulin;

A22K(Nε

-3-(3-{4-[3-(15-carboxypentadecanoylamino)propoxy]butoxy}propylcarbamoyl)propionyl-γ

Glu), B29R desB30 human insulin;

A22K(Nε

-3-(3-{4-[3-(17-carboxyheptadecanoylamino)propoxy]butoxy}propylcarbamoyl)propionyl-γ

Glu), B29R desB30 human insulin;

A22K(N^ε

-tetradecandioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γ

Glu), B29R, desB30 human insulin;

A8H, A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), 829R, desB30 human insulin;

A18L, A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A18L, A22K(N^ε

-octadecandioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-eicosanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-eicosanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A18L, A22K(N^ε

-eicosanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A22K(N^ε

-eicosanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-eicosanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A18L, A22K(N^ε

-eicosanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetyl-amino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A18L, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A18L, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin and A18L, A22K(N^ε

-hexadecanedioyl-γ

Glu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin.