IP Library › Granted Patent US 9,150,633
Granted Patent B2
US 9,150,633 · App. 12/673,516 · Granted Oct 6, 2015

Insulin analogues with an acyl and alkylene glycol moiety

Inventors: Peter Madsen (Bagsværd, DK); Thomas Børglum Kjeldsen (Virum, DK); Thomas Hoeg-Jensen (Klampenborg, DK); Tina Møller Tagmose (Ballerup, DK); Palle Jakobsen (Værløse, DK); János Tibor Kodra (København Ø, DK); Patrick William Garibay (Holte, DK); Dorte Xenia Gram (København Ø, DK)
Assignee: Novo Nordisk A/S
C07K14/62A61K38/00
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Quick Facts
Patent No.
US 9,150,633
App. No.
12/673,516
Granted
Oct 6, 2015
Kind
B2
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 (70)

1. An acylated human insulin analogue, comprising a lysine residue connected C-terminally to the amino acid residue in the A21 position, (A22K), and wherein there is no amino acid residue connected to the C terminal end of said A22K amino acid residue; and which acylated insulin analogue is characterized in that an acyl moiety comprising an alkylene glycol moiety is attached to the epsilon group of the lysine residue in the A22 position; and

wherein there is only one lysine residue in the insulin analogue; and

wherein the amino acid residue in the B30 position of the insulin analogue is absent; and

wherein the acyl moiety has the general formula I:

Acy-AA2 m -AA3 p -  (I),

wherein

m is 0, 1, 2, 3, 4, 5 or 6,

p is 1, 2 or 3,

Acy is a fatty acid or a fatty diacid comprising from 8 to 24 carbon atoms from which 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;

AA2 is an acidic amino acid moiety from which 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 moiety from which 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 AA2 and AA3 appears in the formula can be interchanged independently,

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

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

2. An acylated insulin analogue according to claim 1 , wherein AA2 is an acidic acid moiety selected from γGlu, βAsp, or any of the following compounds:

from which a hydrogen atom has been removed from the amino group and a hydroxy group has been removed from the carboxy group, and wherein the arrows indicate the attachment point to the amino group of AA2 or AA3.

3. The acylated insulin analogue according to claim 1 , which is selected from the group consisting of the following compounds:

A22K(N ε -hexadecandioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γGlu), B29R, desB30 human insulin;

A22K(N ε -hexadecandioyl-(2-aminoethyl-PEG2000-ylacetyl)), B29R desB30 human insulin;

A22K(N ε -3-(3-{4-[3-(5-carboxypentanoylamino)propoxy]butoxy}propylcarbamoyl)propionyl-γGlu), B29R, desB30 human insulin;

A22K(N ε -[2(2-[2-(2-[2-(octadecandioyl-γGlu)amino]ethoxy)ethoxy]acetylamino)ethoxy]-ethoxy)acetyl]), B29R, desB30 human insulin;

A22K(N ε -3-(3-{4-[3-(13-carboxytridecanoylamino)propoxy]butoxy}propylcarbamoyl)-propionyl-γGlu), B29R, desB30 human insulin;

A22K(N ε -[2-(2-[2-(2-[2-(eicosanedioyl-γGlu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)-acetyl]), B29R, desB30 human insulin;

A14E, A22K(N ε -[2-(2-[2-(2-[2-(octadecandioyl-γGlu)amino]ethoxy)ethoxy]acetylamino)-ethoxy]ethoxy)acetyl]), B25H, B29R, desB30 human insulin;

A22K(N ε -octadecandioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)-ethoxy]acetyl), desB29, desB30 human insulin;

A14E, A22K(N ε -eicosanedioyl-γGlu-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)-propionyl)), B25H, B29R, desB30 human insulin;

A18L, A22K(N ε -octadecandioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)-ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N ε -octadecandioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)-ethoxy]acetyl), B29R, desB30 human insulin;

A22K(N ε -octadecandioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)-ethoxy]acetyl-γGlu), B29R, desB30 human insulin;

A22K(N ε -eicosanedioyl-γGlu-(3-{2-[2-(2-{2-[2-(2-amino-ethoxy)ethoxy]ethoxy}ethoxy)-ethoxy]ethoxy}propionyl)), B29R, desB30 human insulin;

A22K(N ε -octadecandioyl-γGlu-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl)), B29R, desB30 human insulin;

A14E, A22K(N ε -octadecandioyl-γGlu-(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-γGlu-γGlu-(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-γGlu-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)-propionyl)-γGlu), B25H, B29R, desB30 human insulin;

A22K(N ε -octadecandioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)-ethoxy]acetyl), B28E, B29R, desB30 human insulin;

A22K(N ε -octadecandioyl-γGlu-[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-γGlu)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-γGlu), B29R, desB30 human insulin;

A22K(N ε -eicosanedioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γGlu), B29R, desB30 human insulin;

A22K(N ε -octadecandioyl-(2-aminoethyl-PEG2000-ylacetyl)), B29R desB30 human insulin;

A22K(N ε -eicosanedioyl-(2-aminoethyl-PEG2000-ylacetyl)), B29R desB30 human insulin;

A22K(Nε-3-(3-{4-[3-(15-carboxypentadecanoylamino)propoxy]butoxy}propylcarbamoyl)-propionyl-γGlu), B29R desB30 human insulin;

A22K(Nε-3-(3-{4-[3-(17-carboxyheptadecanoylamino)propoxy]butoxy}propylcarbamoyl)-propionyl-γGlu), B29R desB30 human insulin;

A22K(N ε -tetradecandioyl-(3-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)propionyl-γGlu), B29R, desB30 human insulin;

A8H, A22K(N ε -octadecandioyl-γGlu-[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 -octadecandioyl-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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 -hexadecanedioyl-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[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-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)-ethoxy]acetyl), B29R, desB30 human insulin;

A8H, A22K(N ε -hexadecanedioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin; and

A18L, A22K(N ε -hexadecanedioyl-γGlu-[2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl), B29R, desB30 human insulin.

4. The acylated insulin analogue according to claim 1 , wherein AA3 is selected from the group consisting of:

wherein r is an integer in the range 1-100;

wherein r is an integer in the range of 1-100;

wherein r is an integer in the range 1-100;

wherein s is an integer in the range 1-30; and

wherein t is an integer in the range of 1-150.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 11, 2010
From: MADSEN, PETER; KJELDSEN, THOMAS BORGLUM; HOEG-JENSEN, THOMAS; TAGMOSE, TINA MOLLER; JAKOBSEN, PALLE; KODRA, JANOS TIBOR; GARIBAY, PATRICK WILLIAM; GRAM, DORTE XENIA
To: NOVO NORDISK A/S
Reel/Frame 024364/0871 →
Priority Claims (1)
EP 07114386 · Aug 15, 2007 · regional
Continuity (2)
Provisional Application 60956396 · Aug 17, 2007
Related Publication 20110098440A1 · Apr 28, 2011