Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids

Patent metadata

Field	Value
Publication number	US-8962794-B2
Application number	US-67333708-A
Country	US
Kind code	B2
Filing date	Aug 15, 2008
Priority date	Aug 15, 2007
Publication date	Feb 24, 2015
Grant date	Feb 24, 2015

Abstract

Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin have satisfactory properties when administered pulmonary.

First claim

What is claimed is:

1. An acylated human insulin, wherein an acyl moiety is attached to the epsilon amino group of B29K of the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue in the parent insulin, wherein the acyl moiety is a group of formula (I):
Acy-AA1 n -AA2 m -AA3 p -  (I),

wherein
n is an integer in the range 1-3,
m is 0 or an integer in the range 1-6,
p is an integer in the range 2-30

Acy is a fatty acid or a fatty diacid comprising 8 to 24 carbon atoms from which a hydroxy group has been removed from the fatty acid and a hydroxy group has been removed from one of the carboxy groups in the fatty diacid,
AA1 is a neutral cyclic amino acid from which a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group, wherein AA1 is selected from

wherein q is 0, 1, 2, 3 or 4,

AA2 is an acidic amino acid from which a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group,
AA3 is a neutral, alkyleneglycol-containing amino acid from which a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group,
the order in which AA1, AA2 and AA3 appears in the group of formula I can be interchanged independently, and
the connections between Acy, AA1, AA2 and/or AA3 are amide bonds.

2. An acylated insulin, according to claim 1 , wherein AA1 is

from which a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group.

3. An acylated insulin, according to claim 2 , wherein AA2 is Glu (α or γ, L or D), Asp (α or β, L or D),

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

4. An acylated insulin according to claim 1 , which is selected from the group consisting of
B29K(N ε [2-(2-[2-(2-[2-(4-[(octadecandioylamino)methyl]-trans-cyclohexanecarboxyl)amino]-ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl], desB30 human insulin; and
B29K(N ε [2-(2-[2-(2-[2-(4-[(eicosanedioylamino)methyl]-trans-cyclohexanecarboxyl)amino]-ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]), desB30 human insulin.

Assignees

• Madsen Peter
• Kjeldsen Thomas Boerglum
• Kodra Janos Tibor
• Novo Nordisk As

Inventors

• Madsen Peter
• Kjeldsen Thomas Boerglum
• Kodra Janos Tibor

Classifications

• C07K14/62 Primary

  Insulins · CPC title

• A61K38/00

  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 title