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