Insulin derivative

1. An insulin derivative having a formula

wherein Ins is a parent insulin moiety and Q 1 -Q 2 -[CH 2 ] n —X 1 —[CH 2 ] n -Q 3 -[CH 2 ] n —X 2 —[CH 2 ] n -Q 4 -[CH 2 ] n —X 3 —[CH 2 ] n -Q 5 -[CH 2 ] n —Z is a substituent and where the Ins is attached to the substituent via an amide bond between the α-amino group of the N-terminal amino acid residue of the B chain of Ins or an ε-amino group of a Lys residue present in the A or B chain of Ins and a CO group in Q 1 or Q 2 of the substituent;

Q 1 is selected from the group consisting of:

an amino acid residue, which residue forms, with its carboxylic acid group, an amide group together with the α-amino group of the N-terminal amino acid residue of the B chain of Ins or together with the ε-amino group of a Lys residue present in the A or B chain of Ins,

a chain composed of two, three or four α-amino acid residues as specified above linked together via amide bonds, which chain is linked via an amide bond to the α-amino group of the N-terminal amino acid residue of the B chain of Ins or to the ε-amino group of a Lys residue present in the A or B chain of Ins, and

a bond

Q 2 is selected from the group consisting of:

—CO—(CH 2 ) 2 —NH—(CH 2 ) 2 —,

—CO—CH 2 —NH—CH 2 —,

—CO—(CH 2 ) p —NR 1 —(CH 2 ) p′ —, and

 where n′=1-6, where R 1 and R 2 , independently of each other can be H, —CH 3 or —(CH 2 ) 1-6 —CH 3 , and where p and p′ independently of each other can be 1-6;

Q 3 is —(CH 2 ) m — where m is an integer in the range of 6 to 32;

X 1 is selected from the group consisting of:

O,

—C═O, and

NCOR 1 , where R 1 can be H, —CH 3 or —(CH 2 ) 1-6 —CH 3 , and

 where R is hydrogen, C 1-3 -alkyl, C 2-3 -alkenyl or C 2-3 -alkynyl;

Q 4 , Q 5 , X 2 and X 3 are bonds and all n are zero;

and

Z is —COOH and any Zn 2+ complex thereof.

2. The insulin derivative according to claim 1 , wherein Q 1 is a bond.

3. The insulin derivative according to claim 1 , wherein X 1 is

where R is hydrogen.

4. The insulin derivative according to claim 1 , wherein Q 3 is —(CH 2 ) m — where m is 12, 13, 14, 15 or 16.

5. The insulin derivative according to claim 1 , wherein the substituent is attached to the ε-amino group of a Lys residue present in the A or B chain of the parent insulin.

6. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, comprising a therapeutically effective amount of the insulin derivative of claim 1 .

7. The pharmaceutical composition according to claim 6 , wherein the composition comprises pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 6 , wherein the composition comprises an insulin analogue which has a rapid onset of action.

9. A method of treating diabetes in a patient in need of such a treatment by the use of a therapeutically effective amount of an insulin derivative having a formula

wherein Ins is a parent insulin moiety and Q 1 -Q 2 -[CH 2 ] n —X 1 —[CH 2 ] n -Q 3 -[CH 2 ] n —X 2 —[CH 2 ] n -Q 4 -[CH 2 ] n —X 3 —[CH 2 ] n -Q 5 -[CH 2 ] n —Z is a substituent and where the Ins is attached to the substituent via an amide bond between the α-amino group of the N-terminal amino acid residue of the B chain of Ins or an ε-amino group of a Lys residue present in the A or B chain of Ins and a CO group in Q 1 or Q 2 of the substituent;

Q 1 is selected from the group consisting of:

an amino acid residue, which residue forms, with its carboxylic acid group, an amide group together with the α-amino group of the N-terminal amino acid residue of the B chain of Ins or together with the ε-amino group of a Lys residue present in the A or B chain of Ins,

a chain composed of two, three or four α-amino acid residues as specified above linked together via amide bonds, which chain is linked via an amide bond to the α-amino group of the N-terminal amino acid residue of the B chain of Ins or to the ε-amino group of a Lys residue present in the A or B chain of Ins, and

a bond

Q 2 is selected from the group consisting of:

—CO—(CH 2 ) 2 —NH—(CH 2 ) 2 —,

—CO—CH 2 —NH—CH 2 —,

—CO—(CH 2 ) p —NR 1 —(CH 2 ) p′ —, and

 where n′=1-6, where R 1 and R 2 , independently of each other can be H, —CH 3 or —(CH 2 ) 1-6 —CH 3 , and where p and p′ independently of each other can be 1-6;

Q 3 is —(CH 2 ) m — where m is an integer in the range of 6 to 32;

X 1 is selected from the group consisting of:

O,

—C═O, and

NCOR 1 , where R 1 can be H, —CH 3 or —(CH 2 ) 1-6 —CH 3 , and

 where R is hydrogen, C 1-3 -alkyl, C 2-3 -alkenyl or C 2-3 -alkynyl;

Q 4 , Q 5 , X 2 and X 3 are bonds and all n are zero;

and

Z is —COOH and any Zn 2+ complex thereof.

10. The method according to claim 9 for pulmonary treatment of diabetes.

11. The insulin derivative of claim 1 , wherein the substituent is attached to the ε-amino group of the Lys residue in position B29 present in the B chain of the parent insulin.

12. The insulin derivative of claim 1 , wherein the parent insulin is an insulin analogue.

13. The insulin derivative of claim 1 , wherein the amino acid residue at position B30 of the parent insulin is Lys or has been deleted.

14. The insulin derivative of claim 1 , wherein the substituent is attached to the ε-amino group of the Lys residue in position B29 in desB30 human insulin.

15. The insulin derivative of claim 1 , wherein the parent insulin is selected from the group consisting of AspB28 human insulin, GlyA21 human insulin, GlyA21desB30 human insulin, GlyA21ArgB31ArgB32 human insulin, LysB28ProB29 human insulin, ThrB29LysB30 human insulin, and LysB3GluB29 human insulin.

16. The insulin derivative of claim 1 , further comprising 2-10 zinc ions per six molecules of insulin derivative bound to form a zinc complex with the insulin derivative.

17. The pharmaceutical composition of claim 8 , wherein the rapid acting insulin analogue is selected from the group consisting of AspB28 human insulin; LysB28ProB29 human insulin and LysB3GluB29 human insulin.