Glucagon analogues

1. A compound having the formula:

R 1 —X—OH

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

and X is a peptide which has the formula:

(SEQ ID NO: 3)

HSQGTFTSDYSKYLDSKAAHDFVEWLLRA

(SEQ ID NO: 13)

H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLSA

(SEQ ID NO: 14)

H-Aib-QGTFTSDYSKYLDEKRAKDFIEWLLSA

or a pharmaceutically acceptable salt thereof.

2. A compound having the formula:

R 1 —X—Z—R 2

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R 2 is OH or NH 2 ;

X is a peptide of SEQ ID NO: 15:

(SEQ ID NO: 15)

H-Aib-QGTFTSDYSKYLDEKAAKDFIEWLESA

or which differs from SEQ ID NO: 15 at up to three of the following positions whereby, if different from SEQ ID NO: 15:

the residue at position 2 is selected from Ser and D-Ser

the residue at position 3 is selected from His and Hse

the residue at position 12 is Arg

the residue at position 15 is Glu

the residue at position 16 is Ser

the residue at position 18 is Arg

the residue at position 20 is selected from His and Glu

the residue at position 21 is Glu

the residue at position 23 is Val

the residue at position 28 is selected from Arg and Glu

the residue at position 29 is absent;

and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 wherein the residue at position 20 is His.

4. A compound according to claim 2 the formula:

R 1 —X—Z—R 2

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R 2 is OH or NH 2 ;

X is a peptide of SEQ ID NO: 15:

(SEQ ID NO: 15)

H-Aib-QGTFTSDYSKYLDEKAAKDFIEWLESA

or which differs from SEQ ID NO: 15 at one or both of the following positions whereby, if different from SEQ ID NO: 15:

the residue at position 21 is Glu

the residue at position 23 is Val

and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn;

or a pharmaceutically acceptable salt thereof.

5. A compound having the formula:

R 1 —X—Z—R 2

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R 2 is OH or NH 2 ;

X is a peptide of SEQ ID NO: 16:

(SEQ ID NO: 16)

H-Aib-QGTFTSDYSKYLDSKAAEDFVEWLESA

or which differs from SEQ ID NO: 16 at up to three of the following positions whereby, if different from SEQ ID NO: 16:

the residue at position 2 is selected from Ser and D-Ser

the residue at position 3 is selected from His and Hse

the residue at position 12 is Arg

the residue at position 15 is Glu

the residue at position 16 is Glu

the residue at position 18 is Arg

the residue at position 20 is selected from Lys and His

the residue at position 21 is Glu

the residue at position 23 is Ile

the residue at position 28 is selected from Arg and Glu

the residue at position 29 is absent

and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 the formula:

R 1 —X—Z—R 2

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R 2 is OH or NH 2 ;

X is a peptide of SEQ ID NO: 16:

(SEQ ID NO: 16)

H-Aib-QGTFTSDYSKYLDSKAAEDFVEWLESA

or which differs from SEQ ID NO: 16 at one or both of the following positions whereby, if different from SEQ ID NO: 16:

the residue at position 21 is Glu

the residue at position 23 is Ile

and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 wherein one or more of the amino acid side chains in the peptide X or Z is conjugated to a lipophilic substituent.

8. A compound according to claim 7 wherein peptide X has the formula:

HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLRA;

H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSA;

or

H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

RAKDFIEWLLSA.

9. A compound according to claim 8 having the formula:

(Compound 3)

H-HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLRA-OH

(Compound 13)

H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLLSA-OH

or

(Compound 14)

H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

RAKDFIEWLLSA-OH

or a pharmaceutically acceptable salt thereof.

10. A compound according claim 2 wherein one or more of the amino acid side chains in the peptide X or Z is conjugated to a lipophilic substituent.

11. A compound according to claim 10 wherein peptide X has the formula:

H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA

H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAEDFVEWLESA

H-Aib-QGTFTSDYSKYLEEK-(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA

H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAEDFIEWLESA

HSQGTFTSDYSKYLEE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA

or

H-DSer-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA.

12. A compound according to claim 11 the formula:

(Compound 15)

H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2

(Compound 16)

H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAEDFVEWLESA-NH 2

(Compound 20)

H-H-Aib-QGTFTSDYSKYLEE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2

(Compound 21)

H-H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAEDFIEWLESA-NH 2

(Compound 22)

H-HSQGTFTSDYSKYLEE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2

(Compound 25)

H-H-DSer-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2

or a pharmaceutically acceptable salt thereof.

13. A compound according claim 5 wherein one or more of the amino acid side chains in the peptide X or Z is conjugated to a lipophilic substituent.

14. A compound according to claim 13 wherein peptide X has the formula:

H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA

H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAEDFVEWLESA

H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAEDFIEWLESA

H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLESA

or

H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAEDFVEWLESA.

15. A compound according to claim 14 having the formula:

(Compound 15)

H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-

AAKDFIEWLESA-NH 2

(Compound 16)

H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-

AAEDFVEWLESA-NH 2

(Compound 21)

H-H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAEDFIEWLESA-NH 2

(Compound 23)

H-H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAHDFVEWLESA-NH 2

(Compound 24)

H-H-Aib-QGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-

AAEDFVEWLESA-NH 2

or a pharmaceutically acceptable salt thereof.