Cyclohexapeptides as selective somatostatin SST5 receptor agonists

1. A compound of the formula (1):

or a salt thereof, wherein;

W is CH or N;

X and Y are CH 2 or O, wherein one of X and Y is CH 2 and the other of X and Y is O;

Z is CHR 7 , NR 8 or O;

m is 1 or 2;

n is 0 to 3;

each R 1 is independently selected from halo, C 1 -C 3 alkyl and C 1 -C 3 alkoxy, wherein the C 1 -C 3 alkyl and alkoxy groups are optionally substituted with up to 6 fluorine atoms;

q is 0 to 2;

R 2 is selected from H and C 1 -C 3 alkyl optionally substituted with up to 6 fluorine atoms;

R 3 is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

R 4 is H or optionally substituted C 1 -C 3 alkyl, where the C 1 -C 3 alkyl group is optionally joined to R 5 to form a ring;

R 5 is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted aryl and optionally substituted heteroaryl, where R 5 is optionally joined to R 4 to form a ring;

R 6 is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted O-aryl or optionally substituted O-heteroaryl;

R 7 is selected from H, optionally substituted C 1 -C 6 alkyl, CONR 10 R 11 , OCONR 10 R 11 , OCOR 10 , OCOOR 10 , COOR 10 or OR 12 ;

R 8 is selected from H, CONR 10 R 11 or COOR 10 ;

R 10 and R 11 are independently selected from H, optionally substituted C 1 -C 6 alkyl and optionally substituted C 2 -C 6 alkyl where any one atom in the C 2 -C 6 alkyl group is replaced by a heteroatom selected from N, O and S, or wherein R 10 and R 11 are optionally joined to form a ring; and

R 12 is optionally substituted aryl or optionally substituted heteroaryl.

2. The compound according to claim 1 which is a compound of formula (1a):

or a salt thereof.

3. The compound according to claim 1 which is a compound of formula (1b):

or a salt thereof.

4. The compound according to claim 1 , wherein X is O and Y is CH 2 .

5. The compound according to claim 1 , wherein Z is CHR 7 .

6. The compound according to claim 1 , wherein R 1 is OMe or Me.

7. The compound according to claim 1 , wherein R 2 is H.

8. The compound according to claim 1 , wherein R 3 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclopentyl or optionally substituted cyclobutyl, wherein the optional substituents are selected from chloro, bromo and fluoro.

9. The compound according to claim 1 , wherein R 4 is H.

10. The compound according to claim 1 , wherein R 5 is optionally substituted phenyl or optionally substituted pyridyl, wherein the optional substituents are selected from chloro, bromo, fluoro and OMe.

11. The compound according to claim 1 , wherein R 4 and R 5 are joined together to form a ring; and wherein the ring moiety formed by R 4 and R 5 is selected from the group consisting of:

wherein said ring moieties are optionally substituted with a group or groups selected from halo, C 1 -C 3 alkyl and C 1 -C 3 alkoxy, wherein the C 1 -C 3 alkyl and alkoxy groups are themselves optionally substituted with up to 6 fluorine atoms.

12. The compound according to claim 1 , wherein R 7 is OCONR 10 R 11 , COOR 10 or OR 12 ; wherein R 10 and R 11 are C 2 -C 6 alkyl where any one atom in the C 2 -C 6 alkyl group is replaced by a heteroatom selected from N, O and S, where R 10 and R 11 are optionally joined via CH 2 to form a ring; and R 12 is pyridyl.

13. The compound according to claim 1 , wherein the moiety formed by Z and m is selected from:

14. The compound according to claim 1 wherein R 6 is phenyl.

15. The compound according to claim 1 which is selected from the group consisting of:

16. The compound according to claim 1 which is selected from the group consisting of:

17. The compound according to claim 1 to having SST 5 receptor agonist activity.

18. The compound according to claim 2 which exhibits selectivity towards the SST 5 receptor compared to the SST 2 receptor.

19. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.

20. A method of treating Cushing's Disease, Cushing's Syndrome, Acromegaly, Neuroendocrine tumours, Thyrotropinomas, Prolactinomas, Non-functioning pituitary adenomas, Nelson's syndrome, Congenital hyperinsulinism, Post-gastric bypass hypoglycaemia, Dumping syndrome, Hyperinsulinemic obesity, Insulinoma, Polycystic kidney disease, Polycystic liver disease, Portal hypertension, Ascites, Pancreatic cancer, Pancreatic fistula, Acute or chronic pancreatitis, Hepatocellular carcinoma, Irritable bowel syndrome/disease or Headache disorders, comprising administering the compound according to claim 1 to a subject in need thereof.

21. A method of treating Carcinoid tumours, migraine, cluster headache, or tension-type headache, comprising administering the compound according to claim 1 to a subject in need thereof.