Glucagon antagonists/inverse agonists

1. A compound of the general formula (I):

wherein

A is

X is a valence bond, —CR 1 R 2 —or —NR 1 —,

Y is >CR 3 — or >N—,

R 1 , R 2 and R 3 independently are hydrogen or C 1-6 -alkyl, or R 1 and R 3 on adjacent atoms may be combined to form a double bond,

E is

C 1-10 -alkyl or C 2-10 -alkenyl,

C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, C 7-10 -bicycloalkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl or C 7-10 -bicycloalkyl-C 1-6 -alkyl,

 wherein the rings may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 and —SCHF 2 ,

aryl, aryloxy, arylthio, aryl-C 1-6 -alkyl, aryloxy-C 1-6 -alkyl, arylthio-C 1-6 -alkyl, diaryl-C 1-6 -alkyl or (C 1-6 -alkyl)(aryl)-C 1-7 -alkyl,

 wherein the non-aromatic and aromatic rings may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 , —SCHF 2 , C 3-10 -cycloalkyl and C 3-10 -cycloalkenyl, or with two substituents on adjacent positions which are combined to form a bridge C 1-6 -alkylene, C 2-6 -alkenylene or —O—C 1-6 -alkylene-O—,

B is

X′ is —CR 8 ═,

Y′ is —S—,

R 8 is hydrogen, C 1-6 -alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 , —SCHF 2 , —SO 2 CF 3 and —SO 2 —C 1-6 -alkyl;

R 9 is hydrogen or C 1-6 -alkyl,

D is aryl,

which may optionally be substituted with one or more substituents selected from

halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, —SO 2 CF 3 and —SO 2 —C 1-6 -alkyl,

C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, aryl and aryl-C 1-6 -alkoxy,

 wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy and C 1-6 -alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,

or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) n —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,

or a substituent on B may be combined with a substituent on D to form a —C(═O)— bridge,

as well as any diastereomer or enantiomer or tautomeric form or mixtures thereof of these or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein

E is

C 1-10 -alkyl or C 2-10 -alkenyl,

C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, which may optionally be substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 and —SCHF 2 ,

 R 4 and R 5 independently are hydrogen, halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 16 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 , —SCHF 2 , C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, or R 4 and R 5 on adjacent positions may be combined to form a bridge —O—C 1-6 -alkylene-O—, C 1-8 -alkylene or C 3-8 -alkenylene,

 R 6 is C 1-6 -alkyl or aryl, wherein aryl may optionally be substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 and —SCHF 2 ,

 n is an integer of from 0 to 6,

 Z is —O— or —S—,

 R 7 is hydrogen or C 1-6 -alkyl,

D is

R 10 , R 11 and R 12 independently are

hydrogen, halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, —SO 2 CF 3 or —SO 2 —C 1-6 -alkyl,

C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, aryl or aryl-C 1-6 -alkoxy,

 wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy and C 1-6 -alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,

or two of R 10 , R 11 and R 12 on adjacent positions are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,

R 13 and R 15 independently are hydrogen, C 1-6 -alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 and —SCHF 2 ,

R 14 is hydrogen or C 1-6 -alkyl,

R 16 , R 17 and R 18 independently are hydrogen, halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy and C 1-6 -alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) q —O—(CH 2 ) r — or —O—(CF 2 ) q —O—(CF 2 ) r —, wherein q is an integer of from 1 to 6, and r is 0 or 1,

or when B is

and D is

R 8 and R 10 may be combined to form a bridge —C(═O)—,

as well as any diastereomer or enantiomer or tautomeric form thereof or mixtures thereof of these or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein A is

4. A compound according to claim 1 , wherein X is —CR 1 R 2 —, wherein R 1 and R 2 are as defined in claim 1 .

5. A compound according to claim 4 , wherein X is —CH 2 —.

6. A compound according to claim 1 , wherein Y is >N—.

7. A compound according to claim 1 , wherein Y is >CH—.

8. A compound according to claim 1 , wherein B is

wherein X′ and Y′ are as defined in claim 1 .

9. A compound according to claim 8 , wherein B is

wherein R 8 is as defined in claim 1 .

10. A compound according to claim 9 , wherein R 8 is hydrogen, C 1-6 -alkyl or phenyl, wherein phenyl is optionally substituted as defined in claim 1 .

11. A compound according to claim 10 , wherein R 8 is hydrogen, C 1-6 -alkyl or phenyl.

12. A compound according to claim 11 , wherein R 8 is hydrogen.

13. A compound according to claim 1 , wherein E is

C 1-10 -alkyl,

C 3-10 -cycloalkyl, which may optionally be substituted as defined in claim 1 ,

wherein R 4 and R 5 are as defined in claim 1 .

14. A compound according to claim 13 , wherein E is

C 1-10 -alkyl,

C 3-10 -cycloalkyl,

wherein R 4 and R 5 independently are hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —OCF 3 , —CF 3 , —SCF 3 , C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, or R 4 and R 5 on adjacent positions may be combined to form a bridge C 1-6 -alkylene or C 2-6 -alkenylene.

15. A compound according to claim 14 , wherein E is

wherein R 4 and R 5 independently are hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —OCF 3 , —CF 3 , —SCF 3 , C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, or R 4 and R 5 on adjacent positions may be combined to form a bridge C 1-6 -alkylene or C 2-6 -alkenylene.

16. A compound according to claim 15 wherein E is

wherein R 4 and R 5 independently are hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —QCF 3 , —CF 3 , —SCF 3 , cyclohexyl or cyclohex-1-enyl, or R 4 and R 5 on adjacent positions may be combined to form a bridge C 1-6 -alkylene.

17. A compound according to claim 16 wherein E is

wherein R 4 is hydrogen and R 5 is C 1-6 -alkyl, cyclohexyl, halogen, —CF 3 or cyclohex-1-enyl, or R 4 and R 5 on adjacent positions may be combined to form a bridge C 1-6 -alkylene.

18. A compound according to claim 17 wherein E is

19. A compound according to claim 1 , wherein E is

wherein n is 1, 2 or 3, and R 4 , R 5 and R 6 are as defined in claim 1 .

20. A compound according to claim 17 , wherein R 4 and R 5 independently are hydrogen, halogen, —OCF 3 , —CF 3 , C 1-6 -alkoxy or C 2-6 -alkenyl, or

R 4 and R 5 on adjacent atoms together form the bridge —O—CH 2 —O—.

21. A compound according to claim 1 , wherein D is

wherein R 10 , R 11 , R 12 , R 15 , R 16 , R 17 and R 18 are as defined in claim 2 .

22. A compound according to claim 1 , wherein D is

wherein R 10 , R 11 and R 12 are as defined in claim 1 .

23. A compound according to claim 21 , wherein R 10 , R 11 and R 12 independently are hydrogen, halogen, —OCF 3 , —CF 3 , —NO 2 , di-C 1-6 -alkylamino, C 1-10 -alkyl, C 1-6 -alkoxy or —CN,

phenyl or phenyl-C 1-6 -alkoxy, which may optionally be substituted with one or two substituents as defined in claim 1 ,

or two of R 10 , R 11 and R 12 in adjacent positions form a bridge —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —O—, —O—CF 2 —O—, —O—CF 2 —O—CF 2 — or —O—CF 2 —CF 2 —O—.

24. A compound according to claim 21 , wherein R 10 , R 11 and R 12 independently are hydrogen, halogen, —OCF 3 , —CF 3 , —NO 2 , di-C 1-6 -alkylamino, C 1-10 -alkyl, C 1-6 -alkoxy or —CN,

phenyl or phenyl-C 1-6 -alkoxy,

or two of R 10 , R 11 and R 12 in adjacent positions form a bridge —O—CH 2 —O—, —O—CH 2 —CH 2 —O— or —O—CH 2 —CH 2 —CH 2 —O—.

25. A compound according to claim 21 , wherein two of R 10 and R 11 are hydrogen, and R 12 is halogen, —OCF 3 , —CF 3 , —NO 2 , di-C 1-6 -alkylamino, C 1-10 -alkyl, C 1-6 -alkoxy or —CN.

26. A compound according to claim 1 , wherein B and D together form

wherein Y′, is as defined in claim 1 , and R 11 and R 12 are as defined in claim 2 .

27. A compound according to claim 26 , wherein B and D together form

28. A compound of the general formula (I 1 ):

wherein R 1 , R 2 , R 8 , E and D are as defined in claim 1 ,

as well as any diastereomer or enantiomer or tautomeric form thereof or mixtures thereof of these or a pharmaceutically acceptable salt thereof.

29. A compound according to claim 1 , which has an IC 50 value of no greater than 5 μM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II).

30. A compound according to claim 29 , which has an IC 50 value of less than 1 μM, preferably of less than 500 nM and even more preferred of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II).

31. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to claim 1 together with one or more pharmaceutically acceptable carriers or excipients.

32. A pharmaceutical composition according to claim 31 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound.