Claims
- 1. A compound of the general formula (I):
- 2. A compound A compound according to claim 1, wherein
E is
C1-10-alkyl or C2-10-alkenyl, C3-10-cycloalkyl or C3-10-cycloalkenyl, which may optionally be substituted with one or two substituents selected from halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, —CF3, —OCF3, —SCF3, —OCHF2 and —SCHF2, 524R4 and R5 independently are hydrogen, halogen, C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C16-thioalkyl, —CF3, —OCF3, —SCF3, —OCHF2, —SCHF2, C3-10-cycloalkyl or C3-10-cyclo-alkenyl, or R4 and R5 on adjacent positions may be combined to form a bridge —O—C1-6-alkylene-O—, C1-8-alkylene or C3-8-alkenylene, R6 is C1-6-alkyl or aryl, wherein aryl may optionally be substituted with one or two substituents selected from halogen, C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-thioalkyl, —CF3, —OCF3, —SCF3, —OCHF2 and —SCHF2, n is an integer of from 0 to 6, Z is —O— or —S—, W is —O—, —S—, or —NR7—, R7 is hydrogen or C1-6-alkyl, D is 525R10, R11 and R12 independently are
hydrogen, halogen, —CF3, —OCF3, —SCF3, —CN, —NO2, C1-10-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, amino, C1-6-alkylamino, di-C1-6-alkylamino, —SO2CF3 or -SO2—C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkenyl, aryl or aryl-C1-6-alkoxy, wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, —CF3, —OCF3, —SCF3, —CN, —NO2, C1-10-alkyl, C2-6-alkenyl, C1-6-alkoxy and C1-6-alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH2)m—O—(CH2)p— or —O—(CF2)m—O—(CF2)p—, wherein m is an integer of from 1 to 6, and p is 0 or 1, or two of R10, R11 and R12 on adjacent positions are combined to form a bridge —O—(CH2)m—O—(CH2)p— or —O—(CF2)m—O—(CF2)p—, wherein m is an integer of from 1 to 6, and p is 0 or 1, X″ is —N═ or —CR13=, Y″ is —S—, —O— or —NR14—, R13 and R15 independently are hydrogen, C1-6-alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, —CF3, —OCF3, —SCF3, —OCHF2 and —SCHF2, R14 is hydrogen or C1-6-alkyl, R16, R17 and R18 independently are hydrogen, halogen, —CF3, —OCF3, —SCF3, —CN, —NO2, C1-10-alkyl, C2-6-alkenyl, C1-6-alkoxy and C1-6-alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH2)q—O—(CH2)r— or —O—(CF2)q—O—(CF2)r—, wherein q is an integer of from 1 to 6, and r is 0 or 1, or when B is 526and D is 527R8 and R10 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 —(CH2)2—COOH.
- 4. A compound according to claim 1, wherein X is —CR1R2—, wherein R1 and R2 are as defined in claim 1.
- 5. A compound according to claim 4, wherein X is —CH2—.
- 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
- 9. A compound according to claim 8, wherein B is
- 10. A compound according to claim 9, wherein R8 is hydrogen, C1-6-alkyl or phenyl, wherein phenyl is optionally substituted as defined in claim 1.
- 11. A compound according to claim 10, wherein R8 is hydrogen, C1-6-alkyl or phenyl.
- 12. A compound according to claim 11, wherein R8 is hydrogen.
- 13. A compound according to claim 1, wherein B is
- 14. A compound according to claim 1, wherein E is
C1-10-alkyl, C3-10-cycloalkyl, which may optionally be substituted as defined in claim 1, 531 wherein R4 and R5 are as defined in claim 1.
- 15. A compound according to claim 14, wherein E is
C1-10-alkyl, C3-10-cycloalkyl, 532 wherein R4 and R5 independently are hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, —OCF3, —CF3, —SCF3, C3-10-cycloalkyl or C3-10-cycloalkenyl, or R4 and R5 on adjacent positions may be combined to form a bridge C1-6-alkylene or C2-6-alkenylene.
- 16. A compound according to claim 15, wherein E is
- 17. A compound according to claim 16 wherein E is
- 18. A compound according to claim 17 wherein E is
- 19. A compound according to claim 18 wherein E is
- 20. A compound according to claim 1, wherein E is
- 21. A compound according to claim 18, wherein R4 and R5 independently are hydrogen, halogen, —OCF3, —CF3, C1-6-alkoxy or C2-6-alkenyl, or
R4 and R5 on adjacent atoms together form the bridge —O—CH2—O—.
- 22. A compound according to claim 1, wherein D is
- 23. A compound according to claim 1, wherein D is
- 24. A compound according to claim 22, wherein R10, R11 and R12 independently are hydrogen, halogen, —OCF3, —CF3, —NO2, di-C1-6-alkylamino, C1-10-alkyl, C1-6-alkoxy or —CN,
phenyl or phenyl-C1-6-alkoxy, which may optionally be substituted with one or two substituents as defined in claim 1, or two of R10, R11 and R12 in adjacent positions form a bridge —O—CH2—O—, —O—CH2—CH2—O—, —O—CH2—CH2—CH2—O—, —O—CF2—O—, —O—CF2—O—CF2— or —O—CF2—CF2—O—.
- 25. A compound according to claim 22, wherein R10, R11 and R12 independently are hydrogen, halogen, —OCF3, —CF3, —NO2, di-C1-6-alkylamino, C1-10-alkyl, C1-6-alkoxy or —CN,
phenyl or phenyl-C1-6-alkoxy, or two of R10, R11 and R12 in adjacent positions form a bridge —O—CH2—O—, —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O—.
- 26. A compound according to claim 22, wherein two of R10 and R11 are hydrogen, and and R12 is halogen, —OCF3, —CF3, —NO2, di-C1-6-alkylamino, C1-10-alkyl, C1-6-alkoxy or —CN.
- 27. A compound according to claim 1, wherein B and D together form
- 28. A compound according to claim 27, wherein B and D together form
- 29. A compound of the general formula (I1):
- 30. A compound according to claim 1, which has an IC50 value of no greater than 5 μM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
- 31. A compound according to claim 30, which has an IC50 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) disclosed herein.
- 32. A method for the treatment of an indication selected from the group consisting of hyperglycemia, IGT, type 2 diabetes, type 1 diabetes, dyslipidemia and obesity comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.
- 33. 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.
- 34. A pharmaceutical composition according to claim 33 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.
- 35. A method for the treatment of disorders or diseases, wherein a glucagon antagonistic action is beneficial, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 34.
- 36. The method according to claim 35, wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| PA 2001 01789 |
Dec 2001 |
DK |
|
| PA 2002 01006 |
Jun 2002 |
DK |
|
| PA 2002 01927 |
Dec 2002 |
DK |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119 of Danish application no. PA 2001 01789 filed Dec. 3, 2001, Danish application no. PA 2002 01006 filed on Jun. 27, 2002 and Danish application no. PA 2002 01927 filed on Dec. 17, 2002 and U.S. application No. 60/394,145 filed on Jul. 3, 2002 and U.S. provisional application No. 60/434,255 filed on Dec. 18, 2002, the contents of which are fully incorporated herein by reference.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60394145 |
Jul 2002 |
US |
|
60434255 |
Dec 2002 |
US |
Patent Application
20040014789
