EP2006286A2

Isoxazole derivative and isothiazole derivative having inhibitory activity on 11 beta -hydroxysteroid dehydrogenase type i

Abstract

Disclosed is a compound useful as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1. A compound represented by the formula: a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a group of the formula: -C(=O)NR4R5, (wherein R4 and R5 are each independently, hydrogen, optionally substituted alkyl or the like) or a group of the formula: -NR6C(=O)R7, (wherein R6 and R7 are each independently, hydrogen, optionally substituted alkyl or the like), X and Y are each independently -0- or the like, Z is a bond or the like, R2 is optionally substituted alkyl, optionally substituted alkenyl or the like, R3 is optionally substituted alkyl, optionally substituted alkenyl or the like.

EP2006286A2, drawing sheet 1
Sheet 1 of 225

Term

Projected expiry 28 March 2027.

  1. Priority
  2. Filed
  3. Published
  4. Today
  5. Projected expiry

26 claims: 3 independent, 23 dependent

  1. 1
    A compound represented by the formula (I):a pharmaceutically acceptable salt or a solvate thereof, wherein R 1 is a group of the formula: -C(=O)NR 4 R 5 , wherein R 4 and R 5 are each independently, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle;or R 4 and R 5 taken together with the adjacent nitrogen atom to which they are attached may form an optionally substituted ring or a group of the formula: NR 6 C(=O)R 7 , wherein R 6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted aralkyl or a group of the formula:-C(=O)R 8 , R 7 and R 8 are each independently, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle;or R 7 a n d R 8 taken together with the adjacent carbon atom to which they are attached may form an optionally substituted ring, X and Y are each independently, -O- or -S-, Z is a bond , -O- or -S-, R 2 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl or optionally substituted carbamoyl, R 3 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted amino, optionally substituted sulfamoyl or a group of the formula: -R 9 -C(R 10 OR 11 )-R 12 -R 13 , R 9 is -(CH 2 ) m -, wherein m is an integer of 0 to 3, R 10 and R 11 are each independently, hydrogen, optionally substituted alkyl or halogen;or R 10 and R 11 taken together with the adjacent carbon atom to which they are attached may form an optionally substituted ring, R 12 is -(CH 2 ) n -, wherein n is an integer of 0 to 3, R 13 is hydrogen, hydroxy, carboxy, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkoxycarbonyl, optionally substituted aralkylcarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted carbamoyloxy, optionally substituted alkoxy, optionally substituted alkylthio, a group of the formula;-C(=O)-NR 14 R 15 , wherein R 14 and R 15 are each independently, hydrogen, optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl or optionally substituted heterocyclesulfonyl;or R 14 and R 15 taken together with the adjacent nitrogen atom to which they are attached may form an optionally substituted ring or a group of the formula: -NR 16 R 17 , wherein R 16 and R 17 are each independently, hydrogen, carboxy, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted alkyloxycarbonyl or optionally substituted sulfamoyl;or R 16 and R 17 taken together with the adjacent nitrogen atom to which they are attached may form an optionally substituted ring, provided that,when R 2 encompasses a cyclic group and Y is -S-, then the compound is any one of compounds shown as follows.
  2. 8
    The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt or a solvate thereof, wherein R 2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle.
  3. 15
    The compound according to any one of claims 12 to 14, a pharmaceutically acceptable salt or a solvate thereof, wherein R 12 is -(CH 2 )n- wherein n is an integer of 0 to 1.
  4. 16
    The compound according to any one of claims 12 to 15, a pharmaceutically acceptable salt or a solvate thereof, wherein R 13 is carboxy, cyano or heterocycle.
  5. 17
    The compound according to any one of claims 12 to 15, a pharmaceutically acceptable salt or a solvate thereof, wherein R 13 is a group of the formula:-C(=O)-NR 14 R 15 , wherein R 14 and R 15 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted heterocyclesulfonyl or optionally substituted heterocycle;or R 14 and R 15 taken together with the adjacent nitrogen atom to which they are attached may form an optionally substituted ring.
  6. 20
    The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt or a solvate thereof, wherein X and/or Z is(are) -O-.
  7. 21
    The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt or a solvate thereof, wherein Y is -S-.
  8. 22
    A pharmaceutical composition which comprises the compound according to any one of claims 1 to 21, a pharmaceutically acceptable salt or a solvate thereof.
  9. 25
    A method for treating and/or preventing diabetes, comprising administering the compound of any one of claims 1 to 21, a pharmaceutically acceptable salt or a solvate thereof.
  10. 26
    A use of the compound of any one of claims 1 to 21, a pharmaceutically acceptable salt or a solvate thereof for the manufacture of a pharmaceutical composition for treating and/or preventing diabetes.