Thiazole derivatives
AssigneeAstellas Pharma Inc.
InventorsTakayuki Inoue, Takashi Tojo, Masataka Morita, Mitsuru Ohkubo, Kousei Yoshihara, Akira Nagashima
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Abstract
A compound of the formula (I): R1—NH—X—Y-Z (I) wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 (VAP-1) inhibitor, a pharmaceutical composition, a method for preventing or treating a VAP-1 associated disease, especially macular edema, which method includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a mammal, and the like.
Claims10
A compound of the formula (I):
- wherein the 1,3-thiazole ring is optionally substituted at the 5-position;
- Y is lower alkylene, lower alkenylene or —CONH—;
- and
- Z is a group of the formula:
- wherein R2 is a group of the formula:
- -A-B-D-E,
- wherein
- A is a bond, lower alkylene, —NH— or —SO2—;
- B is a bond, lower alkylene, —CO— or —O—;
- D is a bond, lower alkylene, —NH— or —CH2NH—;
- provided that B and D are not both simultaneously bonds, and
- E is amino, which may be optionally protected, —N═CH2,
- wherein
- Q is —S— or —NH—;
- and
- R3 is hydrogen, lower alkyl, lower alkylthio, or —NH—R4, wherein R4 is hydrogen, —NH2 or lower alkyl;
- or a pharmaceutically acceptable salt thereof.
A method for producing a compound of formula (I):
- wherein the 1,3-thiazole ring is optionally substituted at the 5-position;
- Y is lower alkylene, lower alkenylene or —CONH—;
- and
- Z is a group of the formula:
- wherein R2 is a group of the formula:
- -A-B-D-E
- wherein
- A is a bond, lower alkylene, —NH— or —SO2—;
- B is a bond, lower alkylene, —CO— or —O—;
- D is a bond, lower alkylene, —NH— or —CH2NH—;
- provided that B and D are not simultaneously bonds, and
- E is amino, which is optionally protected, —N═CH2,
- wherein Q is —S— or —NH—;
- and R3 is hydrogen, lower alkyl, lower alkylthio or —NH—R4, wherein R4 is hydrogen, —NH2 or lower alkyl;
- or a pharmaceutically acceptable salt thereof;
- which method comprises at least one step selected from the group consisting of (ii), (iii), (iv) and (v):
- (ii) reacting Compound (3):
- wherein Z is as defined above and the 1,3-thiazole ring is optionally substituted at the 5-position, or a salt thereof with Compound (4):
- wherein L2 is a leaving group;
- (iii) reacting Compound (6):
- wherein the 1,3-thiazole ring is optionally substituted at the 5-position or a salt thereof with Compound (7):
- L3-CH2-Z, wherein L3 is a leaving group and Z is as defined above, or a salt thereof;
- (iv) reduction of Compound (10):
- wherein Z is as defined above and the 1,3-thiazole ring is optionally substituted at the 5-position, or a salt thereof;
- to Compound (11):
- wherein Z is as defined above and the 1,3-thiazole ring is optionally substituted at the 5-position;
- or a salt thereof;
- and
- (v) reacting Compound (12):
- wherein the 1,3-thiazole ring is optionally substituted at the 5-position or a reactive derivative thereof, or a salt thereof with Compound (13):
- L4-NH-Z, wherein L4 is a hydrogen atom or a protecting group and Z is as defined above;
- or a salt thereof.
Dependencies are inferred from the claim text.