Thiazole derivatives
View Patent ↗A compound of the formula (I): R 1 —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.
1. 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 R 2 is a group of the formula: -A-B-D-E,
wherein
A is a bond, lower alkylene, —NH— or —SO 2 —;
B is a bond, lower alkylene, —CO— or —O—;
D is a bond, lower alkylene, —NH— or —CH 2 NH—; provided that B and D are not both simultaneously bonds, and
E is amino, which may be optionally protected, —N═CH 2 ,
wherein
Q is —S— or —NH—; and
R 3 is hydrogen, lower alkyl, lower alkylthio, or —NH—R 4 , wherein R 4 is hydrogen, —NH 2 or lower alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Z is a group of the formula:
wherein R 2 is a group of the formula:
(wherein G is a bond, —NHCOCH 2 — or lower alkylene and R 4 is hydrogen, —NH 2 or lower alkyl);
—NH 2 ;
—CH 2 NH 2 ;
—CH 2 ONH 2 ;
—CH 2 ON═CH 2 ;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein R 2 is a group of the formula:
(wherein G is a bond, —NHCOCH 2 — or lower alkylene and R 4 is hydrogen or lower alkyl);
—CH 2 NH 2 ;
—CH 2 ONH 2 ;
—CH 2 ON═CH 2 ;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is:
N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,
N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,
N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,
N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide, or
N-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide;
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition, which comprises:
the compound of claim 1 or a pharmaceutically acceptable salt thereof, and
a pharmaceuticaly acceptable carrier or excipient.
6. 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 R 2 is a group of the formula: -A-B-D-E
wherein
A is a bond, lower alkylene, —NH— or —SO 2 —;
B is a bond, lower alkylene, —CO— or —O—;
D is a bond, lower alkylene, —NH— or —CH 2 NH—; provided that B and D are not simultaneously bonds, and
E is amino, which is optionally protected, —N═CH 2 ,
wherein Q is —S— or —NH—; and R 3 is hydrogen, lower alkyl, lower alkylthio or —NH—R 4 , wherein R 4 is hydrogen, —NH 2 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 L 2 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): L 3 -CH 2 -Z, wherein L 3 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): L 4 -NH-Z, wherein L 4 is a hydrogen atom or a protecting group and Z is as defined above; or a salt thereof.
7. A method for treating macular edema comprising:
administering to a subject in need thereof the compound of claim 1 in an amount sufficient to treat said subject for macular edema.
8. The method of claim 7 , wherein the compound is:
N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,
N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,
N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide,
N-{4-[2-(4-{[hydrazino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide, or
N-(4-{2-[4-(2-{[amino(imino)methyl]amino}ethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide,
or a pharmaceutically acceptable salt thereof.
9. The method of claim 7 , wherein said macular edema is diabetic macular edema.
10. The method of claim 7 , wherein said macular edema is non-diabetic macular edema.