Carboxylic acid derivative and salt thereof
Carboxylic acid compound or salt or hydrate thereof useful as insulin sensitizer, represented by the formula wherein R 1 represents hydrogen, hydroxyl, halogen, carboxyl, or C 1-6 alkyl, L represents single bond or C 1-6 -alkylene, C 2-6 -alkenylene, or C 2-6 -alkynylene, M represents single bond or C 1-6 -alkylene, C 2-6 -alkenylene, or C 2-6 -alkynylene, T represents single bond, or C 1-3 -alkylene, C 2-3 -alkenylene, or C 2-3 -alkynylene, W represents carboxyl, represents single bond, X represents single bond, oxygen, —NR X1 CQ 1 O—, —OCQ 1 NR X1 —, —CQ 1 NR X1 O—, ONR X1 CQ 1 —, —Q 2 SO 2 —, or —SO 2 Q 2 —, Y represents 5- to 14-membered aromatic group, and ring Z represents 5- to 14-membered aromatic group.
1. A carboxylic acid compound represented by the following formula (I), a salt thereof, or an ester thereof
wherein
R 1 represents a C 1-6 alkoxy group;
L represents a single bond or a C 1-6 alkylene group which may have one or more substituents selected from C 1-6 alkyl groups;
M represents a C 1-6 alkylene group:
T represents a single bond, a C 1-3 alkylene group, or a C 2-3 alkynylene group;
W represents a carboxyl group;
represents a single bond or a double bond;
X is a group represented by the formula:
wherein n represents 1 to 5; R X2 and R X3 are the same as or different from each other and each represents a hydrogen atom, a hydroxy group, a halogen atom, a C 1-6 alkoxy group, or a C 1-6 hydroxyalkyl group, provided that at least one of R x2 and R x3 in the compound is a group other than a hydrogen atom; and Q 3 and Q 4 are the same as or different from each other and each represents an oxygen atom or (O)S(O);
Y is a phenyl group or a C 3-7 alicyclic hydrocarbon group, each of which may have one to 4 substituents selected from the group consisting of halogen atoms, cyano groups, C 1-6 alkyl groups, C 1-4 alkoxy groups, C 1-6 haloalkyl groups, and C 1-6 hydroxyalkyl groups; and
the ring Z is a phenyl group.
2. The carboxylic acid compound according to claim 1 , a salt thereof, or an ester thereof, wherein in the formula (I), Y is a phenyl group which may have one to 4 substituents selected from the group consisting of a halogen atom, a cyano group, a C 1-4 alkyl group, and a C 1-4 alkoxy group.
3. The carboxylic acid compound according to claim 1 , a salt thereof, or an ester thereof, wherein in the formula (I), X is a group represented by the formula:
wherein Q 3 and Q 4 represent an oxygen atom; and n, R X2 and R X3 are as defined above.
4. The carboxylic acid according to claim 3 , a salt thereof, or an ester thereof, wherein in the formula (I), X is a group represented by the formula:
wherein Q 3 and Q 4 represent an oxygen atom; n represents 2 to 5; and R X2 and R X3 are as defined above; L is a single bond or a C 1-3 alkylene group; and T is a single bond or a C 1-3 alkylene group.
5. The carboxylic acid compound according to claim 4 , a salt thereof, or an ester thereof, wherein in the formula (I), wherein M is a C 1-6 alkylene group; and R 1 is a C 1-6 alkoxy group.
6. The carboxylic acid compound according to claim 5 , a salt thereof, or an ester thereof, wherein in the formula (I), the ring Z is a 1,3-phenylene group.
7. The carboxylic acid compound according to claim 4 or 6 , a salt thereof, or an ester thereof, wherein in the formula (I), X is a group represented by the formula:
wherein Q 3 and Q 4 represent an oxygen atom; n represents 3 to 5; and R X2 and R X3 represent a hydrogen atom, hydroxyl group or fluorine atom.
8. The carboxylic acid compound according to claim 7 , a salt thereof, or an ester thereof, wherein in the formula (I), X is represented by the formula:
9. The carboxylic acid compound according to claim 7 , a salt thereof, or an ester thereof, wherein in the formula (I), X is represented by the formula:
10. The carboxylic acid compound according to claim 7 , a salt thereof or an ester thereof, wherein in the formula (I), M is a methylene group; and R 1 is a C 1-6 alkoxy group.
11. The carboxylic acid compound according to claim 4 , a salt thereof, or an ester thereof, wherein in the formula (I), Y is a phenyl group.
12. The carboxylic acid compound according to claim 1 , a salt thereof, or an ester thereof, wherein in the formula (I), a group represented by the formula:
wherein each symbol represents a group as defined above and a group represented by the formula:
wherein each symbol represents a group as defined above are in a meta-position or a para-position on the ring Z.
13. The carboxylic acid compound according to claim 1 , a salt thereof, or an ester thereof, wherein the compound represented by the formula (I) is one selected from:
3-{3-[3-(4-chloro-2-cyanophenoxy)-2-hydroxypropoxy]phenyl}-2-isopropoxypropanoic acid;
3-{3-[3-(2,4-dichlorophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(4-chloro-2-cyanophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-(3-{2(S)-hydroxy-3-[3-(1-hydroxy-1-methylethyl)phenoxy]propoxy-}-phenyl)-2(S)-isopropoxypropanoic acid;
3-(3-{2(R)-hydroxy-3-[4-chlorophenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
3-(3-{2(S)-hydroxy-3-[2,4-dimethylphenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
3-(3-{2(S)-hydroxy-3-[4-chloro-2-fluorophenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
3-{3-[3-(2,4-dichlorophenoxy)-2 (R)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(4-chloro-2-cyanophenoxy)-2 (R)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-(3-{2(R)-hydroxy-3-[2,4-dimethylphenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
3-{3-[3-(2,4-dichlorophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(4-chlorophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(4-chloro-2-cyanophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(2,4-dichlorophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(4-chlorophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(4-chloro-2-cyanophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
3-{3-[3-(2,4-dimethylphenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid; and
3-{4-[3-(4-chloro-2-cyanophenoxy)-2-hydroxypropoxy]phenyl}-2-isopropoxypropanoic acid.
14. A pharmaceutical composition comprising a carboxylic acid compound represented by the formula (I) as it is defined in claim 1 , a salt thereof, or an ester thereof and a pharmaceutically acceptable carrier.
15. A carboxylic acid compound represented by the following formula, a salt thereof or an ester thereof
wherein
R 1 represents a C 1-3 alkoxy group;
L represents a single bond;
M represents a C 1-3 alkylene group;
T represents a single bond;
W represents a carboxyl group;
represents a single bond;
X is represented by the formula:
Y represents a phenyl group or a C 3-7 alicyclic hydrocarbon group, each of which may have 1 to 4 substituents selected from the group consisting of halogen atoms, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, C 1-6 haloalkyl groups, and C 1-6 hydroxyalkyl groups; and
the ring Z represents a phenyl group.
16. A compound selected from the group consisting of the compounds listed below, a salt thereof, or an ester thereof:
(1) 3-{3-[3-(4-chloro-2-cyanophenoxy)-2-hydroxypropoxy]phenyl}-2-isopropoxypropanoic acid;
(2) 3-{3-[3-(2,4-dichlorophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(3) 3-{3-[3-(4-chloro-2-cyanophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(4) 3-(3-{2(S)-hydroxy-3-[3-(1-hydroxy-1-methylethyl)phenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
(5) 3-(3-{2(R)-hydroxy-3-[4-chlorophenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
(6) 3-(3-{2(S)-hydroxy-3-[2,4-dimethylphenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
(7) 3-(3-{2(S)-hydroxy-3-[4-chloro-2-fluorophenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
(8) 3-{3-[3-(2,4-dichlorophenoxy)-2 (R)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(9) 3-{3-[3-(4-chloro-2-cyanophenoxy)-2 (R)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(10) 3-(3-{2(R)-hydroxy-3-[2,4-dimethylphenoxy]propoxy}phenyl)-2(S)-isopropoxypropanoic acid;
(11)-{3-[3-(2,4-dichlorophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(12) 3-{3-[3-(4-chlorophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(13) 3-{3-[3-(4-chloro-2-cyanophenoxy)-2(R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(14) 3-{3-[3-(2,4-dichlorophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(15) 3-{3-[3-(4-chlorophenoxy)-2(R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(16) 3-{3-[3-(4-chloro-2-cyanophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid;
(17) 3-{3-[3-(2,4-dimethylphenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid; and
(18) 3-{4-[3-(4-chloro-2-cyanophenoxy)-2-hydroxypropoxy]phenyl}-2-isopropoxypropanoic acid.
17. A pharmaceutical composition comprising the carboxylic acid compound according to claim 15 , a salt thereof, or an ester thereof and a pharmaceutically acceptable carrier.
18. The compound 3-{3-[3-(4-chloro-2-cyanophenoxy)-2(S)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid, represented by the following formula, a salt thereof or an ester thereof
19. A pharmaceutical composition comprising the compound according to claim 18 , a salt thereof, or an ester thereof and a pharmaceutically acceptable carrier.