CaSR agonists
By searching various kinds of compounds having CaSR agonistic activity, the present invention provides CaSR agonistic agents, pharmaceutical compositions, preventive or therapeutic agents for diarrhea and kokumi-imparting agents each of which comprise the compound. More specifically, the present invention provides CaSR agonistic agents, pharmaceutical compositions, preventive or therapeutic agents for diarrhea and kokumi-imparting agents each of which comprise a glutamic acid derivative having CaSR agonistic activity or pharmaceutically acceptable salts thereof.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R1, R3, and R5 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, —NH 2 , an optionally substituted alkyl group having 1 to 6 carbon atoms, and an optionally substituted alkoxy group having 1 to 6 carbon atoms;
R4 is selected from the group consisting of a halogen atom, a hydroxyl group, —NH 2 , and an optionally substituted alkoxy group having 1 to 6 carbon atoms;
R2 is selected from the group consisting of a sulfonic acid group,
R6 and R 7 are each independently a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms; and
X is a methylene group or an oxygen atom;
and excluding
a compound wherein X is a methylene group, and R2 is
2. The compound or pharmaceutically acceptable salt thereof according to claim 1 ,
wherein R1, R3, and R5 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, —NH 2 , an optionally substituted alkyl group having 1 to 3 carbon atoms, and an optionally substituted alkoxy group having 1 to 3 carbon atoms;
R2 is selected from the group consisting of a sulfonic acid group,
and
R6 and R 7 are each independently a hydrogen atom or a methyl group.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1 ,
wherein R1, R3, and R5 are each independently selected from the group consisting of a hydrogen atom, a a chlorine atom, a bromine atom, a hydroxyl group, —NH 2 , a methyl group, and a methoxy group;
R2 is selected from the group consisting of a sulfonic acid group,
R6 is a hydrogen atom or a methyl group;
R 7 is a hydrogen atom; and
X is a methylene group.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1 ,
wherein R2 is a sulfonic acid group, a carboxylic acid group, or a phosphonic acid group.
5. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R2 and R5 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, —NH 2 , an optionally substituted alkyl group having 1 to 6 carbon atoms, and an optionally substituted alkoxy group having 1 to 6 carbon atoms;
R4 is selected from the group consisting of a halogen atom, a hydroxyl group, —NH 2 , and an optionally substituted alkoxy group having 1 to 6 carbon atoms;
either of R1 or R3 is a sulfonic acid group and the other is selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted amino group, an optionally substituted alkyl group having 1 to 6 carbon atoms, and an optionally substituted alkoxy group having 1 to 6 carbon atoms;
R6 is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms; and
X is a methylene group or an oxygen atom.
6. The compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein R4 is a halogen atom.
7. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 .
8. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 5 .
9. The compound or pharmaceutically acceptable salt thereof of claim 1 , which is N 5 -(5-chloro-2-hydroxy-3-sulfophenyl)-L-glutamine.
10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein X is methylene.
11. A compound or pharmaceutically acceptable salt thereof, which is
N 5 -(5-chloro-2-hydroxy-3-sulfophenyl)-L-glutamine,
N 5 -(2-hydroxy-3-sulfophenyl)-L-glutamine,
3-(L-(-glutamylamino)-2-hydroxybenzoic acid,
3-bromo-5-(L-(-glutamylamino)benzoic acid,
N 5 -(3-phosphonophenyl)-L-glutamine,
N 5 -(3-chloro-4-methyl-5-sulfophenyl)-L-glutamine,
5-chloro-3-(L-(-glutamylamino)benzoic acid,
O-{[(3-chloro-4-methyl-5-sulfophenyl)amino]carbonyl}-L-serine,
3-{[(2S)-2-amino-2-carboxyethoxycarbonyl]amino}-5-chloro-2-hydroxybenzensulfonic acid, or
O-{[(3-chloro-2-methyl-5-sulfophenyl)amino]carbonyl}-L-serine.
12. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein X is an oxygen atom.
13. The compound or pharmaceutically acceptable salt thereof of claim 1 , which is
O-{[(3-chloro-4-methyl-5-sulfophenyl)amino]carbonyl}-L-serine,
3-{[(2S)-2-amino-2-carboxyethoxycarbonyl]amino}-5-chloro-2-hydroxybenzensulfonic acid, or
O-{[(3-chloro-2-methyl-5-sulfophenyl)amino]carbonyl}-L-serine.
14. The compound or pharmaceutically acceptable salt thereof of claim 11 , which is
3-(L-(-glutamylamino)-2-hydroxybenzoic acid,
3-bromo-5-(L-(-glutamylamino)benzoic acid,
N 5 -(3-phosphonophenyl)-L-glutamine, or
5-chloro-3-(L-(-glutamylamino)benzoic acid.
15. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R4 is a halogen atom.