Prophylactic or therapeutic agent for diabetes or obesity
An object is to provide a CaSR agonist agent that has excellent CaSR agonist effects, and particularly, a pharmaceutical product that can prevent or remedy diabetes or obesity by the effect of CaSR activation. The aforementioned object is achieved by a composition that contains a compound represented by the following General Formula (I) or a salt thereof (refer to the Description for the definitions of the symbols used in the formula).
1. A method for treating diabetes or obesity, comprising administering to a subject in need thereof a compound represented by Formula (I) or a salt thereof:
wherein, R 1 and R 2 , each independently, represent a hydrogen atom or unsubstituted C 1-6 alkyl;
R 3 represents a hydrogen atom;
R 4 and R 5 , each independently, represent a hydrogen atom or C 1-6 alkyl;
X represents CH 2 , an oxygen atom, NH, or a sulfur atom;
Y represents C═O, SO, SO 2 , or C═S;
R 6 represents a hydrogen atom;
G represents R 7 -substituted phenyl or R 7 -substituted pyridyl, where the R 7 -substituted phenyl or the R 7 -substituted pyridyl may further be substituted with one or two R 8 ;
R 7 represents sulfo or carboxyl;
R 8 represents C 1-6 alkyl, halogeno, hydroxy, C 1-6 alkoxy, nitro, sulfo, or C 1-3 alkylcarbonylamino, where they may be different when more than one R 8 exist;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, carboxyl, CONR e R f , CONHNHR g , COR h , phenyl or substituted or unsubstituted oxadiazolyl;
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkylsulfonyl, phenylsulfonyl, C 3-8 cycloalkyl, or hydroxy, or alternatively, R e and R f may integrally form morpholino;
R g represents substituted or unsubstituted C 1-6 alkylcarbonyl; and
R h represents C 1-6 alkoxy,
provided that when X is methylene or an oxygen atom, Y is C═O, all of R 1 -R 5 are hydrogen atoms and G is R 7 -substituted phenyl optionally substituted with one or two R 8 , then, Q is a group other than carboxyl or COR h .
2. The method according to claim 1 , comprising administering a compound represented by Formula (I), or a salt thereof:
wherein, R 1 and R 2 , each independently, represent a hydrogen atom or C 1-6 alkyl;
R 3 represents a hydrogen atom;
R 4 and R 5 , each independently, represent a hydrogen atom or C 1-6 alkyl;
X represents CH 2 , an oxygen atom, NH or a sulfur atom;
Y represents C═O, SO, SO 2 , or C═S;
R 6 represents a hydrogen atom;
G represents R 7 -substituted phenyl or R 7 -substituted pyridyl, where the R 7 -substituted phenyl or the R 7 -substituted pyridyl may further be substituted with one or two R 8 ;
R 7 represents sulfo or carboxyl;
R 8 represents C 1-6 alkyl, halogeno, hydroxy, C 1-6 alkoxy, nitro, or sulfo;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl (wherein the substituent on said substituted C 1-6 alkyl is selected from the group consisting of phenyl, carbamoyl, and cyano), carboxyl, CONR e R f , CONHNHR g , COR h , phenyl or substituted or unsubstituted oxadiazolyl (wherein the substituent on said substituted oxadiazolyl is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with phenyl, phenyl substituted with halogen, phenyl substituted with C 1-6 alkyl, and thiazolyl);
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl (wherein the substituent on said substituted C 1-6 alkyl is selected from the group consisting of phenyl, phenyl substituted with C 1-6 alkyl, phenyl substituted with halogen, and imidazolyl), C 1-6 alkylsulfonyl, phenyl sulfonyl, C 3-8 cycloalkyl, or hydroxy, or alternatively, R e and R f may integrally form morpholino;
R g represents C 1-6 alkylcarbonyl; and
R h represents C 1-6 alkoxy,
provided that when X is methylene or an oxygen atom, Y is C═O, all of R 1 -R 5 are hydrogen atoms and G is R 7 -substituted phenyl optionally substituted with one or two R 8 , then, Q is a group other than carboxyl or COR h .
3. A method for treating diabetes or obesity, comprising administering to a subject in need thereof a compound represented by Formula (I 0 ) or a pharmaceutically acceptable salt thereof as an active component:
wherein, R 1 and R 2 , each independently, represent a hydrogen atom or C 1-6 alkyl;
R 3 represents a hydrogen atom;
R 4 and R 5 , each independently, represent a hydrogen atom or C 1-6 alkyl;
X represents CH 2 , an oxygen atom, NH or a sulfur atom;
Y represents C═O, SO, SO 2 , or C═S;
R 6 represents a hydrogen atom;
G 0 represents unsubstituted or substituted phenyl with one to three R 70 or unsubstituted or substituted pyridyl with one to three R 70 , where the R 70 -substituted phenyl or the R 70 -substituted pyridyl may further be substituted;
R 70 represents C 1-6 alkyl, halogeno, hydroxy, C 1-6 alkoxy, nitro, sulfo, carboxyl, or C 1-3 alkylcarbonylamino, where they may be different when more than one R 70 exist;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, carboxyl, CONR e R f , CONHNHR g , COR h , phenyl or substituted or unsubstituted oxadiazolyl;
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkylsulfonyl, phenylsulfonyl, C 3-8 cycloalkyl, or hydroxy, or alternatively, R e and R f may integrally form morpholino;
R g represents substituted or unsubstituted C 1-6 alkylcarbonyl; and
R h represents C 1-6 alkoxy,
provided that when X is methylene or an oxygen atom, Y is C═O, all of R 1 -R 5 are hydrogen atoms, and G 0 is R 7 -substituted phenyl optionally substituted with one or two R 8 , then, Q is a group other than carboxyl or COR h .
4. The method according to claim 3 , comprising administering a compound represented by Formula (I 0 ) or a pharmaceutically acceptable salt thereof as an active component:
wherein, R 1 and R 2 , each independently, represent a hydrogen atom or C 1-6 alkyl;
R 3 represents a hydrogen atom;
R 4 and R 5 , each independently, represent a hydrogen atom or unsubstituted C 1-6 alkyl;
X represents CH 2 , an oxygen atom, NH or a sulfur atom;
Y represents C═O, SO, SO 2 , or C═S;
R 6 represents a hydrogen atom;
G 0 represents unsubstituted or substituted phenyl with one to three R 70 or unsubstituted or substituted pyridyl with one to three R 70 , where the R 70 -substituted phenyl or the R 70 -substituted pyridyl may further be substituted;
R 70 represents C 1-6 alkyl, halogeno, hydroxy, C 1-6 alkoxy, sulfo, carboxyl, or C 1-3 alkylcarbonylamino, where they may be different when more than one R 70 exist;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl (wherein the substituent on said substituted C 1-6 alkyl is selected from the group consisting of phenyl, carbamoyl, and cyano), carboxyl, CONR e R f , CONHNHR g , COR h , phenyl, or substituted or unsubstituted oxadiazolyl (wherein the substituent on said substituted oxadiazolyl is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with phenyl, phenyl substituted with halogeno, phenyl substituted with C 1-6 alkyl, and thiazolyl);
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl wherein the substituent on said substituted C 1-6 alkyl is selected from the group consisting of phenyl, phenyl substituted with C 1-6 alkyl, phenyl substituted with halogeno, and imidazolyl), C 1-6 alkylsulfonyl, arylsulfonyl, C 3-8 cycloalkyl, or hydroxy, or alternatively, R e and R f may integrally form morpholino;
R g represents C 1-6 alkylcarbonyl; and
R h represents C 1-6 alkoxy,
provided that when X is methylene or an oxygen atom, Y is C═O, all of R 1 -R 5 are hydrogen atoms, and G 0 is R 7 -substituted phenyl optionally substituted with one or two R 8 , then, Q is a group other than carboxyl or COR h .
5. The method according to either one of claims 1 and 2 , comprising administering the compound represented by Formula (I) or a salt thereof,
wherein, in Formula (I):
X represents NH;
Y represents C═O or C═S;
G represents R 7 -substituted phenyl, which may further be substituted with one or two R 8 ;
R 7 represents sulfo, carboxyl or phosphono;
R 8 represents C 1-6 alkyl, halogeno, hydroxy, C 1-3 alkylcarbonylamino or sulfo, where they may be different when more than one R 8 exist; and
Q represents carboxyl, CONR e R f , CONHNHR g or COR h .
6. The method according to claim 5 , comprising administering a compound represented by Formula (I 1 ) or a salt thereof:
wherein, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl;
X represents NH;
Y represents C═O or C═S;
R 7 represents sulfo or carboxyl;
R 8 represents halogeno, or substituted or unsubstituted C 1-6 alkyl;
Q represents carboxyl; and
R 9 to R 11 , each independently, represent a hydrogen atom, C 1-6 alkyl, hydroxy or halogeno.
7. The method according to claim 6 , comprising administering 2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl)carbamoyl]amino}propanoic acid, 2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl)carbamothioyl]amino}propanoic acid, or 2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl)carbamoyl]amino}propanoic acid as an active component.
8. The method according to claim 6 , comprising administering 2-amino-3 -{[(5-chloro-2-hydroxy-3 -sulfophenyl)carbamoyl]amino}propanoic acid as an active component.