Alkylamine derivative
A composition containing a compound represented by General Formula (I) below (see the definition in the specification for the symbols in the formula) or a salt thereof has an excellent CaSR agonistic effect and provides a pharmaceutical agent, a CaSR agonistic agent, a prophylactic or therapeutic agent for a disease that can be ameliorated through CaSR activation as well as seasonings and an agent for imparting kokumi.
1. A method of activating CaSR, comprising:
administering a compound of Formula (I 0 ) or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl, or R 1 and R 2 may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring which may further include a heteroatom(s);
R 3 represents a hydrogen atom, halogeno or substituted or unsubstituted C 1-6 alkyl;
R 4 and R 5 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or halogeno;
X represents NH;
Y represents C═O, SO, SO 2 , C═S or C═NR d , where R d represents a hydrogen atom or C 1-6 alkyl, and R d and R 6 may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring;
R 6 represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or hydroxy;
G 0 represents unsubstitued or substituted aryl with one or more R 70 or unsubstitued or substituted heteroaryl with one or more R 70 , where the R 70 -substituted aryl or the R 70 -substituted heteroaryl may further be substituted, where aryl in G 0 is phenyl or naphthyl, and heteroaryl in G 0 is one of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, furyl, thiophenyl and pyrrolyl;
R 70 represents substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C 1-6 alkoxy, nitro, amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, sulfo, carboxyl, phosphono, C 1-3 alkylcarbonylamino or mono-C 1-6 alkylphosphono, where they may be different when more than one R 70 exist;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, carboxyl, CONR e R f , CONHNHR g , COR h , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted C 3-8 cycloalkyl, hydroxy or C 1-6 alkoxy, or alternatively, R e and R f may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring which may further have a heteroatom(s);
R g represents substituted or unsubstituted C 1-6 alkylcarbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R h represents substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted mercapto, or the following group:
where Z represents a bivalent group of substituted or unsubstituted C 1-6 hydrocarbon; E 1 represents substituted or unsubstituted C 1-6 acyloxy, substituted or unsubstituted C 1-6 alkoxycarbonyloxy, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted C 1-6 alkoxycarbonyl, halogeno, aryl, heteroaryl, substituted or unsubstituted C 1-6 alkoxy or substituted or unsubstituted carbamoyl; E 2 represents a hydrogen atom or C 1-6 alkyl; and Z and E 1 may integrally form a ring.
2. The method according to claim 1 , wherein
G 0 represents substituted aryl with one or more R 70 or substituted heteroaryl with one or more R 70 , where the R 70 -substituted aryl or the R 70 -substituted heteroaryl may further be substituted; and
R 70 represents substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C 1-6 alkoxy, nitro, amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, sulfo, carboxyl, phosphono or mono-C 1-6 alkylphosphono, where they may be different when more than one R 70 exist.
3. A method of treating a disease that is ameliorated through CaSR activation, comprising:
administering a compound of Formula (I 0 ) or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl, or R 1 and R 2 may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring which may further include a heteroatom(s);
R 3 represents a hydrogen atom, halogeno or substituted or unsubstituted C 1-6 alkyl;
R 4 and R 5 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or halogeno;
X represents NH;
Y represents C═O, SO, SO 2 , C═S or C═NR d , where R d represents a hydrogen atom or C 1-6 alkyl, and R d and R 6 may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring;
R 6 represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or hydroxy;
G 0 represents unsubstitued or substituted aryl with one or more R 70 or unsubstitued or substituted heteroaryl with one or more R 70 , where the R 70 -substituted aryl or the R 70 -substituted heteroaryl may further be substituted, where aryl in G 0 is phenyl or naphthyl, and heteroaryl in G 0 is one of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, furyl, thiophenyl and pyrrolyl;
R 70 represents substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C 1-6 alkoxy, nitro, amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, sulfo, carboxyl, phosphono, C 1-3 alkylcarbonylamino or mono-C 1-6 alkylphosphono, where they may be different when more than one R 70 exist;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, carboxyl, CONR e R f , CONHNHR g , COR h , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted C 3-8 cycloalkyl, hydroxy or C 1-6 alkoxy, or alternatively, R e and R f may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring which may further have a heteroatom(s);
R g represents substituted or unsubstituted C 1-6 alkylcarbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R h represents substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted mercapto, or the following group:
where Z represents a bivalent group of substituted or unsubstituted C 1-6 hydrocarbon; E 1 represents substituted or unsubstituted C 1-6 acyloxy, substituted or unsubstituted C 1-6 alkoxycarbonyloxy, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted C 1-6 alkoxycarbonyl, halogeno, aryl, heteroaryl, substituted or unsubstituted C 1-6 alkoxy or substituted or unsubstituted carbamoyl; E 2 represents a hydrogen atom or C 1-6 alkyl; and Z and E 1 may integrally form a ring.
4. The method according to claim 3 , wherein
G 0 represents substituted aryl with one or more R 70 or substituted heteroaryl with one or more R 70 , where the R 70 -substituted aryl or the R 70 -substituted heteroaryl may further be substituted; and
R 70 represents substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C 1-6 alkoxy, nitro, amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, sulfo, carboxyl, phosphono or mono-C 1-6 alkylphosphono, where they may be different when more than one R 70 exist.
5. The method according to claim 3 , wherein the disease is hyperparathyroidism.
6. The method according to claim 4 , wherein the disease is hyperparathyroidism.
7. The method according to claim 3 , wherein the disease is diarrhea.
8. The method according to claim 4 , wherein the disease is diarrhea.
9. The method according to claim 3 , wherein the disease is peptic ulcer.
10. The method according to claim 4 , wherein the disease is peptic ulcer.
11. A method of activating CaSR, comprising:
administering a composition including a compound of Formula (I 0 ) or an edible salt thereof:
wherein the composition is a seasoning or a kokumi-imparting agent;
R 1 and R 2 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl, or R 1 and R 2 may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring which may further include a heteroatom(s);
R 3 represents a hydrogen atom, halogeno or substituted or unsubstituted C 1-6 alkyl;
R 4 and R 5 , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or halogeno;
X represents NH;
Y represents C═O, SO, SO 2 , C═S or C═NR d , where R d represents a hydrogen atom or C 1-6 alkyl, and R d and R 6 may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring;
R 6 represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or hydroxy;
G 0 represents unsubstitued or substituted aryl with one or more R 70 or unsubstitued or substituted heteroaryl with one or more R 70 , where the R 70 -substituted aryl or the R 70 -substituted heteroaryl may further be substituted, where aryl in G 0 is phenyl or naphthyl, and heteroaryl in G 0 is one of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, furyl, thiophenyl and pyrrolyl;
R 70 represents substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C 1-6 alkoxy, nitro, amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, sulfo, carboxyl, phosphono, C 1-3 alkylcarbonylamino or mono-C 1-6 alkylphosphono, where they may be different when more than one R 70 exist;
Q represents a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, carboxyl, CONR e R f , CONHNHR g , COR h , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R e and R f , each independently, represent a hydrogen atom, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted C 3-8 cycloalkyl, hydroxy or C 1-6 alkoxy, or alternatively, R e and R f may integrally form a substituted or unsubstituted 5- or 6-membered hetero ring which may further have a heteroatom(s);
R g represents substituted or unsubstituted C 1-6 alkylcarbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R h represents substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted mercapto, or the following group:
where Z represents a bivalent group of substituted or unsubstituted C 1-6 hydrocarbon; E 1 represents substituted or unsubstituted C 1-6 acyloxy, substituted or unsubstituted C 1-6 alkoxycarbonyloxy, substituted or unsubstituted amino, carboxyl, substituted or unsubstituted C 1-6 alkoxycarbonyl, halogeno, aryl, heteroaryl, substituted or unsubstituted C 1-6 alkoxy or substituted or unsubstituted carbamoyl; E 2 represents a hydrogen atom or C 1-6 alkyl; and Z and E 1 may integrally form a ring.
12. The method according to claim 11 , wherein
G 0 represents substituted aryl with one or more R 70 or substituted heteroaryl with one or more R 70 , where the R 70 -substituted aryl or the R 70 -substituted heteroaryl may further be substituted; and
R 70 represents substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, halogeno, hydroxy, substituted or unsubstituted C 1-6 alkoxy, nitro, amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, sulfo, carboxyl, phosphono or mono-C 1-6 alkylphosphono, where they may be different when more than one R 70 exist.
13. The method according to claim 11 , wherein the composition is a seasoning.
14. The method according to claim 11 , wherein the composition is a kokumi-imparting agent.