TGF-β superfamily production/secretion promoter
View Patent ↗The present invention provides a TGF-β superfamily production/secretion promoter comprising a compound represented by the formula wherein R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group; A is an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxyl group; B is an optionally substituted aromatic group; X is an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom; and Y is a divalent hydrocarbon group or heterocyclic group, or a salt thereof or a prodrug thereof, which is useful as an agent for the prophylaxis or treatment of dysautonomia, bladder dysfunction, hearing impairment, bone disease and the like.
1. A method for promoting the production and/or secretion of a TGF-β superfamily protein in a mammal, which comprises administering a compound represented by the formula:
wherein
R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group;
A is an optionally substituted formyl group, an optionally substituted C 1-10 alkyl-carbonyl group, an optionally substituted C 3-10 cycloalkyl-carbonyl group, an optionally substituted C 2-10 alkenyl-carbonyl group, an optionally substituted C 3-10 cycloalkenyl-carbonyl group, an optionally substituted C 6-12 aryl-carbonyl group, an optionally substituted phosphono group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified carboxyl group;
B is an optionally substituted aromatic group;
X is an oxygen atom; and
Y is a divalent hydrocarbon group or heterocyclic group,
or a salt thereof to the mammal.
2. A method for inducing neuroneogenesis in a mammal, which comprises administering a TGF-β superfamily protein production and/or secretion promoter to the mammal, wherein the TGF-β superfamily protein production and/or secretion promoter is a compound represented by the formula:
wherein
R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted ammo group;
A is an optionally substituted formyl group, an optionally substituted C 1-10 alkyl-carbonyl group, an optionally substituted C 3-10 cycloalkyl-carbonyl group, an optionally substituted C 2-10 alkenyl-carbonyl group, an optionally substituted C 3-10 cycloalkenyl-carbonyl group, an optionally substituted C 6-12 aryl-carbonyl group, an optionally substituted phosphono group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified carboxyl group;
B is an optionally substituted aromatic group;
X is an oxygen atom; and
Y is a divalent hydrocarbon group or heterocyclic group,
or a salt thereof.
3. A method for restoring nerve function in a mammal, which comprises administering a TGF-β superfamily protein production and/or secretion promoter to the mammal wherein the TGF-β superfamily protein production and/or secretion promoter is a compound represented by the formula:
wherein
R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group;
A is an optionally substituted formyl group, an optionally substituted C 1-10 alkyl-carbonyl group, an optionally substituted C 3-10 cycloalkyl-carbonyl group, an optionally substituted C 2-10 alkenyl-carbonyl group, an optionally substituted C 3-10 cycloalkenyl-carbonyl group, an optionally substituted C 6-12 aryl-carbonyl group, an optionally substituted phosphono group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified carboxyl group;
B is an optionally substituted aromatic group;
X is an oxygen atom; and
Y is a divalent hydrocarbon group or heterocyclic group,
or a salt thereof.
4. A method for treating dysautonomia in a mammal, which comprises administering a TGF-β superfamily protein production and/or secretion promoter to the mammal wherein the TGF-β superfamily protein production and/or secretion promoter is a compound represented by the formula:
wherein
R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group;
A is an optionally substituted formyl group, an optionally substituted C 1-10 alkyl-carbonyl group, an optionally substituted C 3-10 cycloalkyl-carbonyl group, an optionally substituted C 2-10 alkenyl-carbonyl group, an optionally substituted C 3-10 cycloalkenyl-carbonyl group, an optionally substituted C 6-12 aryl-carbonyl group, an optionally substituted phosphono group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified carboxyl group;
B is an optionally substituted aromatic group;
X is an oxygen atom; and
Y is a divalent hydrocarbon group or heterocyclic group,
or a salt thereof.
5. A method for treating bladder dysfunction in a mammal, which comprises administering a TGF-β superfamily protein production and/or secretion promoter to the mammal, wherein the TGF-β superfamily protein production and/or secretion promoter is a compound represented by the formula:
wherein
R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group;
A is an optionally substituted formyl group, an optionally substituted C 1-10 alkyl-carbonyl group, an optionally substituted C 3-10 cycloalkyl-carbonyl group, an optionally substituted C 2-10 alkenyl-carbonyl group, an optionally substituted C 3-10 cycloalkenyl-carbonyl group, an optionally substituted C 6-12 aryl-carbonyl group, an optionally substituted phosphono group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified carboxyl group;
B is an optionally substituted aromatic group;
X is an oxygen atom; and
Y is a divalent hydrocarbon group or heterocyclic group,
or a salt thereof.
6. The method of claim 1 , wherein R 1 is an optionally substituted heterocyclic group.
7. The method of claim 1 , wherein R 1 is an optionally substituted 5-membered nitrogen-containing aromatic heterocyclic group.
8. The method of claim 1 , wherein R 1 is an optionally substituted imidazolyl group.
9. The method of claim 1 , wherein A is an optionally substituted hydroxy group.
10. The method of claim 1 , wherein A is an optionally substituted aryloxy group.
11. The method of claim 1 , wherein A is a phenoxy group substituted by an optionally substituted alkyl group.
12. The method of claim 1 , wherein B is an optionally substituted phenyl group.
13. The method of claim 1 , wherein Y is a divalent aliphatic hydrocarbon group.
14. The method of claim 1 , wherein the compound is 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole.
15. The method of claim 1 , wherein the TGF-β superfamily protein is GDNF.
16. The method of claim 1 , wherein the TGF-β superfamily protein is GDF-15.