Bicyclic nitrogen-containing heterocyclic compounds
A nitrogen-containing bicyclic heterocyclic compound represented by the following formula (1) is provided. When the compound or a salt thereof is administered to a human being or an animal, the compound has a strong antagonistic action against EP1 receptors, and is useful, for example, as an active ingredient of a medicine for the prevention and/or treatment of overactive bladder. The compound is also useful as an active ingredient of a medicine for the prevention and/or treatment of symptoms such as frequency urinary, urinary urgency, or urinary incontinence.
1. A compound represented by the following formula (1):
wherein in the formula (1), Ar 1 represents an aryl group which may be substituted, a saturated cyclic hydrocarbyl group which may be substituted, or a saturated heterocyclic group which may be substituted;
X represents a nitrogen atom;
R 1 and R 2 together represent any of the formulas (Q 1 ) to (Q 6 ):
wherein in the formulas (Q 1 ) to (Q 6 ), R 3 and R 4 , which may be identical or different, each independently represents any of a hydrogen atom, a halogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, an aryl group which may be substituted, an aralkyl group which may be substituted, a hydroxy group, an alkoxy group which may be substituted, an aryloxy group which may be substituted, an alkylthio group, an acyl group, an acyloxy group, an alkylsulfinyl group, an alkylsulfonyl group, an alkylcarbamoyl group, —N(R Q1 )(R Q2 ) {wherein R Q1 and R Q2 may be identical or different, and each independently represents a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted; or R Q1 and R Q2 together form a 3- to 7-membered ring to represent a cyclic amine in the form of N(R Q1 )(R Q2 )}, an acylamino group, an acyl(alkyl)amino group, an alkylsulfonylamino group, an alkylsulfonyl(alkyl)amino group, a carboxyl group, —CON(R Q3 )(R Q4 ) {wherein R Q3 and R Q4 may be identical or different, and each independently represents a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted; or R Q3 and R Q4 ether form a 3- to 7-membered ring to represent a cyclic amine in the form of N(R Q3 )(R Q4 )}, and —COOR Q5 {wherein R Q5 represents an alkyl group which may be substituted};
n represents an integer from 1 to 4; and
R 1 and R 2 represent that they are bonded to each of the formulas (Q 1 ) to (Q 6 ) at the position of a and the position of b, respectively;
A 1 represents a single bond, an alkylene group which may be substituted, or an alkenylene group which may be substituted;
G represents any of the formulas (G 1 ), (G 2 ), or (G 3 ):
wherein in the formulas (G 1 ), (G 2 ), and (G 3 ), A 2 represents a single bond, an alkylene group which may be substituted, or an alkenylene group which may be substituted; R 5 represents a carboxyl group, —CON(R 51 )(R 52 ) {wherein R 51 and R 52 may be identical or different, and each independently represents a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted; or R 51 and R 52 together form a 3- to 7-membered ring to represent a cyclic amine in the form of N(R 51 )(R 52 )}, —COOR 53 {wherein R 53 represents an alkyl group which may be substituted}, or a tetrazol-5-yl group; and R 6 represents a hydrogen atom or an alkyl group which may be substituted,
or a salt thereof.
2. The compound or the salt thereof according to claim 1 , wherein R 5 is a carboxyl group.
3. The compound or the salt thereof according to claim 1 , wherein A 2 is a single bond.
4. The compound or the salt thereof according to claim 1 , wherein A 1 is a single bond, or a methylene group which may be substituted with a lower alkyl group.
5. The compound or the salt thereof according to claim 1 , wherein A 1 is a single bond.
6. The compound or the salt thereof according to claim 1 , wherein A 1 is a methylene group which may be substituted with a lower alkyl group.
7. The compound or the salt thereof according to claim 1 , wherein R 1 and R 2 together represent the formula (Q1).
8. The compound or the salt thereof according to claim 1 , wherein R 1 and R 2 together represent the formula (Q 6 ).
9. The compound or the salt thereof according to claim 1 , wherein R 3 and R 4 are groups that are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group which may be substituted, a hydroxy group, an alkoxy group which may be substituted, and —N(R Q1 )(R Q2 ) [wherein R Q1 and R Q2 may be identical or different, and each independently represents a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted; or R Q1 and R Q2 together form a 3- to 7-membered ring to represent a cyclic amine in the form of N(R Q1 )(R Q2 )].
10. The compound or the salt thereof according to claim 1 , wherein Ar 1 is an aryl group which may be substituted.
11. The compound or the salt thereof according to claim 1 , wherein Ar 1 is a phenyl group which may be substituted.
12. The compound or the salt thereof according to claim 1 , wherein Ar 1 is a phenyl group which may be substituted with one or plural groups that are each independently selected from the group consisting of a halogen atom, an alkyl group which may be substituted, a hydroxy group, and an alkoxy group which may be substituted.
13. The compound or the salt thereof according to claim 1 , wherein Ar 1 is a saturated heterocyclic group which may be substituted.
14. A compound selected from the group consisting of:
or a salt thereof.
15. A compound selected from the group consisting of:
or a salt thereof.
16. The compound or the salt thereof according to claim 1 , wherein G is formula (G 1 ).
17. The compound or the salt thereof according to claim 1 , wherein R 1 and R 2 together represent the formula (Q 1 ), (Q 4 ), (Q 5 ), or (Q 6 ).
18. The compound or the salt thereof according to claim 1 , wherein R 1 and R 2 together represent the formula (Q 4 ) or (Q5).
19. A pharmaceutical composition comprising the compound according to any one of claims 1 , 2 , 3 - 6 , 7 , 8 - 13 , 14 , 15 , or 16 - 18 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
20. A method of making a pharmaceutical composition for treating overactive bladder comprising formulating the compound according to any one of claims 1 , 2 , 3 - 6 , 7 , 8 - 12 , 14 , 15 , or 16 - 18 , or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier.
21. A method for treating overactive bladder in a mammal, the method comprising administering to a mammal in need thereof the compound according to any one of claims 1 , 2 , 3 - 6 , 7 , 8 - 13 , 14 , 15 , or 16 - 18 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat overactive bladder.