Aminoalcohol derivatives
The present invention relates to a compound formula[I]: wherein X is bond, —CH 2 —, —O— or —NH—, R 1 and R 12 are each independently hydrogen, halogen, lower alkyl, etc., R 2 is hydrogen or optionally substituted lower alkyl, R 3 is hydrogen or an amino protective group, R 4 , R 5 and R 6 are each independently hydrogen or optionally substituted lower alkyl, R 7 is -Z-R 13 , in which Z is bond, etc., and R 13 is carboxy, lower alkoxycarbonyl, (lower alkylsulfonyl)carbamoyl or lower alkanoylsulfamoyl, R 8 is —Y—R 9 , in which Y is bond, —CH 2 —, —O—, —S—, etc., and R 9 is hydrogen, lower alkyl, cyclo(lower)alkyl, etc., and R 11 is hydrogen, lower alkyl, lower alkoxy, etc., or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiurea or urinary incontinence.
1. A compound of the formula [I]:
wherein
X is a bond, —CH 2 —, —O—, or —NH—,
R 1 and R 12 are each independently hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, nitro, amino, or (lower alkylsulfonyl)amino,
R 2 is hydrogen or optionally substituted lower alkyl,
R 3 is hydrogen or an amino protective group,
R 4 , R 5 , and R 6 are each independently hydrogen or optionally substituted lower alkyl,
R 7 is -Z-R 13 , in which
Z is a bond or —(CH 2 ) n — (in which n is 1), and
R 13 is (lower alkylsulfonyl)carbamoyl or lower alkanoylsulfamoyl,
R 8 is —Y—R 9 , in which
Y is a bond, —CH 2 —, —O—, —S—, —SO—, —SO 2 —, —NH—, or
in which R 10 is lower alkyl, cyclo(lower)alkyl, or aryl), and
R 9 is hydrogen, lower alkyl, cyclo(lower)alkyl, mono(or di or tri)halo(lower)alkyl, lower alkanoyl, lower alkenyl, lower alkoxy(lower)alkyl, nitro, aryl, or a heterocyclic group, and
R 11 is hydrogen, lower alkyl, lower alkoxy, amino or mono(or di)lower(alkyl)amino, or a salt thereof.
2. A compound of claim 1 , which is 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(3-methylbutyl)-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 , which is 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-isobutyl-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 , which is 4′-[2-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino]ethyl]-3-isobutyl-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 , which is 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 , which is 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 , which is 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 , which is 2-[3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylyl]-N-(methylsulfonyl)acetamide or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 , which is N-[[3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl]acetamide or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 , which is N-[[3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl]butanamide or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 , which is 3-(cyclohexylamino)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1 , which is 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylamino)-N-(methylsulfonyl)-4-biphenylcarboxamide or a pharmaceutically acceptable salt thereof.
13. A compound of claim 1 , wherein
X is bond,
R 1 and R 12 are each independently hydrogen or halogen,
R 3 is hydrogen,
R 4 is hydrogen,
R 8 is —Y—R 9 , in which
Y is a bond, —CH 2 —, —O—, —S— or NH—, and
R 9 is lower alkyl or cyclo(lower)alkyl, and
R 11 is hydrogen.
14. A compound of claim 13 , which is selected from the group consisting of
4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(3-methylbutyl)-N-(methylsulfonyl)-4-biphenylcarboxamide,
4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-isobutyl-N-(methylsulfonyl)-4-biphenylcarboxamide,
4′-[2-[[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]amino]ethyl]-3-isobutyl-N-(methylsulfonyl)-4-biphenylcarboxamide,
4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-N-(methylsulfonyl)-4-biphenylcarboxamide,
3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide,
3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide,
2-[3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylyl]-N-(methylsulfonyl)acetamide,
2-[3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-4-biphenylyl]-N-(methylsulfonyl)acetamide,
N-[[3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl]acetamide,
N-[[3-(Cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl]butanamide,
3-(Cyclohexylamino)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide, and
4′-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylamino)-N-(methylsulfonyl)-4-biphenylcarboxamide,
or a pharmaceutically acceptable salt thereof.
15. A compound of claim 13 , which is 2-[3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4-biphenylyl]-N-methylsulfonyl)-acetamide or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with at least one pharmaceutically acceptable carrier or excipient.