Aminoalcohol derivatives
The present invention relates to a compound of the formula [I]: wherein (a), in which —Y—, R 4 , R 5 and R 6 are 4 R 5 each as defined in the description, etc., R 1 is hydrogen, halogen, lower alkyl, hydroxy, etc., R 2 is hydrogen, lower alkyl or hydroxy(lower)alkyl, R 3 is hydrogen or an amino protective group, 20 R7 is hydrogen, lower alkyl, cyclo(lower)alkyl, lower R9 alkenyl, —Z—R 9 or (b), in which —Z— is —0—, —S—, R 9 —SO— or —SO 2 —, and each R 9 is independently hydrogen, lower alkyl, cyclo(lower)alkyl, etc., and R 8 is -D-E-R 10 , in which -D- is —CONHSO 2 — or —S0 2 NHCO—, E is bond or lower alkylene, and R 10 is halogen, cyano, carboxy, etc., or a prodrug thereof 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 ulcer, overactive bladder, and the like.
1. A compound of formula [I] or salt thereof:
wherein
R 1 is hydrogen, halogen, nitro, or amino,
R 2 is hydrogen or lower alkyl,
R 3 is hydrogen,
—X— is
in which —Y— is a bond, —O—, —NH—, or —CH 2 —, and
R 4 , R 5 , and R 6 are each hydrogen,
R 7 is lower alkyl, cyclo(lower)alkyl, —Z—R 9 , or
in which —Z— is —O— or —S—, and
each R 9 is independently lower alkyl or cyclo(lower)alkyl, and R 8 is -D-E-R 10 , in which
-D- is —CONHSO 2 —,
E is lower alkylene selected from the group consisting of ethylene, trimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene and propylene, and R 10 is —OH.
2. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or excipient.
3. A compound or salt thereof, which is selected from the group consisting of
(1) 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4-biphenyl-carboxamide,
(2) 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3-(isopropylthio)-4-biphenylcarboxamide,
(3) 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide,
(4) 3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-4-biphenylcarboxamide,
(5) 3-(cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4-biphenylcarboxamide,
(6) N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-3-isopropoxy-4-biphenylcarboxamide,
(7) 3-(cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylcarboxamide,
(8) N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-3-propoxy-4-biphenylcarboxamide,
(9) 3-cyclopentyl-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethoxy]-N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide,
(10) 4′-[2-[[(2R)-2-(4-aminophenyl)-2-hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl) sulfonyl]-3-isobutyl-4-biphenylcarboxamide,
(11) 4′-[2-[[(2R)-2-(4-aminophenyl)-2-hydroxyethyl]amino]ethoxy]-3-(cyclohexyloxy) -N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide,
(12) 3-(cycloheptyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4-biphenylcarboxamide,
(13) 3-(cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4′-[2-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl ]amino]ethyl]-4-biphenylcarboxamide,
(14) 3-(cyclohexylamino)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethoxy]-N -[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide,
(15) 3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-4-biphenylcarboxamide,
(16) N-[(3-hydroxypropyl)sulfonyl]-4′-[3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-isobutoxy-4-biphenylcarboxamide,
(17) 3-(cyclohexyloxy)-N-[(3-hydroxy-3-methylbutyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylcarboxamide,
(18) 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide,
(19) 4′-[[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-N-[(3-hydroxypropyl)sulfonyl]-3-isobutoxy-4-biphenylcarboxamide,
and pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 3 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or excipient.
5. The compound of claim 1 , wherein the compound is 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4-biphenyl-carboxamide or a salt thereof.
6. The compound of claim 1 , wherein the compound is 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3-(isopropylthio) -4-biphenylcarboxamide or a salt thereof.
7. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide or a salt thereof.
8. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-4-biphenylcarboxamide or a salt thereof.
9. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-4-biphenylcarboxamide or a salt thereof.
10. The compound of claim 1 , wherein the compound is N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isopropoxy-4-biphenylcarboxamide or a salt thereof.
11. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylcarboxamide or a salt thereof.
12. The compound of claim 1 , wherein the compound is N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-propoxy-4-biphenylcarboxamide or a salt thereof.
13. The compound of claim 1 , wherein the compound is 3-cyclopentyl-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethoxy]-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide or a salt thereof.
14. The compound of claim 1 , wherein the compound is 4′-[2-[[(2R)-2-(4-aminophenyl)-2-hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl) sulfonyl]-3-isobutyl-4-biphenylcarboxamide or a salt thereof.
15. The compound of claim 1 , wherein the compound is 4′-[2-[[(2R)-2-(4-aminophenyl)-2-hydroxyethyl]amino]ethoxy]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide or a salt thereof.
16. The compound of claim 1 , wherein the compound is 3-(cycloheptyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-4-biphenylcarboxamide or a salt thereof.
17. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4′-[2-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino]ethyl]-4-biphenylcarboxamide or a salt thereof.
18. The compound of claim 1 , wherein the compound is 3-(cyclohexylamino)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethoxy]-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide or a salt thereof.
19. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[3-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]propyl]-4-biphenylcarboxamide or a salt thereof.
20. The compound of claim 1 , wherein the compound is N-[(3-hydroxypropyl)sulfonyl]-4′-[3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-isobutoxy-4-biphenylcarboxamide or a salt thereof.
21. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-N-[(3-hydroxy-3-methylbutyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4-biphenylcarboxamide or a salt thereof.
22. The compound of claim 1 , wherein the compound is 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide or a salt thereof.
23. The compound of claim 1 , wherein the compound is 4′-[[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-N-[(3-hydroxypropyl) sulfonyl]-3-isobutoxy-4-biphenylcarboxamide or a salt thereof.
24. The compound of claim 1 , wherein E is lower alkylene selected from the group consisting of ethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene and propylene.
25. The compound of claim 1 , wherein E is lower alkylene selected from the group consisting of ethylene, trimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, tetramethylene, pentamethylene, and hexamethylene.
26. The compound of claim 1 , wherein E is trimethylene.
27. The compound of claim 1 , wherein E is propylene.