Aromatic compound and use thereof
Provided is a compound showing a bone formation promoting action (and/or bone resorption suppressive action). A compound of the formula (I) or a pharmacologically acceptable salt: [wherein each substituent is as defined in the DESCRIPTION], has low toxicity, shows good pharmacokinetics, has an action to promote bone formation, and is useful for the prophylaxis or treatment of metabolic bone diseases (osteoporosis, fibrous osteitis (hyperparathyroidism), osteomalacia, Paget's disease that influences the systemic bone metabolism parameter etc.) associated with a decrease in the bone formation ability as compared to the bone resorption capacity.
1. A compound of formula (I) or a pharmacologically acceptable salt thereof:
wherein:
R 1 is cyano group, C1-6 alkylcarbonyl group, C1-6 alkylcarbonylamino group, halogeno C1-6 alkyl group, C2-6 alkenyl group, halogeno C2-6 alkenyl group, carbamoyl group, or hydroxy C1-6 alkyl group;
R 2 is C1-6 alkoxy group, carbamoyl group, C1-6 alkylaminocarbonyl group, or C1-6 alkylcarbonyl group;
R 3 is hydrogen atom or halogen atom;
S, T and U are each ═CH— or ═C— when R 3 is halogen atom;
W is —NH— or —O—;
X is saturated heterocycle-, —CH 2 —(CH 2 ) n —, —O—(CH 2 ) n —, —(CH 2 ) n —O—, or —CH═CH—(CH 2 ) n —;
n is an integer of 1 to 4;
Y is single bond, —O—, or —CO—;
Z is hydrogen atom, saturated heterocyclic group optionally substituted by any group selected from substituent group α, or C1-6 alkyl group optionally substituted by any group selected from substituent group α; and
substituent group α is saturated heterocyclic group, hydroxy C1-6 alkyl group, aminosulfonylamino group, carboxy group, hydroxy group, C1-6 alkoxy group, or C1-6 alkyl group.
2. The compound according to claim 1 , wherein
R 1 is cyano group, acetyl group, acetylamino group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoroethyl group, difluoromethyl group, carbamoyl group, or 1-hydroxyethyl group, or a pharmacologically acceptable salt thereof.
3. The compound according to claim 1 , wherein
R 2 is methoxy group, carbamoyl group, methylaminocarbonyl group, or acetyl group, or a pharmacologically acceptable salt thereof.
4. The compound according to claim 1 , wherein
X is -saturated heterocycle or —O—(CH 2 ) n —, and n is 2, or a pharmacologically acceptable salt thereof.
5. The compound according to claim 1 , wherein
Y is a single bond or —O—, or a pharmacologically acceptable salt thereof.
6. The compound according to claim 1 , wherein
Z is C1-6 alkyl group substituted by a hydroxy group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, or morpholinyl group, or a pharmacologically acceptable salt thereof.
7. A compound selected from the group consisting of:
(4) 4-acetyl-3-{4-[2-(1,1-dioxohexahydro-1λ 6 -thiopyran-4-yloxy)ethoxy]phenylamino}benzamide
(5) 4-acetyl-3-{4-[4-(2-hydroxyethoxy)piperidin-1-yl]phenoxy}benzamide
(6) 4-acetyl-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide
(7) 4-acetyl-3-{4-[2-(2-isopropoxyethoxy)ethoxy]phenoxy}benzamide
(8) 4-difluoromethyl-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide
(9) 4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide
(10) (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide
(12) 4-acetyl-2-{4-[2-(1,1-dioxohexahydro-1λ 6 -thiopyran-4-yloxy)ethoxy]phenylamino}benzamide
(13) 3-{4-[3-(2-hydroxyethoxy)azetidin-1-yl]phenoxy}-4-trifluoromethylbenzamide
(14) 4-acetyl-3-{4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenoxy}benzamide
(15) (S)-4-acetyl-3-{4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenoxy}benzamide
(16) (R)-4-acetyl-3-{4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenoxy}benzamide
(17) 4-[(R)-1-hydroxyethyl]-3-(4-{2-[(S)-tetrahydrofuran-3-yloxy]ethoxy}phenoxy)benzamide
a pharmacologically acceptable salt thereof.
8. A pharmaceutical composition comprising the compound according to claim 1 , 2 , 3 , 4 , 5 , 6 , or 7 , or a pharmacologically acceptable salt thereof, as an active ingredient, and a pharmacologically acceptable additive.
9. The pharmaceutical composition according to claim 8 , which is used for promoting bone formation.
10. The pharmaceutical composition according to claim 8 , which is used for treating osteoporosis.
11. A method of promoting bone formation, comprising administering an effective amount of the pharmaceutical composition according to claim 8 to a mammal.
12. A method of treating osteoporosis, comprising administering an effective amount of the pharmaceutical composition according to claim 8 to a mammal.
13. A compound of formula (Ia) or a pharmacologically acceptable salt thereof:
wherein:
R 1 is cyano group, acetyl group, acetylamino group, nitro group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoroethyl group, difluoromethyl group, carbamoyl group or 1-hydroxyethyl group;
R 2 is methoxy group, carbamoyl group, methylaminocarbonyl group or acetyl group;
S, T and U are each ═CH—;
W is —NH—, —O—, or —S—;
X is -saturated heterocycle- or —O—(CH 2 ) n —;
n is 2;
Y is a single bond or —O—; and
Z is C1-6 alkyl group substituted by a hydroxy group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group or morpholinyl group,
or a pharmacologically acceptable salt thereof.
14. A pharmaceutical composition comprising the compound according claim 13 , or a pharmacologically acceptable salt thereof, as an active ingredient, and a pharmacologically acceptable additive.
15. The pharmaceutical composition according to claim 14 , which is used for promoting bone formation.
16. The pharmaceutical composition according to claim 14 , which is used for treating osteoporosis.
17. A method of promoting bone formation, comprising administering an effective amount of the pharmaceutical composition according to claim 14 to a mammal.
18. A method of treating osteoporosis, comprising administering an effective amount of the pharmaceutical composition according to claim 14 to a mammal.
19. A compound selected from the group consisting of:
(2) 3-{4-[3-(2-hydroxyethoxy)azetidin-1-yl] phenylamino}-4-nitrobenzamide
(3) 3 -{4-[4-(4-fluoro-5 -methoxy-2-nitrophenylamino)phenyl]piperazin -1-yl }-2,2-dimethylpropionic acid
(11) 4-nitro-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenylamino}benzamide
a pharmacologically acceptable salt thereof.
20. A pharmaceutical composition comprising the compound according claim 19 , or a pharmacologically acceptable salt thereof, as an active ingredient, and a pharmacologically acceptable additive.
21. The pharmaceutical composition according to claim 20 , which is used for promoting bone formation.
22. The pharmaceutical composition according to claim 20 , which is used for treating osteoporosis.
23. A method of promoting bone formation, comprising administering an effective amount of the pharmaceutical composition according to claim 20 to a mammal.
24. A method of treating osteoporosis, comprising administering an effective amount of the pharmaceutical composition according to claim 20 to a mammal.