Pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound
To provide a compound usable for treatment of diseases associated with fatty acid amide hydrolase (FAAH), especially for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain. We have found that a novel pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative and its pharmaceutically acceptable salt has a potent FAAH-inhibitory activity. Further, the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of the present invention has an excellent effect for increasing an effective bladder capacity, an excellent effect for relieving urinary frequency and an excellent anti-allodynia effect, and is therefore usable for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain.
1. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of a general formula (III) or its pharmaceutically acceptable salt:
wherein the symbols in formula (III) have the following meanings:
ring A represents benzene ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, or 5- to 7-membered nitrogen-containing hetero ring;
L represents single bond, lower alkylene, lower alkenylene, —N(R 15 )—C(═O)—, —C(═O)—N(R 15 )—, -(lower alkenylene)-C(═O)—, —O—, or —C(═O)—;
R 15 represents H, or lower alkyl;
X represents CH, or N;
R 8 , R 9 , and R 10 are the same or different, each representing
(i) a group selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(ii) aryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(iii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(iv) R 16 —(lower alkylene)-O—;
(v) R 16 —(lower alkylene)-N(R 15 )—; or
(vi) R 17 R 18 N—C(═O)—,
wherein R 16 represents
(i) aryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(ii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl; or
(iii) 3- to 8-membered cycloalkyl,
wherein R 17 and R 18 are the same or different, each representing H, lower alkyl, or 3- to 8-membered cycloalkyl, or R 17 and R 18 may form, together with the N atom bonding thereto, 3- to 8-membered nitrogen-containing hetero ring,
R 11 represents H, lower alkyl, or oxo (═O), and
one of R 12 , R 13 and R 14 is —C(═O)—O-(lower alkyl) or —CO 2 H, and the others are H.
2. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the ring A is benzene ring, cyclohexane ring, piperidine ring, or piperazine ring.
3. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 2 , wherein R 9 , R 10 , R 11 , R 12 and R 13 are H.
4. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of a general formula (IV) or its pharmaceutically acceptable salt:
wherein the symbols in formula (IV) have the following meanings:
ring A 1 represents benzene ring, piperidine ring or piperazine ring;
L 1 represents lower alkylene, lower alkenylene, —N(R 15 )—C(═O)—, or —O—, wherein
R 15 represents H, or lower alkyl;
R 19 represents
(i) a group selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(ii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(iii) R 16 —(lower alkylene)-O—; or
(iv) R 17 R 18 N—C(═O)—;
wherein R 16 represents
(i) aryl optionally substituted with one the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl;
(ii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl; or
(iii) 3- to 8-membered cycloalkyl,
wherein R 17 and R 18 are the same or different, each representing H or lower alkyl, or R 17 and R 18 may form, together with the N atom bonding thereto, 5- or 6-membered nitrogen-containing hetero ring, and R 20 represents —C(═O)—O-(lower alkyl) or —CO 2 H.
5. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of a general formula (V) or its pharmaceutically acceptable salt:
wherein the symbols in formula (V) have the following meanings:
L 2 represents lower alkylene, lower alkenylene, or -(lower alkenylene)-C(═O)—,
R 21 represents H, halo, —CN, —CF 3 , lower alkyl, or —O-lower alkyl, and
R 22 represents —C(═O)—O-(lower alkyl) or —CO 2 H.
6. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , the compound being one among the following group:
5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic acid,
5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid,
5-[({4-[4-(2-cyclohexylethoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid,
5-[({4-[(E)-2-phenylvinyl]piperidin-1-yl}carbonyl)oxy]nicotinic acid,
5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidin-4-yl]propyl}piperidin-1-yl)carbonyl]oxy}nicotinic acid, and
5-(methoxycarbonyl)pyridin-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate.
7. A pharmaceutical composition comprising the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt of claim 1 as an active ingredient thereof.
8. A method for treating urinary frequency, urinary incontinence and/or overactive bladder, comprising administering a therapeutically effective amount of the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of claim 1 or its pharmaceutically acceptable salt to a patient.
9. A method for treating pain, comprising administering a therapeutically effective amount of the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of claim 1 or its pharmaceutically acceptable salt to a patient.
10. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the compound is 5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic acid.
11. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the compound is 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid.
12. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the compound is 5-[({4-[4-(2-cyclohexylethoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid.
13. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the compound is 54({4-[(E)-2-phenylvinyl]piperidin-1-yl}carbonyl)oxy]nicotinic acid.
14. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the compound is 5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidin-4-yl]propyl}piperidin-1-yl)carbonyl]oxy}nicotinic acid.
15. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1 , wherein the compound is 5-(methoxycarbonyl)pyridin-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate.