Nitrogen containing heterocyclic compounds and medicines containing the same
Compounds represented by the following general formula: [wherein X 1 , X 2 , X 3 and X 4 each independently represent a single bond, C 1-6 alkylene, etc.; A 2 represents optionally substituted phenyl, etc.; A 1 represents an optionally substituted 5- to 7-membered heterocyclic group containing —C(=Q 1 )- (wherein Q 1 represents oxygen, sulfur or ═N—R 11 (wherein R 11 represents hydrogen or C 1-6 alkyl)) and nitrogen, etc.; and Z 1 represents piperidin-diyl, etc.], salts thereof and hydrates of the foregoing.
1. A compound represented by the following formula:
a salt or hydrate thereof, wherein:
X 2 represents methylene, 1,2-ethylene or 1,1-ethylene;
—X 3 —X 4 — represents methylene, oxygen, a single bond or a group represented by the formula:
wherein X 40 is (1) methylene having between 0 and 2 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)— or (6) —S(O) 2 —;
X 41 is methylene having 0, 1, or 2 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano;
R 34 represents C 1-6 alkyl;
R 41 represents (1) phenyl having between 0 and 2 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, (2) phenyl-C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano or (3) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, and cyano; and
R 42 represents (1) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, and cyano or (2) hydrogen;
Z 1 represents azetidine-diyl, pyrrolidine-diyl, azepane-diyl, piperazine-diyl, or a group represented by the formula:
wherein Z 1 is substituted with 0-3 groups selected from the group consisting of (1) hydrogen, (2) halogen, (3) cyano, (4) hydroxyl, (5) C 2-7 alkoxycarbonyl, (6) C 1-6 alkyl having 0-4 substituents selected from the group consisting of hydroxyl, C 1-6 alkoxy and halogen, (7) C 1-6 alkoxy having 0-4 substituents selected from the group consisting of hydroxyl, C 1-6 alkoxy and halogen, (8) 2-methylphenyloxymethyl and (9) 2-fluorophenyloxymethyl;
A 2 represents phenyl, 1-naphthyl, 2-naphthyl, an aromatic ring having 5 to 10 atoms in the ring and containing one or more heteroatoms among the atoms of the ring, or a 9- to 11-membered benzene fused ring group,
wherein A 2 is substituted with 0-3 groups selected from the group consisting of (1) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, (2) C 1-6 alkoxy having 0-3 substituents selected from the group consisting of halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, (3) halogen, (4) C 3-8 cycloalkyl, (5) C 2-7 alkoxycarbonyl, (6) C 2-7 acyl, (7) C 1-6 alkylthio, (8) C 1-6 alkylsulfinyl, (9) C 1-6 alkylsulfonyl, (10) cyano, (11) nitro, (12) phenyl, (13) pyridyl, (14) ethylenedioxy, (15) methylenedioxy, (16) a group represented by the formula:
wherein t1 and t2 each independently represents zero or an integer from 1 to 3, and R 80 represents hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl,
and (17) a group represented by the formula:
wherein R 73 and R 74 each independently represents hydrogen, C 1-6 alkyl, C 2-7 acyl, C 1-6 alkylsulfonyl, —CO—NR 75 R 76 or —CS—NR 75 R 76 , and R 75 and R 76 each independently represents hydrogen or C 1-6 alkyl; and
wherein A 1 represents a group represented by the formula:
wherein R 21 represents hydrogen or C 1-6 alkyl, and R 61a and R 62a each independently represents hydrogen, halogen, C 1-6 alkoxy, C 1-6 alkyl or cyano.
2. A compound represented by the following formula:
a salt or hydrate thereof, wherein:
X 2 represents methylene, 1,2-ethylene or 1,1-ethylene;
—X 3 —X 4 — represents methylene, oxygen, a single bond or a group represented by the formula:
wherein X 40 is (1) methylene having between 0 and 2 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)— or (6) —S(O) 2 —;
X 41 is methylene having 0, 1, or 2 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano;
R 34 represents C 1-6 alkyl;
R 41 represents (1) phenyl having between 0 and 2 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, (2) phenyl-C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano or (3) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, and cyano; and
R 42 represents (1) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, and cyano or (2) hydrogen;
Z 1 represents azetidine-diyl, pyrrolidine-diyl, azepane-diyl, piperazine-diyl, or a group represented by the formula:
wherein Z 1 is substituted with 0-3 groups selected from the group consisting of (1) hydrogen, (2) halogen, (3) cyano, (4) hydroxyl, (5) C 2-7 alkoxycarbonyl, (6) C 1-6 alkyl having 0-4 substituents selected from the group consisting of hydroxyl, C 1-6 alkoxy and halogen, (7) C 1-6 alkoxy having 0-4 substituents selected from the group consisting of hydroxyl, C 1-6 alkoxy and halogen, (8) 2-methylphenyloxymethyl and (9) 2-fluorophenyloxymethyl;
A 2 represents a monovalent group derived by removing a hydrogen atom from a compound represented by the formula:
wherein A 2 is substituted with 0-3 groups selected from the group consisting of (1) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, (2) C 1-6 alkoxy having 0-3 substituents selected from the group consisting of halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, (3) halogen, (4) C 3-8 cycloalkyl, (5) C 2-7 alkoxycarbonyl, (6) C 2-7 acyl, (7) C 1-6 alkylthio, (8) C 1-6 alkylsulfinyl, (9) C 1-6 alkylsulfonyl, (10) cyano, (11) nitro, (12) phenyl, (13) pyridyl, (14) ethylenedioxy, (15) methylenedioxy, (16) a group represented by the formula:
wherein t1 and t2 each independently represents zero or an integer from 1 to 3, and R 80 represents hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl,
and (17) a group represented by the formula:
wherein R 73 and R 74 each independently represents hydrogen, C 1-6 alkyl, C 2-7 acyl, C 1-6 alkylsulfonyl, —CO—NR 75 R 76 or —CS—NR 75 R 76 , and R 75 and R 76 each independently represents hydrogen or C 1-6 alkyl; and
A 1 represents a group represented by the formula:
wherein R 21 represents hydrogen or C 1-6 alkyl, and R 61a and R 62a each independently represents hydrogen, halogen, C 1-6 alkoxy, C 1-6 alkyl or cyano.
3. The compound according to claim 1 , wherein —X 3 —X 4 — is a group represented by the formula:
wherein X 42 represents (1) methylene having 0 or 1 substituent selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)—, (6) —S(O) 2 — or (7) —CF 2 —; and
X 43 represents either methylene having 0 or 1 substituent selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, or —CF 2 —.
4. The compound according to claim 1 , wherein —X 3 —X 4 — is a group represented by the formula:
wherein X 45 represents either methylene having 0 or 1 substituent selected from the group consisting of fluorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and cyano, or —CF 2 —.
5. The compound according to claim 1 , wherein —X 3 —X 4 — is
6. The compound according to claim 1 , wherein A 2 is a monovalent group derived by removing a hydrogen atom from a compound represented by the formula:
and wherein A 2 is substituted with 0-3 groups selected from (1) C 1-6 alkyl having 0-3 substituents selected from the group consisting of halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, (2) C 1-6 alkoxy having 0-3 substituents selected from the group consisting of halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, (3) halogen, (4) C 3-8 cycloalkyl, (5) C 2-7 alkoxycarbonyl, (6) C 2-7 acyl, (7) C 1-6 alkylthio, (8) C 1-6 alkylsulfinyl, (9) C 1-6 alkylsulfonyl, (10) cyano, (11) nitro, (12) phenyl, (13) pyridyl, (14) ethylenedioxy, (15) methylenedioxy, (16) a group represented by the formula:
wherein t1 and t2 each independently represents zero or an integer from 1 to 3, and R 80 represents hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl,
and (17) a group represented by the formula:
wherein R 73 and R 74 each independently represents hydrogen, C 1-6 alkyl, C 2-7 acyl, C 1-6 alkylsulfonyl, —CO—NR 75 R 76 or —CS—NR 75 R 76 , and R 75 and R 76 each independently represents hydrogen or C 1-6 alkyl.
7. A compound according to claim 1 , wherein A 2 is substituted with 0-3 groups selected from the group consisting of halogen, C 1-6 alkyl having 0-3 substituents selected from halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, C 1-6 alkoxy having 0-3 substituents selected from halogen, C 1-6 alkoxy, cyano, hydroxyl and C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkylthio and a group represented by the formula:
wherein t1 and t2 each independently represents zero or an integer from 1 to 3, and R 80 represents hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl.
8. The compound according to claim 1 , wherein A is a group represented by the formula
wherein R 81 represents (1) C 1-6 alkyl having 1-3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl and C 1-6 alkoxy, (2) C 1-6 alkoxy having 0-3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl and C 1-6 alkoxy, (3) hydrogen, (4) C 1-6 alkylthio having 0-3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl and C 1-6 alkoxy or (5) halogen.
9. The compound according to claim 1 , wherein A 2 is a group represented by the formula:
10. The compound according to claim 1 , wherein R 21 is hydrogen.
11. The compound according to claim 1 , wherein R 61a and R 62a are both hydrogen.
12. A method for treating neuralgia, comprising administering to a patient a pharmacologically effective dose of a compound according to claim 1 .
13. A method for treating diabetic neuralgia, HIV neuralgia, postherpetic neuralgia, trigeminal neuralgia, stump pain, post spinal injury pain, thalamic pain or post-stroke pain, comprising administering to a patient a pharmacologically effective dose of a compound according to claim 1 .
14. A method for treating low back pain, inflammatory pain, arthralgia, postoperative pain or cancer pain comprising administering to a patient a pharmacologically effective dose of a compound according to claim 1 .
15. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.