Condensed benzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity
To provide a compound having an excellent inhibitory effect on vanilloid receptor subtype 1 (VR1) activity which is effective in treating diseases to which the vanilloid receptor subtype 1 (VR1) activity is involved, such as pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, etc. and a pharmaceutical composition containing the compound. The object has been attained by a condensed benzamide compound represented by the following formula (the symbols in the formula have the same meanings defined in the specification) or its salt:
1. A condensed benzamide compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof:
[wherein Z is
(1) —O—,
(2) —NR 5 — (wherein R 5 is a hydrogen atom or a C1-6 alkyl group),
(3) —S—,
(4) —SO— or
(5) —SO 2 —;
1 is 0, 1 or 2;
m is 0, 1 or 2;
R 1 is
(1) a hydrogen atom or
(2) a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the following Group A:
Group A:
(a) a halogen atom,
(b) a hydroxyl group,
(c) a C1-6 alkoxy group,
(d) a carboxyl group,
(e) a C1-6 alkoxycarbonyl group,
(f) —CONR 6 R 7 (wherein R 6 and R 7 are the same or different and each represents a hydrogen atom, a C1-6 alkyl group or an acyl group and said alkyl group may be substituted with a hydroxyl group or an acyloxy group),
(g) —NR 6 R 7 (wherein R 6 and R 7 are the same as above),
(h) —NR 6 COR 7 (wherein R 6 and R 7 are the same as above),
(i) —NR 8 CONR 6 R 7 (wherein R 6 and R 7 are the same as above, and R 8 is a hydrogen atom or a C1-6 alkyl group); and
(j) —NR 6 SO 2 R 9 (wherein R 6 is the same as above, and R 9 is a C1-6 alkyl group);
R 2 is
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A (wherein the Group A is the same as above),
(4) a carboxyl group,
(5) a C1-6 alkoxycarbonyl group or
(6) —CONR 10 R 11 (wherein R 10 and R 11 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group); or R 2 together with R 1 forms ═O;
R 3 is
(1) a hydrogen atom, or
(2) a C1-6 alkyl group;
R 4 is
(1) a hydrogen atom,
(2) a halogen atom
(3) a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the following Group B,
(4) a C1-6 alkoxy group which may be substituted with 1 to 5 substituents selected from the following Group B,
(5) a cycloalkyl group which may be substituted with 1 to 5 substituents selected from the following Group B,
(6) an aralkyl group which may be substituted with 1 to 5 substituents selected from the following Group B,
(7) an aralkoxy group which may be substituted with 1 to 5 substituents selected from the following Group B, or
(8) a cycloalkylalkoxy group which may be substituted with 1 to 5 substituents selected from the following Group B,
Group B:
(a) a halogen atom,
(b) a halo C1-6 alkyl group,
(c) a hydroxyl group,
(d) a halo C1-6 alkoxy group,
(e) a C1-6 alkoxycarbonyl group,
(f) a C1-6 alkoxy group,
(g) a carboxyl group,
(h) —CONR 12 R 13 (wherein R 12 and R 13 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group);
(i) —NR 12 R 13 (wherein R 12 and R 13 are the same as above),
(j) —NR 12 COR 13 (wherein R 12 and R 13 are the same as above),
(k) —NR 14 CONR 12 R 13 (wherein R 12 and R 13 are the same as above, and R 14 is a hydrogen atom or a C1-6 alkyl group),
(l) —SO 2 R 15 (wherein R 15 is a C1-6 alkyl group), and
(m) —NR 12 SO 2 R 15 (wherein R 12 and R 15 are the same as above);
(9) a hydroxyl group,
(10) —NR 16 R 17 (wherein R 16 and R 17 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group)
(11) —COR 18 (wherein R 18 is a C1-6 alkyl group, a C1-6 alkoxy group, a cycloalkyl group, an aralkyl group, an aralkoxy group, a cycloalkylalkoxy group or a hydroxyl group),
(12) —CONR 16 R 17 (wherein R 16 and R 17 are the same as above),
(13) —NR 19 CONR 16 R 17 (wherein R 16 and R 17 are the same as above, and R 19 is a hydrogen atom or a C1-6 alkyl group),
(14) —NR 16 COOR 20 (wherein R 16 is the same as above, and R 20 is a C1-6 alkyl group or a cycloalkyl group),
(15) —SR 20 (wherein R 20 is the same as above),
(16) —SOR 20 (wherein R 20 is the same as above),
(17) —SO 2 R 20 (wherein R 20 is the same as above),
(18) —SO 2 NR 16 R 17 (wherein R 16 and R 17 are the same as above) or
(19) —NR 16 COR 18 (wherein R 16 and R 18 are the same as above);
V is
(1) a single bond or
(2) —(CR 21 R 22 ) n — (wherein R 21 and R 22 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group, and n is 1 or 2);
P1 and P2 rings are the same or different and each represents
(1) a carbocyclic group which may be substituted with 1 to 5 substituents selected from the following group C or
(2) a heterocyclic group which may be substituted with 1 to 5 substituents selected from the following group
Group C:
(a) a halogen atom,
(b) a hydroxyl group,
(c) a C1-6 alkoxy group which may be substituted with 1 to 5 substituents selected from the Group A,
(d) an C1-6 alkylthio group,
(e) a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A,
(f) —CONR 23 R 24 (wherein R 23 and R 24 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A),
(g) —NR 123 R 124 (wherein R 123 and R 124 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A),
(h) —NR 223 COR 224 (wherein R 223 and R 224 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A),
(i) —NR 25 CONR 323 R 324 (wherein R 323 and R 324 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A),
(j) —SR 26 (wherein R 26 is a C1-6 alkyl group),
(k) —SOR 126 (wherein R 126 is a C1-6 alkyl group),
(l) —SO 2 R 226 (wherein R 226 is a C1-6 alkyl group),
(m) —NR 423 SO 2 R 326 (wherein R 423 is a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A, and R 326 is a C1-6 alkyl group),
(n) —SO 2 NR 523 R 524 (wherein R 523 and R 524 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A),
(o) —COR 27 (wherein R 27 is a C1-6 alkyl group, C1-6 alkoxy group, a cycloalkyl group, an aralkyl group, an aralkoxy group, a cycloalkylalkoxy group or a hydroxyl group),
(p) a carbocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (o) of the Group C,
(q) a heterocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (o) of the Group C,
(r) —O—R 28 (wherein R 28 is an acyl group, a carbocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (o) of the Group C or a heterocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (o) of the Group C),
(s) —O—(CR 121 R 122 ) n —R 128 (wherein R 121 and R 122 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group, n is 1 or 2, and R 128 is an acyl group, a carbocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (i) of the Group C or a heterocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (l) of the Group C),
(t) a nitro group, and
(u) a cyano group.
2. The condensed benzamide compound or pharmaceutically acceptable salt thereof according to claim 1 wherein Z is —O—, —NR 5 —, —S— or —SO—.
3. The condensed benzamide compound or pharmaceutically acceptable salt thereof according to claim 1 wherein R 3 is a hydrogen atom or a C1-4 alkyl group.
4. The condensed benzamide compound or pharmaceutically acceptable salt thereof according to claim 1 wherein the P1 ring is a saturated or unsaturated 5-membered or 6-membered heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a condensed ring of these heterocyclic rings, or a condensed heterocyclic ring of said heterocyclic ring and a carbocyclic ring selected from benzene, cyclopentane and cyclohexane, or a phenyl group (wherein said heterocyclic ring may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A, and a C1-6 alkoxy group which may be substituted with 1 to 5 substituents selected from the Group A).
5. The condensed benzamide compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein the P2 ring is a carbocyclic group which may be substituted with a substituent group selected from the group consisting of
a halogen atom,
a hydroxyl group,
a C1-6 alkoxy group (wherein said alkoxy group may be substituted with a halogen atom, —CONR 623 R 624 (wherein R 623 and R 624 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A), a C3-8 cycloalkyl group, a C1-6 alkoxy group, a carboxyl group or a C1-6 alkoxycarbonyl group),
a C1-6 alkyl group (wherein said alkyl group may be substituted with a halogen atom, a hydroxyl group or a C1-6 alkoxy group),
—NR 123 R 124 (wherein R 123 and R 124 are the same as above),
—NR 223 COR 224 (wherein R 223 and R 224 are the same as above),
—COR 27 (wherein R 27 is a C1-6 alkyl group, C1-6 alkoxy group, a cycloalkyl group, an aralkyl group, an aralkoxy group, a cycloalkylalkoxy group or a hydroxyl group),
—CONR 23 R 24 (wherein R 23 and R 24 are the same as above),
a heterocyclic group as a saturated or unsaturated substituent group which has 1 to 3 nitrogen atoms as hetero atoms (wherein said heterocyclic group may be substituted with a substituent group selected from a hydroxyl group, —CONR 723 R 724 (wherein R 723 and R 724 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group which may be substituted with 1 to 5 substituents selected from the Group A), a C1-6 alkoxy group, a carboxyl group, a C1-6 alkyl group which may be substituted with a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group and an acyloxy group),
—O—R 28 (wherein R 28 is an acyl group, a carbocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (i) of the Group C or a heterocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (l) of the Group C),
—O—(CR 121 R 122 ) n —R 128 (wherein R 121 and R 122 are the same or different and each represents a hydrogen atom or a C1-6 alkyl group, n is 1 or 2, and R 128 is an acyl group, a carbocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (i) of the Group C or a heterocyclic group which may be substituted with 1 to 5 substituents selected from (a) to (l) of the Group C),
a nitro group and
a cyano group, and
a heterocyclic group which may be substituted with a substituent as described for the carbocyclic group (wherein said heterocyclic group means a saturated or unsaturated 5-membered or 6-membered heterocyclic ring which has 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a condensed ring of these heterocyclic rings, or a condensed heterocyclic group of said heterocyclic ring and a carbocyclic ring selected from benzene, cyclopentane and cyclohexane).
6. A pharmaceutical composition comprising a condensed benzamide compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.