Otake, Norikazu (Tsukuba-shi, JP)
Moriya, Minoru (Tsukuba-shi, JP)
Ogino, Yoshio (Tsukuba-shi, JP)
Matsuda, Kenji (Tokyo, JP)
Nagae, Yoshikazu (Tsukuba-shi, JP)
Kanatani, Akio (Tsukuba-shi, JP)
Fukami, Takehiro (Tsukuba-shi, JP)

Plaque It!

10/463390

03/18/2004

06/18/2003

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544/230

546/18, 548/300.700

(IPC1-7): C07D497/14; C07D487/10; C07D487/14

WENDEROTH, LIND & PONACK, L.L.P. (2033 K STREET N. W., WASHINGTON, DC, 20006-1021, US)

1. A compound of the formula (I), 33 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; n is 0 or 1; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (I) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded), and a salt, ester or N-oxide derivative thereof.

2. The compound as claimed in claim 1, wherein n is 0, X is —N(SO₂R⁴)— or —N(COR⁵)— and Y is —C(R⁶)(R⁷)—, or X is —CO— and Y is —O— or —N(R⁸)—.

3. The compound as claimed in claim 1, wherein T, U, V and W are independently methine optionally substituted by halogen, lower alkyl, hydroxy or lower alkoxy.

4. The compound as claimed in claim 1, wherein at least one of T, U, V and W is nitrogen.

5. The compound as claimed in claim 1, wherein one of T, U, V and W is nitrogen, and one of the remainder is methine optionally substituted by halogen, lower alkyl, hydroxy or lower alkoxy.

6. The compound as claimed in claim 1, wherein X is —CO— and Y is —O— or —NH—.

7. The compound as claimed in claim 1, wherein X is —CO— and Y is —O—.

8. The compound of the formula (I-a) as claimed in claim 1, 34 wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; R⁴ is hydrogen, lower alkyl, aralkyl or aryl.

9. The compound of the formula (I-b) as claimed in claim 1, 35 wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R⁰ is hydrogen or hydroxy; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group.

10. The compound as claimed in claim 9, wherein each of T, U, V and W is unsubstituted methine.

11. The compound as claimed in claim 9, wherein one of T, U, V and W is nitrogen.

12. The compound as claimed in claim 9, wherein one of T, U, V and W is nitrogen, and one of the remainder is methine having a substituent selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy.

13. The compound as claimed in claim 9, wherein one of T, U, V and W is nitrogen, and one of the remainder is methine having a substituent selected from the group consisting of fluorine and hydroxy.

14. The compound of the formula (I-c) as claimed in claim 1, 36 wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methane or hydroxy substituted methine; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; and R³ is hydrogen or lower alkyl.

15. The compound as claimed in any one of claims 1, 8, 9, 10, 11, 12, 13 and 14, wherein Ar¹ is phenyl which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar².

16. The compound as claimed in any one of claims 1, 8, 9, 10, 11, 12, 13 and 14, wherein Ar¹ is heteroaryl which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar².

17. The compound as claimed in claim 16, wherein the heteroaryl is pyridyl.

18. The compound as claimed in claim 1, which is selected from the group consisting of 2-[1-methylsulfonylspiro[indoline-3,4′-piperidin]-1′-yl]-5-chlorobenzimidazole, 5,6-dichloro-2-[1-methylsulfonylspiro[indoline-3,4′-piperidin]-1′-yl]benzimidazole, 5-chloro-2-[1-ethylsulfonylspiro[indoline-3,4′-piperidin]-1′-yl]benzimidazole, trans-5-chloro-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-(trifluoromethyl)benzimidazole, trans-5-(4-fluorophenyl)-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]benzimidazole, trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-phenylbenzimidazole, trans-5-(3-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole, trans-5-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole, trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-5-(2-pyridyl)imidazo[4,5-b]pyridine, trans-2-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-6-(2-pyridyl)imidazo[4,5-b]pyridine, trans-5-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]imidazo[4,5-b]pyridine, trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-6-phenylimidazo[4,5-c]pyridine, trans-6-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]imidazo[4,5-c]pyridine, trans-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-5-phenylimidazo[4,5-b]pyrazine, trans-5-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]imidazo[4,5-b]pyrazine, trans-6-(4-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]imidazo[4,5-c]pyridazine, trans-2-(2-fluorophenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(3-fluorophenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(4-fluorophenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2-methoxyphenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(4-methoxyphenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2-methylphenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]--4-yl]-2-(2-trifluoromethylphenyl)purine, trans-2-(2-chloro-4-fluorophenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2-hydroxymethylphenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2-furyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2-(2-thienyl)purine, trans-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]--4-yl]-2-(2-pyrrolyl)purine, trans-2-(3-fluoropyridin-6-yl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2-chloropyridin-6-yl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2-fluorophenoxy)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-2-(2,6-difluorophenoxy)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine, trans-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2-(1-piperidyl)purine, trans-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenylpurine, trans-2-(2-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(3-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(4-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2-chlorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(3-chlorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(4-chlorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2-chloro-4-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(4-methoxyphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2-methylphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2-difluoromethoxyphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(3-difluoromethoxyphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-(2-trifluoromethylphenyl)purine, trans-2-(2,4-difluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2,5-difluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2-bromo-4-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(4-chloro-2-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-(3-quinolyl)purine, trans-8-[5-fluoro-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-phenylpurine, trans-8-[5-fluoro-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-(2-fluorophenyl)purine, trans-2-(2,4-difluorophenyl)-8-[5-fluoro-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(2,5-difluorophenyl)-8-[5-fluoro-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, trans-2-(4-fluorophenyl)-8-[7-hydroxy-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine, 5,6-dichloro-2-[3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidin]-1′-yl]benzimidazole, 2-[3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidin]-1′-yl]-5-phenylbenzimidazole, 8-[3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidin]-1′-yl]-2-phenylpurine, 8-[3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidin]-1′-yl]-2-(2-fluorophenyl)purine, 8-[3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidin]-1′-yl]-2-(4-fluorophenyl)purine, trans-8-[3′,4′-dihydro-3′-oxospiro[cyclohexane-1,1′(2′H)-isoquinolin]-4-yl]-2-phenylpurine, trans-2-[3′,4′-dihydro-3′-oxospiro[cyclohexane-1,1′(2′H)-isoquinolin]-4-yl]-5-phenylbenzimidazole, trans-8-[3′,4′-dihydro-3′-oxospiro[cyclohexane-1,1′(2′H)-isoquinolin]-4-yl]-2-(2-fluorophenyl)purine, trans-8-[3′,4′-dihydro-3′-oxospiro[cyclohexane-1,1′(2′H)-isoquinolin]-4-yl]-2-(4-fluorophenyl)purine, trans-2-(4-fluorophenyl)-8-[7-hydroxy-3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine, trans-2-(4-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine 6-oxide, trans-2-(4-fluoro-2-hydroxyphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine, trans-2-(4-fluorophenyl)-6-hydroxy-8-[3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine, trans-2-(4-hydroxyphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine, trans-2-(4-fluoro-3-hydroxyphenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine, and cis-2-(4-fluorophenyl)-8-[4′-hydroxy-3-oxospiro[6-azaisobenzofuran-1(3H), 1′-cyclohexan]-4′-yl]purine.

19. The compound of claim 1, which is trans-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]-2-phenylpurine.

20. The compound of claim 1, which is trans-2-(2-fluorophenyl)-8-[3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-yl]purine.

21. The compound of claim 1, which is trans-2-(4-fluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine.

22. The compound of claim 1, which is trans-2-(2,5-difluorophenyl)-8-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]purine.

23. The compound of claim 1, which is trans-8-[5-fluoro-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-2-(2-fluorophenyl)purine.

24. The compound of claim 1, which is trans-5-(2-fluorophenyl)-2-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]imidazo[4,5-b]pyridine.

25. A process for preparing a compound of the formula (I-1): 37 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; and n, R³, X and Y have each the same meaning as defined below), or a salt, ester or N-oxide derivative thereof, which comprises reacting a compound of the formula (II): 38 (wherein a, b, c and d are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R^1p)R^2p, -Q^1pAr^1p and optionally protected hydroxy, and at least one of a, b, c and d is said methine group; Ar^1p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino, -Q^2p-Ar^2p, optionally protected hydroxy, optionally protected hydroxy-lower alkyl and optionally protected carboxyl; Ar^2p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, aryl, optionally protected hydroxy-lower alkyl and optionally protected hydroxy; L¹ is a leaving group; P is an imino-protecting group; Q^1p and Q^2p are independently a single bond, oxygen, optionally protected carbonyl or —N(R³)—; R^1p and R^2p are independently an amino-protecting group, an imino-protecting group, hydrogen or lower alkyl, or R^1p and R^2p, taken together, form lower alkylene which may be intervened by oxygen, sulfur or optionally protected imino; and R³ is hydrogen or lower alkyl) with a compound of the formula (III) or its salt: 39 (wherein n is 0 or 1; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; t, u, v and w are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy and optionally protected hydroxy, and at least two of t, u, v and w are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (III) when n is 0, X is —CO— and Y is —O— is excluded), and optionally removing the protecting group(s) from the resulting compound of the formula (IV-1): 40 (wherein a, b, c, d, n, P, t, u, v, w, X and Y have each the same meaning as defined above) and/or oxidizing nitrogen atom(s) of the compound (IV-1).

26. A process for preparing a compound of the formula (I-2): 41 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R⁰ is hydrogen or hydroxy; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; n, R³, X and Y have each the same meaning as defined below) or a salt, ester or N-oxide derivative thereof, which comprises reacting a compound of the formula (V): 42 (wherein a, b, c and d are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R^1p)R^2p, -Q^1p-Ar^1p and optionally protected hydroxy, and at least one of a, b, c and d is said methine group; Ar^1p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino, -Q^2p-Ar^2p, optionally protected hydroxy, optionally protected hydroxy-lower alkyl and optionally protected carboxyl; Ar^2p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, aryl, optionally protected hydroxy-lower alkyl and optionally protected hydroxy; Q^1p and Q^2p are independently a single bond, oxygen, optionally protected carbonyl or —N(R³)—; R^1p and R^2p are independently an amino-protecting group, an imino-protecting group, hydrogen or lower alkyl, or R^1p and R^2p, taken together, form lower alkylene which may be intervened by oxygen, sulfur or optionally protected imino; and R³ is hydrogen or lower alkyl) or its salt with a compound of the formula (VI): 43 (wherein n is 0 or 1; R^0p is hydrogen or optionally protected hydroxy; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, loweralkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; t, u, v and w are independently methine or nitrogen, the said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy and optionally protected hydroxy, and at least two of t, u, v and w are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—) or its salt, subjecting the resulting compound of the formula (VII): 44 (wherein a, b, c, d, n, R^0p, t, u, v, w, X and Y have each the same meaning as defined above) to intramolecular dehydrative ring closure to give a compound of the formula (VIII): 45 (wherein a, b, c, d, n, R^0p, t, u, v, w, X and Y have each the same meaning as defined above), and optionally removing the protecting group(s) from the compound (VIII) and/or oxidizing nitrogen atom(s) of the compound (VIII).

27. A process for preparing a compound of the formula (I-2): 46 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoylamino and aryl; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R⁰ is hydrogen or hydroxy; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; T, U, V and W are independently methine or nitrogen, the said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; n, R³, X and Y have each the same meaning as defined below) or a salt, ester or N-oxide derivative thereof, which comprises reacting a compound of the formula (V): 47 (wherein a, b, c and d are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R^1p)R^2p, -Q^1p-Ar^1p and optionally protected hydroxy, and at least one of a, b, c and d is said methine group; Ar^1p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino, -Q^2p-Ar^2p, optionally protected hydroxy, optionally protected hydroxy-lower alkyl and optionally protected carboxyl; Ar^2p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, aryl, optionally protected hydroxy-lower alkyl and optionally protected hydroxy; Q^1p and Q^2p are independently a single bond, oxygen, optionally protected carbonyl or —N(R³)—; R^1p and R^2p are independently an amino-protecting group, an imino-protecting group, hydrogen or lower alkyl, or R^1p and R^2p, taken together, form lower alkylene which may be intervened by oxygen, sulfur or optionally protected imino; R³ is hydrogen or lower alkyl) or its salt with a compound of the formula (IX): 48 (wherein n is 0 or 1; R^0p is hydrogen or optionally protected hydroxy R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; t, u, v and w are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, and optionally protected hydroxy, and at least two of t, u, v and w are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—), or its salt, and optionally removing the protecting group(s) from the resulting compound of the formula (VIII): 49 (wherein a, b, c, d, n, R^0p, t, u, v, w, X and Y have each the same meaning as defined above) and/or oxidizing nitrogen atom(s) of the compound (VIII).

28. A process for preparing a compound of the formula (I-3): 50 (wherein A¹, B¹, C¹ and D¹ are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Ar¹, and at least one of A¹, B¹, C¹ and D¹ is said methine having a group represented by -Ar¹; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; Q² is a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine; n, R³, X and Y have each the same meaning as defined below), or a salt, ester or N-oxide derivative thereof, which comprises reacting a compound of the formula (X): 51 (wherein a⁰, b⁰, c⁰ and d⁰ are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R^1p)R^2p and optionally protected hydroxy, and at least one of a⁰, b⁰, c⁰ and d⁰ is said methine group having halogen atom or trifluoromethanesulfonyloxy group; EP is nitrogen, methine or methine substituted by optionally protected hydroxy; n is 0 or 1; P is an imino-protecting group; R^1p and R^2p are independently an amino-protecting group, an imino-protecting group, hydrogen or lower alkyl, or R^1p and R^2p, taken together, form lower alkylene which may be intervened by oxygen, sulfur or optionally protected imino; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, loweralkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; t, u, v and w are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy and optionally protected hydroxy, and at least two of t, u, v and w are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (X) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded) with a compound of the formula (XI): Met-Ar^1p (XI) (wherein Ar^1p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, lower alkyl, halo-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino, -Q^2p-Ar^2p, optionally protected hydroxy, optionally protected hydroxy-lower alkyl and optionally protected carboxyl; Ar^2p is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, aryl, optionally protected hydroxy-loweralkyl and optionally protected hydroxy; Q^2p is a single bond, oxygen, optionally protected carbonyl or —N(R³)—; R³ is hydrogen or lower alkyl; Met is a common organometallic atom) in the presence of a catalyst, and optionally removing the protecting group(s) from the resulting compound of the formula (XII): 52 (wherein a¹, b¹, c¹ and d¹ are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-loweralkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R^1p)R^2p, —Ar^1p and optionally protected hydroxy, and at least one of a¹, b^l, c¹ and d¹ is said methine having a group represented by -Ar^1p; Ar^1p, E^p, n, P, R^1p, R^2p, t, u, v, w, X and Y have each the same meaning as defined above) and/or oxidizing nitrogen atom(s) of the compound (XII).

29. A neuropeptide Y receptor antagonist agent comprising a compound of the formula (I): 53 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; n is 0 or 1; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (I) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded), or a salt, ester or N-oxide derivative thereof as an active ingredient.

30. An agent for treatment of bulimia, obesity or diabetes, comprising a compound of the formula (I): 54 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; n is 0 or 1; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (I) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded), or a salt, ester or N-oxide derivative thereof as an active ingredient.

31. A method for treatment of bulimia, obesity or diabetes, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (I): 55 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; n is 0 or 1; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (I) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded), or a salt, ester or N-oxide derivative thereof.

32. Use of a compound of the formula (I): 56 (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R¹)R² and -Q¹-Ar¹, and at least one of A, B, C and D is said methine group; Ar¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q²-Ar²; Ar² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; E is nitrogen, methine or hydroxy substituted methine; n is 0 or 1; Q¹ and Q² are independently a single bond, oxygen, carbonyl or —N(R³)—; R¹ and R² are independently hydrogen or lower alkyl, or R¹ and R², taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino; R³ is hydrogen or lower alkyl; R⁴ is lower alkyl, aralkyl or aryl; R⁵ and R⁸ are independently hydrogen, lower alkyl, aralkyl or aryl; R⁶ and R⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl; T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group; X is —N(SO₂R⁴)—, —N(COR⁵)— or —CO—; Y is —C(R⁶)(R⁷)—, —O— or —N(R⁸)—, provided that the compound (I) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded), or a salt, ester or N-oxide derivative thereof for manufacturing a medicament for treatment of bulimia, obesity or diabetes.

TECHNICAL FIELD

[0001] The present invention is useful in medical fields. In more detail, novel benzimidazole derivatives of the present invention have an effect as neuropeptide Y receptor antagonists and are useful as agents for the treatment of various kinds of cardiovascular disorders, central nervous system disorders, metabolic diseases and the like.

BACKGROUND ART

[0002] Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of 36 amino acids, was first isolated from porcine brain by Tatemoto et al in 1982 (NATURE, vol. 296, p. 659(1982)). NPY is widely distributed in central nervous system and peripheral nervous system, and plays various roles as one of the most abundant peptides in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the mediation of secretion of various hormones or the action of the nervous system. It is known that continuous intracerebroventricular administration of NPY induces obesity and insulin resistance due to these actions (INTERNATIONAL JOUNAL OF OBESITY, vol.19, p.517(1995); Endocrinology, vol.133, p.1753(1993)). It is also known that NPY has central actions such as depression, anxiety, schizophrenia, pain, dementia, circadian rhythm control and the like (DRUGS, vol.52, p.371(1996); THE JOURNAL OF NEUROSCIENCE, vol.18, p.3014(1998)). Furthermore, in the periphery, NPY coexists with norepinephrine in sympathetic-nerve terminals and is related to the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the activities of other vasoconstrictive substances such as norepinephrine (BRITISH JOURNAL OF PHARMACOLOGY, vol.95, p.419(1988)). It is also reported that NPY could participate in the development of cardiac hypertrophy as a result of the sympathetic stimulation (PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol.97, p.1595(2000)).

[0003] On the other hand, it is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual behavior and reproductive function, gastro-intestinal motility, bronchoconstriction, inflammation and alcohol preference (LIFE SCIENCE, vol.55, p.551(1994); THE JOURNAL OF ALLERGY AND IMMUNOLOGY, vol.101, p.S345(1998); NATURE, vol.396, p.366(1998)).

[0004] NPY has a variety of pharmacological effects resulting from NPY binding to the NPY receptors, to some of which other NPY related peptides including peptide YY and pancreatic polypeptide also bind. It is known that these pharmacological effects of NPY are mediated by the action of at least five receptors with or without synergistic interactions (TRENDS IN NEUROSCIENCE, vol.20, p.294(1997)).

[0005] It is reported that the central effects mediated by NPY Y1 receptor include remarkable orexigenic effect (ENDOCRINOLOGY, vol.137, p.3177(1996); ENDOCRINOLOGY, vol.141, p.1011(2000)). Further, NPY Y1 receptor is reported to be involved in anxiety and pain (NATURE, vol.259, p.528(1993); BRAIN RESEARCH, vol.859, p.361(2000). In addition, the pressor effect mediated by the strong vasoconstrictor action in the periphery is also reported (FEBS LETTERS, vol.362, p.192(1995); NATURE MEDICINE, vol.4, p.722(1998)).

[0006] It is known that the effects mediated by NPY Y2 receptor include an inhibitory effect on the release of various neurotransmitters in the sympathetic nerve endings (BRITISH JOURNAL OF PHARMACOLOGY, vol.102, p.41(1991); SYNAPSE, vol.2, p.299(1988)). In periphery, NPY Y2 causes constriction of blood vessel or vas deferens directly or via the control of release of various neurotransmitters (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.261, p.863(1992); BRITISH JOURNAL OF PHARMACOLOGY, vol.100, p.190(1990)). Inhibition of lipolysis in adipose tissues is also known (ENDOCRINOLOGY, vol.131, p.1970(1992)). Further, inhibition of ion secretion in the gastro-intestinal tract is reported (BRITISH JOURNAL OF PHARMACOLOGY, vol.101, p.247(1990)). On the other hand, the effect on the central nervous system functions such as memory, anxiety and the like are also known. (BRAIN RESEARCH, vol.503, p.73(1989); PEPTIDES, vol.19, p.359(1998)).

[0007] It is reported that NPY Y3 receptor exists mainly in brainstem and heart and is related to the regulation of blood pressure and heart rate (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.258, p.633(1991); PEPTIDES, vol.11, p.545(1990)). It is also known that NPY Y3 is involved in the control of catecholamine secretion in adrenal gland (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.244, p.468(1988); LIFE SCIENCE, vol.50, p.PL7(1992)).

[0008] NPY Y4 receptor has high affinity for pancreatic polypeptide in particular. As for the pharmacological effects of NPY Y4, inhibition of pancreatic exocrine secretion and gastrointestinal motility is reported (GASTROENTEROLOGY, vol.85, p.1411(1983)). Further, it is reported that NPY enhances the secretion of sexual hormones in the central nervous system (ENDOCRINOLOGY, vol.140, p.5171(1999)).

[0009] As for the effects mediated by NPY Y5 receptor, fat accumulation effects including orexigenic effect are prominent (NATURE, vol. 382, p.168(1996); AMERICAN JOURNAL OF PHYSIOLOGY, vol.277, p.R1428(1999)). It is also reported that the NPY Y5 receptor mediates some CNS effects, such as seizure and epilepsy, or pain and morphine withdrawal symptoms, and the control of circadian rhythm (NATURE MEDICINE, vol.3, p.761(1997); PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol.96, p.13518(1999); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.284, p.633(1998); THE JOURNAL OF NEUROSCIENCE, vol.21, p.5367(2001). In addition, diuresis effect and hypoglicemic effect in the periphery are reported (BRITISH JOURNAL OF PHARMACOLOGY, vol. 120, p.1335(1998); ENDOCRINOLOGY, vol.139, p.3018(1998)). NPY is also reported to enhance cardiac hypertrophy as a result of the sympathetic accentuation (PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol.97, p.1595 (2000)).

[0010] The effects of NPY are expressed when NPY binds to the NPY receptors in the central or peripheral nervous system. Therefore, the action of NPY can be prevented by blocking its binding to NPY receptors. For this reason, it is expected that substances antagonize NPY binding to NPY receptors may be useful for the prophylaxis or treatment of various diseases related to NPY, for example cardiovascular disorders such as angina, acute or congestive heart failure, myocardial infarction, hypertension, nephropathy, electrolyte abnormality, vasospasm, atherosclerosis, etc., central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal, circadian rhythm disorders, schizophrenia, memory impairment, sleep disorders, cognitive impairment, etc., metabolic diseases such as obesity, diabetes, hormone abnormality, gout, fatty liver, etc., genital or reproductive disorders such as infertility, preterm labor, sexual dysfunction, etc., gastro-intestinal disorders, respiratory disorder, inflammatory diseases or glaucoma, and the like. (TRENDS IN PHARMACOLOGICAL SCIENCE, vol.15, p.153(1994); LIFE SCIENCE, vol.55, p.551(1994); DRUGS, vol.52, p.371(1996); THE JOURNAL OF ALLERGY AND IMMUNOLOGY, vol.101, p.S345(1998); NATURE, vol.396, p.366(1998); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.284, p.633(1998); TRENDS IN PHARMACOLOGICAL SCIENCE, vol.20, p.104(1999); PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol.97, p.1595(2000); THE JOURNAL OF NEUROSCIENCE, vol. 21, p.5367(2001); PHARMACOLOGY & THERAPEUTICS, vol.65, p.397(1995)).

[0011] It was recently found that, as a result of the study by the present inventors, a certain NPY receptor antagonist is useful for the prophylaxis or treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis (International application publication WO99/27965).

[0012] International application publication WO00/27845 and WO01/14376 disclose a variety of carboxamide derivatives, and mention that said derivatives have excellent NPY receptor antagonistic activities. International application publication WO02/48152 discloses a variety of spiro(isobenzofuran-1,4′-piperidine)-3-on derivatives, and mentions that said derivatives have an effect to regulate the NPY binding to NPY5 receptors. However, none of the above international publications describes the compounds of the present invention.

DISCLOSURE OF INVENTION

[0013] The object of the present invention is to provide novel medicines which exhibit NPY antagonistic activities.

[0014] The present inventors have discovered that the compounds of the general formula (I): 2

[0015] (wherein A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R ¹ )R ² and -Q ¹ -Ar ¹ , and at least one of A, B, C and D is said methine group;

[0016] Ar ¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q ² -Ar ² ;

[0017] Ar ² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl;

[0018] E is nitrogen, methine or hydroxy substituted methine (namely methine substituted by hydroxy);

[0019] n is 0 or 1;

[0020] Q ¹ and Q ² are independently a single bond, oxygen, carbonyl or —N(R ³ )—;

[0021] R ¹ and R ² are independently hydrogen or lower alkyl, or R ¹ and R ² , taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino;

[0022] R ³ is hydrogen or lower alkyl;

[0023] R ⁴ is lower alkyl, aralkyl or aryl;

[0024] R ⁵ and R ⁸ are independently hydrogen, lower alkyl, aralkyl or aryl;

[0025] R ⁶ and R ⁷ are independently hydrogen, hydroxy, lower alkyl, aralkyl or aryl;

[0026] T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group;

[0027] X is —N(SO ₂ R ⁴ )—, —N(COR ⁵ )— or —CO—;

[0028] Y is —C(R ⁶ )(R ⁷ )—, —O— or —N(R ⁸ )—, provided that the compound (I) when E is nitrogen, n is 0, X is —CO— and Y is —O— is excluded)

[0029] exhibit NPY antagonistic activities especially on NPY Y5 receptors and show excellent pharmacokinetics such as transport into brain or transport to cerebrospinal fluid, etc., thereby completed the present invention.

[0030] Compounds of the present invention (I) exhibit NPY antagonistic effects especially on NPY Y5 receptors and show excellent pharmacokinetics such as transport into brain or transport to cerebrospinal fluid, etc. Also, the compound of the present invention (I) are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders such as angina, acute or congestive heart failure, myocardial infarction, hypertension, nephropathy, electrolyte abnormality, vasospasm, arteriosclerosis, etc., central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal, circadian rhythm disorders, schizophrenia, memory impairment, sleep disorders, cognitive impairment, etc., metabolic diseases such as obesity, diabetes, hormone abnormality, hypercholesterolemia, hyperlipidemia, gout, fatty liver, etc., genital or reproductive disorders such as infertility, preterm labor, sexual dysfunction, etc., gastro-intestinal disorders, respiratory disorder, inflammatory diseases or glaucoma, and the like, also for example, atherosclerosis, hypogonadism, hyperandrogenism, polycystic ovary syndrome, hirsutism, gastro-intestinal motility disorder, obesity-related gastro-esophageal reflux, obesity hypoventilation (Pickwickian syndrome), sleep apnea, inflammation, systemic inflammation of the vasculature, osteoarthritis, insulin resistance, bronchoconstriction, alcohol preference, metabolic syndrome, Alzheimer's disease, cardiac hypertrophy, left ventricular hypertrophy, hypertriglyceridemia, low HDL cholesterol, cardiovascular disorders such as coronary heart disease (CHD), cerebrovascular disease, stroke, peripheral vascular disease, sudden death, gallbladder diseases, cancer (breast, endometrial, colon), breathlessness, hyperuricemia, impaired fertility, low back pain, or increased anesthetic risk, and the like.

[0031] The compounds of the present invention (I) are particularly useful as agents for the treatment of bulimia, obesity, diabetes and the like.

[0032] The present invention relates to the compounds represented by the general formula (I), or the salts thereof, and the production method and the use thereof.

[0033] The means of terms used in the present specification are defined and more detailed description of this invention is described in the following.

[0034] “Halogen” refers to fluorine, chlorine, bromine and iodine.

[0035] “Lower alkyl” refers to a straight- or branched-chain alkyl group of C1 to C6, and its examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

[0036] “Halo-lower alkyl” refers to said lower alkyl substituted with identically or differently one, two or more, preferably one to three said halogen at the substitutable, arbitrary position(s), and its examples are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl, bromomethyl, iodomethyl and the like.

[0037] “Lower alkoxy” refers to straight- or branched-chain alkoxy of C1 to C6 and its examples are methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy and the like.

[0038] “Halo-lower alkoxy” refers to said lower alkoxy substituted with identically or differently one, two or more, preferably one to three said halogen at substitutable, arbitrary position(s), and its examples are fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, bromomethoxy, iodomethoxy and the like.

[0039] “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group containing said lower alkoxy, that is, an alkoxycarbonyl group of C2 to C7, and its examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like.

[0040] “Lower alkylsulfonyl” refers to a straight- or branched-chain alkylsulfonyl group of C1 to C6, and its examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl and the like.

[0041] “Lower alkylsulfonyloxy” refers to a straight- or branched-chain alkylsulfonyloxy group of C1 to C6, and its examples are methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, sec-butylsulfonyloxy, isobutylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, hexylsulfonyloxy, isohexylsulfonyloxy and the like.

[0042] “Hydroxy-lower alkyl” refers to said lower alkyl substituted with one, two or more, preferably one or two hydroxy at substitutable, arbitrary position(s), and its examples are hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl and the like.

[0043] “Cyclo-lower alkyl” refers to a cycloalkyl group of C3 to C6, and its examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0044] “Lower alkenyl” refers to a straight- or branched-chain alkenyl group of C2 to C6, and its examples are vinyl, 1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl, 4-pentenyl and the like.

[0045] “Lower alkylthio” refers to straight- or branched-chain alkylthio of C1 to C6, and its examples are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio and the like.

[0046] “Lower alkanoyl” refers to an alkanoyl group containing said lower alkyl, that is, an alkanoyl group of C2 to C7, and its examples are acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.

[0047] “Lower alkanoylamino” refers to an amino group mono-substituted with said lower alkanoyl, and its examples are acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino and the like.

[0048] “Aryl” refers to phenyl, naphthyl and the like.

[0049] “Heteroaryl” refers to 5- or 6-membered monocyclic heteroaromatic group which contains one, two or more, preferably one to three hetero atom(s) identically or differently selected from the group consisting of oxygen, nitrogen and sulfur; or condensed cyclic heteroaromatic group, where said monocyclic heteroaromatic group is condensed with said aryl group or condensed each other with the same or different said monocyclic heteroaromatic group, and its examples are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl and the like.

[0050] “Lower alkylamino” refers to an amino group mono-substituted with said lower alkyl, and its examples are methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino and the like.

[0051] “Di-lower alkylamino” refers to an amino group di-substituted with the same or different said lower alkyl, and its examples are dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino, diisopropylamino and the like.

[0052] “Lower alkylene which may be intervened by oxygen, sulfur or imino” refers to an alkylene group of C2 to C5, which is not intervened or intervened by one, two or more, preferably one oxygen, sulfur or imino at optional and intervention capable position(s) of said alkylene chain, and its examples are ethylene, trimethylene, tetramethylene, pentamethylene, 2-oxatetramethylene, 2-oxapentamethylene, 3-oxapentamethylene, 2-thiatetramethylene, 2-thiapentamethylene, 3-thiapentamethylene, 2-azatetramethylene, 2-azapentamethylene, 3-azapentamethylene and the like.

[0053] “Aralkyl” refers to said lower alkyl substituted with one, two or more, preferably one said aryl at substitutable, arbitrary position(s), and its examples are benzyl, 1-phenylethyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.

[0054] The esters of compounds of formula (I) refer to, for example, the pharmaceutically acceptable, common esters of said carboxyl group when the compound has a carboxyl group, and examples thereof are esters with lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl), esters with aralkyl (e.g. benzyl, phenethyl), esters with lower alkenyl (e.g. allyl, 2-butenyl), esters with lower-alkoxy-lower-alkyl (e.g. methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), esters with lower-alkanoyloxy-lower-alkyl (e.g. acetoxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl), esters with lower-alkoxycarbonyl-lower-alkyl (e.g. methoxycarbonylmethyl, isopropoxycarbonylmethyl), esters with carboxy-lower alkyl (e.g. carboxymethyl), esters with lower-alkoxycarbonyloxy-lower-alkyl (e.g. 1-(ethoxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl), esters with carbamoyloxy-lower alkyl (e.g. carbamoyloxymethyl), esters with phthalidyl, esters with (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl (e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) and the like.

[0055] The salts of compounds of formula (I) refer to the pharmaceutically acceptable, common salts, and examples thereof are base addition salt to said carboxyl group when the compound has a carboxyl group, or acid addition salt to said amino or basic heterocyclyl when the compound has an amino or basic heterocyclyl group and the like.

[0056] Said base addition salts include salts with alkali metals (e.g. sodium, potassium); salts with alkaline earth metals (e.g. calcium, magnesium); ammonium salts; salts with organic amines (e.g. trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, N,N′-dibenzylethylenediamine) and the like.

[0057] Said acid addition salts include salts with inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid), salts with organic acids (e.g. maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid), salts with sulfonic acids (e.g. methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid) and the like.

[0058] An N-oxide derivative of the compound represented by the formula (I) means a compound of which any one or more than one nitrogen atoms present in the compound of the formula (I) is or are oxidized to form an N-oxide or N-oxides, and such an N-oxide derivative includes, for example, a compound of which nitrogen atom is oxidized in case when T, U, V or/and W in the formula (I) is or are nitrogen.

[0059] “An agent for treatment” refers to a medicament which is employed for the treatment and/or prophylaxis of various diseases.

[0060] In order to disclose the aforesaid compounds of the general formula (I) of the present invention more specifically, the various symbols used in the formula (I) are explained in more detail by presenting preferred embodiments.

[0061] A, B, C and D are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R ¹ )R ² and -Q ¹ -Ar ¹ , and at least one of A, B, C and D is said methine group.

[0062] “Methine which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R ¹ )R ² and -Q ¹ -Ar ¹ ” refers to unsubstituted methine or methine having a substituent, wherein said substituent may be selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyloxy, —N(R ¹ )R ² and -Q ¹ -Ar ¹ .

[0063] Halogen as said substituent preferably includes fluorine, chlorine and the like.

[0064] Lower alkyl as said substituent preferably includes methyl, ethyl and the like.

[0065] Halo-lower alkyl as said substituent preferably includes difluoromethyl, trifluoromethyl and the like.

[0066] Lower alkoxy as said substituent preferably includes methoxy, ethoxy and the like.

[0067] Halo-lower alkoxy as said substituent preferably includes difluoromethoxy, trifluoromethoxy and the like.

[0068] Lower alkoxycarbonyl as said substituent preferably includes methoxycarbonyl, ethoxycarbonyl and the like.

[0069] Lower alkylsulfonyl as said substituent preferably includes methylsulfonyl, ethylsulfonyl and the like.

[0070] Lower alkylsulfonyloxy as said substituent preferably includes methylsulfonyloxy, ethylsulfonyloxy and the like.

[0071] In a group of formula: —N(R ¹ )R ² as said substituent, R ¹ and R ² are independently hydrogen or lower alkyl, or R ¹ and R ² , taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino.

[0072] Lower alkyl as R ¹ or R ² preferably includes methyl, ethyl, propyl and the like.

[0073] “Lower alkylene which may be intervened by oxygen, sulfur or imino” formed by taking R ¹ and R ² together preferably includes pentamethylene, 3-oxapentamethylene and the like, and it, together with nitrogen next thereto, forms piperidino, morpholino, etc.

[0074] The preferred embodiment of R ¹ and R ² includes the case where at least one of R ¹ or R ² is lower alkyl, or the case where R ¹ and R ² , taken together, form lower alkylene which may be intervened by oxygen, sulfur or imino.

[0075] Thus, a group of formula: —N(R ¹ )R ² includes, for example, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, ethylmethylamino, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl and the like, among which the preferred are methylamino, dimethylamino, piperidino, morpholino and the like.

[0076] In a group of formula: -Q ¹ -Ar ¹ as said substituent, Ar ¹ is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsulfonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q ² -Ar ² ; Q ¹ is a single bond, oxygen, carbonyl or —N(R ³ )—.

[0077] “Aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsufonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q ² -Ar ² ” refers to unsubstituted said aryl or said heteroaryl, or said aryl or said heteroaryl having substituent(s) at the substitutable, arbitrary position(s) wherein said substituent(s) may be one, two or more, preferably one or two member(s) identically or differently selected from the group consisting of halogen, nitro, hydroxy, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, lower alkylthio, lower alkylsufonyl, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkanoylamino and -Q ² -Ar ² .

[0078] Halogen as said substituent preferably includes fluorine, chlorine, bromine and the like.

[0079] Lower alkyl as said substituent preferably includes methyl, ethyl, propyl, isopropyl and the like.

[0080] Halo-lower alkyl as said substituent preferably includes difluoromethyl, trifluoromethyl and the like.

[0081] Hydroxy-lower alkyl as said substituent preferably includes hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl and the like.

[0082] Cyclo-lower alkyl as said substituent preferably includes cyclopropyl, cyclobutyl and the like.

[0083] Lower alkenyl as said substituent preferably includes vinyl, 1-propenyl, 2-methyl-1-propenyl and the like.

[0084] Lower alkoxy as said substituent preferably includes methoxy, ethoxy and the like.

[0085] Halo-lower alkoxy as said substituent preferably includes fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

[0086] Lower alkylthio as said substituent preferably includes methylthio, ethylthio and the like.

[0087] Lower alkylsulfonyl as said substituent preferably includes methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.

[0088] Lower alkanoyl as said substituent preferably includes acetyl, propionyl and the like.

[0089] Lower alkoxycarbonyl as said substituent preferably includes methoxycarbonyl, ethoxycarbonyl and the like.

[0090] Lower alkanoylamino as said substituent preferably includes acetylamino, propanoylamino and the like.

[0091] In a group of formula: -Q ² -Ar ² as said substituent, Ar ² is aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q ² is a single bond, oxygen, carbonyl or —N(R ³ )—.

[0092] “Aryl or heteroaryl, any of which is optionally substituted by a substituent selected from the group consisting of halogen, cyano, loweralkyl, halo-loweralkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl” refers to unsubstituted said aryl or said heteroaryl, or said aryl or said heteroaryl having substituent(s) at the substitutable, arbitrary position(s) wherein said substituent(s) may be one, two or more, preferably one or two member(s) identically or differently selected from the group consisting of halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl.

[0093] Halogen as said substituent preferably includes fluorine, chlorine and the like.

[0094] Lower alkyl as said substituent preferably includes methyl, ethyl, propyl, isopropyl and the like.

[0095] Halo-lower alkyl as said substituent preferably includes difluoromethyl, trifluoromethyl and the like.

[0096] Hydroxy-lower alkyl as said substituent preferably includes hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl and the like.

[0097] Lower alkoxy as said substituent preferably includes methoxy, ethoxy and the like.

[0098] Halo-lower alkoxy as said substituent preferably includes fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

[0099] Lower alkylamino as said substituent preferably includes methylamino, ethylamino and the like.

[0100] Di-lower alkylamino as said substituent preferably includes dimethylamino, diethylamino and the like.

[0101] Lower alkanoyl as said substituent preferably includes acetyl, propionyl and the like.

[0102] Aryl as said substituent preferably includes phenyl and the like.

[0103] The substituent(s) of Ar ² preferably include(s) halogen, cyano, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxy, halo-lower alkoxy and the like.

[0104] Aryl as Ar ² preferably includes phenyl and the like, and heteroaryl as Ar ² preferably includes pyridyl, quinolyl and the like.

[0105] In the group of formula: —N(R ³ )— as Q ¹ and Q ² , R ³ is hydrogen or lower alkyl.

[0106] R ³ preferably includes hydrogen, methyl, ethyl and the like.

[0107] Q ² preferably includes a single bond and the like.

[0108] The substituent(s) of Ar ¹ include(s) preferably halogen, hydroxy, lower alkyl, halo-lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyl, -Q ² -Ar ² and the like, more preferably halogen, hydroxy, halo-lower alkyl, lower alkoxy and the like.

[0109] Aryl as Ar ¹ preferably includes phenyl and the like, and heteroaryl as Ar ¹ includes preferably imidazolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazol, 1,3,4-oxadiazol, pyridyl, pyrazinyl, pyrimidinyl, benzofuranyl, quinolyl and the like, more preferably pyridyl, quinolyl and the like, most preferably pyridyl and the like.

[0110] Consequently, Ar ¹ includes, for example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl, 2-bromo-4-fluorophenyl, 2-bromo-5-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 5-fluoro-2-methoxyphenyl, 3-fluoromethoxyphenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-hydroxy-4-fluorophenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-imidazolyl, 2-furyl, 2-thienyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-6-pyridyl, 2-pyrimidinyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 7-benzo[b]furanyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 8-quinolyl and the like. Preferably, Ar ¹ includes phenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-6-pyridyl, 7-benzo[b]furanyl, 2-quinolyl, 3-quinolyl and the like.

[0111] Q ¹ includes preferably a single bond, oxygen, —N(R ³ )— and the like, more preferably a single bond and the like.

[0112] The substituent(s) of methine as A, B, C or D include(s) preferably halogen, halo-lower alkyl, lower alkoxycarbonyl, —N(R ¹ )R ² , -Q ¹ -Ar ^l and the like, more preferably -Q ¹ -Ar ¹ and the like.

[0113] The preferred embodiment of A, B, C and D includes, for example, the case where A and D are same or differently unsubstituted methine or nitrogen, and one of B and C is methine having -Q ¹ -Ar ¹ and the other is unsubstituted methine or nitrogen, more preferably the case where A is unsubstituted methine, B and/or D are nitrogen, and C is methine having -Q ¹ -Ar ¹ .

[0114] E is methine, hydroxy substituted methine or nitrogen, preferably methine.

[0115] n is 0 or 1, preferably 0.

[0116] T, U, V and W are independently methine or nitrogen, said methine being optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy, and at least two of T, U, V and W are said methine group.

[0117] “Methine which is optionally substituted by a substituent selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy” refers to unsubstituted methine or methine having a substituent, wherein said substituent may be selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy and halo-lower alkoxy.

[0118] Halogen as said substituent preferably includes fluorine, chlorine and the like.

[0119] Lower alkyl as said substituent preferably includes methyl, ethyl and the like.

[0120] Halo-lower alkyl as said substituent preferably includes difluoromethyl, trifluoromethyl and the like.

[0121] Lower alkoxy as said substituent preferably includes methoxy, ethoxy and the like.

[0122] Halo-lower alkoxy as said substituent preferably includes fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

[0123] Said substituent includes preferably halogen, lower alkyl, hydroxy, lower alkoxy and the like, more preferably halogen and the like.

[0124] The preferred embodiment of T, U, V and W includes, for example, the case where T, U, V and W are independently methine optionally having said substituent, preferably halogen, lower alkyl, hydroxy and lower alkoxy,