Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses

• US 7,122,666 B2
• Filed: 01/30/2003
• Issued: 10/17/2006
• Est. Priority Date: 07/21/1999
• Status: Expired due to Fees

• Current Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Original Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Inventors: Yamazaki, Takanori, Ohkawa, Nobuyuki, Nakao, Akira, Kimura, Tomio, Nagasaki, Takayoshi
• Primary Examiner(s): Jiang, Shaojia A.
• Assistant Examiner(s): Krishnan, Ganapathy
• Application Number:
  US10/354,648
• Publication Number:
  US 20040054173A1
• Time in Patent Office: 1,356 Days
• Field of Search: 544/60, 544/141, 544/245, 544/333, 546/193, 546/269.7, 546/271.4, 546/272.7, 546/276.4, 514/247, 514/336, 514/339
• US Class Current: 544/141
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 455/02 containing not further condensed quinolizine ring systems
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds having activity against production of an inflammatory cytokine of formula (I)′:

A′ is pyrrole; R^1′ is phenyl or naphthyl; R^2′ is pyridyl or pyrimidinyl; R^3′ is (IIa)′, (IIb)′ or (IIc)′:

m′ is 1; E′ is nitrogen; D′ is >C(R^5′)—, R^5′ is hydrogen, Substituent α′ or Substituent β′; B′ is nitrogen-containing 5-membered heterocyclic; R^4′ is 1 to 3 substituents from Substituent α′, Substituent β′ and Substituent γ′; R^1′ and R^3′ are bonded to two atoms of the pyrrole adjacent to the pyrrole atom bonded to R^2′; Substituent α′ is hydroxyl, nitro, cyano, halogen, alkoxy, halogeno alkoxy, alkylthio, halogeno alkylthio or —NR^a′R^b′; R^a′ and R^b′ are hydrogen, alkyl, alkenyl, alkynyl, aralkyl or alkylsulfonyl, or R^a′ and R^b′ with the nitrogen atom form a heterocyclyl; Substituent β′ is alkyl, alkenyl, alkynyl, aralkyl or cycloalkyl; Substituent γ′ is oxo, hydroxyimino, alkoxyimino, alkylene, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, aryl, aryloxy, alkylidenyl or aralkylidenyl.

Claims

1. A compound of formula (I)′

, or a pharmacologically acceptable salt, ester or amide thereof;

2. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^1′

is a phenyl group which optionally is substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below;

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups.

3. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^1′

is a phenyl group which optionally is substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups.

4. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^1′

is selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups.

5. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^2′

is a 4-pyridyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

6. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^2′

is a 4-pyridyl which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

7. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^2′

is a 4-pyridyl which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups.

8. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein B′

has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, oxygen atom, sulfur atom, >

SO and >

SO₂, said ring is saturated or unsaturated and optionally is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.

9. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein B′

is saturated or unsaturated and is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.

10. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein B′

is a pyrrolidinyl ring or a pyrrolinyl ring.

11. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^3′

is a group of formula (IIa)′

or formula (IIb)′

.

12. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^3′

is a group of formula (IIa)′

.

13. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^4′

is 1 or 2 substituents which are selected independently from the group consisting of said Substituent group α

, said Substituent group β

′ and

Substituent group γ

^1′

, wherein said Substituent group γ

^1′

is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which optionally are substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

14. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups optionally substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

15. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^4′

is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which is optionally substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

as defined in claim 1.

16. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^4′

is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

17. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^4′

is a substituent selected from the group consisting of aryloxy groups which optionally are substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, alkylidene groups and aralkylidene groups.

18. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

19. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein said compound of formula (I)′

is represented by the formula (I-1)′

or (I-3)′

shown below;

20. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein the compound of formula (I)′

is represented by the formula (I-1)′

below;

21. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is 1 or 2 substituents which are selected independently from the group consisting of said Substituent group α

′

, said Substituent group β

′ and

Substituent group γ

^1′

, wherein said Substituent group γ

^1′

is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

22. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

23. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R¹′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below;

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;

R^2′

is a 4-pyridyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

24. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;

R^2′

is a 4-pyridyl which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

25. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;

R^2′

is a 4-pyridyl which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

26. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, alkylidene groups and aralkylidene groups.

27. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below,

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group, and

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;

R^2′

is a 4-pyridyl which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

, alkylidene groups and aralkylidene groups.

28. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;

R^2′

is a 4-pyridyl which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

, and

R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

29. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein:

R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;

R^2′

is a 4-pyridyl which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups;

R^3′

is a group of formula (IIa)′

, and

R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

30. A compound according to any one of claim 21, 22, 23, 24, 25, 26, 27, 28 or 29 or a pharmacologically acceptable salt, ester or amide thereof, wherein the compound of formula (I)′

is a compound of formula (I-1)′

or (I-3)′

shown below;

31. A compound according to any one of claim 21, 22, 23, 24, 25, 26, 27, 28 or 29 or a pharmacologically acceptable salt, ester or amide thereof, wherein the compound of formula (I)′

is a compound of formula (I-1)′

shown below;

32. A compound according to claim 1 or a pharmacologically acceptable salt, ester or amide thereof, wherein the compound is selected from the group consisting of

2-(3-fluorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-2-(3-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole, and

2-(4-fluorophenyl)-4-[2-phenyl]-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole.

33. A compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-4-[(2R,8aS)-2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

34. A compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-4-[(8aS)-2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

35. A compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-4-[(8aS)-2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

36. A compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-4-[(8aS)-2-methylidene-3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

37. A compound according to claim 1, wherein the compound is 4-[(2S,8aS)-2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-2-(4-flurophenyl)-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

38. A compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-4-[(2S,8aS)-2-propyl-1,2,3,5,6,8hexahydroindolizin-7yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

39. A compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-4-[(2R,8aS)-2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H pyrrole or a pharmaceutically acceptable salt, ester or amide thereof.

40. A pharmaceutical composition comprising a pharmaceutically effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound of formula (I)′

or a pharmacologically acceptable salt, ester or amide thereof;

41. A pharmaceutical composition according to claim 40, wherein R^1′

is a phenyl group which optionally is substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below;

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups.

42. A pharmaceutical composition according to claim 40, wherein R^1′

is a phenyl group which optionally is substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl and halogeno lower alkoxy groups.

43. A pharmaceutical composition according to claim 40, wherein R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4difluorophenyl, 3,4,5trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups.

44. A pharmaceutical composition according to claim 40, wherein R^2′

is a 4-pyridyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

45. A pharmaceutical composition according to claim 40, wherein R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

46. A pharmaceutical composition according to claim 40, wherein R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups.

47. A pharmaceutical composition according to claim 40, wherein B′

has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, oxygen atom, sulfur atom, >

SO and >

SO₂, said ring is saturated or unsaturated and optionally is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.

48. A pharmaceutical composition according to claim 40, wherein B′

is saturated or unsaturated and is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.

49. A pharmaceutical composition according to claim 40, wherein B′

is a pyrrolidinyl ring or a pyrrolinyl ring.

50. A pharmaceutical composition according to claim 40, wherein R^3′

is a group of formula (IIa)′

or formula (IIb)′

.

51. A pharmaceutical composition according to claim 40, wherein R^3′

is a group of formula (IIa)′

.

52. A pharmaceutical composition according to claim 40, wherein R^4′

is 1 or 2 substituents which are independently selected from the group consisting of said Substituent group α

′

, said Substituent group β

′ and

Substituent group γ

^1′

, wherein said Substituent group γ

^1′

is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which optionally are substituted with at least one substituent selected from the group consisting of Substituent group α

′ and

Substituent group β

′

.

53. A pharmaceutical composition according to claim 40, wherein R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups optionally substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

54. A pharmaceutical composition according to claim 40, wherein R^4′

is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which optionally is substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

55. A pharmaceutical composition according to claim 40, wherein R^4′

is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

56. A pharmaceutical composition according to claim 40, wherein R^4′

is a substituent selected from the group consisting of aryloxy groups which optionally are substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

, alkylidene groups and aralkylidene groups.

57. A pharmaceutical composition according to claim 40, wherein R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

58. A pharmaceutical composition according to claim 40, wherein said compound of formula (I)′

is represented by the formula (I-1)′

or (T-3)′

shown below;

59. A pharmaceutical composition according to claim 40, wherein the compound of formula (I)′

is represented by the formula (I-1)′

below;

60. A pharmaceutical composition according to claim 40, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is 1 or 2 substituents which are independently selected from the group consisting of said Substituent group α

′

, said Substituent group β

′ and

Substituent group γ

^1′

, wherein said Substituent group γ

^1′

is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

61. A pharmaceutical composition according to claim 40, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

62. A pharmaceutical composition according to claim 40, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below;

R^3′

is a group of formula (IIa)′

or formula (IIb)′

;

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

63. A pharmaceutical composition according to claim 40, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;

R^2′

is a 4pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

; and

R^3′

is a group of formula (IIa)′

;

R^4′

is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

64. A pharmaceutical composition according to claim 40, wherein:

R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups; and

R^3′

is a group of formula (IIa)′

;

R^4′

is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

65. A pharmaceutical composition according to claim 40, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, alkylidene groups and aralkylidene groups.

66. A pharmaceutical composition according to claim 40, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below,

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group, and

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;

R^2′

is a 4pyridyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, alkylidene groups and aralkylidene groups.

67. A pharmaceutical composition according to claim 40, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

68. A pharmaceutical composition according to claim 40, wherein:

R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;

R^2′

is a 4pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

69. A pharmaceutical composition according to any one of claim 60, 61, 62, 63, 64, 65, 66, 67 or 68, wherein the compound of formula (I)′

is a compound of formula (I-1)′

or (I-3)′

shown below;

70. A pharmaceutical composition according to any one of claim 60, 61, 62, 63, 64, 65, 66, 67 or 68, wherein the compound of formula (I)′

is a compound of formula (I-1)′

;

71. A pharmaceutical composition according to claim 40, wherein the compound of formula (I)′

is selected from the group consisting of

2-(3-fluorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3- (pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3- (pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2methyl-1,2,3,5,6,8a-hexahydroindolizin7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2methoxy-1,2,3,5,6,8a-hexahydroindolizin7yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3- (pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-2-(3-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4yl)-1H-pyrrole,

4-[2ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl]-2-(4 -fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole, and

2-(4-fluorophenyl)4-[2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole, or a pharmacologically acceptable salt, ester or amide thereof.

72. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(2R,8aS)-2-phenyl-1,2,3,5,6,8a-hexahydro-indolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

73. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(8aS)-2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

74. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 2-(4fluorophenyl)-4-[(8aS)-2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H- or a pharmacologically acceptable salt, ester or amide thereof.

75. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(8aS)-2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

76. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 4-[(2S,8aS)-2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

77. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(2S,8aS)-2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

78. A composition according to claim 40, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(2R,8aS)-2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7yl]-3-(pyridin-4-yl)-1-H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

79. A method for the treatment of rheumatoid arthritis which comprises administering to a mammal a pharmaceutically effective amount of a compound of formula (I)′

or a pharmacologically acceptable salt, ester or amide thereof;

80. A method according to claim 79, wherein the mammal is a human.

81. A method according to claim 80, wherein R^1′

is a phenyl group which optionally is substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below;

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups.

82. A method according to claim 80, wherein R^1′

is a phenyl group which optionally is substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups.

83. A method according to claim 80, wherein R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups.

84. A method according to claim 80, wherein R^2′

is a 4-pyridyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

85. A method according to claim 80, wherein R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

86. A method according to claim 80, wherein R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups.

87. A method according to claim 80, wherein B′

has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, oxygen atom, sulfur atom, >

SO and >

SO₂, said ring may be saturated or unsaturated and optionally is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.

88. A method according to claim 80, wherein B′

is saturated or unsaturated and is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.

89. A method according to claim 80, wherein B′

is a pyrrolidinyl ring or a pyrrolinyl ring.

90. A method according to claim 80, wherein R^3′

is a group of formula (IIa)′

or l formula (IIb)′

.

91. A method according to claim 80, wherein R^3′

is a group of formula (IIa)′

.

92. A method according to claim 80, wherein R^4′

is 1 or 2 substituents which are independently selected from the group consisting of said Substituent group α

′

, Substituent group β

′ and

Substituent group γ

^1′

, wherein said Substituent group γ

^1′

is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which optionally are substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

93. A method according to claim 80, wherein R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups optionally substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

94. A method according to claim 80, wherein R^4′

is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which optionally are substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

95. A method according to claim 80, wherein R^4′

is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

96. A method according to claim 80, wherein R^4′

is a substituent selected from the group consisting of aryloxy groups which optionally are substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, alkylidene groups and aralkylidene groups.

97. A method according to claim 80, wherein R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

98. A method according to claim 80, wherein said compound of formula (I)′

is represented by the formula (I-1)′

or (I-3)′

shown below;

99. A method according to claim 80, wherein the compound of formula (I)′

is represented by the formula (I-1)′

below;

100. A method according to claim 80, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is 1 or 2 substituents which are independently selected from the group consisting of said Substituent group α

′

, said Substituent group β

′ and

Substituent group γ

^1′

, wherein said Substituent group γ

^1′

is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group α

′ and

said Substituent group β

′

.

101. A method according to claim 80,

wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

102. A method according to claim 80, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α

^1′

defined below and Substituent group β

^1′

defined below;

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

on formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′

, said Substituent group β

′

, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.

103. A method according to claim 80, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

.

104. A method according to claim 80, wherein:

R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino and α

-methylbenzylamino groups;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

105. A method according to claim 80, wherein:

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

^1′

, said Substituent group β

^1′

alkylidene groups and aralkylidene groups.

106. A method according to claim 80, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from Substituent group α

^1′

defined below and Substituent group defined below,

said Substituent group α

^1′

is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and groups of formula —

NR^a′

R^b′

, wherein one of R^a′

and R^b′

0 represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group,

said Substituent group β

^1′

is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

;

R^3′

is a group of formula (IIa)′

or formula (IIb)′

; and

R^4′

is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

, alkylidene groups and aralkylidene groups.

107. A method according to claim 80, wherein:

R^1′

is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α

′ and

said Substituent group β

′

; and

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

108. A method according to claim 80, wherein:

R^1′

is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;

R^2′

is a 4-pyridyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α

-methylbenzylamino groups;

R^3′

is a group of formula (IIa)′

; and

R^4′

is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.

109. A method according to claim 80, wherein the compound of formula (I)′

is selected from the group consisting of

2-(3-fluorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-2-(3-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-fluorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

2-(3-chlorophenyl)-4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole,

4-[2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,

4-[2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl]-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,

2-(4-fluorophenyl)-4-[2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole, and

2-(4-fluorophenyl)-4-[2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole, or a pharmaceutically acceptable salt, ester or amide thereof.

110. A method according to claim 80, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(2R,8aS)-2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

111. A method according to claim 80, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(8aS)-2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

112. A method according to claim 80, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(8aS)-2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

113. A method according to claim 80, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(8aS)-2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

114. A method according to claim 80, wherein said compound of formula (I)′

is selected from 4-[(2S,8aS)-2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

115. A method according to claim 80, wherein said compound of formula (I)′

is selected from 2-(4-fluorophenyl)-4-[(2S,8aS)-2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

116. A method according to claim 80, wherein the compound is 2-(4-fluorophenyl)-4-[(2R,8aS)-2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl]-3-(pyridin-4-yl)-1H-pyrrole or a pharmacologically acceptable salt, ester or amide thereof.

117. A method according to any one of claims 95 to 103, wherein the compound of formula (I)′

is a compound of formula (I-1)′

or (I-3)′

shown below;

118. A method according to any one of claims 100 to 108, wherein the compound of formula (I)′

is a compound of formula (I-1)′

shown below;