Compounds substituted with bicyclic amino groups

• US 20040147525A1
• Filed: 07/22/2003
• Published: 07/29/2004
• Est. Priority Date: 01/22/2001
• Status: Active Grant

• Current Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Original Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Inventors: Nakao, Akira, Aoki, Kazumasa, Kimura, Tomio
• Granted Patent: US 7,091,352 B2
• Time in Patent Office: Days
• US Class Current: 514/252.04
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 of the formula (I) below, or pharmacologically acceptable salts, esters or other derivatives thereof:

wherein A is furan, thiophene, pyrazole, imidazole, isoxazole or isothiazole;

R¹ is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R² is a substituted or unsubstituted heteroaryl; and R³ is a bicyclic amino group; provided that the substituents R¹ and R² are bonded to the two atoms of the cyclic group A which are adjacent to the atom of the cyclic group A to which the substituent R² is bonded. The compounds inhibit the production of inflammatory cytokines.

Claims

1. A compound of the formula (I) below, or a pharmacologically acceptable salt, ester or other derivative thereof:

2. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted aryl group, or an aryl group which is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group 1.

3. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl or naphthyl group, or a phenyl or naphthyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

.

4. The compounds according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl group, or a phenyl group which is substituted with one or more substituents selected from the group consisting of Substituent group α

¹ and Substituent group β

¹,

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^aR^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

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.

5. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl group, or a phenyl group which is substituted with one or more substituents selected from the group consisting of a halogen atom, a halogeno lower alkyl group and a halogeno lower alkoxy group.

6. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is a phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl or 3-trifluoromethylphenyl group.

7. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R² is a 5- or 6-membered heteroaryl group which has one or two nitrogen atoms, or a 5- or 6-membered heteroaryl group which has one or two nitrogen atoms in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

.

8. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R² is an unsubstituted pyridyl or pyrimidinyl group, or a pyridyl or pyrimidinyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

.

9. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

.

10. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group in which said group is substituted at the 2-position thereof with one substituent selected from the group consisting of Substituent group α

and Substituent group β

.

11. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group which is substituted at the 2-position thereof with one substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino and α

-methylbenzylamino.

12. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which has one ring nitrogen atom and optionally has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom, an >

SO group and an >

SO₂ group, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups.

13. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which comprises the group D, the group E and three or four carbon atoms, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups.

14. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R³ is a group of formula (IIa).

15. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein B is a pyrrolidine ring or a pyrroline ring.

16. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein m is 1.

17. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, Substituent group α

, Substituent group β and

Substituent group γ

¹, wherein

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, unsubstituted aryl groups, and aryl groups which are substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

.

18. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, unsubstituted aryl groups, aryl groups which are substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

;

lower alkylene groups;

lower alkylenedioxy groups and lower alkylsulfonyl groups.

19. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups, unsubstituted phenyl groups and phenyl groups which are substituted with substituents selected from the group consisting of Substituent group α

and Substituent group β

.

20. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁵ is one substituent which is independently selected from the group consisting of hydrogen atoms, methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

21. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁴ is a hydrogen atom, an unsubstituted lower alkyl group, a lower alkyl group which is substituted with one or more substituents from Substituent group α

, an aryl group substituted with one or more substituents selected from the group consisting of Substituent group α

, Substituent group β and

Substituent group γ

;

an unsubstituted heterocyclyl group, or a heterocyclyl group substituted with one or more substituents selected from the group consisting of Substituent group α

, Substituent group β

, and Substituent group γ

.

22. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁴ is a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, or a phenyl group substituted with one or more substituents selected from the group consisting of Substituent group α

, Substituent group β and

Substituent group γ

.

23. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein A is a pyrazole ring having one substituent R⁴ or an imidazole ring having one substituent R⁴.

24. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein A is a pyrazole ring having one substituent R⁴.

25. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted aryl group, or an aryl group which is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

;

R² is a 5- or 6-membered heteroaryl group which has one or two nitrogen atoms, or a 5- or 6-membered heteroaryl group which has one or two nitrogen atoms in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which has one ring nitrogen atom and optionally has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom, an >

SO group and an >

SO₂ group, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups; and

R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, Substituent group α

, Substituent group β and

Substituent group γ

¹, wherein 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, unsubstituted aryl groups, and aryl groups which are substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

.

26. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl or naphthyl group, or a phenyl or naphthyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

;

R² is an unsubstituted pyridyl or pyrimidinyl group, or a pyridyl or pyrimidinyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which has one ring nitrogen atom and optionally has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom, an >

SO group and an >

SO₂ group, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups; and

R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, unsubstituted aryl groups, aryl groups which are substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

lower alkylene groups;

lower alkylenedioxy groups and lower alkylsulfonyl groups.

27. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl or naphthyl group, or a phenyl or naphthyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α

and Substituent group β

;

R² is an unsubstituted pyridyl or pyrimidinyl group, or a pyridyl or pyrimidinyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which comprises the group D, the group E and three or four carbon atoms, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups; and

R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, unsubstituted aryl groups, aryl groups which are substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

lower alkylene groups;

lower alkylenedioxy groups and lower alkylsulfonyl groups.

28. The compounds according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl group, or a phenyl group which is substituted with one or more substituents selected from the group consisting of Substituent group al and Substituent group

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^aR^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

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;

R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which comprises the group D, the group E and three or four carbon atoms, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups; and

R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, unsubstituted aryl groups, aryl groups which are substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

lower alkylene groups;

lower alkylenedioxy groups and lower alkylsulfonyl groups.

29. The compounds according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl group, or a phenyl group which is substituted with one or more substituents selected from the group consisting of Substituent group α

¹ and Substituent group

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^aR^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

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;

R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group in which said group is substituted with one or more substituents selected from the group consisting of Substituent group α and

Substituent group β

;

R³ is a group of formula (IIa) or formula (IIb), and B is a 5- or 6-membered heterocyclic ring which comprises the group D, the group E and three or four carbon atoms, said ring may be saturated or unsaturated and may be fused with a group selected from aryl groups, heteroaryl groups, cycloalkyl groups and heterocyclyl groups; and

R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups, unsubstituted phenyl groups and phenyl groups which are substituted with substituents selected from the group consisting of Substituent group α and

Substituent group β

.

30. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is an unsubstituted phenyl group, or a phenyl group which is substituted with one or more substituents selected from the group consisting of a halogen atom, a halogeno lower alkyl group and a halogeno lower alkoxy group;

R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group in which said group is substituted at the 2-position thereof with one substituent selected from the group consisting of Substituent group α and

Substituent group β

;

R³ is a group of formula (IIa); and

R⁵ is one or two substituents which are independently selected from the group consisting of hydrogen atoms, hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups, unsubstituted phenyl groups and phenyl groups which are substituted with substituents selected from the group consisting of Substituent group α and

Substituent group β

.

31. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is a phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl or 3-trifluoromethylphenyl group;

R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group which is substituted at the 2-position thereof with one substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino and α

-methylbenzylamino;

B is a pyrrolidine ring or a pyrroline ring; and

R⁵ is one substituent which is independently selected from the group consisting of hydrogen atoms, methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

32. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R¹ is a phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl or 3-trifluoromethylphenyl group;

R² is an unsubstituted 4-pyridyl or 4-pyrimidinyl group, or a 4-pyridyl or 4-pyrimidinyl group which is substituted at the 2-position thereof with one substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino and α

-methylbenzylamino;

m is 1; and

R⁵ is one substituent which is independently selected from the group consisting of hydrogen atoms, methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.

33. The compound according to any one of claims 25 to 32, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁴ is a hydrogen atom, an unsubstituted lower alkyl group, a lower alkyl group which is substituted with one or more substituents from Substituent group α

, an aryl group substituted with one or more substituents selected from the group consisting of Substituent group α

. Substituent group β and

Substituent group γ

;

an unsubstituted heterocyclyl group, or a heterocyclyl group substituted with one or more substituents selected from the group consisting of Substituent group α

, Substituent group β and

Substituent group γ

.

34. The compound according to any one of claims 25 to 32, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R⁴ is a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, or a phenyl group substituted with one or more substituents selected from the group consisting of Substituent group α

, Substituent group β and

Substituent group γ

.

35. The compound according to any one of claims 25 to 32, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein A is a pyrazole ring having one substituent R⁴ or an imidazole ring having one substituent R⁴.

36. The compound according to any one of claims 25 to 32, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein A is a pyrazole ring having one substituent R⁴.

37. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-5-phenyl-4-(pyridin-4-yl)-pyrazole.

38. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(3-fluorophenyl)-3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

39. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(4-fluorophenyl)-3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

40. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(4-fluorophenyl)-3-(2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

41. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(4-fluorophenyl)-3-(2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

42. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(4-fluorophenyl)-3-(2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

43. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(3-chlorophenyl)-3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

44. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(3,4-difluorophenyl)-3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

45. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 3-(2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole.

46. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound is 5-(4-fluorophenyl)-3-(2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

47. The compound according to claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof, selected from the group consisting of:

5-(4-fluorophenyl)-3-(2-hydroxy-1,2,3,5,6, 8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

3-(2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole,

3-(2,2-difluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)-5-(3-trifluoromethylphenyl)pyrazole,

5-(4-fluorophenyl)-3-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-1-methyl-4-(pyridin-4-yl)pyrazole,

3-(4-fluorophenyl)-5-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-1-methyl-4-(pyridin-4-yl)pyrazole,

3-(4-fluorophenyl)-1-methyl-5-(2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

3-(4-fluorophenyl)-1-methyl-5-(2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

3-(4-fluorophenyl)-5-(2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-1-methyl-4-(pyridin-4-yl)pyrazole,

3-(4-fluorophenyl)-5-(2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-1-methyl-4-(pyridin-4-yl)pyrazole,

5-(2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)pyrazole,

5-(2,2-difluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)pyrazole,

3-(4-fluorophenyl)-1-methyl-5-(8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-4-(pyridin-4-yl)-3-(3,5,6,8a-tetrahydroindolizin-7-yl)pyrazole,

5-(4-fluorophenyl)-3-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(7-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

4-(4-fluorophenyl)-1-(1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl)-5-(pyridin-4-yl)imidazole,

5-(4-chlorophenyl)-3-(1,2,3,5,6, 8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(2-methyliden-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

3-(2-ethyliden-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(2-propyliden-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-1-methyl-3-(2-methyl-1,2,3,5,6, 8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-1-methyl-3-(2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-1-methyl-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-1-methyl-4-(pyridin-4-yl)pyrazole,

3-(2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-5-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-1-methyl-3-(8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole,

3-(2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl)-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole,

5-(4-fluorophenyl)-3-(2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole, and

5-(4-fluorophenyl)-3-(2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl)-4-(pyridin-4-yl)pyrazole.

49. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 32 or 37 to 46, or a pharmacologically acceptable salt, ester or other derivative thereof, in combination with a pharmaceutically acceptable carrier.

50. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, ester or other derivative thereof in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is for the prophylaxis or treatment of diseases where inflammatory cytokines are involved.

51. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, ester or other derivative thereof in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is an analgesic or an anti-inflammatory drug.

52. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, ester or other derivative thereof in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is for the prophylaxis or treatment of chronic rheumatoid arthritis.

53. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, ester or other derivative thereof in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is for the prophylaxis or treatment of osteoarthritis.

54. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1, wherein the pharmaceutical composition is for the prophylaxis or treatment of septicemia.

55. A method for inhibiting the production of inflammatory cytokines in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof.

56. A method for inhibiting the production of inflammatory cytokines in a human which comprises administering to said human a pharmaceutically effective amount of the compound according to any one of claims 1 to 32 or 37 to 46, or a pharmaceutically acceptable salt, ester or other derivative thereof.

57. A method for the relief of pain and/or the treatment of inflammation in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof.

58. A method for the relief of pain and/or the treatment of inflammation in a human which comprises administering to said human a pharmaceutically effective amount of the compound according to any one of claims 1 to 32 or 37 to 46, or a pharmaceutically acceptable salt, ester or other derivative thereof.

59. A method for the prophylaxis or treatment of chronic rheumatoid arthritis in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof.

60. A method for the prophylaxis or treatment of chronic rheumatoid arthritis in a human which comprises administering to said human a pharmaceutically effective amount of the compound according to any one of claims 1 to 32 or 37 to 46, or a pharmaceutically acceptable salt, ester or other derivative thereof.

61. A method for the prophylaxis or treatment of osteoarthritis in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof.

62. A method for the prophylaxis or treatment of osteoarthritis in a human which comprises administering to said human a pharmaceutically effective amount of the compound according to any one of claims 1 to 32 or 37 to 46, or a pharmacologically acceptable salt, ester or other derivative thereof.

63. A method for the prophylaxis or treatment of septicemia in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of claim 1, or a pharmacologically acceptable salt, ester or other derivative thereof.

64. A method for the treatment of septicemia in a human which comprises administering to said human a pharmaceutically effective amount of the compound according to any one of claims 1 to 32 or 37 to 46, or a pharmacologically acceptable salt, ester or other derivative thereof.

48. A compound of the formula (I) below, or a pharmacologically acceptable salt, ester or other derivative thereof:

65. A process for the preparation of a compound of formula (53) below

66. The process according to claim 65, wherein step (c) comprises

(c1) reacting a compound of formula (50) with a compound of the formula R¹⁴—

NH—

R¹⁵, wherein R¹⁴ and R¹⁵ are the same or different from each other and each independently represents a hydrogen atom, a lower alkyl group or an aralkyl group, or R¹⁴ and R¹⁵, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group, to prepare a compound of formula (51) below

wherein, B, R⁵, R²⁴, R²⁵, R²⁶, R¹⁴ and R¹⁵ have the same meanings as defined above and the configuration based on the carbon atom which is marked by * represents the same configuration as the compound of formula (53);

(c2) reducing an amido moiety of the compound of formula (51) to provide a compound of formula (52) below

wherein, B, R⁵, R²⁴, R²⁵, R²⁶, R¹⁴ and R¹⁵ have the same meanings as defined above and the configuration based on the carbon atom which is marked by * represents the same configuration as the compound of general formula (53); and

(c3) subjecting the compound of formula (52) to a hydrolysis reaction to provide the compound of formula (53).

67. A process for the preparation of a compound of a formula (49) below which comprises subjecting a compound of formula (48) below or a reactive derivative thereof to a ring closure reaction

68. A process for the preparation of a compound of formula (I) below

69. A substantially pure optically active substance of formula (53) below