Novel Thiophene Derivatives as Immunosuppressive Agents

1. Novel thiophene derivatives of the General Formula (I),

General Formula (I) wherein

A represents -CH2CH2-; -CH=CH-, or -NH-CH2-;

R1 represents hydrogen, lower alkyl, and in the case X represents C-R4, R1 in addition represents halogen;

R2 represents hydrogen, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkyl, di-(hydroxy-lower alkyl)- lower alkoxy, 1 -glyceryl, 2-glyceryl, pyridin-3-yl-methoxy, pyridin-4-yl-methoxy;

R3 represents hydrogen, lower alkyl, mono- or di-lower alkylamino, trifluoromethyl, or trifluoromethoxy; and in the case X represents C-R4, R3 in addition represents halogen;

X represents N, or C-R 44.. R4 represents hydrogen, lower alkyl, lower alkoxy, halogen;

and configurational isomers, diastereomers, mixtures of diastereomers, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

2. Thiophene derivatives according to claim 1 wherein A represents -CH=CH-, and R1, R2, R3, and X are as defined in claim 1.

3. Thiophene derivatives according to claim 1 wherein A represents -NH-CH2-, and R1, R2, R3, and X are as defined in claim 1.

4. Thiophene derivatives accoding to claim 1 wherein A represents -CH2CH2-, and R1, R2, R3, and X are as defined in claim 1.

5. Thiophene derivatives according to claim 1 wherein X represents N, and R1, R2, R3, and A are as defined in claim 1.

6. Thiophene derivatives according to claim 1 wherein X represents C-R4, and R1, R2, R3, R4, and A are as defined in claim 1.

7. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, and R2, R3, and A are as defined in claim 1.

8. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 and R3 both represent hydrogen, and R2 and A are as defined in claim 1.

9. Thiophene derivatives according to claim 1 wherein R2 represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R1, R3, A, and X are as defined in claim 1.

10. Thiophene derivatives according to claim 1 wherein R2 represents an (S)-1- glyceryl group, and R1, R3, A and X are as defined in claim 1.

11. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-Iower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R3 and A are as defined in claim 1.

12. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents hydrogen, R1 and R3 both represent a methyl group ortho to R2, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A is as defined in claim 1.

13. Thiophene derivatives according to claim 1 wherein X represents N, A represents -CH2-CH2-, and R1, R2, and R3 are as defined in claim 1.

14. Thiophene derivatives according to claim 1 wherein X represents C-R4, A represents -CH2-CH2-, and R1, R2, R3, and R4 are as defined in claim 1.

15. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, A representsCH2-CH2-, and R2 and R3 are as defined in claim 1.

16. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 and R3 both represent hydrogen, A represents -CH2-CH2-, and R2 is as defined in claim 1.

17. Thiophene derivatives according to claim 1 wherein R2 represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH2-CH2-, and R1, R3, and X are as defined in claim 1. 18. Thiophene derivatives according to claim 1 wherein R2 represents an (S)-1- glyceryl group, A represents -CH2-CH2-, and R1, R3, and X are as defined in claim 1.

19. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, R2 represents hydroxy-lower alkoxy, hydroxy-lower alky!, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH2-CH2-, and R3 is as defined in claim 1.

20. Thiophene derivatives according to claim 1 wherein X represents C-R4, whereby R4 represents hydrogen, R1 and R3 both represent a methyl group ortho to R2, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A represents -CH2-CH2-.

21. Novel thiophene derivatives of the General Formula (II),


General Formula (II)

wherein

A represents -CH2CH2-; -CH=CH-, or -NH-CH2-; R1 represents hydrogen, lower alkyl, and in the case X represents C-R4, R1 in addition represents halogen;

R2 represents hydrogen, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkyl, di-(hydroxy-lower alkyl)- lower alkoxy, 1 -glyceryl, 2-glyceryl, pyridin-3-yl-methoxy, pyridin-4-yl-methoxy;

R3 represents hydrogen, lower alkyl, mono- or di-lower alkylamino, trifluoromethyl, or trifluoromethoxy; and in the case X represents C-R4, R3 in addition represents halogen;

X represents N, or C-R4;

R4 represents hydrogen, lower alkyl, lower alkoxy, halogen;

and configurational isomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

22. Thiophene derivatives according to claim 21 wherein A represents -CH=CH-, and R1, R2, R3, and X are as defined in claim 21.

23. Thiophene derivatives according to claim 21 wherein A represents -NH-CH2-, and R1, R2, R3, and X are as defined in claim 21.

24. Thiophene derivatives accoding to claim 21 wherein A represents -CH2CH2-, and R1, R2, R3, and X are as defined in claim 21.

25. Thiophene derivatives according to claim 21 wherein X represents N, and R1, R2, R3, and A are as defined in claim 21. 26. Thiophene derivatives according to claim 21 wherein X represents C-R4, and R1, R2, R3, R4, and A are as defined in claim 21.

27. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, and R2, R3, and A are as defined in claim 21.

28. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 and R3 both represent hydrogen, and R2 and A are as defined in claim 21.

29. Thiophene derivatives according to claim 21 wherein R2 represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R1, R3, A, and X are as defined in claim 21.

30. Thiophene derivatives according to claim 21 wherein R2 represents an (S)-1- glyceryl group, and R1, R3, A and X are as defined in claim 21.

31. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R3 and A are as defined in claim 21.

32. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents hydrogen, R1 and R3 both represent a methyl group ortho to R2, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower aikyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A is as defined in claim 21.

33. Thiophene derivatives according to claim 21 wherein X represents N, A represents -CH2-CH2-, and R1, R2, and R3 are as defined in claim 21. 34. Thiophene derivatives according to claim 21 wherein X represents C-R4, A represents -CH2-CH2-, and R1, R2, R3, and R4 are as defined in claim 21.

35. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, A representsCH2-CH2-, and R2 and R3 are as defined in claim 21.

36. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 and R3 both represent hydrogen, A represents -CH2-CH2-, and R2 is as defined in claim 21.

37. Thiophene derivatives according to claim 21 wherein R2 represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH2-CH2-, and R1, R3, and X are as defined in claim 21.

38. Thiophene derivatives according to claim 21 wherein R2 represents an (S)-1- glyceryl group, A represents -CH2-CH2-, and R1, R3, and X are as defined in claim 21.

39. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents a methoxy. group, R1 represents hydrogen, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH2-CH2-, and R3 is as defined in claim 21.

40. Thiophene derivatives according to claim 21 wherein X represents C-R4, whereby R4 represents hydrogen, R1 and R3 both represent a methyl group ortho to R2, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A represents -CH2-CH2-. 41. Novel thiophene derivatives of the General Formula (III),

General Formula (III) wherein

A represents -CH2CH2-; -CH=CH-, or -NH-CH2-;

R1 represents hydrogen, lower alkyl, and in the case X represents C-R4, R1 in addition represents halogen;

R2 represents hydrogen, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkyl, di-(hydroxy-lower alkyl)- lower alkoxy, 1 -glyceryl, 2-glyceryl, pyridin-3-yl-methoxy, pyridin-4-yl-methoxy;

R3 represents hydrogen, lower alkyl, mono- or di-lower alkylamino, trifluoromethyl, or trifluoromethoxy; and in the case X represents C-R4, R3 in addition represents halogen;

X represents N, or C-R4;

R4 represents hydrogen, lower alkyl, lower alkoxy, halogen; and configurational isomers, diastereomers, mixtures of diastereomers, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

42. Thiophene derivatives according to claim 41 wherein A represents -CH=CH-, and R1, R2, R3, and X are as defined in claim 41.

43. Thiophene derivatives according to claim 41 wherein A represents -NH-CH2-, and R1, R2, R3, and X are as defined in claim 41.

44. Thiophene derivatives accoding to claim 41 wherein A represents -CH2CH2-, and R1, R2, R3, and X are as defined in claim 41.

45. Thiophene derivatives according to claim 41 wherein X represents N, and R1, R2, R3, and A are as defined in claim 41.

46. Thiophene derivatives according to claim 41 wherein X represents C-R4, and R1, R2, R3, R4, and A are as defined in claim 41.

47. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, and R2, R3, and A are as defined in claim 41.

48. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 and R3 both represent hydrogen, and R2 and A are as defined in claim 41.

49. Thiophene derivatives according to claim 41 wherein R2 represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R1, R3, A, and X are as defined in claim 41.

50. Thiophene derivatives according to claim 41 wherein R2 represents an (S)-1- glyceryl group, and R1, R3, A and X are as defined in claim 41. 51. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyi)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R3 and A are as defined in claim 41.

52. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents hydrogen, R1 and R3 both represent a methyl group ortho to R2, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A is as defined in claim 41.

53. Thiophene derivatives according to claim 41 wherein X represents N, A represents -CH2-CH2-, and R1, R2, and R3 are as defined in claim 41.

54. Thiophene derivatives according to claim 41 wherein X represents C-R4, A represents -CH2-CH2-, and R1, R2, R3, and R4 are as defined in claim 41.

55. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, A representsCH2-CH2-, and R2 and R3 are as defined in claim 41.

56. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 and R3 both represent hydrogen, A represents -CH2-CH2-, and R2 is as defined in claim 41.

57. Thiophene derivatives according to claim 41 wherein R2 represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH2-CH2-, and R1, R3, and X are as defined in claim 41. 58. Thiophene derivatives according to claim 41 wherein R2 represents an (S)-1- glyceryl group, A represents -CH2-CH2-, and R1, R3, and X are as defined in claim 41.

59. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents a methoxy group, R1 represents hydrogen, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-Iower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-gIyceryl, A represents -CH2-CH2-, and R3 is as defined in claim 41.

60. Thiophene derivatives according to claim 41 wherein X represents C-R4, whereby R4 represents hydrogen, R1 and R3 both represent a methyl group ortho to R2, R2 represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A represents -CH2-CH2-.

61. A thiophene derivative according to any one of claims 1 do 20 selected from the group consisting of: (1 aS,5aR)-1 ,1 ,2-Trimethyl-i ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2,4-dimethoxy-benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-ethoxy-2-methoxy-benzylamide, (1aS,5aR)-1 ,1,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methyl-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxy1ic acid 4-((S)-2,3-dihydroxy-propoxy)-2- methoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2- methoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-methyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-methyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-chloro- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-chloro- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-2-chloro- benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2-chloro- benzylamidθ, (1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)- benzylamide, (laS.δaRJ-i .i ^-trimethyl-i .ia.δ.δa-tΘtrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyM ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-methoxy- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- 5 cyclopropa[a]pentalene-4-carboxyIic acid 4-(2-hydroxy-ethoxy)-3-methyl- benzylamide, (1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa4etrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3-chloro- benzylamidθ, 0 (1aS,6aR)-1 ,1,2-trimethyl-1,1a,6,6a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-chloro- benzylamidθ, (laS.δaR^I .I^-trimethyl-i.ia.δ.δa-tetrahydro-S-thia- cyciopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-θthoxy)-benzylamide, δ (1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3,δ- dimethyl-benzylamide, (1aS,δaR)- 1 ,1,2-trimethyl-1,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy- 0 benzylamidθ, (1 aS,δaR)-1 ,1 ,2-trimethyl-i ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-methyl- benzylamide, (1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- δ cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-chloro- benzylamide, (laS.δaRJ-i .i ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-chloro- benzylamide, 0 (1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3,5-dimethyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-methoxy- benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-i ,1 a,5,5a-tθtrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3-methyl- benzylamidθ, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3-chloro- benzylamide, (laS.δaRJ-i .i^-trimethyl-i.ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-chlorc- benzylamide, (1aS,δaR)-1 Λ24rimethyl-1Ja,δ,δa-tetrahydrc>-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-3,δ-dimethyl- benzylamide, (1 aS,δaR)-1 ,1 ,2-trimethyl-i ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-2-methoxy- benzylamide, (1aS,δaR)-1 ,1 ,2-trimethyl-i ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-chloro-4-(2-fluoro-ethoxy)- benzylamide, (1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-benzylamide, (1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxyIic acid 4-(3-fluoro-propoxy)-2-methoxy- benzylamide, (1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyciopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-propoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-isopropoxy-benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-isobutoxy-2-methoxy-benzylamide, 5 (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(6-hydroxy-hexyioxy)-2-methoxy- benzylamide, (laS.δaRH .I ^rimethyM .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-2-hydroxymethyl-propoxy)- 0 3,5-dimethyl-benzylamide, (laS.δaRH.I^-trimethyM .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-(pyridin-3-ylmethoxy)- benzylamide, (1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- δ cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-(pyridin-4-ylmethoxy)- benzylamidθ, (laS.δaR^I .I ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxyiic acid (pyridin-2-ylmethyl)-amidθ, 3-(2-methoxy-phenyl)-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3- 0 thia-cyclopropa[a]penta-len-4-yl)-propan-1 -one, 3-[4-((S)-2,3-dihydroxy-propoxy)-2-methoxy-phenyl]-1-((1aS,δaR)-1 ,1 )2- trimethyl-1 ,1 a.δ.δa-tθtrahydro-S-thia-cyclopropatalpentalen^-yD-propan-i -one, 3-[4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl- 1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one, δ 3-[4-((S)-2,3-dihydroxy-propoxy)-3,δ-dimethyl-phenyl]-1-((1aS,δaR)-1 ,1 ,2- trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one, 3-[4-((R)-2,3-dihydroxy-propoxy)-3,δ-dimethyl-phenyl]-1 -((1 aS,δaR)-1 ,1 ,2- trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropa^pentalen^-yO-propan-i-one, 3-[4-(2-hydroxy-ethoxy)-3,δ-dimethyl-phenyi]-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl- 0 1 ,1 a.δ.δa-tetrahydro-S-thia-cyclopropatalpentalen^-ylJ-propan-i -one, 3-[4-(2-(R/S)-hydroxy-propoxy)-3,δ-dimethyl-phenyl]-1 -(1 ,1 ,2-trimethyl- 1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one, 3-[4-(2-(2-fluoroethoxy)-3,5-dimethyl-phenyI]-1-(1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one, 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one,

and pharmaceutically acceptable salts thereoff.

62. A thiophene derivative according to any of claims 1 do 61 for use as a medicament.

63. A process for the manufacture of compounds as claimed in any one of claims 1 do 61 , which process comprises

a) reacting the compound of Structure 9 or 10 with 2-mercaptoacetic acid in the presence of a base;

Structure 9 Structure 10

b) reacting a compound of Structure 8 with an non-aqueous base;

Structure 8

c) reacting a compound of Structure 7 with an aqueous base;
Structure 7

d) reacting a compound of Structure 1 with a compound of Structure 2 in the presence of activating agents,

Structure 2

e) reacting a compound of Structure 1 with N,O-dimethyIhydroxylamine in the presence of an activating agent;

f) reacting a compound of Structure 3 with a Grignard reagent of Structure 4;

Structure 4

g) reacting a compound of Structure 1 with methyllithium;

h) reacting a compound of Structure 5 with a compound of Structure 6 in the presence of a base;
Structure 5 Structure 6

i) reacting a compound of Structure 11 with hydrogen in the presence of a hydrogenation catalyst.

64. Pharmaceutical compositions containing a compound according to any of claims 1 do 61 and usual carrier materials and adjuvants for the prevention or treatment of disorders associated with an activated immune system.

65. Pharmaceutical compositions containing a compound according to any of claims 1 do 61 and usual carrier materials and adjuvants for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

66. Pharmaceutical compositions containing a compound according to any of claims 1 do 61 and usual carrier materials and adjuvants for the prevention or treatment of diseases or disorders associated with an activated immune system selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto’s thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet’s disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post¬ infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren’s ulcer; ulcerative keratitis; scleritis; Gravesophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn’s disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture’s syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere’s disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow’s disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington’s chorea; Sydenham’s chorea; myocardosis; scleroderma; Wegener’s granuloma; Sjogren’s syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary’s syndrome; chronic adrenal insufficiency; Addison’s disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; “acute-on-chronicliver failure.

67. Pharmaceutical compositions according to claim 66, for the treatment of prevention of disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn’s disease; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

68. Use of one or more compounds of the General Formula (I) in claim 1 for the prevention or treatment of diseases or disorders associated with an activated immune system.

69. Use of one or more compounds of the General Formula (II) in claim 21 for the prevention or treatment of diseases or disorders associated with an activated immune system.

70. Use of one or more compounds of the General Formula (III) in claim 41 for the prevention or treatment of diseases or disorders associated with an activated immune system. 71. Use of one or more compounds of the General Formula (I) in claim 1 for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

72. Use of one or more compounds of the General Formula (II) in claim 21 for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

73. Use of one or more compounds of the General Formula (III) in claim 41 for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

74. Use of one or more compounds of General Formula (I) according to claim 68 for the treatment or prevention of diseases or disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto’s thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet’s disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren’s ulcer; ulcerative keratitis; scleritis; Gravesophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn’s disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture’s syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere’s disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow’s disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington’s chorea; Sydenham’s chorea; myocardosis; scleroderma; Wegener’s granuloma; Sjogren’s syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary’s syndrome; chronic adrenal insufficiency; Addison’s disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; “acute-on-chronicliver failure.

75. Use of one or more compounds of General Formula (II) according to claim 69 for the treatment or prevention of diseases or disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto’s thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet’s disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren’s ulcer; ulcerative keratitis; scleritis; Gravesophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; asthmatic bronchiole; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn’s disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture’s syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere’s disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow’s disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington’s chorea; Sydenham’s chorea; myocardosis; scleroderma; Wegener’s granuloma; Sjogren’s syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary’s syndrome; chronic adrenal insufficiency; Addison’s disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; “acute-on-chronicliver failure.

76. Use of one or more compounds of General Formula (III) according to claim 70 for the treatment or prevention of diseases or disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto’s thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet’s disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; epidermolysis bullosa; angioedema; urticaria; bullous pemphigoid; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren’s ulcer; ulcerative keratitis; scleritis; Gravesophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn’s disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture’s syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere’s disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow’s disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington’s chorea; Sydenham’s chorea; myocardosis; scleroderma; Wegener’s granuloma; Sjogren’s syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary’s syndrome; chronic adrenal insufficiency; Addison’s disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; retinitis pigmetosa; psoriasis; pulmonary emphysema; cataracta; siderosis; lymphoma ; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; “acute-on-chronicliver failure. 77. Use of one or more compounds of General Formula (I) according to claim 68 in which said disorders are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn’s disease; post- infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

78. Use of one or more compounds of General Formula (II) according to claim 69 in which said disorders are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn’s disease; post¬ infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

79. Use of one or more compounds of General Formula (III) according to claim 70 in which said disorders are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn’s disease; post¬ infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

80. Use of one or more compounds of the General Formula (I) in claim 1 in combination with one or several immunosuppressant compounds for the treatment of disorders associated with an activated immune system.

81. Use of one or more compounds of the General Formula (II) in claim 21 in combination with one or several immunosuppressant compounds for the treatment of disorders associated with an activated immune system.

82. Use of one or more compounds of the General Formula (III) in claim 41 in combination with one or several immunosuppressant compounds for the treatment of disorders associated with an activated immune system.

83. Use of one or more compounds of General Formula (I) according to claim 80 wherein said other immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathiopirene, leflunomide, 15-deoxysperguaIin, or other immunosuppressant drugs.

84. Use of one or more compounds of General Formula (II) according to claim 81 wherein said other immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathiopirene, leflunomide, 15-deoxyspergualin, or other immunosuppressant drugs.

85. Use of one or more compounds of General Formula (III) according to claim 82 wherein said other immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathiopirene, leflunomide, 15-deoxyspergualin, or other immunosuppressant drugs.

86. A method for the prevention or treatment of disorders associated with an activated immune system comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (I) in claim 1.

87. A method for the prevention or treatment of disorders associated with an activated immune system comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (II) in claim 21.

88. A method for the prevention or treatment of disorders associated with an activated immune system comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (III) in claim 41. 89. A method for the prevention or treatment of disorders of organ transplant rejection or graft-versus-host diseases comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (I) in claim 1.

90. A method for the prevention or treatment of disorders of organ transplant rejection or graft-versus-host diseases comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (II) in claim 21.

91. A method for the prevention or treatment of disorders of organ transplant rejection or graft-versus-host diseases comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (III) in claim 41.

92. A method according to claim 86 or 89 by administering to a patient a dose of the thiophene derivative of the General Formula (I) in claim 1 between 0.5 mg and 1000 mg per day.

93. A method according to claim 87 or 90 by administering to a patient a dose of the thiophene derivative of the General Formula (II) in claim 21 between 0.5 mg and 1000 mg per day.

94. A method according to claim 88 or 91 by administering to a patient a dose of the thiophene derivative of the General Formula (III) in claim 41 between 0.5 mg and 1000 mg per day.

95. A method according to claim 92 by administering to a patient a dose of the thiophene derivative of the General Formula (I) between 1 mg and 500 mg per day. 96. A method according to claim 93 by administering to a patient a dose of the thiophene derivative of the General Formula (II) between 1 mg and 500 mg per day.

97. A method according to claim 94 by administering to a patient a dose of the thiophene derivative of the General Formula (III) between 1 mg and 500 mg per day.

98. A method according to claim 92 by administering to a patient a dose of the thiophene derivative of the General Formula (I) between 5 mg and 200 mg per day.

99. A method according to claim 93 by administering to a patient a dose of the thiophene derivative of the General Formula (II) between 5 mg and 200 mg per day.

100. A method according to claim 94 by administering to a patient a dose of the thiophene derivative of the General Formula (III) between 5 mg and 200 mg per day.

101. A process for the preparation of a pharmaceutical composition comprising a compound of the General Formula (I) in claim 1, characterized by mixing one or more active ingredients according to any one of claims 1 do 20, i 61 with inert excipients in a manner known per se.

102. A process for the preparation of a pharmaceutical composition comprising a compound of the General Formula (II) in claim 21, characterized by mixing one or more active ingredients according to any one of claims 21 do 40 with inert excipients in a manner known perse.

103. A process for the preparation of a pharmaceutical composition comprising a compound of the General Formula (III) in claim 41 , characterized by mixing one or more active ingredients according to any one of claims 41 do 60 with inert excipients in a manner known per se.

Source: http://www.wipo.int/pctdb/ja/wo.jsp?WO=2006010379&IA=EP2004008501&DISPLAY=CLAIMS

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