Thiazolidin-4-one derivatives

1. A pharmaceutical composition containing at least one thiazolidin-4-one derivative of the Formula (I)

wherein:

R 1 represents a phenyl group independently mono-, di- or trisubstituted with lower alkyl, halogen, lower alkoxy, or —CF 3 ;

R 2 represents lower alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower alkylamino;

R 3 represents —O—CR 7 R 8 —CR 9 R 10 —(CR 11 R 12 ) n —O—R 13 ;

R 4 represents hydrogen; hydroxy; lower alkoxy; lower alkyl; or halogen;

R 5 and R 6 each represents independently lower alkyl;

R 7 represents hydrogen, lower alkyl, or hydroxymethyl;

R 8 , R 9 , R 11 and R 12 each represents independently hydrogen or methyl;

R 10 represents hydrogen or lower alkyl; in case n represents the integer 1, R 10 in addition represents lower alkoxy, hydroxy, —NH 2 , —NHR 5 or —NR 5 R 6 ;

R 13 represents hydrogen; lower alkyl; hydroxycarbonyl-lower lower alkyl; 1-glyceryl or 2-glyceryl;

n represents the integer 0 or 1;

or configurational isomers, optically pure enantiomers, mixtures of enantiomers, enantiomeric racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, or a meso-form thereof, or pharmaceutically acceptable salts thereof, and inert carrier material.

2. The pharmaceutical composition according to claim 1 , in which said thiazolidin-4-one derivatives are (Z,Z)-isomers.

3. The pharmaceutical composition of claim 1 further comprising one or more immunosuppressant compounds.

4. The pharmaceutical composition according to claim 3 , wherein said immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathiopirene, leflunomide, and 15-deoxyspergualin.

5. Thiazolidin-4-one derivatives of the Formula (II)

wherein:

R 14 represents a phenyl group mono-, di- or trisubstituted independently with lower alkyl, halogen, lower alkoxy. or —CF 3 ;

R 15 represents lower alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower alkylamino;

R 16 represents hydrogen; hydroxy: lower alkoxy; lower alkyl or halogen;

R 17 represents hydrogen, lower alkyl, or hydroxymethyl;

R 18 , R 19 , R 21 and R 22 each represents independently hydrogen or methyl;

R 20 represents hydrogen or lower alkyl; and in case m represents the integer 1, R 20 in addition represents lower alkoxy, hydroxy, —NH 2 , —NHR 5 or —NR 5 R 6 ;

R 23 represents hydrogen; lower alkyl; hydroxycarbonyl-lower alkyl; 1-glyceryl or 2-glyceryl;

m represents the integer 0 or 1;

or configurational isomers, optically pure enantiomers, mixtures of enantiomers, enantiomeric racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, or a meso-form thereof, or pharmaceutically acceptable salts thereof.

6. Thiazolidin-4-one derivatives according to claim 5 in which said thiazolidin-4-one derivatives according to formula (II) are (Z,Z) isomers.

7. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group.

8. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen.

9. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 15 represents lower alkyl.

10. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 16 represents halogen or methyl.

11. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein m represents the integer 0, and R 17 , R 18 , R 19 and R 20 represent hydrogen.

12. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein m represents the integer 1, R 17 , R 18 , R 19 , R 21 and R 22 , represent hydrogen, and R 20 represents hydroxy.

13. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 23 represents hydrogen.

14. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein m represents the integer 0, R 17 , R 18 , R 19 , R 20 and R 23 represent hydrogen.

15. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein m represents the integer 1, R 17 , R 18 , R 19 , R 21 , R 22 and R 23 represent hydrogen, and R 20 represents hydroxy.

16. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, and R 15 represents lower alkyl.

17. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, m represents the integer 0, and R 17 , R 18 , R 19 , R 20 and R 23 represent hydrogen.

18. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, m represents the integer 1, R 17 , R 18 , R 19 , R 21 , R 22 and R 23 represent hydrogen, and R 20 represents hydroxy.

19. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, and R 15 represents lower alkyl, R 16 represents methyl or halogen, m represents the integer 0, and R 17 , R 18 , R 19 , R 20 and R 23 each represent hydrogen.

20. Thiazolidin-4-one derivatives according to claim 5 or 6 , wherein R 14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen; and R 15 represents lower alkyl, R 16 represents methyl or halogen, m represents the integer 1, R 17 , R 18 , R 19 , R 21 R 22 , R 23 represent hydrogen, and R 20 represents hydroxy.

21. A thiazolidin-4-one derivative according to claim 5 selected from the group consisting of:

5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-[Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-2-([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-m-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-m-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino) 3-m-tolyl-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-p-tolyl-thiazolidin-4-one,

5-[4-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-p-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-p-tolyl-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-3-(2,3-dimethyl-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[3-fluoro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropyiimino)-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-isopropylimino)thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

3-(2,4-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,

3-(2,6-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,

3-(2-chloro-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2-chloro-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2-chloro-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-(2-methoxy-phenyl)-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-(2-methoxy-phenyl)-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-(4-methoxy-phenyl)-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-(4-methoxy-phenyl)-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

(S)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-thiazolidin-4-one,

5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-3-(2,3-dimethyl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-propylimino)-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-propylimino)-thiazolidin-4-one,

5-[4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ytidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,

2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-o-tolyl-thiazolidin-4-one,

3-(2,3-dimethyl-phenyl)-2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-ethyiimino)-thiazolidin-4-one,

2-([Z]-butylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-tolyl-thiazolidin-4-one,

2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-tolyl-thiazolidin-4-one,

2-([Z]-butylimino)-3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-thiazolidin-4-one,

2-([Z]-butylimino)-5-(3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-thiazolidin-4-one, and

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-methylimino)-thiazolidin-4-one.

22. A thiazolidin-4-one derivative according to claim 5 selected from the group consisting of:

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

(S)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,

5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one, and

5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)-2-([Z]-ethyiimino)-thiazolidin-4-one.

23. A pharmaceutical composition comprising at least one thiazolidin-4-one derivative of claim 5 and inert carrier material.

24. A process for the preparation of a pharmaceutical composition comprising mixing one or more thiazolidin-4-one derivatives of any one of claim 5 , 21 or 22 with inert excipients.

25. A process for the preparation of the pharmaceutical composition of claim 1 , comprising mixing one or more thiazolidin-4-one derivatives according to Formula (I) with inert excipients.

26. The compound, (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one.

27. A pharmaceutical composition comprising the compound of claim 26 and inert carrier material.