Thiazolidin-4-one derivatives
View Patent ↗The invention relates to pharmaceutical compositions containing at least one thiazolidin-4-one derivative to prevent or treat disorders associated with an activated immune system. Furthermore, the invention relates to novel thiazolidin-4-one derivatives notably for use as pharmaceutically active compounds. Said compounds particularly act also as immunosuppressive agents.
1. A pharmaceutical composition containing at least one thiazolidin-4-one derivative of the Formula (I)
wherein:
R 1 represents lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; 5,6,7,8-tetrahydronaphth-2-yl; or an unsubstituted phenyl group;
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 alkyl; 1-glyceryl or 2-glyceryl;
n represents the integer 0 or 1;
in a configurational isomeric, an optically pure enantiomeric, a mixture of enantiomeric, an enantiomeric racemate, a diastereomeric, a mixture of diastereomeric, a diastereomeric racemate, a mixture of diastereomeric racemates, a meso-form, free or pharmaceutically acceptable salt form, and an inert carrier material.
2. The pharmaceutical composition according to claim 1 , in which said thiazolidin-4-one derivatives is a (Z,Z)-isomer.
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. A thiazolidin-4-one derivative of Formula (II)
wherein:
R 14 represents lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; 5,6,7,8-tetrahydronaphth-2-yl; or an unsubstituted phenyl group;
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;
R 5 and R 6 each represents independently lower alkyl;
m represents the integer 0 or 1;
in a configurational isomeric, an optically pure enantiomeric, a mixture of enantiomeric, an enantiomeric racemate, a diastereomeric, a mixture of diastereomeric, a diastereomeric racemate, a mixture of diastereomeric racemates, a meso-form, a free or a pharmaceutically acceptable salt form.
6. The thiazolidin-4-one derivative according to claim 5 in which said thiazolidin-4-one derivative according to formula (II) is a (Z,Z) isomer.
7. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 14 represents an unsubstituted phenyl group.
8. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 15 represents lower alkyl.
9. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 16 represents halogen or methyl.
10. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein m represents the integer 0, and R 17 , R 18 , R 19 and R 20 represent hydrogen.
11. The thiazolidin-4-one derivative 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.
12. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 23 represents hydrogen.
13. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein m represents the integer 0, and R 17 , R 18 , R 19 , R 20 and R 23 represent hydrogen.
14. The thiazolidin-4-one derivative 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.
15. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 14 represents an unsubstituted phenyl group, and R 15 represents lower alkyl.
16. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 14 represents an unsubstituted phenyl group, m represents the integer 0, and R 17 , R 18 , R 19 , R 20 and R 23 represent hydrogen.
17. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 14 represents an unsubstituted phenyl group, 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.
18. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 14 represents an unsubstituted phenyl group, 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.
19. The thiazolidin-4-one derivative according to claim 5 or 6 , wherein R 14 represents an unsubstituted phenyl group, 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 and R 23 represent hydrogen, and R 20 represents hydroxy.
20. The 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-phenyl-thiazolidin-4-one,
{2-[4-(2-([Z]-isopropylimino)-4-oxo-3-phenyl-thiazolidin-5-[Z]-ylidenemethyl)-phenoxy]-ethoxy}-acetic acid,
5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[3-fluoro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
3-allyl-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,
3-allyl-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,
3-allyl-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
2-([Z]-tert-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
2-(dimethyl-hydrazono)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-(dimethyl-hydrazono)-3-phenyl-thiazolidin-4-one,
2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-phenyl-thiazolidin-4-one,
2-([Z]-butylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
2-([Z]-sec-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
2-([Z]-cyclopropylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
3-cyclohexyl-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-cyclohexyl-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin-4-one,
2-([Z]-allylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
2-([Z]-allylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
3-allyl-2-([Z]-allylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-thiazolidin-4-one,
3-allyl-2-([Z]-allylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-thiazolidin-4-one, and
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-methylimino)-3-phenyl-thiazolidin-4-one.
21. The 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-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-thiazolidin -4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thiazolidin-4-one,
2-(dimethyl-hydrazono)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-phenyl-thiazolidin -4-one, and
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopropylimino)-thiazolidin-4-one.
22. A pharmaceutical composition comprising at least one thiazolidin-4-one derivative of claim 5 and inert carrier material.
23. A process for the preparation of a pharmaceutical composition comprising mixing one or more thiazolidin-4-one derivatives of any one of claim 5 , 20 or 21 with an inert excipient.
24. A process for the preparation of the pharmaceutical composition of claim 1 , comprising mixing one or more thiazolidin-4-one derivatives according to claim 1 with an inert excipient.