Claims for Patent: RE43728

Summary for Patent: RE43728

Title:	Thiazolidin-4-one derivatives
Abstract:	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.
Inventor(s):	Binkert; Christoph (Basel, CH), Bolli; Martin (Allschwil, CH), Mathys; Boris (Egerkingen, CH), Mueller; Claus (Weil am Rhien, DE), Scherz; Michael (Ettingen, CH), Nayler; Oliver (Arlesheim, CH)
Assignee:	Actelion Pharmaceuticals Ltd. (Allschwil, CH)
Application Number:	13/194,172
Patent Claims:	1. A pharmaceutical composition containing at least one thiazolidin-4-one derivative of the Formula (I) ##STR00236## wherein: R.sup.1 represents a phenyl group independently mono-, di- or trisubstituted with lower alkyl, halogen, lower alkoxy, or --CF.sub.3; R.sup.2 represents lower alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower alkylamino; R.sup.3 represents --O--CR.sup.7R.sup.8--CR.sup.9R.sup.10--(CR.sup.11R.sup.12).sub.n--O--R.s- up.13; R.sup.4 represents hydrogen; hydroxy; lower alkoxy; lower alkyl; or halogen; R.sup.5 and R.sup.6 each represents independently lower alkyl; R.sup.7 represents hydrogen, lower alkyl, or hydroxymethyl; R.sup.8, R.sup.9, R.sup.11 and R.sup.12 each represents independently hydrogen or methyl; R.sup.10 represents hydrogen or lower alkyl; in case n represents the integer 1, R.sup.10 in addition represents lower alkoxy, hydroxy, --NH.sub.2, --NHR.sup.5 or --NR.sup.5R.sup.6; R.sup.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) ##STR00237## wherein: R.sup.14 represents a phenyl group mono-, di- or trisubstituted independently with lower alkyl, halogen, lower alkoxy. or --CF.sub.3; R.sup.15 represents lower alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower alkylamino; R.sup.16 represents hydrogen; hydroxy: lower alkoxy; lower alkyl or halogen; R.sup.17 represents hydrogen, lower alkyl, or hydroxymethyl; R.sup.18, R.sup.19, R.sup.21 and R.sup.22 each represents independently hydrogen or methyl; R.sup.20 represents hydrogen or lower alkyl; and in case m represents the integer 1, R.sup.20 in addition represents lower alkoxy, hydroxy, --NH.sub.2, --NHR.sup.5 or --NR.sup.5R.sup.6; R.sup.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.sup.14 represents a mono- or disubstituted phenyl group. 8. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.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.sup.15 represents lower alkyl. 10. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.16 represents halogen or methyl. 11. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 0, and R.sup.17, R.sup.18, R.sup.19 and R.sup.20 represent hydrogen. 12. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21 and R.sup.22, represent hydrogen, and R.sup.20 represents hydroxy. 13. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.23 represents hydrogen. 14. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 0, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.23 represent hydrogen. 15. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21, R.sup.22 and R.sup.23 represent hydrogen, and R.sup.20 represents hydroxy. 16. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, and R.sup.15 represents lower alkyl. 17. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, m represents the integer 0, and R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.23 represent hydrogen. 18. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, m represents the integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21, R.sup.22 and R.sup.23 represent hydrogen, and R.sup.20 represents hydroxy. 19. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, and R.sup.15 represents lower alkyl, R.sup.16 represents methyl or halogen, m represents the integer 0, and R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.23 each represent hydrogen. 20. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R.sup.14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen; and R.sup.15 represents lower alkyl, R.sup.16 represents methyl or halogen, m represents the integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21 R.sup.22, R.sup.23 represent hydrogen, and R.sup.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-t- hiazolidin-4-one, 5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-2-([Z]-isopropyli- mino)-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]-isopropylimin- o)-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]-isopropylimi- no) 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]-isopropylimi- no)-3-p-tolyl-thiazolidin-4-one, 3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-is- opropylimino)-thiazolidin-4-one, 5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-3-(2,3-dimethyl-p- henyl)-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-phe- nyl)-2-([Z]-isopropylimino)-thiazolidin-4-one, 3-(2,4-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-is- opropylimino)-thiazolidin-4-one, 3-(2,6-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-is- opropylimino)-thiazolidin-4-one, 3-(2-chloro-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopro- pylimino)-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-metho- xy-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-metho- xy-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-thi- azolidin-4-one, 5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-th- iazolidin-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]-propylim- ino)-3-o-tolyl-thiazolidin-4-one, (S)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim- ino)-3-o-tolyl-thiazolidin-4-one, 3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-pr- opylimino)-thiazolidin-4-one, 5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-3-(2,3-dimethyl-p- henyl)-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-phe- nyl)-2-([Z]-propylimino)-thiazolidin-4-one, 2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-tolyl-thia- zolidin-4-one, 5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-o-t- olyl-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-thia- zolidin-4-one, 2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-t- olyl-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]-isopropylimi- no)-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-phe- nyl)-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]-propylim- ino)-3-o-tolyl-thiazolidin-4-one, (S)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim- ino)-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-phe- nyl)-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]-propylim- ino)-3-o-tolyl-thiazolidin-4-one. 27. A pharmaceutical composition comprising the compound of claim 26 and inert carrier material.