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):	Christoph Binkert, Martin Bolli, Boris Mathys, Claus Mueller, Michael Scherz, Oliver Nayler
Assignee:	Vanda Pharmaceuticals Inc
Application Number:	US13/194,172
Patent Claims:	1. A pharmaceutical composition containing at least one thiazolidin-4-one derivative of the Formula (I) wherein: R1 represents a phenyl group independently mono-, di- or trisubstituted with lower alkyl, halogen, lower alkoxy, or —CF3; R2 represents lower alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower alkylamino; R3 represents —O—CR7R8—CR9R10—(CR11R12)n—O—R13; R4 represents hydrogen; hydroxy; lower alkoxy; lower alkyl; or halogen; R5 and R6 each represents independently lower alkyl; R7 represents hydrogen, lower alkyl, or hydroxymethyl; R8, R9, R11 and R12 each represents independently hydrogen or methyl; R10 represents hydrogen or lower alkyl; in case n represents the integer 1, R10 in addition represents lower alkoxy, hydroxy, —NH2, —NHR5 or —NR5R6; R13 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: R14 represents a phenyl group mono-, di- or trisubstituted independently with lower alkyl, halogen, lower alkoxy. or —CF3; R15 represents lower alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower alkylamino; R16 represents hydrogen; hydroxy: lower alkoxy; lower alkyl or halogen; R17 represents hydrogen, lower alkyl, or hydroxymethyl; R18, R19, R21 and R22 each represents independently hydrogen or methyl; R20 represents hydrogen or lower alkyl; and in case m represents the integer 1, R20 in addition represents lower alkoxy, hydroxy, —NH2, —NHR5 or —NR5R6; R23 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 R14 represents a mono- or disubstituted phenyl group. 8. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen. 9. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R15 represents lower alkyl. 10. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R16 represents halogen or methyl. 11. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 0, and R17, R18, R19 and R20 represent hydrogen. 12. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 1, R17, R18, R19, R21 and R22, represent hydrogen, and R20 represents hydroxy. 13. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R23 represents hydrogen. 14. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 0, R17, R18, R19, R20 and R23 represent hydrogen. 15. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein m represents the integer 1, R17, R18, R19, R21, R22 and R23 represent hydrogen, and R20 represents hydroxy. 16. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, and R15 represents lower alkyl. 17. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, m represents the integer 0, and R17, R18, R19, R20 and R23 represent hydrogen. 18. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, m represents the integer 1, R17, R18, R19, R21, R22 and R23 represent hydrogen, and R20 represents hydroxy. 19. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen, and R15 represents lower alkyl, R16 represents methyl or halogen, m represents the integer 0, and R17, R18, R19, R20 and R23 each represent hydrogen. 20. Thiazolidin-4-one derivatives according to claim 5 or 6, wherein R14 represents a mono- or disubstituted phenyl group, substituted with methyl or halogen; and R15 represents lower alkyl, R16 represents methyl or halogen, m represents the integer 1, R17, R18, R19, R21 R22, R23 represent hydrogen, and R20 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.