RHODANINE CARBOXYLIC ACID DERIVATIVES FOR THE TREATMENT AND PREVENTION OF METABOLIC BONE DISORDERS

Abstract: The object of the present invention are compounds of general formula (I), in which m signifies a number between 0-8, q signifies a number between 0-8, a signifies a number between 0-4, A signifies a single or double bond, R1, R2 signify hydrogen or lower alkyl, whereby R1 and R2 can be the same or different and, when m signifies 2-8, R1 and R2 in the group CR1=CR2 can have various significances within the following sequence, R3 signifies hydrogen or lower alkyl, X signifies hydrogen or -(CH2)b-COR4 with b=0-4, Y signifies hydrogen, -COR4, phenyl or indolyl residue R4 signifies hydroxyl, lower alkoxy or the NR1R2 residue, whereby R1 and R2 can be the same or different, W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments for the prophylaxis or therapy of metabolic bone disorders.

Description: Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders The present invention is concerned with rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders, a process for their manufacture as well as medicaments which contain these compounds. In healthy persons the synthesis and degradation processes in bones is almost in equilibrium, i.e. the activity of the osteoblasts and osteoclasts is balanced. However, if this equilibrium is disturbed in favour of the osteoclasts and/or to the detriment of the osteoblasts, this leads to a reduction in the bone mass and to a negative change in the bone structure and function. Hitherto, bone resorption inhibitors such as oestrogens, calcitonin and biphosphonates have primarily been used for the treatment of metabolic bone disorders. The use of these substances is, however, limited and also does not show the desired effect in all cases. Compounds which have a stimulating activity on bone synthesis and in addition contribute to an increase in an already reduced bone mass are accordingly of especial significance for the treatment of metabolic bone disorders. Compounds having the rhodanine carboxylic acid structural element are known as antidiabetics, cytostatics inflammation inhibitors and for the treatment of cardiovascular illnesses and bacterial infections The parathyroid hormone (PTH), a hormone from the parathyroid gland, is the natural ligand of the receptor and an important regulator for the maintenance of the calcium level in the body. PTH can stimulate bone formation or bone resorption. In this, it acts as a regulatory hormone on a series of enzymes, inter alia, on adenylate cyclase (cAMP synthesis) and on ornithine decarboxylase. PTH mobilizes calcium from bones in the case of calcium deficiency, reduces calcium excretion from the kidneys and simultaneously improves the resorption of calcium from the intestine by an increased synthesis of l,25-(OH) 2 D 3 . A normalization of the calcium level is achieved by the action on these target organs. On the other hand, the incorporation of calcium in bones is stimulated in the case of an elevated calcium level. This osteoanabolic activity of PTH and its fragments has been attributed to the activation of adenylate cyclase and of cAMP-dependent protein kinases (Rixon, R. Whitfield, J. et al JMBR 9 (8) 1179-89 (1994). Surprisingly, it has now been found that rhodanine carboxylic acid derivatives of the present invention stimulate the PTH receptor-mediated cAMP formation. Compounds of the present invention are accordingly suitable for the broad treatment of metabolic bone disorders. They can be used primarily to good effect where the bone synthesis is disturbed, i.e. they are especially suitable for the treatment of osteopenic disorders of the skeletal system such as e.g. osteoporosis, inter alia, osteogenesis imperfecta as well as for the local assistance in bone regeneration and osteoinduction such as e.g. in orthopedic and maxillary medical indications, in fracture healing, osteosyn theses, pseudoarthroses and for the healing in of bone implants. However, having regard to these properties they also find use in the prophylaxis of osteoporosis. By their influence on bone metabolism medicaments with the rhodanine carboxylic acid derivatives of the present invention as active substances furthermore form a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis. The object of the present invention are compounds of general formula (I), in which m signifies a number between 0-8, q signifies a number between 0-8 a signifies a number between 0-4 A signifies a single or double bond R R 2 signify hydrogen or lower alkyl, whereby Ri and R 2 can be the same or different and, when m signifies 2-8, Ri and R 2 in the group CRι=CR 2 can have various significances within the following sequence R 3 signifies hydrogen or lower alkyl X signifies hydrogen or -(CH 2 ) b -COR 4 with b = 0-4 Y signifies hydrogen, -COR 4 , phenyl or indolyl residue R 4 signifies hydroxyl, lower alkoxy or the NRiR 2 residue, whereby Rj and R 2 can be the same or different W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, As a rule, lower alkyl signifies linear or branched alkyl residues with one to six carbon atoms, preferably methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl, particularly methyl. Alkoxy groups signify a combination of a - o-alkyl group in accordance with the above definition with an oxygen atom, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups. Under monocycle there are to be understood optionally mono- or polysubstituted, saturated or unsaturated ring systems with 3-8, preferably 5-7 carbon atoms, which optionally can be interrupted by one or more hetero atoms, such as nitrogen, oxygen or sulphur, especially the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue, as well as residues such as e.g. phenyl phenyl ether, diphenylmethane and biphenyl. Substituents are preferably lower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen. In the case of the bicycle set forth under W, this is preferably a residue such as the naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, chromane, chromene, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinyl residue, especially the indolyl, naphthyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl benzothiophenyl and benzofuranyl residue, which optionally can be mono- or polysubstituted. Substituents are preferably lower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen. In the case of the tricycle set forth under W, this is preferably a residue such as the anthracene, fluorene, dibenzofuran or carbazole. Compounds of formula I wherein W is phenyl or indolyl, m and g are both 0, R 3 is hydrogen and A is a double bond are disclosed e.g. in EP-A-0677 and EP-A-0587377, however for the treatment of Alzheimer's disease or as hypoglycemic agents. Therefore subject of the present invention are also new compounds of formula I in which m signifies a number between 0-8, q signifies a number between 0-8 a signifies a number between 0-4 A signifies a single or double bond R b R 2 signify hydrogen or lower alkyl, whereby Ri and R 2 can be the same or different and, when m signifies 2-8, Ri and R 2 in the group CRι=CR 2 can have various significances within the following sequence R 3 signifies hydrogen or lower alkyl X signifies hydrogen or -(CH 2 ) b -COR 4 with b = 0-4 Y signifies hydrogen, -COR^ phenyl or indolyl residue Ri signifies hydroxyl, lower alkoxy or the NRιR 2 residue, whereby Ri and R 2 can be the same or different W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, whereas W is not phenyl or indolyl, if m and g are both 0, R 3 is hydrogen and A is a double bond, as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers, as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments. Preferred are compounds of general formula I in which m signifies a number between 0 and 4, q signifies the number 0 or 1, a signifies a number of 0 to 4, A signifies a double bond, R 1)2 signify hydrogen or methyl, X signifies hydrogen or -(CH 2 ) b -COR 4 with b = 0- 2 and R equals hydroxyl, methoxy or NRιR 2 , Y signifies hydrogen or COR , the phenyl or indolyl residue, R 3 signifies hydrogen or methyl and W signifies an optionally mono- or polysubstituted benzothiophene, phenyl, benzofuran, thiophene, naphthalene, piperidine, cyclohexenyl or biphenyl residue. The manufacture of the compounds of general formula (I) is possible according to methods known per se. Examples of the methods of synthesis are set forth in Schemes 1 and 2; whereby R signifies the group: Scheme 1 (Lit.: Chem. Pharm. Bull. 38 1911-19 (1990); 40 907-11 (1992)) NaBH 4 Scheme 2 (Lit: Chem. Heterocycl. Compd. EN 3 528-30 (1967)) The rhodanine carboxylic acids and aldehydes used as starting materials are either commercially available, known or can be prepared analogously to the generally known processes. Compounds of formula (I) can be administered (sic) in liquid, solid or aerosol form orally, enterally, parenterally, topically, nasally, pulmonary or rectally in all usual non- toxic pharmaceutically acceptable carrier materials, adjuvants and additives. The compounds of formula (I) can also be applied locally to/in the bones (optionally with surgical intervention). The term parenteral embraces subcutaneous, intravenous and intramuscular delivery or infusions. Oral administration forms can be e.g. tablets, capsules, dragees, syrups, solutions, suspensions, emulsions, elixirs etc., which can contain one or more additives from the following groups, such as flavourings, sweeteners, colouring agents and preservatives. Oral administration forms contain the active ingredient together with non-toxic, pharmaceutically acceptable carrier materials which are suitable for the production of tablets, capsules, dragees etc., such as e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose, talc, highly dispersible silicic acids, high molecular fatty acids (such as stearic acid), groundnut oil, olive oil, paraffin, miglyol, gelatine, agar-agar, magnesium stearate, beeswax, cetyl alcohol, lecithin, glycerol, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycol). Tablets, capsules, dragees etc. can be provided with an appropriate coating, e.g. glyceryl mono- stearate or glyceryl distearate, in order to prevent undesired side effects in the gastrointestinal tract or to give a longer duration of action by the delayed absorption in the gastrointestinal tract. As the injection medium there are preferably used sterile injectable aqueous or oily solutions or suspensions which contain the usual additives such as stabilizers and solubilizers. Such additives can be e.g. water, isotonic saline, 1,3- butanediol, fatty acids (such as oleic acid), mono- and diglycerides or miglyol. For rectal use there can be used all suitable non-irritating additives which are solid at normal temperatures and liquid at rectal temperatures, such as e.g. cocoa butter and polyethylene glycol. Pharmaceutically usual carrier media are used for application as aerosols. Creams, tinctures, gels, solutions or suspensions etc. with the pharmaceutically usual additives are used for external application. The dosage can depend n a variety of factors such as mode of administration, species, age and/or individual condition. The doses to be administered daily or at intervals lie at 1- 1000 mg/individual, preferably at 10-250 mg/individual, and can be taken at one time or divided over several times. The compounds of formula (I) can also be applied locally to/in the bones (optionally with surgical intervention). The application directly to/in the bones (optionally with surgical intervention) can be effected locally or carrier-bonded either in solution or suspension, conveniently by infusion or injection. Carrier-bonded compounds of formula (I) can be administered, for example, as gels, pastes, solids or as a coating on implants. Biocompatible and preferably biodegradable materials are used as the carrier. Preferably, the materials themselves also induce wound healing or osteogenesis. For local application it is preferred that the compounds of formula (I) are imbedded in polymer gels or films in order to immobilize them and to apply these preparations directly on the site of the bone to be treated. Such polymer-based gels or films consist, for example, of glycerine, methylcellulose, hyaluronic acid, polyethylene oxides and/or poloxamers. Also suitable are collagen, gelatines and alginates and are described, for example, in WO 93/00050 and WO 93/20859. Further polymers are pol lactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLPG) (Hollinger el al., J. Biomed. Mater. Res. 17 71-82 ( 1983)) as well as the bone derivative "Demineralized Bone Matrix" (DBM) (Guterman et al. Kollagen Rel. Res. 8419-4319 (1988). Also suitable are polymers as are used, for example, for the adsorption of TGFβ and which are described in EP-A 0 616 814 and EP-A-0 567 391 and synthetic bone matrices in accordance with WO 91/18558. Likewise suitable as carriers for the compounds of formula (I) are materials which are usually used for the implantation of bone substitutes or otherwise of therapeutically active substances. Such carriers are based, for example, on calcium sulphate, tricalcium phosphate, hydroxylapatite (sic) and its biodegradable derivatives and polyanhydrides. Apart from these biodegradable carriers there are also suitable carriers which are not biodegradable, but which are biocompatible. Such carriers are, for example, sintered hydroxylapatite, bioglass, aluminates or other ceramic materials (e.g. calcium aluminium phosphate). These materials are preferably used in combination with the biodegradable materials, such as especially polylactic acid, hydroxylapatite, collagen or tricalcium phosphate. Further non-degradable carriers are described, for example, in US Patent 4,164,560. It is especially preferred to use a carrier which liberates the compounds of formula (I) continuously at the target site. Especially suitable for this are e.g. "slow release pellets" from Innovative Research of America, Toledo, Ohio, USA. Pellets which release the compounds of formula (I) over several days, preferably up to 100 days with a daily dosage of 1-10 mg/kg per day, are especially preferred. Preferred in the scope of the present invention are, apart form the compounds named in the Examples and compounds derivable by a combination of all of the significances of the substituents set forth in the claims, the following derivatives as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments, Preferred Compounds (PC): 1. [5-(9H-Fluoren-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 2. (4-Oxo-5-phenanthren-9-ylmethyl-2-thioxo-thiazolidin-3-yl)-acetic acid 3. [5-(3-Anthracen-9-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 4. 3-[5-(10-Methyl-anthracen-9-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 5. 3-[5-(5-Furan-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 6. 2-(5-Benzylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-succinic acid 7. 2-[5-(2-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 8. [4-Oxo-2-thioxo-5-(2,3,4-trimethoxy-benzyl)-thiazolidin-3-yl]-acetic acid 9. {5- [3-(2,4-Dimethoxy-phenyl)-allylidene] -4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 10. 3-[4-Oxo-2-thioxo-5-(2,4,5-trimethoxy-benzylidene)-thiazolidin-3-yl]- propionic acid 11. 3-{4-Oxo-2-thioxo-5- [3-(2,4,6-trimethoxy-phenyl)-allylidene] -thiazolidin-3- yl} -propionic acid 12. 2-[5-(2,5-Dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinic acid 13. 2-[5-(2-Ethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 14. [5-(2-Hydroxy-3-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 15. {5-[3-(3-Ethoxy-2-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl}- acetic acid 16. 3-[5-(2,3-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 17. 3-{4-Oxo-2-thioxo-5- [3-(2,3,4-trihydroxy-phenyl)-allylidene] -thiazolidin-3-yl}- propionic acid 18. 2-[5-(4-Diethylamino-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- yl]-succinic acid 19. 2-[5-(2-Hydroxy-4-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 20. [5-(2-Hydroxy-5-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 21. {5-[3-(2,5-Dihydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 22. 3- [5-(2-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 23. 3-{5-[3-(4-Methoxy-2,3-dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 24. 2- [4-Oxo-2-thioxo-5-(2,4,6-trimethyl-benzylidene)-thiazolidin-3-yl] -succinic acid 25. 2- [5-(2,5-Dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -pentane- dicarboxylic acid 26. {5-[3-(4-Methoxy-phenoxy)-benzyl] -4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 27. (5-{3-[3-(4-tert-Butyl-phenoxy)-phenyl]-allylidene}-4-oxo-2-thioxo- thiazolidin-3-yl)-acetic acid 28. 3- [4-Oxo-2-thioxo-5-(3-#p!-tolyloxy-benzylidene)-thiazolidin-3-yl] -propionic acid 29. 3-{5-[3-(3-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 30. 2- [5-(3,4-Dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -succinic acid 31. 2-[4-Oxo-2-thioxo-5-(3,4,5-trimethoxy-benzylidene)-thiazolidin-3-yl]- pentanedicarboxylic acid 32. [5-(3,5-Dimethoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 33. {5-[3-(3-Benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 34. 3- [5-(3-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 35. 3-{5-[3-(3-Hydroxy-4-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl} -propionic acid 36. 2-[5-(3,4-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinic acid 37. 2-[5-(3-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 38. [5-(4-Dimethylamino-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 39. {5-[3-(4-Diethylamino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 40. 3- [4-Oxo-5-(4-phenoxy-benzylidene)-2-thioxo-thiazolidin-3-yl] -propionic acid 41. 3-{5-[3-(4-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 42. 2-[5-(3-Benzyloxy-4-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 43. 2- [5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -pentane- dicarboxylic acid 44. [5-(4-Butoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 45. [5-(3-Naphthalen-l-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 46. 3-[5-(2-Methoxy-naphthalen-l-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 47. 3-{5- [3-(2-Hydroxy-naphthalen- 1 -yl)-allylidene] -4-oxo-2-thioxo-thiazolidin-3- yl} -propionic acid 48. 2-[5-(4-Methoxy-naphthalen-l-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 49. 2-(5-Naphthalen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentane- dicarboxylic acid 50. [5-(9-Ethyl-9H-carbazol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 51. {5-[3-(lH-Indol-3-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 52. 3-[5-(5-Methoxy-lH-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 53. 3-[5-(3-Benzo[l,3]dioxol-5-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 54. 2-[5-(4-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 55. [5-(4-Hydroxy-3,5-dimethoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 56. {5-[3-(3-Ethoxy-4-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl}-acetic acid 57. 3-[5-(4-Hydroxy-3,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 58. 3- [5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 59. 2-[5-(4-Isopropyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 60. [5-(4-Ethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 61. [5-(4,4-Diphenyl-but-2-enylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 62. 3-[4-Oxo-5-(2-phenyl-propylidene)-2-thioxo-thiazolidin-3-yl] -propionic acid 63. 3-[5-(4-Methyl-5-phenyl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3- yl] -propionic acid 64. 2-[5-(2-Hexyl-3-phenyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 65. [4-Oxo-5-(5-phenyl-penta-2,4-dienylidene)-2-thioxo-thiazolidin-3-yl] -acetic acid 66. 3-{5- [3-(2-Methoxy-phenyl)-allylidene] -4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 67. 3-{5- [5-(4-Dimethylamino-phenyl)-penta-2,4-dienylidene] -4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 68. [5-(3-Ethoxy-4-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 69. {5-[3-(4-Diethoxymethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 70. 3-[5-(4-Dimethylamino-naphthalen-l-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -propionic acid 71. 2-[5-(2,4-Dimethoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 72. [4-Oxo-5-(4-styryl-benzylidene)-2-thioxo-thiazolidin-3-yl] -acetic acid 73. {5-[4-(3-Dimethylamino-propoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 74. {5-[3-(2,4-Dihydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 75. 3-[5-(2-Methyl-lH-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 76. 3-{5-[3-(4-Hydroxy-3-methyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin- 3-yl}-propionic acid 77. 2-[5-(2-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 78. [4-Oxo-5-(4-propoxy-benzyl)-2-thioxo-thiazolidin-3-yl] -acetic acid 79. {4-Oxo-5-[3-(4-pentyloxy-phenyl)-allylidene]-2-thioxo-thiazolidin-3-yl}-acetic acid 80. 3- [5-(4-Octyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 81. 3-{5-[3-(5-Benzyloxy-lH-indol-3-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl} -propionic acid 82. 2-(5-Benzofuran-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentane- dicarboxylic acid 83. [4-Oxo-5-(2,3,4,5,6-pentamethyl-benzyl)-2-thioxo-thiazolidin-3-yl]-acetic acid 84. {5-[3-(2-Benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 85. 3-[4-Oxo-2-thioxo-5-(2,3,4-trimethoxy-6-methyl-benzylidene)-thiazolidin-3- yl] -propionic acid 86. 3-{5-[3-(3-Ethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 87. 2-[5-(3,4-Dihydroxy-5-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- yl]-pentanedicarboxylic acid 88. [5-(3,4-Dimethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 89. {5-[3-(4-Ethoxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl} -acetic acid 90. 3- [ 5- (4-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 91. 3-{5- [3-(4-Heptyloxy-phenyl)-allylidene] -4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 92. 2-(5-Benzo[l,3]dioxol-4-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)- pentanedicarboxylic acid 93. [4-Oxo-2-thioxo-5-(2,4,5-trimethyl-benzyl)-thiazolidin-3-yl] -acetic acid 94. {5-[3-(4-Decyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 95. 3-{5-[3-(4-tert-Butyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 96. {5-[3-(4-Amino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 97. 3-[5-(2-tert-Butylsulphanyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 98. 3-{5-[3-(4-Butyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- propionic acid 99. 2- [5-(4-tert-Butoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -pentane- dicarboxylic acid 100. [4-Oxo-5-(4-propyl-benzylidene)-2-thioxo-thiazolidin-3-yl] -acetic acid 101. [5-(4-Hexyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 102. {5-[3-(4-Octyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 103. 3-[5-(4-Dodecyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 104. 3-{4-Oxo-5-[3-(4-pentyl-phenyl)-allylidene]-2-thioxo-thiazolidin-3-yl}- propionic acid 105. 2-[5-(3-Amino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 106. [5-(7-Methyl- lH-indol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 107. 3- [4-Oxo-2-thioxo-5-(2-p-tolyl-ethylidene)-thiazolidin-3-yl] -propionic acid 108. 3-{5-[3-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-yl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 109. [5-(4-Hydroxy-2-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 110. {5- [3-(2,2-Dimethyl-chroman-6-yl)-allylidene] -4-oxo-2-thioxo-thiazolidin-3- yl}-acetic acid 111. 3-[5-(4-Isopropoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid 112. 2- [5-(4-Methyl-naphthalen- l-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl] - pentanedicarboxylic acid 113. {5-[3-(2,3-Dihydro-benzofuran-5-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl} -acetic acid 114. 3-(4-Oxo-5-quinolin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-propionic acid 115. 3-{5-[5-(4-Diethylamino-phenyl)-penta-2,4-dienylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 116. 2-[5-(4-Isobutyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pentane- dicarboxylic acid 117. [5-(6-Methoxy-naphthalen-2-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 118. {5-[3-(3,5-Dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 119. 3- [5-( l-Hydroxy-naphthalen-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl] - propionic acid 120. [5-(4-Octadecyloxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 121. {5-[3-(4-Diphenylamino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 122. 3-[4-Oxo-2-thioxo-5-(3,4,5-trihydroxy-benzylidene)-thiazolidin-3-yl]- propionic acid 123. 3-{5- [3-(4-Dimethylamino-2-methoxy-phenyl)-allylidene] -4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 124. {5-[2-(2-Hydroxy-ethoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 125. (5-{3-[4-(2-Hydroxy-ethoxy)-phenyl]-allylidene}-4-oxo-2-thioxo-thiazolidin-3- yl)-acetic acid 126. 3- [5-(2-Benzyloxy-ethylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 127. 3-{5- [3-(4-tert-Butoxycarbonyloxy-3-methoxy-phenyl)-allylidene] -4-oxo-2- thioxo-thiazolidin-3-yl} -propionic acid 128. 2-[5-(2,4-Diethoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 129. [5-(2-Benzyloxy-3-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 130. {5-[3-(4-Methanesulphonyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl} -acetic acid 131. 3-[5-(2-Hydroxy-5-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 132. (4-Oxo-5-thiophen-2-ylmethyl-2-thioxo-thiazolidin-3-yl)-acetic acid 133. [5-(5-Naphthalen-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3- yl] -acetic acid 134. 3- [4-Oxo-5-(3-thiophen-2-yl-allylidene)-2-thioxo-thiazolidin-3-yl] -propionic acid 135. 3-{5-[3-(2-[ l,3]Dioxolan-2-yl-6-fluoro-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl} -propionic acid 136. 2-[5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 137. [5-(4-Benzyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 138. {5-[5,9-Dimethyl-l l-(2,6,6-trimethyl-cyclohex-l-enyl)-undeca-2,4,6,8,10- pentaenylidene]-4-oxo-2-thioxo-thiazolidin-3-yl} -acetic acid 139. 3- [4-Oxo-5-( lH-pyrrol-2-ylmethylene)-2-thioxo-thiazolidin-3-yl] -propionic acid 140. 3- [5-(3-Furan-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -propionic acid 141. 2-{5-[3-(5,6-Diethoxy-benzo[fc]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-pentanedicarboxylic acid 142. (4-Oxo-5-pyridin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-acetic acid 143. [5-(l-Methyl-lH-pyrrol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 144. {5- [3-(2-Hydroxy-4,6-dimethoxy-phenyl)-allylidene] -4-oxo-2-thioxo- thiazolidin-3-yl}-acetic acid 145. 3- [5-(4-Benzyloxy-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] - propionic acid 146. 3-{5-[3-(5-Benzyloxy-2-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 147. 2-{5- [4-(Benzo[ l,3]dioxol-5-ylmethoxy)-benzylidene] -4-oxo-2-thioxo- thiazolidin-3-yl} -pen tanedicarboxylic acid 148. [5-(4-Benzyloxy-3,5-dihydroxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 149. {5-[3-(2,5-Bis-benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- acetic acid 150. 3-[5-(4-Benzyloxy-3,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid 151. 3-[5-(3-Cyclohexyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid 152. 2-{5-[3-Methyl-5-(2,6,6-trimethyl-cyclohex-l-enyl)-penta-2,4-dienylidene]-4- oxo-2-thioxo-thiazolidin-3-yl}-pentanedicarboxylic acid 153. [5-(3,4-Diethoxy-2,5-dimethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid 154. {5-[5-(3,4-Diethoxy-2,5-dimethyl-phenyl)-penta-2,4-dienylidene]-4-oxo-2- thioxo-thiazolidin-3-yl} -acetic acid 155. [5-(2-Carboxymethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] - propionic acid 156. 2-{3-[3-(2-Carboxy-ethyl)-4-oxo-2-thioxo-thiazolidin-5-yliden]-propenyl}- benzoic acid 157. 2- [5-(4-Acetoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -pentane- dicarboxylic acid 158. Methyl 4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benzoate 159. 4-[3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-propenyl]- benzoic acid 160. 3-{4-[3-(2-Carboxy-ethyl)-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl]- phenyl} -acrylic acid 161. 3-{4-Oxo-5-[3-(4-oxo-4H-chromen-3-yl)-allylidene]-2-thioxo-thiazolidin-3- yl} -propionic acid 162. 2- [5-(4-Acetoxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] - pentanedicarboxylic acid 163. 3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benzoic acid 164. 4- [3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-propenyl] -phenyl propionate 165. 3-[5-(5,7-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -propionic acid 166. 3-{5-[3-(2-Ethoxycarbonylmethoxy-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 167. 2-[5-(8-Carboxy-naphthalen-l-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedicarboxylic acid 168. [5-(3,4-Diacetoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 169. {5-[3-(2-Amino-4-oxo-4H-chromen-3-yl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-acetic acid 170. 3-[5-(2-Amino-6,7-dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2- thioxo-thiazolidin-3-yl] -propionic acid 171. 3-{5-[3-(6-Ethyl-4-oxo-4H-chromen-3-yl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-propionic acid 172. 2-[5-(6,8-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -pentanedicarboxylic acid 173. Methyl 2-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benzoate 174. Methyl 3-[3-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-propenyl]- lH-indole-6-carboxylate 175. 3-{5-[3-(4-Acetoxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin- 3 -yl} -propionic acid 176. 3- [4-Oxo-5-(3-phenyl-but-2-enylidene)-2-thioxo-thiazolidin-3-yl] -propionic acid 177. 2-[4-Oxo-2-thioxo-5-(l-#p!-tolyl-ethylidene)-thiazolidin-3-yl]-pentane- dicarboxylic acid 178. {5-[l-(4-Methoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 179. {5-[l-(3,4-Dichloro-phenyl)-ethyl]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid 180. [4-Oxo-5-(3-thiophen-2-yl-but-2-enylidene)-2-thioxo-thiazolidin-3-yl]-acetic acid 181. 3-[4-Oxo-5-(l l-oxo-6,ll-dihydro-dibenzo[fc,e]oxepin-3-ylmethylene)-2- thioxo-thiazolidin-3-yl] -propionic acid 182. 3-{5-[3-(3,5-Dihydroxy-phenyl)-but-2-enylidene]-4-oxo-2-thioxo-thiazolidin- 3-yl}-propionic acid 183. 2- [5-(4-Hydroxy-3-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] - succinic acid 184. 2-[5-(4-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-succinic acid 185. 2-(4-Oxo-5-phenthylidene-2-thioxo-thiazolidin-3-yl)-succinic acid 186. 2-[5-(2,3-Dihydro-benzo[ l,4]dioxin-6-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -succinic acid 187. 2- [4-Oxo-5-(4-styryl-benzylidene)-2-thioxo-thiazolidin-3-yl] -succinic acid 188. 2- [5-(4-Allyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -succinic acid 189. 2- [4-Oxo-5-(4-pyrrolidin- l-yl-benzylidene)-2-thioxo-thiazolidin-3-yl] -succinic acid 190. 2-[5-(3,5-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -succinic acid 191. 2-{5-[3-(4-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- succinic acid 192. 2-[4-Oxo-5-(4-propyl-benzylidene)-2-thioxo-thiazolidin-3-yl]-succinic acid 193. 2-[5-(2-Ethoxy-naphthalen-l-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 194. 2-[5-(3-Furan-2-yl-2-methyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 195. 2-{5-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-succinic acid 196. 2-{5-[3-(4-tert-Butyl-phenyl)-2-methyl-allylidene]-4-oxo-2-thioxo-thiazolidin- 3 -yl} -succinic acid 197. 2-{5-[3-(2-Hydroxy-ethoxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- succinic acid 198. 2-{5-[3-(4-Hydroxy-3,5-dimethoxy-phenyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl}-succinic acid 199. 2-[5-(3-Benzo[fc]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 200. 2- [5-(2,4-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -succinic acid 201. 2-(4-Oxo-5-pyridin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-succinic acid 202. 2-[5-(4-Benzyloxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- yl]- succinic acid 203. 2- [5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -succinic acid 204. 2-[5-(3-Carboxy-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 205. 2-[5-(4-Carboxymethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid 206. 2-[5-(6-Methyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -succinic acid 207. 2-[5-(6-Isopropyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -succinic acid 208. 2-{5-[ l-(4-Methoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}- succinic acid The following Examples show some process variants which can be used for the synthesis of the compounds in accordance with the invention. However, they are not intended to be a limitation of the object of the invention. The structure of the compounds was proven by Η- and, where necessary, by ' C-NMR spectroscopy. The purity of the substances was determined by C, H, N, P analysis as well as by thin-layer chromatography. Example 1 General Process A: 5 mmol of aldehyde of the formula R-CO, wherein R has the significance given above, and 5 mmol of 4-oxo-2-thioxo-thiazolidin-3-ylcarboxylic acid derivative are heated at reflux for 10 hours together with 15 mmol of sodium acetate and 15 ml of glacial acetic acid. After cooling, the mixture is poured into H 2 O. The precipitate is filtered off under suction, rinsed with H 2 O and dried. For purification, it is chromatographed over silica gel with ethyl acetate/heptane (2:1). The preparation of 2-(4-oxo-2-thioxo-thiazolidin-3-yl)-glutaric acid and 2-(4-oxo-2- thioxo-thiazolidin-3-yl)-succinic acid is effected according to Chem. Heterocycl. Compd. EN 3 528-30 (1967). 2-(5-Benzo[b]tlιiophen-2-ylmethylene-4-oxo-2-t ioxo-t azoUdin-3-yl)-succinic acid (I) Yellow crystals; m.p. 240°C (dec.) 2-(5-Benzo[b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-pentanedioic acid (2) Yellow crystals; m.p. 220- 1°C 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3- phenyl-propionic acid (3) Yellow crystals; m.p. 160°C (dec.) 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3- (lH-indol-3-yl)-propionic acid (4) Orange crystals; m.p. 140°C (dec.) [5-(5-Acetylamino-benzo[b]thiophen-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3- yl] -acetic acid (5) Yellow crystals; m.p. >240°C 5-[3-(4-Methoxy-2,5-dimethyl-phenyl)-allyliden]-4-oxo-2-thioxo-thiazolidin-3-yl- acetic acid (6} Red crystals; m.p. >240°C 5- [3- (3,5-Di-tert-butyl-4-hydroxy-phenyl)-allylidene] -4-oxo-2-thioxo-thiazolidin-3-yl- acetic acid (7) Yellow crystals; m.p. >240°C [5-(2,3-Dihydro-benzofuran-5-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (8) Yellow crystals; m.p. 246-7°C (4-Oxo-5-thiophen-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-acetic acid (9) Yellow crystals; m.p. 237-9°C (5-Benzo[b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-acetic acid (10) Yellow crystals; m.p. 292 -4°C [5-(3-Naphthalen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (ll) Orange crystals; 275-7°C [5-(4-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (12) Yellow crystals; m.p. 244-6°C [5-(5-Benzo[b]thiophen-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- acetic acid (13) Red crystals; m.p. >240°C [5- (4-Hydroxy-benzyUdene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid ( 14) Yellow crystals; m.p. 230-2°C [5-(4-Methoxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (15) Yellow crystals; m.p. 240°C [5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazoUdin-3-yl]-acetic acid (16) Orange crystals; m.p. >240°C [5-(4-Methoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (17) Yellow crystals; m.p. 235-6°C 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- pentanedioic acid (18) Yellow crystals; m.p. 130°C (dec.) [5-(4-Benzyloxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (19) M.p. 128-30°C [5-(3 > 4-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (20) Yellow crystals; m.p. 187-8°C [5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (21) Orange crystals; m.p. 130°C (dec.) 5-[l-Methyl-3-(2,6,6-trimethyl-cyclohex-l-enyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl-acetic acid (22) Brown crystals; m.p. 100°C (dec.) [5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (23) Yellow crystals; m.p. >240°C 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- succinic acid (24) Brown crystals; m.p. 240°C (dec.) [5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (25) Orange crystals; m.p. 120- 1°C [5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (26) Yellow crystals; m.p. 205-6°C 5- [ l-(3,5-Dmydroxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (27) Yellow crystals; m.p. 184-8°C 5- [ l-(4-Carboxymethoxy-phenyl)-ethylidene] -4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (28) Yellow crystals; m.p. 111-20°C (dec.) [4-Oxo-2-thioxo-5-(2,3,4-trihydroxy-benzylidene)-thiazolidin-3-yl]-acetic acid (29) Ochre-coloured crystals; m.p. 263°C (dec.) [5-(2-Hydroxy-4,6-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (30) Pale brown crystals; m.p. 194°C (dec.) [5-(3-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (3i) Yellow crystals; m.p. 178-81°C 3-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid (32) Yellow crystals; m.p. 188-91°C 2-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid (33) Yellow crystals; m.p. 125-8°C [5-(5-Benzyloxy-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (34) Orange crystals; m.p. 130-3°C 5- [4-(4-Methoxy-benzyloxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (35) Yellow crystals; m.p. 172-3°C 5-[4-(Benzo[l,3]dioxol-5-ylmetJιoxy)-benzyUdene]-4-oxo-2-thioxo-thiazolidin-3-yl- acetic acid (36) Yellow crystals; m.p. 206-7°C 5-[4-Oxo-2-thioxo-5-(3,4,5-trihydroxy-benzylidene)-thiazolidin-3-yl]- pentanecarboxylic acid (37) m.p. 212-4°C 5-[4-(3-Metlιoxy-benzyloxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (38) Yellow crystals; m.p. 191-3°C [5-(4-Hydroxy-3,5-dmιethyl-benzyUdene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (39) Orange crystals; m.p. 277-9°C [5-(4-Benzyloxy-3,5-dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (40) M.p. 178-80°C [5-(2,5-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (41) Yellow crystals; m.p. 196-8°C [4-Oxo-2-thioxo-5- (3,4,5-triacetoxy-benzylidene)-thiazolidin-3-yl] -acetic acid (42) Orange crystals; m.p. 200°C (dec.) 5-[3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- yl-acetic acid (43) Red crystals; m.p. 252 -3°C (5-Cyclohex-3-enybnethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-acetic acid (44) Beige crystals; m.p. 180-2°C [4-Oxo-5-(3-phenyl-propylidene)-2-thioxo-thiazolidin-3-yl] -acetic acid (45) Orange crystals; m.p. 108-11°C 5-[3-Methyl-5-(2,6,6-trimethyl-cyclohex-l-enyl)-penta-2,4-dienyliden]-4-oxo-2- thioxo-thiazolidin-3-yl-acetic acid (46) Orange crystals; m.p. 153-5°C 5-(3,5-Di-tert-butyl-4-hydroxy-benzyUdene)-3-memyl-2-1_hioxo-thiazolidin-4-one (47) Yellow crystals; m.p. >240°C Methyl [5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- yl] -acetate (48) Yellow crystals; m.p. 165-70°C 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-N,N- diethyl-acetamide (49) Yellow crystals; m.p. 223-5°C Methyl 5-[3-(5,6-diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl-acetate (50) Violet crystals; m.p. 211-5°C 2-5-[3-(5,6-Diemoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thioxo-thiazolidin- 3-yl-N,N-diethyl-acetamide (51) Red crystals; m.p. 210-2°C Benzyl 4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl)-piperidine-l- carboxylate (52) Yellow crystals; m.p. 114-5°C 5-[3,7-Dimethyl-9-(2,6,6-trimethyl-cyclohex-l-enyl)-nona-2,4,6,8-tetraenylidene]-4- oxo-2-thioxo-thiazolidin-3-yl-acetic acid (53) Black (sic) crystals; m.p. 144°C (dec.) [5-(3,4-Dihydroxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (54) Yellow crystals; m.p. >240°C [5-(3 > 4-Diethoxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (55) Ochre coloured crystals; m.p. 185-90°C 5-[3-(3,4-Diethoxy-2,5-dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl- acetic acid (56) Green crystals; m.p. 210°C (dec.) 5-[5-Methyl-7-(2,6 > 6-trimethyl-cyclohex-l-enyl)-hepta-2,4,6-trienyliden]-4-oxo-2- thioxo-thiazolidin-3-yl-acetic acid (57) Black crystals; m.p. 192-5°C 3-(5-Benzo [ 1 ,3] dioxol-5-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-propionic acid (58) Yellow crystals; m.p. 174-6°C 3- [4-Oxo-2-thioxo-5- (2,6,6- trimethyl-cyclohex- l-enylmethylene)-thiazolidin-3-yl]- propionic acid (59) Yellow-orange crystals; m.p. 166-8°C 3-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- propionic acid (60) Yellow crystals; m.p. 218-9°C 3-(5-Naphώalen-l-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-propionic acid (61) Orange crystals; m.p. 159-61°C 3-[5-(3-Benzo[b] iophen-2-yl-aUylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-propionic acid (62) Orange crystals; m.p. 246-8°C [5-(4-Dibutylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (63) Orange crystals; m.p. 186-8°C [4-Oxo-5-(4-pentyl-benzylidene)-2-thioxo-thiazolidin-3-yl]-acetic acid (64) Yellow crystals; m.p. 160-2°C [5-(3-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (65) Yellow crystals; m.p. 193-6°C [4-Oxo-2-tWoxo-5-(2,4,5-trimemyl-benzyUdene)-thiazolidin-3-yl]-acetic acid (66) Yellow crystals; m.p. 234-6°C [5- (2-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (67) Yellow crystals; m.p. 148-50°C [5-(4-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (68) Yellow crystals; m.p. 234-6°C [5- (4-Memoxy-2,3-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (69) Yellow crystals; m.p. 215-7°C [5-(4-Hydroxy-3,5-dimethoxy-benzyUdene)-4-oxo-2-trιioxo-thiazolidin-3-yl]-acetic acid (70) Orange crystals; m.p. 238-40°C 5-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl)-2-hydroxy-benzoic acid (71 ) Yellow crystals; m.p. >260°C 3-5-[l-Methyl-3-(2,6,6-trimethyl-cyclohex-l-enyl)-allylidene]-4-oxo-2-thioxo- thiazolidin-3-yl-propionic acid (72) Orange crystals; m.p. 160-1°C [5- ( 1 ,4-Dihydroxy- 10-methoxy-5,8-dimethyl-3,7-dioxo- 1 ,3-dihydro-7H- benzo[e]furo[3 4':3,4]benzo[b] [l,4]dioxepin-ll-ylmethylene)-4-oxo-2-thioxo- thiazolidin-3-yl] -acetic acid (73) Dark green crystals; m.p. >260°C [5-(2-Methyl- lH-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (74) Brown crystals; m.p. 268-70°C [5- (3,4-Diacetoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid (75) Yellow crystals; m.p. 193-5°C Example 2 Compounds of general formula (I) were investigated in a suitable assay for the capability of stimulating cyclic adenylate cyclase. Table I:

Claims: Patent Claims Use of ompounds of general formula (I) in which m signifies a number between 0-8, q signifies a number between 0-8 a signifies a number between 0-4 A signifies a single or double bond Ri, R 2 signify hydrogen or lower alkyl, whereby Ri and R 2 can be the same or different and, when m signifies 2-8, Ri and R 2 in the group can have various significances within the following sequence R 3 signifies hydrogen or lower alkyl X signifies hydrogen or -(CH 2 ) b -COR 4 with b = 0-4 Y signifies hydroxyl, -COP^, phenyl or indolyl residue R 4 signifies hydroxyl, lower alkoxy or the NRιR 2 residue, whereby Ri and R 2 can be the same or different W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, for the preparation of medicaments for the treatment and prevention of metabolic bone disorders, Compounds of general formula (I) in which m signifies a number between 0-8, q signifies a number between 0-8 a signifies a number between 0-4 A signifies a single or double bond Ri, R 2 signify hydrogen or lower alkyl, whereby Rj; and R 2 can be the same or different and, when m signifies 2-8, R and R 2 in the group CRι=CR 2 can have various significances within the following sequence R 3 signifies hydrogen or lower alkyl X signifies hydrogen or -(CH 2 ) b -CO j with b = 0-4 Y signifies hydroxyl, -COR , phenyl or indolyl residue R 4 signifies hydroxyl, lower alkoxy or the NRiR 2 residue, whereby Ri and R 2 can be the same or different W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, whereas W is not phenyl or indolyl, if m and g are both 0, R 3 , is hydrogen and A is a double bond, as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers, as well as derivatives which can be metabolized in vivo to compounds of general formula (I) Medicament containing at least one compound of general formula (I) according to claim 2 in admixture with usual pharmaceutical adjuvents and carrier material

Inventors: ESSWEIN ANGELIKA, HONOLD KONRAD, KALUZA KLAUS, SCHAEFER WOLFGANG, TSAKLAKIDIS CHRISTOS, ESSWEIN, ANGELIKA, HONOLD, KONRAD, KALUZA, KLAUS, SCHAEFER, WOLFGANG, TSAKLAKIDIS, CHRISTOS
Applicants: ESSWEIN ANGELIKA, HONOLD KONRAD, KALUZA KLAUS, ROCHE DIAGNOSTICS GMBH, SCHAEFER WOLFGANG, TSAKLAKIDIS CHRISTOS, ESSWEIN, ANGELIKA, HONOLD, KONRAD, KALUZA, KLAUS, SCHAEFER, WOLFGANG, TSAKLAKIDIS, CHRISTOS
Application year: 1999
Main classification: C07D277
IPC codes: A61K31, A61P19, C07D277, C07D417, C07D493