Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders

Abstract

1 Compounds of general formula (I), where m is 0-8, q is 0-8, a is between 0-4, A signifies a single or double bond, R.sub.1 and R.sub.2 signify hydrogen or lower alkyl, whereby R.sub.1 and R.sub.2 are the same or different and, when m signifies 2-8, R.sub.1 and R.sub.2 in the group CR.sub.1.dbd.CR.sub.2 can have various significances, R.sub.3 signifies hydrogen or lower alkyl, X signifies hydrogen or --(CH.sub.2).sub.b--COR.- sub.4 with b=0-4, Y signifies hydrogen, --COR.sub.4, phenyl or indolyl residue, R.sub.4 signifies hydroxyl, lower alkoxy or the NR.sub.1R.sub.2 residue, whereby R.sub.1 and R.sub.2 are the same or different, W is optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms, as well as physiologically compatible salts, esters, optically active forms, racemates, tautomers, derivatives which can be metabolized in vivo to compounds of general formula (I), and produces medicaments for prophylaxis or therapy of metabolic bone disorders with the compounds.

Description

[0001] 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.

[0002] 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 ancuor 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.

[0003] 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.

[0004] 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

[0005] 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 cydase (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 1,25-(OH).sub.2D.sub.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 osreoanabolic 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).

[0006] 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, osteosyntheses, pseudoarthroses and for the healing in of bone implants. However, having regard to these properties they also find use in the prophylaxis of osteoporosis.

[0007] 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.

[0008] The object of the present invention are compounds of general formula (I), 2

[0009] in which

[0010] m signifies a number between 0-8,

[0011] q signifies a number between 0-8

[0012] a signifies a number between 0-4

[0013] A signifies a single or double bond

[0014] R.sub.1, R.sub.2 signify hydrogen or lower alkyl, whereby R.sub.1 and R.sub.2 can be the same or different and, when m signifies 2-8, R.sub.1 and R.sub.2 in the group CR.sub.1.dbd.CR.sub.2 can have various significances within the following sequence

[0015] R.sub.3 signifies hydrogen or lower alkyl

[0016] X signifies hydrogen or --(CH.sub.2).sub.b--COR.sub.4 with b=0-4

[0017] Y signifies hydrogen, --COR.sub.4, phenyl or indolyl residue

[0018] R.sub.4 signifies hydroxyl, lower alkoxy or the NR.sub.1R.sub.2 residue, whereby R.sub.1 and R.sub.2 can be the same or different

[0019] W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricyde which can contain one or more hetero atoms,

[0020] 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.

[0021] Alkoxy groups signify a combination of a C.sub.1-C.sub.10-alkyl group in accordance with the above definition with an oxygen atom, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups.

[0022] 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, diphenylmetcne and biphenyl. Substituents are preferably lower alkyl alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chiorophenylsulphanyt, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen.

[0023] 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, alkoxydiakylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen.

[0024] In the case of the tricycle set forth under W, this is preferably a residue such as the anthracene, fluorene, dibenzofuran or carbazole.

[0025] Compounds of formula I wherein W is phenyl or indolyl, m and g are both 0, R.sub.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.

[0026] Therefore subject of the present invention are also new compounds of formula I 3

[0027] in which

[0028] m signifies a number between 0-8,

[0029] q signifies a number between 0-8

[0030] a signifies a number between 0-4

[0031] A signifies a single or double bond

[0032] R.sub.1, R.sub.2 signify hydrogen or lower alkyl, whereby R.sub.1 and R.sub.2 can be the same or different and, when m signifies 2-8, R.sub.1 and R.sub.2 in the group CR.sub.1.dbd.CR.sub.2 can have various significances within the following sequence

[0033] R.sub.3 signifies hydrogen or lower alkyl

[0034] X signifies hydrogen or --(CH.sub.2).sub.b--COR.sub.4 with b=0-4

[0035] Y signifies hydrogen, --COR.sub.4, phenyl or indolyl residue

[0036] R.sub.4 signifies hydroxyl, lower alkoxy or the NR.sub.1R.sub.2 residue, whereby R.sub.1 and R.sub.2 can be the same or different

[0037] W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms,

[0038] whereas W is not phenyl or indolyl, if m and g are both 0, R.sub.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.

[0039] 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.sub.1,2 signify hydrogen or methyl, X signifies hydrogen or --(CH.sub.2).sub.b--COR.sub.4 with b=0-2 and R.sub.4 equals hydroxyl, methoxy or NR.sub.1R.sub.2, Y signifies hydrogen or COR.sub.4, the phenyl or indolyl residue, R.sub.3 signifies hydrogen or methyl and W signifies an optionally mono- or polysubstituted benzothiophene, phenyl, benzofuran, thiophene, naphthalene, piperidine, cyclohexenyl or biphenyl residue.

[0040] 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: 4 5 6

[0041] 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.

[0042] 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, parafen, 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.

[0043] 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.

[0044] Biocompatible and preferably biodegradable materials are used as the carrier. Preferably, the materials themselves also induce wound healing or osteogenesis.

[0045] 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 polylactic 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. 8 419-4319 (1988). Also suitable are polymers as are used, for example, for the adsorption of TGF.beta. 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.

[0046] 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 U.S. Pat. No. 4,164,560.

[0047] 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.

[0048] 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):

[0049] 1. [5-(9H-Fluoren-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-a- cetic acid

[0050] 2. (4-Oxo-5-phenanthren-9-ylmethyl-2-thioxo-thiazolidin-3-yl)-aceti- c acid

[0051] 3. [5-(3-Anthracen-9-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl- ]-acetic acid

[0052] 4. 3-[5-(10-Methyl-anthracen-9-ylmethylene)-4-oxo-2-thioxo-thiazoli- din-3-yl]-propionic acid

[0053] 5. 3-[5-(5-Furan-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-thiazol- idin-3-yl]-propionic acid

[0054] 6. 2-(5-Benzylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-succinic acid

[0055] 7. 2-[5-(2-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pe- ntane-dicarboxylic acid

[0056] 8. [4-Oxo-2-thioxo-5-(2,3,4-trimethoxy-benzyl)-thiazolidin-3-yl]-ac- etic acid

[0057] 9. {5-[3-(2,4-Dimethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazoli- din-3-yl}-acetic acid

[0058] 10. 3-[4-Oxo-2-thioxo-5-(2,4,5-trimethoxy-benzylidene)-thiazolidin-- 3-yl]-propionic acid

[0059] 11. 3-{4-Oxo-2-thioxo-5-[3-(2,4,6-trimethoxy-phenyl)-allylidene]-th- iazolidin-3-yl}-propionic acid

[0060] 12. 2-[5-(2,5-Dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-succinic acid

[0061] 13. 2-[5-(2-Ethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pe- ntanedicarboxylic acid

[0062] 14. [5-(2-Hydroxy-3-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl- ]-acetic acid

[0063] 15. {5-[3-(3-Ethoxy-2-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-th- iazolidin-3-yl}-acetic acid

[0064] 16. 3-[5-(2,3-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-propionic acid

[0065] 17. 3-{4-Oxo-2-thioxo-5-[3-(2,3,4-trihydroxy-phenyl)-allylidene]-th- iazolidin-3-yl}propionic acid

[0066] 18. 2-[5-(4-Diethylamino-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thia- zolidin-3-yl]-succinic acid

[0067] 19. 2-[5-(2-Hydroxy-4-methoxy-benzylidene)-4-oxo-2-thioxo-thiazolid- in-3-yl]-pentanedicarboxylic acid

[0068] 20. [5-(2-Hydroxy-5-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl- ]-acetic acid

[0069] 21. {5-[3-(2,5-Dihydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazol- idin-3-yl}-acetic acid

[0070] 22. 3-[5-(2-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pr- opionic acid

[0071] 23. 3-{5-[3-(4-Methoxy-2,3-dimethyl-phenyl)-allylidene]-4-oxo-2-thi- oxo-thiazolidin-3-yl}-propionic acid

[0072] 24. 2-[4-Oxo-2-thioxo-5-(2,4,6-trimethyl-benzylidene)-thiazolidin-3- -yl]-succinic acid

[0073] 25. 2-[5-(2,5-Dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl- ]-pentane-dicarboxylic acid

[0074] 26. {5-[3-(4-Methoxy-phenoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-- yl}-acetic acid

[0075] 27. (5-{3-[3-(4-tert-Butyl-phenoxy)-phenyl]-allylidene}-4-oxo-2-thi- oxo-thiazolidin-3-yl)-acetic acid

[0076] 28. 3-[4-Oxo-2-thioxo-5-(3-#pl-tolyloxy-benzylidene)-thiazolidin-3-- yl]-propionic acid

[0077] 29. 3-{5-[3-(3-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolid- in-3-yl}-propionic acid

[0078] 30. 2-[5-(3,4-Dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-succinic acid

[0079] 31. 2-[4-Oxo-2-thioxo-5-(3,4,5-trimethoxy-benzylidene)-thiazolidin-- 3-yl]-pentanedicarboxylic acid

[0080] 32. [5-(3,5-Dimethoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acet- ic acid

[0081] 33. {5-[3-(3-Benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolid- in-3-yl}-acetic acid

[0082] 34. 3-[5-(3-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-p- ropionic acid

[0083] 35. 3-{5-[3-(3-Hydroxy-4-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo- -thiazolidin-3-yl}-propionic acid

[0084] 36. 2-[5-(3,4-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-succinic acid

[0085] 37. 2-[5-(3-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pe- ntanedicarboxylic acid

[0086] 38. [5-(4-Dimethylamino-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-ac- etic acid

[0087] 39. {5-[3-(4-Diethylamino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazo- lidin-3-yl}-acetic acid

[0088] 40. 3-[4-Oxo-5-(4-phenoxy-benzylidene)-2-thioxo-thiazolidin-3-yl]-p- ropionic acid

[0089] 41. 3-{5-[3-(4-Methoxy-phenyl)-allylidene)-4-oxo-2-thioxo-thiazolid- in-3-yl}-propionic acid

[0090] 42. 2-[5-(3-Benzyloxy-4-methoxy-benzylidene)-4-oxo-2-thioxo-thiazol- idin-3-yl]-succinic acid

[0091] 43. 2-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- -pentane-dicarboxylic acid

[0092] 44. [5-(4-Butoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0093] 45. [5-(3-Naphthalen-1-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-- yl]-acetic acid

[0094] 46. 3-[5-(2-Methoxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazo- lidin-3-yl]-propionic acid

[0095] 47. 3-{5-[3-(2-Hydroxy-naphthalen-1-yl)-allylidene]-4-oxo-2-thioxo-- thiazolidin-3-yl}-propionic acid

[0096] 48. 2-[5-(4-Methoxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazo- lidin-3-yl]-succinic acid

[0097] 49. 2-(5-Naphthalen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-- pentane-dicarboxylic acid

[0098] 50. [5-(9-Ethyl-9H-carbazol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-- 3-yl]-acetic acid

[0099] 51. {5-[3-(1H-Indol-3-yl)-allylidene]-4-oxo-2-thioxo-thiazoidin-3-y- l}-acetic acid

[0100] 52. 3-[5-(5-Methoxy-1H-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazoli- din-3-yl]-propionic acid

[0101] 53. 3-[5-(3-Benzo [1,3]dioxol-5-yl-allylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-propionic acid

[0102] 54. 2-[5-(4-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-p- entane-dicarboxylic acid

[0103] 55. [5-(4-Hydroxy-3,5-dimethoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-- 3-yl]-acetic acid

[0104] 56. {5-[3-(3-Ethoxy-4-hydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-th- iazolidin-3-yl}-acetic acid

[0105] 57. 3-[5-(4-Hydroxy-3,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazo- lidin-3-yl]-propionic acid

[0106] 58. 3-[5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-- yl]-propionic acid

[0107] 59. 2-[5-[4-Isopropyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- -pentane-dicarboxylic acid

[0108] 60. [5-(4-Ethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0109] 61. [5-(4,4-Diphenyl-but-2-enylidene)-4-oxo-2-thioxo-thiazolidin-3-- yl]-acetic acid

[0110] 62. 3-[4-Oxo-5-[2-phenyl-propylidene)-2-thioxo-thiazolidin-3-yl]-pr- opionic acid

[0111] 63. 3-5-(4-Methyl-5-phenyl-penta-2,4-dienylidene)-4-oxo-2-thioxo-th- iazolidin-3-yl]-propionic acid

[0112] 64. 2-[5-[2-Hexyl-3-phenyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3- -yl]-pentane-dicarboxylic acid

[0113] 65. [4-Oxo-5-(5-phenyl-penta-2,4-dienylidene)-2-thioxo-thiazolidin-- 3-yl]-acetic acid

[0114] 66. 3-{5-[3-(2-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolid- in-3-yl}-propionic acid

[0115] 67. 3-{5-[5-(4-Dimethylamino-phenyl)-penta-2,4-dienylidene]-4-oxo-2- -thioxo-thiazolidin-3-yl}-propionic acid

[0116] 68. [5-(3-Ethoxy-4-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]- -acetic acid

[0117] 69. {5-[3-(4-Diethoxymethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thia- zolidin-3-yl]-acetic acid

[0118] 70. 3-5-(4-Dimethylamino-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-t- hiazolidin-3-yl]-propionic acid

[0119] 71. 2-[5-(2,4-Dimethoxy-3-methyl-benzylidene-1-oxo-2-thioxo-thiazol- idin-3-yl]-pentanedicarboxylic acid

[0120] 72 [4-Oxo-5-(4-styryl-benzylidene)-2-thioxo-thiazolidin-3-yl]-aceti- c acid

[0121] 73. 5-[4-(3-Dimethylamino-propoxy)-benzyl]-4-oxo-2-thioxo-thiazolid- in-3-yl}-acetic acid

[0122] 74. {5-[3-(2,4-Dihydroxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazol- idin-3-yl}-acetic acid

[0123] 75. 3-[5-(2-Methyl-1H-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolid- in-3-yl]-propionic acid

[0124] 76. 3-{5-[3-(4-Hydroxy-3-methyl-phenyl)-allylidene]-4-oxo-2-thioxo-- thiazolidin-3-yl}-propionic acid

[0125] 77. 2-[5-(2-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-- pentane-dicarboxylic acid

[0126] 78. [4-Oxo-5-(4-propoxy-benzyl)-2-thioxo-thiazolidin-3-yl]-acetic acid

[0127] 79. {4-Oxo-5-(3-(4-pentyloxy-phenyl)-allylidene]-2-thioxo-thiazolid- in-3-yl}-acetic acid

[0128] 80. 3-[5-[4-Octyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-- propionic acid

[0129] 81. 3-{5-[3-(5-Benzytoxy-1H-indol-3-yl)-allylidene]-4-oxo-2-thioxo-- thiazolidin-3-yl}-propionic acid

[0130] 82. 2-(5-Benzofuran-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-- pentane-dicarboxylic acid

[0131] 83. [4-Oxo-5-(2,3,4,5,6-pentamethyl-benzyl)-2-thioxo-thiazolidin-3-- yl]-acetic acid

[0132] 84. {5-[3-(2-Benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolid- in-3-yl}-acetic acid

[0133] 85. 3-[4-Oxo-2-thioxo-5-(2,3,4-trimethoxy-6-methyl-benzylidene)-thi- azolidin-3-yl]-propionic acid

[0134] 86. 3-{5-[3-(3-Ethoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidi- n-3-yl}-propionic acid

[0135] 87. 2-[5-(3,4-Dihydroxy-5-methoxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-pentanedicarboxylic acid

[0136] 88. [5-(3,4-Dimethyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceti- c acid

[0137] 89. {5-[3-(4-Ethoxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-th- iazolidin-3-yl}-acetic acid

[0138] 90. 3-[5-(4-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-- propionic acid

[0139] 91. 3-{5-[3-(4-Heptydoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazol- idin-3-yl}-propionic acid

[0140] 92. 2-(5-Benzo[1,3]dioxol-4-ylmethylene-4-oxo-2-thioxo-thiazolidin-- 3-yl)-pentanedicarboxylic acid

[0141] 93. [4-Oxo-2-thioxo-5-(2,4,5-trimethyl-benzyl)-thiazolidin-3-yl]-ac- etic acid

[0142] 94. {5-[3-(4-Decyloxy-phenyl)-allylidene]-4-oxo-.sup.2-thioxo-thiaz- olidin-3-yl}-acetic acid

[0143] 95. 3-{5-[3-(4-tert-Butyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazo- lidin-3-yl}-propionic acid

[0144] 96. {5-[3-(4-Amino-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- -yl}-acetic acid

[0145] 97. 3-[5-(2-tert-Butylsulphanyl-benzylidene)-4-oxo-2-thioxo-thiazol- idin-3-yl]-propionic acid

[0146] 98. 3-{5-[3-(4-Butyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin- -3-yl}-propionic acid

[0147] 99. 2-[5-(4-tert-Butoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-pentane-dicarboxylic acid

[0148] 100. [4-Oxo-5-(4-propyl-benzyldene)-2-thioxo-thiazolidin-3-yl]-acet- ic acid

[0149] 101. [5-(4-Hexyl-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid

[0150] 102. 5-[3-(4-Octyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazolidin-3- -yl)-acetic acid

[0151] 103. 3-(5-(4-Dodecyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-propionic acid

[0152] 104. 3-{4-Oxo-5-[3-(4pentyl-phenyl)-allylidene]-2-thioxo-thiazolidi- n-3-yl}-propionic acid

[0153] 105. 2-[5-(3-Amino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pe- ntane-dicarboxylic acid

[0154] 106. [3-(7-Methyl-1H-indol-3-ylmethyl)-4-oxo-2-thioxo-lLiazolidin-3- -yl]-acetic acid

[0155] 107. 3-[4-Oxo-2-thioxo-5-(2-p-tolyl-ethylidene)-thiazolidin-3-yl]-p- ropionic acid

[0156] 108. 3-{5-[3-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-allylidene]-4-- oxo-2-thioxo-thiazolidin-3-yl}-propionic acid

[0157] 109. [5-(4-Hydroxy-2-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-y- l]-acetic acid

[0158] 110. {5-[3-(2,2-Dimethyl-chroman-6-yl)-allylidene]-4-oxo-2-thioxo-t- hiazolidin-3-yl}-acetic acid

[0159] 111. 3-[5-(4-Isopropoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-propionic acid

[0160] 112. 2-[5-(4-Methyl-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazo- lidin-3-yl]-pentanedicarboxylic acid

[0161] 113. {5-[3-(2,3-Dihydro-benzofuran-5-yl)-allylidene]-4-oxo-2-thioxo- -thiazolidin-3-yl}-acetic acid

[0162] 114. 3-(4-Oxo-5-quinolin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-p- ropionic acid

[0163] 113. 3-{5-[5-(4-Diethylamino-phenyl)-penta-2,4-dienylidene]-4-oxo-2- -thioxo-thiazolidin-3-yl}-propionic acid

[0164] 116. 2-[5-(4-Isobutyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- -pentane-dicarboxylic acid

[0165] 117. [5-(6-Methoxy-naphthalen-2-ylmethyl)-4-oxo-2-thioxo-thiazolidi- n-3-yl]-acetic acid

[0166] 118. {5-[3-(3,5-Dimethyl-phenyl)-allylidene]-4-oxo-2-thioxo-thiazol- idin-3-yl}-acetic acid

[0167] 119. 3-[5-(1-Hydroxy-naphthalen-2-ylmethylene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-propionic acid

[0168] 120. [5-(4-Octadecyloxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-ac- etic acid

[0169] 121. {5-[3-(4-Diphenylamino-phenyl)-allylidene]-4-oxo-2-thioxo-thia- zolidin-3-yl}-acetic acid

[0170] 122. 3-[4-Oxo-2-thioxo-5-(3,4,5-trihydroxy-benzylidene)-thiazolidin- -3-yl]-propionic acid

[0171] 123. 3-{5-[3-(4-Dimethylamino-2-methoxy-phenyl)-allylidene]-4-oxo-2- -thioxo-thiazolidin-3-yl}-propionic acid

[0172] 124. {5-[2-(2-Hydroxy-ethoxy)-benzyl]-4-oxo-2-thioxo-thiazolidin-3-- yl}-acetic acid

[0173] 125. (5-{3-[4-(2-Hydroxy-ethoxy)-phenyl]-allylidene}-4-oxo-2-thioxo- -thiazolidin-3-yl)-acetic acid

[0174] 126. 3-[5-(2-Benzyloxy-ethylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- -propionic acid

[0175] 127. 3-{5-[3-(4-tert-Butoxycarbonyloxy-3-methoxy-phenyl)-allylidene- ]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionic acid

[0176] 128. 2-[5-(2,4-Diethoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazo- lidin-3-yl]-pentanedicarboxylic acid

[0177] 129. [5-(2-Benzyloxy-3-methoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3- -yl]-acetic acid

[0178] 130. {5-[3-(4-Methanesulphonyl-phenyl)-allylidene]-4-oxo-2-thioxo-t- hiazolidin-3-yl}-acetic acid

[0179] 131. 3-[5-(2-Hydroxy-5-methyl-benzylidene)-4-oxo-2-thioxo-thiazolid- in-3-yl]-propionic acid

[0180] 132. (4-Oxo-5-thiophen-2-ylmethyl-2-thioxo-thiazolidin-3-yl)-acetic acid

[0181] 133. [5-(5-Naphthalen-2-yl-penta-2,4-dienylidene)-4-oxo-2-thioxo-th- iazolidin-3-yl]-acetic acid

[0182] 134. 3-[4-Oxo-5-(3-thiophen-2-yl-allylidene)-2-thioxo-thiazolidin-3- -yl]-propionic acid

[0183] 135. 3-{5-[3-(2-[1,3]Dioxolan-2-yl-6-fluoro-phenyl)-allylidene]-4-o- xo-2-thioxo-thiazolidin-3-yl}-propionic acid

[0184] 136. 2-[5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-pentanedicarboxylic acid

[0185] 137. [5-(4-Benzyl-benzyl)-4-oxo-2-thioxo-thiazohidin-3-yl]-acetic acid

[0186] 138. {5-[5,9-Dimethyl-11-(2,6,6-trimethyl-cyclohex-1-enyl)-undeca-2- ,4,6,8,10-pentaenylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid

[0187] 139. 3-[4-Oxo-5-(1H-pyrrol-2-ylmethylene)-2-thioxo-thiazolidin-3-yl- ]-propionic acid

[0188] 140. 3-[5-[3-Furan-2-yl-allylidene)-4-oxo-2-thioxo-thiazoldin-3-yl]- -propionic acid

[0189] 141. 2-{5-[3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo- -2-thioxo-thiazolidin-3-yl}-pentanedicarboxylic acid

[0190] 142. (4-Oxo-5-pyridin-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-acet- ic acid

[0191] 143. [5-(1-Methyl-1H-pyrrol-3-ylmethyl)-4-oxo-2-thioxo-thiazolidin-- 3-yl]-acetic acid

[0192] 144. {5-[3-(2-Hydroxy-4,6-dimethoxy-phenyl)-allylidene]-4-oxo-2-thi- oxo-thiazolidin-3-yl}-acetic acid

[0193] 145. 3-[5-[4-Benzyloxy-2-hydroxy-benzylidene)-4-oxo-2-tioxo-thiazol- idin-3-yl]-propiorlic acid

[0194] 146. 3-{5-[3-(5-Benzyloxy-2-hydroxy-phenyl)-allylidene]-4-oxo-2-thi- oxo-thiazolidin-3-yl}-propionic acid

[0195] 147. 2-{5-[4-(Benzo[1,3]dioxol-5-ylmethoxy)-benzylidene]-4-oxo-2-th- ioxo-thiazolidin-3-yl}-pentanedicarboxylic acid

[0196] 148. [5-(4-Benzyloxy-3,5-dihydroxy-benzyl)-4-oxo-2-thioxo-thiazolid- in-3-yl]-acetic acid

[0197] 149. {5-[3-(2,5-Bis-benzyloxy-phenyl)-allylidene]-4-oxo-2-thioxo-th- iazolidin-3-yl}acetic acid

[0198] 150. 3-[5-(4-Benzyloxy-3,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thi- azolidin-3-yl]-propionic acid

[0199] 151. 3-[5-(3-Cyclohexyl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl- ]-propionic acid

[0200] 152. 2-{5-[3-Methyl-5-(2,6,6-trimethyl-cydohex-1-enyl)-penta-2,4-di- enylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-pentanedicarboxylic acid

[0201] 153. [5-(3,4-Diethoxy-2,5-dimethyl-benzyl)-4-oxo-2-thioxo-thiazolid- in-3-yl]-acetic acid

[0202] 154. {5-[5-(3,4-Diethoxy-2,3-dimethyl-phenyl)-penta-2,4-dienylidene- ]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid

[0203] 155. [5-(2-Carboxymethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- -yl]-propionic acid

[0204] 156. 2-{3-[3-(2-Carboxy-ethyl)-4-oxo-2-thioxo-thiazolidin-5-yliden]- -propenyl}-benzoic acid

[0205] 157. 2-[5-(4-Acetoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-- pentane-dicarboxylic acid

[0206] 158. Methyl 4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethy- l)-benzoate

[0207] 159. 4-[3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-pro- penyl]-benzoic acid

[0208] 160. 3-{4-[3-(2-Carboxy-ethyl)-4-oxo-2-thioxo-thiazolidn-5-ylidenme- thyl]-phenyl}-acrylic acid

[0209] 161. 3-{4-Oxo-5-[3-(4-oxo-4H-chromen-3-yl)-allylidene]-2-thioxo-thi- azolidin-3-yl}-propionic acid

[0210] 162. 2-[5-(4-Acetoxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thia- zolidin-3-yl]-pentanedicarboxylic acid

[0211] 163. 3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-benz- oic acid

[0212] 164. 4-[3-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-yliden)-pro- penyl]-phenyl propionate

[0213] 165. 3-[5-(5,7-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thi- oxo-thiazolidin-3-yl]-propionic acid

[0214] 166. 3-{5-[3-(2-Ethoxycarbonylmethoxy-phenyl)-allylidene]-4-oxo-2-t- hioxo-thiazolidin-3-yl}-propionic acid

[0215] 167. 2-5-(8-Carboxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazo- lidin-3-yl]-pentanedicarboxylic acid

[0216] 168. [5-(3,4-Diacetoxy-benzyl)-4-oxo-2-thioxo-thiazolidin-3-yl]-ace- tic acid

[0217] 169. {5-[3-(2-Amino-4-oxo-4H-chromen-3-yl)-allylidene]-4-oxo-2-thio- xo-thiazolidin-3-yl}-acetic acid

[0218] 170. 3-[5-(2-Amino-6,7-dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-o- xo-2-thioxo-thiazolidin-3-yl -propionic acid

[0219] 171. 3-{5-[3-(6-Ethyl-4-oxo-4H-cchromen-3-yl)-allylidenej -4-oxo-2-thioxo-thiazolidin-3-yl}-propionic acid

[0220] 172. 2-[5-(6,8-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thi- oxo-thiazolidin-3-yl]-pentanedicarboxylic acid

[0221] 173. Methyl 2-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethy- l)-benzoate

[0222] 174. Methyl 3-[3-[3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylid- en)-propenyl]-1H-indole-6-carboxylate

[0223] 175. 3-{5-[3-(4-Acetoxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thiox- o-thiazolidin-3-yl}-propionic acid

[0224] 176. 3-[4-Oxo-5-(3-phenyl-but-2-enylidene)-2-thioxo-thiazolidin-3-y- l]-propionic acid

[0225] 177. 2-(4-Oxo-2-thioxo-5-(1-#pl-tolyl-ethylidene)-thiazolidin-3-yl]- -pentane-dicarboxylic acid

[0226] 178. {5-(1-(4-Methoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidi- n-3-yl}-acetic acid

[0227] 179. {5-[1-(3,4-Dichloro-phenyl)-ethyl]-4-oxo-2-thioxo-thiazolidin-- 3-yl}-acetic acid

[0228] 180. [4-Oxo-5-(3-thiophen-2-yl-but-2-enylidene)-2-thioxo-thiazolidi- n-3-yl]-acetic acid

[0229] 181. 3-[4-Oxo-5-(11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-3-ylmethyle- ne)-2-thioxo-thiazolidin-3-yl]-propionic acid

[0230] 182. 3-{5-[3-(3,5-Dihydroxy-phenyl)-but-2-enylidene]-4-oxo-2-thioxo- -thiazolidin-3-yl}-propionic acid

[0231] 183. 2-[5-(4-Hydroxy-3-methobenzylidene)-4-oxo-2-thioxo-thiazolidin- -3-yl]-succinic acid

[0232] 184. 2-[5-(4-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-s- uccinic acid

[0233] 185. 2-(4-Oxo-5-phenthylidene-2-thioxo-thiazolidin-3-yl)-succinic acid

[0234] 186. 2-5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethylene)-4-oxo-2-thiox- o-thiazolidin-3-yl]-succinic acid

[0235] 187. 2-[4-Oxo-5-(4-styryl-benzylidene)-2-thioxo-thiazolidin-3-yl]-s- uccinic acid

[0236] 188. 2-[5-(4-Allyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- -succinic acid

[0237] 189. 2-[4-Oxo-5-(4-pyrrolidin-1-yl-benzylidene)-2-thioxo-thiazolidi- n-3-yl]-succinic acid

[0238] 190. 2-(5-(3,5-Dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-- yl]-succinic acid

[0239] 191. 2-{5-[3-(4-Methoxy-phenyl)-allylidene]-4-oxo-2-thioxo-thiazoli- din-3-yl}-succinic acid

[0240] 192. 2-[4-Oxo-5-(4-propyl-benzylidene)-2-thioxo-thiazolidin-3-yl]-s- uccinic acid

[0241] 193. 2-[5-(2-Ethoxy-naphthalen-1-ylmethylene)-4-oxo-2-thioxo-thiazo- lidin-3-y]-succinic acid

[0242] 194. 2-[5-(3-Furan-2-yl-2-methyl-allylidene)-4-oxo-2-thioxo-thiazol- idin-3-yl]-succinic acid

[0243] 195. 2-{5-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-4-oxo-2-thiox- o-thiazolidin-3-yl}-succinic acid

[0244] 196. 2-{5-[3-(4-tert-Butyl-phenyl)-2-methyl-allylidene]-4-oxo-2-thi- oxo-thiazolidin-3-yl}-succinic acid

[0245] 197. 2-{5-[3-(2-Hydroxy-ethoxy)-benzylidene]-4-oxo-2-thioxo-thiazol- idin-3-yl}-succinic acid

[0246] 198. 2-{5-[3-(4-Hydroxy-3,5-dimethoxy-phenyl)-allylidene]-4-oxo-2-t- hioxo-thiazolidin-3-yl}-succinic acid

[0247] 199. 2-[5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-succinic acid

[0248] 200. 2-[5-(2,4-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-tniazolidi- n-3-yl]-succinic acid

[0249] 201. 2-(4-Oxo-5-pyridin-2-ylmethylene-2-thioxo-thiazolidin-3-yl-suc- cinic acid

[0250] 202. 2-[5-(4-Benzyloxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-th- iazolidin-3-yl]-succinic acid

[0251] 203. 2-[5-(3-Biphenyl-4-yl-allylidene)-4-oxo-2-thioxo-thiazoiidin-3- -yl]-succinic acid

[0252] 204. 2-[5-(3-Carboxy-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazoli- din-3-yl]-succinic acid

[0253] 205. 2-[5-(4-Carboxymethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin- -3-yl]-succinic acid

[0254] 206. 2-[5-(6-Methyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thioxo-- thiazolidin-3-yl]-succinic acid

[0255] 207. 2-[5-(6-Isopropyl-4-oxo-4H-chromen-3-ylmethylene)-4-oxo-2-thio- xo-thiazolidin-3-yl]-succinic acid

[0256] 208. 2-{5-[1-(4-Methoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazoli- din-3-yl}-succinic acid

[0257] 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 .sup.1H- and, where necessary, by .sup.13C-NMR spectroscopy. The purity of the substances was determined by C, H, N, P analysis as well as by thin-layer chromatography.

EXAMPLE 1

[0258] General Process A

[0259] 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-ylca- rboxylic 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.sub.2O. The precipitate is filtered off under suction, rinsed with H.sub.2O and dried. For purification, it is chromatographed over silica gel with ethyl acetate/heptane (2:1).

[0260] 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).

[0261] 2-(5-Benzo[b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl- )-succinic acid (1) Yellow crystals; m.p. 240.degree. C. (dec.)

[0262] 2-(5-Benzo [b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-y- l)-pentanedioic acid (2) Yellow crystals; m.p. 220-1.degree. C.

[0263] 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-3-phenyl-propionic acid (3) Yellow crystals; m.p. 160.degree. C. (dec.)

[0264] 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-3-(1H-indol-3-yl)-propionic acid (4) Orange crystals; m.p. 140.degree. C. (dec.)

[0265] [5-(5-Acetylamino-benzo[b]thiophen-2-ylmethylene)-4-oxo-2-thioxo-th- iazolidin-3-yl]-acetic acid (5) Yellow crystals; m.p. >240.degree. C.

[0266] 5-[3-(4-Methoxy-2,5-dimethyl-phenyl)-allyliden]-4-oxo-2-thioxo-thia- zoiidin-3-yl-acetic acid (6) Red crystals; m.p. >240.degree. C.

[0267] 5-[3-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-allylidene]-4-oxo-2-thiox- o-thiazolidin-3-yl-acetic acid (7) Yellow crystals; m.p. >240.degree. C.

[0268] [5-(2,3-Dihydro-benzofuran-5-ylmethylene)-4-oxo-2-thioxo-thiazolidi- n-3-yl]-acetic acid (8) Yellow crystals; m.p. 246-7.degree. C.

[0269] (4-Oxo-5-thiophen-2-ylmethylene-2-thioxo-thiazolidin-3-yl)-acetic acid (9) Yellow crystals; m.p. 237-9.degree. C.

[0270] (5-Benzo [b]thiophen-2-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)- -acetic acid (10) Yellow crystals; m.p. 292-4.degree. C.

[0271] [5-(3-Naphthalen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-- acetic acid (11) Orange crystals; 275-7.degree. C.

[0272] [5-(4-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (12) Yellow crystals; m.p. 244-6.degree. C.

[0273] [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.degree. C.

[0274] [5-(4-Hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (14) Yellow crystals; m.p. 230-2.degree. C.

[0275] [5-(4-Methoxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-- 3-yl]-acetic acid (15) Yellow crystals; m.p. 240.degree. C.

[0276] [5-(3-Benzo [b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazoldin-- 3-yl]-acetic acid (16) Orange crystals; m.p. >240.degree. C.

[0277] [5-(4-Methoxy-3-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl- ]-acetic acid (17) Yellow crystals; m.p. 235-6.degree. C.

[0278] 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-pentanedioic acid (18) Yellow crystals; m.p. 130.degree. C. (dec.)

[0279] [5-(4-Benzyloxy-35-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidi- n-3-yl]-acetic acid (19) M.p. 128-30.degree. C.

[0280] [5-(3,4-Bis-benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- -acetic acid (20) Yellow crystals; m.p. 187-8.degree. C.

[0281] [5-(3-Biphenyl-yl-allylidene)-4-oxo-2-thioxo-Lhiazolidin-3-yl]-acet- ic acid (21) Orange crystals; m.p. 130.degree. C. (dec.)

[0282] 5-[1-Methyl-3-[2,6,6-trimethyl-cyclohex-1-enyl)-allylidene]-4-oxo-2- -thioxo-thiazolidin-3-yl-acetic acid (22) Brown crystals; m.p. 100.degree. C. (dec.)

[0283] [5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-- 3-yl]-acetic acid (23) Yellow crystals; m.p. >240.degree. C.

[0284] 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-succinic acid (24) Brown crystals; m.p. 240.degree. C. (dec.)

[0285] [5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazol- idin-3-yl]-acetic acid (25) Orange crystals; m.p. 120-1.degree. C.

[0286] [5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceti- c acid (26) Yellow crystals; m.p. 205-6.degree. C.

[0287] 5-[1-[3,5-Dihydroxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidin-- 3-yl-acetic acid Yellow crystals; m.p. 184-8.degree. C.

[0288] 5-[-(4-Carboxymethoxy-phenyl)-ethylidene]-4-oxo-2-thioxo-thiazolidi- n-3-yl-acetic acid (28) Yellow crystals; m.p. 111-20.degree. C. (dec.)

[0289] (4-Oxo-2-thioxo-5-(2,3,4-trihydroxy-benzylidene)-thiazolidin-3-yl)-- acetic acid (29) Ochre-coloured crystals; m.p. 263.degree. C. (dec.)

[0290] [5-(2-Hydroxy-4,6-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin- -3-yl]-acetic acid (30) Pale brown crystals; m.p. 194.degree. C. (dec.)

[0291] [5-(3-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-aceti- c acid (31) Yellow crystals; m.p. 178-81.degree. C.

[0292] 3-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pro- pionic acid (32) Yellow crystals; m.p. 188-91.degree. C.

[0293] 2-[5-(4-Benzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-pro- pionic acid (33) Yellow crystals; m.p. 125-8.degree. C.

[0294] [5-(5-Benzyloxy-2-hydroxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- -yl]-acetic acid (34) Orange crystals; m.p. 130-3.degree. C.

[0295] 5-[4-(4-Methoxy-benzyloxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-- 3-yl-acetic acid (35) Yellow crystals; m.p. 172-3.degree. C.

[0296] 5-[4-(Benzo[1,3]dioxol-5-ylmethoxy)-benzylidene]-4-oxo-2-thioxo-thi- azolidin-3-yl-acetic acid (36) Yellow crystals; m.p. 206-7.degree. C.

[0297] 5-[4-Oxo-2-thioxo-5-(3,4,5-trihydroxy-benzylidene)-thiazolidin-3-yl- ]-pentanecarboxylic acid (37) m.p. 212-4.degree. C.

[0298] 5-[4-(3-Methoxy-benzyloxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-- 3-yl-acetic acid (38) Yellow crystals; m.p. 191-3.degree. C.

[0299] [5-(4-Hydroxy-3,5dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- -yl]-acetic acid (39) Orange crystals; m.p. 277-9.degree. C.

[0300] [5-(4-Benzyloxy-3,3-dihydroxy-benzylidene)-4-oxo-2-thioxo-thiazolid- in-3-yl]-acetic acid (40) M.p. 178-80.degree. C.

[0301] [5-(2,5-Bisbenzyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-- acetic acid (41) Yellow crystals; m.p. 196-8.degree. C.

[0302] [4-Oxo-2-thioxo-5-(3,4,5-triacetoxy-benzylidene)-thiazolidin-3-yl]-- acetic acid (42) Orange crystals; m.p. 200.degree. C. (dec.)

[0303] 5-(3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxa-2-thiox- o-thiazolidin-3-yl-acetic acid (43) Red crystals; m.p. 252-30C.

[0304] (5-Cyclohex-3-enybnethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-acetic acid (44) Beige crystals; m.p. 180-2.degree. C.

[0305] [4-Oxo-5-(3-phenyl-propylidene)-2-thioxo-thiazolidin-3-yl]-acetic acid (45) Orange crystals; m.p. 108-11.degree. C.

[0306] 5-(3-Methyl-5-(2,6,6trimethyl-cyclohex-1-enyl)-penta-2,4-dienyliden- ]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (46) Orange crystals; m.p. 153-5.degree. C.

[0307] 5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-3-methyl-2-thioxo-thiaz- olidin-4-one (47) Yellow crystals; m.p. >240.degree. C.

[0308] 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.degree. C.

[0309] 2-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-N,N-diethyl-acetamide (49) Yellow crystals; m.p. 223-5.degree. C.

[0310] 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.degree. C.

[0311] 2-5-[3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-4-oxo-2-thi- oxo-thiazolidin-3-yl-N,N-diethyl-acetamide (51) Red crystals; m.p. 210-2.degree. C.

[0312] Benzyl 4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl- )-piperidine-1-carboxylate (52) Yellow crystals; m.p. 114-5.degree. C.

[0313] 5-[3,7-Dimethyl-9-(2,6,6-trimethyl-cyclohex-1-enyl)-nona-2,4,6,8-te- traenylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (53) Black (sic) crystals; m.p. 144.degree. C. (dec.)

[0314] [5-(3,4-Dihydroxy-2,3-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazoli- din-3-yl]-acetic acid (54) Yellow crystals; m.p. >240.degree. C.

[0315] [5-(3,4-Diethoxy-2,5-dimethyl-benzylidene)-4-oxo-2-thioxo-thiazolid- in-3-yl]-acetic acid (55) Ochre coloured crystals; m.p. 185-90.degree. C.

[0316] 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.degree. C. (dec.)

[0317] 5-[5-Methyl-7-[2,6,6-triethyl-cyclohex-1-enyl)-hepta-2,4,6-trienyli- den]-4-oxo-2-thioxo-thiazolidin-3-yl-acetic acid (57) Black crystals; m.p. 192-5.degree. C.

[0318] 3-(5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl- )-propionic acid (58) Yellow crystals; m.p. 174-6.degree. C.

[0319] 3-(4-Oxo-2-thioxo-5-(2,6,6-trimetyl-cyclohex-1-enylmethylene)-thiaz- olidin-3-yl]-propionic acid (59) Yellow-orange crystals; m.p. 166-8.degree. C.

[0320] 3-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2-thioxo-thiaz- olidin-3-yl]-propionic acid (60) Yellow crystals; m.p. 218-9.degree. C.

[0321] 3-(5-Naphthalen-1-ylmethylene-4-oxo-2-thioxo-thiazolidin-3-yl)-prop- ionic acid (61) Orange crystals; m.p. 159-61.degree. C.

[0322] 3-[5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2-thioxo-thiazolidi- n-3-yl]-propionic acid (62) Orange crystals; m.p. 246-8.degree. C.

[0323] [5-(4-Dibutylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-ac- etic acid (63) Orange crystals; m.p. 186-8.degree. C.

[0324] [4-Oxo-5-(4-pentyl-benzylidene)-2-thioxo-thiazolidin-3-yl]-acetic acid (64) Yellow crystals; m.p. 160-2.degree. C.

[0325] [5-(3-Methoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (65) Yellow crystals; m.p. 193-6.degree. C.

[0326] [4-Oxo-2-thioxo-5-(2,4,5-trirmethyl-benzylidene)-thiazolidin-3-yl]-- acetic acid (66) Yellow crystals; m.p. 234-6.degree. C.

[0327] [5-(2-Hexyloxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (67) Yellow crystals; m.p. 148-50.degree. C.

[0328] [5-(4-Methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid (68) Yellow crystals; m.p. 234-6.degree. C.

[0329] [5-(4-Methoxy-2,3-dinethyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-- 3-yl]-acetic acid (69) Yellow crystals; m.p. 215-7.degree. C.

[0330] [5-(4-Hydroxy-3,5-dimethoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin- -3-yl]-acetic acid (70) Orange crystals; m.p. 238-40.degree. C.

[0331] 5-(3-Carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenmethyl)-2-hyd- roxy-benzoic acid (71) Yellow crystals; m.p. >260.degree. C.

[0332] 3-5-[1-Methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-allylidene]-4-oxo- -2-thioxo-thiazolidin-3-yl-propionic acid (72) Orange crystals; m.p. 160-1.degree. C.

[0333] [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][1,4]dioxepin-11-ylmethylene)-4-oxo-2-thiox- o-thiazolidin-3-yl]-acetic acid (73) Dark green crystals; m.p. >260.degree. C.

[0334] [5-(2-Methyl-1H-indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-y- l]-acetic acid (74) Brown crystals; m.p. 268-70.degree. C.

[0335] [5-(3,4-Diacetoxy-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-ace- tic acid (75) Yellow crystals; m.p. 193-53.degree. C.

EXAMPLE 2

[0336] Compounds of general formula (I) were investigated in a suitable assay for the capability of stimulating cyclic adenylate cyclase.

1TABLE I % cAMP Example No. Name (Test conc. 50 .mu.M) 3 2-[5-(3,5-Di-tert-butyl-4-hydrox- y-benzylidene)-4-oxo- 8 2-thioxo-thiazolidin-3-yl]-3-phenyl-propio- nic acid 13 [5-(5-Benzo[b]thiophen-2-yl-penta-2,4-dienylidene)-4- 10 oxo-2-thioxo-thiazolidin-3-yl]-acetic acid 16 [5-(3-Benzo[b]thiophen-2-yl-allylidene)-4-oxo-2- 8 thioxo-thiazolidin-3-yl]-acetic acid 22 5-[1-Methyl-3-(2,6,6-trime- thyl-cydohex-1-enyl)- 10 allylidene]-4-oxo-2-thioxo-thiazolidin-3-- yl-acetic acid 23 [5-(3-tert-Butyl-4-hydroxy-benzylidene)-4-oxo-2- 8 thioxo-thiazolidin-3-yl]-acetic acid 25 [5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo-2- 40 thioxo-thiazolidin-3-yl]-acetic acid 46 5-[3-Methyl-5-(2,6,6-trime- thyl-cyclohex-1-enyl)-penta- 30 2,4-dienylidene]-4-oxo-2-thioxo-th- iazolidin-3-yl-acetic acid 59 3-[4-Oxo-2-thioxo-5-(2,6,6-tr- imethyl-cyclohex-1- 15 enylmethylene)-thiazolidin-3-yl]-propionic acid 60 3-[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-4-oxo- 20 2-thioxo-thiazolidin-3-yl]-propionic acid 72 3-5-[1-Methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)- 15 allylidene]-4-oxo-2-thioxo-thiazolidin-3-yl-propionic acid

Claims

1. Use of compounds of general formula (I) 7in 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.sub.1, R.sub.2 signify hydrogen or lower alkyl, whereby R.sub.1 and R.sub.2 can be the same or different and, when m signifies 2-8, R.sub.1 and R.sub.2 in the group CR.sub.1.dbd.CR.sub.2 can have various significances within the following sequence R.sub.3 signifies hydrogen or lower alkyl X signifies hydrogen or --(CH.sub.2).sub.b--COR.sub.4 with b=0-4 Y signifies hydroxyl, --COR.sub.4, phenyl or indolyl residue R.sub.4 signifies hydroxyl, lower alkoxy or the NR.sub.1R.sub.2 residue, whereby R.sub.1 and R.sub.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,

2. Compounds of general formula (I) 8in 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.sub.1, R.sub.2 signify hydrogen or lower alkyl, whereby R.sub.1 and R.sub.2 can be the same or different and, when m signifies 2-8, R.sub.1 and R.sub.2 in the group CR.sub.1.dbd.CR.sub.2 can have various significances within the following sequence R.sub.3 signifies hydrogen or lower alkyl X signifies hydrogen or --(CH.sub.2).sub.b--COR.sub.4 with b=0-4 Y signifies hydroxyl, --COR.sub.4, phenyl or indolyl residue R.sub.4 signifies hydroxyl, lower alkoxy or the NR.sub.1R.sub.2 residue, whereby R.sub.1 and R.sub.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.sub.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)

3. Medicament containing at least one compound of general formula (I) according to claim 2 in admixture with usual pharmaceutical adjuvents and carrier material