WO2000018746A1

WO2000018746A1 - Thiazolidine derivatives for the treatment and prevention of metabolic bone disorders

Info

Publication number: WO2000018746A1
Application number: PCT/EP1999/007252
Authority: WO
Inventors: Angelika Esswein; Wolfgang Schaefer; Christos Tsaklakidis; Konrad Honold; Klaus Kaluza
Original assignee: Roche Diagnostics Gmbh
Priority date: 1998-09-30
Filing date: 1999-09-30
Publication date: 2000-04-06
Also published as: AU6331099A

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 single or double bond; R1 signifies hydrogen or, when X and Z are oxygen, also -(CH2)-COR4 with a =0-6; R2, R3 signify hydrogen or lower alkyl, whereby R2 and R3 can be the same or different and, when m signifies 2-8, R2 and R3 in the group CR2=CR3 can have various significances within the following sequence; R4 signifies hydroxyl, lower alkoxy or the NR1R2 residue, whereby R1 and R2 can be the same or different; X signifies oxygen or imino; Z signifies oxygen, sulfur or imino; 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

Thiazolidine derivatives for the treatment and prevention of metabolic bone disorders

The present invention is concerned with thiazolidine 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 thiazolidine structural element are known as antidiabetics, cytostatics inflammation inhibitors and for the treatment of cardiovascular illnesses and bacterial infections, with the treatment of osteoporosis in addition to an antidiabetic activity also being described in Applications EP 783888, EP 590793, EP 676398 and EP 708098.

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) D₃. 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 thiazolidine 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.

By their influence on bone metabolism medicaments with the thiazolidine 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 single or double bond

Ri signifies hydrogen or, when X and Z are oxygen, also -CH₂)-COR with a = 0-6

R₂,R₃ signify hydrogen or lower alkyl, whereby R₂ and R₃ can be the same or different and, when m signifies 2-8, R2 and R3 in the group CR₂=CR₃ can have various significances within the following sequence l^_t signifies h droxy, lower alkoxy or the NRιR residue, whereby Rj and R₂ can be the same or different X signifies oxygen or imino Z signifies oxygen, sulphur or imino 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 Cι-C₁₀-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, isothiazol l, 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. As substituents there come into consideration primarily lower alkyl, alkylcarbonyl, alkoxy, alkoxycarbonylalkoxy, amino, benzyl, benzyloxy, carboxyl, dialkylamino, dioxymethylene, diphenylamino, hydroxy, mercaptoalkyl, 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, tetrah droisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinyl residue, especially the indol l, naphthyl, benzimidazolyl, quinoUnyl, tetrahydroquinolinyl benzothiophenyl and benzofuranyl residue, which optionally can be mono- or polysubstituted. As substituents there come into consideration primarily lower alkyl, alkylcarbonyl, alkoxy, alkoxycarbon lalkoxy, amino, benzyl, benzyloxy, carboxyl, dialkylamino, dioxymeth lene, diphenylamino, hydroxy, mercaptoalkyl, 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 residue.

Compounds of formula I wherein W is phenyl, naphthyl, indolyl, benzofuranyl or benzothiophenyl, X is oxygen, m and g are both 0 and Ri is hyxdrogen are disclosed in EP-A-0434394 however for the treatment of inflammatory lowel diseases.

Compounds of formula I wherein W is an amino substituted phenyl or indolyl, X is imino, m and q both are 0 and Ri is hydrogen are disclosed in USP 5.143.929, however for the treatment of inflammatory.

Therefore subject of the present invention are also new compounds of general formula I

in which m signifies a number between 0-8, q signifies a number between 0-8

A signifies a single or double bond

Ri signifies hydrogen or, when X and Z are oxygen, also -CH₂)-COR₄ with a = 0-6

R₂,R₃ signify hydrogen or lower alkyl, whereby R₂ and R₃ can be the same or different and, when m signifies 2-8, R2 and R3 in the group CR₂=CR₃ can have various significances within the following sequence R₄ signifies hydroxy, lower alkoxy or the NRjR₂ residue, whereby Ri and R₂ can be the same or different X signifies oxygen or imino Z signifies oxygen, sulphur or imino 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, naphthyl, indolyl, benzofuranyl and benzothiphen-yl, if X signifies oxygen, m and q are both 0 and Ri is hydrogen,

whereas W is not an aminosubstituted phenyl and indolyl, if X signifies imino, m and q both are 0 and RI is hydrogen,

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 double bond, Ri signifies hydrogen or a group -(CH₂)_a-COR , a preferably signifies a number between 1 and 3, P^ signifies hydroxyl, methoxy or ethoxy, R₂ and, respectively, R₃ signify hydrogen or methyl, X and Z signify oxygen and W signifies an optionally mono- or polysubstituted naphthalene, phenyl, thiophene, indole, furan, benzothiophene, cyclohexenyl or biphenyl residue.

The manufacture of the compounds of general formula (I) is possible according to methods known per se. An overview of the methods of synthesis is set forth in Schemes 1 and 2; whereby R signifies the group:

Scheme 1

RCHXCOOH 1.RCHO (X=Hal) RCHO 2. H÷

A. NH H-, Pd/C

Scheme 2

RCHO

The α-halocarboxylic 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 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 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):

I. 5-(9H-Fluoren-2-ylmethylene)-thiazolidin-2,4-dione 2. 5-Phenanthren-9-ylmethylene-4-thioxo-thiazolidin-2-one

3. 5-Anthracen-9-ylmethylene-4-imino-thiazolidin-2-one

4. 2-Imino-5-(10-methyl-anthracen-9-ylmethylene)-thiazolidin-4-one

5. [5-(3-Furan-2-yl-allylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

6. 5-Benzyl-fhiazolidin-2,4-dione 7. 5-[3-(2-Methoxy-phenyl)-allylidene]-thiazolidine-2,4-dione

8. 5-(2,3-Dimethoxy-benzylidene)-thiazolidine-2,4-dione

9. 4-Thioxo-5-(2,3,4-trimethoxy-benzylidene)-thiazolidin-2-one

10. 5-(2,4-Dimethoxy-benzylidene)-4-imino-thiazolidin-2-one

II. 2-Imino-5-(2,4,5-trimethoxy-benzylidene)-thiazolidin-4-one 12. [2,4-Dioxo-5-(2,4,6-trimethoxy-benzylidene)-thiazohdin-3-yl] -acetic acid

13. 5-(2,5-Dimethoxy-benzyl)-thiazolidine-2,4-dione

14. 5-[3-(2-Ethoxy-phenyl)-allylidene]-thiazolidine-2,4-dione

15. 5-(2-Hydroxy-benzylidene)-thiazolidine-2,4-dione

16. 5-(2-Hydroxy-3-methoxy-benzylidene)-4-thioxo-thiazolidin-2-one 17. 5-(3-Ethoxy-2-hydroxy-benzylidene)-4-imino-thiazolidin-2-one 18. 5-(2,3-Dihydroxy-benzylidene)-2-imino-thiazolidin-4-one

19. [2,4-Dioxo-5-(2,3,4-trihydroxy-benzylidene)-thiazolidin-3-yl] -acetic acid

20. 5-(4-Diethylamino-2-hydroxy-benzyl)-thiazolidine-2,4-dione

21. 5-[3-(2-Hydroxy-4-methoxy-phenyl)-allylidene]-thiazolidine-2,4-dione 22. 5-(2,4,6-Trihydroxy-benzylidene)-thiazolidine-2,4-dione

23. 5-(2-Hydroxy-5-methoxy-benzylidene)-4-thioxo-thiazolidin-2-one

24. 5-(2,5-Dihydroxy-benzylidene)-4-imino-thiazolidin-2-one

25. 2-Imino-5-(2-methyl-benzylidene)-thiazolidin-4-one

26. [5-(4-Methoxy-2,3-dimethyl-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid 27. 5-(2,4,6-Trimethyl-benzyl)-thiazolidine-2,4-dione

28. 5-[3-(2,5-Dimethyl-phenyl)-allylidene]-thiazolidine-2,4-dione

29. 5-(4-Methoxy-2,5-dimethyl-benzylidene)-thiazolidine-2,4-dione

30. 5-[3-(4-Methoxy-phenoxy)-benzylidene] -4-thioxo-thiazolidin-2-one

31. 5-[3-(4-tert-Butyl-phenoxy)-benzylidene]-4-imino-thiazolidin-2-one 32. 2-Imino-5-(3-p-tolyloxy-benzylidene)-thiazolidin-4-one

33. [5-(3-Methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid

34. 5-(3,4-Dimethoxy-benzyl)-thiazolidine-2,4-dione

35. 5-[3-(3,4,5-Trimethoxy-phenyl)-allylidene]-thiazolidme-2,4-dione

36. 5-(4-Benzyloxy-3-methoxy-benzylidene)-thiazolidine-2,4-dione 37. 5-(3,5-Dimethoxy-benzylidene)-4-thioxo-thiazolidin-2-one

38. 5-(3-Benzyloxy-benzylidene)-4-imino-thiazolidin-2-one

39. 5-(3-Hydroxy-benzylidene)-2-imino-thiazolidin-4-one

40. [5-(3-Hydroxy-4-methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

41. 5-(3,4-Dihydroxy-benzyl)-thiazolidine-2,4-dione 42. 5-(3-m-Tolyl-aUylidene)-thiazolidine-2,4-dione

43. 5-(4-Methoxy-3-methyl-benzylidene)-thiazolidine-2,4-dione

44. 5-(4-Dimethylamino-benzylidene)-4-thioxo-thiazolidin-2-one

45. 5-(4-Diethylamino-benzylidene)-4-imino-tbiazolidin-2-one

46. 2-Imino-5-(4-phenoxy-benzylidene)-thiazolidin-4-one 47. [5-(4-Methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

48. 5-(3-Benzyloxy-4-methoxy-benzyl)-thiazolidine-2,4-dione

49. 5- [3-(4-Benzyloxy-phenyl)-allylidene] -thiazolidine-2,4-dione

50. 5-(4-Ethoxy-benzylidene)-fhiazolidine-2,4-dione

51. 5-(4-Butoxy-benzylidene)-4-thioxo-thiazolidin-2-one 52. 4-Imino-5-naphthalen-l-ylmethylene-thiazolidin-2-one 53. 2-Imino-5-(2-methoxy-naphthalen-l-ylmethylene)-thiazolidin-4-one

54. [5-(2-Hydroxy-naphthalen-l-ylmethylene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid

55. 5-(4-Mefhoxy-naphthalen- l-ylmethyl)-thiazolidine-2,4-dione 56. 5-(3-Naphthalen-2-yl-allylidene)-thiazolidine-2,4-dione

57. 5-(3,4-Bis-benzyloxy-benzylidene)-thiazolidine-2,4-dione

58. 5-(9-Ethyl-9H-carbazol-3-ylmethylene)-4-thioxo-thiazolidin-2-one

59. 4-Imino-5-( lH-indol-3-ylmethylene)-thiazolidin-2-one

60. 2-Imino-5-(5-methoxy-lH-indol-3-ylmethylene)-thiazolidin-4-one 61. (5-Benzo[l,3]dioxol-5-ylmethylene-2,4-dioxo-thiazolidin-3-yl)-acetic acid

62. 5-Quinolin-4-ylmethyl-thiazolidine-2,4-dione

63. 5- [3-(4-Hydroxy-phenyl)-allylidene] -thiazolidine-2,4-dione

64. 5-(4-Hydroxy-3-methoxy-benzylidene)-thiazolidine-2,4-dione

65. 5-(4-Hydroxy-3,5-dimethoxy-benzylidene)-4-thioxo-thiazolidin-2-one 66. 5-(3-Ethoxy-4-hydroxy-benzylidene)-4-imino-thiazoUdin-2-one

67. 5-(4-Hydroxy-3,5-dimefhyl-benzylidene)-2-imino-thiazolidin-4-one

68. (5-Biphenyl-4-ylmethylene-2,4-dioxo-thiazolidin-3-yl)-acetic acid

69. 5-(4-Methylsulphanyl-benzyl)-thiazolidine-2,4-dione

70. 5-[3-(4-Isopropyl-phenyl)-allylidene]-thiazolidine-2,4-dione 71. 5-(4-Methyl-benzylidene)-thiazolidine-2,4-dione

72. 5-(4-Ethyl-benzylidene)-4-thioxo-thiazolidin-2-one

73. 5-(2,2-Diphenyl-ethylidene)-4-imino-thiazolidin-2-one

74. [5-(2-Methyl-3-phenyl-allylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid

75. 5-(2-Pentyl-3-phenyl-allyl)-thiazolidine-2,4-dione 76. 5-(4-Hexyl-5-phenyl-penta-2,4-dienylidene)-thiazolidine-2,4-dione

77. 5-Phenethylidene-thiazolidine-2,4-dione-2-one

78. 4-Imino-5-(3-phenyl-allylidene)-thiazolidin-2-one

79. 2-Imino-5-[3-(2-methoxy-phenyl)-allylidene]-thiazolidin-4-one

80. {5-[3-(4-Dimethylamino-phenyl)-allylidene]-2,4-dioxo-thiazolidin-3-yl}-acetic acid

81. 5-(3-Phenyl-propyl)-fhiazolidine-2,4-dione

82. 5-[3-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-allylidene]-thiazolidine-2,4-dione

83. 5-(2,3-Dihydro-benzo[l,4]dioxin-6-ylmethylene)-thiazolidine-2,4-dione

84. 5-(3-Ethoxy-4-methoxy-benzylidene)-4-thioxo-thiazolidin-2-one 85. 5-(4-Diethoxymethyl-benzylidene)-4-imino-thiazolidin-2-one 86. 5-(4-Dimethylamino-naphthalen-l-ylmethylene)-2-imino-thiazolidin-4-one

87. 5-(2,4-Dimethoxy-3-methyl-benzyl)-l:hiazolidine-2,4-dione

88. 5-(4-Styryl-benzylidene)-thiazolidine-2,4-dione

89. 5-[4-(3-Dimefhylamino-propoxy)-benzylidene]-4-thioxo-thiazolidin-2-one 90. 5-(2,4-Dihydroxy-benzylidene)-4-imino-thiazohdin-2-one

91. 2-Imino-5-(2-methyl-lH-indol-3-ylmethylene)-thiazolidin-4-one

92. [5-(4-Hydroxy-3-methyl-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

93. 5-(2-Hexyloxy-benzyl)-thiazolidine-2,4-dione

94. 5-(4-Allyloxy-benzylidene)-thiazolidine-2,4-dione 95. 5-(4-Propoxy-benzylidene)-4-thioxo-thiazolidin-2-one

96. 4-Imino-5-(4-pentyloxy-benzylidene)-thiazolidin-2-one

97. 2-Imino-5-(4-octyloxy-benzylidene)-thiazolidin-4-one

98. [5-(5-Benzyloxy- lH-indol-3-ylmethylene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

99. 5-Benzofuran-2-ylmethyl-thiazolidine-2,4-dione 100. 5-(4-Pyrrolidin-l-yl-benzylidene)-thiazolidine-2,4-dione

101. 5-(2,3,4,5,6-Pentamethyl-benzylidene)-4-thioxo-thiazolidin-2-one

102. 5-(2-Benzyloxy-benzylidene)-4-imino-thiazolidin-2-one

103. 2-Imino-5-(2,3,4-trimethoxy-6-methyl-benzylidene)-thiazolidin-4-one

104. [5-(3-Ethoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid 105. 5-(3,4-Dihydroxy-5-methoxy-benzyl)-thiazolidine-2,4-dione

106. 5-(3,5-Dihydroxy-benzylidene)-thiazolidine-2,4-dione

107. 5-(3,4-Dimethyl-benzylidene)-4-thioxo-thiazolidin-2-one

108. 5-(4-Ethoxy-3-methoxy-benzylidene)-4-imino-thiazolidin-2-one

109. [5-(4-Heptyloxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid 110. 5-Benzo[l,3]dioxol-4-ylmethyl-thiazolidine-2,4-dione

111. 5-[3-(4-Methoxy-phenyl)-allylidene]-thiazolidine-2,4-dione

112. 4-Thioxo-5-(2,4,5-trimethyl-benzylidene)-thiazolidin-2-one

113. 5-(4-Decyloxy-benzylidene)-4-imino-thiazolidin-2-one

114. [5-(4-tert-Butyl-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid 115. (3-Allyl-2-hydroxy-benzylidene)-4-thioxo-thiazolidin-2-one

116. 5-(4-Amino-benzylidene)-4-imino-thiazolidin-2-one

117. [5-(4-Butyl-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

118. 5-(4-ter -Butoxy-benzyl)-thiazolidine-2,4-dione

119. 5-(4-Propyl-benzylidene)-thiazolidine-2,4-dione 120. 5-(4-Hexyl-benzylidene)-4-thioxo-thiazolidin-2-one 121. 4-Imino-5-(4-octyl-benzylidene)-thiazolidin-2-one

122. [2,4-Dioxo-5-(4-pentyl-benzylidene)-fhiazolidin-3-yl] -acetic acid

123. 5-(3-Amino-benzyl)-fhiazolidine-2,4-dione

124. 5-(2-Ethoxy-naphthalen- l-ylmethylene)-thiazolidine-2,4-dione 125. 5-(7-Methyl-lH-indol-3-ylmethylene)-4-thioxo-thiazolidin-2-one

126. 5-[3-(4-tert-Butyl-phenyl)-2-methyl-propylidene]-4-imino-thiazolidin-2-one

127. [5-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethylene)-2,4-dioxo-thiazoUdin-3- yl] -acetic acid 5-(4-Hydroxy-2-methoxy-benzylidene)-4-thioxo-fhiazolidin-2-one

128. 5-(2,2-Dimethyl-chroman-6-ylmethylene)-4-imino-thiazolidin-2-one 129. 5-(4-Mefhyl-naphthalen-l-ylmethyl)-thiazolidine-2,4-dione

130. 5-(3-Furan-2-yl-2-methyl-allylidene)-thiazolidine-2,4-dionepropylidene-2-one; 5-(2,3-Dihydro-benzofuran-5-ylmethylene)-4-imino-thiazolidin-2-one

131. {5-[3-(4-Diethylamino-phenyl)-allylidene]-2,4-dioxo-thiazolidin-3-yl}-acetic acid

132. 5-(4-Isobutyl-benzyl)-thiazolidine-2,4-dione 133. 5-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-thiazolidine-2,4-dione

134. 5-(6-Methoxy-naphthalen-2-ylmethylene)-4-thioxo-thiazolidin-2-one

135. 5-(3,5-Dimethyl-benzylidene)-4-imino-thiazolidin-2-one

136. [2,4-Dioxo-5-(4-phenylethynyl-benzylidene)-thiazolidin-3-yl] -acetic acid

137. 5-[3-(4-tert-Butyl-phenyl)-2-methyl-allylidene]-thiazolidine-2,4-dione 138. 5-(4-Octadecyloxy-benzylidene)-4-thioxo-thiazolidin-2-one

139. 5-(4-Diphenylamino-benzylidene)-4-imino-thiazolidin-2-one

140. [5-(4-Dimethylamino-2-methoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

141. 5-(2-Benzyloxy-4,5-dimethoxy-benzyl)-thiazolidine-2,4-dione 142. 5-[3-(2-Hydroxy-ethoxy)-benzylidene]-thiazolidine-2,4-dione

143. 5-[2-(2-Hydroxy-ethoxy)-benzylidene]-4-thioxo-thiazolidin-2-one

144. 5-[4-(2-Hydroxy-ethoxy)-benzylidene]-4-imino-thiazolidin-2-one

145. [5-(4-tert-Butoxycarbonyloxy-3-methoxy-benzylidene)-2,4-dioxo-thiazolidin-3- yl] -acetic acid 146. 5-[3-(4-Hydroxy-3,5-dimethoxy-phenyl)-allylidene]-thiazolidine-2,4-dione

147. 5-(2-Benzyloxy-3-methoxy-benzylidene)-4-thioxo-thiazolidin-2-one

148. 4-Imino-5-(4-methanesulphonyl-benzylidene)-thiazolidin-2-one

149. (5-Benzo[b]thiophen-2-ylmethylene-2,4-dioxo-thiazolidin-3-yl)-acetic acid

150. 5-(3-Benzo[b]thiophen-2-yl-allylidene)-thiazolidine-2,4-dione 151. 5-Thiophen-2-ylmethylene-4-thioxo-thiazolidin-2-one 152. 4-Imino-5-(3-naphthalen-2-yl-allylidene)-thiazolidin-2-one

153. [5-(2-[l,3]Dioxolan-2-yl-6-fluoro-benzylidene)-2,4-dioxo-thiazolidin-3-yl]- acetic acid

154. 5-(2,4-Bis-benzyloxy-benzylidene)-thiazolidine-2,4-dione 155. 5-(4-Benzyl-benzylidene)-4-thioxo-thiazolidin-2-one

156. 5-[3,7-Dimethyl-9-(2,6,6-trimethyl-cyclohex-l-enyl)-nona-2,4,6,8- tetraenylidene]-4-imino-thiazolidin-2-one

157. (5-Furan-2-ylmethylene-2,4-dioxo-thiazolidin-3-yl)-acetic acid

158. 5-Pyridin-2-ylmethylene-thiazolidine-2,4-dione 159. 5-(l-Mefhyl-lH-pyrrol-3-ylmethylene)-4-thioxo-thiazolidin-2-one

160. 5-(2-Hydroxy-4,6-dimethoxy-benzylidene)-4-imino-thiazolidin-2-one

161. [5-(5-Benzyloxy-2-hydroxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid

162. 5-(4-Benzyloxy-3,5-dimethoxy-benzylidene)-thiazolidine-2,4-dione

163. 5-(4-Benzyloxy-3,5-dihydroxy-benzylidene)-4-thioxo-thiazolidin-2-one 164. 5-(2,5-Bis-benzyloxy-benzylidene)-4-imino-thiazolidin-2-one

165. (5-Cyclohexylmethylene-2,4-dioxo-thiazolidin-3-yl)-acetic acid

166. 5-(3-Biphenyl-4-yl-allylidene)-thiazolidine-2,4-dione

167. 5-(3,4-Diethoxy-2,5-dimethyl-benzylidene)-4-thioxo-thiazolidin-2-one

168. 5-[3-(3,4-Diethoxy-2,5-dimethyl-phenyl)-allylidene]-4-imino-thiazolidin-2-one 169. 2-(3-Carboxymethyl-2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzoic aid

170. 5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-hydroxy-benzoic aid

171. Methyl 4-(2-oxo-4-thioxo-thiazolidin-5-ylidenemethyl)-benzoate

172. 4-(4-Imino-2-oxo-thiazolidin-5-ylidenemethyl)-benzoic acid

173. [2,4-Dioxo-5-(4-oxo-4H-chromen-3-ylmethylene)-thiazolidin-3-yl] -acetic acid 174. [4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-phenoxy] -acetic acid

175. 3-(2-Oxo-4-thioxo-thiazolidin-5-ylidenemethyl)-benzoic acid

176. 4-(4-Imino-2-oxo-thiazolidin-5-ylidenemethyl)-phenyl propionate

177. [5-(2-Ethoxycarbonylmethoxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetic acid 178. 8-(2,4-Dioxo-thiazolidin-5-ylmethyl)-naphthalene-l-carboxylic acid

179. 5-(6-Methyl-4-oxo-4H-chromen-3-ylmethylene)-thiazolidine-2,4-dione

180. 2-Acetoxy-5-(2-oxo-4-thioxo-thiazolidin-5-ylidenemethyl) -phenyl acetate

181. 5-(2-Amino-4-oxo-4H-chromen-3-ylmethylene)-4-imino-thiazolidin-2-one

182. [5-(6-Ethyl-4-oxo-4H-chromen-3-ylmethylene)-2,4-dioxo-thiazolidin-3-yl]- acetic acid 183. 5-(6,8-Dimethyl-4-oxo-4H-chromen-3-ylmethyl)-thiazolidine-2,4-dione

184. 5-(6-Isopropyl-4-oxo-4H-chromen-3-ylmethylene)-thiazolidine-2,4-dione

185. Methyl 2-(2-oxo-4-thioxo-thiazolidin-5-ylidenemefhyl)-benzoate

186. Methyl 3-(4-imino-2-oxo-thiazolidin-5-ylidenemethyl)-lH-indole-6-carboxylate 187. [2,4-Dioxo-5-(l-phenyl-ethylidene)-thiazolidin-3-yl] -acetic acid

188. 5-(l-p-Tolyl-ethyl)-thiazolidine-2,4-dione

189. 5-[l-(4-Methoxy-phenyl)-ethylidene]-thiazolidine-2,4-dione

190. 5-[ l-(3,4-Dichloro-phenyl)-ethylidene] -4-thioxo-thiazolidin-2-one

191. 4-Imino-5-(l-thiophen-2-yl-ethylidene)-thiazolidin-2-one 192. 5-(4-Ethoxy-3-methoxy-benzylidene)-2-imino-thiazolidin-4-one

193. 5-(4-Decyloxy-benzylidene)-2-imino-thiazolidin-4-one

194. 5-(4-Amino-benzylidene)-2-imino-thiazolidin-4-one

195. 2-Imino-5-(4-octyl-benzylidene)-thiazolidin-4-one

196. 5-(2,2-Dimethyl-chroman-6-ylmethylene)-2-imino-thiazolidin-4-one 197. 5-(2,3-Dihydro-benzofuran-5-ylmethylene)-2-imino-thiazolidin-4-one

198. 5-(3,5-Dimethyl-benzylidene)-2-imino-thiazolidin-4-one

199. 5-(4-Diphenylamino-benzylidene)-2-imino-thiazolidin-4-one

200. 5- [4-(2-Hydroxy-ethoxy)-benzylidene] -2-imino-thiazolidin-4-one

201. 2-Imino-5-(4-methanesulphonyl-benzylidene)-thiazolidin-4-one 202. 2-Imino-5-(3-naphthalen-2-yl-allylidene)-thiazolidin-4-one

203. 5-[3,7-Dimethyl-9-(2,6,6-trimethyl-cyclohex-l-enyl)-nona-2,4,6,8- tetraenylidene]-2-imino-thiazolidin-4-one

204. 5-(2-Hydroxy-4,6-dimethoxy-benzylidene)-2-imino-thiazolidin-4-one

205. 5-(2,5-Bis-benzyloxy-benzylidene)-2-imino-thiazolidin-4-one 206. 5-[3-(3,4-Diethoxy-2,5-dimethyl-phenyl)-allylidene] -2-imino-thiazolidin-4-one

207. 4-(2-Imino-4-oxo-thiazolidin-5-ylidenemethyl)-benzoic aid

208. 4-(2-Imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl propionate

209. 5-(2-Amino-4-oxo-4H-chromen-3-ylmethylene)-2-imino-thiazolidin-4-one

210. Methyl 3-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-lH-indole-6-carboxylate 211. 2-Imino-5-(l-thiophen-2-yl-ethylidene)-thiazolidin-4-one

212. {5-[l-(3,5-Dihydroxy-phenyl)-ethylidene]-2,4-dioxo-thiazolidin-3-yl}-acetic acid

213. 5- ( 2,4-Bis-benzyloxy-benzyl) -thiazolidine-2,4-dione

214. 5-Pyridin-2-ylmethyl-thiazolidine-2,4-dione

215. 5-(4-Benzyloxy-3,5-dimethoxy-benzyl)-thiazolidine-2,4-dione 216. 5-(2,4-Dioxo-thiazolidin-5-ylmethyl)-2-hydroxy-benzoic acid 217. [4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenoxy]-acetic acid

218. 5-[3-(2,4-Dimethoxy-3-methyl-phenyl)-allylidene]-thiazolidine-2,4-dione

219. 5-[3-(2-Hexyloxy-phenyl)-allylidene]-thiazoUdine-2,4-dione

220. 5-(3-Benzofuran-2-yl-allylidene)-thiazolidine-2,4-dione 221. 5- [3-(3,4-Dihydroxy-5-methoxy-phenyl)-allylidene] -thiazolidine-2,4-dione

222. 5-(3-Benzo[l,3]dioxol-4-yl-allylidene)-thiazolidine-2,4-dione

223. 5- [3-(4-tert-Butoxy-phenyl)-allylidene] -thiazolidine-2,4-dione

224. 5-[3-(3-Amino-phenyl)-allylidene]-thiazolidine-2,4-dione 5-(5-Furan-2-yl-4- methyl-penta-2,4-dienylidene)-thiazolidine-2,4-dione 225. 5- [5-(4-Hydroxy-3-methoxy-phenyl)-penta-2,4-dienylidene] -thiazolidine-2,4- dione

226. 5-[5-(4-tert-Butyl-phenyl)-4-methyl-penta-2,4-dienyhdene]-thiazolidine-2,4- dione

227. 5-{3-[3-(2-Hydroxy-ethoxy)-phenyl]-allylidene}-thiazolidine-2,4-dione 228. 5-[5-(4-Hydroxy-3,5-dimethoxy-phenyl)-penta-2,4-dienylidene]-thiazolidine- 2,4-dione

229. 5-(5-Benzo[b]thiophen-2-yl-penta-2,4-dienylidene)-thiazolidine-2,4-dione

230. 5-[3-(2,4-Bis-benzyloxy-phenyl)-allylidene]-thiazolidine-2,4-dione

231. 5-(3-Pyridin-2-yl-allylidene)-thiazolidine-2,4-dione 232. 5-[3-(4-Benzyloxy-3,5-dimethoxy-phenyl)-allylidene]-thiazolidine-2,4-dione

233. 5-(5-Biphenyl-4-yl-penta-2,4-dienylidene)-thiazolidine-2,4-dione

234. 5-[3-(2,4-Dioxo-thiazolidin-5-ylidene)-propenyl]-2-hydroxy-benzoic aid

235. 3-[3-(2,4-Dioxo-fhiazolidin-5-ylidene)-propenyl]-benzoic aid

236. 2-Acetoxy-5-[3-(2,4-dioxo-thiazolidin-5-ylidene)-propenyl] -phenyl acetate 237. Methyl 2-[3-(2,4-dioxo-thiazolidin-5-ylidene)-propenyl]-benzoate

238. 5-[3-(3,4-Dichloro-phenyl)-but-2-enylidene]-thiazolidine-2,4-dione

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 1H- and, where necessary, by 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 General Process A:

A solution of 5.4 mmol of aldehyde of the formula R-CHO, wherein R has the significance given above, and 5.4 mmol of thiazolidine-2,4-dione in 30 ml of abs. toluene is treated with catalytic amounts of piperidinium acetate and heated at reflux for 5 to 10 hours. Thereafter, the mixture is cooled to 0°C. The precipitate is filtered off under suction, rinsed with diethyl ether and dried.

5-Benzylidene-thiazolidine-2,4-dione (1) Colourless crystals; m.p. 241-3°C

5-(2-Hydro--y-benzyUdene)-t iazoUdine-2,4-dione (2) Dark yellow crystals; m.p. 249-51°C

5-(4-Methoxy-benzylidene)-thiazolidine-2,4-dione (3) Pale yellow crystals; m.p. 213-5°C

5-(3,4-Dimethoxy-benzylidene)-thiazolidine-2,4-dione (4) Yellow crystals; 215-7°C

5-Benzo [1,3] dioxol-5-ylmethylene-thiazolidine-2,4-dione (5) Yellow crystals; 248-9°C

5-(4 Isopropyl-benzyUdene)-t azoUdine-2,4-dione (6) Colourless crystals; m.p. 149-51°C

5-(4-Dimethylamino-benzylidene)-thiazolidine-2,4-dione (7) Red-brown crystals; m.p. >280°C

5-Naphthalen-2-ylmethylene-thiazolidine-2,4-dione (8) Yellow crystals; m.p. 196-8°C 5-Phenthylidene-thiazolidine-2,4-dione (9) Colourless crystals; m.p. >280°C

5- [2-(2-Hydroxy-phenyl)-ethylidene] -thiazolidine-2,4-dione (10) Yellow crystals (sic); m.p. 212-5°C (dec.)

5-[2-(3,4-Dimetho- y-phenyl)-etJ yfidene]-thiazolidine-2,4-dione (ϋ) Pale yellow crystals; m.p. 282-5°C (dec.)

5-[2-(4-Isopropyl-phenyl)-ethylidene]-thiazolidine-2,4-dione (12) Beige crystals; m.p. >280°C

5- [2-(4-Dimethylamino-phenyl)-ethylidene] -thiazolidine-2,4-dione (13) Orange-yellow crystals; m.p. >280°C

5-Thiophen-2-ylmethylene-thiazolidine-2,4-dione (14) Yellow crystals; m.p. >280°C

5-Thiophen-3-ylmethylene-thiazolidine-2,4-dione (15) Beige crystals; m.p. >280°C

5-Naphthalen- l-ylmethylene-thiazolidine-2,4-dione (16) Pale yellow crystals; m.p. >280°C

5-(lH-Indol-3-ylmethylene)-thiazolidine-2₎4-dione (17) Yellow crystals; m.p. >280°C

5-(4-Benzyloxy-benzylidene)-thiazolidine-2,4-dione (18) Beige crystals; m.p. 215-8°C

5-Furan-2-ylmethylene-thiazolidine-2,4-dione (19) Beige crystals; m.p. 228-30°C

5-(4-Propionyl-benzylidene)-thiazolidine-2,4-dione (20) Pale yellow crystals; m.p. 182-5°C 5-Benzo[b]t ophen-2-ylmethylene-thiazolidine-2,4-dione (21) Yellow crystals; m.p. >240°C

5-(3-Benzo[b]thiophen-2-yl-allylidene)-thiazolidine-2₎4-dione (22) Yellow crystals; m.p. >240°C

5-(5-Benzo[b]thiophen-2-yl-penta-2,4-dienylidene)-thiazolidine-2,4-dione (23) Brown crystals; m.p. 210°C (dec.)

5-(3-Phenoxy-benzyl)-thiazolidine-2,4-dione (24) Beige crystals; m.p. 207°C (dec.)

5-[3-(5,6-Diet_hoxy-benzo[b]thiophen-2-yl)-aUyUdene]-thiazolidine-2,4-dione (25) Orange-red crystals,; m.p. 253-5°C

5-[3-(3,4-Dietlιoxy-2,5-dimethyl-phenyl)-allylidene]-thiazolidine-2,4-dione (26) Yellow crystals; m.p. 193-6°C

Example 2

General Process B:

14 mmol of aldehyde of the formula R-CHO, wherein R has the given significance, and 10 mmol of ethyl 2,4-dioxo-thiazolidin-3-ylacetate (Pharmazie 40.727-8 (1985)) are heated under reflux together with 30 mmol of sodium acetate and 40 ml of glacial acetic acid for 6-18 hours. After cooling the mixture is poured into H₂O The precipitate is filtered off under suction, rinsed with H₂O and dried. For purification, it is chromatographed over silica gel with ethyl acetate/heptane.

Ethyl 5-3-(5,6-diethoxy-benzo [b] thiophen-2-yl)-allylidene] -2,4-dioxo-thiazolidin-3-yl- acetate (27) Orange crystals; m.p. 193-5°C Ethyl 5-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetate

(28)

Yellow crystals; m.p. 138-41°C

Methyl 5- (3,4-Diethoxy-2,5-dimethyl-benzylidene)-2,4-dioxo-thiazolidin-3-yl] -acetate

(29)

Yellow crystals; m.p. 70-5°C

Methyl 5- (3₎4-Dihydroxy-2,5-dimethyl-benzyiidene)-2,4-dioxo-thiazolidin-3-yl] - acetate (30) Ochre-coloured crystals; m.p. 220-3°C

Methyl 5-[3-(5,6-Diethoxy-benzo[b]thiophen-2-yl)-allylidene]-2,4-dioxo-thiazolidin- 3-yl-acetate (31)

Ochre coloured crystals; m.p. 160-4°C

Example 3 General Process C:

7 mmol of the corresponding ethyl acetate derivative are then treated with 0.4 ml of sulphuric acid and 18 ml of formic acid. The formic acid is removed in a vacuum and the residue is recrystallized from water/acetonitrile.

[5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid (32) Pale yellow crystals; m.p. 130-5°C

[5-(3,4-Diethoxy-2,5-dime1_hyl-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid

(33)

Colourless crystals; m.p. 180-3°C

[5-(3,4-Dmydroxy-2,5-dimet yl-benzylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid

(34)

Yellow crystals; m.p. 230°C (dec.) 5-[3-(5,6-Diethoxy-benzo[b]miophen-2-yl)-aUyUdene]-2,4-dioxo-thiazolidin-3-yl- acetic acid (35)

Orange crystals; m.p. 235°C (dec.)

5- [3-Methyl-5-(2,6,6-trimethyl-cyclohex- l-enyl)-penta-2,4-dienylidene]-2,4-dioxo- thiazolidin-3-yl-acetic acid (36) Orange crystals; m.p. 135°C (dec.)

5-[3-(3,4-Dieώoxy-2,5-dimeώyl-phenyl)-allylidene]-2,4-dioxo-thiazolidin-3-yl-acetic acid (37)

Yellow crystals; m.p. 190-3°C

[5-(3-Biphenyl-4-yl-allylidene)-2,4-dioxo-thiazolidin-3-yl]-acetic acid (38) Orange crystals; m.p. 215°C (dec.)

Example 4 General Process D:

a. 10 mmol of 4-thioxo-thiazolidin-2-one (Chem. Heterocycl. Compds. EN 3 533-4 (1967) and 10 mmol of aldehyde R-CHO, wherein R has the given significance, are taken up in 10 ml of glacial acetic acid, treated with 1 g of sodium acetate and heated at reflux for 10-60 min. After cooling 10 ml of H₂O are added thereto, the precipitate is filtered off and rinsed with H₂O and dried. For purification, it is recrystallized from (sic) methanol.

b. 10 mmol of the corresponding 5-alkyl-4-thioxo-thiazolidin-2-one derivative are treated with 3.25 mmol of P₂S₅ in 10 ml of abs. dioxan for 3 to 10 hours. Thereafter, active charcoal is added and the mixture is heated for a further

30 min. The mixture is filtered and the solvent is removed under a vacuum. The residue is recrystallized from water. Example 5 General Process E:

a. 10 mmol of 4-iminothiazolidin-2-one one (Chem. Heterocycl. Compds. EN 4

324-5 (1968)) and 10 mmol of aldehyde R-CHO, wherein R has the given significance, are treated with 1 g of sodium acetate and 10 ml of glacial acetic acid. The mixture is heated at reflux for 10 to 60 min., cooled and poured into 60 ml of water. The precipitate is filtered off under suction, rinsed with water and methanol and dried.

b. 10 mmol of the corresponding 5-alkylidene-4-thioxo-thiazolidin-2-one derivative are heated to 100°C with 6 ml of cone. Ammonia for 10 to 60 min. After cooling the precipitate is filtered off under suction and rinsed with water and methanol. For purification, it is crystallized from dioxan.

Example 6

General process F:

10 mmol of the corresponding 5-alkylidene-2,4-thiazolidinedione derivative are hydrogenated in tetrahydrofuran with 1 g of Pd/C 10% at 50 PSI. The catalyst is filtered off and the solvent is removed in a vacuum.. The residue is purified by chromatography over silica gel (heptane/ ethyl acetate).

Example 7

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

Claims

Patent Claims

1. Use of Compounds of general formula (I)

in which m signifies a number between 0-8, q signifies a number between 0-8

A signifies a single or double bond

Ri signifies hydrogen or, when X and Z are oxygen, also -CH₂)-COR_t with a

= 0-6 R₂,R₃ signify hydrogen or lower alkyl, whereby R₂ and R₃ can be the same or different and, when m signifies 2-8, R₂ and

R₃ in the group CR₂=CR₃ can have various significances within the following sequence R4 signifies hydroxyl, lower alkoxy or the NR^₂ residue, whereby Ri and R₂ can be the same or different X signifies oxygen or imino

Z signifies oxygen, sulphur or imino

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)

in which m signifies a number between 0-8, q signifies a number between 0-8

A signifies a single or double bond Ri signifies hydrogen or, when X and Z are oxygen, also -CH₂)-COR with a = 0-6 R₂,R₃ signify hydrogen or lower alkyl, whereby R₂ and R₃ can be the same or different and, when m signifies 2-8, R₂ and R₃ in the group CR₂=CR₃ can have various significances within the following sequence

Ri signifies hydroxyl, lower alkoxy or the NRiR₂ residue, whereby Ri and R₂ can be the same or different X signifies oxygen or imino

Z signifies oxygen, sulphur or imino 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, naphthyl, indolyl, benzofuranyl and benzothiophen-yl, if X signifies oxygen, m and q are both 0 and Rj is hydrogen,

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