WO2000018745A1

WO2000018745A1 - Oxazolidine derivatives for the treatment and prevention of metabolic bone disorders

Info

Publication number: WO2000018745A1
Application number: PCT/EP1999/007253
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: AU6331199A

Abstract

The object of the present invention are compounds of general formula (I), in which: m signifies a number between 0-8; q signifies 0-8; A signifies a single or double bond; R1 signifies hydrogen or -(CH2)a-COR4 with a =0-6, preferably 1-3; 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; R5 signifies hydrogen or methyl; X signifies oxygen or sulphur; 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

Oxazolidine derivatives for the treatment and prevention of metabolic bone disorders

The present invention is concerned with oxazolidine 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 oxazolidine 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 708098 and EP-A-676398.

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)₂D₃. 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 cydase 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 oxazolidine 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.

By their influence on bone metabolism medicaments with the oxazolidine derivatives of the present invention as active substances furthermore form a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.

The compounds (Z)-5- [ [3,5-bis-tert.butyl)-4-hydroxyphenyl] -methylene] -2-,4- oxazolidinone and (Z)-5-[ [3,5-bis-tert.butyl)-4-hydroxyphenyl]-methylene]-2-thioxo- 4-oxazolidinone with inflammation-inhibiting activity are described in J. Med. Chem. 37322-8 (1994). The compounds 5-[(4-hydroxyphenyl)methyl]2,4-oxazolidinone and 5-[(benzyloxy-4-phenyl)methyl]2,4-oxazolidinone are described as intermediates in J. Med. Chem. 37 3977-85 (1994). The para-substituted 5-phenyl-2-thioxo-4- oxazolidinone derivatives with the substituent R = Br, F, CF₃, CH₃O, CF₃O, benzyl and naphthyl are described as intermediates in J. Med. Chem. 18 1216-23 (1975). The object of the present invention are compounds of general formula (I),

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

A signifies a single or double bond R> signifies hydrogen or -(CH₂)_a-COR with a = 0-6, preferably 1-3

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

R signifies hydroxyl, lower alkoxyl or the NRιR₂ residue, whereby Ri and R₂ can be the same or different

R₅ signifies hydrogen or methyl

X signifies oxygen or sulphur

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 Ci-Cio-alkyl group in accordance with the above definition with an oxygen atom, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups.

Under monocycle there are to be understood optionally mono- or polysubstituted, saturated or unsaturated ring systems with 3-8, preferably 5-7 carbon atoms, which optionally can be interrupted by one or more hetero atoms, such as nitrogen, oxygen or sulphur, especially the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, thiophenyl, imidazolyl thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue, as well as residues such as e.g. phenyl phenyl ether, diphenylmethane and bipheny As substituents there come into consideration primarily lower alkyl, alkoxy, amino, dialkylamino, dioxymethylene, benzonitrile, benzyl, benzyloxy, carboxyl, hydroxy, mercaptoalkyl, styryl, phenoxy, and halogen.

In the case of the bicycle set forth under W, this is preferably a residue such as the naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, chromane, chromene, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofiiranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinyl residue, especially the indolyl, naphthyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl benzothiophenyl and benzofiiranyl residue, which optionally can be mono- or polysubstituted. As substituents there come into consideration primarily lower alkyl, alkoxy, amino, dialkylamino, dioxymethylene, benzonitrile, benzyl, benzyloxy, carboxyl, hydroxy, mercaptoalkyl, styryl, phenoxy, and halogen.

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

Compounds of formula I wherein W is phenol or 2-hydroxypyridine or its bicyclic derivatives, n is 0 and g is unequal 0 are disclosed in EP-A-0612743 however as antidiabetic agents.

Compounds of formula I wherein W is phenol or benzofuran, A is a single bond, X is oxygen and g is 1 or 2 are disclosed in WO-A-97/00249 however as antidiabetic agents.

Compounds of formula I wherein W is phenyl, benzofuran, benzoxazol, m and g together are 0 are disclosed in EP-A-0428312 however as hypoglycemic agents. Therefore subject of the present invention are also new compounds of formula I

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

A signifies a single or double bond

Ri signifies hydrogen or -(CH₂)_a-COR₄ with a = 0-6, preferably 1-3 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 CR =CR₃ can have various significances within the following sequence R₄ signifies hydroxyl, lower alkoxyl or the NR.R₂ residue, whereby Rj and R₂ can be the same or different R₅ signifies hydrogen or methyl X signifies oxygen or sulphur

whereas W is not phenol or 2-hydroxypyridine or its bicyclic derivatives, if m equals 0 and g unequal 0,

whereas W is not phenol and benzofuran, if A is a single bond, X is oxygen and g is 1 or 2,

whereas W is not phenyl, benzofuran, benzoxazol, if m and g together equal 0,

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. Especially preferred are compounds in which m signifies a number between 0 and 2, q signifies the number 0 or 1, A signifies a double bond, Ri signifies hydrogen, R₂/R₃ signify hydrogen or methyl, R₅ signifies hydrogen or methyl, X signifies sulphur and W signifies an optionally mono- or polysubstituted phenyl, phenanthrene, benzofuran, benzothiophene, biphenyl, cyclohexenyl or naphthalene residue.

The manufacture of the compounds of general formula (I) is possible according to methods known per se. Examples are set forth in Schemes 1 to 6; whereby R signifies the group:

w CH, . C ₂-= CR₃

. m

Scheme 1 (Lit.: J. Med. Chem. 373977-85 ( 1994))

Scheme 2 (Lit.: J. Med. Chem. 3_Z 322-8 (1994))

Scheme 3 (Lit. J. Med. Chem. 34 1538-44 (1991))

Scheme 4 (Lit.: J. Med. Chem. 34 1538-44 (1991))

KOLBu + glycolamide + diethyl carbonate

Scheme 5 (Lit.: J. Med. Chem. 18.1216-23 (1975))

RCHO ^KSCN' ^KCN -

Scheme 6 (Lit. JACS 73.4752 (1951)

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 appUcation 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, conveniendy 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 0616 814 and EP-A-0 567391 and synthetic bone matrices in accordance with WO 91/18558.

Likewise suitable as carriers for the compounds of formula (I) are materials which are usually used for the implantation of bone substitutes or otherwise of therapeutically active substances. Such carriers are based, for example, on calcium sulphate, tricalcium phosphate, hydroxylapatite (sic) and its biodegradable derivatives and polyanhydrides. Apart from these biodegradable carriers there are also suitable carriers which are not biodegradable, but which are biocompatible. Such carriers are, for example, sintered hydroxylapatite, bioglass, aluminates or other ceramic materials (e.g. calcium aluminium phosphate). These materials are preferably used in combination with the biodegradable materials, such as especially polylactic acid, hydroxylapatite, collagen or tricalcium phosphate. Further non-degradable carriers are described, for example, in US Patent 4,164,560.

It is especially preferred to use a carrier which liberates the compounds of formula (I) continuously at the target site. Especially suitable for this are e.g. "slow release pellets" from Innovative Research of America, Toledo, Ohio, USA. Pellets which release the compounds of formula (I) over several days, preferably up to 100 days with a daily dosage of 1-10 mg/kg per day, are especially preferred.

Preferred in the scope of the present invention are, apart form the compounds named in the Examples and compounds derivable by a combination of all of the significances of the substituents set forth in the claims, the following derivatives as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments,

Preferred Compounds (PC):

1. 5-(9H-Fluoren-2-ylmethylene)-2-thioxo-oxazolidin-4-one

2. 5-Phenanthren-9-ylmethylene-oxazolidine-2,4-dione 3. 5-Anthracen-9-ylmethyl-2-thioxo-oxazolidin-4-one 4. 5-( 10-Methyl-anthracen-9-ylmethyl)-oxazolidine-2,4-dione

5. 5-(5-Furan-2-yl-penta-2,4-dienylidene)-2-thioxo-oxazolidin-4-one

6. 5-(2-Methoxy-benzylidene)-2-thioxo-oxazolidin-4-one

7. 5-(2,3-Dimethoxy-benzylidene)-oxazolidine-2,4-dione 8. 2-Thioxo-5-(2,3,4-trimethoxy-benzyl)-oxazolidin-4-one

9. 5-(2,4-Dimethoxy-benzyl)-oxazolidine-2,4-dione

10. 2-Thioxo-5- [3-(2,4,5-trimethoxy-phenyl)-allylidene] -oxazolidin-4-one

11. 5-[3-(2,4,6-Trimethoxy-phenyl)-allylidene]-oxazolidine-2,4-dione

12. 5-(2,5-Dimethoxy-benzylidene)-2-thioxo-oxazolidin-4-one 13. 5-(2-Ethoxy-benzylidene)-oxazolidine-2,4-dione

14. 5-(2-Hydroxy-benzyl)-2-thioxo-oxazolidin-4-one

15. 5-(2-Hydroxy-3-methoxy-benzyl)-oxazolidine-2,4-dione

16. 5- [3-(3-Ethoxy-2-hydroxy-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one

17. 5-[3-(2,3-Dihydroxy-phenyl)-allylidene]-oxazolidine-2,4-dione 18. 2-Thioxo-5-(2,3,4-trihydroxy-benzylidene)-oxazolidin-4-one

19. 5-(4-Diethylamino-2-hydroxy-benzylidene)-oxazolidine-2,4-dione

20. 5 - ( 2-Hydroxy-4-methoxy-benzyl) -2 -thioxo-oxazolidin-4-one

21. 5-(2,4,6-Trihydroxy-benzyl)-oxazolidine-2,4-dione

22. 5-[3-(2-Hydroxy-5-methoxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one 23. 5-[3-(2,5-Dihydroxy-phenyl)-allylidene]-oxazolidine-2,4-dione

24. 5-(2-Methyl-benzylidene)-2-thioxo-oxazolidin-4-one

25. 5-(4-Methoxy-2,3-dimethyl-benzy_idene)-oxazolidine-2,4-dione

26. 2-Thioxo-5-(2,4,6-trimethyl-benzyl)-oxazolidin-4-one

27. 5-(2,5-Dimethyl-benzyl)-oxazolidine-2,4-dione 28. 5-[3-(4-Methoxy-2,5-dimethyl-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

29. 5-{3- [3-(4-Methoxy-phenoxy)-phenyl] -allylidene}-oxazolidine-2,4-dione

30. 5-[3-(4-tert-Butyl-phenoxy)-benzylidene]-2-thioxo-oxazolidin-4-one

31. 5-(3-p-Tolyloxy-benzylidene)-oxazolidine-2,4-dione

32. 5-(3-Methoxy-benzyl)-2-thioxo-oxazolidin-4-one 33. 5-(3,4-Dimethoxy-benzyl)-oxazolidine-2,4-dione

34. 2-Thioxo-5- [3-(3,4,5-trimethoxy-phenyl)-allylidene] -oxazolidin-4-one

35. 5- [3-(4-Benzyloxy-3-methoxy-phenyl)-allylidene] -oxazolidine-2,4-dione

36. 5-(3,5-Dimethoxy-benzylidene)-2-thioxo-oxazolidin-4-one

37. 5-(3-Benzyloxy-benzylidene)-oxazoUdine-2,4-dione 38. 5-(3-Hydroxy-benzyl)-2-thioxo-oxazolidin-4-one 39. 5-(3-Hydroxy-4-methoxy-benzyl)-oxazolidine-2,4-dione

40. 5-[3-(3,4-Dihydroxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

41. 5-(3- -Tolyl-allylidene)-oxazolidine-2,4-dione

42. 5-(4-Methoxy-3-methyl-benzylidene)-2-thioxo-oxazolidin-4-one 43. 5-(4-Dimethylamino-benzylidene)-oxazolidine-2,4-dione

44. 5-(4-Diethylamino-benzyl)-2-thioxo-oxazolidin-4-one

45. 5-(4-Phenoxy-benzyl)-oxazolidine-2,4-dione

46. 5-[3-(4-Methoxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

47. 5-[3-(3-Benzyloxy-4-methoxy-phenyl)-allylidene]-oxazolidine-2,4-dione 48. 5-(4-Benzyloxy-benzylidene)-2-thioxo-oxazolidin-4-one

49. 5-(4-Ethoxy-benzylidene)-oxazolidine-2,4-dione

50. 5-(4-Butoxy-benzyl)-2-thioxo-oxazolidin-4-one

51. 5-Naphthalen-l-ylmethyl-oxazolidine-2,4-dione

52. 5-[3-(2-Hydroxy-naphthalen-l-yl)-allylidene]-2-thioxo-oxazolidin-4-one 53. 5-(4-Methoxy-naphthalen-l-ylmethylene)-2-thioxo-oxazolidin-4-one

54. 5-Naphthalen-2-ylmethylene-oxazolidine-2,4-dione

55. 5-(3,4-Bis-benzyloxy-benzyl) -2-thioxo-oxazolidin-4-one

56. 5-(9-Ethyl-9H-carbazol-3-ylmethyl)-oxazolidine-2,4-dione

57. 5-[3-(5-Methoxy-lH-indol-3-yl)-allylidene]-2-thioxo-oxazolidin-4-one 58. 5-Quinolin-4-ylmethylene-oxazolidine-2,4-dione

59. 5-(4-Hydroxy-benzyl)-2-thioxo-oxazolidin-4-one

60. 5-(4-Hydroxy-3-methoxy-benzyl)-oxazolidine-2,4-dione

61. 5-[3-(3-Ethoxy-4-hydroxy-phenyl)-allylidene]-oxazolidine-2,4-dione

62. 5-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-thioxo-oxazolidin-4-one 63. 5-Biphenyl-4-ylmethylene-oxazolidine-2,4-dione

64. 5-(4-Methylsulphanyl-benzyl)-2-thioxo-oxazolidin-4-one

65. 5-(4-Isopropyl-benzyl)-oxazolidine-2,4-dione

66. 5- [3-(4-Ethyl-phenyl)-a_lylidene] -oxazolidine-2,4-dione

67. 5-(2,2-Diphenyl-ethylidene)-2-thioxo-oxazolidin-4-one 68. 5-(2-Phenyl-propylidene)-oxazolidine-2,4-dione

69. 5-(2-Methyl-3-phenyl-allyl)-2-thioxo-oxazolidin-4-one

70. 5-(4-Phenyl-but-2-enylidene)-oxazolidine-2,4-dione

71. 5-(3-Phenyl-prop-2-ynylidene)-2-thioxo-oxazolidin-4-one

72. 5-(3-Phenyl-allylidene)-oxazolidine-2,4-dione 73. 5-(2,3-Dihydro-benzo[ l,4]dioxin-6-ylmethylene)-2-thioxo-oxazolidin-4-one 74. 5-(3-Ethoxy-4-methoxy-benzylidene)-oxazolidine-2,4-dione

75. 5-(4-Diethoxymethyl-benzyl)-2-thioxo-oxazolidin-4-one

76. 5-(4-Dimethylamino-naphthalen- l-ylmethyl)-oxazolidine-2,4-dione

77. 5-[3-(2,6-Dimethoxy-phenyl)-allylidene] -oxazolidine-2,4-dione 78. 5-(2,4-Dimethoxy-3-methyl-benzylidene)-2-thioxo-oxazolidin-4-one

79. 5-(4-Styryl-benzylidene)-oxazolidine-2,4-dione

80. 5-[4-(3-Dimethylamino-propoxy)-benzyl]-2-thioxo-oxazoUdin-4-one

81. 5-(2,4-Dihydroxy-benzyl)-oxazolidine-2,4-dione

82. 5- [3-(4-Hydroxy-3-methyl-phenyl)-allylidene] -oxazolidine-2,4-dione 83. 5-(2-Allyloxy-benzylidene)-2-thioxo-oxazolidin-4-one

84. 5-(2-Hexyloxy-benzylidene)-oxazolidine-2,4-dione

85. 5-(4-Allyloxy-benzyl)-2-thioxo-oxazolidin-4-one

86. 5-(4-Propoxy-benzyl)-oxazolidine-2,4-dione

87. 5-[3-(4-Octyloxy-phenyl)-allylidene]-oxazolidine-2,4-dione 88. 5-(5-Benzyloxy- lH-indol-3-ylmethylene)-2-thioxo-oxazolidin-4-one

89. 5-( 1-Methyl- lH-indol-3-ylmethylene)-oxazolidine-2,4-dione

90. 5-Benzofuran-2-ylmethyl-2-thioxo-oxazolidin-4-one

91. 5-(4-Pyrrolidin-l-yl-benzyl)-oxazolidine-2,4-dione

92. 5-[3-(2-Benzyloxy-phenyl)-allylidene]-oxazolidine-2,4-dione 93. 2-Thioxo-5-(2,3,4-trimethoxy-6-methyl-benzylidene)-oxazolidin-4-one

94. 5-(3-Ethoxy-benzylidene)-oxazolidine-2,4-dione

95. 5-(3,4-Diethoxy-benzyl)-2-thioxo-oxazolidin-4-one

96. 5-(3,4-Dihydroxy-5-methoxy-benzyl)-oxazolidine-2,4-dione

97. 5-[3-(3,4-Dimethyl-phenyl)-allylidene]-oxazolidine-2,4-dione 98. 5-(4-Ethoxy-3-methoxy-benzylidene)-2-thioxo-oxazolidin-4-one

99. 5-(4-Hexyloxy-benzylidene)-oxazolidine-2,4-dione

100. 5-(4-Heptyloxy-benzyl)-2-thioxo-oxazolidin-4-one

101. 5-(7-Methoxy-benzo[ 1,3] dioxol-5-ylmethyl)-oxazolidine-2,4-dione

102. 5-[5-(4-Methoxy-phenyl)-penta-2,4-dienylidene]-oxazolidine-2,4-dione 103. 2-Thioxo-5-(2,4,5-trimethyl-benzylidene)-oxazolidin-4-one

104. 5-(4-Decyloxy-benzylidene)-oxazolidine-2,4-dione

105. 5-(3-Allyl-2-hydroxy-benzylidene)-oxazolidine-2,4-dione

106. 5-(4-Amino-benzyl)-2-thioxo-oxazolidin-4-one

107. 5-(4-Butyl-benzyl)-oxazolidine-2,4-dione 108. 5-[3-(2-Hydroxy-3-methyl-phenyl)-aUylidene]-oxazolidine-2,4-dione 109. 5-(4-terf-Butoxy-benzylidene)-2-thioxo-oxazoli<ϋn-4-one

110. 5-(4-Propyl-benzylidene)-oxazolidine-2,4-dione

111. 5-(4-Hexyl-benzyl)-2-thioxo-oxazolidin-4-one

112. 5-(4-Pentyl-benzyl)-oxazolidine-2,4-dione 113. 5-(4-Nonyloxy-benzylidene)-2-thioxo-oxazolidin-4-one

114. 5-(3-Amino-benzylidene)-oxazolidine-2,4-dione

115. 5-(2-Ethoxy-naphthalen- l-ylmethyl)-2-thioxo-oxazolidin-4-one

116. 5-(4-p-Tolyl-but-2-enylidene)-oxazolidine-2,4-dione

117. 5-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethylene)-2-thioxo-oxazolidin-4-one 118. 5-(2,5-Dimethyl-l-phenyl-lH-pyrrol-3-ylmethylene)-oxazolidine-2,4-dione

119. 5- [3-(2,2-Dimethyl-chroman-6-yl)-allylidene] -oxazolidine-2,4-dione

120. 5-(4-Isopropoxy-benzylidene)-2-thioxo-oxazolidin-4-one

121. 5-(4-Hydroxy-naphthalen-l-ylmethyl)-2-thioxo-oxazolidin-4-one

122. 5-(2,3-Dihydro-benzofuran-5-ylmethylene)-2-thioxo-oxazolidin-4-one 123. 5-Quinolin-2-ylmethylene-oxazolidine-2,4-dione

124. 5- [5-(4-Diethylamino-phenyl)-penta-2,4-dienylidene] -2-thioxo-oxazolidin-4-one

125. 5- [5-(4-Hydroxy-3-methoxy-phenyl)-penta-2,4-dienylidene] -oxazolidine-2,4- dione

126. 5-(6-Methoxy-naphthalen-2-ylmethylene)-2-thioxo-oxazolidin-4-one 127. 5-(3,5-Dimethyl-benzylidene)-oxazolidine-2,4-dione

128. 5-(l-Hydroxy-naphthalen-2-ylmethyl)-2-thioxo-oxazolidin-4-one

129. 5-(4-Phenylethynyl-benzyl)-oxazolidine-2,4-dione

130. 5-[3-(4-rer -Butyl-phenyl)-2-methyl-allylidene]-2-thioxo-oxazolidin-4-one

131. 5-(4-O ctadecyloxy-b enzylidene ) -oxazolidine-2 ,4-dione 132. 5-(4-Diphenylamino-benzyl)-2-thioxo-oxazolidin-4-one

133. 5-(3,4,5-Trihydroxy-benzyl)-oxazolidine-2,4-dione

134. 5- [3-(2-Hydroxy-6-methoxy-phenyl)-allylidene] -oxazolidine-2,4-dione

135. 5-(2-Benzyloxy-4,5-dimethoxy-benzylidene)-2-thioxo-oxazolidin-4-one

136. 5- [3-(2-Hydroxy-ethoxy)-benzylidene] -oxazolidine-2,4-dione 137. 5-[2-(2-Hydroxy-ethoxy)-benzyl]-2-thioxo-oxazolidin-4-one

138. 5-(2-Benzyloxy-ethyl)-oxazolidine-2,4-dione

139. Carbonic acid fert-butyl ester 4-[3-(2,4-dioxo-oxazolidin-5-yliden)-propenyl]-2- methoxy-phenyl ester

140. 5-(3,5-Di-tert-butyl-2-hydroxy-benzylidene)-2-thioxo-oxazolidin-4-one 141. 5-(2,4-Diethoxy-3-methyl-benzylidene)-oxazolidine-2,4-dione 142. 5-[5-(4-Hydroxy-3,5-dimethoxy-phenyl)-penta-2,4-dienylidene]-2-thioxo- oxazolidin-4-one

143. 5-(2-Hydroxy-5-methyl-benzyl)-oxazolidine-2,4-dione

144. 5-Benzo[&]thiophen-2-ylmethylene-2-thioxo-oxazolidin-4-one 145. 5- [3-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-allylidene] -oxazolidine-2,4-dione

146. 5-(5-Naphthalen-2-yl-penta-2,4-dienylidene)-oxazolidine-2,4-dione

147. 5-(3-Thiophen-2-yl-allylidene)-2-thioxo-oxazolidin-4-one

148. 5-(2- [ 1,3] Dioxolan-2-yl-6-fluoro-benzylidene)-oxazolidine-2,4-dione

149. 5- [3-(3-terf-Butyl-4-hydroxy-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one 150. 5-[3-(4-Benzyl-phenyl)-allylidene]-oxazolidine-2,4-dione

151. 5-[3,7-Dimethyl-9-(2,6,6-trimethyl-cyclohex-l-enyl)-nona-2,4,6,8- tetraenylidene]-2-thioxo-oxazolidin-4-one

152. 5-( lH-Pyrrol-2-ylmethylene)-oxazolidine-2,4-dione

153. 5-Furan-2-ylmethyl-2-thioxo-oxazolidin-4-one 154. 5-(3-Pyridin-2-yl-allylidene)-oxazolidine-2,4-dione

155. 5-( 1-Methyl- lH-pyrrol-3-ylmethylene)-2-thioxo-oxazolidin-4-one

156. 5-(2-Hydroxy-4,6-dimethoxy-benzylidene)-oxazolidine-2,4-dione

157. 5-(4-Benzyloxy-2-hydroxy-benzyl)-2-thioxo-oxazolidin-4-one

158. 5-{3-[4-(Benzo[l,3]dioxol-5-ylmethoxy)-phenyl]-allylidene}-oxazolidine-2,4- dione

159. 5-(4-Benzyloxy-3,5-dimethoxy-benzylidene)-2-thioxo-oxazolidin-4-one

160. 5-(4-Benzyloxy-3,5-dihydroxy-benzylidene)-oxazolidine-2,4-dione

161. 5-(2,5-Bis-benzyloxy-benzyl)-2-thioxo-oxazolidin-4-one

162. 5-Cyclohexylmethyl-oxazolidine-2,4-dione 163. 5-(3-Cyclohex-3-enyl-a_lylidene)-oxazolidine-2,4-dione

164. 5-[3-Methyl-5-(2,6,6-trimethyl-cyclohex-l-enyl)-penta-2,4-dienylidene]-2- thioxo-oxazolidin-4-one

165. 5-(3-Biphenyl-4-yl-allylidene)-oxazolidine-2,4-dione

166. 5-(3,4-Diethoxy-2,5-dimethyl-benzyl)-2-thioxo-oxazolidin-4-one 167. 2-(2,4-Dioxo-oxazolidin-5-ylmethyl)-benzoic acid

168. 2-Methoxy-4-(4-oxo-2-thioxo-oxazolidin-5-ylidenemethyl)-phenyl acetate

169. 4-(2,4-Dioxo-oxazolidin-5-ylidenemethyl)-phenyl acetate

170. 2-Hydroxy-5-(4-oxo-2-thioxo-oxazolidin-5-ylmethyl)-benzoic acid

171. Methyl 4- [3-(4-oxo-2-t__ioxo-oxazolidin-5-ylidene)-propenyl]-benzoate 172. 3-{4-[3-(2,4-Dioxo-oxazolidin-5-ylidene)-propenyl]-ρhenyl}-acrylic acid 173. 5-(4-Oxo-4H-chromen-3-ylmethylene)-2-thioxo-oxazolidin-4-one

174. 3-(2,4-Dioxo-oxazolidin-5-ylidenemethyl)-phenyl acetate

175. 2,6-Dimethoxy-4-(4-oxo-2-thioxo-oxazolidin-5-ylmethyl)-phenyl acetate

176. {4-[3-(4-Oxo-2-thioxo-oxazolidin-5-ylidene)-propenyl]-phenoxy}-acetic acid 177. 4-[3-(2,4-Dioxo-oxazolidin-5-ylidene)-propenyl] -phenyl propionate

178. 5-(5,7-Dimethyl-4-oxo-4H-chromen-3-ylmethylene)-2-thioxo-oxazolidin-4-one

179. Ethyl [2-(2,4-dioxo-oxazolidin-5-ylidenemethyl)-phenoxy] -acetate

180. l,4-Dihydroxy-10-methoxy-5,8-dimethyl-ll-(4-oxo-2-thioxo-oxazolidin-5- ylmethyl)-lH-benzo[e]furo[3',4^,:3,4]benzo[fc] [l,4]dioxepin-3,7-dione 181. 8- [3-(4-Oxo-2-thioxo-oxazolidin-5-ylidene)-propenyl] -naphthalene- 1-carboxylic acid

182. 2-Acetoxy-5- [3-(2,4-dioxo-oxazolidin-5-ylidene)-propenyl] -phenyl acetate

183. 5-(2-Amino-4-oxo-4H-chromen-3-ylmethylene)-2-thioxo-oxazolidin-4-one

184. 5-(2-Amino-6,7-dimethyl-4-oxo-4H-chromen-3-ylmethylene)-oxazolidine-2,4- dione

185. 5-(6-Ethyl-4-oxo-4H-chromen-3-ylmethyl)-2-thioxo-oxazolidin-4-one

186. 5-[3-(6,8-Dimethyl-4-oxo-4H-chromen-3-yl)-allylidene]-2-thioxo-oxazolidin-4- one

187. 5- [3-(6-Isopropyl-4-oxo-4H-chromen-3-yl)-allylidene] -oxazolidine-2,4-dione 188. Methyl 2-(4-oxo-2-thioxo-oxazolidin-5-ylidenemethyl)-benzoate

189. Methyl 3-(2,4-dioxo-oxazolidin-5-ylidenemethyl)-lH-indole-6-carboxylate

190. 5-[3-(4-Chloro-phenyl)-but-2-enylidene]-2-thioxo-oxazolidin-4-one

191. 5-(3-p-Tolyl-but-2-enylidene)-oxazolidine-2,4-dione

192. 5-[ l-(4-Methoxy-phenyl)-ethylidene] -2-thioxo-oxazolidin-4-one 193. 5-[l-(3,4-Dichloro-phenyl)-ethylidene]-oxazolidine-2,4-dione

194. 5-( l-Thiophen-2-yl-ethyl)-2-thioxo-oxazolidin-4-one

195. 5-( lH-Pyrrol-2-ylmethyl)-oxazolidine-2,4-dione

196. 5-(4-Benzyloxy-2-hydroxy-benzyl)-oxazolidine-2,4-dione

197. 5-(4-Oxo-4H-chromen-3-ylmethyl)-oxazolidine-2,4-dione 198. Ethyl [2-(2,4-dioxo-oxazolidin-5-ylmethyl)-phenoxy] -acetate

199. 5-(2-Amino-6,7-dimethyl-4-oxo-4H-chromen-3-ylmethyl)-oxazolidine-2,4-dione

200. Methyl 3-(2,4-dioxo-oxazolidin-5-ylmethyl)-lH-indole-6-carboxylate

201. 5-( 1 l-Oxo-6,1 l-dihydro-dibenzo[-',e]oxepin-3-ylmethyl)-oxazolidine-2,4-dione

202. 5- [3-(4-Hydroxy-3,5-dimethyl-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one 203. 5-(4,4-Diphenyl-but-2-enylidene)-2-thioxo-oxazolidin-4-one 204. 5-(5-Phenyl-pent-2-en-4-ynylidene)-2-thioxo-oxazolidin-4-one

205. 5-[3-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-allylidene]-2-thioxo-oxazolidin-4-one

206. 5- [3-(2,4-Dimethoxy-3-methyl-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one

207. 5-[3-(2-Allyloxy-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one

208. 5-[3-(l-Methyl-lH-indol-3-yl)-allylidene]-2-thioxo-oxazolidin-4-one

209. 5-[3-(3,4-Diethoxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

210. 5-[3-(4-Heptyloxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

211. 5-[3-(4-Amino-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one

212. 5-[3-(4-Hexyl-phenyl)-allylidene] -2-thioxo-oxazolidin-4-one

213. 5-[3-(2-Ethoxy-naphthalen-l-yl)-allylidene]-2-thioxo-oxazolidin-4-one

214. 5-[3-(4-Hydroxy-naphthalen- l-yl)-allylidene] -2-thioxo-oxazolidin-4-one

215. 5-[3-(l-Hydroxy-naphthalen-2-yl)-allylidene]-2-thioxo-oxazolidin-4-one

216. 5-[3-(4-Diphenylamino-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

217. 5-{3-[2-(2-Hydroxy-ethoxy)-phenyl]-allylidene}-2-thioxo-oxazolidin-4-one

218. 5-(3-Furan-2-yl-allylidene)-2-thioxo-oxazolidin-4-one

219. 5-[3-(4-Benzyloxy-2-hydroxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

220. 5-[3-(2,5-Bis-benzyloxy-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

221. 5-[3-(3,4-Diethoxy-2,5-dimethyl-phenyl)-allylidene]-2-thioxo-oxazolidin-4-one

222. 5-[3-(3,5-Dihydroxy-phenyl)-but-2-enyliden]-2-thioxo-oxazolidin-4-one

223. 5-[3-(2-Hydroxy-naphthalen-l-yl)-allylidene]-oxazolidine-2,4-dione

224. 5-[3-(5-Methoxy-lH-indol-3-yl)-allylidene]-oxazolidine-2,4-dione

225. 5-[3-(4-Pentyl-phenyl)-allylidene]-oxazolidine-2,4-dione

226. 5-[3-(2-Hydroxy-5-methyl-phenyl)-allylidene]-oxazolidine-2,4-dione

227. 2-[3-(2,4-Dioxo-oxazolidin-5-yliden)-propenyl]-benzoic acid

228. 2,6-Diacetoxy-4-[3-(2,4-dioxo-oxazolidin-5-ylidene)-propenyl]-phenyl acetate

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:

5 mmol of aldehyde R-CHO, wherein R has the significance given above, and 5 mmol of 2-thioxo-oxazolidin-2-one are heated at reflux together with 15 mmol of sodium acetate and 15 ml of glacial acetic acid for 10 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 (2:1).

4-(4-Oxo-2-thioxo-oxazolidin-5-ylidenemethyl)-benzonitrile (l) Yield 46%; ochre coloured crystals; m.p. 239-41°C (dec.)

5-(4-Methoxy-benzylidene)-2-thioxo-oxazolidin-4-one (2) Yield 56%; ochre coloured crystals; m.p. 238-40°C

5-(3-Ethoxy-4-hydroxy-benzylidene)-2-thioxo-oxazolidin-4-one (3) Yield 38%; yellow crystals; m.p. 208-10°C

5-Phenanthren-9-ylmethylene-2-thioxo-oxazolidin-4-one (4) Yield 32%; ochre coloured crystals; m.p. 248-51°C 5-(3,5-Dimethyl-benzylidene)-2-thioxo-oxazolidin-4-one (5) Yield 28%; ochre coloured crystals; m.p. 234-6°C

5-(3-Benzofuran-2-yl-allylidene)-2-thioxo-oxazolidin-4-one (6) Yield 26%; red-brown crystals; m.p. 229-32°C

5- (5-Benzo [ b] thiophen-2-yl-penta-2,4-dienylidene)-2-thioxo-oxazolidin-4-one (7) Yield 18%; red-brown crystals; m.p. 239°C (dec.)

5-(2-Hydroxy-3-methoxy-benzylidene)-2-thioxo-oxazolidin-4-one (8) Yield 39%; yellow crystals; m.p. 252-4°C

5-Biphenyl-4-ylmethylene-2-thioxo-oxazolidin-4-one (9) Yield 22%; ochre coloured crystals; m.p. 237-9°C 5-Naphthalen- 1 -ylmethylene-2-thioxo-oxazolidin-4-one (10) Yield 38%; yellow crystals; m.p. 240-2°C

5-Benzo [ 1 ,3 ] dioxol-5-ylmethylene-2-thioxo-oxazolidin-4-one (11) Yield 27%; yellow crystals; m.p. 211-4°C

5-(3-Hydroxy-2,4-dimethoxy-benzylidene)-2-thioxo-oxazolidin-4-one (12) Yield 59%; yellow crystals; m.p. 216-8°C

5-(2-Hydroxy-naphthalen- l-ylmethylene)-2-thioxo-oxazolidin-4-one (13) Yield 16%; red-brown crystals; m.p. 228-30°C

4-(4-Oxo-2-thioxo-oxazolidin-5-ylidenmethyl)-benzoic acid (1.4) Yield 22%; ochre coloured crystals; m.p. 270°C (dec.)

5-(3,5-Di-fert-butyl-4-hydroxy-benzylidene)-2-thioxo-oxazolidin-4-one (15) Yield 56%; orange-yellow crystals; m.p. 238-40°C

5-(3-Methoxy-benzylidene)-2-thioxo-oxazolidin-4-one (16) Yield 64%; orange-brown crystals; m.p. 215-7°C

5- (3-Hexyloxy-benzylidene)-2-thioxo-oxazolidin-4-one (1,7) Yield 91%; orange-brown crystals; m.p. 112-3°C

5-(4-Dibutylamino-benzylidene)-2-thioxo-oxazolidin-4-one (18) Yield 31%; brown crystals; m.p. 166-8°C

5-(4-Pentyl-benzylidene)-2-thioxo-oxazolidin-4-one (19) Yield 41%; brown crystals; m.p. 134-6°C Example 2 General process B:

1 mmol of 2-thioxo-oxazolidin-4-one derivative (Example 1) is dissolved in 5 ml of dimethylformamide and cooled to 0°C. After the addition of 1.25 mmol of m-chloro- peroxybenzoic acid the mixture is left to come slowly to room temperature. After 12 hours at room temperature it is diluted with ethyl acetate and poured into H₂O. The org. phase is washed with H₂O and saturated NaCl solution, dried over Na₂SO and concentrated. The residue is purified by silica gel chromatography with ethyl acetate/heptane.

5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-oxazolidine-2,4-dione (20) Yield 57%; pale yellow crystals; m.p. 233-5°C

5- (3-Methoxy-benzylidene)-oxazolidine-2,4-dione (21) Yield 46%; pale yellow crystals; m.p. 197-8°C

5-(3-Hexyloxy-benzylidene)-oxazolidine-2,4-dione (22) Yield 51 %; pale yellow crystals; m.p. 109-11°C

Example 3 General Process C:

5 mmol of oxazolidine-2,4-dione derivative (Example 2) are hydrogenated in 30 ml of tetrahydrofuran with 2 g of palladium/ charcoal (10%) at 40 PSI and RT. The reaction mixture is filtered, the filtrate is concentrated and purified by silica gel chromatography with ethyl acetate/heptane.

Example 4

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

Claims

Patent Claims

Use of Compounds of the general formula

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

A signifies a single or double bond

Ri signifies hydrogen or -(CH₂)_a-COR₄ with a = 0-6, preferably 1-3

Ri signifies hydroxyl, lower alkoxy or the NRιR₂ residue, whereby Rj and R₂ can be the same or different Rs signifies hydrogen or methyl X signifies oxygen or sulphur W signifies an optionally mono- or polysubstituted saturated or unsaturated- mono-, bi- or tricycle which can contain one or more hetero atoms,

for the preparation of medicaments for the treatment and prevention of metabolic bone disorders. Compounds of general formula (I)

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

A signifies a single or double bond Ri signifies hydrogen or -(CH₂)_a-COR with a = 0-6, preferably 1-3

R_t signifies hydroxyl, lower alkoxy or the NR1R₂ residue, whereby Ri and R₂ can be the same or different

R₅ signifies hydrogen or methyl

X signifies oxygen or sulphur

whereas W is not phenol or 2-hydroxy pyridine or its bicyclic derivatives, if m equals 0 and g unequal 0,.

whereas W is not phenol and benzofuran, if A is a single bond, X is oxygen and g is 1 or 2, whereas W is not phenyl, benzofuran, benzoxazol, if m and g together equal 0,

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 adjuvent and carrier materials