Thiazolidinecarboxyl acids

Details Thiazolidinecarboxyl acids Thiazolidinecarboxyl acids

2001-01-23

2003-01-14

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S256000, C514S369000, C544S238000, C544S335000, C548S183000

Reexamination Certificate

active

06506755

ABSTRACT:

FIELD OF THE INVENTION
The object of the present invention are thiazolidinecarboxylic acids, a process for their manufacture and medicaments which contain these compounds as well as the use of these compounds in the production of medicaments.
BACKGROUND OF THE INVENTION
Plasmin is a key enzyme for the dissolution of the extracellular matrix, which occurs especially at contact sites of cells to an increasing extent. A strong expression of the uPA/uPAR system takes place especially in tumour cells (N. Behrendt et al.,
Fibrinolysis
&
Proteolysis,
1998, 12(4): The urokinase receptor). By the induction of the strong proteolytically active uPA(urokinase type Plasminogen Activator)/uPAR (membrane-bound urokinase receptor) system it is possible to spread the tumour cells in the body by dissolution of the extracellular matrix as a result of plasmin liberation (P. A. Andreasen et al., Int. J. Cancer, 1997,72: The urokinase-type plasminogen activator system in cancer metastasis: a review). A correlation of the increased expression rate of the uPA/uPAR system with an increased metastasing rate has been demonstrated in patients with different tumour diseases (e.g. R.Hewitt et al.,
Enzyme Protein,
1996,49: Stromal cell expression of components of matrix-degrading protease systems in human cancer). A significant reduction in tumour growth can be achieved in animal experiments with tumour cell lines in mice by blocking the uPAR system with monoclonal antibodies.
In the literature there are already described numerous 5-arylidene-rhodanine-carboxylic acids which differ from the compounds in accordance with the present invention in that the substitution of the phenyl ring differs distinctly from that of the present invention. IN particular, 5-(2,4-bis-benzyloxybenzylidene)rhodanineacetic acid and 5-(3,4-bis-benzyloxybenzylidene)-rhodanineacetic acid and their use for the prophylaxis of maturity onset diabetes are described in Patent Application DE 4318550. A connection between the prophylaxis of maturity onset diabetes and inhibiting the binding of uPA to uPAR, thereby preventing an activation of plasminogen to plasmin, does not exist. In fact, other compounds from Patent Application DE 4318550, which are especially valuable for the treatment of maturity onset diabetes, showed no activity in inhibiting the binding of uPA to uPAR, thereby preventing an activation of plasminogen to plasmin.
BRIEF SUMMARY OF THE INVENTION
The invention relates to a compound of formula I:
wherein
A is a linear C
1
-C
6
-alkyl chain or a group >CHR, wherein R is a C
1
-C
6
-alkyl residue, an aryl residue, an aralkyl residue or a carboxyalkyl residue,
A
1
and A
2
each independently in any combination are a linear or branched saturated or unsaturated C
1
-C
6
-alkylene chain,
R
1
and R
2
each independently in any combination are a group of formula II, formula III or formula IV,
wherein X is an oxygen or sulphur atom and each Y independently is a nitrogen or carbon atom, with the proviso that both Y's can not simultaneously be nitrogen,
Z is a C
1
-C
4
-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C
3
-C
5
-alkenyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, acylamino, (alkyl)aminocarbonyl, C
1
-C
4
-alkyl-carbonyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy group or a chlorine, bromine or fluorine atom
or the aromatic ring in formulae II-IV is substituted with a methylenedioxy or ethylenedioxy group and
n is a whole number between 0 and 3,
whereby the Z substituents can be present in any positions,
with the proviso that the R
1
-A
1
- and R
2
-A
2
-residues can not simultaneously be an unsubstituted benzyl residue when A is a methylene group, or a
pharmaceutically acceptable salt or ester of a compound of formula I, or a position isomer, optically active form, racemate or diastereomer mixture thereof.
In another aspect, the invention relates to a method of preventing tumour growth or metastasis, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of formula I,
in which
A is a linear C
1
-C
6
-alkylene chain or a group >CHR, wherein R is a C
1
-C
6
-alkyl residue, an aryl residue, an aralkyl residue or a carboxyalkyl residue,
A
1
and A
2
each independently in any combination are a linear or branched saturated or unsaturated C
1
-C
6
-alkylene chain,
R
1
and R
2
each independently in any combination are a group of formula II, formula III or formula IV,
wherein X is an oxygen or sulphur atom and each Y is a nitrogen or carbon atom, with the proviso that both Y's can not simultaneously be nitrogen,
Z is a C
1
-C
4
-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C
3
-C
5
-alkenyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, acylamino, (alkyl)aminocarbonyl, C
1
-C
4
-alkyl-carbonyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy group or a chlorine, bromine or fluorine atom
or the aromatic ring in formulae II-IV is substituted with a methylenedioxy or ethylenedioxy group and
n is a whole number between 0 and 3,
whereby the Z substituents can be present in any positions,
or a pharmaceutically acceptable salt or ester of a compound of formula I, or a position isomer, optically active form, racemate or diastereomer mixture thereof.
DETAILED DESCRIPTION OF THE INVENTION
The invention is concerned with the use of 5-arylidene-4-oxo-2-thioxo-3-thiazolidine-carboxylic acids of formula I
as medicaments for the treatment of cancer diseases, especially for the prevention of the growth and the metastasing of tumors,
in which
A signifies a linear C
1
-C
6
-alkylene chain or a group >CHR, wherein R signifies a C
1
-C
6
-alkyl residue, an aryl residue, an aralkyl residue or a carboxyalkyl residue,
A
1
and A
2
each independently in any combination signify a linear or branched saturated or unsaturated C
1
-C
6
-alkylene chain,
R
1
and R
2
each independently in any combination signify a group of general formula II to IV,
wherein X signifies an oxygen or sulphur atom and each Y independently signifies a nitrogen or carbon atom, with the proviso that both Y's can not simultaneously signify nitrogen,
Z signifies a C
1
-C
4
-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C
3
-C
5
-alkenyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, acylamino, (alkyl)aminocarbonyl, C
1
-C
4
-alkyl-carbonyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, nitro, hydroxy or carboxy group or a chlorine, bromine or fluorine atom or the aromatic ring in formulae II-IV is substituted with a methylenedioxy or ethylenedioxy group and
n is a whole number between 0 and 3,
whereby the Z substituents can be present in any positions,
as well as compounds of formula I in which the symbols A, R
1
, R
2
, A
1
, A
2
, Z and n have the significance set forth above, with the proviso that the R
1
-A
1
- and R
2
-A
2
- residues can not simultaneously signify an unsubstituted benzyl residue when A is a methylene group, and their use as medicaments for the treatment of cancer diseases, especially for the prevention of the growth and the metastasing of tumours.
Objects of this invention are also physiologically compatible salts or esters of formula I as well as the position isomers, the optically active forms, the racemates and the diastereomer mixtures of these compounds.
It has surprisingly been found that the compounds of formula I have valuable pharmacological properties. In particular, they inhibit the binding of uPA (urokinase type Plasminogen Activator) to the membrane-bound urokinase receptor (uPAR) and thereby prevent an activation of plasminogen to plasmin.
Accordingly, the compounds in accordance with the invention are valuable, low molecular weight, orally administerable medicaments for the prophylaxis and treatment of cancer diseases, which are especially suitable for preventing the growth and the metastasing of tumours.
In formulae I-IV the C
1
-C
4
-alkyl residues, the C
1
-C
6
-alkyl residues and the C
3
-C
5
-alkenyl residues can be strai

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