EP0224515A1

EP0224515A1 - Substituted thiazolidinyl ether

Info

Publication number: EP0224515A1
Application number: EP86903186A
Authority: EP
Inventors: Angelo Storni
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1985-06-10
Filing date: 1986-06-04
Publication date: 1987-06-10
Also published as: JPS63500032A; WO1986007360A1

Abstract

Dans les composés de formule (I) l'un des symboles R1 et R2 représente un reste alcényle ou alcinyle de 3 à 4 atomes de carbone non saturé en position 2-3, l'autre représentant un tel reste ou un reste alcoyle inférieur, R3 et R4 représentent indépendamment l'un de l'autre l'hydrogène ou méthyl et R est un reste silyle trisubstitué, les substituants du reste silyle R étant éventuellement des restes hydrocarbonés substitués. Ces composés ont une action antitumorale.In the compounds of formula (I) one of the symbols R1 and R2 represents an alkenyl or alkinyl residue of 3 to 4 carbon atoms unsaturated in position 2-3, the other representing such a residue or a lower alkyl residue, R3 and R4 represent, independently of one another, hydrogen or methyl and R is a trisubstituted silyl residue, the substituents of the silyl residue R being optionally substituted hydrocarbon residues. These compounds have an anti-tumor action.

Description

Substituted thiazolidinyl ether

The invention relates to new substituted thiazolidinyl ethers with valuable pharmacological properties, their stereoisomers, processes for the preparation of these new substances, and pharmaceutical preparations which contain these substances, and the use of these substances and preparations containing them.

The compounds according to the invention correspond to the general formula

1 2 wherein one of the symbols R and R is an unsaturated alkenyl or alkynyl radical with 3 or 4 carbon atoms in the 2,3-position

3 and the other represent such a radical or lower alkyl, R and R independently of one another represent hydrogen or methyl and R represents a trisubstituted silyl radical, the substituents of the silyl radical R being optionally substituted hydrocarbon radicals. In the compounds of general formula I contains an in

1 2

2,3-position unsaturated radical R and / or R with 3 or 4 carbon atoms forms a double or triple bond and represents e.g. corresponding lower alkenyl, such as allyl, 1- or 2-methylallyl, or corresponding lower alkynyl, e.g. 2-propynyl.

The three optionally substituted hydrocarbon radicals of the silyl radical R are, independently of one another, primarily aliphatic radicals such as alkyl or alkenyl, in particular lower alkyl or lower alkenyl, aryl radicals such as in particular phenyl or araliphatic radicals such as phenylalkyl, in particular phenyl lower alkyl. Etherified or esterified hydroxy groups, such as lower alkoxy or halogen, and further substituents of aryl radicals are also lower alkyl groups as substituents of these radicals.

The general definitions used have the following meanings in the context of the present invention:

The term "lower", which is used above and below in connection with organic radicals or compounds, unless otherwise stated, defines those with up to and including 7, preferably up to and including 4 and in particular 1 or 2 carbon atoms .

Lower alkyl contains 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms and means e.g. Ethyl, propyl, isopropyl, tert-butyl, n-butyl or methyl.

Lower alkenyl as a component of the radical R contains 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms and means e.g. Vinyl, allyl or 1- or 2-methylallyl.

Aryl means a carbocyclic aromatic radical, preferably phenyl. Phenyl-lower alkyl preferably means benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl or 1-, 2-, 3- or 4-phenylbutyl.

Etherified hydroxy preferably means lower alkoxy or benzyloxy.

Lower alkoxy preferably contains 1 to 4 carbon atoms and is e.g. Methoxy, propoxy, isopropoxy, tert-butoxy or ethoxy.

Esterified hydroxy is hydroxy esterified with an organic or inorganic acid, such as with a hydrohalic acid or an aryl or alkane sulfonic acid, e.g. p-Toluenesulfonic acid, methane or ethanesulfonic acid esterified hydroxy, and in particular means halogen.

Halogen means chlorine, bromine, fluorine or iodine.

3 If R is hydrogen, the compounds of the formula I ^* can be present, for example, as pure enantiomers or mixtures thereof, in particular as a racing mixture. If the number of optically active centers increases, for example if R ^{d is} different from hydrogen, compounds of the formula I can be used not only as pure enantiomers but also as diasteromerically pure racemates or as mixtures of different ones

Diastereomers are present.

The new compounds of the general formula I have valuable pharmacological properties, in particular anti-tumor activity. This can be determined in animal experiments, for example in the case of oral or parenteral, such as intraperitoneal or subcutaneous administration of doses between 10 and 250 mg / kg on Ehrlich carcinoma of the mouse (transplant: 1 x 10 cells (ascites) ip to female mice NMRI) , on the Walker carcinosarcoma 256 of the rat (graft: 0.5 ml of a suspension of solid tumors in Hanks' solution or in male rats (Wistar)), on the transplantable breast adenocarcinoma R 3230 AC of the rat (transplant: 0.5 ml of a suspension of solid tumors in Hanks * solution sc or in female rats (Fischer)), and especially in the breast cancer of the rat induced by 7,12-dimethylbenz [aJ-anthracene (DMBA) (induced by po administration of 15 mg DMBA in 1 ml Sesa oil in 50 day old female rats (Sprague Dawley), whereby multiple tumors can be detected after 6 to 8 weeks).

Particularly noteworthy is that the tumor-inhibiting effect continues long after the end of the application. The compounds according to the invention have a strong depot effect.

In comparison to the strong antitumor activity, the toxicity and the side effects of the compounds according to the invention are low to moderate (one-time, maximum tolerated dose: intraperitoneally or orally between 1250 mg kg and greater than 2500 mg / kg), so that they as such or in particular in the form of pharmaceutical preparations for the treatment of neoplastic diseases in warm-blooded animals by enteral, in particular oral, or parenteral administration of therapeutically effective doses, in particular for the treatment of breast cancer.

The invention particularly relates to those compounds of general

1 2 my formula I, in which one of the radicals R or R in the 2,3-position unsaturated lower alkenyl or lower alkynyl having 3 or 4 carbon atoms and the other such a radical or lower alkyl

3 4 mean, R and R independently of one another represent hydrogen or methyl and R represents a trisubstituted silyl radical, the

Substituents optionally substituted independently of one another

Lower alkyl, lower alkenyl, aryl or phenyl lower alkyl.

The invention further relates to compounds of formula I, wherein

^• i 2 one of the radicals R or R in the 2,3-position unsaturated lower alkenyl with 3 or 4 carbon atoms, such as allyl, 1- or 2-methylallyl, or in the 2,3-position unsaturated lower alkynyl with 3 or

4 carbon atoms, such as 2-propynyl, and the other one

3 radical or lower alkyl having up to 4 carbon atoms, R 4 and R independently of one another represent hydrogen or methyl and

R represents a trisubstituted silyl radical, the substituents of which are, independently of one another, lower alkyl, lower alkenyl, aryl or

Phenyl-lower alkyl, optionally substituted with etherified or esterified hydroxy or, in the case of phenyl, also with lower alkyl.

The invention further relates to compounds of formula I, wherein R

2 or R allyl, 1- or 2-methylallyl or 2-propynyl and each

1 2 other radicals R or R likewise one of these radicals or

3 4 is methyl, R and R independently of one another are hydrogen or methyl and R is a trisubstituted silyl radical, the substituents of which are independently of one another three radicals selected from lower alkyl, lower alkenyl, phenyl, phenyl-lower alkyl or halomethyl.

The invention relates above all to compounds of the formula I in which R

2 1 2

Represent 2-methylallyl and R methyl or R methyl and R allyl, "

3 4

R is methyl or hydrogen and R is hydrogen and R is a trisubstituted silyl radical, the substituents of which are three identical or different lower alkyl groups, three identical phenyl-lower alkyl groups, or one or two identical lower alkyl groups and additionally a lower alkenyl or halomethyl group or two phenyl groups.

The invention particularly relates to compounds of the formula I

1 2 1 2 wherein R 2-methylallyl and R methyl or R methyl and R allyl

3 4 represent, R is methyl or hydrogen and R is hydrogen and R is a trisubstituted silyl radical, the substituents of which are three identical or different C 1 -C 4 lower alkyl groups, three identical phenyl C 1 -C 4 lower alkyl groups, or one or are two identical C - C, - lower alkyl groups and additionally a C "-C, - lower alkenyl group, a halomethyl group, a C - C - lower alkyl group or two phenyl groups. The invention relates in particular to compounds of the formula I in which

R ¹ 2-methylallyl and R ² methyl or R ¹ methyl and R ² allyl

3 4, R is methyl or hydrogen and R is hydrogen and

R is a trisubstituted silyl group, the substituents of which three identical or different C-C-lower alkyl, three of the same phenyl-C _j _-C lower alkyl groups, two of the same C.-C, -Niederalkyl¬ groups together with a C.-C ₇ -Liederalkylgrupρe, or a C ..- C,-Niederalkylgruppe together with two phenyl groups.

The invention relates to compounds of the

1 2 1 2

Formula I, wherein R 2-methylallyl and R methyl or R methyl and R

3 4 *

Represent allyl, R is methyl or hydrogen and R is hydrogen and R for the groups tert-butyldimethylsilyl, triisopropylsilyl, tri-n-butylsilyl, tribenzylsilyl, dimethyl-2- (2,3-dimethyl) butylsilyl, dimethylphenylsilyl or tert-butyldiphenylsilyl.

The invention particularly relates to the compounds mentioned in the examples, their pure enantiomers and, if appropriate, their pure diastereomers in racemic or enantiomerically pure form.

The new compounds of general formula I can be prepared by processes known per se. So you can make them by using a compound of formula

1 2 3 wherein R, R and R have the meanings given under formula I.

4, X is an oxygen atom or the radical -OY together with R and Y is hydrogen or a radical of aliphatic character represents treated with a reagent introducing the radical R and, if desired, separates any isomeric mixtures present into the individual isomers.

In the event that X represents an oxygen atom, the starting material of the formula II is a corresponding 2-substituted thiazolidine-4,5-dione. A reagent introducing the radical R into such compounds of the formula II is a compound H-R (III), in which R has the meanings given under formula I. Since in this reaction the hydrogen of the compound of formula III

4 is attached as R in the end product of the formula I according to the process, only compounds of the formula I are obtainable in this way, in

4 1 2 3 where R is hydrogen, while R, R, R and R are all for

Compounds of the general formula I may have the meanings given.

Silanes of formula III can be known in a known manner directly or in the presence of suitable catalysts, such as noble metal complexes, e.g. Phosphine-halogen-platinum metal compounds, e.g. Tris (triphenylphosphine) chloro-rhodium (I), can be reacted with carbonyl compounds of the formula II.

Silanes of the formula III are known or can be obtained analogously to known ones. Corresponding 2-substituted thiazolidine-4,5-diones of the formula II are new, but can be obtained by known processes, e.g. by proceeding as in the preparation of the corresponding 5-hydroxy compounds (see, for example, DE-OS 2 405 395), but in the ring closure to the second thiazolidine system, but using a more oxidized ring closure component which provides two carbon atoms, such as in particular oxalyl chloride.

4 If X denotes the radical -OY and R and Y are hydrogen, the starting materials of the formula II are hydroxy compounds which belong to the prior art or can be prepared analogously thereto (for example DE-OS 2 405 395) . A reagent which introduces the radical R into such compounds of the formula II is a compound which contains the group R and which, according to the prior art, is suitable for the silylation of hydroxy compounds. These include, for example, reactive esterified silanols RZ of the formula IV, in which Z denotes hydroxy esterified with an inorganic or organic acid. Examples of suitable inorganic acids are hydrohalic acids, but also oxo acids such as sulfuric acid. Aryl or alkane sulfonic acids are particularly suitable as organic acids, in particular halogenated sulfonic acids such as p-toluene or p-bromophenyl sulfonic acid or methane or trifluoromethanesulfonic acid. In particular, a group Z means, for example, halogen such as chlorine, bromine or iodine.

Also included are compounds which carry a silyl group R, mainly to a hetero atom such as oxygen or, especially, nitrogen bonded ^"and its silylation inter alia gain that it insoluble, the reaction equilibrium, for example, action medium by forming gaseous substances or by formation of the Re¬ Shift substances towards the silyl ethers, e.g. disilazanes or silylated acetamides, ureas, imidazoles, secondary amines or sulfonamides. Combinations of reagents with one another are also suitable in individual cases, such as the use of disilazane / Ηalogensilane in a ratio of 1: 1.

The reactions are usually carried out in inert solvents, such as halogenated hydrocarbons, for example methylene chloride, ethers, for example diethyl ether or tetrahydrofuran, lower alkylcarbonitriles, for example acetonitrile, or carboxamides, for example dimethylformamide or dimethylacetamide, and, if appropriate, in the presence of organic bases and / or suitable catalysts. Suitable bases are heterocyclic or acyclic tertiary amines, such as imidazole, pyridine, lutidine, diisopropylethylamine or triethylamine. Suitable catalysts are, for example, ammonium sulfate or trimethylchlorosilane. If Y is an aliphatic radical, the starting materials of the formula II are ethers which are obtainable from the alcohols on which they are based by alkylation in a known manner. A Y aliphatic group is a lower alkyl or a substituted lower alkyl group, such as a phenyl lower alkyl group, for example benzyl.

Reagents introducing the radical R into such heterocyclyl-lower alkyl ethers of the formula II are in particular compounds of the formula R-Hal, in which shark means chlorine, bromine or iodine. Bromosilanes or in particular iodosilanes can be used directly or can also be generated in situ by e.g. a corresponding chlorine compound with an alkali or alkaline earth metal iodide (bromide), such as lithium iodide (bromide), sodium iodide (bromide) or magnesium bromide. Aprotic solvents are suitable as solvents for these reactions, e.g. chlorinated hydrocarbons, such as methylene chloride or carbon tetrachloride, lower alkylcarbonitriles, such as acetonitrile, or carboxamides, such as dimethyl formamide.

The above reactions are carried out in a manner known per se, for example in the absence, but advantageously in the presence of a suitable inert solvent, and if appropriate in the presence of a catalyst and / or a base and usually under mild reaction conditions, preferably at temperatures between about -10 ^U C and about 100 "C, especially at room temperature or slightly elevated temperatures up to about 50 ° C, if necessary, in a closed vessel and or under an inert gas, for example nitrogen atmosphere.

The choice of the reaction conditions in detail is unproblematic for the person skilled in the art because of the extensive prior art in all of these cases. Mixtures of isomers can be separated in a manner known per se, mixtures of diastereomers - inter alia by means of physical separation, for example fractional crystallization or distillation, or chromatography, inter alia high-pressure liquid chromatography, and enantiomeric mixtures, inter alia, using chiral macromolecular supports on which enantiomer separations are carried out using chromatographic methods can.

The invention also relates to those embodiments of the process in which a starting material is formed under the reaction conditions or in which a reaction component is optionally in the form of its salts.

For the implementation of the reactions according to the invention, it is expedient to use those starting materials which lead to the groups of end products which were particularly mentioned at the outset and in particular to the end products which have been specifically described or highlighted.

The invention also relates to the new starting compounds of

1 2 3 Formula II, ie those in which R, R and R are those under formula ^' . have the meanings given and X represents an oxygen atom.

The invention also relates to pharmaceutical preparations which contain at least one compound of the formula I, and to processes for their preparation. These pharmaceutical preparations are for enteral, e.g. oral or rectal or parenteral administration suitable and contain the pharmacological active ingredient alone or together with a corresponding pharmaceutically applicable carrier material.

The new pharmaceutical preparations are, for example, those in unit dose form, for example oral preparations, such as coated tablets, tablets, lacquered tablets or capsules, rectal preparations, such as suppositories, or parenteral preparations, usually ampoules or vials. Oral preparations contain approximately between 10 and 80% by weight. of the active ingredient, non-aqueous injection solutions approximately between 0.5 and 10%, preferably approximately between 0.5 and 5% (g / 100 ml).

The orally administrable pharmaceutical preparations can be produced in a known manner, such as by conventional mixing, granulating or coating processes. Thus, the ^'active compounds can be mixed with solid carriers, a resulting mixture can be granulated, and the mixture or the granules may be nötigen¬ gewünschten- or optionally processed into tablets or cores Dragee¬ after adding suitable auxiliaries.

Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tri-calciuraphosphate or calcium hydrogen phosphate, binders, such as starch paste based e.g. of corn, wheat, rice or potato starch, gelatin, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as the starches mentioned, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar , Alginic acid or a salt thereof, such as sodium alginate or low molecular weight carboxymethyl cellulose. Aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.

Drage cores are provided with suitable, optionally gastric juice-resistant coatings, including concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or aqueous dispersions of ethyl acrylate methyl methacrylate Copolymers used. For the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, or aqueous dispersions of, for example, Methacrylic acid methyl acrylate copolymers. Dyes or pigments can be added to the tablets or coatings, for example for identification or for labeling various active substances.

Other pharmaceutical preparations that can be used orally are plug-in capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active ingredient as a powder or granules, e.g. in a mixture with fillers, such as cellulose or lactose, binders, such as starches, and or lubricants, such as talc or magnesium stearate, and, if necessary, conventional stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers can also be added.

As rectally applicable pharmaceutical preparations, e.g. Suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are e.g. natural or synthetic glycerol esters, paraffin hydrocarbons, polyethylene glycols or higher alkanols or mixtures thereof. In addition, gelatin rectal capsules can also be used which contain a combination of the active ingredient with a base material; the basic dimensions are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons together with suspension stabilizers, such as waxes and other swelling agents.

For parenteral administration by injection or infusion, for example, suspensions of the active ingredient, such as oily injection suspensions, are suitable, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides. The following examples are intended to illustrate the invention described above without in any way limiting the scope thereof. Temperatures are given in degrees Celsius.

Example 1: To an ice-cooled suspension of 32.8 g (0.10 mol) of 5-hydroxy-3-methyl-2-l [5-methyl-3- (2-methylallyl) -4-oxo-2-thia- zolidinylidene] -hydrazono] -4-thiazolidinone in 300 ml of methylene chloride, 22.6 g (0.15 mol) of tert-butyldimethylchlorosilane are added under a nitrogen atmosphere and a solution of 10.2 g (0, 15 mol) of imidazole in 100 ml of methylene chloride. The mixture is stirred for another hour in an ice bath and then for two hours at room temperature. For working up, 800 ml of petroleum ether are added and the mixture is shaken twice with 1000 ml of water each time. The organic phase is dried over magnesium sulfate and evaporated in a water jet vacuum. The residue left is the [3-methyl-2- [[5-methyl-3- (2-methylallyl) -4-oxo-2-thlazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] tert.-bufyl dimethyl silyl ether, which is recrystallized from methylene chloride-hexane, mp. 130-130.5 °. The product obtained is obviously a mixture of diastereomers, since batches of another diastereomer mixture with a melting point of 122-123 "are obtained with the same procedure. However, the two batches are distinguished by agreement in decisive characteristic parameters:

Elemental analysis, percentages calculated / found in the order; C: 48.84 / 48.94; H: 6.83 / 6.85; N 12.66 / 12.66.

IR (in methylene chloride), data in cm, bands etc. at 1740 (s),

1615 (ss), 1380 (m), 1110 (m) and 850 (m).

NMR (in deuterochloroform), data in ppm, based on tetramethylsilane at 6 ^~ 0; 0.25 (s, 6H); 1.05 (s, 9H); 1.75 (d. 3H);

1.87 (s, 3H); 3.37 (s, 3H); 4.13 (q, 1H); 4.45 (s, 2H); 5.01 (s, 2H) and 5.85 (s, 1H). Example 2: Analogously to Example 1, the following are produced:

[3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] tri-n-butyl silyl ether,

M.p. 56-58 °; starting from 32.8 g (0.10 mol) of 5-hydroxy-3-methyl-2-

[[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -

4-thiazolidinone, 25.85 g (0.11 mol) of tri-n-butylchlorosilane and

74.9 g imidazole in 300 ml methylene chloride.

[3-methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] triisopropyl silyl ether,

Mp 91-98 °; starting from 32.8 g (0.10 mol) of 5-hydroxy-3-methyl-2-

[[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -

4-thiazolidinone, 21.2 g (0.11 mol) of triisopropylchlorosilane and.

14.2 g (0.11 mol) of diisopropylethylamine in 400 ml of methylene chloride.

[3-Methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] dimethyl-2- (2,3 -dimethyl) butyl silyl ether; Mp 85.5-88 °; starting from 6.57 g (0.02 mol) of 5-hydroxy-3-methyl-2- [[5-methyl-3- (2-methylallyl) 4-oxo-2-thiazolidinylidene] hydrazono] -4-thiazolidinone , 4.64 g (0.026 mol) of dimethyl-2- (2,3-dimethyl) butyl chlorosilane and 1.77 g (0.026 mol) of imidazole in 20 ml of dimethylformamide.

[3-allyl-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] tert-butyldimethylsilyl ether; M.p. 130-131 °; starting from 30.0 g (0.10 mol) of 3-allyl-5-hydroxy-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-thiazolidinone, 19.6 g (0 , 13 mol) of tert-butyl-dimethylchlorosilane and 8.9 g (0.13 mol) of imidazole in 80 ml of dimethylformamide.

[3-Allyl-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] dimethyl-ρhenyl silyl ether, mp 125-126 °; starting from 30.0 g (0.10 mol) of 3-allyl-5-hydroxy-2 - [(3-methyl-4-oxo - 2-thiazolidinylidene) hydrazono] -4-thiazolidinone, 19.6 g (0.115 mol) of dimethyl-phenylchlorosilane and 7.0 g (0.115 mol) of imidazole in 60 ml of dimethylformamide. [3-Allyl-2 - [(3-raethyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] tert-butyl diphenyl silyl ether, mp 191-192 °; starting from 3.0 g (0.01 mol) of 3-allyl-5-hydroxy-2 - [(3-methyl-4-oxo-2-thiazolidinylidene] hydrazono] -4-thiazolidinone, 3.57 g (0.013 Mol) of tert-butyl-diphenylchlorosilane and 0.88 g (0.013 mol) of imidazole in 10 ml of dimethylformamide.

[3-allyl-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] triisopropyl silyl ether, M.p. 106-107 °; starting from 30.0 g (0.10 mol) of 3-allyl-5-hydroxy-2 - [(3-methyl-4-oxo-2-thiazolidinylidene] hydrazono] -4-thiazolidinone, 25.1 g (0 , 13 mol) of triisopropylchlorosilane and 8.8 g (0.13 mol) of imidazole in 70 ml of dimethylformamide.

[3-Allyl-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] -trl-n-butyl silyl ether, m.p. 102-103 °; starting from 30.0 g (0.10 mol) of 3-allyl-5-hydroxy-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-thiazolidinone, 30.5 g (0.13 mol) tri-n-butylchlorosilane and 8.8 g (0.13 mol) imidazole in 75 ml dimethylformamide.

[3-Methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] tribenzylsilyl ether.

[3-Methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] tert.-butyl-diphenylsilyl - ether.

[3-Allyl-2 - [(3-methyl-4-oxo-2-thiazolidinylidene) hydrazono] -4-oxo-5-thiazolidinyl] tribenzylsilyl ether.

Example 3: 2.72 g (0.01 mol) of 3- (2-methylallyl) -5-methyl-2,4-thiazolidinedione-2- (4-methyl-3-thiosemicarbazone) and 3.9 ml ( 3 g; 0.023 mol) of diisopropylethylamine are dissolved in 20 ml of methylene chloride and under a nitrogen atmosphere and with stirring at -30 to -40 ° with a solution of 0.94 ml (1.4 g; 0.021 mol) of oxalyl chloride in 10 ml of methylene chloride. Then allowed to warm to room temperature and continue stirring at this temperature for 8 hours. For working up, dilute with methylene chloride and shake out with dilute hydrochloric acid and water. The methylene chloride solution is dried over magnesium sulfate and evaporated. The crude 3-methyl-2 - [[5-methyl-3- (2-methyl-allyl) -4-oxo-2-thiazolidinylidene] hydrazono] thiazolidine-4,5-dione remains, which is obtained from ethyl acetate is recrystallized, mp. 204-211 °.

Example 4: Coated tablets containing 300 mg of the compound of Example 1 can be produced as follows:

Compilation for 10,000 tablets

. [3-Methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazonoJ-4-OXO-5-thiazolidinyl] tert-butyl-dimethyl -silyl ether 3,000.0 g

Corn starch 680.0 g

Colloidal silica 200.0 ^* g

Magnesium stearate 20.0 g

Stearic acid 50.0 g

Sodium carboxymethyl starch 250.0 g

Water q.s.

A mixture of the active ingredient, 50 g of corn starch and the colloidal silica is processed with a starch paste from 250 g of corn starch and 2.2 kg of demineralized water to a moist mass. This is passed through a sieve of 3 mm mesh size and dried at 45 ° for 30 minutes in a fluidized bed dryer. The dry granules are pressed through a sieve with a mesh size of 1 mm, mixed with a pre-sieved mixture (1 mm sieve) of 330 g corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to give slightly curved tablets. The compacts are coated in a coating pan of 45 cm in diameter with a solution of 20 g of shellac and 40 g of hydroxypropylmethyl cellulose (low viscosity) in 110 g of methanol and 1350 g of methylene chloride by uniform spraying for 30 minutes; it is dried by simultaneously blowing in air at 60 °.

Claims

1. Compounds of the general formula

3 and the other represent such a radical or lower alkyl, R and

4 R independently of one another are hydrogen or methyl and R is a trisubstituted silyl radical, where substituents of the silyl radical R are optionally substituted hydrocarbon radicals.

2. Compounds of formula I according to claim 1, wherein one of the

1 2 radicals R or R in the 2,3-position of unsaturated lower alkenyl or

Lower alkynyl with 3 or 4 carbon atoms and the other one

3 4 are such a radical or lower alkyl, R and R independently of one another are hydrogen or methyl and R is a tri-substituted silyl radical, the substituents of which are, independently of one another, optionally substituted lower alkyl, lower alkenyl, aryl or phenyl-lower alkyl.

3. Compounds of formula I according to claim 1, wherein one of the

1 2 residues R or R allyl, 1- or 2-methylallyl or 2-propinyl and the other one such residue or lower alkyl with up to 4 carbons

3 4 mean atomic atoms, R and R independently of one another represent hydrogen or methyl and R denotes a trisubstituted silyl radical, the substituents of which are independently of one another lower alkyl, lower alkenyl, aryl or phenyl-lower alkyl, optionally substituted with etherified or esterified hydroxy or, in the case of phenyl, also with lower alkyl , are. 1 2

4. Compounds of formula I according to claim 1, wherein R or R

Allyl, 1- or 2-methylallyl or 2-propynyl and the other

1 2 radical R or R likewise denotes one of these radicals or methyl,

3 4 R and R independently of one another are hydrogen or methyl and R is a trisubstituted silyl radical, the substituents of which are independently of one another three radicals selected from lower alkyl, lower alkenyl, phenyl, phenyl-lower alkyl or halomethyl.

5. Compounds of formula I according to claim 1, wherein R 2-methyl

2 1 2 3 represent allyl and R are methyl or R are methyl and R are allyl, R

4 is methyl or hydrogen and R is hydrogen and R is a trisubstituted silyl radical, the substituents of which are three identical or different lower alkyl groups, three identical phenyl

. Lower alkyl groups, or one or two identical lower alkyl groups and additionally a lower alkenyl or halomethyl group or two phenyl groups.

6. Compounds of formula I according to claim 1, wherein R 2-methyl

2 1 2 represent allyl and R are methyl or R are methyl and R are allyl, R

4 is methyl or hydrogen and R is hydrogen and R is a trisubstituted silyl radical, the substituents of which are three identical or different C 1 -C 4 lower alkyl groups, three identical ones

Phenyl-C-C,-lower alkyl groups, or one or two identical C, -C, -

Lower alkyl groups and in addition a C ~ -C, lower alkenyl group, a halomethyl group, a C.-C.-Nlederalkylgruρρe or two

Are phenyl groups.

7. Compounds of formula I according to claim 1, wherein R 2-methyl

2 1 2 3 represent allyl and R are methyl or R are methyl and R are allyl, R

4 is methyl or hydrogen and R is hydrogen and R is a trisubstituted silyl radical, the substituents of which are three identical or different C.-C.-lower alkyl groups, three identical phenyl-C.-C_-lower alkyl groups, two identical C.-C,-lower alkyl groups groups together with a C, -C, lower alkyl group, or a C.- C, lower alkyl group together with two phenyl groups.

8. Compounds of formula I according to claim 1, wherein R 2-methyl

2 1 2 3 represent allyl and R are methyl or R are methyl and R are allyl, R

4 is methyl or hydrogen and R is hydrogen and R is for the

Groups tert-butyldimethylsilyl, triisopropylsilyl, tri-n-butylsilyl, tribenzylsilyl, dimethyl-2- (2,3-dimethyl) butylsilyl,

Dirnethylphenylsilyl or tert-butyldiphenylsilyl.

9. [3-Methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] tri-n- butyl silyl ether.

10. [3-Methyl-2 - [[5-methyl-3- (2-methylallyl) -4-oxo-2-thiazolidinylidene] hydrazono] -4-oxo-5-thiazolidinyl] triisopropyl silyl ether.

.

11. Pharmaceutical preparations containing at least one compound according to claim 1 together with a pharmaceutically suitable carrier material.

12. Pharmaceutical preparations for the treatment of neoplastic diseases containing an effective amount of a compound according to claim 1 together with a significant amount of a pharmaceutically suitable carrier material.

13. The compounds mentioned in claims 1 to 10 for use in a method for the therapeutic treatment of the human or animal body.

14..Die compounds mentioned in claims 1 to 10 as anti-tumor agents.

15. Use of a compound according to claim 1 for the manufacture of pharmaceutical preparations for the treatment of neoplastic diseases.

16. A process for the preparation of compounds of the formula I in which R ¹ , R ² , R ^J , R * and R have the meanings given in claim 1, characterized in that a compound of the formula

1 2 3 wherein R, R and R have the meanings given under formula I.

4 have, X represents an oxygen atom or the radical -OY together with R and Y represents hydrogen or a radical of aliphatic character, treated with a reagent introducing the radical R and, if desired, separating any isomer mixtures present into the individual isomers.

17. The method according to claim 16, characterized in that X in a compound of formula II represents an oxygen atom and a reagent introducing the radical R is a compound of formula R-H (III).

18. The method according to claim 16, characterized in that X in a compound of formula II is the radical -OH together with R * and a reagent introducing the radical R is a compound of formula RZ (IV), wherein Z is an inorganic or represents organic acid esterified hydroxy.

19. The method according to ss claim 16, characterized in that X in a compound of formula II together with the radical -OY. R * means Y represents an aliphatic radical and a reagent introducing the radical R is a compound of the formula R-Hal, in which shark means chlorine, bromine or iodine.

20. The compounds obtainable by the process of claim 16.

21. Compounds of the general formula

1 2 3 wherein R, R and R have the meanings given in claim 1 and X represents an oxygen atom.

FO 7.4 KB / ch *