Medicaments with cytostatic activity and use of cyclic compounds, in which the heterocyclic n-ring atoms are substituted by several glycidyl groups, in pharmaceutical compositions

It is known that a number of alkylating substances have a cytostatic or cytotoxic effect. The best known compounds are derived from the so-called nitrogen mustard. In addition, it is also known to use at least two compounds containing epoxy groups in the molecule as cancerostats. Such compounds are, for example, 4,4'-bis (2,3-epoxypropyl) -dipiperidinyl- (1, 1 ') and 1,2-15,16-diepoxy-4,7-10,13- tetraoxohexadecane. However, the latter compounds have brought no significant improvement in cytostatic treatment and are rarely used.

The subject of unpublished EP-A-0 014981 is pharmaceutical preparations with cytostatic activity which contain triglycidyl isocyanurate (TGI) as an active ingredient and / or TGI derivatives in which the hydrogen atom of the carbon is in the 2-position of the glycidyl group by an alkyl radical having 1 to 4 carbon atoms can be replaced. In other words, this means that the three N atoms of the isocyanuric acid ring are substituted with glycidyl radicals containing epoxy groups, which can also be substituted in the 2-position with an alkyl radical with 1 to 4 carbon atoms.

The older AT-PA-371 816 relates inter alia to the preparation of compounds of the general formula<chemistry id="chem0001" num="0001"><img file="EP0033503B1_D0001.tif" /></chemistry>in which R has the following meaning: alkyl, aryl, aralkyl, alkaryl, cycloalkyl, which radicals can, if desired, also be unsaturated and / or substituted, have cytostatic activity.

From FR-A-7.153 M it is known that the compound 1,3-bis (glycidyl) -5,5-dimethylhydantoin inhibits the growth of the Walker tumor in animal experiments. However, the person skilled in the art cannot draw any conclusions from this regarding the effectiveness of heterocyclic compounds N-containing glycidyl groups, in which the heterocycle has been modified according to the invention. In particular, it could not be predicted that, in addition to the frequently observed growth inhibition of this model tumor with the substance class mentioned, a life extension can also be observed in test animals to which the tumor P 388 test has been implanted.

The present invention is based on the finding that the N-glycidyl grouping generally has high cytostatic activity when certain conditions, described below, for the incorporation of such N-glycidyl groups into the molecule of the active substance are met.

The invention thus relates to pharmaceutical preparations with cytostatic activity based on polyglycidyl-substituted N-heterocyclic organic ring compounds, characterized in that they are in a heterocyclic ring or in two interconnected heterocyclic rings which either have one or two ring members in common or by a bridge member are linked together, at least 2 ring segments of the formula<chemistry id="chem0002" num="0002"><img file="EP0033503B1_D0002.tif" /></chemistry>or at least one ring segment of the formula<chemistry id="chem0003" num="0003"><img file="EP0033503B1_D0003.tif" /></chemistry>contain in which the glycidyl radical of the formula<chemistry id="chem0004" num="0004"><img file="EP0033503B1_D0004.tif" /></chemistry>corresponds to, in which R is hydrogen or the methyl radical, and that they continue to contain, unless these ring segments themselves are closed to form the ring, carbon and optionally additionally nitrogen as ring-closing members, and that they contain halogens or unsubstituted hydrocarbon radicals as further substituents on the heterocyclic rings cannot have more than 8 carbon atoms, the heterocycles being isocyanurates, Urazoles and hydantoins are excluded and the polyglycidyl-substituted N-heterocycles present therein do not exceed the molecular weight of 1,000.

It was surprisingly found that under the structural conditions described above, N-heterocyclic organic ring compounds in general have cytostatic activity when two or more N-glycidyl groups are present in the molecule, these N-glycidyl groups being mandatory parts of an amide and / or Are imide structure. The nitrogen atom bearing the glycidyl group is therefore adjacent to at least one carbonyl group and this system composed of carbonyl group and nitrogen substituted by a glycidyl group and optionally a further carbonyl group is integrated into the heterocyclic ring system and is therefore a direct ring component.

Even though the mechanism of action of the compounds used in the context of the invention has not been clarified in detail, it can nevertheless be assumed that the importance of the remaining molecular component lies in particular in the influence on the solubility or on the distribution of the lipophilic and hydrophilic preferences. This explains the broad definition of the active substances which can be used according to the invention and which have cytostatic activity and which, as a corresponding structural and active element, always have at least two N-glycidylamide and / or N-glycidylimide functions.

The N-heterocyclic organic ring compounds which are used several times and are substituted by glycidyl groups according to the invention can be characterized more precisely in such a way that they have at least two ring segments of the formula<chemistry id="chem0005" num="0005"><img file="EP0033503B1_D0005.tif" /></chemistry>or at least one ring segment of the formula I.<chemistry id="chem0006" num="0006"><img file="EP0033503B1_D0006.tif" /></chemistry>and that they continue to contain carbon and possibly additional nitrogen, as long as these ring segments are not closed to form a ring. The glycidyl radical corresponds to the general formula given above.

The additional ring closure members which may be present in addition to the ring segments represented by the formula are carbon and optionally additional nitrogen. The carbon can be present as a carbonyl group or as a hydrocarbon group which - taking into account the preferred definitions given below - can also be substituted.

It has also been shown that certain maximum molecular weights of the compounds used according to the invention are expediently not exceeded when creating pronounced cytostatic activity. In general, the molecular weight of the cytostatically active component is not above about 1000. Compounds with a molecular weight of up to about 750 are preferred. N-heterocycles containing several glycidyl substituents, the molecular weight of which does not exceed or only moderately exceeds the limit value of about 500 - for example reaches the value of 550 or at most 600 - and in particular those in the range of about 200 to 500, for example, have proven to be particularly effective from about 300 to 500. These figures apply primarily to N-heterocyclic compounds of the type indicated with 2 to 4, in particular 2 or 3, glycidyl groups in an amide or imide bond.

Different basic types can be distinguished within the scope of the active substances with cytostatic activity used according to the invention. In a first subclass, there are heterocycles with only one heterocyclic ring in the molecule. This ring then contains the previously defined N-glycidyl substituents on amide or imide structures, optionally in addition to further substituted or unsubstituted ring members of the type specified. In this case there is in any case at least two glycidyl residues on amide and / or imide nitrogen atoms on this one ring.

In a further subclass, the cytostatically active ring compound used according to the invention is itself made up of several rings connected to one another. A distinction can be made between two characteristic subclasses: In the first subclass, two individual heterocyclic ring systems are provided, which are, however, connected to each other by a bridge link. In the second subclass, two heterocyclic ring systems are fused together in such a way that one or two ring members are common to two such rings. In both of the subclasses described here, there is the possibility that there is only one N-glycidyl group of the type described per heterocyclic ring system, provided that the molecule as a whole has at least two of these cytostatically active groups. However, it is possible that one or more of the individual rings of the overall multi-ring system contains more than just one glycidyl-N group in an amide or imide bond. In addition, with regard to the remaining ring members and other molecular constituents, their nature is fundamentally of minor importance and presumably has a substantial influence on the distribution of the active substance in the organism.

The N-heterocyclic rings substituted with glycicyl groups are saturated in the active substances used according to the invention or contain double bonds. The number of ring links is again of minor importance and is mainly determined by accessibility and stability considerations. The individual rings preferably had no more than 14 and in particular no more than 12 ring members. For considerations of ring stability, the number of links can be considered as the lower limit. Ring systems with a number of ring members of up to 10 are of particular importance, ring connections with a number of rings of 5 to 7 being particularly important, primarily for reasons of preparative accessibility. Heterocycles with 5 or 6 carbon atoms and NH groups in an amide or imide bond are known in large numbers. They are usually accessible to glycidation on the N atom - either by reaction with epihalohydrin or introduction of an allyl residue with subsequent epoxidation of the double bond. Accordingly, compounds of this type are of primary interest for the invention.

Particularly suitable heterocycle structures according to the invention can thus be assigned to a number of subclasses. A first subclass are the cyclic ureides, see, for example, FIESER / FIESER "Textbook of Organic Chemistry" Verlag Chemie GmbH, Weinheim (1954) pp. 254 to 260. The cyclic ureides suitable according to the invention contain at least 2 in the preliminary stage before the introduction of the glycidyl residues -NH groups adjacent to an oxo group -CO-. By introducing at least 2 glycidyl residues in N substitution and in the vicinity of the oxo group, particularly preferred compounds with cytostatic activity are produced according to the invention.

The cyclic ureides can be compounds with one or more heterocyclic ring systems. If several heterocyclic ring systems are present, these can be fused together or only connected to one another by means of a link. The preferred number of ring links is 5 to 7, in particular 5 and / or 6.

Another particularly preferred subclass of the active compounds according to the invention is derived from cyclic imides, as are discussed in detail below (general formula VII).

Another subclass of the compounds suitable according to the invention are N-glycidyl-substituted cyclic amides with at least 2 N-glycidyl-substituted amide groups in the molecule. Finally, mixed types of the sub-groups listed here are possible.

In particularly important embodiments of the invention, N-heterocyclic ring compounds of the following general formulas substituted with glycidyl groups are thus present in the active compound mixtures:<chemistry id="chem0007" num="0007"><img file="EP0033503B1_D0007.tif" /></chemistry>

In this formula, U is a double-bonded group which closes the heterocycle to form a 5- to 7-membered ring, in particular a 5- or 6-membered ring and has C, N, 0 and / or S as ring members.<chemistry id="chem0008" num="0008"><img file="EP0033503B1_D0008.tif" /></chemistry>

In this general formula, the meaning of V corresponds to the meaning given above for U from the formula for a), p is a number of 2 or 3, preferably 2. The two glycidyl-substituted carbonamide groups can be directly connected to one another, but they can also be by an intermediate link must be separated.<chemistry id="chem0009" num="0009"><img file="EP0033503B1_D0009.tif" /></chemistry>

In this general formula, W is a 4-bonded group which closes the two heterocycles to form 5- to 7-membered rings - in particular to form 5- and / or 6-membered rings - and has C or N as ring members. r and s are numbers from 1 to 3, in particular 1 or 2. r and s can be the same or different. Compounds in which 4 and s each represent 1 are of particular importance.<chemistry id="chem0010" num="0010"><img file="EP0033503B1_D0010.tif" /></chemistry>

In this general formula, X is a 2-bonded group which connects 2 heterocyclic ring systems of the type described under b). X preferably has no more than 8, in particular no more than 6, members. r and s have the meaning explained in c). In the class of compounds shown here, the link X can also be occupied by one or by two heterocyclic radicals which correspond to the formula (a) shown above.

Any substituents on the N-heterocyclic rings - or on the additional ring-closure members present in these rings - or on ring systems, which in turn are fused with the N-heterocyclic rings, can be unsubstituted hydrocarbon radicals or conventional functional substituents with the proviso that they with the Glycidyl groups of the active substances used according to the invention are not reactive at least at normal temperature. A number of special compounds are described below, which are subordinate to the broad definition according to the invention. In connection with these special compounds, specific statements are made regarding substitution options on the N-heterocyclic systems. These statements have general validity in the context of the description of the invention, and are therefore not limited to the particular type of connection in whose explanation they are used. The information also applies accordingly to other basic bodies that can be subsumed under the general definition.

One embodiment of the present invention relates to medicaments which contain certain benzimidazolone derivatives substituted by glycidyl radicals and which have a surprisingly strong cytostatic activity.

Accordingly, in this embodiment, the invention relates to pharmaceutical preparations with cytostatic activity, containing compounds of the general formula 11<chemistry id="chem0011" num="0011"><img file="EP0033503B1_D0011.tif" /></chemistry>in which A is an aromatic, cycloaliphatic or olefinically unsaturated 6-ring, which can also contain a heteroatom - in particular N or 0 -, and the radicals R₁, R_e.g., R₃ and R₄ soeiw glycidyl have the following meaning:<ul id="ul0001" list-style="none"><li>R₁ to R₄: same or different residues and thereby hydrogen, halogen or hydrocarbon residues, each with no more than 8 carbon atoms</li></ul>

Glycidyl: a radical of the general formula<chemistry id="chem0012" num="0012"><img file="EP0033503B1_D0012.tif" /></chemistry>in which R is hydrogen or a methyl radical.

It is therefore proposed according to the invention to use diglycidyl compounds which are benzimidazolone derivatives or which can ultimately be derived from benzimidazolone and which are distinguished by the presence of 2 glycidyl radicals as substituents on the nitrogen atoms of the 5-ring system for the stated purpose. A whole series of compounds of this type are known per se. Their production is described, for example, in DE-A-23 00 010 and in NL-A-73 00 191, various production options being mentioned in these publications. A particularly simple way of production starts from the benzimidazolone base bodies, into which the glycidyl residues on the two N atoms of the multi-ring system are then introduced. The production of a large number of such substituted benzimidazolones is described, for example, in J. Am. Chem. Soc. Vol. 80 (1958) 1657-1664.

Diglycidyl compounds of the type concerned here have so far found only interest in the technical field, in particular in the field of plastics chemistry. When used according to the invention, they show a surprisingly high cytostatic activity, which could be determined in animal experiments.

For the sake of simplicity, the diglycidyl compounds used in the context of the invention are referred to below as benzamidazolone derivatives, even if those derivatives are included in this term in which the 6-ring A from the general formula II is partially or completely saturated.

The ring system A of the general formula II can be in positions R₁ to R₄ be unsubstituted, so that these radicals here mean hydrogen. However, one or more of these residues can also be halogen and / or hydrocarbon residues. If several substituents are present, the same or different substituents may be present. Chlorine and bromine, iodine and fluorine are particularly preferred as halogen, however, are not excluded.

Is at least one of the radicals R₁ to R₄ a hydrocarbon residue, it should not have more than 8 carbon atoms. Residues which contain up to 6 or preferably even only up to 4 carbon atoms can be of particular interest. In addition to hydrogen, methyl and / or ethyl radicals can be of particular importance.

Straight-chain and / or branched alkyl and alkenyl radicals of the stated carbon number are suitable as hydrocarbon radicals. Aryl residues are also suitable. In the sense of the definition according to the invention, this group includes aromatic radicals in the narrower sense, which therefore consist exclusively of the radical of an aromatic ring system, and also substituents containing aromatic radicals of the type of alkaryl radicals or aralkyl radicals. At least one of these radicals means R₁ to R₄ such an aryl radical, 1-ring substituents are particularly preferred here. Typical representatives are phenyl, benzyl, tolyl, xylyl and related compounds, the specified number of carbon.

At least one of the substituents R₁ to R₄ can furthermore mean a cycloalkyl or cycloalkenyl radical. It also applies here that this term includes substituents which have a corresponding cycloalkyl or cycloalkenyl component, as has been explained above for the term aryl radicals. The mononuclear ring systems based on cyclopentyl, cyclohexyl and their derivatives are also preferred in the case of saturated or partially saturated ring-shaped substituents.

In a preferred embodiment of the invention, the substituents R₁ to R₄ in total not more than 12 carbon atoms, preferably not more than 10 carbon atoms. In particular, in a preferred embodiment, the sum of the carbon atoms of these substituents is not more than 8, in particular not more than 4, carbon atoms.

Preferred meanings for R₁ to R₄ are hydrogen, C, -C₄-Alkyl, and / or halogen. It is further preferred that at least one, in particular 2 or 3, of these radicals is hydrogen.

The N, N'-digylcidylbenzimidazolones according to formula II with the following meaning for R, to R are particularly preferred₄. <tables id="tabl0001" num="0001"><img file="EP0033503B1_D0013.tif" /></tables>

The present invention furthermore relates to pharmaceutical preparations with cytostatic activity, containing compounds of the general formula III<chemistry id="chem0013" num="0013"><img file="EP0033503B1_D0014.tif" /></chemistry>in which R ', R ", glycidyl and m have the following meanings:<ul id="ul0002" list-style="none"><li>R ': identical or different radicals from the group hydrogen, hydrocarbon radicals with preferably up to 8 carbon atoms,</li><li>R ": identical or different radicals from the group hydrogen, hydrocarbon radicals with preferably up to 4 carbon atoms,</li><li>m: a number of 0, 1 or 2 as well</li><li>Glycidyl: a radical of the general formula<chemistry id="chem0014" num="0014"><img file="EP0033503B1_D0015.tif" /></chemistry>in which R is hydrogen or a methyl radical.</li></ul>

The glycoluril derivatives selected according to the invention are distinguished by the fact that at least two glycidyl radicals are present on the bicyclic system as substituents on the nitrogen atoms of the ring system. It is particularly preferred to use compounds of the general formula III in which two glycidyl residues are provided in N substitution, these two glycidyl residues attacking the same 5-ring (1,3-position). In particular, however, glycidyl derivatives in which the two glycidyl groups are distributed over the two 5-ring systems (1,5 and 1,7 positions) also fall within the range of the compound of the general formula III which is preferred according to the invention. The presence of three glycidyl groups (1,3,5 or 1,3,7 position) can also lead to compounds to be used according to the invention.

The radicals R 'in the compounds of the general formula 111 are in particular hydrogen, any hydrocarbon radicals, each preferably not having more than 8 carbon atoms. It can be expedient to use hydrocarbon radicals with an even more limited carbon number, so that the upper carbon limit of each of these radicals R 'can be, for example, 4 carbon atoms.

In the case (R ') concerned here, straight-chain and / or branched alkyl and alkenyl radicals of the stated carbon number are suitable as hydrocarbon radicals. Aryl residues are also suitable. In the sense of the definition according to the invention, this group includes aromatic radicals in the narrower sense, which therefore consist exclusively of the radical of an aromatic ring system, and also substituents containing aromatic radicals of the type of alkaryl radicals or aralkyl radicals. If R 'is an aryl, aralkyl or alkaryl radical, 1-ring substituents are particularly preferred here. Typical representatives are phenyl, benzyl, tolyl, xylyl and related compounds.

One or both of the R 'radicals can furthermore be cycloalkyl or cycloalkenyl radicals. It also applies here that this term includes substituents which have a corresponding cycloalkyl or cycloalkenyl constituent, as previously explained for the term aryl radicals. The mononuclear ring systems based on cyclopentyl, cyclohexyl and their derivatives are also preferred in the case of saturated or partially saturated ring-shaped substituents.

In a particularly preferred embodiment of the glycoluril derivatives used according to the invention, the substituting radicals R 'together have no more than 12, in particular no more than 10, carbon atoms. It can be particularly preferred that the sum of the carbon atoms in these radicals R 'is not more than 8, in particular not more than 4 or at most 6 carbon atoms.

The radicals R "which may be present are - unless R" has the meaning of hydrogen, any hydrocarbon radicals which may be the same or different, each of these radicals contains no more than 4 carbon atoms.

Suitable hydrocarbon radicals for R "are, for example, straight-chain and / or branched alkyl and alkenyl radicals of the stated carbon number. Aryl radicals are also suitable. In particular, the corresponding information on the radicals R 'applies, so that alkaryl also applies to the aryl radicals - or aralkyl radicals, mononuclear substituents are also preferred here. The statements made in connection with the definition of R 'on cycloalkyl or cycloalkenyl radicals and on heterocyclic radicals also apply analogously.

Particularly preferred compounds according to formula III are the N, N'-diglycidylglycolurils with the following radicals R 'and R ":<tables id="tabl0002" num="0002"><img file="EP0033503B1_D0016.tif" /></tables>

In a further embodiment, the present invention relates to pharmaceutical preparations with cytostatic activity comprising compounds of the general formula IV<chemistry id="chem0015" num="0015"><img file="EP0033503B1_D0017.tif" /></chemistry>in which the residues R₅, R_e and glycidyl have the following meanings:<ul id="ul0003" list-style="none"><li>R₅ and Rs:<ul id="ul0004" list-style="none"><li>(1) identical or different radicals from the group hydrogen and hydrocarbon radicals, each with up to 12 carbon atoms.</li><li>(2) R₅ and R₆ are closed together to form a ring system</li></ul></li><li>Glycidyl: a radical of the general formula<chemistry id="chem0016" num="0016"><img file="EP0033503B1_D0018.tif" /></chemistry>in which R is hydrogen or a methyl radical.</li></ul>

Formally, this compound is the formula IV, which represents certain barbituric acid derivatives substituted with glycidyl radicals.

The present invention furthermore relates to pharmaceutical preparations with cytostatic activity, containing compounds of the general formula V.<chemistry id="chem0017" num="0017"><img file="EP0033503B1_D0019.tif" /></chemistry>in the case of a double bond in the 5/6 position, the radicals R₂ and R₄ omitted and the residues Rg, R₁₀, R₁₁, R₁₂ and glycidyl have the following meanings:<ul id="ul0005" list-style="none"><li>R₉, R₁₀, R₁₁ and R₁₂: <ul id="ul0006" list-style="none"><li>(1) identical or different radicals from the group hydrogen, halogen and hydrocarbon radicals each having up to 12 carbon atoms, which can also be substituted</li><li>(2) at least two of the radicals R₉ to R,₂ are closed together to form a ring system</li><li>(3) at least one of the pairs R₉/ R₁₀ or R₁₁/ R₁₂ together form the rest<chemistry id="chem0018" num="0018"><img file="EP0033503B1_D0020.tif" /></chemistry>where R,₃ and R₁₄ the meaning of Rg and R₁₀ or R₁₁ and R₁₂ to (1) or (2). According to the invention, it is proposed to use mononuclear or dinuclear uracil or dihydrouracil compounds for the stated purpose, which are distinguished by the presence of two glycidyl radicals as substituents on the nitrogen atoms of the ring system (s) .</li></ul></li></ul>

Depending on the meaning of the residues Rg to R₁₂ Different classes of uracil or dihydrouracil compounds can be distinguished from glycidyl in the compounds of the general formula VI:

If the ring contains two glycidyl residues, then mononuclear glycidyl compounds are present, which in turn depend on the meaning of the residues Rg to R₁₂ can be divided into different sub-groups.

In a first subgroup, R₉ to R₁₂ Hydrogen, halogen or any hydrocarbon radicals, where R₉ to R₁₂ may have the same or different meanings within the scope of this definition. If there are hydrocarbon residues, they each contain up to 12 carbon atoms.

Basically, all halogens can be used. Chlorine, bromine and fluorine, which can be particularly important in the 5-position, can be particularly suitable.

For the meaning of R₉ to R₁₂ As hydrocarbon residues, the previously stated structural and numerical statements and limitations have full and unrestricted validity, as described in connection with the explanations of R₅ and R₆ (Formula IV) or to R₁ to R₄ (Formula 11) have been made. For the sake of simplicity, reference is made to this. If there are spatially bulky substituents in the 5- and / or 6-position, one or at best two such substituents are preferred.

In a particularly preferred embodiment of the subclass of uracil derivatives used according to the invention, the substituting radicals R₉ to R₁₂-together no more than 12 carbon atoms. It can be particularly preferred that the sum of the carbon atoms in these radicals R₉ to R₁₂ does not make up more than 10, in particular not more than 8, carbon atoms. Especially also for corresponding uracil derivatives with no more than 4 carbon atoms in the sum of these radicals R.₉ to R₁₂ high cytostatic activity has been demonstrated.

In a further subgroup of the compounds of the general formula VI used according to the invention, at least 2 of the substituents R₉ to R,₂ together with the carbon atom (s) of the uracil ring which they substituted to form one (or more) cyclic ring system (s). Such ring systems can be saturated or unsaturated isocyclic or heterocyclic in nature.

As indicated above, a further subgroup of the compounds of the general formula V is characterized for the purpose according to the invention in that - in the case of the dihydrouracil compounds - at least one of the pairs R₉/ R₁₀ and R₁₁/ R₁₂ together the rest<chemistry id="chem0019" num="0019"><img file="EP0033503B1_D0021.tif" /></chemistry>form. In this case the residues R₁₃ and R₁₄ the previously given meaning of R₉ to R₁₂. Compounds in which only one of the pairs R₉/ R₁₀ or R₁₁/ R₁₂ such a remainder with R₁₃ and R₁₄ form.

The present invention furthermore relates to pharmaceutical preparations with cytostatic activity comprising compounds of the general formula VI<chemistry id="chem0020" num="0020"><img file="EP0033503B1_D0022.tif" /></chemistry>in which A is an organic radical, which may also contain heteroatoms, m is a number from 2 to 4 and the substituted imide groups<chemistry id="chem0021" num="0021"><img file="EP0033503B1_D0023.tif" /></chemistry>each have imide rings with 4 to 10 ring members and the glycidyl radical has the meaning given earlier.

According to the invention, it is thus proposed in this embodiment to use polycarboximides with at least 2 cyclic imide groups and in each case one glycidyl radical on the nitrogen atom for the stated purpose. It has surprisingly been found that such compounds can have a remarkably high cytostatic activity. The N, N'-digiycidyl-pyromellitic acid diimide (1,2,4,5-benzenetetracarboxylic acid diimide) with attached glycidyl residues shows remarkably high cytostatic activity even at very low concentrations. The T / C rates on the P 338 tumor are under standard test conditions (9 injections)<tables id="tabl0003" num="0003"><img file="EP0033503B1_D0024.tif" /></tables>

The polycarboximides described according to the invention and used as cytostatics contain at least 2 cyclic imide groups of the stated type substituted with glycidyl radicals, but a larger number of such cyclic imide groups can also be present. Advantageously, there are no more than 4 such imide groups in the molecule, with compounds having 2 or 3 such imide groups being particularly preferred.

The imide groups themselves form with component A from the general formula VI imide rings each having at least 4 ring members and preferably not more than 10, in particular not more than 8 ring members. According to the invention, compounds of the general formula VI in which these imide rings have 4 to 7 and in particular 5 or 6 ring members can be of particular importance. In the compound of the general formula VI, the imide rings present therein can have the same number of rings or a different number of rings. It is therefore possible for two five-membered glycidyl-substituted imide rings to be present, but it is also possible, for example, for five-membered and six-membered imide rings to be present in one compound. The members from component A of the compounds of general formula VII required for the respective imide ring closure can originate from different areas of component A, as is the case with the diglycidyl-pyromellitic acid diimide mentioned above, but it is also possible for A to have the same proportions the imide rings are each completed, as is the case, for example, in the case of N, N'-digiycidyi-1,1,2,2-ethanetetracarboxylic acid diimide. It is also possible to mix both principles - that is to say a partial overlap with respect to the elements of component A required for the respective imide ring closure.

In general, component A of formula VI is an organic radical that can also contain hetero atoms. Suitable heteroatoms are, in particular, nitrogen and oxygen, these heteroatoms occurring one or more times depending on the nature of the radical A.

The connecting component A can be open-chain or ring-shaped. In the case of the open-chain structure, it can be a straight-chain or a branched structure - without prejudice to the fact that portions of such a straight-chain structure with the attached substituted carboximide groups form the rings shown above.

Both the open-chain and the ring-shaped components A can be saturated or unsaturated. Particularly suitable unsaturated radicals are mono- or poly-olefinically unsaturated constituents. In the case of the ring-shaped elements A, aromatic rings are also particularly suitable and may even be particularly preferred. Any mixed structures of the possibilities shown here are also possible, so that, for example, ring-shaped components are connected to open-chain ones, the glycidyl-substituted cyclic imide groups being able to attack any parts of this component A.

Component A is usually a hydrocarbon residue. This radical A preferably contains up to 10 chain or. Ring links - for example CH₂-Groups of open-chain or ring-shaped saturated or CH groups of open-chain or ring-shaped unsaturated or aromatic building components. The building component A is characterized by at least one link, it can be represented by two links and, in particularly preferred cases, contains up to 10 links. Any number in this range is possible with open-chain components A, while 4 ring links represent the lower limit for ring-shaped connections. As simple rings, those with 5 or 6 ring members are particularly preferred. In the case of ring systems with multiple rings, these rings can be fused to one another or connected to one another via at least one common link, but they can also be present as isolated rings next to one another and only connected to one another by a chemical bond or by bridge links.

The radical A from the general formula VII represents the radical of polycarboxylic acids with at least 4 carboxyl groups and in particular with 4 to 8 carboxyl groups. Particularly preferred are radicals of such polycarboxylic acids with 4 or 6 carboxyl groups. These radicals can be aliphatic, cycloaliphatic or aromatic and olefinically unsaturated in nature. In particular, heterocyclic radicals for A are also suitable.

An upper limit for the molecular weight of this component A is particularly preferred at about 750. In a further preferred embodiment of the invention, the molecular weights of the entire compound of the general formula VII are in each case at the upper limit values ​​mentioned at the beginning.

In the case of the open-chain construction, characteristic individual examples of the structure of the molecular component A from the formula VI are derived, for example, from polycarboxylic acids of the type 1,1,2,2-ethanetetracarboxylic acid or 1,2,3,4 butanetetracarboxylic acid. Including heteroatoms, polycarboxylic acid residues such as that of ethylenediaminetetraacetic acid are suitable.

For ring-shaped radicals A, reference is made to the aromatic polycarboxylic acids of the pyromellitic acid or naphthalene tetracarboxylic acid type. Another example is benzene hexacarboxylic acid, which in turn can form 3 imide groups. In the case of these ring-shaped compounds, the carboxyl groups on a ring or are present in a coherent ring system, but it is also possible to use the carboxylic acids which in turn are linked to one another with a further dicarboxylic acid, for example via an additional functional group of the type indicated above. Thus, by linking two molecules of trimellitic acid via the third carboxyl group, a tetracarboxylic acid can be obtained. The linkage can take place, for example, via the formation of ester or amide groups. By using more than 2 functional linking elements - for example by using triamines together with trimellitic acid imide, more than just 2 such polycarboxylic acid systems can also be combined.

What is stated here for the aromatic carboxylic acids applies mutatis mutandis to corresponding cycloaliphatic carboxylic acids or to those compounds in which heteroatoms, in particular 0 or N, assume the function of ring members.

In the ring-shaped building blocks A from the compounds of the general formula VII, the imide-forming carboxyl groups are preferably in the o- and / or in the m-position, so that a total of five-membered and / or six-membered imide rings are preferably formed. As already stated, the invention is not limited to this, four-membered imide rings are also possible, but higher-membered ring numbers, for example those with 7 to 10 ring members, can also be expedient.

Numerous polyimides or the carboxylic acids on which they are based, of the type on which the compounds of the general formula VI according to the invention are based, are known from the literature, for example in addition to the pyromellitic acid diimide mentioned at the outset, the following compounds, which are already indicated here as glycidyl-substituted derivatives, are mentioned:<ul id="ul0007" list-style="none"><li>N, N '-diglycidyl-1, 2,3,4-benzenetetracarboxylic acid diimide</li><li>N, N'-diglycidyl-1,4,5,8-naphthalenetetracarboxylic acid diimide</li><li>N, N'-Digiycidyi-2,3,4,5-pyridine tetracarboxylic acid diimide</li><li>N, N'-diglycidyl-2,3,5,6-pyridine tetracarboxylic acid dimide</li><li>N, N'-diglycidyl-1,2,4,5-cyclohexanetetracarboxylic acid diimide</li><li>N, N'-diglycidyl-1,1,2,2-ethane tetracarboxylic acid dimide</li><li>N, N'-Digiycidyi-1,2,3,4-butanetetracarboxylic acid triimide</li><li>N, N ', N "-triglycidyl-benzenehexacarboxylic acid triimide</li><li>N, N'-diglycidyl-tetrahydrofuran tetracarboxylic acid diimide.</li></ul>

The active compounds used according to the invention can be prepared in a manner known per se. It is generally achieved by introducing the glycidyl groups into the N substitution. For this purpose, the heterocyclic mononuclear or polynuclear molecule of the active substance in question is first prepared in a manner known per se, but instead of the N-glycidyl group there is initially an —NH group. Finally, this hydrogen is replaced on the nitrogen by the glycidyl group.

There are two basic options for this final reaction step. One is the direct introduction of the glycidyl grouping by reaction of the NH grouping with epihalohydrins, especially epichlorohydrin or epibromohydrin. The other way completes the molecular structure in two reaction steps. The corresponding allyl-substituted precursors are first formed, whereupon the allyl group is epoxidized in a final process step.

There is extensive literature on the implementation of -NH groups with epihalohydrins. The reaction can be carried out in the presence of a small amount of a quaternary ammonium compound as a catalyst (cf., for example, Houben-Weyl, "Methods of Organic Chemistry" Volume 14/2 (1963), 497, 547). The reaction of allyl halides with NH groups of the type concerned here is described, for example, in US Pat. No. 3,376,301.

The epoxidation of a primarily formed allyl group can be carried out in a manner known per se with peracid. The epoxidation of allyl isocyanarates with peracids is e.g. B. in Houben-Weyl loc. Cit., Volume 6/3, 385 ff. For example, it can be carried out in the presence of a small amount of a quaternary ammonium compound as a catalyst.

The reactions of the precursors formed with epihalohydrins or allyl halides are advantageously carried out in the temperature range from about 50 to 150 ° C., preferably from about 70 to about 125 ° C. Allyl halide or epihalohydrin is used in a molar ratio to the -NH-CO compound used of at least 2: 1, but it is also possible to work with a considerable excess, for example up to a molar ratio of 10: 1. Working with molar ratios in the range of 2 to 4 moles of allyl halide or epihalohydrin per mole of -NHCO starting compound can be particularly expedient. The preferred allyl halides or epihalohydrins contain chlorine or optionally bromine as halogen.

The reaction can be carried out in polar, in particular aprotic, solvents which partially dissolve at least one of the reactants and are not reactive towards the reactants. A particularly useful solvent is the class of dialkylformamides, especially the lower dialkylformamides such as dimethylformamide. The preferred reaction time is 1 to 10 hours, especially 2 to 5 hours.

The epoxidation of the allyl groups by means of peracids is also preferably carried out in solvents. Polar solvents, for example halogenated hydrocarbons or alcohols, are also suitable here. The suitable reaction temperature is usually in the range from 0 to 50 ° C., in particular between about 10 and 30 ° C. The peracid is expediently used in an approximately equivalent amount or only in a slight excess.

m-Chloroperbenzoic acid is readily available as a commercial product and is suitable for carrying out the reaction. The reaction time is usually in the range of 24 hours or more, for example up to 48 hours.

Information about the preparation of compounds of general formula 11 have already been given in connection with their description. Reference is once again made to DE-A-23 00 010 and NL-A-73 00 191.

The compounds of the general formula III to be used according to the invention can be prepared, for example, in the following way, although other routes are in principle also feasible: as described in DE-A-19 32 306, the dicyclic glycoluril starting compounds substituted in the desired manner are used with epihalohydrins implemented with elimination of hydrogen halide with alkali.<ul id="ul0008" list-style="none"><li>1. Reaction of the 1,3-unsubstituted hydantoins or hydantoin derivatives with a halohydrin compound, in particular epichlorohydrin or epibromohydrin, with the elimination of hydrogen halide with alkalis. Details of this type of process are described in DE-A-19 12 281 using the example of 5,5-dimethylhydantoin.</li><li>2nd Epoxidation of the N-allyl-substituted hydantoins or hydantoin derivatives. These acyl-substituted hydantoin starting compounds can in turn be prepared, for example, by reacting 1,3-unsubstituted hydantoins or hydantoin derivatives with allyl halide. Such a production process is described in its principles, for example in DE-OS 21 32 988, but not for hydantoin compounds, but for the case of triglycidyl isocyanurate.</li></ul>

For the relevant literature, reference is made to EH Catsiff, RE. Coulehan et al. At the. Chem. Soc. Div. of Org. Coat. and Plast. Chem. Pap. 39 (1978) pp. 139-145 and to DE-A-21 25355 and DE-A-27 27 266 as well as to USA4 125 516.

The information given here for mononuclear hydantoin derivatives also applies analogously to the production of the dinuclear hydantoin compounds of the general formula IV.

The manufacturing instructions for obtaining the barbituric acid compounds of the general formula V used according to the invention can be used analogously.

The medicaments according to the invention can contain individually defined compounds according to the invention and in particular the formulas 11 to X given, but it has been shown that mixtures of active compounds of several compounds in particular are highly effective cytostatics. In the context of the invention, it may furthermore be expedient to use individual, specific or a mixture of several compounds of the definitions according to the invention in admixture with the TGI compounds in accordance with the earlier patents mentioned. Combination therapy in conjunction with other cytostatics such as derivatives of nitrogen mustard or fluorouracil is also possible.

In general, it applies to the compounds of the general formulas used in the context of the invention that the residues or substituents which may be present in addition to the glycidyl groups should show or should show no or no substantial reactivity with the epoxy groups of the glycidyl substituents, at least under normal conditions. In this way it is ensured that the active ingredients used according to the invention are sufficiently stable in storage and that no undesired reaction takes place while the epoxy groups are destroyed.

The glycidyl-substituted heterocyclic compounds used according to the invention usually occur in various stereoisomeric forms. Basically, all of these different forms are suitable for the purposes of the invention. They can be used in a mixture or in the form of certain isolated isomers.

For use as cancerostatic agents, the active substances should be applied using a suitable vehicle. The usual auxiliaries and excipients for pharmacological preparations are suitable here. The use of aqueous systems with compatible glycol ethers, such as glycol monoethyl ether or butylene glycol methyl ether or propylene glycol methyl ether, has often proven useful here, in particular if the active ingredient is to be administered parenterally. In the case of oral administration, the pharmaceutically customary auxiliaries or carriers can be used, provided that they have a corresponding compatibility with the glycidyl compounds.

In animal experiments, the use of freshly prepared aqueous solutions which are given ip has proven to be expedient.

The compounds used according to the invention are active against various forms of leukemia and malignant neoplasms such as lung carcinoma, colon carcinoma, melanoma, ependymoblastoma and sarcome. In some cases, a clear superiority over known and on the market cytostatic drugs could be determined.

The polyglycidyl-substituted heterocycles described according to the invention are usually present in the pharmaceutical mixtures according to the invention in concentrations of up to about 10 percent by weight, based on the pharmaceutical mixture. The range from 0.05 to 10 percent by weight is particularly suitable, in particular a range from 0.05 to 5 percent by weight.

The following examples describe both the preparation and the use in the context of animal experiments for characteristic compounds of the definition according to the invention. The percentages relate to percentages by weight, unless otherwise specified in individual cases.

example 1

N, N'-digylcidyl benzimidazolone

5 g of benzimidazolone are refluxed with 200 g of epichlorohydrin with the addition of 50 mg of tetraethylammonium bromide for 4 hours. The cooled solution is filtered with 40 g of Na₂S0₄ and 3 g of powdered NaOH were added and the mixture was stirred at room temperature for 1.5 hours. It is filtered off and evaporated to dryness in vacuo. A brown mass remains, which crystallizes after some time. Recrystallization from methanol gives 5 g of crystalline compound, mp. 102 ° C, epoxy content 13.7% (theory 14.2%). The mass spectrum supports the specified structure.

Example 2

Production was carried out analogously to Example 1

<tables id="tabl0004" num="0004"><img file="EP0033503B1_D0025.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0033503B1_D0026.tif" /></tables>

Example 3

The following experiments were carried out according to test instructions from the National Cancer Institute Bethesda, Maryland 200014, published in "Cancer Chemotherapy Reports" Part. 3, September 1972, Vol.3, No. 2. 1,3-Diglycidyl-benzimidazolone from Example 1 above was used as the active substance. The substance was freshly prepared as an aqueous 1% solution for injection immediately before application.

In mice, according to protocol 1200 (page 91, c.), The tumor type P 388 (leukemia) was ip with 10⁶ Cells / mouse set. The untreated animals had an average survival of 9.9 days.

The active ingredient is applied. The active ingredient is administered in 9 doses in different test series, once at 200 mg / kg, in another at 100 mg / kg and in a third test series at 50 mg / kg. In both cases, a significant increase in the lifespan of the treated test animals compared to the control group of the untreated animals is achieved. The average lifespan of the test group with the administration of 200 mg / kg is 20 days, the extension rate T / C is therefore 202%. In the test group with the dose of 100 mg / kg, the average life expectancy of the test animals is 18 days, T / C 181%. The 50 mg / kg dose group had an average life expectancy of 15.3 days, T / C 154%.

The results were confirmed in a repeat experiment.

Other benzimidazolone derivatives were tested in the same way. The values ​​obtained are summarized in Table 1 below.<tables id="tabl0006" num="0006"><img file="EP0033503B1_D0027.tif" /></tables>

Example 4

Diglycidyl-butylglycoluril

10th g of dry N-butylglycoluril (0.05 mol) are heated to 140 ° C. for 4 hours in an autoclave with 0.1 g of tetraethylammonium bromide and 200 g of epichlorohydrin. After cooling, the filtered solution is allowed to boil invensively at reflux at 45 to 50 ° C. and reduced pressure (water jet vacuum) and 8 g of 50% strength aqueous sodium hydroxide solution are added dropwise. The water is continuously removed by distillation. The sodium chloride formed is filtered off and the epichlorohydrin is distilled off. After careful removal of high-boiling components in vacuo (0.1 torr), the product should not be heated to more than 80 ° C., 9.6 g of diglycidylbutylglycoluril are obtained in the form of a light yellow resin; Epoxy content 10.1%, theory 10.3%. The mass spectrum supports the specified structure.

Example 5

3,6 diglycidyl-1,4-dimethylglycoluril

From 30 g of 1,4-dimethylglycoluril, 0.4 g of tetraethylammonium bromide and 350 g of epichlorohydrin, 28.6 g of 50% sodium hydroxide solution, 34.8 g of 3,6-diglycidyl-1,4-dimethylglycoluril are obtained as light yellow by the above process non-crystallizing resin. Epoxy content: 11.0%, theory: 11.4%. The mass spectrum supports the specified structure.

Example 6

The following experiments were carried out according to the test instructions of Example 3. Diglycidyl-butylglycoluril from Example 4 above was used as active substance in a first series of experiments. The substance was freshly prepared as an aqueous 1% solution for injection immediately before application.

In mice, according to protocol 1200 (page 91.c.), the tumor type P 388 (leukemia) was diagnosed ip with 10⁶Cells / mouse set. The untreated animals had an average survival of 9.8 days.

The active ingredient is applied. The active ingredient is administered in 9 doses in different test series, once each at 200 mg / kg, as well as at 100 mg / kg, and in a third test series at 50 mg / kg each. In all cases, a significant increase in the lifespan of the treated test animals compared to the control group of the untreated animals is achieved. The average lifespan of the test group with the administration of 200 mg / kg is 27 days, the extension rate T / C is thus 272%. In the test group with the dose of 100 mg / kg, the average life expectancy of the test animals is 19.3 days, T / C 194%. In a test group of 6 female mice, one test animal survived the test period of 30 days when administered 200 mg / kg per single dose. The test group with 50 mg / kg per single dose survived 16.3 days T / C 164%.

To test the mixture of active substances according to Example 5, test animals are provided with the tumor type P 388 (leukemia) in the same way as before. Here, too, 9 individual doses of the active substance mixture according to the invention are then administered in doses of 200 mg / kg, 100 mg / kg and 50 mg / kg.

The mean life expectancy of the untreated control animals is 9.5. The extension rate T / C is 190% at 200 mg / kg. If the same mixture of active substances is administered in an amount of 100 mg / kg per single dose, the mean survival of the test animals is 15.8 days. The T / C ratio is 157%. When the active ingredient mixture is administered in a single dose of 50 mg / kg, the T / C ratio is 134%.

Example 7

<tables id="tabl0007" num="0007"><img file="EP0033503B1_D0028.tif" /></tables>are heated under reflux for 4 hours (120 ° C.). The barbituric acid dissolves after 20 '. The mixture is then cooled to about 40 to 50 ° C. and 8.0 g (0.2 mol) of NaOH as a 50% solution are added dropwise within 20 '. At the same time, the water is continuously removed by distillation in vacuo. The mixture is stirred at about 45 ° C for 1.5 h. After the table salt has been suctioned off, the mixture is concentrated in a Rotavapor and dried under a high vacuum.<tables id="tabl0008" num="0008"><img file="EP0033503B1_D0029.tif" /></tables>

The mass spectrum supports the structure.

Example 8

<tables id="tabl0009" num="0009"><img file="EP0033503B1_D0030.tif" /></tables>

The above compound was prepared from the starting materials listed above in analogy to Example 10.<tables id="tabl0010" num="0010"><img file="EP0033503B1_D0031.tif" /></tables>The mass spectrum supports the structure.

Example 9

The following experiments were carried out according to the test instructions of Example 3. 1,3-diglycidyl-5,5-diethylbarbituric acid from Example 10 above was used as the active substance. The substance was freshly prepared as an aqueous 1% solution for injection immediately before application.

In mice, according to protocol 1200 (page 91.c.), the tumor type P 388 (leukemia) was diagnosed ip with 10⁶ Cells / mouse set. The untreated animals had an average survival of 10.4 days.

The active ingredient is applied. The active ingredient is administered in 9 doses in different test series once at 100 mg / kg and in another test series at 50 mg / kg. In both cases, a significant increase in the lifespan of the treated test animals compared to the control group of the untreated animals is achieved. The average lifespan of the test group with the administration of 100 mg / kg each is 22 days, the extension rate T / C is therefore 211%. In the test group with the dose of 50 mg / kg, the average life expectancy of the test animals is 15.3 days, T / C 147%.

In further test series, additional test results - as recorded in Table 3 below - are determined.<tables id="tabl0011" num="0011"><img file="EP0033503B1_D0032.tif" /></tables>

Example 10

Preparation of N, N'-diglycidyluracil

11.2 g (0.1 mol) of uracil, 736 g (8 mol) of epichlorohydrin and 0.35 g of tetraethylammonium bromide were refluxed for 4 hours. The uracil dissolved after about 1 hour. The reaction mixture was cooled to 45 to 50 ° C. and brought to the boil intensively in vacuo (15 torr). 8 g of sodium hydroxide as a 50% strength aqueous solution were added dropwise within 20 minutes. The water was continuously removed by azeotropic distillation. After stirring for 2 hours at approx. The resulting sodium chloride was suctioned off at 40 ° C. and epichlorohydrin was distilled off. The light yellow syrup obtained was dried under high vacuum.<ul id="ul0009" list-style="none"><li>There remained 21.5 g of a yellow viscous oil.</li><li>Epoxy content: 13.4% (theory 14.2%)</li><li>The mass spectrum and the IR spectrum support the structure.</li></ul>

Example 11

The following were prepared from the corresponding starting materials in a manner analogous to that given above:<ul id="ul0010" list-style="none"><li>a) N, N'-Diglycidyl-6-methyluracil Yield: 75%, white crystals mp 95 ° C epoxy oxygen 12.9% (theory 13.4%)</li><li>b) N, N'-diglycidyl-5-methyluracil mp 87 to 89 ° C epoxy oxygen 12.82% (theory 13.43%)</li><li>c) N, N'-Diglycidyl-5-bromuracil mp 76 to 79 ° C epoxy oxygen 10.01% (theory 10.56%)</li><li>d) N, N'-diglycidyl-5-iodouracil pale yellow syrup epoxy oxygen 8.66% (theory 9.14%)</li><li>e) N, N'-diglycidyl-5-fluorouracil pale yellow syrup, epoxy oxygen 12.39% (theory 13.21%)</li><li>f) N, N-diglycidyl-1,1'-methylene-bis-uracil not crystalline EpO: 8.1% (theory: 9.2%)</li><li>The 1,1'-methylene-bis-uracil is prepared in accordance with DE-OS 19 12 291.</li></ul>

Example 12

The following experiments were carried out according to the test instructions of Example 3. 1,3-Diglycidyl-uracil from Example 13 above was used as active substance. The substance was freshly prepared as an aqueous 1% solution for injection immediately before application.

In mice, according to protocol 1200 (page 91.c.), the tumor type P 388 (leukemia) was diagnosed ip with 10⁶ Cells / mouse set. The untreated animals had an average survival of 10.4 days.

The active ingredient is applied. The active substance is administered in 9 doses in different test series once at 200 mg / kg and in another test series at 100 mg / kg. In both cases, a significant increase in the lifespan of the treated test animals compared to the control group of the untreated animals is achieved. The average lifespan of the test group with the administration of 200 mg / kg is 24 days, the extension rate T / C is thus 230%. In the test group with the dose of 100 mg / kg, the average life expectancy of the test animals is 16.0 days, T / C 153%. The results were confirmed in a repeat experiment. Here the numerical values ​​T / C were 198% and 152%.

Further test results with uracil compounds are summarized in Table 4 below.<tables id="tabl0012" num="0012"><img file="EP0033503B1_D0033.tif" /></tables>

Example 13

The preparation of N, N'-diglycidylbenzene tetracarboxylic acid (1,2,4,5,) diimide was carried out according to FR-A-15 59 450 in the manner described in detail below.

108 g of pyromellitic diimide, 925 g of epichlorohydrin and 1 g of benzyltrimethylammonium chloride were placed in a 2 l three-necked flask equipped with a stirrer, thermometer and reflux condenser. The mixture was refluxed with stirring for 3 hours. 500 g of epichlorohydrin were then distilled off and the solution was cooled to 2 ° C. The precipitated crystals were filtered off and washed twice with a little ethanol and dried. A further crystallizate was obtained by concentrating the mother liquor to about 150 cc and adding 300 cc of ethanol. The total yield was 118 g of N, N'-diglycidylbenzene tetracarboxylic acid (1,2,4,5) diimide.

A single recrystallization from a mixture of equal parts of epichlorohydrin and ethanol gave a product which had a melting point of 215 to 217 ° C. The epoxy oxygen content was 7.8% (Grennlee method).

Example 14

The following experiments were carried out according to the test instructions of Example 3. The N, N'-diglycidylbenzene tetracarboxylic acid (1,2,4,5) diimide from Example 16 was used as active substance. The substance was freshly prepared as a 1% solution for injection in ethylene glycol monomethyl ether immediately before application.

In mice, according to protocol 1200 (page 91.c.), the tumor type P 388 (leukemia) was diagnosed ip with 10⁶Cells / mouse set.

The mean survival of the animals not treated with the active ingredient according to the invention was determined.

The active ingredient is applied to another group of experimental animals. The active substance is administered in nine doses in different test series once at 12.5 mg / kg and in another test series at 6.25 mg / kg. In all cases, a significant increase in the lifespan of the treated test animals compared to the control group of the untreated animals is achieved. The extension rate T / C is 200% for the administration of 12.5 mg / kg and 156% for the administration of 6.25 mg / kg.