N-substituted polyglycidyl urazol compounds, process for their preparation and pharmaceutical compositions containing them.

DE-OS 29 07 349 relates to pharmaceutical preparations with cytostatic activity which contain triglycidyl isocyanurate (TGI) and / or those TGI derivatives as pharmacological active ingredient 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. Compounds of this type are characterized in that the three N atoms of the isocyanuric 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.

DE-OS 30 37 094.6 relates, inter alia, to pharmaceutical preparations with cytostatic activity, containing compounds of the general formula

<chemistry id="chem0001" num="0001"><img file="EP0056962A2_D0001.tif" /></chemistry> In the R the following interpretation was requested: alkyl, aryl, aralkyl, alkaryl, cycloalkyl, which radicals, if desired, can also be heterocyclic, unsaturated and / or substituted with at least one of the following substituents: halogen, hydroxyl, amino, N-substituted amino , Mercapto, alkylmercapto, arylmercapto, alkylsulfoxy, arylsulfoxy, alkoxy, aroxy, acyloxy and heterocyclic radical. The glycidyl radical has the meaning given above.

The present invention is based on the finding that structurally analogous compounds, which, however, are derived from urazole as the main body, also develop a surprisingly strong cytostatic activity, which can even exceed the activity of TGI.

Accordingly, the invention relates in a first embodiment to new N-substituted polyglycidyl-urazole compounds of the general formula I.<chemistry id="chem0002" num="0002"><img file="EP0056962A2_D0002.tif" /></chemistry>in which the radicals R are a glycidyl radical of the general formula II<chemistry id="chem0003" num="0003"><img file="EP0056962A2_D0003.tif" /></chemistry>mean, where R₁ Is hydrogen or an alkyl radical having 1 to 4 carbon atoms, or two of the radicals R are a glycidyl radical of the general formula II and then the remaining radical R is a carbon, hydrogen and optionally heteroatom-containing radical Z.

In a first particularly preferred embodiment of the invention, the three R radicals present in N substitution are a glycidyl radical of the general formula II. It is particularly preferred that R is present in at least two, preferably all, of the glycidyl radicals₁ Is hydrogen.

The production of 1,2,4-triglycidyl-urazole (TGU) is believed to produce three diastereomers, since only two of the three glycidyl groups have the same chemical environment.<chemistry id="chem0004" num="0004"><img file="EP0056962A2_D0004.tif" /></chemistry>

Statistically, the following isomer distribution should be obtained without mutual interference:<chemistry id="chem0005" num="0005"><img file="EP0056962A2_D0005.tif" /></chemistry>

These three isomers are contained in the crude product obtained after the alkali treatment.

In column chromatography, as described below, the TGU isolated as the primary product from the column consists of only two diastereomers, which are present in a ratio of about 1: 1. Detection: HPLC: silica gel / methylene chloride + 2.5 methanol.

The two diastereomers, which are to be referred to as α- and β-TGU, differ only slightly in the retention times: α-TGU has a somewhat shorter retention time than β-TGU. In the inverse system (mobile phase: water + 1.32% THF), the conditions are reversed and the separation becomes somewhat better, so that this system can also be used for the preparative separation. α- and β-TGU also differ in melting points and in¹H-NMR spectrum, particularly significant in the range of 4.0-4.4 ppm.

The third diastereomer, to be referred to as α-TGU, was eluted from the column after the α-β-TGU. It can also be isolated from the mother liquor after recrystallization of the crude product, which is obtained by the process described below, by purification by column chromatography. This α-TGU is liquid at room temperature and is approximately 15-20% of the raw product (not 50% as would be expected).

The table shows the physical data for the three diastereomers.<tables id="tabl0001" num="0001"><img file="EP0056962A2_D0006.tif" /></tables>

These three diastereomers of 1,2,4-triglycidyl urazole or the process for their preparation and their use in the sense described below are a further subject of the present invention. Those mixtures of these diastereomers which differ in their composition from the diastereomer mixture originally obtained by synthesis also fall within the scope of the invention. Here, in particular, subject matter of the invention are diastereomer mixtures of the TGU, which essentially consist of two of the diastereomer types mentioned. For example, the mixture of essentially α- and β-TGU obtained by column chromatography or its use falls within the scope of the invention.

In a further important embodiment of the invention, only two glycidyl radicals of the general formula II are present on the urazole ring, while the third radical is a radical Z with the meaning given. In this case too, it is preferred that the two glycidyl residues in R₁ Contain hydrogen. Z can in principle be any organic radical which, in addition to carbon and hydrogen atoms, can also contain heteroatoms. 0, N, S and / or P are primarily considered as heteroatoms.

According to the invention, the molecular weight of such a radical Z preferably does not exceed the limit values ​​given below. For example, the molecular weight of this Z radical is advantageously not above about 750 and in particular not above about 500. It may furthermore be preferred that the molecular weight of the Z radical does not exceed the value of approximately 300 or even the value of approximately 200.

In preferred embodiments of the invention, Z can have one of the following meanings: alkyl, aryl, aralkyl, alkaryl, cycloalkyl, which radicals can, if desired, also be heterocyclic in nature, unsaturated and / or substituted with at least one substituent. In particular come as substituents

into consideration: halogen, hydroxyl, amino, N-substituted amino, Kercapto, alkylmercapto, arylmercapto, alkylsulfoxy, arylsulfoxy, alkoxy, aroxy, acyloxy and heterocyclic radical. If a substituted radical is present in Z, substituted alkyl radicals may be preferred, substituted Aryl residues or cycloalkyl residues are not excluded. Olefinically unsaturated radicals are preferred as unsaturated radicals.

The invention furthermore relates to processes for the preparation of the new N-substituted polyglycidyl compounds of the general formula I and pharmaceutical preparations with in particular cytostatic activity, comprising compounds of the general formula I.

The mechanism of action of the compounds used in the context of the invention has not been clarified in detail. The glycidyl groups present here, as in the triglycidyl isocyanurate of DE-OS 29 07 349, are presumably of outstanding importance for the cytostatic action. All compounds of general formula I described according to the invention are characterized by the presence of at least 2 such glycidyl groups. In addition, there is possibly the widely variable radical Z in the relevant connection class. It is possible that this distribution Z influences the distribution of lipophilic and hydrophilic preferences and that the organism's uptake of the compounds can thus be controlled to a certain extent. The meaning of the new substituent Z introduced according to the invention need not be limited to this.

The radical Z is, according to its previous definition, a hydrocarbon radical which can also contain hetcroatomas. N, 0, S and / or P are particularly suitable as heteroatoms. This radical preferably contains a total of not more than 15 carbon atoms, preferably not more than 12 carbon atoms and expediently not more than 8 carbon atoms. In particular, radicals can be of interest which contain up to 6 or preferably even only up to 4 carbon atoms, these numerical values ​​being to be understood independently of the particular structure and relating only to the sum of all carbon atoms in the radical concerned.

If Z is an aryl, aralkyl or alkaryl radical, 1-ring substituents are particularly preferred here. Typical representatives are phenyl, benzyl, tolyl, xylyl and related compounds. Mononuclear ring systems based on cyclopentyl, cyclohexyl and their descendants are also preferred for the cycloaliphatic rings for the Z radical. Corresponding heterocyclic radicals, in particular therefore 1-ring compounds with 0, N and / or S in the system, fall within the scope of the invention. The ring systems can preferably contain 1, 2 or 3 such heteroatoms. These heterocyclic radicals preferably contain 5 or 6 ring members. If desired, all the ring-shaped substituents mentioned here, be they aromatic or cycloaliphatic in nature, may in turn have further substituents. Suitable substituents are, for example, halogen, hydroxyl or alkoxy.

In a particularly preferred embodiment of the invention, the Z radical denotes an optionally substituted alkyl radical. This alkyl radical can be straight-chain or branched and saturated or unsaturated and - with the exclusion of its substituents - preferably contains more than 10, in particular not more than 8, carbon atoms. In this embodiment of the invention, particular preference is given to those compounds of the general formula I in which the radical Z is unsubstituted alkyl having 1 to 6 carbon atoms or a corresponding alkyl radical which is substituted by halogen, hydroxyl, amino, N-substituted amino, mercapto, Alkylmercapto, arylmercapto, alkylsulfoxy, arylsulfoxy, alkoxy, aroxy and / or acyloxy is substituted, the substituent also being heterocyclic in nature.

Residues substituted in this way can be substituted one or more times with the groups mentioned. There are preferably 1 to 3 of the substituents mentioned on the respective radical Z, in a particularly preferred case compounds of the general formula I containing such substituted alkyl radicals of the type mentioned are used in the pharmaceutical preparations according to the invention.

If there are substituting groups on the substituted alkyl radical Z, which in turn contain hydrocarbon radicals - in particular in the case of the radicals N-substituted amino, alkylmercapto, arylmercapto, alkylsulfoxy, arylsulfoxy, alkoxy, aroxy and acyloxy - these substituting groups preferably have no more than 10, expediently not more than 8, carbon atoms. The particularly preferred limit here is 6 carbon atoms, in particular not more than 4 carbon atoms. These substituting hydrocarbon radicals can in turn be aryl, aralkyl, alkaryl, cycloalkyl and / or alkyl radicals which, if desired, can also have substituents such as halogen, hydroxyl, alkoxy and the like. Here too, heteroatom-containing radicals of the type described above, for example beterocyclic ring systems with 1 to 3 heteroatoms of the type described above, in particular mononuclear rings with N, 0 and / or S as heteroatoms, are included. Corresponding 5- or 6-membered heterocycles are preferred.

A particularly preferred embodiment of the invention relates to compounds of the general formula I in which one of the radicals R - that is to say the radical Z - denotes a mono- or disubstituted alkyl radical of the type mentioned, which is selected from the following group: Monohydroxyalkyl, dihydroxyalkyl, halohydroxyalkyl, N-substituted aminohydroxyalkyl, alkylmercaptohydroxyalkyl, substituted alkylmercaptohydroxyalkyl, the corresponding alkylsulfoxyhydroxyalkyls, optionally substituted alkoxyhydroxyalkyl and optionally substituted acyloxyhydroxyalkyl. The alkyl radical can preferably contain up to 7, preferably 3 to 7 and in particular 3,4 or 5 carbon atoms.

In the context of the invention, compounds of the general formula I may be preferred in which the radical Z denotes straight-chain or branched unsubstituted alkyl having up to 6, preferably up to 4, carbon atoms. In particular, the residues methyl, ethyl, propyl, isopropyl and the corresponding C.₄Residues and their olefinically unsaturated analogues. Furthermore, very particular preference is given to those compounds of the general formula I in which one of the radicals is purely mono- or disubstituted alkyl radical of the type mentioned with in particular 3 carbon atoms and preferably has at least one hydroxyl group. So there is always at least one hydroxyl group - preferably next to another substituent on this group - while the other two groups R are the glycidyl group of the general formula II.

In a further preferred embodiment of the invention, these substituting groups in the Z radical are distributed over the 2- and the 3-position of the radical R in question. The hydroxyl group can be present either in the 2-position or in the 3-position. Also particularly preferred are correspondingly substituted compounds of the formula I which, in addition to the hydroxyl group, have no further substituting group in the Z radical or hydroxyl, halogen, an N-substituted amino radical, an optionally substituted alkoxy radical, an optionally substituted alkylmercapto or alkylsulfoxy radical or a further substituent optionally substituted acyloxy. Chlorine and / or bromine are particularly preferred as halogen, but fluorine and iodine are not excluded. The N-substituted amino radicals can have the formulas<chemistry id="chem0006" num="0006"><img file="EP0056962A2_D0007.tif" /></chemistry>correspond. Here, the radicals R₂ or R₃ Hydrocarbon residues, which in turn can be substituted. In the preferred embodiment of the invention, these radicals contain R₂ and, if desired, R₃ up to 12 carbon atoms, the total of the radicals R₂ and R₃ preferably does not exceed 12 carbon atoms. These substituents particularly preferably contain R.₂ and R₃ a total of up to 8 and in particular not more than 5 carbon atoms. The leftovers R₂ and R₃ can also be combined to form a saturated or unsaturated, optionally aromatic and / or heterocyclic ring. Preferably R₂ and optionally R₃ also be alkyl residues. If these best are in turn substituted, then within the scope of the invention such hydroxyl, alkoxy or halopen - preferably chlorine or bromine - are provided as such substituents. If, in addition to the hydroxyl group in Z, there is an acyloxy radical, an alkoxy radical or an alkylmercapto or alkylsulfoxy radical, this radical preferably also contains up to a maximum of 10 carbon atoms, the preferred limit here being 8 carbon atoms. is and is particularly preferred not to introduce more than 5 carbon atoms into the molecule at this point. Alkyl radicals with the corresponding carbon number are also preferred for acyloxy radicals, although aryl radicals are also not excluded. The acyloxy radicals are preferably derived from monocarboxylic acids of the stated carbon number and structure.

The medicaments according to the invention can preferably contain individually defined compounds of the general formula I, but it has been found that mixtures of active substances of several compounds falling under the general formula I are highly effective cytostatics. In the context of the invention it may further be preferred to mix individual or a mixture of several compounds of the definition according to the invention according to formula 1 in admixture with the TGI compounds according to the mentioned German patent application DE-OS 29-07 349 or the German patent application P 30 37 094.6 to use. The compounds according to the invention can be prepared in several ways and form a further subject of the invention:<ul id="ul0001" list-style="none"><li>1. Introduction of the glycidyl groups of the general formula II to the urazole ring in the N substitution. For this purpose, urazole is first prepared in a manner known per se, that is to say the basic compound corresponding to formula I, but in which an -NH group is present instead of the N-glycidyl groupings. This hydrogen is then 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 epi-halohydrins, in particular epi-chlorohydrin or epi-bromohydrin and subsequent dehydrohalogenation. The other route completes the molecular structure in the two reaction steps: First, the corresponding all-substituted precursors are formed, whereupon the allyl group is epoxidized in a final process step. There is extensive literature on the implementation of -NH groups with epi-halohydrins. The reaction can be carried out in the presence of a small amount of a quaternary ammonium compound as a catalyst (see, for example, Houben-Weyl "Methods of Organic Chemistry". Volume 14/2 (1963), 497, 547). Particularly suitable quaternary ammonium compounds belong to the class of phase transfer -Catalysts. As is known, these are quaternary ammonium compounds with increased lipophilicity, which is ensured in particular by the presence of sufficiently large organic residues in the quaternary ammonium compound. Detailed information on the phase transfer catalysts can be found, for example, in WP Weber, GW Gobel "Phase Transfer Catalysis in Organic Synthesis", Springer-Verlag, Berlin, Heidelberg, New York, 1977 and EV Debmlov, SS Dehmlow "Phase Transfer Catalysis", Verlag Chemie, Weinheim, Deerfield Beech (Florida), Basel, 1980. The phase transfer catalysts are preferably used in amounts of about 0.1 to 10 percent by weight, in particular 0.5 to 5 percent by weight, and in particular 0.5 to 3 percent by weight, based on the urazole compound presented. In the subsequent reaction stage, the dehydrohalogenation, which in some cases also takes place through excess epihalohydrin, is completed by adding bases, preferably alkali metal hydroxides. In the second method, the urazole compound is not reacted directly with the epoxy compound. Instead, they are first reacted with allyl halides which correspond to the glycidyl radical of the compounds of the general formula I but have an olefinic double bond instead of the epoxide group, whereupon the resulting allyl-substituted urazoles are epoxidized. The epoxidation can be carried out in a manner known per se using peracids. As a related reaction, for example, the reaction of cyanuric acid with allyl halides is described in US Pat. No. 3,376,301, the epoxidation of allyl isocyanurates with peracids is described, for example, in Houben-Weyl aa0, 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 reaction of the urazole or the monosubstituted urazole compound (see below under 3) with epi-halohydrins or allyl halides is advantageously carried out in the temperature range from about 50 to 150 ° C., preferably from about 70 to about 125 ° C. The reaction can be carried out in an excess of the epi-halohydrin compound as a solvent or in polar 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 complete dehydrohalogenation of the intermediate halohydrins can be carried out by adding solid, powdered alkali, preferably NaOH, or highly concentrated aqueous solutions. This elimination of hydrogen halide is carried out either in excess epi-halohydrin or after distilling it off under reduced pressure in a polar aprotic solvent such as, for example, dimethoxyethane, diglyme or dimethylformamide at temperatures between -10 ° and 60 ° C., preferably between 0 and 45 ° C. The epoxidation of the allyl groups using 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. If unsubstituted urazole is used as the starting material in these reactions, the tri-glycidyl-substituted urazoles can be obtained.</li><li>2nd For the preparation of urazole derivatives according to the invention in which two radicals R from the general formula I are a glycidyl radical and the third radical R is the radical Z; different manufacturing methods are possible. One possibility is the implementation of. Triglycidylurazole (TGU) with a deficit of water, alcohol, primary and / or secondary amines, mercaptans, imines, imides, carboxylic acids, hydrogen halide and the like or hydrogen. Due to the similarity of the three glycidyl groups in the TGU, this reaction always leads initially to product mixtures, which in turn can be therapeutically effective. However, it is also possible and part of the process of the invention described below to separate the corresponding compounds of the general formula 1 from these mixtures by suitable separation processes, for example preparative thin-layer chromatography or column chromatography. In the course of these reactions, a glycidyl group is converted to the Z radical of the compounds of the general formula I. A monohydroxyalkyl radical Z is formed in the reductive treatment of the glycidyl group with hydrogen or hydrogen-providing compounds. For example, hydride compounds, for example complex borohydrides such as sodium borohydride, can be used as hydrogen-providing compounds. In the other cases mentioned, the triglycidy starting compound with a nucleophilic compound H⁺A^- implemented in deficit, whereby a disubstituted radical Z is formed which, in addition to a hydroxyl group, the radical A^- usually contains as second substituent on the neighboring atom to the hydroxylated carbon atom of the radical R. The reaction of the glycidyl groups of a structurally similar compound, namely the triglycidyl isocyanurate (TGI) with such nucleophilic reactants is known in the art and is described, for example, in Angew. Chemistry 80, 851 (1968). In the prior art, however, this reaction is specifically carried out on more than just one TGI epoxy group and is used, for example, in the industrial context to crosslink epoxy resin systems. In the process according to the invention, on the other hand, process conditions are preferably selected which allow the yield to be increased as far as possible in the direction of 1: 1 reaction products and the subsequent isolation and recovery of these 1: 1 reaction products with separation of unreacted portions of the starting material and further reaction products which are made possible by reaction of more as only one epoxy group with the nucleophilic reaction partner. When implementing TGU compounds with nucleophilic reactants H⁺A^- As described above, it can be difficult to obtain the desired 1: 1 reaction products in preferred yields, since the 3 epoxy groups of the molecule of the starting compound are approximately equivalent in reactivity and thus the desired diglycidyl compound often does not form as the preferred reaction product . Attempting to enrich the desired compound by reacting the triglycidyl-urazole with a deficit of nucleophilic reactant sometimes proves to be difficult. It was found; that the preparation of the 1: 1 reaction products is surprisingly easily possible if the triglycidylurazole is used in an excess, preferably in a large excess, of the nucleophilic reactant H⁺A^- reacted, but the reaction terminated prematurely and the excess of the nucleophilic reactant, unreacted TGU and co-formed di- and tri-addition products separated. The remaining crude diglycidyl product can then be purified in a conventional manner, for example by column chromatography. In this process, the nucleophilic reactant is preferably used in a 3 to 30-fold excess, in particular in a 5 to 20-fold excess over the required amount. The reaction can be carried out in solvents, but if desired, the excess of the nucleophilic reactant can also serve as the solvent. If solvents are used, these should advantageously be largely polar, but preferably not reactive under the selected process conditions. The solvent may also not be water-miscible. Particularly suitable solvents are, for example, halogenated hydrocarbons, especially chlorinated hydrocarbons. The reaction temperature is usually between about 30 and 120 ° C, preferably between 40 and 100 ° C and is selected in a particularly expedient embodiment so that the epoxy content of the reaction mixture has decreased by half within 4 to 5 hours. The clear representation and the recovery of the 1: 1 reaction product having 2 epoxy groups from the mixture of the reactants is here and in the other processes described below generally an essential step of the process according to the invention. For the preparation of the sulfoxy compounds from the corresponding mercapto compounds, see Houben-Weyl aa0, Volume 9 (1955), 207-217 and Makromol. Chem. 169, 323 (1979).</li><li>3rd A very elegant general process for the preparation of the compounds of the general formula I is based on the reaction of the mono-N-substituted urazole compound with epi-halohydrins. Mono-N-substituted urazole can be prepared by methods known from the literature. For the relevant literature, reference is made, for example, to Org. Synthesis Vol. 51, 121 (1971).</li></ul>

The substituent introduced into the urazole generally corresponds to the radical Z from the compounds of the general formula I. In the subsequent reaction, the two glycidyl groups are then introduced. For this purpose, the monosubstituted urazole is reacted with the corresponding epi-halohydrin compound, for example with epi-chlorohydrin with subsequent dehydrohalogenation or with allyl halide with subsequent epoxidation of the double bond, as described under number 1. for the tri-glycidylurazole has been described. In another embodiment, the present invention accordingly relates to the process for the preparation of N-substituted polyglycidyl urazole compounds of the general formula I.<chemistry id="chem0007" num="0007"><img file="EP0056962A2_D0008.tif" /></chemistry>in which R has the meaning given.

This process is characterized in that the two glycidyl radicals of the general formula II are introduced into N-substitution in urazole or in a urazole substituted by the radical Z mono-N-substituted or a triplycidylurazole with glycidyl radicals of the general formula 11 is partially reacted with water, Alcohols, compounds with a primary or secondary amino group, keraptans, hydrogen sulfide carboxylic acids, Subjects hydrogen halide or hydrogen or hydrogen-supplying compounds, T formed if desired_HConverts io compounds to corresponding sulfoxy compounds and separates the reaction products of the general formula I formed from the reaction mixture and wins them as such.

If the glycidyl radicals of the general formula II are introduced into urazole or into mono-N-substituted urazole in this process, this can be done by directly reacting the urazole compound optionally substituted with the radical Z with epi-halohydrins, these epi-halohydrin compounds correspond to the glycidyl radicals of the general formula II and then hydrogen halide is split off, or else the urazole compounds are first reacted with corresponding allyl halides, whereupon the allyl radicals or with R₁ substituted allyl residues are converted to the glycidyl group. For the nature of the compounds of general formula I, the radicals R and Z and glycidyl and the reactants for the formation of these radicals, all the information given above applies mutatis mutandis.

The compounds of general formula I, in particular in such a purified and substance-derived form that they are suitable for use in medicinal products, are new compounds. However, the new polyglycidylurazole compounds can also be used in other fields in which polyglycidyl-substituted compounds are usually of importance. The area of ​​plastics, in particular the area of ​​epoxy resins, is known here in particular.

If there is a Z radical in the polyglycidyl compounds in addition to two glycidyl radicals of the general formula II, this can be provided in the 1-, 2- or 4-position. The 4-position can be particularly important for preparative reasons for these compounds with the radical Z.

Finally, the invention further relates to the use of the compounds of the general formula I for the therapy of malignant neoplasms. Single administration of the compounds in the amount of 1 to 200 mg / kg may be appropriate. Individual, specific compounds of the general formula I or mixtures thereof can be used. Their use in admixture with other active ingredient components, for example TGI, 'also falls within the scope of the invention.

The compounds of general formula I used according to the invention 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 cancerostatics, the active substances should be applied using a suitable vehicle. The usual auxiliaries or excipients for pharmacological preparations are suitable here. In the present case, the use of aqueous systems, if appropriate together with compatible glycol ethers such as glycol monoethyl ether or butylene glycol methyl ether or propylene glycol methyl ether, has proven useful, 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 fresh. prepared aqueous solutions, which are given ip or iv, proved to be useful.

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. It has been shown that in some cases there is a clear superiority over cyclophosphamide and fluorouracil.

Combination therapy in conjunction with other cytostatics such as derivatives of nitrogen mustard or fluorouracil is possible.

In general, it applies to the compounds of the general formula I with a radical Z used in the context of the invention that this radical Z, at least under normal conditions or at least under cooling, shows no or no substantial reactivity with the epoxy groups of the glycidyl substituent (s) on the ring system of the general formula I. or should show.

In this way it is ensured that the active ingredients used according to the invention are sufficiently stable in storage and that no undesired conversion takes place while the epoxy groups are destroyed.

This rule must also be taken into account when selecting any substituents on the radical R:

Examples of the radical Z of the compounds of the general formula I used according to the invention with cytostatic activity are the following:

Methyl, ethyl, propyl, butyl, pentyl, hexyl, the corresponding isomeric radicals such as isopropyl, isobutyl, tert-butyl, iscpentyl, corresponding unsaturated, in particular olefinically unsaturated radicals such as vinyl, allyl, butenyl, phenyl, benzyl, xylyl, trimethylphenyl, Isopropylphenyl, naphthyl, cyclopentyl, cyclohexyl, the corresponding cycloaliphatic radicals substituted by 1 to 3 alkyl or alkenyl radicals, the alkyl or alkenyl substituents, preferably have 1 to 4 carbon atoms, 2,3-dihydroxypropyl, 2-hydroxy-3-diethylamino-propyl, 2-hydroxy-3-dimethylamino-propyl, 2-hydroxy-3- (dihydroxyethylamino-propyl, 2 -Hydroxy-3-morpholino-propyl, 2-hydroxy-3-phenoxypropyl, 2-hydroxy-3-methoxypropyl, 2-hydroxy-3-ethoxypropyl, 2-hydroxy-3-propoxypropyl, 2 -Hydroxy-3-acetoxypropyl, 2-hydroxy-3-propyloxypropyl, 2-hydroxy-3-butyloxypropyl, 2-hydroxy-3- (3-carboxypropyloxy) propyl, 3-hydroxy-2 -acetoxy-propyl, 3-hydroxy-2-propyloxypropyl, 3-hydroxy-2-butyloxypropyl, 3-hydroxy-2- (3-carboxypropyloxy) propyl, 2-hydroxy-3-chloropropyl and 2-hydroxy-3- bromopropyl.

Additional examples of the possibilities for R falling within the scope of the invention are the following radicals: general haloalkyl, hydroxyalkylthiopropyl, .2-hydroxy-3-methylaminopropyl, 2-hydroxy-3-ethylamino-propyl, 2-hydroxy-3- di (beta-chloroethyl) aminopropyl, 2-hydroxy-3-benzyloxypropyl and 2-hydroxy-3-hydroxypropyloxypropyl. Other possibilities for the radical R are 2-hydroxy-3-methylthio-propyl, 2-hydroxy-3-butyl-thio-propyl, 2-hydroxy-3-phenylthio-propyl, 2-hydroxy-3- (benzoxazole-2 ' -ylthlo) -propyl, 2-hydroxy-3-acetthio-propyl, 2-hydroxy-3-octylthio-propyl, 2-hydroxy-3 (2 ', 3'-dihydroxy-propylthio) -propyl, 2-hydroxy-3 (benzimidazol-2'-ylthio) propyl, 2-hydroxy-3 (benzthiazol-2'-ylthio) propyl.

Reactants for the conversion of a glycidyl group in the triglycidylurnzene to form a substituted radical Z in the sense of the invention are very generally alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec.-butanol, tert.-Butznol, 1 -Pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 2-ethyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1 propanol, 1-hexanol, 2-ethyl-1-butanol, 4-methyl-1-pentanol, 4-methyl-2-phtanol, 2-methyl-1-pentanol. Examples of suitable unsaturated alcohols are: 2-buten-1-ol, 2-propyn-1-ol, allyl alcohol, crotyl alcohol, 3-buten-2-ol, 2-buten-1-ol and 3-butyn-2- oil. Examples of polyhydric alcohols are ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,2-butanediol, 2,3-butanediol, 1,3-butanediol and 2-butenediol , 2-butyne-1,4-diol, 1,5-pentanediol, 2-methyl-1,4, -butanediol, 2,2-dimethyl-1,3-propanediol, hexanediol, 2,5-dimethyl-3- hexin-2,5-diol, glycerin, 1,2,4-butanetriol, 2-hydroxymethyl-2-ethyl-propanediol, 2-methyl-2-hydroxyraethyl-1,3-propanediol, pentaerythritol. Examples of thiols in this connection are methanethiol, ethanethiol, 1-propanethiol, 2-propanethiol, 2-methyl-2-propanethiol, 2-butanethiol, 2-Mrethyl-1-propanethiol, 1-butanethiol, 1-pentanthlol, 1-hexanethiol as well as 1,2-ethanethiol, 2,2-propanethiol, benzenethiol, p-benzenedithiol, pyridine-2-thiol and thiophene-2-thiol. The sulfoxide compounds obtained from such mercapto residues fall within the scope of the invention. Examples of carboxylic acids include acetic acid, propionic acid, n-butyric acid, n-valeric acid, capric acid, oenanthic acid, isobutyric acid, 3-methylbutanoic acid, 2,2-dimethylpropanoic acid, 2-methylbutanoic acid, 2-ethylbutanoic acid, 2-ethylhexanoic acid. Unsaturated acids are, for example, propenoic acid, 2-methylpropenoic acid, 3-methylpropenoic acid,. 2,3-dimethylpropenoic acid, hexadienoic acid, propiolic acid. Examples of substituted acids are 2-chloroaropanoic acid, 3-chloropropanoic acid, 2,2-dichloropropanoic acid, 2,3-dichloropropanoic acid, 3,3-dichloropropanoic acid, 2,2,3,3,3-pentachloropropanoic acid, 2-chlorobutanoic acid, 3-chlorobutanoic acid , 4-chlorobutanoic acid, 2-chloro-2-methylpropanoic acid, 3-chloro-2-methylpropanoic acid, 2,3-dichlorobutanoic acid, 2,2,3-trichlorobutanoic acid, 2-chloropentanoic acid, 3-chloropentanoic acid, 4-chloropentanoic acid , 5-chloropentanoic acid, 2-chloro-2-methylbutanoic acid, 2-chloro-3-methylbutanoic acid, 3-chloro-2,2-dimethyl-propanoic acid. Examples of aromatic acids are benzoic acid, phthalic acid, isophthalic acid, terephthalic acid and the corresponding acids substituted with methyl or ethyl radicals. Further examples of substituted acids are glycolic acid; Hydroxybutyric acid (α, β, or α-form), hydroxybenzoic acid with the hydroxy group in the o-, m- or p-position, the hydroxybenzoic acid with the position of the hydroxy groups in 3,4-, 2,3-, 2,4 -, 3,5- or 2,5-position, α-hydroxyphenylacetic acid. Examples of suitable phenolic compounds are: phenol, α- or β-naphthol, cresols, xylenols, chlorophenols, chlorocresoles, chlorxylenols, methylphenols with optionally more than one methyl group, for example 2,3,4-trimethylphenol, ethylphenols, propylphenols, Butylphenols and the like. Examples of the reaction of the glycidyl group with amines are: methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, di-n-propylamine, iso-propylamine, di-iso-propylamine, n-butylamine, di-n-butylamine, sec. -Butylamine, di-sec-butylamine, iso-butylamine, di-iso-butylamine, tert-butylamine, n-amylamine, di-n-amylamine, sec.-n-amylamine, iso-amylamine, di-iso- amylamine, allylamine, di-allylamine, cyclohexylamine, N-methylcyclohexylamine, dicyclohexylamine, cyclooctylamine. Examples of cyclic compounds with amino groups are: piperidine, hexamethyleneimine, morpholine, aniline, α- or β-naphthylamine.

The polyglycidyl-substituted urazoles described according to the invention are usually present in the pharmaceutical mixtures according to the invention in concentrations of up to about 20 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 percentages in the examples below relate to percentages by weight, unless otherwise specified in individual cases.

Examples

Examples 1

15.2 (0.15 mol) of urazole were heated under reflux for 3 hours with 4 g of tetramethylammonium bromide and 0.5 g of benzalkone A (mixture of alkylbenzyldimethylammonium chlorides) in 416 g (4.5 mol) of epi-chlorohydrin. After cooling, the solution was mixed with 28.8 g (0.72 mol) of powdered sodium hydroxide and stirred at 45 ° C for 6 hours. The precipitate was then filtered off with suction, the solution was evaporated to dryness under reduced pressure at 40 ° C., the residue was dissolved in a little methylene chloride and column chromatographed on silica gel (Merck) (eluent), methylene chloride / methanol (95: 5).

The individual fractions were pooled after TLC control. The second collection fraction (substance with the second highest R_FValues) gave, after evaporation, 1.5 g of 1,2,4-triglycidylurazole, which melted unchanged at 93 ° to 94 ° C. after recrystallization from ethyl acetate. Epoxy number

<tables id="tabl0002" num="0002"><img file="EP0056962A2_D0009.tif" /></tables>

Elemental analysis and mass spectrum support the structure.

Example 2

1.53 g (0.01 mol) of 4-phenylurazole (preparation according to Org. Syntheses Vol. 51, p. 121 (1971)), 0.08 g of benzalkon A, 0.08 g of tetraethylammonium bromide and 50 g of epi-chlorohydrin Stirred at 60 ° C for 4.5 hours. After cooling to room temperature and adding 20 g of 4 Å molecular sieve, 0.88 g (0.024 mol) of NaOH in 1 ml of H₂0 added dropwise and postperilhrt at 45 ° C for 0.5 hours, then aspirated and concentrated in vacuo at 40 ° C.<tables id="tabl0003" num="0003"><img file="EP0056962A2_D0010.tif" /></tables>

The raw heat product is separated by column chromatography.

Column height: 40 cm, diameter: 4 cm.

Filler: silica gel 60 (Kerck)

Mobile phase: methylene chloride: ethyl acetate: methanol 3: 2: ₁.

The zone with the H_FValue of 0.65 is isolated.

1.85 g of 1,2-diglycidyl-4-phenylurazole are obtained

EpO: 11.9 (theory 12.1)

The structure is supported by mass, IR and NMR spectra.

By S

D

iel 3

The following tests 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. The compounds prepared according to Examples 1 and 2 were used as the effective punch . The substance was freshly prepared as an aqueous 1% solution for injection immediately before application.

In mice, according to protocol 1200 (p. 91c), the tumor type P 388 (leukemia) was diagnosed ip with 10⁶ Cells / mouse set. The mean survival of the untreated animals is determined.

In further test groups, the active ingredient is applied in accordance with pretreated animals.

A significant increase in the lifespan of the treated test animals compared to the mean survival of the animals not treated with the active ingredient is achieved. The rate of prolongation T / C depending on the dosage of the active ingredient is summarized in the following table:<tables id="tabl0004" num="0004"><img file="EP0056962A2_D0011.tif" /></tables>

Example 4

N-dihydroxypropyl-N ', N "-diglycidyl-urazole

5 g of triglycidylurazole (0.019 mol) are stirred in 50 ml of water at 70 ° C. for 3 hours. The solution is concentrated on a Rotavapor and dried in a high vacuum. The colorless, oily crude product (5.8 g) is purified by column chromatography.

<tables id="tabl0005" num="0005"><img file="EP0056962A2_D0012.tif" /></tables>

The desired compound is obtained as a colorless oil. Rf: 0.43 in the above eluent on silica gel plates. Yield: 30 percent by weight,% by weight based on the crude product.

% Epoxy oxygen: 11.02 (calculated 11.14)

IR, MS and ¹H-NMR support the structure.

Example 5

N- (2-Hydroxy-3-propionoxypropyl) -N ', N "-diglycldyl-urazole

5 g of triglycidylurazole (0.019 mol) are stirred with 14 g of propionic acid (0.19 mol) in 100 ml of absolute toluene for 3 hours at 100 to 110 ° C. with the addition of 5 g of 4 Å molecular sieve. After filtering the molecular sieve, the solution is concentrated. The residue is dissolved in methylene chloride and extracted twice with 50 ml of 10% sodium carbonate solution. The methylene chloride phase dried over sodium sulfate is concentrated. The colorless, oily residue obtained (5.2 g) is purified by column chromatography.

<tables id="tabl0006" num="0006"><img file="EP0056962A2_D0013.tif" /></tables>

The desired compound is isolated as a colorless oil.<tables id="tabl0007" num="0007"><img file="EP0056962A2_D0014.tif" /></tables>

% Epoxy oxygen: 9.5 (calculated 9.3) IR and ¹H-NMR support the structure.

example

N- (2-Hydroxy-3-morpholin-N-yl-propyl) -N ', N "-diglycidyl-urazole

5 g of triglycidylurazole (0.019 mol) are stirred with 2 ml of morpholine (0.022 mol) in 100 ml of absolute isopropanol at 50 ° C. for 3 hours. The solution is concentrated and dried in a high vacuum. The yellowish, oily crude product (7.4 g) is purified by column chromatography.

<tables id="tabl0008" num="0008"><img file="EP0056962A2_D0015.tif" /></tables>

% Epoxy oxygen: 9.0 (calculated 9.0) IR and ¹H-NMR support the structure.

Elemental analysis:<tables id="tabl0009" num="0009"><img file="EP0056962A2_D0016.tif" /></tables>

Example 7

1,2-diglycidyl-4-methyl-urazole

8.5 g (0.074 mol) of 4-methylurazole (preparation according to literature: RC Cookson, SS Gupte et al .; Org. Synth. 51 (1971), p. 121) are mixed with 2% tetraethylammonium bromide in 230 ml epichlorohydrin (2, 95 mol) stirred at 80 ° C for 4 hours. After the addition of 65 g of 4 Å molecular sieve, the cooled solution is stirred for 3 hours at 40-50 ° C. with 24 g of 50% sodium hydroxide solution (0.3 mol): after suction filtration, the filtrate is evaporated and the light yellow solid residue is recrystallized from methanol. The 4.5 g (27% of theory) of white crystals obtained, with an epoxy-oxygen content of 14% (calc. 14.1%), melt at 90 ° C.

IR, ¹H-NMR and MS support the structure.

Example 8

1,2-diglycidyl-4-butyl urazole

The procedure is as in Example 7, but 4-butyl-urazole is used as the starting material. The crude product is purified by column chromatography.

<tables id="tabl0010" num="0010"><img file="EP0056962A2_D0017.tif" /></tables>

% Epoxy oxygen: 11.7 (calculated: 11.9) mp of the white crystals: 49-52 ° C.

IR,¹H-NMR support the structure.

Example 9

To prepare or isolate the three stereoisomeric forms of triglycidyl urazole (α, β and α isomer), the procedure is as follows:<ul id="ul0002" list-style="none"><li>The mixture of 12.5 g (0.124 mol) urazole, 174 g (1.88 mol) epichlorohydrin and 0.25 g tetraethylammonium bromide was stirred at 70 ° C. for 14 hours, the volatile constituents were distilled off at a bath temperature of 40 ° C. and under reduced pressure. the residue was taken up in 300 ml of methylene chloride, the solution was filtered and then 70 g of 30% sodium hydroxide solution were added at 20 ° C. with vigorous stirring within 5 minutes. The stirring was continued at 20 ° C. for 1 hour, the methylene chloride phase was separated off and the aqueous phase was extracted 3 more times with 100 ml of methylene chloride each time. The collected methylene chloride phases were evaporated under reduced pressure (bath max. 40 ° C) (finally at about 1 m bar). 23.2 g (69% of theory) of TGU were obtained as a mixture of the three diastereomers (partially crystalline product), which according to quantitative DC analysis 73% α- / β-TGU and approx. 15% α- TGU contained.</li></ul>

By recrystallization from ethyl acetate, α- / β-TGU with a melting point of 92-97 ° C. (sintering at 87 ° C.) was obtained in about 40% yield (composition: α: β-TGU = 50:50 (HPLC)). Further recrystallization caused the melting point to slowly rise to near the de_b Mp from pure β-TGU.

The 1st mother liquor contained the entire α-TGU and part of the α- / β mixture. By column chromatography (^{Kieselgel / CH}₂^C1₂^{: CH}₃^{0H =} 9^8:2) the γ-TGU was obtained in 10% yield after elution of the fraction from the α- / β mixture. γ-TGU is a colorless liquid with a refractive index n<maths id="math0001" num=""><img file="EP0056962A2_D0018.tif" /></maths> : 1,5088.

The α- / β-mixture obtained from the first mother liquors contained significant accumulations of α-TGU.

Example 10

The results below show the effectiveness of the compounds prepared according to Examples 4 to 9 in combating leukemia (tumor P 388) and were carried out as explained in Example 3. In the table below, the T / C values ​​found at variable doses (mg active substance / kg mouse) are shown, depending on the active substances produced according to Examples 4 to 9.

<tables id="tabl0011" num="0011"><img file="EP0056962A2_D0019.tif" /></tables>