DE102015008631A1 - Medicines for cancer therapy - Google Patents

Abstract

The present invention relates to novel chemical compounds, in particular benzophenone derivatives, which are useful as drugs in the medical treatment of cancer.

Description

The present invention relates to the technical field of medical cancer therapy.

More particularly, the present invention relates to novel chemical compounds, especially for use as anticancer drugs.

Moreover, the present invention relates to a process for the preparation of novel chemical compounds as well as a medicament and pharmaceutical combinations comprising the novel chemical compounds.

In the fight against malignant, malignant tumors, the so-called cancerous tumors or tumors, in addition to the surgical removal of the tumor tissue complementary or as a sole therapeutic measure in non-operable tumors, a treatment with drugs, the so-called chemo performed.

In the context of drug treatment, the division of the tumor cells and thus the uncontrolled growth of the tumor is prevented or attenuated or a destruction of the tumor cells is achieved by administration of cytostatic or cytotoxic substances.

The drugs used, also called cytostatics, often have a cytotoxic effect and lead to damage to the tumor cells to apoptosis, d. H. the programmed cell death. For this purpose, damage to the DNA of the tumor cells is brought about by the cytostatic and, if possible, the repair mechanisms of the cells are suppressed, while control mechanisms within the cell, which initiate apoptosis in the event of excessive damage, remain activated. By contrast, cytostatic substances should prevent the growth and division of the tumor cells. Most of the currently used cytotoxic drugs are cytotoxic as well as cytostatic.

The problem with the currently used cytostatics is that they are very unspecific, d. H. damage both degenerated, malignant cells and healthy body cells alike, with the faster dividing malignant cells being more affected by the consequences of the injury. However, since the non-degenerated healthy cells are also damaged, chemotherapy is often associated with a variety of serious side effects.

In order to make the treatment of cancer more efficient and selective, the synthesis of monoclonal antibodies which specifically bind to tumor cells has been increasingly investigated for several years. Among other things, attempts are made to bind highly toxic substances to antibodies and to introduce them selectively into tumor cells, so that healthy tissue is not damaged.

The problem here, however, is that the production of monoclonal antibodies is extremely complicated and requires their use protracted clinical studies. In addition, it must be ensured that the highly toxic substances which are bound to the monoclonal antibodies actually only enter the tumor cells and do not harm healthy tissue as well. The same applies to the metabolic products (metabolites) of the toxins, which can be released after the death of the tumor cell.

Since these difficulties in the synthesis of monoclonal antibodies for cancer therapy have not yet been overcome, there is still a need for substances which are suitable for cancer therapy, d. H. have specific cytotoxic and cytostatic properties and act specifically on malignant cells. Undigested tissue should not be impaired, if possible, in order to at least largely avoid the side effects that occur in the case of drug treatment of tumors, in particular cancer.

As cytostatics, substances are often used which are able to damage cancer cells by the alkylation, in particular methylation, of DNA. This is done, for example, by triazine derivatives substituted with methyl groups, which not only methylate the DNA of cancer cells, but also cause damage to healthy body cells.

There has therefore been no lack of attempts in the prior art to reduce the side effects of methylating compounds, in particular triazene compounds.

For example, describes the WO 2012/122969 A1 Triazene compounds for the treatment of cancer, which have a reduced toxicity to the commonly used substances.

In addition, research is also being conducted on natural substances, for example special benzophenone derivatives, which can be isolated from plants (eg. V. Kuete et al. "Cytotoxicity and modes of action of four naturally occurring benzophenones: 2,2 ', 5,6'-tetrahydroxybenzophenone, guttiferone E, isogarcinol and isoxanthochymol", Phytomedicine 20 (6), pages 528 to 536, 2013 ). A disadvantage of natural products, however, is that they are often contained in the corresponding biological materials only to a small extent or in varying amounts. An isolation of the substances is therefore often difficult or impossible and also leads regularly to non-reproducible results.

As a result, there continues to be a need for novel drugs for combating malignant tumors, which have an increased selective action against tumor cells and a reduced spectrum of side effects in comparison to the previously known medicaments.

Accordingly, it is an object of the present invention to substantially avoid or at least mitigate the problems associated with prior art chemotherapeutic agents.

In particular, it is an object of the present invention to provide novel chemical compounds which are suitable for use as chemotherapeutic agents and which are markedly less toxic, have a selective effect on tumor cells and have fewer side effects compared to the heretofore commonly used agents.

Moreover, it is a further object of the present invention to provide easily manageable and reproducible representable compounds which are useful as cytostatic agents.

To achieve the object described above, the present invention proposes a compound according to claim 1; Further advantageous embodiments are the subject of the relevant dependent claims.

Another object of the present invention is the use of the compounds of the invention according to claim 7.

In addition, another object of the present invention is a pharmaceutical composition according to claim 8.

Yet another subject of the present invention is a pharmaceutical combination according to claim 9.

Finally, another object of the present invention is a process for the preparation of the compounds according to the invention according to claim 10.

It goes without saying that in the following special embodiments, embodiments or the like, which are described only with reference to an aspect of the invention, also apply correspondingly in relation to the other aspects of the invention without this needing explicit mention.

Furthermore, it should be noted in all of the below-mentioned relative or percentage, in particular weight-based quantities, that they are to be selected within the scope of the present invention by a person skilled in the art such that in the sum of the respective ingredients, active ingredients, additives or auxiliaries or the like 100% and 100% by weight, respectively. This is understood by the skilled person but by itself.

Incidentally, the person skilled in the art may deviate from the number, range or quantity information given below, based on the application or the individual case, without departing from the scope of the present invention.

In addition, it is true that all parameters or the like mentioned below can basically be determined or determined using the standard or explicitly specified determination method or else determination methods familiar to the person skilled in the art.

Having said that, the subject of the present invention will now be described in detail.

wobei
X = einen Glucuronid-, Sulfat-, Triflat-, Tosylat-, Polyether-, Carboxy-, Hydroxyl-, Alkoxy- und/oder Aryloxyrest darstellt und
Y = einen stickstoffhaltigen Rest darstellt, insbesondere aufweisend eine chemische Gruppe ausgewählt aus Aminen, Amiden, Triazinen, Triazenen, Nitro und/oder Cyano,
und ihre physiologisch verträglichen Salze, Hydrate, Isomere, Derivate, Prodrugs und/oder Metabolite,
mit der Maßgabe, dass X kein Hydroxylrest ist, wenn Y ein Amin aufweist, und dass X kein Sulfat ist, wenn Y ein Triazen ist.The present invention - according to a first aspect of the present invention - is thus a compound, in particular a benzophenone derivative, of the general formula (I)

in which
X = a glucuronide, sulphate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy radical and
Y = a nitrogen-containing radical, in particular having a chemical group selected from amines, amides, triazines, triazenes, nitro and / or cyano,
and their physiologically acceptable salts, hydrates, isomers, derivatives, prodrugs and / or metabolites,
with the proviso that X is not hydroxyl when Y has an amine and X is not sulfate when Y is triazene.

In the context of the invention, a glucuronide radical is a glucuronic acid radical or its derivatives according to the following formula (1), which are bonded via a glycosidic bond to a molecule or a molecular radical:

For the purposes of the present invention, tosylates are esters of p-toluenesulfonic acid or its derivatives according to formula (2) below:

For the purposes of the present invention, triflates are esters of trifluorosulfonic acid or its derivatives according to the following formula (3):

For the purposes of the present invention, sulfates are esters of sulfuric acid or its derivatives according to the following formula (4):

Physiologically acceptable or harmless salts of the compound of general formula (I) may be, for example, salts with mineral acids, carboxylic acids or sulfonic acids; Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, Acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or else can be mentioned as physiologically acceptable or harmless salts organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or methylpiperidine.

The present invention also includes the hydrates of the compound of the general formulas (I). Hydrates according to the invention are those forms of the compound of the above general formula (I), which form a molecular compound (hydrate) in the solid or liquid state by hydration with water. In the hydrates, the hydrogen molecules are attached by intermolecular forces, especially hydrogen bonds. Solid hydrates contain water as so-called water of crystallization in stoichiometric or non-stoichiometric proportions, whereby the water molecules do not have to be equivalent in terms of their bonding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates, trihydrates, etc. Likewise, according to the invention, the hydrates of salts of the compound of the general formula (I) are also suitable.

The present invention also includes isomers of the compound of the general formula (I). The term isomers in the sense of the present invention is used as a comprehensive term for all possible forms of isomerism. Non-limiting examples of isomers encompassed by the present invention are, in particular, stereoisomers, tautomers and constitutional isomers.

As the Applicant has surprisingly found, the compounds of general formulas (I) are particularly suitable as cytostatic agents. The compounds according to the invention have a selective action against malignant tumors, in particular specific tumor cells, and have only a low cytotoxicity overall. The compounds according to the invention can consequently be administered in larger quantities over a relatively long period of time without harmful side effects occurring or at least not being observed in the quality of life of severely impairing extent.

The compound according to the invention is therefore particularly suitable as a chemotherapeutic agent in the medicinal treatment of malignant tumors.

In the context of the present invention, particularly good results are obtained when the groups X and Y are in the para position to the keto group. The compounds according to the invention are therefore preferably 4,4'-disubstituted benzophenone derivatives.

In the context of the present invention, it is generally provided that X is a glucuronide, sulfate, hydroxyl, C ₁ - to C ₂₀ -alkoxy, in particular C ₁ - to C ₁₅ -alkoxy, preferably C ₁ - to C ₁₀ - Alkoxy, and / or a phenoxy radical, in particular a glucuronide radical, a sulfate radical and / or a hydroxyl radical, preferably a glucuronide radical or a sulfate radical. Compounds of the general formula (I) having the abovementioned substituents, in particular hydroxyl and / or glucuronide and / or sulfate radicals, have an outstanding cytostatic action profile and effectively inhibit the growth of tumors, with glucuronides and sulfates in particular only a very small amount Possess cytotoxicity.

Moreover, it can be provided in the context of the present invention that Y is at least one amine of the formula -NR ¹ R ²
with R ¹ , R ² = C ₁ - to C ₂₀ -alkyl, C ₆ - to C ₂₀ -aryl and / or hydrogen, in particular C ₁ - to C ₁₀ -alkyl, C ₆ - to C ₁₅ -aryl and / or Is hydrogen, preferably C ₁ - to C ₅ -alkyl, C ₆ - to C ₁₀ -aryl and / or hydrogen, preferably C ₁ - to C ₃ -alkyl and / or hydrogen, particularly preferably hydrogen,
wherein R ¹ and R ^{2 are} each independently selected. Preferably, Y is an amine according to the aforementioned formula -NR ¹ R ² .

As the Applicant has surprisingly found, compounds of the general formula (I) with amine radicals have a cytostatic effect.

Similarly, it may be provided that Y is at least one amide of the formula -NR ³ C (O) OR ⁴
with R ³ = C ₁ - to C ₂₀ -alkyl, C ₆ - to C ₂₀ -aryl and / or hydrogen, in particular C ₁ - to C ₁₀ -alkyl, C ₆ - to C ₁₅ -aryl and / or hydrogen, preferably C ₁ - to C ₅ -alkyl, C ₆ - to C ₁₀ -aryl and / or hydrogen, preferably C ₁ - to C ₃ -alkyl and / or hydrogen, more preferably methyl and / or hydrogen, most preferably hydrogen; and
R ⁴ = C ₁ - to C ₂₀ -alkyl and / or C ₆ - to C ₂₀ -aryl, in particular C ₁ - to C ₁₀ -alkyl and / or C ₆ - to C ₁₅ -aryl, preferably C ₁ - to C _5- alkyl and / or C ₆ - to C ₁₀ -aryl, preferably C ₁ - to C ₃ -alkyl, more preferably methyl, and
having. Preferably, Y is an amide according to the aforementioned formula -NR ³ C (O) OR ⁴ .

Compounds of the general formula (I) which are obtained by reacting amines with short-chain carboxylic acids have excellent cytostatic properties.

In addition, it may be provided that Y has at least one triazine, in particular a 1,2,3-triazine, a 1,2,4-triazine and / or a 1,3,5-triazine. In this context, it may be provided that the triazine is monosubstituted or disubstituted, in particular with C ₁ - to C ₂₀ -alkyl and / or C ₆ - to C ₂₀ -aryl radicals, preferably C ₁ - to C ₁₀ -alkyl - and / or C ₆ - to C ₁₅ -aryl radicals, preferably C ₁ - to C ₅ -alkyl and / or C ₆ - to C ₁₀ -aryl radicals, particularly preferably C ₁ - to C ₃ -alkyl radicals.

Similarly, it may be provided in the context of the present invention that Y is at least one triazene of the formula -N = N-NR ⁵ R ⁶
with R ⁵ , R ⁶ = C ₁ - to C ₂₀ -alkyl, C ₆ - to C ₂₀ -aryl and / or hydrogen, in particular C ₁ - to C ₁₀ -alkyl, C ₆ - to C ₁₅ -aryl and / or Is hydrogen, preferably C ₁ - to C ₅ -alkyl, C ₆ - to C ₁₀ -aryl and / or hydrogen, preferably C ₁ - to C ₃ -alkyl and / or hydrogen, more preferably methyl,
wherein R ⁵ and R ^{6 are} independently selected from each other. Preferably, Y is one of the aforementioned triazenes according to the formula -N = N-NR ⁵ R ⁶ .

In the context of the present invention, in particular triazine derivatives are preferred since, in addition to the action of the other benzophenone derivatives, they are also capable of damaging tumor cells by alkylation, in particular methylation, of DNA. In addition, the triazine derivatives of the present invention are also capable of eliminating the repair mechanisms of the tumor cells so that they can not repair the DNA damage caused by the alkylation.

Furthermore, particularly good results are obtained when using amines. Surprisingly, it has been found that the amine-functional compounds according to the invention likewise have excellent cytostatic properties, their mode of action having hitherto still not been elucidated.

• (a) Aminen der Formel -NR¹R² mit R¹, R² = C₁- bis C₃-Alkyl und/oder Wasserstoff, insbesondere Wasserstoff; und/oder
• (b) Amiden der Formel -NR³C(O)OR⁴ mit R³ = C₁- bis C₃-Alkyl, insbesondere Methyl, und/oder Wasserstoff, vorzugsweise Wasserstoff, und R⁴ = C₁- bis C₃-Alkyl, insbesondere Methyl; und/oder
• (c) Triazenen der Formel -N=N-NR⁵R⁶ mit R⁵, R⁶ = C₁- bis C₃-Alkyl und/oder Wasserstoff, insbesondere Methyl,

darstellt, mit der Maßgabe, dass X kein Sulfat ist, wenn Y ein Triazen ist. Die Reste R¹ und R² sowie R⁵ und R⁶ sind dabei jeweils unabhängig voneinander auszuwählen. Im Rahmen der vorliegenden Erfindung hat es sich gezeigt, dass Derivate mit Glucuroniden und Sulfaten einerseits eine besonders gute Wirksamkeit aufweisen, andererseits jedoch nur eine äußerst geringe Zytotoxizität besitzen.In the context of the present invention, it has been found that X is a glucuronide radical and / or a sulfate radical and Y is a chemical group selected from

• (a) amines of the formula -NR ¹ R ² where R ¹ , R ² = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular hydrogen; and or
• (b) amides of the formula -NR ³ C (O) OR ⁴ where R ³ = C ₁ - to C ₃ -alkyl, in particular methyl, and / or hydrogen, preferably hydrogen, and R ⁴ = C ₁ - to C ₃ - Alkyl, especially methyl; and or
• (c) triazenes of the formula -N = N-NR ⁵ R ⁶ with R ⁵ , R ⁶ = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular methyl,

with the proviso that X is not sulfate when Y is a triazene. The radicals R ¹ and R ² and R ⁵ and R ⁶ are each independently selectable. In the context of the present invention, it has been found that derivatives with glucuronides and sulfates, on the one hand, have a particularly good activity but, on the other hand, have only an extremely low cytotoxicity.

• (a) Aminen der Formel -NR¹R² mit R¹, R² = C₁- bis C₃-Alkyl und/oder Wasserstoff, insbesondere Wasserstoff; und/oder
• (b) Amiden der Formel -NR³C(O)OR⁴ mit R³ = C₁- bis C₃-Alkyl, insbesondere Methyl, und/oder Wasserstoff, vorzugsweise Wasserstoff, und R⁴ = C₁- bis C₃-Alkyl, insbesondere Methyl; und/oder
• (c) Triazenen der Formel -N=N-NR⁵R⁶ mit R⁵, R⁶ = C₁- bis C₃-Alkyl und/oder Wasserstoff, insbesondere Methyl,

darstellt. Die Reste R¹ und R² sowie R⁵ und R⁶ sind dabei jeweils unabhängig voneinander auszuwählen. Im Rahmen der vorliegenden Erfindung hat es sich gezeigt, dass Derivate mit Glucuroniden einerseits eine besonders gute Wirksamkeit aufweisen, andererseits jedoch nur eine äußerst geringe Zytotoxizität besitzen.In the context of the present invention, it is furthermore preferred if X is a glucuronide radical and Y is a chemical group selected from

• (a) amines of the formula -NR ¹ R ² where R ¹ , R ² = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular hydrogen; and or
• (b) amides of the formula -NR ³ C (O) OR ⁴ where R ³ = C ₁ - to C ₃ -alkyl, in particular methyl, and / or hydrogen, preferably hydrogen, and R ⁴ = C ₁ - to C ₃ - Alkyl, especially methyl; and or
• (c) triazenes of the formula -N = N-NR ⁵ R ⁶ with R ⁵ , R ⁶ = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular methyl,

represents. The radicals R ¹ and R ² and R ⁵ and R ⁶ are each independently selectable. In the context of the present invention it has been shown that derivatives with glucuronides on the one hand have a particularly good activity, but on the other hand possess only an extremely low cytotoxicity.

In the context of the present invention preferred compounds can thus be described by the general formula (Ia), wherein Y corresponds to the substituent defined above:

Likewise, particularly good results are obtained when X is a sulfate radical and Y is a chemical group selected from amines of the formula -NR ¹ R ² with R ¹ , R ² = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular hydrogen, represents. The radicals R ¹ and R ² are each independently selectable.

Also preferred according to the invention compounds can be described by the general formula (Ib), wherein Y corresponds to the previously defined amines:

mit R⁵, R⁶ = C₁- bis C₃-Alkyl und/oder Wasserstoff, insbesondere Methyl,
und ihre Salze, Hydrate, Isomere, insbesondere Konstitutionsisomere, Tautomere und Stereoisomere, Derivate, Prodrugs und/oder Metabolite beschrieben.According to a preferred embodiment of the present invention, the compound is represented by the general formula (II)

with R ⁵ , R ⁶ = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular methyl,
and their salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and / or metabolites.

und ihre Salze, Hydrate, Isomere, insbesondere Konstitutionsisomere, Tautomere und Stereoisomere, Derivate, Prodrugs und/oder Metabolite beschrieben wird. Bei dieser erfindungsgemäß bevorzugten Verbindung handelt es somit um 4-(3,3-Dimethyltriazenyl)-4'-(β-D-glucuronyl)-benzophenon.In the context of the present invention, it is therefore particularly preferred if the compound is represented by the formula (III)

and their salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and / or metabolites is described. Thus, this preferred compound of the invention is 4- (3,3-dimethyltriazenyl) -4 '- (β-D-glucuronyl) benzophenone.

mit R¹, R² = C₁- bis C₃-Alkyl und/oder Wasserstoff, insbesondere Methyl,
und ihre Salze, Hydrate, Isomere, insbesondere Konstitutionsisomere, Tautomere und Stereoisomere, Derivate, Prodrugs und/oder Metabolite definiert wird. Likewise, particularly good results are obtained when the compound is represented by the formula (IV)

with R ¹ , R ² = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular methyl,
and their salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and / or metabolites is defined.

und ihre Salze, Hydrate, Isomere, insbesondere Konstitutionsisomere, Tautomere und Stereoisomere, Derivate, Prodrugs und/oder Metabolite definiert wird.In this context, it has proven useful when compound through the formula (V)

and their salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and / or metabolites is defined.

und ihre Salze, Hydrate, Isomere, insbesondere Konstitutionsisomere, Tautomere und Stereoisomere, Derivate, Prodrugs und/oder Metabolite beschrieben wird.In addition, particularly good results are obtained when the compound is represented by the formula (VI)

and their salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and / or metabolites is described.

The aforementioned compound and / or its physiologically acceptable salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and metabolites can be used for the prophylactic and / or therapeutic treatment of diseases.

In addition, the compound described above and / or its physiologically acceptable salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and metabolites can be used as pharmaceutical active ingredients and / or pharmaceutically active pharmaceutical ingredients.

According to a preferred embodiment of the present invention, the present invention relates to the previously defined compound and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites for use in the prophylactic and / or therapeutic treatment of Tumors and / or cancers, in particular primary tumors and metastases, and / or precancerous conditions, especially of colon cancer, breast cancer, ovarian carcinoma, uterine carcinoma, lung cancer, stomach cancer, liver cancer, pancreatic carcinoma, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, bone cancer, skin cancer, Kaposi's sarcoma, brain tumors, myosarcomas, neuroblastomas, lymphomas and leukemias.

According to a further embodiment of the present invention, the compound according to the invention, as defined above, or its physiologically tolerated salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites for systemic and / or topical application is provided.

In the context of the present invention it can be provided that the compound according to the invention or its physiologically tolerated salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites in a dosage of 20 to 1500 mg / (kg · d ), in particular 50 to 1200 mg / (kg · d), preferably 70 to 1000 mg / (kg · d), preferably 100 to 800 mg, particularly preferably 200 to 700 mg / (kg · d), in each case based on body weight of the treated individual. It is a peculiarity of the compound according to the invention that it can be administered in high doses without the occurrence of undesirable side effects.

Likewise it can be provided in the context of the present invention that the compound according to the invention is applied without interruption for a period of 3 to 52 weeks, in particular 5 to 40 weeks, preferably 8 to 30 weeks. It also shows again that the use according to the invention has only a low cytotoxicity.

Another object of the present invention - according to a second aspect of the present invention - is the use of the above-described compound and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitution isomers, derivatives, prodrugs and metabolites for prophylactic and / or therapeutic treatment of tumors and / or cancers.

In this context, it may be provided that the compound according to the invention is used for the prophylactic and / or therapeutic treatment of tumors and / or cancers, in particular primary tumors and metastases, and / or precancerous lesions (precancerous lesions).

Likewise, the use described above can be for the prophylactic and / or therapeutic treatment of benign and malignant tumors.

In the context of the present invention, it is preferred if the use for the prophylactic and / or therapeutic treatment of colon cancer (colon carcinoma), breast cancer (breast cancer), ovarian carcinoma, uterine carcinoma, lung cancer, gastric cancer, liver cancer, pancreatic carcinoma, kidney cancer, bladder cancer, prostate cancer, testicular cancer, Bone cancer, skin cancer, Kaposi's sarcoma, brain tumors, myosarcomas, neuroblastomas, lymphomas and leukemias occurs.

In the context of the present invention, particularly good results are obtained when the previously defined compound and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites are administered systemically and / or topically.

Likewise, it has been found that the compounds of general formula (I) as defined above and / or their physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites are used in such a way that cell growth and cell division of tumor and / or cancer cells is inhibited and / or arrested.

In addition, the use according to the invention can be carried out in such a way that the compound described above and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites induce destruction of the DNA of the tumor and / or cancer cells ,

For further details on the use according to the invention, reference may be made to the preceding statements relating to the compound according to the invention, which apply correspondingly in relation to the use according to the invention.

Yet another object of the present invention - according to a third aspect of the present invention - is a pharmaceutical composition or a pharmaceutical, in particular tumor therapeutic, containing the compound described above and / or their physiologically acceptable Salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and metabolites together with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

For the purposes of the present invention, it is customary for the pharmaceutical composition to contain the previously defined compound and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites in therapeutically effective amounts.

Usually, it is provided in the context of the present invention that the pharmaceutical composition or the medicament is intended for systemic and / or topical application.

For further details of the pharmaceutical composition according to the invention, reference may be made to the preceding statements relating to the other aspects of the invention, which apply correspondingly with respect to the pharmaceutical composition according to the invention.

• (A) die zuvor beschriebene erfindungsgemäße Verbindung und/oder ihre physiologisch verträglichen Salze, Hydrate, Isomere, insbesondere Stereoisomere, Tautomere und Konstitutionsisomere, Derivate, Prodrugs und Metabolite; und
• (B) mindestens ein weiteres Chemotherapeutikum, insbesondere einen Proteinkinaseinhibitor, vorzugsweise MAP-Kinase-Inhibitor,

umfasst.Yet another object of the present invention - according to a fourth aspect of the present invention is a pharmaceutical combination, the

• (A) the compound of the invention described above and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites; and
• (B) at least one further chemotherapeutic agent, in particular a protein kinase inhibitor, preferably MAP kinase inhibitor,

includes.

Adriamycin, bleomycin, vinblastine, dacarbazine, cyclophophamide, etoposide, methotrexate, 5-fluorouracil, mitomycin, cisplatin, docetaxel, tamoxifen, epirubicin and / or Herceptin can in particular be used as chemotherapeutic agent in the context of the present invention.

For further details of the pharmaceutical combination according to the invention, reference may be made to the preceding statements relating to the other aspects of the invention, which apply correspondingly in relation to the pharmaceutical combination according to the invention.

• (A) die zuvor beschriebene erfindungsgemäße Verbindung und/oder ihre physiologisch verträglichen Salze, Hydrate, Isomere, insbesondere Stereoisomere, Tautomere und Konstitutionsisomere, Derivate, Prodrugs und Metabolite; und
• (B) mindestens einen Antikörper, insbesondere einen monoklonalen Antikörper, umfasst, insbesondere wobei die erfindungsgemäße Verbindung an den monoklonalen Antikörper gebunden ist.

Yet another aspect of the present invention is a pharmaceutical combination which

• (A) the compound of the invention described above and / or its physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites; and
• (B) at least one antibody, in particular a monoclonal antibody comprises, in particular wherein the compound of the invention is bound to the monoclonal antibody.

The binding of the previously defined compound to an antibody makes it possible to work at significantly lower doses during chemotherapy since the drug is selectively introduced into the tumor cell. In addition, binding to an antibody also allows for the use of higher dosages of compounds with some cytotoxicity since they do not come into contact with the healthy tissue.

For further details of the pharmaceutical combination according to the invention, reference may be made to the preceding statements relating to the other aspects of the invention, which apply correspondingly to the pharmaceutical combination according to the invention which comprises an antibody.

mit
X = Glucuronid-, Sulfat-, Triflat-, Tosylat-, Polyether-, Carboxy-, Hydroxyl, Alkoxy- und/oder Aryloxyrest
zu einem Amin der allgemeinen Formel (VIII)

mit
X = Glucuronid-, Sulfat-, Triflat-, Tosylat-, Polyether-, Carboxy-, Hydroxyl-, Alkoxy- und/oder Aryloxyrest
umgesetzt wird.Finally, another object of the present invention - according to a fifth aspect of the present invention - a process for preparing a compound as defined above, in particular a compound according to the general formula (I), wherein a nitro compound of the general formula (VII)

With
X = glucuronide, sulfate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy
to an amine of the general formula (VIII)

With
X = glucuronide, sulfate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy
is implemented.

According to a preferred embodiment, it is provided that in the general formulas (VII) and (VIII) X is a glucuronide, sulfate, hydroxyl, C ₁ - to C ₂₀ -alkoxy, in particular C ₁ - to C ₁₅ -alkoxy -, Preferably C ₁ - to C ₁₀ alkoxy, and / or a phenoxy radical, in particular a Glucuronidrest, a sulfate radical and / or a hydroxyl radical, preferably a Glucuronidrest and / or a sulfate radical is.

In the context of the present invention, it has proven useful to carry out the reaction of the nitro compound to the amine by hydrogenation, in particular by transition metal-catalyzed hydrogenation.

In the context of the present invention, it is often sufficient to operate the synthesis of the compound according to the invention only up to compounds of the general formula (VIII), since the amines of the general formula (VIII) are cytotoxic and have a tumor growth-inhibiting activity profile. When a compound of general formula (VIII) is to be used as a cytostatic, X is not a hydroxy group; Amines of the general formula (VIII) correspond to compounds of the general formula (I).

In the context of the present invention, however, it may be provided that in a subsequent process step, the amine of the general formula (VIII) is converted by reaction of the amine group into another nitrogen-containing compound, in particular an amide, a triazine and / or a triazene. In the context of the present invention, particularly good results are obtained when the amine is converted to a compound according to the general formula (I) as defined above.

• (a) in einem ersten Verfahrensschritt eine Nitroverbindung der allgemeinen Formel (VII)
  
  mit X = Glucuronid-, Sulfat-, Triflat-, Tosylat-, Polyether-, Carboxy-, Hydroxyl-, Alkoxy- und/oder Aryloxyrest zu einem Amin der allgemeinen Formel (VIII)
  
  mit X = Glucuronid-, Sulfat-, Triflat-, Tosylat-, Polyether-, Carboxy-, Hydroxyl-, Alkoxy- und/oder Aryloxyrest umgesetzt wird und
• (b) in einem nachfolgenden Verfahrensschritt das in Verfahrensschritt (a) erhaltene Amin durch Reaktion der Amingruppe in eine weitere stickstoffhaltige Verbindung, insbesondere ein Amid, ein Triazin und/oder ein Triazen, überführt wird.

According to a further aspect of the present invention, the present invention relates in particular to a process for preparing a compound according to the invention, in particular a compound according to the general formula (I), in particular according to the process described above, wherein

• (a) in a first process step, a nitro compound of the general formula (VII)
  
  with X = glucuronide, sulphate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy radical to give an amine of the general formula (VIII)
  
  with X = glucuronide, sulfate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy is reacted and
• (b) in a subsequent process step, the amine obtained in process step (a) is converted by reaction of the amine group into another nitrogen-containing compound, in particular an amide, a triazine and / or a triazene.

In this context, it may be provided that the process steps (a) and (b) either follow one another directly or that there are further process steps in between, in particular if protective groups are used during the synthesis, for example to protect hydroxyl groups. The protecting groups can be removed prior to the reaction of the amine according to the general formula (VIII) to form further nitrogen-containing compounds.

For further details regarding the methods according to the invention, reference may be made to the preceding statements relating to the further aspects of the invention, which apply correspondingly in relation to the method according to the invention.

Further advantages, features, properties and aspects of the present invention will become apparent from the attached figure representation, which also refers to the embodiments carried out according to the invention. It shows:

1 a study of the DNA damage by the compounds according to the invention 4- (3,3-dimethyltriazenyl) -4 '- (β-D-glucuronyl) benzophenone (A), 4- (3,3-dimethyltriazenyl) -4'- hydroxy-benzophenone (B), 4-amino-4 '- (β-D-glucuronyl) -benzophenone (C) and 4-amino-4'-sulfato-benzophenone (D) compared to the equally alkylating reagent N-methyl -N'-nitro-N-nitrosoguanidine (MNNG) on Chinese ovary hamster cells (CHO-9, MGMT-minus; right column in FIG 1 ) compared to an isogenic cell line with an intact MGMT repair system (MGMT-plus, left column in FIG 1 ).

The object of the present invention is illustrated below by way of example by the exemplary embodiments, which, however, do not limit the subject matter of the present invention.

embodiments

I. Synthesis of compounds of the invention

Preparation of 4- (3,3-dimethyltriazenyl) -4 '- (β-D-glucuronyl) benzophenone

a) Synthesis of 4-nitro-4'-hydroxy-benzophenone 2

A solution of 4-nitro-4'-methoxy-benzophenone 1 (75 g, 0.29 mol), 250 mL of glacial acetic acid and hydrobromic acid (40% solution, 200 mL) is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature and poured onto ice. The filtered crude product is washed several times with water and dried at about 50 ° C in a vacuum. The crude product is recrystallized from ethyl acetate / hexane. There are obtained 58 g (0.24 mol) of 4-nitro-4'-hydroxy-benzophenone 2 (yield: 83%). b) Synthesis of 4-nitro-4 '- (methyl-2,3,4-tri-O-acetyl-β-D-glucuronyl) benzophenone 3

A mixture of 4-nitro-4'-hydroxybenzophenone 2 (25 g, 0.10 mol) and 1-bromo-2,3,4-tri-O-acetyl-glucuronide methyl ester (40 g, 0.10 mol) in anhydrous acetonitrile are stirred with 24 g (0.10 mol) of freshly precipitated silver oxide for 30 minutes at room temperature. 50 ml of ethyl acetate are added and the solid is removed by filtration. The organic phase is washed with 1 M sodium hydroxide solution and water until neutral to pH and then dried over magnesium sulfate. After removal of the solvent under reduced pressure, the resulting oil is crystallized from ethyl ether and then recrystallized with methanol. There are obtained 35 g (0.6 mmol) of 4-nitro-4 '- (methyl-2,3,4-tri-O-acetyl-β-D-glucuronyl) benzophenone 3 (yield: 65%). c) Preparation of 4-amino-4 '- (methyl-2,3,4-tri-O-acetyl-β-D-glucuronyl) benzophenone 4

9.0 g (17 mmol) of 4-nitro-4 '- (methyl-2,3,4-tri-O-acetyl-β-D-glucuronyl) benzophenone 3 are mixed with a 10% by weight mixture of palladium in carbon (0.7 g) in 200 ml of methanol under a hydrogen atmosphere overnight. The reaction mixture is filtered through Zelite and the solvent removed in vacuo. There are obtained 7.8 g (15 mmol) of the product 4 (yield: 88%). d) Preparation of 4-amino-4 '- (β-D-glucuronyl) benzophenone 5

6.0 g (11 mmol) of the product 4 obtained in step c) are dissolved in 100 ml of methanol and stirred with a 3 molar solution of sodium ethoxylate in methanol (1.0 ml) for two hours at room temperature. The solution is then mixed with Amberlite IR-120 cation exchanger, stirred for one hour and then filtered off the ion exchange resin again. The filtrate is concentrated in vacuo to dryness and the residue is crystallized from ethanol. 3.8 g (10 mmol) of product 5 are obtained (yield: 91%). e) Preparation of 4- (3,3-dimethyltriazenyl) -4 '- (β-D-glucuronyl) benzophenone 6

To a suspension of 2.5 g (6 mmol) of product 5 contained in step d) in 40 ml of water is added 15 ml of concentrated hydrochloric acid. The resulting suspension is cooled to 0 to 5 ° C. by means of an ice bath and a solution of 0.62 g (9 mmol) of sodium nitrite in 2 ml of water is added dropwise over a period of 20 minutes so that the temperature does not rise above 10 ° C. , The resulting yellowish suspension is stirred for a further 30 minutes at 0 to 5 ° C and then added at 0 ° C with vigorous stirring within 20 minutes to a 40% solution of dimethylamine in water (10 ml), likewise a yellowish Suspension is obtained. The reaction mixture is extracted four times with 1 ml of chloroform and the resulting organic phase dried over magnesium sulfate. After filtration, the solvent is removed in vacuo. The resulting solid is washed with ethyl acetate and then recrystallized from ethanol. There are obtained 0.9 g (2 mmol) of the target Compound 6 (yield 35%).

II. Application Tests

Subsequently, the compounds 4- (3,3-dimethyltriazenyl) -4 '- (β-D-glucuronyl) benzophenone A, 4- (3,3-dimethyltriazenyl) -4'-hydroxy-benzophenone B, 4-amino-4 '- (β-D-glucuronyl) benzophenone C and 4-amino-4'-sulfato-benzophenone D tested for their cytotoxicity and their activity against tumor cells. It is currently assumed that B, C are also D metabolites of A.

1. SRB cytotoxicity testing

For the determination of the in vitro cytotoxic activity (IC 50 values) of the compounds A, B, C and D according to the invention and for the investigation of the concentration-dependent influence on the cell proliferation, a colorimetric method ( Skehan et. al., 1990 ) with sulforhodamine B ("SRB").

Under acid conditions, the rhodamine dye interacts with cellular proteins. This bond is reversible by increasing the pH. The number of viable cells is proportional to the amount of protein content or amount of bound dye.

The cells were incubated under 5% CO ₂ atmosphere at 37 ° C. Stock solutions of drugs were prepared in DMSO at concentrations of 0.001-3000 mM. In parallel, DMSO controls and cell-free "blanks" were tested under the same conditions to determine background absorption.

100 microliters of corresponding preparation dilutions were added to the cells in microtiter plates. The preparation solutions worked on the cells for 24 hours. Thereafter, they were replaced by 200 microliters of fresh growth medium. The blank controls were also treated identically to determine the protein content as a background value. For a further 48 hours, the cell cultures were incubated (37 ° C / 5% CO ₂ ) to recover from exposure to the compounds of the invention. After this "recovery phase", the growth medium was removed and 50 microliters of ice-cold trichloroacetic acid was added to fix the cells or the blank controls for 1 hour at 4 ° C in the same way.

Thereafter, the cells were washed twice in distilled water. The cells were stained with 0.4% SRB solution (1% acetic acid) for 30 minutes. Unbound dye was then removed. By adding 150 microliters of TRIS-HCl buffer (pH 10.45), the protein-dye complex was released and sulforhodamine B was dissolved in TRIS-HCl buffer. Thereafter, the absorbance was evaluated in a GENIOS plate reader at a wavelength of 565 nm. The mean values of the blank controls were subtracted from the measured values to avoid background absorption.

The absorbance of the growth controls was set as 100% and measured relative to the treated samples. The IC 50 values were calculated using a Sigmastat program and adjusting the values to a Hill function. As a reference (positive control), the known cytotoxic agents dacarbazine and temozolomide were used.

The results are summarized in Table 1 below. It can be seen that compound A, C and D have only a very low in vitro cytotoxicity compared to the reference substances, while compound B has a comparable or even higher in vitro cytotoxicity to the reference substances.

2. DNA repair testing

DNA damage caused by alkylating agents (eg, MNNG: N-methyl-N'-nitrosoguanidine) can be restored by certain cellular repair systems (eg, MGMT: O-6-methylguanine DNA methyltransferase) , ( Knizhnik et al, PLOS: Vol 8: Issue 1; e55665: 2013 ).

Chinese ovary hamster cells (CHO-9; MGMT-minus) were studied compared to an isogenic cell line that has an intact repair system (MGMT-plus). The cells were grown under standard culture conditions. MNNG, a strong DNA-alkylating agent, was used as the reference and compared to the compounds of the present invention at various concentrations corresponding to equivalence toxicities calculated from IC50 values.

Twenty-four hours after the beginning of cell culture growth, the test compounds were added and the viability of the cells was determined at various times. In this test, only the compounds A and B according to the invention were investigated, since only these act alkylating.

The results are in 1 shown.

It was surprisingly found that CHO cells possessing an intact repair system (MGMT-positive) were able to re-suspend DNA damage caused by MNNG damage to the DNA or to repair the damage and restore its viability.

In contrast, CHO cells possessing an intact repair system (MGMT positive), under the action of Compounds A and B of the present invention, were unable to repair the damage to the DNA caused even in the presence of a repair system. As a result of this mode of action, the cells lost their viability under the injurious effect of the compounds of the invention.

3. Animal experiment: tumor model of the rat

The experiments were performed on female Wistar or Sprague-Dawley rats. The animals were kept under standard light and temperature control conditions. They received water and food ad libitum.

The mammary tumors to be treated were produced by repeated benzidine administration (cancerogen) ( Steinhoff; Natural Sciences 61 (1974), 276 ), where the mammary tumors formed after 190 days. The mean life expectancy of the benzidine-treated rats was 365 days. After first tumors (0.5 g) had formed, benzidine was no longer added. Thereafter, rapid tumor growth set in.

The animals were divided into treatment and control groups on the basis of the tumor weights (randomized). Group sizes from 2 to 5 animals were used, based on the number of individual tumors per animal. As a rule, tumor growth and treatment outcome in 2 to 5 animals were evaluated in each group. Occasionally, the treatment outcome was also tracked on individual animals. The effect was calculated as T / C value and compared to the untreated control.

The substances were dissolved as salts dissolved in water administered subcutaneously 5 days a week.

The reference substance used was the cytostatic known 1-phenyl-3,3-dimethyltriazene ( Proc. Soc. exper. Biol. Med. 90, 484 (1955)

The results are shown in Table 2 below. The data in Table 2 show that after an initial increase or later decrease in the T / C value, the values remain constant and are significantly lower than those of the untreated growth control (test tumor). After prolonged treatment (> 30 days) necrosis / oncolysis of the tumor was observed. The claimed compounds thus have a tumor-growth-inhibiting activity compared to untreated control tumors and a pronounced oncocidal effect in the late stage of breast cancer of the rat. Table 2: Results of the rat model Day 0 Day 10 Day 20 Day 30 test tumor Weight [g] 0.5 7.5 11.5 7.5 Reference ¹ T / C 1.1 2 5 7.5 A ² T / C 0.6 3.6 3.8 3.5 B ³ T / C 0.5 3.5 5.8 6.8 C ⁴ T / C 0.7 4.8 6.0 7.2 D ⁵ T / C 0.5 5.3 4.5 5.8 ¹ dose: 100 mg / kg
² dose: 400 mg / kg
³ dose: 100 mg / kg
⁴ dose: 300 mg / kg
⁵ dose: 250 mg / kg

4. Result

It has been found that both the compounds A and C and the compounds B and D are active against an in vivo-generated tumor in the animal model and lead to a growth inhibition or a necrosis or oncolysis of the tumor. It is surprising that the compound A, C and D have no pronounced general / nonspecific cytotoxicity, but rather is almost nontoxic, while compound B has a not inconsiderable cytotoxicity. It is currently believed that, as stated above, B is a metabolite of A and C and D, respectively, which is selectively converted to B in tumor cells, as there has been no adverse effect on healthy cells when A, C or D is given was observed.

The compounds of the invention, in particular the compound A, C and D is therefore suitable because of their good compatibility in an excellent manner as a therapeutic agent for the treatment of malignant tumors, since the compound can be administered in high doses over a long period of time, without adverse effects on the Entire organism - as with classical chemotherapeutic agents - are observed or are to be feared. Rather, tumor cells are selectively damaged.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2012/122969 A1 [0013]

Cited non-patent literature

• V. Kuete et al. "Cytotoxicity and modes of action of four naturally occuring benzophenones: 2,2 ', 5,6'-tetrahydroxybenzophenone, guttiferone E, isogarcinol and isoxanthochymol", Phytomedicine 20 (6), pages 528 to 536, 2013 [0014]
• Skehan et. al., 1990 [0100]
• Knizhnik et al, PLOS: Vol 8: Issue 1; e55665: 2013 [0107]
• Steinhoff; Natural Sciences 61 (1974), 276 [0114]
• Proc. Soc. exper. Biol. Med. 90, 484 (1955) [0117]

Claims (10)

Compound, in particular benzophenone derivative, of the general formula (I)

where X = a glucuronide, sulfate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy radical and Y = a nitrogen-containing radical, in particular having a chemical group selected from amines, amides , Triazines, triazenes, nitro and / or cyano, and their physiologically acceptable salts, hydrates, isomers, derivatives, prodrugs and / or metabolites, with the proviso that X is not hydroxyl when Y has an amine and X is not sulfate is when Y has a triazene. A compound according to claim 1, characterized in that X is a glucuronide, sulfate, hydroxyl, C ₁ - to C ₂₀ -alkoxy, in particular C ₁ - to C ₁₅ -alkoxy, preferably C ₁ - to C ₁₀ -alkoxy -, and / or a phenoxy radical, in particular a glucuronide radical, a sulfate radical and / or a hydroxyl radical, preferably a glucuronide radical or a sulfate radical. A compound according to claim 1 or 2, characterized in that Y is at least one amine of the formula -NR ¹ R ² with R ¹ , R ² = C ₁ - to C ₂₀ -alkyl, C ₆ - to C ₂₀ -aryl and / or hydrogen , in particular C ₁ - to C ₁₀ -alkyl, C ₆ - to C ₁₅ -aryl and / or hydrogen, preferably C ₁ - to C ₅ -alkyl, C ₆ - to C ₁₀ -aryl and / or hydrogen, preferably C ₁ - to C ₃ alkyl and / or hydrogen, more preferably hydrogen, wherein R ¹ and R ^{2 are the} same or different, and / or that Y is at least one amide of the formula -NR ³ C (O) OR ⁴ with R ³ = C ₁ - to C ₂₀ -alkyl, C ₆ - to C ₂₀ -aryl and / or hydrogen, in particular C ₁ - to C ₁₀ -alkyl, C ₆ - to C ₁₅ -aryl and / or hydrogen, preferably C ₁ - to C ₅ alkyl, C ₆ - to C ₁₀ aryl and / or hydrogen, preferably C ₁ - to C ₃ alkyl and / or hydrogen, more preferably methyl and / or hydrogen, most preferably hydrogen, and R ⁴ = C ₁ - to C ₂₀ -alkyl and / or C ₆ - to C ₂₀ -aryl, in particular C ₁ to C ₁₀ alkyl and / or C ₆ to C ₁₅ aryl, preferably C ₁ to C ₅ alkyl and / or C ₆ to C ₁₀ aryl, preferably C ₁ to C ₃ alkyl , particularly preferably methyl, and / or that Y has at least one triazine, in particular a 1,2,3-triazine, a 1,2,4-triazine and / or a 1,3,5-triazine, optionally a or monosubstituted with C ₁ - to C ₂₀ -alkyl and / or C ₆ - to C ₂₀ -aryl radicals, in particular C ₁ - to C ₁₀ -alkyl- and / or C ₆ - to C ₁₅ -aryl radicals, preferably C ₁ - to C ₅ -alkyl and / or C ₆ - to C ₁₀ -aryl radicals, preferably C ₁ - to C ₃ -alkyl radicals, and / or Y is at least one triazene of the formula -N = N-NR ⁵ R ⁶ with R ⁵ , R ⁶ = C ₁ - to C ₂₀ -alkyl, C ₆ - to C ₂₀ -aryl and / or hydrogen, in particular C ₁ - to C ₁₀ -alkyl, C ₆ - to C ₁₅ -aryl and / or hydrogen, preferably C ₁ - to C ₅ -alkyl, C ₆ - to C ₁₀ -aryl and / or hydrogen, preferably C ₁ - to C ₃ -alkyl and / or hydrogen, more preferably methyl wherein R ⁵ and R ^{6 are the} same or different. Compound according to one of the preceding claims, characterized in that X is a glucuronide radical and / or a sulfate radical and Y is a chemical group selected from (a) amines of the formula -NR ¹ R ² where R ¹ , R ^{2 are} each independently of one another = C C ₁ - to C ₃ -alkyl and / or hydrogen, in particular hydrogen; and / or (b) amides of the formula -NR ³ C (O) OR ⁴ where R ³ = C ₁ - to C ₃ -alkyl, in particular methyl, and / or hydrogen, preferably hydrogen, and R ⁴ = C ₁ - to C ₃ alkyl, in particular methyl; and / or (c) triazenes of the formula -N = N-NR ⁵ R ⁶ where R ⁵ , R ^{6 are} each independently of the other = C ₁ - to C ₃ -alkyl and / or hydrogen, in particular methyl, with the proviso in that X is not a sulfate when Y is a triazene. A compound according to any one of claims 1 to 4 and / or its physiologically acceptable salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and metabolites for use in the prophylactic and / or therapeutic treatment of diseases. Compound according to one of the preceding claims and / or its physiologically tolerated salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites, characterized in that the compound in a dosage of 20 to 1500 mg / (kg · d ), in particular 50 to 1200 mg / (kg · d), preferably 70 to 1000 mg / (kg · d), preferably 100 to 800 mg / (kg · d), particularly preferably 200 to 700 mg / (kg · d) , in each case based on the body weight of the treated individual, is applied. Use of the compound according to one of claims 1 to 4 and / or its physiologically tolerated salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites for the prophylactic and / or therapeutic treatment of tumors and / or cancers. Pharmaceutical composition or pharmaceutical, in particular anticancer drug, containing the compound according to any one of claims 1 to 4 and / or its physiologically acceptable salts, hydrates, isomers, especially constitutional isomers, tautomers and stereoisomers, derivatives, prodrugs and metabolites together with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. Pharmaceutical combination, the (A) the compound according to any one of claims 1 to 4 and / or their physiologically acceptable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites; and (B) at least one further chemotherapeutic agent, in particular a protein kinase inhibitor, preferably MAP kinase inhibitor, includes. A process for the preparation of a compound according to any one of claims 1 to 4, in particular a compound according to the general formula (I), characterized in that a nitro compound of the general formula (VII)

with X = glucuronide, sulphate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy radical to give an amine of the general formula (VIII)

with X = glucuronide, sulfate, triflate, tosylate, polyether, carboxy, hydroxyl, alkoxy and / or aryloxy.

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