RU2473562C2 - Conjugates of disorazol, based pharmaceutical compositions, said conjugates for preparing drug, kit and method for preparing them - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to conjugates of Disorazol with cell adhesion molecules, such as peptides, proteins, hormones, blood proteins, and methods for preparing conjugates.

EFFECT: conjugates of Disorazol may be used as drug preparations for treating various tumours.

19 cl, 17 dwg, 2 tbl, 17 ex

Description

FIELD OF THE INVENTION

The invention relates to conjugates of disrazoles and their derivatives with molecules that bind cells, such as peptides and proteins, as well as to new disrazole derivatives and methods for their preparation. These compounds can be used as drugs, in particular for the treatment of various tumors.

State of the art

Over the next few years, a sharp increase in the level of oncogenesis and tumor-related deaths is expected around the world. In 2001, around 10 million people worldwide suffered from cancer and more than 6 million people died from the disease. The development of tumors is the main disease of higher organisms in the plant kingdom, in the animal kingdom and in humans. In general, the recognized multistage model of carcinogenesis suggests that as a result of the accumulation of a number of mutations in an individual cell, it is so modified in the behavior of proliferation and differentiation that, finally, through a benign intermediate stage, a malignant state with metastases is achieved.

The term cancer or tumor includes the clinical picture of more than two hundred different independent diseases. Oncogenesis can occur in a benign or malignant manner. The most important tumors are tumors of the lung, breast, stomach, cervix, prostate, head and neck, colon and small intestine, liver and circulatory system. There is a big difference in terms of course, prognosis and response to treatment. More than 90% of the cases identified are solid tumors, which, in particular, at the advanced stage or at the stage of metastasis are difficult to cure or are incurable. The three main principles of cancer control so far are surgical removal, radiation and chemotherapy. Despite the great advantages, to date it has not been possible to develop drugs that lead to a marked increase in survival time or even complete cure for widespread solid tumors. As a consequence, the invention of new drugs for the fight against cancer is of great importance.

Natural substances represent an important source of promising new structures in pharmaceutical research and, in some cases, are also directly suitable for creating a new drug (see Shu Y, J. Nat. Prod. 1998, 61: 1053-1071). Many natural substances are known to have strong cytotoxic effects (see Ram VJ et al., Drug News Perspect 2001, 14 (8): 465-482).

Natural substances of the group consisting of disrazoles are known to be isolated from the bacterial strain Sorangium cellulosum So ce12 (see Jansen R et al., Liebigs Ann. Chem. 1994, (8): 759-773).

In total, 29 disrazoles were isolated and physicochemically characterized. For disrazole A1, it has been shown to have antiproliferative effects in cell models (see Irschik H et al., J. Antibiotics 1995, 48 (1): 31-35; Elnakady YA, Dissertation 2001, Technische Universitat Carolo-Wilhelmina zu Braunschweig ) However, the use for the treatment of cancer is not described and not intended. A biological study of other disrazoles has not been conducted.

WO 2004/024149 provides evidence that, in particular, E1 and D1 disrazoles have a cytotoxic effect on various lines of human tumor cells. At nano- and picomolar concentrations, inhibition of division occurs, among others, cells of ovarian carcinoma, prostate carcinoma, glioblastoma, lung carcinoma and breast cancer. The action of disrazoles E1 and D1 is in this case dependent on the cell cycle. Even at nanomolar concentrations, the cell cycle is maintained in the G2 / M phase and cancer cells are introduced into apoptosis.

WO 2004/024149 further shows that the antiproliferative effect of disrazoles is based, inter alia, on effective inhibition of tubulin polymerization. In addition, E1 disrazole is active against paclitaxel and vindesine-resistant cell lines. This is important, in particular, because disrazole A1 is unsuitable for use as a cytostatic agent (see Hoefle G, Annual Report 1999/2000 of the Gesellschaft fur Biotechnologische Forschung (GBF), pp. 101/103).

Wipf and colleagues examined the cellular activity of disrazole C and the structure-activity relationship of its eight analogues (see Wipf et al., Chem. Biol. Drug Des. 2006, 67 (1): 66-73).

The general synthesis strategies in terms of the synthesis of A1 and C1 disrazoles have been studied and comprehensively described (see Hillier MC et al., J. Org. Chem. 2001, 66: 6037-6045; Hartung IV et al., Organic Letters 2002, 4 ( 19): 3239-3242; Wipf P et al., J. Am. Chem. Soc. 2004, 126 (47); 15346-15347).

Dissorazole A1 was also further characterized: it was shown to act as an antimitotic agent in the polymerization of tubulin and induces apoptosis in mammalian cells (see Elnakady YA et al., Biochem. Pharmacol. 2004, 67 (5): 927-935). In addition, methanolysis products of disrazole A1 were obtained and tested for potential antiproliferative activity (see Hearn BR et al., J. Nat. Prod. 2006, 69 (1): 148-150).

Documents corresponding to the prior art are directed to the biosynthesis of disrazoles or related compounds: WO 2004/053065 describes polynucleotides that encode disrazole polyketide synthase. Schupp and colleagues characterized the cluster of Sorangium cellulosum genes responsible for the biosynthesis of the macrolide antibiotic sorafen A (see Schupp T et al., Journal of Bacteriology 1995, 177: 3673-3679). The biosynthetic genes responsible for the biosynthesis of disrazole are also characterized by Carvalho R et al. (see Carvalho R et al., Gene 2005, 359: 91-98), Kopp et al. (see Kopp M et al., Chembiochem. 2005, 6 (7); 1277-1286) and WO 2006/075013.

However, none of the above documents corresponding to the prior art disclose or suggest conjugates of disrazoles.

US Pat. No. 6,214,969 describes analogues of the releasing hormone luteinizing hormone (LHRH) with cytotoxic groups. These groups may also be D / L-Mel (4- [bis (2-chloroethyl) amino] -D / L-phenylalanine), cyclopropanalkanoyl, aziridine-2-carbonyl, epoxyalkyl, 1,4-naphthoquinone-5-hydroxycarbonyl -ethyl, doxorubicinil (Doxorubicin, DOX), mitomycin (mitomycin C), esperamycin or methotrexoyl.

However, there is no mention of disrazoles that inhibit polymerization and induce apoptosis, and their use does not become apparent.

US patent No. 5843903 is devoted to cytotoxic anthracycline analogues, such as doxorubicin (DOX) or its derivatives with modified daunosamine. These cytotoxic groups are conjugated to peptide hormones such as LHRH, bombesin and somatostatin and their analogs.

A review by Schally and Nagy focuses on new therapeutic modalities for treating various forms of cancer that consist of targeted cytotoxic analogs of LHRH, bombesin and somatostatin, which include doxorubicin (DOX) or 2-pyrrolino-OOX (see Schally AV et al ., Life Sciences 2003, 72; 2305-2320; Nagy A et al., Current Pharmaceutical Design 2005, 11: 1167-1180).

In all three of the above references, disrazoles are not disclosed or not intended.

Other prior art documents that consider conjugates containing a cytotoxic agent include antibody-cytotoxic agent conjugates for use in treating cancer (see Chen J et al., Expert Opin. Drug DeNv. 2005, 2 ( 5): 873-890), antibody-drug conjugates intended for use in oncology (see Hamann PR article, Expert Opin. Drug DeNv. 2005, 15 (9); 1087-1103), anti-cancer drug conjugates of many classes intended for use in obtaining orientation and tumor (see Jaracz S et at., Bioorganic & Medicinal Chemistry 2005, 13: 5043-5054), conjugates alkaloid cytotoxic factor periwinkle-oligopeptide,

for treating prostate cancer and / or benign prostatic hyperplasia (WO 97/12624, WO 98/10651 and WO 99/02175), prodrug conjugates of vinblastine-peptidyl for treating prostate cancer (see Brady SF et al., J . Med. Chem. 2002, 45: 4706-4715), prodrug-activated prodrug forms for selective anticancer drugs (see Tietze LF et al., Current Pharmaceutical Design 2003, 9: 2155-2175) prodrug forms of natural anthracyclines, intended for use in an antibody-directed enzyme prodrug (see Michel S et al., Studies in Natural Products Chemistry 2000, 21: 157-180).

Again, in all the data of the above references, do not mention disrazoles, which, nevertheless, are tubulin polymerization inhibitors and induce apoptosis, and do not suggest their use.

Disclosure of invention

An object of the present invention is to provide conjugates of disrazoles and their derivatives with molecules that bind to cells. Another objective underlying the invention is the production of new derivatives of disrazoles. The next objective of the present invention is to develop methods for their preparation. Another objective underlying the invention is to obtain conjugates of disorazoles and their derivatives with molecules that bind cells, and new derivatives of disorazoles, which can be used as drugs, in particular, intended for the treatment of various tumors.

The purpose of the invention was unexpectedly achieved in one aspect by the fact that the obtained compounds corresponding to the formula (I)

,

,

where A represents a disrazole group corresponding to formula II

where Ra _n , Rb _n , Rc _n , Rd _n , Re _m , Rf _m , Rg _m , Rh _m , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 , R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 are independently selected from the group consisting of "hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl , heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxyl alkylamino, dialkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl ", which are optionally substituted in alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heterocylalkyl, heterocyclyl , carboxyl, carboxyl ester, amide, carbonate, carbamate, alkoxyl, monoalkylamino, dialkylamino, alkylcyano, disulfidylalkyl 1 and 2 or 3 substituents independently selected from the group consisting of "alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, arylsulfonyl, aryl, aryl -F, -Cl, -Br, -I, -N ₃ , -NO ₂ , = O, = S, = S (O) ₂ , hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, -C (O) OH, —C (O) NH ₂ , amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxylamino, monoa "alkylamino, dialkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl"; optionally any two adjacent R radicals from the radicals Ra _n , Rb _n , Rc _n , Rd _n , Re _m , Rf _m , Rg _m , Rh _m ,, R1, R2, R3, R4, R5, R6, R7, R8, R9 , R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 can form an atomic bond with the formation of a double bond or can form an epoxy (oxirane), aziran (aziridine) , alkyl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, heterocyclyl- and / or heterocyclylalkyl-substituted azirano (aziridine), thiran and / or thiran-S-oxide groups;

B1, B2 independently of one another are a linker that covalently binds A to C1 and / or C2;

C1, C2 independently of one another are a cell-binding molecule selected from the group consisting of "peptide, peptide hormone, protein, protein hormone, receptor ligand, plasma protein, serum protein, antibody, antibody fragment";

n is 0, 1, 2, 3;

m means 0, 1, 2, 3.

To avoid ambiguity, compounds corresponding to the above formulas (I) and (II), but also compounds corresponding to the following formulas (III) to (VI), may be present in the form of all possible double bond isomers, such as “pure” E- or Z-isomers or mixtures of these double bond isomers. In addition, with respect to the above formula (II), as well as the following formulas (III) to (VI), n / o = 0 means that there are only 6 carbon atoms between the oxazole ring on the left and the carboxy group on the right. As for n / o = 1, 2, 3, this means that 8, 10 or 12 carbon atoms are included. Similarly, this applies to m / p = 0, 1, 2, 3, where 6, 8, 10, or 12 carbon atoms are respectively included between the oxazole ring on the right and the carboxy group on the left.

In a preferred embodiment, provide compounds corresponding to the above formulas (I) and (II), where a represents a disrazole group corresponding to formula (III)

where Ri _o , Rj _o , Rk _p , Rl _p , Rm _p , Rn _p , R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40 , R41, R42, R43, R44 are independently selected from the group consisting of "hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, aryl sulfyl, aryl, aryl, aryl, aryl, aryl, , acetyl, carboxyl, carboxyl ester, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxylamino, monoalkylamino, di “alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl groups” which are optionally substituted in alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heteroalkylalkylalkyl, heterocyclylalkylalkyl , carboxyl ester, amide, carbonate, carbamate, alkoxyl, monoalkylamino, dialkylamino, alkylcyano, disulfidylalkyl and / or alk to the sulfyl group 1, 2 or 3 substituents independently selected from the group consisting of "alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, Cl, -Br, -I, -N ₃ , -NO ₂ , = O, = S, = S (O) ₂ , hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, -C (O) OH, -C (O) NH _2, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxylamino, monoalkylamino, d alkylamino, hydrazino, cyano, alkiltsiano, sulfhydryl, disulfidilalkila and / or alkyl sulfides "; optionally any two adjacent R radicals from Ri _o , Rj _o , Rk _p , Rl _p , Rm _p , Rn _p , R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44 can form an atomic bond with the formation of a double bond or can form epoxy (oxirane), aziran (aziridine), alkyl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, arylalkyl- , heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl substituted aziran (aziridine), thiran and / or thiran-S-oxide group;

o means 0, 1, 2, 3;

p means 0, 1, 2, 3.

In a further preferred embodiment, compounds corresponding to the above formulas (I), (II) and (III) and the above embodiments are provided, wherein linkers B1, B2 are independently selected from the group consisting of an “enzymatically cleavable linker proteolytically cleavable linker, self-destructive linker, acid labile linker, disulfide (exchangeable) linker, hydrolytically labile linker, bifunctional linker, multifunctional linker, ester Inker, peptide linker, linker with 1, 2, 3, 4 or 5 amino acid residues, dipeptide linker, tetrapeptide linker, hydrazone linker, the hydrazine linker, a linker based on the dicarboxylic acid residue, polyethylene glycol (PEG) linker ".

In another preferred embodiment, provide compounds corresponding to the above formulas (I), (II) and (III) and the above options for implementation, where the linkers B1, B2 are independently selected from the group consisting of: "X1-alkyl-X2 , X3-cycloalkyl-X4, X5-cycloalkylalkyl-X6, X7-alkylcycloalkylalkyl-X8, X9-aryl-X10, X11-arylalkyl-X12, X13-alkylarylalkyl-X14, X13-heteroaryl-X16, X17-heteroaryl -alkylheteroarylalkyl-X20, X21-heterocyclyl-X22, X23-heterocyclylalkyl-X24, X25-alkylheterocyclylalkyl-X26 ", where X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26 are independently selected from the group consisting of "O-, S -, SS-, С (O) O-, С (O) -, ОС (O) O-, С (O) NH-, OC (O) NH-, NHC (O) -NHC (O) O- , NH-, NY1-, C (O) NY2-, OC (O) NY3- NY4C (O) -, NY5C (O) O-, C = N-NH-, NH-N = C-, C = N -NY6-, NY7-N = C- ", where Y1, Y2, Y3, Y4, Y5, Y6, Y7 are independently selected from the group consisting of" alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl , heterocyclyl, heterocyclylalkyl, halogen, -F, -Cl, -Br, -I, -N ₃ , -NO ₂ , hydroxyl, alkoxyl, amino, imino, hydroxylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl ";

oxalyl, malonyl, succinyl, glutaryl, adipinyl, maleinyl, fumaril; and

linkers based on the following molecules: Gly-Phe-Leu-Gly, Phe-Lys, Val-Cit (citrulline); 1,4-bis (aminomethyl) -cyclohexane, 1,4-bis (aminomethyl) -cycloheptane, 1,3-bis (aminomethyl) -cyclopentane, 1-amino-4- (aminomethyl) -cyclohexane, 1,4-diaminocyclohexane 1,4-bis (aminomethyl) bicyclo [2.2.2] octane, gamma-maleimidoaproyl hydrazide, 4-hydrazinosulfonylbenzoic acid, bifunctional linker SMCC, MDS (methyldisulfanyl), PEG2, PEG3, PEG7;

Linker Lilly:

;

;

Linker Lilly BAMME:

.

.

Linker Lilly VAR:

;

;

cis-aconite linker:

;

;

linker RAVS1:

;

;

linker RAVS2:

;

;

linker RAVS3:

linker RAVS4:

linker RAVS5:

;

;

linker RAVS6:

.

.

The term "linker" in the scope of the present invention is intended to include any linker, linker group, spacer and other molecules / groups that are known to the competent specialist and are suitable for linking groups of disrazoles A with cell binding molecules C1 and / or C2.

The knowledge of a competent specialist includes the use of suitable activated forms and / or radicals of the above preferred linker molecules to create the final conjugates.

Relevant prior art literature relating to suitable linkers includes, for example, articles Michel S et al., Studies in Natural Products Chemistry 2000, 21: 157-180; Tietze LF et at., Current Pharmaceutical Design 2003, 9: 2155-2175; Brady SF et al., J. Med. Chem. 2002, 45: 4706-4715; application WO 99/02175; Jaracz S et al., Bioorganic & Medicinal Chemistry 2005, 13: 5043-5054; Hamann PR, Expert Opin. Drug Deliv. 2005, 15 (9): 1087-1103; Chen J et al., Expert Opin. Drug Deliv. 2005, 2 (5): 873-890; U.S. Patent Nos. 5,843,903 and 6,214,969,

In another preferred embodiment, there are provided compounds corresponding to the above formulas (I), (II) and (III) and the above embodiments, wherein the binding cells of the molecules C1, C2 are independently selected from the group consisting of an “octameric peptide, nonameric peptide , decameric peptide, LHRH analog, LHRH agonist, LHRH antagonist, bombesin, bombesin analog, bombesin antagonist, somatostatin, somatostatin analog, serum albumin, human serum albumin (HSA), ligand retse ptero galanin, GAL1 receptor ligand, GAL2 receptor ligand, galanin (registered in the Chemistry abstract service No. 119418-04-1) and analogues, somatostatin receptor ligand, sst1 receptor ligand, sst2 receptor ligand, sst4 receptor ligand, sst5 receptor ligand, somatostatin (registered in the abstract service in chemistry with No. 38916-34-6) and analogues, octreotide (registered in the abstract service in chemistry with No. 83150-76-9) and analogues, RC-121 (D-Phe-Cys-Tyr- O-Trp-Lys-Val-Cys [cyclo (2 → 7) disulfide] -Thr-NH ₂ ; registered in the abstract service for chemistry with No. 99660-13-6) and analogues, bombesin receptor ligand, BB1 receptor ligand, BB2 receptor ligand, BB3 receptor ligand, gastrin-releasing peptide receptor ligand (GRP-R), bombesin (Bn; registered in the abstract service in chemistry with No. 31362-50-2) and analogues, gastrin-releasing peptide (GRP) and analogues, neuromedin B (registered in the abstract service in chemistry with No. 102577-19-5) and analogues, [D-Tyr ⁶ , β-Ala ¹¹ , Phe ¹³ , Nle (norleucine) ¹⁴ ] -bombesin (6-14) and analogues, RC-3095 (HD-Tpi-Gln-Trp-Ala-Val-Gly-His-Leu-ψ- Leu-NH _2; Registered cited in the abstract service for chemistry with No. 138147-78-1; applications US 5244883; US 5369094) and analogues, Gln-Trp-Ala-Val-Gly-His-ψ-Leu-Leu-NHa (US 5843903) and analogues, gonadotropin-releasing hormone receptor ligand (GnRH-R), GnRH-R type I ligand, GnRH-R type II ligand, luteinizing hormone releasing hormone (LHRH; Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg- Pro-Gly-NH ₂ ) and analogues, [D-Lys ⁶ ] -LHRH, tryptorelin ([D-Trp ⁶ ] -LHRH; registered in the abstract service for chemistry with No. 57773-63-4) and analogues, histrelin (6- [1- (phenylmethyl) -D-histidine] -9- (N-ethyl-L-prolinamide) -10-deglycinamide-LHRH ; registered in the abstract service for chemistry with No. 76712-82-8) and analogues, buserelin (6- [O- (1,1-dimethylethyl) -D-serine] -9- (N-ethyl-L-prolinamide) - 10-deglycinamide-LHRH; registered with the Abstracts Chemistry Service No. 57982-77-1) and analogues, leuprorelin (6-D-leucine-9- (N-ethyl-L-prolinamide) -10-deglycinamide-LHRH; registered in the abstract service for chemistry with No. 53714-56-0) and analogues, joserelin (6- [O- (1,1-dimethylethyl) -D-series ] -LHRH-2- (aminocarbonyl) hydrazide; registered in the Abstracts Service for Chemistry No. 65807-02-5) and analogues, napharelin (6- [3- (2-naphthalenyl) -D-alanine] -LНРН; registered in abstract service in chemistry with No. 76932-56-4) and analogues, LHRH-II (Pyr-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH ₂ ) and analogues, cetrorelix (registered in the abstract chemistry service No. 120287-85-6) and analogues, teverelix / antarelix (registered in the abstract chemistry service No. 144743-92-0) and analogues, ozarelix (D-63153; registered in the abstract service in chemistry with No. 295350-45-7) and analogues, abarelix (registered in the abstract service in chemistry with No. 183552-38-7) and analogues, degarelix (registered in the abstract service in chemistry with No. 214766-78- 6) and analogues, detrirelix (registered in the abstract service for chemistry with No. 89662-30-6) and analogues, ganirelix (registered in the abstract service in chemistry with No. 124904-93-4) and analogs, iturelix / antide (registered in the abstract Chemistry Service No. 112568-12-4) and analogues, ligands of the GPR54 receptor, kisspeptino and analogues, kispeptin-10 / Kr-10 (registered in the abstract service in chemistry with No. 374675-21-5) and analogues, kispeptin-13 / Kr-13 (registered in the abstract service in chemistry with No. 374675-18-0) and analogues, metastin (registered in the abstract service for chemistry with No. 388138-21-4) and analogues, neurokinin receptor ligand, NK1 / NKA receptor ligand, NK2 / NKB receptor ligand, NK3 receptor ligand, substance P (H-Arg-Pro Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH ₂ ; registered in the abstract service for chemistry with No. 33507-63-0) and analogues, H-Asp-Ser-Phe-Val-Gly-Leu-Nle-NH ₂ and analogues, [Sar ⁹ , Met (O ₂ ) ¹¹ ] - substances P and analogues, [Nle ¹⁰ ] -neurokinin A (4-10) and analogues, [MePhe ⁷ ] -neurokinin B and analogues, [β-Ala ⁸ ] -neurokinin A (4-10) and analogues, bradykinin receptor ligand , the ligand of the receptor B1, the ligand of the receptor B2, bradykinin (H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH; registered in the abstract chemistry service No. 58-82-2) and analogues, desArg ⁹ [Leu ⁸ ] -bradykinin and analogues, desArg ^9- bradykinin and analogues, LysdesArg ^9- bradykinin and analogues, LysdegArg9 [Leu ⁸ ] -bradykinin and analogues, [Hyp ³ , Tyr (Me) ⁸ ] bradykinin and analogues, D-Arg [Hyp ³ , D-Phe ⁷ , Leu ⁸ ] bradykinin and analogues, VKM 718 (registered in the Abstracts Chemistry Service No. 259883- 69-7) and analogues, VKM 822 (registered in the abstract service in chemistry with No. 259884-10-1) and analogues, VKM 570 (registered in the abstract service in chemistry with No. 259885-54-6) and analogues, VKM-638 (registered in the abstract service in chemistry with No. 259885-81-9) and analogues, ligand of the GHS receptor, ghrelin (registered in the abstract service in chemistry with No. 304853-26-7) and analogues, hexarelin (registered in online chemistry service with No. 140703-51-1) and analogues, GHRP-1 (registered in the abstract chemistry service with No. 141925-59-9) and analogues, GHRP-2 (registered in the abstract chemistry service with No. 158861-67- 7) and analogues, GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH ₂ ; registered in the abstract service in chemistry with No. 87616-84-0) and analogues, D-Lys ³ -GHRP-6 and analogues, EP-1572 (registered in the abstract service in chemistry with No. 381231-18-1) and analogues, desoctanoylgrelin and analogues, relaxin receptor ligand, LGR7 receptor ligand, LGR8 receptor ligand, relaxin (registered in the Abstracts Chemistry Service No. 9002-69-1) and analogues, insulin-like peptide 3 (INSL3; registered in the Abstracts Chemical Chemistry Service No. 166515- 61-3) and analogues, glucagon-like peptide 1 receptor ligand, glucagon receptor ligand, hl yucagon-like peptide-1 (GLP-1; registered in the abstract service for chemistry with No. 89750-14-1) and analogues, glucagon-like peptide-2 (GLP-2; registered in the abstract service in chemistry with No. 116469-36-4) and analogues, cholecystokinin receptor ligand, CCK1 / CCKA receptor ligand, CCK2 / CCKB receptor ligand, CCKS receptor ligand, cholecystokinin (registered in the Abstracts Chemistry abstract from No. 901 1-97-6) and analogues, neuropeptide Y receptor ligand (NPY), NPY1 receptor ligand, NPY2 receptor ligand, NPY3 receptor ligand, neuropeptide Y (NPY; registered in the abstract service for chemistry with No. 82785-45-3) and analogues, [Leu ³¹ , Pro ³⁴ ] NPY and analogues, NPY- (13-36) and analogues, peptide yy (registered in the abstract service in chemistry with No. 106388 -42-5) and analogues, an endothelin receptor ligand, an ETA receptor ligand, an ETB receptor ligand, endothelin 1 (registered with the Abstracts Chemistry Service No. 123626-67-5) and analogues, endothelin 2 (registered with an Abstracts Chemistry Service with No. 122879-69-0) and analogues, endothelin 3 (registered in the abstract service for chemistry with No. 125692-40-2) and analogues, ligand one of vasoactive intestinal peptides (VPAC1, VIP1), VPAC2 / VIP2 receptor ligand, PAC1 / PACAP receptor ligand, PACAP (1-27) (registered in the Chemical Abstracts Service with No. 137061-48-4) and analogues, PACAP (1- 38) (registered in the abstract service for chemistry with No. 137061-48-4) and analogues, RASAR (6-27) (registered in the abstract service in chemistry with No. 137061-48-4) and analogues, RASAR (6-38) (registered in the abstract service in chemistry with No. 137061-48-4) and analogues, a vasoactive intestinal polypeptide (VIP) (registered in the abstract service in chemistry with No. 37221-79-7) and analog c, VIP (6-28) (registered in the abstract service for chemistry with No. 37221-79-7) and analogues, [(Ac-His ¹ , D-Phe ² , Lys ¹⁵ , Arg ¹⁶ , Leu ²⁷ ) -VIP ( 1-7) -GRF (8-27)] and analogues, [Lys ¹ , Pro ²⁵ , Arg ³⁴ , Tyr ⁶ ] -VIP and analogues, VEGF receptor ligand, NP-1 receptor ligand, neuropilin-1 receptor ligand, factor vascular endothelial growth (VEGF; registered in the abstract service for chemistry with No. 127464-60-2) and analogues, the ligand of the receptor for fibroblast growth factor, fibroblast growth factor (FGF; registered in the abstract service for chemistry with No. 62031-54-3) and analogues "and preferably selected from a group consisting of an “octameric peptide, nonameric peptide, decameric peptide, luteinizing hormone releasing hormone (LHRH), [D-Lys ⁶ ] -LHRH, LHRH analogue, LHRH agonist, tryptorelin ([D-Trp ⁶ ] -LHRH) LHRH antagonist, bombesin, bombesin analog, bombesin antagonist, somatostatin, somatostat analog ina, serum albumin, human serum albumin (HSA). "

All data binding to the cell molecule, and their analogues are well known in the prior art. When available, the Chemical Abstract Services (CAS) registration numbers are given. However, it is not contemplated to limit the volume of cell-binding molecules to only those referenced by the corresponding CAS registration number. The term “cell binding molecule” is intended to include any possible structural and / or functional variant / member of the family.

By the term “analogue” referring to a molecule that binds to a cell, it is intended to include within the scope of the present invention any structurally and / or functionally close analogue of a molecule that binds to a cell, which is known to a competent specialist of the prior art. Non-limiting examples are, for example, LHRH analogues, such as triporelin, cetrorelix, etc.

The term analogue in relation to a molecule that binds to a cell is also intended to include, if used, agonists and antagonists of the molecule in question that binds to the cell, i.e. the term LHRH analogue does include LHRH agonists and LHRH antagonists within the scope of the present invention.

In another preferred embodiment of the present invention, there are provided compounds corresponding to the above formulas (I), (II) and (III) and the above embodiments, in which the linkers B1 and B2 are identical and the molecules that bind the cell, C1 and C2 are identical.

In another preferred embodiment of the present invention, there are provided compounds corresponding to the above formulas (I), (II) and (III) and the above embodiments, wherein the B2 linker and the cell binding molecule C2 are absent according to the formula (IV)

.

.

In yet another preferred embodiment of the present invention, there are provided compounds corresponding to the above formulas (I), (II) and (III) and the above embodiments, wherein A is a disrazole group corresponding to formula (III); Ri _o , Rj _o , Rk _p , Rm _p , R28, R30, R31, R32, R33, R34, R35, R36, R38, R40, R41, R42, R43, R44 are hydrogen; Rl _p , Rn _p together form a double bond or are independently selected from the group consisting of "hydrogen, alkoxyl"; R27, R29 together form a double bond or epoxide (oxirane); R37, R39 together form a double bond or epoxide (oxirane); R25, R26 are independently selected from the group consisting of: “alkyl”, which is optionally substituted in the alkyl group with 1, 2, or 3 substituents independently selected from the group consisting of “alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkyl, halogen, -F, -Cl, -Br, -I , -N _3, -NO _2, = O, = S, = S (O) ₂ , hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, amide, carbonate, carbamate, residues of α-amino acids residues of β-amino acids, alkoxyl, amino, imino, hydroxylamino, monoalkylamino, dialkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl ";

B1 and / or B2 are independently selected from the group consisting of “linker based on dicarboxylic acid, succinyl, glutaryl”;

C1 and / or C2 are independently selected from the group consisting of "LHRH, [D-Lys ⁶ ] -LHRH, somatostatin, somatostatin analogues, human serum albumin (HSA)";

o means 1 or 2;

p is 1 or 2.

In a further preferred embodiment, n or o is 1, m or p is 1. In another preferred embodiment, n or o is 2, m or p is 2.

In yet another further preferred embodiment, the compound is selected from the group consisting of:

"disrazole A1 - succinyl- [D-Lys ⁶ ] LHRH" (regioisomeric compounds 11 and 12):

"disrazole E1 - succinyl- [D-Lys ⁶ ] LHRH" (regioisomeric compounds 13 and 14):

"disrazole A1 - succinyl- [D-Lys ⁶ ] LHRH) ₂ " (compounds 15)

"disrazole Z - succinyl- [D-Lys ⁶ ] LHRH" (compound 16):

"disrazole Z - (glutaryl- [D-Lys ⁶ ] LHRH ₂ " (compound 17):

"disrazole Z - succinyl somatostatin" (compound 18):

In another aspect, the objective of the present compound is unexpectedly achieved by obtaining disrazole compounds corresponding to the formula (V)

where Za _n , Zb _n , Zc _n , Zd _n , Ze _m , Zf _m , Zg _m , Zh _m , Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13 , Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24 are independently selected from the group consisting of "hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl , heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxyl alkylamino, dialkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl ", which are optionally substituted in alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heterocylalkylalkylalkylalkylalkylalkylalkylalkyl , carboxyl, carboxyl ester, amide, carbonate, carbamate, alkoxyl, monoalkylamino, dialkylamino, alkylcyano, disulfidylalkyl 1 and 2 or 3 substituents independently selected from the group consisting of "alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, aryl -F, -Cl, -Br, -I, -N ₃ , -NO ₂ , = O, = S, = S (O) ₂ , hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, -C (O) OH, -C (O) NH _2, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxylamino, mono lkilamino, dialkylamino, hydrazino, cyano, alkiltsiano, sulfhydryl, disulfidilalkila and / or alkyl sulfides "; provided that at least one of the radicals Za _n , Zb _n , Zc _n , Zd _n , Ze _m , Zf _m , Zg _m , Zh _m , Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24 are independently selected from the group consisting of “carboxyl ester, amide, carbonate, carbamate, residues α-amino acids, residues of β-amino acids ";

under the further condition that acetyl is excluded from the “carboxyl ester”;

optionally any two neighboring radicals Z from the radicals Za _n , Zb _n , Zc _n , Zd _n , Ze _m , Zf _m , Zg _m , Zh _m , Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24 can form an atomic bond with the formation of a double bond or can form epoxy (oxiran), aziran (aziridine), an alkyl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, heterocyclyl- and / or heterocyclylalkyl-substituted azirano (aziridino), thiran and / or thiran-S-oxide group;

n is 0, 1, 2, 3;

m means 0, 1, 2, 3.

In a preferred embodiment of the present invention provide disrazole compounds corresponding to the following formula (VI)

Where

Zi _o , Zj _o , Zk _p , Zl _p , Zm _p , Zn _p , Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44 are independently selected from the group consisting of "hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, aryl, aryl, aryl acetyl, carboxyl, carboxyl ester, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues, alkoxyl, amino, imino, hydroxylamino, monoalkylamino, dialkyl lamino, hydrazinyl, cyano, alkyl cyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl "which are optionally substituted in alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkyl , carboxyl ester, amide, carbonate, carbamate, alkoxyl, monoalkylamino, dialkylamino, alkylcyano, disulfidylalkyl and / or alkyls to the lpfidyl group of 1, 2 or 3 substituents independently selected from the group consisting of "alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, aryl, aryl, aryl Cl, -Br, -I, -N ₃ , -NO ₂ , = O, = S, = S (O) ₂ , hydroxyl, carbonyl, acetyl, carboxyl, carboxyl ester, -C (O) OH, -C (O) NH ₂ , amide, carbonate, carbamate, residues of α-amino acids, residues of β-amino acids, alkoxyl, amino, imino, hydroxylamino, monoalkylamino, dialk "amylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl and / or alkylsulfidyl";

provided that at least one of the radicals Zi _o , Zj _o , Zk _p , Zl _p , Zm _p , Zn _p , Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44 are independently selected from the group consisting of “carboxyl ester, amide, carbonate, carbamate, α-amino acid residues, β-amino acid residues”;

under the further condition that acetyl is excluded from the “carboxyl ester”;

optionally any two adjacent radicals Z from the radicals Zi _o , Zj _o , Zk _p , Zl _p , Zm _p , Zn _p , Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44 can form an atomic bond with the formation of a double bond or can form epoxy (oxirane), aziran (aziridine), alkyl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-, arylalkyl- , heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl substituted aziran (aziridine), thiran and / or thiran-S-oxide group;

o means 0, 1, 2, 3;

p means 0, 1,2, 3.

In a further preferred embodiment, disrazole compounds according to formulas (V) and (VI) are provided, where n or o is 1 and m or p is 1. In another preferred embodiment, disrazole compounds according to formulas (V) and (VI) are provided where n or o means 2, m or p means 2.

In yet another preferred embodiment, the disrazole derivative is selected from the group consisting of:

regioisomeric compounds 1 and 2:

compound 3:

compound 4:

regioisomeric compounds 5 and 6:

compound 7:

compound 9:

connection 10:

connection 19:

compound 20:

compound 21:

All connections, i.e. disrazole conjugates and disrazole derivatives illustrated in this context are generally [the above formulas (I) to (VI) and various R radicals] and are hereinafter referred to in detail as compounds corresponding to the (present) invention.

The terms that are required to characterize the above compounds corresponding to the invention, always, unless otherwise specified in the description or in the claims, have the following meanings:

The term “substituted” means that the corresponding radical or group has one or more substituents. When a radical has many substituents and the choice of different substituents is defined, the substituents are selected independently from each other, and they need not be identical. The term “unsubstituted” means that the corresponding group does not have a substituent. The term “optionally substituted” means that the corresponding group is either unsubstituted or substituted with one or more substituents. The term “having up to 3 substituents” means that the corresponding radical or group is substituted with either one, two, or three substituents.

The term “alkyl” includes, for the purposes of this invention, non-cyclic saturated, partially unsaturated or unsaturated hydrocarbons having C1-C12 carbon atoms, which may be unbranched or branched and may include one or more double bonds and / or one or more triple bonds. The term "alkyl" preferably refers to alkyl chains of 1-8, particularly preferably 1-6 carbon atoms. Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 2- or 3- methylpentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n- eicosanil, n-docosanil, ethylene (vinyl), propenyl (-CH ₂ CH = CH ₂ ,; -CH = CH-CH ₃ , -C (= CH ₂ ) -CH ₃ ), butenyl, pentenyl, hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadec-9-enyl, eicosenyl, eicos-11-enyl, (Z) -eycosis-11-enyl, docosanil, docos-13th nyl, (Z) -docos-13-enyl, ethynyl, propynyl (-CH ₂ -C≡CH, -C≡C-CH ₃ ), butynyl, pentynyl, hexynyl, heptinyl and octinyl.

The term “cycloalkyl” is intended to mean a saturated or partially unsaturated non-aromatic cyclic hydrocarbon group / radical, including 1, 2 or 3 cycles, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, and containing a total of 3-20 carbon atoms forming cycles preferably 3-10, most preferably (C ₃ -C ₈ ) cycloalkyl. Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctadienyl.

The term “cycloalkyl-alkyl” refers to a radical in which a cycloalkyl group is linked via an alkyl group, wherein the alkyl and cycloalkyl groups are as defined herein, preferably (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C ₄ ) is an alkyl radical. Examples of these groups are cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexenylethyl. The term “aryl” refers to aromatic hydrocarbon systems having 3-14, preferably 5-14 carbon atoms. The term “aryl” also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially saturated and / or aromatic system, such as an aromatic cycle fused to an “aryl”, “cycloalkyl”, “heteroaryl” or “heterocyclyl "by a group, as defined herein, by any desired and possible member of the aryl radical cycle. These "aryl" radicals can be linked through any member of the cycle. Examples of “aryl” are, among others, phenyl, biphenyl, naphthyl and anthracenyl, as well as indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.

The term “heteroaryl” refers to a 5-, 6- or 7-membered cyclic aromatic radical, which includes at least 1, if appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen and / or sulfur, and heteroatoms same or different. The number of nitrogen atoms is preferably 0, 1, 2 or 3, and the oxygen and sulfur atoms are independently 0 or 1. The term “heteroaryl” also includes systems in which the aromatic ring is part of a bi- or polycyclic saturated, unsaturated and / or aromatic system, such as the aromatic ring fused to an “aryl”, “cycloalkyl”, “heteroaryl” or “heterocyclyl” group, as defined herein, by any desired and possible member of the heteroaryl radical cycle. These "heteroaryl radicals" may be linked via any member of the ring. Examples of “heteroaryl” include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinazylazolidazole, indazylazolidazole , quinoxalinyl, quinazolinyl, pterdinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl, acridinyl.

The terms “arylalkyl” and “heteroarylalkyl” refer to radicals in which an aryl or heteroaryl radical is linked via an alkyl group, wherein the alkyl, aryl and heteroaryl groups have the meanings defined in this context. Preferred “arylalkyl” groups are phenyl- (C ₁ -C ₄ ) -alkyl radicals, preferably benzyl or phenylethyl radicals. Preferred "heteroarylalkyl" groups are indolyl- (C ₁ -C ₄ ) -alkyl radicals, preferably 1H-indol-3-yl-methyl or 2- (1H-indol-3-yl) -ethyl.

The term “heterocyclyl” refers to a mono- or polycyclic system of 3-20, preferably 5-6 to 14, atoms of a cycle comprising carbon atoms and 1, 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur that are the same or different. The cyclic system may be saturated, mono- or polyunsaturated, but may not be aromatic. In the case of a cyclic system consisting of at least two cycles, the cycles may be fused or spiro or otherwise connected. These "heterocyclyl" radicals can be linked via any member of the cycle. The term “heterocyclyl” also includes systems in which the heterocycle is part of a bi- or polycyclic saturated, partially saturated and / or aromatic system, such as where the heterocycle is fused to an “aryl”, “cycloalkyl”, “heteroaryl” or a “heterocyclyl” group, as defined herein, by any desired and possible member of the heterocyclyl radical ring. Examples of “heterocyclyl” include pyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinylpyrhenyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl.

The term “heterocyclylalkyl” refers to radicals in which a heterocyclyl group is linked via an alkyl group, wherein the alkyl and heterocyclyl groups have the meanings defined in this context. Heterocyclyl- (C ₁ -C ₄ ) -alkyl radicals are preferred. The terms “alkylsulfonyl”, “arylsulfonyl” and “aryl-alkylsulfonyl” refer to radicals in which an alkyl, aryl or arylalkyl group is linked via an —SO ₂ group, where the alkyl, aryl and arylalkyl groups are as defined herein. Examples are methylsulfonyl and phenylsulfonyl.

The term "halogen", "halogen atom" or "halogen substituent" (Hal-) refers to one, if necessary, many atoms of fluorine (F, fluorine), bromine (Br, bromine), chlorine (Cl, chlorine) or iodine (I iodine). The names "dihalogen", "trihalogen" and "perhalogen" refer to two, three and four substituents, respectively, where each substituent can be independently selected from the group consisting of fluorine, chlorine, bromine and iodine. "Halogen" preferably means a fluorine, chlorine or bromine atom.

The term “carbonyl” refers to radicals in which an alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl group is linked via a —C (O) group, where alkyl, cycloalkyl, cycloalkylalkyl, , arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups have the meanings defined in this context. Examples are —C (O) —CH ₃ , —C (O) —CH ₂ CH ₃ , —C (O) —isopropyl, and —C (O) —tBu (tBu = tert-butyl).

The term “carboxyl” refers to radicals in which an alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl group is linked via a —C (O) O group, where alkyl, cycloalkyl, cycloalkylalkyl heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups have the meanings defined in this context. Examples are —C (O) O — CH ₃ and —C (O) O-phenyl.

The term “carboxyl ester” refers to radicals in which an alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl group is bonded via an —OC (O) -group, where alkyl, cycloalkyl, cycloalkyl , heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups have the meanings defined in this context. Examples are acetyl, -OC (O) -phenyl, and the like.

The term “carbonate” refers to radicals in which an alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl group is linked via an —OC (O) O-group, where alkyl, cycloalkyl, cycloalkyl heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups have the meanings defined in this context. Examples are —OC (O) O — CH ₃ and —OC (O) O-phenyl.

The term “carbamate” refers to radicals in which an alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl group is linked via an —OC (O) NH group, an —NHC (O) O group, —OC (O) NR groups or —NRC (O) O groups where R is independently selected from the group consisting of “alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, -F , -Cl, -Br, -I, -N _3, -NO _2, hydroxyl, alkoxy, amino, imino, hydroxylamine , Hydrazine, cyano, alkiltsiano, sulfhydryl ", wherein the alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, gidrazinilnaya and / or alkiltsianogruppy are as defined herein.

The term "α-amino acid residue" for the purposes of the present invention refers to all known 20 proteinogenic α-amino acids, as well as natural (i.e., in any biological systems) α-amino acids, such as, for example, selenocysteine, pyrrolisin, citrulline, ornithine , homocysteine, N-methylarginine, N-acetylysine, gamma-carboxyglutamate, 5-hydroxylisine, 3-methylhistidine and / or N, N, N-trimethyllysine. In this regard, the term "residue" refers to the entire group of amino acids, including the side chain attached to the α-carbon atom and the skeleton. The term "α-amino acid residue" for the purposes of the present invention also refers to all known α-amino acids that are neither proteinogenic nor, as is known, present under natural conditions (i.e., in any biological systems). Examples are norleucine, cyclohexylglycine, 2-naphthylalanine, substituted α-amino acids (e.g. halogen-substituted Tyr or Phe), as well as protected side chains of α-amino acids, where a protecting group such as Fmoc, Boc, Cbz, Aloc, trityl, acetyl and / or benzyl, is directly attached / reacts with functionalization (e.g. amino, hydroxy and / or carboxyostatic). In this regard, the term "residue" refers to the entire group of amino acids, including the side chain attached to the α-carbon atom and the skeleton.

Accordingly, the term “β-amino acid residue” for the purposes of the present invention refers to all known β-amino acids that are neither proteinogenic nor, as is known, present under natural conditions (i.e., in any biological systems). In this regard, the term "residue" refers to the entire group of amino acids, including the side chain and skeleton attached to the β-carbon atom.

The term “alkoxyl” refers to radicals in which an “alkyl”, “cycloalkyl”, “cycloalkylalkyl”, “aryl”, “arylalkyl”, “heteroaryl”, “heteroarylalkyl”, “heterocyclyl” and / or “heterocyclylalkyl” group is linked via an oxygen atom (—O— group) where “alkyl”, “cycloalkyl”, “cycloalkylalkyl”, “aryl”, “arylalkyl”, “heteroaryl”, “heteroarylalkyl”, “heterocyclyl” and “heterocyclylalkyl” have the meanings as defined in this context.

The terms "monoalkylamino" and "dialkylamino" refer to radicals in which one or two alkyl groups are respectively bonded via a nitrogen atom, the alkyl group having the meaning defined in this context. Examples are ethylamino, dimethylamino and isopropylethylamino.

The term "hydrazinyl" refers to a C = N-NH-, NH-N = C-, C = N-NR- and / or NR-N = C-group, where R is independently selected from the group consisting of "alkyl, cycloalkyl , cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, -F, -Cl, -Br, -I, -N ₃ , -NO ₂ , hydroxyl, alkoxyl, amino, imino, hydroxylamino, cyano hydrazini , alkylcyano, sulfhydryl ", where alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyl, hydrazine Ordering and / or alkiltsianogruppy are as defined herein.

The term “alkyl cyano” refers to radicals in which an alkyl group is linked via a cyano group, wherein the alkyl group has the meaning defined in this context. Examples are methyl cyano and n-propyl cyano.

The term “disulfide alkyl” refers to radicals in which an alkyl group is linked through an —S — S group, where the alkyl group is as defined herein.

The term “alkyl sulfidyl” refers to radicals in which the alkyl group is linked via a sulfur atom, where the alkyl group has the meaning defined in this context.

All stereoisomers of the compounds of the invention are provided, either in admixture or in pure or substantially pure form. Compounds of the present invention may have asymmetric centers in any of the carbon atoms, including any of the substituent radicals. Therefore, the compounds of the invention can exist in the form of their racemates, in the form of pure enantiomers and / or diastereomers, or in the form of mixtures of these enantiomers and / or diastereomers. Mixtures can have any desired stereoisomer ratio. All of these stereochemical forms and mixtures are included in the scope of the present invention.

For example, compounds of the present invention that have one or more centers of chirality and which exist as racemates or mixtures of diastereomers can be fractionated by methods known per se to their optically pure isomers, i.e. enantiomers or diastereomers. The separation of the compounds of the invention can be accomplished by column separation into the chiral or non-chiral phases or by recrystallization from an optionally optically active solvent or by using an optically active acid or base, or by derivatization with an optically active reagent, such as, for example, optically active alcohol, and subsequent removal of the radical.

To avoid ambiguity, the compounds of the invention may be present in the form of all possible double bond isomers, such as the “pure” E or Z isomers or mixtures of these double bond isomers.

If possible, the compounds of the present invention may be in the form of tautomers.

Similarly, it is possible for the compounds of the invention to be in the form of any desired prodrug forms, such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, when the truly biologically active form is released only through metabolism. Any compound that can be converted in vivo to produce a bioactive agent (i.e., a compound of the invention) is a prodrug form corresponding to the scope and spirit of the invention. Various types of prodrug forms are well known in the art and are described, for example, in:

(i) The Practice of Medicinal Chemistry monographs (Wermuth CG et al., Ch. 31, Academic Press 1996);

(ii) the monograph Design of Prodrugs (Creation of pro-drug forms) (edited by Bundgaard H, Elsevier 1985); and

(iii) Monographs A Textbook of Drug Design and Development (Ed. Krogsgaard-Larson P and Bundgaard H, chap. 5: 113-191, Harwood Academic Publishers 1991).

These materials are incorporated herein by reference. In addition, it is known that chemicals in the body are converted into metabolites, which can, if necessary, similarly cause the desired biological effect, in some cases even in a more pronounced form.

Any biologically active compound that is metabolically converted in vivo from any compound of the invention is a metabolite corresponding to the scope and spirit of the invention.

Compounds according to the invention can, if they have a sufficiently basic group, such as, for example, a primary, secondary or tertiary amine, be converted with inorganic and organic acids into salts. Preferably, the pharmaceutically acceptable salts of the compounds of the invention are formed using hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, grape acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or saparaginic acid. The salts that form are, among others, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarate, stearate, aspartates and glutamates. The stoichiometry of salts formed from the compounds of the invention may, in addition, be a multiple or multiple thereof.

Compounds according to the invention can, if they have a sufficiently acidic group, such as, for example, carboxy, sulfuric acid, phosphoric acid or a phenolic group, be converted with inorganic and organic bases into their physiologically tolerated salts. Examples of suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide and organic bases — ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tert-butylamine, tert-oxylamine, dehydrobisethylamine, cyclohexylamine, dibenzylethylenediamine and lysine. The stoichiometry of salts formed from the compounds of the invention may, in addition, be a multiple or multiple thereof.

Similarly, it is possible for the compounds of the invention to be in the form of their solvates, in particular hydrates, which can be obtained, for example, by crystallization from a solvent or from an aqueous solution. Moreover, it is possible that one, two, three or any number of solvate or water molecules are combined with the compounds of the invention to form solvates and hydrates.

Chemicals are known to form solids that exist in states of various orders, which are called polymorphic forms or modifications. Various modifications of a polymorphic substance can vary significantly in their physical properties. The compounds of the invention may exist in various polymorphic forms, and some modifications may also be metastable. All of these polymorphic forms of the compounds of the invention should be considered as belonging to the invention.

The compounds of the invention are favorably characterized by a strong biological effect. As for the conjugates of the disrazole corresponding to the present invention, they are superior to the conjugates corresponding to the prior art, due to the increased inherent activity. Moreover, especially bis-substituted C1-B1-A-B2-C2 conjugates unexpectedly exhibit higher specificity and reduced toxicity until the cytotoxic group of disrazole is released.

When using the conjugates of the present invention, specific targeting to (tumor) tissues of interest is possible, for example, by using the desired ligand receptor as a cell-binding molecule that directs the conjugate to these receptor-expressing (tumor) tissues. Moreover, the specific orientation mainly results in high local concentrations of conjugates in situ (in the tumor area), leading to significantly increased efficiency. These benefits can translate into reduced doses of the potential drug being administered at the clinic, as well as reduced or no medical ill effects.

In another aspect, the objectives of the present invention are unexpectedly achieved by the fact that a method of producing compounds corresponding to the invention.

In a preferred embodiment, a method for preparing compounds of the invention is provided, comprising the steps of:

a) reacting a disrazole compound with a linker, preferably linker anhydride, to produce a mono- and / or bisfunctionalized disrazole linker group,

b) optionally separating (purifying) the mono- and / or bisfunctionalized disrazole linker group from the reaction products and by-products,

c) linking the optionally separated (purified) mono- and / or bisfunctionalized disrazole linker groups to the molecules that bind to the cell to form a disrazole conjugate of formula (I) C1-B1-A-B2-C2 and / or formula (IV) C1 -B1-A,

d) optionally separating (purifying) the disrazole conjugate of formula (I) C1-B1-A-B2-C2 and / or formula (IV) C1-B1-A from reaction products and by-products.

The compounds of the invention can be administered to various mammalian species, including humans, for the treatment or prevention of physiological and / or pathophysiological conditions.

For the purpose of the present invention, all mammalian species are considered to be included. Preferably, when these mammals are selected from the group consisting of "human, domestic animals, cattle, livestock, pets, cows, sheep, pigs, goats, horses, ponies, donkeys, hinnies, mules, hares, rabbits, cats , dogs, guinea pigs, hamsters, rats, mice. " More preferably, the mammal is a human.

In another aspect, the objectives of the present invention are unexpectedly achieved by the preparation of the compounds of the invention for the preparation of a medicament.

In another aspect, the objectives of the present invention are unexpectedly achieved by the preparation of the compounds of the invention for the preparation of a medicament for the treatment and / or prevention of acute leukemia, adenocarcinoma, basal cell carcinoma, benign tumors, bladder cancer, colon cancer, brain tumors, breast cancer, bronchial carcinoma, carcinoid, carcinoma, cervical cancer, cervical carcinoma, chronic leukemia, colon cancer, colon carcinoma, colorectal cancer, connector cancer tissue, carcinoma of the body, endometrial cancer, cancer of the esophagus, Evig’s sarcoma, gastrinoma, glioblastoma, glioma, gynecological tumors, cancer of the head and / or neck, hepatoblastoma, hepatoma, hyperplasia, hyperproliferative diseases, intraocular melanoma, Kaposi’s carcinoma, carcinoma larynx, leiomyomas, leukemia, liver tumors, lung cancer, non-small cell lung cancer, lymphoma, malignant tumors, breast carcinoma, medulloblastoma, melanoma, multiple myeloma, nephroblastoma, neuroblastoma, neuroendocrine x tumors, osteosarcoma, ovarian cancer, pancreatic tumor, prostate cancer, prostate carcinoma, rectal carcinoma, kidney cancer, kidney cell carcinoma, retinoblastoma, rhabdoid tumor, sarcoma, skin cancer, soft tissue sarcoma, solid tumors, spinalomas, stomach cancer , testicular cancer, thymoma, thyroid cancer, tumors originating from the brain and / or nervous system and / or meninges (WO 99/01764), urinary tract cancer and / or uterine cancer. "

In a further aspect, the objectives of the present invention are unexpectedly achieved by the preparation of the compounds of the invention for the manufacture of a medicament, wherein the medicament further comprises at least one additional pharmaceutically active substance.

In a further aspect, the objectives of the present invention are unexpectedly achieved by the preparation of the compounds of the invention for the manufacture of a medicament, wherein the medicament is administered before, and / or during and / or after treatment with at least one additional pharmaceutically active substance.

In a further aspect, the objectives of the present invention are unexpectedly achieved by the preparation of the compounds of the invention for the manufacture of a medicament, wherein the medicament is administered before, and / or during and / or after radiotherapy treatment and / or surgery.

In the course of the present invention, the compounds of the invention can thus be administered, as illustrated, as separate substances or in combination with all known pharmacologically active substances during a course of combination therapy.

In a preferred embodiment, the compounds of the invention are provided for the aforementioned use, wherein the additional pharmacologically active substance is selected from the group consisting of “DNA topoisomerase 1 and / or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, agonists and / or antagonists of hormone receptors and / or growth factors, signal transduction inhibitors, antibodies to growth factors and their receptors, kinase inhibitors, antimetabolites. "

In a preferred embodiment, the compounds of the invention are provided for the above use, wherein the additional pharmacologically active substance is selected from the group consisting of: actinomycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, docetaxel, doxorubicin (adriamycin), DTIC (dacarbacin), ep rubicin, epothilone, erbitax, erythrohydroxyquinonyladenine, ethinyl estradiol, etoposide, fludarabine phosphate, fluoxymesterone, flutamide, gemcitabine, gliivec / glivec, herceptin, hexamethylmelamine, interferon, hydroxyprogesterone, hydroxyprogesterone, hydroxyprogesteronefen, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, mesna, methotrexate, mitomycin C, mitotan, mitoxantrone, N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, paclitaxel, pentozos Athens, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, rapamycin, semustine, sorafenib, streptozocin, tamoxifen, Tarceva, taxotere, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimetilenamina, uridine vinbalstina, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine monophosphate, 5-azacytidine cladribine, 5-fluorodeoxyuridine, 5-fluorouracil (5-FU), 6-mercaptopurine. "

Compounds of the present invention may be administered in a known manner. The route of administration may thus be any route that effectively delivers the active compound to a suitable or desired site of action, for example, non-oral or oral, in particular intravenous, topical, transdermal, pulmonary, rectal, intravaginal, nasal or parenteral, or by implantation. Intravenous administration is preferred.

The compounds of the invention are converted into a form that can be administered and mixed, if necessary, with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers are described, for example, in Ullman's Encyclopedia of Technical Chemistry, v. 4, (1953), 1-39; Journal of Pharmaceutical Sciences, vol. 52 (1963), 918 ff; H.v. Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie and angrenzende Gebiete" (Excipients for pharmacy and related fields); Pharm. Ind. 2.1961.72 onwards; Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete" (Encyclopedia of Excipients for Pharmacy, Cosmetics and Related Areas), Cantor KG, Aulendorf in Wbirttemberg, 1971.

Non-oral administration can be carried out, for example, by intravenous, subcutaneous, intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or by means of ointments, creams or suppositories. If necessary, it is also possible to administer in the form of a sustained release. The implants may include inert materials, such as biodegradable polymers or synthetic silicones, such as, for example, silicone rubber. Intravaginal administration is possible, for example, using vaginal rings. Intrauterine administration is possible, for example, using diaphragms or other suitable intrauterine devices. Additionally, transdermal administration is provided, in particular by using a preparation suitable for the purpose and / or suitable agents, such as, for example, patches.

Oral administration may take place, for example, in solid form in the form of a tablet, capsule, gel capsule, coated tablet, granular preparation or powder, as well as in the form of a drinking solution. The compounds of the invention intended for oral administration can be combined with known and commonly used physiologically tolerable excipients and carriers, such as, for example, gum arabic, talc, starch, sugars, such as, for example, mannitol, methyl cellulose, lactose, gelatin, surface -active substances, magnesium stearate, cyclodextrins, aqueous or non-aqueous vehicles, diluents, dispersing agents, emulsifiers, glidants, preservatives and flavoring agents (for example, essential oils). The compounds of the invention may also be dispersed in microparticle compositions, for example, nanoparticles.

As already explained above, the compounds of the invention can also be combined with other active pharmaceutical ingredients. For the purpose of combination therapy, it is possible to administer to the patient the active ingredients simultaneously or separately, in particular, either in the same way (for example, intravenously), or in different ways (for example, intravenously and in the form of oral administration). They can be present and administered in the same and different amounts in a single dose. It is also possible to use a specific dosing schedule when necessary. In this regard, it is also possible to combine many new compounds of the invention of general formula with each other.

The dose may vary over a wide range depending on the type and / or severity of the physiological and / or pathophysiological condition, route of administration, age, gender, body weight, and sensitivity of the patient to be treated. It is within the scope of a competent person to define a “pharmacologically effective amount” of a compound of the invention and / or an additional pharmacologically active substance. Administration can be carried out in a single dose or in multiple divided doses.

A suitable unit dose is, for example, from 0.0001 mg to 100 mg of the active ingredient, i.e. at least one compound of the invention and, if necessary, at least one additional pharmacologically active substance per kg of patient body weight.

In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmacologically active amount of at least one compound of the invention, in particular, “disrazole A1-succinyl- [D-Lys ⁶ ] LHRH” (regioisomeric compounds 11 and 12), disrazole E1 -succinyl- [D-Lys ⁶ ] LHRH "(regioisomeric compounds 13 and 14), disrazole A1- (succinyl- [D-Lys ⁶ ] LHRH) ₂ " (compound 15), disrazole Z-succinyl-EO- [D- Lys ^6] LHRH "(compound 16) disorazol Z- (glutaril- [D-Lys ^6] LHRH _2" (compound 17) disorazol Z-succinyl-somatostatin "(compound 18), regioisomeric Connections 1 and 2, compound 3, compound 4, regioisomeric compound 5 and 6, Compound 7, Compound 9, Compound 10, Compound 19, Compound 20, Compound 21 '.

In a further aspect, the pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier and / or excipient and / or may include at least one additional pharmacologically active substance.

In a preferred embodiment, this additional pharmacologically active substance is selected from the group consisting of: “DNA topoisomerase I and / or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, hormone receptor agonists and / or growth factors antagonists, signal transduction inhibitors, antibodies to growth factors and their receptors, kinase inhibitors, antimetabolites. "

In a further preferred embodiment, this additional pharmacologically active substance is selected from the group consisting of “actinomycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, colisplase, cisplase cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, docetaxel, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, epothilone, erbitax, erythrohydroxinonisteradinol, eti oposide, fludarabine phosphate, fluoxymesterone, flutamide, gemcitabine, gliivek / gleevec, herceptin, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, meresa, irinothecorfazole, merochloroferfene merorochlorone methropertazine, lacropertamine, lacropertamine, lacropertamine, merocetroperin, meroceroperin, merocetorinum mesna, methotrexate, mitomycin C, mitotan, mitoxantrone, N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, paclitaxel, pentozostatin, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, rapamitz on, semustine, sorafenib, streptozocin, tamoxifen, Tarceva, taxotere, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimetilenamina, uridine vinbalstina, vincristine, vindesine, vinorelbine, 2 ', 2'-diftordezoksitsitidina, 5-fluorodeoxyuridine monophosphate, 5-azacytidine of cladribine, 5-fluorodeoxyuridine, 5-fluorouracil (5-FU), 6-mercaptopurine. "

Regarding pharmaceutical compositions of the invention, at least one compound of the invention is present in a pharmacologically effective amount, preferably in a unit dose, for example, the aforementioned unit dose, especially and preferably in an administration form that enables intravenous administration. In addition, reference may be made to the foregoing in connection with possible uses and administration of the compounds of the invention.

In a further aspect, the objectives of the present invention are unexpectedly achieved by presenting a kit comprising a pharmacologically active amount of at least one compound of the invention and a pharmacologically active amount of at least one additional pharmaceutically active substance as defined above.

Chemical synthesis

This section provides general synthesis methods for the synthesis of disrazole conjugates of the general formulas (I) C1-B1-A-B2-C2 and (IV) C1-B1-A.

General synthesis strategies and / or excretions aimed at producing disrazoles are known in the prior art and, for example, are described in the following prior art documents: see Jansen R et al., Liebigs Ann. Chem. 1994, (8): 759-773; application WO 2004/024149; Wipf et al., Chem. Biol. Drug Des. 2006, 67 (1): 66-73); Hillier MC et al., J. Org. Chem. 2001, 66: 6037-6045; Hartung IV et al., Organic Letters 2002, 4 (19): 3239-3242; Wipf P et al., J. Am. Chem. Soc. 2004, 126 (47): 15346-15347; Carvalho R et al., Gene 2005, 359: 91-98; Kopp M et al., Chembiochem. 2005, 6 (7): 1277-1286; application WO 2006/075013.

Dysrazole Z

can be either completely chemically synthesized in accordance with the above descriptions corresponding to the prior art, or obtained by fermentation, as illustrated in paragraph II) in the Examples section.

The conjugates of the invention are synthesized by conventional methods of solution-based organic chemistry.

A. Derivatization of the secondary hydroxyl groups of a disrazole via esterification with organic anhydrides

In a typical reaction, solid disrazole is dissolved in anhydrous pyridine, previously dried over a molecular sieve (40 nm). In a nitrogen atmosphere, 1-2.5 mol of equivalents of DMAP and 1.5-10 mol of equivalents of organic anhydride (glutaral anhydride, succinic anhydride) are added, as calculated for either mono- or bis-esterification of the two secondary OH groups available in various molecules of disrazole. A molecular sieve is optionally added to the reaction to ensure anhydrous conditions throughout the entire time. The mixture is stirred for 6 hours - 5 days, optionally at room temperature or in a bath at a temperature of 60 ° C, depending on the corresponding desired derivatives. Esterification is monitored by analytical HPLC-UV.

Typical analytical HPLC conditions

Eluent A: 20 mM NH ₄ OAc, 5% (v / v) AcN, 0.2% (v / v) HOAc.

Eluent B: 95% (v / v) AcN, 5% (v / v) H ₂ O.

Column: Merck LiChrosphere 100 C ₁₈ , 5 μm, 250 × 4 mm.

Flow: 1 ml / min.

Detection: UV-DAD, 220-380 nm.

Gradient: 40% -100% B for 18 min, 100% B for 5 min, 100% -40% B for 2 min.

The purification of mono- or bisesterified disrazole is carried out either by automated rapid liquid chromatography using the Isco Companion system or by preparative HPLC. As a result, excess pyridine in the reaction mixture is removed under reduced pressure and the oil residue is acidified with 10% acetic acid to a pH of 4-6. For purification using Companion, the acidified aqueous phase is extracted several times with ethyl acetate, the organic extracts are combined, dried on sodium sulfate and adsorbed onto the material of the carrier of the reversed phase under reduced pressure. Express chromatography is used to purify bis-esterified disrazoles and is carried out under reverse phase conditions using 5% AcN (v / v), 0.1% HOAc as eluent A and 95% AcN as eluent B.

For preparative HPLC, the acidified aqueous mixture was diluted with the starting eluent (50% B), filtered through a syringe with a filter membrane and injected into the preparative HPLC system.

Typical preparative HPLC conditions.

Eluent A: 20 mM NH ₄ OAc, 5% (v / v) AcN, 0.2% (v / v) HOAc.

Eluent B: 95% (v / v) AcN, 5% (v / v) H ₂ O.

Column: Macherey & Nagel VarioPrep Nucleodur 100 C ₁₈ , 7 μm, 250 × 21 mm.

Flow: 20 ml / min.

Detection: UV.

Gradient: 50% B for 5 minutes, 50% -100% B for 25 minutes, 100% B for 10 minutes.

LC (obtained by liquid chromatography) fractions containing the desired products are examined by analytical HPLC, purified from AcN and HOAc under reduced pressure, and the aqueous concentrate is lyophilized to obtain the corresponding esters as solid compounds.

B. Amide Binding of Mono- and Bis-Hemicarboxyl Ethers of Disrazole to Peptides

Mono- and bis-functionalized carboxyl derivatives of disrazole are coupled to peptides using the classic amide binding strategy. Briefly, the carboxyl disrazole compound is dissolved in dry DMF with 3-6 mol equivalents of DIPEA and activated by adding 1.1-1.5 mol equivalents of HATU / free carboxy residue and then stirring for 15 minutes at room temperature. Then the peptide compound carrying the free amino group is added with a slight molar excess (1.1-1.3 equiv.) And the reaction mixture is stirred for 0.5-12 hours at room temperature. The binding efficiency is monitored by analytical HPLC (as described above).

For purification by preparative HPLC, the DMF solution was acidified to pH 5-6 with 10% HOAc and diluted with 4-6 volumes of the initial eluent (40-50% B). The same typical preparative HPLC method is used as described above. Pure conjugates are obtained after evaluating the appropriate fraction of analytical HPLC by removing AcN and HOAc under reduced pressure and subsequent lyophilization of the aqueous concentrate.

C. Amide Binding of Bis-Hemicarboxyl esters of Disrazole with Serum Albumin

The binding of functionalized disrazole derivatives to larger proteins, such as serum albumin, is carried out by means of the NHS / DCC method. Different molar ratios of the protein and the disrazole compound are used to achieve different load ratios of the disrazole and the carrier protein. In a typical reaction, serum albumin is dissolved in 10 mM PBS pH 7.4 at an initial concentration of 20 mg / ml. The following dilution of 1: 1 (v / v) in DMF gives a clear solution of serum albumin with a final concentration of 10 mg / ml. Disisole bis- or mono-hemicarboxyl esters are dissolved in DMF, 1.2-5 equivalents of DCC and 2-10 equivalents of NHS are added and stirred for 20 minutes to allow formation of an activated NHS ester. Activation efficiency is evaluated by analytical HPLC (see above for a typical method). Separate aliquots of this solution are added dropwise and with vigorous stirring to the solution a serum albumin / DMF buffer. The ratios of disrazole-NHS ester and serum albumin are selected based on various load ratios based on empirical data. Amide binding in an aqueous medium is carried out for 20 minutes at room temperature. The slightly turbid reaction mixture is then suction filtered through a SteriCup Filter (Milipore) and the filter is washed with deionized water. Then the filtrate is diluted with deionized water and low molecular weight compounds are separated by ultrafiltration. For this, the diluted SteriCup filtrate is placed in an AmiconUltra (Milipore) filtration chamber with a size exception of 30,000 Da and centrifuged at 4000 × g for 15 minutes. The concentrated solution of the remaining proteins is washed 3 times with deionized water and centrifuged to remove all excess salts, DMF and unbound disrazole and DCC / NHS. Then, the purified serum albumin conjugate and disrazole conjugate solution is lyophilized to obtain pale yellow crystals. The ultrafiltrate is analyzed for unbound disrazole using analytical HPLC using the typical method described above, with the aim of assessing the average levels of loading of a disrazole / serum albumin molecule.

D. Oxidation of disrazoles with Dess-Martin periodinane solution

Disrazoles (e.g. A1, E1 or Z) are dissolved in dichloromethane. Add 12 mol equivalents of pyridine and cool the mixture to less than 5 ° C in an ice bath. Add 3 mol equivalent of Dess-Martin's periodinan reagent (triacetoxyperiodinane) in several portions and the reaction is allowed to mix in an ice bath for 15 minutes. The mixture was warmed to room temperature and stirring was continued for 30 minutes (TLC control, namely dichloromethane / methanol 95: 5). The reaction mixture was diluted with ethyl acetate and poured onto 0.5 N hydrochloric acid. The organic phase is washed with brine until it becomes almost neutral (pH 6), dried over sodium sulfate and evaporated in vacuo. Subsequent flash chromatography using dichloromethane / methanol gives disrazole-ketone derivatives.

E. Abbreviations

5-FU - 5-fluorouracil

AcN - acetonitrile

A1a - Alanine (silt)

Aloe - allyloxycarbonyl

Arg - arginine (silt)

Asn - Asparagine (Il)

BCNU - carmustine

Boc - tert-butyloxycarbonyl

Cbz - carbobenzoxycarbonyl

CCNU - Lomustine

Cit - Citrulline

DCC - N, N'-Dicyclohexylcarbodiimide

DCM - Dichloromethane

DIPEA - Diisopropylethylamine

DMAP - N, N'-4-dimethylaminopyridine

DMEM - Wednesday Needle in the modification of Dalbekko

DMF - N, N'-dimethylformamide

DMSO - dimethyl sulfoxide

Dox - doxorubicin

DTIC - Dacarbacin

for example - an example is given

EDTA - Ethylenediaminetetraacetic Acid

ELISA - enzyme-linked immunosorbent assay

Fmoc - 9-fluorenylmethoxycarbonyl

Gln - Glutamine (Il)

Glp - pyroglutamate (sludge)

hour. - hours

HATU - N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate

HEPES - N- (2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid

HOAc - acetic acid

HOBt - 1-hydroxybenzotriazole

HSA - Human Serum Albumin

hTyr - homothyrosine (sludge)

Hyp - hydroxyproline

Ile - isoleucine (silt)

IPA - isopropyl alcohol

Leu - Leucine (silt)

LH - Luteinizing hormone

LHRH (GnRH) - Luteinizing hormone releasing hormone

LHRH-R - luteinizing hormone releasing hormone receptor

Lys - lysine (silt)

MDS - Methyl Disulfanyl

Me - methyl

D / L-Mel - (4- [bis (2-chloroethyl) amino] -D / L-phenylalanine)

MeOH - methanol

min - min

ml - milliliter

NHS - N-hydroxysuccinimide

Nle - norleucine

PALA - N-phosphonoacetyl-L-aspartate

PEG2 - a polyethylene glycol consisting of 2 ethylene glycol molecules

PEG3 - polyethylene glycol consisting of 3 ethylene glycol molecules

PEG7 - Polyethylene glycol consisting of 4 ethylene glycol molecules

PMS - N-Methyl Dibenzopyrazine Methyl Sulfate

Ru - pyroglutamate (sludge)

RIA - Radioimmunoassay

CT - room temperature

Sar - Sarcosine

tBu - tert-butyl

TEA - Triethylamine

TFA - trifluoroacetic acid

THF - tetrahydrofuran

TLC - thin layer chromatography

Tpi - tetrahydronorgarman-3-carboxylic acid

Trityl - Triphenylcarbonyl

Tyr - tyrosine (sludge)

Val - Valine (silt)

HTT - Sodium

3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid

Brief Description of the Drawings

In figures 1-17 show the measured H-NMR spectra of the selected compounds corresponding to the invention: compounds 1/2, 3, 4, 5/6, 7, 8, 9, 10, 11/12, 13/14, 15, 16 , 17, 18, 19, 20, 21.

The contents of all references and patents are hereby incorporated by reference. The invention is explained in more detail by means of the following examples, however, without being limited thereto.

The implementation of the invention

Examples

1) Synthesis of compounds of the invention

Example 1

Dysrazole E1 mono-hemisuccinate, both regioisomers (1) and (2)

According to the general synthesis method given under the designation A., 30 mg of disrazole E1, 12 mg of DMAP and 150 mg of succinic anhydride are dissolved in 2 ml of dry pyridine and stirred for 4 days at RT under nitrogen. TLC control: DCM-MeOH 9: 1 / DCM-IPA 9: 1 and analytical HPLC. The reaction mixture was poured onto cold brine / 0.5 M HCl and extracted with ethyl acetate, washed with brine to pH 4, dried over Na ₂ SO ₄ and excess solvent was removed under reduced pressure. Purification of the crude was carried out by LC using an Isco Companion using a DCM / MeOH gradient. 13 mg of purified product is obtained as a 1: 1 mixture of both regioisomers 1 and 2 (combined yield: 39%).

LC-MS: [M + H] ⁺ 875.6,

Calculated mass: 874.

H-NMR spectroscopy: see figure 1.

Example 2

Disrazole E1 bis-hemi-glutarate (3)

According to the general synthetic method described under A., 100 mg of disrazole E1, 30 mg of DMAP and 150 mg of glutaric anhydride are dissolved in 3 ml of dry pyridine and 100 μl of TEA are added and stirred for 4 days at RT under nitrogen. TLC control: DCM-MeOH 9: 1 / DCM-IPA9: 1 and analytical HPLC. The reaction mixture was poured onto cold brine / 0.5 M HCl and extracted with ethyl acetate, washed with brine to pH 4, dried over Na ₂ SO ₄ and excess solvent was removed under reduced pressure. Purification of the crude was carried out by LC using an Isco Companion using a DCM / MeOH gradient. 35 mg of purified product is obtained (yield: 24%).

LC-MS: [M + H] ⁺ 1003.7.

Calculated mass: 1002.

H-NMR spectroscopy: see figure 2.

Example 3

Disorazole E1 bis-hemisuccinate (4)

According to the general synthesis method described under A., 138 mg of disrazole E1, 70 mg of DMAP and 730 mg of succinic anhydride are dissolved in 10 ml of dry pyridine, a molecular sieve (4A) is added on the tip of the spatula and the reaction is stirred for 4 days at RT under CT nitrogen. TLC control: DCM-MeOH 9: 1 / DCM-IPA 9: 1 and analytical HPLC. The reaction mixture was diluted with ethyl acetate, poured onto ice-cold brine / HCl pH 3-4, extracted with ethyl acetate, the organic phase was washed with brine to pH 4-5, dried over Na ₂ SO ₄ and excess solvent was removed under reduced pressure. Purification was carried out by LC using an Isco Companion with a DCM / MeOH gradient to give 80 mg of a solid product (39% yield).

LC-MS: [M + H] ⁺ 975.5.

Calculated mass: 974.

H-NMR spectroscopy: see figure 3.

Example 4

Dysrazole A1 mono-hemisuccinate, both regioisomers (5) and (6)

According to the general synthesis method given under the designation A., 30 mg of disrazole A1, 15 mg of DMAP and 160 mg of succinic anhydride are dissolved in 2 ml of dry pyridine and the reaction is stirred for 4 days at RT under nitrogen. TLC control: DCM-MeOH 9: 1 / DCM-IPA 9: 1 and analytical HPLC. The reaction mixture was diluted with ethyl acetate, poured onto ice-cold brine / HCl pH 3-4, extracted with ethyl acetate, the organic phase was washed with brine to pH 4-5, dried over Na ₂ SO ₄ and excess solvent was removed under reduced pressure. Purification was carried out by LC using an Isco Companion with a DCM / MeOH gradient to give 5.3 mg of a solid product containing both regioisomers in a 1: 1 ratio (combined yield of 15%).

LC-MS: [M + H] ⁺ 859.6.

Calculated mass: 858.

H-NMR spectroscopy: see figure 4.

Example 5

Disrazole A1 bis-hemisuccinate (7)

According to the general synthesis method given under the designation A., 138 mg of disrazole A1, 70 mg of DMAP and 730 mg of succinic anhydride are dissolved in 10 ml of dry pyridine, a molecular sieve (4A) is added at the tip of the spatula and the reaction is stirred for 4 days at a CG under nitrogen. TLC control: DCM-MeOH 9: 1 / DCM-IPA 9: 1. The reaction mixture was diluted with ethyl acetate, poured onto ice-cold brine / HCl pH 3-4, extracted with ethyl acetate, the organic phase was washed with brine to pH 4-5, dried over Na ₂ SO ₄ and excess solvent was removed under reduced pressure. Purification was carried out by LC using Isco Companion using a DCM / MeOH gradient to obtain 37 mg of solid product 7 (yield: 20%).

LC-MS; [M + H] ⁺ 959.4.

Calculated mass: 958.

H-NMR spectroscopy: see figure 5.

Example 6

Dysrazole Z mono-hemisuccinate (8)

According to the general synthesis method given under designation A., 80 mg of disrazole Z, 16 mg of DMAP and 13 mg of succinic anhydride are dissolved in 1.5 ml of pyridine and a small portion of a 4 A. molecular sieve is added to the reaction. The mixture is heated to 60 ° C (temperature oil bath) and stirred for 24 hours. The reaction is monitored by HPLC-UV. After cooling to room temperature, ethyl acetate was added and the molecular sieve was filtered off. The filtrate was evaporated to dryness under reduced pressure, the residue was redissolved in 5 ml of a 40% solvent mixture B (A: 20 mM NH ₄ AcO, 5% AcN, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water) . After filtering through a membrane filter with Luer tips, the solution is introduced into preparative HPLC (40% B → 85% B for 25 min). Peaks of hemi monosuccinate were collected and the fraction was lyophilized to obtain 31 mg of pure product 8 as a light brown solid (35%).

LC-MS: [M + H] ⁺ 847.0.

Calculated mass: 846.

H-NMR spectroscopy: see figure 6.

Example 7

Dysrazole Z bis-hemisuccinate (9)

According to the general synthesis method given under the designation A., 188 mg of disrazole Z, 31 mg of DMAP and 500 mg of succinic anhydride are dissolved in 4 ml of pyridine and a small portion of a 4 A. molecular sieve is added to the reaction. The mixture is heated to 40 ° C (oil bath temperature ) and stirred for 72 hours. The reaction is monitored by HPLC-UV and TLC (DCM / MeOH 9: 1). The reaction was diluted with DCM, transferred to an evaporation flask and the solvent was removed under reduced pressure. The crude oil is redissolved in DCM, adsorbed onto silica gel RP18, separated into two similar fractions and used for reverse phase flash chromatography Isco Companion LC (acetonitrile / water / 0.1% acetic acid) with a 12 g reverse phase column. No. 12-14 from passage number 1 and fraction No. 2-3 from passage number 2 are collected, combined and the solvent removed under reduced pressure / lyophilization. Obtain 105 mg of a pale brown product (45%).

LC-MS: [M + H] ⁺ 947.3.

Calculated mass; 946.

H-NMR spectroscopy: see figure 7.

Example 8

Disrazole Z bis-hemi-glutarate (10)

According to the general synthesis method given under the designation A., 183 mg of disrazole Z, 30 mg of 4-DMAP and 560 mg of glutaric anhydride are dissolved in 4 ml of pyridine and a small portion of a 4 A. molecular sieve is added to the reaction. The mixture is heated to 40 ° C (temperature oil bath) and stirred for 72 hours. The reaction is monitored by HPLC-UV and TLC (DCM / MeOH 9: 1). The reaction was diluted with DCM, transferred to an evaporation flask and the solvent was removed under reduced pressure. The crude oil is then dissolved in ethyl acetate and poured onto ice-cold brine / HCl, washed to pH 4-5 with brine / water, dried over Na ₂ SO ₄ and the solvent removed under reduced pressure. The residue was dissolved in DCM and adsorbed onto RP18 silica gel for reverse phase flash chromatography of Isco Companion LC (acetonitrile / water / 0.1% acetic acid). Removal of AcN / acetic acid under reduced pressure and lyophilization of the aqueous concentrate afforded 75 mg (32%) of pure compound 10 as a pale brown solid.

LC-MS: [M + H] ⁺ 975.3.

Calculated mass; 974.

H-NMR spectroscopy: see figure 8.

Example 9

Dysrazole A1 mono-hemisuccinyl [D-Lys ⁶ ] LHRH, both regioisomers (11) and (12)

According to the general synthesis method given under B., 6 mg of disrazole A1 mono-hemisuccinate (1: 1 mixture of both regioisomers) and 3.2 mg of HATU are dissolved in 0.25 ml of DMF. Add 5 μl of DIPEA and mix for 20 minutes at RT to allow formation of an activated ester complex. 10.1 mg of the peptide [D-Lys ⁶ ] LHRH was dissolved in 0.25 ml of DMF, added to the mixture and the reaction was stirred for 1.5 hours at room temperature. The reaction is monitored by HPLC-UV and then the mixture is subjected to preparative HPLC. For this, the reaction mixture was diluted with 1.5 ml of a 40% mixture of solution B (A: 20 mM NH ₄ AcO, 5% AcN, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water). The solution was acidified to pH 6 with approximately 0.1 ml of 10% HOAc. After filtering through a membrane filter with a Luer tip, the solution is introduced into preparative HPLC (40% B → 85% B for 25 min). The main peak was collected and the fraction was lyophilized to give 5 mg of compounds 11 and 12 as a light brown flake (1: 1 ratio, combined yield: 35%).

HR-ESI-MS: (charged state +2) 1048.0.

calculated mass: 2092.

H-NMR spectroscopy: see figure 9.

Example 10

Disorazole E1 mono-hemisuccinyl [D-Lys ⁶ ] LHRH, both regioisomers (13) and (14)

According to the general synthesis method given by B., 40 mg of disrazole E1 mono-hemisuccinate (1: 1 mixture of both regioisomers) and 18 mg of HATU are dissolved in 1 ml of DMF. 25 μl of DIPEA was added and stirred for 15 minutes at RT to allow the formation of an activated ester complex. 54 mg of the peptide [D-Lys ⁶ ] LHRH was dissolved in 1 ml of DMF, added to the mixture and the reaction was stirred for 2 hours at room temperature. The reaction is monitored by HPLC-UV and then the mixture is subjected to preparative HPLC. For this, the reaction mixture was diluted with 3.5 ml of a 40% mixture of solution B (A: 20 mM NH ₄ AcO, 5% AcN, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water). The solution was acidified to pH 6 with approximately 0.5 ml of 10% HOAc. After filtering through a membrane filter with a Luer tip, the solution is introduced into preparative HPLC (40% B - 85% B for 25 min). The main peak was collected and the fraction was lyophilized to give 29 mg of compounds 13 and 14 as a light brown flake (1: 1 ratio, combined yield: 36%).

HR-ESI-MS: (charged state +2) 1056.0.

Calculated mass: 2108.

H-NMR spectroscopy: see figure 10.

Example 11

Dysrazole A1 bis-hemisuccinyl [D-Lys ⁶ ] LHRH (15)

According to the general synthesis method given by B., 15.7 mg of disrazole A1 bis-hemisuccinate and 7.5 mg of HATU are dissolved in 1 ml of DMF. 11 μl of DIPEA was added and stirred for 20 minutes at RT to allow the formation of an activated ester complex. 23.6 mg of the peptide [D-Lys ⁶ ] LHRH was dissolved in 1 ml of DMF, added to the mixture and the reaction was stirred for 2 hours at room temperature. The reaction is monitored by HPLC-UV and then the mixture is subjected to preparative HPLC. For this, the reaction mixture was diluted with 4.5 ml of a 40% mixture of solution B (A: 20 mM NH ₄ AcO, 5% AcM, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water). The solution was acidified to pH 6 with approximately 0.5 ml of 10% HOAc. After filtering through a membrane filter with a Luer tip, the solution is introduced into preparative HPLC (40% B → 85% B for 25 min). The main peak was collected and the fraction was lyophilized to give 18 mg of compound 15 as white flakes (yield: 32%).

HR-ESI-MS: (charged state +4) 858.4.

Calculated mass: 3426.

H-NMR spectroscopy: see figure 11.

Example 12

Disorazole Z mono-hemisuccinyl [D-Lys ⁶ ] LHRH (16)

According to the general synthesis method given by B., 45 mg of disrazole Z of mono-hemisuccinate and 24 mg of HATU are dissolved in 1 ml of DMF. 37 μl of DIPEA was added and stirred for 20 minutes at RT to allow the formation of an activated ester complex. 76 mg of the peptide [D-Lys ⁶ ] LHRH was dissolved in 1 ml of DMF, added to the mixture and the reaction was stirred for 1.5 hours at room temperature. The reaction is monitored by HPLC-UV and then the mixture is subjected to preparative HPLC. For this, the reaction mixture was diluted with 4.5 ml of a 40% mixture of solution B (A: 20 mM NH ₄ AcO, 5% AcN, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water). The solution was acidified to pH 6 approximately 0.75 ml of 10% HOAc. After filtering through a membrane filter with a Luer tip, the solution is introduced into preparative HPLC (40% B → 85% B for 25 min). The main peak was collected and the fraction was lyophilized to give 42 mg of compound 16 as a light brown flake (yield: 38%).

HR-ESI-MS: (charged state +2) 1042.0.

Calculated mass: 2080.

H-NMR spectroscopy: see figure 12.

Example 13

Disrazole Z bis-hemiglutaryl [D-Lys ⁶ ] LHRH (17)

According to the general synthesis method given under B., 35 mg of disrazole Z bis-hemi-glutarate and 34 mg of HATU are dissolved in 1 ml of DMF. 54 μl of DIPEA was added and stirred for 20 minutes at RT to allow the formation of an activated ester complex. 128 mg of the peptide [D-Lys ⁶ ] LHRH was dissolved in 1 ml of DMF, added to the mixture and the reaction was stirred for 2 hours at room temperature. The reaction is monitored by HPLC-UV and then the mixture is subjected to preparative HPLC. For this, the reaction mixture was diluted with 4.5 ml of a 40% mixture of solution B (A: 20 mM NH ₄ AcO, 5% AcN, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water). The solution was acidified to pH 6 with approximately 1 ml of 10% HOAc. After filtering through a membrane filter with a Luer tip, the solution is introduced into preparative HPLC (40% B → 85% B for 25 min). The main peak was collected and the fraction was lyophilized to give 39 mg of compound 17 as white flakes (yield: 33%).

HR-ESI-MS: (charged state +4) 862.4.

Calculated mass: 3442.

H-NMR spectroscopy: see figure 13.

Example 14

Dysrazole Z mono-hemisuccinyl somatostatin (18)

According to the general synthesis method given by B., 20 mg of disrazole Z of mono-hemisuccinate and 21 mg of HATU are dissolved in 1 ml of DMF. Add 15 μl of DIPEA and mix for 15 minutes at RT to allow the formation of an activated ester complex. 25 mg of the synthetic peptide HD-Phe-Cys-Tyr-D-Trp-Lys (Fmoc) -Val-Cys-Thr-NH ₂ × HCl (with sulphide bridges) are dissolved in 1 ml of DMF, added to the mixture and the reaction is stirred for 4 hour at room temperature. The reaction is monitored by HPLC-UV. The crude reaction mixture was diluted with 2 ml of DMF and piperidine was added to a final concentration of 10% (v / v). After stirring for 5 minutes at RT, the mixture was directly subjected to preparative HPLC. For this, the reaction mixture was diluted with 4.5 ml of a 50% mixture of solution B (A: 20 mM NH ₄ AcO, 5% AcN, 0.2% HOAc pH 4.5; B: 95% AcN, 5% water). The solution was acidified to pH 6 with approximately 1.5 ml of 10% HOAc. After filtering through a membrane filter with a Luer tip, the solution is introduced into preparative HPLC (50% B → 100% B for 25 min). The main peak was collected and the fraction was lyophilized to give 12 mg of compound 18 as beige flakes (yield: 33%).

HR-ESI-MS: (charged state + 2) 937.4.

Calculated mass: 1873.

H-NMR spectroscopy: see figure 14.

Example 15

Compound 19

According to the general synthesis method given under the designation D., 20 mg of E1 disrazole are oxidized in order to obtain 10 mg of the diketone product (56%).

LC-MS: [M + H] ⁺ : 771.5.

Calculated mass: 770.

H-NMR spectroscopy: see figure 15.

Example 16

Compound 20

According to the general synthesis method given under the designation D., 25 mg of disrazole A1 is oxidized to obtain 17 mg of a diketone product (67%).

LC-MS: [M + H] ⁺ : 755.6.

Calculated mass: 754.

H-NMR spectroscopy: see figure 16.

Example 17

Compound 21

According to the general synthesis method given under the designation D., 44 mg of disrazole Z are oxidized to obtain 15 mg of the diketone product (29%).

LC-MS: [M + NG: 743.3.

Calculated mass: 742.

H-NMR spectroscopy: see figure 17.

II) Obtaining disrazole Z by fermentation

Dissorazole Z is obtained by fermentation of the producer strain of myxobacteria Sorangium cellulosum Soce 1875 (available in DSMZ under registration No. DSM53600).

Preferably, the seed culture is grown in shake flasks to inoculate the fermenter. The fermentation process is carried out, for example, as a batch or fed.

As a seed culture, a medium is used that includes the following components: 0.8% soluble starch (Merck 1.01252), 0.2% yeast extract, 0.2% fat-free soy flour, 0.1% CaCl ₂ × 2H ₂ O, 0, 1% MgSO ₄ × 7H ₂ O, 8 mg / L Na-Fe-EDTA, 1% HEPES buffer, 0.2% glucose, 1% XAD resin at pH 7.4 at the beginning of cultivation. Shake flasks with seed culture can be incubated at 30 ° C with shaking from 160 rpm. For fermentation, batch fermentation of 70 liters of medium identical to the seed culture medium, but without HEPES buffer with a pH of 7.9 before autoclaving, is used. Add 1% (v / v) XAD (Amberlite XAD 16, Rohm and Haas) to adsorb disrazole Z.

The fermenter is inoculated with one liter of inoculum. Cultivation is carried out at a temperature of 30 ° C, aeration of 5.5 l / min at a stirrer speed of 80 rpm. If necessary, maintain a constant pH at or above 6.8 by adding a 5% KOH solution during fermentation. Residual starch is controlled by an iodine reaction. The glucose concentration is monitored, for example, using test strips (Roche).

A productive culture is ready for harvest when glucose and starch are mostly metabolized and when the concentration of disrazole Z reaches a plateau. Typically, after twelve days, fermentation is stopped and obtained by collecting XAD resin by filtration. Cells that attach to XAD are included in subsequent extraction and purification steps.

For analytical purposes, an aliquot of the fermentation culture is used to collect XAD resin and cell mass, followed by extraction using methanol, a methanol: ethanol: isopropanol system (80: 15: 5), and a final stage using acetone. The extracts are combined, concentrated and analyzed by HPLC-MS.

When using an alternative strain of Sorangium cellulosum, preferably Soce 427 (listed in DSMZ under registration number DSM53419), the following medium can be used for sowing culture: 0.3% starch (Cerestar SF 12618, Cerestar Deutschland, Krefeld), 0.2% fat-free soy flour (Soyamine 50T, Lucas Meyer, Hamburg), 0.1% yeast extract (Marcor), 0.1% magnesium sulfate (Roth, P027.2), 0.05% calcium chloride (Merck, 1.02382), 8 mg / l sodium-iron salts of ethylenediaminetetraacetic acid (Na-Fe-EDTA) (Merck, 108413) and 0.9% HEPES buffer (Roth, 9105.3), at pH 7.5. After autoclaving, a 20% glucose solution (Riedel-de Haen 16301) is added to a final concentration of 0.3% glucose. The same medium is used for fermentation except that the HEPES buffer is used at pH 7.9 before autoclaving.

After fermentation, as described above, the crude cell mass and XAD resin collected by centrifugation of 70 L of fermentation broth Sorangium cellulosum strain So ce427 are extracted with 3 L of methanol each. The combined filtrate was evaporated to give a residual aqueous mixture. If necessary, add water, obtaining 1.2-1.5 l, which are extracted with three portions of 1.2 l of dichloromethane. The combined organic solutions were dried with anhydrous sodium sulfate and then evaporated to dryness. The residue was redissolved in 1 L of aqueous methanol (97%) and separated by three portions of heptane. The methanol layer was evaporated, diluted with toluene and evaporated to dryness. The residue was separated by gel chromatography using methanol on Sephadex LH-20 (Pharmacia) to obtain an enriched fraction of disrazole Z, which was purified by RP-MPLC (ODS-AQ, 120 A, S 16 μm) using a methanol-water system (65/35 ), obtaining a purified disrazole Z.

III) Antiproliferative effect on various tumor cell lines

Selected compounds of the invention are tested for their antiproliferative activity in a proliferation test on adapted tumor cell lines.

In the test used, the activity of cell dehydrogenase is determined, and it makes it possible to determine cell viability and, indirectly, the number of cells.

The cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the SKOV-3 ovarian adenocarcinoma cell line (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138), and the lung cell carcinoma cell line NCI-H460 (NCI 503473). In addition, to study the specific effect of the compounds of the invention on the cell cycle, the RKOp27 cell system is used (see Schmidt M et al. Oncogene 2000, 19 (20): 2423-2429). RKO is a human colon carcinoma cell line (ATCC CRL-2577) in which the p27 ^kip1 cell cycle inhibitor induced by the ecdysone expression system is expressed and can lead to cell cycle arrest, in particular in G2. Non-specifically active substances inhibit proliferation whether cells in G1 or G2 are blocked or not blocked. However, cell cycle specific substances, such as, for example, tubulin inhibitors, are cytotoxic only if the cells are not blocked and the cell cycle is not stopped.

XTT test for cell dehydrogenase activity

Attached growing tumor cell lines KB / HeLa, SKOV-3, SF-268 and NCI-H460 are cultured under standard conditions in an incubator at 37 ° C, 5% CO ₂ and 95% air humidity. On the day of experiment 1, cells were separated using trypsin / EDTA and pelleted by centrifugation. The cell pellet is then resuspended in an appropriate culture medium with the appropriate number of cells and the reaction is carried out in a 96-well microtiter plate. Then the tablets are cultured overnight in an incubator. Test substances are prepared as 1 mg / ml stock solutions in DMSO and diluted to the appropriate concentrations on day 2 of experiment 2 using culture medium. The substances in the culture medium are then added to the cells and incubated in an incubator for 45 hours. As control use cells that are not treated with the test substance. For XTT analysis, 1 mg / ml XTT (sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid) was dissolved in the RPM 1-1640 without phenol red . Additionally, a solution of 0.383 mg / ml PMS (N-methyldibenzopyrazine methyl sulfate) in phosphate buffered saline (PBS) is prepared. On the day of the experiment, 4 75 μg / well of the XTT-PMS mixture was pipetted onto the plates with cells, which by then were incubated with the test substance and substances for 45 hours. For this, shortly before use, the XTT solution is mixed with the PMS solution in a ratio of 50: 1 (vol./vol.). The cell plates are then incubated in a thermostat for the next 3 hours and the absorbance (OD _490nm ) is _determined in a photometer. Using the established (OD _490nm ), the percent inhibition relative to the control is calculated and a semi-log curve of the concentration and action is plotted. IC _{50 is} calculated by regression analysis based on the concentration dependence of the effect using the Graphpad Prism program.

Cell cycle analysis using the RKOp27 model

The analysis is carried out on 96-well plates. Through inducible expression of p27, _kip1 completely blocks cell growth, but they do not die. Based on the activity of induced and non-induced cells, conclusions can be drawn about the mechanism of action (specificity for the cell cycle) of therapeutic drugs. Induced cells are inoculated in approximately triplicate, since division no longer occurs during analysis compared to uninduced cells (20,000 cells / well induced, 6,250 cells / well non-induced). The controls are untreated cells (+/- induction). Induction is carried out with 3 μM muristerone A. On day 1, the cells are exposed (+/- muristerone A) and incubated at 37 ° C for 24 hours. On day 2, add the test substance (control-DMSO) and continue incubation at 37 ° C for the next 45 hours until a standard XTT assay is performed.

Table 1 shows the cytotoxic and / or inhibitory activity growth of the selected compounds in the presence / absence of p27 _kip1 expression compared with the cytotoxic group of doxorubicin, a prior art conjugate of AN-152 and disrazole groups, disrazole A1, E1 and Z, and selected compounds , corresponding to the invention: Z- (glutaryl- [D-Lys ⁶ ] LHRH) ₂ disrazole - compound 17; disrazole Z - succinyl- [D-Lys ⁶ ] LHRH - compound 16; disrazole E1 - succinyl- [D-Lys ⁶ ] LHRH - compounds 13/14; disrazole A1-succinyl- [D-Lys ⁶ ] LHRH - compounds 11/12; disrazole A1 - (Succinyl- [D-Lys ⁶ ] LHRH) ₂ - compound 15.

The tested compounds did not exhibit cytotoxic activity in the induced state of p27 _kpi1 . The results show a very high level of inhibition of proliferation of selected tumor cell lines with selected compounds of the invention. Moreover, the tested conjugates show a clear reduction in toxicity compared to the free unconjugated disrazole groups.

Table 1 Compound IC ₅₀ [μg / ml] KB / HELA SKOV-3 SF-268 NCI-H460 RKOp27 RKOp27 induced Doxorubicin 0.320 0.347 0,305 0.105 0,082 0.124 AN-152 0.871 1,238 1,258 0.558 0.587 0.632 Dysrazole Z 0.001005 0,000504 0,001284 0,000670 0,000659 > 3.16 Compound 16 0.018915 0.007683 0.017800 0.009235 0.005180 > 3.16 Compound 17 > 3.16 > 3.16 > 3.16 > 3.16 > 3.16 > 3.16 Dysrazole Al 0,000049 0.000027 0.000125 0.000022 0,033960 > 3.16 Connections 11/12 0,058930 0.042800 0.113100 0,029660 0,033960 > 3.16 Compound 15 > 3.16 > 3.16 > 3.16 > 3.16 > 3.16 > 3.16 Dysrazole E1 0.000170 0,000074 0,000474 0.000065 0.000170 > 3.16 Connections 13/14 0.018910 0.016850 0,055660 0.012803 0.017240 > 3.16

IV) GnRH Receptor Proliferation Assay

A dose-dependent receptor-mediated inhibition of cell proliferation by selected compounds of the invention is examined. To study these effects, a cell line positive for the human GnRH receptor (hGnRH-R) (5C6; see Beckers et al., Eur. J. Biochem. 1995, 231: 535-543) and negative for hGnRH-R cell line are used. line (LTK-; ECACC No. 8501 1432).

The respective cells are exposed to 1 ml of culture medium in 24-well titration multiplates (MTPs) with a cell number of 15,000 cells / well. The number of cells is adjusted so that after 5 days of testing the untreated control cells are still in the exponential growth phase.

Test compounds give cultured cells after 4 hours of initial growth (adhesion) in a volume of 100 μl, obtaining the final concentration shown in table 2.

After 30 minutes of incubation at 37 ° C, the whole culture medium is aspirated and the cells are washed twice with culture medium without test compounds. After washing, the cells are placed in a thermostat (at 37 ° C, 5% CO ₂ and 95% air humidity) and incubated for the next 4 days. To determine the number of cells after incubation, the cells are separated using trypsin / EDTA and centrifuged. The number of viable cells and the total number of cells are counted using a Vi-Cell Analyzer (Beckman Coulter).

The number of viable cells is analyzed in comparison with untreated control cells (= 100%). Only groups of cells (corresponding wells) are considered in which the overall cell survival exceeds 90%, i.e. inhibition of cell proliferation by nonspecific activity is excluded.

Table 2 presents the proliferation status after 96 hours of incubation of hGnRH-R-positive and -negative cells in the presence and absence of different concentrations of test compounds. The proliferation status of untreated control cells after 96 hours is taken as 100%. The test compounds used are a conjugate according to the prior art AN-152 and the following selected compounds according to the invention: Z- (glutarin- [D-Lys ⁶ ] LHRH) ₂ disrazole - compound 17, Z-succinyl- [D- disrazole Lys ⁶ ] LHRH-compound 16, the disrazole E1-succinyl- [D-Lys ⁶ ] LHRH-compounds 13 and 14, the disrazole A1-succinyl- [D-Lys ⁶ ] LHRH-compounds 11 and 12; disrazole A1- (succinyl- [D-Lys ⁶ ] LHRH) ₂ - compound 15.

All tested compounds of the invention show dose-dependent inhibition of cell proliferation over a 96-hour study period. This inhibition effect is specific, as can be seen from the results obtained with the hGnRH-R-negative LTK-cell line.

table 2 Compound 5C6 cell line LTK- cell line 100 nM 10 nM 1 nM 0.1 nM 100 nM 10 nM 1nM 0.1 nM The control one hundred% one hundred% AN-152 42.1 101.3 Compound 17 41.7 58.5 85.9 95.5 98.0 98.8 99.8 100.9 The control one hundred% one hundred% AN-152 43.9 102.3 Compound 16 21.9 54.1 80.9 83.8 61.7 103,4 105.8 101.8 The control one hundred% one hundred% AN-152 42.1 101.3 Connections 13/14 14.6 45.9 80.8 85.9 27.0 93.2 98.8 98.6 The control one hundred% one hundred% AN-152 43.9 102.3 Connections 11/12 23.5 52,5 80.3 88.0 77,2 101,4 11.5 109.6 The control one hundred% one hundred% AN-152 43.9 102.3 Compound 15 43.0 66.6 98.6 95.1 101.7 108,0 111.3 108.6

V) GnRH receptor-dependent antiproliferative effect of compound 16 in vivo

Nude mice 30 CD 1 nu / nu were inoculated subcutaneously with a GnRH receptor-positive human ovarian carcinoma cell line OVCAR-3 (5 million cells / animal). The experiment begins after the formation of solid tumors. 5 animals / dose group are used.

On day 0 of the experiment, the volume of an individual tumor is determined by palpation and taken as 100%. Test compounds are administered sequentially on day 0 of the experiment by injection into the tail vein of test animals. A standard volume of 10 ml of 0.9% saline / kg (200 μl / 20 g mouse) containing the test compound in the required concentration is administered once only on day 0 of the experiment.

Tumor size is again determined by palpation on day 18 of the experiment. In the case of additional tumors, the volumes are summed.

During the experiment, no toxic effects are recorded, for example, weight loss.

Group Control (saline) Disrazole Z (0.16 mg / kg = 215 nmol / kg) Compound 16 (0.5 mg / kg = 215 nmol / kg) Compound 16 (0.1 mg / kg = 43 nmol / kg) Median Tumor Size Day 0 86 92 74 79 Standard Deviation Day 0 fifteen 34 59 21 Median Tumor Size Day 18 206 146 40 76 Standard Deviation Day 18 165 97 26 64

The results show the growth of untreated tumors, moderate inhibition of tumor growth by disosol Z in the form of monotherapy and clearly increased dose-dependent antiproliferative efficacy obtained by conjugation of disrazole Z with [D-Lys ⁶ ] -LHRH.

Claims (19)

1. Conjugates of disrazoles covered by the general structural formulas (I) or (IV)

,

,
where a represents a disrazole group covered by the General structural formula (III)

,
where Ri _o , Rj _o , Rk _p , Rm _p , R28, R30, R31, R32, R33, R34, R35, R36, R38, R40, R41, R42, R43 and R44 are hydrogen;
Rl _p and Rn _p together form a double bond or are independently selected from the following group: hydrogen, C ₁ -C ₆ alkoxyl;
R27 and R29 together form a double bond or epoxide (oxirane);
R37 and R39 together form a double bond or epoxide (oxirane);
R25 and R26 represents C ₁ -C ₈ alkyl, which may include one double bond, and which is optionally substituted with one, two or three substituents selected from the group of substituents including hydroxyl and —C (O) O — CH ₃ ;
B1 and / or B2 are independently selected from the following linkers: a dicarboxylic acid-based linker, succinyl, glutaryl;
C1 and / or C2 are independently selected from the following cell-binding molecules: LHRH, [D-Lys ⁶ ] -LHRH, somatostatin, somatostatin analog, human serum albumin (HSA);
o is an integer of 1 or 2;
p is an integer of 1 or 2. 2. The conjugates according to claim 1, which are selected from the following group:
disrazole A1-succinyl- [D-Lys ⁶ ] LHRH (regioisomers of compounds 11 and 12)

disrazole E1-succinyl- [D-Lys ⁶ ] LHRH (regioisomers of compounds 13 and 14)

disrazole A1-succinyl- [D-Lys ⁶ ] LHRH (compound 15)

disrazole Z-succinyl- [D-Lys ⁶ ] LHRH (compound 16)

disazole Z- (glutaryl- [D-Lys ⁶ ] LHRH) ₂ (compound 17)

disrazole Z-succinyl-somatostatin (compound 18)

3. The method of producing the disrazole conjugate according to claim 1 or 2, comprising reacting the disrazole compound with a linker, preferably linker anhydride, to produce a mono- and / or bisfunctionalized disrazole-linker group, optionally separating or purifying the mono- and / or bisfunctionalized disrazole -linker groups from reaction products and by-products, the binding of optionally isolated or purified mono and / or bisfunctionalized disrazole linker groups with molecules that bind to the cell, with obtained using a conjugate of a disrazole of formula (I) C1-B1-A-B2-C2 and / or of a formula (IV) C1-B1-A, optionally separating or purifying a conjugate of a disrazole of formula (I) C1-B1-A-B2-C2 and / or formula (IV) C1-B1-A from reaction products and by-products. 4. A pharmaceutical composition for treating tumors, comprising a pharmacologically active amount of at least one disrazole conjugate according to claim 1 or 2. 5. The composition according to claim 4, in which at least one substance is present in a unit dose from 0.0001 mg to 100 mg per kg of body weight of the patient. 6. The composition according to claim 4, which further includes at least one pharmaceutically acceptable carrier and / or excipient. 7. The composition according to claim 5, which further includes at least one pharmaceutically acceptable carrier and / or excipient. 8. The composition according to any one of claims 4 to 7, which includes at least one pharmacologically active substance. 9. The composition of claim 8, which further includes the following pharmacologically active substance: DNA topoisomerase I and / or II inhibitor, DNA intercalator, alkylating agent, microtubule destabilizer, hormone and / or growth factor receptor antagonist and / or growth factor , signal transduction inhibitor, antibody to growth factor and their receptors, kinase inhibitor, antimetabolite. 10. The composition of claim 8, which further includes the following pharmacologically active substance: actinomycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, cisplatin, col , cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, docetaxel, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, epothilone, erbitax, erythrodinutin phosphonidetin phospholitadine phospholitabide Liivec / Gleevec, Herceptin, Hexamethylmelamine, Hydroxyurea, Hydroxyprogesterone Caproate, Idarubicin, Ifosfamide, Interferon, Iressa, Irinotecan, L-Asparaginase, Leucovorin, Mechlorethamine, Medroxyprogesterone Acetate, Mespertanomethane, Mestrofen Mettelotanomet, Megestrolotan M Megestrolitan, Megestrolotan M Mestrolantane, Megestrolotan Mimetrostanetum, Megestrolitan Methomesotanomet, Methyltrimethanomethane, Megestrolitan Methyltrimethanomet, Megestrolitan Methyltrimethanomet, Megestrone Methenotroman N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, paclitaxel, pentozostatin, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, rapamycin, semustine, sorafenib, streptozocin, tamoxifen, tarcevosion testoster, tresseroside, taxotere, taxotere, propotoster t, thioguanine, thiotepa, topotecan, trimethyleneamine, uridine, vinbalstine, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine monophosphate, 5-azacytidine, cladribine, 5-fluoro-5-fluoro-5-fluoro-5-fluoro-5-fluorodeside ), 6-mercaptopurine. 11. The use of the conjugate of disrazole according to claim 1 or 2 for the manufacture of a medicinal product for the treatment of tumors. 12. The use of the disrazole conjugate according to claim 1 or 2 for the manufacture of a medicament for the treatment and / or prevention of acute leukemia, adenocarcinoma, basal cell carcinoma, benign tumors, bladder cancer, colon cancer, brain tumors, breast cancer, bronchial carcinoma, carcinoids , carcinoma, cervical cancer, cervical carcinoma, chronic leukemia, colon cancer, colon carcinoma, colorectal cancer, connective tissue cancer, body carcinoma, endometrial cancer, esophageal cancer, Evig's sarcoma, gast inomas, glioblastomas, gliomas, gynecological tumors, cancer of the head and / or neck, hepatoblastomas, hepatomas, hyperplasias, hyperproliferative diseases, intraocular melanoma, Kaposi’s sarcoma, laryngeal carcinoma, laryngeal cancer, leiomyoma, leukemia, liver tumor, lung cancer, non-small lung cancer , lymphomas, malignant tumors, breast carcinomas, medulloblastomas, melanomas, multiple myeloma, nephroblastomas, neuroblastomas, neuroendocrine tumors, osteosarcomas, ovarian cancer, pancreatic tumors, cancer p growths, prostate carcinomas, rectal carcinomas, kidney cancer, kidney cell carcinoma, retinoblastoma, rhabdoid tumor, sarcoma, skin cancer, soft tissue sarcoma, solid tumors, spinal cell carcinoma, stomach cancer, testicular cancer, thymoma, thyroid cancer, tumors occurring from the brain and / or nervous system and / or meninges, urinary tract cancer and / or uterine cancer. 13. The use according to claim 11, in which the drug further comprises at least one additional pharmaceutically active substance. 14. The use according to claim 11 or 13, in which the drug is used before, and / or during and / or after treatment with at least one additional pharmacologically active substance. 15. The use according to claim 13, in which the drug contains the following pharmacologically active substance: DNA topoisomerase I and / or II inhibitor, DNA intercalator, alkylating agent, microtubule destabilizer, hormone and / or growth factor receptor antagonist and / or growth factor , signal transduction inhibitor, antibody to growth factor and its receptor, kinase inhibitor, antimetabolite. 16. The use according to claim 13, in which the drug contains the following pharmacologically active substance: actinomycin D, aminoglutetimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, cisplazine, col , cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, docetaxel, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, epothilone, erbitax, erythrohydroxytin phosphonide, phosphonidetin phospholitidine phosphonide bean, gliivec / gleevec, herceptin, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, iressa, irinotecan, L-asparaginase, leucovorin, mechlorethamine, medroxyprogesterone acetate, metanotetan metotanecitan metotanmethan metotan metotan metotan metotan metotan metotan metotan metotan metotan metotan metotan metotren megatrol, metotan metotan metotan metotan metotan metotan metotan metotan metotan metotrena metotan metotan metotan metotan metotan metratana metotan metotan metotan metotan metotan mettanotmetan metotan metotan metotan metotrena methotan metotan metotan metotan; , N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, paclitaxel, pentozostatin, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, rapamycin, semustine, sorafenib, streptozocin, tamoxifen, tarcewerot, taxitere, testotoster, taxotere ropionate, thioguanine, thiotepa, topotecan, trimethyleneamine, uridine, vinbalstine, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine monophosphate, 5-azacytidinacladribine, 5-5-fluoro-5-fluoro-5-fluoro-5-fluoride-5-fluoride 6-mercaptopurine. 17. The use according to any one of paragraphs.11, 13, 15 and 16, in which the drug is administered before, and / or during and / or after radiotherapy treatment and / or surgery. 18. A kit for treating tumors containing a pharmacologically active amount of at least one disrazole conjugate according to claim 1 or 2 and a pharmacologically active amount of at least one additional pharmaceutically active substance selected from the group comprising a DNA topoisomerase I inhibitor and / or II, DNA intercalator, alkylating agent, microtubule destabilizer, hormone and / or growth factor receptor agonist and / or antagonist, signal transduction inhibitor, antibody to growth factor and its receptor, inhibitor Op kinase antimetabolite. 19. The kit of claim 18, wherein the additional pharmaceutically active substance is selected from the group consisting of actinomycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, cisplatin, kolaspazu, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, docetaxel, doxorubicin (adriamycin), DTIC (dakarbatsin), epirubicin, epothilone, erbitaks, eritrogidroksinoniladenin, ethinyl estradiol, etoposide, fludarabine phosphate, fluoxymestrone, flutamide, gemcitabine, Liivec / Gleevec, Herceptin, Hexamethylmelamine, Hydroxyurea, Hydroxyprogesterone Caproate, Idarubicin, Ifosfamide, Interferon, Iressa, Irinotecan, L-Asparaginase, Leucovorin, Mechlorethamine, Medroxyprogesterone Acetate, Mespertanomethane, Mestrofen Methenotromanum, Mespertanomethane, Mestrofen Methenotromanum, Mestrocetan Methyltrimethanomethane, Mestrofen Methenotromanum, Megestrolotan, Mestrocetan Metholtanomethan, Mestrocetan Methyltrimethanomet, Mestrocetan Methyltrimethanomet, Mestrocetan Methyltrimethanomet, Megestrone Metanotroman -phosphonoacetyl-L-aspartate (PALA), oxaliplatin, paclitaxel, pentozostatin, plikamycin, prednisolone, prednisone, procarbazine, raloxifene, rapamycin, semustine, sorafenib, streptozocin, tamoxifen, tarcevozone, propotoster, shadow, testosterone, shadow onate, thioguanine, thiotepa, topotecan, trimethyleneamine, uridine, vinbalstine, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine monophosphate, 5-azacytidine acladribine, 5-fluoride, 5-fluoro-fluoride) 6-mercaptopurine.

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