WO1999043317A1

WO1999043317A1 - Necrosis-affine compounds and the utilization thereof in order to produce preparations for pharmacotherapy

Info

Publication number: WO1999043317A1
Application number: PCT/EP1999/001048
Authority: WO
Inventors: Ulrich Speck; Milos Sovak; Heribert Schmitt-Willich
Original assignee: Schering Aktiengesellschaft
Priority date: 1998-02-25
Filing date: 1999-02-22
Publication date: 1999-09-02
Also published as: DE19824653A1; AU2624299A

Abstract

The invention relates to necrosis-affine compounds and to the utilization thereof in order to produce preparations for pharmacotherapy.

Description

Necrosis-affine compounds and their use in the production of

Pharmacotherapy preparations

The invention relates to the object characterized in the claims, that is to say necrosis-affine compounds and their use for the manufacture of preparations for pharmacotherapy.

Necrosis plays an important role in a number of serious illnesses; Examples are arteriosclerosis, inflammatory and degenerative joint diseases, autoimmune diseases, tumors, infarcts, infections and inflammations. Different therapy principles are offered for many of these diseases, among which drug therapy and radiation therapy are important. In both therapy principles, however, the effectiveness is often limited by the side effects to distant organs or tissues.

Substances with affinity for necrosis can direct drugs and radiation therapy into necrosis. The necrosis itself is not capable of treatment.

The important role of necrosis and hypoxic areas is explained using the example of tumors:

The therapy of tumors is based on different principles such as surgery, radiation, chemotherapy, treatment with heat, cold, light, embolization, injection of ethanol etc. Good healing results have been achieved with some types and locations of tumors. However, the effectiveness of the previously available methods and medications is unsatisfactory in other tumor diseases, in the case of an unfavorable location of the tumors or in advanced stages of the disease. This is mainly due to the low selectivity or specificity of the processes mentioned. In most cases, healthy cells are damaged as much by the treatment as the tumor cells, so that there are side effects with the effective dosage, which often reach a life-threatening extent before a healing success is achieved.

Since the available therapeutic agents themselves make little distinction between tumor cells and normal tissue, various methods have been used to limit the treatment or concentration of the drugs to the tumor-infected tissue as far as possible. In the case of pharmacotherapy, there are a number of more or less successful approaches. Drugs can reach higher concentrations in tumors than in healthy tissue due to the better blood supply, the increased capillary permeability and the low lymph drainage. However, they can also be present in lower concentrations than in healthy tissue because of the increased hydrostatic pressure in the tumor, because of less perfusion and thrombosis.

There are 4 types of therapy for better understanding:

1. Radiation therapy using radioactive isotopes

2. Radiation sensitization using drugs that enhance the effect of (X-ray) radiation on the tissue

3. Photodynamic therapy in which light radiation is converted into cytotoxic effects by dyes

4. Pharmacotherapy in the strict sense by using cytotoxic, cytostatic or other substances that inhibit the growth of tumors, without the effect being initiated directly by radiation. However, combination therapy with one of the principles mentioned under 1-3 is not excluded.

In order to increase the concentration of chemotherapeutic agents in the tumor, active substances have been applied to different carriers, e.g. Macromolecules, antibodies, peptides or carbohydrates bound or administered in the form of emulsions, liposomes and other supramolecular structures. In all cases, the drug concentration ultimately achieved in the tumor remains decisive. Even with high affinity and good selectivity, antibodies binding to tumor cells reach poorly perfused tumor areas only slowly and mostly in too low a concentration.

A distinction is made between the following stages in the process of killing tumor cells:

A) Formation of hypoxic areas

These areas are under-supplied with oxygen. The cells do not divide there at all or only very slowly. However, the process is still reversible, with improved oxygen supply, the cells are fully functional again.

B) Formation of fresh necrotic zones

Fresh necrosis can arise primarily through the following processes: Initial therapy of a tumor using the usual methods such as cold, heat, laser, ultrasound, phototherapy, radiation therapy, focused single-time γ-radiation, pharmacotherapy, embolization, destructive fluids, mechanical destruction, antiangiogenic therapy etc. However, the original tissue structure is still preserved, but irreversibly damaged.

C) Formation of old necrotic zones

It occurs from fresh necrotic zones or through slow tissue death, destroying the original tissue structure.

Hypoxic areas of the tumors represent a particular problem for tumor therapy. These areas are undersupplied with oxygen. The cells do not divide there at all or only very slowly. As a result, they are largely radiation-resistant and also insensitive or less sensitive to many cytostatics. The non-cell cycle-dependent drugs reach too low concentrations in the hypoxic areas of the tumors to be effective because of the reduced blood supply. The result is that radiation or drug therapy can often kill the well-perfused parts of the tumors, but the tumor cells survive in the hypoxic areas and later lead to recurrence, possibly with the development of resistance.

Hypoxic areas often appear spontaneously in solid tumors when a certain size is exceeded. However, they can also be the result of a partially successful tumor therapy if well-circulated areas of the tumor which are easily accessible for the therapy die off, without the therapy being immediately successful. In the vicinity of the necrosis, hypoxic areas and districts arise in which dead and surviving cells coexist. These poorly perfused, hypoxic, largely therapy-resistant tumor areas are in many cases the starting point for the relapse after initially successful therapy.

The problem of hypoxic tumor areas is particularly important if the vascular supply to the tumors is itself the goal of the therapy. If the blood supply to solid tumors z. B. by thrombosis or embolization of the tumor vessels or to interrupt the vascular growth stimulated by the tumor itself, the formation of hypoxic surviving peripheral areas of the tumors is very likely, see MS Pepper in Manipulating Angiogenesis. From Basic Science to the Bedside. Arterioscler. Thromb. Vase. Biol., 17, 605-619, 1997.

In the past, only a few substances have been described that can accumulate in hypoxic tissue. B. Misonidazole and analogs to visualize hypoxic regions and tumor perfusion, such as that of LI Wiebe et al in J. Nucl. Med., 34, No. 6, 885-888, 1993 described ¹²³ l-labeled iodoazomycin arabinoside. For an antibody against an intracellular tumor-specific antigen, B. Desrues et al. (Br. J. Cancer, 72, 1076-1082, 1995) found a somewhat higher concentration in necrotizing tumors than in untreated tumors. However, the concentrations used for this application are far below the concentrations required for pharmacotherapy.

There are also some examples of substances that reach higher concentrations in necrosis foci than in the surrounding healthy tissue. A therapeutic application of these compounds did not appear to be promising so far, since the necrosis itself was not regarded as the goal of therapy, since it is already dead tissue.

Thus, increasing the concentration of the active substance in the tumor and reaching the hypoxic areas of the tumor is a goal that has not yet been satisfactorily achieved in pharmacotherapy.

Porphyrins, metalloporphyrins and numerous derivatives are mainly from the field of phototherapy and also tumor diagnostics (W. Ebert et al, Bis-Gd-DTPA-deutero- and Mn-tetraphenylporphyrindehvatives: tumor-selective contrast agents for MRI.The Society of Magnetic Resonance in Medicine , Proceedings of the Twelfth Annual Scientific Meeting and Exhibition August 14-20, 1993, New York, (Poster), Book of abstracts 2, 780, 1993). They also accumulate in fresh necrosis zones.

By Brunner et al, Chem Ber. 1994, 127, 2141-2149, porphyrins with a platinum residue bonded to two side chains at the same time are known. These compounds have antitumor activity, some of which are comparable to cis-platinum itself. A major problem with these compounds is their very poor solubility in water and their toxicity. P. Anzenbacher et al. (Metallotexaphyrin-cisplatin conjugates, International Symposium on Macrocyclic Chemistry, Turtle Bay, Oaku, Hawai, June 7-12, 1998) are texaphyrins to which a cisplatin derivative is bound via a triethylene glycol linker, known.

The object of the invention is to improve the local effectiveness of therapeutic agents in the area of non-neoplastic necrosis. Examples are necrotic areas in and on blood vessel walls due to e.g. Arteriosclerosis, through angioplasty (vasodilation using mechanical methods), laser ablation or stent implantation as well as serious joint diseases, especially rheumatoid arthritis. Other examples are infarcts and immunological diseases. Furthermore, it is an object of the invention to provide therapeutic agents and therapeutic methods which increase the concentration of the active substance in the tumor and at the same time act on the hypoxic areas of the tumors and thus the prospects of healing in tumor therapy also in conjunction with methods which have already been clinically proven and new ones to improve therapy methods aimed at specific biological properties of the tumors. A lower systemic toxicity than previously found in the prior art is desirable.

Surprisingly, it has now been found that the pharmaceutical formulations of necrosis-affine compounds of the general formula I,

N (-W) n (I)

wherein

N a necrosis-affine connection,

W is an active ingredient and n is the numbers 0-4,

of the general formula II

N-L (-W) n (II)

wherein

N a necrosis-affine connection,

L any linker, W is an active ingredient and n is the numbers 0-4,

and the general formula IM

N- (L-W) n (Hl)

wherein

N is a necrosis-affine compound, L is any linker, W is an active substance and n is the numbers 0 -4, preferably the numbers 1-2, in particular the compounds of the formula IV,

(IV)

Formula V

(V)

and Formula VI

to be used in particular as therapeutic agents in the sense of the task formulated above.

Starting from the necrosis, the surrounding diseased, changed or tissue reacting to the necrosis with accelerated growth or neoangiogenesis is treated surprisingly effectively, although this tissue is particularly poorly reached in the usual systemic therapy.

The compounds according to the invention preferably accumulate in fresh necrosis.

Another object of the invention is the combination of pharmaceutical formulations containing at least one necrosis-affine compound and at least one necrosis-producing agent and the use of this combination for the production of a combination preparation for tumor therapy. Necrosis-affine connections are all connections that accumulate in the necrotic tissue.

The following compounds are suitable for appropriate therapy:

1. Cytotoxic necrosis- or hypoxia-affine compounds such as B. oligopyr role, toxic derivatives of porphyrins, metalloporphyrins with α- or ß-radiation-emitting isotopes. 2. Connections of type N (-W) n

Cytostatics or other tumor therapeutics or isotopes that emit α or β rays, which are coupled to necrosis- or hypoxia-related compounds via stable or biodegradable bonds. 3. Compounds of the type N-L (-W) n and N- (L-W) n cytostatics or other tumor therapeutics that have structural elements

("Linker") average molecular weight (approx. 50-1000 D) are coupled to necrosis- or hypoxia-affine compounds, the linker preferably having the task of releasing the actual active ingredients (eg tumor therapeutics) and thus in the vicinity of the already damaged , but particularly therapy-resistant tumor areas for a persistently elevated

To ensure active ingredient concentration.

Preference is given to the necrosis-affine or hypoxia-affine compounds suitable for therapy, which are mentioned under points 2 and 3. They consist of a target-finding component N and a therapeutic component W and, if necessary, a connecting linker L.

The targeting component can be an oligopyrrole, a tetrapyrrole, a porphyrin or a porphyrin derivative, a metalloporphyrin, a nitroaromatic such as e.g. be a 2-nitroimidazole derivative or an antibody. Fragments and partial sequences of the antibodies mentioned, correspondingly binding peptides, oligonucleotides or carbohydrates are also suitable. Oligopyrroles, tetrapyrroles, porphyrins and porphyrin derivatives are preferred. Porphyrins and porphyrin derivatives are particularly preferred.

The therapeutic component can be an α or β radiation-emitting isotope, a cytostatic or a cytotoxic compound, or a biologically active substance and a carrier of genetic information.

8th The cytostatics known to those skilled in the art are, for example, adriamycin, bleomycin, dactinomycin, daunomycin, daunorubicin, doxorubicin, methotrexate (-COOH), mitomycin A, mitomycin C, mitramycin, phenol mustard and platinum complexes of the formulas A or B.

, NH ₃

; pt.

- o '

A:

R

H (CH ₂ ) _n -O N-

B: ^H with R = -CO ₂ CH ₂ CH ₃ , -C0 ₂ H, hydrogen in question.

Biologically active substances can be any drugs, e.g. Growth inhibitors.

The carrier of genetic information can be nucleic acids or nucleic acid fragments.

For the therapeutic component, β-ray-emitting isotopes or one or more cytostatic or one or more cytotoxic compounds are preferred. One or more cytostatic or one or more cytotoxic compounds are particularly preferred.

Both components can be linked either directly or via a linker.

The active ingredient W can also be linked to the target-finding component via more than one bond.

The bond can be stable or cleavable in the organism, e.g. for the binding of therapeutic compounds to polymers via peptide linkers in British J. Cancer, 57, 147-156, 1988 by R. Duncan et al, by H. Maeda et al, Advantages of macromolecular therapeutics in vivo, via hexanoic acid linkers in Bioconjugate Chem., 3, No. 5, 351-362, 1992 or by Y. Takakura et al in Int. Journal of Pharmaceutics, 37, 135-143, 1987.

Other fissile bonds are known to be e.g. Disulfide bridges, esters, amides and hydrazides. They also find application in the invention.

9 Instead of a covalent bond, components with a high specific affinity for one another can also be used. Examples of this are avidin-porphyrin and biotin-cytostatic or biotin-porphyrin and avidin-cytostatic. Other examples are described in WO 96/39124.

The linker which optionally connects both components should have an average molecular weight of 50-1000D and contain at least one carbon, nitrogen, sulfur or oxygen atom. The linker should preferably have the task of slowly releasing the therapeutic component in vivo. The linker itself can be attached to all chemically possible locations on the porphyrin backbone. Its maximum length is 20 atoms. If the targeting component is a porphyrin with a propionic acid side chain, its binding over the propionic acid residue is preferred. The last atom belonging to the porphyrin to count the atoms is then the carbonyl carbon atom of propionic acid.

One embodiment of the invention is represented by peptide linkers. The number of amino acids is between 1 and 10, preferably 2-5 amino acids. The following peptides are particularly preferred: Gly-Phe-Leu-Gly, Gly-Phe-Ala- Leu, Gly-Phe-Ala-Gly, Gly-Gly-Phe-Leu, Ala-Leu-Ala-Leu, Gly -Phe-Gly, Gly-Phe-Leu, Gly-Phe-Phe, Gly-Gly-Phe.

The following linkers are used in a further embodiment of the invention:

Α = linkage to the active ingredient W and ß = linkage to the porphyrin α-CO-CH (CH ₃ ) -NH-ß α-CO-CH- [CH (CH ₃ ) ₂ ] -NH-ß α-CO- ( CH ₂ ) ₁ . ₁₀ -NH-ß α-CO- (CH ₂ ) _1.10 -N (CH ₂ CO ₂ H) -ß α-CO- (CH ₂ ) _1.5 -CH [(CH ₂ ) ₁ . ₅ CO ₂ H] -NH-ß α-CO-CH - [(CH ₂ ) ₁ . ₁₀ -NH-CO- (CH ₂ ) ₀ . ₅ -CH ₃ ] -NH-ß α-CO- (CH ₂ ) ₁ . ₁₀ -CH (CO ₂ H) -NH-ß α-CO-CH ₂ - (CH ₂ -CH ₂ -O) ₀ . ₅ -CH ₂ -CH ₂ -NH-ß

If the target-seeking component porphyrin is linked to an active ingredient only via a propionic acid side chain (if necessary via a linker), so

10 the remaining second propionic acid side chain can be used to bind, for example, solubility-influencing groups, for example polyethylene glycols.

The porphyrin can contain a paramagnetic metal or a γ-emitter such as ^99m technetium or ¹²³ iodine for the detection of the compound.

The necrosis-affine compounds either accumulate after systemic administration in the necrotic and hypoxic areas of tumors or vessel walls etc. or they get there by selective arterial or venous injection or they linger after direct e.g. intratumoral administration over a long period of time, that is to say over hours or days, in the tumors and, moreover, surprisingly, especially in necrotic tissue, form an active substance depot for a substantially longer time than the free active substances. Due to the cytotoxic effect of the therapeutic component, the tissue surrounding the necrosis can also be killed and is thus available for the absorption and storage of further active ingredient, which in turn can then act on the surrounding tissue. A decisive advantage of the necrosis-affine connections is that the critical hypoxic areas, e.g. of a tumor can be detected, and the required concentrations are guaranteed over a long period of time by the depot formation. If the target-finding component is a porphyrin derivative and is itself suitable for one of the above-mentioned therapy methods (especially radiotherapy or phototherapy, or, if necessary, diagnostics), coupling with a cytostatic agent or a cytotoxic compound results in the possibility of combined therapy by administering a single one Connection.

Oligopyrroles are said to be compounds which contain more than one pyrrole ring and a maximum of 6 pyrrole rings which are linked to one another directly or via bridges containing a maximum of three carbon atoms. Oligopyrroles can be linear or cyclic. Examples include dipyromethanes, dipyromethenes, tripyrrole, pyrrole-methylpyrromethenes, bilanes, bilenes, biladienes, bilines.

The term tetrapyrrole only specifies that four pyrroles are linked together. The tetrapyrroles can be linear or cyclic, the pyrrole rings linked or directly linked. The number of bridging carbon atoms should be

11 Do not exceed 3. Corrole, Corrine, Corrologene, De-hydrocorrine, Cobyrinsäurederivate may be mentioned for example.

Porphyrins are cycetic tetrapyrroles. which are linked by methine bridges. The term porphyrins means, for example, chlorin e ₆ , coproporphyrins, cytoporphyrin, deuteroporphyrins, hematoporphyrins, mesoporphyrins, phylloporphyrins, phytoporphyrins, protoporphyrins, pyrroporphyrins, rhodoporphyrins, uroporphyrins.

A particular embodiment of the invention relates to pharmaceutical formulations in which N is a porphyrin of the formula VII

(VII)

wherein the radicals R ¹ independently of one another are CH (OH) CH ₃ , CH (OCH ₂ CH ₂ OCH ₃ ) CH ₃ , CH ₂ CH ₂ Oglucosyl, CH ₂ CH ₂ Ogalactosyl, CH ₂ CH ₃ , CH = CH ₂ and Y and V each represents a hydrogen atom or together a polyvalent metal ion of an element of atomic number 21-32, 37-39, 42-51 or 57-85.

Another embodiment of the invention relates to pharmaceutical formulations in which N is a porphyrin of the formula VIII

12

(VIII)

wherein the radicals R ^{2 are} independently hydrogen, C ₁ -C ₆ alkyl, C ₇ -C ₁₂

Aralkyl or OR ⁴ with R ⁴ in the meaning of hydrogen or

C _r C ₃ alkyl R ³ independently of one another denote hydrogen or OR ⁴ and Y and V each represent a hydrogen atom or together represent a polyvalent metal ion of an element of atomic number 21-32, 37-39, 42-51 or 57-85, stands.

Another embodiment of the invention relates to pharmaceutical formulations in which N is a porphyrin of the formula IX

13 OR

(IX)

wherein the radicals R ⁵ independently of one another for hydrogen, an alkyl chain - (CH ₂ ) _n -γ with n = 1-6, which can optionally be interrupted by 1-3 oxygen atoms and / or can be substituted by -OH, OCH ₃ or OCH ₂ CH ₃ , -CO- (CH ₂ ) _n -CO-γ or - (CH ₂ ) _n CO-γ, with γ meaning the point of attachment to the active ingredient W, and V and Y in the meaning given above , stands.

The metal ions of Zn, Cu, Fe, Mn are preferred for this embodiment.

With C ^ Ce alkyl all straight-chain or branched saturated alkyl radicals with 1 to 6 carbon atoms are meant.

C ₇ -C ₁₂ aralkyl means, for example, the benzyl radical, the 1-naphthylmethyl radical, the 1-naphthylethyl radical, the 2-naphthylmethyl radical, the 2-naphthylethyl radical.

The tetraphenylporphyrins can be as described in DE 43 05 523.0 or as described by L.R. Milgram in "The colors of life", p. 210, Oxford University Press, 1997 and described in the literature cited there.

14 Another embodiment of the invention relates to pharmaceutical formulations containing porphyrins of the formula X.

CO CO

O O

Pt

NH ₃ NH ₃

(X)

wherein the radicals R ² , R ³ , V and Y have the meanings listed for porphyrins of the formula VIII, for the production of active substance depots in necrosis and their use for necrosis-affine therapy.

The compounds as such are from H. Brunner et al., Inorg. Chim. Acta, Vol. 264, 67-79 (1997) of known.

Porphyrin derivatives are understood to mean all known structures derived from the tetrapyrroles, including porphyrins, metalloporphyrins, boronoporphyrins, benzoporphyrins, cobyrinic acid derivatives, texaphyrins and their conjugates with other substances such as, for example, with oligonucleotides, other biologically active substances or avidin / biotin.

The term metalloporphyrins means all porphyrins or porphyrin derivatives which either contain metal ions complexed by the nitrogen atoms in the center of the ring or have metal ions complexed by complexing agents present on the side chains.

15 As known from the literature, metal ions which are complexed by porphyrins are, for example, the ions of atomic numbers 21-32, 37-39, 42-51 and 57-83. Fe, Cu, Mn, Zn, Co, Gd, for example, are suitable for complexation in porphyrin or via side chains.

The metal ions suitable for radiation therapy are known to the person skilled in the art. The metal ions are said to comprise isotopes emitting α and β rays. A half-life in the range from hours to months is advantageous, as a result of which a very selective therapeutic effect can be achieved in the immediate vicinity of the necrosis zone. Examples include isotopes such as ²¹² Bi, ^{2 0} At, ⁸⁹ Sr, ⁹⁰ Y, ¹⁵³ Sm, ¹⁸⁶ Re, ¹⁸⁸ Re.

The term “radiation-emitting isotope” is intended to include the boron which is decayed by thermal neutrons.

Boronoporphyrins are understood to mean all porphyrin derivatives which have bound boron in any form for the purpose of BNCT. For example, Ni-carboranylphenylporphyrin, 7,12-bis [1, 2- bis [(dicarbododecaboran (12) -1-ylcarbonyl) oxy] ethyl] -3,8,13,17-tetra-methyl-12H, 23H-porphin -2, 18-dipropanoic acid, 2,4-divinyl-o-nidocarboranyl-deutero-porphyrin IX, called boronotetraphenylporphyrin.

Benzoporphyrins are porphyrins that contain aromatic structures in addition to the pyrroles.

Texaphyrins are porphyrin derivatives whose ring structure is expanded, e.g. in US 5,622,946.

Antibodies are understood to mean antibodies against cell components that occur intracellularly in healthy cells or antibodies against extracellular or membrane-bound antigens that are increasingly expressed under conditions of hypoxia.

The necrosis-affine compounds can be administered directly into different types of tissue or into the tumor. A tumor can be achieved by infusing the active substances into tumor-supplying vessels or by intravenous injection or infusion. Other local modes of administration are possible, e.g. instillation into cavities, oral, rectal, topical or bronchial

16 Administration. Repeated administration leads to accumulation in the necrotic areas due to the desired long residence time of the active ingredients and thus to an increased exposure of the active ingredients to the peripheral zones.

If components with high and specific affinity for one another are used instead of necrosis-affine compounds with covalent bonding, the components can be mixed with one another before use, or the target-finding component can be injected minutes to days before the therapeutic component.

The dosage depends on the therapeutic effectiveness of the substances concerned. This can fluctuate over a wide range. The dose for single administration in the case of systemic administration (e.g. intravenous, intraarterial) is between approximately 10 mg and 10 g, preferably between 100 mg and 10 g; with local administration in cavities, tissues or small vessels, the dose can be reduced to approx. 1 mg - 1 g, preferably 10 mg - 500 mg.

The usual concentrations are between 0.1 mg / ml and 100 mg / ml, whereby none of the specified limit values is to be regarded as a strict limit.

In the case of therapeutically effective radioisotopes, the dose and concentration must be measured so that the tissue to be treated receives the dose of approx. 50-100 Gy recognized for radiation therapy; this dose can also be administered in fractions.

The auxiliaries, solubilizers, emulsifiers and stabilizers customary in pharmacy are used for the preparation. The type of preparation, the concentration of the active ingredients and the dosage are adapted to the needs within wide limits. Special, otherwise less common preparations are for direct z. B. provided by ultrasound or computer tomography or by magnetic resonance imaging controlled intratumoral administration. In these cases, e.g. For example, a high-percentage ethanolic solution can be used to create or intensify necrosis. The solution can be used at a deliberately unphysiological pH or have other properties which damage the tissue in the immediate vicinity. The decisive factor is that the substances described spontaneously form a depot in the necrosis, from which a lasting effect on the surrounding structures including the laxative

17 the lymphatic system is exercised. For better control of the distribution of the preparations, in particular after intraarterial, intratumoral or intracavitary administration, it is known that X-rays, computer tomography, magnetic resonance imaging, ultrasound or optically detectable components can be added or, if appropriate, be bound directly to the necrosis-affine component, for example Mn ²⁺ in porphyrins. Such include the known iodinated or magnetic contrast agents, lipids, gases and dyes.

Non-physiological necrosis-producing media that are harmless after dilution are ethanol, other organic bases such as e.g. Ethanolamine, inorganic bases such as e.g. Sodium bicarbonate, inorganic and organic acids such as e.g. Acetic acid.

The pharmaceutical preparations can be in the form of solutions, emulsions or suspensions.

Compounds with affinity for necrosis and hypoxia particularly increase the effectiveness of the embolizing agents for the treatment of tumors, e.g. Hepatocellular carcinoma when added to the embolizing solution at a concentration of 1-500 mmol or when injected or infused into blood vessels that supply the diseased area after the embolizing agent has been administered.

18th The following examples serve to explain the subject matter of the invention in more detail, without wishing to restrict it to them.

example 1

Example 1a

20 mmol of manganese (III) - {tetrakis [3- (carboxylatomethoxy) phenyl] porphyrin} acetate (WO 94/19352) are dissolved in 1000 ml of 0.9% NaCl, adjusted to pH 7.0 using 2N NaOH and sterile filtered. 2 ml of the undiluted solution are slowly infiltrated into the necrotic center of an approximately 15 ml large pancreatic carcinoma. The porphyrin derivative reduces the risk of relapse.

In addition, the treatment can be combined with the usual radiation therapy or chemotherapy.

Example 1b

The solution described in Example 1a is infiltrated into the necrosis cavity after laser therapy of an approximately 6 ml liver metastasis. A recurrence is prevented.

Example 1c

The solution described in Example 1a is thickened with 125 mg / ml hydroxyethyl starch and introduced in this form in a dose of 20 ml into the operating cavity after removal of an approximately 100 ml large osteosarcoma before closure. There is a persistent growth inhibition.

19 Example 2

Example 2a

500 mmol mesoporphyrin-IX-13,17-bis [2-oxo-4,7,10,10-tetra- (carboxylatomethyl) -1,4,7,10-tetraazadecyl] -13,17-diamide (WO 94/07894) are dissolved in 900 ml of water, adjusted to pH 6.5 with 2N NaOH, the solution made up to 1000 ml and sterile filtered. 0.5 ml of the solution in question is infiltrated into the necrotic center of a VX-2 tumor. Within 14 days, the tumor clears from the inside without additional therapeutic measures, in particular without exposure to light.

Example 2b

The porphyrin derivative mentioned under 2a is complexed with 153-samarium ³⁺ in the form of a salt at pH 7. 100 MBq are dissolved in 50 ml of physiological NaCI and slowly infused into the tumor-supplying arteries of a VX-2 tumor. There is rapid uptake in necrotic portions of the tumor. The treatment is particularly effective when parts of the tumor have been necrotized by other therapy (eg radiation) that has been carried out for a short time without the blood supply to the peripheral zones being interrupted.

Example 3

Rhenium complex

Example 3a

Preparation of mesoporphyrin-IX-diacid chloride

Mesoporphyrin-IX (1.0 g; 1.7 mmoles) is suspended in 50 ml of tetrahydrofuran and cooled to 0 ° C. 0.5 g (4.1 mmol) of thionyl chloride are added dropwise from a dropping funnel and the reaction mixture is allowed to warm up again to room temperature. After 12 hours the volatiles are removed, the product is dissolved in chloroform and extracted with dilute bicarbonate. After crystallization, the product is isolated as a solid. Yield (0.75 g), 71%

20th Example 3b

Preparation of mesoporphyrin-lX-dialdehyde

0.75 g (1.2 mmol) of the compound obtained from Example 3a are dissolved in 100 ml of diglyme and the solution is cooled to -10 ° C. 2.6 ml LiAIH (O ^l Bu) ₃ (1M in tetrahydrofuran) are added and the solution is allowed to warm to room temperature. The solution is cooled to 0 ° C and carefully quenched with water. The product is extracted with methylene chloride and purified by crystallization from chloroform / hexane. Yield 0.55g (0.99mmol), 82%

Example 3c

display of

0.5 g (0.90 mmol) of the compound prepared in Example 3b and 1.4 g (1.9 mmol) of 4,7-diaza-5-oxo-2,9-dimethyl-2,9-bis- [ (triphenylmethyl) mercapto] - decane are dissolved in 50 ml of methanol / 20 ml of chloroform and heated gently under reflux for 20 minutes. 0.18 g (2.8 mmol) NaBH ₃ (CN) are dissolved in 10 ml methanol and added for the reaction. After stirring for 3 hours, the volatiles are removed and the product is purified by column chromatography (a chloroform / acetone gradient is used) to obtain a solid. Yield 0.89 g (0.45 mmol), 50%

21 Example 3d

Representation of the ¹⁸⁶ Re rhenium complex

¹⁸⁶ Re is generated from ¹⁸⁶ W as a perrhenate ion and inserted according to a typical literature procedure (eg see Winnard et al. J. Nucl. Med. 1994, 35, 260). ¹⁸⁸ Re can also be complexed.

Example 4

Example 4a

0.2 mCi of the ¹⁸⁶ Re complex obtained in Example 3d in 2 ml of 5% mannitol solution are infiltrated into spontaneously necrotizing tumor areas. The treatment can be repeated after days to weeks.

1fifi 188

Re can be used instead of Re.

The radioactive preparation can also be infiltrated into arterial walls via commercially available special catheters in order to avoid restenosis due to vascular wall hyperplasia after angioplasty. If necessary, the dose should be applied gradually and adjusted by external dosimetry.

Example 4b

30 mCi of the 1 ^l 8 ^o 6 ^o rRe complex obtained in Example 3d, dissolved in 10-100 ml of physiological NaCl, are selectively infused into tumor-supplying vessels. The tumors should contain spontaneous or therapeutically induced necrotizing parts; the infusion takes place within 5 min. up to 2 hours; the treatment can be repeated over the course of days or weeks.

22 Administration can also be selective in arteriosclerotic arteries, e.g. B. after angioplasty and stent implantation. The dosage can be done by simultaneous measurement of the locally deposited radioactivity.

Example 4c

100 mCi / m ^{2 of the} body surface of the ¹⁸⁶ Re complex obtained in Example 3d, dissolved in 500 ml of physiological NaCl, are intravenously infused with spontaneously necrotizing tumors or, as a result of therapeutic measures, partially necrotic tumors.

Example 5

Platinum complex

Example 5a Mesoporphyrin IX dihydrazide is prepared as indicated in WO 94/07894.

Example 5b

display of

1.05 g (5.1 mmol) of D.cyclohexylcarbodiimide, 1.15 g (10 mmol) of N-hydroxylsuccinimide and 0.66 g (3.5 mmol) of 8,9-bis (N, N-dimethylamino) nonanoic acid are dissolved in 100 ml chloroform. After stirring for 3 hours at room temperature, a solution of the mesoporphyrin IX dihydrazide (1.0 g, 1.6 mmol) from example 5a in tetrahydrofuran is quickly added and the mixture is stirred for 24 hours. The volatiles are removed and the crude product is purified by column chromatography to obtain a solid. Yield 1, 19g (1, 2mmol), 78%

23 Example 5c

display of

1.0 g (1.04 mmol) of the compound obtained in Example 5b and 1.03 g (2.3 mmol) of bis (dimethyl sulfide) platinum dichloride are combined in a flask under nitrogen and dissolved in anhydrous chloroform at room temperature. The yellow solution obtained is heated to 60 ° C. for 24 hours. The reaction mixture is cooled to room temperature and the volatile constituents are removed. The crude product is purified by column chromatography (chloroform / methanol) to obtain the platinum compound as a solid. Yield 1, 05g (0.71 mmol), 68%

Example 6

Example 6a

10 mmol of the platinum compound obtained from Example 5c are dissolved in 1000 ml of buffered physiological saline and filtered.

Example 6 b

1 ml of the solution according to Example 6a is infiltrated into a prostate carcinoma immediately after freeze ablation. The treatment is repeated after 3 days.

24 Example 6c

5 ml of the solution according to Example 6a are processed with 10 ml of Lipiodol (Guerbert, Paris) to form an oil in water emulsion. The freshly prepared emulsion is injected in a volume of 10 ml into the tumor-supplying branch of a hepatic artery of a patient with solitary approximately 80 ml hepatocellular carcinoma. The treatment can be repeated if necessary.

Example 6d

50 ml of the solution according to Example 6a are diluted 1: 2 with 5% glucose solution. The solution is infused into the hepatic artery of patients with liver metastases at a rate of 1 ml / hour.

Example 6e

Patients with tumors necrotizing spontaneously or after therapy receive 1 ml / kg body weight of the solution according to Example 6a after dilution with physiological NaCl in a ratio of 1: 1 - 1:10 over a period of 30 min. - Infused intravenously for 12 hours. The treatment can be repeated at intervals of days to weeks until a clear healing success is achieved without unacceptable side effects.

Example 6 f

The treatment according to Example 6d or 6e can also be carried out in patients with severe arteriosclerosis, in particular with ulcerating plaques and after angioplasty with or without stent implantation. In the case of arterial administration, the solution according to Example 6d is infused into the affected or treated vessels in the course of a diagnostic catheterization or a therapeutic intervention.

Example 7

Monoamide from 13,17-bis (2-carboxyethyl) -3,8-diethyl-2,7, 12,18-tetramethyl-porphinato-manganese (III) chloride and glycyl-L-phenylalanyl-L-leucyl- glycyl-doxorubicin amide (Gly-Phe-Ala-Gly-DOX)

7a) Fmoc-Gly-Phe-Leu-Gly-OH

To a solution of 1.76 g (4.5 mmol) glycyl-L-phenylalanyl-L-leucyl-glycine (T. Ouchi et al., Reactive & Functional Polymers 37, 235 (1998)) in 10% aqueous solution.

25th sodium carbonate solution, 1.16 g (4.5 mmol) of 9-fluorenylmethoxycarbonyl chloride in dioxane were added at 0 ° C. and the mixture was then stirred at 20 ° C. for 4 hours. The pH was then adjusted to 2 by adding 1 N HCl and the mixture was shaken first with diethyl ether and then with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate, filtered and the filtrate was evaporated to dryness.

Yield: 2.20 g (80% of theory) of a colorless powder. Elemental analysis: calc .: C 66.44 H 6.23 N 9.11 found - C 66.16 H 6.35 N 8.97

7b) Fmoc-Gly-Phe-Leu-Gly-Doxorubicin

461 mg (0.75 mmol) of Fmoc-Gly-Phe-Leu-Gly-OH were dissolved in 5 ml of dimethylformamide at 10 ° C with 0.19 g (0.9 mmol) of dicyclohexylcarbodiimide and 104 mg (0.9 mmol) of N -Hydroxysuccinimide added and stirred for half an hour. Then 0.38 g (0.65 mmol) of doxorubicin hydrochloride and 111 μl (0.65 mmol) of N, N-diisopropylethylamine in 2 ml of DMF were added and the mixture was stirred at room temperature overnight. The solution was evaporated in vacuo and the crude product was chromatographed on silica gel (eluent: dichloromethane / methanol 9: 1).

Yield: 385 mg (52% of theory) of a reddish powder. MALDI-TOF mass spectrum: m / z = 1140 elemental analysis: calc .: C 64.26 H 5.75 N 6.14 found: C 66.03 H 5.88 N 6.29

7c) Manganese mesoporphyrin hydrochloride

8.5 g (12 mmol) of manganese (III) -mesoporphyrin dimethyl ester (LJ Boucher, J. Amer. Chem. Soc. 92, 2725 (1970)) in 600 ml of tetrahydrofuran / water (1: 1) were mixed with 60 ml of 1N Sodium hydroxide solution added and stirred for 3 hours at room temperature. The organic solvent was then evaporated in vacuo, the aqueous solution by adding conc. HCl adjusted to pH 3.5 and the precipitate formed is suction filtered, washed with water, then resuspended in water and freeze-dried.

26 Yield: 6.5 g (87% of theory) of a deep red powder.

Elemental analysis: calc .: C 62.34 H 5.54 N 8.55 Mn 8.39 Cl 5.41 found - C 62.53 H 5.60 N 8.77 Mn 8.68 Cl 5.17

7d) monoamide from 13,17-bis (2-carboxyethyl) -3,8-diethyl-2,7,12,18-tetra-methyl-porphinato-manganese (III) chloride and glycyl-L-phenylalanyl-L- leucyl-glycyl-doxorubicin amide (Gly-Phe-Ala-Gly-DOX)

A 5% solution of piperidine in tetrahydrofuran was added to 114 mg (0.1 mmol) of Fmoc-Gly-Phe-Leu-Gly doxorubicin (see FIG. 7b) and the mixture was stirred at 25 ° C. for 20 minutes. Diethyl ether was then added until precipitation was complete, and the residue was stirred overnight with diethyl ether. The solid was filtered off, dried (92 mg, quantitative) and the H-Gly-Phe-Leu-Gly doxorubicin obtained reacted without further purification. 131 mg (0.2 mmol) of Mn-mesoporphyrin (Example 7c) were at 0 ° C in tetrahydrofuran with 41.3 mg (0.2 mmol) of dicyclohexylcarbodiimide and 46 mg (0.4 mmol) of N-hydroxysuccinimide added, after 30 minutes a solution of 15 μl (0.5 mmol) of triethylamine and 92 mg (0.1 mmol) of the H-Gly-Phe-Leu-Gly-Doxorubicin released in tetrahydrofuran was added and overnight at 22 ° C stirred. The reaction mixture was evaporated in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol 3: 1). Yield: 83.5 mg (55% of theory) of a deep red powder. MALDI-TOF mass spectrum: m / z = 1519

Elemental analysis: calc .: C 61, 79 H 5.77 N 8.11 Mn 3.53 Cl 2.28 found: C 61, 91 H 5.84 N 8.21 Mn 3.63 CI 2.01

Example 8

Monoamide from 13,17-bis (2-carboxyethyl) -3,8-diethy 1-2,7,12,18-tetramethyl-porphinato-manganese (III) chloride and doxorubicin

0.33 g (0.5 mmol) of Mn-mesoporphyrin (see 7c), 115 mg (1 mmol) of N-hydroxysuccinimide and 60 mg (0J mmol) of doxorubicin hydrochloride were dissolved in dichloro-

27 dissolved methane, with 31 mg (0.15 mmol) of dicyclohexylcarbodiimide and 100 μl

Triethylamine added and stirred overnight at room temperature.

The reaction mixture was evaporated in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol 3: 1).

Yield: 70 mg (59%) of a dark red powder.

Elemental analysis: calc .: C 62.06 H 5.38 N 5.93 Mn 4.65 Cl 3.00 found - C 62.30 H 5.44 N 5.80 Mn 4.71 Cl 2.79

Example 9

Amide from 17- (4-aza-17-carboxy-3-oxo-7,10,13,16-tetraoxa-heptadecyl) -13- (2-carboxyethyl) -3,8-diethyl-2,7,12, 18-tetramethyl-porphinato-manganese (III) - chloride and glycyl-L-phenylalanyl-L-leucyl-glycyl-doxorubicin amide (Gly-Phe-Ala-Gly-DOX)

58 mg (0.5 mmol) of N-hydroxysuccinimide and 103 mg (0.5 mmol) of dicyclohexylcarbodiimide were added to 155 mg (0J mmol) of the title compound from Example 7d at 0 ° C. in dimethylformamide and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo and chromatographed on silica gel (eluent: gradient dichloromethane / dimethylformamide). After evaporation of the dichloromethane in dimethylformamide, 75 mg (0.3 mmol) of 14-amino-3, 6,9,12-tetraoxatetradecanoic acid and 15 μl (0.5 mmol) of triethylamine were added to the active ester obtained in this way, and again at room temperature for 2 days touched. The reaction mixture was mixed with 1 ml of 1N HCl, evaporated in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol 3: 1). Yield: 123 mg (69% of theory) of a deep red powder. Elemental analysis: calc .: C 60.45 H 6.09 N 7.83 Mn 3.07 Cl 1.98 found: C 60.71 H 5.97 N 8.04 Mn 3.21 Cl 1.64

28 Example 10

Bisamide from 13,17-bis (2-carboxyethyl) -3,8-diethy 1-2,7,12,18-tetramethyl-porphinato-manganese (III) chloride and glycyl-L-phenylalanyl-L-leucyl-glycyl - doxorubicin amide (Gly-Phe-Ala-Gly-DOX)

A 5% solution of piperidine in tetrahydrofuran was added to 228 mg (0.2 mmol) of Fmoc-Gly-Phe-Leu-Gly doxorubicin (see FIG. 1b) and the mixture was stirred at 25 ° C. for 20 minutes. Diethyl ether was then added until precipitation was complete, and the residue was stirred overnight with diethyl ether. The solid was filtered off, dried (184 mg, quantitative) and the H-Gly-Phe-Leu-Gly doxorubicin obtained was reacted without further purification. 65 mg (0.1 mmol) of Mn-mesoporphyrin (Example 1c) at 0 ° C in tetrahydrofuran / dimethylformamide (1: 1) with 41.3 mg (0.2 mmol) of dicyclohexylcarbodiimide and 46 mg (0 , 4 mmol) of N-hydroxysuccinimide were added, after 30 minutes a solution of 30 μl of triethylamine and 184 mg (0.2 mmol) of the H-Gly-Phe-Leu-Gly doxorubicin released in tetrahydrofuran were added and overnight at 22 ° C stirred. The reaction mixture was evaporated in vacuo and chromatographed on silica gel (eluent: gradient dichloromethane / dimethylformamide). Yield: 174 mg (71% of theory) of a deep red powder. Elemental analysis: calc .: C 61, 65 H 5.83 N 7.99 Mn 2.24 CI 1.44 found - C 61, 81 H 5.80 N 8.08 Mn 2.33 Cl 1, 18

29

Claims

claims

1. Pharmaceutical formulation containing therapeutically active necrosis-affine compounds.

2. Pharmaceutical formulation according to claim 1, characterized in that it has necrosis-affine compounds of the general formula I.

N (-W) n (I)

wherein

N a necrosis-affine connection,

W contains an active ingredient and n denotes the numbers 0-4.

3. Pharmaceutical formulation, characterized in that it has therapeutically active necrosis-affine compounds of the general

Formula II

N-L (-W) n (II)

wherein

N contains a necrosis-affine compound, L any linker, W an active ingredient and n denotes the numbers 0-4.

4. Pharmaceutical formulation, characterized in that it has therapeutically active necrosis-affine compounds of the general formula III

N- (L-W) n (III)

wherein

N a necrosis-affine connection, L any linker,

W contains an active ingredient and n denotes the numbers 0 -4.

30th

5. Pharmaceutical formulation according to claims 2 to 4, characterized in that the necrosis-affine compound N is an oligopyrrole.

6. Pharmaceutical formulation according to claims 2 to 4, characterized in that the necrosis-affine compound N is a porphyrin, a porphyrin derivative or a texaphyrin.

7. Pharmaceutical formulation according to claim 6, characterized in that the porphyrin, the porphyrin derivative or the texaphyrin contains a metal.

8. Pharmaceutical formulation according to claim 2 to 4, characterized in that the active ingredient W is a cytostatic or a cytotoxic compound.

9. Pharmaceutical formulation of necrosis-affine compounds according to claims 1 to 8, characterized in that it generates drug depots in necrosis.

10. Pharmaceutical formulation of necrosis-affine compounds according to claim 9, characterized in that it produces active substance depots in fresh necrosis.

11. Pharmaceutical formulation according to claims 1 to 7, characterized in that it contains radioactive isotopes suitable for therapy.

12. Pharmaceutical formulation according to claim 11, characterized in that it contains β-radiation-emitting isotopes bound to a necrosis-affine compound.

13. Pharmaceutical formulation according to claims 1 to 9 and 32, characterized in that it is used for the production of preparations for pharmacotherapy.

14. Pharmaceutical formulation according to claim 8 containing a necrosis-affine compound with one or more β-radiation-emitting isotope (s) bound to it for the production of preparations for combined pharmacotherapy and radiation therapy.

15. Pharmaceutical formulation according to claims 1 to 9 including the hematoporphyrin derivatives containing a platinum-II complex bound via the two natural propionic acid side chains, characterized in that it is used for the preparation of preparations for restenosis prophylaxis.

16. Pharmaceutical formulation according to claims 1 to 9, characterized in that it is used for the production of preparations for the treatment of rheumatoid arthritis, arteriosclerosis, immunological diseases,

31 local infection or infarction is used, with no external radiation required.

17. Combination of pharmaceutical formulations containing at least one therapeutically active necrosis-affine compound and at least one necrosis-producing agent.

18. Combination according to claim 17, characterized in that the pharmaceutical formulation of the necrosis-affine compound are the formulations claimed in claims 1 to 8 and 32.

19. Combination according to claims 17 and 18, characterized in that the necrosis-generating agent is an embolizing agent.

20. Combination according to claim 17, characterized in that the pharmaceutical formulation containing a necrosis-affine compound and the pharmaceutical formulation containing necrosis-producing agents are present in separate dose units.

21. Combination according to claim 20, characterized in that the dose units are given separately or simultaneously.

22. Preparations according to claims 1 to 4 and 32 for pharmacotherapy, containing a necrosis-affine compound.

23. Preparations according to claims 1 to 4 and 32 for the production of active substance depots in necrosis, in particular in fresh necrosis, containing a necrosis-affine compound.

24. Sterile, pyrogen-free pharmaceutical preparations of necrosis-affine compounds according to claim Ibis 4 and 32, in physiologically compatible carriers with a maximum of 30% water.

25. Sterile pharmaceutical preparations of necrosis-affine compounds according to claims 1 to 4 and 32, characterized in that they produce local necrosis after injection.

26. Sterile pharmaceutical preparations of necrosis-affine compounds or necrosis-affinity β-radiator-binding compounds according to claim 1, 8, and 32 in necrosis-producing non-physiological media.

27. Sterile pharmaceutical preparations of necrosis-affine compounds according to claims 1 to 4 and 8, to which cytostatic or cytotoxic compounds are bound, in necrosis-producing non-physiological media.

28. Preparations according to claim 24 to 27, characterized in that they additionally contain an additive detectable by means of X-ray, MR, ultrasound or optical methods.

32

29. Preparations according to claim 24 to 27, characterized in that a component detectable by means of X-ray, MR, ultrasound or optical methods is bound to the necrosis-affine compound.

30. Use of the pharmaceutical formulations according to claims 1 to 9 and 32 for the manufacture of preparations for pharmacotherapy.

31. The compounds of formulas IV, V and VI

(IV),

(V) and

33

32. Pharmaceutical formulation containing one or more compounds of the formulas IV, V or VI according to claim 31.

33. Pharmaceutical formulation according to claim 1 to 4 and 32, characterized in that it is applied with a single systemic administration in a dosage of 10 mg to 10 g.

34. Use of pharmaceutical formulations according to claims 1 to 8 and 32 for the manufacture of a medicament for the treatment of tumors after or simultaneously with a necrosis-inducing therapy.

35. Use of pharmaceutical formulations according to claims 1 to 8 and 32 and a pharmaceutical formulation containing necrosis-producing agents for the production of a combination preparation for the treatment of tumors.

36. Pharmaceutical formulations according to claims 1 to 4 containing N porphyrins of the formula VII as necrosis-affine compounds

(VII) wherein the radicals R ¹ independently of one another are CH (OH) CH _3> CH (OCH ₂ CH ₂ OCH ₃ ) CH ₃ , CH ₂ CH ₂ oglucosyl, CH ₂ CH ₂ Ogalactosyl, CH ₂ CH ₃ , CH = CH ₂ mean and Y and V each for a hydrogen atom or together for a polyvalent

Metal ion of an element of atomic number 21-32, 37-39, 42-51 or 57-85. 37. Pharmaceutical formulations according to claims 1 to 4 containing as necrosis-affine compounds N porphyrins of the formula VIII

34

(VIII) wherein the radicals R ² independently of one another are hydrogen, C ₁ -C ₆ alkyl, C ₇ -C ₁₂ aralkyl or OR ⁴ with R ⁴ in the meaning of hydrogen or

C _r C ₃ alkyl R ³ independently of one another are hydrogen or OR ⁴ and Y and V each represent a hydrogen atom or together a polyvalent metal ion of an element of atomic number 21-32,

37-39, 42-51 or 57-85.

38. Pharmaceutical formulations according to claims 1 to 4 containing as necrosis-affine compounds N porphyrins of the formula IX

■ -5

PLACE

OR (IX)

35 wherein the radicals R ^{5 are} independently hydrogen, an alkyl chain - (CH ₂ ) _n -γ with n = 1-6, which can optionally be interrupted by 1-3 oxygen atoms and / or can be substituted by -OH, OCH ₃ or OCH ₂ CH ₃ , -CO- (CH ₂ ) _n -CO-γ or - (CH ₂ ) _n CO-γ, with γ in the meaning of the linkage point to the active ingredient W, and V and Y in the meaning given above.

39. Pharmaceutical formulations according to claims 1 to 4 containing N porphyrins of the formula X as necrosis-affine compounds

(X) in which the radicals R ² independently of one another are hydrogen, C 1 -C 6 -alkyl,

C ₇ -C ₁₂ aralkyl or OR ⁴ with R ⁴ in the meaning of hydrogen or C _r C ₃ alkyl R ^{3 is} hydrogen or OR ⁴ and

Y and V each represent a hydrogen atom or together a polyvalent metal ion of an element of atomic number 21-32, 37-39, 42-51 or 57-85.

40. Pharmaceutical formulations according to claims 1 to 4, characterized in that L stands for a peptide with 1 to 10 amino acids.

41. Pharmaceutical formulations according to claims 1 to 4, characterized in that L stands for a peptide with 1 to 10 amino acids and W for doxorubicin.

36

42. Use of the pharmaceutical formulations according to claims 1-8, 32, 36 to 39 for the manufacture of a medicament for the prevention of local tumor recurrences, or local hyperplasia.

43. Use of the pharmaceutical formulations according to claims 1-8, 32, 36 to 39 for the manufacture of a medicament for the treatment of

Lymph node metastases.

44. Necrosis-affine compounds of the general formula I

N (-W) n (I)

wherein

N contains a necrosis-affine compound, W is an active ingredient and n is the numbers 1-4, with the exception of hematoporphyrin derivatives, which contain a platinum-II complex bonded via the two natural propionic acid side chains and iodinated antibodies.

45. Necrosis-affine compounds of the general formula II

N-L (-W) n (II)

wherein

46. Necrosis-affine compounds of the general formula III

N- (L-W) n (III)

wherein

N contains a necrosis-affine compound, L any linker, W an active substance and n denotes the numbers 0 -4, with the exception that N must not be a texaphyrin if W is a cis-platinum complex and n = 1 .

37

47. Necrosis-affine compounds according to claims 1 to 4, characterized in that L stands for a peptide with 1 to 10 amino acids.

48. Necrosis-affine compounds according to claims 1 to 4, characterized in that L stands for a peptide with 1 to 5 amino acids.

49. Necrosis-affine compounds according to claim 49, characterized in that W is doxorubicin.

50. Necrosis-affine compounds according to claims 46 and 47, characterized in that N is a porphyrin, L Gly-Phe-Leu-Gly and W is doxorubicin.

51. Pharmaceutical formulations according to claims 1-4, characterized in that n means 1 or 2.

52. Pharmaceutical formulation according to claim 7, characterized in that the porphyrin, the porphyrin derivative or the texaphyrin contains as metal Fe, Cu, Mn, Zn, Co or Gd.

38