CA2386069C

CA2386069C - Indolyl-3-glyoxylic acid derivatives as antitumor agents

Info

Publication number: CA2386069C
Application number: CA2386069A
Authority: CA
Inventors: Bernd Nickel; Thomas Klenner; Gerald Bacher; Thomas Beckers; Peter Emig; Jurgen Engel; Erik Bruyneel; Gunter Kamp; Kirsten Peters
Original assignee: Ziopharm Oncology Inc
Current assignee: Ziopharm Oncology Inc
Priority date: 1999-09-28
Filing date: 2000-09-26
Publication date: 2012-08-14
Anticipated expiration: 2020-09-26
Also published as: BG106639A; ATE459356T1; HUP0202788A3; WO2001022954A3; CZ303246B6; YU22702A; EP1218006A2; SK4072002A3; NO20021367L; PL199576B1; EE200200169A; NO322614B1; CN1301712C; IS6319A; KR20030019295A; AU783436B2; DE50015879D1; HK1048941A1; UA75872C2; EP1218006B1

Abstract

The invention relates to the use of N--substituted indole-3-glyoxylamides of the general formula 1 for tumor treatment in particular in the case of pharmaceutical resistance and metastisizing carcinoma, and as angiogenesis inhibitors, with markedly lower side effects in particular markedly lower neurotoxicity, and pharmaceuticals comprising them. (see above formula)

Description

Indolyl-3-Glyoxylic Acid Derivatives as Antitumor Agents Technical Field The invention relates to indole-3-glyoxylamide acid derivatives and uses thereof.

Background of the Invention In connection with chemotherapy, in oncoses the greatest problems result due to the occurrence of pharmaceutical resistance on the one hand and due to the serious side effects of these agents on the other hand.
It is furthermore known that many primary tumors, after reaching a certain size, have a premature tendency to form metastases via the bloodstream and lymph tracts.
The continuing process of tumor invasion and the formation of metastases is the most frequent cause of death of cancer patients.
There are various starting points to explain this spread, inter alia intensified angiogenesis, increased extracellular matrix degradation, tumor cell migration and modulation of cell adhesion. These factors can also act in combination, but until now have been only partially explained.
The metastasis of a tumor is usually accompanied by poor prognoses in the tumor treatment. The prerequisite for metastasis is the detachment of cells from the primary tumor, the migration of the cells to the blood vessels, the invasion into the blood vessels and the invasion of the cells from the blood vessels into other tissue.
An inhibitory action of certain antitumor agents such as tamoxifen on the migration and invasion of cancer cells is known [J Clin Endocrinol Metab 1995 Jan;80(1) :308-13].
The inhibition of tumor cell invasion by verapamil has been reported [Pigment Cell Res 1991 Dec; 4 (5-6) :225-33.]

The influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells has been reported [Cancer res 1998 Oct 1; 58 (19) :4383-901.
The published PCT Application WO 96/23506 demonstrated the overcoming of pharmaceutical resistance with certain tumor pharmaceuticals as a result of the gene amplification of the multi-drug resistance gene (MDR gene) brought about by such antitumor agents. Antitumor agents such as vincristine and taxol furthermore have a not inconsiderable neurotoxicity, which proves disadvantageous in chemotherapy.
Summary of the Invention The object of the invention is now to widen the area of use of N-substituted indole-3-glyoxylamides and thus to enrich the available pharmaceutical wealth. The possibility of a lower, longer-lasting and more tolerable medication for the class of substance having antitumor action described in German Patent Application 19814 838.0, published October 14, 1999, should thereby be opened up. In particular, the disadvantageous development of resistance, such as is known of many antitumor agents, should be circumvented.
Development and spread of the tumor by metastases should moreover be counteracted.
Since, according to more recent knowledge, angiogenesis is obviously also responsible for tumor growth and the development of metastases, the property of inhibition of angiogenesis is a further advantageous pharmaceutical potential, for example in cancertherapy.
The intensification of action achieved with the N-substituted indole-3-glyoxylamides should make pharmaceutical use in tumor therapy more effective. Moreover, it should be possible to shorten the treatment time and to extend it to therapy-resistant cases.
Recurrences and metastases should furthermore be restricted or prevented and thus the survival time of the patients should additionally be increased. The aim is to develop medicaments which can intervene in the metastatic process.

According to an aspect of the present invention there is provided use of a N-substituted indol-3-glyoxylamide of formula I or a physiologically tolerable acid-addition salt thereof, or any combination thereof, in the manufacture of a medicament for treating a multi-drug resistant tumor or inhibiting metastasis:

N,R

N Z
R3 i R2 (I) wherein radicals R, R1, R2, R3, R4, and Z have the following meanings:

R is hydrogen;
R1 is a pyridine structure of formula II:

R6 (II) where the pyridine structure is bonded at either the 2, 3, or 4 position of the ring and is optionally substituted by substituents R5 or R6 or both R5 and R6, wherein R5 and R6 can be identical or different and are independently a(C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6) -alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical or a carboxyalkyloxy group in which the alkyl group has 1-4 C atoms;
R2 is a (C1-C6)-alkyl group, the alkyl group of which is mono- or polysubstituted by phenyl, which is optionally substituted by one or more substituents, wherein at each occurence the substituent is a halogen, (C1-C6)-alkyl, (C3-- 3a -C7)-cycloalkyl, a carboxyl group, a carboxyl group esterified with a C1-C6-alkanol, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a benzyloxy group, a 2-quinolyl group or a 2-, 3- or 4-pyridyl group, wherein the 2-quinolyl and 2-, 3-, or 4-pyridyl groups can both in each case be mono- or polysubstituted by halogen, (C1-C4) -alkyl group or (C1-C4) -alkoxy, R3 and R4 can be identical or different and are independently a hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6) -alkanoyl, (C1-C6) -alkoxy, halogen, benzyloxy, a nitro group, an amino group, a (C1-C4)-mono or dialkyl-substituted amino group, a (C1-C6) alkoxycarbonylamino group or a (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl group; and Z is 0 or S.

According to an embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one N-substituted indol-3-glyoxylamide of formula I or a physiologically tolerable acid-addition salt thereof:

N,R

Z

2 (I) wherein radicals R, R1r R2, R3, R4, and Z have the following meanings:

R is hydrogen;
R1 is a pyridine structure of formula II:

- 3b ->N)2 R6 (II) where the pyridine structure is bonded at either the 2, 3, or 4 position of the ring and is optionally substituted by substituents R5 or R6 or both R5 and R6, wherein R5 and R6 can be identical or different and are independently a(C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6) -alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical or a carboxyalkyloxy group in which the alkyl group has 1-4 C atoms;
R2 is a (C1-C6) -alkyl group, the alkyl group of which is mono- or polysubstituted by phenyl, which is optionally substituted by one or more substituents, wherein at each occurence the substituent is a halogen, (C1-C6) -alkyl, (C3-C7)-cycloalkyl, a carboxyl group, a carboxyl group esterified with a C1-C6-alkanol, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a benzyloxy group, a 2-quinolyl group or a 2-, 3- or 4-pyridyl group, wherein the 2-quinolyl and 2-, 3-, or 4-pyridyl groups can both in each case be mono- or polysubstituted by halogen, (C1-C4) -alkyl group or (C1-C4) -alkoxy, R3 and R4 can be identical or different and are independently a hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen, benzyloxy, a nitro group, an amino group, a (C1-C4)-mono or dialkyl-substituted amino group, a (C1-C6) alkoxycarbonylamino group or a (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl group; and Z is 0 or S; and a pharmaceutically acceptable carrier, - 3c -wherein the composition is for treating a multi-drug resistant tumor or inhibiting metastasis.
Brief Description of the Drawings FIG. 1 shows the cytotoxic action of compound D-24851 against MDR murine leukemic subline L1210/VCR.

FIG. 2 demonstrates the action of compound D-24851 on a multidrug-resistant tumor.

FIG. 3 shows the influence on the multi-drug-resistant murine leukemia L1210 (dose 10% of the LD50)=

FIG. 4 compares the effect compound D-24851 on human leukemia cells with the effect of other neoplastic agents on the same leukemia cells.

FIG. 5 shows the inhibition of migration of M04 cells by compound D-24851.

FIG. 6 shows a comparison of neurotoxicity induced by compound D-24851 versus other neoplastic agents.

FIG. 7 shows the influence of compound D-24851 on nerve conduction velocity in rat.

FIG. 8 compares angiogenesis in human endothelial cells in compound D-24851-treated cells versus DMSO (44 hours after induction of angiogenesis).

FIG. 9 compares angiogenesis in human endothelial cells in compound D-24851-treated cells versus DMSO (22 hours after induction of angiogenesis).

Detailed Description of Preferred Embodiments It has surprisingly been found that the N-substituted indole-3-glyoxylamides described in German Patent Application 19814 838.0, which was published on October 14, 1999, and of the general formula 1 indicated below, which are suitable for the treatment of oncoses, further have advantageous properties for tumor treatment of the type which can widen their area of use.

- 3d -The invention relates to the use of N-substituted indole-3-glyoxylamides according to a general formula 1 for tumor treatment in particular in the case of pharmaceutical resistance and metastatic carcinoma and for the suppression of metastasis formation, as well as angiogenesis inhibitors R
Z
R. N-R, Z
N
R
i R
formula 1 where the radicals R, R1, R2, R3, R4 and Z have the following meaning:

R = hydrogen, (C1-C6) -alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring, for its part, can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoro-methyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups, R is furthermore the benzyloxycarbonyl group (Z group) or the tertiary butoxycarbonyl radical (Boc-radical), furthermore the acetyl group.
R1 can be the phenyl ring which is mono- or poly-substituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with Cl-C6-alkanols, or is a pyridine structure of the formula 2 and its N-oxide s 4 formula 2 PIS
and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R5 and R6. The radicals R5 and R6 can be identical or different and have the meaning (Cl-C6) -alkyl, and the meaning (C3-C7) -cycloalkyl, (C1-C6) -alkoxy, nitro, amino, hydroxyl, halogen and trifluoro-methyl and are furthermore the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
R1 can furthermore be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore the 2-, 3-, 4- and 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, the nitro group, the amino group and the (C1-C6) -alkylamino radical, a 2-, 3- or 4-quinolylmethyl group, where the ring carbons. of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, nitro, amino and (C1-C6)-alkoxycarbonylamino.
R1 can furthermore be, in the case where -R = hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, the following radicals:

5 -CH2COOH; -CH (CH3) -OOOH; - (CH3) 2-CH- (CH2) 2-CH-COO;
H3C-H2C-CH (CH3) -CH (COOH) -; HO-H2C-CH (COON) -;
phenyl-CH2-CH(COOH)-; (4-imidazolyl)-CH2-CH-COOH)-;
HN=C (NH2) -NH- (CH2) 3 -CH (COOH) - ; H2N- (CH2) 4 -CH (COOH) - ;
H2N-CO-CH2-CH- (COOH) -; HOOC (CH2) 2-CH (COON) -;
R1 can furthermore be, in the case where R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, the acid radical of a natural or unnatural amino acid, e.g. the a-glycyl, the a-sarcosyl, the a-alanyl, the a-leucyl, the a-isoleucyl, the a-seryl, the a-phenylalanyl, the a-histidyl, the a-prolyl, the a-arginyl, the a-lysyl, the a-asparagyl and the a-glutamyl radicals, where the amino groups of the respective amino acids can be present in unprotected or protected form. Possible protective groups for the amino function are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R1, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C1-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.
R1 can furthermore be the allylaminocarbonyl-2-methylprop-1-yl group.
R and R1 can furthermore, together with the nitrogen atom to which they are bonded, form a piperazine ring of the formula 3 or a homopiperazine ring, if R1 is an aminoalkylene group in which formula 3 R7 is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, halogen, the nitro group, the amino function and by the (C1-C6)-alkylamino group. R7 is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl group.
R2 can be hydrogen or the (C1-C6)-alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C1-C6)-alkyl group applying for R2 can furthermore be substituted by the 2-quinolyl group and the 2-, 3- or 4-pyridyl structure, which can both each be mono- or polysubstituted by halogen, (C1-C4)-alkyl groups or (C1-C4)-alkoxy groups. R2 is furthermore the aroyl radical, where the aryl moiety on which this radical is based is the phenyl ring, which can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.

R3 and R4 can be identical or different and are hydrogen (C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6) -alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono- or dialkyl-substituted amino group, and the (C1-C6)-alkoxycarbonylamino function or (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function.

Z is O or S.

The designation alkyl, alkanol, alkoxy or alkylamino group for the radicals R, R1, R2, R3, R4, R5, R6, R7 is normally to be understood as meaning either "straight-chain" or "branched" alkyl groups, where "straight-chain alkyl groups" can be, for example, radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and "branched alkyl groups" designates, for example, radicals such as isopropyl or tert-butyl. "Cycloalkyl"
is understood as meaning radicals such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The designation "halogen" stands for fluorine, chlorine, bromine or iodine. The designation "alkoxy group" represents radicals such as, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.
The compounds can also be employed as acid addition salts, for example as salts of mineral acids, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as, for example, acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfoni.c acid, trifluoroacetic acid, succinic acid and 2-hydroxyethanesulfonic acid.
Both the compounds of the formula 1 and their salts are biologically active.
The compounds of the formula 1 can be administered in free form or as salts with physiologically tolerable acids.
Administration can be carried out perorally, parenterally, intravenously, transdermally or by inhalation.
The invention furthermore relates to pharmaceutical preparations containing at least one of the compounds of the formula 1 or their salts with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically utilizable vehicles and/or diluents or excipients.
Suitable administration forms are, for example, tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.
The preparation processes for the substances can be taken from the examples of the German Patent DE 196 36 150 Al.
The therapeutically valuable properties found relate specifically to the following advantages:
no development of resistance was detected parameters were detected which are characteristic of the inhibition of metastasis formation (migration) - parameters were found which confirm the inhibition of angiogenesis in various models, no neurotoxicity was found with the N-substituted indole-3-glyoxylamides of the general formula 1, in contrast to most antitumor preparations.
The absent development of resistance is confirmed in the following pharmacological models and cell cultures:
1. The cytotoxic activity of D-24851 on the MDR
(multidrug-resistant) leukemia cell line of the mouse L
1210/VCR is not influenced in vivo and in vitro (Figure 1, 2 and 3). As illustrated in Figure 1, in contrast to taxol, doxorubicin, vincristine and Epothilone B., D-24851 has the same cytotoxic activity against the MDR mouse leukemic subline L1210/VCR as against the normal L1210.

D-24851 has an unchanged cytoxic activity against the multigrug-resistant mouse leukemia cell subline L1210/VCR in contrast to taxol, doxorubicin, vincristine or epothilone B.

Experimental procedure:

The mouse leukemia cell lines L 1210 was adapted to vincristine. The unadapted (L 1210) and the adapted (L 1210/VCR) cells were exposed to cytostatic agents and the cell growth, which was determined by the metabolic activity, was determined (XTT test).
The curves which connect the XTT data points were calculated using a nonlinear regression program.
These experimental results are also confirmed in vitro on the human resistant LT12/MDR. cell line, see Figure 4.

2. The proof of lacking metastasis formation was furnished by means of the inhibition of migration of M04 cells. As illustrated in Figure 5 D-24851 inhibits the migration of M04 cells in a dose-dependent manner.
From this, an anti-invasive and an antimetastic action can be derived for D-24851.
D-24 851 inhibits the migration of M04 cells in a dose-dependent manner. An antiinvasive and an antimetastatic action for D-24851 can be derived therefrom.

In vitro, the migration ability of M04 cells can be measured by inoculating the cells in the center of a cell culture dish and determining the migration by means of radius or the covered area of the cells after different numbers of days with and without D-24851.
Figure 4 shows that the migration of the cells decreases with increasing D-24851 concentration.
In order to test whether D-24851 also acts antiinvasively, the invasion of M04 fibrosarcoma cells was investigated in chicken heart. It is also seen here that at a concentration of 260 and 1000 nM the invasion is completely inhibited while at lower concentrations the invasiveness of the M04 cells - 9a -increases. On the basis of these findings, it is seen that D-24851 inhibits both the migration and the invasion of tumor cells and thereby has a strong antimetastatic potential.

3. From comparison experiments of the compound according to the invention D-24851 with vincristine and taxol on rats, in which ataxia, traction and reaction were assessed (see Figure 6), it emerges that this compound has no neurotoxic effect, in contrast to taxol and vincristine. As illustrated in Figure 6, in contrast to taxol and vincristine, D-24851 shows no neurotoxicity in maximally antitumor-active doses.

In comparison to taxol and vincristine, D-24851 furthermore has no adverse effect on the nerve conduction velocity, see Figure 7.
This confirms that D-24851, on account of the lacking neurotoxicity.; has markedly lower side effects than other chemotherapeutics.

4. From further investigations, according to Figure 8 and 9 it is evident that the compound D-24851 has a potential as an angiogenesis inhibitor.
As a result of the physiological relationship to tumor growth, angiogenesis inhibitors are at the same time 2"0 also agents for the inhibition of tumor growth, in that the formation of new blood vessels, which should feed the tumor, is inhibited.
In an antiangiogenesis model on endothelial cells, D-24851 causes a complete inhibition of the formation of blood vessels, which is not based on a cytotoxic effect.
In Figure 8, it can be seen that 0.1 pMol/L D 24851 almost completely breaks up existing cell-cell contact (see vital staining). Normally, the cells maintain at least partial contact. Cell migration is markedly reduced and many cells are rounded.
Lethal staining in the monolayer before angiogenesis induction did not show any increased cell mortality with D-24851. Increased cell mortality was also still not detectable in the first 22 hours after induction in comparison to the control.
Lethal staining is evident in Figure 9, by white dots.

- l0a -The cells originated from human umbilical cord vein (arterial function)_ They were employed for the investigation in the third and fourth passage.
Angiogenesis is induced by a natural stimulus. The primary inducer of the endothelial migration is a protein which is expressed to an increased extent in vascularizing tissue. The substances are added to the culture medium shortly before the induction of angiogenesis.
The concentration for the antiangiogenetic action of D-24851 is markedly below the concentration for the cytotoxic activity. It is thereby possible to separate the two qualities of action (cytotoxic activity and antiangiogenetic action) from one another.
Without wanting to restrict the scope of the invention with the following statement, it can be said that doses from approximately 20 mg up to 500 mg daily orally are possible. -In the case of intravenous administration as an injection or as an infusion, up to 250 mg/day or more can be administered depending on the body weight of the patient and individual tolerability.
As a result of the lacking development of resistance and suppression of metastasis, a high effectiveness and wide use of the agents is to be expected to even in patients who are refractory to tumors.
The antiangiogenesis effect is additionally suitable for suppressing the spread of the tumor.
The invention, however, also comprises the use of the N-substituted indole-3-glyoxylamides according to general formula 1 in further diseases in which an angiogenesis-inhibitory effect is functionally desirable. (e.g. wound healing).
The invention furthermore also relates to the fixed or free combination of the N-substituted indole-3-glyoxylamides according to general formula 1 with antitumor agents known per se, and to the replacement of antitumor agents which have become inactive as a result of development of resistance by N-substituted indole-3-glyoxylamides according to general formula 1.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Use of at least one N-substituted indol-3-glyoxylamide of formula I or a physiologically tolerable acid-addition salt thereof, in the manufacture of a medicament for treating a multi-drug resistant tumor or inhibiting metastasis:

wherein radicals R, R1, R2, R3, R4, and Z have the following meanings:

R is hydrogen;

R1 is a pyridine structure of formula II:
where the pyridine structure is bonded at either the 2, 3, or 4 position of the ring and is optionally substituted by substituents R5 or R6 or both R5 and R6, wherein R5 and R6 can be identical or different and are independently a (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical or a carboxyalkyloxy group in which the alkyl group has 1-4 C atoms;

R2 is a (C1-C6)-alkyl group, the alkyl group of which is mono- or polysubstituted by phenyl, which is optionally substituted by one or more substituents, wherein at each occurence the substituent is a halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, a carboxyl group, a carboxyl group esterified with a C1-C6-alkanol, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a benzyloxy group, a 2-quinolyl group or a 2-, 3- or 4-pyridyl group, wherein the 2-quinolyl and 2-, 3-, or 4-pyridyl groups can both in each case be mono- or polysubstituted by halogen, (C1-C4) -alkyl group or (C1-C4)-alkoxy, R3 and R4 can be identical or different and are independently a hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen, benzyloxy, a nitro group, an amino group, a (C1-C4)-mono or dialkyl-substituted amino group, a (C1-C6) alkoxycarbonylamino group or a (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl group; and Z is O or S.

2. The use according to claim 1, wherein R1 is 4-pyridyl;
R2 is benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, or 4-bromobenzyl;
R3 and R4 are hydrogen; and Z is oxygen.

3. The use according to claim 1 or 2, wherein the at least one N-substituted indol-3-glyoxylamide is:
N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide;
N-(pyridin-4-yl)-(1-benzylindol-3-yl) glyoxylamide;
N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide; or N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide, or a physiologically tolerable acid-addition salt thereof, or any combination thereof.

4. The use according to any one of claims 1 to 3, wherein the at least one N-substituted indol-3-glyoxylamide is N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl] glyoxylamide or a physiologically tolerable acid-addition salt thereof.

5. The use according to any one of claims 1 to 4, wherein the acid-addition salt is a salt of a mineral acid or a salt of an organic acid.

6. The use according to claim 5, wherein the mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid, and the organic acid is acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid or 2-hydroxyethanesulfonic acid.

7. The use according to any one of claims 1 to 6, wherein the multi-drug resistant tumor is resistant to paclitaxel, doxorubicin, vincristine or epothilone B, or any combination thereof.

8. The use according to any one of claims 1 to 6, wherein the medicament is formulated for use in a replacement therapy for a multi-drug resistant tumor, and optionally includes an antitumor agent.

9. The use according to claim 8, wherein the antitumor agent is paclitaxel, doxorubicin, vincristine or epothilone B, or any combination thereof.

10. The use according to claim 8, wherein the medicament is formulated for use as a replacement for paclitaxel, doxorubicin, vincristine or epothilone B.

11. The use according to claim 8 or 9, wherein the medicament comprises at least one N-substituted indol-3-glyoxylamide and the antitumor agent together with a pharmaceutically utilizable vehicle, diluent, or excipient.

12. The use according to claim 11, wherein the medicament is formulated as a tablet, coated tablet, capsule, solution for infusion, ampoule, suppository, patch, powder preparation suitable for inhalation, suspension, cream or ointment.

13. A pharmaceutical composition comprising at least one N-substituted indol-3-glyoxylamide of formula I or a physiologically tolerable acid-addition salt thereof:

wherein radicals R, R1, R2, R3, R4, and Z have the following meanings:

R is hydrogen;

R1 is a pyridine structure of formula II:
where the pyridine structure is bonded at either the 2, 3, or 4 position of the ring and is optionally substituted by substituents R5 or R6 or both R5 and R6, wherein R5 and R6 can be identical or different and are independently a (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical or a carboxyalkyloxy group in which the alkyl group has 1-4 C atoms;
R2 is a (C1-C6)-alkyl group, the alkyl group of which is mono- or polysubstituted by phenyl, which is optionally substituted by one or more substituents, wherein at each occurence the substituent is a halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, a carboxyl group, a carboxyl group esterified with a C1-C6-alkanol, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a benzyloxy group, a 2-quinolyl group or a 2-, 3- or 4-pyridyl group, wherein the 2-quinolyl and 2-, 3-, or 4-pyridyl groups can both in each case be mono- or polysubstituted by halogen, (C1-C4)-alkyl group or (C1-C4)-alkoxy, R3 and R4 can be identical or different and are independently a hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen, benzyloxy, a nitro group, an amino group, a (C1-C4)-mono or dialkyl-substituted amino group, a (C1-C6) alkoxycarbonylamino group or a (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl group; and Z is O or S; and a pharmaceutically acceptable carrier, wherein the composition is for treating a multi-drug resistant tumor or inhibiting metastasis.

14. The pharmaceutical composition according to claim 13, wherein R1 is 4-pyridyl;

R2 is benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, or 4-bromobenzyl;

R3 and R4 are hydrogen; and Z is oxygen.

15. The pharmaceutical composition according to claim 13 or 14, wherein the at least one N-substituted indol-3-glyoxylamide is:

N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide;

N-(pyridin-4-yl)-(1-benzylindol-3-yl) glyoxylamide;
N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide; or N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide, or a physiologically tolerable acid-addition salt thereof, or any combination thereof.

16. The pharmaceutical composition according to any one of claims 13 to 15, wherein the at least one N-substituted indol-3-glyoxylamide is N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl] glyoxylamide or a physiologically tolerable acid-addition salt thereof.

17. The pharmaceutical composition according to any one of claims 13 to 16, wherein the acid-addition salt is a salt of a mineral acid or a salt of an organic acid.

18. The pharmaceutical composition according to claim 17, wherein the mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid, and the organic acid is acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid or 2-hydroxyethanesulfonic acid.

19. The pharmaceutical composition according to any one of claims 13 to 18, wherein the multi-drug resistant tumor is resistant to paclitaxel, doxorubicin, vincristine or epothilone B, or any combination thereof.

20. The pharmaceutical composition according to any one of claims 13 to 19, wherein the composition is for use in a replacement therapy for a multi-drug resistant tumor, and optionally includes an antitumor agent.

21. The pharmaceutical composition according to claim 20, wherein the antitumor agent is paclitaxel, doxorubicin, vincristine or epothilone B, or any combination thereof.

22. The pharmaceutical composition according to claim 20, wherein the composition is for use as a replacement for paclitaxel, doxorubicin, vincristine or epothilone B.

23. The pharmaceutical composition according to claim 20 or 21, wherein the composition comprises at least one N-substituted indol-3-glyoxylamide and the antitumor agent, together with a pharmaceutically utilizable vehicle, diluent, or excipient.

24. The pharmaceutical composition according to claim 23, wherein the composition is formulated as a tablet, coated tablet, capsule, solution for infusion, ampoule, suppository, patch, powder preparation suitable for inhalation, suspension, cream or ointment.