SK4072002A3 - Indolyl-3-glyoxylic acid derivatives serving as antitumor agents - Google Patents

Abstract

The invention relates to the use of N-substituted indol-3- glyoxylamides of general formula (I) for treating tumors, in particular, in cases of drug resistance and metastatic carcinoma, and as angiogenesis inhibitors having distinctly fewer side effects, in particular, distinctly lower neurotoxicity. The invention also relates to medicaments containing the inventive compounds.

Description

The invention relates to a further preferred embodiment of the German patent application entitled Indole-3-glyoxylamides with file number 19814 838.0.

BACKGROUND OF THE INVENTION

In cancer chemotherapy, the greatest problems arise due to the emergence of drug resistance on the one hand and the serious side effects of these agents on the other.

Furthermore, many primary tumors are known to have a 'premature ⁷ ' Skion to achieve metastasis in the blood and lymphatic streams when they reach a certain size. The progressive process of tumor invasion and metastasis is the most common cause of cancer patients' death. - · '' t '

To explain this extension there are different starting points, inter alia, enhanced angiogenézay increased degradation of extracellular matrix, migration of tumor ^l cells and modulation of cell adhesion. These factors may also interact, but have only been partially explained so far.

·. Metastasis of tumor "in treated -.jie ^f. Tumors usually accompanied by poor prognosis. The prerequisite of metastasis is the separation of cells from the primary tumor, the migration of these cells to the blood vessels, invasion. blood vessels and invasion-Jaunieks from blood vessels to other tissues ^- .

In certain agents for the treatment of tumors, such as tamoxoifene, there is a known inhibitory effect against the migration and invasion of cancer cells [J Clin Endocrinol Metab 1995 Jan; 80 (1): 308-13].

inhibition of tumor cell invasion by verapamil has already been reported [Pigment Cell Res 1991 Dec; 4 (5-6): 225-33.]

The effect of melantonin on the invasive and metastatic properties of human breast tumor cells MCF-7 has been described [Cancer res 1998 Octl; 58 (19): 4383-90]. PCT Publication No. WO 96/23506 has proven to overcome drug resistance of certain drugs for the treatment of tumors as a result of gene amplification of the multi-drug resistance gene (MDR gene) caused by such tumor treatment agents.

Furthermore, compositions for the treatment of tumors, such as vincristine and taxol, have non-negligible neurotoxicity, which has been shown to be disadvantageous in chemotherapy.

The invention is now expanded Areas · ^ ^f the use of N-substituted indole-3-glyoxylamides, and the enrichment of the existing screen, liečiv.- ·. · '- ^Tým'sa-: íňá'ŤÚ? E class of N-lúčenin antitumor' effect, as described in German patent application 19814 838.0, to provide the possibility of a lower, longer lasting and better tolerated medication. In particular, the disadvantageous development of resistance, which is known with many antitumor agents, should be avoided. '' In addition, -s has ^'8 work against the development and ro'ŕšireni'u' tumor due to metastases.

Since according to the recent findings in the development of tumor growth and metastasis and angiogenesis apparently responsible, the ability to inhibit angiogenesis is another ^- for example, preferred potential drugs for the treatment of cancer. .

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The potentiation of the effect achieved with N-substituted indole-3-glyoxylamides is intended to increase drug consumption in the treatment of tumors. In addition, it should be possible to reduce treatment time and extend it to cases of treatment resistance.

In addition, relapses and metastases should be reduced or prevented, thereby further extending patient survival. The aim is to develop medicaments that may interfere with the metastasis process.

It has now surprisingly been found that the N-substituted indole-3-glyoxylamides described in German patent application 19814 838.0 of the following general formula 1, which are useful in the treatment of cancer, have such advantageous properties for the treatment of tumors that can expand their area. use.

SUMMARY OF THE INVENTION

The subject of the invention is the use of the N-substituted indole-3-glyoxylamidones according to claim 1 of the general formula I for the treatment of tumors, in particular in drug resistance and in metastatic carcinoma - and in suppressing metastasis formation. ·. (-

wherein the radicals R ¹ , R ² , R ³ , R ⁴ and Z have the following meanings:

is hydrogen, Cj_ {} -C ₆ -alkyl, wherein the alkyl group is mono- or polysubstituted by the phenyl ring and the phenyl ring may be substituted one or more times by halogen, (Ci-Ce) -alkyl, (C 3 -C 7) cycloalkyl , carboxyl groups, carboxyl groups esterified with C 1 -C 8 -alkanols, trifluoromethyl groups, hydroxy groups, methoxy groups, ethoxy groups, benzyloxy groups as well as a benzyl group substituted one or more times in the phenyl moiety with (C 1 -C ₆ ) -alkyl, halogen or trifluoromethyl groups;

further represents a benzyloxycarbonyl group (Z group) and a tert-butoxycarbonyl group (Boe residue); and further. acetyl; May be a phenyl ring which is mono- or polysubstituted by (C 1 -C 6) -alkyl, (C 1 -C 6) -alkoxy, cyano, halogen, trifluoromethyl, hydroxy, benzyloxy, nitro, amino / (C 1 -C 6) -alkylamino, ( A C 1 -C 6 -alkoxycarbonylamino and a carboxyl group, optionally with a carboxyl group, esterified with a C 1 -C 6 -alkariol, or a pyridine backbone of formula 2 and its N-oxide

and an N-oxide thereof, wherein the pyridine backbone is optionally attached to ring carbon atoms 2, 3 and 4 and may be substituted with substituents R ⁵ and R ⁶ . Residues R ⁵ and R ⁶ b

may be the same or different and may be (C 1 -C 6) alkyl as well as (C 3 -C 7) -cycloalkyl, (C 1 -C 6) -alkoxy, nitro, amino, hydroxy, halogen and trifluoromethyl, and may also represent ethoxycarbonylamino and carboxyalkyloxy, wherein the alkyl group may have 1 to 4 carbon atoms;

R < ¹ & gt ^; may further be 2- or 4-pyrimidinyl heterocycle, wherein the 2-pyrimidinyl ring may be mono- or polysubstituted by a methyl group, furthermore may be a 2-, 3- and 4- and 8-quinolyl backbone substituted with halogen, nitro, amino and (C 1 -C ₆ ) -alkylamino and 2-, 3- and 4-quinolylmethyl, wherein the ring carbon atoms of the pyridylmethyl radical of the quinolyl group and the quinolylmethyl radical may be substituted by (C 1 -C 6) -alkyl, (C 1 -C ₆ ) -alkoxy, nitro, amino and (C 1 -C 6) -alkoxycarbonylamino;

R ¹ can furthermore when R represents hydrogen, a methyl-benzyl group and also a benzyloxycarbonyl radical (radical Z), a tert-butoxycarbonyl radical (radical

- BOC 1-6 acetyl, means the following radicals: -CH 2 COOH; -CH _(CH3) -COOH; - (CH _{3). 2} -CH ^1; (CH ₂ ) ₂ -CH-COO-; H ₃ CH ₂ C-CH (CH ₃ ) -CH (C 1 OH) -; HO-H ₂ C-CH (COOH) -; phenyl-CH ₂ -CH (COOH) -; (4-imidazolyl) CH ₂ CH (COOH) -; HN = C (NH ₂ ) -NH- (CH ₂ ) ₃ CH (COOH) -; H ₂ N- (CH ₂ ) ₄ -CH (COOH) H ₂ N-CO-CH ₂ -CH (COOH) -; HOOC- (CH _{2) 2} -CH (COOH) -;

R ¹ may additionally, if R e · They represent hydrogen, Z, BOC radical, the acetyl alebo'benzylovú group, this is acid residue of a natural or unnatural amino acid, e.g., α-glycyl, sarcosyl-a, a-alanyl, leucyl-α , .alpha.-isoleucyl, .alpha.-seryl, .alpha.-phenylalanyl, .alpha.-histidyl, .alpha.-prolyl, .alpha.-arginyl, .alpha. Suitable amino protecting groups are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) and also the acetyl radical. In the case of the asparagyl and glutamyl residue claimed for R ¹ , the second unbound carboxyl group is as the free carboxyl group or in the form of an ester with C 1 -C ₆ -alkanol, such as, for example, methyl ester, ethyl ester or tert-butyl ester. Further, R * may be allylaminocarbonyl-2-methylprop-1-yl. '

R 1 and R ¹ together with the nitrogen atom to which they are attached may further form a piperazine ring of formula 3 or a homopiperazine ring if R ¹ represents an aminoalkylene group,

wherein R ⁷ represents an alkyl radical, represents a phenyl ring which may be mono- or polysubstituted by (C 1 -C 6) -alkyl, (C 1 -C 8) -alkoxy, halogen, nitro, amino and (C 1 -C 6) -alkylamino. R ^{7 is} furthermore a behzhydryl group and a bis-p-fluorobenzhydryl group.

R ² denotes hydrogen, _(C-Ce) alkyl group, wherein the alkyl may be substituted one or more times by halogen, and phenyl which may be substituted one or more times by halogen, (Ci-Cio) -alkyl, (C 3 C 7) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxy groups, methoxy groups, ethoxy groups or benzyloxy groups. . The (C 1 -C 8) -alkyl group applicable to R ² may be further substituted by a 2-quinolyl group and a 2-, 3- and 4-pyridyl group, both of which may be mono- or polysubstituted by halogen, (C 1 -C 4) alkyl groups; or. (C 1 -C 4) -alkoxy. groups. R ² below: e are the aroyl, the resulting residue present in the aryl moiety is a phenyl ring which may be substituted one or more times by halogen, (C, -C) -alkyl, (C 3 -C 7) -cycloalkyl, carboxyl groups, carboxylic C1-C6-alkanol esterified, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy groups;

R ³ and R ⁴ can be the same or different and can be hydrogen, (C 1 -C 6) -alkyl, (C 3 -C 7) -cycloalkyl, (C 1 -C 6) -alkanoyl, (C 1 -C 6). ) alkoxy, halogen and benzyloxy. Further, the R ³ and R ⁴ is nitro, amino, (C 1 -C 4) -monoalebo dialkyl amino, and _(Ci-C6) alkoxycarbonylamino, or, (C -C) -alkoxycarbonylamino- (C CFI) -alkyl ..

Z is O and S.

Under the designation alkyl, alkanol, alkoxy or alkylamino are to be R,

R ¹ R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ generally represents an alkyl group of those straight and branched chain, the alkyl groups of straight-chain may be referred to as radicals, such as methyl, ethyl, n propyl, n-butyl, n-pentyl and n-hexyl, and branched chain alkyl groups may, for example, denote residues such as isopropyl or tert-butyl. Cycloalkyl is to be understood as meaning residues such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "halogen" denotes fluorine, chlorine, bromine or. iodine. The designation "alkoxy. represents radicals such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.

The compounds may also be used as acid addition salts, for example as salts with inorganic acids such as hydrochloric acid · ^7, sulfuric acid, phosphoric acid, salts with organic acids such as acetic, lactic, malonic, maleic acid, fumaric acid, gluconic acid, glucofonic acid; citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, and 2-hydroxyethanesulfonic acid. The compounds of the formula I and their salts are also biologically. active. The compounds of formula I may be administered in free form or in the form of salts with physiologically tolerated acids.

Administration can be carried out orally, parenterally, intravenously, transdermally or by inhalation.

The present invention further relates to pharmaceutical compositions comprising at least one of the compounds of formula 1 or salts thereof with physiologically tolerable inorganic or organic acids and optionally pharmaceutically acceptable carriers and / or diluents or auxiliaries.

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Suitable dosage forms are, for example, tablets, dragees, capsules, solutions for infusion or ampoules, suppositories, patches, inhalable powder preparations, suspensions, creams and ointments.

DETAILED DESCRIPTION OF THE INVENTION

The processes for the preparation of the substances can be taken from the examples of German patent DE 196 36 150 A1.

The therapeutically valuable properties found relate specifically to the following advantages:

- no development of resistance has been demonstrated,

- parameters that are characteristic of '' 'inhibition of metastasis formation (migration) have been demonstrated,' '. '

- parameters have been found to demonstrate inhibition of angiogenesis,

- in various models, no neurotoxicity could be detected with the N-substituted indole-3-glyoxylamides according to claim 1 of the general formula I, in contrast to most antitumor agents. '....

The absence of resistance development has been demonstrated in the following pharmacological models or cell cultures:

Cytotoxic activity of D-24851 (see claim 4) against the leukemic MDR (multidrug resistant) cell line of L 1210 / VCR mice was unaffected in vivo or in vitro (see Figure 1, 2 and 3). ·

D-24851 (see claim 4) has unchanged cytotoxic activity against multiple drug-resistant mouse leukemic cell line L 1210 / VCR versus taxol, doxirubicin, vincristine, and epotholone B.

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Perform experiments:

L 1210 murine leukemia cell lines were adapted to vincristine. Unadapted (L1210) and adapted (L1210 / VCR) cells were exposed to cytostatic agents and cell growth (XTT assay) was determined by metabolic activity. ·. ·

The curves that connect the points to the XTT data were calculated using a non-linear regression program. ''

These experimental results were also confirmed in vitro on the human resistant LT12 / MDR cell line, see Figure 4.

2. Evidence of lack of metastasis was reported by inhibiting the migration of MO4 cells, see Figure 5.

D-24 851 (see claim 4) inhibits dose-dependent migration of MO4 cells. This suggests an anti-invasive and antimetastatic effect for D-24851.

The in vitro migration ability of M04 cells can be measured by sowing the cells in the center of the cell culture dish and determining migration using the radius and eventually the cell area covered with D-24851 and without D-24851 after different days. Figure 4 'shows that cell migration decreases with increasing concentration of D-24851. To investigate whether D-24851 is also anti-invasive, invasion of MO4 fibrosarcoma cells in the chicken heart was investigated. Also here, it appears that invasion is completely inhibited at concentrations of 260 and 1000 nM, whereas at lower concentrations the invasiveness of MO4 cells increases. Based on these results, D-24851 appears to inhibit both tumor cell migration and invasion, and thus has a potent antimetastatic potential. - 11

Comparative experiments of Compound D-24851 according to the invention (see claim 4) with vincristine and taxol in rats evaluated for ataxia, traction and reaction (see Figure 6) show that this compound, in contrast to taxol and vincristine, has no no neurotoxic effect.

Furthermore, D-24851 has no negative effect on the rate of nerve impulse propagation compared to taxol and vincristine, see Figure 7.

This confirms that D-24851 has clearly weaker side effects due to the lack of neurotoxicity than other chemotherapists.

From further tests of Figures 8 and 9, it can be seen that compound D-24851 (see claim 4) has the potential as an angiogenesis inhibitor.

Angiogenesis inhibitors are also agents for inhibiting tumor growth by inhibiting the formation of new blood vessels to nourish the tumor due to physiological association with tumor growth. D-24851 induces a complete inhibition of vascular formation, ₇ , which is not based on a cytotoxic effect, in vitro in an anti-angiogenic model in endothelial cells. Figure 8 shows that D-24851 - almost completely cell-cell contacts using 0.1 pmol / L D-24851 (see vital staining). The cells usually maintain at least partial contact. Cell migration clearly decreases, many cells are rounded.

Single layer color staining prior to induction of angiogenesis showed no increased cell mortality by D-24851. Also, within the first 22 hours after induction, no increased mortality of the cells could be detected compared to the control (see lethal staining in Figure 9, white dots).

'12

The cells were derived from human umbilical vein (arterial function). They were used for the third and fourth passages. Angiogenesis is induced by a natural stimulus. The primary trigger of endothelial migration is a protein that is overexpressed in vascularizing tissue. These substances are added to the culture medium shortly before induction of angiogenesis.

The concentration for the anti-angiogenic effect of D-24851 is clearly lower than the concentration for cytotoxic activity. Therefore, both qualities of effects (cytotoxic activity and anti-angiogenic effect) can be separated from each other.

Without limiting the scope of the invention to the following, it can be said that the dosage is orally from about 20 mg to 500 mg per day.

For intravenous administration by injection or infusion, up to 250 mg / day or more may be administered depending on the patient's body weight and individual tolerability.

Due to the lack of development of resistance and inhibition of metastasis, high efficacy and widespread use of the compositions are also expected, also in patients with refractory tumors.

• -; The anti-angiogenic effect is additionally suitable for - = • suppressing tumor spreading.!!: :··> ..... ^:

The present invention also encompasses the use of the N-substituted-indole-3-glyoxylamido according to claim 1 of formula I in other diseases in which an angiogenesis inhibitory effect (e.g. wound healing) is functionally required.

Furthermore, the present invention also provides a stable or free combination of N-substituted indole-3-glyoxylamides according to claim 1 of the general formula Ia with known anti-tumor agents and replacement of anti-tumor agents ineffective as a result of resistance development with N-substituted indole-3-glyoxylamides according to claim 1 of formula la.

Claims (12)

Use of the N-substituted indole-3-glyoxylamides of the general formula 1 according to the main patent application 19 814 838.0 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of a tumor resistant to cancer agents, metastatic cancer, a tumor sensitive to angiogenesis inhibitors, with markedly weaker side effects, in particular with markedly lower neurotoxicity, of formula 1 wherein the residues R ¹ , R ² , R ³ , R ⁴ and Z are as follows: R is hydrogen, (C 1 -C ₆ ) -alkyl, wherein the alkyl group may be substituted one or more times with a phenyl ring and the phenyl ring may be substituted one or more times with halogen, (C 1 -C 6) -alkyl, (C 3 -C 7) - cycloalkyl, carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxy groups, methoxy groups, ethoxy groups, benzyloxy groups as well as a benzyl group substituted one or more times in the phenyl moiety with (C 1 -C ₆ ) -alkyl or halogen atoms ; R further represents a benzyloxycarbonyl group (Z group) and a tert-butoxycarbonyl group (Boe group), and further an acetyl group; R ¹ denotes a phenyl ring which is mono- or poly-substituted by _(Ci-C6) -alkyl, _(Ci-C6) alkoxy, cyano, halo, trifluoromethyl, hydroxy, benzyloxy, nitro, amino, (Οχ-Οβ) -alkylamino, (C 1 -C 6) -alkoxycarbonylamino and a carboxyl group, optionally a carboxy group esterified with a C 1 -C 6 -alkanol, or a pyridine backbone of formula 2 and its N-oxide and its N-oxide, the pyridine backbone optionally being attached to ring carbon atoms 2, 3 and 4 and may be substituted with R ⁵ and R ⁶ . The radicals R ⁵ and R ⁶ may be the same or different and may be (C 1 -C 6) alkyl as well as (C 3 -C 7) -cycloalkyl, (C 1 -C ₆ ) -alkoxy, nitro amino, hydroxy, halogen and trifluoromethyl and furthermore represents an ethoxycarbonylamino radical and a carboxyalkyloxy group, wherein the alkyl group may have 1 to 4 carbon atoms; R ¹ may further be 2- or 4-pyrimidinyl heterocycle, wherein the 2-pyrimidinyl ring may be mono- or poly-substituted by a methyl group, further may be a 2-, 3- and 4- and 8-quinolyl backbone substituted (C x -C ₆ ) -alkyl, halogen, nitro, amino and (C 1 -C ₆ ) -alkylamino, may be 2-, 3- and 415 a quinolylmethyl group, wherein the ring carbon atoms of the pyridylmethyl radical of the quinolyl group and the quinolylmethyl radical may be substituted by (C 1 -C ₆ ) -alkyl, (C 1 -C ₆ ) -alkoxy, nitro, amino and (C 1 -C ₆ ) -alkoxycarbonylamino; ή · R, may also, if R is hydrogen, methyl or benzyl group and the benzyloxycarbonyl radical also (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, represent the following radicals: CH ₂ COOH; -CH (CH ₃ ) -COOH (; - (CH ₃ ) ₂ -CH- (CH ₂ ) 2 -CH-COO-; H ₃ C-H 2 C-CH (CH ₃ ) -CH (COOH) -; HO-H ₂ C-CH (COOH) CH ₂ -phenyl-CH (COOH) -, (4-imidazolyl) CH ₂ CH (COOH) HN = C (NH ₂₎ -NH- _(CH2) 3 CH (COOH) - H ₂ N- (CH ₂ ) 4 -CH (COOH) H ₂ N-CO-CH ₂ -CH (COOH) - HOOC- (CH ₂ ) 2 -CH (COOH) Furthermore, when R is hydrogen, Z, BOC, acetyl or benzyl, it may be an acid residue of a natural or synthetic amino acid, for example α-glycyl, α-sarcosyl, α-alanyl, α-leucyl, α-isoleucyl , α-seryl, α-phenylalanyl, α-histidyl, α-prolyl, α-arginyl, α-lysyl, α-asparagyl and α-glutamyl residues, wherein the amino groups of these amino acids may be protected or unprotected. Suitable amino protecting groups are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) and also the acetyl radical. In the case of the asparagyl and glutamyl residues claimed for R. is a second unbound carboxyl group as a free carboxyl group or in the form of an ester with a C 1 -C 8 -alkanol such as a methyl ester, an ethyl ester, optionally as a tert-butyl ester. Furthermore, R can be allylaminocarbonyl-2-methylprop-1-yl; R @ 1 and R @ 2 may further form, together with the nitrogen atom to which they are attached, a piperazine ring of formula 3 or a homopiperazine ring, provided that R @ 1 represents an aminoalkylene group ^; - N 1 of formula 3 wherein R 1 represents an alkyl radical means a phenyl ring which may be mono- or polysubstituted by (C 1 -C 8) -alkyl, (C 1 -C 8) -alkoxy, halogen, nitro, amino and (C 1 -) - C ₆ ) 7 alkylamino. R1 is furthermore a benzhydryl group and a bis-p-fluorobenzhydryl group; R ² denotes hydrogen, _(Ci-C6) -alkyl, wherein the alkyl may be substituted one or more times by halogen, and phenyl which may be substituted one or more times by halogen, (Ci-Cio) -alkyl, (C 3 C 7) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxy groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C 1 -C 8) -alkyl group valid for R ² may be further substituted by 2-quinolyl and 2-, 3- and 4-pyridyl groups, both of which may be mono- or polysubstituted by halogen, (C 1 -C 4) -alkyl or (C1-C4) -alkoxy. R further represents an aroyl radical, whereby the aryl moiety present represents a phenyl ring which may be mono- or polysubstituted by halogen, (C 1 -C ₆ ) -alkyl, (C 3 -C 7) -cycloalkyl, carboxyl groups, carboxyl groups groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxy groups, methoxy groups, ethoxy groups or benzyloxy groups; R ³ and R ⁴ can be the same or different and can be hydrogen, (C 1 -C 6) -alkyl, (C 3 -C 7) -cycloalkyl, (C 1 -C 6) -alkanoyl, (C 1 -C ₆ ) -alkoxy, halogen and benzyloxy. Further, R ³ and R ^{4 can} be nitro, amino, (C 1 -C 4) -mono or dialkyl-substituted amino and (C ₁ -C ₆₎ alkoxycarbonylamino or (C 1 -C 6) -alkoxycarbonylamino- (C 1 -C 6) -alkyl; Z is O and S. Use of N-substituted indole-3-glyoxylamides according to claim 1 of formula I for the manufacture of a medicament for the treatment of a disease selected from the group consisting of a tumor resistant to antitumor agents, metastatic cancer including metastasis development and spread and / or inhibitor-sensitive tumor. angiogenesis, with markedly weaker side effects, in particular with markedly lower neurotoxicity R is hydrogen, R ¹ is 4-pyridyl, 4-fluorophenyl, R ² is benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl, R ³ and R ⁴ is hydrogen and Z is oxygen. 3. A pharmaceutical composition for the treatment of a disease selected from the group consisting of a tumor resistant to anticancer agents, metastatic carcinoma including the development and spread of metastasis and / or a tumor sensitive to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly less neurotoxicity. by containing at least one compound of the formula I, optionally Ia and optionally acid addition salts thereof, for example salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, salts with organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, emonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2-hydroxyethanesulfonic acid, and if possible, its N-oxides. 4. The use of the N-substituted indole-3-glyoxylamides of the general formula I and Ia as well as their physiologically tolerable acid addition salts for the manufacture of a medicament for the treatment of a disease selected from the group consisting of tumor resistant to cancer agents, metastatic cancer metastasis spread and / or tumor susceptible to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly lower neurotoxicity, in particular of the following compounds, or their salts with physiologically tolerable acids, or possibly their oxides: D-24241 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] -7-glyoxylamide, D-24843 N- (Pyridin-4-yl) - (1-benzylindol-3-yl) glyoxylamide, D-24850 N- (4-Fluorophenyl) - [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide. D-24851 N- (pyridin-4-yl) - [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide; D-25505 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide.HCL. A pharmaceutical composition comprising, as an active ingredient, one or more N-substituted indole-3-glyoxylamides of the formula I or Ia and also their physiologically tolerable acid addition salts with antitumor agents for use in particular in the treatment of a disease selected from the group consisting of anticancer resistant tumor, metastatic carcinoma including development and spread of metastases, and / or tumor susceptible to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly lower neurotoxicity, in particular one or more compounds according to claim 4.. A pharmaceutical composition for the treatment of a disease selected from the group consisting of a tumor resistant to anticancer agents, metastatic carcinoma including the development and spread of metastases and / or a tumor sensitive to angiogenesis inhibitors, with weaker side effects, in particular markedly lower neurotoxicity and active substance D-24241 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide or its hydrochloride. A pharmaceutical composition for the treatment of a disease selected from the group consisting of a tumor resistant to anticancer agents, metastatic carcinoma including the development and spread of metastasis and / or a tumor sensitive to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly less neurotoxicity and especially containing as the active substance D-24843 N- (Pyridin-4-yl) - (1-benzylindol-3-yl) glyoxylamide. A pharmaceutical composition for the treatment of a disease selected from the group consisting of a tumor resistant to anticancer agents, metastatic carcinoma including the development and spread of metastasis and / or a tumor sensitive to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly lower neurotoxicity and especially containing as the active substance D-24850 N- (4-Fluorophenyl) - [1- (-3-pyridylmethyl) indol-3-yl] glyoxylamide. A pharmaceutical composition for the treatment of a disease selected from the group consisting of a tumor resistant to anticancer agents, metastatic carcinoma including the development and spread of metastases and / or a tumor sensitive to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly less neurotoxicity and especially containing as the active substance D-24851 N- (pyridin-4-yl) - [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide. A pharmaceutical composition for the treatment of a disease selected from the group consisting of a tumor resistant to anticancer agents, metastatic carcinoma including the development and spread of metastases and / or a tumor sensitive to angiogenesis inhibitors, with markedly weaker side effects, in particular markedly less neurotoxicity and containing as active ingredient, one or more N-substituted indole-3-glyoxylamides of the formula I, optionally Ia and their physiologically tolerable acid addition salts and preferably N-oxides, in particular one or more compounds according to claims 4 and 6 to 8, and a pharmaceutically acceptable carrier and / or diluent, and optionally an excipient in the form of tablets, dragees, capsules, infusion solutions or ampoules, suppositories, patches, inhalable powder formulations, suspensions, creams and ointments. 11. The use of the N-substituted indole-3-glyoxylamides of the general formula I and / or Ia as well as their physiologically tolerable acid addition salts as angiogenesis inhibitors, in particular of the following compounds or their physiologically tolerable acid salts, if possible their N- oxides: D-24241 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide, D-24843 N- (Pyridin-4-yl) - (1-benzylindol-3-yl) glyoxylamide, D-24850 N- (4-Fluorophenyl) - [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide. D-24851 N- (pyridin-4-yl) - [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide, D-25505 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide.HCL. 12. The use of the N-substituted indole-3-glyoxylamides of the formula I and Ia as well as their physiologically tolerable acid addition salts for the manufacture of a medicament for use in particular in drug resistance and as a substitute for anticancer agents no longer effective as a result of resistance. the compounds: D-24241 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] - D-24843 glyoxylamide. N- (pyridin-4-yl) - (l-benzylindol-3-yl) glyoxylamide. D-24850 N- (4-fluorophenyl) - [1- (3-pyridylmethyl) indol-3-yl] - D-24851 glyoxylamide. N- (pyridin-4-yl) - [1- (4-chlorobenzyl) indol-3-yl] - D-25505 glyoxylamide. N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] - glyoxylamid.HCL. 13th Use of N-substituted indole-3-glyoxylamides and also their physiologically tolerable acid addition salts for the manufacture of a medicament for use, in particular, in drug resistance in fixed or free combination with known anti-tumor agents and as replacements of anti-tumor agents no longer effective as a result of resistance, in particular the following compounds: D-24241 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] - D-24843 glyoxylamide. N- (pyridin-4-yl) - (l-benzylindol-3-yl) glyoxylamide. D-24850 N- (4-fluorophenyl) - [1- (3-pyridylmethyl) indol-3-yl] - D-24851 glyoxylamide. N- (pyridin-4-yl) - [1- (4-chlorobenzyl) indol-3-yl] - D-25505 glyoxylamide. N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl] - glyoxylamid.HCL. 1/9