BG106639A - Indolyl-3-glyoxylic acid derivatives comprising therapeutically valuable properties - Google Patents

Abstract

The invention relates to the use of N-substituted indol-3-glyoxyamides of general formula 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. 13 claims, 9 figures

Description

Technical field

The invention relates to a further useful embodiment of the German patent application for indole-3-glyoxylamides with application number 19814 838.0.

BACKGROUND OF THE INVENTION

In chemotherapy of tumor diseases, the greatest problems are manifested by the onset of drug resistance, on the one hand, and by the severe side effects of these agents, on the other.

In addition, it is known that upon reaching a certain size, many primary tumors tend to produce blood and lymphatic metastases. The advanced process of tumor invasion and the formation of metastases is the most common cause of death in cancer patients.

In explaining this spread, there are various major aspects, among which enhanced angiogenesis, increased extracellular matrix breakdown, tumor cell migration, and modulation of cell adhesion. These factors may interact, but so far, they have only been partially elucidated.

The metastasis of a tumor is usually accompanied by a poor prognosis in the treatment of the tumor. The prerequisite for metastasis is the separation of cells from the primary tumor, the migration of cells to the blood vessels, the entry of cells into the blood vessels, and the entry of cells from the blood vessels into other tissues.

Certain antitumor agents, such as tamoxifen, are known to inhibit cancer cell migration and invasion [J Clin Endocrinol Metab 1995 Jan; 80 (1): 308-313].

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

The effect of melatonin on the invasive and metastatic properties of human breast cancer MCF-7 cells has been reported [Cancer Res 1998 Oct 1; 58 (19): 4383-90].

Published PCT application WO 96/23506 demonstrates the overcoming of drug resistance by certain antitumor pharmaceuticals, which is a consequence of the gene amplification of the "Multi-Drug Resistance Gen" (MDR- = MDR-) induced by such antitumor agents. Gen).

However, antitumor agents such as Vincristine and Taxol have little neurotoxicity, which is considered a drawback in chemotherapy.

SUMMARY OF THE INVENTION

It is an object of the invention to extend the scope of N-substituted indole-3-glyoxylamides and thus enrich the valuable drug provided.

This should open the possibility of a smaller, podalgosrochna and better tolerated medication according to that described in German Patent Application 19814 838.0 class of compounds with \ ^z y \ antitumor activity.

It also creates an opportunity to counteract the development and spread of the tumor through metastases.

Since, according to more recent knowledge, angiogenesis is involved in tumor growth and development of metastases, the ability to suppress angiogenesis represents a new beneficial potential for drugs, for example in the treatment of cancer.

The enhancement of N-substituted indole-3-glyoxylamide action should make the use of drugs more effective in anti-tumor treatment. In addition, it should be possible to shorten the duration of treatment and limit it to treatment-resistant cases. In addition, recurrences and metastases should be reduced, respectively prevented, and thus further enhanced patient survival. The goal is to develop drugs that can affect the metastasis process.

It has 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 suitable for the treatment of tumor diseases, also have other anti-tumor properties * that can expand the scope of their application.

The object of the invention is the use of N-substituted indole3-glyoxylamides according to claim 1 of the general Formula 1a for anti-tumor treatment, especially for drug resistance and metastatic carcinoma, as well as for inhibiting metastasis formation and inhibiting angiogenesis.

wherein the residues R, R), R ₂ , R ₃ , R ₄ and Z have the following meanings:

R = hydrogen, (SgSe) -alkyl, which alkyl group may be a polysubstituted by a phenyl ring and this phenyl ring for its part can be substituted one more places with halogen, (SgSe alkyl, (C ₃ -C ₇ ) -Cycloalkyl, carboxyl groups esterified with C ₂ -C ₆ -alkanols carboxyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and with one benzyl group of the phenyl moiety, which is mono- or polysubstituted by (C 1 -C ₆₎ -alkyl groups halogen atoms or trifluoromethyl the group and.

R means, in addition to loads, a benzyloxycarbonyl group (Z-group) and a tertiary butoxycarbonyl residue (Boc-residue) as well as an acetyl group

Ri

may represent a phenyl ring which is mono- or multiply substituted with (Ci-Ce) alkyl, _(C1-C6) -alkoxy, cyano, halo, trifluoromethyl, hydroxy, benzyloxy, nitro, amino, ( A C ₁ -C ₆ -alkylamino-, (C 1 -C ₆ ) -alkoxycarbonylamino- and a carboxyl group, respectively esterified by a (C 1 -C ₆ ) -alkanol carboxyl group, or a pyridine construct of Formula 2 and its N-oxide

Formula 2, such as the pyridine structure, may optionally be attached to the carbon atoms 2, 3 and 4 of the ring and substituted with the substituents R ₅ and R ₆ . The residues R ₅ and R ₆ may be the same or different and have the meaning of (C 1 -C 6) -alkyl, (C ₂ -C ₆ ) -cycloalkyl, (C ₁ -C ₆ ) -alkoxy-, nitro-, amino-, hydroxy- , halogen and trifluoromethyl, as well as representing the ethoxycarbonylamine moiety and the carboxyalkoxy group, wherein the alkyl group has 1-4 C atoms.

<·

R 1 may also mean a 2- or 4-pyrimidinylheterocycle, the 2-pyrimidinyl ring may be mono- or polysubstituted by a methyl group; further substituted by the (C ₁ -C ₆ ) -alkyl, halogen, nitro, amino group, (C ₂ -C ₆ ) -alkyl-amino residue of the 2-, 3-, 4- and 8-quinolyl constructs; a 2-, 3- and 4-quinolylmethyl group, the carbon atoms of the ring of the pyridylmethyl moiety of the quinolyl group and the quinolylmethyl moiety can be substituted by (C ₁ -C ₆ ) -alkyl, (C 1 -C 6) -alkoxy, nitro- amino - and (C ₁ -C ₆ ) alkoxycarbonylamino group.

Z may, moreover, when R = hydrogen, methyl or benzyl, as well as a benzyloxycarbonyl residue (Z-residue), a third butoxycarbonyl residue (Boc-residue) and an acetyl group, mean the residues:

-CH ₂ COOH; -CH (CH ₃ ) -COOH; - (CH) ₂ -CH- (CH _{2) 2} CH-COO-; H ₃ CH ₂ C-CH (CH ₃ ) -CH- (COOH) -; 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! may furthermore, in the case where R is hydrogen, a Z-group, a moiety, an acetyl or a gasoline group, means the acidic residue of a natural or non-natural amino acid, for example α-glycyl-, α-sarcosyl-, a.alanyl-, α-leucyl-, α-iso-leucyl-, aseryl-, α-phenylalanil-, α-histidyl-, ά-prolyl-, α-arginyl-, allysyl-, α-asparagyl- and α-glutamyl-residue, such as the amino groups of the corresponding amino acids are unprotected or protected. The protecting function of the amino function is the carbobenzoxy residue (Z-residue) and the tert-butoxycarbonyl residue (Boc-residue), as well as the acetyl group. In the case where for R-! an asparagyl- or glutamyl residue was used, the second, unbound carboxyl group being in the form of an ester of C 1 -C 6 -alkanols, for example as methyl, ethyl or tert-butyl ester.

In addition, R5 may mean an allylaminocarbonyl-2-methylprop-1-yl group.

R 1 and R 1 may further form, together with the nitrogen atom to which they are attached, a piperazine ring of Formula 3 / N NR ₇

Λ_ν

Formula 3 or homopiperazine ring, insofar as Rt represents an aminoalkyl group, wherein

R ₇ represents an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (Ci-Ce ^ alkyl, (Ci-C ₆₎ -alkoxy, halogen, nitro group, the amino function and may be substituted with (C _d C ₆ ) -alkylamino group R ₇ is further a benzhydryl group and a bis-p-fluorobenzylhydryl group.

R ₂ may mean hydrogen and a (C 1 -C ₆ ) -alkyl group, the alkyl group being substituted one or more times with halogen and phenyl, which in turn can be substituted one or more times with halogen, ( C ₁ -C ₆ alkyl, (C ₃ -C ₇ ) -cycloalkyl, carboxyl groups with esterified with (C ₁ -C ₆ ) -alkanol carboxyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. for the R ₂ (C ₁ -C ₆ ) -alkyl group may be substituted by a 2-quinolyl group and by a 2-, 3- and 4-pyridyl structure, both of which may at are substituted one or more times with halogen, (C ₂ -C ₄ ) -alkyl groups or (C 1 -C 4 -alkoxy groups) .R ₂ means, in addition, an aroyl moiety, with the aryl moiety underlying it being phenylene a ring which may be substituted one or more times with halogen, (C 1 -C ₆ -alkyl, (C ₃ -C ₇ ) cycloalkyl, carboxyl groups with esterified with (C 1 -C ₆ ) -alkanol carboxyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.

R ₃ and R ₄ may be the same or different and represent hydrogen, (C 1 -C 6) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₁ -C ₆ ) -alkanoyl, (C ₁ -C ₆ ) alkoxy-halogen or benzyloxy -. In addition, R ₃ and R ₄ may denote a nitro group, an amino group, (C 1 -C ₄ ) -mono- or double-substituted alkyl group, and a (C 1 -C ₆ ) -alkoxy-carbonylamino function or (C 1 -C 6) -alkoxy-carbonylamino- (C ₁ -C ₆ ) alkyl function.

Z is O and S.

The term alkyl, alkanol, alkoxy or alkylamino in the residues R, R 1, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R 7 is to be understood in principle both straight or branched alkyl. groups such as "straight chain alkyl groups", for example, may mean residues such as methyl, ethyl, η-propyl, n-butyl, n-pentyl, n-hexyl, and branched alkyl groups "means, for example, residues such as isopropyl or tert -butyl. The term "cycloalkyl" should be understood to mean residues such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "alkoxy group" represents residues such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.

The compounds may also be administered as acid addition salts, for example as salts of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid , gluconic acid, glucuronic acid, citric acid, eubonic acid, methanesulfonic acid, γ-trifluoroacetic acid, succinic acid and 2-hydroxyethanesulfonic acid.

at

Both the compounds of Formula I and their salts are biologically active. The compounds of Formula I can be administered in free form or as salts with physiologically acceptable acids.

Administration can be made by mouth, parenteral, intravenous, transdermal or inhalation.

Furthermore, the invention relates to pharmaceutical compositions containing at least one compound of Formula I or a salt thereof with physiologically acceptable inorganic or organic acids and optionally with pharmaceutically acceptable carriers and / or diluents or excipients, respectively.

Suitable formulations are, for example, tablets, dragees, capsules, infusion solutions or ampoules, suppositories, patches, inhalable powders, suspensions, creams and lipsticks.

Methods for the manufacture of substances can be taken from the examples of German Patent DE 196 36 150 A1.

The pharmaceutically significant properties identified are in particular the following advantages:

- No development of resistance has been demonstrated

- Parameters characteristic of metastasis suppression (migration) have been proven

- Open ca _z parameters which show the suppression of the newly formed vessels (angiogenesis)

- In contrast to most antitumor preparations, neurotoxicity has not been established in various models with N-substituted indole-3-glyoxylamides according to claim 1 of general Formula 1a.

The lack of development of resistance is demonstrated in the following pharmacological models, respectively, cell cultures.

1. The cytotoxic effect of D-24851 (see claim 4) on MDR ("multidrug" "resistant) mouse leukemia cell line L 1210 / VCR is not affected in vivo and in vitro. See Figures 1, 2 and 3. In contrast to Taxol, Doxorubicin and Epotolone B, D-24851 (see claim 4) has unchanged cytotoxic effect against multidrug resistant mouse leukemic cell subline L 1210 / VCR

Conducting the experiment:

The mouse leukemia cell line L 1210 is adapted to Vincristine. Cytostatic agents were administered to non-adapted (L 1210) and adapted (L 1210 / VCR) cells and the cell growth was evaluated according to the metabolic activity (XTtest).

The curves that connect the dots for the XTT data were calculated using a nonlinear regression program.

These test results are also confirmed in vitro in the human resistant LT12 / MDR cell line (see Figure 4).

\ ζ

I 2. Evidence of missing metastasis formation was made by inhibiting the migration of MO4 cells. See Figure 5.

D-24851 (see claim 4) inhibits dose-dependent migration of MO4 cells. This fact demonstrates the anti-invasive and antimetastatic action of D-24851.

The in vitro migration ability of MO4 cells can be measured by seeding cells in the middle of a cell culture plate and determining the distribution by the radius, respectively, of the covered cell surface after a different number of days with and without D-24851. Figure 4 demonstrates that cell migration decreases with increasing D-24851 concentration.

To test whether D-24851 also acts anti-invasively, the invasion of MO4 fibrosarcoma cells in hen hearts was examined. Here again, it is demonstrated that at 260 and 1000 nM concentrations, invasion is completely suppressed, whereas at lower concentrations the invasive capacity of MO4 cells increases. Based on these findings, D-24851 is shown to suppress both migration and invasion of tumor cells and therefore has a strong antimetastatic potential.

3. Comparative examples of the compound D-24851 according to the invention (see claim 4) with Vincristine and Taxol on rats in which ataxia, traction and response were evaluated (see Figure 6), it is clear that this compound has no neurotoxic effect, conversely of Taxol and Vincristine.

In addition, unlike Taxol and Vincristine, D-24851 has no adverse effect on nerve conduction velocity (see Figure 7).

This confirms that due to the lack of neurotoxicity, D-24851 has significantly fewer side effects than other chemotherapeutic agents.

4. Other studies of Figures 8 and 9 show that compound D-24851 (see claim 4) has potential as an inhibitor of angiogenesis.

Because of the physiological link to tumor growth, angiogenesis inhibitors are also a means of inhibiting tumor growth, since it inhibits the formation of new vessels that need to supply the tumor.

In an in vitro model of anti-angiogenesis in endothelial cells, D24851 induces complete inhibition of vasoconstriction, which is not due to cytotoxic action.

Figure 8 shows that D-24851 almost completely destroys existing cell-cell contacts at a concentration of 0.1 pmol / l D24851 (see vital staining). Normally, the cells have at least partial contact. Cell migration is significantly reduced, many cells are rounded.

Lethal single staining prior to induction of angiogenesis did not show increased cell mortality with D-24851. Compared with the control, no increased cell mortality was seen in the first 22 hours after induction (see lethal staining in Figure 9, white dots).

The cells came from a human vein in the umbilical cord (arterial function). In the study, they were applied in the third and fourth passages. Angiogenesis is induced by a natural stimulus. A primary trigger for endothelial migration is a protein that is strongly expressed in vascularizing tissue. Substances are added to the culture medium shortly before the induction of angiogenesis.

/ X The concentration for the anti-angiogenic action of D-24851 is well below the concentration for cytotoxic activity.

Therefore, it is possible to distinguish between the two qualities of action (cytotoxic activity and anti-angiogenic action).

Without limiting the scope of the invention by the following data, it should be said that dosages of about 20 mg to 500 mg daily orally are possible.

When administered intravenously, up to 250 mg / day or more, depending on the patient's body weight and individual tolerability, may be given as an injection or infusion.

The anti-angiogenic effect is suitable to further suppress tumor spread.

The invention also encompasses the use of N-substituted indole-3-glyoxylamides according to claim 1 of the general Formula 1a and in other diseases in which the inhibitory effect on angiogenesis (e.g., wound healing) is functionally targeted.

Furthermore, the object of the invention is the fixed or free combination of N-substituted indole-3-glyoxylamides according to claim 1 of the general Formula 1a with known antitumor agents, as well as the replacement of antitumor agents which, due to the development of resistance, have become ineffective with N -substituted indole-3-glyoxylamides according to claim 1 of the general Formula 1a.

Claims (13)

The use of N-substituted indole-3-glyoxylamides of the general Formula 1 as antitumor agents according to basic Patent Application 19 814 838.0, for the treatment of tumors, especially in drug resistance and metastatic carcinoma, and as inhibitors of angiogenesis, in significant fewer side effects, and especially with significantly lower neurotoxicity Formula 1 wherein the residues R, R _n R ₂ , R ₃ , R ₄ and Z have the following meanings: R is hydrogen, (C ₁ -C ₆ ) -alkyl, the alkyl group being mono- or polysubstituted by the phenyl ring, and this phenyl ring, in turn, may be mono- or polysubstituted by halogen, (C _d C ₆ ) -alkyl, (C ₃ -C ₇₎ -cycloalkyl, carboxyl groups esterified with C _d C ₆ alkanols carboxyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and by a group of the phenyl moiety which is mono- or polysubstituted by (C 1 -C 6) -alkyl groups, halogen atoms or \ trifluoromethyl groups and. / X. / R represents both a benzyloxycarbonyl group (Z-group) and a tertiary butoxycarbonyl residue (Boc-residue) as well as an acetyl group R t may denote 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) -, (C 1 -C 6 -alkoxycarbonylamino- and carboxyl group, respectively with the (C 1 -C 6) -alkanols esterified carboxy group, or pyridine construction of Formula 2 and its N-oxide Formula 2 as the pyridine structure may optionally be attached to the carbon atoms 2, 3 and 4 of the ring and substituted with the substituents R ₅ and R ₆ . The residues R ₅ and R ₆ may be the same or different and have the meaning of (C ₁ -C ₆ ) -alkyl, (C 1 -C ₆ ) -cycloalkyl, (C 1 -C ₆ ) -alkoxy-, nitro-, amino-, hydroxy -, halogen and trifluoromethyl, as well as representing the ethoxycarbonylamine moiety and the carboxyalkoxy group, wherein the alkyl group has 1-4 Satomas. Rf may also mean one 2- or 4-pyrimidinylheterocycle, the 2-pyrimidinyl ring may be mono- or polysubstituted by methyl; moreover, > ⁴ means substituted by (C1-C6-alkyl, halogen, nitro, amino, (O- _C6 ) -alkyl-amino-residue 2-, 3-, 4-, and 8-quinolyl construction; one 2-, 3- and a 4-quinolylmethyl group, the carbon atoms of the ring of the pyridylmethyl residue of the quinolyl group and the quinolylmethyl residue being substituted by (C 1 -C 6) alkyl, (C 1 -C ₆ ) -alkoxy, nitro, amino (C 1 -C ₆ amino) (C 1 -C ₆ amino) group. R1 may, when R = hydrogen, methyl or benzyl, as well as a benzyloxycarbonyl residue (Z-residue), tert-butoxycarbonyl residue (Boc-residue) and acetyl group, denote the residues: -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) -; 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 NCO-CH ₂ -CH- (COOH) -; HOOC- (CH ₂ ) ₂ -CH (COOH) -; Ri may furthermore, in the case where R is hydrogen, a Z-group, a moiety, an acetyl or a benzyl group, denote the acidic residue of a natural or unnatural amino acid, for example α-glycyl, α-sarcosyl, α.alanyl- , α-leucyl-, α-iso-leucyl-, aceryl-, α-phenylalanil-, α-histidyl-, α-prolyl-, α-arginyl-, aa * lysyl-, α-asparagyl-′ and α-glutamyl - a residue such that the amino groups of the corresponding amino acids are unprotected or protected. As a protective group for amino function, the carbobenzoxy residue (Z-residue) and tert-butoxycarbonyl residue (Boc-residue) as well as the acetyl group are considered. In the case where an asparagyl- or glutamyl-residue is used for R ₁ , the second, unbound carboxyl group is in the form of an ester with C 1 -C 6 -alkanols, for example as methyl, ethyl or tert-butyl ester. In addition, R 1 may mean an allylaminocarbonyl-2-methylprop-1-yl group. R and R 1 may further form, together with the nitrogen atom to which they are attached, a piperazine ring of Formula 3 or a homopiperazine ring, insofar as R) represents an aminoalkyl group, wherein / ~ A -N NR ₇ W Formula 3 R ₇ represents an alkyl moiety, a phenyl ring which may be mono- or polysubstituted by (C 1 -C ₆ alkyl, (C (-C ₆ ) alkoxy, halogen, nitro group, amino) and may be substituted by (C 1 -C 6) alkylamino- R ₇ represents, moreover, a benzhydryl group and a bis-p-fluorobenzylhydryl group. R ₂ may mean hydrogen and a (C ₁ -C ₆ ) -alkyl group, the alkyl group being substituted one or more times with halogen and phenyl, which in turn can be substituted one or more times with halogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) cycloalkyl, carboxyl groups with esterified with (C ₂ -C ₆ ) -alkanol carboxyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. Apply at R ₂ (FTTUB / alkyl may be substituted by a 2-quinolyl group and the 2-, 3- and 4-pyridyl \ frame, as two ^'4 respectively may be substituted one or more times by halogen / (C ₄ ) -alkyl groups or (C ₁ -C ₄ ) -alkoxy groups, R _{2 also} means an aroyl moiety, the aryl moiety underlying this moiety being a phenyl ring which may be substituted one or more times with halogen, (C 1 -C ₆₎ -alkyl, (C ₃ -C ₇₎ -cycloalkyl, carboxyl groups esterified with (C _{d 6)} alkanols carboxyl groups trifluoromethy alkyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. R ₃ and R ₄ may be the same or different and represent hydrogen, (C 1 -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₂ -C ₆ ) -alkanoyl, (C ₁ -C ₆₎ ) alkoxy, halogen or benzyloxy. In addition, R ₃ and R ₄ may denote a nitro group, an amino group, (C ₁ -C ₄ ) -mono- or double-substituted alkyl group, and a (C ₁ -C ₆ ) -alkoxy-carbonylamino function or ( C ₁ -C ₆ -alkoxycarbonylamino- (C ₁ -C ₆ ) alkyl function. Z is 0 and S. Use of N-substituted indole-3-glyoxylamides according to claim 1 of the general Formula Ia for the treatment of tumors, especially in drug resistance and metastatic carcinoma, as well as inhibitors of angiogenesis, with less side effects, especially in significantly - low neurotoxicity % Z R T ^N ^ ^Ri / that Z R hours 3 1 hours In 1 <\ r ₂ / h In Formula 1a where the remnants signify R = hydrogen R-! = 4-pyridyl, 4-fluorophenyl R ₂ = benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl R ₃ and R ₄ = hydrogen and Z is oxygen. 3. Pharmaceutical composition for the treatment of tumors, especially in drug resistance and metastatic carcinoma, as well as as an inhibitor of angiogenesis, with less side effects and especially with significantly lower neurotoxicity, containing at least one of the compounds of general Formula 1 , respectively 1a, optionally also as acid-added salts, for example salts of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2hidroksietansulfonoba ^ acid, and their N-oxides. 4. The use of N-substituted indole-3-glyoxylamides of the general Formula I, respectively, and their physiologically acceptable acid addition salts, for the manufacture of antitumor agents for use especially in drug resistance and metastatic carcinoma, and as inhibitors of angiogenesis _h at significantly fewer side effects and / \ particularly at much lower neurotoxicity, and especially of the following compounds, or the salts thereof with physiologically acceptable acids, respectively, where possible, of the safety equipment is N- oxides: D 24241 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -indol-3- or 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 An antitumor agent comprising, as an active ingredient, one or more N-substituted indole-3-glyoxylamides according to the general Formula 1, respectively 1a, and optionally their physiologically acceptable acid addition salts, for use especially in drug resistance and metastatic carcinoma, as appropriate and as an inhibitor of angiogenesis, with significantly less side effects and especially with significantly lower neurotoxicity, and in particular one or more compounds according to claim 4. 6. An antitumor agent for the treatment of tumors, particularly in drug resistance and metastatic carcinoma, as well as as an inhibitor of angiogenesis, with significantly less side effects and especially with significantly lower neurotoxicity, and in particular containing as active ingredient D24241 N- (nDOIDin-4-yl) - [1- (4-fluorobenzyl) -indol-3I X yl] glyoxylamide, respectively its hydrochloride. 7. An antitumor agent for the treatment of tumors, especially in drug resistance and metastatic carcinoma, and as an inhibitor of angiogenesis, with significantly less side effects, and especially with significantly lower neurotoxicity, and in particular containing as active ingredient D 24843 N- (pyridin-4-yl) - (1-benzylindol-3-yl) -glyoxylamide. 8. An antitumor agent for the treatment of tumors, especially in drug resistance and metastatic carcinoma, and as an inhibitor of angiogenesis, with significantly less side effects and especially with significantly lower neurotoxicity, and in particular containing as active ingredient D 24850 N- (4-fluorophenyl) - [1- (3-pyridylmethyl) -indol-3-yl] glyoxylamide 9. An antitumor agent for the treatment of tumors, especially in drug resistance and metastatic carcinoma, as well as as an inhibitor of angiogenesis in significantly less side effects and especially in significantly lower neurotoxicity, and in particular containing as active ingredient D 24851 1 N- (pyridin-4-yl-541- (4-chlorobenzyl) -indol-3-yl] glyoxylamide 10. An antitumor agent for the treatment of tumors, especially in drug resistance and metastatic carcinoma, and as an inhibitor of angiogenesis, with significantly less side effects, and especially with significantly lower neurotoxicity, containing as one active ingredient one or more N-substituted / χ indole-3-glyoxylamides according to the general Formula 1, respectively 1a, and optionally their physiologically acceptable acid addition salts, and, if possible, the N-oxides, and in particular one or more compounds according to claim 4, and 6 to 8, and pharmaceutically applicable carriers and / or diluents, or excipients, respectively, in the form of tablets, dragees, capsules, infusion solutions or ampoules, suppositories, patches, inhalable powders, suspensions, creams and lipsticks. 11. Use of N-substituted indole-3-glyoxylamides of the general Formula 1, respectively 1a, and of their physiologically acceptable acid addition salts, as inhibitors of angiogenesis, and in particular of the following compounds, respectively, of their physiologically salts acceptable acids, if possible, of 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 No. (pyridin-4-yl) - [1- (4-chlorobenzyl) -indol-3-yl] - glyoxylamide D 25505 N (pyridin-4-yl) - [1- (4-fluorobenzyl) -indol-3-yl] ~ glyoxylamide NSG 12. Administration of N-substituted indole-3-glyoxylamides of the general Formula 1 and 1a, respectively, and their physiologically acceptable acid addition salts, especially in drug resistance and as substitutes for already ineffective 1MM ·· antitumor agents due to the development of resistance, and especially of the compounds G \ η A A I and 1 P OLOLO D 24850 D 24851 N- (pyridine-h-yl) - [1 - (N-cell ly'OpueHSHj 1; -ind-1-yl) glyoxylamide N- (pyridin-4-yl) - (1-benzylindol-3-yl) -glyoxylamide N- (4-fluorophenyl) - [1- (3-pyridylmethyl) -indol-3-yl] glyoxylamide 1- {1- (pyridin-4-yl) - [1- (4-chlorobenzyl) -indol-3-yl] - glyoxylamide D 25505 N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -indol-3-yl] - glyoxylamide HCl 13. Use of N-substituted indole-3-glyoxylamides of the general Formula 1, respectively 1a, and their physiologically acceptable acid addition salts, especially at drug resistance, in fixed or free combination with known antitumor agents and as substitutes for already ineffective antitumor agents due to the development of resistance, and most of all the compounds D 24241 N- (Pyridin-4-yl) - [1- (4-fluorobenzyl) -indole-3D 24843 D 24850 D 24851 / \. D 25505 or glyoxylamide N- (pyridin-4-yl- (1-benzylindol-3-yl) -glyoxylamide N- (4-fluorophenyl) - [1- (3-pyridylmethyl) -indol-3-yl] glyoxylamide N- (pyridin-4-yl) - [1- (4-chlorobenzyl) -indol-3-yl] glyoxylamide N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -indol-3-yl] glyoxylamide HCl