ZA200202556B

ZA200202556B - Indolyl-3-glyoxylic acid derivatives comprising therapeutically valuable properties.

Info

Publication number: ZA200202556B
Application number: ZA200202556A
Authority: ZA
Inventors: Bernd Nickel; Thomas Klenner; Gerald Bacher; Thomas Beckers; Peter Emig; Juergen Engel; Erik Bruyneel; Guenter Kamp; Kirsten Peters
Original assignee: Baxter Healthcare Sa
Priority date: 1999-09-28
Filing date: 2002-04-02
Publication date: 2003-08-27
Also published as: EP1218006B1; CZ20021005A3; NO322614B1; IS6319A; WO2001022954A2; GEP20043250B; WO2001022954A3; EP1218006A2; SK287533B6; DE50015879D1; CZ303246B6; HK1048941B; AR025885A1; UA75872C2; BR0014378A; CN1376064A; SK4072002A3; NO20021367D0; HUP0202788A3; PL364811A1

Description

i A : Indolyl-3-glyoxylic acid derivatives having therapeutically valuable properties , 5 The invention relates to the further advan- - tageous development of the German Patent Application - indole-3-glyoxylamides having the reference 19814 838.0.

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

Dbeen only partially explained.

The metastasis of a tumor is usually accom-~ panied 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 tamoxoifen [sic] 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):225-33.1

] The influence of melantonin [sic] on invasive and metastatic properties of MCF-7 human breast cancer cells has been reported {Cancer res 1988

Octl;58(19):4383-90] ] 5 The published PCT Application WO 96/23506 demonstrated the overcoming of pharmaceutical resis- tance 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.

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 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 cancer therapy.

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 treat- ment 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

- 3 = } metastatic process.

It has surprisingly been found that the

N-substituted indole-3-glyoxylamides described in

German Patent Application 19814 838.0 and of the ] 5 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.

The invention relates to the use of

N-substituted indole-3-glyoxylamides according to

Claim 1 general formula la for tumor treatment in particular in the case of pharmaceutical resistance and metastatic carcinoma and for the suppression of meta- stasis formation, as well as angiogenesis inhibitors -

R, : N~R, ] ] pA

N

R, R, formula 1 where the radicals R, R;, Ry, Ri, Ry and 2Z have the following meaning:

R = hydrogen, (Ci-Cg¢)-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-Cg) ~alkyl, (C3-Cy) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with C;-Cg-alkanols, trifluoro- methyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl group which 1s mono- or polysubstituted in the phenyl moiety by (Ci1-Cg)-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.

Ry can be the phenyl ring which is mono- or poly- substituted by (C1-Ce) -alkyl, {C1-Ce) -~alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, ) 5 benzyloxy, nitro, amino, (C1~-Cg)~alkylamino, (C1-C¢) —alkoxycarbonylamino and by the carboxyl ’ group or by the carboxyl group esterified with

Ci-Cg¢-alkanols, or is a pyridine structure of the formula 2 and its N-oxide [sic] 10 4 ; I . formula 2

N 2

R 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

Rs and Rg. The radicals Rs and Rg can be identical or different and have the meaning (C;-Cg)-alkyl, and the meaning (C3-C7)-cycloalkyl, (Ci1-Cg)-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.

R; 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 (Ci1-Cg)-alkyl, halogen, the nitro group, the amino group and the (C1-Cg) ~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-Cg) ~alkyl, (C1-Cg) —alkoxy, nitro, amino and (C;-Cs)-alkoxycarbonylamino.

R; can furthermore be, in the case where R

] R = hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (2 radical), the tert- butoxycarbonyl radical (BOC radical) and the acetyl group, the following radicals: ’ 5 —-CH,COOH; -CH(CH;) -COOH; - (CH3) 2-CH~- (CH;) ,-CH-COOQ;

H3C-H,C~CH (CH; ) -CH (COOH) -; HO-H,C-CH (COOH) -; pPhenyl-CH,-CH(COOH) -; (4-imidazolyl)-CH,-CH-COOQH) -;

HN=C (NH; ) -NH- (CH) 3-CH (COOH) -; H,N- (CH;) 4—CH (COOH) -;

H;N-CO~-CH,~-CH- (COOH) ~; HOOC (CH3) ;-CH(COOQH) -;

Rj 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 o-sarcosyl, the o-alanyl, the o-leucyl, the a-isoleucyl, the a-seryl, the a-phenylalanyl, the a-histidyl, the o~prolyl, the o-arginyl, the o-lysyl, the o-asparagyl and the oa-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 (Zz 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 R;, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C;-Ce¢-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.

Ri; can furthermore be the allylaminocarbonyl- 2-methylprop-1-yl group.

R and R; 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 R; is an aminoalkylene group in which

: / NN —N N—R, _/ formula 3

R; is an alkyl radical, a phenyl ring which can be ’ 5 mono- or polysubstituted by (C;-Cs)-alkyl, (Ci1-Cg)- alkoxy, halogen, the nitro group, the amino function and by the (C;-Cg)-alkylamino group. R; is furthermore the benzhydryl group and the bis-p- fluorobenzylhydryl group.

Ro can be hydrogen or the (C;-C¢)-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, (C;-Cg)-alkyl, (C3-C7) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C;-Cs-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C1-Ce¢) —alkyl group applying for R; 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, (C;-C4)-alkyl groups or (C;-C4)-alkoxy groups. R; 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-Cs) —alkyl, (C3-Cy)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C;-Cg-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.

R; and Ry can be identical or different and are hydrogen (C1-Cs) ~alkyl, (C3-Cy)-cycloalkyl, (C;-Cg)-alkanoyl, (C1-Cg) —alkoxy, halogen and benzyloxy. Rs; and Ry can furthermore be the nitro group, the amino group, the (C;-C4)-mono- or dialkyl-substituted amino group, and the (C;-Cg)-alkoxycarbeonylamino

- 7 = function or (C1-C¢) ~alkoxycarbonylamino- (C,-Cg) - alkyl function. y4 is O or S. } 5

The designation alkyl, alkanol, alkoxy or alkylamino ’ group for the radicals R, Ri, Raz, Ris, Rs, Rs, Rg, Ry; 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, methanesulfonic 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 I 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-gloxylamides [sic] according to Claim 1, general formula la, 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 (see Claim 4) on the MDR (multidrug-resistant) leukemia cell line of the mouse L 1210/VCR is not influenced in vivo and in vitro. See Figure 1, 2 and 3.

D-24851 (see Claim 4) has an unchanged cytotoxic activity against the multidrug-resistant mouse leukemia cell subline L1210/VCR in contrast to taxol, doxirubicin, vincristine or epotholone B [sic].

Experimental procedure:

The mouse leukemia cell lines [sic] L 1210 was adapted to vincristine. The unadapted (L 1210) and the : 5 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

MO4 cells. See Figure 5.

D-24 851 (see Claim 4) inhibits the migration of MO4 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 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 (see Claim 4) 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 - S contrast to taxol and vincristine.

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 (see

Claim 4) has a potential as an angiogenesis inhibitor.

As a result of the physiological relationship to tumor growth, angiogenesis inhibitors are at the same time 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 uMol/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. (see lethal staining in Figure 9, white dots)

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 : 5 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 [sic] 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 Claim 1 general formula la 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 Claim 1 general formula la 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 Claim 1 general formula la.

Claims

Patent Claims

1. Use of N-substituted indol-3-gloxylamides [sic] of the general formula 1 as antitumor agents according ) 5 to main patent application 19 814 838.0 for tumor : treatment in particular in the case of pharmaceutical ’ resistance and metastasizing carcinoma, and as : angiogenesis inhibitors, with markedly lower side effects in particular markedly lower neurotoxicity R Zz \ R, N-g, Z \ R, R, formula 1 where the radicals R, R;, Riz, Ri, Rs and Z have the following meaning: R = hydrogen, (C;-Cg¢)-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-Cs) —alkyl, (C3-C7) ~cycloalkyl, by carboxyl groups, carboxyl groups esterified with C;-C¢-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 (Ci-C¢)-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. R; can be the phenyl ring which is mono- or poly- substituted by (C1-C¢) ~alkyl, (C1~Cs) ~alkoxy, cyano, halogen, trifluoromethyl, hydroxyl,

] benzyloxy, nitro, amino, (C1-Ce) —alkylamino, (C1-C¢) —alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with Ci-Ce-alkanols, or is a pyridine structure of the ) 5 formula 2 and its N-oxide [sic]

. s 4 ; pe . formula 2 N 2 R 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 Rs and Rg. The radicals Rs and Rg can be identical or different and have the meaning (C;-Cg)-alkyl, and the meaning (C3-Cy)-cycloalkyl, (C;-Cg)-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. R; can furthermore be a 2- or 4d-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 (C;-Cg)-alkyl, halogen, the nitro group, the amino group and the (C1-C¢) —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-Cg¢) —alkyl, (C1-Cg) —alkoxy, nitro, amino and (C;-C¢)-alkoxycarbonylamino. RR 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:

] ~CH,COOH; ~CH (CH;3) ~COOH; - (CH;3) 2-CH- (CH; ) ,~-CH-COO; H3C-H;C-CH(CH3) -CH (COOH) -; HO-H,C-CH (COOH) -; phenyl-CH;-CH (COOH) -; (4-imidazolyl)-CH,-CH-COOH) -; HN=C (NH) -NH- (CH) 3-CH (COOH) -; H,N- (CH;) 4—-CH (COOH) -;

) 5 HoN-CO-CH,~-CH~ (COOH) -; HOOC (CH;) ,-CH (COOH) ~;

Ra 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 o-glycyl, the

O-sarcosyl, the o-alanyl, the a-leucyl, the 0-isoleucyl, the a-seryl, the o-phenylalanyl, the Oo-histidyl, the o-prolyl, the «o-arginyl, the o-lysyl, the oa-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 (2 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 R;, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C;-C¢-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.

Ri can furthermore be the allylaminocarbonyl- 2-methylprop-1-yl group.

R and R; 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 R; is an aminoalkylene group in which WV er __/ formula 3

R7; is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (C1-Ce)-alkyl, (C1-Cq)-

alkoxy, halogen, the nitro group, the amino function and by the (C;-C¢)-alkylamino group. R; is furthermore the benzhydryl group and the bis-p- fluorobenzylhydryl group. ’ 5 Ry can be hydrogen or the (C;-Cg)-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, (C;-Cg)-alkyl, (C3-C7) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C:-Cg¢-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C1~Cs) —alkyl group applying for R; 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, (C;-C4)-alkyl groups or (Ci-C4)-alkoxy groups. R; 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-Cs) —alkyl, (C3-Cy)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C;-C¢-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. R3 and Rs can be identical or different and are hydrogen (C1-Cg) alkyl, (C3-Cy)-cycloalkyl, (C1-Cg)-alkanoyl, (C1-C¢) —alkoxy, halogen or benzyloxy. Riz; and Rs can furthermore be the nitro group, the amino group, the (C1-C4) -mono- or dialkyl-substituted amino group, and the (C;-Cg)-alkoxycarbonylamino function or (C1-Cs) —alkoxycarbonylamino- (C;-Cg) ~alkyl function. Z is O or S

2. Use of N-substituted indole-3-gloxylamides [sic] according to Claim 1 general formula la for tumor

] treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects, in particularly markedly lower neurotoxicity : 5

R . Zz \ R, Ng, 2 R Y 3 R, formula 1a where the radicals R = hydrogen R;1 = 4-pyridyl, 4-fluorophenyl Ry = benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3- pyridylmethyl, 4-bromobenzyl Co R3 and Ry; = hydrogen and 2Z is oxygen.

3. Pharmaceutical composition for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects in particular markedly lower neurotoxicity characterized in that they contain at least one of the compounds of the general formula 1 or la if appropriate also they [sic] 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, for example, acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2- hydropOxyethanesulfonic [sic] acid and possible [sic], their N-oxides.

4. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or la and their physiologically tolerable acid addition salts for the production of antitumor agents for use in particular in the case of ) 5 pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side ) effects in particular markedly lower neurotoxicity, to be specific in particular of the following compounds or their salts with physiologically tolerable acids or if possible their N-oxides: D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-y1] glyoxylamide D 24843 N-(pyridin-4-yl)-(l-benzylindol-3-yl) glyoxylamide D 24850 N-(4-fluorophenyl)-[1l-(3-pyridylmethyl)indol- 3-y1l] glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-y1] glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl1] glyoxylamide HCL [sic]

5. Antitumor agent comprising as active compound one or more N-substituted indole-3-gloxylamides [sic] according to the general formula 1 or la and, if appropriate, their physiologically tolerable acid addition salts of antitumor agents for use in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity but in particular one or more compounds according to Claim 4.

6. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound

D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-y1] glyoxylamide or its hydrochloride

7. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and ) 5 metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly } lower neurotoxicity, to be specific in particular comprising as active compound D 24843 N-(pyridin-4-yl)-(l-benzylindol-3-yl)glyoxyl- amide

8. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol- 3-vllglyoxylamide

9. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound D 24851 N-(pyridin-4-yl)-[1- (4-chlorobenzyl)indol-3-y1] glyoxylamide

10. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity comprising as active compound one or more N-substituted indole-3-gloxylamides [sic] according to the general formula 1 or la and, if appropriate, their physiologically tolerable acid addition salts and, if possible, N-oxides, but in particular one or more compounds according to Claims 4 and 6 to 8 and a pharmaceutically utilizable vehicle and/or diluent or excipient in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, Creams and ointments. . 5

11. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or la and their physiologically : tolerable acid addition salts as angiogenesis inhibitors, to be specific in particular of the following compounds or their salts with physiologically tolerable acids or if possible their N-oxides: D 24241 N- (pyridin-4-yl) -[1-(4-fluorobenzyl) indol-3-y1] glyoxylamide D 24843 N-(pyridin-4-yl)-(l-benzylindol-3-yl)glyoxyl- amide D 24850 N- (4-fluorophenyl) - [1- (3-pyridylmethyl) indol- 3-yllglyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-y1] glyoxylamide D 25505 N- (pyridin-4~yl)-[1- (4-fluorobenzyl)indol-3-y1] glyoxylamide HCL [sic]

12. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or la and their physiologically tolerable acid addition salts for use in particular in the case of pharmaceutical resistance and as a replacement for antitumor agents which are no longer active on account of resistance formation in particular of the compounds D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-y1l] glyoxylamide D 24843 N-(pyridin-4-yl)-(l-benzylindol-3-yl)glyoxyl- amide D 24850 N-(4-fluorophenyl)-[1-(3~pyridylmethyl)indol- 3-yllglyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-y1] } glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-vy1]

} glyoxylamide HCL

13. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or la and their physiologically . 5 tolerable acid addition salts for use in particular in the case of pharmaceutical resistance in fixed or free ; combination with known antitumor agents and as a replacement for antitumor agents which are no longer active on account of resistance formation in particular of the compounds D 24241 N- (pyridin-4-yl)-[1-(4~-fluorobenzyl)indol-3-yl] glyoxylamide D 24843 N-(pyridin-4-yl)-(l-benzylindol-3-y1l)glyoxyl- amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol- 3~-yllglyoxylamide D 24851 N- (pyridin-4-yl)-[1-(4-chlorobenzyl)indol- 3~-yllglyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-~fluorobenzyl)indol- 3-yllglyoxylamide HCL