NZ517988A

NZ517988A - Antitumour compositions comprising indolyl-3-glyoxylic acid derivatives

Info

Publication number: NZ517988A
Application number: NZ517988A
Authority: NZ
Inventors: Bernd Nickel; Thomas Klenner; Gerald Bacher; Thomas Beckers; Peter Emig; Jurgen Engel; Erik Bruyneel; Gunter Kamp; Kirsten Peters
Original assignee: Baxter Healthcare Sa
Priority date: 1999-09-28
Filing date: 2000-09-26
Publication date: 2004-10-29
Also published as: CA2386069A1; TWI269654B; EP1218006B1; ZA200202556B; JP2003510274A; GEP20043250B; WO2001022954A2; EE200200169A; HK1048941B; HUP0202788A3; EP1218006A2; RS51302B; ES2342042T3; AR025885A1; DZ3196A1; RU2282444C2; CN1301712C; AU783436B2; KR100759242B1; SK4072002A3

Abstract

Described is the use of N-substituted indol-3-glyoxylamides of the general formula 1 in the manufacture of medicaments. The medicaments are used for treating resistant and/or multidrug resistant (MDR) tumours, development, migration and/or invasion of tumour metastases, and diseases in which an angiogenesis-inhibitory effect is desirable.

Description

<div class="application article clearfix" id="description"> A /«V ^ 5179 8a UNITED STATES PATENT AND TRADEMARK OFFICE I, Susan POTTS BA ACIS, Director of RWS Group pic, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England declare; 1. That I am a citizen of the United Kingdom of Great Britain and Northern Ireland. 2. That the translator responsible for the attached translation is well acquainted with the German and English languages. 3. That the attached is, to the best of RWS Group pic knowledge and belief, a true translation into the English language of the specification in German filed with the application for a patent in the U.S.A. on under the number 4. That I believe that all statements made herein of my own knowledge are true and that all statements made on information and belief are true; and further that these statements were made with the knowledge that willful false statements and the like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code and that such willful false statements may jeopardize the validity of the patent application in the United States of America or any patent issuing thereon. For and on behalf of RWS Group pic The 27th day of July 2000 ^llECTUAL PROPERTY-OFFICE: OF N.Z 2 0 AUG 2004 INTELLECTUAL PROPERTY «i~ hi T uFmuE ur in.*. 2 0 AUG 2001) RECEIVED t.nmm Indolyl-3-glyoxylic acid derivatives serving :as antitumor agents v The invention relates to the further advantageous .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 i-nvasion and the formation of metastases is the most frequent cause of death of cancer patients. There are various starting points to explain this spread, inter alia intensified angiogenesis, increased extracellular matrix degradation, tumor cell migration and, modulation of cell adhesion. These factors can also act in combination, but until now have been only partially explained. The metastasis of a tumor is usually accompanied by poor prognoses in the tumor treatment. The prerequisite for metastasis is the detachment of cells from the primary tumor, the migration of the cells to the blood vessels, the invasion into the blood vessels and the invasion of the cells from the blood . vessels into other tissue. An inhibitory action of certain antitumor agents- such as tamoxo'ifen [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.] 2 The influence of melantonin [ sic] on invasive and metastatic properties on MCG-7 human breast cancer cells has been reported [Cancer res 1998 Octl; 58(19) : 4383-90] 5 The published PCT Application W096/23506 demonstrated the overcoming of pharmaceutical resistance with certain tumor pharmaceuticals as a result of the gene amplification of the multi-drug resistance gene (MDR gene) brought about by such antitumor agents. 10 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 on N-substituted indole-3-glyoxvlamides and 15 thus to enrich the available pharmaceutical wealth or to at least provide a useful choice. The possibility of a lower, longer-lasting and more tolerable medication for the class of substances having antitumor action described in German Patent Application 19814 838.0 should thereby be opened up. In particular, 20 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. 25 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 30 therapy. The intensification of action achieved with the N-substit.uted indole-3-glyoxylamides should make pharmaceutical use in tumor therapy more effective. Moreover, it should be possible to shorten the treat-35 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 - 10 15 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 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 metastasis formation, as well as angiogenesis inhibitors R, R \ N- ■R< R, formula 1 where the radicals R, Ri, R2/ R3, R4 and Z have the 2 0 following meaning: R = hydrogen, (Ci-C6) -alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring, for its part, can be mono- or 25 polysubstituted by halogen, (Cx-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups .esterified with C;L-C6-alkanols, trifluoro-methyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl 30 group which is mono- or polysubstituted in the phenyl moiety by (Ci-Cs)-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. can be the phenyl ring which is mono- or poly- group or by the carboxyl group esterified with Ci-C6-alkanols, or is a pyridine structure of the formula 2 and its N-oxide [sic] and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R5 and R6. The radicals R5 and Rs can be identical or different and have the meaning (Ci-C6)-alkyl, and the meaning (C3-C7)-cycloalkyl, (Ci-C6) -alkoxy, nitro, amino, hydroxyl, halogen and trifluoro-methyl and are furthermore the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms. 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 (Cx-C6)-alkyl, halogen, the nitro group, the amino group and the (C!-C6)-alkylamino radical, a 2-, 3- or 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (Ci-Cs)-alkyl, (Ci-C6)-alkoxy, nitro, amino and (Ci-C6)-alkoxycarbonylamino. can furthermore be, in the case where substituted by (Ci-C6)-alkyl, (C^-Cg) -alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (Ci-C6)-alkylamino, (Ci-Cg) - alkoxycarbonylamino and by the carboxyl formula 2 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: -CH2COOH; -CH (CH3) -COOH; - (CH3) 2-CH-(CH2 ) 2-CH-COO; H3C-H2C-CH (CH3) -CH (COOH) - ; HO-H2C-CH (COOH) - ; phenyl-CH2-CH(COOH)-; (4-imidazolyl)-CH2-CH-COOH)-; HN=C(NH2) -NH- (CH2) 3-CH(C00H) H2N- (CH2) 4-CH (COOH) - ; H2N-CO-CH2-CH- (COOH) HOOC (CH2) 2-CH (COOH) - ; can furthermore be, in the case where R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, the acid radical of a natural or unnatural amino acid, e.g. the a-glycyl, the a-sarcosyl, the a-alanyl, the a-leucyl, the a-isoleucyl, the a-seryl, the a-phenylalanyl, the a-histidyl, the a-prolyl, the a-arginyl, the a-lysyl, the a-asparagyl and the a-glutamyl radicals, where the amino groups of the respective amino acids can be present in unprotected or protected form. Possible protective groups for the amino function are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for Ri, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with Ci-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester. Rx can furthermore be the allylaminocarbonyl-2-methylprop-l-yl group. R and Rx 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 Rx is an aminoalkylene group in which / \ N N-R7 v_y formula 3 R7 is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (C1-C6)-alkyl, (Ci-C5)-alkoxy, halogen, the nitro • group, the amino function and by the (Ci-C5)-alkylamino group. R7 is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl group. can be hydrogen or the (Ci-Cs) -alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified • with Ci-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (Ci-C6)-alkyl group applying for R2 can furthermore be substituted by the 2-guinolyl group and the 2-, 3- or 4-pyridyl structure, which can both each be mono- or polysubstituted by halogen, (C1-C4)-alkyl groups or (C1-C4)-alkoxy groups. R2 is furthermore the aroyl radical, where the aryl moiety on which this radical is based is the phenyl ring, which can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with Ci-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. and R4 can be identical or different and are hydrogen (Ci-C6)-alkyl, (C3-C7)-cycloalkyl, (Ci-Ce) -alkanoyl, (Ci-Cs) -alkoxy, halogen and benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono- or dialkyl-substituted amino group, and the (Cx,-Ce) -alkoxycarbonylamino - 7 - function or (Ci-Cg)-alkoxycarbonylamino- {Cx-C&) -alkyl function. Z is 0 or S. 5 The designation alkyl, alkanol, alkoxy or alkylamino group for the radicals R, Rx, R2, R3, R4, R5, Rs, R7 is normally to be understood as meaning either "straight-chain" or "branched" alkyl groups, where "straight-10 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, 15 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, 20 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, 25 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 2-30 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 35 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, pharrnaceutically 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 19 6 3 6 15 0 A1. 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] . - 9 - 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. 10 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 15 furnished by means of the inhibition of migration of M04 cells. See Figure 5. D-24 851 (see Claim 4) inhibits the migration of M04 cells in a dose-dependent manner. An antiinvasive and an antimetastatic action for D-24851 can be derived 2 0 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 25 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 30 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 35 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 - 10 - 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 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 |iMol/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 - 11 - 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 10 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 2 0 mg up to 50 0 mg daily orally are possible. 15 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 20 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. 2 5 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). 3 0 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 35 inactive as a result of development of resistance by N-substituted indole-3-glyoxylamides according to Claim 1 general formula la. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 12 Patent Claims

1. Use of one or more N-substituted indol-3-glyoxylamides of the general formula 1, their physiologically tolerable acid addition salts and/or their N-oxides for the production of a medicament for the treatment of a disease selected from the group consisting of a resistant and/or multidrug resistant (MDR) tumors, development, migration and/or invasion of tumour metastases, and diseases in which an angiogenesis-inhibitory effect is functionally desirable, whereby the treatment involves lower side effects, in particular lower neurotoxicity, formula 1 where the radicals R, Ri, R2, Rs, R4 and Z have the following meaning; R = hydrogen, (Ci-Ce)-aIkyi, 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, (Ci-C6)-alkyf, (C3-C7)-cycloa]kyl, by carboxyl groups, carboxyl groups esterified with Ci-Ce-alkanols, trifiuoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C-rC6)-alkyl groups, halogen atoms or trifiuoromethyl groups, R is furthermore the benzyloxycarbonyl group (Z group) or the tertiary butoxycarbonyl radical (Boc radical), furthermore the acetyl group. R1 can be the phenyl ring which is mono- or polysubstituted by (C-rC6)-aIkyl, (Ci-C€)-alkoxy, cyano, halogen, trifiuoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-aIkyiamino; (Ci-C6)-alkoxycarbonyIamino and by the carboxyl group or by the carboxyl group esterified with CrC6-alkanols, or is a pyridine structure of the formula 2 ; 0 13 \« * formula 2 N 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 Re. The radicals Rs and Re can be identical or different and have the meaning (Ci-Ge)-aikyl, and the meaning (CrC7)-cycIoalkyl, (C<i-Ce>aikoxy, nitro, amino, hvdrOYV' Viglon^ri anr) frifli inmmathvl and arc fi irthfermnm thA I IJTMI * J « * MIIV VI IIIMWI VlllVkl ijl Ml IM V<l IMI VI IVf I f IV* N' *» «>» ethoxycarbonylamino radical and the group carboxyaikyloxy in which the alkyl group can have 1-4 C atoms, 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-quinoly! structure substituted by (Ci-Ce)-aIkyI, halogen, the nitro group, the amino group and the (CrCe)-aikylamino radical, a 2-, 3- or 4-quinolyimethyI group, where the "ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C-i-C6)-alkyl> (Ci-C6)-alkoxy, nitro, amino and (Ci-C6)-alkoxycarbonylamino. can furthermore be, in the case where R - hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbony! radical (BOC radical) and the acetyl group, the following radicals: -CH2COOH; -CH(CH3)-COOH; -(CH3)2-CH-(CH2)2-CH-COO; H3C-H2C-CH(CH3)-CH(COOH)-; HO-H2C-CH(COOH)-; phenyl-CH2-CH(COOH)-; (4-Imidazolyl)-CH2-CH-COOH)-; ' HN=C(NH2)-NH-(CH2)3-CH(COOH)-; H2N-(CH2VCH(COOH)-;. H2N-CO-CH2-CH-(COOH)-; HOOC(CH2)2-CH(COOH>; can furthermore be, in the case where R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, the acid radical of a natural or unnatural amino acid, e.g. the a-glycyl, the a-sarcosyl, the a-aianyl, the a-leucyl, the . a-isoleucyl, the a-seryl, the a-phenylalanyl, the a-histidyl, the a-prolyi, the a-arginyi, the a-Iysyl, the a-asparagyl and the a-glutamy! radicals, where the 14 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-butcxycarbonyl radical (BOC radical) as well as the acetyl, group. In the case of the asparagyl and glutamyl radical claimed for Ri, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C-rQe-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester. Ri can furthermore be the allylaminocarbonyl-2-methyIprop-l-yl group. R and R-t 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 Ri is an aminoalkylene group in which —N N-FL v_y formula 3 R7 is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (Ci-C6)-alkyl( (Ci-C6)-alkoxy, halogen, the nitro group, the amino function and by the (CrC6)-aikylamino group. R7 is furthermore the benzhydry! group and the bis-p-fluorobenzylhydryl group. R2 can be hydrogen or the (CrC6)-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, (Ci-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyi groups esterified with Cj-Cs-alkanols, trifiuoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (CfC6)-alkyl group applying for R2 can furthermore be substituted by the 2-quinolyl group and the 2-, 3- or 4-pyridyl structure, which can both each be mono- or polysubstituted by halogen, (CrC4)-alkyl groups or (Ci-C4)-.aIkoxy groups. Rz 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, (Ci-Ce)-alkyi, (C3-C7>-cycIoalkyl, carboxyl groups, carboxyl groups esterified with Ci-C6-aikanols, trifiuoromethyl groups, hydroxy! groups, methoxy groups, ethoxy groups or benzyloxy groups. 15 R3 and R4 can be identical or different and are hydrogen (C-rCe)-alkyl, (C3-C7)- cycloalkyl, (C-i-Csy-alkanoyi, (C-rCeJ-aikoxy, halogen or benzyioxy. R3 and R4 can furthermore be the nitro group, the amino group, the (Ci-C4)-mono- or dialkyl-substituted amino group, and the (Ci-Ce)-alkoxycarbonylamino function or (CrC6)-alkoxycarbonylamino-{Ci-C6)-alkyl function. 2 is O or S

2. Use of one or more N-substituted indol-3-glyoxylamides according to Claim 1 of the general formula 1a, their physiologically tolerable acid addition oauo ai iu/ui u ic^ii i^-uaiuco iui li ic pi uuuouui 1 ui a 11 luui^ai 1 id u iui 1110 uccuiiiom ui a disease selected from the group consisting of resistant and/or multidrug resistant (MDR) tumors, development, migration and/or invasion of tumor metastases, and diseases in which an angiogenesis-inhibitory effect is functionally desirable, whereby the treatment involves lower side effects, in particular lower neurotoxicity, R \ formula la where the radicals R = hydrogen Ri = 4-pyridyl, 4-fluorophenyl R2 = benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-brombbenzyl R3 and R4 = hydrogen and Z is oxygen. 16

3. Use of one or more N-substituted indoi-3-glyoxylamides of the general formula 1 or 1a according to claims 1 or 2, their physiologically tolerable acid addition salts and/or their N-oxides, for the production of a medicament for the treatment of a disease selected from the group consisting of resistant and/or multidrug resistant (MDR) tumors, development, migration and/or invasion of tumor metastases, and diseases in which an angiogenesis-inhibitory effect is functionally desirable, whereby the treatment involves lower side effects, in particular lower neurotoxicity, in particular the following compounds, their physiologically tolerable acid'addition salts and/or their N-oxides: r D 24241 N-{pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl] glyoxylamide D 24843 N-(pyria in-4-yl)-(1 -benzyiin doi-3-yi) giyoxyiamiae D 24850 N-(4-f!uorophenyl)-i1-(3-pyridylmethyl)indol- 3-yI] glyoxylamide D 24851 N-(pyrid!n-4-yl)-[1-(4-chlorobenzyl)indol-3-y0 glyoxylamide D 25505 N-(pyridin~4-yl)-[1-(4-fluorobenzyl)indol-3-yi] glyoxylamide HCI salt

4. Use of one or more N-substituted indole-3-gIyoxylamides according to any one of claims 1 to 3, wherein the acid addition salt is selected from the group consisting of 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, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2-hydroxyethanesulfonic acid,

5. Use of one or more N-substituted indole-3-glyoxyIamides according to any one of claims 1 to 4, wherein the physiologically tolerable N-oxide is a chemically possible N-oxide of an N-substituted indole-3-gloxylamide or an acid addition salt thereof.

6. Use of one or more N-substituted indoIe-3-glyoxyIamides according to any one of claims 1 to 5, wherein the resistant and/or multidrug resistant (MDR) tumor is a tumor at least resistant to an antitumor drug selected from the group consisting of taxol, doxirubicine, vincristine and epotholone B.

7. Use of one or more N-substituted indoIe-3-glyoxylamides according to. any one of claims 1 to 6, wherein the diseases in which the functionally desirable angiogenesis-inhibitory effect is wound healing.

8. Use of one or more N-substituted indole-3-glyoxylamldes according to any one of claims 1 to 7, wherein one or more N-substituted indole-3-glyoxylamides, their physiologically tolerable acid addition salts and/or N-oxides as active ingredients are optionally used together with a phanTiaceutically 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.

9. Use of one or more N-substituted indole-3-glyoxylamides of the general formula 1 or 1a according to any one of claims 1 to 8, their physiologically tolerable acid addition salts and/or N-oxides for the preparation of a medicament having angiogenesis inhibitor activity, in particular said use of one or more of the following compounds, their physiologically tolerable acid addition salts and/or N-oxides: N-(pyridin-4-ylHl-(4-fluorobenzyl)indol-3-yl] glyoxylamide N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxylamide N-(4-fIuorophenyl)-[1-(3-pyridylmethyl)indoI- 3-yQglyoxylamide N-(pyridin-4-yiH1-(4-chloroben2yl)indol-3-yl] glyoxylamide N-(pyridin-4-ylH1-(4-fluorobenzyi)indoI-3-yl] glyoxylamide HCI salt.

10. Use of one or more N-substituted indole-3-glyoxylamides of the general formula 1 or 1 a according to any one of claims 1 to 9, their physiologically tolerable acid addition salts and/or N-oxides for the preparation of a medicament for the treatment of pharmaceuticaliy resistant and/or multidrug resistant (MDR) tumors for replacement of one or more antitumor agents which are no longer active on account D 24241 D 24843 D 24850 D 24851 D 25505 of resistance formation, in particular said use of one or more of the following compounds, their physiologically tolerable acid addition salts and/or N-oxides: N-(pyridin-4-yl)-[1 -(4-fluorobenzyl)indoI-3-yl] glyoxylamide N-(pyridin-4-yl)-(1-benzyiindol-3-yI)glyoxyIamide - N-(4-fluorophenyl)-[1 -(3-pyridylmethyl)indol- 3-yI]gIyoxyiamide N-{pyridin-4-yl)-[1-{4-ch!orobenzyI)indol-3-yl] glyoxylamide N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indoi-3-yl] glyoxylamide HCI salt

11. Use according to any one of claims 1 to 10, wherein the resistant and/or multidrug resistant (MDR) tumor is a tumor at feast resistant to an antitumor drug selected from the group consisting of taxoi, doxirubicine, vincristine and epotholone B.

12. Use of one or more N-substituted indole-3-gIyoxylamides of the general formula 1 or 1 a according to any one of claims 1 to 11, their physiologically tolerable acid addition salts and/or N-oxides for the preparation of a medicament comprising a fixed or free combination of said one or more N-substituted.indole-3-glyoxyIamides of the general formula 1 or 1a according to claims 1 or 2 and one or more known antitumor agents (antitumor agent to be combined) for replacement in part or total of one or more antitumor agents (antitumor agent to be replaced) which are no longer active on account of resistance formation, in particular said use of one or more of the following compounds, their physiologically tolerable acid addition salts and/or N- N-(pyridin-4-yl)-[1-(4»fluorobenzyl)indoI-3-y]] glyoxylamide N-(pyridin-4-yl)-(1 -benzylindol-3-yl)glyoxylamide N-(4-fIuorophenyI)-[1 -(3-pyridyImethyl)indol- 3-yI]glyoxylamide N-(pyridin-4-yl)-[1 -(4-chlorobenzy!)indol- 3-yl]glyoxylam/de N-(pyridin-4-yI)-[1 -(4-fIuorobenzyl)indol-3-yl]glyoxyIamide HGI salt D 24241 D 24843 D 24850 D 24851 D 25505 oxides: D 24241 D 24843 D 24850 D 24851 D 25505

13, Use according to any one of claims 1 to 12, wherein the antitumor agent for fixed or free combination (antitumor agent to be combined) is selected from the group consisting of taxol, doxirubicine, vincristine and epotholone B,

14. Use according to any one of claims 1 to 13, wherein the antitumor agent for replacement is selected from the group consisting of taxol, doxirubicine, vincristine and epotholone B,

15. Fixed or free combination of one or more N-substituted indol-3-glyoxylamides of the general formula 1, their physiologically tolerable acid addition salts and/or their N-oxides for the production of a medicament for the treatment of a disease selected from the group consisting of resistant and/or multidrug resistant (MDR) tumors, development, migration and/or invasion of tumor metastases, and diseases in which an angiogenesis-inhibitory effect is functionally desirable, whereby the treatment involves lower side effects, in particular lower neurotoxicity, formula 1 where the radicals R, Ri, R2, R3, R4 and 2 have the following meaning: R = hydrogen, (Ci-CeJ-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, (C-|-C6)-alkyi, (C3-C7)-cycIoalkyI, by carboxyl groups, carboxyl groups esterified with Ci-C6-alkanols, trifiuoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C-rC6)-aIkyI groups, halogen atoms or trifiuoromethyl groups, R is furthermore the benzyioxycarbony! group (Z group) or the tertiary butoxycarbonyi radical (Boc radical), furthermore the acetyl group. 20 can be the phenyl ring which is mono- or polysubstituted by (Ci-Cs)-alkyi, (Ci-CeJ-aikoxy, cyano, halogen, trifiuoromethyl, hydroxyl, benzyloxy, nitro, amino, (Ci-C6)-aikyiamino, (Ci-Ce)-alkoxycarbonylamino and by the carboxyi. group or by the carboxyl group esterified wrth Ci-Ce-aikano!s, or is a pyridine structure of the formula 2 and its N-oxide [sic] 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 Re. The radicals Rs and Rs can be identical or different and have the meaning (C-rCeJ-alkyl, and the meaning (Ca-G^-cycloalkyl, (Ci-C6)-alkoxy, nitro, amino, hydroxyl, halogen and trifiuoromethyl and are furthermore the ethoxycarbonyiamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms. can furthermore be a 2- or4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore the 2-, 3-, 4- and 8-quinofyl structure substituted by (C-rC6)-aIkyl, halogen, the nitro group, the amino group and the (CrC6)-aIkyiamino radical, a 2-, 3- or . 4-quinolylmethyl group, where the ring carbons of the pyridylmethyi radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (Ci-Ce)-alkyl, {CrC6)-alkoxy, nitro, amino and (C-|-C6)-aIkoxycarbonyIamino. can furthermore be, in the case where R = hydrogen, the methyl or benzyl group and the benzyioxycarbonyl radical (Z radical), the tert-butoxycarbonyi radical (BOC radical) and the acetyl group, the following radicals: -CH2COOH; -CH(CH3)-COOH; -(CH3)2-CH-(CH2)2-CH-COO; H3C-H2C-CH(CH3)-CH(COOH)-; HO-H2C-CH(COOH>; phenyl-CH2-CH(COOH)-; (4-imidazo!yi)-CH2-CH-COOH)~; HN=C(NH2)-NH-(CH2)3-CH(COOH)-; H2N-(CH2)4-CH(COOH)-; H2N-CO-CH2-CH-(COOH)~; HOOC(CH2)2-CH(COOH)-; formula 2 can furthermore be, in the case where R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, the acid radical of a natural or unnatural amino acid, e.g. the a-glycyl, the a-sarcosyi, the a-aianyi, the a-Ieucyi, the a-isoleucyi, the a-seryl> the a-phenylalanyl, the a-histidyl, the a-prolyl, the a-arginyl, the a-lysyl, the a-asparagyl and the a-glutamyl radicals, where the amino groups of the respective amino acids can be present in unprotected or protected form. Possible protective groups for the amino function are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R-i, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with CrCe-alkanoIs, e.g. as a methyl, ethyl or as a tert-butyl ester. Ri can furthermore be the aIlylaminocarbonyl-2-methyiprop-l-yl group. R and Rq can furthermore, together with the nitrogen atom to which they are bonded, form a piperazine ring of the formula 3 or a horriopiperazine ring, if Ri is an aminoalkylene group in which / \ — N N-FL v_y formula 3 R7 is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (CrC6)-alkyl, (Ci-Cs)-alkoxy, halogen, the nitro group, the amino function and by the (C-j-Ce^alkylamino group. R7 is furthermore the benzhyd'ryl group and the bis-p-fluorobenzylhydryl group. can be hydrogen or the (Ci-C6)-alkyI group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- or polysubstituted by halogen, (CrC6>alkyI, (C3-C7)-cycIoalkyI, carboxyl groups, carboxyl groups esterified with Ci-Cs-alkanols, trifiuoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups, The (C-i-Ce)-alkyl group applying for R2 can furthermore be substituted by the 2-quinolyl group and the 2-, 3- or 4-pyridyl structure, which can both each be mono- or polysubstituted by halogen, (Ci-C4)-alkyI groups or (C-rC4)-a]koxy groups. R& is furthermore the aroyl radical, where the aryl moiety on which this radical is based is the phenyi ring, which can be mono- or polysubstituted by halogen, (Ci-C6)-aIkyi; (C3-C7)-cycloalkyl> carboxyi groups, carboxyl groups esterified with C-rC6-a)kano!sF trifiuoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups, R3 and R4 can be identical or different and are hydrogen (CrCe)-alkyl, (C3-C7>- cycloalkyl, (CrC6)-alkanoyl, (Gi-Cs)-alkoxy, halogen or benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (Ci-C4)-mono- or dialkyl-substituted amino group, and the (Ci-C6)-alkoxycarbonyIamino function or (Ci-C6)-aikoxycarbonyiamino-(Ci-C6)-aikyi function. Z is 0 or S together with one or more antitiumor agents selected from the group consisting of taxol, doxirubicine, vincristine and epotholone B, optionally together with a pharmaceutical^ 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.

16. Fixed or free combination of one or more N-substituted indole-3-glyoxylamides of the general formula 1a, their physiologically tolerable acid addition salts and/or their N-oxides for the production of a medicament for the treatment of a disease selected from the group consisting of resistant and/or multidrug resistant (MDR) tumors, development, migration and/or invasion of tumor metastases, and diseases in which an angiogenesis-inhibitory effect is functionally desirable, whereby the treatment involves lower side effects, in particular lower neurotoxicity, 23 R \ formula la where the radicals R= hydrogen Ri = 4-pyridyl, 4-fiuorophenyl R2 = benzyl, 4-chIorobenzyl, 4-fluorobenzyl, 3-pyridylmeihyl, 4-bromobenzyI R3 and R4 ~ hydrogen and Z is oxygen. together with one or more antitumor agents selected from the group consisting of taxol, doxirubicine, vincristine and epotholone B, optionally together with a pharmaceutical^ 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.

17. Fixed or free combination of one or more of the following N-substituted indole-3-glyoxylamides, their physiologically tolerable acid addition salts and/or their N-oxides for the production of a medicament for the treatment of a disease selected ' from the group consisting of resistant and/or multidrug resistant (MDR) tumors, development, migration and/or invasion of tumor metastases, and diseases in which an angiogenesis-inhibitory effect is functionally desirable, whereby the treatment involves lower side effects, in particular lower neurotoxicity, D 24241 N-(pyridin-4-y!)-[1-(4-fluorobenzyI)indoI-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)indo[-3-yl] glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-f[uorobenzyl)indoI-3-yI] glyoxylamide HCI salt together with one or more antitumor agents selected from the group consisting of taxol, doxirubicine, vincristine and epotholone B, optionally together with 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.

18. Use according to any one of claims 1, 15, 16, or 17 substantially as herein described with reference to any example thereof. Abstract The invention relates to the use of N-substituted indole-3-gloxylamides [sic] of the general formula 1 for tumor treatment in particular in the case of pharmaceutical resistance and metastisizing carcinoma, and as angiogenesis inhibitors, with markedly lower side effects in particular markedly lower neurotoxicity, and pharmaceuticals comprising them. R„ </div>