WO2009010542A1 - Cyclic amide compounds, method for the production thereof and the use thereof - Google Patents

Abstract

The invention relates to cyclic amide compounds of general formula (I), wherein R1 and R2 are defined in claim 1. The invention also relates to a method for producing compounds of formula (I), pharmaceutical agents containing at least one of these compounds and their use for angiogenesis inhibition and for the prevention and/or therapy of diseases associated with angiogenesis, in particular cancer diseases.

Description

 Cyclic amide compounds, process for their preparation and their use

DESCRIPTION

The present invention relates to novel cyclic amide compounds, their preparation, pharmaceutical compositions containing at least one of these compounds and their use, in particular for the inhibition of protein kinases and angiogenesis inhibition.

As early as 1971, J. Folkman of Harvard University discovered the principle of angiogenesis inhibition. Microtumors or small local metastases do not grow without connection to the vascular system, but form a relatively stable cell population, in which growth and apoptosis balance each other. Only after the vasculature, ie connection with the blood circulation and usually also the lymphatic system, a growth spurt of the tumor occurs. The apoptosis is reduced and a sudden increase in size by a thousand times within a few weeks is the result. At the same time, vascularization also opens the way to forced metastasis if daughter cells can spread to other tissues via the blood and lymph channels. If, however, the necessary neovascularization is prevented, the tumor often remains stable in a minimal space.

What makes the antiangiogenic approach to tumor therapy selective and thus attractive is the fact that basal neovascularization is virtually non-existent in adults. New vessels, including lymph vessels, are not formed by conversion of existing cell aggregates or progenitor cells de novo, but arise by sprouting from existing vessels. In addition to wound healing and ovulation / menstruation, neo-vascularization is found only in pathological processes such as tumors, diabetic retinopathy, and age-related macular degeneration in the eye, as well as some autoimmune and / or inflammatory processes. The basis for vascularization activities is always a local hypoxia of cells, be it in a functional tissue or a growing tumor. Local hypoxia, mediated via cellular oxygen-sensitive heme proteins, induces a range of angiogenic stimuli, in particular the key protein VEGF (Vascular Endothelial Growth Factor). Several tumor cell lines are able to directly secrete VEGF. The growth factor binds to tyrosine kinase-coupled membrane receptors (VEGF receptors, VEGF-R) on quiescent endothelial cells and stimulates them to secrete proteases (eg, plasminogen activator) that make the vessel walls more permeable. Tumor cells that form VEGF subtype C can also induce the growth of lymphatics. At the same time, endothelial cells are also stimulated for proliferation and migrate out of the blood vessel in the direction of the stimulus. Finally, the endothelial cells form into a new lumen and fuse with a perfused vessel. Endothelial cells of such "mature" capillaries remain at rest under normal physiological conditions until re-activated.

Factors which can influence the angiogenesis associated with pathological processes are thus interesting targets for a possible therapy. Angiogenesis inhibitors are mainly developed and used therapeutically as drugs against solid tumors, for which there are hardly any effective therapies: bronchial , Breast and prostate cancers, head and neck tumors (glioblastomas) and carposal sarcoma, but also melanomas, lymphomas and multiple myelomas. The effectiveness of the therapy is greatest in those tumors in which the vascular growth is particularly pronounced and decreases, for example, in the order glioblastoma> adenocarcinoma> sarcoma.

WO2006 / 061212 discloses cyclic imides for which an antiangiogenic effect, in particular the inhibition of protein kinases involved in the angiogenesis process, could be demonstrated (see Peifer et al., J. Med. Chem. 49, 7549-7553 and Combinatorial Chemistry & High Throughput Screening, 9 (8), 613-618.

The object of the present invention is to inhibit new substances capable of inhibiting angiogenesis, in particular the kinases involved in it.

This object is achieved by novel cyclic amide compounds of the general formula I:

wherein one of the radicals Ri or R _{2 is} phenyl which is substituted by 1, 2, 3 or 4 hydroxy or Ci- ₆ -alkoxy and the other of the radicals R ¹ or R ^{2 is} an indole radical of the formula II.

wherein R ^{4 is} selected from

H

Ci-β alkyl,

Ci- ₆ alkyl, which is substituted by a) 1, 2 or 3 hydroxy groups, b) 1, 2 or 3 Ci _-6 alkoxy groups, c) phenoxy, d) phenyl-Ci _-4 alkyloxy

f) Tri(Ci-4-alkyl)silyl-Ci-4-alkoxy;

f) tri (Ci-4-alkyl) silyl-Ci-4-alkoxy;

R ⁵ is H, Ci-e-alkyl or phenyl-Ci _-4 alkyl; and the physiologically acceptable salts thereof as well as the hydrates of

Compounds or salts thereof.

Alkyl groups (also in alkoxy, phenylalkyl, etc.) are straight-chain or branched alkyl groups having 1 to 6, in particular 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl , n-pentyl or n-hexyl.

Salts include, in particular, acid addition salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid or of organic acids, for example formic acid, acetic acid, tartaric acid, lactic acid, citric acid, maleic acid, mandelic acid, ascorbic acid, fumaric acid, gluconic acid, sulfonic acids or other physiologically tolerated acids , to understand. Insofar as the compounds according to the invention have one or more asymmetric centers, the invention encompasses all stereoisomers. These may be pure diastereoisomers or enantiomers, as well as their mixtures.

Formula I comprises the isomeric compounds of the formula Ia and Ib

Ia Ib

wherein R ^{2 is} a phenyl radical which is substituted by 1, 2, 3 or 4 hydroxy or Ci-β-alkoxy groups.

Preferably, the phenyl group 1, 2 or 3 hydroxy or Ci- ₆ alkoxy groups. Particularly preferred is a phenyl group which is substituted by 1, 2, 3 or 4 Ci _-6 - alkoxy groups and in particular by 3 Ci- ₆ -alkoxy. Very particular preference is given to 4-Ci-6-alkoxyphenyl and in particular 3,4,5-tri (Ci-6-alkoxy) phenyl.

When R ⁴ is ₆ -alkyl for Ci, which is substituted by 1, 2 or 3 hydroxy groups, it is preferably hydroxymethyl, hydroxyethyl, 2,3-dihydroxypropyl or 2-methyl-2,3-dihydroxypropyl.

R ³ is preferably H.

R ⁴ is preferably H.

R ⁵ is preferably H.

The invention also relates to processes for the preparation of cyclic amides according to the invention. According to the invention, the synthesis of the cyclic amides of the general structural formula I by means of an internal aldol condensation under suitable reaction conditions starting from an amide of general formula III:

wherein R ¹ and R ² are as defined above and optionally having one or more protecting groups. Suitable protecting groups are known to the person skilled in the art. Particularly suitable is the trimethylsilylethoxymethyl protective group.

The aldol condensation succeeds particularly well in solution in the presence of strong bases, in particular alcoholates, with particularly good results could be achieved with t-BuOK.

To carry out the aldol condensation, the reaction starting materials are preferably reacted in a suitable solvent. Particularly suitable solvents have been found to be CrCβ-alkanols, such as methanol, ethanol, isopropanol, n-butanol, isobutanol or tert-butanol or cyclic ethers, such as tetrahydrofuran or dioxane. The use of tert-butanolate solution in tert-butanol and THF is particularly effective.

Since this aldol condensation is a thermodynamically controlled reaction, the choice of reaction temperature is crucial for successful condensation. This depends on the solvent used. In general, a temperature in the range of 50 to 120 ⁰ C, in particular 50 to 100 ⁰ C is suitable. For example, the optimum temperature when using K-tBuO and tert-butanol is 60 to 100 ⁰ C, especially 70 to 90 ⁰ C.

The starting materials required for the preparation of the amide of general formula III may be substances known per se. Thus, a ketoammonium compound and an aromatic or heterocyclic carboxylic acid can be converted under suitable reaction conditions directly to an amide of the formula III. The choice of the starting compounds determines the structure of the amide, which is closed in the subsequent aldol condensation to the pyrrole-2-one ring and gives the corresponding cyclic amide. In another preferred embodiment, the amide of formula III is derivatized by the introduction of suitable protecting groups to facilitate aldol condensation. Here, protective groups are preferably coupled under basic conditions to the heteroatoms in the ring system of the heteroaromatic cycle in order to prevent the deprotonation of the heteroatom and thus to allow a ring closure of the amide to a pyrrol-2-one ring. Derivatization with SEM and / or MOM protecting groups has proven particularly effective.

After aldol condensation, the deprotection takes place. It can be done by a known method, such as fluoride-induced elimination (eg using TBAF, TBAF / base, HF / pyridine, NaF, BF ₃ - etherate). For some compounds, however, this method provides a complex mix of different products. In such a case, one can remedy by heating the reaction products of the aldol condensation with a catalytic amount of acid in a suitable alcohol (or nucleophile). In this way, the protecting group is replaced by the alcohol residue and a new ether compound is formed. By choosing the alcohol, an additional side chain modification can be achieved according to the invention. If the side chain introduced in this step is undesirable in the final product, it is cleaved in the next step by suitable means, for example, by ether cleavage with catalytic amounts of acid such as HCl in an ethereal solvent such as dimethoxyethane. Resulting Halbaminale can with an alcoholate in the corresponding alcohol. For example, sodium methoxide in methanol, cleaved under Formalsehydverlust, see also the following reaction scheme.

The preparation of the compounds according to the invention is further explained below:

Die Synthese der pharmakologisch aktiven Strukturklasse der 4-(1 H-lndol-3-yl)-3- phenyl-1 ,5-dihydro-2H-pyrrol-2-one wird hier exemplarisch für Verbindung 10 dargestellt und beschrieben.Synthesis of the compounds of the formula Ia which are unsubstituted on the indole nitrogen atom, using the example of the preparation of 4- (1H-indol-3-yl) -3- (3,4,5-trimethoxyphenyl) -1,5-dihvdro-2 / - / - pyrrol-2-one (10)

The synthesis of the pharmacologically active structural class of 4- (1H-indol-3-yl) -3-phenyl-1,5-dihydro-2H-pyrrol-2-ones is illustrated and described here by way of example for compound 10.

The synthesis of the target compound 10 starts from the commercially available phenylacetic acid derivative 3,4,5-thmethoxyphenylacetic acid 3. The acid is activated by CDI in DCM and quantitatively coupled with tryptamine to amide 4. By appropriate variation of the substitution in the phenylacetic acid (starting material 3) and the indole-amine building block (here tryptamine, coupling to 4), the synthesis can be made correspondingly flexible. By means of DDQ in THF / water, the selective oxidation of the indole side chain to compound 5 is achieved in high yield (93%).

All attempts to directly conclude the pyrrol-2-one ring starting from 5 to 10 in the context of an aldol condensation (after deprotonation of the benzyl position, pKs ca. 15) in a broad series of experiments with variation of the base and the solvent showed no success.

The reason for this is to be seen indirectly in the acidity of indole-NH (pKs ca. 10), which is in a vinylogous system with the keto group of the indole side chain (see scheme).

Wird also das azide Indol-NH unter den basischen wasserfreien Bedingungen der Aldolkondensation aufgrund des niedrigeren pKs-Wertes primär deprotoniert, steht das freie Elektronenpaar mit der Ketogruppe in Tautomehe, so dass praktisch keine für die Aldolkondensation essentielle Carbonylreaktivität mehr vorhanden ist.

Thus, if the azide indole-NH is primarily deprotonated under the basic anhydrous conditions of the aldol condensation due to the lower pKa value, the lone pair of electrons with the keto group is in tautomehe, so that virtually no essential carbonyl reactivity is present for the aldol condensation.

The successful aldol condensation to 7 requires a protecting group on the indole nitrogen atom, which prevents the deprotonation of the indole, is stable in the basic state and thus allows the ring closure. From a series of experiments with various protecting groups, the ring closure to 7 was achieved via the SEM-protected derivative 6 in good yield by means of tert-BuOK / THF. Removal of the SEM protecting group in 7 proved to be difficult, however, as the fluoride-induced elimination methods (eg, TBAF, TBAF / base, HF / pyridine, NaF, BF ₃ etherate) provided a complex mixture of unidentified products. For example, the use of TBAF in combination with base oxidizes the methylene group of the pyrrol-2-one ring to the carbonyl function, so that the maleimide derivative (B45.1, which is obtained as a by-product also in the aldol condensation in the basic (see experimental part)) ,

If Compound 7 is heated in methanol with a catalytic amount of HCl, the result is a chloride-induced ethene elimination with subsequent etherification of the remaining N / O hemiacetal with the solvent methanol in quantitative yield, compound 8, in which formally the SEM group is now replaced by a MOM Group is replaced. Thus, in addition to the "reversion" of SEM to MOM functionality, a synthetic approach to side chain modification is given: reacting 7 in other alcohols and a catalytic amount of HCl gives the N / O acetals analogous to compound 8 (ethanol 12, isopropanol 13; Phenol 14; benzyl alcohol 15; butanol 11).

By stepwise degradation of the MOM group in 8 by means of DME / HCl via the intermediate hydroxymethylene 9 succeeds by elimination of formaldehyde (MeOH, catalytic amounts of NaMeO), the preparation of 10. Synthesis of the compounds of the formula Ib using the synthesis of 3- (1H-indol-3-yl) -4- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one as an example 28

br

The synthesis of compound 28 as an analogue of 10 follows in principle the same strategy to build up the pyrrol-2-one ring by means of aldol condensation. In this case, the amide 27 is built up from the ketoammonium compound 25 and the indole acetic acid 26 by means of coupling reagents. The main difference to the more complex synthesis of the isomeric compound 10 is that the aldol condensation of 27 to 28 is possible without protecting group technology, since the free indole-NH is not conjugated to the carbonyl function here. Thus, the carbanion can be generated in the indole side chain, which then allows the ring closure in the sense of an aldol condensation.

Synthesis of compounds of the formula I which are substituted on the indole nitrogen atom, the example of 4- [1- (2,3-dihydroxypropyl) -1 / - / - indole-3-vπ-3- (3,4,5-trimethoxyphenyl ) -1, 5-dihydro-2 / - / - pyrrol-2-one (24)

The synthesis of the indole-N-substituted compound 24 (with functionalized side chain) is analogous to the synthesis of 10 (pyrrol-2-one ring is built up via aldol condensation). Here, the need for an indole-N-protecting group (as described for the synthesis of 10) is exploited by N-substituting compound 5 with 4- (bromomethyl) -2,2-dimethyl-1,3-dioxolane, which the desired subsequent functionalization already protected includes. After ring closure to 23, deprotection to diol 24 is done with a catalytic amount of HCl in DCM.

The compounds of the formula Ib are obtained in a corresponding manner.

The compounds according to the invention have interesting properties for pharmaceutical use, as the activity tests (see exemplary embodiments) show. For the class of compounds, the inhibition of protein kinases could be detected. Furthermore, a concentration-dependent inhibition of sprouting of human endothelial cells was found.

The invention thus also pharmaceutical compositions containing at least one compound as defined above in a suitable pharmaceutical formulation. In addition, agents according to the invention may additionally contain at least one further pharmacological active ingredient which is suitable for Treatment of angiogenesis-associated diseases and cancers.

Other pharmacologically active compounds useful for the treatment of angiogenesis-associated diseases are listed in the following table:

Inhibitor mechanism of action

VEGFR-1 and NRP-1 Bind VEGF-B and PIGF angiopoietin 2 angiopoietin 1 antagonist

Inhibitors of cell migration, proliferation,

TSP-1 and TSP-2 adhesion and survival of endothelial cells

Induce inhibitors of cell proliferation

Angiostatin and analog apoptosis of endothelial cells

Inhibitors of cell migration, proliferation, and endostatin of endothelial cell survival

Inhibitors of cell proliferation of

Vasostatin, caleticin endothelial cells

Platelet factor-4 inhibitor of bFGF and VEGF TIMP and CDAI inhibitors of cell migration of endothelial cells

IFN-α, -beta and -v, CXCL10, IL-4, ^■ inhibitors of the cell-migration of endothelial cells, 12 -18 and downregulation of bFGF

Prothrombin (kringle domain-2), inhibitors of cell proliferation of antithrombin III fragment endothelial cells

Prolactin inhibitor of bFGF and VEGF

Inhibitors of cell proliferation of VEGI endothelial cells

SPARC Inhibits binding and activity of VEGF

Osteopontin Inhibits Integrin Signaling

Maspin protease inhibitor

Bevacizumab binds VEGF

Carboxyamidothiazole inhibitors of cell migration and proliferation

TNP-470 of endothelial cells downregulates angiogenesis stimulators and

IFN-α inhibits cell migration of endothelial cells

Stimulates the formation of endogenous angiogenesis

IL-12 inhibitors

Platelet factor-4

suramin

SU5416 inhibits binding of angiogenesis stimulators

thrombospondin

VEGFR antagonists

Angiostatic steroids (e.g., 2-methoxyestradiol), heparin

Cartilage-Derived Angiogenesis

Inhibitors of basal membrane degradation inhibitory factor

Matrix metalloproteinase inhibitors

Inhibitor of cell proliferation, induces apoptosis

Angiostatin of endothelial cells

(Further angiogenesis inhibitors see http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors)

Other low molecular weight pharmacological agents that are useful in the treatment of cancers are, in particular, imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, nilotinib.

The compounds of the invention are generally used in the form of pharmaceutical agents for the treatment of a mammal, especially a human. Thus, the compounds are administered especially in the form of pharmaceutical compositions comprising a pharmaceutically acceptable carrier with at least one compound of the invention and optionally further active ingredients suitable for the particular desired therapeutic effect. These compositions can be administered, for example, by oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes. The type of pharmaceutical agent or carrier or diluent depends on the desired mode of administration. Oral agents may, for example, be present as tablets or capsules and may contain conventional excipients such as binders (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine), lubricants ( eg magnesium stearate, talc, polyethylene glycol or silica), disintegrating agent (eg starch) or wetting agent (eg sodium lauryl sulfate). Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays, and the like. They may also be in the form of dry powder, which is prepared for reconstitution with water or other suitable carrier. Such liquid preparations may contain conventional additives, for example suspending agents, flavorings, diluents or emulsifiers. For parenteral administration, solutions or suspensions may be employed with conventional pharmaceutical carriers.

The compounds or agents of the invention may be administered to mammals (human or animal) at a dose of from about 0.5 mg to 100 mg per kg of body weight per day. They can be given in a single dose or in multiple doses.

The invention also relates to the use of the compounds of structural formula I for influencing angiogenesis, in particular for inhibiting endothelial cell growth. The invention also relates to the use of the cyclic amides of the invention as reference substances, in particular in angiogenesis assays, e.g. in the study of angiogenesis-influencing properties of substances, especially in drug development, see also R. Auerbach et al., Clinical Chemistry 49: 1. 32-40 (2003).

The present invention furthermore relates to the use of at least one compound of the formula I for the preparation of a pharmaceutical agent for controlling angiogenesis, in particular for the treatment of diseases which are associated with a disorder of angiogenesis, such as arteriosclerosis, hemangioma, neovascular glaucoma, Kaposi syndrome chronic inflammatory diseases such as rheumatoid arthritis, diabetic retinopathy, neuropathy, age-related macular degeneration, psoriasis, endometriosis, growth of solid tumors and their metastases, limb deficiency and myocardial infarction due to occlusion of the coronary arteries and for the treatment of diseases associated with angiogenesis, such as tumor diseases, in particular, colorectal carcinomas, bronchial carcinomas, breast cancers, prostate carcinomas, head and neck tumors (gliablastomas), carposal sarcomas, multiple myelomas, lymphomas, melanomas, gastrointestinal stromal tumors (GIST), kidney tumors; retinopathy; rheumatic diseases; Arthritis, especially rheumatoid arthritis.

The compounds of the invention can be used to prepare pharmaceutical agents for the therapy and / or prevention of these diseases.

Figure 1 shows the efficacy of compound 10 in the in vitro sprouting assay on photographic images.

The following embodiments illustrate the invention without limiting it.

EXAMPLES

working Methods

Reactions with moisture or air-sensitive substances were carried out under an argon atmosphere. The equipment was previously baked. Solids were added in countercurrent nitrogen and liquids via syringes through septa.

Chemicals and solvents

The fine chemicals used for the analysis and synthesis were obtained from the companies ACROS, ALDRICH-CHEMIE, APOLLO SCIENTIFIC, FLUKA and MERCK. They were used, unless otherwise stated, without prior purification. The solvents used were distilled before use and absolutized in moisture-sensitive reactions according to the usual methods.

chromatography

For column chromatography, silica gel 60 with 15-40 μm grain size from MERCK was used. The column chromatography was carried out by preparative flash absorption chromatography (LaFlash from VWR International). The cleaning by means of MPLC was carried out on a MPLC device from LABOMATIC with UV detector. As stationary phase silica gel LiChroprep ^® 60 has been used with 15 micron particle size MERCK. For thin-layer chromatography, silica gel 60 F ₂ S _{4 finished} films from MERCK were used. The detection was carried out by means of a UV lamp with 254 and 366 nm wavelength.

Nuclear Magnetic Resonance Spectroscopy

The NMR spectroscopic investigations were carried out on a Bruker Advance 200 spectrometer with 200 MHz recording frequency for ¹ H NMR spectroscopy and 50 MHz for ¹³ C NMR spectroscopy. The residual signal of the undeuterated solvent portions served as an internal standard. Chemical shifts are reported in parts per million [ppm], followed by the multiplicity, the coupling constant J, in which the amount is given in Hertz [Hz], the integration and the assignment. The following abbreviations were used to describe the signal multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet). The assignment of the carbon signals was carried out by means of dept-135-Expehmente. All ¹³ C NMR spectra and dept-135 experiments are ¹ H broadband decoupled.

IR spectroscopy

To record the IR spectra, a Perkin-Elmer Spectrum One spectrometer measuring ATR technique was used. The location of the absorption bands is indicated in wave numbers i / [cnn ^{~ 1].}

GC-MS

GC-MS spectra were performed on the gas chromatograph Hewlett Packard HP 6890 Series

GC system with mass detector Hewlett Packard HP 5973 Mass Selective Detector. Helium served as a carrier gas. It became a Zebron ZB-5ms -

Capillary column of the company PHENOMENEX used with 30 m length and 5%

Polysilarylene / 95% polydimethylsiloxane. The ionization was carried out by means of El (Electron

Impact).

LC-MS

LC-MS spectra were recorded with a TSQ Quantum triple quadrupole mass spectrometer from Thermo Finigan. The ionization was carried out by means of ESI (Electron Spray Ionization). The mass spectra are expressed as mass to charge ratio (m / z) and the relative intensities are based on the base peak (100%).

melting points The melting points were determined on the Buchi MDB 545 melting point apparatus from BUCHI. The specified values are uncorrected.

EXAMPLE 1 N- (2- (1H-Indol-3-yl) ethyl) -2- (3,4,5-trimethoxyphenyl) acetamide (4)

Approach:

11.5 g (50 mmol) of 3,4,5-trimethoxyphenylacetic acid (3) 10.5 g (65 mmol) of CDI 8 g (50 mmol) of tryptamine

Execution:

3,4,5-Trimethoxyphenylacetic acid (3) is dissolved in 300 ml of anhydrous dichloromethane and mixed with CDI. The reaction mixture is stirred for one hour. A further 500 mg of trimethoxyphenylacetic acid are added and the mixture is again kept for 15 minutes, then tryptamine dissolved in anhydrous dichloromethane is added dropwise. It is stirred for two hours. After completion of the reaction, the solvent is freed and then separated by chromatography (EE / PE 3/1).

Yield:

18.36 g (49.8 mmol) 99%

¹ H-NMR (CDCl ₃ ): δ = 8.31 (bs, 1 H, Ind. NH), 7.53 (d, 1 H, J = 7.7 Hz, Ind. 4-H), 7.34 (d, 1 H, J = 7.8Hz, IndJ-H), 7.18 (m, 1H, Ind.6-H), 7.09 (m, 1H, Ind.5-H), 6.74 (d, 1H, J = 2.1Hz, Ind .2-H), (6.31 s, 2 H, orfΛo-PhH), 5:57 (s, 1 H, NH), 3.83 (s, 6 H, mefa- {O} _CH3), 3.71 (s, 3 H , para- {O} CH ₃ ), 3.53 (q, 1 H, J _NH = 5.9, J _HH = 6.4 Hz, V-H), 3.44 (s, 1 H, 2-H), 2.90 (t, 1 H, J = 6.4 Hz, 2 ^'-H).

¹³ C-NMR (CDCl ₃ ): δ = 170.8 (C 1), 153.4 (2 C, mete-PhC), 136.9 (nd. C-7a), 136.4 (para-PhC), 130.5 (PhC _quar t), 127.2 (lnd.C-2), 122.1 (lnd.C-3), 122.03 (lnd.C-6), 119.3 (ndC-5), 118.5 (lnd.C-4), 112.3 (lnd.C-3 ), 111.3 (lnd.C-7), 106.2 (2 C, ortho PhC), 60.8 (para-C {O} CH ₃ ), 56.00 (2 C, mete-C {O} CH ₃ ), 44.1 (CT), 39.6 (C-2), 24.9 (C-2 ^' ).

IR [cm ^"1 ] = 3287 (v NH), 3058 (v _Aro m CH), 2937 (v CH ₂ ), 1644 (v C = O), 1589 (v _Aro m C = C), 1505, 1456, 1422, 1327, 1231, 1121 (v CO), 1001 (γ _Aro mat CH), 740.

GC / MS for C ₂ IH ₂₄ N ₂ O ₄ + c Fill ms (m / z): 368.0 (M ⁺ ).

EXAMPLE 2

N- (2- (1H-indol-3-yl) -2-oxoethyl) -2- (3,4,5-trimethoxyphenyl) acetamide (5)

Approach:

18.3 g (50 mmol) 4

19.2 g (85 mmol) DDQ (1.7 eq)

Execution:

Dissolve 4 in 300 ml of THF and add 30 ml of water. The reaction mixture is cooled to 0 ^° C., then DDQ dissolved in 50 ml of THF is added. The result is a black solution and a precipitate falls out. It is stirred for 6 hours at room temperature. Subsequently, the solvent is removed under reduced pressure. The product precipitates in the aqueous phase as a brownish solid, which is filtered off and washed thoroughly with ethanol and ether. The product is a white solid. Yield: 11, 12 q (29 mmol) 58%

Rf (EBEtOH 9/1): 0.3

¹ H-NMR (DMSO-de): δ = 12.00 (bs, 1H, Ind. NH), 8.41 (s, 1H, Ind.2-H), 8.33 (m, 1H, NH), 8.14 ( m, 1H, Ind.4-H), 7.48 (m, 1H, Ind.7-H), 7.20 (m, 2H, Ind.5-H, Ind.6-H), 6.67 (s, 2 H, orf / 70-PhH), 4.48 (d, 1 H, J = 5.7 Hz, TH), 3.77 (s, 6 H, mefa- {O} CH ₃ ), 3.62 (s, 3 H, para) {O} _CH3), 3:47 (s, 1 H, 2-H). ¹³ C-NMR (DMSO-de): δ = 190.2 (C-2 ^' ), 170.3 (C-1), 152.5 (2 C, mefa-PhC), 136.3 (para-PhC), 135.9 (lnd.C. 7a), 133.5 (PhC _quar t), 131.9 (ind. C-2), 125.3 (ind. C-3a), 122.8 (nd. C-6), 121.4 (nd. C-5), 121.0 (ind. C-4), 113.9 (lnd.C-7), 112.1 (lnd.C-3), 106.3 (2 C, ortho-PhC), 59.9 (para- {O} _CH3), 55.7 (2 C, MEFA - {O} CH ₃ ), 47.7 (CT), 42.4 (C-2).

IR [cm ^"1 ] = 3182 (v NH), 3058 (v _Aro m CH), 2937 (v CH ₂ ), 1615 (v C = O), 1586 (v _Aro m C = C), 1506, 1431, 1418, 1325, 1312, 1236, 1131 (v CO), 1004 (γ _Aro mat CH), 925, 744.

GC / MS C 21 H ₂₂ N ₂ O ₅ + c filling ms (m / z): 382.0 (M ^+). LC / MS C ₂ IH ₂₂ N ₂ O ₅ - c Fill ms (m / z): 381.2 (MH ⁺ ).

EXAMPLE 3 N- (2-Oxo-2- (1 - ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) ethyl) -2- (3,4,5-trimethoxyphenvdacetamide im

Approach:

1530mg (4mmol) 5

2 ml (4 mmol) NBTSA (2M in THF)

(702mg) (4mmol) SEMCI

Durchführunp:

The entire reaction takes place under argon atmosphere. In a 100 ml three-necked flask, 5 is suspended in 60 ml of anhydrous THF. The suspension is cooled to 0 ^° C. Then the NBTSA solution is added, whereupon the suspension turns brownish. After the addition, stirring is continued for 60 minutes. The reaction is monitored by thin layer chromatography. Now trimethylsilyl chloride is added, whereupon the reaction mixture a Caramel staining, which eventually turns red. Every 30 minutes, a reaction is monitored by thin-layer chromatography. After two hours, the reaction is complete. Now the reaction is quenched with saturated ammonium chloride solution. The aqueous phase is extracted with ethyl acetate and then dried over sodium sulfate, giving a bright red solution. Then the solvent is removed under reduced pressure. It remains a yellow-white solid back, this is washed with diethyl ether to give the pure product as a white solid.

Yield: 1.74 g (3.4 mmol) 84% R _f (EE / PE; 10/1): 0.5

¹ H-NMR (CDCl ₃ ): δ = 8.72 (m, 1H, Ind.4-H), 7.90 (s, 1H, Ind.2-H), 7.52 (m, 1H, IndJ-H) , 6.80 (s, 1H, NH), 6.56 (s, 2H, orfΛo-PhH), 5.50 (s, 1H, Ind. N-CH ₂ ), 4.64 (d, J = 4.3 Hz, 1H, 1 H), 3.88 (s, 6 H, mefa- {O} _CH3), 3.85 (s, 3 H, para- {O} _CH3), 3.61 (s, 1 H, 2-H), 3:49 (t, J = 8.1 Hz, 1H, 1 ^" -H), 0.89 (t, J = 8.1 Hz, 1H, 2 ^" -H), 0.00 (s, 9H, SiCH ₃ )

¹³ C-NMR (CDCl ₃ ): δ = 188.8 (C-2 ^' ), 180.0 (C-1), 153.5 (2 C, mete-PhC), 137.2 (lnd.C-7a), 136.7 (para-PhC ), 134.1 (lnd.C-2), 130.2 (PhC _quar t), 126.3 (lnd.C-3a), 124.1 (lnd.C-6), 123.4 (lnd.C-4), 122.1 (lnd.C -5), 114.6 (lnd.C-3), 110.7 (lnd.C-7), 106.4 (2C, ortho-PhC), 76.04 (Ind. NCH ₂ ), 66.6 (C-1 ^" ), 60.8 ( para- {O} CH ₃ ), 56.1 (2 C, mefa- {O} CH ₃ ), 46.5 (C-1), 43.9 (C-2), 17.7 (C-2 ^" ), 0.00 (3 C, SiCH ₃ ) IR [cm ^"1 ] = 3310 (v NH), 2941 (v _Aro m CH), 2842 (v CH ₂ ), 1635 (v C = O), 1591 (v _Aro m C = C), 1508 , 1447, 1236, 1387, 1126 (v CO), 993 (γ _Aro mat CH) ,, 743, 728, 681 LC-MS for C ₂₇ H ₃₆ N ₂ O ₆ Si (m / z 512): 536 [M + Na] ^Θ , 535 [M + Na] ^® 513 [M + H] ^® , 396, 395

EXAMPLE 4

3- (3,4,5-Trimethoxyphenyl) -4- (1 - ((2- (methylsilyl) ethoxy) methyl) -1H-indol-3-yl) -1H-pyrrole-2,5-dione ( 7)

3- (3,4,5-Thmethoxyphenyl) -4- (1 - ((2- (methylsilyl) ethoxy) methyl) -1H-indol-3-yl) -1H-pyrrole-2 (5 / - / ) -on (B45.1) as a by-product

Approach:

260 mg (0.5 mmol) 6

1.5 ml (1 M) (1.5 mmol) of K-tert-butoxide solution. in tert-butanol

Procedure: The entire reaction takes place under an argon atmosphere. The solvent tert-butanol is treated with potassium hydroxide and heated under reflux for one hour, then fractionally distilled. 20 ml of dry tert-butanol are mixed with 6 and heated to 100 ^° C. under reflux. To the hot colorless solution is added tert-butoxide sol. added and heated for 15 minutes. The solution turns reddish brown immediately. The reaction mixture is cooled in an ice bath and immediately quenched with saturated ammonium chloride solution. The aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. Subsequently, the solvent is removed under reduced pressure. For purification, it is separated by chromatography. The pure product shows a white color, the by-product B45.1 a strong red color.

Yield (7): 160 mg (0.33 mmol) 66% R _f (EE / EtOH; 9/1): 0,6 m.p .: 102.3 ⁰ C ¹ H-NMR (CDCl ₃ ): δ = 8.3 (bs, 1 H, NH), 7.5 (d, J = 8.3 Hz, 1 H, Ind.7-H), 7.2 (t, J =

7.2 Hz, 2H), 7.1 (t, J = 7.2 Hz, 2H), 6.7 (s, 2H, ortho-PhH), 5.4 (s, 2H, NCH ₂ ), 4.6

(s, 2 H, 5-H), 3.85 (s, 3 H, para {O} CH ₃ ), 3.2 (s, 6 H, mefa- {O} CH ₃ ), 3.4 (t, J = 7.8 Hz

2H, CH _2), 0.9 (t, J = 7.8 Hz, 2 H, CH _2), 0 (s, 9 H, SiCH ₃₎

¹³ C-NMR (CDCl ₃ ): δ = 176.3 (C-2), 154.8 (2 C, mete-PhC), 148.0 (C-4), 139.3 (Ind.

3a), 138.1 (para-PhC), 130.3 (lnd.C-2), 129.3 (C-3), 127.2 (PhC _quar t), 124.5 (Ind.

6), 122.9 (lnd.C-5), 122.7 (lnd.C-4), 112.0 (lnd.C-7), 111.4 (lnd.C-3), 108.2 (2C, ortho-PhC), 77.1 (NC), 67.66 (C-2 ^' ), 62.3 (para {O} CH ₃ ), 57.4 (2 C, mefa- {O} CH ₃ ),

50.6 (C-5), 19.1 (C-1 ^' ), 0.0 (SiCH ₃ )

IR [cm ^"1 ] = 3191 (v NH), 2898 (v _Aro m CH), 1666 (v C = O), 1504 (v _Aro m C = C), 1329,

1238, 1127, 835, 743

LC-MS for C ₂₇ H ₃₄ N ₂ O ₅ Si (m / z 494): 517 [M + Na] ^Θ , 496 [M + H] ^® , 495

B45.1

Yield 5% R _f (EE / EtOH; 9/1): 0.9

¹ H-NMR (CDCl ₃ ): δ = 8.1 (s, 1H, ind.2-H), 7.95 (s, 1H, NH), 7.49 (d, 1H, J = 8.2 Hz, Ind.4 -H), 7.19 (t, 1 H, J = 7.8 Hz, Ind.5-H), 6.89 (t, 1 H, J = 7.8 Hz, Ind.6-H), 6.81 (s, 2 H, ortho -PhH), 6:48 (t, 1 H, J = 8.2), 5:56 (s, 2 H, N-CH _2), 3.86 (s, 3 H, para- {O} _CH3), 3:54 (t, 2 H, J = 7.8 Hz, 2 ^'-H), 1.25 (t, 2 H, J = 7.1 Hz, ^1' H), 0.00 (s, 9H, SiCH ₃₎ 1 ³ C-NMR (CDCI _3): δ = 172.6 (C-2), 172.3 (C-5), 153.8 (mefa-PhC), 140.2 (C-3), 137.7 (para-PhC), 134.6 (lnd.C-2), 132.4 (lnd. C-3a), 130.9 (C-4), 126.1 (PhC _quar t), 124.3 (ind. C-5), 123.9 (nd. C-4), 122.3 (nd. C-6), 111.6 (lnd. C-7), 108.9 (2 C, orfΛo-PhC), 106.5 (nd.C-3), 77.2 (NC), 67.4 (C-2 ^' ), 62.0 (para {O} CH ₃ ), 56.9 ( 2 C, meta- (OJCH ₃ ), 18.75 (C-1 ^' ), 0 (Si-CH ₃ ) LC-MS for C ₂₇ H ₃₂ N ₂ O ₆ Si: 507.1 [MH] ^®

EXAMPLE 5

4- (1 - (Methoxymeth-1-dH-indol-3-yl) -3- (3,4,5-trimethoxyphenyl) -1H-pyrrol-2 (5H) -one

(8th)

Approach / Durchführunp: In a 50 ml 3-neck flask, 7 (290 mg, 0.6 mmol) is weighed out and in 20 ml

MeOH solved. You give 10Oμl conc. HCl and stirred at RT. After 15 min is with

EE extracted (EE with 5% EtOH). The purification is carried out by column chromatography

(EE / EtOH 20/1).

Yield: 165 mg (0.4 mmol) 70% mp: 52.8 ° C

¹ H NMR (CDCl ₃ ): 7.5 (d, 1H), 7.3-7.0 (m, 4H, NH, ind. 7, ind. 6H, Ind. 5-H), 6.7 (s , 2H), 5.4 (s, 2H, NCH ₂ ), 4.6 (s, 2H), 3.85 (s, 3H, para {O} CH ₃ ), 3.7 (s, 6H, meta- (OJCH ₃ ), 3.20 (s, 3 H).

¹³ C-NMR (CDCl ₃ ): 174.9 (C = O), 153.4 (2 C, mete-PhC), 146.5 (C-4), 137.8 (Ind. C-7a), 136.5 (para-PhC), 128.9 (Ind. C-6), 128.2 (Ind. C-3), 125.9 (PhC _quar t), 123.1 (Ind. C-2), 121.5 (Ind. C-5), 121.1 (Ind. C-4) , 110.5 (Ind. C-3), 110.0 (Ind. C-7), 106.6 (2 C, ortho-PhC), 77.5 (CH ₂ ), 63.6 (CH ₂ ), 60.5 (para {O} CH ₃ ), 55.6 (2 C, mefa- {O} CH ₃ ), 49.1 (CH ₃ ).

IR [cm ^"1 ] = 2936 (v NH), 2860 (v _Aro m CH), 2937 (v CH ₂ ), 1675 (v C = O), 1578 (v _Aro m C = C), 1528, 1501, 1450, 1403, 1327, 1239, 1122 (v CO), 1003 (γ _Aro mat CH), 913, 828, 744.

LC-MS for C ₂₃ H ₂₄ N ₂ O ₅ (m / z 408.1): 409 [M + H ⁺ ], 377, 242

EXAMPLE 6

4-H- (HvdroxymethvD-1 / - / - indol-3-yl1-3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrole

2-on (9)

4- (1 / - / - indol-3-yl) -3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2H-pyrrol-2-one (10)

4-f1 - (tert -butoxymethyl) -i / - / - indol-3-yl1-3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one ( 11)

Approach / implementation:

In a 50 ml 3-neck flask, 7 (290 mg, 0.6 mmol) is weighed and dissolved in 10 ml tBuOH. 1 ml of conc. HCl and heated to the RF. After 30 min, extract with EA. The purification is carried out by column chromatography (EA / EtOH 20/1). The main product is 9 (55 mg), which can be further converted to 10. Compound 10 (25 mg) and compound 11 (50 mg) are also obtained directly from the batch.

Connection 9

¹ H-NMR: (CDCl ₃ ): 7.47 (d, 1H), 7.25 (m, 2H), 7.0 (m, 2H), 6.70 (s, 2H), 5.5 (s, 2H), 4:32 (s, 2 H), 3.80 (s, 3 H, para- {O} _CH3), 3.60 (s, 6 H, mete- {O} _CH3) 1 ³ C-NMR (CDCI _3): 174.79 (C = O), 171.09 (Cq), 153.1 (2C, mete-PhC), 147.1 (C-4), 137.8 (ind. C-7a), 136.0 (para-PhC), 128.6 (lnd.C. 6), 127.8 (lnd.C-3), 126.9 (PhCquart), 125.5 (nd.C-2), 122.9 (nd.C-5), 121.3 (nd.C-4), 110.2 (lnd.C. 3), 109.7 (lnd.C-7), 106.8 (2 C, orfΛo-PhC), 69.8 _(CH2), 60.8 (para- {O} _CH3), 55.9 (2 C, meta- (OJCH ₃₎ , 49.0 (CH ₂ ) LC-MS for C ₂₂ H ₂₂ N ₂ O ₅ : 395.1 [M + H ⁺ ] Connection 10

¹ H-NMR: (MeOH-ds): 7.5 (s, 1H), 7.39 (dd, 1H), 7.1 (m, 1H), 6.85 (d, 2H), 6.75 (s, 2H) , 4:51 (s, 2 H, CH _2), 3.80 (s, 3 H, para- {O} _CH3), 3.60 (s, 6 H, {O} mefa- _CH3).

¹³ C-NMR (MeOH-ds): 174.48 (C = O), 152.1 (2 C, meta-PhC), 147.5 (C-4), 136.5 (nd.C-7a), 135.98 (para-PhC), 127.97 (Ind. C-6), 125.2 (Ind. C-3), 123.36 (PhC _qua rt), 120.9 (Ind. C-2), 119.8 (Ind. C-5), 118.77 (Ind. C-4 ), 110.4 (lnd.C-3), 108.4 (lnd.C-7), 106.1 (2 C, ortho-PhC), 58.8 (para- {O} _CH3), 54.0 (2 C, mefa- {O } CH ₃ ), 47.9 (CH ₂ ).

LC-MS for C _2I H ₂₀ N ₂ O _4: 365.1 [M + H ⁺ -] LC-MS for C ₂ IH ₂₀ N ₂ O _4: 363.0 [MH ^+]

Note: The synthesis of 10 can also be done from 8, as shown in the general synthetic scheme.

Connection 11

¹ H-NMR: (CDCl ₃ ): 7.5 (d, 1H), 7.4-7.1 (m, 4H), 6.7 (s, 2H), 5.45 (s, 2H, CH ₂ ), 3.85 (s , 3 H, para- {O} _CH3), 3.7 (s, 6 H, mefa- {O} _CH3) .1.25 (s, 9 H, _CH3).

LC-MS for C ₂₆ H ₃₀ N ₂ O _5: 451.1 [M + H ⁺ -]

EXAMPLE 7

4-H - (ethoxymeth-1-dH-indol-3-yl-3- (3A5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one (12)

Ansatz/Durchführung:

Approach / implementation:

In a 50 ml 3-necked flask 7 (290 mg, 0.6 mmol) is weighed and dissolved in 20 ml of ethanol. You give 10Oμl conc. HCl and heated to the RF. After 30 min, EE5% EtOH is extracted with EA. The purification is carried out by column chromatography (EA / EtOH 20/1). Yield 78% (12).

¹ H-NMR: (DMSO-de): 8.3 (bs, 1H, NH), 7.7 (s, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 6.8-7.0 (m , 2 H), 6.7 (s, 2 H), 5.6 (s, 2H), 4.4 (s, 2H), 3.6 (s, 3 H, para- {O} CH ₃ ), 3.4 (s, 6 H, mefa- {O} _CH3), 3.3 (q, 2H), 1.0 (t, 3H).

¹³ C-NMR (DMSO-de): 184.9 (C = O), 173.22 (Cq), 152.7 (2 C, mete-PhC), 145.9 (C-4), 137.3 (Ind. C-7a), 136.7 ( para-PhC), 130.1 (nd. C-6), 128.8 (nd. C-3), 127.8 (PhCquart), 125.3 (nd. C-2), 122.6 (nd. C-5), 121.4 (lnd. C-4), 120. 7, 111.1 (lnd.C-3), 110.0, 107.2 (2 C, orf / 70-PhC), 75.6 _(CH2), 63.6 _(CH2), 60.4 (para- { O} CH ₃ ), 55.7 (2 C, mefa- {O} CH ₃ ), 48.0 (CH ₂ ), 15.05 (CH ₃ ).

LC MS for C ₂₄ H ₂₆ N ₂ O _5: 423.1 [M + H ⁺ -]

EXAMPLE 8

4- [1 - (isopropoxymethyl) -1 / - / - indol-3-yl1-3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2H-pyrrol-2-one (13)

Approach / implementation:

In a 50 ml 3-necked flask 7 (290 mg, 0.6 mmol) is weighed and dissolved in 20 ml of isopropanol. You give 100μl conc. HCl and heated for 1 h to the RF. After cooling, EE5% EtOH is extracted with EA. The purification is carried out by column chromatography (EA / EtOH 20/1). Yield 88% 13. ¹ H-NMR: (CDCl ₃ ): 7.5 (d, 1H), 7.7-7.19 (m, 2H), 7.1 (t, 1H), 6.75 (s, 2H), 5.45 (s, 2H ), 4:58 (s, 2 H), 3.85 (s, 3 H, para- {O} _CH3), 3.68 (s, 6 H, mefa- (OJCH _3), 3:55 (m, 1 H), 1.15 ( s, 3H), 1.10 (s, 3H).

¹³ C-NMR (CDCl ₃ ): 174.9 (C = O), 153.3 (2 C, mete-PhC), 146.6 (C-4), 137.7 (Ind. C-7a), 136.4 (para-PhC), 128.7 (Ind. C-6), 128.2 (Ind. C-3), 127.9 (PhC _quar t), 125.8 (Ind. C-2), 122.9 (Ind. C-5), 121.4 (Ind. C-4) , 121.0, 110.5 (lnd.C-3), 109.8, 106.5, (2C, ortho-PhC), 74.1 (CH ₂ ), 69.59 (CH), 63.6 (CH ₂ ), 60.7 (para- {O} CH ₃ ), 55.9 (2 C, meta- (OJCH ₃ ), 49.0 (CH ₂ ), 21.8 (2 CH ₃ ).

LC-MS for C ₂₅ H ₂₈ N ₂ O ₅ : 437.1 [M + H ⁺ -]

EXAMPLE 9

4-H - (Phenoxymethyl) -I / - / - indol-3-yl1-3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one (14)

Approach / implementation:

In a 50 ml 3-necked flask, weigh 7 (290 mg, 0.6 mmol) and dissolve in 10 ml of phenol. You give 100μl conc. HCl and heated for 2h to 100 ⁰ C. After cooling, extracted with EA EE5% EtOH. The purification is carried out by column chromatography (EA / EtOH 20/1). Yield 73% 14.

¹ H-NMR: (DMSO-de): 9.85 (bs, 1H, NH), 8.25 (s, 1H), 7.7 (s, 1H), 7.5 (q, 1H), 7.2-7.0 (m , 2H), 6.8 (m, 3H), 6.6 (m, 4H), 5.25 (d, 2H), 4.4 (s, 2H), 3.6 (s, 3H, para- (OJCH ₃ ), 3.4 (s, 6 H, mefa- (OJCH _3).

¹³ C-NMR (DMSO-de): 173.39 (C = O), 157.15, 155.08, 152.71 (2C, mefa-PhC), 146.26 (C-4), 137.16 (ind. C-7a), 136.73 (para -PhC), 129.05 (ind. C-6), 128.74 (Ind. 3), 128.48 (PhCquart), 126.94 (ind. C-2), 124.96 (ind. C-5), 123.72 (ind. C-4), 122.2, 121.36, 120.15, 119.27, 115.54, 110.99 (I.C. -3), 109.0, 107.08, {ortho-PhC), 60.4 (para- {O} _CH3), 55.8 (2 C, mete- {O} _CH3), 48.3 _(CH2).

LC-MS for C ₂₈ H ₂₆ N ₂ O _5: 471.1 [M + H ⁺ -]

EXAMPLE 10

4-11 -r (benzyloxy) methyl 1-1 / - / - indol-3-yl) -3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one (15)

Approach / implementation:

In a 50 ml 3-neck flask, weigh 7 (250 mg) and dissolve in 10 ml of benzyl alcohol. You give 10Oμl conc. HCl and heated for 30 min under RF. After cooling, EE5% EtOH is extracted with EA. The purification is carried out by column chromatography (EA / EtOH 20/1). Yield 96% 15.

¹ H-NMR: (DMSO-de): 8.35 (s, 1H, NH), 7.74 (s, 1H), 7.5 (d, 1H), 7.3-7.0 (m, 6H), 6.85 (t , 1H), 6.7 (d, 1H), 6.60 (s, 2H), 5.25 (s, 2H), 4.4 (d, 4H), 3.6 (s, 3H, para- (OJCH ₃ ), 3.4 (s, 6 H, mete- {O} CH ₃ ).

LC-MS for C ₂₉ H ₂₈ N ₂ O _5: 485.1 [M + H ⁺ -]

EXAMPLE 11

Λ / - (2- (1-r (2,2-dimethyl-1,3-dioxolan-4-yl) methyll-1H-indol-3-yl) 2-oxoethyl) -2- (3,4, 5-trimethoxyphenvdacetamide (22)

765 mg of 5, 450 mg of 4- (bromomethyl) -2,2-dimethyl-1,3-dioxolane and 1000 mg of anhydrous K ₂ CO _{3 are} weighed into a dry 100 ml three-necked flask under argon flow. 15 ml of dry DMF are added and the mixture is boiled for 120 minutes. After cooling, water / NaCl is added and shaken out several times with ethyl acetate. The product 22 is purified by flash chromatography (yield 740 mg) and unreacted 5 is recovered.

¹ H-NMR (CDCl ₃ ): δ = 8.3 (m, 1H), 7.9 (s, 1H), 7.3 (m, 3H), 7.8 (bs, 1H, NH), 6.55 (s, 2H ), 4.6 (bs, 2H), 4.5 (m, 1H), 4.2-4.3 (m, 2H), 4.1 (m, 1H), 3.9 (s, 6H, meta- (OJCH ₃ ), 3.70 (s , 3H, para {O} CH ₃ ), 3.7 (m, 1H), 3.6 (s, 2H), 1.4 (s, 3H), 1.3 (s, 3H).

¹³ C-NMR (CDCl ₃ ): δ = 188.8, 163, 153.9 (2 CO), 137.6 (C _quar t), 137.5 (C _quar t), 135.6 (CH), 130.7, 126.35 (C _quar t), 124.2 (CH), 123.5 (CH), 122.7 (CH), 114.6 (C _quar t), 110.7, 110.3, 106.8 (2 C, ortho-PhC), 74.55 (CH), 61.2 (para {O} CH ₃ ) 56.6 (2 C, mefa- {O} _CH3), 49.6 (CH), 46.9 _(CH2), 44.3 _(CH2), 27.2 (CH _3), 25.6 (CH _3).

LC-MS for C ₂₇ H ₃₂ N ₂ O ₇ : 497.0 [M + H ⁺ ]

EXAMPLE 12

4-11 -r (2,2-dimethyl-1,3-dioxolan-4-yl) methyll-1H-indol-3-yl) -3- (3,4,5-trimethoxyphenyl) -1,5-dihydrocarbyl 2 / - / - pyrrol-2-one (23)

In a dry 50 ml 3-neck flask with septum and argon flow in the reflux condenser, weigh 750 mg tBuOK solution 20% w / w in THF), add 10 ml of dry THF and heat at reflux. Then a solution of 750 mg of 22 in 10 ml of dry THF is injected. After 15 minutes reflux, it is cooled in an ice bath and extracted with ethyl acetate. Purification by flash chromatography, yield 88% as a brittle yellowish foam.

¹ H-NMR (DMSO-de): δ = 8.3 (bs, 1H, NH), 7.6 (s, 1H), 7.55 (d, 1H), 7.1 (m, 1H), 6.9 (m, 2H), 6.2, (s, 2H), 4.4 (bs, 2H), 4.35 (m, 1H), 4.2 (m, 1H), 4.0 (q, 1H), 3.70 (s, 3H, para - {O} _CH3), 3.6 (m, 1 H), 3.5 (s, 6H, mefa- {O} _CH3), 3.7 (m, 1 H), 3.6 (s, 2H), 1.2 (s, 6H).

¹³ C-NMR (DMSO-de): δ = 173.37, 152.8 (2 CO), 146.1 (C _quar t), 137.2, 137.1 (C _quar t), 130.7 (CH), 129.2, 127.0, 124.8 (C _quar t ), 122.1 (CH), 121.3 (CH), 120.2 (CH), 110.96 (Cquart), 109.3 (2 C, ortho-PhC), 108.99, 107.13 (CH), 74.8 (CH), 66.29 (CH ₂ ), 60.37 (para {O} CH ₃ ), 55.85 (2 C, mefa- {O} CH ₃ ), 48.54 (CH ₂ ), 48.31 (CH ₂ ), 26.8 (CH ₃ ), 25.57 (CH ₃ ).

LC-MS for C ₂₇ H ₃₀ N ₂ O ₆ : 479.2 [M + H ⁺ -]

EXAMPLE 13

4-H - (2,3-dihydroxypropyl) -1H-indol-3-yl-3- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one (24)

Dissolve 500 mg of 23 in 30 ml of DCM and add 4 drops of HCl. After 3 h the reaction is complete, a white precipitate appears. The batch is concentrated and purified by RP-flash chromatography with ACN / water 1/1. From the purified fractions, a voluminous white precipitate appears as the ACN evaporates. Yield 96%.

¹ H-NMR (DMSO-de): δ = 7.7 (s, 1H), 7.5 (d, 1H), 7.1 (m, 1H), 6.8 (m, 2H), 6.7 (s, 2H ), 6.5 (bs, 2H), 4.4 (s, 2H), 4.3 (dd, 1H), 4.0 (q, 1H), 3.75 (m, 1H), 3.6 (s, 3H, para- { O} _CH3), 3.5 (s, 6H, mefa- {O} _CH3), 3.3 (m, 2H).

¹³ C-NMR (DMSO-de): δ = 173.47, 152.73 (2 CO), 146.40 (C _quar t), 137.2, 137.1 (Cquart), 131.1 (CH), 129.1, 126.5, 124.8 (C _quar t), 121.9 (CH), 121.3 (CH), 119.95 (CH), 110.99 (CH), 108.6 (2 CH, ortho-PhC), 107.27 (CH), 70.93 (CH), 63.61 (CH ₂ ), 60.4 (para) {O} CH ₃ ), 55.88 (2 C, mefa- {O} CH ₃ ), 49.5 (CH ₂ ), 48.4 (CH ₂ ).

LC-MS for C ₂₄ H ₂₆ N ₂ O _6: 439.2 [M + H ^+]

EXAMPLE 14

2- (1H-indol-3-yl) -Λ / -f2- (3,4,5-trimethoxyphenyl) -2-oxoethvnacetamide (27)

100 mg of 26 in 20 ml of dichloromethane (DCM) are dissolved under argon in a 100 ml three-necked flask. 130 mg of 25 are added, forming a white suspension. To the reaction is slowly added dropwise 110 mg of DIEA dissolved in 1 ml of DCM, with the solution becoming increasingly clear. The mixture is stirred overnight, freed from the solvent under reduced pressure and the product is purified by flash chromatography (yield 89.3%).

¹ H-NMR (DMSO-de): δ = 10.9 (bs, 1H, indole-NH), 8.2 (t, 1H, amide-NH), 7.5 (d, 1H), 7.3 (d, 1H ), 7.2 (s, 2H), 6.9-7.1 (bm, 3H, CH), 4.7 (d, 2H, CH ₂ ), 3.8 (s, 6H, meta- (OJCH ₃ ), 3.7 (s, 3 H, para- {O} CH ₃ ), 3.6 (s, 2H, CH ₂ ).

FAB-MS for C21 H ₂₂ N ₂ O _5: 383.2 [M + H ^+]

EXAMPLE 15

3- (1H-indol-3-yl) -4- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2H-pyrrol-2-one (28)

In a dry 250 ml three-necked flask with septum and argon stream, 300 mg of 27 are dissolved in 100 ml of dry tBuOH. Heat to boiling and inject 880 mg of a 20% (w / w) K-tBuO / THF solution. After 20 min reaction is cooled in an ice bath and 90 ml of a 1% HCl solution. It is shaken out several times with ethyl acetate, the organic phase is dried and rotated. Purification is by flash chromatography (yield 62.8%).

¹ H-NMR (DMSO-de): δ = 11.2 (bs, 1H, indole-NH), 8.4 (s, 1H, NH), 7.6 (d, 1H), 7.4 (d, 1H), 7.0 (t, 1H), 6.8 (t, 1H), 6.6 (m, 3H), 4.4 (s, 2H, CH ₂ ), 3.6 (s, 3 H, para {O} CH ₃ ), 3.4 (s, 6H, mefa- {O} CH ₃ ).

¹³ C-NMR (DMSO-de): δ = 173.70 (C = O), 152.77 (2 CO, C _quar t), 146.34, 138.06, 136.36, 129.68 (Cquart), 127.33 (CH), 125.74, 124.96 (C _quar t), 121.38, 120.93, 118.93, 111.96 (CH), 106.46 (C _quar t), 105.50 (2 CH, ortho-PhC), 60.38 (para {O} CH ₃ ), 55.63 (2 C, mefa). {O} CH ₃ ), 47.50 (CH ₂ ). FAB-MS for C ₂ H ₂₀ N ₂ O ₄ : 364.9 [M ⁺ -]

EXAMPLE 16

2- (1-Methyl-1H-indol-3-yl) - / V-r2- (3A5-trimethoxyphenyl) -2-oxoethylacetamide (29)

In a dry 100 ml three-necked flask, 100 mg of N-methylindoleacetic acid, 110 mg of 2-oxo-2- (3,4,5-trimethoxyphenyl) ethanaminiumchlohd and 90 mg of HOBt are dissolved in 5 ml DCM and stirred at RT. After 48h add dropwise DIEA and stir overnight. Add 20 ml DCM and filter from the precipitate. The filtrate is washed with 30 ml of 1% HCl and with brine, dried and concentrated by rotary evaporation. The product precipitates as a white precipitate (yield 92.6%).

¹ H-NMR (DMSO-de): δ = 8.2 (t, 1H, amide-NH), 7.6 (d, 1H), 7.4 (d, 1H), 7.3-6.9 (bm, 5H), 4.6 (d, 2H, CH ₂ ), 3.8 (s, 6H, mete- {O} CH ₃ ), 3.7 (d, 6H, para {O} CH ₃ / N-CH ₃ ), 3.6 (s, 2H , CH ₂ ).

FAB-MS for C ₂₂ H ₂₄ N ₂ O _5: 397.2 [M + H ^+]

EXAMPLE 17

3- (1-Methyl-1H-indol-3-yl) -4- (3,4,5-trimethoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one (30)

In einem trockenen 100 ml Dreihalskolben mit Septum und Argonstrom löst man 500 mg 29 in 30 ml trockenem THF. Man erhitzt zum Sieden und injiziert 710 mg einer 20%igen (w/w) 'BuOK/THF Lösung. Nach 20 min Reaktion kühlt man im Eisbad ab und gibt 50 ml einer 1 %igen HCI-Lsg zu. Man schüttelt mehrmals mit Ethylacetat aus, trocknet die organische Phase und rotiert ein. Die Reinigung erfolgt über Flash- Chromatographie (Ausbeute 67,5%).

In a dry 100 ml three-necked flask with septum and argon stream, 500 mg of 29 in 30 ml of dry THF are dissolved. Heat to boiling and inject 710 mg of a 20% (w / w) BuOK / THF solution. After reaction for 20 minutes, the mixture is cooled in an ice bath and 50 ml of a 1% HCl solution are added. It is shaken out several times with ethyl acetate, the organic phase is dried and rotated. Purification is by flash chromatography (yield 67.5%).

¹ H-NMR (DMSO-de): δ = 8.4 (s, 1H, NH), 7.7 (s, 1H), 7.5 (d, 1H), 7.05 (t, 1H), 6.8 (t, 1 H), 6.7 (s + d, 3H), 4.5 (s, 2H, CH ₂ ), 3.8 (s, 3H, N-CH ₃ ), 3.6 (s, 3 H, para- {O} CH ₃ ) , 3.3 (s, 6H, mete- {O} CH ₃ ).

¹³ C-NMR (DMSO-de): δ = 173.57 (C = O), 152.81 (2 CO), 146.26 (C _quar t), 138.16, 136.86 (Cquart), 131.5 (CH), 129.71, 125.34 (C _quar t), 121.47 (CH), 121.19 (CH), 119.11 (CH), 110.20 (CH), 105.62 (2 C, ortho-PhC), 60.39 (para {O} CH ₃ ), 55.71 (2 C, mefa - {O} _CH3), 47.54 _(CH2), 32.97 _(CH3).

LC-MS for C ₂₂ H ₂₂ N ₂ O _4: 378.2 [M ^+]

EXAMPLE 18

2- (1H-indol-3-yl) - / V-r2- (4-methoxyphenyl) -2-oxoethylacetamide (31)

Cl

560 mg of 26 in 20 ml of dichloromethane are dissolved under argon in a dry 100 ml three-necked flask. 490 mg of 2-oxo-2- (4-methoxyphenyl) ethanaminium chloride are added to form a white suspension. To the reaction is slowly added dropwise 110 mg of DIEA dissolved in 1 ml of DCM, with the solution becoming increasingly clear. The mixture is stirred overnight, freed from the solvent under reduced pressure and the product is purified by flash chromatography (yield 39%).

¹ H-NMR (acetone-de): δ = 10.2 (bs, 1H, indole-NH), 7.9 (d, 2H), 7.6 (d, 1H), 7.4 (m, 2H), 7.2-6.9 (bm, 4H), 4.6 (d, 2H, CH ₂ ), 3.8 (s, 6H, para {O} CH ₃ ), 3.7 (s, 2H, CH ₂ ). FAB-MS for Ci ₉ Hi ₈ N ₂ O ₃ : 323.2 [M + H ⁺ ]

EXAMPLE 19

3- (1H-indol-3-yl) -4- (4-methoxyphenyl) -1,5-dihydro-2 / - / - pyrrol-2-one (32)

400 ml of 31 in 40 ml of dry THF are dissolved in a dry 100 ml three-necked flask with septum and argon stream. Heat to boiling and inject 1390 mg of a 20% (w / w) K-tBuO / THF solution. After 30 min of reaction, the mixture is cooled in an ice bath and 50 ml of a 1% HCl solution. It is shaken out several times with ethyl acetate, the organic phase is dried and rotated. Purification is by flash chromatography (yield 50%).

¹ H-NMR (DMSO-de): δ = 11.3 (bs, 1H, indole-NH), 8.3 (s, 1H, NH), 7.5 (d, 1H), 7.4- 7.2 (m, 3H ), 7.0 (m, 1H), 6.8-6.6 (m, 4H), 4.3 (s, 2H, CH ₂ ), 3.7 (s, 3H, para- {O} CH ₃ ).

¹³ C NMR (DMSO-de): δ = 173.9 (C = O), 159.69 (2 CO), 146.64 (C _quar t), 136.47 (C _quart ), 128.95 (CH), 127.16 (CH), 126.95 ( C _quar t), 125.30 (C _quar t), 124.57 (C _quar t), 121.32 (CH), 120.64 (CH), 118.99 (CH), 114.10 (CH), 111.96 (CH), 106.56 (2 C), 55.47 (para {O} CH ₃ ), 47.65 (CH ₂ ).

FAB-MS for Ci ₉ Hi ₆ N ₂ O ₂ : 304.1 [M ^" ]

EXAMPLE 20

Λ / -r 2 - (4-methoxyphenyl) 2-oxo-ethyl-1,2- (1-methyl-1H-indol-3-yl) -acetamide (33)

Cl

In a dry 100 ml three-necked flask, 300 mg of N-methylindoleacetic acid, 320 mg of 2-oxo-2- (4-methoxyphenyl) ethanaminium chloride, 430 mg of DCC and 240 mg of HOBt were dissolved in 15 ml of DCM and stirred at RT. After 48 h, add dropwise 450 μl DIEA in 1 ml DCM and stir overnight. The batch is washed with 30 ml of 1% HCl and with brine, dried and concentrated by rotary evaporation. Add 20 ml of xylene and refrigerate in the freezer. The product precipitates as a white precipitate (yield 89.9%).

¹ H-NMR (acetone-de): δ = 7.9 (m, 2H), 7.6 (d, 1H), 7.3 (d, 1H), 7.2-6.9 (bm, 5H, CH ₂ ), 4.6 ( d, 2H), 3.8 (s, 3 H, - {O} CH ₃ ), 2.8 (s, 3H), 2.7 (s, 2H, CH ₂ ). LC-MS for C ₂₀ H ₂₀ N ₂ O ₃ : 337.0 [M + H ⁺ ]

EXAMPLE 21

4- (4-Methoxyphenyl) -3- (1-methyl-1H-indol-3-yl) -1,5-dihydro-2 / - / - pyrrol-2-one (34)

In a dry 50 ml three-necked flask with septum and argon stream, 170 mg of 33 in 20 ml of dry THF are dissolved. Heat to boiling and inject 280 mg of a 20% (w / w) BuOK / THF solution. After 20 min reaction is cooled in an ice bath and 20 ml of a 1% HCl solution. It is shaken out several times with ethyl acetate, the organic phase is dried and rotated. Purification is by flash chromatography (yield 56%).

¹ H-NMR (DMSO-de): δ = 8.3 (s, 1H, NH), 7.6 (s, 1H), 7.4 (d, 1H), 7.3 (d, 2H), 7.1 (t, 1 H), 6.6-6.8 (m, 4H), 4.3 (s, 2H, CH ₂ ), 3.8 (s, 3H, para {O} CH ₃ ), 3.7 (s, 3H, N-CH ₃ ).

¹³ C-NMR (DMSO-de): δ = 173.78, 159.71 (2 CO), 146.55 (C _quar t), 136.91 (C _quar t), 131.13, 128.96 (CH), 127.16 (C _quar t), 125.57 ( C _quar t), 124.14 (C _quart ), 121.41 (CH), 120.86 (CH), 119.17 (CH), 110.23 (CH), 105.71 (2 C, ortho-PhC), 55.47 {para- (OJCH ₃ ), 47.67 (CH ₂ ), 32.94 (CH ₃ ).

FAB-MS for C ₂₀ Hi ₈ N ₂ O _2: 319.2 [M + H ⁺ -] Biological data on efficacy

In vitro angiogenesis Assav

The in vitro angiogenesis assay was performed according to the procedure described in Microvasc. Res. Nov; 50 (3): 311 -22 published procedures (see page 34).

Human lung microvascular endothelial cells (HLMEC) are seeded onto Cytodex-3 microcarrier beads and placed in a three-dimensional fibrinogen gel containing 20ng / ml VEGF without (positive control) or test compound (fibrinogen gel without VEGF serves as a negative control). The polymerization of fibrin is started by adding 0.65 U / ml thrombin. The gels are then incubated in MCDB131 (containing appropriate concentrations of growth factors, 5% FCS, 5% human serum and 200 U / ml Trasylol (Bayer Leverkusen, Germany).) After 24 h, the gel was fixed in 1% PFA and the number of sprouts The assay was carried out in triplicate for each concentration of the test compounds The positive / negative controls and the inhibitory action of compound 10 are shown by way of example in FIG.

Test compounds 7, 8, 10 and 14 were tested for anti-angiogenic activity in the in vitro sprouting assay and as active reference substances compounds B45.1 and CPD53 were tested in the assay:

CPD53

For all compounds, a concentration-dependent inhibition of sprouting of the human endothelial cells can be detected. In the test, 10 is determined to be the most effective compound, and in a concentration of the compound of 0.5 μg / ml in the assay, the sprouting of the endothelial cells is significantly inhibited by 92% compared to the positive control. Compared to CPD53 (65% inhibition at 0.5 μg / ml), a clear increase in activity can be measured in this in vitro test. An inhibition comparable to 10 at 0.5 μg / ml achieves CPD53 at the concentration of 5 μg / ml. The chemical modification of the imide CPD53 to the lactam 10 thus proves to be positive in terms of biological activity, which i.a. possibly based on the better bioavailability of lactam 10.

The indole nitrogen-substituted derivatives 7, 8 and 14 are less potent than 10, suggesting an essential influence of the free indole-NH. The same effect can be seen in the comparison of CPD53 to B45.1 (Table 4).

Table 4:

# Compound% inhibition compared to positive control

7 33

8 29

10 92

14 61

B45.1 48

CPD53 65

Since the in vitro activity of CPD53 as an angiogenesis inhibitor is based on the potent inhibition of tyrosine kinases (especially of VEGF-R2 / 3), a similar molecular mechanism is discussed due to the structural similarity for class I compound (for example: 10). For compounds of class I, the inhibition of protein kinases could be detected.

FIG. 1 shows the result of the sprouting assay for compound 10 on the basis of photographic images. At the top left the positive control with sprouting of endothelial cells after stimulation with the growth factor VEGF is shown, at the top right the negative control without stimulation. After stimulation with VEGF and administration of compound 10 (1 μg / ml), endothelial cell growth and sprouting are completely absent (below).

Table 5:

Evaluation of the sprouting assay

In vitro Proteinkinase Testung

In vitro protein kinase testing

The in vitro protein kinase assays for p38αMAPK and JNK3 were performed as described in Analytical Biochemistry 344, 135-137. and Combinatorial Chemistry & High Throughput Screening, 9 (8), 613-618. published procedures.

The following inhibition values could be measured for the indicated test compounds in the concentration of 10 .mu.M:

Table 6:

Compound inhibition inhibition

# p38αMAPK JNK3

8 0% 27%

10 0% 52%

24 20% -

30 53% _

Furthermore, _5-o value of 6.8 uM for inhibition of p38αMAPK could be determined for Compound 30, an IC.

For compound 10, VEGFR2 (Peifer et al., J. Med. Chem. 2008, 51, 3814-3824) gave an IC ₅₀ value of 31 nM.

The following abbreviations have been used in the present description:

ACN acetone itril

CDI carbonylimidazole

DCC dicyclohexylcarbodiimide

DCM dichloromethane

DDQ dichlorodicyanoquinone

DIEA diisopropylethylamine

DME dimethoxyethane

EE ethyl acetate

EtOH ethanol

MOM methoxymethyl

NBTSA N- (Benzylidene) thmethylsilylamine

PE petroleum ether

SEM-CI trimethylsilylethyloxymethyl chloride M.p. melting point

TBAF tetra-n-butylammonium fluoride

⁴ BuOK potassium tert-butoxide

⁴ BuOH tert-butanol

TDI toluene diisocyanate

THF tetrahydrofuran

SEM trimethylsilylethyloxymethyl

Claims

i CIN i rtiNorrcuoπiz 1. Cyclic amide compounds of the general formula I:

wherein one of the radicals R ¹ or R ^{2 is} phenyl which is substituted by 1, 2, 3 or 4 hydroxy or C ₆ -alkoxy groups and the other of the radicals R ¹ or R ^{2 is} an indole radical of the formula II.

wherein R is selected from Hd-e-alkyl, Ci-e-alkyl which is substituted by a) 1, 2 or 3 hydroxy groups, b) 1, 2 or 3 Ci _-6- alkoxy, c) phenoxy, d) phenyl-Ci _-4 -alkyloxy

f) tri (Ci- _C4 alkyl) silyl-Ci-4-alkoxy; R ⁵ is H or Ci _-6 alkyl or phenyl-Ci _-4 alkyl; and the physiologically acceptable salts thereof as well as the hydrates of Compounds or salts thereof. 2. Compounds according to claim 1, wherein one of the radicals R ¹ or R ^{2 is} 3, 4, 5-tri- (Ci- ₆ -alkoxy) phenyl or 4-Ci- ₆ -alkoxyphenyl. 3. Compounds according to claim 1 or 2, wherein R ^{1 is} the radical of the formula II. 4. A compound according to any one of the preceding claims, wherein one of R ¹ or R ² is a radical of the formula IIa

IIa in which R ^{4 has} the meanings given in claim 1. 5. A compound according to any one of claims 1 to 4, wherein R ^{3 is} H. 6. Compounds according to claim 1 of the formulas

8 10

11 12 13

24 28 30

A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 in a pharmaceutically acceptable carrier or diluent. 8. Composition according to claim 7, additionally comprising at least one further pharmacological agent which is suitable for the treatment of angiogenesis-associated diseases. 9. Composition according to claim 7, additionally comprising at least one further pharmacologically active substance which is suitable for the treatment of cancerous diseases. 10. Use of at least one compound according to any one of claims 1 to 6 for the preparation of a pharmaceutical agent for the inhibition of protein kinases and / or for the inhibition of angiogenesis. 11. Use of at least one compound according to any one of claims 1 to 6 for the manufacture of a pharmaceutical composition for the prevention and / or treatment of angiogenesis-associated diseases. 12. Use of at least one compound according to any one of claims 1 to 6 for the preparation of a pharmaceutical agent for the prevention and / or treatment of cancer. 13. A cyclic amide compound according to any one of claims 1 to 6 for the inhibition of protein kinases and / or inhibition of angiogenesis, for the prevention and / or treatment of angiogenesis-associated diseases and for the prevention and / or treatment of cancer. 14. Use of at least one compound according to any one of claims 1 to 6 as a reference substance. A method of treating angiogenesis-associated diseases or cancers comprising administering an angiogenesis-inhibiting or tumor-inhibiting amount of a compound of claim 1 to a subject in need of such treatment.