Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

• the present invention relates to new indole derivatives with improved biological activity, improved tolerance and improved oral bioavailability, which are used as medicaments for the treatment of tumor diseases, in particular in the case of drug resistance to other active substances and in metastatic carcinoma.
• tumor inhibitors The effect of tumor inhibitors is based on a wide variety of mechanisms and is only partially known. It is not uncommon for new mechanisms of action to be found for known tumor drugs. This is also to be expected for the compounds according to the invention. Many tumor drugs work through mechanisms such as blocking the cell's cell division mechanism, preventing the tumor from being supplied with nutrients and oxygen (anti-angiogenesis), preventing metastasis, preventing the reception and transmission of growth signals to the tumor cell or the Forcing the tumor cell into programmed cell death (apoptosis).
• Indole derivatives find a wide variety of uses as pharmacodynamically active compounds and as synthesis components in pharmaceutical chemistry.
• indol-3-yl derivatives with antitumor activity which are associated with numerous groups and others. can also be substituted with 2-, 3-, 4- and 8-quinoline or 2-, 3-, 4-, 5- and 6-pyridine residues.
• a 2-methyl-8-quinolinyl group is mentioned as a substituent on the amide group. However, no biological properties are mentioned.
• WO 02/08225 A1 describes 2- (1 H-indol-3yl) -2-oxoacetamide derivatives with an anti-tumor effect against solid tumors.
• specific embodiments with quinoline, pyridopyrazine or indazolyl residues are not given.
• Patent specification WO 00/67802 describes indoI-3-glyoxylamides which are substituted with higher-chain fatty acids as potential antitumor agents.
• specific embodiments with quinoline, pyridopyrazine or indazolyl radicals are not given. No biological data are also given for such exemplary embodiments.
• N-heterocyclic indolylglyoxylamides are described as orally active compounds with antitumoral activity. However, details of the mechanism of action are not given.
• Glyoxylamidindole and their use as medicines for the anti Tumor treatment described.
• Their general formula includes 6-quinoline derivatives.
• 6-quinoline residue two examples with 6-quinoline residue are named as exemplary embodiments and supported with biological results.
• specific embodiments with pyridopyrazine or indazolyl radicals are not given.
• New indolylgloxamides are described in US application US03 / 0181482A1.
• the compounds according to the invention are described here as antitumor agents with cytotoxic activity and as angiogenesis inhibitors.
• a 6-quinoline derivative is shown as an exemplary embodiment (compound 3; p.10) and supported with antiproliferative data (see p. 19; Table 1 a, 1 b) and antiangiogenic properties (see p. 20).
• specific embodiments with pyridopyrazine or indazolyl radicals are not given.
• One object of the invention is to provide cytotoxic substances with combined mechanisms of action which can be used to treat a large number of tumors, in particular in the case of active substances. resistance to other drugs and metastatic carcinomas. suitable.
• R for one or more heteroatoms selected from the group N,
• R1 unsubstituted or substituted alkyl aryl
• R2 (i) hydrogen
• (CrC 6 ) -alkylcarbonyl preferably acetyl, propionyl, (-C-C 6 ) -alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
• X, Y mean oxygen or sulfur
• R represents an unsubstituted or substituted 2-, 3-, 4-, 5- or 6-pyridyl group and R1-R6 has the above-mentioned meaning
• R7 must not be an acetyl radical or a te / f-butyloxycarbonyl group.
• Another object of the invention are indole derivatives of
• R1 unsubstituted or substituted alkyl aryl
• X, Y mean oxygen or sulfur
• the present invention is a further development of the invention described in WO 02/10152. It was found that when the 2-methyl-6-quinolyl group was replaced by unsubstituted or substituted 2-, 3-, 6-, 7- and 8-pyridopyrazinyl, unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl, show an improved antiproliferative effect on various tumor cell lines.
• the compounds according to the invention have a strong cytotoxic effect which can be based on a wide variety of mechanisms.
• a mechanism of the compounds according to the invention which is proven in the invention is based on the inhibition the tubulin polymerization and on the inhibition of topoisomerase II. This leads to a cell locking of tumorigenic cells in the G2M phase.
• the compounds according to the invention induce apoptosis.
• the compounds according to the invention have improved water solubility and thus also improved oral bioavailability.
• the possibility of a lower, longer-lasting and better tolerated medication with antitumor effect is to be opened than with the classic cytostatics.
• the disadvantageous development of resistance is to be avoided.
• the increase in activity achieved with the indole derivatives according to the invention is intended to make drug consumption more effective.
• Indole derivative of the formula I R unsubstituted 5-quinolyl, unsubstituted 6-quinolyl or unsubstituted 7-quinolyl and R7 acetyl or propionyl.
• Indole derivative of the formula IR unsubstituted 5-quinolyl, unsubstituted 6-quinolyl or unsubstituted 7-quinolyl and R7 methoxycarbonyl, ethoxycarbonyl or propionoxycarbonyl.
• alkyl encompasses acyclic saturated or unsaturated hydrocarbons, which can be straight-chain or branched.
• substituted in the sense of this invention, insofar as not explicitly defined above, means the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-cycloalkyl , OH, O-alkyl, where multiply substituted radicals are to be understood as meaning those which are substituted several times, for example twice or three times, on different or on the same atoms, for example three times on the same C atom as in the case of -CF 3 , -CH 2 CF 3 or at different positions as in the case of -CH (OH) -CH 2 - CH 2 -CHCl 2.
• the multiple substitution can be carried out with the same or different substituents.
• alkyl aryl means (CC 6 ) alkyl (C 6 -C 4 ) aryl and preferably (C 1 -C 6 ) alkyl-C 6 aryl.
• one or more times substituted means the one or more times, for example two, three or four times substitution of one or more Hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, OH, O-alkyl, CF 3 , alkyl, (C 6 -C ⁇ 0 ) aryl, (C 6 -C ⁇ o) aryl - (CRC6) alkyl and / or heterocyclyl, on one or possibly different atoms (where a substituent may in turn be substituted).
• the multiple substitution takes place with the same or with different substituents.
• one or more times substituted means the one or more, for example, two, three or four times substitution of one or more hydrogen atoms of the ring system F, Cl, Br, I, nitro, amino, -CC 6 alkyl, preferably methyl, mono- (CrC 6 ) alkylamino, di (-C 6 ) alkylamino, hydroxy, -C 6 alkoxy , Benzyloxy, carboxy, (-C-C 6 ) alkoxycarbonyl, (CrC 6 ) - alkoxycarbonylamino or mono- or polysubstituted with fluorine (CC 6 ) - alkyl, preferably trifluoromethyl, (C 6 -C ⁇ 0 ) aryl and / or (C 6 -C ⁇ o) -aryl- (-C-C 6 ) - alkyl on one or possibly different
• Formula I have at least one center of asymmetry, they can be in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers.
• the mixtures can be present in any mixing ratio of the stereoisomers. If possible, the compounds of the invention may be in the form of the tautomers.
• the compounds of the general formula I according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
• the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
• the compounds of general formula I according to the invention if they contain a sufficiently acidic group, such as the carboxy group, can be converted into their physiologically tolerable salts with inorganic and / or organic bases.
• Suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine.
• the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
• the compounds of general formula I according to the invention if they have a sufficiently basic group, such as a secondary or tertiary amine, can be converted into salts with inorganic and organic acids.
• the pharmaceutically acceptable salts of the compounds according to the invention are preferably of the general structure I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid , Grape acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid.
• the salts formed include hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, sulfoacetic acid, tosylates, carbonates, bicarbonates, formates, acetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates and glutates.
• the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
• solvates and in particular hydrates of the compounds I according to the invention can be obtained by crystallization from a solvent or from aqueous solution.
• One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
• chemical substances form solids which are in various order states, which are referred to as polymorphic forms or modifications.
• the different modifications of a polymorphic substance can differ greatly in their physical properties.
• the compounds of general formula I according to the invention can exist in various polymorphic forms, certain modifications being metastable.
• Both the compounds of formula I and their salts are biologically active.
• the compounds of formula I can be administered in free form or as salts with physiologically acceptable acids or bases.
• the compounds of the general formula can be administered orally, rectally, buccally (e.g. sublingually), parenterally (e.g. subcutaneously, intramuscularly, intradermally or intravenously), topically or transdermally.
• the invention further relates to medicaments containing at least one of the compounds of the formula I or their salts with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically usable excipients and / or diluents or auxiliaries.
• These drugs are used for the treatment of tumor diseases, in particular for the treatment of tumor diseases with drug resistance to other active substances and / or for tumor diseases with metastatic carcinoma.
• Suitable forms of application are, for example, tablets, tablets, capsules, solutions for infusion or ampoules, suppositories, plasters, inhalable powder preparations, suspensions, creams and ointments.
• the compounds of the invention can also in a microparticulate z. B. be dispersed nanoparticulate composition.
• the compounds according to the invention lock dividing cells in the G2 / M phase
• the compounds according to the invention induce apoptosis; •
• the compounds according to the invention are notable for strong antitumor in vivo activities with, in addition, improved tolerances;
• the compounds of the formula I according to the invention are active in vitro on mdr-resistant Zeil lines, in contrast to paclitaxel, vincristine, doxorubicin or etoposide;
• the compounds (1), (4) and (11) are compounds, the radical R7 being hydrogen.
• the compounds (2), (3), (5) and (6) to (8) contain as group R7 an alkylcarbonyl or alkoxycarbonyl group.
• the starting compounds II, III and IV are either commercially available or can be prepared by methods known per se.
• the starting materials II, III and IV are valuable intermediates for the preparation of the indole derivatives of the formula I according to the invention.
• reaction parameters to be used are known to the person skilled in the art on the basis of his specialist knowledge.
• stages 1, 2 and 3 which are based on the synthesis schemes 1 and 2, the following compounds were synthesized, which can be seen from the following overview by specifying the respective chemical name.
• the compounds according to the invention were characterized analytically by their melting points or by 1 H-NMR spectroscopy and / or mass spectroscopy.
• the chemicals and solvents used were purchased commercially from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.) or synthesized.
• Example 1 (implementation according to scheme 1. 1st stage):
• Example 2 (implementation according to stage 2 of scheme 1):
• Example 17 Antiproliferative effect on various tumor cell lines
• the substances 1, 2, 4, 9, 11, 12, 13 and 15 were examined for their anti-proliferative activity in a proliferation test on established tumor cell lines (D.A. Scuderio et al. Cancer Res. 1988, 48, 4827-4833).
• the test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number.
• the cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line NCI- H460 (NCI 503473).
• V comparative substance
• Table 1 Inhibition of proliferation of the substances according to the invention in the XTT cytotoxicity test on human tumor cells
• substances 1, 2, 4 and 11 against multi-drug-resistant cell lines were examined in comparison to the non-resistant wild-type cell lines.
• the cell lines examined are the murine L1210, the acute myeloid leukemia cell line LT12 and the resistant lines L1210 / mdr and LT12 / mdr.
• murine P388 cell line methyl-cholanthrene-induced lymphoid neoplasm
• the doxorubicin-resistant P388 were used as test systems.
• Table 2 Inhibitory effects of the substances in the XTT proliferation test on human tumor cell lines.
• the substances 1, 2, 4 and 11 show a very potent inhibitory effect on all cell lines tested, while in the case of the classic tubulin-inhibitory substances such as paclitaxel or vincristine also in the topoisomerase II Inhibitors (doxorubicin, mitoxantrone, etoposide) show an at least greatly reduced effect on the MDR1-resistant cell lines.
• the classic tubulin-inhibitory substances such as paclitaxel or vincristine also in the topoisomerase II Inhibitors (doxorubicin, mitoxantrone, etoposide) show an at least greatly reduced effect on the MDR1-resistant cell lines.
• Substances 1, 4, 9, 11, 12, 13 and 15 were tested in an in vitro test for inhibition of the polymerization of bovine tubulin (DM Bollag et al. Cancer Res. 1995, 55, 2325-2333).
• tubulin purified by cycles of polymerization and depolymerization is used, which is brought to polymerization by adding GTP and heating.
• the EC are given 5 o values of polymerization inhibition of tubulin with 30% associated proteins (MAPs).
• Table 3 Inhibition of tubulin polymerization. Average of two independent tests.
• Substance 1 was tested in two different in vitro tests for the inhibition of topoisomerase II.
• kDNA is treated with human DNA topoisomerase II in the absence or presence of the test compounds.
• Compound 1 according to the invention was tested at three different concentrations (100, 31.6 and 10 ⁇ M).
• m-amsacrine m-Amsa
• paclitaxel paclitaxel
• vincristine were used at a respective concentration of 100 ⁇ M.
• reaction batches are placed in the heating block preheated to 37 ° C. and incubated at 37 ° C. for 10 minutes. The incubation is stopped after the addition of 4 ⁇ L 5x stop buffer and the substance is subsequently extracted with CIA. Then 20 vL of the supernatant are applied to a 1% agarose gel with 0.25 g / mL ethidium bromide and separated for 1 h at 100V. Finally, the gel is photographed under UV excitation (see Figure 1). The inhibition of the decatenation of kDNA is quantified using the GelPro ® analyzer software (see FIG. 2). • pRYG relaxation assay for testing topoisomerase II activity:
• Compound 1 according to the invention was tested at three different concentrations (100, 31.6 and 10 ⁇ M).
• the reference compounds m-amsacrine, paclitaxel (Taxol) and vincristine were used at concentrations of 316 and 100 ⁇ M.
• the cell cycle includes the development of the cell from one cell generation to the next.
• the cell During the resting phase (GO) and pre-synthetic phase (G1) the cell has a diploid chromosome set (2c).
• S the amount of DNA is increased by replication.
• G2M pre-critical phase
• M the reduplicated chromosome population
• the subsequent, short-lasting mitosis phase (M) the reduplicated chromosomes are evenly divided into two daughter cells, which then each show a diploid DNA content and are in the G01 phase, so that the cell cycle can start again.
• KB / HeLa cells were treated with the test substances in different concentrations (0.1-1000 nM) for 24 hours at 37 ° C.
• Mitoxantron 25.3 Table 4: Inhibitory concentration for a 50% portion of the cells in the G2 / M phase.
• the compounds 1, 2, 4 and 11 according to the invention have comparable activities to the reference compounds paclitaxel and mitoxantrone.
• Compounds 1 and 2 according to the invention are distinguished in comparison to compounds 10 and 14 by improved water solubilities.
• Example 24 in vivo activity
• Example 25 in vivo activity

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