WO2001019791A2 - 3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments - Google Patents

3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments Download PDF

Info

Publication number
WO2001019791A2
WO2001019791A2 PCT/EP2000/008860 EP0008860W WO0119791A2 WO 2001019791 A2 WO2001019791 A2 WO 2001019791A2 EP 0008860 W EP0008860 W EP 0008860W WO 0119791 A2 WO0119791 A2 WO 0119791A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibition
hepg
mcf
cytotoxicity
vinylpyrrole
Prior art date
Application number
PCT/EP2000/008860
Other languages
German (de)
French (fr)
Other versions
WO2001019791A3 (en
Inventor
Barbara Beck
Alexander Dömling
Original Assignee
Morphochem Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Morphochem Ag filed Critical Morphochem Ag
Priority to AU75178/00A priority Critical patent/AU7517800A/en
Publication of WO2001019791A2 publication Critical patent/WO2001019791A2/en
Publication of WO2001019791A3 publication Critical patent/WO2001019791A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to new 3-vinylpyrrole derivatives, pharmaceutical compositions containing them, their preparation and use, in particular as tumor and cancer-dissolving and antibacterial drugs.
  • Cancer and tumor diseases are among the problematic clinical pictures of civilization. In many cases, the tumor tissue has to be surgically removed and / or treated with chemotherapy. Nevertheless, the survival of the patient over a long period of time is very uncertain. Furthermore, the chemotherapeutic and surgical treatment is often associated with pain and other disadvantages for the cancer patient. Therefore, the provision of new and complementary drugs for the treatment of tumor and cancer diseases is of great interest.
  • Aspergillamides A and B are recently described natural products of marine origin with cytotoxic properties (Fenical et al., Tetrahedron 1998, 54, 13459).
  • M is a substituted peptide, a substituted hydantoin or thiohydantoin, tetrazole, lactam or lactone residue,
  • Y and Z independently of one another are a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl , Cycloaralkenyl, cycloaralkynyl, aryl, alkoxy or aralkoxy or a heterocyclic ring, are preferably a hydrogen atom, a halogen atom, a pseudohalogen, more preferably a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom or fluorine, and
  • X is an optionally substituted and / or an optionally fused or hetero-fused 3-pyrrole ring
  • X and Y or X and Z or N and Z can be part of a cycle.
  • alkyl can represent, for example, a C1- .50 alkyl group, preferably a C ⁇ _i2 alkyl group, preferably a C - ⁇ alkyl 95 group; for example an alkyl group can be a methyl, ethyl, propyl, isopropyl or butyl group;
  • alk e.g. defined in the term “alkoxy” as “alkyl”
  • aromatics or aryls or corresponding radicals preferably substituted or unsubstituted phenyl, benzyl, naphthyl, biphenyl or anthracene groups or aromatic heterocycles with 5 or 6 ring
  • alkenyl can e.g. represent a C2-10 alkenyl group, preferably a C2-6 alkenyl group, which has the double bond (s) at any position and can be unsubstituted or substituted; e.g. an ethenyl, propenyl, isopropenyl or butenyl group;
  • alkynyl e.g. represent a C2-10 alkynyl group, preferably a C2-6 alkynyl group, which has the triple bond (s) at any position and can be unsubstituted or substituted; e.g. a
  • the expression cycloalkyl can, for example, represent a carbocycle having 3 to 20 C atoms, preferably having 5 to 15 C atoms and more preferably having 5 or 6 C atoms, which 125 has no multiple bond in the carbocycle;
  • cycloalkenyl e.g. be a carbocycle with 3 to 20 C atoms, preferably with 5 to 15 C atoms and more preferably with 5 or 6 C atoms, which has at least one double bond in the car 130 bocycle;
  • cycloalkynyl e.g. be a carbocycle with 3 to 20 carbon atoms, preferably with 5 to 15 carbon atoms and more preferably with 5 or 6 carbon atoms, which has at least one triple bond in the carbocycle 135;
  • alkoxy can e.g. be a group of the formula -O- alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-cycloalkenyl, -O-cycloalkynyl, -0-aryl,
  • substituted or substituent e.g. represent any substitution by one or more alkyl, alkenyl, alkynyl, mono- or polyvalent alkanoyl, alkoxyalkanoyl, or alkoxyalkyl groups.
  • fused can e.g. mean that further rings, preferably aromatic rings, are condensed on the 3-pyrrole ring.
  • a substituted hydantoin / thiohydanion residue can be, for example, a hydantoin / thiohydanion residue which has one or two alkyl and / or aryl substituents.
  • the lactam residues and the lactone residues preferably have 155 3,4,5,6,7, 8 or 9 ring atoms.
  • the 3-vinylpyrrole derivatives according to the invention can also be present as racemates, in D or L form or as physiologically tolerable salts.
  • M can preferably be a peptide residue with up to 10 amino acid residues, more preferably a peptide residue with up to 5 amino acid residues, most preferably a peptide residue with up to 3 amino acid residues,
  • 165th peptide e.g. N-terminally acylated or sulfonated or iV-terminal free, repeating units from N-alkylated, iV-arylated or N-unalkylated amide-linked a-, b-, g- or -amino acids of natural or unnatural origin.
  • X can preferably be selected from the following rings:
  • radicals R independently of one another are hydrogen atoms, halogen atoms, pseudohalogens, optionally sub- substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, 190 aryl, alkoxy, aralkoxy radicals or are heterocyclic rings.
  • All radicals R are preferably a hydrogen atom or a radical R is a group of the formula -0-CH 2 -Ph and all other radicals R are hydrogen atoms.
  • 195 M is preferably selected from:
  • R x and R 2 independently of one another hydrogen atoms, halogen atoms, pseudohalogens, optionally substituted
  • Cyclic or heterocyclic rings bonded to alkyl bridges such as cyclohexyl, phenyl, benzyl, phenethyl, tolyl, piperidinyl, indolyl, imidazolyl rings, preferably independently of one another hydrogen atoms, methyl groups
  • R 1 and R 2 together with the carbon tom to which they are attached form a cycloalkyl, cycloalkenyl or cycloalkynyl radical which is unsubstituted or unsubstituted.
  • 240 can optionally contain 1 or 2 heteroatoms selected from oxygen and nitrogen atoms, in particular a cyclohexyl, phenyl, benzyl, phenethyl, piperidinyl residue,
  • R 4 and R 5 independently of one another, preferably both hydrogen atoms or one hydrogen atom and a —CH 2 —CH (CH 3 ) 2 - group, or R 4 and R 5 form together, defined under a) for Ri 250 and R 2 with the carbon atom to which they are bound, that defined under b) for R 1 and R 2 .
  • pharmaceutical compositions according to the invention which contain at least one of the above compounds, if appropriate in combination with conventional carriers and / or adjuvants.
  • the invention further relates to a method a) for producing compounds according to the invention, wherein
  • the reaction can take place in organic solvents, water or without solvent or in a mixture of water and organic solvent.
  • Lewis acids such as BF 3 OEt 2 , TiCl 4 , ZrCl 4 , Ti (OR) 4 , Zr (OR) 4 , ZnCl 2 , Al 2 0 3 , AlCl 3 , BC1 3 , BX 3 , Broenstedt 280 acids such as HCl, HX, H 2 SO 4 , H 3 PO 4 , polyphosphoric acid, or corresponding polymer-bound or catalysts or reaction mediators applied to inorganic materials such as clays can be used.
  • the reaction can e.g. run at temperatures between -70 ° C and 100 ° C and / or under the influence of microwaves,
  • the invention further relates to a process b) for the preparation of compounds according to the invention, e.g. 290 classic multi-stage coupling methods which are known per se to the person skilled in the art can be used (e.g. Bodanszky, M., Bodanszky, A., The Practice of Peptide Chemistry, Springer Verlag, New York, 1994, 2 ed.).
  • a process b) for the preparation of compounds according to the invention e.g. 290 classic multi-stage coupling methods which are known per se to the person skilled in the art can be used (e.g. Bodanszky, M., Bodanszky, A., The Practice of Peptide Chemistry, Springer Verlag, New York, 1994, 2 ed.).
  • protic solvents water, alcohols such as methanol, ethanol, propanol, isopropanol, butanol,
  • polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, acetonitrile
  • non-polar aprotic solvents such as chloroform, dichloromethane 305, carbon tetrachloride, ethyl acetate, ether, hexane, pentane, benzene, toluene, clorbenzene, or any binary or ternary mixtures of the above solvents, 310 or two or three-phase mixtures of the above solvents can be used.
  • the 3-vinylpyrrole derivatives according to the invention and the pharmaceutical composition according to the invention can be used 315 for the therapy or prophylaxis of tumor or cancer diseases. They can also be used as antibiotics.
  • They can be used locally or systemically.
  • Systemic application means e.g. an intravenous, intrapleural, intraperitoneal, rectal, oral, application or the flushing of body cavities and bladder.
  • Local application means e.g. the subcutaneous, intracutaneous, intratumoral, peritumor
  • 325 application e.g. in the form of solutions for injection, suspension for injection, creams, lotions, gels and ointments.
  • the lifetime of tumor cells in vitro is significantly shortened compared to controls by the active substances according to the invention.
  • the active substances according to the invention have a dose-dependent tumor-dissolving effect when used systemically and locally.
  • the dose of the 335 active substances according to the invention is in the order of 0.1 to 100 mg / kg body weight, preferably 2 to 40 mg / kg body weight. In individual cases, the dosage can be larger or smaller than mentioned above.
  • the active compounds according to the invention can be used in a known manner - in accordance with the individual clinical picture - in a formulation, such as plasters, ointments, pastes, creams, soluble powders, emulsions, powders, suspensions and injection solutions.
  • a formulation such as plasters, ointments, pastes, creams, soluble powders, emulsions, powders, suspensions and injection solutions.
  • the active compounds according to the invention can, for example, be dissolved in an injection solution, if appropriate with the aid of solubilizers, in dilute physiologically tolerable bases and brought into an injectable form of pH 6 to 8, in particular 6.9 to 7.5, by adding physiologically tolerable acids.
  • Exemplary physiologically compatible bases can be 355 hydroxides, hydrogen carbonates, carbonates of the alkali and alkaline earth metals, in particular of potassium, sodium and calcium.
  • Exemplary physiologically compatible acids can be 360 lactic acid, citric acid, tartaric acid, oxalic acid, malic acid, acetic acid, formic acid, benzoic acid, salicylic acid, hydrochloric acid, sulfuric acid or phosphoric acid.
  • auxiliary substances can be added.
  • non-toxic and pharmaceutically suitable auxiliaries can be solid, semi-solid or liquid carriers, emulsifiers or dispersants.
  • concentration of invented 370 active substances according to the invention are between 1 and 90% by weight, preferably 5 to 50% by weight.
  • the dosage units of the active compounds according to the invention can consist, for example, of 1, 2, 3 or 4 individual
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or even a quarter of a daily dose.
  • creams, pastes, ointments and gels can include customary excipients known to the person skilled in the art, for example waxes, paraffins, starches, vegetable and animal fats, cellulose derivatives, tragacanth, silica
  • sprays and powders can contain customary excipients known to the person skilled in the art, such as milk sugar, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder or mixtures thereof.
  • Sprays can additionally contain blowing agents, for example chlorofluorocarbons.
  • 395 suppositories can contain customary carriers known to the person skilled in the art, such as polyethylene glycols, fats or mixtures thereof.
  • the present invention also relates to anti-body conjugates of one or more tumor-specific Antibodies and one or more active substances according to the invention which can be split off under tumor-specific physiological conditions of the tumor environment or of the tumor interior.
  • These antibody conjugates can be packaged in liposomes.
  • the active substances according to the invention can be packaged in liposomes in order to achieve better locally relevant active substance concentrations and for better tolerability.
  • combinations with other active substances serving the patient can be administered simultaneously or with a time delay.
  • the present invention also encompasses the use of the described active ingredients and pharmaceutical preparations which contain one or more active ingredients for the treatment of atypical tissues in humans and farm animals which prevent or disrupt the course of normal biological functions.
  • Such tissues can be, for example:
  • Benign and malignant tumors of solid or cystic nature adenomas, cyst adenomas, papillomas, adenocarcinomas, also of the cirrhosis type, basal cell carcinomas, sarcomas, for example Wise fibrosarcoma, liposarcoma, lymphosarcoma, rhabdomyosarcoma, myxosarcoma, chondrosarcoma, reticular cell sarcoma, Hodgkin's disease, embryonic tumors, for example
  • Retroblastoma haemangioma, chordoma, odontoma, craniopharyngoma, hamartoma, for example lymphoangioma, exostoses, neurofibrantosis, melanoma, lymphoma, hepatoblastoma, breast cancer, cervical cancer, choriocarcinoma, adeno-
  • acantoma, androblastoma leiomyoma, arrhenoblastoma, sertoli cell tumor, theca and granulosa cell tumor, germinoma and seminoma, ovarian and vulvar carcinoma, bladder and prostate carcinoma, tumors caused by schistosomiasis, astrocytoma, ectrophobia, ectrophobia, ectrophobia
  • the biological effectiveness of the substances was screened using the cell proliferation assay to determine the acid phosphatase activity.
  • This enzyme provides information about the growth activity of the cells. 620
  • the determination was carried out in 96 format with two different human cancer cell lines.
  • the cells are first split on 96 deep well plates in different concentrations and two
  • the substrate solution is added.
  • the mixture is left to incubate for a further hour at 37 ° C., during which time the solution turns yellow.
  • the enzyme reaction is stopped by adding sodium hydroxide solution, whereby the yellowing is increased somewhat.
  • the IC 50 value must be determined for a more detailed characterization of the biological activity. For this, the cell proliferation assay is carried out in five different concentrations. The mean value of the DMSO controls
  • 645 speaks growth of 100% or inhibition of 0%.
  • the individual measured values are converted into% inhibition and plotted against the logarithm of the concentration.
  • a sigmoidal curve is drawn from these measured values, from which the IC 50 value, at 50% inhibition
  • cytotoxicity is a measure of the resistance of the cell membrane to a chemical 660 compound. If the cell membrane is destroyed, this is a cause of the death of the cell, but it remains functional and the cell nevertheless stops producing protein, which suggests another mechanism of action of the chemical substance.
  • the cells are treated as in the determination of cell growth. After 16 hours of incubation with the various substances, the Cytotoxicity assay performed. For this purpose, 10 ⁇ L lysis buffer are first added to the positive controls and 45 min. incubated at 37 ° C and 5% C0 2 . Then the plates for 4 min. Centrifuged at 250g. 50 ⁇ L of the supernatant solution are aliquoted into a new 96-well plate and 50 ⁇ L of the substrate mix are added. The plate is covered with a film and 30 min. left in the dark at RT, the solution turning red. After the incubation period, 50 ⁇ L stop solution are added and the plate measured at 492 nm.
  • the cytotoxicity determination was carried out with two different cell lines.
  • the breast cancer cell line MCF 7 which is used for pre-screening
  • a human liver cancer cell line HEPG 2 which is used as a liver model.
  • Most of the compounds showed only low cytotoxicity against MCF 7 and HEPG-2.
  • 200 ul of a 100 mM methanolic aldehyde solution are mixed with 200 ul of a 100 mM amine solution and concentrated overnight. Now 200 ul of a 100 mM isonitrile and 200 ul of a 100 mM carboxylic acid solution are added; In order to increase the solubility, 25 ⁇ l dichloromethane are added and the plate is shaken at RT for 24 h.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Cytotoxicity determination (MCF-7, 710 HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: good inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: good inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus good inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: strong inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: no effect
  • Candida albicans good inhibition
  • Staphylococcus aureus no effect.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: strong effect
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, 810 HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: strong effect
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: low inhibition
  • Candida albicans good inhibition
  • Pseudomonas aeruginosa little effect
  • 835 Staphylococcus aureus medium inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Staphylococcus aureus medium inhibition.
  • Bacillus Subtilis strong inhibition
  • Candida albicans good inhibition
  • Pseudo onas aeruginosa good inhibition
  • Staphylococcus aureus medium inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Bacillus Subtilis no effect
  • Candida albicans no effect
  • Staphylococcus aureus good inhibition.
  • MCF-7 910 inhibition
  • HEPG-2 910 inhibition
  • MCF-7 IC 50 ⁇ 50 ⁇ M
  • HEPG-2 HEPG-2
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: strong inhibition
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Cytotoxicity determination (MCF-7, HEPG-2) mean cytotoxicity
  • Bacterial screening Bacillus subtilis: strong inhibition
  • Candida albicans
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition
  • Cytotoxicity determination (MCF-7, HEPG-2) low cytotoxicity toxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: strong inhibition; Staphylococcus aureus: good inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: no effect
  • Candida albicans strong inhibition
  • Staphylococcus aureus good inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria 970 Bacillus subtilis: strong inhibition
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition.
  • MCF-7 Cell proliferation inhibition
  • HEPG-2 Cell proliferation inhibition
  • MCF-7 HEPG-2
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: strong inhibition
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: strong effect; Candida albicans: 1015 strong inhibition; Pseudomonas aeruginosa: little effect; Staphylococcus aureus: strong inhibition.
  • HEPG-2 1025 (HEPG-2) IC 50 ⁇ 100 ⁇ M; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: good effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
  • MCF-7 Cell proliferation inhibition
  • HEPG-2 IC 50 ⁇ 50 ⁇ M
  • Cytotoxicity determination (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria Bacillus subtilis: no effect
  • Candida albicans good 1040 inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Screening for bacteria 1070 Bacillus subtilis: strong effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
  • Bacillus subtilis strong effect
  • Candida albicans good inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: no inhibition
  • Candida albicans strong inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: no inhibition
  • Candida albicans 1125 strong inhibition
  • Staphylococcus aureus no inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • HEPG-2 IC 50 ⁇ 100 ⁇ M; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: 1145 Bacillus subtilis: no inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
  • Bacillus subtilis strong inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus good inhibition.
  • HEPG-2 1165 (HEPG-2) IC 50 ⁇ 100 ⁇ M; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: strong inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus good inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: strong inhibition
  • Candida albicans good 1200 inhibition
  • Staphylococcus aureus good inhibition.
  • HEPG-2 IC 50 100 ⁇ M; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: 1210 Bacillus subtilis: no inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
  • HEPG-2 IC 50 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, 1220 HEPG-2) mean cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: good inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, 1230 HEPG-2) mean cytotoxicity
  • Bacterial screening Bacillus subtilis: good inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • MCF-7 1240 HEPG-2
  • MCF-7 1240 HEPG-2
  • MCF-7 medium cytotoxicity
  • Screening for bacteria Bacillus subtilis: good inhibition
  • Candida albicans good Inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 medium cytotoxicity
  • Bacterial screening Bacillus subtilis: good inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC50 ⁇ 100 ⁇ m
  • Cytotoxicity determination (MCF-7, HEPG-2) mean cytotoxicity
  • Bacterial screening Bacillus subtilis: good inhibition
  • Candida albicans good inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M
  • Determination of cytotoxicity (MCF-7, HEPG-2) low cytotoxicity
  • Bacterial screening Bacillus subtilis: good inhibition
  • Candida albicans good 1295 inhibition
  • Staphylococcus aureus strong inhibition.
  • HEPG-2 IC 50 ⁇ 100 ⁇ M; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity;

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The invention relates to 3-vinylpryrrole derivatives of general formula (I), wherein M represents a substituted peptide, a substituted hydantoin or thiohydantoin, tetrazole, lactam or lactone group, Y and Z independently represent a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl, alkenyl, alkinyl, aralkyl, aralkenyl, aralkinyl, cycloalkyl, cycloalkenyl, cycloalkinyl, cycloaralkyl, cycloaralkenyl, cycloaralkinyl, aryl, alkoxy or aralkoxy group or a heterocyclic ring, and X is an optionally substituted and/or an optionally anellated or heteroanellated 3-pyrrole ring, and X and Y or X and Z or N and Z form part of a cycle. The invention further relates to pharmaceutical compounds that contain at least one of the above-mentioned compounds in combination with conventional excipients and/or adjuvants.

Description

3-Vinylpyrrol-Derivate, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel 3-vinylpyrrole derivatives, process for their preparation and their use as medicines
Die vorliegende Erfindung betrifft neue 3-Vinylpyrrol-De- rivate, sie enthaltende pharmazeutische Zusammensetzungen, ihre Herstellung und Verwendung, insbesondere als tumor- und krebsauflösende und antibakterielle Arzneimittel.The present invention relates to new 3-vinylpyrrole derivatives, pharmaceutical compositions containing them, their preparation and use, in particular as tumor and cancer-dissolving and antibacterial drugs.
Krebs und Tumorerkrankungen gehören zu den problematischen Krankheitsbildern der Zivilisation. In vielen Fällen muss das Tumorgewebe operativ entfernt und/oder chemotherapeutisch behandelt werden. Trotzdem ist das Überleben der Patienten über einen längeren Zeitraum sehr un- gewiss. Weiterhin ist die chemotherapeutische und operative Behandlung häufig mit Schmerzen und anderweitigen Nachteilen für den Krebspatienten verbunden. Deshalb ist die Bereitstellung neuer und komplementärer Arzneimittel zur Behandlung von Tumor- und Krebserkrankungen von gro- ßem Interesse.Cancer and tumor diseases are among the problematic clinical pictures of civilization. In many cases, the tumor tissue has to be surgically removed and / or treated with chemotherapy. Nevertheless, the survival of the patient over a long period of time is very uncertain. Furthermore, the chemotherapeutic and surgical treatment is often associated with pain and other disadvantages for the cancer patient. Therefore, the provision of new and complementary drugs for the treatment of tumor and cancer diseases is of great interest.
Weiterhin besteht ein steigender Bedarf an neuen Antibiotika, da immer mehr Erreger gegen bekannte, bisher gut wirksame Antibiotika resistent werden.There is also an increasing need for new antibiotics, as more and more pathogens become resistant to known, previously effective antibiotics.
Aspergillamide A und B sind kürzlich beschriebene Naturstoffe marinen Ursprungs mit cytotoxischen Eigenschaften (Fenical et al., Tetrahedron 1998, 54, 13459).Aspergillamides A and B are recently described natural products of marine origin with cytotoxic properties (Fenical et al., Tetrahedron 1998, 54, 13459).
Es war daher die Aufgabe der vorliegenden Erfindung, neue Wirkstoffe bereitzustellen, die eine verbesserte bzw. komplementäre Wirkung bei der Prophylaxe bzw. Therapie von Krebs und Tumoren aufweisen.It was therefore the object of the present invention to provide new active ingredients which improve or have complementary effects in the prophylaxis or therapy of cancer and tumors.
Es war eine weitere Aufgabe der vorliegenden Erfindung, neue Wirkstoffe bereitzustellen, die eine verbesserte bzw. komplementäre Wirkung als Antibiotika aufweisen.It was a further object of the present invention to provide new active substances which have an improved or complementary effect as antibiotics.
Diese Aufgaben werden durch die Bereitstellung von 3- Vinylpyrrol-Derivaten der allgemeinen FormelThese tasks are accomplished by providing 3-vinyl pyrrole derivatives of the general formula
|_|| _ |
X N-M (I)X N-M (I)
YY
gelöst, worinsolved in what
M ein substituierter Peptid-, ein substituierter Hydantoin- oder Thiohydantoin-, Tetrazol-, Lactam- oder Lactonrest ist,M is a substituted peptide, a substituted hydantoin or thiohydantoin, tetrazole, lactam or lactone residue,
Y und Z unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, ein gegebenenfalls substituierter Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aral- kenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloal- kinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Alkoxy- oder Aralkoxyrest oder ein heterocycli- scher Ring sind, bevorzugt ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, stärker bevorzugt ein Wasserstoffatom, Fluor, Chlor, Brom oder Jod, am stärksten bevorzugt ein Wasserstoffatom oder Fluor, undY and Z independently of one another are a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl , Cycloaralkenyl, cycloaralkynyl, aryl, alkoxy or aralkoxy or a heterocyclic ring, are preferably a hydrogen atom, a halogen atom, a pseudohalogen, more preferably a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom or fluorine, and
X ein gegebenenfalls substituierter und/oder ein gegebenenfalls anellierter oder heteroanellierter 3-Pyrrolring ist, undX is an optionally substituted and / or an optionally fused or hetero-fused 3-pyrrole ring, and
X und Y oder X und Z oder N und Z Teil eines Cyclus sein können.X and Y or X and Z or N and Z can be part of a cycle.
Diese Verbindungen weisen eine hohe Wirksamkeit insbesondere bei der Krebs- und Tumorprophylaxe und -therapie auf .These compounds are particularly effective in cancer and tumor prophylaxis and therapy.
Außerdem weisen sie bei geringer Toxizität auch ein brei- tes antibakterielles Spektrum, speziell gegen gram-positive Keime und einige gram-negative Bakterien sowie My- cobakterien, Corneybakterien, Hae ophilus influenzae und anaerobe Keime auf. Diese Wirkung erlaubt die Verwendung der erfindungsgemäßen Wirkstoffe als Chemotherapeutika in der Human- und Tiermedizin.In addition, with low toxicity, they also have a broad antibacterial spectrum, especially against gram-positive bacteria and some gram-negative bacteria as well as mycobacteria, corney bacteria, Hae ophilus influenzae and anaerobic bacteria. This effect allows the use of the active compounds according to the invention as chemotherapeutic agents in human and veterinary medicine.
Damit können Krankheiten, ausgelöst durch gram-positive, sowie gram-negative Bakterien und bakterienähnliche Mikroorganismen wie Mycoplasmen, bekämpft oder geheilt wer- den.Diseases triggered by gram-positive and gram-negative bacteria and bacterial-like microorganisms such as mycoplasmas can thus be combated or cured.
Die erfindungsgemäßen Wirkstoffe können damit zur Prophylaxe und Chemotherapie von systemischen oder aber lokalen Infektionen in der Tier- wie in der Humanmedizin ange- wandt werden. In der gesamten Beschreibung und den Ansprüchen kann der Ausdruck "Alkyl" z.B. eine C1-.50 Alkylgruppe, bevorzugt eine Cι_i2 Alkylgruppe, vorzugsweise eine C -β Alkyl- 95 gruppe darstellen; so kann eine Alkylgruppe z.B. eine Methyl-, Ethyl-, Propyl-, Isopropyl- oder Butylgruppe sein;The active compounds according to the invention can thus be used for the prophylaxis and chemotherapy of systemic or local infections in both veterinary and human medicine. Throughout the description and the claims, the expression "alkyl" can represent, for example, a C1- .50 alkyl group, preferably a Cι_i2 alkyl group, preferably a C -β alkyl 95 group; for example an alkyl group can be a methyl, ethyl, propyl, isopropyl or butyl group;
ist der Ausdruck "Alk" z.B. in dem Ausdruck "Alkoxy" wie "Alkyl" definiert;is the term "alk" e.g. defined in the term "alkoxy" as "alkyl";
100 sind Aromaten oder Aryle bzw. entsprechende Reste bevorzugt substituierte oder gegebenenfalls unsubstituierte Phenyl-, Benzyl-, Naphthyl-, Biphenyl- oder Anthracen- gruppen oder aromatische Heterocyclen mit 5 oder 6 Ring-100 are aromatics or aryls or corresponding radicals, preferably substituted or unsubstituted phenyl, benzyl, naphthyl, biphenyl or anthracene groups or aromatic heterocycles with 5 or 6 ring
105 atomen;105 atoms;
ist der Ausdruck "Ar" z.B. in den Ausdrücken "Aralkyl" etc. und "Cycloaralkyl" etc. , wie "Aryl" definiert;the expression "Ar" is e.g. in the terms "aralkyl" etc. and "cycloaralkyl" etc. as defined "aryl";
110 kann der Ausdruck "Alkenyl" z.B. eine C2-10 Alkenyl- gruppe, vorzugsweise eine C2-6 Alkenylgruppe darstellen, die die Doppelbindung (en) an beliebiger Stelle aufweist und unsubstituiert oder substituiert sein kann; z.B. eine Ethenyl- , Propenyl-, Isopropenyl- oder Butenylgruppe;110 the term "alkenyl" can e.g. represent a C2-10 alkenyl group, preferably a C2-6 alkenyl group, which has the double bond (s) at any position and can be unsubstituted or substituted; e.g. an ethenyl, propenyl, isopropenyl or butenyl group;
115 kann der Ausdruck "Alkinyl" z.B. eine C2-10 Alkinyl- gruppe, vorzugsweise eine C2-6 Alkinylgruppe darstellen, die die Dreifachbindung(en) an beliebiger Stelle aufweist und unsubstituiert oder substituiert sein kann; z.B. eine115 the term "alkynyl" e.g. represent a C2-10 alkynyl group, preferably a C2-6 alkynyl group, which has the triple bond (s) at any position and can be unsubstituted or substituted; e.g. a
120 Ethinyl-, Propinyl-, Isopropinyl- oder Butinylgruppe kann der Ausdruck Cycloalkyl z.B. einen Carbocyclus mit 3 bis 20 C-Atomen, vorzugsweise mit 5 bis 15 C-Atomen und stärker bevorzugt mit 5 oder 6 C-Atomen darstellen, der 125 im Carbocyclus keine Mehrfachbindung aufweist;120 ethynyl, propynyl, isopropynyl or butynyl group the expression cycloalkyl can, for example, represent a carbocycle having 3 to 20 C atoms, preferably having 5 to 15 C atoms and more preferably having 5 or 6 C atoms, which 125 has no multiple bond in the carbocycle;
kann der Ausdruck Cycloalkenyl z.B. ein Carbocyclus mit 3 bis 20 C-Atomen, vorzugsweise mit 5 bis 15 C-Atomen und stärker bevorzugt mit 5 oder 6 C-Atomen sein, der im Car- 130 bocyclus mindestens eine Doppelbindung aufweist;the term cycloalkenyl e.g. be a carbocycle with 3 to 20 C atoms, preferably with 5 to 15 C atoms and more preferably with 5 or 6 C atoms, which has at least one double bond in the car 130 bocycle;
kann der Ausdruck Cycloalkinyl z.B. ein Carbocyclus mit 3 bis 20 C-Atomen, vorzugsweise mit 5 bis 15 C-Atomen und stärker bevorzugt mit 5 oder 6 C-Atomen sein, der im Car- 135 bocyclus mindestens eine Dreifachbindung aufweist;the term cycloalkynyl e.g. be a carbocycle with 3 to 20 carbon atoms, preferably with 5 to 15 carbon atoms and more preferably with 5 or 6 carbon atoms, which has at least one triple bond in the carbocycle 135;
kann der Ausdruck Alkoxy z.B. eine Gruppe der Formel -O- Alkyl, -O-Alkenyl, -O-Alkinyl, -O-Cycloalkyl, -O-Cycloal- kenyl, -O-Cycloalkinyl, -0-Aryl sein,the term alkoxy can e.g. be a group of the formula -O- alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-cycloalkenyl, -O-cycloalkynyl, -0-aryl,
140 kann der Ausdruck "substituiert" oder Substituent z.B. eine beliebige Substitution durch eine oder mehrere Alkyl-, Alkenyl-, Alkinyl-, ein- oder mehrwertige Alkanoyl- , Alkoxyalkanoyl-, oder Alkoxyalkylgruppen darstellen.140 the term "substituted" or substituent e.g. represent any substitution by one or more alkyl, alkenyl, alkynyl, mono- or polyvalent alkanoyl, alkoxyalkanoyl, or alkoxyalkyl groups.
145145
Der Ausdruck "anelliert" bzw. "heteroanelliert " kann z.B. bedeuten, daß an den 3-Pyrrolring weitere Ringe, vorzugsweise aromatische Ringe kondensiert sind.The expression "fused" or "hetero fused" can e.g. mean that further rings, preferably aromatic rings, are condensed on the 3-pyrrole ring.
150 Ein substituierte Hydantoin-/Thiohydantionrest kann z.B, ein Hydantoin-/Thiohydantionrest sein, der eine opder zwei Alkyl-und/oder Arylsubstituenten aufweist. Die Lactamreste und die Lactonreste weisen vorzugsweise 155 3,4,5,6,7, 8 oder 9 Ringatome auf.150 A substituted hydantoin / thiohydanion residue can be, for example, a hydantoin / thiohydanion residue which has one or two alkyl and / or aryl substituents. The lactam residues and the lactone residues preferably have 155 3,4,5,6,7, 8 or 9 ring atoms.
Die erfindungsgemäßen 3-Vinylpyrrol-Derivate können auch als Racemate, in D- oder L-Form oder als physiologisch verträgliche Salze vorliegen.The 3-vinylpyrrole derivatives according to the invention can also be present as racemates, in D or L form or as physiologically tolerable salts.
160160
Erfindungsgemäß kann M bevorzugt ein Peptidrest mit bis zu 10 Aminosäureresten, stärker bevorzugt ein Peptidrest mit bis zu 5 Aminosäureresten, am stärksten bevorzugt ein Peptidrest mit bis zu 3 Aminosäureresten sein, wobei un-According to the invention, M can preferably be a peptide residue with up to 10 amino acid residues, more preferably a peptide residue with up to 5 amino acid residues, most preferably a peptide residue with up to 3 amino acid residues,
165 ter Peptid z.B. N-terminal acylierte oder sulfonierte oder iV-terminal freie, sich wiederholende Einheiten aus N-alkylierten, iV-arylierten oder N-unalkylierten Amid- verknüpften a- , b-, g- oder -Aminosäuren natürlicher oder unnatürlicher Herkunft verstanden werden.165th peptide e.g. N-terminally acylated or sulfonated or iV-terminal free, repeating units from N-alkylated, iV-arylated or N-unalkylated amide-linked a-, b-, g- or -amino acids of natural or unnatural origin.
170170
Erfindungsgemäß kann X bevorzugt aus den folgenden Ringen ausgewählt werden: According to the invention, X can preferably be selected from the following rings:
Figure imgf000008_0001
Figure imgf000008_0001
wobei folgende Ringe stärker bevorzugt werden: the following rings are more preferred:
Figure imgf000009_0001
Figure imgf000009_0001
und folgende Ringe am stärksten bevorzugt werden:and the following rings are most preferred:
Figure imgf000009_0002
wobei die Reste R unabhängig voneinander Wasserstoffato- me, Halogenatome, Pseudohalogene, gegebenenfalls sub- stituierte Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralke- nyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloal- kinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl- , 190 Aryl-, Alkoxy-, Aralkoxyreste oder heterocyclische Ringe sind. Vorzugsweise sind alle Reste R ein Wasserstoffatom oder ein Rest R eine Gruppe der Formel -0-CH2-Ph und alle anderen Reste R Wasserstoffatome .
Figure imgf000009_0002
where the radicals R independently of one another are hydrogen atoms, halogen atoms, pseudohalogens, optionally sub- substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, 190 aryl, alkoxy, aralkoxy radicals or are heterocyclic rings. All radicals R are preferably a hydrogen atom or a radical R is a group of the formula -0-CH 2 -Ph and all other radicals R are hydrogen atoms.
195 Vorzugsweise wird M ausgewählt unter:195 M is preferably selected from:
Figure imgf000010_0001
Figure imgf000010_0001
220 worin bedeuten (es gelten die oben für die allgemeinen Substituenten oder Gruppen gegebenen Definitionen und konkreten Beispiele) :220 where mean (the above apply to the general Substituents or groups given definitions and concrete examples):
a) Rx und R2 unabhängig voneinander Wasserstoffatome, Ha- 225 logenatome, Pseudohalogene, gegebenenfalls substituiertea) R x and R 2 independently of one another hydrogen atoms, halogen atoms, pseudohalogens, optionally substituted
Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aral- kinyl-, Alkylaryl-, Cycloalkyl-, Cycloalkenyl-, Cyclo- alkinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl- , Aryl-, Alkoxy-, Aralkoxy- oder Hydroxyalkyl-reste oderAlkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, alkylaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, alkoxy, aralkoxy - or hydroxyalkyl radicals or
230 gegebenenfalls substituierte gegebenenfalls über230 optionally substituted optionally via
Alkylbrücken gebundene cyclische oder heterocyclische Ringe wie Cyclohexyl- Phenyl-, Benzyl-, Phenethyl-, Tolyl-, Piperidinyl, Indolyl-, Imidazolylringe, bevorzugt unabhängig voneinander Wasserstoffatome, MethylgruppenCyclic or heterocyclic rings bonded to alkyl bridges, such as cyclohexyl, phenyl, benzyl, phenethyl, tolyl, piperidinyl, indolyl, imidazolyl rings, preferably independently of one another hydrogen atoms, methyl groups
235 und/oder Gruppen der Formel -CH2-Ph; oder235 and / or groups of the formula -CH 2 -Ph; or
b) Ri und R2 bilden zusammen mit dem Kohlenstoff tom, an das sie gebunden sind, einen Cycloalkyl-, Cycloalkenyl- oder Cycloalkinylrest , der unsubstituiert oder substi-b) R 1 and R 2 together with the carbon tom to which they are attached form a cycloalkyl, cycloalkenyl or cycloalkynyl radical which is unsubstituted or unsubstituted.
240 tuiert sein und gegebenenfalls 1 oder 2 unter Sauerstoff und Stickstoffatomen ausgewählte Heteroatome enthalten kann, insbesondere einen Cyclohexyl- Phenyl-, Benzyl-, Phenethyl-, Piperidinylrest ,240 and can optionally contain 1 or 2 heteroatoms selected from oxygen and nitrogen atoms, in particular a cyclohexyl, phenyl, benzyl, phenethyl, piperidinyl residue,
245 c) R3, R6, R7, Rio, Rn, R12 , R13 und Ri4 das unter a) für Ri und R2 definierte, wobei Rβ auch Teil des gegebenenfalls durch R4 und R5 gebildeten Rings sein kann,245 c) R 3 , R 6 , R 7 , Rio, Rn, R12, R13 and R i4 that defined under a) for Ri and R 2 , where Rβ can also be part of the ring optionally formed by R 4 and R 5 ,
d) R4 und R5 unabhängig voneinander das unter a) für Ri 250 und R2 definierte, vorzugsweise beide Wasserstoffatome oder ein Wasserstoffatom und eine -CH2-CH (CH3) 2- Gruppe, oder R4 und R5 bilden zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, das unter b) für Ri und R2 definierte . Ferner werden erfindungsgemäß pharmazeutische Zusammen- Setzungen offenbart, die mindestens eine der vorstehenden Verbindungen gegebenenfalls in Kombination mit an sich üblichen Trägern und/oder Adjuvantien enthält.d) R 4 and R 5 independently of one another, preferably both hydrogen atoms or one hydrogen atom and a —CH 2 —CH (CH 3 ) 2 - group, or R 4 and R 5 form together, defined under a) for Ri 250 and R 2 with the carbon atom to which they are bound, that defined under b) for R 1 and R 2 . Furthermore, pharmaceutical compositions according to the invention are disclosed which contain at least one of the above compounds, if appropriate in combination with conventional carriers and / or adjuvants.
Weiter betrifft die Erfindung ein Verfahren a) zur Her- Stellung von erfindungsgemäßen Verbindungen, wobeiThe invention further relates to a method a) for producing compounds according to the invention, wherein
mindestens ein Isocyanid der allgemeinen Formel (II)at least one isocyanide of the general formula (II)
Figure imgf000012_0001
worin X, Y und N wie vorstehend definiert sind,
Figure imgf000012_0001
where X, Y and N are as defined above,
im Rahmen einer Ugi-Multi-Komponenten Reaktion mit mindestens einer Oxokomponente, mindestens einer Säurekomponente und gegebenenfalls einer oder mehreren Aminkompo- nenten umgesetzt wird.in the context of a Ugi multi-component reaction with at least one oxo component, at least one acid component and optionally one or more amine components.
Ugi-Multi-Komponentenreaktionen sind an sich bekannt (I. Ugi, editor, Isonitrile Chemistry, Academic Press, 1971, New York and London); der Rest M, der wie vorstehend de- finiert ist, kann dabei durch geeignete Auswahl der Komponenten in an sich üblicher Weise eingeführt werden.Ugi multi-component reactions are known per se (I. Ugi, editor, Isonitrile Chemistry, Academic Press, 1971, New York and London); the rest M, which is defined as above, can be introduced in a conventional manner by suitable selection of the components.
Die Reaktion kann in organischen Lösungsmitteln, Wasser oder ohne Lösungsmittel oder aber in einem Gemisch aus Wasser und organischem Lösungmittel ablaufen. Als Katalysatoren oder Reaktionsvermittler können z.B. Lewis Säuren wie beispielsweise BF3 OEt2, TiCl4, ZrCl4, Ti(OR)4, Zr(OR)4, ZnCl2, Al203, AlCl3, BC13, BX3, Broenstedt 280 Säuren wie beispielsweise HCl, HX, H2S04, H3P04, Polyphos- phorsäure, oder entsprechende polymer gebundene oder auf anorganischen Materialien wie Tonen aufgebrachte Katalysatoren oder Reaktionsvermittler eingesetzt werden.The reaction can take place in organic solvents, water or without solvent or in a mixture of water and organic solvent. Lewis acids such as BF 3 OEt 2 , TiCl 4 , ZrCl 4 , Ti (OR) 4 , Zr (OR) 4 , ZnCl 2 , Al 2 0 3 , AlCl 3 , BC1 3 , BX 3 , Broenstedt 280 acids such as HCl, HX, H 2 SO 4 , H 3 PO 4 , polyphosphoric acid, or corresponding polymer-bound or catalysts or reaction mediators applied to inorganic materials such as clays can be used.
285 Die Reaktion kann z.B. bei Temperaturen zwischen -70°C und 100 °C und/oder unter Einwirkung von Mikrowellen ablaufen,285 The reaction can e.g. run at temperatures between -70 ° C and 100 ° C and / or under the influence of microwaves,
Weiter betrifft die Erfindung ein Verfahren b) zur Herstellung von erfindungsgemäßen Verbindungen, wobei z.B. 290 klassische mehrstufige Kopplungsverfahren, die dem Fachmann an sich bekannt sind, angewendet werden können (z.B. Bodanszky, M. , Bodanszky, A. , The Practice of Peptide Chemistry, Springer Verlag, New York, 1994, 2 ed.).The invention further relates to a process b) for the preparation of compounds according to the invention, e.g. 290 classic multi-stage coupling methods which are known per se to the person skilled in the art can be used (e.g. Bodanszky, M., Bodanszky, A., The Practice of Peptide Chemistry, Springer Verlag, New York, 1994, 2 ed.).
295 Als Lösungsmittel gemäß Variante a. ) können295 As solvent according to variant a. ) can
protische Solventien Wasser, Alkohole wie Methanol, Etha- nol, Propanol, iso-Propanol, Butanol,protic solvents water, alcohols such as methanol, ethanol, propanol, isopropanol, butanol,
300 polar aprotische Solventien wie Dimethylformamid, Dime- thylacetamid, Dimethylsulfoxyd, Hexamethylphosphorsäu- retriamid, Acetonitril300 polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, acetonitrile
unpolar aprotische Solventien wie Chloroform, Dichlor- 305 methan, Tetrachlorkohlenstoff, Essigester, Ether, Hexan, Pentan, Benzol, Toluol, Clorbenzol, oder aber beliebige binäre oder ternäre Mischungen obiger Solventien, 310 oder aber zwei- oder dreiphasige Mischungen obiger Solventien verwendet werden.non-polar aprotic solvents such as chloroform, dichloromethane 305, carbon tetrachloride, ethyl acetate, ether, hexane, pentane, benzene, toluene, clorbenzene, or any binary or ternary mixtures of the above solvents, 310 or two or three-phase mixtures of the above solvents can be used.
Die erfindungsgemäßen 3-Vinylpyrrol-Derivate und die erfindungsgemäßen pharmazeutischen Zusammensetzung können 315 zur Therapie oder Prophylaxe von Tumor- oder Krebserkrankungen verwendet werden. Ferner können sie als Antibiotika verwendet werden.The 3-vinylpyrrole derivatives according to the invention and the pharmaceutical composition according to the invention can be used 315 for the therapy or prophylaxis of tumor or cancer diseases. They can also be used as antibiotics.
Dabei können sie lokal oder systemisch eingesetzt werden.They can be used locally or systemically.
320 Unter systemischer Applikation versteht man z.B. eine intravenöse, intrapleurale, intraperitoneale, rectale, orale, Applikation oder die Spülung von Körperhöhlen und Harnblase. Unter lokaler Applikation versteht man z.B. die subkutane, intrakutane, intratumorale, peritumorale320 Systemic application means e.g. an intravenous, intrapleural, intraperitoneal, rectal, oral, application or the flushing of body cavities and bladder. Local application means e.g. the subcutaneous, intracutaneous, intratumoral, peritumor
325 Applikation, z.B. in Form von Injektionslösungen, Injektionssuspensionen, Cremes, Lotionen, Gelen und Salben.325 application, e.g. in the form of solutions for injection, suspension for injection, creams, lotions, gels and ointments.
Die Lebenszeit von Tumorzellen in vitro wird durch die erfindungsgemäßen Wirkstoffe gegenüber Kontrollen signi- 330 fikant verkürzt.The lifetime of tumor cells in vitro is significantly shortened compared to controls by the active substances according to the invention.
Die erfindungsgemäßen Wirkstoffe besitzen bei systemischer und bei lokaler Application eine dosisabhängige tumorauflösende Wirkung. Die Dosis der erfindungsgemäßen 335 Wirkstoffe liegt bei therapeutischem Einsatz in der Größenordnung von 0,1 bis 100 mg/kg Körpergewicht, vorzugsweise von 2 bis 40 mg/kg Körpergewicht. In individuellen Fällen kann die Dosierung größer oder kleiner sein als oben angegeben.The active substances according to the invention have a dose-dependent tumor-dissolving effect when used systemically and locally. When used therapeutically, the dose of the 335 active substances according to the invention is in the order of 0.1 to 100 mg / kg body weight, preferably 2 to 40 mg / kg body weight. In individual cases, the dosage can be larger or smaller than mentioned above.
340340
Die erfindungsgemäßen Wirkstoffe können in bekannter Weise - dem individuellen Krankheitsbild entsprechend - in einer Formulierung angewendet werden, wie Pflaster, Salben, Pasten, Cremes, lösliche Pulver, Emulsionen, Pu- 345 der, Suspensionen und Injektionslösungen.The active compounds according to the invention can be used in a known manner - in accordance with the individual clinical picture - in a formulation, such as plasters, ointments, pastes, creams, soluble powders, emulsions, powders, suspensions and injection solutions.
Die erfindungsgemäßen Wirkstoffe können beispielhaft in einer Injektionslösung gegebenenfalls unter Zuhilfenahme von Lösungsvermittlern in verdünnten physiologisch ver- 350 träglichen Basen gelöst und durch Zugabe physiologisch verträglicher Säuren in eine injizierbare Form von pH 6 bis 8, insbesondere 6.9 bis 7.5 gebracht werden.The active compounds according to the invention can, for example, be dissolved in an injection solution, if appropriate with the aid of solubilizers, in dilute physiologically tolerable bases and brought into an injectable form of pH 6 to 8, in particular 6.9 to 7.5, by adding physiologically tolerable acids.
Beispielhafte physiologisch verträgliche Basen können 355 Hydroxide, Hydrogencarbonate, Carbonate der Alkali- und Erdalkalimetalle, insbesondere von Kalium, Natrium und Calcium sein.Exemplary physiologically compatible bases can be 355 hydroxides, hydrogen carbonates, carbonates of the alkali and alkaline earth metals, in particular of potassium, sodium and calcium.
Beispielhafte physiologisch verträgliche Säuren können 360 Milchsäure, Citronensäure, Weinsäure, Oxalsäure, Äpfelsäure, Essigsäure, Ameisensäure, Benzoesäure, Salicyl- säure, Salzsäure, Schwefelsäure oder Phosphorsäure sein.Exemplary physiologically compatible acids can be 360 lactic acid, citric acid, tartaric acid, oxalic acid, malic acid, acetic acid, formic acid, benzoic acid, salicylic acid, hydrochloric acid, sulfuric acid or phosphoric acid.
In der Formulierung der erfindungsgemäßen Wirkstoffe - 365 die allein oder zu mehreren eingesetzt werden können - können Hilfsstoffe beigemischt werden. Solche nichttoxischen und pharmazeutisch geeigneten Hilfsstoffe können feste, halbfeste oder flüssige Trägerstoffe, Emulgier- oder Dispergiermitel sein. Die Konzentration der erfin- 370 dungsgemäßen Wirkstoffe liegt zwischen 1 und 90 Gew.%, vorzugsweise 5 bis 50 Gew.%.In the formulation of the active substances according to the invention - 365 which can be used alone or in groups - auxiliary substances can be added. Such non-toxic and pharmaceutically suitable auxiliaries can be solid, semi-solid or liquid carriers, emulsifiers or dispersants. The concentration of invented 370 active substances according to the invention are between 1 and 90% by weight, preferably 5 to 50% by weight.
Die Dosierungseinheiten der erfindungsgemäßen Wirkstoffe können beispielsweise bestehen aus 1, 2, 3 oder 4 Einzel-The dosage units of the active compounds according to the invention can consist, for example, of 1, 2, 3 or 4 individual
375 dosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis. Eine Einzeldosis enthält vorzugsweise die Menge an Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder gar einem Viertel einer Tagesdosis entspricht.375 doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or even a quarter of a daily dose.
380380
Cremes, Pasten, Salben und Gele können neben dem oder den Wirkstoffen übliche dem Fachmann bekannte Trägerstoffe, beispielsweise Wachse, Paraffine, Stärken, pflanzliche und tierische Fette, Cellulosederivate, Traganth, Kiesel-In addition to the active ingredient (s), creams, pastes, ointments and gels can include customary excipients known to the person skilled in the art, for example waxes, paraffins, starches, vegetable and animal fats, cellulose derivatives, tragacanth, silica
385 säure, Talkum, Zinkoxid, Bentonite, Silicone, Polyäthyl- englycole.385 acid, talc, zinc oxide, bentonites, silicones, polyethyleneglycols.
Sprays und Puder können neben dem oder den Wirkstoffen übliche dem Fachmann bekannte Trägerstoffe, wie Milchzuk- 390 ker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsili- kat oder Polyamidpulver oder Gemische davon enthalten. Sprays können zusätzlich Treibmittel, beispielsweise Fluorchlorkohlenwasserstoffe enthalten .In addition to the active ingredient (s), sprays and powders can contain customary excipients known to the person skilled in the art, such as milk sugar, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder or mixtures thereof. Sprays can additionally contain blowing agents, for example chlorofluorocarbons.
395 Suppositorien können neben dem oder den Wirkstoffen übliche dem Fachmann bekannte Trägerstoffe, wie Polyäthylen- glycole, Fette oder Gemische davon enthalten.In addition to the active ingredient or ingredients, 395 suppositories can contain customary carriers known to the person skilled in the art, such as polyethylene glycols, fats or mixtures thereof.
Ebenso Gegenstand der vorliegenden Erfindung sind Anti- 400 körperkonjugate aus einem oder mehreren tumorspezifischen Antikörpern und einem oder mehreren erfindungsgemäßen Wirkstoffen, die unter tumorspezifischen physiologischen Bedingungen der Tumorumgebung oder des Tumorinneren abgespalten werden können. Diese Antikörperkonjugate können in Liposome verpackt sein.The present invention also relates to anti-body conjugates of one or more tumor-specific Antibodies and one or more active substances according to the invention which can be split off under tumor-specific physiological conditions of the tumor environment or of the tumor interior. These antibody conjugates can be packaged in liposomes.
Lokale Applikation der erfindungsgemässen Wirkstoffe kann durch Mikromaschinen erfolgen.Local application of the active ingredients according to the invention can be carried out by micromachines.
Die erfindungsgemäßen Wirkstoffe können zur Erzielung besserer lokal-relevanter Wirkstoffkonzentrationen und zur besseren Verträglichkeit in Liposome verpackt werden.The active substances according to the invention can be packaged in liposomes in order to achieve better locally relevant active substance concentrations and for better tolerability.
Soweit für die Behandlung der Tumorerkrankung oder für das Allgemeinbefinden des Patienten oder seiner Angehörigen von Nutzen können gleichzeitig oder in zeitlicher Versetzung Kombinationen mit anderen dem Patienten dienlichen Wirkstoffen verabreicht werden.To the extent that it is useful for the treatment of the tumor disease or for the general well-being of the patient or his relatives, combinations with other active substances serving the patient can be administered simultaneously or with a time delay.
Die vorliegende Erfindung umfasst auch die Verwendung der beschriebenen Wirkstoffe sowie pharmazeutischer Zubereitungen, die einen oder mehrere Wirkstoffe enthalten, zur Behandlung von atypischen Geweben in Mensch und Nutztier, die den Ablauf der normalen biologischen Funktionen hin- dern oder stören.The present invention also encompasses the use of the described active ingredients and pharmaceutical preparations which contain one or more active ingredients for the treatment of atypical tissues in humans and farm animals which prevent or disrupt the course of normal biological functions.
Solche Gewebe können beispielsweise sein:Such tissues can be, for example:
Gut- und bösartige Tumore solider oder cystischer Natur, Adenome, Cyst-Adenome, Papillome, Adenokarzinome auch vom cirrhoesen Typ, Basalzell-Karzinome , Sarkome, beispiels- weise Fibrosarkom, Liposarkom, Lymphosarkom, Rhab- domyosarkom, Myxosarkom, Chondrosarkom, Retikulumzellsar- kom, Morbus Hodgkin, embryonale Tumore beispielsweiseBenign and malignant tumors of solid or cystic nature, adenomas, cyst adenomas, papillomas, adenocarcinomas, also of the cirrhosis type, basal cell carcinomas, sarcomas, for example Wise fibrosarcoma, liposarcoma, lymphosarcoma, rhabdomyosarcoma, myxosarcoma, chondrosarcoma, reticular cell sarcoma, Hodgkin's disease, embryonic tumors, for example
435 Neuroblastom, Nephroblastom, Teratom, Adamintom,435 neuroblastoma, nephroblastoma, teratoma, adamintoma,
Retroblastom, Haemangiom, Chordom, Odontom, Craniopharyn- gom, Hamartome beispielsweise Lymphoangiom, Exostosen, Neurofibrantose, Melanome, Lymphome, Hepatoblastome, Mammakarzinome, Cervixkarzinom, Choriokarzinom, Adeno-Retroblastoma, haemangioma, chordoma, odontoma, craniopharyngoma, hamartoma, for example lymphoangioma, exostoses, neurofibrantosis, melanoma, lymphoma, hepatoblastoma, breast cancer, cervical cancer, choriocarcinoma, adeno-
440 acantom, Androblastom, Leiomyom, Arrhenoblastom, Sertoli- zelltumor, Theca- und Granulosa-Zell-Tumor , Germinom und Seminom, Ovarial- und Vulvakarzinom, Harnblasen- und Prostatakarzinom, durch Schistosomiasis hervorgerufene Tumoren, Astrocytom, Ependymogliome, Glioblastome, Medullo-440 acantoma, androblastoma, leiomyoma, arrhenoblastoma, sertoli cell tumor, theca and granulosa cell tumor, germinoma and seminoma, ovarian and vulvar carcinoma, bladder and prostate carcinoma, tumors caused by schistosomiasis, astrocytoma, ectrophobia, ectrophobia, ectrophobia
445 blastom, Oligodendrogliom, Spongioblastom, Meningeom sowie Tumoren der Schwan 'sehen Scheidenzellen, Pinealom, Haemangioblastom, Osteoclastom, Ewings Tumor, Multiples Myelom, Mxcosis fungoides, Burkitt-Tumor, Leukaemien, beispielsweise akute und chronische lymphatische Leukae-445 blastoma, oligodendroglioma, spongioblastoma, meningioma and tumors of the swan see vaginal cells, pinealoma, haemangioblastoma, osteoclastoma, Ewings tumor, multiple myeloma, mxcosis fungoides, Burkitt tumor, leukaemias, for example acute and chronic lymphocytic leukemia
450 mie, akute und chronische Granulocytenleukaemie, akute und chronische Monocytenleukaemie sowie Stammzellenleu- kaemie, Basaliom, Fibrom, Myom sowie die bei einem chirurgischen Einriff einer lokalen Injektion zugänglichen Metastasen sämtlicher Tumorformen.450 mie, acute and chronic granulocyte leukemia, acute and chronic monocyte leukemia as well as stem cell leukemia, basalioma, fibroma, myoma as well as the metastases of all types of tumors that are accessible during a surgical intervention by a local injection.
455 455
Beispiele:Examples:
Beispielhafte Arbeitsvorschrift zur Darstellung der ,ß- ungesättigten Isocyanide:Exemplary working procedure for the preparation of the ß-unsaturated isocyanides:
460460
N Na + O — r iϊ " - O -: N Na + O - r iϊ " - O -:
--N--N
Zu einer Lösung von 6,6 mmol Natriumbistrimethylsilylamid in 3 ml THF gibt man bei - 78 °C unter stetigem RührenA solution of 6.6 mmol sodium bistrimethylsilylamide in 3 ml THF is added at - 78 ° C with constant stirring
465 eine Lösung von 3,0 mmol Isocyanomethylphosphonsäuredie- thylester in 5 ml THF hinzu und läßt 15 min. rühren. Nun wird eine Lösung von 3,0 mmol Indol-3-carbaldehyd in 30 ml THF zugegeben und 20 h bei 0 °C gerührt. Zu der Reaktionsmischung werden 3,3 mmol Essigsäure in 1,5 ml THF465 add a solution of 3.0 mmol of isocyanomethylphosphonic acid diethyl ester in 5 ml of THF and leave for 15 min. stir. A solution of 3.0 mmol of indole-3-carbaldehyde in 30 ml of THF is then added and the mixture is stirred at 0 ° C. for 20 h. 3.3 mmol acetic acid in 1.5 ml THF are added to the reaction mixture
470 zugegeben und anschließend das Lösungsmittel abgezogen.470 added and then the solvent removed.
Der Rückstand wird mit 30 ml Essisäureethylester aufgenommen und zunächst mit 15 ml Phosphatpuffer pH 7 und anschließend mit 15 ml Wasser extrahiert. Die organischeThe residue is taken up in 30 ml of ethyl acetate and extracted first with 15 ml of phosphate buffer pH 7 and then with 15 ml of water. The organic
475 Phase wird über Magnesiumsufat getrocknet und eingeengt. Das Produkt wird über eine Kieselgelsäule mit Diethyl- ether gereinigt und sofort eingesetzt.475 phase is dried over magnesium sulfate and concentrated. The product is purified on a silica gel column with diethyl ether and used immediately.
2-( lH-Indol-3-yl)vinyl isocyanid2- (1H-indol-3-yl) vinyl isocyanide
480480
Summenformel: CnH8N2 Molgewicht: 168,20 g/molMolecular formula: C n H 8 N 2 molecular weight: 168.20 g / mol
Figure imgf000019_0001
HPLC/MS: m/z = 169 [M + H]+
Figure imgf000019_0001
HPLC / MS: m / z = 169 [M + H] +
'H-NMR (DMSO, 400 MHz): δ = 11,56 (s, IH, NH ) ; 7,77 - 7,05 (m, 4H, Indol); 7,66 (s, IH, 2-H); 7,25 (d, IH, 3J=14 Hz;'H NMR (DMSO, 400 MHz): δ = 11.56 (s, IH, NH); 7.77 - 7.05 (m, 4H, indole); 7.66 (s, IH, 2-H); 7.25 (d, IH, 3 J = 14 Hz;
485 ß-vinyl-H); 6,64 (d, IH, J=14 Hz; α-vinyl-H)485β-vinyl-H); 6.64 (d, IH, J = 14 Hz; α-vinyl-H)
13C-NMR (CD3OD, 100 MHz): δ = 187,97; 140,42; 133,20; 130,04; 125,77; 124,44; 124,40; 123,20; 122,57; 121,48; 113,97. 13 C NMR (CD 3 OD, 100 MHz): δ = 187.97; 140.42; 133.20; 130.04; 125.77; 124.44; 124.40; 123.20; 122.57; 121.48; 113.97.
490 2-( l-Methyl-lH-indol-3-yl)vinyl isocyanid490 2- (l-methyl-1H-indol-3-yl) vinyl isocyanide
Summenformel: Cλ2H10N2 Molgewicht: 182,23 g/mol Molecular formula: C λ2 H 10 N 2 molecular weight: 182.23 g / mol
Figure imgf000020_0001
Figure imgf000020_0001
HPLC-MS (ESI-TOF): m/z = 183 [M + H]+; 365 [Dimer + H]+ HPLC-MS (ESI-TOF): m / z = 183 [M + H] + ; 365 [dimer + H] +
495 'H-NMR (CDC13, 400 MHz): δ = 8,26 (s, IH, 2-H); 7,93 (d, IH, Ar); 7,51 (m, 3H, Ar); 7,02 (d, IH, ß-vinyl-H); 5,95 (d, IH, α-vinyl-H); 4,13 (s, 3H, CH3).495 'H NMR (CDC1 3 , 400 MHz): δ = 8.26 (s, IH, 2-H); 7.93 (d, IH, Ar); 7.51 (m, 3H, Ar); 7.02 (d, IH, β-vinyl-H); 5.95 (d, IH, α-vinyl-H); 4.13 (s, 3H, CH 3).
13C-NMR (CDC13, 100 MHz): 138.01; 131,00; 130,26; 125,47; 500 123,18; 121,30; 120,21; 110,28; 109,60; 106,60; 106,48; 106,35; 33,48(N-CH3) . 13 C NMR (CDC1 3 , 100 MHz): 138.01; 131.00; 130.26; 125.47; 500 123.18; 121.30; 120.21; 110.28; 109.60; 106.60; 106.48; 106.35; 33.48 (N-CH 3).
2- ( lH-Indol-3-yl ) -1-propenyl isocyanid2- (1H-indol-3-yl) -1-propenyl isocyanide
Summenformel: C12H10N2 Molecular formula: C 12 H 10 N 2
Molgewicht: 182,23 g/molMolecular weight: 182.23 g / mol
Ausbeute: 191 mg (34,9 % d. TH.)
Figure imgf000020_0002
Yield: 191 mg (34.9% of theory)
Figure imgf000020_0002
505 HPLC-MS (ESI-TOF): m/z = 183 [M + H] + ; 365, [Dimer +H] ;505 HPLC-MS (ESI-TOF): m / z = 183 [M + H] + ; 365, [Dimer + H];
547 [Trimer + H]+ 547 [trimer + H] +
'H-NMR (DMSO, 400 MHz): δ = 11,57 (br, IH, NH ) ; 7,77 (d,'H NMR (DMSO, 400 MHz): δ = 11.57 (br, IH, NH); 7.77 (d,
510 IH, 3J = 8,08 Hz, Indol); 7,70 (s, IH, Indol-2-H); 7,39510 IH, 3 J = 8.08 Hz, indole); 7.70 (s, IH, indole-2-H); 7.39
(d, IH, 3J = 7,93 Hz, indol); 7,14-7,04 (m, 2H, Indol);(d, IH, 3 J = 7.93 Hz, indole); 7.14-7.04 (m, 2H, indole);
6,51 (s, IH, ß-vinyl-H); 2,25 (s, 3H, α-vinyl-CH3) .6.51 (s, IH, β-vinyl-H); 2.25 (s, 3H, α-vinyl CH 3 ).
2-[5-(Benzyloxy ) -lH-pyrrolo[ 2 , 3-c ]pyridin-3-yl] vinyliso- 515 cyanid2- [5- (Benzyloxy) -IH-pyrrolo [2,3-c] pyridin-3-yl] vinyl iso-515 cyanide
Summenformel: C17H13N30 Molgewicht: 275,31 g/molMolecular formula: C 17 H 13 N 3 0 Molecular weight: 275.31 g / mol
Figure imgf000021_0001
Figure imgf000021_0001
HPLC-MS (ESI-TOF): m/z = 276 [M + H]+ HPLC-MS (ESI-TOF): m / z = 276 [M + H] +
520 'H-NMR (DMSO, 400 MHz): δ = 11.79 (s, IH, NH ) ; 8,37 (s, IH, 2-H); 7,85 (s, IH, 6-H); 7,42 - 7,20 (m, 5H, Ar);520 'H NMR (DMSO, 400 MHz): δ = 11.79 (s, IH, NH); 8.37 (s, IH, 2-H); 7.85 (s, IH, 6-H); 7.42 - 7.20 (m, 5H, Ar);
6,65 (d, IH, 3J=14,5 Hz, α-vinyl-H); 5,33 (s, 2H, -CH2- ) ;6.65 (d, IH, 3 J = 14.5 Hz, α-vinyl-H); 5.33 (s, 2H, -CH 2 -);
13C-NMR (DMSO, 100 MHz): δ = 162,22; 157,25; 153,05; 525 137,79; 134,95; 132,91; 131,48; 131,13; 129,69; 128,90; 128,29; 127,32; 126,72; 108,66; 108,03; 107,40; 105,56; 98,82; 97,20; 92,73; 67,27 (CH2) 13 C NMR (DMSO, 100 MHz): δ = 162.22; 157.25; 153.05; 525 137.79; 134.95; 132.91; 131.48; 131.13; 129.69; 128.90; 128.29; 127.32; 126.72; 108.66; 108.03; 107.40; 105.56; 98.82; 97.20; 92.73; 67.27 (CH 2 )
530530
1,5,6, 7-Tetrahydro-4H-indol-4-ylidenemethylisocyanid Summenformel : C10H10N2 Molgewicht : 158 , 20 g/mol1,5,6,7-tetrahydro-4H-indol-4-ylidenemethyl isocyanide Molecular formula: C 10 H 10 N 2 molecular weight: 158, 20 g / mol
Figure imgf000022_0001
Figure imgf000022_0001
HPLC-MS (ESI-TOF): m/z = 159 [M + H] + ; 317 [Dimer + H] + ; 475 [Trimer + H]+ HPLC-MS (ESI-TOF): m / z = 159 [ M + H] + ; 317 [dimer + H] + ; 475 [trimer + H] +
'H-NMR (CDC13, 400 MHz): δ = 8,00 ( br , IH, NH); 6,64 (d, IH, 2-H); 5,80 (d, IH, 3-H); 5,25 (s, IH, vinyl-H); 1,73- 2,58 (m, 6H, 3 x CH2)'H NMR (CDC1 3 , 400 MHz): δ = 8.00 (br, IH, NH); 6.64 (d, IH, 2-H); 5.80 (d, IH, 3-H); 5.25 (s, IH, vinyl-H); 1.73 - 2.58 (m, 6H, 3 x CH 2 )
13C-NMR (CDC13, 100 MHz): δ = 164,20; 163,68; 140,19 13 C NMR (CDC1 3 , 100 MHz): δ = 164.20; 163.68; 140.19
138,01; 133,35; 132,71; 117,93; 117,49; 114,84; 114,43138.01; 133.35; 132.71; 117.93; 117.49; 114.84; 114.43
106,87; 102,75; 99,69; 99,57; 29,72(CH2); 26,04(CH2) 22,97 (CH2)106.87; 102.75; 99.69; 99.57; 29.72 (CH 2); 26.04 (CH 2 ) 22.97 (CH 2 )
Beispielhafte Arbeitsvorschrift zur Darstellung der As- pergillamid-Analoga :Exemplary working procedure for the representation of the Aspergillamid analogues:
Figure imgf000022_0002
Figure imgf000022_0002
Man löst zunächst 3 mmol Methylamin in 3 ml Methanol und gibt 3 mmol frisch destillierten Phenylacetaldehyd hinzu. Anschließend werden 3 mmol der acetylierten Aminosäure zugegegeben. Das gereinigte Isonitril wird zugegeben und die Reaktionsmischung bei Raumtemperatur gerührt. Nach 24 h wird das Lösungsmittel abgezogen und der Rückstand mit 5 ml Essigester aufgenommen. Die organische Phase wird mit gesättigter Ammoniumchloridlösung und gesättigter Na- triumcarbonatlösung extrahiert und anschließend über Mag¬3 mmol of methylamine are first dissolved in 3 ml of methanol and 3 mmol of freshly distilled phenylacetaldehyde are added. Then 3 mmol of the acetylated amino acid are added. The purified isonitrile is added and the reaction mixture is stirred at room temperature. After 24 h, the solvent is stripped off and the residue is taken up in 5 ml of ethyl acetate. The organic phase will extracted with saturated ammonium chloride solution and saturated sodium carbonate solution and then over Mag¬
560 nesiumsulfat getrocknet und eingeengt. Zur Reinigung des Produkts wird zunächst über eine Kieselgelsäule mit Essigester als Eluent chromatographiert und anschließend eine weitere Kieselgelsäule mit Diethylether durchgeführt.560 sodium sulfate dried and concentrated. To purify the product, it is first chromatographed on a silica gel column with ethyl acetate as the eluent, and then another silica gel column is carried out with diethyl ether.
565565
2-(Acetylamino)-N-( l-benzyl-2-{ [2-( lH-indol-3- yl)vinyl]amino}-2-oxoethyl)-N, 4-dimethylpentanamid2- (acetylamino) -N- (l-benzyl-2- {[2- (lH-indol-3-yl) vinyl] amino} -2-oxoethyl) -N, 4-dimethylpentanamide
Summenformel: C28H34N403 Molgewicht: 474,61 g/molMolecular formula: C 28 H 34 N 4 0 3 molecular weight: 474.61 g / mol
Figure imgf000023_0001
Figure imgf000023_0001
570 HPLC/MS: 497 [M + Na]+, 475 [M + H]+, 317, 134570 HPLC / MS: 497 [M + Na] +, 475 [M + H] +, 317, 134
'H-NMR (DMSO, 400 MHz): δ = 10,40 (s, IH, NH); 9,20 (d, IH, NH); 7,66 (S,1H, 2H); 7.60-7,40 (m, 4H, Indol) ; 7 , 27- 7,25 (m, 5H, Ar); 7,05 (d, IH NH); 6,80 (m, IH, ß-vinyl-'H NMR (DMSO, 400 MHz): δ = 10.40 (s, IH, NH); 9.20 (d, IH, NH); 7.66 (S, 1H, 2H); 7.60-7.40 (m, 4H, indole); 7.27-7.25 (m, 5H, Ar); 7.05 (d, IH NH); 6.80 (m, IH, ß-vinyl
H); 5,95 (d, 3J=9 , 5 Hz, IH, α-vinyl-H); 5,21 (dd, IH, CH);H); 5.95 (d, 3 J = 9.5 Hz, IH, α-vinyl-H); 5.21 (dd, IH, CH);
575 4,91 (m, IH, CH); 3,36 (m, 2H, CH2); 3,05 (s, 3H, CH3 ) ;575 4.91 (m, IH, CH); 3.36 (m, 2H, CH 2); 3.05 (s, 3H, CH 3);
1,84 (s, 3H, CO-CH3); 1,55 (m, IH, (CH); 1,40 (m, 2H, CH2); 0,82 (d, 3H, CH3 ) ; 0,77 (d, 3H, CH3).1.84 (s, 3H, CO-CH3); 1.55 (m, IH, (CH); 1.40 (m, 2H, CH 2 ); 0.82 (d, 3H, CH 3 ); 0.77 (d, 3H, CH 3 ).
580 1- [ [ (Acetylamino) acetyl ] (methyl ) amino] -N- [ 2- ( lH-indol-3- yl )-l-propenyl]cyclohexanecarboxamid580 1- [[(Acetylamino) acetyl] (methyl) amino] -N- [2- (1H-indol-3-yl) -l-propenyl] cyclohexanecarboxamide
Summenformel: C23H30N4O3 Molecular formula: C 23 H 30 N 4 O 3
Molgewicht; 410,52 g/molmolecular weight; 410.52 g / mol
Figure imgf000024_0001
Figure imgf000024_0001
585 HPLC-MS (ESI-TOF): m/z = 411 [M+H]+ 585 HPLC-MS (ESI-TOF): m / z = 411 [M + H] +
'H-NMR (CD3OD, 400 MHz): δ = 7,83 (d, IH, Indol); 7,36- 7.01 (m, 4H, indol); 4,06 (s, 3H, N-CH3); 3,70 (s, 3H, =CH3); 3,59 (m,2H, CH2); 3,01 (s, 3H, CO-CH3); 2,13-1,16 590 (m, 10H, Cyclohexyl)'H NMR (CD 3 OD, 400 MHz): δ = 7.83 (d, IH, indole); 7.36 - 7.01 (m, 4H, indole); 4.06 (s, 3H, N-CH3); 3.70 (s, 3H, = CH3); 3.59 (m, 2H, CH 2); 3.01 (s, 3H, CO-CH3); 2.13-1.16 590 (m, 10H, cyclohexyl)
13C-NMR (CDC13, 100 MHz): δ =173,91 (C=0); 173,34 (C=0); 171,79 (C=0); 138,62; 126,00; 123,55; 122,53; 121,18; 120,32; 118,30; 117,91; 66,78; 58,32; 43,84; 33,14; 13 C NMR (CDC1 3 , 100 MHz): δ = 173.91 (C = 0); 173.34 (C = 0); 171.79 (C = 0); 138.62; 126.00; 123.55; 122.53; 121.18; 120.32; 118.30; 117.91; 66.78; 58.32; 43.84; 33.14;
595 31,65; 26,56; 23,63; 22,56; 18,50; 15,78595 31.65; 26.56; 23.63; 22.56; 18.50; 15.78
l-[ [ (Acetylamino) acetyl] (methyl) amino ]-N-( 1,5,6, 7-tetra- hydro-4H-indol-4-ylidenemethyl ) cyclohexanecarboxamide1- [[(Acetylamino) acetyl] (methyl) amino] -N- (1,5,6,7-tetra-hydro-4H-indol-4-ylidenemethyl) cyclohexanecarboxamide
Summenformel: C21H30N4O3 Molgewicht: 386,50 g/molMolecular formula: C 21 H 30 N 4 O 3 molecular weight: 386.50 g / mol
Figure imgf000024_0002
Figure imgf000024_0002
600600
HPLC-MS (ESI-TOF): m/z = 387 [M +H] + ; 369 [M -18] + ; 239 [M - C9H12N2 + H] + ; 112 [SB +H] + HPLC-MS (ESI-TOF): m / z = 387 [M + H] + ; 369 [M -18] + ; 239 [M - C 9 H 12 N 2 + H] + ; 112 [SB + H] +
13C-NMR (CD3OD, 100 MHz): δ = 176,44 (C=0); 173,66 (C=0); 605 173,24 (C=0) ; 171,70 (C=0); 131.17 (C); 130,09 (C); 121,28 (C); 120,42 (C); 118,47 (CH); 117,79; 117,47; 115,50; 111,87 (CH); 111,35; 104 , 86 ( =CHNH- ) ; 102,52(=CHNH-) ; 66,87 (C=CHNH); 66,79 (C=CHNH); 44,65; 43,94; 33,25 (CO-CH2-NH); 32,18; 31,84 (N-CH3), 31,73; 610 26,59; 25,79; 25,63; 24,76; 24,14; 23,79; 23,97; 22,76; 22,50 (CO-CH3). 13 C NMR (CD 3 OD, 100 MHz): δ = 176.44 (C = 0); 173.66 (C = 0); 605 173.24 (C = 0); 171.70 (C = 0); 131.17 (C); 130.09 (C); 121.28 (C); 120.42 (C); 118.47 (CH); 117.79; 117.47; 115.50; 111.87 (CH); 111.35; 104, 86 (= CHNH-); 102.52 (= CHNH-); 66.87 (C = CHNH); 66.79 (C = CHNH); 44.65; 43.94; 33.25 (CO-CH 2 -NH); 32.18; 31.84 (N-CH 3), 31.73; 610 26.59; 25.79; 25.63; 24.76; 24.14; 23.79; 23.97; 22.76; 22.50 (CO-CH 3 ).
Bestimmung des Zellwachstums und des IC50-WertesDetermination of cell growth and the IC 50 value
615615
Das Screening auf biologische Wirksamkeit der Substanzen erfolgte anhand des Zellproliferations-Assays über die Bestimmung der sauren Phosphatase Aktivität. Dieses Enzym gibt Aufschluß über die Wachstumsaktivität der Zellen. 620 Die Bestimmung wurde im 96er Format mit zwei verschiedenen humanen Krebzelllinien durchgeführt.The biological effectiveness of the substances was screened using the cell proliferation assay to determine the acid phosphatase activity. This enzyme provides information about the growth activity of the cells. 620 The determination was carried out in 96 format with two different human cancer cell lines.
Die Zellen werden zunächst auf 96er Deep-well-Platten in unterschiedlichen Konzentrationen gesplittet und zweiThe cells are first split on 96 deep well plates in different concentrations and two
625 Tage bei 37 °C mit Nährmedium inkubiert. Anschließend werden die Verbindungen in fünf verschiedenen Konzentrationen in Nährmedium auf die Zellen gegeben und weitere zwei Tage inkubiert. Zur Durchführung des Assays wird zunächst das Nährmedium abgesaugt und mit PBS-Puffer gewaschen,Incubated for 625 days at 37 ° C with nutrient medium. The compounds are then added to the cells in five different concentrations in nutrient medium and incubated for a further two days. To carry out the assay, the nutrient medium is first suctioned off and washed with PBS buffer,
630 anschließend wird die Substratlösung zugegeben. Man läßt eine weitere Stunde bei 37 °C inkubieren, während dieser Zeit verfärbt sich die Lösung gelblich. Die Enzymreaktion wird durch Zugabe von Natronlauge gestoppt, wobei die Gelbfärbung noch etwas verstärkt wird. Zur Kontrolle läßt630 then the substrate solution is added. The mixture is left to incubate for a further hour at 37 ° C., during which time the solution turns yellow. The enzyme reaction is stopped by adding sodium hydroxide solution, whereby the yellowing is increased somewhat. For checking purposes
635 man reines Medium, DSMO-haltiges Medium und ein bekanntes Zellgift mitlaufen. Als Zellgift wurde in dieser Arbeit Doxirubizin und Taxol verwendet. Die Auswertung des Assay erfolgt über die Bestimmung der optischen Dichte bei einer Wellenlänge von 405 nm.635 one run pure medium, DSMO-containing medium and a known cell poison. Doxirubizine and taxol were used as cell poison in this work. Evaluation of the assay is done by determining the optical density at a wavelength of 405 nm.
640640
Zur näheren Charakterisierung der biologischen Aktivität muß der lC50-Wert bestimmt werden. Hierzu wird der Zell- proliferations-Assay in fünf verschiedenen Konzentrationen durchgeführt. Der Mittelwert der DMSO-Kontrollen ent-The IC 50 value must be determined for a more detailed characterization of the biological activity. For this, the cell proliferation assay is carried out in five different concentrations. The mean value of the DMSO controls
645 spricht einem Wachstum von 100 % bzw. einer Inhibition von 0 %. Die einzelnen Messwerte werden in % Inhibition umgerechten und gegen den Logarithmus der Konzentration aufgetragen. Durch diese Messwerten wird eine sigmoidale Kurve gelegt, aus der nun der IC50-Wert, bei 50 % Inhibi-645 speaks growth of 100% or inhibition of 0%. The individual measured values are converted into% inhibition and plotted against the logarithm of the concentration. A sigmoidal curve is drawn from these measured values, from which the IC 50 value, at 50% inhibition
650 tion abgelesen werden kann.650 tion can be read.
Bestimmung der CytotoxizitätDetermination of cytotoxicity
Um die biologische Aktivität einer Substanz besser ein- 655 schätzen zu können, ist es sinnvoll, mehrere unterschiedliche Daten zu gewinnen. So sagt zum Beispiel die Cytotxizität einer Verbindung viel über deren Wirkungsmechanismus aus. Die Cytotoxizität ist ein Maß für die Beständigkeit der Zellmembran gegenüber einer chemischen 660 Verbindung. Wird die Zellmembran zerstört, ist dies eine Ursache für den Tod der Zelle, bleibt sie aber funktionsfähig und die Zelle stellt trotzdem ihre Proteinproduktion ein, so läßt dies auf einen anderen Wirkungsmechanismus der chemischen Substanz schließen.In order to be able to better estimate the biological activity of a substance, 655 it makes sense to obtain several different data. For example, the cytotoxicity of a compound says a lot about its mechanism of action. Cytotoxicity is a measure of the resistance of the cell membrane to a chemical 660 compound. If the cell membrane is destroyed, this is a cause of the death of the cell, but it remains functional and the cell nevertheless stops producing protein, which suggests another mechanism of action of the chemical substance.
665665
Zur Durchführung des Assays werden die Zellen wie bei der Bestimmung des Zellwachstums behandelt. Nach 16 Stunden Inkubation mit den verschiedenen Substanzen wird der Cytotoxizität-Assay durchgeführt. Hierzu werden zunächst zu den positiv Kontrollen 10 μL Lysepuffer zugegeben und 45 min. bei 37 °C und 5% C02 inkubiert. Anschließend werden die Platten für 4 min. bei 250g zentrifugiert . Von der überstehenden Lösung werden 50 μL in eine neue 96er Platte aliquotiert und 50μL des Substrat-Mix zugegeben. Die Platte wird mit einer Folie bedeckt und 30 min. bei RT im Dunkeln stehen gelassen, wobei eine Rotfärbung der Lösung eintritt. Nach der Inkubationszeit werden 50μL Stopp-löung zugegeben und die Platte bei 492 nm vermessen.To carry out the assay, the cells are treated as in the determination of cell growth. After 16 hours of incubation with the various substances, the Cytotoxicity assay performed. For this purpose, 10 μL lysis buffer are first added to the positive controls and 45 min. incubated at 37 ° C and 5% C0 2 . Then the plates for 4 min. Centrifuged at 250g. 50 μL of the supernatant solution are aliquoted into a new 96-well plate and 50 μL of the substrate mix are added. The plate is covered with a film and 30 min. left in the dark at RT, the solution turning red. After the incubation period, 50μL stop solution are added and the plate measured at 492 nm.
Die Cytotoxizitätsbestimmung wurde mit zwei verschiedenen Zelllinien durchgeführt. Zum einen die Brustkrebszelllinie MCF 7 die zum preScreening verwendet wird, und zum anderen eine humane Leberkrebszelllinie HEPG 2, die als Lebermodell Einsatz findet. Von den Verbindungen zeigten die meisten nur eine geringe Cytotoxizität gegen MCF 7 und HEPG-2 auf.The cytotoxicity determination was carried out with two different cell lines. On the one hand, the breast cancer cell line MCF 7, which is used for pre-screening, and on the other hand, a human liver cancer cell line HEPG 2, which is used as a liver model. Most of the compounds showed only low cytotoxicity against MCF 7 and HEPG-2.
Allgemeine Synthese der Verbindungen 5 - 36General synthesis of compounds 5-36
200 μl einer 100 mM methanolischen Aldehydlösung werden mit 200 μl einer 100 mM Aminlösung versetzt und über Nacht eingengt. Nun werden 200 μl einer 100 mM Isonitril- und 200 μl einer 100 mM Carbonsäurelösung zugegeben; um die Löslichkeit zu erhöhen werden 25 μl Dichlormethan zugegeben und die Platte 24 h bei RT geschüttelt.200 ul of a 100 mM methanolic aldehyde solution are mixed with 200 ul of a 100 mM amine solution and concentrated overnight. Now 200 ul of a 100 mM isonitrile and 200 ul of a 100 mM carboxylic acid solution are added; In order to increase the solubility, 25 μl dichloromethane are added and the plate is shaken at RT for 24 h.
Das Lösungsmittel wird vollständig entfernt. Mit Methanol aufgefüllt (definiertes Volumen). Für das biologische 700 Screening werden Aliquots auf eine weitere Platte gegeben, das Lösungsmittel entfernt und mit DMSO auf eine Konzentration von 20 mM auffüllen.The solvent is completely removed. Filled with methanol (defined volume). For the biological 700 screening aliquots are placed on a further plate, the solvent removed and made up to a concentration of 20 mM with DMSO.
Beispiel: 2- (Acetylamino )-N- ( l-benzyl-2-{ [2-( lH-indol-3- 705 yl)vinyl]amino}-2-oxoethyl)-N,4-dimethylpentanamidExample: 2- (acetylamino) -N- (l-benzyl-2- {[2- (lH-indol-3-705 yl) vinyl] amino} -2-oxoethyl) -N, 4-dimethylpentanamide
Figure imgf000028_0001
Figure imgf000028_0001
Molecular Weight =474.61 Molecular Formula =C28H3 N403Molecular Weight = 4 7 4 .61 Molecular Formula = C28H3 N403
[M+H]+. Found ISP-TOF-MS: 475.2762 [M+H]+, 497.2679[M + H] +. Found ISP-TOF-MS: 475.2762 [M + H] +, 497.2679
[M+Na]. Zellproliferationshemmung (MCF-7): IC50 < lμM,[M + Na]. Cell proliferation inhibition (MCF-7): IC 50 <lμM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 710 HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus : starke Hemmung.(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, 710 HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 2- (Acetylamino )-N-benzyl-N- ( 2-{ [ 2- ( lH-indol-3- 715 yl )vinyl ] amino}-l , l-dimethyl-2-oxoethyl ) -4-methylpentan- amidExample: 2- (acetylamino) -N-benzyl-N- (2- {[2- (lH-indol-3-715 yl) vinyl] amino} -l, l-dimethyl-2-oxoethyl) -4-methylpentane - amide
Figure imgf000028_0002
Figure imgf000028_0002
Molecular Weight = 88.64 Molecular Formula =C29H36N 03Molecular Weight = 88.64 Molecular Formula = C29H36N 03
[M+Na]+. Found ISP-TOF-MS: 511.2867 [M+Na]. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; 720 Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cyto- toxizität; Screening auf Bakterien: Bacillus Subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphyloko- kus aureus: starke Hemmung.[M + Na] +. Found ISP-TOF-MS: 511.2867 [M + Na]. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM; 720 cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity toxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphyloccus aureus: strong inhibition.
725 Beispiel: 1- [ [ 2- (Acetylamino)-4-methylpenta- noyl] (cyclohexyl ) amino]-N- [ 2- ( lH-indol-3- y1 )viny1 ]cyclohexanecarboxamide725 Example: 1- [[2- (acetylamino) -4-methylpentanoyl] (cyclohexyl) amino] -N- [2- (1H-indol-3-y1) vinyl1] cyclohexanecarboxamide
Figure imgf000029_0001
Figure imgf000029_0001
Molecular Weight =520.72 Molecular Formula =C31 H44N403Molecular Weight = 520.72 Molecular Formula = C31 H4 4 N 4 03
[M+H]+. Found ISP-TOF-MS: 521.3526 [M+H]+, 543,3155[M + H] +. Found ISP-TOF-MS: 521.3526 [M + H] +, 543.3155
730 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,730 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
735735
Beispiel: 2- (Acetylamino) -N- ( 2-{ [2-( lH-indol-3- yl )vinyl ] amino}-1 , l-dimethyl-2-oxoethyl ) -4-methyl-N- phenylpentanamidExample: 2- (acetylamino) -N- (2- {[2- (lH-indol-3-yl) vinyl] amino} -1, l-dimethyl-2-oxoethyl) -4-methyl-N-phenylpentanamide
Figure imgf000029_0002
Figure imgf000029_0002
Molecular Weight =474.61 Molecular Formula =C28H34N403Molecular Weight = 474.61 Molecular Formula = C28H34N403
740 [M+Na]+. Found ISP-TOF-MS: 597.2660 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphyloko- kus aureus: gute Hemmung.740 [M + Na] +. Found ISP-TOF-MS: 597.2660 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
Beispiel: 2- (Acetylamino )-N- [ l-benzyl-2-( {2-f 5- (benzyloxy)-lH-pyrrolo[2,3-c]pyridin-3-yl]vinyl}amino)-2- oxoethyl]-N, 4-dimethylpentanamidExample: 2- (acetylamino) -N- [l-benzyl-2- ({2-f 5- (benzyloxy) -lH-pyrrolo [2,3-c] pyridin-3-yl] vinyl} amino) -2 - oxoethyl] -N, 4-dimethylpentanamide
Figure imgf000030_0001
Figure imgf000030_0001
Molecular Weight =581.72 Molecular Formula =C3 H39N504Molecular Weight = 581.72 Molecular Formula = C3 H39N504
[M+HJ+. Found ISP-TOF-MS: 582.3274 [M+H]+; 5604.3071[M + HJ +. Found ISP-TOF-MS: 582.3274 [M + H] +; 5604.3071
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 2- (Acetylamino) -N-benzyl-N- [ 2- ( {2- [5- (benzyloxy ) -lH-pyrrolo[ 2 , 3-c ]pyridin-3-yl ]vinyl}amino )- 1 , l-dimethyl-2-oxoethyl]-4-methylpentanamidExample: 2- (acetylamino) -N-benzyl-N- [2- ({2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) - 1 , l-dimethyl-2-oxoethyl] -4-methylpentanamide
Figure imgf000030_0002
Figure imgf000030_0002
Molecular Weight =595 75 Molecular Formula =C35H 1 N504Molecular Weight = 595 75 Molecular Formula = C35H 1 N504
[M+Na]+. Found ISP-TOF-MS: 618,3023 [M+Na]+. Zellprolife- rationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cyto¬[M + Na] +. Found ISP-TOF-MS: 618.3023 [M + Na] +. Zellprolife- ration inhibition (MCF-7): IC 50 < 50 μm, (HEPG-2) IC 50 <100 μm; Cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity
765 toxizität; Screening auf Bakterien: Bacillus Subtilis: keine Wirkung; Candida albicans: gute Hemmung; Staphylo- kokus aureus: keine Wirkung.765 toxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: good inhibition; Staphylococcus aureus: no effect.
Beispiel : 1- [ [ 2- (Acetylamino ) -4-methylpenta- 770 noyl] (cyclohexyl ) amino]-N-{2- [ 5- (benzyloxy )-lH- pyrrolo[ 2 , 3-c ]pyridin-3-yl ]vinyl}cyclohexanecarboxamideExample: 1- [[2- (acetylamino) -4-methylpenta- 770 noyl] (cyclohexyl) amino] -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridine-3 -yl] vinyl} cyclohexane carboxamides
Figure imgf000031_0001
Figure imgf000031_0001
Molecular Weight =627.83 Molecular Formula =C37H49N504Molecular Weight = 627.83 Molecular Formula = C37H49N504
[M+H]+. Found ISP-TOF-MS: 628,3926 [M+H]+; 650,3768[M + H] +. Found ISP-TOF-MS: 628.3926 [M + H] +; 650.3768
[M+Na]+. Zellproliferationshem ung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
775 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: keine Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: keine Wirkung.775 (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: good inhibition; Staphylococcus aureus: no effect.
780 Beispiel: 2- (Acetylamino) -N- [ 2- ( {2- [ 5- (benzyloxy ) -1H- pyrrolo[ 2 , 3-c ] pyridin-3-yl ]vinyl}amino) -1 , l-dimethyl-2- oxoethyl ] -4-methyl-N-phenylpentanamid
Figure imgf000032_0001
780 Example: 2- (acetylamino) -N- [2- ({2- [5- (benzyloxy) -1H- pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) -1, l- dimethyl-2-oxoethyl] -4-methyl-N-phenylpentanamide
Figure imgf000032_0001
Molecular Weight =581.72 Molecular Formula =C34H39N504Molecular Weight = 581.72 Molecular Formula = C34H39N504
[M+H]+. Found ISP-TOF-MS: 582,2747 [M+H]+; 604,299[M + H] +. Found ISP-TOF-MS: 582.2747 [M + H] +; 604.299
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Wirkung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: strong effect; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 4-[ [ 2- (Acetylamino ) -4-methylpentanoyl ] (5- hydroxypentyl ) amino] -l-benzyl-N-[2- ( lH-indol-3- yl)vinyl] -4-piperidinecarboxamidExample: 4- [[2- (acetylamino) -4-methylpentanoyl] (5-hydroxypentyl) amino] -l-benzyl-N- [2- (1H-indol-3-yl) vinyl] -4-piperidinecarboxamide
Figure imgf000032_0002
Figure imgf000032_0002
Molecular Weight =615.82 Molecular Formula =C36H49N504Molecular Weight = 615.82 Molecular Formula = C36H49N504
[M+H]+. Found ISP-TOF-MS: 616,3891 [M+H]+; 638,3887[M + H] +. Found ISP-TOF-MS: 616.3891 [M + H] +; 638.3887
[M+Na] + . Zellproliferationshemmung (MCF-7): IC50 < lμM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lμM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Wirkung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung. Beispiel : 2- (Acetylamino ) -N- [ 2- ( lH-indol-3-yl ) ethyl ] -N- ( 2-{ [ 2- ( lH-indol-3-yl )vinyl ] amino}-2-oxoethyl ) -4-methyl- !05 pentanamid(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: Bacillus subtilis: strong effect; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition. Example: 2- (acetylamino) -N- [2- (lH-indol-3-yl) ethyl] -N- (2- {[2- (lH-indol-3-yl) vinyl] amino} -2- oxoethyl) -4-methyl-! 05 pentanamide
Figure imgf000033_0001
Figure imgf000033_0001
Molecular Weight =513.65 Molecular Formula =C30H35N5O3Molecular Weight = 513.65 Molecular Formula = C30H35N5O3
[M+H]+. Found ISP-TOF-MS: 514,3009 [M+H]+; 536,2802[M + H] +. Found ISP-TOF-MS: 514.3009 [M + H] +; 536.2802
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 810 HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Wirkung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 810 HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: strong effect; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
Beispiel : l-{ [ 2- (Acetylamino) -4-methylpentanoyl ] [ 3- ( 1H- 815 imidazol-1-yl )propyl ] amino}-N- [ 2- ( lH-indol-3- yl)vinyl ]cyclohexanecarboxamidExample: l- {[2- (acetylamino) -4-methylpentanoyl] [3- (1H- 815 imidazol-1-yl) propyl] amino} -N- [2- (lH-indol-3-yl) vinyl] cyclohexanecarboxamid
Figure imgf000033_0002
Figure imgf000033_0002
Molecular Weight =546.72 Molecular Formula =C31 H42N603Molecular Weight = 546.72 Molecular Formula = C31 H42N603
[M+H]+. Found ISP-TOF-MS: 547,3627 [M+H]+; 569,3380 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, 820 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: mittlere Hemmung.[M + H] +. Found ISP-TOF-MS: 547.3627 [M + H] +; 569.3380 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, 820 (HEPG-2) IC 50 <100µM; Cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: strong effect; Candida albicans: good inhibition; Staphylococcus aureus: medium inhibition.
S25 Beispiel: 3- [ 2- (Acetylamino) -4-methylpentanoyl ] -N- [ 2- ( 1H- indol-3-yl ) vinyl ]-2 , 2-dimethyl-l , 3-thiazolidine-4-carbox- a ideS25 Example: 3- [2- (acetylamino) -4-methylpentanoyl] -N- [2- (1H-indol-3-yl) vinyl] -2, 2-dimethyl-l, 3-thiazolidine-4-carbox- a ide
Figure imgf000034_0001
Figure imgf000034_0001
Molecular Weight =456.61 Molecular Formula =C24H32N403SMolecular Weight = 456.61 Molecular Formula = C24H32N403S
[M+H]+. Found ISP-TOF-MS: 457,2211 [M+H]+; 479,2246[M + H] +. Found ISP-TOF-MS: 457.2211 [M + H] +; 479.2246
830 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 6,25μM,830 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <6.25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: geringe Hemmung; Candida albicans: gute Hemmung; Pseudomonas aeruginosa: geringe Wirkung; 835 Staphylokokus aureus: mittlere Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: low inhibition; Candida albicans: good inhibition; Pseudomonas aeruginosa: little effect; 835 Staphylococcus aureus: medium inhibition.
Beispiel: 4-[ [ 2- (Acetylamino) -4-methylpentanoyl ] (5- hydroxypenty1 ) amino ] -1-benzy1-N- {2- [ 5- ( benzyloxy ) -1H- pyrrolo[ 2 , 3-c ]pyridin-3-yl ]vinyl}-4-piperidinecarboxamidExample: 4- [[2- (acetylamino) -4-methylpentanoyl] (5-hydroxypenty1) amino] -1-benzy1-N- {2- [5- (benzyloxy) -1H-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -4-piperidinecarboxamide
Figure imgf000034_0002
Figure imgf000034_0002
Molecular Weight =722.94 84 0 Molecular Formula =C42H54N605 [M+H]+. Found ISP-TOF-MS: 723,4441 [M+H]+; 745,4221Molecular Weight = 722.94 84 0 Molecular Formula = C 4 2H54N605 [M + H] +. Found ISP-TOF-MS: 723.4441 [M + H] +; 745.4221
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 12,5μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <12.5μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: 845 Bacillus Subtilis: keine Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: mittlere Hemmung.(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: 845 Bacillus Subtilis: no effect; Candida albicans: good inhibition; Staphylococcus aureus: medium inhibition.
Beispiel : 2- (Acetylamino ) -N- [ 2- ( {2- [ 5- ( benzyloxy ) -1H- pyrrolo[ 2 , 3-c ]pyridin-3-yl ]vinyl}amino) -2-oxoethyl ] -N- [ 2- 850 ( lH-indol-3-yl)ethyl]-4-methylpentanamideExample: 2- (acetylamino) -N- [2- ({2- [5- (benzyloxy) -1H- pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) -2-oxoethyl] - N- [2-850 (1H-indol-3-yl) ethyl] -4-methylpentanamide
Figure imgf000035_0001
Figure imgf000035_0001
[M+H]+. Found ISP-TOF-MS: 621,3364 [M+H]+; 643,3231[M + H] +. Found ISP-TOF-MS: 621.3364 [M + H] +; 643.3231
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 855 HEPG-2) geringe Cytotoxizität; Screening auf Bakterien:(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 855 HEPG-2) low cytotoxicity; Screening for bacteria:
Bacillus Subtilis: starke Hemmung; Candida albicans: gute Hemmung; Pseudo onas aeruginosa: gute Hemmung; Staphylokokus aureus: mittlere Hemmung.Bacillus Subtilis: strong inhibition; Candida albicans: good inhibition; Pseudo onas aeruginosa: good inhibition; Staphylococcus aureus: medium inhibition.
860860
Beispiel: l-{ [2- (Acetylamino )-4-methylpentanoyl] [3-( 1H- imidazol-1-yl )propyl ] amino}-N-{2- [ 5- (benzyloxy ) -1H- pyrrolof 2 , 3-c ]pyridin-3-yl ]vinyl}cyclohexanecarboxamid Example: 1- {[2- (acetylamino) -4-methylpentanoyl] [3- (1H-imidazol-1-yl) propyl] amino} -N- {2- [5- (benzyloxy) -1H-pyrrolof 2, 3-c] pyridin-3-yl] vinyl} cyclohexanecarboxamide
Figure imgf000036_0001
Figure imgf000036_0001
Molecular Weight =653.83 Molecular Formula =C37H 7N704Molecular Weight = 653.83 Molecular Formula = C37H 7N704
865 [M+H]+. Found ISP-TOF-MS: 654,3931 [M+H]+; 676,3875865 [M + H] +. Found ISP-TOF-MS: 654.3931 [M + H] +; 676.3875
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 6,25μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <6.25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: gute Hemmung; Candida albicans: gute 870 Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: good 870 inhibition; Staphylococcus aureus: good inhibition.
Beispiel : 3- [ 2- (Acetylamino) -4-methylpentanoyl ] -N-{2- [ 5- ( benzyloxy ) -lH-pyrrolo [ 2 , 3-c ] pyridin-3-yl ]vinyl}-2 , 2-di- methyl-1 , 3-thiazolidine-4-carboxamidExample: 3- [2- (acetylamino) -4-methylpentanoyl] -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -2, 2 -dimethyl-1, 3-thiazolidine-4-carboxamide
Figure imgf000036_0002
Figure imgf000036_0002
Molecular Weight =563.72 875 Molecular Formula =C30H37N5O4SMolecular Weight = 563.72 875 Molecular Formula = C30H37N5O4S
[M+H]+. Found ISP-TOF-MS: 564,2397 [M+H]+; 586,2647[M + H] +. Found ISP-TOF-MS: 564.2397 [M + H] +; 586.2647
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 6,25μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <6.25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: 880 Bacillus Subtilis: gute Hemmung; Candida albicans: geringe Hemmung; Staphylokokus aureus: gute Hemmung. Beispiel : 1-Acetyl-N- ( l-benzyl-2-{ [ 2- ( lH-indol-3- yl)vinyl ]amino}-2-oxoethyl ) -N-methyl-2-pyrrolidinecarbox- 885 amid(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: 880 Bacillus Subtilis: good inhibition; Candida albicans: low inhibition; Staphylococcus aureus: good inhibition. Example: 1-acetyl-N- (1-benzyl-2- {[2- (1H-indol-3-yl) vinyl] amino} -2-oxoethyl) -N-methyl-2-pyrrolidinecarbox-885 amide
Figure imgf000037_0001
Figure imgf000037_0001
Molecular Weight =458.57 Molecular Formula =C27H30N4O3Molecular Weight = 458.57 Molecular Formula = C27H30N4O3
[M+H]+. Found ISP-TOF-MS: 459,2508 [M+H]+; 481,2368[M + H] +. Found ISP-TOF-MS: 459.2508 [M + H] +; 481.2368
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lμM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lμM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 890 HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien:(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 890 HEPG-2) low cytotoxicity; Screening for bacteria:
Bacillus Subtilis: keine Wirkung; Candida albicans: keine Wirkung; Staphylokokus aureus: gute Hemmung.Bacillus Subtilis: no effect; Candida albicans: no effect; Staphylococcus aureus: good inhibition.
Beispiel : 1-Acetyl-N-benzyl-N- ( 2-{ [ 2- ( lH-indol-3- 895 yl)vinyl ]amino}-l , l-dimethyl-2-oxoethyl )-2-pyrrolidine- carboxamidExample: 1-acetyl-N-benzyl-N- (2- {[2- (lH-indol-3- 895 yl) vinyl] amino} -l, l-dimethyl-2-oxoethyl) -2-pyrrolidine carboxamide
Figure imgf000037_0002
Figure imgf000037_0002
Molecular Weight =472.59 Molecular Formula =C28H32N403Molecular Weight = 472.59 Molecular Formula = C28H32N403
[M+H]+. Found ISP-TOF-MS: 473,2181 [M+H]+; 495,2520[M + H] +. Found ISP-TOF-MS: 473.2181 [M + H] +; 495.2520
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
900 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: gute Hemmung. 905 Beispiel : 1-Acetyl-N-cyclohexyl-N- [ 1- ( { [ 2- ( lH-indol-3- yl ) vinyl ] amino}carbonyl ) cyclohexyl ] -2-pyrrolidinecarbox- amid900 (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: good inhibition. 905 Example: 1-acetyl-N-cyclohexyl-N- [1- ({[2- (1H-indol-3-yl) vinyl] amino} carbonyl) cyclohexyl] -2-pyrrolidine carboxamide
Figure imgf000038_0001
Figure imgf000038_0001
Molecular Weight =504.68 Molecular Formula =C30H40N4O3Molecular Weight = 504.68 Molecular Formula = C30H40N4O3
[M+H]+. Found ISP-TOF-MS: 505,3526 [M+H]+. Zellprolifera¬[M + H] +. Found ISP-TOF-MS: 505.3526 [M + H] +. Zellprolifera¬
910 tionshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.910 inhibition (MCF-7): IC 50 <50μM, (HEPG-2) IC 50 <100μM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
915915
Beispiel: l-Acetyl-N-[ l-benzyl-2-( {2-[5-(benzyloxy )-lH- pyrrolo [ 2 , 3-c ] pyridin-3-y1 ]vinyl}amino ) -2-oxoethy1 ] -N-me- thyl-2-pyrrolidinecarboxamidExample: l-acetyl-N- [l-benzyl-2- ({2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-y1] vinyl} amino) -2-oxoethy1 ] -N-methyl-2-pyrrolidinecarboxamide
Figure imgf000038_0002
Figure imgf000038_0002
Molecular Weight =565.68 Molecular Formula =C33H35N504Molecular Weight = 565.68 Molecular Formula = C33H35N504
920 [M+H]+. Found ISP-TOF-MS: 566,2932 [M+H]+; 588,2779920 [M + H] +. Found ISP-TOF-MS: 566.2932 [M + H] +; 588.2779
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 6,25μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <6.25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis: starke Hemmung; Candida albicans:(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans:
925 starke Hemmung; Staphylokokus aureus: starke Hemmung. Beispiel : 1-Acetyl-N-benzyl-N- [ 2- ( {2- [ 5- (benzyloxy ) -1H- pyrrolo[2 , 3-c ]pyridin-3-yl ]vinyl}amino)-l , l-dimethyl-2- oxoethyl ] -2-pyrrolidinecarboxamid925 strong escapement; Staphylococcus aureus: strong inhibition. Example: 1-acetyl-N-benzyl-N- [2- ({2- [5- (benzyloxy) -1H-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) -l, l -dimethyl-2-oxoethyl] -2-pyrrolidinecarboxamide
Figure imgf000039_0001
Figure imgf000039_0001
Molecular Weight =579.71Molecular Weight = 579.71
930 Molecular Formula =C34H37N504930 Molecular Formula = C34H37N504
[M+Na]+. Found ISP-TOF-MS: 602,3080 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus Subtilis:[M + Na] +. Found ISP-TOF-MS: 602.3080 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis:
935 geringe Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.935 low inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: l-Acetyl-N-{ 1- [ ( {2- [ 5- (benzyloxy) -1H- pyrrolo[ 2 , 3-c ]pyridin-3-Example: l-acetyl-N- {1- [({2- [5- (benzyloxy) -1H-pyrrolo [2, 3-c] pyridine-3-
940 yl ]vinyl}amino)carbonyl] cyclohexyl}-N-cyclohexy1-2-pyrro- lidinecarboxamid940 yl] vinyl} amino) carbonyl] cyclohexyl} -N-cyclohexy1-2-pyrrolidine carboxamide
Figure imgf000039_0002
Figure imgf000039_0002
Molecular Weight =611.79 Molecular Formula =C36H45N504Molecular Weight = 611.79 Molecular Formula = C36H45N504
[M+Na]+. Found ISP-TOF-MS: 634,8059 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM;[M + Na] +. Found ISP-TOF-MS: 634.8059 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM;
945 Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cyto- toxizität; Screening auf Bakterien: Bacillus Subtilis: keine Wirkung; Candida albicans: starke Hemmung; Staphylokokus aureus: gute Hemmung.945 Cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity toxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: strong inhibition; Staphylococcus aureus: good inhibition.
950 Beispiel : 4- [ [ ( l-Acetyl-2-pyrrolidinyl ) carbonyl ] ( 4- hydroxybuty1 ) amino ] -1-benzy1-N-{2- [ 5- ( benzyloxy ) -1H- pyrrolof 2 , 3-c ]pyridin-3-yl ]vinyl}-4-piperidinecarboxamid950 Example: 4- [[(l-acetyl-2-pyrrolidinyl) carbonyl] (4-hydroxybuty1) amino] -1-benzy1-N- {2- [5- (benzyloxy) -1H-pyrrolof 2, 3-c ] pyridin-3-yl] vinyl} -4-piperidinecarboxamide
Figure imgf000040_0001
Figure imgf000040_0001
Molecular Weight =706.89 Molecular Formula =C41 H50N6O5Molecular Weight = 706.89 Molecular Formula = C41 H50N6O5
[M+H]+. Found ISP-TOF-MS: 707,4131 [M+H]+; 729,4100[M + H] +. Found ISP-TOF-MS: 707.4131 [M + H] +; 729.4100
955 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lOμM,955 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lOμM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: keine Wirkung; Candida albicans: starke Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: strong inhibition; Staphylococcus aureus: good inhibition.
960 960
Beispiel : 1-Acetyl-N- [ 2- ( lH-indol-3-yl ) ethyl ] -N- ( 2-{ [ 2- ( lH-indol-3-yl )vinyl ] amino}-2-oxoethyl ) -2-pyrrolidinecar- boxamideExample: 1-acetyl-N- [2- (1H-indol-3-yl) ethyl] -N- (2- {[2- (1H-indol-3-yl) vinyl] amino} -2-oxoethyl) -2-pyrrolidinecar-boxamide
Figure imgf000041_0001
Figure imgf000041_0001
Molecular Weight =497.60 965 Molecular Formula =C29H31 N503Molecular Weight = 497.60 965 Molecular Formula = C29H31 N503
[M+H]+. Found ISP-TOF-MS: 498,2819 [M+H]+; 520,2493[M + H] +. Found ISP-TOF-MS: 498.2819 [M + H] +; 520.2493
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lOOμM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <100μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: 970 Bacillus subtilis: starke Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: 970 Bacillus subtilis: strong inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: l-Acetyl-N-(2-{ [ 2- ( lH-indol-3-yl )vinyl ] amino}- 1 , l-dimethyl-2-oxoethyl ) -N-phenyl-2-pyrrolidinecarboxamidExample: l-acetyl-N- (2- {[2- (lH-indol-3-yl) vinyl] amino} - 1, l-dimethyl-2-oxoethyl) -N-phenyl-2-pyrrolidinecarboxamide
Figure imgf000041_0002
Figure imgf000041_0002
Molecular Weight =458.57 75 Molecular Formula =C27H30N4O3Molecular Weight = 458.57 75 Molecular Formula = C27H30N4O3
[M+Na]+. Found ISP-TOF-MS: 481,2483 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: 80 starke Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung. Beispiel: 1-Acetyl-N- [ 3- ( lH-imidazol-1-yl )propyl ]-N-[ 1- ( { [2-( lH-indol-3-y1)vinyl ] amino}carbonyl ) cyclohexyl ] -2■ pyrrolidinecarboxamid[M + Na] +. Found ISP-TOF-MS: 481.2483 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: 80 strong inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition. Example: 1-acetyl-N- [3- (1H-imidazol-1-yl) propyl] -N- [1- ({[2- (1H-indol-3-y1) vinyl] amino} carbonyl) cyclohexyl] -2 ■ pyrrolidine carboxamide
Figure imgf000042_0001
Figure imgf000042_0001
Molecular Weight =530.68 Molecular Formula =C30H38N6O3Molecular Weight = 530.68 Molecular Formula = C30H38N6O3
[M+H]+. Found ISP-TOF-MS: 531 , 3342 [M+H] + ; 553,3191[M + H] +. Found ISP-TOF-MS: 531, 3342 [M + H] +; 553.3191
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 ≤ 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: starke Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 ≤ 50μM, (HEPG-2) IC 50 <100μM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 3- [ ( l-Acetyl-2-pyrrolidinyl )carbonyl ] -N- [ 2- ( 1H- indol-3-yl )vinyl ] -2 , 2-dimethyl-l , 3-thiazolidine-4-carbox- amidExample: 3- [(l-acetyl-2-pyrrolidinyl) carbonyl] -N- [2- (1H-indol-3-yl) vinyl] -2, 2-dimethyl-l, 3-thiazolidine-4-carbox- amide
Figure imgf000042_0002
Figure imgf000042_0002
Molecular Weight =440.57 Molecular Formula =C23H28N403SMolecular Weight = 440.57 Molecular Formula = C23H28N403S
[M+H]+. Found ISP-TOF-MS: 441,1898 [M+H]+; 463,1932 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lOμM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: keine Wirkung; Candida albicans: geringe Hemmung; Staphylokokus aureus: geringe Hemmung.[M + H] +. Found ISP-TOF-MS: 441.1898 [M + H] +; 463.1932 [M + Na] +. Inhibition of cell proliferation (MCF-7): IC 50 <100 µm, (HEPG-2) IC 50 <100 µm; Cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: low inhibition; Staphylococcus aureus: low inhibition.
10051005
Beispiel: 1-Acetyl-N- [ 2- ( {2- [ 5- (benzyloxy )-lH- pyrrolo[2 , 3-c ]pyridin-3-yl ]vinyl}amino) -2-oxoethyl ]-N- [2-Example: 1-acetyl-N- [2- ({2- [5- (benzyloxy) -lH- pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) -2-oxoethyl] -N- [2-
( lH-indol-3-yl ) ethyl ] -2-pyrrolidinecarboxamid(1H-indol-3-yl) ethyl] -2-pyrrolidinecarboxamide
Figure imgf000043_0001
1010 [M+H]+. Found ISP-TOF-MS: 605,3043 [M+H]+; 627,2885
Figure imgf000043_0001
1010 [M + H] +. Found ISP-TOF-MS: 605.3043 [M + H] +; 627.2885
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 25μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: starke Wirkung; Candida albicans: 1015 starke Hemmung; Pseudomonas aeruginosa: geringe Wirkung; Staphylokokus aureus: starke Hemmung. (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: strong effect; Candida albicans: 1015 strong inhibition; Pseudomonas aeruginosa: little effect; Staphylococcus aureus: strong inhibition.
Beispiel: l-Acetyl-N-[ 2- ( {2- [ 5- (benzyloxy ) -1H- 1020 pyrrolo[2 , 3-c ]pyridin-3-yl ] vinyl}amino)-l , l-dimethyl-2- oxoethyl ] -N-phenyl-2-pyrrolidinecarboxamidExample: l-acetyl-N- [2- ({2- [5- (benzyloxy) -1H- 1020 pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) -l, l-dimethyl- 2-oxoethyl] -N-phenyl-2-pyrrolidinecarboxamide
Figure imgf000044_0001
Figure imgf000044_0001
Molecular Weight =565.68 Molecular Formula =C33H35N504Molecular Weight = 565.68 Molecular Formula = C33H35N504
[M+H]+. Found ISP-TOF-MS: 566,2974 [M+H]+; 588,3016[M + H] +. Found ISP-TOF-MS: 566.2974 [M + H] +; 588.3016
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
1025 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.1025 (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: good effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
1030 Beispiel: l-Acetyl-N-{ 1- [( {2-[ 5- (benzyloxy )-lH- pyrrolo[ 2 , 3-c ]pyridin-3- yl]vinyl}amino )carbonyl]cyclohexyl}-N-[ 3- ( lH-imidazol-1- yl)propyl]-2-pyrrolidinecarboxamid1030 Example: l-acetyl-N- {1- [({2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} amino) carbonyl] cyclohexyl} -N - [3- (1H-imidazol-1-yl) propyl] -2-pyrrolidinecarboxamide
Figure imgf000044_0002
Figure imgf000044_0002
Molecular Weight =637.79 Molecular Formula =C36H43N704Molecular Weight = 637.79 Molecular Formula = C36H43N704
1035 [M+H]+. Found ISP-TOF-MS: 638,3641 [M+H]+; 660,81871035 [M + H] +. Found ISP-TOF-MS: 638.3641 [M + H] +; 660.8187
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: keine Wirkung; Candida albicans: gute 1040 Hemmung; Staphylokokus aureus: starke Hemmung.[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM; Cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: Bacillus subtilis: no effect; Candida albicans: good 1040 inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 3-[ ( l-acetyl-2-pyrrolidinyl )carbonyl ] -N-{2-[ 5- ( benzyloxy ) -lH-pyrrolo[ 2 , 3-c ]pyridin-3-yl]vinyl}-2 ,2-di- methyl-1 , 3-thiazolidine-4-carboxamidExample: 3- [(l-acetyl-2-pyrrolidinyl) carbonyl] -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -2, 2-dimethyl-1, 3-thiazolidine-4-carboxamide
Figure imgf000045_0001
Figure imgf000045_0001
Molecular Weight =547.68 1 045 Molecular Formula =C29H33N504SMolecular Weight = 547.68 1 045 Molecular Formula = C29H33N504S
[M+H]+. Found ISP-TOF-MS: 548,2397 [M+H]+; 570,2373 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 6,25μM,[M + H] +. Found ISP-TOF-MS: 548.2397 [M + H] +; 570.2373 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <6.25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: 1050 Bacillus subtilis: keine Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: 1050 Bacillus subtilis: no effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 2- [ [ (Acetylamino) acetyl] (methyl ) amino ]-N- [ 2- ( lH-indol-3-y1 ) vinyl ] -3-phenylpropanamidExample: 2- [[(acetylamino) acetyl] (methyl) amino] -N- [2- (1H-indol-3-y1) vinyl] -3-phenylpropanamide
Figure imgf000045_0002
Figure imgf000045_0002
Molecular Weight =418.50 1055 Molecular Formula =C24H26N403Molecular Weight = 418.50 1055 Molecular Formula = C24H26N403
[M+H]+. Found ISP-TOF-MS: 419,2184 [M+H]+; 441,2016 [M+Na] + . Zellproliferationshemmung (MCF-7): IC50 < lμM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: 1060 Bacillus subtilis: starke Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.[M + H] +. Found ISP-TOF-MS: 419.2184 [M + H] +; 441.2016 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <100 µm, (HEPG-2) IC 50 <100 µm; Cytotoxicity determination: (MCF-7, HEPG-2) medium cytotoxicity; Screening for bacteria: 1060 Bacillus subtilis: strong effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 2-[ [ (Acetylamino) acetyl] (benzyl ) amino] -N-[ 2- ( lH-indol-3-yl ) vinyl ] -2-methylpropanamidExample: 2- [[(acetylamino) acetyl] (benzyl) amino] -N- [2- (1H-indol-3-yl) vinyl] -2-methylpropanamide
Figure imgf000046_0001
Figure imgf000046_0001
Molecular Weight =432.53 1065 Molecular Formula =C25H28N403Molecular Weight = 432.53 1065 Molecular Formula = C25H28N403
[M+H]+. Found ISP-TOF-MS: 433,2447 [M+H]+; 455,2284[M + H] +. Found ISP-TOF-MS: 433.2447 [M + H] +; 455.2284
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: 1070 Bacillus subtilis: starke Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: 1070 Bacillus subtilis: strong effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: l-[ [ (Acetylamino) acetyl ] (cyclohexyl ) amino ]-N- [ 2- ( lH-indol-3-yl )vinyl ] cyclohexanecarboxamidExample: l- [[(acetylamino) acetyl] (cyclohexyl) amino] -N- [2- (lH-indol-3-yl) vinyl] cyclohexanecarboxamide
Figure imgf000046_0002
Figure imgf000046_0002
Molecular Weight =464.61 1075 Molecular Formula =C27H36N403Molecular Weight = 464.61 1075 Molecular Formula = C27H36N403
[M+Na]+. Found ISP-TOF-MS: 487,2184 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cyto- toxizität; Screening auf Bakterien: Bacillus subtilis: 1080 starke Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.[M + Na] +. Found ISP-TOF-MS: 487.2184 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50µM, (HEPG-2) IC 50 <100µM; Cytotoxicity determination: (MCF-7, HEPG-2) low cytotoxicity toxicity; Bacterial screening: Bacillus subtilis: 1080 strong effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 4-[ [ (Acetylamino) acetyl ] ( 5-hydroxypen- tyl ) amino] -1-benzyl-N- [ 2- ( lH-indol-3-yl )vinyl ] -4-piperi- 1085 dinecarboxamidExample: 4- [[(acetylamino) acetyl] (5-hydroxypentyl) amino] -1-benzyl-N- [2- (1H-indol-3-yl) vinyl] -4-piperi- 1085 dinecarboxamide
Figure imgf000047_0001
Figure imgf000047_0001
Molecular Weight =559.71 Molecular Formula =C32H41 N504Molecular Weight = 559.71 Molecular Formula = C32H41 N504
[M+H]+. Found ISP-TOF-MS: 560 , 3351 [M+H]+ ; 582,3240[M + H] +. Found ISP-TOF-MS: 560, 3351 [M + H] +; 582.3240
[M+Na] + . Zellproliferationshemmung (MCF-7): IC50 < lμM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lμM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 1090 HEPG-2) geringe Cytotoxizität; Screening auf Bakterien:(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 1090 HEPG-2) low cytotoxicity; Screening for bacteria:
Bacillus subtilis: starke Wirkung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.Bacillus subtilis: strong effect; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: 2-[ [ (Acetylamino) acetyl ] (methyl )amino] -N-{2- [ 5- 1095 (benzyloxy )-lH-pyrrolo[ 2 , 3-c ]pyridin-3-yl ]vinyl}-3- phenylpropanamidExample: 2- [[(acetylamino) acetyl] (methyl) amino] -N- {2- [5- 1095 (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -3 - phenylpropanamide
Figure imgf000047_0002
Figure imgf000047_0002
Molecular Weight =525 61 Molecular Formula =C30H31 N5O4Molecular Weight = 525 61 Molecular Formula = C30H31 N5O4
[M+H]+. Found ISP-TOF-MS: 526,2661 [M+H]+; 548,2448 [M+Na] + . Zellproliferationshemmung (MCF-7): IC50 < 50μM, 1100 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: starke Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.[M + H] +. Found ISP-TOF-MS: 526.2661 [M + H] +; 548.2448 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM, 1100 (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
1105 Beispiel: 2- [[ (Acetylamino) acetyl] (benzyl ) amino] -N-{2- [ 5- (benzyloxy)-lH-pyrrolo[ 2, 3-c]pyridin-3-yl]vinyl}-2-me- thylpropanamid1105 Example: 2- [[(acetylamino) acetyl] (benzyl) amino] -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -2 -methylpropanamide
Figure imgf000048_0001
Figure imgf000048_0001
Molecular Weight =539.64 Molecular Formula =C31 H33N504Molecular Weight = 539.64 Molecular Formula = C31 H33N504
[M+H]+. Found ISP-TOF-MS: 540,2702 [M+H]+; 562,2654[M + H] +. Found ISP-TOF-MS: 540.2702 [M + H] +; 562.2654
1110 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,1110 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: keine Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: no inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: strong inhibition.
11151115
Beispiel: l-[ [ (Acetylamino) acetyl ] (cyclohexyl) amino] -N- {2- [5- (benzyloxy) -lH-pyrrolo[ 2 , 3-c ]pyridin-3- yl ]vinyl}cyclohexanecarboxamidExample: l- [[(acetylamino) acetyl] (cyclohexyl) amino] -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} cyclohexanecarboxamide
Figure imgf000048_0002
Figure imgf000048_0002
Molecular Weight =571.73 Molecular Formula =C33H41 N504 1120 [M+H]+. Found ISP-TOF-MS: 572,3031 [M+H]+; 594,3163Molecular Weight = 571.73 Molecular Formula = C33H41 N504 1120 [M + H] +. Found ISP-TOF-MS: 572.3031 [M + H] +; 594.3163
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: keine Hemmung; Candida albicans: 1125 starke Hemmung; Staphylokokus aureus: keine Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: no inhibition; Candida albicans: 1125 strong inhibition; Staphylococcus aureus: no inhibition.
Beispiel: 4-[ [ (Acetylamino) acetyl ] ( 5-hydroxypen- tyl )amino]-l-benzyl-N-[2- ( lH-indol-3-yl ) vinyl ] -4-piperi- dinecarboxamidExample: 4- [[(acetylamino) acetyl] (5-hydroxypentyl) amino] -l-benzyl-N- [2- (lH-indol-3-yl) vinyl] -4-piperidinecarboxamide
Figure imgf000049_0001
Figure imgf000049_0001
Molecular Weight =559.71 1 130 Molecular Formula =C32H41 N504Molecular Weight = 559.71 1 130 Molecular Formula = C32H41 N504
[M+H]+. Found ISP-TOF-MS: 560,3785 [M+H]+; 582,3672[M + H] +. Found ISP-TOF-MS: 560.3785 [M + H] +; 582.3672
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 6,25μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <6.25μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) mittlere Cytotoxizität; Screening auf Bakterien: 1135 Bacillus subtilis: keine Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung. (HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: 1135 Bacillus subtilis: no inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
Beispiel : 2- (Acetylamino ) -N- [ 2- ( lH-indol-3-yl ) ethyl ] -N- ( 2-{ [ 2- ( lH-indol-3-yl) vinyl ] amino}-2-oxoethyl )acetamideExample: 2- (acetylamino) -N- [2- (lH-indol-3-yl) ethyl] -N- (2- {[2- (lH-indol-3-yl) vinyl] amino} -2- oxoethyl) acetamide
Figure imgf000050_0001
Figure imgf000050_0001
Molecular Weight =457.54 1 140 Molecular Formula =C26H27N503Molecular Weight = 457.54 1 140 Molecular Formula = C26H27N503
[M+H]+. Found ISP-TOF-MS: 458,2363 [M+H]+; 480,2204[M + H] +. Found ISP-TOF-MS: 458.2363 [M + H] +; 480.2204
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 12,5μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <12.5μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: 1145 Bacillus subtilis: keine Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: 1145 Bacillus subtilis: no inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
Beispiel: 2-{ [ (Acetylamino) acetyl ]anilino}-N- [ 2- ( lH-in- 1150 dol-3-yl)vinyl] -2-methylpropanamideExample: 2- {[(acetylamino) acetyl] anilino} -N- [2- (1H-in 1150 dol-3-yl) vinyl] -2-methylpropanamide
Figure imgf000050_0002
Figure imgf000050_0002
Molecular Weight =418.50 Molecular Formula =C24H26N403Molecular Weight = 418.50 Molecular Formula = C24H26N403
[M+H]+. Found ISP-TOF-MS: 419,1467 [M+H]+; 441,1973[M + H] +. Found ISP-TOF-MS: 419.1467 [M + H] +; 441.1973
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 1155 HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien:(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 1155 HEPG-2) low cytotoxicity; Screening for bacteria:
Bacillus subtilis: starke Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung. Beispiel: l-{ [ (Acetylamino) acetyl ] [ 3-( lH-imidazol-1- 1160 yl)propyl]amino}-N-[2-( lH-indol-3- y1 ) vinyl ] cyclohexanecarboxamideBacillus subtilis: strong inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition. Example: l- {[(acetylamino) acetyl] [3- (1H-imidazol-1-1160 yl) propyl] amino} -N- [2- (1H-indol-3-y1) vinyl] cyclohexanecarboxamide
Figure imgf000051_0001
Figure imgf000051_0001
Molecular Weight =490.61 Molecular Formula =C27H34N603Molecular Weight = 490.61 Molecular Formula = C27H34N603
[M+H]+. Found ISP-TOF-MS: 491,3097 [M+H]+; 513,2676[M + H] +. Found ISP-TOF-MS: 491.3097 [M + H] +; 513.2676
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
1165 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: starke Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung.1165 (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
1170 Beispiel: 3- [ (Acetylamino) acetyl ] -N- [ 2- ( lH-indol-3- yl )vinyl ] -2 , 2-dimethyl-l , 3-thiazolidine-4-carboxamide1170 Example: 3- [(acetylamino) acetyl] -N- [2- (1H-indol-3-yl) vinyl] -2, 2-dimethyl-l, 3-thiazolidine-4-carboxamides
Figure imgf000051_0002
Figure imgf000051_0002
Molecular Weight =400.50 Molecular Formula =C20H24N4O3SMolecular Weight = 400.50 Molecular Formula = C20H24N4O3S
[M+H]+. Found ISP-TOF-MS: 401,1733 [M+H]+; 423,1599[M + H] +. Found ISP-TOF-MS: 401.1733 [M + H] +; 423.1599
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lOμM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lOμM,
1175 (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: keine Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung. 1180 Beispiel : 2- (Acetylamino ) -N- [ 2- ( {2- [ 5- ( benzyloxy ) -1H- pyrrolo[ 2 , 3-c ] pyridin-3-y1 ]vinyl}amino) -2-oxoethyl ] -N- [ 2- ( lH-indol-3-yl ) ethyl ] acetamide1175 (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: no inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition. 1180 Example: 2- (acetylamino) -N- [2- ({2- [5- (benzyloxy) -1H-pyrrolo [2, 3-c] pyridin-3-y1] vinyl} amino) -2-oxoethyl] -N- [2- (1H-indol-3-yl) ethyl] acetamide
Figure imgf000052_0001
Figure imgf000052_0001
[M+H]+. Found ISP-TOF-MS: 565,2740 [M+H]+; 587,2597[M + H] +. Found ISP-TOF-MS: 565.2740 [M + H] +; 587.2597
1185 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,1185 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: starke Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
11901190
Beispiel: 2-{ [ (Acetylamino) acetyl] anilino}-N-{2- [ 5- (benzyloxy ) -lH-pyrrolo[ 2 , 3-c ]pyridin-3-yl ]vinyl}-2-me- thylpropanamideExample: 2- {[(acetylamino) acetyl] anilino} -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -2-methylpropanamide
Figure imgf000052_0002
Figure imgf000052_0002
1195 [M+H]+. Found ISP-TOF-MS: 526,6274 [M+H]+; 548,25841195 [M + H] +. Found ISP-TOF-MS: 526.6274 [M + H] +; 548.2584
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: starke Hemmung; Candida albicans: gute 1200 Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: strong inhibition; Candida albicans: good 1200 inhibition; Staphylococcus aureus: good inhibition.
Beispiel: l-{ [ (Acetylamino) acetyl] [ 3-( lH-imidazol-1- yl )propyl ] amino}-N-{2- [ 5- (benzyloxy ) -lH-pyrrolo[ 2 , 3- c ]pyridin-3-yl ]vinyl}cyclohexanecarboxamideExample: l- {[(acetylamino) acetyl] [3- (lH-imidazol-1-yl) propyl] amino} -N- {2- [5- (benzyloxy) -lH-pyrrolo [2, 3- c] pyridin-3-yl] vinyl} cyclohexane carboxamides
Figure imgf000053_0001
Figure imgf000053_0001
Molecular Weight =597.72 1 2 0 5 Molecular Formula =C33H39N704Molecular Weight = 597.72 1 2 0 5 Molecular Formula = C33H39N704
[M+H]+. Found ISP-TOF-MS: 598,3433 [M+H]+; 620,3448[M + H] +. Found ISP-TOF-MS: 598.3433 [M + H] +; 620.3448
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 50μM,
(HEPG-2) IC50 lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) geringe Cytotoxizität; Screening auf Bakterien: 1210 Bacillus subtilis: keine Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Screening for bacteria: 1210 Bacillus subtilis: no inhibition; Candida albicans: good inhibition; Staphylococcus aureus: good inhibition.
Beispiel: 3-[ ( acetylamino) acetyl ]-N-{2- [ 5- (benzyloxy ) -1H- pyrrolo[2 , 3-c ]pyridin-3-yl]vinyl}-2 , 2-dimethyl-l , 3-thia-Example: 3- [(acetylamino) acetyl] -N- {2- [5- (benzyloxy) -1H-pyrrolo [2, 3-c] pyridin-3-yl] vinyl} -2, 2-dimethyl-l, 3-thia
1215 zolidine-4-carboxamide1215 zolidine-4-carboxamides
Figure imgf000053_0002
Figure imgf000053_0002
Molecular Weight =507.62 Molecular Formula =C26H29N504SMolecular Weight = 507.62 Molecular Formula = C26H29N504S
[M+H]+. Found ISP-TOF-MS: 508,2226 [M+H]+; 530,2047[M + H] +. Found ISP-TOF-MS: 508.2226 [M + H] +; 530.2047
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 6,25μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 6.25μM,
(HEPG-2) IC50 lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 1220 HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: starke Hemmung; Staphylokokus aureus: gute Hemmung.(HEPG-2) IC 50 100 µM; Determination of cytotoxicity: (MCF-7, 1220 HEPG-2) mean cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: strong inhibition; Staphylococcus aureus: good inhibition.
Beispiel: N- ( l-Benzyl-2-{ [2-( lH-indol-3-y1 )vinyl ] amino}- 1225 2-oxoethyl)- N, 4-dimethylbenzamideExample: N- (l-benzyl-2- {[2- (lH-indol-3-y1) vinyl] amino} - 1225 2-oxoethyl) - N, 4-dimethylbenzamide
Figure imgf000054_0001
Figure imgf000054_0001
Molecular Weight =43755 Molecular Formula =C28H27N302Molecular Weight = 43755 Molecular Formula = C28H27N302
[M+H]+. Found ISP-TOF-MS: 438,2302 [M+H]+; 460,2129[M + H] +. Found ISP-TOF-MS: 438.2302 [M + H] +; 460.2129
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 1230 HEPG-2 ) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 1230 HEPG-2) mean cytotoxicity; Bacterial screening: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel: N-Benzyl-N- ( 2-{ [ 2- ( lH-indol-3-yl ) vinyl ] amino}- 1235 1, l-dimethyl-2-oxoethyl ) -4-methylbenzamideExample: N-benzyl-N- (2- {[2- (lH-indol-3-yl) vinyl] amino} - 1235 1, l-dimethyl-2-oxoethyl) -4-methylbenzamide
Figure imgf000054_0002
Figure imgf000054_0002
Molecular Weight =451 57 Molecular Formula =C29H29N302Molecular Weight = 451 57 Molecular Formula = C29H29N302
[M+H]+. Found ISP-TOF-MS: 452,1586 [M+H]+; 474,2173[M + H] +. Found ISP-TOF-MS: 452.1586 [M + H] +; 474.2173
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, 1240 HEPG-2 ) mittlere Cytotoxizität; Screening auf Bakterien; Bacillus subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, 1240 HEPG-2) medium cytotoxicity; Screening for bacteria; Bacillus subtilis: good inhibition; Candida albicans: good Inhibition; Staphylococcus aureus: strong inhibition.
Beispiel : N-Cyclohexyl-N- [ 1- ( { [ 2- ( lH-indol-3- 1245 yl )vinyl ] amino}carbonyl ) cyclohexyl ] -4-methylbenzamideExample: N-Cyclohexyl-N- [1- ({[2- (1H-indol-3- 1245 yl) vinyl] amino} carbonyl) cyclohexyl] -4-methylbenzamide
Figure imgf000055_0001
Figure imgf000055_0001
Molecular Weight =483.66 Molecular Formula =C31 H37N302Molecular Weight = 483.66 Molecular Formula = C31 H37N302
[M+H]+. Found ISP-TOF-MS: 485,0894 [M+H]+; 506,2439[M + H] +. Found ISP-TOF-MS: 485.0894 [M + H] +; 506.2439
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7,(HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7,
1250 HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.1250 HEPG-2) medium cytotoxicity; Bacterial screening: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
Beispiel : l-Benzyl-4- [ ( 4-hydroxybutyl ) ( 4-methylben- 1255 zoyl ) amino] -N- [ 2- ( lH-indol-3-yl )vinyl ] -4-piperidinecar- boxamideExample: l-benzyl-4- [(4-hydroxybutyl) (4-methylben-1255 zoyl) amino] -N- [2- (lH-indol-3-yl) vinyl] -4-piperidinecar-boxamide
Figure imgf000055_0002
Figure imgf000055_0002
Molecular Weight =578.76 Molecular Formula =C36H42N403Molecular Weight = 578.76 Molecular Formula = C36H42N403
[M+H]+. Found ISP-TOF-MS: 579,3456 [M+H]+; 601,3362 1260 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lOμM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: gute Hemmung, Staphylokokus aureus: starke Hemmung. 1265 Beispiel: N- [2- (lH-Indol-3-yl) ethyl] -N- (2-{ [2- (lH-indol- 3-yl ) inyl ] amino } -2-oxoethyl ) -4-methylbenzamide[M + H] +. Found ISP-TOF-MS: 579.3456 [M + H] +; 601.3362 1260 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lOμM, (HEPG-2) IC 50 <100 µM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Bacterial screening: Bacillus subtilis: good inhibition; Candida albicans: good inhibition, Staphylococcus aureus: strong inhibition. 1265 Example: N- [2- (1H-indol-3-yl) ethyl] -N- (2- {[2- (1H-indol-3-yl) inyl] amino} -2-oxoethyl) -4- methylbenzamide
Figure imgf000056_0001
Figure imgf000056_0001
Molecular Weight =476.58 Molecular Formula =C30H28N4O2Molecular Weight = 476.58 Molecular Formula = C30H28N4O2
[M+H]+. Found ISP-TOF-MS: 477,2611 [M+H]+; 499,2218 1270 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 ≤ lOOuM,[M + H] +. Found ISP-TOF-MS: 477.2611 [M + H] +; 499.2218 1270 [M + Na] +. Inhibition of cell proliferation (MCF-7): IC 5 0 ≤ lOOuM,
(HEPG-2) IC50 < lOOuM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC50 <100 µm; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Bacterial screening: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
12751275
Beispiel: N- (2- { [2- ( lH-indol-3-yl) vinyl] amino }-l, 1-dime- thyl-2-oxoethyl ) -4-methyl-N-phenylbenzamideExample: N- (2- {[2- (1H-indol-3-yl) vinyl] amino} -l, 1-dimethyl-2-oxoethyl) -4-methyl-N-phenylbenzamide
Figure imgf000056_0002
Figure imgf000056_0002
Molecular Weight =437.55 Molecular Formula =C28H27N302Molecular Weight = 437.55 Molecular Formula = C28H27N302
[M+H]+. Found ISP-TOF-MS: 438,2132 [M+H]+; Zellprolifera- 1280 tionshemmung (MCF-7): IC50 < 50μM, (HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) mittlere Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: gute Hemmung; Staphylokokus aureus: starke Hemmung.[M + H] +. Found ISP-TOF-MS: 438.2132 [M + H] +; Zellprolifera- 1280 inhibition (MCF-7): IC 50 <50μM, (HEPG-2) IC 50 <100μM; Cytotoxicity determination: (MCF-7, HEPG-2) mean cytotoxicity; Screening for bacteria: Bacillus subtilis: good inhibition; Candida albicans: good inhibition; Staphylococcus aureus: strong inhibition.
12851285
Beispiel : N- [ 3- ( lH-Imidazol-1-yl ) propyl ] -N- [ 1- ( { [ 2- ( 1H- indol-3-yl )vinyl ] amino}carbonyl ) cyclohexyl ] -4-methyl- benzamideExample: N- [3- (1H-Imidazol-1-yl) propyl] -N- [1- ({[2- (1H-indol-3-yl) vinyl] amino} carbonyl) cyclohexyl] -4-methyl - benzamide
Figure imgf000057_0001
Figure imgf000057_0001
Molecular Weight =509.66 Molecular Formula =C31 H35N502Molecular Weight = 509.66 Molecular Formula = C31 H35N502
1290 [M+H]+. Found ISP-TOF-MS: 510,3015 [M+H]+; 532,29321290 [M + H] +. Found ISP-TOF-MS: 510.3015 [M + H] +; 532.2932
[M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < 50μM,[M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <50μM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; Screening auf Bakterien: Bacillus subtilis: gute Hemmung; Candida albicans: gute 1295 Hemmung; Staphylokokus aureus: starke Hemmung.(HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity; Bacterial screening: Bacillus subtilis: good inhibition; Candida albicans: good 1295 inhibition; Staphylococcus aureus: strong inhibition.
Beispiel : N- [ 2- ( lH-Indol-3-yl )vinyl ] -2 , 2-dimethyl-3- ( 4- methylbenzoyl ) -1 , 3-thiazolidine-4-carboxamideExample: N- [2- (1H-indol-3-yl) vinyl] -2, 2-dimethyl-3- (4-methylbenzoyl) -1, 3-thiazolidine-4-carboxamide
Figure imgf000057_0002
Figure imgf000057_0002
Molecular Weight =419.55 Molecular Formula =C24H25N302Molecular Weight = 419.55 Molecular Formula = C24H25N302
1300 [M+H]+. Found ISP-TOF-MS: 420,5516 [M+H]+; 442,1731 [M+Na]+. Zellproliferationshemmung (MCF-7): IC50 < lμM,1300 [M + H] +. Found ISP-TOF-MS: 420.5516 [M + H] +; 442.1731 [M + Na] +. Cell proliferation inhibition (MCF-7): IC 50 <lμM,
(HEPG-2) IC50 < lOOμM; Cytotoxizitätsbestimmung: (MCF-7, HEPG-2 ) geringe Cytotoxizität; (HEPG-2) IC 50 <100 µM; Determination of cytotoxicity: (MCF-7, HEPG-2) low cytotoxicity;

Claims

Patentansprüche claims
1. 3-Vinylpyrrol-Derivate der allgemeinen Formel (I)1. 3-vinylpyrrole derivatives of the general formula (I)
13101310
|_|| _ |
X N-M (I)X N-M (I)
YY
worinwherein
13151315
M ein substituierter Peptid-, ein substituierter Hydantoin- oder Thiohydantoin-, Tetrazol-, Lactam- oder Lactonrest ist,M is a substituted peptide, a substituted hydantoin or thiohydantoin, tetrazole, lactam or lactone residue,
1320 Y und Z unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, ein gegebenenfalls substituierter Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aral- kenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloal- kinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-,1320 Y and Z independently of one another are a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl -, cycloaralkenyl, cycloaralkynyl,
1325 Aryl-, Alkoxy,- oder Aralkoxyrest oder ein heterocyc- lischer Ring sind, bevorzugt ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, stärker bevorzugt ein Wasserstoffatom, Fluor, Chlor, Brom, Jod, am stärksten bevorzugt ein Wasserstoffatom,1325 are aryl, alkoxy, or aralkoxy or a heterocyclic ring, preferably a hydrogen atom, a halogen atom, a pseudohalogen, more preferably a hydrogen atom, fluorine, chlorine, bromine, iodine, most preferably a hydrogen atom,
1330 Fluor, und1330 fluorine, and
X ein gegebenenfalls substituierter und/oder ein gegebenenfalls anellierter oder heteroanellierter 3-Pyrrolring 1335 ist , undX is an optionally substituted and / or an optionally fused or hetero-fused 3-pyrrole ring Is 1335, and
X und Y oder X und Z oder N und Z Teil eines Cyclus sein können.X and Y or X and Z or N and Z can be part of a cycle.
1340 2. 3-Vinylpyrrol-Derivate nach Anspruch 1, dadurch gekennzeichnet, daß die Verbindungen als Racemate, in D- oder L-Form oder als physiologisch verträgliche Salze vorliegen.1340 2. 3-vinylpyrrole derivatives according to claim 1, characterized in that the compounds are present as racemates, in D or L form or as physiologically acceptable salts.
1345 3. 3-Vinylpyrrol-Derivate nach einem der vorstehenden Ansprüche, worin das Peptid bis zu 10 Aminosäuren aufweist.1345 3. 3-vinylpyrrole derivatives according to any one of the preceding claims, wherein the peptide has up to 10 amino acids.
4. 3-Vinylρyrrol-Derivate nach einem der vorstehenden Ansprüche, worin das Peptid bis zu 3 Aminosäuren aufweist.4. 3-vinylpyrrole derivatives according to any one of the preceding claims, wherein the peptide has up to 3 amino acids.
13501350
5. 3-Vinylpyrrol-Derivate nach einem der vorstehenden Ansprüche, worin X aus den folgenden Resten ausgewählt wird:5. 3-vinylpyrrole derivatives according to any one of the preceding claims, wherein X is selected from the following radicals:
1355 1355
Figure imgf000061_0001
Figure imgf000061_0001
und die Reste R unabhängig voneinander Wasserstoffatome, Halogenatome, Pseudohalogene, gegebenenfalls substituierte Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkmyl- , Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkmyl-, Aryl-, 1365 Alkoxy- oder Aralkoxyreste oder heterocyclische Ringe sind.and the radicals R independently of one another are hydrogen atoms, halogen atoms, pseudohalogens, optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkmyl, Cycloaralkyl, cycloaralkenyl, cycloaralkmyl, aryl, 1365 alkoxy or aralkoxy radicals or heterocyclic rings.
6. 3-Vinylpyrrol-Derivate nach einem der vorstehenden Ansprüche, worin X aus den folgenden Resten ausgewählt 1370 wird:6. 3-vinylpyrrole derivatives according to any one of the preceding claims, wherein X is selected from the following radicals 1370:
Figure imgf000062_0001
Figure imgf000062_0001
1375 und die Reste R wie vorstehend definiert sind. 1375 and the radicals R are as defined above.
7. 3-Vinylpyrrol-Derivate nach einem der vorstehenden Ansprüche, worin X aus den folgenden Resten ausgewählt wird:7. 3-vinylpyrrole derivatives according to any one of the preceding claims, wherein X is selected from the following radicals:
13801380
Figure imgf000063_0001
Figure imgf000063_0001
und die Reste R wie vorstehend definiert sind.and the radicals R are as defined above.
13851385
8. 3-Vinylpyrrol-Derivate nach einem der vorstehenden Ansprüche, worin M aus den folgenden Resten ausgewählt wird:8. 3-vinylpyrrole derivatives according to any one of the preceding claims, wherein M is selected from the following radicals:
Figure imgf000063_0002
Figure imgf000064_0001
worin bedeuten:
Figure imgf000063_0002
Figure imgf000064_0001
in which mean:
a) Rj und R2 unabhängig voneinander Wasserstoffatome, Halogenatome, Pseudohalogene, gegebenenfalls substituierte 1410 Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aral- kinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkmyl-, Aryl-, Alkoxy- oder Aralkoxyreste oder heterocyclische Ringe,a) Rj and R 2 independently of one another hydrogen atoms, halogen atoms, pseudohalogens, optionally substituted 1410 alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl -, cycloaralkmyl, aryl, alkoxy or aralkoxy radicals or heterocyclic rings,
1415 oder1415 or
b) R1 und R2 bilden zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, Cycloalkenyl- oder Cycloalkinylrest, der unsubstituiert oder substi¬b) R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl, cycloalkenyl or cycloalkynyl radical which is unsubstituted or substi¬
1420 tuiert sein und gegebenenfalls 1 oder 2 unter Sauerstoff und Stickstoffatomen ausgewählte Heteroatome enthalten kann,1420 and can optionally contain 1 or 2 heteroatoms selected from oxygen and nitrogen atoms,
c) R3, R6, R7, R10, Rn, R12, R13 und R14 das unter a) für R1 1425 und R2 definierte,c) R 3 , R 6 , R 7 , R 10 , R n , R 12 , R 13 and R 14 that defined under a) for R 1 1425 and R 2 ,
d) R4 und R5 unabhängig voneinander das unter a) für Rλ und R2 definierte, oder R4 und R5 bilden zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, das unter b) 1430 für Rj und R2 definierte.d) R 4 and R 5 independently of one another that defined under a) for R λ and R 2 , or R 4 and R 5 together with the Carbon atom to which they are bound, defined under b) 1430 for R j and R 2 .
9. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, daß sie mindestens eine Verbindung nach einem der vorstehenden Ansprüche gegebenenfalls in Kombination mit9. Pharmaceutical composition, characterized in that it contains at least one compound according to one of the preceding claims, optionally in combination with
1435 an sich üblichen Trägern und/oder Adjuvantien enthält.1435 contains conventional carriers and / or adjuvants.
10. Verfahren zur Herstellung von Verbindungen nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, daß mindestens ein Isocyanid der allgemeinen Formel (II)10. A process for the preparation of compounds according to any one of claims 1 to 8, characterized in that at least one isocyanide of the general formula (II)
14401440
Figure imgf000065_0001
worin X, Y und N wie vorstehend definiert sind,
Figure imgf000065_0001
where X, Y and N are as defined above,
im Rahmen einer Ugi-Multi-Komponenten Reaktion mit minde- 1445 stens einer Oxokomponente, mindestens einer Säurekomponente und gegebenenfalls einer oder mehreren Aminkompo- nenten umgesetzt wird.in a Ugi multi-component reaction with at least 1445 at least one oxo component, at least one acid component and optionally one or more amine components.
11. Verfahren nach Anspruch 10, dadurch gekennzeichnet, 1450 daß die Reaktion in Gegenwart von mindestens einem Katalysator oder Reaktionsvermittler durchgeführt wird.11. The method according to claim 10, characterized in 1450 that the reaction is carried out in the presence of at least one catalyst or reaction mediator.
12. Verwendung von 3-Vinylpyrrol-Derivaten nach einem der Ansprüche 1 bis 8 oder einer pharmazeutischen Zusammen-12. Use of 3-vinylpyrrole derivatives according to one of claims 1 to 8 or a pharmaceutical composition
1455 setzung nach Anspruch 9 zur Therapie oder Prophylaxe von Tumor- oder Krebserkrankungen. 1455 setting according to claim 9 for the therapy or prophylaxis of tumor or cancer diseases.
13. Verwendung nach Anspruch 12, dadurch gekennzeichnet, daß die Tumor- oder Krebserkrankungen gut- und bösartige13. Use according to claim 12, characterized in that the tumor or cancer diseases benign and malignant
1460 Tumoren solider oder cystischer Natur, Adenome, Cyst-Adenome, Papillome, Adenokarzinome, Adenokarzinome vom cirrhoesen Typ, Basalzell-Karzinome, Sarkome, Fibrosar- kome, Liposarkome, Lymphosarkome, Rhabdomyosarkome, Myxo- sarkome, Chondrosarkome, Retikulumzellsarkome, Morbus1460 tumors of solid or cystic nature, adenomas, cyst adenomas, papillomas, adenocarcinomas, adenocarcinomas of the cirrhosis type, basal cell carcinomas, sarcomas, fibrosarcomas, liposarcomas, lymphosarcomas, rhabdomyosarcomas, myxosarcomas, chondrosarcomas, chondrosarcomas
1465 Hodgkin, embryonale Tumore, Neuroblastome, Nephroblasto- me, Teratome, Adamintome, Retroblastome, Haemangiome, Chordome, Odontome, Craniopharyngome, Hamartome, Lympho- angiome, Exostosen, Neurofibrantose, Melanome, Lymphome, Hepatoblastome, Mammakarzinome, Cervixkarzinome, Chorio-1465 Hodgkin, embryonic tumors, neuroblastomas, nephroblastomas, teratomas, adamintomas, retroblastomas, haemangiomas, chordomas, odontomas, craniopharyngomas, hamartomas, lymphangiomas, exostoses, neurofibrantomas, melanomas, lymphomas, hepatobarzinomas, mammocercinomas, mammary
1470 karzinome, Adenoacantome, Androblastome, Leiomyome, Ar- rhenoblastome, Sertolizelltumore, Theca- und Granulosa- Zell-Tumore, Germinome und Seminome, Ovarial- und Vulva- karzinome, Harnblasen- und Prostatakarzinome, durch Schi- stosomiasis hervorgerufene Tumore, Astrocytome, Ependymo-1470 carcinomas, adenoacantomas, androblastomas, leiomyomas, arrhenoblastomas, sertoli cell tumors, theca and granulosa cell tumors, germinomas and seminomas, ovarian and vulva carcinomas, bladder and prostate carcinomas, caused by schistrocytoma tumors, astroufosomiasis, and astroufosomiasis -
1475 gliome, Glioblastome, Medulloblastome, Oligodendrogliome, Spongioblastome, Meningeome, Tumore der Schwan 'sehen Scheidenzellen, Pinealome, Haemangioblastome, Osteocla- stome, Ewings Tumore, Multiple Myelome, Mxcosis fungoi- des, Burkitt-Tumore, Leukaemien, akute und chronische1475 gliomas, glioblastomas, medulloblastomas, oligodendrogliomas, spongioblastomas, meningiomas, tumors of the swan 'see vaginal cells, pinealomas, hemangioblastomas, osteoclastomas, Ewings tumors, multiple myelomas, mxcosis fungoids, leukemic tumors, leukemic tumors, acute, and leukemia tumors
1480 lymphatische Leukaemien, akute und chronische Granu- locytenleukaemien, akute und chronische Monocytenleukae- mien, Stammzellenleukaemien, Basaliome, Fibrome, Myome, und die bei einem chirurgischen Einriff einer lokalen Injektion zugänglichen Metastasen sämtlicher Tumorformen.1480 lymphatic leukemias, acute and chronic granulocyte leukemias, acute and chronic monocyte leukemias, stem cell leukemias, basaliomas, fibromas, fibroids, and the metastases of all types of tumors that are accessible to a local injection during surgical intervention.
14851485
14. Verwendung von 3-Vinylpyrrol-Derivaten nach einem der Ansprüche 1 bis 8 oder einer pharmazeutischen Zusammensetzung nach Anspruch 9 als Antibiotikum. 14. Use of 3-vinylpyrrole derivatives according to one of claims 1 to 8 or a pharmaceutical composition according to claim 9 as an antibiotic.
1490 15. Verwendung nach Anspruch 14 zur Prophylaxe oder Therapie von Infektionen mit gram-positiven und/oder anaeroben Keimen, Mycobakterien, Corneybakterien oder Haemophilus influenzae.1490 15. Use according to claim 14 for the prophylaxis or therapy of infections with gram-positive and / or anaerobic germs, mycobacteria, corney bacteria or Haemophilus influenzae.
1495 16. Verwendung nach einem der Ansprüche 12 bis 15, dadurch gekennzeichnet, daß die Derivate oder pharmazeutischen Zusammensetzungen lokal oder systemisch eingesetzt werden.1495 16. Use according to one of claims 12 to 15, characterized in that the derivatives or pharmaceutical compositions are used locally or systemically.
1500 17. Verwendung nach einem der Ansprüche 12 bis 16, dadurch gekennzeichnet, daß die Derivate oder pharmazeutischen Zusammensetzungen als Pflaster, Salben, Pasten, Gele, Cremes, lösliche Pulver, Emulsionen, Puder, Suspensionen, Sprays, Supositorien, Liposomen oder Injek-1500 17. Use according to one of claims 12 to 16, characterized in that the derivatives or pharmaceutical compositions as plasters, ointments, pastes, gels, creams, soluble powders, emulsions, powders, suspensions, sprays, supositories, liposomes or injected
1505 tionslösungen angewendet werden.1505 solutions can be used.
18. Verwendung nach Anspruch 12 oder 13, dadurch gekennzeichnet, daß die Derivate oder pharmazeutischen Zusammensetzungen in Form von in Liposomen verpackten 1510 Konjugaten mit tumorspezifischen Antikörpern verwendet werden. 18. Use according to claim 12 or 13, characterized in that the derivatives or pharmaceutical compositions are used in the form of 1510 conjugates packed in liposomes with tumor-specific antibodies.
PCT/EP2000/008860 1999-09-10 2000-09-11 3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments WO2001019791A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75178/00A AU7517800A (en) 1999-09-10 2000-09-11 3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19943508A DE19943508A1 (en) 1999-09-10 1999-09-10 3-vinylpyrene derivatives, process for their preparation and their use as medicines
DE19943508.1 1999-09-10

Publications (2)

Publication Number Publication Date
WO2001019791A2 true WO2001019791A2 (en) 2001-03-22
WO2001019791A3 WO2001019791A3 (en) 2002-02-21

Family

ID=7921629

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/008860 WO2001019791A2 (en) 1999-09-10 2000-09-11 3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments

Country Status (3)

Country Link
AU (1) AU7517800A (en)
DE (1) DE19943508A1 (en)
WO (1) WO2001019791A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045982A1 (en) * 2001-11-29 2003-06-05 The Kitasato Institute Antibiotics fki-9739 and process for producing the same

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1829862A1 (en) * 2006-03-02 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Sigma receptor compounds
CN112028833B (en) * 2020-09-25 2022-07-05 西南大学 Para-aminosalicylic acid azole derivative and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017705A1 (en) * 1979-02-07 1980-10-29 Troponwerke GmbH &amp; Co. KG Phenylalanyl-tryptophan derivatives, pharmaceutical compositions containing them, their preparation and use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01149766A (en) * 1987-12-04 1989-06-12 Otsuka Pharmaceut Co Ltd Indole derivative

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017705A1 (en) * 1979-02-07 1980-10-29 Troponwerke GmbH &amp; Co. KG Phenylalanyl-tryptophan derivatives, pharmaceutical compositions containing them, their preparation and use

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
AZUMI K ET AL: "INHIBITORY EFFECT OF HALOCYAMINE, AN ANTIMICROBIAL SUBSTANCE FROM ASCIDIAN HEMOCYTES, ON THE GROWTH OF FISH VIRUSES AND MARINE BACTERIA" EXPERIENTIA,CH,BIRKHAUSER VERLAG. BASEL, Bd. 46, Nr. 10, 15. Oktober 1990 (1990-10-15), Seiten 1066-1068, XP000161420 ISSN: 0014-4754 *
BECK B ET AL: "One-pot synthesis and biological evaluation of aspergillamides and analogues" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,OXFORD,GB, Bd. 10, Nr. 15, 7. August 2000 (2000-08-07), Seiten 1701-1705, XP004213227 ISSN: 0960-894X *
CHEMICAL ABSTRACTS, vol. 128, no. 24, 15. Juni 1998 (1998-06-15) Columbus, Ohio, US; abstract no. 292580, WITTER, LUDWIG ET AL: "A new inhibitor of synovial phospholipase A2 from fermentations of Penicillium sp. 62-92" XP002169681 & Z. NATURFORSCH., C: BIOSCI. (1998), 53(1/2), 60-64 , *
KAGAMIZONO T ET AL: "Terpeptin, A Novel Mammalian Cell Cycle Inhibitor, Produced by Aspergillus terreus 95F-1" TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, Bd. 38, Nr. 7, 17. Februar 1997 (1997-02-17), Seiten 1223-1226, XP004034240 ISSN: 0040-4039 *
PATENT ABSTRACTS OF JAPAN vol. 013, no. 408 (C-634), 8. September 1989 (1989-09-08) & JP 01 149766 A (OTSUKA PHARMACEUT CO LTD), 12. Juni 1989 (1989-06-12) *
TOSKE S G ET AL: "Aspergillamides A and B: Modified Cytotoxic Tripeptides Produced by a Marine Fungus of the Genus Aspergillus" TETRAHEDRON,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, Bd. 54, Nr. 44, 29. Oktober 1998 (1998-10-29), Seiten 13459-13466, XP004139351 ISSN: 0040-4020 in der Anmeldung erw{hnt *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045982A1 (en) * 2001-11-29 2003-06-05 The Kitasato Institute Antibiotics fki-9739 and process for producing the same

Also Published As

Publication number Publication date
DE19943508A1 (en) 2001-03-15
WO2001019791A3 (en) 2002-02-21
AU7517800A (en) 2001-04-17

Similar Documents

Publication Publication Date Title
DE68907921T2 (en) Substituted pyrrole, pyrazole and triazole angiotensin II antagonists.
EP0934311B1 (en) New heterocyclylmethyl-substituted pyrazol derivates
DE60030574T2 (en) FIVE-LID DERIVATIVES OF HETEROCYCLES AND THEIR USE AS MONOAMINOXIDASE INHIBITORS
DE3788385T2 (en) Pyrimidine derivatives.
DE69212346T2 (en) Diazotized heterocyclic derivatives of nitrogen, substituted by a biphenyl group, their preparation, and pharmaceutical preparations containing them
DE69531956T2 (en) IMIDAZOLE DERIVATIVES WITH PROTEIN KINASE, IN PARTICULAR EGF-R TYROSINKINASE, INHIBITING EFFECT
DE69111619T2 (en) 1,4-BENZOTHIAZEDINE DERIVATIVE.
EP1228044A2 (en) Pyrrolo imidazole derivatives and their use as medicaments
DE3141063A1 (en) NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
DE69108913T2 (en) 4-ALKYLIMIDAZOLE DERIVATIVES.
EP0900198B1 (en) New vitamin d derivatives with carbo- or heterocyclic substituents at c-25, a process for their production, intermediate products and their use for producing medicaments
DE4242675A1 (en) Hydroxyiminoalkylindolcarboxylic acid derivatives, their preparation and use
DE3408127A1 (en) NEW AZOLES, METHOD FOR THEIR PRODUCTION AND THEIR USE
EP0124067B1 (en) 2-(aminoalkyl)-pyrrole derivatives, process for their manufacture and their use
DE69501915T2 (en) Acylated aminoalkanimidazoles and triazoles
EP0445073A1 (en) Benzofurans
WO2001019791A2 (en) 3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments
DE69408674T2 (en) PHENYLPYRROL DERIVATIVES AND THEIR USE AS DOPAMINE D3 ANTAGONISTS
HU184851B (en) Process for producing 4,5-diaryl-alpha-bracket-polyfluoro-alkyl-bracket closed-ih-pyrrol-2-methan-amines and antiphlogistic pharmaceutical kompositions containing them
DE3926365A1 (en) CYCLOALKYLENAZOLES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS THAT CONTAIN THEY AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS
PL149009B1 (en) Method for manufacturing new derivatives of (benzofuran-2-ilo)imidazoles
EP0346683A1 (en) Pyrrole derivatives, their preparation and their use
WO1992010482A1 (en) Pharmaceutical compositions containing functionalized vinylazoles, use of these vinylazoles for producing medicaments, these vinylazoles themselves and process for producing the same
WO2003043983A1 (en) Piperazine derivatives destabilising androgen receptors
EP1121349B1 (en) Substituted thiadiazolsulfonamides used as interleukin-1-beta inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP